Pyridines 2-zincate

When the phosphonium ylide 81 is reacted with zinc amide, the corresponding a-zincated phosphorus yUde is formed. Thermally unstable, it evolves almost quantitatively to zincatacyclobutane 82 which in presence of pyridine leads to the formation of the zincataphosphoniaindane 83. In order to explain this unprecedented cyclometallation reaction, a mechanism is proposed involving a low coordinated zinc center. The new product, reacted with benzaldehyde leads to the diphenylallene 84 (Scheme 27) [106-108]. 

Zincate reagents can add to imines with or without Lewis acid catalysis. Alkylimines require BF3 but imines of pyridine-2-carboxaldehyde react directly. If the imines are derived from chiral amines, diastereoselectivity is observed. Both a-phenylethyl amine and ethyl valinate have been tried. Higher enantioselectivity was observed with mixed magnesium reagents.175... 

The iodination of pyridine, quinoline, and isoquinoline via a-metalation using lithium di-fert-butyltetramethylpi-peridinozincate (TMP-zincate) proceeds smoothly at room temperature using iodine as the electrophile. The chemoselective deprotonative zincation generated 2-iodopyridine 70 and 1-iodoisoquinoline 71 in 76% and 93% yield, respectively. Quinoline metalated preferentially at the 8-position to give 61% yield of the 8-iodo derivative 72 and 26% yield of 2-iodoisoquinoline 73 (Equations 25-27) <1999JA3539>. 

The iodination of pyridine, quinoline, and isoquinoline can be achieved via metallation to the nitrogen using lithium di- rZ-butyltetramethylpiperidinozincate (TMP-zincate) at room temperature. Quinoline metallated preferentially at C (8) to give a 61% yield of the 8-iodoquinoline and isoquinoline gave a good yield of 1-iodoisoquinoline (Scheme 48) <1999JA3539>. 

Difficulties in preparing and handling complex bases, along with their exacting experimental conditions have limited their use. Kondo provided a solution to this with a report on the effectiveness of lithium di-ZerZ-butyltetramethylpiperidinozincate (TMP-zincate) as a highly chemoselective base [9]. It was determined that pre-complexation of LTMP 20 with di-zerz-butylzinc was required to generate the active species 21. The reaction with pyridine at room temperature was found to proceed smoothly to produce the 2-lithio species that could be treated with iodine to afford 2-iodopyridine 22. 

Zinc derivatives are available by transmetallation reactions as discussed in Section 6.02.5.6.4. Most work has been done with pyridines, but coupling reactions seem equally feasible with pyrimidines. An example is provided by 2-iodo-4,6-dimethylpyrimidine which is zincated in the 2-position and Pd-coupled with iodobenzene to furnish the 2-phenyl derivative in 26% yield <93T9713). 

Zinc Derivatives. Zincated and Al-protected 6-iodouracil 155 can be used under Negishi conditions for the preparation of 6-arylated uracil derivatives (Scheme 63). The conversion of the 6-iodouracil derivative is best performed using highly active zinc dust in DMAC.f The oxidative addition of active zinc has also been applied to a number of other iodo- and bromo-substituted 7r-deficient heteroarenes such as pyridine, pyrimidine, and quinoline, giving the corresponding heteroarylzinc halides 156, which are transformed to arylated derivatives by palladium catalysis. ... 

Zinc Derivatives. 2-(Benzopyran-4-yl)pyridine Al-oxide has been prepared from 2-chlorozinciopyridine 7V-oxide and benzopyran-4-yl triflate in a Negishi-type coupling from 2-chlorozinciopyridine N-oxide (Scheme 66). A five-fold excess of the the zincated pyridine A-oxide had to be used for optimal formation of the cross-coupled product 161. 

Zinc Derivatives. Direct zincation of 6-bromoxazolo[4,5-b]pyridmes can be effected using activated zinc (Scheme 69). The zincated species 164 and 165 from oxazolo[4,5- ]pyridin-2(3 0-ones or 2-phenyl- or 2-benzyloxyoxazolo[4,5-b]pyridmes were used in Negishi-type coupling in a one-pot reaction with benzyl bromide for the preparation of 6-benzyl derivatives. ... 

Zinc Reagents. Negishi coupling of a-zincated vinyltrimethylsilanes with 2-bromopyridine yields 2-vinylpyridine functionalized by a silyl substituent at the a-carbon of the vinyl group 214 (Scheme 81). Similarly, the trifluoroethenyl group has been substituted into the 2-position in pyridine 215 nsing zincated trifluoroethene and 2-iodopyridine. ... 

Scheme 2 C-H functionalization of pyridine iV-oxides through deprotonative zincation...

Lichtenberg C, Spaniol TP, OkudaJ. Reactivity of tris(allyl)aluminum toward pyridine coordination versus carbometalation. Organometallics. 2011 30 4409-4417. Heman-Gomez A, Herd E, Uzelac M, et al. Zincate-mediated arylation reactions of acridine pre- and postarylation structural insights. Organometallics. 2015 34 2614-2623. Diaconescu PL. Reactions of early transition metal-carbon bonds with N-heterocycles. Curr Org Chem. 2008 12 1388-1405. 

Various heteroaromatic compounds were similarly deprotonated (Fig. 19) [28]. Among electron-rich cases, thiophene- and furan-carboxylate provided the iodo derivatives after treatment of the intermediate zincates with iodine. Interestingly, bare jt-deficient heteroaromatic compounds were also readily deprotonated. With TMP-zincaie as a base and conducting the reactions at room temperature followed by addition of iodine, pyridine, quinoline, and isoquinoline could be efficiently metalated-iodinated. Under the same conditions, quinoline was deprotonated at both C2 and C8 in a 7 3 ratio, whereas isoquinoline was deprotonated specifically at Cl. 

Similar examples of regioselective metalation of 3-alkylpyridine-BF3 complexes with the use of TMP-zincate were reported by Michl and co-workers in 2002 [70]. The reaction occurred at the less hindered one of the two reactive positions, as evidenced by trapping of the pyridyl zincates with iodine to afford the 2-iodo-5-alkyl pyridine derivatives in good yields (Eq. 19). 

However, aromatic chlorides bearing electron-withdrawing groups proved to be unreactive to zincation, while in the presence of pyridine, related organozinc species had been obtained in satisfactory yields. 

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