Sequential Two-Fold Claisen Rearrangement, One-Pot Ring-Closing Metathesis and Cross-Metathesis as a Route to Substituted Benzo[b]azepine-2-one, Benzo[b]azepine and Benzo[b]oxepine Derivatives

Article abstract of DOI:10.1002/hlca.202000216

A synthetic protocol involving sequential use of three atom-economic processes viz. Claisen rearrangement, ring-closing metathesis and cross metathesis has been developed to access 7-substituted benzo[b]azepine and benzo[b]oxepine derivatives starting from appropriate aniline or phenol in good overall yield. A one-pot RCM-CM protocol has also been developed for the synthesis of benzazepine and benzoxepine derivatives.

Full text of DOI:10.1002/hlca.202000216

HELVETICA
chimica acta
Accepted Article
Title: Sequential two-fold Claisen Rearrangement, One-pot Ring-
closing Metathesis and Cross-metathesis as a Route to
Substituted Benzo[b]azepine-2-one, Benzo[b]azepine and
Benzo[b]oxepine Derivatives
Authors: Shital K Chattopadhyay, Shyamasankar Mandal, Jeet
Banerjee, and Sougata Maity
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Helv. Chim. Acta 10.1002/hlca.202000216
Link to VoR: https://doi.org/10.1002/hlca.202000216
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Helvetica Chimica Acta
10.1002/hlca.202000216
HELVETICA
Sequential two-fold Claisen Rearrangement, One-pot Ring-closing
Metathesis and Cross-metathesis as a Route to Substituted
Benzo[b]azepine-2-one, Benzo[b]azepine and Benzo[b]oxepine
Derivatives
#
#
Shyamasankar Mandal, Jeet Banerjee, Sougata Maity and Shital K Chattopadhyay*
Department of Chemistry, University of Kalyani, Kalyani-741235, West Bengal, India ((Fax: +91+33+25828282, e-mail:
skchatto@yahoo.com))
#
These two authors contributed equally
A synthetic protocol involving sequential use of three atom-economic processes viz. Claisen rearrangement, ring-closing metathesis and cross
metathesis has been developed to access 7-substituted benzo[b]azepine and benzo[b]oxepine derivatives starting from appropriate aniline or
phenol in good overall yield. A one-pot RCM-CM protocol has also been developed for the synthesis of benzoazepine and benzoxepine
derivatives.
Keywords: heterocycles; catalysis; ruthenium, metathesis, Claisen rearrangement.
Introduction
Benzannulated medium ring-sized heterocyclic systems such as benzazepines and benzoxepins represent important pharmaceutical motifs
[
1]
due to the diverse range of biological activity displayed by many of these structures. Compounds 1-4 (Figure 1) are good examples in this
[
2-6]
regard. Consequently, many elegant synthetic methodologies are continuously being developed to access such ring systems.
Recent
[
7-
progress in various metal-catalyzed ring-forming reactions has facilitated access to these classically otherwise difficult-to-make ring systems.
1
4]
[15-28]
In particular, olefin-metathesis mediated transformations,
either in tandem or in sequence with other named and unnamed
have provided rapid access to several structurally embellished entities accommodating the core ring systems. However,
comparatively less attention has been paid to develop synthetic methodologies that simultaneously address incorporation of functionalities
[
29,30]
reactions,
[
31]
within the core ring system. This may become relevant for modification of biological activity. For example, it has been shown
that
incorporation of a long alkyl chain in the benzene ring converted the parent azepine derivative 2a into 2b which proved to be more potent than
the marketed anticonvulsant drug carbamazepine 3. Similarly, the important allelo chemical pterulone B, 4, contains a six carbon substituent
[
32]
in the benzene ring as part of requirement of its biological activity.
R O
P h
O
O
N
N
N H
2
N
N H
O
N
H
2
2
a , R
b , R
=
H
1
, L -6 9 2 4 9 8
=
C 6 H 1 3
C l
N
O
O
H 2 N O C
3
, C arb am a zep in e
4
, P te ru lo n e B
F ig u re 1 . B io lo g ic a lly a c tive a z e p in e a n d o xe p in e d e riv a tive s
1
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Helvetica Chimica Acta
10.1002/hlca.202000216
HELVETICA
[
33-39]
[40,41]
Several years ago, we,
and others,
have developed tandem Claisen rearrangement and ring-closing diene/ enyne metathesis as a
[
42-48]
route to benzo- or hetero-annulated oxepines, oxocines, azepines and azocines. The methodology has found applications.
Herein, we
describe a variation of our earlier protocol incorporating tandem application of a two-fold Claisen rearrangement, and a RCM-CM sequence
that allows simultaneous incorporation of functionality in the benzene ring of the core benzazepin-2-one, benzazepine and benzoxepine ring
systems.
Results and Discussion
Our synthetic approach to substituted benzazepin-2-ones relied on the belief that a two-fold aza-Claisen rearrangement of the N,N-
diallylaniline derivative 6 (Scheme 1) would place the two allyl groups on the benzene ring (leading to 7) one of which would then be utilized
for ring formation by RCM through N-tethering (eg 8), and the second allyl group would sequentially be functionalized through cross-
metathesis reaction. Thus, N,N-diallyl-p-anisidine 6 was prepared by diallylation of p-anisidine for this purpose. Although aza-Claisen
[
49-53]
rearrangement
heterocyclic synthesis, two-fold aza-Claisen rearrangement is comparatively less explored. In continuation of our earlier observations
the BF .etherate catalyzed aza-Claisen rearrangement, we observed that the two-fold rearrangement of 6 to 7 proceeds well under carefully
chosen conditions. The rearranged product 7 was smoothly converted into the N-acryloyl derivative 8 in readiness for a subsequent RCM
of N-allylanilne derivatives, including the catalyzed variant, has evolved over the decades as a reliable methodology in
[
54,55]
on
3
[
56-69]
reaction projected. The sequential RCM and CM has been extensively used
for the preparation of functionalized common ring sized
heterocycles/carbocycles. However, to the best of our knowledge this sequence has little been used
O
NH2
NH2
N
COCl
NH
BF3.OEt2
PhCl
allyl bromide
TEA
pyridine
OMe
OMe
OMe
OMe
5
7 (66%)
6
(69%)
8
(73%)
O
O
HN
HN
O
CO2Me
MeO2C
BnO2C
HN
OMe
OMe
G-I
CO2Bn
1
0, 67%
11, 59%
C10H21
O
O
OMe
BnO
BnO
HN
BnO
BnO
HN
O
H
9
(65%)
O
H
BnO OBn
C10H21
BnO OBn
(13)
OMe
OMe
G-II
1
2, 75%
14, 39%
P(Cy)3
Ru
Mes
Mes
Ph
N
Cl
Cl
Cl
Cl
Ru
Ph
P(Cy)3
P(Cy)3
Grubbs 1st gen
catalyst G-I
Grubbs 2nd gen
catalyst G-II
Scheme 1: Sequential RCM-CM route to substituted benzazepin-2-ones
st
to access functionalized medium ring-sized compounds. Ring-closing metathesis of 8 to 9 proceeded well in the presence of Grubbs’ 1
generation catalyst in refluxing benzene when the substrate concentration was adjusted. Use of the second generation catalyst G-II also
effected the ring closure in refluxing 1,2-dichloroethane in similar yield but at a somewhat faster rate. We opted to use G-I because of its
known operational advantage.
We then focused on the cross metathesis reaction of the substituted azepin-2-one derivative 9. It was found that the CM reaction with electron-
deficient alkenes such as methyl acrylate and benzyl acrylate proceeds only with G-II but in substantial reduced rate and only when the
concentration of the substrate is adjusted to 0.1 molar or less. The CM products 10 and 11 were obtained in good yields. The terminal un-
2
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Helvetica Chimica Acta
10.1002/hlca.202000216
HELVETICA
[
70,71]
activated olefin 1-dodecene unexpectedly gave a better yield of the product 12; but the reaction with the C-allyl glycoside 13
rather sluggishly to give the RCM-CM product 14 in poor yield, possibly due to steric crowding.
proceeded
Compound 7 was utilized in a second manner to prepare substituted benzazepine derivatives 17-21 (Scheme 2) in sequential RCM-CM
manner. Thus, N-tosylation of 7 followed by N-allylation of the resulting sulfonamide 15 smoothly provided the N-tethered diene 16 in good
yield. RCM of the compound 16 proceeded with G-I at a much faster rate and the reaction proved to be lot cleaner than that of the amide 8.
Similarly, the CM reaction also proceeded with much faster rate and at a lower temperature compared to that of the azepinone derivative 9
when G-II was used. The CM reaction with both the activated and un-activated olefins was found to proceed with similar yield and efficiency.
The products 18-21 were thus obtained.
T s
N H
2
N H
N T s
p -T sC l
G -I
a llyl b ro m id e
p yrid in e
K 2 C O 3
O M e
O M e
O M e
7
1 6 (9 8 % )
1
5 (7 3 % )
C
1 0 H 2 1
C O 2 M e
C O 2 B n
C 8 H 1 7
C O 2 M e
Ts N
T sN
Ts N
T sN
T sN
C O 2 B n
C 8 H 1 7
O M e
O M e
O M e
O M e
O M e
1
7
(7 6 % )
C 1 0 H 2 1
1
8 , 6 8 %
1 9 , 6 6 %
2 1 , 5 5 %
2
0 , 5 3 %
G -II
Scheme 2. Sequential RCM-CM route to substituted benzazepines.
The study was then extended to the development of a similar pathway for the synthesis of substituted benzoxepine derivatives. Thus, Claisen
rearrangement of the allyl ether 24 (Scheme 3), obtained by allylation of commercially available 2-allylphenol (22), proceeded quickly in
refluxing N,N-diethylaniline to give the corresponding 2,6-diallyl phenol 26 in very good yield. Further O-allylation of the later provided the
diene 28. A similar sequence of reactions was utilized to prepare the O-tethered diene 29 starting from compound 23 in an overall yield of 56%
over three steps. RCM of each of these dienes 28-29 also proceeded better using G-II at ambient temperature to provide the benzoxepine
derivatives 30 (81%) and 31 (78%) respectively. On the other hand, the sequential CM reaction proceeded again at elevated temperature in
the presence of G-II to provide the products 32-36 in similar facility and yields.
O
O H
O
O H
B r
B r
h e a t
R
R
R
K 2 C O
3
R
K 2 C O
3
2
2
2 , R
3 , R
=
=
H
C l
2 4 ,
2 5 ,
R
R
=
=
H , 8 4 %
C l, 9 0 %
2 6 , R
2 7 , R
=
=
H , 8 3 %
C l, 8 6 %
2 8 , R
2 9 , R
=
=
H , 7 4 %
C l, 7 2 %
B n O 2 C
M e O 2 C
E tO C
O
O
O
C O 2 B n
C O 2 M e
O
C l
G -I
3
2 , 6 6 %
3 3 , 6 0 %
3 4 , 5 7 %
R
C O E t
E tO C
C
8 H 1 7
C
8 H 1 7
3
3
0 , R
1 , R
=
=
H ,8 1 %
C l,7 8 %
O
G -II
O
C l
Scheme 3. Sequential RCM-CM route to substituted benzoxepines
3 6 , 6 4 %
3
5 , 5 5 %
A similar sequence of reactions was utilized to prepare the O-tethered diene 29 starting from compound 23 in an overall yield of 56% over
three steps. RCM of each of these dienes 28-29 also proceeded better using G-II at ambient temperature to provide the benzoxepine
derivatives 30 (81%) and 31 (78%) respectively. On the other hand, the sequential CM reaction proceeded again at elevated temperature in
the presence of G-II to provide the products 32-36 in similar facility and yields.
3
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HELVETICA
We became interested to see whether the two metathesis reactions could be conducted in a one-pot manner to avoid the separation step and
the catalyst loss, in view of ample precedence for such type of conversion in common ring-sized hetero- and carbocyclic systems. However,
little information is available wherein a medium-ring –sized heterocyclic system is formed and functionalized using RCM-CM sequence in a
one-pot procedure. We were aware of the different concentration requirement for the RCM and CM reactions of the reported substrates in the
present work. Thus, an optimization study was undertaken on the concentration difference. After some experimentation, it was found that both
the RCM reaction of the N-tosyl diene 16 and subsequent CM of the azepine 17 with methyl acrylate could be conducted in a one-pot manner
(Scheme 4) when G-II was used for both the steps and the catalyst loading is done in two equal lots. The RCM reaction proceeded rapidly in
refluxing dichloromethane when the substrate concentration was adjusted to 0.5 M which was found to be compatible with the subsequent CM
reaction. The one-pot product 18 was obtained in 61% yield as compared to the two step yield of 52%. The RCM-CM products 19-21 were
similarly prepared in one-pot manner in comparable yields. The O-tethered dienes 28 and 29 also underwent the one pot RCM-CM reaction
with ethyl vinyl ketone under the developed conditions to give the products 34 (60%) and 35 (53%), respectively. Compounds 32, 33 and 36
were analogously prepared. However, the N-tethered diene 8 although underwent RCM in refluxing dichloromethane but failed to undergo
significant CM reaction with methyl acrylate in one-pot manner. In this case, purification of the required product from among some close-
running mixture of compounds also proved to be difficult.
C O 2 M e
N T s
T s N
T sN
C O 2 M e
G -II
D C M ,
re flu x
G -II, D C M ,
re flu x ,
O M e
O M e
O M e
1
6
1 7
1
8 (6 1 % )
E tO C
O
O
G -II
O
G -II
C O E t
D C M ,
re flu x
R
R
D C M , re flu x ,
R
2
2
8 , R
9 , R
=
=
H
C l
3
0 , R
=
=
H
C l
3 4 , R
3 5 , R
=
=
H , 6 0 %
C l, 5 3 %
3 1 , R
O
O
H N
G -II
X
H N
C O 2 M e
M e O 2 C
O M e
O M e
8
Scheme 4. One-pot RCM-CM reactions leading to benzazepines and benzoxepines
Conclusions
In brief, we have developed a simple protocol for the synthesis of a range of pharmaceutically relevant 1-benzazepin-2-one and
benzazepine derivatives with 1,2,3-contiguous substitution pattern involving an atom-economic two-fold aza-Claisen rearrangement and a
RCM-CM sequence as key steps. The procedure has been extended to the preparation of similarly substituted benzoxepine derivatives. A
one-pot RCM-CM procedure could be developed for the synthesis of N-tosylbenzazepines 18-21 and the benzoxepines 32-36 with some
advantages. The methodology developed may provide access to substituted medium ring-sized related compounds of interest, and hence may
complement the existing procedures.
Experimental Section
General:
1
13
Infrared spectra were recorded with a PerkinElmer Infrared Spectrometer model No L120−000A. H and C NMR spectra were recorded with
a Bruker 400MHz Ultrashield NMR spectrometer purchased through a DST-FIST grant. Mass spectra were recorded with a Water Xevo QTOF
mass spectrometer purchased through the DST-PURSE grant.
N, N-diallyl-4-methoxyaniline (6):
Allyl bromide (11.0 mL, 0.13 mol) was added dropwise to an ice cooled solution of p-anisidine 5 (5.000 g, 40.5 mmol) and triethylamine (12.5
ml, 90.0 mmol) in anhyd MeCN (20 mL) under nitrogen atmosphere. The resulting mixture was heated to reflux for 18 h and then allowed to
4
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Helvetica Chimica Acta
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HELVETICA
come to rt. It was then concentrated under vacuo and the residual mass was extracted with EA (2 x 50 mL). The combined organic extracts
were washed with H O and brine and dried over anhyd Na SO . It was filtered and the filtrate was concentrated in vacuo to leave a crude
mass which was purified by column chromatography over silica gel (100-200 mesh) using PE as eluent to give 6
2
2
4
[
54]
as viscous liquid (5.65g,
-
1 1
6
9%). IR (neat): ν 3077, 2831, 1641, 1513, 1441, 1418, 1241, 1180, 1042 cm . H NMR (400 MHz, CDCl
.69-6.67 (m, H-C(3,5), 2 H), 5.88-5.81 (m, =CH, 2 H), 5.19-5.12 (m, =CH , 4 H), 3.85 (d, J = 1.6, -NCH , 4 H), 3.74 (s, -OMe, 3 H). C NMR
): δ = 151.6, 143.5, 135.6, 134.7, 117.1, 116.2, 114.7, 114.6, 57.4, 55.7, 53.7.
3
): δ = 6.81-6.78 (m, H-C(2,6), 2 H),
13
6
2
2
(100 MHz, CDCl
3
2
, 6-diallyl-4-methoxyaniline (7):
.OEt (0.46 mL, 3.69 mmol) solution was added in a drop wise manner to a stirred solution of compound 6 (0.500 g, 2.46 mmol) in anhyd
PhCl (15 mL) under nitrogen atmosphere. The resulting mixture was then heated to reflux for 12 h. The reaction mixture was then allowed to
come to rt and quenched slowly with sat. aq. solution of NaHCO (10 mL). It was extracted with EA (2 x 25 mL), and the combined organic
extracts were washed with H O (2 x 25 mL), and brine (25 mL). It was dried over anhyd Na SO and filtered. The filtrate was concentrated in
vacuo and the residual mass was purified by column chromatography over silica gel (100-200 mesh) using EA-PE (1 :19) as eluent to give the
BF
3
2
3
2
2
4
-
1
1
product as viscous liquid (0.33 g, 66%). IR (neat): ν 3441, 2918, 1635, 1605, 1477, 1253, 1146, 1052 cm . H NMR (400 MHz, CDCl
3
): δ =
6
.58 (s, H-C(3,5), 2 H), 5.97-5.90 (m, =CH, 2 H), 5.13-5.06 (m, =CH
2
, 4 H), 3.73 (s, -OMe, 3 H), 3.44 (brs, -NH, 1 H), 3.29 (d, J = 6.0, -ArCH
2
,
13
+
4
H). C NMR (100 MHz, CDCl
3
): δ = 152.4, 136.8, 135.8, 125.6, 116.3, 114.1, 55.6, 36.9. MS (QTOF ES+): found, 204.1382 [M + H]; calcd
for C13H18NO, 204.1388.
N-(2, 6-diallyl-4-methoxyphenyl)acrylamide (8):
Pyridine (0.20 mL, 2.46 mmol) and acryloyl chloride (0.10 mL, 1.23 mmol) were sequentially added to an ice-cooled stirred solution of
7
(0.100 g, 0.49 mmol) in anhyd DCM ( 3 mL)under nitrogen atmosphere. Then the reaction mixture was slowly allowed to come to rt and stirred
3
for 2 h. It was extracted with DCM (2 x 10 mL), washed successively with cold HCl solution (2N, 2 x 10 mL), sat aq solution of NaHCO ( 2 x
2 2 4 ,
10 mL), H O (10 mL) and brine (10 mL). The combined organic extracts were dried over anhyd Na SO and filtered. The filtrate was
concentrated in vacuo to leave a crude mass which was purified by column chromatography over silica gel (100-200 mesh) using a mixture of
EA-PE (3:7) as eluent to give 8 as colorless solid (0.092 g, 73%).
◦
-1
1
Melting point: 117 -118 C. IR (KBr): ν 3259, 2938, 2838, 1657, 1627, 1604, 1523, 1474, 1409, 1312, 1233, 1141, 1051 cm . H NMR (400
MHz, CDCl ): δ = 6.92 (s, -NH, 1 H), 6.69 (s, H-C(3,5), 2 H), 6.42-6.27 (m, =CH, 2 H), 5.94-5.92 (m, =CH, 2 H), 5.91-5.75 (d, J = 10, =CH, 1
H), 5.09-4.99 (m, =CH
3
13
2
, 4 H), 3.80 (s, -OMe, 3 H), 3.30-3.27 (d, J = 6.0, 5.0, -ArCH
2
, 4 H). C NMR (100 MHz, CDCl
3
): δ = 164.6, 158.8, 138.8,
+
1
36.5, 135.4, 130.6, 127.3, 126.3, 116.8, 116.1, 113.5, 113.4, 55.3, 36.9, 36.6. MS (QTOF ES+): found, 258.1483 [M + H]; calcd for
16 2
C H20NO , 258.1494.
9-Allyl-7- methoxy-1H-benzo[b]azepin-2(5H)-one (9):
To a stirred solution of 8 (0.052g, 0.2 mmol) in degassed toluene (8 mL) under argon atmosphere was added G-I (2.5 mol%) and the mixture
◦
was heated at 80 C for 24 h. It was allowed to come to rt and was concentrated in vacuo to leave a crude mass which was purified by column
chromatography over silica gel (100-200 mesh) using EA-PE (4:6) as eluent to give the product 9 as colorless solid (0.031 g, 65%). Melting
-
1 1
point: 165-166 ºC. IR (KBr): ν 3176, 2916, 2839, 1672, 1612, 1404, 1336, 1289, 1151, 1058 cm . H NMR (400 MHz, CDCl
3
): δ = 7.81 (s, -NH,
1
3
1
H), 6.65-6.58 (m, H-C(4,6,8), 3 H), 6.00-5.89 (m, =CH, 2 H), 5.19 (d, J = 10, =CH, 1 H), 5.08 (d, J = 16.4, =CH, 1 H), 3.78 (s, -OMe, 3 H),
13
.41 (d, J = 5.2, H-C(5), 2 H), 3.31 (d, J = 6.8, -ArCH
2
, 2 H). C NMR (100 MHz, CDCl
3
): δ = 167.8, 157.1, 141.6, 135.4, 135.1, 131.6, 128.5,
+
25.3, 117.3, 114.2, 112.1, 55.5, 37.0, 32.5. MS (QTOF ES+): found, 230.1174 [M + H]; calcd for C14
2
H16NO , 230.1181.
General procedure for the CM reaction for the synthesis of benzazepinones 10,11,12 and 14
To a stirred solution of 9 (0.046 g, 0.2 mmol) in degassed anhyd 1,2-DCE (2 mL) under argon atmosphere was added appropriate olefin (0.3
mmol), and G-II (2.50 mol%). The reaction mixture was heated to reflux for 24-36 h under argon. It was allowed to come to rt, concentrated in
vacuo and the residue was purified by column chromatography over silica gel (100-200 mesh) using a mixture of EA-PE (3:7) to give the
corresponding RCM-CM product.
(E)- Methyl- 4-((Z)-7-methoxy-2-oxo-2, 5-dihydro-1H-benzo[b]azepin-9-yl) but-2-enoate (10):
◦
Colorless solid (0.039 g, 67%) Melting point: 134-135 C. IR (KBr): ν3194, 2952, 2841, 1718, 1660, 1612, 1593, 1410, 1333, 1272, 1204, 1148,
-
1 1
1
1
2
053 cm . H NMR (400 MHz, CDCl
3
): δ = 7.84 (s, -NH, 1 H,), 7.02 (td, J = 16.0, 5.6, =CH, 1 H), 6.58-6.52 (m, H-C(6,8,4), 3 H), 5.82 (d, J =
0.8, =CH, 1 H), 5.66 (d, J = 15.6, =CH, 1 H), 3.71 (s, -OMe, 3 H), 3.65 (s, -OMe, 3 H), 3.50 (d, J = 5.6, H-C(5), 2 H), 3.26 (d, J = 6.8, -ArCH
2
,
13
H). C NMR (100 MHz, CDCl
3
): δ = 168.1, 166.4, 157.2, 145.4, 141.8, 136.1, 130.3, 128.2, 125.1, 122.7, 114.2, 112.6, 55.5, 51.6, 34.9, 32.6.
+
MS (QTOF ES+): found, 288.1227 [M + H]; calcd for C16
4
H18NO , 288.1236.
(E)- Benzyl 4-(7-Methoxy-2-oxo-2, 5-dihydro-1H-benzo[b]azepin-9-yl) but-2-enoate acid benzyl ester (11):
-
1
1
Eluent: EA: PE (4:6). Viscous liquid (0.044 g, 59%). IR (KBr): ν 3423, 2922, 2852, 1730, 1638, 1591, 1459, 1363, 1278, 1166, 1047 cm . H
NMR (400 MHz, CDCl
3
): δ = 7.83 (s, -NH, 1 H), 7.28-7.19 (m, -ArH, 5 H), 7.08 (dt, J = 16.4, 5.6, =CH, 1 H), 6.56-6.50 (m, -ArH + =CH, 3 H),
5
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Helvetica Chimica Acta
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HELVETICA
5
6
1
7
.81 (d, J = 10.8 , =CH, 1 H), 5.65 (d, J = 16, =CH, 1 H), 5.1 (s, -OCH
2
, 2 H), 3.69 (s, -OMe, 3 H), 3.50 (d, J = 5.6, H-C(5), 2 H), 3.24 (d, J =
13
.8, -ArCH
2
, 2 H). C NMR (100 MHz, CDCl
3
): δ = 168.0, 165.8, 157.2, 145.7, 141.9, 136.0, 135.8, 130.1, 128.6, 128.4, 128.3, 128.1, 125.1,
+
22.8, 114.2, 112.7, 66.4, 55.5, 34.9, 32.6. MS (QTOF ES+): found, 364.1549 [M + H]; calcd for C22
H22NO
4
, 364.1549.
-Methoxy-9-tridec-2-enyl-1, 5-dihydro[b]azepin-2-one (12):
◦
Eluent: EA-PE (1:3). Yield: (0.055 g, 75%). Colorless solid; Melting point: 110-111 C. IR (KBr): ν 3179, 2921, 2851, 1673, 1614, 1467, 1405,
-
1
1
1
288, 1150, 1062 cm . H NMR (400 MHz, CDCl
.53 (m, =CH, 2 H), 3.78 (s, -OCH , 3 H), 3.31 (d, J = 7.2, H-C(5), ArCH
, 3 H). C NMR (100 MHz, CDCl ): δ = 167.6, 157.0, 141.5, 135.1, 133.7, 132.5, 128.5, 126.2, 125.4, 114.1, 111.8, 55.5, 36.1, 32.6, 32.5,
1.9, 29.7, 29.6, 29.5, 29.3, 29.2, 22.7, 14.1, 1.0. MS (QTOF ES+): found, 370.2738 [M + H]; calcd for C24
-Methoxy-9-[4-(3, 4, 5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-but-2-enyl]-1, 5-dihydro-benzo[b]azepin-2-one (14):
3
): δ = 7.78 (s, -NH, 1 H), 6.65-6.59 (m, =CH, H-C(6,8), 3 H), 5.90 (d, J = 10.8, =CH, 1 H),
5
3
2
, 4 H), 2.03 (s, -CH , 2 H), 1.35-1.25 (m, -CH , 16 H), 0.87 (t, J = 2.0,
2
2
13
-CH
3
3
+
3
7
2
H36NO , 370.2746.
-
1 1
Eluent: EA: PE (4:6). Viscous liquid (0.061 g, 39%). IR (KBr): ν 3375, 2924, 2853, 1734, 1711, 1649, 1464, 1384, 1261, 1159, 1082 cm . H
NMR (400 MHz, CDCl ): δ = 7.58 (s, -NH, 1 H), 7.26-7.15 (m, -ArH, 17 H), 7.04-7.02 (m, -ArH, 2 H), 6.54-6.48 (m, -ArH, =CH, 2 H), 5.82 (dd,
J = 1.6, 10.8, =CH, 1 H), 5.56-5.43 (m, =CH, 2 H), 4.83 (d, J = 10.8, -OCH , 1 H), 4.71 (d, J = 10.4, -OCH , 2 H), 4.61-4.51 (m, -OCH , 3 H),
, 2 H), 4.04-4.02 (m, -CH, 1 H), 3.72 (s, -OMe, 3 H), 3.69-3.48 (m, -CH, 5 H), 3.26-3.20 (m, -CH , 4 H), 2.43-2.39 (m, -CH
): δ = 167.5, 157.0, 141.5, 138.7, 138.2, 135.3, 132.3, 129.1, 129.0, 128.4, 128.4, 128.3,
3
2
2
2
4
2
1
.39-4.35 (m, -OCH
2
2
2
,
13
H), 1.56 (s, -CH , 2 H). C NMR (100 MHz, CDCl
2
3
28.0, 127.9, 127.8, 127.7, 127.6, 125.4, 114.1, 111.9, 82.3, 79.9, 78.0, 75.5, 75.1, 73.5, 73.4, 73.0, 71.2, 68.7, 55.5, 36.0, 32.6, 28.4. MS
+
(
QTOF ES+): found, 788.3568 [M + Na]; calcd for C49
7
H51NNaO , 788.3563.
N-(Diallyl-4-methoxy-phenyl)-4-methyl-benzenesulfonamide (15):
To a stirred solution of 7 (2.000 g, 9.85 mmol) in anhyd DCM (4.0 mL), pyridine (1.6 mL, 19.7 mmol) followed by p-TsCl (2.820 g, 14.8 mmol)
were added under nitrogen atmosphere at rt. The reaction mixture was allowed to stir at rt for 2 h. It was extracted with EA (2 x 50 mL),
3 2 2 4
washed successively with HCl (2N, 2 x 25 mL), sat aq NaHCO solution (2 x 20 mL), H O (20 mL) and brine. It was dried over anhyd Na SO ,
and filtered. The filtrate was concentrated in vacuo to leave a crude mass that was purified by column chromatography over silica gel (100-200
◦
mesh) using EA-PE (1:9) as eluent to give 15 as colorless solid (2.650 g, 73 %). Melting point: 85-86 C. IR (KBr): ν 3297, 2946, 2835, 1639,
-
1
1
1
600, 1465, 1394, 1321, 1157, 1088 cm . H NMR (400 MHz, CDCl
3
): δ = 7.58 (d, J = 8, -ArH, 2 H), 7.25 (d, J = 8, -ArH, 2 H), 6.60 (s, H-
C(3,5), 2 H), 6.16 (s, -NH, 1 H), 5.77-5.69 (m, =CH, 2 H), 5.02 (d, J = 10, =CH, 2 H), 4.92 (dd, J = 1.2, 17.2, =CH, 2 H), 3.76 (s, -OMe, 3 H),
13
3
.10 (d, J = 6.4, -ArCH
2
, 4 H), 2.42 (s, -CH
3
, 3 H). C NMR (100 MHz, CDCl
3
): δ = 158.8, 143.7, 141.0, 137.6, 136.5, 129.7, 127.2, 125.2,
+
1
16.4, 113.7, 55.3, 36.6, 21.6. MS (QTOF ES+): found, 380.1292 [M + Na]; calcd for C20
3
H23NNaO S, 380.1296.
N-Allyl-N-(2-allyl-6-but-3-enyl-4methoxy-phenyl)-4-methyl-benzenesulfonamide (16):
To a stirred solution of 15 (2.000 g, 5.6 mmol) in anhyd Me CO (6 mL), K CO (2.000 g, 14.5 mmol) and allyl bromide (1.2 mL, 14.0 mmol) was
added under nitrogen atmosphere. The reaction mixture was allowed to reflux for 4 h. It was allowed to come to rt and then concentrated
under reduced pressure. The residual mass was extracted with EA (2 x 50 mL), washed with H O (50 mL), and brine (25 mL). It was dried
over anhyd Na SO and filtered. The filtrate was concentrated in vacuo to leave a crude mass that was purified by column chromatography
over silica gel (100-200 mesh) using EA:PE (1:9) as eluent to give 16 as colorless viscous liquid (2.190 g, 98%). IR (KBr): ν 3077, 2922, 1638,
2
2
3
2
2
4
-
1 1
1
599, 1465, 1439, 1345, 1162, 1090cm . H NMR (400 MHz, CDCl
3
): δ = 7.54 (d, J = 8.4, -ArH, 2 H), 7.16 (d, J = 8.0, -ArH, 2 H), 6.53 (s, H-
, 2 H), 3.62 (s, -OMe, 3 H), 3.0 (d, J = 6.8, -ArCH , 4 H),
): δ = 158.9, 143.4, 142.3, 137.9, 136.9, 133.1, 129.7, 128.5, 127.4, 119.3, 116.7, 113.6, 55.2,
S: C, 69.49, H, 6.85, N, 3.52; Found C, 69.76, H, 7.09 , N, 3.65 %.
-Allyl-7-methoxy-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-benzo[b]azepine (17):
C(3,5), 2 H), 5.77-5.62 (m, =CH, 3 H), 4.95-4.84 (m, =CH, 6 H), 3.97 (d, J = 7.2, -NCH
2
2
13
2
5
9
.30 (s, -CH
3 3
, 3 H). C NMR (100 MHz, CDCl
4.7, 36.2, 21.5. Anal calcd for C23
H
27NO
3
To a stirred solution of 16 (0.500 g, 1.26 mmol) in anhyd toluene (20 mL) G-I (1 mol%) was added under argon atmosphere. The reaction
◦
mixture was heated at 80 C for 2 h. It was concentrated in vacuo to leave a crude mass that was purified by column chromatography over
silica gel (100-200 mesh) using EA-PE (1:19) as eluent to give 17 as a colorless solid (0.362g, 76%). Melting point: 125-126 ºC. IR (KBr): ν
-
1 1
3
456, 2922, 2850, 1598, 1475, 1338, 1216, 1158, 1091 cm . H NMR (400 MHz, CDCl
3
): δ = 7.67 (d, J = 8.4, -ArH, 2 H), 7.22 (d, J = 8.8, -ArH,
2
H), 6.68 (d, J = 2.8, -ArH, 1 H), 6.43 (d, J = 2.8, -ArH, 1 H), 5.92-5.85 (m, =CH, 1 H), 5.53-5.48 (m, =CH, 1 H), 5.35 (m, =CH, 1 H), 5.09-5.05
(m, =CH, 2 H), 4.80 (d, J = 16.6, H-C(2), 1 H), 3.82 (d, J = 16.8, H-C(2), 1 H), 3.76 (s, -OMe, 3 H), 3.63-3.58 (dd, J= 16, 6.8, H-C(5), 1 H),
13
3
.41-3.35 (dd, J= 15.6, 6.4, H-C(5), 1 H), 2.85 (d, J = 16.8, -ArCH
2 2 3
, 1 H), 2.59-2.52 (m, -ArCH , 1 H), 2.40 (s, -CH , 3 H). C NMR (100 MHz,
CDCl
3
): δ = 159.1, 143.4, 143.2, 142.8, 138.9, 137.0, 130.0, 129.5, 127.3, 125.8, 125.2, 116.6, 113.5, 112.9, 55.3, 49.2, 36.6, 32.7, 21.6. MS
+
(
QTOF ES+): found, 392.1293 [M + Na]; calcd for C21H23NNaO S, 392.1296.
3
General procedure for the CM reaction for the synthesis of the N-tosylbenzazepines 18-21:
To a stirred solution of 17 (0.076 g, 0.2 mmol) in anhyd DCM (2 mL), appropriate CM-partner (methyl acrylate/benzyl acrylate/1-dodecene/ 1-
decene, 0.3 mmol) followed by G-II (2.5 mol%) were added under argon atmosphere. The reaction mixture was heated to reflux for 2-4 h. It
was then allowed to come to rt and concentrated in vacuo to leave a crude mass that was purified by column chromatography over silica gel
(230-400 mesh) using EA-PE (1:19) as eluent to give the RCM-CM products 18-21.
6
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Helvetica Chimica Acta
10.1002/hlca.202000216
HELVETICA
4-[7-Methoxy-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-benzo[b]azepin-9-yl]-but-2-enoic acid methyl ester (18):
-
1 1
Colorless viscous liquid (0.058 g, 68%). IR (KBr): ν 3424, 2921, 1720, 1634, 1599, 1477, 1338, 1158, 1091 cm . H NMR (400 MHz, CDCl
7.65 (d, J = 8.4, -ArH, 2 H), 7.24 (d, J = 8.4, -ArH, 2 H), 7.06-6.99 (dt, J = 16, 2.4, =CH, 1 H), 6.62 (d, J = 2.8, -ArH, 1 H), 6.45 (d, J = 2.8, -
ArH, 1 H), 5.87-5.82 (m, =CH, 1 H), 5.49-5.47 (m, =CH, 1 H), 5.39-5.35 (m, =CH, 1 H), 4.84-4.79 (m, H-C(2), 1 H), 3.84-3.80 (m, H-C(2,5), 2
H), 3.78 (s, -OMe, 3 H), 3.73 (s, -OMe, 3 H), 3.54-3.48 (m, H-C(5), 1 H), 2.75 (m, ArCH2, 1 H), 2.59-2.52 (m, -ArCH , 1 H), 2.42 (s, -CH , 3 H).
3
): δ
=
2
3
13
C NMR (100 MHz, CDCl
3
): δ = 166.9, 159.2, 147.4, 143.5, 143.3, 140.7, 138.7, 130.1, 129.5, 127.3, 125.6, 125.1, 122.4, 113.7, 113.6, 55.4,
+
5
1.5, 49.2, 34.9, 32.7, 29.7, 21.6. MS (QTOF ES+): found, 428.1506 [M + H]; calcd for C23
5
H26NO S, 428.1532.
(
E)-Benzyl-4-(7-methoxy-2-oxo-1-tosyl-2,5-dihydro-1H-benzo[b]azepin-9-yl)but-2-enoate (19):
Colorless viscous liquid (0.065g, 66%). IR (KBr): ν 3421, 2924, 1738, 1722, 1651, 1599, 1477, 1339, 1158, 1091 cm . H NMR (400 MHz,
CDCl ): δ = 7.59 (d, J = 8, -ArH, 2 H), 7.30-7.22 (m, -ArH, 5 H), 7.16 (d, J = 8, ArH, 2 H), 7.02 -6.97 (m, =CH, 1 H), 6.54 (d, J = 2.8, H-C(6/8),
H), 6.37 (d, J = 2.8, H-C(8/6), 1 H), 5.81-5.78 (m, =CH, 1 H), 5.44-5.39 (m, =CH, 1 H), 5.29-5.27 (m, =CH, 1 H), 5.10 (s, -OCH , 2 H), 4.75-
.70 (m, H-C(2), 1 H), 3.77-3.72 (m, H-C(2,5), 2 H), 3.67 (s, -OMe, 3 H), 3.45-3.39 (m, H-C(5), 1 H), 2.71 (t, J = 6.2, -ArCH , 1 H), 2.51-2.45
-
1
1
3
1
4
2
2
13
(
m, -ArCH
2
, 1 H), 2.33 (s, -CH
3
, 3 H). C NMR (100 MHz, CDCl
3
): δ = 166.1, 159.2, 147.8, 143.5, 143.4, 140.6, 138.7, 136.0, 130.1, 129.5,
+
1
28.6, 128.3, 127.3, 125.7, 125.1, 122.4, 113.8, 113.6, 66.2, 55.4, 49.3, 35.0, 32.7, 21.6. MS (QTOF ES+): found, 526.1667 [M + Na]; calcd
for C29
-Methoxy-1-(toluene-4-sulfonyl)-9-undec-2-enyl-2,5-dihydro-1H-benzo[b]azepine (20):
Colourless viscous liquid (0.051 g, 53%). IR (KBr): ν 3503, 2955, 2924, 2853, 1599, 1470, 1341, 1159, 1056 cm . H NMR (400 MHz, CDCl
δ = 7.61 (d, J = 8.4, -ArH, 2 H), 7.17 (d, J = 8, -ArH, 2 H), 6.61 (d, J = 2.8, H-C(6/8), 1 H), 6.34 (s, H-C(8/6), 1 H), 5.46-5.38 (m, =CH, 3 H),
.32-5.28 (m, =CH, 1 H), 4.74-4.69 (m, H-C(2), 1 H), 3.76-3.71 (m, H-C(2), 1 H), 3.68 (s, -OMe, 3 H), 3.47-3.41 (m, H-C(5), 1 H), 3.26-3.21 (m,
H-C(5), 1 H), 2.84-2.78 (m, -ArCH , 1 H), 2.52-2.45 (m, -ArCH , 1 H), 2.35 (s, -PhCH , 3 H), 1.95-1.91 (m, -CH , 2 H), 1.54 (s, -CH , 1 H), 1.28-
5
H29NNaO S, 526.1664.
7
-
1 1
3
):
5
2
2
3
2
2
13
1
.19 (m, -CH
2
, 13 H), 0.82-0.79 (m, -CH
3
, 3H). C NMR (100 MHz, CDCl
3
): δ = 159.0, 143.9, 143.2, 143.1, 139.0, 132.9, 129.4, 128.1, 127.3,
+
1
25.8, 113.3, 112.7, 55.2, 49.2, 35.3, 32.7, 32.6, 31.9, 29.7, 29.6,29.5, 29.4, 29.3, 22.7, 21.6, 14.1. MS (QTOF ES+): found, 532.2865 [M +
3
Na]; calcd for C31H43NNaO S, 532.2861.
7
-Methoxy-1-(toluene-4-sulfonyl)-9-tridec-2-enyl-2,5-dihydro-1H-benzo[b]azepine (21):
Colorless viscous liquid (0.056 g, 55%). IR (KBr): ν 3422, 2924, 2852, 1598, 1468, 1341, 1261, 1160, 1091 cm . H NMR (400 MHz, CDCl
7.60 (d, J = 8.4, -ArH, 2 H), 7.16 (t, J = 8, -ArH, 2 H), 6.61 (d, J = 2.8, H-C(6/8), 1 H), 6.34 (s, H-C(8/6), 1 H), 5.45-5.37 (m, =CH, 3 H), 5.30-
.28 (m, =CH, 1 H), 4.74-4.71 (m, H-C(2) 1 H), 3.76-3.71 (m, H-C(2), 1 H), 3.67 (s, -OMe, 3 H), 3.47-3.42 (m, H-C(5), 1 H), 3.26-3.21 (m, H-
C(5), 1 H), 2.83 (d, J = 16, -ArCH , 1 H), 2.51-2.45 (m, -ArCH , 1 H), 2.34 (s, -CH , 3 H), 1.95-1.90 (m, -CH , 2 H), 1.28-1.18 (m, -CH , 12 H),
, 3 H). C NMR (100 MHz, CDCl ): δ = 159.0, 143.8, 143.2, 143.1, 139.0, 132.9, 129.4, 128.1, 127.3, 125.8, 125.4, 125.3,
-
1 1
3
): δ
=
5
2
2
3
2
2
13
0.81-0.78 (m, -CH
3
3
113.4, 112.7, 55.2, 49.2, 35.4, 32.7, 32.6, 31.9, 29.5, 29.3, 29.26, 29.2, 22.7, 21.6, 14.2.
+
MS (QTOF ES+): found, 504.2543 [M + Na]; calcd for C29
H
39NNaO
3
S, 504.2548.
[
73]
Allyl-2-(allyloxy)benzene (24)
[
73]
A mixture of 2-allyl phenol
10 mL) was heated to reflux for 1 h. It was allowed to come to rt, filtered and the filtrate was concentrated in vacuo. It was diluted with H
mL) and then extracted with ether (2 x 25 mL). The combined organic extracts were sequentially washed with aq solution of NaOH (10%, 2 x
0 mL), H O (2 x 25 mL) and brine (20 mL). It was dried over anhyd Na SO , filtered and the filtrate was concentrated in vacuo to leave a pale
yellow mass which was purified by column chromatography over silica gel using petroleum ether as eluent to give 24 as a colorless viscous
22 (2.680 g, 20 mmol), allyl bromide (3.4 mL, 40.0 mmol), anhyd K
2
CO
3
(4.140 g, 30.0 mmol) in anhyd Me
2
CO
(
2
O (20
2
2
2
4
-
1 1
liquid (2.88g, 84%). IR (neat): ν 1585, 1438, 1258, 1089 cm . H NMR (400 MHz, CDCl
3
): δ = 7.10-7.06 (m, -ArH, 2 H), 6.82 (t, J = 7.2, -ArH,
, 2 H), 5.19-5.17 (dd, J = 8.8, 1.6, =CH , 1 H), 5.01-4.94 (m, =CH
, 2 H). C NMR (100 MHz, CDCl ): δ = 156.4, 137.2, 133.7, 130.0, 129.0, 127.4,
1
1
1
2
H), 6.75 (d, J = 8, -ArH, 1 H), 6.01-5.89 (m, =CH, 2 H), 5.37-5.32 (m, =CH
2
2
2
,
13
H), 4.47-4.45 (m, OCH
2
, 2 H), 3.34 (d, J = 6.8, -ArCH
2
3
20.9, 116.9, 115.5, 111.7, 68.8, 34.6.
[
72]
-Allyl-1-(allyloxy)-4-chlorobenzene (25)
This was prepared following exactly the procedure described for 24. Compound 25 was obtained from 23 as a colorless viscous liquid (3.750
-
1 1
g, 90%). IR (neat): ν 1605, 1589, 1435, 1265, 1094 cm . H NMR (400 MHz, CDCl
3
): δ = 7.0 (s, -ArH, 2 H), 6.7 (d, J = 8, -ArH, 1 H), 5.8-6.0
m, =CH, 2 H), 5.4 (dd, J = 8.8,1.2, 8 =CH, 1 H), 5.2 (q, J = 1.6, 1.2, =CH, 1 H), 5.04-5.09 (m, =CH, 2 H), 4.4 (d, J = 1.2, -OCH , 2 H), 3.3 (d, J
): δ = 154.8, 136.1, 133.1, 130.9, 129.7, 126.9, 125.5, 117.2, 116.2, 112.8, 69.0, 34.2.
(
2
13
=
2 3
6.8, -CH , 2 H). C NMR (100 MHz, CDCl
[
73]
2
,6-Diallylphenol (26)
A solution of the allyl ether 24 (1.730 g, 10.0 mmol) in PhNEt
into ice-cooled HCl solution (4N, 25 mL) with continuous stirring with a glass rod. It was then extracted with ether (2 x 25 mL) and the
2
(5 ml) was refluxed for 3h. It was allowed to come to rt and then slowly poured
combined organic extracts were washed successively with HCl (2 N, 25 mL), H
2 2 4
O (25 mL), and brine (20 mL). It was dried over anhyd Na SO ,
7
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Helvetica Chimica Acta
10.1002/hlca.202000216
HELVETICA
filtered and the filtrate was concentrated in vacuo to leave a pale brown mass which was purified by column chromatography over silica gel
[
73]
-1
using EA:PE (1:19) as eluent to give 26
as a colorless viscous liquid (1.44 g, 83%). IR (neat): ν 3415, 1634, 1497, 1449, 1393, 1033 cm .
1
H NMR (400 MHz, CDCl ): δ = 6.92 (d, J = 7.2, H-C(3,5), 2 H), 6.75 (t, J = 7.2, H-C(4), 1 H), 5.98-5.88 (m, =CH, 2 H), 5.09-5.04 (m, =CH , 4
3 2
13
H), 3.32 (d, J = 6.4, -ArCH
,6-diallyl-4-chlorophenol (27)
This was prepared following exactly the procedure described for 26. The product 27 was obtained from 25 as a colorless viscous liquid
2 3
, 2 H). C NMR (100 MHz, CDCl ): δ = 152.7, 138.6, 128.7, 125.7, 120.7, 116.4, 35.3.
[
74, 75]
2
-
1
1
(
1.790g, 86%). IR (neat): ν 3483, 1619, 1444, 1169, 907, 853 cm . H NMR (400 MHz, CDCl
3
): δ = 6.97 (s, H-C(3,5), 2 H), 5.99-5.90 (m,
1
3
=
CH, 2 H), 5.16-5.11 (m, =CH, 4 H), 3.34 (d, J = 6.8, -CH , 4 H). C NMR (100 MHz, CDCl ): δ = 151.2, 135.7, 128.2, 127.5, 125.2, 117.0,
2
3
35.0.
1,3-Diallyl-2-(allyloxy)benzene (28):
To a stirred solution of 26 (1.380 g, 8.0 mmol) in anhyd Me
were added under nitrogen atmosphere. The reaction mixture was heated to reflux for 6 h. It was allowed to come to rt and then concentrated
under reduced pressure. The residual mass was extracted with EA (2 x 50 mL), washed with H O (50 mL), and brine (25 mL). It was dried
over anhyd Na SO and filtered. The filtrate was concentrated in vacuo to leave a crude mass that was purified by column chromatography
over silica gel (100-200 mesh) using PE as eluent to give 28 as colorless viscous liquid (1.260 g, 74%). IR (neat): ν 1650, 1500, 1250, 1000,
2 2 3
CO (5 mL), K CO (1.650 g, 12.0 mmol) and allyl bromide (1.7 mL, 20.0 mmol)
2
2
4
-
1 1
9
80 cm . H NMR (400 MHz, CDCl
CH , 1 H), 5.16 (dd, J = 12.4, 1.2, =CH
ArCH
,3-diallyl-2-(allyloxy)-5-chlorobenzene (29):
This was prepared following exactly the procedure described for 28. The product 29 was obtained from 27 as a colorless viscous liquid (1.430
3
): δ = 6.99-6.91 (m, -ArH, 3 H), 6.05-5.97 (m, =CH, 1 H), 5.95-5.84 (m, =CH, 2 H), 5.34 (dd, J = 16.8, 1.6,
, 1 H), 5.06-4.99 (m, =CH , 2 H), 4.96 (m, =CH , 2 H) 4.20 (d, J = 1.2, -OCH , 2 H), 3.34 (d, J = 6.4,
3
, 4 H). C NMR (100 MHz, CDCl ): δ = 155.1, 137.4, 133.9, 133.3, 128.6, 124.2, 117.1, 115.8, 74.5, 34.2.
=
2
2
2
2
2
13
2
1
-
1 1
g, 72%). IR (neat): ν 1620, 1538, 1430, 1178, 980, 905, 858 cm . H NMR (400 MHz, CDCl
3
): δ = 7.03 (s, H-C(4,6), 2 H), 6.08-6.00 (m, =CH,
1
H), 5.99-5.86 (m, =CH, 2 H), 5.42 (dd, J = 1.2, 17.6, =CH, 1 H), 5.22-5.27 (m, =CH, 1 H), 5.01-5.10 (m, =CH, 4 H), 4.24 (d, J = 4, -OCH
2
, 2
13
H), 3.36 (d, J = 6.4, -ArCH
2
, 4 H). C NMR (100 MHz, CDCl
3
): δ = 153.8, 136.5, 135.1, 133.6, 129.3, 128.3, 117.3, 116.6, 74.6, 34.0.
9-Allyl-2,5-dihydrobenzo[b]oxepine (30):
G-I (1 mol%) was added to a stirred solution of the diene 28 (0.255 g, 1.2 mmol) in degassed and anhyd toluene (20 mL) under argon and the
◦
mixture was stirred at 80 C for 6h. It was then allowed to come to rt and then concentrated in vacuo to leave a crude mass that was purified by
column chromatography over silica gel (230-400 mesh) using EA-PE (1:19) as eluent to give the RCM product 30 as a colorless viscous liquid
1
(
0.180g, 81%). H NMR (400 MHz, CDCl
3
): δ = 6.99-6.90 (m, -ArH, 1 H), 6.88-6.87 (m, ArH, 2 H), 5.95-5.85 (m, =CH, 1 H), 5.78-5.72 (m, =CH,
, 1 H), 4.96-4.95 (m, =CH , 1 H), 4.47-4.45 (m, OCH , 2 H), 3.39-3.38 (m, ArCH , 2 H), 3.37-
): δ = 155.3, 136.4, 135.5, 131.4, 127.5, 126.3, 125.9, 124.6, 122.8, 114.5, 69.4, 33.0. 30.7.
14O: C, 83.83, H, 7.58; Found C, 84.06, H, 7.79 %.
-Allyl-7-chloro-2,5-dihydrobenzo[b]oxepine (31):
1
3
H), 5.38-5.33 (m, =CH, 1 H), 5.00-4.97 (m, =CH
2
2
2
2
13
2 3
.36 (m, ArCH , 2 H). C NMR (100 MHz, CDCl
Anal calcd for C13
H
9
This compound was prepared following exactly the procedure described above for 30. The product 31 was obtained from 29 as a colorless
1
viscous liquid (0.206 g, 78%). H NMR (400 MHz, CDCl
3
): δ = 7.21 (s, -ArH, 1 H), 7.00 (s, -ArH, 1 H), 5.90-5.80 (m, =CH, 1 H), 5.80-5.72 (m,
13
=
CH, 1 H), 5.46-5.41 (m, =CH, 1 H), 5.09-5.04 (m, =CH, 2 H), 4.51 (m, H-C(2), 2 H), 3.40 (m, H-C(4)+ArCH
2
, 4 H). C NMR (100 MHz,
CDCl
3
): δ = 154.9, 138.2, 136.5, 134.3, 128.6, 128.1, 127.4, 126.7, 125.0, 116.3, 70.5, 33.9, 31.4. Anal calcd for C13 13ClO: C, 70.75, H, 5.94;
H
Found C, 71.02, H, 6.22 %.
General procedure for the CM reaction for the synthesis of benzoxepines 32-36:
To a stirred solution of 30/31 (0.20 mmol) in anhyd DCM (2 mL), appropriate CM-partner (benzyl acrylate/ methyl acrylate/ ethyl vinyl ketone/1-
decene, 0.3 mmol) followed by G-II (2.5 mol %) were added under argon atmosphere. The reaction mixture was heated to reflux for 2-6 h. It
was then allowed to come to rt and concentrated in vacuo to leave a crude mass that was purified by column chromatography over silica gel
(230-400 mesh) using EA-PE (1:19) as eluent to give the CM products 32-36.
(E)-Benzyl 4-(2,5-dihydrobenzo[b]oxepin-9-yl)but-2-enoate (32):
-
1
1
It was obtained as a colorless viscous liquid (0.390 g, 66%). IR (neat): ν 1719, 16545, 1476, 1270, 1195, 1035 cm . H NMR (400 MHz,
CDCl ): δ = 7.28-7.22 (m, -ArH, 5 H), 7.09 (td, J = 6.4, 15.6, ArH, 1 H), 6.96-6.86 (m, ArH, 3 H), 5.79-5.73 (m, H-C(3,4), 2 H), 5.38-5.35 (m,
3
1
3
=
CH, 1 H), 5.07 (s, OCH
2
Ph, 2 H), 4.46-4.39 (m, H-C(2), 2 H), 3.48 (d, J = 6.4, H-(C5), 2 H), 3.39-3.38 (m, ArCH
): δ = 166.4, 156.4, 148.3, 136.7, 136.0, 130.1, 128.8, 128.6, 128.3, 127.8, 127.7, 125.6, 124.1, 121.8, 70.6, 66.1, 32.7. 31.8. Anal calcd
: C, 78.73, H, 6.29; Found C, 78.99, H, 6.49 %.
E)-Methyl 4-(7-chloro-2,5-dihydrobenzo[b]oxepin-9-yl)but-2-enoate (33):
It was obtained as a colorless viscous liquid (0.320 g, 60%). IR (neat): ν 1723, 1656, 1470, 1435, 1331, 1274, 1198, 1063 cm . H NMR (400
MHz, CDCl ): δ = 6.90-7.01 (m, = CH + ArH, 3 H), 5.75-5.76 (m, =CH, 1 H), 5.71-5.72 (m, =CH, 1 H), 5.35-5.39 (m, =CH, 1 H), 4.41-4.44 (m,
H-C(2), 2 H), 3.60 (s, -OCH
2
, 2 H). C NMR (100 MHz,
CDCl
3
20 3
for C21H O
(
-
1 1
3
13
3
, 3 H), 3.41 (q, J = 6.6, H-C(5), 2 H), 3.32 (q, J = 5, -ArCH
2
, 2 H). C NMR (100 MHz, CDCl
3
): δ = 166.8, 155.0,
8
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Helvetica Chimica Acta
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HELVETICA
1
46.8, 138.3, 131.9, 128.7, 128.2, 127.5, 127.2, 125.0, 122.2, 70.6, 51.6, 32.4, 31.5. Anal calcd for C15
H15ClO
3
: C, 64.64, H, 5.42; Found C,
64.89, H, 5.60 %.
(
E)-6-(2,5-Dihydrobenzo[b]oxepin-9-yl)hex-4-en-3-one (34):
It was obtained as a colorless viscous liquid (0.270 g, 57%). IR (neat): ν 1700, 1634, 1477, 1339, 1150, 1095 cm . H NMR (400 MHz,
CDCl ): δ = 6.97-6.86 (m, =CH+ArH, 4 H), 6.01 (td, J = 1.2, 16.0, =CH, 1 H), 5.80-5.75 (m, H-C(3/4), 1 H), 5.40-5.37 (m, H-C(4/3), 1 H), 4.47-
.44 (m, H-C(2), 2 H), 3.50-3.48 (m, H-C(5), 2 H), 3.41-3.39 (m, -ArCH
NMR (100 MHz, CDCl ): δ = 201.2, 145.3, 136.7, 130.8, 130.3, 128.7, 127.7, 127.1, 125.7, 124.1, 70.5, 33.1, 32.9, 31.8, 8.1. Anal calcd for
: C, 79.31, H, 7.49; Found C, 79.48, H, 7.61 %.
E)-6-(7-chloro-2,5-dihydrobenzo[b]oxepin-9-yl)hex-4-en-3-one (35):
It was obtained as a colorless viscous liquid (0.300 g, 55%). IR (neat): ν 1698, 1634, 1480, 1342, 1150 cm . H NMR (400 MHz, CDCl
-
1
1
3
13
4
2
, 2 H), 2.49 (q, J=7.2, -COCH
2
, 2 H), 1.00 (t, J= 7.6, -CH
3
, 3 H).
C
3
16 18 2
C H O
(
-
1
1
3
): δ =
.00-6.91 (m, -ArH, 2 H), 6.89-6.80 (m, =CH, 1 H), 6.00 (q, J= 15.8, =CH, 1 H), 5.71-5.80 (m, H-C(3/4), 1 H), 5.43-5.46 (m, H-C(4/3), 1 H),
.41-4.50 (m, -H-C(2), 2 H), 3.50-3.57 (m, H-C(5), 2 H), 3.42 (d, J =1.6, -ArCH , 2 H), 2.59-2.54 (m, -COCH , 2 H), 1.01-1.10 (m, -CH , 3 H).
): δ = 200.9, 155.0, 144.1, 138.3, 132.1, 131.1, 128.7, 128.2, 127.5, 127.2, 125.1, 70.6, 33.3, 32.7, 31.5, 8.0. Anal
: C, 69.44, H, 6.19; Found C, 69.67, H, 6.40 %.
-((E)-Undec-2-enyl)-2,5-dihydrobenzo[b]oxepine (36):
It was obtained as a colorless viscous liquid (0.370 g, 64%). IR (neat): ν 1644, 1572, 1330, 1270, 1100 cm . H NMR (400 MHz, CDCl
7
4
2
2
3
1
3
C NMR (100 MHz, CDCl
3
calcd for C16
H17ClO
2
9
-
1 1
3
): δ =
7.00-6.98 (m, -ArH, 1 H), 6.88-6.86 (m, ArH, 2 H), 5.78-5.75 (m, =CH, 1 H), 5.48-5.36 (m, =CH, 3 H), 4.49-4.46 (m, H-C(2), 2 H), 3.39-3.38 (m,
13
2 2 2
H-C(5), 2 H), 3.28 (d, J= 6.0, -ArCH , 2 H),1.93 (q, J = 6.4, CH , 2 H), 1.19 (br s, -CH , 12 H), 0.80 (t, J = 6.4, 3 H). C NMR (100 MHz,
CDCl
3
): δ = 156.2, 136.5, 133.6, 131.9, 128.5, 127.4, 126.6, 125.7, 123.9, 125.1, 70.5, 32.8, 32.6, 31.9, 31.7, 29.7, 29.5, 29.3, 29.2, 22.7, 14.1.
Anal calcd for C21H30O: C, 84.51, H, 10.13; Found C, 84.69, H, 10.29 %.
General procedure for the one-pot RCM-CM reaction for the synthesis of the N-tosylbenzazepines (18-21):
To a stirred solution of 16 (0.080 g, 0.2 mmol) in anhyd DCM (4 mL) G-II (1 mol%) was added under argon atmosphere. The reaction mixture
was heated to reflux for 2 h. It was allowed to come to rt. Appropriate CM-partner (methyl acrylate/benzyl acrylate/1-dodecene/ 1-decene, 0.3
mmol) followed by another lot of the catalyst G-II (1 mol%) were added and the mixture was heated to reflux for 2-4 h. It was then allowed to
come to rt and concentrated in vacuo to leave a crude mass that was purified by column chromatography over silica gel (230-400 mesh) using
EA-PE (1:19) as eluent to give the RCM-CM products 18-21.Compounds 18 (61%), 19 (58%), 20 (55%) and 21 (54%) were thus prepared.
General procedure for the one-pot RCM-CM reaction for the synthesis of the benzoxepines (18-21):
To a stirred solution of the diene 28/29 ( 0.2 mmol) in anhyd DCM (4 mL) G-II (1 mol%) was added under argon atmosphere. The reaction
mixture was heated to reflux for 2 h. It was allowed to come to rt. Appropriate CM-partner (methyl vinyl ketone/methyl acrylate/benzyl
acrylate/1-dodecene/ 1-decene, 0.3 mmol) followed by another lot of the catalyst G-II (1 mol%) were added and the mixture was heated to
reflux for 2-6 h. It was then allowed to come to rt and concentrated in vacuo to leave a crude mass that was purified by column
chromatography over silica gel (230-400 mesh) using EA-PE (1:19) as eluent to give the RCM-CM products 32-36.Compounds 32 (65%), 33
(61%), 34 (60%), 35 (53%),and 36 (54%) were thus prepared.
Supplementary Material
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/MS-number.
Acknowledgements
We are thankful to DST, New Delhi, for funds (EMR/2017/001336), and University of Kalyani for support under PURSE program, and also for a
fellowship to one of us (JB).
Author Contribution Statement
S. Mandal, J. Banerjee and S. Maity performed the experimental design, optimization, method study, experimental work and spectroscopic
analysis. S. Mandal and J. Banerjee contributed equally. SKC conceptualized the work.
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Entry for the Table of Contents
Y
X
X
i.R C M
ii.C M
R
X = N R , O ; Y = O , H 2
X = N , O
R = C O 2 M e , C O 2 B n ,
C O E t, C n H 2 n + 1
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Synthesis of substituted medium ring-sized heterocycle using atom-economic and catalytic conversions.
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