Accessing dihydro-1,2-oxazine via cloke-wilson-type annulation of cyclopropyl carbonyls: application toward the diastereoselective synthesis of pyrrolo[1,2- b][1,2]oxazine

Article abstract of DOI:10.1021/acs.joc.0c00531

A convenient additive-free synthesis of dihydro-4H-1,2-oxazines via a Cloke-Wilson-type ring expansion of the aryl-substituted cyclopropane carbaldehydes with the hydroxylamine salt is introduced. Comparatively less active cyclopropyl ketones also follow a similar protocol if supplemented by catalytic p-toluene sulfonic acid monohydrate. The transformation is performed in an open-to-air flask as it shows negligible sensitivity toward air/moisture. Dihydro-4H-1,2-oxazines when subjected to cycloaddition with the cyclopropane diester afford a trouble-free formulation of the valued hexahydro-2H-pyrrolo[1,2-b][1,2]oxazine derivatives. A cascade one-pot variant of this two-step strategy offers a comparable overall yield of the final product.

Full text of DOI:10.1021/acs.joc.0c00531

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Article
Accessing Dihydro-1,2-oxazine via Cloke-Wilson type
Annulation of Cyclopropyl Carbonyls: Application towards
the Diastereoselective Synthesis of Pyrrolo[1,2-b][1,2]oxazine
Pankaj Kumar, Rakesh Kumar, and Prabal Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00531 • Publication Date (Web): 24 Apr 2020
Downloaded from pubs.acs.org on April 24, 2020
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Accessing Dihydro-1,2-oxazine via Cloke-Wilson type Annulation of
Cyclopropyl Carbonyls: Application towards the Diastereoselective Synthesis
of Pyrrolo[1,2-b][1,2]oxazine
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Pankaj Kumar, Rakesh Kumar, and Prabal Banerjee*
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road,
Rupnagar, Punjab, India, 140001
Fax: (+91)-1881-223395; e-mail: prabal@iitrpr.ac.in
ABSTRACT
A convenient additive-free synthesis of dihydro-4H-1,2-oxazines via a Cloke-Wilson
type ring expansion of the aryl substituted cyclopropane carbaldehydes (ACC) with
the hydroxylamine salt is introduced. Comparatively less active cyclopropyl ketones
also follow a similar protocol if supplemented by catalytic pTSA.H O. The
2
transformation is performed in an open-to-air flask as it shows negligible sensitivity
towards air/moisture. Dihydro-4H-1,2-oxazines when subjected to cycloaddition with
the cyclopropane diester, affords a trouble-free formulation of the valued hexahydro-
2
H-pyrrolo[1,2-b][1,2]oxazine derivatives. Cascade one-pot variant of this two-step
strategy offers a comparable overall yield of the final product.
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INTRODUCTION
Cyclic oxime ethers1a and their bicyclic derivatives are an interesting class of
compounds for their potential application in the synthesis of naturally occurring as well
as biologically important target molecules. With unique functionalities, these cyclic
oxime ethers contribute to the basic structure of many bioactive molecules and at the
same time, offer as intermediates for the synthesis of pyrroles, pyrrolidines, amino
alcohols and various furan derivatives. In this regard, isoxazoles, isoxazolines and
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hexahydropyrrolo[1,2-b]isoxazole have been studied thoroughly for the synthesis of
various alkaloids, steroids, prostaglandins and many other natural products.1
Although, the pyrrolo[1,2-b][1,2]oxazine moiety does serve as the key structural core
of the two novel alkaloids alsmaphorazine A and alsmaphorazine B, isolated from the
2
alstonia plant (Figure 1), the study of six-membered cyclic oxime-ethers and
especially their bicyclic derivative hexahydro-2H-pyrrolo[1,2-b][1,2]oxazine is very
limited due to the lack of convenient methods of their preparation. At this point, there
lies an obvious urge to standardize a straight-forward route for the synthesis of these
potential cyclic as well as bicyclic oxime ether derivatives from readily available
substrates and so their further exploration.
Figure 1: Alkaloids having pyrrolo[1,2-b][1,2]oxazine as their core structure.
Most of the reports on the synthesis of 5,6-dihydro-4H-1,2-oxazine are based on [4+2]
cycloaddition of nitrosoalkenes to olefins and intramolecular cyclization of the γ-
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functionalized oxime derivatives (Scheme 1, A), most of which require harsh reaction
conditions and sensitive reaction setups.1a, 3 Surprisingly, the involvement of strain
4
driven reactivity of donor-acceptor cyclopropanes for the facile synthesis of six
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membered oxime ethers has been overlooked for years. The only report considering
the intramolecular cyclopropane ring opening by the oxygen atom of the oximino group
was back in 1981 by C. N. Rentzea using cyclopropyl styryl ketone and
hydroxylammonium chloride constructing 3-vinyl- substituted dihydrooxazines
5
(
Scheme 1, A). However, the strategy suffered low yields (29-50%) even under reflux
conditions. Remarkably, for the last four decades, no attempts were reported utilizing
the activated donor-acceptor cyclopropane analogues for a relatively simplified route
for 6-substituted dihydrooxazines and their potential application towards the
cycloaddition reactions. Undoubtedly, the participation of cyclopropyl aldoximes in a
6
possible Cloke-Wilson type ring expansion reaction could serve as an intriguing
technique for the convenient synthesis of dihydrooxazines.
Scheme 1. Available synthetic routes to oxazine derivatives and this work.
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To seize this opportunity, we intended to use the aryl substituted cyclopropane
carbaldehyde (ACC, 1) and the hydroxylamine salt as precursors of cyclopropyl
aldoximes that would undergo the much anticipated Cloke-Wilson type rearrangement
for an effortless construction of 6-aryl-5,6-dihydro-4H-1,2-oxazine (3, Scheme 1, B).
The idea worked smoothly in an open flask at room temperature, without any additive
or a catalytic reagent. So, to carry out the transformation, we have to just stir the two
substrates in an appropriate solvent. Further, the electronegativity of oxygen atom in
the cyclic oxime ether is expected to enhance polarization of the carbon-nitrogen
double bond, and we thought it might serve as an interesting dipolarophile for a
possible cycloaddition process with a dipolar species like the well-known donor-
acceptor cyclopropane our group has been working on. Consequently, we tried this
proposal with the aryl substituted cyclopropane diester (4) in the presence of various
Lewis acids to successfully construct 2,7-diarylhexahydro-2H-pyrrolo[1,2-
b][1,2]oxazine (5, Scheme 1, B). We also attempted this two-step strategy for a
tandem one-pot synthesis of 5 and conveniently managed to capitalize a promising
one-pot approach for the synthesis of 2,7-diarylhexahydro-2H-pyrrolo[1,2-
b][1,2]oxazine with a comparative yield to that of the step-wise process.
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RESULTS AND DISCUSSION
A recent report on the reactivity of cyclopropyl diketones with the hydroxylamine
7
8
hydrochloride and our earlier work on ACCs assisted us to start our trials with trans-
2
-(4-methoxyphenyl)cyclopropane-1-carbaldehyde (1a). We attempted the expected
transformation with hydroxylammine hydrochloride (2) in dimethylsulfoxide (DMSO)
solvent, but this ended up to an isomeric mixture of cyclopropyl oximes and the
cyclopropane ring remained intact. In order to make the hydroxyl group of the
cyclopropyl oxime attack on aryl end of the ACC, we used bases like K
2
CO and NaH
3
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Table 1. Optimization of the reaction conditionsa
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1
1
1
1
1
2
2
2
2
2
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2
2
2
3
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0
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0
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2
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0
entry ACC
2/2´
2
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
additive
-
T (ºC)
yield (%)b
m.o.c
m.o.c
c.m.d
c.m.d
c.m.d
m.o.c
m.o.c
m.o.c
38
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1j
rt
2
K
2
CO
3
/NaH
rt
2
InCl
3
/MgI
2
/TiCl
4
rt
2
p-TSA/CSA
rt
2
-
-
-
-
-
-
-
-
-
80 °C/ reflux
2
rt
rt
rt
rt
rt
rt
rt
1k
1a
1a
1a
1a
1a
1a
2
2
2
CH Cl
2
2
THF
1
0
1
2
3
2
C H
6 6
52
1
1
1
2
toluene
48
2´
2´
C H
6 6
74
toluene
rt
66
a
b
Reactions were carried out with 1 equiv. of 1 and 1.5 equiv. of 2/2´. Isolated % yields
c
d
of 3. m.o. = mixture of oximes. c.m. = complex mixture.
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that might increase the nucleophilicity of oxygen, but was all in vain (entry 2, Table 1).
Further, we longed that the activation of cyclopropane ring might have been the
problem. So, we used more activated ACCs like the trans-2-(3,4,5-
trimethoxyphenyl)cyclopropane-1- carbaldehyde (1k), and also added various Lewis
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as well as Brønsted acids like InCl
3
, MgI
2
, TiCl , p-toluene sulfonic acid (p-TSA) and
4
camphorsulfonic acid (CSA), but again none of them could help (entry 3-4, Table 1).
Later on, we attempted the reaction in different solvents like diethyl ether,
tetrahydrofuran (THF), dichloromethane (CH
2
Cl
2
), methanol, dimethylformamide
(
DMF), benzene (C ) and toluene, where we finally thrived in isolating the expected
6
H
6
product (3a) from THF, benzene and toluene solvents with 38, 52 and 48% of
respective yields. To enhance the yield of this transformation we tried to perform the
reaction at high temperatures under reflux conditions, but the cyclopropane got
decomposed under such harsh conditions. However, when we switched
hydroxylamine hydrochloride (2) with hydroxylamine-O-sulfonic (2´) acid in benzene
solvent, a huge increase in the isolated yield was observed, and we got 3a in 74%
yield (entry 12, Table 1). Finally, we performed the optimized reaction in an open-to-
air flask, in reagent grade benzene solvent to find out how the resulting yield is altered
in open atmosphere. Remarkably, the isolated yield was almost consistent with that
obtained in an inert setup, and so, all the reactions that followed were performed in
open-flasks.
For the study of generality, we carried out this transformation with a variety of
substitutions on the cyclopropane ring (Scheme 2). It was noted that the approach is
fairly compatible with both highly activated as well as less activated ACCs, however,
the best yield (82%) was obtained for the benzyloxyphenyl derivative (3b, scheme 2).
The electron donating groups on the aryl ring enhances the activation of the
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cyclopropane ring and so, reduced the reaction time to a few hours (3a, 3b, 3j-3l),
whereas the less activated ACCs like those substituted with phenyl, naphthyl or tolyl
groups took longer time for the conversion to complete (3c-3h). On the other hand,
negligibly activating or deactivating substitutes like p-bromophenyl, p-chlorophenyl or
the alkyl groups on cyclopropane carbaldehyde, could only afford the isomeric mixture
1
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Scheme 2: Substrate scope for Cloke-Wilson type rearrangement of cyclopropyl
carbonyls with hydroxylamine salts. Unless otherwise mentioned, all reactions were
a
carried out with 1 equiv. of 1/1´ and 1.5 equiv. of 2´. Reactions were carried out with
b
1
.5 equiv. of 2. Reactions were carried out with 2 equiv. of 2 in the presence of
pTSA.H O (0.2 equiv.) at 50 ºC.
2
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of oxime and not the oxazine derivatives. Formulation of (E)-6-styryl-5,6-dihydro-4H-
1
,2-oxazine (3i) from trans-2-((E)-styryl)cyclopropane-1-carbaldehyde (1i) with an
isolated yield of 52% was the fastest of all under normal reaction conditions (Scheme
0
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0
16
2
). The single-crystal X-ray structure of 3b confirmed that the oxazine ring is in half-
chair conformation with an exo orientation of the substituent. To check whether the
reaction is feasible with aryl substituted cyclopropyl ketones, we tried the standard
protocol with (trans-2-(4-methoxyphenyl)cyclopropyl)(phenyl)methnone (1a´), but it
did not show any conversion. After a few changes in the reaction conditions, the
transformation did work out, however, under comparatively harsh circumstances. The
transformation was optimized with hydroxylamine hydrochloride and in the presence
of catalytic amount of p-toluene sulfonic acid monohydrate (pTSA.H
2
O) at 50 ºC (3m-
3
q, Scheme 2). The conversion rates were found to be very low as were the
percentage yields, and it was understandable as ketones are less reactive as
compared to the aldehydes. We also tried to increase the reactivity of the
cyclopropane by having more electron releasing 3,4-dimethoxy phenyl group on the
vicinal position of the cyclopropane but no noticeable change was observed in the
percentage yield (3n). Having an electron withdrawing group like the 4-chlorophenyl,
on the keto group did raised the yield to 49% (3q), but it was the highest we could get
with the aryl substituted cyclopropyl ketones.
With the library of dihydro-4H-1,2-oxazine derivatives in hand, we projected a
promising cycloaddition on the carbon-nitrogen double bond of these cyclic oxime
ethers. Driven by our previous experience on the donor-acceptor cyclopropanes
9
(
DACs), Lewis acid catalysed aryl substituted cyclopropane diester appeared to be a
good precursor for our proposal. We started our trials with diethyl 2-(4-
methoxyphenyl)cyclopropane-1,1-dicarboxylate (4a) as the standard substrate. Its
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Table 2. Optimization of the reaction conditions for the cycloaddition processa
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
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3
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5
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0
Yield (%)b
entry Lewis acid equiv. t (h)
1
2
InCl
MgI
3
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.2
0.4
0.5
5
2
54
44
2
3
MgBr
TMSOTf
TiCl
SnCl
2
12
24
0.5
0.5
0.5
4
28
4
12
5
4
c.m.c
c.m.c
c.m.c
53
6
4
7
BF
Sc(OTf)
Yb(OTf)
3
.OEt
2
8
3
9
3
6
42
10
11
In(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
3
6
38
2
2
2
2
4
55
1
1
1
2
3
4
2
60
2
52
1.5
46
aReactions were carried out in dry CH
Cl with 1 equiv. of 3a and 1 equiv. of 4a.
2
2
b
c
Isolated yield of the major isomer 5a. c.m. = complex mixture.
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reaction with 3a in the presence of 0.2 equivalent InCl , constructed diethyl 2,7-bis(4-
3
methoxyphenyl)hexahydro-5H-pyrrolo[1,2-b][1,2]oxazine-5,5-dicarboxylate (5a, major
isomer) in 54% isolated yield. To capitalize the process, trials were carried out with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
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5
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3
4
5
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0
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2
3
4
5
6
7
8
9
0
varying concentrations of different Lewis acids like MgBr
Sc(OTf) , In(OTf) , Cu(OTf) , BF .OEt , SnCl and TiCl
equivalent of Cu(OTf) in anhydrous dichloromethane solvent to be the pre-eminent
2
, MgI
2
, TMSOTf, Yb(OTf) ,
3
3
3
2
3
2
4
4
, which recommended 0.2
2
reaction condition for this strategy (entry 12, Table 2).
Using the optimized conditions, we moved further to check the substrate scope of this
cycloaddition process in terms of differently substituted dihydro-4H-1,2-oxazine
derivatives and also with various cyclopropane diesters. Here we successfully
synthesized a series of 20 examples with moderate to excellent yields, advocating the
broad generality of this strategy (Scheme 3). To have an overview on the reactivity of
differently substituted dihydro-4H-1,2-oxazine derivatives, we subjected them to the
cycloaddition reaction. All the dihydrooxazine derivatives derived from various ACCs
easily underwent the expected transformation within a few hours, and thus supported
th
the fact that the substitution on 6 position does not have a major role in the reaction
kinetics (5a-5l, Scheme 3). However, the steric bulk of this substituent is found to
actually affect the diastereoselectivity of the transformation. A big mesityl group at the
6th position of dihydro-4H-1,2-oxazine afforded exclusively a single isomer (5d,
Scheme 3), whereas, the less bulky styryl substituent induced the worst
diastereoselectivity (66:34, 5i:5i´). In most of the cases, we could isolate only the major
isomers in pure form, but for 5i/5i´ we managed to isolate both the isomers and their
relative configuration was established by analysing the 2D NMR spectra (Figure 2).
From the 2D NMR elucidations of the two isomers, it was clear that the protons H
d
and
H
f
were in close proximity and the fused pyrrolidine rings in both 5i and 5i´ were having
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3
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0
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0
1
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3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3: Substrate scope for the cycloaddition process. Unless otherwise
mentioned, all reactions were carried out in dry CH
4 and 0.2 equiv. of Cu(OTf) . Isolated yields of the major isomers (5) are reported.
Diastereomeric ratios (5:5´) of major (5) and minor isomers (5´) are reported.
2
Cl with 1 equiv. of 3, 1 equiv. of
2
2
10
the thermodynamically stable cis configuration of its substituents. Diastereomers 5i
and 5i´ differ only in their relative configuration of the proton H with respect to that of
a
H
d
and H
f
. In the minor isomer 5i´, protons H
a
, H
d
and H
and H
f
are in the cis configuration
while in the major isomer 5i, H
a
is trans to both H
d
f
(Figure 2). We generalized
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1
1
1
1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
this stereochemical model of the diastereomers to all other examples also because
1
the respective H NMR patterns were exactly the same except for the relatively upfield
shift of the proton H in case of 5i/5i´, which was anticipated for the styryl substitution
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
here. The diastereomeric ratios for all the products were calculated by examining their
1
crude H NMR spectrum. We also carried out the cycloaddition reaction with differently
substituted cyclopropane diesters and found that the reaction kinetics was directly
affected by the reactivity of DAC. Electron releasing substituents like the 3,4-
dimethoxyphenyl and 3,4,5-trimethoxyphenyl on vicinal position of the cyclopropane
increases the reactivity of DAC and so reduced the reaction time (5m and 5o, Scheme
3). On the other hand, with electron withdrawing substituents like the 4-fluorophenyl
and 4-nitrophenyl on vicinal position of the cyclopropane, the reaction time increased
up to 3 days (5p-5r). With 3,4-dimethoxyphenyl substituted cyclopropane diester (4b),
exclusive formation of the major isomer 5m was observed. Styryl and vinyl substituted
cyclopropane diesters also underwent the proposed cycloaddition reaction, however,
their reaction time and percentage yields were disappointing (5s, 5t, Scheme 3).
Figure 2: 2D NOE correlations determining the diastereomeric structures of 5i:5i´.
Once we standardized this stepwise strategy for a number of hexahydro-5H-
pyrrolo[1,2-b][1,2]oxazine derivatives, we were motivated to attempt a cascade one-
pot route to the final product (5). Accordingly, we carried out the reaction of 1a with
hydroxylamine-O-sulfonic acid (2´) in dry benzene and after 8 hours, confirming the
formation of 3a on TLC, added a benzene solution of 4a and Cu(OTf) into the reaction
2
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mixture. The procedure worked really well and the major isomer of the final product
(
5a) was isolated in 39% overall yield which was comparable to the 44.4% overall yield
of 5a obtained in a stepwise process (Scheme 4).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4: Towards one-pot synthesis of 5a.
The probable mechanistic pathway this process follows is in agreement with the
general reactivity of its precursors4,5,11 involving condensation of the ACC (1) with the
hydroxylamine-O-sulfonic acid (2´) and formation of cyclopropyl oxime-O-sulfonic acid
(
A, Scheme 5). Here, the iminium ion formation and subsequent activation of the
cyclopropane ring is attributable to the presence of acidic proton in the substrate 2´
and thus, no additional activator or reagent is required. Conventionally, a mixture of E
and Z oximes will form (A), however, the geometry of E oxime would restrict it from
taking part in the direct cyclization. Even with the Z oxime, the direct cyclization would
be a 6-endo-tet process which is disfavored according to the Baldwin’s rule for ring
12
closure reactions. To confront both these issues, we propose that the cyclopropane
undergoes ring opening prior to the cyclization and generate a benzyl cation/enamine
intermediate B. The carbon-nitrogen bond in intermediate B is free to rotate and can
easily assume the desired geometry for cyclization. Consequently, through a
nucleophilic attack of oxygen on the carbocation, intermediate B undergoes cyclization
and with loss of sulphur trioxide furnishes a six membered cyclic enamine derivative
C. Intermediate C then undergoes tautomerization to afford the half-chair conformer
of dihydro-4H-1,2-oxazine (3) i.e., the first product of this protocol. In the second step,
product 3 behave as a dipolarophile when subjected to the cycloaddition reaction with
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2
2
3
3
3
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3
3
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5
5
5
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5
5
5
5
5
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0
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0
1
2
3
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5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5: Plausible mechanism.
4 in the presence of Cu(OTf) . The carbon-carbon bond of the DAC is activated by the
co-ordinate interactions of its diester group with Cu(OTf) and it ultimately undergoes
2
2
13
heterolytic cleavage to give a 1,3-zwitterionic species D. Shortly, the imine bond in
product 3 (in half-chair conformation) encounters a nucleophilic attack by the enolate
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group of intermediate D. This reversible carbon-carbon bond formation would ease the
half-chair conformation of the dihydrooxazine ring to a chair conformation which finally
participates in a carbon-nitrogen bond formation between the dihydrooxazine nitrogen
and the benzylic carbocation to complete the cyclization process. The final cyclization
can take place through an approach which is either synfacial or antifacial to substituent
R of the dihyrooxazine ring. In the synfacial approach, the reaction proceeds via a
thermodynamically disfavored 1,4-axial-equitorial transition state F´, leading to the
minor diastereomer 5´ of the final product. On the other hand, the antifacial approach
instigates a thermodynamically favored transition state F with both the bulky
substituents on equitorial positions. This stable 1,4-diequitorial transition state leads
to the formation of major diastereomer 5 of the hexahydro-5H-pyrrolo[1,2-
b][1,2]oxazine derivative (Scheme 5).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After we established the strategy well for a number of substrates, we were curious to
see what further scope can we have for the designed molecules. The diester group in
5
b when subjected to hydrolysis with KOH in methanol under reflux conditions
underwent monodecarboxylation to afford the monocarboxylic acid 6 with the
14
generation of a new stereocentre in the molecule (Scheme 6). The geometry of 6
was established by its single-crystal X-ray structure16 which further helped us to
ascertain the relative stereochemistry of the major diastereomer 5b.
Scheme 6: Monodecarboxylation of 5b.
CONCLUSIONS
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
To sum up, an additive-free technique has been developed for the synthesis of 5,6-
dihydro-4H-1,2-oxazine that works perfectly well in open flask and at ambient
temperatures. Cyclopropyl ketones, though with pTSA.H O as mediator, does follow
2
0
1
2
3
4
5
6
7
8
9
0
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2
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0
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3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the same course at higher temperatures. This approach might serve as a good
synthetic tool for industrial purpose also as it eliminates the sophisticated reaction
setup requirements. Lewis acid catalysed cycloaddition of the dihydrooxazine
derivative with the donor-acceptor cyclopropane, to afford the distinctive hexahydro-
5
H-pyrrolo[1,2-b][1,2]oxazine and its one-pot variant, offers an effortless protocol for
the synthesis of selectively functionalized pyrrolo[1,2-b][1,2]oxazines from simple and
readily available precursors. Monodecarboxylation of the diester functionality in the
final product supplements another stereocentre to the molecule and substantiate it for
further functionalizations as well. This protocol is believed to serve as a convenient
tool for the development of 5,6-dihydro-4H-1,2-oxazine as well as hexahydro-5H-
pyrrolo[1,2-b][1,2]oxazine based chemistry, both for the research and industrial
purposes.
EXPERIMENTAL SECTION
General Information
All solvents and reagents were obtained from commercial sources and were purified
following the standard procedure prior to use (unless otherwise mentioned). Powdered
molecular sieves (4 Å MS) were dried at 200 °C under vacuum prior to use. The
developed chromatogram was analysed by UV lamp (254 nm) or using the p-
anisaldehyde charring solution. Products were purified by flash chromatography on
silica gel (mesh size 230–400). Melting points were determined using a Stuart SMP30
advanced digital melting point apparatus. Infrared (FTIR) spectra were recorded for
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-1
the neat samples and reported in wavenumber (cm ). Mass spectral data (HRMS)
1
13
1
were obtained using XEVO G2-XS QTOF instrument. The H NMR and C{ H} NMR
spectra were recorded at 400 MHz and 100 MHz respectively on 400 MHz JEOL JNM
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ECS400 instrument in CDCl solvent (unless otherwise mentioned). Chemical shifts of
3
1H and 13C{ H} NMR spectra are expressed in parts per million (ppm). All coupling
constants (J) are absolute values and are expressed in hertz (Hz). The description of
the signals includes the following: s = singlet, d = doublet, dd = doublet of doublet, t =
triplet, dt = doublet of triplet, q = quartet, dq = doublet of quartet, br = broad, and m =
multiplet.
1
General procedure for the synthesis of trans-2-arylcyclopropane-1-
8
carbaldehydes (ACCs, 1) : Following the established literature, synthesis of 1 was
carried out by following the known procedures as mentioned below. For the reaction
scheme, see Scheme S1 in the Supporting Information.
1
) To a mixture of triethyl phosphonoacetate (1.1 equiv.), DBU (0.035 equiv.), and
finely ground K CO (2 equiv.) was added ArCHO (1 equiv.) and the resulting mixture
2
3
was stirred using a magnetic stirrer for 4 h at room temperature under argon
atmosphere. Ethyl acetate was added to the crude mixture and the solid was filtered
off. The solid was rinsed with ethyl acetate and the combined filtrate was concentrated.
The resulting oil was distilled under reduced pressure using a bulb-to-bulb apparatus
(
10 mm Hg/240 °C) to give corresponding alkene (yield 84%) (E:Z = 99:1).
) A suspension of TMSOI (2.5 equiv.) and NaH (2.5 equiv.) in anhydrous DMSO (25
2
mL) was stirred at ambient temperature for 30 minutes. A DMSO solution (14 mL) of
alkene (14 mmol, 1 equiv) was added at 0 °C. The reaction mixture was stirred at 55
°
C (on silicone oil bath) for another 48 h. On completion (monitored by TLC), the
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction mixture was poured into a brine solution and extracted 3 times with ethyl
acetate. The combined organic layer was washed with water and brine, dried over
Na
eluent to afford corresponding cyclopropane derivative (60-80% yield).
) To a stirred solution of LAH (1.5 equiv.) in 7 mL diethyl ether was added dropwise
a solution of cyclopropane ester (0.90 mmol, 1equiv.) in 3 mL diethyl ether under N
2
SO , concentrated and purified by silica gel column using ethyl acetate/hexane as
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
atmosphere. After addition was completed the reaction mixture was stirred at room
temperature for another 2 to 6 h. On completion (monitored by TLC), the excess LAH
was destroyed by ice cold water. 15 mL of 10% H
and the aqueous layer was extracted several times with diethyl ether. The combined
organic layer was washed with water and 5% NaHCO , dried over MgSO and
2
SO
4
and 8 mL of ether was added
3
4
concentrated in a rotary evaporator (90-95% yield). Without any further purification,
the crude material (a colorless oil) was used for next step.
4
) To a solution of cyclopropane alcohol (6.8 mmol, 1 equiv.) in dry DCM (14 mL),
PCC (1.5 equiv.) was added in a portion-wise manner through a solid addition tube
under N atmosphere. After 3 h reaction mixture was filtered through a small plug of
2
celite and concentrated in vacuo. The crude mixture was purified by silica gel column
chromatography using ethyl acetate/hexane as eluent. Starting from aryl aldehyde the
2-arylcyclopropanecarbaldehydes was obtained in 40-55% overall yield.
trans-2-(4-methoxyphenyl)cyclopropane-1-carbaldehyde
(1a).
4-
methoxybenzaldehyde (1.0 g, 7.35 mmol), 1a (0.62 g, 3.53 mmol), 48% overall yield,
1
white solid, H NMR (400 MHz): δ 9.30 (d, J = 4.9 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H),
6.83 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H) 2.63-2.56 (m, 1H), 2.13-2.06 (m, 1H), 1.73-1.67
(
m, 1H), 1.51-1.45 (m, 1H)
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trans-2-(4-(benzyloxy)phenyl)cyclopropane-1-carbaldehyde
(1b).
4-
(
benzyloxy)benzaldehyde (1.0 g, 4.71 mmol), 1b (0.55 g, 2.16 mmol), 46% overall
1
yield, yellow solid, H NMR (400 MHz): δ 9.30 (d, J = 4.5 Hz, 1H), 7.44-7.31 (m, 5H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
2
.04 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.04 (s, 2H), 2.62-2.55 (m, 1H), 2.13-
.06 (m, 1H), 1.72-1.67 (m, 1H), 1.51-1.45 (m, 1H)
trans-2-(p-tolyl)cyclopropane-1-carbaldehyde (1c). 4-methylbenzaldehyde (1.0 g,
1
8
.32 mmol), 1c (0.69 g, 4.32 mmol), 52% overall yield, colorless liquid, H NMR (400
MHz): δ 9.30 (d, J = 4.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H),
2
1
.63-257 (m, 1H), 2.32 (s, 3H), 2.16-2.10 (m, 1H), 1.74-1.68 (m, 1H), 1.54-1.48 (m,
H)
trans-2-mesitylcyclopropane-1-carbaldehyde (1d). 2,4,6-trimethylbenzaldehyde (1.0
1
g, 6.75 mmol), 1d (0.53 g, 2.84 mmol), 42% overall yield, pale yellow liquid, H NMR
(
400 MHz): δ 9.28 (d, J = 5.4 Hz, 1H), 6.85 (s, 2H), 2.45-2.39 (m, 1H), 2.33 (s, 6H),
.25 (s, 3H), 1.98-1.91 (m, 1H), 1.82-1.76 (m, 1H), 1.40-1.34 (m, 1H)
trans-2-(4-isopropylphenyl)cyclopropane-1-carbaldehyde (1e).
2
4-
isopropylbenzaldehyde (1.0 g, 6.75 mmol), 1e (0.63 g, 3.37 mmol), 50% overall yield,
1
yellow liquid, H NMR (400 MHz): δ 9.31 (d, J = 4.5 Hz, 1H), 7.17 (d. J = 8.2 Hz, 2H),
7
1
.06 (d, J = 8.2 Hz, 2H), 2.95-2.84 (m, 1H), 2.65-2.58 (m, 1H), 2.19-2.13 (m, 1H), 1.75-
.69 (m, 1H), 1.56-1.49 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H)
trans-2-(naphthalen-2-yl)cyclopropane-1-carbaldehyde (1f). 2-naphthaldehyde (1.0 g,
1
6.41 mmol), 1f (0.53 g, 2.69 mmol), 42% overall yield, off white solid, H NMR (400
MHz): δ 9.37 (d, J = 4.5 Hz, 1H), 7.82-7.74 (m, 3H), 7.58 (s, 1H), 7.49-7.41 (m, 2H),
7
.20 (dd, J = 8.4, 1.8 Hz, 1H), 2.82-2.76 (m, 1H), 2.30-2.23 (m, 1H), 1.83-1.77 (m, 1H),
1.69-1.62 (m, 1H)
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trans-2-(o-tolyl)cyclopropanecarbaldehyde (1g). 2-methylbenzaldehyde (1.0 g, 8.32
1
mmol), 1g (0.60 g, 3.75 mmol), 45% overall yield, colourless liquid, H NMR (400
MHz): δ 9.35 (d, J = 4.6 Hz, 1H), 7.18-7.11 (m, 3H), 7.03-6.99 (m, 2H), 2.65-2.59 (m,
0
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1
H), 2.35 (s, 3H), 2.05-1.99 (m, 1H), 1.73-1.67 (m, 1H), 1.58-1.52 (m, 1H)
trans-2-phenylcyclopropane-1-carbaldehyde (1h). Benzaldehyde (1.0 g, 9.43 mmol),
1
1
h (0.69 g, 4.72 mmol), 50% overall yield, white solid, H NMR (400 MHz): δ 9.32 (d,
J = 4.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.13-7.09 (m, 2H), 2.66-2.60
m, 1H), 2.21-2.14 (m, 1H), 1.76-1.71 (m, 1H), 1.57-1.51 (m, 1H)
(
trans-2-styrylcyclopropanecarbaldehyde (1i). trans-cinnamaldehyde (1.0 g, 7.56
1
mmol), 1i (0.52 g, 3.02 mmol), 40% overall yield, viscous yellow liquid, H NMR (400
MHz): δ 9.25 (d, J = 4.9 Hz, 1H), 7.32-7.29 (m, 4H), 7.24-7.19 (m, 1H), 6.56 (d, J =
16.0 Hz, 1H), 5.76 (dd, J = 16.0, 8.6 Hz, 1H), 2.33-2.25 (m, 1H), 2.08-2.01 (m, 1H),
1
.66-1.60 (m, 1H), 1.34-1.28 (m, 1H)
trans-2-(3,4-dimethoxyphenyl)cyclopropanecarbaldehyde
(1j).
3,4-
dimethoxybenzaldehyde (1.0 g, 6.02 mmol), 1j (0.53 g, 2.59 mmol), 43% overall yield,
1
off white solid, H NMR (400 MHz): δ 9.31 (d, J = 4.4 Hz, 1H), 6.79 (d, J = 7.9 Hz,
1
1
H), 6.69-6.64 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.64-2.58 (m, 1H), 2.15-2.08 (m,
H), 1.73-1.67 (m, 1H), 1.53-1.47 (m, 1H)
trans-2-(3,4,5-trimethoxyphenyl)cyclopropanecarbaldehyde
(1k).
3,4,5-
trimethoxybenzaldehyde (1.0 g, 5.09 mmol), 1k (0.58 g, 2.45 mmol), 48% overall yield,
1
white solid, H NMR (400 MHz): δ 9.31 (d, J = 4.5 Hz, 1H), 6.33 (s, 2H), 3.84 (s, 6H),
3
1
.81 (s, 3H), 2.62-2.56 (m, 1H), 2.18-2.11 (m, 1H), 1.73-1.67 (m, 1H), 1.53-1.47 (m,
H)
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trans-2-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbaldehyde
(1l).
benzo[d][1,3]dioxole-5-carbaldehyde (1.0 g, 6.66 mmol), 1k (0.56 g, 2.93 mmol), 44%
1
overall yield, off white solid, H NMR (400 MHz): δ 9.30 (d, J = 4.6 Hz, 1H), 6.72 (d, J
1
1
1
1
1
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1
1
1
2
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0
=
2
8.1 Hz, 1H), 6.61 (dd, J = 8.0, 1.8 Hz, 1H), 6.56 (d, J = 1.8 Hz, 1H), 5.93 (s, 2H),
.60-2.54 (m, 1H), 2.12-2.05 (m, 1H), 1.71-1.64 (m, 1H), 1.48-1.41 (m, 1H)
General procedure for the synthesis of (trans-2-arylcyclopropyl)(aryl)methnone
1՛): For the reaction scheme, see Scheme S2 in the Supporting Information.
) To a mixture of Ar՛COCH (1 g, 1 equiv.) and benzaldehyde (1.1 equiv.) in ethanol
(
1
3
(10 mL), pellets of KOH (1.2 equiv) were added. Reaction was stirred at ambient
temperature for 4 h then reaction was carefully neutralized with 3 N HCl and extracted
3
times with CH
2
Cl
2
. The combine organic layer was dried over Na
2
SO , concentrated
4
and purified by silica gel column chromatography using ethyl acetate/hexane as eluent
to afford pure chalcone (55-75% yield).
2
) A suspension of TMSOI (2 equiv.) and NaH (2 equiv.) in anhydrous DMSO (10 mL)
was stirred at ambient temperature for 30 minutes. A DMSO solution (5 mL) of
chalcone (1 g, 1 equiv) was added at 0 °C. The reaction mixture was stirred at room
temperature for 2 h and on completion (monitored by TLC), reaction mixture was
poured into a brine solution and extracted 3 times with ethyl acetate. The combined
organic layer was washed with water and brine, dried over Na
2
SO , concentrated and
4
purified by silica gel column using ethyl acetate/hexane as eluent to afford the
corresponding cyclopropane derivative (50-70% yield).
(
trans-2-(4-methoxyphenyl)cyclopropyl)(phenyl)methnone (1a՛). acetophenone (1.0 g,
1
8
.32 mmol), 1a՛ (1.05 g, 4.16 mmol), 50% overall yield, light yellow liquid, H NMR
(400 MHz): δ 7.99 (d, J = 7.9 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H),
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.11 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 3.80 (s, 3H), 2.86-2.80 (m, 1H), 2.69-
.63 (m, 1H), 1.93-1.87 (m, 1H), 1.54-1.49 (m, 1H)
(
trans-2-(3,4-dimethoxyphenyl)cyclopropyl)(phenyl)methnone (1b՛). acetophenone
0
1
2
3
4
5
6
7
8
9
0
1
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5
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7
8
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1
(1.0 g, 8.32 mmol), 1b՛ (1.15 g, 4.08 mmol), 49% overall yield, yellow liquid, H NMR
(
400 MHz): δ 7.99 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H),
6
1
.81 (d, J = 8.6 Hz, 1H), 6.74-6.69 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.87-2.80 (m,
H), 2.70-2.63 (m, 1H), 1.92-1.85 (m, 1H), 1.57-1.50 (m, 1H)
p-tolyl(trans-2-(p-tolyl)cyclopropyl)methnone (1c՛). 1-(p-tolyl)ethan-1-one (1.0 g, 7.45
1
mmol), 1c՛ (0.97 g, 3.88 mmol), 52% overall yield, white solid, H NMR (400 MHz): δ
7
8
.89 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.06 (d, J =
.1 Hz, 2H), 2.87-2.81 (m, 1H), 2.68-2.61 (m, 1H), 2.40 (s, 3H), 2.33(s, 3H), 1.91-1.85
(m, 1H), 1.54-1.47 (m, 1H)
(trans-2-(4-chlorophenyl)cyclopropyl)(phenyl)methnone (1d՛). acetophenone (1.0 g,
1
8
.32 mmol), 1d՛ (0.75 g, 2.91 mmol), 35% overall yield, off white solid, H NMR (400
MHz): δ 7.98 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.27
d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 2.89-2.83 (m, 1H), 2.70-2.64 (m, 1H),
.95-1.89 (m, 1H), 1.55-1.49 (m, 1H)
(4-chlorophenyl)(trans-2-(p-tolyl)cyclopropyl)methnone
(
1
(1e՛).
1-(4-
chlorophenyl)ethan-1-one (1.0 g, 6.47 mmol), 1e՛ (0.79 g, 2.92 mmol), 45% overall
1
yield, colourless oil, H NMR (400 MHz): δ 7.88 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.4
Hz, 2H), 7.09 (d, J = 7.7 Hz, 2H), 7.02 (d, J = 7.7 Hz, 2H), 2.78-2.73 (m, 1H), 2.66-
2
.60 (m, 1H), 2.30 (s, 3H), 1.90-1.84 (m, 1H), 1.55-1.49 (m, 1H)
General procedure for the synthesis of donor-acceptor cyclopropanes (DACs,
4
)9: Following the established literature, synthesis of 4 was carried out by following the
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known procedures as mentioned below. For the reaction scheme, see Scheme S3 in
the Supporting Information.
Sodium hydride (1.5 equiv) was taken in two-neck round bottom flask, washed 3 to 4
1
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times with dry hexane under N atmosphere DMSO and added anhydrous DMSO.
2
The solution of trimethyl sulfoxonium iodide (1.5 equiv.) in anhydrous DMSO was
added to the reaction mixture at 0 ºC. After 30 minutes a solution of
diethylbenzylidenemalonate (1 equiv.) in anhydrous DMSO was added to the stirred
solution at 0 ºC, and the reaction mixture was allowed to stir for 2 h at room
temperature. Upon Completion of the reaction (as monitored by TLC), the reaction
mixture was quenched with ice cold water, and the aqueous layer was extracted 3
times with diethyl ether. The combined organic layer was dried over anhydrous
Na
2
SO and concentrated in vacuo. The crude mixture was further purified by silica
4
gel column chromatography using ethyl acetate/hexane as eluent.
Diethyl 2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate (4a). diethyl 2-(4-
methoxybenzylidene)malonate (1.0 g, 3.59 mmol), 4a (0.77 g, 2.64 mmol), 74% yield,
1
colorless oil, H NMR (400 MHz, CDCl
3
): δ 7.10 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6
Hz, 2H), 4.26-4.17 (m, 2H), 3.87-3.79 (m, 2H), 3.75 (s, 3H), 3.15 (t, J = 8.3 Hz, 1H),
.13-2.08 (m, 1H), 1.69-1.63 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H)
2
Diethyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (4b). diethyl 2-(3,4-
dimethoxybenzylidene)malonate (1.0 g, 3.24 mmol), 4b (0.76 g, 2.36 mmol), 73%
1
yield, colorless oil, H NMR (400 MHz, CDCl
3
): 1H-NMR (400 MHz, CDCl3): δ 6.76-
6
.72 (m, 3H), 4.26-4.20 (m, 2H), 3.87-3.82 (m, 8H), 3.17 (t, J = 7.1 Hz, 1H), 2.14-2.10
(m, 1H), 1.70-1.65 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H)
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Diethyl 2-(benzo[d][1,3]dioxol-5-yl)cyclopropane-1,1-dicarboxylate (4c). diethyl 2-
(
benzo[d][1,3]dioxol-5-ylmethylene)malonate (1.0 g, 3.42 mmol), 4c (0.82 g, 2.67
1
mmol), 78% yield, colorless oil, H NMR (400 MHz, CDCl
3
): δ 6.72–6.64 (m, 3 H), 5.91
0
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2
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(
s, 2 H), 4.28-4.17 (m, 2 H), 3.95-3.88 (m, 2 H), 3.14 (t, J = 7.5 Hz, 1 H), 2.09-2.07 (m,
1
H), 1.67-1.65 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 0.97 (t, J = 7.1 Hz, 3 H)
Diethyl 2-(3,4,5-trimethoxyphenyl)cyclopropane-1,1-dicarboxylate (4d). diethyl 2-
(
3,4,5-trimethoxybenzylidene)malonate (1.0 g, 2.96 mmol), 4d (0.74 g, 2.10 mmol),
1
71% yield, light yellow crystalline solid, H NMR (400 MHz, CDCl
3
): δ 6.42 (s, 2H),
4
1
.31-4.16 (m, 2H), 3.95-3.86 (m, 2H), 3.83 (s, 6H), 3.79 (s, 3H), 3.17 (t, J = 8.6 Hz,
H), 2.11 (dd, J = 8.1, 5.0 Hz, 1H), 1.68 (dd, J = 8.8, 4.0 Hz, 1H), 1.29 (t, J = 7.4 Hz,
3H), 0.91 (t, J = 7.1 Hz, 3H)
Diethyl 2-phenylcyclopropane-1,1-dicarboxylate (4e). diethyl 2-benzylidenemalonate
1
(
1.0 g, 4.03 mmol), 4e (0.71 g, 2.71 mmol), 67% yield, colorless oil, H NMR (400
MHz): δ 7.27-7.17 (m, 5H), 4.30-4.15 (m, 2H), 3.81 (q, J = 14.3, 7.1 Hz, 2H), 3.20 (t, J
= 8.7 Hz, 1H), 2.17 (dd, J = 7.8, 5.0 Hz, 1H), 1.69 (dd, J = 9.2, 5.1 Hz, 1H), 1.28 (t, J
=
7.1 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H)
Diethyl 2-(4-fluorophenyl)cyclopropane-1,1-dicarboxylate
(4f). diethyl
2-(4-
fluorobenzylidene)malonate (1.0 g, 3.75 mmol), 4f (0.73 g, 2.60 mmol), 69% yield,
1
colorless oil, H NMR (400 MHz, CDCl
3
): δ 7.17-7.12 (m, 2H), 6.93 (t, J = 8.7 Hz, 2H),
4.29-4.14 (m, 2H), 3.90-3.79 (m, 2H), 3.16 (t, J = 8.6 Hz, 1H), 2.11 (dd, J = 5.0, 3.6
Hz, 1H), 1.68 (dd, J = 5.3, 3.7 Hz, 1H), 1.27 (t, J = 7.0 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H)
Diethyl
2-(4-nitrophenyl)cyclopropane-1,1-dicarboxylate
(4g). diethyl
2-(4-
nitrobenzylidene)malonate (1.0 g, 3.41 mmol), 4g (0.66 g, 2.15 mmol), 63% yield,
1
cream coloured solid, H NMR (400 MHz, CDCl
3
): δ 8.14 (d, J = 8.6 Hz, 2H), 7.37 (d,
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J = 8.6 Hz, 2H), 4.36-4.17 (m, 2H), 3.96-3.79 (m, 2H), 3.26 (t, J = 8.5 Hz, 1H), 2.20
(
dd, J = 8.1, 5.6 Hz, 1H), 1.79 (dd, J = 8.9, 5.4 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H), 0.92
(t, J = 7.0 Hz, 3H)
Diethyl (E)-2-styrylcyclopropane-1,1-dicarboxylate (E)-2-(3-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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8
9
0
(4h).
diethyl
phenylallylidene)malonate (1.0 g, 3.64 mmol), 4h (0.71 g, 2.47 mmol), 68% yield,
1
yellow liquid, H NMR (CDCl
3
, 400 MHz): δ 7.31-7.26 (m, 4H), 7.24-7.17 (m, 1H), 6.63
(
d, J = 15.6 Hz, 1H), 5.81 (dd, J = 15.6, 8.4 Hz, 1H), 4.29-4.11 (m, 4H), 2.73 (q, J =
8.4 Hz, 1H), 1.81 (dd, J = 7.4, 5.0 Hz, 1H), 1.65 (dd, J = 9.0, 5.0 Hz, 1H), 1.28 (t, J =
.0 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H)
General procedure for the preparation of dimethyl 2-vinylcyclopropane-1,1-
7
15
dicarboxylate (4i) : Following the established literature, synthesis of 4i was carried
out by following the known procedures as mentioned below. For the reaction scheme,
see Scheme S4 in the Supporting Information.
To a freshly prepared solution of NaOMe (prepared by stirring sodium metal (2 equiv.)
in 10 mL methanol for 5 minutes) in a round bottom flask, was added dimethyl
malonate (3 equiv.). The reaction mixture was stirred at room temperature for 5
minutes and added dropwise, a methanol (10 mL) solution of (E)-1,4-Dibromobut-2-
ene (1g, 1 equiv.). The reaction mixture was then stirred under reflux conditions (on
silicone oil bath) for 3 h. On completion, the reaction mixture was concentrated on
rotary evaporator, added ice cold water and extracted 3 times with ethyl acetate. The
combined organic layer was dried over Na
2
SO and concentrated in vacuo. The crude
4
mixture was further purified by silica gel column chromatography using ethyl
acetate/hexane as eluent.
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Dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (4i). (E)-1,4-dibromobut-2-ene (1.0 g,
1
4
.68 mmol), 4i (0.78 g, 4.23 mmol), 90% yield, light yellow liquid, H NMR (CDCl
3
, 400
MHz): δ 5.47-5.35 (m, 1H), 5.29 (d, J = 16.8 Hz, 1H), 5.13 (d, J = 10.5 Hz, 1H), 3.73
s, 6H), 2.58 (q, J = 8.3 Hz, 1H), 1.71 (dd, J = 7.8, 4.9 Hz, 1H), 1.58 (dd, J = 9.1, 5.1
0
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8
9
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6
7
8
9
0
(
Hz, 1H)
Representative procedure for synthesis of 6-aryl-5,6-dihydro-4H-1,2-oxazine (3)
via additive free annulation of trans-2-arylcyclopropane-1-carbaldehyde (1) with
hydroxylamine-O-sulfonic acid (2՛): For the reaction scheme, see Scheme S5 in the
Supporting Information.
An open round-bottom flask, equipped with magnetic stir bar was charged with
cyclopropanecarbaldehyde
(1),
hydroxylamine-O-sulfonic
acid
(2՛)
(or
hydroxylammonium chloride (2)) and benzene (reagent grade). The reaction mixture
was stirred open-to-air at ambient temperatures. Upon completion, as monitored by
TLC, the solvent was evaporated in rotary evaporator and the crude mixture was
further purified by column chromatography on silica gel with ethyl acetate/hexane as
eluent.
6
-(4-methoxyphenyl)-5,6-dihydro-4H-1,2-oxazine (3a). Reaction time: 8 h, 1a (0.050
g, 0.28 mmol), 2՛ (0.047 g, 0.42 mmol), 3a (0.040 g, 0.21 mmol), Yield: 74%, orange
1
sticky solid, mp 89-91 °C, R
CDCl
H), 3.81 (s, 3H), 2.46-2.24 (m, 2H), 2.11-2.04 (m, 2H) 13C{ H} NMR (100 MHz,
CDCl ): δ 159.6, 148.6, 132.0, 128.0, 113.9, 77.3, 55.3, 25.2, 22.6 IR (neat): 2930,
f
= 0.35 (ethyl acetate/hexane 40:60), H NMR (400 MHz,
3
): δ 7.31 (d, J = 8.6 Hz, 3H), 6.91 (d, J = 8.6 Hz, 2H), 4.71 (dd, J = 8.5, 4.7 Hz,
1
1
3
˗
1
2836, 1692, 1605, 1512, 1457, 1245, 1174, 1029, 827, 537 cm HRMS (ESI, Q-TOF)
+
m/z: [M + H] Calcd for C11
H
14NO 192.1025, found 192.1035
2
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6
-(4-(benzyloxy)phenyl)-5,6-dihydro-4H-1,2-oxazine (3b). Reaction time: 12 h, 1b
(
0.050 g, 0.20 mmol), 2՛ (0.034 g, 0.30 mmol), 3b (0.044 g, 0.16 mmol), Yield: 82%,
1
off white solid, mp 84-86 °C, R
f
= 0.40 (ethyl acetate/hexane 40:60), H NMR (400
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CDCl
3
): δ 7.42-7.27 (m, 5H), 7.27 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H),
5
1
1
1
.02 (s, 2H), 4.66 (dd, J = 8.7, 4.6 Hz, 1H), 2.39-2.28 (m, 1H), 2.26-2.17 (m, 1H), 2.08-
13
1
.96 (m, 2H) C{ H} NMR (100 MHz, CDCl ): δ 158.7, 148.5, 136.8, 132.2, 128.5,
3
28.0, 127.9, 127.4, 114.8, 77.1, 69.9, 25.0, 22.4 IR (neat): 2908, 2852, 1609, 1510,
˗1
468, 1376, 1243, 1179, 998, 798, 735, 696, 504 cm HRMS (ESI, Q-TOF) m/z: [M +
+
H] Calcd for C17
H
18NO 268.1338, found 268.1333
2
6
-(p-tolyl)-5,6-dihydro-4H-1,2-oxazine (3c). Reaction time: 48 h, 1c (0.050 g, 0.31
mmol), 2՛ (0.053 g, 0.46 mmol), 3c (0.035 g, 0.20 mmol), Yield: 64%, off white solid,
1
mp 50-52 °C, R
f
= 0.48 (ethyl acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
): δ
7
.32-7.28 (m, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.74 (dd, J = 9.6,
3.5 Hz, 1H), 2.45-2.32 (m, 1H), 2.35 (s, 3H), 2.32-2.22 (m, 1H), 2.11-2.00 (m, 2H)
13
1
C{ H} NMR (100 MHz, CDCl ): δ 148.6, 138.0, 136.9, 129.2, 126.5, 77.4, 25.2, 22.3,
3
2
1.2 IR (neat): 2922, 2853, 1725, 1612, 1511, 1461, 1210, 903, 811, 758, 516 cm˗1
+
HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C11
H
14NO 176.1075, found 176.1053
6
-mesityl-5,6-dihydro-4H-1,2-oxazine (3d). Reaction time: 48 h, 1d (0.050 g, 0.26
mmol), 2՛ (0.044 g, 0.39 mmol), 3d (0.032 g, 0.16 mmol), Yield: 62%, colourless
1
viscous liquid, R
f
= 0.44 (ethyl acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
): δ
7
.34-7.31 (m, 1H), 6.84 (s, 2H), 5.09 (dd, J = 12.4, 2.7 Hz, 1H), 2.48-2.38 (m, 1H),
2.37 (s, 6H), 2.36-2.27 (m, 2H), 2.26 (s, 3H), 1.92-1.83 (m, 1H) 13C{ H} NMR (100
1
MHz, CDCl
3
): δ 148.1, 137.3, 136.3, 132.7, 130.1, 75.5, 22.7, 22.2, 20.8, 20.6 IR
(
neat): 2921, 2853, 1718, 1611, 1450, 1181, 1077, 1005, 894, 850, 822, 734, 572 cm˗1
+
HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C13H18NO 204.1388, found 204.1401
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2
2
2
2
2
2
2
3
3
3
3
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3
3
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5
6
6
-(4-isopropylphenyl)-5,6-dihydro-4H-1,2-oxazine (3e). Reaction time: 48 h, 1e (0.050
g, 0.26 mmol), 2՛ (0.044 g, 0.39 mmol), 3e (0.035 g, 0.17 mmol), Yield: 66%, pale
1
yellow liquid, R
f
= 0.45 (ethyl acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
): δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
2
.30 (d, J = 8.2 Hz, 3H), 7.23 (d, J = 8.1 Hz, 2H), 4.74 (dd, J = 9.2, 3.7 Hz, 1H), 2.97-
.85 (m, 1H), 2.45-2.34 (m, 1H), 2.32-2.23 (m, 1H), 2.15-1.99 (m, 2H), 1.24 (d, J = 6.8
Hz, 6H) 13C{ H} NMR (100 MHz, CDCl
1
3
): δ 149.0, 148.5, 137.2, 126.6, 77.4, 33.9,
2
5
2
5.1, 24.0, 22.4 IR (neat): 2957, 2923, 2852, 1702, 1513, 1459, 1054, 1008, 900, 822,
˗1
+
61 cm HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C13H18NO 204.1388, found
04.1406
6
-(naphthalen-2-yl)-5,6-dihydro-4H-1,2-oxazine (3f). Reaction time: 72 h, 1f (0.050 g,
0.25 mmol), 2՛ (0.043 g, 0.38 mmol), 3f (0.023 g, 0.11 mmol), Yield: 42%, sticky brown
1
solid, mp 84-86 °C, R
f
= 0.60 (ethyl acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
):
δ 7.88-7.81 (m, 4H), 7.51-7.46 (m, 3H), 7.37-7.35 (m, 1H), 4.97 (dd, J = 9.7, 3.2 Hz,
13
1
1H), 2.50-2.39 (m, 1H), 2.35-2.25 (m, 1H), 2.24-2.11 (m, 2H) C{ H} NMR (100 MHz,
CDCl ): δ 148.7, 137.3, 133.3, 133.2, 128.4, 128.1, 127.7, 126.3, 126.2, 125.6, 124.3,
7.5, 25.4, 22.1 IR (neat): 3053, 2922, 2851, 1691, 1600, 1300, 1003, 905, 856, 805,
3
7
7
2
˗
1
+
42, 475 cm HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C14H14NO 212.1075, found
12.1073
6-(o-tolyl)-5,6-dihydro-4H-1,2-oxazine (3g). Reaction time: 48 h, 1g (0.050 g, 0.31
mmol), 2՛ (0.053 g, 0.47 mmol), 3g (0.035 g, 0.20 mmol). In this case, the reaction
could not be capitalized for an exclusively pure 6-(o-tolyl)-5,6-dihydro-4H-1,2-oxazine
(3g), even on heating or addition of pTSA. Thus, traces of cyclopropyl oxime can be
1
seen in its H NMR spectrum along with 3g in major amount as both the compounds
have exactly the same R
f
. However, one can see the NMR signals corresponding to
= 0.55 (ethyl
the major product 3g quite clearly. Yield: 64%, orange liquid, R
f
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acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
): δ 7.41-7.38 (m, 1H), 7.36-7.33 (m,
1
H), 7.25-7.12 (m, 3H), 4.92 (dd, J = 8.4, 5.0 Hz, 1H), 2.51-2.40 (m, 1H), 2.38 (s, 3H),
13
1
2.36-2.29 (m, 1H), 2.11-2.03 (m, 2H) C{ H} NMR (100 MHz, CDCl
3
): δ 148.6, 130.5,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
28.1, 126.3, 126.0, 74.6, 24.5, 22.9, 19.1 IR (neat): 2920, 2851, 1695, 1460, 1007,
˗
1
+
98, 833, 753, 453 cm HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C11H14NO
176.1075, found 176.1082
-phenyl-5,6-dihydro-4H-1,2-oxazine (3h). Reaction time: 72 h, 1l (0.050 g, 0.34
6
mmol), 2՛ (0.058 g, 0.51 mmol), 3l (0.018 g, 0.11 mmol), Yield: 33%, pale yellow liquid,
1
R
f
= 0.55 (ethyl acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
): δ 7.40-7.30 (m,
6
H), 4.78 (dd, J = 9.8, 3.1 Hz, 1H), 2.46-2.35 (m, 1H), 2.32-2.23 (m, 1H), 2.17-2.01
1
3
1
(m, 2H) C{ H} NMR (100 MHz, CDCl
3
): δ 148.6, 139.9, 128.6, 128.3, 126.5, 77.5,
2
5.3, 22.2 IR (neat): 2924, 2853, 1700, 1452, 1291, 1008, 897, 827, 753, 697, 530
˗1
+
cm HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C10
H12NO 162.0919, found 162.0915
(
E)-6-styryl-5,6-dihydro-4H-1,2-oxazine (3i). Reaction time: 4 h, 1h (0.050 g, 0.29
mmol), 2՛ (0.050 g, 0.44 mmol), 3h (0.028 g, 0.15 mmol), Yield: 52%, yellow liquid, R
f
1
=
2
=
0.52 (ethyl acetate/hexane 40:60), H NMR (400 MHz, CDCl
3
): δ 7.40 (d, J = 7.3 Hz,
H), 7.32 (t, J = 7.5 Hz, 2H), 7.29-7.26 (m, 1H), 6.69 (d, J = 16.1 Hz, 1H), 6.21 (dd, J
16.1, 6.3 Hz, 1H), 4.46 (t, J = 8.3 Hz, 1H), 2.36-2.18 (m, 2H), 2.10-2.02 (m, 1H),
1.94-1.83 (m, 1H) 13C{ H} NMR (100 MHz, CDCl
1
3
): δ 148.5, 136.3, 132.9, 128.6,
1
9
28.0, 127.0, 126.6, 75.8, 23.9, 21.1 IR (neat): 2923, 2852, 1677, 1493, 1448, 1176,
˗
1
+
64, 747, 693 cm HRMS (ESI, Q-TOF) m/z: [M + H] Calcd for C12H14NO 188.1075,
found 188.1070
6-(3,4-dimethoxyphenyl)-5,6-dihydro-4H-1,2-oxazine (3j). Reaction time: 12 h, 1i
(
0.050 g, 0.24 mmol), 2 (0.023 g, 0.36 mmol), 3i (0.034 g, 0.15 mmol), Yield: 64%,
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