Novel acid-mediated reactions of phenyl-substituted lactams

Article abstract of DOI:10.1016/j.tetlet.2011.10.032

Treatment of 3-phenylazetidin-2-one and 7-phenylazepin-2-one with triflic acid in benzene gave a novel, high yielding conversion to 3,3- diphenylpropionamide and 6,6-diphenylhexanoic acid amide, respectively. However, with AlCl₃, 7-phenylazepin

Full text of DOI:10.1016/j.tetlet.2011.10.032

Tetrahedron Letters 52 (2011) 6783–6784
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Novel acid-mediated reactions of phenyl-substituted lactams
⇑
Frank D. King , Stephen Caddick
Department of Chemistry, University College, 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:
Treatment of 3-phenylazetidin-2-one and 7-phenylazepin-2-one with triflic acid in benzene gave a novel,
high yielding conversion to 3,3-diphenylpropionamide and 6,6-diphenylhexanoic acid amide, respectively.
However, with AlCl3, 7-phenylazepin-2-one was converted into 3-phenylazepin-2-one via a retro-Beckman
rearrangement.
Received 14 August 2011
Revised 23 September 2011
Accepted 7 October 2011
Available online 17 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lactam
Triflic acid
Aluminium chloride
Retro-Beckman
Rearrangement
We have recently reported that amides derived from a-phenyl
N+
cyclic-amines react with triflic acid in benzene to give diph-
+
enylalkyl amides via the generation of a carbonium ion.1
Ph
O
AlCl3
N
1d
Ph
O
3
R
TfOH
Ph
Ph
N
H
N
(CH2)nCH2NHCOR
N
+
(CH2)n
H2O
Ph
Ph
Ph
n = 1-3
4
5
In this Letter we report our findings on the acid-mediated reac-
tion in benzene of the phenyl-substituted lactams 1a–d, in which
the carbonyl group has been moved from an exocyclic to an endo-
cyclic position. On heating 1a–d in benzene with 10 equiv of triflic
acid under reflux for 1 h,2 1a3 and 1d4 underwent a novel ring-
opening reaction to give good yields of 3,3-diphenylpropionamide5
2a (70% yield) and 6,6-diphenylhexanoic acid amide6 2d (88%
yield), respectively. Based on our earlier findings,1 we presume
that the reaction proceeds via the generation of a carbonium ion,
with amide as the leaving group, followed by a Friedel–Crafts type
reaction with benzene.
Scheme 1. Proposed mechanism for the conversion of 1d–5.
Neither 1b7 nor 1c8 reacted under these conditions, presum-
ably because of the greater stability of the 5- and 6-membered
rings. These results contrast with our findings for the amides of
2-phenylpyrrolidine and 2-phenylpiperidine, both of which gave
diphenylated ring-opened products, while the amide derived from
7-phenylazepine gave a mixture of mono- and di-phenyl ring-
opened products.1
When 1a was heated under reflux with AlCl3 in benzene for
1 h,2 we also obtained a good yield of 2a (73% yield). Again, neither
1b nor 1c gave any diphenylated ring-opened product. However
1d, instead of giving 2d, gave the 3-phenyl isomer 5 (Scheme 1
and 83% yield).9 We propose that the conversion of 1d into 5 pro-
ceeds via a retro-Beckman rearrangement to form the intermediate
3, which gives 5 by the alternative alkyl shift. Presumably under
these conditions a series of equilibria are established, with 5 or
iminium ion 4 being the thermodynamically more stable isomer.
There is literature precedent which supports the proposed reac-
tion shown in Scheme 1. The retro-Beckman reaction has been
reported for a 7-membered lactam in the aza-steroid field, for
O
TfOH
C6H6
Ph
Ph
HN
CONH2
(CH2)
(CH )
n
n
2
Ph
1a n = 1
1b n = 2
1c n = 3
1d n = 4
2a n=1
2d n=4
⇑
Corresponding author.
E-mail address: fd.king@btinternet.com (F.D. King).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.032

6784
F. D. King, S. Caddick / Tetrahedron Letters 52 (2011) 6783–6784
which reaction of 6 with aqueous HBr gave a mixture of products,
which included oxime 7 and ketone 8. These were formed by
hydrolysis of the intermediate related to 3.10 Under our anhydrous
conditions, hydrolysis of 3 cannot occur and is therefore available
for further transformation.
AlCl3. However, the 7-membered lactam 1d undergoes what we
believe to be a retro-Beckman reaction to form the isomeric 3-phe-
nyl lactam 5.
References and notes
1. King, F. D.; Caddick, S. Org. Biomol. Chem. 2011, 4361.
2. Experimental procedure as described in Ref. 1
C8H17
C8H17
3. Crombie, L.; Jones, R. C. F.; Haigh, D. Tetrahedron Lett. 1986, 27, 5147.
4. Lowe (III), J.A. Pfizer, US 5484917 (A), 1996; Chem. Abstr. 1996, 124, 317009.
5. Klumpp, D. A.; Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A. Org. Lett. 2004, 6,
1789.2.
6. Mp 88–89 °C (CHCl3/petroleum ether); 1H NMR (500 MHz, CDCl3) d = 1.27–1.36
(2H, m), 1.66 (2H, quintet, J = 7.6 Hz), 2.07 (2H, q, J = 7.8 Hz), 2.14 (2H, t,
J = 7.5 Hz), 3.90 (1H, t, J = 7.8 Hz), 5.50 (1H, br s), 5.98 (1H, br s), 7.13–7.35
(10H, m); 13C NMR (125 MHz, CDCl3) d = 25.2 (CH2), 27.7 (CH2), 35.5 (CH2), 35.9
(CH2), 51.3 (CH), 126.2 (CH), 128.0 (CH), 128.5 (CH), 145.1 (C), 175.9 (C); FTIR
N
X
O
H
7 X = NOH
6
8 X = O
m
= 3321, 3164, 1639, 1492, 1450, 1420, 745, 696 cmÀ1
; HRMS calcd for
C
18H21NO 267.1624 (M+), found 267.1621.
7. Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1992, 35,
285.
In conclusion, we have shown that the 4- and 7-membered phe-
nyl-substituted lactams 1a and 1d can be ring-opened by triflic
acid in benzene to give terminal diphenyl-substituted alkyl amides
2a and 2d, respectively. Amide 2a is also obtained from 1a with
8. Adapted from Ref. 4
9. Duong, T.; Prager, R. H.; Tippett, J. M.; Ward, A. D.; Kerr, D. I. B. Aus. J. Chem.
1976, 29, 2667.
10. Ahmad, M. S.; Shafiulla; Mushfiq, M. Tetrahedron Lett. 1970, 11, 2739.