Highly chemo- and regioselective thiocarbonylation of conjugated enynes with thiols and carbon monoxide catalyzed by palladium complexes: An efficient and atom-economical access to 2-(phenylthiocarbonyl)-1,3-dienes

Article abstract of DOI:10.1021/jo9824246

The reaction of 1, 3-conjugated enynes bearing a terminal triple bond with thiols and carbon monoxide in the presence of catalytic quantities of Pd(OAc)₂ (3 mol %) and 1,3-bis(diphenylphosphino)propane (6 mol %) in THF at 110 °C gave 2-(phenylt

Full text of DOI:10.1021/jo9824246

2080
J . Org. Chem. 1999, 64, 2080-2084
High ly Ch em o- a n d Regioselective Th ioca r bon yla tion of
Con ju ga ted En yn es w ith Th iols a n d Ca r bon Mon oxid e Ca ta lyzed
by P a lla d iu m Com p lexes: An Efficien t a n d Atom -Econ om ica l
Access to 2-(P h en ylth ioca r bon yl)-1,3-d ien es
Wen-J ing Xiao, Giuseppe Vasapollo,† and Howard Alper*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received December 10, 1998
The reaction of 1, 3-conjugated enynes bearing a terminal triple bond with thiols and carbon
monoxide in the presence of catalytic quantities of Pd(OAc)2 (3 mol %) and 1,3-bis(diphenylphos-
phino)propane (6 mol %) in THF at 110 °C gave 2-(phenylthiocarbonyl)-1,3-dienes in moderate to
good yields. The thiocarbonylation takes place with high chemo- and regioselectivity, with the attack
by the phenylthiocarbonyl group occurring exclusively at carbon-2 of the 1,3-conjugated enyne.
In tr od u ction
propargyl or allylic alcohols in the presence of a pal-
ladium(0) catalyst to afford â-(arylthio)-R,â-unsaturated
lactones or â,γ-unsaturated thioesters, depending on the
Carbonylation chemistry is widely used in organic
synthesis in both academia and industry. Among numer-
ous methods for the introduction of a carbonyl moiety into
an organic molecule, the direct functionalization of a
substrate using carbon monoxide has attracted a great
deal of attention.1 The development of transition-metal-
catalyzed carbonylation involving the formation of a
thiocarbonyl unit and employing chalogen compounds as
substrates represents a challenging goal in organic
synthesis, because the strong thiophilicity of transition
metals2 may make catalytic reactions ineffective.3 Tran-
sition-metal-catalyzed reactions with thiols and carbon
monoxide have been investigated in our laboratories for
some time.4 For example, in 1985, we described the cobalt
carbonyl catalyzed desulfurization and carbonylation of
mercaptans to produce carboxylic esters (eq 1).4a The
reaction conditions (eq
2
and 3).5 Highly regio-
selective carbonylation reactions of thiols with allenes6
and acetylenes7 have been the subject of recent publica-
tions. In 1994, an excellent publication on the palladium-
catalyzed addition of thiophenol to conjugated enynes8
appeared by Backvall and co-workers (eq 4). Stimulated
latter process represented, to our knowledge, the first
effective catalytic carbonylation of organosulfur com-
pounds. Our group and others have subsequently dis-
covered a series of reactions in which chalcogen com-
pounds are used as substrates in transition-metal-
catalyzed reactions. For example, thiols react with
by these results, we reasoned that the thiocarbonylation
of conjugated enynes with thiols should take place,
producing the corresponding phenylthiocarbonyl-1,3-
dienes.
Sulfur-substituted dienes have been widely used in
Diels-Alder and other reactions.9 The sulfur-containing
group not only increases the reactivity of the diene but
also acts as a handle for further functional group
† Present address: Department of Material Science, University of
Lecce, Lecce, Italy.
(1) (a) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414.
(b) Colquhoun, H. M.; Thompson, D. J .; Twigg, M. V. Carbonylation:
Direct Synthesis of Carbonyl Compounds; Plenum Press: New York,
1991.
(5) (a) Xiao, W.-J .; Alper, H. J . Org. Chem. 1997, 62, 3422. (b) Xiao,
W.-J .; Alper, H. J . Org. Chem. 1998, 63, 7939.
(2) Dubois, M. R. Chem. Rev. 1989, 89, 1.
(3) (a) Hegedus, L. L.; McCable, R. W. Catalyst Poisoning; Marcel
Dekker: New York, 1984. (b) Hutton, A. T. In Comprehensive Coor-
dination Chemistry; Wilkinson, G.; Gillard, R. D.; McCleverty, J . A.,
Eds.; Pergamon Press: Oxford, U.K., 1984; Vol. 5, p 1151.
(4) (a) Shim, S. C.; Antebi, S.; Alper, H. J . Org. Chem. 1985, 50,
147. (b) Antebi, S.; Alper, H. Tetrahedron Lett. 1985, 26, 2609. (c)
Antebi, S.; Alper, H. Organometallics 1986, 5, 596. (d) Antebi, S.; Alper,
H. Can. J . Chem. 1986, 64, 2010. (e) Calet, S.; Alper, H. Tetrahedron
Lett. 1986, 27, 3573. (f) Calet, S.; Alper, H. Organometallics 1987, 6,
1625. (g) Wang, M.-D.; Calet, S.; Alper, H. J . Org. Chem. 1989, 54, 20.
(h) Khumtaveeporn, K.; Alper, H. J . Org. Chem. 1994, 59, 1414. (I)
Khumtaveeporn, K.; Alper, H. J . Chem. Soc., Chem. Commun. 1995,
917. (j) Crudden, C. M.; Alper, H. J . Org. Chem. 1995, 60, 5579.
(6) Xiao, W.-J .; Vasapollo, G.; Alper, H. J . Org. Chem. 1998, 63, 2609.
(7) (a) Ogawa, A.; Kawabe, K.; Kawakami, J .; Mihara, M.; Hirao,
T.; Sonoda, N. Organometallics 1998, 17, 3111. (b) Ogawa, A.;
Kawakami, J .; Mihara, M.; Ikeda, T.; Sonoda, N.; Hirao, T. J . Am.
Chem. Soc. 1997, 119, 12380. (c) Ogawa, A.; Takeba, M.; Kawakami,
J .; Ryu, I.; Kambe, N.; Sonoda, N. J . Am. Chem. Soc. 1995, 117, 7564.
(8) Backvall, J . E.; Ericsson, A. J . Org. Chem. 1994, 59, 5850.
(9) (a) Trost, B. M.; Lavoie, A. C. J . Am. Chem. Soc. 1983, 105, 5075.
(b) Back, T. G.; Lai, E. K. Y.; Muralidharan, K. R. J . Org. Chem. 1990,
55, 4595. (c) Chou, S.-S. P.; Wey, S.-J . J . Org. Chem. 1990, 55, 1270.
(d) Padwa, A.; Gareau, Y.; Harrison, B.; Norman, B. H. J . Org. Chem.
1991, 56, 2713. (e) Plobeck, N. A.; Backvall, J .-E. J . Org. Chem. 1991,
56, 4508.
10.1021/jo9824246 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/20/1999

Thiocarbonylation of Conjugated Enynes
J . Org. Chem., Vol. 64, No. 6, 1999 2081
Ta ble 1. Op tim iza tion of Rea ction Con d ition s (eq 6)a
transformations.10 Thus, it is not surprising that consid-
erable effort has been expended in the synthesis of such
compounds.11 From a synthetic point of view, controlling
regioselectivity, as well as chemoselectivity, is always of
great importance. Described here is a highly chemo- and
regioselective thiocarbonylation reaction of conjugated
enynes with thiols and CO catalyzed by a palladium
complex, allowing a one-pot synthesis of 2-(phenylthio-
carbonyl)-1,3-dienes.
temp time yield of
entry
catalyst
Pd(OAc)2
ligand solvent (°C)
(h) 3a (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
none THF
none THF
none THF
none THF
PPh3 THF
dppb THF
dppe THF
dppp THF
dppp THF
100
100
100
100
100
100
100
100
110
24
24
24
24
24
12
24
8
6
6
6
6
0c
20
47
12
38
62
0
70
76
43
8e
62
37
36
7
Pd(PPh3)4
Pt(PPh3)4
Pd2(dba)3‚CHCl3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Resu lts a n d Discu ssion
d
Rea ction of 1-Eth yn ylcycloh exen e w ith Th iop h e-
n ol. Dem on str a tion of P r ocess a n d Yield Op tim iza -
tion . The palladium-catalyzed reaction of 1-ethynylcy-
clohexene (1a ) with thiophenol (2a ) and carbon monoxide
was chosen as a model reaction to determine the viability
of the process and the optimum reaction conditions (eq
5). The reaction conditions previously used for the
dppp CH2Cl2 110
dppp DME
dppp C6H6
110
110
dppp CH3CN 110
6
6
24
60
dppp THF
dppp THF
dppp THF
130
140
110
tr
a
Reaction conditions: 1-ethynylcyclohexene (3 mmol), thiophe-
nol (1 mmol), catalyst (0.03 mmol), PPh3 (0.12 mmol, if used),
bidentate phosphine (0.06 mmol, if used), 400 psi CO, solvent (15
b
mL). Isolated yield based on the amount of thiophenol employed.
thiocarbonylation of allenes6 were initially applied to the
reaction of 1a , 2a , and carbon monoxide (CO) [1 equiv of
enyne, 1 equiv of thiophenol, 3 mol % Pd(OAc)2, 12 mol
% PPh3, 400 psi of CO, THF (3.5 mL per 1 mmol of
thiophenol), and 100 °C]. Two products, 3a and 4a , were
obtained in 18% and 7% yield, respectively. Byproduct
4a may arise by the 1,4-addition of 3a with thiophenol
and, in that event, it should be possible to control the
consecutive reaction by increasing the mole ratio of 1a
to 2a and decreasing the concentrations of the reactants.
Indeed, treatment of 1a (3 mmol) with 2a (1 mmol) in
the presence of Pd(OAc)2 (0.03 mmol) and PPh3 (0.12
mmol) in THF (15 mL) at 100 °C under 400 psi of carbon
monoxide gave exclusively 3a in 38% yield (no 4a was
formed). The effect of varying the catalyst, ligand,
solvent, reaction temperature, and reaction time on the
yield of 3a was examined, and the results are sum-
marized in Table 1.
A series of reactions between 1a and 2a were carried
out under various conditions to optimize the reaction
yield. It was shown that Pd(OAc)2 with 1,3-bis(diphe-
nylphosphino)propane (dppp) was the best catalyst sys-
tem among those examined and the reaction proceeded
efficiently in THF as the solvent (Table 1, entry 8).
Increasing the reaction temperature to 110 °C and
decreasing the reaction time to 6 h further improved the
yield to 76% (Table 1, entry 9). Pd(OAc)2 with 1,4-bis-
(diphenylphosphino)butane (dppb) is also a good catalytic
system for this reaction (Table 1, entry 6); however, Pd-
(OAc)2 with 1,2-bis(diphenylphosphino)ethane (dppe) was
ineffective here (Table 1, entry 7). Other palladium
catalysts, such as Pd(PPh3)4 and Pd2(dba)3‚CHCl3, with-
c The decarbonylation product, phenyl 2-(1′-cyclohexenyl)-ethenyl
d
sulfide, was isolated in 53% yield. 0.015 mmol of the catalyst
was used. e 27% of thiophenol was recovered, and polymerization
of the enyne was observed.
out an added phosphine ligand, were not useful for this
transformation (Table 1, entries 2 and 4). Although Pd-
(OAc)2/4 PPh3 was found to be an excellent catalyst
system for the thiocarbonylation of allenes,6 it was not
of genuine value for this carbonylative coupling reaction.
The reaction of 1a and 2a catalyzed by Pd(OAc)2 with
PPh3 afforded 3a in 38% yield (Table 1, entry 5), whereas
using Pd(OAc)2 without any ligand only gave the decar-
bonylation product (Table 1, entry 1). Tetrakis(triph-
enylphosphine)platinum(0), which was very effective for
the regioselective hydrothiocarbonylation of acetylenes
with thiols,7b does catalyze this thiocarbonylation, but in
appreciably lower yield of 3a when compared with Pd-
(OAc)2 and dppp (Table 1, entry 3).
The nature of the solvent, and the reaction time,
greatly affected the yield of 3a in the model reaction.
With the Pd(OAc)2-dppp catalyst system, THF was
found to be the best solvent for the reaction, whereas 3a
was obtained in only 8% yield when 1,2-dimethoxyethane
(DME) was the reaction solvent (compare entries 9 to 13
in Table 1). The reaction works well at 110 °C in THF
and is complete in 6 h. Raising the reaction temperature
to 140 °C resulted in decomposition of the catalyst, and
prolonged heating proved detrimental for the reaction
(Table 1, entries 14-16), probably because of the facile
polymerization of the product.12
Scop e of th e Th ioca r bon yla tion of En yn es. The
thiocarbonylation reactions of a series of enynes (1a -h )
with thiols (2a -c) were performed using 3 mol % of Pd-
(OAc)2 and 6 mol % of dppp in THF (15 mL per 1 mmol
of thiol) at 400 psi of carbon monoxide for 8-15 h at 110
°C, and the results are summarized in Table 2.
(10) (a) Backvall, J . E.; Chinchilla, R.; Najera, C.; Yus, M. Chem.
Rev. 1998, 98, 2291. (b) Padwa, A.; Gareau, Y.; Harrison, B.; Rodriguez,
A. J . Org. Chem. 1992, 57, 3540. (c) Proteau, P. J .; Hopkins, P. B. J .
Org. Chem. 1985, 50, 141.
(11) (a) Backvall, J . E.; J untunen, S. K. J . Org. Chem. 1988, 53,
2398. (b) Chou, S.-S. P.; Liou, S.-Y.; Tsai, C.-Y.; Wang, A.-J . J . Org.
Chem. 1987, 52, 4468. (c) Pearson, W. H.; Lin, K.-C.; Poon, Y.-F. J .
Org. Chem. 1989, 54, 5814. (d) Seiller-Delevoye, B.; Bruneau, C.;
Dixneuf, P. H. Russ. Chem. Bull. 1998, 47, 914. (e) Wang, Z.; Lu, X.-
Y.; Lei, A.; Zhang, Z.-G. J . Org. Chem. 1998, 63, 3806.
(12) Stevens, M. P. Polymer Chemistry: An Introduction, 2nd ed.;
Oxford University Press: New York, 1990.

2082 J . Org. Chem., Vol. 64, No. 6, 1999
Ta ble 2. P a lla d iu m -Ca ta lyzed Th ioca r bon yla tion of En yn es w ith Th iols a n d COa
Xiao et al.
The thiocarbonylation of enynes was highly chemose-
lective, and only the triple bond was attacked by the
sulfur nucleophile (Table 2). Such behavior was observed
for the palladium-catalyzed chloropalladation13a and hy-
dropalladation of nonconjugated enynes.13b Importantly,
only one regioisomer was formed in these reactions, by
selective attack of the phenylthiocarbonyl group at
carbon-2 of the 1,3-conjugated enyne (Table 2). Both cyclic
and acyclic conjugated enynes can be smoothly and
regioselectively transformed into the corresponding 2-(phe-
nylthiocarbonyl)-1,3-dienes in moderate to good yields of
isolated pure products via the palladium-catalyzed car-
bonylative coupling reactions with thiols (Table 2). This
regiochemical outcome is in excellent accord with the
related transition-metal-catalyzed addition reactions of
alkynes14 and enynes.8 Note that the stereochemical
characteristics of the products were the same as those of
the substrates when 1,2-disubstituted enynes were em-
(13) (a) Ma, S.; Lu, X. J . Org. Chem. 1991, 56, 5120. (b) Trost, B.
M. Acc. Chem. Res. 1990, 23, 34.

Thiocarbonylation of Conjugated Enynes
J . Org. Chem., Vol. 64, No. 6, 1999 2083
ployed as the starting materials (Table 2, entries 6-9
and 12). It further demonstrates that the double bond of
the enyne is not affected by the reaction.
bearing a terminal triple bond with thiols and carbon
monoxide catalyzed by Pd(OAc)2 and dppp to form R,â-
unsaturated thioesters in moderate to good yields. This
methodology is particularly impressive as a one-pot,
atom-economical synthesis of 2-(phenylthiocarbonyl)-1,3-
dienes, which are versatile and useful reagents in organic
synthesis. For example, they are of genuine value in
cycloaddition and Michael addition reactions.
The yields and selectivities using arenethiols or al-
kanethiols as reactants are similar, although the reaction
time for arenethiols is less than that for alkanethiols in
these carbonylative coupling reactions (Table 2, entries
1-4). The higher acidity of aromatic thiols may contrib-
ute to this difference in reactivity. Unlike the palladium-
catalyzed addition of thiols to acetylenes,14b attempts to
thiocarbonylate enynes with internal triple bonds were
unsuccessful (e.g., 2-methyl-1-hepten-3-yne and 3-octen-
5-yne were recovered using the standard reaction condi-
tions for 48 h). An enyne bearing a hydroxyl group (5) in
the allylic position afforded a sulfur-substituted lactone
(6) in 74% yield instead of an R,â-unsaturated thioester
on reaction with thiophenol and CO (eq 7).
Exp er im en ta l Section
Ma ter ia ls. The following enynes were prepared. 3-Nonen-
1-yne (1h ) was obtained by Wittig reaction of propargyltriph-
enylphosphonium bromide with hexanal following a literature
method.17 1-Ethynylcyclopentene (1g), 3,5-dimethyl-3-hexen-
1-yne (1c), 3-methyl-3-penten-1-yne (1d ), and 3-ethyl-3-penten-
1-yne (1e) were prepared by treating the corresponding
propargylic alcohols with POCl3 in pyridine following the
literature procedure.18 2-Phenyl-1-buten-3-yne (1f) was pre-
pared by the Pd-catalyzed reaction of lithium acetylide with
alkenyl halide.19 Other enynes and thiols were commercially
available and were used as received. Pd2(dba)3‚CHCl3 was
prepared according to the reported procedure.20 Tetrahydro-
furan (THF), 1,2-dimethoxyethane (DME), and benzene were
dried and deoxygenated by continuous refluxing over sodium/
benzophenone ketyl under nitrogen, followed by distillation.
CH2Cl2 was distilled from CaH2 under N2 prior to use, and
CH3CN was dried with molecular sieves (4A, 1.6 mm pellets).
Scheme 1 outlines a possible pathway for the pal-
ladium-catalyzed thiocarbonylation of 1 (1b as the ex-
ample) with thiophenol (2a ). The reaction may proceed
by initial palladium acetate reduction to palladium(0),15
followed by oxidative addition of 2a to the palladium(0)
complex to form the PhSPdH species 7, which undergoes
coordination to the triple bond of the enyne and then
insertion of carbon monoxide to form 8. Regioselective
intramolecular acylpalladation of the latter would give
complex 9,16 and subsequent reductive elimination would
produce the observed 2-(phenylthiocarbonyl) 1, 3-diene
and regenerate the palladium(0) catalyst.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Th io-
ca r bon yla tion of En yn es w ith Th iols a n d Ca r bon Mon -
oxid e. To a 45 mL Parr autoclave fitted with a glass liner
and stirring bar was added Pd(OAc)2 (0.03 mmol), dppp (0.06
mmol), enyne (3.0-6.0 mmol), thiol (1.0 mmol), and THF (15
mL). The carbon monoxide line was flushed three times with
CO, the autoclave was filled and vented at least three times
with CO to displace the air, and subsequently the pressure
was increased to 400 psi. The mixture was stirred in the
autoclave at 110 °C (the temperature of the oil bath) for 8-15
h. After cooling, excess carbon monoxide was released, the
reaction mixture was filtered through Florisil, and the solvent
was removed by rotary evaporation. The residue was separated
by preparative silica gel TLC (eluants: n-hexane/ethyl acetate
95:5). Preparative HPLC was used to further purify the
products.
Sch em e 1
S-P h en yl 2-(1′-Cycloh exen yl)-3-p r op en eth ioa te (3a ):
1
oil; IR (neat) 1689 cm-1 (CdO); H NMR (200 MHz, CDCl3) δ
1.58-1.72 (m, 4H), 2.14-2.17 (m, 4H), 5.49 (s, 1H), 5.72 (s,
1H), 6.06 (t, 1H, J ) 7.4 Hz), 7.44-7.45 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 21.71, 22.45, 25.71, 26.00, 116.22, 128.21,
129.10, 129.30, 130.06, 132.01, 134.49, 149.76, 193.20; MS (EI)
m/z 244.1 (M+); HRMS calcd for C15H16OS 244.0938, found
(14) (a) Ishiyama, T.; Nishijima, K.; Miyanra, N.; Suzuki, A. J . Am.
Chem. Soc. 1993, 115, 7219. (b) Kuniyasu, H.; Ogawa, A.; Sato, K.-I.;
Ryu, I.; Kambe, N.; Sonoda, N. J . Am. Chem. Soc. 1992, 114, 5902.
(15) (a) Amatore, C.; J utand, A.; M’Barki, M. Organometallics 1992,
11, 3009. (b) Amatore, C.; Carre, E.; J utand, A.; M’Barki, M. Organo-
metallics 1995, 14, 1818.
(16) A similar mechanism of acetylene insertion into Pd-CO σ bonds
was reported. See: Samsel, E. G.; Norton, J . R. J . Am. Chem. Soc.
1984, 106, 5505.
(17) (a) Xiao, W.-J .; Ding, M.-W.; Huang, W.-F. Huazhong Shida
Xuebao (Ziran Kexueban) 1994, 9, 114. (b) Eiter, K.; Oediger, H. Liebigs
Ann. Chem. 1965, 682, 62.
(18) Pinault, M.; Frangin, Y.; Genet, J .-P.; Zamarlik, H. Synthesis
1990, 935.
(19) King, A. O.; Okukado, N.; Negishi, E. Chem. Commun. 1977,
683.
(20) Ukai, T.; Kawazura, H.; Shii, Y. J . Organomet. Chem. 1974,
65, 253.
Con clu sion
In summary, this research has resulted in the first
chemo- and regioselective thiocarbonylation of enynes

2084 J . Org. Chem., Vol. 64, No. 6, 1999
Xiao et al.
244.0934. Anal. Calcd for C15H16OS: C, 73.73; H, 6.60.
Found: C, 73.65; H, 6.58.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The authors are grateful to the
Natural Sciences and Engineering Council Canada for
support of this research.
J O9824246