Design and synthesis of 1-benzazepine derivatives by strategic utilization of Suzuki-Miyaura cross-coupling, aza-Claisen rearrangement and ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.200700921

A new and simple methodology has been realized for the synthesis of 7-substituted 2,3,4,5-tetrahydro-1-benzazepine derivatives with Suzuki-Miyaura cross-coupling, aza-Claisen rearrangement and ring-closing metathesis (RCM) the key steps. Here, o-allylacet

Full text of DOI:10.1002/ejoc.200700921

FULL PAPER
DOI: 10.1002/ejoc.200700921
Design and Synthesis of 1-Benzazepine Derivatives by Strategic Utilization of
Suzuki–Miyaura Cross-Coupling, Aza-Claisen Rearrangement and Ring-
Closing Metathesis[‡]
Sambasivarao Kotha*[a] and Vrajesh R. Shah[a]
Keywords: Aza-Claisen rearrangement / 1-Benzazepine / Cross-coupling / Metathesis
A new and simple methodology has been realized for the
synthesis of 7-substituted 2,3,4,5-tetrahydro-1-benzazepine
derivatives with Suzuki–Miyaura cross-coupling, aza-
Claisen rearrangement and ring-closing metathesis (RCM)
the key steps. Here, o-allylacetanilide derivatives were ob-
tion catalyst, gave the 1-benzazepine derivatives in moder-
ate-to-good yields. These RCM products were found to be
unstable and so they were hydrogenated to provide stable
tetahydro-1-benzazepine derivatives 25–28. 1H-1-Benz-
azepin-2-one derivatives 44 and 45 were synthesized follow-
tained by Suzuki–Miyaura cross-coupling of the correspond- ing a similar sequence. In addition, the aza-Claisen re-
ing o-iodoacetanilides. The o-allylacetanilides, on N-al-
lylation under phase-transfter catalysis conditions, provided
diallyl derivatives as suitable precursors for RCM. These di-
allyl derivatives, on treatment with Grubbs’ second-genera-
arrangement was utilized as a key step in the preparation of
RCM precursor 17.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ceptor glycine sites which could provide the means to treat
neurodegenerative disorders associated with excitotoxic-
ity.[5] Also, 1-benzazepine derivatives have found applica-
tions in cardiovascular diseases. Gottlieb and co-workers
have carried out a dynamic and static conformational
analysis of acylated tetrahydrobenzazepines by high-field
NMR spectroscopy and molecular mechanics calcula-
tions.[6]
Introduction
1-Benzazepine is an important fused heterocyclic moiety
present as a key structural element in various biologically
active molecules. For example, OPC-31260[1] (1a) and OPC-
41061[2] (1b), potent orally effective non-peptide vasopres-
sin V2-receptor antagonists, and Lotensin (Benzazepril)
(2),[3] an ACE inhibitor used for the treatment of hyperten-
sion, have 1-benzazepine as a key structural element (Fig-
ure 1). Corbel et al. have reported various 1-benzazepine
derivatives as ATP-dependent potassium channel antago-
nists.[4] 8-Chloro-3-hydroxy-1H-1-benzazepine-2,5-dione (3)
acts as an antagonist at N-methyl--aspartate (NMDA) re-
Numerous applications of 1-benzazepine derivatives in
medicinal chemistry[7] have prompted organic chemists to
develop new synthetic methodologies. Most of the method-
ologies developed for assembling 1-benzazepine derivatives
involve the expansion of smaller rings, for example, by the
reaction of indoles with dimethyl acetylenedicarboxylate[8]
or ethyl cyanoacetate,[9] by the Beckman[10] or Schmidt[11]
rearrangement of tetralones, by the treatment of 1,2-dihy-
droquinoline with dibromocarbene followed by dehydro-
bromination[12] or treatment with ethyl azidoformate[13] and
by free-radical ring expansion of six-membered heterocycles
to 1-benzazepines.[14] Recently, Pd-catalyzed reactions have
also been employed in the synthesis of 1-benzazepine deriv-
atives. In this regard, Quadir et al. reported the synthesis
of 1-benzazepine derivatives by tandem Heck isomerisation
Figure 1. Biologically important compounds with 1-benzazepine as and Buchwald–Hartwig aryl amination.[15a] The same
a key structural motif.
group reported the synthesis of 1-benzazepine derivatives
by the intramolecular Heck reaction[15b] and also prepared
[‡] Part of this work was presented at the 233rd ACS Meeting,
higher homologues of 1-benzazepine by RCM.[15c] Dykar
March, 25–29, 2007, Chicago, IL, USA, ORGN-316.
and Markwitz achieved the synthesis of 1-benzazepine de-
rivatives through Pd-catalyzed C–C and C–N bond-forming
reactions.[16] As an alternative, Lete and co-workers re-
ported the synthesis of 1-benzazepine derivatives, em-
[a] Department of Chemistry, Indian Institute of Technology –
Bombay,
Powai, Mumbai-400076, India
Fax: +91-22-2572-3480
E-mail: srk@chem.iitb.ac.in
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Design and Synthesis of 1-Benzazepine Derivatives
ploying Pd-catalyzed arylation and ring-closing metathesis
(RCM) as the key steps.[17]
With the advent of well-defined ruthenium carbene com-
plexes (G-1, G-2 and GH-3, Figure 2),[18] metathesis has
emerged as an important tool for carbon–carbon bond for-
mation in organic synthesis. RCM[19] has received more at-
tention in organic synthesis than other metathesis proto-
cols. In addition, recent advances in metal-catalyzed coup-
ling methods have allowed increasing usage of cross-coup-
ling reactions in synthetic organic chemistry, for example,
the Suzuki–Miyaura (SM)[20] cross-coupling reaction.
Therefore a synergetic combination of these two powerful
protocols for carbon–carbon bond formation has opened
up various synthetic routes to complex targets.[21,22] Herein
we would like to report a new route to 1-benzazepine deriv-
atives involving the strategic use of SM cross-coupling, aza-
Claisen rearrangement and RCM.
Scheme 1. Preparation of diallyl derivatives by the SM cross-coup-
ling reaction as a key step.
Scheme 1). Here we would like to mention that in the re-
ported procedure the authors carried out the reaction under
sonication conditions. However, in our hands the reaction
proceeded without sonication at room temperature. More-
over, under these reaction conditions, about 8–10% of the
isomerized product 17a was also observed.
Next the diallyl derivative 17 was treated with Grubbs’
catalyst (G-1, 3 mol-%) in dry DCM. The reaction was
complete within 1 h (TLC monitoring) and the 1-benzazep-
ine derivative 21 was isolated in 90% yield (Scheme 2). Un-
fortunately the product 21 decomposed when kept at room
temperature. We thought this may be due to the presence
of a ruthenium impurity which might have been separated
from the rest of the reaction mixture with compound 21
during purification by column chromatography. Therefore
the reaction was repeated with Grubbs’ second-generation
catalyst (G-2, 3 mol-%). Although the product 21 was iso-
lated in 90% yield, its decomposition could not be avoided.
These observations indicated that the 1-benzazepine deriva-
tive 21 is unstable in the concentrated form at room tem-
perature, but is stable in solution. To improve the stability
of these compounds, hydrogenation of the RCM product 21
was attempted. Thus, the RCM product 21 was hydroge-
nated under Pd/C catalyst conditions in dry ethyl acetate to
deliver the 1-acetyl-2,3,4,5-tetrahydro-1-benzazepine deriv-
ative 25 in 95% yield. The saturated product 25 was found
to be stable.
Figure 2. Ruthenium carbene metathesis catalysts.
Results and Discussion
Recently, we reported a new and simple methodology for
the allylation of aromatic halides by the SM cross-coupling
reaction between aromatic halides and allyl boronic acid
pinacol cyclic ester 4.[23] As a logical extension of this al-
lylation strategy, we have also developed a new methodol-
ogy for benzannulation that involves a combination of the
SM cross-coupling reaction and RCM as the key steps. The
required o-diallylarenes were obtained by SM cross-coup-
ling of the corresponding o-diiodo derivatives.[22b] The o-
diallyl derivatives were treated with Grubbs’ catalyst G-1
and in situ treatment of the RCM product with DDQ gave
the benzannulated derivatives in good-to-excellent yields.
During the benzannulation strategy we prepared various
2-iodoaniline derivatives which prompted the development
of the present strategy. Realization of this strategy requires
protection of the free amine group to avoid complexation
with ruthenium. Towards this goal, 4-methoxycarbonyl-2-
iodoaniline (5) was treated with acetic anhydride in the
presence of concd. sulfuric acid (catalytic, 1–2 drops)[24] to
deliver the N-acetyl derivative 9 in 89% isolated yield
(Scheme 1). When the N-acetyl derivative 9 was subjected
to SM cross-coupling conditions for allylation using the al-
lylboronate ester 4 as the coupling partner, the correspond-
ing coupling product 13 was isolated in 91% yield.
Scheme 2. Synthesis of 1-benzazepine derivatives by RCM and hy-
drogenation.
Our next goal was to carry out the N-allylation. To this
end, the o-allylacetanilide derivative 13 was treated with al-
lyl bromide under phase-transfer catalysis (PTC) conditions
To generalize this methodology various other 7-substi-
(KOH, TBAI, THF, room temp.)[25] to deliver the corre- tuted 1-acetyl-1-benzazepine derivatives were synthesized
sponding N-allyl derivative 17 in a very good yield (90%, following the reaction sequences depicted in Scheme 1 and
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S. Kotha, V. R. Shah
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Scheme 2. We are pleased to report that N-acetyl derivatives by TLC as the starting material and the product have the
10–12 were isolated in good-to-excellent yields. The al- same Rf value. When the diallyl derivative 34 was subjected
lylated products 14–16 were also isolated in good yields to RCM with the G-2 catalyst, the reaction was complete
(64–93%) under SM coupling conditions. Similarly, the di- after 1 h and the RCM product 36 was isolated in 82%
allyl products 18–20 were isolated in good-to-excellent (61– yield. Similar reaction sequences were carried out with o-
81%) yields under PTC conditions. It is worth mentioning iodoaniline derivative 5 to provide the N-benzoyl derivative
that under PTC conditions for N-allylation of the nitro de- 31 in 92% yield, the allylated cross-coupling product 33 in
rivative 14, the isomerized product 18a was also isolated in 83% yield and the diallyl derivative 35 in 87% yield
27% yield along with the desired product 18 in 61% yield. (Scheme 3). Furthermore, the RCM product 37 was isolated
The diallyl derivatives 18–20 were similarly treated with in 89% yield. The RCM products 36 and 37 were also found
Grubbs’ catalyst (G-2, 3 mol-%) in dry DCM to deliver the to be unstable and decomposed. A similar substrate having
required RCM products 22–24 in moderate-to-good yields no electron-withdrawing group at the 7-position was
(72–96%). Unfortunately, the 1-benzazepine derivative 23 prepared by Quadir et al. by RCM and they found this 1-
was found to be highly unstable and for this reason its isola- benzazepine derivative to be very stable. Moreover, they
tion was found to be extremely difficult. Thus, the RCM provided an X-ray crystal structure of this compound.[15b]
product 23 was subjected in situ to hydrogenation condi- However, in our studies, compounds 36 and 37 have an elec-
tions to deliver the saturated product 27 in good yield (72% tron-withdrawing group at the 7-position which may have a
yield after two steps). When the RCM product 22 was hy- crucial effect on the stability of these products. Thus, unsat-
drogenated under Pd/C conditions using ethyl acetate as the urated products were isolated (but not characterized) and
solvent, the nitro group was also reduced in addition to the immediate hydrogenation of these products furnished satu-
double bond. Moreover, the free amine group thus formed rated derivatives 38 and 39 in 87% and 80% yields, respec-
was protected as the N-ethyl derivative 26 which was con- tively.
firmed by 1H NMR as well as mass spectroscopic data. The
It appears that the instability of the RCM products may
RCM product 24 was found to be stable, possibly due to the be due to the presence of two allylic CH2 groups, one of
absence of an electron-withdrawing group at the 7-position. which (C-5) is flanked by an aromatic ring and ethylene
As the 1-benzazepine derivatives 21–23 with an N-acetyl double bond, and also the two electron-withdrawing groups
protecting group are unstable, we thought of protecting the present at the 1- and 7-positions make the benzylic CH2
free amine group with different N-protecting groups to try group (C-5) amenable to aerial oxidation. Thus, we planned
to understand the factors affecting the stability of these to protect the free amine with a protecting group containing
compounds. Towards this goal, 2-iodoaniline derivative 29 an unsaturated moiety (e.g., an acryloyl group) which may
was treated with benzoyl chloride in the presence of pyr- also be a useful tether for the RCM sequence.
idine as base in dry benzene[26] to deliver the N-benzoyl
In this connection, the free amine of compound 5 was
derivative 30 in 93% isolated yield (Scheme 3). Allylation protected as the acryloyl by using a known literature pro-
of the N-benzoyl derivative 30 under Suzuki cross-coupling cedure[27] to furnish the N-acryloyl derivative 40 in 95%
conditions gave the product 32 in 92% yield. 1H NMR yield (Scheme 4). However, when compound 40 was sub-
analysis of the product 32 revealed that the product was jected to SM cross-coupling conditions to introduce the al-
contaminated with some side-product or impurity which lyl group, the coupling product 42 was isolated in a low
was difficult to separate by silica gel column chromatog- yield (29%). However, no other spot was observed in TLC
raphy.
other than the desired product. Treatment of the compound
42 with the G-2 catalyst in dry DCM at room temperature
delivered the 1-benzazepin-2-one derivative 44 in 90% yield
as a white crystalline solid. Similar reaction sequences were
applied to the 2-iodoaniline derivative 7 to deliver the N-
acryloyl derivative 41 in 93% yield, the allylated cross-coup-
ling product 43 in 25% yield and the RCM product 45 in
Scheme 3. Synthetic approach to 1-benzazepine derivatives with N-
benzoyl protection.
When the allylated product 32 was subjected to N-al-
lylation under PTC conditions, the diallyl derivative 34 was
Scheme 4. Synthesis of 1-benzazepine-2-one derivatives without N-
isolated in 73% yield. This reaction was difficult to monitor protection.
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Design and Synthesis of 1-Benzazepine Derivatives
92% yield. Both the RCM products 44 and 45 are stable at of the Claisen rearrangement. When the reaction was car-
room temperature.
ried out at a higher temperature (155–160 °C), undesired
As the N-protected derivatives 21–23 and 36–37 were product 53 was exclusively observed (TLC monitoring).
found to be unstable, we thought of synthesizing the 1-
benzazepine derivatives without a protecting group which
in turn delivers 1-benzazepine derivatives with a free NH
group. To this end, the o-iodoaniline derivative 5 was N-
allylated using conventional allylation conditions (excess
allyl bromide, K2CO3, acetonitrile, reflux) to give the
monoallylated product 46 as well as the diallylated deriva-
tive 47 in 60 and 20% yields, respectively (based on 25%
starting material recovered). When the monoallyl derivative
46 was subjected to SM cross-coupling conditions for the
allylation, the desired coupling product 48 was isolated in
12% yield along with the 3-methylindole derivative 49 in
40% yield. The formation of the indole derivative 49 from Scheme 6. Synthesis of diallyl derivative 48 by the aza-Claisen re-
arrangement.
N-alkenyl-2-haloanilines 46 under Pd-catalyzed conditions
is very well documented in the literature (Scheme 5).[28]
Next, the compound 48 was treated with the G-2 catalyst
under different reaction conditions (e.g., DCM, room
temp.; DCM, reflux; toluene, 80 °C) and no RCM product
was observed (Scheme 7). With the Grubbs–Hoveyda cata-
lyst (GH-3), no reaction was observed when reaction was
carried out in DCM at room temperature or at reflux. In
view of these observations we concluded that the presence
of the free NH group retarded the RCM due to complex-
ation of the free lone-pair electrons on nitrogen with the
Ru atom. Thus, the protection of the free NH group was
considered. In this respect, when the diallyl derivative 48
was treated with LDA followed by MeI at –78 °C, no reac-
Scheme 5. Synthesis of 7-substituted 1H-1-benzazepine derivatives
tion was observed and the starting material was recovered.
by SM cross-coupling.
Also, we tried solvent-free and formalin-free Clarke’s meth-
ylation conditions developed by Kosma and co-workers
As an alternate route for the synthesis of 1H-1-benzazep-
using paraformaldehyde and oxalic acid dihydrate at 100–
ine derivatives, we thought the diallyl derivative 48 could be
110 °C.[30] However, TLC monitoring showed that the start-
obtained by aromatic aza-Claisen rearrangement.[29]
ing material undergoes further aza-Claisen rearrangement
and is converted into compound 53. When the diallyl deriv-
ative 48 was treated with acetic anhydride (no solvent) at
room temperature for 12 h, the corresponding N-acetyl de-
Towards this end, methyl 4-aminobenzoate (50) was treated
with an excess of allyl bromide (2.5 equiv.) and K2CO3 as
base in refluxing acetonitrile for 12 h to deliver the monoal-
lyl derivative 51 as well as the diallyl derivative 52 in 31%
rivative 17 was isolated in 80% yield.
and 52.4% yields, respectively (based on 10% starting mate-
rial recovered, Scheme 6). When the diallylated derivative
was heated in xylene in the presence of BF3–Et2O (1 equiv.)
at 140 °C (oil bath) for 1.5 h,[29c] the desired aza-Claisen
rearranged product 48 was obtained in 38% yield along
with the doubly rearranged product 53 in 32% yield (based
on 10% starting material recovered, Scheme 6). If the reac-
tion was allowed to continue further until complete con-
sumption of the starting material, the desired product 48
Scheme 7. Attempted RCM conditions and N-acetyl protection of
the diallyl derivative 48.
was converted into the undesired product 53 (TLC monitor-
ing). Also, when undistilled xylene was used for the aza-
Claisen rearrangement, TLC revealed the formation of a
very complex reaction mixture. Thus, the use of freshly dis-
tilled xylene (over CaH2) is crucial for effecting a smooth
Claisen rearrangement. Also, the quantity of BF3·Et2O
used plays an important role in this reaction. When 2 equiv.
Conclusions
We have demonstrated a simple and useful strategy for
of BF3·Et2O was used, TLC revealed the formation of un- the synthesis of 1-protected 2,3,4,5-tetrahydro-1-benzazep-
desired compound 53 as the major product. We also ob- ine derivatives that involves the SM cross-coupling reaction
served a pronounced effect of temperature on the outcome and RCM as key steps. 1H-1-Benzazepin-2-one derivatives
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the reaction mixture was quenched with water and the usual work-
up with DCM gave the crude product which was purified by silica
gel column chromatography. Elution of the column with petroleum
ether/ethyl acetate gave the desired product.
44 and 45 were also synthesized following a similar reaction
sequence. The unsaturated derivatives 42 and 43 were ob-
tained in lower yields under SM cross-coupling conditions.
We also synthesized the RCM precursor 17 by aza-Claisen
rearrangement followed by acetylation. In essence, a strate-
gic combination of the SM cross-coupling reaction, aza-
Claisen rearrangement and RCM has successfully been em-
ployed for the synthesis of 1-benzazepine derivatives. As 1-
benzazepine derivatives are of medicinal importance, the
compounds prepared here, along with the strategy reported,
may find useful applications in drug discovery programs.
General Procedure for Ring-Closing Metathesis: Grubbs’ catalyst
(3 mol-%) was added to a stirred solution of the diolefinic com-
pound in dry DCM. The reaction mixture was stirred at room
temp. At the conclusion of the reaction (TLC monitoring, 45–
60 min), the solvent was removed and the crude product was puri-
fied by column chromatography. Elution of the column with petro-
leum ether/ethyl acetate gave the desired product.
General Procedure for Hydrogenation: Pd/C (10%, 20–40 mol-%)
was added to a stirred solution of the RCM product in ethyl acetate
(5 mL) and the resulting mixture was kept under hydrogen pressure
(balloon pressure) for 24 h. The reaction mixture was filtered
through a Celite pad which was washed with chloroform. The sol-
vent was removed under reduced pressure to give the hydrogenated
product.
Experimental Section
General Remarks: Analytical TLC was performed on glass plates
(10ϫ5 cm) coated with silica gel G or GF 254 (containing 13%
CaSO4 as a binder). Visualization of the spots was achieved either
by exposure to I2 vapour or UV light. Column chromatography
was performed on silica gel (100–200 mesh) usually with EtOAc
and petroleum ether (b.p. 60–80 °C) mixtures as eluent. Melting
General Procedure for N-Benzoyl Protection: Pyridine (1.5 equiv.)
and benzoyl chloride (2 equiv.) were added to a stirred solution of
o-iodoaniline (1 equiv.) in benzene and the resulting mixture was
heated at reflux. At the conclusion of the reaction (TLC monitor-
ing, nearly 5–6 h), the reaction mixture was quenched with water
and extracted with chloroform (3ϫ30 mL). The combined organic
layers were washed with dilute HCL (20 mL) and brine. Then the
solvent was evaporated and the residue was crystallized from etha-
nol to give the desired N-benzoyl derivative as a white crystalline
solid.
1
points are uncorrected. H and 13C NMR spectroscopic data were
recorded with a Varian VXR 300 or Varian VXR 400 spectrometer
using TMS as the internal standard and CDCl3 as solvent. The
coupling constants (J) are given in Hertz (Hz). High-resolution
mass spectroscopic data were recorded with a Q-ToF Micromass
spectrometer. For all the reactions, anhydrous MgSO4 or Na2SO4
was used as the drying agent after work-up.
General Procedure for N-Acryloyl Protection:[27] Acryloyl chloride
was added to a stirred solution of the amine in dry DCM and the
resulting mixture was heated at reflux for 14 h. The reaction mix-
ture was quenched with water and extracted with DCM
(3ϫ20 mL). The combined organic layers were washed with water
and brine and dried with anhydrous Na2SO4. The solvent was re-
moved and the crude product was crystallized from ethanol to pro-
vide the desired product as a white crystalline solid.
All the commercial grade reagents were used without further purifi-
cation. Grubbs’ catalysts G-1, G-2 and GH-3 and allylboronate 4
were purchased from Aldrich Chemical Co., Inc. (Milwaukee, WI,
U.S.A.). 2-Iodoaniline derivatives 5–8,[22b] N-acetyl derivatives 9[24]
and 12,[31] N-benzoyl derivative 31[26] and N-acryloyl derivative
40[27] were prepared according to the reported procedures.
General Procedure for the N-Acetyl Protection of o-Iodoaniline De-
rivatives:[24] One drop of concd. H2SO4 was added to a stirred solu-
tion of the aniline derivative in acetic anhydride. The resulting mix-
ture was stirred at room temp. for 5 min and then quenched with
water and extracted with DCM (3ϫ50 mL). The combined organic
layers were washed with water, brine and dried with anhydrous so-
dium sulfate. The solvent was removed and the crude product was
crystallized from ethanol to give the N-acetyl derivative as a crys-
talline solid.
Preparation of 2-Iodo-4-nitroacetanilide (10): 2-Iodoaniline deriva-
tive 6 (1.2 g, 4.5 mmol), acetic anhydride (8 mL) and concd. H2SO4
(1–2 drops) were treated as described in the general procedure and
crystallization from ethanol gave the desired product 10 (1.25 g,
90%) as a pale yellow solid, m.p. 137–140 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.32 (s, 3 H), 8.23 (dd, J = 2.4, 9.2 Hz, 1 H), 8.54 (d,
J = 9.2 Hz, 1 H), 8.63 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 25.1, 87.4, 119.8, 124.9, 134.2, 143.4,
143.8, 168.6 ppm. HRMS (Q-ToF): calcd. for C8H8N2O3I [M +
H]+ 306.9580; found 306.9581.
General Procedure for Allylation by the Suzuki–Miyaura Cross-
Coupling Reaction: In
a three-necked round-bottomed flask
equipped with a reflux condenser and nitrogen inlet/outlet, the
iodo-derivative (1 equiv.), CsF (2 equiv.), [Pd(PPh3)4] (6 mol-%)
and dry THF (5 mL) were added. The resulting suspension was
stirred at room temp. for 30 min. A solution of allylboronate 4
(2 equiv.) in THF (5 mL) was added to this suspension and the
resulting mixture was heated at reflux. At the conclusion of the
reaction (TLC monitoring), the reaction mixture was quenched
with water and the usual work-up with DCM gave the crude prod-
uct. The product was purified by silica gel column chromatography.
Elution of the column with an appropriate petroleum ether/ethyl
acetate mixture gave the desired product as a crystalline solid.
Preparation of 4-Acetyl-2-iodoacetanilide (11): 2-Iodoaniline deriva-
tive 7 (1.3 g, 4.98 mmol), acetic anhydride (5 mL) and concd.
H2SO4 (1 drop) were treated as described in the general procedure
to give the desired product 11 (1.34 g, 89%) as a pale yellow solid,
1
m.p. 155–158 °C. H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H),
2.57 (s, 3 H), 7.67 (br. s, 1 H), 7.91 (dd, J = 1.6, 8.4 Hz, 1 H), 8.38
(d, J = 1.6 Hz, 1 H), 8.41 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 25.1, 26.5, 89.1, 120.2, 129.9, 134.1,
139.1, 142.2, 168.5, 195.6 ppm. HRMS (Q-ToF): calcd. for
C10H11NO2I [M + H]+ 303.9835; found 303.9845.
General Procedure for the N-Alkylation:[25] A solution of the start-
ing material (1 equiv.) and allyl bromide (1.2 equiv.) in dry THF
was added to a suspension of KOH (1.2 equiv.) and TBAI (2 equiv.)
in dry THF (5 mL) over 2–3 min. The reaction mixture was stirred
at room temp. At the conclusion of the reaction (TLC monitoring),
Preparation of 4-Methoxycarbonyl-2-(2-propenyl)acetanilide (13):
N-Acetyl derivative
9
(100 mg, 0.31 mmol), CsF (95 mg,
0.62 mmol), [Pd(PPh3)4] (22 mg, 6 mol-%) and allylboronate 4
(106 mg, 0.63 mmol) in THF (15 mL) were treated as described in
the general procedure for allylation. At the conclusion of the reac-
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Design and Synthesis of 1-Benzazepine Derivatives
tion (TLC monitoring, 12 h), the reaction mixture was quenched
with water and the usual work-up using DCM gave the crude prod-
uct which was charged onto a silica gel column. Elution of the
column with 30% ethyl acetate/petroleum ether gave the desired
product 13 (66.0 mg, 90%) as a white solid, m.p. 123–125 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.17 (s, 3 H), 3.44 (d, J = 6.0 Hz, 2
H), 3.90 (s, 3 H), 5.14 (d, J = 17.2 Hz, 1 H), 5.24 (d, J = 10 Hz, 1
H), 5.93–6.02 (m, 1 H), 7.50 (br. s, 1 H), 7.87 (s, 1 H), 7.93 (dd, J
ture was quenched with water and the usual work-up using DCM
gave the crude product which was charged onto a silica gel column.
Elution of the column with 20% ethyl acetate/petroleum ether gave
the desired product 17 (53.0 mg, 90%) as a white solid, m.p. 52–
53 °C. 1H NMR (400 MHz, CDCl3): δ = 1.76 (s, 3 H), 3.35 (d, J =
5.6 Hz, 2 H), 3.69–3.75 (m, 1 H, N-CHH-cis), 3.94 (s, 3 H), 4.68–
4.74 (m, 1 H, N-CHH-trans), 5.03 (dq, J = 17.2, 1.6 1.2 Hz, 1 H),
5.10–5.10 (m 3 H), 5.82–5.93 (m, 2 H), 7.15 (d, J = 8.0 Hz, 1 H),
= 2.0, 8.4 Hz, 1 H), 8.13 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR 7.92 (dd, J = 8.0, 2.0 Hz, 1 H), 8.03 (d, J = 2.0 Hz, 1 H) ppm. 13C
(100.5 MHz, CDCl3): δ = 24.3, 36.7, 52.1, 117.3, 122.3, 126.1,
128.8, 129.1, 131.6, 135.6, 140.6, 166.7, 168.7 ppm. HRMS (Q-
ToF): calcd. for C13H14NO3 [M + H]+ 256.0950; found 256.0954.
NMR (100.5 MHz, CDCl3): δ = 22.6, 35.1, 51.7, 52.5, 117.8, 119.0,
128.8, 129.9, 130.4, 132.2, 132.5, 135.2, 138.2, 145.0, 166.4,
170.1 ppm. HRMS (Q-ToF): calcd. for C16H19NO3Na [M + Na]+
296.1263; found 296.1270.
Preparation of 4-Nitro-2-(2-propenyl)acetanilide (14): N-Acetyl de-
rivative 10 (200 mg, 0.65 mmol), CsF (200 mg, 1.3 mmol),
Preparation of Diallyl Derivative 18: Allyl derivative 14 (100.0 mg,
[Pd(PPh3)4] (45.3 mg, 6 mol-%) and allylboronate 4 (220 mg, 0.46 mmol), KOH (28.0 mg, 0.5 mmol), TBAI (336 mg, 0.92 mmol)
1.3 mmol) in THF (15 mL) were treated as described in the general
procedure for allylation. At the conclusion of the reaction (TLC
monitoring, 24 h), the reaction mixture was quenched with water
and the usual work-up using DCM gave the crude product which
was charged onto a silica gel column. Elution of the column with
20% ethyl acetate/petroleum ether gave the desired product 14
(87.0 mg, 64%) as a white solid, m.p. 133–136 °C. 1H NMR
and allyl bromide (61.0 mg, 0.5 mmol) were treated as described in
the general procedure for the N-alkylation. At the conclusion of
the reaction (TLC monitoring, 4.5 h), the reaction mixture was
quenched with water and the usual work-up using DCM gave the
crude product which was charged onto a silica gel column. Elution
of the column with 3.5% ethyl acetate/petroleum ether gave the
desired product 18 (72.0 mg, 61%) as a light-yellow low-melting
1
(400 MHz, CDCl3): δ = 2.20 (s, 3 H), 3.50 (dd, J = 6.0, 1.6 Hz, 2 solid. H NMR (400 MHz, CDCl3): δ = 1.79 (s, 3 H), 3.41 (d, J =
H), 5.21 (dq, J = 17.2, 2.0, 1.6 1.2 Hz, 1 H), 5.33 (dq, J = 10.0,
1.6, 1.2, 1.2 Hz, 1 H), 5.95–6.04 (m, 1 H), 7.54 (br. s, 1 H), 8.09 (d,
J = 2.4 Hz, 1 H), 8.15 (dd, J = 2.4, 8.8 Hz, 1 H), 8.34 (d, J =
6.0 Hz, 2 H), 3.75 (dd, J = 14.4, 7.6 Hz, 1 H), 4.73 (dd, J = 14.4,
6.0 Hz, 1 H), 5.27–5.02 (m, 4 H), 5.95–5.82 (m, 2 H), 7.28 (d, J =
8.8 Hz, 1 H), 8.13 (dd, J = 8.8, 2.4 Hz, 1 H), 8.24 (d, J = 2.0 Hz,
8.8 Hz, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 24.8, 36.2, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 22.7, 35.2, 51.8,
118.4, 121.7, 123.5, 125.7, 128.7, 134.6, 142.4, 142.4, 143.7, 118.9, 119.6, 122.8, 126.0, 130.9, 32.2, 134.2, 140.2, 146.7, 147.7,
168.5 ppm. HRMS (Q-ToF): calcd. for C11H13N2O3 [M + H]+
221.0926; found 221.0931.
169.6 ppm. HRMS (Q-ToF): calcd. for C14H16N2O3 [M + H]+
261.1231; found 261.1240.
Preparation of 4-Acetyl-2-(2-propenyl)acetanilide (15): N-Acetyl de-
rivative 11 (250 mg, 0.83 mmol), CsF (250 mg, 1.6 mmol),
[Pd(PPh3)4] (57.0 mg, 6 mol-%) and allylboronate 4 (277 mg, m.p. 109–112 °C. H NMR (400 MHz, CDCl3): δ = 1.78 (s, 3 H),
Further elution of the column with 5% ethyl acetate/petroleum
ether gave isomerized product 18a (32 mg, 27%) as a yellow solid,
1
1.6 mmol) in THF (15 mL) were treated as described in the general
procedure for allylation. At the conclusion of the reaction (TLC
monitoring, 16 h), the reaction mixture was quenched with water
and the usual work-up using DCM gave the crude product which
was charged onto a silica gel column. Elution of the column with
25% ethyl acetate/petroleum ether gave the desired product 15
(135 mg, 76%) as a white solid, m.p. 126–128 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.18 (s, 3 H), 2.58 (s, 3 H), 3.45 (d, J =
6.0 Hz, 2 H), 5.12–5.26 (m, 2 H), 5.93–6.03 (m, 1 H), 7.59 (br. s, 1
H), 7.80 (s, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 7.2 Hz, 1
H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 24.4, 26.5, 36.6,
117.3, 122.4, 128.1, 129.2, 130.2, 133.2, 135.4, 140.7, 168.8,
197.4 ppm. HRMS (Q-ToF): calcd. for C13H16NO2 [M + H]+
218.1181; found 218.1186.
1.97 (dd, J = 1.6, 6.4 Hz, 3 H), 4.67–4.72 (m, 1 H), 5.04 (dd, J =
1.2 16.8 Hz, 1 H), 5.12 (dd, J = 0.8, 10.0 Hz, 1 H), 5.80–5.90 (m,
2 H), 6.39 (dd, J = 1.6, 15.6 Hz, 1 H), 6.46–6.55 (m, 1 H), 7.24 (d,
J = 8.4 Hz, 1 H), 8.08 (dd, J = 2.8, 8.4 Hz, 1 H), 8.24 (d, J =
2.8 Hz, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 19.1, 22.8,
51.6, 119.5, 121.8, 122.4, 124.2, 130.8, 132.2, 133.2, 137.8, 144.6,
147.8, 169.8 ppm. HRMS (Q-ToF): calcd. for C14H16N2O3 [M +
H]+ 261.1231; found 261.1235.
Preparation of Diallyl Derivative 19: Allyl derivative 15 (50.0 mg,
0.23 mmol), KOH (16.0 mg, 0.25 mmol), TBAI (170 mg,
0.46mmol) and allyl bromide (31.0 mg, 0.25 mmol) were treated as
described in the general procedure for the N-alkylation. At the con-
clusion of the reaction (TLC monitoring, 4 h), the reaction mixture
was quenched with water and the usual work-up using DCM gave
the crude product which was charged onto a silica gel column. Elu-
tion of the column with 15% ethyl acetate/petroleum ether gave the
desired product 19 (48 mg, 81%) as a colourless thick liquid. 1H
NMR (400 MHz, CDCl3): δ = 1.77 (s, 3 H), 2.62 (s, 3 H), 3.37 (d,
J = 6.4 Hz, 2 H), 3.72 (dd, J = 14.4, 7.6 Hz, 1 H, N-CH2-cis), 4.72
(dd, J = 14.4, 6.0 Hz, 1 H, N-CH2-trans), 5.01–5.19 (m, 4 H), 5.83–
5.95 (m, 2 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.84 (dd, J = 8.0, 2.0 Hz,
1 H), 7.94 (d, J = 1.6 Hz, 1 H) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 22.7, 26.8, 35.2, 51.8, 117.9, 119.1, 127.7, 130.2, 131.0,
132.6, 135.2, 137.2, 138.5, 145.3, 170.1, 197.5 ppm. HRMS (Q-
ToF): calcd. for C16H20NO2 [M + H]+ 258.1494; found 258.1496.
Preparation of 2-(2-Propenyl)acetanilide (16): N-Acetyl derivative
12 (300 mg, 1.14 mmol), CsF (314 mg, 2.28 mmol), [Pd(PPh3)4]
(78.0 mg, 6 mol-%) and allylboronate 4 (386 mg, 2.28 mmol) in
THF (15 mL) were treated as described in the general procedure
for allylation. At the conclusion of the reaction (TLC monitoring,
22 h), the reaction mixture was quenched with water and the usual
work-up using DCM gave the crude product which was charged
onto a silica gel column. Elution of the column with 15% ethyl
acetate/petroleum ether gave the desired product 16 (187.0 mg,
93%) as a white crystalline solid, m.p. 91–94 °C (ref.[32] 87–89 °C).
Preparation of Diallyl Derivative 17: Allyl derivative 13 (50.0 mg,
0.214 mmol), KOH (13.2 mg, 0.23 mmol), TBAI (158 mg, Preparation of Diallyl Derivative 20: Allyl derivative 16 (56.0 mg,
0.42 mmol) and allyl bromide (29.0 mg, 0.23 mmol) were treated
as described in the general procedure for the N-alkylation. At the
conclusion of the reaction (TLC monitoring, 3 h), the reaction mix-
0.33 mmol), KOH (22.3 mg, 0.39 mmol), TBAI (245 mg,
0.66mmol) and allyl bromide (48.0 mg, 0.39 mmol) were treated as
described in the general procedure for the N-alkylation. At the con-
Eur. J. Org. Chem. 2008, 1054–1064
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1059

S. Kotha, V. R. Shah
FULL PAPER
clusion of the reaction (TLC monitoring, 4 h), the reaction mixture
was quenched with water and the usual work-up using DCM gave
the crude product which was charged onto a silica gel column. Elu-
tion of the column with 15% ethyl acetate/petroleum ether gave the
desired product 20 (56 mg, 82%) as a colourless thick oil. 1H NMR
(400 MHz, CDCl3): δ = 1.76 (s, 3 H), 3.32 (d, J = 5. 6 Hz, 2 H),
3.71 (dd, J = 14.6, 7.6 Hz, 1 H, N-CHH-cis), 4.70 (dd, J = 14.6,
6.0 Hz, 1 H, N-CHH-trans), 5.02–5.13 (m 4 H), 5.84–5.94 (m, 2
H), 7.15 (d, J = 7.6 Hz, 1 H), 7.11–7.35 (m, 3 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 22.6, 35.2, 51.8, 117.1, 118.5, 127.6,
127.8, 128.5, 128.6, 129.4, 130.9, 132.9, 135.9, 137.6, 141.1,
170.7 ppm. HRMS (Q-ToF): calcd. for C14H18NO [M + H]+
216.1388; found 216.1388.
128.1, 128.5, 129.2, 139.9, 142.5, 170.2 ppm. HRMS (Q-ToF):
calcd. for C12H14NO [M + H]+ 188.107; found 188.1076.
Preparation of 1-Acetyl-7-methoxycarbonyl-2,3,4,5-tetrahydro-1-
benzazepine (25): The RCM product 21 (21.0 mg, 0.09 mmol) and
Pd/C (10%) (34.5 mg, 20 mol-%) in ethyl acetate (5 mL) were
treated as described in the general procedure for hydrogenation to
give the desired product 25 (20.1 mg, 95%) as a thick colourless
1
liquid. H NMR (400 MHz, CDCl3): δ = 1.24–1.30 (m, 2 H), 1.87
(s, 3 H), 2.04–1.71 (m, 2 H), 2.62–2.56 (m, 1 H), 2.81 (t, J = 4.8,
5.6 Hz, 2 H), 3.93 (s, 3 H), 4.73–4.70 (m, 1 H), 7.21 (d, J = 8.4 Hz,
1 H), 7.91, (dd, J = 2.0, 8.4 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 1 H) ppm.
13C NMR (100.5 MHz, CDCl3): δ = 22.8, 26.3, 28.9, 34.6, 47.1,
52.4, 127.9, 128.9, 129.7, 131.7, 140.9, 147.9, 166.6, 169.2 ppm.
HRMS (Q-ToF): calcd. for C14H18NO3 [M + H]+ 248.1287; found
248.1287.
Preparation of 1-Acetyl-7-methoxycarbonyl-2,5-dihydro-1-benzazep-
ine (21): Diallyl derivative 17 (45 mg, 0.17 mmol) in dry DCM
(5 mL) was treated with Grubbs’ catalyst G-2 (4.2 mg, 3 mol-%) as
in the general procedure for RCM. At the conclusion of the reac-
tion (TLC monitoring, 35 min), the reaction mixture was quenched
with water and the usual work-up using DCM gave the crude prod-
uct which was charged onto a silica gel column. Elution of the
column with 22% ethyl acetate/petroleum ether gave the desired
product 21 (39.0 mg, 90%) as a white solid, m.p. 108–112 °C.
(Note: product decomposes when kept in concentrated form.) 1H
NMR (400 MHz, CDCl3): δ = 1.86 (s, 3 H), 3.13–3.07 (m, 1 H),
3.43–3.38 (m, 1 H), 3.81–3.77 (m, 1 H), 3.94 (s, 3 H), 5.41–5.36 (m,
1 H), 5.53–5.49 (m, 1 H), 5.80–5.74 (m, 1 H), 7.28 (d, J = 8.0 Hz,
1 H), 7.93 (d, J = 2.0 Hz, 1 H), 7.98 (dd, J = 2.4, 8.0 Hz, 1 H) ppm.
13C NMR (100.5 MHz, CDCl3): δ = 22.3, 31.9, 44.9, 52.5, 124.9,
127.0, 128.1, 129.5, 1130.2, 140.2, 146.5, 166.4, 169.6 ppm. HRMS
(Q-ToF): calcd. for C14H16NO3 [M + H]+ 246.1130; found
246.1129.
Preparation of 1-Acetyl-7-(ethylamino)-2,3,4,5-tetrahydro-1-benz-
azepine (26): The RCM product 22 (10.0 mg, 0.04 mmol) and Pd/
C (10%,10.0 mg, 20 mol-%) in ethyl acetate (5 mL) were treated as
described in the general procedure for hydrogenation to give the
product 26 (9.3 mg, 92%) as a thick colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.15–1.42 (m, 4 H), 1.77–1.98 (m, 6 H),
2.69 (t, J = 8.4 Hz, 1 H), 3.15 (q, J = 7.2 Hz, 2 H), 4.65 (d, J =
13.2 Hz, 1 H), 6.40–6.44 (m, 2 H), 6.90 (d, J = 8.0 Hz, 1 H) ppm.
13C NMR (100.5 MHz, CDCl3): δ = 15.3, 22.7, 27.0, 29.2, 34.9,
38.7, 47.6, 110.5, 113.6, 128.4, 133.7, 141.5, 148.0, 170.6 ppm.
HRMS (Q-ToF): calcd. for C14H21N2O [M + H]+ 233.1654; found
233.1664.
Preparation of 1,7-Diacetyl-2,3,4,5-tetrahydro-1-benzazepine (27):
Diallyl derivative 23 (12 mg, 0.05 mmol) in dry DCM (2 mL) was
treated with Grubbs’ catalyst G-2 (2.0 mg, 3 mol-%) as in the gene-
ral procedure for RCM. At the conclusion of the reaction (TLC
monitoring), Pd/C (10%, 20 mg, 40 mol-%) and dry ethyl acetate
(5 mL) were added to the same reaction vessel. The reaction mix-
ture was then kept under a hydrogen pressure of 1 atm. (balloon
pressure) for 24 h. After that, the reaction mixture was filtered
through a Celite pad which was successively washed with chloro-
form (3 ϫ10 mL). The solvent was removed in vacuo to provide
the desired product 27 (7.3 mg, overall 72% yield for two steps) as
a thick liquid. 1H NMR (400 MHz, CDCl3): δ = 1.38–1.40 (m, 1
H), 1.78–2.05 (m, 6 H), 2.56–2.62 (m, 4 H), 2.82 (t, J = 5.2 Hz, 2
H), 4.73 (d, J = 12.8 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.83 (dd,
J = 1.6, 8.0 Hz, 1 H), 7.86 (d, J = 1.6 Hz, 1 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 22.9, 26.4, 26.8, 29.0, 34.7, 47.2, 127.7,
128.1, 130.4, 136.7, 141.1, 148.1, 169.2, 197.5 ppm. HRMS (Q-
ToF): calcd. for C14H18NO2 [M + H]+ 232.1338; found 232.1328.
Preparation of 1-Acetyl-7-nitro-2,5-dihydro-1-benzazepine (22): Di-
allyl derivative 18 (33.0 mg, 0.13 mmol) in dry DCM (5 mL) was
treated with Grubbs’ catalyst G-2 (3.2 mg, 3 mol-%) as in the gene-
ral procedure for RCM. At the conclusion of the reaction (TLC
monitoring, 25 min), the reaction mixture was quenched with water
and the usual work-up using DCM gave the crude product which
was charged onto a silica gel column. Elution of the column with
25% ethyl acetate/petroleum ether gave the desired product 22
(28.2 mg, 96%) as a liquid. (Note: product decomposes when kept in
concentrated form.) 1H NMR (400 MHz, CDCl3): δ = 1.88 (s, 3 H),
3.17 (m, 1 H), 3.38–3.43 (m, 1 H), 3.82–3.86 (m, 1 H), 5.40–5.45
(m, 1 H), 5.52–5.56 (m, 1 H), 5.75–5.81 (m, 1 H), 7.39 (d, J =
8.8 Hz, 1 H), 8.14 (d, J = 2.4 Hz, 1 H), 8.19 (dd, J = 2.4, 8.8 Hz,
1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 22.4, 31.9, 44.8,
123.3, 123.4, 124.4, 127.2, 129.1, 141.8, 1447.4, 148.1, 169.2 ppm.
HRMS (Q-ToF): calcd. for C12H13N2O3 [M + H]+ 233.0926; found
233.0931.
Preparation of 1-Acetyl-2,3,4,5-tetrahydro-1H-benzazepine (28):
The RCM product 24 (13.3 mg, 0.09 mmol) and Pd/C (10%,
30.0 mg, 20 mol-%) in ethyl acetate (5 mL) were treated as de-
scribed in the general procedure for hydrogenation to give the de-
Preparation of 1-Acetyl-2,5-dihydro-1-benzazepine (24): Diallyl de-
rivative 20 (29.0 mg, 0.13 mmol) in dry DCM (5 mL) was treated
with Grubbs’ catalyst G-2 (2.3 mg, 3 mol-%) as described in the
general procedure for RCM. At the conclusion of the reaction
(TLC monitoring, 45 min), the reaction mixture was quenched with
water and the usual work-up using DCM gave the crude product
which was charged onto a silica gel column. Elution of the column
with 15% ethyl acetate/petroleum ether gave the desired product
24 (18 mg, 72%) as a while solid, m.p. 102–104 °C. (Note: product
1
sired product 28 (10.8 mg, 81%) as a liquid. H NMR (400 MHz,
CDCl3):[6] δ = 1.34–1.43 (m, 1 H), 1.76–2.00 (m, 4 H), 2.57–2.81
(m, 2 H), 7.13 (d, J = 3.2 Hz, 1 H), 7.22–7.27 (m, 2 H) ppm.
Preparation of Ethyl 4-Benzoylamino-3-iodobenzoate (30): o-
Iodoaniline derivative 29 (600 mg, 2.06 mmol), pyridine (4 mL) and
benzoyl chloride (434 mg, 3.0 mmol) in dry benzene (15 mL) were
treated as described in the general procedure for N-benzoylation.
At the conclusion of the reaction (TLC monitoring, 32 h), the reac-
tion mixture was quenched with water and the usual work-up using
DCM gave the crude product. Crystallization of the crude from
ethanol (8 mL) gave the desired product 30 (760 mg, 93%) as a
white crystalline solid. 1H NMR (400 MHz, CDCl3): δ = 1.40 (t, J
= 7.2 Hz, 3 H), 4.38 (q, J = 7.2 Hz, 2 H), 7.53–7.74 (m 3 H), 7.89
1
decomposes when kept in concentrated form.) H NMR (400 MHz,
CDCl3): δ = 1.86 (s, 3 H), 2.97–3.03 (m, 1 H), 3.42 (d, J = 17.6 Hz,
1 H), 3.74–3.79 (m, 1 H), 5.32–5.39 (m, 1 H), 5.47–5.52 (m, 1 H),
5.72–5.79 (m,
(100.5 MHz, CDCl3): δ = 22.3, 32.0, 45.1, 124.5, 127.0, 127.8,
1 H), 7.18–7.32 (m, 4
H) ppm. 13C NMR
1060
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1054–1064

Design and Synthesis of 1-Benzazepine Derivatives
(dd, J = 1.2, 7.8 Hz, 2 H), 8.07 (dd, J = 1.6, 8.8 Hz, 1 H), 8.52 (br.
s, 1 H), 8.50 (d, J = 1.6 Hz, 1 H), 8.62 (d, J = 8.8 Hz, 1 H) ppm.
13C NMR (100.5 MHz, CDCl3): δ = 14.5, 61.5, 88.9, 120.2, 127.4,
127.6, 129.3, 131.2, 132.8, 134.2, 140.3, 142.2, 164.9, 165.5 ppm.
HRMS (Q-ToF): calcd. for C16H14NIO3Na [M + Na]+ 417.9916;
found 417.9921.
procedure for the N-alkylation. At the conclusion of the reaction
(TLC monitoring, 1.5 h), the reaction mixture was quenched with
water and the usual work-up using DCM gave the crude product
which was charged onto a silica gel column. Elution of the column
with 9% ethyl acetate/petroleum ether gave the desired product 35
(47.3 mg, 87%) as a colourless thick liquid. 1H NMR (400 MHz,
CDCl3): δ = 3.13–3.19 (m, 1 H), 3.32–3.38 (m, 1 H), 3.87 (s, 3 H),
4.09–4.14 (m, 1 H), 4.73 (dd, J = 6.0, 14.4 Hz, 1 H), 5.06–5.17 (m,
4 H), 5.67–5.71 (m, 1 H), 5.97–6.03 (m, 1 H), 7.11–7.27 (m, 6 H),
7.77–7.82 (m, 2 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 35.1,
52.4, 53.3, 117.9, 119.1, 127.9, 128.4, 128.6, 129.5, 129.9, 130.2,
132.1, 132.4, 135.3, 135.5, 137.5, 145.7, 166.5, 170.2 ppm. HRMS
(Q-ToF): calcd. for C21H222NO3 [M + H]+ 336.1600; found
336.1605
Preparation of Ethyl 4-Benzoylamino-3-(2-propenyl)benzoate (32):
N-Benzoyl derivative 30 (250 mg, 0.63 mmol), CsF (191.0 mg,
1.26 mmol), [Pd(PPh3)4] (44.0 mg, 6 mol-%) in THF (15 mL) and
allylboronate 4 (212.0 mg, 1.3 mmol) in THF (5 mL) were treated
as described in the general procedure for allylation. Elution of the
column with 8% ethyl acetate/petroleum ether gave the desired
product 32 (178.0 mg, 92%) as a white solid. (Note: 1H and 13C
1
NMR show that compound 32 is an inseparable mixture.) H NMR
(400 MHz, CDCl3): δ = 1.41 (t, J = 7.6 Hz, 3 H), 3.53 (d, J =
6.0 Hz, 2 H), 4.37 (q, J = 7.6 Hz, 2 H), 5.16 (dd, J = 1.2, 17.2 Hz,
1 H), 5.31 (dd, J = 2.0, 7.6 Hz, 1 H), 6.01–6.11 (m, 1 H), 7.47–7.58
(m, 3 H), 7.83–7.85 (m, 2 H), 7.92 (d, J = 2.4 Hz, 1 H), 8.02 (dd,
J = 2.4, 8.8 Hz, 1 H), 8.18 (br. s, 1 H), 8.35 (d, J = 8.8 Hz, 1
H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 14.5, 37.2, 61.1,
117.8, 121.9, 126.6, 127.2, 128.4, 129.0, 129.5, 132.0, 132.3, 134.7,
135.6, 140.8, 165.6, 166.4 ppm. HRMS (Q-ToF): calcd. for
C19H20NO3 [M + H]+ 310.1443; found 310.1451.
Preparation of Tetrahydro-1-benzazepine Derivative 38: Diallyl de-
rivative 34 (27 mg, 0.077 mmol) in dry DCM (2 mL) was treated
with Grubbs’ catalyst (2.0 mg, 3 mol-%) as in the general procedure
for RCM. At the conclusion of the reaction (TLC monitoring,
45 min), the solvent was removed and the crude product was puri-
fied by silica gel column chromatography. Elution of the column
with 9% ethyl acetate/petroleum ether gave RCM product 36
(17.2 mg, 82%) which was used further without characterization.
Preparation of Methyl 4-(Benzoylamino)-3-(2-propenyl)benzoate
Pd/C (10%, 20 mg, 40 mol-%) was added to a stirred solution of
(33): N-Benzoyl derivative 31 (150 mg, 0.39 mmol), CsF (120 mg, compound 36 (12.0 mg, 0.04 mmol) in dry ethyl acetate (5 mL).
0.78 mmol), [Pd(PPh3)4] (27 mg, 6 mol-%) in THF (15 mL) and al-
lylboronate 4 (132 mg, 0.78 mmol) in dry THF (5 mL) were treated
as described in the general procedure for allylation by the SM
cross-coupling reaction. At the conclusion of the reaction (TLC
monitoring, 4 h), the reaction mixture was quenched with water
and the usual work-up using DCM gave the crude product which
was charged onto a silica gel column. Elution of the column with
9% ethyl acetate/petroleum ether gave the desired product 33
(96.5 mg, 83%) as a white solid, m.p. 111–114 °C. 1H NMR
The reaction mixture was then kept under a hydrogen pressure of
1 atm. (balloon pressure) for 24 h. After that, the reaction mixture
was filtered through a Celite pad which was successively washed
with chloroform (3ϫ10 mL). The solvent was removed in vacuo to
provide the desired product 38 (10.6 mg, 87%) as a thick liquid.
1H NMR (400 MHz, CDCl3): δ = 1.36 (t, J = 7.2 Hz, 3 H), 1.41
(br. s, 1 H), 1.95 (br. s, 2 H), 2.10 (br. s, 1 H), 2.76 (br. s, 1 H),
2.99–3.02 (m, 2 H), 4.33 (q, J = 7.2 Hz, 2 H), 5.02 (br. s, 1 H), 6.66
(d, J = 8.0 Hz, 1 H), 7.15–7.25 (m, 5 H), 7.56 (d, J = 8.0 Hz, 1 H),
(400 MHz, CDCl3): δ = 3.51 (dd, J = 1.6, 4.4 Hz, 2 H), 3.91 (s, 3 7.92 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ
H), 5.13–5.18 (dq, J = 1.6, 17.2 Hz, 1 H), 5.28–5.32 (dq, J = 1.6, = 14.5, 26.1, 29.6, 35.1, 47.8, 61.3, 128.1, 128.2, 128.4, 128.6, 129.0,
7.6 Hz, 1 H), 6.01–6.09 (m, 1 H), 7.48–7.52 (m, 3 H), 7.83–7.85 (m, 130.0, 131.6, 135.2, 139.3, 148.3, 166.2 ppm. HRMS (Q-ToF):
2 H), 7.93 (d, J = 2.0 Hz, 1 H), 8.00 (dd, J = 2.0, 8.4 Hz, 1 H),
8.19 (br. s, 1 H), 8.33 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 37.2, 52.2, 117.8, 121.9, 126.2, 127.2,
128.4, 129.0, 129.5, 132.0, 132.4, 134.7, 135.6, 140.9, 165.6,
166.8 ppm. HRMS (Q-ToF): calcd. for C18H18NO3 [M + H]+
296.1287; found 296.1282.
calcd. for C14H18NO2 [M + H]+ 324.1600; found 324.1585.
Preparation of Tetrahydro-1-benzazepine Derivative 39: Diallyl de-
rivative 35 (20 mg, 0.06 mmol) in dry DCM (2 mL) was treated
with Grubbs’ catalyst (1.5 mg, 3 mol-%) as in the general procedure
for RCM. At the conclusion of the reaction (TLC monitoring,
40 min), the solvent was removed and the crude product was puri-
fied by silica gel column chromatography. Elution of the column
with 9% ethyl acetate/petroleum ether gave RCM product 37
(16.2 mg, 89%) which was used further without characterization.
Preparation of Ethyl 4-[Benzoyl(2-propenyl)amino]-3-(2-propenyl)-
benzoate (34): Allyl derivative 32 (83.0 mg, 0.27 mmol), KOH
(17.0 mg, 0.3 mmol), TBAI (198 mg, 0.5 mmol) and allyl bromide
(35.0 mg, 0.3 mmol) were treated as described in the general pro-
cedure for the N-alkylation. Elution of the column with 8% ethyl
acetate/petroleum ether gave the desired product 34 (68 mg, 73%)
as a thick colourless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.38
(t, J = 7.6 Hz, 3 H), 3.13–3.19 (m, 1 H), 3.32–3.38 (m, 1 H), 4.09–
4.14 (m, 1 H), 4.32 (q, J = 7.6 Hz, 2 H), 4.73 (dd, J = 6.0, 14.4 Hz,
1 H), 5.06–5.17 (m, 4 H), 5.67–5.71 (m, 1 H), 5.97–6.03 (m, 1 H),
Pd/C (10%, 16.5 mg, 40 mol-%) was added to a stirred solution of
compound 37 (12.0 mg, 0.04 mmol) in dry ethyl acetate (5 mL).
The reaction mixture was then kept under a hydrogen pressure of
1 atm (balloon pressure) for 24 h. Then the reaction mixture was
filtered through a Celite pad which was successively washed with
chloroform (3ϫ10 mL). The solvent was removed in vacuo to pro-
vide the desired product 39 (9.7 mg, 80%) as a thick liquid. 1H
NMR (400 MHz, CDCl3): δ = 1.41 (br. s, 1 H), 1.95 (br. s, 2 H),
2.10 (br. s, 1 H), 2.76 (br. s, 1 H), 2.99–3.03 (m, 2 H), 3.87 (s, 3 H),
5.03 (br. s, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 7.14–7.23 (m, 5 H), 7.55
(d, J = 8.0 Hz, 1 H), 7.92 (d, J = 1.6 Hz, 1 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 26.1, 29.6, 35.1, 47.7, 52.9, 128.1, 128.2,
128.4, 128.7, 130.1, 131.6, 135.9, 139.4, 148.4, 166.6, 169.4 ppm.
HRMS (Q-ToF): calcd. for C19H20NO3 [M + H]+ 310.1443; found
310.1431.
7.11–7.27 (m,
6 H), 7.77–7.82 (m, 2
H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 14.4, 35.1, 53.3, 61.4, 117.9, 119.1, 127.8,
128.3, 128.6, 129.6, 129.9, 130.2, 132.1, 132.5, 135.3, 135.6, 137.5,
145.6, 166.0, 170.2 ppm. HRMS (Q-ToF): calcd. for C22H24NO3
[M + H]+ 350.1756; found 350.1764.
Preparation of Methyl 4-[Benzoyl(2-propenyl)amino]-3-(2-propenyl)-
benzoate (35): Allyl derivative 33 (48 mg, 0.17 mmol), KOH
(12.0 mg, 0.21 mmol), TBAI (130 mg, 0.34 mmol) and allyl bro-
mide (26.0 mg, 0.21 mmol) were treated as described in the general
Eur. J. Org. Chem. 2008, 1054–1064
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1061

S. Kotha, V. R. Shah
FULL PAPER
Preparation of 3-Iodo-4-(acrylamido)acetophenone (41): Aniline de-
rivative 7 (180 mg, mmol) and acryloyl chloride (135.5 mg, mmol)
in dry DCM were treated as described in the general procedure
for N-acryloyl protection. At the conclusion of the reaction (TLC
monitoring, 7 h), the reaction mixture was quenched with water
and the usual work-up gave the crude. Crystallization of the crude
product from ethanol gave the desired product 41 (180 mg, 93%)
CDCl3): δ = 3.44 (d, J = 6.4 Hz, 2 H), 3.91 (s, 3 H), 6.01 (d, J =
10.8 Hz, 1 H), 6.66 (td, J = 4.0, 6.8, 10.8 Hz, 1 H), 7.15 (d, J =
8.0 Hz, 1 H), 7.85 (d, J = 1.6 Hz, 1 H), 7.90 (dd, J = 1.6, 8.0 Hz,
1 H), 9.80 (br. s, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ =
32.3, 52.5, 120.6, 125.7, 126.9, 129.5, 130.6, 131.0, 140.9, 141.9,
166.6, 168.5 ppm. HRMS (Q-ToF): calcd. for C12H12NO3
[M + H]+ 218.0817; found 218.0819.
1
as a white crystalline solid, m.p. 148–150 °C. H NMR (400 MHz,
Preparation of 7-Acetyl-2-oxo-2,5-dihydro-1-benzazepine (45): The
precursor 43 (10.4 mg, 0.03 mmol) and G-2 (1.1 mg, 5 mol-%) in
dry DCM were treated as described in the general procedure for
RCM. At the conclusion of the reaction (TLC monitoring, 1.5 h),
the solvent was removed to give the crude product which was puri-
fied by silica gel column chromatography. Elution of the column
with 35% ethyl acetate/petroleum ether gave the desired product 45
(8.1 mg, 93%) as a white solid, m.p. 152–154 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.44 (d, J = 6.4 Hz, 2 H), 3.91 (s, 3 H),
6.01 (d, J = 10.8 Hz, 1 H), 6.66 (td, J = 4.0, 6.8, 10.8 Hz, 1 H),
7.15 (d, J = 8.0 Hz, 1 H), 7.85 (d, J = 1.6 Hz, 1 H), 7.90 (dd, J =
1.6, 8.0 Hz, 1 H), 9.80 (br. s, 1 H) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 26.7, 32.4, 120.7, 125.7, 128.5, 129.3, 131.1, 134.1,
141.1, 141.9, 168.5, 196.9 ppm. HRMS (Q-ToF): calcd. for
C12H12NO2 [M + H]+ 202.0868; found 202.0861.
CDCl3): δ = 2.58 (s, 3 H), 5.90 (dd, J = 0.8, 16.8 Hz, 1 H), 6.34
(dd, J = 10.0, 16.8 Hz, 1 H), 6.50 (dd, J = 0.8, 16.8 Hz, 1 H), 7.82
(br. s, 1 H), 7.94 (dd, J = 2.4, 8.8 Hz, 1 H), 8.41 (d, J = 2.4 Hz, 1
H), 8.54 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3):
δ = 26.6, 89.5, 120.4, 129.2, 130.1, 131.2, 134.3, 139.2, 142.1, 163.7,
195.7 ppm. HRMS (Q-ToF): calcd. for C11H11NIO2 [M + H]+
315.9835; found 315.9825.
Preparation of Diene 42: N-Acryloyl derivative 40 (70 mg,
0.21 mmol), CsF (64 mg, 0.42 mmol), [Pd(PPh3)4] (12.1 mg, 6 mol-
%) and allylboronate 4 (71 mg, 0.42 mmol) in dry THF (10 mL)
were treated as described in the general procedure for allylation by
the SM cross-coupling reaction. At the conclusion of the reaction
(TLC monitoring, 5 h), the reaction mixture was quenched with
water and the usual work-up using DCM gave the crude product
which was charged onto a silica gel column. Elution of the column
with 17% ethyl acetate/petroleum ether gave the desired product
42 (15.2 mg, 29%) as a white solid, m.p. 146–148 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.47 (d, J = 6.0 Hz, 2 H), 3.91 (s, 3 H),
5.17 (dd, J = 1.4, 17.6 Hz, 1 H), 5.27 (dd, J = 1.4, 10.0 Hz, 1 H),
5.81 (d, J = 10 Hz, 1 H), 6.03 (m 1 H), 6.20 (dd, J = 15.6, 18.4 Hz,
1 H), 6.42 (d, J = 16.8 Hz, 1 H), 7.60 (br. s, 1 H), 7.89 (d, J =
2.0 Hz, 1 H), 7.96 (dd, J = 2.0, 8.4 Hz, 1 H), 8.25 (d, J = 8.4 Hz,
1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 37.2, 52.3, 117.7,
121.9, 126.3, 128.4, 129.5, 131.3, 131.9, 135.8, 140.7, 163.6,
166.8 ppm. HRMS (Q-ToF): calcd. for C14H16NO3 [M + H]+
246.1130; found 246.1136.
Preparation of N-Allyl Derivative 46: 2-Iodoaniline derivative 5
(200 mg, 0.72 mmol), K2CO3 (100 mg, 0.73 mmol) and allyl bro-
mide (88 mg, 0.74 mmol) were heated in dry acetonitrile (5 mL) at
reflux for 4 d. Heating was then stopped, the reaction mixture al-
lowed to cool to room temp. and then filtered through a Celite pad
which was washed with ethyl acetate (3ϫ25 mL). The solvent was
removed and the crude product was purified by silica gel column
chromatography. Elution of the column with 3% ethyl acetate/pe-
troleum ether gave diallyl derivative 47 (22 mg, 12%) as a colourless
liquid. Further elution of the column with 6% ethyl acetate/petro-
leum ether gave the monoallyl derivative 46 (102 mg, 60%) as a
colourless liquid (based on 25% starting material recovered). Con-
tinued elution with 15% ethyl acetate/petroleum ether gave the
starting material 5 (50 mg, 25%).
Spectral Data for Compound 46: 1H NMR (400 MHz, CDCl3): δ =
3.85 (s, 3 H), 3.87–3.91 (m, 2 H), 4.83 (br. s, 1 H), 5.12–5.31 (m, 2
H), 5.89–5.97 (m, 1 H), 6.50 (d, J = 8.8 Hz, 1 H), 7.87 (dd, J = 2.0,
8.8 Hz, 1 H), 8.35 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 46.3, 51.9, 83.8, 109.4, 117.2, 120.1, 131.6, 133.7,
140.9, 150.5, 166.2 ppm. HRMS (Q-ToF): calcd. for C11H13NO2I
[M + H]+ 317.9991; found 317.9994.
Preparation of Diene 43: N-Acryloyl derivative 41 (80 mg,
0.25 mmol), CsF (77 mg, 0.5 mmol), [Pd(PPh3)4] (11.7 mg, 4 mol-
%) and allylboronate 4 (85 mg, 0.5 mmol) in dry THF (10 mL) were
treated as described in the general procedure for the SM cross-
coupling reaction. At the conclusion of the reaction (TLC monitor-
ing, 5.5 h), the reaction mixture was quenched with water and the
usual work-up using DCM gave the crude product which was
charged onto a silica gel column. Elution of the column with 22%
ethyl acetate/petroleum ether gave the desired product 43 (14.3 mg,
25%) as a white solid, m.p. 128–131 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.59 (s, 3 H), 3.45 (dt, J = 1.6, 6.0 Hz, 2 H), 5.18 (dq,
J = 1.6, 17.6 Hz, 1 H), 5.28 (dq, J = 1.6, 10.0 Hz, 1 H), 5.81 (dd,
J = 0.8, 10.4 Hz, 1 H), 6.03–5.95 (m 1 H), 6.19 (dd, J = 10.4,
16.8 Hz, 1 H), 6.42 (dd, J = 0.8, 16.8 Hz, 1 H), 7.64 (br. s, 1 H),
7.82 (d, J = 2.0 Hz, 1 H), 7.88 (dd, J = 2.0, 8.0 Hz, 1 H), 8.30 (d,
J = 8.0 Hz, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 26.7,
37.3, 117.8, 121.8, 128.5, 128.7, 130.5, 131.2, 133.5, 137.5, 140.9,
163.6, 197.4 ppm. HRMS (Q-ToF): calcd. for C14H16NO2 [M +
H]+ 230.1181; found 230.1188.
Preparation of the Diallyl Derivative 48 by the SM Cross-Coupling
Reaction: N-Allyl derivative 46 (59 mg, 0.18 mmol), CsF (52 mg,
0.37 mmol), [Pd(PPh3)4] (6.5 mg, 3 mol-%) in dry THF (8 mL) and
allylboronate 4 (62.5 mg, 0.37 mmol) in THF (15 mL) were treated
as described in the general procedure for allylation. At the conclu-
sion of the reaction (TLC monitoring, 48 h), the reaction mixture
was quenched with water and the usual work-up using DCM gave
the crude product which was charged onto a silica gel column. Elu-
tion of the column with 3% ethyl acetate/petroleum ether gave the
1
desired product 48 (5.4 mg, 12%) as a colourless liquid. H NMR
(400 MHz, CDCl3): δ = 3.32 (d, J = 6.0 Hz, 2 H), 3.83–3.85 (m, 5
H), 4.33 (br. s, 1 H), 5.09–5.28 (m, 4 H), 5.88–5.98 (m, 2 H), 6.58
(d, J = 8.4 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 7.84 (dd, J = 2.0,
8.4 Hz, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 36.5, 46.0,
51.7, 109.6, 116.8, 117.1, 118.4, 122.6, 130.4, 131.8, 134.5, 135.5,
150.1, 167.7 ppm. HRMS (Q-ToF): calcd. for C14H18NO2 [M +
H]+ 232.1338; found 232.1347.
Preparation of Methyl 2-Oxo-2,5-dihydro-1H-benzazepine-7-car-
boxylate (44): The precursor 42 (8.0 mg, 0.03 mmol) and G-2
(1.3 mg, 5 mol-%) in dry DCM were treated as described in the
general procedure for the RCM reaction. At the conclusion of the
reaction (TLC monitoring, 1.5 h), the solvent was removed to give
the crude product which was purified by silica gel column
chromatography. Elution of the column with 20% ethyl acetate/
petroleum ether gave the desired product 44 (7.3 mg, 90%) as a
Further elution of the column with 5% ethyl acetate/petroleum
white solid, m.p. 190–194 °C (decomp.). 1H NMR (400 MHz, ether gave the indole derivative 49 (14.2 mg, 40%) as a yellow solid,
1062
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1054–1064

Design and Synthesis of 1-Benzazepine Derivatives
m.p. 142–144 °C. 1H NMR (400 MHz, CDCl3):[33] δ = 2.36 (d, J =
0.8 Hz, 3 H), 3.94 (s, 3 H), 7.02 (d, J = 0.8 Hz, 1 H), 7.33 (d, J =
8.4 Hz, 1 H), 7.89 (dd, J = 1.6, 8.4 Hz, 1 H), 8.21 (br. s, 1 H), 8.36
(s, 1 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 9.7, 52.0, 110.8,
113.4, 121.3, 122.1, 123.0, 123.4, 128.1, 139.0, 168.6 ppm.
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi (Grant No. SR/S1/OC-42-2004) and the Industrial Re-
search & Consultancy Centre, IIT-Bombay (Grant No. 06RPA002)
for financial support. Also, V. R. S. thanks the Council for Scien-
tific and Industrial Research (CSIR), New Delhi for the award of
a research fellowship.
Preparation of N-Allyl Derivative 51 and N,N-Diallyl Derivative 52:
Methyl 4-aminobenzoate (50) (300 mg, 1.98 mmol) in acetonitrile
(10 mL) was heated with allyl bromide (1 mL) in the presence of
K2CO3 (0.98 g, 4.00 mmol) at 80 °C. After 12 h, the heating was
stopped and the reaction mixture was filtered through a Celite pad
and washed with ethyl acetate. The solvent was removed and the
crude product was purified by silica gel column chromatography.
Elution of the column with 4% ethyl acetate/petroleum ether gave
the diallyl derivative 52 (240 mg, 52.4%) as a colourless thick li-
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1
quid. H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 3.93 (dt, J =
1.6, 4.4 Hz, 4 H), 5.19–5.12 (m, 4 H), 5.79–5.87 (m, 2 H), 6.63 (d,
J = 9.2 Hz, 2 H), 7.8 (d, J = 9.2 Hz, 2 H) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 51.6, 52.7, 111.1, 116.6, 117.4, 131.5,
132.5, 153.1, 167.5 ppm. HRMS (Q-ToF): calcd. for C14H18NO2
[M + H]+ 232.1338; found 232.1328.
Continued elution of the column with 7% ethyl acetate/petroleum
ether gave the monoallyl derivative 51 (120 mg, 31%) as a white
1
crystalline solid, m.p. 77–78 °C. H NMR (400 MHz, CDCl3): δ =
3.82–3.84 (m, 5 H), 4.30 (br. s, 1 H), 5.17–5.21 (m, 1 H), 5.25–5.31
(m, 1 H), 5.87–5.96 (m, 1 H), 6.56 (d, J = 8.8 Hz, 2 H), 7.86 (d, J
= 8.8 Hz, 2 H) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 46.0,
51.7, 111.8, 116.9, 118.7, 131.7, 134.5, 151.9, 167.5 ppm. HRMS
(Q-ToF): calcd. for C11H14NO2 [M + H]+ 192.1025; found
192.1021.
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Preparation of Diallyl Derivative 48 by Aza-Claisen Rearrangement:
BF3·Et2O (100 mg, 0.86 mmol) was added to a solution of diallyl
derivative 52 (200 mg, 0.86 mmol) in freshly distilled xylene (5 mL),
and the resulting mixture was heated at 140 °C in an oil bath for
1.5 h. The reaction was quenched with a saturated solution of so-
dium hydrogen carbonate and general work-up with chloroform
gave the crude product which was purified by silica gel column
chromatography. Elution of the column with 3% ethyl acetate/pe-
troleum ether gave the starting material 52 (20 mg, 20%). Contin-
ued elution gave the desired diallyl derivative 48 (69 mg, 38%,
based on starting material recovered) as a colourless liquid which
turned yellow when kept open to air (1H NMR spectroscopic data
identical to those of the compound obtained by the SM cross-coup-
ling reaction). Continued elution of the column with 5% ethyl ace-
tate/petroleum ether gave side-product 53 (50 mg, 32%) as a
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1
colourless liquid that turned yellow. H NMR (400 MHz, CDCl3):
δ = 3.33 (dt, J = 1.6, 6.4 Hz, 4 H), 3.86 (s, 3 H), 4.15 (br. s, 2 H),
5.08–5.17 (m, 4 H), 5.90–5.97 (m, 2 H), 7.69 (s, 2 H) ppm. 13C
NMR (100.5 MHz, CDCl3): δ = 36.7, 51.8, 116.9, 119.5, 123.1,
130.7, 135.4, 148.1, 167.6 ppm. HRMS (Q-ToF): calcd. for
C14H18NO2 [M + H]+ 232.1338; found 232.1334
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Eur. J. Org. Chem. 2008, 1054–1064
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Kotha, V. R. Shah
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Published Online: December 17, 2007
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Eur. J. Org. Chem. 2008, 1054–1064