β-olefination of 2-alkynoates leading to trisubstituted 1,3-dienes

Article abstract of DOI:10.1021/ol2011677

A phosphine-mediated olefination of 2-alkynoates with aldehydes forming 1,3-dienes with high E-selectivity and up to 88% yield is described. Reaction conditions are optimized and reactions are demonstrated for various aryl, alkyl, and alkenyl aldehydes an

Full text of DOI:10.1021/ol2011677

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3418–3421
β-Olefination of 2-Alkynoates Leading to
Trisubstituted 1,3-Dienes
Mathias J. Jacobsen, Erik Daa Funder, Jacob R. Cramer, and Kurt V. Gothelf*
Danish National Research Foundation: Centre for DNA Nanotechnology (CDNA) and
Sino-Danish Centre for Molecular Assembly on Surfaces at Department of Chemistry
and iNANO, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark
kvg@chem.au.dk
Received May 2, 2011
ABSTRACT
A phosphine-mediated olefination of 2-alkynoates with aldehydes forming 1,3-dienes with high E-selectivity and up to 88% yield is described.
Reaction conditions are optimized and reactions are demonstrated for various aryl, alkyl, and alkenyl aldehydes and for ethyl 2-alkynoates with
different substituents in the δ-position. Proof of concept is shown for the generation of a β,γ-unsaturated lactone by intramolecular olefination,
and furthermore the use of the generated 1,3-dienes in the DielsꢀAlder reaction has been demonstrated.
Conjugated dienes are abundant in a wide range of
natural products,1 and furthermore dienes constitute im-
portant scaffolds in the construction of complex organic
molecules.2 Preparation of 1,3-dienes can be facilitated e.g.
by Wittig reactions,3 the Julia olefination,4 transition-
metal-catalyzed cross-coupling reactions,5 and the enyne
metathesis reactions.6 In 1992, Trost reported the isomer-
ization of 2-alkynoates into R,β,γ,δ-dienes by a catalytic
amount of triphenylphospine.7 The proposed mechanism8
for this transformation is initiated by a nucleophilic attack
of phosphine on the β-carbon of the alkynoate. By a series
of proton transfer reactions and phosphine elimination,
the substrate is subsequently converted into a 1,3-diene
with a phoshonium ylide as a key intermediate.
Phosphine-mediated reactions of 2-allenoates lead-
ing to e.g. γ-substituted R,β-unsaturated esters and
5-membered carbo- and heterocycles have been inves-
tigated extensively.9
Recently, Xu et al. and others have reported novel
syntheses of 1,3-dienes by highly E-selective olefination
of electron-deficient allenes withaldehydes in high yields.10
However, allenes are relatively unstable and less readily
available compounds.
Here we report on a new approach where ethyl 2-al-
kynoates are employed as reactants for olefination
reactions instead of the corresponding allenes. Alkynes
serve as versatile building blocks for a wide range of
useful synthetic transformations.11 In the past decades
(1) (a) DellaGreca, M.; Marino, C. D.; Zarrelli, A.; D’Abrosca, B. J.
Nat. Prod. 2004, 67, 1492–1495. (b) Roth, G. N.; Chandra, A.; Nair,
M. G. J. Nat. Prod. 1998, 61, 542–545. (c) Trisuwan, K.; Rukachaisirikul,
V.; Sukpondma, Y.; Preedanon, S.; Phongpaichit, S.; Rungjindamai, N.;
Sakayaroj, J. J. Nat. Prod. 2008, 71, 1323–1326.
(2) (a) Deagostino, A.; Prandi, C.; Zavattaro, C.; Venturello, P. Eur.
J. Org. Chem. 2006, 2463–2483. (b) Takeuchi, D.; Osakada, K. Polymer
2008, 49, 4911–4924.
(3) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
(4) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(5) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442–4489.
(9) For representative reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc.
Chem. Res. 2001, 34, 535–544. (b) Nair, V.; Menon, R. S.; Sreekanth,
A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520–530. (c)
Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140–1152. (d)
Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035–1050.
(10) (a) Xu, S.; Zhou, L.; Zeng, S.; Ma, R.; Wang, Z.; He, Z. Org.
Lett. 2009, 11, 3498–3501. (b) Xu, S.; Zou, W.; Wu, G.; Song, H.; He, Z.
Org. Lett. 2010, 12, 3556–3559. (c) Ma, R.; Xu, S.; Tang, X.; Wu, G.; He,
Z. Tetrahedron 2011, 67, 1053–1061. (d) Khong, S. N.; Tran, Y. S.;
Kwon, O. Tetrahedron 2010, 66, 4760–4768. (e) He, Z.; Tang, X.; He, Z.
Phosphorus Sulfur Silicon Relat. Elem. 2008, 183, 1518–1525.
(6) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382.
(7) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114,
7933–7935. For a review on the phosphine-catalyzed isomerization, see:
Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.; Toy, P. H. Synthesis 2008,
2307–2317.
(11) For representative reviews, see: (a) Doucet, H.; Hierso, J.-C.
Angew. Chem., Int. Ed. 2007, 46, 843–871. (b) Hein, J. E.; Fokin, V. V.
ꢀ
ꢀ~
Chem. Soc. Rev. 2010, 39, 1302–1315. (c) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Commun. 2007, 333–346. (d) Severin, R.; Doye, S. Chem. Soc.
Rev. 2007, 36, 1407–1420. (e) Hintermann, L.; Labonne, A. Synthesis 2007,
1121–1150.
(8) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659–2660.
r
10.1021/ol2011677
Published on Web 06/07/2011
2011 American Chemical Society

Figure 1. Examples of phosphine-mediated transformations utilizing electron-deficient 2-alkynoates.
phosphine-activated 2-alkynoates have been utilized in
numerous reactions including Michael additions,12
R-addition,13 γ-addition,14 pyrrole15 and furan16 synthesis,
and [3 þ 2] cycloaddition reactions17 (Figure 1). Here it is
demonstrated how in situ generated phosphonium ylides
can be trapped with aldehydes in a Wittig olefination,
transforming alkynoates into trisubstituted conjugated
dienes and thereby expanding the scope of phosphine-
mediated reactions of 2-alkynoates.
Based on the initial result we have optimized the condi-
tions for the reaction between alkynoate 1a and aldehyde
2a, and the results are given in Table 1. Various phosphines
Table 1. Optimization of Reaction Conditions for the Olefina-
tion of Alkynoate 1a with 2-Chlorobenzaldehyde 2aa
temp
time
(h)
conversion
(%)e,f
entry
PR3
solvent
CH2Cl2
(°C)
1b
PBu3
rt
18
18
18
18
18
18
18
18
72
72
72
72
72
72
72
16
16
ꢀ
d
2b
PTA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
rt
15
3b
MePPh2
P(2-furyl)3
rt
32
Figure 2. Reaction of 1a with 2-chlorobenzaldehyde 2a.
4b
rt
ꢀ
5b
PMe3
rt
5
d
6b
PCy3
rt
ꢀ
d
In our preliminary investigations we discovered that
ethyl alkynoate 1a underwent reaction with triphenylpho-
sphine (1 equiv) and 2-chlorobenzaldehyde 2a (0.8 equiv)
in dichloromethane toaffordthe trisubstituted (E,E)-diene
3a in 10% yield (Figure 2).
7b
PCl3
rt
ꢀ
8b
P(OEt)3
PPh3
PPh3
PPh3
MePPh2
MePPh2
PTA
rt
ꢀ
9c
100
100
100
100
100
100
100
100
100
9
10c
11c
12c
13c
14c
15c
16c
17c
14
1,4-dioxane
CH2Cl2
MeCN
31
60
33
(12) (a) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 22,
241–244. (b) Yavari, I.; Ramazano, A. Synth. Commun. 1997, 27,
1449–1454. (c) Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A. Tetrahedron
Lett. 1998, 39, 2391–2392. (d) Trofimov, B. A.; Glotova, T. E.; Dvorko,
M. Y.; Ushakov, I. A.; Schmidt, E. Y.; Mikhaleva, A. I. Tetrahedron 2010,
66, 7527–7532. (e) Kuroda, H.; Tomita, I.; Endo, T. Polymer 1997, 38,
3655–3662. (f) Kuroda, H.; Tomita, I.; Endo, T. Macromolecules 1995, 28,
433–436. (g) Kuroda, H.; Tomita, I.; Endo, T. Macromolecules 1995, 28,
6020–6025. (h) Grossman, R. B.; Pendharkar, D. S.; Patrick, B. O. J. Org.
Chem. 1999, 64, 7178–7183. (i) Sriramurthy, V.; Barcan, G. A.; Kwon, O.
J. Am. Chem. Soc. 2007, 129, 12928–12929. (j) Yavari, I.; Souri, S.;
Sirouspour, M.; Djahaniani, H. Synthesis 2006, 3243–3249. (k) Tejedor,
CH2Cl2
MeCN
<5
PTA
99 (62)
99 (75)
99 (86)
PTA
MeCN
PTA
1,4-dioxane
a Reaction conditions: 2a (0.5 mmol), phosphine (0.6 mmol), and 1a
(0.6 mmol) were stirred in 1 mL of solvent in a sealed vial. b Reaction was
performed under inert conditions. c Reaction was performed at ambient
conditions. d The phosphine was used as its HBF4-salt; 2 equiv of
distilled Et3N were added for activation of the phosphine. e Conversions
were determined by 1H NMR spectroscopy based on 2a. f Isolated yields
are reported in parentheses.
ꢀ
ꢀ
ꢀ
D.; Santos-Exposito, A.; Mendez-Abt, G.; Ruiz-Perez, C.; Garcıa-Tellado,
´
F. Synlett 2009, 1223–1226. (l) Sriramurthy, V.; Kwon, O. Org. Lett. 2010,
12, 1084–1087.
Org. Lett., Vol. 13, No. 13, 2011
3419

were screened using dichloromethane as solvent at rt. In
addition to PPh3, application of 1,3,5-triaza-7-phospha-
adamantane (PTA) and Ph2PMe as reagents led to pro-
mising conversions in the olefination reaction.
2k, gave none of the desired product. The reaction of
heteroaromatic aldehydes as well as aliphatic aldehydes
afforded good to moderate yields. Furthermore, it was
demonstrated how the (E,E,E)-triene 3p can be formed by
employing R,β-unsaturated aldehyde 2p.
Interestingly, increasing the temperature and changing the
solvent from dichloromethane to acetonitrile or 1,4-dioxane
led to a significant increase in conversion, especially when
using PTA as the phosphine reagent. Furthermore, when
increasing the reaction time beyond 20 h the isolated yield
decreased due to degradation of the product or other side
reactions over time at elevated temperatures. It was noted
that application of acetonitrile as the solvent led to a lower
isolated yield than use of 1,4-dioxane; hence 1,4-dioxane was
used as the solvent in later reactions. To investigate whether
traces of water influenced the yield of 3a, a series of reactions
were performed in 1,4-dioxane with varying water content.
For reactions performed in 1,4-dioxane with a water content
varying from 0.1 to 3.2 mg/mL, high conversions (>95%)
to the olefination product were observed.
Figure 3. General structure of (E,E)-3.
Except for 3m and 3q the dienes 3 are formed exclu-
sively with (E,E)-configuration. The E-configuration
of the disubstituted alkene was confirmed by a coupling
constant of 16 Hz whereas the configurations of the
trisubstituted alkenes in dienes 3 have been deter-
mined by 1D NOESY experiments (see Supporting
Information) showing an NOE effect from Ha to Hb/Hc
(Figure 3).
Table 2. Synthesis of 1,3-Dienes 3 from Aldehydes 2 and
Alkynoate 1aa
Table 3. Olefination of Alkynes 1 with 2-Chlorobenzaldehyde
2aa
entry
R1
time (h)
yield (%)b
E/Zc
1
2
2-ClC6H4 (2a)
19
16
16
19
19
15
16
19
16
16
16
15
15
15
15
16
15
86 (3a)
57 (3b)
81 (3c)
77 (3d)
ꢀ
E only
E only
E only
E only
ꢀ
3-ClC6H4 (2b)
3
4-ClC6H4 (2c)
4
4-FC6H4 (2d)
5
2-(NO2)C6H4 (2e)
3-(NO2)C6H4 (2f)
C6H5 (2g)
6
19 (3f)
68 (3g)
83 (3h)
73 (3i)
ꢀ
E only
E only
E only
E only
ꢀ
entry
R2
R3
yield (%)b,c
7
8
2-(CH3)C6H4 (2h)
4-(CH3)C6H4 (2i)
4-(CH3O)C6H4 (2j)
3-(CH3O)C6H4 (2k)
3-pyridyl (2l)
1
2
3
4
5
CHdCH2
H
CO2Et (1b)
CO2Et (1c)
CO2Et (1d)
CO2Et (1e)
CN (1f)
17 (3r)
8 (3s)
52 (3t)
55 (3u)
0
9
10
11
12
13
14
15
16
17
n-C3H7
n-C6H13
Ph
ꢀ
ꢀ
88 (3l)
70 (3m)
ꢀ
E only
7:2
2-furyl (2m)
CHdCH2 (2n)
(E)-CHdCHPh (2o)
(E)-CHdCHCH3 (2p)
n-C4H9 (2q)
ꢀ
a Reaction conditions: aldehyde 2a (0.5 mmol), PTA (2 mmol), and
alkyne 1 (1 mmol) were stirred in 1,4-dioxane (1 mL) at 100 °C in a sealed
vial. b Isolated yields. c The products have (E,E)-geometry exclusively.
ꢀ
ꢀ
42 (3p)
53 (3q)
E only
5:1
a Reaction conditions: 2 (0.5 mmol), PTA (2 mmol), and 1a (1 mmol)
were stirred in 1,4-dioxane (1 mL) at 100 °C in a sealed vial. b Isolated
yields. c Geometry of trisubstituted alkene, determined by 1H NMR
spectroscopy and 1D NOESY experiments.
(13) (a) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595–
7596. (b) Meng, L.-G.; Tang, K.; Liu, H.-F.; Xiao, J.; Xue, S. Synlett
2010, 1833–1836. (c) Xue, S.; Zhou, Q.-F.; Zheng, X.-Q. Synth. Com-
mun. 2005, 35, 3027–3035.
(14) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167–
3168. (b) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819–
10820. (c) Trost, B. M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670–5671.
Having established satisfactory conditions for the olefi-
nation of 1a with 2a the reactions of a variety of different
aldehydes were investigated (Table 2). Moderately elec-
tron-deficient aldehydes (2aꢀ2d) provided fair to good
yields, whereas strongly electron-deficient nitrobenzalde-
hydes (2e and 2f) led to unsatisfactory yields. Neutral or
slightly electron-rich benzaldehydes gave rise to good
yields while very electron-rich aldehydes, such as 2j and
ꢀ
ꢀ
(d) Alvarez-Ibarra, C.; Csaky, A. G.; Gomez de la Oliva, C. Tetrahedron
ꢀ
ꢀ
Lett. 1999, 40, 8465–8467. (e) Alvarez-Ibarra, C.; Csaky, A. G.; Gomez
de la Oliva, C. J. Org. Chem. 2000, 65, 3544–3547. (f) Chung, Y. K.; Fu,
G. C. Angew. Chem., Int. Ed. 2009, 48, 2225–2227.
(15) Anary-Abbesinejad, M.; Charkhati, K.; Anaraki-Ardakani, H.
Synlett 2009, 1115–1117.
(16) (a) Jung, D.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc.
2004, 126, 4118–4119. (b) McDougal, N. T.; Schaus, S. E. Angew. Chem.,
Int. Ed. 2006, 45, 3117–3119.
(17) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906–2908.
3420
Org. Lett., Vol. 13, No. 13, 2011

The diversity of substrates applicable for the olefination
reaction was further investigated by the reaction of differ-
ent alkynes 1 with aldehyde 2a (Table 3). Interestingly,
changing the phenyl substituent in 1a with an alkyl chain
(1d and 1e) gave rise to fair yields of 1,3-dienes 3t and 3u
while 1b afforded 1,3,5-triene 3r. Exchanging the ethyl
ester with electron-poor aryls, a methyl ketone, or a nitrile
(entry 5) showed no product, thereby indicating the crucial
role of an activating ester moiety adjacent to the alkyne.
present the proposed ylide 8 reacts in a Wittig reaction
forming the trisubstituted 1,3-diene 3. Trace amounts of
water present in the solvent might support the isomeriza-
tion of 7 to 8 since rapid proton shifts are favored in the
presence of a proton donor/acceptor as described in earlier
studies of phosphine-mediated reactions of allenes.20
Figure 4. Annulation of 4 by an intramolecular Wittig olefina-
tion and DielsꢀAlder reaction of 1,3-diene 3a with N-
methylmaleimide.
Cyclization reactions are of great value in the syntheses
of complex structures.18 Strategic incorporation of an
aldehyde in an alkynoate could be used in the syntheses
of cyclic structures, and as an example a novel synthesis of
5 was performed (Figure 4). Subjecting 4 to olefination
conditions resulted in annulation to 5. In spite of the low
yield the example provides proof of concept for the gen-
eration of β,γ-unsaturated lactones by taking advantage of
an intramolecular Wittig olefination.
An important synthetic application of dienes leading to
a variety of complex products is the DielsꢀAlder
reaction.19 Hence, the diene 3a was tested in a [4 þ 2]
cycloaddition with N-methylmaleimide affording 67%
yield of the endo-isomer 6 (Figure 4).
In Figure 5 we have proposed a mechanism for the novel
olefination reaction. The mechanism is derived from earlier
studies on related internal redox reactions of alkynoates.8
The reaction is initiated by a nucleophilic attack of the
phosphine on the β-position of alkynoate 1 followed by a
range of proton shifts leading to phosphonium ylide 8. In
the absence of an aldehyde, alkynoate 1 is known to
isomerize into diene 10. Nevertheless, if an aldehyde is
Figure 5. Proposed mechanism for the formation of 3 and 10.
In summary, a highly stereoselective olefination of
ethyl alkynoates yielding a variety of conjugated trisub-
stituted dienes in good yields has been demonstrated.
The key step in this reaction is the trapping of in situ
generated phosphonium ylides with aldehydes expanding
the wide range of applications of alkynes. Furthermore,
it has been shown how this olefination can be used in a
cyclization reaction yielding a β,γ-unsaturated lactone
while the generated 1,3-dienes show good reactivity in
the DielsꢀAlder reaction. Further investigation on utilizing
in situ generated ylides in synthetic transformations will
be considered.
Acknowledgment. The Danish National Research
Foundation through Centre for DNA Nanotechnology,
Sino-Danish Centre for Molecular Self-assembly on Sur-
faces, Centre of Functionally Integrative Neuroscience,
and OChem graduate school are greatly acknowledged for
financial support.
(18) For representative reviews, see: (a) Langer, P.; Freiberg, W.
Chem. Rev. 2004, 104, 4125–4149. (b) Dounay, A. B.; Overman, L. E.
Chem. Rev. 2003, 103, 2945–2963.
(19) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698.
(20) (a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.;
Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470–3471.
(b) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Chem.;Eur. J. 2008,
14, 4361–4373.
Supporting Information Available. Experimental pro-
cedures, characterization, and 1H NMR, 13C NMR, and
1D NOESY spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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