An Efficient Synthesis of Methyl 3-Carboxy-2-oxohexahydroazepine-1-acetate

Article abstract of DOI:10.1081/SCC-120027270

The title compound 1 is prepared from ε-caprolactam in a five-step sequence involving N-alkylation of the azepine ring from a 3-(phenylselanyl)-3-(benzyloxycarbonyl) derivative 4 and the generation of the 3-carboxyazepine moiety from the resulting diester

Full text of DOI:10.1081/SCC-120027270

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An Efficient Synthesis of Methyl 3-Carboxy-2-
oxohexahydroazepine-1-acetate
Rosa Griera a , Joan Huguet b & Joan Bosch a
a Laboratory of Organic Chemistry, Faculty of Pharmacy , University of Barcelona , Av.
Joan XXIII s/n, 08028, Barcelona, Spain
b Laboratorios Vita S.A. , Sant Joan Despí , Barcelona, Spain
Published online: 18 Oct 2011.
To cite this article: Rosa Griera , Joan Huguet & Joan Bosch (2004) An Efficient Synthesis of Methyl 3-Carboxy-2-
oxohexahydroazepine-1-acetate, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:2, 323-330, DOI: 10.1081/SCC-120027270
To link to this article: http://dx.doi.org/10.1081/SCC-120027270
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 2, pp. 323–330, 2004
An Efficient Synthesis of Methyl 3-Carboxy-
2-oxohexahydroazepine-1-acetate
Rosa Griera,1 Joan Huguet,2 and Joan Bosch1,
*
1Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, Barcelona, Spain
2
´
Laboratorios Vita S.A., Sant Joan Despı, Barcelona, Spain
ABSTRACT
The title compound 1 is prepared from 1-caprolactam in a five-step
sequence involving N-alkylation of the azepine ring from a 3-
(phenylselanyl)-3-(benzyloxycarbonyl) derivative 4 and the generation
of the 3-carboxyazepine moiety from the resulting diester 5 by ozonolysis
followed by catalytic hydrogenation.
Key Words: Methyl 3-carboxy-2-oxohexahydroazepine-1-acetate; ACE
inhibitors; NEP inhibitors, 1-Caprolactam.
*
Correspondence: Joan Bosch, Laboratory of Organic Chemistry, Faculty of
Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain;
E-mail: joanbosch@ub.edu.
323
DOI: 10.1081/SCC-120027270
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Griera, Huguet, and Bosch
The synthesis of angiotensin-coverting enzyme (ACE) and neutral
endopetidase (NEP) inhibitors has received a considerable attention during the
last decade.[1–4] Many of these compounds, for instance omapatrilat,[5]
incorporate a core seven-membered lactam ring. We report here a convenient
and efficient preparation of 3-carboxyazepinone 1, an interesting building
block for the synthesis of new potential dual ACE/NEP inhibitors.
Starting from the commercially available 1-caprolactam, the synthesis
requires the introduction of carboxy group and the acetate chain on the
carbonyl a carbon and the nitrogen, respectively, of the azepinone ring. These
apparently simple synthetic transformations were performed following the
multistep sequence depicted in Sch. 1. A latent carboxy group, in the form of
benzyl ester, was introduced at the beginning of the synthesis from an
N-protected lactam, whereas alkylation of the nitrogen was performed from a
Scheme 1.

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Synthesis of Methyl 3-Carboxy-2-oxohexahydroazepine-1-acetate
325
3,3-disubstituted azepinone derivative to avoid the alkylation at the a-position
of the b-dicarbonyl system. We used a benzyl ester to avoid hydrolytic
conditions during the deprotection step, and a phenylselanyl group to block
the azepinone 3-position because this group can be easily introduced on the
carbonyl a-carbon and then easily removed by ozonolysis, generating a
carbon–carbon double bond.
Thus, sequential treatment of the N-silylated lactam 3, prepared as
reported previously,[6] with LDA (2.3 equiv), benzyl chloroformate, and
phenylselanyl chloride gave the 3,3-disubstituted azepinone 4 in 66% yield.
Alkylation of 4 with potassium hydride and methyl bromoacetate satis-
factorily afforded (65% yield) the azepine-1-acetate 5, which was converted
by ozonolysis to the unsaturated lactam 6 in essentially quantitative yield.
Finally, hydrogenation of 6 in the presence of palladium on charcoal brought
about both the reduction of carbon–carbon double bond and the hydro-
genolysis of the benzyl ester to give the target lactam acid 1 in 90% yield.
An alternative route to unsaturated lactam 6, involving the alkylation of
the nitrogen from unsaturated lactam 7 was not successful. Thus, although 7
could be prepared in good yield (76%) by ozonolysis of the seleno derivative
4, all attempts to convert 7 to azepine-1-acetate 6 by alkylation with methyl
bromoacetate resulted in failure. The use of LiHMDS as the base was
ineffective, whereas with KH the alkylation took place at the carbonyl a
carbon to give the C-alkylated lactam 8 (Sch. 2), a result that can be rational-
ized by considering the high acidity of the protons at the 5-position of the ring,
which are activated by two carbonyl groups. When an excess (2 equiv) of KH
Scheme 2.

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Griera, Huguet, and Bosch
and methyl bromoacetate was used, the C, N-dialkylated azepinone 9 was
isolated in 40% yield.
EXPERIMENTAL
Melting points were determined in a capillary tube and are uncorrected.
Unless otherwise indicated, NMR spectra were recorded at 200 or 300 MHz
(1H) and 50.3 or 75 MHz (13C), and chemical shifts are reported in d values
downfield from TMS. Only noteworthy IR absorptions are listed. Thin-layer
chromatography was done on SiO2 (silica gel 60 F254), and the spots were
located with aqueous potassium permanganate solution. Column chromatog-
raphy was carried out using the flash chromatography technique. All non-
aqueous reactions were performed under inert atmosphere. Solvents for
chromatography were distilled at atmospheric pressure prior to use and dried
following standard procedures. Drying of the organic extracts during the
workup of reactions was performed over anhydrous Na2SO4 or MgSO4.
Evaporation of solvents was accomplished with a rotatory evaporator. Micro-
´
analyses were performed by Centre d’Investigacio i Desenvolupament
(CSIC), Barcelona.
Benzyl 2-oxo-3-(phenylselanyl)hexahydro-1H-azepine-3-carboxylate
(4). A solution of 1-(trimethylsilyl)-azepin-2-one[6] (3, 2.6 g, 13.8 mmol) in
anhydrous THF (30 mL) was slowly added at 2788C to a solution of LDA
(21 mL, 1.5 M in THF, 31.8 mmol), and the resulting mixture was stirred for
45 min. Then, benzyl chloroformate (2.5 mL, 15 mmol) in THF (30 mL) and,
after 30 min of continuous stirring at 2788C, PhSeCl (3.4 g, 18 mmol) in THF
(30 mL) were sequentially added to the solution. The resulting mixture was
stirred at 2788C for 2 h and at room temperature for 1 h, and poured into
water. The aqueous solution was extracted with Et2O, and the combined
organic extracts were washed with brine, dried, and concentrated. The residue
was chromatographed (1 : 1 EtOAc-hexane) to give 4 (3.7 g, 66%). Mp 117–
1
1188C. IR (KBr) 1718, 1655 cm21; H-NMR (CDCl3, 200 VMHz) d 1.41–
1.71 (m, 4H), 1.92–2.17 (m, 2H), 2.66–2.82 (m, 1H), 2.95–3.10 (m, 1H),
5.23 (s, 2H), 6.27 (brs, 1H, NH), 7.20–7.41 (m, 10H); 13C-NMR (CDCl3,
50.3 MHz) d 26.69 (CH2), 28.57 (CH2), 32.68 (CH2), 41.83 (CH2), 60.78 (C),
66.93 (CH2), 128.10 (C), 128.20 (CH), 128.33 (CH), 128.47 (CH), 129.48
(CH), 135.24 (C), 138.83 (CH), 168.08 (C), 172.95 (C). Anal. Calcd for
C20H21NO3Se: C, 59.70; H, 5.26; N, 3.48. Found: C, 59.75; H, 5.52; N, 3.49.
Methyl
3-(benzyloxycarbonyl)-2-oxo-3-(phenylselanyl)hexahydro-
1H-azepine-1-acetate (5). A solution of hexahydroazepine (4) (560 mg,
1.37 mmol) in THF (10 mL) was slowly added at 08C to a suspension of KH
(370 mg, 30% dispersion in mineral oil, 2.7 mmol) in THF (10 mL). After

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327
30 min of stirring, methyl bromoacetate (267 mL, 2.7 mmol) was added, the
temperature was slowly raised to 258C, and stirring was continued for another
2 h. Then, water (10 mL) was slowly added, and the aqueous solution was
extracted with EtOAc. The combined organic extracts were dried and concen-
trated under reduced pressure. The resulting crude oil was chromatographed
(hexane to 25 : 75 EtOAc-hexane) to give the alkylated product 5 (430 mg,
65%). IR (film) 1766, 1723, 1644 cm21; 1H-NMR (CDCl3, 300 MHz) d 1.57–
1.79 (m, 4H), 2.01–2.17 (m, 2H), 2.99–3.16 (m, 2H), 3.68 (s, 3H), 4.01
(d, J ¼ 16 Hz, 1H), 4.33 (d, J ¼ 16 Hz, 1H), 5.23 (s, 2H), 7.23–7.40 (m, 10H);
13C-NMR (CDCl3, 75.4 MHz) d 25.91 (CH2), 26.71 (CH2), 32.40 (CH2), 50.30
(CH2), 51.89 (CH3), 52.00 (CH2), 61.10 (C), 66.80 (CH2), 128.50 (C), 128.13
(CH), 128.31 (CH), 128.37 (CH), 129.36 (CH), 135.10 (C), 138.67 (CH),
167.83 (C), 169.12 (C), 170.33 (C). Anal. Calcd for C23H25NO5Se.3/4 H2O:
C, 56.52; H, 5.47; N, 2.87. Found: C, 56.54; H, 5.36; N, 2.64.
Methyl 3-(benzyloxycarbonyl)-2-oxo-2,5,6,7-tetrahydro-1H-azepine-
1-acetate (6). A stream of ozone gas was bubbled through a cooled (2788C)
solution of selenide 5 (430 mg, 0.9 mmol) in anhydrous CH2Cl2 (25 mL) until
it turned pale blue. The solution was purged with Ar, and the temperature was
slowly raised to 258C. After 30 min of stirring, the mixture was poured into
brine (20 mL), and the aqueous solution was extracted with CH2Cl2. The
combined organic extracts were dried and concentrated under reduced
pressure. The resulting crude oil was chromatographed (1 : 1 EtOAc-hexane)
to give tetrahydroazepine 6 (280 mg, 98%) as an oil. IR (film) 1732, 1651,
1620 cm21; 1H-NMR (CDCl3, 200 MHz) d 1.96–2.09 (ddd, J ¼ 6.6, 6.6 and
13.4 Hz, 2H), 2.46–2.57 (dd, J ¼ 7.4 and 14.8 Hz, 2H), 3.35–3.42 (t,
J ¼ 6.6 Hz, 2H), 3.74 (s, 3H), 4.30 (s, 2H), 5.25 (s, 2H), 7.32–7.40 (m, 5H);
13C-NMR (CDCl3, 50.3 MHz) d 23.44 (CH2), 27.82 (CH2), 47.61 (CH2), 48.89
(CH2), 52.04 (CH3), 66.45 (CH2), 127.69 (CH), 127.84 (CH), 128.24 (CH),
131.43 (C), 135.58 (C), 145.25 (CH), 163.56 (C), 166.31 (C), 169.54 (C).
.
Anal. Calcd for C17H19NO5 1/3 H2O: C, 63.16; H, 5.86; N, 4.37. Found: C,
63.05; H, 5.86; N, 4.37.
1-(Methoxycarbony1methy1)-2-oxohexahydro-1H-azepine-3-carboxylic
acid (1). A mixture of benzyl ester 6 (280 mg, 0.87 mmol) and 10% Pd-C
(50 mg) in EtOAc (10 mL) was stirred under H2 for 15 h at room temperature.
The mixture was filtered through Celite, and the filtrate was evaporated to
afford the acid 1 (180 mg, 90%) as an oil. IR (film) 1747, 1648 cm21; 1H-NMR
(CDCl3, 300 MHz) d 1.76–1.88 (m, 4H), 2.10–2.15 (m, 1H), 2.34–2.42 (m,
1H), 3.24–3.34 (m, 1H), 3.51–3.56 (m, 1H), 3.75–3.78 (m, 1H), 3.77 (s, 3H,
OCH3), 4.22 (s, 2H, CH2N); 13C-NMR (CDCl3, 75.4 MHz) d 26.26 (CH2),
28.37 (CH2), 28.90 (CH2), 47.40 (CH2), 50.60 (CH2), 50.84 (CH2), 52.28
.
(CH3), 168.83 (C), 172.53 (C), 175.41 (C). Anal. Calcd for C10H15NO5 1/2
H2O: C, 50.42; H, 6.77; N, 5.88. Found: C, 50.38; H, 6.76; N, 5.83.

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Griera, Huguet, and Bosch
Benzyl 2-oxo-2,5,6,7-tetrahydro-1H-azepine-3-carboxylate (7). A
stream of ozone gas was bubbled through a cooled (2788C) solution of
selenide 4 (1.0 g, 2.5 mmol) in anhydrous CH2Cl2 (40 mL) until it turned pale
blue. The solution was purged with Ar, and the temperature was slowly raised
to 258C. After 30 min of stirring, the mixture was poured into brine (20 mL),
and the aqueous solution was extracted with CH2Cl2. The combined organic
extracts were dried and concentrated under reduced pressure. The resulting
crude oil was chromatographed (1 : 1 EtOAc-hexane to EtOAc) to give
tetrahydroazepine 7 (463 mg, 76%) as a solid. Mp 86–878C. IR (KBr) 3213,
1715, 1668 cm21 1H-NMR (CDCl3, 200 MHz) d 1.85-1.98 (ddd, J ¼ 6.6, 6.6
and 13.6 Hz, 2H), 2.36–2.48 (dd, J ¼ 7.4 and 14.2 Hz, 2H), 3.15–3.24
(dd, J ¼ 6.6 and 12.6 Hz, 2H), 5.25 (s, 2H), 7.33–7.40 (m, 5H); 13C-NMR
(CDCl3, 50.3 MHz) d 24.27 (CH2), 28.59 (CH2), 39.30 (CH2), 66.80 (CH2),
128.05 (CH), 128.11 (CH), 128.46 (CH), 131.54 (C), 135.68 (C), 145.97 (CH),
163.96 (C), 168.93 (C). Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N,
5.71. Found: C, 68.63; H, 6.14; N, 5.78.
Methyl 3-(benzyloxycarbonyl)-2-oxo-2,3,6,7-tetrahydro-1H-azepine-
3-acetate (8). A solution of tetrahydroazepine 7 (400 mg, 1.6 mmol) in THF
(10 mL) was slowly added at 08C to a suspension of KH (216 mg, 30%
dispersion in mineral oil, 1.6 mmol) in THF (10 mL). After 30 min of stirring,
methyl bromoacetate (156 mL, 1.6 mmol) was added, the temperature was
slowly raised to 258C, and stirring was continued for another 2 h. Then, water
(5 mL) was added, and the aqueous solution was extracted with EtOAc. The
combined organic extracts were dried and concentrated under reduced
pressure. The resulting crude oil was chromatographed (1 : 1 EtOAc-hexane to
7 : 3 EtOAc-hexane) to give 8 (200 mg, 40%). IR (film) 3358, 1732, 1667,
1
1651 cm21; H-NMR (CDCl3, 200 MHz) d 2.14–2.34 (m, 2H), 2.98–3.04
(m, 3H), 3.30–3.49 (m, 1H), 3.61 (s, 3H), 5.20 (s, 2H), 5.50 (d, J ¼ 10 Hz,
1H), 5.90 (d, J ¼ 10 Hz, 1H), 6.56 (brs, 1H), 7.30–7.36 (m, 5H); 13C-NMR
(CDCl3, 50.3 MHz) d 29.47 (CH2CH2), 38.48 (CH2), 42.15 (CH2), 51.77
(CH3), 56.67 (C), 67.66 (CH2), 125.38 (CH), 128.20 (CH); 128.32 (CH),
128.47 (CH), 131.46 (CH), 135.18 (C), 170.29 (C), 170.96 (C), 171.85 (C).
.
Anal. Calcd for C17H19NO5 1/3 H2O: C, 63.16; H, 6.13; N, 4.33. Found: C,
63.04; H, 6.35; N, 4.22.
Dimethyl 3-(benzyloxycarbonyl)-2-oxo-2,3,6,7-tetrahydro-1H-aze-
pine-1,3-diacetate (9). A solution of tetrahydroazepine 7 (1 g, 4 mmol) in
THF (50 mL) was slowly added at 08C to a suspension of KH (1.08 g, 30%
dispersion in mineral oil, 8 mmol) in THF (50 mL). After 30 min of stirring,
methyl bromoacetate (780 mL, 8 mmol) was added, the temperature was
slowly raised to 258C, and stirring was continued for another 2 h. Then, water
(50 mL) was slowly added, and the aqueous solution was extracted with
EtOAc. The combined organic extracts were dried and concentrated under

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329
reduced pressure. The resulting crude oil was chromatographed (hexane to
1 : 1 EtOAc-hexane) to give the dialkylated compound 9 (620 mg, 40%). IR
1
(film) 1732, 1651 cm21; H-NMR (CDCl3, 200 MHz) d 2.03–2.16 (m, 1H),
2.43–2.60 (m, 1H), 2.97–3.04 (m, 2H), 2.98 (s, 2H), 3.58 (s, 3H), 3.64 (s, 3H),
3.73–3.89 (m, 1H), 4.01 (d, J ¼ 17.6 Hz, 1H), 4.26 (d, J ¼ 17.6 Hz, 1H), 5.19
(s, 3H), 5.51 (d, J ¼ 12 Hz, 1H), 5.76 (d, J ¼ 12 Hz, 1H), 7.28–7.34 (m, 5H);
13C-NMR (CDCl3, 50.3 MHz) d 28.08 (CH2), 42.86 (CH2), 46.74 (CH2),
51.20 (CH2), 51.75 (CH3), 52.10 (CH3), 56.78 (C), 67.67 (CH2), 125.51 (CH),
128.25 (CH), 128.27 (CH), 128.42 (CH), 131.41 (CH), 135.21 (C), 169.51 (C),
169.94 (C), 170.40 (C), 170.87 (C). Anal. Calcd for C20H23NO7: C, 61.69; H,
5.95; N, 3.60. Found: C, 61.20; H, 6.24; N, 3.46.
ACKNOWLEDGMENT
Thanks are due to the DURSI, Generalitat de Catalunya, for Grant
2001SGR-0084.
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