Amide activation by Tf2O: Reduction of amides to amines by NaBH4 under mild conditions

Article abstract of DOI:10.1055/s-0030-1258111

An expeditious and practical method for the reduction of amides to amines is reported. The method is consisted of activation of amides with Tf ₂O followed by reduction with sodium borohydride in THF at room temperature. Various amides/lactams gave the corresponding amines in good to excellent yields, even with hindered amides and secondary amides. This method also presents other advantages such as TBDPS-group tolerance, short reaction time, simple workup and purification procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258111

LETTER
1829
Amide Activation by Tf2O: Reduction of Amides to Amines by NaBH4 under
Mild Conditions
Amide
Activa
h
O
2 ao-Hua Xiang,a Jian Xu,a Hong-Qiu Yuan,a Pei-Qiang Huang*a,b
a
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
Fax +86(592)2186400; E-mail: pqhuang@xmu.edu.cn
b
The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Received 7 April 2010
30 minutes, and to the resultant activated intermediate
was added a reducing agent. However, no reduction reac-
tion occurred neither with triethylsilane (TES) (r.t. or re-
flux), Ph3SiH, H2 and Pd/C, nor NaBH4 in CH2Cl2
Abstract: An expeditious and practical method for the reduction of
amides to amines is reported. The method is consisted of activation
of amides with Tf2O followed by reduction with sodium borohy-
dride in THF at room temperature. Various amides/lactams gave the
corresponding amines in good to excellent yields, even with hin- (Table 1). The reaction with NaBH4 in ethanol at room
dered amides and secondary amides. This method also presents oth-
er advantages such as TBDPS-group tolerance, short reaction time,
simple workup and purification procedure.
temperature gave, after workup, the desired pyrrolidine 2
in 37% yield, alongside with the recovered starting mate-
rial 1 in 38% yield. Similar reaction in methanol at room
Key words: reduction, amides, amines, amide activation, triflic an-
temperature gave pyrrolidine 2 in 20% yield, along with
hydride
the recovered starting material 1 in 75% yield.
Table 1 Attempted Tf2O-Activated Reduction of Lactam 1 under a
Variety of Conditions
Amines are of great medicinal interest and are an impor-
tant class of compounds in chemistry.1 The direct reduc-
Tf2O, CH2Cl2
0–5 °C
tion of amides constitutes one of the main entries to
O
N
N
amines.2 Lithium aluminum hydride (LAH)3 and diborane
or borane complex4 are, among others,5 the most widely
used reducing agents for amides reduction. The draw-
backs of the reduction with LAH are the harsh conditions
required for the reduction that renders the method low
functionality tolerance,6 difficulties in the reduction of
secondary amides, and side reactions such as C–N bond
cleavage with hindered tertiary amides.7 In addition, diffi-
culties are often encountered in the isolation of the prod-
uct from the reaction mixture with these reducing agents
due to formation of complex with the resultant amines.8
Recently, transition-metal-complex-catalyzed organosi-
lane reductions have emerged as attractive alternatives for
amides reduction.9,10 More recently, Charette and co-
workers reported a highly chemoselective metal-free
method for the reduction of tertiary amides via Tf2O
activation11 and Hantzsch ester (HEH) reduction.12 In
connection with a recent work on the sequential reductive
alkylation of amides via activation with Tf2O,13 we under-
took an investigation on Charette’s reduction aiming at
the substitution of HEH by more commonly used reducing
agents, and overcame the difficulty in the reduction of
hindered tertiary amides as well as the reduction of sec-
ondary amides. The results are reported herein.
reduction reagent
solvent, temp.
Bn
2
Bn
1
Entry Reducing reagent
Temp
r.t.
Result
n.r.
1
2
3
4
5
6
TES, CH2Cl2
TES, CH2Cl2
reflux
r.t.
n.r.a
n.r.
Ph3SiH, CH2Cl2
10% Pd/C, H2, CH2Cl2
NaBH4, CH2Cl2
NaBH4, EtOH
r.t.
n.r.
r.t.
n.r.a
r.t.
yield of 2: 37%
recovered 1: 38%
7
NaBH4, MeOH
r.t.
yield of 2: 20%
recovered 1: 75%
a Only a small amount of starting material consumed with complex
products formed as indicated by TLC.
On the basis of these preliminary trials, we next investi-
gated the reduction of amide with NaBH4 in THF. To our
satisfaction, the reduction of lactam 1 with 1.3 mol equiv-
alents of NaBH4 in THF at room temperature for one hour
afforded the desired pyrrolidine 2 in 75% yield.14 It was
observed that when 1.0 mol equivalent of NaBH4 was
used, the reaction was incomplete; while the use of 2.0 or
more mol equivalents of NaBH4 led to a borane complex
of the desired pyrrolidine 2, which required additional
steps to deliver the free pyrrolidine 2.15
N-Benzyl-2-pyrrolidone (1) was selected as a substrate for
our initial investigation. Thus, lactam 1 was treated with
Tf2O (1.1 mol equiv) in CH2Cl2 (0.1 M) in an ice bath for
SYNLETT 2010, No. 12, pp 1829–1832
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258111; Art ID: W05110ST
© Georg Thieme Verlag Stuttgart · New York

1830
S.-H. Xiang et al.
LETTER
Table 2 Tf2O-Activated Reduction of Amides/Lactams with
NaBH4 in THF (continued)
The reaction was then extended to a series of lactams and
amides and the results are summarized in Table 2. As can
be seen from Table 2, all reactions gave good to excellent
yields (Table 2, entries 1–12), even with hindered amides
(Table 2, entries 13–17). It should be noted that the reduc-
tion of hindered amides such as 1m–q by Tf2O–HEH gave
only less than 5% yield.12 Moreover, the reduction of sec-
ondary amides proceeded smoothly to give the desired
amines in 75% and 73% yields (entries 18 and 19). While
the reduction of (S)-pyroglutamate gave the fully reduced
product prolinol (entry 20), the reduction of OTBDPS-
protected (S)-2-oxoprolinol afforded the corresponding
OTBDPS-protected (S)-prolinol in 70% yield (entry 21).
These results showed that the reducing system Tf2O–
NaBH4 is not only powerful for hindered amides, but also
offers some chemoselectivity, because TBDPS was
shown to be metal unstable in the reduction with LiAlH4.6
Reduction of chiral pyrrolidinone 1v16 gave pyrrolidine
2v (entry 22), which is an intermediate for the synthesis of
novel potential HIV protease inhibitors.17
O
H
1) Tf2O (1.1 equiv), CH2CI2
(H)
R2
(H)
R2
H
R3
0–5 °C, 30 min
N
R1
R3
N
R1
2) NaBH4 (1.3 equiv), THF
r.t., 1 h
Entry Amide 1
Amine 2
Isolated
yield (%)
O
O
N
7
80
81
N
O
2g
1g
Bn
Bn
N
8
Bn
N
Bn
O
2h
1h
OMe
Bn
OMe
Bn
N
9
79
84
80
72
87
74
83
91
Bn
N
Table 2 Tf2O-Activated Reduction of Amides/Lactams with
NaBH4 in THF
Bn
O
2i
1i
O
H
1) Tf2O (1.1 equiv), CH2CI2
0–5 °C, 30 min
(H)
R2
(H)
R2
H
R3
Bn
N
R1
R3
Bn
N
R1
2) NaBH4 (1.3 equiv), THF
r.t., 1 h
N
10
N
Bn
Bn
O
2j
Entry Amide 1
Amine 2
Isolated
yield (%)
1j
Cl
Bn
Cl
Bn
N
11
Bn
N
O
Bn
1
2
75
82
N
N
Bn
O
2k
Bn
1k
1a
2a
Bn
Bn
N
N
12
Bn
Bn
N
O
N
Bn
Cl
O
Cl
Bn
1l
2l
2b
1b
1c
N
N
13
3
80
N
N
Bn
O
O
2m
Bn
1m
1n
1o
2c
OMe
OMe
Bn
Bn
N
N
14
15
16
N
N
4
5
6
83
87
79
N
Bn
Bn
O
O
2d
2n
1d
Bn
N
Bn
N
N
Bn
Bn
O
O
O
O
2e
2o
1e
Bn
N
Cl
Cl
Bn
N
Bn
N
N
Bn
2f
1f
2p
1p
Synlett 2010, No. 12, 1829–1832 © Thieme Stuttgart · New York

LETTER
Amide Activation by Tf2O
1831
Table 2 Tf2O-Activated Reduction of Amides/Lactams with
BH3
NaBH4 in THF (continued)
OTf
OTf
H
O
Tf2O
NaBH4
R2
R2
O
R2
H
1) Tf2O (1.1 equiv), CH2CI2
0–5 °C, 30 min
N+
R1
R3
(H)
R2
N
R1
R3
(H)
R2
N
R1
R3
H
R3
TfO–
N
R1
R3
N
R1
2) NaBH4 (1.3 equiv), THF
r.t., 1 h
A
B
C
H
H
H
R3
NaBH4
R2
R2
Entry Amide 1
Amine 2
Isolated
yield (%)
N+
R3
N
R1
TfO–
R1
TfOBH3
D
E
Scheme 1 Plausible mechanism for the amide/lactam reduction via
activation with Tf2O
N
N
17
93
75
O
Cl
Cl
1q
1r
2q
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
H
H
N
N
18
O
Acknowledgment
2r
2s
The authors are grateful to the NSF of China (No. 20832005) and
the National Basic Research Program (973 Program) of China
(Grant No. 2010CB833200) for financial support.
O
19
20
21
73
69
70
N
N
H
H
1s
References and Notes
(1) (a) Ricci, M. A. Modern Amination Methods; Wiley: New
York, 2000. (b) Encyclopedia of the Alkaloids; Glasby, J. S.,
Ed.; Plenum Press: New York, 1975.
(2) (a) Handbook of Reagents for Organic Synthesis Oxidizing
and Reducing Agents; Burke, S. D.; Danheiser, R. L., Eds.;
Wiley and Sons: West Sussex, 1999. (b) Seyden-Penne, J.
Reductions by the Alumino and Borohydrides in Organic
Synthesis, 2nd ed.; Wiley: New York, 1997.
HOH2C
MeOOC
O
N
N
PMB
PMB
1t
2t
TBDPSO
TBDPSO
O
N
N
Bn
Bn
1u
2u
(3) Brown, H. C.; Weissman, P. M.; Yoon, N.-M. J. Am. Chem.
Soc. 1966, 88, 1458.
BnO
BnO
(4) (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.
(5) For reduction with other agents/systems, see: (a) DIBAL-
H: 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) 9-BBN: Collins, C. J.; Lanz, M.;
Singaram, B. Tetrahedron Lett. 1999, 40, 3673.
Ph
Ph
22
72
O
N
N
PMB
PMB
1v
2v
A plausible mechanism12 for the lactam/amide reduction
via activation with Tf2O is shown in Scheme 1. The reac-
tion of Tf2O with the carbonyl of amide A generates a
highly electrophilic iminium triflate intermediate B,
which reacts with NaBH4 to give N,O-acetal C. Then,
elimination of –OTf assisted by both the nitrogen lone pair
of electrons and BH3 complexation leads to the formation
of iminium ion D, which is trapped by a second hydride to
give amine E.
(e) LiH3BNMe2: Flaniken, J. M.; Collins, C. J.; Lanz, M.;
Singaram, B. Org. Lett. 1999, 1, 799.
(6) (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.
(7) Akamatsu, H.; Kusumoto, S.; Fukase, K. Tetrahedron Lett.
2002, 43, 8867.
(8) (a) Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912.
(b) Brown, H. C.; Choi, Y.-M.; Narasimhan, S. J. Org.
Chem. 1982, 47, 3153. (c) Hercouet, M. B.; Le Corre, M.
Synth. Commun. 1991, 21, 1579.
(9) For selected examples, see: (a) Motoyama, Y.; Mitsui, K.;
Ishida, T.; Nagashima, H. J. Am. Chem. Soc. 2005, 127,
13150. (b) Ohta, T.; Kamiya, M.; Nobutomo, M.; Kusui, K.;
Furukawa, I. Bull. Chem. Soc. Jpn. 2005, 78, 1856.
(c) Fernandes, A. C.; Romão, C. C. J. Mol. Catal. A: Chem.
2007, 272, 60. (d) Núňez Magro, A. A.; Eastham, G. R.;
To summarize, we have developed an expeditious method
for the reduction of amides and lactams with NaBH4 un-
der mild conditions. The method is not only efficient for
the reduction of hindered tertiary amides, but also works
well with secondary amides, which complements the
method of Charette. Comparing with the classical meth-
ods utilizing lithium aluminum hydride, diborane or bo-
rane complex as the reducing agents, this new method is
more efficient, milder, with simpler workup and purifica-
tion procedure.
Synlett 2010, No. 12, 1829–1832 © Thieme Stuttgart · New York

1832
S.-H. Xiang et al.
LETTER
Cole-Hamilton, D. J. Chem. Commun. 2007, 3154.
(e) Zhou, S.-L.; Junge, K.; Addis, D.; Das, S.; Beller, M.
Angew. Chem. Int. Ed. 2009, 48, 9507. (f) Sunada, Y.;
Kawakami, H.; Imaoka, T.; Motoyama, Y.; Nagashima, H.
Angew. Chem. Int. Ed. 2009, 48, 9511. (g) Hanada, S.;
Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem.
Soc. 2009, 131, 15032; and references cited therein.
General Procedure for the Preparation of Amines from
Amides
To a solution of an amide (1.0 mmol) in anhyd CH2Cl2 (10
mL) was added Tf2O (1.1 mmol) in an ice bath. After stirring
for 30 min, NaBH4 (1.3 mmol) was added in one portion, and
THF (5 mL) was added dropwise. After stirring for 60 min
at r.t., the reaction was quenched with H2O (5 mL). The
solution was brought to pH 10.5–11.0 by addition of a sat. aq
Na2CO3 solution at 0 °C. The cooled aqueous solution was
extracted with Et2O (5 × 15 mL). The combined organic
layers were washed with brine (5 mL), dried over anhyd
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica
gel to give the corresponding amine (yields 69–93%). All
new compound gave satisfactory spectral and analytical data
(see Supporting Information).
(10) For two mild Lewis acid catalyzed amide reduction methods,
see: (a) InBr3, TES: Sakai, N.; Fujii, K.; Konakahara, T.
Tetrahedron Lett. 2008, 49, 6873. (b) Zn(OAc)2, silanes:
Das, S.; Addis, D.; Zhou, S.-L.; Junge, K.; Beller, M. J. Am.
Chem. Soc. 2010, 132, 1770.
–
(11) For other methods of amides activation, see: (a) Et3O+BF4 :
Borch, R. F. Tetrahedron Lett. 1968, 1, 61. (b) POCl3/PCl5:
Atta-ur-Rahman, A. B.; Ahmed, S. Tetrahedron Lett. 1976,
3, 219. (c) POCl3: Kuehne, M. E.; Shannon, P. J. J. Org.
Chem. 1977, 42, 2082.
(15) (a) Bisseret, P.; Bouix-Peter, C.; Jacques, O.; Henriot, S.;
Eustache, J. Org. Lett. 1999, 1, 1181. (b) Hall, D. G.;
Laplante, C.; Manku, S.; Nagendran, J. J. Org. Chem. 1999,
64, 698.
(12) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18.
(13) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q.
Angew. Chem. Int. Ed. 2010, 49, 3037.
(14) All new compounds gave satisfactory analytical and spectral
(16) Xiang, S.-H.; Yuan, H.-Q.; Huang, P.-Q. Tetrahedron:
Asymmetry 2009, 20, 2021.
data.
(17) (a) Courcambeck, J.; Bihel, F.; Michelis, C.; Quelever, G.;
Kraus, J. L. J. Chem. Soc., Perkin Trans. 1 2001, 1421.
(b) Huang, P.-Q.; Deng, J. Synlett 2004, 247.
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