Functionalization of Aliphatic Amines
Scheme 1: Syntheses of β-functionalized aliphatic amines
5.3 Reaction of aliphatic acyclic amines with aldehydes
During the development of direct α-C-H arylation of amine, pyrrolidine was reacted in the presence of 9-fluorenone and p-nitrophenol in refluxing benzene. However, it was observed that, instead of desired C-H arylated product, compound 5.18 was formed with 26% yield (eq.
6). It was realized that the reaction would provide the opportunity to achieve direct β-C-H
Chapter 5
74 functionalization of aliphatic amines under simple reaction conditions without using metal- or oxidant-based reagents or catalyst.30 Furthermore, the method will have potential to provide privileged structures in single step without using pre-oxidized or pre-functionalized substrates.
Therefore, investigation of the reaction was performed further for acyclic saturated secondary amines as the potential substrates for β-C-H functionalization. A reaction of N,N- dibutylamine 5.19 with p-chloro benzaldehyde was performed under the reaction conditions optimized for N-heterocycles. However, the homologated unsaturated aldehyde 5.21 was isolated with 50% yield instead of desired unsaturated imine 5.20 (eq. 7). Unsaturated aldehydes were widely used in organic synthesis for the preparation of bioactive natural and unnatural compounds.31 Specially, 2-alkyl substituted cinnamaldehyde derivatives find direct application in perfume and cosmetic industry.32 Syntheses of these compounds, primarily via cross-aldol reaction, remained inefficient due to the associated undesired self-condensation and polymerization reaction.33 For example, cross-aldol reactions with acetaldehyde enolates yielded self-condensation products with aliphatic aldehyde partners.34 This difficulty can be circumvented with C-silated imines35 but the preparation and purification of these C-silated imines are difficult.Wittig,36 Horner-Emmons,37 and Peterson type reagents38 are generally not compatible with base sensitive functional groups and sometimes require additional synthetic steps to generate enals. Methodologies utilizing transmetalation strategy often meets with incompatibility with other functional groups. These complications could be potentially avoided during their syntheses via this operationally simple method utilizing amine as the formal aldol-donor.
As the best yield was observed for β-functionalization of aliphatic amines in xylene at reflux temperature, the same solvent was utilized for the transformation.30 Various reactions were performed changing the conditions like temperature and equivalent of dibutylamine.
Amount of additive (3,5-dinitro benzoic acid) also varied for the improvement of yield of desired compound. When 2.5 equivalent of dibutylamine and 1 equivalent of aldehyde was reacted in presence of 0.6 equivalent of additive, 50% of product 5.21a was isolated as the highest yield. When no additive was added, only 24% of desired product was isolated. Using
Synthesis of Conjugated Aldehydes ... Through Direct β-C(sp3)-H Functionalization of Aliphatic Amines
75 of 4 eq. of dibutylamine gave slightly lower yield of target product (43 %) (Table 1).
Table 1: Reaction optimization for homologation of aldehydes
Entry Dibutyl amine (equiv.)
Additives (equiv.)
Solvent,Temp Time (h)
Yield (%) 1 2.5 3,5-(NO2)2PhCO2H(0.6) xylene, 140 oC 26 50 2 1 3,5-(NO2)2PhCO2H(0.6) xylene, 140 oC 26 39
3 2.5 ….. xylene, 140 oC 26 24
4 2.5 3,5-(NO2)2PhCO2H (1) xylene, 140 oC 26 48 5 2.5 3,5-(NO2)2PhCO2H(0.6) xylene, 140 oC 26 24 6 4.0 3,5-(NO2)2PhCO2H(0.6) xylene, 140 oC 26 43
After having the initial result, it was realized that the reaction will provide the opportunity to achieve direct homologation of aromatic aldehyde from aliphatic amines under simple reaction conditions without using metal-catalyst or oxidant-based reagents. Furthermore, the method will have potential to provide privileged structures in a single step without using pre- oxidized or pre-functionalized substrates. Therefore, the reaction was investigated further for a wide range of substrates. Different dialkylamines were reacted with various aldehydes providing structurally diverse 2-alkylated cinnamaldehyde derivatives 5.21a-r (Scheme 2, eq. 8). Many of them can be considered as potential aroma substances for use in fragrance industry. Particularly, hexyl cinnamal (5.21m) is a natural aroma found in essential oil of chamomile and used in perfume. Aldehydes with or without electron donating or electron withdrawing substituent in the aryl moiety were equally efficient in providing corresponding conjugated aldehyde. Electron donating group present in aromatic ring (5.21a-c) gave good yield. Aromatic aldehyde containing nitro- and N,N-dimethyl amine in para- position gave lower yield (5.21d, 5.21f). Relatively lower yield of the product 5.21g (34%) was obtained using anthranaldehyde. Dihexylamine, dioctyl amine and dodecyl amine were utilized and gave good yields when reacted with different aromatic aldehydes (5.21i-o). Hexyl cinnamal (5.21m) which is used as a natural aroma in perfume industry was successfully prepared by the reaction of benzaldehyde and dioctylamine.
Chapter 5
76 Scheme 2: Preparation of unsaturated aldehydes
Similarly, 2-phenyl cinnamaldehyde derivative was also employed successfully to obtain conjugated aldehydes (5.21q-r) with good yields. Conjugated aldehydes were found to have thermodynamically more stable E-geometry in the double bond. Geometry of 5.21b and 5.21q were assigned from the NOE studies (see in Chapter 7, Experimental Section). However, mixtures of E- and Z-isomers were found for aldehyde 5.21g and dienals 5.21q-r.
5.4 Scope of β-functionalization of acyclic amines with salicylaldehydes
Various reports for the preparation of coumarin and their derivatives have appeared in literature.39 Coumarin derivatve 5.23 can be afforded by means of Pechmann condensation,39a starting from a phenol and a carboxylic acid or ester 5.22 in the presence of AlCl3 (Scheme 3, eq. 9). McNab and co-workers described a Wittig type reaction of the aldehyde 5.24 with the phosphoranes 5.25 by flash vaccum pyrrolysis to give coumarin derivative 5.26 (Scheme
Synthesis of Conjugated Aldehydes ... Through Direct β-C(sp3)-H Functionalization of Aliphatic Amines
77 3, eq. 10). 40 In 2011, a number of 3-benzyl-chromen-2-ones derivative 5.28 were synthesized by Chen and co-workers by N-heterocyclic carbene- catalyzed (5.29) selective condensation reactions between cinnamaldehydes 5.27 and salicylaldehyde (Scheme 3, eq. 11).41In 2015, Wang and co-workers developed Cp*Co(III)-catalyzed annulations of 2-alkenylphenols 5.30 with CO for the synthesis of coumarin derivatives 5.31 (Scheme 3, eq. 12).42 The drawback of the above methodologies include either use of metal reagent/catalyst or requirement of very high temperature to obtain the desired product.