Mercury(II)-mediated cleavage of cyclopropylcarbinols by an intramolecular sulfinyl group as a stereo-and regioselective route to stereotriads and stereotetrads

Article abstract of DOI:10.1021/jo1019909

Mercury(II) salt mediated opening of cyclopropylcarbinols by an intramolecular sulfinyl group is disclosed. All four diastereomeric stereotriads have been prepared from cis-and trans-disubstituted cyclopropanes. The trisubstituted cyclopropanes also react regio-and stereoselectively to afford products possessing quaternary stereogenic centers. The reaction is clean and general.

Full text of DOI:10.1021/jo1019909

pubs.acs.org/joc
Mercury(II)-Mediated Cleavage of Cyclopropylcarbinols by an
Intramolecular Sulfinyl Group as a Stereo- and Regioselective Route to
Stereotriads and Stereotetrads
Sadagopan Raghavan,*,† Vaddela Sudheer Babu,† and B. Sridhar‡
‡
†Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India, and Lab of X-ray
Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
sraghavan@iict.res.in
Received October 13, 2010
Mercury(II) salt mediated opening of cyclopropylcarbinols by an intramolecular sulfinyl group is
disclosed. All four diastereomeric stereotriads have been prepared from cis- and trans-disubstituted
cyclopropanes. The trisubstituted cyclopropanes also react regio- and stereoselectively to afford
products possessing quaternary stereogenic centers. The reaction is clean and general.
Introduction
Alternating hydroxy- and methyl-substituted subunits are
a characteristic feature of polypropionate derived natural
products (Figure 1). The importance1 of these natural prod-
ucts as antibiotics, antifungals, antitumors, antiparasitics,
and immunosuppressants together with their structural and
stereochemical complexity has led to the design and devel-
opment of several unique methodologies to prepare these
structures.2 A common strategy has been the disconnection
of the polypropionate chain into smaller subunits containing
alternating methyl and hydroxy groups and uniting them by
coupling reactions.
In our abiding interest in utilizing the sulfinyl group as an
intramolecular nucleophile,3 we have investigated the oxy-
mercuration-demercuration of cyclopropylcarbinols with
the aim of obtaining products possessing such a subunit.
Cyclopropanes have been reported to undergo highly regio-
FIGURE 1. Some natural products possessing alternating methyl
and hydroxy substituents.
and stereoselective intermolecular oxymercuration4 pro-
moted by mercury(II) salts to furnish 1,3-diols after demer-
curation, Scheme 1.5
While Collum and co-workers reported on mercuric per-
chlorate-mediated intramolecular opening of cyclopropanes
by carboxylic acid and its derivatives,6 Cossy and co-workers
reported on a stereoselective route to subunits possessing
(1) (a) Omura, S. Macrolide Antibiotics: Chemistry, biology and practice,
2nd ed.; Academic Press: San Diego, CA, 2002; p 637. (b) O’Hagan, D. Nat.
Prod. Rep. 1995, 12, 1. (c) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod.
Rep. 1998, 15, 477.
(2) (a) Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193. (b)
Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. Rev. 2005, 34, 677. (c) Faul,
M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407.
(3) For the oxidative functionalization of disubstituted alkenes see: (a)
Raghavan, S.; Rasheed, M. A.; Joseph, S. C.; Rajender, A. Chem Commun.
1999, 1845. (b) Raghavan, S.; Ramakrishna Reddy, S.; Tony, K. A.; Naveen
Kumar, Ch.; Varma, A. K.; Nangia, A. J. Org. Chem. 2002, 67, 5838. (c)
Raghavan, S.; Rajender, A.; Joseph, S. C.; Rasheed, M. A.; Ravikumar, K.
Tetrahedron: Asymmetry 2004, 15, 365. For the oxidative functionalization
of trisubstituted alkenes see: (d) Raghavan, S.; Sreekanth, T. Tetrahedron
Lett. 2008, 49, 1169.
(4) (a) Collum, D. B.; Still, W. C.; Mohamadi, F. J. Am. Chem. Soc. 1986,
108, 2094. (b) Barrett, A. G. M.; Tam, W. J. Org. Chem. 1997, 62, 4653. (c)
Kocovsky, P.; Grech, J. M.; Mitchell, W. L. J. Org. Chem. 1995, 60, 1482. (d)
Kocovsky, P.; Grech, J. M.; Mitchell, W. L. Tetrahedron Lett. 1996, 37, 1125.
(e) Kocovsky, P.; Dunn, V.; Grech, J. M.; Srogl, J.; Mitchell, W. L.
Tetrahedron Lett. 1996, 37, 5585.
DOI: 10.1021/jo1019909
r
Published on Web 12/30/2010
J. Org. Chem. 2011, 76, 557–565 557
2010 American Chemical Society

Raghavan et al.
JOCArticle
SCHEME 1. Mercuric Trifluoroacetate Promoted Cyclo-
propane Ring-Opening
TABLE 1. Stereoselective Preparation of cis-Cyclopropylcarbinolsb
SCHEME 2. Intramolecular Opening of the Cyclopropane Ring
SCHEME 3. Preparation of Stereotriads by Cyclopropane
Ring-Opening
alternating hydroxy and methyl substituents via mercuric
trifluoroacetate-promoted opening of cyclopropylcarbinols
possessing a remote hydroxy group protected as an ester,
Scheme 2.7 The oxymercuration-demercuration of cyclo-
propylcarbinols thus compliments epoxide ring-opening
with carbon nucleophiles as a strategy for securing the
methyl-hydroxyl array.
We disclose herein for the first time on the stereospecific
opening of cyclopropylcarbinols by an intramolecular sul-
finyl group promoted by mercuric trifluoroacetate to furnish
stereotriads and stereotetrad, Scheme 3.
Results and Discussion
Preparation of Cyclopropylcarbinols. The cis-disubstituted
cyclopropanes 12 and 13 were prepared starting from alkynyl
aldehyde8 8, Table 1. Reaction of 8 with the lithio anion
(5) For some applications of the ring-opening of cyclopropanes with
mercury(II) salts, see: (a) Landais, Y.; Parra-Rapado, L. Tetrahedron Lett.
1996, 37, 1209. (b) Kocovsky, P.; Srogl, J.; Pour, M.; Gogoll, A. J. Am. Chem.
Soc. 1994, 116, 186. (c) Kocovsky, P.; Srogl, J. J. Org. Chem. 1992, 57, 4565.
(d) Kocovsky, P.; Dunn, V.; Gogoll, A.; Langer, V. J. Org. Chem. 1999, 64,
101. (e) Misslitz, U.; Primke, H.; de Meijere, A. Chem. Ber. 1989, 122, 537. (f)
Lautens, M.; Tam, W.; Blackwell, J. J. Am. Chem. Soc. 1997, 119, 623. (g)
Lautens, M.; Blackwell, J. Synthesis 1998, 537. (h) Cossy, J.; Blanchard, N.;
Defosseux, M.; Meyer, C. Angew. Chem., Int. Ed. 2002, 41, 2144. (i)
Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004,
69, 4626.
aThe allylic alcohols 10 and 11 were isolated in roughly equimolar
amounts by column chromatography. bReagents and conditions: (a)
LDA, THF, -40 °C, 30 min, cool to -78 °C, add 8. (b) Ni(OAc)2 6H2O,
3
NaBH4, H2NCH2CH2NH2, EtOH, rt. (c) CH2I2, Et2Zn, CH2Cl2, 1,2-
DME, 0 °C to rt. (d) DMP, CH2Cl2, 0 °C. (e) Dibal-H, ZnCl2, THF,
-78 °C. (f) Dibal-H, THF, -78 °C.
(6) Collum, D. B.; Mohamadi, F.; Hallock, J. S. J. Am. Chem. Soc. 1983,
105, 6882.
(7) (a) Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. Tetrahedron
2005, 61, 7632. (b) Cossy, J.; Blanchard, N.; Meyer, C. Org. Lett. 2001, 3,
2567. (c) Cossy, J.; Blanchard, N.; Hamel, C.; Meyer, C. J. Org. Chem. 1999,
64, 2608. (d) Cossy, J.; Blanchard, N.; Meyer, C. Synthesis 1999, 1063. (e)
Cossy, J.; Blanchard, N.; Meyer, C. Eur. J. Org. Chem. 2001, 2841. (f) Cossy,
J.; Blanchard, N.; Meyer, C. Tetrahedron Lett. 1999, 40, 8361. (g) For an
account concerning the ring-opening of cyclopropylcarbinols with mercury-
(II) salts, see: Meyer, C.; Blanchard, N.; Defosseux, M.; Cossy, J. Acc. Chem.
Res. 2003, 36, 766.
of (S)-methyl p-tolyl sulfoxide9 afforded roughly an equi-
molar inseparable mixture of propargylic alcohols 9.
Chemoselective partial reduction of the alkyne with nickel
boride10 furnished a separable mixture of cis-allylic alcohols
10 and 11. Hydroxy group directed cyclopropanation
558 J. Org. Chem. Vol. 76, No. 2, 2011

Raghavan et al.
JOCArticle
following the Furukawa protocol11 yielded cyclopropylcar-
binols 12 and 13, respectively. Epimeric alcohol 16 was
obtained by diastereoselective reduction of ketone 14, ob-
tained by oxidation of 12 with Dess-Martin periodinane,12
using Dibal-H in the presence of anhydrous zinc chloride.13
Likewise oxidation of alcohol 13 to ketone 15 followed by
diastereoselective reduction exploiting the chirality of the
sulfinyl group furnished alcohol 17, Table 1. The diastereo-
meric carbinols were prepared to investigate the influence of
the configuration of hydroxy and sulfinyl groups on the
outcome of the reaction.
TABLE 2. Stereoselective Preparation of trans-Disubstituted and
Trisubstituted Cyclopropylcarbinolsa
The trans-disubstituted cyclopropylcarbinols were pre-
pared by the reaction14 of the lithio anion of 7 with unsatu-
rated esters 18-21 to furnish β-keto sulfoxides 22-25,
respectively. Diastereoselective reduction with Dibal-H in
the presence of anhydrous zinc chloride yielded β-hydroxy
sulfoxides 26-29, respectively. Hydroxy group directed
cyclopropanation afforded cyclopropanes 30-33, Table 2.
Epimeric alcohols 37-39 were prepared from 30, 32, and 33,
respectively, by an oxidation-reduction sequence.
The racemic alcohols 46 and 47 were prepared as depicted
in Scheme 4. Aldehyde 40, readily obtained by conjugate
addition of thiophenol to methacolein,15 was subjected to the
Corey-Fuchs reaction.16 Thus aldehyde 40 was reacted with
carbon tetrabromide to yield the intermediate dibromo-
alkene that on treatment with n-BuLi and quenching with
an excess of acetaldehyde afforded an equimolar inseparable
mixture of propargylic alcohols 41. Selective hydrogenation
of the alkyne with nickel boride yielded allylic alcohols17 42
and 43 as separable isomers. Oxidation of sulfides individu-
ally afforded the corresponding sulfoxides as inseparable
diastereomers, and further cyclopropanation yielded com-
pounds 46 and 47.
Oxymercuration-Demercuration of Cyclopropane Deriva-
tives. Treatment of cyclopropane 12 with 2 equiv of mercuric
trifluoroacetate in the presence of 0.5 equiv of mercuric
oxide,18 1.3 equiv of water in 1,2-dichloroethane as the
solvent in the dark overnight, afforded organomercurial 48
after treatment with aq potassium bromide. Demercuration
of 48 with lithium borohydride19 yielded 1,3-diol 49 as the
(8) See the Supporting Information for the preparation. No efforts were
made to prepare single diastereomers since the product distribution from
diastereomeric β-hydroxy sulfoxides was to be investigated.
(9) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem., Int. Ed.
2005, 44, 7221.
(10) Richardson, T.; Rychnovsky, S. D. J. Org. Chem. 1996, 61, 4219.
(11) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 7, 3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron
1968, 24, 53.
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(13) (a) Solladie, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985, 26,
435. (b) Solladie, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem.
1986, 51, 1912. (c) Carreno, M. C.; Garcia Ruano, J. L.; Martin, A.; Pedregal,
C.; Rodrigues, J. H.; Rubio, A.; Sanchez, J.; Solladie, G. J. Org. Chem. 1990,
55, 2120.
(14) Solladie, G.; Frechou, C.; Hutt, G.; Demailly, G. Bull. Soc. Chim. Fr.
1987, 827.
(15) Raghavan, S.; Ramakrishna Reddy, S.; Tony, K. A.; Naveen
Kumar, Ch.; Varma, A. K.; Nangia, A. J. Org. Chem. 2002, 67, 5838.
(16) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(17) The structure could not be assigned to cyclopropanes 46 and 47 at
this stage. It could be assigned only based on the NOE analysis of the
acetonide derived from 59.
(18) Mercuric oxide sequesters the liberated trifluoroacetic acid thus
preventing the reaction mixture from becoming acidic. For the use of HgO
see: Giese, B.; Hueck, K. Tetrahedron Lett. 1980, 21, 1829.
(19) Takacs, J. M.; Helle, M. A.; Takusagawa, F. Tetrahedron Lett. 1989,
30, 7321.
aReagents and conditions: (a) LDA, THF, -40 to 0 °C. (b) Dibal-H,
ZnCl2, THF, -78 °C. (c) CH2I2, Et2Zn, CH2Cl2, 1,2-DME, 0 °C to rt. (d)
DMP, CH2Cl2, 0 °C. (e) Dibal-H, THF, -78 °C.
J. Org. Chem. Vol. 76, No. 2, 2011 559

Raghavan et al.
JOCArticle
SCHEME 4. Synthesis of Racemic Cyclopropylcarbinols
46 and 47
TABLE 3. Mercuric Trifluoroacetate Promoted Sulfinyl Group
Opening of Cyclopropylcarbinola
SCHEME 5. Stereo- and Regioselective Preparation of a
Syn-Syn Stereotriad
sole product. Compound 48 is obtained stereoselectively via
intramolecular 6-endo opening of the cyclopropane ring by
the sulfinyl group,20 TS1, Scheme 5. While compound 48 was
characterized, the organomercuric bromides resulting from
other cyclopropylcarbinols were not characterized and
were directly subjected to demercuration with n-tributyltin
hydride21 in the presence of catalytic amounts of triethylbor-
ane in an oxygen atmosphere.22 The sulfinyl group reduction
to the corresponding sulfide, observed as a minor side
reaction while using lithium borohydride as the reducing
agent, was avoided by using n-tributyltin hydride. The results
of oxymercuration-demercuration are collected in Table 3.
Cyclopropane 13, wherein the sulfinyl oxygen and the
hydroxy groups are relatively syn-disposed, furnished syn
1,3-diol 50 under the standard conditions. Diastereomers 12
and 13 are expected to react at different rates; however, in
practice both of them were consumed after overnight stir-
ring. Cyclopropane 16 afforded the anti-syn stereotriad 51
while 17 furnished diol 52. These results clearly point to the
absence of any influence of sulfur chirality on the regio- and
stereoselectivity of diol formation and that it is controlled
only by the relative configuration of the stereogenic centers
aReagents and conditions: (i) All reactions were carried out on 0.25
mmol scale in the presence of 2 equiv of Hg(OTFA)2, 0.5 equiv of HgO,
1.3 equiv of water in 1,2-dichloroethane as solvent in the dark at rt for
16 h; (ii) Aq KBr; (iii) nBu3SnH, Et3B, CH2Cl2. bRecovered unreacted
starting material.
(20) The inversion of sulfur configuration is expected based on prece-
dented electrophile promoted nucleophilic sulfinyl group heterofunctionali-
zation of alkenes, see ref 3.
(21) (a) Whitesides, G. M.; San Fillipo, J., Jr. J. Am. Chem. Soc. 1970, 92,
6611. (b) Kang, S. H.; Lee, J. H.; Lee, S. B. Tetrahedron Lett. 1988, 39, 59 and
references cited therein. (c) Evans, D. A.; Bender, S. L.; Morris, J. J. Am.
Chem. Soc. 1988, 110, 2506.
of the cyclopropane ring. This in practical terms avoids the
necessity of working with diastereomerically pure sulfoxides
and preparing the cyclopropylcarbinols only via the route
(22) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143.
560 J. Org. Chem. Vol. 76, No. 2, 2011

Raghavan et al.
JOCArticle
indicated earlier, using unsaturated carbonyl compounds
and optically pure methyl p-tolyl sulfoxide. Many a route
can be envisioned for the preparation of chiral allylic
alcohols23 and chiral cyclopropanes.24 The trans-cyclopro-
pane 30 cleanly afforded the syn-anti stereotriad 53. In a
similar fashion, cyclopropane 37 afforded the anti-anti
stereotriad 54. On the basis of the kinetic preference for 5-
versus 6-membered ring formation in neighboring group
assisted reactions25 it was interesting to observe exclusive
6-endo opening of cyclopropylcarbinols. This can be ratio-
nalized by the deactivating inductive effect of the hydroxy
group, which would destabilize a partial positive charge at
the adjacent carbon. Given this backdrop, it is noteworthy
that cyclopropane 31 underwent ring-opening and also
regioselectively to furnish 55 as the only product. Thus
beginning with cis- and trans-cyclopropylcarbinols all four
stereotriads can be synthesized. Cyclopropane 38 afforded
exclusively 1,2-diol 56 constituting adjacent tertiary and
quaternary stereogenic centers. This result is significant since
asymmetric dihydroxylation of trisubstituted alkenes has
been reported to afford 1,2-diols with poor enantioselec-
tivity26 and diastereoselectivity.27 Cyclopropane 32 furn-
ished 1,3-diol 57 regio- and stereoselectively. The 2,2-di-
methyl-1,3-diol motif of 57 is commonly observed in many
natural products, Figure 1. The formation of 56 can be
rationalized by Markonikov’s rule, the methyl group at C3
in the putative transition state TS2 probably stabilizes the
developing partial positive charge. The formation of 57 can
be explained by the presence of A1,2 steric interactions
between the hydroxy and cyclopropyl ring in transition state
TS3 during 5-exo opening, which is avoided in a twist chair
conformation in transition state TS4 during 6-endo opening,
Scheme 6.
SCHEME 6. Probable Transition States for the Formation of
56 and 57
SCHEME 7. Rationalization of Unreactivity of 39 and 47
oxymercuration-demercuration sequence. Compound 46
reacted without incident to furnish anti-syn-syn stereote-
trad 59 via 5-exo opening. On the other hand 47 returned
only unreacted starting material.28 The recalcitrant behavior
of 47 probably may be rationalized by the presence of
unfavorable A1,3 steric interactions between the Me- and
OH-substituents in the 5-exo opening transition state TS6,
Scheme 7.
The intramolecular opening of the cyclopropane ring by a
sulfilimine group was next explored as a possible stereo-
selective route to 1,3-amino alcohols. The sulfilimines 61 and
63 were prepared by treatment of sulfides, obtained by the
reduction29 of sulfoxides 13 and 30, respectively, with
NaNClBoc30 in acetonitrile. Oxymercuration-demercura-
tion under standard conditions returned only unreacted
starting materials after prolonged reaction periods. The
reason for the sulfilimines failing to open the cyclopropyl
ring is probably due to the unfavorable steric interactions
between the nitrogen substituent and the cyclopropane ring
in the transition state for ring-opening. See the Supporting
Information for the preparation of sulfilimines.
Cyclopropane 33 cleanly afforded 58, the product of
6-endo opening expected due to the inductive stabilizing
effect of the methyl group. Entries 7 and 10 are to the best
of our knowledge the only examples of successful oxymer-
curation of cyclopropanes flanked by hydroxy substituents
on both carbon atoms.4b Cyclopropane 39 returned only
unreacted starting material even after prolonged reaction
periods. This may be explained due to the unfavorable A1,3
steric interactions between OH- and Me-groups in transition
state TS5, Scheme 7. The cyclopropanes 46 and 47 flanked by
stereogenic centers on both sides were next subjected to the
(23) For the preparation of allylic alcohols by asymmetric vinylation of
aldehydes see: (a) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2007, 129, 16119. (b) Lurain, A. E.; Carroll, P. J.;
Walsh, P. J. J. Org. Chem. 2005, 70, 1262. (c) Oppolzer, W.; Radinov, R. N.
J. Am. Chem. Soc. 1993, 115, 1593. (d) Wipf, P.; Ribe, S. J. Org. Chem. 1998,
63, 6454. (e) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449. (f) Hart, D. W.;
Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115.
(24) For the asymmetric synthesis of cyclopropanes see: (a) Li, A.-H.;
Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341. (b) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977. (c)
Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611. (d) Doyle, M. P.;
Protopopova, M. N. Tetrahedron 1998, 54, 7919.
(25) McManus, S. P.; Capon, B. Neighbouring Group Participation;
Plenum Press: New York, 1976; Vol. 1.
(26) Koppisch, A. T.; Poulter, C. D. J. Org. Chem. 2002, 67, 5416.
(27) Konig, C. M.; Gebhardt, B.; Schleth, C.; Dauber, M.; Koert, U. Org.
Lett. 2009, 11, 2728.
On the basis of the mechanism, an inversion of configura-
tion is expected at sulfur and at the electrophilic carbon. The
structure of diol 53, obtained from 30, was proven by X-ray
crystallography. The structure of the other products was
assigned based on analogy and further confirmed by 1H
NMR-NOE analysis of the acetonides derived from the
diols.
(28) The trans-cyclopropanes corresponding to 46 and 47 are expected to
react without any incident to furnish anti-anti-syn and syn-anti-syn
stereotetrads. Unlike cis-allylic alcohols 42 and 43 that could be separated,
the corresponding trans-allylic alcohols, obtained by reduction of 41 with
Red-Al, could not be separated. Therefore further sulfoxide preparation and
cyclopropanation was not attempted.
(29) Drabowicz, J; Oae, S Synthesis 1977, 6, 404.
(30) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996,
35, 2813.
J. Org. Chem. Vol. 76, No. 2, 2011 561

Raghavan et al.
JOCArticle
Conclusion
1638, 1459, 1386, 1083, 1028, 752 cm-1; H NMR (500 MHz,
CDCl3) δ 7.55 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.31
(d, J = 7.8 Hz, 4H), 4.83-4.75 (m, 2H), 3.27 (dd, J = 12.7, 6.8
Hz, 1H), 3.07 (dd, J = 12.7, 8.8 Hz, 1H), 2.98-2.90 (m, 2H),
2.42 (s, 6H), 2.21-2.12 (m, 4H), 1.5-1.20 (m, 16H), 0.92-0.83
(m, 6H); 13C NMR (50 MHz, CDCl3) δ 141.7, 141.6, 139.5,
139.1, 124.1, 123.9, 87.3, 86.7, 78.5, 78.4, 64.4, 63.9, 58.2, 56.9,
31.1, 28.3, 28.2, 22.3, 21.2, 18.5, 13.8; MS (ESI) 315 [M þ Na]þ;
HRMS (ESI) m/z [M þ Na]þ calcd for C17H24O2NaS 315.1552,
found 315.1546.
1
The following conclusions can be drawn: (a) The reaction
is general in nature and proceeds with equal facility on di-
and trisubstituted cyclopropylcarbinols. (b) The reaction
proceeds highly regioselectively and the outcome can be
rationalized by the destabilizing inductive effect of the
hydroxy/stabilizing inductive effect of the methyl groups.
(c) The reaction proceeds with clean inversion of configura-
tion at the electrophilic carbon and sulfur atoms. (d) The
reaction can be considered to be complementary to other
routes to stereotriads/stereotetrads such as the two-step
epoxidation followed by dimethyl cuprate opening of allylic
alcohols, hydroboration, and hydrosilylation reactions. (e)
The methodology has predictive value for use in total synth-
esis. (f) The products in addition to possessing alternating
hydroxy and methyl groups also possess the sulfinyl group
that provides a versatile handle for further carbon-carbon
and carbon-heteroatom bond formations. The sulfinyl
group may be exploited for further carbon-carbon bond
forming reactions like alkylation,31 Pummerer followed by
ene reaction,32 and as chiral ligands.33 Also the rich chem-
istry of R-chloro sulfides34 can be taken advantage of by
reduction of sulfoxides to sulfides.
In summary, we have disclosed for the first time a highly
regio- and stereoselective synthesis of diastereomeric stereo-
triads and tetrads by oxymercuration-demercuration of
cyclopropylcarbinols employing an intramolecular sulfinyl
group as the nucleophile. The reaction proceeds with equal
facility on di- and trisubstituted alkenes to furnish products
possessing tertiary and quaternary stereogenic centers. It is
noteworthy that the sulfinyl group is tolerated under the
Furukawa’s cyclopropanation conditions. However, there
are some limitations: the reaction did not proceed using
sulfilimines as intramolecular nucleophiles. The application
of the methodology in the synthesis of polypropionate con-
taining natural products is currently underway and shall be
disclosed in due course.
General Procedure for the Reduction of Propargylic Alcohols
to Allylic Alcohols. To a suspension of Ni(OAc)2 4H2O (1 equiv)
3
in ethanol (0.11 M) was added sodium borohydride (1 equiv)
portionwise at rt. The mixture was maintained under hydrogen
atmosphere and stirred at rt for 1 h. Ethylenediamine (4 equiv)
was added, followed by a solution of propargylic alcohol
(1 equiv) in ethanol (0.5 M). After completion of the reaction,
the reaction mixture was filtered and the solids washed with
ethanol twice. The combined filtrates were evaporated. The
crude residue was diluted with ethyl acetate washed successively
with aq 1 N HCl, aq saturated sodium bicarbonate, water, and
brine, dried over Na2SO4, and concentrated to furnish the crude
product.
The crude compound obtained from 9 following the general
procedure detailed above was purified by column chromatog-
raphy (22% EtOAc/hexanes, v/v) to afford the allylic alcohols
10 and 11 in an equimolar ratio in 89% combined yield.
Compound 10: colorless liquid; Rf 0.25 (35% EtOAc/hexanes,
v/v); [R]25D -63 (c 1, CHCl3); IR (neat) 3356, 2955, 2925, 2855,
1459, 1397, 1083, 1030, 809 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.52 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.45-5.29
(m, 2H), 5.01-4.90 (m, 1H), 3.10 (dd, J = 13.6, 10.0 Hz, 1H),
2.50 (dd, J = 13.6, 1.7 Hz, 1H), 2.44 (s, 3H), 1.91-1.56 (m, 2H),
1.46-1.05 (m, 8H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 140.9, 139.6, 132.1, 129.7, 129.6, 123.6, 62.9, 62.2,
31.4, 29.1, 28.7, 27.4, 22.3, 21.1, 13.8; MS (ESI) 295 [M þ H]þ;
HRMS (ESI) m/z [M þ Na]þ calcd for C17H26O2NaS 317.1565,
found 317.1551.
Compound 11: colorless liquid; Rf 0.25 (40% EtOAc/hexanes,
v/v); [R]25D -18.2 (c 1, CHCl3); IR (neat) 3356, 2955, 2925, 2855,
1459, 1397, 1083, 1030, 809 cm-1; 1H NMR (200 MHz, CDCl3)
δ 7.52 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 5.56-5.30
(m, 2H), 4.97 (dt, J = 8.3, 3.8 Hz, 1H), 3.05 (dd, J = 12.8, 8.3
Hz, 1H), 2.65 (dd, J = 12.8, 3.8 Hz, 1H), 2.42 (s, 3H), 2.14-1.92
(m, 2H), 1.45-1.15 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 141.5, 140.1, 132.9, 129.7, 129.6, 124.0,
63.8, 63.7, 31.3, 29.1, 28.6, 27.4, 22.3, 21.1, 13.8; MS (ESI) 295
[M þ H]þ.
Experimental Section
Compound 9: To a solution of diisopropylamine (1.47 mL,
10.6 mmol) in dry THF (20 mL) at 0 °C under nitrogen atmo-
sphere was added n-BuLi (3.85 mL, 2.5 M in hexanes, 9.64
mmol) dropwise with stirring for 15 min. The mixture was then
cooled to -40 °C and a solution of sulfoxide 7 (1.36 g, 8.84
mmol) in dry THF (8 mL) was added dropwise with stirring for
30 min. The reaction mixture was then cooled to -78 °C and a
solution of the crude aldehyde obtained above (1.2 g, 8.84
mmol) in dry THF (16 mL) was added dropwise. After 30 min
at -78 °C the reaction was quenched by the addition of an
aqueous saturated ammonium chloride solution. The reaction
mixture was diluted with ether (20 mL) and the layers were
separated. The organic layer was washed with water and brine,
dried over Na2SO4, and evaporated to afford the crude product,
which was purified by column chromatography (30% EtOAc/
hexanes, v/v) to afford a ∼1:1 mixture of diastereomers in 90%
combined yield (2.32 g, 7.96 mmol). Pale yellow liquid; Rf 0.25
(30% EtOAc/hexanes, v/v); IR (neat) 3416, 2958, 2925, 2855,
General Procedure for Cyclopropanation with Furukawa’s
Protocol. A mixture of dichloromethane (0.15 M) and 1,2-
dimethoxyethane (3 equiv) was cooled to -10 °C with an ice-
salt bath. Diethyl zinc (1 M/hexane, 3 equiv) was added followed
by diiodomethane (6 equiv) over a period of 10 min while the
temperature was maintained below -5 °C. After the addition
was complete, the resulting clear solution was stirred for 45 min
at 0 °C. A solution of allylic alcohol (1 equiv) in dichloro-
methane (0.25 M) was added via canula under argon atmo-
sphere over a 5-10 min period while maintaining the
temperature below -5 °C. The cooling bath was removed and
the reaction mixture was allowed to warm to room temperature
and stirred for 12-18 h at that temperature. The reaction was
quenched with aq saturated ammonium chloride and aq 10%
hydrochloric acid. The two layers were separated and the aq
layer was extracted with dichloromethane twice. The combined
organic phases were washed successively with aq saturated
sodium sulphite, aq saturated sodium bicarbonate, and brine.
The organic layer was dried over Na2SO4, filtered, and concen-
trated to furnish the crude product.
(31) Sato, T.; Itoh, T.; Fujisawa, T. Tetrahedron Lett. 1987, 28, 5677.
(32) (a) Raghavan, S.; Mustafa, S. Tetrahedron 2008, 64, 10055. (b)
Ishibashi, H.; Komatsu, H.; Ikeda, M. J. Chem. Res. (S) 1987, 296.
(33) Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5, 3281.
(34) Raghavan, S.; Vinoth Kumar, V.; Raju Chowhan, L. Synlett 2010,
1807.
562 J. Org. Chem. Vol. 76, No. 2, 2011

Raghavan et al.
JOCArticle
Compound 12: The crude compound was purified by column
chromatography (35% EtOAc/hexanes, v/v) to afford the cy-
clopropylcarbinol 12 (277 mg, 0.90 mmol) as a single diaster-
eomer in 90% yield. Colorless liquid; Rf 0.25 (40% EtOAc/
the crude product, water and EtOAc were added at this stage,
then the solution was adjusted to pH 2 by the addition of 5% aq
H2SO4 solution. The aqueous phase was extracted with ethyl
acetate. The combined organic layers were washed successively
with water and brine, dried over Na2SO4, and concentrated to
furnish the crude product. The crude compound was purified by
column chromatography (35% EtOAc/hexanes, v/v) to afford
the cyclopropylcarbinol 17 (120 mg, 0.39 mmol) as a single
diastereomer in 86% yield. Colorless liquid; Rf 0.25 (40%
hexanes, v/v); [R]25 -90 (c 1, CHCl3); IR (neat) 3370, 2955,
D
1
2924, 2854, 1459, 1399, 1299, 1027, 810, 504 cm-1; H NMR
(300 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3
Hz, 2H), 3.69-3.58 (m, 1H), 3.10 (dd, J = 12.8, 9.8 Hz, 1H),
2.67 (dd, J = 12.8, 1.5 Hz, 1H), 2.37 (s, 3H), 1.32-1.06 (m,
10H), 0.84 (t, J = 6.8 Hz, 3H), 0.76-0.58 (m, 3H), 0.15-0.06
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 141.1, 139.5, 129.7,
123.7, 67.3, 62.1, 31.5, 29.9 28.8, 28.1, 22.4, 21.6, 21.1, 15.7, 13.8,
10.1; MS (ESI) 309 [M þ H]þ; HRMS (ESI) m/z [M þ Na]þ
calcd for C18H28O2NaS 331.1720, found 331.1707.
General Procedure for the Oxidation of Cyclopropylcarbinols
to Cyclopropylketones. Dess-Martin periodinane (1.3 equiv)
was added to the solution of cyclopropyl carbinol (1 equiv) in
dichloromethane (0.2 M) at 0 °C and the reaction mixture was
stirred for 30 min at the same temperature. The reaction mixture
was diluted with dichloromethane, the precipitated solid was
filtered, and the filtrate was washed with aq saturated sodium
bicarbonate, water, and brine, dried over Na2SO4, and concen-
trated to furnish the crude product.
EtOAc/hexanes, v/v); [R]25 -79.5 (c 1, CHCl3); IR (neat)
D
3370, 2955, 2924, 2854, 1459, 1399, 1299, 1027, 810, 504 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz, 2H), 7.33 (d,
J = 8.1 Hz, 2H), 3.74 (td, J = 9.8, 1.7 Hz, 1H), 3.12 (dd, J =
13.4, 9.8 Hz, 1H), 2.84 (dd, J = 13.4, 1.7 Hz, 1H), 2.42 (s, 3H),
1.62-1.47 (m, 1H), 1.46-0.93 (m, 11H), 0.87 (t, J = 7.0 Hz,
3H), 0.67-0.56 (m, 1H), -0.22-0.31 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 141.3, 139.9, 129.9, 123.9, 67.4, 63.1,
31.7, 29.8, 29.1, 28.4, 22.6, 22.0, 21.3, 17.1, 14.0, 9.1; MS (ESI)
309 [M þ H]þ.
General Procedure for Preparation of β-Keto Sulfoxides. A
solution of n-BuLi (1.6 M/hexanes 1.05 equiv) was added to a
solution of diisopropylamine (1.1 equiv) in dry THF (0.33 M) at
0 °C. After 15 min the resulting lithium diisopropylamide
solution was cooled to -40 °C and the solution of (S)-methyl
p-tolylsulfoxide (1 equiv) in dry THF (0.88 M) was added
dropwise and stirred at the same temperature for 30 min. The
temperature was allowed to rise to 0 °C and the solution of
the ester (0.5 equiv) in THF (0.88 M) was added dropwise. The
reaction was stirred further for a period of 1 h at 0 °C. The
reaction was quenched by the addition of an aq saturated
NH4Cl solution and then the solution adjusted to pH 2 by the
addition of aq 5% H2SO4 solution. The two layers were
separated and the aqueous phase extracted with ethyl acetate.
The combined organic layers were washed successively with
water and brine, dried over Na2SO4, and concentrated to furnish
the crude product.
Compound 14: The crude compound obtained following the
procedure detailed above was purified by column chromatog-
raphy (30% EtOAc/hexanes, v/v) to afford the ketone 14 (0.44
mmol) in 89% yield. Viscous liquid; Rf 0.25 (30% EtOAc/
hexanes, v/v); [R]25 -13 (c 1, CHCl3); IR (neat) 2976, 2930,
D
2107, 1727, 1546, 1373, 1282, 1188, 1026, 804 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1
Hz, 2H), 3.96 (d, J = 13.6 Hz, 1H), 3.91 (d, J = 13.6 Hz, 1H),
2.41 (s, 3H), 2.15-2.05 (m, 1H), 1.55-1.44 (m, 1H), 1.43-1.34
(m, 2H), 1.33-1.14 (m, 8H), 1.12-0.97 (m, 2H), 0.86 (t, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 200.0, 141.9, 139.6,
129.9, 124.1, 69.6, 39.6, 29.7, 28.8, 27.9, 27.4, 26.0, 22.4, 21.3,
16.4, 13.9; MS (ESI) 307 [M þ H]þ; HRMS (ESI) m/z [M þ H]þ
calcd for C18H27O2S 307.1734, found 307.1731.
Compound 22: The crude compound obtained following the
general procedure was purified by column chromatography
(30% EtOAc/hexanes, v/v) to afford the β-keto sulfoxide 22
(6.4 mmol) in 64% yield. Viscous liquid; Rf 0.25 (45% EtOAc/
hexanes, v/v); [R]25D -75.2 (c 1, CHCl3); IR (neat) 2925, 2856,
1669, 1622, 1496, 1453, 1327, 1130, 1044, 809 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.50 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3
Hz, 2H), 7.28-7.10 (m, 5H), 6.86 (td, J = 15.9, 6.8 Hz, 1H), 6.12
(d, J = 15.9 Hz, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.81 (d, J = 13.6
Hz, 1H), 2.77 (t, J = 6.8 Hz, 2H), 2.55 (q, J = 6.8 Hz, 2H), 2.44
(s, 3H); 13C NMR (50 MHz, CDCl3) δ 190.1, 149.7, 141.3, 139.8,
139.3, 130.0, 129.4, 127.9, 127.7, 125.6, 123.6, 65.6, 33.6, 33.4,
20.8; MS (ESI) 335 [M þ Na]þ; HRMS (ESI) m/z [M þ H]þ
calcd for C18H21O2S 313.1270, found 313.1262.
Compound 16: A solution of the mixture of the keto sulfoxide
14 (132 mg, 0.43 mmol) and anhydrous ZnCl2 (70 mg, 0.52
mmol) in dry THF (4 mL) was stirred at rt for 30 min. The
mixture was cooled to -78 °C and DIBAL-H (0.46 mL, 1.4M/
toluene) was added dropwise. After 1 h at -78 °C the reaction
was quenched by the addition of methanol (1 mL). The reaction
mixture was allowed to warm to rt. The volatiles were evapo-
rated under reduced pressure to afford the crude product. Water
and EtOAc were added at this stage and the solution was
adjusted to pH 2 by the addition of 5% aq H2SO4 solution.
The aqueous phase was extracted with ethylacetate. The com-
bined organic layers were washed successively with water and
brine, dried over Na2SO4, and concentrated to furnish the crude
product. The crude compound was purified by column chro-
matography (35% EtOAc/hexanes, v/v) to afford the cyclopro-
pylcarbinol 16 (122 mg, 0.39 mmol) as a single diastereomer in
90% yield. Yellow liquid; Rf 0.25 (40% EtOAc/hexanes, v/v);
Compound 26: The crude compound, obtained following the
procedure detailed for the preparation of 16 from 14, was
purified by column chromatography (50% EtOAc/hexanes,
v/v) to afford the hydroxy sulfoxide 26 (1.79 mmol) as a single
diastereomer in 89% yield. Colorless liquid; Rf 0.27 (50%
[R]25 -40.5 (c 1, CHCl3); IR (neat) 3370, 2955, 2924, 2854,
D
EtOAc/hexanes, v/v); [R]25 -87.4 (c 1, CHCl3); IR (neat)
1
1459, 1399, 1299, 1027, 810, 504 cm-1; H NMR (300 MHz,
D
3349, 2923, 2855, 1494, 1453, 1304, 1085, 1030, 972, 810, 700
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 8.3 Hz, 2H),
7.33 (d, J = 8.3 Hz, 2H), 7.28-7.09 (m, 5H), 5.82 (dt, J = 15.1,
6.7 Hz, 1H), 5.47 (dd, J = 15.1, 6.0 Hz, 1H), 4.76-4.67 (m, 1H),
2.96 (dd, J = 12.8, 9.1 Hz, 1H), 2.72 (dd, J = 12.8, 3.1 Hz, 1H),
2.69 (t, J = 8.3 Hz, 2H), 2.43 (s, 3H), 2.35 (q, J = 7.5 Hz, 2H);
13C NMR (50 MHz, CDCl3) δ 141.4, 141.2, 140.1, 131.9, 130.6,
129.7, 128.1, 127.9, 125.5, 123.9, 68.4, 63.4, 35.0, 33.5, 21.1; MS
(ESI) 315 [M þ H]þ; HRMS (ESI) m/z [M þ Na]þ calcd for
C19H22O2NaS 337.1234, found 337.1238.
CDCl3) δ 7.53 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 3.82
(td, J = 8.8, 2.8 Hz, 1H), 3.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.88
(dd, J = 13.1, 2.8 Hz, 1H), 2.43 (s, 3H), 1.71-1.57 (m, 1H),
1.55-1.39 (m, 2H), 1.39-1.14 (m, 7H), 1.05-0.83 (m, 5H),
0.72-0.63 (m, 1H), -0.01-0.07 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 141.6, 140.5 129.9, 123.8, 69.5, 63.3, 31.9, 29.7, 29.1,
28.4, 22.5, 22.1, 21.3, 16.8, 13.9, 9.2; MS (ESI) 309 [M þ H]þ.
Compound 17: To a solution of ketone 15 (138 mg, 0.45 mmol)
in anhydrous THF (4.5 mL) cooled at -78 °C was added a
solution of DIBAL-H (0.48 mL, 1.4 M/toluene). After 1 h at
-78 °C, the reaction was quenched by the addition of methanol.
The volatiles were evaporated under reduced pressure to afford
Compound 41: A two-necked round-bottomed flask,
equipped with a magnetic stir bar, rubber septum, an additional
J. Org. Chem. Vol. 76, No. 2, 2011 563

Raghavan et al.
JOCArticle
funnel fitted with a rubber septum, and an argon inlet, is charged
with carbon tetrabromide (8 g, 24 mmol) and then dry dichloro-
methane (30 mL) is added. The solution is cooled in an ice bath
and a solution of triphenylphosphine (12.6 g, 48 mmol) in dry
dichloromethane (30 mL) is then added dropwise via the addi-
tional funnel over 20 min. The reaction mixture is stirred at 0 °C
for 10 min, and then the solution of the aldehyde (2.16 g,
12 mmol) in dichloromethane (20 mL) is added over 5 min via
cannula. The solution is stirred at 0 °C for 1 h, and then water is
added. The water layer is separated, then extracted 3 times with
CH2Cl2 (30 mL). The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated. The
residue was diluted with diethyl ether (50 mL), cooled to 0 °C,
and filtered. This was repeated 4 times. The ether layers were
concentrated and the residue was purified by small flash column
chromatography. The product was directly used in the next step.
Yield 95% (11.4 mmol). To a solution of the above dibromo
compound in tetrahydrofuran (95 mL) cooled at -78 °C was
added n-butyllithium (10.1 mL, 2.5 M, 25 mmol). The reaction
mixture was stirred at the same temperature for 30 min, then a
solution of acetaldehyde (14 mmol) in tetrahydrofuran (15 mL)
was added dropwise with cannula. After 30 min the reaction was
quenched by adding aq saturated ammonium chloride. The aq
layer was separated and reextracted with ether. The combined
organic layers were washed successively with water and brine,
dried over Na2SO4, and evaporated. The crude product was
purified by column chromatography with 15% EtOAc/hexanes
(v/v) to afford the sulfide 41 as an inseperable mixture (9.69
mmol) in 80% yield. Orange liquid; Rf 0.25 (20% EtOAc/
hexanes, v/v); IR (neat) 3418, 2975, 2926, 1634, 1582, 1442,
1326, 1074, 1023, 740 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.27
(d, J = 7.4 Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H), 7.10 (t, J = 7.0 Hz,
1H), 4.45-4.31 (m, 1H), 3.01 (dd, J = 13.0, 6.6 Hz, 1H), 2.79
(dd, J = 13.0, 7.3 Hz, 1H), 2.68-2.39 (m, 1H), 1.30 (d, J = 6.6
Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
135.9, 129.5, 128.7, 126.1, 86.5, 83.6, 58.0, 40.4, 26.1, 24.3, 19.9;
MS (ESI) 221 [M þ H]þ; HRMS (ESI) m/z [M þ H]þ calcd for
C13H17OS 221.0994, found 221.1000.
anhydrous Na2SO4, and evaporated. The crude product was
purified by column chromatography with (50% EtOAc/
hexanes, v/v) to afford an equimolar inseparable mixture of
diastereomeric sulfoxides 44 (5.60 mmol) in 92% yield. Viscous
liquid; Rf 0.25 (60% EtOAc/hexanes, v/v); IR (neat) 3394, 2965,
1
2925, 1723, 1447, 1294, 1086, 1020, 750, 694 cm-1; H NMR
(300 MHz, CDCl3) δ 7.64-7.56 (m, 4H), 7.55-7.43 (m, 6H),
5.68 (dd, J = 10.5, 9.4 Hz, 1H), 5.37 (dd, J = 10.5, 9.4 Hz, 1H),
5.27 (t, J = 10.7 Hz, 1H), 5.12 (t, J = 10.7 Hz, 1H), 4.72-4.58
(m, 2H), 3.48-3.22 (m, 2H), 2.91 (dd, J = 12.4, 4.1 Hz, 1H), 2.85
(dd, J = 13.2, 6.9 Hz, 1H), 2.62 (dd, J = 13.2, 6.2 Hz, 1H), 2.46
(dd, J = 12.4, 11.7 Hz, 1H), 1.26 (d, J = 6.2 Hz, 3H), 1.23 (d,
J = 6.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 143.6, 143.3, 135.5, 134.3,
133.3, 133.0, 131.5, 131.2, 129.4, 129.3, 124.0, 123.9, 64.1,
63.8, 63.1, 62.4, 28.3, 27.8, 23.2, 22.6, 21.2, 20.8; MS (ESI) 239
[M þ H]þ; HRMS (ESI) m/z [M þ Na]þ calcd for C13H18O2NaS
261.0929, found 261.0925.
Compound 48: To a solution of cyclopropylcarbinol (0.25
mmol) in 1,2-dichloroethane (2 mL, 0.13 M) and water (0.33
mmol) was added mercuric trifluoroacetate (0.5 mmol) and
HgO (0.13 mmol). The reaction was stirred in the dark at rt
for 16 h under nitrogen atmosphere. The reaction was quenched
by the addition of aq KBr and extracted with dichloromethane.
The organic layer was washed with water and brine, dried over
Na2SO4, and evaporated to furnish the crude organomercuric
bromide, which was purified by column chromatography to
afford the compound 48 (133 mg, 0.22 mmol) as a single
diastereomer in 89% yield. Amorphous solid; mp 155-156
°C; Rf 0.25 (40% EtOAc/hexanes, v/v); [R]25D þ37 (c 1, CHCl3);
IR (neat) 3446, 2929, 2855, 1636, 1512, 1249, 1089, 1035, 835
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H),
7.36 (d, J = 8.3 Hz, 2H), 4.70-4.58 (m, 1H), 4.07-3.94 (m, 1H),
3.32 (dd, J = 12.8, 9.8 Hz, 1H), 2.81 (dd, J = 12.8, 1.8 Hz, 1H),
2.44 (s, 3H), 2.15-2.06 (m, 1H), 1.66-1.44 (m, 2H), 1.43-1.17
(m, 10H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 142.5, 138.6, 130.3, 124.5, 74.2, 71.7, 60.9, 46.2, 34.8, 31.7,
29.5, 29.1, 25.9, 22.5, 21.4, 14.0; MS (ESI) 606 [M]þ; HRMS
(ESI) m/z [M þ Na]þ calcd for C18H29O3NaSHgBr 629.1045,
found 629.1049.
Compounds 42 and 43: The crude compound obtained by
reduction of 41, following the procedure mentioned earlier for
the synthesis of 10 and 11 from 9, was purified by column
chromatography (12% EtOAc/hexanes, v/v) to afford the allylic
alcohols roughly as a 1:1 mixture of diasteriomers in 85%
combined yield. Compound 42: pale yellow liquid; Rf 0.22
(20% EtOAc/hexanes, v/v); IR (neat) 3376, 2965, 2924, 1582,
Compound 49: To the solution of the organomercuric bromide
48 (130 mg, 0.22 mmol) in THF (2.2 mL) cooled at -78 °C was
added lithium borohydride (0.14 mL, 2 M in THF, 0.28 mmol)
dropwise when mercury began to precipitate almost immedi-
ately. The reaction mixture was stirred at -78 °C for 1 h. The
reaction mixture was quenched with aq saturated NH4Cl solu-
tion and extracted with ethyl acetate. The combined extracts
were washed with brine, dried over Na2SO4, and concentrated to
furnish the crude product. The crude compound was purified by
column chromatography (40% EtOAc/hexanes, v/v) to afford
the diol 49 (68 mg, 0.21 mmol) as a single diastereomer in 85%
1
1478, 1442, 1371, 1059, 1027, 740 cm-1; H NMR (300 MHz,
CDCl3) δ 7.36-7.22 (m, 4H), 7.22-7.11 (m, 1H), 5.44 (dd, J =
10.9, 8.8 Hz, 1H), 5.25 (dd, J = 9.8, 8.8 Hz, 1H), 4.54-4.42 (m,
1H), 2.95-2.72 (m, 3H), 1.24 (d, J = 6.2 Hz, 3H), 1.13 (d, J =
6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 136.5, 134.4, 133.8,
128.8, 128.7, 125.7, 63.9, 40.6, 32.0, 23.6, 20.7; MS (ESI) 261
[M þ O þ H]þ. Compound 43: pale yellow liquid; Rf 0.20 (20%
EtOAc/hexanes, v/v); IR (neat) 3376, 2965, 2924, 1582, 1478,
1442, 1371, 1059, 1027, 740 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.38-7.22 (m, 4H), 7.22-7.13 (m, 1H), 5.46 (dd, J = 10.5, 9.0
Hz, 1H), 5.16 (dd, J = 10.5, 9.6 Hz, 1H), 4.50-4.37 (m, 1H),
2.95 (dd, J = 12.0, 3.7 Hz, 1H), 2.87-2.75 (m, 1H), 2.71 (dd, J =
12.0, 8.3 Hz, 1H), 1.19 (d, J = 6.0 Hz, 3H), 1.08 (d, J = 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 136.2, 134.5, 134.4, 129.1,
128.9, 126.1, 63.3, 40.6, 32.4, 22.9, 21.0; MS (ESI) 261 [M þ O þ
H]þ; HRMS (ESI) m/z [M þ H]þ calcd for C13H19O2S 239.1110,
found 239.1105.
yield. Viscous liquid; Rf 0.25 (45% EtOAc/hexanes, v/v); [R]25
D
þ39 (c 1, CHCl3); IR (neat) 3446, 2929, 2855, 1636, 1512, 1249,
1089, 1035, 835 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.52 (d,
J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 4.44 (dt, J = 9.8, 2.6
Hz, 1H), 3.91-3.77 (m, 1H), 3.04 (dd, J = 12.9, 9.1 Hz, 1H),
2.70 (dd, J = 12.9, 2.3 Hz, 1H), 2.43 (s, 3H), 1.92-1.73 (m, 2H),
1.62-1.13 (m, 9H), 0.91 (d, J = 7.6 Hz, 3H), 0.89 (t, J = 8.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 142.1, 140.2, 130.2, 123.9,
75.5, 73.2, 60.7, 41.6, 34.9, 31.8, 29.3, 26.0, 22.6, 21.4, 14.1, 5.4;
MS (ESI) 327 [M þ H]þ; HRMS (ESI) m/z [M þ H]þ calcd for
C18H31O3S 327.2006, found 327.1993.
Compound 44: To a solution of the sulfide 42 (1.48 g, 6 mmol)
in dichloromethane (30 mL) cooled at -40 °C was added m-
CPBA (6 mmol) and the progress of the reaction was followed
by TLC. After 1 h the reaction mixture was diluted with
dichloromethane, washed successively with aq saturated NaH-
SO3, aq saturated NaHCO3, water, and brine, dried over
General Procedure for Oxymercuration-Demercuration of
Cyclopropylcarbinols. To a solution of cyclopropylcarbinol
(0.25 mmol) in 1,2-dichloroethane (2 mL, 0.13 M) and water
(0.33 mmol) was added mercuric trifluoroacetate (0.5 mmol)
and HgO (0.13 mmol). The reaction was stirred in the dark at rt
for 16 h under nitrogen atmosphere. The reaction was quenched
564 J. Org. Chem. Vol. 76, No. 2, 2011

Raghavan et al.
JOCArticle
by the adittion of aq KBr and extracted with dichloromethane.
The organic layer was washed with water and brine, dried over
Na2SO4, and evaporated to furnish the crude organomercuric
bromide, which was subjected to demercuration. To the solution
of the organomercuric bromide in THF (2.5 mL, 0.1 M) at rt was
added triethylborane (5 mol %) and oxygen through a syringe.
Tributyltin hydride (0.5 mmol) was added dropwise when
mercury began to precipitate almost immediately. The reaction
mixture was stirred at rt for 3 h. The reaction mixture was
treated with aq saturated KF solution and stirred for 30 min. It
was diluted with ethyl acetate and filtered. The residue was
washed twice with ethyl acetate. The combined filtrates were
dried over Na2SO4 and concentrated to furnish the crude
product.
3H), 1.09 (d, J = 6.9 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.76 (d,
J = 6.9 Hz, 3H); MS (ESI) 271 [M þ H]þ; HRMS (ESI) m/z [M þ
H]þ calcd for C14H23O3S 271.1372, found 271.1367. The sulf-
oxides were oxidized to a single sulfone as detailed hereunder
and characterized. To a solution of the inseparable mixture of
sulfoxide diols 59 (40 mg, 0.15 mmol) in dichloromethane (1.5
mL) cooled at 0 °C was added m-CPBA (34.4 mg, 0.20 mmol)
with stirring at rt for 30 min. The reaction mixture was diluted
with dichloromethane, washed successively with aq saturated
NaHSO3, aq saturated NaHCO3, water, and brine, dried over
anhydrous Na2SO4, and evaporated. The crude product was
purified by column chromatography (35% EtOAc/hexanes, v/v)
to afford a single sulfone (39 mg, 0.14 mmol) in 93% yield.
Viscous liquid; Rf 0.25 (40% EtOAc/hexanes, v/v); IR (neat)
3383, 2924, 2854, 1729, 1374, 1087, 1020, 800, 751, 692 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.93 (d, J = 7.3 Hz, 2H), 7.70-7.61
(m, 1H), 7.61-7.53 (m, 2H), 4.09-4.00 (m, 1H), 3.61 (dd, J =
14.1, 3.0 Hz, 1H), 3.52 (dd, J = 9.6, 1.8 Hz, 1H), 2.93 (dd, J =
14.1, 7.9 Hz, 1H), 2.35-2.20 (m, 1H), 1.68-1.55 (m, 1H), 1.20
(d, J = 6.2 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 140.1, 133.6, 129.3, 127.8,
79.6, 72.8, 59.5, 38.8, 32.6, 29.7, 21.7, 16.9; MS (ESI) 309 [Mþ
Na]þ; HRMS (ESI) m/z [MþNa]þ calcd for C14H22O4NaS
309.1122, found 309.1136.
Compound 50. The crude compound was purified by column
chromatography (40% EtOAc/hexanes, v/v) to afford the diol
50 (68 mg, 0.21 mmol) as a single diastereomer in 84% yield.
Viscous liquid; Rf 0.25 (50% EtOAc/hexanes, v/v); [R]25D þ83.2
(c 1, CHCl3); IR (neat) 3446, 2929, 2855, 1636, 1512, 1249, 1089,
1035, 835 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 8.3
Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 4.69-4.58 (br s, 1H, -OH),
4.45-4.36 (m, 1H), 3.93-3.82 (m, 1H), 3.09 (dd, J = 12.8, 10.6
Hz, 1H), 2.59 (dd, J = 12.8, 1.5 Hz, 1H), 2.44 (s, 3H), 1.53-1.14
(m, 11H), 0.90 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 141.5, 139.8, 130.0, 123.9, 75.7, 70.4,
61.9, 41.2, 35.1, 31.7, 29.2, 25.9, 22.5, 21.4, 14.0, 5.4; MS (ESI)
327 [M þ H]þ.
Acknowledgment. S.R. is thankful to Dr. J. M. Rao,
Head, Org. Div. I, and Dr. J. S. Yadav, Director, IICT, for
constant support and encouragement. V.S.B. is thankful to
Compound 59: The crude compound was purified by column
chromatography (50% EtOAc/hexanes, v/v) to afford the diol
59 (224 mg, 0.83 mmol) as a mixture of diastereomers differing
at sulfur in 83% yield. Viscous liquid; Rf 0.25 (60% EtOAc/
hexanes, v/v); IR (neat) 3383, 2924, 2854, 1729, 1374, 1087,
ꢀ
the CSIR, New Delhi for a fellowship. Financial assistance
from DST (New Delhi) is gratefully acknowledged. We
thank Dr. A. C. Kunwar for the NMR spectra and Dr. R.
Srinivas for the mass spectra.
1020, 800, 751, 692 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.69-7.58 (m, 4H), 7.57-7.44 (m, 6H), 4.24-4.13 (m, 2H),
3.75 (dd, J = 10.2, 2.4 Hz, 1H), 3.69 (dd, J = 10.2, 2.4 Hz, 1H),
3.31 (dd, J = 13.2, 3.2 Hz, 1H), 3.17 (dd, J = 13.2, 4.7 Hz, 1H),
2.69 (dd, J = 13.2, 6.9 Hz, 1H), 2.57 (dd, J = 13.2, 9.2 Hz, 1H),
2.25-2.10 (m, 1H), 2.09-1.96 (m, 1H), 1.93-1.81 (m, 1H),
1.72-1.55 (m, 1H), 1.20 (d, J = 6.6 Hz, 6H), 1.13 (d, J = 6.9 Hz,
Supporting Information Available: Experimental procedure
for the preparation of 8, 13, 15, 18, 20, 21, 23, 24, 25, 27-39,
45-47, 51-58, and 60-78, an ORTEP of 53, and copies of
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 565