Base-Free and Catalyst-Free Synthesis of Functionalized Dihydrobenzoxazoles via Vinylogous Carbonate to Carbamate Rearrangement

Article abstract of DOI:10.1021/acs.orglett.7b02733

An unexpected, catalyst-free, and base-free intramolecular cyclization of N-aryloxyacrylate aldimines, under thermal conditions leading to the synthesis of functionalized dihydrobenzoxazoles, is reported. The reaction features a unique rearrangement of vi

Full text of DOI:10.1021/acs.orglett.7b02733

Letter
pubs.acs.org/OrgLett
Base-Free and Catalyst-Free Synthesis of Functionalized
Dihydrobenzoxazoles via Vinylogous Carbonate to Carbamate
Rearrangement
Tamal Kanti Das,†,§ Santigopal Mondal,†,§ Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†,§
‡
†Organic Chemistry Division and Centre for Material Characterization, CSIR-National Chemical Laboratory (CSIR-NCL), Dr.
Homi Bhabha Road, Pune 411008, India
§Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
S
* Supporting Information
ABSTRACT: An unexpected, catalyst-free, and base-free
intramolecular cyclization of N-aryloxyacrylate aldimines,
under thermal conditions leading to the synthesis of
functionalized dihydrobenzoxazoles, is reported. The reaction
features a unique rearrangement of vinylogous carbonates to
vinylogous carbamates resulting in a new carbon−oxygen and
carbon−nitrogen bond construction. The reaction tolerates a
broad range of functional groups and the desired products are formed in moderate to good yields.
n an effort to expand the scope of N-heterocyclic carbene
benzoxazole derivative 4a was possibly formed by the
intramolecular nucleophilic addition of imine onto the
vinylogous carbonate followed by a unique vinylogous
carbonate to carbamate rearrangement. Herein, we report this
base- and catalyst-free annulation of N-aryloxyacrylate
aldimines to dihydrobenzoxazole derivatives.
I
(NHC)-organocatalyzed transformations1 beyond the um-
polung of aldehydes2 and Michael acceptors,3 we have recently
reported the NHC-catalyzed umpolung of aldimines for the
synthesis of 2,3-disubstituted indoles (Scheme 1, eq 1).4,5 As a
Scheme 1. Reported and Envisioned NHC-Catalyzed
Umpolung of Imines
The nucleophilic reactivity of imines using the nitrogen
center for the construction of carbon−nitrogen bonds is a
convenient method for the synthesis of nitrogen heterocycles.
Discovered in 1907, the Staudinger reaction employs the imines
as nucleophiles (via the nitrogen center) to couple with ketenes
for the synthesis of β-lactams.6 Notably, recent experimental
and computational studies on the mechanism of this reaction
reveal that the addition of imines to ketenes is not concerted
but stepwise (Scheme 2, eq 1).7−9 Moreover, the imines having
an α-hydrogen are nucleophilic via the carbon center, and this
mode of reactivity is well-known in enamine catalysis.10 The
observed reactivity of imines in the present case prompted us to
investigate this further. It is reasonable to believe that the imine
1 undergoes intramolecular nucleophilic attack on the carbon−
carbon double bond generating the enolate A, which undergoes
the carbon−oxygen bond-rupture to form the zwitterion B
(Scheme 2, eq 2). Intramolecular cyclization of B could result
in the formation of the dihydrobenzoxazole derivative 4. It may
be noted in this context that although the conjugate addition of
carbon-centered nucleophiles to vinylogous carbonates is
known, the related oxa- and aza-conjugate addition has received
only scant attention.11,12
part of this program to extend the substrate scope of NHC-
catalyzed umpolung of imines, we envisaged that the NHC-
catalyzed umpolung of N-aryloxyacrylate aldimine 1a using the
NHC generated from the triazolium salt 2 and using KO-t-Bu
as the base could result in the formation of the benzoxazine
derivative 3a. Interestingly, this reaction did not afford the
expected product 3a but instead resulted in the formation of
the dihydrobenzoxazole derivative 4a in 41% yield (Scheme 1,
eq 2). To our surprise, when the reaction was performed in the
absence of 2 and KO-t-Bu, 4a was formed in 50% yield. The
At the outset, the optimization of reaction conditions for this
annulation reaction has been investigated. Treatment of the
Received: September 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02733
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Organic Letters
Letter
Scheme 2. Nucleophilic Reactivity of Imines via the N
Center
Figure 1. ORTEP diagram of 4a drawn with 50% probability
displacement ellipsoids.
a
Scheme 3. Substrate Scope of the Reaction
aldimine 1a in DMF for 12 h at 100 °C resulted in the
formation of the dihydrobenzoxazole derivative 4a in 50% yield
(Table 1, entry 1). When the reaction was carried out in
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
DMF
temp (°C)
time (h)
yield of 4a (%)
1
2
4
4
5
6
7
8
100
100
140
140
100
140
140
140
12
24
48
36
24
48
60
36
50
38
<5
55
62
83
74
77
toluene
DMSO
CH3CN
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
a
See the Supporting Information for the experimental details.
Isolated yield on a 0.5 mmol scale.
b
toluene, the yield of 4a was dropped to 38%, whereas the
reaction did not work at all when performed in DMSO (Table
1, entries 2 and 3). The use of CH3CN furnished 4a in 55%
yield (Table 1, entry 4). Interestingly, the use of chlorobenzene
as solvent at 100 °C improved the yield of 4a to 62% (Table 1,
entry 5). Increasing the reaction temperature to 140 °C
enhanced the yield of 4a to 83% (Table 1, entry 6). The
reaction time of 48 h was found to be optimal and heating the
reaction mixture for 60 and 36 h was not found to be beneficial
(Table 1, entries 7 and 8).13
a
Conditions: 1 (0.5 mmol) and chlorobenzene (2 mL) stirred at 140
°C for 48 h. Isolated yields of products are given.
The compound 4a was characterized using standard
spectroscopic analysis. Finally, the structure of 4a was
confirmed, and the configuration of the vinylogous carbamate
was found to be trans using single-crystal X-ray analysis (Figure
1).14
With the optimized reaction conditions in hand, we
evaluated the substrate scope of this reaction (Scheme 3). A
series of aldimines derived from aldehydes having electron-
releasing and -withdrawing groups at the 4-position of the ring
underwent smooth vinylogous carbonate to carbamate
rearrangement leading to the synthesis of dihydrobenzoxazoles
in 26−90% yield (4a−h). As expected, with strongly electron-
withdrawing groups at the 4-position (CF3 and NO2), the
yields of 4 are only moderate because of the reduced
nucleophilicity of the imines in these cases. Moreover, a variety
of electronically dissimilar imines synthesized from aromatic
aldehydes substituted at the 3-position and 2-position afforded
the desired product in moderate to good yield (4i−n). In
addition, the disubstituted aldehyde-derived imines as well as
the imines synthesized from heterocyclic aldehydes furnished
the expected products in moderate to good yields (4o−r). The
reactions using the methyl ester instead of ethyl ester worked
well (4s,t), and imines synthesized from 4-chloro 2-amino-
phenol also resulted in the formation of the annulated product
in moderate yield (4u). Disappointingly, the present annulation
did not work with imines synthesized from aliphatic aldehydes
(4v).15,16
B
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Letter
A few experiments have been performed to gain insight into
the mechanism of this transformation. Treatment of the imine
5a with ethyl propiolate in the presence of catalytic amounts of
N-methylmorpholine at 0 °C followed by heating at 100 °C in
CH3CN afforded the dihydrobenzoxazole 4a in 72% yield
without the formation of the dihydrobenzoxazole 6a (Scheme
4, eq 1). This is equivalent of a one-pot reaction where the
To gain insight into the intramolecular nature of this
rearrangement, a crossover experiment was performed between
substrates 1a and 1s. Mixing 1a and 1s under the present
reaction conditions afforded the mixture of dihydrobenzox-
azoles 4a and 4s in 45% and 48%, respectively (determined by
1H NMR of the crude products).13 The crossover products 4a′
and 4s′ are not formed under these conditions, indicating the
intramolecular nature of the rearrangement (Scheme 4, eq 4).
Moreover, to gain information on the possible involvement of
radicals in the present annulation, an experiment was carried
out in the presence of TEMPO (Scheme 4, eq 5). The
formation of 4a in 69% yield in the presence of TEMPO rules
out the participation of radicals in this annulation reaction.
We also examined the kinetics of the present annulation
reaction. It is interesting to note that only traces of 4a was
formed when quenched after 3 h (Figure 2). The reaction
Scheme 4. Studies toward the Mechanism of the Reaction*
Figure 2. Kinetics of the reaction.
1
afforded 9% of 4a after 6 h (determined by H NMR of the
crude products). At the end of 12 h, 28% of 4a was formed.13
The amount of 4a formed increases with respect to time and at
the end of 48 h, 83% of 4a was formed. We also tried to get
information on the unreacted imine 1a at the given time.
However, as part of the imine is breaking into the
corresponding aldehyde and amine, we were not able to
quantify the amount of imine recovered.
In conclusion, we have observed an unexpected intra-
molecular cyclization of N-aryloxyacrylate aldimines in an
envisioned NHC-catalyzed umpolung of imines. This base- and
catalyst-free reaction afforded dihydrobenzoxazoles in moderate
to good yields and tolerates various functional groups. The
reaction proceeds via a unique rearrangement involving
vinylogous carbonates to vinylogous carbamates. Our prelimi-
nary mechanistic studies indicate that the vinylogous carbonate
migration is intramolecular in nature.
*
a
See the Supporting Information for details. Isolated yield of 4a
b
1
Yield was determined by H NMR analysis of the crude product
using CH2Br2 as the internal standard.
vinylogous carbonate 1a was formed in situ. Since 6a was not
formed, this indicates that the reaction is not proceeding via the
initial cyclization of 5a followed by an aza-Michael addition to
the ethyl propiolate. This also sheds light on the fact that a
retro-Michael reaction of 1a (generating the propiolate and
phenoxide) followed by the cyclization is not operating in the
present case.
Moreover, when the reaction was performed under the
optimized conditions in the presence of methyl acrylate, the
product 4a was formed in 81% yield and the formation of the
related crossover product 7a was not observed (Scheme 4, eq
2). This indicates that the vinylogous carbonate to carbamate
rearrangement takes place in an intramolecular manner. This
was also confirmed with the crossover experiment with methyl
propiolate where the rearranged product 4a was formed in 56%
yield without the formation of the crossover product 8a when
the reaction was performed in DMF (Scheme 4, eq 3).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02733.
Details on experimental procedure, characterization, and
NMR spectra of functionalized dihydrobenzoxazoles
(PDF)
X-ray data of 4a (CIF)
C
DOI: 10.1021/acs.orglett.7b02733
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Organic Letters
Letter
520. (b) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
(9) For the addition of imines to benzynes, see: Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128,
11040.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: at.biju@ncl.res.in.
ORCID
(10) For a review on enamine catalysis, see: Mukherjee, S.; Yang, J.
Rajesh G. Gonnade: 0000-0002-2841-0197
Akkattu T. Biju: 0000-0002-0645-8261
Present Address
∥(A.T.B.) Department of Organic Chemistry, Indian Institute
of Science, Bangalore 560012, India.
W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
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Eur. J. Org. Chem. 2013, 2981. (b) Gharpure, S. J.; Sathiyanarayanan,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the Science and Engineering
Research Board (SERB-DST), Government of India (Grant
No. SR/S1/OC/12/2012), is kindly acknowledged. T.K.D.
thanks CSIR and S.M. thanks UGC for senior research
fellowships. We thank Dr. T. G. Ajithkumar and Dr. Udaya
Kiran Marelli (both CSIR-NCL) for the excellent NMR
support and Dr. B. Santhakumari (CSIR-NCL) for the
HRMS data.
(13) For details, see the Supporting Information.
(14) CCDC 1568724 (4a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from Data Centre via www.ccdc.cam.ac.uk/data_request/cif. For the
details, see the Supporting Information.
(15) In an effort to extend this rearrangement to alkyl migration, we
have synthesized the benzyl derivative and heated it under the
optimized conditions. This reaction did not afford the rearranged
product indicating that the present migration is limited to vinylogous
carbonate to carbamate at present. For a related rearrangement, see:
Fischer, G. W. J. Prakt. Chem. 1980, 322, 99.
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Org. Lett. XXXX, XXX, XXX−XXX