Stereoselective alkylidenation of ketones with 2-(p-toluenesulfinyl)benzyl iodide: Synthesis of enantiomerically pure trisubstituted epoxides

Article abstract of DOI:10.1021/ol8005387

(Chemical Equation Presented) Alkylidenation of arylmethyl, dialkyl, and cyclic ketones with 2-(p-toluenesulfinyl)benzyl iodide in the presence of NaN(SiMe₃)₂ takes place with a high or complete control of the facial selectivity at the carbonyl group (up to 98% de) and the carbanion (>98% de), respectively, yielding mixtures of only two optically pure trisubstituted epoxides (E/Z ratio ranges between 2:1 and >50:1). Removal of the p-tolylsulfinyl group with t-BuLi provides the corresponding (E)-3-phenyl-2,2-disubstituted epoxides without affecting their optical purity.

Full text of DOI:10.1021/ol8005387

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2151-2154
Stereoselective Alkylidenation of
Ketones with 2-(p-Toluenesulfinyl)benzyl
Iodide: Synthesis of Enantiomerically
Pure Trisubstituted Epoxides
,†
†
†
´
Yolanda Arroyo,* Angela Meana, M. Ascensio´n Sanz-Tejedor, and Jose´ Luis
Garc´ıa Ruano*,‡
Departamento de Qu´ımica Orga´nica (ETSII), UniVersidad de Valladolid, P° del Cauce
s/n, 47011 Valladolid, Spain, and Departamento de Qu´ımica Orga´nica (C-I),
UniVersidad Auto´noma, Cantoblanco, 28049 Madrid, Spain
yarroyo@eis.uVa.es; joseluis.garcia.ruano@uam.es
Received March 10, 2008
ABSTRACT
Alkylidenation of arylmethyl, dialkyl, and cyclic ketones with 2-(p-toluenesulfinyl)benzyl iodide in the presence of NaN(SiMe3)2 takes place with
a high or complete control of the facial selectivity at the carbonyl group (up to 98% de) and the carbanion (>98% de), respectively, yielding
mixtures of only two optically pure trisubstituted epoxides (E/Z ratio ranges between 2:1 and >50:1). Removal of the p-tolylsulfinyl group with
t-BuLi provides the corresponding (E)-3-phenyl-2,2-disubstituted epoxides without affecting their optical purity.
Enantiomerically pure trisubstituted epoxides with two
stereocenters are versatile and powerful intermediates for
synthesizing a wide range of chiral molecules bearing
connected tertiary and quaternary stereocenters, via nu-
cleophilic opening of the oxiranic ring. Trisubstituted
epoxides can be obtained by asymmetric epoxidation of
trisubstituted double bonds,1 but despite recent advances
in the development of effective asymmetric epoxidation
catalysts, these have not proven generally useful in the
context of trisubsubstituted alkenes. An alternative method
for preparing these compounds involves alkylidenation of
ketones using ylides, carbenoids or Darzens reagents as
the nucleophilic species.2 Once again, low or moderate
success had been achieved for trisubstituted epoxides till
Aggarwal reported the reactions between a chiral benzyl
sulfonium ylide and carbonyl compounds.3 The results
were extraordinary with aldehydes, but the only four
studied ketones provided poorer results. Cyclohexanone
and 4-tert-butyl cyclohexanone evolved in high ee’s but
acetophenone and p-nitro acetophenone afforded epoxides
with modest E/Z or enantio- selectivities, the (Z)-epoxides
being the major isomers. This indicates that non symmetric
(1) For leading reviews, see: Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1933; Chapter 4.1.
Besse, P.; Veschambre, H. Tetrahedron 1994, 50, 8885–8927. Jacobsen,
E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
1933; Chapter 4.2. Katsuki, T. Synlett 2003, 281–297. Shi, Y. Acc. Chem.
Res. 2004, 37, 488–496. Yang, D. Acc. Chem. Res. 2004, 37, 497–505.
McGarrigle, E. M.; Gilheany, D. G. Chem. ReV. 2005, 105, 1563–1602.
Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. ReV. 2005,
105, 1603–1662. Rose, E.; Andrioletti, B.; Zrig, S.; Quelquejeu-Ethe`ve,
M. Chem. Soc. ReV. 2005, 34, 573–583. Sello, G.; Fumagalli, T.; Orsini,
F. Curr. Org. Synth. 2006, 3, 457–476.
(2) For leading reviews see: Li, A.-H.; Dai, L.-X.; Aggarwal, V. K.
Chem. ReV. 1997, 97, 2341–2372. Aggarwal, V. K.; Winn, C. L. Acc. Chem.
Res. 2004, 37, 611–620. AggarwalV. K. BadineD. M. MoorthieV. A. In
Aziridines and Epoxides in Organic Synthesis; Yudin A. K., Ed.; Wiley-
VCH Verlag: Weinheim, 2006; pp 1-22.
(3) Aggarwal, V. K.; Bae, H.; Lee, H.-Y.; Richardson, J.; Williams,
D. T. Angew. Chem., Int. Ed. 2003, 42, 3274–3278.
† Universidad de Valladolid.
‡ Universidad Auto´noma.
10.1021/ol8005387 CCC: $40.75
Published on Web 05/09/2008
2008 American Chemical Society

ketones are still challenging substrates for direct trans-
formation into epoxides.
less reactive ketones 2e and 2j (Table 1, entries 5 and 10).
In these reactions, a significant amount of byproduct 4 was
recovered. In reactions with 2f, 2k, and 2l, a small amount
of 4 was also detected (entries 6, 11, and 12). All attempts
to minimize the extent of this side reaction by using an excess
of ketone were unsuccesful.
We have recently reported the almost completely stereo-
selective transference of chiral benzyl groups to different
electrophiles starting from R-trimethylsilyloxy,4 R-alkyl,5 and
R-methylthiolithium6 benzylcarbanions. Anionic intermedi-
ates with the lithium chelated by the sulfinyl oxygen and
the benzyl carbon7 (Scheme 1, eq 1) seem to be involved in
Reaction starting from benzophenone 2a (entry 1) gave
the desired epoxide 3a in a high yield and complete
diastereoselectivity (>98% de), which proved that the sulfinyl
group completely controls the configuration at its benzylic
carbon. The reactions with alkyl aryl ketones 2b-g, where
two stereogenic centers were simultaneously formed, evolved
into a mixture of only two (E)-3 and (Z)-3 epoxides, with
high (E)-selectivity. E/Z ratio ranges from 6/1 to >49/1
except for isobutyrophenone 2g, which yielded a 2/1 mixture
of (E)-3g and (Z)-3g (entry 7). For ketones 2b-d, bearing
neutral or electron-donating groups, the E/Z ratio increases
when the electron-donating ability of the substituent became
stronger (entries 2-4). Complete E-selectivity was achieved
in reactions with ketones 2e and 2f bearing the bulkier
2-bromophenyl and naphthyl groups, although only 2f
evolved in good yield (Table 1, entries 5 and 6). Reactions
with aryl ketones containing electron-withdrawing groups,
such as p-trifluoromethyl, were less successful, and mixtures
of the four possible epoxides were formed with low diaste-
reoselectivities. The method was also found to be successful
for acyclic dialkylketones 2 h-k, furnishing the corresponding
epoxides (E)-3 as the major or exclusive diastereoisomers
(entries 8-11). Once again, the E/Z ratio increases (from
86/14 up to >98/2) when the differences in size of the R
groups become higher. The low yield obtained for 2j could
be due to its lower reactivity (see above).
Cyclic ketones also proved the effectiveness of the process
(entries 12-14). Starting from symmetrical 2l and 2m
ketones the corresponding spiroepoxides 3l and 3m were
obtained as single diatereoisomers in 46% and 98% yields
respectively. Reaction with 5-methoxy-1-tetralone 2n evolved
with high de (E/Z ) 93:7) affording the major spiroepoxide
3n in 79% isolated yield.
Spiroepoxides 3l-n in Cl3CD underwent spontaneous
ring-opening reaction (presumably catalyzed by the acidic
traces contained in the solvent) to afford the corresponding
allylic alcohols 5 in quantitatively yield and total stereose-
lectivity. Reaction was complete in 1 h starting from 3l and
3n, whereas 48 h was needed to get the complete evolution
of 3m (Figure 1). These differences can be rationalized on
the basis of the relative stability of the resulting cycloalkenes
or the relative easiness of the formation the carbocations from
compounds 3l, 3m and 3n.
Scheme 1
.
Reactions of the 2-(p-Tolylsulfinyl)carbanions with
N-Sulfinylimines
these tranformations. Highly stereoselective quaternization
at benzylic position on R-alkyl R-oxygenated (or nitroge-
nated) benzylcarbanions has been possible with KHMDS,
presumably through non chelated carbanions (Scheme 1, eq
2).8 Bearing in mind these antecedents, we thought that the
reactions of 2-p-tolylsulfinylbenzyl iodide (S)-1 with ketones
could provide a new strategy for synthesizing trisubstituted
epoxides. In this paper, we report the results of this study.
Optically pure iodo derivative (S)-1 was prepared starting
from (S)-2-(p-tolylsulfinyl)-R-(tributyltin)toluene9 by treat-
ment with iodine in CCl4. We then studied the reaction of
(S)-1 with different ketones 2. After exhaustive experimental
work, we found that optimal conditions involve the addition
of NaN(SiMe3)2 to a THF solution containing (S)-1 and the
electrophile at -78 °C (Barbier conditions). As summarized
in Table 1, this process evolved in a highly stereoselective
manner with a wide range of diaryl-, alkylaryl-, and dialkyl-
(cyclic and acyclic) ketones. Alkylidenation competes with
the homocoupling reaction yielding (E)-1,2-di(2-p-tolylsulfi-
nylphenyl) ethylene 4.10 After 1 min, starting products had
disappeared in all the cases, and epoxides 3 were obtained
in a high yield except for the sterically hindered and therefore
(4) Garc´ıa-Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513–4516.
(5) (a) Garc´ıa-Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.; Aguirre,
J. M.; Aranda, M. T.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736–
2737. (b) Garc´ıa-Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003,
5, 677–680. (c) Garc´ıa-Ruano, J. L.; Aranda, M. T.; Aguirre, J. M.
Tetrahedron 2004, 60, 5383–5392. (d) Garc´ıa-Ruano, J. L.; Alema´n, J.;
Parra, A. J. Am. Chem. Soc. 2005, 127, 13048–13054. (e) Garc´ıa-Ruano,
J. L.; Aleman, J.; Cid, B. Synthesis 2006, 687–691.
Taking into account the S configuration exhibited by all
compounds of Table 1 at the benzylic carbon (the opposite
one to that observed in reactions of the benzylcarbanions
shown in Scheme 1, eq 1), the stereochemical results for
(6) (a) Arroyo, Y.; Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-
Tejedor, M. A.; Garc´ıa-Ruano, J. L. J. Org. Chem. 2005, 70, 3914–3920.
(b) Arroyo, Y.; Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor,
M. A.; Garc´ıa-Ruano, J. L. J. Org. Chem. 2007, 72, 1035–1038.
(7) Garc´ıa-Ruano, J. L.; Alema´n, J.; Alonso, I.; Marcos, V.; Parra, A.;
Aguirre, J. Chem. Eur. J. 2007, 13, 6179–6195.
(10) The formation of these homocoupling products from halobenzyl
carbanions has been previously reported. See: Wakefield, B. J. In Orga-
nolithium Methods; Academic Press: London, 1988. Capriati, V.; Florio,
S.; Luisi, R.; Rochetti, M. T. J. Org. Chem. 2002, 67, 759–763. Braun, M.
In The Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I.,
Eds.; John Wiley & Sons: New York, 2004; Chapter 13, pp 829-898.
(8) (a) Garc´ıa Ruano, J. L.; Mart´ın Castro, A. M.; Tato, F.; Pastor, C. J.
J. Org. Chem. 2005, 70, 7346–7352. (b) Garc, J. L.; Mart´ın Castro, A. M.;
Tato, F.; Alonso, I. J. Org. Chem. 2007, 72, 5994–6005.
(9) Garc´ıa-Ruano, J. L.; Alema´n, J.; Padwa, A. Org. Lett. 2004, 6, 1757–
1760.
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Org. Lett., Vol. 10, No. 11, 2008

Table 1. Stereoselective Alkylidenation of Ketones with (S)-1 Using a Single Asymmetric Induction Process
b
a Yield of isolated product. Determined by H NMR from the crude reaction product.
1
(S)-1 could be explained by assuming the formation of the
structure I, stabilized by steric and electrostatic factors, with
the p-tolyl group oriented toward the lower face in Figure
2, and therefore only allowing the access of the electrophile
to the upper face. It would explain the complete control of
the configuration at the benzyl carbon (only compounds with
S configuration at this center are formed). The relative
stability of the two possible aproaches of the ketones to
species I determines the E/Z selectivity. Steric effects favor
the approach A (the larger RL group does not interact with
Ar) evolving into E-epoxides and explain the de changes
observed for aliphatic ketones. The increase in the E-
selectivity with the electron-donating power of the substituent
in aromatic ketones could be explained as the result of the
electronic repulsion (Ar/RL) between two electron-riched
rings (RL is also aromatic) in the approach B (Figure 2).
Org. Lett., Vol. 10, No. 11, 2008
2153

yields. The optical purity of 6a, 6b, and 6f, determined by
chiral HPLC with a Chiralcel OD column, indicates that
starting epoxides 3 are not significantly epimerized under
the reaction conditions.
The absolute configurations of compounds (E)-3b and 5n
were unequivocally established by X-ray diffraction studies.
They allowed us to assign the S configuration to both oxiranic
carbons at (E)-3b and the R configuration to the benzylic
carbon at 5n (which means that configuration at C3 in the
starting epoxide 3n is S). Additionally, the absolute config-
uration of 6a was assigned as S by comparison of optical
rotation and HPLC retention times with those reported in
the literature.11 The similar behavior observed in all the
epoxidation reactions summarized in Table 1, all of them
evolving with complete control of the configuration at the
benzyl carbon and high E/Z diastereoselectivities, suggests
that the absolute configuration for the epoxides 3c-k is also
2S,3S. For the same reasons, 3l and 3m must be assigned as
3S. Additionally, the (E)-stereochemistry of epoxides 3h-3k,
synthesized from alkyl alkyl ketones, was based on the NOE
experiments performed on pure sample of the major isomer
of 3i (see the experimental methods, Supporting Information).
The absolute configuration of the minor (Z)-3b isomer was
established as (2R,3S) by desulfinylation with 1.2 equiv of
tert-BuLi at -78 °C, and comparison of the HPLC retention
time of the resulting 2-methyl-2,3-diphenyldioxirane with that
reported in the literature for the (2R,3S)-isomer.3
Figure 1. Allylic alcohols resulting from the ring opening of
spiroepoxides 3l-n.
Figure 2. Rationalization of the stereochemical results.
Desulfinylation of epoxides 3 can be easily achieved in
very mild conditions by treatment with 1.2 equiv of t-BuLi
at -78 °C. Thus, as summarized in Table 2, compounds 3a,
In summary, we have described the highly enantio- and
diastereoselective reaction of ketones with chiral R-iodo-2-
(p-tolylsulfinyl)toluene (S)-1 to generate trisubstituted ep-
oxides.
Table 2. Desulfinylation of Epoxides 3
Acknowledgment. We thank professor V. K. Aggarwal
and Dr. O. Illa Soler, University of Bristol, for the HPLC
chromatogram of racemic 2-methyl-2,3-diphenyloxirane. We
thank the Spanish Government for financial support (Grant
No. CTQ2006-06741).
entry
substrate
product
yielda (%)
eeb (%)
Supporting Information Available: General experimental
1
2
3
4
5
(3S)-3a
(3S)-6a
75
68
88
75
69
95.6
>99
96.6
methods, chromatograms for the determination of ee values,
(2S,3S)-3b
(2S,3S)-3f
(2S,3S)-3i
(2R,3S)-3b
(2S,3S)-6b
(2S,3S)-6f
(2S,3S)-6i
(2R,3S)-6b
1
X-ray sturcture data (CIF) for (E)-3b and 5n, and H and
c
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
-
c
-
a Isolated yield. b Determined by chiral HPLC. c Not determined.
OL8005387
(11) (a) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378–
4380. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224–11235.
3b, 3f, and 3i were transformed into the corresponding
3-phenyl-2,2-disubstituted epoxides 6a, 6b, 6f, and 6i in good
2154
Org. Lett., Vol. 10, No. 11, 2008