Reactions of thiobenzoylketene S,N-acetals with silyl enol ethers of cyclic ketones in the presence of desilylating reagents: formation and desulfurization of thienolactams

Article abstract of DOI:10.1039/b102922n

Medium-sized thienolactams can be directly prepared from thiobenzoylketene S,N-acetals, Hg(OAc)2, and silyl enol ethers of cyclic ketones, and either TBAF or TASF. However, by adding either water or alcohol to the foregoing mixture, 3-methylamino-5-phenylthiophenes, in which the ω-position of long-chain alkanoic acids and alkanoic esters are bonded to C-2 of the thiophene ring, can be obtained albeit in low yields. Sequential treatment of the thienolactams with Raney nickel and Adam's catalyst result in completely reductive desulfurization of thienolactams molecules.

Full text of DOI:10.1039/b102922n

View Article Online / Journal Homepage / Table of Contents for this issue
Reactions of thiobenzoylketene S,N-acetals with silyl enol ethers
of cyclic ketones in the presence of desilylating reagents:
formation and desulfurization of thienolactams
1
Jong Seok Lee, Dong Joon Lee, Bo Sung Kim and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul National University, 151-742, Korea
Received (in Cambridge, UK) 30th March 2001, Accepted 16th August 2001
First published as an Advance Article on the web 10th October 2001
Medium-sized thienolactams can be directly prepared from thiobenzoylketene S,N-acetals, Hg(OAc)2, and silyl enol
ethers of cyclic ketones, and either TBAF or TASF. However, by adding either water or alcohol to the foregoing
mixture, 3-methylamino-5-phenylthiophenes, in which the ω-position of long-chain alkanoic acids and alkanoic
esters are bonded to C-2 of the thiophene ring, can be obtained albeit in low yields. Sequential treatment of the
thienolactams with Raney nickel and Adam’s catalyst results in completely reductive desulfurization of thieno-
lactam molecules.
Introduction
Owing to the importance of lactams as starting materials for
the preparation of a large range of antibacterial agents,
methods of synthesis and interconversion of the functional
group are of great significance to a large number of practicing
organic chemists. Information about the synthesis of lactams
may be found in numerous review articles.1 However, there are
few known examples of methods for introducing a substituent α
to the ring nitrogen of lactams larger than a seven-membered
ring. That is, intramolecular cyclization of amino esters
provides medium-sized lactams.2 The Beckmann rearrange-
ment is used in the preparation of the desired lactams.3 The
Schmidt reaction has been widely employed for the preparation
of lactams from cyclic ketones.4 Ultraviolet and ultraviolet–
visible irradiation of a large variety of substituted amides
would give lactams.5 Sodium peroxide oxidation of substituted
benzothiazepinones and benzoxazepinones has produced the
corresponding nine-membered benzothiazoninediones and
benzoxazoninediones.6 Medium-sized keto lactams were syn-
thesized by a three-atom condensative ring expansion of the
related fused tricyclic oxaziridines.7
Recently we reported a new, versatile synthetic method for
2-substituted 3-alkylamino-5-arylthiophenes by treatment of
thioaroylketene S,N-acetals 1 with enolizable compounds in
the presence of Hg(OAc)2 in CH2Cl2 at rt.8 We tried to extend
this methodology to monocyclic ketones in order to obtain
ω-(2-thienyl)alkanoic acids 2 in a single step since compound
2-bearing chains longer than four carbon units have been
achieved by the acylation of thiophene using ω-chloroalkanoyl
chlorides in the presence of Lewis acid, followed by an
appropriate transformation of the functional group(s).9 We
have studied this possibility by employing cyclohexanone,
decanone, dodecanone, and 5α-cholestan-3-one. We now report
the results of our study of these reactions.
Since cyclohexanone did not participate as a nucleophile, the
reaction with the trimethylsilyl enol ether of cyclohexanone was
carried out. However, compound 3 was again isolated as a
major product along with unknown mixtures. This result
suggests that the silyl enol ether does not act as a nucleophile by
itself without assistance from an activating agent. Therefore,
tris(dimethylamino)(trimethylsilyl)sulfur difluoride (TASF),
which is known to be a good desilylating reagent,10 was added
to a stirred mixture of 1a, Hg(OAc)2, and the trimethylsilyl enol
ether of cyclohexanone. The mixture was stirred until no spot
corresponding to 1a–mercury complex was observed on TLC.
Unexpectedly the reaction mixture gave thienolactam 4a (n = 4)
in 30% yield (Scheme 1). Similarly, the reactions with the tri-
methylsilyl enol ethers of decanone and dodecanone under the
same reaction conditions yielded the corresponding thieno-
lactams 4b,c. To test this methodology for polycyclic ketones, a
mixture of regioisomers 5 and 6, prepared by the reaction of
5α-cholestan-3-one with TMSCl11 whose ratio was determined
to be 74 : 26 based on the intensities of the vinyl protons
appearing at δ 4.76 and 4.48, respectively, was subjected to the
same conditions (Scheme 2). Interestingly, only a single thieno-
lactam, assigned to be 4d, was isolated in 46% yield along with
unknown mixtures. The absence of a product originating
from 6 may be due to a severe steric hindrance arising from
the interaction between 1a–mercury complex and 6 to form the
corresponding dihydrothiophene intermediate.8 Reaction times,
yields, and mps are summarized in Table 1.
Results and discussion
(A) In the presence of desilylating reagents
Treatment of 1a (Ar = Ph, R1 = R2 = Me) with Hg(OAc)2 in
CH2Cl2, followed by addition of cyclohexanone gave, however,
2-methyl-5-phenylisothiazol-3-one 3 as a major product (64%).
It is known that compound 3 is formed in the absence of an
active nucleophile.8
As an alternative desilylating agent, tetrabutylammonium
fluoride (TBAF)12 was tried but it turned out to be inferior to
TASF except for the reaction with the dodecanone derivative
(entry 3). On the other hand, treatment with benzyltrimethyl-
2774
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102922n

View Article Online
Table 1 Reaction times, yields, and mps of thienolactams 4
Yielda (%)
TASF
Time (t/min)
Step A
Time (t/h)
Step B
Mp
(T /ЊC)
Entry
Trimethylsilyl enol ether of
Compd
TBAF
1
2
3
4
Cyclohexanone
Decanone
Dodecanone
5
5
5
5
48
4
5
4a (n = 4)
4b (n = 8)
4c (n = 10)
4d
30
44
16
46
28b
31
33
Liquid
150–151c
Liquid
5α-Cholestan-3-one
72
25
201–203c
a Isolated yields. b 5-(3-Methylamino-5-phenylthien-2-yl)pentanoic acid 9a (n = 4, R = H) (5%) was isolated. c Recrystallized from a mixture of Et2O
and n-hexane.
ketones,8 is attacked by a new nucleophile in the solvent to give
a reactive intermediate (Scheme 3). Intramolecular nucleophilic
Scheme 3
Scheme 1
attack by the methylamino group at C-3 of the thiophene
ring on the nucleophilic center of the reactive intermediate
should give 4. One can envisage acetic acid generated from
Hg(OAc)2 as a possible nucleophile. Acetolysis of 7 would give
an anhydride 8, which undergoes intramolecular cyclization to
give 4.
(B) Trapping of intermediate 7 with hydroxy nucleophiles
Since lactams 4 were envisaged to be formed via a nucleophilic
attack of acetic acid on the intermediate 7 during a prolonged
reaction time, the stirring time, following the addition of
desilylating reagent, was reduced to 1 h, and then hydroxy
nucleophiles, i.e., EtOH, MeOH, and water, were added to trap
the intermediate 7 (Scheme 4). From the reaction mixture we
isolated ω-(2-thieno)alkanoic acids or their esters, depending
on the hydroxy nucleophiles. The results are summarized in
Table 2.
Although yields of compound 9 and 10 are not satisfactory,
one can directly obtain ω-(2-thieno)alkanoic acids and their
esters by this methodology. When the intermediate 7 (n = 4)
was quenched with phenylmethanethiol, thioester 11 (42%)
was obtained as a major product, whereas quenching with
n-propylamine resulted only in 9a (29%), presumably due to the
involvement of moisture in wet n-propylamine. Similar treat-
ment with morpholine in toluene for 10 h at reflux afforded
thienolactam 4a (n = 4) (25%) and 9a (6%) in addition to a trace
amount of amide 12 whose structure was assigned based on its
mass number, m/z = 385, equal to its relative molecular mass.
Therefore the intermediate 7 may be unsuitable for the prepar-
Scheme 2
ation of thiophenes having an alkanamide moiety at C-2.
ammonium fluoride hydrate (BTAF)13 gave 4a and 4b in 23 and
16% yield, respectively. Addition of BTAF, followed by use of
(C) Reductive desulfurization
molecular sieves (4 Å) in order to remove the hydrate water, was
not useful. Unchanged 1 (28%) was recovered along with an
unknown mixture. The results suggest that BTAF is not effec-
tive for the preparation of compounds 4. Yields obtained when
TBAF was used are summarized in Table 1.
The formation of medium-size lactams 4a–d suggests that
the corresponding intermediate 7, proposed for the formation
of thiophene derivatives from 1, Hg(OAc)2, and enolizable
Destruction of the thiophene ring by Raney nickel is known
to be one of the major methods for increasing carbon chains
by four carbon units, from which the thiophene derivatives
are transformed into a plethora of open-chain products not
easily accessible by other routes.14 In fact, oximation of 6,7-
dihydrobenzo[b]thiophen-4(5H)-ones, followed by Beckmann
rearrangement, gave C-substituted ξ-thienolactams which
underwent desulfurization by Raney nickel to give the
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780
2775

View Article Online
Table 2 Synthesis of ω-(2-thieno)alkanoic acids 9a, 9e,f, and 10a and ω-(2-thieno)alkanoic esters 9b–d, 9g, and 10b
Trimethylsilyl enol ether
of ketone
Time (t/min)
Time (t/h)
Time (t/h)
Yieldd
(%)
Entry
Step Aa
Step Bb
Step Cc
Temp.
R
Compd
1
2
3
4
5
6
7
8
9
Cyclohexanone
Cyclohexanone
Cycloheptanone
Cyclooctanone
Cyclododecanone
Cyclopentadecanone
Cyclopentadecanone
1-Tetralone
5
5
3
3
5
1
1
1
1
1
2
3
4
4
1
3
3
3
5
4
0.5
0.5
0.5
rt
Reflux
rt
rt
rt
rt
Reflux
rt
rt
H
9a (n = 4)
9b (n = 4)
9c (n = 5)
9d (n = 6)
34
44
39
36
26
31
32
46
56
Et
Et
Et
H
H
Me
H
9e (n = 10)
9f (n = 13)
9g (n = 13)
10a
5
10
10
10
1-Tetralone
Me
10b
a Stirring time after silyl enol ether was added to the mixture of 2a and Hg(OAc)2. b Stirring time after TBAF was added. c Stirring time after
nucleophile was added. d Isolated yields.
eight-membered lactams have been reported by this method.14c
Similar treatment of compound 4a (n = 4) with Raney nickel
in MeOH for 24 h, however, gave 1-methyl-8-(2-phenylethyl-
idene)azocin-2-one 13a (n = 4) and 1-methyl-8-(2-phenylethyl)-
azocin-2-one 14a (n = 4) in 23 and 42% yield, respectively
(Scheme 5). Compounds 13a and 14a were separated by
chromatography.
Scheme 5
The structures of compounds 13a and 14a were determined
based on spectroscopic and analytical data. In particular, 2D
NMR techniques are informative regarding the position of the
olefinic double bond of compound 13a. Since compound 4a
was incompletely reduced by Raney Ni to give a mixture of
compounds 13a and 14a, the mixture was isolated by chrom-
atography and subsequent treatment of the mixture with
a catalytic amount of PtO2 (3 wt%) in HOAc15 gave the 8-(2-
Scheme 4
cyclohexylethyl)heptanolactam (15a, n = 4) (58%). Similar
treatment of compounds 4b–d with Raney nickel and PtO2 in
sequence under the same conditions gave compounds 15b–d
in moderate to good yields. To the best of our knowledge, this
is the first example of the synthesis of larger-than eight-
membered lactams bearing a 2-cyclohexylethyl group at the
carbon α to the ring nitrogen. Direct treatment of 4a with PtO2
for 72 h under the same conditions did not give reduced
products, with almost quantitative recovery of starting lactam.
Reaction times, and yields of lactams 15 are summarized in
Table 3.
1
1
Apart from the H NMR spectroscopic data for 15a, the H
NMR spectra of compounds 15b, 15c and 15d show that each
compound consists of two isomers, presumably conformational
isomers in view of reports14f showing undecanolactam is
present only as a trans isomer having two different ring con-
formations. The ratio of the isomers of compound 15b were
determined to be 1.43 : 1, based on the intensities of N-CH3
(δ 2.72, 2.79) and methine (δ 3.74–3.76, 4.71–4.75) proton
corresponding ξ-alkyl-ξ-enantholactams. This methodology
for ξ-enantholactams and ε-caprolactams was extensively
studied by Shalavina and co-workers.15 However, no-larger than
2776
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780

View Article Online
Table 3 Reaction times and yields of lactams 15
Time (t/day)
28.6 (C-8), 33.5 (C-6), 35.7 (NCH3), 119.2 (C-3), 125.2, 127.8,
129.0, 133.7 (C-2), 135.9 (C-9a), 139.2 (C-3a), 140.4 and 174.7
(C᎐O).
᎐
Yielda
(%)
4-Methyl-2-phenyl-6,7,8,9,10,11,12,13-octahydrothieno[3,2-b]-
Thienolactam
Step A
Step B
Compd
azacyclododecan-5(4H)-one 4b. In accordance with the above
general procedure, the residue obtained from a stirred solution
of a mixture of compound 1a (50 mg, 0.224 mmol), Hg(OAc)2
(100 mg, 0.314 mmol), (cyclodecen-1-yloxy)trimethylsilane
(61 mg, 0.269 mmol), and TASF (74 mg, 0.269 mmol) was
chromatographed to give title compound 4b (32 mg, 44%),
mp 150–151 ЊC (from Et2O–n-hexane) (Found: C, 73.6; H,
7.7; N, 4.3; S, 9.8. C20H25NOS requires C, 73.35; H, 7.7; N, 4.3;
S, 9.8%); νmax (neat)/cmϪ1 2928, 1657, 1440, 1386 and 756;
δH (600 MHz; CDCl3) 0.93–0.96 (1 H, m), 1.13–1.15 (1 H, m),
1.25–1.28 (2 H, m), 1.31–1.41 (3 H, m), 1.42–1.51 (2 H, m),
1.75–1.86 (2 H, m), 1.97–2.03 (1 H, m), 2.11–2.16 (1 H, m,
COCH2), 2.35 (1 H, ddd, J 16.2, 10.5, 3.4, COCH2), 2.73 (1 H,
dt, J 15.1, 4.4, H-13), 2.88–2.93 (1 H, ddd, J 15.4, 12.0, 4.3,
H-13), 3.22 (3 H, s, NCH3), 6.94 (1 H, s, thienyl), 7.28–7.30
(1 H, m, ArH), 7.36–7.39 (2 H, m, ArH) and 7.54–7.56 (2 H,
m, ArH); δ (75 MHz; CDCl3) 24.4, 24.5, 25.3, 25.8, 26.7,
27.4, 29.4, 32.1 (C-6), 36.4 (NCH3), 122.0 (C-3), 125.1, 127.8,
128.9, 133.7 (C-2), 139.2 (C-13a), 139.5 (C-3a), 140.6 and 174.3
4a
4b
4c
4d
(n = 4)
(n = 8)
(n = 10)
1
1
1
1
1
1
1
4
15a
15b
15c
15d
58
66
43
81
a Isolated yields.
signals. Similarly, that of compound 15c was 1.16 : 1, which was
determined based on those of N-CH3 (δ 2.76, 2.70) and methine
(δ 4.66–4.73, 3.71–3.77) proton signals. That of compound 15d
was 2.36 : 1, which was determined based on those of N-CH3
(δ 2.95, 2.96) and methine (δ 5.21–5.25, 4.90–4.91) proton
signals. However, more information is needed to clearly assign
the spectral data of compounds 15b–d.
Experimental
The H NMR spectra were recorded at 300, 500, or 600 MHz
1
(C᎐O).
᎐
in CDCl3 solution containing tetramethylsilane as internal
standard: J-values are given in Hz. IR spectra were recorded
in KBr or thin-film samples on KBr plates. Mass spectra
were obtained by electron impact at 70 eV. Elemental anal-
yses were determined by the National Center for Inter-
University Research Facilities, Seoul National University.
Column chromatography was performed using silica gel
(Merck, 230–400 mesh ASTM), unless otherwise stated. Mps
were determined on a Fisher-Johns melting-point apparatus
and are uncorrected. Dichloromethane was pre-dried over
calcium hydride. 1-Methylamino-1-methylsulfanyl-3-phenyl-3-
thioxopropene 1a was prepared according to the documented
procedure.8
4-Methyl-2-phenyl-6,7,8,9,10,11,12,13,14,15-decahydrothieno-
[3,2-b]azacyclotetradecan-5(4H)-one 4c. In accordance with
the above general procedure, the residue obtained from a stirred
solution of a mixture of compound 1a (50 mg, 0.224 mmol),
Hg(OAc)2 (100 mg, 0.314 mmol), (cyclododec-1-enyloxy)-
trimethylsilane (68 mg, 0.269 mmol), and TASF (74 mg,
0.269 mmol) was chromatographed to give title compound 4c
(13 mg, 16%) as a colorless liquid (Found: C, 74.4; H, 8.3; N,
4.0; S, 9.0. C22H29NOS requires C, 74.3; H, 8.2; N, 3.9; S,
9.0%); νmax (neat)/cmϪ1 2928, 1656, 1435, 1387 and 755; δH (600
MHz; CDCl3) 1.21–1.25 (6 H, m), 1.27–1.36 (3 H, m), 1.37–1.42
(4 H, m), 1.49–1.55 (1 H, m), 1.71–1.79 (1 H, m), 1.82–1.89
(1 H, m), 2.10 (1 H, dt, J 15.7, 6.5, COCH2), 2.28–2.34 (1 H,
m, COCH2), 2.67 (1 H, dt, J 15.3, 6.9, H-15), 2.79-2.84 (1 H, m,
H-15), 3.20 (3 H, s, NCH3), 7.01 (1 H, s, thienyl), 7.28–7.30
(1 H, m, ArH), 7.37–7.39 (2 H, m, ArH) and 7.51–7.55 (2 H, m,
ArH).
Thienolactam 4d. In accordance with the above general
procedure, the residue obtained from a stirred solution of a
mixture of compound 1a (100 mg, 0.448 mmol), Hg(OAc)2 (200
mg, 0.627 mmol), [5α-cholest-2(3)-en-3-yloxy]trimethylsilane
(4.11 mg, 0.895 mmol), which is a mixture of regioisomers 5
and 6, and TASF (185 mg, 0.672 mmol) was chromatographed
to give title compound 4d (115 mg, 46%) as a white solid, mp
201–203 ЊC (from Et2O–n-hexane); νmax (neat)/cmϪ1 2935, 1654,
1458, 752 and 726; δH (600 MHz; CDCl3) 0.69 (3 H, s, CH3),
0.77 (3 H, s, CH3), 0.86 (3 H, d, J 2.9, CH3), 0.87 (3 H, d, J 2.9,
CH3), 0.91 (3 H, d, J 6.5, CH3), 1.01–1.04 (5 H, m), 1.09–1.14
(7 H, m), 1.50–1.55 (1 H, m), 1.57–1.62 (2 H, m), 1.62–1.66
(2 H, m), 1.69–1.74 (1 H, m), 1.79–1.85 (2 H, m), 2.02–2.05
(1 H, m, COCH2), 2.23 (1 H, d, J 14.7, COCH2), 2.56 (1 H, dd,
J 15.2, 10.4, H-9), 3.09 (1 H, d, J 14.7, H-9), 3.29 (3 H, s,
NCH3), 7.07 (1 H, s, thienyl), 7.28–7.30 (1 H, m, ArH), 7.37–
7.39 (2 H, m, ArH) and 7.54–7.57 (2 H, m, ArH); δ (75 MHz;
CDCl3) 12.2, 13.1, 18.6, 22.2, 22.6, 22.8, 23.8, 24.2, 28.0, 28.3,
32.0, 32.7, 35.5, 35.7, 35.8, 36.1, 36.9, 37.6, 37.8, 39.5, 40.1,
42.4, 48.6, 52.3, 56.1, 56.7, 118.7 (C-3), 125.2, 127.8, 129.0,
General procedure for the synthesis of thienolactams 4a–d
(i) In the presence of tris(dimethylamino)(trimethylsilyl)-
sulfur difluoride (TASF). To a mixture of compound 1a (0.224–
0.448 mmol) and Hg(OAc)2 (0.314–0.627 mmol) in CH2Cl2
(8–10 cm3) at rt was added the trimethylsilyl enol ether of a
cyclic ketone (0.296–0.672 mmol). The mixture was stirred for
5 min under argon atmosphere, followed by addition of TASF
(0.269–0.672 mmol). The mixture was stirred for an additional
time (refer to Table 1) until no spot corresponding to the
complex formed from 1a and Hg(OAc)2 was observed on TLC
(Rf = 0, n-hexane–EtOAc 4 : 1). After the solid formed was
filtered off, the filtrate was sequentially washed with 20% aq.
NaHCO3 and brine, and dried over MgSO4. After removal of
the solvent in vacuo, the residue was chromatographed on a
silica gel (1 × 30 cm) using a mixture of EtOAc and n-hexane
(2 : 1) to give a compound 4a–d.
4-Methyl-2-phenyl-6,7,8,9-tetrahydrothieno[3,2-b]azocin-
5(4H)-one 4a. In accordance with the above general procedure,
the residue obtained from a stirred solution of a mixture of
compound 1a (50 mg, 0.224 mmol), Hg(OAc)2 (100 mg, 0.314
mmol), (cyclohexen-1-yloxy)trimethylsilane (46 mg, 0.269
mmol), and TASF (74 mg, 0.269 mmol) was chromatographed
to give title compound 4a (18 mg, 30%) as a colorless liquid
(Found: C, 70.7; H, 6.3; N, 5.2; S, 11.85. C16H17NOS requires
C, 70.8; H, 6.3; N, 5.2; S,11.8%); νmax (neat)/cmϪ1 2920, 1656,
1558, 1437, 1364, 1078 and 757; δH (600 MHz; CDCl3) 1.38
(1 H, ddd, J 25.9, 13.0, 4.3, H-8), 1.69–1.82 (1 H, m, H-7),
1.97–2.06 (2 H, m, H-7 and H-8), 2.20 (1 H, t, J 12.2, COCH2),
2.42–2.45 (1 H, m, COCH2), 2.45–2.51 (1 H, m, H-9), 2.95 (1 H,
dd, J 14.8, 6.8, H-9), 3.29 (3 H, s, NCH3), 7.06 (1 H, s, thienyl),
7.29–7.31 (1 H, m, ArH), 7.37–7.40 (2 H, m, ArH) and 7.53–
7.74 (2 H, m, ArH); δ (75 MHz; CDCl3) 25.6 (C-7), 26.2 (C-9),
131.8 (C-2), 133.7 (C-9a), 140.2 (C-3a), 140.6 and 174.6 (C᎐O);
᎐
m/z HRMS (FAB) Calc. for C37H53NOS: [M ϩ H]; 560.3926.
Found: m/z, 560.3932.
(ii) In the presence of tetrabutylammonium fluoride (TBAF).
The reactions were carried out according to the general
procedure described in (i) except for using TBAF in place of
TASF. Exactly the same amounts of reactants for each reaction
were used. Yields of 4a–d are listed in Table 1.
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780
2777

View Article Online
(iii) In the presence of benzyltrimethylammonium fluoride
hydrate (BTAF). (A) The reaction was carried out using BTAF
(55 mg, 0.320 mmol) in place of TASF according to the pro-
cedure described in (i). Exactly the same amounts of reactants
for each reaction were used. Compounds 4a (16 mg, 26%) and
4b (20 mg, 27%) were obtained.
(B) The reaction was carried out in the presence of BTAF
(55 mg, 0.320 mmol) and molecular sieves (4 Å) (500 mg)
according to the procedure described in (i). However, com-
pound 1a (14 mg, 28% recovery) along with unknown mixtures
were obtained.
t, J 7.1, CH2(CH2)4], 2.91 (3 H, s, NCH3), 4.12 (2 H, q, J 7.1,
CH2CH3), 6.95 (1 H, s, thienyl), 7.21–7.24 (1 H, m, ArH), 7.30–
7.35 (2 H, m, ArH) and 7.52–7.55 (2 H, m, ArH).
Ethyl 7-[2-(3-methylamino-5-phenyl)thieno]heptanoate 9d. In
accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound
1a (48 mg, 0.216 mmol), Hg(OAc)2 (99 mg, 0.311 mmol),
(cycloocten-1-yloxy)trimethylsilane (50 mg, 0.252 mmol) and
TBAF (70 mg, 0.268 mmol) and EtOH (3 cm3) was chromato-
graphed to give title compound 9d (27 mg, 36%) as a yellow
liquid (Found: C, 69.50; H, 7.9; N, 4.1; S, 9.2. C20H27NO2S
requires C, 69.5; H, 7.9; N, 4.05; S, 9.3%); νmax (neat)/cmϪ1 3384,
2929, 1725, 1568, 1388, 1178 and 755; δH (300 MHz; CDCl3)
1.25 (3 H, t, J 7.1, CH3), 1.38–1.42 (4 H, m, 2 × CH2), 1.62–1.66
(4 H, m, 2 × CH2), 2.30 (2 H, t, J 7.1, CH2CH2CO2), 2.58 [2 H,
t, J 7.1, CH2(CH2)5], 2.92 (3 H, s, NCH3), 4.13 (2 H, q, J 7.1,
CH2CH3), 6.95 (1 H, s, thienyl), 7.21–7.24 (1 H, m, ArH), 7.30–
7.35 (2 H, m, ArH) and 7.52–7.55 (2 H, m, ArH).
General procedure for the synthesis of ω-(2-thieno)alkanoic acids
9a, 9e,f and 10a and their esters 9b–d, 9g and 10b
To a mixture of 1a (0.224 mmol) and Hg(OAc)2 (0.314–0.317
mmol) in CH2Cl2 (8 cm3) at rt was added the trimethylsilyl enol
ether of a cyclic ketone (0.260–0.288 mmol). The mixture was
stirred for an appropriate time (3–10 min), followed by addition
of TBAF (0.245–0.275 mmol), which was stirred for an
additional time (1–3 h). Subsequent addition of water (5 cm3)
or alcohol (5 cm3) gave a mixture, which was stirred for an
additional time (0.5–5 h) and worked up as described in (i) of
the general procedure for the synthesis of compounds 4. The
residue was chromatographed (1.5 × 15 cm) using a mixture
of EtOAc and n-hexane (1 : 4) to give compounds 9 and 10.
Consult Table 2 for the reaction time and temperature.
11-[2-(3-Methylamino-5-phenyl)thieno]undecanoic acid 9e.
In accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound
1a (50 mg, 0.224 mmol), Hg(OAc)2 (100 mg, 0.314 mmol),
(cyclododec-1-enyloxy)trimethylsilane (68 mg, 0.267 mmol)
and TBAF (59 mg, 0.226 mmol) and water (1 cm3) was chrom-
atographed to give title compound 9e (22 mg, 26%) as a yellow
liquid (Found: C, 70.8; H, 8.4; N, 3.7; S, 8.5. C22H31NO2S
requires C, 70.7; H, 8.4; N, 3.75; S, 8.6%); νmax (neat)/cmϪ1 2920,
1700, 1586, 1453 and 755; δH (300 MHz; CDCl3) 1.24–1.37 (12
H, m, 6 × CH2), 1.61–1.65 (4 H, m, 2 × CH2), 2.35 (2 H, t, J 7.5,
CH2CH2CO2), 2.59 [2 H, t, J 7.5, CH2(CH2)9], 2.92 (3 H, s,
NCH3), 6.97 (1 H, s, thienyl), 7.21–7.26 (1 H, m, ArH), 7.30–
7.36 (2 H, m, ArH) and 7.53–7.56 (2 H, m, ArH).
5-[2-(3-Methylamino-5-phenyl)thieno]pentanoic acid 9a. In
accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound
1a (50 mg, 0.224 mmol), Hg(OAc)2 (101 mg, 0.317 mmol),
(cyclohexen-1-yloxy)trimethylsilane (49 mg, 0.288 mmol) and
TBAF (72 mg, 0.275 mmol) was chromatographed to give title
compound 9a (22 mg, 34%) as a pale yellow liquid (Found: C,
66.4; H, 6.6; N, 4.9; S, 11.0. C16H19NO2S requires C, 66.4; H,
6.6; N, 4.8; S, 11.1%); νmax (neat)/cmϪ1 2928, 1706 and 1568;
δH (300 MHz; CDCl3) 1.67–1.74 (4 H, m, 2 × CH2), 2.40 (2 H, t,
J 7.1, CH2CO2H), 2.62 [2 H, t, J 7.1, CH2(CH2)3CO2H], 2.91
(3 H, s, NCH3), 6.96 (1 H, s, thienyl), 7.21–7.24 (1 H, m, ArH),
7.30–7.35 (2 H, m, ArH) and 7.52–7.55 (2 H, m, ArH).
14-[2-(3-Methylamino-5-phenyl)thieno]tetradecanoic acid 9f.
In accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound
1a (50 mg, 0.224 mmol), Hg(OAc)2 (100 mg, 0.314 mmol),
(cyclopentadec-1-enyloxy)trimethylsilane (77 mg, 0.260 mmol)
and TBAF (64 mg, 0.245 mmol) and water (1 cm3) was chrom-
atographed to give title compound 9f (29 mg, 31%) as a yellow
liquid (Found: C, 72.2; H, 9.0; N, 3.3; S, 7.8. C25H37NO2S
requires C, 72.2; H, 9.0; N, 3.4; S, 7.7%); νmax (neat)/cmϪ1 2920,
1698, 1585, 1453 and 755; δH (300 MHz; CDCl3) 1.23–1.38 (18
H, m, 9 × CH2), 1.62–1.66 (4 H, m, 2 × CH2), 2.33 (2 H, t, J 7.5,
CH2CH2CO2), 2.58 [2 H, t, J 7.5, CH2(CH2)12], 2.92 (3 H, s,
NCH3), 6.97 (1 H, s, thienyl), 7.21–7.26 (1 H, m, ArH), 7.30–
7.36 (2 H, m, ArH) and 7.53–7.56 (2 H, m, ArH).
Ethyl 5-[2-(3-methylamino-5-phenyl)thieno]pentanoate 9b.
In accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound 1a
(50 mg, 0.225 mmol), Hg(OAc)2 (100 mg, 0.314 mmol),
(cyclohexen-1-yloxy)trimethylsilane (46 mg, 0.270 mmol) and
TBAF (71 mg, 0.271 mmol) and EtOH (5 cm3) was chromato-
graphed to give title compound 9b (30 mg, 44%) as a yellow
liquid (Found: C, 68.2; H, 7.3; N, 4.4; S, 10.0. C18H23NO2S
requires C, 68.1; H, 7.3; N, 4.4; S, 10.1%); νmax (neat)/cmϪ1 3384,
2928, 1726, 1568, 1388, 1178 and 755; δH (300 MHz; CDCl3)
1.25 (3 H, t, J 7.1, CH2CH3), 1.67–1.74 (4 H, m, 2 × CH2), 2.34
(2 H, t, J 7.1, CH2CH2CO2), 2.60 [2 H, t, J 7.1, CH2(CH2)3CO],
2.91 (3 H, s, NCH3), 3.02 (1 H, br, s, NH), 4.12 (2 H, q, J 7.1,
CH2CH3), 6.95 (1 H, s, thienyl), 7.21–7.24 (1 H, m, ArH),
7.0–7.35 (2 H, m, ArH) and 7.52–7.55 (2 H, m, ArH).
Methyl 14-[2-(3-methylamino-5-phenyl)thieno]tetradecanoate
9g. In accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound
1a (40 mg, 0.179 mmol), Hg(OAc)2 (86 mg, 0.270 mmol),
(cyclopentadec-1-enyloxy)trimethylsilane (64 mg, 0.216 mmol)
and TBAF (56 mg, 0.214 mmol) and MeOH was chromato-
graphed to give title compound 9g (25 mg, 32%) as a yellow
solid, mp 40–41 ЊC (from n-hexane–EtOAc) (Found: C, 72.6; H,
9.1; N, 3.2; S, 7.5. C26H39NO2S requires C, 72.7; H, 9.15; N, 3.3;
S, 7.5%); νmax (neat)/cmϪ1 3388, 2912, 1726, 1566, 1494, 1454,
1430, 1386, 1163 and 752; δH (300 MHz; CDCl3) 1.25–1.38
(18 H, m, 9 × CH2), 1.62–1.64 (4 H, m, 2 × CH2), 2.30 (2 H, t,
J 7.5, CH2CO2), 2.58 [2 H, t, J 7.5, CH2(CH2)12], 2.92 (3 H, s,
NCH3), 3.66 (3 H, s, OCH3), 6.96 (1 H, s, thienyl), 7.21–7.26
(1 H, m, ArH), 7.30–7.36 (2 H, m, ArH) and 7.53–7.56 (2 H, m,
ArH).
Ethyl 6-[2-(3-methylamino-5-phenyl)thieno]hexanoate 9c. In
accordance with the above general procedure, the residue
obtained from a stirred solution of a mixture of compound 1a
(52 mg, 0.234 mmol), Hg(OAc)2 (100 mg, 0.314 mmol),
(cyclohepten-1-yloxy)trimethylsilane (46 mg, 0.250 mmol) and
TBAF (67 mg, 0.256 mmol) and EtOH (3 cm3) was chromato-
graphed to give title compound 9c (30 mg, 39%) as a yellow
liquid (Found: C, 68.8; H, 7.6; N, 4.3; S, 9.65. C19H25NO2S
requires C, 68.85; H, 7.6; N, 4.2; S, 9.7%); νmax (neat)/cmϪ1 3384,
2929, 1725, 1568, 1388, 1178 and 755; δH (300 MHz; CDCl3)
1.25 (3 H, t, J 7.1, CH3), 1.42–1.45 (2 H, m, CH2), 1.62–1.66
(4 H, m, 2 × CH2), 2.30 (2 H, t, J 7.1, CH2CH2CO2), 2.58 [2 H,
2-{2-[2-(3-Methylamino-5-phenyl)thieno]ethyl}benzoic acid
10a. In accordance with the above general procedure, the resi-
due obtained from a stirred solution of a mixture of compound
2778
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780

View Article Online
1a (40 mg, 0.179 mmol), Hg(OAc)2 (86 mg, 0.270 mmol),
(3,4-dihydronaphthalen-1-yloxy)trimethylsilane (47 mg, 0.215
mmol) and TBAF (56 mg, 0.214 mmol) and a mixture of THF
and water (5 : 1, 10 cm3) was chromatographed to give title
compound 10a (28 mg, 46%) as a pale yellow solid, mp 173–174
ЊC (from CH2Cl2–Et2O) (Found: C, 71.25; H, 5.6; N, 4.2; S,
9.5. C20H19NO2S requires C, 71.2; H, 5.7; N, 4.15; S, 9.5%);
νmax (neat)/cmϪ1 2920, 1576, 1324, 936, 704 and 690; δH (300
MHz; CDCl3 ϩ DMSO-d6) 2.86–2.91 (5 H, m, CH2 and
NCH3), 3.21 (2 H, t, J 7.6, CH2), 6.95 (1 H, s, thienyl), 7.21–7.30
(5 H, m, ArH), 7.42–7.45 (1 H, m, ArH), 7.53–7.56 (2 H, m,
ArH) and 7.98–8.01 (1 H, m, ArH).
5.7%); νmax (neat)/cmϪ1 3488, 2912, 2864, 1632, 1450, 1392,
1235, 1082, 749 and 698; δH (600 MHz; CDCl3) 0.91–0.95 (1 H,
m), 1.35–1.37 (1 H, m), 1.57–1.59 (1 H, m), 1.67–1.71 (2 H, m),
1.80–1.88 (3 H, m), 1.96–1.98 (1 H, m), 2.26–2.29 (3 H, m),
2.52–2.56 (1 H, m), 2.70–2.73 (1 H, m), 2.81 (3 H, s, NCH3),
3.75–3.80 (1 H, m, methine), 7.16–7.17 (2 H, m, ArH), 7.19–
7.22 (1 H, m, ArH) and 7.27–7.31 (2 H, m, ArH); δ (75 MHz;
CDCl3) 22.92, 24.35, 25.95 (NCH3), 28.42, 31.47 (benzylic C),
33.02, 33.39, 33.83, 52.83 (C-8), 125.16, 127.40, 127.54, 140.07
and 176.00 (C᎐O); m/z 245 (Mϩ, 56%), 202 (7), 154 (18), 148
᎐
(77), 140 (100), 132 (19), 126 (72), 91 (74). Continuous elution
with the same solvent gave 1-methyl-8-(2-phenylethylidene)-
azocin-2-one 13a (n = 4) (6 mg, 0.025 mmol) as a colorless
liquid (Found: C, 78.9; H, 8.6; N, 5.75. C16H21NO requires C,
79.0; H, 8.7; N, 5.8%); νmax (neat)/cmϪ1 3424, 2928, 2864, 1715,
1635, 1440, 1376, 1254, 1235, 1110, 1072 and 1021; δH (500
MHz; CDCl3) 1.02–1.06 (1 H, m), 1.61–1.68 (2 H, m), 1.71–1.74
(1 H, m), 1.80–1.85 (1 H, m), 2.03–2.06 (1 H, m), 2.22–2.24
(2 H, m), 2.43–2.49 (2 H, m), 2.55–2.61 (1 H, m), 2.66–2.69
(1 H, m), 2.96 (3 H, s, NCH3), 5.32–5.35 (1 H, m, vinyl), 7.10–
7.15 (3 H, m, ArH) and 7.19–7.24 (2 H, m, ArH); δ (75 MHz;
CDCl3) 23.97, 24.39, 28.68, 30.69, 32.05, 32.63, 33.77 (C-7),
122.94, 125.15, 127.21, 127.48, 139.04 (C-8) and 139.91 (C-1 of
Ph group); m/z 243 (Mϩ, 70%), 215 (20), 174 (41), 146 (64), 138
(26), 124 (100). The 13C NMR absorption corresponding to the
amide carbonyl carbon was not observed.
Methyl
2-{2-[2-(3-methylamino-5-phenyl)thieno]ethyl}-
benzoate 10b. In accordance with the above general procedure,
the residue obtained from a stirred solution of a mixture
of compound 1a (40 mg, 0.180 mmol), Hg(OAc)2 (86 mg,
0.270 mmol), (3,4-dihydronaphthalen-1-yloxy)trimethylsilane
(47mg, 0.215 mmol) and TBAF (56 mg, 0.214 mmol) and
MeOH (2 cm3) was chromatographed to give title compound
10b (35 mg, 56%) as a pale yellow liquid (Found: C, 71.9; H,
6.05; N, 4.0; S, 9.1. C21H21NO2S requires C, 71.8; H, 6.0; N, 4.0;
S, 9.1%); νmax (neat)/cmϪ1 3392, 2944, 1715, 1570, 1501, 1429,
1392, 1253, 1189, 1072 and 755; δH (300 MHz; CDCl3) 2.86–
2.91 (5 H, m, CH2 and NCH3), 3.20 (2 H, t, J 7.6, CH2), 3.91
(3 H, s, OCH3), 6.69 (1 H, s, thienyl), 7.21–7.30 (5 H, m, ArH),
7.42–7.45 (1 H, m, ArH), 7.54–7.57 (2 H, m, ArH) and 7.91–
7.94 (1 H, m, ArH).
General procedure for the completely reductive desulfurization of
thienolactams 4a–d
Desilylation with TBAF in the presence of phenylmethanethiol
Compound 4 was treated with excess of Raney nickel as
described in the preparation of compounds 13a and 14a. A
mixture of the incompletely reduced products 13 and 14,
obtained by chromatography using a mixture of EtOAc and
n-hexane (2 : 1), was subsequently treated with PtO2 (3 wt%) in
HOAc (5 cm3) for an appropriate time at rt. The acids were
filtered off and the filtrate was neutralized with 20% aq.
NaHCO3, which was extracted with CH2Cl2 (3 × 20 cm3). The
extracts were dried over MgSO4. Removal of the solvent in
vacuo, followed by chromatography (1 × 15 cm) of the residue
with a mixture of EtOAc and n-hexane (2 : 1), gave lactams
15a–d.
To a mixture of 1a (40 mg, 0.179 mmol) and Hg(OAc)2 (38 mg,
0.223 mmol) in CH2Cl2 (8 cm3) was added (cyclohexen-1-
yloxy)trimethylsilane (40 mg, 0.236 mmol). The mixture was
stirred for 5 min at rt, followed by addition of TBAF (62 mg,
0.237 mmol), and the mixture was stirred for an additional
1 h, followed by addition of phenylmethanethiol (28 mg,
0.224 mmol). The mixture was stirred for 30 min and worked
up in the usual manner. Chromatography (1 × 20 cm) of the
residue with a mixture of EtOAc and n-hexane (4 : 1) as eluent
gave S-benzyl 5-[2-(3-methylamino-5-phenyl)thieno]pentanoate
11 (30 mg, 42%) as a yellow liquid (Found: C, 69.9; H, 6.35; N,
3.6; S, 16.15. C23H25NOS2 requires C, 69.8; H, 6.4; N, 3.5; S,
16.2%); νmax (neat)/cmϪ1 3392, 2920, 1686, 1570, 1501, 1389 and
755; δH (300 MHz; CDCl3) 1.64–1.72 (2 H, m, CH2), 1.73–1.81
(2 H, m, CH2), 2.60 (4 H, m, 2 × CH2), 2.90 (3 H, s, SCH2, and
NH), 4.12 (3 H, s, NCH3), 6.94 (1 H, s, vinyl), 7.19–7.36 (8 H,
m, ArH) and 7.52–7.55 (2 H, m, ArH).
8-(2-Cyclohexylethyl)-1-methylazocin-2-one 15a. In accord-
ance with the above general procedure, the incompletely
reduced products obtained from 4a (28 mg, 0.103 mmol) and
excess of Raney nickel were treated with PtO2 (0.8 mg) in HOAc
for 24 h and the mixture was worked up. Chromatography of
the residue gave title compound 15a (15 mg, 58%) as a colorless
liquid (Found: C, 76.3; H, 11.6; N, 5.4. C16H29NO requires C,
76.4; H, 11.6; N, 5.6%); νmax (neat)/cmϪ1 3344, 2912, 2848, 1731,
1629, 1446, 1392, 1258, 1133 and 1075; δH (600 MHz; CDCl3)
0.85–0.99 (3 H, m), 1.13–1.25 (8 H, m), 1.33–1.40 (1 H, m),
1.41–1.49 (1 H, m), 1.59–1.80 (8 H, m), 1.85–1.92 (1 H, m),
1.92–1.99 (1 H, m), 2.38–2.45 (1 H, m, COCH2), 2.61–2.68
(1 H, m, COCH2), 2.71 (3 H, s, NCH3) and 3.79–3.84 (1 H, m,
methine); m/z 251 (Mϩ, 18%), 208 (12), 166 (47), 154 (43), 140
(100), 112 (15).
Desilylation with TBAF in the presence of n-propylamine
To the mixture obtained by treatment of a mixture of 1a
(50 mg, 0.224 mmol), Hg(OAc)2 (101 mg, 0.317 mmol)
and (cyclohexen-1-yloxy)trimethylsilane (45 mg, 0.266 mmol)
with TBAF (71 mg, 0.272 mmol) as described above was added
n-propylamine (59 mg, 0.998 mmol). The mixture was stirred
for 24 h and worked up as usual. Chromatography (1.5 × 10 cm)
of the residue with a mixture of EtOAc and n-hexane (4 : 1) as
eluent gave compound 9a (19 mg, 29%).
12-(2-Cyclohexylethyl)-1-methylazacyclododecan-2-one 15b.
In accordance with the above general procedure, the
incompletely reduced products obtained from 4b (55 mg, 0.17
mmol) and excess of Raney nickel were treated with PtO2
(1 mg) in HOAc for 24 h. The mixture was worked up. Chrom-
atography of the residue gave title compound 15b (34 mg,
66%) as a colorless liquid (Found: C, 78.1; H, 12.05; N, 4.4.
C20H37NO requires C, 78.1; H, 12.1; N, 4.55%); νmax (neat)/cmϪ1
3344, 2912, 2848, 1750, 1629, 1440 and 1395; δH (600 MHz;
CDCl3) 0.80–0.91 (4 H, m, conformer B), 1.05–1.12 (4 H, m,
conformer A), 1.13–1.52 (22 H, m), 1.53–1.63 (3 H, m), 1.71–
Desulfurization of 4a with Raney nickel
According to the documented procedure, a mixture of excess of
Raney nickel and 4a (29 mg, 0.107 mmol) in MeOH (8 cm3) was
stirred for 24 h at rt under hydrogen atmosphere, followed by
filtration to remove the solids. The filtrate was washed with 20%
aq. NaHCO3, followed by evaporation in vacuo. Chromato-
graphy (1 × 30 cm) of the residue using a mixture of EtOAc and
n-hexane (2 : 1) gave 1-methyl-8-(2-phenylethyl)azocin-2-one
14a (n = 4) (11 mg, 0.045 mmol) as a colorless liquid (Found: C,
78.1; H, 9.4; N, 5.7. C16H23NO requires C, 78.3; H, 9.45; N,
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780
2779

View Article Online
1.90 (2 H, m), 1.97–2.03 (1 H, m, COCH2 of conformer A),
2.12–2.20 (1 H, m, COCH2 of conformer B), 2.61–2.67 (1 H, m,
COCH2 of conformer A), 2.72 (3 H, s, NCH3 of conformer B),
2.79 (3 H, s, NCH3 of conformer A), 2.79–2.83 (1 H, m,
COCH2 of conformer B), 3.74–3.76 (1 H, m, methine of con-
former B) and 4.71–4.75 (1 H, m, methine of conformer A).
References
1 Refer to the following monograph for a list of both general and
specific articles: M. A. Ogliaruso and J. F. Wolfe, in Synthesis of
Lactones and Lactams, ed. S. Patai and Z. Rappoport, Wiley,
New York, 1993.
2 (a) P. Cefelin, A. Frydrychova, J. Labsky, P. Schmidt and J. Sebenda,
Collect. Czech. Chem. Commun., 1967, 32, 2787; (b) A. Bladé-Fort,
Tetrahedron Lett., 1980, 21, 2443; (c) S. E. de Laszlo, S. V. Ley
and R. A. Porter, J. Chem. Soc., Chem. Commun., 1986,
344; (d ) R. Pellegata, M. Pinza and G. Pifferi, Synthesis, 1978,
614.
3 (a) R. Fuhrmann, A. A. Tunick and S. Sifniades, U.S. Pat., 3 922
265, 1975 (Chem. Abstr., 1976, 84, 121193h); (b) T. Sundararamaiak,
S. K. Ramraj, K. L. Rao and V. V. Bai, J. Indian Chem. Soc., 1976,
53, 664; (c) I. Sakai, N. Kawabe and M. Ohno, Bull. Chem. Soc. Jpn.,
1979, 52, 3381.
4 (a) B. M. Trost, M. Vaultier and M. L. Santiago, J. Am. Chem. Soc.,
1980, 102, 7929; (b) T. Duong, R. H. Prager, J. M. Tippett,
A. D. Ward and D. I. B. Kerr, Aust. J. Chem., 1976, 29, 2667;
(c) H. Shechter and J. C. Kirk, J. Am. Chem. Soc., 1951, 73, 3087;
(d ) R. T. Conley, J. Org. Chem., 1958, 23, 1330; (e) L. Ruzicka,
M. W. Goldberg, M. Hürbin and H. A. Boeckenoogen, Helv. Chim.
Acta, 1933, 16, 1323.
14-(2-Cyclohexylethyl)-1-methylazacyclotetradecan-2-one
15c. In accordance with the above general procedure, the
incompletely reduced products obtained from 4c (47 mg,
0.13 mmol) and excess of Raney nickel were treated with PtO2
(1 mg) in HOAc for 24 h. The mixture was worked up. Chrom-
atography of the residue gave title compound 15c (19 mg, 43%)
as a colorless liquid (Found: C, 78.7; H, 12.3; N, 4.1. C22H41NO
requires C, 78.7; H, 12.3; N, 4.2%); νmax (neat)/cmϪ1 3344, 2912,
2848, 1728, 1635, 1446 and 1395; δH (600 MHz; CDCl3) 0.80–
0.91 (5 H, m), 1.13–1.25 (7 H, m), 1.28–1.49 (19 H, m), 157–
1.63 (3 H, m), 1.81–1.89 (1 H, m, conformer B), 2.01–2.08 (1 H,
m, conformer A), 2.11–2.17 (1 H, m, COCH2 of conformer A),
2.17–2.22 (1 H, m, COCH2 of conformer B), 2.54–2.61 (1 H, m,
COCH2 of conformer A), 2.61–2.66 (1 H, m, COCH2 of con-
former B), 2.70 (3 H, s, NCH3 of conformer A), 2.76 (3 H, s,
NCH3 of conformer B), 3.71–3.77 (1 H, m, methine of con-
former A) and 4.66–4.73 (1 H, m, methine of conformer B); m/z
335 (Mϩ, 7%), 224 (100), 154 (14).
5 (a) O. Yonemitsu, P. Cerutti and B. Witkop, J. Am. Chem. Soc., 1966,
88, 3941; (b) O. Yonemitsu, T. Tokuyama, M. Chaykovsky and
B. Witkop, J. Am. Chem. Soc., 1968, 90, 776.
6 A. K. Bose, W. A. Hopffmanm and M. S. Manhas, J. Chem. Soc.,
Perkin Trans. 1, 1976, 2343.
7 D. St. C. Black and L. M. Johnstone, Aust. J. Chem., 1984, 37,
599.
8-(2-Cyclohexylethyl)azocin-2-one derivative 15d. In accord-
ance with the above general procedure, the incompletely
reduced products obtained from 4d (115 mg, 0.21 mmol) and
excess of Raney nickel were treated with PtO2 (3 mg) in HOAc
for 4 days. The mixture was worked up as usual. Chromato-
graphy of the residue gave title compound 15d (90 mg, 81%) as
a colorless liquid (Found: C, 82.25; H, 12.01; N, 2.4. C37H65NO
requires C, 82.3; H, 12.1; N, 2.6%); νmax (neat)/cmϪ1 1 3344,
2928, 2240, 1715, 1642, 1443 and 1373; δH (600 MHz; CDCl3)
0.65 (3 H, s), 0.73 (3 H, s), 0.85–0.87 (9 H, m), 0.88–0.90 (4 H,
m), 0.95–1.03 (3 H, m), 1.08–1.16 (7 H, m), 1.17–1.28 (8 H, m),
1.30–1.39 (6 H, m), 1.41–1.57 (6 H, m), 1.58–1.64 (3 H, m),
1.67–1.73 (2 H, m), 1.79–1.85 (2 H, m), 1.93–2.01 (1 H, m),
2.12–2.17 (1 H, m), 2.19–2.26 (1 H, m), 2.31 (1 H, dd, J 13.1,
7.2, COCH2), 2.69 (1 H, dd, J 11.9, 9.6, COCH2), 2.95 (3 H, s,
NCH3 of conformer B), 2.96 (3 H, s, NCH3 of conformer A),
4.90–4.91 (1 H, m, methine of conformer B) and 5.21–5.25
(1 H, m, methane of conformer B).
8 B. S. Kim and K. Kim, J. Org. Chem., 2000, 65, 3690.
9 (a) L. I. Belen´ kii and Ya. L. Gol’dfarb, in The Chemistry of
Heterocyclic Compounds, ed. A. Weissberger and E. C. Taylor,
Wiley, New York, 1985, vol. 44, pp. 457–569; (b) S. Z. Taits,
O. A. Kalinovskii, V. S. Bogdanov and Ya. L. Gol’dfarb, Khim.
Geterotsikl. Soedin., 1972, 2, 170.
10 T. V. RajanBabu, J. Org. Chem., 1984, 49, 2083.
11 (a) Z. A. Fataftah, I. E. Kopka and M. W. Rathke, J. Am. Chem.
Soc., 1980, 102, 3959; (b) E. J. Corey and A. W. Gross, Tetrahedron
Lett., 1984, 25, 495; (c) H. O. House, M. Gall and H. D. Olmstead,
J. Org. Chem., 1971, 36, 2361.
12 G. S. Hammond and C. S. Wu, J. Am. Chem. Soc., 1973, 95,
8215.
13 (a) I. Kuwajima and E. Nakamura, J. Am. Chem. Soc., 1975, 97,
3257; (b) I. Kuwajima, E. Nakamura and M. Shimizu, J. Am. Chem.
Soc., 1982, 104, 1025.
14 (a) M. Nagai, H. Urimoto, K. Uetake, N. Sakikawa and
R. D. Gonzalez, Bull. Chem. Soc. Jpn., 1989, 62, 557; (b) S. Becker,
Y. Fort, R. Vanderesse and P. Caubere, J. Org, Chem., 1989, 54,
4848; (c) Ya. L. Gol’dfarb, B. P. Fabrichnyi and I. F. Shalavina,
Tetrahedron, 1962, 18, 21; (d ) G. Borgen and F. Rise, Magn. Reson.
Chem., 1993, 31, 51; (e) G. Borgen, J. Dale and F. Rise, Magn. Reson.
Chem., 1993, 31, 855; ( f ) G. Borgen, J. Dale and F. Rise, Magn.
Reson. Chem., 1996, 34, 289.
Acknowledgements
This work was supported by Korea Research Foundation Grant
(KRF-2000-DP0261).
15 Ya. L. Gol’dfarb, B. P. Farbrichnyi and I. F. Shalavina, Zh. Obshch.
Khim., 1961, 31, 315.
2780
J. Chem. Soc., Perkin Trans. 1, 2001, 2774–2780