Synthesis of Unsymmetrical Heterobiaryls Using Palladium-Catalyzed Cross-Coupling Reactions of Lithium Organozincates

Abstract

Several unsymmetrical heterobiaryls have been synthesized through palladium-catalyzed cross-coupling reactions of lithium triorganozincates. The latter have been prepared by deprotonative lithiation followed by transmetalation using non-­hygroscopic ZnCl₂˙TMEDA (0.33 equiv).

Key words

cross-coupling - heterocycle - metalation - palladium - zinc

References and Notes

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  Compound 9a: white powder; mp 124 ˚C. The physical data were found identical to those previously described in ref. 29b. ^¹H NMR (200 MHz, CD₃COCD₃): δ = 7.17 (dd, J = 7.5, 5.7 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.59 (dd, J = 7.5, 1.5 Hz, 1 H), 7.82 (dd, J = 5.7, 1.5 Hz, 1 H), 8.53 (d, J = 8.1 Hz, 1 H). ^¹³C NMR (50 MHz, CD₃COCD₃): δ = 113.7, 128.8, 129.2, 131.8, 140.5, 159.5, 161.7, 162.0.

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15

For discussions on the advantages of palladium over nickel, see refs. 4c and 5b.

21

Slightly lower cross-coupling yields have been observed with higher order zincate compared with lithium triorganozincate, see ref. 9.

22

No reaction takes place in the absence of transition metal. Note that product 2a has previously been obtained by addition of 2-benzofuryllithium at the 4-position of 2-chloropyrimidine followed by rearomatization using DDQ in 38% yield, see ref. 20b.

25

Compound 4: white powder; mp 88 ˚C. The spectral data were found identical to those previously described, see. ref. 20b. ^¹³C NMR (50 MHz, CDCl₃): δ = 113.1, 113.1, 114.5, 146.2, 150.4, 158.1, 159.9, 161.7.

27

Compound 8a: pale yellow powder; mp 198 ˚C. The spectral data were found identical to those previously described, see ref. 20b. ^¹³C NMR (50 MHz, CDCl₃): δ = 114.5, 122.9, 125.2, 125.3, 126.3, 126.9, 139.8, 140.1, 141.8, 159.7, 161.9, 162.3.

28

Compound 8b: white powder; mp 126 ˚C. The physical and spectral data were found identical to those of a commercial sample (Aldrich).

35

Compound 16: beige powder; mp <50 ˚C. ^¹H NMR (200 MHz, CDCl₃): δ = 7.25-7.37 (m, 2 H), 7.72-7.91 (m, 2 H), 8.25 (d, J = 3.2 Hz, 1 H), 8.47-8.58 (m, 1 H), 8.72 (d, J = 4.8 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 122.1 (d, J = 4.3 Hz), 122.6, 123.2, 124.3 (d, J = 10.4 Hz), 136.8, 141.6 (d, J = 3.8 Hz), 147.7 (d, J = 15.1 Hz), 150.0, 151.4 (d, J = 6.8 Hz), 160.9 (d, J = 241 Hz). HRMS: m/z calcd for C₁₀H₇N₂F [M⁺]: 174.0593; found: 174.0595.