One-step conversion to tertiary amines: InBr3/Et3SiH-mediated reductive deoxygenation of tertiary amides

Article abstract of DOI:10.1016/j.tetlet.2008.09.086

We have developed a simple and practical procedure for a direct reductive conversion from a variety of tertiary amides to the corresponding tertiary amines using an InBr₃/Et₃SiH reducing system. This reducing system can be applied to the reduction of a secondary amide and provides a more efficient alternative to conventional methods that use aluminum and boron hydrides.

Full text of DOI:10.1016/j.tetlet.2008.09.086

Tetrahedron Letters 49 (2008) 6873–6875
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Tetrahedron Letters
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One-step conversion to tertiary amines: InBr3/Et3SiH-mediated
reductive deoxygenation of tertiary amides
*
Norio Sakai , Kohji Fujii, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a simple and practical procedure for a direct reductive conversion from a variety of
tertiary amides to the corresponding tertiary amines using an InBr3/Et3SiH reducing system. This reduc-
ing system can be applied to the reduction of a secondary amide and provides a more efficient alternative
to conventional methods that use aluminum and boron hydrides.
Received 19 August 2008
Revised 11 September 2008
Accepted 16 September 2008
Available online 19 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Reduction
Amide
Amine
Indium
Silane
The reductive transformation of an amide to an amine has occu-
pied a central and important position in organic syntheses.1 Con-
ventionally, aluminum hydride reagents such as LiAlH4 and
DIBAL,2 boron hydrides such as NaBH4 and (BH3)2,3 or a reducing
system that combines hydrides with an additive4 has been utilized
to achieve this objective. Generally, these relatively strong reduc-
ing reagents have several disadvantages that often restrict the util-
ity of the synthetic procedure: the undesirable reduction of
substituted groups other than the carbonyl group, the production
of several byproducts, the removal of the aluminum residue from
the crude product, and laborious handling in an usual laboratory.
Recently, a convenient and selective procedure using either a Lewis
acid or a transition metal and a milder and an easier-handling
hydrogen source, a hydrosilane, has been demonstrated.5 In this
context, during the last decade several groups have reported that
a reducing system comprises an indium salt and a milder reducing
reagent, a hydrosilane, functions as a highly effective tool for the
reductive conversion of a functional group involving the dehalo-
genation of organic halides, the reduction of alcohols, the 1,4-
reduction of enones, and reductive aldol reactions.6 We also found
that an InBr3–Et3SiH reducing system effectively promotes direct
and selective reduction of a carbonyl group on esters to produce
the corresponding ethers.7 Herein, we report that this InBr3–Et3SiH
reducing system can be adapted to successfully complete a selec-
tive reduction of the carbonyl group of tertiary amides, which leads
to the production of the corresponding tertiary amines. Also, the
reducing reagents accommodated the reductive transformation of
a secondary amide to a secondary amine.
Initially, reduction of N,N-dibenzylacetamide (1a) with an in-
dium catalyst and a hydrosilane was examined as a model reac-
tion.8 Based on our previous study,7 when the reaction was
conducted with 5% InBr3 and 4 equiv of Et3SiH in chloroform at
60ꢀC, the expected reduction proceeded cleanly to produce the de-
sired tertiary amine 2a in 90% yield (run 1 in Table 1). However,
when a similar reaction was carried out with InCl3 and In(OTf)3,
Table 1
Examination of reaction conditions
5% InX3
silane (4 equiv)
Ph
N
Ph
Ph
N
Ph
H
solv, 60 °C, 20 h
O
H
1a
2a
Run
InX3
Silane
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
InBr3
InCl3
Et3SiH
Et3SiH
Et3SiH
PhMe2SiH
Ph2SiH2
(Me2SiH)2O
Et3SiH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
PhH
(90)
Trace
48
65
46
51
Trace
Trace
In(OTf)3
InBr3
InBr3
InBr3
InBr3
InBr3
Et3SiH
* Corresponding author.
E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
a
GC yield (isolated yield).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.086

6874
N. Sakai et al. / Tetrahedron Letters 49 (2008) 6873–6875
Table 2
a recovery of the starting material and a drastic decline of product
yield was observed (runs 2 and 3). Thus, it was found that only
InBr3 was highly effective for reduction of the tertiary amide and
showed outstanding catalytic activity. Running this reaction with
PhMe2SiH, Ph2SiH2, and (Me2SiH)2O, instead of Et3SiH, resulted in
a reduced product yield (runs 4–6). Interestingly, use of CH3CN, a
solvent that is widely used in reductive functional group conver-
sions in the presence of an indium halide and a silane compound,
did not give the desired product. Instead, it led to the recovery of
the starting material (run 7). Also, when the reaction was con-
ducted in PhH, the reaction did not proceed (run 8). Consequently,
a reducing system composed of 5% InBr3 and 4 equiv of Et3SiH in
CHCl3 proved to give the best results.
Reduction of amides to amines
O
H
H
5% InBr3, Et3SiH (4 equiv)
CHCl3, 60 o
R1
R1
R3
N
R2
R3
N
C
R2
1a-o
2a-o
Run
1
Amide
Time (h)
20
Amine
Yielda (%)
90
Ph
N
Ph
Ph
N
H
Ph
(2a)
(2b)
(2c)
(2d)
H
O
O
H
H
2
3
4
20
20
20
66
64
94
With the optimized conditions shown in Table 1, the generality
of this reduction was examined using a variety of tertiary amides
(Table 2). In all cases using a tertiary amide derived from benzam-
ide, the reductive deoxygenation proceeded cleanly, producing the
corresponding benzylamine derivatives 2b–d in moderate to good
yields (runs 2–4). The substrates comprises an acetanilide moiety
also converted to the expected aniline derivatives 2f–i in practical
yields (runs 5–9). In particular, this InBr3–Et3SiH reducing system
was also applicable to the reduction of amide 1f involving a hetero-
cyclic skeleton such as indoline (run 6). In addition, it was found
that a cyano group on the benzene ring, which is sensitive to a
common reducing reagent, such as BH3 and LiAlH4, is tolerant of
our reducing system (run 7). Similarly, aliphatic groups, such as a
t-butyl group and a cyclopropane ring, on the carbonyl group did
not influence the reducing system (runs 10 and 11).9 Interestingly,
for an aliphatic amide having a benzyl moiety or a benzene ring
somewhere in the substrate, although the reduction of the ali-
phatic amide required quite long reaction times to complete, the
corresponding amines 2l,m were obtained in relatively good yields
(runs 12 and 13). It was found that a bromide substituent on the
benzene ring would not reduce with the present reducing agent.
In contrast, the use of the aliphatic amide without a benzene ring
gave the aliphatic amine derivatives 2n,o in low yields with the
recovery of the starting materials after 72 h (runs 14 and 15).
On attempted reaction of N-methyl-N-phenylformamide (3),
the expected N,N-dimethylaniline (4) was obtained in 47% yield
with 23% yield of unexpected dimerized product 5 (Scheme 1).10
To extend the application of the present reducing agent, the
reaction using a secondary amide was examined under our stan-
dard conditions (Scheme 2). Thus far, success in the reduction of
a secondary amide using a silane has been limited to several tran-
sition-metal complexes besides a highly reactive reducing reagent,
such as aluminum and boron hydrides.5d,5g,5h Thus, when reduc-
tion using acetanilide (6a) and benzanilide (6b), which was derived
from aniline, was performed with the InBr3–Et3SiH reducing
system, the expected reaction proceeded to produce N-ethyl-
anilne (7a) and N-benzylaniline (7b) in 45% and 72% yields,
respectively.11
Ph
NEt2
Ph
NEt2
N
O
H
H
Ph
N
Ph
O
H
H
Ph
N
Ph
N
O
H
O
O
H
Ph
Ph
5
20
(2e)
86
N
N
N
N
6
7
20
20
(2f)
81
85
H
O
H
Bn
N
Bn
N
(2g)
H
CN
H
O
CN
N
H
N
8
9
15
15
(2h)
(2i)
81
80
Ph
H
O
N
N
H
H
O
N
N
10
11
12
30
(2j)
84
56
Ph
Ph
H
H
H
O
O
N
N
(2k)
Ph
Ph
Br
H
Br
12
72
(2l)
65
For the reaction mechanism of the present reducing system, we
assume that the reduction proceeds via the following path shown
in Scheme 3: (i) first, hydroindation of a starting amide with HInBr2
and an exchange reaction of the formed indium intermediate with
Et3SiBr consecutively occur to generate an N,O-acetal intermedi-
ate;12 (ii) the intermediate further transforms to an iminium
(imine) intermediate through InBr3-promoted desioxylation; and
(iii) reduction of the iminium ion occurs, finally leading to the
corresponding amine with regeneration of InBr3. In addition, no
ring-opening product was obtained during the reduction of an
amide having a cyclopropane ring (run 11 in Table 1),13 and neither
was there a corresponding ring product from a substrate having a
cyano group through 5-exo-zig cyclization (run 7 in Table 1).14
These results strongly imply that the reduction proceeds via not
a radical path, but an ionic mechanism.
Et2N
N
H
Et2N
N
O
H
Ph
Ph
O
13
14
48
72
(2m)
(2n)
73
34
H
H
N
N
H
H
H
O
O
H
15
72
(2o)
27
NEt2
NEt2
a
Isolated yield.

N. Sakai et al. / Tetrahedron Letters 49 (2008) 6873–6875
6875
References and notes
N
4: 47%
5: 23%
5% InBr3
Et3SiH (4 equiv)
N
H
1. (a) Encyclopedia of the Alkaloids; Glasby, J. S., Ed.; Plenum Press: New York,
1975; (b) Handbook of Reagents for Organic Synthesis Oxidizing and Reducing
Agents; Burke, S. D., Danheiser, R. L., Eds.; Wiley & Sons Ltd: West Sussex, 1999;
(c) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18.
+
CHCl3
60 oC, 12 h
O
CH2
N
3
2. (a) Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1948, 70, 3738; (b) Morrison,
A. L.; Long, R. F.; Königstein, M. J. Chem. Soc. 1951, 952; (c) Stoll, A.; Hofmann,
A.; Petrzilka, T. Helv. Chim. Acta 1951, 34, 1544; (d) Micovic, V.; Mihailovic, M. J.
Org. Chem. 1953, 18, 1190; (e) Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50,
2443; (f) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita, M.; Abe, R. J.
Org. Chem. 1991, 56, 5263.
3. (a) Brown, H. C.; Rao, B. C. S. J. Am. Chem. Soc. 1960, 82, 681; (b) Brown, H. C.;
Heim, P. J. Am. Chem. Soc. 1964, 86, 3566; (c) Brown, H. C.; Yoon, N. M. J. Am.
Chem. Soc. 1966, 88, 1464; (d) Kornet, M. J.; Thio, P. A.; Tan, S. I. J. Org. Chem.
1968, 33, 3637.
4. (a) Borch, R. F. Tetrahedron Lett. 1968, 9, 61; (b) Satoh, T.; Suzuki, S.; Suzuki, Y.;
Miyaji, Y.; Imai, Z. Tetrahedron Lett. 1969, 10, 4555; (c) Umino, N.; Iwakuma, T.;
Itoh, N. Tetrahedron Lett. 1976, 17, 763; (d) Kano, S.; Tanaka, Y.; Sugino, E.;
Hibino, S. Synthesis 1980, 695; (e) Mataloni, M.; Petrini, M.; Profeta, R. Synlett
2003, 1129.
2
Scheme 1.
5% InBr3
Et3SiH (4 equiv)
CHCl3, 60 oC, 20 h
O
H
H
R
N
R
N
H
H
6a: R = Me
6b: R = Ph
7a: 45%
7b: 72%
Scheme 2.
5. (a) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; García Ruano, J. L.
Tetrahedron Lett. 1994, 35, 2053; (b) Bower, S.; Kreutzer, K. A.; Buchwald, S. L.
Angew. Chem. Int. Ed. 1996, 35, 1515; (c) Kuwano, R.; Takahashi, M.; Ito, Y.
Tetrahedron Lett. 1998, 39, 1017; (d) Igarashi, M.; Fuchikami, T. Tetrahedron Lett.
2001, 42, 1945; (e) Matsubara, K.; Iura, T.; Maki, T.; Nagashima, H. J. Org. Chem.
2002, 67, 4985; (f) Motoyama, Y.; Mitsui, K.; Ishida, T.; Nagashima, H. J. Am.
Chem. Soc. 2005, 127, 13150; (g) Ohta, T.; Kamiya, M.; Nobutomo, M.; Kusui, K.;
Furukawa, I. Bull. Chem. Soc. Jpn. 2005, 78, 1856; (h) Hanada, S.; Ishida, T.;
Motoyama, Y.; Nagashima, H. J. Org. Chem. 2007, 72, 7551.
6. (a) Miyai, T.; Ueba, M.; Baba, A. Synlett 1999, 182; (b) Yasuda, M.; Onishi, Y.;
Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66, 7741; (c) Yasuda, M.; Saito,
T.; Ueba, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 1414; (d) Miura, K.;
Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985; (e) Hayashi, N.; Shibata,
I.; Baba, A. Org. Lett. 2004, 6, 4981; (f) Miura, K.; Tomita, M.; Yamada, Y.;
Hosomi, A. J. Org. Chem. 2007, 72, 787.
InBr3 + Et3SiH
HInBr2 + Et3SiBr
O
C
R1
Et3SiBr
NR2
H
H
C
HInBr2
Et3SiH
InBr3
InBr2
NR2
R1
NR2
O
+
C
R1
Et3SiOSiEt3
H
Et3SiBr
InBr3
(i)
(iii)
HInBr2
+
7. Sakai, N.; Moriya, T.; Konakahara, T. J. Org. Chem. 2007, 72, 5920.
8. General procedure for reduction of amides to amines: To a CHCl3 solution (0.6 mL)
Et3SiBr
SiEt3
in a screw-capped vial under a N2 atmosphere, amide 1a (142 mg,
H
O
C
H
0.593 mmol), InBr3 (10.5 mg, 0.0300 mmol), and Et3SiH (380 mL, 2.40 mmol)
were successively added. During the stirring of the reaction mixture at 60 °C
(bath temperature), the solution turned from colorless to yellow, then to
orange. After the reaction, 1 N HCl aq (5 mL) was added to the resulting
mixture. The aqueous layer was basified with 1 N NaOH aq, and was extracted
with CH2Cl2 (5 mL Â 3). The combined organic layer was dried over anhydrous
Na2SO4, which was filtered, then evaporated under reduced pressure to give
tertiary amine 2a (120 mg, 90%), which is almost pure. Spectral data for
selected compound: dibenzylethylamine (2a); yellow oil; 1H NMR (500 MHz,
CDCl3): d = 1.06 (t, 3H, J = 7.0 Hz), 2.50 (q, 2H, J = 7.0 Hz), 3.56 (s, 4H), 7.22 (m,
2H), 7.30 (m, 4H), 7.37 (m, 4H); 13C NMR (125 MHz, CDCl3) d = 11.9, 47.1, 57.7,
126.7, 128.1, 128.7, 140.0; MS(FAB): m/z 226 (M++H, 100%).
R1 NR2
Et3SiO
(ii)
Br3In
R1
NR2
InBr3
+
Et3SiH
SiEt3
NR2
O
C
H
R1
Scheme 3. Plausible mechanism for reduction of amides.
9. Starting amide 1k was recovered in 37% yield.
In summary, we have developed a highly efficient reduction
procedure for the direct conversion of a variety of amides to the
corresponding tertiary and secondary amines. Also, we found that
the present reducing system can be applied to the reduction of a
secondary amide. The present method using the InBr3–Et3SiH sys-
tem provides a simpler and more convenient alternative to tradi-
tional methods.
10. We confirmed the formation of compound 5 in comparison with spectral data
of the identical compound, which was made via another route; however, we
have not been able to rationalize the formation of the side product. This result
implies the existence of another route for the reduction of formamide
derivatives. Spectral data for bis[4-(N,N-dimethylamino)phenyl]methane (5):
1H NMR (500 MHz, CDCl3) d 2.89 (s, 12H), 3.80 (s, 2H), 6.68 (d, 4H, J = 9.0 Hz),
7.05 (d, 4H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) d 39.9, 40.9, 113.0, 129.4,
130.3, 149.1; MS(FAB): m/z 255 (M++H).
11. Reduction with an N -alkylacetamide type of secondary amine did not proceed,
see Ref. 7.
12. Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004,
43, 711.
13. (a) Kochi, J. K.; Krusic, P. J.; Eaton, D. R. J. Am. Chem. Soc. 1969, 91, 1877; (b)
Kochi, J. K.; Krusic, P. J.; Eaton, D. R. J. Am. Chem. Soc. 1969, 91, 1879; (c) Griller,
D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317; (d) Kulicke, K. J.; Giese, B. Synlett
1990, 91.
14. For selected papers for intramolecular cyclization of a carbon radical onto a
cyano group, see: (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. Tetrahedron Lett.
2000, 41, 8989; (b) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.;
Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58.
Acknowledgments
This work was partially supported by a fund for the ‘High-Tech
Research Center’ Project for Private Universities: a matching fund
subsidy from MEXT, 2000–2004 and 2005–2007. The authors
thank Shin-Etsu Chemical Co., Ltd, for the gift of triethylsilane
(Et3SiH).