Palladium-Catalyzed Enantioselective Redox-Relay Heck Alkynylation of Alkenols To Access Propargylic Stereocenters

Article abstract of DOI:10.1002/anie.201703089

An enantioselective redox-relay Heck alkynylation of di- and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods.

Full text of DOI:10.1002/anie.201703089

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Communications
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International Edition: DOI: 10.1002/anie.201703089
German Edition: DOI: 10.1002/ange.201703089
À
C C Coupling
Palladium-Catalyzed Enantioselective Redox-Relay Heck
Alkynylation of Alkenols to Access Propargylic Stereocenters
Zhi-Min Chen, Christine S. Nervig, Ryan J. DeLuca, and Matthew S. Sigman*
Abstract: An enantioselective redox-relay Heck alkynylation
of di- and trisubstituted alkenols to construct propargylic
stereocenters is disclosed using a new pyridine oxazoline
ligand. This strategy allows direct access to chiral b-alkynyl
carbonyl compounds employing allylic alcohol substrates in
contrast to more traditional conjugate addition methods.
I
ntermolecular Heck reactions generally feature the coupling
of an sp2-hybridized reaction partner to an alkene followed by
b-hydride elimination towards the site of initial migratory
insertion. This formally yields a sp2–sp2 carbon–carbon
connection.[1] Recently, this reaction has been expanded
through both substrate and catalyst design to preferentially
undergo b-hydride elimination away from the site of initial
migratory insertion to both set a stereocenter and allow the
formation of a sp –sp C C bond.[2] Specifically, our group has
reported a suite of such enantioselective redox-relay Heck
reactions of acyclic alkenyl alcohols using aryldiazonium
salts,[3] arylboronic acids,[4] and alkenyl triflates,[5] which
provides direct preparation of carbonyl compounds that
contain remote alkenyl/aryl stereocenters (Scheme 1A).
However, this emerging strategy has thus far been limited
to sp2-hybridized nucleophiles/electrophiles as coupling part-
ners.
2
3
À
Scheme 1. Proposed redox-relay Heck alkynylation to access propar-
gylic stereocenters.
In an effort to expand the breadth of products one can
access with this approach, we selected to investigate the
enantioselective Heck alkynylation of alkenols to construct
substrates. Using a traditional conjugate addition approach,
only one report of conjugate alkynylation of b,b-disubstituted
carbonyl compounds to establish propargylic quaternary
stereocenters has appeared to date and is limited to b-aryl-
b-trifluoromethyl enones.[10]
propargylic stereocenters and forge sp–sp3 C C bonds
À
(Scheme 1B). The successful development of an alkynyl
Heck reaction would allow direct access to chiral b-alkynyl
carbonyl compounds, which are versatile intermediates that
have extensive applications in organic synthesis.[6] Tradition-
ally, these types of compounds have been synthesized using
enantioselective conjugate addition technologies, pioneered
by Carreira,[7] Hayashi,[8] and others, through organometallic
acetylide addition to a,b-unsaturated carbonyl substrates.[9]
However, we envisioned that a redox-relay Heck approach
that utilized allylic alcohol substrates would provide an
attractive alternative to this field due to the ease of
preparation, handling and improved stability of such alkenols.
In addition, it was deemed possible, on the basis of our
previous reports, that trisubstituted alkenols may be viable
To achieve a successful alkynylative redox-relay Heck
transformation three main challenges were carefully consid-
ered: 1) the identification of a suitable sp-hybridized carbon
reagent (such as benziodoxole derived triisopropylsilyl var-
iant (TIPS-EBX) initially developed by Waser), 2) avoiding
competitive transmetallation with Pd-alkynyl species 3 (Sche-
me 1C), which would ultimately lead to Pd-bis(alkynyl)
intermediate 4 followed by reductive elimination to yield
homocoupling product 5, and 3) selective b-hydride elimina-
tion of Hb (6) since b-hydride elimination of Ha would
produce the traditional Heck-type product (not shown) and
remove the newly established propargylic stereocenter.
Herein, we disclose the development of an enantioselective
redox-relay Heck alkynylation of allylic alkenols as a comple-
mentary approach to access enantiomerically enriched b-
alkynyl carbonyl compounds. This method utilizes easily
accessible alkenol substrates, a simple chiral ligand, and
a benziodoxole derived reagent as the alkyne source.
[*] Dr. Z.-M. Chen, C. S. Nervig, Dr. R. J. DeLuca, Prof. M. S. Sigman
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
E-mail: sigman@chem.utah.edu
To initiate our studies, cis-2-penten-1-ol (1a, Table 1) and
TIPS-EBX[11] were selected as model coupling partners with
Pd(CH3CN)2(OTs)2 as a precatalyst, a chiral pyridine-oxazo-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201703089.
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Table 1: Reaction optimization.[a]
group can be easily removed and the resulting terminal
alkyne is amenable to many well vetted transforms.
Under the optimized conditions (entry 5), the scope of
allylic alkenols was explored (Table 2). In general, the desired
alkynyl carbonyl compounds were obtained with moderate to
good yields and excellent enantiomeric ratios. The mass
Entry Catalyst (mol%)
Ligand Solvent Yield [%] er
Table 2: Evaluation of disubstituted alkenol substrates.[a]
1
2
3
4
Pd(CH3CN)2(OTs)2 (8)
Pd(CH3CN)2(OTs)2 (8)
Pd(CH3CN)2(OTs)2 (8)
Pd(CH3CN)2(OTs)2 (8)
Pd(CH3CN)2(OTs)2 (8)
Pd(CH3CN)2(OTs)2 (8)
Pd2(dba)3 (4)
L1
L1
L1
L1
L2
L2
L2
CH2Cl2 40
THF 48
98:2
92:8
91:9
97:3
96.5:3.5
96.5:3.5
–
EtOAc 42
dioxane 60
dioxane 65
dioxane 63
dioxane <5
dioxane 65
5
6[b]
7
8[c]
Buchwald precatalyst (4) L2
96:4
[a] Each entry represents the isolated yield on 0.20 mmol scale. er values
were determined by SFC. [b] The reaction was performed at 158C. [c] The
Buchwald precatalyst (4 mol%) was heated to 808C for 10 min prior use
to generate Pd0 and TsOH (25 mol%) was added.
line ligand (PyrOx, L1), and CH2Cl2 as solvent (see SI for
additional ligands and alkyne sources explored). Promisingly,
the desired product (2a) was produced in 40% yield and 98:2
er (entry 1). To improve the reaction yield, a solvent screen
was performed (entries 2–4). As a result, dioxane was found
to increase the product yield to 60%. Replacing the t-Bu
group (L1) on the PyrOx ligand with an i-Pr group and adding
a gem-dimethyl moiety on the oxazoline portion (L2) gave
a slight boost in yield to 65% while maintaining high
enantioselectivity (entry 5). The CF3 group on the pyridine
moiety of the ligand produces a more electrophilic catalyst,
which has been reported to deliver higher product yields and
enantioselectivities.[3] In addition, no significant change was
observed when the reaction temperature was decreased to
158C (entry 6). Surprisingly, switching to a Pd0 precatalyst
(Pd2(dba)3) resulted in < 5% product formation (entry 7). In
contrast, Buchwaldꢀs precatalyst, known to form Pd0 in situ
upon heating or adding base,[12] furnished the desired product
(2a) in 65% yield and 96:4 er (entry 8). These results suggest
that the alkyne source (TIPS-EBX) can react with both Pd0
and PdII, presumably through oxidative addition and trans-
metallation mechanisms, respectively. It remains unclear why
Pd2(dba)3 is unable to catalyze this transformation.
[a] Each entry represents the isolated yield on 0.20 mmol scale. er values
were determined by SFC. [b] 64% yield and 96:4 er on 2.0 mmol scale.
[c] 38% yield and 24:76 er when trans-1d was used. [d] 4.0 equiv of
alkenol 1o were used. [e] Ligand L1 was used.
balance in all examples was overall excellent with mainly
consumption of the TIPS-EBX reagent to the homocoupling
byproduct (5, Scheme 1C). Compared with alkenol 1a,
increasing the alkyl chain length at R1 did not have
a significant effect (2b, 2c). Enhancing the size of the
substituent at R1 to a benzyl or cyclohexylmethyl group led to
slightly decreased yields (2d, 2e). It should be noted that
when trans-1d was used instead of cis-1d the yield decreased
to 38% with 24:76 er (ent-2d). Alkenol 1 f, a substrate
containing both di- and trisubstituted alkenes, reacted selec-
tively at the less-hindered disubstituted alkene to afford the
desired product (2 f) in 62% yield and 97:3 er. The reaction
also tolerates an ester (1g), an alcohol (1h) and a benzyl ether
(1i) delivering the corresponding products in good yields and
high enantioselectivites. Substrates containing a primary
In should be noted that in addition to the TIPS protecting
group, a range of other groups were also investigated on the
benziodoxole derived alkyne reagent. The tert-butyldiphenyl-
silyl variant (TBDPS-EBX) resulted in 61% yield and 95:5 er
using the conditions shown in entry 5. Unfortunately, smaller
groups such as TBS and phenyl gave significantly lower yields
and enantioselectivites presumably due to other competitive
processes including homocoupling (see SI for complete
details). While this is a limitation, the TIPS protecting
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tosylate (1j) or primary chloride (1k) could also be subjected
to competitive alkyne homocoupling. Efforts to improve the
to the reaction conditions to yield products 2j and 2k in 55%
yield and 95.5:4.5 er and 60% yield and 97:3 er, respectively.
A nitrile group was also well suited under the reaction
conditions providing product 2l in 62% yield and 96.5:3.5 er.
Alkenols containing a phthalimide (1m) or a sulfide (1n)
were also viable substrates resulting in a modest reduction in
yield of products 2m and 2n. Finally, a substrate containing
a secondary alcohol (1o) furnished ketone product 2o in 41%
yield and 83:17 er. The er of product 2o could be improved to
94:6 when ligand L1 was employed. The absolute configu-
ration for product 2d was determined to be (R) through [a]D
comparison with the previously reported (S)-compound. All
other compounds were assigned by analogy to product 2d.[8b]
As homoallylic substrates (and longer chain alkenols)
have previously been excellent substrates in sp2 coupling
processes, we evaluated these substrates under the reaction
conditions. Unfortunately, the reactions delivered low
amounts of the desired redox-relay product (< 20% yield).
In these cases, the major byproduct was the traditional Heck
product. This indicates that b-hydride elimination is not
selective when an additional methylene unit is added between
the alkene and the alcohol moiety suggestive that the biasing
of b-hydride elimination is significantly reduced with the sp-
center installed. Likely, a substantial redesign of the system
will be required to overcome this limitation.
Given the difficulty associated with the enantioselective
formation of propargylic quaternary stereocenters using
metal-catalyzed conjugate addition approaches, we sought
to extend this methodology to trisubstituted alkenol sub-
strates. Due to the sluggish migratory insertion associated
with trisubstituted alkenes,[13] we were cognizant that com-
petitive transmetallation with Pd-alkynyl species 3 (Sche-
me 1c) would lead to homocoupling byproduct 5. To increase
the relative rate of migratory insertion, four equivalents of
alkenol were used. As a result, when a simple alkyl group was
positioned at R (1p, Table 3), the desired product containing
a proparygylic quaternary stereocenter was obtained in 36%
yield and 94:6 er (2p). The incorporation of a benzyl group at
R delivered product 2q in 25% yield and 95:5 er. Lastly, the
presence of an additional trisubstituted alkene was also
tolerated furnishing product 2r in 31% yield and 94:6 er. The
lower yields for trisubstituted alkene substrates are attributed
product yield by increasing the relative rate of migratory
insertion or slowing the rate of transmetallation have been
unsuccessful thus far.
In order to interrogate the reaction mechanism to
determine if Pd migrates toward the alcohol functional
group in a similar fashion to our previous reports, deuterated
alkenol 1a-d2 was subjected to the optimized Heck alkyny-
lation reaction conditions (Scheme 2). As a result, one
Scheme 2. Deuterium labeling study.
deuterium atom was transposed to the b carbon of the
newly formed aldehyde delivering 2a-d2, in accordance with
our previous mechanistic reports. This implies that 1a-d2
undergoes a migratory insertion with the Pd-alkynyl species
resulting in Pd-alkyl intermediate 7. Through selective b-
deuteride elimination (8) and reinsertion, intermediate 9 is
formed resulting in the transposition of one deuterium atom.
Furthermore, this suggests if intermediate 9 is formed the
reaction terminates through alcohol oxidation and establish-
ment of Pd0, presumably through b-hydride elimination or an
E2-type elimination. Moreover, since Pd0 is formed with each
catalytic turnover, TIPS-EBX (or TsO-EBX, a possible
byproduct of transmetallation) must oxidize Pd0 back to PdII
in this case.
In summary, we have developed an enantioselective
redox-relay Heck alkynylation of disubstituted alkenols in
good yields and high enantioselectivity. The b-alkynyl car-
bonyl compounds obtained using this methodology contain
a vast array of functionality. The ability to use allylic alcohol
substrates provides a complementary approach to access such
products to the more traditional conjugate addition strategies.
Finally, promising results using trisubstituted allylic alkenol
substrates to access propargylic quaternary stereocenters are
provided. Future efforts are aimed at developing ligands and
systems that prevent homocoupling of the alkyne to over-
come this limitation.
Table 3: Evaluation of trisubstituted alkenol substrates.[a]
Acknowledgements
The work was supported by the National Institutes of Health
(NIGMS R01GM063540). C.S.N. acknowledges the NSF for
a graduate research fellowship. Z.-M.C. would like to thank
Shanghai Jiao Tong University for a postdoctoral fellowship.
[a] Each entry represents the isolated yield on 0.20 mmol scale. er values
were determined by SFC.
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Keywords: alkenes · alkynylation · Heck reaction ·
propargylic stereocenter
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Manuscript received: March 24, 2017
Final Article published: && &&, &&&&
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Communications
À
C C Coupling
Z.-M. Chen, C. S. Nervig, R. J. DeLuca,
M. S. Sigman*
&&&& — &&&&
Palladium-Catalyzed Enantioselective
Redox-Relay Heck Alkynylation of
Alkenols to Access Propargylic
Stereocenters
Heck alkynylation: A convenient redox-
relay Heck strategy to synthesize enan-
tiomerically enriched b-alkynyl carbonyl
compounds from allylic alcohols with
high functional group tolerance is de-
scribed. Trisubstituted allylic alcohols are
also promising substrates allowing for
the formation of propargylic quaternary
stereocenters.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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