The triflic acid-mediated cyclisation of N-benzyl-cinnamamides

Article abstract of DOI:10.1016/j.tet.2012.11.035

N-Benzyl-cinnamamides cyclise with triflic acid to form 5-aryl-benzazepinones and/or cinnamamides.

Full text of DOI:10.1016/j.tet.2012.11.035

Tetrahedron 69 (2013) 487e491
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The triflic acid-mediated cyclisation of N-benzyl-cinnamamides
*
Frank D. King , Stephen Caddick
Dept. of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 August 2012
Received in revised form 20 October 2012
Accepted 7 November 2012
Available online 14 November 2012
N-Benzyl-cinnamamides cyclise with triflic acid to form 5-aryl-benzazepinones and/or cinnamamides.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cinnamamides
Triflic acid
Benzazepin-3-ones
Intramolecular cyclisation
Carbocations
1. Introduction
formation of a small amount of cinnamamide 5. Previously cyclisa-
tion of N-benzyl-cinnamamides had been reported using poly-
We have recently reported that N-benzyl-4-aryl-azetidinones
(exemplified by 1 in Scheme 1) undergo ring opening with TfOH in
CHCl3 to give 5-phenyl-benzazepin-3-ones via N-benzyl-
cinnamamides.1
Further investigation confirmed that 2a underwent TfOH-
mediated cyclisation to 4a (Table 1, entry 1) together with the
phosphoric acid, but was restricted to N-methyl-N-3-methoxybenzyl
derivatives.2 5-Phenyl-benzazepinones and derivatives related to 4a
have potential use as antiarrhythmics and memory enhancers3,4
and are intermediates to 5-phenyl-benzazepines related to 6,
which have been reported to have opioid receptor antagonist5 and
triple re-uptake inhibitor activity.2 Therefore, we were interested
in investigating the scope of the TfOH-mediated cyclisation of N-
benzyl-cinnamamides to produce novel analogues for biological
testing.
O
TfOH
Ph
O
N
H
Ph
2a
Table 1
N
Ph
TfOH
Yields of benzazepinones 4aee
Ph
TfOH
1
Ph
O
R
Ph
N
H
Ph
+
5
O
R
O
NH
2a-e
4a-e
X
NH
+
Ph
NH2
Entry
Amide
R
Product
Yield %
5 Yield %
5
4a X = C=O
1
2
3
4
2a
2b
2c
2d
2e
2e
H
4a
4b
4c
4d
4e
4e
69
0
7
25
15
61
0
6
X = CH2
4-Me
3-Me
4-Cl
3-MeO
3-MeO
37a
0
Scheme 1.
5
0
28
6b
3
a
Mixture of the 8- and 6-Me isomers in a 2:1 ratio.
See text.
* Corresponding author. E-mail addresses: f.d.king@ucl.ac.uk, fd.king@btinter-
net.com (F.D. King).
b
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.035

488
F.D. King, S. Caddick / Tetrahedron 69 (2013) 487e491
2. Results and discussion
Wewere particularly interested in synthesizing the 2-Cl analogue
4i, as the bulk of the ortho substituent should affect the preferred
conformation of the molecule. However, we reported previously that
the 4-(2-chlorophenyl)-azetidinone failed to give any 4i.1 In contrast,
2i, heated under reflux in dichloroethane for 5 h (entry 5) gave an
inseparable 1:1 mixture of 4i and 5i. Pure 4i was obtained by for-
mation7 and purification of the N-BOC derivative 8 (overall 30% yield
from 2i) followed by BOC cleavage with HCl (90% yield).
2.1. Cyclisations of N-benzyl-cinnamamidesdsubstituted
benzyl
Previously we have shown that substitution on the N-benzyl
group of the 4-phenyl-azetidinone considerably reduced the yield
of 5-phenyl-benzazepin-3-one.1 Similarly, in this study both the N-
4-Me-benzyl 2b (Table 1, entry 2) and the N-4-Cl-benzyl 2d (entry
4) gave no cyclised products, only cinnamamide 5. However, the 3-
Me 2c (entry 3) gave 4c as a 2:1 mixture of the 8- and 6-isomers
together with cinnamamide 5, an improvement over the conver-
sion of the azetidinone to 4c (24% yield).1 3-MeO-benzyl analogues
have been reported to cyclise in moderate yields using poly-
phosphoric acid to give the 8-methoxy isomer.2 The 3-MeO com-
pound 2e (entry 5) rapidly reacted with TfOH (30 min) under reflux
in CHCl3 to give a complex mixture of products. However, with
Eaton’s reagent in 1,2-dichloroethane (DCE) at reflux overnight
(entry 6), an inseparable mixture of the 6-MeO and 8-MeO isomers
(ratio 2:1) was obtained.
Cl
O
N
BOC
8
The reaction of 3-Cl 4j (entry 6) was also slow and after 5 h reflux
in DCE, 30% of starting material was recovered, together with a 49%
yield of a 3.5:1 inseparable mixture of the cinnamamide 5j and
benzazepinone 4j. Similarly to the 4-(2-naphthyl)-azetidinone,1 the
2-naphthyl 2k (entry 7) gave only insoluble, unidentified products.
Reaction of the tetrahydro-naphthalene 7 gave only cinnama-
mide 5, probably due to the enhanced stability of the benzylic
carbonium ion6 facilitating N-debenzylation.
2.3. Cyclisations of N-benzyl-cinnamamidesdN-alkyl
analogues
O
Unlike the azetidinones, the use of cinnamamides allowed us to
investigate N,N-disubstituted derivatives. The N-methyl derivative
9a8 cyclised to give the benzazepinone 10a in good yield (entry 1,
Table 3), with no evidence of the formation of N-methyl-
cinnamamide.
N
H
7
Table 3
2.2. Cyclisations of N-benzyl-cinnamamidesdsubstituted
cinnamamides
Yields of N-methyl-benzazepinones 10aek
R1
The cyclisation reaction was much more successful for
substituted cinnamamides (Table 2).
O
R2
R1
R2
N
The 4-Me 2f (entry 1) and 4-Br 2h (entry 4) cyclised to give the
benzazepinones 4f and 4h, respectively, together with small
amounts of cinnamamides. However, the 3-Me 2g (entry 2) cyclised
to 4g with no evidence of formation of the cinnamamide. Repeating
the reaction of 2g (entry 3) in the presence of 10% P2O5 (to remove
any water present) increased the yield of 4g.
O
N
9a-k
Entry Amide R1
10a-k
R2
Product Yield N-methyl-cinnamamide
%
yield %
Table 2
1
2
3
4
5
6
9a
9c
9e
9i
9j
9k
H
H
H
2-Cl
3-Cl
H
3-Me
3-MeO 10e
H
H
H
10a
10c
83
0
5
3
54
60
0
37a
64b
27
Yields of benzazepinones 4fek
R
10i
10j
10k
20
35
3,4-benzo
a
O
55:45 mixture of 8- and 6-isomers.
5:3 mixture of 6- and 8-isomers.
O
4f-j
R
b
NH
N
H
Ph
+
As cyclisation of the N-methyl derivative appeared to give
O
a higher yield with reduced formation of the cinnamamide, we re-
investigated the cyclisations of substituted cinnamamides, which
had given poor yields with the NH amides. Thus, cyclisation of the
3-methylbenzyl 9c (entry 2) gave a similar yield of benzazepinone,
but as a 55:45 mixture of the 8- and 6-isomers together with
a small amount of N-methyl-cinnamamide. Cyclisation of the 3-
methoxy 9e (entry 3) was very rapid (30 min) and gave a 5:3
mixture of the 6- and 8-isomers. Cyclisation of the 2-Cl 9i (entry 4)
gave a 2:1 mixture of the N-methyl-cinnamamide and 10i. The
cinnamamide was removed by conversion into its N-BOC derivative
and separation using column chromatography to give the pure 10i
(overall yield 25% from 9i). The 1H NMR spectrum of 10i at room
temperature showed broadening of some of the peaks indicating
a slow conformational change. Whereas cyclisation of the naphthyl
R
NH2
2f-j
5f-j
Entry
Amide
R
Time h
Product
Yield
%
5fej yield %
1
2
3
4
5
6
7
2f
2g
2g
2h
2i
4-Me
3
3
3
4f
4g
4g
4h
4i
76
50
70a
85
43
11
0
2
0
0
3-Me
3-Me
4-Br
2-Cl
3-Cl
3b
5b
3b
3
7
43
38
0
2j
2k
4j
4k
3,4-benzo
a
With 10% P2O5/TfOH.
In 1,2-dichloroethane (DCE).
b

F.D. King, S. Caddick / Tetrahedron 69 (2013) 487e491
489
2k gave no cyclic product, the N-methyl analogue 9k (entry 6) gave
the desired benzazepinone 10k.
The acryloyl amide 2113 failed to give either the benzazepinone
22 or the 3-phenylpropionamide 23 with TfOH in benzene. Thus,
we believe that the stabilisation of the carbonium ion by the phenyl
of the cinnamoyl group assists in the protonation and subsequent
cyclisation.
O
N
O
O
R
N
O
N
R
N
Me
Me
11 R = CH2Ph
12 R = CH2Ph
21
PhCH2CH2CON(Me)CH2Ph
22
23
O
N
O
H
N
3. Conclusion
13
14 (+)
In summary, we have shown that N-benzyl-cinnamamides can
undergo a TfOH-mediated cyclisation in an inert solvent to give 5-
phenyl-benzazepin-3-ones. However, with substituted N-benzyl
analogues, the major product is cinnamamide, resulting from N-de-
benzylation, exceptions being where the electronics of the sub-
stituent favours cyclisation. In contrast, good yields of benzazepi-
nones can be obtained from cinnamamides with substituents in the
phenyl ring. N-Benzyl-N-methyl-cinnamamides cyclise more rap-
idly and generally in higher yields. Seven-membered cyclisation is
less favoured than six-membered.
Cyclisation of the N-dibenzyl 11 gave the N-benzyl-benzazepi-
none 12 (68% yield) together with 4a (12% yield). The TfOH-
mediated cyclisation of the 2-phenylpyrrolidine derivative 13 gave
14 (35% yield). Although we obtained a lower yield than previously
obtained by the iminium ion cyclisation,9 this method could be ap-
plied to analogues with substituents on the 7-phenyl ring, as ana-
logues of 13 can be prepared from readily available cinnamic acids.
4. Experimental section
4.1. General
16
All reagents were commercially available, unless otherwise
specified, and used without purification. The chloroform used was
stabilised with amylene. Commercial dry benzene was stored over
molecular sieves. Petroleum ether was 40e60 ꢀC fraction. Infrared
spectra were run neat on a Perkin Elmer 100 FT IR spectrometer.
Solution 1H and 13C NMR spectra, in CDCl3 unless otherwise stated,
were recorded on a Bruker NMR spectrometer DRX500 or Avance III
400, equipped with z-gradient facilities. 1H and 13C chemical shifts
are given relative to TMS. Unless otherwise specified, spectra were
recorded at 300 K. Mass spectra were run on a Thermo Mat900XP
for EI and a Waters Micromaldi for TOF. Melting points were de-
termined on a Sanyo-Gallenkamp capillary melting point apparatus
and are uncorrected.
N
O
O
N
17
15
O
N
We also found that the cyclisation of the N-phenyl-N-benzyl
derivative 15, gave the six-membered 16 (80% yield) with only a 7%
yield of the seven-membered 17. N-Phenyl-cinnamamide has pre-
viously been reported to undergo a facile TfOH-mediated cyclisa-
tion to give 4-phenyl-tetra-hydroquinolin-2-one.10
4.2. General procedure for the synthesis of the cinnamamides
A solution of the cinnamic acid (5.0 mmol) and oxalyl chloride
(5.5 mmol) in DCM (50 mL) and 2 drops of DMF was stirred at room
temperature for 2 h, until evolution of CO2 had ceased. The DCM
was removed by rotary evaporation, the residue dissolved in CHCl3
(30 mL) and the CHCl3 removed by rotary evaporation to remove
any excess oxalyl chloride. The residue was dissolved in DCM
(20 mL) and added to a stirred solution of the benzylamine
(6.5 mmol) and triethylamine (7.0 mmol) in DCM (100 mL) at 0 ꢀC.
The reaction was stirred at room temperature for 1 h, washed with
2 M aq HCl (30 mL), water (30 mL) and 2 M aq K2CO3 (30 mL) and
dried (MgSO4). Removal of the solvent gave a solid, which was
recrystallised from EtOAc/petroleum ether.
Previously, we have shown that appropriately substituted N-
acyl-iminium ions cyclise with TfOH to give the eight-membered
benzazocin-4-ones.11 However, the N-phenethyl derivative 1812
with TfOH failed to give any benzazocin-4-one 19, although with
benzene the 3,3-diphenyl-propionamide 20 was formed. Thus it
appears that 18 is protonated by the TfOH, but cyclisation to the
eight-membered ring is not favoured.
O
O
N
H
NH
4.2.1. (E)-N-(3-Methyl-benzyl)-3-phenyl-acrylamide (2c). White
solid (93% yield), mp 107e109 ꢀC, 1H NMR (500 MHz, CDCl3)
d
¼3.45 (3H, s), 4.50 (2H, d, J¼5.7 Hz), 5.93 (1H, br t), 6.41 (1H, d,
18
19
J¼15.6 Hz), 7.09e7.15 (3H, m), 7.24 (1H, t, J¼7.6 Hz), 7.33e7.39 (3H,
m), 7.47e7.51 (2H, m), 7.67 (1H, d, J¼15.6 Hz); 13C NMRþDEPT
Ph2CHCH2CONHCH2CH2Ph 20

490
F.D. King, S. Caddick / Tetrahedron 69 (2013) 487e491
(125 MHz, CDCl3)
d
¼21.4 (CH3), 43.9 (CH2), 120.5 (CH), 125.1 (CH),
followed by an excess of solid K2CO3 until CO2 evolution ceased. The
product was extracted into DCM (2ꢂ50 mL), dried (MgSO4), con-
centrated in vacuo and the product purified by column chroma-
tography on SiO2.
127.9 (CH), 128.4 (CH), 128.8 (CH), 128.8 (CH), 128.9 (CH), 129.8
(CH), 134.9 (C), 138.2 (C), 138.6 (C), 141.5 (CH), 165.8 (C); nmax
(solid) 3310, 1653, 1614, 1542, 1341, 1215, 987, 976, 769, 719,
689 cmꢁ1; HRMS (EI) Mþ, found 251.1303, C17H17NO requires
251.1305.
4.3.1. 5-(p-Tolyl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(4f). Following the general procedure for cyclisation, 2f (0.45 g,
2 mmol) was converted into 4f (0.34 g, 76% yield), Rf (Et2O) 0.1,
purified using 0.5% MeOH/DCM as eluant and isolated as a white
solid, mp 190e191 ꢀC, spectroscopically identical to that previously
prepared from the azetidinone.1
4.2.2. (E)-N-(3-Methoxy-benzyl)-3-phenyl-acrylamide (2e). White
solid (92% yield), mp 114e115 ꢀC; 1H NMR (500 MHz, CDCl3)
d¼3.79
(3H, s), 4.55 (2H, d, J¼5.8 Hz), 5.98 (1H, br s), 6.42 (1H, d, J¼15.6 Hz),
6.83 (1H, dd, J¼2.1, 8.2 Hz), 6.86e6.88 (1H, m), 6.91 (1H, dd, J¼0.5,
7.7 Hz), 7.26 (1H, t, J¼7.7 Hz), 7.34e3.37 (3H, m), 7.46e7.50 (2H, m),
7.67 (1H, d, J¼15.6 Hz); 13C NMRþDEPT (125 MHz, CDCl3)
d¼43.9
4.3.2. 5-(2-Chlorophenyl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(4i). Following the general procedure for cyclisation, but using DCE
as solvent, 2i (0.78 g, 2.9 mmol) was heated under reflux with TfOH
(3.0 mL, 30 mmol) for 3 h. Purification by column chromatography
on SiO2, eluting with 2% MeOH/DCM gave a product (0.57 g), which,
by NMR spectroscopy analysed for a 1:1 mixture of 4i and 5i. The
impure product from two reactions (0.95 g) was dissolved in DCM
(30 mL), treated with BOC anhydride (2.0 g, 8.5 mmol), Et3N (2 mL,
14 mmol) and DMAP (1.0 g, 8 mmol) and stirred at room temper-
ature for 2 days. The solvent was removed by rotary evaporation
and the residue partitioned between EtOAc (50 mL) and 2 M aq
H2SO4 (50 mL). The organic layer was dried (MgSO4), concentrated
and purified by column chromatography on SiO2, eluting with
DCMd5% Et2O/DCM to give the N-BOC derivative 8, recrystallised
from DCM/petroleum ether as a pale yellow solid (0.55 g, overall
30% yield from 2i), mp 139e140 ꢀC; 1H NMR (500 MHz, CDCl3)
(CH2), 55.3 (CH3), 113.2 (CH), 113.5 (CH), 120.2 (CH), 120.5 (CH), 127.9
(CH),128.9 (CH),129.8 (CH),129.9 (CH),134.8 (C),139.8 (C),141.5 (CH),
160.0 (C), 165.8 (C); nmax (solid) 3233, 3061, 1651, 1610, 1584,
1489,1438,1265,1223,1157,1146,1045,990, 873,770,739cmꢁ1;LRMS
(EI) 281, 204; HRMS (EI) Mþ, found 267.1256, C17H17NO2 requires
267.1254.
4.2.3. (E)-3-Phenyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acrylam-
ide (7). White solid (83% yield), mp 188e190 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
¼1.80e1.95 (2H, m), 2.05e2.18 (1H, m),
2.75e2.87 (2H, m), 5.30e5.37 (1H, m), 5.90 (1H. br d), 6.39 (1H, d,
J¼15.6 Hz), 7.11 (1H, d, J¼6.5 Hz), 7.14e7.21 (2H, m), 7.28e7.40
(4H, m), 7.49 (3H, d, J¼6.2 Hz), 7.67 (1H, d, J¼15.6 Hz); 13C
NMRþDEPT (125 MHz, CDCl3)
d
¼20.0 (CH2), 29.3 (CH2), 30.2
(CH2), 47.7 (CH), 120.9 (CH), 126.4 (CH), 127.4 (CH), 127.8 (CH),
128.9 (CH), 129.0 (CH), 129.3 (CH), 129.7 (CH), 134.9 (C), 136.7 (C),
137.7 (C), 141.3 (CH), 165.1 (C); nmax (solid) 3263, 1650, 1615, 1540,
1350, 1218, 990, 976, 768, 748, 724, 671 cmꢁ1; LRMS (EI) 277, 146,
131, 130, 103, 91, 77; HRMS (EI) Mþ, found 277.1464, C19H19NO
requires 277.1461.
d
¼1.49 (9H, s), 3.15e3.35 (2H, br m), 4.98 (1H, d, J¼16.4 Hz),
5.02e5.09 (1H, br m), 5.14 (1H, d, J¼16.4 Hz), 6.73e6.80 (1H, br m),
6.91 (1H, dd, J¼4.4, 5.8 Hz), 7.09 (1H, t, J¼7.5 Hz), 7.14 (1H, dt, J¼1.7,
7.5 Hz), 7.17e7.20 (2H, m), 7.23e7.26 (1H, m), 7.37 (1H, dd, J¼1.3,
7.9 Hz); 13C NMRþDEPT (125 MHz, CDCl3)
¼28.1 (CH3), 42.1 (CH2),
d
43.0 (CH), 49.3 (CH2), 83.3 (C), 127.0 (CH), 127.3 (CH), 128.3 (CH),
128.7 (CH), 129.7 (CH), 129.9 (CH), 130.6 (CH), 131.8 (CH), 133.1 (C),
134.8 (C), 139.0 (C), 142.4 (C), 151.8 (C), 171.4 (C); nmax (solid) 1728,
4.2.4. (E)-N-(3-Methyl-benzyl)-N-methyl-3-phenyl-acrylamide
(9c). To a stirred solution of N-methyl-cinnamamide14 (0.65 g,
4.0 mmol) and 3-methyl-benzyl bromide (0.74 g, 4.4 mmol) in THF
(20 mL) at 0 ꢀC was added KOt-Bu (0.46 g, 4.0 mmol) and the so-
lution stirred at room temperature for 1 h. The THF was removed by
rotary evaporation and the residue partitioned between water
(50 mL) and DCM (100 mL). The lower organic layer was separated,
dried (MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography, eluting with 0.5% MeOH/DCM to give
the product, isolated as a colourless oil (88% yield); Rf (DCM) 0.43;
NMR shows two rotamers about the amide bond in a 1:1 ratio, 1H
1698, 1367, 1300, 1281, 1236, 1145, 1099, 854, 776, 763, 740 cmꢁ1
;
LRMS (TOF) 396, 394, 337, 335, 215, 213, 178; HRMS (electrospray
TOF) MNaþ, found 394.1183, C21H2235ClNNaO3 requires 394.1186. A
solution of 8 (0.40 g, 1 mmol) in DCM (10 mL) and 4 M HCl in dioxan
(1.0 mL) was stirred at room temperature for 1 h. The solvent was
removed by rotary evaporation and the residue purified by column
chromatography on SiO2, eluting with 0.5% MeOH/DCM to give 4i as
an orange solid, recrystallised from EtOAc/petroleum ether (0.26 g,
90% yield), mp 160e162 ꢀC; 1H NMR (500 MHz, CDCl3)
d¼3.10 (2H,
NMR (500 MHz, CDCl3)
d¼2.35, 2.35 (3H, 2s), 3.06 (1.5H, s), 3.08
d, J¼6.6 Hz), 4.47 (1H, dd, J¼6.3, 16.3 Hz), 4.52 (1H, dd, J¼4.6,
16.3 Hz), 5.06 (1H, t, J¼6.6 Hz), 6.82e6.87 (1H, m), 6.93 (1H, d,
J¼7.6 Hz), 7.07e7.19 (5H), 7.25 (1H, br s), 7.39 (1H, dd, J¼1.3, 7.9 Hz);
(1.5H, s), 4.65 (1H, s), 4.69 (1H, s), 6.88 (0.5H, d, J¼15.4 Hz), 6.95
(0.5H, d, J¼15.4 Hz), 7.00e7.05 (1H, m), 7.06e7.12 (2H, m), 7.19e7.29
(1H, m), 7.30e7.42 (3H, m), 7.45e7.50 (1H, m), 7.55 (1H, m), 7.76
(0.5H, d, J¼15.4 Hz), 7.79 (0.5H, d, J¼15.4 Hz); 13C NMRþDEPT
13C NMRþDEPT (125 MHz, CDCl3)
¼38.9 (CH2), 41.4 (CH), 46.5
d
(CH2), 126.7 (CH), 127.2 (CH), 128.1 (CH), 128.3 (CH), 128.6 (CH),
129.8 (CH), 130.5 (CH), 131.6 (CH), 133.3 (C), 135.9 (C), 140.1 (C),
142.4 (C), 174.5 (C); nmax (solid) 1673, 1471, 1435, 1033, 769,
750, 725 cmꢁ1; LRMS (EI) 273, 271, 236, 214, 212, 193, 178, 165, 86,
84; HRMS (EI) Mþ, found 271.0758, C16H1435ClNO requires
271.0752.
(125 MHz, CDCl3)
d
¼21.5 (CH3), 34.5 (CH3), 35.0 (CH3), 51.3 (CH2),
53.5 (CH2), 117.5 (CH), 123.6 (CH), 125.3 (CH), 127.2 (CH), 127.9 (CH),
128.2 (CH), 128.8 (CH), 128.9 (CH), 128.9 (CH), 129.6 (CH), 129.7
(CH),135.4 (C), 135.4 (C), 136.8 (C), 137.3 (C), 138.4 (C), 138.8 (C),
143.0 (CH), 143.1 (CH), 166.7 (C), 167.3 (C); nmax (film) 1648,
1603, 1397, 1114, 976, 762, 699, 684 cm-1; LRMS (EI) 266, 134,
131, 105; HRMS (EI) Mþ, found 266.1546, C18H20NO requires
266.1545.
4.3.3. 5-(2-Chlorophenyl)-N-methyl-1,2,4,5-tetrahydro-benzo-[c]
azepin-3-one (10i). Following the general procedure for cyclisa-
tion, 9i (0.57 g, 2.0 mmol) was converted into a 2:1 mixture of the
N-methyl cinnamamide and 10i (0.37 g, 82% conversion). This
mixture was reacted with BOC anhydride (1.0 g, 4.3 mmol) as
described for 4i. Column chromatography on SiO2, eluting first
with 1:1 DCM/petroleum ether to remove the BOC derivative of the
cinnamamide, then DCM to give 10i, isolated as an oil (0.15 g, 25%
4.3. General procedure for the TfOH-mediated ring cyclisa-
tion reactions
Triflic acid (20 mmol) was added to a stirred solution of the
lactam or cinnamamide (2.0 mmol) in CHCl3 (20 mL) and the re-
action mixture was heated under gentle reflux for 3 h. The reaction
mixture was cooled to room temperature, water (20 mL) was added
yield from 9i). 1H NMR (400 MHz, CDCl3, 330 K)
m including 3.07, 3H, s), 3.29 (1H, dd, J¼10.3, 13.8 Hz), 4.37 (1H, d,
d¼3.05e3.11 (4H,

F.D. King, S. Caddick / Tetrahedron 69 (2013) 487e491
491
J¼16.2 Hz), 4.90 (1H, d, J¼16.2 Hz), 5.05 (1H, dd, J¼5.2, 10.3 Hz),
6.85e6.90 (1H, m), 6.90e6.93 (1H, m), 7.10e7.40 (6H, m); 13C NMR
143.4 (C), 146.4 (C), 171.5 (C); nmax (solid) 1663, 1596, 1491, 1438,
1399, 1206, 1101, 1076, 787, 758, 739, 697 cmꢁ1; LRMS (EI) 313, 265,
201, 192, 179, 178; HRMS (EI) Mþ, found 313.1458, C22H19NO re-
quires 313.1458.
(100 MHz, CDCl3, 330 K)
d¼34.8 (CH3), 39.9 (CH2), 42.6 (CH), 55.1
(CH2), 126.6 (CH), 127.3 (CH), 128.1 (CH), 128.6 (CH), 128.9 (CH),
130.0 (CH), 130.7 (CH), 132.3 (CH), 133.4 (C), 135.1 (C), 140.1 (C),
143.5 (C), 171.7 (C); nmax (film) 1643, 1475, 1395, 1103, 1035, 758,
745 cmꢁ1; LRMS (EI) 287, 285, 250, 214, 212, 193, 191, 178, 165, 110,
109, 97, 95; HRMS (EI) Mþ, found 285.0919, C17H1635ClNO requires
285.0915.
Acknowledgements
The authors would like to thank Dr. Lisa D. Haigh for the mass
spectra and Dr. Abil E. Aliev for assistance with NMR interpretation.
4.3.4. N-Benzyl-5-phenyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(12). Following the general procedure for cyclisation, 1115
(0.66 g, 2.0 mmol) was converted into 12 (0.16 g, 35% yield) by
heating under reflux with TfOH (2.0 mL, 20 mmol) in CHCl3
(10 mL) for 1 h, purified using 1:1 Et2O/petroleum ether as el-
uant and isolated as a white solid, mp 130e131 ꢀC; 1H NMR
Supplementary data
Supplementary data contains experimental procedures and
characterizing data for 2a, 2b, 2d, 2h, 2i, 2f, 2g, 2k, 2j, 4a, 4e, 4g, 4h,
9a, 9e, 9i, 9j, 9k, 10a, 10c, 10e, 10j, 10k, 13, 14 and 20. NMR (1H and
13C) spectra are included for the novel compounds 2c, 2e, 2f, 2g, 4i,
7, 8, 9c, 9i, 10c, 10i, 10k, 12, 13, 15, 17, and 20. Supplementary data
related to this article can be found online at http://dx.doi.org/
10.1016/j.tet.2012.11.035.
(500 MHz, CDCl3)
d
¼3.07 (1H, dd, J¼5.1, 13.8 Hz), 3.38 (1H, dd,
J¼11.5, 13.8 Hz), 4.14 (1H, d, J¼16.3 Hz), 4.43 (1H, d, J¼14.9 Hz),
4.57e4.58 (1H, m), 4.91 (1H, d, J¼14.9, 16.3 Hz), 6.91 (1H, d,
J¼7.6 Hz), 6.96 (1H, d, J¼7.7 Hz), 7.05 (1H, t, J¼7.5 Hz), 7.08e7.15
(2H, m), 7.19e7.35 (9H, m); 13C NMRþDEPT (125 MHz, CDCl3)
References and notes
d
¼42.9 (CH2), 45.8 (CH), 50.0 (CH2), 52.0 (CH2), 126.2 (CH), 126.7
(CH), 127.6 (CH), 128.3 (CH), 128.3 (CH), 128.4 (CH), 128.7 (CH),
128.8 (CH), 129.0 (CH), 132.7 (CH), 134.7 (C), 137.2 (C), 140.4 (C),
146.4 (C), 172.1 (C); nmax (solid) 1640, 756, 735, 695 cmꢁ1; LRMS
(EI) 327, 194, 179, 178; HRMS (EI) Mþ, found 327.1620, C23H21NO
requires 327.1618.
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4.3.5. N-Benzyl-4-phenyl-1,2,3,4-tetrahydroquinolin-2-one (16) and
2,5-diphenyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one (17). Following
the general procedure for cyclisation, 15 (0.62 g, 2 mmol) was
converted into 16 (0.50 g, 80% yield) and 17 (0.04 g, 7% yield) by
heating under reflux with TfOH (2.0 mL, 20 mmol) in CHCl3 (10 mL)
for 1 h. Elution with 3:1 DCM/petroleum ether gave 16 as a white
solid, Rf (DCM) 0.42, spectroscopically identical to the literature
6. Olah, G. A.; Liao, Q.; Casanova, J.; Bau, R.; Golam Rasul, G.; Prakash, G. K. S. J.
Chem. Soc., Perkin Trans. 2 1998, 2239e2242.
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material.16 Elution with DCM gave 17 as a white solid, mp
1
11. King, F. D.; Aliev, A. E.; Caddick, S.; Tocher, D. A.; Courtier-Murias, D. Org. Biomol.
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197e198 ꢀC; Rf (DCM) 0.10; H NMR (500 MHz, CDCl3)
d¼3.18 (1H,
dd, J¼4.9, 13.6 Hz), 3.46 (1H, dd, J¼11.2, 13.6 Hz), 4.61e4.70 (2H, m),
5.41 (1H, d, J¼16.4 Hz), 7.03 (1H, d, J¼7.3 Hz), 7.10e7.39 (13H, m);
12. Hong, W.-H.; Connors, K. A. Anal. Chem. 1968, 40, 1273e1276.
13. Kuhnert, N.; Le-Gresley, A. Org. Biomol. Chem. 2005, 3, 2175e2182.
14. Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett. 2011, 13, 3278e3281.
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Chem. Soc., Perkin Trans. 1 2000, 22, 3765e3774.
13C NMRþDEPT (125 MHz, CDCl3)
¼43.4 (CH2), 45.9 (CH), 56.5
d
(CH2), 125.8 (CH), 126.7 (CH), 126.8 (CH), 128.3 (CH), 128.6 (CH),
128.9 (CH), 129.0 (CH), 129.1 (CH), 132.9 (CH), 135.2 (C), 140.3 (C),
16. Park, J. O.; Youn, S. W. Org. Lett. 2010, 12, 2258e2261.