VOLUME 21 NUMBER 2
`VOLUME 21 NUMBER 2
`
`OF
`OF
`
`ACCOUNTS
`ACCOUNTS
`CHEMlf:AL
`CHEMICAL
`RESEARCH
`RESEARCH
`
`FEBRUARY,1988
`FEBRUARY,1988
`
`Registered in U.S. Patent and Trademark Office; Copyright 1988 by the American Chemical Society
`Registered in U.S. Patent and Trademark Office; Copyright 1988 by the American Chemical Society
`
`Olefin Synthesis via Organometallic Coupling Reactions of
`Olefin Synthesis via Organometallic Coupling Reactions of
`Enol Triflates
`Enol Triflates
`
`WILLIAM J. SCOTT*t and JOHN E. McMURRY*~
`WILLIAM J. SCOTT*t and JOHN E. McMURRy*t
`
`Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, and Department of Chemistry, Cornell University,
`Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, and Department of Chemistry, Cornell University,
`Ithaca, New York 14853
`Ithaca, New York 14853
`
`Received August 26, 1987 (Revised Manuscript Received October 27, 1987)
`Received August 26, 1987 (Revised Manuscript Received October 27, 1987)
`
`The carbonyl group has been called the most versatile
`The carbonyl group has been called the most versatile
`functionality available to the synthetic organic chemist.
`functionality available to the synthetic organic chemist.
`One major reason is the ability to convert a carbonyl
`One major reason is the ability to convert a carbonyl
`compound into the corresponding olefin, a result nor(cid:173)
`compound into the corresponding olefin, a result nor(cid:173)
`mally achieved by addition of a nucleophile followed
`mally achieved by addition of a nucleophile followed
`by dehydration of the intermediate alcohol. Neither
`by dehydration of the intermediate alcohol. Neither
`of the two steps is necessarily straightforward, however.
`of the two steps is necessarily straightforward, however.
`For example, sterically hindered ketones are often inert
`For example, sterically hindered ketones are often inert
`to nucleophilic addition. Similarly, sterically hindered
`to nucleophilic addition. Similarly, sterically hindered
`nucleophiles either will not add to, or can act as re(cid:173)
`nucleophiles either will not add to, or can act as re(cid:173)
`ducing agents toward, ketones. Even more troublesome
`ducing agents toward, ketones. Even more troublesome
`is the fact that dehydration of the intermediate alcohol
`is the fact that dehydration of the intermediate alcohol
`is rarely regioselective. A mixture of olefin products
`is rarely regioselective. A mixture of olefin products
`often results from alcohol dehydration, lessening the
`often results from alcohol dehydration, lessening the
`value of the procedure for synthesis. Because of these
`value of the procedure for synthesis. Because of these
`problems, much research has been directed at the de(cid:173)
`problems, much research has been directed at the de(cid:173)
`velopment of new methods for the regioselective syn(cid:173)
`velopment of new methods for the regioselective syn(cid:173)
`thesis of olefins from ketones.
`thesis of olefins from ketones.
`An attractive alternative to the nucleophilic addi(cid:173)
`An attractive alternative to the nucleophilic addi(cid:173)
`tion/ dehydration route would be to take advantage of
`tion/ dehydration route would be to take advantage of
`known methods l for regioselectively generating an
`known methods l for regioselectively generating an
`enolate ion. Thus, formation and trapping of an enolate
`enolate ion. Thus, formation and trapping of an enolate
`ion, followed by substitution of the enol derivative with
`ion, followed by substitution of the enol derivative with
`a nucleophile, would lead to regiospecific formation of
`a nucleophile, would lead to regiospecific formation of
`an olefin.
`an olefin.
`
`6-[6]
`6-[6]
`
`The key step, displacement of a leaving group from
`The key step, displacement of a leaving group from
`an enol derivative, requires a nucleophilic substitution
`an enol derivative, requires a nucleophilic substitution
`reaction at an Sp2 center. Although similar substitution
`reaction at an Sp2 center. Although similar substitution
`reactions at the Sp2 centers of vinylic halides have been
`reactions at the Sp2 centers of vinylic halides have been
`known since 1968,2 it was not until 1976 that Blaszczak
`known since 1968,2 it was not until 1976 that Blaszczak
`demonstrated the replacement of an enolate oxygen by
`demonstrated the replacement of an enolate oxygen by
`reaction of an enol diphenyl phosphate with lithium
`reaction of an enol diphenyl phosphate with lithium
`dibutylcopper. 3 Unfortunately, use of the less reactive
`dibutylcopper. 3 Unfortunately, use of the less reactive
`lithium dimethylcopper led to low product yields.
`lithium dimethylcopper led to low product yields.
`Since sulfonates are often used as leaving groups in
`Since sulfonates are often used as leaving groups in
`nucleophilic substitution reactions, it occurred to us
`nucleophilic substitution reactions, it occurred to us
`that trapping of an enolate ion as its enol sulfonate,
`that trapping of an enolate ion as its enol sulfonate,
`followed by displacement, might constitute a general
`followed by displacement, might constitute a general
`Elcheme for olefin synthesis. Enol p-toluenesulfonates
`Elcheme for olefin synthesis. Enol p-toluenesulfonates
`(tosylates) are not easily prepared, but the corre(cid:173)
`(tosylates) are not easily prepared, but the corre(cid:173)
`sponding enol trifluoromethanesulfonates (triflates) are
`sponding enol trifluoromethanesulfonates (triflates) are
`well-known and have been much studied as a source of
`well-known and have been much studied as a source of
`vinylic cations. 4 Thus, the conversion of ketones into
`vinylic cations. 4 Thus, the conversion of ketones into
`olefins via the corresponding enol triflates was inves(cid:173)
`olefins via the corresponding enol triflates was inves(cid:173)
`tigated.
`tigated.
`
`William J. Scott received a B.S. degree from the University of Rochester
`William J. Scott received a B.S. degree from the University of Rochester
`in 1973, an M.S. from Wright State University In 1978, and the Ph.D. (with
`in 1973, an M.S. from Wright State University In 1978, and the Ph.D. (with
`John McMurry) from Cornell University In 1983. Following postdoct9l'al work
`John McMurry) from Cornell University In 1983. Following postdoct9l'al work
`with John Stille at Colorado State University, he Joined the faculty at The
`with John Stille at Colorado State University, he Joined the faculty at The
`University of Iowa, where he Is presently Assistant Professor of Chemistry.
`University of Iowa, where he Is presently Assistant Professor of Chemistry.
`His research interests Include natura!-produc1s synthesis, the use of transition
`His research interests Include natural-produc1s synthesis, the use of transition
`metals In synthetic methodology, and polymer synthesis.
`metals In synthetic methodology, and polymer synthesis.
`A short biography of John E. McMurry appeared previously in Ace.
`A short biography of John E. McMurry appeared previously in Acc.
`Chern. Res. 1983, 16, 405.
`Chern. Res. 1983, 16, 405.
`0001-4842/88/0121-0047$01.50/0
`0001-4842/88/0121-0047$01.50/0
`
`tThe University of Iowa.
`tThe University of Iowa.
`I Cornell University.
`I Cornell University.
`(1) d'Angelo, J. Tetrahedron 1976,32,2979-2990.
`(1) d'Angelo, J. Tetrahedron 1976,32,2979-2990.
`(2) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968,90,5615-5616.
`(2) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968,90,5615-5616.
`(3) Blaszczak, L.; Winkler, J.; O'Kuhn, S. Tetrahedron Lett. 1976, 17,
`(3) Blaszczak, L.; Winkler, J.; O'Kuhn, S. Tetrahedron Lett. 1976, 17,
`4405-4408.
`4405-4408.
`(4) Stang, P. J.; Rappoport, Z.; Hanack, M. C.; Subramanian, L. R.
`(4) Stang, P. J.; Rappoport, Z.; Hanack, M. C.; Subramanian, L. R.
`Vinyl Cations; Academic: New York, 1979.
`Vinyl Cations; Academic: New York, 1979.
`© 1988 American Chemical Society
`© 1988 American Chemical Society
`
`NPC02230599
`
`NOVARTIS EXHIBIT 2127
`Par v Novartis, IPR 2016-00084
`Page 1 of 8
`
`

`
`entry
`entry
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`0°
`0°
`ib
`ib
`if:u~I."
`if:u~I."
`ib
`ib
`
`A
`A
`°
`°
`iJ
`iJ
`°
`°
`
`O°T!
`O°T!
`. £b
`,)cb
`1&0T!
`1&0T!
`
`TlO
`
`.....-:
`
`b,T!2HPh
`b,T!2HPh
`
`•. LDA
`•. LDA
`b TI.NPtl
`b TI.NPtl
`
`•. MeLI
`•. MeLI
`b TI~NPh
`b TI~NPh
`
`I. LI/NH~
`I. LI/NH~
`b,TI 2NPh
`b,TI 2NPh
`
`,,)j)
`'T)J)
`•. i!1!1CULI .,ep
`•. i!1!1CULI 'W
`TlO
`TlO
`OT!
`OT!
`•. {M'~2CuL! . ~
`•. {M'~2CuL! ~
`OTi
`OTi
`{)
`.L-Sllletrld. {)
`
`b Tl2NPh
`b Tl2NPh
`
`b.Tl2NPh
`b.Tl 2NPh
`
`b.Tl 2NPh
`b.Tl 2NPh
`
`ref
`ref
`
`11
`11
`
`11
`11
`
`11
`11
`
`11
`11
`
`11
`11
`
`11
`11
`
`14
`14
`
`65
`65
`
`97
`97
`
`65
`65
`
`65
`65
`
`65
`65
`
`93
`93
`
`48
`48
`
`6-[6J
`6-[6]
`
`Synthesis of Enol Triflates
`Synthesis of Enol Triflates
`The first step of the projected transformation in(cid:173)
`The first step of the projected transformation in(cid:173)
`volves conversion of a ketone into its enol triflate, a
`volves conversion of a ketone into its enol triflate, a
`reaction that has been accomplished in two general
`reaction that has been accomplished in two general
`ways. The most common method is the reaction of a
`ways. The most common method is the reaction of a
`ketone with trifluoromethanesulfonic anhydride (triflic
`ketone with trifluoromethanesulfonic anhydride (triflic
`anhydride) in the presence of a mild nonnucleophilic
`anhydride) in the presence of a mild nonnucleophilic
`base.5 The enol triflate is thought to be formed by
`base.5 The enol triflate is thought to be formed by
`initial reaction of triflic anhydride with the ketone,
`initial reaction of triflic anhydride with the ketone,
`followed by loss of a proton, and the reaction normally
`followed by loss of a proton, and the reaction normally
`leads to production of the more thermodynamically
`leads to production of the more thermodynamically
`stable product. For example, treatment of 2-methyl(cid:173)
`stable product. For example, treatment of 2-methyl(cid:173)
`cydohexanone (4) with triflic anhydride and base gives
`cyclohexanone (4) with triflic anhydride and base gives
`2-methyl-1-cyclohexenyl triflate (5) as the major prod(cid:173)
`2-methyl-1-cyclohexenyl triflate (5) as the major prod(cid:173)
`uct.6
`uct.6
`The second general method of enol triflate synthesis
`The second general method of enol triflate synthesis
`is by conversion of a ketone into its enolate ion followed
`is by conversion of a ketone into its enolate ion followed
`by trapping. Although stable enolate ions derived from
`by trapping. Although stable enolate ions derived from
`highly acidic ketones can be trapped with triflic anhy(cid:173)
`highly acidic ketones can be trapped with triflic anhy(cid:173)
`dride in good yield,7 the more reactive enolates derived
`dride in good yield,7 the more reactive enolates derived
`from monoketones tend to C-sulfonate, affording a-keto
`from monoketones tend to C-sulfonate, affording a-keto
`sulfone products.8
`sulfone products.8
`In order to find a more general method of enolate
`In order to find a more general method of enolate
`trapping, we initiated a comparative study of a number
`trapping, we initiated a comparative study of a number
`of potential sulfonating agents. Using as our test system
`of potential sulfonating agents. Using as our test system
`the enolate ion prepared by deprotonation of 4-tert(cid:173)
`the enolate ion prepared by deprotonation of 4-tert(cid:173)
`butylcyclohexanone (1) with lithium diisopropylamide
`butylcyclohexanone (1) with lithium diisopropylamide
`(LDA), we found that reaction with triflic anhydride
`(LDA), we found that reaction with triflic anhydride
`failed to yield any of the desired product 2, but that
`failed to yield any of the desired product 2, but that
`reaction with (trifluoromethanesulfonyl)imidazole9
`reaction with (trifluoromethanesulfonyl)imidazole9
`provided 2 in 48% yield and reaction with N-phenyl(cid:173)
`provided 2 in 48% yield and reaction with N-phenyl(cid:173)
`triflimide10 (3) gave 2 in 82% isolated yield,u
`triflimide10 (3) gave 2 in 82% isolated yield,u
`
`One of the most important features of the enolate(cid:173)
`One of the most important features of the enolate(cid:173)
`trapping method is its ability to define the regiochem(cid:173)
`trapping method is its ability to define the regiochem(cid:173)
`istry of the enol triflate, as exemplified by the selective
`istry of the enol triflate, as exemplified by the selective
`conversion of 2-methylcyclohexanone (4) into either its
`conversion of 2-methylcyclohexanone (4) into either its
`thermodynamic (5) or kinetic (6) enol triflate by choice
`thermodynamic (5) or kinetic (6) enol triflate by choice
`of reaction conditions. Treatment of 4 with LDA,
`of reaction conditions. Treatment of 4 with LDA,
`followed by trapping, gives enol triflates 6 and 5 in a
`followed by trapping, gives enol triflates 6 and 5 in a
`19:1 ratio,ll whereas treatment with bromomagnesium
`19:1 ratio,ll whereas treatment with bromomagnesium
`diisopropylamide12 followed by trapping gives the two
`diisopropylamide12 followed by trapping gives the two
`products in a 1:19 ratio. 13 By contrast, treatment of
`products in a 1:19 ratio. 13 By contrast, treatment of
`
`(5) Stang, P. J.; Hanack, M. c.; Subramanian, L. R. Synthesis 1982,
`(5) Stang, P. J.; Hanack, M. c.; Subramanian, L. R. Synthesis 1982,
`85-126.
`85-126.
`(6) Collins, C. J.; Garcia-Martinez, A.; Martinez-Alvarez, R.; Arranz(cid:173)
`(6) Collins, C. J.; Garcia-Martinez, A.; Martinez-Alvarez, R.; Arranz(cid:173)
`Aguirre, J. Chem. Ber. 1984,117,2815-2824.
`Aguirre, J. Chem. Ber. 1984,117,2815-2824.
`(7) Stang, P. J.; Treptow, W. L. J. Med. Chem. 1981, 24, 468-472.
`(7) Stang, P. J.; Treptow, W. L. J. Med. Chem. 1981, 24, 468-472.
`(8) Subramanian, L. R.; Bentz, H.; Hanack, M. C. Synthesis 1973,
`(8) Subramanian, L. R.; Bentz, H.; Hanack, M. C. Synthesis 1973,
`293-294.
`293-294.
`(9) Effenberger, F.; Mack, K. E. Tetrahedron Lett. 1970, 11,
`(9) Effenberger, F.; Mack, K. E. Tetrahedron Lett. 1970, 11,
`3947-3948.
`3947-3948.
`(10) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14,
`(10) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14,
`4607-4610.
`4607-4610.
`(11) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983,24,979-982.
`(11) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983,24,979-982.
`(12) Krafft, M. E.; Holton, R. E. Tetrahedron Lett. 1983, 24,
`(12) Krafft, M. E.; Holton, R. E. Tetrahedron Lett. 1983, 24,
`1345-1348.
`1345-1348.
`(13) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986,108,3033-3040.
`(13) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986,108,3033-3040.
`
`Scott and McMurry
`Scott and McMurry
`
`Accounts of Chemical Research
`Accounts of Chemical Research
`
`Table I
`Table I
`Preparation of Enol Trinates from Ketones
`Preparation of Enol Trinates from Ketones
`yield, %
`yield, %
`80
`80
`
`4 with triflic anhydride and sodium carbonate gives 6
`4 with triflic anhydride and sodium carbonate gives 6
`and 5 in a 1:3 ratio.6
`and 5 in a 1:3 ratio.6
`
`a. ba.e
`a. ba.e
`
`N-Phenyltriflimide was also found to be effective for
`N-Phenyltriflimide was also found to be effective for
`trapping a variety of enolates generated in a number
`trapping a variety of enolates generated in a number
`of different ways (Table 1).11,14 Enolate ions prepared
`of different ways (Table 1).11,14 Enolate ions prepared
`by treatment of silyl enol ethers with methyllithium,
`by treatment of silyl enol ethers with methyllithium,
`by addition of diorganocuprate reagents to conjugated
`by addition of diorganocuprate reagents to conjugated
`ketones, and by reduction of conjugated ketones with
`ketones, and by reduction of conjugated ketones with
`either sodium in liquid ammonia or with L-Selectride,
`either sodium in liquid ammonia or with L-Selectride,
`can all be converted into the corresponding enol triflate
`can all be converted into the corresponding enol triflate
`by reaction with N-phenyltriflimide.
`by reaction with N-phenyltriflimide.
`Finally, enol triflates can be equilibrated under an(cid:173)
`Finally, enol triflates can be equilibrated under an(cid:173)
`hydrous acidic conditions in a manner similar to that
`hydrous acidic conditions in a manner similar to that
`used for silyl enol ethers.15,16 Thus, treatment of 6-
`used for silyl enol ethers.15,16 Thus, treatment of 6-
`methyl-1-cyclohexenyl triflate (6) with a catalytic
`methyl-1-cyclohexenyl triflate (6) with a catalytic
`amount of anhydrous triflic acid yields the thermody(cid:173)
`amount of anhydrous triflic acid yields the thermody(cid:173)
`namically more stable 2-methyl-1-cyclohexenyl triflate
`namically more stable 2-methyl-1-cyclohexenyl triflate
`(5).17,18
`(5).17,18
`
`OTI (y
`OTI (y
`
`TlOH
`TlOH
`
`•
`
`&
`&
`
`Coupling Reactions of Enol Triflates with
`Coupling Reactions of Enol Triflates with
`Diorganocuprates
`Diorganocuprates
`With efficient methods for the regioselective prepa(cid:173)
`With efficient methods for the regioselective prepa(cid:173)
`ration of enol triflates available, we turned our attention
`ration of enol triflates available, we turned our attention
`to reactions of the triflates with organometallic reagents.
`to reactions of the triflates with organometallic reagents.
`We found in short order that, although alkyllithiums
`We found in short order that, although alkyllithiums
`effect sulfur-oxygen bond cleavage with enol triflates,
`effect sulfur-oxygen bond cleavage with enol triflates,
`diorganocuprates effect carbon-oxygen cleavage and
`diorganocuprates effect carbon-oxygen cleavage and
`
`(14) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335-337.
`(14) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335-337.
`(15) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968,90,4262-4264.
`(15) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968,90,4262-4264.
`(16) House, H. 0.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org.
`(16) House, H. 0.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org.
`Chem. 1969, 34, 2324-2336.
`Chem. 1969, 34, 2324-2336.
`(17) Scott, W. J., unpublished results.
`(17) Scott, W. J., unpublished results.
`(18) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1980, 21,
`(18) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1980, 21,
`4313-4316.
`4313-4316.
`
`NPC02230600
`
`NOVARTIS EXHIBIT 2127
`Par v Novartis, IPR 2016-00084
`Page 2 of 8
`
`

`
`Vol. 21, 1988
`Vol. 21, 1988
`
`Coupling Reactions of Enol Triflates
`Coupling Reactions of Enol Triflates
`
`49
`49
`
`Table II
`Table II
`Coupling Reactions of Enol Trifiates with Organocopper
`Coupling Reactions of Enol Trifiates with Organocopper
`Reagents
`Reagents
`organocopper
`organocopper
`reagent
`reagent
`
`product
`product
`
`isolated
`isolated
`ref
`yield, %
`yield, % ref
`19
`19
`75
`75
`
`Me2CuLi N Me
`Me2CuLi N Me
`( -?},cuM9a• ~ 62
`( -?},cuM9a• ~ 62
`( t>t, cuMga. ff 68
`( t>t, cuMga. ff 68
`DPh 75
`DPh 75
`
`entry
`entry
`
`triflate
`triflate
`
`1 Non
`Non
`
`!
`!
`
`2
`2
`
`3
`3
`
`4
`4
`
`5
`5
`
`6
`6
`
`au
`au
`TlO
`TIO
`
`SU
`SU
`
`8u
`8u
`
`~
`~
`7 Tfo'oo
`7 Tfo'oo
`
`19
`19
`
`19
`19
`
`19
`19
`
`19
`19
`
`19
`19
`
`19
`19
`
`Ph2CuLi
`Ph2CuLi
`
`TIO.>==,/u
`TIO.>==,/u
`
`Me2CuLi
`Me2CuLi
`
`Me
`Me
`
`Bu
`Bu
`
`Me2CuLi
`Me2CuLi
`
`auld
`auld
`M.
`M.
`
`~
`~
`
`au
`au
`
`au
`au
`
`95
`95
`
`95
`95
`
`(~cuMga. ~ 71
`(~cuMga. ~ 71
`
`convert the triflate into the corresponding 01efin.19
`convert the triflate into the corresponding 0lefin.19
`Thus, our initial hope of devising a regioselective olerm
`Thus, our initial hope of devising a regioselective olefm
`synthesis complementary to the standard nucleophilic
`synthesis complementary to the standard nucleophilic
`addition/ dehydration scheme had been realized.
`addition/ dehydration scheme had been realized.
`
`•
`
`~
`
`As shown in Table II, yields of olefin products are
`As shown in Table II, yields of olefin products are
`high for a wide variety of diorganocuprates, including
`high for a wide variety of diorganocuprates, including
`n-butyl, phenyl, vinyl, and cyclopropyl. Particularly
`n-butyl, phenyl, vinyl, and cyclopropyl. Particularly
`noteworthy is the fact that yields remain high even
`noteworthy is the fact that yields remain high even
`when dimethylcuprate is used, in contrast to the result
`when dimethylcuprate is used, in contrast to the result
`previously observed for reactions of enol diphenyl
`previously observed for reactions of enol diphenyl
`phosphates.3
`phosphates.3
`The stereospecificity of the coupling reactions was
`The stereospecificity of the coupling reactions was
`demonstrated by treatment of pure (Z)-5-((trifluoro(cid:173)
`demonstrated by treatment of pure (Z)-5-((trifluoro(cid:173)
`methanesulfonyl)oxy)-5-decene with lithium di(cid:173)
`methanesulfonyl)oxy)-5-decene with lithium di(cid:173)
`methylcopper to give (E)-5-methyl-5-decene of greater
`methylcopper to give (E)-5-methyl-5-decene of greater
`than 99% stereochemical purity (Table II, entry 5).
`than 99% stereochemical purity (Table II, entry 5).
`Similarly, reaction of (E)-5-((trifluoromethane(cid:173)
`Similarly, reaction of (E)-5-((trifluoromethane(cid:173)
`sulfonyl)oxy)-5-decene gave (Z)-5-methyl-5-decene of
`sulfonyl)oxy)-5-decene gave (Z)-5-methyl-5-decene of
`greater than 99% purity. Although a preliminary result
`greater than 99% purity. Although a preliminary result
`suggested that a small amount of isomerization occurred
`suggested that a small amount of isomerization occurred
`during the coupling reaction, subsequent analysis has
`during the coupling reaction, subsequent analysis has
`indicated this not to the case.20
`indicated this not to the case.20
`Palladium-Catalyzed Coupling Reactions of
`Palladium-Catalyzed Coupling Reactions of
`Enol Trifiates with Organostannanes
`Enol Trifiates with Organostannanes
`Transition metals have recently been found to cata(cid:173)
`Transition metals have recently been found to cata(cid:173)
`lyze the coupling reactions of a number of enol deriv(cid:173)
`lyze the coupling reactions of a number of enol deriv(cid:173)
`atives with carbon nucleophiles.21 For example, zero-
`atives with carbon nucleophiles.21 For example, zero-
`(19) McMurry, J. E.; Scott, W. J. Tetrahedron Lett 1980, 21,
`(19) McMurry, J. E.; Scott, W. J. Tetrahedron Lett 1980, 21,
`4313-4316.
`4313-4316.
`(20) Scott, W. J. Ph.D. Dissertation, Cornell University, Ithaca, NY,
`(20) Scott, W. J. Ph.D. Dissertation, Cornell University, Ithaca, NY,
`1983.
`1983.
`(21) (a) Collman, J. P.; Hegedus, L. S.; Norton; J. R.; Finke, R. G.
`(21) (a) Collman, J. P.; Hegedus, L. S.; Norton; J. R.; Finke, R. G.
`Principles and Applications of Organotransition Metal Chemistry;
`Principles and Applications of Organotransition Metal Chemistry;
`University Science Books: Mill Valley, CA, 1987. (b) Colquhoun, H. M.;
`University Science Books: Mill Valley, CA, 1987. (b) Colquhoun, H. M.;
`Holton, J.; Thompson, D. J.; Twigg, M. V. New Pathways for Organic
`Holton, J.; Thompson, D. J.; Twigg, M. V. New Pathways for Organic
`Synthesis. Practical Applications of Transition Metals; Plenum: New
`Synthesis. Practical Applications of Transition Metals; Plenum: New
`York,1984. (c) Yamamoto, A. Organotransition Metal Chemistry; Wiley:
`York,1984. (c) Yamamoto, A. Organotransition Metal Chemistry; Wiley:
`New York, 1986. (d) Heck, R. F. Palladium Reagents in Organic Syn(cid:173)
`New York, 1986. (d) Heck, R. F. Palladium Reagents in Organic Syn(cid:173)
`thesis; Academic: London, 1985.
`thesis; Academic: London, 1985.
`
`Scheme I
`Scheme I
`An Intramolecular Enol Trifiate/Organostannane Coupling
`An Intramolecular Enol Trifiate/Organoatannane Coupling
`Route to Dolastane Sesquiterpenes
`Route to Dolastane Seaquiterpenea
`
`~I'
`
`a.LDA
`a.LDA
`b.TI,NPh
`b.TI,MPh
`c. Pd (PPh3 ).
`
`~
`
`L
`
`~
`
`• •
`
`~
`
`valent nickel complexes catalyze the coupling of Grig(cid:173)
`valent nickel complexes catalyze the coupling of Grig(cid:173)
`nard reagents with methyl enol ethers22,23 and silyl enol
`nard reagents with methyl enol ethers22,23 and silyl enol
`ethers24 to yield alkene products. Similarly, palladium
`ethers24 to yield alkene products. Similarly, palladium
`complexes have been shown to catalyze the coupling of
`complexes have been shown to catalyze the coupling of
`enol phosphates with alanes.25
`enol phosphates with alanes.25
`Enol triflates are also capable of undergoing transi(cid:173)
`Enol triflates are also capable of undergoing transi(cid:173)
`tion-metal-catalyzed coupling with nucleophiles. Thus,
`tion-metal-catalyzed coupling with nucleophiles. Thus,
`treatment of 4-tert-butyl-l-cyc1ohexenyl triflate (3) with
`treatment of 4-tert-butyl-l-cyc1ohexenyl triflate (3) with
`an organostannane26 in the presence of 2 mol % of
`an organostannane26 in the presence of 2 mol % of
`tetrakis(triphenylphosphine)palladium(O) and an excess
`tetrakis(triphenylphosphine)palladium(O) and an excess
`of Liel gives the coupled alkene product in high
`of Liel gives the coupled alkene product in high
`yields. 13,27 The coupling can be carried out in most
`yields. 13,27 The coupling can be carried out in most
`polar solvents except for chloroform. Even some water
`polar solvents except for chloroform. Even some water
`or air can be tolerated, but the reaction will not take
`or air can be tolerated, but the reaction will not take
`place unless added salt is present. The reaction is
`place unless added salt is present. The reaction is
`general for a variety of organostannanes, including alkyl,
`general for a variety of organostannanes, including alkyl,
`vinyl, acetylenic, and allyl (Table III). Aryl- and
`vinyl, acetylenic, and allyl (Table III). Aryl- and
`benzylstannanes yield only traces of coupled products,
`benzylstannanes yield only traces of coupled products,
`however.
`however.
`One of the more important results shown in Table III
`One of the more important results shown in Table III
`is that palladium-catalyzed coupling of an enol triflate
`is that palladium-catalyzed coupling of an enol triflate
`with hexamethyldistannane gives the corresponding
`with hexamethyldistannane gives the corresponding
`vinylic stannane in good yield. Such regioselectively
`vinylic stannane in good yield. Such regioselectively
`formed vinylic stannanes can then be further converted
`formed vinylic stannanes can then be further converted
`into vinylic iodides by reaction with 1228 or into vinylic
`into vinylic iodides by reaction with 12
`28 or into vinylic
`lithium reagents by reaction with methyllithium.29
`lithium reagents by reaction with methyllithium.29
`Surprisingly, however, attempts to form vinylic stan(cid:173)
`Surprisingly, however, attempts to form vinylic stan(cid:173)
`nanes by palladium-catalyzed coupling of enol triflates
`nanes by palladium-catalyzed coupling of enol triflates
`with hexabutyldistannane,13,29 or diethyl(trimethyl(cid:173)
`with hexabutyldistannane,13,29 or diethyl(trimethyl(cid:173)
`stannyl)aluminum were unsuccessful.3o
`stannyl)aluminum were unsuccessful.3o
`Both the organocopper reaction and the palladium(cid:173)
`Both the organocopper reaction and the palladium(cid:173)
`catalyzed coupling of enol triflates with organo(cid:173)
`catalyzed coupling of enol triflates with organo(cid:173)
`stannanes are compatible with the presence of severe
`stannanes are compatible with the presence of severe
`steric hindrance about both the electrophilic and the
`steric hindrance about both the electrophilic and the
`nUcleophilic sites. Hindrance in the enol triflate affects
`nUcleophilic sites. Hindrance in the enol triflate affects
`
`(22) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc.
`(22) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc.
`1979,101, 2246-2247.
`1979,101, 2246-2247.
`(23) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org.
`(23) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org.
`Chem. 1984,49,4894-4899.
`Chem. 1984,49,4894-4899.
`(24) HaY!l8hi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett. 1980,
`(24) HaY!l8hi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett. 1980,
`21, 3915-3918.
`21, 3915-3918.
`(25) Takai, K; Sato, M.; Oshima, K; Nozaki, M. Bull. Chem. Soc. Jpn.
`(25) Takai, K; Sato, M.; Oshima, K; Nozaki, M. Bull. Chem. Soc. Jpn.
`1984,57, 106-115.
`1984,57, 106-115.
`(26) For a recent review of the palladium-catalyzed coupling reactions
`(26) For a recent review of the palladium-catalyzed coupling reactions
`of electrophiles with organostannanes, see: Stille, J. K Angew. Chem.,
`of electrophiles with organostannanes, see: Stille, J. K Angew. Chem.,
`Int. Ed. Engl. 1986, 25, 508-524.
`Int. Ed. Engl. 1986, 25, 508-524.
`(27) Scott, W. J.; Crisp, G. T.; Stille, J. K J. Am. Chem. Soc. 1984,
`(27) Scott, W. J.; Crisp, G. T.; Stille, J. K J. Am. Chem. Soc. 1984,
`106,4630-4632.
`106,4630-4632.
`(28) Kashin, A. N.; Beletskaya, 1. P.; Malkasyan, A. T.; Reutov, O. A.
`(28) Kashin, A. N.; Beletskaya, 1. P.; Malkasyan, A. T.; Reutov, O. A.
`J. Org. Chern. USSR (Eng/. Transl.) 1974, 10,2257-2261.
`J. Org. Chern. USSR (Eng/. Transl.) 1974, 10,2257-2261.
`(29) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K-S.; Faron,
`(29) Wulff, w. D.; Peterson, G. A.; Bauta, W. E.; Chan, K-S.; Faron,
`K L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K J. Org.
`K L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K J. Org.
`Chem. 1986,51,277-279.
`Chem. 1986,51,277-279.
`(30) Matsubara, S.; Hibino, J.; Morizawa, Y.; Oshima, K; Nozaki, H.
`(30) Matsubara, S.; Hibino, J.; Morizawa, Y.; Oshima, K; Nozaki, H.
`J. Organomet. Chem. 1985,285,163-172.
`J. Organomet. Chem. 1985,285,163-172.
`
`NPC02230601
`
`NOVARTIS EXHIBIT 2127
`Par v Novartis, IPR 2016-00084
`Page 3 of 8
`
`

`
`50
`50
`
`Scott and McMurry
`Scott and McMurry
`
`Accounts of Chemical Research
`Accounts of Chemical Research
`
`Table III
`Table III
`Palladium-Catalyzed Coupling of Enol Trifiates with Organostannanes
`Palladium-Catalyzed Coupling of Enol Trifiates with Organostannanes
`isolated
`isolated
`yield, %
`yield, %
`
`entry
`entry
`
`2
`
`3
`
`4
`4
`
`5
`5
`
`6
`6
`
`7
`
`triflate
`triflate
`
`DOTl
`DOTl
`
`'-
`'-
`
`cf=~'
`cf=~'
`OT'
`OT'
`=< Bu
`=< Bu
`GrOT.
`GrOT.
`
`organostannane
`organostannane
`
`BU3Sn~
`BU3Sn~
`
`Bu,sn~
`Bu,sn~
`
`Bu,Sn
`Bu,Sn
`
`MegSnSnMeg
`MegSnSnMeg
`
`Bu,sn")-
`Bu,sn")-
`
`i SiM
`i SiM
`
`•
`•
`
`3
`3
`
`Me3Sn
`Me3Sn
`
`~snBu'
`~snBu'
`I \
`I \
`°
`°
`
`product
`product
`
`~ 91
`~ 91
`~ 96
`~ 96
`
`80
`80
`
`xO 'BU
`xO 'BU
`
`73
`73
`
`80
`80
`
`V SnMe3
`V SnMe3
`ro-
`ro-
`~BU
`~BU
`~O 75
`~O 75
`
`90
`90
`
`ref
`ref
`
`13
`13
`
`13
`13
`
`13
`13
`
`13
`13
`
`13
`13
`
`13
`13
`
`13
`13
`
`nUcleophile, is a regioselective alternative to the
`nUcleophile, is a regioselective alternative to the
`standard nucleophilic addition/dehydration scheme for
`standard nucleophilic addition/dehydration scheme for
`olefin synthesis. In the same way, conversion of a ke(cid:173)
`olefin synthesis. In the same way, conversion of a ke(cid:173)
`tone to an enol triflate, followed by reduction, would
`tone to an enol triflate, followed by reduction, would
`be a regioselective alternative to the standard reduc(cid:173)
`be a regioselective alternative to the standard reduc(cid:173)
`tion/ dehydration scheme.
`tion/ dehydration scheme.
`
`..
`
`H -
`
`H
`
`In practice, reduction of enol triflates with standard
`In practice, reduction of enol triflates with standard
`hydride reducing agents such as LiAIH4 or (i-BuhAIH
`hydride reducing agents such as LiAIH4 or (i-BuhAIH
`results only in sulfur-oxygen bond cleavage, regener(cid:173)
`results only in sulfur-oxygen bond cleavage, regener(cid:173)
`ating the enolate ion.13,34 The desired reaction can be
`ating the enolate ion.13,34 The desired reaction can be
`accomplished smoothly, however, when tributyl(cid:173)
`accomplished smoothly, however, when tributyl(cid:173)
`stannane,13,27 various organosilanes, or formic acid35 is
`stannane,13,27 various organosilanes, or formic acid35 is
`used in the presence of a palladium catalyst (Table IV).
`used in the presence of a palladium catalyst (Table IV).
`The overall sequence represents an extremely mild
`The overall sequence represents an extremely mild
`method for preparing olefins and should find use in
`method for preparing olefins and should find use in
`natural-products synthesis. Of particular importance
`natural-products synthesis. Of particular importance
`is the fact that dienol triflates reduce smoothly to yield
`is the fact that dienol triflates reduce smoothly to yield
`dienes, a conversion that is difficult or impossible to
`dienes, a conversion that is difficult or impossible to
`achieve cleanly by other methods.
`achieve cleanly by other methods.
`
`Palladium-Catalyzed Olefination of Enol
`Palladium-Catalyzed Olefination of Enol
`Trifl