A microwave-assisted heck reaction in poly(ethylene glycol) for the synthesis of benzazepines

Article abstract of DOI:10.1002/ejoc.200600680

The Heck reaction of alkylated 2-(trimethylsilyl)ethanesulfonyl (SES)-protected β-amino esters provides benzazepines in good yields. Good selectivity towards cyclisation was obtained when the reaction was performed in PEG 3400 as the solvent under microwa

Full text of DOI:10.1002/ejoc.200600680

FULL PAPER
DOI: 10.1002/ejoc.200600680
A Microwave-Assisted Heck Reaction in Poly(ethylene glycol) for the Synthesis
of Benzazepines
Valérie Declerck,[a] Patrice Ribière,[a] Yannig Nédellec,[b] Hassan Allouchi,[c]
Jean Martinez,[a] and Frédéric Lamaty*[a]
Keywords: Microwaves / Nitrogen heterocycles / Nanoparticles / Palladium / Solvent effects
The Heck reaction of alkylated 2-(trimethylsilyl)ethanesulfo- solvent under microwave activation. Cleavage of the SES
nyl (SES)-protected β-amino esters provides benzazepines in
good yields. Good selectivity towards cyclisation was ob-
tained when the reaction was performed in PEG 3400 as the
group with HF provides the corresponding free benzazepine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
its dielectric properties.[4] Because of their lack of volatility,
Microwave activation has emerged as a powerful tech- ionic liquids have proven to be efficient and less prone to
nique in organic synthesis to accelerate the preparation of pressure build up compared to low boiling solvents under
molecules.[1–6] Many examples have demonstrated that this microwave heating.[7–22] Another family of solvents which
technique can be adapted to most organic transformations. can substitute volatile organic solvents are poly(ethylene
Reactions are generally faster and consequently cleaner and glycol)s (PEGs). They present some common characteristics
sometimes more selective. Furthermore, the focused heating with ionic liquids (high polarity, high boiling points) and
generated by the microwave enables a high temperature to have been used to a certain extent in substitution, oxi-
be reached in a short time. Under microwave irradiation the dation, reduction and organometallic reactions.[23] Further-
heating characteristics of a solvent or chemical depend on more they present low toxicity. So far, PEGs have not been
Scheme 1. Functionalized β-amino ester 1.
used extensively in reactions involving microwave acti-
[a] Laboratoire des Amino acides, Peptides et Protéines (LAPP),
vation.[24–35] We now report that novel benzazepines can be
CNRS – Universités Montpellier 1 et 2,
Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
obtained by a palladium-catalysed Heck reaction in a PEG
solvent under microwave heating.
[b] Laboratoire des Agrégats Moléculaires et Matériaux Inor-
ganiques (LAMMI), CNRS – Université Montpellier 2,
Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
[c] Laboratoire de Chimie Physique, SPOT E.A. 3857, Université
François Rabelais, Faculté de Pharmacie,
The 2-(trimethylsilyl)ethanesulfonyl (SES)-protected α-
methylene β-amino ester 1, obtained by an aza-Baylis–Hill-
man reaction, is a useful synthon for the preparation of
heterocyclic structures because of the multiple functional
groups present on this molecule (Scheme 1). We have pre-
viously reported that an alkylation/ring closing metathesis/
31 Avenue Monge, 37200 Tours, France
Fax: +33-4-67-14-48-66
E-mail: frederic.lamaty@univ-montp2.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 201–208
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
201

F. Lamaty et al.
FULL PAPER
aromatisation sequence leads to the efficient preparation of the sample mixtures were not homogeneous, this resulted in
2,3-disubstituted pyrroles.[36] We report herein the investiga- different heating profiles, which could explain the difficulty
tion of microwave-enhanced palladium-catalysed cyclis- in reproducing the experiments. To test this hypothesis, and
ation of 2, obtained by alkylation of 1 with 2-bromobenzyl reduce the starting temperature ramp to a minimum, the
bromide.
starting heating power was set to the maximum level
Recently, mixtures of Pd salts and PEG have been (300 W) for a reaction at 100 °C (Entry 4). Full conversion
studied as catalytic systems for Pd-catalysed transforma- was obtained with no by-products, and this experiment
tions.[27,37–46] Consequently, following our experience with could be reproduced several times.
PEG-improved Heck reactions,[47,48] we explored the use of
According to the same procedure, the reaction could also
PEG 3400 with Pd(OAc)2 under microwave conditions to take place at lower temperature (Entries 5 and 6), and the
perform the expected cyclisation.
amount of catalyst could be decreased to 1 mol-% without
slowing down the kinetics of the reaction (Entry 7). Switch-
ing from an inorganic to an organic base reduced the speed
of the reaction (Entry 8). Since low molecular weight PEGs
Results and Discussions
Compound 2a was heated in the presence of K2CO3 and are liquid at room temperature, we tried to substitute PEG
a catalytic amount of Pd(OAc)2 in PEG 3400 in the micro- 3400 by PEG 300 (Entry 9). This led to a very complicated
wave synthesiser at 100 °C for 10 min (Scheme 2 and mixture of products containing 3a, 4a and 5a. Conse-
Table 1) to yield only the expected cyclized product 3a (En- quently, the use of a higher molecular weight PEG seems
try 1). When the experiment was repeated under the same necessary. We also used a mixture of PEG 300 and PEG
conditions, the reaction did not go to completion (Entry 2). 3400 but the results did not improve (Entry 10), nor did
Increasing the reaction time resulted in the formation of by- they with a mixture of DMF and PEG. The amount of
products 4a and 5a, most probably by a Tsuji–Trost re- DMF should be limited to obtain satisfactory results (En-
arrangement (Entry 3). These preliminary results demon- tries 11 and 12). In the absence of PEG, the reaction in
strated the importance of the heating mode of the sample. DMF was slower and not very clean (Entry 13). The reac-
This may be due to the fact that the reaction temperature tion carried out in PEG under thermal conditions was
was entered as the heating instruction in the instrument. slower and only 23% conversion was obtained after 30 min
The synthesiser therefore adjusted the magnetron power to of reaction (Entry 14).
reach the selected instruction (T = 100 °C). Starting from
The choice of the solvent is important to direct the trans-
room temperature, this could take several seconds or min- formation of the starting material towards formation of the
utes. This temperature ramp would include the time needed cyclized product as otherwise the transformations are in-
to melt PEG 3400 (a solid which melts at 45–55 °C). Since complete or the Tsuji–Trost rearrangement occurs to pro-
Scheme 2. Palladium-catalysed reaction of 2a.
Table 1. Reaction conditions for microwave-assisted Heck reaction.
Entry
Pd(OAc)2
[equiv.]
Base
PEG
(wt. [mg])
Solvent
(vol. [mL])
T
[°C]
t
Conditions
2a
3a
4a
5a
[min]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.1
0.1
0.1
0.01
0.1
0.1
0.1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Oct3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
3400 (220)
3400 (220)
3400 (220)
3400 (220)
3400 (220)
3400 (220)
3400 (220)
3400 (220)
–
3400 (50)
3400 (50)
3400 (50)
–
–
–
–
–
–
–
–
–
100
100
100
100
80
10
10
30
30
30
30
30
30
30
30
30
30
30
30
30
MW
MW
MW
0
22
0
0
0
0
0
40
100
78
80
100
100
100
100
60
0
0
14
0
0
0
0
0
6
0
0
0
0
0
MW 300W
MW 300W
MW 300W
MW 300W
MW 300W
MW 300W
MW 300W
MW 300W
MW 300W
MW 300W
thermal
60
100
100
100
100
100
100
100
100
100
0
0
PEG 300 (0.5)
PEG 300 (0.5)
DMF (1)
DMF (0.5)
DMF (0.5)
–
complicated mixture
complicated mixture
31
0
–
77
14
62
100
84[a]
23
6
0
–
0
7
1
0
–
0
3
3400 (220)
precipitate from Entry 4 was used
MW 300W
76
[a] 3a was formed along with unidentified products.
202
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 201–208

A Microwave-Assisted Heck Reaction
FULL PAPER
duce a large amount of 4a. When PEG 300 or a mixture of
PEG 3400 and PEG 300 was used, the reaction was slowed
down dramatically. Addition of DMF produced the same
results. The best conditions were obtained using PEG 3400
as solvent in the presence of K2CO3. In addition, the
workup conditions are easy to carry out. After dissolving
the reaction mixture in CH2Cl2, precipitation in diethyl
ether followed by filtration to remove the PEG/Pd/base
mixture provides the expected product in the filtrate, which
was isolated by evaporation of the diethyl ether.
The structure of benzazepine 3a, especially the position
of the trisubstituted olefin, was ascertained by X-ray analy-
sis (Figure 1).
Figure 2. TEM image of a mixture of Pd(OAc)2, PEG 3400 and
K2CO3 after microwave irradiation at 100 °C for 30 min.
tion was not as efficient. This was also checked in the case
of an intermolecular Heck reaction (coupling of phenyl
iodide with tert-butyl acrylate) under the conditions used
for the intramolecular reaction. While the first cycle yielded
100% conversion, the second cycle yielded only 75% con-
version. Clearly, the colloidal system does not have the
same efficiency after microwave irradiation and this differ-
ence may be due to a change in structure, probably a modi-
fication of the size of the particles.[49] It is also worth noting
that after one cycle, the catalytic system has accumulated
1 equiv. of KBr as a Heck reaction side-product, which may
Figure 1. X-ray structures of benzazepine 3a.
The catalytic system was investigated for the presence of then change the structure of the catalyst and hence the re-
nanoparticles, and we were able to observe nanoparticles of sult in the next cycle.
palladium by TEM (Figure 2).
Various benzazepines could be prepared by varying the
The experimental results described herein can be corre- aldehyde leading to β-amino ester 1 and the alkylating
lated to the fast formation of nanoparticles of palladium in agent (Scheme 3). All of them were obtained in good yield
PEG 3400. Literature results show that larger PEGs (with (Table 2), except in the case of 3f, where deprotection of the
an average molecular weight equal to, or higher than, 2000) TMS group on the alkyne substituent occurred.
rapidly reduce metallic salts such as Pd(OAc)2 and provide
The next step was the deprotection of the SES protecting
better stabilisation of the particles.[44] When the catalytic group (Scheme 4 and Table 2). The SES group is usually
system was used again in a second cycle (Entry 15) the reac- cleaved in the presence of fluoride ions to yield the free
Scheme 3. Preparation of diverse benzazepines by Heck cyclisation.
Eur. J. Org. Chem. 2007, 201–208
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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203

F. Lamaty et al.
FULL PAPER
Table 2. Yields of isolated 2a–h, 3a–h, 8a–h.
[a] Partial deprotection of the TMS group occurred. [b] Partial deprotection of the ester group on the aryl substituent (R1) occurred. [c]
Deprotection resulted in a complicated mixture. [d] Not performed.
amine by elimination of ethylene and sulfur dioxide.[50,51] the first PEG-stabilized palladium nanoparticles obtained
When benzazepine 3a was subjected to classical deprotec- under microwave activation. This system promotes the ex-
tion reaction conditions (CsF, DMF),[50] the free amine 6a clusive formation of benzazepines. Deprotection of the ni-
was obtained along with the imine 7a resulting from the trogen function provides the heterocycle in good yield. Fur-
oxidative elimination of the SES group.[36] Other fluoride ther studies to improve this catalytic system for recycling
sources also gave mixtures of 6a and 7a. A deprotection/ are currently underway in our laboratory.
reduction sequence[52] was performed by treating the 6a/7a
mixture with hydrogen in the presence of palladium on
Experimental Section
charcoal, which yielded 6a as the sole product. As an alter-
native, we used hydrofluoric acid,[53] which gave 8a, the
fluorohydrate of 6a, as the sole product in quantitative
yield. We finally chose to treat 3b–e and 3g,h with HF. The
corresponding benzazepines 8 were obtained as their fluo-
General Remarks: 1H and 13C NMR analyses were performed with
a Bruker AC 300 MHz spectrometer, and calibrated using residual
undeuterated solvents as an internal reference. Electrospray ionis-
ation mass spectra were recorded with a Micromass Platform II
ride salts, except for 3d (partial deprotection of the side fitted with an electrospray interface. The mass spectrometer was
calibrated in the positive- and negative-ion ESI mode. The samples
were dissolved in H2O/CH3CN (50:50, v/v). FAB and high-resolu-
tion mass spectra were recorded with a JEOL JSM DX300-SX 102
in positive mode using 3-nitrobenzyl alcohol (NBA) as matrix. In-
frared spectra were recorded with a Perkin–Elmer Paragon 1000 by
diffuse reflectance or by transmittance in KBr salt plates. Melting
points were measured with a Büchi melting point B-540 apparatus
and are uncorrected. Microwave-assisted reactions were performed
with a Biotage Initiator 60 EXP®. The temperature was measured
with an IR sensor on the outer surface of the reaction vial.
chain methyl ester occurred) and 3e, which decomposed.
General Procedure for the Alkylation of β-Amino Esters 1: A mix-
ture of β-amino ester 1 (0.3 mmol, 1 equiv.), 2-benzyl bromide or
a related reagent (0.36 mmol, 1.2 equiv.) and K2CO3 (414 mg,
3 mmol, 10 equiv.) in 3.5 mL of CH3CN was refluxed for 6 h. After
evaporation of the solvent, the residue was diluted with EtOAc,
washed successively with a solution of 5% KHSO4 and brine, dried
with MgSO4, and the solvents were evaporated. Silica gel
chromatography (Et2O/cyclohexane) yielded the corresponding N-
(2-bromobenzyl)-β-amino ester 2.
Methyl 2-{[N-(2-Bromobenzyl)-2Ј-(trimethylsilyl)ethylsulfonamido]-
(phenyl)methyl}acrylate (2a): Alkylation of the β-amino ester 1a
with 2-bromobenzyl bromide yielded 128 mg (81%) of the title
compound as a white solid after silica gel chromatography (Et2O/
Scheme 4. Deprotection of the SES-protected benzazepines 3.
cyclohexane, 1:9). M.p. 72.7–73.9 °C. IR: ν = 3054 (m), 2955 (m),
˜
1
1723 (s), 1264 (s) cm–1. H NMR (CDCl3, Me4Si): δ = –0.07 (s, 9
Conclusions
H), 0.90–1.05 (m, 2 H), 2.50–2.80 (m, 2 H), 3.59 (s, 3 H), 4.76 (s,
2 H), 5.88 (d, J2 = 1.4 Hz, 1 H), 6.15 (s, 1 H), 6.44 (s, 1 H), 7.02
(dt, J2 = 1.6, J3 = 7.7 Hz, 1 H), 7.10–7.45 (m, 8 H) ppm. 13C NMR
(CDCl3, Me4Si): δ = –1.9, 10.3, 50.5, 50.7, 52.2, 62.2, 122.7, 122.2,
128.3, 128.8, 128.9, 129.0, 129.5, 130.4, 132.5, 136.5, 137.5, 139.1,
We have prepared original benzazepines using Heck
chemistry performed in PEG. We have shown that the tem-
perature ramp experienced by the sample could have a
strong influence on the selectivity of the reaction. To the
best of our knowledge, we have prepared and characterised 166.2 ppm. ESIMS: m/z = 524.0/526.0 [M + H]+. FAB+: m/z =
204
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A Microwave-Assisted Heck Reaction
FULL PAPER
524/526 [M + H]+. HRMS: calcd. for C23H31BrNO4SSi 524.0926;
found 524.0922.
7.5, J3 = 7.9 Hz, 1 H), 6.80 (dd, J4 = 1.5, J3 = 7.9 Hz, 1 H), 7.00
(dt, J4 = 1.6, J3 = 7.7 Hz, 1 H), 7.15 (dt, J4 = 1.2, J3 = 7.6 Hz, 1
H), 7.35–7.45 (m, 2 H) ppm. 13C NMR (CDCl3, Me4Si): δ = –1.9,
10.3, 50.3, 50.6, 52.2, 57.4, 101.1, 108.8, 119.5, 121.8, 122.1, 122.5,
127.0, 128.7, 129.8, 132.4, 136.5, 138.1, 145.4, 147.5, 166.0 ppm.
ESIMS: m/z = 567.9/569.9 [M + H]+. FAB+: m/z = 567/569 [M –
e–]+, 568/570 [M + H]+. HRMS: calcd. for C24H30BrNO6SSi
567.0746; found 567.0776.
Methyl 2-{[N-(2-Bromobenzyl)-2Ј-(trimethylsilyl)ethylsulfonamido]-
(3,5-dimethylphenyl)methyl}acrylate (2b): Alkylation of the β-
amino ester 1b with 2-bromobenzyl bromide yielded 151 mg (91%)
of the title compound as a white solid after silica gel chromatog-
raphy (Et O/cyclohexane, 1:9). M.p. 100.1–101.5 °C. IR: ν = 3054
˜
2
(m), 2954 (m), 1722 (s), 1265 (s) cm–1. H NMR (CDCl3, Me4Si):
1
δ = –0.05 (s, 9 H), 0.90–1.10 (m, 2 H), 2.28 (s, 6 H), 2.60–2.85 (m, Methyl 2-([N-(2-Bromobenzyl)-2Ј-(trimethylsilyl)ethylsulfonamido]-
2 H), 3.59 (s, 3 H), 4.68 (d, J2 = 16.9 Hz, 1 H), 4.77 (d, J2
16.9 Hz, 1 H), 5.89 (d, J2 = 1.4 Hz, 1 H), 6.09 (s, 1 H), 6.44 (s, 1
=
{4-[2-(trimethylsilyl)ethynyl]phenyl}methyl)acrylate (2f): Alkylation
of the β-amino ester 1f with 2-bromobenzyl bromide yielded
H), 6.78 (s, 1 H), 6.90 (s, 2 H), 7.04 (dt, J2 = 1.6, J3 = 7.6 Hz, 1 116 mg (62%) of the title compound as a white solid after silica gel
H), 7.15 (dt, J2 = 1.1, J3 = 7.6 Hz, 1 H), 7.30–7.45 (m, 2 H) ppm. chromatography (Et O/cyclohexane, 1:9). M.p. 47.6–49.1 °C. IR: ν
˜
2
13C NMR (CDCl3, Me4Si): δ = –2.0, 10.4, 21.4, 50.1, 50.4, 52.2,
61.8, 122.4, 126.6, 126.9, 128.5, 129.9, 130.3, 132.1, 136.5, 136.8,
138.2, 139.3, 166.2 ppm. ESIMS: m/z = 552.0/553.9 [M + H]+,
574.0/576 [M + Na]+. FAB+: m/z = 552/554 [M + H]+. HRMS:
calcd. for C25H35BrNO4SSi 552.1239; found 552.1216.
= 3065 (m), 2955 (m), 2158 (m), 1723 (s), 1250 (s) cm–1. H NMR
(CDCl3, Me4Si): δ = –0.04 (s, 9 H), 0.23 (s, 9 H), 0.90–1.10 (m, 2
H), 2.55–2.80 (m, 2 H), 3.59 (s, 3 H), 4.73 (s, 2 H), 5.84 (d, J2 =
1.4 Hz, 1 H), 6.10 (s, 1 H), 6.46 (d, J2 = 0.7 Hz, 1 H), 7.04 (dt, J2
= 1.7, J3 = 7.6 Hz, 1 H), 7.18 (dt, J2 = 1.2, J3 = 7.6 Hz, 1 H), 7.26
(d, J3 = 8.6 Hz, 2 H), 7.37 (d, J3 = 8.4 Hz, 2 H), 7.35–7.50 (m, 2
H) ppm. 13C NMR (CDCl3, Me4Si): δ = –1.9, 0.1, 10.4, 50.7, 50.8,
52.3, 62.1, 95.2, 104.5, 122.9, 123.2, 127.3, 128.7, 129.0, 129.8,
130.4, 132.2, 132.7, 136.2, 137.8, 138.8, 166.2 ppm. ESIMS: m/z =
620.0/622.0 [M + H]+. FAB+: m/z = 620/622 [M + H]+, 642/644
[M + Na]+.
1
Methyl 2-{[N-(2-Bromobenzyl)-2Ј-(trimethylsilyl)ethylsulfonamido]-
(3-fluorophenyl)methyl}acrylate (2c): Alkylation of the β-amino es-
ter 1c with 2-bromobenzyl bromide yielded 128 mg (79%) of the
title compound as a white solid after silica gel chromatography
(Et O/cyclohexane, 1:9). M.p. 78.6–79.4 °C. IR: ν = 3064 (m), 2954
˜
2
(m), 1722 (s), 1251 (s) cm–1. H NMR (CDCl3, Me4Si): δ = –0.03
1
(s, 9 H), 0.90–1.10 (m, 2 H), 2.60–2.90 (m, 2 H), 3.62 (s, 3 H), 4.72 Methyl 2-{[N-(2-Bromo-5-methoxybenzyl)-2Ј-(trimethylsilyl)ethyl-
(d, J2 = 17.2 Hz, 1 H), 4.78 (d, J2 = 17.2 Hz, 1 H), 5.89 (d, J2 = sulfonamido](phenyl)methyl}acrylate (2g): Alkylation of the β-
1.4 Hz, 1 H), 6.14 (s, 1 H), 6.49 (d, J2 = 0.6 Hz, 1 H), 6.90 (dt, J2
= 1.8, J3 = 8.4 Hz, 1 H), 6.95–7.30 (m, 5 H), 7.41 (dd, J3 = 1.0, J4
= 8.0 Hz, 2 H) ppm. 13C NMR (CDCl3, Me4Si): δ = –1.9, 10.4,
50.7, 50.8, 52.3, 61.67 (d, J4 = 1.9 Hz), 115.2 (d, J2 = 21.2 Hz),
115.9 (d, J2 = 22.3 Hz), 122.8, 124.4 (d, J4 = 2.9 Hz), 127.3, 129.0,
129.9, 130.3 (d, J3 = 8.2 Hz), 130.4, 132.6, 136.2, 138.6, 140.1 (d,
J3 = 6.8 Hz), 162.8 (d, J1 = 247.2 Hz), 166.1 ppm. ESIMS: m/z =
541.9/543.9 [M + H]+. FAB+: m/z = 542/544 [M + H]+. HRMS:
calcd. for C23H30BrFNO4SSi 542.0832; found 542.0817.
amino ester 1a with 2-bromo-5-methoxybenzyl bromide yielded
127 mg (76%) of the title compound as a white solid after silica gel
chromatography (Et2O/cyclohexane, 2:8). M.p. 119.5–121.7 °C. IR:
ν = 3065 (m), 2953 (m), 1723 (s), 1292 (s), 1251 (s) cm–1. 1H NMR
˜
(CDCl3, Me4Si): δ = –0.07 (s, 9 H), 0.90–1.15 (m, 2 H), 2.50–2.80
(m, 2 H), 3.60 (s, 3 H), 3.74 (s, 3 H), 4.73 (s, 2 H), 5.86 (d, J2 =
1.4 Hz, 1 H), 6.17 (s, 1 H), 6.43 (s, 1 H), 6.60 (dd, J2 = 3.1, J3 =
8.7 Hz, 1 H), 6.96 (d, J2 = 3.0 Hz, 1 H), 7.20–7.40 (m, 6 H) ppm.
13C NMR (CDCl3, Me4Si): δ = –2.0, 10.3, 50.4, 50.6, 52.2, 55.5,
62.1, 112.9, 115.2, 115.5, 128.3, 128.7, 128.8, 129.7, 133.0, 137.4,
Methyl 2-{[N-(2-Bromobenzyl)-2Ј-(trimethylsilyl)ethylsulfonamido]-
[4-(methoxycarbonyl)phenyl]methyl}acrylate (2d): Alkylation of the
β-amino ester 1d with 2-bromobenzyl bromide yielded 125 mg
(72%) of the title compound as a white solid after silica gel
137.7, 139.2, 158.9, 166.3 ppm. ESIMS: m/z
= 553.9/555.9
[M + H]+, 576.0/557.9 [M + Na]+. FAB+: m/z = 554/556
[M + H]+. HRMS: calcd. for C24H33BrNO5SSi 554.1032; found
554.1064.
chromatography (Et O/cyclohexane, 2:8). M.p. 44.5–46.1 °C. IR: ν
˜
2
= 3066 (m), 2954 (m), 1721 (s), 1284 (s), 1251 (s) cm–1. H NMR Methyl 2-{[N-(2-Bromo-5-fluorobenzyl)-2Ј-(trimethylsilyl)ethylsul-
1
(CDCl3, Me4Si): δ = –0.06 (s, 9 H), 0.90–1.05 (m, 2 H), 2.55–2.85
(m, 2 H), 3.59 (s, 3 H), 3.86 (s, 3 H), 4.71 (d, J2 = 16.7 Hz, 1 H),
4.78 (d, J2 = 16.7 Hz, 1 H), 5.84 (d, J2 = 1.4 Hz, 1 H), 6.16 (s, 1
H), 6.48 (d, J2 = 0.6 Hz, 1 H), 7.00 (dt, J2 = 1.7, J3 = 7.6 Hz, 1
H), 7.15 (dt, J2 = 1.2, J3 = 7.6 Hz, 1 H), 7.35–7.45 (m, 4 H), 7.91
(dd, J3 = 1.7, J4 = 6.7 Hz, 2 H) ppm. 13C NMR (CDCl3, Me4Si):
δ = –2.0, 10.3, 50.7, 50.8, 52.21, 52.25, 61.9, 122.8, 127.2, 128.7,
fonamido](phenyl)methyl}acrylate (2h): Alkylation of the β-amino
ester 1a with 2-bromo-5-fluorobenzyl bromide yielded 121 mg
(74%) of the title compound as a white solid after silica gel
chromatography (Et O/cyclohexane, 2:8). M.p. 86.1–86.9 °C. IR: ν
˜
2
= 3064 (m), 2954 (m), 1724 (s), 1252 (s) cm–1. H NMR (CDCl3,
1
Me4Si): δ = –0.04 (s, 9 H), 0.90–1.10 (m, 2 H), 2.55–2.90 (m, 2 H),
3.65 (s, 3 H), 4.73 (s, 2 H), 5.82 (d, J2 = 1.5 Hz, 1 H), 6.21 (s, 1
129.0, 129.81, 129.83, 130.1, 130.3, 132.6, 136.0, 138.5, 142.7, H), 6.45 (d, 1 = H, J = 0.8 Hz), 6.75 (dt, J2 = 3.1, J3 = 8.2 Hz, 1
166.0, 166.50 ppm. ESIMS: m/z = 581.9/583.9 [M + H]+, 603.9/
H), 7.12 (dd, J2 = 3.0, J3 = 9.8 Hz, 1 H), 7.15–7.40 (m, 6 H) ppm.
605.9 [M + Na]+. FAB+: m/z = 582/584 [M + H]+. HRMS: calcd. 13C NMR (CDCl3, Me4Si): δ = –1.9, 10.3, 50.4, 52.3, 61.9, 115.9
for C25H33BrNO6SSi 582.0981; found 582.0936.
(d, J2 = 22.9 Hz), 116.2 (d, J4 = 3.1 Hz), 117.1 (d, J2 = 24.7 Hz),
128.5, 128.6, 128.9, 129.5, 133.5 (d, J3 = 7.9 Hz), 137.3, 139.1 (d,
J3 = 7.2 Hz), 139.2, 162.0 (d, J1 = 247.0 Hz), 166.1 ppm. ESIMS:
m/z = 541.9/544.0 [M + H]+, 563.9/565.9 [M + Na]+. FAB+: m/z =
542/544 [M + H]+. HRMS: calcd. for C23H30BrFNO4SSi 542.0832;
found 542.0818.
Methyl 2-{[N-(2-Bromobenzyl)-2Ј-(trimethylsilyl)ethylsulfonamido]-
(benzo[d][1,3]dioxol-4-yl)methyl}acrylate (2e): Alkylation of the β-
amino ester 1e with 2-bromobenzyl bromide yielded 152 mg (89%)
of the title compound as a white solid after silica gel chromatog-
raphy (Et O/cyclohexane, 2:8). M.p. 79.7–80.9 °C. IR: ν = 3068
˜
2
(m), 2953 (m), 1723 (s), 1251 (s) cm–1. H NMR (CDCl3, Me4Si): General Protocol for the Heck Reaction with PEG as Solvent: A
1
δ = –0.03 (s, 9 H), 0.95–1.15 (m, 2 H), 2.70–2.85 (m, 2 H), 3.60 (s, mixture (220 mg) of Pd(OAc)2/PEG 3400-OH (1 mg/1 g) [corre-
3 H), 4.70 (d, J2 = 17.1 Hz, 1 H), 4.85 (d, J2 = 17.1 Hz, 1 H), 5.91
(d, J2 = 1.3 Hz, 1 H), 5.95 (m, 2 H), 6.24 (s, 1 H), 6.43 (d, J2
1.0 Hz, 1 H), 6.66 (dd, J4 = 1.5, J3 = 7.5 Hz, 1 H), 6,74 (dd, J3 =
sponding to 0.001 mmol Pd(OAc)2, 0.01 equiv.] and finely pow-
dered K2CO3 (41 mg, 0.3 mmol, 3 equiv.) was added to N-(2-bro-
mobenzyl)-β-amino ester 2 (0.1 mmol, 1 equiv.). The reaction mix-
=
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205

F. Lamaty et al.
FULL PAPER
ture was heated under microwave irradiation at 100 °C (initial
power 300 W) for 30 min, cooled, dissolved in CH2Cl2, precipitated
with diethyl ether, filtered and the solvents were evaporated. Silica
gel chromatography (Et2O/cyclohexane) yielded the corresponding
benzazepine 3.
13C NMR (CDCl3, Me4Si): δ = –2.1, 9.9, 47.6, 50.2, 52.3, 52.8,
60.9, 128.5, 128.8, 128.9, 130.0, 130.1, 130.6, 131.5, 132.1, 135.4,
140.3, 141.4, 146.00, 166.8 167.2 ppm. ESIMS: m/z = 502.0 [M +
H]+, 524.0 [M + Na]+. FAB+: m/z = 502 [M + H]+. HRMS: calcd.
for C25H32NO6SSi 502.1720; found 502.1722.
Methyl 3-Phenyl-2-[2-(trimethylsilyl)ethylsulfonyl]-2,3-dihydro-1H-
benzo[c]azepine-4-carboxylate (3a): Heck reaction of the N-(2-bro-
mobenzyl)-β-amino ester 2a according to the general procedure
yielded 42 mg (95%) of the title compound as a white solid after
silica gel chromatography (Et2O/cyclohexane, 1:9). M.p. 83.3–
Methyl 3-(Benzo[d][1,3]dioxol-4-yl)-2-[2-(trimethylsilyl)ethylsulfo-
nyl]-2,3-dihydro-1H-benzo[c]azepine-4-carboxylate (3e): Heck reac-
tion of the N-(2-bromobenzyl)-β-amino ester 2e according to the
general procedure yielded 25 mg (51%) of the title compound as a
white solid after silica gel chromatography (Et2O/cyclohexane, 2:8).
85.1 °C. IR: ν = 3064 (m), 2953 (m), 1712 (s), 1250 (s) cm–1. 1H M.p. 111.8–113.0 °C. IR: ν = 3055 (m), 2954 (m), 1708 (s), 1271
˜
˜
NMR (CDCl3, Me4Si): δ = –0.22 (s, 9 H), 0.60–0.85 (m, 2 H), 2.25–
2.60 (m, 2 H), 3.68 (s, 3 H), 4.12 (d, J2 = 17.0 Hz, 1 H), 4.43 (dd,
(s), 1252 (s) cm–1. 1H NMR (CDCl3, Me4Si): δ = –0.16 (s, 9 H),
0.70–0.85 (m, 2 H), 2.40–2.70 (m, 2 H), 3.71 (s, 3 H), 4.34 (d, J2 =
J2 = 17.0, J4 = 1.5 Hz, 1 H), 6.42 (s, 1 H), 7.20–7.45 (m, 8 H), 17.1 Hz, 1 H), 4.49 (dd, J2 = 17.1, J4 = 1.5 Hz, 1 H), 5.96 (d, J2 =
7.50–7.60 (m, 1 H), 8.00 (s, 1 H) ppm. 13C NMR (CDCl3, Me4Si): 1.3 Hz, 1 H), 5.98 (d, J2 = 1.3 Hz, 1 H), 6.43 (s, 1 H), 6.70–6.85
δ = –2.1, 9.9, 47.5, 50.1, 52.7, 61.7, 128.2, 128.3, 128.78, 128.81,
(m, 3 H), 7.20–7.30 (m, 1 H), 7.30–7.45 (m, 2 H), 7.50–7.60 (m, 1
130.4, 132.21, 132.24, 135.3, 140.6, 140.8, 141.0, 167.4 ppm. ES- H), 7.95 (s, 1 H) ppm. 13C NMR (CDCl3, Me4Si): δ = –2.0, 10.0,
IMS: m/z = 444.0 [M + H]+, 466.0 [M + Na]+. FAB+: m/z = 444 [M
48.5, 50.0, 52.6, 57.0, 101.3, 108.8, 121.8, 122.3, 122.6, 128.2, 128.6,
130.3, 131.9, 132.1, 135.6, 140.6, 141.0, 145.3, 148.1, 167.1 ppm.
ESIMS: m/z = 488.0 [M + H]+, 510.0 [M + Na]+. FAB+: m/z =
487 [M – e–]+, 488 [M + H]+. HRMS: calcd. for C24H29NO6SSi
487.1485; found 487.1480.
+ H]+. HRMS: calcd. for C23H30NO4SSi 444.1665; found 444.1703.
Methyl
3-(3,5-Dimethylphenyl)-2-[2-(trimethylsilyl)ethylsulfonyl]-
2,3-dihydro-1H-benzo[c]azepine-4-carboxylate (3b): Heck reaction
of the N-(2-bromobenzyl)-β-amino ester 2b according to the gene-
ral procedure yielded 45 mg (98%) of the title compound as a white
solid after silica gel chromatography (Et2O/cyclohexane, 1:9). M.p.
Methyl 3-{4-[2-(Trimethylsilyl)ethynyl]phenyl}-2-[2-(trimethylsilyl)-
ethylsulfonyl]-2,3-dihydro-1H-benzo[c]azepine-4-carboxylate
(3f):
81.9–83.6 °C. IR: ν = 3066 (m), 2953 (m), 1710 (s), 1252 (s) cm–1.
Heck reaction of the N-(2-bromobenzyl)-β-amino ester 2f accord-
˜
1H NMR (CDCl3, Me4Si): δ = –0.21 (s, 9 H), 0.65–0.85 (m, 2 H), ing to the general procedure yielded 20 mg (37%) of the title com-
2.29 (s, 6 H), 2.25–2.60 (m, 2 H), 3.70 (s, 3 H), 4.16 (d, J2 = 17.0 Hz,
1 H), 4.42 (dd, J2 = 17.1, J4 = 1.5 Hz, 1 H), 6.35 (s, 1 H), 6.92 (s,
1 H), 6.96 (s, 2 H), 7.20–7.30 (m, 1 H), 7.30–7.45 (m, 2 H), 7.50–
7.60 (m, 1 H), 7.98 (s, 1 H) ppm. 13C NMR (CDCl3, Me4Si): δ =
–2.1, 9.9, 21.5, 47.6, 50.1, 52.7, 61.0, 126.6, 128.3, 128.8, 130.0,
130.3, 132.3, 132.5, 135.4, 138.3, 140.6, 140.77, 140.82, 167.6 ppm.
ESIMS: m/z = 472.0 [M + H]+, 494.0 [M + Na]+. FAB+: m/z =
472 [M + H]+. HRMS: calcd. for C25H34NO4SSi 472.1978; found
472.2005.
pound as a white solid after silica gel chromatography (Et2O/cyclo-
hexane, 1:9). M.p. 59.3–60.7 °C. IR: ν = 3056 (m), 2956 (m), 2158
˜
1
(m), 1711 (s), 1250 (s) cm–1. H NMR (CDCl3, Me4Si): δ = –0.22
(s, 9 H), 0.24 (s, 9 H), 0.60–0.80 (m, 2 H), 2.25–2.55 (m, 2 H), 3.67
(s, 3 H), 4.06 (d, J2 = 17.0 Hz, 1 H), 4.42 (dd, J2 = 17.0, J4
=
1.4 Hz, 1 H), 6.37 (s, 1 H), 7.20–7.60 (m, 8 H), 8.00 (s, 1 H) ppm.
13C NMR (CDCl3, Me4Si): δ = –2.1, 0.1, 9.9, 47.5, 50.2, 52.7, 60.9,
95.2, 104.6, 123.0, 128.5, 128.7, 128.9, 130.5, 131.7, 132.2, 132.4,
135.4, 140.4, 141.2, 141.4, 167.3 ppm. ESIMS: m/z = 540.0 [M +
H]+, 562.1 [M + Na]+. FAB+: m/z = 540 [M + H]+. HRMS: calcd.
for C28H38NO4SSi2 540.2060; found 540.2076.
Methyl 3-(3-Fluorophenyl)-2-[2-(trimethylsilyl)ethylsulfonyl]-2,3-di-
hydro-1H-benzo[c]azepine-4-carboxylate (3c): Heck reaction of the
N-(2-bromobenzyl)-β-amino ester 2c according to the general pro-
cedure yielded 42 mg (91%) of the title compound as a white solid
after silica gel chromatography (Et2O/cyclohexane, 1:9). M.p. 81.5–
Methyl 8-Methoxy-3-phenyl-2-[2-(trimethylsilyl)ethylsulfonyl]-2,3-
dihydro-1H-benzo[c]azepine-4-carboxylate (3g): Heck reaction of
the N-(2-bromobenzyl)-β-amino ester 2g according to the general
82.8 °C. IR: ν = 3055 (m), 2954 (m), 1710 (s), 1252 (s) cm–1. 1H procedure yielded 40 mg (83%) of the title compound as a white
˜
NMR (CDCl3, Me4Si): δ = –0.22 (s, 9 H), 0.60–0.80 (m, 2 H), 2.25–
2.55 (m, 2 H), 3.70 (s, 3 H), 4.11 (d, J2 = 17.0 Hz, 1 H), 4.46 (dd,
solid after silica gel chromatography (Et2O/cyclohexane, 2:8). M.p.
46.4–47.7 °C. IR: ν = 3054 (m), 2954 (m), 1706 (s), 1268 (s), 1262
˜
1
J2 = 17.1, J4 = 1.6 Hz, 1 H), 6.39 (s, 1 H), 6.95–7.05 (m, 1 H), (s) cm–1. H NMR (CDCl3, Me4Si): δ = –0.19 (s, 9 H), 0.65–1.85
7.05–7.45 (m, 6 H), 7.50–7.60 (m, 1 H), 8.01 (s, 1 H) ppm. 13C
NMR (CDCl3, Me4Si): δ = –2.2, 9.9, 47.5, 50.2, 52.7, 60.7 (d, J4 = J2 = 16.9 Hz, 1 H), 4.38 (dd, J2 = 17.2, J4 = 1.6 Hz, 1 H), 6.40 (s,
(m, 2 H), 2.35–2.65 (m, 2 H), 3.67 (s, 3 H), 3.82 (s, 3 H), 4.08 (d,
1.7 Hz), 115.2 (d, J2 = 21.1 Hz), 115.8 (d, J2 = 22.1 Hz), 124.42 (d,
J4 = 2.9 Hz), 128.48, 128.9, 130.3 (d, J3 = 8.2 Hz), 130.6, 131.6,
1 H), 6.74 (d, J4 = 2.6 Hz, 1 H), 6.87 (dd, J3 = 8.5, J4 = 2.6 Hz, 1
H), 7.25–7.45 (m, 5 H), 7.47 (d, J3 = 8.6 Hz, 1 H), 7.96 (s, 1 H)
ppm. 13C NMR (CDCl3, Me4Si): δ = –2.1, 10.0, 47.6, 50.1, 52.5,
55.6, 61.0, 113.2, 114.5, 125.0, 128.1, 128.7, 128.8, 137.4, 140.7,
141.0, 142.6, 161.2, 167.7 ppm. ESIMS: m/z = 474.0 [M + H]+.
FAB+: m/z = 474 [M + H]+. HRMS: calcd. for C24H32NO5SSi
474.1770; found 474.1767.
132.1, 135.4, 140.4, 141.2, 143.6 (d, J3 = 6.7 Hz), 163.0 (d, J1
247.2 Hz), 167.2 ppm. ESIMS: m/z = 462.0 [M + H]+, 484.0 [M +
Na]+. FAB+: m/z H]+. HRMS: calcd. for
462 [M
=
=
+
C23H29FNO4SSi 462.1571; found 462.1544.
Methyl 3-[4-(Methoxycarbonyl)phenyl]-2-[2-(trimethylsilyl)ethylsul-
fonyl]-2,3-dihydro-1H-benzo[c]azepine-4-carboxylate (3d): Heck re-
action of the N-(2-bromobenzyl)-β-amino ester 2d according to the
general procedure yielded 41 mg (82%) of the title compound as a
white solid after silica gel chromatography (Et2O/cyclohexane, 2:8).
Methyl 8-Fluoro-3-phenyl-2-[2-(trimethylsilyl)ethylsulfonyl]-2,3-di-
hydro-1H-benzo[c]azepine-4-carboxylate (3h): Heck reaction of the
N-(2-bromobenzyl)-β-amino ester 2h according to the general pro-
cedure yielded 35 mg (76%) of the title compound as a white solid
after silica gel chromatography (Et2O/cyclohexane, 1:9). M.p. 45.3–
M.p. 114.6–116.8 °C. IR: ν = 3065 (m), 2954 (m), 1719 (s), 1285
˜
(s), 1250 (s) cm–1. 1H NMR (CDCl3, Me4Si): δ = –0.22 (s, 9 H),
46.6 °C. IR: ν = 3053 (m), 2955 (m), 1710 (s), 1252 (s) cm–1. 1H
˜
0.60–0.85 (m, 2 H), 2.25–2.55 (m, 2 H), 3.68 (s, 3 H), 3.90 (s, 3 H), NMR (CDCl3, Me4Si): δ = –0.17 (s, 9 H), 0.65–0.90 (m, 2 H), 2.35–
4.06 (d, J2 = 16.9 Hz, 1 H), 4.43 (dd, J2 = 17.1, J4 = 1.3 Hz, 1 H),
6.44 (s, 1 H), 7.20–7.60 (m, 6 H), 8.01 (s, 1 H), 8.03 (s, 2 H) ppm.
2.65 (m, 2 H), 3.68 (s, 3 H), 4.09 (d, J2 = 17.2 Hz, 1 H), 4.40 (dd,
J2 = 17.2, J4 = 1.6 Hz, 1 H), 6.40 (s, 1 H), 6.95 (dd, J3 = 8.7, J4 =
206
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Eur. J. Org. Chem. 2007, 201–208

A Microwave-Assisted Heck Reaction
FULL PAPER
2.6 Hz, 1 H), 7.06 (dt, J3 = 8.2, J4 = 2.6 Hz, 1 H), 7.25–7.40 (m, 5
H), 7.51 (dd, J3 = 8.6, J4 = 5.6 Hz, 1 H), 7.96 (s, 1 H) ppm. 13C
Methyl
8-Fluoro-3-phenyl-2,3-dihydro-1H-benzo[c]azepine-4-car-
boxylate Hydrofluoride (8h): Deprotection of the benzazepine 3h
NMR (CDCl3, Me4Si): δ = –2.1, 10.0, 47.3, 50.2, 52.7, 61.2, 115.2 according to the general procedure yielded 15.7 mg (99%) of the
(d, J2 = 21.4 Hz), 116.0 (d, J2 = 22.3 Hz), 128.3, 128.6 (d, J4 title compound as a white solid. M.p. 194.8–196.5 °C (decom-
3.5 Hz), 128.8, 128.9, 131.4 (d, J6 = 3.0 Hz), 137.5 (d, J3 = 8.8 Hz), posed). IR: ν = 3053 (m), 2955 (m), 1710 (s), 1252 (s) cm–1. 1H
=
˜
139.7, 140.6, 143.6 (d, J3 = 7.5 Hz), 163.4 (d, J1 = 254.9 Hz),
167.3 ppm. ESIMS: m/z = 462.0 [M + H]+, 484.0 [M + Na]+.
FAB+: m/z = 462 [M + H]+. HRMS: calcd. for C23H29FNO4SSi
462.1571; found 462.1562.
NMR (CD3OD, Me4Si): δ = 3.66 (s, 3 H), 4.26 (d, J2 = 15.9 Hz, 1
H), 4.35 (d, J2 = 15.9 Hz, 1 H), 6.04 (s, 1 H), 7.23 (dd, J4 = 9.1, J5
= 2.6 Hz, 1 H), 7.28 (dd, J3 = 8.5, J4 = 2.7 Hz, 1 H), 7.40–7.50 (m,
5 H), 7.76 (dd, J4 = 8.5, J5 = 5.6 Hz, 1 H), 8.11 (s, 1 H) ppm. 13C
NMR (CD3OD, Me4Si): δ = 47.6, 53.0, 63.2, 117.2 (d, J2
=
General Protocol for the SES Deprotection with HF: Benzazepine 3
(0.05 mmol) was treated with 1 mL of anhydrous HF in a Teflon
vessel at 0 °C for 1 h. Unreacted HF was then removed by distil-
lation. The residue was dissolved in methanol and and the mixture
concentrated to give the HF·benzazepine salt 8.
21.7 Hz), 117.9 (d, J2 = 23.6 Hz), 128.6 (d, J3 = 2.4 Hz), 129.6 (d,
J3 = 3.3 Hz), 130.39, 130.44, 130.8, 136.4, 138.6 (d, J4 = 8.8 Hz),
138.8, 140.9, 164.8 (d, J1 = 252.5 Hz), 167.5 ppm. ESIMS: m/z =
298.2 [M – F]+. FAB+: m/z = 298 [M + H]+. HRMS: calcd. for
C18H17FNO2 298.1243; found 298.1242.
Methyl 3-Phenyl-2,3-dihydro-1H-benzo[c]azepine-4-carboxylate Hy-
drofluoride (8a): Deprotection of the benzazepine 3a according to
the general procedure yielded 14.6 mg (98%) of the title compound
as a white solid. M.p. 195.4–197.9 °C (decomposed). 1H NMR
(CD3OD, Me4Si): δ = 3.67 (s, 3 H), 4.31 (d, J2 = 15.7 Hz, 1 H),
4.41 (d, J2 = 15.7 Hz, 1 H), 6.01 (s, 1 H), 7.35–7.60 (m, 8 H), 7.72
(d, J3 = 7.0 Hz, 1 H), 8.15 (s, 1 H) ppm. 13C NMR (CD3OD,
Me4Si): δ = 48.0, 53.0, 63.0, 129.1, 130.4, 130.5, 130.9, 131.9, 133.0,
135.6, 136.1, 136.3, 141.6, 167.5 ppm. ESIMS: m/z = 280.1 [M –
F]+. FAB+: m/z = 280 [M – F]+. HRMS: calcd. for C18H18NO2
280.1338; found 280.1337.
X-ray Analysis: Data for compound 3a were collected with an
XCALIBUR-2 4-circle CCD diffractometer with graphite-mono-
chromated Mo-Kα radiation. The structure was solved by direct
methods and expanded using Fourier techniques. The non-hydro-
gen atoms were refined anisotropically. The hydrogen atoms in-
volved in hydrogen bonding were located in electron density maps.
The remainder of the hydrogen atoms were placed in idealised posi-
tions and allowed to ride on the C atoms to which they are bonded.
Crystal data: Mr = 443.62; 0.25ϫ0.35ϫ0.50 mm; colourless block;
T = 170 K, monoclinic; space group P21/n; Z = 4; a = 11.9397(8),
b
= 14.6956(8), c = 13.5913(9) Å; β = 106.004(7)°; V =
Methyl 3-(3,5-Dimethylphenyl)-2,3-dihydro-1H-benzo[c]azepine-4-
carboxylate Hydrofluoride (8b): Deprotection of the benzazepine 3b
according to the general procedure yielded 16.2 mg (99%) of the
title compound as a white solid. M.p. 192.9–194.6 °C (decom-
posed). 1H NMR (CD3OD, Me4Si): δ = 2.32 (s, 6 H), 3.71 (s, 3 H),
4.32 (d, J2 = 15.7 Hz, 1 H), 4.39 (d, J2 = 15.7 Hz, 1 H), 6.02 (s, 1
H), 7.08 (s, 2 H), 7.11 (s, 1 H), 7.40–7.65 (m, 3 H), 7.74 (d, J3 =
7.3 Hz, 1 H), 8.15 (s, 1 H) ppm. 13C NMR (CD3OD, Me4Si): δ =
21.3, 47.9, 53.1, 63.1, 128.0, 128.9, 130.6, 130.9, 131.9, 132.5, 133.0,
135.2, 135.9, 136.1, 140.4, 141.4, 167.5 ppm. ESIMS: m/z = 308.3
[M – F]+. FAB+: m/z = 308 [M – F]+. HRMS: calcd. for
C20H22NO2 308.1651; found 308.1654.
2292.3(2) Å3; ρcalcd. = 1.285 gcm–3; θmax = 33.25°; R1 = 4.74%.
CCDC-616640 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new compounds.
Acknowledgments
We thank the MENRT and the CNRS for financial support.
Methyl 3-(3-Fluorophenyl)-2,3-dihydro-1H-benzo[c]azepine-4-car-
boxylate Hydrofluoride (8c): Deprotection of the benzazepine 3c
according to the general procedure yielded 15.7 mg (99%) of the
title compound as a white solid. M.p. 193.6–195.2 °C (decom-
[1] S. Caddick, Tetrahedron 1995, 51, 10403–10432.
[2] A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault,
D. Mathé, Synthesis 1998, 1213–1234.
[3] Microwaves in Organic Synthesis (Ed.: A. Loupy), Wiley-VCH,
Weinheim, 2002.
[4] a) C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250–6284; b)
C. O. Kappe, Angew. Chem. 2004, 116, 6408–6443.
[5] A. Loupy, C. R. Chim. 2004, 7, 103–112.
[6] Microwave Assisted Organic Chemistry (Eds.: J. P. Tierney, P.
Lidström), Blackwell Publishing, Oxford, UK, 2005.
[7] K. G. Mayo, E. H. Nearhoof, J. J. Kiddle, Org. Lett. 2002, 4,
1567–1570.
1
posed). H NMR (CD3OD, Me4Si): δ = 3.72 (s, 3 H), 4.36 (d, J2
= 15.7 Hz, 1 H), 4.45 (d, J2 = 15.7 Hz, 1 H), 6.12 (s, 1 H), 7.15–
7.40 (m, 3 H), 7.40–7.65 (s, 4 H), 7.75 (d, J3 = 7.3 Hz, 1 H), 8.19
(s, 1 H) ppm. 13C NMR (CD3OD, Me4Si): δ = 48.4, 53.1, 62.6,
117.3 (d, J2 = 22.9 Hz), 117.7 (d, J2 = 21.3 Hz), 126.4 (d, J4
=
2.9 Hz), 128.8, 130.6, 130.9, 132.0, 132.3 (d, J3 = 8.3 Hz), 132.9,
135.7, 136.1, 139.0 (d, J3 = 7.3 Hz), 142.0, 164.4 (d, J1 = 246.9 Hz),
167.3 ppm. ESIMS: m/z = 298.1 [M – F]+. FAB+: m/z = 298 [M –
F]+. HRMS: calcd. for C18H17FNO2 298.1243; found 298.1237.
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title compound as a white solid. M.p. 194.8–196.4 °C (decom-
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4.16 (d, J2 = 15.9 Hz, 1 H), 4.24 (d, J2 = 15.9 Hz, 1 H), 5.94 (s, 1
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Received: August 4, 2006
Published Online: November 17, 2006
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