Development of an anomalous heck reaction: Skeletal rearrangement of divinyl and enyne carbinols

Article abstract of DOI:10.1021/ol052382p

(Chemical Equation Presented) A general set of conditions that achieves the union of aryl halides and divinyl or enyne carbinols to afford tri- or tetrasubstituted olefins in good yields (up to 83%) is described. The mechanism by which this proceeds is believed to involve the intermediacy of a cyclopropanol, followed by a novel skeletal reorganization. The ability to suppress β-hydride elimination of organopalladium intermediates appears to be critical to the success of these processes.

Full text of DOI:10.1021/ol052382p

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5845-5848
Development of an Anomalous Heck
Reaction: Skeletal Rearrangement of
Divinyl and Enyne Carbinols
J. Maina Ndungu, Kimberly K. Larson, and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received October 3, 2005
ABSTRACT
A general set of conditions that achieves the union of aryl halides and divinyl or enyne carbinols to afford tri- or tetrasubstituted olefins in
good yields (up to 83%) is described. The mechanism by which this proceeds is believed to involve the intermediacy of a cyclopropanol,
followed by a novel skeletal reorganization. The ability to suppress
critical to the success of these processes.
â
-hydride elimination of organopalladium intermediates appears to be
The formation of carbon-carbon bonds is of fundamental
importance in the synthesis of complex organic molecules.
Among the metal-catalyzed methods available for C-C bond
construction, the Heck reaction is arguably one of the most
useful because it employs relatively stable and easily
accessible starting materials.1 As part of a general synthetic
program aimed at the facile construction of seven-membered
ring containing compounds (e.g., 3, Scheme 1), we became
reaction that employed ditriflate 1 and divinyl carbinols (e.g.,
2) for this purpose. Surprisingly, a complex mixture, which
included enal and bisenal products (4 and 5, respectively),
was realized under standard Heck reaction conditions
employing PdCl2(PPh3)2 (3 mol %) and Hu¨nig’s base (3
equiv) at 80 °C with DMF as solvent.
We decided to pursue this transformation further with the
aim of developing a wide-ranging and high-yielding method
as well as added insight into the mechanism of this novel
rearrangement. However, the reaction of 2 with a variety of
simple aryl halides and triflates was found not to be general,
as these predominantly formed the standard Heck products.
Perusal of the literature revealed a single, isolated example
of this reaction reported by Gribble as part of a study of the
Pd-mediated synthesis of 3-vinyl and 3- alkynyl indoles.3
Scheme 1
(1) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley and Sons: Hoboken,
2002; Vol. 1, pp 1133-1178.
(2) (a) Scott, W. J.; Pen˜a, M. R.; Swa¨rd, K.; Stoessel, S. J.; Stille, J. K.
J. Org. Chem. 1985, 50, 2302-2308. (b) Cacchi, S.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1984, 25, 2271-2274.
(3) Gribble, G. W.; Conway, S. C. Synth. Commun. 1992, 22, 2129-
2141.
interested in utilizing a Stille-Ortar variant2 of the Heck
10.1021/ol052382p CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/25/2005

In our hands, the reaction of 3-indolyl triflate with 2 under
the conditions reported by Gribble proceeded in only 35%
isolated yield, prompting further study.
in a complete recovery of starting material (entry 2). This
result points to the importance of Hu¨nig’s base, likely by
initial reduction of the Pd(II) complex to the active Pd(0)
catalyst, in initiating oxidative addition.7 Recently, bis(tri-
tert-butylphosphine)palladium(0) has emerged as an effective
catalyst for C-C bond formation involving saturated cou-
pling partners due in part to the stability of the organopal-
ladium intermediates in these coupling reactions toward
â-hydride elimination.8 Although the desired product 9 was
successfully realized with this catalyst (entry 3), it was
obtained in low yield along with several other byproducts.
An investigation of additives (entries 4-6) in an effort to
suppress â-hydride elimination using the initial conditions
unveiled Et4NCl as the most effective.9
In this letter, we report the development of this interesting
transformation of divinyl carbinols (e.g., 2 f 4) as well as
enyne carbinols with reactive aryl and vinyl coupling partners
into a general and useful reaction. This anomalous Heck
reaction provides efficient access to stereochemically defined
tri- and tetrasubstituted olefins, which are otherwise chal-
lenging to obtain. Importantly, this reaction manifold pro-
vides the basis for a variety of novel ring expansion and
annulation reactions, examples of which are reported for the
first time herein. Additionally, a series of experiments that
provide insight into the mechanism of the reaction is
presented.
Substituting DMA for DMF as solvent led to the discovery
of optimal reaction conditions, whereby a 10:3 ratio of 9/8
was obtained (entry 7).10
The study was initiated using bromobenzene (6)4 and 1,4-
pentadien-3-ol (2) as substrates (Table 1). Under the initially
Using these optimized conditions, we investigated the
substrate scope of this novel rearrangement for the synthesis
of a variety of substituted enals, enones, and dienones (Table
2). Secondary alcohols provide moderate yields of the
Table 1. Reaction Condition Screen for the Anomalous Heck
Reaction
Table 2. Scope of the Carbinol Component
product ratio
entry
catalyst
additive
base
solvent
DMF
(9:8)b
1
2
3
4
5
6
7
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PtBu3)2
iPr2NEt
TMEDA DMF
Cy2NMe THF
<1:9
no reaction
1:9
3:4
5:6
3:2
10:3
PdCl2(PPh3)2 Bu4NCl iPr2NEt
DMF
DMF
DMF
DMA
PdCl2(PPh3)2 LiBr
PdCl2(PPh3)2 Et4NCl iPr2NEt
PdCl2(PPh3)2 Et4NCl iPr2NEt
iPr2NEt
a All reactions were run with 3 mol % catalyst loading, 1 equiv of
additive, and 3 equiv of base as a 0.2 M solution at 120 °C for 5 h. b Product
1
ratios were determined using integration of H NMR resonances.
established conditions that afford 4 and 5, predominant
formation of products resulting from the standard Heck
reaction (8a-c) was observed (entry 1, Table 1), rather than
the desired rearranged products. On the basis of a hypothesis
that 8 and 9 formed from the same initial oxidative addition
intermediate (7), we focused on catalyst, solvent, and additive
variations that would disfavor â-hydride elimination and
presumably launch the Heck insertion intermediate toward
the formation of 9a/b.5 The use of TMEDA6 as base resulted
a A single olefin regioisomer and stereoisomer (as shown) were obtained
unless otherwise indicated.
corresponding enal products (entry 1), and tertiary alcohols
(4) Iodobenzene and phenyl triflate react similarly to bromobenzene.
(5) Only a trace amount of 9b was observed in this initial screen and in
subsequent studies.
(6) TMEDA has been shown to be a useful additive for preventing
â-hydride elimination in other systems. See: Nakamura, M.; Matsuo, K.;
Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686-3687.
(7) Although mixtures of TMEDA and Hu¨nig’s base did provide the
desired products, thus supporting the necessity of Hu¨nig’s base, no increase
in the amount of the anomalous Heck product was observed relative to
entry 1.
(8) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 5749-5752 and references therein.
5846
Org. Lett., Vol. 7, No. 26, 2005

(substitution at R1) are well tolerated and lead to good yields
of the desired enone products (entries 2 and 3). In contrast,
substitution at the internal vinyl carbon (R2) leads to
diminished yields of the anomalous Heck product (entry 4),
accompanied by a significant amount of the standard Heck
product.11 Although substitution only at the terminal vinyl
carbon (R3) completely favors the standard Heck products
(not shown), a tertiary alcohol that is also substituted at the
terminal vinyl carbon provides useful yields of the desired
anomalous Heck product (entry 5). Gratifyingly, enyne
carbinol substrates (entries 6 and 7) react chemoselectively
and lead to good yields of dienone products. In all cases,
the free alcohol on the divinyl and enyne carbinol substrates
was found to be critical to the success of the reaction. The
corresponding methyl and silyl ethers did not react at all or
provided only trace quantities of the standard Heck products
over prolonged reaction times.
Table 3. Scope of the “Halide” Component
In addition to an investigation of the carbinol component
(Table 2), a study of the coupling partner to establish the
general applicability of the reaction conditions was also
undertaken.
As shown in Table 3, various halides and triflates readily
participate in the reaction under our conditions. Aryl halides
bearing a variety of substitution patterns and functional
groups engage in the reaction to provide respectable yields
of the desired products (entries 1-4). Furthermore, a range
of heteroaryl halides provide the R,â-unsaturated enone
products in good to excellent yield (entries 5-8). Finally,
vinyl triflate compounds serve as competent substrates for
the reaction as well (entry 9).
The results obtained appear to be consistent with the
following mechanistic picture (Scheme 2), which is illustrated
with bromobenzene 6 and divinyl carbinol 2. This mecha-
nistic proposal is supported by experiments reported herein.12
a Reaction was run using 6 mol % catalyst loading. b Product is a 3:1
mixture of trans and cis isomers. Major product is shown.
Initial oxidative addition of an in situ generated Pd(0)
active catalyst to 6 provides organopalladium intermediate
10 that undergoes migratory insertion of 2 to yield interme-
diate 11, where addition across the olefin likely occurs on
the same face that the hydroxyl resides.13
the hydroxyl (or corresponding alkoxide) enhances the initial
migratory insertion to provide 11, consistent with previous
observations by Cacchi and Ortar and also by Oestreich.13
Under the conditions of the reaction, with â-hydride
elimination significantly compromised by coordination to the
The accelerated rate of reaction of substrates such as 2,
which bear a free hydroxyl, relative to the corresponding
methyl and silyl ethers under our reaction conditions, strongly
suggests that a precoordination of the palladium center to
Scheme 2. Proposed Mechanism of the Anomalous Heck
(9) Interestingly, ample precedent exists for the dramatic effect of
quaternary ammonium salts on the efficiency of the standard Heck reaction
as well. See: (a) Soderberg, B. C. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon
Press: Oxford, NY, 1995; Vol. 12, Chapter 3.5, p 259. (b) Bra¨se, S.; de
Meijere, A. In Metal Catalyzed Coupling Reactions; Stang, P. J., Diederich,
F., Eds.; John Wiley & Sons: New York, 1998 and references therein.
(10) Other solvents that were examined include N-methyl pyrrolidone,
dimethylimidazolidone, and acetonitrile.
Reaction
(11) See Supporting Information.
(12) Our mechanistic proposal takes into consideration our observations
of reactivity of both divinyl and enyne carbinols in the anomalous Heck
reaction.
(13) Coordination of hydroxyl functionality to cationic palladium
intermediates during the vinylation of aryl triflates has been proposed
previously and should predicate the stereochemistry indicated. See: (a)
Oestreich, M.; Sempere-Culler, F.; Machotta, A. B. Angew. Chem., Int. Ed.
2005, 44, 149-152. (b) Bernocchi, E.; Cacchi, S.; Ciattini, P. G.; Morera,
E.; Ortar, G. Tetrahedron Lett. 1992, 33, 3073-3076.
Org. Lett., Vol. 7, No. 26, 2005
5847

hydroxyl (see 11), excess halide (from the Et4NCl additive),
or alkene, ensuing migratory insertion produces cyclopro-
panol 13.14
The development of this anomalous Heck reaction sets
the stage for a range of applications. Illustrated in eq 2 is an
efficient complexity-building annulation reaction whereby
dienynol 22 undergoes a tandem anomalous Heck/6-π
electrocyclization reaction to provide tricyclic cyclohexadiene
24 (along with a small quantity of the corresponding
aromatized compound) in an unoptimized 55% overall
yield.20
At this stage, two alternate pathways (path A or B) may
account for product formation. In path A, which is favored
in the original Gribble report of this reaction, a decarbopal-
ladative rearrangement of 13 that has ample precedent in
the work of Negishi provides organopalladium intermediate
14.15 Ensuing â- or â′-hydride elimination (loss of Ha or Hb,
respectively) from 14 then yields â,γ-unsaturated aldehyde
15.16-18 Conversely, in path B, base abstraction of Ha from
13 with concomitant fragmentation of the cyclopropanol,
followed by loss of Pd(0), affords 15. Isomerization of 15
under the reaction conditions yields 9a, the alkene geometry
of which was confirmed by nuclear Overhauser effect (NOE)
experiments and determined to be under thermodynamic
control.19
In summary, we report the first study of a Pd-mediated
skeletal rearrangement that converts divinyl and enyne
carbinols to a series of enals, enones, and dienones that
cannot be readily accessed otherwise. Our mechanistic
proposal suggests that suppression of â-hydride elimination
is important for the formation of these products. Also of note
is the importance of the hydroxyl functionality of the divinyl
(or enyne) carbinol in facilitating these processes. Further
studies on the scope of this reaction as well as on the
mechanism and applications thereof are underway and will
be reported in due course.
Additional insight into this unique reaction is gained by
considering the mechanism by which cyclic substrates such
as 18 may react (eq 1), which reveals that a potential
coordination between the Pd(II) metal center and alkene is
sufficient to deter â-hydride elimination of 20. Instead, a
Acknowledgment. The authors are grateful to UC
Berkeley, GlaxoSmithKline (postdoctoral support to J.M.N.),
and the NSF (predoctoral fellowship to K.K.L.) for generous
financial support. The authors also thank the Bartlett, Toste,
Trauner, Bergman, Francis, Vollhardt, and Ellman labs for
chemicals and pertinent discussions. Mr. Alexandre Savari
is acknowledged for his contributions to this project.
facile ring expansive rearrangement, likely facilitated by the
antiperiplanar relationship between the hydroxyl group and
the C-Pd bond in 20, results to yield 21 in fair yield. In
this case, a decarbopalladative rearrangement (i.e., path A,
see Scheme 2) necessary for ring expansion is highly
compromised because a coplanar arrangement between the
breaking C-C bond and the C-Pd bond cannot be achieVed.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Heteroatom-bound organopalladium intermediates have been shown
to be recalcitrant toward â-hydride elimination. See: Oestreich, M.;
Dennison, P. R.; Kodanko, J. J.; Overman, L. E. Angew. Chem., Int. Ed.
2001, 40, 1439-1442. The Et4NCl additive may serve to augment this effect,
or the added halide might competitively bind to the metal center to further
minimize â-hydride elimination.
OL052382P
(15) (a) Owzarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E.-i. J. Am.
Chem. Soc. 1992, 114, 10091-10092. See also: (b) Trost, B. M.; Dumas,
J. Tetrahedron Lett. 1993, 34, 19-22. (c) Brown, D.; Grigg, R.; Sridharan,
V.; Tambyrajah, V.; Thornton-Pett, M. Tetrahedron 1998, 54, 2595-2606.
(16) The â,γ-unsaturated enal 15 may also result from alkene-bound
organopalladium intermediate i via ii.
(18) Loss of Hb via â-hydride elimination is not a strict requirement for
product formation, as enynol substrates such as 16, which lack Hb, readily
undergo the anomalous Heck reaction to provide very good yields of the
desired product.
(19) The enal 9a was isomerized to a 3:1 E/Z mixture of olefin iosmers
under photochemical irradiation (medium-pressure Hanovia Hg lamp), which
when subjected to the reaction conditions readily reverts to 9a.
(17) Loss of Hb via â-hydride elimination will require a syn coplanar
relationship between the C-Pd and C-Hb bonds to provide an enol that
tautomerizes to 15. The intermediacy of 15 is supported by the isolation of
styrenyl products (see entry 5, Table 2).
(20) A 9:1 ratio of cyclohexadiene 29 and the corresponding aromatized
1
compound was obtained in 55% yield, as determined by integration of H
NMR resonances using 1,2-dichloroethane as an internal standard.
5848
Org. Lett., Vol. 7, No. 26, 2005