Synthesis of the first monoaromatic B-ring 13-azasteroid ring system by sequential angular annulation

Article abstract of DOI:10.1016/j.tet.2003.10.041

A sequential angular annulation of an aromatic ring B is used to construct the 13-azasteroid ring system in efficient overall yield.

Full text of DOI:10.1016/j.tet.2003.10.041

Tetrahedron 59 (2003) 10019–10023
Synthesis of the first monoaromatic B-ring 13-azasteroid ring
system by sequential angular annulation
a
b
Charles M. Marson,a Jennifer H. Pink and Christopher Smith
,
*
aDepartment of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
Rhone-Poulenc Rorer Ltd, Rainham Road South, Dagenham, Essex RM10 7XS, UK
b
ˆ
Received 1 July 2003; revised 12 September 2003; accepted 9 October 2003
Abstract—A sequential angular annulation of an aromatic ring B is used to construct the 13-azasteroid ring system in efficient overall yield.
q 2003 Published by Elsevier Ltd.
Azasteroids and their analogous ring systems have played
important roles in medicinal chemistry.1 4-Azasteroids,2
17b-substituted aza-androstanes, and 6-azasteroids3 can act
as inhibitors of 5a-reductase. Early work on the total
synthesis of 8-azasteroids included the total synthesis of
(^)-8-aza-oestrone,4 and analgesic activity has been
observed with 8,13-diazasteroids.5 8,16-Diazasteroids and
their heterocyclic variants show anti-inflammatory, anti-
allergic and immunotropic activities, and can be cardiotonic
and hypotensive agents.6 However, there is a need for
diversity in azasteroid synthesis, in order to generate
derivatives that lack the hormonal activity that frequently
complicates the use of azasteroids in medicine.
1-halo-6-arylhex-3-ene and involves a stereospecific double
cyclization.10 We here report a new route to 13-azasteroids
based on assembly of the BCD portion by acyliminium
cyclization,11 followed by angular fusion of ring A by a
Haworth sequence (Scheme 1).12 Reaction of 2-(4-methoxy-
phenyl)ethylamine with succinic anhydride in dichloro-
methane (Scheme 2) gave the intermediate N-[2-(4-meth-
oxyphenyl)ethyl]-4-amidobutanoic acid which was cyclised
by heating in acetyl chloride to give the imide 1 in an overall
yield of 84%. Reduction of 1 with sodium borohydride was
carried out in ethanol at 0–58C, with the dropwise addition
of 6 M hydrochloric acid to keep the pH at 8–10,13 and
afforded a 7:3 mixture of hydroxy- and ethoxy-lactams 2a
and 2b in a total yield of 96%. Treatment of that mixture
with trifluoromethanesulfonic acid (10% in CH2Cl2, 208C,
2.5 h) afforded the tricyclic lactam 3 in almost quantitative
yield. The use of trifluoromethanesulfonic acid for such
cyclizations appears to be novel, and was suggested by
related work involving the condensation of b,g-unsaturated
amides14 with carbonyl compounds.15
13-Azasteroids occupy a central area in heterosteroidal
research; 13-aza and 13-aza-D-homo-analogues of equi-
lenin methyl ethers were synthesised by alkylation of
6-(2-methyoxy-1-naphthyl)ethyl bromide with the respec-
tive potassium salts of succinimide and glutarimide.7 In a
synthesis of (^)-8,9-dehydro-13-aza-oestrone methyl ether,
Speckamp and co-workers8 used succinimide in an
approach related to the Torgov cyclization.9
The very efficient route to 3 is notable since the
tetrahydropyrrolo[2,1-a]isoquinoline ring system has
attracted widespread interest16 and is also present in the
An elegant and flexible route to 13-azasteroids starts with a
Scheme 1. A sequential angular annulation strategy for aromatic 13-azasteroids.
Keywords: angular annulation; cyclization; succinimide.
*
Corresponding author. Present address: Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London
WC1H 0AJ, UK. Tel.: þ44-2076794712; fax: þ44-20-7679-7463; e-mail: c.m.marson@ucl.ac.uk
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/j.tet.2003.10.041

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C. M. Marson et al. / Tetrahedron 59 (2003) 10019–10023
Scheme 2.
erythrina alkaloids, a skeleton that can confer sedative,
hypotensive activities and the blocking of neuromuscular
activity.17 A Haworth-type cyclization12 was envisaged as
the means of appending the A ring of the azasteroid.
Monomethyl succinate18 was converted into 3-carbo-
methoxypropionyl chloride by treatment with thionyl
chloride. As expected, Friedel–Crafts acylation of 3
occurred ortho to the methoxy group at the less hindered
of the two unsubstituted sites activated by the phenolic
hydroxyl group, and with concomitant demethylation of the
methyl ether to afford the phenol 4 in 61% yield.
Clemmensen reduction (Hg/Zn, 4 M HCl in 3:1 aqueous
methanol) of 4 afforded a mixture of the acid 6 and its
methyl ester 5. The mixture was treated with 2:1 aqueous
methanolic sodium hydroxide (1.3 M, 208C, 16 h), resulting
in saponification of the remaining ester; after neutralization,
the carboxylic acid 6 was isolated in 98% yield.
reactive mixed anhydride, the phenolic carboxylic acid 6
was treated with SOCl2 followed by CF3SO3H.19 However,
a tar resulted, from which no products could be isolated.
The ring closure was also attempted by treating the
acid chloride with AlCl3, but the desired azasteroid
skeleton was not detected, and lactonisation appeared
to have occurred. Accordingly, the phenolic group of 6
was protected under conditions of Williamson ether
synthesis (MeI, K2CO3, Me2CO; 20 h at reflux; Scheme 1)
which also served to esterify the carboxylic acid group.
Again, the ester 7 was smoothly hydrolyzed by stirring
the crude product in aqueous methanolic 1 M sodium
hydroxide for 20 h, giving a quantitative yield of the
carboxylic acid 8, the phenolic group being protected as
the methyl ether. Ring closure of 8 proceeded smoothly via
Lewis-acid induced cyclization of the acid chloride
(5 equiv. of AlCl3; 208C, 4.5 h). The desired tetracyclic
lactam 9 was isolated in 79% yield, thus demonstrating the
success and efficiency of this new route to 13-azasteroid
In an attempt to form the tetracyclic system via a highly

C. M. Marson et al. / Tetrahedron 59 (2003) 10019–10023
10021
nucleus (38% overall yield from 2-(4-methoxyphenyl)ethyl-
amine.
(CDCl3) d 177.0 (s), 158.4 (s) 130.0 (s), 129.8 (d), 113.9 (d),
55.2 (q), 40.1 (t), 32.6 (t), 28.1 (t). LRMS (EI) m/e 233 (Mþ,
22%), 134 (100), 121 (57); HRMS calcd for C13H15NO3
233.1052, found 233.1052.
It had been anticipated that dearomatization of ring B could
be achieved by Birch reduction, and that quenching of
the anionic intermediate would deliver the 10-methyl group
of the 13-azasteroids. By this means, a-tetralone can be
reductively alkylated to 8a-methyl-1,2,3,4,6,8a-hexahydro-
naphthalen-1-one.20 A similar procedure was followed, in
which ketone 9 in dry liquid ammonia and tert-butanol
(1.2 equiv.) was treated with potassium (2 equiv.). After
stirring for 10 min at 2788C, LiBr (2 equiv.) was added,
followed by excess methyl iodide. However, proton NMR
spectroscopy did not indicate formation of the desired 10,
but instead a complex mixture. Modification of this, or a
related procedure, is warranted.
1.1.2. N-[2-(4-Methoxyphenyl)ethyl]-5-hydroxy-2-pyrro-
lidinone (2a) and N-[2-(4-methoxyphenyl)ethyl]-5-
ethoxy-2-pyrrolidinone (2b). N-[2-(4-Methoxyphenyl)-
ethyl]succinimide (1) (4.00 g, 17.1 mmol) was dissolved
in ethanol (500 mL) and water (40 mL) and the solution
cooled in an ice-bath. Sodium borohydride (4.00 g,
106 mmol) was added and the mixture stirred at 0–58C.
During the reaction period hydrochloric acid (6 M) was
added dropwise at 10 min intervals so as to keep the pH at
8–10. After 2.5 h a further portion of sodium borohydride
(4.00 g, 106 mmol) was added and stirring was continued
for 3.5 h. The pH was then adjusted to 4–5 (6 M HCl) and
the mixture poured into water (1.5 L). The aqueous layer
was extracted with dichloromethane (5£500 mL). The
combined organic extracts were dried over magnesium
sulfate, filtered and the solvent was evaporated. The residue
was subjected to column chromatography (9:1 ethyl
acetate–light petroleum) and gave the hydroxy-2-pyrro-
lidinone 2a as white prisms, (1.14 g, 28%), mp 136–1398C;
1H NMR (CDCl3) d 7.07 (2H, d, J¼9.0 Hz), 6.77 (2H, d,
J¼9.0 Hz), 4.87 (1H, bd t, J¼6.0 Hz), 3.73 (3H, s), 3.60
(1H, m), 3.36 (1H, m), 2.78 (2H, t, J¼7.0 Hz), 2.55–1.65
(4H, m); 13C NMR (CDCl3) d 175.3 (s), 158.2 (s), 130.9 (s),
129.6 (d), 113.9 (d), 90.3 (d), 55.2 (q), 42.2 (t), 33.1 (t), 29.0
(t), 23.8 (t). Anal. calcd for C13H17NO3: C, 66.36; H, 7.28;
N, 5.95%; found: C, 66.26; H, 7.22; N, 5.73%; and the
ethoxy-2-pyrrolidinone (2b) as a colourless oil, (3.06 g,
68%); IR (film) lmax 1700 cm21; 1H NMR (CDCl3) d 7.12
(2H, d, J¼9.0 Hz), 6.82 (2H, d, J¼9.0 Hz), 4.69 (1H, dd,
J¼6.0, 1.0 Hz), 3.75 (3H, s), 3.70 (1H, m), 3.38 (2H, dq,
J¼6.0, 1.0 Hz), 3.25 (1H, m), 2.82 (2H, m), 2.60-1.30 (4H,
m), 1.18 (3H, t, J¼6.0 Hz); 13C NMR (CDCl3) d 174.9 (s),
158.2 (s), 131.1 (s), 129.6 (d), 113.9 (d), 89.5 (d), 61.4 (t),
55.2 (q), 42.2 (t), 33.2 (t), 29.0 (t), 24.8 (t), 15.3 (q). LRMS
(EI) m/e 263 (Mþ, 31%), 217 (24), 134 (100), 121 (48), 96
(27), 68 (25); HRMS calcd for C15H21NO3 263.1521, found
263.1527.
In conclusion, a sequential angular annulation of an
aromatic ring B has been used to construct the 13-azasteroid
ring system in an overall yield of 38% from a monocyclic
precursor. The efficiency and flexibility of this route,
particularly by using an enantiopure chiral pure chiral
succinimide, e.g. derived from (S)-malic acid, would allow
an enantioselective total synthesis of 13-azasteroids.
1. Experimental
1.1. General
All melting points were determined on a microscope hot-
1
stage apparatus. H and 13C NMR spectra were run on a
Bruker AM-250 instrument at 250 and 68.8 MHz, respec-
tively. Microanalytical data were obtained on a Perkin–
Elmer 2400 CHN elemental analyser. Mass spectra were
obtained on a Kratos MS-25 or Fisons Prospec 3000
instrument. Infrared spectra were recorded on a Perkin–
Elmer Paragon 100 FT-IR instrument. Thin-layer chroma-
tography was performed on Merck 0.2 mm aluminium-
backed silica gel 60 F254 plates and visualized using an
alkaline KMnO4 spray or by ultraviolet light. Flash column
chromatography was performed using Sorbsil C60 40/60H
silica gel. Petroleum ether (40–60 fraction) and ethyl
acetate were distilled before use; tetrahydrofuran was
distilled over sodium and benzophenone; dichloromethane
was distilled over calcium hydride. Evaporation refers to the
removal of solvent under reduced pressure.
1.1.3. 1,2,3,5,6,10b-Hexahydro-9-methoxy-1H-benzo[g]-
indolizidin-3-one (3). A 7:3 mixture of the reduced imides
2a and 2b (4.30 g) was stirred in dichloromethane (23 mL)
under nitrogen. The solution was cooled in an ice-bath and
to it was added trifluoromethanesulfonic acid (2.5 mL).
After stirring at 208C for 2.5 h, the mixture was neutralised
with saturated aqueous sodium hydrogen carbonate. The
aqueous layer was separated and was extracted with
dichloromethane (3£20 mL). The combined organic layers
were washed with water (2£15 mL), dried over sodium
sulfate and the solvent evaporated to give the lactam 3 as a
1.1.1. N-[2-(4-Methoxyphenyl)ethyl]succinimide (1). A
solution of 2-(4-methoxyphenyl)ethylamine (10.0 g, 66.1
mmol) and succinic anhydride (7.94 g, 79.4 mmol) in
dichloromethane (300 mL) was heated under reflux for 48 h.
The mixture was then cooled and the solvent evaporated.
The residue was recrystallised from hot ethyl acetate,
filtered and dried. The intermediate N-[2-(4-methoxy-
phenyl)ethyl]-4-amido-1-butanoic acid was treated with
acetyl chloride (30 mL) under reflux for 3 h and the volatile
materials were then removed by distillation to give a residue
which was recrystallised from ethyl acetate to give the
succinimide 1 as white prisms, (13.0 g, 84%), mp 1148C; IR
viscous yellow oil (3.50 g, 98%); IR (film) lmax 1685 cm21
;
1H NMR (CDCl3) d 7.06 (1H, d, J¼8.5 Hz), 6.76 (1H, dd,
J¼8.5, 2.5 Hz), 6.63 (1H, d, J¼2.5 Hz), 4.75 (1H, m), 4.26
(1H, m), 3.81 (3H, s), 2.40 (6H, m), 0.86 (1H, m); 13C NMR
(CDCl3) d 169.5 (s), 158.2 (s), 138.4 (s), 129.8 (d), 127.2 (s),
112.2 (d), 110.7 (d), 57.0 (d), 55.4 (q), 40.0 (t), 32.2 (t), 30.5
(t), 28.1 (t). LRMS (EI) m/e 217 (Mþ, 88%), 216 (100), 202
(19), 186 (28), 160 (18); HRMS calcd for C13H15NO2
217.1103, found 217.1103.
1
(nujol) lmax 1695 cm21; H NMR (CDCl3) d 7.06 (2H, d,
J¼9.0 Hz), 6.74 (2H, d, J¼9.0 Hz), 3.70 (3H, s), 3.62 (2H, t,
J¼8.0 Hz), 2.75 (2H, t, J¼8.0 Hz), 2.57 (4H, s); 13C NMR

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C. M. Marson et al. / Tetrahedron 59 (2003) 10019–10023
1.1.4. 1,2,3,5,6,10b-Hexahydro-8-[3-(methoxycarbonyl)-
1-oxopropyl]-9-hydroxy-1H-benzo[g]indolizidin-3-one
(4). The benzo[g]indolizidin-3-one 3 (3.70 g, 17.1 mmol)
was stirred in dichloromethane (20 mL) and the solution
cooled in ice. Aluminium chloride (9.15 g, 68.6 mmol) was
added, followed by the dropwise addition of 3-carbo-
methoxypropionyl chloride (2.31 g, 17.1 mmol) in dichloro-
methane (5 mL). The mixture was stirred at 208C for 16 h.
Water (50 mL) was added cautiously, the layers separated
and the aqueous layer extracted with dichloromethane
(3£30 mL). The combined organic extracts were washed
with water (2£30 mL), dried over magnesium sulfate,
filtered and the solvent was evaporated. The residue was
purified by column chromatography (3% methanol in ethyl
acetate) to give the benzo[g]indolizidin-3-one 4 as white
prisms (3.29 g, 61%), mp 121–1238C; IR lmax (nujol) 1735,
(1H, s), 6.55 (1H, s), 4.65 (1H, t, J¼8.0 Hz), 3.98 (1H, dt,
J¼12.0, 4.0 Hz), 2.94 (1H, m), 2.70 (7H, m), 2.19 (2H, t,
J¼8.0 Hz), 1.80–1.70 (3H, m); 13C NMR ((CD3)2SO) d
174.9 (s), 172.5 (s), 154.2 (s), 136.7 (s), 130.5 (d), 127.0 (s),
123.7 (s), 111.2 (d), 56.2 (d), 37.2 (t), 33.8 (t), 31.7 (t), 29.2
(t), 27.7 (t), 27.6 (t), 25.2 (t); LRMS (EI) m/e 289 (Mþ,
67%), 271 (38), 215 (42), 202 (100), 186 (18), 160 (14);
HRMS calcd for C16H19NO4 289.1314, found 289.1318.
1.1.7. 1,2,3,5,6,10b-Hexahydro-8-(3-carboxypropyl)-9-
methoxy-1H-benzo[g]indolizidin-3-one (7). The acid 6
(1.80 g, 5.93 mmol), methyl iodide (2.53 g, 17.8 mmol) and
potassium carbonate (1.64 g, 11.9 mmol) were heated at
reflux in dry acetone (20 mL) for 20 h. The solvent was then
evaporated, water (50 mL) was added and the mixture
extracted with dichloromethane (4£30 mL). The combined
organic extracts were washed with water (50 mL) and brine
(50 mL), dried over magnesium sulfate, filtered and the
solvent was evaporated to give the methyl ester 7 as a
1
1690, 1645 cm21; H NMR (CDCl3) d 11.9 (1H, s), 7.58
(1H, s), 6.73 (1H, s), 4.72 (1H, m), 4.27 (1H, m), 3.71 (3H,
s), 3.33 (2H, t, J¼6.5 Hz), 3.15–2.40 (8H, m) 1.88 (1H, m).
Anal. calcd for C17H19NO5: C, 64.33; H, 6.04; N, 4.42%;
found: C, 64.29; H, 5.91; N, 4.68%.
viscous oil (1.85 g, 98%); IR lmax (film) 1730, 1680 cm21
;
1H NMR (CDCl3) d 6.87 (1H, s), 6.52 (1H, s), 4.74 (1H, m),
4.27 (1H, m), 3.79 (3H, s), 3.65 (3H, s), 3.00 (1H, m), 2.90–
2.40 (5H, m), 2.59 (2H, t, J¼7.5 Hz), 2.32 (2H, t, J¼
7.5 Hz), 1.96–1.80 (3H, m); 13C NMR (CDCl3) d 174.1 (s),
173.3 (s), 156.4 (s), 136.0 (s), 130.6 (d), 128.9 (s), 124.9 (s),
111.4 (d), 56.9 (q), 55.4 (q), 51.5 (d), 37.3 (t), 33.6 (t), 31.8
(t), 29.2 (t), 27.6 (t), 27.5 (t), 25.0 (t); LRMS (EI) m/e 317
(Mþ, 72%), 316 (76), 286 (31), 216 (100); HRMS calcd for
C18H23NO4 317.1627, found 317.1621.
1.1.5. 1,2,3,5,6,10b-Hexahydro-8-[3-(methoxycarbonyl)-
propyl]-9-hydroxy-1H-benzo[g]indolizidin-3-one
(5).
Zinc dust (13.2 g, 0.202 mol) was amalgamated by stirring
for 10 min at 208C with a solution of mercury(II) chloride
(0.92 g, 3.40 mmol) in water (66 mL) and concentrated
hydrochloric acid (0.8 mL, 10 M). Decantation of the
solution left the amalgam to which was added water
(46 mL), followed by 10 M hydrochloric acid (46 mL) and
then a solution of the keto ester 4 (3.30 g, 10.4 mmol) in
methanol (33 mL). The mixture was heated under reflux for
4 h, cooled and extracted with dichloromethane (3£50 mL).
The combined extracts were dried over sodium sulfate,
filtered under suction, and the solvent evaporated to give a
mixture of the acid 6 and its methyl ester 5. The ester 5
was purified by dissolving in dichloromethane (200 mL),
washing successively with aqueous sodium hydroxide
(100 mL, 1 M), water (100 mL) and brine (100 mL), drying
over sodium sulfate, followed by filtration and evaporation
of the solvent to give ester 5 as a viscous oil (2.20 g, 70%);
IR lmax 1730, 1660 cm21; 1H NMR (CDCl3) d 6.85 (1H, s),
6.63 (1H, s), 4.70 (1H, m), 4.25 (1H, m), 3.73 (3H, s),
3.10–2.45 (8H, m), 2.41 (2H, t, J¼6.0 Hz), 2.00–1.80 (3H,
m); 13C NMR (CDCl3) d 175.2 (s), 173.7 (s), 153.7 (s),
136.3 (s), 130.5 (d), 126.6 (s), 124.4 (s), 111.6 (d), 56.9 (q),
51.9 (d), 37.5 (t), 32.9 (t), 31.8 (t), 29.1 (t), 27.6 (t), 27.4 (t),
25.0 (t); LRMS (EI) m/e 303 (Mþ, 54%), 216 (97), 202
(100), 186 (37); HRMS calcd for C17H21NO4 303.1471,
found 303.1466.
1.1.8. 1,2,3,5,6,10b-Hexahydro-8-(3-carboxypropyl)-9-
methoxy-1H-benzo[g]indolizidin-3-one (8). The ester 7
(1.90 g, 5.93 mmol) was stirred in methanol (15 mL) and
aqueous sodium hydroxide (15 mL, 2 M) for 20 h at 208C.
The methanol was then evaporated, and the residual solution
was diluted with water (50 mL) and acidified (6 M HCl)
before extraction with dichloromethane (3£30 mL). The
combined organic extracts were washed with brine (30 mL),
dried over magnesium sulfate, filtered and the solvent was
evaporated to give the acid 8 as a green foam (1.75 g, 99%);
IR lmax (nujol) 1725, 1650 cm21; 1H NMR (CDCl3) d 6.88
(1H, s), 6.52 (1H, s), 4.75 (1H, bd t, J¼8.0 Hz), 4.28 (1H,
m), 3.80 (3H, s), 3.10–2.45 (8H, m), 2.36 (2H, t, J¼7.5 Hz),
2.00–1.80 (3H, m); 13C NMR (CDCl3) d 178.2 (s), 173.8
(s), 156.5 (s), 135.8 (s), 130.6 (d), 129.0 (s), 124.8 (s), 106.2
(d), 57.1 (d), 55.4 (q), 37.5 (t), 33.6 (t), 31.8 (t), 29.1 (t), 27.6
(t), 27.5 (t), 24.9 (t); LRMS (EI) m/e 303 (Mþ, 37%), 302
(47), 216 (100); HRMS calcd for C17H21NO4 303.1471,
found 303.1476.
1.1.9. 1,2,3,5,6,7,8,9,10,10b-Decahydro-11-methoxy-7-
oxo-1H-naphtho[g]indolizidin-3-one (9). The acid 8
(1.65 g, 5.44 mmol), was stirred in thionyl chloride
(12 mL) at 408C for 3 h. The excess thionyl chloride was
then distilled off under reduced pressure. The residual acid
chloride, lmax (liquid film) 1795 cm21, was dissolved in
dichloromethane (15 mL) and cooled in an ice-bath.
Aluminium chloride (3.63 g, 27.2 mmol) was added and
the mixture was stirred at 208C for 4.5 h. The mixture was
then cooled in ice and water (75 mL) which was added
cautiously to destroy excess aluminium chloride. The layers
were separated, and the aqueous layer was extracted with
dichloromethane (3£50 mL) and the combined organic
1.1.6. 1,2,3,5,6,10b-Hexahydro-8-(3-carboxypropyl)-9-
hydroxy-1H-benzo[g]indolizidin-3-one (6). The crude
ester 5 (2.20 g, 7.25 mmol) was stirred in methanol
(20 mL) and aqueous sodium hydroxide (40 mL, 2 M) for
20 h at 208C. The mixture was acidified and the precipitate
filtered and dissolved in methanol (50 mL). Benzene
(10 mL) was added to the solution and the solvent was
evaporated. Further portions of benzene (3£10 mL) were
added successively. The solvent was then evaporated, and
the residue dried in a desiccator overnight to give acid 6
(2.05 g, 98%), as white prisms, mp 226–2288C; IR lmax
(nujol) 3340, 1695, 1655 cm21; 1H NMR ((CD3)2SO) d 6.81

C. M. Marson et al. / Tetrahedron 59 (2003) 10019–10023
10023
4. Meltzer, R. I.; Lustgarten, D. M.; Stanaback, R. J.; Brown,
R. E. Tetrahedron Lett. 1963, 1581.
extracts washed with water (2£30 mL), saturated aqueous
sodium hydrogen carbonate (30 mL) and brine (30 mL),
dried over sodium sulfate and filtered. The solvent was
evaporated to give lactam 9 as a green glassy solid (1.23 g,
5. Burckhalter, J. H.; Abramson, H. N. D. J. Chem. Soc., Chem.
Commun. 1966, 805.
1
79%); lmax (nujol) 1680 cm21; H NMR (CDCl3) d 6.65
6. Akhrem, A. A.; Lakhvich, F. A.; Pshenichnyi, V. N.;
Lakhvich, O. F.; Kuz’mitskii, B. B. Dokl. Akad. Nauk. SSSR
1978, 240, 595. Chem. Abstr. 1978, 89, 215649.
(1H, s), 4.71 (1H, m) 4.20 (1H, m), 3.80 (3H, s), 3.30–2.30
(10H, m), 2.10–1.65 (3H, m); 13C NMR (CDCl3) d 200.7
(s), 173.0 (s), 155.3 (s), 136.9 (s), 134.1 (s), 132.3 (s), 127.1
(s), 110.2 (d), 57.0 (d), 55.7 (q), 40.9 (t), 37.1 (t), 31.8 (t),
28.0 (t), 27.2 (t), 23.4 (t), 22.2 (t); LRMS (EI) m/e 285 (Mþ,
100%), 284 (82), 270 (49), 229 (85), 228 (46); HRMS calcd
for C17H19NO3 285.1365, found 285.1364.
7. Birch, A. J.; Subba Rao, G. S. R. J. Chem. Soc. 1965, 3007.
8. Hubert, J. C.; Speckamp, W. N.; Huisman, H. O. Tetrahedron
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Acknowledgements
ˆ
Financial support from Rhone-Poulenc Rorer and the
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