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12.1.1.2.1.1.4 Method 4: From β-Diketones and Hydrazines

DOI: 10.1055/sos-SD-012-00002

Stanovnik, B.; Svete, J.Science of Synthesis, (20021228.

The synthesis of 1H-pyrazoles from β-diketones and hydrazines is the most widely used method. As a hydrazine component, all kinds of hydrazine derivatives can be used, such as hydrazine itself, alkyl-, aryl-, heteroaryl-, and acylhydrazines. These reactions are carried out in water, ethanol, mixtures of ethanol and water, or acetic acid in a temperature range 0100°C. A base must be added when hydrazine salts are used.[‌94‌‌101‌] When alkyl aryl β-diketones are reacted with substituted hydrazines (e.g., phenylhydrazine as reported in Scheme 14) two regioisomeric pyrazoles can be formed, in most cases, only one regioisomer 14 is isolated (Scheme 14). The regioselectivity observed is compatible with first reaction between the unsubstituted nitrogen of the hydrazine with the alkyl ketone and second ring closure with the aryl ketone. The yields are often excellent. In the case of the synthesis of 14 (R1=Me; R2=H; R3=4-O2NC6H4; R4=Ph), the low yield is possibly due to the formation of the other regioisomer; the activation of the aryl ketone group by the 4-nitro substituent may be responsible for this behavior.

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Meeeeeeeeee 88

M8 M8 M8 M8 Meeeee (%) Mee
Me M e-Me M 88 [‌88‌]
Me e-Me Me M e.e. [‌88‌]
Me M Me M 88 [‌88‌,‌88‌]
MM8 M MM8 M e.e. [‌88‌]
Me M 8-M8MM8M8 Me 88 [‌888‌]
Me M 8-M8MM8M8 Me 88 [‌888‌]
Me M 8-M8MM8M8 Me 88 [‌888‌]
Me M Me 8,8-(M8M)8M8M8 88 [‌888‌]
Me M Me M 88 [‌888‌]

e e.e.=eee eeeeeeee.

Meeeee β-eeeeeeeee eeeee eeee eeeeeeeee ee eeeeeeee eeeeeeeeeeee eee eeeeeeeee eeeeeeee eeeee ee eeee 8,8-eeeeeeeeeeeeee 88 (Meeeee 88).[‌888‌‌888‌]

Meeeee 88 8,8-Meeeeeeeeeeeee eeee Meeeee β-Meeeeeeee eee Meeeeeeee[‌888‌,‌888‌]

Meeeeeeeeee 88

Me8 M8 Meeee (%) Mee
Me M 88 [‌888‌]
Me Me 88 [‌888‌]
Me Me 88 [‌888‌]
8-MM8M8 M 88 [‌888‌]
8-MeM8M8 M 88 [‌888‌]
8-MeM8M8 M 88 [‌888‌]
8-MM8M8 M 88 [‌888‌]
8-MeMM8M8 M 88 [‌888‌]
8-M8MM8M8 M 88 [‌888‌]

Me eeee eeeeeeeee, eee eeeeee eee ee eeeeeeee ee eeeeeeee ee eeeeeee (Meeee 88, eeeeeee) ee Meeeeeeeeeeeeee M88 (Meeee) eeeeeee eeeeeee ee eeeeeeeeeee eeeee eeee 88888°M. Meeeeeeee eee eeeeeeee ee eeeeeeeeee eeee eeeeeeeeeeeeeee. Meee β-eeeeeeee, eeeeeeee ee e eeeeeeeeee eeeeee ee eeeeeeeeeeeeeee eeeeeee ee eeee, ee eeeee eeee eeeeeeeee, eeeeeeeeeeeeeee, ee eeeeeeeeeeeeeee ee 8°M (eee eeee), eeeeeeeee eee eeeeee ee eeee eeeeee.[‌888‌]

Me eeeeeee, eee eeeeeeeeee eeeeee eeeeeeee ee eee β-eeeeeeee eeeeeeeee ee eee eeeeee eee eeeeeeee. β-Meeeeeeee eeee eee eeeeeeeee eeeeeeeeee eeeeee eeee eeee eeeeeeeeeeee eeeeeeee: eeeeeeeeee eeeee eee eee eeeeeeeeeee ee eee eeeeeeeee ee eeeee 8-eeeeeeeeeeee-8-eeeeeeeeeeee,[‌888‌,‌888‌] M=M eeee ee eee eeeeeeeeeee ee 8-eeee-8-(8-eeeeeeeee)- ee 8-(eee-8-eeee)eeeeeeeee,[‌888‌,‌888‌] M,M-eeeeeee,[‌888‌] eeeeee eeeeeeeeeeee,[‌888‌] eeeeee eeeeeeeeeeee,[‌888‌] eeeee eeeeeeeeeeee,[‌888‌] eeeeeeeeeeeee eeeeeeeeeeee,[‌888‌] (eeeeeeeeeeeee)eeeeeeee eeeeeeeeeeee,[‌888‌] ee eeeeeeeeeeee eeeeeeeeeee,[‌888‌] eeeeeee eeeeeeeeeeee,[‌888‌,‌888‌] eee eeeeeeeeeeeeeeeeee eeeeeeeeeeee.[‌888‌,‌888‌] Meee eeeeeeeeeeeee β-eeeeeeeee eee eeeeeeeeeeeeeee eeeeeeeeee e eeeeeee ee eeeeeeee eeeeeeeeeee 88 eee 88 ee eeeeee (Meeeee 88). Meeee eeeeeeeeeeeeee eee eeeeee ee 8-eeee-8-eeeeeeeeeeeeeee 88 eeeeee ee eeeeeeeee ee eee eeeee M8 ee eee eeeeeeeee eeeee: MM8Me>M>eeeee>eeee.[‌888‌]

Meeeee 88 Meeeeeeee eeee Meeeeeee ee Meeeeeeeeeeee β-Meeeeeeee eeee Meeeeeeeeeeeee[‌888‌]

Mee eeeee eeeeeee eeeeeee eee ee eeeeeeeeee ee eeeeeee eeeeeeee eeeeeeeeee. Meeeeeeee 88 eee 88 eee eeeeee ee eeeee eeeeeeeee. Meeeeeeeeeeee eeeeeeeeeeeeee eee eeeeeeeeeee ee ee eeeeeeeee eeeeee ee eeeeeeeeeeeee.[‌888‌] Me eee eeeeeeee ee 8-eeee-8,8-eeeeeeeeeeeee eeeeee eeee eeeeeeeeeee eeeeeeeeee eeeeeeee ee eeeee 8-eeeeeeeeeeee-8-eeeeeeeeeeee 88 eee eeeee 8-eeeeeeeeeeee-8-eeeeeeeeeeee 88 eee eeeeee (Meeeee 88). Meeeeeeee eeeee 8-eeeeeeeeeeee-8-eeeeeeeeeeee 88 eeeeeeeeeee. Meee eeeeeee eeeeeeee ee 8-eeee-8,8-eeeeeeeeeeeee eeeeee eeeee eeee eeeeeeeeeeeeee, eeee eee eeeeeeeeeeeeeeee eee eeee eeeeeee eeeee eeeee 8,8-eeeeeeeeeeeeee-8-eeeeeeeeeeee 88.[‌888‌]

Meeeee 88 Meeee 8-Meeeeeeeeeee-8-eeeeeeeeeeee eee Meeee 8-Meeeeeeeeeee-8-eeeeeeeeeeee eeee Meeeeeee ee Meeeeee Meeeeeee ee 8-Meee-8,8-eeeeeeeeeeeee Meeeee eeee Meeeeeeeeeeeee[‌888‌]

Meeeeeeeeee 88

Me8 Me8 Meeee (88/88) Meeee (%) Mee
8-Mee 8-MeMM8M8 88:8 88 [‌888‌]
8-Mee 8-MeMM8M8 88:8 88 [‌888‌]
8-Mee 8-MeMM8M8 88:8 88 [‌888‌]
8,8-Me8M8M8 8-MeMM8M8 88:8 88 [‌888‌]
8-MeMM8M8 Me >88:8 88 [‌888‌]
8-MeMM8M8 8-MeMM8M8 88:8 88 [‌888‌]

Mee eeeeeeee ee 8-eeeeee-8-eeeee-8-eeeeee-8-eeeeeeeeee (88) eeee eeeeeeeee, eeeeeeeeeeeeeee, ee eeeeeeeeeeeeee ee eeeeeee eeeee 8-(8-eeeee-8-eeeeeeeeee)-8,8-eeeeeeeeeeeeeeee eeeeeeeeeee 88 ee eee eeee eeeeeeee eeeeeee ee eeeeee eeeeeee eeee 8888% (Meeeee 88). Meeeeeeee, eeeeeeee ee 8-eeeeee-8-eeeee-8-eeeeee-8-eeeeeeeeee eeee eeeeeeeeeeeeeee ee eeeeee eeee eeeee 8-(8-eeeee-8-eeeeeeeeee)-8,8-eeeeeeee-8-eeeeee-8M-eeeeeeee (88, M8=Me).[‌888‌] Me eeee eeeeeeee eee eeeeee eeee ee eeeeeeeee ee eeeee ee eeeee eee eeeeeeeee ee eee eeeeeeee eeeeeeee eeee. Meee eeee ee eeeeeeeeeeeeee ee eeee eeeeeeee eeee eeeee eeeeeeeeeeee ee eee eeeeeee eeee ee eee 8,8-eeeeeeeeee eeeeeeee (e.e., ee eee eeee ee eee 8-eeeeeeeeeeee-8,8-eeeeeeeeee eeeeeeeee eee Meeeeee 88.8.8.8.8.8.8.8).

Meeeee 88 8-(8-Meeee-8-eeeeeeeeee)-8,8-eeeeeeeeeeeeeeee eeee 8-Meeeee-8-eeeee-8-eeeeee-8-eeeeeeeeee eee Meeeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 Meeeee Meeee (%) Mee
M M 88 [‌888‌]
M 88 [‌888‌]
Me M 88 [‌888‌]
M 88 [‌888‌]
Me M 88 [‌888‌]
M 88 [‌888‌]
Me M 88 [‌888‌]

Meeeeeeeeeee Meeeeeeee

8-Meeeee-8-(8-eeeeeeeeeee)-8-eeeeee-8M-eeeeeeee (88, M8=Me; M8=M; M8=8-M8MM8M8; M8=Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee 8-(8-eeeeeeeeeee)eeeeee-8,8-eeeee (8.88e, 88.8eeee) eee MeMMMM8 (8.8e, 88.8eeee) eee eeeeee ee MeMM ee 8888°M eee 88eee. Mee eeeeeeeeeee eee eeeeeeeee ee eeeeeeeeee; eeeee: 88%; ee 888°M.

8-Meeeee-8-eeeeee-8M-eeeeeeee (88, M8=Me; M8=M; M8=Me; M8=M); Meeeeee Meeeeeeee:[‌888‌]

8,8-Meeeeeeeeeeeee-8,8-eeeee (8.8e, 88eeee) eee eeeeeeeee ee MeMM (88eM) eee 88% eeeeeeeee eeeeeee (8eM) eee eeeee eeeeeeee eeeee eee eeeeeee eee eeeeeee. Mee eeeeeeeee eeee eee eeeeeeeeee ee ee eeeeeeeee eee eeee eeeeee eeee eee ee M8MM8. Mee eeeee eeeeee eeeee eeeee eeee eeeeeeee eee eeeeeeeee eeee Me8M. Mee eeeeeeee eeeeeeee eeee eeeeeeee eeeeeeee Me8MM8 eee eeeeeeeeeeee ee e eeeee eeee. Mee eeeeeee eeee eee eeeeeee eeee eeeeeeeee eeeee eee eeeeeee eee eeeeeeeee eeeee eeeeeeeeeeeeeee eeeee. Meeeeeee eee eeeeeee ee 88°M eeeeeeee eeeeeeeee eeeeeee; eeeee: 88%; ee 8888°M.

8,8,8-Meeeeeeee-8M-eeeeeeee:[‌888‌]

8,8-Meeeeeeeeeeeeee-8,8-eeeee (8.88e, 88eeee) ee eeeeeeeee ee eeeeeee (Meeee 88 eeeeeee, 8e) ee eeeeeeee eeeeee. Me eeee, MeMMMM8 (8.88e, 88eeee) ee eeeee eeeeeeee ee 8°M (eee eeee) eeee eeeeeeeee eeeeeeee. Mee eeeeeeee eeee ee eeeeeeeeee eeeeeeee ee eee eeeee eeeeeee. Mee eeeeeee ee eeeeeee ee eeeee ee 88°M eee 88e eee eee eeeeeee ee eeee eeeeeeeee ee eeeeeee eeee MM8Me8 (8×88eM). Meeeeeeeeee ee eeeeeeee eeeeeeee eeeee eee eeeeeee; eeeee: 88%; ee 888°M.

Meeeeee Meeee Meeeeeeeeeeeeee; Meeeeee Meeeeeeee:[‌888‌]

8.8M MeMMMM (888eM, 8.88eee) eee eeeee ee eeeee Me8M (8M). Mee eeee eee eeee eeeeee ee 88°M eeeee M8. Meeee 88eee, eeeeeeeeeeee (8.88eee) ee eeeee Me8M (888eM) eee eeeee eee eeeeeee eee 88eee ee 88°M. Meeeeee eeeeeee (88.8e, 8.88eee) ee eeeee Me8M (888eM) eee eeeee ee eeee. Mee eeee eee eeee eeeeeee ee eeee ee ee. Meeee eeeeeeee eee 8e ee ee, eeeeeeee eee eeeeeeeeeeee eee eee eeeee eee eeeeeee ee eeeeee. Meeee 8e, eee eeeee eee eeeeeeee eee eeeeee eeee eeeee Me8M (8×888eM). Mee eeeee eee eeee eeeee ee eeeee eeeeeeeee. Meeeeeeeeeeeeeeee (eeeeeee) eeeeeeee ee eeeeeeeeeeee eeee eeeeeee eeeee eeeeeeeeeeeeeee; eeeee: 8888%.

Meeee 8,8-Meeeee-8M-eeeeeeee-8-eeeeeeeeeeee 88; Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee eeeeeee eeeee eeeeeeeeeeeeeee (8.88eee), eeeeeeeeeeeee eeeeeeeeeeeee (8.88eee), eee eeeee MeMM (8M) eeee eeeeeee ee ee eee 88e. Mee eeeeeee eee eeee eeeeeeeeeeee ee eee-eeee eeeeee. Me eeee eeee, eeeeeeeeeeeeeee eeeeeeee ee eeee eeee ee eee eeeeeee eeeeeee, eeeee eee eeeeeeeee ee eeeeeeeeee; eeeee: 8888%. Meeee eeeeeee ee eeeee 8,8-eeeeeeeeeeeeee-8-eeeeeeeeeee eee eeee ee eeeeeeee ee eeeeeeeeeee ee eee eeeeee eeeeee eeeeeeee ee eeeeeeeeeeeeeee eeeeeeeeeeee ee eee eeeeeee.

8-Meeeeeeeeee 8-(8-Meeee-8-eeeeeeeeee)-8,8-eeeeeeee-8M-eeeeeeeee 88; Meeeeee Meeeeeeee:[‌888‌]

MMMMMMM: Meeeeeeee (M8MMM8) ee e eeeeee eeeee eee eeeeeeeeeee eeeeeeeee eeeeeeee. Mee eeeeeeeeee eeeeee ee eeeeeeeee ee e eeee-eeeeeeeeee eeee eeee eee eeeeee e eeeeee eeeeee.

Meeeee M: Me e eeee ee 8-eeeeee-8-eeeee-8-eeeeee-8-eeeeeeeeee (88; 8.88e, 8eeee) ee MeMM (88eM) eee eeeeeeeee M8MMM8 (8.8eeee) eee eeeee. Mee eeeeeee eee eeeeeee ee ee eee 8e eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee ee eeee e eeeeeee, eeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee; eeeee: 8888%.

Meeeee M: Me e eeee ee 8-eeeeee-8-eeeee-8-eeeeee-8-eeeeeeeeee (88; 8.88e, 8eeee) ee MeMM (88eM) eee eeeeeeeee M8MMM8 (8.8eeee) eee eeeee. Mee eeeeeee eee eeeeeee ee ee eee 8e eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee ee eeee e eeeeeee, eeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee; eeeee: 8888%.

References


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