Conformation analyses, dynamic behavior and amide bond distortions of medium-sized heterocycles. 1. Partially and fully reduced 1-benzazepines

Article abstract of DOI:10.1021/jo048118b

(Chemical Equation Presented) Five 1-benzazepine heterocycles were synthesized by utilizing transition-metal-catalyzed processes in key bond-forming steps. exo-Methylene and methyl substituents were introduced at position 5, as well as a unit of unsaturat

Full text of DOI:10.1021/jo048118b

Conformation Analyses, Dynamic Behavior and Amide Bond
Distortions of Medium-sized Heterocycles. 1. Partially and Fully
Reduced 1-Benzazepines
Maryiam Qadir,† Jonathan Cobb,† Peter W. Sheldrake,‡, Neil Whittall,‡ Andrew J. P. White,§
King Kuok (Mimi) Hii,*,§ Peter N. Horton,| and Michael B. Hursthouse|
Department of Chemistry, King’s College London, Strand WC2R 2LS, U.K. GlaxoSmithKline,
Old Powder Mills, Nr. Leigh, Tonbridge, Kent TN11 9AN, U.K. Department of Chemistry,
Imperial College London, Exhibition Road, South Kensington SW7 2AZ, U.K., and
EPSRC X-ray Crystallography Service, Southampton University, Highfield SO17 1BJ, U.K.
mimi.hii@imperial.ac.uk
Received October 23, 2004
Five 1-benzazepine heterocycles were synthesized by utilizing transition-metal-catalyzed processes
in key bond-forming steps. exo-Methylene and methyl substituents were introduced at position 5,
as well as a unit of unsaturation between positions 3 and 4, with benzoyl or benzyl N-substituents.
Solution- and solid-state structures were examined, using dynamic NMR spectroscopy and X-ray
crystallography, corroborated by molecular mechanics calculations. Greater amide distortion is
associated with a more stable ground-state structure, which is in turn more reluctant to undergo
conformational changes.
Introduction
Broadly termed as benzazepines, benzo-fused seven-
membered nitrogen heterocyclic rings are interesting
structural motifs in medicinal chemistry. In recent years,
2,3,4,5-tetrahydro-1-benzazepines of types I1 and II2
(Figure 1) have been identified as orally active, highly
potent selective nonpeptide agonists for the arginine
vasopressin (AVP) V2 receptor, which may be used in the
treatment of certain diabetic conditions.3 Subsequent
FIGURE 1. Biologically active 1-benzazepine structures.
* To whom correspondence should be addressed. Fax: +44-20-7594-
5804. Tel: +44-20-7594-1142.
SAR studies have revealed key structural features that
are important for high potency and selectivity: (1) the
presence of a N-benzoyl functionality; (2) a fully saturated
aliphatic ring, and (3) substitution at benzylic carbon-5,
which may contain an exocyclic double bond. These
uniquely combine to confer a distinct conformation in the
core structure, permitting highly selective binding with
the receptor site.
The reactivity of benzazepine rings may also be dic-
tated by their conformations. In an elegant study cor-
relating the structure, chemical and cytotoxic activities
of CC-1065 and Duocarmycin analogues, N-acylation of
a 1-benzazepine intermediate was found to be dependent
on the degree of hybridization at the remote carbon-5.4
† King’s College London.
‡ GlaxoSmithKline.
§ Imperial College London.
| Southampton University.
Current affiliation: Institute of Cancer Research, 15, Cotswold
Rd, Belmont, Sutton, Surrey SM2 5NG, U.K.
(1) Kondo, K.; Ogawa, H.; Shinohara, T.; Kurimura, M.; Tanada,
Y.; Kan, K.; Yamashita, H.; Nakamura, S.; Hirano, T.; Yamamura, Y.;
Mori, T.; Tominaga, M.; Itai, A. J. Med. Chem. 2000, 43, 4388-4397.
(2) Matsuhisa, A.; Kikuchi, K.; Sakamoto, K.; Yatsu, T.; Tanaka,
A. Chem. Pharm. Bull. 1999, 47, 329-339.
(3) (a) Kondo, K.; Kan, K.; Tanada, Y.; Bando, M.; Shinohara, T.;
Kurimura, M.; Ogawa, H.; Nakamura, S.; Hirano, T.; Yamamura, Y.;
Kido, M.; Mori, T.; Tominaga, M. J. Med. Chem. 2002, 45, 3805-3808.
(b) Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.;
Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.;
Mori, T.; Tominaga, M. Bioorg. Med. Chem. 1999, 7, 1743-1754. (c)
Kondo, K. Expert Opin. Ther. Pat. 2002, 12, 1249-1258.
10.1021/jo048118b CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/29/2005
J. Org. Chem. 2005, 70, 1545-1551
1545

Qadir et al.
SCHEME 1. Synthesis of Benzazepine via Intramolecular Heck Reactiona
a Reagents and conditions: (i) (a) NaH, THF, rt, 3 h, (b) CH2dCH(CH2)3OTs, reflux, 2-3 h; (ii) intramolecular Heck reaction (Table 1).
TABLE 1. Product Distribution Afforded by
Herein, we report our studies on a series of benza-
Intramolecular Heck Arylation (Scheme 1)a
zepine structures, introducing units of unsaturation, as
% yield
well as specific substituents at the heteroatom and
position-5. The conformation and dynamic behavior of
these heterocycles were examined using a combination
of dynamic NMR spectroscopy and X-ray crystal structure
analysis. The results were corroborated by molecular
mechanics calculations.
entry
precursor
ligandb
PPh3 (4)
dppp (2)
dppf (2)
PPh3 (3)
PPh3 (3)
PPh3 (3)
(o-tolyl)3P (3)
PPh3 (4)
temp
3c
4 + 5d
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2b
2b
140
140
140
120
130
140
130
130
63
31
35
51
58
60
80
88
17
10
>10
10
Results and Discussion
0
Synthesis. Previously, we reported an expedient
synthetic route to 1-benzyl-2,3,4,5-tetrahydro-benza-
zepines, including nonbulky alkyl and aryl substituents
at position-2 of the heterocyclic ring.5 Herein, comple-
mentary methodologies for the synthesis of five 1-benz-
azepine structures from N-(2-iodophenyl)-benzamide 1
are described, utilizing transition-metal-catalyzed reac-
tions for the formation of key carbon-carbon bonds
(Scheme 1).
Intramolecular Heck arylation was first explored for
the construction of the seven-membered ring structure.4
Following alkylation of the N-2-(halo)phenyl-N-benza-
mides 1 (X ) Br, I) with pent-4-enyl-4-toluenesulfonate,
the products 2 were subjected to palladium catalysis,
giving a mixture of 7-exo and 8-endo-trig cyclization
products.6
a Reaction conditions: Pd(OAc)2 (5 mol %) or Pd2dba3‚CHCl3
(2.5 mol %), PR3 ligand, LiCl (1.1 equiv), NEt3 (2 equiv), DMF, 22
h. b Number in parentheses corresponds to equivalents of phos-
phine ligand employed, with respect to Pd; dppp ) 1,3-bis(diphen-
ylphosphino)propane; dppf ) 1,1′-bis(diphenylphosphino)ferrocene.
c Isolated yield following column chromatography. d Inseparable
mixtures of 4 (major) and 5 (minor).
SCHEME 2. Synthesis of Benzazepine Structure
by RCMa
The distribution of products was found to be dependent
on the conditions under which palladium catalysis was
effected (Table 1). The aryl bromide precursor required
an elevated reaction temperature of 140 °C for cyclization
to proceed, affording the 7-exo-trig product 3 in modest
yield (entry 1). Replacement of triphenylphosphine with
bidentate phosphine ligands led only to a decrease in the
yield (entries 2 and 3).
By adopting the aryl iodide precursor, the reaction
temperature may be lowered. Employing 3 equiv of PPh3
ligand, competitive formation of the 8-endo-cyclized benz-
azocines 4 and 5, as an inseparable mixture, was
observed (entries 4-6).7 Replacement of PPh3 with the
P(o-tolyl)3 ligand led to an improvement in the yield of
the benzazepine product (entry 7). Interestingly, forma-
tion of the larger ring may be avoided altogether by using
4 equiv of PPh3 (entry 8).
a Reagents and conditions: (i) Pd(OAc)2, PPh3, LiCl, allyltribut-
yltin, DMA, heat, 91%; (ii) NaH, allyl bromide, THF, reflux, 21 h,
89%; (iii) (Cy3P)2Ru(dCHPh)Cl2, toluene, 60 °C, 86%.
benzazepine rings (Scheme 2). 2-Allyl-benzamide 6 was
obtained from palladium-catalyzed Stille cross-coupling
of N-(2-iodophenyl)-benzamide 1b with allyltributyltin.
Subsequent alkylation with allyl bromide gave the diene
precursor 7, which underwent RCM smoothly in the
presence of Grubbs catalyst, furnishing the unsaturated
benzazepine 8 in good yield (86%). Best yields of the
cyclized product were obtained using a sealed Young’s
tube. Presumably, this prevents ethylene loss, which is
critical for the stability of the ruthenium catalyst in the
highly diluted solution necessary to promote intra-
molecular C-C bond formation.
In a separate approach, we employed ring-closing
metathesis (RCM)8 for the preparation of unsubstituted
(4) Boger, D. L.; Turnbull, P. J. Org. Chem. 1997, 62, 5849-5863.
(5) Qadir, M.; Priestley, R. E.; Rising, T. W. D. F.; Gelbrich, T.; Coles,
S. J.; Hursthouse, M. B.; Sheldrake, P. W.; Whittall, N.; Hii, K. K.
Tetrahedron Lett. 2003, 44, 3675-3678.
(6) Caddick, S.; Kofie, W. Tetrahedron Lett. 2002, 43, 9347-9350.
(7) The identity of compound 5 was verified via an independent
synthesis; see Part 2 (the following paper).
The double bonds of 3 and 8 were reduced by hydro-
genation to give N-benzoyl-benzazepines 9 and 11, re-
spectively, and borane-dimethyl sulfide complex was
(8) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199-2238.
1546 J. Org. Chem., Vol. 70, No. 5, 2005

Partially and Fully Reduced 1-Benzazepines
SCHEME 3. Reduction of the Benzazepine Ringsa
a Reagents and conditions: (i) Pd/C, H2; (ii) BH3‚SMe2.
FIGURE 2. Equilibrating mixture of conformers (phenyl
substituent and hydrogens omitted for clarity) and key NOE
correlations for the major isomer of 9.
employed to reduce the N-benzoyl moiety, affording
N-benzyl benzazepine rings 10 and 12 (Scheme 3).
Notably,
1-benzyl-2,3,4,5-tetrahydro-5-methyl-benz-
(calculated from the equilibrium constant at 298 K).
azepine 10 was obtained as a single diastereomeric
product, i.e., the methyl and benzyl substituents have
distinct relative stereochemistry.
NMR Studies of (Dynamic) Solution Structures.
In previous studies, Hassner et al. proposed several
interesting structural features of 1-acylated 2,3,4,5-
tetrahydrobenzazepines by performing dynamic NMR
and molecular mechanics calculations.9,10
Subsequent line shape analysis yielded ∆Gq values of 14.3
kcal mol-1 11
.
Benzazepine 8, containing an endocyclic double bond,
also displayed slow conformational changes at ambient
temperature; the interconversion barrier is approxi-
mately 15.6 kcal mol-1. When the unit of unsaturation
is removed, the activation energy for benzazepine 11 to
undergo conformational changes increases to 16.1 kcal
mol-1 12
which is comparable to that of the 5-methyl-
,
As expected, 5-methylene-substituted benzazepine 3
undergoes slow conformational flipping in solution at
ambient temperatures. This behavior was examined by
substituted 9. This implies that the introduction of a
methyl substituent at the 5-position does not lead to
significant changes in the barrier to ring inversion of the
saturated ring.
1
recording its H NMR spectra at variable temperatures
(Supporting Information). At the slow exchange limit, one
of the two diastereotopic H-2 proton resonances is located
at about 5.2 ppm, some 2.5 ppm downfield from its
partner. This unusual downfield shift was also previously
observed by Hassner,9 who ascribed the phenomenon to
coplanarity between the exocyclic amide bond and the
equatorial proton on the adjacent carbon (H-2R). Below
253 K, the spectra continued to broaden, presumably due
to increased viscosity of the solution and/or slow molec-
ular tumbling. An average ∆Gq of 13.7 kcal mol-1 was
estimated from the coalescence behavior of diastereotopic
methylene protons H-2, H-3 and H-4.
Ring inversion of the unsubstituted tetrahydrobenz-
azepine ring 12 is rapid at ambient temperature.5 In
1
contrast, the H NMR spectrum of the N-benzyl benz-
azepine 10 showed a single methyl resonance at 1.32
ppm, and distinctive resonances were observed for each
of the diastereotopic protons (including the benzylic
protons), which did not exhibit exchange even at 373 K.
Thus impying that the reduction of the exocyclic amide
functionality had led to the formation of a rigid confor-
mational structure.
Solid-State Structures (Figure 3, Table 2). All four
N-benzoyl benzazepines (3, 8, 9, 11) are sufficiently
crystalline to allow the solid-state structures to be
determined by single-crystal X-ray diffraction. As pre-
dicted by Hassner’s theoretical studies,10 the most stable
chair conformation is found to be adopted by compounds
3, 9 and 11; the introduction of an endocyclic double bond
led to a flattening of the heterocycle in 8 to a half-chair.
The carbonyl group is oriented anti to the fused aromatic
ring in all of the solid-state structures. A small dihedral
angle of -6.2° is observed between the C(2)-H(2) and
N-C(O) bonds. Therefore, it would appear that the high
deshielding of the H-2R resonance is largely due to its
close proximity to the amide oxygen’s lone pair of
electrons, rather than anisotropic effects of the exocyclic
amide bond as previously suggested.9 Rather interest-
The reduction of the exocyclic double bond of compound
3 creates a stereogenic center and diastereomeric mix-
tures. The 1H NMR spectrum of the 5-methyl-substituted
benzazepine 9 displayed dynamic exchange between two
species in a 4:1 ratio. The 2D-NOESY spectrum revealed
that the major isomer contains the methyl substituent
in the axial position, syn to the N-benzoyl substituent
(Figure 2), as indicated by the observation of cross-peaks
between H-5 with H-4R and H-4â resonances, while the
methyl protons showed only one cross-peak with H-4R.
Additionally, irradiation of the dominant methyl reso-
nance led to a small NOE enhancement of the benzoyl
aromatic protons.
Molecular mechanics calculations revealed an energy
difference of 1.2 kcal mol-1 between the axial and
equatorial chair conformers (Figure 2), which is in good
agreement with the experimental value of 0.9 kcal mol-1
(11) Eyring plot derived from the coalescence spectra yielded a ∆Gq
value of 15.1 kcal mol-1 and negligible entropic contribution to the
process (see Supporting Information).
(9) Hassner, A.; Amit, B. Tetrahedron Lett. 1977, 18, 3023-3026.
(10) Hassner, A.; Amit, B.; Marks, V.; Gottlieb, H. E. J. Org. Chem.
2003, 68, 6853-6858.
(12) Hassner (ref 10) calculated an inversion barrier of 16.0 kcal
mol-1
.
J. Org. Chem, Vol. 70, No. 5, 2005 1547

Qadir et al.
TABLE 2. Parameters Reflecting Amide Distortiona
d
e
f
g
h
i
structure
bb
θc
ω1
ω2
ω3
ω4
øN
øC
τj
Rk
3
116.5
115.3
115.2
116.7
360.0
357.3
359.1
358.4
+187.5
+182.3
+180.7
+188.1
+188.0
+200.2
+191.1
+200.0
+6.3
+0.8
+0.2
+4.8
+9.3
+21.7
+11.6
+23.3
+1.8
+19.4
+10.9
+15.2
+1.3
+1.5
+0.5
+3.3
+187.8 (7.8)
1.4
8
+191.3 (11.3)
+185.9 (5.9)
+194.1 (14.1)
15.7
8.6
9
11
12.5
a ω1, ω2, ω3 and ω4 assignments are made as for trans amides where C1 ) H. All values are in degrees. b Angle C1-N-C2. c Sum of
angles around N (a + b + c). d ω1 ) CR′-C′-N-C2 torsion angle. e ω2 ) O′-C′-N-C1 torsion angle. f ω3 ) O′-C′-N-C2 torsion angle.
g ω4 ) CR′-C′-N-C1 tosion angle. h øN ) (ω2 - ω3 + π)(mod 2π) and has a value between 0° (planar) and 60° (complete pyramidization).
i øC ) (ω1 - ω3 + π)(mod 2π). j τ ) [(ω1 + ω2)/2](mod 2π), where |ω1 - ω2| < π (else τ is mod π). Value in parentheses corresponds to
deviation from 180°. k R is the angle between the {C1-N-C2} plane and the N-C′ vector.
FIGURE 4. Structural parameters reflecting amide distor-
tion.
lengths are only slightly lengthened (1.36 Å, a normal
CdN amide bond is 1.33 Å), all four structures exhibit
varying extents of nonplanarity around the exocyclic
amide bond. Particularly, in structures 8, 9 and 11 the
nitrogen is noticeably pyramidized (øN up to 19.4°), while
the carbonyl carbon is essentially unaffected (øC < 3.3°).
This amide bond distortion may be delineated more
closely by examining three structural parameters (Figure
4): (i) sum of the three valence angles around nitrogen
(θ), (ii) the out-of-plane twist of the amide bond (τ), and
(iii) the angle between the plane defined by nitrogen and
its substituents with the N-C′ vector (R).13
Overall, these parameters are within the range previ-
ously recorded for monocyclic amides.14 All four benza-
zepines have a very similar internal ring angle (b) at the
nitrogen heteroatom of 115-116°, and there is a good
overall correlation between the amide twist (τ) and the
out-of-plane distortion (R). Among the four structures,
benzazepine ring 3 shows the least amide pyramidization
(R ) 1.4°, θ ) 360.0°); the planar nitrogen displays a
FIGURE 3. Molecular structures of benzazepines 3, 8, 9 and
small τ of 7.8° from planarity (Table 2, entry 1). When
11 (with chemical numbering scheme) and accompanying ball-
the double bond is hydrogenated to give benzazepine 9,
b becomes slightly more acute. Correspondingly, the
nitrogen atom becomes slightly more pyramidal (R ) 8.6°,
θ ) 359.1°), although there is little change in τ (5.9°). In
contrast, both of the unsubstituted benzazepine rings 8
and 11 (entries 2 and 4) show substantial N-pyramidiza-
tion (R ) 15.7 and 12.5°), which is accompanied by
corresponding τ values of 11° and 14°, respectively.
Examining the dihedral angles around the amide bond
(Figure 4), it is apparent that the distortion is due almost
entirely to a torsional twist of the CR′-C′-N-C(2) moiety
(ω4), which can be as much as 23.3° for 11.
and-stick models of the views along the N-C′ axes, illustrating
the nature of the amide twist.
ingly, the 5-methyl substituent in the solid-state struc-
ture of compound 9 was found in the equatorial position
(anti to the benzoyl substituent), corresponding to the
minor solution conformer. Since the energy barrier
between the two conformers is fairly surmountable under
ambient conditions (14.3 kcal mol-1), this could be the
result of a better crystal packing arrangement.
Amide Distortions (Table 2). As the benzoyl sub-
stituent adopts a pseudoaxial position, this will invari-
ably disrupt the π-interaction of the nitrogen with the
adjacent aromatic ring system. On the other hand,
participation of the heteroatom in π-bonding with the
exocyclic carbonyl functionality (amide bond) may be
interrupted by geometry constraints imposed by the
heterocyclic ring and/or steric interactions between the
two aromatic rings. Although the exocyclic C-N bond
To rationalize the above observations, molecular me-
chanics calculations were performed (Table 3), which
(13) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169-182.
(14) (a) Ohwada, T.; Achiwa, T.; Okamoto, I.; Shudo, K. Tetrahedron
Lett. 1998, 39, 865-868. (b) Otani, Y.; Nagae, O.; Naruse, Y.; Inagaki,
S.; Ohno, M.; Yamaguchi, K.; Yamamoto, G.; Uchiyama, M.; Ohwada,
T. J. Am. Chem. Soc. 2003, 125, 15191-15199.
1548 J. Org. Chem., Vol. 70, No. 5, 2005

Partially and Fully Reduced 1-Benzazepines
TABLE 3. Relative Energies (kcal mol-1) of
Benzazepines 3, 8, 9 and 11, Calculated Using Spartan
Molecular Mechanics Programa
(5/1). Found: C, 62.90; H, 5.45; N, 4.20. Calcd for C18H18-
NOBr: C, 62.79; H, 5.28; N, 4.07. νmax(thin film)/cm-1 1651 s
(CO); δH (360 MHz; CDCl3) 1.57-1.62 (1H, m, CH2CH2N),
1.65-1.85 (1H, m, CH2CH2N), 2.05 (2H, br m, CH2CH2CH2N),
3.42 (1H, ddd, J 3.1, 5.2 and 10.5, CH2N), 4.15 (1H, ddd, J
3.0, 5.1 and 10.5, CH2N), 4.88-4.97 (2H, m, CH2dCH), 5.68-
5.79 (1H, m, CH2dCH), 6.97-7.01 (2H, m Ar-H), 7.04-7.28
(6H, Ar-H), 7.45 (1H, d, J 7.9, Ar-H); δC (90.6 MHz; CDCl3)
26.8 (CH2CH2N), 31.6 (CH2CH2CH2N), 49.3 (CH2N), 115.4
(CH2dCH), 123.8 (Ar-C), 128.0 (Ph-Cortho), 128.4 (Ph-Cmeta),
128.5 (Ar-C), 129.3 (Ar-C), 130.0 (Ph-Cpara), 132.2 (Ar-C), 134.2
(Ar-C), 136.5 (Ph-Cipso), 138.1 (CH2dCH), 142.4 (Ar-C), 169.6
(CO); m/z (EI) 343/345 (M+, 19/19%), 301/303 (6/6), 288/290
(21/21), 275/277 (37/37), 264 (96), 196 (32), 105 (100), 77 (96).
structure
total
torsional
electrostatic
vdW
3
+78.3
+71.2
+70.4
+63.1
+21.9
+17.4
+16.6
+15.5
+13.1
-10.3
-5.4
+46.5
+45.0
+46.6
+43.6
8
9
11
-5.2
a All other components are e7.6 kcal mol-1
.
revealed that structures 8 and 9 are very similar in
energy. In contrast, the least distorted structure (3) is
approximately 15 kcal mol-1 higher in energy than the
most distorted structure (11). Examining the energy
contributions, it is apparent that 1,4-interactions are
significant in these heterocycles. Among these, the van
der Waals forces, albeit sizable, showed little variance
between the structures. In contrast, torsional strain is a
significant contributor in all of the benzazepines (except
compound 3, which contains an additional electrostatic
contribution). The relative values of the torsional energies
suggest that the ring strain in tetrahydrobenzazepine 11
is effectively relieved by the ability of the amide bond to
distort. A change in the hybridization at carbon-5 pro-
hibited amide distortion, thus leading to larger torsional
strain in benzazepine 3.
It has been previously suggested that ring inversion
of these heterocycles is closely associated with the amide
bond rotation, where the carbonyl moiety is forced out of
conjugation with the nitrogen in the transition state.10
In the present work, a higher barrier to ring inversion
was observed in the order 3 ≈ 9 > 8 > 11. This suggests
that greater amide distortion is associated with a more
stable ground-state structure, which is more reluctant
to undergo conformational changes.
N-(2-Iodophenyl)-N-(pent-4-en-1-yl)-benzamide (2b).
Yield: 83% as a colorless syrup that slowly crystallized upon
standing, Rf ) 0.23, hexanes/EtOAc (5/1). Found: C, 55.40;
H, 4.75; N, 3.75. Calcd for C18H18NIO: C, 55.25; H, 4.65; N,
3.58. νmax(thin film)/cm-1 1647 s (CO); δH (360 MHz; CDCl3)
1.58-1.65 (1H, br m, CH2CH2N), 1.81-1.87 (1H, br m, CH2-
CH2N), 1.97-2.12 (2H, br m, CH2CH2CH2N), 3.31 (1H, ddd, J
2.9, 5.0 and 10.7, CH2N), 3.57 (br s, rotamer), 4.22 (1H, ddd,
J 2.8, 5.6 and 10.7, CH2N), 4.88-4.98 (2H, br m, CH2dCH),
5.69-5.80 (1H, m, CH2dCH), 5.52 (br s, rotamer), 6.65-6.80
(1H, Ar-H), 6.97 (1H, d, J 7.0, Ar-H), 7.06-7.74 (6H, m, Ar-
H), 7.73 (1H, d, J 7.4, Ar-H), 7.90 (br s, rotamer); δC (90.6 MHz;
CDCl3) 26.8 (1C, CH2CH2N), 31.6 (1C, CH2CH2CH2N), 49.6
(1C, CH2N), 100.5 (Ar-C), 115.5 (1C, CH2dCH), 128.0 (Ph-
Cortho), 128.6 (Ph-Cmeta), 129.3 (Ar-C), 129.4 (Ph-Cpara), 130.0
(Ar-C), 131.9 (Ar-C), 136.5 (Ph-Cipso), 138.1 (CH2dCH), 140.7
(Ar-C), 145.5 (Ar-C), 170.7 (CO); m/z (EI) 391 (M+, 5%), 323
(14), 264 (100), 230 (5), 196 (21), 105 (68), 77 (33).
1-Benzoyl-5-methylene-2,3,4,5-tetrahydro-1H-benz-
azepine (3). An oven-dried Young’s tube was charged with
Pd(OAc)2 (5 mol %), PPh3 (20 mol %) and LiCl (1.1 equiv) under
a N2 atmosphere. Triethylamine (2 equiv) was added, followed
by anhydrous DMF (4 mL) and the mixture was stirred at
ambient temperature for 15 min. The amide precursor 2b (0.50
g) was added as a solution in anhydrous DMF (1 mL), after
which the Young’s tube was sealed and heated in a thermo-
stated oil bath at 130 °C for 22 h. The reaction mixture was
filtered through a small pad of Celite, which was washed
repeatedly with EtOAc. The collected filtrate was concentrated
in vacuo to give a dark, viscous oil that was subjected to
column chromatography. The 7-exo-trig cyclized product 3 was
obtained as a colorless, viscous oil which crystallized upon
standing for a few hours. The solids were recrystallized from
EtOH to yield colorless prisms for X-ray crystallography.
Yield: 88%, Rf ) 0.18, hexanes/EtOAc (3/1); mp 108.5-109.5
°C (from EtOAc/hexanes). Found: C, 81.85; H, 6.30; N, 5.25.
Calcd for C18H17NO: C, 82.09; H, 6.52; N, 5.32. νmax(KBr)/cm-1
1636 s (CO); δH (360 MHz; CDCl3; 253 K) 2.00 (1H, br s, H-3â),
2.07-2.16 (1H, br m, H-3R), 2.43 (1H, br m, H-4R), 2.76-2.82
(1H, br m, H-4â), 3.00-3.06 (1H, br m, H-2â), 5.00-5.03 (1H,
br m, H-2R), 5.33 (1H, s, CH2dC), 5.25 (1H, s, CH2dC), 6.64
(1H, dd, J 1.0 and 7.9, Ar-H), 6.95-6.99 (1H, m, Ar-H), 7.14-
7.24 (6H, m, Ar-H), 7.35 (1H, dd, J 1.3 and 7.6, Ar-H); δC (90.6
MHz; CDCl3) 29.0 (C-3), 34.9 (1C, C-4), 47.5 (1C, C-2), 116.4
(CH2dC), 127.6 (Ar-C), 128.0 (Ph-Cortho), 128.3 (Ph-Cmeta), 128.4
(Ar-C), 128.8 (Ar-C), 129.2 (Ar-C), 129.8 (Ar-C), 136.8 (Ph-Cipso),
140.6 (Ar-C), 141.3 (Ar-C), 149.9 (C-5), 170.2 (CO); m/z (EI)
263 (M+, 86%), 249 (6), 235 (10), 158 (15), 143 (23), 130 (10),
105 (100), 77 (37). Crystal data for 3 (CCDC 251225): C18H17-
NO, MW ) 263.33, monoclinic, P21/c (No. 14), a ) 14.6421(5),
b ) 7.4495(4), c ) 14.4893(7) Å, â ) 116.974(2)°, V )
1408.51(11) Å3, Z ) 4, Dc ) 1.242 g cm-3, µ(Mo KR) ) 0.077
mm-1, T ) 120 K, colorless blocks; 3219 independent measured
reflections, F2 refinement, R1 ) 0.044, wR2 ) 0.095, 2082
independent observed absorption-corrected reflections [|Fo| >
4σ(|Fo|), 2θmax ) 55°], 250 parameters.
In conclusion, solid- and solution-state structures of
substituted benzazepine rings have been examined. The
study revealed important effects imposed by substituents
on the N-heteroatom and at position-5 on ring conforma-
tion, dynamic behavior and N-pyramidization. These
insights may prove to be important for rationalization
of the biological and chemical behavior of these hetero-
cyclic rings.
Experimental Section
N-(2-Halophenyl)-N-(pent-4-en-1-yl)-benzamides (2).
An oven-dried Schlenk tube was charged with a suspension
of NaH (60% dispersion in oil, 1.5 equiv) in dry THF under an
argon atmosphere. While cooling in an ice-bath, N-(2-bromo-
phenyl)benzamide 1a or N-(2-iodophenyl)benzamide 1b was
added slowly as a solution in dry THF. When addition was
completed, the ice-bath was removed and the pale yellow
mixture stirred at ambient temperature for 3 h. A solution of
pent-4-enyl tosylate (1.1 equiv) in dry THF was added to the
yellow-colored mixture and the reaction mixture was subse-
quently heated to gentle reflux for 2.5 h. Excess NaH was
quenched by the slow addition of water and diluted with
EtOAc. The organic layer was separated and the aqueous layer
extracted thrice with EtOAc. The combined organic extracts
were washed with brine and dried over MgSO4. Filtration
through a pad of Celite, followed by evaporation of the ensuing
filtrate afforded a dark yellow oily residue that was subjected
to column chromatography.
N-(2-Bromophenyl)-N-(pent-4-en-1-yl)-benzamide (2a).
Yield: 77% as a pale yellow syrup, Rf ) 0.21, hexanes/EtOAc
N-(2-Allylphenyl)benzamide (6). An oven-dried Young’s
tube was charged with Pd(OAc)2 (33.6 mg, 0.31 mmol, 4 mol
J. Org. Chem, Vol. 70, No. 5, 2005 1549

Qadir et al.
%), PPh3 (0.33 g, 1.24 mmol, 4 equiv with respect to Pd) and
LiCl (0.36 g, 8.51 mmol). Anhydrous DMA (5 mL) was added
and the mixture stirred at ambient temperature for 20 min in
order to generate the catalyst. To the ensuing yellow solution
was added 1b (2.50 g, 7.74 mmol) as a solution in DMA (7
mL) and allyltributyltin (3.60 mL, 11.6 mmol, 1.5 equiv). The
Young’s tube was sealed and subsequently heated in an oil
bath at 100 °C for 21 h. Filtration through Celite followed by
evaporation, yielded a viscous, yellow residue that was purified
by column chromatography to furnish white solids. Further
purification was achieved by recrystallization from EtOAc-
Et2O. Yield: 91% as translucent, feathery needles, Rf ) 0.23,
hexanes/EtOAc (4/1); mp 120.8-121.9 °C (from EtOAc/Et2O)
(lit.15 118-119 °C). Found: C, 80.70; H, 6.20; N, 5.75. Calcd
for C16H15NO: C, 80.97; H, 6.38; N, 5.90. νmax(KBr)/cm-1 1651
s (CO); δH (400 MHz; CDCl3) 3.51 (2H, close doublets, ArCH2),
5.14-5.19 (1H, m, CHdCH2), 5.28-5.31 (1H, m, CHdCH2),
6.05-6.15 (1H, m, CHdCH2), 7.18-7.22 (1H, m, Ar-H), 7.27
(1H, dd, J 1.5 and 7.5, Ar-H), 7.35-7.40 (1H, m, Ar-H), 7.51-
7.62 (3H, Ph-Hmeta and Ph-Hpara), 7.89-7.91 (2H, m, Ph-Hortho),
8.03 (1H, br s, NH), 8.11 (1H, d, J 8.0, Ar-H); δC (100.6 MHz;
CDCl3) 37.5 (ArCH2), 117.3 (CHdCH2), 123.8 (Ar-C), 125.7 (Ar-
C), 127.4 (Ph-Cortho), 128.1 (Ar-C), 129.2 (Ph-Cmeta), 130.2 (Ar-
C), 130.3 (Ar-C), 132.3 (Ph-Cpara), 135.4 (Ph-Cipso), 136.7 (CHd
CH2 and Ar-C), 165.9 (CO); m/z (EI) 237 (M+, 31%), 197 (10),
105 (100), 76 (75).
cm-1 1644 s (CO); δH (400 MHz; Tol-d8; 243 K) 2.53 (1H, dd, J
8.5 and 16.2, H-5â), 3.27-3.31 (1H, br m, H-2â), 3.71 (1H, br
d, J 16.2, H-5R), 5.21-5.24 (1H, m, H-3), 5.52-5.57 (1H, m,
H-2R), 5.73-5.78 (1H, br m, H-4), 6.36 (1H, d, J 7.6, Ar-H),
6.51 (1H, td, J 2.5 and 7.8, Ar-H), 6.65-6.69 (2H, m, Ar-H),
6.76-6.82 (3H, m, Ar-H), 7.32-7.34 (2H, m, Ar-H); δC (100.6
MHz; CDCl3) 31.2 (C-5), 44.4 (C-2), 123.0 (C-4), 125.2 (C-3),
126.0 (Ar-C), 126.1 (Ar-C), 126.3 (Ar-C), 126.5 (Ar-C), 127.2
(Ar-C), 127.3 (Ar-C), 128.4 (Ar-C), 134.2 (Ph-Cipso), 137.4 (Ar-
C), 141.4 (Ar-C), 167.8 (CO); m/z (EI) 249 (M+, 91%), 144 (22),
129 (37), 105 (100), 91 (4) 77 (41). Crystal data for 8 (CCDC
251226): C17H15NO, MW ) 249.30, monoclinic, P21/n (No. 14),
a ) 10.2478(3), b ) 10.1404(2), c ) 12.6013(3) Å, â )
95.2080(10)°, V ) 1304.08(6) Å3, Z ) 4, Dc ) 1.270 g cm-3
,
µ(Mo KR) ) 0.079 mm-1, T ) 120 K, colorless blocks; 2927
independent measured reflections, F2 refinement, R1 ) 0.038,
wR2 ) 0.093, 2498 independent observed absorption-corrected
reflections [|Fo| > 4σ(|Fo|), 2θmax ) 55°], 233 parameters.
Typical Procedure for Hydrogenation of Endocyclic/
Exocyclic Double Bond (Synthesis of 9 and 11). To a
solution of unsaturated benzazepine (0.50 g) in MeOH (15 mL)
was added 10% Pd/C (10 mol %). The suspension was stirred
vigorously at room temperature under a hydrogen atmosphere
for 2 days. The reaction mixture was then filtered through a
thin pad of Celite, washing the residue with a mixture of
EtOAc and MeOH. The collected filtrate was evaporated to a
crude viscous oil that was purified by column chromatography.
Preparation of N-Allyl-N-(2-allylphenyl)benzamide (7).
To a suspension of NaH (60% dispersion in oil, 0.66 g, 16.5
mmol, 1.5 equiv) in dry THF (15 mL) was added N-(2-
allylphenyl)benzamide 6 (3.00 g, 11.0 mmol) portionwise.
Additional THF (15 mL) was added and the pale colored
suspension stirred rapidly at ambient temperature for 3 h,
after which allyl bromide (1.42 mL, 16.5 mmol, 1.5 equiv) was
added, and the reaction subsequently was refluxed for 21 h.
After dilution with water (20 mL), the organic layer was
separated. The remaining aqueous phase was extracted with
EtOAc (3 × 30 mL), and the organic fractions washed with
brine, dried over MgSO4, filtered and evaporated. The dark
yellow oily residue was purified by column chromatography.
Yield: 89% as a pale yellow oil, Rf ) 0.35, hexanes/EtOAc
(4/1). Found: C, 82.45; H, 7.10; N, 5.15. Calcd for C19H19NO:
C, 82.26; H, 6.92; N, 5.05. νmax(thin film)/cm-1 1645 s (CO); δH
(360 MHz; CDCl3) 3.15 (1H, dd, J 6.6 and 9.5, ArCH2), 3.35
(1H, dd, J 6.6 and 9.1, ArCH2), 3.45 (br m, rotamer), 3.98-
4.02 (br m, rotamer), 4.12 (1H, dd, J 6.0 and 7.4, CH2N), 4.17
(br m, rotamer), 4.76 (1H, dd, J 6.0 and 8.4, CH2N), 4.89 (br
m, rotamer), 5.04-5.19 (4H, m, CH2dCHCH2N and ArCH2-
CHdCH2), 5.68-5.75 (1H, m, ArCH2CHdCH2), 5.77 (br m,
rotamer), 5.98-6.08 (1H, m, CH2dCHCH2N), 6.09-6.20 (br
m, rotamer), 7.11-7.59 (9H, m, Ar-H); δC (90.6 MHz; CDCl3)
35.4 (ArCH2), 53.7 (CH2N), 117.4 (ArCH2CHdCH2), 118.9
(CH2dCHCH2N), 127.4 (Ar-C), 127.9 (Ar-C), 128.2 (Ar-C),
128.9 (Ar-C), 130.0 (Ar-C), 130.1 (Ar-C), 130.8 (Ar-C), 133.1
(CH2dCHCH2N), 136.3 (ArCH2CHdCH2 and Ph-Cipso), 137.4
(Ar-C), 141.8 (Ar-C), 170.6 (CO); m/z (EI) 277 (M+, 64%), 262
(5), 236 (93), 218 (11), 172 (61), 105 (100), 91 (10), 77 (70).
1-Benzoyl-2,5-dihydro-1H-1-benzazepine (8). A dry
Young’s tube was charged with Grubbs catalyst (5-10 mol %)
and the corresponding diene 7 (0.50 g) as a 0.1 M solution in
dry toluene. The ensuing dark purple colored solution was
stirred at ambient temperature for 10 min. The Young’s tube
was then sealed and heated in an oil bath at 60 °C for 24 h.
The reaction mixture was concentrated in vacuo and purified
by column chromatography, to afford the product as a viscous
oil that crystallized upon standing overnight. For X-ray
crystallography, recystallisation was carried out with EtOH
to obtain colorless prisms. Yield: 86%, Rf ) 0.36, hexanes/
EtOAc (3/1); mp 96.6-97.3 °C. Found: C, 82.00; H, 6.20; N,
5.55. Calcd for C17H15NO: C, 81.89; H, 6.08; N, 5.62. νmax(KBr)/
1-Benzoyl-5-methyl-2,3,4,5-tetrahydro-1H-1-benzaz-
epine (9). The product was isolated as a colorless syrup that
crystallized upon standing overnight. The solids were recrys-
tallized from EtOAc/hexanes to obtain colorless prisms suitable
for X-ray crystallography. Yield: 86%, Rf ) 0.29, hexanes/
EtOAc (3/1); mp 87.8-88.6 °C (from EtOAc/hexanes). Found:
C, 81.45; H, 7.35; N, 5.30. Calcd for C18H19NO: C, 81.46; H,
7.23; N, 5.28. νmax(KBr)/cm-1 1638 s (CO). m/z (EI) 256 (M+,
74%), 222 (7), 160 (66), 144 (19), 130 (12), 105 (100), 77 (46).
Axial conformer: δH (360 MHz; CDCl3) 1.34-1.39 (1H, br
m, H-4â), 1.48 (3H, d, J 7.0, CH3), 1.68-1.73 (1H, br m, H-3â),
1.95-2.06 (2H, br m, H-3R and H-4R), 3.02-3.08 (1H, br m,
H-2â), 3.27-3.72 (1H, br m, H-5), 4.70 (1H, ddd, J 3.1, 7.0
and 13.2, H-2R), 6.64 (1H, d, J 7.7, Ar-H), 6.90-6.94 (1H, m,
Ar-H), 7.07-7.31 (7H, m, Ar-H); δC (125.8 MHz; CDCl3) 18.8
(CH3), 25.8 (C-3), 33.2 (C-4), 33.6 (1C, C-5), 45.8 (C-2), 124.0
(Ar-C), 125.3 (Ar-C), 125.9 (Ar-C), 126.3 (Ph-Cortho), 126.4 (Ph-
Cmeta), 126.9 (Ar-C), 128.3 (Ar-C), 135.0 (Ph-Cipso), 140.7 (Ar-
C), 141.4 (Ar-C), 168.3 (CO). Equatorial conformer: δH (360
MHz; CDCl3) 1.34-1.39 (1H, br m, H-4), 1.53 (3H, d, J 7.4,
CH3), 1.79-1.86 (1H, br m, H-3R), 1.95-2.06 (1H, br m, H-4),
2.29-2.33 (1H, br m, H-3â), 2.70-2.76 (1H, br m, H-2R), 3.27-
3.72 (1H, br m, H-5), 5.14-5.18 (1H, br m, H-2â), 6.57 (1H, d,
J 7.6, Ar-H), 6.86-6.88 (1H, m, Ar-H), other aromatic protons
overlapped by resonances of the axial conformer; δC (125.8
MHz; CDCl3) 17.5 (CH3), 22.9 (C-4), 31.1 (C-3), 39.6 (C-5), 47.1
(C-2), 125.5 (Ar-C), 126.1 (Ar-C), 127.3 (Ar-C), 127.7 (Ar-C),
128.2 (Ar-C), 129.4 (Ar-C), (1C, Ar-C). Crystal data for 9
(CCDC 251227): C18H19NO, MW ) 265.34, monoclinic, P21/n
(No. 14), a ) 10.1500(2), b ) 8.3473(2), c ) 16.6953(4) Å, â )
92.6330(10)°, V ) 1413.02(6) Å3, Z ) 4, Dc ) 1.247 g cm-3
,
µ(Mo KR) ) 0.077 mm-1, T ) 120 K, colorless prisms; 3221
independent measured reflections, F2 refinement, R1 ) 0.046,
wR2 ) 0.110, 2813 independent observed absorption-corrected
reflections [|Fo| > 4σ(|Fo|), 2θmax ) 55°], 183 parameters.
1-Benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine (11).
Yield: 90% as colorless, needlelike crystals, Rf ) 0.26, hexanes/
EtOAc (3/1); mp 94.2-95.4 °C (from Et2O/hexanes; lit.16 86-
87 °C, from n-hexane). Found: C, 81.40; H, 6.90; N, 5.45. Calcd
for C17H17NO: C, 81.23; H, 6.83; N, 5.57. νmax(KBr)/cm-1 1640
s (CO); δH (400 MHz; CDCl3) 1.41-1.47 (1H, m, H-4â), 1.87-
2.03 (3H, br m, H-4R, H-3R and H-3â), 2.66-2.69 (1H, m,
(15) Padwa, A.; Austin, D. J.; Price, A. T.; Weingarten, M. D.
Tetrahedron 1996, 52, 3247-3260.
(16) Ikeda, M.; Ohno, K.; Takahashi, M.; Uno, T.; Tamura, Y. J.
Chem. Soc., Perkin Trans. 1 1982, 741-748.
1550 J. Org. Chem., Vol. 70, No. 5, 2005

Partially and Fully Reduced 1-Benzazepines
H-2â), 2.72-2.82 (1H, m, H-5â), 2.94-3.00 (1H, m, H-5R),
4.94-4.97 (1H, br m, H-2R), 6.54 (1H, d, J 7.7, Ar-H), 6.79-
6.83 (1H, m, Ar-H), 6.96-7.19 (7H, m, Ar-H); δC (100.6 MHz;
CDCl3) 26.8 (C-4), 30.1 (C-3), 35.3 (C-5), 48.0 (C-2), 127.3, 127.5
(Ar-C), 128.1 (Ph-Cortho), 128.5 (Ph-Cmeta), 128.8 (Ar-C), 129.6
(Ar-C), 130.4 (Ar-C), 136.7 (Ph-Cipso), 139.7 (Ar-C), 144.5 (Ar-
C), 169.5 (CO); m/z (EI) 251 (M+, 65%), 145 (15), 130 (26), 105
(100), 77 (38). Crystal data for 11 (CCDC 251228): C17H17-
J 13.6, PhCH2), 4.33 (1H, d, J 13.6, PhCH2), 6.87-6.93 (2H,
m, ArH), 7.07-7.12 (2H, m, ArH), 7.16-7.20 (1H, m, ArH),
7.24-7.28 (2H, m, ArH), 7.35 (2H, d, J 7.4, ArH); δC (90.6 MHz;
CDCl3) 20.3 (CH3), 27.2 (C-3), 33.6 (C-4), 35.9 (C-5), 53.3 (1C,
C-2), 59.1 (PhCH2), 118.3 (Ar-C), 121.9 (Ar-C), 126.5 (Ph-Cpara),
126.8 (Ar-C), 127.3 (Ar-C), 128.7 (Ph-Cortho), 128.8 (Ph-Cmeta),
139.8 (C2), 140.2 (Ph-Cipso), 151.5 (C1); m/z (EI) 251 (M+, 22%),
160 (57), 118 (5), 84 (100).
Fully reduced benzazepine 12 was prepared similarly from
compound 11. Characterization data for 12 was identical to a
genuine sample previously prepared via a complementary
route.5 δH (500 MHz, CDCl3, free amine): 1.52-1.54 (4H, m,
CH2); 2.80-2.83 (4H, m, CH2); 4.24 (2H, s, CH2Ph); 6.80-6.83
(1H, m, Ar-H); 6.89-6.92 (1H, m, Ar-H); 7.05-7.09 (2H, m,
Ar-H); 7.16-7.17 (1H, m, Ar-H); 7.24-7.28 (2H, m, Ar-H);
7.35-7.37 (2H, d, J 7.1, Ar-H).
NO, MW
) 251.32, monoclinic, P21/c (No. 14), a )
6.19210(10), b ) 15.5228(3), c ) 14.0870(3) Å, â ) 99.3150-
(10)°, V ) 1336.17(4) Å3, Z ) 4, Dc ) 1.249 g cm-3, µ(Mo KR)
) 0.077 mm-1, T ) 120 K, colorless shards; 3038 independent
measured reflections, F2 refinement, R1 ) 0.050, wR2 ) 0.117,
2470 independent observed absorption-corrected reflections
[|Fo| > 4σ(|Fo|), 2θmax ) 55°], 173 parameters.
1-Benzyl-5-methyl-2,3,4,5-tetrahydro-1H-1-benzaz-
epine (10). To a solution of the benzazepine 9 (0.50 g) in dry
THF (15 mL) was added BH3‚SMe2 (2 M solution in THF, 1.1
equiv) dropwise under an inert atmosphere. The reaction
mixture was then heated to gentle reflux for 3 h, after which
the solvent was removed in vacuo. DCM (15 mL) and water
(10 mL) were added and the organic layer separated. The
remaining aqueous layer was extracted with DCM (2 × 15 mL).
The combined organic extracts were washed with saturated,
aqueous NaHCO3 (15 mL) solution, brine (10 mL) and dried
over MgSO4. Filtration, followed by evaporation of the solvent
afforded a crude, pale yellow oil which was purified by column
chromatography. The furnished product was obtained in 84%
yield as a colorless oil, Rf ) 0.6, hexanes/EtOAc (3/1). Found:
C, 85.95; H, 8.55; N, 5.45. Calcd for C18H21N: C, 86.00; H, 8.44;
N, 5.57. δH (360 MHz; CDCl3) 1.20-1.28 (1H, br m, H-4â), 1.32
(3H, d, J 7.1, CH3), 1.45-1.51 (2H, br m, H-3), 1.65-1.70 (1H,
br m, H-4R), 2.62 (1H, ddd, J 3.8, 6.6 and 12.0, H-2R), 2.87-
2.93 (1H, br m, H-2â), 3.22-3.26 (1H, br m, H-5), 4.12 (1H, d,
Acknowledgment. The synthetic work was con-
ducted at the Department of Chemistry, King’s College
London by M.Q., who was supported by an EPSRC
industrial CASE award by GlaxoSmithKline (grant
00314292). We thank Johnson Matthey plc for the
generous loan of palladium salts and Dr. Sarah Wilsey
(EPSRC National Computation Service) for help with
theoretical calculation/interpretation.
Supporting Information Available: Thermal ellipsoid
1
plots of compounds 3, 8, 9 and 11; H NMR of the mixture of
compounds 4 and 5; and Eyring plot for benzazepine 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048118B
J. Org. Chem, Vol. 70, No. 5, 2005 1551