An Efficient Synthesis of Substituted Hydrazides

Abstract

Routes for the selective synthesis of 1-, or 2-substituted hydrazides, and 1,2-disubstituted hydrazides are reported. These routes proceed via cyanoborohydride reduction of stable acyl ­hydrazone intermediates.

aminations - reductions - hydrazones - condensation - ­regioselectivity

References

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Data for acyl hydrazone 4c: ¹H NMR (250 MHz, CDCl₃): δ = 7.55 (2 H, d, J = 8.0 Hz, ArH), 7.25 (2 H, d, J = 8.0 Hz, ArH), 6.45 (1 H, d, J = 10.6 Hz, N=CH _a H_b), 6.25 (1 H, d, J = 10.6 Hz, N=CH_a H _b ), 3.41 [3 H, s, (CO)NCH ₃], 2.39 (3 H, s, ArCH ₃). ¹³C NMR (63 MHz, CDCl₃): δ = 171.29, 140.45, 131.81, 129.34 (2 C), 128.92, 128.07 (2 C), 27.53, 21.31. MS (ESI+): m/z = 177 [M + H]⁺.

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Data for acyl hydrazone 7c: ¹H NMR (250 MHz, CDCl₃): δ = 8.79 [1 H, br s, C(O)NH], 7.65 (2 H, d, J = 8.1 Hz, ArH), 7.25 (2 H, d, J = 8.1 Hz, ArH), 2.35 (3 H, s, ArCH ₃), 2.12 (3 H, s, CCH ₃), 1.93 (3 H, s, CCH ₃). ¹³C NMR (63 MHz, CDCl₃): δ = 163.6, 155.6, 142.0, 130.5, 129.0 (2 C), 127.0 (2 C), 25.3, 21.3, 16.4. MS (ESI+): m/z = 191 [M + H]⁺.

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Data for 2-isopropyl hydrazides:
Compound 8a: ¹H NMR (250 MHz, CDCl₃): δ = 7.54 (5 H, m, ArH), 3.26 [1 H, sept, J = 6.3 Hz, CH(CH₃)₂], 1.13 [6 H, d, J = 6.3 Hz, CH(CH ₃)₂]. ¹³C NMR (63 MHz, CDCl₃): δ = 167.3, 132.8, 131.7, 128.6 (2 C), 126.7 (2 C), 51.2, 20.7 (2 C). MS (ESI+): m/z = 179 [M + H]⁺.
Compound 8b: ¹H NMR (250 MHz, CDCl₃): δ = 7.74 (2 H, d, J = 8.8 Hz, ArH), 6.93 (2 H, d, J = 8.8 Hz, ArH), 3.85 (3 H, s, ArOCH ₃), 3.20 [1 H, sept, J = 6.3 Hz, CH(CH₃)₂], 1.11 [6 H, d, J = 6.3 Hz, CH(CH ₃)₂]. ¹³C NMR (63 MHz, CDCl₃): δ = 166.9, 162.3, 128.5 (2 C), 125.0, 113.7 (2 C), 55.3, 51.2, 20.7 (2 C). MS (ESI+): m/z = 231 [M + Na]⁺.
Compound 8c: ¹H NMR (250 MHz, CDCl₃): δ = 8.63 [1 H, s, C(O)NH], 7.65 (2 H, d, J = 8.1 Hz, ArH), 7.21 (2 H, d, J = 8.1 Hz, ArH), 4.83 (1 H, NHNH), 3.23 [1 H, sept, J = 6.4 Hz, CH(CH₃)₂], 2.37 (3 H, s, ArCH ₃), 1.08 [6 H, d, J = 6.4 Hz, CH(CH ₃)₂]. ¹³C NMR (63 MHz, CDCl₃): δ = 167.3, 142.2, 129.9, 129.2 (2 C), 126.7 (2 C), 51.2, 21.3, 20.7 (2 C). MS (ESI+): m/z = 193 [M + H]⁺.
Compound 8d: ¹H NMR (250 MHz, CDCl₃): δ = 7.64 (2 H, d, J = 8.6 Hz, ArH), 7.36 (2 H, d, J = 8.6 Hz, ArH), 3.17 [1 H, sept, J = 6.3 Hz, CH(CH₃)₂], 1.05 [6 H, d, J = 6.3 Hz, CH(CH ₃)₂]. ¹³C NMR (63 MHz, CDCl₃): δ = 166.3, 137.9, 131.1, 128.8 (2 C), 128.2 (2 C), 51.2, 20.7 (2 C). MS (ESI+): m/z = 213 [³⁵M + H]⁺, 215 [³⁷M + H]⁺.
Compound 8e: ¹H NMR (360 MHz, CDCl₃): δ = 8.29 (2 H, d, J = 8.9 Hz, ArH), 7.95 (2 H, d, J = 8.9 Hz, ArH), 3.25 [1 H, sept, J = 6.3 Hz, CH(CH₃)₂], 1.11 [6 H, d, J = 6.3 Hz, CH(CH ₃)₂]. ¹³C NMR (90 MHz, CDCl₃): δ = 165.2, 149.6, 138.3, 128.0 (2 C), 123.8 (2 C), 51.4, 20.7 (2 C). MS (ESI+): m/z = 224 [M + H]⁺.

For recent examples of the use of the use of 2-tert-butylhydrazides, see:

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