Palladium- and copper-catalyzed 1,4-additions of organozinc compounds to conjugated aldehydes

Article abstract of DOI:10.1021/ol062154a

Conjugated aldehydes undergo smooth Pd(OAc)₂·PPh ₃- or Me₂CuCNLi₂-catalyzed 1,4-addition of dialkylzinc reagents.

Full text of DOI:10.1021/ol062154a

ORGANIC
LETTERS
2
006
Vol. 8, No. 24
505-5508
Palladium- and Copper-Catalyzed
,4-Additions of Organozinc Compounds
5
1
to Conjugated Aldehydes
James A. Marshall,* Martin Herold, Hilary S. Eidam, and Patrick Eidam
Department of Chemistry, UniVersity of Virginia, P.O. Box 400319,
CharlottesVille, Virginia 22904
jam5x@Virginia.edu
Received August 31, 2006
ABSTRACT
2 3 2 2
Conjugated aldehydes undergo smooth Pd(OAc) ‚PPh - or Me CuCNLi -catalyzed 1,4-addition of dialkylzinc reagents.
In recent years, we have developed a methodology for
converting enantiopure propargylic mesylates to chiral al-
lenylindium and -zinc reagents. Additions of these reagents
to aldehydes afford anti-homopropargylic alcohols of high
seen side reaction in which an ethyl group from the
diethylzinc was transferred to the â-position of (E)-2-heptenal
2
in a 1,4-addition reaction (Figure 2). In a separate experi-
1
enantiomeric and diastereomeric purity. The allenyl reagents
are formed in situ from the mesylate and InI or Et
2
Zn in the
presence of 5 mol % of Pd(OAc) ‚PPh (Figure 1).
2
3
Figure 2. Unexpected 1,4-addition of diethylzinc to an enal
accompanying the in situ generation of an allenylzinc reagent.
ment, we found that the 1,4-ethyl adduct was produced in
high yield from the enal and diethylzinc in the presence of
5
mol % of Pd(OAc)
reaction was observed in the absence of the Pd catalyst.
,4-Additions to conjugated double bonds are generally
2
without the propargylic mesylate. No
Figure 1. Preparation of allenylindium and -zinc reagents from
propargylic mesylates and in situ additions to aldehydes.
1
effected with organocuprates. However, reactions of cuprates
with enals typically afford mixtures of 1,4- and 1,2-adducts.
3
In the course of recent studies on additions of allenylzinc
reagents, prepared from propargylic mesylates as described
above, to conjugated aldehydes, we encountered an unfore-
The use of less-nucleophilic cyanocuprates or Normant
4,5
magnesio cuprates tends to favor the 1,4-adducts compared
to reactions involving Gilman-type cuprates. Also, perform-
(
1) (a) Marshall, J. A. Chem. Rev. 1996, 96, 31. (b) Marshall, J. A. Chem.
(2) Marshall, J. A.; Eidam, P.; Eidam, H. S. J. Org. Chem. 2006, 71,
4840.
ReV. 2000, 100, 3163.
1
0.1021/ol062154a CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/31/2006

ing the additions in the presence of TMSCl leads to enhanced
ratios of 1,4- to 1,2-adducts.3,5,6 These reactions are strongly
accelerated by the added TMSCl.
Table 1. Pd(0)-Catalyzed 1,4-Additions of Organozinc
Reagents to Conjugated Enals 1 and 6-9 and Enone 10
Kurosawa and co-workers studied Pd(0)-catalyzed 1,4-
additions of disilanes to cinnamaldehyde and crotonaldehyde
in the presence of TMSOTf, which led to mixtures of (E)-
and (Z)-enol silanes of the 1,4-adducts together with silyl
7
R1
R2
R3
product yield, %a yield, %b
ethers of the 1,2-adducts. On the basis of X-ray crystal
2
3
structures, they surmised that η and η palladium complexes
C6H13
H
H (1)
H (6)
H (7)
H (8)
2
11
12
13
14
15
83
73
89
52
80
79
92
76
90
51
80
-
of the enal substrates are involved in these reactions.
TBDPSO(CH2)3
c-C6H11
H
H
H
Additionally, the Pd complex of acrolein coordinated to BF
3
C6H5
undergoes O-methylation with methyl triflate to produce the
8
(CH3)2CdCH(CH2)2 CH3 H (9)
corresponding enol ether Pd complex. Nickel-catalyzed 1,4-
c-C6H11
H
CH3 (10)
additions of organozinc reagents to enals and (mainly) enones
9
,10
a
L ) PPh3. b No ligand.
are known, but analogous palladium-catalyzed additions
have not been reported. To appraise the scope and potential
synthetic applications of such additions, we undertook the
following investigations.
conjugated acyl oxazolidinones, esters, or nitriles were
unsuccessful. Only starting materials were recovered from
these experiments.
Following the precedent of cuprate 1,4-additions, we
investigated the effect of added TMSCl on the Pd-catalyzed
Using (E)-2-nonenal (1) as our prototype aldehyde, we
found that the commercially available diethyl-, dimethyl-,
and diphenylzinc reagents afford the 1,4-adducts 2-4 in
satisfactory yield in the presence of 5 mol % of the
1
,4-addition of diethylzinc to (E)-2-nonenal. Unlike the
2 3
Pd(OAc) ‚PPh precatalyst in THF (Scheme 1). Dibutylzinc,
enhancements observed in cuprate reactions, the presence
of TMSCl in the palladium-catalyzed reactions inhibited the
addition and resulted in diminished yields of the 1,4-adduct
and multiple side products. On the other hand, yields of the
Scheme 1. Pd(0)-Catalyzed 1,4-Additions of Organozinc
Reagents to (E)-Nonenal
1
,4-adducts were comparable or slightly higher when the
reaction mixtures were quenched with TBSOTf to afford the
isolable enol silane adducts (Table 2). Presumably, this
Table 2. Pd(0)-Catalyzed 1,4-Additions of Organozinc
Reagents to Conjugated Enals and Subsequent in Situ Enolate
Trapping with TBSOTf
prepared according to Noller,11 was also a ready participant
in the 1,4-addition.
The diethylzinc additions were extended to a number of
different conjugated aldehydes and a representative enone
(
Table 1). Comparable yields of 1,4-adducts were obtained
R1
R
product
yield, %
(E)/(Z)
from reactions in which the PPh ligand was not present.
3
C6H13 (1)
C6H13 (1)
TBDPSO(CH2)3 (6)
c-C6H11 (7)
C6H5 (8)
Et
16
17
18
19
20
92
62
95
70
51
>20:1
12:1
>20:1
>20:1
7:1
However, purification of the products was more difficult in
those reactions owing to the precipitation of persistent
palladium byproducts. Attempts to effect 1,4-additions to
Bu
Et
Et
Et
(
3) (a) Dieter, R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron 2000,
5
3
6, 2767. (b) Linderman, R. J.; McKenzie, J. R. J. Organomet. Chem. 1989,
61, 31.
procedure minimizes side reactions of the intermediate zinc
enolates such as oxidation, aldol condensation, and Michael
additions. The (E) isomers were highly favored products
of these reactions. A possible mechanistic pathway is outlined
in Figure 3.
Our next series of experiments was conducted to determine
the effect of a γ-stereocenter on the stereoselectivity of the
addition. Aldehyde 21 was prepared by Wittig homologation
(
4) (a) Chuit, C.; Foulon, J. P.; Normant, J. F. Tetrahedron 1981, 37,
1
385. (b) Bourgain-Commercon, M.; Foulon, J.-P.; Normant, J. F. J.
Organomet. Chem. 1982, 228, 321. (c) Drouin, J.; Rousseau, G. J.
Organomet. Chem. 1985, 289, 223. (d) Horiguchi, Y.; Matsuzawa, S.;
Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025. (e)
Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron
Lett. 1986, 27, 4029.
12
(5) Lipshutz, B. H.; Wood, M. R.; Tirado, R. J. Am. Chem. Soc. 1995,
1
17, 6126.
(
(
6) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019.
7) Ogoshi, S.; Tomeyasu, S.; Morita, M.; Kurosawa, H. J. Am. Chem.
Soc. 2002, 124, 11598.
8) (a) Ogoshi, S.; Yoshida, T.; Nishida, T.; Morita, M.; Kurosawa, H.
J. Am. Chem. Soc. 2001, 123, 1944. (b) Ogoshi, S.; Morita, M.; Kurosawa,
H. J. Am. Chem. Soc. 2003, 125, 9020. (c) Morita, M.; Inoue, K.; Ogoshi,
S.; Kurosawa, H. Organometallics 2003, 22, 5468.
(
(9) (a) Petrier, C.; de Souza Barbosa, J. C.; Dupuy, C.; Luche, J.-L. J.
Org. Chem. 1985, 50, 5761. (b) Ikeda, S.-i.; Yamamoto, H.; Kondo, K.;
Sato, Y. Organometallics 1995, 14, 5015. (c) Review: Erdik, E. Tetrahedron
1992, 48, 9577.
5506
Org. Lett., Vol. 8, No. 24, 2006

2
3
nate with η and/or η complexes of the palladium catalyst
8
with the substrate enal. Likely possibilities for enals 21 and
5 are illustrated in Figure 4.
1
7
2
Figure 3. Possible mechanistic pathway for Pd(0)-catalyzed 1,4-
additions of R Zn to conjugated enals.
2
13
of the known aldehyde precursor with ethyl phosphonoac-
etate followed by reduction of the conjugated ester and MnO
oxidation of the resulting allylic alcohol. Interestingly, the
Me Zn reaction afforded a single diastereomer whereas the
2
2
ethyl and butylzinc reagents yielded mixtures favoring one
isomer (Table 3). The stereochemistry of the methyl adduct
Figure 4. Transition-state rationale for stereoselectivity in 1,4-
Table 3. Pd(0)-Catalyzed 1,4-Additions of Organozinc
enal additions.
Reagents to the Chiral γ-Methyl-Substituted Conjugated Enal 21
Considering the obvious analogy between these conjugate
additions and 1,4-cuprate additions, we decided to briefly
explore a direct comparison of the two. As noted in the
introduction, cuprate additions to enals are typically plagued
by competing 1,2-additions. Indeed, reactions of enal 21 with
lithio cyanocuprate and Normant magnesiocuprate reagents
afforded mixtures of 1,4- and 1,2-adducts accompanied by
a
Ratios determined from integration of the 1H NMR spectra. Not
b
4
determined because of overlapping signals.
unidentified byproducts. Following these unsuccessful at-
tempts, we came across a recent study by Lipschutz and co-
2 2
workers in which Me CuCNLi was used to catalyze the 1,4-
5
was determined by silyl cleavage and oxidation to the known
cis-â,γ-dimethyl δ-valerolactone.14 The ethyl and butyl
analogues 23 and 24 were assigned by analogy.
addition of organozinc compounds to enones. The reported
reactions were markedly accelerated by the presence of
TMSCl. In the published report, 5-20 mol % of cyanocu-
prate was employed with up to 10 equiv of TMSCl,
depending on the nature of the zinc reagent and the enone.
We applied the Lipschutz procedure to (E)-2-nonenal (1) with
15
16
Additions to the γ-benzyloxy and silyloxy enals 25 and
8 by dimethyl- and diethylzinc proceeded analogously
2
(Scheme 2). Here, too, the methyl reagent proved more
1
0 mol % of the cuprate catalyst. Under these conditions,
the 1,4-adduct 2 was obtained in 42% yield along with 40%
of the derived enol silanes 31 as a 1:1.4 mixture of the (E)
and (Z) isomers (Table 4). When TMSCl was replaced with
TBSCl, the reaction rate greatly decreased and the enol silane
adducts were obtained in low yield, also as a 1:1.4 E/Z
Scheme 2. Pd(0)-Catalyzed 1,4-Additions of Organozinc
Reagents to Chiral γ-Benzyloxy- and Silyloxy-Substituted
Conjugated Enals
Table 4. Silyl-Promoted Copper-Catalyzed 1,4-Additions of
Et
2
Zn to (E)-2-Nonenal
silylCl
yield, %
(E)/(Z)
selective. The stereochemistry of the 1,4-adducts 26 and 29
was ascertained through independent synthesis (see the
Supporting Information for details).
a
TMSCl
TBSCl
none
40 (31)
1:1.4
1:1.4
>20:1
15 (16)
15 (16)
b
In light of the previously cited findings of Kurosawa and
co-workers on Pd(0) complexes of crotonaldehyde, the
stereochemical preferences for the 1,4-additions must origi-
a
2% of the aldehyde 1,4-adduct was obtained. b The reaction was
4
quenched with TBSOTf.
Org. Lett., Vol. 8, No. 24, 2006
5507

mixture. As expected, in the absence of a silylating reagent,
the copper-catalyzed addition was extremely slow. However,
upon quenching with TBSOTf, this reaction afforded the (E)-
enol silane 16 as the sole product in 15% yield along with
recovered enal. Evidently, the silane reagents, when initially
present, play a direct role in the addition phase of the
reaction.6 Additional examples of the copper-catalyzed
additions are shown in Scheme 3.
Scheme 5. Competition Experiment to Assess Relative
Reactivity of Enals vs Enones in Cuprate-Catalyzed
1,4-Additions
Scheme 3. Copper-Catalyzed 1,4-Additions of Et
2
Zn to
adduct 12 in 42% yield along with an inseparable mixture
of starting materials and unidentified byproducts, whereas
the cuprate-catalyzed addition showed excellent selectivity
for the enal. The 1,4-adduct 12 was obtained in 82% yield,
and most of the unreacted enone was recovered.
Representative Enals
In summary, we have found conditions for effecting
selective Pd-catalyzed 1,4-additions of organozinc reagents
to conjugated enals without competing 1,2-additions. The
intermediate zinc enolates can be efficiently trapped with
TBSOTf to afford (E)-enol silanes. We have also found that
the Lipschutz methodology for cyanocuprate-catalyzed 1,4-
additions of dialkylzinc reagents to conjugated ketones can
be applied to aldehydes. The diastereoselectivity of addi-
tions to conjugated aldehydes possessing a stereocenter at
the γ-position is consistent with the intermediacy of a π-allyl
Pd or Cu species. Finally, we have conducted a preliminary
experiment that suggests a useful selectivity for conjugated
enals over enones in the copper-catalyzed additions.
Extending the comparison between copper- and palladium-
catalyzed 1,4-additions, we applied the Lipschutz procedure
to the chiral enals 21 and 25 (Scheme 4). Both dimethyl-
Scheme 4. Copper-Catalyzed 1,4-Additions of Organozinc
Reagents to Chiral γ-Methyl- and Benzyloxy-Substituted
Conjugated Enals 21 and 25
Supporting Information Available: Experimental pro-
cedures, spectra, and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL062154A
(10) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69, 908.
This paper contains a well-documented literature survey of conjugate
additions to R,â-unsaturated carbonyl compounds by various organometallic
reagents.
(
11) Noller, C. R. Org. Synth. 1943, Coll. Vol. 2, 184.
(12) Enolates derived from R-substituted enals and cuprates are prone
to oxidative decarbonylation leading to ketone byproducts. Clive, D. L. J.;
Farina, V.; Beaulieu, P. L. J. Org. Chem. 1982, 47, 2572.
(13) Johns, B. A.; Grant, C. M.; Marshall, J. A. Org. Synth. 2005, Coll.
Vol. 10, 170.
and diethylzinc added rapidly at -78 °C affording the 1,4-
adducts 22, 23, and 26 after brief treatment with TBAF, in
high yield and with stereoselectivity comparable to that of
the Pd-catalyzed reactions.
To evaluate potential selectivity issues, we conducted a
competition experiment between (E)-3-cyclohexyl-2-propenal
(
14) (a) Ozegowski, R.; Kunath, A.; Schick, H. Liebigs Ann. Org.
Biochem. 1996, 1443. (b) Mori, K.; Ueda, H. Tetrahedron 1982, 38, 1227.
15) Enders, D.; Jandeleit, B.; von Berg, S. J. Organomet. Chem. 1997,
33, 219.
16) Savage, I.; Thomas, E. J.; Wilson, P. D. J. Chem. Soc., Perkin Trans.
1 1999, 22, 3291.
(
5
(
(
17) A Felkin-Anh transition state for cuprate additions to chiral
(7) and the related enone 10 for 1 equiv of diethylzinc
γ-oxygenated enals has previously been advanced. Roush, W. R.; Lesur,
B. M. Tetrahedron Lett. 1983, 24, 2231.
(Scheme 5). The Pd-catalyzed reaction afforded the 1,4-
5508
Org. Lett., Vol. 8, No. 24, 2006