A Pd(0)-catalyzed direct dehydrative coupling of terminal alkynes with allylic alcohols to access 1,4-enynes

Article abstract of DOI:10.1021/ja406025p

A direct dehydrative coupling of terminal alkynes with allylic alcohols catalyzed by Pd(PPh₃)₄ with an N,P-ligand assisted by Ti(OiPr)₄ has been developed. The coupling reaction tolerates various functional groups, providing a valuable synthetic tool to access 1,4-enynes.

Full text of DOI:10.1021/ja406025p

Communication
pubs.acs.org/JACS
A Pd(0)-Catalyzed Direct Dehydrative Coupling of Terminal Alkynes
with Allylic Alcohols To Access 1,4-Enynes
Yang-Xiong Li,† Qing-Qing Xuan,† Li Liu,*,† Dong Wang,† Yong-Jun Chen,† and Chao-Jun Li*,‡
†Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 0B8
S
* Supporting Information
directly from allylic alcohols and terminal alkynes under
ABSTRACT: A direct dehydrative coupling of terminal
alkynes with allylic alcohols catalyzed by Pd(PPh3)4 with
an N,P-ligand assisted by Ti(OiPr)4 has been developed.
The coupling reaction tolerates various functional groups,
providing a valuable synthetic tool to access 1,4-enynes.
transition-metal catalysis is still a challenging task.
Herein we report a direct dehydrative coupling reaction of
terminal alkynes with allylic alcohols catalyzed by Pd(PPh3)4
with an N,P-ligand assisted by Ti(OiPr)4 to access 1,4-enynes
(Figure 1), which significantly extends the scope of the Trost−
Tsuji reaction.
he Pd-catalyzed allylation of carbon nucleophiles with
T
allylic compounds via π-allylpalladium intermediates (the
Trost−Tsuji reaction) represents one of the most important
developments in modern synthetic chemistry1 and has a broad
range of applications in the synthesis of natural products and
bioactive compounds such as (+)-nigellamine A and
aeruginosin 98B.1e−h In general, the leaving groups of
functionalized allylic compounds include halides, acetates,
ethers, sulfones, carbamates, and phosphates. However, there
are very few examples of the use of allylic alcohols in the
Trost−Tsuji reaction because of the very poor leaving ability of
the hydroxyl group.2 On the other hand, the reaction is also
very sensitive to the acidity of the C−H bond of the
pronucleophile;1,3 thus, terminal alkynes have never been
successfully used as pronucleophiles under the standard
conditions of the Trost−Tsuji reaction.4 In fact, the reaction
of terminal alkynes with allylic electrophiles catalyzed by
palladium generally affords 1,4-diene products, and the 1,4-
enyne product has never been observed.5−7
Figure 1. Pd-catalyzed dehydrative coupling of allylic alcohols with
terminal alkynes.
We began our study by using the reaction of
(triisopropylsilyl)acetylene (1a) with Morita−Baylis−Hillman
(MBH) alcohol 2a in the presence of Pd(PPh3)4 (10 mol %) as
a catalyst (Table 1). No desired product 3a was detected, and
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
additive
none
yield (%)
1
2
3
4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
none
0
0
1,4-Enynes are versatile reagents in organic synthesis and
important structural motif in natural products and biologically
active compounds.8 Stoichiometric syntheses of 1,4-enynes
from functionalized allylic compounds with terminal alkynes
involving metalated species have been described.9 It is
noteworthy that the stable and readily available allyl substrates
for transition-metal-catalyzed allylic substitutions are usually
prepared from the corresponding allylic alcohols. For synthetic
efficiency, it would be much more desirable to generate the 1,4-
enynes directly from allylic alcohols and terminal alkynes.10 It
was reported that Ni(0) could catalyze the coupling of allyl
esters with terminal alkynes to give 1,4-enynes through a
different mechanism from the Pd-catalyzed coupling reactio-
n.7a−c Although in limited cases dehydrative coupling of some
active allylic alcohols with terminal alkynes can proceed under
the catalysis of a Lewis acid such as Cu(OTf)2 via a carbocation
mechanism,11 the Pd(0)-catalyzed direct coupling reaction of
allylic alcohols with terminal alkynes has not been demon-
strated to date. How to access diverse 1,4-enyne derivatives
Cu(OMe)2
Al(OiPr)3
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
0
91
6
c
5
6
0
a
Conditions: 1a (0.5 mmol), 2a (0.2 mmol), catalyst (10 mol %),
b
c
additive (25 mol %), dioxane, N2, 90 °C. Isolated yields Pd(PPh3)4
(5 mol %).
only mostly dimerized 1a was obtained. The direct activation of
allylic alcohols to generate π-allyl species is a key challenge in
transition-metal-catalyzed nucleophilic allylic substitution,
which can be facilitated by a Lewis acid.2 However, the
addition of Cu(OMe)2 or Al(OiPr)3 did not improve the yield
of 3a at all. It was reported that in the Pd-catalyzed amination
Received: June 16, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja406025p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
of allylic alcohols, Ti(OiPr)4 as a Lewis acid helped to activate
the allylic alcohol in generating a π-allylpalladium intermedi-
ate.12 To our delight, the desired 1,4-enyne product 3a was
obtained in 91% yield directly from allylic alcohol 2a and
terminal alkyne 1a with exclusive γ-regioselectivity in the
Pd(PPh3)4/Ti(OiPr)4 catalytic system. When the Pd(0)
catalyst loading was decreased to 5 mol %, the yield of 3a
decreased sharply to 6%. No reaction was observed in the
absence of Pd(PPh3)4 using Ti(OiPr)4 alone. Thus, the
combination of Pd(PPh3)4 and Ti(OiPr)4 is essential and
synergistically catalyzes the direct coupling of allylic alcohols
with terminal alkynes.
Figure 2. Bidentate ligands tested.
Using bisphosphine ligands L2 and L3 in the coupling reaction
afforded the 3g in yields of 61% and 0%, respectively.
Surprisingly, the combination of N,P-ligand L4 with PPh3 led
to a remarkable increase in the yield of 3g up to 82%. When L5
was used, the coupling reaction afforded 3g in only 55% yield.
Reducing the loadings of L4 and Pd(PPh3)4 decreased the yield
sharply. The use of L4 together with Pd2(dba)3 led to a sharp
decrease in the yield of 3g to 13%.
With the further-optimized conditions in hand, various allylic
alcohols 2g−q (poor substrates under the previous conditions)
were reacted with terminal alkyne 1a, and the corresponding
products 3g−q were obtained in good to excellent yields (66−
99%) (Scheme 1). The coupling constant (JH = 15.7 Hz)
Subsequently, under the standard conditions with the
Pd(PPh3)4/Ti(OiPr)4 catalyst, various allylic alcohols were
reacted with terminal alkyne 1a (Table 2). MBH alcohols 2a−d
Table 2. Pd(0)-Catalyzed Allylation of 1a with 2a−i Assisted
a
by Ti(IV)
a
Scheme 1. Pd-Catalyzed Coupling of 1a with 2g−q
b
entry
2 (R1, R2)
product
yield (%)
1
2
3
4
2a (C6H5, COOMe)
2b (2-MeC6H4, COOMe)
2c (3-MeC6H4, COOMe)
2d (3-MeOC6H4, COOMe)
2e (C6H5, Me)
3a
3b
3c
3d
3e
3f
91
92
84
93
99
98
c
5
c
6
2f (4-MeC6H4, Me)
2ga (C6H5, H)
d
7
8
9
3g
3h
3i
0, 18
2h (4-MeC6H4, COOMe)
2i (Me, H)
0
13
a
Conditions: 1a (0.5 mmol), 2 (0.2 mmol), Pd(PPh3)4 (10 mol %),
b
c
Ti(OiPr)4 (25 mol %), dioxane, N2, 90 °C. Isolated yields. Reaction
time 10 h. From cinnamyl alcohol (2gb).
d
reacted efficiently to give the corresponding 1,4-enyne products
3a−d (entries 1−4). Allylic alcohols 2e and 2f also reacted
smoothly to give the corresponding products 3e and 3f almost
quantitatively (entries 5 and 6). The configuration of the newly
generated double bond in the products was deduced to be E by
nuclear Overhauser effect spectroscopy (NOESY) analysis,
which suggested that the geometries of the π-allylpalladium
complexes generated from MBH alcohols and normal allylic
alcohols (e.g., 2e) could be different.13 However, the
Pd(PPh3)4/Ti(OiPr)4 catalyst system was very sensitive to
the structure of the allylic alcohol: a minor change of the
substituent from methyl to H derailed the reaction completely
(reducing the yield of 3 to 0% from 99%; entry 5 vs 7), and
MBH alcohol 2h similarly failed to give any desired product 3h
(entry 8). In addition, the use of alkyl-substituted allylic alcohol
2i resulted in a very low yield of the desired product 3i (entry
9). In all cases of low yields of the coupling reaction, only
dimerization of 1a was observed.
Thus, major efforts were made to further optimize the
coupling reaction in order to extend its scope. Bidentate ligands
are known to facilitate Pd(0)-catalyzed cross-coupling reac-
tions.14 Thus, several bidentate ligands (Figure 2) were
examined using allylic alcohol 2ga as the benchmark testing
substrate. The use of diamine ligand L1 together with the
Pd(PPh3)4/Ti(OiPr)4 catalyst system in the reaction of 2ga
with 1a gave only a trace of the desired coupling product 3g.
a
b
c
Conditions: see the Supporting Information. From 2ga. From 2gb.
indicated the E configuration of the newly formed double bond.
The structural diversity of the 1,4-enyne cross-coupling
products was greatly enhanced under the Pd(PPh3)/L4
conditions.
Notably, under the catalysis of Pd(0)/L4/Ti(OiPr)4, 2ga and
its isomer 2gb gave the same product 3g in excellent yields with
exclusive γ-regioselectivity, which indicated the generation of
the same π-allylpalladium intermediate in the two palladium-
catalyzed allylation reactions. In constrast, low yields of 3g (0%
or 18%, respectively) were obtained under the earlier
conditions (Table 2, entry 7). Among allylic alcohol 2ga
derivatives, both para- and meta-substituted substrates gave the
desired products 3m−o in good yields. Interestingly, less
reactive alkylallylic alcohols also provided the coupling products
3i−l in excellent yields (83−99%).
B
dx.doi.org/10.1021/ja406025p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Subsequently, we examined the coupling of arylacetylenes 4
with cinnamyl alcohol 2gb (Scheme 2). In these cases, a
a
Scheme 2. Pd(0)-Catalyzed Coupling of 4 with 2gb
Figure 3. Tentative mechanism for the Pd-catalyzed catalytic coupling
of terminal alkynes with allylic alcohols.
a
b
Conditions: see the Supporting Information. From 2ga.
Pd(PPh3)4 assisted by Ti(OiPr)4, and the scope of the coupling
is further extended by using a N,P-ligand. The coupling
reaction tolerates various functional groups, providing a
valuable synthetic tool to access 1,4-enynes readily. The
scope, mechanism, and synthetic applications of this novel
coupling are under further investigation.
catalytic amount of diisopropylethylamine (DIPEA) (2 mol %)
was found to be beneficial to activate the alkynyl C−H bond.
Various substituted phenylacetylenes 4a−f (R = H, Ph, NO2, p-
CH3, o-CH3, m-CH3) were successfully transformed into the
desired products 5a−f in 57−71% isolated yield.
Hypoxoside is a norlignan diglucoside isolated from the
corms of Hypoxis plants [African potato (AP)].9,15 The inactive
hypoxoside is deglucosylated by β-glucosidase to form rooperol
(Scheme 3). In pharmacological studies, the derivatives of
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
Scheme 3. Synthesis of Compound 6
AUTHOR INFORMATION
Corresponding Author
lliu@iccas.ac.cn; cj.li@mcgill.ca
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Foundation of China
(21072193, 21232008), the Ministry of Science and Technol-
ogy (2011CB808600), and the Chinese Academy of Sciences
for financial support. C.-J.L. is a Canada Research Chair at
McGill University.
rooperol exhibited good anticancer bioactivities.15 Among
them, compound 6 showed the best anticancer activity for
the inhibition of human esophageal carcinoma cell growth
(IC50 = 10 μg/mL; 2.5 times more active than rooperol).16 To
illustrate the potential synthetic application of this novel
coupling, 6 was efficiently synthesized through the direct
reaction of 4-methoxyphenylacetylene (7) with 2gb in 58%
yield under the conditions of Pd(0)/L4/DIPEA catalysis. Both
substrates are commercially available, and the synthetic
protocol is very convenient.
The proposed mechanism for this novel coupling is shown in
Figure 3. The hydroxyl group of the allylic alcohol is activated
by Ti(OiPr)4 to generate allylic titanate A, which reacts with
the Pd(0)/L4 species to form a π-allylpalladium intermediate
B. The amino group of the N,P-ligand in B can help to
deprotonate the terminal alkyne intramolecularly to form
intermediate C. Subsequently, C can be transformed into the
1,4-enyne via the formation of intermediate D followed by
reductive elimination.
REFERENCES
■
(1) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965,
6, 4387. (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95,
292. (c) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(d) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(e) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem. Soc.
1987, 109, 4335. (f) Bian, J. W.; Van Wingerden, M.; Ready, J. M. J.
Am. Chem. Soc. 2006, 128, 7428. (g) Trost, B. M.; Kaneko, T.;
Andersen, N. G.; Tappertzhofen, C.; Fahr, B. J. Am. Chem. Soc. 2012,
134, 18944. (h) Arthuis, M.; Beaud, R.; Gandon, V.; Roulland, E.
Angew. Chem., Int. Ed. 2012, 51, 10510.
(2) For an excellent review, see: Sundararaju, B.; Achard, M.;
Bruneau, C. Chem. Soc. Rev. 2012, 41, 4467.
(3) (a) Organ, M. G.; Arvanitis, E. A.; Dixon, C. E.; Cooper, J. T. J.
Am. Chem. Soc. 2002, 124, 1288. (b) Trost, B. M.; Verhoeven, T. R. J.
Am. Chem. Soc. 1980, 102, 4730.
(4) For examples of Pd-catalyzed decarboxylative coupling of alkynyl
carboxylic acids with allylic electrophiles, see: (a) Rayabarapu, D. K.;
Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510. (b) Zhang, W. W.;
Zhang, X. G.; Li, J. H. J. Org. Chem. 2010, 75, 5259.
In conclusion, a palladium-catalyzed direct dehydrative
coupling of terminal alkynes with allylic alcohols to give 1,4-
enynes has been developed. The reaction is catalyzed by
C
dx.doi.org/10.1021/ja406025p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(5) (a) Huang, J.; Zhou, L.; Jiang, H. Angew. Chem., Int. Ed. 2006, 45,
1945. (b) Fukushima, M.; Takushima, D.; Satomura, H.; Onodera, G.;
Kimura, M. Chem.Eur. J. 2012, 18, 8019.
(6) For the Ru-catalyzed reaction of terminal alkynes with allylic
alcohols to provide β,γ- or γ,δ-unsaturated carbonyl compounds, see:
(a) Trost, B. M.; Dyker, G.; Kulawiec, R. J. J. Am. Chem. Soc. 1990,
112, 7809. (b) Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1992,
́
114, 5579. (c) Derien, S.; Jan, D.; Dixneuf, P. H. Tetrahedron 1996, 52,
5511. (d) Derien, S.; Dixneuf, P. H. J. Chem. Soc., Chem. Commun.
1994, 2551.
(7) For Ni(0)-catalyzed coupling reactions of allyl esters with
terminal alkynes, see: (a) Catellani, M.; Chiusoli, G. P.; Salerno, G.;
Dallatomasina, F. J. Organomet. Chem. 1978, 146, 19. (b) Leadbeater,
N. E. J. Org. Chem. 2001, 66, 7539. (c) Ikeda, S.; Suzuki, K.; Odashima,
K. Chem. Commun. 2006, 457. For other methods providing 1,4-
enynes, see: CuI-catalyzed coupling of allylic halides and alkynes:
(d) Bieber, L. W.; da Silva, M. F. Tetrahedron Lett. 2007, 48, 7088.
(e) Liang, Z. Q.; Ma, S. M.; Yu, J. H.; Xu, R. R. J. Org. Chem. 2007, 72,
9219. Pd(0)-catalyzed coupling of allenic/propargylic zinc reagents:
(f) Ma, S. M.; Zhang, A. B. J. Org. Chem. 2002, 67, 2287.
(8) (a) Nair, V. P.; Dairam, A.; Agbonon, A.; Arnason, J. T.; Foter, B.
C.; Kanfer, A. I. J. Agric. Food Chem. 2007, 55, 1707. (b) Liebenberg,
R. W.; Kruger, P. B.; Bouic, P. J. D.; Albrecht, C. F. V.; E.U. Patent
93307030.2, 1993. (c) Maudene, P.; George, L. W.; Siegfried, E. D.
Phytochemistry 1988, 127, 1101. (d) Kazuo, D.; Takashi, J.; Tomoo, S.;
Shigetoshi, T. Bull. Chem. Soc. Jpn. 1988, 61, 4353. (e) Nicoletti, M.;
Galeffi, C.; Messana, I.; Marini-Bettolo, G. B. J. Ethnopharmacol. 1992,
36, 95.
(9) (a) Keyes, R. F.; Carter, J. J.; Englund, E. E.; Daly, M. M.; Stone,
G. G.; Nilius, A. M.; Ma, Z. J. Med. Chem. 2003, 46, 1795.
(b) Nishikawa, T.; Isobe, M. Biosci., Biotechnol. Biochem. 1999, 63, 238.
(c) Cui, D.-M.; Hashimoto, N.; Ikeda, S.; Sato, Y. J. Org. Chem. 1995,
60, 5752. (d) Yohei, K.; Yuichi, K. J. Org. Chem. 2009, 74, 7489.
(e) Chen, H.; Deng, M. Z. J. Organomet. Chem. 2000, 603, 189.
(10) For review of dehydrative coupling strategies, see: Kumar, R.;
Van Der Eycken, E. V. Chem. Soc. Rev. 2013, 42, 1121.
(11) (a) Ren, K.; Li, P.-H.; Wang, L.; Zhang, X.-L. Tetrahedron 2011,
67, 2753. (b) Wu, C.; Zeng, H.; Liu, Z.; Liu, L.; Wang, D.; Chen, Y.-J.
Chin. J. Chem. 2011, 29, 2732.
(12) (a) Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M. J. Org. Chem.
1997, 62, 4877. (b) Yang, S.-C.; Hung, C.-W. J. Org. Chem. 1999, 64,
5000. (c) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett.
2005, 7, 2993. (d) Yang, S.-C.; Tsai, Y.-C. Organometallics 2001, 20,
763. (e) Shue, Y.-J.; Yang, S.-C.; Lai, H.-C. Tetrahedron Lett. 2003, 44,
1481.
(13) Trost, B. M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000,
122, 3534.
(14) (a) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 4321. (b) Birkholz, M.-N.; Freixab, Z.;
van Leeuwen, P. W. N. M. Chem. Soc. Rev. 2009, 38, 1099.
(c) Lundgren, R. J.; Stradiotto, M. Chem.Eur. J. 2012, 18, 9758.
(15) Albrecht, C. F.; Theron, E. J.; Kruger, P. B. S. Afr. Med. J. 1995,
85, 853.
(16) Drewes, S.; Liebenberg, R. W. U.S. Patent 4,652,636, 1987.
D
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