Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

Article abstract of DOI:10.1021/jacs.0c12565

Selective carbon-carbon (C-C) bond formation in chemical synthesis generally requires prefunctionalized building blocks. However, the requisite prefunctionalization steps undermine the overall efficiency of synthetic sequences that rely on such reactions, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without prefunctionalized building blocks. In this transformation several classes of unactivated internal acceptor alkynes can be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. This method is facilitated by a tailored P,N-ligand that enables regioselective addition and suppresses secondary E/Z-isomerization of the product. The reaction is scalable and can operate effectively with as low as 0.5 mol % catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.

Full text of DOI:10.1021/jacs.0c12565

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Article
Atom-Economical Cross-Coupling of Internal and Terminal Alkynes
to Access 1,3-Enynes
Mingyu Liu, Tianhua Tang, Omar Apolinar, Rei Matsuura, Carl A. Busacca, Bo Qu, Daniel R. Fandrick,
Olga V. Zatolochnaya, Chris H. Senanayake, Jinhua J. Song, and Keary M. Engle*
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ABSTRACT: Selective carbon−carbon (C−C) bond formation in
chemical synthesis generally requires prefunctionalized building
blocks. However, the requisite prefunctionalization steps under-
mine the overall efficiency of synthetic sequences that rely on such
reactions, which is particularly problematic in large-scale
applications, such as in the commercial production of pharma-
ceuticals. Herein, we describe a selective and catalytic method for
synthesizing 1,3-enynes without prefunctionalized building blocks.
In this transformation several classes of unactivated internal acceptor alkynes can be coupled with terminal donor alkynes to deliver
1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols,
(homo)propargyl amine derivatives, and (homo)propargyl carboxamides. This method is facilitated by a tailored P,N-ligand that
enables regioselective addition and suppresses secondary E/Z-isomerization of the product. The reaction is scalable and can operate
effectively with as low as 0.5 mol % catalyst loading. The products are versatile intermediates that can participate in various
downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II)
catalytic cycle.
participate in diverse downstream transformations makes
them extremely valuable building blocks in organic synthesis.3,4
In addition, the 1,3-enyne moiety is found in bioactive natural
products,5,6 clinical therapeutics,7 and supramolecular assem-
blies.8 Herein, we describe a ligand-promoted, palladium-
catalyzed method to couple donor alkynes with a variety of
acceptor alkynes that takes advantage of coordination of a
native Lewis basic functional group on the acceptor to enhance
reactivity and control selectivity.
Previous research has demonstrated the viability of the
envisioned coupling, while also illustrating challenges to be
anticipated in pursuing a general terminal donor/internal
acceptor cross-coupling (Scheme 2A). Trost reported pioneer-
ing work on redox-neutral, palladium-catalyzed terminal alkyne
homocoupling in 1987,12 with improved scope and selectivity
subsequently being realized by Trost, Pfaltz, Gevorgyan, and
others over the ensuing decades.3,11−29 Cross-coupling
between a terminal alkyne and an electronically activated
(i.e., conjugated) alkyne has also been described.11−29 Relevant
to the approach described herein, Trost has also described
INTRODUCTION
■
Catalytic methods that couple two distinct carbogenic
fragments in a selective fashion constitute a core technology
in organic synthesis with important applications in the
pharmaceutical industry.1 Classical palladium- and nickel-
catalyzed C−C cross-coupling reactions between organo-
halides and organometallic reagents (Scheme 1A) are widely
used but require prefunctionalized coupling partners that must
be prepared in advance via multiple nonstrategic steps,
detracting from the overall efficiency of the process.
Thus, the development of C−C cross-coupling alternatives
that directly employ unfunctionalized substrates and enable
access to high-value products is of vital importance.2 To this
end, integrating π-systems (e.g., alkenes and alkynes) as cross-
coupling components (Scheme 1B) is an attractive approach
given the ability of π-systems to provide potential energy to the
reaction, the ambiphilic reactivity profiles of these coupling
partners, and their widespread availability as feedstock
chemicals. Specifically, the cross-coupling of two different
alkynesa terminal donor alkyne capable of forming a metal−
acetylide in situ and an internal acceptor alkyne capable of
undergoing hydrofunctionalizationrepresents a promising
strategy for C(sp)−C(sp2) bond formation. If fully developed,
this transformation would provide direct access to a range of
1,3-enynes without relying on prefunctionalization events that
are typically required in the state-of-art methods, such as
Sonogashira coupling.4,9,10 The ability of 1,3-enynes to
Received: December 2, 2020
Published: March 8, 2021
https://dx.doi.org/10.1021/jacs.0c12565
J. Am. Chem. Soc. 2021, 143, 3881−3888
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Scheme 1. Comparison of Different Approaches to C−C
Cross-Coupling
Scheme 2. Approaches to Redox-Neutral Alkyne Coupling
and Optimization of Conditions
examples in which silyl-substituted and terminal propargyl
alcohols are coupled with terminal alkynes, leading to C(sp)−
C(sp2) bond formation proximal to the alcohol.14 While useful
in their own right, existing methods are limited in scope,
regioselectivity, stereoselectivity/specificity, and efficiency.
Therefore, widespread adoption in preparative syntheses has
been hampered.
We envisioned that the challenges outlined above could be
surmounted by adopting a substrate directivity approach, in
which a Lewis basic site on the acceptor alkyneideally a
native functional group, like a free alcohol, would coordinate to
the metal catalyst to facilitate downstream elementary steps. In
particular, the bidentate coordination between the catalyst and
acceptor alkyne would serve to activate the π-system through
induced π-Lewis acid activation. An alkynylpalladium(II)
species would be formed from the donor alkyne followed by
directed 1,2-migratory insertion of the alkynylpalladium(II)
species to the acceptor alkyne. This process would lead to the
regioselective formation of the alkenyl-palladacycle intermedi-
ate through stabilization of one of regioisomeric transition
states (Scheme 2B). The chelation-stabilized intermediate
structure would then undergo protodepalladation to close the
catalytic cycle. This hypothesis builds on our previous work
using bidentate directing groups for alkyne hydro-
functionalizations30,31 but would obviate auxiliary attachment
and removal steps.32
a
1H NMR yield with CH2Br2 as internal standard. n.r. = no reaction.
RESULTS AND DISCUSSION
■
b
1
Determined by H NMR analysis of crude reaction mixture. r.r. =
1. Reaction Optimization. To reduce this idea to practice,
we selected 2-propyn-1-ol, an internal propargyl alcohol, as a
model acceptor alkyne and TIPS-acetylene as the donor alkyne
(Scheme 2C). Pilot experiments with various ligand/
precatalyst combinations (data not shown) indicated that the
initial cross-coupling is fast and quickly followed by E/Z-
isomerization. Hence, we deliberately used an extended
reaction time of 16 h in order to identify conditions and
ancillary ligands that would allow selective coupling while
c
regioisomeric ratio. Isolated yield.
suppressing secondary isomerization. In summary, we found
that phosphine ligands are essential for the reaction, as shown
in previous studies.3 In previous methodologies reported by
Trost, L5 was the optimal ligand,12−14 but, in this case it barely
provided any regiodifferentiation (entry 5). In contrast, the
reaction was highly regioselective when P,N-bidentate ligands
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a
Table 1. Substrate Scope
a
Percentages represent isolated yields. In cases where two or more isomers were formed, percentages represent combined yields of isolated samples
of each of the different isomers. Stereoisomeric ratios are shown in parentheses (syn:anti) and reflect the mass ratio of isolated samples unless
1
otherwise specified; these ratios are consistent with those observed via H NMR analysis of the crude reaction mixtures. See the Supporting
b
c
Information (SI) for details. 0.5 mol % Pd(OAc)2, 0.55 mol % L2, without NH4OAc, 1.2 equiv donor alkyne, 20−48 h. MeCN:t-AmylOH = 1:1.
d
e
f
1
Pd(OAc)2 catalyst, without NH4OAc. 10 mol % Pd(dba)2, 11 mol % L1. Stereoisomers were inseparable; ratio determined by H NMR.
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are important for reactivity (entry 6−12). The combination of
Pd(dba)2 and ammonium acetate provides the best yield.
These general trends also held with a representative propargyl
carboxyamide substrate that is more prone to secondary E/Z
isomerization (see the Supporting Information (SI)).
2. Substrate scope. The substrate scope was tested with
the optimized conditions (Table 1). Excellent reactivity and
selectivity was maintained for propargyl alcohols with different
substitution patterns (1−7). Notably, the reaction proceeds
with the opposite sense of regioselectivity compared to the
previously reported system by Trost,14 consistent with the
hypothesis that the hydroxyl group is serving as a directing
group in this case. Heterocycles are well tolerated in this
reaction, with only slightly diminished E/Z selectivity (8−10).
Furthermore, we examined the reactivities of other native
directing groupsincluding amides, sulfonamides, and
aminesnone of which had been previously explored in
alkyne cross-coupling. Propargyl benzamide (11), N-Boc-
protected propargyl amine (12), and N-Ph propargyl amine
(14) were all converted to the corresponding 1,3-enyne
products, with the same selectivity as propargyl alcohols.
Homopropargyl benzamide (15) and N-tosyl-protected
homopropargyl amine (16) were also compatible, albeit with
lower regioselectivity than propargyl amine derivatives. We
also conducted a systematic study on the reactivities of
(homo)propargyl carboxamides (18−42), which are highly
challenging acceptors because their activated α-position can
cause side reactions and secondary E/Z isomerization. We
demonstrated that amides derived from various anilines and
aliphatic amines worked well in the reaction, providing the
products in good to excellent yield and with high selectivity.
However, amides with small substituent groups (37 and 38)
were more prone to isomerization, resulting in eroded
stereoselectivity (vide infra). We further observed good yield
and excellent selectivity with the different alkyl-substituted
alkynes (39−42). Introducing alkyl branching at the α-position
(41) or introducing an additional methyl spacer between the
alkyne and the directing group (42) led to comparable
reactivity compared to the substrates discussed above.
Figure 1. Representative examples of anti-selective cross-coupling.
aPercentages represent combined yields of isolated samples of each of
the different isomers. Stereoisomeric ratios are shown in parentheses
(anti:syn) and reflect the mass ratio of isolated samples; these ratios
are consistent with those observed via 1H NMR analysis of the crude
b
reaction mixtures. 10 mol % Pd(OAc)2, 11 mol % L1.
Different donor alkynes were also examined (43−50). We
found that alkynes possessing different degrees of steric
hindrance (46−48) or assorted functional groups (44 and
49) worked well as donor. Consequently, 1,3-enynes with a
variety of substitution patterns can be accessed directly,
without the need for TIPS deprotection and further
functionalization.
To evaluate the viability of this method in more structurally
intricate settings, we introduced bioactive molecules and
natural products onto each of the alkyne coupling partners
and tested whether reaction performance was impacted. Biotin
(13), tryptophan (34), and citronellic ester (50) were all
found to be compatible with this method. This suggests the
potential of applying this method for late-stage modification of
complex targets.
Figure 2. Product transformations and formal syntheses of natural
products.
We performed several representative examples on larger
scale. First, we found that by directly applying the standard
conditions, product 25 could be prepared on 1.5 mmol scale in
slightly improved yield compared to the small-scale experiment
(71% versus 63%). Next, we evaluated more demanding
conditions, with an eye toward further scale-up. We employed
Pd(OAc)2 instead of Pd(dba)2, given that the former is more
widely used in process chemistry. In addition, we decreased the
catalyst, ligand, and donor alkyne loadings to 0.5 mol %, 0.55
were used (entry 2−4). After examining L2−L4, we found that
a bulky and rigid N-coordinating arm is beneficial for favoring
the syn-product by suppressing secondary isomerization. In
particular, the phosphinoimidazoline ligand L1, which is
derived from diphenylethlenediamine and was previously
developed at Boehringer Ingelheim,33−37 was identified as
the best ligand in terms of regio- and stereoselectivity. Further
screening showed that the palladium source and the additive
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Scheme 3. Mechanistic Studies and Proposed Mechanism
mol %, and 1.2 equiv, respectively. We also used structurally
simplified ligand L2 in lieu of L1, noting that with this ligand it
was necessary to monitor reaction progress more carefully to
avoid secondary E/Z isomerization. Under these modified
conditions, products 5 and 6 were prepared on 1 mmol scale.
While the yield and selectivity for acceptor 5 was comparable
to the small-scale reaction (75% versus 74%; > 20:1 in both
cases), sterically hindered acceptor 6 was not fully consumed,
even after elongated reaction time, resulting in diminished
yield compared to the small-scale trial (32% versus 82%). The
decrease in this case could be due to the slower rate of donor−
acceptor cross-coupling, which allows the donor alkyne to be
competitively consumed via homodimerization. Last, using
these modified conditions, we prepared product 1 on 10 mmol
scale (gram-scale) in 94% yield.
3. Stereodivergent Alkyne Cross-Coupling. As men-
tioned above, during the course of this study we found that the
propargyl carboxamide products are especially prone to
isomerization, presumably due to the presence of acidic α-
protons.38 By taking advantage of the fact that the anti-isomer
is thermodynamically favored (see SI), we identified conditions
that allowed in situ isomerization to deliver the anti-isomer as
the major product with synthetically useful levels of anti/syn
selectivity (Figure 1).39 In this way, the transformation could
be rendered stereodivergent by simply changing the palladium
source and the additive.
alkyne-functionalizing reactions such as Sonogashira arylation
(58),40 hydrozirconation/iodination (59),41 and 1,2,3-triazole
formation via click chemistry (60).42 Additional trans-
formations were carried out on the 1,3-enyne derived from
propargyl carboxamides. Upon TIPS deprotection of com-
pound 24, the resulting product underwent in situ isomer-
ization to the conjugated allenyl alkene (51), likely due to the
acidity of the α-protons. Compound 51 could then be
transformed to highly substituted benzenes 53 and 54 through
Diels−Alder cycloaddition.43
1,3-Enynes are important building blocks that are often
involved in total syntheses of natural products.4 For instance,
62 is a common intermediate in the syntheses of brevisamide44
and vitamin A.45 Ghosh and co-workers synthesized 62 in 37%
́
yield over four steps. Lopez and co-workers followed a
procedure reported by Mori and prepared 62 in 4% yield over
two steps.46 In contrast, by using the alkyne cross-coupling
method, we obtained 62 in 61% yield over two steps from
commercially available materials. This improvement of
efficiency is significant given that 62 is an early stage
intermediate in both syntheses (Figure 2).
5. Mechanistic Studies. We next probed the mechanism
of the reaction by first investigating the oxidation state of the
catalytically active palladium species. At the outset we
considered three potential scenarios: (1) Pd(II)-assisted
metal−acetylide formation followed by migratory insertion
and protodepalladation; (2) oxidative addition of Pd(0) into
the C(alkynyl)−H bond followed by acetylide insertion and
C(alkenyl)−H reductive elimination; (3) oxidative addition of
Pd(0) into the C(alkynyl)−H bond followed by hydride
insertion and C(sp2)−C(sp) reductive elimination. First, we
4. Product Transformations. Various transformations of
the 1,3-enyne products were examined to underscore the
preparative utility of this method (Figure 2). Epoxidation (55)
on the alkene moiety and conversion of the alcohol to a
bromide (56) were successfully carried out. Removing the
TIPS protecting group on the alkyne moiety enabled other
1
monitored the reaction by in situ H NMR and did not
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Accession Codes
observe a signal consistent with metal−hydride, ruling out such
a species as a possible catalyst resting state (Figure S14−S17).
Reactions performed with Pd(OAc)2 as precatalyst and
Pd(dba)2 as precatalyst led to formation of the same
intermediate, as observed by in situ 31P NMR (29.64 ppm),
suggesting the oxidation state of the precatalyst does not
dictate catalyst speciation to an appreciable extent. The
chemical shift of the catalyst resting state is consistent with a
Pd(II)−phosphine complex.47 An isotope labeling experiment
was then carried out with deuterated TIPS-acetylene, and less
than 30% of deuterium was incorporated at the alkenyl
position (Scheme 3A). The mixture of H/D incorporation is
consistent with a protodepalladation pathway but not with a
metal hydride pathway.
CCDC 2036755 and 2036758−2036759 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Keary M. Engle − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-2767-6556; Email: keary@
scripps.edu
In the particular case of propargyl carboxamide substrates, a
possible pathway is initial alkyne isomerization to an allene
(63) followed by migratory insertion.48 To test whether this
pathway is operative, 63 was prepared and subjected to syn-
and anti-selective conditions (Scheme 3B). In both cases, 1,3-
enynes with opposite regioselectivity were obtained (64 and
65). Thus, the desired products are not generated from allene
intermediates.
Authors
Mingyu Liu − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-4649-7393
Tianhua Tang − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Omar Apolinar − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Rei Matsuura − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0002-3334-6492
Carl A. Busacca − Department of Chemical Development,
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,
Connecticut 06877-0368, United States
Bo Qu − Department of Chemical Development, Boehringer
Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
06877-0368, United States; orcid.org/0000-0001-7347-
0108
Daniel R. Fandrick − Department of Chemical Development,
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,
Connecticut 06877-0368, United States
Olga V. Zatolochnaya − Department of Chemical
Development, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Connecticut 06877-0368, United States;
orcid.org/0000-0003-3680-2913
Chris H. Senanayake − Department of Chemical
Development, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Connecticut 06877-0368, United States
Jinhua J. Song − Department of Chemical Development,
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,
Connecticut 06877-0368, United States
Consistent with earlier literature reports,37 by combining
Pd(MeCN)2Cl2 and P,N-ligands, we were able to cleanly
prepare L•PdCl2 complexes ligated with P,N-ligands, which
could be characterized by NMR (see the SI). While PdCl2•L1
could not be characterized by crystallography, the X-ray crystal
structure of model complex 66 where the phenyl groups on the
phosphorus atom are replaced with cyclohexyl groups
demonstrates that the ligand adopts a bidentate coordination
mode in the solid state (Scheme 3C). In this arrangement one
of the Ph groups of the diphenylethlenediamine moiety is
brought into close proximity to a chloride ligand. A possible
explanation for L1’s unique ability to suppress secondary
isomerization is thus that its steric bulk effectively crowds out
reassociation of the trisubstituted alkene moiety of the
product.49,50
CONCLUSION
■
In conclusion, we have developed a selective method to deliver
1,3-enynes from two different alkynes by taking advantage
various synthetically useful native directing groups. Gram-scale
synthesis with 0.5 mol % catalyst loading was demonstrated.
The 1,3-enyne products were successfully transformed by
different diversification reactions. Furthermore, preliminary
mechanistic studies shed light on a possible reaction
mechanism (Scheme 3C), in which Pd(II) serves as the active
catalyst with the reaction initiated by Brønsted-base-assisted
palladium−acetylide formation from the donor alkyne. Next,
the palladium−acetylide undergoes syn-1,2-migatory insertion
into the acceptor alkyne. Finally, protodepalladation releases
the 1,3-enyne product with concomitant regeneration of the
active Pd(II) catalyst.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12565
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Boehringer Ingelheim
Pharmaceuticals and the National Institutes of Health
(R35GM125052). We gratefully acknowledge the Nankai
University College of Chemistry for an International Research
Scholarship (T.T.), the National Science Foundation for an
REU Fellowship (DBI-1759544, O.A.) and Graduate Research
Fellowship (DGE-1842471, O.A.), and the Honjo Interna-
tional Scholarship Foundation for a Scholarship (R.M.). We
thank Prof. Arnold L. Rheingold and Dr. Milan Gembicky
(UCSD) for X-ray crystallographic analysis. We are grateful to
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12565.
Experimental details, NMR, X-ray, and other data (PDF)
(ZIP)
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