Construction of 1,5-enynes by stereospecific Pd-catalyzed allyl-propargyl cross-couplings

Article abstract of DOI:10.1021/ja302329f

The palladium-catalyzed cross-coupling of chiral propargyl acetates and allyl boronates delivers chiral 1,5-enynes with excellent levels of chirality transfer and can be applied across a broad range of substrates.

Full text of DOI:10.1021/ja302329f

Communication
pubs.acs.org/JACS
Construction of 1,5-Enynes by Stereospecific Pd-Catalyzed Allyl−
Propargyl Cross-Couplings
Michael J. Ardolino and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
couplings.7 However, the Pd-catalyzed cross-coupling of
ABSTRACT: The palladium-catalyzed cross-coupling of
chiral propargyl acetates and allyl boronates delivers chiral
1,5-enynes with excellent levels of chirality transfer and can
be applied across a broad range of substrates.
organometallic reagents and branched propargylic electrophiles
generally favors the allene as opposed to the 1,5-enyne
product.7,8 This regioselectivity likely arises from steric effects;
complex A is less hindered than complex B, and this leads to
allene products on reductive elimination. This reaction
manifold renders traditional palladium catalysis ineffective for
the construction of chiral alkyne-containing compounds from
chiral propargylic electrophiles.
In contrast to the cross-coupling of alkyl, aryl, and vinyl
metal reagents, cross-couplings of allyl metal reagents may
occur with allyl migration. To exploit this feature, our lab has
studied cross-couplings of allyl metal reagents and allylic
electrophiles and has found that these reactions appear to occur
by an inner sphere 3,3′-reductive elimination.9−11 In the
presence of appropriately selected ligands (bidentate, small
bite-angle diphosphines), allyl−allyl cross-couplings occur with
excellent levels of regio- and stereocontrol. Along these lines,
we considered that allyl−propargyl cross-couplings might also
occur by 3,3′-elimination and, if the elimination occurred from
an allenyl(allyl)Pd complex (C, Scheme 2), this might provide a
method for the stereocontrolled construction of nonracemic
1,5-enynes from readily available enantiomerically enriched
propargylic alcohols.12
1,5-Enynes are important and versatile synthetic intermediates.
In addition to offering differentiated π-systems for selective
functionalization, 1,5-enynes can be transformed into a diverse
array of cyclic structures.1 A current challenge to reaction
methodology surrounding 1,5-enynes lies in the preparation of
these structures in an enantiomerically enriched fashion.
Synthesis of 1,5-enynes is commonly accomplished by allylation
of propargylic electrophiles, employing either stoichiometric or
catalytic Lewis acid activation.2 While high levels of
regiocontrol have been observed in these processes, they
appear to proceed through an achiral carbocation intermediate
and this feature precludes the transfer of chirality from
enantiomerically enriched starting materials to 1,5-enyne
products (Scheme 1, eq 1).3,4 Transition metal catalysis could
Scheme 1
Scheme 2
To initiate these studies, cross-couplings of allylB(pin) and
propargylic chlorides were examined in the presence of
Pd2(dba)3 and CsF. With dppf as the ligand, the reaction
furnished the 1,5-enyne product regioselectively for both
aromatic (entry 1) and aliphatic (entry 2) substrates. More
conveniently prepared propargylic acetates were also found to
participate in the coupling, and while the regioselectivity was
moderate with dppf (entries 3 and 4), a marked improvement
was observed when rac-binap was employed. These reactions
occurred with high levels of selectivity for the 1,5-enyne
product and in exceptional yields (entries 5 and 6). In light of
prior studies on the impact of ligand structure on
regioselectivity,9a it was not surprising that a monodentate
provide a solution to this limitation: palladium undergoes
stereospecific anti SN2′ oxidative addition with propargylic
electrophiles.5 This reaction delivers an η1-(allenyl)palladium
complex (A, Scheme 1) whose configuration reflects that of the
starting material. While (allenyl)palladium complexes can
undergo isomerization to η1-(propargyl)palladium species
(A→B), this transformation is also stereospecific.5,6 With
appropriately substituted substrates, both the propargyl (B) and
the allenyl (A) palladium complexes are chiral and the fact that
they are configurationally stable enables stereospecific cross-
Received: March 9, 2012
Published: May 17, 2012
© 2012 American Chemical Society
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Communication
ligand such as triphenyl phosphine (entries 7 and 8) favored
allene products. Lastly, internal alkynes appear to react with
diminished levels of selectivity (entry 9), perhaps because the
added substituent at C1 of the allenyl palladium intermediate
(C, Scheme 2) suffers an interaction with the ligand framework.
Fortunately, this synthetic limitation is easily addressed: C-
alkylation of the terminal alkyne-derived products (D, R2 = H,
Table 1) provides ready access to the corresponding internal
alkyne allylation products.
Table 2. Conservation of Enantiomeric Enrichment in Allyl−
a
Propargyl Couplings
a
Table 1. Selectivity in Allyl−Propargyl Coupling
a
Reactions employed 1.2 equiv of the allylboronate. Yield refers to
isolated yield of the regioisomer mixture. Ratio of D:E was determined
by 1H NMR analysis; enantiomer ratios were determined by GC
b
analysis on a chiral stationary phase. For entry 2, (R)-methoxy-
(furyl)biphep (2.5%) used as the ligand; rac-binap gave a product er of
87:13, 77% cee, 93:7 D:E, and 80% yield.
Table 3. Substrate Scope of Propargyl−Allyl Cross-
a
Coupling
a
Reactions employed 1.2 equiv of allylB(pin). Regioselectivity was
1
determined by H NMR analysis; yield refers to isolated yield of the
regioisomer mixture.
With an effective protocol for enyne-selective coupling, the
capacity for chirality transfer from enantiomerically enriched
propargylic acetate substrates was explored. As depicted in
Table 2, the reaction showed excellent conservation of
enantiomeric enrichment (>99% cee) with aliphatic substrates
(entries 1, 3, and 4). While the aromatic substrate in entry 2
suffered some loss of optical purity with rac-binap (77% cee),13
high levels of chirality transfer (>99% cee) were obtained when
(R)-methoxy(furyl)biphep14 was employed as the ligand (entry
2). Of special interest was the ability to utilize tertiary acetates
to access enantiomerically enriched 1,5-enynes bearing all-
carbon quaternary centers (entry 4). Despite slightly
diminished regioselection, the ability to establish quaternary
centers with high cee (>99%) and yield could prove especially
useful in the construction of complex products.
In addition to the substrates in Table 2, a broad array of
other propargylic acetates were found to participate in the
regioselective allyl−propargyl coupling and generally delivered
1,5-enyne products in good to excellent yields. As depicted in
Table 3, substrates can possess silyl and benzyl ethers, remote
alkenes, indoles, and aryl chloride groups. Of particular note is
reaction product 13, which results from regioselective reductive
elimination from a conjugated (enallenyl)palladium intermedi-
ate.
a
Reactions were conducted for 14 h at 60 °C with 1:1 ligand/Pd(0)
and employed 1.2 equiv of the allylboronate relative to the propargyl
acetate. Yield refers to isolated yield of the regioisomeric mixture.
Regioselectivity was determined by H NMR analysis.
1
examine this feature in more detail, both enantiomers of ligand
were employed with enantiomerically enriched substrate 1. As
shown in Scheme 3 (eq 3), there is a slight level of double
diastereodifferentiation but both reactions deliver the product
with net inversion of configuration at carbon as the
predominant outcome. These experiments indicate that the
product configuration is dictated almost exclusively by the
starting material structure. To learn more about the innate basis
for the product regioselectivity, the experiment in eq 4 was
Aspects of the allyl−propargyl coupling reactions described
above merit mention. First the high level of chirality transfer
observed with rac-binap suggests that the catalyst configuration
may have little impact on the product stereochemistry. To
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Journal of the American Chemical Society
Communication
good yield required use of enantiomerically enriched substrate
(R)-3 and (R)-methoxy(furyl)biphep. With these conditions,
the reaction was efficient, and while both crotyl- (H) and cis-2-
butenyl derivatives (J) were generated, the reaction exhibited a
strong preference for the alkyne product. Similarly, efficient
production of 24 and 25 could be accomplished with the use of
the (R)-propargylic acetate and (S,S)-QuinoxP*. In these
reactions, when the opposite ligand enantiomer was employed
diminished levels of selectivity were observed. A rationale for
the observed matched and mismatched interactions is
presented in Figure 1 and is based on a stereochemical
Scheme 3
conducted. In this experiment, the reaction of allenyl B(pin)
and cinnamyl acetate was found to deliver 1,5-enyne 20 as the
predominant reaction product. In this experiment, the
presumed reactive intermediate bears an interconverting allyl/
propargyl ligand without a steric bias between the two isomers
(F and G). This reaction delivers the 1,5-enyne selectively, an
outcome that is most consistent with 3,3′-reductive elimination
from allenyl complex G. Thus, even in the absence of a steric
bias, the innate preference appears to be for reductive
elimination through the allenyl palladium intermediate.
Allylboronates substituted at the β and γ positions are readily
available by catalytic hydroboration of dienes and by catalytic
borylation of allylic electrophiles.15 To learn about the broader
generality of the allyl−propargyl cross-coupling, the utility of
these substituted nucleophiles was examined. As depicted in
Table 4, β-substituted allyl boronates maintain high levels of
regioselectivity in coupling with propargyl acetates (products
21 and 22). γ-Substituted allyl boronates can also exhibit high
levels of reactivity and selectivity; however, they require
modifications to the reaction. To produce compound 23 in
Figure 1. Matched and mismatched catalyst substrate interactions in
propargyl−allyl couplings.
model for related allyl−allyl couplings. As depicted, the
matched pairing appears to minimize nonbonded interactions
between the pseudoequatorial furyl ring and the allyl/allenyl
ligands as the latter couple to form a staggered C−C bond.
Synthetically, the allyl−propargyl coupling serves as a
strategically useful link between methodologies for the
synthesis of enantiomerically enriched propargyl alcohols and
methods for the transformation of enyne substrates. For
example, Kozmin and co-workers have described a straightfor-
ward protocol for the synthesis of substituted cyclohexenones
through cyclization of siloxy alkynes derived from 1,5-enynes.16
Using the allyl−propargyl coupling described above, the
requisite substrates can be prepared in an enantiomerically
enriched fashion thereby facilitating the use of the Kozmin
transformation in asymmetric synthesis; as depicted in Scheme
4, coupling of methallylB(pin) converts 1 to 26 with excellent
Table 4. Propargyl−Allyl Cross-Coupling with Substituted
a
Allylboronates
Scheme 4
stereocontrol. From 26, disubstituted cyclohexenone 27 can be
easily produced in high yield and without racemization. With a
general procedure to access a broad range of highly
enantiomerically enriched enynes bearing aliphatic, aromatic,
and all carbon quaternary substitution, the allyl−propargyl
coupling should serve as a useful new route to a myriad of other
optically enriched synthetic intermediates.
a
Reactions were conducted for 14 h at 60 °C with 1:1 ligand/Pd(0)
and employed 1.2 equiv of the allylboronate relative to the propargyl
acetate. Yield refers to isolated yield of the regioisomeric mixture.
b
Regioselectivity was determined by 1H NMR analysis. (R)-
Methoxyfurylbiphep employed as the ligand, and 10 equiv of CsF
were employed. (S,S)-QuinoxP* employed as the ligand, and 10 equiv
of CsF were employed.
c
In conclusion, the development of a new Pd(0)-catalyzed
allyl−propargyl coupling has opened a general method for the
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Journal of the American Chemical Society
Communication
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provides a simple method for their construction in enantiomeri-
cally enriched form.
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ASSOCIATED CONTENT
* Supporting Information
Procedures, characterization and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
morken@bc.edu
■
(10) For other recent allyl−allyl couplings, see: (k) Flegeau, E. F.;
Schneider, U.; Kobayashi, S. Chem.Eur. J. 2009, 15, 12247.
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(l) Jimenez-Aquino, A.; Flegeau, E. F.; Schneider, U.; Kobayashi, S.
Notes
Chem. Commun. 2011, 47, 9456.
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The authors declare no competing financial interest.
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́
ez-Bengoa, E.; Car
́
denas, D.
J.; Echavarren, A. M. Chem.Eur. J. 2002, 8, 3620. (b) Car
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ACKNOWLEDGMENTS
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The NIH (GM-064451) is acknowledged for financial support;
Frontier Scientific is acknowledged for a generous donation of
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preliminary experimental assistance.
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