The palladium-catalyzed anti-Markovnikov hydroalkylation of allylic alcohol derivatives

Article abstract of DOI:10.1021/ol303129p

A palladium-catalyzed hydroalkylation reaction of protected allylic alcohols using alkylzinc bromide reagents is reported. This account includes numerous allylic, homoallylic, and bishomoallylic alcohol derivatives, all with a uniform selectivity of >20:1

Full text of DOI:10.1021/ol303129p

ORGANIC
LETTERS
2013
Vol. 15, No. 1
92–95
The Palladium-Catalyzed Anti-Markovnikov
Hydroalkylation of Allylic Alcohol
Derivatives
Ryan J. DeLuca and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States
sigman@chem.utah.edu
Received November 13, 2012
ABSTRACT
A palladium-catalyzed hydroalkylation reaction of protected allylic alcohols using alkylzinc bromide reagents is reported. This account includes
numerous allylic, homoallylic, and bishomoallylic alcohol derivatives, all with a uniform selectivity of >20:1 for the anti-Markovnikov product. The
reaction features the ability to deliver enantiomerically enriched alcohols in unfunctionalized regions, which results from the catalyst avoiding
β-hydride elimination at the allylic position.
The remote functionalization of organic molecules is a
preeminent challenge in chemical synthesis.1 Common
isolated functional groups often displayed in natural prod-
ucts are alcohols, which are generally installed biosynthe-
tically via oxidation processes.2 In contrast to this elegant
enzymatic solution, the preparation of compounds con-
taining remote chiral alcohols often requires the use of
classical methods including organometallic additions to
preformed chiral epoxides3 or enantioselective dialkylzinc
additions to aldehydes,4 which each have fundamental syn-
thetic limitations. Additionally, enantioselective ketone re-
ductions (such as the CBS reduction or various transfer
hydrogenation reactions) are not capable of effectively dis-
criminating the prochiral faces of dialkyl ketones generally
required for installation of a remote chiral alcohol in natural
product synthesis.5 With a limited number of methods avail-
able for accessing these important structural motifs, we
became interested in developing an alternative synthetic
strategy. Specifically, we wished to expand our recently
reported Pd-catalyzed anti-Markovnikov hydroalkylation
of allylic amine derivatives to allylic alcohols.6 The successful
(1) (a) Bigi, M. A.; Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2012,
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Synthesis; Wiley: NewYork, 1994.
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r
10.1021/ol303129p
Published on Web 12/19/2012
2012 American Chemical Society

second equivalent of the alkyl zinc halide (FfGfA).8
Several complications could arise including alkene isomer-
ization via a consecutive β-hydride elimination/reinsertion
sequence, which isattributabletothe instability ofPd-alkyl
species.7 This could also result in a mixture of cross-
coupling product isomers and potentially erode the enan-
tiomeric excess if an optically enriched substrate is used. In
our previous report using allylic amine derivatives, generally
good selectivity is observed for the anti-Markovnikov pro-
duct albeit with some unexplained site-selectivity loss for
certain substrates. This is a consequence of indiscriminate
insertion of the alkene, both 1,2 and 2,1 insertion, into the
Pd-hydride and an actively functioning Pd-alkyl rearrange-
ment based on the analysis of isotopic labeling experiments.6
While a single example of an allylic ester was reported, only a
modest yield was observed and it was unclear if these
substrates would be generally compatible with the desired
reaction class, as allylic esters are well-known precursors for
π-allyl Pd-chemistry.9 We report herein the optimization and
scope of a Pd-catalyzed anti-Markovnikov hydroalkylation
reaction of both allylic and homoallylic alcohols with alkyl-
zinc halides to access remote alcohol derivatives. Addition-
ally, key mechanistic insight is garnered into the preferred
formation of the anti-Markovnikov product.
Figure 1. (a) Remote chiral alcohol accessed through a
Pd-catalyzed hydroalkylation reaction of readily accessible
allylic alcohol derivatives. (B) Proposed catalytic cycle.
Table 1. Reaction Optimization
development of this reductive cross-coupling reaction would
provide an attractive unconventional method for the pre-
paration of compounds containing remote chiral alcohols
(A, Figure 1). Moreover, this approach utilizes the appealing
features of cross-coupling technologies7 in that the starting
materials, allylic alcohol derivatives (enantiomerically en-
riched and racemic) and alkylzinc halides, can be easily
prepared incorporating diverse and useful functionality.
Conceptually, the proposed method relies on two dis-
tinct mechanistic processes to facilitate the hydroalkyla-
tion reaction. The first is the production of a Pd-hydride
intermediate (E, Figure 1), which then mediates the hy-
dridometalation of the alkene (BfF). Based on our pre-
vious efforts in Pd-catalyzed alkene hydroalkylation reac-
tions, a reliable method to access the necessary Pd-hydride
is to use a sacrificial equivalent of an alkylzinc halide,
which undergoes transmetalation (CfD) followed by
β-hydride elimination (DfE). The second distinct process
is alkene insertion into the Pd-hydride (BfF) followed by
the transmetalation/reductive elimination sequence with a
entry
x
temp
additive
% yielda
˚
1
2
3
4
5
6
7
7
7
7
0 °C
0 °C
0 °C
rt
3 A MS
69
74
79
54
61
˚
3 A MS
À
À
À
À10 °C
a Measured by GC using an internal standard. Each entry had a
>20:1 ratio of linear/branched product isomers, as determined by GC.
To optimize the reaction conditions, modest changes
were found to enhance the isolated yield of the product.
Specifically, under our previously reported hydroalkyla-
tion conditions, a 69% GC yield of the anti-Markovnikov
product of 1a was achieved (entry 1, Table 1). A slight
increase in catalyst loading to 7 mol % led to a 74% yield
(entry 2). The reaction conditions were further simplified
˚
with the removal of 3 A molecular sieves, which gave a
(7) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674.
(c) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691.
(d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527. (e) Netherton,
79% yield (entry 3). We also found the optimal tempera-
ture of the reaction to be 0 °C (entries 3À5). It should be
noted that >20:1 selectivity is observed for the formation
of the linear product, as depicted.
Using these conditions, we began examining the sub-
strate scope of allylic alcohol derivatives. Our standard
€
M. R.;Dai, C.;Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099.
(f) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910. (g)
Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718. (h) Bissember,
A. C.; Levina, A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 14232. (i) Stokes,
B. J.; Opra, S. M.; Sigman, M. S. J. Am. Chem. Soc. 2012, 134, 11408.
(8) At the end of the cross-coupling sequence, Pd(0) is converted back
to Pd(II) using benzoquinone as the oxidant. Zn(OTf)2 likley acts as a
Lewis acid to facilitate this transformation.
(9) For a review, see: Trost, B. M.; Crawley, M. L. Chem. Rev. 2003,
103, 2921.
Org. Lett., Vol. 15, No. 1, 2013
93

Table 2. Pd-Catalyzed Hydroalkylation of Protected Allylic Alcohols with Alkylzinc Reagentsa
a Each entry had a >20:1 ratio of linear/branched product isomers, as determined by GC. Each entry represents the isolated yield on 0.5 mmol scale.
Naphth = 1-naphthoyl, PMP = para-methoxyphenyl. b 8 equiv of R1ZnBr were used.
benzoyl-protected substrate 1a reacted to give a 73% iso-
lated yield of the anti-Markovnikov product (2a, Table 2).
Various acyl protecting groups are well-tolerated in this
reaction such as para-methoxybenzoyl and 1-naphthoyl
groups, which gave 72% and 65% yields, respectively (2b,
2c). Allylic acetates also gave excellent selectivity, albeit with
lower yields (2d, 2e). It should be noted that these substrates
are common precursors of π-allyl intermediates,9 but pro-
ducts resulting from these reactions are not observed. Next,
the substitution at the carbon bearing the protected alcohol
was varied: incorporation of a larger group, such as a
cyclohexyl ring, resulted in a 72% yield (2f), and substrates
containing benzyloxyl (2g) and benzyl (2h) groups both led
to good yields for the linear products. Next, a variety of
alkylzinc reagents were successfully incorporated includ-
ing an alkyl chloride (2i), a bulky methylcyclohexyl group
(2j), a pivalate ester (2k), a TBDPS-protected alcohol (2l),
a benzoyl group (2m), and a morpholine-derived amide (2n).
A hypothesized origin of the high anti-Markovnikov
selectivity for the hydroalkylation reaction may be the
coordinating ability of the ester (or the amide in our
previous report).6,10 Therefore, a substrate containing a
tert-butyl ether, which is unlikely to participate in coordi-
nation with the catalyst, was evaluated and afforded
>20:1 selectivity for the linear product, albeit in 35% yield
(2o). This resultstrongly suggests that the selectivity for the
anti-Markovnikov product does not arise from coordina-
tion of the Lewis base, although enhanced yields are
generally observed when these groups are incorporated.
This improvement may be due to superior binding of
substrates with Lewis bases, as an equivalent of the
unfunctionalized alkene, derived from the alkylzinc re-
agent, may be competitively coordinating to the catalyst.
Figure 2. Benzoyl-protected homoallylic alcohol 3a illustrating
substitution in the allylic position is necessary for high yields and
selectivity.
The competence of the hindered substrate leading to 2o
and other noncoordinating allylic substituents,6 all of
which deliver high levels of anti-Markovnikov selectivity,
suggest that the selectivity is not dictated by the electronic
nature of the allylic group.11 To probe this hypothesis, a
protected homoallylic alcohol, lacking substitution at the
allylic position, was submitted to the reaction (Figure 2).
Consistent with a model that includes a steric bias, the
reaction of substrate 3a afforded a 2.8:1 mixture of anti-
Markovnikov (4a) and Markovnikov (4b) products in low
yield (<20%). Additionally, significant isomerization to
the internal alkene was also observed.12
(11) Vinylcyclohexane is selectively functionalized albeit in <30%
yield.
(12) Internal alkenes and 1,1 disubstituted alkenes were also sub-
mitted to the reaction conditions, which resulted in mainly unreacted
starting material.
(10) Weiner, B.; Baeza, A.; Jerphagnon, T.; Feringa, B. L. J. Am.
Chem. Soc. 2009, 131, 9473.
94
Org. Lett., Vol. 15, No. 1, 2013

Table 3. Hydroalkylation of Substrates with Methyl
Substitution in the Allylic Positiona
Scheme 1. (a) Proposed Mechanism Illustrating β-Hydride
Elimination Does Not Occur in the Allylic Position;
(b) Evaluation of Retention of Enantiomeric Excess
a Each entry had a >20:1 ratio of linear/branched product isomers,
as determined by GC. Each entry represents the isolated yield on
0.5 mmol scale.
This observation encouraged us to evaluate a homo-
allylic alcohol derivative with methyl substitution at the
allylic position, which is a product of aldehyde crotylation,
a common motif in synthesis. Submission of this substrate
afforded a 46% yield of the anti-Markovnikov product
(6a, Table 3) with no observedMarkovnikovaddition. The
remainder of the mass balance was unreacted starting
material and a small amount (<10%) of alkene isomeriza-
tion. Again, this is consistent with a steric bias influencing
product distribution. Therefore, several substrates with alkyl
substitution at the allylic site were tested including a TBDPS-
protected homoallylic alcohol with geminal dimethyl sub-
stitution (6b) (incapable of β-hydride elimination). Addition-
ally, benzoyl-protected homoallylic and bishomoallylic
alcohols, both with dimethyl substitution at the allylic site,
resulted in high yields, indicating the placement of the
protected alcohol is not important for selectivity (6c, 6d).
These data suggest that the high anti-Markovnikov
selectivity observed might be a direct result of a steric effect
whereby only the primary alkyl-Pd complex undergoes
transmetalation, presumably under CurtinÀHammett
control.6 Moreover, the secondary alkyl-Pd complex does
not β-hydride eliminate toward the carbon containing the
heteroatom, thereby leaving the adjacent CÀH unper-
turbed (I’fJ’, Scheme 1a). However, it should be noted
in the case of methyl substitution in the allylic position (6a,
Table 3) a small amount of β-hydride elimination was
observedin the form of internal alkene isomers. As a result,
this reductive coupling can deliver highly enantiomerically
enriched protected alcohols. To showcase this process, an
enantiomerically enriched allylic benzoate with 96% ee
was subjected to the reaction conditions and the product
was found to retain its enantiomeric excess (Scheme 1b).
In summary, we have developed a Pd-catalyzed hydro-
alkylation reaction of protected allylic alcohols. This un-
conventional method is highlighted by the ability to access
products with a stereocenter embedded in an unfunction-
alized alkyl region common in natural products. This
feature is a mechanistic consequence of the reaction,
whereby β-hydride elimination does not occur at the
heteroatom substituted allylic position. Additionally,
homo- and bishomoallylic alcohols that contain methyl-
substitution also afford the anti-Markovnikov product
selectively. Future work will be focused on applying this
catalyst system to synthetic goals as well as investigating
alternative hydride sourcesand couplingpartners in alkene
hydrofunctionalization reactions.
Acknowledgment. This research was supported by the
National Institutes of Health (RO1GM3540).
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and chiral separations
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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