The acid-mediated ring opening/cyclisation reaction of N-benzyl-α- aryl-azetidinones

Article abstract of DOI:10.1016/j.tet.2012.09.046

N-Benzyl-4-aryl-azetidinones undergo ring opening with triflic acid to form N-benzyl-cinnamamides, which either undergo cyclisation to give 5-aryl-benzazepin-3-ones or N-debenzylation to give cinnamamides.

Full text of DOI:10.1016/j.tet.2012.09.046

Tetrahedron 68 (2012) 9350e9354
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journal homepage: www.elsevier.com/locate/tet
The acid-mediated ring opening/cyclisation reaction of N-benzyl-a-aryl-
azetidinones
*
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 14 July 2012
Received in revised form 17 August 2012
Accepted 10 September 2012
Available online 13 September 2012
N-Benzyl-4-aryl-azetidinones undergo ring opening with triflic acid to form N-benzyl-cinnamamides,
which either undergo cyclisation to give 5-aryl-benzazepin-3-ones or N-debenzylation to give
cinnamamides.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azetidinone
Triflic acid
Cinnamamides
Benzazepin-3-ones
Intramolecular cyclisation
O
1. Introduction
Ph
N
H
Ph
We have recently shown that 4-aryl-azetidinones undergo ring
opening with triflic acid (TfOH) in benzene to give cinnamamides,
which undergo further reaction to give 3-phenyl-3-aryl propiona-
mides (Scheme 1), most likely via a dication.1,2
TfOH
2a
Ph
Ph
O
TfOH
C6H6
N
Ph
O
Ph
N
H
Ph
1a
Ar
C6H6
TfOH
Ph O
3a
O
TfOH
Ar
NHR
Ar
NHR
N
Ph
CHCl3
R
O
O
X
NH
+
R = H, Me
Ph
NH2
5
Scheme 1.
4a X = C=O
X = CH2
6
During our further investigations on this reaction, we found that
the N-benzyl derivative 1a (Scheme 2) also rapidly underwent
a TfOH-mediated ring opening to give N-benzylcinnamamide 2a
(85% yield). In benzene, 2a reacted further to give N-benzyl-3,3-
diphenylpropionamide 3a (83% yield), together with a small
amount (w5%) of a mixture of the benzazepinone 4a and cinna-
mamide 5. However, in CHCl3, 1a cyclised to give 4a (65% yield) and
5 (7% yield).
Scheme 2.
The ability to produce benzazepinones and derivatives related
to 4a was intriguing because such structures have potential use as
antiarrhythmics and memory enhancers,3e5 and are intermediates
to benzazepines 6, which have been reported to have opioid re-
ceptor antagonist6 and triple re-uptake inhibitor activity.7 We
were therefore interested in investigating this ring-opening/
cyclisation reaction to synthesize novel analogues for biological
evaluation.
* Corresponding author. E-mail address: fd.king@btinternet.com (F.D. King).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.046

F.D. King, S. Caddick / Tetrahedron 68 (2012) 9350e9354
9351
2. Results
Initially, we investigated what the effect of modifications of the
products were obtained. For 4f and 4g, the cinnamamides could be
separated by column chromatography. However, for 4h we could
not entirely remove all of the cinnamamide side-product. The im-
pure 4h was purified by conversion to the N-BOC derivative (65%
yield) with BOC anhydride and DMAP,8 the N-BOC derivative 7h
being readily purified by column chromatography. BOC cleavage
with HCl regenerated pure 4h in almost quantitative yield.
N-benzyl group had on the ring-opening/cyclisation reaction
(Table 1). The N-benzyl azetidinones were readily prepared from
the azetidinones using KOt-Bu and benzyl bromide in THF. One
equivalent of the benzyl bromide gave only moderate yields of the
N-benzyl derivatives (35e60%), but 3 equiv gave much improved
yields (>90%). In order to effect the ring-opening/cyclisation re-
action, the N-benzyl-azetidinones were heated under reflux in
CHCl3 with 10 equiv of TfOH for 3 h.
Br
Table 1
Acid-mediated ring opening of N-substituted-benzyl-
a
-phenyl-azetidinones 1aee
O
N
BOC
R
R
7h
N
+
5
O
O
NH
We were particularly interested in synthesizing the 2-Cl analogue
4i, as the bulk of the ortho substituent should affect the preferred
conformation of the molecule. In our previous study on the reaction
with benzene, 4-(2-chloro-phenyl)azetidinone did not ring open to
give thecinnamamide, but gave products derived from cleavage of the
amide bond.2 Inthis case, after 3hreaction, the2-chloro 1igave the N-
benzylcinnamamide (23% yield) together with a more polar complex
mixture, which from NMR spectroscopyand MS did appear to contain
4i and 5i. The 2-naphthyl 1j gave only unidentified insoluble material.
1a-e
4a-e
Entry
Lactam
R
Product
Yield %
5 Yield %
1
2
3
4
5
1a
1b
1c
1d
1e
H
4a
4b
4c
4d
4e
60
0
20
65
5
73
65
4-Me
3-Me
4-Cl
4-F
24a
0
0
a
Mixture of the 8- and 6-Me isomers in a 2:1 ratio.
3. Conclusion
In cases where there was an electron rich 4-Me 1b and electron
deficient 4-Cl 1d and 4-F 1e substituent, only N-de-benzylation was
observed with little or no evidence for cyclisation. However, the 3-
Me substituted analogue gave a 24% yield of a 2:1 mixture of the 8-
and 6-Me isomeric compounds along with 5 as a minor side-
product. From this study it would appear that this method would
be of little use for the synthesis of benzo-substituted analogues.
We then undertook an investigation on the effect of different
In summary, N-benzyl-a-phenyl-azetidinone 1a undergoes ring
opening and cyclisation with TfOH in CHCl3 to give 5-phenyl-ben-
zazepin-3-one 4a. A competing reaction is loss of the N-benzyl group
to give cinnamamide 5, which for substituted N-benzyl derivatives,
1b,1c and 1d, is the major pathway. In contrast, reaction of N-benzyl-
a-substituted-phenyl-azetidinones 1fei gives moderate to good
yields of 5-substituted-phenyl-benzazepin-3-ones 4fei. Occasion-
ally it can be difficult to separate the cinnamamide side-product, in
which case the benzazepinone can be purified by conversion to the
N-BOC derivative, followed by acid cleavage. By this ring opening/
cyclisation we have prepared novel 5-aryl-benzazepin-3-ones.
substituents in the a-phenyl group on the ring-opening/cyclisation
reaction and the results are summarised in Table 2.
Table 2
Acid-mediated ring opening of N-benzyl-
a
-substituted-phenyl-azetidinones 1fej
R
4. Experimental section
4.1. General
R
O
R
NH2
N
+
O
Ph
All reagents were commercially available, unless otherwise
specified, and used without purification. The chloroform used was
stabilized 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 FTIR spectrometer.
Solution 1H- and 13C NMR spectra in CDCl3, unless stated otherwise,
wererecorded on Bruker NMR spectrometer DRX500 equipped with
z-gradient facilities. 1H and 13C chemical shifts are given relative to
TMS. Mass spectra were run on a Thermo Mat900XP for EI and
a Waters Micromaldi for TOF. Unless otherwise specified, spectra
were recorded at 25 ꢀC. Melting points were determined on a Sanyo-
Gallenkamp capillary melting point apparatus and are uncorrected.
O
NH
1f-j
4f-j
5f-j
Entry
Lactam
R
Product
Yield %
Amide
Yield %
1
2
3
4
5
1f
1g
1h
1i
4-Me
3-Me
4-Br
2-Cl
3,4-benzo
4f
4g
4h
4i
82
56
5f
5g
5h
5i
5
<5
78
7
a
a
1j
4j
0
5j
0
a
See text.
We had previously shown that the p-methoxyphenyl azetidi-
none only gave a poor yield of ring-opened product, and phenyl
groups containing strongly electron withdrawing groups, for ex-
ample, CF3, did not undergo the TfOH-mediated ring opening/
phenylation reaction2 and therefore these examples were elimi-
nated from our investigation. For the
rivatives, 1fe1h, the TfOH-mediated cyclisation was much more
successful. In most cases, moderate to good yields of cyclised
4.2. General procedure for N-benzyl-4-arylazetidinones
To a stirred solution of the appropriate azetidinone2 (10 mmol)
and the benzyl bromide (30 mmol) in THF (100 mL) at 0 ꢀC was
added KOt-Bu (12 mmol) and the reaction stirred at room tem-
perature for 1 h. 2 M aq HCl (20 mL) and water (50 mL) were added
a-substituted-phenyl de-

9352
F.D. King, S. Caddick / Tetrahedron 68 (2012) 9350e9354
and the THF removed by rotary evaporation. The product was
extracted into DCM (3ꢁ50 mL), dried (MgSO4) and concentrated.
Purification by column chromatography on SiO2, initially eluting
with 1:1 petroleum ether/DCM to remove the excess benzyl bro-
mide, then DCM to 1% MeOH/DCM to give the product.
14.7 Hz), 3.73 (1H, d, J¼15.0 Hz), 4.36e4.39 (1H, m), 4.80 (1H, d,
J¼15.0 Hz), 7.12e7.20 (6H, m), 7.24e7.33 (3H, m); 13C NMRþDEPT
(125 MHz)
d¼21.3 (CH3), 44.6 (CH2), 46.9 (CH2), 53.4 (CH), 126.6
(CH), 127.7 (CH), 128.6 (CH), 128.8 (CH), 129.7 (CH), 134.9 (C), 135.8
(C), 138.4 (C), 167.4 (C); nmax (liquid film) 1743, 1387, 1352, 940, 822,
726, 715, 703 cmꢂ1; LRMS (EI) 251, 208, 119, 118; HRMS (EI): Mþ,
found 251.1307. C17H17NO requires 251.1305.
4.2.1. N-Benzyl-4-phenyl-azetidin-2-one (1a). Colourless oil (93%
yield); spectroscopically consistent with the literature data.9 Rf
(Et2O) 0.5; 1H NMR (500 MHz)
d
¼2.87 (1H, dd, J¼2.2, 14.7 Hz), 3.34
4.2.7. N-Benzyl-4-(3-methylphenyl)-azetidin-2-one (1g). Colourless
oil (92% yield); Rf (DCM) 0.3; 1H NMR (500 MHz)
d
¼2.30 (3H, s),
(1H, dd, J¼5.1, 14.7 Hz), 3.76 (1H, d, J¼15.0 Hz), 4.40 (1H, dd, J¼2.2,
2.87 (1H, dm, J¼14.6 Hz), 3.35 (1H, dd, J¼5.2, 14.6 Hz), 3.72 (1H, d,
J¼14.9 Hz), 4.39e4.42 (1H, m), 4.80 (1H, d, J¼14.9 Hz), 6.91e6.97
(2H, m), 7.08 (1H, d, J¼7.6 Hz), 7.18 (1H, t, J¼7.5 Hz), 7.24e7.27 (2H,
5.1 Hz), 4.80 (1H, d, J¼15.0 Hz), 7.14 (2H, d, J¼7.2 Hz), 7.20e7.40 (8H,
m); 13C NMRþDEPT (125 MHz)
¼44.8 (CH2), 47.0 (CH2), 53.6 (CH),
d
126.6 (CH), 127.8 (CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 135.6 (C),
138.0 (C), 167.3 (C).
m), 7.30e7.39 (3H, m); 13C NMRþDEPT (125 MHz)
¼21.4 (CH3),
d
44.7 (CH2), 47.0 (CH2), 53.6 (CH), 125.6 (CH), 126.6 (CH), 128.5 (CH),
128.6 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH), 135.5 (C), 138.1 (C),
138.5 (C), 167.3 (C); nmax (liquid film) 1743, 1456, 1387, 1360, 939,
766, 739, 696 cmꢂ1; LRMS (EI) 251; HRMS (EI): Mþ, found 251.1306.
C17H17NO requires 251.1305.
4.2.2. N-(4-Methylbenzyl)-4-phenyl-azetidin-2-one (1b). Colourless
oil (85% yield); Rf (Et2O) 0.5; 1H NMR (500 MHz)
d
¼2.33 (3H, s), 2.86
(1H, ddd, J¼0.8, 2.3, 14.7 Hz), 3.32 (1H, dd, J¼5.2, 14.7 Hz), 3.71 (1H,
d, J¼14.9 Hz), 4.39 (1H, dd, J¼2.3, 5.2 Hz), 4.78 (1H, d, J¼14.9 Hz),
7.03 (2H, d, J¼8.0 Hz), 7.10 (2H, d, J¼8.0 Hz), 7.23e7.27 (2H, m),
7.30e7.40 (3H, m); 13C NMRþDEPT (125 MHz)
¼21.2 (CH3), 44.5
d
4. 2. 8 . N-(Benzyl) -4-(4-bromophenyl)-azetidin-2-one
(1h). Colourless oil (89% yield); Rf (DCM) 0.3; 1H NMR (500 MHz)
(CH2), 46.9 (CH2), 53.4 (CH), 126.6 (CH), 128.5 (CH), 128.6 (CH), 129.0
(CH), 129.5 (CH), 132.6 (C), 137.5 (C), 138.1 (C), 167.2 (C); nmax (liquid
film) 1743, 1455, 1387, 1359, 770, 750, 698 cmꢂ1; LRMS (EI) 251, 105,
104; HRMS (EI): Mþ, found 251.1300. C17H17NO requires 251.1305.
d
¼2.82 (1H, dm, J¼14.7 Hz), 3.34 (1H, dd, J¼5.2, 14.7 Hz), 3.76 (1H,
d, J¼14.9 Hz), 4,35 (1H, dd, J¼2.3, 5.2 Hz), 4.77 (1H, d, J¼14.9 Hz),
7.09e7.13 (4H, m), 7.25e7.32 (3H, m), 7.48 (2H, d, J¼8.4 Hz); 13C
NMRþDEPT (125 MHz) ¼44.9 (CH2), 47.0 (CH2), 53.0 (CH), 122.5
d
(C), 127.9 (CH), 128.3 (CH), 128.7 (CH), 129.1 (CH), 132.1 (CH), 135.4
(C), 142.6 (C), 167.0 (C); nmax (liquid film) 1744, 1487, 1385, 1072,
1009, 938, 825, 717, 708, 695 cmꢂ1; LRMS (EI) 317, 315, 184, 182, 86;
HRMS (EI): Mþ, found 315.0255. C16H1479BrNO requires 315.0253.
4.2.3. N-(3-Methylbenzyl)-4-phenyl-azetidin-2-one (1c). Colourless
oil (93% yield); Rf (Et2O) 0.5; 1H NMR (500 MHz)
d
¼2.30 (3H, s), 2.87
(1H, dm, J¼14.6 Hz), 3.35 (1H, dd, J¼5.2, 14.6 Hz), 3.72 (1H, d,
J¼14.9 Hz), 4.39e4.42 (1H, m), 4.80 (1H, d, J¼14.9 Hz), 6.91e6.97
(2H, m), 7.08 (1H, d, J¼7.6 Hz), 7.18 (1H, t, J¼7.5 Hz), 7.24e7.27 (2H,
4. 2. 9. N -(Benzyl) -4-(2-chlorophenyl)-azetidin-2-one
m), 7.30e7.39 (3H, m); 13C NMRþDEPT (125 MHz)
¼21.4 (CH3),
d
(1i). Colourless oil (95% yield); Rf (DCM) 0.3; 1H NMR (500 MHz)
44.7 (CH2), 47.0 (CH2), 53.6 (CH), 125.6 (CH), 126.6 (CH), 128.5 (CH),
128.6 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH), 135.5 (C), 138.1 (C),
138.5 (C), 167.3 (C); nmax (liquid film) 1743, 1386, 1349, 777,
699 cmꢂ1; LRMS (EI) 251, 105, 104; HRMS (EI): Mþ, found 251.1300.
C17H17NO requires 251.1305.
d
¼2.79 (1H, dd, J¼2.2, 14.7 Hz), 3.42 (1H, dd, J¼5.4, 14.7 Hz), 3.92
(1H, d, J¼14.9 Hz), 4.84 (1H, d, J¼14.9 Hz), 4.87 (1H, dd, J¼2.2,
5.4 Hz), 7.18 (2H, d, J¼7.2 Hz), 7.22e7.37 (7H, m); 13C NMRþDEPT
(125 MHz)
d¼45.5 (CH2), 46.3 (CH2), 50.4 (CH), 126.6 (CH), 127.5
(CH),127.9 (CH), 128.6 (CH), 128.9 (CH), 129.3 (CH), 130.0 (CH), 133.3
(C), 135.4 (C), 136.0 (C), 167.4 (C); nmax (liquid film) 1746, 1443, 1385,
1348, 1035, 754, 709, 696 cmꢂ1; LRMS (EI) 273, 271, 140, 138; HRMS
(EI): Mþ, found 271.0753. C16H14ClNO requires 271.0758.
4.2.4. N-(4-Chlorobenzyl)-4-phenyl-azetidin-2-one (1d). Colourless
oil (87% yield); Rf (Et2O) 0.5; 1H NMR (500 MHz)
d¼2.89 (1H, ddd,
J¼0.7, 2.3, 14.7 Hz), 3.35 (1H, dd, J¼5.2, 14.7 Hz), 3.77 (1H, d,
J¼15.1 Hz), 4.39 (1H, dd, J¼2.3, 5.2 Hz), 4.75 (1H, d, J¼15.1 Hz), 7.07
(2H, d, J¼8.4 Hz), 7.20e7.27 (4H, m), 7.31e7.39 (3H, m); 13C
4.2.10. N-(Benzyl)-4-(2-naphthyl)-azetidin-2-one (1j). White solid
(88% yield), mp 85e87 ꢀC (Et2O/petroleum ether); Rf (Et2O) 0.5; 1H
NMRþDEPT (125 MHz) ¼44.2 (CH2), 47.0 (CH2), 53.8 (CH), 126.6
d
NMR (500 MHz)
d
¼2.97 (1H, dd, J¼2.2, 14.7 Hz), 3.42 (1H, dd, J¼5.2,
(CH), 126.7 (CH), 129.0 (CH), 129.1 (CH), 130.0 (CH), 133.7 (C), 134.2
(C), 137.8 (C), 167.2 (C); nmax (liquid film) 1742, 1491, 1386, 1090,
1015, 804, 768, 753, 698 cmꢂ1; LRMS (EI) 273, 271, 192, 86; HRMS
(EI): Mþ, found 271.0753. C16H1435ClNO requires 271.0758; spec-
troscopically consistent with the literature material.10
14.7 Hz), 3.81 (1H, d, J¼15.0 Hz), 4.58 (1H, dd, J¼2.2, 5.2 Hz), 4.85
(1H, d, J¼15.0 Hz), 7.16e7.19 (2H, m), 7.22e7.27 (3H, m), 7.38 (1H, dd,
J¼1.7, 8.5 Hz), 7.44e7.47 (2H, m), 7.69 (1H, s), 7.81 (1H, dd, J¼3.4,
8.5 Hz), 7.81e7.85 (2H, m); 13C NMRþDEPT (125 MHz)
¼44.9 (CH2),
d
47.0 (CH2), 53.8 (CH), 123.5 (CH), 126.3 (CH), 126.5 (CH), 126.7 (CH),
127.8 (CH), 127.9 (CH), 127.9 (CH), 128.6 (CH), 128.9 (CH), 129.2 (CH),
133.4 (C), 133.5 (C), 135.4 (C), 135.7 (C), 167.3 (C); nmax (solid) 1740,
1380,1307, 863, 829, 789, 751, 722, 703 cmꢂ1; LRMS (EI) 287,154, 91;
HRMS (EI): Mþ, found 287.1301. C20H17NO requires 287.1305.
4.2.5. N-(4-Fluorobenzyl)-4-phenyl-azetidin-2-one (1e). Colourless
oil (88% yield); Rf (Et2O) 0.5; 1H NMR (500 MHz)
d
¼2.87 (1H, ddd,
J¼0.6, 2.3 14.7 Hz), 3.33 (1H, dd, J¼5.2, 14.7 Hz), 3.78 (1H, d,
J¼15.0 Hz), 4.38 (1H, dd, J¼2.3, 5.2 Hz), 4.68 (1H, d, J¼15.0 Hz), 6.95
(2H, J¼8.7 Hz), 7.10 (2H, dd, J¼5.4, 8.6 Hz), 7.20e7.25 (2H, m),
4.3. N-Benzyl-cinnamamide 2a from 1a
7.30e7.38 (3H, m); 13C NMRþDEPT (125 MHz)
¼44.1 (CH2), 47.0
d
(CH2), 53.7 (CH), 115.6 (CH, d, J¼21.4 Hz), 126.6 (CH), 128.6 (CH),
129.1 (CH), 130.3 (CH, d, J¼8.3 Hz), 131.5 (C, d, J¼3.4 Hz), 137.9 (C),
A stirred mixture of triflic acid (0.50 mL, 5 mmol) and 1a (0.24 g,
1 mmol) in CHCl3 (10 mL) was heated under gentle reflux for
30 min. The reaction mixture was cooled to room temperature,
water (10 mL) was added and the mixture basified with an excess of
solid K2CO3. The product was extracted into DCM (2ꢁ50 mL), dried
(MgSO4), concentrated in vacuo and the product purified by column
chromatography on SiO2, eluting with DCMd1% MeOH/DCM to
give 2a (0.21 g, 85% yield), mp 106e108 ꢀC (EtOAc/petroleum ether)
(lit. 108e110 ꢀC11) identical to material prepared from cinnamoyl
chloride and benzylamine by the literature procedure.12 Rf (Et2O)
162.3 (C, d, J¼246 Hz), 167.2 (C); 19F NMR (282 MHz)
¼114.9 (tt,
d
J¼8.5, 5.6 Hz); nmax (liquid film) 1742, 1509, 1389, 1220, 1157, 840,
826, 753, 699 cmꢂ1; LRMS (EI) 255, 212; HRMS (EI): Mþ, found
251.1056. C16H14FNO requires 255.1054.
4. 2. 6. N-(Benzyl)-4-(4-methylphenyl)-azetidin-2-one
(1f). Colourless oil (90% yield); Rf (DCM) 0.3; 1H NMR (500 MHz)
d¼2.36 (3H, s), 2.85 (1H, dm, J¼14.7 Hz), 3.32 (1H, dd, J¼5.2,

F.D. King, S. Caddick / Tetrahedron 68 (2012) 9350e9354
9353
0.5; 1H NMR (500 MHz)
d
¼4.42 (2H, d, J¼5.6 Hz), 6.36 (1H, brs),
NMR (500 MHz)
d
¼2.33 (3H, s), 3.01 (1H, dd, J¼4.5, 14.4 Hz),
6.52 (1H, d, J¼15.6 Hz), 7.20e7.36 (8H, m), 7.40e7.50 (2H, m), 7.66
3.10 (1H, dd, J¼10.0, 14.4 Hz), 4.31 (1H, dd, J¼5.2, 16.0 Hz),
4.40e4.51 (2H, m), 6.92e6.96 (1H, m), 7.03 (2H, d, J¼8.1 Hz),
7.08e7.18 (5H, m), 7.88 (1H, brt, J¼5.4 Hz); 13C NMRþDEPT
(1H, d, J¼15.6 Hz); 13C NMRþDEPT (125 MHz)
¼43.9 (CH2), 120.6
d
(CH), 127.6 (CH), 127.9 (CH), 128.0 (CH), 128.8 (CH), 128.9 (CH), 129.8
(CH), 134.9 (C), 138.3 (C), 141.4 (CH), 166.0 (C).
(125 MHz)
d
¼21.2 (CH3), 41.7 (CH2), 44.3 (CH), 46.3 (CH2), 126.5
(CH), 128.1 (CH), 128.7 (CH), 129.5 (CH), 131.8 (CH), 135.9 (C),
4.4. N-Benzyl-3,3-diphenylpropionamide (3a)
136.3 (C), 141.2 (C), 142.2 (C), 175.2 (C); nmax (solid) 3270 (br),
1618, 1465, 1446, 1352, 1326, 1088, 818, 752, 721, 655 cmꢂ1
;
A stirred mixture of triflic acid (1.0 mL, 10 mmol) and 1a (0.24 g,
1 mmol) in dry benzene (10 mL) was heated under gentle reflux for
1 h. The reaction mixture was cooled to room temperature, water
(10 mL) was added and the mixture basified with an excess of solid
K2CO3. The product was extracted into DCM (2ꢁ50 mL), dried
(MgSO4), concentrated in vacuo and the product purified by column
chromatography on SiO2. Elution with DCMd0.5% MeOH/DCM
gave the title compound 3a (0.26 g, 83% yield), recrystallised from
DCM/petrol, mp 142e144 ꢀC (lit. 142e144 ꢀC) and spectroscopically
consistent with the literature material.13 Rf (Et2O) 0.5; 1H NMR
LRMS (EI) 251, 192, 86; HRMS (EI): Mþ, found 251.1306.
C17H17NO requires 251.1305.
4.5.4. 5-(m-Tolyl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(4g). White solid (56% yield); mp 158e160 ꢀC; Rf (Et2O) 0.1; 1H
NMR (500 MHz)
d
¼2.30 (3H, s), 2.95 (1H, dd, J¼4.4, 10.3 Hz), 3.12
(1H, dd, J¼10.3, 14.5 Hz), 4.27 (1H, dd, J¼5.4, 16.0 Hz), 4.46e4.55
(2H, m), 6.88e6.95 (3H, m), 7.03 (1H, d, J¼7.6 Hz), 7.08e7.21 (4H,
m); 13C NMRþDEPT (125 MHz)
¼21.6 (CH3), 41.6 (CH2), 44.8 (CH),
d
46.4 (CH2),125.3 (CH), 126.6 (CH),127.6 (CH),128.2 (CH),128.7 (CH),
128.9 (CH), 131.9 (CH), 135.7 (C), 138.4 (C), 141.1 (C), 145.1 (C), 174.9
(C); nmax (solid) 1665, 1487, 1403, 1358, 796, 778, 753, 710, 681,
657 cmꢂ1; LRMS (EI) 251, 192, 86; HRMS (EI): Mþ, found 251.1306.
C17H17NO requires 251.1305.
(500 MHz)
d
¼2.94 (2H, d, J¼7.9 Hz), 4.29 (2H, d, J¼5.7 Hz), 4.62 (1H,
t, J¼7.9 Hz), 5.68 (1H, brs), 6.86e6.92 (2H, m), 7.18e7.30 (13H, m);
13C NMRþDEPT (125 MHz)
¼43.5 (CH2), 43.5 (CH2), 47.6 (CH),
d
126.6 (CH), 127.3 (CH), 127.5 (CH), 127.9 (CH), 128.6 (CH), 128.7 (CH),
138.1 (C), 143.7 (C), 171.0 (C). Further elution with 2% MeOH/DCM
gave a product spectroscopically consistent with being a 1:1 mix-
ture of 5-phenyl-benzazepin-3-one 4a and 5 (10 mg w5% yield).
4.5.5. 5-(4-Bromophenyl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(4h). Isolated as a mixture in 85% yield, which includes 7% cin-
namamide, Rf (Et2O) 0.1. The impure product (0.55 g, 1.8 mmol)
was dissolved in DCM (30 mL), treated with BOC anhydride (0.50 g,
2.3 mmol), Et3N (0.50 mL, 3.5 mmol) and DMAP (0.24 g, 2.0 mmol)
and stirred at room temperature overnight. The solvent was re-
moved by rotary evaporation and the residue portioned between
EtOAc (50 mL) and 2 M aq H2SO4 (50 mL). The organic layer was
dried (MgSO4), concentrated and purified by column chromatog-
raphy on SiO2, eluting with DCMd5% Et2O/DCM to give the N-BOC
derivative 7h, recrystallised from DCM/petroleum ether (0.44 g,
4.5. General procedure for the TfOH-mediated ring opening/
cyclisation
Triflic acid (20 mmol) was added to a stirred solution of the
lactam or cinnamamide (2 mmol) in CHCl3 (20 mL) and the reaction
mixture was heated under gentle reflux for 3 h. The reaction mix-
ture was cooled to room temperature, water (20 mL) was added and
the mixture basified with an excess of solid K2CO3. The product was
extracted into DCM (2ꢁ50 mL), dried (MgSO4), concentrated in
vacuo and the product purified by column chromatography on SiO2
(0.5e1% MeOH/DCM).
59% yield); Rf (Et2O) 0.6; mp 133e5 ꢀC; 1H NMR (500 MHz)
d
¼1.51
(9H, s), 3.19e3.31 (2H, m), 4.56 (1H, dd, J¼5.1, 9.6 Hz), 4.96 (1H, d,
J¼16.4 Hz), 5.11 (1H, d, J¼16.4 Hz), 6.92 (2H, d, J¼8.4 Hz),
6.93e6.96 (1H, m), 7.18e7.22 (2H, m), 7.23e7.26 (1H, m), 7.39 (2H,
4.5.1. 5-Phenyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(4a). White solid (65% yield); mp 181e183 ꢀC (EtOAc/petroleum
ether) (lit. 182e3 ꢀC)3 and spectroscopically identical to the re-
d, J¼8.4 Hz); 13C NMRþDEPT (125 MHz)
¼28.1 (CH3), 45.0 (CH2),
d
45.6 (CH), 49.2 (CH2), 83.4 (C), 120.8 (C), 127.1 (CH), 128.7 (CH),
129.9 (CH), 132.0 (CH), 132.1 (CH), 134.6 (C), 138.8 (C), 144.3 (C),
151.7 (C), 171.5 (C); nmax (solid) 1709, 1483, 1391, 1367, 1284, 1239,
1143, 1100,1073,1010, 851, 831, 771, 741, 721 cmꢂ1; LRMS (TOF ESþ)
440, 438, 381, 379, 259, 257, 178; HRMS (TOF ESþ):MNaþ, found
438.0679. C21H2279BrNNaO requires 438.0681. A solution of 7h
(0.40 g) in DCM (10 mL) and 4 M HCl in dioxan (1 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 pure 4h, recrystal-
lised from EtOAc/petroleum ether (0.28 g, 95% yield), mp
ported material.6 Rf (Et2O) 0.1; 1H NMR (500 MHz)
d
¼3.02 (1H, dd,
J¼4.5, 14.4 Hz), 3.13 (1H, dd, J¼10.2, 14.4 Hz), 4.31 (1H, dd, J¼5.3,
16.1 Hz), 4.50 (1H, dd, J¼5.3, 16.1 Hz), 4.54 (1H, dd, J¼4.5, 10.2 Hz),
6.92e6.96 (1H, m), 7.08e7.30 (8H, m), 7.76 (1H, t, J¼5.3 Hz); 13C
NMRþDEPT (125 MHz) ¼41.6 (CH2), 44.6 (CH), 46.3 (CH2), 126.6
d
(CH), 126.8 (CH), 128.0 (CH), 128.2 (CH),128.6 (CH), 131.9 (CH),136.0
(C), 141.0 (C), 145.2 (C), 175.2 (C).
4.5.2. Mixture of 6-methyl-5-phenyl-1,2,4,5-tetrahydro-benzo[c]aze-
pin-3-one and 8-methyl-5-phenyl-1,2,4,5-tetrahydro-benzo[c]azepin-
3-one (4c). Elution with 1% MeOH/DCM gave the product mixture
4c, as a colourless oil (24% yield); Rf (Et2O) 0.1; 1H NMR (500 MHz)
181e183 ꢀC; 1H NMR (500 MHz)
d
¼3.07 (2H, d, J¼7.0 Hz), 4.39 (1H,
dd, J¼5.2,16.2 Hz), 4.50 (1H, dd, J¼5.2, 16.2 Hz), 4.52 (1H, t,
J¼7.0 Hz), 6.60 (1H, brm), 6.85e6.88 (1H, m), 6.99 (2H, d, J¼8.4 Hz),
7.09e7.13 (1H, m), 7.15e7.20 (2H, m), 7.40 (2H, d, J¼8.4 Hz); 13C
d
¼2.00 (1H, s), 2.29 (2H, s), 2.90e3.20 (2H, m), 4.19e4.60 (3H, m),
6.80e7.40 (9H, m), 13C NMRþDEPT (125 MHz)
d
¼minor isomer,
NMRþDEPT (125 MHz) ¼41.3 (CH2), 44.5 (CH), 46.5 (CH2), 120.8
d
20.7 (CH3), 41.9 (CH2), 42.5 (CH), 47.1 (CH2); major isomer, 20.9
(CH3), 41.7 (CH2), 44.6 (CH), 46.5 (CH2): unassignedd126.5 (CH),
126.7 (CH),126.8 (CH),127.0 (CH),127.6 (CH),128.2 (CH), 128.7 (CH),
128.7 (CH), 128.9 (CH), 129.4 (CH), 131.1 (CH), 131.9 (CH), 135.6 (C),
136.2 (C), 136.3 (C),137.8 (C),138.3 (C),144.0 (C), 145.4 (C),175.0 (C);
nmax (liquid film) 1164, 1649, 1488, 1446, 778, 743, 726, 710, 699,
682, 657 cmꢂ1; LRMS (EI) 251, 192, 86; HRMS (EI): Mþ, found
251.1308. C17H17NO requires 251.1305.
(C), 126.9 (CH), 128.4 (CH), 128.8 (CH), 129.9 (CH), 131.9 (CH), 132.0
(CH), 135.6 (C), 140.2 (C), 144.1 (C), 174.1 (C); nmax (solid) 1666,
1486, 1407, 1353, 1329, 1072, 1011, 808, 771, 761, 738, 653 cmꢂ1
;
LRMS (EI) 317, 315, 258, 256, 88, 86; HRMS (EI): Mþ, found
315.0254. C16H14BrNO requires 315.0253.
Acknowledgements
4.5.3. 5-(p-Tolyl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
The authors would like to thank Dr. Lisa D. Haigh for the mass
spectra and Dr. Abil E. Aliev for assistance with NMR interpretation.
(4f). White solid (82% yield); mp 190e191 ꢀC; Rf (Et2O) 0.1; 1H

9354
F.D. King, S. Caddick / Tetrahedron 68 (2012) 9350e9354
5. Johnson, R. E.; Busacca, C. A. Tetrahedron Lett. 1992, 33, 165e168.
Supplementary data
6. Wuensch, P.; Hasebein, P.; Schepmann, D.W.O. Patent 2010012812A1, 2010;
Chem. Abstr. 2010, 152, 238800.
Supplementary data contains NMR (1H and 13C) spectra for
1bej, 2a, 3a, 4a, 4c, 4g, 4h and 7h. Supplementary data related to
this article can be found online at http://dx.doi.org/10.1016/
j.tet.2012.09.046.
7. Molino, B.F.; Liu, S.; Sambandam, A.; Guzzo, P.R.; Hu, M.; Zha, C.; Nacro, K.;
Manning, P.D.; Isherwood, M.L.; Fleming, K.N.; Cui, W.; Olson, R.E.W.O. Patent
2007011820A2, 2007; Chem. Abstr. 2007, 146, 184383.
8. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48, 2424e2426.
9. Ahn, C.; Kennington, J. W.; DeShong, P. J. Org. Chem. 1994, 59,
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