Surprisingly facile addition of thiols to the double bonds of bicyclopropylidene and other methylenecyclopropanes

Article abstract of DOI:10.1002/(SICI)1099-0690(199808)1998:8<1535::AID-EJOC1535>3.0.CO;2-P

The addition of thiols 8a-h onto the double bonds of bicyclopropylidene (1) and methylenespiropentane (2) proceeds quantitatively in benzene at 20 to 75 °C in the absence of catalysts or radical initiators to give products 9, 10 with complete retention of

Full text of DOI:10.1002/(SICI)1099-0690(199808)1998:8<1535::AID-EJOC1535>3.0.CO;2-P

FULL PAPER
Cyclopropyl Building Blocks for Organic Synthesis, 46[᭛]
Surprisingly Facile Addition of Thiols to the Double Bonds of
Bicyclopropylidene and Other Methylenecyclopropanes
Sergei I. Kozhushkov, Melanie Brandl, and Armin de Meijere*
Institut für Organische Chemie der Georg-August-Universität Göttingen,
Tammannstrasse 2, D-37077 Göttingen, Germany
Fax (internat.): ϩ 49 (0)551/ 399475
E-mail: ameijer1@uni-goettingen.de
Received March 11, 1998
Keywords: Radical reactions / Spiro compounds / Additions / Sulfides / Amino acids
The addition of thiols 8a–h onto the double bonds of
bicyclopropylidene (1) and methylenespiropentane (2)
proceeds quantitatively in benzene at 20 to 75 °C in the
cyclopropylacetic acid (15), and the amino acids 17, 19
containing bicyclopropylidene or methylenespiropentane
fragments, does not proceed stereoselectively, though in all
absence of catalysts or radical initiators to give products 9, cases the mercapto function adds to the double bond with
10 with complete retention of both three-membered rings.
Methylenespiropentane (2) yields exclusively the anti-
Markovnikov adduct 10. The unsubstituted methylene-
cyclopropane (3) gives 9% of the ring-opened compound 12
in addition to the anti-Markovnikov adduct 11. The addition
of thiols to n-heptylbicyclopropylidene (13), methylene-
retention of the cyclopropane ring to give interesting new
amino acids containing bicyclopropyl and spiropentyl
fragments, respectively. The probable mechanism of this
thiol addition is discussed in the light of a test with the
cyclizing intramolecular addition of 2-(2-methylene-
cyclopropyl)ethanethiol 27.
Strain in an organic molecule often correlates with in-
creased reactivity, at least for certain types of reactions[1]
.
Thus the chemistry of highly strained alkenes like the un-
usual tetrasubstituted alkene, bicyclopropylidene (1), as
well as methylenespiropentane (2) and methylenecyclopro-
pane (3) has proved to be fruitful both towards synthetic
applications of such units[2][3], as well as understanding cer-
tain reaction principles[4]. Bicyclopropylidene (1) and meth-
ylenespiropentane (2) are both more highly strained cyclo-
propanated derivatives[2] of methylenecyclopropane (3), a
molecule which occurs as a subunit in the particularly
physiologically active natural amino acids α-(methylene-
cyclopropyl)glycine (4)[5] and hypoglycine A (5)[6]. As a
consequence of its high lying HOMO[7] in addition to its
high total strain energy[2], bicyclopropylidene is uniquely
reactive towards a wide range of electrophiles and cyclo-
ring-opening and ring-enlargement reactions to give com-
plex mixtures of products. This is a consequence of cationic
intermediates in the bromination of alkenes. As thiols nor-
mally add to C,C-multiple bonds via radical or carbanionic
intermediates[9], we have tested the chemical behaviour of
the peculiar alkenes 1Ϫ3 towards thiols.
In only a few cases so far reported in the literature does
the addition of thiols onto a double bond not require rad-
ical initiators or acidic (basic for acceptor-activated olefins)
catalysts, and all are highly strained allenes of the type 6.
While the radical addition of thiophenol (8a) onto these
alkenylidenecyclopropanes 6 occurs without an initiator in
benzene at 25°C[10], the addition of 8a onto FeistЈs methyl
ester (7) has been reported to require heating at 100°C for
15 h in the presence of di-tert-butyl peroxide[11]. The readily
proceeding addition of 8a to highly strained CϪC single
bonds like the central ones in [1.1.1]propellanes[12] or bi-
philes[2]
.
Unexpectedly, however, the relative rates of bromine ad-
dition to bicyclopropylidene (1), methylenespiropentane (2)
as well as methylenecyclopropane (3) were found to be al-
most the same as those to analogously oligomethyl-substi-
tuted ethene derivatives[8], i.e. strain and reactivity of these
compounds do not directly correlate, at least for the bro-
mination which for 1 and 2 was mostly accompanied by
[᭛] Part 45: C. Zorn, A. Goti, A. Brandi, K. Johnsen, S. I. Kozhush-
kov, A. de Meijere, J. Chem. Soc., Chem. Commun. 1998, sub-
mitted; Part 44: M. Brandl, S. I. Kozhushkov, S. Bräse, A. de
Meijere, Eur. J. Org. Chem. 1998, 453Ϫ457.
Eur. J. Org. Chem. 1998, 1535Ϫ1542
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0808Ϫ1535 $ 17.50ϩ.50/0
1535

S. I. Kozhushkov, M. Brandl, A. de Meijere
FULL PAPER
cyclobutanes[13] without added radical initiators are also
believed to be radical reactions.
But -cysteine [8i, R ϭ CH2CH(NH2)COOH] did not re-
act with bicyclopropylidene (1), neither in benzene nor in
Surprisingly, the addition of 8a onto the double bonds of methanol solution.
the alkenes 1Ϫ3 in deuterobenzene occurs at room tempera-
ture in the dark and exothermally. The reactions of all three
hydrocarbons were complete within 1 h, 1 and 2 gave the
adducts 9a, 10 quantitatively with complete retention of
both three-membered rings, as detected by H-NMR spec-
troscopy, and the spectrum indicated such a purity as if 9a,
n-Heptylbicyclopropylidene (13) also reacted quantitat-
ively and without ring opening with 8a at 75°C, but un-
selectively to give an unseparable mixture of all four pos-
sible regio- and diastereoisomers 14 (ratio 6:5:3:1, Scheme
2). According to the 13C-NMR spectrum of the mixture,
the two major isomers bear the phenylthio and the heptyl
group on the same three-membered ring.
1
10 had been purified by column chromatography (Scheme
1).
(Methylenecyclopropyl)acetic acid (15) which has been
shown to be formed by enzymatic degradation of hypogly-
cine A (5) and is believed to play a crucial role in the bio-
logical action of 5[6], also reacts with thiols 8a, d, i giving
mixtures of cis- and trans-isomers of the 2-substituted
cyclopropylacetic acid derivatives 16a, b, c (Scheme 3).
Scheme 1
These additions to 15, especially that of mercaptoetha-
nol (8d), proceeded more slowly than those to 1, 2, and
3, and the isolated yields are lower, but the main feature
Ϫ addition onto the double bond with retention of the
cyclopropane fragment Ϫ remains the same. Only in the
reaction with thiophenol (8a) were traces of ring-opened
1
products detected upon H-NMR monitoring. In contrast
to bicyclopropylidene (1), compound 15 really did un-
dergo the reaction with -cysteine (8i), but only when
performed in water (75°C, 14 h) to give amino acid 16i
in 99% crude yield.
From methylenespiropentane (2), exclusively the anti-
Markovnikov type adduct 10 was obtained. But for methyl-
enecyclopropane (3), in addition to the anti-Markovnikov
product 11[14] (91%), 9% of the ring-opened vinyl sulfide 12
was formed, as detected by 1H-NMR spectroscopy (Scheme
1). When run on a preparative (9 mmol) scale, these reac-
tions proceed as cleanly with 77% isolated yield. These ad-
ditions appear to be inhibited by palladium catalysts[15], e.g.
the reaction of bicyclopropylidene (1) with thiophenol (8a)
The spirocyclopropanated analogs of hypoglycine A (5),
namely the amino acids 17 and 19[16], reacted with mercap-
toethanol (8d) in H2O at 35°C to give complex mixtures of
diastereomers 18 and 20, respectively (Scheme 4). But in
both cases the NMR spectra corroborate that the additions
onto the double bonds occurred with complete retention of
the three-membered rings.
As far as the mechanism of these additions is concerned,
had reached only 15% conversion after 2 h at 20°C in the there appear to be some contradictions at the first glance.
.
presence of 5 mol% of Pd(OAc)2 2 PPh3.
It is obvious only that the product 12 from methylenecyclo-
Apparently, these thiol additions are not initiated by pro- propane (3) and thiophenol (8a) is formed by a radical
tonation of the double bonds in 1, 2, 3, since phenol, p- mechanism, i. e. via a (1-phenylthiocyclopropyl)methyl rad-
nitrophenol and acetic acid do not add under these con- ical 21 which undergoes the well-established rapid (k ഠ 108
ditions, and not even upon heating to 80°C for 3 h. Diphen-
s )
Ϫ1 [17] ring opening to the corresponding homoallyl radical
yldisulfide did not react with bicyclopropylidene (1) as well. 22 before it scavenges a hydrogen. In view of the relative
But, like in common cases[9a], strong acids do accelerate the kinetic stabilities of the cyclopropyl[18] and spiropentyl[19]
addition of thiophenol onto the double bond of hydro- radicals, it is not too surprising that the anti-Markovnikov
carbon 1. The rate coefficients kBCP for this reaction of 1 products 11 and 10 from 3 and 2 are formed without ring
derived from kinetic measurements at 19°C under the con- opening. FeistЈs ester 6 adds thiophenol (8a) in the anti-
ditions of a pseudo-first order rate law [five-fold excess of Markovnikov sense under typical radical-reaction con-
thiophenol (8a)] were equal to 2.85·10Ϫ4 sϪ1 in the absence ditions, i. e. initiated with di-tert-butyl peroxide[10], also
and 2.06·10Ϫ3 sϪ1 in the presence of p-toluenesulfonic acid with retention of the cyclopropane ring. But it is surprising
(5 mol%).
that the 1-(1-phenylthiocyclopropyl)cyclopropyl radical (23)
Aliphatic and functionally substituted thiols 8b؊h also which would be the first intermediate in a radical addition
undergo this clean and quantitative addition onto bicyclo- of thiophenol (8a) to bicyclopropylidene (1) would not un-
propylidene (1), but 2 to 4 h heating is necessary to achieve dergo rapid ring opening to the corresponding homoallyl
complete conversion (Scheme 2). Isolated yields after col- radical 24[20]. In different contexts it has been shown re-
umn chromatography were 89Ϫ99%. Dithiols 8g,h react cently[21] that neither α-[21a] nor β-sulfur substitution[21b] do
with two equivalents of 1 to give bis(bicyclopropyl) deriva- significantly influence the propensity for ring-opening of
tives 9g, h.
cyclopropylcarbinyl radicals.
1536
Eur. J. Org. Chem. 1998, 1535Ϫ1542

Cyclopropyl Building Blocks for Organic Synthesis, 46
Scheme 2
FULL PAPER
cyclopropane (25)[23] was lithiated with tert-butyllithium,
the resulting lithio derivative reacted with elemental sulfur
to give the disulfide 26 which in turn was reduced with tri-
butylphosphane/H2O[24] to yield 27 (Scheme 5).
Scheme 3
Scheme 5
Scheme 4
The thiyl radical formed from 27 by homolytic SϪH
cleavage would be a hex-5-en-1-yl type and thus expected
to undergo a 5-exo-trig cyclization[25] to give the bicyclic
cyclopropylcarbinyl radical intermediate 32, just as it has
been observed for several 2Ј-substituted 3-(2-methylene-
cyclopropyl)prop-1-yl radicals[26]
.
However, upon heating the methylenecyclopropylethane-
thiol 27 in C6D6 at 75°C for 14 h, two products were ob-
served in about equal amounts along with 5% of unreacted
starting material 27. These products were unequivocally
identified as 3-thiabicyclo[4.1.0]heptane (29) and 3-methyl-
In order to probe whether the mechanism of these thiol 5,6-dihydro-2H-thiopyran (31)[27] by their 1H- and 13C-
additions is a concerted [2σ ϩ 2π] or a stepwise radical NMR spectra. Both products are clearly derived from the
addition by applying the so-called “endocyclic restriction same bicyclic cyclopropyl radical intermediate 28 which
test“[22], the 2-(2-methylenecyclopropyl)ethanethiol (27) must have formed by a 6-endo-trig ring closure of the thiyl
was prepared. Towards this, the 2-(2-iodoethyl)methylene- radical from 27 (Scheme 5). The ring opening of the cyclo-
Eur. J. Org. Chem. 1998, 1535Ϫ1542
1537

S. I. Kozhushkov, M. Brandl, A. de Meijere
FULL PAPER
lets, oils as a film between NaCl plates. Ϫ MS (EI) and MS (HR-
EI): Finnigan MAT 95 spectrometer (70 eV). MS (HR-EI): pre-
selected ion peak matching at R >> 10000 to be within ±2 ppm of
the exact masses. Ϫ CI-MS: with NH3. Ϫ M. p.: Büchi 510 capil-
lary melting point apparatus, uncorrected. Ϫ TLC: Macherey-Na-
gel precoated sheets, 0.25 mm Sil G/UV254. Ϫ Column chromatog-
raphy: Merck silica gel, grade 60, 230Ϫ400 mesh. Ϫ GC: Siemens
Sichromat 1Ϫ4. Ϫ Preparative GC: Intersmat 130, 20% SE 30 on
Chromosorb W-AW-DMCS, 1000 ϫ 8.2 mm column.
propyl radical 28 to the allyl radical 30 must be facilitated
by the bicyclic nature of 28. In a control experiment, the
thiabicycloheptane 29 did not rearrange to the dihydrothi-
opyran 31 in 24 h at 80°C. Apparently, 5-exo-trig ring clos-
ure of the initial thiyl radical from 27 to the bicyclic cyclo-
propylcarbinyl radical 32 does not occur, as the latter would
at best have given the 2-methyl-5,6-dihydro-4H-thiopyran
35 which was not detected. In any event, although the 6-
endo-trig ring closure of 27 is unusual, the formation of the
ring-opened product 31 is a clear-cut evidence for a radical
mechanism of this intramolecular thiol addition. Most
probably, therefore, all of these thiol additions onto the
double bonds of methylenecyclopropanes occur via radical
intermediates. The apparent reason, then, for the 1-(1-phe-
nylthiocyclopropyl)cyclopropyl 23 and analogous radicals
from bicyclopropylidene (1) not to ring-open to 24 and its
analogs is the increase in strain energy upon going to such
a homoallyl radical which at the same time has a methylene-
cyclopropyl moiety. In fact, the ring opening of 23 to 24
would probably be reversible, as an analogous 3-exo-trig
ring closure of a 1,1-bis(alkoxycarbonyl) substituted 3-
cyclopropylidenepropyl radical to a 1-(2,2-dialkoxycarbon-
ylcyclopropyl)cyclopropyl radical has previously been ob-
Starting Materials: Anhydrous diethyl ether and THF were ob-
tained by distillation from sodium benzophenone ketyl. Com-
pounds 1[29], 2[30], 13[31], 15[32], and 25[23] were prepared according
to published procedures. All other chemicals were used as commer-
cially available. Organic extracts were dried over MgSO4.
General Procedure (GP1) for the Preparation of Sulfides 9aϪh,
10, 11, 16, 18, 20, 29, 31: Under argon, an NMR tube was charged
with the alkene (0.55 mmol or 1.05 mmol for 9g, h), thiol (0.5
mmol) and anhydrous deuterobenzene or D2O (H2O) (for 16i (18),
20) (0.7 ml), hermetically closed and stored for 1 h at room temp.
(for 9a, 10, 11), at 35°C (14 h for 18, 20) or at 75°C (2 h for
9bϪe,g,h, 4 h for 16a, 6 h for 9f, 14 h for 16i, 29, 31 and 72 h for
16d) in the dark. The conversion of starting materials was moni-
tored by 1H-NMR spectroscopy and secured to be complete before
the work-up. After evaporation of the solvent, analytically pure
samples were obtained by column chromatography (20 g of silica
gel, 2 ϫ 20 cm column) or recrystallization.
served[28]
.
In conclusion, the addition of a thiol onto the double
bond of a methylenecyclopropane derivative occurs with
surprising facility, and, although by a radical mechanism,
with retention of the cyclopropane ring in most cases. In
contrast to the relative reactivities of the methylenecyclo-
propane moieties in hydrocarbons 1Ϫ3 towards bromine
addition which follow a polar mechanism, the reactivities
towards radical thiol additions appear to follow a strain-
reactivity correlation. As methylenecyclopropane fragments
are contained in certain biologically active natural products
like the amino acids 4, 5, and as several enzymes contain
thiol functional groups, it is justified to raise the question
whether such thiol additions may play a role in the biologi-
cal action of such compounds. To test this hypothesis, a
solution of coenzyme A and methylenecyclopropylacetic
acid (15) in D2O was monitored by 1H NMR. However, no
reaction was detected after 72 h at 20°C and 72 h at 35°C.
Only after 120 h at 70°C were new signals of cyclopropyl
protons visible in the same region where thiol adducts of
15 would absorb, but the coenzyme A had completely de-
composed.
1-Cyclopropyl-1-(phenylthio)cyclopropane (9a): From bicyclopro-
pylidene (1) (44 mg, 52 µl, 0.55 mmol) and thiophenol (8a) (55 mg,
52 µl, 0.5 mmol), 93 mg (98%) of the adduct 9a was obtained after
˜
column chromatography: Rf ϭ 0.33 (hexane). Ϫ IR: ν ϭ 3079
cmϪ1, 3004, 1584, 1479, 1439, 1418, 1089, 1025, 737, 691. Ϫ 1H
NMR: δ ϭ 0.06Ϫ0.12 (m, 2 H, Cpr), 0.22Ϫ0.28 (m, 2 H, Cpr),
0.53Ϫ0.58 (m, 2 H, Cpr), 0.84Ϫ0.90 (m, 2 H, Cpr), 1.14Ϫ1.22 (m,
1 H, Cpr), 6.99Ϫ7.05 (m, 1 H, Ph), 7.10Ϫ7.16 (m, 2 H, Ph),
7.50Ϫ7.54 (m, 2 H, Ph). Ϫ 13C NMR: δ ϭ 4.40, 13.94 (2 CH2),
128.92, 129.14 (2 CH), 17.38, 125.79 (CH), 27.01, 137.76 (C). Ϫ
MS (EI), m/z (%): 190 (100) [Mϩ], 161 (13) [Mϩ Ϫ H Ϫ C2H4],
157 (30) [Mϩ Ϫ SH], 129 (42) [Mϩ Ϫ SH Ϫ C2H4], 115 (20), 99
(20), 91 (68), 85 (58) [SC4H5ϩ]. Ϫ MS (HR-EI): 190.0816 (C12H14S,
calcd. 190.0816). Ϫ C12H14S (190.3): calcd. C 75.74, H 7.41; found
C 75.63, H 7.61.
1-Cyclopropyl-1-(ethylthio)cyclopropane (9b): From bicyclopro-
pylidene (1) (44 mg, 52 µl, 0.55 mmol) and ethanethiol (8b) (31 mg,
37 µl, 0.5 mmol), 67 mg (94%) of the adduct 9b was obtained after
˜
column chromatography: Rf ϭ 0.45 (hexane). Ϫ IR: ν ϭ 3080
cmϪ1, 3003, 2970, 2928, 2871, 1457, 1448, 1417, 1018, 885, 821. Ϫ
1H NMR: δ ϭ Ϫ0.05 to 0.08 (m, 2 H, Cpr), 0.21Ϫ0.31 (m, 2 H,
Cpr), 0.35Ϫ0.46 (m, 2 H, Cpr), 0.79Ϫ0.85 (m, 2 H, Cpr), 1.02 (t,
J ϭ 7.6 Hz, 3 H, CH3), 1.15Ϫ1.25 (m, 1 H, Cpr), 2.61 (q, J ϭ 7.6
Hz, 2 H, SCH2). Ϫ 13C NMR: δ ϭ 15.11 (CH3), 3.66, 13.35 (2
CH2), 25.63 (CH2), 17.77 (CH), 26.09 (C). Ϫ MS (EI), m/z (%):
142 (13) [Mϩ], 141 (17) [Mϩ Ϫ H], 127 (33) [Mϩ Ϫ CH3], 114 (39)
[Mϩ Ϫ C2H4], 113 (100) [Mϩ Ϫ C2H5], 85 (38) [Mϩ Ϫ C4H9], 81
(35) [Mϩ Ϫ SC2H5], 79 (65) [C6H7ϩ], 73 (34). Ϫ MS (HR-EI):
142.0816 (C8H14S, calcd. 142.0816).
This work was supported by the Deutsche Forschungsgemein-
schaft (SFB 416, project A3) and the Fonds der Chemischen Indus-
trie. We are grateful to the companies BASF AG, Bayer AG, Cheme-
tall GmbH, Degussa AG, Hoechst AG, and Hüls AG for generous
gifts of chemicals and to Dr. B. Knieriem for his careful reading of
the manuscript.
1-Butylthio-1-cyclopropylcyclopropane (9c): From bicyclopro-
pylidene (1) (44 mg, 52 µl, 0.55 mmol) and butanethiol (8c) (45 mg,
Experimental Section
1H- and 13C-NMR spectra: Measured at 250, 500 (1H) and 62.9
MHz [13C, additional DEPT (Distortionless Enhancement by Pola-
rization Transfer)] on Bruker AM 250 and Varian INOVA-500 in-
struments in C6D6 soln, if not otherwise specified, CD5H/C6D6 as
54 µl, 0.5 mmol), 83 mg (97%) of the adduct 9c was obtained after
˜
column chromatography: Rf ϭ 0.41 (hexane). Ϫ IR: ν ϭ 3080
cmϪ1, 3004, 2958, 2930, 2872, 1465, 1416, 1017, 877, 820. Ϫ 1H
NMR: δ ϭ Ϫ0.02 to 0.08 (m, 2 H, Cpr), 0.21Ϫ0.32 (m, 2 H, Cpr),
internal reference. Ϫ FT-IR: Bruker IFS 66, measured as KBr pel- 0.37Ϫ0.48 (m, 2 H, Cpr), 0.67Ϫ0.75 (m, 2 H, Cpr), 0.85 (t, J ϭ
1538 Eur. J. Org. Chem. 1998, 1535Ϫ1542

Cyclopropyl Building Blocks for Organic Synthesis, 46
FULL PAPER
7.4 Hz, 3 H, CH3), 1.15Ϫ1.23 (m, 1 H, Cpr), 1.23Ϫ1.45 (m, 2 H, 0.21Ϫ0.33 (m, 4 H, Cpr), 0.35Ϫ0.44 (m, 4 H, Cpr), 0.63Ϫ0.72 (m,
CH2), 1.45Ϫ1.61 (m, 2 H, CH2), 2.64 (t, J ϭ 7.4 Hz, 2 H, SCH2). 4 H, Cpr), 1.10Ϫ1.25 (m, 2 H, Cpr), 3.0 (s, 4 H, SCH2). Ϫ 13C
Ϫ
13C NMR: δ ϭ 13.90 (CH3), 3.71, 13.50 (2 CH2), 22.55, 31.48, NMR: δ ϭ 3.84, 13.51 (4 CH2), 32.51 (2 CH2), 17.88 (2 CH), 26.32
32.27 (CH2), 17.81 (CH), 26.24 (C). Ϫ MS (EI), m/z (%): 260 (100) (2 C). Ϫ MS (EI), m/z (%): 254 (3) [Mϩ], 195 (10) [Mϩ Ϫ SC2H3],
[Mϩ ϩ HSC4H9], 203 (31) [Mϩ ϩ SH], 170 (4) [Mϩ], 155 (4), 147 174 (13) [Mϩ Ϫ C6H8], 145 (19), 141 (100) [Mϩ Ϫ SC6H9], 113 (36)
(8), 141 (14) [Mϩ Ϫ H Ϫ C2H4], 127 (8), 114 (40) [Mϩ Ϫ C4H8], [SC6H9ϩ], 85 (39) [SC4H5ϩ], 81 (52) [C6H9ϩ], 79 (50) [C6H7ϩ]. Ϫ
113 (39) [Mϩ Ϫ C4H9], 85 (20) [SC4H5ϩ], 81 (10) [C6H9ϩ], 79 (15) MS (HR-EI): 254.1162 (C14H22S2, calcd. 254.1163). Ϫ C14H22S2
[C6H7ϩ]. Ϫ C10H18S (170.3): calcd. C 70.52, H 10.65; found C (254.4): calcd. C 66.08, H 8.72; found C 65.91, H 8.48.
70.78, H 10.61.
meso-1,4-Bis(1-cyclopropylcyclopropylthio)-2,3-butanediol (9h):
From bicyclopropylidene (1) (84 mg, 99 µl, 1.05 mmol) and meso-
1,4-dimercapto-2,3-butanediol (8h) (77 mg, 0.5 mmol), 156 mg
(99%) of almost pure compound 9h was obtained after evaporation
of the solvent: m. p. 25°C (hexane). Ϫ 1H NMR: δ ϭ Ϫ0.03 to
0.07 (m, 4 H, Cpr), 0.24Ϫ0.35 (m, 4 H, Cpr), 0.36Ϫ0.48 (m, 4 H,
Cpr), 0.64Ϫ0.78 (m, 4 H, Cpr), 1.16Ϫ1.32 (m, 2 H, Cpr), 2.87 (dd,
J ϭ 8.6, 13.4 Hz, 2 H, SCH2), 3.10 (s, 2 H, 2 OH), 3.34 (dd, J ϭ
3.3, 13.4 Hz, 2 H, SCH2), 3.91 (dd, J ϭ 3.3, 8.6 Hz, 2 H, 2 CHOH).
2-(1-Cyclopropylcyclopropylthio)ethanol (9d): From bicyclopro-
pylidene (1) (44 mg, 52 µl, 0.55 mmol) and mercaptoethanol (8d)
(39 mg, 35 µl, 0.5 mmol), 74 mg (93%) of the adduct 9d was ob-
tained after column chromatography: Rf ϭ 0.29 (hexane/Et2O, 1:1).
˜
Ϫ IR: ν ϭ 3363 cmϪ1, 3080, 3003, 2924, 2876, 1463, 1447, 1417,
1046, 1017, 876, 822. Ϫ 1H NMR: δ ϭ Ϫ0.04 to 0.01 (m, 2 H, Cpr),
0.24Ϫ0.30 (m, 2 H, Cpr), 0.37Ϫ0.42 (m, 2 H, Cpr), 0.65Ϫ0.71 (m,
2 H, Cpr), 1.13Ϫ1.20 (m, 1 H, Cpr), 2.80 (t, J ϭ 6.5 Hz, 2 H,
SCH2), 3.70 (t, J ϭ 6.5 Hz, 2 H, OCH2). Ϫ 13C NMR: δ ϭ 3.83,
13.51 (2 CH2), 34.93, 61.57 (CH2), 17.82 (CH), 26.06 (C). Ϫ MS
(EI), m/z (%): 158 (2) [Mϩ], 127 (100) [Mϩ Ϫ CH2OH], 114 (26)
[Mϩ Ϫ C2H4O], 113 (37) [Mϩ Ϫ C2H4OH], 99 (11) [Mϩ Ϫ SC2H3],
93 (22), 85 (73) [SC4H5ϩ], 81 (30) [C6H9ϩ], 79 (52) [C6H7ϩ]. Ϫ MS
Ϫ
13C NMR: δ ϭ 3.76, 4.21, 12.90, 14.10, 36.06 (2 CH2), 17.76,
72.34 (2 CH), 26.32 (2 C). Ϫ MS (EI), m/z (%): 314 (8) [Mϩ], 286
(4) [Mϩ Ϫ C2H4], 233 (18) [Mϩ Ϫ C6H9], 200 (20) [Mϩ Ϫ C6H9 Ϫ
SH], 157 (100) [C6H9SCH2CHOHϩ], 113 (52) [SC6H9ϩ], 85 (50)
[SC4H5ϩ], 81 (58) [C6H9ϩ], 79 (45) [C6H7ϩ]. Ϫ MS (HR-EI):
314.1374 (C16H26O2S2, calcd. 314.1374).
(HR-EI): 158.0765 (C8H14OS, calcd. 158.0765).
Ϫ C8H14OS
(158.3): calcd. C 60.71, H 8.92; found C 60.76, H 8.79.
(Phenylthiomethyl)spiropentane (10): From methylenespiropen-
tane (2) (44 mg, 0.55 mmol) and thiophenol (8a) (55 mg, 52 µl, 0.5
3-(1-Cyclopropylcyclopropylthio)propionic Acid (9e): From bi-
cyclopropylidene (1) (44 mg, 52 µl, 0.55 mmol) and 3-mercaptopro-
pionic acid (8e) (53 mg, 44 µl, 0.5 mmol), 83 mg (89%) of the
mmol), 92 mg (97%) of the adduct 10 was obtained after column
˜
chromatography: Rf ϭ 0.29 (hexane). Ϫ IR: ν ϭ 3060 cmϪ1, 2997,
2915, 1585, 1480, 1438, 1420, 1238, 1090, 1025, 997, 855, 737, 690.
adduct 9e was obtained after column chromatography: Rf ϭ 0.38
Ϫ
1H NMR (CDCl3): δ ϭ 0.69 (dd, J ϭ 7.5, 3.3 Hz, 1 H, Cpr),
˜
(hexane/Et2O, 1:1). Ϫ IR: ν ϭ 3380 cmϪ1, 3080, 3004, 2263, 1711,
0.75Ϫ0.86 (m, 4 H, Cpr), 1.08 (dd, J ϭ 7.5, 4.3 Hz, 1 H, Cpr),
1.38Ϫ1.48 (m, 1 H, Cpr), 2.92 (dd, J ϭ 12.5, 7.0 Hz, 1 H, SCH2),
3.03 (dd, J ϭ 12.5, 7.0 Hz, 1 H, SCH2), 7.15Ϫ7.22 (tt, J ϭ 7.1, 1.5
Hz, 1 H, Ph), 7.25Ϫ7.32 (m, 2 H, Ph), 7.35Ϫ7.40 (dm, J ϭ 7.0 Hz,
2 H, Ph). Ϫ 13C NMR (CDCl3): δ ϭ 3.27, 6.17, 13.20, 38.08 (CH2),
128.69, 129.28 (2 CH), 16.78, 125.72 (CH), 13.20, 136.98 (C). Ϫ
MS (EI), m/z (%): 190 (28) [Mϩ], 175 (8), 161 (6) [Mϩ Ϫ H Ϫ
C2H4], 135 (16) [Mϩ Ϫ C4H7], 123 (44), 110 (58) [Mϩ Ϫ H Ϫ
C6H7], 109 (22) [SPhϩ], 81 (100) [Mϩ Ϫ SPh], 79 (50) [C6H7ϩ]. Ϫ
MS (HR-EI): 190.0816 (C12H14S, calcd. 190.0816). Ϫ C12H14S
(190.3): calcd. C 75.74, H 7.41; found C 75.61, H 7.23. In the re-
peated large-scale preparation, 1.676 g (97%) of sulfide 10 was ob-
tained from olefin 2 (727 mg, 9.08 mmol) and 8a (1 g, 0.932 ml,
9.08 mmol) after column chromatography (50 g of silica gel, 20 ϫ
3 cm column).
1417, 1336, 1263, 1195, 1020, 932, 886, 822. Ϫ 1H NMR: δ ϭ
Ϫ0.06 to 0.04 (m, 2 H, Cpr), 0.23Ϫ0.26 (m, 2 H, Cpr), 0.35Ϫ0.38
(m, 2 H, Cpr), 0.64Ϫ0.66 (m, 2 H, Cpr), 1.12Ϫ1.19 (m, 1 H, Cpr),
2.50 (t, J ϭ 7.5 Hz, 2 H, CH2), 2.84 (t, J ϭ 7.5 Hz, 2 H, SCH2),
12.06 (s, 1 H, OH). Ϫ 13C NMR: δ ϭ 3.71, 13.24 (2 CH2), 26.41,
35.13 (CH2), 17.54 (CH), 26.05, 179.32 (C). Ϫ MS (EI), m/z (%):
186 (48) [Mϩ], 157 (23) [Mϩ Ϫ H Ϫ C2H4], 141 (40) [Mϩ Ϫ CO2H],
127 (32) [Mϩ Ϫ CO2H Ϫ CH2], 114 (42), 113 (90) [Mϩ Ϫ CO2H
Ϫ C2H4], 85 (100) [SC4H5ϩ], 81 (50) [C6H9ϩ], 79 (80) [C6H7ϩ]. Ϫ
MS (HR-EI): 186.0714 (C9H14O2S, calcd. 186.0715). Ϫ C9H14O2S
(186.3): calcd. C 58.03, H 7.58; found C 57.60, H 7.23.
Ethyl (1-Cyclopropylcyclopropylthio)acetate (9f): From bicyclo-
propylidene (1) (44 mg, 52 µl, 0.55 mmol) and ethyl mercaptoacet-
ate (8f) (60 mg, 55 µl, 0.5 mmol), 95 mg (95%) of the adduct 9f
was obtained after column chromatography: Rf ϭ 0.47 (hexane/
(Phenylthiomethyl)cyclopropane (11)[14] and 2-(Phenylthio)-1-
butene (12)[33]: After stirring a mixture of methylenecyclopropane
(3) (ca. 30 mg, ca. 35 µl, 0.55 mmol) and thiophenol (8a) (55 mg,
52 µl, 0.5 mmol) at room temp. for 1 h according to GP1, a mixture
of compounds 11 (91%) and 12 (9%) was obtained, as detected by
˜
Et2O, 10:3). Ϫ IR: ν ϭ 3081 cmϪ1, 3002, 2937, 1734, 1464, 1447,
1416, 1366, 1269, 1131, 1031, 923, 877, 824. Ϫ 1H NMR: δ ϭ
Ϫ0.03 to 0.03 (m, 2 H, Cpr), 0.23Ϫ0.30 (m, 2 H, Cpr), 0.39Ϫ0.44
(m, 2 H, Cpr), 0.68Ϫ0.73 (m, 2 H, Cpr), 1.02 (t, J ϭ 7.1 Hz, 3 H,
CH3), 1.26Ϫ1.32 (m, 1 H, Cpr), 3.29 (s, 2 H, SCH2), 3.97 (q, J ϭ
7.1 Hz, 2 H, OCH2). Ϫ 13C NMR: δ ϭ 14.13 (CH3), 3.63, 13.24
(2 CH2), 33.63, 60.88 (CH2), 17.14 (CH), 26.75, 170.41 (C). Ϫ MS
(EI), m/z (%): 200 (100) [Mϩ], 127 (88) [Mϩ Ϫ CO2C2H5], 113 (90)
[Mϩ Ϫ CH2CO2C2H5], 93 (22), 85 (60) [SC4H5ϩ], 81 (41) [C6H9ϩ],
79 (92) [C6H7ϩ]. Ϫ MS (HR-EI): 200.0871 (C10H16O2S, calcd.
200.0871). Ϫ C10H16O2S (200.3): calcd. C 59.96, H 8.05; found C
59.69, H 8.06.
1
1H NMR spectroscopy. Ϫ 11: H NMR: δ ϭ 0.20Ϫ0.33 (m, 2 H,
Cpr), 0.52Ϫ0.65 (m, 2 H, Cpr), 0.98Ϫ1.05 (m, 1 H, Cpr), 2.89 (d,
J ϭ 7.0 Hz, 2 H, SCH2), 7.11Ϫ7.51 (m, 5 H, Ph). Ϫ 13C NMR:
δ ϭ 5.52 (2 CH2), 39.39 (CH2), 128.97, 129.83 (2 CH), 10.54,
1
125.67 (CH), 136.96 (C). Ϫ 12: H NMR: δ ϭ 1.13 (t, J ϭ 7.4 Hz,
3 H, CH3), 2.29 (qd, J ϭ 7.4, 1.1 Hz, 2 H, CH2), 4.95 (d, J ϭ 1.1
Hz, 1 H, ϭCH2), 5.21 (s, 1 H, ϭCH2), signals of Ph group are
covered. Ϫ 13C NMR: δ ϭ 13.17 (CH3), 29.55, 111.83 (CH2),
128.68, 132.93 (2 CH), 127.55 (CH), 136.96 (C), the signals of qua-
1,2-Bis(1-cyclopropylcyclopropylthio)ethane (9g): From bicyclo-
propylidene (1) (84 mg, 99 µl, 1.05 mmol) and ethanedithiol (8g) ternary atoms could not be reliable interpreted. In the repeated
(47 mg, 42 µl, 0.5 mmol), 121 mg (95%) of the adduct 9g was large-scale preparation, 1.143 g (77%) of sulfide 11 was obtained
obtained after column chromatography: Rf ϭ 0.46 (hexane/Et2O,
from olefin 3 (ca. 0.49 g, ca. 0.58 ml, 9.1 mmol) and thiophenol
(8a) (1 g, 0.932 ml, 9.08 mmol) after column chromatography (50
˜
20:1). Ϫ IR: ν ϭ 3079 cmϪ1, 3002, 2930, 2871, 1462, 1446, 1416,
1019, 876, 822. Ϫ 1H NMR: δ ϭ Ϫ0.11 to 0.03 (m, 4 H, Cpr), g of silica gel, 20 ϫ 3 cm column).
Eur. J. Org. Chem. 1998, 1535Ϫ1542
1539

S. I. Kozhushkov, M. Brandl, A. de Meijere
FULL PAPER
cis- and trans-[2-(Phenylthiomethyl)cyclopropyl]acetic Acid
(16a): From (methylenecyclopropyl)acetic acid (15) (56 mg, 0.5
Reaction of β-Bicyclopropylidenyl-,-alanine (17) with 2-Mer-
captoethanol (8d): From 17 (46 mg, 0.28 mmol) and mercaptoetha-
mmol) and thiophenol (8a) (55 mg, 52 µl, 0.5 mmol), 79 mg (71%) nol (8d) (23.5 mg, 21 µl, 0.3 mmol), 68 mg (100%) of a complex
of the adduct 16a was obtained after column chromatography as a mixture of adducts 18 as an oil was obtained after evaporation of
1:2 mixture of cis- and trans-isomers: Rf ϭ 0.33 (hexane/Et2O, 1:1), H2O. The spectral data of the mixture are rather complicated to be
1
m. p. 34Ϫ36°C (hexane). Ϫ cis-16a: 1H NMR: δ ϭ Ϫ0.20 (dd, J ϭ interpreted, but H- as well as 13C-NMR spectra (D2O) reveal the
5.3, 5.3 Hz, 1 H, Cpr), 0.50Ϫ0.57 (m, 1 H, Cpr), 0.70Ϫ0.82 (m, 2
typical groups of signals like compound 20 (see below). Ϫ MS (CI),
H, Cpr), 1.98 (dd, J ϭ 7.5, 16.6 Hz, 1 H, CH2), 2.22 (dd, J ϭ 6.6, m/z (%): 263 (12) [Mϩ ϩ NH4], 246 (80) [Mϩ ϩ H], 202 (3) [Mϩ
16.6 Hz, 1 H, CH2), 2.60 (d, J ϭ 7.0 Hz, 2 H, SCH2), 6.95Ϫ7.33
ϩ H Ϫ CO2], 185 (8) [Mϩ Ϫ NH2 Ϫ CO2], 180 (20), 172 (30), 163
(m, 5 H, Ph), 11.71 (s, 1 H, OH). Ϫ 13C NMR: δ ϭ 11.98, 33.51, (100) [Mϩ ϩ NH4 Ϫ CCH2CH(NH2)CO2H], 146 (81) [Mϩ ϩ H
38.17 (CH2), 129.21, 129.63 (2 CH), 12.80, 15.0, 126.05 (CH), Ϫ CCH2CH(NH2)CO2H].
137.10, 179.26 (C). Ϫ trans-16a: 1H NMR: δ ϭ 0.11Ϫ0.18 (m, 1
β-[2-(2-Hydroxyethylthiomethyl)spiropentyl]-,-alanine
(20)
H, Cpr), 0.23Ϫ0.33 (m, 1 H, Cpr), 0.50Ϫ0.65 (m, 1 H, Cpr), 0.97
(pseudosept, J ϭ 7.3, 1 H, Cpr), 1.81 (dd, J ϭ 7.3, 16.3 Hz, 1 H,
CH2), 1.92 (dd, J ϭ 7.0, 16.3 Hz, 1 H, CH2), 2.46 (dd, J ϭ 7.3,
13.0 Hz, 1 H, SCH2), 2.67 (dd, J ϭ 6.8, 13.0 Hz, 1 H, SCH2),
6.95Ϫ7.33 (m, 5 H, Ph), 11.71 (s, 1 H, OH). Ϫ 13C NMR: δ ϭ
12.45, 34.27, 38.17 (CH2), 129.14, 129.37 (2 CH), 15.21, 18.01,
125.93 (CH), 137.55, 179.02 (C). Ϫ MS (EI), m/z (%): 222 (100)
[Mϩ], 181 (18), 163 (6) [Mϩ Ϫ CH2CO2H], 135 (15), 123 (60) [Mϩ
Ϫ C5H7O2], 113 (32) [Mϩ Ϫ SPh], 110 (84) [HSPhϩ], 109 (36)
[SPhϩ], 71 (53). Ϫ MS (HR-EI): 222.0714 (C12H14O2S, calcd.
222.0715). Ϫ C12H14O2S (222.3): calcd. C 64.83, H 6.35; found C
64.56, H 6.06.
From β-(2-methylenespiropentyl)-,-alanine (19) (44 mg, 0.26
mmol) and mercaptoethanol (8d) (23.5 mg, 21 µl, 0.3 mmol), 63
mg (99%) of almost pure compound 20 was obtained after evapor-
ation of H2O, washing of the residue with acetone and drying in
vacuo (24 h/0.1 Torr) as a mixture of diastereomers: m. p.
166Ϫ168°C (dec.). Ϫ 1H NMR (D2O): δ ϭ Ϫ0.45 to 1.35 (m, 5 H,
Cpr), 1.55Ϫ1.76 (m, 2 H, CH2), 1.76Ϫ1.87 (m, 1 H, Cpr),
2.45Ϫ2.55 (m, 4 H, SCH2), 3.40Ϫ3.56 (m, 3 H, CH and OCH2).
Ϫ
13C NMR (D2O, the signals of the individual diastereomers
could not be reliable interpreted): δ ϭ 1.44, 1.65, 3.71, 3.88, 4.04,
7.00 (CH2, Cpr), 13.98, 18.26, 20.65, 20.85, 20.89, 24.44 (CH, Cpr),
22.24, 24.66, 29.91, 31.04, 31.12, 31.39, 33.84, 34.29, 35.08 (CH2,
SCH2), 55.64, 55.71, 55.88 (CH), 59.98, 61.04 (OCH2), 175.33,
175.41, 175.90 (C). Ϫ MS (CI), m/z (%): 263 (4) [Mϩ ϩ NH4], 246
(32) [Mϩ ϩ H], 202 (8) [Mϩ ϩ H Ϫ CO2], 187 (12), 185 (19) [Mϩ
cis- and trans-[2-(2-Hydroxyethylthiomethyl)cyclopropyl]acetic
Acid (16d): From (methylenecyclopropyl)acetic acid (15) (56 mg,
0.5 mmol) and mercaptoethanol (8d) (39 mg, 35 µl, 0.5 mmol), 56
mg (59%) of the adduct 16d was obtained after column chromatog-
raphy as a 1:1.4 mixture of cis- and trans-isomers: Rf ϭ 0.34 (Et2O).
Ϫ NH2 Ϫ CO2], 168 (19) [Mϩ Ϫ S(CH2)2OH], 163 (100) [Mϩ
ϩ
NH4
Ϫ
CCH2CH(NH2)CO2H], 146 (69) [Mϩ
ϩ H
Ϫ
1
Ϫ cis-16d: H NMR (CDCl3): δ ϭ 0.03 (dd, J ϭ 5.3, 5.3 Hz, 1 H,
CCH2CH(NH2)CO2H]. Ϫ C11H19NO3S (245.3): calcd. C 53.85, H
Cpr), 0.81Ϫ0.98 (m, 2 H, Cpr), 1.15Ϫ1.18 (m, 1 H, Cpr), 2.19 (d,
J ϭ 6.8 Hz, 1 H, CH2), 2.33 (d, J ϭ 6.8 Hz, 1 H, CH2), 2.48 (m,
J ϭ 16.5, 7.3, 7.2 Hz, 2 H, SCH2), 2.71 (t, J ϭ 6.1 Hz, 2 H, SCH2),
3.67 (t, J ϭ 6.1 Hz, 2 H, OCH2), 7.0 (s, 1 H, OH), 10.1 (s, 1 H,
COOH). Ϫ 13C NMR (CDCl3): δ ϭ 11.73, 31.88, 33.29, 34.62,
60.46 (CH2), 12.08, 15.12 (CH), 177.94 (C). Ϫ trans-16d: 1H NMR
(CDCl3): δ ϭ 0.44 (ddd, J ϭ 1.7, 5.7, 7.4 Hz, 2 H, Cpr), 0.76Ϫ0.81
(m, 1 H, Cpr), 1.05 (pseudosept, J ϭ 7.4, 1 H, Cpr), 2.21 (d, J ϭ
6.8 Hz, 1 H, CH2), 2.31 (d, J ϭ 7.5 Hz, 1 H, CH2), 2.46 (m, J ϭ
16.3, 7.5, 7.3 Hz, 2 H, SCH2), 2.71 (t, J ϭ 6.1 Hz, 2 H, SCH2),
3.66 (t, J ϭ 6.1 Hz, 2 H, OCH2), 7.0 (s, 1 H, OH), 10.1 (s, 1 H,
COOH). Ϫ 13C NMR (CDCl3): δ ϭ 12.13, 34.41, 35.84, 38.06,
60.46 (CH2), 14.73, 18.46 (CH), 177.56 (C). Ϫ MS (EI), m/z (%):
190 (16) [Mϩ], 113 (52) [Mϩ Ϫ S(CH2)2OH], 101 (31), 84 (25),
71 (20), 59 (41) [CH2CO2Hϩ], 43 (100). Ϫ MS (HR-EI): 190.0663
(C8H14O3S, calcd. 190.0664). Ϫ C8H14O3S (190.3): calcd. C 50.50,
H 7.42; found C 51.05, H 7.39.
7.81; found C 53.78, H 7.63.
2-(2-Methylenecyclopropyl)ethanethiol (27): a) To a stirred solu-
tion of 2-(2-iodoethyl)methylenecyclopropane 25[23] (4.202 g, 20.2
mmol) in anhydrous Et2O (35 ml), tBuLi (24.5 ml of 1.65  solution
in pentane, 40.4 mmol) was added at Ϫ75°C over a period of 1 h.
The mixture was stirred at the indicated temp. for an additional 1
h, and then sublimed sulfur powder (1.293 g, 2 equiv.) was added
in one portion. The resulting suspension was allowed to warm to
20°C, quenched with 20.2 ml of 1  HCl solution, extracted with
Et2O (2 ϫ 30 ml), dried and concentrated under reduced pressure.
Column chromatography (60 g of silica gel, 3 ϫ 20 cm column,
hexane) gave 1.91 g (84%) of bis[2-(2-methylenecyclopropyl)ethyl]-
disulfide (26) as a mixture of two diastereomers (ratio 2:1), Rf ϭ
0.47. Ϫ 1H NMR (CDCl3, major diastereomer): δ ϭ 0.78Ϫ0.85 (m,
2 H, Cpr), 1.24Ϫ1.31 (m, 2 H, Cpr), 1.50Ϫ1.56 (m, 2 H, Cpr),
1.75Ϫ1.85 (m, 4 H, CH2), 2.96 (t, J ϭ 7.0 Hz, 4 H, SCH2), 5.37
(br. s, 2 H, ϭCH2), 5.44 (d, J ϭ 1.3 Hz, 2 H, ϭCH2). Ϫ 13C NMR
(CDCl3, major diastereomer): δ ϭ 9.52, 32.33, 38.32, 103.27 (2
CH2), 14.60 (2 CH), 135.62 (2 C). Ϫ MS (EI), m/z (%): 145 (80)
[C6H9S2ϩ], 113 (100) [C6H9Sϩ], 86 (65) [C4H5Sϩ], 84 (95), 79 (80),
S-{[2-(Carboxymethyl)cyclopropyl]methyl}--cysteine
(16i):
From (methylenecyclopropyl)acetic acid (15) (56 mg, 0.5 mmol)
and -cysteine (8i) (61 mg, 0.5 mmol), 116 mg (99%) of almost
pure compound 16i was obtained after evaporation of D2O as a
mixture of two main diastereomers: m. p. 154°C (dec.) (H2O/ace-
tone). Ϫ 1H NMR (D2O): δ ϭ Ϫ0.09, 0.32, 0.71, and 0.95 (m, total
4 H, Cpr), 1.95Ϫ2.45 (m, total 4 H, CH2 and SCH2), 2.85Ϫ2.94
(m, 2 H, SCH2), 3.71 (m, 1 H, CH). Ϫ 13C NMR (D2O, the chemi-
cal shift of the major diastereomer is marked as “m” in parenth-
57 (78), 41 (60). Ϫ MS (CI), m/z (%): 261 (100) [Mϩ ϩ NH4
ϩ
NH3], 244 (45) [Mϩ ϩ NH4], 227 (20) [Mϩ ϩ H], 145 (29)
[C6H9S2ϩ], 113 (55) [C6H9Sϩ].
Disulfide 26 (1.291 g, 5.7 mmol) was treated with nBu3P (2.31 g,
2.85 ml, 11.4 mmol) in a mixture of DME (25 ml) and H2O (5 ml)
eses): δ ϭ 11.82, 12.55(m), 32.62(m), 32.91, 34.07(m), 34.17, at 0°C for 1 h, poured into ice-cold water (50 ml) and extracted
36.48(m), 36.56 (CH2), 12.71, 15.32, 15.41(m), 18.35(m), 54.37(m), with Et2O (2 ϫ 30 ml). The combined organic phases were washed
54.38 (CH), 173.63(m), 173.65, 179.28(m), 179.61 (C). Ϫ MS (CI), with brine (2 ϫ 30 ml), dried and concentrated under reduced
m/z (%): 251 (45) [Mϩ ϩ NH4], 234 (83) [Mϩ ϩ H], 190 (6) [Mϩ
pressure at 0°C. Rapid column chromatography (50 g of silica gel,
ϩ H Ϫ CO2], 181 (48) [Mϩ ϩ NH4 Ϫ CO2 Ϫ C2H2], 164 (100) 3 ϫ 20 cm column, hexane/Et2O, 4:1) gave 0.972 g (75%) of thiol
[Mϩ ϩ H Ϫ CO2 Ϫ C2H2], 147 (15), 130 (25), 116 (10). Ϫ
27 as a colorless oil, Rf ϭ 0.70. Ϫ H NMR: δ ϭ 0.56Ϫ0.61 (m, 1
1
C9H15NO4S (233.3): calcd. C 46.33, H 6.48; found C 46.96, H 6.48. H, Cpr), 1.04Ϫ1.18 (m, 1 H, Cpr), 1.15 (s, 1 H, SH), 1.29Ϫ1.32
1540 Eur. J. Org. Chem. 1998, 1535Ϫ1542

Cyclopropyl Building Blocks for Organic Synthesis, 46
FULL PAPER
[2]
[3]
Review: A. de Meijere, S. I. Kozhushkov, A. F. Khlebnikov, Zh.
Org. Khim. 1996, 32, 1607Ϫ1626; Russ. J. Org. Chem. (Engl.
Transl.) 1996, 32, 1555Ϫ1575.
(m, 1 H, Cpr), 1.37Ϫ1.45 (m, 2 H, CH2), 2.28 (t, J ϭ 6.5 Hz, 2 H,
SCH2), 5.41Ϫ5.44 (m, 2 H, ϭCH2). Ϫ 13C NMR: δ ϭ 9.13, 24.10,
37.42, 103.00 (CH2), 14.55 (CH), 135.60 (C). Ϫ MS (EI), m/z (%):
114 (100) [Mϩ], 113 (38) [Mϩ Ϫ H], 99 (35), 86 (20) [Mϩ Ϫ C2H4],
81 (95) [Mϩ Ϫ SH], 79 (60), 61 (80), 41 (55). Ϫ MS (HR-EI):
114.0503 (C6H10S, calcd. 114.0503).
[3a] P. Binger, H. M. Büch, Top. Curr. Chem. 1987, 135, 77Ϫ151.
[3b]
Ϫ
P. Binger, T. Schmidt in Houben-Weyl, Vol. E 17c (Ed.:
A. de Meijere), Thieme, Stuttgart 1996, pp. 2217Ϫ2294.
A. de Meijere, I. Erden, W. Weber, D. Kaufmann, J. Org. Chem.
1988, 53, 152Ϫ161.
[4]
[5]
[6]
[7]
[8]
N. Kurokava, Y. Ohfune, Tetrahedron Lett. 1985, 26, 83Ϫ84,
and references cited therein.
b) The lithio compound prepared as described above from the
same quantity of 25 was treated with thiirane (1.336 g, 1.32 ml,
22.2 mmol) at Ϫ75°C. The mixture was allowed to warm to room
temp. and extracted with ice-cold solution of NaOH (1 g) in H2O
(40 ml). The water layer was acidified to pH 2 (3.9 ml of 12  HCl
solution was used) and extracted with Et2O (2 ϫ 30 ml). After
drying and concentration of the combined ethereal extracts, the
residue was condensed “bulb-to-bulb” (20°C/0.5 Torr) to give 634
mg (28%) of essentially pure 27.
J. E. Baldwin, R. M. Adlington, D. Bebbington, A. T. Russell,
Tetrahedron 1994, 50, 12015Ϫ12028, and ref. [2] therein.
R. Gleiter, R. Haider, J.-M Conia, J.-P. Barnier, A. de Meijere,
W. Weber, J. Chem. Soc. Chem. Commun. 1979, 130Ϫ132.
T. Späth, S. I. Kozhushkov, T. Fiebig, B. Galland, M.-F. Ruasse,
K. Albrecht, Y. Apeloig, A. de Meijere, J. Org. Chem., to be
submitted.
[9] [9a]
A. Schöberl, A. Wagner in Houben-Weyl, Vol. 9 (Ed.: E.
[9b]
Müller), Thieme, Stuttgart, 1955, pp. 97Ϫ147. Ϫ
K. Gries-
baum, Angew. Chem. 1970, 82, 276Ϫ290; Angew. Chem. Int. Ed.
Engl. 1970, 9, 273Ϫ287.
3-Thiabicyclo[4.1.0]heptane (29) and 3,6-Dihydro-5-methyl-2H-
thiopyran (31): A sample of 2-(2-methylenecyclopropyl)ethanethiol
(27) (300 mg, 2.6 mmol) was heated in C6D6 for 14 h with period-
ical GC and NMR monitoring. After disappearance of the olefinic
proton signals, GC analysis proved the reaction mixture to consist
of 29 (47%), 31 (48%), and 5% of unreacted 27 which were sepa-
rated by preparative GC (70°C in column, 120°C injector and
150°C detector temperatures).
[10] [10a]
P. M. Cairns, L. Crombie, G. Pattenden, Tetrahedron Lett.
[10b]
1982, 23, 1405Ϫ1408. Ϫ
D. J. Pasto, M. F. Miles, J. Org.
Chem. 1976, 41, 2068Ϫ2070.
[11]
[12]
T. L. Gilchrist, C. W. Rees, J. Chem. Soc. (C) 1968, 776Ϫ778.
K. B. Wiberg, S. T. Waddell, J. Am. Chem. Soc. 1990, 112,
2194Ϫ2216.
[13]
[14]
G. Szeimies, A. Schloßer, F. Philipp, P. Dietz, W. Mickler, Chem.
Ber. 1978, 111, 1922Ϫ1937.
Other methods of preparation:
[14a]
T. Masuda, T. Numata, N.
1
Furukawa, S. Oae, J. Chem. Soc., Perkin Trans. 2, 1978,
29: H NMR (500 MHz): δ ϭ 0.39 (dd, J7Ј,7 ca. 0, J7Ј,1 ϭ 7.8,
[14b]
1302Ϫ1308. Ϫ
E. J. OЈConnor, S. Brandt, P. Helquist, J.
J7Ј,6 ϭ 8.5 Hz, 7Ј-H), 0.40 (dd, J7,7Ј ca. 0, J7,1 ϭ 5.7, J7,6 ϭ 6.5 Hz,
Am. Chem. Soc. 1987, 109, 3739Ϫ3747. Ϫ[14c] G. A. Kutyrev,
A. A. Kapura, R. A. Cherkasov, A. N. Pudovik, Zh. Obshch.
Khim. 1985, 55, 2162Ϫ2175; J. Gen. Chem. USSR (Engl.
Transl.) 1985, 55, 1919Ϫ1930.
7-H), 0.57 (ddddd, J6,5 ϭ 3.1, J6,5Ј ϭ 7.9, J6,7 ϭ 6.5, J6,7Ј ca. J6,1 ϭ
8.5 Hz, 6-H), 0.70 (ttd, J1,2 ϭ 3.1, J1,2Ј ca. J1,7 ϭ 5.7, J1,7Ј ϭ 7.8,
J1,6 ϭ 8.5 Hz, 1-H), 1.51 (dddd, J5,5Ј ϭ 14.0, J5,4Ј ϭ 10.1, J5,4
ϭ
[15]
[16]
The Pd-catalyzed addition of thiols to alkenes and alkynes has
5.1, J5,6 ϭ 3.1 Hz, 5-H), 1.85 (ddt, J5Ј,5 ϭ 14.0, J5Ј,4 ca. J5Ј,4Ј
ϭ
[15a]
been reported:
H. Kuniyasu, A. Ogawa, K.-I. Sato, I. Ryu,
4
5.1, J5Ј,6 ϭ 7.9 Hz, 5Ј-H), 2.02 (dtd, J4,4Ј ϭ 13.2, J4,2 ϭ 1.0, J4,5
ca. J4,5Ј ϭ 5.1 Hz, 4-H), 2.07 (ddd, J4Ј,4 ϭ 13.2, J4Ј,5Ј ϭ 5.1, J4Ј,5 ϭ
N. Kambe, N. Sonoda, J. Am. Chem. Soc. 1992, 114,
[15b]
5902Ϫ5903, and ref. [2e] therein. Ϫ
A. Ogawa, M. Takeba,
4
J.-i. Kawakami, I. Ryu, N. Kambe, N. Sonoda, J. Am. Chem.
Soc. 1995, 117, 7564Ϫ7565.
10.1 Hz, 4Ј-H), 2.47 (ddd, J2,2Ј ϭ 13.5, J2,4 ϭ 1.0, J2,1 ϭ 3.1 Hz,
2-H), 2.83 (dd, J2Ј,2 ϭ 13.5, J2Ј,1 ϭ 5.7 Hz, 2Ј-H). The assignments
A. de Meijere, K. Ernst, B. Zuck, M. Brandl, S. I. Kozhushkov,
Eur. J. Org. Chem., to be submitted.
of the 1H-NMR signals were established by a COSY correlation
experiment. Ϫ 13C NMR: δ ϭ 9.32, 23.90, 24.58, 26.81 (CH2), 9.10, [17] [17a] A. L. J. Beckwith, K. U. Ingold, Rearrangements in Ground
9.39 (CH). Ϫ MS (EI), m/z (%): 114 (100) [Mϩ], 86 (88) [Mϩ
Ϫ
and Excited States, Vol. 1 (Ed.: P. de Mayo), Academic Press,
[17b]
New York, 1980, pp. 161Ϫ310. Ϫ
J. C. Walton in Houben-
C2H4], 73 (86) [Mϩ Ϫ C3H5], 68 (76) [Mϩ Ϫ SCH2], 45 (78), 43
(58). Ϫ MS (HR-EI): 114.0503 (C6H10S, calcd. 114.0503).
Weyl, Vol. E 17c (Ed.: A. de Meijere), Thieme, Stuttgart, 1997,
pp. 2438Ϫ2525.
[18]
G. Boche, H. M. Walborsky, Cyclopropane Derived Reactive In-
termediates (Eds.: S. Patai, Z. Rappoport), Wiley, Chichester,
1990, and references therein.
A. J. Kennedy, J. C. Walton, K. U. Ingold, J. Chem. Soc., Perkin
Trans. 2, 1982, 751Ϫ757.
31: 1H NMR: δ ϭ 1.57Ϫ1.66 (m, 2 H, CH2), 1.72Ϫ1.88 (m, 2
H, CH2), 1.85 (s, 3 H, CH3), 2.52Ϫ2.56 (m, 2 H, SCH2), 5.35Ϫ5.37
(m, 1 H ϭCH). Ϫ 13C NMR: δ ϭ 23.89 (CH3), 22.20, 24.52, 27.17
(CH2), 116.35 (CH), 128.54 (C). Ϫ MS (EI), m/z (%): 114 (100)
[19]
[20]
1,1Ј-Bicyclopropyl has been photochlorinated in the gas phase
giving 1-chloro-1-cyclopropylcyclopropane as the major prod-
uct without ring opening. Cf. J. A. Landgrebe, L. W. Becker, J.
Am. Chem. Soc. 1968, 90, 395Ϫ400.
[Mϩ], 113 (78) [Mϩ Ϫ H], 99 (83) [Mϩ Ϫ CH3], 85 (92) [Mϩ
Ϫ
CH3 Ϫ CH2], 79 (39), 71 (25), 59 (20), 45 (18). Ϫ MS (HR-EI):
114.0503 (C6H10S, calcd. 114.0503).
[21] [21a]
W. Adam, M. Heil, J. Am. Chem. Soc. 1991, 113,
[21b]
Kinetic Measurements: Under argon, an NMR tube was charged
with bicyclopropylidene (1) (17.1 mg, 20 µl, 0.213 mmol), thio-
phenol (8a) (117.3 mg, 109 µl, 1.065 mmol) and anhydrous deutero-
benzene (1 ml), hermetically closed, placed into the probe of an
NMR instrument, and the reaction was monitored by recording the
1H-NMR spectrum after measured intervals. In a second kinetic
experiment, p-TsOH·H2O (2 mg, 0.01 mmol, 4.9 mol%) was also
added. The pseudo-first-order rate coefficients kBCP derived from
these measurements at 19°C were equal to 2.85·10Ϫ4 sϪ1 in the
absence and 2.06·10Ϫ3 sϪ1 in the presence of p-toluenesulfonic acid
with the correlation coefficients r ϭ 0.951 and 0.998, respectively.
1730Ϫ1736. Ϫ
C. C. Huval, K. M. Church, D. A. Single-
ton, Synlett 1994, 273Ϫ274. Ϫ [21c] J.-M. Mattalia, M. Chanon,
C. J. M. Stirling, J. Org. Chem. 1996, 61, 1153Ϫ1154.
P. Beak, D. J. Allen, W. K. Lee, J. Am. Chem. Soc. 1990, 112,
1629Ϫ1630, and references [1Ϫ6] cited therein.
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[23]
T. Heiner, S. I. Kozhushkov, M. Noltemeyer, T. Haumann, R.
Boese, A. de Meijere, Tetrahedron 1996, 52, 12185Ϫ12196.
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J. L. Wardell in The Chemistry of the Thiol Group, Vol. 1
[24b]
(Ed.: S. Patai), New York, 1974, pp. 163Ϫ269. Ϫ
A. G.
Myers, P. S. Dragovich, E. Y. Kuo, J. Am. Chem. Soc. 1992,
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J. O. Metzger in Houben-Weyl, Vol. E 19a (Eds.: M. Regitz, B.
Giese), Thieme, Stuttgart, 1989, pp. 60Ϫ147.
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1365Ϫ1368. Ϫ [26b] C. Destabel, J. D. Kilburn, J. Knight, Tetra-
hedron 1994, 50, 11289Ϫ11302.
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A. Greenberg, J. F. Liebman, Strained Organic Molecules,
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[1b]
M. S. J. Briggs, M. Helliwell, D. Moorcroft, E. J. Thomas, J.
Academic Press, New York, 1978. Ϫ
D. Cremer, E. Kraka
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ein.
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A. L. J. Beckwith, M. J. Tozer, Tetrahedron Lett. 1992, 33,
4975Ϫ4978.
Eur. J. Org. Chem. 1998, 1535Ϫ1542
1541

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FULL PAPER
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[31]
S. Arora, P. Binger, Synthesis 1974, 801Ϫ803.
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1542
Eur. J. Org. Chem. 1998, 1535Ϫ1542