Synthesis of acyclic α,β-unsaturated ketones via Pd(II)-catalyzed intermolecular reaction of alkynamides and alkenes

Article abstract of DOI:10.1021/ja068886f

We report an intermolecular oxidative coupling of alkynamides and terminal alkenes to synthesize E-α,β-unsaturated ketones under very mild conditions using catalytic Pd(II) and an oxidant. An ¹⁷O isotope labeling experiment implicates a cyclic

Full text of DOI:10.1021/ja068886f

Published on Web 02/06/2007
Synthesis of Acyclic r,â-Unsaturated Ketones via Pd(II)-Catalyzed
Intermolecular Reaction of Alkynamides and Alkenes
Norie Momiyama, Matthew W. Kanan, and David R. Liu*
Howard Hughes Medical Institute and Department of Chemistry & Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received December 12, 2006; E-mail: liu@chemistry.harvard.edu
Table 1. Initial Observationsa
Transition-metal-catalyzed reactions of alkynes with alkenes have
proven to be reliable and important strategies for carbon-carbon
bond formation.1 Previous efforts have focused primarily on non-
oxidative reactions such as isomerizations of enynes to synthesize
cyclic dienes and cyclopropyl derivatives,1a-g or cross-metathesis
entry
n
Pd(II) (equiv)/oxidant (equiv)
additive
yield (%)b
to synthesize acyclic dienes.1e,h Extending alkyne-alkene reactivity
to include oxidative couplings2 could provide convenient access to
additional organic functionality. We recently used DNA-templated
synthesis and in vitro selection to discover a Pd(II)-mediated
alkyne-alkene cyclization reaction that generates a macrocyclic
R,â-unsaturated ketone.3 Here we describe the development of an
analogous intermolecular oxidative coupling reaction between
alkynamides and terminal alkenes to generate acyclic R,â-unsat-
urated ketones4 (eq 1). Our results reveal that amides can mediate
this mode of alkyne reactivity and provide efficient access to acyclic
R,â-unsaturated ketones under very mild conditions.
1
2
3
4
5
6
7
8
0, 1 Na2PdCl4 (1)/-
0, 1 Na2PdCl4 (1)/-
none
H2O (1.6 mL)
none
H2O (1.6 mL)
H2O (1.6 mL)
<1
<1
<1
53
8
58
54
<1
2
2
2
2
3
4
Na2PdCl4 (1)/-
Na2PdCl4 (1)/-
Na2PdCl4 (0.2)/-
Na2PdCl4 (0.2 )/p-benzoquinone (1.5) H2O (1.6 mL)
Na2PdCl4 (0.2 )/p-benzoquinone (1.5) H2O (1.6 mL)
Na2PdCl4 (0.2)/p-benzoquinone (1.5)
H2O (1.6 mL)
a Reactions were conducted at room temperature with 0.15 mmol of
alkene in MeCN (2.4 mL) and 0.1 mmol of alkyne added dropwise over 5
h. b Isolated yield.
acyclic intermediate that would result from the direct hydration of
a Pd(II)-alkyne complex (eq 3).7
We began the development of this reaction by defining its basic
requirements with respect to the alkyne substrate and the reaction
conditions. Several alkynes were examined for their ability to react
with styrene in the presence of various palladium salts. We
discovered that alkynamides possessing a pentyn- or hexynamide
backbone were required for efficient R,â-unsaturated ketone forma-
tion (Table 1). For example, slow addition of N-benzyl-N-
methylpent-4-ynamide to a mixture of 1.5 equiv of styrene and 1.0
equiv of Na2PdCl4 in MeCN-H2O (3:2) at room temperature
provided the E-R,â unsaturated ketone product in 53% isolated yield
(Table 1, entry 4), whereas the analogous propyn-, butyn- and
heptynamide substrates did not generate significant desired product
under these conditions (Table 1, entries 2 and 8). Furthermore, no
R,â-unsaturated ketone was observed when water was omitted from
the reaction (Table 1, entry 3). The use of p-benzoquinone as a
stoichiometric oxidant enabled multiple turnovers with 0.2 equiv
of Pd(II) to provide enone products in 54-58% yield (Table 1,
entry 6 and 7).
On the basis of the requirement for a pentynamide or hexynamide
backbone, we hypothesized that R,â-unsaturated ketone formation
proceeds through a cyclic oxypalladation intermediate.5 To test this
proposal, we performed an 17O labeling experiment. When the
reaction between N-benzyl-N-methylpent-4-ynamide (1) and styrene
was conducted in MeCN-17OH2 (3:2), 17O NMR revealed the
presence of broad peak at 318.5 ppm that is characteristic of an
amide Cd17O (eq 2) but inconsistent with an enone Cd17O (eq
3).6 This result strongly suggests that the reaction proceeds through
a cyclic oxypalladation intermediate (eq 2), rather than through an
The scope of the reaction was further examined under optimized
conditions using 0.15 equiv of Na2PdCl4, 0.2 equiv of CuCl2, and
molecular oxygen as the terminal oxidant in MeCN-H2O (5:1)
(Table 2). Pentyn- or hexynamides containing both secondary and
tertiary amides were reactive under these conditions. In addition
to styrene and R-methylstyrene, a variety of terminal alkenes were
effective substrates, including long-chain unactivated alkenes.
Desired R,â-unsaturated ketone products in Table 2 were obtained
with >99:1 E/Z stereoselectivity and >5:1 (for long-chain alkenes)
to >20:1 (for styrenes) regioselectivity. The reaction is compatible
with ester, carbamate, nitrile, acetate, and alkyl bromide function-
alities. The high stereoselectivity in the reaction of long-chain
unactivated terminal alkenes (Table 2, entries 10-16) is noteworthy
in comparison with the intermolecular Heck reaction of unactivated
alkenes, which typically exhibits lower selectivity (E/Z ) ∼2.5:1
to ∼6:18).
Although a cyclic oxypalladation intermediate has been proposed
in the Pd(II)-catalyzed hydration of alkynyl ketones,5 pentynyl
ketones such as hex-5-yn-2-one and 2-prop-2-ynylcyclopentanone
were not reactive under the above conditions, further demonstrating
the necessity of the amide group. We also note that the Wacker
9
2230
J. AM. CHEM. SOC. 2007, 129, 2230-2231
10.1021/ja068886f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Scope of Pd(II)-Catalyzed Intermolecular
the oxygen from water is incorporated into the amide carbonyl.
Intermediate B reacts with an alkene substrate through a Heck-
like process10 resulting in Pd-alkyl species C. â-Hydride elimination
generates a Pd-alkene complex such as D and sequential olefin
insertion-â-hydride elimination steps result in migration of the
olefin to the R,â position in E.11 Release of R,â-unsaturated ketone
product followed by reductive elimination results in Pd(0), which
is oxidized to regenerate Pd(II).
Reaction of Alkynamides and Alkenesa
In summary, we have demonstrated the Pd(II)-catalyzed inter-
molecular oxidative coupling of alkynamides and alkenes to provide
R,â-unsaturated ketones with high stereo- and regioselectivity under
very mild conditions. These findings identify alkynamides as
efficient oxypalladation precursors that undergo hydration followed
by a Heck-type process. Further studies to explore the reactivity
of intermediates proposed in Scheme 1 are underway.
Acknowledgment. We thank Prof. Andrew G. Myers for helpful
discussions and Dr. Shaw Huang for assistance with 17O NMR.
This research was supported by NIH Grant R01GM065865 and by
the Howard Hughes Medical Institute. N.M. acknowledges a Damon
Runyon Cancer Research Foundation Postdoctoral Fellowship
(DRG:1869-05).
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) (a) Trost, B. M. Acc. Chem. Res. 1990, 23, 34-42. (b) Trost, B. M.;
Krische, M. J. Synlett 1998, 1-16. (c) Tsuji, J. Transition Metal Reagents
and Catalysts: InnoVations in Organic Synthesis; Wiley: Chichester, U.K.,
2000; pp 227-277. (d) Thiel, O. R. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany,
2004, Vol. 1 pp 321-333. (e) Diver, S. T.; Giessert, A. J. Chem. ReV.
2004, 104, 1317-1382. (f) Bruneau, C. Angew. Chem., Int. Ed. 2005,
44, 2328-2334. (g) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal.
2006, 348, 2271-2296. (h) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900-1923. (i) Gibson, S. E.; Stevenazzi, A. Angew.
Chem., Int. Ed. 2003, 42, 1800-1810.
(2) For recent representative examples of oxidative coupling reactions
catalyzed by Pd(II) see (a) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-
Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130-3131. (b) Lee, J. M.;
Ahn, D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.; Chang, S. J. Am.
Chem. Soc. 2006, 128, 12954-12962. (c) Silva, F.; Reiter, M.; Mills-
Webb, R.; Sawicki, M.; Kla¨r, D.; Bensel, N.; Wagner, A.; Gouverneur,
V. J. Org. Chem. 2006, 71, 8390-8394. (d) Hull, K. L.; Lanni, E. L.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047-14049.
a Reactions were conducted at room temperature or 40 °C with 15 mol
% of Na2PdCl4‚3H2O, 20 mol % of CuCl2‚2H2O, 1 atm O2, 1.5 equiv of
alkene in MeCN-H2O (5:1), and 1.0 equiv of alkyne added by dropwise
addition for 8-12 h. b Isolated yield. c Linear:branched regioselectivity >99:
1. d Linear:branched regioselectivity >5:1.
(3) Kanan, M. W.; Rozenman, M. M.; Sakurai, K.; Snyder, T. M.; Liu, D. R.
Scheme 1. Proposed Mechanism
Nature 2004, 431, 545-549.
(4) For representative examples of R,â-unsaturated ketone synthesis via
oxidative reaction catalyzed by Pd(II) see (a) Ito, Y.; Hirao, T.; Saegusa,
T. J. Org. Chem. 1978, 43, 1011-1013. (b) Ito, Y.; Aoyama, H.; Hirao,
T.; Mochizuki, A.; Saegusa, T. J. Am. Chem. Soc. 1979, 101, 494-496.
(5) Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127-3130.
(6) (a) Delseth, C.; Nguyeˆn, T. T.; Kintzinger, J.-P. HelV. Chem. Acta 1980,
63, 498-503. (b) Reference guide provided by Bruker, published in 1994.
(7) A Pd-alkynl intermediate may be considered as another possibility; we
disfavor such an intermediate as a major contributor to product formation,
however, because it is inconsistent with the requirement for a pentynamide
or hexynamide backbone.
(8) For a representative example and additional references see Littke, A. F.;
Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000.
(9) For representative reviews of the Wacker oxidation see (a) Smidt, J. Chem.
Ind. 1962, 54-62. (b) Tsuji, J. Synthesis 1984, 5, 369-384. (c) Feringa,
B. L. Transition Met. Org. Synth. 1998, 2, 307-315. (d) Takacs, J. M.;
Jiang, X.-T. Curr. Org. Chem. 2003, 7, 369-396.
(10) For reviews of the Heck reaction see (a) Heck, R. F. Org. React. 1982,
27, 345-390. (b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
oxidation product9 derived from styrene, acetophenone, was not
observed under these conditions.
On the basis of the above observations, a possible mechanism
for the reaction is shown in Scheme 1. We propose that the initial
step involves the activation of the alkynamide with Pd(II) to provide
the cyclic oxypalladation intermediate A. This intermediate is then
hydrated to generate acyclic oxypalladation intermediate B in which
(11) For representative examples of olefin migration mediated by PdH see (a)
Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi,
K.; Moriguchi, K. Organometallics 1993, 12, 4188-4196. (b) Loiseleur,
O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1996, 35, 200-202. (c)
Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056-2057.
(d) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704-4705.
(e) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005,
127, 17778-17788.
JA068886F
9
J. AM. CHEM. SOC. VOL. 129, NO. 8, 2007 2231