Ligand- and base-free Pd(II)-catalyzed controlled switching between oxidative heck and conjugate addition reactions

Article abstract of DOI:10.1021/ol400539h

A simple change of solvent allows controlled and efficient switching between oxidative Heck and conjugate addition reactions on cyclic Michael acceptor substrates, catalyzed by a cationic Pd(II) catalyst system. Both reactions are ligand- and base-free and tolerant of air and moisture, and the controlled switching sheds light on some of the factors which favor one reaction over the other.

Full text of DOI:10.1021/ol400539h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ligand- and Base-Free Pd(II)-Catalyzed
Controlled Switching between Oxidative
Heck and Conjugate Addition Reactions
Sarah E. Walker, Julian Boehnke, Pauline E. Glen, Steven Levey, Lisa Patrick,
James A. Jordan-Hore, and Ai-Lan Lee*
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh,
EH14 4AS Scotland, United Kingdom
A.Lee@hw.ac.uk
Received February 26, 2013
ABSTRACT
A simple change of solvent allows controlled and efficient switching between oxidative Heck and conjugate addition reactions on cyclic Michael
acceptor substrates, catalyzed by a cationic Pd(II) catalyst system. Both reactions are ligand- and base-free and tolerant of air and moisture, and
the controlled switching sheds light on some of the factors which favor one reaction over the other.
The Pd(0)-catalyzed MizorokiꢀHeck reaction is one of
the most widely used CꢀC bond forming reactions in
organic synthesis.1 However, Pd(0)-catalyzed Heck condi-
tions generally do not work as well with cyclic enones due
to the tendency to form conjugate addition products
instead, as well as being stereochemically precluded from
undergoing the final step in the traditional Heck cycle: the
syn β-H elimination.2 In recent years, the Pd(II)-catalyzed
boron oxidative Heck reaction3 has emerged as a promis-
ing new method which enables Heck-type couplings on
cyclic systems. Generally, a ligand, base, or both are
required, and the reactions can be carried out under mild
conditions in air. Nevertheless, reports using cyclic enone
substrates are still rare,4 and obtaining either the oxidative
Heck or conjugate addition product selectively with cyclic
enones can still pose a challenge.5 Indeed, the conditions
utilized for Pd(II)-catalyzed conjugate addition reac-
tions6,7 can often appear quite similar to the oxidative
Heck conditions, prompting us to question the factors
which might favor one reaction over its competitor. As far
asweareaware, there are no reportedstudies on the Pd(II)-
catalyzed switching between oxidative Heck and conjugate
addition reactions8,9 or reports on factors which might
influence the formation of one product over the other.
(1) Review on Pd-catalysis: Tsuji, J. Palladium Reagents and Cata-
lysts: New Perspectives for the 21st Century, 2nd ed.; John Wiley & Sons:
Chichester, U.K., 2004.
(2) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(3) Review: (a) Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan,
P. F.; Esfahani, F. K.; Zamani, A. Synthesis 2010, 1399. Selected papers:
(b) Cho, C. S.; Uemura, S. J. Organomet. Chem. 1994, 465, 85. (c) Du, X.;
Suguro, M.; Hirabayashi, K.; Mori, A. Org. Lett. 2001, 3, 3313. (d) Inoue,
A.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 1484.
(e) Andappan, M. M. S.; Nilsson, P.; Von Schenck, H.; Larhed, M.
J. Org. Chem. 2004, 69, 5212. (f) Andappan, M. M. S.; Nilsson, P.; Larhed,
M. Chem. Commun. 2004, 218. (g) Delcamp, J. H.; Brucks, A. P.; White,
M. C. J. Am. Chem. Soc. 2008, 130, 11270. (h) Zheng, C.; Wang, D.; Stahl,
S. S. J. Am. Chem. Soc. 2012, 134, 16496. (i) Werner, E. W.; Sigman, M. S.
J. Am. Chem. Soc. 2010, 132, 13981. (j) Jung, Y. C.; Mishra, R. K.; Yoon,
C. H.; Jung, K. W. Org. Lett. 2003, 5, 2231. (k) Su, Y.; Jiao, N. Org. Lett.
2009, 11, 2980. (l) Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S.;
O’Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933. (m) Yoo, K. S.; Yoon,
C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384. (n) Ruan, J.; Li, X.;
Saidi, O.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 2424. (o) Xiong, D.-C.;
Zhang, L. H.; Ye, X.-S. Org. Lett. 2009, 11, 1709. (p) Sun, P.; Zhu, Y.;
Yang, H.; Yan, H.; Lu, L.; Zhang, X.; Mao, J. Org. Biomol. Chem. 2012,
10, 4512. (q) He, Z.; Kirchberg, S.; Frohnlich, R.; Studer, A. Angew.
(4) For example, see: (a) Gottumukkala, A. L.; Teichert, J. F.;
Heijnen, D.; Eisink, N.; van Dijk, S.; Ferrer, C.; van den Hoogenband,
A.; Minnaard, A. J. J. Org. Chem. 2011, 76, 3498. (b) Li, Y.; Qi, Z.;
Wang, H.; Fu, X.; Duan, C. J. Org. Chem. 2012, 77, 2053 and ref 3m.
(5) For example, see: Yamamoto, T.; Iizuka, M.; Takenaka, H.;
Ohta, T.; Ito, Y. J. Organomet. Chem. 2009, 694, 1325.
(6) For reviews, see: (a) Gutnov, A. Eur. J. Org. Chem. 2008, 4547.
(b) Yamamoto, Y.; Nishikata, T.; Miyaura, N. Pure Appl. Chem. 2008,
80, 807. (c) Berthon, G.; Hayashi, T. Rhodium- and Palladium-
Catalyzed Asymmetric Conjugate Additions. In Catalytic Asymmetric
€
Chem., Int. Ed. 2012, 51, 3699. (r) Crowley, J. D.; Hanni, K. D.; Lee, A.-L.;
ꢀ
Conjugate Reactions; Cordova, A., Ed.; Wiley-VCH: Weinheim, 2010.
Leigh, D. A. J. Am. Chem. Soc. 2007, 129, 12092.
r
10.1021/ol400539h
XXXX American Chemical Society

We have recently reported a mild and ligand-free cation-
icPd(II)2þ systemfor diastereoselective conjugateaddition
reactions to sterically hindered cyclic enones.10 As part of
our ongoing studies to evaluate the utility of the new
ligand-free catalyst system, we were keen to address the
issue of competition between the oxidative Heck and
conjugate addition reactions on cyclic enones. Thus, our
aims were twofold: to successfully and efficiently control
switching between the two outcomes by changing a vari-
able in the reaction, thereby shedding some light on the
factors which influence the switching.
Table 1. Initial Studies: Conditions for Switching from
Pd(II)-Catalyzed Conjugate Addition to Oxidative Heck Reaction
entry
solvent
yield 3 (%)b
yield 4 (%)b
With the conjugate addition conditions for the forma-
tion of 3 already in hand (entry 1, Table 1), our investiga-
tions commenced with screening of reaction conditions to
switch the outcome fully to oxidative Heck product 4
(Table 1). An in situ method for generating the cationic
Pd(OTf)2 catalyst was used in this screen, utilizing
Pd(OAc)2 and TfOH. Pleasingly, a clear shift toward the
oxidative Heck product 4 is observed upon adoption of
more polar solvents, although conversions are poor
(entries 2ꢀ9). Finally, DMSO was found to change
the outcome of the reaction successfully to favor only 4
(entry 9). Warming to 50 °C pushed the reaction to
completion, yielding 4 in a good 84% yield, thereby
successfully obtaining a complete switch in reactivity from
conjugate addition 3 (entry 1) to oxidative Heck 4 (entry 10)
by a simple change of solvent (ClCH2CH2Cl to DMSO).
With these pleasing results in hand, substitution around
the cyclohexenone core was investigated next (Table 2,
entries 3ꢀ8). 6-Substituted cyclohexenone 5 undergoes the
conjugate addition (entry 3) as well as oxidative Heck
reactions smoothly (entry 4). 5-Substituted cyclohexenone 8
undergoes conjugate addition in good yield (75%, entry 5),
but an oxidative Heck reaction under the usual conditions
1
ClCH2CH2Cl
ClCH2CH2Cl þ
DMF (4 equiv)
DMF
94c
ꢀ
2
79c
20c
3
ꢀ
trace
14
4
acetone
ꢀ
5
MeCN
DMAd
trace
trace
ꢀ
trace
trace
4
6
7
MeOH
NMPe
8
12
ꢀ
4
9
10f
DMSO
33c
84c
DMSO
ꢀ
a Commercial arylboronic acid was heated under vacuum to generate
boroxine. b Determined by H NMR analysis of crude mixture, unless
1
otherwise stated. c Isolated yield. d Dimethyl acetamide. e N-Methylpyr-
rolidone. f 50 °C, 48 h.
produced a poor 25% conversion. Fortunately, reversing
the stoichiometry (from 1:2 8/2 to 3:1 8/2) and setting the
temperature at 70 °C successfully promotes the oxidative
Heck reaction (60%, entry 6). Moving the substituent
even closer to the reactive alkene (11) does not hinder the
conjugate addition, but clearly slows down the oxidative
Heck reaction (entries 7ꢀ8). With the latter, dimerization
of the arylboroxine becomes competitive, resulting in only
a low conversion to the desired 13. This is perhaps un-
surprising as γ-substituted cyclohexenones are notoriously
difficult substrates for any Heck-type reaction.2
Next, more electron-rich alkene substrates were evalu-
ated (entries 9ꢀ14). With these systems, it was found that
the premade cationic catalyst (MeCN)4Pd(OTf)2 (B) often
performs better. Thus, the switching from conjugate addi-
tion to oxidative Heck reaction proceeds smoothly with
lactone 14 (entries 9ꢀ10). Dihydropyridones11 17 and 20
also switch between the two reactions smoothly, although
the oxidative Heck reaction does require portionwise
addition of the catalyst and 2a to push the reaction to
completion (entries 11ꢀ14). Changing the ring size from
six-membered systems to five-membered cyclopentenone 23
results in a smooth conjugate addition reaction (entry 15),
but surprisingly, switching to an oxidative Heck reaction in
DMSO is now no longer as efficient (1:1 24/25, entry 16).
Having explored the alkene substrate scope, we turned
our attention to the arylboroxine scope (Table 3). Premade
(MeCN)4Pd(OTf)2 catalyst was found to be more general
for the range of arylboroxines studied and was thus
employed inthe general procedure. Theconjugateaddition
(7) For selected Pd(II)-catalyzed conjugate additions, see: (a)
Gottumukkala, A. L.; Matcha, K.; Lutz, M.; de Vries, J. G.; Minnaard,
A. J. Chem.;Eur. J. 2012, 18, 6907. (b) Lan, Y.; Houk, K. N. J. Org.
Chem. 2011, 76, 4905. (c) Kikushima, K.; Holder, J. C.; Gatti, M.; Stolz,
B. M. J. Am. Chem. Soc. 2011, 133, 6902. (d) Brozek, L. A.; Sieber, J. D.;
Morken, J. P. Org. Lett. 2011, 13, 995. (e) Lin, S.; Lu, X. Org. Lett. 2010,
12, 2536. (f) Xu, Q.; Zhang, R.; Zhang, T.; Shi, M. J. Org. Chem. 2010,
75, 3935. (g) Lin, S.; Lu, X. Tetrahedron Lett. 2006, 47, 7167.
(h) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Lett. 2007, 36,
1442. (i) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Adv. Synth. Catal.
2007, 349, 1759. (j) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651. (k) Gini,
F.; Hessen, B.; Minaard, A. J. Org. Lett. 2005, 7, 5309. (l) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Organometallics 2004, 23, 4317. (m)
Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int. Ed.
2003, 42, 2768.
(8) In contrast, there are several investigations on the Rh-catalyzed
counterparts. For example, for cyclic alkene substrates, see: (a) Kuuloja,
ꢀ
N.; Vaismaa, M.; Franzen, R. Tetrahedron 2012, 68, 2313. Acyclic:
(b) Zou, G.; Guo, J.; Wang, Z.; Huang, W.; Tang, J. Dalton Trans. 2007,
3055. (c) Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K.
€
€
J. Am. Chem. Soc. 2001, 123, 10774. (d) Noel, T.; Gok, Y.; Van der
Eycken, J. Tetrahedron: Asymmetry 2010, 21, 540. (e) Amengual, R.;
^
Michelet, V.; Genet, J.-P. Tetrahedron Lett. 2002, 43, 5905. (f) Zou, G.;
Wang, Z.; Zhu, J.; Tang, J. Chem. Commun. 2003, 2438.
(9) For a related, but mechanistically distinct, study using aryl iodide
substrates and Pd(0)-catalysis to switch between Pd(0) MizorokiꢀHeck
and conjugate additions, see: (a) Gottumukkala, A. L.; de Vries, J. G.;
Minnaard, A. J. Chem.;Eur. J. 2011, 17, 3091 and references cited
therein. See also: (b) Fall, Y.; Doucet, H.; Santelli, M. Tetrahedron 2009,
65, 489. Intramolecular Pd(0): (c) Friestad, G. K.; Branchaud, B. P
Tetrahedron Lett. 1995, 36, 7047.
(10) Jordan-Hore, J. A.; Sanderson, J. N.; Lee, A.-L. Org. Lett. 2012,
14, 2508.
(11) For conjugate additions to dihydropyridones see: Xu, Q.;
Zhang, R.; Zhang, T.; Shi, M. J. Org. Chem. 2010, 75, 3935.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Alkene Substrate Scope
Table 3. Arylboroxine/Boronic Acid Scope
entry
aryl
cond.
yield (%)c
3b 77
1
Ph
X
X
X
X
X
X
X
X
X
X
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Yh
Ye
2
p-HOC6H4
m-MeC6H4
o-MeC6H4
2-naphthalene
2-fluorene
m-ClC6H4
m-MeO2CC6H4
m-O2NC6H4
p-BrC6H4
3c 67
3d 68
3e 76
3f 84
3
4
5
6
3g 51
3h 82
3i 75
7
8
9
3j 59
10d
11e
12e
13
14
15
16
17
18
19
20
21
22
3k 71
4b 68
4c 60
4d 66
4e 57
4f 68
4g 48f
4h 53g
4i 43g
4j 50% convg
4k 24g
4d 66
4d 46
Ph
p-HOC6H4
m-MeC6H4
o-MeC6H4
2-naphthalene
2-fluorene
m-ClC6H4
m-MeO2CC6H4
m-O2NC6H4
p-BrC6H4
m-MeC6H4
m-MeC6H4
a Commercial boronic acid was heated under vacuum to generate
boroxine. 2 equiv used. NaNO3 (2 equiv) added.10 b Arylboronic acid
recrystallized from water. 2 ꢁ 2 equiv used. c Isolated yield. d O2 atm.
e Arylboroxine used. f 34% 3g also isolated. g Three portions of 5 mol %
catalyst. h Commercial arylboronic acid þ water (1.5 equiv).
portionwise addition of the catalyst (2 ꢁ 5 mol %) and
arylboroxine (2ꢁ 2equiv) improved theyields for Ar= Ph
and p-HOC6H4 (entries 11ꢀ12). However, the conversions
were still low for other aryls (e.g., entry 22). At this point,
we discovered that while the conjugate addition reactions
require arylboroxines (formed by heating commercial
“boronic acid” under vacuum),10 the oxidative Heck reac-
tion behaves in the opposite manner, performing better
when arylboronic acids (formed by recrystallization from
water) are used. This is presumably why the different aryls
behave differently when used straight out of a commercial
bottle, as they tend to lie on different ends of the arylboro-
nic acid/boroxine equilibrium12 and may also hydrate at
different rates in the DMSO solution. Thus, using freshly
recrystallized arylboronic acids and optimized general
conditions Y, the oxidative Heck was successfully carried
out using a range of aryls: o-, m-, and p-substitutions
(entries 13ꢀ18) as well as electron-donating (entries
12ꢀ14), polycyclic aromatic (entries 15ꢀ16), and electron-
withdrawing groups (entries 17ꢀ18). Of these, only the
a Isolated yield. b 0.33 equiv of 2a. c NaNO3 added (1ꢀ2 equiv).10 d
equiv of 2a. e 10 þ 5 mol % cat., 2 þ 0.5 equiv of 2a.
3
reaction to form 3aꢀ3j progressed smoothly for a range of
aryls, including those that were electron-rich, electron-
poor, and para-, meta-, and ortho-substituted (entries
1ꢀ10). Even easily oxidizable 2-fluorene performs reason-
ably well (entry 6).
The oxidative Heck reaction, however, proved more
challenging and was initially hampered by poor or incom-
plete conversions. After optimization, we found that
(12) Korich, A. L.; Iovine, P. M. Dalton Trans. 2010, 39, 1423.
Org. Lett., Vol. XX, No. XX, XXXX
C

large 2-fluorene reaction struggled to produce an efficient
switch (48% 4g, 34% of 3g, entry 16). Reactions with
m-O2NC6H4 and p-BrC6H4 did not proceed to full con-
version; in these two cases ArꢀAr homocoupling domi-
nates (entries 19ꢀ20). Finally, we found that using
commercial “arylboronic acid” straight from the bottle,
but with 1.5 equiv of water added to the reaction (which
presumably generates arylboronic acid in situ), performs
just as well as using freshly recrystallized arylboronic acid
(entry 21 vs 13) and far better than with arylboroxine
(entry 22).
DMSO must be stabilizing the cationic Pd center [see
Supporting Information for (DMSO)4Pd(OTf)2 crystal
structure],14 and possibly affecting the equilibrium be-
tween I, II, and I0. Second, since syn β-H elimination is
not possible in cyclic intermediates such as I, it is usually
assumed that epimerization of the R-C in I via enolization
to form I0 must take place in order to allow for the syn-β-H
elimination required to form the oxidative Heck product.
Following this argument, the use of polar and relatively
basic DMSO solvent15 must be facilitating the epimeriza-
tion (IfI0) compared to nonpolar ClCH2CH2Cl.16
A third possibility is that the DMSO conditions allow a
conjugate addition followed by oxidation,17 rather than a
true oxidative Heck reaction. To rule out this possibility, a
control reaction was carried out whereby the conjugate
addition product 3a was subjected to the DMSO oxidative
Heck conditions. Only a trace of oxidative Heck prod-
uct 4a is formed after 2 days,18 confirming that 4a is not
formed via 3a and that the reactions in DMSO shown in
Tables 1ꢀ3 are true oxidative Heck reactions.
Scheme 1. Proposed Mechanism of the Oxidative Heck and
Conjugate Addition Reactions
In conclusion, we have developed an efficient way of
switching between oxidative Heck and conjugate addition
reactions on cyclic alkenes using a simple switch of solvent,
in a base- and ligand-free Pd(II)2þ system. In doing so, we
have discovered several important subtleties regarding the
competition between these two reactions. First, the con-
jugate addition requires arylboroxines whereas the oxida-
tive Heck reaction performs better with arylboronic acids
under our reaction conditions. Second, more polar sol-
vents promote the oxidative Heck reaction over conjugate
addition. We hope our studies shed some light onto the
often encountered, but rarely investigated, competition
between conjugate addition and oxidative Heck reactions
in Pd(II)-catalyzed systems, thus leading the way for more
selective reactions in the future.
The mechanism of the two reactions is thought to
diverge after the transmetalation and migratory insertion
steps (Scheme 1).13 Intermediate I can either undergo β-H
elimination to produce the oxidative Heck product or
protonolysis (either directly or more often described as
via Pd-enolate II) to produce the conjugate addition
product. In order to promote the oxidative Heck reaction
over conjugate addition, it is clear that the β-H elimination
must be facilitated. We thus propose that the solvent
switch from nonpolar ClCH2CH2Cl to polar DMSO
causes such a dramatic switch in the selectivity due to
two possible reasons. First, in our “ligand-free” cationic
Pd(II) conditions, the polar and more coordinating
Acknowledgment. We thank the Leverhulme Trust
(F/00 276/O), EPSRC (S.E.W.), Nuffield Undergraduate
Bursary (L.P.), and Erasmus (J.B.) for funding; EPSRC
NMSCC for analytical services; Johnson Matthey for
Pd(OAc)2; and Georgina M. Rosair (Heriot-Watt University)
for crystallography.
(13) See ref 6c, p 57.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and NMR spectra for all new
compounds; crystal structure of (DMSO)4Pd(OTf)2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) When 4 equiv of DMSO are added to (MeCN)4Pd(OTf)2,
(DMSO)4Pd(OTf)2 is produced, with 2 S-bound and 2 O-bound DMSO
(cis). This complex is catalytically active in the oxidative Heck reaction.
(15) Jessop, P. G. Green Chem. 2011, 13, 1391.
(16) When entry 10, Table 1 is carried out with the catalyst made
in situ in DMSO (40 mol %) and then diluted with ClCH2CH2Cl as the
solvent, the resulting poor 3.4:1 3/4 ratio implies that, for a full switch to
4, DMSO is also required as a solvent rather than simply for producing
(DMSO)4Pd(OTf)2.
(18) See Supporting Information for further details.
The authors declare no competing financial interest.
(17) Oxidation: Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133,
14566.
D
Org. Lett., Vol. XX, No. XX, XXXX