Amide activation by TMSCl: Reduction of amides to amines by LiAlH 4 under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2013.06.144

An expeditious and practical method for the reduction of amides to amines is reported. The method consists of activation of amides with TMSCl followed by reduction with LiAlH₄. Various amides/lactams including hindered amides and secondary amides gave the corresponding amines in good to excellent yields. This novel protocol has a wide substrate scope and shows good functional group tolerance with high stereoretention.

Full text of DOI:10.1016/j.tetlet.2013.06.144

Accepted Manuscript
Amide activation by TMSCl: Reduction of amides to amines by LiAlH4 under
mild conditions
B. Ravinder, S. Rajeswar Reddy, A. Panasa Reddy, Rakeshwar Bandichhor
PII:
S0040-4039(13)01129-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.144
TETL 43197
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 March 2013
27 June 2013
28 June 2013
Please cite this article as: Ravinder, B., Rajeswar Reddy, S., Panasa Reddy, A., Bandichhor, R., Amide activation
by TMSCl: Reduction of amides to amines by LiAlH4 under mild conditions, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.06.144
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Amide activation by TMSCl: Reduction of amides to amines by LiAlH4 under
mild conditions
Ravinder B.1, Rajeswar Reddy S.1, Panasa Reddy A.2, Rakeshwar Bandichhor1*
1Integrated Product Development, Innovation Plaza, Dr.Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur, R.R.Dist.500072, Andhra Pradesh, India and
2Department of Chemistry, Osmania University, Hyderabad-5000007.
ARTICLE INFO
ABSTRACT
An expeditious and practical method for the reduction of amides to amines is reported. The method
consists of activation of amides with TMSCl followed by reduction with LiAlH4. Various
amides/lactams including hindered amides and secondary amides gave the corresponding amines in
good to excellent yields. This novel protocol has a wide substrate scope and shows good functional
group tolerance with high stereoretention.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Reductive amination
Trimethylsilyl chloride
Lithium aluminum hydride
Amines and their derivatives are of great pharmaceutical
significance and are an important class of compounds for the
drug development, due to their affinity towards various receptors
in the biological system.1 In this regard; wide scope and broad
tolerance toward functional groups are the key factors for the
acceptance and application of a newly developed methodology
involving readily available reagents. Direct conversion of amides
and lactams to the corresponding amines is one of the most
important facets of chemistry but it is not as facile as it seems.
There are many procedures available for the reduction of amides
and lactams to amines. Lithium aluminum hydride (LAH)2,
diborane or borane complex3 and others4 are the widely used
reducing agents for amide reductions. Recently, there have been
impetus given for the reduction of amides, particularly, reduction
are also encountered. Interestingly, the use of aluminum hydride
for such reduction provides a convenient alternative to the use of
lithium aluminum hydride-aluminum chloride mixtures.18 During
the reagent preparation, the lithium chloride precipitates and an
ether solution of the reagent is obtained. Unfortunately, such
solutions are metastable and, on standing, the aluminum hydride
associates and precipitates from solution that led to the poor
reducing profile of this reagent.19 Considering all these
limitations, we carried out an investigation on reduction by
selecting commonly used Lewis acid, trimethylsilyl chloride over
aluminium chloride in combination with LAH.20
This combination turned out to be very effective in the reduction
of hindered tertiary amides as well as the reduction of secondary
amides. Here in, we disclose the novel protocol for reduction and
its application to various amide substrates including the drug
molecule, Azenapine.
By taking a lead from a report disclosing LAH and TMSCl used
in the reduction of phosphonate to phosphine we attempted this
system for the first time to reduce amides to amines as shown in
Scheme 1. Azenapine amide (1a) was selected as a model
substrate for our initial investigation. Thus, lactam 1a was
treated with LAH (1.4 mol equiv) in THF in an ice bath for 1 h
and complete conversion of the substrate with less yield and
purity was obtained (Table 1). The reaction with LAH/AlCl3
(1.4/1.1 mol equiv) in THF in an ice bath for 1 h offered
complete conversion with moderate yield and purity. In spite of
its utility, unstable nature of AlH3 and concomitant formation of
salt byproducts makes it difficult to optimize this procedure.
In our continued endeavor, lactam 1a was treated with
LAH/TMSCl (1.4/1.2 mol equiv) in THF in an ice bath for 1 h,
only 30% conversion was observed. In order to achieve better
conversion, reverse mode of addition of reagent was employed
and it afforded complete conversion. In a typical procedure,
lactam 1a was treated with TMSCl (1.2 mol equiv) in THF in an
ice bath for 15 min and to the resultant reaction mass was added
a reducing agent, LAH (1.4 mol equiv). The reaction was
of
less
reactive
secondary
amides
employing
hydrosiloxane,5aCbz/LiBH4,5b and TMDS/Cu(OTf)2.6 The other
reducing agents e.g. DodBMS,7 Red-Al,8a,b NaBH4 in ionic
liquids,9 have been employed for reduction of secondary
amides.. But reduction of tertiary amides into amines was carried
out by using 9-BBN,10 Zn(OTf)2/methyl diethoxy silane11 and
hydrosilanes activated by Rh,12a Ru,12b,c Pt,12d,e Ti,12f In,12g Ir,12h,i
Mn,12j Re,12j Os,12j Pd,12j Fe,12k,l Mo,
and Zn12n derived
12m
catalysts/reagents. Reductive alkylation on tertiary amide
yielding amine derivative is also reported.13 In addition to this,
Charette and coworkers reported a highly chemoselective metal-
free method for the reduction of tertiary amides using Tf2O and
Hantzsch ester (HEH).14 Primary amides were reduced using
NaBH4/diglyme.15
The reduction of amides and lactams to amines with lithium
aluminum hydride2 has many limitations. The drawback of using
LAH is that it requires harsh conditions for the reduction that
renders the method with poor efficiency,16 and quite often it
proceeds with great difficulty, particularly where secondary
amines are to be generated. In addition to this, the side reactions
due to NH proton acidity such as C–N bond cleavage with
hindered tertiary amides17 and formation of insoluble complexes

2
completed in less than 1 h. By this observation, we envisaged
that the lactam 1a might have been activated with TMSCl by
forming imine in situ thereafter the reduction of amide to amine
with LAH would have proceeded. When the same reaction was
conducted in DCM, the results were comparable to that in THF
medium.
Table 3 Reduction of amides/lactams with LAH/TMSCl in
DCM
TMSCl/
LAH
(equiv)
Yield
(%)b
Substrate
Producta
1b
h
1.2/1.4
0.45
85c
1.2/1.4
1.2/1.4
0.75
1.0
78d
2b
3b
Scheme 1. Novel amide reduction approach to 1b
79 d
Table 1. Reduction of lactam 1a under various Lewis acid-LAH
reaction conditions.
Lewis
acid
(equiv)
--
AlCl3/
(1.1)
TMSCl
(1.2)
Yielda
(%)
(Purity)
55(70)
1.2/1.5
1.2/1.5
1.0
77 d
4b
5b
LAH
(equiv)
T
(°C)
Conv.
(%)
S.No.
Sol.
1
2
1.4
1.4
THF
THF
5
5
100
100
70(98)
85(98)
85(98)
0.75
81d
3
1.4
THF
5
5
100
100
TMSCl
(1.2)
DC
M
4.
1.4
a isolated as maleate salt
1.2/1.5
1.2/1.4
1.25
1.25
75 d
6b
7b
On the basis of these preliminary trials, we next focused on
optimization of critical reaction parameters (Table 2) for the
reduction of amide with LAH/TMSCl in DCM. As expected,
only 45% conversion occurred with 0.5 mol of TMSCl. In
contrast, with 1.2 mol of TMSCl, complete conversion with high
isolated yield and purity were obtained. At higher temperature,
we encountered poor yields which could possibly be due to the
77 d
destabilized Lewis acid
activated amides leading to
decompostion of transient amide. The results are summarized in
Table 2 (entry 3).
Table 2. Screening of the reaction conditions for reduction of
Lactam (1a)
1.2/1.5
1.2/1.4
0.75
1.0
81 d
8b
9b
LAH
(equiv)
1.0
TMSCl
(equiv)
1.0
Yieldb
(%)
35
Entry
T (°C) Conva.(%)
1
2
3
4
5
5
50
70
1.2
1.0
55
74 d
84 d
1.3
1.2
5
100
100
85
1.3
1.2
25
50
a Determined by TLC
b isolated as maleate salt
1.2/1.5
1.2/1.4
1.25
1.0
10b
11b
With optimized conditions in hand, the scope of LAH in
presence of Lewis acid, TMSCl for reduction of hindered tertiary
and secondary amides was explored. The reaction was then
extended to a series of lactams and amides including aromatic
and aliphatic and the results are summarized in Table 3.
Delightfully, all the reactions afforded good to excellent yields
(Table 3), even with hindered amides and the structure of the
products are shown in Figure 1.
79 e
aThe products were characterized by IR, 1H NMR data
bYields of the isolated pure compound
cisolated as maleate salt in IPA
disolated as hydrochloride salt in diisopropyl ether
eisolated as amine

3
It is well established that the use of LAH for reductions can
potentially cause racemization of chiral center(s) present in the
system.21 In most of the cases, when the reduction of chiral
amides was carried out with LAH, it ended with racemic
amines. Therefore, we explored the possibility of reduction on
such compounds, to investigate the fate of chirality of reduced
chiral amines by reduction with lithium aluminum hydride in the
presence of trimethylsilyl chloride. As it can be seen from Table
4, all the reactions afforded good to excellent yields, with
excellent ee/de of the products. The results are summarized in
Table 4 and the structure of products is shown in Figure 2. This
strategy was also employed to access pharmaceutically relevant
molecules like Asenapine maleate (1b') and Dexpramipexole
(KNS-760704) (12b).
5
6
81d
1.1
1.3
99 f
14b
15b
79d
99 f
7
8
82d
1.2
1.4
>98.5 f
>98.5 f
16b
17b
79d
aThe product were characterized by IR, 1H NMR data
bYields of the Isolated pure compound
cisolated as maleate salt in IPA
disolated as hydrochloride salt in diisopropyl ether
e%de; f%ee
Figure 1. Structure of amines (1b-11b)
Table 4 Reduction of chiral Amides/Lactams with LAH/TMSCl
in DCM
%ee/
de
Yieldb
(%)
Entry
Substrate
Producta
h
1
85c
79c
0.45
99e
1b’
Figure 2. Structure of chiral amines (1b’-17b)
2
1.0
99 e
1b’’
3
4
77d
72d
0.50
1.0
>98.5f
>98.5 f
12b
13b
Scheme 2. Plausible mechanism for the amide/lactam reduction
via activation with TMSCl

4
1945. (k) Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama,
Mechanistically, trimethylsilyl chloride as a Lewis acid activates
the carbonyl functionality and provides very reactive electrophile
source. In situ generated imine can further be reduced with
lithium aluminum hydride affording the products as shown in
Scheme 2. Our approach allowed us to have quick access of the
products as the rate of the reaction was found to be very fast in
comparison with the lithium aluminum hydride-aluminum
Y.; Nagashima, H. Angew. Chem., Int. Ed. 2009, 48, 1. (l) Zhou,
S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem., Int.
Ed. 2009, 48, 9507. (m) Fernandes, A. C.; Roma˜o, C. C. J. Mol.
Catal. A: Chem. 2007, 272, 60. (n) Das, S.; Addis, D.; Zhou, S.;
Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770.
13. Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q.
Angew. Chem. Int. Ed. 2010, 49, 3037.
14. Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130 , 1, 18.
15. Hua-Jie Zhu, Kai-Tao Lu, Guang-Ri Sun, Jin-Bao He, Hai-Qing
Li and Charles U. Pittman, Jr. New J. Chem. 2003, 27, 409.
16. (a) Rajashekhar, B.; Kaiser, E. T. J. Org. Chem. 1985, 50, 5480.
(b) McWilliams, J. C.; Clardy, J. J. Am. Chem. Soc. 1994, 116,
8378. (c) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003,
1663. (d) Campbell, A. L.; Pilipauqkas, D. R.; Khanna, I. K.;
Rhodes, R. A. Tetrahedron Lett. 1987, 28, 2331.
chloride mixtures-mediated reactions22,23 and
experimental procedure is described in reference section.24
a
typical
In conclusion, we have reported the reducing system employing
lithium aluminum hydride, (LAH) activated by trimethylsilyl
chloride (TMSCl) which reduces even the tertiary and secondary
amides to the corresponding amines with high enantio-or
diastereoretention and excellent yields.
17. Akamatsu, H.; Kusumoto, S.; Fukase, K. Tetrahedron Lett. 2002,
43, 8867.
18. (a) Finholt, A. E.; Bond, A. C.; Schlesinger, H. I. ibid. 1947, 69,
1999. (b) Wiberg, E.; Graf, H.; Schmidt, M.; Uson, R. Z.
Nuturforsch., 1952, 7b, 578.
Supplementary Material
19. (a) Wiberg, E.; Jahn, A. ibid. 1952, 7b, 581. (b) Jorgenson, M. J.
Tetrahedron Letters, 1962, 13, 559.
20. Barral, K.; Priet, S.; Michelis, C.D.; Sire, J.; Neyts, J.; Balzarini,
J.; Canard, B.; Alvarez, K. Eur. J. Med. Chem. 2010, 45, 849.
21. Donohue, A.C.; Jackson,.W.R. Aust. J. Chem. 1995, 48, 1741 –
1746.
Experimental procedures and compound characterization data are
described in supplementary material.
References
22. (a) Finholt, A. E.; Bond, A. C.; Schlesinger, H. I. J. Am. Chem.
Soc. 1947, 69, 1197. (b) Brown H. C.; Yoon, N. M. J. Am. Chem.
Soc. 1966, 88, 1464.
23. (a) Wiberg, E. Angew. Chem., 1953, 65, 16. (b) Brewster J. H.;
Bayer, H. O. J. Org. Chem., 1964, 29, 105. (c) Eliel, E. E. Record
Chem. Progr. 1961, 22, 129. (d) Seyden-Penne, J. Reductions by
the Alumino and Borohydrides in Organic Synthesis, 2nd ed.;
Wiley: New York, 1997. (e) Gribble, W. G. Chem. Soc. ReV.
1998, 27, 395.
1. (a) Ricci, M. A. Modern Amination Methods; Wiley: New York,
2000. (b) Bo¨hm, H.-J.; Klebe, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 2588. (c) Encyclopedia of the Alkaloids; Glasby, J. S.,
Ed.; Plenum Press: New York, 1975.
2. (a) Brown, H. C.; Weissman, P. M.; Yoon, N.-M. J. Am. Chem.
Soc. 1966, 88, 1458. (b) Cha, J. S.; Lee, J. C.; Lee, H. S.; Lee, S.
E.; Kim, J. M.; Kwon, O. O.; Min, S. J. Tetrahedron Lett. 1991,
32, 6903. (c) Uffer A.; Schlittler, E. Helv. Chim. Acta, 1946, 31,
1397.
24. In a typical experimental procedure, amide, 1a (10 g, 33.43
mmol) and dichloromethane (100 mL) were charged into a round
bottomed flask and stirred under nitrogen atmosphere for 10-15
min and cooled to 0-5 ˚C. Trimethylsilyl chloride (5.1 mL, 40.12
mmol) was then added to the mixture over 10-15 min. and stirred
for 10-15 min. at same temperature. Lithium aluminum hydride
(19.5 mL, 46.81 mmol) in tetrahydrofuran solution is added
dropwise at -10 to 0 ˚C. After complete addition, the solution is
allowed to stir for 1-2 h at 0 to 10 ˚C. After completion of
reaction (TLC), the reaction mass was quenched by slow
dropwise addition of 2M sodium hydroxide (30 mL) and reaction
mixture was extracted with dichloromethane (25 mL). The
organic layers were combined, washed with 20% sodium chloride
solution. The solvent was evaporated under reduced pressure to
get the crude material which was dissolved in isopropyl alcohol
(50 mL). Then maleic acid (5.0 g, 43.46 mmol) was added and
stirred for 2-3 h at ambient temperature followed by cooling it to
0-10 ˚C for additional 2-3 h. The obtained solid was collected by
filtration, washed with isopropyl alcohol (10 mL) and dried at 50-
55 ˚C to afford the title compound 1b‘ as white solid (11.5 g,
85%).
3. (a) Kornet, M. J.; Tan, S. I. J. Org. Chem. 1968, 33, 3637. (b)
Brown, H. C.; Heydkamp, W. R.; Breuer, E.; Murphy, W. S. J.
Am. Chem. Soc. 1964, 86, 3566. (c) Brown, H. C.; Bigley, D. B.;
Arora, S. K.; Yoon, N. M. J. Am. Chem. Soc. 1970, 92, 7161. (d)
Godjoian, G.; Singaram, B. Tetrahedron Lett. 1997, 38, 1717.
4. For reduction with other agents/systems, see: (a) DIBALH:
Winterfeldt, E. Synthesis 1975, 617. (b) NaBH4–TFA and
NaBH4–TFAA: Gribble, G. W.; Nataitis, C. F. Org. Prep.
Proced. Int. 1985, 17, 317. (c) NaBH4–I2: Mckennon, M. J.;
Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58,
3568. (d) LiH3BNMe2: Flaniken, J. M.; Collins, C. J.; Lanz, M.;
Singaram, B. Org. Lett. 1999, 1, 799.
5. (a) Hanada, S.; Ishida, T.; Motoyama, Y.; Nagashima, H. J. Org.
Chem. 2007, 72, 7551. (b) Brown, H. C.; Heim, P. Tetrahedron
Letters. 1999, 40, 643.
6. Das, S.; Join, B.; Junge, K.; Beller, M. Chem. Commun., 2012, 48,
2683.x
7. Patra, P. K.; Nishide, K.; Fuji, K.; Node, M. Synthesis 2004, 7,
1003.
8. (a) Reily, M. D.; Uhlendorf, S. E.; Zisek, K. A. J. Heterocycl.
Chem. 1991, 28, 517. (b) Voight, E. A.; Bodenstein, M. S.;
Ikemoto, N.; Kress, M. H. Tetrahedron Letters 2006, 47, 1717.
9. Lampariello, L. R.; Peruzzi, D.; Sega, A.; Taddei, M. Letters in
Organic Chemistry 2005, 2, 3, 265.
10. Gayane Godjoian, G.; Singaram, B. Tetrahedron Letters, 1997,
38, 10, 1717.
11. Das, S.; Addis, D.; Junge, K.; Beller, M. Chem. Eur. J. 2011, 17,
12186.
12. (a) Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron Lett. 1998,
39, 1017–1020. (b) Motoyama, Y.; Mitsui, K.; Ishida, T.;
Nagashima, H. J. Am. Chem. Soc. 2005, 127, 13150. (c)
Sasakuma, H.; Motoyama, Y.; Nagashima, H. Chem. Commun.
2007, 4916. (d) Hanada, S.; Motoyama, Y.; Nagashima, H.
Tetrahedron Lett. 2006, 47, 6173. (e) Hanada, S.; Tsutsumi, E.;
Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc. 2009, 131,
15032. (f) Selvakumar, K.; Rangareddy, K.; Harrod, J. F. Can. J.
Chem. 2004, 82, 1244. (g) Sakai, N.; Fujii, K.; Konakahara, T.
Tetrahedron Lett. 2008, 49, 6873. (h) Motoyama, Y.; Aoki, M.;
Takaoka, N.; Aoto, R.; Nagashima, H. Chem. Commun. 2009,
1574. (i) Park, S.; Brookhart, M. J. Am. Chem. Soc. 2012, 134 , 1,
640. (j) Igarashi, M.; Fuchikami, T. Tetrahedron Lett. 2001, 42,

Graphical Abstract
Amide activation by TMSCl: Reduction of amides to
amines by LiAlH4 under mild conditions
Leave this area blank for abstract info.
Ravinder B., Rajeswar Reddy S., Panasa Reddy A., Rakeshwar Bandichhor*