Parallel copper catalysis: Diastereoselective synthesis of polyfunctionalized azetidin-2-imines

Article abstract of DOI:10.1021/ol4010323

An efficient and diastereoselective synthesis of highly functionalized azetidin-2-imines has been achieved through a parallel catalysis strategy, including a copper-catalyzed azide-alkyne cycloaddition, a copper-catalyzed C_sp-Csp² cr

Full text of DOI:10.1021/ol4010323

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Parallel Copper Catalysis:
Diastereoselective Synthesis
of Polyfunctionalized Azetidin-2-imines
Yanpeng Xing, Hongyang Zhao, Qiongyi Shang, Jing Wang, Ping Lu,* and
Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
orgwyg@zju.edu.cn; pinglu@zju.edu.cn
Received April 8, 2013
ABSTRACT
An efficient and diastereoselective synthesis of highly functionalized azetidin-2-imines has been achieved through a parallel catalysis strategy,
including a copper-catalyzed azideꢀalkyne cycloaddition, a copper-catalyzed CspꢀCsp2 cross-coupling reaction, and an intermolecular [2 þ 2]
cycloaddition. The products could be conveniently converted into the structurally interesting dihydroazeto[1,2-a]benzo[e]azepin-2(4H)-imines.
As a new concept, cascade catalysis1 or concurrent
tandem catalysis2 is becoming a rapid, efficient, and con-
venient strategy in organic synthesis. This strategy inte-
grates multiple catalytic cycles in a single procedure and
allows sophisticated compounds to be easily prepared
from commercially available starting materials.3 Since
both time and resources can be efficiently saved by simpli-
fying the operating procedures, this concept fits the basic
requirements of green chemistry and is of unique impor-
tance for unstable intermediates.
Recently, copper-catalyzed azideꢀalkyne cycloadditions
(CuAACs) were developed for the formation of keteni-
mines,4,5 which could be efficiently transformed into a
variety of nitrogen-containing heterocyclic compounds
with economic and ecological values.6,7 Inspired by our
previous success with ketenimine chemistry3d,7 and the
literature on the copper-catalyzed CspꢀCsp2 cross-coupling
reaction,8 we became interested in cascade reactions that
can combine a copper-catalyzed azideꢀalkyne cycloaddi-
tion and a copper-catalyzed CspꢀCsp2 cross-coupling in a
parallel catalysis approach (Figure 1).
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Chang, S. J. Am. Chem. Soc. 2005, 127, 16046. (b) Yoo, E. J.; Ahlquist,
M. R.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. J. Org. Chem.
2008, 73, 5520. (c) Li, S.; Luo, Y.; Wu, J. Org. Lett. 2011, 13, 4312. (d)
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r
10.1021/ol4010323
XXXX American Chemical Society

Both aromatic alkynes (Table 2, entries 1ꢀ5) and aliphatic
alkynes (Table 2, entry 6) reacted smoothly with 2a and 3a
to afford the corresponding azetidin-2-ones 4aꢀ4f in yields
Table 2. Preparation of Azetidin-2-imines 4: Scope with Respect
to the Terminal Alkyne Componenta
Figure 1. Cascade strategy involving parallel catalysis.
Our investigation started with the reaction of phenyla-
cetylene (1a), 4-methylbenzenesulfonyl azide (2a), and
imidoyl chloride (3a) as the model reaction using CuI as
a single catalyst source (Table 1, entry 1). Primarily, a four-
component adduct 4a was isolated in 64% yield after the
reaction was conducted in THF at room temperature for
6 h. The relative configuration of 4a was comparatively
confirmed by X-ray crystallographic analysis of its analogs
4b and 4q as well as its derivative 7a,9 while an 85:15
cis/trans ratio for 4a was determined with 1H NMR
spectroscopy. Since 4a contains an azetidin-2-one core,
which is the key structure unit of a large class of antibiotics
and might potentially possess biological activity,10 we
screened the reaction conditions to develop an efficient
approach to the azetidin-2-one ring system. As shown in
Table 1, the best yield and stereoselectivity were obtained
when the reaction was carried out in dichloromethane
(DCM) using 10 mol % CuI as the catalyst and 3 equiv
of Et3N as the base (Table 1, entries 5 and 13).
entry
1 (R1)
product
yield (%)b
drc
1
1a (C6H5)
4a
4b
4c
4d
4e
4f
76
70
68
71
63
76
>95:5
84:16
77:23
>95:5
>95:5
>95:5
2
1b (p-MeC6H4)
1c (p-MeOC6H4)
1d (p-PhC6H4)
1e (p-BrC6H4)
3
4
5
6d
1f (n-C5H11)
a Reaction conditions: 1 (2.5 mmol), 2a (1.2 mmol), 3a (1 mmol),
Et3N (3 mmol), and Cu(I) (0.1 mmol), DCM (5 mL), room temperature,
6 h. b Isolated yield based on 3a. c Determined from the 1H NMR spectra
of the crude product. d 40 °C, 12 h.
between 63% and 76%. The electronic effect of the sub-
stituent on aromatic ring of aromatic alkynes was not
apparent. However, it indeed affected the diastereomeric
ratio (dr) of the products. 1-Ethynyl-4-methylbenzene (1b)
and 1-ethynyl-4-methoxybenzene (1c) produced 4b and 4c
with dr values of 84:16 and 77:23, respectively, while
excellent diastereoselectivity (dr > 95:5) was observed
for 4a and 4dꢀ4f.
Both aryl sulfonyl azides (Table 3, entries 1ꢀ6) and alkyl
sulfonyl azide (Table 3, entry 7) worked for the reaction to
afford the desired products 4gꢀ4m in moderate to excellent
yields. Among these tested azides, naphthalene-2-sulfonyl
azide furnished 4k in the best yield (95%) with the highest dr
value (>95:5) (Table 3, entry 5), while 2,4,6-trimethylbenze-
nesulfonyl azide produced 4j in the lowest yield (60%) with the
lowest dr value (77:23) although a higher reaction temperature
and a longer reaction time were applied (Table 3, entry 4).
To further examine the generality of this method, var-
ious imidoyl chlorides 3 were allowed to react with 1aꢀ1b
and 2a under the established conditions (Table 4). Imidoyl
chlorides 3 were prepared from the corresponding amides
and sulfonyl chlorides at refluxing temperature for 3 h.
When the imidoyl chlorides 3bꢀ3f derived from N-benzyl
amides were used as the substrates, 4nꢀ4r were obtained in
yields between 66% and 83% with excellent diastereos-
electivities (Table 4, entries 1ꢀ5). For the imidoyl chlorides
Table 1. Optimization of the Reaction Conditionsa
entry
solvent
base
Et3N
cat.
yield (%)b
drc
1
THF
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuI
CuI
64
85:15
84:16
>95:5
>95:5
>95:5
_
2
CH3CN
toluene
DCE
Et3N
44
3
Et3N
53
4
Et3N
67
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et3N
76
6
pyridine
DBU
<10
<10
<10
NF
39
7
_
8
K2CO3
DABCO
Et3N
_
9
_
10
11
12d
13e
>95:5
>95:5
>95:5
>95:5
Et3N
47
Et3N
59
Et3N
78
(9) For ORTEPs of products 4b, 4q, and 7a, please see the Supporting
Information. CCDC 930258 (4b), CCDC 930259 (4q), and CCDC
930262 (7a) contain supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(10) (a) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem. Rev.
2005, 105, 395. (b) Massovaand, I.; Mobashery, S. Acc. Chem. Res. 1997,
30, 162. (c) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418. (d)
Palomo, C.; Aizpurua, J. M.; Ganboaand, I.; Oiarbide, M. Eur. J. Org.
Chem. 1999, 3223. (e) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26,
377.
a Reaction conditions: 1a (2.5 mmol), 2a (1.2 mmol), 3a (1 mmol),
base (3 mmol), and Cu(I) (0.1 mmol), solvent (5 mL), room temperature,
6 h. b Isolated yield based on 3a. c Determined from the 1H NMR spectra
of the crude product. d For 3 h. e For 12 h.
Under the optimized reaction conditions, we investi-
gated the scope of substrates. A variety of terminal alkynes
1aꢀ1f were examined for this transformation (Table 2).
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Preparation of Azetidin-2-imines 4: Scope with Respect
to the Azide Componenta
Table 4. Preparation of Azetidin-2-imines 4: Scope with Respect
to the Imidoyl Chloride Componenta
entry
2 (R2)
2b (C6H5)
product
yield (%)b
drc
entry
1
3 (R3, R4)
product/yield (%)b
drc
1
4g
4h
4i
89
92
87
60
95
88
66
>95:5
84:16
>95:5
77:23
>95:5
>95:5
>95:5
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
3b (p-MeC6H4, Bn)
3c (m-ClC6H4, Bn)
3d (p-MeOC6H4, Bn)
3e (o-BrC6H4, Bn)
3f (p-BrC6H4, Bn)
3g (C6H5, n-C4H9)
3h (C6H5, o-ClBn)
4n/72
4o/66
4p/83
4q/69
4r/75
4s/87
4t/93
4u/88
4v/73
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
77:23
80:20
2
2c (p-MeOC6H4)
2d (p-ClC6H4)
3
4d
5
2e (2,4,6-Me3C6H2)
2f (2-naphthalenyl)
2g (p-NO2C6H4)
2h (CH3)
4j
4k
4l
6
7
4m
3i (C6H5, c-C6H11
)
a Reaction conditions: 1a (2.5 mmol), 2 (1.2 mmol), 3a (1 mmol),
Et3N (3 mmol), and Cu(I) (0.1 mmol), DCM (5 mL), room temperature,
6 h. b Isolated yield based on 3a. c Determined from the 1H NMR spectra
of the crude product. d 40 °C, 12 h.
3j (C6H5, p-MeC6H4)
a Reaction conditions: 1 (2.5 mmol), 2a (1.2 mmol), 3 (1 mmol), Et3N
(3 mmol), and Cu(I) (0.1 mmol), DCM (5 mL), room temperature, 6 h.
b Isolated yield based on 3. c Determined from the 1H NMR spectra of
the crude product.
3gꢀ3j derived from benzamides with different substituents
at the nitrogen atom, 4sꢀ4v were prepared in 73ꢀ93%
yields with dr values varied from 77:23 to >95:5 (Table 4,
entries 6ꢀ9).
Scheme 1. Preparation of Azetidin-2-imine 4v Step-by-Step
We assumed that the ynimine 5, generated in situ from
terminal alkyne 1 and imidoyl chloride 3 via a copper-
catalyzed coupling, might be a key intermediate in this
transformation. Therefore, we prepared ynimine 5 from 1b
and 3j in the presence of CuI and then employed 5 for the
subsequent reaction with 2a and 1b (Scheme 1). As we
expected, the desired 4v was obtained with the same dr
value as the one obtained from the one-pot procedure
(Table 4, entry 9).
Since 2 equiv of the terminal alkynes 1 were used in
this transformation, two different terminal alkynes were
sequentially added. As shown in Scheme 2, after the reac-
tion of 1a with 3a was conducted in dichloromethane in the
presence of CuI at room temperature for 2 h, 1-heptyne
(1f), 2a, and additional CuI were sequentially added in one
pot to allow the reaction to proceed for an additional 6 h.
Finally, 6 was obtained in 61% yield with excellent dia-
stereoselectivity (>95:5 dr).
Scheme 2. Preparation of Azetidin-2-imine 6 from Mixed Alkynes
The stereochemistry of this transformation is attractive.
Two aryl groups in the azetidin-2-imine rings are in
cis-configurations (for 4f and 6, heptyl and phenyl are in
a cis-configuration). These results prompted us to look for
theoretical support. 4a, 4h, and 4u were therefore selected
as three representatives, which have excellent (>95:5 dr), good
(84:16 dr), and moderate (77:23 dr) diastereoselectivities,
respectively (Figure 2). We calculated these three pairs of
azetidin-2-imines and found that the energy difference between
cis-4a and trans-4a is the largest, while the energy difference
between cis-4u and trans-4u is the smallest. The tendency for
the energy difference eventually supported what we observed
in the diastereoselectivity and implied that cis-azetidin-2-
imines (cis-4) were the thermodynamically favored products.
Based on these results, a possible mechanism is outlined
in Scheme 3. Inthe presenceofa base, the copper-catalyzed
CspꢀCsp2 coupling reaction between terminal alkyne 1a
and imidoyl chloride 3a forms the ynimine intermediate
A.11 Meanwhile, the copper-catalyzed alkyneꢀazide cyclo-
addition occurs to form the ketenimine intermediate B.4,5
Subsequently, a [2 þ 2] cycloaddition between A and B
takes place to furnish azetidin-2-imine 4a. The remarkable
diastereoselectivity for the formation of cis-4a can
be contributed to the thermodynamic stability of the
cis-product.
(11) (a) Li, S.; Zhu, J.; Xie, H.; Chen, Z.; Wu, Y. J. Fluorine Chem.
2011, 132, 196. (b) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett.
2001, 3, 1109. (c) Isobe, A.; Takagi, J.; Katagiri, T.; Uneyama, K. Org.
Lett. 2008, 10, 2657.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Preparation of Dihydroazeto[1,2-a]benzo[e]azepin-
2(4H)-imines 7 from 4
Figure 2. Rrelative potential energy (kJ/mol) of cis/trans-4a,
cis/trans-4h, and cis/trans-4u, calculated by Spartan 10, using
the DF B3LYP/6-31G* method.
azetidin-2-imines in good to excellent yield with high
diastereoselectivity. Starting materials are easily accessible.
This one-pot reaction proceeded smoothly at room tem-
perature with easy operation. It occurred in a parallel
catalysis manner, including a copper-catalyzed CspꢀCsp2
coupling, a copper-catalyzed alkyneꢀazide cycloaddition,
and a [2 þ 2] cycloaddition. All of these separate reactions
represent the frontier of modern organic chemistry and fit
the basic requirements of green chemistry with high atom
economy. Moreover, the synthesized azetidin-2-imines
could be conveniently converted into the structurally
interesting dihydroazeto[1,2-a]benzo[e]azepin-2(4H)-imines.
Further research on synthetic applications of this method is
underway in our laboratory.
Scheme 3. Proposed Mechanism for the Formation of
Azetidin-2-imines
Acknowledgment. We are thankful for the financial
support from the National Natural Science Foundation
of China (Nos. 21272204, 21032005, and J1210042).
As a synthetic application of this method, the synthe-
sized azetidin-2-imines 4 were conveniently converted into
dihydroazeto[1,2-a]benzo[e]azepin-2(4H)-imines 7 via an
electrophilic cyclization using 10 equiv of H2SO4 in DCE
(Scheme 4). The structure of 7a was unambiguously con-
firmed by the X-ray crystallographic analysis.9
In conclusion, we have developed a Cu-catalyzed four-
component reaction of imidoly chlorides, sulfonyl azides, and
two terminal alkynes, which afforded polyfunctionalized
Supporting Information Available. Experimental pro-
cedures, characterization data as well as 1H and 13C
NMR spectra for all products, and crystallographic
information files (CIF) for compounds 4b, 4q, and 7a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX