Bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides

Article abstract of DOI:10.1039/c4cc05578k

A new bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides has been developed. A series of amidines were prepared with moderate to good yields via a Csp³-Csp³ bond cleavage. This journal is

Full text of DOI:10.1039/c4cc05578k

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Bromoform reaction of tertiary amines with
N,N-dibromosulfonamides or NBS/sulfonamides†
Cite this: Chem. Commun., 2014,
50, 12367
Jie Chen, Yu-Ping Guo, Ming-Hui Sun, Guo-Tao Fan and Ling Zhou*
Received 19th July 2014,
Accepted 22nd August 2014
DOI: 10.1039/c4cc05578k
www.rsc.org/chemcomm
A new bromoform reaction of tertiary amines with N,N-dibromo-
sulfonamides or NBS/sulfonamides has been developed. A series of
amidines were prepared with moderate to good yields via a Csp3–Csp3
bond cleavage.
Haloform reaction is one of the most fundamental transformations
in organic chemistry, studies on it has a history of more than
100 years.1 As a classic textbook reaction, the haloform reaction
was widely used to identify the structure of organic compounds
before spectroscopic methods became available for structural
elucidation.2 Presently, the reaction is used as an efficient
method for the preparation of carboxylic acids with one less
carbon atom.3 Yet, despite this rich history, the substrate scope of
this reaction remains undeveloped. Only compounds containing
the methyl ketone functional group or compounds that can be
oxidized to methyl ketones by hypohalites are suitable for the
transformation (Scheme 1, eqn (1)).4
During the course of our studies on the N,N-dibromosulfonamide
promoted regioselective bromocyclization of unsaturated N-tosyl-
carbamates,5 we noticed that small amounts of amidine 3a
were formed when triethylamine (TEA) was employed as a base
(Scheme 1, eqn (2)). Amidine is the fundamental unit of natural
products,6 bioactive molecules,7 organocatalysts,8 and metal
complexation ligands.9 Amidine derivatives are key building blocks
for the synthesis of various heterocyclic compounds and metal
complexes.9,10 Many research endeavors have been dedicated to the
development of efficient approaches to the synthesis of these com-
pounds.11,12 For example, imidation of tertiary amines by using
sulfonyl azides in the presence of diethyl azodicarboxylate or a metal
catalyst has been explored.12 Herein we wish to describe a novel,
efficient, and selective haloform reaction of tertiary amines using N,N-
dibromosulfonamides or NBS/sulfonamides, leading to the formation
of amidine derivatives and bromoform (Scheme 1, eqn (2)).
Scheme 1 Haloform reactions.
To the best of our knowledge, there is no report on such
reactions, then we decided to study this unprecedented reaction on
both of the mechanism and its scope. Simply mixing N,N-dibromo-
4-methylbenzenesulfonamide (TsNBr2) and TEA in CH2Cl2 gave 3a
in 32% yield (Table 1, entry 1), indicating that the unsaturated
N-tosylcarbamate substrate is unrelated to this reaction.
a
Table 1 Bromoform reaction of TEA with TsNBr2
Entry
1a : 2a
Base (equiv.)
Solvent
Yieldb (%)
1
2
1 : 1
1 : 1
CH2Cl2
CHCl3
THF
EtOAc
ACN
32
19
16
41
42
43c
0
15
14
33
45
51
68
76
72
3
4
1 : 1
1 : 1
5
6
1 : 1
1 : 1
ACN
7
1 : 2
2 : 1
1.5 : 1
1.2 : 1
1 : 1
EtOAc
EtOAc
EtOAc
EtOAc
ACN
ACN
ACN
8d
9d
10d
11
12
13
14
15e
Pyridine (1.0)
K2CO3 (3.0)
DBU (1.0)
DBU (1.5)
DBU (1.5)
1 : 1
1 : 2.5
1 : 2.5
1 : 2.5
ACN
ACN
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education, College of Chemistry & Materials Science, Northwest University,
Xi’an 710069, P. R. China. E-mail: zhoul@nwu.edu.cn
a
Reactions were carried out with TEA (0.20 mmol), TsNBr2 in solvent (2 mL)
at r.t. for 4 h. Isolated yields. Reaction temperature is 80 1C. d 0.20 mmol
TsNBr2 was used. 0.02 mmol BHT was used.
b
c
† Electronic supplementary information (ESI) available: Experimental details, and
spectroscopic and analytical data for new compounds. See DOI: 10.1039/c4cc05578k
e
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We hypothesized that this amidine product arose from a pathway
in which the a, b Csp3–Csp3 bond of TEA is cleaved, and this
reaction may follow a haloform-type reaction mechanism.13
As shown in Scheme 2, TEA first attacks TsNBr2 and forms a
bromo ammonium intermediate I, next I releases an a proton
with the assistance of a base to form an iminium intermediate II,
which can be in equilibrium with enamine III. Then III attacks a
bromine source to form a bromo iminium intermediate IV, a
result similar to a secondary amine catalyzed a-bromination of
aldehyde (or ketone).14 The process of II to IV was repeated to
give an iminium intermediate V bearing a tribromomethyl group,
to which is then added a tosyl amide ion to form an aminal
Scheme 2 Proposed mechanism.
a
Table 2 Bromoform reaction of tertiary amines with RNBr2
Entry
Substrate
R
Product
Yieldb (%)
1
2
3
1a
1a
1a
Ts
3a
3o
3l
77c
68
63
4-NO2PhSO2
PhSO2
4
Ts
78d
5
6
Ts
Ts
65
42
3c
7
Ts
66
8
Ts
Ts
Ts
26
45
9
3a
10
11
Ts
Ts
12
Complex mixture
a
b
c
Reactions were carried out on a 0.20 mmol scale, under the standard reaction conditions, see Table 1, entry 14. Isolated yields. The reaction
was conducted on a 10.0 mmol scale. E : Z = 2 : 1, determined by 1H NMR analysis. E : Z = 1 : 1.
d
e
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Table 3 Bromoform reaction of TEA with sulfonamides and NBSa
intermediate VI. Finally, deprotonation of the sulfonamide group of
VI and liberation of a tribromomethane result in the formation of
amidine 3a. In a balanced equation (Scheme 2, eqn (4)), 2 mol TEA
plus 2 mol TsNBr2 result in 1 mol amidine 3a, 1 mol CHBr3, 1 mol
TsNH2 and 1 mol TEA–HBr. This means that TEA participates in
the reaction not only as a substrate, but also as a base.
Entry
Sulfonamide
R
Product
Yieldb (%)
To probe the mechanism and optimize the reaction, several
experiments were conducted. Firstly, extensive screening of solvents
was carried out with a mixture of TEA and TsNBr2 in a ratio of 1 : 1
(Table 1, entries 1–5). We found that both acetonitrile (ACN) and
EtOAc are suitable solvents. Increasing the reaction temperature
resulted in a slight effect on this reaction (Table 1, entry 6). Next,
changing the ratio of the two reactants resulted in significant
difference in the reaction yields. When the reaction was carried
out in a ratio of 1:2 (TEA:TsNBr2), no desired product was
detected (Table 1, entry 7); and a ratio of 2 : 1 also resulted in a
clear decrease of the yield (Table 1, entry 8). These results indicate
that TEA may participate in the reaction as both a substrate and a
base, and excess TsNBr2 would be needed. Then external bases
were employed, to our delight, the reaction yields increased clearly
(Table 1, entries 11 and 12). Further optimization of this reaction
using excess TsNBr2 returned amidine 3a in 76% yield in a
ratio of 1 : 2.5 (TEA : TsNBr2) in the presence of 1.5 equiv. of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Table 1, entry 14).
To gain more insight into this reaction, the reaction mixture was
tested by 1H NMR and GC-MS. Indeed, both tribromomethane and
TsNH2 were detected.15 Additionally, using 10 mol% of radical
scavenger 2,6-di-tert-butyl-4-methylphenol (BHT) returned a compar-
able yield (Table 1, entries 15 vs. 14). These results demonstrated
that this reaction may not follow a radical-type mechanism, further
suggesting that the mechanism may follow our proposed cationic
proposal.
Under the optimized conditions, the reaction scalability and
the substrate scope were investigated. As shown in Table 2, a
50-fold increase in the scale resulted in a small change in the yield
(Table 2, entry 1). Besides TsNBr2, other N,N-dibromosulfonamides
are also suitable for this reaction. N,N-Dibromo-4-nitro-benzene-
sulfonamide and N,N-dibromobenzenesulfonamide returned the
desired amidines in 68% and 63% yields, respectively (Table 2,
entries 2 and 3). N-Ethyl-N-methylethanamine 1b resulted in
amidine 3b in 78% yield as a mixture (E : Z = 2 : 1). N,N-Dimethyl-
ethanamine 1c returned 3c in 65% yield. The cleavage of the
Csp3–Csp3 bond of tertiary amine occurred in both cases no
matter the substrates containing one or two ethyl groups
(Table 2, entries 4 and 5). Meanwhile, trimethyl amine also
resulted in amidine 3c in 42% yield (Table 2, entry 6).16 The
high chemoselectivity may be attributed to the stability of the
iminium intermediates. Surprisingly, the generally used bulky
tertiary amine N,N-diisopropylethylamine also gave the desired
amidine 3d in 66% yield as a sole product (Table 2, entry 7).
Cyclic tertiary amine N-ethylpiperidine was a modest but
encouraging substrate (Table 2, entry 8). In order to investigate
the electronic effects of the substituents, tertiary amines 1f–h
were examined. However, two reaction pathways with different
chemoselectivity were observed (Table 2, entries 9–11). Wherein
the electron rich substituents are prior to be cleaved, the reason
1
2a
2a
2a
2k
2l
2m
2n
2o
2p
2q
2r
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Et-C6H4
Ph-
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
4-CF3O-C6H4
3-Me-C6H4
3-NO2-C6H4
2-Me-C6H4
2,4,6-Me3-C6H4
3a
3a
3a
3k
3l
3m
3n
3o
3p
3q
3r
79
36
Trace
91
76
80
95
91
94
87
81
68
72
2c
3d
4
5
6
7
8
9
10
11
12
13
2s
2t
3s
3t
a
Reactions were carried out with TEA (0.20 mmol), RSO2NH2 (0.50 mmol),
NBS (0.50 mmol) and DBU (0.30 mmol) in ACN (2 mL) at r.t. for 4 h.
b Isolated yields. NIS (0.50 mmol) was used. NCS (0.50 mmol) was used.
c
d
may be ascribed to the fact that the nucleophilicity of the
enamine intermediates is enhanced. Unfortunately, N,N-diethyl-
aniline returned a complex mixture with aromatic brominated
side products (Table 2, entry 12).
In the proposed mechanism of this novel reaction, TsNBr2
acts as a bromine-oxidant, a proton scavenger and an amine
source. We envisioned that the reaction can also be performed
by using commercially available sulfonamides and halogen
sources in the presence of a base. Thus, reaction of TEA with
TsNH2 and NBS in the presence of DBU was conducted, as
expected, the desired amidine 3a was obtained in 79% yield
(Table 3, entry 1). However, NIS and NCS diminished the
reaction (Table 3, entries 2 and 3). Other sulfonamides contain-
ing several functional groups such as alkyl, halo, and nitro could
be well tolerated, and the desired amidines were obtained with
good to excellent yields (Table 3, entries 4–13).
In summary, we have developed a new haloform reaction of
tertiary amines with N,N-dibromosulfonamides or NBS/sulfo-
namides for the first time. A series of amidines were prepared
with moderate to good yields. The electron property plays an
important role in the chemoselectivity. A multistep cationic
mechanism for this novel reaction is proposed. Further inves-
tigations to better understand the mechanism and to develop
new applications of this reaction are underway.
We thank the National Natural Science Foundation of China
(NSFC-21203148, 21302151), Science and Technology Department
of Shaanxi Province (2013JQ2012), Education Department of
Shaanxi Province (2013JK0644), the Scientific Research Foundation
for the Returned Overseas Chinese Scholars, Ministry of Education,
and the Northwest University for financial support.
Notes and references
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12370 | Chem. Commun., 2014, 50, 12367--12370
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