Diastereoselective 1,3-Dipolar Cycloadditions of N,N′-Cyclic Azomethine Imines with Iminooxindoles for Access to Oxindole Spiro-N,N-bicyclic Heterocycles

Article abstract of DOI:10.1021/acs.orglett.6b00139

In the presence of CuI, 1,3-dipolar cycloadditions of N,N′-cyclic azomethine imines with iminooxindoles proceeded readily and furnished novel oxindole spiro-N,N-bicyclic heterocycles in moderate to excellent chemical yields with excellent diastereoselecti

Full text of DOI:10.1021/acs.orglett.6b00139

Letter
pubs.acs.org/OrgLett
Diastereoselective 1,3-Dipolar Cycloadditions of N,N′‑Cyclic
Azomethine Imines with Iminooxindoles for Access to Oxindole
Spiro‑N,N‑bicyclic Heterocycles
Hong-Wu Zhao,* Bo Li, Hai-Liang Pang, Ting Tian, Xiao-Qin Chen, Xiu-Qing Song, Wei Meng,
Zhao Yang, Yu-Di Zhao, and Yue-Yang Liu
College of Life Science and Bio-engineering, Beijing University of Technology, No. 100 Pingleyuan, Chaoyang District, Beijing
100124, China
S
* Supporting Information
ABSTRACT: In the presence of CuI, 1,3-dipolar cycloadditions of N,N′-
cyclic azomethine imines with iminooxindoles proceeded readily and
furnished novel oxindole spiro-N,N-bicyclic heterocycles in moderate to
excellent chemical yields with excellent diastereoselectivities.
N,N′-Cyclic azomethine imines constitute a class of stable and
easily accessible 1,3-dipoles and act as versatile and robust
building blocks in numerous 1,3-dipolar cycloadditions (1,3-
DCs) for the construction of structurally diverse N,N-bicyclic
heterocycles with potential biological activities.1 As reported
in the literature, these kinds of 1,3-dipoles have been widely
applied in 1,3-DCs with diverse and highly functionalized
alkynes,2 allenes,3 and alkenes.4 For example, in 2011, Mizuno
and co-authors established the Cu(OH)x/Al2O3-catalyzed 1,3-
DC of N,N′-cyclic azomethine imines with terminal alkynes,
furnishing N,N-bicyclic pyrazolidinones (Scheme 1a).5 Later,
excellent advances have been achieved with N,N′-cyclic
azomethine imines in 1,3-DCs in recent years. However,
exploration of 1,3-DCs of N,N′-cyclic azomethine imines with
synthetically important and useful iminooxindoles,9 which can
produce oxindole spiro-N,N-bicyclic heterocycles with spi-
rooxindole derivatives with potential bioactivities,10 has not
been reported in the literature to date.
On the basis of the above-mentioned findings and
developments in the chemistry of N,N′-cyclic azomethine
imines, we designed unknown 1,3-DCs using N,N′-cyclic
azomethine imines as dipoles and iminooxindoles as
dipolarophiles.11 Our studies demonstrated that 1,3-DCs
between N,N′-cyclic azomethine imines and iminooxindoles
proceed readily, thus furnishing the desired novel oxindole
spiro-N,N-bicyclic heterocycles bearing potential bioactivities
in moderate to excellent chemical yields with excellent
diastereoselectivities. To the best of our knowledge, such a
work has not been reported in the literature so far.
Scheme 1. N,N′-Cyclic Azomethine Imines Involved in 1,3-
Dipolar Cycloadditions
First, we screened the effect of a wide range of catalysts on
the 1,3-DC between N,N′-cyclic azomethine imine 1a and
iminooxindole 2a at room temperature, as shown in Table 1.
These catalysts could promote the 1,3-DC through the
different activation modes, for example, metal chelation,12
hydrogen bonding,13 conjugated nucleophilic addition,7,14 etc.
Remarkably, the used catalysts affected the chemical yield
significantly and the diastereoselectivity slightly. In the case of
most catalysts, they gave product 3aa in excellent diaster-
eoselectivity (Table 1, entries 1, 3, 5−13, 19, and 20). Even
without catalyst, the distereoselectivity of 1,3-DC still reached
>99:1 dr (Table 1, entry 21). Consequently, we deduced that
the diastereoselectivity of 1,3-DC has no close relation to the
Wu and co-workers developed the gold-catalyzed 1,3-DC of
N,N′-cyclic azomethine imines with N-allenyl amides,
delivering pyrazolyl-based bicyclic heterocycles (Scheme
1b).6 In 2014, Guo and co-workers discovered the
phosphine-catalyzed 1,3-DC of N,N′-cyclic azomethine imines
with electron-deficient alkenes, yielding N,N-bicyclic hetero-
cycles (Scheme 1c).7 Moreover, in this context, some
enantioselective variants have been built for the construction
of enantioenriched N,N-bicyclic heterocycles under the
catalysis of chiral Lewis acids and organocatalysts.8 Therefore,
Received: January 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Screening of Catalysts
Table 2. Screening of Solvents
b
b
c
temp
time
(h)
CuI
yield
entry
cat.
temp
rt
time (h)
yield (%)
dr
c
entry
solv.
(°C)
(x mol %)
(%)
dr
1
2
CuI
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
20
20
40
42
38
40
trace
32
37
23
32
28
23
25
14
11
>99:1
>80:20
>99:1
1
2
toluene
EtOH
60
60
60
60
60
60
60
60
60
60
80
100
20
20
20
20
20
20
20
20
20
20
10
6
10
10
10
10
10
10
10
20
30
50
20
20
77
trace
60
>99:1
Cu(OAc)2
CuBF4
Yb(OTf)3
Zn(OTf)2
SnCl2
rt
3
rt
3
1,2-DCE
THF
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
4
rt
4
29
5
rt
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
5
CHCl3
1,4-dioxane
CH3CN
toluene
toluene
toluene
toluene
toluene
68
6
rt
6
28
7
CuCl
rt
7
41
8
CuBr
rt
8
88
9
Na2CO3
K2CO3
NaOAc
Et3N
rt
9
80
10
11
12
13
14
15
16
17
18
19
20
21
rt
10
11
12
77
rt
50
rt
10
quinine
DABCO
TFA
rt
a
d
Reactions were carried out with 0.12 mmol of 1a and 0.1 mmol of 2a
in the presence of x mol % of CuI in 1.0 mL of solvent at specified
temperature. Isolated yield. Determined by H NMR spectroscopy.
rt
nr
d
rt
nr
b
c
1
d
p-TSA
stearic acid
HOAc
CuI
rt
nr
d
rt
nr
d
temperature dramatically decreased the chemical yield of 3aa
(Table 2, entries 8 vs 11 and 12). Therefore, at the current
stage, we determined the optimal reaction conditions: 1a/2a/
CuI = 1.2:1:0.2, toluene, 60 °C.
rt
nr
40 °C
60 °C
rt
47
51
16
>99:1
>99:1
>99:1
CuI
a
Next, under the optimal reaction conditions, we extended
the reaction scope of 1,3-DC between N,N′-cyclic azomethine
imines 1 and iminooxindoles 2, as outlined in Table 3. In
most cases, the 1,3-DCs gave rise to products 3 in excellent
diastereoselectivities (Table 3, entries 1−26). In comparison,
the chemical yield of the 1,3-DCs was clearly affected by
substrates 1 and 2. Reaction of 1p with 2a did not take place
at all in 40 h (Table 3, entry 27). The same negative result
was observed with the reaction between 1q and 2a (Table 3,
entry 28). The 1,3-DCs of 1h with 2a and 1l with 2a
generated products 3ha and 3la in similar chemical yields
(Table 3, entries 19 vs 23). In the case of the rest of the 1,3-
DCs examined, the chemical yield of 3 ranged from 80 to
95% (Table 3, entries 1−18, 20−22, and 24−26).
Simultaneously, the relative configuration of 3aa was
determined by single-crystal X-ray analysis, as depicted in
Figure 1. On the basis of the relative stereochemistry of 3aa,
we similarly assigned the relative configurations of other 3
products as shown in Table 3.15 Moreover, we carried out 1,3-
DC of 1i and 2a on a gram scale, and 3ia was obtained in
97% yield (see details in Supporting Information, SI).
Meanwhile, the asymmetric catalytic 1,3-DC of 1a and 2a
was attempted using chiral Lewis acids and organocatalysts;
however, 3aa was isolated as a racemate in all cases (see
details in SI).
Reactions were carried out with 0.12 mmol of 1a and 0.1 mmol of 2a
in the presence of 10 mol % of catalyst in 1.0 mL of CH2Cl2 at
b
c
specified temperature. Isolated yield. Determined by 1H NMR
d
spectroscopy. No reaction.
organocatalysts used. By comparison, the chemical yield of
3aa highly depended on the structural nature of the catalysts
examined. Using DABCO, TFA, p-TSA, stearic acid, and
HOAc as catalysts did not produce product 3aa in 40 h
(Table 1, entries 14−18). Catalyzed by Yb(OTf)3, the 1,3-DC
yielded 3aa in a trace amount in 40 h (Table 1, entry 4). For
other catalysts, the chemical yield of 3aa ranged from 11 to
42% (Table 1, entries 1−3 and 5−13). Moreover, it was
noted that increasing the reaction temperature could increase
the chemical yield of 3aa in the different degrees (Table 1,
entries 1 vs 19 and 20).
In the presence of 10 mol % of CuI at 60 °C, we explored
the effect of various organic solvents on the 1,3-DC between
N,N′-cyclic azomethine imine 1a and iminooxindole 2a as
presented in entries 1−7 of Table 2. Noticeably, the used
solvents influenced the chemical yield of 3aa largely and did
not change the diastereoselectivity of 3aa at all. In all the
solvents checked, the 1,3-DC reaction went smoothly, thus
furnishing 3aa in excellent diastereoselectivity (Table 2,
entries 1−7). Regarding the chemical yield of 3aa, it was
significantly affected by the solvent used. For example, use of
EtOH gave 3aa in a trace amount after 20 h (Table 2, entry
2). In the case of THF and 1,4-dioxane, 3aa was obtained in
similar chemical yields (Table 2, entries 4 and 6). With
respect to other solvents, the chemical yield of 3aa changed
from 41 to 77% (Table 2, entries 1, 3, 5, and 7).
Simultaneously, the catalytic loading of CuI was screened in
the range from 10 to 50 mol %, and 3aa was obtained in the
highest yield when CuI was loaded in 20 mol % (Table 2,
entries 1 and 8−10). Moreover, the increase in the reaction
Conformational analysis of 3aa indicated that its N,N-
bicyclic moiety adopts a concave conformation. By virtue of
the nonplanar structure of the N,N-bicyclic subunit, the two
protons of the NCH2 group in the pyrazolidinone ring
become chemically nonequivalent: one proton resides in the
deshielding area of the monosubstituted benzene ring of 1,2,4-
triazolidine; the other one positions at the shielding area of
the same benzene ring. As a consequence, the two protons
1
should exhibit quite different behaviors in H NMR. Actually,
1
this assumption was in full agreement with the obtained H
B
DOI: 10.1021/acs.orglett.6b00139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Extension of the Reaction Scope
b
c
entry
1 (R1, R4)
1a (C6H5, H)
2 (R2, R3)
time (h)
3
yield (%)
dr
1
2
2a (H, Me)
2b (5-F, Me)
2c (5-Cl, Me)
2d (5-OMe, Me)
2e (5-Me, Me)
2f (5-Br, Me)
2g (5-NO2, Me)
2h (6-Cl, Me)
2i (6-Br, Me)
2j (H, Bn)
20
20
12
20
20
12
20
20
12
20
20
20
20
40
40
20
40
20
12
12
40
40
40
40
40
20
40
40
3aa
3ab
3ac
3ad
3ae
3af
88
92
90
87
94
91
90
83
85
87
83
88
83
94
85
80
86
91
78
95
88
81
77
82
80
86
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1a (C6H5, H)
3
1a (C6H5, H)
4
1a (C6H5, H)
5
1a (C6H5, H)
6
1a (C6H5, H)
7
1a (C6H5, H)
3ag
3ah
3ai
8
1a (C6H5, H)
9
1a (C6H5, H)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1a (C6H5, H)
3aj
1a (C6H5, H)
2k (H, allyl)
2l (H, MOM)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
2a (H, Me)
3ak
3al
1a (C6H5, H)
1b (4-F-C6H4, H)
1c (3-F-C6H4, H)
1d (2-F-C6H4, H)
1e (4-Cl-C6H4, H)
1f (2-Cl-C6H4, H)
1g (3-Cl-C6H4, H)
1h (4-Br-C6H4, H)
1i (2-Br-C6H4, H)
1j (4-Me-C6H4, H)
1k (3-Me-C6H4, H)
1l (4-MeO-C6H4,H)
1m (3-MeO-C6H4, H)
1n (3,4-di-MeO-C6H3, H)
1o (4-pyridine, H)
1p (2-thiophene, H)
1q (Me, Me)
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
d
nr
d
nr
a
b
Reactions were carried out with 0.12 mmol of 1 and 0.1 mmol of 2 in the presence of 20 mol % of CuI in 1.0 mL of toluene at 60 °C. Isolated
c
d
1
yield. Determined by H NMR spectroscopy. No reaction.
Scheme 2. Proposed Mechanism for the Formation of 3aa
Figure 1. X-ray single-crystal structure of 3aa (with thermal ellipsoils
shown at the 50% probability level).
NMR experimental results (see details in SI): one proton
resonates at 3.17 ppm, and the other one signals at 3.43 ppm.
Moreover, we shed light on the diastereoselective formation
of anti-3aa on the basis of the proposed reaction mechanism
as described in Scheme 2. First, the chelation interaction of 2a
to CuI affords 4a. Then, 4a will attack 1a by the two different
orientations, as shown in transition states TS1 and TS2,
which lead to the formation of anti-3aa and syn-3aa,
respectively. With the aid of the molecular model, we found
strong steric repulsion between the benzene ring and Boc
group in TS2. Compared to TS2, the same destabilizing effect
does not exist at all in TS1. As a consequence, transition state
TS1 should be more stable than TS2 and mainly accounts for
the formation of anti-3aa. According to literature,16 it is
assumed that 1,3-DC of 1a and 2a follows a concerted
process. Moreover, DFT calculations have located the
concerted transition states TS1 and TS2 and disclosed that
the formation of anti-3aa is kinetically and thermodynamically
favored (see details in SI).
In conclusion, in the presence of 20 mol % of CuI, the 1,3-
dipolar cycloadditions of N,N′-cyclic azomethine imines 1
with iminooxindoles 2 proceeded efficiently and provided easy
access to the oxindole spiro-N,N-bicyclic heterocycles in
C
DOI: 10.1021/acs.orglett.6b00139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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diastereoselectivities. Furthermore, exploration of new cyclo-
additions of N,N′-cyclic azomethine imines with various
structurally diverse and complex dipolarophiles is ongoing in
our organic lab and will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00139.
Experimental details and NMR spectra for the obtained
compounds 3 (PDF)
X-ray data for 3aa (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hwzhao@bjut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foun-
dation (Nos. 7102010, 2122008), Basic Research Foundation
of Beijing University of Technology (X4015001201101),
Funding Project for Academic Human Resources Develop-
ment in Institutions of Higher Learning Under the
Jurisdiction of Beijing Municipality (No. PHR201008025),
and Doctoral Scientific Research Start-up Foundation of
Beijing University of Technology (No. 52015001200701) for
financial support.
(15) CCDC 1446365 contains the supplementary crystallographic
data for compound 3aa. These data can be obtained free of charge
from The Cambridge Crystallographic Data Center at www.ccdc.cam.
ac.uk/data_request/cif.
(16) Pleshchev, M. I.; Gupta, N. V. D.; Struchkova, M. I.;
Goloveshkin, A. S.; Bushmarinov, I. S.; Khakimov, D. V.; Makhova,
N. N. Mendeleev Commun. 2015, 25, 188.
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DOI: 10.1021/acs.orglett.6b00139
Org. Lett. XXXX, XXX, XXX−XXX