The triflic acid-mediated cyclization reactions of N-cinnamoyl-1- naphthylamines

Article abstract of DOI:10.1021/jo4018827

N-Cinnamoyl-1-naphthylamines undergo a cyclization reaction with triflic acid to form 4-phenyl-3,4-dihydro-1H-naphth[1,8-bc]azepin-2-ones and 4-phenyl-3,4-dihydro-1H-benzo[h]quinolin-2-ones. However, the N-benzyl analogues also undergo a unique cascade re

Full text of DOI:10.1021/jo4018827

Article
pubs.acs.org/joc
The Triflic Acid-Mediated Cyclization Reactions of N‑Cinnamoyl-1-
Naphthylamines
Frank D. King,* Abil E. Aliev, Stephen Caddick, and Derek A. Tocher
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
S
* Supporting Information
ABSTRACT: N-Cinnamoyl-1-naphthylamines undergo a cyclization reaction with triflic acid to form 4-phenyl-3,4-dihydro-1H-
naphth[1,8-bc]azepin-2-ones and 4-phenyl-3,4-dihydro-1H-benzo[h]quinolin-2-ones. However, the N-benzyl analogues also
undergo a unique cascade reaction to form novel heptacyclic structures via a 1,2-addition followed by a 4-addition to the
naphthalene. With an electron-rich N-benzyl substituent, the heptacycle is the sole product.
cyclization to 6b (70% yield) still predominated. Increasing the
size of the N-alkyl group to n-butyl (5c; entry 3) gave yet again
an incremental increase in the yield of the seven-membered
product 7c (45% yield), and the isopropyl analogue 5d (entry
4) gave seven-membered 7d as the major product (62% yield).
Thus, it would appear that increasing the bulk of the N-
substituent favors seven-membered cyclization. Interestingly,
whereas the 1H NMR spectra of 6a−c at ambient temperatures
were time-averaged through facile conformational mobility, the
spectrum of 6d was poorly resolved. However, upon cooling to
INTRODUCTION
■
An amine and one or more aryl groups are key structural
features of many modulators of G-protein-coupled receptors.
We are therefore interested in approaches to the synthesis of
structures that have a unique special disposition of these
functional groups in order to identify more potent and selective
modulators. We have recently reported that N-benzylcinnama-
nilide (2a) reacts with triflic acid (TfOH) to form 1-benzyl-4-
phenyl-2,4-dihydro-1H-quinoline-2-one (3a) (80% yield) and
2,5-diphenylbenzazepin-3-one 4a (7% yield) (Scheme 1).1 A
further study of factors determining the course of the reaction,
with particular emphasis on improving the yield of the
benzazepinone, has recently been published.2
This paper describes the results obtained from investigating
the TfOH-mediated cyclization of N-cinnamoyl-1-naphthyl-
amines, for which either a six-membered cyclization onto the 2-
position or a seven-membered cyclization onto the 8-position
could occur.
1
−30 °C, an H NMR spectrum of two conformers for 6d was
obtained. In contrast, the 1H NMR spectra of 7a−c were poorly
resolved at ambient temperatures, but again, upon cooling to
−30 °C, well-resolved spectra of two conformers were
1
obtained. For 7d, a well-resolved H NMR spectrum of two
conformers was obtained at ambient temperatures.
The expected products from the cyclization of N-benzyl-
substituted 5e (entry 5) were 6e, 7e, and 8, the latter formed
via cyclization onto the benzyl group. From the TLC of the
reaction mixture, it appeared that three products were formed.
From a separation using a SiO2 column, the least polar product
was identified as 7e (32% yield). The most polar fraction from
the SiO2 column gave a product that had the same molecular
weight as 5e (14% yield) and showed nine aliphatic protons in
RESULTS AND DISCUSSION
■
The N-substituted-N-cinnamoyl-1-naphthylamines required for
this study were readily prepared in high yield by the alkylation
of N-cinnamoyl-1-naphthylamine3 with KOt-Bu and the
appropriate alkyl halide. The results of the TfOH-mediated
cyclizations of the N-alkyl derivatives are shown in Table 1.
Previously, it had been reported that 5a was photolytically
converted to 6a in 12% yield;3 no other products were
reported, and 5b did not react. In contrast, the reaction of 5a
with TfOH (Table 1, entry 1) gave mainly the six-membered
cyclization product 6a (78% yield) together with only a small
amount of the seven-membered 7a (11% yield). However, the
N-methyl analogue 5b (entry 2) gave a higher yield of seven-
membered product 7b (26% yield), though six-membered
1
the H NMR spectrum due to CH2, CH2CH, and CHCH2CH
fragments. In the aromatic area, 12 protons were observed, the
multiplicities of which indicated the presence of three ortho-
disubstituted benzene rings. From a detailed analysis of 2D
1
1H,1H NOESY, H,13C HMBC, and 13C,13C INADEQUATE
spectra combined with initial molecular mechanics calculations,
Received: August 30, 2013
© XXXX American Chemical Society
A
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Scheme 1
Table 1. Cyclization of N-Alkyl-N-cinnamoyl-1-naphthylamines
entry
amide
R
product
yield (%)
product
yield (%)
1
2
3
4
5a
5b
5c
5d
5e
H
6a
6b
6c
6d
6e
78
70
47
31
0
7a
7b
7c
7d
7e
11
26
45
62
0
Me
n-Bu
i-Pr
Bn
a
5
a
See the text.
the structure was assigned as 9e (Table 2 and Figure 1).
Further quantum-mechanical calculations were carried out
using M06-2X/cc-pVTZ geometry optimizations, which have
been shown to predict reliable molecular geometries in
agreement with neutron and X-ray diffraction methods in the
case of cyclic molecules, and gave the final geometry of 9e.4
The middle fraction contained two compounds that were
readily separable by column chromatography on Al2O3. The
more polar compound was identified as 6a (12% yield).
However, the less polar compound again had the same
molecular weight as the starting material 5e (10% yield) and
1
gave H and 13C NMR spectra similar to those of 9e. In a
manner analogous to that for 9e, the structure of this
compound was established as 10e, a diastereomer of 9e, and
the two structures 9e and 10e were distinguished on the basis
of the NOEs observed (see Figure 1). The structure of 9e was
confirmed by single-crystal X-ray analysis (Figure 1).
Satisfyingly, the calculated interproton distances between the
8-CH and 19-CH protons and between the 19CH proton and
one of the 9-CH2 protons are in close agreement with the
values of 2.08 and 4.26 Å measured from the structure
determined by X-ray analysis.
Figure 1. (a) Structure of 9e from NMR/QM analysis. A strong NOE
between the 8- and 19-CH protons is observed. The interproton
distance of 2.16 Å is from M06-2X/cc-pVTZ IEFPCM(CHCl3)
calculations. For comparison, the corresponding calculated distance in
10e is 3.60 Å. (b) Structure of 10e from NMR/QM analysis. A strong
NOE between the 19-CH proton and a 9-CH2 proton is observed.
The interproton distance of 2.49 Å is from M06-2X/cc-pVTZ
IEFPCM(CHCl3) calculations. For comparison, the corresponding
distance in 9e is 4.36 Å. (c, d) Two views of 9e from the X-ray
structure.
B
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We believe that 9e and 10e are formed via initial addition of
the carbocation to the 1-position of the naphthalene to form
spiro carbocation intermediate 11. This would bring the benzyl
group into close proximity to the carbocation, which cyclizes to
give the 1,2-dihydro derivative 12. Under the strongly acidic
conditions, the olefin is protonated to give yet another benzylic
carbocation, which cyclizes onto the phenyl ring A to form the
seven-membered ring in 9e. The diastereomer 10e would be
formed by the alternative initial addition of the carbocation to
the naphthalene.
PPA had previously been reported to promote the cyclization
of cinnamanilide.6 Satisfyingly, 9h and 10h were now obtained
in reasonable yields of 46% and 27% respectively. A key feature
1
in the H NMR spectrum that defines the assignment of the
stereochemistry is the chemical shifts of the 11-CH protons,
which for 9e−h appear at δ 4.67−4.76 and 4.93−4.99, whereas
for 10e−h they appear at δ 4.56−4.65 and 5.20−5.38.
Following the successful cyclization of 5h with PPA, the
cyclizations of other cinnamoylnaphthylamines were inves-
tigated. In contrast to the literature,7 PPA-mediated cyclization
of 5a gave 7a (10% yield) in addition to 6a (82% yield), very
similar to the results obtained with TfOH (Table 1, entry 1).
However, PPA-mediated cyclization of 5e gave none of the
polycyclic products 9e and 10e. Instead a complex mixture of
products was obtained within an Rf band of 0.1 in multiple
solvent systems. However, a product isolated through
crystallization of a partially purified mixture from Et2O was
identified as 14. In particular, the signal for the 5-CH proton
was a singlet at δ 7.02, and NOEs were observed between the 7-
CH proton and the benzylic CH2 protons and between the 10-
CH proton and the NH proton. From NMR comparisons and
MS, it would appear that the other products are isomers of 14,
with the benzyl group at other positions on the naphthalene
rings. None of these products were found in the reaction of 5e
with TfOH. We believe that these compounds are formed
through cyclization to give 6e. N-Debenzylation then gives a
benzyl carbocation, which reacts intermolecularly to alkylate the
naphthalene ring. Indeed 6e, prepared from 6a by N-
benzylation, reacted with PPA to give a similar mixture of
products.
In order to test this hypothesis, 5a was reacted with TfOH in
benzene in an attempt to trap the NH-spiro intermediate
related to 11. However, the only products isolated were 13
(77% yield) and 6a (19% yield). The structure of 13 was
confirmed by an independent synthesis from 3,3-diphenylpro-
pionyl chloride5 and 1-naphthylamine.
CONCLUDING REMARKS
■
N-Alkyl-N-cinnamoyl-1-naphthylamines undergo a TfOH-
mediated cyclization to give 4-phenyl-3,4-dihydro-1H-benzo-
[h]quinolin-2-ones and 4-phenyl-3,4-dihydro-1H-naphth[1,8-
bc]azepin-2-ones via cyclization onto the 2- and 8-positions of
the naphthalene, respectively. Although cyclization onto the 2-
position is inherently more favored, as the size of the N-alkyl
group increases, relatively more of the azepinone is formed.
However, N-benzyl analogues also undergo a unique cascade
reaction to form a diastereomeric pair of novel heptacycles. The
presence of electron-donating substituents on the benzyl group
favors formation of the heptacycle.
If the proposed mechanism for the formation of 9e and 10e
is correct, the introduction of electron-donating groups onto
the benzyl group should facilitate the trapping of the initial
carbocation 11 and result in a greater preference for the
formation of the polycyclic amides. The results obtained with
substituted benzyls are shown in Table 2. The reaction of 4-
methyl-substitued 5f (entry 2) with TfOH did indeed give the
two polycycles 9f and 10f in higher yields (44% and 25% yields
respectively) together with 6a (22% yield). However, 3,5-
dimethyl-substituted 5g (entry 3) gave almost exclusively the
polycycles 9g (46% yield) and 10g (39% yield). Surprisingly,
from the reaction of 3,5-dimethoxy-substituted 5h with TfOH
(entry 4), none of the less polar polycycle and only a 10% yield
of the more polar polycycle was obtained. Instead, products
expected from a benzyl group with electron-withdrawing
substituents were obtained, viz., 6h (37% yield) and 7h (30%
yield). On the basis of the hypothesis that the 3,5-
dimethoxybenzyl group is protonated by TfOH and thus acts
more like an electron-withdrawing substituent, the cyclization
using the weaker polyphosphoric acid (PPA) was investigated.
EXPERIMENTAL SECTION
■
General Experimental. Commercial reagents and solvents were
used as received, unless otherwise stated. Thin-layer chromatography
was performed on aluminum plates precoated with silica gel 60 F254
and developed by exposure to UV light and/or potassium
permanganate solution followed by heating. Flash chromatography
was carried out on silica gel (32−70 μm). Proton and carbon NMR
spectra were obtained in CDCl3 at 400, 500, or 600 MHz and at 127
or 151 MHz, respectively. Chemical shifts (δ) are expressed in parts
per million (ppm) and are referenced to the residual solvent peak. The
C
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Table 2. Cyclization of N-(Substituted benzyl)-N-cinnamoyl-1-naphthylamines
entry
amide
R
acid
product
yield (%)
product
yield (%)
product
yield (%)
product
yield (%)
1
2
3
4
5
6
5e
5f
H
TfOH
TfOH
TfOH
TfOH
PPA
6a
6a
6a
6h
6a
6a
12
22
0
7e
7f
32
0
9e
9f
14
44
46
10
46
0
10e
10f
10
25
39
0
4-Me
5g
5h
5h
5e
3,5-di-Me
3,5-di-OMe
3,5-di-OMe
H
7g
7h
7h
7e
0
9g
9h
9h
9e
10g
10h
10h
10e
37
7
30
16
0
27
0
a
PPA
0
a
See the text.
following abbreviations are used to describe the multiplicities: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Gaussian
resolution enhancement and zero filling were used for accurate
measurements of JHH couplings and for the analysis of overlapping
signals. Low- and high-resolution mass spectra were recorded on a
double-focusing magnetic sector mass spectrometer. Melting points
are uncorrected.
N-n-Butyl-N-cinnamoyl-1-naphthylamine (5c). Isolated as a solid
(89%), mp 114−116 °C; Rf 0.6 (2:1 Et2O/PE); 1H NMR (CDCl3, 500
MHz) δ 0.90 (3H, t, J = 7.4 Hz), 1.26−1.43 (2H, m), 1.52−1.61 (1H,
m), 1.63−1.72 (1H, m), 3.42 (1H, ddd, J = 5.1, 10.1, 13.2 Hz), 4.35
(1H, ddd, J = 6.0, 10.1, 13.2 Hz), 6.05 (1H, d, J = 15.5 Hz), 7.12−7.21
(5H, m), 7.37 (1H, dd, J = 1.0, 7.2 Hz), 7.50−7.58 (3H, m), 7.70 (1H,
d, J = 15.5 Hz), 7.83−7.87 (1H, m), 7.90−7.96 (2H, m); 13C NMR
(CDCl3, 125 MHz) δ 13.9 (CH3), 20.3 (CH2), 30.4 (CH2), 49.4
(CH2), 118.9 (CH), 123.1 (CH), 125.6 (CH), 126.9 (CH), 127.1
(CH), 127.5 (CH), 127.9 (CH), 128.6 (CH), 128.6 (CH), 128.8
(CH), 129.4 (CH), 130.9 (C), 134.8 (C), 135.2 (C), 138.4 (C), 142.1
(CH), 166.6 (C); FTIR (solid) 1649, 1608, 1399, 1365, 1240, 1213,
980, 808, 781, 763, 706, 683, 534, 488 cm−1; EI-MS m/z (relative
intensity) 329 (19), 199 (52), 131 (100) 103 (31); HMRS (EI) M+
calcd for C23H23NO 329.17742, found 329.17729.
N-Isopropyl-N-cinnamoyl-1-naphthylamine (5d). Isolated as a
solid (89%), mp 113−115 °C; Rf 0.5 (1:1 Et2O/PE); 1H NMR
(CDCl3, 500 MHz) δ 0.95 (3H, d, J = 6.8 Hz), 1.38 (3H, d, J = 6.8
Hz), 5.16 (1H, heptet, 6.8 Hz), 5.90 (1H, d, J = 15.5 Hz), 7.04−7.07
(2H, m), 7.11−7.19 (3H, m), 7.36 (1H, dd, J = 1.0, 7.2 Hz), 7.49−
7.55 (3H, m), 7.69 (1H, d, J = 15.5 Hz), 7.89−7.95 (3H, m); 13C
NMR (CDCl3, 125 MHz) δ 20.0 (CH3), 22.0 (CH3), 48.5 (CH),
119.8 (CH), 124.0 (CH), 125.4 (CH), 126.7 (CH), 127.3 (CH),
127.8 (CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 129.1 (CH),
129.3 (CH), 132.9 (C), 134.5 (C), 135.3 (C), 135.6 (C), 141.8 (CH),
166.4 (C); FTIR (solid) 1642, 1589, 1571, 1376, 1345, 1234, 1129,
979, 784, 764, 709, 681, 653 cm−1; EI-MS m/z (relative intensity) 315
(26), 185 (30), 172 (21), 131 (100), 103 (34); HMRS (EI) M+ calcd
for C22H21NO 315.16177 found 315.16167.
N-Benzyl-N-cinnamoyl-1-naphthylamine (5e). Isolated as an oil
(82%), mp 100−101 °C; Rf 0.4 (DCM); 1H NMR (CDCl3, 500 MHz)
δ 4.36 (1H, d, J = 14.0 Hz), 5.78 (1H, d, J = 14.0 Hz), 6.09 (1H, d, J =
15.5 Hz), 7.01 (1H, dd, J = 1.1, 7.2 Hz), 7.12−7.28 (10H, m), 7.38
(1H, dd, J = 7.3, 8.3 Hz), 7.51−7.58 (2H, m), 7.79 (1H, d, J = 15.5
Hz), 7.89 (1H, d, J = 8.3 Hz), 7.95 (1H, dd, J = 1.7, 7.3 Hz); 13C NMR
(CDCl3, 125 MHz) δ 52.9 (CH2), 118.5 (CH), 122.8 (CH), 125.5
(CH), 126.8 (CH), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.4
(CH), 128.6 (CH), 129.0 (CH), 129.2 (C), 129.4 (CH), 129.6 (CH),
130.7 (C), 134.8 (C), 135.1 (C), 137.7 (C), 142.8 (CH), 166.8 (C);
FTIR (solid) 1653, 1611, 1494, 1380, 1352, 1226, 980, 779, 765, 682,
530, 434 cm−1; EI-MS m/z (relative intensity) 363 (58), 233 (89), 131
(100), 103 (40); HMRS (EI) M+ calcd for C26H21NO 363.16177,
found 363.16210.
N-Cinnamoyl-1-naphthylamine (5a). Cinnamoyl chloride (2.5
g, 15 mmol) was added to a stirred suspension of 1-naphthylamine
(2.1 g, 15 mmol) in EtOAc (150 mL) and N,N-dimethylaniline (2.5
mL, 20 mmol) at room temperature. A thick precipitate started to
form, and after 2 h, the solid was collected, washed with Et2O (2 × 50
mL), and dried to give 5a (4.1 g, 83%) as a gray solid; mp 225−227 °C
3
1
(MeOH) (lit. 225−227 °C ); H NMR (CDCl3, 500 MHz) δ 7.16
(1H, d, J = 15.8 Hz), 7.41 (1H, t, J = 7.2 Hz), 7.46 (2H, t, J = 7.3 Hz),
7.52 (1H, t, J = 7.9 Hz), 7.56 (2H, ddt, J = 1.6, 7.5, 7.7 Hz), 7.64 (1H,
d, J = 15.8 Hz), 7.66 (2H, d, J = 7.0 Hz), 7.77 (1H, d, J = 8.2 Hz), 7.91
(1H, d, J = 7.2 Hz), 7.95 (1H, dd, J = 1.6, 8.2 Hz), 8.15 (1H, d, J = 7.9
Hz), 10.20 (1H, s); 13C NMR (CDCl3, 125 MHz) δ 120.9 (CH),
122.3 (CH), 122.5 (CH), 125.1 (CH), 125.6 (CH), 125.9 (CH),
127.8 (CH), 128.2 (CH), 129.0 (CH), 129.8 (CH), 133.5 (C), 133.7
(C), 134.9 (C), 140.3 (CH), 164.3 (C).
General Procedure for the Synthesis of N-Alkyl-N-cinnamo-
yl-1-naphthylamines 5b−h. N-Cinnamoyl-1-naphthylamine (1.4 g,
5.0 mmol), alkyl iodide (10 mmol) or benzyl bromide (5.0 mmol),
and KButO (0.55 g, 5.0 mmol) in THF (100 mL) were stirred and
heated under reflux for 2 h. After the mixture was cooled, the THF was
removed by rotary evaporation, and the residue was portioned
between H2O (50 mL) and EtOAc (100 mL). The EtOAc was
separated, washed with brine (50 mL), and dried (MgSO4). Removal
of the solvent gave the crude product, which was either recrystallized
from EtOAc/petroleum ether (PE) or purified by column chromatog-
raphy on SiO2, eluting with a solvent gradient from 1:2 DCM/PE to
DCM.
N-Methyl-N-cinnamoyl-1-naphthylamine (5b). Isolated as a solid
(97%), mp 102−103 °C (heptane) (lit. 87−89 °C3); Rf 0.6 (Et2O); 1H
NMR (CDCl3, 500 MHz) δ 3.48 (3H, s), 6.11 (1H, d, J = 15.5 Hz),
7.13−7.20 (5H, m), 7.40 (1H, dd, J = 1.1, 7.2 Hz), 7.53 (1H, dd, J =
7.3, 8.2 Hz), 7.55−7.58 (2H, m), 7.72 (1H, d, J = 15.5 Hz), 7.83−7.86
(1H, m), 7.92 (1H, d, J = 8.3 Hz), 7.94−7.98 (1H, m); 13C NMR
(CDCl3, 125 MHz) δ 37.6 (CH3), 118.5 (CH), 122.8 (CH), 125.9
(CH), 126.1 (CH), 126.9 (CH), 127.6 (CH), 127.9 (CH), 128.6
(CH), 128.6 (CH), 128.9 (CH), 129.5 (CH), 130.5 (C), 134.8 (C),
135.2 (C), 139.9 (C), 142.1 (CH), 167.0 (C); FTIR (solid) 1650,
1613, 1396, 1365, 1084, 975, 776, 763, 700, 677, 651 cm−1.
N-4-Methylbenzyl-N-cinnamoyl-1-naphthylamine (5f). Isolated as
1
a solid (90%), mp 153−154 °C; Rf 0.6 (1:1 Et2O/PE); H NMR
D
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(CDCl3, 500 MHz) δ 2.31 (3H, s), 4.29 (1H, d, J = 14.0 Hz), 5.80
(1H, d, J = 14.0 Hz), 6.08 (1H, d, J = 15.5 Hz), 7.00 (1H, dd, J = 1.0,
7.2 Hz), 7.06 (2H, d, J = 7.8 Hz), 7.11−7.21 (7H, m), 7.38 (1H, dd, J
= 7.3, 8.2 Hz), 7.51−7.58 (2H, m), 7.78 (1H, d, J = 15.5 Hz), 7.82−
7.85 (1H, m), 7.89 (1H, d, J = 8.3 Hz), 7.93−7.96 (1H, m); 13C NMR
(CDCl3, 125 MHz) δ 21.2 (CH3), 52.6 (CH2), 118.6 (CH), 122.9
(CH), 125.5 (CH), 126.8 (CH), 127.5 (CH), 127.6 (CH), 127.9
(CH), 128.6 (CH), 128.9 (CH), 129.1 (CH), 129.4 (CH), 129.5
(CH), 130.7 (C), 134.8 (C), 135.2 (C), 137.1 (C), 137.8 (C), 142.6
(C), 166.7 (C); FTIR (solid) 1652, 1609, 1379, 1350, 1227, 983, 781,
766, 680, 538, 478, 450 cm−1; EI-MS m/z (relative intensity) 377
(85), 247 (93), 131 (100), 105 (90), 103 (46); HMRS (EI) M+ calcd
for C27H23NO 377.17742, found 377.17765.
(21); HMRS (EI) M+ calcd for C19H15NO 273.1148, found 273.1147.
Further elution with 10% EtOAc/DCM gave 4-phenyl-3,4-dihydro-
1H-naphth[1,8-bc]azepin-2-one (7a) (0.06 g, 11%). Mp 209−221 °C;
1H NMR (CDCl3, 500 MHz) δ 3.28 (1H, dd, J = 1.5, 14.7 Hz), 3.40
(1H, ddd, J = 1.8, 7.1, 14.7 Hz), 4.83 (1H, d, J = 7.1 Hz), 6.97 (C10−
H, dd, J = 1.3, 7.5 Hz), 7.06 (C2′−H, C6′−H, d, J = 7.6 Hz), 7.12
(C4′−H, t, J = 7.6 Hz), 7.16−7.23 (2H, m), 7.4 (C6−H, C9−H, t, J =
7.6 Hz), 7.68 (C8−H, dd, J = 1.3, 8.1 Hz), 7.83 (C7−H, dd, J = 1.4,
8.2 Hz), 8.74 (1H, brs); 13C NMR (CDCl3, 125 MHz) δ 42.5 (CH2),
47.3 (CH), 118.3 (CH), 124.4 (C), 125.8 (CH), 126.0 (CH), 126.7
(CH), 127.8 (CH), 128.5 (CH), 129.0 (CH), 129.3 (CH), 134.2 (C),
136.5 (C), 137.8 (C), 142.1 (C), 173.6 (C); FTIR (solid) 1677, 1406,
1263, 830, 768, 745, 726, 698, 568 cm−1; CI-MS (m/z, relative
intensity) 302 (M + Na+, 11), 274 (MH+ 100), 273 (46), 230 (18),
220 (19), 202 (18), 85 (16); HMRS (CI) MH+ calcd for C19H16NO
274.1232, found 274.1231.
(b). With TfOH in Benzene. Following the general procedure for
cyclization, 5a (0.54 g, 2.0 mmol) was heated under reflux for 2 h in
benzene (10 mL). TLC showed two products, a major one (Rf 0.5,
Et2O) and a minor one (Rf 0.4, Et2O). Purification by column
chromatography on SiO2, eluting with 1% EtOAc/DCM, gave 3,3-
diphenylpropionyl-1-naphthylamine (13) (0.54 g 77%). Mp 191−192
°C; 1H NMR (CDCl3 500 MHz) δ 3.22 (2H, d, J = 7.9 Hz), 4.67 (1H,
d, J = 7.9 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.00−7.40 (14H, m), 7.64
(2H, t, J = 8.0 Hz), 7.90 (1H, d, J = 8.1 Hz); 13C NMR (CDCl3, 125
MHz) δ 44.4 (CH2), 48.0 (CH), 121.0 (CH), 121.7 (CH), 125.6
(CH), 126.0 (CH), 126.2 (CH), 126.9 (CH), 127.5 (C), 127.9 (CH),
128.5 (CH), 129.0 (CH), 132.1 (C), 134.0 (C), 143.6 (C), 170.2 (C);
FTIR (solid) 1650, 1596, 1537, 1493, 1396, 1276, 796, 769, 742, 698
cm−1; EI-MS m/z (relative intensity) 352 (25) 351 (100), 167 (81),
165 (69), 143 (53), 115 (62), 86 (32), 84 (55); HMRS (EI) M+ calcd
for C25H21NO 351.1623, found 351.1613. Further elution with 2%
EtOAC/DCM gave 6a (0.10 g, 19% yield) identical to that obtained
before.
(c). With PPA. A solution of 5a (0.54 g, 2.0 mmol) in CHCl3 (10
mL) was stirred and heated with PPA (10.0 g) in an open flask to 120
°C for 2 h, allowing the CHCl3 to distill off. The reaction mixture was
cooled, treated with ice (20 g), and then partitioned between DCM
(50 mL) and water (20 mL). The organic layer was separated, and the
aqueous layer was further extracted with DCM (2 × 50 mL). The
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. Purification by column chromatography on
SiO2, eluting with 2% EtOAc/DCM, gave 4-phenyl-3,4-dihydro-1H-
benzo[h]quinolin-2-one (6a) (0.44 g, 82%). Further elution with 10%
EtOAc/DCM gave 4-phenyl-3,4-dihydro-1H-naphth[1,8-bc]azepin-2-
one (7a) (0.055 g, 11%).
Reaction of N-Methyl-N-cinnamoyl-1-naphthylamine (5b). Fol-
lowing the general procedure for cyclization, 5b (0.80 g, 2.5 mmol)
was heated under reflux for 1.5 h. Purification by column
chromatography, eluting with DCM, gave 6b (0.56 g, 70%). Mp
107−109 °C (lit. an oil8); Rf 0.5 (Et2O); 1H NMR (CDCl3 500 MHz)
δ 2.99 (1H, dd, J = 5.5, 14.9 Hz), 3.03 (1H, dd, J = 6.7, 14.9 Hz), 3.55
(3H, s), 4.32 (1H, t, J = 6.1 Hz), 7.10−7.16 (3H, m), 7.28 (1H, d, J =
7.3 Hz), 7.33 (2H, t, J = 7.4 Hz), 7.47−7.55 (2H, m), 7.59 (1H, d, J =
8.3 Hz), 7.86 (1H, dd, J = 1.3, 8.1 Hz), 7.96 (1H, d, J = 8.5 Hz); 13C
NMR (CDCl3, 125 MHz) δ 37.9 (CH3), 40.2 (CH2), 42.5 (CH),
123.7 (CH), 125.1 (CH), 125.6 (CH), 125.6 (C), 125.8 (CH), 125.9
(CH), 127.3 (CH), 127.9 (CH), 128.9 (CH), 129.0 (CH), 129.6 (C),
134.4 (C), 138.4 (C), 140.7 (C), 172.5 (C); FTIR 1674, 1510, 1488,
1433, 1390, 1371, 1313, 1188, 1107, 817, 742, 709, 680 cm−1; EI-MS
m/z (relative intensity) 287 (100), 244 (42), 210 (16); HMRS (EI)
M+ calcd for C20H17NO 287.1305, found 287.1298. Further elution
with 2% EtOAC/DCM gave 7b (0.20 g, 26%) as an oil. Rf 0.3 (Et2O);
1H NMR (CDCl3 400 MHz, −30 °C; a 3:17 ratio of conformers, only
data for the major conformer are presented) δ 3.15 (3H, s), 3.21 (1H,
dd, J = 6.7, 14.2 Hz), 3.34 (1H, dd, J = 1.4, 14.2 Hz), 4.88 (1H, d, J =
6.3 Hz), 7.13 (2H, d, J = 7.2 Hz), 7.20−7.34 (4H, m), 7.41 (1H, d, J =
6.3 Hz), 7.48 (1H, t, J = 7.1 Hz), 7.55 (1H, t, J = 7.8 Hz), 7.80 (1H,
dd, J = 0.6, 8.1 Hz), 7.88 (1H, dd, J = 1.0, 8.1 Hz); 13C NMR (CDCl3,
100 MHz, −30 °C) δ 39.3 (CH), 42.0 (CH2), 48.0 (CH3), 121.6
N-3,5-Dimethylbenzyl-N-cinnamoyl-1-naphthylamine (5g). Iso-
1
lated as a solid (83%), mp 120−121 °C; Rf 0.6 (1:1 Et2O/PE); H
NMR (CDCl3, 500 MHz) δ 2.23 (3H, s), 4.24 (1H, d, J = 14.0 Hz),
5.79 (1H, d, J = 14.0 Hz), 6.09 (1H, d, J = 15.5 Hz), 6.85 (2H, s), 6.88
(1H, s), 7.03 (1H, dd, J = 0.7, 7.2 Hz), 7.12−7.22 (5H, m), 7.39 (1H,
t, J = 7.8 Hz), 7.51−7.58 (2H, m), 7.78 (1H, d, J = 15.5 Hz), 7.83 (1H,
d, J = 7.8 Hz), 7.89 (1H, d, J = 8.3 Hz), 7.94 (1H, dd, J = 1.6, 8.1 Hz);
13C NMR (CDCl3, 125 MHz) δ 21.3 (CH3), 52.8 (CH2), 118.6 (CH),
122.9 (CH), 125.5 (CH), 126.8 (CH), 127.1 (CH), 127.5 (CH),
127.6 (CH), 127.9 (CH), 128.6 (CH), 128.9 (CH), 129.1 (CH),
129.5 (CH), 130.7 (C), 134.8 (C), 135.2 (C), 137.6 (C), 137.8 (C),
137.9 (C), 142.6 (CH), 166.7 (C); FTIR 1651, 1609, 1402, 1379,
1204, 977, 807, 777, 763, 698, 546, 527, 438 cm−1; EI-MS m/z
(relative intensity) 391 (86), 261 (100), 131 (74), 119 (63), 103 (33);
HMRS (EI) M+ calcd for C28H25NO 391.19307, found 391.19337.
N-3,5-Dimethoxybenzyl-N-cinnamoyl-1-naphthylamine (5h).
1
Isolated as a solid (85%), mp 115−117 °C; Rf 0.7 (Et2O); H NMR
(CDCl3, 500 MHz) δ 3.69 (6H, s), 4.28 (1H, d, J = 14.2 Hz), 5.79
(1H, d, J = 14.2 Hz), 6.09 (1H, d, J = 15.5 Hz), 6.35 (1H, t, J = 2.3
Hz), 6.40 (2H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 1.0, 7.2 Hz), 7.12−
7.21 (5H, m), 7.40 (1H, dd, J = 7.3, 8.2 Hz), 7.50−7.57 (2H, m), 7.76
(1H, d, J = 15.5 Hz), 7.80−7.83 (1H, m), 7.89 (1H, d, J = 8.3 Hz),
7.92−7.95 (1H, m); 13C NMR (CDCl3, 125 MHz) δ 53.0 (CH2), 55.4
(CH3), 99.9 (CH), 107.2 (CH), 118.5 (CH), 122.8 (CH), 125.6
(CH), 126.8 (CH), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.6
(CH), 128.6 (CH), 129.0 (CH), 129.6 (CH), 130.7 (C), 13.8 (C),
135.1 (C), 137.8 (C), 140.0 (C), 142.7 (CH), 160.7 (C), 166.8 (C);
FTIR (solid) 1656, 1593, 1383, 1201, 1146, 1055, 979, 828, 780, 766,
700, 532, 442 cm−1; EI-MS m/z (relative intensity) 423 (69), 293
(100), 292 (76), 151 (52), 131 (91), 103 (43); HMRS (EI) M+ calcd
for C28H25NO3 423.18290, found 423.18267.
General Procedure for the TfOH-Mediated Cyclization. Triflic
acid (10-fold excess) was added to a stirred solution of the amine in
CHCl3 (1 mmol/10 mL), and the reaction mixture was heated under
gentle reflux until no starting material was present by TLC. The
reaction mixture was cooled to room temperature, and water (20 mL)
was added. The mixture was basicified with an excess of solid K2CO3
until CO2 evolution ceased. The product was extracted into EtOAc (3
× 50 mL), dried (MgSO4), concentrated in vacuo, and purified by
column chromatography on SiO2 and/or Al2O3.
Reaction of N-Cinnamoyl-1-naphthylamine (5a). (a). With TfOH
in CHCl3. Following the general procedure for cyclization, 5a (0.54 g,
2.0 mmol) was heated under reflux for 2 h in CHCl3. TLC showed two
products, a major one (Rf 0.5, Et2O) and a minor one (Rf 0.4, Et2O).
Purification by column chromatography on SiO2, eluting with 2%
EtOAc/DCM, gave 4-phenyl-3,4-dihydro-1H-benzo[h]quinolin-2-one
(6a) (0.42 g, 78%). Mp 195−196 °C (EtOAc/PE) [lit. 201 °C
(benzene)]; 1H NMR (CDCl3, 500 MHz) δ 3.04 (1H, dd, J = 7.2, 16.0
Hz), 3.12 (1H, dd, J = 6.6, 16.0 Hz), 4.47 (1H, t, J = 6.9 Hz), 7.12
(1H, d, J = 8.4 Hz), 7.19−7.34 (5H, m), 7.49−7.54 (2H, m), 7.58
(1H, ddd, J = 1.3, 6.9, 8.2 Hz), 7.84 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J
= 8.3 Hz); 8.86 (1H, s); 13C NMR (CDCl3, 125 MHz) δ 38.9 (CH2),
42.6 (CH), 119.9 (CH), 122.2 (C), 122.6 (C), 123.4 (CH), 126.2
(CH), 126.7 (CH), 127.3 (CH), 127.8 (CH), 128.0 (CH), 128.7
(CH), 129.0 (CH), 132.1 (C), 133.3 (C), 141.8 (C), 171.0 (C); FTIR
(solid) 1671, 1376, 811, 767, 745, 707, 670, 563, 498, 454, 422 cm−1;
EI-MS m/z (relative intensity) 273 (100), 244 (13), 230 (25), 196
E
dx.doi.org/10.1021/jo4018827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(CH), 125.7 (CH), 125.9 (CH), 126.9 (CH), 127.1 (C), 127.2 (CH),
128.2 (CH), 128.3 (CH), 128.6 (CH), 129.5 (CH), 135.4 (C), 137.8
(C), 140.3 (C), 141.9 (C), 172.0 (C); FTIR (film) 1656, 1575, 1432,
1385, 1282, 1116, 1077, 909, 824, 731, 698 cm−1; EI-MS m/z (relative
intensity) 287 (64), 259 (28), 244 (100), 182 (23); HMRS (EI) M+
calcd for C20H17NO 287.1305, found 287.1306.
(0.25H, d, J = 11.6 Hz), 4.79 (0.75H, d, J = 6.2 Hz), 6.79 (0.25H, d, J
= 7.0 Hz), 7.00−7.50 (0.75H, brm), 7.15−7.47 (8.25H, m), 7.69
(0.25H, d, J = 7.9 Hz), 7.76 (0.75H, d, J = 8.4 Hz), 7.81 (0.75H, d, J =
8.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 20.5 (CH3), 20.7 (CH3),
22.5 (CH3), 22.7 (CH3), 41.9 (CH2), 44.8 (CH2), 48.0 (CH), 48.5
(CH), 53.5 (CH), 54.2 (CH), 122.4 (CH), 123.0 (CH), 124.7 (CH),
124.9 (CH), 125.0 (CH), 125.4 (CH), 126.6 (CH), 126.8 (CH),
127.7 (CH), 127.7 (CH), 128.0 (CH), 128.2 (CH), 128.6 (CH),
128.9 (CH), 129.1 (CH), 129.8 (CH), 135.3 (C), 135.7 (C), 138.0
(C), 138.7 (C), 141.1 (C), 142.0 (C), 146.8 (C), 171.3 (C), 172.9
(C); FTIR (film) 1658, 1574, 1434, 1401, 1381, 1259, 826, 768, 733,
697 cm−1; EI-MS m/z (relative intensity) 315 (73), 272 (36), 244
(39), 231 (37) 230 (100), 229 (58); HMRS (EI) M+ calcd for
C22H21NO 315.1618, found 315.1606.
Reaction of N-n-Butyl-N-cinnamoyl-1-naphthylamine (5c). Fol-
lowing the general procedure for cyclization, 5c (0.76 g, 2.0 mmol)
was heated under reflux for 2 h. Purification by column
chromatography, eluting with 3:1 DCM/PE, gave 6c (0.36 g, 47%)
as an oil. Rf 0.55 (2:1 Et2O/PE); 1H NMR (CDCl3 500 MHz) δ 0.72
(3H, t, J = 7.3 Hz), 1.02−1.15 (2H, m), 1.26−1.38 (2H, m), 2.91 (1H,
dd, J = 4.6, 14.9 Hz), 3.07 (1H, dd, J = 9.2, 14.9 Hz), 3.95−4.04 (1H,
m), 4.16−4.24 (1H, brm), 4.31 (1H, dd, J = 4.6, 9.2 Hz), 7.06 (1H, d,
J = 8.2 Hz), 7.24 (2H, d, J = 7.3 Hz), 7.29 (1H, dt, J = 1.8, 7.3 Hz),
7.33−7.37 (2H, m), 7.45−7.52 (2H, m), 7.57 (1H, d, J = 8.3 Hz), 7.85
(1H, dd, J = 1.5, 8.6 Hz), 7.91 (1H, d, J = 8.4 Hz); 13C NMR (CDCl3,
125 MHz) δ 13.7 (CH3), 20.2 (CH2), 30.4 (CH2), 40.2 (CH2), 42.2
(CH), 48.7 (CH2), 123.5 (CH), 124.9 (CH), 125.4 (CH), 125.7
(CH), 125.8 (CH), 125.8 (C), 127.3 (CH), 128.3 (CH), 128.8 (CH),
128.9 (CH), 131.6 (C), 134.1 (C), 137.3 (C), 140.3 (C), 172.9 (C);
FTIR (film) 1670, 1390, 1289, 1223, 816, 749, 736, 698 cm−1; EI-MS
m/z (relative intensity) 329 (100), 286 (29), 273 (71), 244 (34), 230
(21); HMRS (EI) M+ calcd for C23H23NO 329.17742, found
329.17762. Further elution with DCM gave 7c (0.34 g, 45%) as a
Reaction of N-Benzyl-N-cinnamoyl-1-naphthylamine (5e).
(a). With TfOH. Following the general procedure for cyclization, 5e
(0.72 g, 2.0 mmol) was heated under reflux for 2 h in CHCl3. TLC
showed no 5e but revealed three potential products at Rf 0.7, 0.5, and
0.3 (Et2O). Purification by column chromatography, eluting with 2%
EtOAc/DCM, gave 1,4-diphenyl-3,4-dihydro-1H-naphth[1,8-bc]-
azepin-2-one (7e) (0.23 g, 32%) as a solid. Mp 75−77 °C; 1H
NMR (CDCl3, −20 °C) δ 2.98 (0.25H, d, J = 12.9 Hz), 3.33 (0.75H,
dd, J = 6.8, 13.7 Hz), 3.52 (0.75H, d, J = 13.7 Hz), 3.59 (0.25H, t, J =
12.9 Hz), 4.43 (0.75H, d, J = 16.1 Hz), 4.75 (0.25H, d, J = 11.6 Hz),
4.91−5.05 (1.75H, m including 4.95 (0.75H, d, J = 6.8 Hz) and 4.99
(0.75H, d, J = 16.1 Hz)), 5.33 (0.25H, d, J = 15.7 Hz), 6.82 (0.25H, d,
J = 7.3 H), 7.19 (1.5H, t, J = 7.0 Hz), 7.23−7.51 (12.25H, m), 7.73
(0.75H, d, J = 7.9 Hz), 7.77 (0.75H, dd, J = 2.0, 7.1 Hz), 7.87 (0.5H, d,
J = 7.8 Hz); 13C NMR (CDCl3, −20 °C) δ 41.7 (CH2), 43.7 (CH2),
47.8 (CH), 47.9 (CH), 55.2 (CH2), 55.9 (CH2), 121.2 (CH), 121.8
(CH), 124.9 (CH), 125.1 (CH), 126.7 (CH), 126.7 (CH), 126.8
(CH), 127.6 (CH), 127.7 (CH), 128.1 (CH), 128.2 (CH), 128.3
(CH), 128.4 (CH), 128.6 (CH), 128.9 (CH), 129.7 (CH), 135.2 (C),
135.7 (C), 137.7 (C), 138.0 (C), 138.2 (C), 139.7 (C), 139.8 (C),
141.0 (C), 141.8 (C), 171.5 (C), 173.0 (C); FTIR (solid) 1665, 1434,
1388, 825, 768, 729, 697 cm−1; EI-MS m/z (relative intensity) 364
(29), 363 (100), 272 (27), 244 (43), 230 (94); HMRS (EI) M+ calcd
for C26H21NO 363.1618, found 363.1613. Further elution with 2−4%
EtOAc/DCM gave a fraction that NMR proved to be a mixture of
compounds. These were readily separated by chromatography on
Al2O3 (basic, Brockman I), eluting with 25% PE/DCM, to give
(1S,8R,19S,20S)- and (1R,8S,19R,20R)-11-azaheptacyclo-
[17.7.1.02,7.08,20.011,20.013,18.021,26]heptacosa-2(7),3,5,13,15,17,21,23,25-
1
solid. Mp 105−107 °C; H NMR (CDCl3 400 MHz, −30 °C; a 1:3
ratio of conformers, only data for the major conformer are presented)
δ 0.75 (3H, t, J = 7.3 Hz), 1.04−1.45 (4H, m), 3.23 (1H, dd, J = 6.7,
14.0 Hz), 3.32−3.45 (2H, m including 3.35 (1H, dd, J = 1.8, 14.0
Hz)), 3.83−3.93 (1H, m), 4.89 (1H, d, J = 6.0 Hz), 7.20 (2H, d, J =
7.3 Hz), 7.22−7.42 (5H, m), 7.48 (1H, t, J = 8.0 Hz), 7.52 (1H, t, J =
8.0 Hz), 7.90 (1H, dd, J = 0.6, 7.7 Hz), 7.87 (1H, dd, J = 1.2, 8.1 Hz);
13C NMR (CDCl3, 100 MHz, −30 °C) δ 14.2 (CH3), 20.6 (CH2),
30.2 (CH2), 41.5 (CH2), 47.9 (CH), 51.1 (CH2), 121.8 (CH), 125.5
(CH), 125.6 (CH), 126.8 (CH), 127.4 (CH), 127.9 (C), 128.2 (CH),
128.5 (CH), 128.6 (CH), 129.9 (CH), 135.7 (C), 137.7 (C), 139.1
(C), 141.8 (C), 171.4 (C); FTIR (solid) 1659, 1573, 1437, 1404,
1221, 827, 773, 740, 698 cm−1; EI-MS m/z (relative intensity) 329
(100), 286 (48), 273 (29), 258 (46), 244 (52), 243 (59), 230 (71),
167 (34), 127 (24); HMRS (EI) M+ calcd for C23H23NO 329.17742,
found 329.17735.
Reaction of N-Isopropyl-N-cinnamoyl-1-naphthylamine (5d).
Following the general procedure for cyclization, 5d (0.32 g, 1.0
mmol) was heated under reflux for 2 h. Purification by column
chromatography, eluting with 3:1 PE/Et2O, gave 6d (0.10 g, 31%) as
1
nonaen-10-one (10e) as a solid (0.06 g, 8%). Mp 205−207 °C; H
NMR (CDCl3) δ 2.05 (20-CH, 1H, ddd, J = 3.6, 9.1, 12.7 Hz), 2.69
(9-CH, 1H, dd, J = 12.3, 16.3 Hz), 3.06 (20-CH, 1H, ddd, J = 3.2, 9.6,
12.7 Hz), 3.11 (9-CH, 1H, dd, J = 8.2, 16.3 Hz), 3.59 (8-CH, 1H, dd, J
= 8.9, 12.1 Hz), 3.76 (19-CH, 1H, t, J = 9.3 Hz), 4.05 (1-CH, 1H, t, J
= 3.2 Hz), 4.56 (12-CH, 1H, d, J = 16.7 Hz), 5.38 (12-CH, 1H, d, J =
16.7 Hz); 7.01−7.43 (12H, m); 13C NMR (CDCl3) δ 33.4 (CH), 35.2
(CH2), 39.7 (CH2), 40.5 (CH2), 47.8 (CH), 49.3 (CH), 63.6 (C),
121.8 (CH), 126.0 (CH), 126.5 (CH), 127.2 (CH), 127.3 (CH),
127.8 (CH), 127.9 (CH), 128.2 (CH), 128.9 (CH), 129.1 (CH),
131.5 (C), 136.0 (C), 138.8 (C), 139.1 (C), 140.1 (C), 141.4 (C),
174.7 (C); FTIR (solid) 1693, 1439, 1390, 752, 699 cm−1; EI-MS m/z
(relative intensity) 364 (27), 363 (100); HMRS (EI) M+ calcd for
C26H21NO 363.1618, found 363.1628. Further elution with DCM gave
6a (0.060g, 11%), identical to that obtained previously. Further elution
of the initial SiO2 column with 10% EtOAc/DCM gave
(1R,8R,19R,20R)- and (1S,8S,19S,20S)-11-azaheptacyclo-
[ 1 7 . 7 . 1 . 0 2 , 7 . 0 8 , 2 0 . 0 1 1 , 2 0 . 0 1 3 , 1 8 . 0 2 1 , 2 6 ] - h e p t a c o s a - 2 -
(7),3,5,13,15,17,21,23,25-nonaen-10-one (9e) (0.10 g, 14%) as a solid.
Mp 223−224 °C; 1H NMR (CDCl3, 600 MHz) δ 2.48 (9-CH, 1H, dd,
J = 12.9, 15.5 Hz), 2.86 (20-CH, 1H, ddd, J = 3.9, 6.6, 10.5 Hz), 3.03
(9-CH, 1H, dd, J = 7.6, 15.7 Hz), 3.07 (20-CH, 1H, dd, J = 10.4, 12.3
Hz), 3.64 (19-CH, 1H, dd, J = 3.4, 10.2 Hz), 3.86 (8-CH, 1H, dd, J =
7.6, 12.7 Hz), 4.09 (1-CH, 1H, d, J = 6.3 Hz), 4.80 (12-CH, 1H, d, J =
17.9 Hz), 4.99 (12-CH, 1H, d, J = 17.9 Hz), 6.93−6.98 (1H, m),
7.01−7.21 (9H, m), 7.21−7.25 (2H, m); 13C NMR (CDCl3, 150
MHz) δ 32.4 (20-CH2), 35.8 (9-CH2), 42.8 (12-CH2), 44.5 (19-CH),
1
an oil. H NMR (CDCl3 400 MHz, −30 °C) δ 0.69 (1.2H, d, J = 6.6
Hz), 1.4 (1.8H, d, J = 6.6 Hz), 1.95 (1.2H, d, J = 6.8 Hz), 2.09 (1.8H,
d, J = 6.8 Hz), 2.75 (0.6H, dd, J = 3.2, 14.8 Hz), 2.94 (0.6H, t, J = 14.8
Hz), 3.00 (0.4H, dd, J = 5.7, 15.1 Hz), 3.24 (0.4H, dd, J = 2.1, 15.1
Hz), 4.04 (0.4H, heptet, J = 6.7 Hz), 41.4 (0.6H, heptet, J = 6.7 Hz),
4.27 (0.4H, d, J = 3.9 Hz), 4.37 (0.6H, dd, J = 3.2, 15.0 Hz), 6.74
(0.6H, d, J = 8.4 Hz), 7.02 (0.6H, brs), 7.21−7.62 (7.2H, m), 7.75
(0.4H, d, J = 8.2 Hz), 7.86 (0.6H, d, J = 7.6 Hz), 7.90−8.00 (1.6H, m);
13C NMR (CDCl3, 100 MHz, −30 °C) δ 18.9 (CH3), 19.9 (CH3),
22.7 (CH3), 22.9 (CH3), 39.7 (CH2), 40.7 (CH), 42.7 (CH), 42.8
(CH2), 56.1 (CH), 57.0 (CH), 123.4 (CH), 123.5 (CH), 124.6 (CH),
124.8 (CH), 125.2 (CH), 125.8 (CH), 125.8 (CH), 126.1 (CH),
126.2 (CH), 127.0 (CH), 127.1 (CH), 127.7 (CH), 127.9 (CH),
128.6 (CH), 129.0 (CH), 129.2 (CH), 129.3 (CH), 130.4 (C), 130.8
(CH), 133.2 (C), 133.8 (C), 134.3 (C), 139.0 (C), 140.2 (C), 140.3
(C), 173.1 (C), 174.4 (C); FTIR (film) 1671, 1407, 1380, 1284, 1238,
1125, 816, 770, 752, 732, 696, 612, 431 cm−1; EI-MS m/z (relative
intensity) 315 (63), 273 (100), 244 (22), 230 (29), 196 (27); HMRS
(EI) M+ calcd for C22H21NO 315.1618, found 315.1618. Further
1
elution with 2:1 PE/Et2O gave 7d (0.20 g, 62%) as an oil. H NMR
(CDCl3 500 MHz) δ 0.97 (2.25H, d, J = 6.84 Hz), 1.10 (0.75H, d, J =
6.8 Hz), 1.25 (2.25H, d, J = 6.7 Hz), 1.56 (0.75H, d, J = 6.5 Hz), 2.72
(0.25H, d, J = 12.8 Hz), 3.12 (0.75H, dd, J = 6.8, 13.9 Hz), 3.35
(0.75H, dd, J = 1.3, 13.9 Hz), 3.40 (0.25H, t, J = 12.2 Hz), 3.95
(0.75H, heptet, J = 6.8 Hz), 4.51 (0.25H, heptet, J = 6.7 Hz), 4.65
F
dx.doi.org/10.1021/jo4018827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
46.5 (1-CH), 50.7 (8-CH), 65.4 (20-C), 125.1 (22-CH), 125.5 (25-
CH), 126.4 (15,17-CH), 126.9 (14-CH), 127.0 (23-CH), 127.2 (4,16-
CH), 127.4 (5-CH), 128.2 (3-CH), 128.3 (24-CH), 129.2 (6-CH),
130.5 (13-C), 133.9 (21-C), 135.0 (7-C), 136.7 (18-C), 143.3 (26-C),
143.9 (2-C), 174.1 (10-C); FTIR (solid) 1685, 1492, 1449, 1397, 773,
747, 722 cm−1; EI-MS m/z (relative intensity) 364 (27), 363 (100),
362 (31); HMRS (EI) M+ calcd for C26H21NO 363.1618, found
363.1609.
(CH), 127.0 (CH), 127.1 (CH), 127.3 (C), 127.3 (CH), 128.1 (CH),
129.1 (CH), 133.9 (C), 135.0 (C), 136.4 (C), 136.5 (C), 143.2 (C),
143.8 (C), 174.0 (C); FTIR (film) 1695, 1403, 741 cm−1; EI-MS m/z
(relative intensity) 377 (43), 363 (59), 362 (100); HRMS (EI) M+
calcd for C27H23NO 377.1774, found 377.1757.
Reaction of N-3,5-Dimethylbenzyl-N-cinnamoyl-1-naphthyl-
amine (5g). Following the general procedure for cyclization, 5g (1.2
g, 3.0 mmol) was heated under reflux in CHCl3 (30 mL) for 2 h.
Purification by column chromatography on SiO2, eluting with 1:3 PE/
DCM, gave (1S,8R,19S,20S)- and (1R,8S,19R,20R)-13,15-dimethyl-11-
azaheptacyclo[17.7.1.02,7.08,20.011,20.013,18.021,26]-heptacosa-2-
(7),3,5,13,15,17,21,23,25-nonaen-10-one (10g) (0.47 g, 39%). Rf 0.5
(10% Et2O in DCM); mp 238−240 °C; 1H NMR (CDCl3, 500 MHz)
δ 1.73 (1H, ddd, J = 3.4, 9.9, 13.0 Hz), 2.21 (3H, s), 2.22 (3H, s), 2.70
(1H, dd, J = 12.1, 16.4 Hz), 3.09 (1H, dd, J = 8.8, 16.0 Hz), 3.12 (1H,
ddd, J = 3.4, 9.1, 12.6 Hz), 3.57 (1H, dd, J = 8.8, 12.0 Hz), 3.74 (1H, t,
J = 10.6 Hz), 4.01 (1H, t, J = 3.2 Hz), 4.62 (1H, d, J = 16.6 Hz), 5.20
(1H, d, J = 16.6 Hz), 6.78 (1H, s), 6.81 (1H, s), 7.03−7.07 (1H, m),
7.17 (1H, dt, J = 1.0, 7.3 Hz), 7.23 (1H, dd, J = 1.3, 7.4 Hz), 7.25−7.33
(4H, m), 7.42 (1H, d, J = 7.6 Hz); 13C NMR (CDCl3, 125 MHz) δ
20.6 (CH3), 22.5 (CH3), 33.5 (CH), 35.3 (CH2), 38.4 (CH2), 41.0
(CH2), 47.9 (CH), 49.8 (CH), 63.9 (C), 122.3 (CH), 124.6 (CH),
126.0 (CH), 127.2 (CH), 127.7 (CH), 129.0 (CH), 129.1 (CH),
131.1 (CH), 132.7 (C), 134.2 (C), 135.3 (C), 136.1 (C), 137.3 (C),
138.7 (C), 140.3 (C), 141.5 (C), 174.5 (C); EI-MS m/z (relative
intensity) 392 (25), 391 (70), 376 (100); HRMS (EI) M+ calcd for
C28H25NO 391.1931, found 391.1938. Further elution with DCM +
4% Et2O gave (1R,8R,19R,20R)- and (1S,8S,19S,20S)-13,15-dimethyl-
11-azaheptacyclo[17.7.1.02,7.08,20.011,20.013,18.021,26]-heptacosa-2-
(7),3,5,13,15,17,21,23,25-nonaen-10-one (9g) (0.55 g, 46%). Mp
(b). With PPA. A solution of 5e (0.72 g, 2.0 mmol) in CHCl3 (10
mL) was stirred and heated with PPA (10.0 g) in an open flask to 120
°C for 2 h, allowing the CHCl3 to distill off. The reaction mixture was
cooled, treated with ice (20 g), and then partitioned between DCM
(50 mL) and water (20 mL). The organic layer was separated, and the
aqueous layer was further extracted with DCM (2 × 50 mL). The
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on SiO2. The elution with DCM gave only partial
separation, and three fractions were collected. From the first fraction,
trituration with Et2O gave 6-benzyl-4-phenyl-3,4-dihydro-1H-benzo-
1
[h]quinolin-2-one (14) as a white solid. Mp 174−176 °C; H NMR
(CDCl3, 600 MHz) δ 3.02 (3-CH, dd, J = 6.5, 15.9 Hz), 3.13 (3-CH,
dd, J = 16.0, 6.7 Hz), 4.30 (Ph−CH, d, J = 16.0 Hz), 4.37 (Ph−CH, d,
J = 16.0 Hz), 4.44 (4-CH, t, J = 6.6 Hz), 7.02 (5-H, s), 7.11 (2H, d, J =
7.3 Hz), 7.13−7.33 (8H, m), 7.47 (8-H, ddd, J = 8.5, 6.9, 1.1 Hz), 7.55
(9-H, ddd, J = 8.5, 6.9. 1.2 Hz), 7.94 (10-H, d, J = 8.5 Hz), 7.97 (7-H,
d, J = 8.5 Hz), 8.83 (1H, s); 13C NMR (CDCl3, 150 MHz) δ 39.0 (3-
CH2), 39.0 (Ph-CH2), 42.5 (4-CH), 120.2 (10-CH), 121.7 (4a-C),
123.0 (10a-C), 125.5 (7-CH), 126.2 (4′-CH), 126.4 (8-CH), 127.3
(4″-CH), 127.8 (2″-CH), 128.0 (5-CH), 128.5 (2′-CH), 128.6 (3′-
CH), 129.1 (3″-CH), 131.1 (10b-C); 131.9 (6a-C), 132.0 (6-C), 140.6
(1′-C), 141.7 (1″-C), 170.7 (2-CO); FTIR (solid) 3279, 1666,
1493, 1472, 1459, 1390, 1253, 1150, 767, 745, 726, 699, 678, 568, 492,
457 cm−1; EI-MS m/z (relative intensity) 364 (24), 363 (100); HRMS
(EI) M+ calcd for C26H21NO 363.1623, found 363.1620. NMR and
MS analysis of the mixed fractions were consistent with their being
mixtures of isomers of 14.
1
160−162 °C; Rf 0.4 (10% Et2O in DCM); H NMR (CDCl3, 500
MHz) δ 2.19−2.35 (9H, m including 2.20 (3H, s) and 2.31 (3H, s)),
2.94 (1H, dd, J = 7.4, 15.6 Hz), 3.37 (1H, t, J = 12.9 Hz), 3.77−3.88
(1H, m), 4.00 (1H, m), 4.67 (1H, d, J = 17.7 Hz), 4.93 (1H, d, J = 17.7
Hz), 6.77 (1H, s), 6.84 (1H, s), 7.02−7.30 (8H, m); 13C NMR
(CDCl3, 125 MHz) δ 20.6 (CH3), 23.0 (CH3), 35.4 (CH2), 38.3
(CH2), 42.0 (CH2), 44.5 (CH), 47.8 (CH), 53.0 (CH), 63.9 (C),
124.9 (CH), 124.9 (CH), 125.5 (CH), 127.0 (CH), 127.1 (CH),
127.6 (CH), 128.3 (CH), 128.9 (CH), 129.3 (CH), 130.2 (C), 131.3
(CH), 132.8 (C), 133.8 (C), 134.8 (C), 135.7 (C), 137.0 (C), 142.1
(C), 144.8 (C), 174.3 (C); FTIR (solid) 1690, 1393, 851, 751, 740,
590, 506 cm−1; EI-MS m/z (relative intensity) 392 (30), 391 (100),
376 (39), 246 (18), 178 (22), 84 (26), 51 (29); HRMS (EI) M+ calcd
for C28H25NO 391.1931, found 391.1943.
Reaction of N-4-Methylbenzyl-N-cinnamoyl-1-naphthylamine
(5f). Following the general procedure for cyclization, 5f (1.1 g, 3.0
mmol) was heated under reflux in CHCl3 (30 mL) for 2 h. Purification
by column chromatography on SiO2, eluting with 2% EtOAc/DCM,
gave a product mixture (0.50 g) that was repurified by column
chromatography on Al2O3, eluting with 1:1 PE/DCM, to give
(1S,8R,19S,20S)- and (1R,8S,19R,20R)-14-methyl-11-azaheptacyclo-
[ 1 7 . 7 . 1 . 0 2 , 7 . 0 8 , 2 0 . 0 1 1 , 2 0 . 0 1 3 , 1 8 . 0 2 1 , 2 6 ] - h e p t a c o s a - 2 -
(7),3,5,13,15,17,21,23,25-nonaen-10-one (10f) (0.27 g, 25%). Mp
Reaction of N-3,5-Dimethoxybenzyl-N-cinnamoyl-1-naphthyl-
amine (5h). (a). With TfOH. Following the general procedure for
cyclization, 5h (1.27 g, 3.0 mmol) was heated under reflux in CHCl3
(30 mL) for 6 h. Purification by column chromatography on SiO2,
eluting with DCM, gave 1-(3,5-dimethoxybenzyl)-4-phenyl-3,4-dihy-
dro-1H-benzo[h]quinolin-2-one (6h) (0.47 g, 37%) as an oil. Rf 0.8
1
240−241 °C; H NMR (CDCl3, 500 MHz) δ 2.04 (1H, ddd, J = 3.5,
9.1, 12.6 Hz), 2.23 (3H, s), 2.67 (1H, dd, J = 12.4, 16.4 Hz), 3.04 (1H,
ddd, J = 3.0, 9.6, 12.6 Hz), 3.10 (1H, dd, J = 8.8, 16.4 Hz), 3.57 (1H,
dd, J = 9.0, 12.1 Hz), 3.72 (1H, t, J = 9.2 Hz), 4.03 (1H, t, J = 2.8 Hz),
4.52 (1H, d, J = 16.5 Hz), 5.33 (1H, d, J = 16.5 Hz), 6.89−6.98 (3H,
m), 7.01−7.04 (1H, m), 7.18 (1H, t, J = 7.3 Hz), 7.21−7.31 (5H, m),
7.38 (1H, d, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 21.2 (CH3),
33.3 (CH), 35.2 (CH2), 39.7 (CH2), 40.3 (CH2), 47.8 (CH), 49.2
(CH), 63.6 (C), 121.8 (CH), 125.8 (CH), 126.5 (CH), 126.9 (CH),
127.2 (CH), 127.7 (CH), 127.8 (CH), 128.5 (C), 128.6 (CH), 128.8
(CH), 129.1 (CH), 136.0 (C), 136.7 (C), 138.8 (C), 138.9 (C), 140.2
(C), 141.4 (C), 174.7 (C); FTIR (solid) 1645, 1608, 1446, 754, 736,
585, 527 cm−1; EI-MS m/z (relative intensity) 377 (93), 247 (21), 246
(22), 131 (55), 86 (62), 84 (97), 51 (100); HRMS (EI) M+ calcd for
C27H23NO 377.1774, found 377.1773. Further elution with DCM gave
6a (0.18 g, 22%). Further elution of the SiO2 column with 10%
EtOAc/DCM gave (1R,8R,19R,20R)- and (1S,8S,19S,20S)-14-methyl-
11-azaheptacyclo[17.7.1.02,7.08,20.011,20.013,18.021,26]-heptacosa-2-
(7),3,5,13,15,17,21,23,25-nonaen-10-one (9f) (0.48 g, 44%) as an oil.
1H NMR (CDCl3, 500 MHz) δ 2.26 (3H, s), 2.80−2.89 (1H, m),
2.97−3.10 (2H, m), 3.61 (1H, dd, J = 3.5, 10.2 Hz), 3.84 (1H, dd, J =
7.7, 12.7 Hz), 4.05 (1H, d, J = 6.2 Hz), 4.72 (1H, d, J = 17.7 Hz), 4.95
(1H, d, J = 17.7 Hz), 6.89−7.25 (11H, m); 13C NMR (CDCl3, 125
MHz) δ 21.4 (CH3), 32.5 (CH2), 35.7 (CH2), 42.5 (CH2), 44.3 (CH),
46.5 (CH), 50.7 (CH), 65.3 (C), 125.1 (CH), 125.4 (CH), 126.9
1
(Et2O); H NMR (CDCl3, 500 MHz) δ 2.98 (1H, dd, J = 4.9, 14.6
Hz), 3.07 (1H, dd, J = 9.2, 14.6 Hz), 3.64 (6H, s), 4.27 (1H, dd, J =
4.9, 9.2 Hz), 5.12 (1H, d, J = 15.1 Hz), 5.31 (1H, d, J = 15.1 Hz), 6.23
(2H, d, J = 2.2 Hz), 6.30 (1H, t, J = 2.2 Hz), 7.01 (1H, d, J = 8.3 Hz),
7.07 (2H, d, J = 6.7 Hz), 7.24−7.32 (3H, m), 7.44−7.49 (2H, m), 7.56
(1H, d, J = 8.3 Hz), 7.81−7.85 (1H, m), 7.95−7.99 (1H, m); 13C
NMR (CDCl3, 125 MHz) δ 38.8 (CH2), 42.5 (CH), 52.2 (CH2), 55.3
(CH3), 99.6 (CH), 105.7 (CH), 123.7 (CH), 125.2 (CH), 125.5
(CH), 125.7 (C), 125.8 (CH), 126.2 (CH), 127.2 (CH), 128.2 (CH),
128.9 (CH), 128.9 (CH), 131.2 (C), 134.2 (C), 137.7 (C), 140.4 (C),
140.4 (C), 160.7 (C), 172.7 (C); FTIR (film) 1665, 1641, 1599, 1489,
1416, 1131, 823 cm−1; EI-MS m/z (relative intensity) 423 (100), 272
(37); HRMS (EI) M+ calcd for C28H25NO3 423.1829, found 423.1810.
Further elution with DCM + 5% MeOH gave 1-(3,5-methoxyphenyl)-
4-diphenyl-3,4-dihydro-1H-naphth[1,8-bc]azepin-2-one (7h) (0.38 g,
1
30%). Mp 131−132 °C; Rf 0.5 (Et2O); H NMR (CDCl3 400 MHz,
−30 °C; a 3:7 ratio of conformers) δ 2.97 (0.3H, d, J = 12.7 Hz), 3.27
(0.7H, dd, J = 6.7, 13.5 Hz), 3.49 (0.7H, d, J = 13.5 Hz), 3.58 (0.3H, t,
J = 12.7 Hz), 3.70 (1.8H, s), 3.76 (4.2H, s), 4.20 (0.7H, d, J = 16.1
Hz), 4.75 (0.3H, d, J = 11.0 Hz), 4.75−5.02 (1.7H, m), 5.26 (0.3H, d,
G
dx.doi.org/10.1021/jo4018827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 15.8 Hz), 6.25−6.45 (3H, m), 6.81 (0.6H, d, J = 7.0 Hz), 7.03−
7.60 (8.7H, m), 7.59−7.81 (1.0H, m), 7.87 (0.7H, d, J = 7.7 Hz); 13C
NMR (CDCl3, 100 MHz, −30 °C) δ 41.9, 43.7, 48.0, 55.5, 56.5, 98.4,
104.2, 104.8, 121.6, 125.0, 125.4, 125.6, 125.7, 126.8, 127.0, 127.8,
127.9, 128.3, 128.7, 129.1, 129.7, 135.1, 135.5, 137.7, 139.9, 140.5,
141.2, 141.8, 146.4, 160.6, 160.7, 171.3, 172.9; FTIR (solid) 1667,
1597, 1200, 1158, 824, 768, 751, 702 cm−1; EI-MS m/z (relative
intensity) 423 (100), 273 (60), 230 (22); HRMS (EI) M+ calcd for
C28H25NO3 423.1829, found 423.1828.
128.3 (CH), 128.9 (CH), 128.9 (CH), 131.4 (C), 134.1 (C), 137.7
(C), 138.0 (C), 140.3 (C), 172.7 (C); FTIR (solid) 1676, 1376, 1281,
819, 771, 752, 723, 689, 672, 660 cm−1; EI-MS m/z (relative intensity)
363 (100), 272 (32); HMRS (EI) M+ calcd for C26H21NO 363.1618,
found 363.1615.
Quantum-Mechanical Calculations. All of the quantum
mechanical calculations were carried out using Gaussian 09.9
Geometry optimizations were performed using M06-2X/cc-pVTZ
calculations. The “nosymm” keyword of Gaussian 09 was employed in
order to carry out QM calculations with the symmetry of molecules
disabled. For DFT geometry optimizations of 9e and 10e, the ultrafine
numerical integration grid (with 99 radial shells and 590 angular points
per shell) was used, combined with the “verytight” convergence
condition (requesting the root-mean-square forces to be smaller than 1
× 10−6 hartree bohr−1). Additional frequency calculations were also
undertaken in order to verify that the optimized geometries
correspond to true minima. Chloroform solvent effects were used in
all of the quantum-mechanical calculations using the reaction field
method IEFPCM.10
(b). With PPA. A solution of 5h (1.27 g, 3.0 mmol) in CHCl3 (10
mL) was stirred and heated with PPA (10.0 g) in an open flask to 110
°C for 2 h, allowing the CHCl3 to distill off. The reaction mixture was
cooled, treated with ice (20 g), and then partitioned between DCM
(50 mL) and water (20 mL). The organic layer was separated, and the
aqueous layer was further extracted with DCM (2 × 50 mL). The
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on SiO2, initially eluting with 1:1 PE/ether, to give
7h (0.21 g, 16%); further elution gave 6a (0.10 g, 7%). Increasing the
polarity to 1:3 PE/ether gave (1S,8R,19S,20S)- and (1R,8S,19R,20R)-
13,15-dimethoxy-11-azaheptacyclo[17.7.1.02,7.08,20.011,20.013,18.021,26]-
heptacosa-2(7),3,5,13,15,17,21,23,25-nonaen-10-one (10h) (0.34 g,
ASSOCIATED CONTENT
* Supporting Information
■
S
1
27%). Mp 183−185 °C; H NMR (CDCl3, 500 MHz) δ 1.64 (1H,
1H NMR and 13C NMR spectra of all novel compounds and
the crystallographic data for 9e (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org. CCDC
953621 contains the supplementary crystallographic data for 9e.
These data can be obtained free of charge via the Internet at
http://www.ccdc.cam.ac.uk/conts/retrieving.html or from The
Cambridge Crystallographic Data Centre (12 Union Road,
Cambridge CB2 1EZ, U.K.; Tel (+44)1223 336 408; E-mail:
deposit@ccdc.cam.ac.uk).
ddd, J = 3.4, 97, 13.2 Hz), 2.69 (1H, dd, J = 12.2, 16.4 Hz), 3.07 (1H,
dd, J = 8.6, 15.9 Hz), 3.32 (1H, ddd, J = 3.4, 8.8, 12.2 Hz), 3.54 (1H,
dd, J = 8.4, 12.2 Hz), 3.69 (3H, s), 3.73−3.75 (4H, m including 3.74
(3H, s)), 3.97 (1H, t, J = 3.4 Hz), 4.56 (1H, d, J = 16.6 Hz), 5.21 (1H,
d, J = 16.6 Hz), 6.23 (1H, d, J = 2.4 Hz), 6.26 (1H, d, J = 2.4 Hz),
7.00−7.04 (1H, m), 7.17−7.31 (H, m), 7.40 (1H, d, J = 7.6 Hz); 13C
NMR (CDCl3, 125 MHz) δ 31.4 (CH), 35.3 (CH2), 38.3 (CH2), 41.0
(CH2), 48.1 (CH), 49.6 (CH), 55.1 (CH3), 55.4 (CH3), 63.7 (C),
97.8 (CH), 101.2 (CH), 119.8 (C), 122.1 (CH), 126.1 (CH), 127.2
(CH), 127.5 (CH), 127.6 (CH), 129.0 (CH), 129.1 (CH), 134.6 (C),
136.2 (C), 139.0 (C), 140.2 (C), 142.0 (C), 158.8 (C), 159.5 (C),
174.8 (C); FTIR (solid) 1694, 1589, 1394, 1201, 1149, 760 cm−1; EI-
MS m/z (relative intensity) 423 (100), 177 (80); HRMS (EI) M+
calcd for C28H25NO3 423.1829, found 423.1827. Further elution with
ether gave (1R,8R,19R,20R)- and (1S,8S,19S,20S)-13,15-dimethoxy-
11-azaheptacyclo[17.7.1.02,7.08,20.011,20.013,18.021,26]-heptacosa-2-
(7),3,5,13,15,17,21,23,25-nonaen-10-one (9h) (0.59 g, 46%). Mp
AUTHOR INFORMATION
Corresponding Author
*E-mail: f.d.king@ucl.ac.uk.
■
Notes
The authors declare no competing financial interest.
1
241−243 °C; H NMR (CDCl3, 500 MHz) δ 2.25 (1H, ddd, J = 4.9,
ACKNOWLEDGMENTS
7.4, 12.4 Hz), 2.35 (1H, dd, J = 12.9, 15.8 Hz), 2.92 (1H, dd, J = 7.4,
15.8 Hz), 3.45 (1H, ddd, J = 2.2, 10.1, 12.4 Hz), 3.68−3.77 (7H, m,
including 3.74 (3H, s) and 3.75 (3H, s)), 3.97 (1H, dd, J = 2.4, 4.9
Hz), 4.62 (1H, d, J = 17.8 Hz), 4.96 (1H, d, J = 17.8 Hz), 6.24 (1H, d,
J = 2.0 Hz), 6.29 (1H, d, J = 2.0 Hz), 7.02 (1H, d, J = 7.5 Hz), 7.05
(1H, d, J = 7.5 Hz), 7.11−7.19 (5H, m), 7.28 (1H, d, J = 7.3 Hz); 13C
NMR (CDCl3, 125 MHz) δ 35.5 (CH2), 37.6 (CH2), 41.9 (CH2),
42.3 (CH), 48.1 (CH), 2.9 (CH), 55.2 (CH3), 55.4 (CH3), 63.7 (C),
97.8 (CH), 101.6 (CH), 119.1 (C), 125.0 (CH), 125.3 (CH), 126.9
(CH), 127.0 (CH), 128.2 (CH), 129.0 (CH), 129.2 (CH), 132.2 (C),
132.8 (C), 134.8 (C), 142.5 (C), 145.3 (C), 159.1 (C), 159.4 (C),
174.3 (C); FTIR (solid) 1697, 1606, 1586, 1394, 1206, 1147, 744
cm−1; EI-MS m/z (relative intensity) 423 (48), 202 (54), 191 (48),
178 (51), 177 (100), 151 (30); HRMS (EI) M+ calcd for C28H25NO3
423.1829, found 423.1820.
■
We thank Karen Joiner for assistance in naming the heptacyclic
structures. We also thank John Hill and Vincent Gray for the
mass spectrometry data.
REFERENCES
■
(1) King, F. D.; Caddick, S. Tetrahedron 2012, 68, 9350.
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(6) (a) Seth, D. S.; Banerji, B. C.; Ittyerah, P. I. Curr. Sci. 1979, 48,
859. (b) Gnanadoss, L.; Swarnalakshmi, S. Ind. J. Chem. 1978, 16B,
425.
(7) Strods, V.; Lielbriedis, I.; Neilands, O. Khim. Geterotsik. Soedin
1977, 977.
1-Benzyl-4-phenyl-3,4-dihydro-1H-benzo[h]quinolin-2-one
(6e). Following the general procedure for the alkylation of N-alkyl-N-
cinnamoyl-1-naphthylamines 5b−h, but with heating under reflux for 4
h, 6a (1.44 g, 5.3 mmol) gave 1-benzyl-4-phenyl-3,4-dihydro-1H-
benzo[h]quinolin-2-one (6e), which was purified by column
chromatography on silica, eluting with 1:1 DCM/PE, and isolated as
(8) Strods, V.; Kampare, R.; Lielbriedis, I.; Neilands, O. Latv. PSR
Zinat. Akad. Vestis, Kim. Ser. 1977, 344.
1
a white solid (1.5g, 79% yield). Mp 141−143 °C; H NMR (CDCl3,
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
500 MHz) δ 2.95 (1H, dd, J = 4.8, 14.7 Hz), 3.07 (1H, dd, J = 9.6, 14.7
Hz), 4.20 (1H, dd, J = 4.8. 9.6 Hz), 6.99 (1H, d, J = 8.3 Hz), 7.10−
7.11 (4H, m), 7.15−7.20 (3H, m), 7.24−7.31 (3H, m), 7.40−7.49
(2H, m), 7.56 (1H, d, J = 8.3 Hz), 7.84 (1H, dd, J = 1.6, 8.5 Hz), 7.94
(1H, d, J = 8.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 40.4 (CH2), 42.4
(CH), 52.3 (CH2), 123.7 (CH), 125.1 (CH), 125.4 (CH), 125.7 (C),
125.7 (CH), 127.2 (CH), 127.2 (CH), 127.8 (CH), 128.2 (CH),
H
dx.doi.org/10.1021/jo4018827 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
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(b) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem.
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I
dx.doi.org/10.1021/jo4018827 | J. Org. Chem. XXXX, XXX, XXX−XXX