Palladium-Catalyzed Synthesis of Alkynes via a Tandem Decarboxylation/Elimination of (E)-Enol Triflates

Article abstract of DOI:10.1021/acs.orglett.6b01904

A mild catalytic synthesis of alkynes via a tandem Pd-catalyzed decarboxylation/elimination of enol triflates is described. Key attributes of the method include readily available starting materials, broad functional group tolerance, and the ability to access terminal, internal, and halogenated alkynes. The preliminary scope of the reaction is demonstrated on 25 different examples with yields ranging from 63% to 96%.

Full text of DOI:10.1021/acs.orglett.6b01904

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of Alkynes via a Tandem
Decarboxylation/Elimination of (E)‑Enol Triflates
Charissa Munteanu and Doug E. Frantz*
Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: A mild catalytic synthesis of alkynes via a tandem Pd-
catalyzed decarboxylation/elimination of enol triflates is described. Key
attributes of the method include readily available starting materials, broad
functional group tolerance, and the ability to access terminal, internal,
and halogenated alkynes. The preliminary scope of the reaction is
demonstrated on 25 different examples with yields ranging from 63% to
96%.
lkynes represent one of the most fundamental building
blocks in synthetic chemistry. The ubiquitous roles they
Scheme 1. Vinyl/Enol Triflates as Alkyne Precursors
A
play as substrates in various catalytic methodologies, as key
pharmacophores in biologically active molecules, in bioconju-
gation, and in material science have solidified this functional
group as an indispensable tool in the synthetic chemist’s
toolbox.1,2 In response, the synthetic community has devoted
significant effort to devise new approaches to alkynes with an
ever-evolving goal of practicality and robustness pertinent to
both academic and industrial applications.
Despite these efforts, gaps remain in the syntheses of alkynes,
in particular with respect to methodologies capable of accessing
multiple classes of alkynes (i.e., terminal, internal, halogenated)
from a common precursor that would complement more
traditional unilateral approaches. Perhaps more importantly, the
discovery and development of catalytic methodologies that
obviate the requirement of stoichiometric strong bases
commonly employed in alkyne syntheses would broaden
functional group tolerance and expand application to more
structurally complex alkynes. Nonetheless, progress has been
made in this area, particularly in the synthesis of internal
alkynes where modern catalytic cross-coupling strategies
between terminal alkynes and various partners have expanded
the scope beyond the classical Sonagashira reaction.3 This
includes the recent seminal work of Fu,4 Li,5 Yu,6 Wang,7 and
others8 where nontraditional transition-metal-catalyzed modal-
ities have allowed access to a wide array of functionalized
internal alkynes. The only caveat of these approaches is the
requirement of the corresponding starting terminal alkyne that
may be nontrivial to acquire synthetically.
One substrate class that has been exploited successfully
toward the synthesis of alkynes has been vinyl and/or enol
triflates (Scheme 1). Early work by Craig demonstrated the
feasibility of base-mediated elimination of triflic acid from in
situ generated vinyl triflates as a convenient approach to alkynyl
sulfones.9 This was subsequently followed by work from the
groups of Kuwajima,10 Brummond,11 Dudley,12 Lepore,13 and
Fleming14 where the elimination of triflic acid from either vinyl
or enol triflates led to the corresponding alkynes. In spite of
these successes, a catalytic elimination of triflic acid (or its
equivalent) from either vinyl or enol triflates has yet to be
reported.
Our group has exploited enol triflates15 in a number of Pd-
catalyzed transformations to obtain 1,3-dienoates,16 substituted
pyrazoles,17 and enantioenriched chiral allenes.18 During the
Received: June 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01904
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Organic Letters
Letter
course of these studies, we consistently found that enol triflates
containing an allylic ester functionality were incompatible in all
of these methodologies. In hindsight, this outcome is not
surprising given the multitude of Pd-catalyzed reactions that
allylic esters serve as substrates.19 Upon closer inspection, we
were able to determine that enol triflates with allylic esters were
undergoing a tandem decarboxylation/elimination sequence to
yield the corresponding alkyne. With this knowledge in hand,
we set out to optimize this approach as a practical and robust
synthesis of alkynes.
Our initial optimization studies utilized (E)-enol triflate 1
along with various combinations of Pd(0) sources, phosphorus-
based ligands, and triethylamine. The culmination of our efforts
is summarized in Table 1. Gratifyingly, we found that several
Table 1. Selected Optimization Studies for the Tandem Pd-
Catalyzed Decarboxylation/Elimination of 1 to 2
a
b
entry
catalyst (mol %)
ligand (mol %)
time
24 h
yield (%)
1
Pd2dba3 (2.5)
none
none
7
2
PPh3 (5)
24 h
0
3
Pd2dba3 (2.5)
PPh3 (5)
20 min
10 min
20 min
24 h
91
85
9
4
PPh3 (50)
P(2-furyl)3 (5)
PPh(Et)2 (5)
P(OPh)3 (5)
5
6
39
91
8
7
20 min
24 h
c
8
dcpb (2.5)
d
9
dppb (2.5)
24 h
13
92
92
92
10
11
12
Pd(PCy3)2 (5)
Pd(PPh3)4 (5)
Pd(PtBu3)2 (5)
−
−
−
3 h
20 min
45 min
Figure 1. Substrate scope for the Pd-catalyzed decarboxylation/
elimination of (E)-enol triflates. Isolated yields reported are an average
of two separate runs.
a
All reactions were performed at 0.25 M in THF using 2.5 equiv of
b
c
Et3N. Isolated yields. dcpb = 2-(dicyclohexylphosphino)biphenyl.
d
dppb = 1,4-bis(diphenylphosphino)butane.
2). We were also pleased to find that the catalyst loading can be
reduced down to 0.05 mol % (using Pd(PPh3)4) with no
detriment to yield (93%) albeit with longer reaction times (70
h). Furthermore, the method is applicable to the synthesis of
terminal alkynes but with slightly lower yields due to competing
simultaneous Sonogashira cross-coupling with the starting enol
triflate. Finally, halogenated terminal alkynes such as 28 can
also be accessed in good overall yield.
Nonetheless, there are several important limitations that we
wish to divulge at this time. The corresponding (Z)-enol
triflates (such as 29) do participate in the tandem
decarboxylation/elimination to yield alkynes but in much
lower yields and at higher temperatures (Scheme 3). We
believe this to be a direct reflection of the higher energy barrier
associated with the required E1cb-type mechanism that is likely
occurring with these substrates. In addition, cyclic (E)-enol
triflates fail to react under our standard conditions to provide
cyclic alkynes (i.e., 30 to 31). Lastly, we have also attempted to
utilize (E)-enol tosylates,20 for example 32, in this chemistry
but have failed to identify reaction conditions that would lead
to productive formation of alkynes.
Pd-catalyst systems provide high yields of the corresponding
internal alkyne 2. However, it is important to note that the
reaction requires both ligand and a Pd-source to be successful
(entries 1 and 2). Interestingly, excess ligand (entry 4) does not
seem to inhibit the reaction. We ultimately chose the
combination of Pd2dba3 (2.5 mol %) and PPh3 (5 mol %) as
our catalyst system of choice (entry 3) for our preliminary
substrate scope although we believe other catalysts would be
equally effective at promoting this reaction across a broad range
of substrates.
Figure 1 highlights the scope of the method in its current
state of development for the synthesis of internal alkynes.
Overall, isolated yields are generally high with reaction times of
less than 1 h in most cases. In addition, the reaction displays
high functional group tolerance that includes terminal and
internal olefins (as in 6 and 19), ketones (14), acetals (18),
protected amines (21), ethers and esters (24).
We also wish to report several highlights as well as limitations
of this method. First, the reaction performs equally well on
large scale (20 mmol) providing alkyne 2 in 92% yield (Scheme
B
DOI: 10.1021/acs.orglett.6b01904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Highlights of the Method
ACKNOWLEDGMENTS
■
We would like to thank the National Science Foundation
(CHE-1362953) for supporting this work. High-resolution
mass spectrometry data were obtained through the support
from the National Institute of Minority Health and Health
Disparities (G12MD007591) within the NIH.
REFERENCES
■
(1) (a) Diederich, F., Stang, P. J., Tykwinski, R. R., Eds. Acetylene
Chemistry. Chemistry, Biology, and Material Science; Wiley-VCH:
Weinheim, Germany, 2005. (b) Modern Acetylene Chemistry; Stang,
P. J., Diederich, F., Eds.; VCH: Weinheim, Germany, 1995.
́
(c) Chinchilla, R.; Najera, C. Chem. Rev. 2014, 114, 1783.
(2) Chemistry and Biology of Naturally-Occurring Acetylenes and
Related Compounds; Lam, J., Breteler, H., Arnason, T., Hansen, L.,
Eds.; Elsevier: Amsterdam, 1988.
(3) For selected reviews on the Sonogashira cross-coupling reaction,
see: (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
́
(b) Negishi, E.-i.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442. (d) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed.
2007, 46, 834.
(4) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
(5) Liu, X.; Wang, Z.; Cheng, X.; Li, C. J. Am. Chem. Soc. 2012, 134,
14330.
Scheme 3. Limitations of the Method
(6) He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013,
135, 3387.
(7) (a) Ye, F.; Ma, X.; Xiao, Q.; Li, H.; Zhang, Y.; Wang, J. J. Am.
Chem. Soc. 2012, 134, 5742. (b) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J.
Am. Chem. Soc. 2010, 132, 13590. (c) Xia, Y.; Feng, S.; Liu, Z.; Zhang,
Y.; Wang, J. Angew. Chem., Int. Ed. 2015, 54, 7891.
(8) For selected related references, see: (a) Zhao, Y.; Wang, H.; Hou,
X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128,
15048. (b) Yi, J.; Sun, Y.-Y.; Xiao, B.; Liu, L. Angew. Chem., Int. Ed.
2013, 52, 12409. (c) Cahiez, G.; Gager, O.; Buendia, J. Angew. Chem.,
Int. Ed. 2010, 49, 1278. (d) Dubbaka, S. R.; Kienle, M.; Mayr, H.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 9093. (e) Luo, F.-X.; Xu,
X.; Wang, D.; Cao, Z.-C.; Zhang, Y.-F.; Shi, Z.-J. Org. Lett. 2016, 18,
2040.
(9) Clasby, M. C.; Craig, D. Synlett 1992, 1992, 825.
(10) Sugai, M.; Tanino, K.; Kuwajima, I. Synlett 1997, 1997, 461.
(11) Brummond, K. M.; Gesenberg, K. D.; Kent, J. L.; Kerekes, A. D.
Tetrahedron Lett. 1998, 39, 8613.
(12) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028.
(13) Maity, P.; Lepore, S. D. J. Org. Chem. 2009, 74, 158.
(14) Fleming, I.; Ramarao, C. Org. Biomol. Chem. 2004, 2, 1504.
(15) Babinski, D.; Soltani, O.; Frantz, D. E. Org. Lett. 2008, 10, 2901.
(16) Crouch, I. T.; Dreier, T.; Frantz, D. E. Angew. Chem., Int. Ed.
2011, 50, 6128.
In conclusion, we have discovered and developed a Pd-
catalyzed tandem decarboxylation/elimination of (E)-enol
triflates to the corresponding alkynes. Salient features of this
method include high functional group tolerance, low catalyst
loadings, and the ability to access terminal, internal, and
halogenated alkynes. Work continues in our laboratories to
identify additional nontraditional catalytic pathways of enol
triflates and related substrates.
(17) Babinski, D. J.; Aguilar, H. A.; Still, R.; Frantz, D. E. J. Org.
Chem. 2011, 76, 5915.
(18) Crouch, I. T.; Neff, R. K.; Frantz, D. E. J. Am. Chem. Soc. 2013,
135, 4970.
ASSOCIATED CONTENT
* Supporting Information
■
(19) For reviews on the Tsuji−Trost reaction, see: (a) Trost, B. M.
S
Acc. Chem. Res. 1980, 13, 385. (b) Backvall, J. E. Acc. Chem. Res. 1983,
̈
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01904.
16, 335. (c) Trost, B. M.; Van V-ranken, D. L. Chem. Rev. 1996, 96,
395. (d) Tsuji, J. Pure Appl. Chem. 1999, 71, 1539. (e) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921. (f) Hyland, C. Tetrahedron
2005, 61, 3457. (g) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(20) (a) Nakatsuji, H.; Ueno, K.; Misaki, T.; Tanabe, Y. Org. Lett.
2008, 10, 2131. (b) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies,
I. W. Org. Lett. 2005, 7, 215.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: doug.frantz@utsa.edu.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01904
Org. Lett. XXXX, XXX, XXX−XXX