A facile access to the 1,5-dihydro- and 1,3,4,5-tetrahydro,benzo[b]azepin-2-one ring systems via a new ring enlargement

Article abstract of DOI:10.1055/s-2002-32948

Synthesis of a 1,5-dihydro-benzo[b]azepin-2-one is reported. The key reaction is a silver nitrate-induced rearrangement of N-benzyl quinolinium bromide. Its reduction leads to the 1,3,4,5-tetrahydro-benzo[b] azepin-2-one ring system found in several pharm

Full text of DOI:10.1055/s-2002-32948

1350
LETTER
A Facile Access to the 1,5-Dihydro- and 1,3,4,5-Tetrahydro-benzo[b]azepin-2-
one Ring Systems via a New Ring Enlargement
1
, 5-Dihydro- and 1,3,4
i
,5-Tetr
c
ahydro-be
n
k
zo-[
b
]azepin
a
-2-one Rin
ë
Laboratoire de Synthèse Organique, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208- 44322 Nantes Cedex 03,
France
Fax +33(251)125402; E-mail: Andre.Guingant@chimie.univ-nantes.fr
Received 12 April 2002
diltiazem (e.g. CGS 14831, Scheme 1). Other members of
Abstract: Synthesis of a 1,5-dihydro-benzo[b]azepin-2-one is re-
this family exhibit activities as human growth hormone
ported. The key reaction is a silver nitrate-induced rearrangement of
N-benzyl quinolinium bromide. Its reduction leads to the 1,3,4,5-
tetrahydro-benzo[b] azepin-2-one ring system found in several
(hGH) secretagogues3 and calcium channel blockers
(CCBs).4
pharmacological important compounds.
Key words: quinolinium salt, silver nitrate, 1,5-dihydro-ben-
zo[b]azepin-2-one, 1,3,4,5-tetrahydro-benzo[b] azepin-2-one, ring
enlargement
1,3,4,5-tetrahydro-benzo[b]azepin-2-one derivatives are
attractive targets in medicinal chemistry due to their wide
ranging biological activities. Several compounds having
Scheme 1 The 1,3,4,5-tetrahydro-benzo[b]azepin-2-one skeleton.
the common subunit 1 were demonstrated to exhibit activ-
ity against cyclin-dependent kinases (CDKs) and the an-
giotensin-converting enzyme (ACE). This is the case, for
example, for the paullone group1 and for compounds2
which are structural analogues of the benzothiazepinone
In the course of an ongoing synthetic investigation we re-
quired efficient access to the 1,5-dihydro-benzo[b]azepin-
2-one 5 (Scheme 2). Although the known 1H-ben-
zo[b]azepine-2,5-dione appeared, at the onset, as an ideal
Leaving group
X
H
X
O
masked
carbonyl group
X
acidic
hydrogen
X = Cl,Br,I
MeO
a
MeOH
N
O
a
O
Bn
b
5
N
N
b
O
c
Br
Ph
Ph
OMe
3
4
MeOH
N
O
Bn
6
7
c
OMe
N
Bn
O
Scheme 2 Reaction of quinolinium salt 3 with a [ CO] equivalent: the three possible pathways.
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1350,1352,ftx,en;D07902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
1,5-Dihydro- and 1,3,4,5-Tetrahydro-benzo-[b]azepin-2-one Ring Systems
1351
starting material, the low yield (<10%) of its preparation yield along with unreacted salt (12%) and small amounts
from naphthoquinone5 led us to devise a different strategy of 1-methylquinolin-2(1H)-one. The trichloromethyl an-
that would allow for the preparation of the target com- ion could also be generated by decarboxylation of sodium
pound in useful quantities. We reasoned that the 1,2-addi- trichloroacetate induced by sonication at 20 °C in acetoni-
tion reaction of a potential [ CO] equivalent to a trile as reported by Grignon–Dubois et al.8 Methyl quino-
quinolinium salt would give a transient carbonyl cation linium bromide reacted under these conditions to give the
equivalent 4 which, in the presence of an extra nucleo- 1,2 addition product in good yield (70%). With these re-
phile (e.g. MeOH), could rearrange towards the desired sults in mind we first prepared the 1,2-dihydro-quinoline
lactam compound 5 (path a, Scheme 2). Of course, we 8 from salt 3 by using the Duchardt–Kröhnke protocol
were aware that the reaction could follow a different (CH3CN/H2O, 1/1, r.t.). This somewhat unstable deriva-
course to give the 1-benzyl-3-methoxy-1,3-dihydro-ben- tive was not purified but diluted in methanol and treated
zo[b]azepin-2-one 6 or the 1,2-dihydro-quinoline-2-car- with an excess of silver nitrate (3 equiv in water, r.t., 1h)
boxylic acid methyl ester 7 (path b and c, respectively, to give a new compound which was isolated in 50% over-
Scheme 2).
all yield after purification by flash column chromatogra-
phy on silica. Its IR, mass and NMR data9 were consistent
with a structure like 5 (rather than 6) and definitely ex-
cluded the formation of the ester candidate 7.
We disclose herein that the anticipated reaction, pictured
in Scheme 2, can be accomplished via a new ring enlarge-
ment to give the 1,5-dihydro-benzo[b]azepin-2-one 5 as
the sole identified compound.
In order to firmly establish its structure, the presumed lac-
tam 5 was catalytically reduced (quantitative yield) and
the resulting product compared to the 1,3,4,5-tetrahydro-
benzo[b]azepin-2-ones 9 and 10 (Scheme 3), which were
synthesised by non-ambiguous routes.
As depicted in Scheme 2, bromoform certainly represents
the most simple [ CO] synthetic equivalent. The literature
reports few examples of the addition of CX3 anions to
quinolinium salts. In 1977, Duchardt and Kröhnke6 first
reported that trihalogenomethyl anions (X = Cl, Br), gen- Thus, the lactam 9 was prepared from the known keto-lac-
erated by the action of potassium hydroxide on the corre- tam 1110 in a straightforward three-step sequence, which
sponding haloform, added to 1-ethyl- or 1-(2,6-dichloro- entails N-benzylation, reduction of the carbonyl group (
benzyl)-quinolinium bromides to give the 1,2-addition 12) and methylation of the resulting alcohol. For the prep-
products in good yields (80–85%). More recently, Maeda7 aration of an authentic sample of lactam 10, the known
described the reaction of trichloromethyl anion (from hydroxy ketone 1311 was O-methylated and then subject-
chloroform and methanolic KOH) with 1-methylquinolin- ed to the action of hydroxylamine to yield oxime 14. Sub-
ium iodide. The 1,2- addition product was isolated in 66% sequent Beckman rearrangement12 and N-benzylation
Scheme 3 Ring enlargement induced by silver nitrate.
Scheme 4 Synthesis of reference compounds 9 and 10. Reagents and conditions: (i) NaH, BnBr, DMF, r.t., 16 h (26%); (ii) NaBH4, MeOH,
r.t., 15 min (95%); (iii) NaH, MeI, DMF, r.t., 15 min (89%); (iv) Ag2O, MeI, CH3CN, reflux, 16 h (83%); (v) NH2OH HCl, MeOH, r.t., 36 h
(71%); (vi) PPA, 80 °C, 1 h (45%); (vii) NaH, BnBr, DMF, r.t., 16 h (84%).
Synlett 2002, No. 8, 1350–1352 ISSN 0936-5214 © Thieme Stuttgart · New York

1352
M. Pauvert et al.
LETTER
Scheme 5 Mechanistic interpretation.
(6) Duchardt, K. H.; Kröhnke, F. Chem. Ber. 1977, 110, 2669.
(7) Maeda, M. Chem. Pharm. Bull. 1990, 38, 2577.
(8) Grignon-Dubois, M.; Diaba, F.; Grellier-Marly, M.-C.
Synthesis 1994, 800.
ultimately delivered lactam 10 (Scheme 4). With the key
lactams 9 and 10 in hands13 it became easy to recognise 5
as the compound arising from the action of silver nitrate
on the 1-benzyl-2-tribromomethyl-1,2-dihydro-quinoline
8 (Scheme 3). This result can be accommodated by the
mechanism shown in Scheme 5. Thus, we believe that the
six-membered ring enlargement14 proceeds via the silver-
induced formation of a transient aziridinium species 15,
which rearranges by regioselective attack of MeOH at car-
bon C4 and subsequent cleavage of the C2–N bond to give
the water-sensitive , -dibromoamine 16, ultimately
transformed in1,5-dihydro-benzo[b]azepin-2-one 5.
(9) Spectral Data for Compound 5:
IR (KBr): 1659, 1615, 1595 cm–1. 1H NMR (200 MHz,
CDCl3): = 3.40 (s, 3 H, OCH3), 4.82 (br s, 1 H, CHOCH3),
5.08 and 5.40 (AB system, J = 15.2 Hz, 2 H, NCH2), 5.84 (d,
J = 11.2 Hz, 1 H, COCH=CH), 6.51 (dd, J = 11.2 and 4.0
Hz, 1 H, COCH=CH), 7.05–7.45 (m, 9 H, Ar). 13C NMR (50
MHz, CDCl3): = 52.4, 57.7, 77.2, 121.3, 122.6, 123.1,
125.7, 127.3, 127.4, 127.5 (2 C), 128.5 (2 C), 137.7, 138.3 (2
quaternary carbons), 146.1, 166.5. MS: m/z (relative
intensity) = 279(8) [M+], 264(19), 246(30), 91(100), 65(18).
HRMS (SIMS) calcd for C18H17NO2 + H: 280.1338; found:
280.1342.
In conclusion, we have reported a novel ring homologa-
tion that permits the easy formation of both 1,5-dihydro-
and 1,3,4,5-tetrahydro-benzo[b]azepin-2-one ring sys-
tems in a few steps from quinoline. Work is now in
progress to exploit and expand the synthetic usefulness of
the new rearrangement and details will be reported in due
course.
(10) (a) MacPhillamy, H. B.; Dziemian, R. L.; Lucas, R. A.;
Kuehne, M. E. J. Am. Chem. Soc. 1958, 80, 2172.
(b) Kunick, C. Arch Pharm. 1991, 324, 579.
(11) (a) Hauser, F. M.; Prasanna, S. Synthesis 1980, 621.
(b) Baskaran, S.; Das, J.; Chandrasekaran, S. J. Org. Chem.
1989, 54, 5182.
(12) For a close example of Beckmann rearrangement, see ref.2b
(13) Spectral Data for Compounds 9 and 10:
9: IR (KBr): 1667 cm–1. 1H NMR (200 MHz, CDCl3):
= 1.70–1.90 (m, 1 H, CH2CHOCH3), 2.15–2.35 (m, 2 H,
CH2CO), 2.45–2.65 (m, 1 H, CH2CHOCH3), 3.06 (s, 3 H,
OCH3), 4.01 (dd, J = 10.4 and 6.8 Hz, 1 H, CHOCH3), 4.63
and 5.37 (AB system, J = 14.4 Hz, 2 H, NCH2), 7.10–7.35
(m, 9 H, Ar). 13C NMR (50 MHz, CDCl3): = 31.8, 35.4,
51.3, 57.6, 77.5, 123.3, 124.6, 126.7, 127.5, 128.1, 128.5 (4
C; the ortho and meta carbons of the phenyl ring are
identical), 135.9, 137.6, 140.5, 172.6. MS: m/z (relative
intensity) = 281(24) [M+], 194(58), 130(100), 91(90),
65(22). HRMS (SIMS) calcd for C18H19NO2 + H: 282.1494;
found: 282.1491.
References
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Portmann, R. E.; Sedelmeier, G. H.; Wetter, H. F. Helv.
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10: IR (KBr): 1674 cm–1; 1H NMR (200 MHz, CDCl3):
= 2.00–2.20 (m, 1 H of the CH2CH2 motif), 2.30–2.60 (m,
3 H of the CH2CH2 motif), 3.32 (s, 3 H, OCH3), 3.70–3.85
(m, 1 H, CHOCH3), 4.90 and 5.24 (AB system, J = 14.8 Hz,
2 H, NCH2), 7.05–7.30 (m, 9 H, Ar). 13C NMR (50 MHz,
CDCl3): = 27.8, 36.2, 51.8, 57.9, 78.1, 123.1, 126.7, 127.5,
127.8, 128.3 (2 C), 128.5 (2 C), 129.1, 136.1, 137.6, 140.7,
171.6. MS: m/z (relative intensity) = 281(96) [M+], 132(79),
118(76), 91(100), 65(20). HRMS (SIMS) calcd for
C18H19NO2 + H: 282.1494; found: 282.1495.
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Synlett 2002, No. 8, 1350–1352 ISSN 0936-5214 © Thieme Stuttgart · New York