Nucleophilic substitution reactions of sulfur-substituted cyclohexanone acetals: An analysis of the factors controlling stereoselectivity

Article abstract of DOI:10.1021/jo060077r

The reactions of cyclohexanone acetals substituted with thiophenyl groups (and other heteroatoms) at C-2 demonstrate the powerful influence that these substituents have on the stereoselectivity of nucleophilic substitution reactions. The trans selectivities of these reactions correlate with the behavior of the corresponding ketones. These experiments lend support to the possibility that the reactions of the acetals, which proceed via oxocarbenium ions, are operating under Felkin-Anh control.

Full text of DOI:10.1021/jo060077r

Nucleophilic Substitution Reactions of Sulfur-Substituted
Cyclohexanone Acetals: An Analysis of the Factors Controlling
Stereoselectivity
Susan B. Billings and K. A. Woerpel*
Contribution from the Department of Chemistry, UniVersity of California, IrVine, California 92696-2025
kwoerpel@uci.edu
ReceiVed January 13, 2006
The reactions of cyclohexanone acetals substituted with thiophenyl groups (and other heteroatoms) at
C-2 demonstrate the powerful influence that these substituents have on the stereoselectivity of nucleophilic
substitution reactions. The trans selectivities of these reactions correlate with the behavior of the
corresponding ketones. These experiments lend support to the possibility that the reactions of the acetals,
which proceed via oxocarbenium ions, are operating under Felkin-Anh control.
Introduction
The stereoselective synthesis of 2-deoxysugars remains an
important challenge in carbohydrate chemistry.1 Because sub-
stitution reactions of 2-deoxyglycosyl donors are poorly ster-
eoselective,1 control of diastereoselectivity is achieved by
incorporation of a heteroatom, usually sulfur1 or iodine,2-5 at
C-2 to control the stereochemical outcome of glycosylation,
followed by removal of the directing substituent. Nucleophilic
attack onto the carbocationic reactive intermediate typically
occurs anti to the heteroatom at C-2, providing the trans product
with high selectivity (eq 1).6 These nucleophilic substitution
reactions are believed to be controlled by the stereospecific ring
opening of the three-membered ring episulfonium ion intermedi-
ate 3 rather than a stereoselective reaction of thiophenyl-
substituted oxocarbenium ion 4.
be involved when an oxygen substituent is attached to the cation
(as in oxocarbenium ion 4). Glycosylation reactions that should
proceed through episulfonium ions9-11 (and their related epise-
lenonium11,12 or iodonium ions3,4) do not always provide trans
products exclusively, raising the possibility that oxocarbenium
ions such as 4 are involved. This analysis is supported by the
observation that benzylic episulfonium ions open rapidly at low
temperatures.13 Experimental studies of carbocation stability also
indicate that episulfonium ions are less stable than oxocarbenium
ions.14 Computational studies of processes such as those shown
in eq 1 do not locate episulfonium ions as low-energy
Although three-membered ring onium ions resembling 3 are
intermediates in many reactions,7,8 these intermediates may not
(1) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385-8417.
(2) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541-
3542.
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(4) Durham, T. B.; Roush, W. R. Org. Lett. 2003, 5, 1871-1874.
(5) For an example of a selective reaction of an iodine-substituted
N-acyliminium ion, see: Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett.
2005, 7, 5163-5165.
(6) Nicolaou, K. C.; Rodr´ıguez, R. M.; Mitchell, H. J.; Suzuki, H.;
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3095-3115.
(7) For reviews, see: (a) Smit, W. A.; Zefirov, N. S.; Bodrikov, I. V.
Acc. Chem. Res. 1979, 12, 282-288. (b) Smit, W. A.; Caple, R.;
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8825-8836.
(10) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53,
8837-8852.
(11) Viso, A.; Poopeiko, N.; Castillo´n, S. Tetrahedron Lett. 2000, 41,
407-411.
(12) Poopeiko, N.; Ferna´ndez, R.; Barrena, M. I.; Castillo´n, S.; Fornie´s-
Ca´mer, J.; Cardin, C. J. J. Org. Chem. 1999, 64, 1375-1379.
(13) Pasquato, L.; Modena, G. Chem. Commun. 1999, 1469-1470.
10.1021/jo060077r CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/17/2006
J. Org. Chem. 2006, 71, 5171-5178
5171

Billings and Woerpel
structures.15-17 In cases where five-18 and six-membered19 ring
sulfonium ions related to 3 were observed, the stereochemical
courses of their substitution reactions may19 or may not18 be
consistent with direct displacement reactions of the sulfonium
ion. The reactions of acyclic acetals bearing sulfur or related
substituents are also not consistent with the intermediacy of
episulfonium ions.20,21
The reactions of 2-heteroatom-substituted cyclohexanone
acetals revealed consistent periodic trends in selectivity for both
the chalcogens and the halogens (eq 3 and Table 2). Proceeding
In this paper, we examine the reactions of substituted cyclo-
hexanone acetals 5 and provide an explanation for the stereo-
selectivities of their reactions. The use of exocyclic acetals per-
mits a comparison of the behavior of an oxocarbenium ion elec-
trophile to its ketone analogue 6,22-25 a comparison that cannot
be made in the case of carbohydrate-derived acetals. The para-
llels between the behavior of the ketones and their derived ace-
tals suggest that similar forces likely control the conformational
biases and facial preferences for nucleophilic attack in both
cases. We propose that the outcomes of these reactions can be
understood without invoking episulfonium ions as reactive
intermediates.
TABLE 2. Influence of C-2 Heteroatom on Stereoselectivity (Eq 3)
entry
acetal
X
12:13
yield (%)
1
2
3
4
11a
11b
11c
11d
F
Cl
I
55:45
83:17
g97:3
65:35
42
73
79
87
OPh
down the group, trans selectivity increased (OPh < SPh and F
< Cl < I). Similar to the observations of endocyclic acetals,
substrates containing sulfur and iodine substituents at C-2
resulted in the highest selectivities.1-4
The highly selective formation of the trans products bearing
sulfur substituents at C-2 are consistent with three transition
states. Backside displacement on episulfonium7 ion 14 would
provide the observed trans product. This rationalization, how-
ever, ignores the concerns of the stability and reactivity of these
intermediates raised in the Introduction (vide supra). It is also
unnecessary to invoke an episulfonium ion intermediate to
explain trans selectivity; addition to the 2-methyl-substituted
oxocarbenium ion also proceeded with high trans selectivity,30
and, in that case, anchimeric assistance is impossible. Conse-
quently, the trans product could result from equatorial addition
to equatorial oxocarbenium ion 15eq (eq 4). This explanation
would be consistent with observations that additions of larger
nucleophiles to cyclohexanone and its related oxocarbenium ion
occur from equatorial trajectories.31,32 A third possibility
involves axial attack on the axial conformer 15ax. An approach
anti to the sulfur atom of 15ax could be the result of either
steric protection of the top face16 or by a stereoelectronically
preferred Felkin-Anh-type addition.33-36 The Felkin-Anh
mode of addition has been invoked to explain the high
Results and Discussion
The stereochemical courses of substitution reactions of sulfur-
substituted cyclohexanone acetal 726-28 are consistent with
observations of C-glycosylation reactions.8 In all cases, nucleo-
philic substitutions under Lewis acid mediated conditions
provided the 1,2-trans products (eq 2 and Table 1).29 Control
TABLE 1. Nucleophilic Substitution Reactions of
Sulfur-Substituted Acetal 7 (Eq 2)
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85.
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55, 4990-4991.
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311.
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285-288.
experiments suggested that the addition of cyanotrimethylsilane
proceeded under kinetic control.
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98, 4887-4902.
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1999, 64, 1247-1253 and references therein.
(29) The syntheses of all substrates are provided as Supporting Informa-
tion. The nucleophiles allyltrimethylsilane and methallyltrimethylsilane were
generally employed with acetals, because nucleophilic attack provided clean
reactions in high yields. The diastereoselectivities of all reactions were
determined by gas chromatography and confirmed by 1H NMR spectroscopy.
The stereochemical courses of the reactions were assigned either by X-ray
crystallographic analysis of the product (or a derivative) or by spectroscopic
analysis (NOE measurements and 1H NMR coupling constants); details of
stereochemistry proofs are provided as Supporting Information.
(30) Nakamura, E.; Horiguchi, Y.; Shimada, J.-i.; Kuwajima, I. J. Chem.
Soc., Chem. Commun. 1983, 796-797.
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Org. Chem. 2003, 68, 686-691.
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Hayford, A.; Smit, W. A.; Shashkov, A. S. Tetrahedron Lett. 1998, 39,
8787-8790.
(19) Kim, J.-H.; Yang, H.; Park, J.; Boons, G.-J.; J. Am. Chem. Soc.
2005, 127, 12090-12097.
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K. J. Org. Chem. 1993, 58, 579-587.
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6429-6431.
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5172 J. Org. Chem., Vol. 71, No. 14, 2006

Sulfur-Substituted Cyclohexanone Oxocarbenium Ions
selectivities of nucleophilic additions to 2-thioalkyl-substituted
ketones.24,37,38
substituents) exhibit the highest trans selectivities for reactions
of the corresponding acetals. If a hyperconjugative interaction
between σC-S and π*C-O contributes to the conformational
preference of the sulfur-substituted ketone,45-48 an oxocarbe-
nium ion should have a much higher preference for an axial
conformer because its π* is lower in energy than for a carbonyl
group.48-50 Because a σC-H bond is more electron-donating than
σ
C-O and σC-F bonds,50,51 in the case of cations bearing fluorine
and oxygen substituents, the equatorial conformer 15eq may
be more favored in the oxocarbenium ion.52-54
Computational studies provided insight into the viability of
the three possible reactive intermediates (episulfonium ion 14
and oxocarbenium ions 15eq and 15ax). The analysis for the
hyperconjugative donation of σC-S in 15ax is supported by ab
initio calculations (HF/6-31G*): for the thiomethyl analogue
of this cation, the axial conformer 15ax is considerably lower
in energy (by 7.6 kcal/mol) than the equatorial isomer 15eq
(eq 4). These calculations do not support the explanation
involving episulfonium ion 14. In accord with previous com-
putational studies,15-17 episulfonium ion 14 was not found to
be an energy minimum, so it must be less stable than the
equatorial oxocarbenium ion 15eq. Consequently, of the three
possible reactive intermediates, the axially substituted oxocar-
benium ion 15ax is the most plausible.
The explanation invoking the equatorial cation 15eq is
unconvincing because it likely does not coincide with the
conformational preference of the cation. Cyclohexanone-derived
oxocarbenium ions 15eq and 15ax should exhibit conformational
preferences similar to those of the corresponding cyclohex-
anones. A correlation can be found between the preference for
the axial conformer of the ketones39-47 (eq 5, Table 3) and the
The preference for Felkin-Anh attack on the axial oxocar-
benium ion 15ax is also consistent with the trends in selectivity
illustrated in Tables 1 and 2. For the chalcogens, Felkin-Anh
effects in additions to ketones are stronger for sulfur24,37 than
for oxygen.38,55 In the sulfur-substituted acetal, the strong
preference for the axial conformer of the oxocarbenium ion
(15ax) and the inherent Felkin-Anh selectivity are comple-
mentary, leading to high trans selectivity. Halogenated cyclo-
hexanones and related compounds also undergo Felkin-Anh-
selective additions.56-59 In constrained cyclohexanones, the
heavier halogens exerted higher selectivity: a chlorine atom
increased anti reduction, whereas fluorine (and oxygen) atoms
exerted little influence on selectivity.60
TABLE 3. Conformational Preferences of C-2
Heteroatom-Substituted Cyclohexanones (Eq 5)45
equatorial/axial
entry
X
(CDCl3)
1
2
3
4
5
OMe
SMe
F
Cl
I
72:28
15:85
83:17
55:45
12:88
selectivity of the reactions of the derived oxocarbenium ions
(Tables 1 and 2): the two cyclohexanones with the highest
preference for axial conformers 16ax (bearing SMe and I
The inherent Felkin-Anh bias of a fluorine atom,35 which
has been questioned,61 was confirmed. Nucleophilic addition
to cyclohexanone62 17 proceeded with high diastereoselectivity
(eq 6). In the case of the fluorine-substituted acetal, the
(32) Noyori, R.; Murata, M.; Suzuki, M. Tetrahedron 1981, 37, 3899-
3910.
(33) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199-2204.
(48) White, J. M.; Lambert, J. B.; Spiniello, M.; Jones, S. A.; Gable, R.
W. Chem.sEur. J. 2002, 8, 2799-2811.
(49) For example, protonation of a cyclopropyl ketone on oxygen renders
the carbonyl group more electron-accepting: Childs, R. F.; Kostyk, M. D.;
Lock, C. J. L.; Mahendran, M. J. Am. Chem. Soc. 1990, 112, 8912-8920.
(50) Alabugin, I. V.; Manoharan, M. J. Org. Chem. 2004, 69, 9011-
9024.
(51) Apeloig, Y.; Schleyer, P. v. R.; Pople, J. A. J. Am. Chem. Soc.
1977, 99, 5901-5909.
(52) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859-864.
(34) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-70.
(35) Wong, S. S.; Paddon-Row, M. N. J. Chem. Soc., Chem. Commun.
1990, 456-458.
(36) For a review discussing the competing models of nucleophilic attack
to cyclohexanones, see: Gung, B. W. Chem. ReV. 1999, 99, 1377-1386.
(37) Enders, D.; Piva, O.; Burkamp, F. Tetrahedron 1996, 52, 2893-
2908.
(38) Dimitroff, M.; Fallis, A. G. Tetrahedron Lett. 1998, 39, 2531-
2534.
(39) Allinger, N. L.; Allinger, J.; Freiberg, L. A.; Czaja, R. F.; LeBel,
N. A. J. Am. Chem. Soc. 1960, 82, 5876-5882.
(40) Allinger, N. J.; Blatter, H. M. J. Org. Chem. 1961, 27, 1523-1526.
(41) Garbisch, E. W., Jr. J. Am. Chem. Soc. 1964, 86, 1780-1782.
(42) O¨ zbal, H.; Zajac, W. W., Jr. Tetrahedron Lett. 1979, 20, 4821-
4824.
(43) The conformational preference of 2-nitrocyclohexanone has also
been examined: Zajac, W. W., Jr.; O¨ zbal, H. J. Org. Chem. 1980, 45, 4154-
4157.
(53) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521-15528.
(54) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 10879-10884.
(55) Brown, M. J.; Harrison, T.; Herrinton, P. M.; Hopkins, M. H.;
Hutchinson, K. D.; Mishra, P.; Overman, L. E. J. Am. Chem. Soc. 1991,
113, 3, 5365-5378.
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N. Tetrahedron Lett. 1994, 35, 8627-8630.
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1993, 58, 7865-7869.
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51, 5573-5584.
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2003, 95, 313-321.
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9005-9018.
(47) Yoshinaga, F.; Tormena, C. F.; Freitas, M. P.; Rittner, R.; Abraham,
R. J. J. Chem. Soc., Perkin Trans. 2 2002, 1494-1498.
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8991-9004.
J. Org. Chem, Vol. 71, No. 14, 2006 5173

Billings and Woerpel
conformational effects,45,47 favoring the equatorial conformer
(Table 3, entry 3), and the Felkin-Anh effects oppose each
other, so the selectivity for the reaction of the oxocarbenium
ion is attenuated.
to 2-thiophenylcyclohexanone24,37 likely involve addition to the
preferred axial conformer45,46 through Felkin-Anh transition
states.33,34
Because epimerization at C-2 occurred during preparation of
the acetal for the equatorial ketone cis-25,65 a substrate that
would shift the bias of the ketone to the equatorial conformer
was designed. Geminal substitution at C-4 of a cyclohex-
anone28,66 would develop an unfavorable syn-pentane interaction
between the methyl group at C-4 and the sulfur substituent at
C-2, destabilizing the axial conformer 29 (eq 10).67,68 This effect
may not be significant enough to force the equilibrium toward
the equatorial conformer 28, however, because the axial
conformer 29 was calculated (HF/6-31G*) to be lower in energy
by 2.5 kcal/mol. The computational result was supported by
the experiment: nucleophilic substitution of acetal 30 proceeded
with high 1,2-trans selectivity (eq 11), suggesting that the axial
conformer 29 was favored.69
The powerful influence of a sulfur atom on the facial
preference of nucleophilic attack is illustrated by the reaction
of conformationally constrained exocyclic acetal 19.60 When
three different nucleophiles were employed, nucleophilic sub-
stitution was highly stereoselective (eq 7 and Table 4). The tert-
TABLE 4. Nucleophilic Substitution Reactions of
Sulfur-Substituted Acetal 19 (Eq 7)
butyl substituent at C-4 of intermediate 23 should strongly bias
the ring to a conformation where the tert-butyl group adopts
an equatorial orientation,63 positioning the sulfur substituent in
its favored axial orientation. Consequently, the nucleophile
approached from an axial trajectory to give the product 24,
where the nucleophile was introduced cis to the tert-butyl group
(eq 8). This facial selectivity is diametrically opposed to the
high (95:5) 1,4-trans selectivity exhibited by the reactions of
4-tert-butylcyclohexanone acetals,32 which results from equato-
rial attack.30 The results shown in Table 4 reveal that a sulfur
atom is capable of completely reversing the approach of a
nucleophile onto an oxocarbenium ion.64
The high 1,2-trans selectivity of nucleophilic addition was
also observed for a sterically encumbered substrate that incor-
porated geminal substitution at C-5 to impede steric approach
from the axial face. Nucleophilic substitutions of acetal 3270,71
occurred with high selectivity, favoring the trans stereoisomer
(eq 12 and Table 5). The trans products could arise from the
preferential formation of the axial conformer 35, followed by
axial attack of the incoming nucleophile (eq 13). The destabiliz-
ing syn-pentane interaction72 that would develop in the transition
state is not destabilizing enough to dominate the axial preference
(60) For a discussion comparing the models for nucleophilic attack to
cyclohexanones and an examination of the reactions of conformationally
constrained 2-substituted cyclohexanones, see: Rosenberg, R. E.; Abel, R.
L.; Drake, M. D.; Fox, D. J.; Ignatz, A. K.; Kwiat, D. M.; Schaal, K. M.;
Virkler, P. R. J. Org. Chem. 2001, 66, 1694-1700.
Reduction reactions of the conformationally constrained
ketones trans-25 and cis-25 provided additional support for the
involvement of Felkin-Anh selectivity (eq 9). In the course of
preparing the 2,4-trans disubstituted acetal 19, we reduced a
mixture of the ketones trans-25 and cis-25 (3:1) to resolve the
stereoisomers. This reduction proceeded with exclusive trans
selectivity for the axial sulfide trans-25, consistent with the
Felkin-Anh model and results with other 2-substituted 4-tert-
butylcyclohexanones with the substituent oriented axially.60
Conversely, the equatorial sulfide cis-25 underwent nucleophilic
addition with low selectivity, consistent with reactions of
cyclohexanones with substituents constrained equatorially.60
These results reinforce the fact that diastereoselective additions
(61) Myers, A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001,
123, 7207-7219.
(62) Welch, J. T.; Seper, K. W. J. Org. Chem. 1988, 53, 2991-2999.
(63) Manoharan, M.; Eliel, E. L. Tetrahedron Lett. 1984, 25, 3267-
3268.
(64) Axial attack of a nucleophile onto a cyclohexanone was achieved
using a Lewis acid additive: Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am.
Chem. Soc. 1985, 107, 4573-4576.
(65) Attempts to equilibrate the mixture to one diastereomer were
unsuccessful, because the 3:1 ratio is the thermodynamic ratio.
(66) Bordwell, F. G.; Wellman, K. M. J. Org. Chem. 1963, 28, 1347-
1352.
(67) Corey, E. J. J. Am. Chem. Soc. 1953, 75, 2301-2304.
5174 J. Org. Chem., Vol. 71, No. 14, 2006

Sulfur-Substituted Cyclohexanone Oxocarbenium Ions
attack (eq 15). Alternatively, axial attack on the more populated
axial conformer 40ax would be favored by Felkin-Anh effects.
In either case, the selective addition can be explained without
invoking cyclic onium ions, so the same arguments likely hold
for the selectivity exhibited by acetal 32 (Table 5, vide supra).
TABLE 5. Nucleophilic Substitution Reactions of
Sulfur-Substituted Acetal 32 (Eq 12)
of the cation (7.6 kcal/mol, as shown in eq 4) and the inherent
Felkin-Anh selectivity. For comparison, similar geminal sub-
stitution alters the diastereoselectivity of nucleophilic additions
to ketones, but product ratios indicated that axial attack still
occurred.73-75
Conclusion
The nucleophilic substitution reactions of 2-thiophenyl-
substituted acetals are strongly influenced by the sulfur sub-
stituent. In all cases, the nucleophile was introduced trans to
the sulfur substituent, regardless of the steric congestion present.
Because the behavior of the oxocarbenium ions and their related
ketones correlate, similar factors likely operate for both elec-
trophiles. Ketones with sulfur substituents at C-2 prefer axial
conformers,45,46 and these ketones react with nucleophiles in
accord with the Felkin-Anh model. Sulfur-substituted oxocar-
benium ions should show a similar conformational preference,
as demonstrated by computational data. In analogy to the
behavior of the ketones, nucleophilic addition to these oxocar-
benium ions through Felkin-Anh-type transition states would
lead to the observed products. Although explanations involving
episulfonium ions are consistent with the stereochemistry of the
reactions of sulfur-substituted acetals, such explanations do not
reconcile other data (vide supra) and cannot be applied to explain
the behavior of the sulfur-substituted ketones. This paper
provides an alternative explanation of stereochemistry that
acknowledges the similarities between the reactivities of ketones
and the reactivities of their related acetals.
A control experiment demonstrated the powerful influence
of a sulfur atom on the nucleophilic addition to sterically
congested ketones. Although the acetal of 3,3,5,5-tetramethyl-
cyclohexanone (37)76 was synthetically inaccessible due to
formation of the enol ether, nucleophilic addition reactions of
Grignard reagents proceeded cleanly to provide the trans
products with high selectivity (eq 14 and Table 6). These
Experimental Section
Details of the syntheses of previously reported ketones 1762 and
37,76 in addition to acetals 7,26-28,77 11b,78 and 11c,79,80 are provided
as Supporting Information.
TABLE 6. Nucleophilic Additions to Sulfur-Substituted Ketone 37
(Eq 14)
General Procedure for Acetalization of Cyclohexanones:81
A
entry
nucleophile
product
dr
yield (%)
solution of cyclohexanone in MeOH (0.15 M) was treated with
trimethyl orthoformate (4.00 equiv) and 3 drops of concentrated
H2SO4. The reaction mixture was heated to 50 °C and stirred for
12 h before it was poured into a separatory funnel containing
saturated aqueous NaHCO3 (1 mL per mmol of cyclohexanone).
The aqueous layer was extracted with 3 portions of CH2Cl2 (1 mmol
per cyclohexanone). The combined organic layers were washed with
a saturated sodium chloride solution, dried (Na2SO4), and concen-
trated in vacuo to provide a pale yellow residue.
1
2
PhMgBr
MeMgBr
38
39
g97:3
g97:3
88
77
products could arise from equatorial attack on the higher energy
equatorial conformer 40eq to avoid steric interactions with the
two axial methyl groups in the transition state of nucleophilic
(68) The coupling constants (6.0 and 12.0 Hz) at C-2 of the ketone
corresponding to acetal 30 indicate that the thiophenyl group is predomi-
nantly equatorial. The coupling values are consistent with those observed
for equatorially substituted ketone cis-25, not the axially constrained isomer
trans-25 (ref 45). The preference for the equatorial conformer corresponds
to Corey’s observations of the analogous bromine-substituted ketone (ref
67). Calculations (HF/6-31G*) of the ketone corresponding to acetal 30
suggest that the equatorial conformer is favored by 0.5 kcal/mol.
(69) Additions of Grignard reagents to the ketone corresponding to 30
were highly diastereoselective, but we were unable to obtain crystals suitable
for X-ray crystallographic analysis. Therefore, we do not know the
stereochemical courses of those reactions.
tert-Butyl Acetal 19. The standard acetalization procedure was
followed with 2526,82 (2.50 g, 9.60 mmol) in 32 mL of MeOH with
(74) Wu, Y.-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991,
113, 5018-5027.
(75) Artau, A.; Ho, Y.; Kentta¨maa, H.; Squires, R. R. J. Am. Chem. Soc.
1999, 121, 7130-7137.
(76) Fuchigami, T.; Shimojo, M.; Konno, A. J. Org. Chem. 1995, 60,
3459-3464.
(77) Mursakulov, I. G.; Guseinov, M. M.; Kasumov, N. K.; Zefirov, N.
S.; Samoshin, V. V.; Chalenko, E. G. Tetrahedron 1982, 38, 2213-2220.
(78) Masilamani, D.; Manahan, E. H.; Vitrone, J.; Rogic´, M. M. J. Org.
Chem. 1983, 48, 4918-4931.
(70) Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J. J. Am. Chem. Soc.
1989, 111, 1351-1358.
(71) House, H. O.; Fischer, W. F., Jr. J. Org. Chem. 1968, 33, 949-
956.
(79) D’Auria, M.; D’Onofrio, F.; Piancetelli, G.; Scettri, A. Synth.
Commun. 1982, 12, 1127-1138.
(80) Horiuchi, C. A.; Kiji, S. Bull. Chem. Soc. Jpn. 1997, 70, 421-426.
(81) De Amici, M.; De Micheli, C.; Molteni, G.; Pitre`, D.; Carrea, G.;
Riva, S.; Spezia, S.; Zetta, L. J. Org. Chem. 1991, 56, 67-72.
(72) Wiberg, K. B.; Murcko, M. A. J. Am. Chem. Soc. 1988, 110, 8029-
8038.
(73) McMahon, R. J.; Wiegers, K. E.; Smith, S. G. J. Org. Chem. 1981,
46, 99-101.
J. Org. Chem, Vol. 71, No. 14, 2006 5175

Billings and Woerpel
trimethyl orthoformate (11.0 mL, 96.0 mmol) and H2SO4 (3 drops).
Purification of the resultant residue by silica gel chromatography
(0:100 to 5:95 EtOAc/hexanes) yielded product 19 as a yellow oil
(2.25 g, 77%): 1H NMR (500 MHz, CDCl3) δ 7.21-7.46 (m, 5H),
3.63 (m, 1H), 3.25 (s, 3H), 3.21 (s, 3H), 1.91 (m, 1H), 1.68 (m,
4H), 1.53 (m, 1H), 1.14 (m, 1H), 0.77 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 135.4, 132.9, 129.2, 127.3, 101.2, 51.2, 48.0, 47.8, 40.8,
32.2, 28.9, 28.6, 27.8, 23.5; IR (thin film) 2960, 1478, 1208, 1023
cm-1; HRMS (CI) m/z calcd for C18H28NaO2S [M + Na]+,
331.1708; found, 331.1705. Anal. Calcd for C18H28O2S: C, 70.08;
H, 9.15. Found: C, 70.31; H, 9.09.
Acetal 30. The standard acetalization procedure was followed
with 4,4-dimethyl-2-thiophenylcyclohexanone26,28 (0.160 g, 0.68
mmol) in 2.2 mL of MeOH with trimethyl orthoformate (0.373
mL, 3.41 mmol) and H2SO4 (3 drops). Purification of the resultant
residue by silica gel chromatography (5:95 EtOAc/hexanes) yielded
product 30 as a yellow oil (0.147 g, 77%): 1H (500 MHz, CDCl3)
δ 7.40 (m, 2H), 7.26 (m, 2H), 7.18 (m, 1H), 3.50 (dd, J ) 9.4, 4.6
Hz, 1H), 3.35 (s, 3H), 3.30 (s, 3H), 1.93 (ddd, J ) 13.7, 7.2, 3.8
Hz, 1H), 1.70 (m, 3H), 1.41 (ddd, J ) 13.6, 10.2, 3.8 Hz, 1H),
1.31 (m, 1H), 1.01 (s, 3H), 0.90 (s, 3H); 13C (125 MHz, CDCl3) δ
137.0, 130.7, 129.1, 126.4, 101.3, 50.9, 50.0, 49.2, 43.7, 35.7, 31.4,
30.8, 27.7, 27.4; IR (thin film) 2952, 1584, 1439 cm-1; HRMS
(ESI) m/z calcd for C16H24NaO2S [M + Na]+, 303.1395; found,
303.1403. Anal. Calcd for C14H18OS: C, 68.53; H, 8.63. Found:
C, 68.35; H, 8.37.
Acetal 32. The standard acetalization procedure was followed
with 5,5-dimethyl-2-thiophenylcyclohexanone83 (0.355 g, 1.51
mmol) in 15 mL of MeOH with trimethyl orthoformate (1.20 mL,
10.6 mmol) and H2SO4 (3 drops). Purification of the resultant
residue by silica gel chromatography (2:98 EtOAC/hexanes) yielded
product 32 as a yellow oil (0.380 g, 89%): 1H NMR (400 MHz,
CDCl3) δ 7.19-7.45 (m, 5H), 3.62 (br s, 1H), 3.26 (s, 3H), 3.21
(s, 3H), 1.93 (dddd, J ) 12.5, 12.0, 3.5, 3.3 Hz, 1H), 1.81 (ddd, J
) 13.3, 13.0, 3.2 Hz, 1H), 1.68 (dt, J ) 14.6, 1.8 Hz, 1H), 1.57
(m, 1H), 1.48 (d, J ) 14.6 Hz, 1H), 1.06 (m, 1H), 1.02, (s, 3H),
0.97 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 135.7, 132.0, 129.2,
126.9, 101.7, 50.8, 48.7, 47.5, 40.1, 33.6, 33.5, 31.6, 26.5, 24.2;
IR (thin film) 3059, 2938, 2829 cm-1; HRMS (CI) m/z calcd for
C15H20OS [M - MeOH]+, 249.1313; found, 249.1309. Anal. Calcd
for C16H24O2S: C, 68.53; H, 8.63. Found: C, 68.78; H, 8.78.
Fluoro Acetal 11a. The standard acetalization procedure was
followed with 2-fluorocyclohexanone 1762 (1.81 g, 15.7 mmol) in
50 mL of MeOH with trimethyl orthoformate (14.0 mL, 94.7 mmol)
and H2SO4 (3 drops). Purification of the resultant residue by silica
gel chromatography (0:100 to 3:97 EtOAc/hexanes) yielded the
product 11a as a pale yellow oil (0.960 g, 38%): 1H NMR (500
MHz, CDCl3) δ 4.55 (dt, J ) 48.9, 2.1, 1H), 3.25 (d, J ) 1.7 Hz,
3H), 3.19 (d, J ) 1.7 Hz, 3H), 1.94 (m, 1H), 1.68 (m, 3H), 1.52
(m, 2H), 1.42 (m, 1H), 1.34 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 98.9 (J ) 21.5 Hz), 88.2 (d, J ) 175.3 Hz), 47.8, 28.7, 28.4 (J
) 13.3 Hz), 21.8, 20.0 (J ) 2.1 Hz); IR (thin film) 2927, 1063
cm-1; HRMS (ESI) m/z calcd for C8H15FNaO2 [M + Na]+,
185.0954; found, 185.0947. Anal. Calcd for C8H15O2F: C, 59.24;
H, 9.32. Found: C, 59.54; H, 9.30.
1.53 (m, 1H), 1.38 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 157.8,
129.7, 121.2, 116.4, 100.3, 73.7, 47.9, 47.8, 28.5, 26.5, 22.2, 20.1;
IR (thin film) 3040, 2862, 1240 cm-1; HRMS (CI) m/z calcd for
C13H17O2 [M - CH3O]+, 205.1228; found, 205.1222. Anal. Calcd
for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.26; H, 8.61.
General Procedure for Allylation of Acetals: A solution of
acetal in CH2Cl2 (0.10 M) was treated with allyltrimethylsilane or
2-methylpropenyltrimethylsilane (4.0 equiv) and then cooled to -78
°C. The appropriate Lewis acid (1.2 equiv, 1.0 M in CH2Cl2) was
added dropwise, and the reaction mixture was allowed to warm to
22 °C for 24 h. The reaction mixture was poured into a separatory
funnel containing saturated aqueous Na2HPO4 (1 mL per mmol
acetal). The aqueous layer was extracted with three portions of CH2-
Cl2 (1 mL per mmol acetal). The combined organic layers were
washed with a saturated sodium chloride solution, dried (Na2SO4),
and concentrated in vacuo. The unpurified mixture was analyzed
1
by GC and H NMR spectroscopy and then purified as indicated.
Allyl Product 8. The standard allylation procedure was followed
with acetal 726-28,77 (0.11 g, 0.47 mmol), allyltrimethylsilane (0.30
mL, 1.90 mmol), and BF3‚OEt2 (0.072 mL, 0.56 mmol). GC and
1H NMR spectroscopic analysis of the unpurified product detected
only a single isomer. Purification of the resultant residue by silica
gel chromatography (0:100 to 2:98 EtOAc/hexanes) yielded product
as a colorless oil (0.071 g, 61%): 1H NMR (500 MHz, CDCl3) δ
7.40 (m, 2H), 7.26 (t, J ) 7.5 Hz, 2H), 7.18 (m, 1H), 5.82 (ddt, J
) 17.0, 12.4, 4.9 Hz, 1H), 5.16 (dd, J ) 17.0, 1.8 Hz, 1H), 5.10
(dd, J ) 10.1, 2.0 Hz, 1H), 3.25 (s, 3H), 3.10 (dd, J ) 11.1, 4.1
Hz, 1H), 2.80 (dd, J ) 13.3, 7.6 Hz, 1H), 2.41 (dd, J ) 13.3, 7.3
Hz, 1H), 1.90 (m, 2H), 1.78 (m, 1H), 1.70 (m, 1H), 1.47 (m, 3H),
1.14 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 136.7, 134.0, 131.6,
129.1, 126.5, 118.9, 77.8, 54.7, 48.8, 40.3, 30.9, 30.0, 25.9, 21.4;
IR (thin film) 3074, 2935, 2858, 1444 cm-1; HRMS (CI) m/z calcd
for C16H22OS [M]+, 262.1391; found, 262.1393. Anal. Calcd for
C16H22OS: C, 73.23; H, 8.45. Found: C, 73.50; H, 8.68.
Methallyl Product 9. The standard allylation procedure was
followed with acetal 726-28,77 (0.376 g, 1.50 mmol), 2-methylpro-
penyltrimethylsilane (1.02 mL, 5.96 mmol), and BF3‚OEt2 (0.225
1
mL, 1.80 mmol). GC and H NMR spectroscopic analysis of the
unpurified product detected only a single isomer was present.
Purification by silica gel chromatography (0:100 to 2:98 EtOAc/
hexanes) yielded the product as a colorless solid (0.260 g, 63%).
X-ray quality crystals were grown from a 3:1 mixture of CHCl3
and hexanes in which slow evaporation provided the crystal: mp
1
35-38 °C; H NMR (500 MHz, CDCl3) δ 7.35 (d, J ) 7.3 Hz,
2H), 7.26 (m, 2H), 7.16 (t, J ) 7.3 Hz, 1H), 4.91 (m, 1H), 4.89
(m, 1H), 3.30 (dd, J ) 4.2, 10.1 Hz, 1H), 3.28 (s, 3H), 2.77 (d, J
) 13.3 Hz, 1H), 2.39 (d, J ) 13.3 Hz, 1H), 1.93 (m, 2H), 1.86 (s,
3H), 1.86 (m, 1H), 1.80 (m, 1H), 1.47 (m, 3H), 1.22 (m, 1H); 13
C
NMR (125 MHz, CDCl3) δ 142.1, 136.6, 130.7, 129.1, 126.2, 115.8,
78.6, 53.8, 48.9, 41.6, 31.9, 31.9, 30.1, 25.3, 21.9; IR (thin film)
3074, 2928, 2855, 1444 cm-1; HRMS (CI) m/z calcd for C17H24-
OS [M]+, 276.1548; found, 276.1549. Anal. Calcd for C17H24OS:
C, 73.86; H, 8.75. Found: C, 73.89; H, 8.73.
Chlorocyclohexanes 12b and 13b. The standard allylation
procedure was followed with chloroacetal 11b78 (0.212 g, 1.20
mmol), allyltrimethylsilane (0.754 mL, 4.70 mmol), and BF3‚OEt2
Phenoxy Acetal 11d. The standard acetalization procedure was
followed with 2-phenoxycyclohexanone84 (0.363 g, 1.92 mmol) in
19 mL of MeOH with trimethyl orthoformate (1.05 mL, 9.60 mmol)
and H2SO4 (3 drops). Purification of the resultant residue by silica
gel chromatography (3:97 EtOAc/hexanes) yielded product 11d as
a colorless oil (0.44 g, 97%): 1H NMR (500 MHz, CDCl3) δ 7.26
(m, 2H), 6.94 (m, 3H), 4.44 (t, J ) 3.1 Hz, 1H), 3.24 (s, 3H), 3.17
(s, 3H), 1.96 (m, 1H), 1.85 (m, 2H), 1.67 (m, 1H), 1.59 (m, 1H),
1
(0.179 mL, 1.42 mmol). GC and H NMR spectroscopic analysis
of the unpurified product indicated a pair of diastereomers in a
17:83 ratio. Purification of the resultant residue by silica gel
chromatography (0:100 to 2:98 EtOAc/hexanes) yielded the product
as a clear oil (0.160 g, 73%). The major isomer 12b was isolated
as a pure sample, while the minor isomer 13b was isolated as a
mixture of 12b and 13b. IR, mass spectrometry, and combustion
analysis data were obtained for the major isomer (12b) and the
minor isomer (13b) as a mixture of diastereomers. IR (thin film)
2956, 1075, 742 cm-1; HRMS (ESI) m/z calcd for C10H17ClNaO
[M + Na]+, 211.0866; found, 211.0871. Anal. Calcd for C10H17-
ClO: C, 63.65; H, 9.08. Found: C, 63.35; H, 9.13.
(82) Tanikaga, R.; Nishikawa, T.; Tomita, N. Bull. Chem. Soc. Jpn. 1999,
72, 1057-1062.
(83) Bartel, S.; Bohlmann, F. Tetrahedron Lett. 1989, 30, 685-688.
(84) Koreeda, M.; Patel, P. D.; Brown, L. J. Org. Chem. 1985, 50, 5910-
5913.
Major Isomer (12b). 1H NMR (500 MHz, CDCl3) δ 5.80 (ddt,
5176 J. Org. Chem., Vol. 71, No. 14, 2006

Sulfur-Substituted Cyclohexanone Oxocarbenium Ions
J ) 17.2, 10.4, 7.5 Hz, 1H), 5.19 (d, J ) 17.0 Hz, 1H), 5.14 (d, J
) 10.1 Hz, 1H), 3.94 (dd, J ) 10.7, 3.8 Hz, 1H), 3.28 (s, 3H),
2.57 (dd, J ) 13.4, 7.7 Hz, 1H), 2.37 (dd, J ) 13.3, 7.5 Hz, 1H),
2.11 (dq, J ) 4.2, 12.1 Hz, 1H), 1.91 (m, 2H) 1.41 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 133.4, 119.2, 77.1, 65.5, 48.9, 39.2,
32.2, 30.6, 25.5, 20.9.
13.4 Hz, 1H), 0.77 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 135.9,
133.4, 133.4, 129.1, 127.2, 118.1, 53.9, 48.8, 40.5, 36.3, 32.2, 30.8,
28.1, 27.8, 27.5, 23.7; IR (thin film) 2948, 2869, 1480, 1077 cm-1
;
HRMS (ESI) m/z calcd for C20H30ONaS [M + Na]+, 341.1915;
found, 341.1921. Anal. Calcd for for C20H30OS: C, 75.42; H, 9.49.
Found: C, 75.02; H, 9.67.
1
Minor Isomer (13b). H NMR (500 MHz, CDCl3, distinctive
Methallyl Product 21. The standard allylation procedure was
followed with acetal 19 (0.072 g, 0.23 mmol), 2-methylpropenyl-
trimethylsilane (0.160 mL, 0.93 mmol), and TiCl4 (0.28 mL, 0.28
mmol, 1.0 M in CH2Cl2). GC and 1H NMR spectroscopic analysis
of the unpurified product detected only a single isomer was present.
Purification of the resultant residue by silica gel chromatography
(0:100 to 2:98 EtOAc/hexanes) yielded the product as a pale yellow
oil (0.066 g, 86%): 1H NMR (500 MHz, C6D6) δ 7.49 (m, 2H),
7.05 (m, 2H), 6.97 (tt, J ) 2.0, 1.2 Hz, 1H), 4.95 (s, 1H), 4.87 (s,
1H), 3.60 (m, 1H), 3.23 (s, 3H), 2.28 (ddd, J ) 14.0, 11.7, Hz,
2H), 2.01 (td, J ) 13.5, 4.3 Hz, 1H), 1.89 (s, 3H), 1.87 (dt, J )
12.6, 3.6 Hz, 1H), 1.80 (dq, J ) 13.0, 2.8 Hz, 1H), 1.75 (ddt, J )
15.0, 3.5 Hz, 1H), 1.59 (ddt, J ) 13.4, 6.5, 3.4 Hz, 1H), 1.24 (ddd,
J ) 14.4, 12.5, 3.3 Hz, 1H), 1.08 (dq, J ) 3.8, 13.2 Hz, 1H), 0.79
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 142.4, 136.3, 133.4, 129.2,
127.3, 115.0, 78.5, 54.3, 48.9, 40.5, 38.3, 32.4, 32.2, 28.5, 27.9,
24.2, 24.1; IR (thin film) 3059, 2949, 1468 cm-1; HRMS (EI) m/z
calcd for C21H32OS [M]+, 332.2174; found, 332.2180.
Allyl Product 31. The standard allylation procedure was
followed with acetal 30 (0.071 g, 0.25 mmol), allyltrimethylsilane
(0.161 mL, 1.01 mmol), and BF3‚OEt2 (0.038 mL, 0.30 mmol).
GC and 1H NMR spectroscopic analysis of the unpurified product
detected only a single isomer was present. Purification of the
resultant residue by silica gel chromatography (0:100 to 2:98
EtOAc/hexanes) yielded the product as a colorless oil (0.067 g,
92%): 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H), 7.28 (m, 2H),
7.15 (m, 1H), 5.82 (ddt, J ) 17.2, 12.4, 7.5 Hz, 1H), 5.18 (d, J )
17.0 Hz, 1H), 5.11 (d, J ) 12.2 Hz, 1H), 3.27 (m, 1H), 3.26 (s,
3H), 2.80 (dd, J ) 12.9, 7.7 Hz, 1H), 2.41 (dd, J ) 12.9, 7.4 Hz,
1H), 1.89 (t, J ) 12.9 Hz, 1H), 1.80 (dt, J ) 15.0, 3.3 Hz, 1H),
1.60 (td, J ) 14.5, 3.9 Hz, 1H), 1.49 (ddd, J ) 13.3, 4.1, 2.5 Hz,
1H), 1.42 (td, J ) 13.2, 3.7 Hz, 1H), 1.12 (ddd, J ) 12.9, 6.0, 2.9
Hz, 1H), 0.89 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 137.1, 134.1, 130.4, 129.1, 126.2, 119.2, 76.8, 50.8, 48.9, 43.1,
40.4, 33.9, 32.6, 31.8, 26.7, 24.1; IR (thin film) 3074, 2951, 1481
cm-1; HRMS (CI) m/z calcd for C18H26NaOS [M + Na]+, 313.1602;
found, 313.1608. Anal. Calcd for C18H26OS: C, 74.43; H, 9.02.
Found: C, 74.69; H, 9.26.
Allyl Product 33. The standard allylation procedure was
followed with acetal 32 (0.091 g, 0.33 mmol), allyltrimethylsilane
(0.206 mL, 1.33 mmol), and BF3‚OEt2 (0.050 mL, 0.39 mmol).
GC and 1H NMR spectroscopic analysis of the unpurified product
detected only a single isomer was present. Purification of the
resultant residue by silica gel chromatography (0:100 to 2:98
EtOAc/hexanes) yielded the product as a pale yellow oil (0.084 g,
89%): 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 2H), 7.28 (m, 2H),
7.19 (m, 1H), 5.81 (ddt, J ) 17, 12, 4.8 Hz, 1H), 5.19 (m, 1H),
5.12 (m, 1H), 3.24 (s, 3H), 2.98 (dd, J ) 12.2, 4.2 Hz, 1H), 2.79
(dd, J ) 13.0, 7.6 Hz, 1H), 2.34 (dd, J ) 13.0, 7.4 Hz, 1H), 2.10
(m, 1H), 1.78 (dd, J ) 15.1, 2.7 Hz, 1H), 1.73 (m, 1H), 1.41 (m,
1H), 1.20 (d, J ) 15.1 Hz, 1H), 1.10 (m, 1H), 1.10 (s, 3H), 0.88
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 136.8, 134.4, 131.4, 129.1,
126.5, 119.2, 78.8, 54.9, 49.2, 41.7, 40.9, 40.0, 34.1, 30.9, 26.9,
25.8; IR (thin film) 3075, 2951, 2868, 1438 cm-1; HRMS (CI) m/z
calcd for C18H26NaOS [M + Na]+, 313.1602; found, 313.1613.
Anal. Calcd for C18H26OS: C, 74.43; H, 9.02. Found: C, 74.32;
H, 9.06.
peaks) δ 4.08 (m, 1H), 3.25 (s, 3H), 2.44 (dd, J ) 15.0, 7.5 Hz,
1H), 2.19 (m, 1H); 13C NMR (125 MHz, CDCl3, distinctive peaks)
δ 132.6, 118.6, 62.1, 49.1, 37.4, 20.9.
Iodocyclohexane 12c. The standard allylation procedure was
followed with iodo acetal 11c79,80 (0.168 g, 0.62 mmol), allyltri-
methylsilane (0.395 mL, 2.48 mmol), and TiCl4 (0.746 mL, 0.746
mmol, 1.0 M in CH2Cl2). GC and 1H NMR spectroscopic analysis
of the unpurified product detected only a single isomer was present.
Purification of the resultant residue by silica gel chromatography
(2:98 EtOAc/hexanes) yielded the product as a colorless oil (0.137
g, 79%): 1H NMR (500 MHz, CDCl3) δ 5.72 (ddt, J ) 17.0, 12.4,
5.0 Hz, 1H), 5.22 (d, J ) 16.9 Hz, 1H), 5.14 (d, J ) 10.1 Hz, 1H),
4.23 (dd, J ) 10.2, 4.2 Hz, 1H), 3.24 (s, 3H), 2.39 (m, 3H), 2.13
(m, 1H), 1.97 (m, 1H), 1.52 (m, 4H), 1.31 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 133.2, 119.4, 76.2, 49.0, 43.8, 36.1, 29.7, 21.5; IR
(thin film) 3076, 1440, 2935, 669 cm-1; HRMS (CI) m/z calcd for
C10H17INaO [M + Na]+, 303.0222; found, 303.0127. Anal. Calcd
for C10H17OI: C, 42.87; H, 6.12. Found: C, 43.12; H, 5.95.
Phenoxycyclohexanes 12d and 13d. The standard allylation
procedure was followed with acetal 11d (0.190 g, 0.81 mmol),
allyltrimethylsilane (0.511 mL, 3.20 mmol), and BF3‚OEt2 (0.121
1
mL, 0.97 mmol). GC and H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 34:66 ratio.
Separation of the diastereomers was achieved by purification of
the resultant residue by silica gel chromatography (3:97 EtOAc/
hexanes) to yield the product as a colorless oil (0.171 g, 87%).
Mass spectrometry data was obtained for major isomer (12d) and
minor isomer (13d) as a mixture of diastereomers: HRMS (ESI)
m/z calcd for C16H22NaO2 [M + Na]+, 269.1518; found, 269.1513.
1
Major Isomer (12d). H NMR (500 MHz, CDCl3) δ 7.13 (m,
2H), 6.83 (m, 3H), 5.78 (ddt, J ) 17.2, 12.2, 5.2 Hz, 1H), 4.99 (d,
J ) 10.1 Hz, 1H), 4.98 (d, J ) 17.1 Hz, 1H), 4.08 (dd, J ) 10.5,
3.7 Hz, 1H), 3.37 (s, 3H), 2.54 (dd, J ) 13.6, 7.5 Hz, 1H), 2.47
(dd, J ) 13.6, 7.2 Hz, 1H), 1.94 (m, 1H), 1.76 (m, 2H), 1.58 (m,
2H), 1.24 (m, 1H), 1.13 (ddd, J ) 13.9, 12.1, 4.1 Hz, 1H), 1.04
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 158.5, 133.9, 129.7, 120.9,
118.5, 116.1, 80.3, 77.6, 49.8, 38.2, 31.7, 26.1, 24.2, 21.0; IR (thin
film) 2929, 2860, 1597, 1493 cm-1. Anal. Calcd for C16H22O2: C,
78.01; H, 9.00. Found: C, 78.18; H, 9.07.
1
Minor Isomer (13d). H NMR (500 MHz, CDCl3) δ 7.24 (m,
2H), 6.90 (m, 3H), 5.78 (ddt, J ) 21.1, 12.8, 8.6 Hz, 1H), 5.03 (d,
J ) 12.8 Hz, 1H), 4.95 (d, J ) 21.2 Hz, 1H), 4.26 (t, J ) 3.6 Hz,
1H), 3.25 (s, 3H), 2.44 (dd, J ) 18.5, 9.6 Hz, 1H), 2.36 (dd, J )
18.1, 8.5 Hz, 1H), 1.78 (m, 4H), 1.48 (m, 3H), 1.36 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 157.9, 133.4, 129.7, 120.9, 118.3, 116.2,
77.6, 75.1, 48.6, 36.8, 28.9, 24.6, 21.1, 20.2; IR (thin film) 2933,
2826, 1598, 1495 cm-1. Anal. Calcd for C16H22O2: C, 78.01; H,
9.00. Found: C, 78.16; H, 9.19.
Allyl Product 20. The standard allylation procedure was
followed with acetal 19 (0.070 g, 0.23 mmol), allyltrimethylsilane
(0.144 mL, 0.91 mmol), and MeAlCl2 (0.27 mL, 0.27 mmol, 1.0
M in hexane). GC and 1H NMR spectroscopic analysis of the
unpurified product detected only a single isomer was present.
Purification of the resultant residue by silica gel chromatography
(0:100 to 2:98 EtOAc/hexanes) yielded the product as a pale yellow
oil (0.062 g, 87%): 1H NMR (500 MHz, C6D6) δ 7.48 (m, 2H),
7.05 (t, J ) 7.5 Hz, 2H), 6.97 (m, 1H), 5.92 (ddt, J ) 17.2, 10.2,
6.97 Hz, 1H), 5.10 (m, 2H), 3.58 (m, 1H), 3.33 (s, 3H), 2.31 (dd,
J ) 15.0, 7.5 Hz, 1H), 2.22 (dd, J ) 15.0, 7.1 Hz, 1H), 2.00 (td,
J ) 13.3, 3.8 Hz, 1H), 1.82 (tt, J ) 12.5, 3.7 Hz, 1H), 1.76 (dq, J
) 13.1, 1.8 Hz, 1H), 1.67 (ddt, J ) 15.2, 3.1 Hz, 1H), 1.56 (m,
1H), 1.15 (ddd, J ) 14.3, 12.4, 3.4 Hz, 1H), 1.01 (dq, J ) 3.8,
General Procedure for Cyanation of 2-Phenylsulfanylcyclo-
hexanone Dimethyl Acetals: A solution of the acetal in CH2Cl2
(0.10 M) was treated with Me3SiCN (4.0 equiv) and then cooled
to -78 °C. The appropriate Lewis acid (1.2 equiv) was added
dropwise, and the reaction mixture was allowed to warm to 22 °C.
After 18 h, the reaction mixture was cooled to -78 °C and treated
J. Org. Chem, Vol. 71, No. 14, 2006 5177

Billings and Woerpel
with a 1:1:1 solution of Et3N, MeOH, and CH2Cl2 (1 mL per mL
of reaction volume). The reaction mixture was poured into a
separatory funnel containing saturated aqueous NaHCO3 (1 mL per
mL of reaction volume) and extracted with 3 portions of CH2Cl2
(1 mL per mL of acetal). The organic layers were washed with a
saturated sodium chloride solution, dried (Na2SO4), and concen-
trated in vacuo. The unpurified mixture was analyzed by GC and
1H NMR spectroscopy and then purified as indicated.
dure was followed with 1762 (0.036 g, 0.31 mmol) and phenyl-
magnesium bromide (0.75 mL, 0.75 mmol, 1.0 M in THF). GC
and 1H NMR spectroscopic analysis of the unpurified product
indicated a single isomer was present. Purification of the resultant
residue by silica gel chromatography (2:98 EtOAc/hexanes) yielded
the product as a white solid (0.057 g, 95%). X-ray quality crystals
were grown from CHCl3 in which slow evaporation provided the
crystal: mp 74 °C; 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J ) 7.5
Hz, 2H), 7.37 (t, J ) 7.8 Hz, 2H), 7.28 (m, 1H), 4.98 (dt, J )
40.4, 8.4 Hz, 1H), 2.27 (t, J ) 2.3 Hz, 1H), 2.02 (tdd, J ) 9.0, 8.9,
3.8 Hz, 2H), 1.94 (m, 1H), 1.83 (m, 1H), 1.73 (ddt, J ) 25.8, 12.9,
3.6 Hz, 1H), 1.60 (m, 1H), 1.52 (m, 1H), 1.39 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 145.7, 128.7, 127.5, 125.2, 95.2 (d, J ) 176.3
Hz), 75.2 (d, J ) 17.5 Hz), 39.3 (d, J ) 15.0 Hz), 27.8 (d, J )
70.0 Hz), 23.9 (d, J ) 45.0 Hz), 21.1 (d, J ) 5.0 Hz); IR (thin
film) 3419, 2924, 1458 cm-1; HRMS (ESI) m/z calcd for C12H15-
FNaO [M + Na]+, 217.1005; found, 217.1004. Anal. Calcd for
C12H15FO: C, 74.97; H, 8.23. Found: C, 74.90; H, 8.16.
Nitrile 10. The standard cyanation procedure was followed with
acetal 7,26-28,77 Me3SiCN (0.198 mL, 1.50 mmol), and BF3‚OEt2
1
(0.056 mL, 0.45 mmol). GC and H NMR spectroscopic analysis
of the unpurified product detected only a single isomer was present.
Purification of the resultant residue by silica gel chromatography
(0:100 to 5:95 EtOAc/hexanes) yielded the product as a white solid
(0.086 g, 93%). X-ray quality crystals were grown from a 3:1
mixture of CHCl3 and hexanes in which slow evaporation provided
the crystal: mp 80-83 °C; 1H NMR (500 MHz, CDCl3) δ 7.29-
7.53 (m, 5H), 3.46 (s, 3H), 3.34 (m, 1H), 2.32 (m, 1H), 1.94 (m,
2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.35 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 135.0, 133.3, 129.4, 128.0, 119.4, 78.2, 55.2, 53.1,
32.7, 29.6, 23.8, 20.5; IR (thin film) 2943, 2082, 2866, 2260, 1444
cm-1; HRMS (CI) m/z calcd for C14H18NOS [M + H]+, 248.1071;
found, 248.1073. Anal. Calcd for C14H17NOS: C, 67.98; H, 6.93;
N, 5.66. Found: C, 67.97; H, 7.00; N, 5.63.
Cyclohexanol 38. The standard Grignard addition procedure was
followed with 3776 (0.044 g, 0.19 mmol) and phenylmagnesium
1
bromide (0.45 mL, 0.45 mmol, 1.0 M in THF). GC and H NMR
spectroscopic analysis of the unpurified product detected only a
single isomer was present. Purification of the resultant residue by
silica gel chromatography (3:97 EtOAc/hexanes) yielded the product
as a white solid (0.054 g, 84%). X-ray quality crystals were grown
from a 3:1 mixture of hexanes and CH2Cl2 in which slow
evaporation provided the crystal: mp 108-110 °C; 1H NMR (500
MHz, CDCl3) δ 7.12 (m, 2H), 6.98 (m, 4H), 6.89 (m, 2H), 6.79
(m, 2H), 3.35 (s, 1H), 3.00 (d, J ) 2.6 Hz, 1H), 1.81 (dd, J )
14.8, 2.9 Hz, 1H), 1.66 (dd, J ) 14.1, 2.9 Hz, 1H), 1.63 (dd, J )
14.8, 2.5 Hz, 1H), 1.52 (d, J ) 14.1 Hz, 1H), 1.41 (s, 3H), 1.38 (s,
3H), 1.34 (s, 3H), 0.90 (s, 3H); 13C (125 MHz, CDCl3) δ 148.4,
136.8, 133.1, 128.4, 127.6, 126.6, 126.4, 125.3, 79.1, 71.1, 54.5,
52.3, 36.9, 36.6, 35.4, 31.3, 27.9, 24.8; IR (thin film) 3505, 3030,
2951, 1445 cm-1; HRMS (ESI) m/z calcd for C22H28NaOS [M +
Na]+, 363.1758; found, 363.1751. Anal. Calcd for C22H28OS: C,
77.60; H, 8.29. Found: C, 77.41; H, 8.43.
Nitrile 22. The standard cyanation procedure was followed with
acetal 19 (0.366 g, 1.41 mmol), Me3SiCN (0.750 mL, 5.63 mmol),
1
and BF3‚OEt2 (0.213 mL, 1.68 mmol). GC and H NMR spectro-
scopic analysis of the unpurified product detected only a single
isomer was present. Purification of the resultant residue by silica
gel chromatography (0:100 to 2:98 EtOAc/hexanes) yielded the
product as a white solid (0.321 g, 89%): 1H NMR (500 MHz,
CDCl3) δ 7.49 (m, 2H), 7.30 (m, 3H), 3.87 (m, 1H), 3.45 (s, 3H),
2.07 (m, 1H), 2.03 (dd, J ) 13.2, 3.9 Hz, 1H), 1.99 (m, 1H), 1.89
(m, 1H), 1.70 (ddd, J ) 14.2, 12.3, 3.3 Hz, 1H), 1.60 (m, 1H),
1.40 (ddd, J ) 25.8, 13.3, 4.2 Hz, 1H), 0.83 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 134.2, 133.7, 129.4, 128.2, 119.1, 78.9, 53.0,
52.6, 40.8, 32.2, 31.7, 30.2, 27.7, 24.4; IR (thin film) 3060, 2960,
2870, 2260 cm-1; HRMS (EI) m/z calcd for C18H25NOS [M]+,
303.1657; found, 303.1659. Anal. Calcd for C18H25NOS: C, 71.24;
H, 8.30; N, 4.62. Found: C, 71.51; H, 8.46; N, 4.68.
Cyclohexanol 39. The standard Grignard addition procedure was
followed with 3776 (0.033 g, 0.13 mmol) and methylmagnesium
1
bromide (0.10 mL, 0.30 mmol, 3.0 M in Et2O). GC and H NMR
Nitrile 34. The standard cyanation procedure was followed with
acetal 32 (0.222 g, 0.79 mmol), Me3SiCN (0.423 mL, 3.17 mmol),
spectroscopic analysis of the unpurified product detected only a
single isomer was present. Purification of the resultant residue by
silica gel chromatography (3:97 EtOAc/hexanes) yielded the product
as a colorless oil (0.027 g, 77%): 1H NMR (400 MHz, CDCl3) δ
7.45 (m, 2H), 7.28 (m, 2H), 7.18 (m, 1H), 2.89 (s, 1H), 2.17 (d, J
) 2.2 Hz, 1H), 1.82 (dd, J ) 14.4, 2.9 Hz, 1H), 1.57 (dd, J )
14.0, 2.9 Hz, 1H), 1.29 (m, 2H), 1.32 (s, 3H), 1.24 (s, 6H), 1.14 (s,
3H), 0.89 (s, 3H); 13C (125 MHz, CDCl3) δ 139.3, 130.6, 129.3,
126.5, 69.8, 54.6, 50.8, 37.1, 36.5, 35.3, 33.6, 30.9, 27.7, 24.4, 22.7;
IR (thin film) 3529, 2951, 1481 cm-1; HRMS (CI) m/z calcd for
C17H25S [M - OH]+, 261.1677; found, 261.1674. Anal. Calcd for
C17H26OS: C, 73.33; H, 9.41. Found: C, 73.14; H, 9.65.
1
and BF3‚OEt2 (0.120 mL, 0.95 mmol). GC and H NMR spectro-
scopic analysis of the unpurified product indicated a pair of
diastereomers in a ratio of 92:8. Purification of the resultant residue
by silica gel chromatography (3:97 EtOAc/hexanes) yielded the
product as a white solid (0.198 g, 91%). The purified products were
characterized as a mixture of diastereomers: 1H NMR (400 MHz,
CDCl3) δ 7.53 (m, 2.3H), 7.31 (m, 3.3H), 3.50 (s, 3H), 3.47 (s,
0.4H), 3.19 (dd, J ) 11.1, 4.4 Hz, 1.1H), 2.23 (dd, J ) 14.8, 2.2
Hz, 1H), 2.01 (m, 2.4H), 1.24 (m, 1.7H), 1.09 (s, 0.5H), 1.06 (s,
3H), 1.01 (s, 0.5H), 0.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
135.2, 133.3, 133.2, 129.4, 129.2, 128.0, 127.9, 119.6, 56.5, 53.7,
53.2, 43.4, 38.4, 32.2, 31.4, 26.7, 26.5; IR (thin film) 3059, 2953,
2866, 2850 cm-1; HRMS (ESI) m/z calcd for C16H21NNaOS [M +
Na]+, 298.1241; found, 298.1248. Anal. Calcd for C16H21NOS: C,
69.78; H, 7.69; N, 5.09. Found: C, 69.92; H, 7.76; N, 5.06.
General Procedure for Grignard Addition to Cyclohex-
anones: A cooled (-78 °C) solution of cyclohexanone derivative
(1.00 equiv) in THF (0.10 M) was treated with Grignard nucleophile
(2.40 equiv). The reaction mixture was warmed to 22 °C and stirred
for 1.5 h before it was cooled to 0 °C and treated with H2O (1 mL
per mmol cyclohexanone). The aqueous layer was extracted with
3 portions of Et2O (1 mL per mmol cyclohexanone). The combined
organic layers were washed with a saturated sodium chloride
solution (1 mL per mL of Et2O), dried (Na2SO4), and concentrated
in vacuo. The unpurified mixture was analyzed by GC and 1H NMR
spectroscopy and then purified as indicated.
Acknowledgment. This research was supported by the
National Institutes of Health, National Institute of General
Medical Sciences (GM-61066). S.B.B. thanks Novartis for a
graduate research fellowship. K.A.W. thanks Amgen, Lilly, and
Merck Research Laboratories, and Johnson & Johnson for
awards to support research. We thank Dr. John Greaves for mass
spectrometric data and Dr. Joe Ziller for X-ray crystallographic
analyses.
Supporting Information Available: Complete experimental
procedures, product characterization, stereochemical proofs, X-ray
crystallographic data, and GC and spectral data for selected
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
Fluorocyclohexanol 18. The standard Grignard addition proce-
JO060077R
5178 J. Org. Chem., Vol. 71, No. 14, 2006