20
Pergamon Tetrahedron, Vol. 53. No. 3. pp. 10251044. 1997 CopyrIght 0 1996 Elsewer Science Ltd Printed in Great Britain. All rights reserved 0040.4020/97 $17.00 + 0.00 PII: SOO40-4020(96)01027-7 Selective Palladium-Mediated Carbon-Oxygen Bond and Carbon-Sulfur Bond Forming Reactions Which Involve Functionalized C+Hybridized Halides or Triflates and C&-Hybridized Halides Renzo Rossi,*a Fabio Bellina*a and Luisa Manninab Dipartimento di Chtmica e Chimica Industriale. University of Piss. Via Risorgimento 35, I-56126 Pisa. Itz~ly,~ and Istituto di Strutturistica Chimica de1 CNR, Area della Ricerca di Roma, Via Salaria Km 29.3, l-o0016 Monterotondo Staz., Italyb Alrstracf: (0 and (Z)-2.3~dibromopropenoates were found to be able to react with Bu$SnXR1 (X = 0,s; R1 = alkyl. aryl) in NMP solution at 20 “C in the presence of Pd(PPh3)4 to give the corresponding 3- alkoxy. 3-arylthio and 3-alkylthio substituted products. Under similar conditions methyl (E)- and (Z)-3- bromopropenoate. methyl (Z)-3-iodo-2-octenorte. 3-alkoxycarbonyl substituted (cyclo)alkenyl triflates as well as methyl 3-bromopropiolate, were converted into the corresponding 3-methylthio or 3-phenylthio substituted products when compounds BtqSnSR’ (RI = Me, Ph) were used as nucleophiles. On the contrary. 2-bromo substituted c&unsaturated esters or lactones as well as a ‘L-substituted alkyl 3- bromopropenoate did not undergo Pd-mediated substitution reactions by treatment with Bu3SnOR1 and 3- substituted (E)-2.3-dibromopropenoates. and 3substituted (Z)-34odopropenoates afforded the corresponding a$-acetylenic esters. when reacted with BugSnOR in the presence of Pd(PPh3)4. A selective monosubstitution reaction also occurred when 1,2-dibromobenzene, was reacted with PhSSnBu) in toluene in the presence of Pd(PPh3)4. Finally. compounds (E)- and (Z)-22a, which were prepared by Pd-mediated C-S bond forming reactions. were used as direct precursors to some natural carboxyamides. Copyright 0 1996 Elsevier Science Ltd Although transition metal-mediated reactions between Csp?,-hybridized halides and heteroatom-centered nucleophiles can allow the efficient formation of C sp?-heteroatom bonds in mild conditions, these substitution reactions have been seldom used to prepare synthetic and naturally-occurring bioactive compounds characterized by Csp2-0 bonds,lnz Csp2-S bondsl~3~~ or C$-N bonds.45 Aromatic aminations have been performed by Pd-mediated reactions either of aryl bromides with (N,N- dialkylamino)tributylstannanes, which were preformedh-8 or prepared irt situ,Y or of aryl bromides or iodides with amines in the presence of I-BuOK,]Oa f-BuONa’Ob,C or LiN(SiMej), 711 Similarly, aryl sulfides have been synthesized by Pd-mediated reaction of aryl halides with sodium alkyl- or arylthiolates,1Z~13 or 1025

Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Embed Size (px)

Citation preview

Page 1: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Pergamon Tetrahedron, Vol. 53. No. 3. pp. 10251044. 1997

CopyrIght 0 1996 Elsewer Science Ltd

Printed in Great Britain. All rights reserved

0040.4020/97 $17.00 + 0.00 PII: SOO40-4020(96)01027-7

Selective Palladium-Mediated Carbon-Oxygen Bond and Carbon-Sulfur Bond Forming Reactions Which Involve Functionalized C+Hybridized Halides or Triflates and

C&-Hybridized Halides

Renzo Rossi,*a Fabio Bellina*a and Luisa Manninab

Dipartimento di Chtmica e Chimica Industriale. University of Piss. Via Risorgimento 35, I-56126 Pisa. Itz~ly,~ and

Istituto di Strutturistica Chimica de1 CNR, Area della Ricerca di Roma, Via Salaria Km 29.3, l-o0016 Monterotondo Staz., Italyb

Alrstracf: (0 and (Z)-2.3~dibromopropenoates were found to be able to react with Bu$SnXR1 (X = 0,s; R1 = alkyl. aryl) in NMP solution at 20 “C in the presence of Pd(PPh3)4 to give the corresponding 3-

alkoxy. 3-arylthio and 3-alkylthio substituted products. Under similar conditions methyl (E)- and (Z)-3- bromopropenoate. methyl (Z)-3-iodo-2-octenorte. 3-alkoxycarbonyl substituted (cyclo)alkenyl triflates as well as methyl 3-bromopropiolate, were converted into the corresponding 3-methylthio or 3-phenylthio substituted products when compounds BtqSnSR’ (RI = Me, Ph) were used as nucleophiles. On the contrary. 2-bromo substituted c&unsaturated esters or lactones as well as a ‘L-substituted alkyl 3- bromopropenoate did not undergo Pd-mediated substitution reactions by treatment with Bu3SnOR1 and 3-

substituted (E)-2.3-dibromopropenoates. and 3substituted (Z)-34odopropenoates afforded the corresponding a$-acetylenic esters. when reacted with BugSnOR in the presence of Pd(PPh3)4. A selective monosubstitution reaction also occurred when 1,2-dibromobenzene, was reacted with PhSSnBu) in toluene in the presence of Pd(PPh3)4. Finally. compounds (E)- and (Z)-22a, which were prepared by

Pd-mediated C-S bond forming reactions. were used as direct precursors to some natural carboxyamides. Copyright 0 1996 Elsevier Science Ltd

Although transition metal-mediated reactions between Csp?,-hybridized halides and heteroatom-centered

nucleophiles can allow the efficient formation of C sp?-heteroatom bonds in mild conditions, these substitution

reactions have been seldom used to prepare synthetic and naturally-occurring bioactive compounds

characterized by Csp2-0 bonds,lnz Csp2-S bondsl~3~~ or C$-N bonds.45

Aromatic aminations have been performed by Pd-mediated reactions either of aryl bromides with (N,N-

dialkylamino)tributylstannanes, which were preformedh-8 or prepared irt situ ,Y or of aryl bromides or iodides

with amines in the presence of I-BuOK,]Oa f-BuONa’Ob,C or LiN(SiMej), 711 Similarly, aryl sulfides have been

synthesized by Pd-mediated reaction of aryl halides with sodium alkyl- or arylthiolates,1Z~13 or

1025

Page 2: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1026 R. ROSSI et al.

(alkylthio)tributylstannanes’+’ or alkylthiols in the presence of Et3N. ‘5 Moreover, alkenyl sulfides have been

prepared by reaction of alkenyl bromides with lithium aryl- or alkylthiolates, in the presence of a Pd(0)16 or a

Ni(II) catalyst precursor,17 as well as by treatment of alkenyl bromides with (phenylthio)tributylstannane in the

presence of catalytic amounts of Pd(PPh3)4. ‘8 It has also been found that when stereoisomeric mixtures of l-

bromo-I-alkenes are used in this last type of substitution reaction, the (E)-stereoisomers of these halides react

faster than the corresponding (Z)-stereoisomers affording diastereoselectively (E)-l-alkenyl phenyl sulfides

having high stereoisomeric purity.‘8

On the other hand, there are few data in the literature on selective transition metal-mediated carbon-

heteroatom bond forming reactions which involve aryl dihalides or functionalized and stereodefined alkenyl

mono or dihalides. In particular, to the best of our knowledge, the selective synthesis of 4-

chlorophenyldiethylamine, 3, by treatment of 4-chlorobromobenzene, 1, with BtqSnNEt2, 2, in the presence of

PdCl2[P(o-tol)&,6a represents the only example of a catalytic substitution reaction involving a polyhaloarene.

Furthermore, recently the first examples of Pd-mediated chemo-, regio- and stereospecific Csp2-0 bond and

&,2-S bond forming reactions, which involve stereodefined and functionalized 1,2-dibromoethenes, have been

shortly reported.‘9 These reactions, which were performed by treatment of alkyl (Z)- and (Q-2,3-

dibromopropenoates, (Z)- and (E)-4, with (alkoxy), (arylthio)- or (alkylthio)tributylstannanes, 5, in NMP

solution, in the presence of catalytic amounts of Pd(PPh$a, afforded alkyl (Z)- and (E)-3-(alkoxy)-, 3-

(arylthio)- and 3-(alkylthio)-2-bromopropenoates, (Z)- and (E)-6, respectively, in satisfactory yields.19

Br NEt, Bu3SnEt2

Cl 1 2 3

H Br H

Br Bu&nXR’ R’X H

Br Br Br Br

(Z)-4 (E)-4 5:x=o,s (Z)-6 : X = 0, S (/q-6 : x = 0, s

Owing to our continuing interest in transition metal-mediated carbon-carbon bond and carbon-

heteroatom-bond forming reactions, which involve functionalized Csp2-20-22 and &p-hybridized

electrophiles,?3 and their synthetic applications to the synthesis of bioactive natural compounds and their

structural analogues, more recently we have studied more in depth these substitution reactions by examining

also those which involve C+hybridized functionalized electrophiles different from compounds 4 as well as a

functionalized I-bromo-1-alkyne.

We now wish to describe and comment in detail the results of our preliminary studyI as well as those

obtained in the investigation of Pd-mediated reactions between (alkoxy)-, (arylthio)- or (alkylthiohributyl-

stannanes, 5, and 3-substituted (E)-2,3-dibromopropenoates, (Q-7, 2-bromo substituted a&unsaturated

lactones or esters, such as 8 and (.Z)-9a, unsubstituted, 3- or 2-substituted 3-bromopropenoates, i.e. (E)- and Q-

10, Q-11 and (E)l(L7-12, respectively, 2-alkoxycarbonyl-1-(cyclo)alkenyl triflates. such as 13 and (E)-14. a

functionalized 1-bromo-1-ethyne, i.e. 15, and a symmetrically substituted dihaloarene, i.e. 16.

An application of two stereoisomerically pure compounds, which have been prepared in high yields by

these selective Pd-mediated C-S bond forming reactions, to the synthesis of some unusual naturally-occurring

Page 3: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1027

sulfur-containing carboxyamidesj will also described.

R’

Br COOEt

\ Br m 1; 0 0

H COOEt

(E)-7a : R’ = Ph 8 (Z)-9a

(E)-7b : R’ = COOEt (E)-7c : R’ = Me

R’

Br+COOMe BrbCOOMe

I& \H H&

\ /

COOR COOEt (E)-10 (Z)-10 (Z)-lla : R’ = C5Hlt; R = Me (.JY(Z)-12

(Z)-llb : R’ = Ph: R = Et

Q ’ OTf

cOOEt

13

Me TfO Br*COOMe

(El-14 15

Br

Br

16

RESULTS AND DISCUSSION

Recently, we reported that alkyl (z)- and (E)-2,3-dibromopropenoates, (Z)- and (E)-4, as well as variously

3-substituted alkyl (E)-2Jdibromopropenoates. (E)-7, are able to undergo regioselective and stereospecific C-

C bond forming reactions by treatment with small molar excesses of organozinc or organotin compounds. in the

presence of a suitable Pd catalyst precursor. to give the corresponding 3-substituted and 3,3-disubstituted 2-

bromo derivatives, (Z)- and (E)-17-70 and 1821, respectively.

H R,

Br

g-17

R’ H

Br

(E)-17

R’

R2 COOR

18

These results allowed LIS to envisage that compounds (Z)- and (15).4 as well (E)-7 might also undergo

analogous Pd-mediated C-O bond and C-S bond forming reactions by treatment with suitable oxygen-centered

and sulfur-centered nucleophiles, respectively. Thus, we examined the Pd-mediated reactions of these 1,2-

dibromoethene derivatives with (alkoxy)-, (arylthio). and (alkylthio)tributylstannanes, respectively. We chose

this type of nucleophiles since in preliminary experiments we had found that the chemoselectivity and the

yields of the monosubstitution reactions performed using these compounds were much higher than those

obtained when lithium or sodium alkoxides or thiolates were employed.

After several endeavours for optimizing the reaction parameters, we found that treatment of (Z)-da with

1.15 equiv of MeOSnBug, Sa, in NMP solution at 20 “C for 96 h, in the presence of 3 mol % Pd(PPhj)d,

afforded stereoisomerically pure (Z)-2-bromo-3-(methoxy)propenoate, (Z)-6a, in 63 % yield (eq l)(entry 1,

Table 1).

Page 4: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1028 R. ROSSI et cd.

H H

COOMe + MeOSnBu3 Pd(PPh&, NMP

Br 20 “C Me0 (I)

Br Br (Z)-4a 5a (Z)-6a

Interestingly, similar unprecedented regioselective and stereospecific Pd-mediated C-O bond and C-S

bond forming reactions were found to occur in satisfactory yields when compounds (Z)-4b, (E)-4b and (Z)-4a

were reacted with EtOSnBux, 5b, PhSSnBuj, 5c, MeSSnBug, 5d and 5a, respectively, under experimental

conditions similar to those employed to prepare (Z)-6a (entries 2-6, Table 1). All these mosubstitution reactions

were also highly chemoselective. In fact, the crude reaction mixtures obtained in entries 3, 4 and 6 reported in

Table 1 contained the desired products, i.e. (Z)-6c. (Z)-6d and (E)-6e, respectively, free of compounds derived

from undesired transesterification reactions’4

Table 1. Pd-Mediated Reactions between (Alkoxy). (Arylthio)- or (Alkylthio)tributylstannanes. 5, and Unsubstituted or 3Substituted Alkyl 2&Dibromopropenoates of General Formula (Z)- and (Q-4 and (E)-7, Respective1y.a)

Entry Tributylstannyl Substrate 4 or 7 Reaction time (h) Product Yield (%)b)

derivative

1 MeOSnBug, 5a (Z)-4a 96 (Z)-6a 63

2 EtOSnBus, 5b (Z)-4b 172 (Z)-6b 45

3c) PhSSnBus, 5c (Z)-4a 24 (Z)-6c 84

4 MeSSnBua, 5d (Z)-4a 5 (Z)-6d 86

5 5a (E)-4a 71 (E)-6a 46

6 5a (E)-4b 168 (E)-6e 42

7 5a (Z)-7a 43.5 PheCOOEt (16) 19a

8 5b (Z)-7b 91e) EtOOC=-COOEt

19b (6)

9 5c (Z)-7c 770 Me~COOEt ,19c

+

Br

x

COOEt

Me SPh

(13)

(21)

a) Unless otherwise reported, these reactioos were carried out in NMP at room temperature win, u 1.15 equiv of tributylstannyl reagent

and 5 mol% of Pd(PPh3)4; b) Isolated yields: GLC yields are reported in parenthesis: c) Reaction carried out using 2.5 equiv of SC; d) Reaction carried out for 25 h at 20 ‘T and for 18.5 h at 40 “C; e) Reaction carried out for 91 h at 100 “C using 2.3 equiv of 5b: f) Reaction carried out at 20 “C for 54 h and at 50 “C for 23 h.

It must be noted that stereoisomerically pure compounds (Z)-6a-cl, (E)da,b and (06e so obtained are

highly functionalized electrophiles not previously reported in the literature.‘5 The fact that the C-Br bond in the

Page 5: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1029

3-position of compounds (z)- and (Ej-4 was exclusively involved in the Pd-mediated substitution reactions was

rationalized by supposing that the mesomeric effect of the alkoxycxbonyl group present in these dibromides

overcomes its inductive effect. Thus, this group might be able to render the C-Br bond in the 3-position more

electron poor than that in the l-position and, therefore, more suitable for the oxidative addition reaction with

the Pd(0) species present in the reaction mixtures.‘6

On the other hand, we demonstrated that 2-bromo substituted a&unsaturated esters or lactones are unable

to undergo substitution reactions by treatment with BujSnOR’ either in experimental conditions similar to

those employed to prepare compounds (Z)- and (E)-6 or in harsher conditions. In fact, by treatment of 2-

bromocoumarin, 8, with 1.15 equiv of 5a in NMP solution at 20 “C for 24 h and at 50 “0 for 24 h, in the

presence of 3 mol % Pd(PPh$;I, the substitution reaction did not occur and compound 8 could be recovered

quantitatively from the reaction mixture.

H Br

Br Br Br

(Z)-4a : R = Me (Z)-4b : R = Et

(E)-4a : R = Me (E)-4b : R = Et

H

+ R’X \ COOR

Br

(Z)-6a : R’X = MeO; R = Me (Z)-6b : R’X = EtO; R = Et (Z)-6c : R’X = PhS; R = Me (Z)-6d : R’X = MeS; R = Me

XR’

& \ COOR

Br

(E)-6a : R’X = MeO; R = Me (E)-6b : R’X = EtO; R = Et (E)-6e : R’X = EtO; R = Me

Moreover, a GLC/MS analysis of the reaction mixture, which was obtained by treatment of ethyl (Z)-2-

bromo-3-phenylpropenoate, (Z)-9a. with 5a in toluene at 110 “C for 12 h. in the presence of 5 mol %

Pd(PPhjj4, showed that it contained (Z)-9a and the corresponding methyl ester, (Z)-9b, in a cu. 1 : 1 ratio (eq

2).

Ph Ph

H + MeOSnBu3 PdW’W4 _ H

COOEt toluene, A

COOMe

(Z)-9a 5a (Z)-9b

However, unexpected results were obtained when ethyl (E)-2,3-dibromo-3-phenylpropenoate, (E)-7a, and

diethyl 2,3-dibromofumarate, (Q-7b, were reacted with 5a and 5b, respectively, in NMP solution in the

presence of 3 mol % Pd(PPh3)d (entries 7 and 8, Table 1). In fact, GC and W/MS analyses of the resulting

reaction mixtures showed that they contained the unreacted dibromides together with small but significant

amounts of the corresponding a&unsaturated acetylenic esters, 19a and 19b, respectively. Moreover, a similar

reaction between 5c and ethyl (E)-2.3.dibromo-2-butenoate, (E)-7c, gave rise to a complex reaction mixture

which contained ethyl 2-butynoate, 19~. unreacted (E)-7c, and a compound which had MS spectrum

corresponding to that of the expected substitution product, i.e. ethyl (E)-2-bromo-3-(phenylthio)-2-butenoate,

Page 6: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1030 R. ROSSI et al.

(Q-20 (entry 9, Table 1).

Similarly to what observed for the Pd-mediated reaction between arylzinc chlorides and compounds (E)-

7, 2* compounds 19a-c could derive from a rru,ls-elimination reaction involving the oxidative addition

complexes which result from (E)-‘la-c and the Pd(0) species present in the reaction mixtures (Scheme 1).

Ph~COOEt 19a

EtOOC~COOEt 19b

Me+COOEt 19c

$Ph

Me Br

(E)-20

R’ - L2

Br + PdL, - - Rl--=-_ COOR + Pd’-zBr2

COOR (Q-7 (L = PPllJ) 19 21

However, the molar amounts of compounds 19a and 19~. which were obtained in entries 7 and 9 of Table

1, respectively, were higher than those of the Pd(0) catalyst precursor used in these reactions. This result could

be explained by supposing that PdBr2(PPh$z, 21. which was formed in the above mentioned rj.a/ls-elimination

reaction, is reduced to a catalytically active Pd(0) species by the tributylstannyl reagents Sa and SC.

respectively. Although we have not obtained so far evidences concerning the products obtained in the presumed

reduction step when (E)-7a was reacted with 5a (entry 7, Table l), it must be noted that a GLUMS analysis of

the reaction mixture, which was obtained from the Pd-mediated reaction of (E)-7c with 5c (entry 9, Table l),

showed the presence of diphenyl disulfide in a molar amount similar to that of compound 19~.

In order to evaluate deeply the scope and limitations of the Pd-mediated C-O bond and C-S bond forming

reactions which involve BPfunctionalized 1-alkenyl halides, we also examined the reactions between

compounds 5a-d and variously substituted or not substituted alkyl 3-halopropenoates such as (El- and (Z)-10,

(Z)-lla, (Z)-llb. and (E)/(Z)-12. These reactions were also carried out in NMP solution at 20 “C in the

presence of 3 mol % Pd(PPhR)+ Thus. we observed that the reactions of 5d with (E)- and (ZJ-10 as well as that

between 5c and (Z)-lla gave the desired stereoisomerically pure substitution products, i.e. (El-22a, (Z)-22a and

(Z)-22b, respectively, in high yields (entries 1, 2 and 4, Table 7). Nevertheless, the Pd-mediated reaction

between (z)-lla and 5a (entry 3, Table 2) as well as that between (Z)-llb and 5b (entry 5, Table 2) afforded

exclusively elimination reaction products, i.e. 19c and 19a, respectively.

We explained these last results taking into account that (i) compounds 5a and 5b are bases stronger than

PhSSnBuj, 5c and worse nucleophiles and that (ii) the reaction between alkyl 3-halopropenoates and bases such

as sodium alkoxides gives rise to alkyl arylpropiolates.‘7 On the other hand. a confirmation of the hypothesis

that a&acetylenic esters 19 could derive from a reaction between (Z)-11 and (alkoxy)tributylstannanes without

the participation of the Pd catalyst was obtained by examining the reaction of (Z)- 1 la with 1.15 eyuiv of 5a in

NMP solution at 20 “C for 10 h. This reaction (eq 3) gave compound 19c in 25 % GLC yield.

Page 7: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1031

(3) C5H11

1% \H + MeOSnBu3 NMP

20 “C C5%1 - aCOOMe

COOMe (Z)-lla 5a 19c

It was also observed that the presence of a substituent in the 2-position of alkyl 3-bromopropenoates

inhibits the substitution reaction when (alkoxy)tributylstannanes are used as nucleophiles.

Table 2. Pd-Mediated Reactions between (Alkoxy)-, (Arylthio)- or (Alkylthio)tributylstannanes, 5, and Variously Substituted or Unsubstituted Alkyl 3-Halopropen0ates.a)

Entry Tributylstannyl

derivative

3-Halopropenoate Reaction time (h) Product Yield (%)b’

1 MeSSnBug

5d

2 5d

Br H

x H COOMe

(E)-10

5

(E)-22a

H,SMe 5

(Z)-22a

3 MeOSnBus

5a

4 PhSSnBus

SC

5 EtOSnBu3

5b

6’) 5b

‘Y C5H11

MeOOCA H

(Z)-lla

(Z)-1 la 38

(Z)-llb

24 CSHl, - COOMe

19c

(Z)-22b

93 Ph------COOEt

19a

9oc)

63

45

84

86

46

-

a) Unless otherwise reported. these reachons WCTC carried out in Nh4P 31 room lempemture using 1.15 cquiv of tributylstarmyl reagent and 5 mol?L ol’ Pd(PPhj)d: b) Isolated yicldb: GLC yields are reporled in parenthesis; c) Rcactlon carrlcd out a~ 20 “C for 24 11 and ;11 80 “C for 66 h.

In fact, the reaction mixture, which was obtained by treatment of ethyl (E)/(Z)-3-bromo-2-(2-

propenyl)propenoate, (E)/(Z)-12 with 5b for 20 h at 20 “C and for 66 h at 80 ‘C, contained exclusively the

unreacted starting materials (entry 6, Table 2). Interestingly, we also noticed that, similarly to alkyl 3-

halopropenoates, a&unsaturated esters which contain a (trifluoromethyl)sulfonyloxy group in their 3-position

Page 8: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1032 R. ROSSI et al.

are able to participate efficiently to Pd-mediated regioselective and stereospecific C-S bond forming

reactions.28 In fact, reaction of ethyl 2-[(trifluoromethyl)sulfonyloxy]-l-cyclopentene-l-c~boxylate, 13, with

1.15 equiv of 5c and 2 equiv of LiCl in NMP solution at 20 “C for 5h, in the presence of 5 mol % Pd(PPhg)4,

gave rise to ethyl 2-(phenylthioj-1 cyclopentene-1-carboxylate, 23, in 96 % yield (eq 4). Similarly, by treatment

of ethyl (E)-2-methyl-3-[(trifluoromethyl)sulfonyloxy]-2-butenoate, (E)-14, with 5c under very similar

experimental conditions, ethyl (El-2-methyl-3-(phenylthio)-2-butenoate, (E)-24, was obtained in 92 % yield (eq

5).

COOEt

+ PhSSnBu3 Pd(PPh&, NMP LiCl, 20 “C, 5 h

(4)

COOEt 13 5C 23

COOEt COOEt

M + PhSSnBu, Pd(PPh3)4, NMP

- LiCI, 20 “C, 5 h OTf SPh

(5)

(E)-14 SC (E)-24

A functionalized 1-bromo- I-alkyne proved also to be a suitable substrate for a Pd-mediated C-S bond

forming reaction. In fact, when easily available methyl 3-bromopropiolate, 1.5,” was reacted with 1.15 equiv of

Sd in NMP solution at 20 “C for 5 h in the presence of 5 mol % Pd(PPh& methyl (methylthio)propiolate, 25,

was obtained in 41 % yield (eq 6). To the best of our knowledge, this reaction represents the first example of a

Pd-mediated Csn-heteroatom bond forming reaction.

Br+COOMe + MeSSnBu3 yM~‘~k?j)~DC - MeSeCOOMe > 3

15 5d 25

(6)

Finally, we examined the possibility to convert selectively a symmetrically substituted aryl dibromide

into the corresponding (arylthio)aryl bromide. This reaction, if possible and efficient, could represent a good

alternative to the classical procedure which involves treatment of an iodoarene with a potassium thiophenate

and copper-bronze in refluxing toluene. 30 It was so found that the Pd-mediated reaction between 1,2-dibromo-

benzene, 16, and an equimolar amount of 5c in NMP solution at 20 “C for several hours did not give a

satisfactory result. However. when compound 16 was treated with 0.77 equiv of 5c in toluene at 100 “C for 18

h in the presence of 3 mol %# Pd(PPhj)a, a crude reaction mixture, which contained 2-

(phenylthio)bromobenzene. 26, and 1,2-bis(phenylthio)benzene, 27, in a cu. 80 : 20 molar ratio. respectively,

was obtained (eq 7). Purification of this mixture by MPLC on silica gel allowed to isolate 26 in 67 % yield

based on 5c.

Br + PhSSnBu,

Pd(PPh&, toluene

Br 18 h, 100 ‘C

16 5c 26 27

(7)

Finally, as a continuation of our preliminary study on the synthetic utility of some compounds prepared

by the above mentioned C,$-heteroatom bond forming reactions, 3’ we explored the use of methyl (E)- and (Z)-

Page 9: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1033

3-(methylthio)propenoate, (E)- and (Z)-22a, as direct precursors to some unusual naturally-occurring sulfur-

containing carboxyamides, i.e. sinharine, (E)-28, J’a&’ methylsinharine, (E)-29,3a,“f penangin, (E)-30,3bsd

isopenangin, (Z)-30,3b,d and entadamide A, (E-31.3’

Compounds (E)-28 and (E)-29, which exhibit antifungal activity against spores of Clados~o~i~n? cludo-

spor.oides, have been isolated from G/ycosmis cyunocur~pu, 3~ whereas compounds (E)- and (a-30 have been

found to be present in G. chlorospermu. 3h On the other hand, compound (E)-31, which is able to inhibit the

arachidonate 5lipoxygenase activity of rat basophilic leukemia cells, 32 has been isolated from E~rrudu phuseo-

loides seeds.je

0 Me

MeS 2

N’

‘H

(Q-28 : R = H; R’ = CH2CH2Ph (E)-29 : R = Me; R’ = CHzCH?Ph (E)-30 : R = H; R’ = Me (E)-31 : R = H; R’ = CHICHIOH

(Z)-30

Thus, according to a general method for conversion of esters into amides.33 a CH2C12 solution of (022a

34 was reacted at 40 “C with a CH2Cl2 solution of 2 equiv of dimethylaluminum amides 32a-d, which were

prepared irr sirzr by treatment of CH$.X2 solutions of the corresponding amines with a 2 M hexane solution of

AlMe (eq Q.33

R’ MeSACOOMe + )N-AlMe,

R

I) CHzCII, A P’ 2) H30+

(E)-22a 32a : R = H; R’ = CH&H2Ph 32b : R = Me; R’ = CHzCH2Ph 32c : R = H; R’ = Me 32d : R = H; Rt = CH2CH20AlMe2

(Q-28 : R = H; R’ = CH2CH2Ph (Q-29 : R = Me; R’ = CHzCH2Ph (Q-30 : R = H; R’ = Me (E-31 : R = H; Rt = CH2CH20H

Hydrolysis of the reaction mixtures followed by purification of the crude reaction products by

recrystallization or MPLC on silica gel gave chemically and stereoisomerically pure compounds (E)-28,-f5(E)-

29,36 (/I?)-30,“and (Q-31,-@ in 95, 39,43 and 32 % yield, respectively.

Surprisingly, the reaction which afforded methylsinharine, (E)-29, produced also in 17 % yield a by-

product, which was identified as (E)-N-methyl-N-(2-phenylethyl)-3-(methoxy)propenamide, (E)-33.

(E)-33

We also tested the use of compound (Z)-22ajY as a direct precursor to stereoisomerically pure

isopenangin, (Z-30, by a protocol similar to that used to prepare the corresponding stereoisomer. Thus, we

performed some attempts for optimizing the nature of the solvent, the reaction temperature and, particularly, the

stereospecificity of the reaction. However. it was found that also in the best conditions tested, by treatment of

Page 10: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1034 R. ROSSI et al.

(Z)-22a with a benzene. solution of 2 equiv of (N-methylamido)chloro(methyl)aluminum, 34,40 at 80 “C for 5 h,

the crude reaction mixture, which was obtained after hydrolysis, contained (E)- and (Z)-30 in a cu. 3 : 1 ratio,

respectively (eq 9). Purification of this mixture by MPLC OII silica gel allowed to obtain (E)- and (Z)-30 in 45

and 9 % yield, respectively.

It must be noted that some preliminary fungicidal activity tests involving compounds (E)-28, (E)-29, (E)-

30 and (E)-31 showed that these compounds exhibited low activity against Bo~yris cirrereu. Moreover, it was

found that 100 ppm of (E)-28 inhibited 65 % of the mycelial growth of Phytoyht~a irlfesrarls and that the

percentage of inhibition was lower for compounds (E)-29, (E)-30 and (E)-31.

MeS -COOMe +

(Z)-22a

Me, Ye ,N-AI,

H Cl

34

1 j benzene. 80 “C / 2) H30+ 3) MPLC L

Ye MeS /

T

NH

(E)-30

Me MeS

i-Y?- - yH

(Z)-30

(9)

In conclusion, the results of our investigations on Pd-mediated C-O bond and C-S bond focming reactions

have shown that: (i) alkyl (E)- and (Z)-2Jdibromopropenoates. (E)- and (Z)-4, are able to react in very mild

conditions with (alkoxy)-, (arylthio)- and (alkylthio)tributyIstannanes to give regioselectively and

stereospecifically products of general formula (E)- and (Z)-6, which derive from monosubstitution reactions in

the 3-position of these substrates; (ii) the rates and yields of the Pd-mediated reactions involving (arylthio)- or

(alkylthio)tributylstannanes and compounds (2).4 are higher than those obtained when

(alkoxy)tributylstannanes are used as nucleophiles; (iii) when 2-bromo substituted a&unsaturated esters or

lactones are treated with (alkoxy)tributylstannanes in experimental conditions similar to those employed to

prepare compounds (Z)- and (E)-6, substitution reactions do not occur: (iv) Pd-mediated reactions of

(alkoxy)tributylstannanes with 3-substituted (E)-2,3-dibromopropenoates. (E)-7, or 3-substituted 3-

iodopropenoates, (Z)-11, give rise to a,P-acetylenic esters, 19, instead of to products derived from substitution

reactions. However. a compound. which derives from a substitution reaction, has been obtained in low yield

together with the corresponding c&acetylenic ester when PhSSnBuj was reacted with (E)-7c in the presence of

Pd(PPh$4; (1~) on the contrary, methyl (E)- and Q-3-bromopropenoate, (E)- and (Z)-10, a 3-alkyl substituted

3-iodopropenoate, i.e. (z)-lla, 3-(trifluoromethyl)sulfonyloxy substituted a&unsaturated esters such as 13 and

(E)-14, as well as methyl 3-bromopropiolate, 15. have proven to be able to undergo efficient Pd-mediated

substitution reactions when reacted with MeSSnBuj or PhSSnBu3; (vi) a typical symmetrically substituted

dibromoarene, i.c. 16, is able to undergo an efficient and selective monosubstitution reaction when reacted with

0.77 equiv of PhSSnBuj in toluene at 100 “C in the presence of a catalytic amount of Pd(PPh&

Finally. we have demonstrated the synthetic utility of two new compounds, i.e. (E)- and (.Z-22a, which

have been very efficiently prepared by Pd-mediated C-S bond forming reactions, by their direct conversion into

some naturally-occurring carboxyamides. Interestingly, the simple protocol used to prepare these amides allows

to obtain all these substances as chemically pure crystalline solids, even though two of these compounds, i.e.

(Q-28 and (E)-31 isolated from natural sources,3u~b~ 3-7 as well as synthetic (E)-293f have been reported to be

oils.

Page 11: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1035

EXPERIMENTAL

All boiling and melting points are uncorrected. Precoated plastic silica gel sheets Merck 60 F2.j~ were

used for TLC analyses. GLC analyses were performed on a Dani 6500 gas-chromatograph with a PTV injector

and equipped with a Dani data station 86.01. Two types of capillary columns were used: a SE-30 bonded FSOT

column (30 m x 0.25 mm i.d.) and a AT-WAX bonded FSOT column (30 m * 0.25 mm i.d.). Purifications by

MPLC were performed on a Biichi instrument, using a Bischoff 8100 differential refractometer as detector.

CiLC/MS analyses were performed using a Q-mass 910 spectrometer interfaced with a Perkin-Elmer 8500 gas-

chromatograph. ‘H and t3C NMR spectra were recorded on a Varian Gemini 200 MHz spectrometer or a

Brucker AMX 600 spectrometer using TMS and CDC13 as an internal standard, respectively. IR spectra were

recorded on a Perkin-Elmer 1725-X FT-IR spectrophotometer. All reactions of air- and water-sensitive

materials were performed in flame dried glassware under an atmosphere of argon or nitrogen. Air and water

sensitive solutions were transferred with hypodermic syringes or double ended needles. Solvents were dried and

distilled before use. Methyl phenylpropiolate, 19a. diethyl acetylenedicarboxylate, 19b. methyl 2-octynoate,

19c, (methoxy)tributylstannane, Sa, and (ethoxy)tributylstannane, 5 b, were commercially available.

Compounds 5a and Sb were distilled before use. The following compounds were prepared according to the

literature: Pd(PPh3)4,11 methyl (Z)-2,3-dibromopropenoate, (Z)-4a,- ‘& ethyl (Z)-2,3-dibromopropenoate, (q-

4b,‘@ methyl (El-2,3-dibromopropenoate, (E)-4a,‘ou ethyl (E)-2$dibromopropenoate, (E)4b,20a,c ethyl (E)-

2,3-dibromo-3-phenylpropenoate, (E)-7a.z” ethyl (E)-2,3-dibromofumarate, (E)-7b.?’ ethyl (E)-2,3-dibromo-2-

butenoate, (E)-7c,” ethyl (Z)-3-bromo-3-phenylpropenoate, (Z)-9a,- ‘(j( 2-bromocoumarin, 18,2~~C methyl (Z)-

and (E)-3-bromopropenoate, Q- and (E)-l0.1’ ethyl (Z)-3-iodo-3-phenylpropenoate, (Z)-llb,$3 ethyl 2-

[(trifluoromethyl)suIfonyloxy]-l-cyclopentene-l-carboxylate. 13, 41 and methyl 3-bromopropiolate, 15.‘y Ethyl

(E)/(Z)-3-bromo-2-(2.propenyl)propenoate, (E)/(Z)-12 [ b.p. 61-62 “C/l Tar. For (E)-12: ‘H NMR (CDC13): 6

6.53 (lH, t, J = 1.4 Hz, H-3), 5.91-5.72 (IH. m. H-2’). 5.20-5.03 (2H. ITI, H-3’ and H-3”). 4.27 (2H, q, J = 7.2

Hz, OCH?), 3.09 (2H, dq. J = 6.4 and 1.4 Hz, H-l’). 1.33 ppm (3H, t, J = 7.2 Hz, CH3). For (Z)-12: tH NMR

(CDClj): F 7.60 (lH, s, H-3’), 3.27 ppm (2H. dt, J = 6.4 and 1.7 Hz, H-l’)] was prepared according to the

procedure reported for the synthesis of the corresponding methyl ester.45

Methyl (Z)-3-iodo-_3-O(.fe/lOut(‘, (Zblla:. This compound. which was prepared in 85 7~ yield from methyl

2-octynoate. 19~. according to the general procedure for the synthesis of alkyl (Z)-3-iodo-2-alkenoates!j had:

b.p.82-83 “C/O.05 Torr. tH NMR (CDClx): 6 6.34 (lH, t. J = 1.1 Hz, H-2). 2.70 (2H, dt, J = 7.1 and 1.1 Hz, H-

4), 1.50-1.26 (6H. br m, H-5, H-6 and H-7), 0.90 ppm (3H, t, J = 6.5 Hz, H-8). MS, u?/: (8): 282 (20), 226 (26),

155 (ll), 123 (13), 99 (30), 95 (100). 81 (40), 71 (18). 67 (33). 59 (50), 55 (42), 53 (34). Anal. Calcd for

C9Ht5102: C, 38.52; H. 5.36. Found: C, 38.40; H, 5.52.

(Phe/l.~lthioitt’iDlr~~stu/l,rcrlrr, SC.. A 1.87 M hexane solution of BuLi (82.6 ml), 0.155 mol) was added dropwise

to a solution of thiophenol (17.1 g, 0.155 mol) in THF (200 ml) and the resulting mixture was refluxed for 1 h

and then cooled to 20 ‘C. A solution of chlorotributylstamlane (48.8 g, 0.150 mol) in THF (150 ml) was added

and the mixture was refluxed for 22 h. It was then cooled to room temperature, diluted with Et20 and washed

sequentially with cold 5 N NaOH, diluted acetic acid and brine until neutrality. The organic phase was dried,

concentrated irl WC’IIO and the residue was fractionally distilled to give SC (37.4 g, 63 8 yield): b.p. 140 “C/O.04

Torr. The spectral properties of this compound were in good agreement with those previously rep0rted.l”

Page 12: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides
Page 13: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1037

(E)- and (Z)-22a, (Z)-22b, 23, (E)-24 and 25.

As shown in Tables 1 and 2, when the Pd-mediated reactions involved (alkoxy)tributylstannanes and

compounds (E)-7a, (E)-7b, (Q-1 la and (Z)-llb, respectively, a$-acetylenic esters 19a, 19b, 19c and 19a,

respectively were obtained (entries 7 and 8, Table 1 and entries 3 and 5, Table 2). These esters were identified

by comparison with authentic samples of these substances. On the other hand, the Pd-mediated reaction

between (I!?)-7c and 5c afforded a mixture of 19c and (Q-20 in 13 and 21 % GLC yield, respectively (entry 9,

Table 1).

Mefhyl (Z~-2-br~on~o-3-(n~efho.~~ipr~op~~~1oare, (ZJ-6~. The crude reaction product, which was obtained by Pd-

mediated reaction between (Z)-4a and MeOSnBug, 5a (entry 1, Table l), was purified by MPLC on silica gel,

using a mixture of hexane and Et20 (80 : 20 V/V) as eluant, to give in 63 % yield chemically and

stereoisomerically pure (Z)-6a as a colourless crystalline solid: m.p. 31-32 ‘C. IH NMR (CDC13): 6 7.78 (lH, s.

H-3), 3.99 (3H, s, OMe), 3.60 ppm (3H, s, OMe). IR (melted): 3034, 2998, 2951. 2847, 1719, 1631, 1437,

1280, 1245, 1142, 1068, 983, 906, 757 cm-*. MS, nl/: (%): 196 (34). 194 (33), 165 (loo), 163 (92). 122 (43).

120 (45), 115 (68j, 107 (11). 75 (82). Anal. Calc. for CsH7Br03: C, 30.80; H. 3.62. Found: C, 30.52: H, 3.44.

Ethyl (Z)-2-br.or7lo-3-(~tho.~~~~~~.~~~~[~~~~~ur~, (Z)-6b. The crude reaction product, which was obtained by Pd-

mediated reaction between (Z)-4b and EtOSnBq 5b (entry 2, Table 1). was purified by MPLC on silica gel,

using a mixture of hexane and Et20 (80 : 20 V/V) as eluant, to give in 45 % yield chemically and

stereoisomerically pure (Z)-6b as a colourless oil. ‘H NMR (CDQ): 6 7.85 (lH, s, H-3), 4.23 (4H, br q, J = 7.1

Hz, O-CH2), 1.40 (3H, t, J = 7.6 Hz, -C-CH$, 1.31 ppm (3H, t, J = 7.1 Hz, C-CH3). MS, m/z (%): 224 (24),

222 (25), 196 (18), 194 (19). 177 (171, 168 (80). 166 (74). 150 (100). 148 (98). Anal. Calc for C7Hl IBrOj: C.

37.69; H, 4.97. Found: C, 37.89; H, 4.85.

Mefhyl (Zi--3-b~c~n7o-3-(yher~ylrhioJyr.o~~e,rour~, (Z)-6c. The crude reaction product, which was obtained by Pd-

mediated reaction between (Z)-4a and PhSSnBq, SC (entry 3, Table 1). was purified by MPLC on silica gel,

using a mixture of hexane and benzene (70 : 30 \>/\a) as eluant, to give in 84 % yield chemically and

stereoisomerically pure (z)dc as a pale yellow crystalline solid: m.p. 51-53 “C. ‘H NMR (CDC13): S 8.29 (lH,

s, H-3). 7.55-7.35 (5H, m, Ph), 3.81 ppm (3H. s, OMe). MS, n~/z (%): 274 (57). 272 (55), 194 (13). 193 (loo),

192 (5); 161 (66). 134 (75), 133 (39), 109 (56). Anal. Calc for CloH9BrO?S: C, 43.97; H, 3.32. Found: C,

44.34; H, 3.11.

Methyl (Zi-2-bl.omo-3-(nl~~/~y/~~;~~~/~/.~~~~~/1~~~~, (ZJ-6d. The crude reaction product, which was obtained by Pd-

mediated reaction between (Z)Aa and MeSSnBuj, 5d (entry 4, Table 1). was purified by MPLC on silica gel,

using a mixture of hexane and benzene (60 : 40 V/V) as eluant, to give in 86 % yield chemically and

stereoisomerically pure (Z)-6d as a pale yellow oil. IH NMR (CDC13): 6 8.12 (lH, s, H-3), 3.81 (3H, s. OMe),

2.52 ppm (3H, s, SMe). 1R (film): 3025, 2951, 2929, 1718, 1558, 1434, 1326, 1222, 1047, 988, 940, 902, 870,

848, 740 cm-l. MS, 4: (95): 212 (12). 210 (12), 181 (9), 179 (9). 131 (45), 99 (13). 57 (18). 53 (34). 45 (100).

Anal. Calc for CsH7Br02S: C, 28.45: H, 3.34. Found: C, 28.95; H, 3.33.

Methyl (E)-2-bl.omo-3-(nlet~l~.~-~Jpt.~)~e~~~)ute, (E)-6a. The crude reaction product, which was obtained by Pd-

mediated reaction between (E)-4a and Sa (entry 5, Table 1). was purified by MPLC on silica gel, using a

Page 14: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1038 R. ROSS1 et al.

mixture of hexane and Et20 (80 : 20 V/V) as eluant, to give in 46 % yield chemically and stereoisomerically

pure (E)-6a as a colourless crystalline solid: m.p. 46-48 ‘C. IH NMR (CDC13): F 7.06 (lH, s, H-3) 3.93 (3H, s,

OMe), 3.75 ppm (3H, s, OMe). IR (melted): 2950, 2847, 1713, 1618, 1435, 1372, 1289, 1055. 992, 973, 921,

882, 833, 805, 763 cm-l. MS, nriz (%): 196 (37) 194 (36) 167 (12), 165 (loo), 163 (93), 122 (28) 120 (30);

115 (53). 75 (73). Anal. Calc for CgH7BrOj: C, 30.80; H, 3.62. Found: C, 30.61; H, 3.37.

Ethyl (E)-2-b/.onlu-3-(etho~-~l)~~l.o~elloate, (Ekbe. The crude reaction product, which was obtained by Pd-

mediated reaction between (E)-4b and 5a (entry 6, Table l), was purified by MPLC on silica gel, using a

mixture of hexane and Et20 (80 : 20 V/V) as eluant, to give in 42 % yield chemically and stereoisomerically

pure compound (E)-6e as an oil. ‘H NMR (CDC13): S 7.05 (lH, s, H-3). 4.23 (2H. q. J = 7.1 Hz, OCH2), 3.92

(3H, S, OMe), 1.32 ppm (3H, t, J = 7.1 Hz, -C-CH3). Anal. Calc for CgHgBrOj: C, 34.47; H, 4.34. Found: C.

34.22; H, 4.47.

Methyl (E)-3-(methylthio)j.~~e~~~ute, (El-22~. An Et20 solution of the crude reaction product, which was

obtained by Pd-mediated reaction between 5d and methyl (E)-3-bromopropenoate, (Q-10 (entry 1, Table 2).

was partly purified by treatment with a 50 % aqueous KF solution according to the general procedure above

reported. The Et20 solution so obtained was concentrated under reduced pressure and the residue was diluted

with pentane and filtered over Celite. The filtrate was dried, concentrated under reduced pressure and the

residue was fractionally distilled to give chemically and stereoisomerically pure (E)-22a in 89 % yield: b.p. 45

“C/O.06 Torr. lH NMR (CDClj): 6 7.75 (lH, d, J = 14.8 Hz, H-3) 5.66 (lH, d, J = 14.8 Hz, H-2), 3.79 (3H, s,

OMe), 2.34 ppm (3H, s, SMe). MS, m/z (%): 133 (4) 132 (ho), 117 (55) 101 (100) 85 (21) 73 (39) 72 (14)

59 (21) 57 (27). Anal. Calc for CgHgOzS: C, 45.43; H, 6.10. Found: C, 45.03; H, 6.24.

Methyl (ZI-3-(nlethylthio)/.o~e/~~~ute, (ZJ-22a. The crude reaction product, which was obtained by Pd-mediated

reaction between 5d and methyl (Z)-3-bromopropenoate, (Z-10 (entry 2, Table 2), was purified by a procedure

similar to that used for the preparation of the corresponding stereoisomer to give chemically and

stereoisomerically pure (2).22a in 90 % yield: b.p. 51-52 C/O.01 Ton. tH NMR (CDC13): 6 7.08 (lH, d, J =

10.1 Hz, H-3) 5.85 (lH, d, J = 10.1 Hz, H-2), 3.73 (3H, s, OMe), 2.41 ppm (3H. s. SMe). MS, m/z (7%): 133 (4).

132 (67), 117 (57), 101 (100). 100 (39), 85 (19). 73 (40). 59 (20) 58 (66). Anal. Calc for C5H8O?S: C, 45.43;

H,6.10. Found: C45.80; H. 6.19.

Methyl (Z1-3-(~he/~ylthio)-2-octenncrre, (Zi-22b. The crude reaction product. which was obtained by Pd-

mediated reaction of 5c with methyl Q-3-iodo-2-octenoate, (Z)-lla (entry 4, Table 2) was purified by MPLC

on silica gel, using a mixture of hexane and benzene (60 : 40 V/V) as eluant to give pure (Z)-22b in 95 % yield.

‘H NMR (CDC13): 67.56-7.35 (5H, m, Ph), 5.85 (lH, s, H-2), 3.74 (3H, s, OMe), 2.09 (2H, t, J = 7.3 Hz, H-4),

1.52-0.95 (6H, br m, H-5, H-5 and H-7) 0.76 ppm (3H, t, J = 6.6 Hz, H-8). IR (film): 2954, 2932, 2861, 1708,

1581, 1477, 1435, 1201, 1023, 926, 828, 753, 707, 694 cm-l. MS, mk (%): 265 (5), 264 (28), 233 (25), 189

(19). 147 (31). 135 (64) 134 (loo), 110 (73). 95 (48). Anal. Calc for C15H2002S: C, 68.15; H, 7.63. Found: C.

67.91; H, 7.35.

Ethyl 2-(~heny/rhio~-I-cyclo~e~rtrr~e-l-~u~bo.~ylute, 23. The crude reaction product, which was obtained by Pd-

mediated reaction of 5c with ethyl 2-[(trifluoromethyl)sulfonyloxy]-l-cyclopentene-l-carboxylate, 13, and LiCl

Page 15: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1039

in NMP solution for 5 h at 20 ‘C (eq 4) according to the above mentioned general procedure, was purified by

MPLC on silica gel using a mixture of benzene and hexane (60 : 40 V/V) as eluant, to give in 96 % yield

chemically pure 23 as an oil. lH NMR (CDC13): 6 7.60-7.50 (2H, m, H,,,), 7.42-7.27 (3H, m, Ha,.&, 4.26

(2H, q, J = 7.0 Hz, OCH2), 2.69 (2H, tt, J = 7.3 and 2.1 Hz, H-3), 2.29 (2H. tt. J =7.3 and 2.1 Hz, H-5). 1.80

(2H, quint, J = 7.3 Hz, H-4), 1.33 ppm (3H. t, J = 7.0 Hz, -C-CH3). IR (film): 2977, 2855, 1693, 1576, 1476,

1264, 1150, 1076, 1025, 767, 752, 705, 694 cm-l. MS, m/z (%): 249 (15), 248 (loo), 203 (59). 201 (46). 175

(35), 173 (43), 147 (29), 127 (12), 65 (17). Anal. Calc for Cl4H160zS: C, 67.71; H, 6.49. Found: C. 68.08; H.

6.71.

Ethyl (E)-2-mefhyl-3-(~l~e~rylthioi-2-Dute~~oute, (E)-24. Tile crude reaction product, which was obtained by Pd-

mediated reaction of SC with ethyl (E)-2-methyl-3-[(trifluoromethyl)sulfonyloxy]-2-butenoate, (E)-14 and LiCl

in NMP solution at 20 ‘C for 5 h (eq 5) according to the above mentioned general procedure, was purified by

MPLC on silica gel, using a mixture of hexane and benzene (60 : 40 Y/V) as eluant. to give in 93 % yield pure

(E)-24 as a colourless oil. tH NMR (CDCIj): 67.37 (2H, br s, H arom). 7.34 (3H, br, H,,,), 4.20 (2H, q, J = 7.1

Hz, OCH2). 2.13 (3H, S, H-4). 2.08 (3H, s. =C-CH3), 1.30 ppm (3H, t, J = 7.1 Hz, -C-CH3). IR (film): 2980,

2929, 1703, 1582, 1477, 1440, 1260, 1175, 1073, 768. 750, 708, 693 cm1. MS, m/r (%): 237 (13), 236 (72),

191 (73), 190 (41). 147 (66), 127 (5.5), 110 (loo), 99 (96). Anal. Calc for C13H1602S: C, 66.07; H, 6.82.

Found: C, 65.87; H, 6.56.

Methyl (methylthio)~r.o~iolare, 25. The crude reaction product, which was obtained by Pd-mediated reaction

between 5c and methyl 3-bromopropiolate, 15. in NMP solution at 20 “C for 5 h (eq 6) according to the above

reported general procedure, was purified by fractional distillation pure 25 to give in 41 % yield: b.p. 38-39

“C/O.1 Torr. ‘H NMR (CDCI?): 6 3.77 (3H, s, OMe), 2.49 ppm (3H, s, SMe). Anal. Calc for C5Hb02S: C,

45.98; H, 4.63. Found: C, 46.03; H, 4.75.

Pd-mediated synthesis of’2-(~ket~ylrhioibr~onrobet~~et~e, 26. Compound SC (11.98 g, 30.0 mmol) was added to a

solution of Pd(PPhj)J (1.35 g, 1.17 mmol) and 1,2-dibromobenzene, 16 (9.20 g, 39.0 mmol) in deareated

toluene (120 ml) and the resulting mixture was stirred at 100 “C for 18 h under argon atmosphere. After this

period, a GLC analysis of a sample of the reaction mixture showed the absence of 16 and the presence of two

new compounds in a cu. 80 : 20 molar ratio, which, by comparison with authentic samples prepared according

to the literature,30 were identified as 26 and 1.2-bis(phenylthio)benzene. 27, respectively. The mixture was

cooled to room temperature and stirred with a large molar excess of a 50 % aqueous KF solution at room

temperature for 6 h. The resulting mixture was filtered over Celite and the filtrate was repeatedly extracted with

EtzO. The collected organic extracts were dried and concentrated in ~YKU~. The residue was diluted with

hexane and filtered over Celite. The filtrate was concentrated in vacua and the residue was purified by MPLC

on silica gel, using hexane as eluant, to give 98 8 chemically pure 26 (5.34 g, 67 % yield): b.p. 112-l 14

“C/O.02 TOIT (litjO b.p. 203 “C/6 mm). ‘H NMR (CDC13): 6 7.54 (lH, dd, J = 7.6 and 1.5 Hz, H-6), 7.50-7.30

(5H, m, Ph), 7.12 (lH, dt. J = 7.6 and 1.5 Hz, H-4), 7.00 (lH, dt, J = 7.6 and 1.9 Hz, H-5), 6.91 ppm (lH, dd, J

= 7.6 and 1.9 Hz, H-3). MS, w/r (%): 266 (76), 264 (73), 185 (loo), 184 (70), 152 (20). 108 (25), 92 (31). 75

(16), 51 (56).

Getled procedure for the synthe.sis cf curlm~yumides (El-28, {E)-29, (Ei-30 utrd (Ei-31. A 2.0 M hexane

Page 16: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1040 R. ROW et al.

solution of AlMe (10 ml, 20 mmol) was added dropwise to a solution of an amine (20 mmol) in dry and

deareated CHzC12 (60 ml), which was stirred at room temperature under argon. After the mixture was stirred

for 0.5 h a solution of methyl (E)-3-(methylthio)propenoate, (E)-22a (1.32 g, 10.0 mmol) in dry CH2C12 (15

ml) was added to the solution of dimethylaluminum amide 32 so obtained and the resulting mixture was stirred

at room temperature until a GLC analysis of a sample of this mixture, which was hydrolyzed with cold 10 %

HCI, showed the absence of (E)-22a. The mixture was then cooled to 0 ‘C, cautiously hydrolyzed with cold 10

% HCl and extracted with CH2Cl2. The organic exwact was washed with water, dried and concentrated in

vucuo and the residue was purified by recrystallization or MPLC on silica gel. The amines used to prepare

compounds (Q-28, (E)-29 and (E)-30 were 2_phenylethylamine, N-methyl-2-phenylethylamine and

methylamine, respectively. For the preparation of compound (E)-31 a CH2C12 solution of dimethylaluminum

amide 32d was prepared by addition of a 2.0 M hexane solution of AlMe to ethanolamine, but the molar ratio

between these reagents was 2 : 1. Moreover, the reaction time employed to obtain 32d was 1.5 h. The

subsequent procedure for obtaining (E)-31 was identical to that used for the synthesis of compounds (E)-28,

(E)-29 and (E)-30.

tE)-3-(Methylthio)-N-(2-phcnylethyl~yr~o~e~zamide (sinharim), (E)-28. The crude reaction product, which was

obtained by treatment of (022a with a CH2C12 solution of dimethylaluminum amide 32a at 20 “C for 21 h and

the under reflux for 65 h. was purified by recrystallization from 95 % EtOH to give in 95 % yield chemically

and stereoisomerically pure (E)-28 as a colourless crystalline solid: m.p. 105-106 “C (lit3fm.p. 104-105 “C). lH

NMR (CDC13): 67.58 (lH, d, J = 14.6 Hz, H-3), 7.38-7.10 (5H, br m, Ph), 5.86 (lH, br s, NH), 5.60 (lH, d, J =

14.6 Hz, H-2), 3.56 (2H, q, J = 7.0 Hz, CHzN), 2.83 (2H, t, J = 7.0 Hz, N-C-CH2), 2.27 ppm (3H. S, SMe). t3C

NMR (CDC13): 6 164.6, 142.3, 138.9, 128.7, 128.6, 126.4, 115.9, 40.7, 35.7, 14.6 ppm. Anal. Calc for

Ct2HtsNOS: C. 65.12; H, 6.83. Found: C, 65.50; H, 7.04. The spectral properties of this compound were in

good agreement with those previously reported either for naturally-occurring sinharine3Q or a synthetic sample

of this carboxyamide.35C

(E)-N-Mcthyl-3-(methylthioJ-N-(2-yhe~~ylethyl)y~o~enamide (methylsinhar-ine), (E)-29. The crude reaction

product, which was obtained by treatment of (E)-22a with a CH2Cl2 solution of dimethylaluminum amide 32b

for 33.5 h under reflux and for 12 h at room temperature, was purified by MPLC on silica gel, using a mixture

of hexane and Et20 (50: 50 V/V) as eluant. Concentration of the first eluted chromatographic fractions allowed

to obtain in 39 % yield chemically and stereoisomerically pure (E)-29 as a colourless crystalline solid: m.p. 55-

56 “C. lH NMR (CDCl$: F, 7.47 (lH, br, H-3), 7.31 (2H, dd, J = 7.4 and 7.4 Hz, H-3’ and H-5’), 7.24 (lH, dd,

J = 7.4 and 7.3 Hz, H-4’), 7.15 (2H, d, J = 7.3 Hz, H-2’ and H-6’), 5.04 (lH, br s, H-2), 3.42 (2H, br, N-CH2),

2.85 (2H, t, J = 7.5 Hz, -2.Ph), 2.78 (3H, br s, N-Me), 2.31 ppm (3H, s, SMe). Interestingly, the tH NMR

spectrum registered at 600 MHz in hexadeuteroacetone showed that the signal at 4.92 ppm, which was assigned

to the H-2 proton, was a doublet (J = 12.5 Hz). Similarly, the signal centered at 7.40 ppm, which was attributed

to the H-3 proton, was a doublet (J = 12.5 Hz). l3C NMR (CDCl3): 6 186.2 (CO), 150.2 (C-3), 139.9 (C-l’),

130.1 (C-3’ and C-5’), 129.7 (C-2’ and C-6’), 127.6 (C-4’), 94.9 (C-2), 60.1 (C-N), 36.3 (C-Ph), 36.0 (Me-N),

11.0 ppm (SMe). MS, m/z (%): 235 (4). 189 (24), 188 (loo), 170 (7), 105 (70), 103 (10). 91 (lo), 79 (18), 77

(19). The physical properties of (E)-29 did not match those previously reported.jf However, its spectral

properties were in satisfactory agreement with those of the natural compound.-‘”

On the other hand, concentration of the intermediate chromatographic fractions allowed to obtain in 17 %

Page 17: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions 1041

yield an oily substance, which had chemical purity higher than 92 %. The structure of this compound

corresponded to that of (E)-N-methyl-N-(2-phenylethy1)-3-(methoxy)propenamide, (E)-33. *H NMR (CDC13):

6 7.42 (IH, d, J = 12.9 Hz, H-3). 7.33-7.12 (5H, br m, Ph), 4.54 (lH, d, J = 12.9 Hz, H-2), 3.65 (3H. s, OMe),

3.39 (2H, t, J = 7.0 Hz, N-CH?), 2.83 (2H, t, J = 7.0 Hz, CHz-Ph), 2.77 ppm (3H, s, N-Me). MS, m/z (a): 220

(5). 219 (32). 189 (4), 188 (30), 129 (17), 128 (loo), 105 (34j, 104 (50). 91 (16).

(EJ-3-(Methylrhio)-N-(n~ethyl)yt~o~et~un~ide (petmgitt), (E)-30. The crude reaction product, which was obtained

by treatment of (022a with a CH2Q solution of dimethylaluminum amide 31c at 40 “C for 24 h, was purified

by MPLC on silica gel. using a mixture of AcOEt and hexane (90 : 10 V/V) as eluant, to give in 43 % yield

chemically and stereoisomerically pure (E)-30 as a colourless crystalline solid: m.p. 65-66 “C. tH NMR

(CDC13): 67.57 (IH, d, J = 14.5 Hz. H-3), 6.60 (lH, brs, NH), 5.76 (lH, d, J = 14.5 Hz, H-2). 2.86 (3H, d, J =

4.6 Hz, N-Me), 2.31 ppm (3H, s, SMe). The spectra1 properties of this compound were in satisfactory

agreement with those previously reported.jd

(E)-3-(MethylthinJ-N-(2’hydt’o.~y~thylJyt.c)~ettamide (entudunzide AJ, (E)-31. The crude reaction product, which

was obtained by treatment of (E)-22a with a CH2Cl2 solution of dimethylaluminum amide 32d at 40 “C for 41

h, was purified by MPLC on silica gel, using a mixture of CH2Cl2 and methanol (94 : 6 V/L;) as eluant, to give in

32 % yield chemically and stereoisomerically pure (E)-31 as a colourless crystalline solid: m.p. 43-44 “C. tH

NMR (CDC13): 67.61 (IH, d, J = 14.6 Hz, H-31, 6.73 (lH, br, NH), 5.71 (lH, d, J = 14.6 Hz, H-2), 4.11 (lH, br

s, OH), 3.71 (2H, br, OCHz), 3.45 (2H, q, J = 5.2 Hz, 0-C-CH2), 2.31 (3H, s, SMe). l3C NMR (CDC13): 6

165.9 (C-l), 143.2 (C-3), 115.5 (C-2), 61.9 (C-2’), 42.5 (C-l’), 14.6 ppm (SMej. Anal. Calc for C6HtlN@S:

C, 55.76; H, 8.58. Found: C, 55.64; H, 8.71. The t3C NMR data were in very good agreement with those of the

natural product?’

Synthesis of (Z)-3-(metl?vlthioJ-N-(methyli~t’opetlatnide (isapetmgin), (Zj-30. A 2.0 M toluene solution of

AlMe (10 ml, 20 mmol) was added dropwise to a suspension of methylamine hydrochloride (1.35 g, 20 mmol)

in dry and deareated benzene (80 ml) and the resulting mixture was stirred at room temperature for 2 h. A

solution of methyl (Zj-3-(methylthio)propenoate, (Z)-22a (1.32 g, 10 mmol) in deareated benzene (20 ml) was

then added to the solution of aluminamide 34 so obtained and the mixture was refluxed for 5 h. It was then

cooled to 5 “C and cautiously hydrolyzed with 10 % HCI and extracted with AcOEt. The organic extract was

washed with water and brine, dried and concentrated under reduced pressure. A GLC analysis of the residue

showed the presence of two compounds in a cu. 3 : 1 ratio, which were subsequently identified as (E)- and (Z)-

30, respectively. The residue was purified by MPLC on silica gel, using a mixture of AcOEt and hexane (90 : 10 V/V) as eluant. Concentration of the first eluted chromatographic fractions allowed to obtain pure (2).30

(0.12 g, 9.2 % yield) as a colourless crystalline solid: m.p. 114-l 16 “C. tH NMR (CDC13); 6 6.74 (lH, d, J =

9.9 Hz, H-3), 6.75 (1H. br, NH), 5.95 (lH, d, J = 9.9 Hz, H-2). 2.83 (3H, d, J = 4.8 Hz, N-Me). The spectra1

properties of this compound were in satisfactory agreement with those previously reported for a synthetic

sample of (Zj-30.jd On the other hand, concentration of the last eluted chromatographic fractions allowed to

obtain pure (E)-30 (0.59 g, 45 % yield). The physical and spectral properties of this compound were in a very

good agreement with those of a sample of this carboxyamide prepared from (E)-22a.

Acknowledaements: This work was supported in part by the Progetto Finalizzato Beni

Page 18: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1042 R. ROSSI et al.

Culfurali (CNR, Roma) and the Minister0 dell’Universita e della Ricerca Scientifica e

Tecnologica (MLJRST)

1.

2.

3.

4.

5.

6.

I.

8.

9.

10.

11.

12.

REFERENCES AND NOTES

For some post-emergence herbicides characterized by O-C,,2 (hetero)aryl bonds or S-C,,? (hetero)aryl

bonds, see: Piccardi, P. Lu Chimira P L’lrdlrstria 1996, 7R, 53 - 57.

For natural and synthetic fungicides characterized by O-C ,$ olefinc bonds, see: (uJ Clough, J. M. Nut..

Plod. Rep. 1993, 10, 565 - 574; (0) Beautement, K.; Clough, J. M.; de Fraine, P. J.; Godfrey, C. R. A.

Pestic. Sci. 1991,31,449 - 519.

For unusual naturally-occurring bioactive carboxyamides, which are characterized by S-C,,2 olefinic

bonds, see: (ui Greger. H., Hofer, 0.; Kahlig. H.; Hadeck, G. T~rr.ohed~o/r 1992,48, 1209 1218; (b)

Greeger. H.; Hadacek, F.; Hofer, 0: Wurz, G.; Zechner, G. Phytochmistry 1993.32,933 - 936; (c) Greger,

H.; Zechner, G.; Hofer, 0.; Hadacek, F.; Wurz, G. Phytochemistry 1993,34, 175 179; (d) Hinterberger,

S.; Hofer, 0.; Greger, H. Tetruhedmr 1994,50, 627%6286; (ej Ikegami, F.; Shibasaki, 1.; Ohmiya, S.;

Ruangrungsi, N.; Murakoshi, I. Clzem. Phum. Bull. 1985.33, 5153 - 5154: (fi Johnson, W. M. Littler, S.

W.; Strauss, C. R. Amt. J. Chem. 1994,47,751 - 772.

For many examples of these compounds, see: The Me~~ck Imle.\-, 1 lth Edn., Merck and Co., Inc., Rhaway,

N. J. USA, 1989.

Broekamp, C. L. E.: Leysen, D. B.; Peeters, W. M. M.; Pinder, P. M. J. Med. C’hem. 1995.38, 46 15 -

4633.

(ui Kosugi, M.; Mameyama, M.; Migita, T. Chem. Lrrt. 1983, 927 928: (D) Kosugi, M.;Kameyame. M.;

Sano, H.; Migita, T. Nippm Kaguk~ Kuishi 1985,3, 547 - 551; (0 Paul, F.; Patt, J.; Hartwig, J. Am. Chem.

SM. 1994, 116,5969 - 5970.

For a mechanistic study of these reactions. see: Louie, J.; Hartwig, J. F. J. An?. Chem. Sot. 1995, 117,

11598. 11.599.

For related intramolecular aromatic aminations using stoichiometric amounts of Pd(PPh& see: Boger, D.

L.; Duff, S. R.; Panek. J. S.; Yasuda. M. ./. 01.g. C/rent. 1985, 50, 5872 5789.

Guram, A. S.; Buchwald, S. L. J. Am. Chm. Sot. 1994, l/6,7901 - 7902.

(a) Zhao, S-H.; Miller, A. K.; Berger, J.; Flippin, L. A. Tmuhedrml Lett. 1996,37, 4463 - 4466; (hi

Driver, M. S.; Hartwig, J. F. J. An?. Chew. Sot. 1996, 118, 7217-7218; (c) Wolfe, J. P.; Wagaw, S.;

Buchwald, S. L. J. An7. Chem. Sot. 1996, 118, 7215-7216.

Louie, J.; Hartwig, J. F. Tetr-uhedm Lett. 1995,36, 3609 - 3612.

(ui Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M. Bdl. Chetn. Sor. Jp. 1980,53,

1385 - 1389; (b) Rajagopalan, S.: Radke, G.; Evans, M.; Tomich, J. M. Syth. Comnwr. 1996,26, 1431 -

1440.

13. For a stoichiometric reaction between 4ClCgHqPdI(dppe) and sodium t-butylthiolate, see: Baraiiano, D.;

Hartwig, J. F. J. An7. Chem. Sot. 1995, 117, 2937 2938.

Page 19: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

Palladium-mediated C-O bond and C-S bond forming reactions I043

14. (a, Kosugi, M.; Ogata, T.; Terada, M.; Sano, H.; Migita, T. Bull. Chew. Sot. J,m. 1985,.58, 3657 3658; (

b) Dickens, M. J.; Gilday, J. P.; Mowlem, T. J.; Widdowson, D. A. Terrahedrotz 1991,47,X621 - 8634; (c)

Bumagin, N. A.; Gulevich, Yu, V.: Beletskaya, I. P. Iz~J. Akud. Nulrk SSR, Ser. Khinl. 1984,4, 953 - 957;

(di Ref 7.

15. Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1995, 36, 4133.4136.

16. Murahashi, S-I.; Yamamura, M.; Yanigisawa, K.; Mita, N.; Kondo, K. J. Org. Chenz. 1979, 44, 2408-

2417.

17. Cristau, H. J.; Chabaud, B.; Labaudiniere, B.; Christol, H. J. Oq. Chew. 1986.51, 875 - 878.

18. Carpita, A.; Rossi, R.; Scamuzzi, B. Tewahedrm Lett. 1989, 30, 2699 - 2702.

19. Rossi, R.; Bellina, F.; Carpita. A. Sylett 1996. 356 - 358.

20. (a) Bellina, F.; Carpita, A.; De Santis, M.; Rossi, R. Tetruhedrm Lett. 1994,3_5. 6913 6916; (h) Rossi,

R.; Bellina, F.: Carpita, A.; Gori, R. Syfrlett 1995. 343 346; (c) Rossi, R.: Bellina. F.; Carpita, A.; Gori,

R. Gazz. Chin?. Itul. 1995, l-75, 381 - 392; (d) Bellina, F.; Carpita, A.; Rossi, R. National Meeting on

O~‘ier&mer~ti e Metodologie irl Chimica Furnzucewicu, Organica e Bioorgunica, Numana (AN), Italy,

June 2-6, 1995, Abstracts, 021.

21. Rossi, R.; Bellina, F.; Carpita, A.; Mazzarella, F. Tetrahedron 1996, 52, 4095 - 4110.

22. Rossi, R.; Bellina, F. 01%. P~u. P/.or. Iru., in press.

23. Rossi, R. Carpita, A.; Bellina, F. 01;~. PI.ep. PI.OC. Int. 1995, 27. 127 160.

24. For transesterification reactions involving carboxylic acid esters and equimolar amounts of tin alkoxides,

see: Valade, J.; Pereyre, M. C. R Acod. Sri. Paris 1962,254, 3693-3695.

25. For a synthesis of (Z)/E)Xia, see: Paliichuk, Y. A.; Kozhushko, B. N.; Shokol, V. A. Zh. Obshch. Khim

1989,59, 307 - 3 16; Chm. Absrr.. 1989, 11 I, 13433 1.

26. A similar hypothesis could explain the results of the regioselective Pd-mediated reactions of organozinc or

organotin derivatives either with (E)- and (Z)-4 or with (E)-7,l~,zo

27. Youssef, A-H. A.: Abdel-Maksoud, H. M. J. Oq. Chem. 1975,40, 3227 3229.

28. For a regioselective but not stereospecific synthesis of alkenyl sulfides by Pd-mediated reaction between

alkenyl triflates and lithium thiolates, see: Martinez. A. G.; Barcina, J. 0.; de Fresno, C. A.; Subramanian,

L. R. Sylett 1994, 561 - 562.

29. Leroy, J. Syth Commurr. 1992, 22, 567 572.

30. Gilman, H.; Stuckwitsch, C. G. J. Am. Chrm. Sot. 1943,65. 1461 - 1465

31. For an application of methyl (7,.2-bromo-3-(methoxy)propenoate, (Z)-6a, to the synthesis of structural

analogues of strobilurins, see: Ref. 19.

32. Ikegami, F.; Sekine, T.; Aburada. M.; Fuji. Y.; Komatsu, Y.; Murakoshi, I. Chem. /‘harm. Bull. 1989, 37,

1932 - 1933.

33. (u) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977.4171 - 4174; (bj Lipton, M. F.; Basha,

A.; Weinreb, S. M. Oq. Syrrth. Coil. Vol VI, 492 495; (c.J Levin, J. I.; Turos, E.; Weinreb, S. M. Sy&z.

Page 20: Selective palladium-mediated CarbonOxygen bond and CarbonSulfur bond forming reactions which involve functionalized Csp2-Hybridized halides or triflates and Csp-Hybridized halides

1044 R. ROSSI et al.

Commutt. 1982,12,989 - 993.

34.

35

This compound was not previously reported in the literature. For a low yielding preparation of the

corresponding carboxylic acid, see: (a, Ref. 3d; (b) Ikegami, F.; Sekine, T.; Duangteraprecha, S.;

Matsushita, N.; Matsuda, N.; Ruangrungsi, N.; Murakoshi, I. Phyrochenlistry 1989.28, 881 - 882.

For previous syntheses of (Q-28, see: (a) Ref. 3d; (0) Ref. 3f; (c) Blaya, S.; Chinchilla, R.; Najera, C.

Terruhedron 1995,51,3617 3626.

36.

31.

38.

39.

For previous syntheses of (Q-29, see: (a) Ref. 3d; (D) Ref 3f.

For a previous synthesis of (E)-30, see: Ref. 3d.

For a previous synthesis of (E)-31, see: Ref. 31.

This compound was not previously reported in the literature. For a synthesis of the corresponding

carboxylic acid, see: De Meideiros, E. F.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Sot. Perkirl I 1991,

2125 - 2730.

40.

41.

42.

43.

44.

45.

46.

47.

We supposed that the structure of this compound, which was prepared from AlMe and methylamine

hydrochloride,32c was similar to that of the aluminum amide obtained from AlMe and dimethylamine

hydrochloride [Sidler, D. R.; Lovelace, T. C.; McNamara, J. M.; Reider. P. C. J. Oq. Chem. 1994,59,

1231 - 12331.

Coulson, D. R. Inorg. Syttth. 1972, 13, 121 - 124.

Carpita, A.; Neri, D.; Rossi, R. GUZ Chin?. Itul. 1987, If 7, 481 489.

Piers, E. Wong, T.; Coish, P. D.; Rogers, C. Ccrtl. J. Chem. 1994, 72, 1816 - 1819.

Lipshutz, B. H.; Reuter. D. C.; Ellsworth, E. L. J. O/x. Chem. 1989, 54, 4975 - 4977.

Kosugi, M.; Sakaya, T.; Ogawa, S.; Migita, T. Bull. Chem. Sot. Jptt. 1993,66, 3058 - 3061.

Peach, M. E. Curl. J. Chem. 1968,46,211 - 215.

Keenam, R. M.; Weinstock, J.; Finkelstein, J. A.; Franz, R. G.; Gaitanopulos, D. E.; Girard, G. R.; Hill, D.

T.; Morgan, T. M.; Samanen, J. M.; Hempel, J.; Eggleston, D. S.; Aiyar, N.; Ohlstein, E. M.; Stack, E. J.;

Weidley, E. F.; Edwards, R. J. Med. Chem. 1992,35,3858 - 3872.

(Received in UK 9 September 1996; revised 1 November 1996; accepted 7 November 1996)