Enantioselective redox-relay oxidative heck arylations of acyclic alkenyl alcohols using boronic acids

Article abstract of DOI:10.1021/ja402916z

A general, highly selective asymmetric redox-relay oxidative Heck reaction using achiral or racemic acyclic alkenols and boronic acid derivatives is reported. This reaction delivers remotely functionalized arylated carbonyl products from acyclic alkenol substrates, with excellent enantioselectivity under mild conditions, bearing a range of useful functionality. A preliminary mechanistic investigation suggests that the regioselectivity of the initial migratory insertion is highly dependent on the electronic nature of the boronic acid and more subtle electronic effects of the alkenyl alcohol.

Full text of DOI:10.1021/ja402916z

Communication
pubs.acs.org/JACS
Enantioselective Redox-Relay Oxidative Heck Arylations of Acyclic
Alkenyl Alcohols using Boronic Acids
Tian-Sheng Mei, Erik W. Werner, Alexander J. Burckle, and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
S
* Supporting Information
ABSTRACT: A general, highly selective asymmetric
redox-relay oxidative Heck reaction using achiral or
racemic acyclic alkenols and boronic acid derivatives is
reported. This reaction delivers remotely functionalized
arylated carbonyl products from acyclic alkenol substrates,
with excellent enantioselectivity under mild conditions,
bearing a range of useful functionality. A preliminary
mechanistic investigation suggests that the regioselectivity
of the initial migratory insertion is highly dependent on
the electronic nature of the boronic acid and more subtle
electronic effects of the alkenyl alcohol.
n existing challenge in synthetic chemistry is setting chiral
Acenters via carbon−carbon bond formation remote to
functional groups.1 Besides directly functionalizing specific C−
H bonds in an enantioselective manner, addition of carbon
Figure 1. (a) Enantioselective β-functionalization reactions. (b)
Enantioselective redox-relay Heck reactions. (c) Mechanistic analysis.
nucleophiles to alkenes using a metal catalyst is an especially
attractive approach as the alkene is an easily accessible, robust
functional group. This strategy requires addition of the carbon
nucleophile−metal species to the alkene, which is often
electronically biased toward site-selective addition (e.g., a
conjugated alkene). The resultant metal−alkyl complex needs
to be efficiently transformed to avoid deleterious reaction
pathways available to metal−alkyls. One successful tactic is the
metal-catalyzed conjugate addition of carbon-nucleophiles to
α,β-unsaturated carbonyls wherein the metal−enolate formed
in the process is hydrolyzed to reform the active catalyst for a
subsequent catalytic cycle (Figure 1a).2 These methods allow
for the formation of a wide range of β-substituted carbonyl
products in high enantiomeric excess.
We have recently reported an alternative conceptual
approach to setting remote chiral centers using an alkenyl
substrate.3 Specifically, we have developed an enantioselective
Heck-type reaction4−6 of racemic acyclic alkenol substrates
using aryl diazonium salts as the coupling partners, which
delivers β-aryl carbonyl products similarly to conjugate addition
methods (Figure 1b).3 The approach also allows direct access
to γ- or δ-substituted aryl carbonyl products in high
enantioselectivity by using a redox-relay strategy7 wherein the
unsaturation in the alkene is migrated toward the alcohol.8 This
transformation occurs presumably through an iterative β-
hydride elimination/migratory insertion process to ultimately
be trapped by formal oxidation of the alcohol resulting in a
carbonyl product (Figure 1c).9
significant question arises as to why preferential insertion is
observed at the site distal from the alkyl alcohol.10 Additionally,
the use of aryl diazonium salts limits both the scope and
potentially the practical application of this method. Therefore,
we became interested in developing an oxidative variant of the
enantioselective redox-relay Heck reaction using ubiquitous aryl
boronic acid derivatives11 as the aryl source to improve the
synthetic utility and also to begin to probe the origin of site
selective migratory insertion. Herein, we report an enantiose-
lective redox-relay oxidative Heck reaction with acyclic alkenols
and aryl boronic acids, delivering remotely functionalized
carbonyl products in high enantioselectivity and generally high
site selectivity.
We began our investigation by exploring our previously
developed catalytic system for oxidative Heck reactions of
electronically nonbiased olefins.12 These conditions employ a
cationic Pd salt ligated with an N-heterocyclic carbene and
catalytic Cu(OTf)2 under an O2 atmosphere. To initiate the
optimization, the N-heterocyclic carbene was replaced with the
chiral pyridine oxazoline ligand 1,3,13 resulting in poor
conversion of a cis-homoallylic alcohol 3, albeit with good
mass balance for the desired product (entry 1, Table 1). Poor
conversion in Pd-catalyzed aerobic oxidations is often
attributed to catalyst deactivation through aggregation of Pd
While this method leads to high enantioselectivity for a range
Received: March 22, 2013
of alkenol substrates (mainly allylic and homoallylic alcohols), a
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
site selectivity, although in high enantioselectivity (4j−l).
Interestingly, the minor isomeric product is also formed in high
enantioselectivity (4l), which has several important mechanistic
implications, as discussed below. A racemic secondary alkenyl
alcohol (4m) performs similarly as does an E-alkene, which
yields the other enantiomer as the major product (4n). Scaling
of this method from 0.5 to 10 mmol resulted in very similar
results (4). Finally, several heteroaromatic boronic acid
derivatives were evaluated (4o−q). In all cases, excellent site
and enantioselectivity is observed although the conversion of
the alkene is poor possibly due to observed higher levels of
homocoupling and phenol formation for these boronic acids.
A series of both primary and racemic secondary substituted
alkenyl alcohols were selected as substrates to probe whether a
steric effect can influence the site and enantioselectivities
(Table 3, 5a−e). Excellent enantioselectivity is observed in all
cases, although an apparent steric effect influences site
selectivity, with smaller groups leading to more of the β-
insertion product (compare 5a (-Me), 4l (-Et), 5d (-iPr)). Of
note, this minor product is formed in similar enantioselectivity
to that of the major product. Next, the effect of chain-length
(i.e., the distance from the alcohol to alkene) was probed by
systematically evaluating ethyl-substituted alkenyl alcohols
(Table 3, 5f−j). Again, the enantioselectivity is consistently
high for all substrates evaluated, suggesting that the alcohol is
not involved directly in face selection. This is also supported by
the successful use of racemic alcohol substrates (5d, 5e, 5j). A
clear trend emerges in terms of site selectivity for alkene
insertion: as the alcohol is further removed from the alkene the
selectivity is diminished. As an important synthetic note, many
of these enantiomerically enriched products would be very
cumbersome to synthesize using conventional approaches as
the chiral centers are quite remote from the carbonyl.
Table 1. Reaction Optimization
Pd/Cu/ligand
(mol %)
2
3 Å MS
conv.
a
a
entry
(equiv) (mg/mmol)
(%)
yield (%)
15
1
2
3
4
5
5/5/11
5/5/11
5/5/11
5/5/11
5/5/11
2
2
2
2
3
−
40
17
58
50
70
67
150
400
150
80
78
b
c
>90
82 (99:1 er)
a
b
Determined by GC analysis using an internal standard. Isolated
c
yield. er value was determined with SFC after reducing the aldehyde
to the primary alcohol.
metal during the process. This is a result of retarded oxidation
of Pd(0) to Pd(II) with O2 (or Cu(II)), which can be
circumvented by the addition of molecular sieves (MS).14
Indeed, the addition of 3 Å MS significantly improved the
reaction outcome with enhanced yields of the desired product
(entries 2−4). Increasing the boronic acid and catalyst loadings
gave complete conversion in 82% yield (entry 5), 19:1
regioselectivity (γ:β), and excellent enantioselectivity (er:
99:1). Of note, removing Cu(OTf)2 significantly reduces the
yield, and in the absence of Pd, no significant reaction is
observed.
With this catalytic system in hand, we initially investigated a
wide array of arylboronic acids with homoallylic alcohols
substrates (Table 2), which deliver γ-aryl carbonyl chiral
building blocks in uniformly high enantioselectivity (er up to
99:1) with moderate to good yields. In general, the observed
site selectivity (γ vs β) for alkene functionalization is good to
excellent. High site- and enantioselectivity is observed for
ortho-substituted aryl boronic acids (4a, 4b). In the case of
meta- or para-substituted aryl boronic acids, electron-deficient
examples afford high site selectivity (4c−h). In contrast,
electron-rich arylboronic acids give considerably lower levels of
In many asymmetric catalytic reactions, enantioselectivity is
highly sensitive to the nature of the substrates used in the
reaction.15 In this case, enantioselectivity is essentially
independent of the nature of both reaction partners. In
contrast, the site selectivity of the alkene insertion is controlled
Table 2. Scope of the Enantioselective Redox-Relay Heck Reaction of Homoallylic Alcohols and Aryl Boronic Acids
a
Yields are reported as a combination of isomers and reaction performed on 0.5 mmol scale. Enantioselectivity determined by SFC equipped with a
b
1
chiral column. Ratio of γ to β-product as determined by either H NMR or gas chromatography. Enantioselectivity of β-product is 99:1 er.
c
Reaction performed on 10 mmol scale.
B
dx.doi.org/10.1021/ja402916z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
scenarios cannot be ruled out, this observation is also suggestive
of electronic effects governing site selectivity.
Table 3. Evaluation of Various Alkenol Substrates
Considering the above discussion, an important question
concerning the relationship of site selection to face selection
arises as high enantiomeric excess is also observed for minor
isomers analyzed (eq 1). Therefore, the absolute configuration
was determined for addition to cis-homoallylic alcohol 6a,
revealing that the enantiomer formed from γ-insertion product
5a is (R) whereas the β-insertion product 5k is (S) (see
Supporting Information for details). Addition to an allylic
alcohol 6b also yields product 5k as the only product in high
enantioselectivity (eq 2). In this case, though, the opposite
enantiomer is observed to that of 5k formed from a homoallylic
substrate.3
Taken together, these data suggest that, as the opposite faces
of the alkene are presented to the catalyst, a highly
enantioselective insertion takes place but at different alkene
carbons (Scheme 1). For the major pathway, the alkene
a
Yields are reported as a combination of isomers. Enantioselectivity
determined by SFC equipped with a chiral column. Ratio of γ to β-
product as determined by either H NMR or gas chromatography.
1
both by the nature of the arylboronic acid and the substitution
and chain length of the alkenyl alcohol. To quantify the
electronic effect of aryl boronic acids on the site selection, a
linear free energy relationship was identified using Hammett σ-
values of both meta- and para-substituted boronic acids versus
the log of the ratio of site selectivity, which is proportional to
relative rates of isomer formation (Figure 2).16 The resultant
Scheme 1. Mechanistic Analysis of Stereochemical Course
Figure 2. (Left) Plot of Log of site-selectivity versus Hammett σ-
values derived from the scope presented in Table 2. (Right) Plot of
Log of site-selectivity versus Δδ 13C chemical shift.
Hammett plot has a ρ-value of 1.42, suggesting that the
orientation of insertion is sensitive to the electronic nature of
the Pd−Ar species formed (vide infra). In conjunction with this
correlation is the trend of site selectivity as a function of chain-
length (Table 3). To probe the origin of this interesting
observation, the relative 13C chemical shifts for each alkene
carbon were compared.17 For all cases, the most downfield-
shifted carbon is distal from the alcohol. Interestingly,
correlating the Δδ 13C chemical shifts versus the log of the
ratio of site selectivity reveals a clear trend. Although various
presumably undergoes migratory insertion in the orientation as
depicted in the transformation of A→B to account for the
observed enantioselectivity. Of particular note, the site
selectivity is decreased as the Pd−aryl species becomes less
electrophilic (i.e., when the aryl group is more electron-rich).
This is coupled to diminished site selectivity as a function of a
less electronically biased alkene, which suggests that an
electronic bias is required for enhanced site-selectivity and
that this is a highly sensitive event considering the magnitude of
C
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Journal of the American Chemical Society
Communication
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pathway is that the redox-relay product is formed even though
this would formally require translation of the metal through the
initially fashioned C−C bond. As this product is also formed in
high enantioselectivity as the opposite enantiomer, the initial
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orientation of the alkene as depicted in D→E. To form the
aldehyde product, β-hydride elimination should yield the
trisubstituted alkene in F followed by insertion of the resultant
Pd−H to deliver G. Subsequent repetitive events ultimately will
yield the aldehyde. The high level of enantioselection suggests
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In conclusion, we report a highly enantioselective oxidative
Heck reaction of alkenyl alcohols that operates through a
redox-relay process. The products formed using this method
would be difficult to access rapidly using traditional approaches.
Preliminary efforts to understand the origin of site selectivity in
this process are reported, wherein Hammett and other
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major role in controlling site selection. Understanding the rules
governing migratory insertion of relatively unbiased alkenes has
not been extensively defined. Research is underway to probe
this important organometallic mechanistic question, apply this
method to synthetic endeavors, and expand the concept of
redox-relay Heck reactions to new substrate and reaction types.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for new
substances. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
■
(12) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132,
13981.
Notes
(13) For recent examples of using pyridine/quinoline oxazoline
ligands in Pd-catalyzed reactions, see: (a) Kikushima, K.; Holder, J. C.;
Gatti, M.; Stoltz, B. M. J. Am. Chem. Soc. 2011, 133, 6902.
(b) McDonald, R. I.; White, P. B.; Weinstein, A. B.; Tam, C. P.;
Stahl, S. S. Org. Lett. 2011, 13, 2830. (c) Jensen, K. H.; Pathak, T. P.;
Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2009, 131, 17074.
(d) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S. J.
Am. Chem. Soc. 2009, 131, 6076.
(14) For the studies on roles of molecular sieves in Pd-catalyzed
aerobic oxidations, see: (a) Steinhoff, B. A.; King, A. E.; Stahl, S. S. J.
Org. Chem. 2006, 71, 1861. (b) Nishimura, T.; Maeda, Y.; Kakiuchi,
N.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 4301.
(15) For an example, see: Harper, K. C.; Vilardi, S. C.; Sigman, M. S.
J. Am. Chem. Soc. 2013, 135, 2482.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Institutes of Health
(NIGMS RO1 GM063540).
■
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