Catalytic Asymmetric Chlorocyclization of 2-Vinylphenylcarbamates for Synthesis of 1,4-Dihydro-2H-3,1-benzoxazin-2-one Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b00272

A facile synthetic approach to a series of chiral 4-chloromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives has been described. This transformation is achieved through the catalytic asymmetric chlorocyclization of 2-vinylphenylcarbamates using a newly developed organocatalyst. Furthermore, the resulting products can be easily converted into diverse bioactive agents.

Full text of DOI:10.1021/acs.orglett.7b00272

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Chlorocyclization of 2‑Vinylphenylcarbamates
for Synthesis of 1,4-Dihydro‑2H‑3,1-benzoxazin-2-one Derivatives
Yan-Min Yu,† Ya-Nan Huang,† and Jun Deng*,†,‡
†School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University,
Tianjin 300072, China
‡School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, China
S
* Supporting Information
ABSTRACT: A facile synthetic approach to a series of chiral 4-chloromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives
has been described. This transformation is achieved through the catalytic asymmetric chlorocyclization of 2-
vinylphenylcarbamates using a newly developed organocatalyst. Furthermore, the resulting products can be easily converted
into diverse bioactive agents.
chlorocyclization reaction,9 we wish to communicate here our
ompounds owning the skeleton of 1,4-dihydro-2H-3,1-
Cbenzoxazin-2-one (Figure 1) have received much attention success in achieving the practical and novel synthesis of the chiral
1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives via the hal-
ocyclization of carbamates catalyzed by organocatalysts.
for their potential biological applications such as progesterone
receptor antagonist, HIV-1 reverse transcriptase inhibitor.1 For
instance, Efavirenz, as a potent nonnucleoside reverse tran-
scriptase inhibitor, is still one of the first-line drugs in the clinical
treatment of AIDS (Figure 1).2
We commenced our studies by using t-butyl N-[2-(1-
phenylethenyl)phenyl]carbamate 1a, which was easily synthe-
sized from corresponding 2-alkenylanilines as the model
substrate to search for the optimal reaction conditions.10
Reactions for screening the catalysts were carried out in n-
PrOH at −40 °C for 24 h with 1,3-dichloro-5,5-dimethylhy-
dantoin (DCDMH) as the chlorenium source. (DHQD)2PHAL
gave the desired product 2a in a slightly low yield with poor
enantioselectivity (Table 1, entry 1). Although the Cinchoni-
dine-based thiourea catalyst II was able to impart excellent yield,
the enantioselectivity was unacceptable (Table 1, entry 2).
Eventually, we are pleased to find that by using the chiral ester III
as catalyst, which was assembled by Cinchonidine and 2-
(diphenylphosphino)benzoic acid, the ee value could be
increased to 45% (Table 1, entry 3). Replacing the phosphorus
atom of III with nitrogen atom made no difference on the
enantioselectivity surprisingly (Table 1, entry 4). p-Tolyl
substitution on the nitrogen led to the same ee (Table 1, entry
5). These results promoted us to believe that increasing the steric
bulk of the substituents on the nitrogen could increase the
enantioselectivity. Then the catalyst with bulk substituent has
been synthesized and applied in this reaction. To our delight, this
was indeed the case. The o-tolyl-substituted catalyst VI brought a
tremendous improvement to the enantioselectivity (Table 1,
Figure 1. Representative bioactive 1,4-dihydro-2H-3,1-benzoxazin-2-
one and its derivatives.
Although a series of strategies for the construction of the 1,4-
dihydro-2H-3,1-benzoxazin-2-one skeleton have been reported,
there are few reports on the asymmetric synthesis of these
compounds.3 To facilitate the biological evaluation of optically
active 1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives, the
development of a catalytic system for the enantioselective
synthesis of these chiral derivatives are highly desirable.
The past few years have witnessed much work in the area of
catalytic asymmetric halocyclization reactions,4 for example,
halolactonizations,5 haloetherifications,6 haloaminocyclizations,7
and related reactions.8 Particularly inspired by the success of
Received: January 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00272
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Letter
a
Table 1. Studies on Reaction Condition
Scheme 1. Effect of Chlorenium Source
b
c
entry
cat.
solvent
n-PrOH
temp (°C)
yield (%)
ee (%)
1
I
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−60
−78
35
78
71
64
76
72
87
74
69
12
13
0
2
II
n-PrOH
n-PrOH
n-PrOH
n-PrOH
n-PrOH
MeOH
3
III
IV
V
45
45
45
77
80
80
75
35
4
5
6
VI
VI
VI
VI
VI
VI
VI
VI
VI
a
7
Scheme 2. Scope of Substrates
8
EtOH
9
n-BuOH
CH2Cl2
CHCl3
10
11
12
13
14
d
N.D.
e
CHCl3/hexane
MeOH
<5
78
86
31
86
90
MeOH
a
The reaction was carried out with 1a (0.10 mmol), DCDMH (0.12
mmol), and chiral catalyst (0.01 mmol) in solvent (2.0 mL) unless
otherwise stated; DCMDH = 1,3-dichloro-5,5-dimethylhydantoin.
b
c
Isolated yield. Determined by HPLC analysis on a chiral stationary
d
e
phase. Not detected. CHCl3/hexane = 1/1.
entry 6), and the X-ray crystallography of VI further confirmed
the steric hindrance on the nitrogen (Figure 2).11 To determine
Figure 2. Selected examples of chiral catalysts examined.
a
the optimal reaction conditions with catalyst VI, the solvents
were first screened (Table 1, entries 7−12). The results indicated
that alcoholic solvents showed obvious advantage, and the
solvent effect is consistent with the reported literature.9 Among
the tested alcohols, methanol provided the best result in terms of
the enantioselectivity and the yield. Decreasing the reaction
temperature resulted in a further increase of enantioselectivity.
The best enantioselectivity and yield were achieved at −78 °C.
The effect of other chlorenium source such as trichloroisocya-
nuric acid (TCCA), N-chlorosuccinimide (NCS), and 1,3-
dichloro-5,5-diphenylimidazolidine-2,4-dione (DCDPH) was
also explored (Scheme 1). However, none of them could provide
favorable results.
Reaction conditions: 1 (0.10 mmol), DCDMH (0.12 mmol), and
catalyst VI (0.01 mmol) in MeOH (2.0 mL) at −78 °C, isolated yields.
phenyl groups afforded the corresponding products in good
yields with more than 90% ee (Scheme 2, 2b−2e). Substrates
with para-methyl, para-F, para-Cl, and para-CF3 on the phenyl
ring also gave high enantioselectivities (Scheme 2, 2f−2i). In
contrast, there is a sharp loss of ee value when it is methoxyl
group (Scheme 2, 2j), which could be ascribed to the enhanced
background reaction. The yield and ee of the o-Me substituted
substrate were only 65% and 55% (Scheme 2, 2k) probably due
to the steric effect. Using 2-naphthyl substituted t-butyl 2-
vinylphenylcarbamate as the substrate, product 2l could be
obtained in moderate yield and good ee. For aliphatic substrates,
chlorocyclizations were both achieved in excellent yields, but
lower enantioselectivities (Scheme 2, 2m and 2n). The absolute
With the optimized conditions in hand, the scope of the
reaction with other substrates has been investigated. First, the t-
butyl 2-vinylphenylcarbamates bearing various substituents was
studied (Scheme 2). All the substrates bearing meta-substituted
B
DOI: 10.1021/acs.orglett.7b00272
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Letter
configuration of 2 was confirmed by an X-ray study on the
product 2a.11
Subsequently, the effects of substituents residing on the
aromatic moiety of t-butyl 2-vinylphenylcarbamates have been
further investigated (Scheme 3). The electronic nature of
coupling. Furthermore, the conversion of the carbamate group
to the thiocarbamate was also achieved with good stereochemical
integrity by heating with Lawesson’s reagent in m-xylene at 130
°C for 6 h.
In conclusion, we have described an efficient catalytic
asymmetric synthesis of 1,4-dihydro-2H-3,1-benzoxazin-2-ones
using a newly developed organocatalyst. Notably, the versatile
transformations of the product warrant the synthetic utility of
this methodology in the areas of organic and medicinal
chemistry. The investigations on the biological evaluation of
these optically active 1,4-dihydro-2H-3,1-benzoxazin-2-one
derivatives and further application of the new catalyst in
asymmetric catalysis are currently underway in our laboratory.
a
Scheme 3. Scope of Substrates
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00272.
Detailed experimental procedures and spectral data
(PDF)
X-ray crystallographic data of compounds VI (CIF)
X-ray crystallographic data of compound 2a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jdeng@cqu.edu.cn.
ORCID
a
Reaction conditions: 1 (0.10 mmol), DCDMH (0.12 mmol), and
chiral catalyst (0.01 mmol) in MeOH (2.0 mL) at −78 °C, isolated
yields.
Jun Deng: 0000-0002-6547-0244
Notes
substituent para to the aromatic ring of amino moiety exerted
obvious impact on the enantioselectivity (Scheme 3, 4a−4e).
Electron-withdrawing groups F and Cl provided higher ee value
than electron-donating groups (Scheme 3, 4c and 4d).
Unfortunately, substrate with the strong electron-withdrawing
group NO2 at the para position appeared to have completely
retarded the reaction (Scheme 3, 4i). For substrates bearing
halogen group para to the alkene moiety, good yields and high
ees were generally obtained (Scheme 3, 4g and 4h). For the
substrates bearing para- and meta-methoxyl group (Scheme 3, 4a
and 4f), however, relatively low ees were observed, which were
consistent with the previous observations.
The synthetic utility of this methodology is demonstrated in
Scheme 4. As a novel class of potent, selective, and orally active
progesterone receptor antagonists, the 6-aryl-1,4-dihydroben-
zoxazin-2-ones 7 could be obtained in 65% total yield without
any loss of ee through a three-step sequence of reduction with n-
Bu3SnH, bromination using NBS, and a standard Suzuki
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is founded by the Scientific Research Foundation for
the Returned Overseas Chinese Scholars, State Education
Ministry, and the National Natural Science Foundation of
China (grant no. 21572154). We also thank Dr. Hong-Gen
Wang of Nankai University for providing X-ray analysis.
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