Highly regio- and stereoselective Heck reaction of allylic esters with arenediazonium salts: Application to the synthesis of kavalactones

Article abstract of DOI:10.1021/ol901416e

Image Presented A highly efficient palladium-catalyzed Heck reaction of allylic esters with arenediazonium salts is described. The reaction proceeds under mild conditions, with excellent to total regio- and stereochemical control and with retention of the traditional leaving group. Furthermore, the generality of the present methodology is illustrated by the short total synthesis of the natural kavalactones, yangonine, (±)-methysticin, and (±)-dihydromethysticin.

Full text of DOI:10.1021/ol901416e

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3642-3645
Highly Regio- and Stereoselective Heck
Reaction of Allylic Esters with
Arenediazonium Salts: Application to
the Synthesis of Kavalactones
Ange´lica Venturini Moro, Fla´vio Sega Pereira Cardoso,
and Carlos Roque Duarte Correia*
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP,
C.P. 6154, CEP. 13084-971, Campinas, Sa˜o Paulo, Brazil
roque@iqm.unicamp.br
Received June 22, 2009
ABSTRACT
A highly efficient palladium-catalyzed Heck reaction of allylic esters with arenediazonium salts is described. The reaction proceeds under mild
conditions, with excellent to total regio- and stereochemical control and with retention of the traditional leaving group. Furthermore, the
generality of the present methodology is illustrated by the short total synthesis of the natural kavalactones, yangonine, (()-methysticin, and
(()-dihydromethysticin.
The Heck arylation of olefins has been a powerful tool for
the efficient formation of Csp2-Csp2 bonds.1 When allylic
alcohols are used as substrates for the Heck arylation, a
problem with the regioselectivity arises leading to mixtures
of ꢀ and γ aryl allylic alcohols, together with the formation
of carbonyl products via isomerization of the allylic double
bond.2 In addition, the use of allylic esters poses additional
challenges since these are common substrates for the well-
known Tsuji-Trost reaction in which Pd(0) undergoes
oxidative addition to the allylic C-O bond followed by the
formation of a π-allyl palladium species.3 However, some
recent reports concerning the Heck reaction of allylic esters
have demonstrated selectivity in favor of the Heck products
when using aryl halides,4,5 boronic acids,6 or iodonium
salts.7
In this regard, it is worth mentioning the recent reports of
Jiao and co-workers which use aryl iodides and bromides in
the presence of AgCO3 at refluxing benzene for several
hours4 and the use of a very interesting oxidative Heck
(2) (a) Calo`, V.; Nacci, A.; Monopoli, A.; Ferola, V. J. Org. Chem.
2007, 72, 2596. (b) Bouquillon, S.; Ganchegui, B.; Estrine, B.; He´nin, F.;
Muzart, J. J. Organomet. Chem. 2001, 634, 153. (c) Ambrogio, I.; Cacchi,
S.; Fabrizi, G.; Goggiamani, A.; Sgalla, S. Synlett 2009, 620. (d) Zawisza,
A. M.; Ganchegui, B.; Gonza´lez, I.; Bouquillon, S.; Roglans, A.; He´nin,
F.; Muzart, J. J. Mol. Catal. A: Chem. 2008, 283, 140. (e) Liu, S.; Thomson,
N.; Pettman, A.; Hyder, Z.; Mo, J.; Xiao, J. J. Mol. Catal. A: Chem. 2008,
279, 210. (f) Batt, F.; Gozzi, C.; Fache, F. Chem. Commun. 2008, 5830.
(g) Scrivanti, A.; Bertoldini, M.; Beghetto, V.; Matteoli, U. Tetrahedron
2008, 64, 543. (h) Alacid, E.; Na´jera, C. AdV. Synth. Catal. 2007, 349,
2572. (i) Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2005,
1367. (j) Kang, S.; Lee, H.; Jang, S.; Kim, T.; Pyun, S. J. Org. Chem.
1996, 61, 2604. (k) Bernocchi, E.; Cacchi, S.; Ciattini, P. G.; Morera, E.;
Ortar, G. Tetrahedron Lett. 1992, 33, 3073. (l) Ono, K.; Fugami, K.; Tanaka,
S.; Tamaru, Y. Tetrahedron Lett. 1994, 35, 4133. (m) Jeffery, T. Tetrahedron
Lett. 1991, 32, 2121. (n) Masllorens, J.; Bouquillon, S.; Roglans, A.; He´nin,
F.; Muzart, J. J. Organomet. Chem. 2005, 690, 3822. (o) Barbero, M.;
Cadamuro, S.; Dughera, S. Synthesis 2006, 3443. (p) Cacchi, S.; Fabrizi,
G.; Goggiamani, A.; Sferrazza, A. Synlett 2009, 973. (q) Perez, R.; Veronese,
D.; Coelho, F.; Antunes, O. A. C. Tetrahedron Lett. 2006, 47, 1325. (r)
Sengupta, S.; Sadhukhan, S. K. Tetrahedron Lett. 1998, 39, 1237.
(3) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 106, 395.
(1) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(b) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61, 11771.
(c) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I. Ed.; Wiley-Interscience: New York, 2002. (d) Tsuji, J.
Palladium Reagents and Catalyst; Wiley: Chichester, U.K., 2004.
10.1021/ol901416e CCC: $40.75
Published on Web 07/28/2009
 2009 American Chemical Society

reaction with arylboronic acids to perform the regioselective
arylation of allylic esters.6b In spite of these important
advances by the Jiao group, their best results were obtained
with aryl iodides under relatively harsh conditions or, in the
case of the oxidative Heck arylations, with an excess of the
key allylic esters in a sealed tube and the presence of oxidants
and other additives in superstoichiometric amounts (AgOAc,
CuF2, and KHF2).
Scheme 1. Heck Arylation of Allyl Acetate 1a
Herein we present part of our ongoing research which uses
a very mild, operationally simple, and synthetically attractive
alternative for the highly stereo- and regioselective Heck
arylation of allylic esters employing arenediazonium salts.
This new Heck arylation protocol was also extended to a
vinylic lactonesa conformationally restricted “allylic ester”s
which was key to the efficient and straightforward synthesis
of yangonin, (()-methysticin, and (()-dihydromethysticin,
which constitute some of the major components of the kava
extracts.8 These syntheses illustrate the point that these new
Heck arylations of allylic esters can also be performed
without the assistance of the ester carbonyl, although more
vigorous conditions are needed in these cases.
With these initial results in hands, we decided to extend
the scope of the arylation reaction to other allylic esters as
well as to investigate a broader range of arenediazonium salts
with respect to their electronic nature. As shown in Table 1,
Table 1. Heck Arylation of Allylic Esters 1 with Diazonium
Salts 2
Among the several arylating agents available to perform
the Heck reaction, the arenediazonium salts offer consider-
able advantages over traditional electrophiles.9 They undergo
an extremely facile oxidative addition with Pd(0), operating
under “ligand-free” conditions to generate a highly reactive
cationic ArPd(II) species.10
We started our investigation of the Heck arylation with
allyl acetate 1a using optimal conditions described in our
recent work.11 This procedure uses the more complex
benzonitrile as solvent, Pd2(dba)3 as catalyst, and NaOAc
as base. Under these conditions, the Heck adduct 3a was
obtained in 88% yield, at room temperature after only 1 h,
with total regio- and stereochemical control in faVor the E
isomer (Scheme 1). The desired Heck adduct was obtained
with retention of the traditional leaving group, and no product
was observed from the usual π-allyl palladium pathway, the
so-called Tsuji-Trost reaction. Attempts at fine-tuning the
reaction parameters such as lowering the amount of pal-
ladium from 4 to 2 mol % and changing the solvent from
PhCN to MeCN resulted in decreased yields.
entry
R1
R2
product yield (%)
1
2
3
4
5
6
7
8
H
4-OMe
4-OMe
4-OMe
H
3a, 88
3b, 68
3c, 95
3d, 88
3e, 96
3f, 96
3g, 92
3h, 95
3i, 93
3j, 89
3k, 95
3l, 92
3m, 85
3n, 93
n-Bu
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
4-Me
2-naphthyl
3,4-(OMe)2
4-F
9
4-Cl
4-Br
4-I
3-NO2
10
11
12
13
14
2-OMe
3,4-(-OCH2O-)
a variety of substitution patterns are tolerated in the arene-
diazonium salts. Both electron-rich and electron-poor are-
nediazonium salts furnish the desired products in high yields.
Halogen substituents are also well tolerated under the reaction
conditions, and it is particularly important to mention that
4-iodobenzenediazonium tetrafluoroborate underwent selec-
tive oxidative addition at the C-N2 bond, yielding the iodine-
containing product 3k in isolated high yields.
In all cases, the reactions proceeded within 1 h, at room
temperature, with the Heck adducts formed with complete
regiochemical control, with C-C bond formation exclusively
at the terminal position of the double bond. Additionally,
the arylation process is highly stereoselective, providing the
E isomer as the only observable product. The only exception
was the more congested 2-methoxybenzenediazonium salt
(entry 13), providing the E Heck adduct together with the Z
stereoisomer and the product of internal arylation in a ratio
of 30:1:1.
(4) Pan, D.; Chen, A.; Su.; Zhou, W.; Li, S.; Jia, W.; Xiao, J.; Liu, Q.;
Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2008, 47, 4729.
(5) For Heck arylations followed by ꢀ-acetoxy elimination, see: (a)
Mariampillai, B.; Herse, C.; Lautens, M. Org. Lett. 2005, 7, 4745. (b)
Lautens, M.; Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005, 127, 72.
(6) (a) Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128,
15076. (b) Su, Y.; Jiao, N. Org. Lett. 2009, 11, 2980.
(7) Aydin, J.; Larsson, J. M.; Selander, N.; Szabo´, K. J. Org. Lett. 2009,
11, 2852.
(8) (a) Bilia, A. R.; Scalise, L.; Bergonzi, M. C.; Vincieri, F. F.
J. Chromatogr. B 2004, 812, 203. (b) Coˆte´, C. S.; Kor, C.; Cohen, J.;
Auclair, K. Biochem. Biophys. Res. Commun. 2004, 322, 147.
(9) Roglans, A.; Pla-Quitana, A.; Moreno-Manas, M. Chem. ReV. 2006,
106, 4622.
(10) (a) Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia,
C. R. D. Org. Lett. 2003, 5, 305. (b) Meira, P. R. R.; Moro, A. V.; Correia,
C. R. D. Synthesis 2007, 2279. (c) Burtoloso, A. C. B.; Garcia, A. L. L.;
Miranda, K. C.; Correia, C. R. D. Synlett 2006, 3145. (d) Pastre, J. C.;
Correia, C. R. D. Org. Lett. 2006, 8, 1657. (e) da Silva, K. P.; Godoi, M. N.;
Correia, C. R. D. Org. Lett. 2007, 9, 2815. For other Pd pre-catalysts
operating under ligand-free conditions, see: Gruber, A. S.; Pozebon, D.;
Monteiro, A. L.; Dupont, J. Tetrahedron Lett. 2001, 42, 7345.
(11) Moro, A. V.; Cardoso, F. S. P.; Correia, C. R. D. Tetrahedron Lett.
2008, 49, 5668.
The nature of the electrofuge group on the allylic moiety
is an important aspect of this reaction. When the acetate
Org. Lett., Vol. 11, No. 16, 2009
3643

group was replaced by the trifluoroacetate no Heck adduct
was obtained. In this specific case, we believe that the π-allyl
palladium complex is probably formed, which in the absence
of a suitable nucleophile halts the catalytic cycle, leading to
decomposition of the active palladium species (Scheme 2).
arylation of the lactone 4, which is structurally related to the
allylic esters investigated, except for its cyclic nature. Besides
putting the new methodology to a considerable new challenge,
such an investigation might shed some light on the actual
participation of the ester carbonyl during Heck arylation and
its potential limitations. Moreover, an efficient arylation of this
cyclic substrate is synthetically relevant, since this can provide
advanced intermediates in the total synthesis of the kavalactone
natural products such as yangonine and methysticin.12 Yango-
nine is a major component of the kava extracts that is reported
to display biological activities such as anxiolytic, sedative, anti-
inflammatory, and analgesic.13
Scheme 2
Applying the conditions depicted in Table 1 to the olefin 4,
the Heck arylation product was obtained in only 30% isolated
yield, thus confirming, at least in part, the ancillary participation
of the carbonyl group in the Heck process. Due to the decreased
reactivity of this unsaturated lactone under those conditions, a
larger screening of the reaction parameters was necessary.
Therefore, different palladium catalysts, solvents, and micro-
wave heating were evaluated as depicted in Table 2.
The putative catalytic cycle proposed for the Heck
arylation of allylic esters with arenediazonium tetrafluorobo-
rates is shown in Scheme 3 and parallels the one described
recently by Jiao and co-workers.4 Oxidative addition of the
Pd(0) species into the C-N2 bond occur with exclusion of
nitrogen to produce a cationic palladium species B. This
arenepalladium intermediate then coordinates to the olefin
and to the acetate carbonyl oxygen. The insertion of the aryl
group to the γ-position is favored by steric reasons as well
as by the formation of a chelated struture D. Such an
arrangement probably explains the high regioselectivity
observed during the migratory insertion. In this step, the aryl
group is transferred to the terminal carbon while the cationic
palladium stays complexed to the oxygen of the ester group.
This structure hinders a syn-relationship between the pal-
ladium and the hydrogen atom on the carbon bearing the
ester group, therefore favoring ꢀ-elimination with the ben-
zylic hydrogen atom.2a Thus, subsequent rotation of the C-C
bond occurs to minimize steric interaction followed by ꢀ-H
elimination to give the corresponding Heck adduct and the
cationic hydropalladium species F. Coordination of cationic
palladium in a six-membered ring at species E prevents the
ꢀ-elimination of the hydrogen next to the alcoholic oxygen
of the ester group. Neutralization of the hydropalladium by
sodium acetate (the reductive elimination step) regenerates
the Pd(0), which reinitiates the catalytic cycle.
Table 2. Screening of the Reaction Conditions for the Heck
Arylation of Olefin 4 with Arenediazonium 2a
entry
Pd cat.
solvent
PhCN
25
MeOH 80
PhCN
PhCN
MeCN 80 (Mw)
80 (Mw)
T (°C)
25
time (h) yield (%)
1
Pd2(dba)3
Pd(OAc)2/CO PhCN
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
12
12
12
5
30
20
nr
68
85
60
41
2
3a
4
80
80 (Mw)
5
6
7
0.5
0.5
0.5
Pd(OAc)2/CO PhCN
a Reaction performed without NaOAc.
Motivated by the success of the Heck arylation of allylic
esters under mild conditions, we turned our attention to the
Changing the Pd precatalyst to Pd(OAc)2/CO or Pd(OAc)2
did not result in yield improvements. However, when the
Scheme 3. Proposed Catalytic Cycle
3644
Org. Lett., Vol. 11, No. 16, 2009

Heck arylation reaction was performed with Pd2(dba)3 in
PhCN at 80 °C the desired Heck adduct was obtained in an
improved 68% yield after 5 h. Further increases in yields
were obtained by performing the Heck reaction under
microwave heating. The Heck adduct 5 was obtained in 85%
isolated yield after 30 min.
Scheme 5. Synthesis of Methysticin and Dihydromethysticin
With the Heck adduct 5 available, the synthesis of
yangonine 6 was completed by a straighforward oxidation
with DDQ in benzene as previously described in the
literature12 (Scheme 4).
Scheme 4. Completion of the Synthesis of Yangonine
total synthesis of natural kavalactones, yangonine, (()-
methysticin, and (()-dihydromethysticin. In these syntheses,
more vigorous conditions were required for the arylation
Heck reaction of a vinylic lactone, a conformationally
restricted “allylic ester”. These results suggest that a con-
formationally mobile ester group has indeed some participa-
tion in the Heck arylation process, mainly directing the
regiochemistry of the arylation during the migratory insertion
in the acyclic system, but it is not a requirement for obtaining
an effective reaction.
Finally, to extend the scope of the methodology we also
accomplished the concise total synthesis of (()-methysticin
and (()-dihydromethysticin by Heck arylation of olefin 4
with the arenediazonium salt 2n. Under the same conditions
employed for the synthesis of the yangonine precursor, except
for the higher temperature, (()-methysticin was obtained in
59% isolated yield (95% based on recovered starting ma-
terial). Regioselective catalytic hydrogenation of the exocy-
clic double bond of methysticin allowed the synthesis of (()-
dihydromethysticin in 95% yield from methysticin (Scheme
5).
In summary, we describe herein a very efficient, mild, and
operationally simple Heck arylation of allylic esters employ-
ing arenediazonium salts under palladium catalysis. The Heck
reaction proceeds with excellent to total regio- and stereo-
chemical control, affording the corresponding arylated allylic
esters in high yields and with complete retention of the
traditional leaving group. Furthermore, the present methodol-
ogy was successfully applied to a conformationally restricted
analogue, the vinyl lactone 4, thus permitting the concise
Acknowledgment. We thank FAPESP and CNPq for
financial support and fellowships (Fapesp 05/05150-4 to
A.V.M., 07/03033-6 to F.S.P.C., and CNPq 308320/2006-9
to C.R.D.C.).
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901416E
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Gallori, S.; Vincieri, F. F. Life Sci. 2002, 70, 2581.
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3645