Direct transformation of secondary amides into secondary amines: Triflic anhydride activated reductive alkylation

Article abstract of DOI:10.1002/anie.201204098

Versatile and mild: The first general method for the title transformation has been developed (see scheme; 2-F-Py=2-fluoropyridine; Tf=trifluorosulfonyl). The amines are synthesized in good yields and the ketimine intermediates can be isolated before the r

Full text of DOI:10.1002/anie.201204098

Angewandte
Chemie
DOI: 10.1002/anie.201204098
Synthetic Methods
Direct Transformation of Secondary Amides into Secondary Amines:
Triflic Anhydride Activated Reductive Alkylation**
Kai-Jiong Xiao, Ai-E Wang, and Pei-Qiang Huang*
Amines are an important class of compounds that constitute
the major body of bioactive natural products (alkaloids) and
pharmaceuticals.[1] Amides are a class of easily available and
highly stable compounds.[2] Consequently, the synthesis of
amines by reductive alkylation of amides is of high relevance
in organic synthesis,[3] and has been the focus of recent
research.[4–6] The transformation of tertiary amides into
amines has been achieved by indirect methods via thio-
amides.[4] Very recently, the direct transformation of tertiary
amides into amines by reductive alkylation has been
reported.[5,6] However, although the reductive mono- or di-
allylation of secondary lactams/amides[7,8] has been reported,
a general method for the synthesis of secondary amines, with
a variety of substituent patterns, has not yet been described.
a one-pot synthesis of secondary amines by the reductive
alkylation of secondary amides with organocerium
reagents[11,12] using trifluoromethanesulfonic anhydride
(Tf2O)[13,14] as the activation reagent (Scheme 2).
Scheme 2. One-pot transformation of secondary amides into secon-
dary amines.
In addition, the secondary amide also serves as a powerful
The conversion of N-cyclohexylbenzamide 1a into amine
2a was chosen as a prototype reaction (Table 1). A CH2Cl2
solution of amide 1a and 2-fluoropyridine[13j] (2-F-Py,
1.2 equiv) was successively treated with 1.1 molar equivalents
of Tf2O (À788C, then 08C), 3.0 molar equivalents of RM/
[9]
À
directing group in C H activation. Consequently, the
development of a general and direct method for the trans-
formation of secondary amides into secondary amines is
highly desirable in synthetic organic chemistry.
As a continuation of our endeavour to develop step-
economical syntheses,[10] we recently reported a direct method
for the reductive alkylation of lactams/amides with Grignard
and organolithium reagents (Scheme 1).[5] Herein, we report
Table 1: Influence of the reducing agent on the reductive alkylation of
secondary amides.
Entry
Reductant [H]
Equiv
Yield[%][a]
1
2
3
4
5
Et3SiH
LiAlH4
NaBH4
NaBH4, MeOH
NaBH4, MeOH
3.0
3.0
3.0
3.0
2.0
no product
86
75
87
88
Scheme 1. One-pot transformation of tertiary amides into amines.
Tf2O=trifluoromethanesulfonic anhydride; DTBMP=2,6-di-tert-butyl-4-
methylpyridine.
[a] Yield of the isolated product. 2-F-Py=2-fluoropyridine; cHex=cyclo-
hexyl.
[*] K.-J. Xiao, Dr. A.-E Wang, Prof. Dr. P.-Q. Huang
Department of Chemistry and
CeCl3 (À788C), and a reducing agent. It was found that
triethylsilane was inactive in this reaction (Table 1, entry 1),
while lithium aluminum hydride (Table 1, entry 2) and
sodium borohydride (Table 1, entry 3) worked well to provide
the desired amine in good yield. NaBH4 was selected as the
reducing agent as it is cheaper, less hazardous, and more
easily handled than LiAlH4. Moreover, the addition of
methanol was found to accelerate the reaction (Table 1,
entries 4 and 5). Thus, the optimized protocol for the direct
conversion of secondary amides into amines was identified as
successive treatment of a dichloromethane solution of amide
and 2-fluoropyridine (1.2 equiv) with 1.1 molar equivalents of
Tf2O (À788C, then 08C), and 3.0 molar equivalents of RM/
Fujian Provincial Key Laboratory for Chemical Biology
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen, Fujian 361005 (P.R. China)
E-mail: pqhuang@xmu.edu.cn
[**] The authors are grateful to the National Basic Research Program
(973 Program) of China (Grant No. 2010CB833200), the NSF of
China (21072160; 20832005), and the Fundamental Research Funds
for the Central Universities of China (Grant No. 201112G001)for
financial support, and for a Scholarship Award for Excellent
Doctoral Student granted by Ministry of Education of China (2010).
We are grateful to Prof. Dr. G. M. Blackburn for valuable discussions
and to Y.-H. for the preparation of some starting materials.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204098.
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CeCl3 (À788C), followed by reduction with 2.0 molar equiv-
alents of NaBH4 in methanol.
Under these optimized reaction conditions, the scope of
this transformation was studied. As can be seen from Table 2,
a variety of secondary amides, including aroyl (Table 2,
entries 1–12), alkanoyl (Table 2, entries 13–19), and alkenoyl
(Table 2, entry 20) amides, were transformed into the corre-
sponding secondary amines in good to excellent yields. The
substituents on the nitrogen atom of the secondary amides did
not have much influence on the reaction efficiency, regardless
Table 2: Direct transformation of secondary amides 1 into amines 2.
Entry
Substrate
RM
Product
Entry
11
Substrate
RM
Product
(Yield [%])[a]
(Yield [%])[a]
1
nBuLi
nBuMgBr
1a
2a (88)
1g
2j (84)
2
3
iPrMgBr
12
13
nBuMgBr
nBuMgBr
1a
1a
2b (84)
2c (82)
1h
1i
2k (79)
2l (89)
PhMgBr
4
14
nBuMgBr
1a
1b
1b
1c
2d (79)
2e (86)
2e (91)
2 f (85)
1j
1k
1l
2m (90)
2n (64)
2o (82)
2p (84)
5
6
7
nBuLi
15
16
17
nBuMgBr
nBuLi
nBuMgBr
nBuMgBr
BnMgBr
1l
8
nBuLi
18
nBuMgBr
1d
1e
1 f
2g (75)
2h (68)
2i (81)
1m
1n
1o
2q (76)
2r (81)
2s (75)
9
nBuLi
19
20
BnMgBr
10
nBuMgBr
nBuMgBr
[a] Reaction conditions: 1) amide (1.0 mmol), 2-fluoropyridine (1.2 mmol), Tf2O (1.1 mmol), CH2Cl2 (4 mL), À788C, then 08C, 10 min; 2) RM/
CeCl3 (3.0 mmol), À788C, 1 h; 3) NaBH4 (2.0 mmol), MeOH (5 mL), RT, 3 h. [b] Yield of the isolated product. Bn=benzyl.
2
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of their identity: n-alkyl (Table 2, entries 5–7, 11–13, 15, 18–
20), sec-alkyl (Table 2, Table 2, entries 1–4, 8–10, 16–17), or
aryl (Table 2, entry 14). The reaction also went smoothly with
hindered amides, such as 1m (Table 2, entry 18). Functional
groups such as an ether (Table 2, entry 9), an aromatic
bromide (Table 2, entry 10), thiophene (Table 2, entry 12),
Experimental Section
General procedure for the direct transformation of secondary amides
1 into secondary amines 2. Tf2O (185 mL, 1.1 mmol, 1.1 equiv) was
added dropwise to a cooled (À788C) solution of amide 1 (1.0 mmol,
1.0 equiv) and 2-fluoropyridine (103 mL, 1.2 mmol, 1.2 equiv) in
dichloromethane (4 mL). The reaction was warmed to 08C in an ice
bath and stirred for 10 min. The mixture was then cannulated into
freshly prepared organocerium reagent (3.0 mmol, 3.0 equiv) in THF
(15 mL) at À788C and stirred for 1 h. Methanol (5 mL) and sodium
borohydride (76 mg, 2.0 mmol) were added. The reaction mixture was
warmed to RT and stirred for 3 h. The reaction was quenched with
a saturated aqueous NaHCO3 solution and extracted with dichloro-
methane (3 ꢀ 10 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chroma-
tography on silica gel (eluting with 5–10% ethyl acetate in n-hexane)
to afford the desired amine 2.
=
a terminal C C double bond (Table 2, entry 19), and a con-
=
jugated C C double bond (Table 2, entry 20) were well
tolerated. It should be noted that the reaction of a,b-
unsaturated amides led to a highly selective 1,2-addition
(Table 2, entry 20).
With regard to the organocerium reagents, alkyl (Table 2,
entries 1, 2, 5–16, 18, 20), benzyl (Table 2, entries 17 and 19),
aryl (Table 2, entry 3), and alkynyl (Table 2, entry 4) cerium
reagents, generated from either organolithiums or Grignard
reagents, worked well for the direct conversion of secondary
amides into secondary amines.
A plausible mechanism for the direct transformation of
secondary amides 1 into secondary amines 2 is shown in
Scheme 3. The reaction may involve the formation of the
highly electrophilic nitrilium ion intermediate A[11] upon the
action of Tf2O/2-fluoropyridine (2-F-Py). Trapping of the
nitrilium ion A with an organocerium reagent (RM/CeCl3)
forms ketimine 3,[15] which upon further reduction gives the
corresponding secondary amine.
Received: May 26, 2012
Published online: && &&, &&&&
À
Keywords: amide activation · amines · C C bond formation ·
.
cerium · synthetic methods
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Scheme 3. Proposed reaction mechanism.
In summary, the first general method for the direct
transformation of secondary amides into secondary amines
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Supporting information for details).
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Synthetic Methods
K.-J. Xiao, A.-E Wang,
P.-Q. Huang*
&&&& — &&&&
Direct Transformation of Secondary
Amides into Secondary Amines: Triflic
Anhydride Activated Reductive Alkylation
Versatile and mild: The first general
method for the title transformation has
been developed (see scheme; 2-F-Py=2-
fluoropyridine; Tf=trifluorosulfonyl). The
amines are synthesized in good yields
and the ketimine intermediates can be
isolated before the reduction. This
method should find applications in the
synthesis of nitrogen-containing bio-
active molecules and medicinal agents.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!