Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

Article abstract of DOI:10.1016/j.chempr.2018.10.003

The enantioselective dearomative [3 + 2] cycloaddition reaction of benzazoles with aminocyclopropanes has been successfully developed. In the presence of a copper complex, derived from Cu(OTf)₂ and bisoxazoline, a series of hydropyrrolo-benzazole derivatives containing quaternary stereogenic centers were obtained in high yields with excellent enantioselectivity. This method could also provide 2-amino cyclopropanes with high enantiomeric purity by an efficient kinetic resolution. In addition, products could be transformed to pyrrolo-benzothiazines and 1,5-benzothiazepines. Chiral compounds are of great significance in many areas given that two corresponding enantiomers could have completely different properties in chiral environments. Therefore, technologies used to produce chiral compounds in their enantiopure form are particularly attractive and highly desirable. Catalytic asymmetric dearomatization reactions have become efficient methods for the construction of chiral fused- or spiro-heterocycles from simple aromatics. Polyheterocyclic structures containing a hydropyrrolo-azole motif are found extensively in natural products and biologically active compounds. Therefore, efficient methods for constructing complex chiral hydropyrrolo-azole compounds will benefit the lead identification in drug discovery. Herein, we report the highly enantioselective construction of hydropyrrolo-benzazoles via copper-catalyzed dearomative [3 + 2] cycloaddition of benzazoles with donor-acceptor aminocyclopropanes. Heterocycles are a very important class of compounds that exist extensively as structural cores in natural products and biologically active molecules. Catalytic asymmetric dearomatization (CADA) is an efficient strategy for the construction of chiral fused- or spiro-heterocycles from simple planar aromatic compounds. Herein, we report the development of enantioselective dearomative [3 + 2] cycloaddition reactions of benzazoles with aminocyclopropanes via kinetic resolution. In the presence of a copper complex, derived from Cu(OTf)₂ and bisoxazoline, a series of hydropyrrolo-benzazole derivatives containing quaternary stereogenic centers were obtained in high yields (up to 99%) with excellent enantioselectivity (up to 99% enantiomeric excess [ee]). With the same catalytic system, 2-amino cyclopropane-1,1-dicarboxylates with a high enantiomeric purity (up to 98% ee) were also obtained by an efficient kinetic resolution (s values of up to 95). In addition, the utility of this method was showcased by the facile transformation of products into several important heterocyclic frameworks, including pyrrolo-benzothiazine and 1,5-benzothiazepine.

Full text of DOI:10.1016/j.chempr.2018.10.003

Article
Cu-catalyzed Asymmetric Dearomative [3 + 2]
Cycloaddition Reaction of Benzazoles with
Aminocyclopropanes
Meng-Cheng Zhang,
Dong-Chao Wang, Ming-Sheng
Xie, Gui-Rong Qu, Hai-Ming
Guo, Shu-Li You
ghm@htu.edu.cn (H.-M.G.)
slyou@sioc.ac.cn (S.-L.Y.)
HIGHLIGHTS
Construction of quaternary
stereogenic center
Asymmetric dearomatization of
benzazoles without preactivation
Highly enantioselective
construction of hydropyrrolo-
benzazoles
DATA AND SOFTWARE
AVAILABILITY
1818461
1818462
1818597
1818598
The enantioselective dearomative [3 + 2] cycloaddition reaction of benzazoles with
aminocyclopropanes has been successfully developed. In the presence of a
copper complex, derived from Cu(OTf)2 and bisoxazoline, a series of
hydropyrrolo-benzazole derivatives containing quaternary stereogenic centers
were obtained in high yields with excellent enantioselectivity. This method could
also provide 2-amino cyclopropanes with high enantiomeric purity by an efficient
kinetic resolution. In addition, products could be transformed to pyrrolo-
benzothiazines and 1,5-benzothiazepines.
Zhang et al., Chem 5, 1–12
January 10, 2019 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.10.003

Please cite this article in press as: Zhang et al., Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Amino-
cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Article
Cu-catalyzed Asymmetric Dearomative [3 + 2]
Cycloaddition Reaction
of Benzazoles with Aminocyclopropanes
Meng-Cheng Zhang,1,3 Dong-Chao Wang,1,3 Ming-Sheng Xie,1 Gui-Rong Qu,1 Hai-Ming Guo,1,
*
and Shu-Li You2,4,
*
SUMMARY
The Bigger Picture
Chiral compounds are of great
significance in many areas given
that two corresponding
Heterocycles are a very important class of compounds that exist extensively as
structural cores in natural products and biologically active molecules. Catalytic
asymmetric dearomatization (CADA) is an efficient strategy for the construction
of chiral fused- or spiro-heterocycles from simple planar aromatic compounds.
Herein, we report the development of enantioselective dearomative [3 + 2]
cycloaddition reactions of benzazoles with aminocyclopropanes via kinetic res-
olution. In the presence of a copper complex, derived from Cu(OTf)2 and bisox-
azoline, a series of hydropyrrolo-benzazole derivatives containing quaternary
stereogenic centers were obtained in high yields (up to 99%) with excellent
enantioselectivity (up to 99% enantiomeric excess [ee]). With the same catalytic
system, 2-amino cyclopropane-1,1-dicarboxylates with a high enantiomeric pu-
rity (up to 98% ee) were also obtained by an efficient kinetic resolution (s values
of up to 95). In addition, the utility of this method was showcased by the facile
transformation of products into several important heterocyclic frameworks,
including pyrrolo-benzothiazine and 1,5-benzothiazepine.
enantiomers could have
completely different properties in
chiral environments. Therefore,
technologies used to produce
chiral compounds in their
enantiopure form are particularly
attractive and highly desirable.
Catalytic asymmetric
dearomatization reactions have
become efficient methods for the
construction of chiral fused- or
spiro-heterocycles from simple
aromatics. Polyheterocyclic
structures containing a
INTRODUCTION
hydropyrrolo-azole motif are
found extensively in natural
products and biologically active
compounds. Therefore, efficient
methods for constructing
Azoles, a very important class of nitrogen-containing aromatic heterocycles, are the
core structure of many natural and unnatural compounds with diverse biological ac-
tivities, which include anti-bacterial, anti-fungal, anti-malarial, anti-parasitic, and
anti-cancer activities.1–5 Polyheterocyclic structures containing a non-aromatic azole
motif are widely found in natural products, biologically active compounds, and their
analogs (Figure 1).6–9 In addition, these structures are often used as key intermedi-
ates in organic synthesis.10–19 Therefore, efficient methods for constructing complex
chiral heterocycles are in high demand.
complex chiral hydropyrrolo-
azole compounds will benefit the
lead identification in drug
discovery. Herein, we report the
highly enantioselective
Aromatic compounds are readily available and inexpensive starting materials that
are used in many fields, such as polymers, paints, cosmetics, and pharmaceuti-
cals.20–23 Catalytic asymmetric dearomatization (CADA) is an efficient strategy
for constructing various chiral fused- or spiro-ring systems from simple planar aro-
matic compounds. Compared with electron-rich aromatics,24–27 including indoles,
pyrroles, and furans, little research has been performed on CADA reactions of
electron-deficient N-heteroarenes despite the fact that these reactions would
deliver highly interesting heterocycles. Previous dearomatization reactions of elec-
tron-deficient N-heteroarenes have focused on asymmetric hydrogenation,28,29
hydrosilylation, hydroboration,30 and Reissert-type reactions.31–33 In the Reissert-
type reactions electron-deficient N-heteroarenes, such as pyridines and quinolines,
construction of hydropyrrolo-
benzazoles via copper-catalyzed
dearomative [3 + 2] cycloaddition
of benzazoles with donor-
acceptor aminocyclopropanes.
Chem 5, 1–12, January 10, 2019 ª 2018 Elsevier Inc.
1

Please cite this article in press as: Zhang et al., Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Amino-
cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Figure 1. Examples of Natural Products and Bioactive Compounds Containing Pyrrolo-Azole
Motifs
are often first activated by N-acylation or alkylation. The development of CADA re-
actions of electron-deficient N-heteroarenes that have not been preactivated has
been challenging and was only reported recently. You and coworkers22,34,35
reported iridium-catalyzed allylic dearomatization reactions of electron-deficient
N-heteroaromatic compounds. Smith and coworkers36 conducted direct dearoma-
tive [3 + 3] cycloaddition reactions using benzazoles containing nucleophiles as
1,3-dipoles. We37 recently developed a direct asymmetric dearomative [3 + 2]
cycloaddition reaction for benzothiazoles with 2-aryl cyclopropane-1,1-dicarboxy-
lates (Scheme 1A). Using benzothiazoles as dipolarophiles, a series of pyrrolo-thia-
zole compounds were obtained with excellent enantioselectivity and yields.
However, the attempts to construct a quaternary stereogenic center38–42 using
2-methyl benzothiazole (2a) failed because of the low reactivity of 2-aryl cyclopro-
pane-1,1-dicarboxylates. Inspired by the pioneering work from the Waser
group43–47 on various aminocyclopropane transformation reactions, we envisioned
that the employment of D-A aminocyclopropanes with high reactivities might
address the construction issues of quaternary stereogenic centers. To our knowl-
edge, CADA reactions of azole compounds with D-A aminocyclopropanes have
not yet been studied.
In this article, we report the development of enantioselective dearomative [3 + 2]
cycloaddition reactions of benzazoles with 2-amino cyclopropane-1,1-dicarboxy-
lates via kinetic resolution. These reactions delivered hydropyrrolo-benzazoles
containing quaternary stereogenic centers in good yields with excellent enantiose-
lectivity (Scheme 1B). In addition, the dearomatized products were able to undergo
diverse transformations.
RESULTS AND DISCUSSION
For construction of the quaternary stereogenic center during the dearomatization of
benzazoles, racemic phthalimido-substituted cyclopropane (1a0) and 2-methyl ben-
zothiazole (2a) were first employed as model substrates for optimization of the reac-
1School of Chemistry and Chemical Engineering,
Henan Key Laboratory of Organic Functional
Molecules and Drugs Innovation, Collaborative
tion conditions. We began our experiments by using previously established optimal
conditions (see Table S1). However, dearomatized product 3a0 was obtained in a
Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, Henan Normal
sis of the enantioselective transformation of D-A aminocyclopropanes reported by
University, Xinxiang, Henan 453007, China
lower yield and enantiomeric excess (ee) value than previously reported. On the ba-
the Waser group,46 the screening of Lewis acids in the presence of BOX ligand L1
was performed in 1,2-dichloroethane (DCE) at 0ꢀC. As shown in Table 1, several
2State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
Lewis acids were indeed able to catalyze dearomative cycloaddition reactions,
and the desired dearomatized product 3a0 was isolated in varied yields but with
low enantioselectivity (Table 1, entries 1–4). The utilization of Cu(OTf)2 delivered
3a0 in 61% yield and 15% ee (Table 1, entry 2), which inspired us to further examine
a series of chiral ligands in the presence of Cu(OTf)2 (Table 1, entries 5–10). Reac-
tions with bisoxazolines L1–L5 gave the desired cycloadducts in good yields and
low enantioselectivity, and among them the desired cycloadduct 3a0 was obtained
3These authors contributed equally
4Lead Contact
*Correspondence: ghm@htu.edu.cn (H.-M.G.),
slyou@sioc.ac.cn (S.-L.Y.)
https://doi.org/10.1016/j.chempr.2018.10.003
2
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Please cite this article in press as: Zhang et al., Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Amino-
cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
A
B
Scheme 1. Asymmetric Dearomative [3 + 2] Cycloaddition Reactions of Benzazoles with
Cyclopropane-1,1-Dicarboxylates
in 64% yield and 52% ee when the bisoxazoline ligand L3 was used (Table 1, entry 6).
The desired dearomative cycloaddition reactions did not proceed in the presence of
Pybox L6 or L7 (Table 1, entries 9 and 10). To our delight, the utilization of succini-
mido-substituted cyclopropane 1a instead of cyclopropane 1a0 in the presence of
Cu(OTf)2 and ligand L3 afforded the desired cycloadduct 3a in 39% yield and 95%
ee (Table 1, entry 11). Obviously, changing the substrate is a key parameter in the
construction of highly enantioselective quaternary stereogenic centers. Interest-
ingly, the combination of succinimidyl cyclopropane 1a with L3 in the current dear-
omative cycloaddition has been described in previous [3 + 2] cycloaddition reactions
of aminocyclopropanes with enol ethers or aldehydes.46 Therefore, we began to
employ succinimido-substituted cyclopropane 1a for the subsequent optimization
of reaction conditions. After screening various solvents and molecular sieves (MS)
˚
(Table 1, entries 12–17; see also Table S1), the use of 4-A MS and dichloromethane
resulted in the isolation of the desired product in 37% yield and 97% ee (Table 1, en-
try 12). Consequently, counteranion effects were studied. The use of Cu(ClO4)2 gave
product 3a in 20% yield and 93% ee, and the use of Cu(SbF6)2 led to no product for-
mation (see Table S1). To improve the yield, we performed additional screenings for
optimizing the reaction temperature and substrate ratio (Table 1, entries 18 and 19;
see also Table S1). When the ratio of rac-1a and 2a was 4:1 at 0ꢀC, the yield and
enantioselectivity were highest (Table 1, entry 19, 83% yield and 97% ee). Thus,
the following optimized reaction conditions were obtained: 10 mol % of Cu(OTf)2,
12 mol % of L3, 1.0 equivalent of 2a, and 4.0 equivalents of 1a in DCM at 0ꢀC (Table 1,
entry 19).
After optimizing the reaction conditions, the substrate scope of this dearomative
cycloaddition process was examined under these optimized conditions. As shown
in Scheme 2, substituents located at the different positions of the substrates were
well tolerated, and the desired dearomatized products were generally obtained in
moderate to excellent yields and excellent ee values. When benzothiazoles bearing
different alkyl groups (Me, Et, n-Pr, and PhCH2) at the 2-position were tested, their
corresponding dearomatized cycloadducts were obtained in 47%–83% yields and
94%–97% ee (Scheme 2, 3a–3d). Due to the steric hindrance and electron-deficient
nature of the substituents, benzothiazoles 2e–2g failed to deliver the target products
3e–3g. Benzothiazoles bearing either electron-rich or electron-deficient substituents
at the 5- or 6-positions reacted well with aminocyclopropane (1a), affording the
desired products in good to excellent yields and ee values (Scheme 2, 3h–3p).
In addition to benzothiazoles, benzoxazoles were also observed to be suitable
Chem 5, 1–12, January 10, 2019
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cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Table 1. Optimization of the Reaction Conditions for the Dearomatization of 2-Methyl Benzothiazoles
O
O
O
N
CO2Et
CO2Et
N
S
LA/L, solvent
MS, 0 o
N
N
Me
+
C
CO2Et
CO2Et
O
S
Me
3a (3a')
( )-1a (1a')
2a
Bn
Bn
N
O
O
N
O
O
O
O
O
N
O
Ph
Ph
N
N
N
N
N
t-Bu
Ph
i-Pr
t-Bu
Ph
i-Pr
L4
L2
L1
L3
Ar
O
Ar
O
O
O
O
O
N
N
N
N
N
N
N
N
t-Bu
t-Bu
i-Pr
i-Pr
L5
Ar = 3,5-di-tert-butylphenyl
L6
L7
˚
Entry
1
Lewis Acida
MgBr2
L
MS (A)
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
PhCl
CHCl3
DCM
DCM
DCM
DCM
DCM
3
Yield (%)b
15
ee (%)c
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L3
L3
L3
L3
L3
L3
L3
L3
L3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
–
3
5
4
4
3a0
3a0
3a0
3a0
3a0
3a0
3a0
3a0
3a0
3a0
3a
3a
3a
3a
3a
3a
3a
3a
3a
2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
61
15
6
3
68
4
74
7
5
55
13
52
15
13
–
6
64
7
51
8
77
9
NR
<5
10
11
12
13
14
15
16
17
18
19
3
39
95
97
96
97
37
47
11
d
trace
42
–
92
13
97
67
97e
97f
83
aUnless otherwise noted, the reactions were carried out with Lewis acid (10 mol %), L (12 mol %), 2a (1.0 equiv), 1 (2.0 equiv) in solvent (1.0 mL) under N2 at 0ꢀC for
65 hr. NR, not recorded.
bIsolated yield.
cDetermined by HPLC analysis with a chiral stationary phase.
dWithout MS.
e2a (1.0 equiv), 1a (3.0 equiv).
f2a (1.0 equiv), 1a (4.0 equiv).
4
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cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Scheme 2. Substrate Scope of 2-Substituted Benzazole Derivatives
Unless otherwise noted, the reactions were carried out with Cu(OTf)2 (10 mol %), L3 (12 mol %), 2, 4, or 6 (1.0 equiv), and 1a (4.0 equiv) in DCM (1.0 mL) under N2 at
0ꢀC for 65 hr. Yields of isolated products are reported. The ee values were determined by HPLC analysis with a chiral stationary phase. The conversion of 2b to 3b
was 50%, as determined by 1H NMR analysis of the reaction mixture. The conversions to 3b, 5c, 5f, 5h, and 5i occurred at ꢁ20ꢀC for 5 days.
Chem 5, 1–12, January 10, 2019
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cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Scheme 3. Substrate Scope of Benzazole Derivatives with 2-H Substituents
O
O
N
O
Cu(OTf)2/L3, DCM
N
X
CO2Et
CO2Et
R
+
R
N
4Å MS, 0 o
C
N
CO2Et
CO2Et
O
X
2
4
6
X = S
H
X = O
( )-1a
3q-3x, 5j, 7
X = NTs
O
O
2q, R = H
3q, 81% yield, 96% ee
3r, 83% yield, 97% ee
3s, 81% yield, 96% ee
3t, 81% yield, 96% ee
3u, 49% yield, 95% ee
N
R
R
2r, R = Br
2s, R = NO2
2t, R = Cl
2u, R = Me
N
S
N
S
CO2Et
CO2Et
H
O
O
N
3v, 78% yield, 97% ee
3w, 75% yield, 97% ee
CO2Et 3x, 83% yield, 96% ee
CO2Et
2v, R = Cl
2w, R = Br
2x, R = NO2
N
S
N
R
R
S
H
O
O
N
N
5j, 78% yield, 96% ee
7c, 53% yield, 62% ee
N
4j
O
CO2Et
CO2Et
O
H
O
O
N
N
N
6c
N
Ts
CO2Et
CO2Et
N
H
Ts
Unless otherwise noted, the reactions were carried out with Cu(OTf)2 (10 mol %), L3 (12 mol %), 2, 4, or 6
(1.0 equiv), and 1a (4.0 equiv) in DCM (1.0 mL) under N2 at ꢁ20ꢀC for 5 days. Yields of isolated products are
reported. The ee values were determined by chiral-phase HPLC analysis. The conversion to 7c occurred in
DCE (1.0 mL) under N2 at 35ꢀC for 72 hr.
substrates, and the desired products were obtained in excellent yields and enantio-
selectivity (Scheme 2, 5a–5h). When naphtho[2,3-d]oxazole 4i was employed, the
desired product was successfully obtained in 99% yield and 95% ee (Scheme 2,
5i). However, 2-methyl-benzimidazoles 6a and 6b were not suitable for this
dearomative cycloaddition process (Scheme 2, 7a and 7b). In addition, the absolute
configuration of product 3j was determined to be (1R,3aS) via single-crystal X-ray
diffraction analysis.
To further explore the versatility of this procedure, we tested a series of benzazoles with
2-H substituents under the optimized reaction conditions. As shown in Scheme 3, ben-
zoxazole and benzothiazole derivatives could react smoothly, thus affording their
corresponding cycloadducts in good yields (up to 83%) and excellent enantioselectivity
(95%–97% ee). However, benzimidazole 6b gave the desired cycloadduct 7b in only
53% yield and 62% ee. Additionally we also employed pyridine and quinolone in the
optimized reaction conditions, but the desired products could not be obtained.
To test the practicality of the current methodology, we conducted a gram-scale
reaction under the optimized reaction conditions. The reaction of 2j using the
conditions shown in Scheme 4 at a 7-mmol scale afforded product 3j in 78% yield
(2.57 g) and excellent enantioselectivity (97% ee).
6
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cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Scheme 4. Gram-Scale Synthesis of the [3 + 2] Cycloadduct 3j
Consequently, the kinetic resolution of aminocyclopropanes was studied. When
the ratio of rac-1a and 2 (or 4) was 1:4, the dearomatized cycloaddition product 3 or 5
wasobtained in 35%–60% yieldand67%–96% ee (Table 2, entries 1–5). Meanwhile, ami-
nocyclopropane 1a was recovered in a range of 32%–58% yield and 73%–98% ee. In
summary, this method provided easy access to both polyheterocyclic compounds con-
taining either a pyrrolo-thiazole or pyrrolo-oxazole motif and aminocyclopropanes with
high enantiomeric purity. To the best of our knowledge, catalytic methods for obtaining
highly enantioenriched aminocyclopropanes have not yet been reported. According to
the results shown in Table 2 and the absolute configuration of product 3j confirmed by
single-crystalX-ray diffractionanalysis, the mechanismofthisdearomativecycloaddition
isin agreementwith thepreviously reported mechanismof (Z)-aldiminedescribedby the
Johnson group.48
To determine the absolute configuration of recovered aminocyclopropane 1a, we
conducted the kinetic resolution experiment of aminocyclopropane 1b with benzo-
thiazole 4i. As shown in Scheme 5, 1b was recovered in 41% yield and 98% ee. The
absolute configuration of recovered 1b was determined to be (S) via single-crystal
X-ray diffraction analysis of an enantiopure sample (Scheme 5). The absolute config-
uration of the recovered aminocyclopropane 1a in Table 2 was then determined to
be (S) by comparing its circular dichroism spectrum with that of 1b.
To enhance understanding of the stereocontrol of the current dearomatization reaction,
we employed (S)-1a in a dearomative cycloaddition catalyzed by Cu(OTf)2 without addi-
tional ligand. Interestingly, enantioenriched (S)-1a (98% ee) reacted smoothly with 2j in
thepresence of Cu(OTf)2 to afford (1S,3aR)-3j with almost no erosion of the enantiomeric
purity (96% ee) (Scheme 6). Thus, both enantiomers of the dearomatized cycloadducts
could be prepared easily with only one enantiomer of the chiral ligand.
To further demonstrate the synthetic utility of this new method, we conducted deriv-
atization experiments on dearomatized cycloadducts. Cycloadduct 3j was converted
to pyrrolo-benzothiazine derivative 9 in 90% yield and 97% ee in the presence of
Cu(OTf)2 in air (Scheme 7A). The structure of benzothiazine 9 was determined by sin-
gle-crystal X-ray diffraction analysis. Of particular note, benzothiazine derivatives ex-
hibited various important biological activities,49 and pyrrolo-benzothiazines were
reported as a new class of calcium antagonists.50
The 1,5-benzothiazepine derivatives also exhibited various important biological ac-
tivities.51–55 As shown in Scheme 7B, in the presence of Cu(OTf)2 under air, dearom-
atized cycloadduct 3q was smoothly converted to 1,5-benzothiazepine derivative
10 in 93% yield and 95% ee. The structure of 1,5-benzothiazepine 10 was also
confirmed by single-crystal X-ray diffraction analysis. In addition, treatment of 3j
with LiAlH4 gave product 11 in 93% yield and 98% ee (Scheme 7C). In all these cases,
the enantiomeric purity of the products was well maintained.
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cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Table 2. Kinetic Resolution of Aminocyclopropane 1a with Benzazoles
O
O
O
Cu(OTf)2 (10 mol %)
L3 (12 mol %)
DCM, 4Å MS, 0 oC
N
O
N
X
CO2Et
CO2Et
N
R
+
Me
R
N
+
N
O
CO2Et
CO Et
CO2Et
EtO2C
O
X
Me
2
1a
3, 5
( )-1a
2, 4
Entry
2 or 4
Time (hr)
3 or 5
1a
sc
Yield (%)a
43 (5i)
ee (%)b
96
Yield (%)a
ee (%)b
90
1
2
3
4
5
4i
4i
11
16
25
48
34
51
39
32
33
58
95
81
28
19
60
55 (5i)
91
96
4i
60 (5i)
72
98
4e
2j
57 (5e)
35 (3j)
67
96
93
73
Reaction conditions: Cu(OTf)2 (10 mol %), L3 (12 mol %), 2 or 4 (4.0 equiv), and 1a (1.0 equiv) in 1.0 mL of DCM under N2 at 0ꢀC.
aIsolated yield.
bDetermined by chiral HPLC.
cs = ln[(1 ꢁ C) (1 ꢁ ee1)]/ln[(1 ꢁ C) (1 + ee1)]; C = ee1/(ee3 + ee1), where ee1 = ee of the recovered substrate and ee3 = ee of the product.
In summary, we have developed the first enantioselective dearomative [3 + 2] cycload-
dition reaction of benzazoles with D-A aminocyclopropanes via kinetic resolution. A se-
ries of hydropyrrolo-benzazole derivatives, including hydropyrrolo-benzazoles with a
quaternary stereogenic center, were obtained in high yields with excellent enantioselec-
tivity. These results indicated that a highly efficient kinetic resolution process dominates
this dearomative cycloaddition reaction. Using the same catalytic system, an efficient ki-
netic resolution of 2-amino cyclopropane-1,1-dicarboxylates was also realized. In addi-
tion, the combination of asymmetric cycloaddition and kinetic resolution and cycloaddi-
tion provided a facile way to access both enantiomers of the dearomatized cycloadducts
without switching the chiral catalyst. The robustness and practicality of the current
method were demonstrated by large-scale synthesis. The utility of this dearomative
cycloaddition reactionwasfurthershowcasedbythe synthesisofafew important hetero-
cyclic frameworks, such as pyrrolo-benzothiazine and 1,5-benzothiazepine.
EXPERIMENTAL PROCEDURES
Representative Procedure for the CADA of Benzazoles with D-A
Aminocyclopropanes and Characterization of Products
To an oven-dried Schlenk tube equipped with a magnetic stir bar, Cu(OTf)2 (3.6 mg,
˚
0.01 mmol, 10 mol %), L3 (3.5 mg, 0.012 mmol, 12 mol %), and activated 4-A MS
Scheme 5. Stereoselectivity of the Current Cycloaddition Process
8
Chem 5, 1–12, January 10, 2019

Please cite this article in press as: Zhang et al., Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Amino-
cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Scheme 6. Synthesis of Both Enantiomers of Product 3j
(40 mg) were added. The tube was sealed with a threaded rubber stopper, evacuated,
and backfilled with N2 (this process was repeated three times). The tube was then
charged with DCM (0.5 mL) via syringe and was allowed to stir at room temperature until
a bright-green complex formed (approximately 0.5 hr). To this complex, a solution of
aminocyclopropane 1a (113.2 mg, 0.4 mmol, 4.0 equiv) and benzothiazole 2
(0.1 mmol, 1.0 equiv) in DCM (0.5 mL) was added at 0ꢀC. The reaction was allowed to
proceed until the starting material disappeared, which was confirmed by TLC analysis.
A
B
C
Scheme 7. Transformation Reactions of the Dearomatized Products
(A) Synthesis of benzothiazine 9.
(B) Synthesis of 1,5-benzothiazepine 10.
(C) Alcoholysis of compound 3j.
Chem 5, 1–12, January 10, 2019
9

Please cite this article in press as: Zhang et al., Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Amino-
cyclopropanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.003
Upon completion of the reaction, the mixture was passed through a short silica gel col-
umn with DCM as the mobile phase. The solvent was then concentrated in vacuo to give
the crude product, which was then purified by silica gel column chromatography using
ethyl acetate/petroleum ether (petroleum ether/ethyl acetate = 4:1 to 2:1) to afford the
desired product 3a as a white solid. m.p. = 182–185ꢀC, 35.8 mg, 83% yield, 97% ee.
High-performance liquid chromatography (HPLC) CHIRALCEL OD-H, n-hexane/2-prop-
anol = 80/20, flow rate = 0.8 mL/min, l = 254 nm, retention time: 25.955 min (minor),
29.898 min (major). [a]D = ꢁ6.4 (c = 1.54, CH2Cl2). 1H NMR (600 MHz, CDCl3)
25
d 6.94–6.89 (m, 2H), 6.76 (t, J = 7.8 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 6.00 (t, J =
8.4 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.05–3.98 (m, 1H), 3.98–3.91 (m, 1H), 3.42 (dd,
J = 13.8, 9.0 Hz, 1H), 2.76 (s, 4H), 2.47 (dd, J = 13.8, 7.2 Hz, 1H), 2.05 (s, 3H), 1.34
(t, J = 7.2 Hz, 3H), 0.82 (t, J = 6.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) d 176.7, 169.4,
168.0, 147.5, 128.7, 125.3, 121.6, 120.6, 110.8, 83.8, 71.7, 70.2, 62.3, 62.0, 32.9,
31.8, 28.2, 14.1, 13.2. High-resolution mass spectrometry (electrospray ionization):
exact mass calculated for C21H24N2O6SNa (M + Na)+ requires m/z 455.1247, found
m/z 455.1254.
DATA AND SOFTWARE AVAILABILITY
The structures of compounds 3j, (S)-1b, rac-9, and rac-10 in this article have
been deposited in the Cambridge Crystallographic Data Center under accession
numbers CCDC: 1818461, CCDC: 1818462, CCDC: 1818597, and CCDC:
1818598, respectively.
SUPPLEMENTAL INFORMATION
Supplemental Information includes 125 figures, 5 tables, and 4 data files and can be
found with this article online at https://doi.org/10.1016/j.chempr.2018.10.003.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Key R&D Program of
China (2016YFA0202900), the National Natural Science Foundation of China
(21472037 and U1604283), the Program for Innovative Research Team in Science
and Technology in University of Henan Province (15IRTSTHN003), and the 111 Proj-
ect (D17007).
AUTHOR CONTRIBUTIONS
Methodology, G.-R.Q., H.-M.G., and S.-L.Y.; Investigation, M.-C.Z. and D.-C.W.;
Writing – Original Draft, D.-C.W.; Writing – Review & Editing, M.-S.X., H.-M.G.,
and S.-L.Y.; Supervision, H.-M.G. and S.-L.Y.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: February 3, 2018
Revised: May 3, 2018
Accepted: October 2, 2018
Published: October 25, 2018
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