Palladium-catalyzed carboauration of alkynes and palladi cross-coupling

Article abstract of DOI:10.1021/om801206g

A new palladium-catalyzed syn carboauration of alkynes proceeds in 2 h at ambient temperature with complete regioselectivity. The resulting α-ester vinyl-gold intermediates are resistant to rapid protodemetalation, permitting their participation in new on

Full text of DOI:10.1021/om801206g

Copyright 2009
Volume 28, Number 5, March 09, 2009
American Chemical Society
Communications
Palladium-Catalyzed Carboauration of Alkynes and Palladium/Gold
Cross-Coupling
Yili Shi, Stephen D. Ramgren, and Suzanne A. Blum*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
ReceiVed December 19, 2008
a
1
Table 1. Effect of Catalyst Composition on Product H NMR Yield
Summary: A new palladium-catalyzed syn carboauration of
alkynes proceeds in 2 h at ambient temperature with complete
regioselectiVity. The resulting R-ester Vinyl-gold intermediates
are resistant to rapid protodemetalation, permitting their
participation in new one-pot palladium-and-gold cross-coupling
reactions and electrophilic trapping reactions.
entry
cat.
1H NMR yield (%)
Recently, transient vinyl-gold intermediates have been
reported to participate in a variety of intramolecular trapping
and rearrangement reactions.1-3 Carboauration of alkynes offers
an attractive possibility for accessing vinyl-gold intermediates
from readily available starting materials; however, the uncata-
lyzed intermolecular carborauration of alkynes requires multiple-
week reaction times and Puddephatt reports it for only one
substrate, bis(trifluoromethyl)acetylene.4,5 A general intermo-
lecular carboauration reaction would permit access to vinyl-gold
intermediates for application in coupling and functionalization
reactions for the synthesis of regiochemically and diasteromeri-
cally pure di- and trisubstituted olefins. As part of our ongoing
work employing the unique reactivity of two metals to develop
dual-catalyzed reactions,6-8 we now report a new Pd-catalyzed
carborauration of alkynes that proceeds in 2 h at ambient
1
2
3
Pd2(dba)3
Pd(PPh3)4
PdCl2(PPh3)2
none
BF3 · OMe2
Sc(OTf)3
PPh3AuPF6
trace
5
73
0
0
4
5b
6b
7b
0
0
a Relative to mesitylene internal standard. b Conditions: 20% catalyst.
temperature with complete regioselectivity and diastereoselec-
tivity for the product of syn addition.
Treatment of dimethyl acetylenedicarboxylate (DMAD) with
vinyl(triphenylphosphine)gold9 in the presence of 5 mol % of
PdCl2(PPh3)2 gave the carboaurated product 1 in 73% 1H NMR
yield (Table 1, entry 3). Palladium was required for conversion;
in its absence, 1 was not produced. We considered the
* To whom correspondence should be addressed. Tel: 949-824-8178.
E-mail: blums@uci.edu.
(1) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
(2) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180.
(3) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(4) Johnson, A.; Puddephatt, R. J. J. Chem. Soc., Dalton Trans. 1978,
115, 980.
(5) For a photochemical carboauration of tetrafluoroethylene, see:
Mitchell, C. M.; Stone, F. G. A. J. Chem. Soc., Dalton Trans. 1972, 102.
(6) Duschenk, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2008, 47, 5703.
(7) Shi, Y.; Peterson, S. M.; Haberaecker, W. W., III.; Blum, S. A. J. Am.
Chem. Soc. 2008, 130, 2168.
(8) For a review on bimetallic catalysis by late transition metals, see:
van den Beuken, E. K.; Feringa, B. L. Tetrahedron 1998, 54, 12985.
(9) See the Supporting Information for synthetic procedures and full
characterization data of new organogold compounds. For the original
reference for vinyl(triphenylphosphine)gold, see: Nesmeyanov, A. N.;
Perevalova, E. G.; Krinikh, V. B.; Kosina, A. N.; Grandberg, K. I.;
Smyslova, E. I. Bull. Acad. Sci. USSR, DiV. Chem. Sci. 1972, 618.
10.1021/om801206g CCC: $40.75
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1276 Organometallics, Vol. 28, No. 5, 2009
Communications
Table 2. Scope of the Pd-Catalyzed Carboauration Reaction
participates in two sequential transmetalation reactions and the
Pd(II) oxidation state remains constant throughout the reaction.
A possible equilibrium between the gold/palladium transmeta-
lation partners would be driven toward product formation by
the carbon-carbon bond-forming step (formation of migratory-
insertion product 12),15 in analogy to the driving forces for the
Nozaki-Hiyama-Kishi reaction.16,17 Migratory insertion of
DMAD into sp2-carbon-palladium bonds has been previously
reported.18,19 The transmetalation step to form product 10 could
be initiated by PPh3AuCl or PPh3AuR (i.e., X ) Cl, R).20 In
cycle B, the mechanism proceeds through an oxidative addition,
transmetalation, reductive elimination cycle that involves both
Pd(II) and Pd(0) in analogy to the mechanisms of palladium-
catalyzed cross-coupling reactions.15,17 In this case, the back-
bonding from the Pd(0) center is invoked to establish a formal
“oxidative addition” to the electron-deficient alkyne.7,21,22
1
Although intermediates could not be observed by H NMR
a Relative to mesitylene internal standard. b Conditions: 15 mol % Pd,
48 h. c Conditions: 2.0 equiv of DMAD, 30 min.10
spectroscopy in the above reaction, we identified an analogous
reaction, with carboauration across two alkynes rather than one,
in which an intermediate could be isolated (eq 1). Addition of
DMAD to stoichiometric Pd2(dba)3 resulted in formation of the
known metallacycle 15,23 by oxidative cyclization. Subsequent
addition of methyl-gold produced the carboauration product
17 (>98% NMR yield, 73% isolated). This reaction is consistent
with the intermediacy of 16, which demonstrates the viability
of a vinyl transmetalation reaction between Pd and Au which
is similar to that proposed in Scheme 1, cycles A and B (in
cycle A, when X ) R).24 This reaction is also consistent with
the accessibility of an oxidative addition, transmetalation, and
reductive elimination cycle for the mixed Pd/Au system, as
proposed in cycle B.
Figure 1. ORTEP structures of 8 (left) and 9 (right). Thermal
ellipsoids are shown at the 50% probability level. Hydrogen atoms
are omitted for clarity.
Since Pd(0) and Pd(II) precatalysts are known to access both
Pd(0) and Pd(II) catalyst states for cross-coupling reactions,
either oxidation state of palladium is possible, regardless of the
oxidation state of our precatalyst.15 To further probe the
oxidation state requirements of the palladium during the reaction,
we examined the reaction’s sensitivity to oxygen by performing
the carboauration reaction under an atmosphere of oxygen gas
in the presence of the PdCl2(PPh3)2 catalyst. No change in
conversion was observed under these oxidizing conditions
when compared to performing the reaction under rigorously air-
hypothesis that the Pd catalyst served as a Lewis acid to activate
DMAD toward Michael addition of vinyl(triphenylphosphine)-
gold. Replacement of Pd by either hard or soft Lewis acids (i.e.,
BF3, Sc(OTf)3, PPh3AuPF6), however, did not result in formation
of 1 (entries 5-7), suggesting an alternative catalytic role for
Pd that is more closely tied to its specific reactivity.
The utility of the Pd-catalyzed carboauration reaction is
illustrated by a range of gold starting materials (i.e., sp, sp2,
sp3, electron-poor and electron-rich aryl; Table 2).10 Each gold
starting material was synthesized in one step from commercially
available reagents.9 We identified two classes of reactivity: one
that proceeds in the highest conversion with PdCl2(PPh3)2 as
the precatalyst and the other with Pd2(dba)3.11 The carborau-
ration of methyl propiolate and methyl butynoate further
expanded the substrate scope (entries 2, 4, and 5). The reaction’s
insensitivity to water and oxygen permitted employment of
commercial solvents and open glassware. The carboaurated
products 1-9 were resistant to protodemetalation by mild acids,
permitting isolation by silica gel and alumina chromatography.
In all cases, a reaction selectivity for syn addition yielded
(13) A gold-hydride complex was recently shown to participate in anti-
hydroauration of DMAD: Tsui, E. Y.; Mu¨eller, P.; Sadighi, J. P. Angew.
Chem., Int. Ed. 2008, 47, 8937.
(14) The absence of reentry of products 1-9 into the catalytic cycle
could derive from changes in steric and electronic factors relative to the
starting vinyl-gold complex.
(15) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
(16) In the nickel- and chromium-cocatalyzed Nozaki-Hiyama-Kishi
reaction, equilibrating transmetalation partners are driven toward product
formation by creation of a new carbon-carbon bond: Jin, H.; Uenishi, J.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 4644–5644.
(17) Hegedus, L. S., Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; University Science Books: Sausalito, CA, 1999.
(18) Vicente, J.; Abad, J.-A.; Fortsch, W.; Lopez-Saez, M.-J.; Jones,
P. G. Organometallics 2004, 23, 4414.
(19) Yagyu, T.; Osakada, K.; Brookhart, M. Organometallics 2000, 19,
2125.
(20) Addition of DMAD to isolated (PPh3)2PdAr(I) in the absence of a
gold trapping agent results in rapid polymerization and oligomerization.
(21) Stahl, S. S.; Thorman, J. L.; de Silva, N.; Guzei, I. A.; Clark, R. W.
J. Am. Chem. Soc. 2003, 125, 12.
1
diastereomerically pure products, as confirmed by H NMR
spectroscopy and by X-ray crystallographic studies of 8 and 9
(Figure 1). Syn addition is opposite to the selectivity reported
by Toste for the uncatalyzed intramolecular carboauration of
alkynes.12-14
Two proposed mechanisms for the Pd-catalyzed carboauration
reaction are detailed in Scheme 1. In cycle A, the gold reagent
(22) For an example of a proposed oxidative addition of Pd(0) to an
electron-poor enone as part of a catalytic cycle, see: Sieber, J. D.; Liu, S.;
Morken, J. P. J. Am. Chem. Soc. 2007, 129, 2214.
(23) Kelley, E. A.; Maitlis, P. M. J. Chem. Soc., Dalton Trans. 1979,
167.
(10) Formation of 15 (vide infra) was competitive with formation of 9,
accounting for the lower yield of product 9.
(11) Experiments are underway to identify the cause of this reactivity
difference.
(12) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526.
(24) Yoshida, H.; Shirakawa, E.; Nakao, Y.; Honda, Y.; Hiyama, T.
Bull. Chem. Soc. Jpn. 2001, 74, 637.

Communications
Organometallics, Vol. 28, No. 5, 2009 1277
Scheme 1. Proposed Catalytic Cycles for the Pd-Catalyzed Carboauration of Alkynes
Scheme 2. One-Pot Carboauration/Functionalizationa
free conditions, suggesting that a low-oxidation-state pal-
ladium(0) complex may not be critical for reactivity; however,
currently cycle B cannot be ruled out.
We next explored the reactivity of the vinyl-gold products.
The resistance of this class of R-ester vinyl-gold complexes
to rapid protodemetalation permits their participation in inter-
molecular functionalization reactions, rather than being limited
by intramolecular trapping,25 which greatly expands their
synthetic utility. A range of Pd and Au cross-coupling reactions
proceeded in high yield with retention of configuration, opening
synthetic access to trisubstituted olefins with complete regio-
and diastereocontrol (Scheme 2; 18, 20, and 22).26 In each
functionalization reaction, the crude vinyl-gold species 2 was
employed without isolation, and the residual Pd catalyst from
the carboauration reaction remained viable for the subsequent
cross-coupling step, establishing a one-pot tandem carboaura-
tion/functionalization protocol. For example, after 2 h, addition
of allyl bromide to crude 2 in the same solution used for the
carboauration reaction produced allylated product 18 (87%, two
steps), presumably through a π-allyl-palladium intermediate.27
Palladium was required for cross-coupling reactivity. When
intermediate 2 was isolated, no product formation was observed
in the absence of Pd with allyl bromide, methyl iodide, or
4-iodotoluene. Addition of 2.5 mol % of Pd2(dba)3 to isolated
2 restored the cross-coupling reactivity. These new cross-
coupling reactions proceed through a fully characterized ho-
mogeneous gold intermediate, removing ambiguity pertaining
to the nature of the reactive gold species.28
1
a
Two-step H NMR yields relative to mesitylene internal standard.
reactivity similar to that of crude 2. Mechanistic work in this
paper suggests a reinterpretation of the catalytic carbostanny-
lation reaction we previously reported, to include the interme-
diacy of a vinyl-gold compound.7
In conclusion, we have developed a diastereo- and regiose-
lective Pd-catalyzed carboauration reaction of alkynes. This
reaction provides synthetic access to fully characterized
vinyl-gold intermediates. These intermediates participate in a
series of intermolecular palladium-catalyzed cross-coupling
reactions and electrophilic trapping reactions to produce di- and
trisubstituted olefins with high diastereoselectivity and absolute
regioselectivity. In a broader sense, the reactions reported herein
provide a demonstration of reactivity available to Au/Pd systems
and expand the synthetic utility of vinyl-gold intermediates.
Application of these principles to the development of new Au-
and Pd-cocatalyzed reactions (i.e., catalytic in both metals rather
than just palladium) are ongoing in our laboratory. Given the
prolific role of both Pd and Au separately in organic synthesis,
more “combined concepts” are likely forthcoming as this
fundamental understanding grows.
The strongly electrophilic reagents HCl and Bu3SnOTf
trapped the vinyl-gold species 2 in the absence of a Pd catalyst
(both 97%, two steps).29 In these cases, purified 2 displayed
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and the University of California, Irvine for funding,
the Allergan Foundation for fellowships to Y.S. and S.D.R.,
and the UCI UROP for fellowships to S.D.R. We thank Dr.
Joseph Ziller for X-ray crystallography assistance.
(25) Dube´, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12062.
(26) Isolated examples of Au/Pd cross-coupling reactions have been
reported: Jones, L. A.; Sanz, S.; Laguna, M. Catal. Today 2007, 122, 403.
(27) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442.
(28) For an example of a gold-catalyzed Sonogashira reaction that does
not require palladium, see: Gonza´lez-Arellano, C.; Abad, A.; Corma, A.;
García, H.; Iglesias, M.; Sa´nchez, F. Angew. Chem., Int. Ed. 2007, 46, 1536.
(29) While this paper was under review, an example of an isolable
vinyl-gold compound that reacts with I2 and a proton electrophile was
reported: Liu, L.-P.; Xu, B.; Mashuta, M. S.; Hammond, G. B. J. Am. Chem.
Soc. 2008, 130, 17642.
Supporting Information Available: Text, figures, and tables
giving experimental procedures and compound characterization data
and CIF files giving crystal data for 8 and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
OM801206G