Palladium-catalyzed conjugate allylation reactions of α,β- unsaturated N- acylpyrroles

Article abstract of DOI:10.1021/ol801830h

(Chemical Equation Presented) Conjugate allylation reactions of α,β-unsaturated N-acylpyrroles using allylboronic ester are catalyzed by a palladium complex that is ligated by a bidentate N-heterocyclic carbene. A variety of functional groups are tolerate

Full text of DOI:10.1021/ol801830h

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4743-4746
Palladium-Catalyzed Conjugate Allylation
Reactions of r,ꢀ-Unsaturated
N-Acylpyrroles
Michael B. Shaghafi, Benjamin L. Kohn, and Elizabeth R. Jarvo*
Natural Sciences I 4114, Department of Chemistry, UniVersity of California,
IrVine, California 92697
erjarVo@uci.edu
Received August 6, 2008
ABSTRACT
Conjugate allylation reactions of r,ꢀ-unsaturated N-acylpyrroles using allylboronic ester are catalyzed by a palladium complex that is ligated
by a bidentate N-heterocyclic carbene. A variety of functional groups are tolerated, and substrates functionalized with electron-withdrawing
groups react to afford the highest yields of products. Regioselectivity for 1,4-allylation over 1,2-allylation is demonstrated, and mechanistic
experiments are consistent with formation of nucleophilic allylpalladium intermediates.
Conjugate additions of carbon-based nucleophiles to enoate
derivatives are important methods for organic synthesis.
Although excellent methods exist for the transition-metal-
catalyzed addition of certain aryl and alkyl substituents,1
relatively few catalytic methods have been described for
conjugate allylation reactions.2,3 Several metal-catalyzed
allylation reactions of enones afford products resulting from
regioselective 1,2-addition of the allylic nucleophile.4 In
significant advances, Morken and co-workers have recently
reported enantioselective Ni- and Pd-catalyzed conjugate
allylation reactions of dialkylidene ketones such as diben-
zylidene acetone,5 and Snapper and co-workers have reported
enantioselective copper-catalyzed Hosomi-Sakurai allyla-
tions of cyclic ketoesters.6 Catalyst-controlled regioselective
1,4-addition reactions of simple enones and enoate deriva-
tives, however, are not currently available.
(1) For a recent review, see: Christoffers, J.; Koripelly, G.; Rosiak, A.;
Ro¨ssle, M. Synthesis 2007, 9, 1279–1300.
To address this unmet need, we undertook development
of a method for conjugate allylation reactions of R,ꢀ-
unsaturated N-acylpyrroles, practical substrates for conjugate
(2) Conjugate allylation reactions using stoichiometric organometallic
compounds. Allylsilane: (a) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc.
1977, 99, 1673–1675. (b) Majetich, G.; Casares, A. M.; Chapman, D.;
Behnke, M. Tetrahedron Lett. 1983, 24, 1909–1912. Allylcopper: (c)
Lipshutz, B. H.; Hackmann, C. J. Org. Chem. 1994, 59, 7437–7477.
Allylstannane: (d) Williams, D. R.; Mullins, R. J.; Miller, N. J. Chem. Soc.,
Chem. Commun. 2003, 2220–2221. Allylbarium: (e) Yanagisawa, A.;
Habaue, S.; Yasue, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6130–
6141. Allyltantalum: (f) Shibata, I.; Kano, T.; Kanazawa, N.; Fukuoka, S.;
(4) Representative catalytic enantioselective 1,2-allylation reactions of
enones, catalyzed byCuCl: (a) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 6536–6537. CuF2: (b)
Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8910–8911. AgF: (c) Wadamoto, M.; Yamamoto, H. J. Am. Chem.
Soc. 2005, 127, 14556–14557.
Baba, A. Angew. Chem., Int. Ed. 2002, 41, 1389–1392
.
(3) Stereoselective additions of chiral allyl and crotyl phosphonamides:
(a) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve´, Y.; Beaudoin, S. J.
Org. Chem. 1993, 58, 5032–5034. (b) Hanessian, S.; Gomtsyan, A.
Tetrahedron Lett. 1994, 35, 7509–7512. (c) Bennani, Y. L.; Hanessian, S.
(5) (a) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 2214–2215. (b) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008,
130, 4978–4983.
(6) Shizuka, M.; Snapper, M. L. Angew. Chem., Int. Ed. 2008, 47, 5049–
5051.
Chem. ReV. 1997, 97, 3161–3195
.
10.1021/ol801830h CCC: $40.75
Published on Web 10/02/2008
2008 American Chemical Society

Table 1. Palladium-Catalyzed Allylation of N-Acylpyrrole 5aa
entry
catalyst
none
1
2
3
4
base
alcohol
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
solvent
yield (%)b
1
2
3
4
5
6
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
<5
<5
7c
24c
<5
<5
PdCl2(NCPh)2,
d
P(OPh)3
7
8
9
10
11
12f
3
3
3
3
3
3
t-BuOK
t-BuOK
t-BuOK
t-BuOLi
K2CO3
t-BuOK
b
t-BuOH
t-BuOH
THF
29c
46c
dioxane
dioxane
dioxane
dioxane
dioxane
tert-amyl alcohole
tert-amyl alcohole
tert-amyl alcohole
tert-amyl alcohole
1
44c
<10
21
71c
a See the Supporting Information for reaction conditions. Yield of 6a as determined by H NMR spectroscopy using PhSiMe3 as an internal standard.
c Isolated yield of 6a after column chromatography. d 10 mol % of PdCl2(NCPh)2 and 30 mol % of phosphite were added. e Performed with 3.0 equiv of
tert-amyl alcohol. f Performed with 5.0 equiv of allylB(pin).
addition reactions. N-Acylpyrroles are versatile building
blocks because, as Weinreb amide equivalents, they undergo
facile functionalization to the alcohol, aldehyde/ketone, or
acid oxidation states.7 Further, R,ꢀ-unsaturated N-acylpyr-
roles display similar reactivity to R,ꢀ-unsaturated ketones8
and undergo arylation, epoxidation, amination, and cyanation
reactions.9 To the best of our knowledge, however, neither
catalytic nor reagent-controlled conjugate allylation reactions
of N-acylpyrroles have been reported.
(Table 1). In the absence of catalyst, no reaction occurs.
Catalyst 3, which is ligated by a bidentate NHC-phosphine,
is unique in affording a significant yield of the desired
product (entry 4). Other palladium complexes, including
complexes 1 and 2, containing alternative bidentate NHC
ligands, afford <10% yield of the desired product.
We reasoned that allylpalladium complexes 1-3 would
catalyze allylation reactions of enoate derivatives. Our prior
studies have demonstrated that the bidentate N-heterocyclic
carbene (NHC) ligands in complexes 1-3 impart nucleo-
philicity to the Pd-bound allyl groups.10,11 These complexes
undergo stoichiometric reactions with aldehydes and catalyze
allylstannylation of aldehydes. In contrast, allylpalladium
complex 4, ligated by a monodentate NHC ligand, does not
react with aldehydes.
Figure 1. NHC-ligated allylpalladium complexes 1-4.
We examined allylation of N-acylpyrrole 5a by the pinacol
ester of allylboronic acid using palladium complexes 1-4
A screen of solvents and alcohols demonstrated that a
combination of dioxane and tert-amyl alcohol afforded the
highest yield of allylation product 6a. The use of tert-amyl
alcohol suppressed formation of ester byproducts resulting
from alkoxide attack on the N-acylpyrrole.12 A variety of
bases were screened, and potassium tert-butoxide gave the
highest yields of product. Lithium tert-butoxide or an
inorganic base such K2CO3 or K3PO4 had a detrimental effect
on the yield. Increasing the quantity of boronic ester to 5
equiv provided the highest yield of product, affording 71%
yield of N-acylpyrrole 6a.13
(7) (a) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem., Int. Ed.
2002, 41, 3188–3191. (b) Lee, S. D.; Brook, M. A.; Chan, T. H. Tetrahedron
Lett. 1983, 24, 1569–1572.
(8) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M.
J. Am. Chem. Soc. 2004, 126, 7559–7570.
(9) Arylation: (a) Shintani, R.; Kimura, T.; Hayashi, T. J. Chem. Soc.,
Chem. Commun. 2005, 321, 3–3214. (b) Arai, Y.; Kasai, M.; Ueda, K.;
Masaki, Y. Synthesis 2003, 151, 1–1516. Epoxidation: ref 3 and (c)
Kinoshita, T.; Okada, S.; Park, R.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2003, 42, 4680–4684. Amination: (d) Yamagiwa, N.; Qin,
H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419.
Cyanation: (e) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 514–515.
(10) Barczak, N. T.; Grote, R. E.; Jarvo, E. R. Organometallics 2007,
26, 4863–4865
.
(11) For a recent review of catalysis by nucleophilic allylpalladium
(12) These byproducts were formed in approximately 10% yield when
t-BuOH was employed. The use of more sterically encumbered alcohols,
e.g., trityl alcohol or 1-adamantanol, did not improve the yield further.
complexes, see: Zanoni, G.; Pontiroli, A.; Marchetti, A.; Vidari, G. Eur. J.
Org. Chem. 2007, 359, 9–3611
.
4744
Org. Lett., Vol. 10, No. 21, 2008

A variety of N-acylpyrroles with aromatic substituents at
the ꢀ-position reacted smoothly under these reaction condi-
tions (Table 2). Electron-deficient substrates afforded prod-
(eq 1). Regioselective conjugate addition occurs to afford
product 8 in 75% yield. Products resulting from ketone allylation
comprised less than 10% of the unpurified reaction mixture.
Table 2. Allylation Reactions of N-Acylpyrrolesa
We propose that the mechanism of the reaction proceeds
according to the mechanism shown in Scheme 1. The η1-
Scheme 1. Proposed Mechanism
a Reaction conditions A: tert-amyl alcohol (3 equiv). Reaction conditions
B: t-BuOH (1.1 equiv). See the Supporting Information for full details.
b Isolated yield after column chromatography. c Starting material 5i was
recovered in near-quantitative yield.
and η3-allylpalladium complexes are in equilibrium under
the reaction conditions. We hypothesize, based on our prior
studies of stoichiometric allylation reactions, that the η1-
allylpalladium complex attacks the N-acylpyrrole to initiate
the catalytic cycle.10 The palladium-bound enolate may be
protonated by tert-butyl alcohol to generate a palladium
alkoxide. The catalyst is subsequently regenerated by trans-
metalation, in analogy to related palladium-catalyzed ally-
lation reactions of imines and aldehydes.16
ucts in the highest yields, and for these substrates 2 equiv
of the allyl boronic ester was sufficient to obtain acceptable
yields (cf. entries 2 and 3, 9 and 10). A variety of functional
groups, including cyano, carbethoxy, and pyridine, were
tolerated (entries 7, 8, and 11). Substrates 5d and 5g,
containing aryl bromides, underwent facile conjugate addition
with no competitive side reactions.14 N-Acylpyrroles with
electron-rich aromatic and aliphatic substitutents reacted more
slowly and in lower yields.15 Reactions were generally clean,
however, and near-quantitative recovery of unreacted R,ꢀ-
unsaturated N-acylpyrrole was possible. For most substrates,
tert-amyl alcohol and t-BuOH could be used interchangeably
(reaction conditions A and B, respectively, Table 2). For
certain substrates, however, use of tert-amyl alcohol provided
a modest increase in yield (cf. entries 4 and 5).
To test for this mechanism, we examined the reaction of
deuterated allylboronic ester 9,17,18 for which equilibration
between η1- and η3-allylpalladium complexes would scramble
the deuterium label (eq 2). Treatment of substrate 5c with 9
The chemoselectivity of the allylation was examined by
subjecting substrate 7, containing both an R,ꢀ-unsaturated
N-acylpyrrole and a ketone, to our standard reaction conditions
(13) Competitive decomposition pathways consume allylB(pin) to afford,
for example, 1,5-hexadiene.
(14) Aryl chlorides and fluorides react to afford products in lower yields,
e.g., p-chlorophenyl-substituted N-acylpyrrole [(2E)-3-(4-chlorophenyl)-1-
pyrrol-1-yl-2-propene-1-one] affords 32% yield of allylation product under
conditions A. The cause of this effect is under investigation.
under our reaction conditions afforded a 1.1:1 mixture of
products 10a and 10b, consistent with the proposed mech-
anism. An alternative mechanism,19 involving Lewis acid
catalysis by the palladium complex and attack of an
Org. Lett., Vol. 10, No. 21, 2008
4745

allylboronate, would be regiospecific, affording only 10b,
and is not consistent with our observations.20
Acknowledgment. Support for this research has been
provided by the School of Physical Sciences of the University
of California, Irvine. Amgen and the Eli Lilly Foundation
are gratefully acknowledged for additional research support.
Dr. Phil Dennison is acknowledged for assistance with NMR
spectroscopic techniques, and Dr. John Greaves is acknowl-
edged for mass spectrometric data.
We report the palladium-catalyzed conjugate allylation
reactions of R,ꢀ-unsaturated N-acylpyrroles. Several func-
tional groups, including bromo, cyano, pyridyl, and carbonyl
groups, are tolerated. Mechanistic experiments are consistent
with catalysis by nucleophilic allylpalladium complexes.
Current studies include expanding the scope of the reaction,
developing an enantioselective variant of the reaction and
further mechanistic studies.
Supporting Information Available: Experimental details
and spectroscopic and analytical data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For example, p-methoxyphenyl-substituted N-acylpyrrole [(2E)-3-(4-
methoxyphenyl)-1-pyrrol-1-yl-2-propene-1-one] affords 13% of allylated prod-
uct and 80% recovered starting material under reaction conditions A.
(16) (a) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc.
1996, 118, 6641–6647. (b) Solin, N.; Kjellgren, J.; Szabo´, K. J. J. Am.
Chem. Soc. 2004, 126, 7026–7033.
OL801830H
(17) Morken and co-workers have demonstrated that Pd-catalyzed
allylation of a dialkylidene ketone with 9 provides a single product, due to
rapid reductive elimination of a σ-allyl-π-allylpalladium intermediate. See
ref 5b.
(18) Palladium-catalyzed crotylation reactions of imines are regioselec-
tive and not regiospecific, consistent with rapid isomerization of crotylpal-
ladium intermediates. See: Nakamura, K.; Nakamura, H.; Yamamoto, Y.
J. Org. Chem. 1999, 64, 2614–2615. Crotylation of acylpyrrole 5c under
our current reaction conditions is prohibitively slow, unfortunately.
(19) Piechaczyk, O.; Cantat, T.; Me´zailles, N.; Le Floch, P. J. Org.
Chem. 2007, 72, 4228–4237.
(20) Isomerization of 9 followed by Lewis acid catalysis of allylation
has been ruled out by performing the following control experiment: a
mixture of 9, catalyst 3, t-BuOK, and t-BuOH in dioxane was monitored
2
by H NMR spectroscopy. No isomerization was observed, and 9 decom-
poses under these conditions.
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Org. Lett., Vol. 10, No. 21, 2008