Catalytic enone cycloallylation via concomitant activation of latent nucleophilic and electrophilic partners: Merging organic and transition metal catalysis

Article abstract of DOI:10.1021/ja0301469

Upon exposure of mono-enone mono-allylic carbonates to tributylphosphine and 1 mol % Pd(Ph₃P)₄, efficient conversion to the corresponding cycloallylated products is achieved. This transformation combines the nucleophilic features of the Morita-Baylis-Hillman reaction with the electrophilic features of the Trost-Tsuji reaction. Copyright

Full text of DOI:10.1021/ja0301469

Published on Web 06/05/2003
Catalytic Enone Cycloallylation via Concomitant Activation of Latent
Nucleophilic and Electrophilic Partners: Merging Organic and Transition
Metal Catalysis
Bradley G. Jellerichs, Jong-Rock Kong, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received March 3, 2003; E-mail: mkrische@mail.utexas.edu
Scheme 1. Proposal: Catalytic Cycloallylation via Concommitant
Activation of Latent Nucleophilic and Electrophilic Partners
Modular design of catalytic transformations based on the use of
enones as latent enolates is currently under development in our
lab.1 Through variation of the method of enone nucleophilic activa-
tion (hydrometalation, carbometalation or nucleophilic organoca-
talysis), coupled with the use of diverse electrophilic partners, a
family of catalytic cycloreductions,2 cycloadditions3 and cycloisom-
erizations4 has emerged. While use of “classical” electrophilic part-
ners such as appendant aldehydes, ketones and enones has been
demonstrated,1-4 an opportunity for further development resides
in catalytic couplings to “nonclassical” electrophiles, such as allylic
carbonates. The use of allylic carbonates as latent electrophiles man-
dates activation via metallo-π-allyl formation. In this regard,
palladium complexes have proven especially effective.5 The compat-
ibility of palladium-based catalysts and tertiary phosphines suggests
the feasibility of catalytic enone allylation processes, whereby acti-
vation of latent nucleophilic (enone) and electrophilic (allyl carbo-
nate) partners is achieved through phosphine addition and π-allyl
formation, respectively. Such “two-component catalyst systems”
are uncommon.6 Moreover, the use of nucleophilic catalysis as a
means of enolate generation in metal-catalyzed cross-coupling is
without precedent.5,7 The feasibility of this proposal is borne out
by the results reported herein. Upon exposure of mono-enone mono-
allylic carbonates to tributylphosphine and substoichiometric quan-
tities of Pd(Ph3P)4, efficient conversion to the corresponding
cycloallylated products is achieved. This transformation combines
the nucleophilic features of the Morita-Baylis-Hillman reaction
with the electrophilic features of the Trost-Tsuji reaction (eq 1).
Table 1. Optimization of the Catalytic Cycloallylation of 1a
entry
R
solvent
(Ph3P)4Pd (mol %) PBu3 (mol %) T (°C) yielda (%)
1
2
3
4
5
COCH3 THF
10
4
4
5
1
50
50
100
100
100
60
30
60
60
60
6
21
67
92
92
COCH3 t-BuOH
COCH3 t-BuOH
CO2CH3 t-BuOH
CO2CH3 t-BuOH
a Isolated yields after purification by silica gel chromatography.
Scheme 2. Synthesis of Mono-enone Mono-allylic Carbonates
1a-8a
Recently, the present author and Roush disclosed a trialkylphos-
phine-catalyzed cycloisomerization of electron-deficient 1,5- and
1,6-dienes.4,8,9 This discovery stimulated interest in the design of
related transformations potentially developed through variation of
the electrophilic partner. In accordance with this goal, and the
aforementioned rationale for concomitant activation of latent
nucleophilic and electrophilic partners, the following mechanism
for catalytic enone cycloallylation was envisioned. In this scenario,
catalysis is contingent upon the separate yet concomitant action of
organic and metallic promoters (Scheme 1).
To assess the feasibility of the proposed transformation, catalytic
intramolecular cycloallylation of mono-enone mono-allylic acetate
1a was attempted using tributylphosphine and Pd(Ph3P)4 as nu-
cleophilic and electrophilic activators, respectively. Initial experi-
ments performed in aprotic media using 10 mol % Pd(Ph3P)4 and
50 mol % PBu3 resulted in a poor yield of cycloallylation product
1b (Table 1, entry 1). It was postulated that capture of the metallo-
π-allyl intermediate would be facilitated were the lifetime of the
transiently generated enolate to be extended through solvation in
the form of hydrogen-bond interactions. Accordingly, the use of
tert-butyl alcohol as solvent increased the yield of 1b to 21% at
reduced loading of Pd(Ph3P)4 (Table 1, entry 2). To further promote
trapping of the metallo-π-allyl, the loading of PBu3 was doubled,
which raised the yield of cycloallylation product to 67% (Table 1,
entry 3). The preceding experiments were performed using the
allylic acetate of 1a, which upon ionization generates acetate ion
and, ultimately, acetic acid. It was recognized that the corresponding
methyl carbonate would generate methoxide ion upon ionization,
potentially facilitating â-elimination of PBu3 in the final step of
the catalytic cycle (Scheme 1). Indeed, the allylic carbonate of 1a
provides cycloallylation product 1b in 92% yield (Table 1, entry
4). This yield was found to persist at 1% loading of Pd(Ph3P)4
(Table 1, entry 5).
Given the preceding result, a concise and modular synthetic route
to cycloallylation substrates 1a-8a was sought. Remarkably,
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C O M M U N I C A T I O N S
valent transition-metal complexes.10 Whereas enoate 7a provides
only trace quantities of cycloallylation product 7b, the corresponding
thioenoate 8a is readily cyclized (Table 2, entry 7). This result is
consistent with the enhanced performance of thioenoates in Morita-
Baylis-Hillman-type cyclizations11,4b and is remarkable in view
of the well-established susceptibility of thioesters to oxidative addi-
tion by low-valent palladium.12 Finally, as demonstrated by the
catalytic cycloallylation of substrates 9a-11a, six-membered ring
formation proceeds smoothly, albeit in diminished yield (Table 2,
entries 8-10).
Table 2. Catalytic Cycloallylation of Mono-enone Mono-allylic
Carbonatesa
In summary, we demonstrate the feasibility of nucleophilic ca-
talysis as a means of enolate generation in metal-catalyzed cross
coupling, as evidenced by the development of a catalytic enone
cycloallylation methodology. This transformation is achieved
through the use of a two-component catalyst system that unites the
nucleophilic features of the Morita-Baylis-Hillman reaction with
the electrophilic features of the Trost-Tsuji reaction. Future studies
will be devoted to the development of related catalytic transforma-
tions, including enantioselective variants of the methodology
described herein.
Acknowledgment. Acknowledgment is made to the Robert A.
Welch Foundation (F-1466), the NSF-CAREER program (CHE-
0090441), the Herman Frasch Foundation (535-HF02), the NIH
(RO1 GM65149-01), donors of the Petroleum Research Fund ad-
ministered by the ACS (34974-G1), the Research Corporation
Cottrell Scholar Award (CS0927), the Alfred P. Sloan Foundation,
the Camille and Henry Dreyfus Foundation, and Eli Lilly for partial
support of this research.
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS) (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For a review, see: Jang, H.-Y.; Cauble, D. F.; Huddleston, R. R.; Krische
M. J. Acc. Chem. Res. 2003, 36, submitted.
(2) For catalytic hydrometallative and carbometallative aldol and Michael
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a Procedure: Tributylphosphine (100 mol %) and Pd(PPh3)4 (1 mol %)
were added to a 0.1 M solution of substrate in tert-butyl alcohol, and the
reaction was allowed to stir at 60 °C until complete consumption of starting
material, at which point the reaction mixture was evaporated onto silica
and purified via silica gel chromatography. b Isolated yields were calculated
after purification by silica gel chromatography. c 5 mol % of Pd(PPh3)4
was used for this single example. At 1 mol % catalyst loading the yield of
6b was 65%.
exposure of methyl allyl carbonate and 4-penten-1-ol to the second-
generation Grubb’s catalyst provides the cross-metathesis product
in moderate yield. Tandem Moffatt-Swern oxidation-Wittig
olefination then affords substrates 1a-8a (Scheme 2).
With a set of structurally diverse cycloallylation substrates in
hand, the scope of the catalytic cycloallylation was examined. As
demonstrated by the catalytic cycloallylation of substrates 1a-6a,
aromatic, heteroaromatic and aliphatic enones represent viable react-
ing partners (Table 2, entries 1-6). The cycloallylation of cyclo-
propyl substituted enone 6a is noteworthy, as cyclopropanes pos-
sessing adjacent π-unsaturation are known to react readily with low-
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Chem. ReV. 2003, 103, 811.
(10) For reviews, see: (a) Sarel, S. Acc. Chem. Res. 1978, 11, 204. (b) Ohta,
T.; Takaya, H. Metal Catalyzed Cycloaddition of Small Ring Compounds.
In ComprehensiVe Organic Synthesis; Trost, B., Fleming, I., Eds.;
Permagon: Oxford, 1991; Vol. 5, pp 1185-1205.
(11) Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687.
(12) See, for example: Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc.
1990, 112, 7050.
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