Modular synthesis of cyclic cis-and trans-1 , 2-diamine derivatives †

Structurally diverse carbocycles with two vicinal nitrogen-substituents were prepared in expedient threecomponent reactions from simple amines, aldehydes, and nitroalkenes. trans,trans-6-Nitrocyclohex-2enyl amines were obtained in a one-pot domino reaction involving condensation, tautomerisation, conjugate addition, and nitro-Mannich cyclisation. Upon employment of less nucleophilic carboxamides, a concerted Diels–Alder cycloaddition mechanism operated to give the corresponding cis,trans-nitrocyclohexenyl amides. Both types of substituted carbocycles offer ample opportunities for chemical manipulations at the core and periphery. Ring oxidation with MnO2 affords substituted nitroarenes. Reduction with Zn/HCl provides access to various transand cis-diaminocyclohexenes, respectively, in a straight-forward manner. With enantiopure secondary amines, a two-step synthesis of chiral nitrocyclohexadienes was developed (82–94% ee).


Introduction
Functionalised cyclohexanes are one of the most prevalent molecular architectures in nature and synthesis.Today, a plethora of synthetic procedures is available to provide access to various saturation states and peripheral substitution patterns.The majority of syntheses involve functionalisation of already cyclic precursors whereas de-novo-syntheses of functionalised cyclohexanes from two or more acyclic starting materials exhibit much higher modularity and provide access to a large chemical space. 1 The most prominent examples of such intermolecular cyclisation reactions include cyclo-additions 2 and many variants of sequential condensation-addition reactions with carbonyl compounds. 3Heteroatom(X)-substituted cyclohexanes are arguably the most interesting structures for active pharmaceutical ingredients and fine chemical building blocks due to the distinct stereoelectronic properties and chemical reactivities of polar C-X bonds and the available lone pairs at X. 4 Aminodienes were widely used in method developments, syntheses of pharmaceutically active molecules, natural products and materials (Scheme 1). 5 Aminodienes can be easily prepared from condensations of unsaturated carbonyl compounds and amines and exhibit high reactivity in normal-electron demand cycloadditions and nucleophilic additions due to their high-lying HOMO (highest occupied molecular orbital). 6Further N-based substituents can be incorporated into the product structure by employment of α-electrophilic nitrogen compounds.Nitroolefins are a readily available class of vinylogous nitrogenous electrophiles with widespread applications in Michael-type additions and cycloadditions. 7We envisioned a domino process involving initial condensation of unsaturated aldehydes with amines followed by selective cyclisation of the resultant 1-amino-1,3-dienes with nitroolefins. 8Such strategy would provide an expedient access to highly functionalised cyclohexenes containing two chemically orthogonal N-based substituents in vicinal positions (NR 2 , NO 2 ).1,2-Diaminocyclohexane motifs constitute important building blocks of pharmacologically active molecules, fine chemicals and catalysts (Scheme 2). 9he electronic nature of the intermediate aminodienes can be easily tuned by the introduction of various N-substituents.It has been demonstrated that highly nucleophilic aminodienes bearing electron-donating (EDG) alkyl substituents engage in rapid Michael-type additions to electrophiles. 10 However, a change of mechanism can be effected by electron-withdrawing (EWG) N-substituents.1-N-Acyl-amino-1,3-butadienes undergo concerted [4 + 2]-cycloadditions with electron-deficient dienophiles. 6Here, we report the viability of controlling the reaction mechanism and stereoselectivity by the employment of secondary amines (R 1 = EDG) or less nucleophilic acylamines (R 1 = EWG) in three-component cyclisations with α,β-unsaturated aldehydes and nitroalkenes to give trans-or cis-1,2-diaminocyclohexenes (Scheme 3).

Synthesis of trans-nitrocyclohexenyl amines
As an extension of earlier work on functionalised aminocyclohexenes, 8 we optimised reaction conditions for the three-component cyclisation of secondary amines, α,β-unsaturated aldehydes and nitroalkenes.We chose pyrrolidine, crotonaldehyde and β-nitrostyrene as model substrates (Table 1).High selectivities were observed in toluene as solvent and upon slow addition of a slight excess of the aldehyde. 10apid aldehyde addition resulted in oligomer formation.The three-component cycloadduct 1-(6-nitro-5-phenylcyclohex-2-enyl)pyrrolidine (1) was obtained with high thermodynamic stereocontrol (trans,trans/cis,trans = 19/1).The minor diastereomer exhibited a cis-relation of the amino and nitro groups.The preferential formation of the all-trans stereoisomer and the observation of an identical outcome from reactions with (Z)-β-nitrostyrene suggest the operation of a stepwise mechanism (Scheme 4). 10 Initial condensation between the amine and aldehyde gives rise to the formation of an equilibrating mixture of imine, enamine and aminal derivatives, of which the aminodiene undergoes reversible conjugate addition to the nitroolefin. 11Subsequent nitro-Mannich ring-closure affords the thermodynamic product containing three vicinal equatorial substituents. 12heme 2 Applications of trans-(top) and cis-1,2-diaminocyclohexanes.

Scheme 3
The stereoselectivity switch: amines vs. N-acyl amines.We extended the reaction conditions to various other amines, aldehydes and nitroolefins (Table 2). 13The trans,transisomers were preferentially formed in diastereomeric ratios of >10/1. 10Diastereomeric ratios (dr) were assigned based on high-resolution 1 H-NMR spectra.The trans-configurations of the vicinal amino/nitro and nitro/aryl groups, respectively, at the cyclohexene result in dihedral angles of 170-180°and 3 J HH coupling constants of 10-12 Hz.Employment of morpholine gave lower dr values (13, 14).Products with substituents in the 2-position formed rather slowly (15, 18, 19), possibly due to steric congestion with the amine substituent in the planar aminodiene species.Similarly, crotonaldehydes bearing γ-substituents reacted very slow due to steric inhibition of the Michael-type attack onto β-nitrostyrenes (14, 19).The latter  trend allowed selective conversion of citral to the 3-alkyl cycloadduct via the terminal aminodiene isomer (20, kinetic control).Cyclisation with diallylamine proceeded highly effective to give 21 which allows facile access to the free amine.

Reactions of trans-nitrocyclohexenyl amines
We have studied various structural manipulations at the core and periphery of the synthesised cycloadducts.Eliminations, oxidations, and reductions were realised to give access to diene, arene and diamine derivatives (Scheme 7).
Oxidation of nitrocyclohexenyl amines with manganese dioxide (MnO 2 ) resulted in unselective decomposition involving dehydrogenation and amine or nitrite elimination. 15imilarly, various Nef conditions (base (NaH/n-BuLi), then acid (HCl); TiCl 3 ; KMnO 4 ) 16 afforded complex mixtures.In no case was the desired ketone detected (GC-MS, IR).The solid cycloadducts appeared to be stable toward air and water; their solutions in dichloromethane or toluene withstood exposure to weak acids and bases.The equatorial amino group inhibits base-mediated elimination (E1cb pathway).However, benzoic acid effected slow elimination of pyrrolidine to nitrocyclohexadienes (Scheme 8).Stronger acids (HCl, TFA) allowed elimination of prolinols to give the nitrocyclohexadienes 36, 37, 39 and 41 in good enantiomeric purity (82-94% ee, Table 3). 13mine/acid-co-catalyzed reactions of aldehydes and nitroalkenes gave low selectivities. 13,17he nitrocyclohexadienes were prone to oxidation under aerobic conditions but could be stored under nitrogen at 0 °C for days.However, selective dehydrogenation would render a   straight-forward access to substituted nitroarenes.Several methods for the aromatisation of carbocycles were reported (Pt, Pd, Ni catalysts, elemental sulfur or selenium, quinones, oxygen, MnO 2 , SeO 2 etc.). 18We obtained good yields of 2-aryl nitrobenzenes with 5 equiv.MnO 2 at 80 °C (Scheme 9).This strategy allows the three-step synthesis of 2-nitrobiaryls.
The reduction of a nitro function to a primary amine is an especially useful manipulation. 19Application of such selective manipulation of one substituent of our three-component cycloadducts renders an expedient access to carbocyclic 1,2trans-diamines (Scheme 10).The overall two-step sequence thus involves stereoselective three-component cyclisation with nitroolefins followed by reduction of the nitro substituents in with Zn/HCl in ethanol.The nitrocyclohexenyl amines 1, 11 and 21 were cleanly converted to the corresponding diamine derivatives 48-50 in excellent yields with complete retention of stereochemistry. 13e stereoselectivity switch: synthesis of cis-nitrocyclohexenyl amides The nature of the N-substituents controls all three elemental steps in the Michael/Mannich-type mechanism with amines.
The nucleophilicity of the amine directly affects the rate of condensation with the α,β-unsaturated aldehyde and the nucleophilic reactivity of the aminodiene intermediate at the terminal δ-position (Scheme 4).Stereoelectronics also govern the formation of the 1-amino-2-nitroethylene moiety via a formal nitro-Mannich reaction.It is therefore obvious that fine-tuning of the N-substituents directly effects the cyclisation mechanism.Literature reports on Diels-Alder mechanisms of cyclisations of 1-N-acylaminodienes with electron-deficient olefins are in full accord with this notion. 5,6The significantly lower nucleophilicity of carboxamides (vs.amines) favours an orbital-controlled, more or less concerted, cycloaddition pathway (over a stepwise charge-controlled Michael-Mannich pathway).In order to provide a stereo-chemical complement of the three-component synthesis of trans-nitrocyclohexenyl amines, we have replaced the secondary amines with simple carboxamides.Indeed, formation of the cis-nitrocyclohexenyl amides was observed in high diastereoselectivities (Scheme 11).The major product results from an endo-selective [4 + 2]-cycloaddition and bears the carboxamide in axial position.Despite the presence of an axial hydrogen atom at the CH-NO 2 moiety, the low propensity of carboxamide to act as leaving group under the reaction conditions prevents E2-type elimination (cf.Scheme 6).Table 4 shows a selection of cycloadducts prepared from three-component reactions of carboxamides, unsaturated aldehydes and nitrostyrenes. 13he initial amide/aldehyde condensation required elevated Scheme 8 Acid-mediated elimination of pyrrolidine.temperature (100 °C).The trans,trans-N-acyl-6-nitrocyclohex-2enyl amines were formed as minor stereoisomers.
The relative configurations were assigned based on the 3 J HH coupling constants from 1 H-NMR spectra.Crystal structure analyses of cis,trans-51 and trans,trans-51 confirmed the relative configurations of the substituents (Fig. 3).

Reactions of cis-nitrocyclohexenyl amides
Similar post-synthesis modifications as for the amine series were evaluated with the synthesised cis-nitrocyclohexenyl amides.We were delighted to observe that direct oxidation of 57 with MnO 2 proceeded with good selectivity (Scheme 12). 15owever, the related C3-substituted cyclohexenyl amines 51, 53 and 54 exhibited poor dehydrogenation selectivity.Competing NO 2 -elimination was observed which resulted in mixtures of nitro-acetanilides (62-64) and benzoxazoles (65-67, Scheme 13). 20e have also applied the Zn/HCl reduction protocol to the cycloaddition products.19b Clean reduction of the nitro substituents gave the corresponding cis-diamines in excellent yields with retention of stereochemistry (Scheme 14).The overall Scheme 11 Endo-selective Diels-Alder mechanism with carboxamides.a Amide, aldehyde, β-nitrostyrene (each 3 mmol) in PhMe, 100 °C, 24 h.
Scheme 13 Oxidative formation of acetanilides and benzoxazoles.
Scheme 14 Synthesis of cis-1,2-diaminocyclohexenes.synthetic strategy allows the straight-forward preparation of carbocyclic 1,2-diamine derivatives with high cis-stereocontrol in a modular manner starting from simple amide, aldehyde, and nitroethylene precursors.

Conclusions
We have applied an operationally simple one-pot protocol to the synthesis of multi-substituted carbocycles upon three-component reaction of amines, aldehydes, and nitroalkenes.The synthesis is highly modular, operates under practical reaction conditions with cheap starting materials (20-100 °C, toluene as solvent), and tolerates ester, ether, chloro, fluoro, thioether, and carbamate substituents.Upon wide variations of the starting materials, the synthesis allows the access to diverse cycloadducts in combinatorial fashion.The electronic properties of the employed amine component dictate the reaction mechanism and product stereochemistry.Reactions with secondary amines proceed via reversible Michael/nitro-Mannich reactions 12 to give trans,trans-6-nitrocyclohex-2-enyl amines.
The less nucleophilic carboxamides trigger a Diels-Alder-type mechanism toward N-acyl cis,trans-6-nitrocyclo-hex-2-enyl amines. 6Reduction with Zn/HCl afforded the corresponding 1,2-diamine derivatives.The tri-, tetra-, and penta-substituted carbocycles constitute derivatives of cis-and trans-1,2-diaminocyclo-hexanes which are key building blocks of various natural products, fine chemicals, drugs and catalysts. 9In the presence of enantiopure prolinols, one enantiomerically pure set of diastereomers was formed. 21Acid-mediated amine eliminations resulted in the formation of chiral cyclohexadienes.Oxidative aromatisations proceeded with MnO 2 to give 2-nitrobiaryls.It is important to note that the presence of two chemically orthogonal N-based substituents (NHR, NO 2 ) allows various selective manipulations of the general structure.Likewise, the electronic polarisation ( push-pull substitution) is of high relevance to photoactive materials.

General
Unless otherwise noted, all synthesised cycloadducts are racemic mixtures of one diastereomer.For reasons of clarity, only one enantiomer is depicted in the schemes.For atom numbering used in the spectroscopic data assignment, see chemical structures in schemes and tables above.All chemicals were purchased from commercial suppliers and used without further purification unless otherwise noted.Solvents were dried and distilled before use.Chiral HPLC spectra were recorded on a Merck Hitachi HPLC with D-6000 interface, L-4000A UV-detector, L-6200A intelligent pump, and a Merck differential refractometer RI-71.Mixtures of n-hexane and 2-propanol were used as mobile phase.Crystal structure data were collected on a Nonius Kappa CCD diffractometer using monochromated Mo-Kα radiation, structures refined by shelxs97 and shelxl97 (Table 5). 22neral procedures (selected examples) 13 Three-component cyclisation with secondary amines.A 50 mL test tube was charged with the sec-amine (4 mmol), the nitroalkene (4 mmol) in toluene (10 mL).The mixture was stirred at 30 °C and the aldehyde (4.8 mmol) was slowly added over 2 h.After another 18 h, the solvent and other volatile compounds were removed in oil pump vacuum.The crude product was purified by SiO 2 flash column chromatography (ethyl acetate (ea)/cyclohexane (ch)) or crystallised from solution (for details see below).

Scheme 5
Scheme 5 Rate of aldehyde addition governs selectivity.

Table 2
Three-component synthesis of trans,trans-nitrocyclohexenyl amines a

Table 3
Acid-mediated elimination of chiral prolinols

Table 4
Three-component synthesis of cis-nitrocyclohexenyl amides a