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The results obtained in the same work with a,f-unsaturated imines 58 are more interesting. Imines 58 proved to be a particu- larly useful class of substrates giving rise to the a-nitroamine prod- ucts 59 in high enantiomeric excesses under optimized reaction conditions [60] (Scheme 26). Several a-amido sulfones 61 derived from aromatic and het- eroaromatic aldehydes were treated with nitromethane under opti- mized reaction conditions to furnish the corresponding optically active N-Boc B-nitroamines 62 with fairly good yields and enanti- omeric excesses. In the first asymmetric aza-Henry reaction N- carbamoyl imines generated in situ from a-amido sulfones 61 were used under phase-transfer conditions by the help of the commer- Scheme 26.

Figure 14 The results obtained in the same work with a,f-unsaturated imines 58 are more interesting. Imines 58 proved to be a particu- larly useful class of substrates giving rise to the a-nitroamine prod- ucts 59 in high enantiomeric excesses under optimized reaction conditions [60] (Scheme 26). Several a-amido sulfones 61 derived from aromatic and het- eroaromatic aldehydes were treated with nitromethane under opti- mized reaction conditions to furnish the corresponding optically active N-Boc B-nitroamines 62 with fairly good yields and enanti- omeric excesses. In the first asymmetric aza-Henry reaction N- carbamoyl imines generated in situ from a-amido sulfones 61 were used under phase-transfer conditions by the help of the commer- Scheme 26.

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These reactions are important as they both lead to the formation of a carbon-nitrogen bond which has a pharmaceutical interest.
These reactions are important as they both lead to the formation of a carbon-nitrogen bond which has a pharmaceutical interest.
4,4'-(2-nitropropane-1,3-diyl) bis(1-phenylpiperazine) (9) [16] (Scheme 3). does normally not follow the other possible route (step C and D). However, some successful reactions between hydroxymethyl de- rivatives 6 and alkylamines to give a Mannich base 5 should be mentioned. The reactive species in acidic medium is the iminium ion 4, derived from methylene-bis-amine 3 and from hy- droxylmethylamine 2. The electrophilic attack of 4 on the nitroal- kane follows a SE? mechanism on the enol rather than on the car- banion, whereas in basic medium the reactant is postulated to be 2 or more probably 3.
4,4'-(2-nitropropane-1,3-diyl) bis(1-phenylpiperazine) (9) [16] (Scheme 3). does normally not follow the other possible route (step C and D). However, some successful reactions between hydroxymethyl de- rivatives 6 and alkylamines to give a Mannich base 5 should be mentioned. The reactive species in acidic medium is the iminium ion 4, derived from methylene-bis-amine 3 and from hy- droxylmethylamine 2. The electrophilic attack of 4 on the nitroal- kane follows a SE? mechanism on the enol rather than on the car- banion, whereas in basic medium the reactant is postulated to be 2 or more probably 3.
Scheme 5.
Scheme 5.
Synthesis of the 7H-pyrimido[4,5-b][1,4]diazepine ring system has been achieved by treating 5,6-diaminopyrimidine-2,4-diol hy- dro-chloride (26) with nitromethane and formaldehyde, in presence
Synthesis of the 7H-pyrimido[4,5-b][1,4]diazepine ring system has been achieved by treating 5,6-diaminopyrimidine-2,4-diol hy- dro-chloride (26) with nitromethane and formaldehyde, in presence
The reaction takes place in two steps: treating nitromethane with formaldehyde to form the 2-nitropropane-1,3-diol (20)(A), which then reacts with the aromatic amines in presence of tetraethyl ammonium hydroxide as a basic catalyst (B) [16]. Mardia and Af- sah have synthesized 4,4'-(2-nitropropane-1,3-diyl)bis (azanediyl) bis(1,5-dimethy]-2-phenyl-1H-pyrazol-3(2H)-one) (22) by the reac- tion of 4-amino antipyrine with the non-isolated nitrodiol 20 which is prepared as intermediate from the reaction of nitromethane and formaldehyde [16] (Scheme 9).
The reaction takes place in two steps: treating nitromethane with formaldehyde to form the 2-nitropropane-1,3-diol (20)(A), which then reacts with the aromatic amines in presence of tetraethyl ammonium hydroxide as a basic catalyst (B) [16]. Mardia and Af- sah have synthesized 4,4'-(2-nitropropane-1,3-diyl)bis (azanediyl) bis(1,5-dimethy]-2-phenyl-1H-pyrazol-3(2H)-one) (22) by the reac- tion of 4-amino antipyrine with the non-isolated nitrodiol 20 which is prepared as intermediate from the reaction of nitromethane and formaldehyde [16] (Scheme 9).
Scheme 12.
Scheme 12.
5-Nitrotetrahydropyrimidine-2(1)-thione (36) was synthesized by treating thiourea with nitromethane and formaldehyde in pres- ence of triethylamine [16] (Scheme 15).
5-Nitrotetrahydropyrimidine-2(1)-thione (36) was synthesized by treating thiourea with nitromethane and formaldehyde in pres- ence of triethylamine [16] (Scheme 15).
Scheme 15. reduced electrophilicity of an imine (compared to an aldehyde), as well as a catalyst inhibition from basic amines present in the reac- tion. The latter recently led to the development of reaction method- ologies that use organocatalysts with excellent results. In the first catalytic enantioselective and diastereo-selective nitro-Mannich reaction a second-generation heterobimetallic complex was used as reported [28-32]. In the case of nitromethane and aryl-imines (39) the used catalyst was YbKH,[(R)-binaphthoxide]; (40) [33] to give the nitro-Mannich bases (41) in yields of 92-96% and ee of 83-91% (Scheme 17).
Scheme 15. reduced electrophilicity of an imine (compared to an aldehyde), as well as a catalyst inhibition from basic amines present in the reac- tion. The latter recently led to the development of reaction method- ologies that use organocatalysts with excellent results. In the first catalytic enantioselective and diastereo-selective nitro-Mannich reaction a second-generation heterobimetallic complex was used as reported [28-32]. In the case of nitromethane and aryl-imines (39) the used catalyst was YbKH,[(R)-binaphthoxide]; (40) [33] to give the nitro-Mannich bases (41) in yields of 92-96% and ee of 83-91% (Scheme 17).
Synthesis of B-Nitroamines via Classical Mannich and Aza-Henry Reactions In the proposed mechanism for the transformation the thiourea moiety coordinates the two oxygens of the nitro group, while the tertiary amine facilitates enolization, so that it was considered to be a bifunctional (multifunctional) organocatalyst. Thioureas them- selves have been found to be strong hydrogen bonding donors and function in a similar fashion as traditional metal containing Lewis acids [43,44] (Scheme 20).
Synthesis of B-Nitroamines via Classical Mannich and Aza-Henry Reactions In the proposed mechanism for the transformation the thiourea moiety coordinates the two oxygens of the nitro group, while the tertiary amine facilitates enolization, so that it was considered to be a bifunctional (multifunctional) organocatalyst. Thioureas them- selves have been found to be strong hydrogen bonding donors and function in a similar fashion as traditional metal containing Lewis acids [43,44] (Scheme 20).
Scheme 23.
Scheme 23.
Working hypothesis for thiourea-based organocatalysis.
Working hypothesis for thiourea-based organocatalysis.
Gold and co-workers [64] reported that contrary to older reports in literature 2,2-dinitroethanol can be liberated from its salts by treatment with mineral acid and that the product can be distilled using molecular sieves and stored for reasonably long periods of time at -20 °C. They also found that 2,2-dinitropropanediol under- goes further condensation with formaldehyde to the cyclic formal 5,5-dinitro-1,3-dioxane (70) (Scheme 31).
Gold and co-workers [64] reported that contrary to older reports in literature 2,2-dinitroethanol can be liberated from its salts by treatment with mineral acid and that the product can be distilled using molecular sieves and stored for reasonably long periods of time at -20 °C. They also found that 2,2-dinitropropanediol under- goes further condensation with formaldehyde to the cyclic formal 5,5-dinitro-1,3-dioxane (70) (Scheme 31).
Scheme 30. Feuer and co-workers [63] reported that the bismethylol deriva- tive of dinitromethane (2,2-dinitropropane-1,3-diol) (64) was read- ily prepared by treating potassium dinitromethane (69) with an excess of formaline in the presence of acetic acid. The reaction is reversed on treatment with a base (Scheme 30).
Scheme 30. Feuer and co-workers [63] reported that the bismethylol deriva- tive of dinitromethane (2,2-dinitropropane-1,3-diol) (64) was read- ily prepared by treating potassium dinitromethane (69) with an excess of formaline in the presence of acetic acid. The reaction is reversed on treatment with a base (Scheme 30).
Scheme 33.
Scheme 33.
1.1.3. Mannich Reaction of Trinitro-Methane
1.1.3. Mannich Reaction of Trinitro-Methane
Scheme 46. Mannich reactions of nitroethane tend to yield nitro bis-bases of the type (124) as has been reported [12-14]. The reaction was car- ried out with two different methods similar to the reaction of ni- tromethane. Nitroethane also reacts with aromatic amines and for- maldehyde in presence of tetraethyl-ammonium hydroxide (TEAH), to give N,N -di(aryl)-2-methyl-2-nitro-1,3-propane diamine (126) (Scheme 47).
Scheme 46. Mannich reactions of nitroethane tend to yield nitro bis-bases of the type (124) as has been reported [12-14]. The reaction was car- ried out with two different methods similar to the reaction of ni- tromethane. Nitroethane also reacts with aromatic amines and for- maldehyde in presence of tetraethyl-ammonium hydroxide (TEAH), to give N,N -di(aryl)-2-methyl-2-nitro-1,3-propane diamine (126) (Scheme 47).
Scheme 49. Also catalytic enantioselective nitro-Mannich reaction and its diastereoselective, using a second generation heterobimetallic cata- lyst have been reported. Using a second complex of nitroethane and arylimines (39) the catalyst used was YbKH,[(R)-binaphthoxide]; (40) to give the nitro-Mannich base (128) [28-32] (Scheme 49).
Scheme 49. Also catalytic enantioselective nitro-Mannich reaction and its diastereoselective, using a second generation heterobimetallic cata- lyst have been reported. Using a second complex of nitroethane and arylimines (39) the catalyst used was YbKH,[(R)-binaphthoxide]; (40) to give the nitro-Mannich base (128) [28-32] (Scheme 49).
An asymmetric nitro-Mannich reaction using N-protected a- amino esters (42) and nitroethane has been reported by Jorgensen in 2001 for the synthesis of optically active B-nitro-a-amino ester (129) in presence of the catalyst 43 [40,41] (Scheme 50). Scheme 50.
An asymmetric nitro-Mannich reaction using N-protected a- amino esters (42) and nitroethane has been reported by Jorgensen in 2001 for the synthesis of optically active B-nitro-a-amino ester (129) in presence of the catalyst 43 [40,41] (Scheme 50). Scheme 50.
Frankel and Klager [77,78], studied the reaction of 2,2- dinitropropanol (134) produced by the reaction of potassium 1,1- dinitroethane (133) with formaldehyde together with ammonia,
Frankel and Klager [77,78], studied the reaction of 2,2- dinitropropanol (134) produced by the reaction of potassium 1,1- dinitroethane (133) with formaldehyde together with ammonia,
Mannich reaction of the polynitroamines (80), (98) and 2,2- dinitropropanol (134) give the polynitro-Mannich bases (140) and (141) [67] (Scheme 55).
Mannich reaction of the polynitroamines (80), (98) and 2,2- dinitropropanol (134) give the polynitro-Mannich bases (140) and (141) [67] (Scheme 55).
While the condensation of 2,2-dinitrobutanol (157) given from the reaction of dinitropropane with formaldehyde and ammonia led to the formation of tetranitro-Mannich base (158) [77] it was ob- served that little or no Mannich type product were formed with ammonia unless the reaction mixture was buffered with ammonium acetate (Scheme 64). Mannich reaction of the dinitropropane (155) was extended by the use of glycine, hydrazine and glycine methyl ester. When hy- drazine was used as base with 2,2-dinitrobutanol (157) the symmet- rical bis condensation product (159) was isolated [77] (Scheme 65). Scheme 68.
While the condensation of 2,2-dinitrobutanol (157) given from the reaction of dinitropropane with formaldehyde and ammonia led to the formation of tetranitro-Mannich base (158) [77] it was ob- served that little or no Mannich type product were formed with ammonia unless the reaction mixture was buffered with ammonium acetate (Scheme 64). Mannich reaction of the dinitropropane (155) was extended by the use of glycine, hydrazine and glycine methyl ester. When hy- drazine was used as base with 2,2-dinitrobutanol (157) the symmet- rical bis condensation product (159) was isolated [77] (Scheme 65). Scheme 68.
Scheme 63. Scheme 67.
Scheme 63. Scheme 67.
1,3,5-Triazine derivative (174) was produced by Mannich reac- tion of the diol derivative (173) and 3,3-dinitrobutylamine with formaldehyde [66] (Scheme 71). Mannich reaction of 2,2-dinitropentanol given by the reaction of 1,1-dinitrobutane (162) with formaldehyde and ammonia led to the formation of the nitro-Mannich of type (163) [77] (Scheme 67).
1,3,5-Triazine derivative (174) was produced by Mannich reac- tion of the diol derivative (173) and 3,3-dinitrobutylamine with formaldehyde [66] (Scheme 71). Mannich reaction of 2,2-dinitropentanol given by the reaction of 1,1-dinitrobutane (162) with formaldehyde and ammonia led to the formation of the nitro-Mannich of type (163) [77] (Scheme 67).
Methyl-4,4-dinitrobutyl ester (164) reacts with formaldehyde to give pentanol derivative (165) which undergoes condensation reac- tion with ammonia or glycine to give the Mannich products (166) and (167) [77] (Scheme 68).
Methyl-4,4-dinitrobutyl ester (164) reacts with formaldehyde to give pentanol derivative (165) which undergoes condensation reac- tion with ammonia or glycine to give the Mannich products (166) and (167) [77] (Scheme 68).
1.4.2. Mannich Reaction of Other Substituted Nitroalkanes Condensation reaction of nitroethyl ester of acetic acid (168) with formaldehyde and hydrazine hydrate led to the formation of the unexpected product (169) [66] (Scheme 69).
1.4.2. Mannich Reaction of Other Substituted Nitroalkanes Condensation reaction of nitroethyl ester of acetic acid (168) with formaldehyde and hydrazine hydrate led to the formation of the unexpected product (169) [66] (Scheme 69).
Feuer and co-workers reported the synthesis and properties of the various methylol derivatives 176, 177, 179, and 180 derived from 1,4-dinitrobutane (175) and 1,5-dinitropentane (178), which further reacted with amines to give the expected Mannich products [82] (Scheme 72).
Feuer and co-workers reported the synthesis and properties of the various methylol derivatives 176, 177, 179, and 180 derived from 1,4-dinitrobutane (175) and 1,5-dinitropentane (178), which further reacted with amines to give the expected Mannich products [82] (Scheme 72).
1,4-Dinitrocyclohexane (181) gives its diol derivative (182) when reacted with formaldehyde, which readily gives the nitro- Mannich products (183) [83] as a mixture of epimers under smooth conditions (Scheme 73).
1,4-Dinitrocyclohexane (181) gives its diol derivative (182) when reacted with formaldehyde, which readily gives the nitro- Mannich products (183) [83] as a mixture of epimers under smooth conditions (Scheme 73).
Scheme 74. 2-(2-Nitro-1-phenylethyl)-2-phenyl-1,3-indandione (184a) and 2-[2-nitro-1-(indol-3-yl)ethyl]-2-phenyl-1,3-indandione (184b) reacted with formaldehyde and piperidine or morpholine to give the Mannich bases 2-(3-piperidino-2-nitro-1-phenylpropyl)-2-phenyl- 1,3-indandione (185a) and 2-(3-morpholino-2-nitro-1-phenyl pro- pyl)-2-phenyl-1,3-indandione (185b) [84] (Scheme 74).
Scheme 74. 2-(2-Nitro-1-phenylethyl)-2-phenyl-1,3-indandione (184a) and 2-[2-nitro-1-(indol-3-yl)ethyl]-2-phenyl-1,3-indandione (184b) reacted with formaldehyde and piperidine or morpholine to give the Mannich bases 2-(3-piperidino-2-nitro-1-phenylpropyl)-2-phenyl- 1,3-indandione (185a) and 2-(3-morpholino-2-nitro-1-phenyl pro- pyl)-2-phenyl-1,3-indandione (185b) [84] (Scheme 74).
Addition of primary or secondary amines to activated double bonds has been successfully used as a route to special types of Mannich bases [85,86]. In particular, it has been reported earlier [87] that the nitro-base (188), derived from nitromethane, benzalde- hyde and p-toluidine has been obtained by treating p-nitrostyrene (186) with p-toluidine, route (a) (Scheme 75).
Addition of primary or secondary amines to activated double bonds has been successfully used as a route to special types of Mannich bases [85,86]. In particular, it has been reported earlier [87] that the nitro-base (188), derived from nitromethane, benzalde- hyde and p-toluidine has been obtained by treating p-nitrostyrene (186) with p-toluidine, route (a) (Scheme 75).
Scheme 76. nitromethane [16]. Therefore, 1-(4-antipyrinylamino)-2-nitro-1- phenyl ethane (189a), 1-(2-pyridylamino) and 1-(2-pyridylamino)- 2-nitro-1-phenyl ethane (189b,c) were obtained. The formation of compounds (189a-c) has been found to take place smoothly and with yields of 80%, 72% and 82% respectively. This reaction has been extended to prepare a series of 1-acylhydrazino-2-nitro-1- phenyl ethanes (190a-c) by treating (186) with isonicotinic hydraz- ide, phenyl acetic hydrazide and benzene sulfonyl hydrazide, re- spectively (Scheme 76).
Scheme 76. nitromethane [16]. Therefore, 1-(4-antipyrinylamino)-2-nitro-1- phenyl ethane (189a), 1-(2-pyridylamino) and 1-(2-pyridylamino)- 2-nitro-1-phenyl ethane (189b,c) were obtained. The formation of compounds (189a-c) has been found to take place smoothly and with yields of 80%, 72% and 82% respectively. This reaction has been extended to prepare a series of 1-acylhydrazino-2-nitro-1- phenyl ethanes (190a-c) by treating (186) with isonicotinic hydraz- ide, phenyl acetic hydrazide and benzene sulfonyl hydrazide, re- spectively (Scheme 76).
The nitroformaldehyde aryl hydrazone derivative (198) con- densed with formaldehyde, primary and secondary amines to give 2-ary1-6-nitro-2,3,4,5-tetrahydro-1,2,4-triazine derivative (199) and 1,3-dihydrazono-1,3-dinitropropane (200) [95] (Scheme 79).
The nitroformaldehyde aryl hydrazone derivative (198) con- densed with formaldehyde, primary and secondary amines to give 2-ary1-6-nitro-2,3,4,5-tetrahydro-1,2,4-triazine derivative (199) and 1,3-dihydrazono-1,3-dinitropropane (200) [95] (Scheme 79).
Scheme 79.
Scheme 79.
Scheme 81.
Scheme 81.
Mannich bases (152) are hydrogenated to the corresponding polyamines (215). These reduction products have been reported by Johnson [84] (Scheme 85). Scheme 85.
Mannich bases (152) are hydrogenated to the corresponding polyamines (215). These reduction products have been reported by Johnson [84] (Scheme 85). Scheme 85.
Nitro-Mannich bases (149) were reduced with metals into cor- responding diamines (210) [41] which gave the free diamine (211) on hydrolysis (Scheme 83).
Nitro-Mannich bases (149) were reduced with metals into cor- responding diamines (210) [41] which gave the free diamine (211) on hydrolysis (Scheme 83).
The nitro bis-Mannich base (18) was [NR= PhCH,NH] reduced by H, and Raney Ni to give the amine (218) which on further hy- drogenation led to triamine (219) which on acetylation gave its acetylated product (220). However, on reducing the nitro bis- Mannich base (18) by using Pd/C as a catalyst the amine (219) was formed as a final product [18] (Scheme 88). The nitro group of the nitro-Mannich product 130 was readily reduced to generate anti-1,2-diamine, indicating the synthetic utility
The nitro bis-Mannich base (18) was [NR= PhCH,NH] reduced by H, and Raney Ni to give the amine (218) which on further hy- drogenation led to triamine (219) which on acetylation gave its acetylated product (220). However, on reducing the nitro bis- Mannich base (18) by using Pd/C as a catalyst the amine (219) was formed as a final product [18] (Scheme 88). The nitro group of the nitro-Mannich product 130 was readily reduced to generate anti-1,2-diamine, indicating the synthetic utility
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