Three-component and nonclassical reaction of phosphines with enynes and aldehydes: Formation of γ-lactones featuring α-phosphorus ylides

Article abstract of DOI:10.1021/ol200527t

Chemical equations presented. Inverted carbenoid species, generated from attack of phosphines at the α(ss′)-carbon of hex-2-en-4-ynedioic acid dialkyl esters, react with aldehydes to give γ-lactones possessing an α-phosphorus ylide moiety.

Full text of DOI:10.1021/ol200527t

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2248–2251
Three-Component and Nonclassical
Reaction of Phosphines with Enynes and
Aldehydes: Formation of γ-Lactones
Featuring r-Phosphorus Ylides
Jie-Cheng Deng and Shih-Ching Chuang*
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan,
ROC 30010
jscchuang@faculty.nctu.edu.tw
Received February 26, 2011
ABSTRACT
Inverted carbenoid species, generated from attack of phosphines at the R(δ0)-carbon of hex-2-en-4-ynedioic acid dialkyl esters, react with
aldehydes to give γ-lactones possessing an R-phosphorus ylide moiety.
Michael addition, a type of nucleophilic conjugate addi-
tion, is a well-known addition pattern that takes place in
the reaction of R,β-unsaturated carbonyl compounds with
nucleophilic reagents.1 Chemists take this as a common
methodology for the syntheses of a wide range of organic
compounds for applications.2 In parallel to this concept,
this addition model has been used to account for the
reaction outcomes of organophosphines with electron-
deficient alkenes and alkynes.3 This organophosphorus
system can assemble molecules in a catalytic manner.4
Asymmetric versions of such phosphine-catalysis5 and
their synthetic applications have also been elaborated.6
Recently, Fu,7 Kwon,8 and others9 further demonstrated
versatile reactions within this regime. The accepted me-
chanisms for these phosphine-mediated reactions with
alkynes (1a) or allenoates (1b) have been proposed; in
these studies, phosphines attack at the β-carbon of these
substrates and form zwitterionic carbenoid species A or B
followed by the subsequent steps (Scheme 1).
In our recent study, we find that [60]fullerene is a good
electrophile for the carbenoid species generated from phos-
phines with dimethyl acetylenedicarboxylate (DMAD),
resulting in a new class of cyclopropanofullerenes.10 We
(1) (a) Michael, A. J. Prakt. Chem. 1887, 35, 349. (b) March, J.
Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992.
(2) Jung, M. E. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds; Pergamon: Oxford, UK, 1991;
Vol. 4, pp 1ꢀ67.
(6) Wang, J. C.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855.
(7) (a) Sinisi, R.; Sun, J.; Fu, G. C. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20652. (b) Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 4568. (c)
Wilson, J. E.; Sun, J.; Fu, G. C. Angew. Chem., Int. Ed. 2010, 49, 161. (d)
Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225.
(8) (a) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318.
(b) Creech, G. S.; Kwon, O. Org. Lett. 2008, 10, 429. (c) Henry, C. E.;
Kwon, O. Org. Lett. 2007, 9, 3069. (d) Tran, Y. S.; Kwon, O. J. Am.
Chem. Soc. 2007, 129, 12632. (e) Zhu, X.-F.; Henry, C. E.; Kwon, O.
J. Am. Chem. Soc. 2007, 129, 6722.
(3) For selected reviews, see: (a) Ye, L.-W.; Zhou, J.; Tang, Y. Chem.
Soc. Rev. 2008, 37, 1140. (b) Methot, J. L.; Roush, W. R. Adv. Synth.
Catal. 2004, 346, 1035.
(4) (a) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985. (b) Lu,
X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (c) Zhang, C.; Lu,
X. J. Org. Chem. 1995, 60, 2906.
(5) Selected examples, see: (a) Smith, S. W.; Fu, G. C. J. Am. Chem.
Soc. 2009, 131, 14231. (b) Fang, Y.-Q.; Jacobsen, E.-N. J. Am. Chem.
Soc. 2008, 130, 5660. (c) Voituriez, A.; Panossian, A.; Fleury-Bregeot,
N.; Retailleau, P.; Marinetti, A. J. Am. Chem. Soc. 2008, 130, 14030. (d)
Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129,
12928. (e) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(f) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
ꢀ
(9) (a) Lecercle, D.; Sawicki, M.; Taran, F. Org. Lett. 2006, 8, 4283.
(b) Zhang, X.-C.; Cao, S.-H.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 1142.
(c) Guan, X.-Y.; Wei, Y.; Shi, M. Org. Lett. 2010, 12, 5024.
(10) (a) Chen, S.-Y.; Cheng, R.-L.; Tseng, C.-K.; Lin, Y.-S.; Lai,
L.-H.; Venkatachalam, R. K.; Chen, Y.-C.; Cheng, C.-H.; Chuang,
S.-C. J. Org. Chem. 2009, 74, 4866. (b) Yamaguchi, H.; Murata, S.;
Akasaka, T.; Suzuki, T. Tetrahedron Lett. 1997, 38, 3529.
r
10.1021/ol200527t
Published on Web 04/07/2011
2011 American Chemical Society

Table 1. Condition Optimization Studya
Scheme 1
entry
solvent
time (h)
temp (°C)
yield (%)b
1c
2c
THF
24
24
3
rt
43 (68)
21 (39)
32 (56)
35 (57)
37 (70)
21 (76)
46 (50)
69 (79)
74
CH2Cl2
DCEh
THF
rt
3c
60
60
60
60
60
60
rt
4c
5c
3
THF
5
think that desymmetrization of DMAD through insertion
of an ethylenyl unit to give 1c11 will generate distinguishable
alkynyl carbons; such enyne substrate gives unusual 1,3-
dipolarophile C through attack of phosphines at the R(δ0)-
carbon (R relative to its proximate ester carbon and δ0
relative to its farthest ester carbon) of the reactive alkyne.
The unusual conjugate addition (R or δ0 attack)12 pattern
was less being considered as a possible route for organic
syntheses since such type of acceptors were rare.13 Here we
show that R(δ0)-addition products dominate exclusively in
the reaction of phosphines with enyne (1c,d) and aldehydes,
unambiguously evidenced by X-ray crystallographic ana-
lyses and density functional theory (DFT) results.
6c,d
7e
THF
3
THF
3
8f
9g
THF
3
THF
24
3
10g
11g
12d,g
THF
60
rt
92
CH2Cl2
THF
24
3
49
60
80
a Reaction was carried out under anhydrous condition unless other-
1
wise noted. b Yields were determined by H NMR with mesitylene as an
internal standard and yields in parentheses were determined based on
converted aldehydes. c Molar ratio of 1c:2a:3a = 1:1:1. d With 1 equiv of
H2O as an additive. e Molar ratio of 1c:2a:3a = 1.5:1:1. f Molar ratio of
1c:2a:3a = 1.5:1.5:1. g Molar ratio of 1c:2a:3a = 2:2:1. h 1,2-Dichloroethane.
1c and 3a (Table 2). We found that reactions with triar-
ylphosphines generally gave moderate to good yields
(55ꢀ79%; 62ꢀ88% based on converted aldehydes; entries
1ꢀ6). Phosphines with electron-releasing aryl groups
(entries 1ꢀ3) outperformed those with electron-withdraw-
ing moieties (entries 4 and 5). Heteroaryl phosphine (2g)
also produced product 4g with relatively lower yields
(entry 6). Phosphine equipped with an alkyl group (2h)
caused labile products; in this case, we could only isolate
product 4h incorporating PMePh2 in 38% yield (entry 7).
We further evaluated other substituted aldehydes 3bꢀd or
enyne 1dwith representativephosphines. Weobserved that
reactions with 3-NO2 (3b, entries 8ꢀ12), 4-Cl-3-NO2 (3c,
entries 13ꢀ15), and 4-CN (3d, entries 19ꢀ21) substituted
aldehydes or enyne 1d (entries 16ꢀ18) gave comparable
yields at the same conditions. However, attempts at using
more electron-rich aromatic aldehydes or aliphatic alde-
hydes did not give desirable products.14
We first investigated the reaction conditions of 1c, PPh3
(2a), and 4-nitrobenzaldehyde (3a), providing novel lac-
tone 4a, in a 1:1:1 molar ratio (Table 1). We found that the
reaction proceeded smoothly in THF at room tempera-
ture, giving 43% yield (68% based on converted 3a), and
was superior to that in CH2Cl2 (entries 1 and 2). The
reaction proceededtonearcompletion att = 3 h in THF at
60 °C (entries 4 and 5). Increasing the molar ratios of 1c
and 2a with respect to 3a gave higher yields: 46% and 69%
yields respectively for ratios of 1.5:1:1 and 1.5:1.5:1 (entries
7 and 8). We found that a molar ratio of 2:2:1 for 1c:2a:3a
was optimal for full consumption of 3a, giving 74% and
92% yields at room temperature and 60 °C, respectively
(entries 9 and 10). Reactions performed poorly in chlori-
nated solvents as compared to those in THF (entries 2, 3,
and 11). Finally, we observed that the reaction perfor-
mance was deteriorated upon addition of 1 equiv of water
(entries 6 and 12).
To gain insightful scope of this nonclassical addition, we
next evaluated reactivity of various phosphines 2bꢀh with
We characterized the isolated compounds 4aꢀv using
infrared (IR) and 1H, 13C, and 31P nuclear magnetic
resonance (NMR) spectroscopy, electron-impact or elec-
tron-spray mass spectrometry (EI-MS or ESI), and X-ray
crystallographic analyses. Some isolated compounds tend
to crystallize upon slow evaporation of their dichloro-
methane solution. We obtained an X-ray crystal structure
(11) Wenkert, E.; Adams, K. A. H.; Leicht, C. L. Can. J. Chem. 1963,
41, 1844.
(12) For a review, see: Lewandowska, E. Tetrahedron 2007, 63, 2107.
For selected examples of R-Michael additions, see: (a) Li, Y.; Xu, X.;
Tan, J.; Liao, P.; Zhang, J.; Liu, Q. Org. Lett. 2010, 12, 244. (b) Bi, X.;
Zhang, J.; Liu, Q.; Tang, J.; Li, B. Adv. Synth. Catal. 2007, 349, 2301. (c)
Klumpp, G. W.; Mierop, A. J. C.; Vrielink, J. J.; Brugman, A.; Schakel,
M. J. Am. Chem. Soc. 1985, 107, 6740. (d) Shim, J. G.; Park, J. C.; Cho,
C. S.; Shim, S. C.; Yamamoto, Y. Chem. Commun. 2002, 852. (e) Guo,
C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921. (f) Dong, D.; Bi, X.;
Liu, Q.; Cong, F. Chem. Commun. 2005, 3580. (g) Li, Y.; Liang, F.; Bi,
X.; Liu, Q. J. Org. Chem. 2006, 71, 8006.
(14) Reactions with aldehydes, such as benzaldehyde, 4-tert-butyl-
benzaldehyde, 4-methylbenzaldehyde, 4-chlorobenzaldehyde, 4-fluoro-
benzaldehyde, 2,4-difluorobenzaldehyde, 4-methoxybenzaldehyde, and
1-butanal did not provide the corresponding products under the in-
vestigated conditions. In these reactions, polar dark-brown materials
were obtained, likely due to polymerization of enynes.
(13) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595.
Org. Lett., Vol. 13, No. 9, 2011
2249

Table 2. Reaction of 1cꢀd, Phosphines 2, and Aldehydes 3a
enyne
substituent product yield
entry
1
phosphine PR3 (2)
X (3)
4
(%)b
Figure 1. Thermal ellipsoids of compound 4a drawn at the 30%
level of probability.
1
2
1c P(p-tolyl)3 (2b)
4-NO2 (3a)
4b
4c
4d
4e
4f
79 (88)
78
1c PPh2(p-tolyl) (2c) 4-NO2 (3a)
1c P(4-OMe-Ph)3 (2d) 4-NO2 (3a)
3
77
4
1c P(4-Cl-Ph)3 (2e)
1c P(4-F-Ph)3 (2f)
4-NO2 (3a)
4-NO2 (3a)
65 (76)
62 (66)
55 (62)
38 (45)
66
deprotonation takes place to form product 4. More elec-
tron-rich aromatic or aliphatic aldehydes may cause the
CꢀH protons of Id to be less reactive for deprotonation
and thus did not form lactone 4.
5
6
1c P(2-thienyl)3 (2g) 4-NO2 (3a)
1c PMePh2 (2h) 4-NO2 (3a)
1c P(4-OMe-Ph)3 (2d) 3-NO2 (3b)
1c P(p-tolyl)3 (2b) 3-NO2 (3b)
1c PPh2(p-tolyl) (2c) 3-NO2 (3b)
4g
4h
4i
7
8
9
4j
74(94)
81
10
11
12
13
14
15
16
17
18
19
20
21
4k
4l
1c PPh3 (2a)
3-NO2 (3b)
3-NO2 (3b)
80
1c P(4-Cl-Ph)3 (2e)
4m
56 (71)
70
Scheme 2. Mechanism for Formation of 4
1c P(4-OMe-Ph)3 (2d) 4-Cl-3-NO2 (3c) 4n
1c PPh3 (2a)
4-Cl-3-NO2 (3c) 4o
4-Cl-3-NO2 (3c) 4p
76
1c P(4-Cl-Ph)3 (2e)
1d P(p-tolyl)3 (2b)
1d PPh3 (2a)
59(67)
68
4-NO2 (3a)
4-NO2 (3a)
4-NO2 (3a)
4q
4r
4s
4t
68
1d P(4-Cl-Ph)3 (2e)
61 (64)
72
1c P(4-OMe-Ph)3 (2d) 4-CN (3d)
1c PPh3 (2a)
4-CN (3d)
4-CN (3d)
4u
4v
68
1c P(4-Cl-Ph)3 (2e)
51 (57)
a Reaction was carried out under anhydrous condition unless other-
wise noted; molar ratio of 1cꢀd:2:3 = 2:2:1. b Yields were determined by
1H NMR with mesitylene as an internal standard and yields in pa-
rentheses were determined based on converted aldehydes.
The formation of these nonclassical products led us to
realize electronic properties of 1c. We evaluated Mulliken
charges and LUMO coefficients along the z-axis of 1c. We
found that the R(δ0)-carbon, with Mulliken charge values
of ꢀ0.018, 0.049, and 0.147 respectively, exhibited more
positive charge density than the β(γ0)-carbon, with values
of ꢀ0.058, 0.000, and 0.032 using HF/6-31(G) and DFT at
B3LYP/3-21G and B3LYP/6-31G(d) levels of theory
(Table 3, entries 1ꢀ3).16 This electropositive notion is also
consistent with their experimental 13C NMR chemical
shifts, 86.7 and 81.8 ppm for the R(δ0) and β(γ0) carbons,
respectively. We envisaged that absolute values of LUMO
coefficients (2Pz) on R(δ0)-carbon are larger that those of
β(γ0)-carbon along the z-axis of 1c (entries 1ꢀ3). Hence, we
conclude that the R(δ0)-carbon is more susceptible to
nucleophilic attack than the β(γ0)-carbon on the basis of
higher level theory results. Computed chemical shifts of
R(δ0) and β(γ0) carbons corroborate with experimental
ones (entry 4).
of compound 4a (Figure 1).15 The phosphorus atom (P1)
clearly bonds to carbon (C2), the R(δ0)-carbon of enyne 1c,
˚
with a bond length of 1.7406(17) A. Due to the delocaliza-
tion of negative charge from ylidic carbon C2 to the
carbonyl π bond (C1ꢀO4), the C1ꢀC2 bond is shorter
˚
(1.424(2) A) than a lactone ring without an R-phosphorus
ylide moiety. The P1 atom does not stay in the same plane
with the lactone ring due to steric encumbrance, evidenced
from the dihedral angle (ψO4ꢀC1ꢀC2ꢀP1) of 17.6(3)°.
We account for the formation of ylide 4 by nucleophilic
attack of phosphine PR3 at the R(δ0)-position of the enyne
1c (Scheme 2), generating a reactive zwitterionic species Ia
bearing a carbenoid moiety at the β(γ0)-carbon. Addition
of Ia to the carbonyl carbon of aldehydes followed by
intramolecular cyclization gives Ic (via intermediate Ib).
Then,
a methoxide molecule is released. Finally,
(15) See the Supporting Information for spectroscopic assignment
and X-ray data for compound 4a (The crystallographic coordinates have
been deposited with the Cambridge Crystallographic Data Centre;
deposition no. 818904. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre, 12 Union Rd., Cambridge
CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/retrieving.html).
(16) Gaussian 09 program, see the Supporting Information (SI) for
the full citation.
2250
Org. Lett., Vol. 13, No. 9, 2011

In another viewpoint, the presently studied reaction can be
considered as a 1,6-nucleophilic conjugate addition at the
δ0 position; one may name it anti-Michael or contra-
Michael addition or to a newer R-Michael addition termi-
nology if original Michael addition equals conceptually to
the broad conjugate addition.12 Finally, the studied reac-
tions are multicomponent reactions (MCRs)17 with un-
usual addition patterns that are applicable to the
preparation of useful molecules through a single reactant
replacement (SRR) approach.18 In addition, γ-lactones
are core structures of many natural products,19 for
example, acetogenin gigantecin20 and lignans.21 Nair’s
previous example provided cyclopentenylphosphoranes
with electron-deficient styrenes;22 however, a combination
of lactones with Wittig moiety, to the best of our
knowledge, is synthetically unavailable through previous
MCRs.
In summary, our findings reveal the first example of
nonclassical Michael addition of phosphine nucleophiles
to the R(δ0)-position of an electron-deficient enyne.
The generated dipolar intermediates react with aldehydes
and form γ-lactone compounds featuring R-phosphorus
ylides. This opens up a new window from which a
new synthetic methodology can be utilized. Currently,
we are establishing a library (sortiment) of compounds
utilizing this approach with other nucleophiles, π-electro-
philes, and electron-deficient alkynes in our laboratory.
Further investigation of such types of lactones having
Wittigmoietyfor application in naturalproducts syntheses
is now underway. These results will be reported in due
course.
Table 3. Computed Mulliken Charges and LUMO Coefficients
along z-Axis on R(δ0) and β(γ0) Carbons of 1c
Mulliken charge
LUMO coefficient (2Pz)
δ (ppm)
entry
R(δ0)
β(γ0)
R(δ0)
β(γ0)
R(δ0) β(γ0)
1a
2b
3c
4d
ꢀ0.02
0.05
ꢀ0.06
0.00
0.21
0.20
0.23
ꢀ0.18
ꢀ0.15
ꢀ0.18
0.15
0.03
99.4 84.8
a HF/6-31(G); structure optimized with B3LYP/6-31G(d). b B3LYP/
3-21G. c B3LYP/6-31G(d). d B3LYP/6-311Gþ(2d,p); structure opti-
mized with B3LYP/6-31G(d).
The addition pattern of currently studied enyne (1c) can
be scrutinized into two modes. 1c is formally named hex-2-
en-4-ynedioic acid dimethyl ester (IUPAC nomenclature).
The reactive alkynyl carbons (the fourth and fifth carbons)
are formulated at the γ,δ-positionifGreek nomenclature is
in compliance with the IUPAC numbering order. On the
other hand, these two reactive alkynyl carbons can be
regarded as R,β-carbon if we consider the alkenyl group as
a substituent and designatethe alkynyl carbonswithGreek
letters starting from its proximate ester group. Whichever
these two thoughts are applied, the position of phosphine
addition is inverted as compared to previous examples of
alkynes with phosphines upon displacement of the alkyl to
alkenyl group in alkynoates (1a, Scheme 1). The original
definition of Michael addition1a states that it is the addi-
tion of a nucleophile to the β-carbon of R,β-unsaturated
carbonyl compounds. Our studied enyne 1c gives neither
β-addition nor 1,4-addition with phosphine nucleophiles.
Acknowledgment. We thank the National Science
Council and NCTU for supporting this research finan-
cially and the National Center for High-Performance
Computing (NCHC) for computations. We also thank
Mr. C.-C. Che and Mrs. G.-L. Pong (National Precious
Instrument Center) for mass spectrometric and NMR
spectroscopic analyses, respectively.
(17) (a) Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856. (b) Pan, H.-R.; Li,
Y.-J.; Yan, C.-X.; Xing, J.; Cheng, Y. J. Org. Chem. 2010, 75, 6644. (c)
Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, R.; Mathen,
Supporting Information Available. Experimental pro-
cedures and spectral data (1H, 31P, and 13C NMR) for
compounds 4aꢀv and X-ray crystallographic data of 4a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (d) Toure, B. B.; Hall,
D. G. Chem. Rev. 2009, 109, 4439. (e) Candeias, N. R.; Montalbano, F.;
Cal, P. M. S. D.; Gois, P. M. P. Chem. Rev. 2010, 110, 6169.
(18) Ganem, B. Acc. Chem. Res. 2008, 42, 463.
ꢁ
(19) (a) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269. (b) Zeng, L.; Ye,
Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J. L. Nat.
Prod. Rep. 1996, 13, 275H. (c) Hoffmann, M. R.; Rabe, J. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 94. (d) Zheng, N.; Shimizu, Y. Chem. Commun.
1997, 399. (e) Collins, I. J. Chem. Soc., Perkin Trans. 1 1999, 1377. (f)
Bradley, A.; Motherwell, W. B.; Ujjainwalla, F. Chem. Commun. 1999,
917. (g) Pilli, R. A.; d Oliveira, M. d C. F. Nat. Prod. Rep. 2000, 17, 117.
(20) Spurr, I. B.; Brown, R. C. D. Molecules 2010, 15, 460.
(21) Sagar, K. S.; Chang, C.-C.; Wang, W.-K.; Lin, J.-Y.; Lee, S.-S.
Bioorg. Med. Chem. 2004, 12, 4045.
(22) Nair, V.; Deepthi, A.; Benessh, P. B.; Eringathodi, S. Synthesis
2006, 9, 1443.
Org. Lett., Vol. 13, No. 9, 2011
2251