Sodium Naphthalenide

[3481-12-7]  · C10H8Na  · Sodium Naphthalenide  · (MW 151.17)

(one-electron donor promoting ketyl-alkene3 and ketyl-alkyne2 radical cyclizations; facilitates coupling of ketone4 and thiocarbonyl5 functionalities; removes mesylate, tosylate, and benzyl protecting groups11,13-15 to generate the corresponding alkene or alcohol)

Solubility: sol diethyl ether, THF; forms complexes with diethyl ether and THF.

Preparative Method: typically prepared from the reduction of naphthalene by Sodium metal in THF solvent.1

Handling, Storage, and Precautions: stability is a matter of contention.1 THF apparently contributes substantially to the stability of the complex by solvating the resulting ion pairs.

Reductive Cyclization.

Sodium naphthalenide is a good electron donor and promotes the reductive cyclization of steroidal acetylenic ketones in high yield (eq 1).2 The resulting allylic alcohol is the only observed product and no overreduction occurs as with more powerful reducing agents.

Similarly, radical cyclization of an alkenyl aldehyde with sodium naphthalenide provides the product resulting from 5-exo ring closure in moderate yield. This method has been utilized in the synthesis of a key intermediate leading to a-cuparenone, which presents a challenge synthetically because of the steric congestion around the cyclopentane ring (eq 2).3

Ketone and Thiocarbonyl Coupling.

More recently, sodium naphthalenide in conjunction with Titanium(IV) Chloride has been used to perform a McMurry-like coupling reaction in an intramolecular process, providing a bicyclic structure in good yield (eq 3).4

Sodium naphthalenide further provides a method for the bridging of macrocycles. Nicolaou has recently used this method in the preparation of cis- and trans-fused oxabicyclic and oxapolycyclic systems, which are common structural components of marine and other natural products (eq 4).5 This process is thought to proceed by initial electon transfer to the thiocarbonyl group of the macrodithionolide system generating the radical anion; this initiates a sequence leading to the bridged product which is quenched with methyl iodide to generate the more stable disulfide. The disulfide may then be further transformed chemically to either the cis- or trans-fused polycycle.

Reduction of Epoxides.

The ability to relocate the allylic alcohol moiety within a molecule is another synthetic strategy for which sodium naphthalenide has been found useful. This ability is demonstrated in the transformation of geraniol to linalool (eq 5) by epoxidation of the allylic alcohol, mesylation, and subsequent treatment with sodium naphthalenide to produce the allylic alcohol in good yield.6 Similarly, this method has been utilized in the synthesis of isocarbacyclin, a therapeutic agent for cardiovascular disease. Treatment of the epoxidized and protected allylic alcohol with sodium naphthalenide provides the desired allylic alcohol with the exocyclic double bond as a mixture of diastereomers (eq 6).7 Apparently, the t-butyldimethylsilyl ether is unaffected under these reaction conditions.

Sodium naphthalenide with N,N,N,N-Tetramethylethylenediamine effects a carbon-carbon bond-forming reaction between carboxylic acids and conjugated alkenes (eq 7) to produce the substituted carboxylic acid in moderate yield.8,9 This method has been utilized in the preparation of dihydrolavandulol (eq 8) in fair yield.8

Treatment of benzimidazoline-2-thione with alkyl halide and sodium naphthalenide in THF affords the 1-alkyl-2-(alkylthio)benzimidazoles in excellent yield. These substrates may be further transformed by additional sodium naphthalenide to provide the 1-alkylbenzimidazoline-2-thiones in high yield (eq 9).10 Thus, sodium naphthalenide provides an alternative to other known methods which generally proceed in much lower yield and require longer reaction times and more vigorous reaction conditions.

Protecting Group Removal; Alkene Formation.

Sodium naphthalenide also facilitates the removal of protecting groups. It has been utilized in the debenzylation of nucleosides (eq 10).11 Sodium naphthalenide also effects the reductive cleavage of toluenesulfonates. Both menthyl tosylate and bridged bicyclic tosylates are quantitatively reduced under mild reaction conditions (eqs 11 and 12).

Cyanohydrins with a-methyl thiomethyl ether or a-methyl thiomethyl sulfone substituents are converted regio- and stereospecifically to the corresponding alkenes (eqs 13 and 14).12 The cis-substituted cyanohydrin undergoes elimination to generate the cis-alkene while the trans-substituted cyanohydrin provides the trans-alkene upon treatment with sodium naphthalenide/HMPA. This provides an excellent method for the preparation of either cis- or trans-alkenes in large ring systems.

Treatment of methanesulfonates of vicinal diols with sodium naphthalenide in THF or DME results in the rapid and high conversion to the alkene (eqs 15 and 16).13 Although the reaction is highly regiospecific, the more stable alkene generally predominates in close to the equilibrium ratio. This method has recently been utilized in the synthesis of (±)-20-deethylcatharanthine (eq 17) in which the diol is converted to the dimesylate followed by subsequent treatment with sodium naphthalenide, providing the desired alkaloid analog in good yield.14

Similar conversion of the bicyclic vicinal diol to the dimesylate followed by treatment with sodium naphthalenide provides an efficient strategy for the deoxygenation of the vicinal diol to form an immediate precursor to the natural product (+)-(1S,5R,7S)-exobrevicomin (eq 18).15 This method provides significantly higher yield than xanthate formation followed by reduction with Tri-n-butylstannane.

Sodium naphthalenide further affords a useful procedure for the conversion of cyclic sulfates into alkenes, providing an efficient synthesis of deoxygenated vicinal diols (eq 19).16 This reaction is highly regiospecific but, in examples where (E)/(Z) isomerization is possible, the thermodynamically preferred alkene predominates. Additionally, carbonyl functionalities and other easily reduced species are incompatible with these reaction conditions.


1. (a) Wang, H. C.; Levin, G.; Szwarc, M. JACS 1978, 100, 3969. (b) Stevenson, G. R.; Valentín, J.; Meverden, C.; Echegoyen, L.; Maldonado, R. JACS 1978, 100, 353.
2. Pradhan, S. K.; Radhakrishnan, T. V.; Subramanian, R. JOC 1976, 41, 1943.
3. Srikrishna, A.; Sundarababu, G. T 1990, 46, 3601.
4. Clive, D. L. J.; Keshava Murthy, K. S.; Zhang, C.; Hayward, W. D.; Daigneault, S. CC 1990, 509.
5. Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E.; Reddy, K. B.; Marron, B. E.; McGarry, D. G. JACS 1986, 108, 6800.
6. Yasuda, A.; Yamamoto, H.; Nozaki, H. TL 1976, 2621.
7. Bannai, K.; Tanaka, T.; Okamura, N.; Hazato, A.; Sugiura, S.; Manabe, K.; Tomimori, K.; Kato, Y.; Kurozumi, S.; Noyori, R. T 1990, 46, 6689.
8. Fujita, T.; Watanabe, S.; Suga, K.; Nakayama, H. S 1979, 310.
9. Fujita, T.: Watanabe, S.; Suga, K.; Miura, T.; Sugahara, K.; Kikuchi, H. J. Chem. Technol. Biotechnol. 1982, 32, 476.
10. Lee, T. R.; Kim, K. JHC 1989, 26, 747.
11. Philips, K. D.; Horwitz, J. P. JOC 1975, 40, 1856.
12. Marshall, J. A.; Karas, L. J. JACS 1978, 100, 3615.
13. Carnahan, J. C., Jr.; Closson, W. D. TL 1972, 3447.
14. Sundberg, R. J.; Gadamasetti, K. G. T 1991, 47, 5673.
15. Schultz, M.; Waldmann, H.; Vogt, W.; Kunz, H. TL 1990, 31, 867.
16. Beels, C. M. D.; Coleman, M. J.; Taylor, R. J. K. SL 1990, 479.

Gary A. Molander & Christina R. Harris

University of Colorado, Boulder, CO, USA



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