Polymethylhydrosiloxane (PMHS)/trifluoroacetic acid (TFA): a novel system for reductive amination reactions

Article abstract of DOI:10.1016/j.tetlet.2009.08.048

Polymethylhydrosiloxane (PMHS)/trifluoroacetic acid (TFA) was discovered as a novel metal-free system for reductive amination reactions. A variety of (het)aryl amines as well as a representative carbamate and urea were successfully alkylated by benzaldehyde in the presence of PMHS and TFA in dichloromethane at room temperature in moderate to excellent yields (28-87%). Furthermore, this reaction protocol was successfully applied to the alkylation of p-nitroaniline with a wide range of aldehydes, ketones, and a representative acetal to obtain the alkylated products in yields ranging from 40% to 92%. The current work represents one of the very few examples of PMHS being activated by a Br?nsted acid.

Full text of DOI:10.1016/j.tetlet.2009.08.048

Tetrahedron Letters 50 (2009) 5975–5977
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Polymethylhydrosiloxane (PMHS)/trifluoroacetic acid (TFA): a novel system
for reductive amination reactions
a
Jay P. Patel b, , An-Hu Li a, , , Hanqing Dong a, Vijaya L. Korlipara b, , Mark J. Mulvihill
*
*
a Department of Cancer Chemistry, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA
b College of Pharmacy and Allied Health Professions, St. John’s University, Queens, NY 11439, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Polymethylhydrosiloxane (PMHS)/trifluoroacetic acid (TFA) was discovered as a novel metal-free system
for reductive amination reactions. A variety of (het)aryl amines as well as a representative carbamate and
urea were successfully alkylated by benzaldehyde in the presence of PMHS and TFA in dichloromethane
at room temperature in moderate to excellent yields (28–87%). Furthermore, this reaction protocol was
successfully applied to the alkylation of p-nitroaniline with a wide range of aldehydes, ketones, and a rep-
resentative acetal to obtain the alkylated products in yields ranging from 40% to 92%. The current work
represents one of the very few examples of PMHS being activated by a Brønsted acid.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 July 2009
Revised 15 August 2009
Accepted 17 August 2009
Available online 20 August 2009
Polymethylhydrosiloxane (PMHS) has been reported as an air
and moisture stable, inexpensive, non-toxic, versatile, and widely
used reducing agent in organic synthesis.1
amination reactions. The reaction system was also found to be suc-
cessful with a primary carbamate and a urea as the amine source,
as well as an acetal as the alkylating agent. This work represents
one of the very few examples of PMHS being activated by a
Brønsted acid.
Me
Me Si
Me
Si
Me
Stirring a solution of benzaldehyde (106 mg, 1.0 mmol), aniline
(112 mg, 1.2 mmol), and PMHS (120 mg, 2.0 mmol of –MeSi(H)O–
unit) in dichloromethane overnight at room temperature did not
afford any desired product. However, upon addition of the
Brønsted acid TFA to the reaction mixture, the desired reductive
amination product was observed. Screening an array of solvents
(dichloromethane, toluene, THF, etc.), PMHS reagent quantities
(1–5 equiv), and reaction concentrations (0.1–5 M) led to the iden-
tification of more optimal reaction conditions. Thus, in a typical
operation,13 a carbonyl compound and an amine were stirred in
a mixture of TFA and dichloromethane [1:2 (v/v) ratio] at room
temperature for circa 12 h to form an imine intermediate, which
was reduced in situ by the addition of PMHS with continuous stir-
ring for another 8–10 h at the same temperature at which point,
the reaction was usually complete as indicated by TLC analysis.
The results for reductive amination of benzaldehyde with various
amines, a primary carbamate, and a primary urea under these opti-
mized conditions are shown in Table 1.
It was found that anilines bearing a variety of functionalities
were alkylated smoothly in good yields (entries 1–4) with func-
tional groups, such as NO2, CN, and methylsulfonyl, remaining
unaffected. Reaction of a heteroaromatic 4-aminopyridine gave
only a modest yield (entry 7). It is interesting to note that a pri-
mary carbamate and a urea underwent successful alkylation with
benzaldehyde (entries 5 and 6), however, phenylhydrazine and
phenoxyamine gave only trace amounts of the desired products
(entries 8 and 9). There was no reaction with an alkyl amine (entry
O
O
Si Me
Me
PMHS:
n
Me
H
This reagent has minimal or no reducing ability in the absence of
an activator, usually a transition metal catalyst or fluoride. Examples
of such activators include Pd(0, II),2 Ti(IV),3 Zn(II),4 Ru(0),5 Cu(I, II),6
In(III)7a and Cd(II),7a Ir(I, III),7b Tin(IV),8 fluoride,9 B(C6F5)3,10 and I2.11
Once activated, PMHS becomes a powerful reagent that can effec-
tively perform a wide range of reactions, such as dehalogenation
of halogenated arenes,2e,f reduction of ketones3a,4a–c,6c and esters3d
,
reduction of imines,3b,4c,d,7a,b,8 carboxamides,5 nitro compounds,2d
and amine N-oxides2b, conversion of acid chlorides to aldehydes,2c
conjugate reductions,6a,b,10b and hydroiodination of alkenes and
alkynes.11a In addition, PMHS together with CsF has been reported
to facilitate the Sonogashira reaction9c and cross-couplingof alkynes
or benzothiazoles with various halides.9b
In efforts focused on the reductive amination of poorly reactive,
electron-deficient anilines, we found that conventional reductive
amination reaction conditions12 gave either meager yields or were
completely ineffective. Pursuit of a more efficient method led to
the discovery of the PMHS/TFA combination which offered a novel,
simple, efficient, inexpensive, and safe system for direct reductive
* Corresponding authors. Tel.: +1 631 962 0780/+1 718 990 5369; fax: +1 631 845
5671/+1 718 990 1877.
E-mail addresses: ali@osip.com (A.-H. Li), korlipav@stjohns.edu (V.L. Korlipara).
These two authors contributed equally to this research.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.048

5976
J. P. Patel et al. / Tetrahedron Letters 50 (2009) 5975–5977
Table 1
Table 2
Reductive amination of benzaldehyde with various amines as well as with
a
Reductive amination of p-nitroaniline with various carbonyl compounds and a
representative carbamate and ureaa
representative acetala
O
1) TFA, CH2Cl2, rt, 12 h
+
R1
R2
CHO
R
NH2
1) TFA, CH2Cl2, rt, 12 h
2) PMHS, rt, 8-10 h
HN
R
2) PMHS, rt, 8-10 h
NH
R1
O2N
or
OMe
+
NH2
R2
O2N
Entry
Amine
Product
Isolated
Ph
OMe
yieldc (%)
Entry
1
Carbonyl compound
or acetal
Product
Isolated
yieldb (%)
1
2
3
4
87
O2N
NH2
O2N
NH
Cl
73
77
57
75
55
40
50
40
92
Cl
CHO
O2N
O2N
O2N
O2N
O2N
NH
NH
NH
NH
NH
67
65
65
NC
NH2
NC
NH
CF3
2
3
4
5
6
7
8
9
MeSO2
NH2
.HCl
F3C
Me2N
N
CHO
MeSO2
F3CO
NH
F3CO
NH2
NMe2
NH
CHO
O
O
O
O
NH2
NH
NH
N
5
75
CHO
O
O
CHO
NH2
6
7
8
66
NH
NH
28b
N
NH2
CHO
N
NH
O2N
NH
HN NH2
HN NH
O
Trace
O2N
O2N
NH
NH
O
O
NH2
O
NH
9
Trace
0
OMe
OMe
O2N
NH
10
—
NH
a
Reaction conditions: carbonyl compound or acetal (1.0 mmol), p-nitroaniline
a
Reaction conditions: benzaldehyde (1.0 mmol), amine (1.2 mmol), PMHS
(1.2 mmol), PMHS (2.0 mmol of –MeSi(H)O– unit) in TFA (1 mL) and CH2Cl2 (2 mL),
rt.
(2.0 mmol of –MeSi(H)O– unit) in TFA (1 mL) and CH2Cl2 (2 mL), rt.
b
b
Purity: 90%.
Average yields of at least two runs of the same reaction.
c
Average yields of at least two runs of the same reaction.
tion (entries 7 and 8) as was benzaldehyde dimethyl acetal which
10). One possible explanation is that the nucleophilicity of this
highly basic aliphatic amine is greatly reduced in the TFA-contain-
ing reaction solution, which prevents the amine from reacting with
the carbonyl reactant. It was also noted that the HCl salt of an
aniline can be used directly in this reaction without desalting
(entry 3).
Results from the reactions of p-nitroaniline with a variety of
carbonyl compounds and an acetal are shown in Table 2. Aromatic
aldehydes with electron-withdrawing and electron-donating
groups (entries 1–3), a heteroaromatic aldehyde (entry 4), and ali-
phatic aldehyde (entry 5) all reacted smoothly to generate the de-
sired products in good yields. The reaction with cinnamic
alkylated p-nitroaniline in 92% yield (entry 9).
Direct reductive aminations of carbonyl compounds with PMHS
3c,e
activated by Ti(OPr-i)4
or an Ir (I, III) catalyst7b have been pro-
posed to proceed through active metal-hydride intermediates.1a
In our metal-free PMHS/TFA system, we hypothesize that TFA plays
a dual role in facilitating intermediate imine formation and activat-
ing PMHS through hypervalent silicon intermediates for the reduc-
tion of in situ formed imine.15,16
In conclusion, we have developed an effective, inexpensive, and
versatile one-pot reductive amination method using a novel PMHS/
TFA system. A variety of aromatic and heteroaromatic amines as
well as a primary carbamate and a urea were successfully alkylated
aldehyde, an
a,b-unsaturated aldehyde, was also successful except
with a wide range of aromatic, heteroaromatic, aliphatic, a,b-
that the carbon–carbon double bond was reduced (entry 6), a re-
sult consistent with a report by Pearlman and co-workers,14 who
observed a carbon–carbon double bond reduction of a steroid
derivative using the related PMHS/hexamethyldisiloxane/pTSA
system. Ketones were proven to be useful substrates in this reac-
unsaturated aldehydes, and an aliphatic ketone, acetophenone,
and an acetal. The reaction conditions are mild enough to tolerate
functionalities, such as nitro, cyano, sulfonyl, and chloro. The cur-
rent reaction represents one of the very few examples of PMHS
being activated by a Brønsted acid.

J. P. Patel et al. / Tetrahedron Letters 50 (2009) 5975–5977
5977
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Acknowledgments
8. Lopez, R. M.; Fu, G. C. Tetrahedron 1997, 53, 16349.
J.P. is thankful to OSI Pharmaceuticals, Inc. for providing him
the summer studentship award. The authors would like to thank
Dr. Andy Crew for his critical review of the manuscript.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.048.
11. (a) Das, B.; Srinivas, Y.; Holla, H.; Narender, R. Chem. Lett. 2007, 36, 800; (b)
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References and notes
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13. General procedure: To a stirred solution of carbonyl compound (1.0 mmol) and
amine (1.2 mmol) in dichloromethane (2 mL) was added TFA (1 mL). The
mixture was stirred at room temperature for 12 h. PMHS [2.0 mmol of –
MeSi(H)O– unit, Aldrich (cat#: 176206), average Mn: 1700–3200] was then
added and the resulting mixture was again stirred for 8–10 h at rt. Upon
completion (by TLC or LC–MS), the reaction mixture was basified with 1 M aq
sodium hydroxide to pH ꢀ 8 and extracted with dichloromethane (30 mL Â 3).
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purified by preparative TLC or column chromatography to give the desired
product.
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