C O M M U N I C A T I O N S
steric impact on rate remained to be addressed. Thus, t-butylacety-
lene was carboaluminated overnight using our standardized reaction
parameters (Scheme 3). Subsequent quenching with NBS led to
the derived E-vinyl bromide in good isolated yield. By capillary
GC, none of the regioisomer could be detected.
Catalyst levels on the order of 5% are effective, the inexpensive
additive MAO can be employed in limited quantities to accelerate
carboaluminations, and the process can now be effected in an
environmentally friendly solvent, toluene, at ambient temperatures.
Acknowledgment. Financial support provided by Zymes, LLC
(Hasbrouck Heights, NJ) is gratefully acknowledged. We are
indebted to Boulder Scientific Co. for supplying most of the
zirconocenes used in this study.
Scheme 3. Carboalumination of an R-Branched Alkyne
Supporting Information Available: Procedures and spectral data
for all new products. This material is available free of charge via the
Scheme 4. Synthesis of a Precursor (13) to Coenzyme Q10
References
(1) Kurti, L.; Czako, B. In Strategic Applications of Named Reactions in
Organic Synthesis; Elsevier: Burlington, MA, 2005.
(2) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252.
(3) Metallocenes in Regio- and StereoselectiVe Synthesis; Takahashi, T., Ed.;
Spinger Verlag: Heidelberg, Germany, 2005.
(4) For ligand variation in ethyl alumination, see Shibata, K.; Aida, T.; Inoue,
S. Tetrahedron Lett. 1992, 33, 1077.
(5) Yoshida, T.; Negishi, E. J. Am. Chem. Soc. 1981, 103, 4985. Negishi, E.
Chem. Scr. 1989, 29, 457. Negishi, E.; Takahashi, T. Acc. Chem. Res.
1994, 27, 124. Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem.
Soc. 1985, 107, 6639. Matsushita, H.; Negishi, E. Org. Synth. 1984, 63,
31. Negishi, E. Pure Appl. Chem. 1981, 53, 2333.
(6) (a) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. 1993, 32, 1068. (b) Rebe,
S.; Wipf, P. Chem. Commun. 2001, 299. (c) Wipf, P.; Nunes, R. L.; Rebe,
S. HelV. Chim. Acta 2002, 85, 3478.
Carboalumination of the 48-carbon polyenyne 1117 (Scheme 4),
derived from the nine prenoidal unit allylic alcohol solanesol, in
toluene at room temperature using 5% Cp2ZrCl2, 5% MAO, and
Me3Al leads to only a 90:10 mix of regioisomeric vinylalanes.
Switching to catalyst 3, however, upon subsequent Ni(0)-catalyzed
cross-coupling18 with benzylic chloride 12, leads to known coen-
zyme Q10 (CoQ10) precursor 13 in excellent isolated yield.19
An alternative, more direct route to this series of naturally
occurring quinones uses known19 chloromethylated para-quinone
14. Carboalumination/coupling of farnesyl-derived acetylene 11 (n
) 3)20 led to the lower homologue, CoQ4 (15a; Scheme 5), in good
isolated yield (98.8:1.2 regiochemistry). Identical conditions applied
to 11, n ) 9, led in one pot to CoQ10 (15b; regioselectivity
g98.5%).21,22
(7) Negishi, E.; Kondakov, D. Y.; Choueiry, D.; Kasai, K.; Takahashi, T. J.
Am. Chem. Soc. 1996, 118, 9577.
(8) For a listing of zirconocene dichlorides at Boulder Scientific from which
(9) ICH Harmonised Tripartite Guideline, Q3C Impurities: Residual Solvents.
(10) Wild, W. P.; Zsolnai, L.; Huttner, G.; Brintzinger, H. H. J. Organomet.
Chem. 1982, 232, 233. Wild, F. W. R. P.; Wasiucionek, M.; Huttner, G.;
Brintzinger, H. H. J. Organomet. Chem. 1982, 288, 63.
(11) Brintzinger, H. H.; Fischer, D.; Mu¨lhapt, R.; Rieger, B.; Waymouth, R.
M. Angew. Chem., Int. Ed. Engl. 1995, 34, 1143. Brunner, H.; Schindler,
H. D. J. Organomet. Chem. 1973, 55, C71. Tirouflet, J.; Dormond, A.;
LeBlanc, J. C.; LeMoigne, F. Tetrahedron Lett. 1973, 257. Fryzuk, M.
D.; Bosnich, B. J. Am. Chem. Soc. 1978, 100, 5491.
(12) Jones, M. B.; Platz, M. S. J. Org. Chem. 1991, 56, 1694.
(13) Resconi, L.; Piemontesi, F.; Camurati, I.; Sudmeijer, O.; Nifant’ev, I. E.;
Ivchenko, P. V.; Kuz’mina, L. G. J. Am. Chem. Soc. 1998, 120, 2308.
(14) It is appreciated that early work by Negishi and co-workers indicates that
direct carboalumination by a zirconium-modified alane is equally plausible;
cf. Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,
107, 6639.
(15) Lipshutz, B. H.; Dimock, S. H. J. Org. Chem. 1991, 56, 5761.
(16) Negishi, E.; Matsushita, H.; Okukado, N. Tetrahedron Lett. 1981, 22, 2715.
(17) Lipshutz, B. H.; Mollard, P.; Pfeiffer, S.; Chrisman, W. J. Am. Chem.
Soc. 2002, 124, 14282.
Scheme 5. Synthesis of CoQ4 and CoQ10
(18) Lipshutz, B. H.; Bulow, G.; Lowe, R.; Stevens, K. J. Am. Chem. Soc.
1996, 118, 5512.
(19) Lipshutz, B. H.; Kim, S.; Mollard, P.; Stevens, K. Tetrahedron 1998, 54,
1241.
(20) Lipshutz, B. H.; Bulow, G.; Fernandez-Lazaro, F.; Kim, S.; Lowe, R.;
Mollard, P.; Stevens, K. J. Am. Chem. Soc. 1999, 121, 11664.
(21) Negishi, E.; Liou, S.-Y.; Xu, C.; Huo, S. Org. Lett. 2002, 4, 261.
(22) Lipshutz, B. H.; Lower, A.; Berl, V.; Schein, K.; Wetterich, F. Org. Lett.
2005, 7, 4095.
(23) Negishi, E.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596.
(24) Standard carboalumination of alkynes (1.0 mmole scale) using catalytic
rac-(ebi)ZrCl2, catalytic MAO, and excess Me3Al: To a flame dried argon
purged 25 mL round bottomed (rb) flask was added rac-ethylenebis-
(indenyl)zirconocene dichloride 3 (20.9 mg, 0.05 mmol, 5.0 mol %),
followed by the dropwise addition at room temperature of Me3Al (2.0 M
solution in toluene, 0.75 mL, 1.50 mmol, 1.5 equiv). While stirring at
room temperature, MAO (10% w/w solution in toluene, 33 µL, 0.05 mmol,
5 mol %) was then added. The alkyne (1.00 mmol) was then introduced,
and the homogeneous golden orange solution was stirred at room
temperature until TLC analysis (5% CH2Cl2/petroleum ether) indicated
that the carboalumination was complete.
In summary, new technology has been developed that signifi-
cantly advances the fundamental utility of Negishi carboalumina-
tions.24 From mechanistic considerations, selection of the appro-
priate ligand on zirconium has been found to impart a very high
degree of regiocontrol to these valued multicomponent couplings.
JA065769B
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15398 J. AM. CHEM. SOC. VOL. 128, NO. 48, 2006