Boron reagents for reductive amination - CHIMICA OGGI ...

ABSTRACT
Two classes of boron compounds, amine boranes and
sodium triacyloxyborohydride, are very effective reagents
for reductive aminations. The mildness of the reduction
spares functional groups susceptible to hydrogenation or
harsh reduction conditions of other reagents. This review
highlights some large-scale reductive aminations in the
synthesis of drug candidates.
REDUCTIVE AMINATION
Amines are common in current drugs and drug
candidates (1). Reductive amination is an effective way to
introduce an amino functionality into a molecule. First, an
aldehyde or ketone reacts with a primary or secondary
amine to form an imine or enamine intermediate. Then, in
the presence of mild reducing agents, such as amine
boranes and sodium triacetoxyborohydride reagents, the
in situ generated imine is reduced to the amine (2). The
reagents in this article avoid the formation of cyanide
which is an issue when using sodium cyanoborohydride.
In many cases, isolation of the imine, iminium salt or
enamine prior to addition of the reducing agent is not
necessary.
Via Amine Boranes
Amine boranes are very effective for the
reduction of imine and oxime functionalities,
while leaving a wide variety of substituent
functionalities unaffected. The reduction
proceeds rapidly when conducted in the
presence of a Bronsted or Lewis acid to give
secondary amines in excellent yields. Since
many amine borane reagents are not
hydrolyzed in aqueous solution and are stable
until a pH of 5, they can even be used in water
or methanol for mild reductive amination
reactions.
The solubility of pyridine borane (PYB), 2picoline
borane (PICB), tert-butylamineborane
(TBAB) triethylamine borane (TEAB) and
trimethylamine borane (TMAB) in various
aprotic solvents such as toluene or THF as well
as their stability in presence of acids, make
these reducing agents very suitable for reductive
amination. PYB with acetic acid as an activator
gave the highest yield in a comparison of
several reducing agents for the synthesis of
intermediate 2 used in HIV drugs (3). (Scheme
1, Rxn 1).
Ketones and aldehydes can be aminated quite
easily with 2-picoline borane (PICB) (4). The
reduction proceeds rapidly when conducted in
KARL MATOS
STEFAN PICHLMAIR
ELIZABETH R. BURKHARDT
Boron reagents
for reductive amination
methanol/AcOH, water/AcOH or even without solvent to
give secondary amines in excellent yields.
tert-Butylamineborane (TBAB) is very advantageous for
reductive aminations due to the low boiling point of tertbutylamine
(45 o C) (5). TBAB was effectively used to
reduce enamine intermediates for the synthesis of a
dopamine D1 antagonist (6). Substituted tetralone 3 was
condensed with an amine to the enamine and reduced in
situ with TBAB to a 9:1 mixture of cis/trans isomers (4,
Scheme 1, Rxn 2). In a subsequent step, the benzazepine
ring in 5 was formed via cyclization with CH 3SO 3H
followed by reduction using TBAB.
In another example, a robust, plant-scale process was
developed by optimization of the TBAB reduction to get
20 percent higher yields with shorter processing times (7).
The acidity of the reaction was moderated by tertbutylamine
released from TBAB.
These amine boranes are also effective for amination in
aqueous medium. For example, amination of 1,2,3trisubstituted
tri-aminopropane 6 with 40 percent
aqueous glyoxal and triethylamine borane (TEAB) gave 7
in quantitative yield (Scheme 1, Rxn 3) (8).
Oximes are usually formed in aqueous media, therefore,
amine borane complexes are ideal for this reduction
because of their stability in aqueous acidic solution up to
Scheme 1. Reductive Amination with Amine Boranes
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Scheme 2. Reductive Amination Examples Using STAB
pH 5. The mild reduction of oxime 8 by TBAB in the
synthesis of a drug candidate for treatment of allergy and
asthma, S-5751 (9) delivered the desired amino ester
product 9 without reduction of the alkyne or the ester
(Scheme 1, Rxn 4) (10).
During the synthesis of Fredericamycin A, oxime
intermediate 10 was reduced with PYB to the
corresponding hydroxylamine 11 (Scheme 1, Rxn 5). The
key aspect of the reaction was the use of 20 percent HCl
solution in ethanol solvent, which allowed the reaction to
be completed in just thirty minutes (11).
Overall, the above examples have shown that amine
boranes are excellent reagents for reductive amination
because of functional group tolerance and especially
where acidic or aqueous media are required.
Via Sodium Triacetoxyborohydride
Sodium triacetoxyborohydride (STAB) is the reagent of
choice for reductive aminations under non-aqueous
conditions at ambient temperature. Use of STAB in
reductions has been recently reviewed (12). Reductions
with STAB at temperatures higher than 50 o C for
extended periods of time may cause degradation of the
reducing agent via acetate reduction producing
Scheme 3. Reductive Amination with Appended Functional Groups
acetaldehyde and ethanol. Acetaldehyde
can undergo imine formation and in
particular may give unwanted ethylamine
by-products.
Mode Of Addition
Abdel-Magid et al. explored the reductive
amination of aldehydes, acyclic and cyclic
ketones with a variety of primary, secondary
and weakly basic amines, such as aniline
without prior formation of the intermediate
imine or iminium salt (13). Their best
procedure consisted of mixing the carbonyl
compound and the amine (1 and 1.05
equivalents respectively) in 1,2dichloroethane,
THF or acetonitrile at room
temperature followed by addition of STAB
(1.3-1.6 equivalents) and stirring at ambient
temperature until the amine was consumed
(~3 h). The reductive amination with weakly basic
amines, such as aniline, is slower leading to competing
ketone reduction and thus lower yields. In these cases,
excess ketone or acetic acid (1 to 3 equivalents) is
recommended to accelerate the reduction.
The following two examples (Scheme 2, Rxn 1 and 2)
demonstrate kilogram scale production of drug
intermediates. Synthesis of cis-3-methylamino-4methylpiperidines
used a process where the best yields
were obtained upon addition of piperidine 12 and
benzaldehyde to a slurry of STAB in toluene (14)
(Scheme 2, Rxn 1).
L-756423, useful for the treatment of HIV infection, was
prepared via reductive amination with 3 Kg of STAB
(Scheme 2, Rxn 2). Aldehyde 15 was premixed with
amine 14 in isopropyl acetate and acetic acid followed
by addition of solid STAB over 15 min at ambient
temperature (15).
Use of Additives to Accelerate the Reaction
Organic acids, such as acetic acid (16), trifluoroacetic
acid (17) and sulfonic acids are commonly added to
accelerate the reduction by protonation of the imine or
enamine intermediates. Molecular sieves are sometimes
beneficial to aid in formation of the imine (18).
For example, during the synthesis of L-779575, a
STAB reductive amination of piperizone 17,
(Scheme 2, Rxn 3) was driven to completion by
addition of crushed molecular sieves to remove
water (19).
To convert aldehyde 20 to the N-methyl
benzylamine derivative 21 (Scheme 2, Rxn 4) a
modification of the usual STAB reduction included
the use of 3Å molecular sieves and acetic acid in
combination with sodium acetate (20, 21). The
crude product was acylated to give an 80 percent
yield over two steps. In addition, imine formation
has been accelerated by use of TiCl(Oi-Pr) 3 as a
Lewis acid (22).
Reductive amination with STAB under pressure (1
Mpa) significantly shortened the reaction time
and increased yields (23).
Functional Group Tolerance
Due to the three electron withdrawing acetoxy
groups in STAB, a very mild reduction of imines
and iminium salts occurs in the presence of
other functional groups such as halides (24),
ketones, esters, cyano (25, 26), nitro (27),
benzyl (28), double (29) and triple (30) bonds.
In many cases, catalytic hydrogenation is not
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Scheme 4. Stereoselective Reductive Aminations with STAB
suitable because of carbon-halogen bond cleavage or
undesired reduction occurring. For example, a
carbamate group in 24 was not reduced during the
reductive amination with STAB (Scheme 3, Rxn 1). In
addition, racemisation of the amino aldehyde
derivative 23 was not observed (31).
LY426965, a serotonin antagonist, was effectively
prepared in 93 percent yield by the reductive amination
of aldehyde 25 in the presence of ketone group with
STAB (Scheme 3, Rxn 2). The high chemo-selectivity was
attributed to the β-quaternary center, which would
interfere with the formation of imine intermediate
consequently preventing ketone reduction (32).
STAB was favored over triethylamine borane in a
convergent approach due to amine borane impurities
formed at the dimethylamine end of triazole 30 (Scheme
2, Rxn 3). Because of its good solvating ability,
dimethylacetamide (DMAC) was the preferred solvent.
The hemiacetal functionality in 28 and triazole in 29
survived the reductive amination conditions to prepare
triazole intermediate 30 in 95 percent isolated yield as
the HCl salt (33).
One of the few examples of a reductive amination with
an α,β-unsatured aldehyde and aniline is the synthesis
of aniline derivative 33 for farnesyl pyrophosphate
analogues. The mild reducing conditions with STAB
gave yields consistently higher (85 percent) and with
fewer side products than NaBH 3CN, PYB or catalytic
hydrogenation. In this particular case, no 1,4-addition
product was reported (Scheme 3, Rxn 4) (34).
Stereoselective Reductive
Aminations
In the preparation of 3-endotropamine
35, an intermediate in the
synthesis of Zatosetron, STAB was used
for reductive amination of ketone 34
(Scheme 4, Rxn 1) (35).
A 12:1 mixture of amine 35 favoring
the desired endo-N-benzylamine (8:1
selectivity via hydrogenation) was
obtained and only low levels of
benzylacetamide 36 (2-4 percent)
were seen. Based on statistically
designed experiments, the optimal
reaction conditions were a
stoichiometry of 1.5 drug candidate
equivalents STAB, 0.75 equivalents of
acetic acid to accelerate the reaction
rate, and 1.35 equivalents of
benzylamine to account for the loss of
reagent to benzylacetamide formation.
A bulky acyloxyborohydride gave a
better endo:exo ratio (>30:1) but the
slower reaction rate compared to STAB
required 2 equivalents of tris[(2ethylhexanoyl)oxy]borohydride
reagent to complete the reaction in a similar
time (36).
Use of a chiral amine 38 as an auxiliary
allowed diastereoselective formation of
diketopiperizine intermediate 39 (6:1 ratio,
Scheme 4, Rxn 2) (37). Several 1,4,5trisubstituted-2,3-diketopiperazines
were
prepared via this tandem reductive amination
and acylation.
Methylation with Aqueous Formalin
Although not as common with STAB as amine
boranes, systems containing aqueous reagents can be
used. Reductive amination of formalin is an excellent
methodology to incorporate methyl groups in an amine
compound (38, 39). The key introduction of the methyl
group in the enantioselective synthesis of (-)-Saframycin
A, a potent antitumor agent, was accomplished by
reaction of 40 with formalin (2 equivalents) in the
presence of STAB (1.5 equivalents) in acetonitrile (40).
The N-methylated compound 41 was obtained in 94
percent yield and the labile morpholino nitrile
functionality was unaffected (Scheme 5, Rxn 1).
Pre-formation of Imine and Enamine
Intermediates
In some cases, the reductive amination works better
by preparing the imine intermediate prior to
reduction with STAB (41). Pre-forming the imine is
especially beneficial when dialkylation of the amine
is undesirable. For example, during the synthesis of
Trecetilide hemi-fumarate, a compound for treatment
of chronic atrial arrhythmia (42), the iminium
intermediate was formed prior to transfer into a STAB
slurry at 0-4 o C to afford 44 with > 90 percent
chemical purity and yield (Scheme 5, Rxn 2).
Enamines are effectively reduced with STAB in the
presence of acetic acid to protonate the enamine. For
example, the reduction of enamine 45 by addition of
solid STAB in portions gave the desired amine
product 46 in 71 percent isolated yield (Scheme 5,
Rxn 3) (43).
Scheme 5. Reductive Methylation, Pre-formed Imine and Enamine Reductions
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CONCLUSION
The preferred methods for reductive amination of
aldehydes or ketones with various appended functional
groups utilize STAB or amine boranes. Numerous
other examples of reductive amination with STAB to
synthesize active pharmaceutical ingredients
containing secondary and tertiary amines as the
structural feature have been reported (44). The unique
selectivity and effectiveness of these reagents in the
preparation of synthetic amine intermediates promise
to have a positive impact on production efficiencies of
drug candidates. The high yield and economical
formation of functionalized amines will dramatically
increase the usefulness of boron mediated reductive
aminations in industrial applications.
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KARL MATOS, STEFAN PICHLMAIR,
ELIZABETH R. BURKHARDT*
*Correspondent author
BASF Corporation
1424 Mars-Evans City Road
Evans City, PA 16033, USA
chimica oggi • Chemistry Today • Vol 25 nr 1 • January/February 2007