Intramolecular capture of a cyclobutylthionium ion for the synthesis of new strained heterocycles and carbocycles: A rapid assembly of the BCD ring sequence of penitrems

Article abstract of DOI:10.1055/s-2006-949646

The first example of intramolecular interception of a cyclobutyl thionium ion for the synthesis of cyclobutathiochromenes, hexahydrocyclobutaquinolines and hexahydrocyclobutanaphthalenes is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949646

LETTER
2241
Intramolecular Capture of a Cyclobutylthionium Ion for the Synthesis of New
Strained Heterocycles and Carbocycles: A Rapid Assembly of the BCD Ring
Sequence of Penitrems
I
ntramolecular Cap
u
ture of
a
Cy
i
clobuty
d
lthionium Io
o
n
Alberti, Angela M. Bernard, Angelo Frongia,* Pier Paolo Piras,* Francesco Secci, Marco Spiga
Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Mon-
serrato (Cagliari), Italy
Fax +39(070)6754388; E-mail: pppiras@unica.it
Received 13 June 2006
We started by examining the reactivity of derivatives 1a–
Abstract: The first example of intramolecular interception of a cy-
d prepared by nucleophilic addition of the appropriate
clobutyl thionium ion for the synthesis of cyclobutathiochromenes,
thiophenol on the cyclopropyl epoxide 7 (Scheme 2).
hexahydrocyclobutaquinolines and hexahydrocyclobutanaphtha-
lenes is reported.
Derivatives 4a–d were obtained in reasonable yields (40–
Key words: heterocycles, carbocycles, ring expansion, tandem re- 72%) as mixtures of diastereoisomers deriving from the
action, rearrangement
different cis or trans ring fusion (Table 1). The derivative
4b was obtained as a single geometric isomer, mixture of
two regioisomers in a 70:30 ratio.
The preparation of complex carbocyclic1 and
heterocyclic2 compounds continues to be an important tar-
R
get in organic synthesis that requires a constant develop-
C6H5S
SC6H5
OH
SC6H5
ment of new methodologies and a strategic deployment of
known methods. One way of constructing molecular com-
plexity is by combining two or more distinct reactions into
a single transformation. In this context the generation of a
thionium ion from a sulfoxide in a Pummerer reaction and
its intramolecular interception by carbon- or hetero-nu-
cleophiles, represents an important tool for the synthesis
of both carbocycles and heterocycles.3 We recently re-
ported that a cyclobutylthionium ion, generated through
an acid-catalyzed cyclopropylcarbinyl–cyclobutyl ring
(i)
(ii)
R
S
SH
O
H
SAr
4a–d
7
1a–d
O
a: R = H
b: R = m-OMe
c: R = p-F
+
SAr
d: R = p-Me
8a,8c
Scheme 2 Reagents and conditions: (i) MeOH, MeONa, r.t.; (ii)
expansion, was captured by a pendant aryloxy group to PTSA 10%, dry benzene, reflux, 2 h.
furnish new strained versatile cyclobutachromenes.4 The
synthetic potential of this method is greatly increased by
the results we are here reporting on the synthesis of deriv-
atives 4–6 by the tandem acid-catalyzed ring-enlarge-
ment–annulation reaction of the cyclopropyl carbinols 1–
3 (Scheme 1).
Table 1 Synthesis of Cyclobutathiochromenes 4a–d
Compd
R
Yield of 1 Yield of 4 Ratioofgeometric
(%)
(%)
isomers (4)a
a
b
c
H
75
72
75:25
m-OMe
p-F
72
70
100:0
R'
65
40
80:20
SC6H5
R'
PTSA
C6H5S
X
d
p-Me
70
70
80:20
benzene, reflux
2 h
a The cis or trans configuration was not attributed for each individual
R
OH
X
isomer.
R
1: X = S
4: X = S
2: X = NH
3: X = CH2
5: X = NH
6: X = CH2
Variable, but small, amounts of cyclobutanones 8 were al-
ways present except in the case of 4a and 4c where the
corresponding cyclobutanones 8a and 8c were obtained in
10% and 20% probably as a consequence of the reduced
nucleophilicity of the aromatic ring in comparison with 4b
and 4d.
Scheme 1
SYNLETT 2006, No. 14, pp 2241–2245
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949646; Art ID: G18406ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.0
9
.2
0
0
6
The synthesis of nitrogen-containing heterocycles by the
tandem acid-catalyzed ring-enlargement–annulation reac-
tion of cyclopropyl carbinols 2 presents a real challenge.

2242
G. Alberti et al.
LETTER
Within the acidic reaction conditions used to generate the a sequential, tandem cascade or domino reaction.7a–d,8a–e
thionium ion, the nitrogen atom should be the first to be In connection with this, our previous attempt to cyclize a
protonated, being more basic than the oxygen atom of the type 3 cyclopropyl carbinol which lacks the ipso-oxygen4
hydroxyl group and hence the nucleophilicity of the aro- led only to the corresponding cyclobutanone probably as
matic ring will be reduced. A successful strategy would a consequence of the insufficient nucleophilicity of the ar-
require the generation of a leaving group under non-acidic omatic ring. We therefore reasoned that the introduction
conditions (a subject of current research) or the fine-tun- of an electron-donating substituent in the aromatic ring
ing of the basicity of the nitrogen atom with minimal det- should favor the capture of the intermediate cyclobutyl
riment to the nucleophilicity of the aromatic ring.
thionium ion.
Next we prepared the cyclopropyl carbinols 2a–c through
nucleophilic ring-opening of the cyclopropyl epoxide 7 by
the corresponding aniline and treated them with TsOH in
refluxing benzene (Scheme 3). Unexpectedly the ring ex-
pansion of derivatives 2 occurred cleanly only in the case
of 2c where a p-OMe group was present in the aromatic
ring, leading to moderate yields of the dihydroquinoline
5c (42% yield) to which the cis geometry was tentatively
assigned. In all the other cases, the starting material was
recovered even after long refluxing.
Table 2 Synthesis of Hexahydrocyclobutanaphthalenes 6b–e
R
R¢
R¢¢
Yield of 3 Yield of 6
(%)
61
60
70
60
(%)
a
b
c
Me
Me
Me
H
p-OMe
m-OMe
m-Me
H
H
H
H
0
68
79a
67
d
e
m-OMe
m-Me
Finally, we directed our attention to the reactivity of the
cyclopropyl carbinols of type 3 (X = CH2). They appeared
to our eyes particularly interesting because their success-
ful cyclization to give type 6 derivatives would represent
an easy access to the important BCD ring sequence
present in the family of the biologically active penitrems
(Figure 1).5 The penitrems represent a class of novel in-
dole alkaloids that have attracted attention as a result of
their potent neurotoxic activity and complex architec-
tures.6
H
COOMe 66
65a
a Traces of cyclobutanone were evident.
Consequently, we prepared the derivative 3a (path i) with
a p-OMe substituent in the aromatic ring by reaction of
the lithium salt of cyclopropylphenylsulfide9 with 9a
(Scheme 4). Ring expansion of 3a by treatment with
PTSA in C6H6 led only to the formation of the cyclobu-
tanone 11a. Next we prepared, in the same way, the deriv-
atives 3b–d with a methoxy or a methyl group in the meta
position of the aromatic ring that is suitably placed to ac-
tivate an electrophilic attack to form a six-membered ring.
Successive acid-catalyzed ring expansion, gratifyingly,
led cleanly to the formation of the expected three-ring car-
bocycles 6b–d (Table 2).10,11 Ring expansion of 3e ob-
tained by reaction of 10 with 1-phenylthiocyclopropyl
carboxaldehyde (path ii) led successfully to 6e10,11 carry-
ing an ester group as a suitable precursor of the double
bond present in the cyclohexyl moiety of the BCD ring se-
quence of penitrems.
O
H
OH
B
OH
A
H
F
C
E
O
D
NH
penitrem D
Figure 1
In summary, we have demonstrated that the synthetic po-
tentialities of the acid-catalyzed ring expansion of 1-phen-
ylthio cyclopropyl carbinols can be extended to create
new carbo- and heterocyclic derivatives containing the
In addition, there are relatively few examples in the liter-
ature of cationic cyclization reactions for the synthesis of
carbocycles involving the intramolecular cyclization of
carbon-centered nucleophiles onto, in situ generated car-
benium ion or heteroatom-stabilized carbocation, through
no reaction
2a,2b
SC6H5
SC6H5
OMe
(i)
(ii)
OH
O
R
NH2
2c
C6H5S
NHAr
7
2a–c
NH
a: R = H
b: R = Me
c: R = OMe
H
5c
Scheme 3 Reagents and conditions: (i) dry EtOH, reflux; (ii) PTSA 1.1 equiv, dry benzene, reflux, 2 h.
Synlett 2006, No. 14, 2241–2245 © Thieme Stuttgart · New York

LETTER
Intramolecular Capture of a Cyclobutylthionium Ion
2243
O
SC6H5
Li
+
R
R'
9a–d
(i) for 3a–d
R'
O
C6H5S
SC6H5
OH
R'
(iii)
or
R
R
R''
R''
6b–e
C6H4-p-OMe
3a–e
11a
(ii) for 3e
a: R = Me, R' = p-OMe, R'' = H
b: R = Me, R' = m-OMe, R'' = H
c: R = Me, R' = m-Me,
d: R = H, R' = m-OMe, R'' = H
e: R = H, R' = m-Me, R''' = COOMe
R'' = H
COOMe
SC6H5
CHO
+
10
Scheme 4 Reagents and conditions: (i) THF, 0 °C to r.t.; (ii) LDA, THF, –78 °C; (iii) PTSA (10 mol%), dry benzene, reflux, 2 h.
(5) (a) Smith, A. B. III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J.
Am. Chem. Soc. 2000, 122, 11254. (b) Rivkin, A.;
Gonzàlez-Lòpez de Turiso, F.; Nagashima, T.; Curran, D. P.
J. Org. Chem. 2004, 69, 3719. (c) Smith, A. B. III; Kanoh,
N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hartz, R. A.;
Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. Chem. Soc. 2003,
125, 8228.
(6) (a) Wilson, B. J.; Wilson, C. H.; Hayes, A. W. Nature
(London) 1968, 220, 77. (b) de Jesus, A. E.; Steyn, P. S.; van
Heerrden, F. R.; Vleggar, R.; Wessels, P. L.; Hull, W. E. J.
Chem. Soc., Perkin Trans. 1 1983, 1857.
(7) (a) Smit, W. A.; Krimer, M. Z.; Vorobeva, E. A.
Tetrahedron Lett. 1975, 2451. (b) Smit, W. A.; Semenovski,
A. V.; Kucherov, V. F.; Chernova, T. N.; Krimer, M. Z.;
Lubinskaya, O. V. Tetrahedron Lett. 1971, 3101.
(c) Alderdice, M.; Weiler, L. Can. J. Chem. 1981, 59, 2239.
(d) Edstrom, E.; Livinghouse, T. J. Chem. Soc., Chem.
Commun. 1986, 279.
(8) (a) Trost, B. M.; Chen, D. W. C. J. Am. Chem. Soc. 1996,
118, 12541. (b) Overman, L. E.; Pennington, L. D. J. Org.
Chem. 2003, 68, 7143. (c) Ando, S.; Minor, K. P.; Overman,
L. E. J. Org. Chem. 1997, 62, 6379. (d) Gahman, T. C.;
Overman, L. Tetrahedron 2002, 58, 6473. (e) Hirst, G. C.;
Johnson, T. O.; Overman, L. E. J. Am. Chem. Soc. 1993, 115,
2992.
(9) Cyclopropylphenyl sulfide is a rather expensive commercial
product, which can be conveniently prepared using cheap
starting materials: Tanaka, K.; Uneme, H.; Matsui, S.; Kaji,
A. Bull. Chem. Soc. Jpn. 1982, 55, 2965.
(10) Derivatives 6b–e are inseparable mixtures of the two
possible regioisomers of cyclization (6b and 6d in the ratio
of 90:10, while 6c in a ratio of 82:18 and 6e in a ratio of
66:34).
(11) A cis geometry was tentatively assigned to the R group and
the phenylthio group of derivatives 6b–e, on the basis of the
steric constraints present during the cyclization step. In any
case, we were not able to register any NOE effects between
the protons of the phenylthio and the methyl group of
compound 6b, but we recorded the presence of a NOE effect
between the benzylic proton and the methyl group of the
cyclobutyl moiety if a suitably activated aromatic ring is
tethered to the cyclopropyl ring.12 New examples of the
capture of a cyclobutylthionium ion to create new hetero-
cycles will be reported in due course.
Acknowledgment
Financial support from the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica, Rome, and by the University of Cagliari
(National Project ‘Stereoselezione in Sintesi Organica. Metodolo-
gie ed Applicazioni’) and from CINMPIS is gratefully acknowled-
ged.
References and Notes
(1) (a) Bernard, A. M.; Frongia, A.; Secci, F.; Delogu, G.;
Ollivier, J.; Piras, P. P.; Salaun, J. Tetrahedron 2003, 59,
9433. (b) Bernard, A. M.; Frongia, A.; Secci, F.; Piras, P. P.
Chem. Commun. 2005, 3853. (c) Namyslo, J. C.; Kaufmann,
D. E. Chem. Rev. 2003, 103, 1485. (d) Lee-Ruff, E.;
Mladenova, G. Chem. Rev. 2003, 103, 1449. (e) Murakami,
M.; Kadowaki, S.; Fujimoto, A.; Ishibashi, M.; Matsuda, T.
Org. Lett. 2005, 7, 2059. (f) Imagawa, H.; Iyenaga, T.;
Nishizawa, M. Org. Lett. 2005, 7, 451.
(2) (a) Bernard, A. M.; Floris, C.; Frongia, A.; Secci, F.; Piras,
P. P. Tetrahedron 2004, 60, 449. (b) Bernard, A. M.;
Frongia, A.; Secci, F.; Piras, P. P. Org. Lett. 2003, 5, 2923.
(c) Bernard, A. M.; Frongia, A.; Secci, F.; Piras, P. P.; Spiga,
M. Org. Lett. 2005, 7, 4565. (d) Fox, D. J.; House, D.;
Warren, S. Angew. Chem. Int. Ed. 2002, 41, 2462.
(3) (a) Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch,
S. M. Synlett 2002, 851. (b) Padwa, A.; Bur, S. K. Chem.
Rev. 2004, 104, 2401. (c) Witulski, B.; Bergstraßer, U.;
Goßmann, M. Tetrahedron 2000, 56, 4747.
(4) Bernard, A. M.; Cadoni, E.; Frongia, A.; Secci, F.; Piras, P.
P. Org. Lett. 2002, 4, 2565.
Synlett 2006, No. 14, 2241–2245 © Thieme Stuttgart · New York

2244
G. Alberti et al.
LETTER
compound obtained by desulfuration of 6b with Raney
S, 9.76. Found: C, 73.10; H, 7.37; S, 9.78.
nickel.
Procedure for the Synthesis of Methyl 3-Hydroxy-2-(3-
methylbenzyl)-3-[1-(phenylthio)cyclopropyl]propanoate
(3e).
(12) All new compounds have been fully characterized by 1H
NMR (300 MHz), 13C NMR (75.4 MHz), IR, GLC mass
spectra (70 eV) and elemental analyses. Selected analytical
data for some representative derivatives are reported.
General Procedure for the Synthesis of 1a–d.
To a stirred solution of lithium diisopropylamide (LDA),
prepared from diisopropylamine (1.3 mL, 9.2 mmol) and n-
BuLi (1.2 M in hexane; 7.66 mL, 9.2 mmol) in dry THF (30
mL) in the customary manner, cooled at –78 °C, a solution
of methyl 3-(3-methylphenyl)propanoate (1.64 g, 9.2 mmol)
in THF (10 mL) was added dropwise. After stirring for 1 h
at the same temperature, the 1-(1-phenylsulfanyl)cyclo-
propyl carbaldehyde (1.64 g, 9.2 mmol) in THF (10 mL) was
added. After 16 h, the mixture was diluted with Et2O and
washed with 10% NaHCO3. The organic layer was dried
over anhyd Na2SO4 and concentrated under vacuum. The
residue was purified by chromatography on a silica gel
column using light PE–Et2O (1:1) as eluent. Spectral data
refer to a 50:50 mixture of two inseparable diastereoisomers.
Yellow oil; yield 66%. IR (neat): 3470, 1740 cm–1. 1H NMR
(CDCl3): d = 0.85–1.26 (m, 8 H), 2.28 (s, 3 H), 2.31 (s, 3 H),
2.82–2.92 (m, 2 H), 3.13–3.20 (m, 2 H), 3.39–3.68 (m, 4 H),
3.49 (s, 3 H), 3.61 (s, 3 H), 6.92–7.50 (m, 18 H). 13C NMR:
d = 11.5, 13.6, 13.9, 14.6, 21.3, 22.6, 29.3, 31.9, 33.8, 36.2,
49.8, 51.4, 51.8, 52.1, 74.3, 75.9, 125.8, 126.3, 126.4, 127.0,
127.2, 128.1, 128.3, 128.7, 128.8, 129.5, 129.9, 135.3,
135.8, 137.8, 138.0, 138.9, 174.8, 176.0.
To a stirred solution of Na (119.8 mg, 5.21 mmol) in MeOH
(20 mL) at r.t. under argon, thiophenol (0.57 mg, 5.21 mmol)
in MeOH (5 mL) was added dropwise. After 30 min, epoxide
7 (1 g, 5.21 mmol) was added and the reaction mixture was
stirred for 16 h. After this time the MeOH was evaporated
under vacuum and the residue dissolved in Et2O. The
ethereal solution was washed with 1 N NaOH, brine, dried
on anhyd Na2SO4 and concentrated under vacuum. The
crude product was purified by chromatography on silica gel
column using light PE–Et2O (1:1) as eluent.
2-(Phenylsulfanyl)-1-[1-(phenylsulfanyl)cyclopropyl]eth-
anol (1a): yellow oil; yield 75%. IR (neat): 3420 cm–1. 1H
NMR (CDCl3): d = 0.90–1.21 (m, 4 H), 2.60 (br s, 1 H), 2.95
(dd, 1 H, J = 14.0, 9.9 Hz), 3.51–3.58 (m, 2 H), 7.12–7.42
(m, 10 H). 13C NMR (CDCl3): d = 12.0, 14.4, 29.3, 39.8,
72.0, 126.0, 126.2, 128.7, 128.9, 128.9, 129.3, 135.0, 135.8.
MS: m/z (%) = 302 (45) [M+], 285 (2), 193 (43), 175 (62),
162 (28), 149 (28), 123 (91), 109 (100), 91 (58), 77 (67), 45
(58). Anal. Calcd for C17H18OS2: C, 67.51; H, 6.00; S, 21.20.
Found: C, 67.48; H, 6.01; S, 21.22.
General Procedure for the Synthesis of Derivatives 4a–d,
5c, 6b–e.
General Procedure for the Synthesis of 2a–c
A solution of the appropriate amine (2.3 mmol) and of the
2-[1-(phenylsulfanyl)cyclopropyl]epoxide (7, 450 mg, 2.3
mmol) in dry EtOH (10 mL) was refluxed for 16 h. After this
time the solvent was evaporated under vacuum and the
residue was purified by chromatography on a silica gel
column using light PE–Et2O (1:1) as eluent.
1-[1-(Phenylsulfanyl)cyclopropyl]-2-(4-toluidino)ethanol
(2b): yellow oil; yield 45%. IR (neat): 3340 cm–1. 1H NMR
(CDCl3): d = 0.96–1.19 (m, 4 H), 2.22 (s, 3 H), 3.11 (dd, 1
H, J = 9.3, 12.0 Hz), 3.13 (br s, 1 H), 3.48 (dd, 1 H, J = 3.3,
12.0 Hz), 3.59 (dd, 1 H, J = 3.3, 9.3 Hz), 6.49 (d, 2 H, J = 8.4
Hz), 6.57 (d, 2 H, J = 8.4 Hz), 6.94 (d, 2 H, J = 8.4 Hz),
7.14–7.29 (m, 2 H), 7.46 (d, 1 H, J = 6.9 Hz). 13C NMR
(CDCl3): d = 12.7, 13.8, 20.3, 28.8, 48.9, 73.4, 113.5, 115.2,
126.2, 128.8, 129.1, 129.7, 136.1, 145.6. MS: m/z (%) = 299
(16) [M+], 190 (3), 172 (2), 120 (100), 109 (2), 91 (12), 77
(9). Anal. Calcd for C18H21NOS: C, 72.20; H, 7.07; N, 4.68;
S, 10.71. Found: C, 72.18; H, 7.08; N, 4.69; S, 10.71.
General Procedure for the Synthesis of 3a–d
To a solution of cyclopropylphenylsulfide (1.8 g, 12 mmol)
in dry THF (40 mL), under Argon n-BuLi (7.5 mL, 12 mmol,
1.6 M solution in hexane) was added dropwise at 0 °C. After
stirring for 5 h the resulting mixture was cooled to –40 °C
and the ketone or aldehyde (12 mmol) was added. After 16
h, the reaction mixture was quenched with sat. aq NH4Cl (10
mL) and extracted with Et2O. The organic layer was dried on
anhyd Na2SO4 and concentrated under vacuum. The crude
oil was purified by chromatography on a silica gel column
using light PE–Et2O (1:1) as eluent.
A stirred solution of cyclopropylcarbinol 1–3 (1.2 mmol)
and PTSA (20 mg, 0.12 mmol for 1a–d, 3a–d; 220 mg, 1.3
mmol for 2c and 3e) in dry benzene (10 mL) was refluxed for
2 h in a Dean–Stark apparatus. The reaction mixture was
then washed with 10% NaHCO3 and brine, dried over anhyd
Na2SO4 and concentrated under vacuum. The residue was
chromatographed on a silica gel column using Et2O–light PE
(1:1) as eluent.
8b-(Phenylsulfanyl)-1,2a,3,8b-tetrahydro-2H-cyclo-
buta[c]thiochromene (4a): mixture of cis/trans isomers
(75:25).
Major isomer: yellow oil; yield 51%. 1H NMR (CDCl3): d =
1.78–1.86 (m, 1 H), 2.29–2.40 (m, 1 H), 2.47–2.56 (m, 2 H),
2.78 (dd, 1 H, J = 13.2, 9.0 Hz), 3.16 (dd, 1 H, J = 12.9, 5.4
Hz), 2.85–2.91 (m, 1 H), 3.10–3.16 (m, 1 H), 7.04–7.44 (m,
9 H). 13C NMR (CDCl3): d = 21.8, 32.1, 35.7, 44.2, 55.2,
125.7, 126.4, 128.2, 128.4, 129.5, 132.9, 134.6, 135.0,
140.1. MS: m/z (%) = 284 (35) [M+], 256 (3), 175 (100), 160
(10), 147 (90), 134 (30), 109 (45), 89 (10), 65 (30). Anal.
Calcd for C17H16S2: C, 71.79; H, 5.67; S, 22.54. Found: C,
71.68; H, 5.61; S, 22.8.
Minor isomer: yellow oil; yield 21%. 1H NMR (CDCl3): d =
1.94–2.13 (m, 4 H), 2.76–2.90 (m, 1 H), 3.01 (dd, 1 H,
J = 13.2, 10.5 Hz), 3.16 (dd, 1 H, J = 13.2, 4.8 Hz), 7.19–
7.63 (m, 9 H). 13C NMR (CDCl3): d = 23.2, 32.1, 34.9, 46.5,
65.8, 126.2, 128.0, 128.7, 128.9, 129.9, 132.4, 134.2, 135.8,
136.4. MS: m/z (%) = 284 (20) [M+], 256 (3), 221 (5), 175
(100), 160 (15), 147 (95), 134 (34), 109 (65), 91 (9), 77 (16),
65 (26). Anal. Calcd for C17H16S2: C, 71.79; H, 5.67; S,
22.54. Found: C, 71.70; H, 5.60; S, 22.7.
4-(3-Methoxyphenyl)-2-[1-(phenylsulfanyl)cyclo-
propyl]butanol (3b): colorless oil; yield 60%. IR (neat):
3460 cm–1. 1H NMR (CDCl3): d = 0.92–1.32 (m, 4 H), 1.25
(s, 3 H), 1.78 (s, 1 H), 1.90–2.10 (m, 2 H), 2.65–2.77 (m, 2
7-Methoxy-8b-(phenylsulfanyl)-1,2,2a,3,4,8b-hexahydro-
cyclobuta[c]quinoline (5c): colorless oil; yield 42%. 1H
NMR (CDCl3): d = 1.83–1.91 (m, 2 H), 2.12–2.19 (m, 1 H),
2.41–2.51 (m, 1 H), 2.84–2.89 (m, 3 H), 3.76–3.80 (m, 1 H),
3.77 (s, 3 H), 6.47 (d, 1 H, J = 8.7 Hz), 6.66 (dd, 1 H J = 8.7,
3.0 Hz), 7.14–7.38 (m, 6 H). 13C NMR (CDCl3): d = 18.6,
36.9, 41.3, 42.7, 51.0, 55.8, 114.0, 114.9, 116.2, 128.2,
128.5, 133.2, 135.8, 138.8, 152.5. MS: m/z (%) = 297 (11)
[M+], 268 (10), 253 (5), 188 (100), 173 (10), 160 (11), 145
H), 3.78 (s, 3 H), 6.71–6.77 (m, 4 H), 7.15–7.48 (m, 5 H). 13
C
NMR (CDCl3): d = 13.4, 24.6, 30.3, 35.0, 42.2, 55.1, 74.6,
111.0, 114.0, 120.7, 126.0, 128.6, 129.2, 129.4, 136.9,
144.0, 159.5. MS: m/z (%) = 219 (4) [M+ – 109], 189 (13),
179 (14), 150 (24), 135 (39), 121 (100), 109 (22), 91 63), 77
(29), 43 (27). Anal. Calcd for C20H24O2S: C, 73.13; H, 7.36;
Synlett 2006, No. 14, 2241–2245 © Thieme Stuttgart · New York

LETTER
(6), 117 (7), 96 (5), 71 (5), 57 (6), 43 (4). Anal. Calcd for
Intramolecular Capture of a Cyclobutylthionium Ion
(41), 109 (100), 91 (4), 77 (15), 65 (32).
2245
C18H19NOS: C, 72.69; H, 6.12; N, 4.71; S, 10.78. Found: C,
72.60; H, 6.05; N, 4.73; S, 10.80.
Third isomer (10%): MS: m/z (%) = 338 (100) [M+], 295
(50), 250 (64), 235 (50), 221 (27), 202 (31), 197 (25), 189
(11), 147 (20), 128 (17), 115 (24), 91 (10), 77 (8), 59 (21).
Fourth isomer (24%): MS: m/z (%) = 338 (100) [M+], 295
(60), 250 (62), 235 (45), 221 (27), 202 (45), 197 (25), 189
(20), 169 (75), 155 (32), 141 (44), 128 (37), 115 (47), 91
(12), 77 (21), 59 (51).
6-Methoxy-2a-methyl-8b-(phenylsulfanyl)-1,2,2a,3,4,8b-
hexahydrocyclobuta[a]naphthalene (6b): spectral data refer
to a 90:10 mixture of two inseparable regioisomers.
Colorless oil; yield 68%. 1H NMR (CDCl3): d = 1.43 (s, 6 H),
1.45–1.89 (m, 8 H), 2.15–2.24 (m, 2 H), 2.43–2.64 (m, 6 H),
3.71 (s, 3 H), 3.77 (s, 3 H), 6.53–7.53 (m, 16 H).
Major isomer: MS: m/z (%) = 228 (2) [M+ – 28], 267 (2), 233
(4) 201 (100), 185 (4), 159 (35), 144 (10), 128 (20), 109 (85),
91 (13), 77 (30), 65 (60), 39 (40).
Procedure for the Synthesis of 2-[1-(Phenylsulfanyl)cy-
clopropyl]epoxide (7).
To a solution of dimethyloxosulfonium methylide, prepared
under Argon from pentane washed NaH (0.2 g, 4.9 mmol,
60% mineral oil dispersion) trimethyloxosulfonium iodide
(1 g, 4.9 mmol) and 10 mL of DMSO, was added at r.t. a
solution of 1-(phenylthio)cyclopropane carbaldehyde (0.8 g,
4.5 mmol) in 5 mL of DMSO. After 6 h, 20 mL of brine was
added and the mixture was extracted with Et2O. The ethereal
solution was dried on anhyd Na2SO4 and concentrated under
vacuum. The crude product was purified by chromatography
on silica gel column using light PE–Et2O (1:1) as eluent.
Colorless oil; yield 82%. 1H NMR (CDCl3): d = 0.88–1.26
(m, 4 H), 2.49 (dd, 1 H, J = 2.4, 5.1 Hz), 2.70 (dd, 1 H,
J = 3.9, 5.1 Hz), 3.22 (dd, 1 H, J = 2.4, 3.9 Hz), 7.17–7.45
(m, 5 H). 13C NMR (CDCl3): d = 11.2, 13.9, 25.1, 46.8, 54.1,
126.2, 128.7, 129.1, 135.7. MS: m/z (%) = 192 (4) [M+], 147
(6), 123 (82), 110 (33), 91 (35), 77 (33), 65 (58), 45 (89), 39
(100). Anal. Calcd for C10H10OS: C, 67.38; H, 5.65; S,
17.99. Found: C, 67.30; H, 5.68; S, 18.04.
Minor isomer: MS: m/z (%) = 201 (5) [M+ – 109], 189 (100),
185 (10), 173 (7), 156 (10), 147 (17), 121 (25), 109 (45), 91
(62), 77 (51), 65 (64), 51 (30), 39 (65).
Methyl-6-methyl-8b-(phenylsulfanyl)-1,2,2a,3,4,8b-hexa-
hydrocyclobuta[a]naphthalene-3-carboxylate (6e): yellow
oil; yield 65%. Mixture of four inseparable isomers
(50:16:10:24). IR (neat): 1740 cm–1. 1H NMR (CDCl3): d =
1.62–1.86 (m, 8 H), 2.02–2.64 (m, 12 H), 2.30 (s, 3 H), 2.32
(s, 3 H), 2.46 (s, 3 H), 2.47 (s, 3 H), 2.66–3.20 (m, 12 H),
3.64 (s, 3 H), 2.65 (s, 3 H), 2.67 (s, 3 H), 2.71 (s, 3 H), 6.90–
7.42 (m, 32 H).
First isomer (50%): MS: m/z (%) = 338 (4) [M+], 229 (62),
197 (11), 169 (93), 154 (45), 141 (35), 128 (32), 109 (100),
91 (4), 77 (10), 65 (28).
Second isomer (16%): MS: m/z (%) = 338 (7) [M+], 261
(14), 229 (75), 197 (25), 169 (93), 154 (50), 141 (52), 128
Synlett 2006, No. 14, 2241–2245 © Thieme Stuttgart · New York