Tandem Reactions to Construct Heterocycles via Phosphine-Catalyzed Umpolung Addition and Intramolecular Conjugate Addition

Article abstract of DOI:10.1021/ol0270733

(Matrix Presented) A highly efficient method for constructing heterocycles was achieved by phosphine-catalyzed tandem umpolung addition and intramolecular conjugate addition. This strategy offers a simple and promising method for constructing syntheticall

Full text of DOI:10.1021/ol0270733

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4677-4679
Tandem Reactions to Construct
Heterocycles via Phosphine-Catalyzed
Umpolung Addition and Intramolecular
Conjugate Addition
Cheng Lu and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
xylu@pub.sioc.ac.cn
Received October 10, 2002
ABSTRACT
A highly efficient method for constructing heterocycles was achieved by phosphine-catalyzed tandem umpolung addition and intramolecular
conjugate addition. This strategy offers a simple and promising method for constructing synthetically useful heterocycles under neutral conditions
with high atom economy.
Heterocycles are of broad interest for both synthetic and
pharmaceutical chemists.1 Among the well-documented
synthetic methods, tandem reactions are always chosen to
construct heterocycles with high efficiency.2 However,
efficient and applicable approaches to form heterocycles via
tandem nucleophilic additions still remain rare. Tandem
nucleophilic additions can be achieved by adding a bifunc-
tional nucleophile to an electron-deficient multiple bond (a
bifunctional electrophile, e.g., an allene or an alkyne) and
intramolecular trapping of the intermediary monofunctional
nucleophile with the properly located electrophilic center
formed from the preceding addition reaction. With this in
mind, our attention was turned to the phosphine-catalyzed
umpolung (R- or γ-) addition reaction.3,4 If a bifunctional
nucleophile was used in the addition reaction with an
electron-deficient alkyne or allene, the resulting umpolung
adduct would have not only a nucleophilic center but also
an electrophilic center (the electron-deficient double bond)
required for an intramolecular conjugate addition. Although
there were some reports concerning this strategy, a general
approach to construct heterocycles on the basis of this
strategy still needs to be developed.5 Furthermore, conjugate
(3) (a) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 3167. (b)
Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 10819. (c) Trost, B.
M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670. (d) Dake, G. R.; Trost, B.
M. J. Am. Chem. Soc. 1997, 119, 7595. (e) Zhang, C.; Lu, X. Synlett 1995,
645. (f) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (g)
Alvarez-Ibarra, C.; Csa´ky¨, A. G.; de la Oliva, C. G. Tetrahedron Lett. 1999,
40, 8465.
(4) For recent reports on phosphine-catalyzed reactions, see: (a) Wang,
L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 2402. (b) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am.
Chem. Soc. 2002, 124, 2404.
(5) (a) Trost et al. reported that the ring-opening product of the γ-adduct
of Meldrum’s acid and alkynone was sufficiently active to effect cyclization
to afford γ-butyrolactone; see ref 3a. (b) Liu et al. reported a phosphine-
catalyzed annulation of thioamides and 2-alkynoates or 2,3-dienoates for
constructing substituted thiazolines; see: Liu, B.; Davis, R.; Joshi, B.;
Reynolds, D. W. J. Org. Chem. 2002, 67, 4595.
(1) Newkome, G. R.; Paudler, W. W. Contemporary Heterocyclic
Chemistry: Syntheses, Reactions and Application; Wiley: New York, 1982.
(2) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
10.1021/ol0270733 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/23/2002

addition can also be catalyzed by a tertiary phosphine,6
implying that the heterocycles could be formed by the
phosphine-catalyzed tandem reactions (Scheme 1). In this
Table 1. Phosphine-Catalyzed Tandem Nucleophilic
Additions8,a
Scheme 1
regard, we report herein tandem reactions involving um-
polung addition and conjugate addition of a bifunctional
nucleophile to an electron-deficient alkyne or allene catalyzed
by triphenylphosphine.7
Initial efforts focused on the tandem γ- and â-additions.
Heating a mixture of cyclohexan-1,3-dione (a carbonucleo-
phile as well as an oxygenucleophile) with ethyl 2,3-
butadienoate in toluene at 110 °C using 5 mol % tri-
phenylphosphine as the catalyst gave 29% yield of the
expected cyclized product 5a and 48% yield of the γ-adducts
6a and 6b (Scheme 2). Using other phosphines such as
Scheme 2
a Reaction conditions: a solution of bifunctional nucleophile (0.5 mmol),
allene or alkyne (0.5 mmol), and Ph3P (0.1 mmol) were heated at the
indicated temperature. For details of the reaction conditions, see ref 8.
b Isolated yield. c Used 0.025 mmol of Ph3P. d Solution of 1 equiv of
allenone in toluene was added dropwise to the solution of 5 equiv of 1,3-
dicarbonyl compound in toluene, and the yields were based on the allenone.
e CH3CN was used as solvent. f Toluene-CH3CN(v:v ) 4:1) was used as
a solvent. g Alkynone (1.1 equiv) in toluene or CH3CN was added dropwise.
tributylphosphine, dppe, a more polar solvent (THF, CH3CN)
or a buffer system (HOAc, NaOAc) did not give satisfactory
results. In view of the fact that conjugate addition can also
be catalyzed by tertiary phosphines,6 the catalyst loading was
enhanced. To our delight, 68% yield of 5a was obtained
when 20 mol % triphenylphosphine was used (Table 1, entry
1).
by the reaction of a number of 1,3-dicarbonyl compounds
as well as other bifunctional nucleophiles with electron-
deficient allenes or alkynes, and the results are summarized
in Table 1.
Reaction of 1,3-dicarbonyl compounds with electron-
deficient allenes catalyzed by triphenylphosphine afforded
dihydrofuran derivatives with good yields (entries 1-5).
Switching the electron-withdrawing group from an ester
group to a ketone group (entries 2-5) resulted in lower
catalyst loading (5 mol %) and more smooth conversion to
the cyclized product, indicating that tandem nucleophilic
additions were favored by a stronger electron-withdrawing
group.
With the preliminarily optimized condition in hand, the
scope of the phosphine-catalyzed tandem reactions was tested
(6) For phosphine-catalyzed conjugate addition to electron-deficient
alkenes, see: (a) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 3597.
(b) Yoshida, T.; Saito, S. Chem. Lett. 1982, 1587. (c) Go´mez-Bengoa, E.;
Cueva, J. M.; Mateo, C.; Echavarren, A. M. J. Am. Chem. Soc. 1996, 118,
8553. (d) Lumbierres, M.; Marchi, C.; Moreno-Mana˜s, M.; Sebastia´n, R.
M.; Vallribera, A.; Lago, E.; Molins, E. Eur. J. Org. Chem. 2001, 2321.
(7) For stoichiometric multistep additions on vinyl-triphenylphosphonium
salt to afford heterocycles, see: Cristau, H. J.; Fonte, M.; Torreiles, E.
Synthesis 1989, 301 and references therein.
Electron-deficient alkynes, synthetically equivalent to the
electron-deficient allenes in the phosphine-catalyzed um-
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Org. Lett., Vol. 4, No. 26, 2002

polung addition reactions,3 were subject to similar reaction
conditions and gave cyclized products in good to excellent
yield (entries 6 and 7).
Scheme 3
Reaction of bifunctional nitrogen-nucleophile 1,2-bis(p-
toluenesulfonylamino) ethane with electron-deficient alkynes
afforded piperazine derivatives in good to excellent yields
(entries 8-10). When the nitrogen-oxygen bifunctional
nucleophile 2-(p-toluenesulfonylamino) ethanol was used,
morpholine derivatives were obtained in moderate yields
(entries 11 and 12).9 Encouraged by the above results, tandem
R- and â-additions were also realized by the reaction of
1-hexyn-3-one or ethyl propiolate with the bifunctional
nucleophile 1d (entries 13 and 14). It is noteworthy that the
seven-membered heterocycle, a diazepane derivative, was
also obtained in high yield (entry 15). Moreover, the synthetic
utility of the tandem reactions was exemplified by the
synthesis of piperazine-2-carboxylic acid,10 a precursor for
the synthesis of CPP10b,11 and Crixivan.12 Detosylation and
hydrolysis of the ester group of 5m in one pot using 48%
HBr gave piperazine-2-carboxylic acid dihydrobromide in
71% yield.
A possible mechanism was illustrated in Scheme 3. The
reaction was triggered by nucleophilic addition of a tri-
phenylphosphine to the electron-deficient multiple bond.
Then, the zwitterionic intermediate deprotonated the pro-
nucleophile, which facilitated the umpolung addition. Proton
transfer and elimination of the triphenylphosphine from the
resulting zwitterionic intermediate gave the corresponding
umpolung adduct (γ- or R-adduct). Finally, the umpolung
adduct effected intramolecular conjugate addition reaction
in the presence of the triphenylphosphine. Although a
detailed mechanistic study was not undertaken, preliminary
results concerning the role of phosphine in the intramolecular
conjugate addition step were given by the control experiment.
Heating cis-γ-adduct 6a in toluene at 110 °C in the presence
of 20 mol % triphenylphosphine gave 92% yield of the
cyclized product 5a, while a disordered result was obtained
in the absence of triphenylphosphine. Similar results for
R-adduct 6c were obtained (see Supporting Information).
In summary, we have developed a highly efficient method
for constructing heterocycles via phosphine-catalyzed um-
polung addition and intramolecular conjugate addition. This
strategy offers a simple and promising method for construct-
ing heterocycles under neutral conditions with high atom
economy.
(8) Typical reaction conditions: to a solution of a bifunctional nucleophile
(0.5 mmol) and triphenylphosphine (0.1 mol) in toluene (1.5 mL) at the
indicated temperature under nitrogen was added a solution of an electron-
deficient allene or alkyne (0.5 mmol) in toluene (1 mL).
(9) Structure of compound 5l was confirmed by X-ray crystallography,
indicating that the tandem nucleophilic addition reactions of oxygen-
nitrogen bifunctional nucleophile with electron-deficient alkyne started from
the nitrogen nucleophilic center.
(10) For synthesis of piperazine-2-carboxylic acid, see: (a) Me´rour, J.
Y.; Coadou, J. Y. Tetrahedron Lett. 1991, 32, 2469. (b) Bigge, C. F.; Hays,
S. J.; Novak, P. M.; Drummond, J. T.; Johnson, G.; Bobovski, T. P.
Tetrahedron Lett. 1989, 30, 5193.
(11) CPP is a high-affinity competitive antagonist of the NMDA subtype
of the glutamate receptor. For references, see: (a) Davis, J.; Evans, R.;
Herrling, P. L.; Jones, A. W.; Olverman, H. J.; Pook, P.; Watkins, J. C.
Brain Res. 1986, 382, 169. (b) Hays, S. J.; Bigge, C. F.; Novak, P. M.;
Drummond, J. T.; Bobovski, T. P.; Rice, M. J.; Johnson, G.; Brachce, L.
J.; Coughenour, L. L. J. Med. Chem. 1990, 10, 2916.
(12) An HIV protease inhibitor indinavir; for references, see: (a) Dorsey,
B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J. P.; Darke, P.
L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J. C.; Lin, J. H.;
Chen, I. W.; Holloway, M. K.; Fizgerald, P. M. D.; Axel, M. G.; Ostovic,
D.; Anderson, P. S.; Huff, J. R. J. Med. Chem. 1994, 37, 3443. (b) Hamner,
S. M.; Squires, K. E.; Huges, M. D.; Grimes, J. M.; Demeter, L. M.; Currier,
J. S.; Eron, J. J.; Fienberg, J. E.; Balfour, H. H.; Deyton, L. R.; Chodakewitz,
J. A.; Fischl, M. A. N. Engl. J. Med. 1997, 337, 725.
Acknowledgment. We thank the Major State Basic
Research Program (Grant G20000077502-A). We also thank
the National Natural Sciences Foundation of China and
Chinese Academy of Sciences for financial support.
Supporting Information Available: Spectroscopic data,
1
analytical data, and copies of H NMR and 13C NMR for
new compounds 5a-l,n,o and 6a-c, copies of 1H NMR and
13C NMR for 5m, and X-ray crystallography of 5l. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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