Efficient Synthesis of Substituted Vinyl Ethers Using the Julia Olefination

Article abstract of DOI:10.1021/ol035918k

(Equation Presented) Julia olefination between α sulfones 2a-c and a wide variety of ketones or aldehydes afforded substituted vinyl ethers in 46-90% yields. Sulfones 2a-c were readily prepared in two steps from commercially available reagents in 68-80% yields. Optimization revealed that the nature of the base, the solvent, and the temperature were crucial to obtaining the desired vinyl ethers.

Full text of DOI:10.1021/ol035918k

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4851-4854
Efficient Synthesis of Substituted Vinyl
Ethers Using the Julia Olefination
Simon Surprenant, Wing Yan Chan, and Carl Berthelette*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
P.O. Box 1005, Pointe-Claire/DorVal, Que´bec, Canada, H9R 4P8
carl_berthelette@merck.com
Received September 30, 2003
ABSTRACT
Julia olefination between r-alkoxy sulfones 2a−c and a wide variety of ketones or aldehydes afforded substituted vinyl ethers in 46−90%
yields. Sulfones 2a−c were readily prepared in two steps from commercially available reagents in 68−80% yields. Optimization revealed that
the nature of the base, the solvent, and the temperature were crucial to obtaining the desired vinyl ethers.
Vinyl ethers1 have received considerable attention for their
utility in many useful organic reactions such as Diels-Alder
reaction,2 Claisen rearrangement,3 and aldehyde homologa-
tion,4 as well as for their applications in the synthesis of
polymers5 and surfactants.6 Formation of vinyl ethers through
olefination of carbonyl compounds may suffer from low
yields, the high temperature required, and the phosphine
oxide formation, which may be difficult to remove from the
desired products.7,8 Alkoxymethyltriphenylphosphorane ylides
are reportedly unstable and afford low yields of vinyl ethers
with enolizable substrates.7b,9 As part of our medicinal
chemistry efforts, we were seeking an efficient method to
prepare substituted vinyl ethers from ketones and aldehydes.
We decided to explore the possibility of using R-alkoxy
heteroaryl sulfones in a Julia olefination reaction as a
potentially new way to synthesize vinyl ethers from enoliz-
able carbonyl compounds.
The S. Julia olefination was used extensively in the last
decade for the construction of alkenes present in many natural
products (Scheme 1, eq 1).10-11 However, to our knowledge,
no such olefination has been achieved with an R-alkoxy
substituent on the sulfone moiety. In this paper, we wish to
Scheme 1. Extension of the Modified Julia Olefination
(1) (a) Maercker, A. Org. React. 1965, 14, 270. (b) See enol ethers and
vinyl ethers in ComprehensiVe Organic Synthesis; Trost B. M.; Fleming I.,
Eds; Pergamon: Oxford, 1991; Vol. 9, Cumulative Indexes.
(2) (a) Martin, J. G.; Hill, R. K. Chem. ReV. 1961, 61, 537. (b) Pindur,
U.; Gundula, L.; Otto, C. Chem. ReV. 1993, 93, 741. (c) Oppolzer, W. In
ComprehensiVe Organic Synthesis; Trost B. M., Fleming I., Eds.; Perga-
mon: Oxford, 1991; Vol. 5, Part 4.1, pp 315.
(3) (a) Wipf, P. In ComprehensiVe Organic Synthesis; Trost B. M.,
Fleming I., Eds.; Pergamon: Oxford, 1991; Vol. 5, Part 7.2, pp 827. (b)
Ziegler, F. E. Chem. ReV. 1988, 88, 1423.
(4) Levine, S. G. J. Am. Chem. Soc. 1958, 80, 6150.
(7) For Wittig olefination see: (a) Wittig, G.; Schollkopf, U. Chem. Ber.
1954, 87, 1318. (b) Wittig, G.; Bo¨ll, W.; Kru¨ck, K.-H. Chem. Ber. 1962,
95, 2514. (c) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (d)
Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. (e) Kelly, S. E.
In ComprehensiVe Organic Synthesis; Trost B. M.; Fleming I., Eds;
Pergamon: Oxford, 1991; Vol. 1, Part 3.1, pp 729.
(5) (a) Reyntjens, W. G. S.; Goethals, E. J. Polym. AdV. Technol. 2001,
12, 107-122. (b) Mu¨ller, H. W. J. Vinyl Ethers Polymers, 2nd ed.; Marcel
Dekker: New York, 2001.
(6) Jong-Mok, K.; Thomson, D. H. Dispersion Sci. Technol. 2001, 22,
399.
10.1021/ol035918k CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/11/2003

report the first examples of a modified Julia olefination using
R-alkoxyheteroaryl sulfones to yield vinyl ethers (Scheme
1, eq 2).
Table 1. Exploration of the Reaction Conditions
Syntheses of the starting sulfone substrates were ac-
complished employing a two-step process from commercially
available reagents. Three electronically and sterically dif-
ferent alkylating agents such as BOMCl, R,4-dichloroanisole,
and MEMCl were coupled first with 2-mercaptobenzo-
thiazole (BTSH) to afford the corresponding R-alkoxy-
substituted thioethers in quantitative yields (Scheme 2).12
entry
basea
solvent
additiveb
yield (%)c
(E:Z)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
KHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LDA
DME
THF
DCM
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
THF
13
16
39
21
52
87
70e
84f
61
35
86
74
75g
44
44
84:16
85:15
86:14
80:20
58:42
50:50
50:50
50:50
50:50
42:58
37:63
50:50
58:42
42:58
50:50
HMPA
Scheme 2. Synthesis of R-Alkoxysulfones 2a-c
12-C-4
DMPU
HMPA
TMEDA
a Base was added to a solution of ketone and sulfone 2a at 0 °C.
Oxidation of these thioethers proceeded smoothly with a
catalytic amount of sodium tungstate13 in the presence of
hydrogen peroxide to afford the desired R-alkoxysubstituted
sulfones 2a-c in 68-80% yields.
b Additive was added in the reaction mixture prior to base. c Isolated yields
1
after purification. d E:Z ratio determined by H NMR spectroscopy. e Per-
formed with 1.5 equiv of base. f LiHMDS (1 M)/hexanes was used.
g Reaction was run at -78 °C.
We first explored the coupling between sulfone 2a and
4′-methoxyacetophenone (Table 1). The desired vinyl ether
3 was obtained in low yield with moderate E:Z selectivity
by using KHMDS or NaHMDS (entries 1-4). Addition of
HMPA to the reaction mixture increased the yield to 52%
with a decrease in E:Z selectivity (entry 5). We were pleased
to obtain the corresponding vinyl ether 3 in 87% yields by
simply changing the base to LiHMDS (entry 6). Furthermore,
we investigated the effect of temperature (-78 to 25 °C);
reaction time;14 amount of sulfone, base, and additive;15
solvent (DMF, THF, DME, DCM, toluene); and order of
addition16 (Barbier or premetalate) on the vinyl ether
formation. The best condition was the addition of LiHMDS
to a mixture of sulfone and a carbonyl compound in THF at
0 °C.
To evaluate the scope and limitations of this method, we
performed the modified Julia olefination between sulfone 2a
and a variety of carbonyl compounds under the optimized
reaction conditions (Table 2).
Enolizable carbonyl compounds bearing electron-donating
and electron-withdrawing substituents afforded vinyl ethers
3-7 in 75-90% yields (entries 1-5).17 Trifluoroaceto-
phenone also underwent olefination in 82% yield (entry 6).
Furthermore, a variety of enolizable aliphatic ketones,
including a functionalized cyclopentanone and cyclo-
hexanone, were successfully employed in this Julia
(8) For Horner-Emmons-Wadsworth olefination, see: (a) Kluge, A.
F. Tetrahedron Lett. 1978, 19, 3629. (b) Kluge, A. F.; Cloudsdale, I. S. J.
Org. Chem. 1979, 44, 4847.
(9) See ref 4 and: Ferwanah, A.; Pressler, W.; Reichardt, C. Tetrahedron
Lett. 1973, 3979.
(16) Barbier ) base added to a mixture of sulfone and carbonyl;
premetalate ) base added to sulfone and then carbonyl added. Addition of
base using a syringe pump over 30 min did not increase the yield or the
E:Z ratio of vinyl ether 3.
(10) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.;
Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856. (c) Baudin, J. B.; Hareau,
G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336.
(11) For an excellent review on the modified Julia olefination, see:
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 23, 2563.
(12) Other heterocycles have been used. For PT, see: (a) Blakemore, P.
R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26. (b)
Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Synthesis 1996,
285. For PYR, see: Charette, A. B.; Berthelette, C.; St-Martin, D.
Tetrahedron Lett. 2001, 42, 5149 and 6619. For TBT, see: Kocienski, P.
J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365.
(13) (a) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem.
1963, 28, 1140. (b) Blacklock, T. J.; Sohar, P.; Butcher, J. W.; Lamanec,
T.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 1672.
(14) Progress of the reaction was followed using a React-IR instrument,
and all the reactions were completed between 15 and 90 min.
(15) Addition of 12-C-4, TMEDA, and DMPU failed to improve the
yields and the E:Z selectivity.
(17) Representative Procedure for the Synthesis of Vinyl Ether 3.
To a solution of sulfone 2a (498 mg, 1.56 mmol, 1.2 equiv) and
4′methoxyacetophenone (195 mg, 1.3 mmol, 1.0 equiv) in THF (15 mL,
0.085M) at 0 °C was added LiHMDS (3.1 mL, 3.1 mmol, 2.4 equiv, 1 M
in THF) dropwise over 2 min. The reaction was stirred at 0 °C for 90 min,
quenched with 20 mL of saturated NH4Cl, extracted three times with 50
mL of EtOAc, washed with 20 mL of brine, dried over MgSO4, and
concentrated. The product was purified by flash chromatography (0-20%
EtOAc/Hex) to give vinyl ether 3 (287 mg, 87% yield) as a 1:1 E:Z mixture.
1H NMR (500 MHz, acetone-d6): δ (trans) 7.42-7.34 (m, 5H), 7.23 (d, J
) 7.2 Hz, 2H), 6.84 (m, 2H), 6.66 (s, 1H), 4.94 (s, 2H), 3.74 (s, 3H), 1.96
(s, 3H); δ (cis) 7.63 (d, J ) 7.3 Hz, 2H), 7.42-7.29 (m, 5H), 6.84 (m,
2H), 6.33 (s, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 1.86 (s, 3H). 13C NMR (125
MHz, acetone-d6): δ (mixture of cis and trans) 153.03, 158.68, 143.69,
143.19, 139.06, 138.90, 133.72, 131.77, 129.39, 128.25, 128.59, 128.31,
128.23, 126.59, 114.49, 113.90, 110.88, 74.86, 74.39, 55.40, 55.33, 18.46,
12.93. HRMS (FAB) calcd for C17H19O2 255.1385, found 255.1385.
4852
Org. Lett., Vol. 5, No. 25, 2003

Table 2. Synthesis of Vinyl Ethers Using Sulfones 2a
Table 3. Steric and Electronic Effects of Sulfone 2b for the
Formation of Vinyl Ethers
a Isolated yields after purification, average of two runs. b E:Z ratio
1
determined by H NMR spectroscopy.
We then turned our attention to a phenol substituent on
the sulfone moiety in order to explore electronic and steric
effects on the olefination reaction (Table 3).
Sulfone 2b was first reacted with ethyl (2-oxocyclohexyl)
acetate to afford vinyl ether 15 in 76% yield (entry 1).
Similarly, the cyclopentanone analogue gave vinyl ether 16
in 75% yield (entry 2). Vinyl ether 17 was obtained in 83%
yield from the corresponding 4-methylbenzaldehyde (entry
3). Furthermore, an R,â-unsaturated cyclohexenone was
converted smoothly to vinyl ether 18 in 71% yield (entry
4). Finally, we explored the Julia olefination with an indolone
and were pleased to form the corresponding vinyl ether 19
in 65% yield with an E:Z ratio of 74:26 (entry 5). All
attempts to form vinyl ethers from indolones using conven-
tional methods (Wittig or Horner-Emmons-Wadsworth)
gave only low yields in our hands. The electronic and steric
nature of the sulfone 2b did not affect the yield or the
selectivity of the Julia olefination.
a Isolated yields after purification, average of two runs. b E:Z ratio
determined by H NMR spectroscopy.
1
olefination to afford vinyl ethers 10 and 11 in 70 and 71%
yields, respectively (entries 8 and 9). In our hands, conven-
tional methods using phosphonate or phosphorane reagents
gave only low yields (10-40%) for the synthesis of vinyl
ethers from cyclopentanone substrates. Finally, aliphatic and
aromatic aldehydes gave vinyl ethers 12-14 in 46-73%
yields (entries 10-12).18
It was reported that substituted vinyl ethers could be
generated in moderate yields (38-63%) from the coupling
of ketones with a MEM-phosphorane.8 Therefore, we then
decided to compare these results with our modified Julia
olefination using sulfone 2c (Table 4). Reaction of sulfone
2c with acetophenone afforded the desired vinyl ether 20 in
86% yield (entry 1). This represents an improvement over
the reported 37% using the MEM-phosphorane. Again,
(18) Purification of vinyl ethers from aldehydes was conducted with Et3N-
treated silica gel to avoid decomposition to the homologated aldehydes.
Org. Lett., Vol. 5, No. 25, 2003
4853

electron-rich or electron-poor acetophenone reacted well to
afford the desired vinyl ethers 21 and 22 in 87 and 76%
yield, respectively (entries 2-3). The reaction with aliphatic
ketone afforded product 23 in 83% yield (entry 4).
Table 4. Effect of a MEM Substituent on the Sulfone Moiety
In summary, we have demonstrated that substituted vinyl
ethers are readily available from enolizable and nonenolizable
carbonyl compounds in moderate to good yields (46-90%).
We are currently extending this methodology to include other
heterocycles on the sulfone moiety as well as attempting to
improve the E:Z selectivity of this transformation.
Acknowledgment. S.S. is grateful to NSERC for an
Undergraduate Student Research Award. We also thank Dr.
Francis Gosselin, Dr. Lianhai Li, Dr. Claudio F. Sturino, and
Dr. Zhaoyin Wang for helpful discussions and for proofread-
ing this manuscript.
Supporting Information Available: Experimental pro-
cedure and characterization data for all new compounds (1H,
13C, HRMS). This material is available free of charge via
the Internet at http://pubs.acs.org.
a Isolated yields after purification. b E:Z ratio determined by 1H NMR
spectroscopy.
OL035918K
4854
Org. Lett., Vol. 5, No. 25, 2003