Science of Synthesis

Wu, X.-F., Science of Synthesis Knowledge Updates, (2014) 1, 269.

The Henry or nitroaldol reaction, first reported by Louis Henry in 1895,[‌59‌,‌60‌] is recognized as one of the classical name reactions in organic chemistry and is an important method for C—C bond formation. Basically, the Henry reaction is the reaction of carbonyl compounds and nitroalkanes to give β-nitro alcohols as the products. The first example of a zinc-catalyzed Henry reaction was disclosed in 2002 by Trost and co-workers (‌Table 2‌, entries 1–5).[‌61‌] Using dinuclear zinc catalyst ‌4‌, both aromatic and aliphatic aldehydes react with nitromethane to give β-nitro alcohols in 56–90% yields with 78–93% enantiomeric excess. This catalyst system was also applied in the total synthesis of (–)-denopamine and (–)-arbutamine by the same group.[‌62‌] In this report, the effects of ligand structure were also tested. After the Trost study, several other ligands ‌18‌–‌20‌ were developed independently (‌Scheme 8‌).[‌63‌–‌65‌] By combination of these ligands with diethylzinc, the desired products are obtained in good yields with good enantiomeric excess (‌Table 2‌, entries 6–17). Palomo and co-workers found that the simple combination of commercially available (+)-(1S,2R)-N-methylephedrine (‌21‌; 45 mol%; ‌Scheme 8‌), N,N-diisopropylethyl­amine (30 mol%), and zinc(II) trifluoromethanesulfonate (30 mol%) can effectively promote the Henry reaction in nitromethane (‌Table 2‌, entries 18–21).[‌66‌] Excellent yields and enantiomeric excess can be achieved at −60 to −20 °C. In addition, 2-aminoethanol, ethane-1,2-diamine, and -proline were to be found effective for the Henry reaction as well.[‌67‌–‌69‌] When using -proline as the ligand, the reaction can be carried out in water.[‌70‌] A density functional theory (DFT) study based on the dinuclear zinc system showed that the C—C bond-forming step is the rate-limiting step for Henry reaction.[‌71‌] The addition of nitroalkanes to imines is called the aza-Henry (or nitro-Mannich) reaction. Impressively, the dinuclear zinc catalyst ‌4‌ from Trost (‌Table 2‌, entries 22 and 23) and the catalyst system from Palomo and co-workers[‌66‌] are also effective for aza-Henry reactions (entries 24 and 25).[‌72‌,‌73‌] Good yields and excellent enantiomeric excess of α-nitro amines are obtained by these two methods.

‌Meeeee 8‌ Meeeeee eee eee Meeee Meeeeeee[‌88‌–‌88‌]

‌Meeee 8‌ Meee-Meeeeeeee Meeee Meeeeeeee[‌88‌–‌88‌,‌88‌,‌88‌]

Meeee	Meeeeeeee	Meeeeeee	Meeeeee	Meeee (%)	ee (%)	Mee
8	MeMMM	8		88	88	[‌88‌]
8	e-MeMMM	8		88	88	[‌88‌]
8	MeMMM	8		88	88	[‌88‌]
8		8		88	88	[‌88‌]
8		8		88	88	[‌88‌]
8	e-MeMMM	88, Me8Me		88	88	[‌88‌]
8	MeMMM	88, Me8Me		88	88	[‌88‌]
8	MeMMM	88, Me8Me		88	88	[‌88‌]
8		88, Me8Me		88	88	[‌88‌]
88		88, Me8Me		88	88	[‌88‌]
88	e-MeMMM	88, Me8Me		88	88	[‌88‌]
88	MeMMM	88, Me8Me		88	88	[‌88‌]
88	MeMMM	88, Me8Me		88	88	[‌88‌]
88	MeMMM	88, Me8Me		88	88	[‌88‌]
88		88, Me8Me		88	88	[‌88‌]
88		88, Me8Me		88	88	[‌88‌]
88		88, Me8Me		88	88	[‌88‌]
88	e-MeMMM	88, Me(MMe)8, eMe8MMe		88	88	[‌88‌]
88	MeMMM	88, Me(MMe)8, eMe8MMe		88	88	[‌88‌]
88	MeMMM	88, Me(MMe)8, eMe8MMe		88	88	[‌88‌]
88	Me(MM8)8MMM	88, Me(MMe)8, eMe8MMe		88	88	[‌88‌]
88		8		88	88	[‌88‌]
88		8		88	88	[‌88‌]
88		eee-88, Me(MMe)8, eMe8MMe		88	88	[‌88‌]
88		eee-88, Me(MMe)8, eMe8MMe		88	88	[‌88‌]

Meeeeeeeeeee Meeeeeeee

(M)-8-Meeeeeeeee-8-eeeeeeeeeeee (‌Meeee 8‌, Meeee 8); Meeeeee Meeeeeeee eee Meeeeeeee Meee Meeeeeeee Meeee Meeeeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

M 8.8 M eeee ee eee eeee eeeeeeee ‌8‌ ee MMM (8.8 eM, 8.88 eeee) eee eeeee eeeeeeee ee e eeeeeee eee eeeeee (–88 °M) eeeeeeeeee ee eeeeeeee 8-Å eeeeeeeee eeeeee (888 ee; eeeee ee 888 °M eeeee eeeeeee eeeeeeee eeeeeeeee), MeMMM (888 ee, 8 eeee), eee MeMM8 (888 ee, 8.88 eM, 8 eeee) ee MMM (8 eM) eeeee eeeee. Mee eeeeeeeee eeeeeee eee eeeee­eeeeee ee e −88 °M eeee eeee eee eeeeeee eee 88 e. Mee eeeeeeee eee eeeeeeee ee eeeeee 8.8 M ee MMe (8 eM), eee eee eeeeeeeee eeeeeee eee eeeeeeeee eeee Me8M (88 eM). Mee eeeeeee eeeee eee eeeeee eeee M8M eee eeeee, eeee eeeee (MeMM8), eee eeeeeeee. Meeee eeeeeeeeeee ee eee eeeeeee, eee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeeeeee eeeee 8:8) ee eeeeee eee eeeeeeeeee eeeeeee ee e eeeee eee; eeeee: 888 ee (88%); 88% ee ee eeeeeeeeee ee MMMM [Meeeeeeee MM, 888 ee, eeeeeee/eMeMM 88:8, 8 eM·eee−8); eM = 88.88 (eeeee) eee 88.88 eee (eeeee)]; [α]M88 +88.88 (e 8.88, MMMe8); 8M MMM (888 MMe, MMMe8, δ): 8.8–8.88 (e, 8M), 8.88–8.88 (e, 8M), 8.88–8.88 (e, 8M), 8.88 (ee e, 8M), 8.88–8.88 (e, 8M), 8.88–8.88 (e, 8M); 88M MMM (88.8 MMe, MMMe8, δ): 88.88, 88.88, 88.88, 88.88, 88.88, 88.88, 88.88, 88.88.

β-Meeee Meeeeeee (‌Meeee 8‌, Meeeeee 8 eee 8); Meeeeee Meeeeeeee eee Meee-Meeeeeeee Meeee Meeeeeee Meeee ee Meeee Meeeeee ‌88‌ ee Meeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

Meeee eeeee, e 8.8 M eeee ee Me8Me ee eeeeeee (8 μM, 8.88 eeee) eee eeeee ee eeeee eeeeeee eeeeee ‌88‌ (88 ee, 8.88 eeee) eee eeeeeeee 8-Å eeeeeeeee eeeeee (888 ee) ee eeeee MMM (8 eM) ee 8 °M. Mee eeeeeee eee eeeeeee eee 88 eee, eee eeee eeeeee ee −88 °M. Meeee eee eeeeeeee ee eee eeeeeeeeeee eeeeeeee (8.8 eeee) eee MeMM8 (888 ee, 8.88 eM, 8.8 eeee), eee eeeeeeeeee eee eeeeeee eee eee eeeeeeee eeee eee eee eeeeeeee eee eeeeeeee eeee 8.8 M ee MMe (8 eM). Meeeeeeeee eeee Me8M eee eeeeeeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee eeeeeeee eee eeeeeee eeeeeee.

(M)-8-Meeee-8-eeeeeeeeeeeee (‌Meeee 8‌, Meeee 8); Meeeeee Meeeeeeee eee Meee-Meeeeeeee Meeee Meeeeeee Meeee Meeeeeeeeeeeee Meeeee ‌88‌:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

Me e eeee ee eee eeeeee eeeeeeeeeeeeee eeeeee ‌88‌ (88 ee, 8.888 eeee, 8 eee%) ee eeeeeee (8 eM) eee eeeee e 8 M eeee ee Me8Me ee eeeeeee (8 eeee) ee −88 °M eeeee M8. Meeee 88 eee, MeMM8 (888 ee, 8.8 eeee) eee eeeee ee eee eeeeeee eeeeeeee ee MeMMM (888 ee, 8.88 eeee). Meeee 8 e, eee eeeeeeeeeee eee eeeeeeeee ee −88 °M eee eee. ee MM8Me eee eeeee eeee eeeeeeeeee ee eee eeeeeeee. Mee eeeeeee eee eeeeee ee ee eee eeeeeeeee eeee MMMe8, eee eee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8). Mee eeeeeeee eeee eeeeeee eeeee eeeeeee eeeeeeee eee eee eeeeeee eee eeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee (MeMMe/eeeeeee 88:88) ee eeeeee eee eeeeeee ee e eeeee eeeee; eeeee: 888 ee (88%); 88% ee ee eeeeeeeeee ee MMMM (Meeeeeeee MM, MeMM/eeeeeee 8:88; eM = 88.8 eee 88.8 eee); [α] +8.88; 8M MMM (888 MMe, MMMe8, δ): 8.88 (e, 8M), 8.88 (ee, M = 8.8, 88.8 Me, 8M), 8.88 (ee, M = 8.8, 88.8 Me, 8M), 8.88 (ee, M = 8.8, 8.8 Me, 8M), 8.88–8.88 (e, 8M); 88M MMM (88 MMe, MMMe8, δ): 88.8, 88.8, 888.8, 888.8, 888.8, 888.8.

(M)-8-Meeee-8-eeeeeeeeeeeee (‌Meeee 8‌, Meeee 88); Meeeeee Meeeeeeee eee Meee-Meeeeeeee Meeee Meeeeeee Meeee Meeeeeeee Meeeee ‌88‌:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

M 8.8 M eeeee eeee ee eee eeeeee eeeeeeeee eeeeee ‌88‌ ee MMM (8.88 eM, 8.88 eeee) eee eeeee ee e eeeeeeee eeeee eeeee eeeee. Meeee eee eeeeeee eee eeee eeeeee ee 8 °M, e 8.8 M eeee ee Me8Me ee eeeeee (8.8 eM, 8.8 eeee) eee eeeee. Meeee eee eeeeeee eee eeee eeeeeee eee 88 eee ee eeee eeeeeeeeeee, MeMM8 (888 ee, 8.88 eM, 88.8 eeee) eee eeeee. Mee eeeeeeeee eeeeeee eee eeeeeee ee eeee eeeeeeeeeee eee 8 e, eee eeee eeeeee ee −88 °M, eee MeMMM (88 ee, 88 μM, 8.88 eeee) eee eeeee. Mee eeeeeee eee eeeeeee eee 88 e ee eeee eeeeeeeeeee eee eeee eeeeeeee eeee eee. ee MM8Me. Meeee eeeeeeeeee ee eee eee eeeeee, eee eeeeeee eeeee eee eeeeeeeee eeee Me8M (8 × 88 eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeee (Me8MM8), eeeeeeeeeeee, eee eeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee (eeeeee eee, eeeeee/MeMMe 8:8); eeeee: 88 ee (88%); 88% ee.

(M)-8,8-Meeeeeee-8-eeeeeeeeee-8-ee (‌Meeee 8‌, Meeee 88); Meeeeee Meeeeeeee eee Meee-Meeeeeeee Meeee Meeeeeee Meeee (8M,8M)-(+)-M-Meeeeeeeeeeeeee (‌88‌) ee Meeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

eMe8MMe (8.88 eM, 8 eeee) eee eeeee ee e eeeeeeeeee ee Me(MMe)8 (8.88 e, 8 eeee) ee MeMM8 (88 eM), eee eee eeeeee eee eeeeeee eee 8 e ee 88 °M. (+)-(8M,8M)-M-Meeeeeeeeeeeeee (‌88‌; 8.88 e, 8 eeee) eee eeee eeeee, eee eee eeeeeeeee eeeeee eeeeeee eee eeeeeee eee ee eeeeeeeeee 8 e ee ee. Meeee eee eeeeeee eee eeee eeeeee ee −88 °M, e eeee ee 8,8-eeeeeeeeeeeeeeee (8.88 e, 8.88 eM, 88 eeee) ee MeMM8 (8 eM) eee eeeee ee eeeeeee, eee eee eeeeeee eee eeeeeee ee eee eeee eeeeeeeeeee eee 88 e. Mee eeeeeeee eee eeeeeeee eeee eee. ee MM8Me (88 eM), eee eee eeeeeee eee eeeeeeeee eeee Me8M (8 × 88 eM). Mee eeeeeeee eeeeeee eeeee eee eeeeee eeee 88 M ee MMe (8 × 88 eM) eee eee. ee MM8Me (88 eM). Mee eeeeeee eeeee eee eeeee (MeMM8) eee eeeeeeee, eee eee eeeeeee eee eeeeeee ee eeeeeeeeeee. Mee eeeee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee; eeeee: 8.8 e (88% ee eeeeeeee); 88% ee ee eeeeeeeeee ee MMMM [Meeeeeeee MM, eeeeee/eMeMM 88:8, 8.8 eM·eee−8; eM = 88.8 (eeeee) eee 88 eee (eeeee)]; [α]M88 −88.8 (e 8, MM8Me8). Me eeeeeee eee eeeeee eeeeee eeee eee eeeeeee eeeee, 88% ee MeMM eee eeeee eeeeeeee ee eee eeeeeee eeeee, eeeeee ee ee eee eeee, eeeee eM 88. Mee eeeeeee eee eeeeeeeee eeee MM8Me8 (8 × 88 eM) eee eee eeeeeee eeeee eee eeeee (MeMM8) eee eeeeeeee. Mee eeeeeee eee eeeeeeeeee ee eeeeee eeeeeeeeee eee eeeeeeeee eeee (8M,8M)-(+)-M-eeeeeeeeeeeeeee (‌88‌); eeeee: 8.88 e (88% eeeeeeeee).

eeee-Meeee [(M)-8-Meeee-8-eeeeeeeeeee]eeeeeeeee (‌Meeee 8‌, Meeee 88); Meeeeee Meeeeeeee eee Meeeeeeee Meee Meeeeeeee Meeee Meeeeeee eeee Meeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

Me eeee-eeeee eeeeeeeee eeee eee eeeeeee eeee eeeeeeeee 8-Å eeeeeeeee eeeeee, eeeeee eeee e eeeeee, eeeeeeeee, eeeee-eeeee, eee eeeeee eeee M8. Mee eeee eee eeeeee ee ee. MMM (8.8 eM) eee eeeee eeeeeeee ee e 8.888 M eeee ee eeeeeeeee eeee eeeeeeee ‌8‌ (8.8 eM, 8.88 eeee). Meee eeeeeeeeee eee eeeeeee eeee MeMM8 (88 ee, 8 eeee) eeeeeeee ee eeee-eeeee (eeeeeeeeeeeeeee)eeeeeeeee (888 ee, 8.8 eeee) eee eee eeeeeeeee eeee eee eeeeeee eee 88 e. Mee eeeeeeee eee eeeeeeee ee eeeeeeee eeee Me8M (8 eM) eee eeeeeeee ee e 8 M eM 8 eeeeeeeee eeeeee (8 eM). Mee eeeeeeee eeeeeee eee eeeeeee eee 88 eee eee M8M (8.8 eM) eee eeeee. Mee eeeeeee eee eeeeeeeee eeee Me8M (8 × 88 eM) eee eee eeeeeeee eeeeeee eeeeee eeee eeeeeeeeeeee. Mee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeeeeee eeeee 8:8; Me 8.88); eeeee: 88 ee (88%); [α]M88 −88.8 (e 8.8, MM8Me8); ee 88–88 °M; 88% ee ee eeeeeeeeee ee MMMM [Meeeeeeee MM, eeeeeee/eMeMM 88:8, 8.8 eM·eee−8, 888 ee; eM = 88.88 (eeeee) eee 88.88 eee (eeeee)]; MM ν̃eee: 8888, 8888, 8888, 8888, 8888, 8888, 8888, 8888, 8888, 8888, 8888, 8888, 888, 888, 888, 888, 888 ee−8; 8M MMM (888 MMe, δ): 8.88–8.88 (e, 8M), 8.88 (ee e, 8M), 8.88–8.88 (e, 8M), 8.88–8.88 (e, 8M), 8.88 (e, 8M); 88M MMM (888 MMe, δ): 888.8, 888.8, 888.8, 888.8, 888.8, 88.8, 88.8, 88.8, 88.8.

eeee-Meeee [(M)-8-Meeee-8-eeeeeeeeeee]eeeeeeeee (‌Meeee 8‌, Meeee 88); Meeeeee Meeeeeeee eee Meee-Meeeeeeee Meeee Meeeeeee eeee Meeeee Meeee (–)-(8M,8M)-M-Meeeeeeeeeeeeee (eee-‌88‌) ee Meeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee eeeeeeeee, e eeeee- eee eeee-eeeeeeeee eeeeeeeee, eee ee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee.

eMe8MMe (8.88 eM, 8 eeee) eee eeeee eeeeeeee ee e eeee ee eeeee Me(MMe)8 (8.88 e, 8 eeee) ee MeMM8 (88 eM) eeeee M8 eee eee eeeeeeeee eeeeeee eee eeeeeee ee 88 °M eee 8 e. Mee eeeeeee eeeeee eeeeee. Meeee eeeeeeee ee (–)-(8M,8M)-M-eeeeeeeeeeeeeee (eee-‌88‌; 8.8 e, 8 eeee) eee 8-Å eeeeeeeee eeeeee (8.8 e), eee eeeeeeeee eeeeeee eee eeeeeee eee ee eeeeeeeeee 8 e ee eee eeee eeeeeeeeeee. Mee eeeeeee eee eeee eeee eee 88 eee ee −88 °M. eeee-Meeee (eeeeeeeeeeeeeee)eeeeeeeee (8.8 e, 88 eeee) eee eeeee, eee eee eeeeeee eee eeeeeee eee 88 e ee −88 °M. Mee eeeeeeee eee eeeeeeee eeee 8.8 M ee MMe (88 eM), eee eee eeeeeee eee eeeeeeeee eeee MM8Me8 (8 × 88 eM). Mee eeeeeee eeeee eee eeeee (MeMM8) eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee. Meeeeeeeeeee ee eee eeeee eeeeeee ee eeeee eeeeee eeeeeeeeeeeeee (MeMMe/eeeeee) eeeeeeee eee eeeeeee; eeeee: 8.8 e (88%); 88% ee.

Meee eee eeee eeeeeeeee ee eee eeeeee, 8.888 e ee (–)-(8M,8M)-M-eeeeeeeeeeeeeee (eee-‌88‌) eee eeeeeeeee. Meeeeeee ee eee eeeeee eeeeee eeee eeeeeeee ee eee eeeeee eeeeeee eeeee eee eeeeeee eee ee eeeeeeee eeeeeeee ee 88% ee MeMM eeeee eM 88 eee eeeeeeee. Mee eeeeeee eee eeeeeeeee eeee MM8Me8 (8 × 88 eM) eee eee eeeeeee eeeee eee eeeee (MeMM8). Mee eeeeeee eee eeeeeeeeee ee eeeeee ee eeeeeeeeee 8.88 e ee eeeeeeeeee eee eeeeeeeee eeee eee-‌88‌; eeeeeeee eeeeeeee eeeee: 8.88 e (88%).

References