ortho-Ketimines of 1,8-Bis(dimethylamino)naphthalene: Synthesis, Hydrolytic Stability and Transfer of Basicity from Proton Sponge Moiety to the Imino Function

Abstract

A series of 2-ketimines and 2,7-diketimines of 1,8-bis(dimethylamino)naphthalene (proton sponge, DMAN) have been obtained and converted into the corresponding ketones via acidic hydrolysis. Investigation of structural and spectral properties of DMAN-based imines led to the conclusion that their unusual hydrolytic stability results from a combination of different factors the most important of which is a strong electron-donor effect of peri-dimethylamino groups.Imines are of common interest in organic synthesis, medicinal chemistry, and biochemistry. 1 However, in many cases handling imines, especially those with an unsubstituted NH group, is difficult due to the ease of their hydrolysis. Recently, we obtained two 2-ketimino derivatives of 1,8-bis(dimethylamino)naphthalene (1a, proton sponge, DMAN), namely 3a,b, and turned our attention to their enhanced hydrolytic stability. 2 To shed light on the origin of this phenomenon, in the present work we have prepared a number of new representatives of these compounds with widely varied structure and studied their properties (Scheme 1). In particular, we have focused on their hydrolytic activity, molecular structure, and mutual influence of the formally conjugated peri-NMe 2 and imino groups.Monoketimines 3a-f were synthesized in 60-89% yields by combining aryl and hetaryl cyanides with 1,8-bis(diamino)-1-lithionaphthalene (2, 2-Li-DMAN) generated from bromide 1b [Scheme 1 (a)]. 3 The reaction proceeded with more difficult for alkyl cyanides, apparently due to the enhanced acidity of their α-CH bonds causing protolysis of 2 [compare with the reactions of 2-lithium and 2,7-dilithium derivatives of 1,8-bis(dimethylamino)naphthalene with acetyl chloride 3 ]. Thus, on treatment of 2-Li-DMAN 2 with acetonitrile or valeronitrile the corresponding imines were not formed at all and only unsubstituted DMAN 1a was isolated from the reaction mixture. Use of tert-butyl cyanide, containing no α-CH bonds, was more successful and the yield of imine 3f reached 43%. Scheme 1To overcome this difficulty, we were forced to employ the reversed approach to synthesize alkyl(naphthyl)ketimines 3f-h by the interaction of ortho-cyanide 4 with alkyllithium reagents [Scheme 1 (b); notably the use of alkylmagnesium halides for this purpose failed]. To our satisfaction, imines with butyl and methyl groups 3g,h were obtained in good yields. Even for imine 3f containing the tert-butyl group the protocol increased the yield by 12% to 55%. Actually, both approaches were merged when 2-Li-DMAN 2 was allowed to react with nitrile 4 to produce symmetrical binaphthylketimine 3i (44%). Taking into account the higher nucleophilicity of 1,8-bis(dimethylamino)-2,7-dilithionaphthalene (6, 2,7-Li 2 -DMAN) in comparison with 2-Li-DMAN 2 and to confirm that two NMe 2 groups can stabilize two ortho-imino functionalities towards hydrolysis, it was also important to synthesize 2,7-diketimines of 1a. Interaction of 2,7-Li 2 -DMAN 6 with benzonitrile or 4-methoxybenzonitrile gave diimines 7a,b in 14% and 11% yields, respec...

1,8-Bis(dimethylamino)naphthyl-2-ketimines: Inside vs outside protonation

“…In other words, in the case of 7b’ , steric pressure of the trimethoxyphenyl substituent facilitates the 1-NMe 2 group’s out -inversion which is stabilised by an IHB, forming N(sp 3 )/N(sp 2 ) type of proton sponges, which were recently reported in our paper [18]. It was previously shown that the in,out -conformation can be stabilised by placing the following functionalities in position 2(7): tertiary alcoholic groups which are able to form the O–H···N IHB [16–17 19], bulky substituents rendering a steric pressure onto the 1-NMe 2 group [7,20], or a metal atom coordinating the NMe 2 group as a ligand causing its inversion [21] (Scheme 9). A possibility of out -protonation of 1,8-bis(dimethylamino)naphthalene was discussed in our recent paper [15], while it is experimentally demonstrated here for the first time.…”

“…Indeed, the X-ray analysis shows that compound 6a in the solid state exists in the E -form stabilised by the N−H···O intramolecular hydrogen bond (IHB) with an ortho -OMe group (Fig. 2), while compound 4a , as it was revealed in our previous work [7], exists exclusively as a Z -isomer (Fig. 2).…”

“…Target compounds 4a – 7a were synthesised by techniques previously developed in our laboratory (Scheme 4) [7–8]. Compounds 4a – 6a were obtained by the treatment of the ortho -lithium derivative 8 with the corresponding nitrile (path a).…”

“…In our recent work, we observed for the first time that the ortho -ketimino group in 4a can compete with the proton sponge moiety for the proton, which results in the formation of equilibria between the forms 4b (protonated to the proton sponge fragment) and 4b’ (protonated to the imino group) in the DMSO solution (Scheme 3) [7]. The aim of the present work is to investigate the major factors influencing the effective basicity of the imino functionality.…”

Non-covalent Li···H interaction in the synthesis of peri-disubstituted naphthalene proton sponges.

“…Organometallics play a key role in the preparation of naphthalene proton sponges, which are widely known for their outstanding basicity (pKa (1) = 12.1 in H2O [5], 18.62 in MeCN [6], 7.5 in DMSO [7]). Dozens of ortho-, para-and even meta-derivatives of 1 were obtained from organolithiums 2-6 (Scheme 1) [8][9][10], which not only made it possible to establish the relation between structure and basicity of these interesting compounds [11,12], but also revealed their unusual reactivity leading to the formation of key heterocyclic systems, such as indoles [10,13], pyrazoles [14], isoxazoles [14], quinolines [15], quinasolines [16]. Moreover, in the past two decades, naphthalene proton sponges drew additional attention as a convenient core for the development of superbasic heterogeneous catalysts [17][18][19][20][21].…”