Highly Chemo- and Diastereoselective Dearomative [3 + 2] Cycloaddition Reactions of Benzazoles with Donor-Acceptor Oxiranes

Article abstract of DOI:10.1021/acs.orglett.8b03615

A Sc(OTf)₃-catalyzed dearomative [3 + 2] cycloaddition of benzazoles with donor-acceptor oxiranes through chemoselective C-C bond cleavage of oxiranes was developed under mild conditions. This reaction provides an efficient method to construct benzazolo[3,2-c]oxazole compounds in good yields and with high diastereoselectivity. The reaction has a general substrate scope, and the donor-acceptor oxiranes with electron-donating and electron-withdrawing groups on the aromatic ring afforded the desired cycloadducts.

Full text of DOI:10.1021/acs.orglett.8b03615

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Chemo- and Diastereoselective Dearomative [3 + 2]
Cycloaddition Reactions of Benzazoles with Donor−Acceptor
Oxiranes
Shan-Shan Zhang, Dong-Chao Wang,* Ming-Sheng Xie, Gui-Rong Qu, and Hai-Ming Guo*
Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation, Collaborative Innovation Center of Henan Province
for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
S
* Supporting Information
ABSTRACT: A Sc(OTf)3-catalyzed dearomative [3 + 2] cycloaddition of benzazoles with donor−acceptor oxiranes through
chemoselective C−C bond cleavage of oxiranes was developed under mild conditions. This reaction provides an efficient
method to construct benzazolo[3,2-c]oxazole compounds in good yields and with high diastereoselectivity. The reaction has a
general substrate scope, and the donor−acceptor oxiranes with electron-donating and electron-withdrawing groups on the
aromatic ring afforded the desired cycloadducts.
enzazoles are an indispensable structural motif in drug
Recently, we developed a novel strategy to synthesize complex
Bdiscovery and found to have a broad spectrum of polyheterocyclic compounds by direct dearomative [3 + 2]
cycloaddition reactions of benzothiazoles and D−A cyclo-
propanes (Scheme 1a).14 As a part of our ongoing efforts on
dearomative reactions of benzazole compounds, herein, we
report an efficient Lewis acid-catalyzed [3 + 2] cycloaddition of
D−A oxiranes and benzazoles via C−C bond cleavage of
oxiranes for the preparations of benzazolo[3,2-c]oxazole
derivatives in excellent yields and with high chemo- and
diastereoselectivities (Scheme 1b).
therapeutic applications such as anticancer, antihypertensive,
anticoagulant, antibacterial, antifungal, antimalarial, anticonvul-
sant, antiviral, and analgesic.1,2 In particular, 10 drugs in the top
200 pharmaceutical products are benzazole derivatives.3
Dearomatized benzazole motifs are found as core skeletons in
natural and unnatural polycyclic molecules.4 Recently, dear-
omatization reactions of benzazoles for the rapid preparation of
three-dimensional fused heterocyclic compounds have attracted
much attention.2,5 Therefore, development of efficient methods
to construct complex benzazole derivatives is highly desirable.
Carbonyl ylides, a useful class of 1,3-dipoles in [3 + 2]
cycloaddition reactions, have been often used to construct oxa-
heterocyclic skeletons such as 1,3-dioxolane, oxazolidine, and
tetrahydrofuran.6,7 Donor−acceptor (D−A) oxiranes received
remarkable attention as an economical and mild source of
carbonyl ylide. Various [3 + 2] cycloaddition reactions of D−A
oxiranes with different unsaturated double bonds such as C
C,8,9 CO,10 CN,11 CS,12 and CN13 have been
reported in the literature. Among them, Zhang and co-workers8a
developed a dearomative [3 + 2] cycloaddition of D−A oxiranes
and indoles via selective C−C bond cleavage of oxirane for the
synthesis of furo[3,4-b]indole compounds for the first time.
Subsequently, Feng and co-workers8b demonstrated an efficient
catalytic asymmetric system for dearomative [3 + 2] cyclo-
addition of D−A oxiranes and indoles. To the best of our
knowledge, dearomative [3 + 2] cycloadditions of D−A oxiranes
with other aromatic compounds have not been reported.
Scheme 1. Dearomative [3 + 2] Cycloaddition Reactions of
Benzazoles
Received: November 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our investigation began with the 1,3-dipolar cycloaddition of
oxirane 2a with benzothiazole 1a. We initially carried out the
screening of Lewisacids at room temperature in the presence of 4
Å molecular sieves (MS) using DCE as a solvent. As shown in
Table 1, Ni(ClO4)2·6H2O, Yb(OTf)3, and Sc(OTf)3 success-
(Table 1, entry 15). When the dearomative cycloaddition
reaction was conducted on gram scale, cycloadduct 3aa was
isolated in 87% yield (see Scheme S1).
After optimizing the reaction conditions, we explored the
scope of this dearomative cycloaddition reaction by varying
substituent R1 of benzothiazole substrates. As shown in Scheme
2, benzothiazoles bearing electron-donating or electron-with-
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Benzothiazoles for the
a
Dearomative [3 + 2] Cycloaddition
b
c
entry
catalyst (mol %)
temp (°C)
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
toluene
CHCl3
MeCN
1,4-dioxane
DCE
DCE
DCE
DCE
yield (%)
1
2
3
4
5
7
8
9
Ni(ClO4)2·6H2O (20)
Yb(OTf)3 (20)
Sc(OTf)3 (20)
Zn(OTf)2 (20)
Cu(OTf)2 (20)
MgI2 (20)
Ni(OTf)2 (20)
Sc(OTf)3 (20)
Sc(OTf)3 (20)
Sc(OTf)3 (20)
Sc(OTf)3 (20)
Sc(OTf)3 (20)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (5)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
rt
86
79
92
17
<10
<10
24
86
81
43
nr
10
11
12
13
14
15
16
17
nr
47
93
62
0
d
d
e
Sc(OTf)3 (10)
a
Reaction conditions: catalyst (20 mol %), 1a (0.1 mmol), 1.0 mL of
solvent, 2a (0.2 mmol), and activated 4 Å MS (60 mg) under N2 at
b
c
room temperature for 16 h. Reaction temperature. Isolated yields;
1
the dr value was >20:1, as determined by H NMR analysis of the
d
e
crude reaction mixture. Reaction time: 3 days. Without MS. DCM
= dichloromethane, DCE = 1,2-dichloroethane, MS = molecular
sieves, Tf = trifluoromethanesulfonyl. nr = no reaction.
a
Reaction conditions: Sc(OTf)3 (10 mol %), 1 (0.1 mmol), 2a (0.2
fully catalyzed the cycloaddition reaction and afforded the
desired product 3aa with high diastereoselectivities (>20:1) and
excellent chemoselectivity (only C−C bond cleavage of oxirane)
in satisfactory yields using 20 mol % catalyst loading (Table 1,
entries 1−3). Among them, Sc(OTf)3 showed the highest
efficiency and gave the product 3aa in 92% yield (Table 1, entry
3). However, the other Lewis acids showed a lower catalytic
activity (Table 1, entries 4−8). DCE was found to be the best
solvent among the screened solvents. Then we optimized other
conditions such as catalyst amount, reaction time, and
temperature. When the reaction was carried out with 10 mol %
of Sc(OTf)3 for 16 h, the isolated yield of desired cycloadduct
3aa was only 47% (Table 1, entry 14). On the other hand, when
the reaction was carried out for 3 days with 10 mol % of
Sc(OTf)3, the cycloadduct 3aa was obtained in 93% yield (Table
1, entry 15). When 5 mol % of Sc(OTf)3 was used, the
conversion rate was still low even after the reaction was carried
out at 60 °C for 3 days, and the isolated yield of cycloadduct 3aa
was only 62% (Table 1, entry 16). Considering the efficiency of
reaction, 10 mol % catalyst loading at room temperature was
selected as the optimized reaction condition. In addition, the
dearomatized cycloadduct was not observed in the absence of
MS (Table 1, entry 17). Thus, the optimized reaction conditions
are as follows: 10 mol % of Sc(OTf)3, 1.0 equiv of 1a, and 2.0
equiv of 2a in 1.0 mL of DCE at room temperature for 3 days
mmol), and activated 4 Å MS (60 mg) in DCE (1.0 mL) under N2 at
room temperature for 3 days.
drawing substituents reacted smoothly with oxirane 2a and led to
the corresponding cycloadducts (3aa−la) in good yields and
with excellent diastereoselectivities.
We next examined the scope of this dearomative cycloaddition
by varying R2 and Ar of oxiranes under the optimized conditions.
In general, compared with the substratescope in the dearomative
cycloaddition of indoles with epoxides, the current dearomative
cycloaddition has a more general scope for the oxiranes. As
shown in Scheme 3, the D−A oxiranes with electron-donating
and electron-withdrawing groups on the aromatic ring were able
to afford the desired cycloadducts. Obviously, D−A oxiranes
with electron-rich aryl groups exhibited a higher reactivity than
those with electron-deficient aryl groups (Scheme 3, 3ab−ao).
Furthermore, the reactivity of oxiranes varied depending on the
position of halogen on the aryl groups. For example, using
oxiranes with 4-halogen substituted aryl group under the optimal
conditions, the desired cycloadducts were obtained in 62−78%
yields (Scheme 3, 3ab−ad). 3-Halogen-substituted oxiranes
afforded products in 67−72% yields using 20 mol % catalyst
loading (Scheme 3, 3ae, 3af). The structure of product 3af was
confirmed by single-crystal X-ray diffraction analysis. On the
B
DOI: 10.1021/acs.orglett.8b03615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of Oxiranes for Dearomative [3 +
2] Cycloaddition
Scheme 4. Dearomative [3 + 2] Cycloaddition of
Benzimidazoles 4a−d with Oxirane 2a
a
a
a
Unless otherwise noted, the reaction conditions are as follows:
Sc(OTf)3 (20 mol %), 4 (0.1 mmol), 2a (0.2 mmol), and activated 4
b
Å MS (60 mg) in DCE (1.0 mL) under N2 at 60 °C for 48 h. 10 mol
% of Sc(OTf)3 at at room temperature for 3 days. Product 7 was
purified by neutral alumina column chromatography.
by single-crystal X-ray diffraction analysis. The other sub-
stituents such as acetyl, tert-butyloxyformyl, and vinyl gave a
relatively low yield (Scheme 3, 5ba−da). However, dearomat-
ized cycloadducts were not observed with N1-methyl and -benzyl
benzimidazoles, perhaps due to the effect of electron-donating
alkyl groups. However, the desired reaction of benzoxazole with
oxirane 2a proceeded smoothly, and the corresponding
cycloadduct 7 was obtained in 86% yield. It should be noted
that the product 7 is easily decomposed on a silica gel column.
Finally, the conversion of products into other products with
useful functional groups was also studied. As shown in Scheme 5,
a
Reaction conditions: Sc(OTf)3 (10 mol %), 1a (0.1 mmol), 2 (0.2
mmol), and activated 4 Å MS (60 mg) in DCE (1.0 mL) under N2 at
room temperature for 3 days. 20 mol % of Sc(OTf)3 at 60 °C for 6
days, 20 mol % of Sc(OTf)3.
b
c
Scheme 5. Further Transformation of the Cycloadduct 3aa
other hand, the reactions of 2-chlorophenyl oxirane 2g required
20 mol % catalyst loading, higher reaction temperature, and
longer reaction time to afford the desired product 3ag (Scheme
3, 57% yield). In addition, 3,4-dichlorophenyl oxirane 2h with 20
mol % catalyst loading afforded the adduct in 53% yield (Scheme
3, 3ah). In contrast, all of the D−A oxiranes with electron-
donating groups gave the corresponding products in 89−94%
yields (Scheme 3, 3ai−ao). Moreover, the 1-naphthyl-
substituted oxirane furnished the corresponding product in
94% yield (Scheme 3, 3ap). In the end, the oxiranes with various
R2 showed a slight effect on the reactivity and afforded the
desired dearomatized products in 96% and 92% yields (Scheme
3, 3aq, 3ar). In addition, 3-(thiophene-3-yl)oxirane 2s gave the
desired product 3as (Scheme 3) in 86% yield.
As shown in Scheme 4, we also examined the reactivity of
benzimidazoles and benzoxazole under the optimal conditions.
Obviously, benzimidazoles are less reactive than benzothiazoles,
and the dearomative [3 + 2] cycloaddition of benzimidazoles
required 20 mol % catalyst loading at 60 °C. Effect of various N1
substituent groups of benzimidazoles on their reactivity was also
explored. When N1-tosyl (Ts) benzimidazole was employed, the
dearomatized cycloadduct 5aa was obtained in 81% yield
(Scheme 4). The structure of compound 5aa was also confirmed
selective reduction of ester groups of 3aa was achieved with
NaBH4 in CH3OH by varying temperature and time. The
reduction of monoester was achieved at 0 °C in 6 h, affording 8 in
64% yield (Scheme 5a), whereas the reduction of both the ester
groups to the corresponding alcohols (9, Scheme 5b) was
observed at 60 °C in 12 h.
In summary, we have successfully developed an efficient
dearomative [3 + 2] cycloaddition of benzazoles with donor−
acceptor oxiranes through chemoselective C−C bond cleavage
of oxiranes under mild conditions. In the presence of Sc(OTf)3
catalyst, a series of benzazolo[3,2-c]oxazoles were synthesized in
good yields and with high diastereoselectivities. The reaction has
a general substrate scope for oxiranes with electron-donating and
electron-withdrawing groups on the aromatic ring.
C
DOI: 10.1021/acs.orglett.8b03615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03615.
■
S
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Experimental procedures and compound characterization
data (PDF)
Accession Codes
CCDC 1873311 (3af), 1873309 (5aa) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
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AUTHOR INFORMATION
Corresponding Authors
■
́
́
Derdour, A.; Roisnel, T.; Saez, J. A.; Perez, P.; Chamorro, E.; Domingo,
L. R.; Mongin, F. J. Org. Chem. 2009, 74, 2120. (e) Sheng, J.; Chang, H.;
Qian, Y.; Ma, M.; Hu, W. Tetrahedron Lett. 2018, 59, 2141. For
tetrahydrofuran, see: (f) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60,
6258. (g) Liu, R.;Zhang, M.; Zhang, J. Chem. Commun. 2011, 47, 12870.
(h) Zhou, J.-L.; Liang, Y.; Deng, C.; Zhou, H.; Wang, Z.; Sun, X.-L.;
Zheng, J.-C.; Yu, Z.-X.; Tang, Y. Angew. Chem., Int. Ed. 2011, 50, 7874.
(i) Suga, H.; Hashimoto, Y.; Yasumura, S.; Takezawa, R.; Itoh, K.;
Kakehi, A. J. Org. Chem. 2013, 78, 10840. (j) Suga, H.; Sekikawa, Y.;
Misawa, S.; Kinugawa, D.; Oda, R.; Itoh, K.; Toda, Y.; Kiyono, R. J. Org.
Chem. 2015, 80, 6687. (k) Liu, Y. F.; Wang, Z.; Shi, J. W.; Chen, B. L.;
Zhao, Z. G.; Chen, Z. J. Org. Chem. 2015, 80, 12733. (l) Sharp, P. P.;
Mikusek, J.; Ho, J.; Krenske, E. H.; Banwell, M. G.; Coote, M. L.; Ward,
J. S.; Willis, A. C. J. Org. Chem. 2018, 83, 13678.
*E-mail: wangdc@htu.edu.cn.
*E-mail: ghm@htu.edu.cn.
ORCID
Dong-Chao Wang: 0000-0002-5037-4727
Ming-Sheng Xie: 0000-0003-4113-2168
Hai-Ming Guo: 0000-0003-0629-4524
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (Nos.
2167255 and U1604283), Program for Youth BackboneTeacher
Training in University of Henan Province (2017GGJS042), and
the 111 Project (No. D17007).
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DOI: 10.1021/acs.orglett.8b03615
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