Sulfoxides in Julia-Lythgoe olefination: Efficient and stereoselective preparation of di-, tri-, and tetrasubstituted olefins

Article abstract of DOI:10.1021/ol050649e

(Chemical Equation Presented) A novel modification of the classical Julia-Lythgoe olefination, using sulfoxides instead of sulfones, affords, after in situ benzoylation and Sml₂/HMPA- or DMPU-mediated reductive elimination, 1,2-di-, tri-, and tetrasubstituted olefins in moderate to excellent yields and E/Z selectivity. The conditions are mild, and the procedure is broadly applicable.

Full text of DOI:10.1021/ol050649e

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2373-2376
Sulfoxides in Julia−Lythgoe Olefination:
Efficient and Stereoselective Preparation
of Di-, Tri-, and Tetrasubstituted Olefins
Jir´ı Posp´ısˇil, Toma´sˇ Posp´ısˇil, and Istva´n E. Marko´*
UniVersite´ Catholique de LouVain, De´partement de Chimie, Baˆtiment LaVoisier,
Place Louis Pasteur 1, B-1348 LouVain-la-NeuVe, Belgium
marko@chim.ucl.ac.be
Received March 26, 2005
ABSTRACT
A novel modification of the classical Julia−Lythgoe olefination, using sulfoxides instead of sulfones, affords, after in situ benzoylation and
SmI2/HMPA- or DMPU-mediated reductive elimination, 1,2-di-, tri-, and tetrasubstituted olefins in moderate to excellent yields and E/Z selectivity.
The conditions are mild, and the procedure is broadly applicable.
The formation of olefins from sulfones and carbonyl
compounds, known as the Julia-Lythgoe olefination, is one
of the most powerful tools of modern organic chemistry.1
The initial reductive elimination of the intermediate â-hy-
droxysulfones using Na-Hg has been gradually superseded
by mild, more selective, and less toxic reducing agents such
Scheme 1. Julia-Lythgoe Olefination
2
as SmI2 or Mg3 (Scheme 1).
Disappointingly, this widely used method still suffers from
several drawbacks. One of them is the relatively high stability
of the sulfonyl anion which limits its reactivity. For example,
if an additional electron-withdrawing substituent is present
(1) (a) Dumeunier, R.; Marko´, I. E. Modern Carbonyl Olefination;
Takeda, T., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 104. (b)
Kociensky, P. J. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 6. (c) Julia, M.; Paris, J. M.
Tetrahedron Lett. 1973, 4833. (d) Kocienski, P. J.; Lythgoe, B.; Waterhouse,
I. J. Chem. Soc., Perkin Trans. 1 1980, 1045. (e) Kocienski, P. J. Phosphorus
Sulphur 1985, 24, 97.
(2) (a) Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto,
K. Synlett 1994, 859. (b) Keck, G. E.; Savin, K. A.; Welgarz, M. A. J.
Org. Chem. 1995, 60, 3194. (c) Marko, I. E.; Murphy, F.; Dolan, S.
Tetrahedron Lett. 1996, 37, 2089. (d) Kagan, H. B. Tetrahedron 2003, 59,
10351. (d) Inanaga, J. Trends Org. Chem. 1990, 1, 23.
on the anion-bearing carbon, this organometallic species
becomes so stable that it does not add even to activated
(4) I. Kuwajima, S.-J.; Sato, Y.; Kurata, A. Tetrahedron Lett. 1972, 13,
737.
(5) (a) Satoh, T.; Hanaki, N.; Yamada, N.; Asano, T. Tetrahedron 2000,
56, 6223. (b) Satoh, T.; Yamada, N.; Asano, T. Tetrahedron Lett. 1998,
39, 6935.
(6) The pKa of the hydrogen on the carbon bearing sulfinyl group is
four orders higher than the pKa of the equivalent hydrogen on the carbon
bearing sulfonyl group.
(3) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S.
Tetrahedron Lett. 1995, 36, 5607.
10.1021/ol050649e CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/19/2005

Scheme 2. Sulfoxide Version of the Julia-Lythgoe
Table 2. Synthesis of 1,2-Disubstituted Olefins
Olefination
aldehydes.2c Moreover, in the case of the reaction of nonsta-
bilized sulfones with some aldehydes and with ketones, the
position of the equilibrium between the starting carbonyl
compound and the sulfone anion is shifted toward the starting
materials. The desired adduct (tertiary alkoxide) is therefore
present in the reaction mixture as a minor component. Trap-
ping this intermediate in situ with several electrophiles, such
as benzoyl chloride, mesyl chloride, or acyl chloride, is a com-
mon trick employed to shift the equilibrium toward the pro-
ducts. It is interesting to note that these â-acyloxy, benzoy-
loxy, and mesyloxy sulfone derivatives undergo smoother
reductive elimination than the parent â-hydroxy sulfones.
Table 1. Optimization of Reductive Elimination Step Using
SmI2
a Overall yields refer to pure, isolated products. b Determined by 1H NMR
spectroscopy.
the carbonyl compound. Recently, Satoh et al. reintroduced4
sulfoxides as a sulfone equivalent in the Julia-Lythgoe
olefination.5 As an advantage, the carbanion generated R to
the sulfoxide group is far less stabilized6 than in the case of
the corresponding sulfone and the addition reaction, leading
to the formation of the C-C bond, is favored even in the
case of ketones. The reductive elimination was carried out
via sulfoxide/lithium exchange, followed by elimination of
the â-mesyloxy or acyloxy group (Scheme 2).
Using this method, stilbene derivatives could be prepared
via this Julia-Lythgoe modification for the first time, though
with rather modest E/Z selectivity. On the other hand, the
use of an excess (4 equiv) of a strong base (n-BuLi) can be
rather inconvenient in the case of functionalized substrates.
For some time, we have been interested in various
modifications of the Julia-Lythgoe reaction2c,7 and have
recently introduced the SmI2/HMPA-mediated reductive
elimination of â-benzoyloxysulfones, formed by the addition
of R-sulfone anions to ketones, as an efficient and stereo-
selective route toward trisubstituted olefins.
entry
additive
equiv to SmI2
yielda (%)
E/Zb
1
2
3
4
5
-
-
0.25
0.5
0.75
1.0
2.0
15.0
15.0
15.0
15.0
-
25
34
43
67
64
12
32
48
10
na
HMPA
HMPA
HMPA
HMPA
HMPA
DMPU
DMPU
DMPU
DMPU
>95:1
>95:1
>95:1
>95:1
>95:1
na
>95:1
>95:1
na
6
7c
8d
9e
10f
a Overall yields refer to pure, isolated products. b Determined by capillary
GC. c Reaction carried out at -50 °C. d Reaction carried out at -25 °C.
e Reaction carried out at 0 °C. f Reaction carried out at rt.
Nevertheless, such modifications are useless when the
generated sulfonyl anion is so stable that it does not add to
Based upon our previous results, we envisaged that the
(7) Marko, I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.; Craig,
D.; Carballaresb, S.; Dolan, S. Tetrahedron 2001, 57, 2609.
SmI2-mediated reductive-elimination of â-benzoyloxy sul-
2374
Org. Lett., Vol. 7, No. 12, 2005

Table 3. Preparation of Trisubstitted Olefins
Table 4. Preparation of Tetrasubstituted Olefins
a Overall yields refer to pure, isolated products. b Determined by 1H NMR
spectroscopy.
adding more of this cosolvent did not increase the yield of
the reaction (Table 1, entries 5 and 6).
a Overall yields refer to pure, isolated products. b Determined by 1H NMR
spectroscopy.
DMPU was explored as an alternative, nontoxic HMPA
equivalent. However, under all reaction conditions tested,
the yields remained lower than with HMPA (Table 1, entries
7-10). Moreover, a large excess of DMPU and higher
temperature (0 °C to rt) had to be employed (Table 1, entries
9 and 10).
Having devised suitable reaction conditions to effect this
sulfoxide variant of the Julia-Lythgoe olefination, we
explored its scope and limitations. A selection of pertinent
results are collected in Tables 2 and 3.
The phenyl bearing sulfoxide 1a gave, upon reaction with
aryl and alkyl aldehydes, the corresponding disubstituted
olefins 4a and 4b in good yields. Only the thermodynami-
cally more stable (E)-double bond isomer was observed
(Table 2, entries 1 and 2). The iso-propyl substituted
sulfoxide 1b afforded, upon reaction with dihydrocinnama-
ldehyde, the desired disubstituted olefin 4d in good yield
and a respectable 94:6 E/Z ratio (Table 2, entry 4). To our
surprise, when 1b was reacted with benzaldehyde, the
resulting product 4c was obtained with a modest E/Z ratio
of 76:24 (Table 2, entry 3). When 1a was reacted with methyl
isopropyl ketone, the E-isomer 5b was formed as the major
product in a 91:9 ratio (Table 3, entry 2). Moreover, we were
delighted to observe that even acetophenone did react under
these conditions and afforded the desired olefin 5a in 51%
yield and with an E/Z ratio of 76:24. Essentially the same
ratio of isomers was observed when 1b was condensed with
acetophenone. Olefin 5c was formed in 64% yield and a 74:
26 E/Z ratio (Table 3, entry 3). The reaction of 1b with other
foxides might produce the desired olefins in high yield and
with good E/Z selectivity.
To test our hypothesis, the coupling of sulfoxide 1a with
aldehyde 2a was carried out (Table 1).8 In the first step of
this reaction, a new C-C bond is formed. As a consequence,
two new stereogenic centers are created which, added to the
one present in the sulfoxide moiety, leads to four different
diastereoisomers of 3a. To avoid their tedious separation, it
was decided to use the mixture of adduct 3a in the subsequent
reductive elimination step.9 Some pertinent results are
collected in Table 1.
As can be seen in Table 1, SmI2 itself does not promote
the reaction (Table 1, entry 1). HMPA and DMPU were then
tested as additives in order to increase the reduction power
of SmI2.10 Gratifyingly, the presence of small amounts of
HMPA already resulted in olefin formation, though the rate
of the reaction was rather slow (Table 1, entry 2). The use
of one equivalent of HMPA was found to be optimal, and
(8) All the reactions presented in Table 1 are carried out on the mixture
of adduct 3a.
(9) The excess of benzoyl chloride was reacted with N,N-dimethyl-3-
aminopropanol and the amines was removed upon acidic workup.
(10) (a) Shabangi, M.; Sealy, J. M.; Fuchs, J. R.; Flowers, R. A., II.
Tetrahedron Lett. 1998, 39, 4429. (b) Shabangi, M.; Flowers, R. A., II.
Tetrahedron Lett. 1997, 38, 1137. (c) Hasegawa, E.; Curran, D. P. J. Org.
Chem. 1993, 58, 5008. (d) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem.
2004, 3393.
(11) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1979, 44, 713.
Org. Lett., Vol. 7, No. 12, 2005
2375

dialkyl substituted ketones (Table 3, entries 4 and 5) gave
olefins 5d and 5e in a respectable 88:12 and a reasonable
68:32 E/Z ratio, respectively.
Finally, to test the robustness of our method, the prepara-
tion of tetrasubstituted alkenes was attempted, using the
sterically hindered sulfoxide 6.11 We were delighted to
observe that the expected olefins 7 were formed in an
excellent E/Z ratio and still acceptable yields (Table 4).
In summary, we have developed a novel, highly stereo-
selective method for the synthesis of 1,2-di-, tri-, and
tetrasubstituted olefins.12 Under our conditions, sterically
hindered sulfoxide anion (such as the one derived from
sulfoxide 6) and unreactive ketones (e.g., acetophenone)
could be coupled in good to acceptable yields. A variety of
functions and protecting groups are also tolerated (Table 2,
entries 5-7).
(12) Typical Experimental Procedure. Coupling Step. A solution of
sulfoxide (1.0 mmol) in dry THF (10 mL, 0.1 M solution) was cooled to
-78 °C and LDA (550 µL, 1.1 mmol) was added dropwise. The color of
the mixture changed from slightly yellow to orange/red. After the mixture
was stirred at -78 °C for 30 min, the aldehyde/ketone (1.05 mmol),
dissolved in dry THF (0.5 mL), was added dropwise, and the mixture was
stirred for an additional 2 h at -78 °C. Benzoyl chloride (1.5 mmol) in dry
THF (0.5 mL) was then added, the resulting mixture was stirred for 30
min at -78 °C and then allowed to warm to rt over 1 h. After an additional
30 min at rt, Me2N(CH2)3OH (1.55 mmol) was added and the resulting
suspension was stirred for 10 min at rt. The suspension was then diluted
with Et2O/H2O ) 1:1 (10 mL), and the layers were separated. The aqueous
layer was extracted with Et2O (3 × 10 mL), and the combined organic
layers were washed with 1.0 M aq HCl (10 mL), H2O (10 mL), and brine
(10 mL), dried over MgSO4, and evaporated under reduced pressure to give
the crude product, which was used without additional purification in the
subsequent step. Reductive Elimination. To a solution of SmI2 (35 mL,
0.1 M in THF, 3.5 equiv) was added HMPA (613 µL, 3.5 equiv), and the
mixture was cooled to -78 °C. The crude coupled product (1.0 mmol) in
dry THF (0.5 mL) was added dropwise, and the resulting mixture was stirred
at -78 °C for an additional 30 min. Then, aqueous satd NH4Cl (20 mL)
was added, and the whole was allowed to warm to rt. The layers were
separated, and the aqueous phase was extracted with Et2O (3 × 20 mL).
The pooled organic layers were washed with 10% aq Na2S2O3 (20 mL),
H2O (20 mL), and brine (20 mL), dried over MgSO4, and evaporated under
reduced pressure. The crude product was then purified by chromatography
on silicagel.
Further studies are now directed toward optimizing these
conditions, broadening the scope of this method and applying
it to relevant natural product synthesis.
Acknowledgment. Financial support by the Universite´
Catholique de Louvain, Rhodia Ltd. (studentship to J.P) and
Socrates-Erasmus program (studentship to T.P.) is gratefully
acknowledged. I.E.M. is grateful to Rhodia for the 2001
Rhodia Outstanding Award.
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds, and references
to known compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL050649E
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Org. Lett., Vol. 7, No. 12, 2005