Three-component reaction of propargyl amines, sulfonyl azides, and alkynes: One-pot synthesis of tetrasubstituted imidazoles

Article abstract of DOI:10.1021/ol303023y

An efficient and straightforward strategy for the synthesis of tetrasubstituted imidazoles from propargyl amines, sulfonyl azides, and terminal alkynes is described. N-Sulfonyl ketenimine and aminoallene are believed to be the key intermediates for this t

Full text of DOI:10.1021/ol303023y

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6266–6269
Three-Component Reaction of
Propargyl Amines, Sulfonyl Azides,
and Alkynes: One-Pot Synthesis
of Tetrasubstituted Imidazoles
Zheng Jiang, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Received November 3, 2012
ABSTRACT
An efficient and straightforward strategy for the synthesis of tetrasubstituted imidazoles from propargyl amines, sulfonyl azides, and terminal
alkynes is described. N-Sulfonyl ketenimine and aminoallene are believed to be the key intermediates for this two-step one-pot transformation.
Imidazole and its derivatives are an important class of
heterocyclic compounds, which are widely used in biology
as inhibitors,1 and are also used in medicinal chemistry2
and as functionalized materials.3 Classic methods for
the synthesis of imidazoles include DebusÀRadziszewski
imidazole synthesis,4 Weidenhagen imidazole synthesis,5
and Van Leusen imidazole synthesis.6 Recently, a number
of multicomponent syntheses of imidazoles have also
been developed.7 Nonetheless, the development of more
efficient and versatile approaches to functionalized im-
idazoles remains very important.
Since Staudinger and Hauser prepared the first keteni-
mine in 1921,8 this class of reactive intermediates has been
(1) (a) Chabin, R. M.; McCauley, E.; Calaycay, J. R.; Kelly, T. M.;
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r
10.1021/ol303023y
Published on Web 11/30/2012
2012 American Chemical Society

explored and applied in the construction of various
heterocycles.9 The most attractive and sustainable method
for generating ketenimines is the copper catalyzed azideÀ
alkyne cycloaddition (CuAAC).10 Chang,10,11 our group,12
and others13 developed a number of three-component reac-
tions by trapping ketenimines generated in situ from sulfo-
nyl azides and terminal alkynes via this CuAAC process.
Amines, alcohols, and water could all be the nucleophiles.
The skeletons of diverse heterocycles, such as coumarins,12a,h
quinolines,12c pyrrolines,12b pyrimidines,12e azetidines,13c
and oxetanes,13d were successfully constructed by this
strategy. Encouraged by these results, we used substituted
propynyl amines, which could be easily prepared from
aldehydes, amines, and alkynes via a Mannich-type reaction14
to trap the in situ generated ketenimines for the synthesis
of cyclization products in a cascade process. Herein, we
would like to report the result of this effort.
reaction occurred in these cases. I2 and NIS16 were also
tried, and complex mixtures were yielded. As the next step,
we focused our attention on the base-promoted cyclization
of 4a. In this case, fortunately, we obtained tetrasubsti-
tuted imidazole 5a (Table 2). Then we studied the reaction
conditions for cyclization of 4a in the presence of base
(Table 2). Various bases, such as K2CO3, Cs2CO3, KOH,
t-BuONa, Et3N, and DBU were examined in MeCN at
80 °C, and Cs2CO3 gave the best yield (Table 2, entries
1À6). Other solvents, such as DCE, toluene, THF, and
DMF, were also screened, but they gave lower yields as
compared with MeCN (Table 2, entries 7À10). Decreasing
the reaction temperature led to a lower yield (Table 2,
entries 11 and 12). Cs2CO3 could be reduced to 0.2 equiv,
while the reaction time could be reduced to 2 h (Table 2,
entries 13À17).
Primarily, when the mixture of N-(1,3-diphenylprop-2-
yn-1-yl)aniline (1a), ethynylbenzene (2a), 4-methylbenze-
nesulfonyl azide (3a), CuI, and Et3N was stirred at 25 °C
for 6 h, we obtained a three-component product 4a in good
yield. Optimization of reaction conditions for the forma-
tion of 4a was then conducted (Table 1). Several solvents,
such as acetonitrile, toluene, dichloroethane (DCE), di-
chloromethane (DCM), and tetrahydrofuran (THF), were
screened for this transformation, and acetonitrile was
found to be the best one (Table 1, entries 1À5). Triethyla-
mine was the best base in comparison with pyridine and
potassium carbonate (Table 1, entries 4, 6 and 7). Altering
the copper source to CuBr, the yield actually decreased
(Table1, entry 8). Thus, the bestreaction conditionsforthe
formation of 4a were established (Table 1, entry 4).
Table 2. Screening for the Reaction Conditionsa
temp
time
(h)
yieldb
(%)
entry
base/equiv
solvent
(°C)
1
K2CO3/2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
DCE
80
80
80
80
80
80
80
80
80
80
50
25
80
80
80
80
80
4
ndc
80
2
Cs2CO3/2
KOH/2
0.5
4
3
trace
28
4
t-BuONa/2
Et3N/2
0.5
4
5
trace
69
6
DBU/2
1.5
1.5
4
Table 1. Screening for the Reaction Conditionsa
7
Cs2CO3/2
Cs2CO3/2
Cs2CO3/2
Cs2CO3/2
Cs2CO3/2
Cs2CO3/2
Cs2CO3/1.5
Cs2CO3/1
Cs2CO3/0.5
Cs2CO3/0.2
Cs2CO3/0.1
78
8
trace
72
9
THF
1
10
11
12
13
14
15
16
17
DMF
0.5
2
34
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
74
4
38
0.5
0.5
0.5
2
81
80
entry
catalyst
base
solvent
time (h)
yieldb (%)
79
80
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Et3N
Et3N
Et3N
Et3N
Et3N
Py
DCM
6
6
6
6
6
6
6
6
70
71
83
89
75
45
76
62
4
55
DCE
toluene
MeCN
THF
a Reaction conditions: 4a (1 mmol), solvent (10 mL), equivalent
molar to 4a. b Isolated yield referred to 4a. c nd = not detected.
MeCN
MeCN
MeCN
K2CO3
Et3N
(12) (a) Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8, 4517.
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Jiang, Z.; Wang, Y. G. Synlett. 2009, 2023. (e) Lu, W.; Song, W. Z.;
Hong, D.; Lu, P.; Wang, Y. G. Adv. Synth. Catal. 2009, 351, 1768.
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2010, 75, 3481. (g) Li, Y.; Hong, D.; Zhu, Y. X.; Lu, P.; Wang, Y. G.
Tetrahetron 2011, 67, 8086. (h) Shen, Y.; Cui, S. L.; Wang, J.; Chen,
X. P.; Lu, P.; Wang, Y. G. Adv. Synth. Catal. 2010, 352, 1139.
a Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), 3a (1.2 mmol),
base (1.2 mmol), catalyst (0.1 mmol), solvent (10 mL). b Isolated yield
referred to 1a.
We envisioned that the cyclization of 4a could lead tothe
formation of a heterocyclic compound using a Lewis acid
or a base as catalyst. First, we examined several silver and
palladium salts that could activate the triple bond,15 but no
(13) (a) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int.
Ed. 2006, 45, 3154. (b) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed.
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X. Q.; Ma, C. Angew. Chem., Int. Ed. 2010, 49, 9210.
Org. Lett., Vol. 14, No. 24, 2012
6267

Table 3. One-Pot Synthesis of 5a
entry
1 (R1/R2/R3)
2 (R4)
2a (Ph)
3 (R5)b
5/ yield (%)c
1
1a (Ph/Ph/Ph)
3a (4-MeC6H4)
5a/69
5b/62
5c/60
5d/52
5e/59
5f/52
5g/58
5h/65
5i/66
2
1a
2a
3b (Ph)
3
1b (Ph/Ph/PhCH2)
2a
3c (CH3)
4
1a
2a
3d (4-ClC6H4)
5
1b
2a
3e (2-naphthyl)
6
1a
2b (2-BrC6H4)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
7
1a
2c (3-BrC6H4)
8
1a
2d (4-MeC6H4)
9
1a
2e (n-C4H9)
10
11
12
13
14
15
16
17
18
19
20
1b
2f (4-MeOC6H4)
5j/39
1b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
5k/78
5l/71
1c (Ph/Ph/4-MeC6H4)
1d (Ph/Ph/n-C8H17
)
5m/83
5n/49
5o/50
5p/59
5q/64
5r/57
5s/56
5k/75d
1e (Ph/4-BrC6H4/Ph)
1f (Ph/4-MeC6H4/Ph)
1g (Ph/2-furanyl/PhCH2)
1h (Ph/3-OMeC6H4/ Ph)
1i (4-OMeC6H4/Ph/Ph)
1j (2-BrC6H4/ Ph/PhCH2)
1b
a Reaction conditions: 1 (1 mmol), 2 (1.1 mmol), 3 (1.2 mmol), Et3N (1.2 mmol), CuI (0.1 mmol), Cs2CO3 (0.5 mmol), MeCN (10 mL). b Although the
mixture of sulfonyl azides is the safest of a group of diazo compounds, one should keep in mind the inherent instability, shock sensitivity, and explosive
power of azides. All users should exercise appropriate caution. c Isolated yield referred to 1. d The reaction was performed on 3 mmol scale, 0.2 M.
We then tried to combine the formation and cycliza-
tion of 4a in one pot by adding Cs2CO3 after the three-
component reaction of 1a, 2a, and 3a. Thus, the two-step
one-pot reaction was accomplished successfully. In this
case, the total yield for the two-step reaction was 69%
when 0.5 equiv of Cs2CO3 was used and the reaction was
carried out at 80 °C for 4 h.
With the optimized reaction conditions in hand, we
investigated the substrate scope for this transformation
(Table 3). Several substituted sulfonyl azides 3aÀe were
examined, and the yields ranged from 52% to 69% (Table 3,
entries 1À5). The substituent effect on the alkynes 2aÀf was
also explored (Table 3, entry 1 and entries 6À10). Thestrong
electron-donating group substituted ethynylbenzene (Table 3,
entry 10) gave a much lower yield (39%) than ethynyl-
benzene (Table 3, entry 5). An aliphatic alkyne, hex-1-yne
(2e), could also work with a 66% yield (Table 3, entry 9).
For substituted propynyl amines, it was found that benzyl
amine 1b (Table 3, entry 11) and aliphatic amine 1d
(Table 3, entry 13) gave higher yields than the aromatic
amines 1a, 1c, and 1eÀ1j (Table 3, entries 1, 12, and
14À19) due to the stronger nucleophilicity of 1b and 1d.
The gram scale reaction was performed using 3 mmol of
1b, 3.3 mmol of 2a, and 3.6 mmol of 3a. In this case, we
obtained 1.28 g of 5k in 75% yield (Table 3, entry 20). The
structure of 5k was established by X-ray crystal analysis
(Figure 1).
To gain good insight into the cyclization mechanism,
especially the sulfonyl group shift, we investigated the pos-
sibility of a cross reaction between 4b and 4c (Scheme 1).
Only two products 5o and 5t were detected in the reaction
mixture. This result suggested that the migration of the
sulfonyl group should undergo an intramolecular process.
According to these results, a possible mechanism for this
cascade reaction is proposed in Scheme 2. In the first step,
ketenimine A is generated in situ from 2a and 3a via a
CuAAC process. Then, the nitrogen of 1a nucleophilically
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transitional metal salts as Lewis acids, see: (a) Peshkov, V. A.; Pereshivko,
O. P.; Sharma, S.; Meganathan, T.; Parmar, V. S.; Ermolat’ev, D. S.; Eycken,
E. V. V. D. J. Org. Chem. 2011, 76, 5867. (b) Giles, R. L.; Sullivan, J. D.;
Steiner, A. M.; Looper, R. E. Angew. Chem., Int. Ed. 2009, 48, 3116. (c)
Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3,
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2011, 13, 4208.
(16) For selected examples for the activation of a triple bond using I2
or NIS as a Lewis acid, see: (a) Okitsu, T.; Sato, K.; Wada, A. Org. Lett.
2010, 12, 3506. (b) Zhang, X. X.; Larock, R. C. J. Am. Chem. Soc. 2005,
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6268
Org. Lett., Vol. 14, No. 24, 2012

Scheme 2. Proposed Mechanism for the Transformation
Figure 1. X-ray analysis of 5k.
Scheme 1. Reaction Design To Validate the Migration of
Sulfonyl Group
C1 and C2. Finally, the outcome of imidazole 5a occurs via
a sulfonyl 1,3-shift.19
In summary, we have developed an efficient approach to
tetrasubstituted imidazoles via a two-step one-pot reaction
of propargyl amines, N-sulfonyl azides, and alkynes. A
possible mechanism for this reaction was proposed, which
involves the formation of a N-sulfonyl ketenimine inter-
mediate and an aminoallene intermediate, a 6π-ECR, and
a sulfonyl 1,3-shift. Further investigations on the synthetic
applications of this chemistry are ongoing in our laboratory.
Acknowledgment. We thank the National Nature Science
Foundation of China (20972137, 21032005).
attacks the central carbon of ketenimine A to generate 4a.
In the second step, in the presence of base, the propargyl
moiety of 4a may transform into allene B,17 which under-
goes a 6π-ECR18 to form C with two resonance structures
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) (a) Xin, X. Y.; Wang, D. P.; Li, X. C.; Wan, B. S. Angew. Chem.,
Int. Ed. 2012, 51, 1693. (b) Saito, A.; Konishi, T.; Hanzawa, Y. Org. Lett.
2010, 12, 372.
(18) For recent examples, see: (a) Hayashi, R.; Walton, M. C.;
Hsung, R. P.; Schwab, J. H.; Yu, X. L. Org. Lett. 2010, 12, 5768.
(b) Tang, X. Y.; Wei, Y.; Shi, M. Org. Lett. 2010, 12, 5120. (c) Hayashi,
R.; Feltenberger, J. B.; Hsung, R. P. Org. Lett. 2010, 12, 1152. (d) Hayashi,
R.; Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G. Org. Lett. 2009, 11,
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(19) Prasad, B.; Adepu, R.; Sandra, S.; Rambabu, D.; Krishna,
G. R.; Reddy, C. M.; Deora, G. S.; Misra, P.; Pal, M. Chem. Commun.
2012, 48, 10434.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
6269