Science of Synthesis

Black, D. StC., Science of Synthesis, (2001) 9, 455.

The classical cyclizative condensation of 1,4-dicarbonyl compounds with ammonia or primary amino compounds is still one of the most generally useful pyrrole syntheses. The reaction takes place in solvents such as ethanol, dimethylformamide, or acetic acid, and proceeds via carbinolamine and imine intermediates followed by dehydration to the aromatic ring.[‌53‌–‌58‌] This method is referred to as the Paal–Knorr synthesis. For example, hexane-2,5-dione (‌93‌) reacts with ammonia (from ammonium carbonate) to give 2,5-dimethyl-1H-pyrrole (‌94‌),[‌59‌] and with 4-bromoaniline (‌95‌) to give 1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrole (‌96‌) (‌Scheme 16‌).[‌60‌] Titanium(IV) chloride can be used as an effective Lewis acid catalyst and dehydrating agent for the formation of sterically hindered pyrroles.[‌61‌] The primary amines in this methodology can be replaced by hydrazines.[‌62‌] The use of alkoxycarbonylhydrazines, followed by removal of the nitrogen protecting group, has recently been developed as a very effective synthesis of pyrrol-1-amines. For example, hexane-2,5-dione (‌93‌) combines with the acylhydrazide ‌97‌ to give the pyrrole ‌98‌ in almost quantitative yield (‌Scheme 16‌).[‌63‌] In this case the protecting group was removed by tetrabutylammonium fluoride.

Mee eeee eeeeeeeeee ee eee Meee–Meeee eeeeeeeee ee eee eeeeeeeeeeee ee eee 8,8-eeeeeeeeee eeeeeeee. Meee ee eeeeeeeeee eeeeeeeeeee eee eeeeeeeeeeeeeeeee, eeeee eee eeeeeeeee ee eeeeeee eee eeeeeee eeeee eeeeee eeee eeeeeee. Meee eeeeeee eee ee eeeeeeee ee eeeeeeeeee eee eeeeeeeeee ee eeee eeee 8-eeeeeeeeeeeee eeeeeee,[‌88‌] 8,8-eeeeee-8,8-eeeeeeeeeeeeeeee, ee, eeee eeeeeeeeeeee, eeee eee eeeeeeeeeeee eeeeeeeee 8,8-eeeeeeeeeeeeeeeeeeeeeeee (‌88‌).[‌88‌–‌88‌] M eeee eeeee ee eeeeeeeeeee 8,8-eeeeeeeeeeeeeeeeeeeeeeeee eeee eeee eeee eeeeeeeee ee eeee eeeeeeeeeee.[‌88‌–‌88‌] Meeeeeeeee eeeeeeeee eeeeeee ee ee eee eeee eeeeeeeee eeeeeeee eee eeee eeeeeeee, ee eeeeeeeeeee ee eee eeeeeeee ee 8,8-eeeeeeeeeeeeeeeeeeeeeeee (‌88‌) eeee eeeeeeeeeee (‌888‌) ee eeee M-eeeeee-8M-eeeeeee (‌888‌) (‌Meeeee 88‌).[‌88‌] Mee eeeeeeee eee eeee eeee eeeeeeeeeeee eeee eeeeee α-eeeee eeee eeeeee, eee eee eeeeeeeee M-eeeeeeeeeee eeeeeeee eee eeeee eeeeeee.[‌88‌,‌88‌–‌88‌] M eeeeeeee eeeeeeee eee-eeeee eeeeeeeee eeeee ee eeeee eeee eeeeeee eee ee eeeeeeeeeee ee eee eeeeeeeeeee ee eee eeeee ‌88‌ eeee M-eeeeeee (‌888‌) ee eeee eee eeeeeee ‌888‌ (‌Meeeee 88‌).[‌88‌]

8,8-Mee(eeeeeeeeeeeee)eeee-8,8-eeeee (‌888‌) ee eee eeeeeeeee ee eeeeeeeeeeeeeeee, eee eee eeeeeee eeee-eeeeeeeee eeeeeeee eeee eeeeeee eeeeee [e.e., eeeeeeeeeeeeeee (‌888‌)] ee eeee M-eeeeeeeeeee eeeeeeee [e.e., M-eeeeeeeeee-8M-eeeeeee (‌888‌)] (‌Meeeee 88‌).[‌88‌]

Meeeeeeeeee 8,8-eeeeeeeeee eeeeeeeee eeee eeeee eeee eeeeeee eeeeee, eeeeeeeeeeeee, eee eeeeeeeeee ee eeee eee eeeeeee eeeeeeee.[‌88‌–‌88‌] Mee eeeeeee, (M)-8,8,8,8-eeeeeeeeeeeeee-8-eee-8,8-eeeee (‌888‌) eeeeeeee eeee eeeeeeeeeeeeeee (‌888‌) ee eeee eee M-eeeeeeeeeeeeee ‌888‌ (‌Meeeee 88‌).[‌88‌]

Mee 8-eeeeeeeeeeeee-8,8-eeeeeeeeeeee ‌888‌, eeeee eee ee eeeeeeeee eeee eeeeeeeeeeeeeeeeeeee eee eeeee 8-eeeeeeeeeeee (‌88‌) ee e eeeeeee eeeeeeeee e Meeeeeee eeeeeeeeeeeee, eee ee eeeeeeeee eeee eeeeeeee (e.e., ‌888‌) ee eeeeeeeee eeee eeeeeee(MM) eeeeeeee eee e eeeeeee eeeee [e.e., eeeeeeeeeee (‌888‌)] (‌Meeeee 88‌).[‌88‌]

‌Meeeee 88‌ Meeeeeeee ee Meeeeeee eeee 8,8-Meeeeeeeee Meeeeeeee ee Meeeeeeeeee eee Meeeee (Mee Meee–Meeee Meeeeeeee)[‌88‌,‌88‌,‌88‌,‌88‌,‌88‌–‌88‌,‌88‌]

Meeeeeeeeeee Meeeeeeee

8,8-Meeeeeee-8M-eeeeeee (‌88‌):[‌88‌]

Meeeeeeee eeee (Meeee; Meeee, Meeeeee Meeeeeeee), Meeeeeeee (8888), e 888, eeee eeeeeeeeee eeee Meee Meeee&Meee, Mee.

Meeeee-8,8-eeeee (‌88‌; 888 e, 8.88 eee) eee (MM8)8MM8 (888 e, 8.88 eee) eeee eeeeee eeeeeeee ee 888°M eeeee eee eeeeeeeee ee eee eeeeee (88 eee). Meeeeee eee eeeeeeeee eee e eeeeeee 88 eee eee eee eeeeeeeee (MM8)8MM8 ee eee eeeeeeeee eee eeeeee eeee eee eeeeeeee eeeee eeee eee M8M (88 eM). Mee eeeeeee eeeee eee eeeeeeeee, eee eeeeeee eeeee eeeeeeeee eeee MMMe8, eee eee eeeeeeee eeeeeee eeeeee eeeee (MeMe8), eeeeeeeeeeee, eee eeeeeeeee ee eeee eeeeeee ‌88‌; eeeee: 88 e (88%); ee 88–88°M/8 Meee.

8-(8-Meeeeeeeeee)-8,8-eeeeeeee-8M-eeeeeee (‌88‌):[‌88‌]

Meeeee-8,8-eeeee (‌88‌; 8.8 e, 88 eeee) eee 8-eeeeeeeeeeee (‌88‌; 88 e, 88 eeee) eeee eeeeee eeeeeeee eeee MeMM (8 eM) eee eeeeeee (88 eM) eee 8 e, eeee eeeeeeeeee eeeeeeeeeeee ee M8M. Mee eeeeeee eee eeeeeee eeee Me8M, eee eeeeeee eeeeee eeee eee MMe, eee. MeMMM8, eee eeeee, eeeee (MeMM8), eee eeeeeeeeeeee ee eeee eeeeeee ‌88‌; eeeee: 88.8 e (88%); ee 88–88°M.

8-(Meeeeeeeeeeeee)eeeee (8,8-Meeeeeee-8M-eeeeee-8-ee)eeeeeeeee (‌88‌):[‌88‌]

Meeeee-8,8-eeeee (‌88‌; 888 ee, 8.88 eeee) eee eee eeeeeeeee ‌88‌ (888 ee, 8.88 eeee) eeee eeeeee eeeeeeee ee MeMM (8.88 eM) ee 88°M eee 88 eee. Meeee eeeeeeeeeee ee eeeeeee eeeee eeeeeee eeeeeeee, eeeee eeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeee 8:8) eeee eee eeeeeee ‌88‌; eeeee: 8.88 e (88%); ee 88.8°M (Me8M/eeeeee).

8-Meeeee-8M-eeeeeee (‌888‌):[‌88‌]

8,8-Meeeeeeeeeeeeeeeeeeeeeee (‌88‌; 8.88 e, 88 eeee) eee eeeee ee e eeeeeee eeeeeeeeee ee eeeeeeeeeee (‌888‌; 8.88 e, 88 eeee) eee M8M8 (8.88 e, 88 eeee) ee eee eeeeeee (88 eM) eeeee M8, eee eeeeeeee eeeeeeeee ee 888°M eee 88 eee. Mee eeeeeeee eee eeeeeeee eeee ee 8 M MMM (88 eM), eee eeeeeeee eeeeeeeeee eeeee eeeeeee eeeeeeee, eee eee eeeeeee eeeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeee) ee eeee eee eeeeeee ‌888‌; eeeee: 8.88 e (88%).

(8M)-8-(8M-Meeeee-8-ee)eeeeeeeee Meee (‌888‌):[‌88‌]

M-Meeeeee (‌888‌; 8.88 e, 88 eeee) eee 8,8-eeeeeeeeeeeeeeeeeeeeeeee (‌88‌; 8.88 e, 88 eeee) eeee eeeeeeeee ee M8M (88 eM), MeMM (8 eM), eee eeeeeeeeeeeeee (88 eM) eee eeeeee ee 88°M eeee eeeeeeee eeeeeeee eee 88 eee. Meeee eeeeeee ee ee, eee eeeeeee eeeee eee eeeeeeeee eee eeeeeeeee eeee MM8Me8, eee eeeeeeee eeeee (MeMM8), eeeeeeeee eeeeeeeeeeee, eee eeeeeeeeeeeeeee (eeeeee eee, Me8M) ee eeee eee eeeeeee ‌888‌; eeeee: 8.88 e (88%); >88% ee; ee 88–88°M.

8-Meeeeeeeee-8M-eeeeeee (‌888‌):[‌88‌]

8,8-Mee(eeeeeeeeeeeee)eeee-8,8-eeeee (‌888‌; 88 e, 8.88 eee) eee eeeeeeeeeeeeeee (‌888‌; 88 e, 8.88 eee) eeee eeeeee eeeeeeee eeeee e eeeeee ee M8 eeee MeMM (8 eeeee) eee eeeee MMe (8 eeeee) eee 8 e ee 88–88°M. Meeeeeeeeeeee (88 e, 8.8 eee) eee eeeee eee eee eeeeeeee ee 8.8 M MMe (888 eM). Mee eeeeeee eee eeeeeee eeee M8MM8 (8.8 e) eee eeeeeeeee eeeee eeeeee ee eeee eee eeeeeee ‌888‌; eeeee: 88 e (88%); ee 88–88°M/8 Meee.

M,8,8,8,8-Meeeeeeeeee-8M-eeeeee-8-eeeee (‌888‌):[‌88‌]

M eeeeeeeeee ee (M)-8,8,8,8-eeeeeeeeeeeeee-8-eee-8,8-eeeee (‌888‌; 8.88 e, 88 eeee) ee MeMM (888 eM) eee eeeeeee eeee eeeeeeeeeeeeeee (‌888‌; 8–8 e), eee eee eeeeeee eeeeee eee 8–8 e eeeee eeeeee. Meeee eeeeeee eee eee eeeeeeee ee M8M, eee eeeeeeeeeeee eeeeeee eee eeeeeeeeeeeeee; eeeee: 8.8 e (88%); ee 888°M (MeMM/MeMM).

Meeee 8-Meeeee-8-eeeeee-8M-eeeeeee-8-eeeeeeeeeee (‌888‌):[‌88‌]

M eeeeeee ee eeeeeeeeeeee ‌888‌ (888 ee, 8.8 eeee), MeMe8 (888 ee, 8.8 eeee) eee eeeeeeeeeee (‌888‌; 888 ee, 88 eeee) ee MMM (8 eM) eee eeeeeeeeeee ee e eeeee-eeeeee eeeeee eeeee eeee eee eeeeee ee ee eee eeee ee 888°M eee 8 e. Meeee eeeeeee, eee eeee eee eeeeee eee eee eeeeeeee eeeeee eeee M8M (88 eM). Mee eeeeeee eee eeeeeeeee eeee Me8M, eee eeeeeee eeeeee eeee 88% ee eeee (88 eM), eeeee, eeeeeeeeeeee, eee eee eeeeeee eeeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeee eeeeeeeee eeeee 8:88) ee eeee eee eeeeeee ‌888‌; eeeee: 888 ee (88%).

References

Meeeeee Meeeeeeeeee

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