Facile conversion of 1,2-dicyanobenzene into chiral bisamidines

Nucleophilic catalysis by N -acetyl cysteine permits the smooth reaction of 1,2-diarylethylene-1,2-diamines with 1,2-dicyanobenzene forming chiral bisamidines in yields up to 94% in a single step. Such bisamidines can be used as Brønsted bases or, in the protonated state, as electrophilic catalysts to promote Diels-Alder reactions with medium levels of enantioselectivity


Results and Discussion
The obvious starting material for the synthesis of bisamidines 6 is 1,2-dicyanobenzene 4 (Figure 2).This compound, however, has a tendency to form phthalocyanines.In the presence of NaOMe, for example, we observed the formation of dark blue solutions.To avoid such byproducts, we used N-acetyl cysteine as a nucleophilic catalyst. 30,31In the presence of 1.2 equivalents of this thiol, the conversion of 4 into bisamidine 6a can be achieved in 94% yield simply by refluxing with 2.2 equivalents of diamine 5a in dry methanol.No colored byproducts are formed.The yield of bisamidines however drops with increasing steric demand of the diamines (Figure 3).While diamines 5a and 5b are commercial compounds, 5c-e had to be prepared by stereoselective reactions. 32In the present study, we have applied the method of Chin based on a [3,3]sigmatropic rearrangement of bisimines formed from aldehydes and (R,R)-diamine 5b yielding the (S,S)configurated products 5c-e. 33Crystals of high quality could be obtained by slow diffusion of n-pentane into a solution of bisamidine 6a in EtOAc.The crystal structure (Figure 4 and Supporting Information) shows the close proximity of the amidine nitrogens that, in the doubly protonated form, may accommodate and activate a carbonyl guest molecule.Initially we speculated the OH groups present in bisamidine 6b might form additional hydrogen bonds with a substrate thus causing increased electrophilic activation.NMR evidence, however, does not support this idea: The NH signals of the other bisamidines in DMSO appear around 8.50 ppm and shift to 12.0 ppm upon protonation with HCl.In the 2-hydroxyphenyl analog, the NH signal moves from 9.61 (6b) to 11.26 ppm (7b).Interestingly, bisamidine protonation also induces a major shift of the OH signal from 3.17 (6b) to 10.28 ppm (7b) indicating hydrogen bonds between NH as donor and OH as acceptor.A similar type of intramolecular H-bonds is well known from TADDOLs. 34Thus, in contrast to other bisamidine hydrochlorides 7 and BAr F 4 salts 8, OH but no longer NH groups are expected to act as H-bond donors in the 2-hydroxyphenyl analogs 7b and 8b.
The Diels-Alder reaction of Dane's diene 9 and diketone 10 has been suggested decades ago as a synthetic approach towards steroids (Figure 5). 35Depending on solvents, the cycloaddition may preferentially form the constitutional isomers rac-13 or rac-14 36 which slowly tautomerize forming compounds rac-15 and rac-16.In the presence of chiral Lewis acids, isomer 13 can be obtained with excellent constitutional and enantioselectivity.This reaction represents the key step in one of the total syntheses of estrone. 37Hydrogen bond mediated association of diketone 10 to amidinium ions also accelerated the cycloaddition with Dane's diene 38 and low to medium levels of enantioselective control were observed in the presence of chiral amidines. 39The BAr F 4 salt of bisamidine 1 (100 mol %) for example selectively formed the correct constitutional isomer ent-15 with ee values ranging from 14% at 5 °C, 25% at -16 °C and up to 47% at -70 °C. 25sing a specifically designed axially chiral amidine, the reaction could be further optimized yielding 24% for the complete multistep synthesis from Dane's diene 9 to enantiopure (+)-estrone. 40In the present study, we have repeated this well established reaction in the presence of BAr F 4 salt 8a (20 mol %): In toluene at -20 °C diketone ent-13 was formed in 65% yield with 28% ee.This result comes close to the selectivities observed for bisamidine 1.However, it is clearly inferior to the variant using the axially chiral amidine.
Cycloadditions of Dane's diene and compounds 11 and 12 are further options to synthesize (+)-estrone from diene 9.Both reactions can be catalyzed with excellent stereoselectivities by protonated chiral oxazaborolidines. 41,42Although mono carbonyl groups should nicely fit into the cationic cleft of BAr F 4 salt 8a, we could not detect any product from the reaction of 9 and 11.Similarly, even after 3 days at 40 °C (10 mol % 8a, CH2Cl2) not more than 9% of the racemic cycloadduct could be isolated from a test reaction of 9 and cyclopentenone 12. Thus, in comparison to protonated oxazaborolidines, the bisamidinium salts seem to be less potent electrophilic catalysts.Deprotonation of anthrone 17 forms an electron rich diene which readily undergoes Diels-Alder reactions with dienophils such as 18 (Figure 6). 435][46][47][48][49] We have previously used this reaction to evaluate the chiral guanidine 3 and observed ee values of product 19 around 30%. 28 Based on this protocol, we have now tested bisamidine 6a.In the presence of 10 mol % of 6a in THF, 86% of product 19 with 46% ee could be isolated.No subsequent base induced retro aldol reaction occured as observed in the presence of guanidine 3. The ee of product 19 increased to 84% upon recrystallization.

Conclusions
By nucleophilic catalysis with N-acetyl cysteine, the conversion of 1,2-dicyano benzene 4 into chiral bisamidines becomes a simple and effective procedure.Recent advances in the synthesis of enantiopure 1,2disubstituted ethylene-1,2-diamines further increase the usefulness of this method. 32,33The resulting products 6a-e have some potential as chiral Brønsted bases.When converted into salts with non-coordinating counterions, BAr F 4 salts 8a-e can also play a role as chiral hydrogen bond donors.Like Lewis acids, they can activate substrates for Diels-Alder reactions.However, they are clearly less potent as protonated oxazaborolidines.Furthermore, bisamidines 1 and 6 may be of interest as chiral ligands in coordination chemistry.

Figure 1 .
Figure 1.Structures of the chiral bisamidines 1 and 2 and of the guanidine 3.