Palladium-catalyzed additions of terminal alkynes to acceptor alkynes

Article abstract of DOI:10.1021/ja9624937

The development of addition reactions wherein the product is the simple sum of the reactants plus anything else (only needed catalytically) constitutes an important goal for enhanced synthetic efficiency. The C-H bond of terminal alkynes (the donor alkyne

Full text of DOI:10.1021/ja9624937

698
J. Am. Chem. Soc. 1997, 119, 698-708
Palladium-Catalyzed Additions of Terminal Alkynes to
Acceptor Alkynes
Barry M. Trost,* Mark T. Sorum, Chuen Chan, Arthur E. Harms, and
Gerd Ru1hter
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
ReceiVed July 18, 1996X
Abstract: The development of addition reactions wherein the product is the simple sum of the reactants plus anything
else (only needed catalytically) constitutes an important goal for enhanced synthetic efficiency. The C-H bond of
terminal alkynes (the donor alkynes) can be added to either terminal alkynes (self-coupling) or activated internal
alkynes (cross-coupling) (the acceptor alkynes) in the presence of a catalytic amount of palladium acetate and an
electron rich sterically encumbered ligand, tris(2,6-dimethoxyphenyl)phosphine. The activated internal alkynes for
cross-coupling (the acceptor alkyne) include alkynes bearing an ester, sulfone, and ketone. Self-coupling is completely
overwhelmed by cross-coupling, even at 1:1 ratios of donor and acceptor alkynes. The reaction exhibits extraordinary
chemoselectivity with free carboxaldehydes, alcohols, ketones (saturated and conjugated), esters (saturated and
conjugated), sulfones (saturated and conjugated), malonates, and silyl ethers all proving to be compatible. A 1:2
donor/acceptor alkyne adduct can also be optimized. Ethyl propiolate fails as an acceptor but its C-silylated analogue
serves with the proper choice of silyl substituent. The products of the latter serve as useful precursors to â-keto
esters. An iterative sequence is readily performed and led to a novel conformationally rigid retinoid analogue. The
mechanism of this mild method for construction of conjugated enynes, versatile building blocks, is discussed.
Addition reactions constitute an atom economical way to build
group metals, are characterized by the ability of the C-M or
H-M bonds to undergo cis-syn additions to relatively unpo-
larized π-unsaturation like that of unactivated double and triple
bonds. In an oxidative addition process, the metal may be
simply thought of as a base, wherein complex 1 would result.
This complex, in principle, can undergo either a carbametalation
or a hydrometalation, for which the latter is normally believed
to be kinetically faster.6 On the other hand, the metal complex
2 may derive from the equivalent of a substitution reaction. In
such an event, it may undergo only a carbametalation in
subsequent reactions.
more complex structures from simpler building blocks.1 Un-
fortunately, few of our synthetic reactions fall within this
category. The excellent coordinating ability of alkynes for
transition metals makes transition metal catalyzed additions of
alkynes a promising area for exploration. Two general modes
of behavior may be discerned: additions involving the π-system
and insertions into the C-H bond of terminal acetylenes. We
report a reaction which combines both modes of reaction and
provides a general entry to conjugated enynes which represent
a novel class of versatile building blocks as well as a key
fragment of increasingly populated classes of biologically
interesting molecules represented by neocarzinostatin chro-
mophore2 and calicheamycin.3,4
In the course of our investigations of the metal-catalyzed
cycloisomerization of enynes,7 we found that the use of an
electron rich ligand like tris(2,6-dimethoxyphenyl)phosphine
(TDMPP) completely changed the course of the reaction from
cycloisomerization to diyne coupling of the type represented
generically in eq 2.8-10 This reaction may be envisioned to
The insertion of a transition metal into a C-H bond (exemp-
lified for the terminal alkynes in eq 1) creates the new complexes
1 or 2 whose potential reactivity profile imparts great interest
into such processes.5 Transition metals, in contrast to main
involve reactive intermediates like complex 1 or 2. In order to
examine the nature of this reaction, we undertook a more
extensive study of its scope. A particularly intriguing question
is the feasibility of a “cross-coupling” process, as illustrated in
eq 3, which represents a particularly useful synthetic protocol.
X Abstract published in AdVance ACS Abstracts, January 1, 1997.
(1) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. Trost, B.
M. Science 1991, 254, 1471.
(2) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N.;
Ishida, N. Tetrahedron Lett. 1985, 26, 331. For a review, see: Goldberg,
I. H. Acc. Chem. Res. 1991, 24, 191. For a leading reference, see: Myers,
A. G.; Arvedson, S. P.; Lee, R. W. J. Am. Chem. Soc. 1996, 118, 4725.
(3) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M.
M.; Morton, G. O.; McGahren, W. S.; Borders, D. B. J. Am. Chem. Soc.
1987, 109, 3466.
(4) For overviews, see: Nicolaou, K. C.; Dai, W. M.; Tsay, S. C.;
Estevez, V. A.; Wrasidlo, W. Science 1992, 256, 1172. Nicolaou, K. C.;
Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387.
(5) Canty, A. J. In ComprehensiVe Organometallic Chemistry; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Puddephatt, R. J., Eds.; Pergamon:
Oxford, 1995; Vol. 9, Chapter 5, pp 251-5.
(6) Brookhart, M.; Lincoln, D. M. J. Am. Chem. Soc. 1988, 110, 8719.
(7) Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; McPherson, D.
T. J. Am. Chem. Soc. 1994, 116, 4255. Trost, B. M.; Lautens, M.; Chan,
C.; Jebaratnam, D. J.; Mueller, T. J. Am. Chem. Soc. 1991, 113, 423.
(8) For examples of terminal alkyne-alkyne couplings with early
transition metals, see: (Sc) Thompson, M. E.; Baxter, S. M.; Bulls, A. R.;
Burger, B. J.; Nolan, M. C.; Santarsiero, B. D.; Schaefer, W. P.; Bercaw,
J. E. J. Am. Chem. Soc. 1987, 109, 203. St. Claire, M.; Schaefer, W. P.;
Bercaw, J. E. Organometallics 1991, 10, 525. (Y, Ce, La) Heeres, H. J.;
Teuben, J. H. Organometallics 1991, 10, 1980. (Sm) Evans, W. J.; Keyer,
R. A.; Ziller, J. W. Organometallics 1993, 12, 2618. (Ti) Akita, M.; Yasuda,
H.; Nakamura, A. Bull. Chem. Soc. Jpn. 1984, 57, 480. (Zr) Horton, A. D.
J. Chem. Soc., Chem. Commun. 1992, 185. (Cr) Hagihara, N.; Tamura,
M.; Yamazaki, H.; Fujiwara, M. Bull. Chem. Soc. Jpn. 1961, 34, 892.
S0002-7863(96)02493-6 CCC: $14.00 © 1997 American Chemical Society

Palladium-Catalyzed Additions of Alkynes
J. Am. Chem. Soc., Vol. 119, No. 4, 1997 699
Table 1. Cycloisomerization vs Self-Coupling of Enynesa
ratio
diastereomers
yield
yield
entry
substrate
L
cycloisomer (%)
ratio 2:3
of 2
self-coupling 4 (%)
1b
2
3
1a
1a
1a
1a
1b
1b
1b
1b
none
Ph3P
Ph3As
(o-CH3C6H4)3P
none
Ph3P
(o-CH3C6H4)3P
TDMPP
23
19
47
12
6
41
33
4
only 2
6:1
4:1
2:1
2:1
1:1
1:2
only 3
5:4
1:2
1:1
2:1
3:1
7:2
2:1
NDc
9-22
9-22
66
4
5b
6b
7b
8
NDc
NDc
NDc
71
a All reactions were run with 5 mol % of Pd(OAc)2 in PhH at room temperature unless otherwise noted. b Performed at 60 °C. c ND ) not
detected.
We record our observations of the scope of these processes and
of three compounds, the cycloisomerization products 2a (a
mixture of diastereomers) and 3a and the self-coupling product
4a (eq 4), as summarized in Table 1. While small amounts of
a few initial mechanistic insights.11
Self-Coupling. The reaction of enyne 1a with palladium
acetate in the presence of various ligands produced a mixture
(9) For examples of terminal alkyne-alkyne couplings with late transition
metals, see: (Ru) (a) Wakatsuki, Y.; Yamazaki, H.; Kumegawa, N.; Satoh,
T.; Satoh, J. Y. J. Am. Chem. Soc. 1991, 113, 9604. (b) Bianchini, C.;
Peruzzini, M.; Zanobini, F.; Frediani, P.; Albinati, A. J. Am. Chem. Soc.
1991, 113, 5453. (c) Echevarren, A. M.; Lo´pez, J.; Santos, A.; Montoya, J.
J. Organomet. Chem. 1991, 414, 393. (d) Dahlenburg, L.; Frosin, K.-M.;
Kerstan, S.; Werner, D. J. Organomet. Chem. 1991, 407, 115. (e) Sasaki,
Y.; Dixneuf, P. H. J. Chem. Soc., Chem. Commun. 1986, 790 and references
cited therein. (Rh) (f) Ohshita, J.; Furumori, K.; Matsuguchi, A.; Ishikawa,
M. J. Org. Chem. 1990, 55, 3277. (g) Scha¨fer, M.; Mahr, N.; Wolf, J.;
Werner, H. Angew. Chem., Int. Ed. Engl. 1993, 32, 1315. (h) Boese, W.
T.; Goldman, A. S. Organometallics 1991, 10, 782. (i) Kovalev, I. P.;
Yevakov, K. V.; Strelenko, Y. A.; Vinogradov, M. G.; Nikishin, G. I. J.
Organomet. Chem. 1990, 386, 139. (j) Scha¨fer, H.-A.; Marcy, R.; Ru¨ping,
T.; Singer, H. J. Organomet. Chem. 1982, 240, 17. (k) Aresta, M.; de Fazio,
M. J. Organomet. Chem. 1980, 186, 109. (l) Carlton, L.; Read, G. J. Chem.
Soc., Perkin Trans. 1 1978, 1631. (m) Schmitt, H. J.; Singer, H. J.
Organomet. Chem. 1978, 153, 165. (n) Yoshikawa, S.; Kiji, J.; Furukawa,
J. Makromol. Chem. 1977, 178, 1077. (o) Singer, H.; Wilkinson, G. J. Chem.
Soc., A 1968, 849 and references cited therein. (Ni) (p) Ishikawa, M.;
Ohshita, J.; Ito, Y.; Minato, A. J. Chem. Soc., Chem. Commun. 1988, 804.
(q) Giacomelli, G.; Marcacci, F.; Caporusso, A. M.; Lardicci, L. Tetrahedron
Lett. 1979, 3217. (r) Akopyan, L. A.; Grigoryan, S. G.; Chukhadzhyan, G.
A.; Matsoyan, S. G. J. Org. Chem. U.S.S.R. 1973, 2020. (s) Meriwether,
L. S.; Colthup, E. C.; Kennerly, G. W.; Reusch, R. N. J. Org. Chem. 1961,
26, 5155. (Pd) (t) Dzhemilev, U. M.; Khusnutdinov, R. I.; Shchnadeva, N.
A.; Nefedov, O. M.; Tolstikov, G. A. Bull. Acad. Sci. U.S.S.R. 1990, 2171.
(u) Selimov, F. A.; Rutman, O. G.; Dzhemilev, U. M. J. Organomet. Chem.
1988, 346, C58. (w) Sabourin, E. T. J. Mol. Catal. 1984, 26, 363. (x)
Colthup, E. C.; Meriwether, L. S. J. Org. Chem. 1962, 27, 3930. (y) Singer,
H.; Wilkinson, G. J. Chem. Soc., A 1968, 190. (Cu) (z) Akhtar, M.; Weedon,
B. C. L. Proc. Chem. Soc. 1958, 303. (aa) Nieuwland, J. A.; Calcott, W.
S.; Downing, F. B.; Carter, A. S. J. Am. Chem. Soc. 1931, 53, 4197. (bb)
Strauss, F. Annalen 1905, 342, 201.
(10) For some other transition metal catalyzed 1,3-enyne syntheses,
see: (a) Meyer, C.; Marek, I.; Normant, J.-F.; Platzer, N. Tetrahedron Lett.
1994, 35, 5645. (b) Darcel, C.; Bruneau, C.; Dixneuf, P. H. J. Chem. Soc.,
Chem. Commun. 1994, 1845. (c) Yamaguchi, M.; Omata, K.; Hirama, M.
Tetrahedron Lett. 1994, 35, 5689. (d) Ikeda, S.-I.; Sato, Y. J. Am. Chem.
Soc. 1994, 116, 5975. (e) Hinkle, R. J.; Poulter, G. T.; Stang, P. J. J. Am.
Chem. Soc. 1993, 115, 11626. (f) Guegnot, S.; Linstrumelle, G. Tetrahedron
Lett. 1993, 34, 3853. (g) Mandai, T.; Tsujiguchi, Y.; Matsuoka, S.; Tsuji,
J. Tetrahedron Lett. 1993, 34, 7615. (h) Takahashi, T.; Aoyagi, K.; Denisov,
V.; Suzuki, N.; Choueiry, D.; Negishi, E.-I. Tetrahedron Lett. 1993, 34,
8301. (c) Kosugi, M.; Kimura, T.; Oda, H.; Migita, T. Bull. Chem. Soc.
Jpn. 1993, 66, 3522. (j) Beaudet, I.; Parrain, J.-L.; Quintard, J.-P.
Tetrahedron Lett. 1992, 33, 3647. Jeffery, T. Synthesis 1987, 70 and
references cited therein. (k) Barluenga, J.; Gonza´lez, J. M.; Llorente, I.;
Campos, P. J. Angew. Chem., Int. Ed. Engl. 1993, 32, 893. (l) Trost, B.
M.; Kottirsch, G. J. Am. Chem. Soc. 1990, 112, 2816.
the self-coupling product 4 were observed with several ligands
(entries 2 and 3), the use of a sterically demanding ligand which
creates more coordinatively unsaturated palladium, tri-o-
tolylphosphine,12 produces 4 in 65% isolated yield (entry 4).
With the desmethyl substrate 1b, even the use of tri-o-tolyl-
phosphine as a ligand still produces the cycloisomer (entry 7).
Only upon going to TDMPP10l,13 does the self-coupling product
4b form satisfactorily, and it is isolated in 71% yield (entry 8).
Spectroscopy confirms the structure of the self-coupling
products 4a and 4b. Mass spectroscopy establishes their
molecular formulae as dimers. The disubstituted alkyne is
indicated by the IR absorption at 2050 cm-1 and the 13C NMR
shifts at δ 80.8 and 83.9. The terminal methylene of the 1,1-
1
disubstituted alkene is indicated by the H NMR absorption at
δ 5.53-5.55 and 5.43-5.45.
The presence of the additional double bond is irrelevant to
this coupling protocol, as illustrated in Table 2, entries 1-4.
These examples illustrate the compatibility of both a free alcohol
(entry 4) and a monosubstituted malonate (entry 3). The enyne
substrates (entries 5-8) all show good to excellent selectivity
for the self-coupling event at the expense of the cycloisomer-
ization. Even an activated acceptor such as an acrylate (entry
8), which promotes the cycloisomerization, produces the ho-
modimer 5f with the cycloisomer being only a minor product
(13% yield). On the other hand, this example ilustrates that
such an acrylate does not suffice as an acceptor for the
alkynylpalladium intermediate compared to a triple bond, even
an unactivated one.
Cross-Coupling. The facility of the homocoupling makes
it a challenge to define what may be able to intercept the reactive
(11) For preliminary reports of portions of this work, see: Trost, B. M.;
Chan, C.; Ru¨hter, G. J. Am. Chem. Soc. 1987, 109, 3486. Trost, B. M.;
Harms, A. E. Tetrahedron Lett. 1996, 37, 3971.
(12) Paul, F.; Path, J.; Hartwig, J. F. Organometallics 1995, 14, 3030.
(13) Wada, M.; Higashizaki, S. J. Chem. Soc., Chem. Commun. 1984,
482.

700 J. Am. Chem. Soc., Vol. 119, No. 4, 1997
Trost et al.
Table 3. Cross-Couplings with Alkyl- and Aryl-Substituted
Table 2. Self-Coupling of Terminal Alkynesa
Acceptor Alkynesa
dimer
isolated
yield
starting
alkyne
isolated yield
(%)
acceptor alkyne
compd
no.
entry
of dimer
entry
1b
2
donor alkyne R
R′
CH3
EWG
(%) product
TMS
Ph
CO2CH3
CO2CH3
CO2CH3
CO2C2H5
CO2CH3
CO2CH3
CO2CH3
SO2Ph
95
92
67
87
11
84
90
91
68
68
72
83
6a
6b
6c
6d
6e
6f
6g
7a
7c
7c
8a
8b
CH3
CH3
CH3
CH3
CH3
3
HOCH2
4
(CH3O2C)2CHCH2
PhSO2CH2
OHCCH2CH2CH2
5
6
7
(PhSO2)2CHCH2CH2CH2CH2 CH3
Ph
n-C4H9
TBDMSOCH2
Ph
8
CH3
CH3
CH3
Ph
9
SO2Ph
10
11
SO2Ph
COCH3
12c Ph
n-C6H13 COCH3
a All reactions were performed with 2 mol % of Pd(OAc)2 and 2
mol % of TDMPP with approximately a 1:1 ratio of donor and acceptor
alkyne in benzene at ambient temperature unless otherwise noted.
b Reaction performed with 3 mol % of catalyst in THF at ambient
temperature. c Reaction performed with a 2:1 ratio of donor to acceptor
alkyne.
Scheme 1.a Chemical Correlation of the Structure of
Adduct 6a
a All reactions were run with 2 mol % Pd(OAc)2 and mol % of
TDMPP in PhH or PhH-d6 at room temperature unless otherwise noted.
b Tri-o-tolylphosphine employed as ligand. c Reaction run at 60 °C.d In
addition, a 21% yield of trimer was isolated.
a (a) DIBAL-H, PhCH3, 59%; (b) NBS, Ph3P, CH2Cl2, 73%; (c)
C4H9Li, TMS-Cl, 80%; (d) CBr4, Ph3P, CH3CN, 66%.
intermediate to achieve a cross-coupling event. We previously
established that activated allenes can serve this role efficiently
and even simple allenes suffice.10l Given the above results, it
appeared that another alkyne seemed more probable than an
alkene if it can be activated. Viewing the carbametalation event
as having some characteristics analogous to the Heck reaction,14
wherein acrylates are particularly good acceptors, our attention
turned to alkynoates as candidates.
Methyl butynoate was chosen as an acceptor rather than
methyl propynoate because of the high reactivity of the terminal
C-H bond of the latter. The dimerization of phenylacetylene,
which occurs at room temperature in less than 40 min, is
completely eliminated by addition of approximately 1 equiv
of methyl butynoate to give a single product (see eq 5 and
Table 3).
â. In conjunction with another project, the structure of the
adduct 6a was proven by correlation with the commercially
available enyne 9, as illustrated in Scheme 1. The allyl bromide
10, which was used in subsequent alkylation reactions, was
identical as prepared by the two routes.
The examples illustrate the high chemoselectivity of the
process. It is obvious from the nature of the product that
sensitive π-systems, even activated ones, are compatible.
Compounds containing acidic protons whose pKa normally
would make them more easily deprotonated than a terminal
alkyne such as alcohols (entry 3), malonates (entry 4), bis-
sulfonylmethanes (entry 7), etc., participate normally. Perhaps,
more remarkably, carbonyl groups including aldehydes (entry
6) and ketones (entries 11, 12), which normally would undergo
facile carbonyl additions of acetylide anions, do not interfere.
When 3-decyn-2-one is employed as the acceptor, the reaction
using a 1:1 ratio of reactants was incomplete after 24 h at room
temperature. Since separation of starting material and products
proved difficult, a 2:1 ratio of donor to acceptor alkyne was
employed, in which case the reaction went to completion within
18 h at room temperature. It is likely that using elevated
temperatures would suffice to enforce full conversion with the
1:1 ratio of reactants.
In the addition of propargyl alcohol to 1-(phenylsulfonyl)-
1-propyne under the standard conditions, a 1:2 adduct (12)
formed in addition to the 1:1 adduct 11 (eq 6) in 24% and 40
yields, respectively. Part of the effect derives from the presence
of the free OH, since the silyl ether participated without such a
complication (Table 3, entry 10) under the same conditions.
Adding a protonic medium such as tert-butyl alcohol gave a
nearly 1:1 ratio of 11 and 12. Changing from benzene to THF
Initially, the regioselectivity and alkene geometry were
assigned on the basis of 1H NMR shifts. Notably, the
absorptions for the vinyl methyl group and the vinylic hydrogen
for adducts 6a-g appear at δ 2.26 ( 0.14 and 6.04 ( 0.10,
respectively. Thus, the downfield shift of the vinyl methyl group
is consistent with its being deshielded by the ester, since it is
cis and â to this anisotropic group. The high-field shift of the
vinylic hydrogen is consistent with its being R to the ester, not
(14) Heck, R. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4,
Chapter 4.3, pp 833-864.

Palladium-Catalyzed Additions of Alkynes
J. Am. Chem. Soc., Vol. 119, No. 4, 1997 701
Table 4. Cross-Coupling with Ethyl
3-(Dimethylphenylsilyl)propiolatea
TDMPP-Pd(OAc)2
isolated
concn yield (%) product
entry donor alkyne R
(mol %)
1
2
3
4
5
6
7
Ph
Ph
Ph
2
3
5
3
3
0.25
0.5
0.5
33b
83b
86
42
66
14a
14a
14a
14b
14b
14c
14d
(CH3O2C)2CHCH2
(CH3O2C)2CHCH2
OHCCH2CH2CH2
AcOCH2CH2
0.5
0.05
0.25
0.5
2
10
73
48b
a All reactions were performed in PhH at room temperature using a
catalyst derived from a 1:1 ratio of TDMPP and Pd(OAc)2 unless
indicated otherwise. b Reaction performed at 45 °C.
had no effect. The one variable that had a major effect was
concentration of the reaction medium. Typically, the reactions
were performed at 0.25 M in both reactants. Increasing the
concentration of both to 1.0 M led to formation of, predomi-
nantly, the 1:2 adduct 12 which was isolated in 48% yield. On
the other hand, decreasing the concentration of both to 0.05 M
gave only the 1:1 adduct 11 in 88% yield. Changing the ratio
of the reactants from 1:1 to 1:2 propargyl alcohol to alkynyl-
sulfone at 1.0 M concentration with respect to the latter gave a
54% yield of the 1:2 adduct 12 and a 38% yield of the 1:1
adduct 11. Thus, by adjusting concentrations, an excellent yield
of the 1:1 adduct and a satisfactory yield of the 1:2 adduct may
be obtained.
Since the role of the hydroxyl group in this reaction was not
obvious, its requirement was tested by using a non-hydroxyl-
bearing alkyne in a cross-coupling reaction at high concentration.
As shown in eq 7, a 1:2 ratio of phenylacetylene and the
alkynylsulfone at 2.0 M in the latter gave the 1:2 adduct 13 in
59% yield along with 21% of the 1:1 adduct 7a. This result
contrasts with a 91% yield of the 1:1 adduct 7a under normal
conditions (Table 3, entry 8).
keeping all other parameters the same, produced a 33% yield
of the desired adduct 14a (Table 4, entry 1). The low yield
was mainly associated with a poor conversion due to the catalyst
dying because of the long reaction times required (48 h).
Increasing both the mole percent of the catalyst and concentra-
tion improved the process immensely (entries 2 and 3). At 3
mol % of catalyst and 0.5 M substrates, the reaction required
only 20 h at 45 °C, and at 5 mol %, it was complete within 20
h at room temperature. In both cases, excellent yields of the
cross-coupling product 14a were observed. The reaction with
dimethyl propargylmalonate as donor alkyne exhibited lower
yields of the 1:1 adduct 14b at 0.5 M (Table 4, entry 4). In
this case, formation of a 1:2 adduct accounts for the diminished
yield. As observed before, lowering the concentration of the
reactants increased the yield of the normal 1:1 adduct (entry
5). The excellent participation of the aldehyde alkyne as a donor
(entry 6) led to smooth reaction, even under the standard
conditions. Once again, this example highlights the excellent
chemoselectivity of the process.
An Iterative Cross-Coupling Sequence. The ease by which
these additions proceed led us to test the ability to use this
methodology in an iterative fashion. The retinoids, because of
their myriad of biological roles, including cell differentiation,
cell proliferation, embryonic development, etc., beyond their
well-known role in vision, has been targeted for analoguing.16,17
In particular, the generation of conformationally rigid analogues
haas been quite illuminating concerning the biological activity.18
Replacing the two disubstituted double bonds with alkynes
provides an intriguing rigidification.19
Scheme 2 outlines a synthesis of a bis-dehydro derivative,
methyl 7,8,11,12-tetradehydroretinoate (20). The ability to
dehydrate methyl ketones to terminal alkynes20 led to the
exploration of the cross-coupling of alkyne 15, which is in a
2.5:1 diastereomeric ratio, with 2-pentyn-4-one. In the event,
this addition proceeded smoothly to provide 16 (R ) CH3) under
standard conditions, but with THF as solvent, in 80% yield.
Surprisingly, attempts to continue via this route were thwarted
Terminal acetylenic acceptors bearing an electron-withdraw-
ing group were prevented from being employed because of the
exceptional reactivity of the acetylenic hydrogen which leads
to polymerization. The use of a silyl substituent as a hydrogen
surrogate should help resolve this problem. The ethyl propiolate
system was chosen as the test system because of the ease of
direct silylation of the lithiated species.15 The trimethylsilyl
substituent proved too labile. The triethylsilyl substituent was
more satisfactory, but the yields of adducts were still rather low.
The dimethylphenylsilyl group ultimately proved satisfactory
as summarized in eq 8 and Table 4.
(16) For a few recent overviews, see: The Retinoids: Biology, Chemistry
and Medicine, 2nd ed.; Sporn, M. B., Roberts, A. B., Goodman, D. S.,
Eds.; Raven: New York, 1993. Linney, E. Curr. Top. DeV. Biol. 1992, 27,
309. Bollag, W.; Holdener, E. Ann. Oncol. 1992, 3, 513. Hashimoto, Y.;
Shudo, K. Cell. Biol. ReV. 1991, 25, 209. Chemistry and Biology of Synthetic
Retinoids; Dawson, M. I., Okamura, W. H., Eds.; CRC Press: Boca Raton,
FL, 1990.
(17) For a few recent leading references, see: Torrado, A.; Iglesias, B.;
Lo´pez, S.; deLera, A. R. Tetrahedron 1995, 51, 2435. Shimasaki, H.;
Kagechika, H.; Fukasawa, H.; Kawachi, E.; Shudo, K. Chem. Pharm. Bull.
1995, 43, 100. Wada, A.; Tode, C.; Hiraishi, S.; Tanaka, Y.; Ohfusa, T.;
Ito, M. Synthesis 1995, 1107. Giraud, M.; Andriamialisoa, Z.; Valla, A.;
Zennache, S.; Potier, P. Tetrahedron Lett. 1994, 35, 3077. Kim, C. U.;
Misco, P. F.; Luh, B. Y.; Mansuri, M. M. Tetrahedron Lett. 1994, 35, 3017.
(18) Pfahl, M. In From Molecular Biology to Therapeutics; Bernard, B.
A., Shroot, B., Eds.; Karger: Basel, Switzerland, 1993; pp 83-93. Pfahl,
M. In Retinoids: From Basic Science to Clinical Applications; Liorea, M.
A., Vidali, G., Eds.; Birkha¨user: Basel, Switzerland, 1994; pp 113-126.
Initial results using our standard conditions led to a very slow
reaction. Raising the temperature to 45 °C, but otherwise
(15) Midland, M. M.; Tramatano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28.

702 J. Am. Chem. Soc., Vol. 119, No. 4, 1997
Scheme 2.a An Iterative Cross-Coupling Sequence
Trost et al.
a (a) 3% Pd(OAc)2, 3% TDMPP, THF, room temperature, 88% R ) OCH3, 80% R ) CH3; (b) POCl3, C5H5N, reflux, 64%; (c) (i) DIBAL-H,
PhCH2, -78 °C, 63%; (ii) Dess-Martin periodinane, CH2Cl2, 0 °C, Q or NMO, TPAP, 3 Å MS, CH2Cl2, rt, 87%; (d) TMSCHN2, LDA, THF, -78
°C to room temperature, 72% or Ph3P, CBr4, CH2Cl2, 0 °C then n-C4H9Li, -78 °C to room temperature, 58%; (e) see a, 53%.
by the inability to dehydrate the mono alcohol 16 (R ) CH3)
to the dienyne 17 (R ) CH3).
convenient protocol involved direct treatment of aldehyde 18
with lithiated (trimethylsilyl)diazomethane, wherein the yield
increased to 72%. Gratifyingly, the terminal alkyne 19 added
smoothly to methyl 2-butynoate to give the conformationally
rigid analog 20 in 53% yield.
An alternative path to diyne 19 involves direct homologation
of an aldehyde to a terminal alkyne via Wittig21 or Peterson22
type olefination protocols. For this purpose, the terminal alkyne
15 was added to methyl 2-butynoate to give 16 (R ) OCH3) in
88% yield as a single regioisomer and olefin geometry. Since
15 is a mixture of diastereomers with respect to the ring, a
mixture of stereochemical isomers with respect to the ring was
isolated. Since this stereochemistry is lost in the next step, the
individual stereoisomers were not pursued. This ester undergoes
dehydration under classical conditions with phosphorus oxy-
chloride in pyridine to the dienyne 17 (R ) CH3), which is a
single isomer confirming the homogeneity with respect to both
regiochemistry and alkene geometry.
Access to the diyne 19 was effected by a classical sequence
which proceeded efficiently. Reduction with DIBAL-H pro-
ceeded readily to the alcohol even at -78 °C. Thus, we chose
to oxidize the latter rather than pursue stopping the ester
reduction at the stage of the aldehyde. The Dess-Martin
periodinane23 effected oxidation quantitatively. On the other
hand, the procedure of Ley employing catalytic tetra-n-propy-
lammonium perruthenate (TPAP) with NMO (4-methylmor-
pholine N-oxide) as the stoichiometric reoxidant24 is more
convenient. It effected the same oxidation in somewhat lower
but still quite satisfactory yield (87%). Dibromomethylenation
with triphenylphosphine and carbon tetrabromide gave the vinyl
dibromide in 76% yield. Subjection of the latter to n-
butyllithium provides the desired terminal acetylene 19 in 76%
yield, for an overall 58% yield from aldehyde 18. A more
Discussion
The addition of the C-H bond of terminal alkynes across
the π-bond of an internal or terminal alkyne creates a valuable
and versatile product, a conjugated enyne. While such reactions
have been observed with a variety of transition metal cata-
lysts,9,10 they frequently produce mixtures arising from the
reactivity of the initial adducts toward further additions. In some
cases, mixtures of regioisomers result. In other cases, especially
those involving lanthanide and actinide catalysts, the reactions
are limited to hydrocarbons. Furthermore, the reaction involving
some later transition metal catalysts, such as rhodium and
ruthenium, involves a mechanism that restricts the reaction to
terminal alkynes.
The catalyst system reported herein obviates many, if not all,
of these problems and limitations and gives excellent yields of
the 1:1 homo- and cross-coupling products. The outstanding
chemoselectivity exhibited engenders the notion that any
functionality will be compatible with this reaction.
The understanding of the effectiveness of this reacion requires
an understanding of the mechanism. The reaction consists of
three phases: (1) the activation of the C-H bond of the terminal
alkyne, (2) the addition to the π-system of the acceptor alkyne,
and (3) the protonation of the vinylpalladium intermediate. In
addition, the question of the palladium species responsible for
the actual catalytic cycle is not necessarily obvious.
Our initial working hypothesis outlined in Scheme 3 is a
modification of our earlier proposal to better take into account
the regioselectivity of the process. It invokes the insertion of
palladium into the C-H bond of a terminal alkyne that becomes
kinetically accessible by coordination of the triple bond with
Pd(2+). The beneficial effect of a sterically demanding and
electron rich ligand is envisioned to arise from the requirement
to maintain a coordinatively unsaturated palladium species that
still is electron rich enough to participate in an oxidative
addition. While 21 may not be expected to be stable relative
to loss of acetic acid, its intermediacy on the way to 22 cannot
be excluded. This mechanism accounts for the overall event
of a cis addition in a Markovnikov fashion for the homo-
coupling and in a Michael fashion for the cross-coupling.
(19) For chemistry and biology of some dehydroretinoids, see: Khitrina,
L. V.; Eremin, S. V.; Khodonov, A. A.; Kaulen, A. D. Biol. Membr. 1994,
11, 575. Jaeger, E. P.; Jurs, P. C.; Stouch, T. R. Eur. J. Med. Chem. 1993,
28, 275. Sarkar, R.; Das, S. K. Neoplasma 1992, 39, 87. Danshina, S. V.;
Drachev, A. L.; Drachev, L. A.; Kaulen, A. D.; Mitsner, B. I.; Khitrina, L.
V.; Khodonov, A. A. Bioorg. Khim. 1989, 15, 307. Wuest, H. H.; Janssen,
B.; Frickel, F. Biochem. Soc. Trans. 1986, 14, 933. Niculescu-Duvaz, I.;
Simon, Z.; Voiculet, N. Carcinogenesis 1985, 6, 479. Hopf, H.; Krause, N.
Tetrahedron Lett. 1985, 26, 3323. Gaertner, W.; Oesterhelt, D.; Seifert-
Schiller, E.; Towner, P.; Hopf, H.; Boehm, I. J. Am. Chem. Soc. 1984,
106, 5654. Newton, D. L.; Henderson, W. R.; Sporn, M. B. Cancer Res.
1980, 40, 3413. Lotan, R.; Neumann, G.; Lotan, D. Cancer Res. 1980, 40,
1097. Olive, J. L.; Mousseron-Canet, M.; Dornand, J. Bull. Soc. Chim. Fr.
1969, 3247.
(20) Negishi, E.; King, A. O.; Tour, J. M. Org. Synth. 1985, 64, 44.
(21) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(22) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107
(23) Dess, B. D.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(24) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.

Palladium-Catalyzed Additions of Alkynes
J. Am. Chem. Soc., Vol. 119, No. 4, 1997 703
Scheme 3. A Working Hypothesis
However, several features were somewhat discomforting. The
formation of the substitution product 22 normally involves a
base-catalyzed reaction; however, except for the phosphine, no
base is present.5 Since only a 1:1 ratio of phosphine to
palladium is employed, it would seem the phosphine is tied up
as a ligand to the palladium and therefore unavailable to serve
this function. Invoking the Pd(4+) species 21 is suggested to
obviate this problem. The donor ligand then helps stabilize the
high oxidation state of palladium.25 On the other hand, it is
less obvious how this route accommodates the cross-coupling
event. If the selectivity derives from alkyne coordination of
22, a Pd(2+) species bearing an electronegative group, such as
acetate, would have to preferentially coordinate an electron
deficient alkyne over an electron rich alkyne to preclude any
homo-coupling, a requirement that appears less likely. Alter-
natively, this selectivity may derive from the migratory insertion
in going from 23 to 24.26
However, we did not seriously question this working hy-
pothesis until we were confronted with the 1:2 adducts 12 and
13. According to this mechanism, a competition between
protonation of the vinylpalladium species 24 and its reaction
with another molecule of acceptor alkyne is responsible for the
product ratio. However, this competition did not respond to
increasing the concentration of protons, even to the extent of
using a protonic solvent.
We also explored the question of whether this reaction
involves a Pd(0) or Pd(2+) resting state in the catalytic cycle,
since palladium acetate is known to be rather easily reduced to
Pd(0). We, therefore, examined the feasibility of Pd(0) to
catalyze this reaction. Using the self-coupling of diethyl
propargylmalonate as an example (Table 2, entry 3), we exposed
it to (dba)3Pd2‚CHCl3 in the presence of TDMPP (Pd/P ratio of
1:1) and found that reaction did proceed but somewhat more
slowly and incompletely. After 19 h at room temperature, the
reaction was 50% complete, and the reaction was stopped at
65% conversion after 27.5 h. In order to keep everything as
constant as possible, a Pd(2+) species was generated in situ by
adding allyl acetate to the above Pd(0) catalyst system. After
17 h, the reaction was 87% complete, and after 23.5 h, it was
94% complete.
working hypothesis in which the resting state of the catalyst
may be a dialkynylpalladium complex (25, see Scheme 4).
Formation of such complexes from both Pd(2+) and Pd(0)
precursors are documented5,27 and account for the ability of both
to serve as precursors. The strong donor properties of the
acetylides predict preferential coordination of an acceptor alkyne
with a low-lying antibonding orbital in 26. Thus, the ability of
electron deficient alkynes to compete successfully with the
terminal alkyne even at a 1:1 ratio is nicely accommodated by
this species. Further, the differential rate of migratory insertion
of an electron deficient versus an electron rich alkyne may act
synergistically to give the high selectivity observed for cross-
coupling. Invoking a migratory insertion in Pd(2+) complex
26 leads to complex 27 and accounts for the 1:1 versus 1:2
adduct formation. The complex 27 may react with another
acceptor alkyne in similar fashion to form the 1:2 adduct or
another terminal alkyne to give a Pd(4+) complex 28. The
presence of strong donor ligands on palladium as in 26 and 27
should facilitate formation of the higher oxidation state complex.
It also accounts for the absence of any effect of an external
proton source. Unfortunately, any attempts to establish the
terminal alkyne as the source of the vinylic hydrogen in the
product in the presence of an external proton source by
deuterium labeling is thwarted by a rapid exchange between
these protons in the presence of the palladium catalyst. This
latter mechanism does not attribute any difference on catalyst
precursor, Pd(0) or Pd(2+). While qualitatively they are the
same, there appear to be quantitative differences. One way to
rationalize the differences is to invoke a hybrid scheme whereby
the dummy ligand in Scheme 4 is an acetate, rather than a
second acetylide, for the palladium acetate precatalyst as
illustrated in Scheme 5. Formation of the active catalyst 22
may occur as outlined in Scheme 3 or via direct deprotonation
of the coordinated terminal alkyne to ligated palladium acetate.28
At present, we cannot differentiate unambiguously among these
possibilities.
The regiochemistry of the carbametalation of the acceptor
alkyne reflects both steric and electronic effects. Thus, the
dimerization preferentially involves placing the palladium at the
less-substituted carbon, as in 29, rather than the reverse, as in
The fact that Pd(0) could catalyze the reaction, albeit
somewhat less efficiently that Pd(2+), suggests an alternative
(27) Also, see: Nelson, J. H.; Verstuyft, A. W.; Kelley, J. D.; Jonassen,
H. B. Inorg. Chem. 1974, 13, 27. Sonogashira, K.; Yatake, T.; Tohda, Y.;
Takahashi, S.; Hagihara, N. J. Chem. Soc., Chem. Commun. 1977, 291.
Sebald, A.; Stader, C.; Wrackmeyer, B.; Bensch, W. J. Organomet. Chem.
1986, 311, 233.
(25) Cf.: Canty, A. J. Acc. Chem. Res. 1992, 25, 83.
(26) Cf.: Yasuda, T.; Kai, Y.; Yasuoka, N.; Kasai, N. Bull. Chem. Soc.
Jpn. 1977, 50, 2888.

704 J. Am. Chem. Soc., Vol. 119, No. 4, 1997
Scheme 4. An Alternative Working Hypothesis
Trost et al.
Scheme 5. A Hybrid Mechanistic Rationale
30, both to minimize steric hindrance and to provide the most
stable C-Pd bond. The latter presumably dominates in the
cross-coupling thereby preferring adduct 31 over 32. It was
not surprising, then, that a preliminary examination of the self-
coupling of (trimethylsilyl)acetylene gave the reverse regiose-
lectivity from normal (eq 9), since the trimethylsilyl group is
(28) The details of the activation of the C-H bond of the terminal alkyne
remain to be established. The possibility of a series of equilibria as shown
in the following equation is also quite reasonable:
expected to stabilize the adjacent C-Pd bond in the carbam-
etalation step.
LPd(OAc)2 h [LPdOAc]+ -OAc h
[LPd(η2sCHtCR)OAc]+ -OAc h 22 + HOAc
We thank one of the referees for drawing attention to this additional
possibility. While this represents one of several possibilities that we have
considered, the lack of any experimental data led us not to include details
regarding this step in Scheme 5.
Synthetically, this reaction appears to hold much promise.
The ease of operation and the excellent yields under mild

Palladium-Catalyzed Additions of Alkynes
J. Am. Chem. Soc., Vol. 119, No. 4, 1997 705
Table 5. Experimental Details for Homocoupling
starting alkyne,
mg (mmol)
Pd(OAc)2,
mg (µmol)
TDMPP,
mg (µmol)
entry
PhH, mL
time, h
product, mg, yield (%), Rf (solvent)
1
2
3
4
5
6
7
8
46.4 (0.42)
53.8 (0.53)
56.1 (0.33)
54.9 (0.65)
38.3 (0.16)
39 (0.15)
1.9 (8.4)
2.4 (10)
1.5 (6.6)
2.9 (13)
1.7 (7.9)
6.3 (7.6)a
1.9 (8.3)
2.2 (2.6)a
3.7 (8.4)
4.7 (10)
3.0 (6.6)
5.8 (13)
3.5 (7.9)
1.0
1.0
1.0
0.65
0.5
0.5
0.5
0.5
64
0.67
19
24
0.67
43
29.4, 63, 0.44 (hexane)
33.6, 63, 0.18 (hexane)
45.5, 81, 0.09 (40% ether/hexane)
35.3, 64, 0.24 (80% ether/hexane)
27.2, 71, 0.15 (10% ether/hexane)
25.2, 65, 0.06 (10% ether/hexane)
37.4, 90, 0.67 (10% ether/hexane)
13.4, 83, N.D.b (30% ether/hexane)
41.8 (0.17)
16.1 (0.05)
3.7 (8.3)
40.75
16
a Catalyst is preformed bis(tri-o-tolylphosphine)palladium acetate. b N.D. ) not determined.
6.6 µmol, 2 mol %) in 0.5 mL of benzene-d6. 1H NMR spectroscopy
revealed reaction was complete after 19 h. Direct chromatography (50%
ether-pentane) gave 45.5 mg (81% yield) of 1,1,7,7-tetrakis(car-
bomethoxy)-5-methylenehept-3-yne (5c).
conditions attest to its practicality. The extraordinary chemose-
lectivity and excellent regio- and diastereoselectivity enhance
its value in organic synthesis. The fact that these reactions
constitute simple additions using 1:1 ratio of reactants and
anything else being required only catalytically makes them
closely approach the ideal in synthetic efficiency. The products
are also quite versatile from the point of view of their
functionality, since either the double or triple bonds can be
selectively manipulated. For example, the adduct of one of the
terminal alkynes with ethyl 3-(dimethylphenylsilyl)propynoate
undergoes selective epoxidation of the double bond with
m-chloroperbenzoic acid (MCPBA, eq 10) in 63% yield.
Solvolysis of the silyl epoxide effects elimination to produce
the â-keto ester in 68% yield. The utility of this reaction for
natural products synthesis will be the subject of future investiga-
tions.
(C) Characterization Data for Homocoupled Products. 4a: IR
1
(neat) 2235, 1605, 1580, 1505 cm-1; H NMR (270 MHz, CDCl3) δ
7.24 (d, J ) 8.5 Hz, 4H), 6.83 (d, J ) 8.5 Hz, 4H), 5.55 (s, 1H), 5.45
(s, 1H), 5.06 (t, J ) 7.1 Hz, 2H), 4.70 (d, J ) 11.3 Hz, 1H), 4.41 (d,
J ) 11.3 Hz, 1H), 4.53 (d, J ) 11.3 Hz, 1H), 4.23 (d, J ) 11.3 Hz,
1H), 4.18 (t, J ) 6.6 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76 (t, J )
7.0 Hz, 1H), 2.13 (q, J ) 7.3 Hz, 2H), 2.03 (q, J ) 7.4 Hz, 2H), 1.83-
1.68 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H); HRMS calcd for C34H44O4
516.3239, found 516.3204.
4b: IR (neat) 1608, 1580, 1500 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.23 (d, J ) 8.3 Hz, 4H), 6.82 (d, J ) 8.3 Hz, 4H), 5.53 (d, J ) 1.7
Hz, 1H), 5.43 (d, J ) 1.7 Hz, 1H), 5.40-5.34 (m, 4H), 4.68 (d, J )
11.3 Hz, 1H), 4.40 (d, J ) 11.3 Hz, 1H), 4.52 (d, J ) 11.3 Hz, 1H),
4.21 (d, J ) 11.3 Hz, 1H), 4.16 (t, J ) 6.5 Hz, 1H), 3.76 (s, 3H), 3.75
(s, 3H), 3.75 (t, J ) 7.3 Hz, 1H), 2.14-2.00 (m, 4H), 1.83-1.68 (m,
4H), 1.59 (s, 3H), 1.57 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.3,
159.2, 132.2, 130.7, 130.2, 129.6 (3C), 129.4 (3C), 125.5, 125.2, 122.4,
113.8 (4C), 89.9, 83.9, 80.8, 70.1, 70.0, 68.2, 55.3 (2C), 35.6, 34.6,
28.5, 28.4, 17.8 (2C). Anal. Calcd for C32H40O4: C, 78.65; H, 8.25
(MW 488.2926). Found: C, 78.66; H, 8.30 (MW 488.2950).
1
5a: IR (neat) 2210, 1605, 1455, 885 cm-1; H NMR (270 MHz,
CDCl3) δ 5.18 (d, J ) 2.1 Hz, 1H), 5.10 (d, J ) 2.1 Hz, 1H), 2.28 (t,
J ) 6.9 Hz, 2H), 2.09 (t, J ) 7.4 Hz, 2H), 1.6-1.2 (m, 16H), 0.87 (t,
J ) 6.8 Hz, 3H), 0.86 (t, J ) 6.8 Hz, 3H); HRMS calcd for C16H28
220.2191, found 220.2190.
Experimental Section
1
5b: IR (neat) 2190, 1595, 1570, 1485, 1440, 1330 cm-1; H NMR
All reactions were performed in a flame-dried flask or test tube under
nitrogen as an inert atmosphere. Solvents were distilled prior to use
and transferred with syringe to the reaction vessel. 1H and 13C NMR
spectra were recorded on a Varian Gemini 200 or 300, an XL-400, or
a Brucker 270 spectrometer, at the indicated frequencies. IR spectra
were recorded either neat or as a film on sodium chloride plates or as
potassium bromide pellets. Combustion analyses were performed by
M-H-W Laboratories, Phoenix, Arizona. Mass spectra were provided
by the UCSF Mass Spectronomy facility employing a Kratos MS-9
instrument with an ionization current of 98 mA and ionizing voltage
of 70 eV. For thin layer chromatograhy, Merck precoated glass plates
were used and detection was carried out by either a UV lamp, KMnO4
solution, vanillin/sulfuric acid, or ammonium molybdate/ceric sulfate
in sulfuric acid. Flash chromatography employed E. Merck silica gel,
Kieselgel 60, 230-400 mesh.
Homocoupling. (A) General Procedure. A solution of the alkyne
in benzene (1 M) was added to a solution of 2 mol % of palladium
acetate and 2 mol % of TDMPP in an equal volume of benzene at
room temperature. Stirring was continued until the starting material
disappeared as determined by TLC or 1H NMR spectroscopy (benzene-
d6 employed in such cases). The solvent was removed in Vacuo, and
the residue was purified by flash chromatography to give the product.
In some cases, the reaction was directly chromatographed to give the
pure product. Table 5 summarizes the results for each of the specific
cases.
(200 MHz, CDCl3) δ 7.74-7.69 (m, 2H), 7.53-7.50 (m, 2H), 7.41-
7.31 (m, 6H), 5.98 (d, J ) 1.0 Hz, 1H), 5.75 (d, J ) 1.0 Hz, 1H)
HRMS calcd for C16H12 204.0939, found 204.0938.
1
5c: IR (neat) 2220, 1730, 1615, 1433, 1340 cm-1; H NMR (270
MHz, CDCl3) δ 5.28 (bs, 1H), 5.25 (d, J ) 1.2 Hz, 1H), 3.76 (s, 6H),
3.71 (s, 6H), 3.70 (t, J ) 7.7 Hz, 1H), 3.59 (t, J ) 7.7 Hz, 1H), 2.88
(d, J ) 7.4 Hz, 2H), 2.68 (d, J ) 7.5 Hz, 2H). Anal. Calcd for
C16H20O8: C, 56.46; H, 5.92 (MW 340.1158). Found: C, 56.58; H,
5.94 (MW 340.1159).
5d: Mp 77-8 °C IR (neat) 3570, 3400 (br), 1600, 1455, 1375, 1360
1
cm-1; H NMR (270 MHz, CDCl3) δ 5.47 (s, 1H), 5.32 (s, 1H), 2.95
(bs, 1H), 2.29 (bs, 1H), 1.52 (s, 6H), 1.38 (s, 6H); HRMS calcd for
C10H16O2 168.1150, found 168.1145.
5e: IR (neat) 2205, 1670, 1605 cm-1; 1H NMR (270 MHz, CDCl3)
δ 5.19 (s, 1H), 5.11-5.05 (m, 3H), 4.45 (dt, J ) 8.1, 5.3 Hz, 1H),
4.30 (q, J ) 7.2 Hz, 1H), 2.34-2.25 (m, 2H), 2.16-2.08 (m, 2H),
1.76-1.47 (m, 4H), 1.67 (s, 6H), 1.62 (d, J ) 1.0 Hz, 3H), 1.60 (d, J
) 1.3 Hz, 3H), 0.86 (s, 18H), 0.025 (s, 3H), 0.005 (s, 3H), -0.008 (s,
3H), -0.02 (s, 3H); HRMS calcd for C26H47O2Si2 (M+ - C4H9)
447.3114. found 447.3092. Anal. Calcd for C30H56O2Si2: C, 71.36;
H, 11.18. Found: C, 71.41; H, 11.27.
5f: IR (neat) 1710, 1650, 1260 cm-1; 1H NMR (270 MHz, CDCl3)
δ 6.78-6.71 (m, 2H), 5.48 (d, J ) 1.6 Hz, 1H), 5.40 (bs, 1H), 4.49 (t,
J ) 6.1 Hz, 1H), 4.162 (q, J ) 7.1 Hz, 2H), 4.157 (q, J ) 7.1 Hz,
2H), 4.16-4.15 (m, 1H), 2.31 (q, J ) 7.4 Hz, 2H), 2.16 (q, J ) 7.5
Hz, 2H), 1.82 (s, 3H), 1.79 (s, 3H), 1.8-1.7 (m, 4H), 1.27 (t, J ) 7.1
(B) Specific Example. A solution of dimethyl propargylmalonate
(56.1 mg, 0.33 mmol) in 0.5 mL of benzene-d6 was added to a solution
of palladium acetate (1.5 mg, 6.6 µmol, 2 mol %) and TDMPP (3 mg,

706 J. Am. Chem. Soc., Vol. 119, No. 4, 1997
Trost et al.
Table 6. Experimental Details for Cross-Couplings
acceptor alkyne
mg, mmol
Pd(OAc)2
(mg, µmol) (mg, µmol)
TDMPP
PhH
(mL)
time
(h)
entry
1
donor alkyne mg, mmol
product, mg, yield (%), Rf (solvent)
TMS-t
2950, 30
Ph-t
53.4, 0.523
HOCH2CtCH
606, 10.8
(CH3O2C)2CHCH2CtCH
61.3, 0.40
PhSO2CH2CtCH
43, 0.24
OHC(CH2)3CtCH
1290, 13.4
CH3CtCCO2CH3
3000, 30
CH3CtCCO2CH3
62.4, 0.63
CH3CtCCO2CH3
12.72, 13.0
CH3CtCCO2CH3
54, 0.48
CH3CtCCO2CH3
28, 0.29
CH3CtCCO2CH3
1580, 16.1
210, 900
2.3, 10
49.9, 220
1.8, 8
250, 900
4.6, 10
98.7, 220
3.6, 8
30a
0.7b
10
0.7b
0.2b
50
0.5
4
1
0.5
7
6a, 5700, 95, 0.5
(90:10 hexane/ethyl acetate)
6b, 96, 92, 0.39
(10% ether in hexane)
6c, 99, 87, 0.28
(70% ether in hexane)
6d, 99, 87, 0.28
2
3
4
5
15.5
25
18
18
3
(40% ether in hexane)
6e, 7.5, 11, 0.13
1.1, 5
2.2, 5
(40% ether in hexane)
6
60, 267
1.3, 6
120, 272
2.7, 6
6f, 2200, 84, N.D.c
(15% ether in hexane)
6g, 125, 90, N.D.c
7
(PhSO2)2CH(CH2)3CtCH CH3CtCCO2CH3
108.6, 0.3
PhCtCH
102.1, 1.0
n-C4H9CtCH
82.2, 1.0
TBDMSOCH2CtCH
170, 1.0
PhCtCH
51.1, 0.5
PhCtCH
102.2, 1.0
HOCH2CtCH
28.0, 0.5
HOCH2CtCH
28.0, 0.5
PhCtCH
51.1, 0.5
PhCtCH
51.1, 0.5
(CH3O2C)2CHCH2CtCH
85.1, 0.5
29.4, 0.3
CH3CtCSO2Ph
180.2, 1.0
CH3CtCCO2Ph
180.2, 1.0
CH3CtCCO2Ph
180.2, 1.0
CH3CtCCOCH3
72.2, 0.5
n-C6H13CtCCOCH3
76.3, 0.5
CH3CtCSO2Ph
90.1, 0.5
CH3CtCSO2Ph
180.2, 1.0
CH3CtCSO2Ph
180.2, 1.0
DMPSCtCCO2C2H5
116.2, 0.50
DMPSCtCCO2C2H5
116.2, 0.50
DMPSCtCCO2C2H5
116.2, 0.50
(15% ether in hexane)
8
4.5, 20
4.5, 20
4.5, 20
2.2, 10
2.2, 10
2.2, 10
2.2, 10
2.2, 10
3.4, 15
3.4, 15
2.2, 10
11.3, 50
8.9, 20
8.9, 20
8.9, 20
4.5, 10
4.5, 10
4.5, 10
4.5, 10
4.5, 10
6.9, 15
6.9, 15
4.5, 10
22.3, 50
7a, 252, 89, N.D.c
(15:85 ethyl acetate/hexane)
7b, 242, 92, N.D.c
9
4
24
16
24
18
5
(20:80 ethyl acetate/hexane)
10
11
12
13
14
15
16
17
18
19
4
7c, 236, 68, N.D.c
(25:75 ethyl acetate/hexane)
8a, 88.9, 72, N.D.c
2
(25:75 ethyl acetate/hexane)
8b, 105.3, 83, N.D.c
(10:90 ethyl acetate/hexane)
11, 104.3, 88, N.D.c
(15:85 ethyl acetate/hexane)
11, 48.3, 40; 12, 122.6, 59
(25:75 ethyl acetate/hexane)
7a, 29.0, 21; 13, 137.0, 59
(20:80 ethyl acetate/hexane)
14a, 138.2, 83
(5:95 ethyl acetate/hexane)
14b, 132.6, 66
(5:95 ethyl acetate/hexane)
14c, 119.3, 73
2
10
1
16
24
20d
48
16
18
0.5
0.5
10
2
e
e
e
OHC(CH2)3CtCH
48.2, 0.5
AcOCH2CH2CtCH
55.7, 0.497
(5:95 ethyl acetate/hexane)
14d, 82, 48
(10% ether in hexane)
DMPSCtCCO2C2H5
133, 0.573
1
a THF employed as solvent instead of PhH. b Benzene-d6 employed as solvent. c N.D. ) not determined. d At 45 °C. e DMPS ) (CH3)2PhSi.
Hz, 6H), 0.88 (s, 18H), 0.11 (s, 3H), 0.09 (s, 3H), 0.03 (s, 3H), 0.01
(s, 3H); HRMS calcd for C30H51O6Si2 (M+ - C4H9) 563.3225, found
563.3222.
6c: IR (neat) 3400 (br), 2220, 1710, 1620 cm-1; 1H NMR (270 MHz,
CDCl3) δ 6.06 (q, J ) 1.5 Hz, 1H), 4.43 (s, 2H), 3.72 (s, 3H), 2.29 (d,
J ) 1.5 Hz, 3H), 2.18 (s, 1H); HRMS calcd for C8H10O3 154.0630,
found 154.0623.
Cross-Coupling. (A) General. A 1:1 mixture of palladium acetate
(2 mol %) and TDMPP (2 mol %) in benzene (volume to make reaction
0.5-1.0 M in each reactant alkyne) was stirred 5-15 min at which
point the acceptor alkyne was added, all at room temperature. After
an additional 5 min, the donor alkyne was added at room temperature.
After consumption of starting material, the reaction mixture was
concentrated in Vacuo and the residue was chromatographed to give
the pure product. In some cases, the reaction mixture was directly
chromatographed to give the pure product. The details for each run
are summarized in Table 6.
1
6d: IR (neat) 2220, 1750, 1735, 1710, 1615 cm-1; H NMR (270
MHz, CDCl3) δ 5.95 (q, J ) 1.2 Hz, 1H), 4.13 (q, J ) 7.1 Hz, 2H),
3.75 (s, 6H), 3.59 (t, J ) 7.7 Hz, 1H), 2.92 (d, J ) 7.7 Hz, 2H), 2.20
(d, J ) 1.4 Hz, 3H), 1.24 (t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.1 (2C), 165.9, 137.4, 124.1, 90.0, 84.6, 59.9, 52.8 (2C),
50.8, 19.8, 19.5, 14.2. Anal. Calcd for C14H18O6: C, 59.57; H, 6.43.
Found: C, 59.70; H, 6.50.
6e: IR (neat) 2208, 1710, 1615, 1440, 1430, 1160, 1130, 1080 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.95 (dd, J ) 8.7, 1.0 Hz, 2H), 7.73-
7.56 (m, 3H), 5.95 (d, J ) 1.5 Hz, 1H), 4.10 (s, 2H), 3.69 (s, 3H), 2.1
(d, J ) 1.5 Hz, 3H); HRMS calcd for C14H14SO4 278.0613, found
278.0611.
(B) Specific Example. A mixture of palladium acetate (60 mg, 0.27
mmol) and TDMPP (120 mg, 0.27 mmol) in 45 mL of benzene was
stirred 15 min at room temperature. A solution of 5-hexynal (1.29 g,
13.4 mol) and methyl 2-butynoate (1.6 mL, 1.6 g, 16 mmol) in 5 mL
of benzene was added. After 18 h of stirring at room temperature, the
reaction was concentrated in Vacuo and the residue was purified by
flash chromatography (15% ether-hexane) to give 2.2 g (84% yield)
of 6f.
6f: IR (CDCl3) 2725, 2210, 1715, 1620, 1435 cm-1; 1H NMR (300
MHz, CDCl3) δ 9.79 (t, J ) 1.3 Hz, 1H), 5.97 (q, J ) 1.4 Hz, 1H),
3.68 (s, 3H), 2.58 (td, J ) 7.1, 1.3 Hz, 2H), 2.41 (t, J ) 6.9 Hz, 3H),
2.24 (d, J ) 1.4 Hz, 3H), 1.86 (p, J ) 7.0 Hz, 2H); HRMS calcd for
C11H14O3 (M+ - OCH3) 194.0932, found 194.0932.
(C) Characterization Data. 6a: IR (neat) 2150, 1715, 1610 cm-1
;
6g: IR (neat) 2210, 1710, 1620, 1450, 1360 cm-1; H NMR (200
1
1H NMR (300 MHz, CDCl3) δ 6.06, (s, 1H), 3.67 (s, 3H), 2.14 (s,
3H), 0.17 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.4, 137.8, 124.4,
106.3, 99.3, 51.2, 19.7, 0.3. Anal. Calcd for C10H16O2Si: C, 61.18;
H, 8.21. Found: C, 61.45; H, 7.97.
MHz, CDCl3) δ 8.04-7.87 (m, 4H), 7.76-7.48 (m, 6H), 5.97 (s, 1H),
4.49 (t, J ) 5.4 Hz, 1H), 3.72 (s, 3H), 2.41-2.24 (m, 4H), 2.37 (s,
3H), 1.92-1.84 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 167.1, 139.0,
138.3, 135.3, 130.2, 129.7, 123.9, 94.1, 84.6, 83.7, 51.8, 27.0, 25.6,
20.7, 19.7. Anal. Calcd for C23H24S2O6: C, 59.98; H, 5.25 (MW
460.1014). Found: C, 59.88; H, 5.09 (MW 460.1022).
1
6b: IR (neat) 2200, 1714, 1612, 1485, 1430 cm-1; H NMR (270
MHz, CDCl3) δ 7.47-7.43 (m, 2H), 7.34-7.31 (m, 3H), 6.14 (q, J )
1.5 Hz, 1H), 3.71 (s, 3H), 2.38 (d, J ) 1.5 Hz, 3H). Anal. Calcd for
C13H12O2: C, 77.98; H, 6.04 (MW 200.0837). Found: C, 78.00; H,
5.94 (MW 200.0837).
7a: IR (CHCl3) 2190, 1585, 1315 cm-1; 1H NMR (200 MHz, CDCl3)
δ 7.98-7.93 (m, 2H), 7.65-7.33 (m, 8H), 6.63 (q, J ) 1.4 Hz, 1H),
2.38 (d, J ) 1.4 Hz, 3H); 13C NMR (300 MHz, C6D6) δ 142.0, 135.5,

Palladium-Catalyzed Additions of Alkynes
J. Am. Chem. Soc., Vol. 119, No. 4, 1997 707
135.2, 133.6, 132.4, 130.2, 129.7, 129.1, 127.8, 122.3, 96.2, 89.9, 19.1.
Anal. Calcd for C17H14SO2: C, 72.31; H, 5.00 (MW 282.0715).
Found: C, 72.40; H, 4.82 (MW 282.0724).
Hz, 2H), 2.68 (t, J ) 7.0 Hz, 2H), 2.05 (s, 3H), 1.16 (t, J ) 7.2 Hz,
3H), 0.42 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 170.7, 164.7, 153.1,
138.8, 133.5, 130.8, 128.8, 127.7, 87.9, 80.3, 62.1, 61.5, 20.8, 19.9,
13.9, -1.9; HRMS calcd for C19H24O4S 344.1444, found 344.1449.
Preparation of 16a. Following the general protocol for cross-
coupling, terminal alkyne 15 (1.0 g, 6.0 mmol), 3-pentyn-5-one (0.5
g, 6.0 mmol), palladium acetate (42.8 mg, 0.19 mmol), TDMPP (53.1
mg, 0.19 mmol) in 3.2 mL of THF gave, after 5 d at room temperature
(rt) and flash chromatography [60:40 hexane-ether, Rf 0.36 (minor),
0.47 (major)], 1.2 g (80% yield) of 16a. For 16a: IR (neat) 3600-
7b: IR (neat) 2210, 1585, 1300 cm-1; 1H NMR (200 MHz, CDCl3)
δ 8.04-7.87 (m, 2H), 7.60-7.51 (m, 3H), 6.43 (q, J ) 1.4 Hz, 1H),
2.29 (t, J ) 6.5 Hz, 2H), 2.22 (d, J ) 0.8 Hz, 3H), 1.47-1.23 (m,
4H), 0.87 (t, J ) 6.8 Hz, 3H); 13C NMR (200 MHz, CDCl3) δ 142.2,
137.4, 133.9, 133.2, 129.8, 127.7, 99.1, 81.4, 30.7, 22.4, 19.9, 19.6,
14.0. Anal. Calcd for C15H18SO2: C, 68.67; H, 6.91 (MW 262.1028.
Found: C, 68.42; H, 6.77 (MW 262.1030).
1
1
7c: IR (neat) 2216, 1589, 1447, 1372, 1322 cm-1; H NMR (300
3200, 2206, 1677, 1586, 1172 cm-1; H NMR (300 MHz, CDCl3) δ
MHz, CDCl3) δ 7.92-7.89 (m, 2H), 7.62-7.56 (m, 3H), 6.50 (s, 1H),
4.42 (s, 2H), 2.27 (s, 3H), 0.88 (s, 9H), 0.09 (s, 6H); 13C NMR (300
MHz, CDCl3) δ 141.9, 135.9, 134.3, 134.0, 128.8, 127.8, 85.5, 84.8,
52.3, 26.2, 19.3, 18.7, -4.7. Anal. Calcd for C18H26SSiO3: C, 61.68;
H, 7.48. Found: C, 61.58; H, 7.62.
6.40 (s, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 2.10-1.79 (m, 2H), 1.74-
1.14 (m, 6H), 1.15-1.02 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 197.9,
136.0, 130.5, 95.1, 89.7, 79.0, 39.2, 38.1, 37.1, 32.8, 31.8, 26.9, 21.1,
20.4, 19.8, 16.5. Anal. Calcd for C16H24O2: C, 77.38; H, 9.74.
Found: C, 77.50; H, 9.84.
1
8a: IR (neat) 2197, 1807, 1688, 1598, 1443, 1355 cm-1; H NMR
Preparation of 16b. Following the general protocol for cross-
coupling, terminal alkyne 15 (700 mg, 4.2 mmol), methyl 2-butynoate
(400 mg, 4.2 mmol), palladium acetate (28.2 mg, 0.13 mmol), and
TDMPP (34.9 mg, 0.13 mmol) in 2.1 mL of THF gave, after 5 d at
room temperature and flash chromatography [60:40 hexane-ether, Rf
0.56 (minor), 0.66 (major)], 1.0 g (88% yield) of 16. On a 63.2 mmol
scale, the reaction yielded 14.4 g of enynoate for an 86% yield. For
16b, Minor isomer: IR (neat) 3600-3300, 2210, 1720, 1615, 1343
(300 MHz, CDCl3) δ 7.51-7.49 (m, 4H), 7.48-7.43 (m, 4H), 7.42-
7.35 (m, 2H), 6.63 (s, 1H), 2.01 (s, 3H); 13C NMR (300 MHz, C6D6):
δ 197.6, 137.5, 135.4, 135.0, 132.4, 129.6, 129.5, 129.4, 129.0, 128.8,
123.2, 96.1, 91.3, 30.6. Anal. Calcd for C18H14O: C, 87.77; H, 5.73
(MW 246.1045). Found: C, 88.00; H, 5.51 (MW 246.1049).
8b: IR (neat) 2193, 1713, 1685, 1597, 1459, 1311, 1176, 1070 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.37-7.35 (m,
3H), 6.53 (s, 1H), 2.80 (t, J ) 7.5 Hz, 2H), 2.24 (s, 3H), 1.64-1.60
(m, 2H), 1.38-1.30 (m, 6H), 0.90 (t, J ) 6.9 Hz, 3H); 13C NMR (300
MHz, CDCl3) δ 198.2, 142.3, 132.5, 131.1, 129.6, 129.1, 123.0, 95.1,
91.5, 32.9, 32.5, 32.2, 29.6, 29.0, 23.2, 14.7; HRMS calcd for C18H22O
(M+) 254.1093, found 254.1087.
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.06 (s, 1H), 3.70 (s, 3H), 2.31
(s, 3H), 2.10 (bs, 1H), 1.95-1.81 (m, 1H), 1.62-1.37 (m, 3H), 1.37-
1.13 (m, 3H), 1.10 (s, 3H), 1.00-0.97 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 166.4, 137.9, 123.5, 95.0, 89.1, 78.9, 51.2, 39.2, 38.1, 37.0,
32.8, 26.8, 21.1, 20.0, 19.7, 16.5. For 16b, Major isomer: IR (neat)
3600-3300, 2210, 1720, 1710, 1616 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.10 (s, 1H), 3.70 (s, 3H), 2.31 (s, 3H), 2.10 (bs, 1H), 1.89 (m, 1H),
1.62-1.39 (m, 4H), 1.38-1.15 (m, 2H), 1.09 (s, 3H), 0.92 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 166.4, 138.0, 123.5, 96.8, 86.7, 76.4,
51.1, 38.6, 36.1, 33.6, 28.6, 26.3, 23.7, 21.0, 19.9, 17.1. Anal. Calcd
for C16H24O3: C, 72.60; H, 9.13. Found: C, 72.81; H, 8.96.
Preparation of Methyl 6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-
methyl-(E)-2-penten-4-ynoate (17b). The hydroxyalkynoate 16b (1.2
g, 4.5 mmol) was added to a solution of phosphorus oxychloride (1.0
g, 6.8 mmol) in pyridine (24 mL) at room temperature. After 15 min
of stirring at room temperature and 7 h at reflux, the reaction was cooled
to 0 °C and saturated aqueous sodium bicarbonate was added (24 mL).
After extraction with ether, the combined organic layers were washed
with 10% aqueous hydrochloric acid and brine, dried (MgSO4), and
evaporated in Vacuo to give, after flash chromatography (70:30 hexane-
ether, Rf 0.78), 700 mg (64% yield) of dienyne 17b. For 17b: IR
(neat) 2182, 1717, 1602 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.98 (s,
1H), 3.69 (s, 3H), 2.34 (s, 3H), 2.03 (t, J ) 6.6 Hz, 2H), 1.87 (s, 3H),
1.64-1.53 (m, 2H), 1.48-1.42 (m, 2H), 1.07 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 166.7, 144.2, 139.3, 123.6, 121.5, 95.6, 93.9, 51.0,
37.4, 33.8, 32.1, 28.9, 22.7, 20.1, 18.8. Anal. Calcd for C16H22O2:
C, 77.90; H, 8.89. Found: C, 78.11; H, 8.73.
1
11: IR (neat) 3470, 2210, 1580, 1300 cm-1; H NMR (200 MHz,
CDCl3) δ 7.89-7.84 (m, 2H), 7.65-7.49 (m, 3H), 6.50 (s, 1H), 4.36
(s, 2H), 2.23 (d, J ) 1.3 Hz, 3H), 2.15 (s, 1H); 13C NMR (200 MHz,
CDCl3) δ 141.6, 136.0, 134.4, 134.2, 129.9, 127.8, 95.0, 85.3, 51.6,
19.3. Anal. Calcd for C12H12SO3: C, 61.00; H, 5.12 (MW 236.0507).
Found: C, 60.87; H, 5.19 (MW 236.0503).
1
12: IR (neat) 3517, 2203, 619, 1583, 1447, 1318 cm-1; H NMR
(300 MHz, CDCl3) δ 7.83-7.81 (m, 2H), 7.68-7.65 (m, 3H), 7.64-
7.53 (m, 3H), 7.41-7.35 (m, 1H), 5.85 (s, 1H), 4.26 (s, 2H), 2.61 (s,
3H), 2.35 (s, 3H), 2.20 (s, 1H); 13C NMR (300 MHz, CDCl3) δ 149.4,
146.1, 141.2, 140,0, 134.5, 134.3, 133.9, 132.8, 129.9, 129.8, 128.5,
127.9, 100.8, 84.7, 51.6, 20.2, 19.1. Anal. Calcd for C21H20S2O5: C,
60.56; H, 4.84. Found: C, 60.60; H, 5.11.
13: IR (neat) 2188, 1770, 1619, 1583, 1478, 1321, 1178, 1085, 1072
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.85-7.82 (m, 3H), 7.68-7.34
(m, 12H), 5.96 (s, 1H), 2.51 (s, 3H), 2.34 (s, 3H); 13C NMR (300 MHz,
CDCl3) δ 149.5, 141.7, 140.2, 134.5, 134.0, 133.2, 132.7, 130.4, 130.2,
129.8, 129.7, 129.2, 128.6, 128.0, 121.9, 101.9, 88.6, 20.7, 19.3; HRMS
calcd for C20H17SO3 (M+ - PhSO) 337.0898, found: 337.0907.
14a: IR (neat) 2207, 1724, 1559, 1443, 1328 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.62-7.58 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.34
(m, 6H), 7.09 (s, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 1.28 (t, J ) 7.2 Hz,
3H), 0.52 (s, 6H); 13C NMR (300 MHz, CDCl3) δ 165.2, 154.1, 139.5,
134.2, 132.3, 131.4, 129.5, 129.2, 128.4, 123.4, 92.0, 88.2, 62.2, 14.6,
-1.3. Anal. Calcd for C21H22SiO2: C, 75.41; H, 6.63 (MW 334.1358).
Found: C, 75.34; H, 6.68 (MW 334.1397).
Preparation of 5-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-3-methyl-
(E)-2-penten-4-yn-1-ol. To a solution of the unsaturated ester 17b
(61.7 mg, 0.25 mmol) in toluene (0.5 mL) at -78 °C was added
DIBAL-H (0.4 mL, 0.62 mmol, 1.5 M in toluene). Reaction was
allowed to warm to ambient temperature. Upon completion, the
reaction was cooled to 0 °C, and 20% aqueous hydrochloric acid was
slowly introduced until the solids were completely dissolved. The
mixture was extracted with diethyl ether (2 × 1 mL). The combined
organic layers were dried (MgSO4), concentrated, and flash chromato-
graphed (60:40 hexane-ether, Rf 0.33) to yield the desired alcohol (45
mg, 83% yield). On a 10.0 mmol scale, the yield was 1.3 g (63%
yield). For title compound: IR (neat) 3600-3200, 2181, 1660, 1615,
14b: IR (neat) 2260, 2240, 1740, 1440, 1340, 1320 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.35-7.27 (m, 3H), 6.88 (s,
1H), 4.08 (q, J ) 7.2 Hz, 2H), 3.78 (s, 6H), 3.65 (t, J ) 7.8 Hz, 1H),
2.97 (d, J ) 7.2 Hz, 2H), 1.19 (t, J ) 7.2 Hz, 3H), 0.43 (s, 6H); 13C
NMR (300 MHz, CDCl3) δ 168.8, 165.2, 154.0, 139.4, 134.1, 131.2,
129.4, 128.3, 88.2, 81.3, 62.0, 53.4, 51.5, 20.1, 14.5, -1.3. Anal. Calcd
for C21H26O6Si: C, 62.66; H, 6.51 (MW 402.1499). Found: C, 62.47;
H, 6.31 (MW 402.1487).
14c: IR (neat) 1722, 1606, 1446, 1370 cm-1; 1H NMR (300 MHz,
CDCl3) δ 9.82 (s, 1H), 7.55-7.52 (m, 2H), 7.35-7.33 (m, 3H), 6.88
(s, 1H), 4.09 (q, J ) 7.2 Hz, 2H), 2.62 (t, J ) 7.2 Hz, 2H), 2.46 (t, J
) 7.2 Hz, 2H), 1.89 (t, J ) 7.2 Hz, 2H), 1.19 (t, J ) 7.2 Hz, 3H), 0.45
(s, 6H); 13C NMR (300 MHz, CDCl3) δ 202.3, 165.7, 152.9, 139.5,
134.1, 133.6, 129.4, 128.3, 92.0, 80.7, 62.0, 43.2, 21.5, 19.4, -1.3;
HRMS calcd for C19H24SiO3 (M+) 328.1372, found 328.1355.
14d: 1H NMR (400 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 7.34-
7.30 (m, 3H), 6.90 (s, 1H), 4.18 (t, J ) 7.0 Hz, 2H), 4.06 (q, J ) 7.1
1
1455 cm-1; H NMR (300 MHz, CDCl3) δ 5.96 (t, J ) 6.8 Hz, 1H),
4.24 (d, J ) 6.8 Hz, 2H), 2.02 (t, J ) 6.1 Hz, 2H), 1.88 (s, 3H), 1.87
(s, 3H), 1.70-1.56 (m, 3H), 1.50-1.44 (m, 2H), 1.10 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 141.1, 133.2, 123.8, 121.8, 95.3, 87.0, 59.2, 37.6,
33.9, 31.9. 28.8, 22.6, 18.8, 18.7, 17.8; HRMS calcd for C15H22O (M+))
218.1671 found 218.1671.
Preparation of 5-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-3-methyl-
(E)-2-penten-4-yn-al (18). Method A. The Dess-Martin periodinane
(400 mg, 0.93 mmol) was added to a solution of the above dienynol

708 J. Am. Chem. Soc., Vol. 119, No. 4, 1997
Trost et al.
1
(170 mg, 0.77 mmol) in 1.6 mL of dichloromethane at 0 °C. After 10
min, diethyl ether was added, and the resultant suspension was added
to 2 N aqueous sodium hydroxide. The organic layer was washed with
additional 2 N aqueous sodium hydroxide and water. After the organic
layer was dried (MgSO4) and concentrated in Vacuo, the residue was
flash chromatographed (80:20 hexane-ether, Rf 0.50) to give 170 mg
(100% yield) of the aldehyde 18.
1611, 1567, 1163 cm-1; H NMR (300 MHz, CDCl3) δ 6.02 (s, 1H),
5.83 (s, 1H), 3.79 (s, 3H), 2.32 (s, 3H), 2.08 (s, 3H), 2.03 (t, J ) 6 Hz,
2H), 1.86 (s, 3H), 1.65-1.54 (m, 2H), 1.50-1.43 (m, 2H), 1.10 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 166.5, 143.0, 138.3, 134.4, 123.9,
122.8, 112.5, 99.8, 95.2, 94.1, 91.8, 51.1, 37.5, 33.9, 32.1, 29.0, 22.8,
20.8, 19.8, 18.8; HRMS calcd for C21H26O2 310.9334, found 310.9335.
Preparation of Ethyl (E)-2,3-Epoxy-3-(dimethylphenylsilyl)-5-
phenyl-4-pentynoate. To a solution of silylated enyne 14a (1.0 g,
3.0 mmol) in 10 mL of methylene chloride was added MCPBA (517.7
mg, 3.0 mmol). After 24 h of stirring at room temperature and 48 h
at reflux, concentration in Vacuo and flash chromatography (5:95 ethyl
acetate-hexane) of the residue gave 704.5 mg (67%) of the titled
epoxide: IR (neat) 2226, 1751, 1602, 1491, 1307 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.58-7.56 (m, 2H), 7.47-7.44 (m, 2H), 7.40-7.38
(m, 3H), 7.32-7.26 (m, 3H), 4.00 (q, J ) 7.2 Hz, 2H), 2.98 (s, 1H),
1.23 (t, J ) 7.2 Hz), 0.45 (s, 3H), 0.43 (s, 3H); 13C (300 MHz, CDCl3)
δ 168.5, 137.2, 135.6, 133.7, 131.3, 130.6, 129.9, 129.6, 123.3, 86.8,
85.2, 63.8, 62.7, 54.5, 15.3, -2.0, -3.3; HRMS: calcd for C21H22O2-
Si 350.1338, found 350.1331.
Method B. TPAP (112 mg, 0.30 mmol) was added to a mixture of
the above dienynol (1.4 g, 6.4 mmol), NMO (1.1g, 94. mmol), and 3
Å MS (3.5 g) in 12 mL of dichloromethane at room temperature. After
TLC indicated complete reaction, the mixture was filtered through a
short plug of silica gel, concentrated in Vacuo, and chromatographed
as above to give 1.2 g (87% yield) of the same aldehyde: IR (neat)
1
1737, 1447, 1234 cm-1; H NMR (300 MHz, CDCl3) δ 9.97 (d, J )
8.0 Hz, 1H), 6.15 (d, J ) 8.0 Hz, 1H), 2.30 (s, 3H), 2.03 (t, J ) 6.8
Hz, 2H), 1.85 (s, 3H), 1.65-1.50 (m, 2H), 1.50-1.39 (m, 2H), 1.07
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 190.1, 145.8, 141.7, 132.0, 123.8,
99.5, 95.4, 37.4, 33.8, 32.2, 29.0 (2C), 22.8, 18.7; HRMS calcd for
C15H20 216.1515, found 216.1513.
Preparation of Methyl 7,8,11,12-Tetradehydroretinoate (20).
(Trimethylsilyl)diazomethane (3.0 mL, 6.0 mmol, 2.0 M in hexanes)
was added to a solution of LDA (6.0 mmol) in 40.7 mL of THF at
-78 °C. After 30 min of stirring at -78 °C, the aldehyde 18 (1.1 g,
5.0 mmol) was added, and the resultant reaction was kept at -78 °C
for an additional 30 min, at which time it was allowed to warm to
room temperature. After TLC (hexane, Rf 0.45) indicated completion,
the reaction was quenched by addition of water (20 mL). Extraction
of the aqueous mixture with diethyl ether (3 × 20 mL) was followed
by careful (bath temperature 0 °C) removal of solvent in Vacuo to give
alkyne 18 (780 mg, 72% yield) which was used without further
Preparation of Ethyl 3-Oxo-5-phenyl-4-pentynoate. Concentrated
sulfuric acid (0.1 mL) was added to a solution of the above epoxide
(10.0 mg, 0.029 mmol) in 1 mL of distilled ethanol. After 10 min of
heating at 90 °C, potassium carbonate (50 mg) was added. The mixture
was filtered and concentrated in Vacuo. The residue was purified by
flash chromatography (2:98 ethyl acetate-hexane) to give 4.1 mg (65%
yield) of the titled compound: IR (neat) 2203, 1737, 1709, 1671, 1490
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.54-7.44 (m, 5H), 4.25 (q, J )
7.2 Hz, 2H), 3.71 (s, 2H), 1.31 (t, J ) 7.2 Hz, 3H); 13C NMR (300
MHz, CDCl3) δ 169.3, 155.7, 134.6, 132.2, 130.2, 121.3, 87.6, 82.3,
63.6, 53.1, 15.5; HRMS calcd for C13H12O3 216.0936, found 216.0934.
1
purification: IR (neat) 3311, 2183, 1611, 1580 cm-1; H NMR (300
Acknowledgment. We thank the National Science Founda-
tion and the National Institutes of Health, General Medical
Sciences Institute, for their generous support of our programs.
We also thank Joseph J. Caringi who performed two of the
cross-couplings reported herein. Mass spectra were recorded
by the Mass Spectrometry Facility of the University of
California-San Francisco supported by the NIH Division of
Research Resources.
MHz, CDCl3) δ 5.69 (s, 1H), 3.35 (s, 1H), 2.10 (s, 3H), 2.03 (t, J )
6.8 Hz, 2H), 1.87 (s, 3H), 1.64-1.52 (m, 2H), 1.50-1.42 (m, 2H),
1.20 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 142.3, 134.1, 124.0, 112.2,
94.8, 92.8, 85.3, 81.2, 37.7, 33.9, 32.1, 29.0 (2C), 22.7, 20.6, 18.9.
Following the general protocol, dienediyne 20 (100 mg, 0.47 mmol),
methyl 2-butynoate (46.2 mg, 0.47 mmol), palladium acetate (3.2 mg,
14.2 µmol), and TDMPP (3.8 mg, 14.2 µmol) in 0.5 mL of THF gave,
after 3 d and flash chromatography (90:10 hexane-ether, Rf 0.33), 77
mg (53% yield) of 20. On a 3.6 mmol scale, this procedure gave 500
mg (44% yield). For 20: IR (neat) 2990, 2981, 2865, 2161, 1717,
JA9624937