Aldrichimica Acta Vol. 45, No. 3 - Sigma-Aldrich

80
Transition-Metal-Mediated Fluorination, Difluoromethylation, and Trifluoromethylation
Zhuang Jin, Gerald B. Hammond,* and Bo Xu*
R 1
NHR2 TMSCF3
AgF (1.5 equiv), H2O (1 equiv)
n dioxane, µw, 100 oC, 40 min
R
N
1 n'
F3C
R
87–95%
2
n = 1–3; n' = 1–2; R 1 = H, n-Bu; R 2 = Ph, Bn, allyl, Ph(Me)CH
(a) Ar H
(b) Ar H
1.5 equiv
ICF3 (3 equiv)
FeSO4 or Cp2Fe
(0.3–0.5 equiv)
H2O2 (2–6 equiv)
H2SO4, DMSO, 40–50 o 1 equiv
C
Ar = Ph, substituted benzene, heteroaryl
5b (1 equiv)
MeReO3 (5–10 mol %)
CDCl3, 70 o C, overnight
Ar CF3
66, 6–96%
Ar CF3
66, 11–77%
Ar = substituted benzene, heteroaryl, ferrocenyl
eq 2 (Ref. 104)
Scheme 23. Trifluoromethylation of Aromatics Presumed to Proceed
through a Free Radical Mechanism. (Ref. 105,106)
(a)
H
O
R
R = functionalized alkyl, cycloalkyl, aryl
(b) Ar H
ClSO2CF3 (1–4 equiv)
Ru(phen)3Cl2 (1–2 mol %)
20
K2HPO4 (anhyd, 3 equiv)
MeCN, hν, 23 oC, 24 h
Ar = Ph, substituted benzene, aryl, heteroaryl
ICF3 (5 equiv)
CuOAc (20 mol %)
(c) Ar B(OH)2
20
Ru(bpy)3Cl2 6H2O (1 mol %)
K2CO3 (1 equiv)
DMF, hν, 60 oC, 12 h
Ar = Ph, substituted benzene, heteroaryl
O Me
Me
N
+
N
H2
t-Bu
CF3CO2 –
A
(organocatalyst)
ICF3 (~ 8 equiv)
A (20 mol %) + B (0.5 mol %)
2,6-lutidine (1.1 equiv), DMF
hν, –20 o C, 7.5–8 h
t-Bu
t-Bu
PF6 –
N
N
N
Ir
N
B
(photocatalyst)
O
R
H
CF3
61–86%
90–99% ee
Ar CF3
70–94%
Ar CF3
39–93%
Scheme 24. Trifluoromethylation through Photocatalysis. (Ref. 107,110,111)
+
The first enantioselective, organocatalytic a-trifluoromethylation
and a-perfluoroalkylation of aldehydes have been accomplished using
a readily available iridium photocatalyst and a chiral imidazolidinone
catalyst by MacMillan and co-workers (Scheme 24, Part (a)). 107
A range of a-trifluoromethyl and a-perfluoroalkyl aldehydes were
obtained from commercially available perfluoroalkyl halides in high
efficiency and enantioselectivity. The resulting a-trifluoromethyl
aldehydes were subsequently shown to be versatile precursors for
the construction of a variety of enantioenriched trifluoromethylated
building blocks. MacMillan’s group also reported an efficient method
for the α-trifluoromethylation of carbonyl compounds and enolsilanes
through this photoredox catalysis strategy. 108 Ando and co-workers
similarly published a rhodium-catalyzed α-trifluoromethylation of
ketones via silyl enol ethers. 109
Nagib and MacMillan were able to generate CF 3 radicals from
a light-induced reaction involving a ruthenium photocatalyst and
trifluoromethanesulfonyl chloride (ClSO 2CF 3), a reagent that can be a
useful CF 3 radical precursor (Scheme 24, Part (b)). They demonstrated
that their approach can add CF 3 groups to already functionalized aryl
groups in molecules such as ibuprofen. 110
Very recently, Ye and Sanford reported a mild and general approach
for the merged Cu-catalyzed–Ru-photocatalyzed trifluoromethylation
and perfluoroalkylation of arylboronic acids (Scheme 24, Part
(c)). This method also takes advantage of visible-light photoredox
catalysis to generate CF 3• under mild conditions, and merges it with
copper-catalyzed arylboronic acid functionalization. 111 Baran’s team
prepared CF 3 radicals using tert-butyl hydroperoxide as an oxidant to
controllably decompose sodium trifluoromethylsulfinate, NaSO 2CF 3.
This method can be employed for the trifluoromethylation of pyridines
and other nitrogen-based heteroaromatics using CF 3 radicals; 112 but,
since a transition metal is not involved in the reaction, it is not covered
in this review.
4. Transition-Metal-Promoted Difluoromethylation
Difluoromethylation has received less attention than trifluoromethylation,
but in theory, many of the methods employed for
trifluoromethylation could also be applied to difluoromethylation.
4.1. Difluoromethylation through an RCF 2Cu Intermediate
Amii and co-workers have prepared difluoromethylated arenes via
copper-mediated cross-coupling followed by decarboxylation. 113 Both
electron-rich and electron-deficient aromatic iodides were crosscoupled
with a-silyldifluoroacetates to give low-to-high yields of
a-aryldifluoroacetates, which were subjected to base hydrolysis and
decarboxylation to produce the corresponding difluoromethylated
arenes in moderate-to-high yields (Scheme 25, Part (a)). However, the
intermediate a-aryldifluoroacetic acid that possess an electron-donating
group failed to deliver the corresponding difluoromethyated arenes.
Zhang and co-workers reported a copper-catalyzed cross-coupling
of 2-iodobenzoates with bromozinc difluorophosphonate (Scheme 25,
Part (b)), generated from BrCF 2P(O)(OEt) 2 and zinc in dioxane. Notable
features of this reaction are its high efficiency, excellent functionalgroup
compatibility, and operational simplicity. This protocol provides
a useful and facile access to aryldifluorophosphonates, of interest in
life sciences. 114 Qing and co-workers 115 reported a copper-mediated
oxidative cross-coupling reaction of terminal alkynes with readily
available a-silyldifluoromethylphosphonates under mild conditions
(Scheme 25, Part (c)). This method allows for the efficient synthesis
of a series of synthetically useful a,a-difluoropropargylphosphonates
with excellent functional-group compatibility.