General and selective head-to-head dimerization of terminal alkynes proceeding via hydropalladation pathway

Article abstract of DOI:10.1021/ol3010936

A general highly regio- and stereoselective palladium-catalyzed head-to-head dimerization reaction of terminal acetylenes is presented. This methodology allows for the efficient synthesis of a variety of 1,4-enynes as single E stereoisomers. Computational studies reveal that this dimerization reaction proceeds via the hydropalladation pathway.

Full text of DOI:10.1021/ol3010936

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
General and Selective Head-to-Head
Dimerization of Terminal Alkynes
Proceeding via Hydropalladation Pathway
Claire Jahier,† Olga V. Zatolochnaya,† Nickolay V. Zvyagintsev,‡
Valentine P. Ananikov,*,‡ and Vladimir Gevorgyan*,†
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois, 60607-7061, United States, and Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, Moscow,
119991, Russia
val@ioc.ac.ru; vlad@uic.edu
Received April 24, 2012
ABSTRACT
A general highly regio- and stereoselective palladium-catalyzed head-to-head dimerization reaction of terminal acetylenes is presented. This
methodology allows for the efficient synthesis of a variety of 1,4-enynes as single E stereoisomers. Computational studies reveal that this
dimerization reaction proceeds via the hydropalladation pathway.
Dimerization of terminal alkynes is a very practical and
atom-economical approach toward conjugated enynes,
important building blocks widely used in synthetic organic
chemistry, medicinal chemistry, and materials science.1
A number of transition metal complexes efficiently catalyze
alkyne dimerization.4ꢀ12 However, in most cases a mixture
of different regio- and stereoisomeric enynes 2ꢀ4 is ob-
tained(eq1). Thehighlyselective head-to-tail Pd-catalyzed
dimerization of terminal alkynes toward 1,3-enynes 4 has
been developed by Trost.4a,b However, Pd-catalyzed head-
to-head dimerization of terminal alkynes usually leads to
mixtures of stereoisomeric 1,4-enynes 2 and 34eꢀh or is
limited to particular substrates.4d,e For example, our re-
search group has developed the palladium-catalyzed head-
to-head dimerization of terminal aryl acetylenes toward
E-enynes 2.4d However, despite the achieved high regio- and
stereoselectivity, this method involving agostic interaction
is limited to terminal aryl acetylenes possessing a requisite
† University of Illinois at Chicago.
‡ Zelinsky Institute of Organic Chemistry.
(1) For review, see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B.
Chem. Rev. 2001, 101, 2067. For selected examples, see: (b) Trost, B. M.
Science 1991, 254, 1471. (c) Nicolaou, K. C.; Dai, W. M.; Tsay, S. C.;
Estevez, V. A.; Wrasidlo, W. Science 1992, 256, 1172. (d) Kinoshita, H.;
Ishikawa, T.; Miura, K. Org. Lett. 2011, 13, 122. (e) Geary, L. M.; Woo,
S. K.; Leung, J. C.; Krische, M. J. Angew. Chem., Int. Ed. 2012, 51, 2972.
(2) Hubner, H.; Haubmann, C.; Utz, W.; Gmeiner, P. J. Med. Chem.
2000, 43, 756.
(5) For Al-catalyzed dimerization reaction of terminal acetylenes,
see: Dash, A. K.; Eisen, M. S. Org. Lett. 2000, 2, 737.
(3) Liu, Y.; Nishiura, M.; Wang, Y.; Hou, Z. J. Am. Chem. Soc. 2006,
128, 5592.
(6) For Fe-catalyzed dimerization reaction of terminal acetylenes,
see: Midya, G. C.; Paladhi, S.; Dhara, K.; Dash, J. Chem. Commun.
2011, 6698.
(7) For Ir-catalyzed dimerization reaction of terminal acetylenes, see:
(a) Ghosh, R.; Zhang, X.; Achord, P.; Emge, T. J.; Krogh-Jespersen, K.;
Goldman, A. S. J. Am. Chem. Soc. 2007, 129, 853. (b) Ogata, K.; Toyota,
A. J. Organomet. Chem. 2007, 692, 4139.
(8) For lanthanide-catalyzed dimerization reaction of terminal acet-
ylenes, see: (a) Nishiura, M.; Hou, Z.; Wakatsuki, Y.; Yamaki, T.;
Miyamoto, T. J. Am. Chem. Soc. 2003, 125, 1184. (b) Nishiura, M.; Hou,
Z. J. Mol. Catal. A: Chem. 2004, 213, 101. (c) Ge, S.; Quiroga
Norambuena, V. F.; Hessen, B. Organometallics 2007, 26, 6508.
(4) For Pd-catalyzed dimerization reaction of terminal acetylenes,
see: (a) Trost, B. M.; Chan, C.; Ruhter, G. J. Am. Chem. Soc. 1987, 109,
3486. (b) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter,
G. J. Am. Chem. Soc. 1997, 119, 698. (c) Gevorgyan, V.; Radhakrishnan,
U.; Takeda, A.; Rubina, M.; Rubin, M.; Yamamoto, Y. J. Org. Chem.
2001, 66, 2835. (d) Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2001,
123, 11107. (e) Yang, C.; Nolan, S. P. J. Org. Chem. 2002, 67, 591. (f)
Katayama, H.; Nakayama, M.; Nakano, T.; Wada, C.; Akamatsu, K.;
Ozawa, F. Macromolecules 2004, 37, 13. (g) Wu, Y.-T.; Lin, W.-C.; Liu,
C.-J.; Wua, C.-Y. Adv. Synth. Catal. 2008, 350, 1841. (h) Hsiao, T.-H;
Wu, T.-L.; Chatterjee, S.; Chiu, C.-Y.; Lee, H. M.; Bettucci, L.;
Bianchini, C.; Oberhauser, W. J. Organomet. Chem. 2009, 694, 4014.
r
10.1021/ol3010936
XXXX American Chemical Society

ortho-H atom. Moreover, despite the number of proce-
dures reported,4 there is no consensus on the mechanism of
the palladium-catalyzed dimerization reaction of terminal
acetylenes. Usually, the carbometalation pathway (eq 1,
path I) is proposed.4a,b,d,g,13 Alternatively, a hydrometala-
tion pathway (eq 1, path II) has also been suggested.4a,13ꢀ16
Herein, we report a highly regio- and stereoselective palladium-
catalyzed head-to-head dimerization of a wide range of
terminal acetylenes toward E-enynes 2. DFT calculations
unambiguously support the hydropalladation pathway for
this transformation (eq 2).
Table 1. Palladium-Catalyzed Head-to-Head Dimerization of
Terminal Acetylenesa
In the course of our investigations,17 we found that the
bis-N-heterocyclic carbene palladium complex (IPr-Pd-
IPr), in the presence of electron-rich and bulky phosphine
(9) For Ni-catalyzed dimerization reaction of terminal acetylenes,
see: Ogoshi, S.; Ueta, M.; Oka, M.-A.; Kurosawa, H. Chem. Commun.
2004, 2732.
(10) For Re-catalyzed dimerization reaction of terminal acetylenes,
see: Kawata, A.; Kuninobu, Y.; Takai, K. Chem. Lett. 2009, 38, 836.
(11) For Rh-catalyzed dimerization reaction of terminal acetylenes,
€
see: (a) Schafer, M.; Wolf, J.; Werner, H. Organometallics 2004, 23,
€
5713. (b) Kruger, P.; Werner, H. Eur. J. Inorg. Chem. 2004, 481. (c) Lee,
C.-C.; Lin, Y.-C.; Liu, Y.-H.; Wang, Y. Organometallics 2005, 24, 136.
€
(d) Schafer, M.; Wolf, J.; Werner, H. Dalton Trans. 2005, 1468. (e) Weng,
W.; Guo, C.; C-elenligil-C-etin, R.; Foxman, B. M.; Ozerov, O. V. Chem.
Commun. 2006, 197. (f) Peng, H. M.; Zhao, J.; Li, X. Adv. Synth. Catal.
2009, 351, 1371.
(12) For Ru-catalyzed dimerization reaction of terminal acetylenes:
(a) Gao, Y.; Puddephatt, R. J. Inorg. Chim. Acta 2003, 350, 101. (b)
Bassetti, M.; Pasquini, C.; Raneri, A.; Rosato, D. J. Org. Chem. 2007,
72, 4558. (c) Hijazi, A.; Parkhomenko, K.; Djukic, J.-P.; Chemmi, A.;
Pfeffer, M. Adv. Synth. Catal. 2008,350, 1493. (d) Tripathy, J.; Bhattacharjee,
ꢀ
M. Tetrahedron Lett. 2009, 50, 4863. (e) Jimenez-Tenorio, M.; Puerta, M. C.;
Valerga, P. Organometallics 2009, 28, 2787. (f) Field, L. D.; Magill, A. M.;
Shearer, T. K.; Dalgarno, S. J.; Bhadbhade, M. M. Eur. J. Inorg. Chem. 2011,
´
3503–3510. (g) Coniglio, A.; Bassetti, M.; Garcıa-Garrido, S. E.; Gimeno, J.
Adv. Synth. Catal. 2012, 354, 148.
(13) For a carbometalation pathway on other metal-catalyzed dimer-
izations of terminal alkynes, see refs 5, 6, 8a, 8b, and 11c.
(14) (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. J. Organomet.
Chem. 1976, 110, C53. (b) Yasuda, T.; Kai, Y.; Yasuoka, N.; Kasai, N.
Bull. Chem. Soc. Jpn. 1977, 50, 2888.
(15) For hydropalladation pathway on other palladium-catalyzed
reactions, see: (a) Grushin, V. V. Chem. Rev. 1996, 96, 2011. (b)
Yamamoto, Y.; Al-Masum, M.; Fujiwara, N.; Asao, N. Tetrahedron
a Reaction conditions: 1 (0.5 mmol), IPrꢀPdꢀIPr (2 mol %),
TDMPP (2 mol %), toluene (1 M), 60 °C. b Isolated yields; previously
reported yields4d are in parentheses. c Reaction conditions: 1a (5 mmol),
IPrꢀPdꢀIPr (0.5 mol %), TDMPP (1 mol %), toluene (1 M), 60 °C.
ligand TDMPP (TDMPP = P[(2,6-OMe)2C6H3]3),18 effi-
ciently catalyzedthe head-to-head dimerization reaction of
phenylacetylene 1a to give the corresponding E-enyne 2a
with high yield and perfect regio- and stereoselectivity
(Table 1, entry 1).19 Importantly, in contrast to our pre-
vious work,4d it was found that this transformation is
ꢀ
Lett. 1995, 36, 2811. (c) Villarino, L.; Lopez, F.; Castedo, L.;
~
Mascarenas, J. L. Chem.;Eur. J. 2009, 15, 13308.
(16) For a hydrometalation pathway on other metal-catalyzed
dimerizations of terminal alkynes, see refs 7 , 9, 11c, and 11e.
(17) See Supporting Information for details.
(18) The role of TDMPP is not completely understood. Most likely
the TDMPP ligand helps regenerate the active catalyst by removing the
product from the catalyst-bound product complex H0 (Scheme 1).
Hence, the dimerization of phenylacetylene in the presence of the
IPrꢀPdꢀIPr complex without any additives is perfectly regio- and
stereoselective. However, addition of TDMPP to the reaction mixture
led to the improvement of the reaction yield. See Table S1 of the
Supporting Information for details.
(19) For reasonably selective head-to-head dimerization of alkynes
in the presence of a palladiumꢀimidazolium saltꢀCs2CO3 system,
see ref 4e.
B
Org. Lett., Vol. XX, No. XX, XXXX

equally efficient with terminal aryl acetylenes possessing
one or even two substituents at the ortho position of the
aromatic ring (entries 2ꢀ5). These results clearly indicate
that this reaction does not involve agostic interactions.4d
Thus, we investigated the generality of this process. To our
delight, it was found that 1-naphtylacetylene 1f and
a variety of para-substituted aryl acetylenes, including
electron-donating (methoxy 1g and methyl 1h) or electron-
withdrawing (cyano 1i, ester 1j, and chloro 1k) groups,
were competent substrates for this dimerization reaction
(entries 6ꢀ11). Likewise, a variety of terminal alkynes
possessing heterocyclic groups, such as thiophene 1l or
pyridine 1m, 1n and quinoline 1o, gave the corresponding
E-enynes 2lꢀo with good to excellent yields (entries
12ꢀ15). In addition, the reaction of alkyl acetylenes 1p
and 1q proceeded highly selectively as well (entries 16, 17).
Importantly, this reaction was perfectly compatible with
various functional groups at the terminal alkynes, includ-
ing propargyl ether 1r and acetal 1s, dimethylaminopro-
pyne 1t, and the protected and unprotected alcohol moiety
1u and 1v (Table 1, entries 18ꢀ22). The reaction was easily
scalable, producing a comparable yield of 2a even with a
0.5 mol % catalyst load (entry 1).
complex is discussed (Scheme 1, L = NHC, R = Ph). The
catalytic cycle including both pathways was investigated,
and it is discussed below in terms of ΔG and ΔE energy
surfaces (Figure 1).20 Starting with π-complex A, the first
step of the catalytic reaction involves CꢀH bond oxidative
addition to the metal via the transition state B-TS, which
leads to the formation of complex C (Scheme 1). According
to the calculated energy surface, this process is endothermic,
ΔGAfC = 14.8 (16.8) kcal/mol, with overcoming an energy
barrier of ΔG‡
= 17.6 (20.4) kcal/mol (Figure 1a).
AfB‑TS
Coordination of a second alkyne molecule to the Pd center of
complex C may result in two different π-complexes retaining
square planar geometry D and D0 in which an η2-coordi-
nated alkyne is differently oriented toward the σ-alkynyl
palladium moiety. Thus, the carbopalladation pathway
leading to the product 2 starts with the complex D, while
the hydropalladation pathway proceeds through the forma-
tion of D0. A small energy difference between the complexes
D and D0 (<3 kcal/mol) indicates that both structures
should be accessible in the studied system.
Naturally, we were interested in elucidating the mechan-
ism of this dimerization reaction. As generally believed, the
reaction begins with the oxidative addition of the acetylene 1
into the palladium complex (eq 1, M = Pd).4a,b,d,g However,
two distinct pathways are possible for the migratory inser-
tion of the second molecule of alkyne (eq 1, Scheme 1). The
alkyne can undergo migratory insertion into either a PdꢀC
bond (path I: carbopalladation)4a,b,d,g or a PdꢀH bond
(path II: hydropalladation).4a,14 Finally, reductive elimina-
tion with the formation of CꢀH or CꢀC bonds, respec-
tively, gives E-enyne 2 and regenerates the Pd(0) catalyst.
Scheme 1. Proposed Mechanism for the Pd-Catalyzed Head-to-
Head Dimerization of Terminal Acetylenes
Figure 1. (a) Calculated ΔE and ΔG energy surfaces (in kcal/
mol) of Pd-catalyzed head-to-head dimerization of terminal
acetylenes (L = NHC, R = Ph; see Scheme 1 for structures
AꢀH); starting from the intermediate C hydropalladation is
shown with a solid line, and carbopalladation, with dashed line.
(b) Optimized molecular structure of E-TS. (c) Optimized
molecular structure of E0-TS.
In the carbopalladation pathway, coordinated alkyne
=
ꢀ13.9 (ꢀ17.8) kcal/mol, though it requires 18.6 (17.3) kcal/mol
of activation energy. The optimized molecular structure
of the transition state E-TS clearly shows the necessary
insertion into the PdꢀC bond is exothermic, ΔGDfF
In order to distinguish between these two pathways of
the reaction, the DFT computational studies were per-
formed at the B3LYP/SDD&6-311G(d) level.17 As a
relevant model for experimental study (Table 1), computa-
tional rationalization of the head-to-head dimerization
of phenylacetylene catalyzed by an NHCꢀpalladium
(20) The discussion in the text is based on chemically reliable ΔG
values (and ΔE values are given for comparison in parentheses).
Org. Lett., Vol. XX, No. XX, XXXX
C

geometry arrangement to undergo alkyne insertion in the
desired fashion (Figure 1b). In the next step, CꢀH reduc-
tive elimination occurs with a small activation barrier
(G-TS, bound as an alkenyl π-complex). In sharp contrast
to the carbopalladation route, the hydropalladation path-
way was calculated to be much more facile. Thus, alkyne
insertion into the PdꢀH bond was found to be more
entropy contribution on the alkyne coordination step
(CfD and CfD0). With the overall energy surface taken
into consideration, the carbopalladation pathway with
alkyne insertion via the transition state E-TS was found
to be the highest point on the calculated energy surface,
38.0 (26.3) kcal/mol. As far as hydropalladation is con-
cerned, alkyne insertion proceeds more easily through E0-
TS with a calculated energy of 24.2 (13.3) kcal/mol.
A pronounced difference in the energies of E0-TS and E-TS
provides doubtless support in favor of the hydropallada-
tion mechanism.
In order to verify the generality of these findings,
computation of carbopalladation and hydropalladation
alkyne insertion steps for 1-hexyne was also performed,17
which revealed exactly the same trend as in the case of
phenylacetylene (vide supra). Therefore, a clear kinetic
preference for an alkyne insertion into the PdꢀH bond
over the PdꢀC bond was found for both aryl and alkyl
acetylenes.
In conclusion, we have developed a general and highly
regio- and stereoselective method for the palladium-cata-
lyzed head-to-head dimerization reaction of terminal alkynes
toward 1,4-enynes. This methodology is general for a variety
of terminal acetylenes possessing various functional groups
such as aryl, heteroaryl, alkyl, hydroxyl, propargyl ether, and
amino groups. DFT calculations revealed that the reaction
proceeds via a hydropalladation pathway.
0
0
exothermic, ΔGD fF = ꢀ16.9 (ꢀ19.1) kcal/mol. Remark-
ably, the activation barrier for this process is equal to only
ΔG‡D fE ‑TS = 2.1 (2.1) kcal/mol. Furthermore, the opti-
mized molecular structure of E0-TS highlights the differ-
ence in the nature of the transition states (cf. Figure 1b, c).
Formation of the product 2 through the hydropalladation
pathway is completed via the Y-shaped transition state G0-
TS, typical for the en-yne reductive elimination,21 which
requires overcoming a relatively small activation barrier of
3.0 (2.3) kcal/mol. The calculated D0fE0-TS hydropalla-
dation barrier is more then 8 times lower compared to the
DfE-TS carbopalladation barrier. Clearly, it is a tremen-
dous difference in reactivity between these two pathways.
Thus, if the PdꢀH bond is available for alkyne insertion, it
should react first. Alkyne insertion into the PdꢀC bond
becomes possible only if the PdꢀH moiety is not available
for reaction. Therefore, path II predominantly contributes
to the product formation in the considered mechanism.
The formation of both complexes H and H0 is highly
exothermic, thus providing the necessary driving force
for the catalytic transformation. The difference between
the alkenyl(H) and alkynyl (H0) binding modeof product 2
to the metal had a minor influence on the stability of these
complexes: ꢀ27.6 and ꢀ28.2 kcal/mol, respectively. Finally,
coordination of a new molecule of alkyne to H or H0 releases
the 1,4-enynes 2 and initiates the next catalytic cycle by
regeneration of the catalytically active complex A.
0
0
Acknowledgment. The support of the National Science
Foundation (CHE-1112055) and Russian Foundation for Basic
Research (RFBR 10-03-00370) is gratefully acknowledged.
Supporting Information Available. Detailed experimen-
tal procedures, characterization data for all new com-
pounds, details of computational procedure, optimized
structures, and calculated energy and geometry param-
eters. This material is available free of charge via the
Internet at http://pubs.acs.org.
Thus, the relativereactivity within pathwaysI and IIis in
excellent agreement on both ΔE and ΔG surfaces, with the
marked upward shift of the latter being due to the expected
(21) (a) Ananikov, V. P.; Musaev, D. G.; Morokuma, K. Organo-
metallics 2005, 24, 715. (b) Ananikov, V. P.; Musaev, D. G.; Morokuma,
K. Eur. J. Inorg. Chem. 2007, 5390.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX