Synthesis of novel poly(ethylene glycol) supported benzazepines: the crucial role of PEG on the selectivity of an intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tet.2006.08.009

Poly(ethylene glycol) (PEG 3400) was used as a soluble polymeric support for the synthesis of a series of novel benzazepines. The key step for the preparation of these heterocycles was a phosphine-free palladium-catalyzed Heck reaction. Palladium nanopart

Full text of DOI:10.1016/j.tet.2006.08.009

Tetrahedron 62 (2006) 10456–10466
Synthesis of novel poly(ethylene glycol) supported
benzazepines: the crucial role of PEG on the
selectivity of an intramolecular Heck reaction
a
Patrice Ribiere, Valerie Declerck, Yannig Nedellec, Neerja Yadav-Bhatnagar,
a
b
c
ꢀ
ꢁ
ꢁ
a
a,
*
ꢁ ꢁ
Jean Martinez and Frederic Lamaty
a
´
´
Laboratoire des Aminoacides, Peptides et Proteines (LAPP), CNRS-Universites Montpellier 1 et 2,
Place Eugeꢀne Bataillon, 34095 Montpellier Cedex 5, France
b
´
Laboratoire des Agregats Moleculaires et Materiaux Inorganiques (LAMMI), CNRS-Universite Montpellier 2,
´
´
´
Place Eugeꢀne Bataillon, 34095 Montpellier Cedex 5, France
cAventis Pharma, 102 route de Noisy, 93325 Romainville Cedex, France
Received 16 May 2006; revised 26 July 2006; accepted 2 August 2006
Available online 11 September 2006
Abstract—Poly(ethylene glycol) (PEG 3400) was used as a soluble polymeric support for the synthesis of a series of novel benzazepines. The
key step for the preparation of these heterocycles was a phosphine-free palladium-catalyzed Heck reaction. Palladium nanoparticles formed
during the course of the reaction were characterized. The presence of PEG 3400 influenced the outcome of the reaction in terms of selectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
also as stabilizer for in situ generated nanoparticles. To the
best of our knowledge, this is the first reaction performed
on the end group of a PEG polymer with simultaneous for-
mation of nanoparticles, which have been unambiguously
characterized by Transmission Electronic Microscopy and
Light Scattering experiments. Furthermore, the efficiency
and selectivity induced by the presence of PEG 3400 were
demonstrated when using PEG 3400-OH as a solvent in
a non-supported version of the reaction. Interestingly
smaller liquid PEGs such as PEG 300 do not exert the
same influence. This reaction was applied to the synthesis
of a series of original benzazepines.
For economical, environmental, and practical reasons,
organicsynthesisreliesmoreandmoreoncatalysis.1 Organo-
metallic catalysis has proven to be a major field in carbon–
carbon and carbon–heteroatom bond formations, key to the
efficient building of more complex molecules. Major break-
through has been performed in the field of homogeneous
catalysis by the design and preparation of new ligands
leading to efficient catalytic systems.2 A complementary
approach was the discovery that finely divided and stabilized
metallic particles are also active in catalytic transforma-
tions.3–6 Nanoparticles are generally generated in the pres-
ence of a protector providing either an electrostatic or
steric stabilization.3 Several types of macromolecules have
been described for their ability of stabilizing metallic parti-
cles by steric shielding (polymers, cyclodextrins, surfac-
tants.)4 including poly(ethylene glycol) (PEG), a polymer
widely used for biomedical applications7 and in supported
synthesis.8 Among the different metals employed in cataly-
sis, palladium has found a special place due to the number
of transformations, which can be mediated by this metal.9
2. Results and discussion
Bifunctional poly(ethylene glycol) with an average molecu-
lar weight of 3400 was used as a polymeric support for
the preparation of a-methylene b-aminoesters 1a–g by an
aza-Baylis–Hillman reaction involving PEG-SES-NH2, an
aldehyde, and methyl acrylate in the presence of DABCO
(Scheme 1).10–12 Compound 2a, obtained by alkylation of
1a with 2-bromobenzyl bromide, was subjected to different
Heck reaction conditions using Pd(OAc)2 as catalyst in the
presence of a base in DMF. After 12 h at 80 ꢀC, 2a was fully
converted to the cyclized benzazepine 3a using either
K2CO3 or Oct3N as a base. The reaction time was shortened
to 6 h in the absence of solvent. The reaction was very selec-
tive since only 3a was obtained among the different prod-
ucts, which could be formed during the reaction.13 Since
We now report that a soluble PEG 3400 polymer supporting
a substrate involved in a Pd-catalyzed Heck cyclization acts
Keywords: Polymer supported chemistry; Heterocycles; Heck reaction;
Nanoparticles; Immobilization; Palladium; Solvent effects.
* Corresponding author. Tel.: +33 4 67 14 38 47; fax: +33 4 67 14 48 66;
e-mail: frederic.lamaty@univ-montp2.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.009

P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
10457
R3
R3
R3
R1 NH2
+
R2CHO
+
Pd(OAc)2
R1 HN
Br
R1
N
R1
N
Br
Br
DABCO
Base
Solvent
Additive
K2CO3
CH3CN
R2
CO2Me
R2
CO2Me
R2
CO2Me
2a-k
CO2Me
1a-k
3a-k
Ts
N
PEG-OH = H-(O-CH2-CH2)n-OH
with an average MW = 3400
SO2
R1
PEG-SES
=
PEG
MeO
Si
CO2Me
OMe
OAc
R3 = H R2
=
O
S
g
a
b
c
d
e
f
SO2
R1
SES =
=
Me3Si
MeO
OMe
R3 = H i : R2
=
j : R2 =
k : R2 =
R3 = H
h : R2 =
R
3 = OMe
R
3 = F
Scheme 1.
the reaction product was isolated by precipitation in Et2O
and filtration, the use of lipophilic Oct3N was preferred
because it was readily eliminated during this operation.14
solid at room temperature but liquid at 80 ꢀC, was used as
the solvent (entry 5). In this case, excellent results were
obtained, similar to those obtained in the supported reaction,
with exclusive formation of 3h. Interestingly, replacing solid
PEG 3400-OH by liquid PEG 300-OH with either Oct3N or
K2CO3 yielded only a sluggish mixture of products. Further-
more, the presence of the hydroxyl groups on PEG is neces-
sary, since the use of PEG 3400-OMe instead of PEG-OH as
a solvent did not give the cyclized product (entry 6).
In a non-supported version of the reaction,12 substrate 2h,
which is not linked to PEG, was reacted in the Pd-catalyzed
cyclization using similar conditions as for the transformation
of 2a in 3a (Table 1). In sharp contrast with the results
previously obtained, we could not reach the same results
in terms of rate, selectivity, and reproducibility using ‘clas-
sical’ Heck reaction conditions.
Using Et3N, the reaction was slower and a side product 4
arising from a competing Tsuji–Trost rearrangement was
formed (entry 1 and Eq. 1).15–17 Using Oct3N, the reaction
was complete but the formation of side product 4 increased
(entry 2). Jeffery’s conditions18 were tried but resulted in
a slower reaction and the exclusive formation of 4 (obtained
in this case as an E/Z mixture with a 4/1 diastereomeric ratio)
(entry 3). Since the presence of PEG seemed to be of prime
significance in the catalytic system, we explored the
improvement of the results by adding PEG 3400-OH to the
reaction mixture, in the same weight amount as in the case
of the polymer supported substrate. The reaction was not
complete within 12 h but only formation of the cyclized
product 3h was observed (entry 4). Finally, PEG 3400-OH,
Br
PdLn
Br
SES
N
Br
SES
Ph
N
SES
N
PdLn
Ph
CO2Me
CO2Me
Ph
CO2Me
2h
4
ð1Þ
Various substrates were used in the reaction described within
thisstudy. Structuresandthecorrespondingyieldofthealkyl-
ated aminoesters 2a–k are presented in Figure 1. Amino-
esters 2a–k were cyclized to benzazepines 3a–k, which are
presented in Figure 2. In all cases, complete conversion of
the starting material to the expected product was obtained.
Table 1. Conversion of 2h under Pd catalysisa
Entry
Base
Solvent
Additive
Reaction time (h)
2h (%)
3h (%)
4 (%)
1
2
3
4
5
6
Et3N
DMF
DMF
DMF
DMF
PEG 3400-OH
PEG 3400-OMe
36
12
48
12
12
12
10
0
0
54
0
100
68
50
0
46
100
0
22
50
100
0
0
0
Oct3N
K2CO3
K2CO3
K2CO3
K2CO3
n-Bu4NCl
PEG 3400-OH
a
Reaction conditions: 2h (1 equiv), Pd(OAc)2 (0.1 equiv), K2CO3 (3 equiv), and PEG 3400-OH (100 mg/mg of Pd(OAc)2) were stirred during the indicated
time at 80 ꢀC.

10458
P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
Br
Br
Br
PEG-SES
N
Br
PEG-SES
MeO
N
PEG-SES
AcO
N
PEG-SES
MeO2C
N
CO2Me
CO2Me
2b (78%)
CO2Me
CO2Me
2d (72%)
2a (88%)
2c (81%)
OMe
Br
Br
Br
PEG-SES
N
PEG-SES
N
PEG-SES
N
CO2Me
CO2Me
CO2Me
2g (86%)
O
S
2e (85%)
2f (75%)
OMe
F
Br
Br
SES
N
Br
SES
N
Br
SES
N
SES
N
CO2Me
CO2Me
CO2Me
2i (64%)
MeO
CO2Me
2j (81%)
2h (80%)
2k (76%)
OMe
Figure 1.
PEG-SES
PEG-SES
SES
N
PEG-SES
MeO
N
PEG-SES
AcO
N
PEG-SES
MeO2C
N
CO2Me
CO2Me
CO2Me
CO2Me
3a (81%)
3b (79%)
3c (83%)
3d (81%)
OMe
N
PEG-SES
N
PEG-SES
N
CO2Me
CO2Me
CO2Me
O
S
3f (79%)
3e (86%)
3g (85%)
MeO
F
SES
MeO
N
N
SES
N
SES
N
CO2Me
CO2Me
CO2Me
CO2Me
3j (82%)
3h (86%)
3i (85%)
3k (81%)
OMe
Figure 2.
Purity of the PEG-supported molecule was further ascer-
tained by 1H NMR and HPLC.19 The diversity of cyclic struc-
tures in the supported version of the reaction originated from
the aldehydes employed in the aza-Baylis–Hillman reaction
(Scheme 1 and Fig. 1). In the case of the non-supported syn-
thesis of benzazepines, we have shown that further diversity
could be obtained by adding a substituent on the aromatic
ring of the alkylating agent (Scheme 1 and Fig. 2).
The catalytic systems described above for the supported and
non-supported reactions are quite simple. No phosphine was
necessary to achieve good conversion and selectivity and the
presence of ammonium salts did not improve the results.
Furthermore, direct observation of a mixture of Pd(OAc)2,
Oct3N, and DMF in the presence of PEG 3400-OH showed
a dramatic difference in the homogeneity of the mixture
(Fig. 3).

P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
10459
with palladium catalysts providing an easy medium for
catalyst recycling.24–26 However, a larger polymer is more
prone to stabilize nanoparticles20 while in the case of smaller
PEGs additional stabilizers26 are needed to induce these
nanostructures. As we have shown in this study, the absence
of selectivity with smaller PEGs is indeed not comparable
with the results obtained with larger PEGs. Additionally, it
has been reported that stabilization by ammonium salts
(Jeffery’s conditions) can also yield nanoparticles that differ
in size and probably in structure, explaining the discrepancy
with the results presented herein.27 The importance of the
size effect of larger PEGs in stabilizing nanoparticles can
be correlated to similar adsorption effects, which have
been reported either on proteins,28 on silica particles,29 or
on surfaces.30,31 Nevertheless, the question of the actual
catalytic species is still pending, since some literature data
advocate that nanoparticles may serve as a reservoir for
small quantities of leaching active palladium species.32–-35
In the present case, PEG 3400 would then influence the
nature of this reservoir.
Figure 3. Left: mixture of Pd(OAc)2, Oct3N, DMF; right: mixture of
Pd(OAc)2, Oct3N, DMF, PEG 3400-OH.
Since PEG has been recently described as nanoparticle
stabilizer,20–22 we investigated the possible presence of
nanoparticles by analyzing the reaction mixture after 12 h
of 2a with Pd(OAc)2 and Oct3N in DMF, by Transmission
Electronic Microscopy (TEM) either directly after evapora-
tion of the solvent or through a layer of carbon. The images
resulting from both techniques revealed the presence of
homogeneously dispersed nanoparticles of palladium of 5–
10 nm diameter (Fig. 4). This was further confirmed by light
scattering experiments. Nanoparticles were also obtained
when a mixture of PEG 3400-OH, Pd(OAc)2, and K2CO3
was heated at 80 ꢀC.
Modified PEGs were previously used as support for Pd cat-
alysts.36–39 These PEGs are usually terminated by a ligand
such as a phosphine to generate a soluble supported complex
of palladium that have been in some cases characterized by
solution NMR. Nonetheless, one cannot rule out in these
examples the additional stabilizing effect exerted by the
polymer on the metallic centers and probably the concomi-
tant existence of two forms of palladium. Most probably,
the involvement of in situ generated Pd nanoparticles must
be also considered in these cases.40
The most striking results were obtained when larger PEGs
were used as solvent for unsupported reactions. The use of
PEG as the sole solvent has a strong influence on the out-
come of the reaction in terms of stereo- and regioselectivity.
The use of co-solvents generated the formation of side prod-
ucts or slowed down the reaction. One plausible hypothesis
is that the presence of palladium species stabilized by PEG
may play a role on the kinetics of the different steps of the
reaction and orients the outcome of the process to one path-
way (mainly Heck cyclization) versus another (mainly
Tsuji–Trost allylation). It has indeed been shown in the liter-
ature that ionic liquid-stabilized nanoparticles can accelerate
such steps.23 Furthermore, smaller PEGs, liquids at room
temperature, have also been used as solvent in conjunction
3. Conclusion
In conclusion, we have shown that a PEG polymer support-
ing an organic substrate can also stabilize a Pd catalyst. This
phenomenon leads to a very efficient and selective Heck
cyclization of the supported organic molecule for the prepa-
ration of novel heterocyclic structures. These results seem to
be general in PEG-supported chemistry since our group41,42
and others43 have reported few years ago the positive effect
of larger PEG polymeric support on a Heck reaction. Addi-
tionally, following the recent results concerning the use of
larger PEG/Pd as catalytic medium for intermolecular
Heck reaction,20,22,44 we have shown herein that this system
could be used in its intramolecular version to elaborate more
complex and heterocyclic structures. Further studies to
assess recycling of this catalytic system and to broaden its
scope to other Pd-catalyzed reactions are underway in our
laboratories.
4. Experimental
4.1. General remarks
All reagents were purchased from Aldrich Chemical Co. and
used without further purification. 1H and 13C NMR analyses
were performed with a Bruker AM 300 MHz spectrometer,
and calibrated using residual undeuterated solvents as an
internal reference. Mass spectra (electrospray ionization
mode, ESIMS) were recorded on a Platform II (Micromass,
Figure 4. TEM of reaction mixture of 2a with Pd(OAc)2 and OctN3 in DMF
deposited on a copper-grid.

10460
P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
Prepared according to the general procedure with 1b
(900 mg, 0.20 mmol) to afford 750 mg (78%) of the title
compound.
Manchester, U.K.) quadrupole mass spectrometer fitted with
an electrospray interface. The mass spectrometer was
calibrated in the positive- and negative-ion ESI mode. The
sample was dissolved in H2O/CH3CN (50/50 v/v). FAB
mass spectra and HRMS (High-Resolution Mass Spectrum)
were recorded on a JEOL JMS DX300-SX 102 in positive
mode using NBA (3-nitrobenzylalcohol) as matrix.
1H NMR (CDCl3, Me4Si) d ꢁ0.08 (s, 6H), 0.41–0.49 (m,
2H), 0.96–1.05 (m, 2H), 1.14–1.30 (m, 2H), 1.50–1.64
(m, 2H), 2.44 (s, 3H), 2.65–2.82 (m, 2H), 3.14 (t,
J¼7.0 Hz, 2H), 3.30 (t, J¼7.0 Hz, 2H), 3.50–3.70 (large
s, 154H), 3.61 (s, 3H), 3.75 (s, 6H), 4.76 (s, 2H), 5.89
(s, 1H), 6.12 (s, 1H), 6.30 (s, 1H), 6.43 (s, 1H), 6.49 (s,
2H), 7.01–7.08 (m, 1H), 7.11–7.34 (m, 3H), 7.41 (d,
J¼8.9 Hz, 1H), 7.47 (d, J¼8.0 Hz), 7.71 (d, J¼7.7 Hz,
2H); 13C NMR (CDCl3, Me4Si) d ꢁ3.77, 8.84, 14.41,
20.65, 21.47, 32.31, 47.57, 49.00, 50.02, 50.37, 52.10,
55.32, 61.56, 70.08–70.47, 99.90, 106.72, 122.46,
122.46, 126.96, 127.12, 128.61, 129.40, 129.62, 130.17,
132.25, 136.37, 136.85, 138.76, 139.60, 143.10, 160.85,
165.98.
The preparation of unsaturated b-aminoesters 1a–g and 1k
has been previously described.10–12
4.2. General procedure for the alkylation of PEG
3400-supported b-aminoesters
A mixture of PEG 3400-supported sulfonamide (1 equiv),
2-bromobenzyl bromide (8 equiv), and K2CO3 (10 equiv)
in CH3CN (5 mL/100 mg de PEG) was heated to reflux
for 6 h. After concentration, the residue was diluted in
CH2Cl2, filtered over Celite, and precipitated in ether. After
filtration, the solid was dried in vacuo to yield the corre-
sponding N-2-bromobenzyl-b-aminoester.
4.2.3. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(3-acyloxyphenyl)methyl)acrylate (2c).
4.2.1. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(phenyl)methyl)acrylate (2a).
Br
O
Si
N
PEG
N
Ts
S
O2
Br
CO2Me
O
Si
N
PEG
N
Ts
S
O2
OAc
CO2Me
Prepared according to the general procedure with 1c
(600 mg, 0.13 mmol) to afford 520 mg (81%) of the title
compound.
Prepared according to the general procedure with 1a
(900 mg, 0.20 mmol), 2-bromobenzyl bromide (800 mg,
3.2 mmol), and K2CO3 (550 mg, 4 mmol) to afford
850 mg (88%) of the title compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.12 (s, 6H), 0.36–0.48
(m, 2H), 0.90–0.99 (m, 2H), 1.10–1.25 (m, 2H), 1.46–
1.58 (m, 2H), 2.26 (s, 3H), 2.39 (s, 3H), 2.55–2.78 (m,
2H), 3.10 (t, J¼7.5 Hz, 2H), 3.26 (t, J¼7.5 Hz, 2H),
3.50–3.70 (large s, 154H), 3.57 (s, 3H), 4.72 (s, 2H),
5.87 (s, 2H), 6.11 (s, 1H), 6.44 (s, 1H), 6.93–7.20 (m,
5H), 7.24–7.42 (m, 5H), 7.66 (d, J¼8.3 Hz, 1H); 13C
NMR (CDCl3, Me4Si) d ꢁ3.77, 8.73, 14.36, 20.64,
21.13, 21.48, 32.30, 47.55, 49.01, 50.29, 52.14, 61.61,
70.06–71.00, 121.30, 122.10, 122.62, 125.65, 127.11,
127.20, 128.78, 129.56, 129.63, 129.91, 130.18, 132.43,
136.05, 136.29, 136.81, 138.53, 138.83, 139.09, 143.03,
150.80, 165.96, 168.93.
1H NMR (CDCl3, Me4Si) d ꢁ0.17 (s, 6H), 0.32–0.42 (m,
2H), 0.86–0.94 (m, 2H), 1.06–1.22 (m, 2H), 1.44–1.55
(m, 2H), 2.37 (s, 3H), 2.49–2.65 (m, 2H), 3.08 (t,
J¼7.0 Hz, 2H), 3.20–3.27 (m, 2H), 3.50–3.70 (large s,
154H), 3.53 (s, 3H), 4.71 (s, 2H), 5.82 (s, 1H), 6.10 (s,
1H), 6.39 (s, 1H), 6.98 (dt, J¼1.5, 7.7 Hz, 1H), 7.09–
7.37 (m, 10H), 7.65 (d, J¼8.3 Hz, 2H); 13C NMR
(CDCl3, Me4Si) d ꢁ3.18, 9.11, 14.78, 21.02, 21.89,
32.67, 47.96, 49.40, 50.51, 50.86, 52.47, 62.28, 70.37–
70.86, 122.96, 127.45, 127.50, 128.60, 128.98, 129.05,
129.09, 129.88, 130.03, 132.74, 136.68, 137.18, 137.70,
139.28, 143.52, 166.42.
4.2.4. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(4-methyloxycarbonyl-phenyl)methyl)acrylate
(2d).
4.2.2. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(3,5-dimethoxyphenyl)methyl)acrylate (2b).
Br
Br
O
Si
N
O2
O
Si
N
PEG
N
Ts
S
PEG
N
Ts
S
O2
CO2Me
CO2Me
MeO
MeO2C
OMe

P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
10461
Prepared according to the general procedure with 1d
(900 mg, 0.20 mmol) to afford 700 mg (72%) of the title
compound.
5.94 (s, 1H), 6.28 (s, 1H), 6.26 (s, 1H), 6.42 (s, 2H), 6.93–
7.54 (m, 9H), 7.66 (d, J¼8.2 Hz, 2H).
4.2.7. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(2-isobutyl)methyl)acrylate (2g).
1H NMR (CDCl3, Me4Si) d ꢁ0.11 (s, 6H), 0.34–0.54 (m,
2H), 0.89–1.04 (m, 2H), 1.10–1.26 (m, 2H), 1.42–1.64 (m,
2H), 2.40 (s, 3H), 2.62–2.82 (m, 2H), 3.11 (t, J¼7.7 Hz,
2H), 3.22–3.33 (m, 2H), 3.50–3.75 (large s, 154H), 3.87
(s, 3H), 4.73 (s, 2H), 5.84 (s, 1H), 6.16 (s, 1H), 6.48 (s,
1H), 7.00 (dt, J¼1.7, 7.5 Hz, 1H), 7.15 (dt, J¼1.3,
7.4 Hz, 1H), 7.23–7.53 (m, 6H), 7.67 (d, J¼8.2 Hz, 2H),
7.91 (d, J¼8.2 Hz, 2H).
Br
O
Si
N
PEG
N
Ts
S
O2
CO2Me
4.2.5. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(furan-2-yl)methyl)acrylate (2e).
Prepared according to the general procedure with 1g
(900 mg, 0.21 mmol) to afford 830 mg (86%) of the title
compound.
1H NMR (CDCl3, Me4Si) d 0.00 (s, 3H), 0.01 (s, 3H), 0.42–
0.57 (m, 2H), 0.76 (d, J¼6.1 Hz, 3H), 0.84 (d, J¼6.1 Hz,
3H), 0.88–1.07 (m, 2H), 1.15–1.34 (m, 4H), 1.39–1.80 (m,
3H), 2.43 (s, 3H), 2.72–3.04 (m, 2H), 3.15 (t, J¼7.4 Hz,
2H), 3.25–3.35 (m, 2H), 3.50–3.80 (large s, 154H), 3.79
(s, 3H), 4.47–4.65 (m, 3H), 4.89–4.99 (m, 1H), 5.83 (s,
1H), 6.52 (s, 1H), 7.13 (dt, J¼1.7, 7.4 Hz, 1H), 7.27–7.37
(m, 3H), 7.50 (dd, J¼1.3, 8.0 Hz, 1H), 7.63–7.74 (m, 3H);
13C NMR (CDCl3, Me4Si) d ꢁ3.79, 8.79, 14.51, 20.70,
21.37, 21.46, 23.17, 24.92, 32.32, 41.12, 47.54, 49.00,
49.36, 52.23, 55.43, 70.07–70.44, 122.55, 127.09, 127.33,
128.85, 129.45, 129.61, 130.78, 132.49, 136.84, 137.07,
137.13, 143.08, 166.99.
Br
O
Si
N
O2
PEG
N
Ts
S
CO2Me
O
Prepared according to the general procedure with 1e
(500 mg, 0.11 mmol) to afford 460 mg (85%) of the title
compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.10 (s, 6H), 0.39–0.49 (m,
2H), 0.86–1.01 (m, 2H), 1.12–1.28 (m, 2H), 1.48–1.60 (m,
2H), 2.41 (s, 3H), 2.62–2.79 (m, 2H), 3.12 (t, J¼7.0 Hz,
2H), 3.23–3.30 (m, 2H), 3.50–3.75 (large s, 154H), 3.57
(s, 3H), 4.58 (d, J¼17.2 Hz, 1H), 4.86 (d, J¼17.2 Hz, 1H),
5.86 (s, 1H), 6.20 (s, 1H), 6.26 (s, 1H), 6.33–6.38 (m, 2H),
7.06 (dt, J¼1.5, 7.4 Hz, 1H), 7.20–7.56 (m, 6H), 7.68 (d,
J¼8.0 Hz, 2H); 13C NMR (CDCl3, Me4Si) d ꢁ3.82, 8.38,
14.42, 20.65, 21.47, 32.33, 47.59, 48.45, 49.04, 49.49,
52.09, 54.91, 70.10–70.47, 109.84, 110.78, 122.43, 127.07,
128.61, 129.63, 129.75, 130.04, 130.12, 132.32, 136.71,
136.81, 136.94, 142.83, 143.12, 151.12, 165.31.
4.3. General procedure for the alkylation of
non-supported b-aminoesters
A mixture of sulfonamide (1 equiv), 2-bromobenzyl bro-
mide or a related reagent (1.2 equiv), and K2CO3 (10 equiv)
in CH3CN was heated to reflux for 6 h. After concentration,
the residue was diluted in ether, washed successively with
a solution of 5% KHSO4 and brine, dried over MgSO4,
and evaporated. Purification by silica gel chromatography
(hexane/Et2O) afforded the corresponding N-2-bromo-
benzyl-b-aminoester.
4.2.6. Methyl 2-(N-2-bromobenzyl-(PEG 3400-SES-
amido)(thiofuran-2-yl)methyl)acrylate (2f).
4.3.1. Methyl 2-((N-2-bromobenzyl-2-(trimethylsilyl)-
ethan-3-ylsulfonamido)(phenyl)methyl)acrylate (2h).
Br
O
Si
N
O2
PEG
N
Ts
S
Br
CO2Me
Si
N
S
S
O2
CO2Me
Prepared according to the general procedure with 1f
(900 mg, 0.20 mmol) to afford 730 mg (75%) of the title
compound.
Prepared according to the general procedure with 1h
(100 mg, 0.28 mmol), 2-bromobenzyl bromide (85 mg,
0.34 mmol), and K2CO3 (390 mg, 2.83 mmol) to afford
118 mg (80%) of the title compound after silica gel chroma-
tography (hexane/Et2O, 8/2).
1H NMR (CDCl3, Me4Si) d ꢁ0.16 (s, 6H), 0.31–0.49 (m,
2H), 0.83–0.95 (m, 2H), 1.06–1.26 (m, 2H), 1.42–1.60 (m,
2H), 2.39 (s, 3H), 2.47–2.73 (m, 2H), 3.04–3.14 (m, 2H),
3.21–3.29 (m, 2H), 3.50–3.75 (large s, 154H), 3.54 (s,
3H), 4.61 (d, J¼17.5 Hz, 1H), 4.74 (d, J¼17.5 Hz, 1H),
1H NMR (CDCl3, Me4Si) d ꢁ0.05 (s, 9H), 0.95–1.05 (m,
2H), 2.55–2.77 (m, 2H), 3.61 (s, 3H), 4.78 (s, 2H), 5.90 (d,

10462
P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
J¼1.48 Hz, 1H), 6.17 (s, 1H), 6.46 (s, 1H), 7.04 (dt, J¼1.48,
7.6 Hz, 1H), 7.16–7.45 (m, 7H); 13C NMR (CDCl3, Me4Si)
d ꢁ2.05, 10.20, 50.35, 50.62, 52.04, 62.07, 122.63, 127.08,
128.19, 128.64, 128.68, 129.33, 130.29, 132.38, 136.34,
137.34, 139.02, 166.08; HPLC tR¼14.50 min; ESIMS
m/z 524.2 (M+H)+ (monoisotopic); HRMS calcd for
C23H31BrNO4SSi 524.0926 (monoisotopic), found
524.0952; Rf (hexane/Et2O, 8/2) 0.31.
116.98 (J¼24.8 Hz), 128.34, 128.42, 128.78, 129.39,
133.40 (J¼7.9 Hz), 138.95 (J¼7.4 Hz), 139.10, 161.85
(J¼246.6 Hz), 166.00; HPLC tR¼14.58 min; ESIMS
m/z 541.9 (M+H)+ (monoisotopic); HRMS calcd for
C23H30BrFNO4SSi 542.0832 (monoisotopic), found
542.0825; Rf (hexane/Et2O, 8/2) 0.39.
4.3.4. Methyl 2-((N-2-bromobenzyl-2-(trimethylsilyl)-
ethan-3-ylsulfonamido)(3,5-dimethoxyphenyl)methyl)-
acrylate (2k).
4.3.2. Methyl 2-((N-2-bromo-5-methoxy-benzyl-2-(tri-
methylsilyl)ethan-3-ylsulfonamido)(phenyl)methyl)acryl-
ate (2i).
Br
MeO
Si
N
S
O2
CO2Me
Br
MeO
Si
N
S
OMe
O2
CO2Me
Prepared according to the general procedure with 1k (75 mg,
0.18 mmol) and 2-bromobenzyl bromide (55 mg,
0.22 mmol) to afford 80 mg (76%) of the title compound
after silica gel chromatography (hexane/Et2O, 8/2).
Prepared according to the general procedure with 1i (75 mg,
0.21 mmol) and 5-methoxy-2-bromobenzyl bromide
(71 mg, 0.25 mmol) to afford 75 mg (64%) of the title com-
pound after silica gel chromatography (hexane/Et2O, 85/15).
1H NMR (CDCl3, Me4Si) d ꢁ0.04 (s, 9H), 0.98–1.08 (m,
2H), 2.64–2.85 (m, 2H), 3.61 (s, 3H), 3.75 (s, 6H), 4.77 (s,
2H), 5.90 (s, 1H), 6.12 (s, 1H), 6.30 (t, J¼2.2 Hz, 1H),
6.43 (s, 1H), 6.50 (d, J¼2.2 Hz, 2H), 7.04 (dt, J¼1.5,
8.0 Hz, 1H), 7.21 (t, J¼7.7 Hz, 1H), 7.41 (d, J¼8.0 Hz,
1H), 7.48 (d, J¼8.0 Hz, 1H); 13C NMR (CDCl3, Me4Si)
d ꢁ2.10, 10.29, 50.19, 50.46, 52.11, 55.32, 61.61,
99.92, 106.92, 122.49, 127.00, 128.62, 129.38, 130.22,
132.27, 136.40, 138.81, 139.65, 160.87, 166.00; HPLC
tR¼14.39 min; ESIMS m/z 584.1 (M+H)+ (monoisotopic);
HRMS calcd for C25H34BrNO6SSi 583.1059 (monoiso-
topic), found 583.1066; Rf (hexane/Et2O, 7/3) 0.22.
1H NMR (CDCl3, Me4Si) d ꢁ0.05 (s, 9H), 0.96–1.04 (m,
2H), 2.56–2.80 (m, 2H), 3.61 (s, 3H), 3.75 (s, 3H), 4.74 (s,
2H), 5.87 (d, J¼1.5 Hz, 1H), 6.19 (s, 1H), 6.45 (s, 1H),
6.61 (dd, J¼3.0, 8.9 Hz, 1H), 6.97 (d, J¼3.0 Hz, 1H),
7.25–7.40 (m, 6H); 13C NMR (CDCl3, Me4Si) d ꢁ1.98,
10.18, 50.29, 50.47, 52.04, 55.38, 61.98, 112.17, 115.02,
115.38, 128.22, 128.57, 128.72, 129.58, 132.91, 137.32,
137.53, 139.03, 158.81, 166.14; HPLC tR¼14.56 min;
ESIMS m/z 554.3 (M+H)+ (monoisotopic); HRMS calcd
for C24H33BrNO5SSi 554.1032 (monoisotopic), found
554.1039; Rf (hexane/Et2O, 7/3) 0.33.
4.4. General procedure for the Heck reaction on
PEG 3400-supported substrate
4.3.3. Methyl 2-((N-2-bromo-5-fluoro-benzyl-2-(tri-
methylsilyl)ethan-3-ylsulfonamido)(phenyl)methyl)acryl-
ate (2j).
To a mixture of PEG 3400-supported N-2-bromobenzyl-
b-aminoester (1 equiv) and Pd(OAc)2 (0.1 equiv) in DMF
(1 mL/50 mg de PEG) was added (n-octyl)3N (3 equiv).
The solution was stirred at room temperature for few
minutes under nitrogen. The mixture was then heated at
80 ꢀC for 6 h, filtered over Celite, and precipitated in ether.
After filtration, the solid was dried in vacuo to yield the
corresponding benzazepine.
F
Br
Si
N
S
O2
CO2Me
4.4.1. 2-(PEG 3400-SES)-3-phenyl-2,3-dihydro-1H-benzo-
[c]azepine-4-carboxylic acid methyl ester (3a).
Prepared according to the general procedure with 1j (75 mg,
0.21 mmol) and 5-fluoro-2-bromobenzyl bromide (68 mg,
0.25 mmol) to afford 93 mg (81%) of the title compound
after silica gel chromatography (hexane/Et2O, 85/15).
O
Si
N
O2
1H NMR (CDCl3, Me4Si) d ꢁ0.03 (s, 9H), 0.98–1.06 (m,
2H), 2.61–2.86 (m, 2H), 3.65 (s, 3H), 4.74 (s, 2H), 5.83 (d,
J¼1.5 Hz, 1H), 6.22 (s, 1H), 6.46 (s, 1H), 6.75 (dt, J¼3.0,
7.7 Hz, 1H), 7.13 (dd, J¼3.0, 7.7 Hz, 1H), 7.21–7.39 (m,
6H); 13C NMR (CDCl3, Me4Si) d ꢁ2.06, 10.22, 50.23,
52.18, 61.75, 115.79 (J¼22.8 Hz), 116.07 (J¼3.1 Hz),
PEG
N
Ts
S
CO2Me
Prepared according to the general procedure with 2a
(500 mg, 0.10 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), and

P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
10463
(n-octyl)3N (222 mg, 0.63 mmol) to afford 410 mg (81%) of
the title compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.27 (s, 3H), ꢁ0.26 (s, 3H),
0.24–0.40 (m, 2H), 0.68–0.77 (m, 2H), 0.96–1.14 (m, 2H),
1.43–1.60 (m, 2H), 2.29 (s, 3H), 2.44 (s, 3H), 2.27–2.56
(m, 2H), 3.10–3.22 (m, 2H), 3.25–3.35 (m, 2H), 3.55–3.75
(large s, 154H), 4.12 (d, J¼17.4 Hz, 1H), 4.47 (d,
J¼17.4 Hz, 1H), 6.41 (s, 1H), 7.05–7.55 (m, 10H), 7.71
(d, J¼8.2 Hz, 2H), 8.02 (s, 1H).
1H NMR (CDCl3, Me4Si) d ꢁ0.26 (s, 3H), ꢁ0.25 (s, 3H),
0.24–0.32 (m, 2H), 0.68–0.76 (m, 2H), 1.00–1.14 (m, 2H),
1.46–1.58 (m, 2H), 2.44 (s, 3H), 2.27–2.56 (m, 2H), 3.11
(t, J¼7.9 Hz, 2H), 3.27–3.33 (m, 2H), 3.55–3.75 (large s,
154H), 3.70 (s, 3H), 4.14 (d, J¼16.8 Hz, 1H), 4.46 (d,
J¼16.8 Hz, 1H), 6.43 (s, 1H), 7.22–7.44 (m, 10H), 7.54–
7.60 (m, 1H), 7.72 (d, J¼8.3 Hz, 2H), 8.02 (s, 1H); 13C
NMR (CDCl3, Me4Si) d ꢁ4.07, 8.35, 14.32, 20.59, 21.50,
32.27, 47.37, 47.56, 49.06, 49.83, 52.57, 61.02, 70.09–
71.03, 127.12, 128.04, 128.29, 128.63, 128.69, 129.64,
130.30, 132.02, 132.05, 135.27, 136.81, 140.40, 140.67,
140.83, 143.12, 167.26.
4.4.4. 2-(PEG 3400-SES)-3-(4-methyloxycarbonylphenyl)-
2,3-dihydro-1H-benzo[c]azepine-4-carboxylic acid
methyl ester (3d).
O
Si
N
O2
PEG
N
Ts
S
CO2Me
4.4.2. 2-(PEG 3400-SES)-3-(3,5-dimethoxyphenyl)-2,3-
dihydro-1H-benzo[c]azepine-4-carboxylic acid methyl
ester (3b).
CO2Me
Prepared according to the general procedure with 2d
(500 mg, 0.10 mmol) to afford 370 mg (81%) of the title
compound.
O
Si
N
O2
PEG
N
Ts
S
CO2Me
OMe
1H NMR (CDCl3, Me4Si) d ꢁ0.30 (s, 6H), 0.19–0.29 (m,
2H), 0.62–0.76 (m, 2H), 0.94–1.12 (m, 2H), 1.40–1.58 (m,
2H), 2.39 (s, 3H), 2.24–2.51 (m, 2H), 3.01–3.15 (m, 2H),
3.21–3.29 (m, 2H), 3.50–3.80 (large s, 154H), 3.88 (s, 3H),
4.03 (d, J¼17.4 Hz, 1H), 4.41 (d, J¼17.4 Hz, 1H), 6.40 (s,
1H), 7.16–7.59 (m, 8H), 7.66 (d, J¼7.4 Hz, 2H), 7.96–8.04
(m, 3H); 13C NMR (CDCl3, Me4Si) d ꢁ3.77, 8.34, 14.27,
20.55, 21.47, 32.30, 46.91, 47.44, 47.55, 49.01, 49.90,
52.18, 52.61, 60.73, 70.05–70.98, 127.10, 128.46, 128.59,
128.73, 129.63, 129.81, 129.96, 130.53, 131.31, 135.27,
136.82, 140.05, 141.21, 143.12, 145.76, 166.59, 166.98.
MeO
Prepared according to the general procedure with 2b
(500 mg, 0.10 mmol) to afford 380 mg (79%) of the title
compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.29 (s, 3H), ꢁ0.28 (s, 3H),
0.21–0.29 (m, 2H), 0.64–0.74 (m, 2H), 0.97–1.09 (m, 2H),
1.43–1.61 (m, 2H), 2.23–2.40 (m, 2H), 2.44 (s, 3H), 3.05–
3.13 (m, 2H), 3.25–3.31 (m, 2H), 3.55–3.75 (large s,
154H), 3.71 (s, 3H), 3.71 (s, 6H), 4.20 (d, J¼17.4 Hz, 1H),
4.45 (d, J¼17.4 Hz, 1H), 6.32 (s, 1H), 6.38 (t, J¼2 Hz,
1H), 6.53 (d, J¼2.0 Hz, 2H), 7.19–7.56 (m, 6H), 7.69 (d,
J¼8.0 Hz, 2H), 7.95 (s, 1H); 13C NMR (CDCl3, Me4Si)
d ꢁ4.09, 8.36, 14.33, 20.60, 21.49, 32.36, 47.45, 47.57,
49.07, 49.83, 52.61, 55.37, 60.96, 70.10–71.07, 99.81,
106.97, 127.14, 128.25, 128.65, 129.58, 129.65, 130.31,
131.85, 132.05, 135.27, 136.86, 140.39, 140.55, 143.14,
160.89, 167.24.
4.4.5. 2-(PEG 3400-SES)-3-furan-2-yl-2,3-dihydro-1H-
benzo[c]azepine-4-carboxylic acid methyl ester (3e).
O
Si
N
O2
PEG
N
Ts
S
CO2Me
O
4.4.3. 2-(PEG 3400-SES)-3-(3-acyloxyphenyl)-2,3-
dihydro-1H-benzo[c]azepine-4-carboxylic acid methyl
ester (3c).
Prepared according to the general procedure with 2e
(300 mg, 0.063 mmol) to afford 250 mg (86%) of the title
compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.15 (s, 3H), ꢁ0.14 (s, 3H),
0.30–0.53 (m, 2H), 0.80–0.96 (m, 2H), 1.10–1.30 (m, 2H),
1.46–1.60 (m, 2H), 2.44 (s, 3H), 2.65–2.80 (m, 2H), 3.10–
3.30 (m, 4H), 3.27–3.33 (m, 2H), 3.50–3.80 (large s,
154H), 3.76 (s, 3H), 4.28 (d, J¼16.7 Hz, 1H), 4.57 (d,
J¼16.7 Hz, 1H), 6.22 (d, J¼4.2 Hz, 1H), 6.34–6.40 (m,
2H), 7.25–7.60 (m, 7H), 7.72 (d, J¼8.3 Hz, 2H), 7.91 (s,
1H); 13C NMR (CDCl3, Me4Si) d ꢁ3.94, 8.56, 14.38,
20.61, 21.47, 32.24, 47.02, 47.58, 49.03, 49.84, 52.55,
55.74, 70.08–71.00, 110.53, 110.88, 127.11, 128.09,
O
Si
N
O2
PEG
N
Ts
S
CO2Me
OAc
Prepared according to the general procedure with 2c
(500 mg, 0.10 mmol) to afford 400 mg (83%) of the title
compound.

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P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
128.23, 129.63, 129.75, 130.34, 131.60, 135.37, 136.83,
140.47, 140.72, 143.12, 152.56, 166.97.
(100 mg/mg de Pd(OAc)2) and finely powdered K2CO3
(3 equiv). The resulting mixture was heated at 80 ꢀC with
strong stirring for 12 h. After cooling, the crude is solubi-
lized in CH2Cl2 and precipitated in ether. After filtration,
the filtrate was concentrated to yield the corresponding
benzazepine.
4.4.6. 2-(PEG 3400-SES)-3-thiofuran-2-yl-2,3-dihydro-
1H-benzo[c]azepine-4-carboxylic acid methyl ester (3f).
4.5.1. 3-Phenyl-2-(2-(trimethylsilanyl)ethylsulfonyl)-2,3-
dihydro-1H-benzo[c]azepine-4-carboxylic acid methyl
ester (3h).
O
Si
N
O2
PEG
N
Ts
S
CO2Me
S
Prepared according to the general procedure with 2f
(500 mg, 0.10 mmol) to afford 380 mg (79%) of the title
compound.
Si
N
O2
S
CO2Me
1H NMR (CDCl3, Me4Si) d ꢁ0.24 (s, 6H), 0.19–0.29 (m,
2H), 0.62–0.76 (m, 2H), 0.94–1.12 (m, 2H), 1.40–1.58 (m,
2H), 2.42 (s, 3H), 2.43–2.57 (m, 2H), 3.01–3.15 (m, 2H),
3.21–3.29 (m, 2H), 3.50–3.80 (large s, 154H), 3.88 (s,
3H), 4.32 (d, J¼17.2 Hz, 1H), 4.52 (d, J¼17.2 Hz, 1H),
6.56 (s, 1H), 6.87–6.97 (m, 2H), 7.18–7.54 (m, 7H), 7.68
(d, J¼7.5 Hz, 2H), 7.89 (s, 1H); 13C NMR (CDCl3, Me4Si)
d ꢁ4.17, 8.30, 14.18, 20.44, 21.33, 32.16, 47.34, 47.42,
48.88, 49.89, 52.48, 56.64, 69.92–70.32, 126.59, 126.64,
126.96, 127.82, 128.04, 128.30, 129.49, 130.23, 131.61,
131.81, 135.18, 136.67, 142.98, 144.11, 166.96.
Prepared according to the general procedure with 2h (29 mg,
0.055 mmol), Pd(OAc)2 (1.2 mg, 5.5 mmol), PEG-OH
(120 mg), and K2CO3 (25 mg, 0.18 mmol) to afford 21 mg
(86%) of the title compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.20 (s, 9H), 0.70–0.80 (m,
2H), 2.32–2.58 (m, 2H), 3.71 (s, 3H), 4.15 (d, J¼17.0 Hz,
1H), 4.45 (dd, J¼17.0, 1.5 Hz, 1H), 6.45 (s, 1H), 7.23–
7.44 (m, 8H), 7.55–7.59 (m, 1H), 8.02 (s, 1H); 13C NMR
(CDCl3, Me4Si) d ꢁ2.97, 9.07, 46.70, 49.32, 51.88, 60.35,
127.35, 127.53, 127.97, 128.00, 131.37, 131.41, 134.54,
139.80, 140.02, 140.20, 166.66; HPLC tR¼13.92 min;
ESIMS m/z 444.2 (M+H)+, 887.5 (2M+H)+; HRMS calcd
for C23H30NO4SSi 444.1665, found 444.1677.
4.4.7. 2-(PEG 3400-SES)-3-(2-isobutyl)-2,3-dihydro-1H-
benzo[c]azepine-4-carboxylic acid methyl ester (3g).
4.5.2. 8-Methoxy-3-phenyl-2-(2-(trimethylsilanyl)ethyl-
sulfonyl)-2,3-dihydro-1H-benzo[c]azepine-4-carboxylic
acid methyl ester (3i).
O
Si
N
PEG
N
Ts
S
CO2Me
O2
MeO
Prepared according to the general procedure with 2g
(500 mg, 0.10 mmol) to afford 410 mg (85%) of the title
compound.
Si
N
1H NMR (CDCl3, Me4Si) d ꢁ0.31 (s, 3H), ꢁ0.29 (s, 3H),
0.20–0.27 (m, 2H), 0.64–0.76 (m, 2H), 0.95 (d, J¼6.5 Hz,
3H), 1.06 (d, J¼6.5 Hz, 3H), 1.13–1.30 (m, 2H), 1.40–
1.72 (m, 4H), 2.09–2.23 (m, 1H), 2.42 (s, 3H), 2.25–2.47
(m, 2H), 3.06–3.20 (m, 2H), 3.24–3.32 (m, 2H), 3.50–3.75
(large s, 154H), 3.84 (s, 3H), 4.45 (d, J¼17.0 Hz, 1H),
4.69 (d, J¼17.0 Hz, 1H), 5.16–5.22 (m, 1H), 7.10–7.56
(m, 6H), 7.64 (s, 1H), 7.69 (d, J¼8.3 Hz, 2H); 13C NMR
(CDCl3, Me4Si) d ꢁ4.09, 8.22, 14.31, 20.59, 21.48, 23.61,
23.77, 32.34, 43.79, 46.56, 47.55, 49.05, 49.22, 52.44,
56.28, 70.09–71.04, 127.13, 128.29, 128.62, 128.69,
129.64, 130.08, 132.52, 134.75, 135.35, 136.85, 138.08,
139.61, 143.12, 167.55.
S
CO2Me
O2
Prepared according to the general procedure with 2i
(40 mg, 0.072 mmol) to afford 29 mg (85%) of the title
compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.16 (s, 9H), 0.71–0.85 (m,
2H), 2.35–2.70 (m, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 4.09 (d,
J¼17.3 Hz, 1H), 4.41 (dd, J¼17.3, 1.7 Hz, 1H), 6.43 (s,
1H), 6.77 (d, J¼2.6 Hz, 1H), 6.90 (dd, J¼2.6, 8.3 Hz, 1H),
7.27–7.44 (m, 5H), 7.50 (d, J¼8.5 Hz, 1H), 7.99 (s, 1H);
13C NMR (CDCl3, Me4Si) d ꢁ2.25, 9.83, 47.54, 50.01,
52.39, 55.53, 60.92, 113.14, 114.36, 124.88, 127.99,
128.67, 128.72, 137.31, 140.54, 140.87, 142.53, 161.13,
167.54; HPLC tR¼13.53 min; ESIMS m/z 474.1 (M+H)+,
947.6 (2M+H)+; HRMS calcd for C24H32NO5SSi
474.1770, found 474.1757.
4.5. General procedure for the Heck reaction with PEG
as solvent
To N-2-bromobenzyl-b-aminoester (1 equiv) and Pd(OAc)2
(0.1 equiv) was added a mixture of PEG 3400-OH

P. Ribieꢀre et al. / Tetrahedron 62 (2006) 10456–10466
10465
4.5.3. 8-Fluoro-3-phenyl-2-(2-(trimethylsilanyl)ethylsul-
fonyl)-2,3-dihydro-1H-benzo[c]azepine-4-carboxylic
acid methyl ester (3j).
Pd(OAc)2) was added a base (K2CO3 or Oct3N (3 equiv)).
The resulting mixture was heated at 80 ꢀC with strong
stirring for 12 h. The mixture was diluted with AcOEt, and
the organic layer was washed with water and brine, dried
over MgSO4, filtered, and evaporated to give the crude
product, which was then analyzed by 1H NMR.
F
References and notes
Si
N
S
CO2Me
ꢁ
1. Encyclopedia of Catalysis, 1st ed.; Horvath, I. T., Ed.; Wiley:
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O2
2. Applied Homogeneous Catalysis with Organometallic Com-
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Prepared according to the general procedure with 2j
(20 mg, 0.036 mmol) to afford 14 mg (82%) of the title
compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.15 (s, 9H), 0.70–0.88 (m,
2H), 2.41–2.67 (m, 2H), 3.71 (s, 3H), 4.11 (d, J¼17.2 Hz,
1H), 4.42 (dd, J¼17.2, 1.8 Hz, 1H), 6.42 (s, 1H), 6.98 (dd,
J¼2.7, 8.6 Hz, 1H), 7.08 (dt, J¼2.7, 8.0 Hz, 1H), 7.28–
7.41 (m, 5H), 7.55 (dd, J¼5.6, 8.6 Hz, 1H), 7.98 (s, 1H);
13C NMR (CDCl3, Me4Si) d ꢁ2.24, 9.90, 47.15, 50.13,
52.59, 61.05, 115.03 (d, J¼21.5 Hz), 115.89 (d, J¼
22.2 Hz), 128.20, 128.48 (d, J¼3.6 Hz), 128.62, 128.79,
131.35, 131.33 (d, J¼2.9 Hz), 137.39 (d, J¼8.7 Hz),
139.53, 140.53, 143.45 (d, J¼7.3 Hz), 163.27 (d, J¼
255.1 Hz), 167.20; HPLC tR¼14.08 min; ESIMS m/z
462.2 (M+H)+; HRMS calcd for C23H29FNO4SSi
462.1571, found 462.1611.
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Si
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CO2Me
OMe
O2
MeO
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Prepared according to the general procedure with 2k (20 mg,
0.034 mmol) to afford 14 mg (81%) of the title compound.
1H NMR (CDCl3, Me4Si) d ꢁ0.20 (s, 9H), 0.67–0.80 (m,
2H), 2.25–2.59 (m, 2H), 3.74 (s, 3H), 3.80 (s, 6H), 4.23 (d,
J¼17.0 Hz, 1H), 4.49 (dd, J¼1.7, 17.0 Hz, 1H), 6.34 (s,
1H), 6.41 (t, J¼2.2 Hz, 1H), 6.56 (d, J¼2.2 Hz, 2H), 7.22–
7.46 (m, 3H), 7.51–7.59 (m, 1H), 7.99 (s, 1H); 13C NMR
(CDCl3, Me4Si) d ꢁ2.29, 9.77, 47.46, 50.00, 52.59, 55.38,
60.98, 99.85, 106.99, 128.18, 128.66, 130.25, 131.90,
132.09, 135.22, 140.47, 140.57, 143.21, 160.91, 167.29;
HPLC tR¼13.56 min; ESIMS m/z 504.2 (M+H)+; HRMS
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