Palladium-Catalyzed Synthesis of Conjugated Allenynes via Decarboxylative Coupling

Article abstract of DOI:10.1021/acs.orglett.7b01751

A new strategy to access conjugated allenynes via a decarboxylative coupling of propargyl esters of propiolates has been developed. In this process, allenyl-palladium intermediates are coupled with acetylides that are generated in situ to form the conjuga

Full text of DOI:10.1021/acs.orglett.7b01751

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of Conjugated Allenynes via
Decarboxylative Coupling
Mary K. Smith and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
S
* Supporting Information
ABSTRACT: A new strategy to access conjugated allenynes
via a decarboxylative coupling of propargyl esters of
propiolates has been developed. In this process, allenyl-
palladium intermediates are coupled with acetylides that are
generated in situ to form the conjugated allenynes. Finally, the
coupling is demonstrated to be highly stereospecific, providing
a route to enantioenriched allenes.
llenes, when appropriately functionalized, are important
synthetic targets due to their presence in both natural
stoichiometric organometallics or metal salt additives. The use
of decarboxylation to generate acetylide intermediates should,
in principle, allow this sp−sp2 coupling, producing only CO2 as
a byproduct.6
A
products and biologically active compounds,1 as well as their
utility as uniquely reactive intermediates.2 While there are a
myriad of ways to synthesize allenes,1,3 cross-coupling of
propargyl or allenyl substrates with organometallics remains a
common method to make conjugated allenynes (Scheme 1).4
Decarboxylative coupling has gained significant attention as a
method for the formation of carbon−carbon bonds.7 Since the
development of decarboxylative allylation by Tsuji8 and
Saegusa,9 palladium-catalyzed decarboxylative coupling has
been broadly applied to both allylic and benzylic electro-
philes.6b,d,10 Comparatively, propargyl electrophiles have
received far less attention.11−13 This may be due to the higher
degree of difficulty in achieving chemo- and regioselectivity.11b
Previous efforts to develop palladium-catalyzed decarboxylative
Scheme 1. Palladium-Catalyzed Allenyne Synthesis
coupling of propargyl electrophiles by Bienyame12
and later
́
Stoltz13 employed enolates as the nucleophiles; however, both
are extremely limited in scope and exhibit different
regioselectivities (Scheme 2). The method described herein
aims to use acetylide nucleophiles which would significantly
expand the scope of these decarboxylative reactions.
The palladium-catalyzed cross-coupling protocols, while power-
ful, have inherent issues related to the required use of
preformed organometallics and/or stoichiometric amounts of
base and metal salts.
Our initial studies focused on the palladium(0)-catalyzed
decarboxylative coupling of butynyl phenylpropiolate 1a to
form allenyne 2a. A brief screening of solvents revealed to our
delight that the reaction proceeds cleanly when catalyzed by
Pd(PPh3)4 in a variety of solvents (Table 1, entries 1−3, 5),
though the reaction time is decreased in more polar solvents.
Furthermore, it was determined that the amount of palladium
could be reduced to 5 mol % without any detriment to the yield
(Table 1, entry 4).
Though palladium tetrakis(triphenylphosphine) was shown
to be a competent catalyst for the coupling, a ligand screening
was performed in order to probe the regioselectivity of the
reaction; it has previously been shown that ligand choice can
influence the regioselectivity of couplings with propargyl
electrophiles.14 In all cases the coupling proved to be
An early example of palladium-catalyzed cross-coupling of a
propargyl bromide with a stoichiometric amount of zinc
acetylide to form a conjugated allenyne was reported by
Vermeer.5 Later, Linstrumelle and Jeffery-Luong synthesized
allenynes via cross-coupling of allenyl bromides and copper
acetylides under Sonogashira conditions.4a While this method
utilized catalytic amounts of copper to achieve transmetalation,
the reaction still required the use of basic diethylamine as the
solvent. Tsuji further developed the Sonogashira cross-coupling
by employing propargyl carbonates as the electrophilic partner;
however, superstoichiometric salt additives as well as diethyl-
amine cosolvent were required for a clean, high yielding
reaction.4b,c Guegnot and Linstrumelle also demonstrated the
need for salt additives (3 equiv of ZnCl2) when propargyl
acetates were utilized in the coupling.4d We envisioned that the
use of palladium-catalyzed decarboxylative coupling of
propargyl esters would allow the synthesis of conjugated
allenynes under base-free conditions without the need for
Received: June 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction was more successful with monodentate aryl phosphine
ligands (Table 1, entries 7−8) than with trialkyl phosphine
(Table 1 entry 9) or bidentate ligands (Table 1, entries 10−
12). Overall, Pd(PPh3)4 was determined to be the most ideal
catalyst system.
Scheme 2. Decarboxylative Coupling with Propargyl
Electrophiles
With the optimized conditions in hand, the substrate scope
of the reaction was explored. A variety of propargyl esters were
synthesized via the coupling of readily available propargyl
alcohols and propiolic acids. Treatment of primary propargyl
esters under the standard conditions lead to the formation of
disubstituted allenynes in moderate to good yields (Scheme 3).
a
Scheme 3. Disubstituted Allene Synthesis
Table 1. Optimization of Reaction Conditions
time
(h)
conv
a
yield
a
entry
1
Pd source
ligand
none
solvent
(%)
(%)
Pd(PPh3)4
10 mol %
DMSO-d6
2
100
100
100
100
100
0
17
80
78
77
2
Pd(PPh3)4
10 mol %
none
none
none
none
none
PPh3
20 mol %
Xphos
20 mol %
PnBu3
10 mol %
toluene-d8
CD3CN
CD3CN
THF
4
3
Pd(PPh3)4
10 mol %
2
a
Yield of isolated product. All products were stored under argon at ca.
4
Pd(PPh3)4
5 mol %
3
b
c
d
e
−15 °C upon isolation. 4.5 h. 18 h. 5 h 60 °C for 5 min then
cooled to 50 °C for 18 h.
b
5
Pd(PPh3)4
5 mol %
4
88
6
Pd2(dba)3
5 mol %
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
4
0
76
62
0
The coupling tolerated aromatic, alkyl, and vinyl propiolates
(2a−c). Electron-rich substituents at the para position of the
phenylpropiolate (2d,e) provided the allene in high yield,
whereas electron-poor substituents (2f,g) lead to decreased
yields and longer reaction times. Additionally, the reaction was
tolerant of halogen substituents at various positions on the
phenyl ring, (2h,j) as well as an o-methyl substituent (2i).
Further, the terminal position of the propargyl ester tolerated
methyl, long-chain, and cyclic alkyl groups (2a, 2b, 2k) as well
as protected propargyl alcohols (2l). Unfortunately benzyl
substitution at the propargyl terminus was not as well tolerated
(2m), giving the allene in only 39% yield.
To further expand the scope of the reaction we then explored
the coupling utilizing secondary propargyl esters to synthesize
trisubstituted allenynes (Scheme 4). Unfortunately, initial
efforts into the synthesis of trisubstituted allenynes proved to
be unsuccessful, as when the coupling of hexynyl phenyl-
propiolate (3a) was attempted, only 27% of the desired
7
Pd2(dba)3
5 mol %
4.5
2
100
100
0
8
Pd2(dba)3
5 mol %
9
Pd2(dba)3
5 mol %
22
15
6
10
11
12
Pd2(dba)3
5 mol %
rac-binap
10 mol %
16
7
Pd2(dba)3
5 mol %
dppb
10 mol %
12
11
13
Pd2(dba)3
5 mol %
dppf
10 mol %
23
100
a
Conversion of starting material 1a and yield of 2a as determined by
b
1H NMR spectroscopy with 1,4 dioxane as internal standard. Isolated
yield.
completely selective for the allenyne regioisomer, as no change
in regioselectivity was observed. However, it was found that the
B
DOI: 10.1021/acs.orglett.7b01751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
known processes suggest that the process will occur with
inversion of stereochemistry.4e,h
Scheme 4. Trisubstituted Allene Synthesis
Scheme 5. Stereospecific Decarboxylative Coupling
In conclusion, we have developed a decarboxylative coupling
that forms conjugated allenynes. To our knowledge, this is the
first example of a stereospecific palladium-catalyzed decarbox-
ylative coupling involving propargyl electrophiles. The coupling
is a more waste-free alternative to previous methods used to
synthesize similar conjugated allenes, as CO2 is the only
stoichiometric byproduct.
a
Yield of isolated product. All products were stored under argon at ca.
b
c
d
−15 °C upon isolation. 6 h. 18 h 0.5 h
ASSOCIATED CONTENT
* Supporting Information
■
S
allenyne (4a) was isolated. Reasoning that the low yield of
product may be the result of volatility of the allene, we chose to
make modification to the starting ester. To our delight, when
the p-OMe phenylpropiolate was employed as the nucleophile,
the coupling proceeded with a satisfactory 74% yield.
Additionally, increasing the size at the propargyl terminus of
the ester with a cyclohexyl group (3c) allowed for the isolation
of the desired allenyne (4c) in high yield. Combining the two
previous modifications of the diyne starting material (3d) lead
to a further increase in the yield (4d). Additionally, other alkyl
groups were tolerated at the secondary position (4e,f), as well
as an aromatic group (4g); however, the bulky isopropyl group
required a longer reaction time (18 h), while the aryl group
accelerated the reaction.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01751.
1
Experimental procedures, H, 13C, NMR spectra, HPLC,
and characterization data of all novel products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tunge@ku.edu.
ORCID
Jon A. Tunge: 0000-0002-5849-0888
Notes
Finally, it has been observed that palladium addition to
propargyl electrophiles occurs in an anti-SN2′ fashion.15 With
this knowledge, we hypothesized that the reported decarbox-
ylative coupling could occur stereospecifically.4e To test this, we
first synthesized the enantioenriched propargyl ester (S)-3g in
95% ee, from the corresponding propargyl alcohol.16 Dis-
appointingly, attempting the stereospecific coupling under the
previously optimized conditions led to the isolation of the
nearly racemic 4g. The palladium-catalyzed racemization of
allenes has previously been observed.17 With that in mind, we
decreased the catalyst loading by half, as well as limited the
reaction time to 20 min. Indeed, these conditions allowed for
the stereospecific coupling to occur, yielding the enantioen-
riched allenyne in 88% ee with 93% conservation of
enantiomeric excess (cee) (Scheme 5). While the absolute
stereochemistry for the product was not determined, analogy to
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1465172)
and the Kansas Bioscience Authority Rising Star program for
financial support. Support for the NMR instrumentation was
provided by NSF Academic Research Infrastructure Grant No.
9512331, NIH Shared Instrumentation Grant No.
S10RR024664, and NSF Major Research Instrumentation
Grant No. 0320648.
REFERENCES
■
(1) Hoffmann-Roeder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43,
1196−1216.
(2) (a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
Rev. 2000, 100, 3067−3125. (b) Wegner, H. A.; De Meijere, A.;
C
DOI: 10.1021/acs.orglett.7b01751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Wender, P. A. J. Am. Chem. Soc. 2005, 127, 6530−6531. (c) Yu, S.; Ma,
S. Angew. Chem., Int. Ed. 2012, 51, 3074−3112.
(3) (a) Neff, R. K.; Frantz, D. E. ACS Catal. 2014, 4, 519−528.
(b) Hayashi, T.; Ogasawara, M. Transition Metal-Catalyzed Synthesis
of Allenes. In Modern Allene Chemistry; Hashmi, S. K., Krause, N., Eds.;
Wiley-VCH Verlag GmbH & Co.: Weinheim, 2004; Vol. 1, pp 93−
140.
(4) (a) Jeffery-Luong, T.; Linstrumelle, G. Synthesis 1983, 1983, 32−
34. (b) Mandai, T.; Nakata, T.; Murayama, H.; Yamaoki, H.; Ogawa,
M.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1990, 31, 7179−7180.
(c) Mandai, T.; Murayama, H.; Nakata, T.; Yamaoki, H.; Ogawa, M.;
Kawada, M.; Tsuji, J. J. Organomet. Chem. 1991, 417, 305−311.
(d) Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 3853−
3856. (e) Dixneuf, P. H.; Dixneuf, P. H.; Guyot, T.; Ness, M. D.;
Roberts, S. M. Chem. Commun. 1997, 2083−2084. (f) Tsutsumi, K.;
Ogoshi, S.; Kakiuchi, K.; Nishiguchi, S.; Kurosawa, H. Inorg. Chim.
Acta 1999, 296, 37−44. (g) Condon-Gueugnot, S.; Linstrumelle, G.
Tetrahedron 2000, 56, 1851−1857. (h) Yoshida, M.; Hayashi, M.;
Shishido, K. Org. Lett. 2007, 9, 1643−1646.
(5) Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer, P.
Tetrahedron Lett. 1981, 22, 1451−1452.
(6) (a) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127,
13510−13511. (b) Torregrosa, R. R. P.; Ariyarathna, Y.;
Chattopadhyay, K.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 9280−
9282. (c) Park, K.; Lee, S. RSC Adv. 2013, 3, 14165−14182.
(d) Mendis, S. N.; Tunge, J. A. Org. Lett. 2015, 17, 5164−5167.
(e) Tummanapalli, S.; Muthuraman, P.; Vangapandu, D. N.;
Shanmugavel, G.; Kambampati, S.; Lee, K. W. RSC Adv. 2015, 5,
49392−49399.
(7) Rodriguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030−
5048.
(8) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199−202.
(9) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6381−6384.
(10) (a) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem.
Rev. 2011, 111, 1846−1913. (b) You, S.-L.; Dai, L.-X. Angew. Chem.,
Int. Ed. 2006, 45, 5246−5248. (c) Trost, B. M. J. Org. Chem. 2004, 69,
5813−5837. (d) Recio, A., III; Heinzman, J. D.; Tunge, J. A. Chem.
Commun. 2012, 48, 142−144.
(11) (a) Ambler, B. R.; Peddi, S.; Altman, R. A. Org. Lett. 2015, 17,
2506−2509. (b) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1996,
34, 2589−2612. (c) Zhu, F.-L.; Zou, Y.; Zhang, D.-Y.; Wang, Y.-H.;
Hu, X.-H.; Chen, S.; Xu, J.; Hu, X.-P. Angew. Chem., Int. Ed. 2014, 53,
1410−1414. (d) Zou, Y.; Zhu, F.-L.; Duan, Z.-C.; Wang, Y.-H.; Zhang,
D.-Y.; Cao, Z.; Zheng, Z.; Hu, X.-P. Tetrahedron Lett. 2014, 55, 2033−
2036. (e) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J.
Tetrahedron Lett. 1993, 34, 2161−2164. (f) Ohmiya, H.; Yang, M.;
Yamauchi, Y.; Ohtsuka, Y.; Sawamura, M. Org. Lett. 2010, 12, 1796−
1799.
(12) (a) Bienayme, H. Tetrahedron Lett. 1994, 35, 7387−7390.
(b) Bienayme, H. Tetrahedron Lett. 1994, 35, 7383−7386.
(13) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.;
Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.;
McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D. E.; Levine, S.
R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. - Eur.
J. 2011, 17, 14199−14223.
(14) Locascio, T. M.; Tunge, J. A. Chem. - Eur. J. 2016, 22, 18140−
18146.
(15) (a) Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P.
J. Org. Chem. 1983, 48, 1103−1105. (b) Elsevier, C. J.; Kleijn, H.;
Boersma, J.; Vermeer, P. Organometallics 1986, 5, 716−720.
(16) Frantz, D. E.; Faessler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806−1807.
(17) (a) Burks, H. E.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 8766−8773. (b) Molander, G. A.; Sommers, E. M.; Baker, S. R. J.
Org. Chem. 2006, 71, 1563. (c) Horvath, A.; Baeckvall, J.-E. J. Org.
Chem. 2001, 66, 8120−8126. (d) Elsevier, C. J.; Kleijn, H.; Boersma,
J.; Vermeer, P. Organometallics 1986, 5, 716−720.
D
DOI: 10.1021/acs.orglett.7b01751
Org. Lett. XXXX, XXX, XXX−XXX