Palladium- and Copper-Catalyzed Aryl Halide Amination ...
Palladium- and Copper-Catalyzed Aryl Halide Amination ...
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REVIEW 1<br />
<strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> <strong>Aryl</strong> <strong>Halide</strong> <strong>Amination</strong>, Etherification <strong>and</strong><br />
Thioetherification Reactions in the Synthesis of Aromatic Heterocycles<br />
<strong>Palladium</strong>- Jessie <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis E. R. Sadig, Michael C. Willis*<br />
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK<br />
Fax +44(1865)285002; E-mail: michael.willis@chem.ox.ac.uk<br />
Received 4 August 2010; revised 13 August 2010<br />
Abstract: This article reviews the use of palladium- <strong>and</strong> coppercatalyzed<br />
aryl halide amination, etherification <strong>and</strong> thioetherification<br />
processes in the synthesis of heteroaromatic molecules. The review<br />
is structured by the nature of the key C–X bond being formed,<br />
<strong>and</strong> then by heterocycle type. Where applicable individual heterocycles<br />
are further divided into syntheses based on intermolecular,<br />
intramolecular <strong>and</strong> cascade processes. In order to limit the length of<br />
the article, processes that do not deliver an aromatic heterocycle<br />
from the key C–X bond-forming event are excluded. Processes for<br />
the functionalization of intact heteroaromatics are also not included.<br />
1 Introduction<br />
2 Carbon–Nitrogen Bond Formation<br />
2.1 Indoles<br />
2.2 Carbazoles<br />
2.3 Benzimidazoles <strong>and</strong> Benzimidazolones<br />
2.4 Indazoles <strong>and</strong> Indazolones<br />
2.5 Pyrroles<br />
2.6 Pyrazoles<br />
2.7 Oxazoles<br />
2.8 Quinolones<br />
2.9 Quinazolines, Quinazolinones <strong>and</strong> Quinazolinediones<br />
2.10 Phenazines<br />
2.11 Cinnolines<br />
3 Carbon–Oxygen Bond Formation<br />
3.1 Benzofurans<br />
3.2 Benzoxazoles<br />
3.3 Isocoumarins<br />
4 Carbon–Sulfur Bond Formation<br />
4.1 Benzothiophenes<br />
4.2 Benzothiazoles<br />
4.3 Oxathioles<br />
5 Conclusion<br />
Key words: palladium catalysis, copper catalysis, aromatic heterocycles,<br />
amination, etherification<br />
1 Introduction<br />
Given the numerous applications of aromatic heterocycles<br />
in medicine, agriculture <strong>and</strong> materials, it is not surprising<br />
that a whole host of methods have been developed for<br />
their preparation. Prominent amongst these are routes<br />
based on transition metal catalyzed transformations. 1–8 Indeed,<br />
many transition metal catalyzed processes have<br />
been developed with the explicit goal of delivering new<br />
synthetic routes to heteroaromatics. This forging of new<br />
SYNTHESIS 2011, No. 1, pp 0001–0022xx.xx.2010<br />
Advanced online publication: 12.10.2010<br />
DOI: 10.1055/s-0030-1258294; Art ID: E27810SS<br />
© Georg Thieme Verlag Stuttgart · New York<br />
routes, allowing the introduction of new classes of starting<br />
materials, or access to alternative substitution patterns, is<br />
one of the key advantages offered by transition metal catalysis.<br />
The last fifteen years has seen the development of<br />
efficient <strong>and</strong> user-friendly methods, based on both palladium<br />
<strong>and</strong> copper catalysis, for the formation of carbon–<br />
nitrogen, carbon–oxygen <strong>and</strong> carbon–sulfur bonds using<br />
aryl halide substrates. Collectively, these processes<br />
present almost ideal tools for aromatic heterocycle synthesis,<br />
as witnessed by the rapidly increasing number of<br />
applications that have been published during this time.<br />
For example, reference to the first edition of Li <strong>and</strong><br />
Gribble’s excellent treatise on the use of palladium catalysis<br />
in heterocyclic chemistry, 1 published in 2000, shows<br />
only a h<strong>and</strong>ful of examples of palladium-catalyzed aryl<br />
amination reactions being employed in the synthesis of aromatic<br />
heterocycles. This is certainly not the case today.<br />
Migita described the palladium-catalyzed coupling of<br />
aminostannanes with aryl halides as early as 1983; 9 however,<br />
it was not until the report of tin-free catalytic amination<br />
reactions, by Buchwald10 <strong>and</strong> Hartwig, 11 that the<br />
synthetic potential of these processes began to be realized.<br />
<strong>Copper</strong>-based aryl halide amination (<strong>and</strong> amidation)<br />
chemistry has an even longer history, dating back to the<br />
original reports by Ullmann12 <strong>and</strong> Goldberg, 13 but again,<br />
it was not until the development of mild catalytic variants<br />
of these reactions that the majority of applications began<br />
to be developed. In recent years both processes have undergone<br />
enormous development <strong>and</strong> now encompass a<br />
myriad of different nitrogen nucleophiles <strong>and</strong> aryl halide<br />
(<strong>and</strong> equivalent) coupling partners. Advances to carbon–<br />
oxygen <strong>and</strong> carbon–sulfur bond-forming variants have<br />
also been achieved. It is beyond the scope of this review<br />
to examine the development <strong>and</strong> mechanistic details of<br />
these underpinning catalytic methods, but extensive reviews<br />
of both the palladium14–17 <strong>and</strong> copper18–23 chemistries<br />
exist. The following discussion is divided by the key<br />
catalytic bond construction – carbon–nitrogen, carbon–<br />
oxygen or carbon–sulfur – <strong>and</strong> then by heterocycle type.<br />
Where appropriate, individual heterocycles are then subdivided<br />
into intermolecular, intramolecular or cascade<br />
processes. The review is focused on the formation of aromatic<br />
heterocyles, <strong>and</strong> accordingly we have not included<br />
reports of the functionalization of intact heterocyclic<br />
cores, nor processes that lead to non-aromatic systems.
2 J. E. R. Sadig, M. C. Willis REVIEW<br />
2 Carbon–Nitrogen Bond Formation<br />
2.1 Indoles<br />
A number of new indole syntheses based on aryl halide<br />
amination have been developed; however, one of the first<br />
heterocycle syntheses to be reported using palladiumcatalyzed<br />
amination chemistry was concerned with intercepting<br />
reaction intermediates from a very well established<br />
route to indoles. 24 In 1998 Buchwald demonstrated<br />
that a variety of aryl halides could be combined with benzophenone<br />
hydrazone using intermolecular palladiumcatalyzed<br />
amination reactions to generate the corresponding<br />
N-arylhydrazones (1, Scheme 1). 25 A palladium(II)<br />
acetate/XantPhos (2) catalyst system, in combination with<br />
sodium tert-butoxide, was found to be optimal. The Narylhydrazones<br />
could either be isolated or, after simple<br />
filtration through a silica plug, treated directly with an<br />
enolizable ketone under acid hydrolysis conditions. The<br />
ensuing Fischer cyclization provided the corresponding<br />
indoles in good to excellent yields. Variations to access either<br />
N-alkyl- or N-arylindoles were also developed, although<br />
in these cases functionalization of the isolated Narylhydrazones<br />
was necessary.<br />
A limitation of the benzophenone hydrazone methodology<br />
is the difficulty in removing benzophenone from the<br />
final indole products, particularly in large-scale<br />
applications. Cho <strong>and</strong> Lim reported a related procedure, in<br />
which N-Boc arylhydrazines were employed in Fischer<br />
cyclizations. 26 The required N-Boc arylhydrazines were<br />
prepared using palladium-catalyzed amination chemistry,<br />
but in these cases were isolated before indole formation.<br />
The use of intramolecular carbon–nitrogen bond formation<br />
onto an aryl halide has proved to be a popular method<br />
to achieve indole synthesis. In one of the first routes based<br />
Biographical Sketches<br />
Jessie Sadig received her<br />
MChem degree from the<br />
University of Oxford in July<br />
2008, where she carried out<br />
her final year project under<br />
Michael Willis received his<br />
undergraduate education at<br />
Imperial College London,<br />
<strong>and</strong> his PhD from the University<br />
of Cambridge working<br />
with Prof. Steven V.<br />
Ley, FRS. After a postdoctoral<br />
stay with Prof. David<br />
A. Evans at Harvard University,<br />
as a NATO/Royal<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
on this approach, Watanabe et al. demonstrated that N,Ndimethylhydrazones<br />
derived from o-chloroarylacetaldehydes<br />
(4) underwent cyclization under the action of palladium<br />
catalysis to provide the corresponding N-aminoindoles<br />
(Scheme 2). 27 Tri(tert-butyl)phosphine <strong>and</strong> the<br />
ferrocene derivative 5 were found to be the optimal<br />
lig<strong>and</strong>s. The authors went on to demonstrate that if an appropriately<br />
functionalized substrate was employed, then a<br />
second palladium-catalyzed transformation could be<br />
achieved in the reactions. For example, dichloride 6 could<br />
N<br />
Ph Ph<br />
NH2<br />
+<br />
MeO<br />
MeO<br />
Scheme 1<br />
65%<br />
Br<br />
Me<br />
N<br />
H<br />
Me Me<br />
PPh 2<br />
the supervision of Dr. Jeremy<br />
Robertson. She then<br />
joined the Willis group <strong>and</strong><br />
is currently working towards<br />
her DPhil degree. Her<br />
Society Research Fellow, he<br />
was appointed to a lectureship<br />
at the University of<br />
Bath in November 1997. In<br />
January 2007 he moved to<br />
the University of Oxford,<br />
where he is a University<br />
Lecturer <strong>and</strong> Fellow of<br />
Lincoln College. He was<br />
awarded an EPSRC Ad-<br />
O<br />
i) Pd(OAc) 2 (0.1 mol%)<br />
XantPhos (0.11 mol%)<br />
NaOt-Bu, toluene, 80 °C<br />
ii) TsOH.<br />
H2O, EtOH<br />
reflux<br />
O<br />
Me<br />
Me<br />
Pent<br />
Ph<br />
Ph<br />
N<br />
HN<br />
Me<br />
1<br />
PPh 2<br />
N<br />
H<br />
Ph Ph<br />
79%<br />
Pent<br />
N<br />
H<br />
Pent<br />
N<br />
H<br />
Me<br />
Me<br />
70% 70%<br />
(BINAP used as lig<strong>and</strong>)<br />
XantPhos (2) (rac)-BINAP (3)<br />
PPh2<br />
PPh2<br />
research focuses on palladium-<br />
<strong>and</strong> copper-catalyzed<br />
cascade processes for heterocycle<br />
synthesis.<br />
vanced Research Fellowship<br />
in 2005 <strong>and</strong> the 2008<br />
AstraZeneca Research<br />
Award for Organic Chemistry.<br />
His group’s research interests<br />
are based on the<br />
development <strong>and</strong> application<br />
of new catalytic processes<br />
for organic synthesis.
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 3<br />
be reacted under the st<strong>and</strong>ard conditions but with the addition<br />
of phenyl boronic acid, to provide 4-phenylindole<br />
7, resulting from t<strong>and</strong>em carbon–carbon <strong>and</strong> carbon–<br />
nitrogen bond formation. In addition to aryl boronic acids<br />
being introduced by Suzuki couplings, a range of azoles<br />
<strong>and</strong> amines could also be effectively incorporated via a<br />
second carbon–nitrogen bond-forming process.<br />
F<br />
Cl<br />
4<br />
6<br />
Scheme 2<br />
Doye <strong>and</strong> co-workers demonstrated that N-alkyl imines<br />
corresponding to hydrazones 4 can also be effectively cyclized<br />
under the action of palladium catalysis to provide<br />
N-alkylindoles. 28 In their approach, the imine substrates<br />
were prepared from the corresponding alkynes using a<br />
titanium-catalyzed hydroamination process. In this onepot<br />
protocol, the imines were then subjected to palladium<br />
catalysis to deliver the indole products. Scheme 3 shows<br />
an example in which alkyne 8 was converted in a one-pot<br />
process into indole 9. N-Heterocyclic carbene (NHC)<br />
lig<strong>and</strong> 10 was most effective. Substrates containing a tethered<br />
amine nucleophile could also be included, leading to<br />
the formation of N–C2 annulated indoles.<br />
Scheme 3<br />
H<br />
N<br />
Cl NMe2<br />
H<br />
N<br />
Cl NMe2<br />
Pd(dba) 2 (3 mol%)<br />
5 (4.5 mol%)<br />
NaOt-Bu<br />
o-xylene, 120 °C<br />
PhB(OH) 2<br />
Pd(dba)2 (5 mol%)<br />
5 (7.5 mol%)<br />
Cs 2CO 3<br />
o-xylene, 120 °C<br />
Fe<br />
NMe2 Pt-Bu2<br />
5<br />
N<br />
60% NMe2 N<br />
NMe2 7, 56%<br />
10<br />
8<br />
MeO<br />
Pr i) [Cp2TiMe2] (5 mol%)<br />
toluene<br />
110 °C, 24 h<br />
MeO<br />
+ H2N Me<br />
ii) Pd2(dba)3 (5 mol%)<br />
Cl Me<br />
Me<br />
(10 mol%)<br />
KOt-Bu, dioxane 9, 65%<br />
N<br />
Pr<br />
Me<br />
110 °C<br />
Me Me<br />
Me<br />
Me<br />
Isolated dehydrohalophenylalinate derivatives have been<br />
converted into indoles using related cyclizations. For example,<br />
Brown was the first to report the cyclization of<br />
enamines such as 11 (Scheme 4) into the corresponding<br />
indole-2-carboxylates. In this report from 2000, a simple<br />
dppf-derived catalyst was employed in combination with<br />
F<br />
Ph<br />
Me Me Me<br />
Cl<br />
N N<br />
Me<br />
–<br />
10<br />
+<br />
potassium acetate as base. 29 Kondo <strong>and</strong> co-workers subsequently<br />
showed that polymer-supported substrates corresponding<br />
to 11 can also be cyclized effectively. 30<br />
O 2N<br />
Scheme 4<br />
11<br />
HN<br />
I<br />
Br<br />
CO2Et<br />
PdCl 2(dppf)<br />
(5 mol%)<br />
KOAc, DMF<br />
90 °C<br />
PPh 2<br />
Fe dppf (12)<br />
PPh2<br />
O2N 83%<br />
Br<br />
Lautens <strong>and</strong> co-workers established gem-dihalovinylanilines<br />
as versatile substrates for indole synthesis based<br />
on a series of t<strong>and</strong>em metal-catalyzed processes. The substrates<br />
were readily accessed from the relevant o-nitrobenzaldehyde<br />
derivatives via Ramirez olefinations<br />
followed by reduction of the nitro group. The early chemistry<br />
focused on t<strong>and</strong>em palladium-catalyzed intramolecular<br />
amination reactions <strong>and</strong> intermolecular Suzuki<br />
couplings to deliver a series of variously substituted indoles.<br />
31a,b For example, reaction of gem-dibromoaniline<br />
13 with thienyl-3-boronic acid delivered the expected<br />
indole in 86% yield (Scheme 5). The electron-rich<br />
biphenyl-based phosphine SPhos (14), developed by<br />
Buchwald, proved to be optimal. Significant variation in<br />
the substitution pattern of the substrates <strong>and</strong> in the type of<br />
organoboron coupling partner was possible. For example,<br />
it was possible to prepare indoles with individual substituents<br />
at positions C2–C7; N-aryl substrates could also be<br />
employed. <strong>Aryl</strong>, alkenyl <strong>and</strong> alkyl boron reagents were all<br />
used successfully. For many of the examples it was possible<br />
to use palladium loadings of only 1 mol%. Although<br />
no reaction intermediates were detected, a brief mechanistic<br />
investigation suggested that the intramolecular amination<br />
reaction preceded the intermolecular Suzuki<br />
coupling. It is interesting to note that the amination reactions<br />
took place on alkenyl halides, 32 as opposed to the<br />
usual aryl halide substrates. To demonstrate the synthetic<br />
utility of the method, indole 15, prepared in 86% yield<br />
from the corresponding gem-dibromovinylaniline <strong>and</strong> 2methoxyquinoline<br />
boronic acid, was utilized in a short<br />
synthesis of KDR kinase inhibitors. 31c Bisseret <strong>and</strong> coworkers<br />
also reported a single example of the synthesis of<br />
a 2-arylindole using a similar strategy. 33<br />
In an elegant extension of this chemistry the same group<br />
was able to demonstrate that the corresponding pyridinederived<br />
substrates could be utilized to access azaindoles.<br />
31d The example shown in Scheme 6 illustrates the<br />
preparation of a 7-azaindole using reaction conditions almost<br />
identical to those for the parent indole series. An important<br />
modification from the parent system, needed to<br />
achieve high yields, was the use of a nitrogen-protecting<br />
group. It was also possible to extend the chemistry to the<br />
preparation of 6-azaindoles; however, the synthesis of the<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
N<br />
CO2Et
4 J. E. R. Sadig, M. C. Willis REVIEW<br />
BnO<br />
13<br />
+<br />
(HO) 2B<br />
MeO<br />
O<br />
Scheme 5<br />
N<br />
Scheme 6<br />
Br<br />
NH2<br />
S<br />
Br<br />
Pd(OAc) 2 (1 mol%)<br />
SPhos (2 mol%) S<br />
N<br />
H<br />
Ph<br />
NH<br />
Me<br />
Me<br />
N<br />
86% 73%<br />
77%<br />
15, 86%<br />
(2 mol% Pd)<br />
Br<br />
NH<br />
Bn<br />
Br<br />
+<br />
N<br />
H<br />
MeO<br />
(HO) 2B Ph<br />
K3PO .<br />
4 H2O toluene, 90 °C<br />
regioisomeric 5- <strong>and</strong> 4-azaindoles was more challenging<br />
<strong>and</strong> required the use of N-oxide substrates. Thienopyrroles<br />
could also be prepared starting from the corresponding<br />
thiophene-derived substrates.<br />
The same gem-dihalovinylaniline substrates have been<br />
utilized in a number of different t<strong>and</strong>em processes. For example,<br />
as Scheme 7 illustrates, the initial intramolecular<br />
amination reactions have been partnered with a number of<br />
alternative reactions, including Heck olefinations (16 →<br />
17), 31e carbonylations (16 → 18) 34 <strong>and</strong> Sonogashira couplings<br />
(16 → 19), 31f to deliver acrylate-, ester- <strong>and</strong> alkynesubstituted<br />
indoles, respectively. Bisseret <strong>and</strong> co-workers<br />
used the same substrates in t<strong>and</strong>em palladium-catalyzed<br />
amination/phosphonation sequences to deliver 2-phosphonate-substituted<br />
indoles. 33 Tethered substrates were<br />
used in the Heck chemistry to provide polycyclic products<br />
via an intramolecular second step. 31e Related tethered substrates,<br />
invoking a second intramolecular amination reaction,<br />
31g or an intramolecular direct arylation reaction, 31h<br />
were also developed to access alternative polycyclic scaffolds.<br />
It is interesting to note that the double amination<br />
processes were achieved using copper catalysis. Lautens<br />
<strong>and</strong> co-workers also demonstrated that the reactivity of<br />
gem-dibromovinylanilines can be controlled to allow access<br />
to 2-bromoindoles by a single (as opposed to a t<strong>and</strong>em)<br />
palladium-catalyzed intramolecular amination<br />
reaction. 31i<br />
The Willis research group has developed cascade catalytic<br />
amination strategies to access a range of indole deriva-<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
N<br />
Me<br />
Pd(OAc) 2 (3 mol%)<br />
SPhos (14) (6 mol%)<br />
K3PO .<br />
4 H2O toluene, 100 °C<br />
N<br />
H<br />
Me<br />
86%<br />
(dichloro substrate)<br />
Cy2P OMe<br />
MeO<br />
SPhos (14)<br />
N<br />
N<br />
Bn<br />
74%<br />
Ph<br />
t-BuO 2C<br />
Scheme 7<br />
Br<br />
NH<br />
16<br />
R<br />
SiMe 3<br />
Pd(OAc) 2 (4 mol%)<br />
Me4NCl (100 mol%)<br />
K3PO4 .<br />
H2O, Et3N<br />
toluene, reflux<br />
Br<br />
PdCl2(PPh3) 2<br />
Ph3P (10 mol%)<br />
CO (10 atm)<br />
DIPEA, THF<br />
MeOH, 110 °C<br />
P(p-MeOC6H4)3 (8 mol%)<br />
Pd/C (2 mol%)<br />
CuI (4 mol%)<br />
i-Pr2NH, toluene, 100 °C<br />
tives. They focused on the use of 2-(2-haloalkenyl)aryl<br />
halides, together with the corresponding alkenyl triflates,<br />
as indole substrates. 35a,b Scheme 8 shows examples of<br />
both the aryl halide/alkenyl triflate (20) <strong>and</strong> the aryl halide/alkenyl<br />
halide (21) substrates in palladium-catalyzed<br />
indole-forming reactions. Both reactions feature an initial<br />
intermolecular amination reaction followed by an intramolecular<br />
amination as the second step of the cascade,<br />
to deliver N-functionalized indole products. The authors<br />
noted that it was possible to employ either Z- or E-configured<br />
alkene isomers in the process, a consequence of the<br />
initial amination reaction taking place at the alkenyl halide<br />
<strong>and</strong> generating a configurationally unstable enamine<br />
intermediate. Reactions employing the triflate substrates<br />
were best achieved using DPEPhos (22) or XantPhos (2)<br />
lig<strong>and</strong>s, while the dihalide substrates delivered best yields<br />
with the Buchwald diphenyl lig<strong>and</strong>s, such as SPhos (14).<br />
By selecting the appropriate class of substrate it was possible<br />
to access a number of indole substitution patterns.<br />
Significant variation of the nitrogen coupling partner was<br />
possible, with examples of aniline, amine, amide, hydrazine<br />
<strong>and</strong> sulfonamide nucleophiles all being reported.<br />
Sterically dem<strong>and</strong>ing nitrogen nucleophiles, such as tertbutylamine,<br />
could also be introduced; 35c the ability to access<br />
indoles bearing bulky N-substituents was exploited<br />
in a synthesis of the natural product demethylasterriquinone<br />
A, in which N-(reverse prenyl)indole 23 was utilized as<br />
a key intermediate. A recent extension of the chemistry<br />
has seen trihalogenated substrates employed, allowing access<br />
to 4-, 5-, 6- <strong>and</strong> 7-chloroindoles. 35d The Li research<br />
group has adapted the method to encompass trifluoromethyl-substituted<br />
substrates in order to prepare a series<br />
of N-aryl-2-trifluoromethyl-substituted indoles. 36 A related<br />
intramolecular amination reaction between an aniline <strong>and</strong><br />
an alkenyl triflate was employed by Smith <strong>and</strong> co-workers<br />
in their synthesis of the nodulisporic acids tetracycle. 37<br />
The Willis research group also demonstrated that similar<br />
palladium-catalyzed cascade processes can be achieved<br />
using pyridine-derived substrates to provide access to the<br />
corresponding azaindole products. 35e For example, reaction<br />
of dihalopyridine substrate 24 with p-anisidine, using<br />
a DPEPhos-derived catalyst, delivered the corresponding<br />
N<br />
Bn<br />
17, 79%<br />
CO2t-Bu<br />
CO2Me N<br />
18, 70%<br />
Bn<br />
N<br />
H<br />
SiMe3<br />
19, 57%
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 5<br />
Br OTf<br />
Cl<br />
+<br />
20 H2N<br />
N<br />
71%<br />
Ph<br />
Scheme 8<br />
7-azaindole in good yield (Scheme 9). The process was<br />
shown to work well for 7-azaindoles; however, access to<br />
the remaining regioisomers was less successful.<br />
Scheme 9<br />
The 2-(2-haloalkenyl)aryl halide substrates have also<br />
been shown to undergo cascade copper-catalyzed amination<br />
reactions to deliver N-functionalized indoles. 35f An<br />
example featuring a carbamate coupling partner is shown<br />
in Scheme 10. Although some overlap in scope with the<br />
palladium-catalyzed version of the process was established,<br />
there were also significant differences in reactivity.<br />
In general, the copper-catalyzed variant was more<br />
limited, with chloro-substituted substrates performing<br />
poorly; however, greater success was achieved with<br />
amide nucleophiles, relative to the palladium system.<br />
Scheme 10<br />
Pd2(dba)3 (2.5 mol%)<br />
DPEPhos (6 mol%)<br />
Cs2CO3 toluene, 100 °C<br />
Br Cl<br />
Ph<br />
21, E/Z 2:7<br />
+ H2N<br />
Ph<br />
Pd2(dba)3 (2.5 mol%)<br />
SPhos (14) (7.5 mol%)<br />
NaOt-Bu<br />
toluene, 80 °C<br />
N Cl Br<br />
+<br />
O<br />
OEt<br />
24<br />
H2N OMe<br />
O<br />
PPh2 PPh2<br />
DPEPhos (22)<br />
N<br />
Ph 81%<br />
OMe<br />
Pd2(dba) 3 (5 mol%)<br />
DPEPhos (22) (12 mol%)<br />
Cs2CO3 toluene, 110 °C<br />
Br Br<br />
25<br />
MeO<br />
CuOAc (10 mol%)<br />
MeO<br />
MeO<br />
H2N<br />
+<br />
Ot-Bu<br />
(20 mol%)<br />
Cs2CO3<br />
toluene, 110 °C<br />
MeO<br />
O<br />
MeN NMe<br />
H H 25<br />
75%<br />
94%<br />
N<br />
N<br />
Ph<br />
N<br />
23, 77%<br />
Me Me<br />
N<br />
83%<br />
N<br />
t-BuO<br />
82%<br />
OEt<br />
O<br />
OMe<br />
N<br />
O<br />
Cl<br />
Ackermann <strong>and</strong> co-workers developed efficient indole<br />
syntheses based on a cascade amination process starting<br />
from o-alkynylhaloarenes. 38 In his original report,<br />
Ackermann described both palladium- <strong>and</strong> copper-catalyzed<br />
variants of the process (Scheme 11). 38a For example,<br />
the combination of o-alkynylchloroarene 26 with<br />
benzylamine under the action of an NHC-derived palladium<br />
catalyst delivered indole 27 in 66% yield. The original<br />
copper-catalyzed protocol simply employed copper(I) iodide<br />
to combine o-alkynylchoroarenes with anilines furnishing<br />
the corresponding N-arylindoles in good yields.<br />
The reactions proceed via initial intermolecular N-arylation,<br />
followed by cyclization onto the alkyne. The two<br />
different metal systems were shown to display differing,<br />
<strong>and</strong> complementary, reactivities; for example, the palladium-catalyzed<br />
methods were effective for N-alkyl <strong>and</strong> Naryl<br />
nucleophiles, while the copper system tolerated Naryl<br />
<strong>and</strong> N-acyl substrates. 38b The N-acyl systems required<br />
the use of diamine lig<strong>and</strong> 25. Scheme 11 shows several<br />
examples of products obtained using the copper methodology,<br />
including an N-acyl indole, as well as an azaindole.<br />
An indole corresponding to the Chek1/KDR kinase inhibitor<br />
pharmacophore was also prepared. The palladiumcatalyzed<br />
version of the chemistry was shown to be effective<br />
for the preparation of indoles bearing sterically dem<strong>and</strong>ing<br />
substituents; for example, the adamantylsubstituted<br />
indole 28 was obtained in 94% yield. 38c,d The<br />
Hu 39 <strong>and</strong> Sanz 40 research groups have reported related<br />
indole-forming chemistries.<br />
F3C<br />
Scheme 11<br />
29<br />
26<br />
Hex<br />
Pd(OAc)2 (5 mol%)<br />
(5 mol%)<br />
+<br />
H2N<br />
Cl<br />
Ph<br />
K3PO4<br />
toluene, 105 °C<br />
Bu<br />
i-Pr i-Pr<br />
Cl<br />
+<br />
N N<br />
–<br />
F 3C<br />
N<br />
27, 66% Bn<br />
Hex<br />
H2N<br />
Cl<br />
+ OMe<br />
CuI (10 mol%)<br />
KOt-Bu<br />
toluene, 105 °C<br />
N<br />
Bu<br />
OMe<br />
69%<br />
t-BuO<br />
61%<br />
N<br />
O<br />
S<br />
N<br />
N<br />
t-BuO<br />
86%<br />
O<br />
i-Pr i-Pr<br />
29<br />
Ph<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
N<br />
28, 94%<br />
F
6 J. E. R. Sadig, M. C. Willis REVIEW<br />
The Hsung research group employed related cascade processes<br />
for the synthesis of 2-aminoindoles. 41 Scheme 12<br />
shows an example in which ynamide 30 was combined<br />
with p-toluamine to deliver indole 31 in 85% yield. An<br />
XPhos-derived palladium catalyst was found to be optimal,<br />
<strong>and</strong> a variety of 2-carbamate-substituted indoles<br />
were prepared in good yields. The ynamide substrates<br />
were prepared, in a separate operation, by a copper-catalyzed<br />
amidation of the corresponding bromo-alkynes.<br />
30<br />
Br<br />
Scheme 12<br />
Ackermann <strong>and</strong> colleagues were able to extend their original<br />
methodology to a three-component system, featuring<br />
the in situ formation of the key o-alkynylhaloarenes. 38a,e<br />
The process involved the initial combination of an ochloroiodobenzene<br />
with an alkyne in the presence of a<br />
mixed palladium/copper catalyst system (Scheme 13); after<br />
two hours the required nitrogen nucleophile was introduced<br />
along with additional base, resulting in arylamination<br />
followed by a 5-endo ring closure. A variety of<br />
1,2-disubstituted indoles were obtained in good yields. A<br />
possible limitation of the method is the poor commercial<br />
availability of alternative o-chloroiodobenzene derivatives.<br />
Scheme 13<br />
O<br />
N<br />
O Pd2(dba) 3 (2.5 mol%)<br />
XPhos (5 mol%)<br />
Cs2CO3 +<br />
Ph toluene, 110 °C<br />
H2N p-Tol<br />
Cy2P i-Pr<br />
i-Pr<br />
XPhos (32)<br />
N N<br />
p-Tol<br />
Ph<br />
31, 85%<br />
The Barluenga research group developed a successful cascade<br />
process, based on palladium-catalyzed aza-enolate<br />
a-arylation followed by intramolecular N-arylation, for<br />
the synthesis of a variety of indole derivatives. 42 The process<br />
is outlined in Scheme 14: Initial palladium-catalyzed<br />
aza-enolate arylation joins N-phenylimine 33 with 1,2-dibromobenzene,<br />
to provide imine 34. <strong>Palladium</strong>-catalyzed<br />
intramolecular amination, presumably via enamine intermediate<br />
35, then delivers the expected indole in an excel-<br />
i-Pr<br />
29<br />
I i) Pd(OAc) 2 (10 mol%)<br />
CuI (10 mol%), (10 mol%)<br />
Cs2CO3 Cl toluene, 105 °C<br />
H<br />
+<br />
Ph<br />
ii) KOt-Bu<br />
H2N p-Tol<br />
Ph<br />
65%<br />
Cl<br />
Ph<br />
N<br />
p-Tol<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
O<br />
O<br />
lent 86% yield. The same XPhos-derived catalyst proved<br />
optimal for both steps of the cascade. A wide range of<br />
imine derivatives could be incorporated. The use of mixed<br />
halogen systems, such as 1-bromo-2-iodobenzenes, allowed<br />
the regioselective synthesis of substituted indoles<br />
by exploiting the greater reactivity of the aryl iodide substituent.<br />
The authors were also able to show that mixed<br />
halide/sulfonate substrates were efficient reaction components,<br />
with both triflate <strong>and</strong> nonaflate systems being successfully<br />
employed. The ability to generate the required<br />
sulfonate derivatives from the parent o-chlorophenols significantly<br />
widened the scope of the process <strong>and</strong> allowed<br />
unusual substitution patterns to be accessed, such as the<br />
2,4,6-trisubstituted example 36. 42b Although an N-aryl or<br />
N-alkyl substituent was a requirement of the imine components,<br />
the authors demonstrated that N-tert-butylsubstituted<br />
indoles could be deprotected under a variety of<br />
conditions. For example, the N-H indole derived from Ntert-butylindole<br />
37 was obtained in 97% yield for the indole<br />
formation <strong>and</strong> deprotection (AlCl 3) sequence. The<br />
group also reported a three-component variant of the<br />
methodology, in which an initial palladium-catalyzed alkenyl<br />
halide amination was used to prepare the imine reaction<br />
components.<br />
Scheme 14<br />
33 86%<br />
Br<br />
+<br />
Br Me<br />
N<br />
Ph<br />
Ph<br />
Pd2(dba)3 (2 mol%)<br />
XPhos (32) (4 mol%)<br />
NaOt-Bu, dioxane<br />
110 °C<br />
N<br />
Ph<br />
N<br />
86% Ph<br />
Br Ph<br />
N<br />
2.2 Carbazoles<br />
Ph<br />
Br Ph<br />
HN<br />
34 35<br />
OMe<br />
Catalytic amination chemistry has a number of applications<br />
in carbazole synthesis. Nozaki was one of the first to<br />
exploit cascade amination processes for the preparation of<br />
a wide range of carbazole architectures. 43 An example of<br />
the general process developed by the Nozaki research<br />
group is shown in Scheme 15; the key heterocycle-forming<br />
reaction is a coupling between a nitrogen nucleophile<br />
<strong>and</strong> a doubly activated biphenyl. In this particular example,<br />
ditriflate 37 was coupled with tert-butylcarbamate using<br />
a XantPhos-derived catalyst to deliver carbazole 38 in<br />
70% yield. 43b Deprotection of the Boc group from carbazole<br />
38 revealed the natural product mukinone. The same<br />
group has exploited their methodology in the synthesis of<br />
heteroacenes, 43d,e chiral carbazole variants, 43a as well as<br />
Ph<br />
Ph<br />
36, 74%<br />
N<br />
Ph<br />
Ph<br />
N<br />
37, 91%<br />
Me<br />
Ph<br />
Me<br />
Me<br />
(from Cl/ONf substrate) (from I/Cl substrate)<br />
Cl
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 7<br />
helicenes. 43b The second example shown in Scheme 15<br />
was reported by Chida <strong>and</strong> colleagues, <strong>and</strong> shows that related<br />
strategies developed using dibromobiphenyls are<br />
also effective in carbazole synthesis. 44a The example<br />
shows the preparation of a key intermediate in the synthesis<br />
of the natural product murrayazoline. 44b In order to<br />
achieve an efficient transformation using the sterically dem<strong>and</strong>ing<br />
amine 39, it was necessary to employ a high catalyst<br />
loading (20 mol%). A copper-catalyzed version of<br />
these transformations has also been reported. 45 The cascade<br />
coupling of nitrogen nucleophiles with doubly activated<br />
bi-aromatics has proven to be a powerful method for<br />
carbazole synthesis <strong>and</strong> has been exploited by several other<br />
groups. For example, Samyn <strong>and</strong> co-workers utilized<br />
dibromo-2,2¢-bithiophene substrates to prepare<br />
dithienopyrroles, 46 as did the Barlow research group. 47<br />
MeO<br />
Me<br />
O<br />
37<br />
OMOM<br />
Scheme 15<br />
O<br />
OMe<br />
OTf<br />
OTf<br />
Pd2(dba)3.CHCl3<br />
(5 mol%)<br />
XantPhos (2) (10 mol%)<br />
K3PO4<br />
o-xylene, 100 °C<br />
Br<br />
Pd2(dba) 3 (20 mol%)<br />
XPhos (32) (60 mol%)<br />
Br<br />
H2N +<br />
Me<br />
Me<br />
NaOt-Bu<br />
toluene, 130 °C<br />
O<br />
+<br />
t-BuO<br />
NH2<br />
39<br />
O<br />
MeO2C<br />
Bedford et al. developed a cascade sequence based on intermolecular<br />
aryl-amination followed by intramolecular<br />
direct C–H arylation as a route to carbazole derivatives;<br />
several examples are shown in Scheme 16. 48 The process<br />
combines o-chloroanilines with aryl bromides using palladium<br />
catalysis. Use of the bulky electron-rich tri(tertbutyl)phosphine<br />
lig<strong>and</strong> in combination with palladium(II)<br />
acetate was the optimal catalyst system <strong>and</strong> allowed the<br />
preparation of a range of carbazoles in good yields. Significant<br />
substitution could be tolerated on the coupling<br />
partners, as illustrated by the preparation of the natural<br />
product clausine P (40).<br />
Ackermann et al. developed a related aryl-amination <strong>and</strong><br />
direct C–H arylation sequence for carbazole synthesis. 49<br />
In the Ackermann approach, 1,2-dihaloaromatics were<br />
combined with anilines to deliver carbazole products<br />
(Scheme 17). A combination of palladium(II) acetate <strong>and</strong><br />
Me<br />
N<br />
OMe<br />
Boc<br />
70%<br />
N-Boc mukonine (38)<br />
MOMO<br />
murrayazoline<br />
59%<br />
O O<br />
Me<br />
N<br />
Me<br />
F 3C<br />
Me<br />
Scheme 16<br />
tricyclohexylphosphine was found to be optimal <strong>and</strong> allowed<br />
a wide range of carbazoles to be prepared. Using<br />
this catalyst system it was possible to employ inexpensive<br />
1,2-dichloroarenes as coupling partners, as well as heterocyclic<br />
derivatives, illustrated by the preparation of pyrazine<br />
<strong>and</strong> pyridine derivatives 41 <strong>and</strong> 42. The authors<br />
exploited the methodology in a synthesis of the natural<br />
product murrayafoline A (43). 49b Although less accessible,<br />
1,2-dihaloalkenes could also be employed as substrates,<br />
allowing the same cascade sequence to be applied<br />
to indole synthesis.<br />
+<br />
+<br />
N<br />
H<br />
43%<br />
Cl<br />
H<br />
N<br />
N<br />
Cl<br />
Scheme 17<br />
Ph<br />
N<br />
Ph<br />
41, 93%<br />
Bn<br />
NH<br />
Cl<br />
Br<br />
N<br />
Pd(OAc)2 (4 mol%)<br />
t-Bu3P (5 mol%)<br />
NaOt-Bu<br />
toluene, reflux<br />
OMe<br />
Pd(OAc)2 (5 mol%)<br />
Cy3P (10 mol%)<br />
NaOt-Bu<br />
NMP, 130 °C<br />
N<br />
Ph<br />
42, 93%<br />
N<br />
69% Bn<br />
Kan <strong>and</strong> co-workers reported a palladium-catalyzed cascade<br />
route to carbazoles based on initial intermolecular<br />
Suzuki coupling followed by an intramolecular aryl amination.<br />
A small scoping study was described, although a<br />
possible limitation is the availability of suitably functionalized<br />
boronic acids. 50 Fujii <strong>and</strong> Ohno have also described<br />
a cascade route to carbazoles. In their approach, an intermolecular<br />
aryl amination between an aryl triflate <strong>and</strong> an<br />
aniline was used to construct a diphenylamine which then<br />
underwent an oxidative coupling to generate a carbazole<br />
product. The efficiency of the oxidative step was shown to<br />
be dependent on the substitution pattern of the diphenylamine<br />
intermediates. 51<br />
N<br />
F 3C<br />
MeO<br />
N<br />
H<br />
69%<br />
clausine P (40)<br />
CF 3<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Me<br />
Me<br />
N<br />
Ph<br />
85%<br />
OMe<br />
N<br />
MeO H<br />
murrayafoline A (43)<br />
74% from Br/Cl-Ar<br />
72% from Cl/Cl-Ar<br />
Me<br />
Me
8 J. E. R. Sadig, M. C. Willis REVIEW<br />
2.3 Benzimidazoles <strong>and</strong> Benzimidazolones<br />
A host of approaches to benzimidazoles <strong>and</strong> related derivatives,<br />
featuring inter- <strong>and</strong> intramolecular <strong>and</strong> cascade reactions,<br />
as well as both palladium <strong>and</strong> copper catalysts,<br />
have been reported. Ma <strong>and</strong> co-workers developed a number<br />
of copper-catalyzed routes to these important heterocycles.<br />
52 In 2007, they demonstrated that o-haloacetanilides<br />
could be combined with primary amines to deliver<br />
benzimidazoles (Scheme 18). For example, a copper(I)<br />
iodide/proline catalyst system was effective for the union<br />
of aryl iodide 44 with allylamine, to furnish benzimidazole<br />
45 in 94% yield. 52a When more sterically dem<strong>and</strong>ing<br />
amines, or less activated aryl units, were employed it was<br />
necessary to use either heat or an acid/heat combination to<br />
achieve cyclization to the aromatic system; for example,<br />
the formation of cyclohexyl-substituted benzimidazole 46<br />
required the addition of acid. A broad range of amines <strong>and</strong><br />
aryl units, including pyridine derivatives, could be included<br />
in the method, delivering benzimidazoles in good to<br />
excellent yields. Although Scheme 18 shows only aryl iodide<br />
substrates, aryl bromides were also used. When the<br />
starting substrates were changed to o-iodoarylcarbamates,<br />
the same reaction system was used to access benzimidazolones<br />
(47 → 48). 52b Aqueous ammonia could also be<br />
employed as the nitrogen nucleophile in both reaction<br />
pathways, leading to the corresponding N–H derivatives.<br />
52c<br />
44<br />
+<br />
H2N +<br />
H2N 47<br />
+<br />
H2N<br />
H<br />
N<br />
Scheme 18<br />
I<br />
H<br />
N<br />
I<br />
H<br />
N<br />
I<br />
O<br />
O<br />
O<br />
CF3<br />
O<br />
OMe<br />
N Boc<br />
CuI (10 mol%)<br />
L-proline (20 mol%)<br />
K 2CO 3, DMSO, r.t.<br />
i) CuI (10 mol%)<br />
L-proline (20 mol%)<br />
K2CO3, DMSO, 40 °C<br />
ii) AcOH, 140 °C<br />
CuI (10 mol%)<br />
L-proline (20 mol%)<br />
K 2CO 3, DMSO<br />
50 °C then 130 °C<br />
OH<br />
N<br />
H H<br />
O<br />
L-proline<br />
N<br />
45, 94%<br />
46, 73%<br />
48, 74%<br />
Buchwald <strong>and</strong> co-workers developed a related palladiumcatalyzed<br />
route to aryl-substituted benzimidazoles. For<br />
example, the coupling of o-bromacetanilide 49 with otoluamine<br />
using an XPhos-derived catalyst provided the<br />
corresponding N-arylbenzimidazole in 94% yield<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
N<br />
N<br />
N<br />
H<br />
N<br />
N<br />
N<br />
CF3<br />
O<br />
Boc<br />
O<br />
(Scheme 19). 53a A good range of anilines <strong>and</strong> aryl substrates<br />
(both Br <strong>and</strong> Cl) were described; Scheme 19 also<br />
shows an aza-example, derived from the corresponding<br />
pyridine substrate, as well as a cyclopropyl-substituted<br />
product. Some variation of lig<strong>and</strong> between XPhos (32)<br />
<strong>and</strong> RuPhos (50) was needed for certain substrates. In<br />
2006, Scott reported a palladium-catalyzed synthesis of<br />
imidazopyridinones (aza-benzimadazolones) in a process<br />
analogous to the conversion of 47 into 48 shown in<br />
Scheme 18. 54<br />
Me<br />
N<br />
H2N<br />
Me<br />
Scheme 19<br />
Buchwald <strong>and</strong> Zheng also described a complementary<br />
copper-catalyzed protocol, based on aryl halide amidation<br />
(as opposed to amination), for benzimidazole synthesis. 53b<br />
The basic process is shown in Scheme 20; copper(I)<br />
iodide/diamine-catalyzed coupling of hexamide with oiodo-N-alkylaniline<br />
51, followed by base-promoted cyclization,<br />
delivered the desired N-alkylbenzimidazole 52<br />
in 87% yield. Alkyl, alkenyl <strong>and</strong> aryl amides could all be<br />
incorporated effectively.<br />
Scheme 20<br />
N<br />
N<br />
(from ArCl using lig<strong>and</strong> 50)<br />
F 3C<br />
49<br />
Br<br />
H<br />
N Me<br />
Pd2(dba) 3 (1 mol%)<br />
+<br />
O<br />
Br<br />
XPhos (32) (8 mol%)<br />
K3PO4 t-BuOH, 110 °C<br />
88%<br />
H2N<br />
51<br />
+<br />
O<br />
H<br />
N<br />
I<br />
Pent<br />
N<br />
Me<br />
Me<br />
Me<br />
N<br />
Me<br />
Me<br />
83%<br />
(using lig<strong>and</strong> 50)<br />
i) CuI (5 mol%)<br />
25 (20 mol%)<br />
Cs2CO3, dioxane, 90 °C<br />
ii) K3PO4<br />
t-BuOH, 110 °C<br />
F3C<br />
94%<br />
Intramolecular aryl amidation using urea substrates has<br />
been achieved using both palladium <strong>and</strong> copper catalysis<br />
<strong>and</strong> provides a further route to benzimidazolones<br />
(Scheme 21). The cyclization of urea 53, using a palladium(II)<br />
acetate/XPhos catalyst system, was described by<br />
the process group at Merck. 55 Chloro-, bromo- <strong>and</strong> iodoaryl<br />
derivatives could all be employed as substrates, as<br />
could chloropyridines. <strong>Copper</strong>-catalyzed variants of similar<br />
cyclizations have also been reported, 56 including a<br />
polymer-supported example; 57 the second reaction shown<br />
in Scheme 21, reported by SanMartin, Domínguez <strong>and</strong> co-<br />
Me<br />
Br<br />
N<br />
N<br />
Cy 2P Oi-Pr<br />
i-PrO<br />
RuPhos (50)<br />
52, 87%<br />
N<br />
N<br />
Pent<br />
Me<br />
Me<br />
Me
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 9<br />
MeO<br />
Scheme 21<br />
workers, 58 illustrates a copper(I) iodide catalyzed cyclization<br />
using water as the solvent.<br />
Intramolecular reactions to access benzimidazoles can be<br />
achieved using amidines as substrates. An example, reported<br />
by Brain et al., 59 is shown in Scheme 22 in which<br />
amidine 54 was converted into the corresponding benzimidazole<br />
under the action of a Pd2(dba) 3/triphenylphosphine<br />
catalyst. The authors were also able to show that use<br />
of a ‘catch-<strong>and</strong>-release’ purification strategy, 59b involving<br />
Amberlyst resin, allowed the benzimidazoles to be obtained<br />
in pure form without recourse to chromatography.<br />
Related cyclizations in which the amidine is embedded<br />
within a heterocycle have also been described. 60,61<br />
De Meijere <strong>and</strong> Lygin reported that amidines, generated<br />
in situ from an isocyanide <strong>and</strong> a primary amine, can also<br />
be cyclized using copper(I) conditions to access N-alkylbenzimidazoles.<br />
62<br />
Me<br />
53<br />
54<br />
Scheme 22<br />
PMB PMB<br />
Pd(OAc) 2 (1 mol%)<br />
N O XPhos (32) (3 mol%)<br />
N<br />
NH2<br />
Cl<br />
Bn<br />
N<br />
O<br />
NH2 Br<br />
NaHCO3<br />
i-PrOH, 83 °C<br />
CuI (8.5 mol%)<br />
TMEDA (3.5 equiv)<br />
H 2O, 120 °C<br />
MeO<br />
92%<br />
92%<br />
Batey <strong>and</strong> Evindar used related cyclizations employing<br />
guanidine substrates to access 2-aminobenzimidazoles. 63<br />
Efficient reactions were achieved using either palladium<br />
or copper catalysis; Scheme 23 gives an example of the<br />
reaction conditions needed for each metal. In general, the<br />
copper conditions were found to be superior, providing<br />
higher yields <strong>and</strong> more selective reactions. Both aryl iodides<br />
<strong>and</strong> aryl bromides could be employed as substrates,<br />
allowing a broad range of 2-aminobenzimidazoles to be<br />
Me<br />
Br<br />
HN<br />
Bn<br />
N<br />
Scheme 23<br />
N<br />
N Me<br />
NHMe<br />
Br<br />
Pd2(dba)3, (1.5 mol%)<br />
Ph3P (12 mol%)<br />
NaOH, H 2O–DME<br />
160 °C, MW<br />
Pd(PPh3)4 (10 mol%)<br />
Cs2CO3, DME, 80 °C<br />
or<br />
CuI (5 mol%)<br />
1,10-Phen (10 mol%)<br />
Cs2CO3, DME, 80 °C<br />
Me<br />
Me<br />
82%<br />
N<br />
N<br />
Bn N<br />
Pd: 66%<br />
Cu: 90%<br />
N<br />
N<br />
N<br />
H<br />
Bn<br />
N<br />
N<br />
H<br />
Me<br />
O<br />
O<br />
Me<br />
prepared in good yields. Szczepankiewicz et al. applied<br />
this type of copper-catalyzed cyclization to substrates<br />
based on uracil templates to prepare purine <strong>and</strong> related<br />
fused imidazole systems. 64 2-Mercaptobenzimidazoles<br />
can similarly be accessed using copper-catalyzed cyclization<br />
of in situ generated isothioureas. 65<br />
The research groups of both Zhang66<strong>and</strong> Wu67 showed<br />
that o-halophenylimidoyl chlorides are effective substrates<br />
for copper-catalyzed benzimidazole synthesis.<br />
Scheme 24 presents an example from the Zhang group,<br />
<strong>and</strong> shows how imidoyl chloride 55 can be combined with<br />
benzylamine using a copper(I) iodide catalyst, to deliver<br />
the expected benzimidazole in excellent yield. Both alkyl<strong>and</strong><br />
arylamines could be employed. In both reports it was<br />
necessary to include an electron-withdrawing substituent<br />
on the imidoyl chloride substrate; for example, the trifluoromethyl<br />
substituent on imidoyl chloride 55.<br />
N<br />
Scheme 24<br />
Maes <strong>and</strong> co-workers explored a range of cascade amination<br />
strategies to access a variety of benzo-fused benzimidazole<br />
systems. 68 In their lead publication, they were able<br />
to combine 2-chloro-3-iodopyridine with 2-picoline to<br />
generate dipyridoimidazole 56 in 96% yield (Scheme 25).<br />
The example shown employs a palladium(II) acetate/<br />
BINAP catalyst, although XantPhos (2) was also shown to<br />
be an effective lig<strong>and</strong>. 68a The chemistry has been extended<br />
to the preparation of a number of benzo-fused <strong>and</strong> aza analogues,<br />
68a–c,69 <strong>and</strong> in an interesting application a temperature/halide<br />
dependent regioselectivity switch was<br />
developed. 68d<br />
Scheme 25<br />
I<br />
H2N Ph<br />
N<br />
55<br />
+<br />
I<br />
Cl<br />
+<br />
CF3<br />
Cl N NH 2<br />
CuI (10 mol%)<br />
TMEDA (20 mol%)<br />
Cs 2CO 3<br />
toluene, 110 °C<br />
Pd(OAc) 2 (3 mol%)<br />
BINAP (3) (3 mol%)<br />
Cs2CO3<br />
toluene, reflux<br />
98%<br />
Batey <strong>and</strong> co-workers described a copper-catalyzed cascade<br />
route to benzimidazoles from the combination of a<br />
1,2-dihalobenzene with an amidine, although only a single<br />
example was reported. 70 Deng et al. reported a related<br />
cascade in which amidines were exchanged for<br />
guanidines, leading to the synthesis of 2-aminobenzimidazoles<br />
(Scheme 26). The majority of examples delivered<br />
N–H products, although N-substitution could also be introduced.<br />
71<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
N<br />
N<br />
N<br />
CF3<br />
Ph<br />
N<br />
N<br />
56, 96%
10 J. E. R. Sadig, M. C. Willis REVIEW<br />
Me<br />
HN<br />
H2N<br />
+<br />
N<br />
Scheme 26<br />
2.4 Indazoles <strong>and</strong> Indazolones<br />
Indazoles have proven to be popular targets for amination<br />
chemistry. A number of groups have described the cyclization<br />
of appropriately substituted arylhydrazones.<br />
Scheme 27 illustrates an intramolecular coupling of bromo-substituted<br />
arylhydrazone 57 to deliver 1H-indazole<br />
58 in 85% yield. 72 The DPEPhos-derived catalyst system<br />
was effective for a wide range of substrates, although aryl<br />
chloride substrates performed poorly. Analogous N-tosylhydrazones<br />
were also established as effective indazole<br />
precursors, 73a <strong>and</strong> were utilized in a synthesis of the natural<br />
product nigellicine. 73b 3-Amino-1H-indazoles were<br />
also prepared by similar palladium-catalyzed cyclizations.<br />
74 Song <strong>and</strong> Yee demonstrated that appropriately<br />
substituted hydrazines are also useful indazole precursors.<br />
For example, palladium-catalyzed ring closure using hydrazine<br />
59 delivered the corresponding aromatic 1H-indazole<br />
directly in 87% yield, following intramolecular<br />
amination <strong>and</strong> spontaneous aromatization. 75 The mechanism<br />
of aromatization was not established. The authors<br />
noted the instability of certain hydrazine substrates to<br />
long-term storage, <strong>and</strong> as alternatives established that the<br />
corresponding N-triphenylphosphonium bromide salts<br />
provided convenient stable precursors that could be cyclized<br />
under identical reaction conditions.<br />
MeO<br />
57<br />
Scheme 27<br />
Br<br />
I<br />
Br<br />
N<br />
O<br />
CuI (15 mol%)<br />
25 (30 mol%)<br />
Cs2CO3<br />
DMA, 165 °C<br />
N<br />
N O<br />
N<br />
H<br />
53%<br />
There are a number of reports of halo-substituted hydrazones<br />
being formed in situ <strong>and</strong> then cyclized to yield 1Hindazoles;<br />
Scheme 28 presents examples using both palladium<br />
<strong>and</strong> copper catalysis. Cho et al. were able to show<br />
that o-bromobenzaldehydes could be combined with phenylhydrazine<br />
using a palladium(II) chloride/dppp catalyst<br />
system to furnish the corresponding indazoles in good<br />
yields (60 → 61). 76 The copper example, reported by<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Me<br />
Me<br />
H<br />
N<br />
Pd(dba)2 (2 mol%<br />
N<br />
DPEPhos (22) (2 mol%)<br />
N<br />
Me<br />
NH<br />
K 3PO 4<br />
toluene, 110 °C<br />
MeO<br />
Pd(OAc) 2 (5 mol%)<br />
dppf (12) (7.5 mol%)<br />
Me<br />
58, 85%<br />
Br HN<br />
NaOt-Bu<br />
toluene, 90 59 °C<br />
87%<br />
N<br />
N<br />
Me<br />
Pabba et al., required a two-step one-pot approach in<br />
which a ten-minute microwave reaction was used to form<br />
the hydrazone before a copper(I)/diamine catalyst was<br />
added to the system (62 → 63). 77 Del Olmo <strong>and</strong> co-workers<br />
reported a related copper-catalyzed process which also<br />
allowed the use of aryl carboxylic acid substrates to deliver<br />
1-hydroxy-1H-indazoles. 78<br />
MeO<br />
MeO<br />
F<br />
Scheme 28<br />
Guillaumet <strong>and</strong> co-workers reported an intermolecular<br />
copper-catalyzed amination method for the preparation of<br />
pyrazolopyridines (azaindazoles). 79 3-Cyano-2-chloropyridine<br />
was combined with a range of hydrazines using a<br />
copper(I) iodide/phenanthroline catalyst to deliver 3-amino-1H-azaindazoles<br />
in good yields (Scheme 29). The 3amino<br />
products were converted into the corresponding 3iodo<br />
derivatives by way of their diazonium salts, <strong>and</strong> were<br />
employed in a range of palladium-catalyzed coupling processes<br />
including Stille, Heck <strong>and</strong> Suzuki reactions.<br />
N<br />
CN<br />
Cl<br />
Scheme 29<br />
O<br />
60<br />
O<br />
+<br />
62<br />
H<br />
+ H2N<br />
Br<br />
H<br />
+ H2N<br />
Br<br />
Et<br />
H<br />
N NH2<br />
NH<br />
Ph<br />
NH<br />
Ph<br />
PdCl 2 (2 mol%)<br />
dppp (3 mol%) MeO<br />
NaOt-Bu<br />
toluene, 100 °C<br />
i) NMP, 160 °C<br />
10 min, MW<br />
ii) CuI (5 mol%)<br />
64 (10 mol%)<br />
K2CO 3, 160 °C<br />
10 min, MW<br />
NHMe<br />
NHMe<br />
MeO<br />
61, 65%<br />
N<br />
N<br />
N<br />
N<br />
The less thermodynamically stable 2H-indazole isomers<br />
can also be accessed using amination chemistry. In an approach<br />
mirroring their route to the 1H-isomers (see<br />
Scheme 27), Song <strong>and</strong> Yee employed a palladium-catalyzed<br />
cyclization of appropriately substituted hydrazines.<br />
80 For example, N-alkyl-N-arylhydrazine 65 was<br />
converted into 2-aryl-2H-indazole 66 in 60% yield<br />
(Scheme 30). Katayama <strong>and</strong> co-workers showed that N2–<br />
C3-fused examples can also be prepared using similar<br />
chemistry. 81<br />
64<br />
CuI (5 mol%)<br />
1,10-phenanthroline<br />
(10 mol%)<br />
Cs 2CO 3<br />
DMF, 60 °C<br />
N N<br />
1,10-phenanthroline<br />
F<br />
63, 84%<br />
NH 2<br />
N<br />
N N<br />
86% Et
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 11<br />
N Ph<br />
MeO<br />
Pd(OAc) 2 (5 mol%)<br />
MeO<br />
dppf (12) (7.5 mol%)<br />
NH2 Br<br />
NaOt-Bu<br />
toluene, 90 °C<br />
65<br />
Scheme 30<br />
Hall<strong>and</strong>, Lindenschmidt <strong>and</strong> co-workers reported an alternative<br />
route to the 2H-indazole isomers employing the<br />
same o-alkynylhaloarene substrates used successfully by<br />
others to access indoles (see Schemes 11 <strong>and</strong> 12). The reactions<br />
proceeded via an initial regioselective amination<br />
reaction using a monosubstituted hydrazine to generate an<br />
N,N¢-disubstituted hydrazine, which then underwent intramolecular<br />
hydroamination to form a dihydroindazole<br />
intermediate (67, Scheme 31). 82 Isomerization from these<br />
intermediates to the aromatic 2H-indazoles occurred<br />
spontaneously under the reaction conditions of palladium(II)<br />
chloride/tri(tert-butyl)phosphine with cesium carbonate<br />
in N,N-dimethylformamide. Good functional<br />
group tolerance was demonstrated <strong>and</strong> an extensive range<br />
of substituted products was described; three examples are<br />
shown in Scheme 31.<br />
67<br />
Scheme 31<br />
Indazolones can be prepared by the copper-catalyzed cyclization<br />
of o-halobenzohydrazides. For example, treatment<br />
of hydrazide 68 with a copper(I) iodide/proline<br />
catalyst system delivered indazolone 69 in 60% yield<br />
(Scheme 32). 83 Iodo substrates delivered the most efficient<br />
reactions; the bromo <strong>and</strong> chloro substrates were also<br />
shown to deliver the desired products, albeit in reduced<br />
yields.<br />
Scheme 32<br />
Ph<br />
+ H2N<br />
Cl<br />
O<br />
I<br />
Ph<br />
N Ph<br />
N<br />
H<br />
N<br />
H<br />
H<br />
N<br />
2.5 Pyrroles<br />
PdCl2 (5 mol%)<br />
Pt-Bu3 HBF4 (10 mol%)<br />
NH<br />
Cs2CO<br />
Ph<br />
3<br />
DMF, 110–130 °C<br />
.<br />
93%<br />
CO2t-Bu<br />
N Ph<br />
N<br />
CuI (10 mol%)<br />
L-proline (20 mol%)<br />
K 2CO 3, DMSO<br />
r.t. to 70 °C<br />
68 69, 60%<br />
N Ph<br />
N<br />
66, 60%<br />
N Ph<br />
N<br />
79%<br />
OEt<br />
The Buchwald <strong>and</strong> Li research groups both reported cascade<br />
copper-catalyzed alkenyl amidation routes to pyr-<br />
Ph<br />
N Ph<br />
N<br />
55%<br />
O<br />
OEt<br />
NH<br />
N<br />
roles. The Buchwald group utilized a copper(I) iodide/<br />
diamine 25 catalyst system to combine carbamates (<strong>and</strong> a<br />
limited number of amides) with 1,4-diiodo-1,3-dienes to<br />
generate highly substituted pyrrole products (70 → 71,<br />
Scheme 33). 84 The methodology displayed excellent<br />
functional group tolerance <strong>and</strong> was applied to the synthesis<br />
of a wide range of pyrroles, including tetrasubstituted<br />
examples. The method was also applicable to the synthesis<br />
of heteroarylpyrroles, such as thienopyrrole 72. The Li<br />
approach exploited similar diene substrates in combination<br />
with a range of amide coupling partners. 45,85 For example,<br />
diiododiene 73 was combined with phenylacetamide<br />
using a copper(I) iodide/diamine 64 catalyst to<br />
deliver the expected pyrrole in 86% yield (Scheme 33).<br />
Pr<br />
S<br />
Bu<br />
Bu<br />
SiMe3<br />
Pr<br />
70<br />
73<br />
Scheme 33<br />
I O<br />
I<br />
+<br />
H2N Ot-Bu<br />
Me<br />
Pr<br />
CuI (5 mol%)<br />
25 (20 mol%)<br />
Cs 2CO 3<br />
THF, 80 °C<br />
CuI (20 mol%)<br />
64 (20 mol%)<br />
Cs 2CO 3<br />
dioxane, 100 °C<br />
Pr<br />
N<br />
Boc<br />
71, 86%<br />
N<br />
SiMe3<br />
Pr<br />
N<br />
SiMe3<br />
N<br />
Boc<br />
Boc<br />
Boc<br />
98% 80%<br />
72, 83%<br />
I O<br />
+<br />
I<br />
H2N Ph<br />
Buchwald <strong>and</strong> colleagues reported a complementary stepwise<br />
approach to pyrroles also based on copper-catalyzed<br />
alkenylation reactions. 86 N,N¢-Di(Boc)-protected alkenylhydrazides<br />
74, themselves prepared by copper-catalyzed<br />
alkenylation reactions, were coupled with a second alkenyl<br />
iodide to generate bis(ene)hydrazide 75 (Scheme 34).<br />
Thermolysis triggered a [3,3] rearrangement to generate<br />
bis-imine 76, cyclization of which provided the pyrrole<br />
Pr<br />
Pr<br />
Pr<br />
Boc<br />
Oct<br />
N<br />
Boc<br />
N<br />
N<br />
H<br />
Boc<br />
74<br />
+<br />
Boc<br />
N<br />
Pr Oct<br />
I<br />
[3,3]<br />
Bu<br />
(i) CuI (10 mol%)<br />
1,10-phenanthroline<br />
(20 mol%)<br />
Cs2CO3, DMF<br />
80 °C, 30 h<br />
ii) o-xylene, 140 °C, 30 h<br />
iii) p-TsOH, r.t.<br />
Boc Boc<br />
N N<br />
Pr<br />
Pr Oct<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Pr<br />
S<br />
Bu<br />
N<br />
Bu<br />
O<br />
86% Ph<br />
75 76 77<br />
Scheme 34<br />
Pr<br />
Pr<br />
Pr Oct<br />
N<br />
68% Boc<br />
Boc<br />
N<br />
Pr Oct<br />
SiMe3<br />
H<br />
NBoc
12 J. E. R. Sadig, M. C. Willis REVIEW<br />
via intermediate 77. For certain substrates it was necessary<br />
to add acid to achieve complete conversion into the<br />
aromatic system. The bis(ene)hydrazides could be isolated,<br />
or more conveniently used directly in the next step of<br />
the sequence with no purification. The overall method<br />
represents a modified Piloty–Robinson reaction.<br />
The final pyrrole synthesis considered here comprises a<br />
copper-catalyzed cascade alkenyl amidation/hydroamination<br />
sequence. The process is essentially a pyrroleforming<br />
version of the indole synthesis described in<br />
Scheme 11. In this approach, described by Buchwald <strong>and</strong><br />
co-workers, haloenynes such as 78 replace the alkynylhaloarenes<br />
used for indole synthesis, <strong>and</strong>, when combined<br />
with tert-butyl carbamate <strong>and</strong> a copper(I) iodide/diamine<br />
catalyst, provide the corresponding pyrroles in good<br />
yields (Scheme 35). 87 A broad range of di- <strong>and</strong> trisubstituted<br />
pyrroles were prepared, <strong>and</strong> although the study focused<br />
on the use of iodoenynes, it was also possible to<br />
employ bromoenynes. A brief mechanistic study established<br />
that the reactions likely proceed via initial intermolecular<br />
aryl carbon–nitrogen bond formation followed by<br />
a 5-endo-dig intramolecular hydroamination.<br />
Pent<br />
78<br />
OTIPS<br />
I<br />
+<br />
t-BuO NH2<br />
Scheme 35<br />
O<br />
2.6 Pyrazoles<br />
25<br />
CuI (5 mol%)<br />
(20 mol%) OTIPS<br />
Cs2CO3 THF, 80 °C<br />
Pent<br />
N<br />
Boc<br />
83%<br />
Buchwald <strong>and</strong> co-workers utilized haloenyne substrates<br />
in a t<strong>and</strong>em copper-catalyzed pyrazole synthesis. 87 For<br />
example, combination of iodoenyne 78 with bis(Boc)hydrazine<br />
using a copper(I) iodide/diamine catalyst provided<br />
pyrazole 79 in 78% yield after Boc-deprotection with<br />
trifluoroacetic acid (Scheme 36). As in the related pyrrole<br />
syntheses, a good range of di- <strong>and</strong> trisubstituted aromatics<br />
were prepared. The mechanism was again established as<br />
proceeding via intermolecular aryl carbon–nitrogen bond<br />
formation followed by intramolecular hydroamination, although<br />
the cyclizations were in this case 5-exo-dig processes.<br />
Cho <strong>and</strong> Patel reported a pyrazole synthesis based on the<br />
palladium-catalyzed combination of b-bromovinyl aldehydes<br />
with hydrazines. 88 For example, treatment of<br />
Pent<br />
25 78<br />
(i) CuI (5 mol%)<br />
(20 mol%)<br />
Pent<br />
I<br />
+<br />
H<br />
N<br />
Boc NH<br />
Boc<br />
OTIPS<br />
Cs2CO3 THF, 80 °C<br />
ii) TFA, CH2Cl2, r.t.<br />
Scheme 36<br />
N<br />
N<br />
H<br />
79, 78%<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
OTIPS<br />
bromo-enal 80 with phenylhydrazine in the presence of a<br />
dppf-derived catalyst yielded pyrazole 81 in 77%<br />
(Scheme 37). Both cyclic <strong>and</strong> acyclic substrates could be<br />
employed, although no ketone-derived substrates were reported.<br />
Haddad <strong>and</strong> co-workers developed a pyrazole synthesis<br />
in which aryl benzophenone hydrazones, prepared<br />
by the palladium-catalyzed coupling of benzophenone hydrazone<br />
with aryl halides, were treated with a range of<br />
1,3-bifunctional substrates under acidic conditions. 89 1,3-<br />
Diketones, keto esters <strong>and</strong> ester/acid chlorides could be<br />
combined with the hydrazones to provide a range of substituted<br />
pyrazole products.<br />
80<br />
O<br />
H<br />
+<br />
Br<br />
Scheme 37<br />
H2N Pd(OAc) 2 (5 mol%)<br />
dppf (12) (7.5 mol%)<br />
NH NaOt-Bu, toluene<br />
Ph 125 °C<br />
N<br />
N<br />
Ph<br />
81, 77%<br />
2.7 Oxazoles<br />
Buchwald <strong>and</strong> co-workers utilized copper-catalyzed alkenyl<br />
iodide amidation reactions as the key step in a route to<br />
oxazoles. 90 For example, enamides such as 82 could be<br />
treated with iodine <strong>and</strong> base to provide the expected<br />
trisubstituted oxazoles in good yields (Scheme 38). The<br />
required enamides were prepared from the corresponding<br />
alkenyl bromides using a copper(I) iodide/diamine-catalyzed<br />
coupling with the appropriate amide; both aryl <strong>and</strong><br />
alkyl amides could be used. Depending on the substitution<br />
pattern of the oxazole product, certain examples required<br />
the addition of p-toluenesulfonic acid to achieve complete<br />
conversion into the aromatic molecule. Attempts to prepare<br />
mono- <strong>and</strong> disubstituted oxazoles using this method<br />
resulted in complex reaction mixtures, <strong>and</strong> an alternative<br />
process, based on the use of 1,2-dihaloalkene substrates,<br />
was developed.<br />
Ph Br<br />
+<br />
O<br />
Ph<br />
H2N Ph<br />
Scheme 38<br />
Ph<br />
Ph<br />
H<br />
N<br />
82<br />
O<br />
2.8 Quinolones<br />
i) CuI (5 mol%)<br />
(20 mol%)<br />
25<br />
Cs2CO3, THF, 80 °C<br />
ii) I2, DBU<br />
r.t. to 80 °C<br />
Ph<br />
Ph<br />
Ph<br />
Manley <strong>and</strong> Bilodeau used palladium-catalyzed intermolecular<br />
aryl halide amidation followed by an in situ aldol<br />
condensation to prepare 2-quinolones. 91 In this way o-bromobenzaldehydes<br />
were combined with a range of enolizable<br />
amides to deliver the quinolone products. Scheme 39<br />
I<br />
H<br />
N<br />
O<br />
Ph<br />
Ph<br />
Ph<br />
N<br />
O<br />
77%<br />
Ph
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 13<br />
illustrates the combination of the parent aldehyde (83)<br />
with phenylacetamide using a XantPhos-derived catalyst<br />
in combination with cesium carbonate as base. A variety<br />
of substituted amides could be employed, as could ketonebased<br />
substrates, allowing the synthesis of 4-substituted<br />
products such as quinolone 84. Pyridine derivatives could<br />
also be employed, thus providing a route to naphthyridinones.<br />
Ester- <strong>and</strong> nitrile-substituted aryl bromides were<br />
also examined <strong>and</strong> allowed access to hydroxy- <strong>and</strong> aminosubstituted<br />
products, respectively. For a small number of<br />
amide coupling partners, the researchers were able to employ<br />
a copper(I) iodide/diamine catalyst system.<br />
83<br />
Scheme 39<br />
O<br />
O<br />
H<br />
+ H2N<br />
Br<br />
N<br />
H<br />
94%<br />
O<br />
N<br />
Ph<br />
Pd 2(dba)3 (1 mol%)<br />
XantPhos (2) (3 mol%)<br />
Cs2CO3<br />
toluene, 100 °C<br />
N<br />
H<br />
84, 55%<br />
N<br />
H<br />
94%<br />
Huang et al. utilized the related o-acetylbromoarenes as<br />
substrates in a palladium-catalyzed synthesis of 4-quinolones.<br />
The simplest version of the process employed formamide<br />
as the nitrogen nucleophile <strong>and</strong>, when coupled<br />
with bromide 85, delivered quinolone product 86 in 77%<br />
yield (Scheme 40). 92 The reactions proceeded via initial<br />
palladium-catalyzed amidation followed by a base-promoted<br />
intramolecular condensation step. A XantPhosderived<br />
catalyst in combination with cesium carbonate as<br />
base was optimal for the amidation step, <strong>and</strong> the addition<br />
of sodium tert-butoxide as a second base was found to be<br />
necessary to achieve high yields for the combined process.<br />
As can be seen from the examples presented in<br />
Scheme 40, a range of substituted amides could be employed,<br />
including lactams, which allowed the synthesis of<br />
N-fused products such as quinolone 87. The Buchwald research<br />
group reported a related process based on coppercatalyzed<br />
amidation, although in their case it was neces-<br />
MeO<br />
N<br />
H<br />
Scheme 40<br />
85<br />
O<br />
Ph<br />
Ph<br />
O<br />
Me<br />
Br H O<br />
Pd2(dba) 3 (1 mol%)<br />
XantPhos (2) (2.5 mol%)<br />
+<br />
2N H<br />
Cs2CO3, dioxane<br />
100 °C, 2–48 h then<br />
NaOt-Bu, 100 °C<br />
MeO<br />
O<br />
N<br />
H<br />
O<br />
N<br />
N<br />
H<br />
75%<br />
Ph<br />
O<br />
Ph<br />
O<br />
O<br />
N<br />
H<br />
86, 77%<br />
S<br />
82% 91% 87, 85%<br />
Me<br />
O<br />
N<br />
sary to isolate the initial amidation products before cyclization.<br />
93<br />
A t<strong>and</strong>em Heck/intramolecular amidation strategy was reported<br />
by Cacchi <strong>and</strong> co-workers as a route to 4-aryl-2quinolones.<br />
94 Using molten tetrabutylammonium acetate/<br />
tetrabutylammonium bromide as the reaction medium <strong>and</strong><br />
a simple palladium(II) acetate catalyst, the combination of<br />
o-bromophenylacrylamides (88) <strong>and</strong> aryl iodides provided<br />
the quinolone products in moderate to good yields<br />
(Scheme 41). Although only a single acrylamide substrate<br />
was employed, a good range of aryl iodide coupling partners<br />
could be incorporated. A brief mechanistic investigation<br />
supported the Heck followed by intramolecular<br />
amidation pathway.<br />
88<br />
+<br />
Br<br />
Scheme 41<br />
Willis <strong>and</strong> co-workers exploited 2-(2-haloalkenyl)aryl halide<br />
substrates, previously employed in indole syntheses<br />
(see Scheme 8), in the preparation of 2-quinolones. 95 A<br />
cascade palladium-catalyzed carbonylation/intramolecular<br />
amidation sequence was employed to access a range of<br />
quinolone products. For example, combination of the simple<br />
dibromide 89 <strong>and</strong> p-methoxybenzylamine under a balloon<br />
pressure of carbon monoxide delivered quinolone 90<br />
in 80% yield (Scheme 42). Although all of the products<br />
shown in Scheme 42 were obtained using a dppp-derived<br />
catalyst, the researchers found that lig<strong>and</strong> variation was<br />
needed for particular substrate/amine combinations. In<br />
addition, purging the reaction of carbon monoxide was<br />
shown to benefit the efficiency of certain amidation reactions.<br />
By delaying the introduction of the carbon monoxide<br />
<strong>and</strong> running the reaction in a two-stage process, it was<br />
also possible access the regioisomeric isoquinolone products,<br />
although in these cases competing indole formation<br />
was problematic.<br />
O<br />
Scheme 42<br />
O<br />
I<br />
NH 2<br />
+<br />
H2N<br />
Br<br />
Br<br />
89<br />
Pd(OAc)2 (5 mol%)<br />
n-Bu4NOAc, n-Bu4NBr<br />
120 °C<br />
CO (balloon)<br />
Pd2(dba)3 (3 mol%)<br />
dppp (6 mol%)<br />
Cs2CO3, toluene<br />
100 °C<br />
OMe<br />
N<br />
H<br />
75%<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
O<br />
N O<br />
PMB<br />
90, 80%<br />
O N O<br />
MeO<br />
N O N N O<br />
Oct<br />
O Oct<br />
Oct<br />
69% 65% 73%
14 J. E. R. Sadig, M. C. Willis REVIEW<br />
2.9 Quinazolines, Quinazolinones <strong>and</strong><br />
Quinazolindiones<br />
In 2006 Willis <strong>and</strong> co-workers reported the palladiumcatalyzed<br />
coupling of o-bromobenzoate esters with<br />
monosubstituted ureas as a route to 3-alkylated quinazolinediones.<br />
96 The reactions proceeded via initial intermolecular<br />
carbon–nitrogen bond formation followed by<br />
intramolecular, base-promoted, amidation. A XantPhosderived<br />
catalyst in combination with cesium carbonate allowed<br />
efficient <strong>and</strong> regioselective processes; for example,<br />
bromobenzoate 91 was combined with N-butyl urea to<br />
provide quinazolinedione 92 in 77% yield as a single regioisomer<br />
(Scheme 43). A variety of substituents were<br />
tolerated on both the aryl bromide <strong>and</strong> urea coupling partners.<br />
The observed regiocontrol originates from the initial<br />
aryl carbon–nitrogen bond formation taking place at the<br />
least hindered nitrogen of the urea nucleophile.<br />
Cl<br />
91<br />
Scheme 43<br />
O<br />
OMe<br />
Br<br />
+<br />
Bu<br />
N<br />
H<br />
O<br />
Pd 2(dba) 3 (2.5 mol%)<br />
XantPhos (2) (5 mol%)<br />
NH2<br />
Cs 2CO 3<br />
dioxane, 100 °C<br />
N<br />
H<br />
92, 77%<br />
The Fu research group reported a related strategy for the<br />
synthesis of quinazolinones <strong>and</strong> quinazolines. In their<br />
original report, they exploited a copper-catalyzed coupling<br />
of amidines with o-bromobenzoic acids to access<br />
quinazolinones. For example, acid 93 was combined with<br />
acetimidamide 94 to provide quinazolinone 95 in 81%<br />
yield (Scheme 44). 97a The reaction conditions consisted of<br />
copper(I) iodide without any added lig<strong>and</strong>, in N,N-dimethylformamide<br />
at room temperature. The ability to use<br />
such low-temperature conditions was attributed to the formation<br />
of a chelated intermediate involving the oxygen<br />
atom of the ortho-positioned carboxylic acid. The reaction<br />
was applicable to a broad range of amidines <strong>and</strong> benzoic<br />
acids. The researchers next extended the chemistry to include<br />
guanidines as the nitrogen nucleophiles, resulting in<br />
the formation of 3-aminoquinazolinone products such as<br />
96. 97b The carboxylic acid substrates could also be replaced;<br />
the use of the related ketones in combination with<br />
guanidines resulted in the synthesis of 3-aminoquinazolines<br />
such as 97. Ding <strong>and</strong> co-workers reported an alternative<br />
copper-catalyzed route to quinazolinones based on<br />
the use of o-iodobenzamide substrates. 98 A typical reaction<br />
is shown in Scheme 44: coupling of benzamide 98<br />
with formimidamide, using copper(I) iodide as catalyst,<br />
provided quinazolinone 99 in 77% yield. The method was<br />
shown to tolerate reasonable variation of both reaction<br />
components.<br />
Li <strong>and</strong> co-workers reported a cascade process involving in<br />
situ amidine formation followed by palladium-catalyzed<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Cl<br />
O<br />
N<br />
Bu<br />
O<br />
O<br />
93 95, 81%<br />
94<br />
OH<br />
CuI (20 mol%)<br />
NH<br />
+<br />
H2N<br />
Br<br />
NH.HCl Cs2CO3 DMF, r.t. N Me<br />
Me<br />
75%<br />
O<br />
N<br />
cyclization as an entry into ring-fused quinazolinone derivatives.<br />
The key amidine intermediates were generated<br />
from intramolecular amide addition to a nitrile; the nitrile<br />
group also being introduced by a palladium-catalyzed<br />
process. 99 Scheme 45 outlines the overall conversion,<br />
with aryl iodide 100 being transformed into quinazolinone<br />
101 in 91% yield. A DPEPhos-derived catalyst was effective<br />
for both the initial cyanation reaction to generate nitrile<br />
102, <strong>and</strong> then to achieve the final ring closure from<br />
the proposed amidine intermediate to give quinazolinone<br />
101. Using a bromoquinoline-derived substrate, the authors<br />
were able to apply the methodology to a synthesis of<br />
the natural product luotonin (103).<br />
Scheme 45<br />
NH<br />
2.10 Phenazines<br />
O<br />
N<br />
96, 81%<br />
NH<br />
The Kamikawa <strong>and</strong> Beifuss groups have both reported intramolecular<br />
palladium-catalyzed aryl-amination routes<br />
to phenazines. Both explored the ring-closure of 2-amino-<br />
2¢-bromodiphenylamines to access the target systems.<br />
Scheme 46 shows an example from Beifuss <strong>and</strong> co-workers,<br />
in which a JohnPhos-derived catalyst was used to convert<br />
aniline 104 into phenazine 105 in 76% yield. 100 The<br />
Kamikawa research group utilized BINAP-derived cata-<br />
N<br />
O<br />
O<br />
Ph<br />
N<br />
97, 56%<br />
98<br />
O<br />
O<br />
I<br />
Scheme 44<br />
Ph<br />
N<br />
H<br />
+ H2N NH<br />
AcOH<br />
CuI (10 mol%)<br />
K2CO3 DMF, 80 °C<br />
N<br />
99, 77%<br />
N<br />
Ph<br />
O<br />
NH<br />
Pd(OAc)2 (5 mol%)<br />
DPEPhos (22) (10 mol%)<br />
O<br />
I<br />
Br<br />
+ KCN<br />
dioxane, reflux<br />
then dppf (10 mol%)<br />
K2CO3<br />
N<br />
N<br />
100 101, 91%<br />
N<br />
H<br />
O<br />
CN Br<br />
102<br />
N<br />
N<br />
O<br />
N<br />
N<br />
91%<br />
luotonin (103)<br />
N
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 15<br />
MeO<br />
Scheme 46<br />
lysts. 101 In both cases the phenazine ring system was isolated<br />
directly from the amination reactions.<br />
2.11 Cinnolines<br />
An intermolecular copper-catalyzed aryl amination was<br />
used by Nishida <strong>and</strong> co-workers to access cinnoline derivatives.<br />
In the example shown in Scheme 47, hydrazonesubstituted<br />
aryl iodide 107 was converted into N-acyldihydrocinnoline<br />
108 using a copper(I) iodide/diamine<br />
catalyst. 102 The use of superstoichiometric amounts of catalyst<br />
led to mixtures of N-acyl product 108 together with<br />
smaller amounts (up to 40%) of the aromatic cinnoline being<br />
obtained. Cyclization of hydrazines derived from hydrazone<br />
107 allowed access to 1-aminoindoles.<br />
I<br />
NH2<br />
107<br />
Scheme 47<br />
H<br />
N<br />
Br<br />
104<br />
OTBS<br />
CO2t-Bu HN<br />
Ac<br />
N<br />
3 Carbon–Oxygen Bond Formation<br />
Initially, the development of catalytic carbon–oxygen<br />
bond-forming processes using aryl halide substrates<br />
lagged behind the corresponding carbon–nitrogen forming<br />
reactions; however, efficient methods, using both palladium<br />
<strong>and</strong> copper catalysts, are now well established.<br />
3.1 Benzofurans<br />
Pd 2(dba) 3 (3 mol%)<br />
JohnPhos (6 mol%)<br />
NaOt-Bu<br />
toluene, 100 °C MeO<br />
P(t-Bu)2<br />
JohnPhos (106)<br />
CuI (10 mol%)<br />
25 (10 mol%)<br />
Cs 2CO 3<br />
DMSO, r.t.<br />
N N<br />
Ac<br />
108, 89%<br />
Few examples of benzofuran syntheses that proceed via a<br />
metal-catalyzed intermolecular (aryl)carbon–oxygen<br />
bond-forming reaction exist. In one example, Buchwald<br />
<strong>and</strong> co-workers were able to apply their palladium-catalyzed<br />
phenol synthesis to the preparation of benzofurans.<br />
103 The chemistry was based on the use of<br />
potassium hydroxide as a nucleophile in the palladiumcatalyzed<br />
hydroxylation of aryl halides to provide phenols.<br />
When applied to benzofuran synthesis, o-chloroarylalkyne<br />
substrates reacted with potassium hydroxide in the<br />
presence of t-Bu-XPhos as catalyst, to give o-hydroxyalkynylarenes,<br />
which, as previously shown, 104 undergo<br />
N<br />
N<br />
105, 76%<br />
OTBS<br />
CO2t-Bu cyclization to the required benzofurans (109 → 110,<br />
Scheme 48). You’s research group went on to develop a<br />
copper-catalyzed version of the hydroxylation reaction<br />
<strong>and</strong> also demonstrated its use in benzofuran synthesis, in<br />
this case from an o-iodoarylalkyne to generate benzofuran<br />
112. 105<br />
F 3C<br />
Cl<br />
109<br />
Scheme 48<br />
A greater number of research groups have utilized intramolecular<br />
carbon–oxygen bond formation as the key<br />
step in benzofuran syntheses. In 2004 Willis et al. demonstrated<br />
the use of a-(o-haloaryl) ketones as precursors to<br />
the required oxygen heterocycles via an enolization/palladium-catalyzed<br />
intramolecular O-arylation reaction, with<br />
a Pd 2(dba) 3/DPEPhos catalyst system proving optimum<br />
for the process (Scheme 49). 106 The starting ketones were<br />
themselves formed by a palladium-catalyzed ketone arylation;<br />
however, attempts to achieve a one-pot combination<br />
of these processes was not straightforward, <strong>and</strong> after<br />
optimization only a single high-yielding example of the<br />
cascade could be achieved. Kotschy <strong>and</strong> co-workers<br />
showed that the same cyclization of o-bromobenzyl ketones,<br />
which they accessed from aromatic aldehydes <strong>and</strong><br />
2-bromobenzyl bromide using dithiane chemistry, is possible<br />
using a palladium–NHC catalyst system. 107<br />
O<br />
Scheme 49<br />
Cl<br />
I<br />
O<br />
Br<br />
Me<br />
86%<br />
(NaOt-Bu)<br />
Ph<br />
S<br />
KOH<br />
F3C<br />
Pd2(dba) 3 (2 mol%)<br />
t-BuXPhos (8 mol%)<br />
H2O, dioxane<br />
100 °C<br />
KOH<br />
Ph CuI (10 mol%)<br />
1,10-phenathroline<br />
(20 mol%)<br />
H 2O, DMSO<br />
100 °C<br />
t-Bu2P i-Pr<br />
i-Pr<br />
t-BuXPhos (111)<br />
Cs2CO3<br />
toluene, 100 °C<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Cl<br />
i-Pr<br />
Pd 2(dba) 3 (2.5 mol%)<br />
DPEPhos (22) (6 mol%)<br />
N<br />
O<br />
86%<br />
(NaOt-Bu)<br />
(chloro substrate)<br />
F<br />
O<br />
110, 87%<br />
O<br />
112, 86%<br />
O<br />
95%<br />
O<br />
74%<br />
(NaOt-Bu)<br />
Ph<br />
S
16 J. E. R. Sadig, M. C. Willis REVIEW<br />
Chen <strong>and</strong> Dormer reported a copper(I) iodide catalyzed,<br />
lig<strong>and</strong>-free modification of this benzofuran synthesis using<br />
o-iodo- or o-bromoaromatic ketones. 108 A range of<br />
substituents at the resulting 2- <strong>and</strong> 3-positions of the product<br />
benzofuran were tolerated, <strong>and</strong> the first use of an aldehyde<br />
substrate was demonstrated, yielding 3benzylbenzo[b]furan<br />
113 in 92% yield (Scheme 50). An<br />
on-water variant of this protocol was described by the<br />
SanMartin <strong>and</strong> Domínguez group, with the use of a diamine<br />
lig<strong>and</strong> being required. 109 Ackermann <strong>and</strong> Kaspar<br />
also utilized a related copper-catalyzed cyclization in<br />
combination with alkyne hydration chemistry to access<br />
benzofurans. 110<br />
O<br />
Br<br />
Scheme 50<br />
Willis <strong>and</strong> co-workers developed a second strategy to<br />
access benzofurans, again based on an intramolecular<br />
carbon–oxygen bond-forming reaction. Scheme 8 highlighted<br />
the use of aryl halide/alkenyl triflate substrates in<br />
the synthesis of indole derivatives; the research group was<br />
able to further demonstrate the utility of these substrates<br />
as general heterocycle precursors, through their use in a<br />
copper-catalyzed benzofuran synthesis. 111 Coupling of the<br />
same substrates with potassium hydroxide yielded benzofurans<br />
via presumed enolate intermediates.<br />
Lautens <strong>and</strong> co-workers reported an approach to 2-bromobenzofurans<br />
using an intramolecular carbon–oxygen<br />
coupling of gem-dibromovinyl phenols. 31i As in the related<br />
indole chemistry (see Scheme 5), the dibromovinyl<br />
phenol substrates were synthesized using a Ramirez olefination<br />
process. As shown in Scheme 51, a lig<strong>and</strong>-free<br />
copper(I) iodide catalyst was found to be effective, providing<br />
the benzofurans in excellent yields.<br />
Br<br />
Scheme 51<br />
H<br />
Br<br />
OH<br />
Br<br />
Cl<br />
CuI (10 mol%)<br />
K3PO4 DMF, 105 °C<br />
CuI (5 mol%)<br />
K3PO4<br />
THF, 80 °C<br />
H<br />
O<br />
113, 92%<br />
In 1999 Miura <strong>and</strong> co-workers developed a t<strong>and</strong>em palladium-catalyzed<br />
intermolecular carbon–carbon/intramolecular<br />
carbon–oxygen bond-forming reaction of benzyl<br />
phenyl ketones with o-dibromoarenes to yield benzofurans.<br />
112 A palladium(II) acetate/triphenylphosphine catalyzed<br />
system was found to be optimal, with high reaction<br />
temperatures also being used (Scheme 52). The reactions<br />
proceeded via initial palladium-catalyzed enolate C-arylation,<br />
followed by palladium-catalyzed O-arylation. The<br />
protocol was extended to the use of phenol coupling part-<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Br<br />
O<br />
96%<br />
Br<br />
Cl<br />
ners in place of ketones, to give dibenzofuran products<br />
(114 → 115). SanMartin, Domínguez <strong>and</strong> co-workers reported<br />
a similar method for the synthesis of benzofurans;<br />
113 in their account they compared the use of<br />
homogeneous <strong>and</strong> heterogeneous polymer-supported palladium<br />
catalysis, with the latter affording the heterocycles<br />
in slightly inferior yields.<br />
MeO<br />
MeO<br />
t-Bu<br />
OH<br />
114<br />
Scheme 52<br />
Ma <strong>and</strong> co-workers reported a related copper-catalyzed<br />
cascade route to benzofurans. In the optimized system, bketo<br />
esters were combined with 1-bromo-2-iodobenzenes<br />
to provide benzofurans via initial intermolecular carbon–<br />
carbon bond formation followed by intramolecular formation<br />
of the carbon–oxygen bond (Scheme 53). 114 Substitution<br />
on both the aryl halide <strong>and</strong> keto ester was well<br />
tolerated, providing benzofurans in good yields.<br />
Ph<br />
Cl<br />
O<br />
Scheme 53<br />
+<br />
+<br />
Br<br />
Br<br />
O<br />
Ph<br />
3.2 Benzoxazoles<br />
+<br />
O<br />
I<br />
Br<br />
OEt<br />
Pd(OAc) 2 (5 mol%)<br />
Ph3P (20 mol%)<br />
Cs2CO3 o-xylene, 160 °C<br />
Br<br />
Pd(OAc)2–4Ph3P<br />
(5 mol%)<br />
O<br />
78%<br />
CsCO3<br />
Br o-xylene, 160 °C<br />
O<br />
t-Bu<br />
115, 66%<br />
CuI (10 mol%)<br />
K2CO3 THF, 100 °C<br />
The use of catalytic intramolecular carbon–oxygen bondforming<br />
reactions has proved to be a popular route to<br />
benzoxazoles. In 2006 Batey <strong>and</strong> Evindar developed a<br />
copper-catalyzed cyclization of o-halobenzanilides to<br />
generate a variety of alkyl, aryl, benzyl, alkenyl, dienyl<br />
<strong>and</strong> heterocyclic 2-substituted benzoxazoles (as well as a<br />
h<strong>and</strong>ful of benzothiazoles – see section 4.2). As shown in<br />
Scheme 54 the optimal catalyst was a copper(I) iodide/<br />
phenanthroline combination. 115 The majority of examples<br />
employed aryl bromide substrates, although the iodo derivatives<br />
also performed well. A single aryl chloride example<br />
was included. SanMartin, Domínguez <strong>and</strong> coworkers<br />
reported a similar copper-catalyzed cyclization to<br />
access benzoxazoles. They developed two catalyst systems,<br />
using either copper(I) chloride or copper(II) triflate<br />
in combination with N,N,N¢,N¢-tetramethylethylenediamine<br />
(TMEDA), on water, to yield the desired heterocy-<br />
Cl<br />
O<br />
78%<br />
Ph<br />
CO2Et<br />
OMe<br />
OMe<br />
Ph
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 17<br />
cles in good yields from either the o-iodo, o-bromo- or ochlorobenzanilides.<br />
116 Similar cyclizations have also been<br />
reported by Jiang <strong>and</strong> Ma 117 <strong>and</strong> Kantam <strong>and</strong> co-workers.<br />
118<br />
H<br />
N<br />
Br<br />
N<br />
Scheme 54<br />
In 2009 Sun <strong>and</strong> co-workers extended this type of cyclization<br />
to the synthesis of 2-substituted oxazolopyridines. 119<br />
As shown in Scheme 55, a copper(I) iodide/diamine or<br />
copper(I) iodide/phenanthroline catalyst system proved to<br />
be optimal, yielding the desired heterocycles from the cyclization<br />
of o-chloro- or o-bromopyridylamides, respectively.<br />
Me<br />
N<br />
Scheme 55<br />
CuI (5 mol%)<br />
1,10-phenanthroline<br />
(10 mol%)<br />
O OMe Cs 2CO 3<br />
DME, relfux<br />
O Ph<br />
89%<br />
N N<br />
O<br />
90%<br />
Cbz<br />
25<br />
H<br />
N<br />
CuI (5 mol%)<br />
(10 mol%)<br />
N<br />
O<br />
Cl<br />
K2CO3 toluene, reflux<br />
N O<br />
91%<br />
N<br />
H<br />
N<br />
O<br />
Br<br />
Ph<br />
Cl<br />
CuI (5 mol%)<br />
1,10-phenanthroline<br />
(10 mol%)<br />
Cs2CO3<br />
THF, reflux<br />
MeO<br />
N<br />
The Batey research group developed a further synthesis of<br />
benzoxazoles involving intramolecular carbon–oxygen<br />
bond formation. The substrates were again o-halobenzanilides;<br />
however, these were formed in situ from the reaction<br />
of o-bromoanilines <strong>and</strong> acyl chlorides. 70 A copper(I)<br />
iodide/1,10-phenanthroline combination was found to be<br />
the optimal catalyst system for this one-pot strategy. In<br />
addition, the use of microwave irradiation gave substantially<br />
better results than conventional heating. A library of<br />
24 benzoxazoles was prepared, examples of which are<br />
shown in Scheme 56.<br />
A t<strong>and</strong>em approach to benzoxazoles was reported by<br />
Glorius <strong>and</strong> Altenhoff, in which reaction of o-dihalobenzenes<br />
with amides underwent copper(I) iodide/diamine<br />
catalyzed carbon–nitrogen followed by carbon–oxygen<br />
cross-couplings to yield the desired heterocycles. 120 Examples<br />
of diiodo-, dibromo- <strong>and</strong> mixed dihalobenzenes,<br />
as well as dihalopyridines (Br <strong>and</strong> Cl) were successfully<br />
coupled to benzamide affording 2-phenylbenzoxazoles<br />
(Scheme 57). The dibromobenzene substrate was utilized<br />
to demonstrate variation of the amide partner, giving aryl,<br />
Me<br />
N<br />
O<br />
99%<br />
N<br />
O<br />
90%<br />
97%<br />
N<br />
O<br />
Ph<br />
Ph<br />
Cl<br />
Me<br />
S<br />
O<br />
+<br />
Scheme 56<br />
alkyl, vinyl <strong>and</strong> heterocyclic 2-substituted benzoxazoles.<br />
The use of o-bromochlorobenzenes allowed the regioselective<br />
synthesis of substituted benzoxazoles, with the reaction<br />
proceeding via initial amidation at the aryl bromide<br />
position. Batey <strong>and</strong> co-workers had previously reported<br />
on investigations of related processes, but had not<br />
achieved an efficient system. 70<br />
Scheme 57<br />
Cl<br />
O<br />
NH 2<br />
Br<br />
N<br />
3.3 Isocoumarins<br />
CuI (10 mol%)<br />
1,10-phenanthroline<br />
(20 mol%)<br />
Cs 2CO3, MeCN<br />
210 °C, 15 min, MW<br />
O<br />
91%<br />
In 1999 Shen <strong>and</strong> Wang described the synthesis of isocoumarins<br />
from a palladium-catalyzed reaction of gem-dibromovinyl<br />
benzoates with an organostannane. 121 For<br />
example, reaction of benzoate 114 with phenyltrimethylstannane<br />
using a trifurylphosphine-derived palladium catalyst<br />
delivered isocoumarin 115 in 92% yield (Scheme<br />
58). The t<strong>and</strong>em process is believed to proceed via an initial<br />
Stille reaction of the ‘E’ bromide with the stannane,<br />
which is followed by an intramolecular carbon–oxygen<br />
bond-forming cyclization <strong>and</strong> ensuing elimination of methyl<br />
bromide. Examples using phenyl, furyl, thienyl <strong>and</strong><br />
vinyl tin reagents gave the 3-substituted isocoumarins in<br />
mostly excellent yields, <strong>and</strong> both esters <strong>and</strong> methoxy<br />
groups could be tolerated on the aromatic ring. Willis <strong>and</strong><br />
co-workers reported a palladium-catalyzed carbonylative<br />
isocoumarin synthesis, commencing from the same a-(o-<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Me<br />
O O Ph<br />
F3C<br />
O<br />
66%<br />
85%<br />
Br<br />
+<br />
Br<br />
O OMe<br />
114<br />
85% O<br />
Scheme 58<br />
O<br />
H 2N Ph<br />
Br<br />
Br<br />
+<br />
PhSnMe3 O<br />
O<br />
CuI (5 mol%)<br />
25 (10 mol%)<br />
K2CO 3<br />
toluene, 110 °C<br />
80%<br />
Pd2(dba)3 (2.5 mol%)<br />
P(2-furyl)3 (15 mol%)<br />
toluene, 100 °C<br />
O<br />
O<br />
S<br />
MeO<br />
N<br />
MeO<br />
N<br />
N<br />
O<br />
90%<br />
115, 92%<br />
81%<br />
O<br />
O<br />
S<br />
Ph<br />
O<br />
O<br />
Ph<br />
Ph
18 J. E. R. Sadig, M. C. Willis REVIEW<br />
haloaryl) ketone substrates previously used in benzofuran<br />
synthesis (see Scheme 49). 122<br />
4 Carbon–Sulfur Bond Formation<br />
Relative to the carbon–nitrogen <strong>and</strong> carbon–oxygen<br />
bond-forming reactions discussed above, there are far<br />
fewer examples of catalytic aryl carbon–sulfur bondforming<br />
processes in the literature. However, reactions<br />
are beginning to be developed that exploit the highly nucleophilic<br />
character of thiols (<strong>and</strong> related functional<br />
groups) <strong>and</strong> synthetically useful methods with very low<br />
catalyst loadings are being reported. 123 The number of applications<br />
of these reactions to the synthesis of heterocycles<br />
is also growing.<br />
4.1 Benzothiophenes<br />
Although a number of metal-catalyzed benzothiophene<br />
syntheses exist, 1,2 few of these involve a key carbon–sulfur<br />
bond formation using an aryl halide substrate. As discussed<br />
in section 3.1, Willis et al. demonstrated the use of<br />
a palladium-catalyzed intramolecular O-enolate arylation<br />
in the synthesis of benzofurans (see Scheme 49). 106 Similarly,<br />
the same group showed that thio ketones, derived<br />
from the same a-(o-haloaryl) ketone substrates using<br />
phosphorus pentasulfide, could also undergo this enolization–cyclization,<br />
again using a DPEPhos catalyst system<br />
to afford benzothiophenes. 106 Scheme 59 shows an aryl<br />
bromide example, although the corresponding aryl chloride<br />
also underwent cyclization, albeit in a reduced 44%<br />
yield.<br />
Br S<br />
Scheme 59<br />
Pd2(dba)3 (2.5 mol%)<br />
DPEPhos (22) (6 mol%)<br />
Cs2CO3 S<br />
toluene, 100 °C 74%<br />
In 2009 Lautens <strong>and</strong> co-workers extended the use of gemdihalovinylanilines<br />
in indole synthesis (see Scheme 5) to<br />
establish similar thiophenols as precursors for benzothiophenes.<br />
124 The combination of a palladium-catalyzed<br />
carbon–sulfur bond-forming reaction with a second<br />
cross-coupling process, such as a Suzuki–Miyaura, Heck<br />
or Sonogashira reaction, yielded diversely functionalized<br />
benzothiophenes. For example, combination of thiophenol<br />
116 with thiophene-3-boronic acid using an SPhos-derived<br />
catalyst delivered benzothiophene 117 in 99% yield<br />
(Scheme 60). The majority of examples reported involved<br />
Suzuki chemistry; a broad range of boronic acids, as well<br />
as other boron reagents, were readily included <strong>and</strong> allowed<br />
the introduction of aryl, alkenyl <strong>and</strong> alkyl C2 substituents.<br />
Application of the methodology to a variety of<br />
thiophenol backbones afforded the required heterocycles<br />
in mostly excellent yields.<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
S<br />
Scheme 60<br />
4.2 Benzothiazoles<br />
Two research groups have established benzothiazole syntheses<br />
based on a key catalytic intermolecular carbon–sulfur<br />
bond-forming step. In the first approach, Itoh <strong>and</strong><br />
Mase utilized a palladium-catalyzed thioetherification of<br />
o-bromoanilides using a thiol surrogate coupling partner.<br />
125 For example, reaction between aryl bromide 118<br />
<strong>and</strong> thiol 119, an odorless thiol surrogate, using a<br />
XantPhos-derived catalyst, ultimately delivered benzothiophene<br />
120 in 75% yield (Scheme 61). The reaction<br />
proceeded via intermediate sulfide 121, which was<br />
cleaved under basic conditions <strong>and</strong> then cyclized in the<br />
presence of acid to generate the aromatic product. p-<br />
Methoxybenzylthiol could also be employed as the thiol<br />
surrogate, allowing sulfide cleavage under acid conditions.<br />
Scheme 61<br />
Br<br />
Br<br />
SH<br />
116<br />
+<br />
B(OH) 2<br />
PdCl2 (3 mol%)<br />
SPhos (14) (3 mol%)<br />
K 3PO4, Et3N<br />
dioxane, 110 °C<br />
S<br />
117, 99%<br />
118<br />
121<br />
F<br />
+<br />
H<br />
N<br />
O<br />
Br<br />
Me<br />
Pd2(dba)3 (5 mol%)<br />
XantPhos (2) (10 mol%)<br />
i-Pr2NEt, dioxane<br />
reflux<br />
F<br />
H<br />
N<br />
S<br />
O<br />
Me<br />
O<br />
SH O<br />
OR<br />
O<br />
119<br />
Me<br />
Me<br />
NaOEt, THF, r.t.<br />
then TFA, reflux<br />
S<br />
120, 75%<br />
Rather than use a thiol surrogate, Ma <strong>and</strong> co-workers exploited<br />
metal sulfides in copper-catalyzed couplings with<br />
o-haloanilides to generate benzothiazoles. 126 They were<br />
able to show that sodium sulfide nonahydrate could be<br />
coupled with o-iodoanilides, <strong>and</strong> following acidic workup,<br />
deliver the desired benzothiazole products. For o-bromo<br />
substrates, the use of potassium sulfide was optimal.<br />
Both systems utilized a lig<strong>and</strong>less copper(I) iodide catalyst;<br />
significant variation of the substrate substituents was<br />
possible, delivering benzothiazoles in good to excellent<br />
yields (Scheme 62).<br />
The use of an intramolecular carbon–sulfur bond-forming<br />
reaction has proved more popular in the synthesis of benzothiazoles.<br />
In 1982, Bowman, Heaney <strong>and</strong> Smith reported<br />
an intramolecular, copper-catalyzed S-arylation in the<br />
synthesis of 2-alkyl- <strong>and</strong> 2-aryl-1,3-benzothiazoles from<br />
F<br />
N<br />
S<br />
Me
REVIEW <strong>Palladium</strong>- <strong>and</strong> <strong>Copper</strong>-<strong>Catalyzed</strong> Heterocycle Synthesis 19<br />
F<br />
H<br />
N<br />
I<br />
O<br />
Me<br />
Na2S<br />
CuI (10 mol%)<br />
DMF, 80 °C<br />
then HCl, r.t. F<br />
N<br />
S<br />
75%<br />
.9H2O<br />
+<br />
Scheme 62<br />
o-halothioacetanilides <strong>and</strong> o-halothiobenzanilides, respectively.<br />
127 Castillón <strong>and</strong> co-workers extended this<br />
methodology to a more efficient palladium-catalyzed cyclization<br />
of o-bromothioamides (Scheme 63). 128 It was<br />
also shown that cyclization of o-bromothioureas, prepared<br />
from o-bromophenylisothiocyanates <strong>and</strong> amines, afforded<br />
2-aminobenzothiazoles under similar reaction conditions<br />
(122 → 123).<br />
H<br />
N<br />
S<br />
Br<br />
122<br />
Scheme 63<br />
Batey <strong>and</strong> co-workers reported a comparison of the copper-<br />
<strong>and</strong> palladium-catalyzed syntheses of 2-aminobenzothiazoles<br />
based on this same cyclization of obromothioureas.<br />
129 The use of copper catalysis generally<br />
led to higher yields <strong>and</strong> conversions. Both metals were<br />
also shown to catalyze an example of a one-pot thiourea<br />
formation–cyclization reaction in the same excellent<br />
yield. Batey’s research group also demonstrated that cyclization<br />
of o-bromothioamides under the same copper(I)<br />
iodide/1,10-phenanthroline catalyst system afforded benzothiazoles<br />
in excellent yields; 115 a representative example<br />
is shown in Scheme 64. Jiang <strong>and</strong> Ma reported a<br />
related copper-catalyzed cyclization employing oxazolidin-2-one<br />
as the lig<strong>and</strong>; a number of aryl chloride substrates<br />
were included in their study, <strong>and</strong> effectively<br />
converted into benzothiazoles. 117 Pan <strong>and</strong> co-workers reported<br />
a related preparation of 2-aminobenzothiazoles using<br />
a copper(I) iodide/oxazoline catalyst system. 130<br />
Scheme 64<br />
H<br />
N Ph<br />
+<br />
O<br />
Br<br />
Me Me<br />
Me<br />
H<br />
N NMe 2<br />
S<br />
Br<br />
H<br />
N<br />
S<br />
Br<br />
K 2S<br />
CuI (10 mol%)<br />
DMF, 140 °C<br />
then HCl, r.t.<br />
Pd2(dba)3 (5 mol%)<br />
JohnPhos (106)<br />
(5.5 mol%)<br />
Cs2CO 3<br />
dioxane, 80 °C<br />
Pd 2(dba) 3 (5 mol%)<br />
P(t-Bu)3 (5.5 mol%)<br />
OMe<br />
Cs2CO 3<br />
dioxane, 80 °C<br />
CuI (5 mol%)<br />
1,10-phenanthroline<br />
(10 mol%)<br />
Cs 2CO3, reflux<br />
88%<br />
N<br />
S<br />
Me<br />
Ph<br />
N Me<br />
Me<br />
S Me<br />
88%<br />
N<br />
S<br />
123, 92%<br />
N<br />
S<br />
93%<br />
NMe 2<br />
OMe<br />
The Wu research group described the synthesis of 2-aminobenzothiazoles<br />
by the reaction of o-iodobenzamines<br />
with isothiocyanates using a copper(I) iodide/phenanthroline<br />
catalyst system (Scheme 65). 131 The method was useful<br />
as it eliminated the need to generate an ohalobenzothiourea<br />
cyclization precursor in a separate<br />
step, with the addition/carbon–sulfur coupling reaction<br />
occurring in one pot. The authors exploited the method in<br />
the preparation of an 18-membered library.<br />
F<br />
Scheme 65<br />
A number of benzothiazole syntheses that involve t<strong>and</strong>em<br />
processes have also appeared in the literature. Vera <strong>and</strong><br />
Pelletier utilized t<strong>and</strong>em palladium-catalyzed carbon–<br />
sulfur <strong>and</strong> carbon–nitrogen arylation reactions to prepare<br />
a series of aminobenzothiazoles. 132 For example, the<br />
combination of dibromothiobenzamide 124 <strong>and</strong> isopropylamine,<br />
using a JohnPhos catalyst, delivered 4-aminobenzothiazole<br />
125 in 47% yield (Scheme 66). As can be seen<br />
from the remainder of the examples in Scheme 66, it was<br />
possible to alter the position of the second bromine substituent,<br />
to generate 5-, 6-, <strong>and</strong> 7-amino-substituted products.<br />
Scheme 66<br />
NH 2<br />
I<br />
+<br />
SCN<br />
CuI (10 mol%)<br />
1,10-phenanthroline<br />
(20 mol%)<br />
DABCO<br />
toluene, 50 °C<br />
99%<br />
Br NHi-Pr<br />
124<br />
i-PrHN<br />
H<br />
N Ph<br />
+<br />
H2N(i-Pr)<br />
S<br />
Br<br />
16%<br />
N<br />
S<br />
Ph<br />
Pd 2(dba) 3 (10 mol%)<br />
JohnPhos (106) (20 mol%)<br />
i-PrHN<br />
Patel <strong>and</strong> co-workers showed that 2-arylthiobenzothiazoles<br />
can be accessed from cascade intra- <strong>and</strong> intermolecular<br />
carbon–sulfur bond-forming reactions using a single<br />
catalytic system. 133 A combination of o-iodo- or o-bromodithiocarbamates<br />
<strong>and</strong> iodoarenes were subjected to a<br />
copper(I) iodide/diamine catalyst system yielding the substituted<br />
benzothiazoles in mostly excellent yields<br />
(Scheme 67). The methodology was successfully applied<br />
to the synthesis of a cathespin-D inhibitor analogue.<br />
The same research group developed a cascade protocol for<br />
the synthesis of 2-thio- or 2-oxa-benzothiazoles by the<br />
copper-catalyzed reaction of o-iodo- or o-bromoarylisothiocyanates<br />
with a sulfur or oxygen nucleophile, respectively.<br />
134 The required dithiocarbamates or<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
F<br />
Cs 2CO 3, NaOt-Bu<br />
toluene-dioxane<br />
80 °C<br />
50%<br />
N<br />
S<br />
Ph<br />
N<br />
S<br />
NH<br />
N<br />
S<br />
125, 47%<br />
N<br />
S<br />
NHi-Pr 39%<br />
Ph<br />
Ph
20 J. E. R. Sadig, M. C. Willis REVIEW<br />
Me<br />
I<br />
Scheme 67<br />
thiocarbamates, which were formed in situ under basic<br />
conditions, readily underwent copper-catalyzed intramolecular<br />
carbon–sulfur bond formation. Thiophenols <strong>and</strong><br />
phenols showed the greatest reactivity; however, the corresponding<br />
alkyl series could also be employed, albeit to<br />
generate the products in reduced yields (Scheme 68).<br />
73%<br />
+<br />
Scheme 68<br />
4.3 Oxathioles<br />
Bao <strong>and</strong> co-workers reported a novel one-pot synthesis of<br />
2-iminobenzo-1,3-oxathioles using a cascade addition/<br />
intramolecular carbon–sulfur coupling process. 135 o-Iodophenols<br />
<strong>and</strong> isothiocyanates were combined using a<br />
copper(I) iodide/phenanthroline catalyst system to afford<br />
the desired heterocycles in good to excellent yields. A<br />
representative example is shown in Scheme 69.<br />
Scheme 69<br />
H<br />
N<br />
5 Conclusion<br />
I<br />
S<br />
NCS<br />
+<br />
Br<br />
HS Ph<br />
N<br />
S<br />
OPh<br />
S HNEt3<br />
CuI (5 mol%)<br />
(10 mol%)<br />
126<br />
OMe<br />
K 2CO 3<br />
DMSO, 90 °C<br />
126<br />
NH2<br />
NH2<br />
CuI (5 mol%)<br />
1,10-phenanthroline<br />
(10 mol%)<br />
K2CO 3<br />
dioxane, 90 °C<br />
N<br />
SBn<br />
S<br />
69%<br />
(iodo substrate)<br />
By definition, palladium- <strong>and</strong> copper-catalyzed aryl amination,<br />
aryl etherification <strong>and</strong> aryl thioetherification reactions<br />
are transformations designed to fashion bonds<br />
between heteroatoms <strong>and</strong> aromatic rings. It is perhaps not<br />
surprising that these reactions have enjoyed considerable<br />
success when applied to the synthesis of aromatic heterocycles.<br />
The examples presented above show how these re-<br />
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York<br />
Me<br />
OH<br />
CuI (10 mol%)<br />
1,10-phenanthroline<br />
O<br />
SCN<br />
+<br />
I<br />
OMe<br />
(20 mol%)<br />
Cs2CO3<br />
toluene, 70–90 °C<br />
S<br />
86%<br />
Cl<br />
72%<br />
N<br />
S<br />
Ar = 4-MeOC 6H 4<br />
N<br />
S<br />
76%<br />
N<br />
S<br />
54%<br />
N<br />
O<br />
SPh<br />
SAr<br />
Ph<br />
OMe<br />
actions have been exploited towards a wide range of<br />
heterocyclic targets. They also show these reactions being<br />
used to provide new entries to existing, classic synthetic<br />
routes, as well as in the formulation of completely new<br />
disconnections. As advances in the underpinning transformations<br />
continue to develop – new coupling partners,<br />
more active catalysts <strong>and</strong> milder reaction conditions – the<br />
number of applications will undoubtedly continue to<br />
grow. The importance of heteroaromatic molecules virtually<br />
assures it.<br />
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