Synthesis of substituted 2,3-dihydro-1H-2-benzazepines and 1,2-dihydroisoquinolines using an isomerization-ring-closing metathesis strategy: Scope and limitations

Article abstract of DOI:10.1002/ejoc.200700473

An isomerization-ring-closing metathesis (RCM) approach was used for the synthesis of substituted 2,3-dihydro-1H-2-benzazepines and 1,2- dihydroisoquinolines. The 2,3-dihydro-1H-2-benzazepines were obtained from N-protected N-{2-[(1E)-prop-1-en-1-yl]benzy

Full text of DOI:10.1002/ejoc.200700473

FULL PAPER
DOI: 10.1002/ejoc.200700473
Synthesis of Substituted 2,3-Dihydro-1H-2-benzazepines and
1,2-Dihydroisoquinolines Using an Isomerization-Ring-Closing Metathesis
Strategy: Scope and Limitations
Jenny-Lee Panayides,[a] Rakhi Pathak,[a] Charles B. de Koning,[a] and
Willem A. L. van Otterlo*[a]
Keywords: Isomerization / Ring-closing metathesis / Benzazepines / Dihydroisoquinolines
An isomerization-ring-closing metathesis (RCM) approach
was used for the synthesis of substituted 2,3-dihydro-1H-2-
benzazepines and 1,2-dihydroisoquinolines. The 2,3-dihy-
dro-1H-2-benzazepines were obtained from N-protected N-
{2-[(1E)-prop-1-en-1-yl]benzyl}prop-2-en-1-amines by RCM
reaction. A double isomerisation reaction on the N-protected
N-(2-allylbenzyl)prop-2-en-1-amines and a subsequent RCM
afforded the substituted 1,2-dihydroisoquinolines. Finally, a
selective isomerization of the allylamine group of N-pro-
tected N-(2-allylbenzyl)prop-2-en-1-amines by [RuClH(CO)-
(PPh3)3], followed by RCM, did not afford the expected 2,5-
dihydro-1H-2-benzazepines but afforded products resulting
from deallylation and isomerization of the starting material.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
antibacterial,[2] and compound 4, a potent histamine H3 re-
ceptor antagonist.[3]
Introduction
Benzazepines 1 as possible pharmaceutical scaffolds have
caught the attention of the medicinal chemistry community.
Benzazepine examples include compounds such as caps-
azepine 2,[1] a commercially available competitive agonist
for the vanilloid receptor (VR1) used in the treatment of
neuropathic pain (Figure 1), compound 3, a Gram-positive
Tetrahydroisoquinolines 5 (THIQs) and, of particular
interest to us, 1,2-dihydroisoquinolines 6 (DHIQs), have
also been incorporated into pharmaceutical compounds.
Examples with the latter skeleton include a number of anti-
cancer 1,2-dihydroellipticines 7,[4] as well as some DHIQ
derivatives of KNI-279, a potent HIV protease inhibitor
(see 8 in Figure 2).[5]
Figure 1. Benzazepine-containing compounds.
Figure 2. 1,2-DHIQ-containing compounds.
[a] Molecular Sciences Institute, School of Chemistry, University
of the Witwatersrand,
The use of benzazepines with an unsaturation in the het-
erocyclic ring, such as 2,3-dihydro-1H-2-benzazepine (9) or
2,5-dihydro-1H-2-benzazepine (10), have however seen very
PO Wits, 2050, Johannesburg, South Africa
Fax: +27-11-717-6749
E-mail: Willem.vanOtterlo@wits.ac.za
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little synthetic application (Figure 3). In addition, com- strate 15, using similar conditions, only DHIQ 14c was iso-
pounds such as 9 and 10 have not seen much pharmaceuti- lated, due to the competitive isomerization of the allyl
cal investigation, perhaps due to the lack of general syn- group prior to RCM.
thetic methods for their synthesis. This is surprising as the
Our research group has been investigating the application
availability of an alkene in the heterocycle would also offer of isomerization reactions followed by RCM[9] as a strategy
opportunities for the further functionalization of the benz- to afford substituted benzannulated heterocycles. In this
azepine skeleton. Of the few examples we could find, work way we have successfully synthesized a range of benzo-fused
by Kogen and co-workers described the synthesis of a small heterocycles.[10] Recently we communicated the synthesis of
set of substituted 2,3-dihydro-1H-benzazepines (Fig- a solitary 2,3-dihydro-1H-2-benzazepine and 1,2-dihydro-
ure 3).[6] This group used a ring closing metathesis (RCM) isoquinoline by way of an isomerisation-RCM strategy.[11]
strategy by reaction of a styrene and an allylamine, as In this paper we wish to demonstrate that this strategy, il-
shown in the conversion of compound 11 to afford 12. lustrated by the retrosyntheses shown in Figure 5, is firstly
Compounds of this type were then tested as acetylcho- amenable to the synthesis of a number of protected 2,3-
linesterase (AChE) and serotonin (SERT) dual inhibitors. dihydro-1H-2-benzazepines (i.e. 18Ǟ17). In addition, the
In addition, Dieltiens and Stevens have recently reported a 1,2-dihydroisoquinoline skeleton 19 could also be accessed
ring-closing enyne metathesis-cross metathesis approach to by the RCM of substrate 20. Finally, we describe attempts
afford 1-phosphonylated benzazepines.[7]
towards the synthesis of a regioisomeric 2,5-dihydro-1H-2-
benzazepine (i.e. 22Ǟ21) by the selective isomerization of
the N-allyl group prior to RCM. In this paper we will also
discuss the scope and limitations of the isomerisation-RCM
approach towards the benzannulated compounds of general
structure 17, 19 and 21 (Figure 5). This work was per-
formed using the readily prepared 3-isopropoxy-4-methoxy
compound 23 (Scheme 1) as described in some of our pre-
vious work.[10]
Figure 3. Kogen’s RCM approach to 2,3-dihydro-1H-benzazepines.
The application of RCM to the synthesis of 1,2-DHIQs
has also seen little work reported in the literature. Bennasar
and co-workers were however able to synthesize a small li-
brary of simple DHIQs by an interesting sequential N-acyl-
amide methylenation followed by RCM (13Ǟ14, Fig-
ure 4).[8] However, when the same workers attempted to
synthesize the 2,5-dihydro-1H-2-benzazepine 16 from sub-
Figure 5. Retrosynthetic analysis of target structures.
Results and Discussion
Synthesis of 2,3-Dihydro-1H-2-benzazepines
For the synthesis of the 2,3-dihydro-benzazepines we
needed to synthesize the general diene substrate 18 which
contained a styrene functionality. To this end we isomerized
the allyl group of the substituted benzaldehyde 23 to the
thermodynamically preferred styrene 24 (mainly E)
with [RuClH(CO)(PPh3)3],[12] as described previously
(Scheme 1).[10c] Treatment of benzaldehyde 24 with allyl-
amine, followed by a sodium borohydride reduction, then
afforded amine 25 in good yield. At this point the amine
was protected with a tosyl- (26a), benzylsulfonyl- (26b) and
acetyl-protecting (26c) group to determine if these protect-
ing groups would have an effect on the subsequent RCM
reaction.
Figure 4. Bennesar’s approach to 1,2-DHIQs.
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Benzazepine and Isoquinoline Derivatives by RCM-Type Reaction
HRMS on these mixtures provided tentative evidence of the
desired ring-closed products but we were unable to obtain
pure desired unsaturated benzazepines 33a and 33b. A pos-
sible reason for these poor results is that the highly hindered
and electron-rich diphenyl styrene functionality is not a
good alkene partner for this metathesis reaction.[16]
Furthermore, the steric crowding at the styrene is likely fur-
ther exacerbated by peri interactions between the isopro-
pyloxy and phenyl groups on substrate 32.
Scheme 1. (i) [RuClH(CO)(PPh3)3] (2%), toluene, 80 °C, quantita-
tive, see ref.[10c]; (ii) allylamine (1.4 equiv.), room temp., 22 h; (iii)
NaBH4 (1.2 equiv.), MeOH, 0 °C, 2 h, 89% over two steps; (iv) 26a
R = Ts, NEt3 (1.4 equiv.), tosyl chloride (1.2 equiv.), CH2Cl2, 0 °C
to room temp., 3 h, 77%; 26b R = SO2Bn, NEt3 (2.5 equiv.), ben-
zylsulfonyl chloride (1.1 equiv.), CH2Cl2, room temp., 18 h, 29%;
26c R = Ac, acetic anhydride (1.5 equiv.), pyridine (2.5 equiv.),
room temp., 3 h, 72%; (v) for 27a, 5% 28, 60 °C, 20 h, 82%; for
27b, 10% 28, 80 °C, 20 h, 39%; for 27c, complex mixture.
The RCM reaction was then performed on substrates
26a–c with varying success (Scheme 1).[13] The treatment of
26a (R = Ts) with 5% Grubbs second-generation catalyst
28 gratifyingly afforded the corresponding tosyl-protected
2,3-dihydro-1H-2-benzazepine 27a in good yield (82%).
However, the RCM reactions on substrate 26b gave less
than desirable results. Even doubling the catalyst loading
for 26b resulted in a poor yield of the desired benzazepine
27b (39%). Finally, the RCM reactions of substrate 26c
only gave a complex mixture of products, which we were
unable to purify and identify. This was probably due to
competitive isomerizations and deallylation reactions as
discussed later in the paper.
Scheme 2. (i) Allylamine (1.4 equiv.), room temp., 21 h; (ii) NaBH4
(1.2 equiv.), MeOH, 0 °C, 2 h, quantitative over 2 steps; (iii) 32a R
= Ts, NEt3 (1.4 equiv.), tosyl chloride (1.2 equiv.), CH2Cl2, 0 °C to
room temp., 3 h, 71%; 32b R = SO2Bn, NEt3 (2.5 equiv.), benzyl-
sulfonyl chloride (1.1 equiv.), CH2Cl2, room temp., 4 h, 45%; (iv)
5–8% 28, 60–80 °C, 22–23 h, complex mixtures.
Synthesis of 1,2-Dihydroisoquinolines
At this point in the project we decided to isomerize both
We were also interested in using our approach to access the allyl groups of previously synthesized[10a] compounds
structures containing a phenyl ring directly attached to the 34 with [RuClH(CO)(PPh3)3], to afford products 35 as a
benzylic position located on the heterocyclic ring (see for mixture of E/Z isomers, and then to see if we could perform
instance the AChE and SERT dual inhibitor 29 designed by the metathesis reaction on these substrates (Scheme 3). Ini-
Kogen and co-workers, Scheme 2).[6b] We thus synthesized tially 34a was exposed to [RuClH(CO)(PPh3)3] and NMR
compound 30,[14] in which the styrene was already in place, spectroscopy was used to confirm the success of the iso-
and subjected this compound to the same reductive amin- merisation. However, 35a was not isolated and catalyst 28
ation as described before, to afford allylamine 31 in good was added directly to the reaction mixture to facilitate the
yield. The amine group in this compound was then pro- metathesis process. To our satisfaction, 1,2-DHIQ 36a was
tected with the two sulfonamide protecting groups to afford obtained in a yield of 76% over the two steps, after chroma-
32a and 32b (Scheme 2). We were now in a position to see tographic purification. This methodology proved difficult
if the RCM would tolerate the presence of the sterically to repeat when using substrates 34b and 34c, and so we
hindered, electron-rich styrene functionality. Unfortunately, decided to isolate the intermediate bis-isomerized com-
when substrates 32a and 32b were subjected to metathesis pounds 35b and 35c. Compound 35c (R = Ac) was readily
with catalyst 28 none of the desired cyclized product 33 obtained in high yield (94%) from 34c. However, when 34b
1
was obtained. The H NMR spectra from both substrates (R = SO2Bn) was treated with [RuClH(CO)(PPh3)3], under
indicated the possibility of compounds with two isomerized high temperature conditions (solventless, 135–140 °C), only
allyl groups. This would suggest that the allylamine group compound 37b[17] was obtained, a product from which the
had been isomerized under the reaction conditions.[15] N-allyl group had been cleaved under the reaction condi-
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J.-L. Panayides, R. Pathak, C. B. de Koning, W. A. L. van Otterlo
FULL PAPER
tions.[18] A subsequent reaction at lower temperature (90–
100 °C) did afford the bis-isomerized compound 35b. Un-
fortunately we were unable to obtain the desired 1,2-DHIQ
36b by RCM of 35b, but compound 35c readily afforded
the ring-closed 1,2-DHIQ 36c in a good yield of 78%, when
treated with catalyst 28.
Scheme 4. (i) [RuClH(CO)(PPh3)3], 1 mol-%, toluene, Ar, 80 °C,
18–20 h, 38a 84%, 38b 90%, 38c 77%; (ii) Catalyst 28, 5–10 mol-
%, toluene, 60 °C, 19–25 h, for RCM of 38a, obtained 37a 47%
(note: reaction performed on small scale with 0.5 mol-equiv. of cat-
alyst 28), for RCM of 38b, obtained mixture of 37b and 40b (ratio
ca. 1:1), 58%, for RCM of 38c, complex mixture.
Scheme 3. (i) [RuClH(CO)(PPh3)3], 5 mol-%, toluene, Ar, 90–
110 °C, ca. 20 h, 35a not isolated, 35b 87% (at 135–140 °C only
37b 56%), 35c 94%; (ii) catalyst 28, 5–10 mol-%, toluene, 110 °C,
2–3 h, 36a 76% (over 2 steps), 36b complex mixture, 36c 78%.
Conclusions
In this paper we have demonstrated the applicability of
an isomerization-RCM approach to the synthesis of 2,3-
dihydro-1H-2-benzazepines and 1,2-dihydroisoquinolines.
Attempted Synthesis of 2,5-Dihydro-1H-2-benzazepines
During our investigations into the synthesis of the 1,2- Unfortunately the attempt to synthesize the 2,5-dihydro-
DHIQs it was discovered that the N-allyl group of a com- 1H-2-benzazepines was foiled due to competitive isomeriza-
pounds 34a–c could be isomerized in the presence of the tion and devinylation reactions occurring during the RCM.
aryl allyl group using the catalyst [RuClH(CO)(PPh3)3], as We intend to use the compounds synthesized as potential
long as the reaction temperatures were moderate (ca. scaffolds for biologically active compounds. In addition, we
80 °C). This observation thus presented a promising route will continue to investigate the isomerization-RCM strategy
to the synthesis of the 2,5-dihydro-1H-2-benzazepines. with other catalysts and conditions to afford potentially
Compounds 38a–c were thus synthesized by the treatment interesting benzo-fused heterocycles.
of 34a–c with [RuClH(CO)(PPh3)3] under moderate condi-
tions (1% catalyst, 80 °C in toluene), as depicted in
Experimental Section
Scheme 4. It was noted that above 80 °C the aryl allyl group
also started to isomerize and prolonged heating resulted in
other decomposition products. This particular isomeriza-
tion is of interest as there are very few examples in the lit-
erature where a catalyst demonstrates complete selectivity
1H- and 13C-NMR spectra were recorded either on a Bruker AC-
200, Bruker 300 or Bruker DRX 400 spectrometer at the frequency
indicated. Infrared spectra were recorded on either a Bruker IFS 25
Fourier Transform spectrometer or on a Bruker Vector 22 Fourier
for one allyl group over another.[19] These compounds 38a– Transform spectrometer. Mass spectra were recorded on a Kratos
c, containing a protected vinylamine group,[20] were then
MS 9/50, VG 70E MS or a VG 70 SEQ mass spectrometer. Mach-
erey–Nagel kieselgel 60 (particle size 0.063–0.200 mm) was used for
conventional silica gel chromatography. All solvents used for reac-
submitted to RCM with catalyst 28 (Scheme 4). Unfortu-
nately the metathesis of substrates 38a–c led to complex
tions and chromatography were distilled prior to use.[21] The
product mixtures which were purified with difficulty. In ad-
Carousel Reaction Station used in this work was manufactured by
dition we were disappointed to not isolate any of the desired
Radleys Discovery Technologies.
2,5-dihydro-1H-2-benzazepines. For the reaction on 38a (R
= Ts) we were only able to isolate 37a, indicating that deal-
lylation had occurred, in addition to an isomerization of
the aryl allyl group. Furthermore, reaction of 38b only pro-
N-({3-Isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]phenyl}meth-
ylene)prop-2-en-1-amine: Benzaldehyde 24 (0.436 mmol, 0.102 g)
was placed in a flask that was under an Ar atmosphere and to this
was added allylamine (0.67 mmol, 0.050 cm3). The mixture was
duced a mixture of 37b and 40b (ratio ca. 1:1). These results
then stirred at room temp. for 22 h. After this time the excess allyl-
concur with those obtained by Bennasar and co-workers[8]
amine was removed in vacuo to yield the desired imine as a yellow-
orange oil. The product was essentially pure by 1H NMR spec-
troscopy and no further purification was required (0.119 g, 100%).
A mixture of E/Z isomers (E:Z ≈ 6:1) was observed by NMR spec-
in which it was found that RCM of protected enamides was
in competition with isomerization and, in addition with N-
devinylation reactions under our reaction conditions.
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Benzazepine and Isoquinoline Derivatives by RCM-Type Reaction
troscopy. IR (NaCl plate): νmax/cm–1 = 1520, 1424, 1216. 1H NMR
(300 MHz, CDCl3, only E isomer listed): δ = 1.22–1.28 [6 H, m,
(br. d, 3 H, J = 6.5 Hz, CHCH3), 2.44 (s, 3 H, ArCH3), 3.66 (br.
d, 2 H, J = 6.4 Hz, NCH2C), 3.81 (s, 3 H, OCH3), 4.10–4.32 [3 H,
˜
OCH(CH3)2], 1.94 (dd, 3 H, J = 5.6 and 1.2 Hz, CH3), 3.86 (s, 3 m, ArCH2N and OCH(CH3)2], 4.85–4.96 (m, 2 H, CH=CH2),
H, OCH3), 4.20 (dd, 2 H, J = 5.6 and 1.2 Hz, NCH2C), 4.38 [1 H, 5.35–5.48 (m, 1 H, CH=CH2), 5.84–5.98 (m, 1 H, CH=CHCH3),
sept, J = 6.1 Hz, OCH(CH3)2], 5.12–5.23 (m, 2 H, CH=CH2), 5.68– 6.36 (1 H, dd, J = 16.0 and 1.5 Hz, ArCH=CH), 6.73 (d, 1 H, J =
5.74 (m, 1 H, CH=CH2), 5.88–6.11 (m, 1 H, ArCH=CHCH3), 6.60 8.5 Hz, 5-H), 7.02 (d, 1 H, J = 8.5 Hz, 6-H), 7.31 (d, 2 H, J =
(dd, 1 H, J = 16.0 and 1.5 Hz, ArCH=CHCH3), 6.84 (d, 1 H, J =
8.6 Hz, 5-H), 7.71 (d, 1 H, J = 8.6 Hz, 6-H), 8.41 (s, 1 H, ArCH=N)
8.2 Hz, 2 ArH), 7.73 (d, 2 H, J = 8.2 Hz, 2 ArH) ppm. 13C NMR
(50 MHz, CDCl3, only E isomer listed, one aromatic C not ob-
ppm. 13C NMR (50 MHz, CDCl3): δ = 19.0 (CH3), 22.5 and 22.6 served in spectrum): δ = 19.0 (CH3), 21.5 (ArCH3), 22.4
[OCH(CH3)2], 55.6 and 55.7 (OCH3), 63.5 and 63.7 (NCH2C), 74.7 [OCH(CH3)2], 48.2 (ArCH2N), 49.5 (NCH2C), 55.7 (OCH3), 75.0
and 75.1 [OCH(CH3)2], 110.2 and 110.7 (CH), 115.7 (CH), 123.0 [OCH(CH3)2], 110.1 (CH), 118.5 (CH), 124.5 (CH), 126.7 (CH),
and 123.3 (CH), 124.3 (CH), 127.0 (C), 134.0 (CH), 134.8 (C), 127.3 (2 CH), 129.6 (2 CH), 132.4 (CH), 132.8 (CH), 133.5 (C),
136.3 (CH), 144.2 (C), 154.3 (C), 160.5 and 161.8 (ArCH=N) ppm.
137.3 (C), 143.1 (C), 144.7 (C), 152.5 (C) ppm. MS: m/z (%) = 429
MS: m/z (%) = 273 (4) [M+], 258 (26), 234 (37), 216 (21), 193 (21), (3) [M+], 275 (18), 274 (100), 233 (9), 232 (56), 215 (20), 177 (13),
192 (22), 178 (12), 177 (100), 175 (10), 91 (10), 77 (9), 41 (11).
HRMS calculated for C17H23NO2: 273.1729, found: 273.1729.
176 (22), 161 (11), 117 (9), 91 (14). HRMS calculated for
C24H31NO4S: 429.1974, found: 429.1978.
N-{3-Isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]benzyl}prop-2-
en-1-amine (25): The aforementioned imine (0.402 mmol, 0.110 g)
was dissolved in MeOH (1 cm3) and the solution was cooled to
0 °C in an ice/water bath. To this methanolic solution was added
sodium borohydride (0.56 mmol, 0.021 g), and the reaction mixture
was left to stir at 0 °C under Ar for 2 h. After this time H2O was
added to destroy the excess sodium borohydride and the pH was
neutralised using 1  HCl and saturated NaHCO3 solutions. The
MeOH was removed on the rotary evaporator and the remaining
aqueous layer was extracted with EtOAc (3ϫ5 cm3). The combined
organics were then dried (MgSO4) and the solvent was removed in
vacuo to yield 25 as a yellow oil (0.0985 g, 89%), which was pure
by NMR spectroscopy and required no further purification. A mix-
ture of E/Z isomers (E:Z ≈ 7:1) was observed by NMR spec-
N-Allyl-N-{3-isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]benzyl}-
1-phenylmethanesulfonamide (26b): The amine 25 (0.744 mmol,
0.205 g) was dissolved in CH2Cl2 (2 cm3); to this was added NEt3
(1.86 mmol, 0.260 cm3) and the solution was stirred at room temp.
for 15 min. Benzylsulfonyl chloride (0.834 mmol, 0.159 g) was dis-
solved in CH2Cl2 (2 cm3) and added dropwise to the amine solution
and a cloudy white gas evolved during the addition. The reaction
mixture was then stirred at room temp. under an Ar atmosphere
for 18 h, before the solvent was removed in vacuo to yield a pink-
orange oil that solidified on standing. The crude mixture was puri-
fied by column chromatography (5–20% EtOAc/hexane) to yield
the desired product 26b as a yellow oil (0.0927 g, 29%). Mixtures
of E/Z isomers were observed in the spectra (E:Z ≈ 7:1). IR (NaCl
plate): νmax/cm–1 = 1481, 1439, 1334, 1215. 1H NMR (300 MHz,
˜
troscopy. IR (NaCl plate): νmax/cm–1 = 3010, 2977, 1642, 1598,
CDCl3): δ = 1.21 [d, J = 6.2 Hz, 6 H, OCH(CH3)2], 1.88 (d, J =
6.4 Hz, 3 H, CH3), 3.55 (d, J = 6.5 Hz, 2 H, NCH2C), 3.81 (s, 3
H, OCH3), 4.14 (s, 2 H, ArCH2N), 4.23 (s, 2 H, ArCH2SO2), 4.31
[sept, J = 6.2 Hz, 1 H, OCH(CH3)2], 5.01–5.12 (m, 2 H, CH=CH2),
5.55–5.81 (m, 2 H, CH=CH2 and ArCH=CH), 6.34 (d, J =
16.1 Hz, 1 H, ArCH=CH), 6.76 (d, J = 8.5 Hz, 1 H, 5-H), 7.08 (d,
˜
1
1573, 1428, 1439, 1381, 1273. H NMR (300 MHz, CDCl3, only E
isomer listed): δ = 1.23 [6 H, d, J = 6.2 Hz, OCH(CH3)2], 1.68 (1
H, broad s, NH), 1.90 (dd, 3 H, J = 6.5 and 1.5 Hz, CH3), 3.24
(br. d, 2 H, J = 6.0 Hz, NCH2C), 3.73 (s, 2 H, ArCH2NH), 3.81
(s, 3 H, OCH3), 4.32 [1 H, sept, J = 6.2 Hz, OCH(CH3)2], 5.10–
5.18 (m, 2 H, CH=CH2), 5.90–5.95 (m, 1 H, CH=CH2), 6.10–6.20 J = 8.5 Hz, 1 H, 6-H), 7.35–7.36 (m, 5 H, 5 ArH) ppm. 13C NMR
(m, 1 H, ArCH=CHCH3), 6.43 (dd, 1 H, J = 16.0 and 1.5 Hz,
ArCH=CHCH3), 6.73 (d, 1 H, J = 8.4 Hz, 5-H), 6.99 (d, 1 H, J =
8.4 Hz, 6-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 19.2 (CH3),
(50 MHz, CDCl3, 1 aromatic C signal not observed in spectrum):
δ = 19.1 (CH3), 22.5 [OCH(CH3)2], 48.2 (ArCH2N),a 49.8
(NCH2C),a 55.7 (OCH3), 59.4 (ArCH2SO2), 75.0 [OCH(CH3)2],
22.5 [OCH(CH3)2], 51.0 (ArCH2N),a 51.8 (NCH2C),a 55.7 (OCH3), 110.3 (CH), 119.0 (CH), 124.5 (CH), 124.8 (CH), 126.3 (C), 128.6
75.0 [OCH(CH3)2], 110.1 (CH), 115.9 (CH), 124.4 (CH), 124.9 (2 CH), 129.2 (CH), 130.8 (2 CH), 132.4 (CH), 132.9 (CH), 133.2
(CH), 130.8 (C), 131.7 (CH), 132.8 (C), 136.9 (CH), 145.0 (C), (C), 144.7 (C), 152.5 (C) ppm. MS: m/z (%) = 429 (7) [M+], 275
152.2 (C) ppm. MS: m/z (%) = 275 (12) [M+], 232 (100), 218 (31),
216 (44), 192 (41), 178 (28), 177 (55), 176 (58), 175 (55), 161 (51), 41
(52). HRMS calculated for C17H25NO2: 275.1885, found: 275.1875.
(20), 274 (100), 233 (10), 232 (70), 216 (17), 177 (13), 176 (13), 91
(49). HRMS calculated for C24H31NO4S: 429.1974, found:
429.1962.
N-Allyl-N-{3-isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]benzyl}-
4-methylbenzenesulfonamide (26a): The amine 25 (1.68 mmol,
0.463 g) was dissolved in CH2Cl2 (5 cm3) and then cooled to 0 °C
in an ice/water bath. To this solution was added NEt3 (2.5 mmol,
0.35 cm3) and it was stirred for 5 min before the addition of the
tosyl chloride (2.05 mmol, 0.391 g). The reaction mixture was
stirred at 0 °C to room temp. for 3 h. After this time, H2O (5 cm3)
was added and the aqueous layer was extracted with CH2Cl2
(5 cm3). The combined organics were then extracted with H2O
(2ϫ5 cm3) and were dried (MgSO4). The solvent was then removed
in vacuo to yield a dark yellow-orange oil that was purified by silica
gel column chromatography (5–10% EtOAc/hexane). The desired
product 26a was obtained as a cream-white solid (0.553 g, 77%),
with NMR spectroscopy showing a mixture of E/Z isomers (E:Z ≈
N-Allyl-N-{3-isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]benzyl}-
acetamide (26c): A solution was prepared of amine 25 (0.740 mmol,
0.204 g) and pyridine (0.74 mmol, 0.060 cm3) and was cooled to
0 °C in an ice/water bath. To this was added dropwise a solution
of Ac2O (1.16 mmol, 0.110 cm3) in pyridine (1.2 mmol, 0.10 cm3).
The reaction mixture was stirred at room temp. under an Ar atmo-
sphere for 3 h, after which time the reaction mixture was diluted
with EtOAc (5 cm3) and stirred for 5 min. The organic layer was
subsequently extracted with brine (3ϫ10 cm3) and the combined
aqueous layers were extracted with CH2Cl2 (3ϫ10 cm3). The or-
ganic layers were combined and extracted with saturated NH4Cl
(40 cm3) that had been basified to pH 11 with a 25% ammonia
solution. The combined organics were then dried (MgSO4), filtered
and the solvent was removed in vacuo to yield a pale yellow oil.
The crude compound was then purified by column chromatography
(5–10% EtOAc/hexane) to yield the desired product 26c as a clear
oil (0.168 g, 72%). Significant broadening occurred in the NMR
8:1), m.p. 62–64 °C. IR (NaCl plate): νmax/cm–1 = 1522, 1479, 1427,
˜
1
1339, 1216. H NMR (300 MHz, CDCl3, only E isomer listed): δ
= 1.23 [6 H, d, J = 6.2 Hz, OCH(CH3)2], 1.86 and rest under 1.23
Eur. J. Org. Chem. 2007, 4953–4961
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4957

J.-L. Panayides, R. Pathak, C. B. de Koning, W. A. L. van Otterlo
FULL PAPER
spectra due to rotamers about the acetyl group (ratio 1:1). IR
(m, 5 H, 5 ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.5
1
(NaCl plate): νmax/cm–1 = 1630, 1522, 1478, 1424, 1216. H NMR [OCH(CH3)2], 50.7 (3-C),a 51.7 (1-C),a 55.8 (OCH3), 58.6
˜
(300 MHz, CDCl3): δ = 1.21–1.25 [m, 6 H, OCH(CH3)2], 1.86–1.92 (ArCH2SO2), 75.5 [OCH(CH3)2], 111.0 (CH), 123.5 (CH), 124.2
(m, 3 H, CHCH3), 2.08 and 2.13 (2 s, 3 H, COCH3), 3.69 and 3.96 (C), 125.3 (CH), 128.3 (CH), 128.4 (CH), 128.5 (2 CH), 128.9 (C),
(2 H, 2 d, J = 4.7 and, J = 5.8 Hz, NCH2CH), 3.81 and 3.83 (2 s,
3 H, OCH3), 4.27–4.36 [m, 1 H, OCH(CH3)2], 4.23 and 4.62 (2 s, 387 (28) [M+], 205 (20), 190 (49), 189 (42), 163 (67), 161 (13), 147
2 H, ArCH2N), 5.04–5.18 (m, 2 H, CH=CH2), 5.60–6.10 (m, 2 H, (90), 92 (10), 91 (100), 65 (10). HRMS calculated for C21H25NO4S:
129.7 (C), 130.6 (2 CH), 145.3 (C), 152.8 (C) ppm. MS: m/z (%) =
CH=CH2CH3 and ArCH=CHCH3), 6.32 (br. d, J = 16.1 Hz, 1 H, 387.1504, found: 387.1496.
ArCH=CHCH3), 6.71–6.87 (m, 2 H, 5-H and 6-H) ppm. 13C NMR
N-{3-Isopropoxy-4-methoxy-2-[(1E)-1-phenylprop-1-en-1-yl]benzyl}-
(50 MHz, CDCl3): δ = 19.0 and 19.1 (CH3), 21.4 and 21.5
(COCH3), 22.4 and 22.5 [OCH(CH3)2], 45.6 and 47.9 (ArCH2N),a
49.1 and 49.3 (NCH2C),a 55.7 (OCH3), 75.0 and 75.1 [OCH-
(CH3)2], 110.2 and 110.4 (CH), 116.5 and 117.2 (CH), 120.8 (CH),
123.6 (CH), 124.2 and 124.6 (CH), 126.7 and 127.4 (C), 132.1 and
132.4 (C), 133.1 and 133.2 (CH), 144.8 and 145.2 (C), 152.2 and
152.3 (C), 170.7 and 171.0 (C=O) ppm. MS: m/z (%) = 317 (72)
[M+], 234 (22), 232 (30), 218 (24), 194 (40), 193 (86), 177 (31), 176
(80), 175 (100), 161 (30), 43 (21). HRMS calculated for
C19H27NO3: 317.1991, found: 317.1999.
prop-2-en-1-amine (31): Benzaldehyde 30 (1.77 mmol, 0.550 g) was
transferred to a flask using Et2O which was then removed under
vacuum. To the aldehyde was added allylamine (2.67 mmol,
0.200 cm3) and the reaction mixture was stirred at room temp. un-
der an Ar atmosphere for 21 h. A small amount of the mixture was
removed and analysed by 1H NMR spectroscopy. It was found that
imine formation had occurred and the reaction mixture was sub-
sequently dissolved in MeOH (5.5 cm3) and cooled to 0 °C in an
ice/water bath. Sodium borohydride (2.1 mmol, 0.081 g) was added
and the reaction mixture was left to stir under an Ar atmosphere
at 0 °C for 2 h. After this time H2O (10 cm3) was added and the
pH was neutralised using 1  HCl and saturated NaHCO3 solu-
tions. The reaction mixture was then extracted with CH2Cl2
(10 cm3) and EtOAc (3ϫ10 cm3) and the combined organics were
dried (MgSO4). The solution was then filtered and the solvent was
removed in vacuo. The desired product 31 was obtained as an es-
sentially pure orange oil and no further purification was deemed
necessary (0.620 g, 100%). A mixture of E/Z isomers (E:Z ≈ 6:1)
General Procedure for RCM Reactions: The substrate (0.1–
0.4 mmol) was dissolved in toluene (5–20 cm3) and the solution was
heated to 60–80 °C under an Ar atmosphere. Grubbs II catalyst 28
(5 mol-%) was added and the reaction mixture was stirred at 60 °C
under an Ar atmosphere for 18–24 h. If the reaction mixture still
contained starting material (by tlc) a further portion of 28 (5 mol-
%) was added and the mixture was heated at 60 °C for a further
18–24 h. The reaction mixture was then cooled to room temp. and
the solvent was removed in vacuo to yield a dark brown oil. The
crude mixture was subsequently purified by silica gel column
chromatography (5–10 % EtOAc/hexane) to obtain the desired
product.
was observed by NMR spectroscopy. IR (NaCl plate): νmax/cm–1
=
˜
3494, 1646, 1595, 1479, 1439, 1377, 1340, 1267. 1H NMR
(300 MHz, CDCl3, only E isomer listed): δ = 1.04 and 1.13 [6 H,
2 d, J = 6.2 Hz, OCH(CH3)2], 1.36 and 1.64 (3 H, 2 d, J = 6.1 and
6.9 Hz respectively, CHCH3), 1.42 (br. s, 1 H, NH), 3.02–3.04 (m,
2 H, NCH2CH), 3.46 (2 H, distorted AB system, J ≈ 8 Hz,
ArCH2N), 3.84 (s, 3 H, OCH3), 4.27 [1 H, sept, J = 6.2 Hz,
OCH(CH3)2], 4.96–5.06 (m, 2 H, CH=CH2), 5.69–5.82 (m, 1 H,
CH=CH2), 6.41 (q, 1 H, J = 6.9 Hz, C=CHCH3), 6.88 (d, 1 H, J =
8.4 Hz, 5-H), 7.12–7.36 (m, 6 H, 6 ArH) ppm. 13C NMR (50 MHz,
CDCl3, only peaks for major E-isomer listed, 1 aromatic C signal
not observed in spectrum): δ = 16.1 (CH3), 22.4 and 22.7
[OCH(CH3)2], 50.7 (ArCH2N),a 51.7 (NCH2CH),a 55.5 (OCH3),
74.7 [OCH(CH3)2], 110.8 (CH), 115.6 (CH), 124.1 (CH), 125.3
(CH), 125.9 (2 CH), 126.6 (CH), 128.2 (2 CH), 131.5 (C), 133.4
(C), 136.8 (CH), 141.4 (C), 144.8 (C), 152.3 (C) ppm. MS: m/z (%)
= 351 (8) [M+], 310 (9), 253 (7), 252 (17), 219 (30), 131 (18), 69
(100), 32 (14), 28 (88). HRMS calculated for C23H29NO2: 351.2198,
found: 351.2197.
6-Isopropoxy-7-methoxy-2-[(4-methylphenyl)sulfonyl]-2,3-dihydro-
1H-2-benzazepine (27a): Compound 26a (0.473 mmol, 0.203 g) in
toluene (20 cm3) was treated with Grubbs II catalyst 28
(0.025 mmol, 0.021 g) at 60 °C for 19.5 h. After chromatography
(5–10 % EtOAc/hexane), 27a was isolated as a pale yellow oil
(0.149 g, 82%), that solidified on standing, m.p. 147–149 °C. IR
(NaCl plate): νmax/cm–1 = 1598, 1577, 1490, 1438, 1403, 1382, 1342.
˜
1H NMR (300 MHz, CDCl3): δ = 1.17 [d, J = 6.2 Hz, 6 H,
OCH(CH3)2], 2.32 (s, 3 H, ArCH3), 3.81 (s, 3 H, OCH3), 4.09–4.17
[m, 3 H, 3-H and OCH(CH3)2], 4.33 (s, 2 H, 1-H), 5.66–5.73 (m, 1
H, 5-H), 6.72–6.80 (m, 2 H, 4-H and 8-H), 6.93 (d, J = 8.3 Hz, 1
H, 9-H), 7.11 (d, J = 8.3 Hz, 2 H, 2 ArH), 7.45 (d, J = 8.3 Hz, 2
H, 2 ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 21.3 (ArCH3),
22.5 [OCH(CH3)2], 50.1 (3-C),a 51.6 (1-C),a 55.8 (OCH3), 75.8
[OCH(CH3)2], 110.8 (CH), 123.6 (CH), 125.5 (CH), 127.1 (2 CH),
127.2 (CH), 129.1 (2 CH), 129.3 (C), 130.3 (C), 136.5 (C), 142.7
(C), 145.2 (C), 152.6 (C) ppm. MS: m/z (%) = 387 (66) [M+], 295
(18), 232 (23), 190 (83), 189 (100), 175 (38), 163 (55), 161 (40), 103
(33), 91 (91). HRMS calculated for C21H25NO4S: 387.1504, found:
387.1505.
N-Allyl-N-{3-isopropoxy-4-methoxy-2-[(1E)-1-phenylprop-1-en-1-
yl]benzyl}-4-methylbenzenesulfonamide (32a): Amine 31 (1.38
mmol, 0.484 g) in CH2Cl2 (5 cm3) and at 0 °C was treated with
NEt3 (1.9 mmol, 0.27 cm3) and tosyl chloride (1.64 mmol, 0.312 g)
as described previously for compound 26a. After work-up and
chromatography (5–15 % EtOAc/hexane) 32a was obtained as a
pale pink oil that solidified on standing (0.493 g, 71%). A mixture
of E/Z isomers (E:Z Ͼ ca. 8:1) was observed by NMR spec-
2-(Benzylsulfonyl)-6-isopropoxy-7-methoxy-2,3-dihydro-1H-2-benz-
azepine (27b): Compound 26b (0.122 mmol, 0.0526 g) in toluene
(5 cm3) was treated with Grubbs II catalyst 28 (0.013 mmol, troscopy, m.p. 110–103 °C. IR (NaCl plate): νmax/cm–1 = 1601,
˜
0.011 g) at 80 °C for 21 h. After chromatography (5% EtOAc/hex-
1520, 1481, 1430, 1338. 1H NMR (300 MHz, CDCl3, only major
ane), 27b was obtained as a yellow oil (0.0184 g, 39%). IR (NaCl E isomer listed): δ = 1.00 and 1.10 [6 H, two d, J = 6.2 Hz,
plate): νmax/cm–1 = 1666, 1598, 1575, 1490, 1456, 1439, 1354. 1H OCH(CH3)2], 1.60 (d, 3 H, J = 6.8 Hz, CHCH3), 2.40 (s, 3 H,
˜
NMR (300 MHz, CDCl3): δ = 1.28 [d, J = 6.2 Hz, 6 H, OCH-
(CH3)2], 3.79 (s, 2 H, 3-H), 3.84 (s, 3 H, OCH3), 4.09–4.11 (m, 2
ArCH3), 3.68–3.71 (m, 2 H, NCH2C), 3.85 (s, 3 H, OCH3), 4.05 (2
H, distorted AB system, J ≈ 8 Hz, ArCH2N), 4.25 [1 H, sept, J =
H, 1-H), 4.33 (s, 2 H, ArCH2SO2), 4.46 [sept, J = 6.2 Hz, 1 H, 6.2 Hz, OCH(CH3)2], 4.79–4.87 (m, 2 H, CH=CH2), 5.30–5.44 (m,
OCH(CH3)2], 5.76 (dt, J = 12.6 and 3.9 Hz, 1 H, 5-H), 6.78 (d, J
= 8.2 Hz, 1 H, 8-H), 6.92–6.99 (m, 2 H, 4-H and 9-H), 7.16–7.29
1 H, CH=CH2), 6.33 (q, 1 H, J = 6.8 Hz, C=CHCH3), 6.92 (d, 1
H, J = 8.6 Hz, 5-H), 7.15–7.30 (m, 8 H, 7 ArH and 6-H), 7.55 (d,
4958
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4953–4961

Benzazepine and Isoquinoline Derivatives by RCM-Type Reaction
2 H, J = 8.2 Hz, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 16.0
(CH3), 21.5 (ArCH3), 22.4 and 22.6 [OCH(CH3 )2 ], 47.9
6.1 Hz, OCH(CH3)2], 1.52 (br. d, 3 H, J = 6.6 Hz, CHCH3), 1.85
(br. d, 3 H, J = 6.5 Hz, CHCH3), 3.77 (s, 3 H, OCH3), 4.07 (s,
(ArCH2N),a 50.6 (NCH2C),a 55.5 (OCH3), 74.7 [OCH(CH3)2], 2 H, ArCH2N), 4.42–4.44 [4 H, m, OCH(CH3)2, SO2CH2Ar and
111.0 (CH), 118.8 (CH), 122.6 (CH), 125.5 (CH), 125.8 (2 CH),
126.6 (CH), 127.2 (2 CH), 127.6 (CH), 128.2 (2 CH), 129.5 (2 CH),
132.1 (C), 136.1 (C), 132.6 (C), 137.1 (C), 140.7 (C), 143.0 (C),
144.6 (C), 152.4 (C) ppm. MS: m/z (%) = 505 (7) [M+], 350 (100),
308 (34), 253 (32), 252 (69), 81 (37), 69 (80), 55 (31), 42 (37), 41
(50). HRMS calculated for C30H35NO4S: 505.2287, found:
505.2290.
NCH=CHCH3], 5.45–5.52 (m, 1 H, CH=CHCH3), 6.28 (br. d, 1
H, J = 16.0 Hz, CH=CHCH3), 6.38 (br. d, 1 H, J = 15.5 Hz,
CH=CHCH3), 6.72 (d, 1 H, J = 8.6, 5-H), 6.99 (d, 1 H, J = 8.6,
6-H), 7.39 (br. s, 5 H, 5 ArH) ppm. 13C NMR (50 MHz, CDCl3,
only major isomer listed, 1 CH signal not observed in aromatic
portion of spectrum): δ = 15.2 (CH3), 19.0 (CH3), 22.4 [OCH-
(CH3)2], 48.5 (ArCH2N), 55.5 (OCH3), 58.5 (SO2CH2Ar), 75.0
[OCH(CH3)2], 106.9 (CH), 110.6 (CH), 121.6 (CH), 124.1 (C),
124.6 (CH), 126.0 (CH), 128.7 (C), 128.8 (2 CH), 131.0 (2 CH),
131.8 (C), 131.9 (CH), 144.3 (C), 151.7 (C) ppm. MS: m/z (%) =
429 (1) [M+] 373 (30), 274 (17), 219 (38), 216 (13), 178 (12), 177
(100), 175 (10), 145 (20), 117 (18), 91 (49). HRMS calculated for
C24H31NO4S; 429.1974, found: 429.1983.
N-Allyl-N-{3-isopropoxy-4-methoxy-2-[(1E)-1-phenylprop-1-en-1-
yl]benzyl}-1-phenylmethanesulfonamide (32b): Amine 31 (1.34
mmol, 0.470 g) in CH2Cl2 (5 cm3) was treated with NEt3
(3.6 mmol, 0.50 cm3) and benzylsulfonyl chloride (1.49 mmol,
0.284 g) in CH2Cl2 (2 cm3), as described for compound 26b. After
work-up and chromatography (5–15% EtOAc/hexane) 32b was ob-
tained as an orange solid (0.302 g, 45%). A mixture of E/Z isomers
(E:Z Ͼ ca. 8:1) was observed by NMR spectroscopy, m.p. 105–
N-[3-Isopropoxy-4-methoxy-2-(prop-1-en-1-yl)benzyl]-N-(prop-1-en-
1-yl)acetamide (35c): Acetamide 34c (0.956 mmol, 0.303 g) was dis-
solved in toluene (30 cm3) and was treated with [RuClH(CO)-
(PPh3)3] (0.0478 mmol, 0.0450 g) at 105 °C as described in the pre-
vious procedure. Column chromatography (5–15% EtOAc/hexane)
afforded the desired product 35c as a yellow oil (0.285 g, 94%).
The product was found to consist of rotamers (60:40) by NMR
108 °C. IR (NaCl plate): νmax/cm–1 = 1482, 1442, 1377, 1337, 1249.
˜
1H NMR (300 MHz, CDCl3, only major E isomer listed): δ = 1.00
and 1.08 [6 H, 2 d, J = 6.1 Hz, OCH(CH3)2], 1.49 (d, 3 H, J =
7.0 Hz, CHCH3), 3.56–3.80 (m, 4 H, NCH2C and ArCH2N), 3.83
(s, 3 H, OCH3), 4.11–4.24 [3 H, m, ArCH2SO2 and OCH(CH3)2],
4.92–5.01 (m, 2 H, CH=CH2), 5.41–5.55 (m, 1 H, CH=CH2), 6.32
(q, 1 H, J = 7.0 Hz, C=CHCH3), 6.90 (d, 1 H, J = 8.6 Hz, 5-H),
7.14–7.28 (m, 11 H, 10 ArH and 6-H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 16.0 (CHCH3), 22.4 and 22.6 [OCH(CH3)2], 48.3
(ArCH2N),a 50.1 (NCH2C),a 55.5 (OCH3), 59.1 (ArCH2SO2), 74.7
and 74.8 [OCH(CH3)2], 111.2 (CH), 119.2 (CH), 122.7 (CH), 125.6
(CH), 125.7 (2 CH), 126.7 (CH), 127.5 (CH), 128.3 (2 CH), 128.4
(CH), 128.5 (2 CH), 129.0 (C), 130.6 (2 CH), 132.3 (C), 132.7 (C),
136.0 (C), 140.8 (C), 144.5 (C), 152.4 (C) ppm. MS: m/z (%) = 505
(19) [M+], 350 (100), 308 (49), 256 (76), 254 (62), 91 (55), 70 (35),
69 (76), 60 (53), 56 (66), 53 (63), 42 (78), 41 (79). HRMS calculated
for C30H35NO4S: 505.2287, found: 505.2290.
spectroscopy. IR (NaCl plate): νmax/cm–1 = 1645, 1481, 1410, 1380,
˜
1216. 1H NMR (300 MHz, CDCl3): δ = 1.22–1.26 [m, 6 H,
OCH(CH3)2], 1.59–1.66 (m, 3 H, CHCH3), 1.90–1.95 and under
2.06 (m, 3 H, CHCH3), 2.06 and 2.30 (2 s, 3 H, COCH3), 3.79 and
3.81 (2 s, 3 H, OCH3), 4.30–4.39 [m, 1 H, OCH(CH3)2], 4.65–4.85
(m, 3 H, ArCH2N and CH=CHCH3), 5.94–5.97 (m, 1 H,
CH=CHCH3), 6.41–6.73 and 7.31–7.36 (m, 4 H, 2 ArH and 2
CH=CHCH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.3 and
15.5 (CHCH3), 19.0 and 19.1 (CHCH3), 22.1 and 22.2 (COCH3),
22.4 and 22.5 [OCH(CH3)2], 44.8 and 48.2 (ArCH2N), 55.6
(OCH3), 75.0 and 75.1 [OCH(CH3)2], 106.9 and 109.0 (CH), 110.5
and 110.6 (CH), 119.9 and 120.8 (CH), 124.3 and 124.7 (CH), 126.3
and 126.9 (C), 128.0 (CH), 131.6 (C), 132.2 and 132.5 (CH), 144.7
and 145.0 (C), 151.6 and 152.0 (C), 169.1 and 169.4 (C=O) ppm.
MS: m/z (%) = 317 (29) [M+] 317 (29), 261 (19), 219 (14), 178 (15),
177 (100), 176 (12), 175 (18), 162 (14), 145 (29), 117 (22), 115 (8), 43
(10). HRMS calculated for C19H27NO3; 317.1991, found: 317.1986.
Attempted Synthesis of 6-Isopropoxy-7-methoxy-2-[(4-methylphen-
yl)sulfonyl]-5-phenyl-2,3-dihydro-1H-2-benzazepine 33a and 2-(Ben-
zylsulfonyl)-6-isopropoxy-7-methoxy-5-phenyl-2,3-dihydro-1H-2-
benzazepine (33b): Compounds 32a [0.154 g, toluene (15 cm3), 8%
cat 28, 80 °C, 22 h] and 32b [0.093 g, toluene (15 cm3), 5% cat 28,
60 °C, 23 h] were subjected to RCM as described for compounds
27. After work-up, column chromatography only afforded complex
mixtures which included unreacted starting material (by NMR
spectroscopy).
5-Isopropoxy-6-methoxy-2-[(4-methylphenyl)sulfonyl]-1,2-dihydro-
isoquinoline (36a): To a degassed solution of methylbenzenesulfon-
amide 34a (0.120 g, 0.279 mmol) in toluene (10 cm3) was added
[RuClH(CO)(PPh3)3] (0.0013 mmol, ca. 0.002 g). The reaction mix-
ture was heated at 110 °C for 2 h under a N2 atmosphere. Catalyst
28 (0.014 mmol, 0.012 g) was added and the reaction mixture was
stirred for another 3 h at 110 °C under N2. After cooling, the tolu-
ene was evaporated under reduced pressure and the organic residue
was then subjected to silica gel column chromatography (5–20%
EtOAc/hexane) to afford the desired product 36a as a brown oil
N-[3-Isopropoxy-4-methoxy-2-(prop-1-en-1-yl)benzyl]-1-phenyl-N-
(prop-1-en-1-yl)methanesulfonamide (35b): Sulfonamide 34b
(0.707 mmol, 0.304 g) was dissolved in distilled toluene (30 cm3)
and the solution was degassed with N2 for 15 min. [RuClH-
(CO)(PPh3)3] (0.0354 mmol, 0.0326 g) was added and the reaction
mixture was allowed to stir at 90–100 °C under an Ar atmosphere
for 19 h. A 1H NMR spectrum of the crude reaction mixture
showed that isomerisation of the double bonds had occurred and
the solvent was removed in vacuo to yield a dark brown-black oil.
This was then purified by column chromatography (5–10% EtOAc/
hexane) to yield the desired product 35b as a pale yellow oil
(0.265 g, 87%). A complex mixture of E/Z isomers was observed
by NMR spectroscopy. [When this reaction was initially attempted
under high temperature (135–140 °C), solventless conditions only
deallylated compound 37b was obtained. See reference31 for experi-
mental details and an X-ray structure of the compound 37b]. IR
(0.079 g, 76%). IR (NaCl plate): νmax/cm–1 = 1625, 1597, 1486,
˜
1
1461, 1439, 1400, 1283. H NMR (300 MHz, CDCl3): δ = 1.21 [d,
J = 6.2 Hz, 6 H, CH(CH3)2], 2.37 (s, 3 H, ArCH3), 3.77 (s, 3 H,
OCH3), 4.35 [sept, J = 6.2 Hz, 1 H, CH(CH3)2], 4.48 (s, 2 H, 1-H),
6.22 (d, J = 7.9 Hz, 1 H, 4-H), 6.64 (br. d, 2 Historted AB system,
7-ArH and 8-ArH), 6.74 (d, J = 7.9 Hz, 1 H, 3-H), 7.25 (d, J =
8.1 Hz, 2 H, 2 ArH), 7.67 (d, J = 8.1 Hz, 2 H, 2 ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 21.4 (ArCH3), 22.4 [CH(CH3)2], 46.8
(NCH2), 55.7 (OCH3), 75.2 [CH(CH3)2], 106.3 (CH), 110.7 (CH),
120.4 (CH), 120.7 (C), 125.3 (C), 126.1 (CH), 126.9 (C), 127.1 (2
CH), 129.2 (C), 129.7 (2 CH), 143.9 (C), 152.4 (C) ppm. MS: m/z
(%) = 374 (24), 373 (90) [M+], 218 (18), 176 (100), 175 (89), 161
(NaCl plate): νmax/cm–1 = 1521, 1426, 1354, 1216. 1H NMR
˜
(300 MHz, CDCl3, only major isomer listed): δ = 1.19 [6 H, d, J =
Eur. J. Org. Chem. 2007, 4953–4961
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4959

J.-L. Panayides, R. Pathak, C. B. de Koning, W. A. L. van Otterlo
FULL PAPER
(35), 144 (45), 132 (30), 91 (43). HRMS calculated for
C20H23NSO4: 373.1348, found: 373.1348.
N-(2-Allyl-3-isopropoxy-4-methoxybenzyl)-1-phenyl-N-[(1E)-prop-1-
en-1-yl]methanesulfonamide (38b): Compound 34b (0.488 mmol,
0.210 g) in toluene (20 cm3) was treated with [RuClH(CO)(PPh3)3]
(0.005 mmol, 0.005 g). After chromatography (5% EtOAc/hexane)
38b was isolated as a pale yellow oil (0.188 g, 90%). A mixture of
2-Acetyl-5-isopropoxy-6-methoxy-1,2-dihydroisoquinoline (36c):
Acetamide 35c (0.321 mmol, 0.102 g) was dissolved in toluene
(8 cm3) and degassed using N2 for 15 min. After this time the solu-
tion was heated to 110 °C before the addition of catalyst 28
(0.016 mmol, 0.014 g). The reaction mixture was then left to stir at
110 °C, under Ar for 3 h. The reaction mixture was cooled to room
temp. and the solvent was removed in vacuo to yield a brown-black
oil. This oil was then purified by column chromatography (5–30%
EtOAc/hexane) to yield the desired product 36c as a clear oil
E/Z isomers (E:Z ≈ 3:1) was observed by NMR spectroscopy. IR
1
(NaCl plate): νmax/cm–1 = 1663, 1489, 1439, 1355, 1272, 1216. H
˜
NMR (300 MHz, CDCl3, only major E isomer listed): δ = 1.21 [6
H, d, J = 6.2, OCH(CH3)2], 1.53 (m, 3 H, CHCH3), 3.28 (br. d, 2
H, J = 5.8 Hz, ArCH2C), 3.77 (s, 3 H, OCH3), 4.07 (br. s, 2 H,
ArCH2N), 4.37–4.46 (m, 2 H, ArCH2SO2), 4.35–4.56 [2 H, m,
OCH(CH3)2 and NCH=CH], 4.74 [1 H, dd, J = 17.2 and 1.6 Hz,
CH=C(H)H], 4.94 [1 H, dd, J = 1.6 and 10.2 Hz, CH=C(H)H],
5.65–5.80 (m, 1 H, CH2CH=CH), 6.30–6.44 (m, 1 H, NCH=CH),
6.72 (d, 1 H, J = 8.6 Hz, 5-H), 6.96 (d, 1 H, J = 8.6 Hz, 6-H), 7.38–
7.39 (m, 5 H, 5 ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.2
(CH3), 22.5 [OCH(CH3)2], 30.1 (ArCH2C), 48.0 (ArCH2N), 55.5
(OCH3), 58.5 (ArCH2SO2), 74.5 [OCH(CH3)2], 107.0 (CH), 110.2
(CH), 115.2 (CH), 121.0 (CH), 125.9 (C), 124.6 (CH), 126.8 (CH),
128.9 (2 CH), 130.3 (C), 131.9 (2 CH), 133.0 (C), 135.8 (CH), 144.7
(C), 151.6 (C) ppm. MS: m/z (%) = 429 (1) [M+] 387 (15), 373 (10),
274 (15), 219 (29), 178 (13), 177 (100), 176 (12), 145 (16), 117 (14),
91 (35). HRMS calculated for C24H31NO4S: 429.1974, found:
429.1981.
(0.0655 g, 78%). IR (NaCl plate): νmax/cm–1 = 1661, 1625, 1575,
˜
1488, 1462, 1440, 1408, 1386, 1351, 1270. 1H NMR (300 MHz,
CDCl3): δ = 1.29 [d, J = 6.2 Hz, 6 H, OCH(CH3)2], 2.21 (s, 3 H,
COCH3), 3.81 (s, 3 H, OCH3), 4.23 [sept, J = 6.2 Hz, 1 H,
OCH(CH3)2], 4.84 (s, 2 H, 1-H), 6.17 (d, J = 8.0 Hz, 1 H, 4-H),
6.64- 6.79 (m, 3 H, 3-H, 7-H and 8-H) ppm. 13C NMR (50 MHz,
CDCl3, only major rotamer listed): δ = 21.3 (CH3), 22.5
[OCH(CH3)2], 43.8 (1-C), 55.8 (OCH3), 75.4 [OCH(CH3)2], 105.3
(CH), 110.9 (CH), 120.8 (CH), 122.7 (C), 125.0 (C), 125.8 (CH),
141.6 (C), 152.2 (C), 168.4 (C=O) ppm. MS: m/z (%) = 261 (52)
[M+], 265 (22), 262 (10), 261 (52), 219 (28), 218 (18), 177 (29), 176
(100), 175 (42), 161 (15), 160 (19), 145 (14), 131 (23), 43 (11).
HRMS calculated for C15H19NO3; 261.1365, found: 261.1370.
N-(2-Allyl-3-isopropoxy-4-methoxybenzyl)-N-[(1E)-prop-1-en-1-yl]-
acetamide (38c): Acetamide 34c (0.648 mmol, 0.206 g) was treated
with [RuClH(CO)(PPh3)3] (0.006 mmol, 0.006 g) as described
above. After chromatography (5–15% EtOAc/hexane) 38c was ob-
tained as a pale yellow oil (0.159 g, 77%). A mixture of E/Z isomers
(E:Z ratio difficult to determine due to the peak broadening be-
cause of 1:1 Ac rotamers) was observed by NMR spectroscopy.
General Procedure for Isomerization Reactions: These reactions
were set up in a Carousel Reactor with the reaction tubes being
evacuated and placed under Ar three times before the substrates
(0.4–0.6 mmol) were added. This was followed by the addition of
toluene (20 cm3) and the solution was degassed using N2 for 5 min.
The solution was heated to 80 °C before the addition of
[RuClH(CO)(PPh3)3] (1 mol-%), and the reaction mixture was then
stirred under Ar for 20 h. The reaction mixture was cooled to room
temp. and the solvent was removed in vacuo to yield yellow oils.
These oils were purified by column chromatography (5–10 %
EtOAc/hexane) to afford the desired products 38a–c. The following
four compounds were synthesized in this manner.
IR (NaCl plate): νmax/cm–1 = 1645, 1522, 1486, 1216. 1H NMR
˜
(300 MHz, CDCl3): δ = 1.24–1.30 [m, 6 H, OCH(CH3)2], 1.61–1.66
(m, 3 H, CHCH3), 2.04 and 2.30 (2 s, 3 H, COCH3), 3.51 (br. s, 2
H, ArCH2C), 3.79 and 3.82 (2 s, 3 H, OCH3), 4.42–4.58 [m, 1 H,
OCH(CH3)2], 4.61 and 4.75 (2 s, 2 H, ArCH2N), 4.80–5.10 (m, 3
H, CH=CH2 and NCH=CH), 5.85–5.96 (m, 1 H, CH=CH2), 6.53–
6.73 (m, 2 H, 5-H and 6-H), 7.35 (and rest under previous mul-
tiplet, NCH=CH, J = 14.5 Hz, 1 H, d) ppm. 13C NMR (50 MHz,
CDCl3): δ = 15.3 and 15.5 (CHCH3), 22.2 (COCH3), 22.6
[OCH(CH3)2], 30.2 and 30.4 (ArCH2C), 44.8 and 48.2 (ArCH2N),
55.5 (OCH3), 74.5 and 75.0 [OCH(CH3)2], 106.9 and 109.0 (CH),
110.3 and 110.5 (CH), 115.2 (CH), 119.5 and 120.1 (CH), 126.2
and 128.4 (CH), 130.2 and 130.9 (C), 131.2 and 132.5 (C), 135.7
and 136.0 (CH), 145.2 (C), 151.4 and 151.8 (C), 169.0 and 169.6
(C=O) ppm. MS: m/z (%) = 317 (20) [M+], 275 (12), 177 (100), 176
(46), 175 (13), 161 (15), 145 (33), 117 (31), 115 (16), 43 (13). HRMS
calculated for C19H27NO3: 317.1991, found: 317.1992.
N-(2-Allyl-3-isopropoxy-4-methoxybenzyl)-4-methyl-N-[(1E)-prop-
1-en-1-yl]benzenesulfonamide (38a): Compound 34a (0.482 mmol,
0.207 g) was treated with [RuClH(CO)(PPh3)3] (0.005 mmol,
0.005 g) as described above. After chromatography (5–10% EtOAc/
hexane) 38a was obtained as a pale yellow oil (0.0532 g, 26%) as
well as unreacted starting material (0.120 g, 58% recovery). A mix-
ture of E/Z isomers (E:Z ≈ 4:1) was observed by NMR spec-
troscopy. IR (NaCl plate): νmax/cm–1 = 1638, 1599, 1580, 1487,
˜
1
1439, 1342, 1273. H NMR (300 MHz, CDCl3, only major E iso-
mer listed): δ = 1.22–1.26 [9 H, m, OCH(CH3)2 and CHCH3], 2.44
(s, 3 H, ArCH3), 3.38 (br. d, 2 H, J = 4.2 Hz, ArCH2C), 3.79 (s, 3
H, OCH3), 4.01 (2 H, distorted AB system, J ≈ 7 Hz, ArCH2N),
4.47–4.50 [2 H, m, OCH(CH3)2 and NCH=CHCH3], 4.74 [1 H, dd,
J = 17.2 and 1.7 Hz, CH=C(H)H], 4.93 [1 H, dd, J = 10.6 and
1.7 Hz, CH=C(H)H], 5.78–5.90 (m, 1 H, NCH=CH2), 5.95–6.23
(and under d at 7.31, 1 H, m, NCH=CH), 6.69 (d, 1 H, J = 8.4 Hz,
5-H), 6.86 (d, 1 H, J = 8.4 Hz, 6-H), 7.31 (d, 2 H, J = 8.1 Hz, 2
Attempted Synthesis of 6-Isopropoxy-7-methoxy-2-[(4-methylphen-
yl)sulfonyl]-2,5-dihydro-1H-2-benzazepine 39a. Formation of N-{3-
Isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]benzyl}-4-methyl-
benzenesulfonamide (37a): According to the general RCM pro-
cedure, benzenesulfonamide 38a (0.0294 mmol, 0.0126 g) was
dissolved in toluene (10 cm3) and treated with catalyst 28
ArH), 7.75 (d, 2 H, J = 8.1 Hz, 2 ArH) ppm. 13C NMR (50 MHz, (0.015 mmol, 0.013 g) at 60 °C for 25 h. After chromatography (5%
CDCl3, signals for 1 aromatic C and 1 aromatic CH not observed): EtOAc/hexane) 37a was obtained as a pale yellow oil (0.0053 g,
δ = 14.2 (CHCH3), 21.5 (ArCH3), 22.6 [OCH(CH3)2], 30.5 47%). A mixture of E/Z isomers (E:Z = Ͼ5:1) was observed by
(ArCH2C), 45.0 (ArCH2N), 55.5 (OCH3), 74.6 [OCH(CH3)2], 110.1
NMR spectroscopy. IR (NaCl plate): νmax/cm–1 = 1599, 1522, 1429,
(CH), 115.2 (CH), 124.7 (CH), 127.2 (2 CH), 127.3 (CH), 129.6 (2 1334, 1272. 1H NMR (300 MHz, CDCl3, only major E isomer
CH), 132.6 (C), 136.7 (C), 137.1 (CH), 143.4 (C), 145.2 (C), 152.7 listed): δ = 1.19 [6 H, d, J = 6.2 Hz, OCH(CH3)2], 1.77 (dd, 3 H,
(C) ppm. MS: m/z (%) = 429 (1) [M+] 389 (38), 192 (50), 191 (17), J = 6.5 and 1.4 Hz, CHCHCH3), 2.43 (s, 3 H, ArCH3), 3.79 (s, 3
˜
177 (22), 176 (100), 175 (18), 161 (26), 144 (18), 91 (24). HRMS
calculated for C24H31NO4S: 429.1974, found: 429.1976.
H, OCH3), 4.08 (2 H, distorted AB system, J ≈ 5.8 Hz, ArCH2N),
4.27 [1 H, sept, J = 6.2 Hz, OCH(CH3)2], 4.48 (br. s, 1 H, NH),
4960
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4953–4961

Benzazepine and Isoquinoline Derivatives by RCM-Type Reaction
Hara, A. Aoyagi, Y. Abe, T. Kaneko, H. Kogen, Bioorg. Med.
Chem. 2003, 11, 4389.
[7] N. Dieltiens, C. V. Stevens, Synlett 2006, 2771.
[8] M. L. Bennasar, T. Roca, M. Monerris, D. García-Díaz, J. Org.
Chem. 2006, 71, 7028.
[9] For a review discussing the interesting relationship between
metathesis and isomerization see: B. Schmidt, Eur. J. Org.
Chem. 2004, 1865.
5.90–6.02 (m, 1 H, CHCHCH3), 6.21 (dd, 1 H, J = 16.1 and 1.4 Hz,
CHCHCH3), 6.65 (d, 1 H, J = 8.4 Hz, 5-H), 6.83 (d, 1 H, J =
8.4 Hz, 6-H), 7.30 (d, 2 H, J = 8.1 Hz, 2 ArH), 7.73 (d, 2 H, J =
8.1 Hz, 2 ArH) ppm. 13C NMR (50 MHz, CDCl3, only major E
isomer listed): δ = 19.1 (CHCHCH3), 21.5 (ArCH3), 22.5
[OCH(CH3)2], 45.6 (NCH2), 55.7 (OCH3), 75.2 [OCH(CH3)2],
110.3 (CH), 124.2 (CH), 124.9 (CH), 126.2 (C), 127.2 (2 CH), 129.6
(2 CH), 132.6 (CH), 133.0 (C), 136.9 (C), 143.4 (C), 145.1 (C),
153.0 (C) ppm. MS: m/z (%) = 389 (11) [M+], 264 (31), 218 (90),
192 (61), 176 (27), 131 (61), 91 (47), 117 (31), 69 (100). HRMS
calculated for C21H27NO4S: 389.1661, found: 389.1643.
[10]
a) J.-L. Panayides, R. Pathak, H. Panagiotopoulos, H. Davids,
M. A. Fernandes, C. B. de Koning, W. A. L. van Otterlo, Tetra-
hedron 2007, 63, 4737; b) R. Pathak, J.-L. Panayides, T. D.
Jeftic, C. B. de Koning, W. A. L. van Otterlo, S. Afr. J. Chem.
2007, 60, 1 (http://blues.sabinet.co.za/sajchem/); c) E. M. Co-
yanis, J.-L. Panayides, M. A. Fernandes, C. B. de Koning,
W. A. L. van Otterlo, J. Organomet. Chem. 2006, 691, 5222; d)
W. A. L. van Otterlo, E. L. Ngidi, S. Kuzvidza, G. L. Morgans,
S. S. Moleele, C. B. de Koning, Tetrahedron 2005, 61, 9996; e)
W. A. L. van Otterlo, G. L. Morgans, L. G. Madeley, S. Kuz-
vidza, S. S. Moleele, N. Thornton, C. B. de Koning, Tetrahe-
dron 2005, 61, 7746; f) W. A. L. van Otterlo, E. M. Coyanis, J.-
L. Panayides, C. B. de Koning, M. A. Fernandes, Synlett 2005,
501; g) W. A. L. van Otterlo, E. L. Ngidi, C. B. de Koning,
M. A. Fernandes, Tetrahedron Lett. 2004, 45, 659.
Attempted Synthesis of 2-(Benzylsulfonyl)-6-isopropoxy-7-methoxy-
2,5-dihydro-1H-2-benzazepine 39b. Formation of Mixture of N-{3-
Isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]benzyl}-1-phenylmeth-
anesulfonamide 37b and N-(2-Allyl-3-isopropoxy-4-methoxybenzyl)-
1-phenylmethanesulfonamide 40b: According to the general RCM
procedure, benzylsulfonamide 38b (0.169 mmol, 0.0726 g) in tolu-
ene (7 cm3) was treated with catalyst 28 (0.009 mmol, 0.008 g) at
60 °C for 18.5 h. After chromatography (5–10% EtOAc/hexane), a
mixture of 37b (mainly E) and 40b (ca. 1:1) were obtained as a
milky oil which slowly solidified (0.038 g, 58%). The 1H and 13C
NMR spectra contained all the signals for 37b (see ref.[17]). In ad-
dition signals at 3.46 (br. d, 2 H, J = 5.5 Hz, ArCH2CHCH2), 4.82–
[11]
[12]
W. A. L. van Otterlo, R. Pathak, C. B. de Koning, Synlett 2003,
1859.
a) N. Kuz´nik, S. Krompiec, Coord. Chem. Rev. 2007, 251, 222;
b) S. Krompiec, N. Kuz´nik, M. Krompiec, R. Penczek, J. Mrzi-
god, A. Tórz, J. Mol. Catal. A 2006, 253, 132; c) S. Krompiec,
N. Kuz´nik, M. Urbala, J. Rzepa, J. Mol. Catal. A 2006, 248,
198.
For representative examples describing an isomerization pro-
cess followed by RCM and related papers see: a) A. Vik, L.-L.
Gundersen, Tetrahedron Lett. 2007, 48, 1931; b) E. Banaszak,
C. Comoy, Y. Fort, Tetrahedron Lett. 2006, 47, 6235; c) A.
Núnˇez, A. M. Cuadro, J. Alvarez-Builla, J. J. Vaquero, Org.
Lett. 2004, 6, 4125; d) T. Nguyen Van, N. De Kimpe, Tetrahe-
dron Lett. 2004, 45, 3443; e) T. Nguyen Van, S. Debenedetti,
N. De Kimpe, Tetrahedron Lett. 2003, 44, 4199; f) U. Martínez-
Estíbalez, N. Sotomayor, E. Lete, Tetrahedron Lett. 2007, 48,
2919.
4.96 (m,
2 H, ArCH2CHCH2) and 6.00–6.05 (m, 1 H,
1
ArCH2CHCH2) in the H NMR spectrum were characteristic for
compound 40b. A signal at 30.6 was also readily identified for the
ArCH2CHCH2 in the 13C NMR spectrum. Finally, the structures
of the compounds were supported by the mass spectra: MS: m/z
(%) = 389 (11) [M+], 264 (31), 234 (19), 218 (90), 192 (100), 176
(27), 130 (61), 91 (60), 69 (100). HRMS calculated for
C21H27NO4S: 389.1661, found: 389.1671.
[13]
Acknowledgments
This work was supported by the National Research Foundation
(NRF), GUN 2053652), Pretoria, and the University of the Wit-
watersrand (University and Science Faculty Research Councils,
Friedel Sellschop Award). Prof. J. P. Michael is thanked for many
helpful discussions. Mr G. L. Morgans is thanked for contributions
to the manuscript. We also gratefully acknowledge Mr R. Mampa
and Mr T. van der Merwe for providing the NMR and MS spec-
troscopy services, respectively.
[14]
C. B. de Koning, J. P. Michael, A. L. Rousseau, J. Chem. Soc.
Perkin Trans. 1 2000, 787.
[15] For an interesting review highlighting side-reactions occurring
during RCM see: B. Alcaide, P. Almendros, Chem. Eur. J. 2003,
9, 1259.
[16] For a related example where the RCM was successful see: S.-R.
Li, L.-Y. Chen, J.-C. Tsai, J.-Y. Tzeng, I.-L. Tsai, E.-C. Wang,
Tetrahedron Lett. 2007, 48, 2139.
[17] W. A. L. van Otterlo, J.-L. Panayides, M. A. Fernandes, Acta
Crystallogr., Sect. E 2004, 60, o1586.
[18] For examples see the following references and citations listed
therein: a) B. Alcaide, P. Almendros, J. M. Alonso, Chem. Eur.
J. 2003, 9, 5793; b) B. Alcaide, P. Almendros, J. M. Alonso,
Chem. Eur. J. 2006, 12, 2874.
[19] See an example in the following paper: W. A. L. van Otterlo,
G. L. Morgans, S. D. Khanye, B. A. A. Aderibigbe, J. P.
Michael, D. G. Billing, Tetrahedron Lett. 2004, 45, 9171.
[20] See the following two reviews concerning metathesis with het-
eroatom-bearing alkenes: a) R. C. D. Brown, V. Satcharoen,
Heterocycles 2006, 70, 705; b) P. Van de Weghe, P. Bisseret, N.
Blanchard, J. Eustache, J. Organomet. Chem. 2006, 691, 5078;
See the following recent representative examples: c) G. Liu, W.-
Y. Tai, Y.-L. Li, F.-J. Nan, Tetrahedron Lett. 2006, 47, 3295; d)
S. Fustero, M. Sánchez-Roselló, D. Jiménez, J. F. Sanz-Cerv-
era, C. del Pozo, J. L. Acenˇa, J. Org. Chem. 2006, 71, 2706.
[21] D. D. Perrin, W. L. F. Armarego, Purification of laboratory
chemicals, Pergamon Press, London, 1988.
[1] See: J. Lee, J. Lee, T. Szabo, A. F. Gonzalez, J. D. Welter, P. M.
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[4] J. Jurayj, R. D. Haugwitz, R. K. Varma, K. D. Paull, J. F. Bar-
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[6] a) H. Kogen, N. Toda, K. Tago, S. Marumoto, K. Takami, M.
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Received: May 25, 2007
Published Online: July 30, 2007
Eur. J. Org. Chem. 2007, 4953–4961
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4961