REGIOMERS

http://www.google.com/patents/US7514563

FIG. 1 is a gHMBC spectrum of the borylation products of 4-chlorobenzonitrile. BELOW
 







FIG. 2 is a gHMBC spectrum of the borylation products of 4-bromobenzonitrile.
 






FIG. 3 is a gHMBC spectrum of the borylation product of 4-iodobenzonitrile.


 





FIG. 4 is a gHMBC spectrum of the borylation products of 4-methoxybenzonitrile.
FIG. 5 is a gHMBC spectrum of the borylation products of 4-thiomethylbenzonitrile.
FIG. 6 is a gHMBC spectrum of the borylation product of 4-dimethylaminobenzonitrile.
FIG. 7 is a gHMBC spectrum of the borylation product of methyl 4-cyanobenzoate.
FIG. 8 is a gHMBC spectrum of the borylation product of 4′-cyanoacetanilide.
FIG. 9 is a gHMBC spectrum of the borylation products of 1,5-dimethyl-2-pyrrolecarbonitrile.
FIG. 10 is a gHMBC spectrum of the borylation products of 5-methyl-2-furonitrile.



Regioisomer Assignment by NMR Spectroscopy:

From gHMBC NMR experiments, the two regioisomers for the borylation of 4-substituted benzonitriles can be distinguished unambiguously as in FIGS. 1 to 10. In isomer A, carbon atoms represented as C1 and C4 on the benzene ring, as well as C7 (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C3 is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (³J_C-H), which can be observed using gHMBC spectroscopy. In the gHMBC spectrum, carbon atoms C1 and C7 should show one cross peak each to proton H_c, whereas carbon atom C4 should show two cross peaks to protons H_a and H_b. Therefore the resulting number of cross peaks for C1, C4, and C7 should be 1, 2, and 1, respectively.
In Isomer B, carbon atoms represented as C1′, C4′, on the benzene ring, as well as C7′ (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C2′ is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (³J_C-H). In the gHMBC spectrum, carbon atoms C1′ and C7′ should show two cross peaks each, to protons H_d and H_e, whereas carbon atom C4′ should show only one cross peak to proton H_f. Therefore the resulting number of cross peaks for C1′, C4′, and C7′ should be 2, 1, and 2, respectively. Hence isomers A and B can be unambiguously assigned from gHMBC data.
For isomer A, with proton H_c unambiguously assigned by gHMBC, H_a and H_b can be assigned from their multiplicities. Proton H_a appears as a doublet, coupled to proton H_b with J≈2-3 Hz. Proton H_b appears as a doublet of doublets due to coupling to protons H_a and H_c. Carbon atoms C2, C6, and C5 were then assigned from the correlations in the gHMQC spectra. Carbon atom C7 (nitrile carbon) usually appears around δ 119. Depending on the substituent, carbon atom C1 was usually found shifted downfield around δ 130-170 (except in 4-iodobenzonitrile for which it appears around δ 100). Carbon atom C4 is shifted upfield, and was usually found around δ 100-115. Similarly, all the carbons of isomer B can be assigned.
In the five membered heterocycles, the ⁴J_H-H coupling was used together with gHMBC and NOESY1D spectroscopy to identify the major isomer. Regioisomers in the fluorine containing benzonitriles were assigned by ¹³C spectroscopy (with the help of the fact that the boron bearing carbon is not observed due to broadening from and coupling with boron). In the case of 1,3-dicyanobenzene, ¹H NMR spectroscopy was employed to assign the major and minor isomers.
Experimental Details and Spectroscopic Data EXAMPLE 1 Borylation of 4-fluorobenzonitrile

General procedure A was applied to 4-fluorobenzonitrile (242 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 8 h. The ratio of the two isomers in the crude reaction mixture by GC was 11:89. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (88.5 mg, 72%) as a white solid. The ratio of the two isomers in the isolated product by GC was 8:92. ¹³C NMR spectroscopy was used to assign the major isomer as 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. ¹H NMR (CDCl₃, 500 MHz): δ (major isomer) 8.04 (dd, ⁴J_H-F=5.4 Hz, J=2.2 Hz, 1H, H_d), 7.7 (ddd, J=8.5, 2.2 Hz, ⁴J_H-F=4.9 Hz, 1H, H_e), 7.1 (t, J=8.5 Hz, 1H, H_f), 1.32 (br s, 12H), (minor isomer) 7.67 (dd, J=8.8 Hz, ⁴J_H-F=4.9 Hz, 1H, H_c), 7.52 (dd, ³J_H-F=8.5 Hz, J=2.9 Hz, 1H, H_a), 7.17 (dt, J=8.3, 2.9 Hz, 1H, H_b) 1.34 (br s, 12H); ¹³C NMR {¹H} (CDCl₃, 125 MHz): δ (major isomer) 169.0 (d, ¹J_C-F=261.3 Hz, C1′), 141.6 (d, ³J_C-F=9.6 Hz, C3′), 137.0 (d, ³J_C-F=10.5 Hz, C5′), 117.9 (nitrile C7′), 116.7 (d, ²J_C-F=25.6 Hz, C6′), 108.2 (d, ⁴J_C-F=3.8 Hz, C4′), 84.5 (C8′), 24.7 (C9′), (minor isomer) 164.2 (d, ¹J_C-F=257.1 Hz, C1), 135.9 (d, ³J_C-F=8.8 Hz, C5), 122.8 (d, ²J_C-F=21.0 Hz, C2), 118.5 (d, ²J_C-F=22.2 Hz, C6), 118.1 (nitrile C7), 113.1 (C4), 85.1 (C8), 24.7 (C9); ¹¹B NMR (CDCl₃, 96 MHz): δ 29.92; ¹⁹F NMR (CDCl₃, 282 MHz): δ (major isomer) −92.62 (m), (minor isomer) −104.84 (m); FT-IR (neat): 3076, 2982, 2934, 2231, 1608, 1487, 1429, 1412, 1373, 1350, 1236, 1143, 1070, 964, 852, 835, 571 cm⁻¹; LRMS (% rel. int.): m/e (major isomer) 247 M⁺ (26), 232 (100), 205 (12), 188 (20), (minor isomer) 247 M⁺ (29), 232 (97), 206 (100), 189 (74), 148 (97), 121 (25); Anal. Cacld for C₁₃H₁₅BFNO₂: C, 63.20; H, 6.12; N, 5.67. Found: C, 63.52; H, 6.20; N, 5.56. HRMS Calcd for C₁₃H₁₅BFNO₂: 247.1180. Found: 247.1171.





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