A Csp3-Csp3 bond forming reductive condensation of α-keto esters and enolizable carbon pronucleophiles

Article abstract of DOI:10.1021/ol401276b

The preparation of densely functionalized unsymmetrical 1,4-dicarbonyl structural motifs by a phosphorus(III)-mediated reductive condensation of α-keto esters and enolizable carbon pronucleophiles is described. The reaction, which is initiated by Kukhtin-Ramirez addition of commercially available tris(dimethylamino)phosphine to the α-keto ester substrate, proceeds rapidly under mild conditions.

Full text of DOI:10.1021/ol401276b

ORGANIC
LETTERS
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Vol. XX, No. XX
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A Csp3ÀCsp3 Bond Forming Reductive
Condensation of r‑Keto Esters and
Enolizable Carbon Pronucleophiles
Wei Zhao, Darla M. Fink, Carolyn A. Labutta, and Alexander T. Radosevich*
Department of Chemistry, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States
radosevich@psu.edu
Received May 7, 2013
ABSTRACT
The preparation of densely functionalized unsymmetrical 1,4-dicarbonyl structural motifs by a phosphorus(III)-mediated reductive condensa-
tion of R-keto esters and enolizable carbon pronucleophiles is described. The reaction, which is initiated by KukhtinÀRamirez addition of
commercially available tris(dimethylamino)phosphine to the R-keto ester substrate, proceeds rapidly under mild conditions.
Highly functionalized unsymmetrical 1,4-dicarbonyl
compounds are versatile intermediates in organic syn-
thesis,1 as well as common target motifs in natural products
and biologically active small molecules.2 Among the de-
monstrated approaches to 1,4-dicarbonyl compounds, the
union of two C2 carbonyl fragments to forge the C2ÀC3
linkage is appealing in its convergency.3 Synthetically, this
bond construction is typically achieved via diverse pre-
functionalized enolonium synthetic equivalents,4 or alter-
natively via a two-electron oxidation of a preformed
intermediate enolate.5 New direct and mild methods for
the formation of 1,4-dicarbonyls operating under alterna-
tive conditions might serve as a valuable complement to
these traditional synthetic approaches.6
(1) (a) Paal, C. Ber. Dtsch. Chem. Ges. 1884, 17, 2756. (b) Knorr, L.
Ber. Dtsch. Chem. Ges. 1884, 17, 2863.
(2) For instance, see: Whittaker, M.; Floyd, C. D.; Brown, P.;
Gearing, A. J. H. Chem. Rev. 1999, 99, 2735.
(3) For alternative syntheses of 1,4-dicarbonyl compounds via C1
acyl anion equivalents, see: (a) Stetter, H.; Kuhlmann, H. Org. React.
1991, 40, 407. (b) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv.
Chim. Acta 1996, 79, 1899. (c) Kerr, M. S.; Read de Alaniz, J.; Rovis, T.
J. Am. Chem. Soc. 2002, 124, 10298. (d) Kerr, M. S.; Rovis, T. J. Am.
Chem. Soc. 2004, 126, 8876. (e) Pesch, J.; Harms, K.; Bach, T. Eur. J.
ꢀ
We recently reported a phosphorus(III)-mediated meth-
od for the synthesis of R-heterofunctionalized carbonyl
derivatives via reductive condensation of R-keto esters and
XÀH pronucleophiles.7 This method hinges on the
Org. Chem. 2004, 2025. (f) Mennen, S. M.; Blank, J. T.; Tran-Dube,
M. B.; Imbriglio, J. E.; Miller, S. J. Chem. Commun. 2005, 195. (g)
Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc.
2004, 126, 2314. (h) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D.
Synthesis 2002, 2725. (i) Custar, D. W.; Le, H.; Morken, J. P. Org. Lett.
2010, 12, 3760. (j) Smith, A. B.; Adams, C. M. Acc. Chem. Res. 2004, 37,
ꢀ
365. (k) Fernandez, M.; Uria, U.; Vicario, J. L.; Reyes, E.; Carrillo, L. J.
Am. Chem. Soc. 2012, 134, 11872. Via C3 homoenolate equivalents: (l)
Shen, Z. -L.; Goh, K. K. K.; Cheong, H. -L.; Wong, C. H. A.; Lai, Y. -C.;
Yang, Y. -S.; Loh, T. -P. J. Am. Chem. Soc. 2010, 132, 15852.
(5) For representative syntheses of 1,4-dicarbonyls via oxidation of
enolates and related nucleophiles, see: (a) Ramig, K.; Kuzemko, M. A.;
McNamara, K.; Cohen, T. J. Org. Chem. 1992, 57, 1968. (b) Renaud, P.;
Fox, M. A. J. Org. Chem. 1988, 53, 3745. (c) Baran, P. S.; Hafensteiner,
B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem.
Soc. 2006, 128, 8678. (d) Jang, H. -Y.; Hong, J. -B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2007, 129, 7004. (e) Clift, M. D.; Thomson, R. J.
J. Am. Chem. Soc. 2009, 131, 14579. (f) Martin, C. L.; Overman, L. E.;
Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894. (g) Casey, B. M.;
Flowers, R. A. J. Am. Chem. Soc. 2011, 133, 11492.
(4) For representative syntheses of 1,4-dicarbonyls from prefunctio-
nalized C2 substrates, see: (a) Wender, P. A.; Erhardt, J. M.; Letendre,
L. J. J. Am. Chem. Soc. 1981, 103, 2114. (b) Lin, J.; Chan, W. H.; Lee,
A. W. M.; Wong, W. Y. Tetrahedron 1999, 55, 13983. (c) Miura, K.;
Fujisawa, N.; Saito, H.; Wang, D.; Hosomi, A. Org. Lett. 2001, 3, 2591.
(d) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc.
2002, 124, 7440. (e) Korboukh, I.; Kumar, P.; Weinreb, S. M. J. Am.
Chem. Soc. 2007, 129, 10342. (f) Kumar, P.; Li, P.; Korboukh, I.; Wang,
T. L.; Yennawar, H.; Weinreb, S. M. J. Org. Chem. 2011, 76, 2094. (g)
Sengupta, R.; Witek, J. A.; Weinreb, S. M. Tetrahedron 2011, 67, 8229.
(h) Witek, J. A.; Weinreb, S. M. Org. Lett. 2011, 13, 1258. (i) Muthusamy,
S.; Srinivasan, P. Tetrahedron Lett. 2006, 47, 6297.
€
(6) For instance, see: Rossle, M.; Werner, T.; Baro, A.; Frey, W.;
Christoffers, J. Angew. Chem., Int. Ed. 2004, 43, 6547.
(7) Miller, E. J.; Zhao, W.; Herr, J. D.; Radosevich, A. T. Angew.
Chem., Int. Ed. 2012, 51, 10605.
r
10.1021/ol401276b
XXXX American Chemical Society

intermediacy of dipolar adducts 1 (Scheme 1) derived from
the well-known KukhtinÀRamirez addition of trivalent
phosphorus reagents to 1,2-dicarbonyl compounds.8 Ad-
ducts of the type 1 have been demonstrated to exhibit a rich
reaction chemistry. For instance, treatment of 1 with elec-
trophilic reagents gives rise to alkoxyphosphonium species
2, which in turn may themselves then serve as electrophiles
for nucleophilic displacement (Scheme 1).7,9À13
pair via bond-forming nucleophilic displacement would then
furnish a new Csp3ÀCsp3 bond with expulsion of a phos-
phine oxide byproduct.16 In sum, the overall reductive pro-
cess would result in the preparation of versatile 1,4-dicar-
bonyl compounds by condensation of R-keto esters and
carbon pronucleophiles under mild reductive conditions.
Scheme 2. P(III)-Mediated Reductive Coupling of Methyl
Benzoylformate and Dimethyl Malonate
Scheme 1. Ambivalent Reactivity of KukhtinÀRamirez Redox
Adducts
Capitalizing on this reactivity trend, we considered the
consequence of introducing a readily enolizable carbonyl
derivative to KukhtinÀRamirez adducts in solution (see
Schemes 2, 3). In principle, a proton transfer yielding an
alkoxyphosphonium ion 4 and the corresponding enolate
could be envisioned.14,15 Subsequent collapse of this ion
In a specific embodiment of the reaction sequence out-
lined above, the dropwise addition of tris(dimethylamino)-
phosphine to a methylene chloride solution containing
equimolar amounts of methyl benzoylformate and di-
methyl malonate at ambient temperature gave the 1,4-
dicarbonyl product of reductive condensation (5), isolated
in 86% yield following extractive workup and chromato-
graphic purification (Scheme 2). A modest increase in
yield was obtained if the addition of tris(dimethylamino)-
phosphine was initiated at À78 °C, with subsequent warm-
ing to rt over ∼30 min. Under these optimal conditions, 5
was isolated in 91% yield.
This Csp3ÀCsp3 bond forming event is both rapid and
high-yielding and proceeds under mild conditions in a
single step and without elaborate prefunctionalization of
the condensation partners.17 Moreover, the use of com-
mercially available tris(dimethylamino)phosphine as the
promoter for this reaction offers a significant operational
advantage since the water-soluble phosphoric triamide
byproduct can be easily eliminated in workup by aqueous
extraction.
(8) (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.
(9) Burger, K. Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I. G., Ed.; Academic Press: London, U.K., 1979; pp 467À510.
(10) For related reactivity of phosphine-enone adducts, see: (a)
McClure, C. K.; Jung, K.-Y. J. Org. Chem. 1991, 56, 867. (b) McClure,
C. K.; Grote, C. W. Tetrahedron Lett. 1991, 32, 5313. (c) McClure, C. K.;
Jung, K.-Y.; Grote, C. W.; Hansen, K. Phos. Sulfur Relat. Elem. 1993,
75, 23. (d) McClure, C. K.; Mishra, P. Tetrahedron Lett. 2002, 43, 5249.
(11) (a) Mark, V. J. Am. Chem. Soc. 1963, 85, 1884. (b) Newman,
M. S.; Blum, S. J. Am. Chem. Soc. 1964, 86, 5598. (c) Griffin, G. W.;
Gibson, D. M.; Ishikawa, K. J. Chem. Soc., Chem. Commun. 1975, 595.
(d) Griffin, G. W.; Gibson, D. M.; Ishikawa, K. J. Chem. Soc., Chem.
Commun. 1976, 616. (e) Muller, A. J.; Nishiyama, K.; Griffin, G. W.;
Ishikawa, K.; Gibson, D. M. J. Org. Chem. 1982, 47, 2342. (f) Ramirez,
F.; Gulati, A. S.; Smith, C. P. J. Org. Chem. 1968, 33, 13. (g) Liu, X.;
Verkade, J. G. J. Org. Chem. 2000, 65, 4560.
(12) (a) Corre, E.; Foucaud, A. J. Chem. Soc. D 1971, 570. (b)
Fauduet, H.; Burgada, R. Synthesis 1980, 642. (c) Romanova, I. P.;
Bogdanov, A. V.; Mironov, V. F.; Shaikhutdinova, G. R.; Larionova,
O. A.; Latypov, S. K.; Balandina, A. A.; Yakhvarov, D. G.; Gubaidullin,
A. T.; Saifina, A. F.; Sinyashin, O. G. J. Org. Chem. 2011, 76, 2548.
(13) (a) Harpp, D. N.; Mathiaparanam, P. Tetrahedron Lett. 1970,
11, 2089. (b) Harpp, D. N.; Mathiaparanam, P. J. Org. Chem. 1971, 36,
2540. (c) Harpp, D. N.; Mathiaparanam, P. J. Org. Chem. 1972, 37,
1367.
(14) For an intramolecular proton transfer of KukhtinÀRamirez-
like adducts, see: (a) Zhang, W.; Shi, M. Chem. Commun. 2006, 1218. (b)
Shi, M.; Liu, X. -G.; Guo, Y. -W.; Zhang, W. Tetrahedron 2007, 63,
12731.
(15) For an intermolecular proton transfer to KukhtinÀRamirez-
like adducts, see: Griffiths, D. V.; Jamalia, H. A. R.; Tebby, J. C. Phos.
Sulfur Relat. Elem. 1985, 25, 173.
(16) For displacement of phosphine oxide from alkoxyphosphonium
intermediates by a malonate anion, see the Mitsunobu reaction: (a)
Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan
Kumar, K. V. P. Chem. Rev. 2009, 109, 2551and references therein. For
Arbuzov and related reactions, see: (b) Castro, B. R. Org. React. 1983,
29, 1.
An investigation of various R-keto esters revealed the
versatility of this methodology (Scheme 3). The R-keto
ester substrates for this survey are available in a single step
from commercial compounds either by FriedelÀCrafts
(17) For recent examples of phosphorus(III)-mediated reductive
CÀC bond formation, see: (a) Jung, C.-K.; Wang, J.-C.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4118. (b) Fan, R.-H.; Hou, X.-L.;
Dai, L.-X. J. Org. Chem. 2004, 69, 689. (c) Low, K. H.; Magomedov,
N. A. Org. Lett. 2005, 7, 2003. (d) McDougal, N. T.; Schaus, S. E.
Angew. Chem., Int. Ed. 2006, 45, 3117. (e) Lu, Y.; Arndtsen, B. A. Org.
Lett. 2009, 11, 1369. (f) Xu, S.; Zou, W.; Wu, G.; Song, H.; He, Z. Org.
Lett. 2010, 12, 3556. (g) Xie, P.; Huang, Y.; Chen, R. Chem.;Eur. J.
2012, 18, 7362. (h) Wang, S. R.; Radosevich, A. T. Org. Lett. 2013, 15,
1926.
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Org. Lett., Vol. XX, No. XX, XXXX

alkoxyphosphonium 4 should be facilitated by electron-
rich substrates.20
Scheme 3. P(III)-Mediated Reductive Coupling of Methyl
Benzoyl Formate and Dimethyl Malonatea
Heteroaromatic substrates, both π-excessive (furanyl
14, thiophenyl 12) and π-deficient (pyridinyl 13), are well
tolerated and give the corresponding products in moderate
to good yield. Pendant unsaturated functionality (16) that
might otherwise complicate enolate heterocoupling reac-
tions proceeding via open-shell intermediates is fully com-
patible with the mild reaction conditions described here.21
Initial attempts to extend these standard reductive con-
densation conditions to alkyl substituted R-keto esters led
to unsatisfactory yields of the desired CÀC coupled pro-
duct 15 (<50%). Instead, epoxide products arising from
reductive dimerization of the R-keto ester substrate
predominated.11 In order to overcome this limitation, a
minor experimental modification was necessary: inverse
addition of the alkyl R-keto ester to a rt solution of
P(NMe2)3 and 1.5 equiv of dimethyl malonate restored
the desired reductive condensation reactivity. Under these
slightly modified conditions, the alkyl substituted succi-
nate derivative 15 could be isolated in 65% yield.
The method may be readily extended to carbon pronu-
cleophiles other than dimethyl malonate, offering signifi-
cant opportunity for structural diversity (Scheme 4). 1,3-
Diketone and 1,3-keto ester pronucleophiles exhibit reac-
tivity in the reductive condensation reaction yielding the
target 1,4-dicarbonyl products (18 and 19, respectively),
although in both instances products arising from compe-
titive O-alkylation of these pronucleophiles may be iden-
tified in the crude reaction mixtures. This issue of regios-
electivity is eliminated in the case of nitrile substituted
pronucleophiles. R-Cyano esters and amides couple
smoothly with both alkyl (23 and 24) and aryl (22 and
25) substituted keto ester substrates under the P(NMe2)3-
promoted conditions.
This method also proves useful for the construction of
sterically congested Csp3ÀCsp3 bonds. For instance, the
reductive condensation of methyl benzoylformate and
dimethyl methylmalonate gives the R,R-disubstituted
malonate derivative 26 in 55% yield.22 Related reactivity
with R-substituted cyanoacetate derivatives correspond-
ingly gives products 27 and 28 bearing differentially sub-
stituted quaternary carbon centers in excellent yield.
The mild conditions and broad functional group com-
patibility of the P(NMe2)3-mediated reductive condensa-
tion method permits the synthesis of functionally diverse
products with rich potential for further synthetic function-
alization (Scheme 5). For instance, oxazolone 29 may be
prepared by reductive condensation of methyl benzoylfor-
mate with 30 in 90% yield as a separable mixture of
diastereomers. The major isomer of this functionalized
acylation with ethyl oxalyl chloride18 or by selective mono-
addition of a Grignard reagent to ethyl oxalate.19 Electro-
nically diverse para substituted benzoylformate derivatives
prepared in these ways react smoothly to give a series of
1,4-diesters (6, 8À11). In this series, a mild preference for
electron-rich substituents is apparent (compare 9 and 11).
This observation is consistentwiththe mechanism outlined
in Scheme 2; both the proton transfer from the carbon
pronucleophile to the KukhtinÀRamirez adduct 3 and
CÀC bond forming nucleophilic displacement from
(21) For reviews of oxidative radical cyclizations, see: (a) Schmittel,
M. Top. Curr. Chem. 1994, 169, 183. (b) Hintz, S.; Heidbreder, A.;
Mattay, J. Top. Curr. Chem. 1996, 177, 77. (c) Snider, B. B. Chem. Rev.
1996, 96, 339. (d) Moeller, K. D. Top. Curr. Chem. 1997, 185, 49. (e)
Ischay, M. A.; Yoon, T. Eur. J. Org. Chem. 2012, 18, 3359.
(22) For an approach to regioisomeric products by addition to
alkylidene Meldrum’s acid derivatives, see: (a) Wilsily, A.; Fillion, E.
Org. Lett. 2008, 10, 2801. (b) Dumas, A. M.; Fillion, E. Acc. Chem. Res.
2010, 43, 440.
(18) (a) Ianni, A.; Waldvogel, S. R. Synthesis 2006, 2103. (b) Meng,
^
Q.; Sun, Y.; Ratovelomanana-Vidal, V.; Genet, J. P.; Zhang, Z. J. Org.
Chem. 2008, 73, 3842.
(19) Creary, X. J. Org. Chem. 1987, 52, 5026.
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Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 4. P(III)-Mediated Reductive Coupling of R-Keto
Scheme 5. Synthetic Diversification of Reductive Condensation
Products
Esters and Various Carbon Pronucleophilesa
In summary, we have demonstrated a new method for
preparation of functionalized unsymmetrical 1,4-dicarbo-
nyl compounds via a phosphorus(III)-mediated reductive
condensation reaction. The method is characterized by
the following attributes: (1) the reaction results in the
formation of new Csp3ÀCsp3 bonds under mild conditions
compatible with a wide range of functionality; (2) no
stoichiometric preactivation (i.e., synthetic prefunctiona-
lization, deprotonation with strong exogenous base) of
either condensation partner is required; (3) readily avail-
able, bench stable reactants and a commercially available
reagent are employed; and (4) the sole stoichiometric
byproduct of the reaction is water-soluble and can be
eliminated by routine aqueous extraction. We anticipate
that the practicality and operational simplicity illustrated
by these attributes should make this Csp3ÀCsp3 bond form-
ing method a valuable complement to existing routes to
unsymmetrical 1,4-dicarbonyl motifs. As a corollary, the
results presented here further illustrate the synthetic poten-
tial of the KukhtinÀRamirez adducts. Additional reaction
development arising from the interception of KukhtinÀRamirez
intermediates is a current focus of ongoing investigation.
1,4-carbonyl product may be further derivatized to furnish
densely substituted R-amino ester 31 by opening of the
azlactone moiety.23 Alternatively, selective nitrile hydro-
genation of substituted cyanoacetate 32, the product of
reductive condensation of methyl benzoylformate and
ethyl benzylcyanoacetate (33) isolated in 91% yield as a
separable mixture of diastereomers, gives access to pyrro-
lidinone product 34.
Acknowledgment. We thank the Pennsylvania State
University for generous financial support of this research.
E. J. Miller and J. D. Herr (Penn State) are acknowledged
for preliminary experiments.
Supporting Information Available. Synthetic proce-
dures for the preparation of starting materials and pro-
ducts, analytical data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(23) Yields of 31 and 34 in Scheme 5 are reported for transformations
on the major stereoisomer of 29 and 32, respectively. Major diastereo-
mers assigned by X-ray diffraction of single crystals.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX