Palladium-catalyzed conjugate addition of terminal alkynes to enones

Article abstract of DOI:10.1021/ol300988n

A practical protocol for the hydroalkynylation of enones using Pd catalysis is reported. The reaction proceeds efficiently with a variety of alkynes as well as with several cyclic and acyclic enones, providing synthetically relevant β-alkynyl ketones in good to excellent yields.

Full text of DOI:10.1021/ol300988n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Conjugate Addition
of Terminal Alkynes to Enones
†
Lara Villarino, Rebeca Garcıa-Fandino, Fernando Lopez,* and Jose L. Mascarenas*
†
,‡
,†
~
ꢀ
ꢀ
~
´
ꢀ
´
ꢀ
Centro Singular de Investigacion en Quımica Bioloxica e Materiais Moleculares
´
ꢀ
(CIQUS) and Departamento de Quımica Organica, Unidad Asociada al CSIC,
Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain, and
´
ꢀ
Instituto de Quımica Organica General, CSIC, Juan de la Cierva 3, 28006, Madrid, Spain
joseluis.mascarenas@usc.es; fernando.lopez@iqog.csic.es
Received April 17, 2012
ABSTRACT
A practical protocol for the hydroalkynylation of enones using Pd catalysis is reported. The reaction proceeds efficiently with a variety of alkynes
as well as with several cyclic and acyclic enones, providing synthetically relevant β-alkynyl ketones in good to excellent yields.
The transition-metal-catalyzed conjugate addition of
organometallic reagents to Michael acceptors is an extre-
mely powerful methodology for the construction of CꢀC
bonds.1 Particularly interesting is the metal-promoted
conjugate addition of terminal alkynes to R,β-unsaturated
carbonyl compounds because of the synthetic utility of the
resulting β-alkynyl carbonyls. Classical ways to promote
these conjugate additions involve the use of stoichiometric
amounts of metal alkynylide species,2 which unavoidably
leads to the generation of significant metallic waste.
including the development of some enantioselective
variants, have been achieved using Rh,3 Cu,4 Zn,5 Ru,6 or
Co7 catalysts. Curiously, and despite the preponderance of
Pd in organometallic catalysis, there are very few precedents
on the use of Pd complexes to induce 1,4-additions of
terminal alkynes to R,β-unsaturated carbonyls.8,9 Perhaps
this could be due to the tendency of terminal alkynes to
react with themselves under Pd catalysis.10 Moreover, the
examples reported so far are restricted to the use of
β-unsubstituted acyclic enones and acrylates.8 Herein, we
In this context, the development of alternative, atom-
economical approaches, based on the catalytic generation
of the reactive organometallic species from terminal alkynes,
is a highly desirable goal. Recent advances in this field,
(4) (a) Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M.
€
J. Am. Chem. Soc. 2003, 125, 6054. (c) Yazaki, R.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 10275. (d) Fujimori, S.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4964.
J. Am. Chem. Soc. 2005, 127, 9682. (b) Knopfel, T. F.; Carreira, E. M.
† Universidad de Santiago de Compostela.
€
(5) (a) Knopfel, T. F.; Boyall, D.; Carreira, E. M. Org. Lett. 2004, 6,
‡
2281. (b) Kidwai, M.; Jain, A.; Bhardwaj, S. Catal. Lett. 2011, 141, 183.
(6) (a) Nishimura, T.; Washitake, Y.; Uemura, S. Adv. Synth. Catal.
2007, 349, 2563. (b) Uemura, S.; Nishimura, T.; Washitake, Y.; Nishi-
guchi, Y.; Maeda, Y. Chem. Commun. 2004, 1312. (c) Chang, S.; Na, Y.;
Choi, E.; Kim, S. Org. Lett. 2001, 3, 2089. (d) Picquet, M.; Bruneau, C.;
Dixneuf, P. H. Tetrahedron 1999, 55, 3937.
(7) Nishimura, T.; Sawano, T.; Ou, K.; Hayashi, T. Chem. Commun.
2011, 47, 10142.
(8) (a) Jiang, H. F.; Zhou, L.; Chen, L.; Skouta, R.; Li, C. J. Org. Biol.
Chem. 2008, 6, 2969. (b) Li, C. J.; Chen, L. Chem. Commun. 2004, 2362.
(9) For Pd-catalyzed hydroalkynylations of ynoates and allenoates,
ꢀ
Instituto de Química Organica General, CSIC.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series 9; Pergamon Press: Oxford, 1992.
(2) For instance, see: (a) Schwartz, J.; Carr, D. B.; Hansen, R. T.;
Dayrit, F. M. J. Org. Chem. 1980, 45, 3053. (b) Kim, S.; Lee, J. M.
Tetrahedron Lett. 1990, 31, 7627. (c) Sinclair, J. A.; Molander, G. A.;
Brown, H. C. J. Am. Chem. Soc. 1977, 99, 954. (d) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2005, 127, 3244. (e) Larionov, O. V.; Corey, E. J.
Org. Lett. 2010, 12, 300. (f) Woo, J. C. S.; Cui, S.; Walker, S. D.; Faul,
M. M. Tetrahedron 2010, 66, 4730. (g) Cui, S.; Walker, S. D.; Woo,
J. C. S.; Borths, C. J.; Mukherjee, H.; Chen, M. J.; Faul, M. M. J. Am.
€
€
Chem. Soc. 2009, 132, 436. For a review, see: (h) Fujimori, S.; Knopfel,
T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem.
Soc. Jpn. 2007, 80, 1635.
(3) (a) Chisholm, J. D.; Lerum, R. V. Tetrahedron Lett. 2004, 45,
6591. (b) Nishimura, T. J. Synth. Org. Chem. Jpn. 2008, 66, 1160. (c)
Nishimura, T.; Sawano, T.; Hayashi, T. Angew. Chem., Int. Ed. 2009, 48,
8057. (d) Nishimura, T.;Guo, X. X.;Uchiyama, N.;Katoh, T.;Hayashi, T.
J. Am. Chem. Soc. 2008, 130, 1576. (e) Fillion, E.; Zorzitto, A. K. J. Am.
Chem. Soc. 2009, 131, 14608.
see: (a) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G.
J. Am. Chem. Soc. 1997, 119, 698. (b) Trost, B. M.; Kottirsch, G. J. Am.
Chem. Soc. 1990, 112, 2816. (c) Rubin, M.; Markov, J.; Chuprakov, S.;
Wink, D. J.; Gevorgyan, V. J. Org. Chem. 2003, 68, 6251.
(10) The homodimerization of terminal alkynes is a well-known
process. For selected examples, see: (a) Trost, B. M.; Chan, C.; Ruhter,
G. J. Am. Chem. Soc. 1987, 109, 3486. (b) Rubina, M.; Gevorgyan, V.
J. Am. Chem. Soc. 2001, 123, 11107. (c) Nishiura, M.; Hou, Z.; Wakatsuki,
Y.; Yamaki, T.; Miyamoto, T. J. Am. Chem. Soc. 2003, 125, 1184.
r
10.1021/ol300988n
XXXX American Chemical Society

report a Pd-based catalytic system which promotes efficient
conjugate additions of terminal alkynes to a range of R,β-
unsaturated carbonyls. Importantly, the reaction also works
with prochiral β-substituted acyclic and cyclic enones, there-
fore allowing the generation of stereocenters in the product.
We also include experimental and theoretical data that suggest
a mechanistic pathway involving a hydropalladation rather
than the more commonly proposed alkene carbopalladation.
This work emerged in the context of our research in
transition-metal-catalyzed alkylidenecyclopropane cycloaddi-
tions,11 in particular after finding that treatment of terminal
alkynes (1) and alkylidenecyclopropanes (2) with specific Pd
catalysts generates hydroalkynylated products of type 3
(Scheme 1),12 instead of the initially expected (3 þ 2) cyclo-
adducts.13 The formation of 3was explained through an initial
CꢀH activation process that yields a hydroalkynylpalladium-
(II) species A, which subsequently hydropalladates the alkyli-
denecyclopropane leading to B. A β-carboelimination followed
by reductive elimination would complete the catalytic cycle.
Table 1. Preliminary Screening on the Pd-catalyzed Conjugate
Addition of Triisopropylsilylacetylene to Cyclopenten-2-one.a
yield
equiv
L
[Pd]
temp
(%)
of 5aab
entry
(1a)
(mol %)
(mol %)
(°C)
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
1
L1 (20)
Pd2(dba)3 (6)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
105
90
90
90
90
90
90
90
20
68
40
36
47
0c
L1 (10)
L1 (12.5)
L1 (5)
L1 (10)
2.5
2.5
2.5
P(OPh)3 (10) Pd2(dba)3 (5)
P(OiPr)3 (10) Pd2(dba)3 (5)
0c
L1 (0ꢀ10)
Pd(PPh3)4 (5)
0c
a Conditions: 4a (1 equiv) and 1a at a concentration of 0.1 M.
b Isolated yields. c Analysis of the crude reaction mixtures indicated the
presence of starting materials and enynes 6a and 6a0 (NMR, GCꢀMS).
Scheme 1. Previous Pd-Catalyzed Hydroalkynylations of 212
the conjugate addition over the alkyne dimerization, and
thus, 5aa couldbeobtainedinagood68%yield(entry2).15 As
can be seen in entries 3 and 4, other Pd/L1 ratios turned out to
be less efficient, providing 5aa in lower yields. On the other
hand, the use of an excess of alkyne (2.5 equiv) was found to be
important but not essential for the reaction, as the product
could still be obtained in 47% yield using a 1:1 ratio of 1a and
4a (entry 5). Other phosphites such as P(OPh)3 or P(OiPr)3, as
well as alternative Pd sources (i.e., Pd(PPh3)4), were ineffective,
leading to the recovery of 4a and the formation of mixtures
of enynes 6a/6a0 (entries 6ꢀ8). We also tested conditions
previously used for the Pd-catalyzed alkynylation of R,β-
Encouraged by these results, we decided to explore
the performance of this Pd catalyst (Pd2(dba)3/L1)12 in
the hydroalkynylation of alkenes lacking the cyclopropane
moiety. Thus, in a preliminary screening, we tested the
hydroalkynylation of styrene and cyclopenten-2-one (4a)
using triisopropylsilylacetylene (1a) as the alkyne partner.
Although styrene did not provide any coupling product,14
cyclopenten-2-one participated in the reaction, leading to
the desired β-alkynyl cyclopentanone 5aa in a low 20%
yield (Table 1, entry 1). Enyne products 6a and 6a0, arising
from the dimerization of the alkyne 1a, were detected as
major side products.10 Further optimization of the reac-
tion conditions determined that the use of a Pd/L1 ratio of
1:1, as well as a slightly lower temperature (90 °C), favors
8
unsaturated systems: Pd(OAc)2/PMe3 and Pd(OAc)2/
tris(2.6-dimethoxyphenyl)phosphine.9 However, none of the
reactions produced the alkyne 5aa but instead a mixture of side
products mostly consisting of alkyne dimers.16
With optimal conditions in hand, we next screened the
addition of triisopropylsilylacetylene (1a) to different
Michael acceptors (Table 2). Other cyclic enones such as
cyclohexen-2-one (4b) or cyclohepten-2-one (4c) cleanly
provided the expected adducts in 70% and 94% yield,
respectively (Table 2, entries 2 and 3). Except for two Rh-
promoted cases,3d results from entries 1ꢀ3 represent the
only examples reported so far involving a direct catalytic
conjugate addition of terminal alkynes to cyclic unsatu-
rated systems. Simple acyclic enones such as methyl vinyl
ketone (4d) also participated in the process, providing the
~ ꢀ
´
(11) Mascarenas, J. L.; Gulıas, M.; Lopez, F. Pure. Appl. Chem. 2011,
83, 495.
ꢀ
~
(12) Villarino, L.; Lopez, F.; Castedo, L.; Mascarenas, J. L. Chem.;
Eur. J. 2009, 15, 13308.
~
(13) (a) Gulıas, M.; Garcıa, R.; Delgado, A.; Castedo, L.; Mascarenas,
´ ´
~
J. L. J. Am. Chem. Soc. 2006, 128, 384. (b) Mascarenas, J. L.; Garcı
´
a-
~
Fandino, R.; Gulı
´
as, M.; Castedo, L.; Granja, J. R.; Cardenas, D. J.
ꢀ
Chem.;Eur. J. 2008, 14, 272. (c) Duran, J.; Gulıas, M.; Castedo, L.;
´
~
ꢀ
Mascarenas, J. L. Org. Lett. 2005, 7, 5693. (d) Trillo, B.; Gulı
´
as, M.; Lopez,
~
F.; Castedo, L.; Mascarenas, J. L. Adv. Synth. Catal. 2006, 348, 2381. (e)
ꢀ
~
´
guez, J. R.; Castedo, L.; Mascarenas, J. L.
Lopez, F.; Delgado, A.; Rodrı
J. Am. Chem. Soc. 2004, 126, 10262. (f) Mascarenas, J. L.; Delgado, A.;
Rodrıguez, J. R.; Castedo, L. J. Am. Chem. Soc. 2003, 125, 9282. (g) Trillo,
B.; Gulı
~
´
ꢀ
~
´
as, M.; Lopez, F.; Castedo, L.; Mascarenas, J. L. J. Organomet.
(15) The reaction could also be performed in other solvents but 5aa
was obtained in lower yields (toluene: 57% yield; 1,2-DCE: 37% yield).
(16) The catalyst reported in ref 14, (Ni(COD)2/PMePh2), also failed
to give 5aa, leading to mostly enynes 6.
Chem. 2005, 690, 5609.
(14) For a Ni-catalyzed hydroalkynylation of styrenes, see: Shirakura,
M.; Suginome, M. Org. Lett. 2009, 11, 523.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Pd-Catalyzed Conjugate Addition of Triisopropylsily-
lacetylene to R,β-Unsaturated Carbonylsa
Table 3. Pd-Catalyzed 1,4-Addition of Terminal Alkynes to 4ea
a Conditions: 1a (2.5 equiv) added over 10 h to a solution of 4 (1
equiv), Pd2(dba)3 (5%), and L1 (10%) in dioxane (0.1 M) at 90 °C, unless
otherwise noted. Reaction times: 16ꢀ24 h. b Isolated yields. c Alkyne 1b
was added in one portion. d Analysis of the crude reaction mixtures
indicated the presence of starting materials and enynes 6b and 6b0.
e Carried out with L2 (20%) and Pd2(dba)3 (5%).
a Conditions: 1a (2.5 equiv), 4 (1 equiv), Pd2(dba)3 (5%), and L1
(10%) in dioxane (0.1 M) at 90 °C for 16ꢀ24 h, unless otherwise noted.
b Isolated yields. c Analysis of the crude reaction mixtures indicated the
presence of starting materials and enynes 6a and 6a0 (NMR, GCꢀMS).
d Yield corresponds to a 3:1 mixture of 5al and 5al0.
corresponding addition products could be isolated in yields
ranging from 45% to 98% (entries 3ꢀ7). Remarkably, while
the silyl-protected prop-2-yn-1-ol derivative 1h gave a poor yield
of the desired product (entry 8), the bulkier analogue 1i gave the
desired adduct in excellent yield (89%, entry 9), probably
because the steric bulk minimizes the homodimerization process.
At this point, we performed a preliminary test on the
viability of rendering the methodology asymmetric by using
chiral phosphorus ligands. Among several chiral phosphines,
phosphites, or phosphoramidites tested, only phosphite L219
was able to promote the conjugate addition reaction of 1a to
4e. Thus, the catalyst generated from Pd2(dba)3 (5%) and L2
(20%) afforded 5ae in an excellent 96% yield, whereas ketone
5be, resulting from the addition of 1b to 4e, could be isolated
in 50% yield (entries 10, 11).20 The enantiomeric excesses of
the products in both cases are promising (ca. 40% ee), thus
warranting further investigations in this area.
When deuterated phenylacetylene (1b-d) was treated with
4e under the reaction conditions, the corresponding mono-
deuterated product 5be-d was obtained (deuterium content:
40%).21,22 This result is consistent with a reaction mechanism
involving insertion of Pd(0) into the alkyne sp-CꢀH bond,
followed by either hydropalladation or carbopalladation
of the enone and final reductive elimination.
addition product 5ad in an excellent 92% yield (entry 4).
More significantly, β-substituted acyclic enones (4eꢀ4h)
reacted with 1a to give the corresponding addition products
5aeꢀah in good to excellent yields (60ꢀ92% yield, entries
5ꢀ8). However, further substitution in the β-position of
the enone, such as in 4i, precludes the coupling reaction
(entry 9).17 Ethyl vinyl ketone (4j) is also an excellent
addition partner for 1a, providing the ketone 5aj in 94%
yield (entry 10). Interestingly, the conjugate addition of 1a is
not limited to R,β-unsaturated ketones; thus, more challen-
ging enals and enoates like 4k or 4l can also participate in the
process,18 leading to synthetically appealing β-alkynyl alde-
hydes and esters, albeit with modest yields (entries 11 and 12).
The scope of the reaction with respect to the alkyne compo-
nent was studied using (E)-pent-3-en-2-one (4e) as the alkene
partner (Table 3). Although the treatment of phenylacetylene
(1b) with this enone under standard conditions produced only
undesired alkyne dimers (entry 1), slow addition of the alkyne
to the reaction mixture allowed us to obtain the product 5be in
50% yield (entry 2). Using this modified protocol, the addition
of other aryl-substituted alkynes, incorporating methyl groups at
the ortho, meta, and para positions, as well as electron-donating
or -withdrawing groups, proceeded satisfactorily, and the
(17) Preliminary tests indicated that R-substituted enones were also
unreactive under these conditions.
(18) There are very few precedents in the direct alkynylation of these
types of Michael acceptors. See references 3c (enals) 4c, (thioamides),
and 6a and 8a (acrylates).
(19) Reetz, M. T.; Guo, H.; Ma, J.-A.; Goddard, R.; Mynott, R. J.
J. Am. Chem. Soc. 2009, 131, 4136.
(20) Yields of these two examples are equivalent to those with
phosphite L1, see table 2, entry 5, and table 3, entry 2.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. DFT Profile of the Pd-Catalyzed Conjugate Addition of 1j to 4e
To distinguish between the hydro- or the carbometala-
tion alternative, as well as to obtain a more reliable
mechanistic picture of the process, we performed preliminary
DFT calculations using enone 4e, prop-1-yne (1j), and
Pd(PH3) as model reactant and catalyst (Scheme 2).23 The
computed data indicate that the reaction starts with the
coordination of the Pd catalyst to the CꢀC triple bond
prior to an oxidative addition to the sp-CꢀH bond. This
process, which proceeds through transition state TS1,
involves an energy barrier of 26.3 kcal/mol (ΔG value)
and yields a hydroalkynylpalladium(II) intermediate
int-1. Coordination of the enone followed by carbopalla-
dation generates int-30 through TS20 (energy barrier of
9.6 kcal/mol). Alternatively, hydropalladation through TS2
would generate intermediate int-3, which gains stability by
coordination of the carbonyl oxygen to the Pd center to
give int-4. The hydropalladation process presents an en-
ergy cost of 4.0 kcal/mol and, therefore, seems to be
kinetically favored over the carbometalation. Finally, re-
ductive elimination from int-4 or int-30 leads to the final
adduct 5je.24 Although the reductive elimination from the
carbopalladation intermediate int-30 is favored compared
to that from int-4, overall the higher energy cost associated to
the carbopalladation pathway (via TS20) suggests that, at
least in this model system, the hydropalladation route might
be preferred.25 This mechanistic scenario is therefore different
from that proposed for other metal-catalyzed alkynylations
of R,β-unsaturated carbonyls,3ꢀ8 which have been suggested
to proceed via carbometalation pathways.26 The structures
of the key stationary points of the current pathway can be
seen in Figure S1 and S2 of the Supporting Information.
In summary, we have developed a simple and practical
Pd-catalyzed methodology for the conjugate addition of
terminal alkynes to Michael acceptors that is particularly
efficient in the case of enones. Worth mentioning are the
additions to prochiral β-substituted enones, which had no
precedents using Pd catalysts, as well as the additions to
cyclic enones for which only two isolated examples using a
Rh catalyst had been reported.3d The development of a
highly asymmetric variant, based on our preliminary find-
ings, is under investigation.
Acknowledgment. This work was supported by the
Spanish MINECO [SAF2007-61015, SAF2010-20822-C02,
Consolider Ingenio 2010 CSD2007-00006], the ERDF and
the Xunta de Galicia INCITE09209084PR, GRC2010/12.
L.V. and R.G.-F. thank the Spanish MEC and MINECO
for an FPU fellowship and a Juan de la Cierva contract,
respectively. Johnson-Matthey is acknowledged for a gift
of metals.
(21) (a) Reaction of 1b-d with 4e:
Supporting Information Available. Experimental pro-
cedures, spectroscopy data, DFT calculations, energies,
and Cartesian coordinates. This material is available free
of charge via the Internet at http://pubs.acs.org The
authors declare no competing financial interest.
(22) 2H NMR confirmed that deuterium was only incorporated at the
internal R position of the ketone 5be-d.
(23) (a) All the calculations were carried using the Gaussian 03 rev.
D.01 suite of programs. ZPE-corrected energies (B3LYP/6-31G(d) þ
LANL2DZ for Pd). Energy values (kcal/mol) are referred to 1jþPd-
(PH3)þ4e. Gibbs energy is considered for drawing. For more computa-
tional details, see the Supporting Information. (b) We also performed
DFT calculations with a Pd catalyst incorporating two PH3 ligands.
However, after the initial C-H activation, the hydro-or carbo-palladation
mustproceed withjust one PH3 attachedtothe Pdlike inthe scheme2. See
the Supporting Information for further details.
(25) In qualitative agreement with the experimental results, the
theoretical calculations also predict that a hydropalladation of enone
4i, disubstituted at the β-position, is more difficult.
(26) Related hydrometalation pathways have only been previously
suggested in a Rh- and a Ru-catalyzed process, see references 3a and 6d.
(24) Reductive elimination from int-3, which lacks the carbonyl-Pd
coordination, is 5.2 kcal more costly than that from int-4.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX