Et3N-promoted tandem ring-opening reaction of N-tosylaziridines with terminal alkynoates: A straightforward synthesis of functionalized enamines

Article abstract of DOI:10.1039/c2cc30317e

A tandem ring-opening reaction of N-tosylaziridines with terminal alkynoates promoted by Et₃N has been described. A variety of N-tosylaziridines reacted with terminal alkynoates to give functionalized enamines in moderate to good yields under s

Full text of DOI:10.1039/c2cc30317e

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COMMUNICATION
Et3N-promoted tandem ring-opening reaction of N-tosylaziridines with
terminal alkynoates: a straightforward synthesis of functionalized
enaminesw
Ling-Guo Menga and Lei Wang*ab
Received 14th January 2012, Accepted 31st January 2012
DOI: 10.1039/c2cc30317e
A tandem ring-opening reaction of N-tosylaziridines with terminal
alkynoates promoted by Et3N has been described. A variety
of N-tosylaziridines reacted with terminal alkynoates to give
functionalized enamines in moderate to good yields under simple
reaction conditions.
Development of efficient methods to construct complex molecules
is of great importance in synthetic organic chemistry. In recent
years, electron-deficient alkynes have often been used as
Scheme 1 Distinct ring-opening reactions of aziridines.
nucleophile precursors for the formation of multi-functionalized
compounds1 and recent studies on the chemistry of organo-
catalysts via conjugate addition of N- and P-nucleophiles have
reaction of N-tosylaziridines with terminal alkynoates to synthesis
of functionalized enamines under simple reaction conditions
uncovered many interesting reactions,2 such as a-addition,3
(Scheme 1, eqn (2)). It is noteworthy that enamines are some
of the most useful intermediates for introducing a nitrogen-
g-addition,4 cycloaddition reaction,5 etc. We are also interested
containing fragment in a synthetic sequence due to their
in the application of various organic bases catalyzed reactions
versatile reactivity.12
based on electron-deficient alkynes.6
Our studies were initiated by addition of 1.0 equiv. of Et3N
to a solution of 2-phenyl-1-tosylaziridine (1a) with ethyl
propiolate (2a) under various reaction conditions, and the
results are shown in Table 1. The reaction of 1a with 2a in the
presence of Et3N (1.0 equiv.) at 100 1C for 16 h afforded 3a as
a pale yellow oil in 63% yield, and this compound was
Aziridine, a three-membered cyclic amine, is one kind of the
most important intermediates and versatile building blocks in
organic synthesis due to high strain energy associated with the
ring.7 For example, they are widely used as substrates in
transition-metal-catalyzed annulation reactions.8 On the other
hand, ring-opening reactions of aziridines with nucleophiles
provide a useful protocol, and many reagents have been
developed to realize the opening of aziridine rings. However,
the most often used reagents are O-, S-, N-nucleophiles;9 only
a few examples were reported using C-nucleophiles.10
1
characterized by H and 13C NMR spectroscopy and HRMS
analysis. The amount of Et3N has an obvious effect on this
reaction. The desired product 3a was given in 27% yield when
0.5 equiv. of Et3N was used and the yield was not improved
by further increasing the amount of Et3N (Table 1, entries 2
and 3).11 The yield was unsuccessfully improved when the
reactants were stirred at 120 1C but decreased sharply when
the reaction occurred at low temperature (Table 1, entries 4–6).
Next, we examined the influence of the solvent and the base on
the model reaction. Among the solvents tested, CH3CN was
found to be the best one. Low yields of 3a (36 and 13%) were
obtained when dichloromethane and toluene were used as
solvents, respectively (Table 1, entries 7 and 8). Only a trace
amount of the desired product was detected by TLC when
CHCl3, DMF or THF was used as solvent (Table 1, entries 9–11).
With the utilization of DMSO or 1,4-dioxane, the desired
product 3a was not found (Table 1, entries 12 and 13). Further
investigations on various bases showed that Et3N is the optimal
base for the model reaction. Slight lower yield of 3a was afforded
when (n-Bu)3N was used as the promoter (Table 1, entry 14).
However, no desired product was detected when the reaction was
Recently, the [3+3] cyclization of aziridines with allenoates
mediated by phosphine to produce highly functionalized tetra-
hydropyridines was developed by Kwon et al. (Scheme 1,
eqn (1)).11 However, to the best of our knowledge, aziridines
have not been used as substrates to couple with electron-
deficient alkynes in the presence of an organic base. Herein,
we wish to report a novel Et3N-promoted tandem ring-opening
a Department of Chemistry, Huaibei Normal University, Huaibei,
Anhui 235000, P. R. China. E-mail: leiwang@chnu.edu.cn;
Fax: +86 561-380-2047
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P. R. China
w Electronic supplementary information (ESI) available: General
information, detailed experimental procedures, deuterium labeling
experiment results and characterization data for all products. See
DOI: 10.1039/c2cc30317e
c
3242 Chem. Commun., 2012, 48, 3242–3244
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Table 1 Tandem ring-opening reaction of 2-phenyl-1-tosylaziridine
(1a) with ethyl propiolate (2a)a
Table 2 Et3N-promoted tandem ring-opening reaction of aromatic
N-tosylaziridines with ethyl propiolatea
Entry
Solvent
Base
Yieldb (%)
Entry
Ar
Product
Yieldb (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
Toluene
CHCl3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
(n-Bu)3N
Et2NH
CH3(CH2)3NH2
DABCO
DMAP
Pyridine
DBU
63
27c
1
2
3
4
5
6
7
8
C6H5
4-FC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
63
70
72
75
55
57
25
70
71
60
53
63d
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-MeC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
2-Naphthyl
4-CH3COOC6H4
o10e
45f
62g
36h
13
9
Trace
Trace
Trace
NDi
9
10
11
10
11
12
13
14
15
16
17
18
19
20
21
22
DMF
THF
3j
3k
DMSO
1,4-Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Et3N (0.2 mmol),
b
NDi
CH3CN (2.0 mL), 100 1C, in air, 16 h. Isolated yield.
60
Complicated
NRj
respectively (Table 2, entries 8 and 9). Notably, 2-(naphthalen-
2-yl)-1-tosylaziridine and 2-(4-acetoxyphenyl)-1-tosylaziridine
also could be converted to desired products in moderate yields
(Table 2, entries 10 and 11).
Complicated
Complicated
Complicated
Complicated
NRj
Ph3N
K2CO3
To evaluate the scope of the ring-opening reaction in more
detail, other aziridines and electron-deficient alkynes were
examined under the optimized reaction conditions. The reac-
tions of substrates 1l–n with 2a gave the desired products 3l–n
in 75, 72 and 65% yields, respectively (Table 3, entries 1–3).
However, when aliphatic aziridine 1o or 2-methyl-2-phenyl-1-
tosylaziridine (1p) was used as one of the substrates, the
reaction was complicated and the desired product could not
be isolated (Table 3, entries 4 and 5). On the other hand, the
desired product 3o was obtained in 61% yield when methyl
propiolate was in place of ethyl propiolate. As expected, other
benzyl propiolates also reacted smoothly with 1a to give the
corresponding products in 58–62% yields (Table 3, entries 7–9).
To our delight, dimethyl but-2-ynedioate also could be
converted to corresponding product 3s, albeit the yield was so
low (Table 3, entry 10). In many cases, the lower yields obtained
can be accounted for by the formation of other by-products,
which could not be isolated by column chromatography.
On the basis of these experiments and previous investigations,
a mechanistic pathway for the Et3N-promoted tandem ring-
opening reaction of N-tosylaziridines with terminal alkynoates
is proposed in Scheme 2. The reaction could be triggered by
the nucleophilic addition of Et3N to the electron-deficient
multiple bond to produce zwitterion 4. Then ring-opening of
N-tosylaziridine was caused by zwitterion 4 to afford the
intermediate 5, which underwent an intramolecular nucleophilic
attack of the nitrogen anion to the double bond to generate 6A,
followed by proton transfer to give its isomer 6B, then both 6A
and 6B could afford their isomer 6C. Subsequently, 6C might
undergo an intramolecular nucleophilic substitution to obtain
7, which further proceeded the ring-opening step to produce the
desired product 3a. It should be noted that isomers 6A, 6B and
6C could be interconverted through a water-catalyzed proton
shift process.13 To better understand the mechanism of the
intriguing processes, deuterium labeling experiments were
NRj
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (0.2 mmol),
b
c
solvent (2.0 mL), 100 1C, in air, 16 h. Isolated yields. 0.5 equiv. of
Et3N was used. 1.5 equiv. of Et3N was used. At room temperature.
d
e
f
g
h
i
At 80 1C. At 120 1C. At 60 1C. ND = no desired product was
detected. NR = no reaction occurred.
j
proceeded in the presence of primary or secondary amine
(Table 1, entries 15 and 16). The reactions were complicated
when other tertiary amines were used instead of Et3N (Table 1,
entries 17–20). Meanwhile, no reaction occurred when Ph3N
or K2CO3 was used as the base.
With the best reaction conditions in hand, various aromatic
aziridines have been examined, and the results are listed in
Table 2. It was found that the reaction of ethyl propiolate with
aromatic N-tosylaziridines afforded the corresponding products
in moderate to good yields. Clearly, the substitutes on the
aromatic N-tosylaziridines had an effect on the yields of the
reactions. The substrate with an electron-withdrawing group on
the aromatic ring gave a better yield than that of an electron-
donating group on the aromatic ring. For example, when the
substrate contained an electron-withdrawing group, such as
fluoro, chloro or bromo, on its phenyl ring, the yields of the
corresponding enamines derivatives were isolated in good yields
(Table 2, entries 2–4). While the methoxyl and methyl group
were at the para-position of the benzene ring, the desired
products were afforded in 55 and 57% yields, respectively
(Table 2, entries 5 and 6). However, when a chloro group
was located at the ortho-position of its benzene ring, the
corresponding product 3g was obtained only in 25% yield,
which might be ascribed to steric hindrance (Table 2, entry 7).
Furthermore, treatment of 2-(3-chlorophenyl)-1-tosylaziridine
and 2-(3-bromophenyl)-1-tosylaziridine with ethyl propiolate
gave the corresponding products in 70 and 71% yields,
c
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Chem. Commun., 2012, 48, 3242–3244 3243

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Table 3 Et3N-promoted tandem ring-opening reaction of aziridines
with electron-deficient alkynesa
Entry Substrate
Alkynoate
Product, yieldb
1
2
3
2a
2a
Scheme 2 A plausible mechanism for the tandem ring-opening reaction.
reactions between electron-deficient alkynes and aziridines
are currently underway.
This work was financially supported by the National
Science Foundation of China (No. 21172092 and 20972057).
4
5
2a
2a
Complicated
Complicated
Notes and references
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7
8
9
1a
1a
1a
1a
10
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a
Reaction conditions:
1
(0.2 mmol),
2
(0.4 mmol), Et3N
b
(0.2 mmol), CH3CN (2.0 mL), 100 1C, in air, 16 h. Isolated yield.
Cbs = 4-chlorobenzenesulfonyl. Bs = 4-bromobenzenesulfonyl.
c
d
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e
Ns = 4-nitrobenzenesulfonyl.
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conducted, and the results also indicated that the trace amount
of the water in the system had played an important role in the
reaction (see Fig. S1 in ESIw for details).
In summary, we have developed a novel tandem ring-opening
reaction of N-tosylaziridines with terminal alkynoates promoted
by Et3N under simple reaction conditions. The reaction is
operationally simple and generates functionalized enamines in
moderate to good yields. The detailed mechanistic study and
further applications of organic base-catalyzed or -promoted
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c
3244 Chem. Commun., 2012, 48, 3242–3244
This journal is The Royal Society of Chemistry 2012