Conformation analyses, dynamic behavior, and amide bond distortions of medium-sized heterocycles. 2. Partially and fully reduced 1-benzazocines, benzazonines, and benzazecines

Article abstract of DOI:10.1021/jo048117j

(Chemical Equation Presented) Partially and fully reduced forms of benzo-fused eight- to ten-membered nitrogen heterocycles (1-benzazecines, 1-benzazonines and 1-benzazecines) have been prepared. Conformational features, transannular distances and dynamic

Full text of DOI:10.1021/jo048117j

Conformation Analyses, Dynamic Behavior, and Amide Bond
Distortions of Medium-sized Heterocycles. 2. Partially and Fully
Reduced 1-Benzazocines, Benzazonines, and Benzazecines
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 Chermistry, King’s College London, Strand WC2R 2LS, U.K., GlaxoSmithKline,
Old Powder Mills, Tonbridge, Kent, 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
Partially and fully reduced forms of benzo-fused eight- to ten-membered nitrogen heterocycles (1-
benzazecines, 1-benzazonines and 1-benzazecines) have been prepared. Conformational features,
transannular distances and dynamic behavior were studied using X-ray crystallography and VT
NMR spectroscopy. The amide moiety in the nine-membered benzazonine ring 5b favors N-
pyramidization, whereas the ten-membered benzazecine 5c adopts an amide twist. Molecular
mechanics calculations reveals a correlation between the amide twist (τ) and ring stability. The
dynamic behavior of the heterocycles in solution were also found to be dependent on the extent
and nature of the amide distortion. We thus conclude that ring strain of these medium-sized
heterocyclic rings is relieved through amide distortion, which leads to a more stable structure.
Introduction
In the preceding paper, we described expedient transi-
tion-metal-catalyzed synthetic routes to 1-benzazepine
structures. Substitutions introduced at key positions of
the heterocyclic ring lead to changes to the solid- and
solution-state structures, which were examined using a
combination of X-ray crystallography, NMR spectroscopy
and molecular mechanics calculations. Part of this study
revealed that the reduction of the endocyclic double bond
in benzazepine 1 (Figure 1) introduces flexibility to the
fully saturated ring 2, which is able to relieve ring strain
by amide distortion. As a result of its greater stability,
compound 2 undergoes slower ring inversion than 1.
Subsequent development of the work led us to extend
the study to larger rings. Compared to the 1-benz-
azepines, corresponding benzo-fused eight-membered
heterocyclic rings (1-benzazocines) are relatively uncom-
FIGURE 1. Dihydro- and tetrahydro-1-benzazepines.
mon, whereas very few examples of larger nine- and ten-
membered analogues (1-benzazonines and 1-benzaze-
cines,respectively)areknownbeyondthepatentliterature.1,2
Results and Discussion
Synthesis of Eight to Ten-Membered Hetero-
cycles (Scheme 1). Following the general procedures
described in the preceding article, alkylation of N-2-
(1) (a) Shiraishi, M.; Baba, M.; Aikawa, K.; Kanzaki, N.; Seto, M.;
Iizawa, Y. Preparation of 1-benzazocine-5-carboxamides and related
bicyclic compounds as CCR-5 antagonists for use against HIV infection
and other diseases. World Patent WO2003/014105, 2003. (b) Ham-
minga, D.; van Wjingaarden, I.; Jansen, J. W. C. M. Preparation of
8,9-annelated-1,2,3,4-tetrahydro-â-carboline derivatives as fibrino-
lytics. European Patent EP380155, 1990.
(2) Alder, R. W.; White, J. M. In Conformational Analysis of
Medium-Sized Heterocycles; Glass, R. S., Ed.; VCH: New York, 1988;
Chapter 3.
* To whom correspondence should be addressed. Fax: +44-20-7594-
5804. Tel: +44-20-7594-1142.
† 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.
10.1021/jo048117j CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/29/2005
1552
J. Org. Chem. 2005, 70, 1552-1557

1-Benzazocines, Benzazonines, and Benzazecines
SCHEME 1. Synthesis of Heterocycles (Bz )
benzoyl; Bn ) benzyl)a
zation (entries 5-8). The alkene moiety in all of these
heterocycles possesses exclusive Z-geometry, as verified
by NMR (NOESY) experiments.
The fully saturated forms of the eight- and nine-
membered heterocycles 6a,b were then obtained via
hydrogenolysis over Pd/C.4 Reduction of the amide bond
is carried out with borane, to give the N-benzyl-
substituted forms 7a and 7b as dense oils.
Fortuitously, N-benzoyl compounds 5a-c and 6a,b are
sufficiently crystalline to allow analysis of these unusual
eight- to ten-membered rings via single-crystal X-ray
diffraction. Thus, structural features such as ring con-
formation, transannular distances and distortion of the
exocyclic amide bond may be examined in a systematic
manner, as reflected in the amide bond twist and/or
N-pyramidization through θ, τ, and R values.
Solid-State Structures (Figure 2, Table 2). Both
benzazocines 5a and 6a display the boat-chair (BC)
conformation, with 5a having an unusually wide internal
angle about nitrogen [b ) 119.86(11)°]. Overall, trans-
annular interactions in these eight-membered ring struc-
tures are negligible; the closest nonbonding distance in
5a is observed between H-3R and H-6R of approximately
2.39 Å, increasing to 2.59 Å upon reduction of the double
bond to 6a. The nitrogen heteroatom in both structures
are relatively planar, the reduced benzazocine 6a being
slightly more distorted than 5a, presumably due to
greater conformational flexibility.
a Reagents and conditions: (i) NaH, THF; (ii) (allyl)SnBu3,
Pd(OAc)2, PPh3, LiCl; (iii) Grubb’s catalyst, toluene or CH2Cl2
(Table 1); (iv) H2, Pd/C; (v) BH3‚SMe2.
TABLE 1. Reaction Conditions Adopted for RCM
Reactiona
product
catalytic
temp
(°C)
yieldb
(%)
entry (ring size) loading (mol %)
solvent
The nine-membered benzazonines 5b and 6b adopt
boat-chair conformations in the solid state. Unlike the
benzazocines, the unsaturated heterocycle 5b has an
amide bond more distorted than that of 6b, displaying
substantial N-pyrimidization, due entirely to a øN twist
of 31.0° (θ ) 352.8°, R ) 26.0°). This is accompanied by
a lengthening of the amide bond [1.373(2) Å]. Notably,
there is a very close transannular distance in 5b between
H-4R and H-7R of 2.07 Å. A slight overlap of the van der
Waals radii of the two nuclei could be observed in the
space-filling model, which could suggest the presence of
a small repulsive interaction. When the endocyclic double
bond is reduced, the transannular distance between H-4R
and H-7R in 6b becomes greater (2.15 Å). The C-N bond
length returns to a more expected value [1.354(2) Å], as
the amide moiety becomes essentially planar (θ ) 359.7°,
R ) 5.4°) with negligible twist (τ ) 0.4°).
Exhibiting the boat-chair-boat (BCB) conformation, the
closest transannular distance in the ten-membered
benzoazecine ring 5c is between H-5R and H-8R (2.10 Å).
Interestingly, the nature of the amide distortion is
entirely different in this molecule: while the smaller
seven- to nine-membered heterocyclic rings distort by
N-pyramidization (large øN), the planarity of the N-C(O)
amide bond in the ten-membered ring is retained (θ )
360.0°, R ) 0.7°). However, a significant twist between
the plane and the N-C′ vector of the amide bond was
observed (τ ) -16.2°), which implies that the nitrogen
lone pair may be able to conjugate with the fused
aromatic ring.
1
5a (8)
5b (9)
5b (9)
5b (9)
5c (10)
5c (10)
5c (10)
5c (10)
5
5
10
5
5
5
10
10
60
60
60
35
60
80
60
40
toluene
toluene
toluene
DCM
toluene
toluene
toluene
DCM
81
35
67
78
15
13
17
15
2
3
4c
5
6
7c
8c
a Reaction conducted in 0.1 M solutions in sealed Young’s tubes
for 22-24 h unless otherwise stated. b Isolated yield after column
chromatography. c Reaction time of 7 days.
iodophenyl-N-benzamide with respective 1-alkenyl p-
toluenesulfonates followed by Stille cross-coupling with
allyltributyltin afforded the diene compounds 4a-c.3
These were subjected to RCM effected by Grubb’s catalyst
Ru(dCHPh)Cl2(PCy3)2 to furnish the novel series of
medium-sized heterocycles 5a-c, containing one unit of
unsaturation within the ring.
The yield of the RCM reaction is dependent on the ring
size being formed, as well as the reaction conditions
under which catalysis was effected (Table 1). The eight-
membered dehydrobenzazocine ring 5a was obtained in
high yield using previously optimized conditions (entry
1). However, the formation of the larger rings were
significantly slower, such that catalyst decomposition
became a competitive process under these conditions.
Hence, 5b can only be obtained in moderate to good yields
either by adopting higher catalytic loading at 60 °C (entry
3) or a prolonged reaction time at 35 °C (entry 4), whereas
the ten-membered benzazecine ring 5c was only obtained
in very small quantities despite our attempts at optimi-
Examining the IR spectra of the solid samples (as KBr
disks), structures containing the most pyramidized amide
bonds (1, 2, and 5b, where R > 12°) exhibit CdO
(3) The yields of the N-alkylation reactions were poor if they were
performed after the Stille reaction, presumbly due to reduced electro-
philicity of these alkenyl tosylates.
(4) Benzoazecine 5c was not hydrogenated due to the small quantity
available.
J. Org. Chem, Vol. 70, No. 5, 2005 1553

Qadir et al.
FIGURE 3. Variation of τ and R values with ring size.
Columns ) 180 - |τ|; data points ) |R|; green ) unsaturated
rings; red ) saturated rings.
FIGURE 4. Relative energies of seven- to ten-membered
rings. Circle ) unsaturated rings; squares ) saturated rings.
Trends in the Amide Distortions (Figure 3). Previ-
ously, we have demonstrated that benzazepine rings are
stabilized by amide distortions and the proportional
relationship between τ and R. Examining the series of
saturated rings (2, 6a, and 6b), an increase in the ring
size appears to lead to a corresponding increase in amide
planarity (Figure 3, red columns), accompanied by a
smaller amide twist (Figure 3, red squares).
In the unsaturated series (1, 5a, 5b, and 5c), the above
trend is only observed for the seven- and eight-membered
heterocycles (Figure 3, green columns and squares). The
nine-membered ring seemed to favor N-pyramidization
(large R) over amide twist, whereas the opposite is true
for the ten-membered ring (large τ).
Molecular Modeling. Assignment of stable conforma-
tions of these larger rings by molecular modeling has to
be made with great caution. In addition to ring strain, a
number of other factors such as entropic freedom and
transannular forces are also envisaged to be important,
all of which may be affected by crystal packing forces in
the solid-state structure. With this in mind, we calculated
the energies of the solid-state structures using Spartan
mechanics, and the values obtained were plotted against
each other to assess the effect of ring expansion (Figure
4). For both the unsaturated and saturated ring systems,
there appears to be an overall increase in energy with
FIGURE 2. Molecular structures of 5a-c, 6a, and 6b, with
chemical numbering scheme, illustrating transannular dis-
tances (middle) and amide distortions (right). Aromatic hy-
drogens are omitted for clarity.
stretching frequencies approximately 10 cm-1 higher
than the rest.
1554 J. Org. Chem., Vol. 70, No. 5, 2005

1-Benzazocines, Benzazonines, and Benzazecines
TABLE 2. Crystal Structure and Spectroscopic Parameters Reflecting Amide Deformationsa
d
e
f
g
h
i
compound
bb
θc
ω1
ω2
ω3
+0.8 +21.7 +19.4 +1.5 +191.3 (+11.3) 15.7 1.3662(14)
+1.6 +6.5 +5.2 -0.3 +184.1 (+4.3) 4.5 1.359(2)
+3.1 -31.0 -31.0 -3.2 +166.0 (-14.0) 26.0 1.373(2)
+0.9 -3.1 +164.8 (-16.2) 0.7 1.366(2)
ω4
øN
øC
τj
Rk
C-N (Å)
νCOl (cm-1
)
1
115.31(8)
357.3 +182.3 +200.2
1644
1634
1640
1630
1640
1626
1632
5a
5b
5c
2
119.86(11) 359.8 +181.3 +186.8
115.58(14) 352.8 +179.9 +152.1
116.84(10) 360.0 +162.8 +166.8 -14.1 -16.3
116.67(11) 358.4 +188.1 +200.0
115.67(11) 359.3 +178.1 +169.1
+4.8 +23.3 +15.2 +3.3 +194.1 (+14.1) 12.5 1.368(2)
-0.3 -12.5 -10.6 -1.6 +173.6 (-6.4)
+4.7 -3.8 -6.5 -2.0 +180.4 (+0.4)
6a
6b
8.4 1.353(2)
5.4 1.354(2)
117.39(9)
359.7 +182.7 +178.1
a Data for 1 and 2 had been reported in the preceding paper and are reproduced here for comparison. ω1, ω2, ω3, and ω4 assignments
are made as for trans amides where C1 ) H. Unless otherwise stated, 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 )
TORS[CR′,C′,N,C1]. 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 plane and the N-C′ vector. l Recorded as KBr disks.
1
FIGURE 5. Variable temperature H NMR spectra of compound 5b (resonances of heterocyclic ring protons).
ring size. There is a remarkable correlation between the
trends of relative energies with the amide twist (Figure
3): an increase in the τ leads to a corresponding rise in
stability (lower energy). This reinforced the notion es-
tablished in our previous study of benzazepine structures,
that ring strain of these systems is largely alleviated
through amide twist.
Dynamic NMR Behavior. Since greater amide dis-
tortion is associated with a more stable ground-state
structure, we would also expect a larger activation energy
for ring inversion. Although the variable NMR spectra
of the larger rings are more complicated, the larger
benzazocine rings do indeed appear to have a higher
activation barrier to ring flipping than the smaller
benzazepine rings. As both benzazocine structures dis-
play very little amide distortion, they also have very
similar activation energies toward ring inversion, which
are estimated to be 16.7 and 17.0 kcal mol-1 for 5a and
6a, respectively. This is in marked contrast to that
observed for benzazepines, where the saturated ring
(more distorted amide) is conformationally more stable
than the unsaturated ring.
to undergo conformational changes. Distinct diaste-
reotopic proton resonances were observed in the NMR
spectra of compounds 5b, 5c, and 6b, which undergo very
slow exchange on the NMR time scale. As the unsatur-
ated nine-membered benzazonine 5b has the most dis-
torted amide bond, ring inversion would be expected to
be a very unfavorable process. Indeed, the resolution of
the resonance signals corresponding to the heterocyclic
ring protons is well-preserved over a broad temperature
range, showing very little broadening, even at 373 K
(Figure 5).
Since the saturated benzazonine 6b possesses an
amide bond less distorted than that of the unsaturated
5b, we will expect the latter to be conformationally more
stable. Qualitative comparison of the VT NMR spectra
of 5b and 6b indicates that the saturated ring is, indeed,
more labile than the unsaturated ring, as indicated by
greater broadening of the resonance signals of 6b at
elevated temperatures (Supporting Information).
It is clear from our study that the dynamic behavior
of these heterocycles is highly dependent on the nature
of the amide bond. Indeed, when the N-benzoyl is
transformed to an N-benzyl moiety, the resultant tetra-
hydro-benzazocine and benzazonine rings 7a and 7b
Having more distorted amide bonds, the nine-mem-
bered rings also require much higher activation energies
J. Org. Chem, Vol. 70, No. 5, 2005 1555

Qadir et al.
1
N-(2-Allylphenyl)-N-(pent-4-en-1-yl)-benzamide (4b).
Yield: 84% as a pale yellow syrup, Rf ) 0.23, hexanes/EtOAc
(5/1). Found: C, 82.80; H, 7.75; N, 4.75. Calcd for C21H23NO:
C, 82.57; H, 7.61; N, 4.59. νmax (neat)/cm-1 1644br s (CO); δH
(400 MHz; CDCl3) 1.62-1.76 (2H, br m, CH2CH2N), 1.98-2.09
(2H, CH2CH2CH2N), 3.10 (1H, dd, J 6.3 and 9.4, ArCHH), 3.27
(1H, dd, J 6.8 and 9.4, ArCHH), 3.42 (1H, ddd, J 2.7, 5.2 and
10.5, CHHN), 4.05 (1H, ddd, J 2.7, 5.7 and 10.5, CHHN), 4.87-
5.03 (4H, m, ArCH2CHdCH2, CH2dCHCH2), 5.58-5.76 (2H,
m, ArCH2CHdCH2, CH2dCHCH2), 5.77 (br s, rotamer), 6.98-
7.19 (9H, ArH), 7.21-7.38 (br m, rotamer); δC (100.6 MHz;
CDCl3) 26.8 (CH2CH2N), 31.7 (CH2CH2CH2N), 35.3 (ArCH2),
50.4 (CH2N), 115.4 (CH2dCHCH2), 117.5 (ArCH2CHdCH2),
127.4, 127.9, 128.8, 130.1, 130.9 (ArC), 136.2 (ArCH2CHdCH2),
136.5, 137.4 (Ar-C), 138.2 (CH2dCHCH2), 141.9 (Ar-C), 170.7
(1C, CO); m/z (EI) 305 (M+, 66%), 262 (100), 236 (30), 200 (68),
105 (99), 77 (79).
N-(2-Allylphenyl)-N-(hex-5-en-1-yl)-benzamide (4c).
Yield: 87% as a pale yellow syrup, Rf ) 0.27, hexanes/EtOAc
(5/1). Found: C, 82.85; H, 8.10; N, 4.55. Calcd for C22H25NO:
C, 82.70; H, 7.90; N, 4.39. νmax (thin film)/cm-1 1643 br vs (CO);
δH (400 MHz; CDCl3) 1.19 (br s, rotamer), 1.32-1.41 (2H, br
m, CH2CH2CH2N), 1.50-1.69 (2H, br m, CH2CH2N), 1.85 (br
s, rotamer), 1.97-2.03 (2H, m, CH2dCHCH2), 3.18 (1H, dd, J
6.3 and 9.3, ArCHH), 3.27 (1H, dd, J 6.8 and 9.3, ArCHH),
3.41 (1H, ddd, J 2.8, 5.4 and 10.3, CHHN), 4.05 (1H, ddd, J
2.9, 5.8 and 10.3, CHHN), 4.84-5.03 (4H, br m, ArCH2CHd
CH2, CH2dCHCH2), 5.58-5.76 (2H, br m, ArCH2CHdCH2,
CH2dCHCH2), 6.98-7.19 (9H, m, ArH), 7.25 (rotamer); δC
(100.6 MHz; CDCl3) 26.8 (CH2CH2CH2N), 27.2 (CH2CH2N),
33.9 (CH2dCHCH2), 35.3 (ArCH2), 50.7 (1C, CH2N), 115.1
(CH2dCHCH2), 117.5 (ArCH2CHdCH2), 127.4, 127.9, 128.1,
128.7, 129.9, 130.1, 130.9 (Ar-C), 136.2 (ArCH2CHdCH2),
136.6, 137.4 (Ar-C), 138.9 (CH2dCHCH2), 141.9 (Ar-C), 170.7
(CO); m/z (EI) 319 (M+, 30%), 250 (10), 236 (14), 196 (9), 105
(100), 77 (30).
(4Z)-1-Benzoyl-1,2,3,6-tetrahydro-1-benzazocine (5a).
Colorless crystals, Rf ) 0.27, hexanes/EtOAc (3/1); mp 83.9-
84.3 °C (from EtOAc/hexanes). Found: C, 82.20; H, 6.65; N,
5.40. Calcd for C18H17NO: C, 82.09; H, 6.52; N, 5.32. νmax (KBr)/
cm-1 1634vs (CO); δH (400 MHz; CDCl3) 2.33-2.40 (1H, m,
H-3â), 2.67-2.75 (1H, m, H-3R), 2.79-2.85 (1H, m, H-2â), 3.16
(1H, dd, J 6.9 and 14.3, H-6â), 3.65 (1H, dd, J 7.3 and 14.3,
H-6R), 4.95 (1H, ddd, J 2.2, 7.5 and 13.1, H-2R), 5.76-5.83
(1H, m, H-4), 5.90-6.98 (1H, m, H-5), 7.08-7.10 (1H, m, ArH),
7.14-7.56 (8H, m, ArH); δC (100.6 MHz; CDCl3) 26.9 (C-3),
33.6 (C-6), 49.0 (C-2), 127.7, 128.0, 128.2, 128.5 (Ar-C), 129.2
(C-4), 129.6, 130.1, 130.2 (Ar-C), 131.2 (C-5), 137.0, 140.7, 142.4
(Ar-C), 170.5 (CO); m/z (EI) 263 (M+, 85%), 158 (27), 130 (5),
105 (100), 77 (40). Crystal data for 5a (CCDC 251229):
C18H17NO, MW ) 263.33, monoclinic, P21/c (No. 14), a )
8.20040(10), b ) 22.6060(5), c ) 8.51990(10) Å, â ) 117.5990-
(10)°, V ) 1399.69(4) Å3, Z ) 4, Dc ) 1.250 g cm-3, µ(Mo KR)
) 0.077 mm-1, T ) 120 K, colorless plates; 3171 independent
measured reflections, F2 refinement, R1 ) 0.050, wR2 ) 0.126,
2772 independent observed absorption-corrected reflections
[|Fo| > 4σ(|Fo|), 2θmax ) 55°], 182 parameters.
display extremely fluxional H NMR spectra. Signals of
individual geminal methylenes could not be resolved,
even at the lowest temperature of 183 K (Supporting
Information), indicating rapid ring inversion of the fully
reduced forms.
In conclusion, a series of seven- to ten-membered
benzo-fused nitrogen heterocycles have been prepared.
X-ray crystallography revealed that most of the struc-
tures contain distorted amides, which may occur through
N-pyramidization (largely øN twist) or by an out-of-plane
twist (τ). Molecular modeling revealed a correlation
between ring stability and amide twist τ. As a conse-
quence, the dynamic behavior of these rings is dependent
on the nature and the extent of the amide distortion. On
the whole, greater amide distortion is accompanied by a
larger barrier to ring inversion.
Experimental Section
N-But-3-en-1-yl-N-(2-iodophenyl)benzamide
(3a).
Yield: 88% as colorless, rock-like crystals, Rf ) 0.25, hexanes/
EtOAc (5/1); mp 66.2-67.8 °C (from EtOAc/hexanes). Found:
C, 54.90; H, 4.10; N, 3.55. Calcd for C17H16NIO: C, 55.12; H,
3.91; N, 3.39. νmax (KBr)/cm-1 1634vs br (CO), δH (360 MHz;
CDCl3) 2.39-2.45 (1H, br m, CHHCH2N), 2.48-2.54 (1H, br
m, CHHCH2N), 3.37-3.45 (1H, br m, CHHN), 4.40-4.48 (1H,
br m, CHHN), 5.08-5.16 (2H, br m, CH2dCHCH2), 5.80-5.92
(1H, br m, CH2dCHCH2), 6.89-6.94 (1H, br m, Ar-H), 7.08
(1H, d, J 7.4, Ar-H), 7.13-7.23 (4H, m, Ar-H), 7.35 (2H, br d,
J 7.3, Ar-H), 7.82 (1H, d, J 7.8, Ar-H); δC (100.6 MHz; CDCl3)
32.1 (1C, CH2CH2N), 49.1 (1C, CH2N), 100.5 (1C, C2), 117.2
(1C, CH2dCHCH2), 128.0, 128.6, 129.3, 129.5, 130.0 (Ar-C),
132.2 (1C, C6), 135.7 (1C, CH2dCHCH2), 136.5, 140.6, 145.4
(Ar-C), 170.8 (1C, CO); m/z (EI) 377 (M+, 4%), 336 (22), 323
(12), 250 (47), 208 (3), 196 (6), 105 (100), 77 (27).
N-Hex-5-en-1-yl-N-(2-iodophenyl)benzamide
(3c).
Yield: 80% as a pale yellow syrup which crystallized upon
standing, Rf ) 0.23, hexanes/EtOAc (4/1); mp 65.0-66.6 °C
(from EtOAc/hexanes). Found: C, 56.20; H, 4.75; N, 3.30. Calcd
for C19H20NIO: C, 56.30; H, 4.98; N, 3.46. νmax (KBr)/cm-1
1623br vs (CO); δH (360 MHz; CDCl3) 1.27 (br s, rotamer),
1.41-1.63 (3H, br m, CHHCH2N, CH2CH2CH2N,), 1.76-1.85
(1H, br m, CHHCH2N), 1.91 (br s, rotamer), 2.08-2.13 (2H,
br m, CH2dCHCH2), 3.32-3.40 (1H, br m, CHHN), 3.65 (br s,
rotamer), 4.33 (1H, ddd, J 3.5, 5.7 and 10.1, CHHN), 4.94-
5.03 (2H, br m, CH2dCHCH2), 5.75-5.86 (1H, m, CH2d
CHCH2), 6.89-6.93 (1H, m, Ar-H), 7.05 (1H, d, J 7.1, Ar-H),
7.13-7.24 (4H, m, Ar-H), 7.35 (2H, d, J 7.2, Ar-H), 7.48-7.67
(br s, rotamer), 7.82 (1H, d, J 7.9, Ar-H), 7.97 (br s, rotamer);
δC (100.6 MHz; CDCl3) 26.8 (1C, CH2CH2N), 27.1 (1C, CH2-
CH2CH2N), 33.9 (1C, CH2dCHCH2), 49.8 (1C, CH2N), 100.5
(1C, C2), 115.1 (1C, CH2dCHCH2), 128.0, 128.6 (4C, Cortho
,
C
meta), 129.3, 129.4, 130.5, 132.0, 136.3 (Ar-C), 138.9 (1C, CH2d
CHCH2), 140.7, 145.6 (Ar-C), 170.7 (1C, CO); m/z (EI) 405 (M+,
4%), 323 (13), 278 (100), 196 (20), 105 (78), 77 (28).
N-(2-Allylphenyl)-N-(but-3-en-1-yl)-benzamide (4a).
Yield: 68% as a colorless syrup, Rf ) 0.22, hexanes/EtOAc
(5/1). Found: C, 82.55; H, 7.50; N, 4.90. Calcd for C20H21NO:
C, 82.42; H, 7.28; N, 4.81. νmax (thins film)/cm-1 1644vs br (CO);
δH (360 MHz; CDCl3) 2.32-2.42 (2H, br m, CH2CH2N), 3.11
(1H, dd, J 6.3 and 9.4, ArCHH), 3.28 (1H, dd, J 6.8 and 9.4,
ArCHH), 3.44 (1H, ddd, J 4.3, 6.3 and 9.0, CHHN), 4.18 (1H,
ddd, J 4.1, 6.3 and 9.0, CHHN), 4.97-5.06 (4H, br m, ArCH2-
CHdCH2, CH2dCHCH2), 5.61-5.79 (2H, br m, ArCH2CHd
CH2, CH2dCHCH2), 6.99-7.48 (9H, m, ArH); δC (90.6 MHz;
CDCl3) 32.1 (CH2CH2N), 35.3 (ArCH2), 49.9 (CH2N), 117.1
(CH2dCHCH2), 117.5 (ArCH2CHdCH2), 127.4, 127.9, 128.2,
128.7, 129.9, 130.3, 130.9 (Ar-C), 135.7 (CH2dCHCH2), 136.2
(ArCH2CHdCH2), 136.5, 137.4, 141.8 (Ar-C), 170.8 (CO); m/z
(EI) 291 (M+, 12%), 250 (46), 236 (6), 186 (5), 105 (100), 77
(25).
(5Z)-1-Benzoyl-2,3,4,7-tetrahydro-1H-1-benzazonine
(5b). Colorless crystals, Rf ) 0.31, hexanes/EtOAc (3/1); mp
122.6-124 °C (from EtOH/Et2O). Found: C, 82.35; H, 7.05;
N, 5.15. Calcd for C19H19NO: C, 82.26; H, 6.92; N, 5.05. νmax
(KBr)/cm-1 1640vs (CO); δH (400 MHz; CDCl3) 1.41-1.50 (1H,
m, H-3â), 2.04-2.11 (1H, m, H-4â), 2.80-2.86 (1H, m, H-3R),
2.92-3.05 (3H, m, H-7â, H-2â and H-4R), 4.17 (1H, ddd, J 2.0,
4.2 and 13.2, H-2R), 4.23-4.29 (1H, m, H-7R), 5.52 (1H, td, J
6.0 and 10.7, H-5), 5.72 (1H, td, J 6.0 and 10.7, H-6), 6.73 (1H,
dd, J 1.3 and 7.8, ArH), 6.93-6.98 (1H, m, ArH), 7.08-7.26
(5H, m, ArH), 7.35-7.38 (2H, m, ArH); δC (100.6 MHz; CDCl3)
22.9 (C-4), 26.4 (C-3), 31.8 (C-7), 51.9 (C-2), 127.9, 128.2, 128.4,
124.0 (Ar-C), 129.0 (C-5), 129.4 (C-6), 130.1, 130.2, 131.4 (Ar-
C), 136.8, 137.6, 145.8 (Ar-C), 172.8 (CO); m/z (EI) 277 (M+,
42%), 249 (22), 222 (6), 172 (71), 130 (21), 105 (100), 91 (8), 77
1556 J. Org. Chem., Vol. 70, No. 5, 2005

1-Benzazocines, Benzazonines, and Benzazecines
(58). Crystal data for 5b (CCDC 251230): C19H19NO, MW )
277.35, monoclinic, P21/c (No. 14), a ) 9.5717(4), b )
8.2880(3), c ) 18.8257(8) Å, â ) 92.399(2)°, V ) 1492.14(10)
Å3, Z ) 4, Dc ) 1.235 g cm-3, µ(Mo KR) ) 0.076 mm-1, T )
120 K, colorless shards; 3402 independent measured reflec-
tions, F2 refinement, R1 ) 0.049, wR2 ) 0.100, 1946 indepen-
dent observed absorption-corrected reflections [|Fo| > 4σ(|Fo|),
2θmax ) 55°], 191 parameters.
(3/1); mp 102.5-103.8 °C (from EtOAc/hexanes). Found: C,
81.90; H, 7.75; N, 5.10. Calcd for C19H21NO: C, 81.67; H, 7.60;
N, 5.01. νmax (KBr)/cm-1 1632vs (CO); δH (400 MHz; CDCl3)
0.88-0.93 (1H, br m, ArCH2CH2CH-5R), 1.38-1.61 (4H, br m,
H-6, H-5â and 2 × H-4), 1.62-1.74 (2H, br m, H-6, H-3â),
2.11-2.20 (1H, br m, H-3R), 2.25 (1H, dt, J 4.4 and 14.0, H-7â),
2.73 (1H, ddd, J 4.1, 11.7 and 14.0, H-7R), 3.10-3.17 (1H, m,
H-2â), 4.65 (1H, ddd, J 4.3, 5.9 and 13.7, H-2R), 6.94 (1H, d, J
7.2, ArH), 7.02-7.21 (8H, ArH); δC (90.6 MHz; CDCl3) 22.5
(C-5), 24.2 (C-4), 26.7 (C-3), 29.2 (C-6), 30.4 (C-7), 50.8 (C-2),
127.6, 127.7, 128.4, 128.5, 128.8, 129.5, 131.0, 137.1, 140.5,
144.2 (Ar-C), 170.6 (CO); m/z (EI) 279 (M+, 79%), 236 (5), 211
(20), 174 (42), 134 (8), 118 (14), 105 (100), 77 (41). Crystal
data for 6b (CCDC 251233): C19H21NO, MW ) 279.37,
monoclinic, P21/c (No. 14), a ) 11.3938(4), b ) 14.0951(6), c )
9.4791(4) Å, â ) 92.901(2)°, V ) 1520.36(11) Å3, Z ) 4, Dc )
1.221 g cm-3, µ(Mo KR) ) 0.075 mm-1, T ) 120 K, colorless
blocks; 3442 independent measured reflections, F2 refinement,
R1 ) 0.043, wR2 ) 0.098, 2526 independent observed absorp-
tion-corrected reflections [|Fo| > 4σ(|Fo|), 2θmax ) 55°], 191
parameters.
(6Z)-1-Benzoyl-1,2,3,4,5,8-hexahydro-1-benzazecine (5c).
Unreacted diene was recovered in 30% yield while TLC
analysis indicated significant amounts of polymerized side
products. Colorless crystals, Rf ) 0.34, hexanes/EtOAc (3/1);
mp 134.6-135.7 °C (from EtOAc/hexanes). Found: C, 82.25;
H, 7.00; N, 4.70. Calcd for C20H21NO: C, 82.42; H, 7.28; N,
4.81. νmax (KBr)/cm-1 1630vs (CO); δH (400 MHz; CDCl3) 1.24-
1.31 (2H, m, H-3), 1.40-1.47 (1H, m, H-4â), 1.83-1.90 (1H,
m, H-4R), 1.95-1.99 (1H, m, H-5â), 2.21 (1H, dd, J 6.0 and
13.0, H-8â), 2.61-2.71 (1H, m, H-5R), 3.36 (1H, dd, J 11.0 and
13.0, H-8R), 3.55 (1H, dt, J 3.5 and 13.4, H-2R), 4.81-4.87 (1H,
m, H-2â), 5.17 (1H, td, J 4.8 and 11.0, H-6), 5.45 (1H, td, J 6.1
and 11.0, H-7), 6.91 (1H, dd, J 1.3 and 7.7, ArH), 7.00-7.17
(4H, m, ArH), 7.18-7.20 (3H, m, ArH), 7.31 (1H, dd, J 1.0 and
7.9, ArH); δC (100.6 MHz; CDCl3) 20.9 (C-3), 22.7 (C-5), 28.9
(C-4), 30.1 (C-8), 51.1 (C-2), 127.5, 127.7, 127.9, 128.2 (ArC),
129.1 (C-7), 129.1, 129.8 (ArC), 130.5 (C-6), 131.3, 137.1, 139.6,
140.6 (Ar-C), 170.5 (CO); m/z (EI) 291 (M+, 34%), 263 (34), 237
(8), 209 (6), 186 (76), 144 (5), 130 (11), 105 (100), 77 (38).
Crystal data for 5c (CCDC 251231): C20H21NO, MW )
291.38, monoclinic, C2/c (No. 15), a ) 11.1017(3), b )
11.9013(4), c ) 24.0165(7) Å, â ) 101.880(2)°, V ) 3105.21-
(16) Å3, Z ) 4, Dc ) 1.247 g cm-3, µ(Mo KR) ) 0.076 mm-1, T
) 120 K, light brown blocks; 3459 independent measured
reflections, F2 refinement, R1 ) 0.041, wR2 ) 0.092, 2687
independent observed absorption-corrected reflections [|Fo| >
4σ(|Fo|), 2θmax ) 55°], 200 parameters.
1-Benzyl-1,2,3,4,5,6-hexahydro-1-benzazocine
(7a).
Yield: 89% as a colorless oil, Rf ) 0.86, hexanes/EtOAc (3/1).
Found: C, 86.25; H, 8.55; N, 5.45. Calcd for C18H21N: C, 86.00;
H, 8.44; N, 5.57. δH (360 MHz; CDCl3) 1.09-1.16 (2H, br m,
H-3), 1.45-1.54 (2H, m, H-4), 1.59-1.65 (2H, m, H-5), 2.64
(2H, t, J 5.9, H-2), 2.86 (2H, t, J 5.8, H-6), 4.08 (2H, s, PhCH2),
7.00-7.03 (1H, m, ArH), 7.09 (1H, dd, J 1.2 and 7.4, ArH),
7.14-7.19 (3H, m, ArH), 7.22-7.26 (2H, m, ArH), 7.40 (2H, d,
J 7.4, ArH); δC (100.6 MHz; CDCl3) 27.2 (C-3), 28.5 (C-4), 33.2
(C-6 and C-5), 59.3 (C-2), 61.3 (PhCH2), 123.1, 125.5, 127.2,
127.4, 128.6, 129.1, 129.9, 140.6, 143.2, 150.9 (Ar-C); m/z (EI)
251 (M+, 100%), 160 (95), 132 (16), 118 (21), 91 (56).
1-Benzyl-2,3,4,5,6,7,-hexahydro-1H-1-benzazonine (7b).
Yield: 91% as a colorless oil, Rf ) 0.67, hexanes/EtOAc (3/1).
Found: C, 86.15; H, 8.60; N, 5.05. Calcd for C19H23N: C, 85.97;
H, 8.75; N, 5.28. δH (400 MHz; Tol-d8; 373 K) 0.98-1.04 (2H,
m, H-3), 1.26-1.32 (2H, m, H-4), 1.39-1.43 (2H, m, H-5), 1.50-
1.55 (2H, m, H-6), 2.63-2.66 (2H, m, H-7), 2.72 (2H, t, J 5.6,
H-2), 3.76 (2H, s, PhCH2), 6.80-6.97 (7H, m, ArH), 7.07-7.09
(2H, m, ArH); δC (100.6 MHz; CDCl3) 25.5 (C-3), 26.9, 27.1 (C-6
and C-4), 29.6 (C-5), 32.9 (C-7), 57.1 (C-2), 62.6 (PhCH2), 124.6,
126.0, 127.2, 127.3, 128.4, 129.9, 136.6, 140.0, 143.9, 151.6 (Ar-
C); m/z (EI) 265 (M+, 46%), 222 (6), 208 (16), 174 (89), 145
(14), 118 (36), 91 (100).
1-Benzoyl-1,2,3,4,5,6-hexahydro-1-benzazocine (6a).
Yield: 93% as colorless crystals, Rf ) 0.21, hexanes/EtOAc
(3/1); mp 95.1-95.5 °C (from EtOAc/hexanes). Found: C, 81.25;
H, 7.05; N, 5.05. Calcd for C18H19NO: C, 81.46; H, 7.23; N,
5.28. νmax (KBr)/cm-1 1626vs (CO); δH (400 MHz; CDCl3) 1.28-
1.45 (3H, br m, H-5R, H-4 and H-3R), 1.53-1.59 (1H, br m,
H-4), 1.72-1.78 (1H, br m, H-3â), 1.80-1.87 (1H, m, H-5â),
2.43 (1H, dt, J 4.0 and 13.0, H-6â), 2.69 (1H, td, J 3.8 and
13.0, H-6R), 2.94 (1H, ddd, J 3.0, 7.5 and 13.3, H-2â), 4.81-
4.87 (1H, m, H-2R), 6.98-7.15 (7H, m, ArH), 7.19-7.48 (2H,
m, ArH); δC (100.6 MHz; CDCl3) 26.4, 26.5 (C-4 and C-3), 31.3,
31.6 (C-6 and C-5), 51.8 (C-2), 127.5, 127.7, 128.2, 128.7, 129.0,
129.4, 130.2, 136.8, 141.5, 142.0 (Ar-C), 170.9 (CO); m/z (EI)
265 (M+, 98%), 160 (70), 144 (65), 129 (25), 118 (22), 105 (100),
77 (74). Crystal data for 6a (CCDC 251232): C18H19NO, MW
) 265.34, orthorhombic, Pna21 (No. 33), a ) 10.5641(3), b )
15.7433(5), c ) 8.3622(2) Å, V ) 1390.75(7) Å3, Z ) 8, Dc )
1.267 g cm-3, µ(Mo KR) ) 0.078 mm-1, T ) 120 K, colorless
blocks; 3148 independent measured reflections, F2 refinement,
R1 ) 0.035, wR2 ) 0.077, 2747 independent observed absorp-
tion-corrected reflections [|Fo| > 4σ(|Fo|), 2θmax ) 55°], 182
parameters. The absolute structure of 6a could not be reliably
determined [x+ ) +0.1(13)].
Acknowledgment. The synthetic work was con-
ducted at the Department of Chemistry, King’s College
London by M.Q., supported by an EPSRC industrial
CASE award by GlaxoSmithKline (number: 00314292).
We thank Johnson Matthey plc for the generous loan
of palladium salts.
Supporting Information Available: Crystallographic
data for compounds 5a, 5b, 5c, 6a, and 6b and selected NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
1-Benzoyl-2,3,4,5,6,7-hexahydro-1H-1-benzazonine (6b).
Yield: 91% as colorless prisms, Rf ) 0.33, hexanes/EtOAc
JO048117J
J. Org. Chem, Vol. 70, No. 5, 2005 1557