Phosphine-mediated regio- and stereoselective hydrocarboxylation of enynes

Article abstract of DOI:10.1021/ol4031556

A phosphine-mediated regio- and stereoselective addition reaction of diverse nucleophiles to yne-enones leading to polysubstituted 1,3-diene scaffolds in moderate to good yields has been reported.

Full text of DOI:10.1021/ol4031556

Letter
pubs.acs.org/OrgLett
Phosphine-Mediated Regio- and Stereoselective Hydrocarboxylation
of Enynes
Wenbo Li and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P.R. China
S
* Supporting Information
ABSTRACT: A phosphine-mediated regio- and stereoselective addition
reaction of diverse nucleophiles to yne-enones leading to polysubstituted
1,3-diene scaffolds in moderate to good yields has been reported.
unctionalized 1,3-dienes are important building blocks in
Forganic synthesis, which have been successfully employed
in Diels−Alder reactions,1 cycloadditions,2 and asymmetric
hydrogenation reactions.3 Surprisingly, the stereocontrolled
synthesis of functionalized 1,3-dienes has rarely aroused
extensive attention, despite the fact that different stereoisomers
often have different reactivity and give different stereoisomers
in organic reactions.4 For example, 1,3-alkadien-2-yl carbox-
ylates have been synthesized either by addition of organic
carboxylic acids to vinylacetylene5 or through rearrangement of
2-alkynyl carboxylates6 or 2,3-allenyl carboxylates.7 Pu and co-
workers found that γ-hydroxyl-α,β-acetylenic esters could be
catalyzed by DMAP in acetic anhydride to generate γ-acetoxy
dienoates.8 As an alternative method for the synthesis of 1,3-
butadienes, the application of a ring-opening strategy of
cyclobutenes at extremely high temperature has been reported.9
via regio- and stereoselective addition to the alkyne moiety
Even though some recent progress10 has been made in this
under the catalysis of phosphine (eq 3).
field, the substitutions are almost limited to the 3,4-position of
We began our investigation using (E)-2-benzylidene-1-
1,3-alkadienes with unsatisfied stereoselectivity.
phenylbut-3-yn-1-one (1a) and HOAc as a model reaction
During the past decade, tertiary phosphines have emerged as
efficient and mild nucleophilic catalysts for an impressive range
of transformations involving activated allenes and alkynes as
starting materials.11,12 Recently, we disclosed the phosphine13
or base14-catalyzed tandem reactions of yne-enones as good
Michael acceptors with various nucleophiles to prepare acyclic
and cyclic compounds. It is to be noted that the addition
reactions of yne-enones and weak nucleophiles such as
malonates and 1,3-diketones lead to substituted 1,2-allenes,
whereas the addition reactions of yne-enones and heteroatom
nucleophiles such as thiols and pyrrolidine produce fuctional-
ized 1,3-dienes (eq 1). The regioselectivity is controlled by the
nature of the nucleophile. Our group15 and others16 reported a
series of metal-catalyzed cyclizations of yne-enones with various
nucleophiles including alcohols or acetic acid, which attach
onto an alkene (eq 2). Herein, we describe a novel method for
the stereoselective synthesis of functionalized 1,3-butadiene
derivatives from yne-enones and various O-based nucleophiles
(Table 1). This test reaction was carried out in the presence of
20 mol % PPh3 at room temperature to provide 3-benzoyl-4-
phenylbuta-1,3-dien-2-yl acetate 2a in 34% yield (entry 1).
With increasing reaction temperature, the better result was
obtained at 35 °C to afford the desired product in 62% yield
with E/Z = 6.2:1 (entries 2−3). Other solvents such as DCE,
CH3CN, THF, and CH2Cl2 had unfavorable consequences on
the reaction yield and stereoselectivity (entries 4−7). Increasing
the amount of acetic acid gradually improved the reactivity
(entries 8−10). When the reaction was performed using 5
equiv of acetic acid, the desired addition product 2a was
obtained in 72% yield with E/Z = 7.2:1 (entry 9). The yield
improved to 77% by increasing the concentration of the
reactants (2 M) (entry 11). Furthermore, the E/Z ratio
increased to 11.0:1 with a slightly lower yield when the reaction
Received: November 1, 2013
Published: December 9, 2013
© 2013 American Chemical Society
162
dx.doi.org/10.1021/ol4031556 | Org. Lett. 2014, 16, 162−165

Organic Letters
Letter
a
with perfect stereoselectivity (entries 2−5 and 8). Reactions of
substrates bearing an electron-withdrawing substituent were
faster than those of substrates bearing an electron-donating
substituent. Compounds 1g and 1h were transformed into the
corresponding dienes 2g and 2h in 81% and 83% yield,
respectively, whereas the E/Z ratio of 2h was somewhat lower
(2.7:1) (entries 6 and 7). Surprisingly, besides dienes, triene 2j
could be synthesized using this method in 50% yield as a
mixture of E/Z stereoisomers along with 20% unreacted
substrate 1j (entry 9). It is also noteworthy that the reaction of
enyne 1k with a formyl group could give the desired product 2k
in 48% yield with moderate E/Z (entry 10). Finally, we
expanded the reaction to (E)-methyl 3-benzylidene-2-oxopent-
4-ynoate 1l, which afforded the corresponding product 2l in
62% yield after 1 h (entry 11).
Table 1. Optimization of Reaction Conditions
b
c
entry
x equiv
solvent
T (°C) t (h) yield (%)
E/Z
--
1
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
5.0
10.0
5.0
5.0
−
toluene
toluene
toluene
DCE
25
35
50
35
35
35
35
35
35
35
35
25
25
25
36
36
36
36
36
36
36
24
18
18
9
34
62
38
43
16
n.r.
39
68
72
64
77
72
17
n.r.
6.2:1
3.7:1
4.4:1
4.3:1
--
3
4
5
CH3CN
THF
6
7
CH2Cl2
toluene
toluene
toluene
toluene
toluene
HOAc
toluene
11.0:1
7.4:1
7.2:1
7.8:1
8.0:1
11.0:1
>20:1
−
8
Next, other weak nucleophiles were examined, and the
results are listed in Table 3. Besides acetic acid, arylcarboxylic
9
10
d
11
a
d
Table 3. Scope of Nucleophile Component 3
12
9
d
13
36
9
de
,
14
5.0
a
Reaction conditions unless otherwise noted: 1a (0.25 mmol), HOAc
b
(x equiv), PPh3 (20 mol %), solvent (2.5 mL). Isolated yield.
c
d
1
Determined by H NMR of crude product. Reaction conditions: 1a
(0.5 mmol), HOAc (x equiv), PPh3 (20 mol %), solvent (2.5 mL).
e
No PPh3 was added.
was performed at room temperature (entry 12). Reactions
using acetic acid as the solvent gave 2a in only 17% yield as a
single E isomer after 36 h (entry 13). It was clear that the
reaction cannot occur without the PPh3 catalyst (entry 14).
With the optimal reaction conditions in hand (Table 1, entry
12), we next examined the scope and limitation of this
transformation by variation of the terminal yne-enone 1
component (Table 2). It was found that, in addition to
aromatic enone, aliphatic enone 1b could be compatible to
finish the addition adduct almost as a single geometrical isomer
(entry 1). For terminal yne-enones, both electron-withdrawing
and -donating groups on the alkenyl moiety gave good yields
a
Reaction conditions: 1a (0.5 mmol), NuH (1.5 mmol), PPh3 (20 mol
%), toluene (2.5 mL) at room temperature. E/Z was determined by
1H NMR of crude product.
acids such as 2-furoic acid, 2-thenoic acid, benzoic acid, and 4-
nitrobenzoic acid also turned out to be viable substrates for the
SN2′ reaction of terminal yne-enones, producing the corre-
sponding dienes 3a−3d in good yields and excellent stereo-
selectivites. Excitingly, the addition of phenols to enynes can be
also achieved under the standard conditions. Phenol and 2-
iodophenol reacted with yne-enone 1b to provide the
corresponding dienes 3e−3f in moderate yields,17 as E isomers
exclusively.
To our delight, a wide variety of internal yne-enones were
well tolerated in the addition reaction, providing reaction
products 5 in good yields and selectivitites using a more
nucleophilic phosphine catalyst (Table 4). The reaction of (E)-
3-benzylidene-5-phenylpent-4-yn-2-one (4a) with acetic acid
proceeded smoothly to produce tetrasubstituted diene (1E,3E)-
5a in 70% yield as a single geometrical isomer after 5 h at room
temperature (entry 1). Not only aromatic but also aliphatic-
substituted yne-enones on the alkynyl moiety were tolerated
even if a 3.6:1 mixture of stereoisomers was observed in the
case of the n-butyl-substituted yne-enone 4d (entries 2−4).
Yne-enones containing electron-donating and -withdrawing aryl
substituents on the alkenyl moiety provided products 5e−5g as
a single isomer in good yields in only 1−3 h (entries 5−7). The
a
Table 2. Variation of Terminal Yne-Enone 1 Component
b
c
entry
R1/R2 (1)
Me/Ph (1b)
time (h)
yield (%)
2, E/Z
1
5
12
48
8
83
71
74
73
79
81
83
66
50
48
62
2b, 18.0:1
2c, >20:1
2d, >20:1
2e, >20:1
2f, 14.0:1
2g, 10.0:1
2
Me/4-MeC6H4 (1c)
Me/4-MeOC6H4 (1d)
Me/4-ClC6H4 (1e)
Me/4-NCC6H4 (1f)
4-MeOC6H4/Ph (1g)
4-ClC6H4/Ph (1h)
Ph/1-naphthyl (1i)
Ph/styryl (1j)
3
4
5
4
6
24
12
88
48
5
e
7
2h, 2.7:1
8
2i, >20:1
d
9
2j, 2.9:1
e
10
11
H/Ph (1k)
2k, 6.3:1
CO2Me/Ph (1l)
1
2l, 11.9:1
a
Reaction conditions: 1 (0.5 mmol), HOAc (2.5 mmol), PPh3 (20
mol %), toluene (2.5 mL) at room temperature. Isolated yield.
Determined by H NMR of crude product. Reaction performed at
b
c
d
1
e
50 °C, recovery of 20% 1j. Isolated ratio of two isomers.
163
dx.doi.org/10.1021/ol4031556 | Org. Lett. 2014, 16, 162−165

Organic Letters
Letter
a
We proposed a mechanism for this phosphine-mediated
regioselective addition reaction as shown in Scheme 2. The
Table 4. Variation of Internal Yne-Enone 4 Component
Scheme 2. Possible Mechanism
b
entry
R1/R2/R3 (4)
Me/Ph/Ph (4a)
t (h)
5, yield (%)
1
5
2
3
2
3
1
1
2
2
2
2
5a, 70
5b, 76
5c, 74
2
Me/Ph/4-MeOC6H4 (4b)
Me/Ph/4-MeOCC6H4 (4c)
Me/Ph/n-C4H9 (4d)
Me/4-MeOC6H4/Ph (4e)
Me/4-ClC6H4/Ph (4f)
Me/4-NCC6H4/Ph (4g)
Ph/Ph/Ph (4h)
3
c
4
5d, 66 (3.6:1)
5e, 77
5
6
5f, 67
7
5g, 64
d
8
5h, 84
c
9
4-MeOC6H4/Ph/Ph (4i)
4-ClC6H4/Ph/Ph (4j)
H/Ph/Ph (4k)
5i, 67 (2.6:1)
5j, 88 (3.7:1)
c
10
11
c
5k, 55 (3.3:1)
nucleophilic addition of phosphine to the yne-enone gives the
corresponding zwitterionic intermediate, enolate A, and its
resonance form progargylic carbanion B and allenyl carbanion
C.13b Subsequent protonation by the acetic acid would produce
the allenyl ketone type intermediate D and acyloxy anion.
Nucleophilic addition followed by β′-elimination of the
phosphine or SN2′ type substitution of the phosphine by the
acyloxy anion would afford the highly functionalized 1,3-diene
and regenerate the phosphine catalyst.
In conclusion, we have described a phosphine-mediated
regioselective addition reaction between yne-enones and
various nucleophiles (carboxylic acids, phenols), furnishing
highly functionalized 1,3-dienes in good to excellent yields with
high levels of selectivity for the olefin geometry. The
transformation is general with respect to a broad range of
substrates including terminal and internal yne-enones, with the
latter requiring a more nucleophilic phosphine catalyst. Further
studies focusing on extending the scope of substrates and
synthetic applications will be reported in due course.
a
Reaction conditions: 4 (0.3 mmol), HOAc (1.5 mmol), MePPh2 (20
b
mol %), toluene (2.5 mL) at room temperature. Isolated yield. No
other isomers were found unless otherwise noted. Isolated ratio of
two major isomers. Trace amounts of two other isomers were
detected by H NMR analysis of the crude product.
c
d
1
substrate 4h, which has a phenyl group on the α-position of
ketone, was converted to buta-1,3-diene 5h in 84% isolated
yield for the major stereoisomer (entry 8). Notably, electron-
rich and halide-substituted groups on the phenyl ring of R1
were compatible, and the reactions gave compounds 5i and 5j
in good to excellent yields as mixtures of two stereoisomers
(entries 9−10). To our delight, even the reaction of enyne 4k
with an aldehydyl group also proceeded to afford the
corresponding diene 5k in 55% yield, albeit as a 3.3:1 mixture
of two stereoisomers (entry 11). The relative configuration of
5g was confirmed via X-ray crystallographic analysis to be (1E,
3E) (Figure 1).18 Moreover, treatment of (E)-3-(4-chloroben-
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. X-ray crystallographic analysis of 1,3-diene 5g.
AUTHOR INFORMATION
Corresponding Author
■
zylidene)-4-oxopent-1-en-2-yl acetate 2e with Selectfluor
generated the corresponding fluorinated ketone 6 in 64%
yield.7c Notably, the reaction of diene 2e with hydrazine
hydrate in DMA under air was complete within 1 h to give the
corresponding pyrazole 7 in 62% yield (Scheme 1).
*E-mail: jlzhang@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China, the 973 Program (2011CB808600), Fok Ying Tung
Education Foundation (121014), and Science and Technology
Commission of Shanghai Municipality (12XD1402300).
Scheme 1. Synthetic Application of the Diene 2e
REFERENCES
■
(1) For examples, see: (a) Fringuelli, F.; Taticchi, A. Dienes in the
Diels−Alder Reaction; John Wiley & Sons: New York, 1990.
(b) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (c) Pollini, G. P.; Bianchi, A.; Casolari, A.; Risi,
C.; Zanirato, V.; Bertolasi, V. Tetrahedron: Asymmetry 2004, 15, 3223.
(d) Kobayashi, S.; Furuya, T.; Otani, T.; Saito, T. Tetrahedron 2008,
164
dx.doi.org/10.1021/ol4031556 | Org. Lett. 2014, 16, 162−165

Organic Letters
Letter
64, 9705. (e) Kobayashi, S.; Semabs, T.; Takahashi, T.; Yoshida, S.;
Dai, K.; Otani, T.; Saito, T. Tetrahedron 2009, 65, 920. (f) Dunn, T.
B.; Ellis, J. M.; Kofink, C. C.; Manning, J. R.; Overman, L. E. Org. Lett.
2009, 11, 5658.
(2) (a) Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press:
Greenwich, 1993; Vol. 3. (b) Roversi, E.; Vogel, P. Helv. Chim. Acta
2002, 85, 761.
T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679. (e) Oh, C.
H.; Reddy, V. R.; Kim, A.; Rhim, C. Y. Tetrahedron Lett. 2006, 47,
5307. (f) Cho, C.-H.; Larock, R. C. ACS Comb. Sci. 2011, 13, 272.
(17) (a) Olsen, R. K.; Feng, X.; Campbell, M.; Shao, R.; Math, S. K. J.
Org. Chem. 1995, 60, 6025. (b) Geary, L. M.; Hultin, P. G. J. Org.
Chem. 2010, 75, 6354.
(18) CCDC 967650 (5g) contains the supplementary crystallo-
graphic data for this paper. www.ccdc.cam.ac.uk/data_request/cif.
(3) Boaz, N. W. Tetrahedron Lett. 1998, 39, 5505.
(4) (a) Wilker, S.; Erker, G. J. Am. Chem. Soc. 1995, 117, 10922.
(b) Varela, J. A.; Castedo, L.; Saa, C. Org. Lett. 2003, 16, 2841.
́
(5) (a) Werntz, J. H. J. Am. Chem. Soc. 1935, 57, 204. (b) Mitsudo,
T.; Hori, Y.; Yamakawa, Y.; Watanabe, Y. J. Org. Chem. 1987, 52, 2230.
(c) Zhao, Y.-L.; Liu, Q.; Zhang, Y.-F.; Sun, S.-G.; Li, Y.-N. Synlett
2006, 231.
(6) For examples, see: (a) Miki, K.; Fujita, M.; Uemura, S.; Ohe, K.
Org. Lett. 2006, 8, 1741. (b) Wang, S.; Zhang, L. Org. Lett. 2006, 8,
4585. (c) Li, G.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130,
3740. (d) Cho, E. J.; Lee, D. Adv. Synth. Catal. 2008, 350, 2719.
́
(e) Bray, C. V.-L.; Derien, S.; Dixneuf, P. H. Angew. Chem., Int. Ed.
2009, 48, 1439. (f) Wang, Y.; Lu, B.; Zhang, L. Chem. Commun. 2010,
46, 9179. (g) Cho, E. J. Chem.Eur. J. 2012, 18, 4495.
(7) For examples, see: (a) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Org.
Lett. 2007, 9, 985. (b) Zhang, X.; Fu, C.; Ma, S. Org. Lett. 2011, 13,
1920. (c) Jin, Z.; Hidinger, R. S.; Xu, B.; Hammond, G. B. J. Org.
Chem. 2012, 77, 7725.
(8) Yue, Y.; Yu, X.-Q.; Pu, L. Chem.Eur. J. 2009, 15, 5104.
(9) Murakami, M.; Miyamoto, Y.; Ito, Y. J. Am. Chem. Soc. 2001, 123,
6441.
(10) (a) Potman, R. P.; Kleef, F. J.; Scheeren, H. W. J. Org. Chem.
1985, 50, 1955. (b) Seltzer, S. J. Org. Chem. 1995, 60, 1189. (c) Kalita,
B.; Bezbarua, M. S.; Barua, N. C. Synth. Commun. 2002, 32, 3181.
(d) Kumar, N. N. B.; Reddy, M. N.; Swamy, K. C. K. J. Org. Chem.
2009, 74, 5395. (e) Geary, L. M.; Hultin, P. G. J. Org. Chem. 2010, 75,
6354. (f) Xu, S.; Chen, R.; He, Z. J. Org. Chem. 2011, 76, 7528.
(g) Yang, Y.-L.; Wei, Y.; Xu, Q.; Shi, M. Tetrahedron 2013, 69, 3593.
(11) For recent reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535. (b) Valentine, D. H.; Hillhouse, J. H. Synthesis
2003, 317. (c) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004,
346, 1035. (d) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985.
(e) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.
Acc. Chem. Res. 2006, 39, 520. (f) Denmark, S. E.; Beutner, G. L.
Angew. Chem., Int. Ed. 2008, 47, 1560. (g) Ye, L.; Zhou, J.; Tang, Y.
Chem. Soc. Rev. 2008, 37, 1140.
(12) For some pioneering examples, see: (a) Martin, T. J.; Vakhshori,
V. G.; Tran, Y. S.; Kwon, O. Org. Lett. 2011, 13, 2586. (b) Szeto, J.;
Sriramurthy, V.; Kwon, O. Org. Lett. 2011, 13, 5420. (c) Zhao, Q.;
Han, X.; Wei, Y.; Shi, M.; Lu, X. Chem. Commun. 2012, 48, 970.
(d) Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2012,
51, 767. (e) Zhong, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.;
Lu, Y. Angew. Chem., Int. Ed. 2013, 52, 943. (f) Li, E.; Huang, Y.;
Liang, L.; Xie, P. Org. Lett. 2013, 15, 3138. (g) Zheng, J.; Huang, Y.;
Li, Z. Org. Lett. 2013, 15, 5064.
(13) (a) Chen, Z.; Zhang, J. Chem.Asian J. 2010, 5, 1542. (b) Yu,
X.; Cao, Z.; Zhang, J. Org. Biomol. Chem. 2010, 8, 5059.
(14) (a) Yu, X.; Ren, H.; Xiao, Y.; Zhang, J. Chem.Eur. J. 2008, 14,
8481. (b) Xiao, Y.; Zhang, J. Chem. Commun. 2009, 3594. (c) Li, W.;
Xiao, Y.; Zhang, J. Adv. Synth. Catal. 2009, 351, 3083. (d) Yu, X.; Du,
B.; Wang, K.; Zhang, J. Org. Lett. 2010, 12, 1876. (e) Yu, X.; Zhang, J.
Adv. Synth. Catal. 2011, 353, 1265. (f) Yu, X.; Zhou, G.; Zhang, J.
Chem. Commun. 2012, 48, 4002. (g) Yu, X.; Zhang, J. Chem.Eur. J.
2012, 18, 12945.
(15) (a) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903.
(b) Liu, R.; Zhang, J. Chem.Eur. J. 2009, 15, 9303. (c) Xiao, Y.;
Zhang, J. Adv. Synth. Catal. 2011, 353, 36. (d) Xiao, Y.; Zhang, J.
Chem. Commun. 2010, 46, 752. (e) Li, W.; Zhang, J. Chem. Commun.
2010, 46, 8839. (f) Liu, R.; Zhang, J. Chem.Asian J. 2012, 7, 294.
(16) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164. (b) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem.
2005, 70, 4531. (c) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609. (d) Yao,
165
dx.doi.org/10.1021/ol4031556 | Org. Lett. 2014, 16, 162−165