A highly stereoselective synthesis of α-halo vinyl ethers and their applications in organic synthesis [3]

Full text of DOI:10.1021/ja000903s

9840
J. Am. Chem. Soc. 2000, 122, 9840-9841
Scheme 1
A Highly Stereoselective Synthesis of r-Halo Vinyl
Ethers and Their Applications in Organic Synthesis1
Wensheng Yu and Zhendong Jin*
DiVision of Medicinal and Natural Products Chemistry
College of Pharmacy, The UniVersity of Iowa
Iowa City, Iowa 52242
Scheme 2
ReceiVed March 14, 2000
ReVised Manuscript ReceiVed July 21, 2000
It is known that many reagents can undergo electrophilic
addition to acetylenic ethers.8 However, the addition of HX to
acetylenic ethers has not been systematically studied. The problem
associated with this type of reactions lies in the difficulty of
accurate addition of commercially available HX and the formation
of a mixture of stereoisomers and side products caused by excess
of HX.8c,18d In addition, R-halo vinyl ethers are quite labile and
are prone to decomposition during aqueous workup and silica
gel column chromatography. We have found that hydrogen halide
generated in situ by addition of 0.99 equiv of trimethylsilyl halide9
to a solution of 1.0 equiv of acetylenic ether10 and 0.99 equiv of
MeOH in CH2Cl2 at low temperature exclusively gave R-halo
vinyl ether in a completely regio- and stereospecific manner
(Scheme 2). The yield was nearly quantitative (excess of acid
resulted in poorer selectivity). Since MeOTMS could be evapo-
rated easily, neither work up nor column chromatography was
necessary.
Table 1 summarized the preparation of a variety of R-halo vinyl
ethers using our procedure. It should be noted that the reaction
employing in situ generation of HCl was not only faster than that
using commercially available HCl in ether (entries 4 and 5), but
also gave better stereoselectivity (entry 3). We believe that this
is due to the solvent effect. In addition, higher temperature gave
better stereoselectivity (entries 3 and 5). Although R-halo vinyl
ethers are prone to decomposition to the corresponding esters,
they can be stored in frozen benzene for a month. Because of the
simplicity of our procedure, we often prepare them before use.
We next examined the reaction between R-bromo vinyl ethers
and BuLi.11 t-BuLi reacted with R-bromo vinyl ethers very quickly
at -78 °C and afforded R-alkoxy vinyllithiums quantitatively.12
The geometry of the double bond was fully retained in all
instances. Entries 1-4 in Table 2 are several examples of the
application of this type of acyl anions for organic synthesis.
The quantitative generation of the R-alkoxy vinyllithium
enabled us to study the formation of organo copper reagents.13
Low-order,13 high-order,14 and mixed-high-order cuprates15 have
The use of acyl anion equivalents in the formation of C-C
bonds is a powerful strategy in the development of new synthetic
methods.2 Among all the acyl anion equivalents, the R-alkoxy
vinyl anions are notable for their low cost, high reactivity, and
easy deprotection of the resultant vinyl ether functionality.
R-Alkoxyvinyllithiums can be prepared by metalation of the
commercially available methyl vinyl ether or ethyl vinyl ether
using t-BuLi or super base (BuLi/KO-t-Bu).3 This methodology
was subsequently extended to cyclic systems (Scheme 1) by
Boeckman.4 In addition, metalation of 1,3-dienyl ethers, 1,3,5-
trienyl ethers, and alkoxyallenes was also realized under the
similar conditions.5
Chemical applications of more substituted acyclic R-alkoxy
vinyl anions is still in its infancy compared to other acyl anion
equivalents. The reason for the underdevelopment in this field is
that clean metalation of a variety of acyclic vinyl ethers with
â-alkyl substituents is quite difficult.6 Although (Z)-1-propenyl
2-tetrahydropyranyl ether and 2-methyl-1-propenyl 2-tetrahydro-
pyranyl ether react with s-BuLi/KO-t-Bu to give the corresponding
anions, it only works in the case of tetrahydropyranyl ether for
additional chelation and stability of such reagents.7 Metalation
of (Z)-1-ethoxy-propene required 24 h at -30 °C and gave only
70% yield of the corresponding anion. Metalation of compounds
bearing more sterically demanding alkyl groups were uniformly
unsuccessful even employing super bases.6
To solve this problem, Kocienski and co-workers developed a
procedure to prepare R-alkoxy vinylstannanes as the precursor
of R-alkoxy vinyl anions.6 However, this method suffered from
low yields due to the formation of the undesired regioisomer and
the decomposition of the products during column chromatography.
In connection with a project in our laboratories, we required
to generate â-alkyl substituted R-alkoxy vinyl cuprates. R-Alkoxy
vinyllithium was envisaged to be generated by lithium-halogen
exchange between butyllithium and R-halo vinyl ether. However,
we were surprised to find that there was no general literature
procedure for the regio- and stereoselective preparation of R-halo
vinyl ethers. Thus, our first task was to secure a new method for
the preparation of R-halo vinyl ethers.
(8) (a) Kazankova, M. A.; Satina, T. Ya.; Lun’kov, V. D.; Lutsenko, I. F.
J. Gen. Chem. USSR (Engl. Transl.) 1978, 48, 58. (b) Van Den Bosch, G.;
Bos, H. J. T.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1970, 89, 133. (c)
Arth, G. E.; Poos, G. I.; Lukes, R. M.; Robinson, F. M.; Johns, W. F.; Feurer,
M.; Sarett, L. H. J. Am. Chem. Soc. 1954, 76, 1715. (d) Herrmann, M.;
Bo¨hlendorf, B.; Irschik, H.; Reichenbach, H.; Ho¨fle, G. Angew. Chem., Int.
Ed. 1998, 37, 1253. (e) Regio- and stereoselective syn-monoaddition of gaseous
HCl to alkynyl tosylates has been reported: Stang, P. J.; Roberts, K. A. J.
Org. Chem. 1987, 52, 5213.
(9) Both TMSCl and TMSBr were distilled and stored over polyvinyl
pyridine in a flame-dried bottle. TMSI (purchased from Aldrich) was used
without further purification.
(10) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987, 52,
2919 and references therein.
(1) Synthesis via R-halo vinyl ethers 1.
(2) For recent reviews on acyl anion equivalents, see: (a) Albright, J. D.
Tetrahedron 1983, 39, 3207. (b) Otera, J. Synthesis 1988, 88, 95. (c) Seebach,
D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (d) Hase, T. A.; Koskimies,
J. K. Aldrichimica Acta 1982, 15, 35 and references therein.
(3) (a) Schollkopf, U.; Hanssle, P. Justus Liebigs Ann. Chem. 1972, 763,
208. (b) Baldwin, J. E.; Hofle, G. A.; Lever, O. W., Jr. J. Am. Chem. Soc.
1974, 96, 7125. (c) Verkruijsse, H. D.; Brandsma, L.; Schleyer, P. V. R. J.
Organomet. Chem. 1987, 332, 99.
(4) (a) Boeckman, R. K., Jr.; Bruza, K. J. Tetrahedron Lett. 1977, 4187.
(b) Boeckman, Jr, R. K.; Bruza, K. J. Tetrahedron 1981, 37, 3997. (c) Riobe,
O.; Lebouc, A.; Delaunay, J. C. R. Hebd. Seances Acad. Sci. 1977, 284, 281.
(d) Schlosser, M.; Schaub, B.; Spahie, B.; Sleiter, G. HelV. Chim. Acta 1973,
36, 2166.
(5) (a) Everhardus, R.; Grafing, R.; Brandsma, L. Recl. TraV. Chim. Pays-
Bas 1978, 97, 69. (b) Soderquist, J. A.; Hassner, A. J. Am. Chem. Soc. 1980,
102, 1577. (c) McDougal, P. G.; Rico, J. G. J. Org. Chem. 1987, 52, 4817.
(6) Casson, S.; Kocienski, P. Synthesis 1993, 1133.
(11) For references of Li-halogen exchange of 2-bromofuran, 2-bromo-
2,3-dihydrofuran, and 2-bromopyran see: (a) Knight, D. W.; Rustidge, D. C.
J. Chem. Soc., Perkin. Trans. 1 1981, 679. (b) Perri, S. T.; Moore, H. W. J.
Am. Chem. Soc. 1990, 112, 1897.
(12) (a) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210. (b)
Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847.
(13) Boeckman, R. K., Jr.; Bruza, K. J.; Baldwin, J. E.; Lever, O. W., Jr.
Chem. Commun. 1975, 519.
(7) (a) Hartmann, J.; Stahle, M.; Schlosser, M. Synthesis 1974, 888. (b)
Schlosser, M. Organometallics in Synthesis: A Manual; Wiley: Chichester,
1994; pp 110-111.
(14) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron 1984,
40, 5005 and references therein.
(15) Lipshutz, B. H. Synthesis 1987, 87, 325 and references therein.
10.1021/ja000903s CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/26/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 40, 2000 9841
Table 1. A Stereoselective Synthesis of R-Halo Vinyl Ethers
Table 2. Application of R-Halo Vinyl Ethers in Organic Synthesis
a R3) (-)-menthol, R4) [(1S)-endo]-(-)-Borneol. b All reactions
were run in CH2Cl2. c The geometry of double bonds were determined
by NOESY spectra. d All yields are isolated yields. The Z/E ratios were
measured by integration of well-resolved signals in the 1H NMR.
Method A: TMSBr (0.99 equiv), MeOH (0.99 equiv), -40 °C, 10 min;
Method B: TMSI (0.99 equiv), MeOH (0.99 equiv), -78 °C, 10 min;
Method C: TMSCl (0.99 equiv), MeOH (0.99 equiv).
been successfully prepared from R-alkoxy vinyllithium, and their
conjugate additions to R,â-unsaturated ketones were examined
(Table 2, entries 5-7). All reactions afforded excellent yields
and retention of the stereochemistry of the double bond.
a R3) (-)-menthol, R4) [(1S)-endo]-(-)-Borneol. b The geometry
of double bonds were determined by NOE or NOESY spectra. c All
yields are isolated yields. Method A: (1) t-BuLi (2 equiv., ether, -78
°C. (2) CuCN, LiCl (2 equiv), THF, -40 °C, 30 min. (3) 2-cyclohexen-
1-one, -78 °C, 5 min. Method B: (1) t-BuLi, ether, -78 °C. (2) CuCN,
MeLi, THF, -40 °C, 30 min. (3) 2-cyclohexen-1-one, -78 °C, 5 min.
R-Halo vinyl ethers can undergo many important transforma-
tions catalyzed by transition metals such as palladium and nickel.16
In the presence of a catalytic amount of palladium catalyst,
compound 8-Br underwent Stille coupling17 with tributylvinyltin
to provide functionalized 1,3-diene 22 which could not be easily
access Via known procedures, and can be used in asymmetric
Diels-Alder reactions (Table 2, entry 8). It was interesting to
observe that the geometry of the double bond was cleanly inverted.
R-Bromo vinyl ether 10-Br could also undergo Sonogashira
coupling18 to give enyne 23 in excellent yield with complete
retention of the geometry of the double bond (Table 2, entry 9).
Palladium(0)-catalyzed carbonylation19 between R-bromo vinyl
ether 12-Br and CO in the presence of methanol gave R-methoxy-
R,â-unsaturated ester 24 in nearly quantitative yield (Table 2,
entry 10). In this case, the geometry of the double bond was
stereospecifically inverted. R-Halo vinyl ethers also couple with
Grignard reagents catalyzed by an organonickel catalyst. Com-
pound 12-Br reacted with EtMgBr in the presence of a catalytic
amount of NiCl2dppp2 to give 25 in 71% after hydrolysis the enol
ether (Table 2, entry 11). The same reaction also worked with
PhMgBr to afford 26 with retention of the geometry of the double
bond (Table 2, entry 12).20
In summary, we have successfully developed a highly regio-
and stereoselective method for the synthesis of R-halo vinyl ethers.
We have demonstrated that R-halo vinyl ethers can serve as
excellent latent acyl anions for carbon-carbon bond formation.
The quantitative generation of R-alkoxyvinyllithium enables the
formation of a variety of cuprates that were not accessible via
the previous known literature procedures. Furthermore, we have
also discovered that R-halo vinyl ethers are highly versatile
substrates for transition metal catalyzed cross-coupling reactions.
Currently, we are studying the asymmetric reactions employing
the substrates bearing a chiral R1 group as chiral auxiliary.
Application of these methodologies to the total synthesis of natural
products is underway, and will be reported in due course.
Acknowledgment. This work was financially supported by a Research
Project Grant RPG-00-030-01-CDD from the American Cancer Society,
the Central Investment Fund for Research Enhancement (CIFRE) of the
University of Iowa, and a fellowship from The Center for Biocatalysis
and Bioprocessing at The University of Iowa (to W.Y.). Thanks are due
to Mei Su for performing experiment 10 (entry 10, Table 2).
(16) Ni(acac)2 was in the coupling reaction between 1-bromo-1-ethoxy-
ethene and a Grignard reagent, Glazunova, E. Yu.; Lutsenko, S. V.; Efimova,
I. V.; Trostyanskaya, I. G.; Kazankova, M. A.; Beletskaya, I. P. Russian J.
Org. Chem. 1969, 34, 4, 1104. In addition, both nickel and palladium catalysts
have been used in the preparation of dialkylaminovinyl-phosphonates from
1-bromo-1-ethoxy-ethene, Kazankova, M. A.; Trostyanskaya, I. G.; Lutsenko,
S. V.; Beletskaya, I. P. Tetrahedron Lett, 1999, 40, 569; Kazankova, M. A.;
Chirkov, E. A.; Kochetkov, A. N.; Efimova, I. V.; Beletskaya, I. P. Tetrahedron
Lett. 1999, 40, 573.
(17) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
(18) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467
(19) Tour, J. M.; Negishi, E.-I. J. Am. Chem. Soc. 1985, 107, 8289.
(20) Tamao, K.; Zembayashi, M.; Kumada, M. Chem. Lett. 1976, 76, 1237.
Supporting Information Available: Experimental procedures and
spectroscopic data for all the compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA000903S