Reductive homocondensation of benzylidene- and alkylidenepyruvate esters by a P(NMe2)3-mediated tandem reaction

Article abstract of DOI:10.1021/ol400576e

A reductive homocondensation of E-benzylidenepyruvate esters mediated by P(NMe₂)₃ is described. The transformation, initiated by the Kukhtin-Ramirez addition of the phosphorus reagent to the vinyl-substituted α-dicarbonyl substrate, proceeds via a resonance delocalized oxyphosphonium dienolate intermediate to provide access to diverse oxygenated heterocycles as a function of the substituent.

Full text of DOI:10.1021/ol400576e

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1926–1929
Reductive Homocondensation of
Benzylidene- and Alkylidenepyruvate
Esters by a P(NMe2)3‑Mediated
Tandem Reaction
Sunewang Rixin Wang and Alexander T. Radosevich*
Department of Chemistry, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States
radosevich@psu.edu
Received March 2, 2013
ABSTRACT
A reductive homocondensation of E-benzylidenepyruvate esters mediated by P(NMe2)3 is described. The transformation, initiated by the
KukhtinꢀRamirez addition of the phosphorus reagent to the vinyl-substituted R-dicarbonyl substrate, proceeds via a resonance delocalized
oxyphosphonium dienolate intermediate to provide access to diverse oxygenated heterocycles as a function of the substituent.
Trivalent phosphorus derivatives are known to undergo
an addition reaction with R-dicarbonyl compounds to give
1:1 adducts (KukhtinꢀRamirez reaction).1 The products
of this event, formulated as either dioxaphospholene 1 or
oxyphosphonium enolate 10 (Scheme 1), have been the
subject of extensive structural investigation1c,d,2 and have
been shown to undergo a variety of reactions of both
synthetic and mechanistic interest.3ꢀ7 For instance, treat-
ment of 1/10 with electrophilic reagents may give rise to
alkoxyphosphonium intermediates 2, which in turn them-
selves may serve as electrophiles toward nucleophilic dis-
placement (Scheme 1).8 The resultant reactivity of
intermediates 1/10 has been exploited to effect epoxida-
tion,4 cyclopropanation,5 formal SꢀCl insertion,6 and
XꢀH functionalization (X = O, N) reactions.7
We considered the possibility of extending this basic
reactivity by vinylogy.9 In outline, KukhtinꢀRamirez
addition of vinyl-substituted keto ester 3 with a trivalent
phosphine reagent would generate oxyphosphonium
(1) (a) Kukhtin, V. A. Dokl. Akad. Nauk SSSR 1958, 121, 466. (b)
Ramirez, F. Pure Appl. Chem. 1964, 9, 337. (c) Ramirez, F. Acc. Chem.
Res. 1968, 1, 168. (d) Osman, F. H.; El-Samahy, F. A. Chem. Rev. 2002,
102, 629.
(2) (a) Ramirez, F.; Desai, N. B. J. Am. Chem. Soc. 1963, 85, 3252. (b)
Ramirez, F.; Patwardhan, A. V.; Kugler, H. J.; Smith, C. P. Tetrahedron
Lett. 1966, 7, 3053.
(3) (a) Ramirez, F.; Desai, N. B. J. Am. Chem. Soc. 1960, 82, 2652. (b)
Ramirez, F.; Bhatia, S. B.; Smith, C. P. J. Am. Chem. Soc. 1967, 89, 3026.
(c) Ramirez, F.; Bhatia, S. B.; Smith, C. P. J. Am. Chem. Soc. 1967, 89,
3030. (d) Lathourakis, G. E.; Litinas, K. E. J. Chem. Soc., Perkin Trans.
1 1996, 491. (e) Zhang, W.; Shi, M. Chem. Commun. 2006, 1218.
(4) (a) Mark, V. J. Am. Chem. Soc. 1963, 85, 1884. (b) Newman,
M. S.; Blum, S. J. Am. Chem. Soc. 1964, 86, 5598. (c) Ramirez, F.; Gulati,
A. S.; Smith, C. P. J. Org. Chem. 1968, 33, 13. (d) Muller, A. J.;
Nishiyama, K.; Griffin, G. W.; Ishikawa, K.; Gibson, D. M. J. Org.
Chem. 1982, 47, 2342. (e) Liu, X.; Verkade, J. G. J. Org. Chem. 2000, 65,
4560.
(5) (a) Corre, E.; Foucaud, A. J. Chem. Soc. D 1971, 570. (b) Fauduet,
H.; Burgada, R. Synthesis 1980, 642.
(6) (a) Harpp, D. N.; Mathiaparanam, P. J. Org. Chem. 1971, 36,
2540. (b) Harpp, D. N.; Mathiaparanam, P. J. Org. Chem. 1972, 37,
1367.
(7) Miller, E. J.; Zhao, W.; Herr, J. D.; Radosevich, A. T. Angew.
Chem., Int. Ed. 2012, 51, 10605.
(8) Burger, K. In Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I. G., Ed.; Academic Press: London, 1979; pp 467ꢀ510.
(9) (a) Fuson, R. C. Chem. Rev. 1935, 16, 1. (b) Krishnamurthy, S.
J. Chem. Educ. 1982, 59, 543. (c) Bruneau, P.; Taylor, P. J.; Wilkinson,
A. J. J. Chem. Soc., Perkin Trans. 2 1996, 2263.
r
10.1021/ol400576e
Published on Web 04/11/2013
2013 American Chemical Society

dienolate adduct 4, wherein a formal negative charge
would be delocalized over both R- and γ-positions with
respect to the ester moiety (Scheme 1). In analogy to the
reactivity of canonical dienolate intermediates,10 we con-
sidered the possibility of engaging the γ-nucleophilicity of
4, thereby leading to new transformations. Here, we report
a P(III)-mediated reductivehomocondensation reaction of
unsaturated keto esters emanating from intermediate 4
that evidence this proposed γ-nucleophilicity.11,12
Scheme 2. Reductive Trimerization of 5 with P(NMe2)3
As shown in Scheme 3, a range of E-benzylidenepyru-
vate esters with variations on both the ester group and the
aryl motif are suitable substrates. Substitution of the aryl
ring only modestly affects the reaction outcome, and yields
of the trimerization reaction across both electron-deficient
(9ꢀ11) and electron-rich (12ꢀ13) substrates are good. The
yield of the corresponding furanyl derivative (14) by con-
trast is significantly diminished. In all cases investigated,
the products, which contain three stereocenters and two
unsymmetrical acyclic double bonds, are formedas a single
observable stereoisomer.
Scheme 1. Vinylogation of KukhtinꢀRamirez Redox Adducts
Table 1. Screening of Reaction Conditions
As a point of departure, we investigated the reaction of
methyl E-benzylidenepyruvate 5 with tris(dimethylamino)-
phosphorus under typical KukhtinꢀRamirez conditions.
Specifically, P(NMe2)3 was added to a solution of sub-
strate 5 at ꢀ78 °C in tetrahydrofuran. Upon warming, the
formation of dihydropyran 6 was observed (Scheme 2).
This product, whose structure was confirmed by single-
crystal X-ray analysis, corresponds to a reductive trimer-
ization of substrate 5; it is isolated as a single diastereo-
isomer. In surveying this reactivity, we have found that
tris(dimethylamino)phosphorus is uniquely suited to this
transformation; trimethyl phosphite by contrast is not an
effective promoter (Table 1, entry 2). A range of solvents
were found to be serviceable, but reactions performed in
toluene were foundtobehighest yielding (Table 1, entry 5).
Consistent with the stoichiometry of the trimerization
process, which requires the consumption of two molecules
of tris(dimethylamino)phosphorus for each molecule of
dihydropyran formed, the use of 0.7 equiv of P(NMe2)3
relative to the benzylidenepyruvate substrate was found to
only minimally impact the observed yield.
entry
PR3
solvent
yield (%)a
1
2
3
4
5
6
P(NMe2)3, 1.05 equiv
P(OMe)3, 1.05 equiv
P(NMe2)3, 1.05 equiv
P(NMe2)3, 1.05 equiv
P(NMe2)3, 1.05 equiv
P(NMe2)3, 0.70 equiv
THF
71
THF
<5%
70
51b
78
Et2O
CH2Cl2
PhCH3
PhCH3
74
a Isolated yield. b Undetermined byproducts were observed.
A mechanistic proposal consistent with the observed
stereoselective reductive trimerization of E-benzylidene-
pyruvate esters is offered in Scheme 4.13 The sequence
is initiated by the KukhtinꢀRamirez addition of tris-
(dimethylamino)phosphorus to the unsaturated keto ester
substrate 15 giving oxyphosphonium dienolate intermedi-
ate 16.1 Subsequent conjugate addition of the nucleophilic
γ-position10ꢀ12 of 16 to an additional equivalent of sub-
strate 15, followed by intramolecular oxycyclization,
would then give dipolar intermediate 18. The trans stereo-
chemistry about the newly formed CꢀC bond would be
expected to be controlled by nonbonding steric interac-
tions in thestepwiseprocess. Thissequenceofeventswould
regenerate a reactive oxyphosphonium enolate, which
could then be expected to engage a third equivalent of 15
to produce 20 via stepwise polar cyclopropanation.5
(10) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
Rev. 2000, 100, 1929. (b) Soriente, A.; De Rosa, M.; Villano, R.; Scettri,
A. Curr. Org. Chem. 2004, 8, 993. (c) Denmark, S. E.; Heemstra, J. R.,
Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (d) Kalesse, M.
Top. Curr. Chem. 2005, 244, 43. (e) Casiraghi, G.; Battistini, L.; Curti,
C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076.
(11) The γ-nucleophilicity of allylic ylides is reported; see: (a)
Dauben, W. G.; Ipaktschi, J. J. Am. Chem. Soc. 1973, 95, 5088. (b)
Corey, E. J.; Erickson, B. W. J. Org. Chem. 1974, 39, 821. (c) Padwa, A.;
Brodsky, L. J. Org. Chem. 1974, 39, 4199. (d) Moorhoff, C. M. Synlett
1997, 126. (e) Wang, Q.-G.; Deng, X.-M.; Zhu, B.-H.; Ye, L.-W.; Sun,
X.-L.; Li, C.-Y.; Zhu, C.-Y.; Shen, Q.; Tang, Y. J. Am. Chem. Soc. 2008,
130, 5408. (f) Zhu, B.-H.; Zhou, R.; Zheng, J.-C.; Deng, X.-M.; Sun,
X.-L.; Shen, Q.; Tang, Y. J. Org. Chem. 2010, 75, 3454.
(13) For deoxygenations by P(III) reagents, see: Rowley, A. G. In
Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.;
Academic Press: London, 1979; pp 295ꢀ350.
(12) For a related γ-nucleophilic intermediate, see: Winkler, T.;
Bencze, W. L. Helv. Chim. Acta 1980, 63, 402.
Org. Lett., Vol. 15, No. 8, 2013
1927

Scheme 3. Scope of P(NMe2)3-Mediated E-Benzylidenepyruvate
Ester Reductive Condensation
Scheme 4. A Proposed Pathway for the Reductive Trimerization
The keto ester moiety of 20 is itself susceptible to the
KukhtinꢀRamirez addition with tris(dimethylamino)-
phosphorus. Ring opening of the pushꢀpull cyclopropyl
intermediate 21 and final elimination then lead to the for-
mation of 24, terminating the trimerization sequence.14,15
In order to validate the terminal steps of this mechanistic
sequence, we synthesized cyclopropyl R-keto ester 2516 and
found that exposure to P(NMe2)3 gave diene 26 with a E/Z
ratio greater than 20:1 (Scheme 5), albeit in low isolated
yield. The diastereomeric cyclopropyl R-keto ester 250
converges on the same result.
Consistent with this mechanistic proposal, the γ-nucleo-
philicity of oxyphosphonium dienolates 4 may be attenu-
ated by increasing the steric congestion at that position.
For instance, whenthestericallyhinderedmesityl substrate
27 is reacted with 1.05 equiv of P(NMe2)3, a single diaste-
reoisomer of the formal [4 þ 1] cycloadduct 30 was isolated
from the reaction in 61% yield. The relative configuration
of the two stereocenters in 30 was confirmed by single-
crystal X-ray analysis (Scheme 6). After initiation by the
KukhtinꢀRamirez condensation of 27 with P(NMe2)3, a
nucleophilic attack from the less hindered R-position of
oxyphosphonium dienolate 28 to the second molecule of
27 affords intermediate 29, which would finally cyclize to
the dihydrofuran derivative 30 via a staggered transition
state minimizing steric interactions (Scheme 6).
Scheme 5
(14) Sequential cyclopropanation/ring opening of electron-deficient
double bonds activated by phosphoranes with electrophilic iron carbe-
noids has been reported; see: (a) Wang, S. R.; Zhu, C.-Y.; Sun, X.-L.;
Tang, Y. J. Am. Chem. Soc. 2009, 131, 4192. (b) Wang, P.; Ling, L.; Liao,
S.-H.; Zhu, J.-B.; Wang, S. R.; Li, Y.-X.; Tang, Y. Chem.;Eur. J. 2013,
DOI: 10.1002/chem.201204182.
(15) For examples of ring opening of donorꢀacceptor-substituted
cyclopropanes, see: (a) Doyle, M. P.; Van Leusen, D. J. Am. Chem. Soc.
1981, 103, 5917. (b) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103,
1151.
(16) Preparation of 25 and 250: Rasmy, O. M.; Vaid, R. K.; Semo,
M. J.; Chelius, E. C.; Robey, R. L.; Alt, C. A.; Rhodes, G. A.; Vicenzi,
J. T. Org. Process Res. Dev. 2006, 10, 28.
Reactions of alkylidene pyruvate esters with P(NMe2)3
differ from their benzylidene counterparts. The reaction of
ethyl (E)-neopentylidenepyruvate (31) with P(NMe2)3
gives a mixture of 2,5-dihydrooxepin 3217 along with
vinylcyclopropane 33 in moderate yield (Scheme 7). Pre-
sumably, absent of any benzylic stabilization, the Kukhtinꢀ
Ramirez adduct arising from the reaction of 31 and
1928
Org. Lett., Vol. 15, No. 8, 2013

Scheme 6. Reductive Dimerization of 27
Scheme 7. Reaction of Alkylidenepyruvate Esters with
P(NMe2)3
intermediates by the KukhtinꢀRamirez reaction. The
observation of the γ-nucleophilicity of oxyphosphonium
dienolate intermediates and the notable effect of substitu-
ents on R-/γ-nucleophilicity modulation offers the poten-
tial for new synthetic transformations initiated by the
KukhtinꢀRamirez reaction. Investigations aimed at the
interception of the oxyphosphonium dienolate intermedi-
ates evidenced here with external electrophilic reagents are
underway.
P(NMe2)3 does not exhibit significant γ-nucleophilicity,
with the reaction instead emanating from the R-nucleo-
philic character. Methyl (E)-ethylidenepyruvate (34) be-
haves similarly (albeit with low yield), indicating that the
preference for R-nucleophilic reactivity is not steric in
origin.
In summary, the reaction of benzylidenepyruvate esters
with P(NMe2)3 initiates a reductive homocondensation,
leading to diverse oxygenated hetereocyclic products de-
pending on the substitution of the starting substrate.
Mechanistically, this reaction can be understood as pro-
ceeding via initial formation ofoxyphosphonium dienolate
Acknowledgment. We gratefully acknowledge the
Pennsylvania State University for financial support of this
work and Wei Zhao (Department of Chemistry, The
Pennsylvania State University) for the preparation of a
starting material.
Supporting Information Available. Detailed experimen-
tal procedures, analytical data of all new compounds, and
X-ray data in CIF format for 6 and 30. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(17) Both dihydrooxepins 32 and 35 and vinylcyclopropane 33 were
isolated as single diastereomers, with tentative stereochemical assign-
ment as shown in Scheme 7 based on the assumption that 32 is derived
from the cis-diastereoisomer (the keto ester moiety relative to vinyl
group) of 33 via a hetero-Cope rearrangement.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
1929