Phosphine-mediated olefination between aldehydes and allenes: An efficient synthesis of trisubstituted 1,3-dienes with high E-selectivity

Article abstract of DOI:10.1021/ol901334c

The phosphine-mediated olefination of aldehydes with electron-deficient allenes to afford trisubstituted conjugated dienes in fair to excellent yields with high E-selectivity is described. The reaction represents a new reactivity pattern of allenes with aldehydes and also provides a highly stereoselective synthetic method for preparing conjugated dienes. In the reaction, the phosphine acts as a nucleophilic promoter to generate in situ an active phosphorus ylide which mediates the intermolecular olefination.

Full text of DOI:10.1021/ol901334c

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3498-3501
Phosphine-Mediated Olefination between
Aldehydes and Allenes: An Efficient
Synthesis of Trisubstituted 1,3-Dienes
with High E-Selectivity
Silong Xu, Lili Zhou, San Zeng, Renqin Ma, Zhihong Wang, and Zhengjie He*
The State Key Laboratory of Elemento-Organic Chemistry and Department of
Chemistry, Nankai UniVersity, Tianjin 300071, P. R. China
zhengjiehe@nankai.edu.cn
Received June 14, 2009
ABSTRACT
The phosphine-mediated olefination of aldehydes with electron-deficient allenes to afford trisubstituted conjugated dienes in fair to excellent
yields with high E-selectivity is described. The reaction represents a new reactivity pattern of allenes with aldehydes and also provides a
highly stereoselective synthetic method for preparing conjugated dienes. In the reaction, the phosphine acts as a nucleophilic promoter to
generate in situ an active phosphorus ylide which mediates the intermolecular olefination.
Conjugated dienes represent one class of widely occurring
and important organic compounds. Their importance stems
largely from their versatility in organic transformations1 and
the widespread occurrence of the 1,3-diene substructure in
a vast array of natural products of biological and medicinal
interest.2 The development of methods for the efficient,
stereoselective, and practical synthesis of conjugated dienes
has attracted much interest from synthetic organic chemists.
Apart from the conventional P-, S-, and Si-based carbonyl
olefination reactions3 represented by P-based Wittig
olefination3a and its variants, including the Horner-
Wadsworth-Emmons3b and Z-selective Still-Gennari3c
(1) For leading reviews, see: (a) Deagostino, A.; Prandi, C.; Zavattaro,
C.; Venturello, P. Eur. J. Org. Chem. 2006, 2463–2483. (b) Nicolaou, K. C.;
Snyder, S. S.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668–1698. (c) Friebe, L.; Nuyken, O.; Obrecht, W. AdV.
Polym. Sci. 2006, 204, 1–154. (d) Fischbach, A. A.; Anwander, R. AdV.
Polym. Sci. 2006, 204, 155–281.
(3) For representative reviews, see Wittig reaction: (a) Vedejs, E.;
Peterson, M. J. In AdVances in Carbanion Chemistry; Snieckus, V., Ed.;
Jai Press Inc.: Greenwich, CT, 1996; Vol. 2. Horner-Wadsworth-Emmons
reaction: (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863–
927. Julia olefination: (c) Blakemore, P. R. J. Chem. Soc., Perkin Trans.
2002, 1, 2563–2585. Peterson olefination: (d) Ager, D. J. Org. React. 1990,
38, 1–223.
(2) (a) Ref 1a and references cited therein. (b) Negishi, E.-I.; Huang,
Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41,
1474–1485, and references cited therein. (c) Glasby, J. S. Encyclopaedia
of the Terpenoids; Wiley: Chichester, UK, 1982. (d) Devon, T. K.; Scott,
A. I. Handbook of Naturally Occurring Compounds; Academic: New York,
NY, 1972; Vol. II. (e) DellaGreca, M.; Marino, C. D.; Zarrelli, A.;
D’Abrosca, B. J. Nat. Prod. 2004, 67, 1492–1495. (f) Lu, F.; Deng, Z.; Li,
J.; Fu, H.; Van Soest, R. W. M.; Proksch, P.; Lin, W. J. Nat. Prod. 2004,
67, 2033–2036. (g) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li,
Z.; Hamburger, M. J. Nat. Prod. 2004, 67, 1854–1858. (h) Rogers, E. W.;
Molinski, T. F. J. Nat. Prod. 2005, 68, 450–452. (i) Mohamad, H.; Lajis,
N. H.; Abas, F.; Ali, A. M.; Sukari, M. A.; Kikuzaki, H.; Nakatani, N. J.
Nat. Prod. 2005, 68, 285–288. (j) Maskey, R. P.; Grun-Wollny, I.; Laatsch,
H. J. Nat. Prod. 2005, 68, 865–870.
(4) For leading reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4442–4489. (b) Diver, S. T.; Giessert,
A. J. Chem. ReV. 2004, 104, 1317–1382. (c) Poulsen, C. S.; Madsen, R.
Synthesis 2003, 1–18. (d) Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006,
39, 509–519. (e) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew.
Chem., Int. Ed. 2005, 44, 6630. (f) Aubert, C.; Buisine, O.; Malacria,
M. Chem. ReV. 2002, 102, 813. (g) Trost, B. M.; Toste, F. D.; Pinkerton,
A. B. Chem. ReV. 2001, 101, 2067. (h) Schore, N. E. Chem. ReV. 1988, 88,
1081.
10.1021/ol901334c CCC: $40.75
Published on Web 07/06/2009
 2009 American Chemical Society

modifications, the S-based Julia olefination,3d and the Si-
based Peterson olefination,3 many powerful synthetic meth-
ods for dienes have been discovered,2d,4 primarily involving
transition-metal-catalyzed alkenyl-alkenyl cross-coupling
reactions,2b,4a enyne cross-metathesis,4b-d and alkene-
alkyne codimerization.4e-h Despite the effectiveness of these
transformations, there remains significant room for the
development of additional complementary processes. As a
result, a number of new examples of the conjugated diene
synthesis have been witnessed recently.5
Over the past decade, chemical transformations involving
electron-deficient allenes have attracted much research inter-
est, with a number of new allene-based reactions with high
synthetic potentials having emerged.6 For example, the
phosphine- or amine-catalyzed annulations of allenoates with
activated olefins, imines, and aldehydes provide attractive
approaches for constructing carbocycles and heterocycles.7
In our latest studies on the phosphine-catalyzed [3 + 2]
annulation of γ-methyl allenoates with aldehydes,8 we found
that under the influence of (4-FC6H4)3P γ-benzyl allenoate
(2a) underwent a stoichiometric olefination with o-chlo-
robenzaldehyde (1a), to give the (E,E)-diene 3a exclusively
in 80% isolated yield (eq 1). This reaction unveiled a new
reactivity pattern of allenoates with aldehydes, while repre-
senting an efficient and stereoselective synthesis of trisub-
stituted (E,E)-dienes via the P-based olefination of an
aldehyde. Herein we wish to report more preliminary results
from further studies on this reaction.
Table 1. Optimization of Conditions for the
Phosphine-Mediated Olefination of Aldehydes 1 with Allenoate
2aa
time
(h)
yield
of 3 (%)b c
,
entry
R1
PR3
PPh3
solvent
toluene
CH3CN
THF
DMF
ethanol
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
72
72
72
72
72
72
72
40
24
24
17
17
24
24
85
62
79
62
64
82
87
80
<5d
35d
99
92
81
91
2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
3
4
5
6
7
8
9
4-CH3OC6H4 PPh3
10
11
12
13
14
C6H5
C6H5
C6H5
C6H5
C6H5
PPh3
Ph2PMe CH2Cl2
PhPMe2 CH2Cl2
PBu3
PTA
CH2Cl2
CH2Cl2
a Reaction conditions: for entries 1-7, both 2a and the phosphine were
used in 1.5 equiv; for entries 8-14, the two substrates used in 1.2 equiv.
A typical procedure: a mixture comprising aldehyde 1 (0.5 mmol), allenoate
2a (0.75 or 0.6 mmol), and phosphine (0.75 or 0.6 mmol) in the specified
solvent (2 mL) was stirred at room temperature. b Isolated yield based on
1. c E,E-isomer only. d The isomerization product 4 was isolated in 74%
(based on 2a, entry 9) and 62% (entry 10) yields, respectively.
applied to the relatively electron-rich benzaldehyde (1l) and
4-methoxybenzaldehyde (1n), however, the corresponding
olefination products 3l and 3n were only obtained in
significantly reduced yields (35% and <5%, respectively)
with the isomerization byproduct, ethyl (E,E)-5-phenyl-2,4-
pentadienoate (4) from 2a, being the major product (Table
1, entries 9 and 10). Employing the olefination reaction of
2a with 1l as a model, a few tertiary phosphines with
relatively stronger nucleophilicity compared to PPh3 were
explored, generally furnishing the olefination product 3l in
good to excellent yields (Table 1, entries 11-14). 1,3,5-
Triaza-7-phosphaadamantane (PTA) is a readily available,
air-stable, and water-soluble phosphine with comparable
nucleophilicity to trialkylphosphines (Figure 1).9 Given the
Optimization of the reaction conditions for the olefination
of aldehydes 1 with the allenoate 2a was first carried out
(Table 1). In place of P(4-FC6H4)3, the convenient and cost-
saving PPh3 was used in the olefination of 2a, giving
comparable yields of the diene 3. Using the PPh3-mediated
reaction of 2a with 1a as a probe, several common solvents
were screened. Dichloromethane was found to afford the best
yield of 3a, although the other solvents gave comparable
yields (Table 1, entries 1-7). When similar conditions were
(5) (a) Mundal, D. A.; Lutz, K. E.; Thomson, R. J. Org. Lett. 2009, 11,
465–468. (b) Shibata, Y.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 2829–
2831. (c) Lipshutz, B. H.; Ghorai, S.; Boskovic, Z. V. Tetrahedron 2008,
64, 6949–6954. (d) He, Z.; Tang, X.; He, Z. Phosphorus Sulfur Silicon
Relat. Elem. 2008, 183, 1518–1525. (e) Murelli, R. P.; Snapper, M. L. Org.
Lett. 2007, 9, 1749–1752. (f) McDougal, N. T.; Schaus, S. E. Angew. Chem.,
Int. Ed. 2006, 45, 3117–3119. (g) Low, K. H.; Magomedov, N. A. Org.
Lett. 2005, 7, 2003–2005.
Figure 1. Structures of 3 and PTA.
(6) For recent reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535–544. (b) Methot, J. L.; Roush, W. R. AdV. Synth. Catal.
2004, 346, 1035–1050. (c) Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520–530. (d) Ma, S.
Chem. ReV. 2005, 105, 2829–2871. (e) Ma, S. Aldrichimica Acta 2007, 40,
91–102.
high yield of 3l obtained with PTA (Table 1, entry 14) and
its unique properties which benefit the handling and workup
of the olefination reaction, PTA was chosen as the preferable
phosphine for the less reactive aldehydes.
With the optimized conditions in hand, a variety of
aromatic and aliphatic aldehydes were explored in the
(7) For typical reviews, see: (a) Ye, L.-W.; Zhou, J.; Tang, Y. Chem.
Soc. ReV. 2008, 37, 1140–1152. (b) Shi, Y.-L.; Shi, M. Org. Biomol. Chem.
2007, 5, 1499–1504.
(8) Xu, S.; Zhou, L.; Ma, R.; Song, H.; He, Z. Chem.sEur. J. 2009, in
press.
Org. Lett., Vol. 11, No. 15, 2009
3499

phosphine-mediated olefination with allenoate 2a, giving rise
to a series of trisubstituted dienes 3 in moderate to excellent
yields (Table 2, entries 1-18). Aromatic aldehydes with
corresponding dienoates 3 in moderate yields (Table 2,
entries 19-24).
The structures of dienes 3 were identified by X-ray
crystallography, in some cases, as well as 1H and 13C NMR
spectroscopy, which included NOESY analyses for repre-
sentative compounds (see Supporting Information). Most of
the isolated dienes 3 were the (E,E)-isomers except for 3r
and 3x which both were an (E,E)- and (E,Z)-isomeric mixture
Table 2. Synthesis of Dienes 3 from Aldehydes 1 and
Allenoates 2a
1
with a ratio of 8:1 according to their H and 13C NMR
1
spectra. H NMR data provided diagnostic evidence on the
(E)-configurational assignment: the coupling constant mag-
nitude (ca. 16 Hz) between the olefinic protons Ha and Hb
clearly indicated (E)-geometry of disubstituted alkene sub-
structure in 3 (Figure 1). For the trisubstituted alkene subunit
in 3, the cross peak between the olefinic protons Hb and Hc
in the NOESY spectra confirmed the (E)-configurational
assignment. Furthermore, X-ray crystallographic analyses11
for 3c and 3t provide unambiguous evidence for the structure
determination of 3.
For the olefination reaction, a mechanism is proposed in
which the phosphine fulfills two roles: a nucleophilic
promoter and a mediator of the Wittig olefination (Scheme
1). The reaction is initiated by nucleophilic attack of the
time
yield
,
entry
R1 in 1
R2 in 2 phosphine (h) of 3 (%)b c
1
2-ClC6H4 (1a)
2-NO2C6H4 (1b)
3-NO2C6H4 (1c)
4-NO2C6H4 (1d)
4-CF3C6H4 (1e)
2-CNC6H4 (1f)
2-furyl (1g)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PTA
PTA
PTA
PTA
PPh3
PTA
PTA
PTA
PTA
PTA
PTA
PTA
PTA
40
32
22
28
12
13
16
20
24
36
40
24
46
12
46
40
52
48
37
48
64
48
65
48
80 (3a)
99 (3b)
99 (3c)
92 (3d)
80 (3e)
99 (3f)
72 (3g)
70 (3h)
76 (3i)
76 (3j)
71 (3k)
91 (3l)
51 (3m)
50 (3n)
43 (3o)
30 (3p)
44 (3q)
46 (3r)
54 (3s)
73 (3t)
70 (3u)
63 (3v)
33 (3w)
71 (3x)
2
3
4
5
6
7
8
2-pyridyl (1h)
3-pyridyl (1i)
4-pyridyl (1j)
2-thiofuryl (1k)
C6H5 (1l)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-CH3C6H4 (1m)
4-CH3OC6H4 (1n) Ph
4-Me2NC6H4 (1o) Ph
E-2-Ph vinyl (1p) Ph
C2H5 (1q)
Ph
Ph
Scheme 1. Proposed Mechanism of Formation of 3 and 4
n-C3H7 (1r)
2-ClC6H4 (1a)
3-NO2C6H4 (1c)
4-CF3C6H4 (1e)
C6H5 (1l)
CO2Me
CO2Me
CO2Me
CO2Me
4-CH3OC6H4 (1n) CO2Me
2-HOC6H4 (1s) CO2Me
a See Supporting Information for experimental details. b Isolated yield
based on 1. c E,E-isomer only except 3r and 3x both obtained as an E,E-
1
and E,Z-isomeric mixture with an E,E/E,Z ratio of 8:1 determined by H
NMR.
electron-withdrawing groups were more reactive, furnishing
the dienes 3 in high yield (Table 2, entries 2-6). Heteroaro-
matic aldehydes readily gave rise to the corresponding 3 in
good yield following treatment with PPh3 (Table 2, entries
7-11). For relatively electron-rich benzaldehydes and ali-
phatic aldehydes, the olefination with 2a was best effected
by the more nucleophilic PTA, affording the corresponding
dienes 3 in moderate to excellent yield (Table 2, entries
12-15, 17, and 18). R,ꢀ-Unsaturated aldehydes like trans-
cinnamaldehyde (1p) were the former also effective in the
PPh3-mediated olefination with 2a, giving the (E,E,E)-triene
3p in 30% yield (Table 2, entry 16).
Given the prevalence and synthetic utility of conjugated
diene-carbonyl compounds,10 γ-(methoxycarbonyl)methyl
allenoate (2b) was also studied. Under the mediation of PTA,
a group of representative aromatic aldehydes bearing electron-
withdrawing or electron-donating substituents readily un-
dergo the expected olefination with 2b, affording the
phosphine on the allenoate 2 to generate the phosphonium
dienolate 5, which stands in two resonance forms 5a and
(10) (a) Kobayashi, M.; Tanaka, J.; Katori, T.; Kitagawa, I. Chem.
Pharm. Bull. 1990, 38, 2960. (b) Abe, N.; Murata, T.; Hirota, A. Biosci.
Biotechnol. Biochem. 1998, 62, 661. (c) The Retinoids; Sporn, M. B.,
Roberts, A. B., Goodman, D. S., Eds.; Academic Press: New York, 1984;
Vols. 1-2. (d) De la Herran, G.; Murcia, C.; Csakye, A. G. Org. Lett.
2005, 7, 5629. (e) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen,
E. J. J. Am. Chem. Soc. 2003, 125, 5393. (f) Trost, B. M.; Pinkerton, A. B.;
Seidel, M. J. Am. Chem. Soc. 2001, 123, 12466, and references cited therein.
(g) Juhl, M.; Monrad, R.; Sotofte, I.; Tanner, D. J. Org. Chem. 2007, 72,
4644–4654.
(9) (a) Philips, A. D.; Gonsalvi, L.; Romerosa, A.; Vizza, F.; Peruzzini,
M. Coord. Chem. ReV. 2004, 248, 955–993. (b) He, Z.; Tang, X.; Chen,
Y.; He, Z. AdV. Synth. Catal. 2006, 348, 413–417. (c) Tang, X.; Zhang, B.;
He, Z.; Gao, R.; He, Z. AdV. Synth. Catal. 2007, 349, 2007–2017.
3500
Org. Lett., Vol. 11, No. 15, 2009

5b. Through a series of stepwise proton transfers under the
aid of water,12 5 reversibly converts to the phosphorus ylide
6, which also presumably exists in two resonance forms 6a
and 6b. When R2 is a conjugative group such as phenyl or
methoxycarbonyl, it is believed that the more stable reso-
nance form 6b represents a common intermediate which is
responsible for the formations of 3 and 4. Thus, 6b undergoes
a set of proton transfers to generate the intermediate 7, which
eliminates the phosphine leading to the isomerization product
4; in another scenario, while 6b is intercepted by an aldehyde
via a Wittig olefination, the diene 3 is formed.
new reactivity pattern for allenoates with aldehydes. An in
situ generated phosphorus ylide is believed to be the key
intermediate involved in the olefination. Recently, in situ
formed phosphorus ylides have gained renewed interest in
the discovery of new organic transformations.5d,f,g,14 Further
efforts in our laboratory will be reported on the utility of
this kind of in situ-generated phosphorus ylide in novel
carbon-carbon bond forming reactions.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant No. 20872063;
20672057) is gratefully acknowledged. The authors also
thank the referees for their valuable comments about the
olefination mechanism in this study.
Similar mechanisms13 were also proposed for the phos-
phine-catalyzed isomerization of alkynoates into (E,E)-
dienoates. An independent experiment confirmed that, under
the catalysis of PPh3 (20 mol %), the allenoate 2a can be
readily isomerized into its corresponding (E,E)-dienoate 4
in 78% isolated yield (eq 2). As the experimental results
(Table 1, entries 9 and 10) show, isomerization and olefi-
nation take place competitively, presumably via the common
intermediate 6b (Scheme 1). Confirmation on the (E)-
configuration of the disubstituted alkene subunits in 3 and 4
implies that the ylide 6b has an (E)-geometry alkene subunit.
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901334C
(11) The ORTEP presentations and CIF files of 3c and 3t are available
in the Supporting Information
.
(12) (a) Ref 8, in our prior study, the deuterium-labeling experiments
implied that proton transfers occurred under the aid of water. For the related
reports, see: (b) 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. (c) Liang,
Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Chem.sEur. J. 2008, 14, 4361. (d)
Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Tetrahedron
Lett. 2007, 48, 3617
.
(13) (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933.
(b) Kazmaier, U. Tetrahedron 1998, 54, 1491–1496. (c) Kwong, C. K.-
W.; Fu, M. Y.; Lam, C. S.-L.; Toy, P. H. Synthesis 2008, 2307–2317
.
In summary, a highly stereoselective phosphine-mediated
olefination of aldehydes with electron-deficient allenes,
leading to an efficient synthesis of trisubstituted conjugated
dienes, has been demonstrated. The reaction exemplifies a
(14) (a) Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42,
1035. (b) Feng, J.; Lu, X.; Kong, A.; Han, X. Tetrahedron 2007, 63, 6035.
(c) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.; Tang, Y. Angew. Chem., Int. Ed.
2007, 46, 5951. (d) Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem.
Soc. 2003, 125, 3682
.
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