Pd-catalyzed carbonylative conjugate addition of dialkylzinc reagents to unsaturated carbonyls

Article abstract of DOI:10.1021/ol1013476

The Pd-catalyzed addition of organozinc reagents to unsaturated carbonyls in the presence of carbon monoxide provides 1,4-diketones in good yield. The reaction was studied with a number of substituted cyclic and acyclic ketones as well as α,β-unsaturated aldehydes.

Full text of DOI:10.1021/ol1013476

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3760-3763
Pd-Catalyzed Carbonylative Conjugate
Addition of Dialkylzinc Reagents to
Unsaturated Carbonyls
Daniel W. Custar, Hai Le, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
morken@bc.edu
Received June 11, 2010
ABSTRACT
The Pd-catalyzed addition of organozinc reagents to unsaturated carbonyls in the presence of carbon monoxide provides 1,4-diketones in
good yield. The reaction was studied with a number of substituted cyclic and acyclic ketones as well as r,ꢀ-unsaturated aldehydes.
The catalytic conjugate addition of organometallic nucleo-
philes to unsaturated carbonyls is an important method for
organic synthesis. In this regard, successful catalytic addition
reactions have been registered for a broad range of nucleo-
philes, be they aryl-, vinyl-, alkyl-, or acetylide-based
reagents.1 The conjugate addition of acyl anions represents
a special class of transformations since these nucleophiles
are often unstable and are therefore generated in situ during
the course of a reaction.2 The Stetter3 and silyl-Stetter4
reactions are two important strategies to accomplish the
disonant bond connection that conjugate addition of an acyl
anion to an unsaturated carbonyl achieves. While remarkable
advances have been documented in both of these acyl anion
addition strategies, complementary strategies that expand the
substrate scope would prove valuable. In this regard, we have
begun to study the catalytic carbonylative addition of simple
organometallic reagents to enones, and this report describes
our initial findings.5,6
Recent studies in our laboratory have focused on the
catalytic enantioselective addition of allylboron reagents to
unsaturated carbonyls.7 These reactions are postulated to
proceed by oxidative addition of Pd(0) or Ni(0) to a Lewis
acid-activated enone (1 to 2, Scheme 1) followed by
(1) (a) Alexakis, A.; Ba¨ckval, J. E.; Krause, N.; Pa`mies, O.; Die´guez,
M. Chem. ReV. 2008, 108, 2796. (b) Harutyunyan, S. R.; Hartog, T.; Geurts,
K.; Minnaard, A. J.; Feringa, B. L. Chem. ReV. 2008, 108, 2824. (c)
Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin,
1999; Vol. 3, p 1105. Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001,
171. Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. Feringa, B. L.;
Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; p 224.
(5) For recent metal-catalyzed carbonylative conjugate additions, see:
(a) Chochois, H.; Sauthier, M.; Maerten, E.; Castanet, Y.; Mortreux, A.
Tetrahedron 2006, 62, 11740. (b) Sauthier, M.; Castanet, Y.; Mortreux, A.
Chem Commun. 2004, 1520. (c) Hanzawa, Y.; Tabuchi, N.; Taguchi, T.
Tetrahedron Lett. 1998, 39, 8141. (d) Shirakawa, E.; Yamamoto, Y.; Nakao,
(2) (a) Corey, E. J.; Hegedus, L. S. J. Am. Chem. Soc. 1969, 91, 4926.
(e) Lipshutz, B. H.; Elworthy, T. R. Tetrahedron Lett. 1990, 31, 477. (f)
Thomas, S. E. J. Chem. Soc., Chem. Commun. 1987, 266. (g) Hegedus,
L. S.; Perry, R. J. J. Org. Chem. 1985, 50, 4955. (h) Cooke, M. P., Jr.;
Parlman, R. M. J. Am. Chem. Soc. 1977, 99, 5222. (i) Seyferth, D.; Hui,
R. C. J. Am. Chem. Soc. 1985, 107, 4551.
Y.; Tsuchimoto, T.; Hiyama, T. Chem. Commun. 2001, 1926
.
(6) For other recent metal-catalyzed carbonylative C-C bond-forming
reactions, see: (a) Dheur, J.; Sauthier, M.; Castanet, Y.; Mortreux, A. AdV.
Synth. Catal. 2007, 349, 2499. (b) Menard, F.; Weise, C. F.; Lautens, M.
Org. Lett. 2007, 9, 5365. (c) Aksin, O.; Dege, N.; Artok, L.; Tu¨rkmen, H.;
(3) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639.
(4) (a) Degl’Innocenti, A.; Ricci, A.; Mardini, A.; Reginato, G.; Colotta,
V. Gazz. Chim. Ital. 1987, 117, 645. (b) Mattson, A. E.; Bharadwaj, A. R.;
Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314. (c) Nahm, M. R.; Linghu,
X.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew. Chem.,
Int. Ed. 2005, 44, 2377.
C¸ etinkaya, B. Chem. Commun. 2006, 3187
.
(7) (a) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 224. (b) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130,
4978.
10.1021/ol1013476  2010 American Chemical Society
Published on Web 08/05/2010

as the catalyst. Also of note, Ni(cod)2/PCy3 and Pt(dba)3/PCy3
were ineffective at the carbonylative conjugate addition with
the former not delivering any product at all and the latter only
yielding the direct conjugate addition product. Similarly, a
survey of other Lewis acids (BF3·OEt2, Sc(OTf)3, TiCl2(iOPr)2)
was unproductive with these promoting the direct noncarbo-
nylative conjugate addition of the ethyl group to the enone.10
In the absence of any Lewis acid at all, the reaction did not
occur (Table 1, entry 3). Surprisingly, the quantity of organo-
metallic reagent could be reduced with 0.65 equiv of Et2Zn
being sufficient for effective reaction (entry 8). Lastly, the
quantity of the catalyst could be reduced with as little as 0.25
mol % of Pd2(dba)3 furnishing excellent yields of carbonylative
conjugate addition product (entries 6 and 7).
With efficient conditions established, the influence of the
enone substitution was examined. Both Pd2(dba)3/PCy3 and
Pd2(dba)3/PPh3 were studied as catalysts, and it was found
that, in addition to chalcone, other aryl-substituted enones
also undergo efficient carbonylative conjugate addition
(entries 1 and 2). While the data in entries 4 and 5 suggest
that electron-donating and electron-withdrawing groups are
both tolerated and ultimately lead to similar reaction yields,
a significant rate difference can be observed if conversions
are measured at 1 h (data not shown) with the 4-methoxy-
substituted enone affording 28% conversion and the 4-car-
bomethoxy derivative achieving 97% conversion.11 Notably,
aryl substitution is not a requirement as 2-penten-3-one reacted
in excellent yield (entry 8). Importantly, cyclic substrates were
also found to be effective. The example with cyclohexenone
(entry 10) is particularly noteworthy. Orito reported that
cyclohexenone undergoes carbonylative conjugate addition in
22% yield with benzylzinc chloride;7 however, with the
improved conditions described above, good yields of carbonyl-
ative addition product are obtained. Lastly, a sterically encum-
bered 4,4-disubstituted enone also afforded the desired product,
although a higher catalyst loading was required for the reaction
to be completed in less than 24 h (Table 2, entry 11). Note that
in entry 11 an increased amount of Et2Zn was employed to
account for the fact that carbonylative addition to dba is
generally observed and was expected to be more problematic
at higher catalyst loadings.
Scheme 1
transmetalation (2 to 3) and reductive elimination. The
intermediacy of Pd π-allyl complexes in this catalytic cycle
provides an opportunity for bond formation that is not often
observed in catalytic conjugate addition reactions.8 Indeed,
Orito and co-workers reported that the carbonylative con-
jugate addition of benzylzinc chloride to enones occurs in
the presence of Pd catalysts, and they have suggested that
the reaction may proceed by a CO insertion that occurs with
an intermediate similar to 3.9 Unfortunately, this process is
restricted to unsubstituted enones; for those possessing a ꢀ
substituent, significantly diminished reaction yields were
observed. In this paper, we document our studies on this
reaction and describe improvements that render it operative
with many unsaturated carbonyl substrates.
Our initial investigations focused on the addition of simple
alkyl metal reagents to enones under carbonylative condi-
tions. With conditions similar to those laid out by Orito
(catalytic Pd(PPh3)4 in the presence of TMSCl and LiCl) but
employing Et2Zn in place of benzylzinc chloride, we found
that the carbonylative conjugate addition of chalcone pro-
ceeds efficiently, even though the enone bears a substituent
at the ꢀ-carbon (Table 1, entry 1). Notably, the reaction yield
Table 1. Effect of Reaction Conditions on Carbonylative
Conjugate Additions to Chalconea
To further broaden the substrate scope, R,ꢀ-unsaturated
aldehydes were subjected to the reaction. With the optimized
reaction conditions described above, the carbonylative
conjugate addition product derived from nonenal was not
produced, but rather a compound tentatively assigned as aldol
adduct 5 (Scheme 2). It was considered that 5 might arise
from a pathway involving conversion of nonenal to 4 and
entry
catalyst
ligand
additive
% yield
1
2
3
4
5
6
7
8
9
5% Pd(PPh3)4
5% Pd(PPh3)4
5% Pd(PPh3)4
2.5% Pd2(dba)3
2.5% Pd2(dba)3
0.25% Pd2(dba)3
0.25% Pd2(dba)3
2.5% Pd2(dba)3
5% Ni(cod)2
TMSCl + LiCl
TMSCl
70
82
N.R.
85
82
PPh3
PCy3
PPh3
PCy3
PCy3
PCy3
PCy3
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
86
86
83b
N.R.
0
(8) For mechanistically related Pd- and Ni-catalyzed conjugate additions,
see: (a) Grisso, B. A.; Johnson, J. R.; Mackenzie, P. B. J. Am. Chem. Soc.
1992, 14, 5160. (b) Ogoshi, S.; Yoshida, T.; Nishida, T.; Morita, M.;
Kurosawa, H. J. Am. Chem. Soc. 2001, 123, 1944. (c) Marshall, J. A.;
Herold, M.; Eidam, H. S.; Eidam, P. Org. Lett. 2006, 8, 5505. (d) Hirano,
K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1541.
10
5% Pt(dba)3
a Reaction with 1.3 equiv of Et2Zn, 2.3 equiv of TMSCl, 1 atm of CO,
4 h. After completion of the reaction, the mixture was quenched at 0 °C
with acetic acid (1.5 equiv) and TBAF (1.5 equiv) for 10 min and then
treated with saturated Na2CO3. b Reaction with 0.65 equiv of Et2Zn.
(9) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69, 908.
(10) For Lewis acid promoted direct addition of organozincs to
aldehydes, see: Ochiai, H.; Nishihara, T.; Tamaru, Y.; Yoshida, Z. J. Org.
Chem. 1988, 53, 1343.
(11) This reactivity pattern finds parallel in rates of ligand substitution
at Pd(0), see: Stahl, S. S.; Thorman, J. L.; de Silva, N.; Guzei, I. A.; Clark,
R. W. J. Am. Chem. Soc. 2003, 125, 12.
improved when LiCl was omitted, and it could be improved
even further by employing Pd2(dba)3/PCy3 or Pd2(dba)3/PPh3
Org. Lett., Vol. 12, No. 17, 2010
3761

Scheme 2
Table 2. Carbonylative Conjugate Addition of Et2Zn To
R,ꢀ-Unsaturated Ketonesa
that this trimethylsilyl enol ether might be reactive enough
to undergo a Mukaiyama-aldol reaction12 with unreacted
nonenal in the presence of zinc salts. To minimize this side
reaction, TESCl was used as the additive in the carbonylative
addition. This strategy afforded the 1,4-dicarbonyl com-
pounds in good yields (Table 3).
Employing TESCl instead of TMSCl as the additive, R,ꢀ-
unsaturated aldehydes were examined in the carbonylative
Table 3. Catalytic Carbonylative Conjugate Addition of Et2Zn
to R,ꢀ-Unsaturated Aldehydesa
a Reaction with 1.3 equiv of Et2Zn, 2.3 equiv of TMSCl, 1 atm of
CO, 4 h (7 h for entry 4; 24 h for entry 11). After completion of the
reaction, the mixture was quenched at 0 °C with acetic acid (1.5 equiv)
and TBAF (1.5 equiv) for 10 min and then treated with saturated Na2CO3.
b Yield adjusted to account from unremovable impurity (ca. 10%). c 10%
Pd2(dba)3, 24% ligand, and 1.95 equiv of Et2Zn employed.
a Reaction with 1.3 equiv of Et2Zn, 2.3 equiv of TMSCl, 1 atm CO; 4 h
for entries 1 and 2; 20 h for entries 3 and 4; 24 h for entries 5 and 6. After
completion of the reaction, the mixture was quenched at 0 °C with acetic
acid (1.5 equiv) and TBAF (1.5 equiv) for 10 min and then treated with
saturated Na2CO3. b Quench (footnote a) was omitted from this reaction.
c A 2:1 mixture of olefin isomers was obtained.
3762
Org. Lett., Vol. 12, No. 17, 2010

conjugate addition. As shown in Table 3, ꢀ-substituted enals
are converted to the 1,4-addition product in good yields. With
substitution at the R-carbon, protodesilylative workup fur-
nished a 1:1 mixture of stereoisomeric compounds. However,
with a neutral workup (entry 3), the derived enol silyl ether
could be obtained as a single stereoisomer and was found to
be in the E configuration by NOE analysis. Interestingly,
with two substituents at the ꢀ-carbon of the enal, the product
of 1,2-carbonylative addition was generated in preference
to the 1,4-product. With TESCl, the product was isolated in
lower yields (41% for entry 4), but this was easily remedied;
use of more Lewis acidic Ph3SiCl provided the carbonylative
addition product in excellent yield, but for entry 5 as a
mixture of olefin stereoisomers. Lastly, benzaldehyde was
examined and found to be unreactive, an observation that
suggests a role for R,ꢀ unsaturation even in transformations
that furnish the 1,2 addition product.13
Scheme 3
reaction (72% yield), a feature that may be significant when
more precious reagents would be required.
In conclusion, the Pd(0)-catalyzed carbonylative conjugate
addition of organozinc reagents to R,ꢀ-unsaturated carbonyl
compounds is an efficient reaction and accomplishes a
transformation that can otherwise require multiple synthesis
steps. Further efforts to broaden the scope of this reaction
are currently ongoing and will be reported in due course.
To ascertain whether the carbonylative conjugate addition
reaction is limited to Et2Zn, we examined the reaction with
i-Pr2Zn (Scheme 3). This reaction provided comparable yields
as the reaction with Et2Zn, without requiring increased
catalyst loading. Similar to the reaction with Et2Zn, the use
of 0.65 equiv of the diisopropylzinc sufficed for an effective
Acknowledgment. This work was supported by the NIH
(GM 64451).
Supporting Information Available: Complete experi-
mental procedures and characterization data (1H and 13C
NMR, IR, and mass spectrometry). This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011.
(13) Ogoshi, S.; Yoshida, T.; Nishida, T.; Morita, M.; Kurosawa, H.
J. Am. Chem. Soc. 2001, 123, 1944.
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