The Palladium-Catalyzed Cross-Coupling Reactions of
`The Palladium-Catalyzed Cross-Coupling Reactions of
`Organotin Reagents with Organic Electrophiles
`Organotin Reagents with Organic Electrophiles
`
`By John K. StiJIe*
`By John K. StiJIe*
`
`New Synthetic
`New Synthetic
`Methods (58)
`Methods (58)
`
`The cross-coupling of organotin reagents with a variety of organic electrophiles, catalyzed
`The cross-coupling of organotin reagents with a variety of organic electrophiles, catalyzed
`by palladium, provides a novel method for generating a carbon-carbon bond. Because this
`by palladium, provides a novel method for generating a carbon-carbon bond. Because this
`mild, versatile reaction is tolerant of a wide variety of functional groups on either coupling
`mild, versatile reaction is tolerant of a wide variety of functional groups on either coupling
`partner, is stereospecific and regioselective, and gives high yields of product, it is ideal for
`partner, is stereospecific and regioselective, and gives high yields of product, it is ideal for
`use in the synthesis of elaborate organic molecules. When the coupling reaction is carried
`use in the synthesis of elaborate organic molecules. When the coupling reaction is carried
`out in the presence of carbon monoxide, instead of a direct coupling, carbon monoxide
`out in the presence of carbon monoxide, instead of a direct coupling, carbon monoxide
`insertion takes place, stitching the two coupling partners together and generating a ke(cid:173)
`insertion takes place, stitching the two coupling partners together and generating a ke(cid:173)
`tone.
`tone.
`
`1. Introduction
`1. Introduction
`
`There are relatively few basic reaction types that gener(cid:173)
`There are relatively few basic reaction types that gener(cid:173)
`ate a new carbon-carbon bond, although this is one of the
`ate a new carbon-carbon bond, although this is one of the
`most critical operations in the synthesis of organic mole(cid:173)
`most critical operations in the synthesis of organic mole(cid:173)
`cules. Group VIII transition metals, particularly nickel and
`cules. Group VIII transition metals, particularly nickel and
`palladium, are effective in catalyzing the cross-coupling of
`palladium, are effective in catalyzing the cross-coupling of
`organometallic reagents with organic halides and related
`organometallic reagents with organic halides and related
`electrophiles [Eq. (1)].[I·-IOJ
`electrophiles [Eq. (1)].[I·-IOJ
`
`RM
`RM
`
`• R'X
`• R'X
`
`M'
`M'
`
`R-R' + MX
`R-R' + MX
`
`(1)
`(1)
`
`In order for the coupling reaction to be useful, it should
`In order for the coupling reaction to be useful, it should
`be relatively straightforward and require only a small
`be relatively straightforward and require only a small
`amount of catalyst. Moreover, the reaction conditions and
`amount of catalyst. Moreover, the reaction conditions and
`reagents, particularly the organometallic partner, should
`reagents, particularly the organometallic partner, should
`tolerate a wide variety of functional groups so that tedious
`tolerate a wide variety of functional groups so that tedious
`protection-deprotection reactions are not necessary. Of
`protection-deprotection reactions are not necessary. Of
`the organometallic reagents available, many will not toler(cid:173)
`the organometallic reagents available, many will not toler(cid:173)
`ate sensitive functionality on the coupling partners, are dif(cid:173)
`ate sensitive functionality on the coupling partners, are dif(cid:173)
`ficult to prepare, or are air or moisture sensitive, and few
`ficult to prepare, or are air or moisture sensitive, and few
`can be purified and stored.
`can be purified and stored.
`Various organometallic reagents, RM, have been used in
`Various organometallic reagents, RM, have been used in
`coupling reactions with disparate success. High conver(cid:173)
`coupling reactions with disparate success. High conver(cid:173)
`sions often are not obtained with lithium or Grignard rea(cid:173)
`sions often are not obtained with lithium or Grignard rea(cid:173)
`gents, neither of which will tolerate a wide variety of func(cid:173)
`gents, neither of which will tolerate a wide variety of func(cid:173)
`tional groups on either coupling partner,f2.3J and often ho(cid:173)
`tional groups on either coupling partner,f2.3J and often ho(cid:173)
`mocoupling of the organic halide is observed. The copper(cid:173)
`mocoupling of the organic halide is observed. The copper(cid:173)
`promoted coupling of alkenyl or aryl compounds is more
`promoted coupling of alkenyl or aryl compounds is more
`successful, but it often results in extensive homocou(cid:173)
`successful, but it often results in extensive homocou(cid:173)
`pling.fIJJ In addition, the methods of synthesis of copper
`pling.fIJJ In addition, the methods of synthesis of copper
`reagents do not always allow the presence of the more
`reagents do not always allow the presence of the more
`reactive functional groups on the organocopper partner.
`reactive functional groups on the organocopper partner.
`The use of organometallic reagents containing metals of
`The use of organometallic reagents containing metals of
`intermediate electropositive character generally leads to
`intermediate electropositive character generally leads to
`higher yields of coupled product and fewer side reactions.
`higher yields of coupled product and fewer side reactions.
`Many of these organometallic compounds tolerate a wide
`Many of these organometallic compounds tolerate a wide
`range of functional groups in either or both of the coupling
`range of functional groups in either or both of the coupling
`partners. Organozinc compounds are particularly good in
`partners. Organozinc compounds are particularly good in
`
`[*) Prof. Dr. J. K. Stille
`[*) Prof. Dr. J. K. Stille
`Department of Chemistry, Colorado State University
`Department of Chemistry, Colorado State University
`Fort Collins, CO 80523 (USA)
`Fort Collins, CO 80523 (USA)
`
`this regard, although the methods of synthesis limit the va(cid:173)
`this regard, although the methods of synthesis limit the va(cid:173)
`riety of structures that can be incorporated into the organic
`riety of structures that can be incorporated into the organic
`portion of the organozinc reagent. Organomercurials also
`portion of the organozinc reagent. Organomercurials also
`tolerate functionality, but the methods for their synthesis
`tolerate functionality, but the methods for their synthesis
`are somewhat limiting; moreover, methods for the alkyla(cid:173)
`are somewhat limiting; moreover, methods for the alkyla(cid:173)
`tion of organomercurials are unfortunately limited to a few
`tion of organomercurials are unfortunately limited to a few
`examples with organic halides.[I2.I3J Organometallic part(cid:173)
`examples with organic halides.[I2.I3J Organometallic part(cid:173)
`ners in which the metal is boron or aluminum often are not
`ners in which the metal is boron or aluminum often are not
`conveniently synthesized or the structure of the organic
`conveniently synthesized or the structure of the organic
`portion is limited by the methods of synthesis available,
`portion is limited by the methods of synthesis available,
`usually hydroboration or hydroalumination.14-7J Organozir(cid:173)
`usually hydroboration or hydroalumination.14-7J Organozir(cid:173)
`conium reagents have the advantage that ether or acetal
`conium reagents have the advantage that ether or acetal
`groups are tolerated in the hydrozirconation reaction and
`groups are tolerated in the hydrozirconation reaction and
`carbonyl and ester groups may be present in the alkenyl
`carbonyl and ester groups may be present in the alkenyl
`halide partner.[l4J In coupling reactions, low turnovers of
`halide partner.[l4J In coupling reactions, low turnovers of
`catalyst are observed, however.
`catalyst are observed, however.
`One of the most versatile organometallic reagents in pal(cid:173)
`One of the most versatile organometallic reagents in pal(cid:173)
`ladium-catalyzed coupling reactions is the organotin rea(cid:173)
`ladium-catalyzed coupling reactions is the organotin rea(cid:173)
`gent. Organotin compounds containing a variety of reac(cid:173)
`gent. Organotin compounds containing a variety of reac(cid:173)
`tive functional groups can be prepared by a number of
`tive functional groups can be prepared by a number of
`routes; moreover, these reagents are not particularly oxy(cid:173)
`routes; moreover, these reagents are not particularly oxy(cid:173)
`gen or moisture sensitive. Because of their value in cou(cid:173)
`gen or moisture sensitive. Because of their value in cou(cid:173)
`pling reactions, a brief survey of their syntheses, particu(cid:173)
`pling reactions, a brief survey of their syntheses, particu(cid:173)
`larly some of the more recent ones, is presented.
`larly some of the more recent ones, is presented.
`In the palladium-catalyzed coupling of organic electro(cid:173)
`In the palladium-catalyzed coupling of organic electro(cid:173)
`philes with organotin reagents, essentially only one of the
`philes with organotin reagents, essentially only one of the
`groups on tin enters into the coupling reaction [Eq. (2)].
`groups on tin enters into the coupling reaction [Eq. (2)].
`
`RX + R'SnR:i
`RX + R'SnR:i
`
`R-R' + XSnR:i
`R-R' + XSnR:i
`
`(2)
`(2)
`
`This is not a problem if a relatively simple organic group,
`This is not a problem if a relatively simple organic group,
`for example, methyl, is to be transferred, since tetramethyl(cid:173)
`for example, methyl, is to be transferred, since tetramethyl(cid:173)
`tin can be used. If the group is more expensive or difficult
`tin can be used. If the group is more expensive or difficult
`to synthesize, however, then the utilization of only one of
`to synthesize, however, then the utilization of only one of
`four identical groups would be a distinct disadvantage.
`four identical groups would be a distinct disadvantage.
`Fortunately, different groups are transferred with different
`Fortunately, different groups are transferred with different
`selectivities from tin, the simple alkyl group having the
`selectivities from tin, the simple alkyl group having the
`slowest transfer rate (see Section 3.1). Thus, an unsymme(cid:173)
`slowest transfer rate (see Section 3.1). Thus, an unsymme(cid:173)
`trical organotin reagent containing three simple alkyl
`trical organotin reagent containing three simple alkyl
`groups (such as methyl or butyl) is chosen; the fourth
`groups (such as methyl or butyl) is chosen; the fourth
`group, which undergoes transfer, is usually an alkynyl, al(cid:173)
`group, which undergoes transfer, is usually an alkynyl, al(cid:173)
`kenyl, aryl, benzyl, or allyl group.
`kenyl, aryl, benzyl, or allyl group.
`
`508 © VCH Verlagsgese/lschaji mbH, D-6940 Weinheim, 1986
`508 © VCH Verlagsgese/lschaji mbH, D-6940 Weinheim, 1986
`
`0570-0833/86/0606-0508 $ 02.50/0
`0570-0833/86/0606-0508 $ 02.50/0
`
`Angew. Chern. Int. Ed. EngL 25 (/986) 508-524
`Angew. Chern. Int. Ed. EngL 25 (/986) 508-524
`
`NPC02231268
`
`NOVARTIS EXHIBIT 2126
`Par v Novartis, IPR 2016-00084
`Page 1 of 17
`
`

`
`2. Synthesis of Organotin Reagents
`2. Synthesis of Organotin Reagents
`
`2.1. Synthesis from Electrophilic and Nucleophilic
`2.1. Synthesis from Electrophilic and Nucleophilic
`Triorganotin Compounds
`Triorganotin Compounds
`
`A variety of methods for the synthesis of unsymmetrical
`A variety of methods for the synthesis of unsymmetrical
`organostannanes are known.[l5-18J Although the reaction of
`organostannanes are known.[l5-18J Although the reaction of
`a triorganotin halide with an organometallic compound is
`a triorganotin halide with an organometallic compound is
`widely used, its scope of application is limited since the
`widely used, its scope of application is limited since the
`organometallic compound (usually M = Li, AI, Mg) does
`organometallic compound (usually M = Li, AI, Mg) does
`not allow a large variety of functional groups to be intro(cid:173)
`not allow a large variety of functional groups to be intro(cid:173)
`duced into the organotin product. There are a number of
`duced into the organotin product. There are a number of
`valuable synthetic procedures involving organic anions,
`valuable synthetic procedures involving organic anions,
`however. Lithiation of an enol ether followed by reaction
`however. Lithiation of an enol ether followed by reaction
`with trimethyl- or tributyltin chloride gives a vinyItin rea(cid:173)
`with trimethyl- or tributyltin chloride gives a vinyItin rea(cid:173)
`gent 1 that can serve as an acyl anion equivalent.[19.2oJ
`gent 1 that can serve as an acyl anion equivalent.[19.2oJ
`_ fBu l l [~O.Me]
`_ fBu l l [---.lOMe]
`-78 ~ -20°C F\
`-78~-200[ /~\i
`R
`LI
`
`OMe
`OMe
`
`r-=<
`r-=<
`
`R
`R
`
`SnMe3
`SnMe3
`
`OMe
`OMe
`
`r=<
`r=<
`
`R
`R
`
`H
`H
`
`corresponding (E)- and (Z)-~-chloroacrylates.[23J The reac(cid:173)
`corresponding (E)- and (Z)-~-chloroacrylates.[23J The reac(cid:173)
`tion of a tin cuprate with an a,p-unsaturated P-iodo ketone
`tion of a tin cuprate with an a,p-unsaturated P-iodo ketone
`gives high yields of the corresponding tin reagent 5.[17. IS)
`gives high yields of the corresponding tin reagent 5.[17. IS)
`
`F\
`F\
`C01R
`Cl
`Cl
`C01R
`
`F\
`F\
`nBu3Sn
`COlR
`+ nBu3SnCu
`-
`COlR
`nBu3SnCu ~- nBu3Sn
`+
`
`o
`o
`
`(~~ +
`(~~ +
`
`[PhS{Me 3SnICu] Li
`[PhS{Me 3SnICu] Li
`
`80%
`80%
`
`n = 2 ,3 ; R = H , CH j
`n = 2 ,3 ; R = H , CHj
`
`4
`4
`
`5
`5
`
`An especially useful reaction is the stereospecific addi(cid:173)
`An especially useful reaction is the stereospecific addi(cid:173)
`tion of a complex containing a copper-tin bond across a
`tion of a complex containing a copper-tin bond across a
`triple bond. The stereochemistry of addition depends on
`triple bond. The stereochemistry of addition depends on
`the particular copper reagent and the reaction conditions.
`the particular copper reagent and the reaction conditions.
`Acetylene undergoes a cis addition with the copper(I) rea(cid:173)
`Acetylene undergoes a cis addition with the copper(I) rea(cid:173)
`gents Ph}SnCu and [(Ph3Sn)2Cu]Li [Eq. (3)1.124) The initially
`gents Ph}SnCu and [(Ph3Sn)2Cu]Li [Eq. (3)1.124) The initially
`
`HC == CH
`HC == CH
`
`or
`or
`[{Ph 3Sn)1 Cu ]li
`[{Ph 3Sn)l Cu ]li
`
`[ r=\] E@
`[Ph 3S:="M] ~ Ph3S~E
`
`Ph 3Sn
`
`F\
`E
`M - - Ph 3Sn
`
`131
`131
`
`6
`6
`
`n =1-4,6 ; X=OH, OTHP, OSitBuMel ,Cl
`n =1-4,6 ; X=OH, OTHP, OSitBuMel ,Cl
`
`formed anion can be trapped with a variety of electro(cid:173)
`formed anion can be trapped with a variety of electro(cid:173)
`philes to yield the substituted vinyltin reagents 6. When
`philes to yield the substituted vinyltin reagents 6. When
`Me}SnCu· SMez is used, the regiochemistry of addition to
`Me}SnCu· SMez is used, the regiochemistry of addition to
`a monoalkyl-substituted acetylene is that expected for an(cid:173)
`a monoalkyl-substituted acetylene is that expected for an(cid:173)
`ionic addition; the alkyne can bear a variety of alkyl
`ionic addition; the alkyne can bear a variety of alkyl
`groups (THP= tetrahydropyranyl).[Z5J Methylmagnesium
`groups (THP= tetrahydropyranyl).[Z5J Methylmagnesium
`tributylstannate in the presence of copper(I) cyanide, how(cid:173)
`tributylstannate in the presence of copper(I) cyanide, how(cid:173)
`ever, yields product 7 of opposite regiochemistry. A vari-
`ever, yields product 7 of opposite regiochemistry. A vari-
`
`1. BU3SnMg Me.
`1. BU3SnMg Me,
`CuCN
`CuCN
`2. E
`2. E
`
`R
`R
`
`E
`E
`
`>=<
`>=<
`
`H
`H
`
`SnBu3
`SnBu3
`
`R = Ph/"-..O~ , Ph, n - [10 H11 ;
`R=Ph/"-..O~, Ph, n- CIO H11 ;
`
`7,65-88%
`7,65-88%
`
`E=H(!), RI ,~Br, PhCHO
`E=H@, RI ,~Br, PhCHO
`ety of electrophiles may be used to trap the vinyl anion.1261
`ety of electrophiles may be used to trap the vinyl anion.1261
`Either cis or trans addition of trimethylstannyl copper rea(cid:173)
`Either cis or trans addition of trimethylstannyl copper rea(cid:173)
`gents to substituted and unsubstituted propiolate esters
`gents to substituted and unsubstituted propiolate esters
`can be achieved to yield either (£)-8 or (Z)-9, depending
`can be achieved to yield either (£)-8 or (Z)-9, depending
`on the cu prate and the reaction conditions (TH F = tetrahy(cid:173)
`on the cu prate and the reaction conditions (TH F = tetrahy(cid:173)
`drofuran).[27.28J
`drofuran).[27.28J
`
`R
`
`H
`
`>=<
`
`TH
`TH
`3
`3
`R = H, [Hl=CH ,CHl=C
`,Ph
`R = H, CHl=CH ,CHl=C
`,Ph
`
`The reaction of propargyl alcohol with lithium alumi(cid:173)
`The reaction of propargyl alcohol with lithium alumi(cid:173)
`num hydride followed by tributyltin trifluoromethanesul(cid:173)
`num hydride followed by tributyltin trifluoromethanesul(cid:173)
`fonate (triflate) yields the Z-vinyltin reagent 2.[21J Cu(cid:173)
`fonate (triflate) yields the Z-vinyltin reagent 2.[21J Cu(cid:173)
`prates also undergo cis addition to acetylenes, generating a
`prates also undergo cis addition to acetylenes, generating a
`vinyl metal compound, which reacts with tributyltin triflate
`vinyl metal compound, which reacts with tributyltin triflate
`to yield the (Z)-vinyltin compound.[22J
`to yield the (Z)-vinyltin compound.[22J
`LiAlH" [H H]
`H-=-CHlOH ~ , >=<
`
`Al, /[H l
`/'
`0/
`
`The inverse reaction of a trimethyl- or tributyltin anion
`The inverse reaction of a trimethyl- or tributyltin anion
`with an organic electrophile is more versatile. The dis(cid:173)
`with an organic electrophile is more versatile. The dis(cid:173)
`placement of a halide or tosylate by a trimethyltin anion
`placement of a halide or tosylate by a trimethyltin anion
`can be made to take place with inversion of configuration
`can be made to take place with inversion of configuration
`at an Sp3 carbon. Reaction of sodium trimethylstannate
`at an Sp3 carbon. Reaction of sodium trimethylstannate
`with an aryl bromide takes place under mild conditions,
`with an aryl bromide takes place under mild conditions,
`without reaction at other electrophilic substituents, to yield
`without reaction at other electrophilic substituents, to yield
`aryltin reagents 3.[16.17]
`aryltin reagents 3.[16.17]
`o °C
`
`E-C6 H"SnMej
`E-C6 H"SnMej
`3,60-80%
`3,60-80%
`
`o
`o
`1/
`1/
`E = P - CN, a - ,m - ,p - CCH3 ,0Ac
`E = P - CN, a - ,m - ,p - CCH3 ,OAc
`The reaction of lithium tributylstannate with (Z)-~-chlo­
`The reaction of lithium tributylstannate with (Z)-~-chlo­
`rostyrene occurs with retention of configuration of the
`rostyrene occurs with retention of configuration of the
`double bond. This reaction provides a method of synthesis
`double bond. This reaction provides a method of synthesis
`of either pure (E)- or (Z)-~-tributyltin acrylates 4 from the
`of either pure (E)- or (Z)-~-tributyltin acrylates 4 from the
`
`R = Me
`R = Me
`
`R =Me
`R =Me
`
`R =Me
`R =Me
`
`[Me 3SnCuSPh]li, -78°C, MeOH/THF
`[Me 3SnCuSPh]li, -78°C, MeOH/THF
`
`[Me,SnCu5Ph] Li, -48°(, THF
`[Me,SnCu5Ph] Li, -48°C, THF
`
`[Me3SnCuC=CR]ll
`[Me3SnCuC=CR]ll
`or
`or
`MelSnCu'LIBr Me2S , -48°C, THF
`
`[Me 3SnCuSPh] LI, -100°C. EtOH/THF
`[Me 3SnCuSPh] LI, -100°C. EtOH/THF
`
`99
`99
`
`99
`99
`
`97
`97
`
`9
`
`98
`98
`
`3
`
`509
`509
`
`Angew. Chern. Int. Ed. Engl. 25 (1986) 508-524
`Angew. Chern. Int. Ed. Engl. 25 (1986) 508-524
`
`NPC02231269
`
`NOVARTIS EXHIBIT 2126
`Par v Novartis, IPR 2016-00084
`Page 2 of 17
`
`

`
`2.2. Synthesis from Tin Amides and Oxides
`2.2. Synthesis from Tin Amides and Oxides
`
`Weakly acidic hydrogen can be replaced by tin in a reac(cid:173)
`Weakly acidic hydrogen can be replaced by tin in a reac(cid:173)
`j This serves as a mild
`j This serves as a mild
`tion with tin amides or oxidesJ J5- 17
`tion with tin amides or oxidesJ J5- 17
`.29
`.29
`method for the synthesis of acetylenic tin reagents 10 and
`method for the synthesis of acetylenic tin reagents 10 and
`a-stannyl ketones 11.
`a-stannyl ketones 11.
`
`or
`or
`
`112 RlSnOSnR3
`112 R3SnOSnR3
`
`R-C=C-SnR3
`R-C=C-SnR3
`10
`10
`
`R = alkyl, aryl, CN , CH=CHOMe , OEt
`R = alkyl, aryl, CN , CH=CHOMe , OEt
`
`o
`o
`0
`0
`II
`II
`II
`II
`H3C-C-CHICH3Iz + nBu3SnNMez - - (CH3IzCH-C-CHzSnnBu3
`H3C-C-CHICH3Iz + nBu3SnNMez -
`(CH3IzCH-C-CHzSnnBu3
`
`11
`11
`
`Radical addition to propiolate esters generally yields
`Radical addition to propiolate esters generally yields
`one regioisomer 14 as an (E)/(Z) mixture.[I5.35) In the ab(cid:173)
`one regioisomer 14 as an (E)/(Z) mixture.[I5.35) In the ab(cid:173)
`sence of catalyst, especially in polar solvents, cyanoacety(cid:173)
`sence of catalyst, especially in polar solvents, cyanoacety(cid:173)
`lene yields the vinyltin reagents 15.
`lene yields the vinyltin reagents 15.
`
`RJSnH - -
`
`HC =C - CN
`HC =C - CN
`
`+ R3SnH
`+ R3SnH
`
`(Z)-14
`(Z)-14
`
`~ 15
`~ 15
`R3Sn
`R3Sn
`CN
`CN
`
`H
`H
`
`R3Sn
`R3Sn
`1[1-14
`1[1-14
`
`H
`H
`
`COzR
`COzR
`
`>=<
`>=<
`
`Triorganotin hydrides also react with diazoalkanes, giv(cid:173)
`Triorganotin hydrides also react with diazoalkanes, giv(cid:173)
`ing the tin reagents 16 containing various functional
`ing the tin reagents 16 containing various functional
`groupS.IISj However, these tin reagents will be useful in
`groupS.IISj However, these tin reagents will be useful in
`coupling reactions only if selective transfer of the added
`coupling reactions only if selective transfer of the added
`alkyl group is realized.
`alkyl group is realized.
`
`2.3. Tin Hydride Additions to Alkenes and Alkynes
`2.3. Tin Hydride Additions to Alkenes and Alkynes
`
`The free radical addition of triorganotin hydrides to ole(cid:173)
`The free radical addition of triorganotin hydrides to ole(cid:173)
`fins takes place regiospecifically,[15j This reaction has lim(cid:173)
`fins takes place regiospecifically,[15j This reaction has lim(cid:173)
`ited use, however, since the product 12 is a mixed alkyltin
`ited use, however, since the product 12 is a mixed alkyltin
`reagent, which will not necessarily transfer the newly ad(cid:173)
`reagent, which will not necessarily transfer the newly ad(cid:173)
`ded group exclusively in a catalytic coupling reaction.
`ded group exclusively in a catalytic coupling reaction.
`
`R' = COzEt , COCH 3 , COC 6 Hs , CN
`R' = COzEt , COCH 3 , COC 6 Hs , CN
`
`The radical addition of tributyltin hydride to an olefin
`The radical addition of tributyltin hydride to an olefin
`containing an allylic tosylate leaving group leads to the al(cid:173)
`containing an allylic tosylate leaving group leads to the al(cid:173)
`lyltin reagents 17a, bearing a nitrile, ester, or tosyl group,
`lyltin reagents 17a, bearing a nitrile, ester, or tosyl group,
`or 17b, bearing an enolacetate group.I36)
`or 17b, bearing an enolacetate group.I36)
`
`radical
`radical
`
`E = CONH z , CH(OEtiz , CHzOH , CN
`E = CONH z , CH(OEtiz , CHzOH , CN
`
`The radical addition of triorganotin hydrides to mono(cid:173)
`The radical addition of triorganotin hydrides to mono(cid:173)
`substituted acetylenes to give substituted vinylstannanes
`substituted acetylenes to give substituted vinylstannanes
`13 is mostly regiospecific, the (E)-isomer being favored, al(cid:173)
`13 is mostly regiospecific, the (E)-isomer being favored, al(cid:173)
`though an (E)/(Z) mixture is often obtained (AIBN =azo(cid:173)
`though an (E)/(Z) mixture is often obtained (AIBN =azo(cid:173)
`bisisobutyronitrile ).130-34j
`bisisobutyronitrile ).130-34j
`
`AIBN
`
`13a
`13a
`
`R
`R
`
`HO~snnBu3
`HO~snnBu3
`
`13b
`13b
`
`hv
`hv
`(R=H,Phi
`(R=H,Phi
`
`R
`R
`
`HO~
`HO~
`~
`~
`"H
`"H
`
`R
`R
`I
`I
`== -(-R' + Me 3SnH
`=-(-R'
`I
`I
`OH
`OH
`
`AIBN
`AIBN
`
`AIBN ~OH
`AIBN ~OH
`SnnBu3
`SnnBu3
`
`13d
`13d
`
`~ + ~E
`
`+ ~E
`
`Tos
`Tos
`
`E = eN , COzMe , Tos
`E = eN , COzMe , Tos
`
`OAc
`OAc
`~Tos
`~Tos
`
`tBuOK, tBuOHITHF
`tBuOK, tBuOHITHF.
`O°C
`
`O°C ~E
`
`Tos
`Tos
`
`nBu3sn~E
`nBu3sn~E
`
`17 a
`17 a
`
`17b
`17b
`
`2.4. Reactions of Hexaalkyldistannanes with Organic
`2.4. Reactions of Hexaalkyldistannanes with Organic
`Halides
`Halides
`
`The mild, palladium-catalyzed coupling of hexaalkyl(cid:173)
`The mild, palladium-catalyzed coupling of hexaalkyl(cid:173)
`distannanes with aryl, benzyl, or allyl halides provides a
`distannanes with aryl, benzyl, or allyl halides provides a
`unique method of synthesis of organotin reagents in which
`unique method of synthesis of organotin reagents in which
`the organic group derived from the organic halide can
`the organic group derived from the organic halide can
`have reactive substituents.I37-39) This synthetic procedure is
`have reactive substituents.I37-39) This synthetic procedure is
`especially valuable for the synthesis of trialkylaryltin rea(cid:173)
`especially valuable for the synthesis of trialkylaryltin rea(cid:173)
`gents 18.
`gents 18.
`
`y@rX
`y@rX
`
`o
`o
`1/
`1/
`x= Br, I· Y=C-CH 3 , CN, NOz ; R=Me, nBu
`x= Br, I Y=C-CH 3 , CN, NOz ; R=Me, nBu
`
`18
`18
`
`5\0
`5\0
`
`Angew. Chern. Int. Ed. Eng/. 25 (1986) 508-524
`Angew. Chern. Int. Ed. Eng/. 25 (1986) 508-524
`
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`

`
`2.5. Elaboration of Organotin Reagents
`2.5. Elaboration of Organotin Reagents
`
`Tin-carbon bonds in organotin reagents are relatively
`Tin-carbon bonds in organotin reagents are relatively
`stable, the bond energy being about 50 kcal/mol.[15J Thus,
`stable, the bond energy being about 50 kcal/mol.[15J Thus,
`it is not surprising that a wide variety of reactions can be
`it is not surprising that a wide variety of reactions can be
`performed at other functional groups in the molecule with(cid:173)
`performed at other functional groups in the molecule with(cid:173)
`out breaking the Sn-C bond. For example, the permanga(cid:173)
`out breaking the Sn-C bond. For example, the permanga(cid:173)
`nate oxidation of primary alcohols to carboxylic acids[15J
`nate oxidation of primary alcohols to carboxylic acids[15J
`and the chromium trioxide oxidation of secondary alco(cid:173)
`and the chromium trioxide oxidation of secondary alco(cid:173)
`hols to ketones,[16. 17J as well as the lithium aluminum hy(cid:173)
`hols to ketones,[16. 17J as well as the lithium aluminum hy(cid:173)
`dride reduction of esters, nitriles, and ketones to alcohols
`dride reduction of esters, nitriles, and ketones to alcohols
`and amines,[15-17.40J can be carried out without cleavage of
`and amines,[15-17.40J can be carried out without cleavage of
`the carbon-tin bonds. Thus, the substituted vinyltin rea(cid:173)
`the carbon-tin bonds. Thus, the substituted vinyltin rea(cid:173)
`gent 19, containing a primary OH group, was obtained by
`gent 19, containing a primary OH group, was obtained by
`an isomerization-reduction sequence (LDA=lithiumdiiso(cid:173)
`an isomerization-reduction sequence (LDA=lithiumdiiso(cid:173)
`propyl amide ). [41 J
`propyl amide ). [41 J
`
`Olefinic groups on an organotin reagent can be hydro(cid:173)
`Olefinic groups on an organotin reagent can be hydro(cid:173)
`borated[17J and acetylenic groups add alkylboranes.[16J Cy(cid:173)
`borated[17J and acetylenic groups add alkylboranes.[16J Cy(cid:173)
`clopropanation of an acetylenic group can be achieyed
`clopropanation of an acetylenic group can be achieyed
`with diazoalkanes.l16J A 1,3-diene containing a trimethyl(cid:173)
`with diazoalkanes.l16J A 1,3-diene containing a trimethyl(cid:173)
`stannylmethyl group in the 2-position will undergo the
`stannylmethyl group in the 2-position will undergo the
`Diels-Alder reaction with an electron-poor dienophile,l45J
`Diels-Alder reaction with an electron-poor dienophile,l45J
`thereby providing a new a\lylic tin reagent 22.
`thereby providing a new a\lylic tin reagent 22.
`
`2Z
`22
`
`A Diels-Alder reaction between methyl tributylstannyl(cid:173)
`A Diels-Alder reaction between methyl tributylstannyl(cid:173)
`propiolate and substituted butadienes at 120°C gives good
`propiolate and substituted butadienes at 120°C gives good
`yields of the 1,4-cyclohexadiene adduct 23a, which can be
`yields of the 1,4-cyclohexadiene adduct 23a, which can be
`dehydrogenated to the aryltin reagent 23b.146J
`dehydrogenated to the aryltin reagent 23b.146J
`
`1.LDA, THF
`1.LDA, THF
`-78~ O°C
`-78~ O°C
`2 HOAc/Et20
`2 HOAc/Et20
`-78°C
`-78°C
`
`1 LiAIH.
`1 LiAIH.
`-20°C
`-20°C
`2. H20
`2.H 20
`
`19
`19
`
`Rl
`
`The Sn-C bond survives reactions of Grignard reagents,
`The Sn-C bond survives reactions of Grignard reagents,
`either when the Grignard reagent is allowed to react with
`either when the Grignard reagent is allowed to react with
`an organotin compound containing an appropriate func(cid:173)
`an organotin compound containing an appropriate func(cid:173)
`tional group or when a halogen-containing organotin com(cid:173)
`tional group or when a halogen-containing organotin com(cid:173)
`pound is converted into a Grignard reagent.[15.17J Cyano
`pound is converted into a Grignard reagent.[15.17J Cyano
`and carbonyl groups on one of the organic groups of an
`and carbonyl groups on one of the organic groups of an
`unsymmetrical organotin reagent undergo Grignard reac(cid:173)
`unsymmetrical organotin reagent undergo Grignard reac(cid:173)
`tions in the usual manner. An unsymmetrical organotin
`tions in the usual manner. An unsymmetrical organotin
`compound containing an a-chloroether function reacts
`compound containing an a-chloroether function reacts
`with allyl magnesium bromide, for example, to yield the al(cid:173)
`with allyl magnesium bromide, for example, to yield the al(cid:173)
`lylic tin reagent 20.[42J
`lylic tin reagent 20.[42J
`
`nBu 3Sn-1H-OEt
`
`nBu3Sn-CH-OEt
`I
`Cl
`Cl
`
`SnnBu 3
`SnnBu 3
`~OEt
`+ ~ MgBr
`+ ~ MgBr -~ ~OEt
`-
`
`20
`20
`
`The NH2 group undergoes typical reactions with various
`The NH2 group undergoes typical reactions with various
`electrophiles;143J for example, amines may be converted
`electrophiles;143J for example, amines may be converted
`into isocyanates with phosgene.1 16J Unsymmetrical orga(cid:173)
`into isocyanates with phosgene.1 16J Unsymmetrical orga(cid:173)
`nostannanes undergo the Wittig reaction, either by reac(cid:173)
`nostannanes undergo the Wittig reaction, either by reac(cid:173)
`tion of an aldehyde function on the organotin compound
`tion of an aldehyde function on the organotin compound
`with methylenetriphenylphosphorane[15.16J or by reaction
`with methylenetriphenylphosphorane[15.16J or by reaction
`of an organotin-containing Wittig reagent with an alde(cid:173)
`of an organotin-containing Wittig reagent with an alde(cid:173)
`hyde. 117J This reaction has been used in the synthesis of the
`hyde. 117J This reaction has been used in the synthesis of the
`organotin reagent 21 containing an a,~-unsaturated ke(cid:173)
`organotin reagent 21 containing an a,~-unsaturated ke(cid:173)
`tone.144]
`tone.144]
`
`o
`o
`nBu3Sn~Ph
`nBu3Sn~Ph
`
`THF
`THF
`84%
`84%
`
`21
`21
`
`120°C,48h
`120 0 (,48h.
`
`-HI
`
`RI:(xCOIMe
`I
`I
`
`SnnBu3
`
`R3
`
`23a
`23a
`
`23b
`23b
`
`The ability to generate relatively stable anions on an or(cid:173)
`The ability to generate relatively stable anions on an or(cid:173)
`ganic group attached to tin, without carbon-tin bond
`ganic group attached to tin, without carbon-tin bond
`cleavage, provides a versatile method of elaboration of or(cid:173)
`cleavage, provides a versatile method of elaboration of or(cid:173)
`ganostannanes. The stabilized allyl anion 24, for example,
`ganostannanes. The stabilized allyl anion 24, for example,
`undergoes l,4-addition to cyclopentenone to yield the vi(cid:173)
`undergoes 1,4-addition to cyclopentenone to yield the vi(cid:173)
`reagent 25
`(HMPA = hexamethylphosphoram(cid:173)
`nyltin
`(HMPA = hexamethylphosphoram(cid:173)
`nyltin
`reagent
`25
`ide).(47J
`ide).(47J
`
`o o THF
`o o ~
`
`2 HMPA
`2 HMPA
`
`25
`25
`
`PhS~SnnBu3
`PhS~SnnBu3
`
`Lie
`Lie
`
`24
`24
`
`In a related reaction, aldehydes react with 9-borabicy(cid:173)
`In a related reaction, aldehydes react with 9-borabicy(cid:173)
`clononane(9-BBN)-substituted organotin compounds with
`clononane(9-BBN)-substituted organotin compounds with
`allylic rearrangement to yield the vinyltin reagents 26.(48J
`allylic rearrangement to yield the vinyltin reagents 26.(48J
`
`+ RCHO
`+ RCHO
`
`OH
`
`26
`26
`
`R = Ph , nBu , Ph~
`R = Ph , nBu , Ph~
`
`90 - 98 % threo
`90 - 98 % threo
`
`An anionic center in the a-position to tin reacts with a
`An anionic center in the a-position to tin reacts with a
`variety of electrophiles (such as aldehydes, ketones, and
`variety of electrophiles (such as aldehydes, ketones, and
`
`Angew. Chern. Int. Ed. Eng/. 25 (1986) 508-524
`Angew. Chern. Int. Ed. Eng/. 25 (1986) 508-524
`
`511
`511
`
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`
`allyl bromides) to give the organostannanes 27. [49J In the
`allyl bromides) to give the organostannanes 27. [49J In the
`example shown, however, the alkyl group could not neces(cid:173)
`example shown, however, the alkyl group could not neces(cid:173)
`sarily be expected to undergo selective transfer in transi(cid:173)
`sarily be expected to undergo