Fused-ring nitrogen and sulfur heterocycles by a tandem SN2-Michael addition reaction

Article abstract of DOI:10.1002/jhet.5570390531

A tandem S_N2-Michael addition reaction has been developed for the synthesis of cis- and trans-fused nitrogen and sulfur heterocycles from the cis and trans isomers of ethyl (±)-(2E)-3-[2-(iodomethyl)cyclohexyl]-2-propenoate. Octahydro-1H-isoindole-1-acetic acid and octahydrobenzo[c]thiophene-1-acetic acid derivatives have been prepared and their stereochemistries elucidated using NMR and X-ray crystallographic methods. Cyclization substrates for both the cis- and the trans-fused rings are readily available in four steps from known compounds. Yields for the cyclization range from 80-85% and stereochemical selectivities with respect to the side chain vary from 12.5-16:1 for the cis-fused structures to 6-7.5:1 for the transfused structures. Steric interactions in the transition states for ring closure are proposed to rationalize the observed preferences.

Full text of DOI:10.1002/jhet.5570390531

Sep-Oct 2002
Fused-Ring Nitrogen and Sulfur Heterocycles by a Tandem
1049
S 2-Michael Addition Reaction
N
Richard A. Bunce,* Sharadsrikar V. Kotturi, Christopher J. Peeples and Elizabeth M. Holt
Department of Chemistry, Oklahoma State University
Stillwater, Oklahoma 74078-3071, USA
Received May 21, 2002
A tandem S 2-Michael addition reaction has been developed for the synthesis of cis- and trans-fused
N
nitrogen and sulfur heterocycles from the cis and trans isomers of ethyl (±)-(2E)-3-[2-(iodomethyl)cyclo-
hexyl]-2-propenoate. Octahydro-1H-isoindole-1-acetic acid and octahydrobenzo[c]thiophene-1-acetic acid
derivatives have been prepared and their stereochemistries elucidated using NMR and X-ray crystallo-
graphic methods. Cyclization substrates for both the cis- and the trans-fused rings are readily available in
four steps from known compounds. Yields for the cyclization range from 80-85% and stereochemical selec-
tivities with respect to the side chain vary from 12.5-16:1 for the cis-fused structures to 6-7.5:1 for the trans-
fused structures. Steric interactions in the transition states for ring closure are proposed to rationalize the
observed preferences.
J. Heterocyclic Chem., 39, 1049 (2002).
Introduction.
A previous report from this laboratory described a
tandem S 2-Michael addition reaction for the synthesis of
N
monocyclic 5- and 6-membered nitrogen and sulfur hetero-
cycles [1]. While some of these simple ring systems have
valuable biological activity [2-4] there are many other
active compounds that incorporate fused-ring heterocycles
[5]. Thus, we wished to explore this heterocylization pro-
cedure for the synthesis of more complex targets. The via-
bility of the S 2-Michael sequence to prepare fused-ring
N
structures hinges on the degree of selectivity one can
achieve in the Michael cyclization step. In the current
study, we have employed this strategy to synthesize octa-
hydro-1H-isoindole-1-acetic acid and octahydrobenzo[c]-
thiophene-1-acetic acid derivatives. Elucidation of the
product stereochemistries indicates that the ring closures
proceed with good to excellent selectivity.
Results and Discussion.
The synthesis of our cyclization substrates started from
the known cis [6] and trans [7] isomers of 2-hydroxy-
methylcyclohexylmethanol (1a and 1b, respectively,
Scheme 1). Selective oxidation [8] of 1a using o-iodoxy-
benzoic acid (IBX) [9] in dimethyl sulfoxide gave lactol 2a
[9]. Wittig olefination [10] of 2a with (carbethoxymethyl-
ene)triphenylphosphorane in benzene then yielded
hydroxy acrylate ester 3a. Finally, alcohol 3a was con-
verted via its mesylate 4a [11] into iodide 5a [1] that
served as the cis-fused heterocycle precursor. A similar
sequence was used to prepare the trans-fused heterocycle
precursor 5b.
The results of our cyclization studies are summarized in
Schemes 2 and 3. Nitrogen heterocycles were prepared in
one step by refluxing each iodo acrylate 5 with 1.1 equiva-
lent of benzylamine in ethanol containing 1.1 equivalent of
triethylamine [1]. The sulfur heterocycles were prepared
in two steps by: 1) reacting each isomer of 5 with 1.0
equivalent of thiourea in refluxing ethanol to give the cor-
responding isothiuronium salt 10 and 2) heating each salt
in 10% aqueous potassium hydroxide [1,12]. Both
cyclizations proceed via a favorable 5-exo-trig transition
state [13]. The formation of the nitrogen heterocycles was
found to be relatively selective yielding a 16:1 mixture of
6:7 from 5a and a 6:1 mixture of 8:9 from 5b. These prod-
uct mixtures were readily separated by preparative thin
layer chromatography. The sulfur ring systems were
formed with similar selectivities giving a 12.5:1 ratio of
11:12 from 5a and a 7.5:1 ratio of 13:14 from 5b. The

1050
R. A. Bunce, S. V. Kotturi, C. J. Peeples and E. M. Holt
Vol. 39
major products from the sulfur heterocyclizations were
purified by crystallization.
nitrogen heterocycles. A single crystal X-ray structure of
11 confirmed the assignment for the cis-fused octahy-
drobenzo[c]thiophene derivative.
Several earlier reports suggested that closure of cis sub-
strate 5a would favor the all-cis product (side chain cis to
the cis-oriented bridgehead hydrogens) [16]; formation of
the trans-fused system from 5b, however, had no prece-
dent. Previous syntheses of 6,5-fused carbocyclic systems
using the Michael reaction involved closure of a cyclo-
hexanone enolate on a side chain acceptor to form two new
stereocenters α and β to the carbonyl. The reaction proto-
cols for these cyclizations varied depending on the struc-
ture of the substrate but were invariably carried out under
equilibrating conditions that led to the thermodynamic
products. In each case, the all-cis 6,5-fused bicyclic struc-
ture was produced as the major product. This stereochem-
ical outcome was attributed primarily to steric effects in
the transition state [16a].
In the current work, the stereochemistry of the ring junc-
tion is set prior to the ring closure and cyclization creates
only one new stereocenter at C1. Again, the reaction con-
ditions should favor the thermodynamic products and
steric factors should control the selectivity (Scheme 4). In
the transition state leading to the cis-fused product 6,
rotamer A would be preferred since it minimizes the 1,3-
diaxial-like interaction between the Michael donor (CH -
2
X:) and the acrylate acceptor found in rotamer B.
Additionally, the cyclization of B forces the side chain into
the molecular cavity created by the cis-fused rings and
results in eclipsing of the side chain methylene with C7 of
the octahydroisoindole. Thus, product 6 predominates
over 7. In the transition state leading to the trans-fused
product 8, a similar rotamer preference applies, though the
steric differentiation is less pronounced. Furthermore,
eclipsing of the side chain with C7 is still present, but the
two groups are not as close. Thus, the preference for prod-
uct 8 over 9 is significantly reduced.
Structural assignments for the products were derived
from COSY-45 [14] and NOESY [15] spectra of 6-9, 11
and 13 and X-ray crystallographic analysis of 11. Proton
signals were initially assigned from the COSY-45 spec-
trum. In the NOESY spectrum of 6, correlation of the side
chain methylene protons with the protons on C7a and C3a
established that the C1 acetic acid residue is cis to both
bridgehead hydrogens; the minor isomer 7 lacked these
interactions, but a correlation was observed between the
cis-oriented protons on C1 and C7a. A similar study of 8
indicated that the acetic acid side chain is cis to the adja-
cent C7a hydrogen but trans to the C3a hydrogen. In 9, a
correlation between the protons on C1 and C7a confirmed
that the side chain was trans to the C7a bridgehead hydro-
gen. Finally, correlations were also noted between the
bridgehead protons in the cis-fused products 6 and 7, but
not in the trans-fused products 8 and 9. The NOESY
results for 11 and 13 paralleled those observed for the

Sep-Oct 2002
Fused-Ring Nitrogen and Sulfur Heterocycles
1051
column eluted with increasing concentrations of ether in hexane.
In summary, we have applied the S 2-Michael addition
N
Compound 3a (3.44 g, 16.2 mmoles, 48%) was isolated from
reaction to the preparation of cis and trans 6,5-fused nitro-
gen and sulfur heterocycles. The reactions are efficient and
proceed with useful selectivities. The stereochemical results
are easily rationalized by analysis of steric effects in the
transition state. We are continuing to explore this process
for the preparation of other polycyclic ring systems.
-1
1
band 3 as a colorless oil; ir: 3425, 1723, 1652 cm ; H nmr: δ
7.16 (dd, 1H, J = 15.5, 9.1), 5.88 (d, 1H, J = 15.5), 4.19 (q, 2H, J
= 7.1), 3.45 (d, 2H, J = 7.3), 2.67 (m, 1H), 1.84 (m, 1H), 1.73 (m,
1H), 1.70-1.43 (complex, 6H), 1.38 (m, 2H), 1.29 (t, 3H, J = 7.1);
13
C nmr: δ 166.7, 149.7, 121.6, 64.4, 60.1, 42.3, 39.1, 30.1, 24.9,
24.6, 22.1, 14.0; hrms: m/z Calcd. for C
Found: 212.1418.
H O : 212.1412;
12 20 3
Anal. Calcd. for C
67.77; H, 9.40.
H O : C, 67.92; H, 9.43. Found: C,
12 20 3
EXPERIMENTAL
Ethyl (±)-(2E)-3-[(1R*,2S*)-2-(Hydroxymethyl)cyclohexyl]-2-
propenoate (3b).
All solvents were distilled prior to use; other reagents were
used as received from the vendors. All reactions were run under
dry nitrogen in oven-dried glassware. Reactions were monitored
by one of the following methods: 1) thin layer chromatography
on hard layer silica gel GF plates (Analtech) using ultraviolet or
phosphomolybdic acid detection or 2) capillary gas chromatogra-
phy (SE-30 column, 6 m x 0.25 mm i.d., 0.25 µm film thickness)
with flame ionization detection programmed between 50-300°.
Preparative separations were performed using one of the follow-
ing methods: 1) preparative thin layer chromatography on 20 cm
x 20 cm silica gel GF plates (Analtech) or 2) flash chromatogra-
phy [17] on silica gel (Grace, grade 62, 60-200 mesh) containing
ultraviolet-active phosphor (Sorbent Technologies no. 5). In
each case, band elution was monitored using a hand-held ultravi-
olet lamp. Melting points were uncorrected. Ir spectra were run
as thin films on sodium chloride disks and were referenced to
polystyrene. Unless otherwise noted, H nmr and C nmr spec-
tra were measured in deuteriochloroform at 300 MHz and 75
MHz, respectively, and were referenced to internal tetramethylsi-
lane; coupling constants (J) have been given in Hz. COSY-45
and NOESY spectra were recorded at 400 MHz. Unless other-
wise specified, high resolution mass spectra (direct probe/elec-
tron impact) were obtained at 70 electron volts.
This compound (3.38 g, 16.0 mmoles, 47%) was isolated as a
-1
1
colorless oil; ir: 3422, 1723, 1652 cm ; H nmr: δ 6.81 (dd, 1H,
J = 15.6, 9.5), 5.79 (d, 1H, J = 15.6), 4.15 (q, 2H, J = 7.1), 3.58
(dd, 1H, J = 10.9, 3.8), 3.42 (dd, 1H, J = 10.9, 6.2), 2.04 (m, 1H),
1.95-1.50 (complex, 6H), 1.43-1.25 (complex, 4H), 1.29 (t, 3H, J
13
= 7.1);
C nmr: δ 166.8, 153.0, 120.8, 66.1, 60.3, 43.9, 43.2,
32.4, 28.8, 25.6, 25.4, 14.3; hrms: m/z Calcd. for C
H O :
12 20 3
212.1412; Found: 212.1415.
Anal. Calcd. for C
H O : C, 67.92; H, 9.43. Found: C,
12 20 3
67.84; H, 9.38.
Representative Procedure for Methanesulfonate Ester Preparation:
Ethyl (±)-(2E)-3-{(1R*,2R*)-2-[(Methanesulfonyloxy)-
methyl]cyclohexane}-2-propenoate (4a).
1
13
This compound was prepared from 3a using the general proce-
dure of Crossland and Servis [11]. Compound 4a (2.41 g, 8.31
mmoles, 96%) was isolated as a light yellow oil and used directly
-1
1
in the next reaction; ir: 1720, 1655, 1360, 1181 cm ; H nmr: δ
7.10 (dd, 1H, J = 15.5, 9.1), 5.89 (d, 1H, J = 15.5), 4.20 (q, 2H, J
= 7.1), 3.99 (m, 2H), 2.99 (s, 3H), 2.69 (m, 1H), 2.10 (m, 1H),
1.76 (m, 1H), 1.65 (m, 2H), 1.57 (m, 3H), 1.41 (m, 2H), 1.30 (t,
13
3H, J = 7.1); C nmr: δ 166.2, 147.7, 122.8, 71.4, 60.3, 39.4,
Representative Procedure for the Oxidation-Wittig Olefination
Sequence: Ethyl (±)-(2E)-3-[(1R*,2R*)-2-(Hydroxymethyl)-
cyclohexyl]-2-propenoate (3a).
38.8, 37.1, 29.9, 24.6, 24.2, 21.7, 14.1; ms (chemical ionization,
+
isobutane): m/z 291 (M +1, 39).
Ethyl (±)-(2E)-3-{(1R*,2S*)-2-[(Methanesulfonyloxy)-
methyl]cyclohexane}-2-propenoate (4b).
The procedure of Corey and Palani [8] was adapted. To a
stirred mixture of 3.60 g (12.9 mmoles) of o-iodoxybenzoic acid
(IBX) [9] in 2 mL of dimethyl sulfoxide was added 1.50 g (10.4
mmoles) of 1a. The white paste was stirred at 23° for 2 hours,
then quenched with 5 mL of water. The mixture was filtered
through Celite and the filter cake was washed with water and
dichloromethane. The layers were separated and the aqueous
phase was extracted with dichloromethane (two times). The
combined organic extracts were dried (magnesium sulfate), and
concentrated under vacuum to afford 1.20 g (8.45 mmoles, 81%)
of 2a as a colorless oil; the product from 4 runs was combined
and used without further purification. The spectral data matched
those reported previously [8].
A solution of 4.80 g (33.8 mmoles) of 2a and 17.4 g (50.0
mmoles) of (carbethoxymethylene)triphenylphosphorane in 125
mL of benzene was stirred and heated under reflux for 16 hours.
The mixture was cooled to 25° and concentrated under vacuum to
afford a brown semisolid mass. The residue was layered onto a
20 cm x 12 cm plug of silica gel in a sintered glass frit and 2 L of
75:25 hexane:ether was poured through under aspirator vacuum.
Concentration of the filtrate afforded an viscous yellow oil that
was purified by flash chromatography on an 80 cm x 2.5 cm
This compound (2.38 g, 8.20 mmoles, 94%) was isolated as a
light yellow oil and used directly in the next step; ir: 1714, 1659,
-1
1
1360, 1182 cm ; H nmr: δ 6.77 (dd, 1H, J = 15.6, 9.6), 5.85 (d,
1H, J = 15.6), 4.16 (q, 2H, J = 7.1), 4.12 (dd, 1H, J = 9.6, 3.7),
3.99 (dd, 1H, J = 9.6, 6.2), 2.98 (s, 3H), 2.04 (m, 1H), 1.94 (m,
1H), 1.87-1.55 (complex, 4H), 1.39-1.19 (complex, 4H), 1.29 (t,
13
3H, J = 7.1); C nmr: δ 166.2, 150.9, 121.6, 72.6, 60.2, 42.7,
40.7, 36.9, 32.1, 28.4, 25.0, 24.9, 14.1; ms (chemical ionization,
+
isobutane): m/z 291 (M +1, 100).
Representative Procedure for Iodide Formation: Ethyl (±)-(2E)-
3-[(1R*,2R*)-2-(Iodomethyl)cyclohexyl]-2-propenoate (5a).
A solution of 0.68 g (2.34 mmoles) of 4a and 1.74 g (11.6
mmoles) of sodium iodide in 25 mL of acetone was stirred and
heated under reflux for 14 hours. The reaction was cooled and con-
centrated under vacuum to afford an orange solid. This residue was
dissolved in 30 mL of water and extracted with ether (two times).
The combined ether extracts were washed with water, 5% sodium
thiosulfate and saturated sodium chloride, then dried (magnesium
sulfate), and concentrated to afford 0.62 g (1.92 mmoles, 82%) of 5a

1052
R. A. Bunce, S. V. Kotturi, C. J. Peeples and E. M. Holt
Vol. 39
as a yellow oil. This product was used without further purification;
Representative Procedure for the Tandem S 2-Michael Synthesis
of Trans-Fused Octahydro-1H-isoindole-1-acetates.
N
-1
1
ir: 1727, 1652 cm ; H nmr: δ 7.02 (dd, 1H, J = 15.6, 9.3), 5.98 (d,
1H, J = 15.6), 4.19 (q, 2H, J = 7.1), 3.08 (dd, 1H, J = 9.8, 7.3), 2.93
(dd, 1H, J = 9.8, 8.0), 2.88 (m, 1H), 1.91 (m, 1H), 1.78-1.55 (com-
Compound 5b (360 mg, 1.12 mmoles) was reacted in the same
manner to give a mixture of 8 and 9. Preparative thin layer chro-
matography showed four bands. Bands 3 and 4 contained prod-
ucts 9 and 8, respectively.
13
plex, 4H), 1.52-1.26 (complex, 4H), 1.30 (t, 3H, J = 7.1); C nmr: δ
166.4, 147.5, 123.0, 60.3, 42.7, 41.3, 30.4, 28.8, 24.9, 21.6, 14.2,
+
11.4; ms (chemical ionization, isobutane): m/z 323 (M +1, 68).
Ethyl (±)-(1S*,3aS*,7aS*)-2-Benzyl-2,3,3a,4,5,6,7,7a-octahy-
dro-1H-isoindole-1-acetate (9).
Ethyl (±)-(2E)-3-[(1R*,2S*)-2-(Iodomethyl)cyclohexyl]-2-
propenoate (5b).
This compound (40 mg, 0.13 mmoles, 12%) was isolated as a
This compound (0.63 g, 1.96 mmoles, 84%) was isolated as a
-1
1
light yellow oil; ir: 1725 cm ; H nmr: δ 7.25 (m, 5H), 4.11 (q,
2H, J = 7.2), 4.04 (d, 1H, J = 12.9), 3.61 (d, 1H, J = 12.9), 3.45
(m, 1H), 2.91 (m, 1H), 2.32 (m, 2H), 1.97 (m, 1H), 1.87-1.46
(complex, 6H), 1.27-0.98 (complex, 4H), 1.25 (t, 3H, J = 7.2);
C nmr: δ 173.0, 140.1, 128.8, 128.1, 126.7, 62.5, 61.0, 60.2,
59.4, 47.5, 42.1, 39.0, 29.5, 26.6, 26.2, 25.7, 14.2; hrms: m/z
-1
1
yellow oil; ir: 1727, 1652 cm ; H nmr: δ 6.70 (dd, 1H, J =
15.6, 9.6), 5.94 (d, 1H, J = 15.6), 4.19 (q, 2H, J = 7.1), 3.28 (dd,
1H, J = 9.9, 2.6), 3.06 (dd, 1H, J = 9.9, 6.0), 2.03 (m, 1H), 1.96-
1.52 (complex, 5H), 1.40-1.18 (complex, 4H), 1.30 (t, 3H, J =
13
13
7.1); C nmr: δ 166.5, 151.2, 121.8, 60.3, 45.9, 41.3, 32.2, 31.9,
25.4, 25.2, 16.1, 13.2; ms (chemical ionization, isobutane): m/z
Calcd. for C
H NO : 301.2036; Found: 301.2033.
19 27 2
+
323 (M +1, 100).
Anal. Calcd. for C
H NO : C, 75.75; H, 8.97; N, 4.65.
19 27 2
Representative Procedure for the Tandem S 2-Michael Synthesis
of Cis-Fused Octahydro-1H-isoindole-1-acetates.
Found: C, 75.61; H, 9.01; N, 4.68.
N
Ethyl (±)-(1R*,3aS*,7aS*)-2-Benzyl-2,3,3a,4,5,6,7,7a-octahy-
dro-1H-isoindole-1-acetate (8).
A solution of 356 mg (1.11 mmoles) of 5a, 132 mg (0.13 mL,
1.23 mmoles) of benzylamine and 111 mg (0.15 mL, 1.23
mmoles) of triethylamine in 5 mL of ethanol was stirred and
heated under reflux for 120 hours. The mixture was cooled to
25° and concentrated to afford a dark brown residue that was
diluted with 20 mL of water and extracted with ether (two times).
The combined ether extracts were washed with water, 5% sodium
thiosulfate and saturated sodium chloride, then dried (magnesium
sulfate), and concentrated to yield a brown oil that was purified
on two 20 cm x 20 cm silica gel preparative thin layer chro-
matography plates. Elution with 99:1 hexane:ether (two times),
95:5 hexane:ether (two times), 90:10 hexane:ether (two times)
and 85:15 hexane:ether (two times) showed four bands. Bands 3
and 4 contained products 7 and 6, respectively.
This compound (236 mg, 0.78 mmoles, 70%) was isolated as a
-1
1
light yellow oil; ir: 1730 cm ; H nmr: δ 7.27 (m, 5H), 4.13 (q,
2H, J = 7.2), 3.96 (d, 1H, J = 13.8), 3.51 (d, 1H, J = 13.8), 2.84
(m, 1H), 2.60 (m, 2H), 2.50 (m, 2H), 1.84-1.72 (complex, 4H),
1.46 (m, 1H), 1.29 (m, 1H), 1.24 (t, 3H, J = 7.2), 1.22 (m, 1H),
13
1.08 (m, 3H); C nmr: δ 172.8, 140.7, 128.5, 128.2, 126.6, 66.5,
60.2, 59.8, 57.3, 51.0, 43.0, 39.1, 29.3, 28.7, 25.9, 25.8, 14.2;
hrms: m/z Calcd. for C
H
NO : 301.2036; Found: 301.2034.
19 27
2
Anal. Calcd. for C
H
NO : C, 75.75; H, 8.97; N, 4.65.
19 27
2
Found: C, 75.50; H, 9.05; N, 4.73.
Representative Procedure for the Preparation of Isothiuronium
Salt 10a from 5a.
Ethyl (±)-(1S*,3aR*,7aS*)-2-Benzyl-2,3,3a,4,5,6,7,7a-octahy-
dro-1H-isoindole-1-acetate (7).
The procedure of Speziale [12] was used. A solution of 660
mg (2.05 mmoles) of 5a and 156 mg (2.05 mmoles) of thiourea
in 5 mL of ethanol was refluxed with stirring for 120 hours.
The resulting mixture was cooled and concentrated to yield 800
mg (2.01 mmoles, 98%) of 10a as a tan solid that was used
without further purification; ir: 3540-2850, 1720, 1660, 1620
This compound (18 mg, 0.06 mmoles, 5%) was isolated as a
-1
1
light yellow oil; ir: 1730 cm ; H nmr: δ 7.26 (m, 5H), 4.13 (q,
2H, J = 7.2), 3.92 (d, 1H, J = 13.8), 3.41 (d, 1H, J = 13.8), 3.21
(m, 1H), 2.92 (m, 1H), 2.49 (m, 2H), 2.31 (m, 2H), 2.02 (m, 1H),
-1
1
13
cm ; H nmr (deuteriodimethyl sulfoxide): δ 9.07 (br s, 4H),
1.71 (m, 1H), 1.63-1.12 (complex, 7H), 1.25 (t, 3H, J = 7.2);
C
7.02 (dd, 1H, J = 15.6, 7.2), 5.93 (d, 1H, J = 15.6), 4.13 (q, 2H,
nmr: δ 172.9, 140.7, 128.3, 128.1, 126.6, 65.3, 60.2, 58.7, 54.8,
J = 7.1), 3.00 (m, 2H), 2.71 (m, 1H), 1.84 (m, 1H), 1.62 (m,
41.0, 35.4, 35.4, 25.5, 24.8, 22.9, 20.9, 14.2; hrms: m/z Calcd.
13
4H), 1.37 (m, 4H), 1.22 (t, 3H, J = 7.1);
C nmr (deuterio-
for C
H NO : 301.2036; Found: 301.2036.
19 27 2
dimethyl sulfoxide): δ 169.8, 165.5, 148.4, 122.5, 60.0, 40.1,
Anal. Calcd. for C
H NO : C, 75.75; H, 8.97; N, 4.65.
19 27 2
33.1, 29.1, 27.0 (2), 23.7, 21.7, 14.2; ms (fast atom bombard-
ment, thioglycerol): m/z 271 (M -I).
Found: C, 75.67; H, 9.08; N, 4.74.
+
Ethyl (±)-(1R*,3aR*,7aS*)-2-Benzyl-2,3,3a,4,5,6,7,7a-octahy-
dro-1H-isoindole-1-acetate (6).
Isothiuronium Salt 10b from 5b.
This compound (268 mg, 0.89 mmoles, 80%) was isolated as a
light yellow oil; ir: 1735 cm ; H nmr: δ 7.26 (m, 5H), 4.12 (q,
2H, J = 7.2), 4.02 (d, 1H, J = 13.2), 3.59 (d, 1H, J = 13.2), 2.98
This salt (790 mg, 1.99 mmoles, 97%) was obtained as a
light brown oil and was used without further purification; ir:
3650-2720, 1730, 1655, 1645 cm ; H nmr (deuteriodimethyl
sulfoxide): δ 9.03 (br s, 4H), 6.75 (dd, 1H, J = 15.6, 6.9), 5.89
(d, 1H, J = 15.6), 4.11 (q, 2H, J = 7.1), 3.19 (m, 1H), 2.94 (m,
-1
1
-1
1
(m, 1H), 2.80 (m, 1H), 2.45 (m, 2H), 2.30 (m, 2H), 1.82 (m, 1H),
13
1.58 (m, 4H), 1.35 (m, 4H), 1.25 (t, 3H, J = 7.2);
C nmr: δ
172.7, 140.2, 128.6, 128.1, 126.7, 66.7, 60.6, 60.2, 56.0, 43.7,
41.3, 35.8, 28.4, 25.7, 24.6, 22.5, 14.3; hrms: m/z Calcd. for
1H), 2.07 (m, 1H), 1.85 (m, 1H), 1.64 (m, 4H), 1.22 (t, 3H, J =
13
7.1), 1.17 (m, 3H), 1.10 (m, 1H);
C nmr (deuteriodimethyl
C
H NO : 301.2036; Found: 301.2035.
sulfoxide): δ 170.0, 165.6, 151.5, 121.6, 59.8, 45.0, 39.7, 35.5,
19 27 2
Anal. Calcd. for C
Found: C, 75.64; H, 9.07; N, 4.77.
H NO : C, 75.75; H, 8.97; N, 4.65.
19 27 2
31.7, 29.8, 24.9, 24.7, 14.2; ms (fast atom bombardment, thio-
glycerol): m/z 271 (M -I).
+

Sep-Oct 2002
Fused-Ring Nitrogen and Sulfur Heterocycles
1053
Representative Procedure for the Synthesis of Sulfur
Heterocycles: (±)-(1R*,3aR*,7aS*)-1,3,3a,4,5,6,7,7a-Octahydro-
benzo[c]thiophene-1-acetic Acid (11).
015) is greatly appreciated. Funds for the 300 and 400 MHz nmr
spectrometers of the Oklahoma Statewide Shared NMR Facility
were provided by NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation, and
Conoco, Inc. Partial support for our mass spectrometer by the
NSF and the Oklahoma Center for the Advancement of Science
and Technology is also appreciated.
The procedure of Speziale [12] was modified. A mixture of
800 mg (2.01 mmoles) of 10a and 10.0 mL of 10% aqueous
potassium hydroxide was stirred and heated under reflux for 8
hours. The mixture was cooled to 0-5° and cautiously acidified
by dropwise addition of 9 M sulfuric acid to pH 2. The resulting
mixture was extracted with ether (two times) and the combined
organic layers were washed with water and saturated sodium
chloride, then dried (sodium sulfate), and concentrated.
Compound 11 (300 mg, 1.50 mmoles, 75%) was obtained as col-
orless needles from ether-hexane, mp 83-84°; ir: 3580-2870,
REFERENCES AND NOTES
[*] Corresponding author. E-mail: rab@okstate.edu
[1] R. A. Bunce, C. J. Peeples and P. B. Jones, J. Org. Chem.,
57, 1727 (1992).
-1
1
1725 cm ; H nmr: δ 11.20-10.40 (br s, 1H), 3.48 (m, 1H), 2.90
[2a] A. R. Pinder, Nat. Prod. Reports, 1, 225 (1984); [b] A. R.
Pinder, Nat. Prod. Reports, 3, 171 (1986); [c] A. R. Pinder, Nat.
Prod. Reports, 4, 527 (1987); [d] A. R. Pinder, Nat. Prod. Reports, 6,
67 (1989); [e] A. O. Plunkett, Nat. Prod. Reports, 11, 581 (1994).
[3] Simple N heterocyclic ketones: [a] J. C. Craig, S.-Y. C.
Lee and S. K. Roy, J. Org. Chem., 43, 347 (1978); [b] I. R. C. Bick,
J. W. Gillard and H.-M. Leow, Aust. J. Chem., 32, 2523 (1979); [c]
C. E. Turner, M. A. Elsohly, L. Hanus and H. N. Elsohly,
Phytochemistry, 20, 1403 (1981); [d] J. A. Lamberton, Y. A.
Geewananda, P. Gunawardana and I. R. C. Bick, J. Nat. Prod., 46,
235 (1983); [e] D. H. G. Medina, M. Pusset, J. Pusset and H.-P.
Husson, J. Nat. Prod., 46, 398 (1983); [f] T. Langenskiöld and M.
Lounasmaa, Heterocycles, 20, 671 (1983); [g] R. Ghirlando, A. S.
Howard, R. B. Katz and J. P. Michael, Tetrahedron, 40, 2879 (1984);
[h] K. Irie, K. Aoe, T. Tanaka and S. Saito, J. Chem. Soc. Chem.
Commun., 633 (1985); [i] J. J. Tufariello and J. M. Puglis,
Tetrahedron Lett., 27, 1265 (1986); [j] J. F. Stevens, H. Hart, H.
Hendriks and T. M. Malingré, Phytochemistry, 31, 3917 (1992); [k]
H. Neuhoefer, L. Witte, M. Gorunovic and F. C. Czygan, Pharmazie,
48, 389 (1993); [l] J. H. Kim, H. Hart and J. F. Stevens,
Phytochemistry, 41, 1319 (1996); [m] A. B. Pomilio, M. D.
González and C. C. Eceizabarrena, Phytochemistry, 41, 1393 (1996).
[4] Simple N, O and S heterocyclic esters: [a] I. Felner-
Caboga and K. Schenker, German Patent 2,100,422 (1971); Chem.
Abstr., 75, 129657x (1971); [b] E. Vedejs, M. J. Mullins, J. M.
Renga and S. P. Singer, Tetrahedron Lett., 519 (1978); [c] T.
Nikiforov, S. Stanchev, B. Milenkov and V. Dimitrov, Synth.
Commun., 20, 1977 (1990); [d] R. A. Bunce and M. J. Bennett,
Synth. Commun., 23, 1009 (1993).
(m, 1H), 2.75 (m, 2H), 2.56 (m, 1H), 2.40 (m, 1H), 1.92 (m, 1H),
1.57 (m, 6H), 1.37 (m, 2H); C nmr: δ 177.5, 48.2, 46.3, 42.2,
42.1, 34.8, 26.5, 26.1, 23.2, 23.0; hrms: m/z Calcd. for
13
C
H SO : 200.0866; Found: 200.0869.
10 16 2
Anal. Calcd. for C
H O S: C, 60.00; H, 8.00. Found: C,
10 16 2
60.28; H, 8.05.
Minor product 12 (6% by gas chromatography) could not be
isolated completely free of compound 11.
(±)-(1R*,3aS*,7aS*)-1,3,3a,4,5,6,7,7a-Octahydrobenzo[c]thio-
phene-1-acetic Acid (13).
This compound (299 mg, 1.50 mmoles, 75%) was obtained as
colorless needles from ether-hexane, mp 131-132°; ir: 3294-
-1
1
2340, 1700 cm ; H nmr: δ 8.20 (br s, 1H), 3.29 (td, 1H, J = 9.8,
3.7), 2.89 (m, 2H), 2.55 (dd, 1H, J = 9.9, 7.7), 2.50 (dd, 1H, J =
13.1, 9.9), 1.94 (m, 2H), 1.79 (tm, 2H, J = 9.1), 1.59 (m, 1H),
13
1.23-0.97 (complex, 5H);
C nmr: δ 177.8, 53.0, 48.6, 48.3,
39.9, 36.6, 31.8, 30.0, 25.5, 25.4; hrms: m/z Calcd. for
SO : 200.0866; Found: 200.0865.
C
H
10 16
2
Anal. Calcd. for C
H O S: C, 60.00; H, 8.00. Found: C,
10 16 2
60.23; H, 8.02.
Minor product 14 (10% by gas chromatography) could not be
isolated completely free of compound 13.
Experimental X-ray Data for 11.
Intensity data were measured on a Brucker P4 diffractometer
with MoK radiation (λ = 0.71073 Å) at room temperature [18].
α
[5] Fused-ring N heterocycles: [a] C. J. Blankley, European
Patent 58,567 (1982); Chem. Abstr., 98, 54484c (1983); [b] R. K.
Boeckman, Jr., J. P. Sabatucci, S. W. Goldstein, D. M. Springer and P.
F. Jackson, J. Org. Chem., 51, 3740 (1986); [c] J. D. Elliott, R. G.
Franz, M. A. Lago and A. Gao, U.S Patent 5,736,564 (1998); Chem.
Abstr., 128, 270534z (1998); [d] See ref. 2a.
All non-hydrogen positions were determined using the SHELXS
[19] structure solution program and refined by full matrix least
2
squares methods on the basis of F using the SHELXL97 [20]
refinement program. Hydrogen atoms were placed in calculated
positions using idealized geometry and constrained to those posi-
[6] J. M. Photis and L. A. Paquette, Organic Syntheses, Wiley:
New York, NY, Coll. Vol. VI, 1988, pp 482-488.
tions during final refinements.
C H O S, formula weight:
10 16 2
200.29, a = 7.164(3) Å, b = 13.375(4) Å, c = 21.708(8) Å, β =
3
[7] The trans-1,2-cyclohexanedimethanol was prepared from
diethyl trans-1,2,3,6-tetrahydrophthalate by (1) hydrogenation over
5% palladium-on-carbon followed by (2) reduction with lithium alu-
minum hydride. Diethyl trans-1,2,3,6-tetrahydrophthalate was pre-
pared using the method described in T. E. Sample, Jr. and L. F. Hatch,
Organic Syntheses, Wiley, New York, NY, Coll. Vol. VI, 1988, pp
454-458.
91.24(4)˚, V = 2135.5(13) Å , Z = 8, monoclinic space group
3
P2 /a, density(calculated) = 1.246 Mg/m , 2361 unique reflec-
1
tions, R = 0.0658.
Structural and atomic parameters have been deposited with the
Cambridge Crystallographic Data Center as deposition no.
177360. Copies may be obtained from the Director, Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge CB2
1EZ.
[8] E. J. Corey and A. Palani, Tetrahedron Lett., 36, 3485
(1995).
[9] D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 113, 7277
(1991).
Acknowledgment.
Support of this work by the Oklahoma Center for the
Advancement of Science and Technology (HR1-035 and HR01-
[10] A. Maercker, Org. React., 14, 270 (1965).
[11] R. K. Crossland and K. L. Servis, J. Org. Chem., 35, 3195

1054
R. A. Bunce, S. V. Kotturi, C. J. Peeples and E. M. Holt
Vol. 39
(1970).
[16a] D. N. Brattesani and C. H. Heathcock, J. Org. Chem., 40,
2165 (1975); [b] C. H. Heathcock, K. M. Smith and T. A.
Blumenkopf, J. Am. Chem. Soc., 108, 5022 (1986); [c] B. Chenera,
C.-P. Chuang, D. J. Hart and C.-S. Lai, J. Org. Chem., 57, 2018
(1992); [d] R. A. Bunce and C. R. Harris, Synth. Commun., 26, 1969
(1996).
[17] W. C. Stille, M. Kahn and A. Mitra, J. Org. Chem., 43,
2923 (1978).
[18] XSCANS Users Manual; Siemens Analytical X-ray
Instruments, Inc., Madison, WI, USA (1991).
[12] A. J. Speziale, Organic Syntheses, Wiley, New York, NY,
Coll. Vol. IV, 1963, pp 401-403.
[13] J. E. Baldwin, J. Chem. Soc., Chem. Commun., 734
(1976).
[14a] A. E. Derome, Modern NMR Techniques for Chemistry
Research, Elsevier Science, New York, NY, 1987, pp 227-230; [b] T.
D. W. Claridge, High-Resolution NMR Techniques in Organic
Chemistry, Elsevier Science, New York, NY, 1999, pp 158, 188 and
197-199.
[15] D. Neuhaus, M. P. Williamson, The Nuclear Overhauser
Effect in Structural and Conformational Analysis, VCH, New York,
NY, 1989, pp 253-306.
[19] G. M. Sheldrick, Acta Cryst., A46, 467 (1990).
[20] G. M. Sheldrick, SHELXL97 Program for the Refinement
of Crystal Structures; University of Gottingen, Germany (1997).