Tert -Butyl nitrite promoted transamidation of secondary amides under metal and catalyst free conditions

Article abstract of DOI:10.1039/c8ob03010c

A mild and efficient method is demonstrated for the transamidation of secondary amides with various amines including primary, secondary, cyclic and acyclic amines in the presence of tert-butyl nitrite. The reaction proceeds through the N-nitrosamide intermediate and provides the transamidation products in good to excellent yields at room temperature. Moreover, the developed methodology does not require any catalyst or additives.

Full text of DOI:10.1039/c8ob03010c

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tert-Butyl nitrite promoted transamidation of
secondary amides under metal and catalyst free
Cite this: DOI: 10.1039/c8ob03010c
conditions†
Popuri Sureshbabu,‡ Sadaf Azeez,‡ Priyanka Chaudhary and
Jeyakumar Kandasamy
*
A mild and efficient method is demonstrated for the transamidation of secondary amides with various
amines including primary, secondary, cyclic and acyclic amines in the presence of tert-butyl nitrite. The
reaction proceeds through the N-nitrosamide intermediate and provides the transamidation products in
good to excellent yields at room temperature. Moreover, the developed methodology does not require
any catalyst or additives.
Received 3rd December 2018,
Accepted 2nd January 2019
DOI: 10.1039/c8ob03010c
rsc.li/obc
Amides are key functional groups that exist in many bio- reagent for the generation of N-nitrosamides in situ which can
molecules, natural products, drugs, etc. (Fig. 1).1 On the other be directly subjected to the transamidation process without
hand, amides are also employed as valuable precursors in isolation of the N-nitrosamide intermediate. In fact, such pro-
organic synthesis.2 Transamidation is an important reaction tocols will reduce not only the number of steps but also
that has received significant interest in recent years.3 Owing to tedious workup procedures. Moreover, it will be an alternative
the high stability of amide bonds, transamidation of secondary to N-Boc and N-tosyl amide mediated transamidation pro-
amides was considered to be a more challenging task in cesses. In this context, here we report an efficient, metal and
organic synthesis.3i–l In this context, Garg and coworkers devel- catalyst free method for the transamidation of secondary
oped a two-step process for the efficient transamidation of sec- amides using tert-butyl nitrite at room temperature
ondary amides under mild conditions.4 In the Garg method, (Scheme 1).
secondary amides are converted into non-planar N-Boc amides
The N-nitrosation of secondary amides has been achieved
in the first step and subjected to transamidation with different using different nitrosyl sources including NaNO2-HCl,8c nitro-
amines in the presence of nickel catalysts. Later, Szostak et al. gen oxide-NaOAc,8e,f nitrosyl chloride-KOAc,9 nitrosyl tetra-
demonstrated the activation of N-Boc and N-tosyl protected fluoroborate-pyridine,10 and tert-butyl nitrite.11 However, some
secondary amides using palladium catalysts.5 Moreover, of these reagents may not be suitable for the one-pot transami-
recently the Szostak group has also successfully demonstrated dation process. For example, the NaNO2-HCl system requires
the base promoted transamidation and esterification of N-Boc aqueous acidic conditions which may lead to different side
and N-tosyl amides under metal free conditions.6
reactions. On the other hand, nitrogen oxide and nitrosyl
N-Nitrosamines are valuable precursors in organic syn-
thesis.7 In contrast, the applications of N-nitrosamides are less
explored in synthetic organic chemistry.8 In 1983, Garcia et al.
reported that N-nitrosamides undergo transamidation efficien-
tly with different amines in the absence of any catalysts or
bases.8e,f However, this transamidation approach remained
unpopular in organic synthesis because the preparation, iso-
lation and handling of N-nitrosamides are quite difficult. In
this context, our aim was to identify a suitable nitrosating
Department of chemistry, Indian Institute of Technology (BHU), Varanasi,
Uttar Pradesh-221005, India. E-mail: jeyakumar.chy@iitbhu.ac.in
†Electronic supplementary information (ESI) available: NMR spectra are avail-
able for all the products. See DOI: 10.1039/c8ob03010c
Fig. 1 Some important natural products and drug molecules bearing
‡These authors contributed equally to this work.
amide bonds.
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presence and absence of pyridine. The maximum yield of
N-nitrosamide 1aa (i.e. 92%) was obtained in acetonitrile in
the presence of pyridine after 12 hours at room temperature
(Table 1, entry 3). However, the other conditions gave relatively
low yields of N-nitrosamide 1aa. Nevertheless, after 12 hours,
benzylamine (the external nucleophile) was added to the reac-
tion mixture containing N-nitrosamide and the reaction
mixture was allowed to stir for an additional 12 hours at room
temperature. The transamidation proceeded efficiently in di-
chloromethane in the absence of pyridine and gave the
desired product 3a in 54% yield (Table 1, entry 2). However,
only 20% yield of 3a was obtained in acetonitrile (Table 1,
Scheme 1 Transamidation of secondary amides in the presence of
TBN.
chloride are gases that are difficult to prepare and handle. In
this context, we have envisioned that nitrosyl tetrafluoroborate entry 1). It is surprising to note that the transamidation
process was significantly suppressed in the presence of pyri-
dine in both acetonitrile and dichloromethane solvents
(Table 1, entries 3 and 4).
or tert-butyl nitrite might be more appropriate for one-pot
transamidation reactions because these reagents are relatively
milder and also commercially available.
tert-Butyl nitrite (TBN) is an acid free nitrating and nitrosat-
ing reagent used in many synthetic transformations.12 Over
At the outset, transamidation of N-methylbenzamide (1a)
was investigated with benzylamine (2a) in the presence of
nitrosyl tetrafluoroborate (Table 1, entries 1–4). Initially, the the past few years, our research work has focused on the chem-
istry of N-nitrosamines13 and we have reported solvent free syn-
formation of N-nitrosamide (1aa) was assessed with nitrosyl
thesis of N-nitrosamines,13a radical dimerization of thiobenza-
1
tetrafluoroborate using crude H NMR. The reaction was per-
formed in acetonitrile and dichloromethane solvents in the mides13d and triazole formation of o-phenylenediamine13f
Table 1 Optimization of transamidation of N-methylbenzamidea
Nitrosation
Time (h)
Transamidation
Time (h)
S. no.
Nitroso source
Solvent
Bases
Yield 1aa b (%)
Yield 3a c (%)
1
2
3
4
5
6
7
8
NOBF4
NOBF4
NOBF4
NOBF4
AcCN
DCM
AcCN
DCM
DCM
DCE
—
—
Py
Py
—
—
—
—
—
—
—
—
—
—
—
12
12
12
12
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
65
74
92
74
95
91
50
35
30
80
70
<5
<5
<5
97
75
82
78
68
67
70
83
—
—
12
12
12
12
3
20
54
30
15
91
87
15
30
17
60
40
nr
nr
nr
47
48
48
44
45
42
51
64
10d
nre
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
iso-AmylONO
n-BuONO
t-BuONO
t-BuONO
3
THF
12
12
12
12
12
12
12
12
12
3
3
3
3
3
Toluene
Benzene
AcCN
1,4-Dioxane
MeOH
EtOH
H2O
Solvent-free
DCM
DCM
DCM
DCM
DCM
DCM
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Pyridine
Et3N
Et(i-Pr)2N
DBU
DABCO
—
—
—
—
1
1
1
—
—
3
3
6
6
DCM
DCM
DCM
a Reaction conditions: Substrate (1 mmol) and TBN (1.5 equiv.) stirred in appropriate solvents (5 mL) for appropriate times after which benzyl-
amine (2.2 equiv.) was added. b Crude yield was obtained using 1H NMR. c Isolated yield. d TBN was added to the pre-stirred solution of
N-methylbenzamide and benzylamine. e N-Methylbenzamide was added to the pre-stirred solution of benzylamine and TBN.
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Table 2 One-pot transamidation of N-methylbenzamide with different
aminesa,b
using tert-butyl nitrite. Recently, N-nitrosation of secondary
amides using tert-butyl nitrite has been demonstrated by Bhanage
et al.11 Therefore, the one-pot transamidation reaction was investi-
gated with tert-butyl nitrite in different solvents.
Initially, the conversion of N-methylbenzamide into the
corresponding N-nitrosamide (1aa) was assessed in the pres-
ence of TBN in different solvents including dichloromethane,
dichloroethane, THF, toluene, benzene, acetonitrile and
1
dioxane using H NMR (Table 1, entries 5–11). Among them,
dichloromethane was found to be the most efficient which pro-
vided the N-nitrosamide 1aa in 95% yield within 1 h (Table 1,
entry 5). On the other hand, polar protic solvents such as
methanol, ethanol and water failed to provide the
N-nitrosamide 1aa (Table 1, entries 12–14). As reported by
Bhanage et al. the N-nitrosamide 1aa was obtained in 97%
yield under solvent free conditions (Table 1, entry 15).
Nevertheless, after 1 hour, benzylamine (2.2 equiv.) was added
to the reaction mixture containing N-nitrosamide and the reac-
tion mixture was allowed to stir up to 12 h at room temperature.
To our delight, the one-pot transamidation was successfully
achieved with 91% yield in dichloromethane within 3 h while
other conditions gave the desired product 3a in low yields. It is
also worth mentioning that the transamidation product 3a was
obtained only in 47% yield under solvent free conditions even
after 12 h at room temperature (Table 1, entry 15).
Encouraged, we have studied the effect of the different
bases including pyridine, Et3N, Et(i-Pr)2N, DBU and DABCO in
the transamidation process in dichloromethane (Table 1,
entries 16–20). It was observed that in the presence of a base,
not only nitrosamide formation but also the transamidation
process was significantly suppressed. Furthermore, the transa-
midation reaction was investigated with other alkyl nitrites
a Reaction conditions: Substrate (1 mmol), TBN (1.5 equiv.) and amine
(2.2 equiv.) in DCM (5 mL) at room temperature. b Isolated yields.
such as iso-amyl nitrite and n-butyl nitrite in dichloro- piperazine, N-phenyl piperazine, N-benzhydryl piperazine,
methane. These reagents gave the desired product 3a in 70% N-benzoyl piperazine and 1,2,3,4-tetrahydroisoquinoline par-
and 83% yields, respectively (Table 1, entries 21 and 22). ticipated in the transamidation process smoothly and gave the
Furthermore, transamidation of N-methylbenzamide was exe- desired products in good to excellent yields (Table 2, 3g–3o).
cuted in two other conditions in dichloromethane using Interestingly, heteroaromatic amines such as 2-aminomethyl
tert-butyl nitrite (TBN), namely, (i) TBN was added to the pyridine and 2-aminoethyl pyridine also acted as efficient
pre-stirred solution of N-methylbenzamide and benzylamine nucleophiles in the transamidation process and provided the
(Table 1, entry 23) in dichloromethane and (ii) desired products 3p and 3q in 85% and 78% yields, respect-
N-methylbenzamide was added to the pre-stirred solution of ively. However, transamidation was not successful when
benzylamine and TBN (Table 1, entry 24) in dichloromethane. aniline was used as a nucleophile, perhaps due to less nucleo-
In the first case, the desired product 3a was obtained only in philicity of the amine (Table 2, 3r).
10% yield while the latter conditions failed to yield the desired
transamidation product.
The scope of the developed methodology was further exam-
ined with different N-alkyl benzamides under optimized
Having established the optimized conditions (Table 1, conditions (Table 3). Similar to N-methylbenzamides,
entry 5), transamidation of N-methylbenzamide was investi- N-ethyl (1b), N-propyl (1c), N-butyl (3b), N-hexyl (3c) and
gated with various amines in the presence of tert-butyl nitrite N-benzylbenzamides (3a) also underwent nitrosation followed
(Table 2). Initially, N-methylbenzamide was subjected to trans- by transamidation very efficiently with different primary and
amidation with different primary amines such as n-butyl, secondary amines (cyclic and acyclic) under optimized con-
n-hexyl, cyclohexyl, iso-propyl and cyclopropyl-amines under ditions (Table 3). These reactions provided the desired transa-
optimized conditions. All these reactions proceeded smoothly midation products in 54–88% yields. Moreover, irrespective of
at room temperature while the desired transamidation pro- the substitutes present on the aryl ring (i.e. electron donating
ducts were obtained in 73–95% yields (Table 2, 3b–3f). or withdrawing), nitrosation followed by transamidation
Similarly, cyclic and acyclic secondary amines such as diethyl- occurred smoothly to provide the desired products in good to
amine, dipropylamine, piperidine, morpholine, N-methyl excellent yields (Table 4, 5a–5r).
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Table 3 One-pot transamidation of N-alkyl benzamides with different
aminesa,b
Table 4 One-pot transamidation of various N-methylbenzamides with
different aminesa,b
Entry
1
Amide
Nucleophile
Product
Yield (%)
83
3a
2
1b
3d
79
3
4
1b
1b
3e
76
58
3h
5
6
1b
3i
62
85
2a
3a
7
8
9
10
11
1c
1c
1c
1c
2d
2e
2h
2i
3d
3e
3h
3i
81
80
57
63
86
2a
3a
12
13
14
15
16
3b
3b
3b
3b
2d
2e
2h
2i
3d
3e
3h
3i
82
74
56
60
88
2a
3a
17
18
19
20
21
3c
3c
3c
3c
2d
2e
2h
2i
3d
3e
3h
3i
85
78
56
60
54
a Reaction conditions: Substrate (1 mmol), TBN (1.5 equiv.) and amine
(2.2 equiv.) in DCM (5 mL) at RT. b Isolated yields.
2d
3d
22
23
3a
3a
2e
2i
3e
3i
72
63
a Reaction conditions: Substrate (1 mmol), TBN (1.5 equiv.) and amine
(2.2 equiv.) in DCM (5 mL) at RT. b Isolated yields.
Scheme 2 Transamidation of N-benzoyl o-phenylenediamine via
N-acyl benzimidazole.
It is also interesting to note that the transamidation of
N-benzoyl o-phenylenediamine (6) with different amines was
achieved with excellent yields (Scheme 2). The reaction pro-
ceeds through the N-acyl benzimidazole intermediate under
optimized conditions.
A proposed mechanism for the transamidation process is
Having explored the transamidation of various shown in Scheme 4. In the first step, the secondary amide
N-substituted benzamides, an alkyl secondary amide, i.e. N- undergoes N-nitrosation to form N-nitrosamide in the pres-
methyloctanamide (7), was subjected to transamidation with ence of tert-butyl nitrite. In the second step, N-nitrosamide
benzylamine and pyrrolidine under optimized conditions. To undergoes nucleophilic addition with an external amine to
our delight, the one-pot transamidation proceeded smoothly form the intermediate A. This unstable intermediate under-
in the presence of tert-butyl nitrite to provide the desired pro- goes elimination to provide the desired product and alkyl
ducts 8a and 8b in high yields (Scheme 3).
N-nitrosamine.
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Scheme 4 Proposed mechanism for the transamidation reaction.
In conclusion, a mild and practical method for the one-pot
transamidation of various secondary amides was demonstrated
with different amines in the presence of tert-butyl nitrite. The
reaction proceeds through the N-nitrosamide intermediate. All
the reactions were carried out at room temperature to obtain
the desired products in good to excellent yields. Moreover, the
developed methodology does not require any catalyst, acidic
medium or high temperature which demonstrates the broad
scope of the methodology.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
J. K. acknowledges the Max-Planck Society, Germany and DST,
India (DST/INT/MPG/P-09/2016) for financial support through
the Indo-Max Planck partner group project. S. A. acknowledges
the CSIR for Senior Research Fellowship (SRF) (09/013(0650)/
2016-EMR-I). J. K. acknowledges the Central Instrumentation
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