A convenient and general iron-catalyzed reduction of amides to amines

Article abstract of DOI:10.1002/anie.200904677

While the iron is hot: The first general and efficient iron-catalyzed reduction of secondary and tertiary amides into amines using polymethylhydrosiloxane (PMHS) has been developed (see scheme).

Full text of DOI:10.1002/anie.200904677

Angewandte
Chemie
DOI: 10.1002/anie.200904677
Homogeneous Catalysis
A Convenient and General Iron-Catalyzed Reduction of Amides to
Amines**
Shaolin Zhou, Kathrin Junge, Daniele Addis, Shoubhik Das, and Matthias Beller*
Amines constitute an important class of compounds in
chemistry and biology. They are widely used in the pharma-
ceutical industry for crop protection and natural product
synthesis, as well as for the preparation of advanced
materials.[1] Among the different procedures for their syn-
thesis, the reduction of amides is one of the most fundamental
methods. In general, reactive alkali metal hydrides or boron
hydrides are used for such reduction processes. However,
their air and moisture sensitivty, their low functional group
tolerance, and tedious purification procedures are draw-
backs.[2] Interestingly, Cole-Hamilton and co-workers showed
that catalytic hydrogenation of amides using molecular
hydrogen constitutes a highly attractive access to amines,
but the vigorous reaction conditions, that is, high pressures
and elevated temperature, limit this methodology.[3]
During the last decade, metal-catalyzed hydrosilylations
of amides have received considerable interest. Although
various catalyst systems including Rh,[4a–c] Ru,[4c–g] Pt,[4c,h]
Pd,[4c] Ir,[4c] Os,[4c] Re,[4c] Mn,[4c] Mo,[4i] In,[4j] and Ti[4k] have
proven to be effective for this reduction, the development of
cost-efficient and environmentally benign catalysts for this
transformation is still desirable. In addition, most of the
known catalyst systems either require expensive silanes or
have limited functional group tolerance.
During our recent studies on iron-catalyzed dehydrations
of primary amides in the presence of hydrosilanes,[5] we
isolated the corresponding secondary amine as a by-product.
Thus, our attention focused on this side-reaction of reducing
carboxamides to amines. The abundant availability of iron
makes it a highly attractive candidate for catalysis and a
“cheap metal for noble tasks”.[6,7] Herein we report the first
general iron-catalyzed hydrosilylation of amides to generate
amines. Initially, the reaction of N,N-dimethylbenzamide (1a)
with PhSiH3 in toluene was investigated as a model system to
identify and optimize critical reaction parameters (Table 1).
As expected the reaction did not occur in the absence of any
catalyst (Table 1, entry 1). In contrast, when using 2 mol% of
Table 1: Iron-catalyzed reduction of N,N-dimethylbenzamide.[a]
Entry Catalyst
(mol%)
Silane (equiv)
Solvent Yield[b] [%]
1
2
3
4
5
6
7
8
–
PhSiH3 (2)
PhSiH3 (2)
PhSiH3 (2)
PhSiH3 (2)
PhSiH3 (2)
PhSiH3 (2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0
9
[Fe2(CO)9] (3)
[Fe3(CO)12] (2)
Fe(OAc)2 (5)
[Fe(acac)2] (5)
[Fe(acac)3] (5)
[Fe(stearate)2] (5) PhSiH3 (2)
FeF2 (5)
Fe3O4 (5)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
[Fe3(CO)12] (2)
97
22
57
58
2
PhSiH3 (2)
PhSiH3 (2)
Me(EtO)2SiH (3.0)
Et3SiH (3.0)
(EtO)3SiH (3.0)
Et2MeSiH (3.0)
4
0
9
10
11
12
13
14
15
16
17
18
19
20[d]
14
18
20
18
30
99
93
89
60
90
37
TMSOSiMe2H (3.0) toluene
Ph2SiH2 (2.0)
PMHS (5.0)[c]
PMHS (4.0)
PMHS (3.0)
PMHS (4.0)
PMHS (4.0)
toluene
toluene
toluene
toluene
nBu2O
nBu2O
[a] Reaction conditions: 1a (1.0 mmol), catalyst (2–5 mol%), silanes,
solvent (2 mL), 8–24 h. [b] Determined by GC methods using hexade-
À
cane as an internal standard. [c] 1 mmol Si H=0.06 mL. [d] Run at
808C. acac=acetylacetonate, TMS=trimethylsilyl.
cheap [Fe3(CO)12], an excellent yield (97%) of N,N-dime-
thylbenzylamine (2a) was obtained (Table 1, entry 3). Other
iron sources, such as [Fe2(CO)9], Fe(OAc)2, [Fe(acac)2], and
[Fe(acac)3] are also reactive but resulted in lower product
yields (Table 1, entries 2 and 4–9).
Next, we investigated the influence of different silanes on
the reaction. To our delight the reduction also took place in
the presence of inexpensive polymethylhydrosiloxane
(PMHS) to give the desired product in 93% yield (Table 1,
entry 16).[8] Advantageously, this silane is also easily sepa-
rated from the reaction mixture. Additional studies revealed
that the reduction proceeded best in the presence of an excess
[*] S. Zhou, Dr. K. Junge, D. Addis, S. Das, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
À
of four equivalents of Si H (Table 1, entry 17). Among the
different solvents tested, toluene and di-n-butyl ether gave
the best results (Table 1, entries 17 and 19).
[**] This work has been funded by the State of Mecklenburg-Western
Pomerania, the BMBF, the DFG (Leibniz prize). We thank Dr. W.
Baumann, Dr. C. Fischer, S. Buchholz, S. Schareina, A. Kammer, A.
Koch, S. Rossmeisl, and K. Mevius (all at the LIKAT) for their
excellent technical and analytical support.
With respect to the mechanism, we propose that the iron-
catalyzed reduction of tertiary amides proceeds somewhat
similarly to the ruthenium-catalyzed procedure reported by
Nagashima and co-workers.[4e] Reaction of the hydrosilane
with the iron precursor should yield an activated species,[9,10]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904677.
Angew. Chem. Int. Ed. 2009, 48, 9507 –9510
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9507

Communications
which hydrosilylates the carbonyl group of the amide to
with the amide reduction giving the corresponding hetero-
cyclic amines in good to excellent yields (Table 2, entries 13,
14, 21, and 25). However, ketoamides gave a mixture of
products. Notably, the reaction is easily scaled up to
100 mmol: 15 g of 4b is obtained from 19 g (100 mmol) of
3b (Table 2, entry 27). Secondary amides are also reduced to
the corresponding amine in 99% yield by using PhSiH3 as a
hydrogen source (Table 2, entry 28).
generate the corresponding O-silylated N,O-acetal A. Inter-
mediate A is then transformed into an iminium species B.
Finally, B is reduced to the corresponding amine by reaction
with a second equivalent of the activated species (Scheme 1).
In summary, we have established the first iron-catalyzed
reduction of secondary and tertiary amides with inexpensive
PMHS. The new protocol proceeds with high selectivity and
exhibits a broad substrate scope and functional group
tolerance providing a variety of amines in good to excellent
yield. Direct catalytic hydrogenation does not occur under
these conditions.
Experimental Section
General procedure for the reduction of tertiary amides: A 25 mL
oven dried Schlenk tube containing a stir bar was charged with the
respective tertiary amides (1.0 mmol) and [Fe3(CO)12] (0.02–
0.1 mmol). PMHS (4.0–8.0 mmol) and dry toluene or Bu2O (5 mL)
was added respectively after purging the Schlenk tube with argon.
The mixture was stirred at 1008C for 1day. The cooled reaction
mixture was filtered through Celite and washed with diethyl ether.
The combined fractions were concentrated under reduced pressure.
The residue was purified by filtering through a short column of
neutral alumina or by silica gel column chromatography. The
combined fractions were concentrated under reduced pressure
giving the corresponding amine. Tribenzylamine (2b): neutral alu-
mina column [washed with ethyl acetate/n-hexane (1:10)], 89% yield,
white solid; 1H NMR (300.1 MHz, CDCl3): d = 3.48 (s, 6H), 7.11–7.17
(m, 3H), 7.20–7.26 (m, 6H), 7.32–7.35 ppm (m, 6H); 13C NMR
(75.5 MHz, CDCl3): d = 57.92, 126.83, 128.20, 128.72, 139.64 ppm.
ATR-IR (neat): n = 3102 (w), 3082 (w), 3061 (w), 3025 (w), 2932 (w),
2880 (w), 2836 (w), 2798 (w), 2749 (w), 2714 (w), 1601 (w), 1492 (m),
1449 (m), 1365 (m), 1307 (w), 1245 (m), 1205 (w), 1119 (m), 1070 (w),
1027 (m), 988 (m), 971 (m), 903 (w), 879 (w), 824 (w), 740 (s), 694 (s),
618 (w), 591 (w), 491 (m), 463 (w), 418 (w). MS (EI): m/z (rel. int.) 288
(7), 287 (31), 286 (7), 211 (6), 210 (38), 197 (4), 196 (26), 181 (5), 92
(13), 91 (100), 65 cmÀ1 (12). HRMS (EI, m/z) calcd. for C21H21N,
287.1669; found 287.1668.
Scheme 1. Proposed reaction mechanism.
Indeed, this mechanistic proposal is supported by the reaction
of 1 f with Ph2SiD2. Here, both deuterium atoms are
incorporated on the carbonyl carbon atom of [D2]2 f
[Eq. (1)]. Moreover, the reduction of the aldimine 5 pro-
ceeded in excellent yield to the corresponding amine 6
[Eq. (2)].
Received: August 22, 2009
Published online: September 25, 2009
Once the optimized reaction conditions were identified,
the scope and limitations of the iron-catalyzed reduction of
amides using PMHS were explored. A variety of amides,
including aromatic, aliphatic, heteroaromatic, and heterocy-
clic amides were reduced smoothly to the corresponding
amines (Table 2). Arenes substituted with electron-donating
or electron-withdrawing groups at either the para or meta
position gave the desired products (Table 2, entries 2, 3, 5–10,
and 27). In contrast, the system is more sensitive to steric
hindrance on both the carbonyl (Table 2, entries 4, 16, and 17)
and the amine side (Table 2, entries, 1, 20–23, 26, and 27).
Here, more catalyst and PMHS are needed to achieve full
conversion. Notably, a broad range of functional groups
including halide, ether, ester, cyclopropane, and alkene
groups (Table 2, entries 5–10, 16, and 18) are well-tolerated
by the catalyst. In addition, heteroarenes as well as hetero-
cyclic compounds such as 1n, 1o, 1v, and 1z do not interfere
Keywords: amides · amines · homogeneous catalysis · iron ·
reduction
.
[1] A. Ricci, Modern Amination Methods, Wiley, New York, 2000.
[2] J. Seyden-Penne, Reductions by the Alumino and Borohydrides
in Organic Synthesis, 2nd ed., Wiley, New York, 1997.
[3] A. A. Nfflæez Magro, G. R. Eastham, D. J. Cole-Hamilton, Chem.
Commun. 2007, 3154 – 3156.
[4] a) T. Ohta, M. Kamiya, M. Nobutomo, K. Kusui, I. Furukawa,
Bull. Chem. Soc. Jpn. 2005, 78, 1856 – 1861; b) R. Kuwano, M.
Takahashi, Y. Ito, Tetrahedron Lett. 1998, 39, 1017 – 1020; c) M.
Igarashi, T. Fuchikami, Tetrahedron Lett. 2001, 42, 1945 – 1947;
d) H. Motoyama, K. Mitsui, T. Ishida, H. Nagashima, J. Am.
Chem. Soc. 2005, 127, 13150 – 13151; e) S. Hanada, T. Ishida, Y.
Motoyama, H. Nagashima, J. Org. Chem. 2007, 72, 7551 – 7559;
f) K. Matsubara, T. Iura, T. Maki, H. Nagashima, J. Org. Chem.
2002, 67, 4985 – 4988; g) H. Sasakuma, Y. Motoyama, H.
9508 www.angewandte.org
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Table 2: [Fe3(CO)12]-catalyzed reduction of amides to amines.[a]
Entry
Amide
Cat. [%] Silane
(equiv)
Yield[b] [%]
Entry Amide
Cat. [%] Silane
(equiv)
Yield[b] [%]
1
1b
1c
1d
1e
1 f
1g
1h
1i
4
4
4
8
4
4
4
4
4
4
PMHS (4) 89 (2b)
15[c]
16
1p
1q
1r
4
6
PMHS (4) 89 (2p)
PMHS (6) 82 (2q)
PMHS (8) 98 (2r)
PMHS (4) 76 (2s)
PMHS (4) 63 (2t)
PMHS (4) 94 (2u)
PMHS (4) 80 (2v)
PMHS (8) 59 (2w)
PMHS (4) 81 (2x)
PMHS (4) 50 (2y)
2
PMHS (4) 93 (2c)
3
PMHS (4) 93 (2d)
PMHS (6) 94 (2e)
PMHS (4) 93 (2 f)
PMHS (4) 84 (2g)
PMHS (4) 95 (2h)
PMHS (4) 92 (2i)
PMHS (4) 83 (2j)
PMHS (4) 58 (2k)
17
8
4
18[c]
19[c]
20
1s
1t
4
5
4
6
1u
1v
1w
1x
1y
3
7
21
3
8
22
10
4
9[d]
1j
23
10[c]
1k
24
4
11
12
13
1l
4
4
PMHS (4) 77 (2l)
PMHS (4) 84 (2m)
PMHS (8) 82 (2n)
25[c]
26[c]
27[c,e]
1z
3a
3b
10
3
PMHS (8) 61 (2z)
PMHS (4) 90 (4a)
1m
1n
10
2
PMHS (4) 85 (4b)
PhSiH3
(2.5)
PMHS
(6.0)
4
4
99[f] (4c)
25[f] (4c)
14
1o
10
PMHS (8) 84 (2o)
28[c]
3c
[a] Reaction conditions: Amide (1 mol), [Fe3(CO)12] (2–10 mol%), PMHS (4–8 mmol), nBu2O (5 mL), 1008C, 24 h. [b] Yield of isolated product.
[c] Toluene as solvent. [d] Contained 10% tribenzylamine. [e] Run on 100 mmol scale. [f] Yield determined by GC methods.
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Communications
Nagashima, Chem. Commun. 2007, 4916 – 4918; h) S. Hanada, Y.
J. Kischel, A. Zapf, M. Beller, Angew. Chem. 2005, 117, 3981 –
3985; Angew. Chem. Int. Ed. 2005, 44, 3913 – 3917; e) K. M.
Driller, H. Klein, R Jackstell, M. Beller, Angew. Chem. 2009,
121, 6157 – 6160; Angew. Chem. Int. Ed. 2009, 48, 6041 – 6044.
[8] An excellent review about PMHS, see N. J. Lawrence, M. D.
Drew, S. M. Bushell, J. Chem. Soc. Perkin Trans. 1 1999, 3381 –
3391.
Motoyama, H. Nagashima, Tetrahedron Lett. 2006, 47, 6173 –
6177; i) A. C Fernandes, C. C. Rom¼o, J. Mol. Catal. A 2007, 272,
60 – 63; j) N. Sakai, K. Fuhji, T. Konakahara, Tetrahedron Lett.
2008, 49, 6873 – 6875; k) K. Selvakumar, J. F. Harrod, Angew.
Chem. 2001, 113, 2187 – 2189; Angew. Chem. Int. Ed. 2001, 40,
2129 – 2131.
[5] a) S. Zhou, D. Addis, K. Junge, S. Das, M. Beller, Chem.
Commun. 2009, 4883 – 4885; b) S. Zhou, K. Junge, D. Addis, S.
Das, M. Beller, Org. Lett. 2009, 11, 2461 – 2464.
[6] For reviews see: a) C. Bolm, J. Legros, J. L. Paith, L. Zani, Chem.
Rev. 2004, 104, 6217 – 6254; b) S. Enthaler, K. Junge, M. Beller,
Angew. Chem. 2008, 120, 3363 – 3367; Angew. Chem. Int. Ed.
2008, 47, 3317 – 3321; c) A. Correa, O. G. Mancheæo, C. Bolm,
Chem. Soc. Rev. 2008, 37, 1108 – 1117; d) B. D. Sherry, A.
Fürstner, Acc. Chem. Res. 2008, 41, 1500 – 1511.
[7] Selected reports on iron-catalyzed reductions and carbonyla-
tions from our group: a) S. Enthaler, G. Erre, M. K. Tse, K.
Junge, M. Beller, Tetrahedron Lett. 2006, 47, 8095 – 8099; b) S.
Enthaler, B. Hagemann, G. Erre, K. Junge, M. Beller, Chem.
Asian J. 2006, 1, 598 – 604; c) J. Kischel, I. Jovel, K. Mertins, A.
Zapf, M. Beller, Org. Lett. 2006, 8, 19 – 22; d) I. Iovel, K. Mertins,
[9] Formation of iron silyl compounds, see review J. Y. Corey, J.
Braddock-Wilking, Chem. Rev. 1999, 99, 175 – 292.
[10] For iron-catalyzed hydrosilylations, see: a) N. S. Shaikh, S.
Enthaler, K. Junge, M. Beller, Angew. Chem. 2008, 120, 2531 –
2535; Angew. Chem. Int. Ed. 2008, 47, 2497 – 2501; b) N. S.
Shaikh, K. Junge, M. Beller, Org. Lett. 2007, 9, 5429 – 5432;
c) A. M. Tondreau, E. Lobkovsky, P. J. Chirik, Org. Lett. 2008,
10, 2789 – 2792; d) H. Nishiyama, A. Furuta, Chem. Commun.
2007, 760 – 762; e) A. Furuta, H. Nishiyama, Tetrahedron Lett.
2008, 49, 110 – 113; f) A. M. Tondreau, J. M. Darmon, B. M.
Wile, S. K. Floyd, E. Lobkovsky, P. J. Chirik, Organometallics
2009, 28, 3928 – 3940; g) B. K. Langlotz, H. Wadepohl, L. H.
Gade, Angew. Chem. 2008, 120, 4748 – 4752; Angew. Chem. Int.
Ed. 2008, 47, 4670 – 4674.
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