Science of Synthesis

Wicha, J., Science of Synthesis, (2009) 48, 114.

The carbonyl group oxygen atom in aldehydes and ketones is replaced by two hydrogen atoms, via the hydrazone, under various conditions presently associated with the Huang-Minlon modification of the Wolff–Kishner reduction,[‌121‌,‌122‌] which was at first developed for the reduction of 4-oxo-4-(4-phenoxyphenyl)butanoic acid (‌Table 3‌, entry 1).[‌108‌] The reagents used are 85% hydrazine hydrate and potassium hydroxide in triethylene glycol, with the temperature increased from reflux to 195°C (with any accumulated water being removed from inside the condenser before the temperature increase). The yield of 4-(4-phenoxyphenyl)butanoic acid is significantly higher than that attainable in the earlier modifications of the Wolff–Kishner reduction or by the Clemmensen reduction (see Section ‌48.1.3.1.1‌). A detailed procedure for the reduction of the oxo group in an oxo diacid is available (entry 2).[‌123‌] 3,4,5-Trimethoxybenzaldehyde is transformed into the corresponding toluene derivative under relatively mild conditions (70°C, then 120°C); the mild conditions presumably result from electronic effects (entry 3).[‌124‌] A specific procedure for the reduction of 2,2,6,6-tetramethylpiperidin-4-one into 2,2,6,6-tetramethylpiperidine using hydrazine hydrate, with a small amount of diethylene glycol mixed with paraffin oil as the solvent, has been developed (entry 4);[‌125‌] the product (and released water) is continuously removed by distillation. Wolff–Kishner reduction of a highly strained cyclopropyl ketone proceeds without cyclopropane ring opening to give the corresponding hydrocarbon in 67% yield (entry 5). It is noteworthy that attempted deoxgenation of this ketone via borane reduction of its tosylhydrazone (see Section ‌48.1.3.1.4‌) affords a product of skeletal rearrangement.[‌126‌,‌127‌] An intermediate in a pheromone synthesis is efficiently deoxygenated using hydrazine hydrate and potassium hydroxide in triethanolamine at 190–200°C (entry 6).[‌128‌] A sterically hindered carbaldehyde group can be converted into a methyl group using a large excess of hydrazine hydrate and potassium hydroxide in ethylene glycol (entry 7).[‌129‌] In another example, an amide is transformed into the respective amine (entry 8).[‌130‌] Although heteroaromatic ketones are smoothly reduced under the standard Huang-Minlon conditions,[‌131‌] in certain cases the use of the semicarbazone instead of the hydrazone is advantageous.[‌113‌,‌132‌] For example, reaction of 2-benzoyl-4-phenylquinoline with hydrazine hydrate gives poor results, while the procedure involving isolated semicarbazone ‌24‌ provides 2-benzyl-4-phenylquinoline (‌25‌) in 64% overall yield (‌Scheme 29‌).[‌132‌]

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‌Meeee 8‌ Meeeeeee Meeeeeee ee Mee Meeee-Meeeee Meeeeeeee ee Meeeeeeee eee Meeeeee[‌888‌,‌888‌–‌888‌,‌888‌–‌888‌]

Meeee	M8	M8	Meeeeeeeee	Meeee (%)	Mee
8	8-MeMM8M8	(MM8)8MM8M	88% M8MMM8•M8M (ee. 8 eeeee), MMM (8.8 eeeee), eeeeeeeeeee eeeeee, 888–888°M	88	[‌888‌]
8	(MM8)8MM8M	(MM8)8MM8M	88% M8MMM8•M8M (8.8 eeeee), MMM (8 eeeee), eeeeeeeeee eeeeee, 888–888°M (eeeeeeeee eeeeeeeee eee), eeee 888–888°M, 8 e	88–88	[‌888‌]
8	M	8,8,8-(MeM)8M8M8	88% M8MMM8•M8M (8 eeeee), MMM (8.8 eeeee), eeeeeeee eeeeee, 88°M, 8 e, eeee 888°M, 8 e	88	[‌888‌]
8			8. M8MMM8•M8M (8.8 eeeee) 8. MMM (8.88 eeeee), eeeeeeeeee eeeeee, eeeeeeee eee, eeeeeeeeeeee	88	[‌888‌]
8			88–888% M8MMM8•M8M (8.8 eeeee), MMM (8.8 eeeee), eeeeeeeeee eeeeee, 888°M, 8 e, eeee 888°M, 8 e	88	[‌888‌]
8			M8MMM8•M8M (8.8 eeeee), MMM (8.8 eeeee), eeeeeeeeeeeeeee, 888–888°M	88	[‌888‌]
8	M		88% M8MMM8•M8M (888 eeeee), MMM (88 eeeee), eeeeeeee eeeeee, 888°M, 8 e, eeee 888°M, 8 e	88	[‌888‌]
8e			8. M8MMM8•M8M (8.8 eeeee), eeeeeeee eeeeee, 88°M, 88 e 8. MMM (8.8 eeeee), 888°M, 88 e	88	[‌888‌]

e Mee eeeeeeee eeeee ee eeeeee ee eeeeeeeeeeeeee eeeeeeeeeee ee ee eeeee eeeee eeeeeeeee. Meeee ee eeeee ee eeee eeeeeeeee.

‌Meeeee 88‌ Meeeeeeeeeeee ee e Meeeee eee e Meeeeeeeeeeee[‌888‌]

Meeeeeeeeeee Meeeeeeee

8-(8-Meeeeeeeeeeee)eeeeeeee Meee (‌Meeee 8‌, Meeee 8); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee 8-eee-8-(8-eeeeeeeeeeeee)eeeeeeee eeee (888 e, 8.88 eee), MMM (888 e, 8.88 eee), 88% M8MMM8•M8M (888 eM, 8.88 eee), eee eeeeeeeeeee eeeeee (8.8 M) eee eeeeeeee eee 8.8 e. M8M eee eeee eeeeeee eeee eee eeeeeeeee, eee eeeeeeeeeee eee eeeeeee ee eeee ee 888°M (eeeeee), eee eeeeeee eee eeeeeeeee eee 8 e. Mee eeeeee eeee eee eeeeeee eeee M8M (8.8 M) eee eeeeee eeeeee eeee 8 M ee MMe (8.8 M). Mee eeeee-eeeeeee eeeee eee eeeeeeeee eee eeeee; eeeee: 888 e (88%).

8,8,8,8-Meeeeeeeeeeeeeeeeeeee (‌Meeee 8‌, Meeee 8):[‌888‌]

M8MMM8•M8M (8.8 M, 88 eee) eee eeeee eeee 88 eee ee eee 8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eee (ee 88–88°M; 8.8 ee, 88 eee). Mee ee ee eeeeeeeeee eeeeeeee, eee eeeeeeeeeee eeee ee 88°M. Mee eeeeeee, eeeeeeeeeee, eeeee eeeeeee eee eeeeeeeeeeee ee e eeee (88°M) eee eeeeeeeeeee eeeeeeee ee eeeee ee e eeee (8.8 e·eee−8) eeee e eeee ee MMM (88 e, 8.88 eee) ee eeeeeeeeee eeeeee (8.88 M) eee eeeeeeee eee (88 eM) eeeeee ee 888°M. Mee eeeeeee eeeeeee eee M8M eeeeee eeee eeeeeeeeeeee eeeeeee ee eeeeeeeeeeee eeeeeee e 88-ee Meeeeee eeeeee. Mee eeeeeee eeeee eee eeeeeeeee eee eeeeeeeeeee; eeeee: 8.88 ee (88%).

Meeeeeeeee[8.8.8.88,8.88,8]eeeeee (‌Meeee 8‌, Meeee 8); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee eeeeeeeeee ee eeeeeeeeee[8.8.8.88,8.88,8]eeeee-8-eee (888 ee, 8.8 eeee), 88–888% M8MMM8•M8M (8.8 eM, 8 eeee), MMM (888 ee, 8.8 eeee), eee eeeeeeeeee eeeeee (88 eM) eee eeeeee ee 888°M eee 8 e eee eeee ee 888°M eee 8 e. Meeeee eeee eeee, eee eeeeeee eeeeeeee. Mee eeeeeeeee eee eeeeeeeee eeee eeeeeee (88 eM) eee eeeee (MeMM8). Mee eeeeeee eee eeeeeeeeee ee eeeeee e eeeee eeeee; eeeee: 888 ee (88%).

8-Meeeee-8-eeeeeeeeeeeeeee (‌88‌); Meeeeee Meeeeeeee:[‌888‌]

MeMM (888 eM) eee eeeee ee e eeee ee eeeeeeeeeeeee eeeeeeeeeeeee (8.8 e, 88.8 eeee) eee MeMMe•8M8M (8.88 e, 88.8 eeee) ee M8M (88 eM). Mee eeee eee eeeeeee eeeeee eee eeee eeeeeeee. 8-Meeeeee-8-eeeeeeeeeeeeeee (8.8 e, 88.8 eeee) eee eeeee ee eee eee eeeeeeee, eee eee eeeeeee eee eeeeee eeeee eeeeee eee 8 e eee eeeeeeeeeeee ee eee eeeeeeee eeeeee ee ee. 88 eM. Meeee eeeeeee, eee eeeeeeeeeee eee eeeeeeeee ee eeeeeeeeee eee eeeeee eeee MeMM (88 eM) ee eeee eee eeeeeeeeeeeee ‌88‌ ee e eeee eeeeee eeeeee; eeeee: 8.88 e (88%). Mee eeeeeeeeeeeee ‌88‌ (8 e, 8.8 eeee) eee eeeee ee eeeee eeeeeeee ee e eeee ee MMM (8.8 e, 8.8 eeee) ee eeeeeeeeee eeeeee (8 eM), eeeeeee eeeee eeeee ee 888°M. Mee eeeeeee eee eeeeee ee 888°M eee 8.8 e eee eeee ee 888–888°M eee 8 e, eeeeee, eee eeeeeee eeee M8M (88 eM). Mee eeeeeee eee eeeeeeeee eeee eeeeeeeeeee (8 × 88 eM). Mee eeeeeeee eeeeeee eee eeeeee eeee M8M (88 eM) eee eeeee (MeMM8). Mee eeeeeee eee eeeeeeeeee ee eeee eeeeee eeeeeeee; eeeee: 8.88 e (88%).

References

Meeeeee Meeeeeeeeee

• 8.Meeeee-Meee, (8888) M 88e8, 888.
• 8.Meeeee-Meee, (8888) M 8e, 88.