A general and highly selective chelate-controlled intermolecular oxidative heck reaction

Article abstract of DOI:10.1021/ja804120r

A novel chelate-controlled intermolecular oxidative Heck reaction is reported that proceeds with a wide range of nonresonance stabilized α-olefin substrates and organoboron reagents to afford internal olefin products in good yields and outstanding regio- and E:Z stereoselectivities. Pd-H isomerization, common in many Heck reactions, is not observed under these mild, oxidative conditions. This is evidenced by outstanding E:Z selectivities (>20:1 in all cases examined), no erosion in optical purity for proximal stereogenic centers, and a tolerance for unprotected alcohols. Remarkably, a single metal/ligand combination, Pd/bis-sulfoxide complex 1, catalyzes this reaction over a broad range of coupling partners. Given the high selectivities and broad scope, we anticipate this intermolecular Heck reaction will find heightened use in complex molecule synthesis. Copyright

Full text of DOI:10.1021/ja804120r

Published on Web 07/31/2008
A General and Highly Selective Chelate-Controlled Intermolecular Oxidative
Heck Reaction
Jared H. Delcamp, Alexandria P. Brucks, and M. Christina White*
UniVersity of Illinois Urbana-Champaign, 600 S. Mathews, Urbana, Illinois 61801
Received June 1, 2008; E-mail: white@scs.uiuc.edu
Table 1
C-C bond forming reactions are vital to the synthesis of natural
products and pharmaceuticals. The intermolecular Heck reaction is
unique among cross-coupling reactions due to the direct formation of
C-C bonds from vinylic C-H bonds of R-olefins.1 The inertness of
R-olefins relative to the oxidized substrates needed for other C-C bond
forming methods means that fewer steps are required for their
installation and maintenance throughout a synthetic sequence. Despite
significant advances in the scope of the arylating reagent, the
intermolecular Heck reaction has enjoyed limited application in
complex molecule synthesis due to restricted olefin scope.2 Generally,
resonance bias on the olefin is necessary for high reactivity and for
control of the regioselectivity of insertion (internal vs terminal olefin
products) and direction of ꢀ-hydride elimination (styrenyl vs allylic
internal olefin products), limiting the olefin scope to R,ꢀ-unsaturated-
carbonyls, styrenes, and enol ethers (Figure 1). Herein we report a
chelate-controlled intermolecular, oxidative Heck reaction catalyzed
by a versatile Pd(II)/sulfoxide catalyst 1 that proceeds with excellent
selectivities for a wide range of non-resonance biased R-olefins with
proximal oxygen and nitrogen functionality.
Figure 1. Selectivities for chelate-controlled oxidative Heck reaction.
We reported a Pd(II)/sulfoxide-catalyzed sequential one-pot allylic
esterification/vinylic arylation of R-olefins.3a In addition to allylic esters,
allylic ethers and N-Boc amines all served as a non-resonance directing
groups for an oxidative Heck arylation4 that occurred rapidly (ca. 4 h)
at ambient temperature with outstanding yields, regio- and E:Z
stereoselectivities (>20:1). Allylic methyl substitution yielded signifi-
cantly poorer selectivities (internal:terminal 8:1)3a despite being larger
than many of the allylic oxygenates evaluated, suggesting that sterics
is not the major directing factor in this reaction. We hypothesized that
the high selectivities were due to in situ formation of an active, cationic
Pd(II) complex5 sensitive to subtle inductive and/or chelation effects6
by neighboring oxidized functionality on the olefin substrate.
Inductive effects decrease rapidly based on distance from the reactive
site. We therefore examined chelation effects by moving the oxidized
functionality away from the allylic position. We found homoallylic
a Isolated yield isomerically pure material (except 14, 15). Average 2
runs. b 2.0 equiv. of arylboronic acid. c 13:1 styrene:diene, crude
(Supporting Information). d 45 °C, 1.2 equiv. of arylboronic acid
e Replacing BQ with O2 (1 atm), air (1 atm.), or H2O2 gave <10% yield
(GC). f 24 h. g 2.5 h. h 45 °C, 48 h. i PhB(OH)2 under identical
conditions gave diminished styrenyl:allylic ratios of 1:4. j THF (0.33 M).
carbonyl functionality and bis-homoallylic carbonyl, alcohol, and thiol
functionality that could effect 5- and 6-membered ring chelation
(respectively) gave outstanding selectivities (Table 1, entries 1-12).
Distal carbonyl functionality that would require a 7-membered chelate
for direction gave regioselectivities comparable to those seen for
unsubstituted olefins (Table 1, entries 13 vs 14).
Heck arylation routes to stereochemically well-defined isolated olefins like
2, 3, and 4 lead to inseparable mixtures of E:Z olefins.7 Under these mild
oxidative Heck-arylation conditions, E-olefin products are exclusiVely
Several aspects of these oxidative, Heck arylations relative to state-of-
the-art processes are noteworthy. Wittig olefination and high temperature
9
11270 J. AM. CHEM. SOC. 2008, 130, 11270–11271
10.1021/ja804120r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2
In summary, we have described a general oxidative Heck reaction
catalyzed by a versatile Pd/bis-sulfoxide catalyst 1 that proceeds with
excellent selectivities for a broad range of non-resonance biased olefins.
Electrophilic catalyst 1 is sensitive to chelation effects from proximal
oxygen and nitrogen moieties that result in excellent regioselectivities
for olefin insertion. It is noteworthy that Pd-H isomerization15 is not
observed under these mild, oxidative conditions as evidenced by
excellent E:Z selectivities (>20:1 in all cases examined), no erosion
in optical purity for proximal stereogenic centers, and a tolerance for
unprotected alcohol moieties. This report represents a significant
expansion in scope for the intermolecular Heck reaction that brings it
a step closer to realizing its tremendous streamlining potential in
complex molecule synthesis.
Acknowledgment. M.C.W. acknowledges the NSF (CAREER
CHE-0548173), Merck, Bristol-Myers Squibb, and Pfizer for financial
support. Sigma-Aldrich is thanked for a generous gift of Pd(II)/
sulfoxide catalyst 1 and a Graduate Innovation Award to J.H.D. E.
Stang confirmed entry 7, Table 1.
Supporting Information Available: Experimental procedures, full
characterization, complete ref 8a, and additional experiments. This material
is available free of charge via the Internet at http://pubs.acs.org.
a 2,6-Dimethylbenzoquinone (2 equiv.), AcOH (4 equiv.), boronic
ester (1.5 equiv.), dioxane (1.0 M), rt, 48 h. b BQ (2 equiv.), AcOH (4
equiv.), ArBF3K (1.5 equiv.), B(OH)3 (2.0 equiv.), dioxane (0.33 M), rt,
4 h. c Crude int.:term. ) 16:1.
formed for all substrates eValuated (Table 1 and 2). Selective Heck
arylations for amino acid-derived pent-4-enones, -enoic acids, and -enoates
like (-)-5, (+)-6, and (+)-7 require different Pd(0) catalyst systems that
must be empirically determined through extensive ligand and additive
screens (Table 1, entries 4-6).8 In contrast, the versatile Pd(II)/bis-sulfoxide
complex 1 is a general catalyst, furnishing a wide range of coupled
products in uniformly good yields and outstanding selectivities. Finally,
standard Heck arylations with olefinic alcohols give aldehyde or ketone
products via palladium hydride mediated migration of the double bond.9
Chiral bis-homoallylic alcohols undergo 1-catalyzed oxidative Heck
arylation without oxidation or erosion in optical purity (Table 1, entry 7;
Table 2). Interestingly, bis-homoallylic thioethers which are often incom-
patible moieties with Pd(II)-mediated catalysis serve as excellent directing
groups in this reaction (Table 1, entry 8).
We found that under our oxidative, acidic Heck arylation conditions
we could rapidly synthesize 4-arylated-but-2-enoates and -enones
generally as single olefin isomers (Table 1, entries 9-12). This method
represents the state-of-the-art for synthesizing arylated R,ꢀ-unsaturated
esters with strongly electron deficient aryl moieties. Horner-Wad-
sworth-Emmons (HWE) routes to compounds 12 and 13 afford the
styrenyl compounds as the major isomer (Table 1, entries 11 and 12).10
References
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In addition to the demonstrated broad range of aryl boronic acids,
styrenylpinacol boronic esters, aryl potassium trifluoroborates, and aryl
stannanes are also competent coupling partners (Table 2).11 Optically
enriched allylic ethers and amines couple with styrenylpinacol boronic
esters to form stereochemically defined (E,E)-dienes in good yields,
outstanding stereoselectivities (>20:1), and no erosion in enantiopurity.
In an example of synthetic streamlining, diene (-)-16, an intermediate
toward a myosin light chain kinase inhibitor, was synthesized in two
fewer steps and 20% higher overall yield using an oxidative Heck
route rather than the alternative olefination route beginning from the
same starting material.12 Indole potassium trifluoroborate was found
to be a competent transmetallating reagent in a reaction to generate
19 upon addition of 2 equiv. of boric acid.13
Substantial steric bulk is tolerated on the olefin substrate in this
intermolecular Heck reaction without diminished reactivity. Even an
R-olefin comprising a quaternary center and adjacent to an exocyclic
methyl group underwent oxidative Heck arylation via relatively mild
conditions to afford 21, a glucocorticoid receptor modulator, in
preparatively useful yields (eq 1).14
(13) Boric acid is likely a fluoride acceptor that opens a p-orbital on the aryl boron
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(15) A PdH(OAc) intermediate should be short-lived under these oxidative
conditions [PdH(OAc) + AcOH T Pd(0) + 2 AcOH + BQ f Pd(II)OAc2 +
DHQ). For an important study on PdH in Heck reactions, see: Hills, I. D.; Fu,
G. C. J. Am. Chem. Soc. 2004, 126, 13178.
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