Indium-catalyzed reduction of secondary amides with a hydrosiloxane leading to secondary amines

Article abstract of DOI:10.1016/j.tetlet.2015.09.148

Described herein is that the selective reduction of aromatic/aliphatic secondary amides using a combination of InI₃ and TMDS (1,1,3,3-tetramethyldisiloxane), which led to the production of the corresponding secondary amines. This reducing system showed a relatively high tolerance to a variety of functional groups, such as an alkyl, an alkoxy, a halogen, a cyano, an ether, a thioether, a heterocyclic ring, and a terminal alkene group.

Full text of DOI:10.1016/j.tetlet.2015.09.148

Accepted Manuscript
Indium-Catalyzed Reduction of Secondary Amides with a Hydrosiloxane Lead-
ing to Secondary Amines
Norio Sakai, Masashi Takeoka, Takayuki Kumaki, Hirotaka Asano, Takeo
Konakahara, Yohei Ogiwara
PII:
S0040-4039(15)30189-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.148
TETL 46820
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 July 2015
27 September 2015
30 September 2015
Please cite this article as: Sakai, N., Takeoka, M., Kumaki, T., Asano, H., Konakahara, T., Ogiwara, Y., Indium-
Catalyzed Reduction of Secondary Amides with a Hydrosiloxane Leading to Secondary Amines, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.148
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Indium-Catalyzed Reduction of Secondary
Amides with a Hydrosiloxane Leading to
Secondary Amines
Leave this area blank for abstract info.
Norio Sakai,* Masashi Takeoka, Takayuki Kumaki, Hirotaka Asano, Takeo Konakahara, and Yohei Ogiwara

1
Tetrahedron Letters
Indium-Catalyzed Reduction of Secondary Amides with a Hydrosiloxane
Leading to Secondary Amines
Norio Sakai,* Masashi Takeoka, Takayuki Kumaki, Hirotaka Asano, Takeo Konakahara, and Yohei
Ogiwara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Described herein is that the selective reduction of aromatic/aliphatic secondary amides using a
combination of InI3 and TMDS (1,1,3,3-tetramethyldisiloxane), which led to the production of
the corresponding secondary amines. This reducing system showed a relatively high tolerance to
a variety of functional groups, such as an alkyl, an alkoxy, a halogen, a cyano, an ether, a
thioether, a heterocyclic ring, and a terminal alkene group.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium
Hydrosiloxane
Secondary amide
Secondary amine
Reduction
1. Introduction
hydrosilylation of secondary amides, producing corresponding
secondary amines.7 Beller and co-workers found that
a
The approach to secondary amines through a catalytic
reduction of the corresponding secondary amides is a central and
important functional group transformation in organic synthesis,
because this transformation is a simple and straightforward
procedure in a laboratory-scale experiment, and the basic
frameworks of secondary amines are widely found in naturally
occurring products and biologically active substances.1
Traditionally, to achieve the reduction of a secondary amide with
one hydrogen on the nitrogen atom, the use of relatively strong
hydride reagents that are derived from group 13 metalloids or
metals, such as (BH3)2, BH3•THF, LiAlH4, and DIBAL, has been
required.2 However, these reagents directly influence undesirable
functional groups, which leads to the production of unnecessary
side-products, and produces large amounts of aluminum residue,
which makes it difficult to isolate the desired product. Thus, to
solve these problems, the combination of a transition metal
catalyst with an easier-handling and mild reducing reagent, a
hydrosilane has been recently utilized.3,4
combination of either Cu(OTf)2 or Zn(OTf)2 and TMDS, or a
combination of a heterocyclic boronic acid and PhSiH3 catalyzed
the reduction of secondary amides.8 Moreover, Brookhart
reported that an Ir(I) complex effectively catalyzed the
hydrosilylation of secondary amides.9 In this context, by using
the Hantzsch ester and triethylsilane, a metal-free reduction of
secondary amides has been developed.10 Quite recently, Cantat
and Adronov independently reported the B(C6F5)3-catalyzed
hydrosilylation of secondary amides.11
Compared with the catalytic reduction of tertiary amides with
a metal catalyst,5-7,12 that of secondary amides using a main group
catalyst has not been studied systematically with the exception of
examples using zinc and boron catalysts. We also found that a
reducing system consisting of an indium(III) compound and a
hydrosilane showed chemoselective activation to nitrogen-
containing functional groups, such as an amide and a nitro
group.13,14 However, for secondary amides, the substrate
employed under our reducing conditions (5 mol % of InBr3, 4
equiv (Si-H) of Et3SiH and CHCl3 reflux) was limited to two
examples (acetanilide and benzanilide), and the application of the
reducing system to secondary amides with a variety of functional
groups remained still unclear.13c Thus, after re-examinations of
the reaction conditions, we found that a novel reducing system
composed of InI3 and TMDS successfully promoted the selective
reduction of a variety of secondary amides, which led to the
production of the corresponding secondary amines. In this letter,
we report the results.
For example, Fuchikami reported that the reduction of
secondary amides with a hydrosilane was catalyzed by a Ru
complex either with or without EtI as a cocatalyst.5 Ohta
described the Rh(I)-catalyzed reduction of secondary amides, but
this catalytic system produced a mixture of secondary amines and
imines.6 Also, Nagashima et al. found that transition metal
complexes containing Ru or Pt, effectively catalyzed the
 Corresponding author. Tel.: +81-4-7122-1092; fax: +81-4-
7123-9890; e-mail: sakachem@rs.noda.tus.ac.jp (N. Sakai).

2
Tetrahedron Letters
2. Results and Discussion
Table 2. Reduction of benzanilide derivatives leading to N-
arylbenzylamine derivatives
On the basis of the results shown in an indium-catalyzed
deoxygenation of esters and tertiary amides in the presence of
triethylsilane,13c,d when reduction of benzanilide was initially
conducted with InBr3 (0.05 equiv) and Et3SiH (Si-H: 4 equiv)
under CHCl3 reflux conditions, the expected N-benzylaniline (1)
was obtained in only a 21% yield (entry 1 in Table 1). Therefore,
a solvent effect was then examined using several solvents
including THF, CH3CN and DMF, but these solvents showed no
effect for this reduction (entries 2-4). Among several
hydrosilanes examined, TMDS showed the highest reduction
effect (entries 5-9). The use of InCl3, In(OAc)3 and In(OTf)3
resulted in the recovery of the starting amide, but the use of InI3
caused an outstanding activation of the amide to produce the
secondary amine in a good yield (entries 10-13). Finally, two
conditions composed of InI3 and TMDS (Si-H: 6 equiv) in CHCl3
at 60 ˚C or in toluene at 100˚C gave the best result (entries 14
and 15).
Table 1. Examination of reaction conditions with an
secondary aromatic amide
a A complex mixture was formed.
Next, the reduction of secondary amides with some type of
substituent either on the benzoyl moiety or on both benzene rings
was examined (Table 3). With a substituent, such as a methyl or a
chloro group, the expected deoxygenation was smoothly
completed within 1 h to produce secondary amines 11 and 12 in
excellent yields. In sharp contrast to the result from compound 8,
the amide with a 4-methoxy substituted benzene ring next to the
carbonyl group did not undertake the reduction, resulting in the
formation of unidentified compounds without the recovery of the
starting amides.16 There was no clear reason for this result at this
stage, probably due to the low electrophilicity of the carbonyl
Entry
InX3
Hydrosilane
(Si-H: equiv)
Et3SiH (4)
Et3SiH (4)
Et3SiH (4)
Et3SiH (4)
PhSiH3 (4)
Me2PhSiH (4)
(EtO)3SiH (4)
PMHS (4)
TMDS (4)
TMDS (4)
TMDS (4)
TMDS (4)
TMDS (4)
TMDS (6)
TMDS (6)
Solvent
Yield
(%)a
21
1
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InCl3
In(OAc)3
In(OTf)3
InI3
CHCl3
THF
2
trace
trace
trace
23
3
CH3CN
DMF
4
5
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhMeb
6
24
7
trace
trace
40
Table 3. Reduction of various secondary amides leading to
secondary amines
8
9
10
11
12
13
14
15
trace
trace
trace
87
InI3
99 (60)c
InI3
(95)
a GC (Isolated) yield based on the sample after quenching with H2O. b Bath
temperature at 100 ˚C for 1 h. c TMDS (Si-H: 2 equiv).
Then, the scope and limitations to this reduction of secondary
amides that derived from benzoic acid and a variety of aniline
derivatives with the optimal conditions were examined (Table
2).15 In most amides with either electron-donating or electron-
withdrawing groups, such as a methyl group, a methoxy group
and halogens, on an aniline moiety, the expected reduction
proceeded smoothly to produce the corresponding secondary
amines 2-9 in good to excellent yields. Also, the location of a
substituent on the benzene ring had no direct effect on the
chemical yield. When the amide with a nitro group on the
benzene ring was treated with the InI3-TMDS system, the
consumption of the starting amide was observed, and finally
resulted in the formation of a complicating mixture.16
a Temp = 60 ˚C.

3
group. An iodide substituent on the benzene ring remained after
reduction, and the corresponding secondary amine 14 was
obtained in a good yield. On the other hand, unlike the result with
a B(C6F5)3-TMDS system,11b when the reaction was carried out
using an amide with a cyano group, the desired amine 15, in
which the cyano group remained after reduction, was produced in
a relatively good yield. As extension of the substrate, when using
the secondary amide with a furan ring, the reaction proceeded to
produce the corresponding amine 16 in a moderate yield. Four
types of amides with an electron-donating and/or electron-
withdrawing group on two benzene rings produced the
corresponding secondary amine derivatives 17-20 in good yields.
amine 27 in only a 25% isolated yield with the recovery of the
starting amide (eq 2 in Scheme 2). It seemed that the stability of
an imine intermediate with both aliphatic groups would be rather
lower than that of an imine with only one aromatic group, which
hinders the forward drive of the reaction.
Scheme 1. Application to the reduction of N-alkylated
secondary amides
Then, to show the utility of the reducing system, N-phenylated
secondary amides with an aliphatic group on the acyl group side
were reduced under optimal conditions, as summarized in Table
4. In most cases, the alkyl chain on the acyl moiety had no
influence on the chemical yield. Interestingly, a terminal alkene
moiety on the amide showed a high tolerance, and the expected
amine 22 was obtained. By contrast, the amide with a conjugated
double bond was totally reduced by this reducing system to
produce saturated secondary amine 21 without the expected
amine 23. The result agreed with the results from a B(C6F5)3-
TMDS system reported by Cantat et al.11a On the other hand, a
reductive conversion of the secondary amide with an ether
moiety was rather low, producing the amine 24 in a low yield.
When the reduction of the secondary amide with a thioether unit
was carried out, the corresponding amine 25 was produced in a
moderate yield.
We proposed a plausible reaction path for the reduction of
secondary amines as well as that suggested by a Fe3(CO)12-
catalyzed reduction of tertiary amides with a hydrosilane
(Scheme 2).12e First, hydrosilylation of an amide activated by InI3
occurs to give an N,O-acetal intermediate. Then, the generated
acetal would be converted to a thermodynamically stable imine
intermediate by liberation of a silanol. Finally, the imine is
reduced again by a further hydrosilane to produce the
corresponding secondary amine after a common work-up.
Table 4. Reduction of several N-arylated secondary amides
leading to secondary amines
Scheme 2. A plausible reaction path for the reduction of
secondary amides
3. Conclusions
We have demonstrated the direct conversion of a variety of
secondary amides to the corresponding secondary amines with an
InI3-TMDS reducing system, and have found that the present
reducing system tolerates a variety of functional groups: an alkyl,
a cyano, halogens, a heterocyclic ring, an ether chain, a sulfide
unit and a terminal alkene. Also, via an increase in the reaction
temperature the present method could be applied to the reduction
of N-alkylated secondary amide to a certain extent.
a GC yield. b Temp = 60 ˚C.
Moreover, to confirm whether this reducing system activates
an N-alkyl substituted amide or not, we attempted the reduction
of several secondary amides with an aliphatic substituent
(Scheme 1). Contrary to our expectations, under the toluene
reflux conditions, product 26 derived from N-benzylbenzamide
was obtained in a low yield (41%) and the recovery of the
starting amide. Thus, when the reaction temperature was raised to
the xylene reflux conditions (140 ˚C), this problem was
successfully solved, producing 26 in a 91% yield (eq 1 in Scheme
1).17 On the other hand, when the reaction of the N-alkylated
secondary amide, which was prepared from both an aliphatic
amine and acid chloride, was conducted with the InI3-TMDS
reducing system under the xylene reflux conditions, the
conversion of the amide was rather low to give the corresponding
Acknowledgments
This work was partially supported by a Grant-in-Aid for
Scientific Research (C) (No. 25410120) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
We deeply thank Shin-Etsu Chemical Co., Ltd., for the gift of
hydrosilanes.

4
Tetrahedron Letters
13. (a) Sakai, N.; Asama, S.; Anai, S.; Konakahara, T. Tetrahedron
References and notes
2014, 70, 2027-2033. (b) Sakai, N.; Fujii, K.; Nabeshima, S.;
Ikeda, R.; Konakahara, T. Chem. Commun. 2010, 46, 3173-3175.
(c) Sakai, N.; Fujii, K.; Konakahara, T. Tetrahedron Lett. 2008,
49, 6873-6875. (d) Sakai, N.; Moriya, T.; Konakahara, T. J. Org.
Chem. 2007, 72, 5920-5922.
1.
(a) Glasby, J. S. Encyclopedia of the Alkaloids, Plenum Press:
New York, 1975. (b) Suvire, F. D.; Sortino, M.; Kouznetsov, V.
V.; Vargas M, L. Y.; Zacchino, S. A.; Cruz, U. M.; Enriz, R. D.
Biorg. Med. Chem. 2006, 14, 1851-1862. (c) Yu, M. J.; McCowan,
J. R.; Phebus, L. A.; Towner, R. D.; Ho, P. P. K.; Keith, P. T.;
Luttman, C. A.; Saunders, R. D.; Ruterbories, K. J. J. Med. Chem.
1993, 36, 1262-1271.
14. For selected examples of an indium(III) compound has been
widely utilized for
a variety of reductive functional group
transformations with a hydrosilane: (a) Baba, A.; Shibata, I. Chem.
Rec. 2005, 5, 323-335. (b) Pehlivan, L.; Métay, E.; Delbrayelle,
D.; Mignani, G.; Lemaire, M. Eur. J. Org. Chem. 2012, 4689-
4693. (c) Tsuchimoto, T.; Wagatsuma, T.; Aoki, K.; Shimotori, J.
Org. Lett. 2009, 11, 2129-2132. (d) Miura, K.; Tomita, M.;
Yamada, Y.; Hosomi, A. J. Org. Chem. 2006, 72, 787-792. (e)
Miura, K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004,
1985-1989. (f) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J.
Am. Chem. Soc. 2002, 124, 13690-13691. (g) Yasuda, M.; Onishi,
Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66, 7741-
7744.
2.
3.
Larock, R. C. Comprehensive Organic Transformations, 2nd Ed.,
John Wiley & Sons; New York, 1999.
(a) Larson, G. L. Ionic and Organometallic-Catalyzed
Organosilane Reductions, John Wiley & Sons; New Jersey, 2010.
(b) Addis, D.; Das, S.; Junge, K.; Beller, M. Angew. Chem. Int.
Ed. 2011, 50, 6004-6011.
4.
For selected review of a metal-catalyzed reduction of amides with
H2, see: Werkmeister, S.; Junge, K.; Beller, M. Org. Process Res.
Dev. 2014, 18, 289-302.
15. General procedure for the indium-catalyzed reductive preparation
of secondary amines: To a 5 mL screw-capped vial containing a
freshly distilled toluene (0.6 mL) were successively added under
N2 secondary amide (0.6 mmol), InI3 (0.030 mmol, 15 mg) and
1,1,3,3-tetramethyldisiloxane (1.80 mmol, 318 L). After the vial
was sealed with a cap that contained a PTFE septum, the mixture
was stirred at 100 ˚C (bath temperature), and monitored by GC
analysis. After completion of the reaction, the reaction was
quenched with H2O. The aqueous layer was extracted with CHCl3
(6 mL x 3), the organic phases were dried over anhydrous Na2SO4,
filtered and evaporated under reduced pressure. The crude product
was purified by silica gel chromatography (hexane/AcOEt = 9/1)
to give the corresponding secondary amine. If necessary, the
5.
6.
7.
Igarashi, M.; Fuchikami, T. Tetrahedron Lett. 2001, 42, 1945-
1947.
Ohta, T.; Kamiya, M.; Nobutomo, M.; Kusui, K.; Furukawa, I.
Bull. Chem. Soc. Jpn. 2005, 78, 1856-1861.
For a quite recent review, see: (a) Nagashima, H. Synlett 2015, 26,
866-890. (b) Hanada, S.; Ishida, T.; Motoyama, Y.; Nagashima, H.
J. Org. Chem. 2007, 72, 7551-7559.
(a) Das, S.; Join, B.; Junge, K.; Beller, M. Chem. Commun. 2012,
48, 2683-2685. (b) Das, S.; Addis, D.; Junge, K.; Beller, M. Chem.
Eur. J. 2011, 17, 12186-12192. (c) Li, Y.; Molina de La Torre, J.
A.; Grabow, K.; Bentrup, U.; Junge, K.; Zhou, S.; Brückner, A.;
Beller, M. Angew. Chem. Int. Ed. 2013, 52, 11577-11580.
Cheng, C.; Brookhart, M. J. Am. Chem. Soc. 2012, 134, 11304-
11307.
8.
9.
isolated product was subjected to
a
gel permeation
chromatography with chloroform as an eluent. All secondary
amine prepared by this procedure were known compounds, and
the characterization was confirmed by NMR spectra shown in the
literature. For detailed procedure and spectra, see supporting
information.
10. Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc.
2010, 132, 12817-12819.
11. (a) Blondiaux, E.; Cantat, T. Chem. Commun. 2014, 50, 9349-
9352. (b) Chadwick, R. C.; Kardelis, V.; Lim, P.; Adronov, A. J.
Org. Chem. 2014, 79, 7728-7733.
16. See supporting information.
12. For selected papers of a metal-promoted reduction of tertiary
amides with a hydrosilane, see: (a) Kovalenko, O. O.; Volkov, A.;
Adolfsson, H. Org. Lett. 2015, 17, 446-449. (b) Bornschein, C.;
Lennox, A. J. J.; Werkmeister, S.; Junge, K.; Beller, M. Eur. J.
Org. Chem. 2015, 1915-1919. (c) Pisiewicz, S.; Junge, K.; Beller,
M. Eur. J. Inorg. Chem. 2014, 2345-2349. (d) Xie, W.; Zhao, M.;
Cui, C. Organometallics 2013, 32, 7440-7444. (e) Zhou, S.;
Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem. Int. Ed.
2009, 48, 9507-9510. (f) Barbe, G.; Charette, A. B. J. Am. Chem.
Soc. 2008, 130, 18-19. (g) Motoyama, Y.; Mitsui, K.; Ishida, T.;
Nagashima, H. J. Am. Chem. Soc. 2005, 127, 13150-13151. (h)
Matsubara, K.; Iura, T.; Maki, T.; Nagashima, H. J. Org. Chem.
2002, 67, 4985-4988. (i) Kuwano, R.; Takahashi, M.; Ito, Y.
Tetrahedron Lett. 1998, 39, 1017-1020. (j) Bower, S.; Kreutzer,
K. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1996, 35, 1515-
1516. (k) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M.
C.; García Ruano, J. L. Tetrahedron Lett. 1994, 35, 2053-2056.
17. Although Cantat's group reported the formation of dibenzylamine
from N-benzylbenzamide, Adronov et al confirmed no formation
of the same secondary amine under almost the same conditions.
Both opposite results confused us to discuss our result, see ref 11a
and 11b.
Supplementary Material
1
Copies of the H and 13C NMR spectra of the secondary
amines that were produced by this procedure were supplied.