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

Anna K. Weber a, Josef Schachtner b, Robert Fichtler a, Timo M. Leermann a, Jörg M. Neudörfl a and Axel Jacobi von Wangelin *ab
aDepartment of Chemistry, University of Cologne, Germany
bInstitute of Organic Chemistry, University of Regensburg, Germany. E-mail:; Fax: +49 (0)941 943 4617; Tel: +49 (0)941 943 4802

Received 4th May 2014 , Accepted 6th June 2014

First published on 9th June 2014

Structurally diverse carbocycles with two vicinal nitrogen-substituents were prepared in expedient three-component reactions from simple amines, aldehydes, and nitroalkenes. trans,trans-6-Nitrocyclohex-2-enyl 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 trans- and cis-diaminocyclohexenes, respectively, in a straight-forward manner. With enantiopure secondary amines, a two-step synthesis of chiral nitrocyclohexadienes was developed (82–94% ee).


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-additions2 and many variants of sequential condensation-addition reactions with carbonyl compounds.3 Heteroatom(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
image file: c4ob00913d-s1.tif
Scheme 1 1-Amino-1,3-butadienes in organic synthesis.

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).6 Further 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.7 We 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.8 Such strategy would provide an expedient access to highly functionalised cyclohexenes containing two chemically orthogonal N-based substituents in vicinal positions (NR2, NO2). 1,2-Diaminocyclohexane motifs constitute important building blocks of pharmacologically active molecules, fine chemicals and catalysts (Scheme 2).9

image file: c4ob00913d-s2.tif
Scheme 2 Applications of trans- (top) and cis-1,2-diaminocyclohexanes.

The 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.6 Here, we report the viability of controlling the reaction mechanism and stereoselectivity by the employment of secondary amines (R1 = EDG) or less nucleophilic acylamines (R1 = EWG) in three-component cyclisations with α,β-unsaturated aldehydes and nitroalkenes to give trans- or cis-1,2-diaminocyclohexenes (Scheme 3).

image file: c4ob00913d-s3.tif
Scheme 3 The stereoselectivity switch: amines vs. N-acyl amines.

Results and discussion

Synthesis of trans-nitrocyclohexenyl amines

As an extension of earlier work on functionalised aminocyclo-hexenes,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.10
Table 1 Selected optimisation experimentsa

image file: c4ob00913d-u1.tif

Entry Conditions Yieldb [%]
a Optimised conditions: Pyrrolidine (2 mmol), β-nitrostyrene (2 mmol), PhMe (3 mL), slow addition of crotonaldehyde (2.4 mmol in 1 mL PhMe) over 2 h, 30 °C, 20 h. b GC yields vs. internal hexadecane. c 60 °C. d Diastereomeric ratio (dr). e 83% isolated yield.
1 CH3CN 27 (40)c
2 CH2Cl2 58
3 DMF 72
4 PhMe 76
5 PhMe, 2 equiv. aldehyde 68
6 PhMe, 2 equiv. amine 29
7 PhMe, slow addition (∼2 h) of 1.2 equiv. aldehyde 90 (19/1)d,e
8 As entry 8, but with pyrrolidine/benzoic acid (1/1) 64 (18/1)d

Rapid 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.11 Subsequent nitro-Mannich ring-closure affords the thermodynamic product containing three vicinal equatorial substituents.12

image file: c4ob00913d-s4.tif
Scheme 4 Nitro-Mannich mechanism with secondary amines.

We extended the reaction conditions to various other amines, aldehydes and nitroolefins (Table 2).13 The trans,trans-isomers were preferentially formed in diastereomeric ratios of >10/1.10 Diastereomeric ratios (dr) were assigned based on high-resolution 1H-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 3JHH 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. Highly electrophilic methyl 2-methyl-4-oxobut-2-enoate dimerised upon rapid aldehyde addition (Scheme 5).14

image file: c4ob00913d-s5.tif
Scheme 5 Rate of aldehyde addition governs selectivity.
Table 2 Three-component synthesis of trans,trans-nitrocyclohexenyl aminesa

image file: c4ob00913d-u2.tif

Major isomer Substituents   dr Yieldb [%] Major isomer Substituents   dr Yieldb [%]
a Amine (4 mmol), aldehyde (1.2 equiv.) and nitroalkene in PhMe were stirred for 20 h at 30 °C. b Isolated yields of isomer mixtures. c After treatment with SiO2 or wet CDCl3. d Major diastereomer shown, other isomers not assigned. e From citral. f Ar = 3,5-bis(trifluoromethyl)phenyl.
image file: c4ob00913d-u3.tif R′′ = Ph 1 19[thin space (1/6-em)]:[thin space (1/6-em)]1 83 image file: c4ob00913d-u4.tif 20 6[thin space (1/6-em)]:[thin space (1/6-em)]1 82e
2,3-(MeO)2–C6H3 2 15[thin space (1/6-em)]:[thin space (1/6-em)]1 69
3,4-(OCH2O)–C6H3 3 34[thin space (1/6-em)]:[thin space (1/6-em)]1 59
2,6-Cl2–C6H3 4 30[thin space (1/6-em)]:[thin space (1/6-em)]1c 66
image file: c4ob00913d-u5.tif R′′ = Ph 5 28[thin space (1/6-em)]:[thin space (1/6-em)]1 94 image file: c4ob00913d-u6.tif 21 35[thin space (1/6-em)]:[thin space (1/6-em)]1 93
2,3-(MeO)2–C6H3 6 14[thin space (1/6-em)]:[thin space (1/6-em)]1 62
3,4-(OCH2O)–C6H3 7 34[thin space (1/6-em)]:[thin space (1/6-em)]1 78
2-F–C6H4 8 18[thin space (1/6-em)]:[thin space (1/6-em)]1 91
2,4-Cl2–C6H3 9 15[thin space (1/6-em)]:[thin space (1/6-em)]1 90
2-NO2–C6H4 10 5[thin space (1/6-em)]:[thin space (1/6-em)]1 90
2,6-Cl2–C6H3 11 10[thin space (1/6-em)]:[thin space (1/6-em)]1c 91
2-Furyl 12 12[thin space (1/6-em)]:[thin space (1/6-em)]1 90
image file: c4ob00913d-u7.tif R′ = 3-Me 13 13[thin space (1/6-em)]:[thin space (1/6-em)]1 70 image file: c4ob00913d-u8.tif 22 10[thin space (1/6-em)]:[thin space (1/6-em)]1 46
R′ = 4-Me 14 7[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1d 53
image file: c4ob00913d-u9.tif 15 2[thin space (1/6-em)]:[thin space (1/6-em)]1 38 image file: c4ob00913d-u10.tif R′′ = Ph 23 28[thin space (1/6-em)]:[thin space (1/6-em)]1[thin space (1/6-em)]:[thin space (1/6-em)]1 86
2,4-Cl2–C6H3 24 19[thin space (1/6-em)]:[thin space (1/6-em)]1 82
3,4-(OCH2O)–C6H3 25 27[thin space (1/6-em)]:[thin space (1/6-em)]1 75
2-Furyl 26 11[thin space (1/6-em)]:[thin space (1/6-em)]1 69
2-NO2–C6H4 27 2[thin space (1/6-em)]:[thin space (1/6-em)]1 74
2-F–C6H4 28 11[thin space (1/6-em)]:[thin space (1/6-em)]1 96
image file: c4ob00913d-u11.tif 16 6[thin space (1/6-em)]:[thin space (1/6-em)]1 72 image file: c4ob00913d-u12.tif 29 15[thin space (1/6-em)]:[thin space (1/6-em)]1 68
image file: c4ob00913d-u13.tif 17 50[thin space (1/6-em)]:[thin space (1/6-em)]1 90 image file: c4ob00913d-u14.tif R′′ = Ph 30 40[thin space (1/6-em)]:[thin space (1/6-em)]1 82
2,4-Cl2–C6H3 31 6[thin space (1/6-em)]:[thin space (1/6-em)]1 82
image file: c4ob00913d-u15.tif R′ = H 18 3[thin space (1/6-em)]:[thin space (1/6-em)]1d 16 image file: c4ob00913d-u16.tif R′′ = Ph 32 14[thin space (1/6-em)]:[thin space (1/6-em)]9[thin space (1/6-em)]:[thin space (1/6-em)]1 63
Me 19 28[thin space (1/6-em)]:[thin space (1/6-em)]6[thin space (1/6-em)]:[thin space (1/6-em)]1d 39 2-F–C6H4 33 1.5[thin space (1/6-em)]:[thin space (1/6-em)]1 69
2,4-Cl2–C6H3 34 4[thin space (1/6-em)]:[thin space (1/6-em)]3[thin space (1/6-em)]:[thin space (1/6-em)]1 62

The three contiguous stereocenters evolve under thermo-dynamic control. We have employed prolinol derivatives (22–34) among which bulky diarylprolinols exhibited the most effective facial discrimination of the intermediate iminium ion. Consistently, the trans,trans-isomers were formed preferentially. Crystal structure analysis confirmed the absolute and relative configuration of 24 (Fig. 1). However, bulky 1-nitro-2-(2′,6′-dichlorophenyl)ethylene preferentially gave cis,trans-35 (cis,trans[thin space (1/6-em)]:[thin space (1/6-em)]trans,trans 5[thin space (1/6-em)]:[thin space (1/6-em)]1). Slow epimerisation at C-1 occurred during work-up (SiO2) or in the presence of acid (wet CDCl3, HCl) to give the thermodynamic trans,trans-35 (cis,trans[thin space (1/6-em)]:[thin space (1/6-em)]trans,trans ∼1[thin space (1/6-em)]:[thin space (1/6-em)]1) possibly via elimination of the axial amine group (Scheme 6, Fig. 2).13

image file: c4ob00913d-f1.tif
Fig. 1 Crystal structure of trans,trans-24.

image file: c4ob00913d-s6.tif
Scheme 6 Kinetic cis,trans-35 and thermodynamic trans,trans-35.

image file: c4ob00913d-f2.tif
Fig. 2 Crystal structure of the kinetic product cis,trans-35.

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).
image file: c4ob00913d-s7.tif
Scheme 7 Core and peripheral reactions to dienes, arenes and diamines.

Oxidation of nitrocyclohexenyl amines with manganese dioxide (MnO2) resulted in unselective decomposition involving dehydrogenation and amine or nitrite elimination.15 Similarly, various Nef conditions (base (NaH/n-BuLi), then acid (HCl); TiCl3; KMnO4)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).13 Amine/acid-co-catalyzed reactions of aldehydes and nitroalkenes gave low selectivities.13,17

image file: c4ob00913d-s8.tif
Scheme 8 Acid-mediated elimination of pyrrolidine.
Table 3 Acid-mediated elimination of chiral prolinols

image file: c4ob00913d-u17.tif

Cyclohexenyl amine Cyclohexadiene   eea [%] Yieldb [%]
a Enantiomeric excess (ee) determined by chiral HPLC. b Isolated yields. c Ar = 3,5-bis(trifluoromethyl)phenyl.
image file: c4ob00913d-u18.tif R′′′ = Ph 36 94 54
2-F–C6H4 37 85 29
2,4-Cl2–C6H3 39 93 60
2-Furyl 41 82 29
image file: c4ob00913d-u19.tif image file: c4ob00913d-u20.tif 39 92 55

The 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, MnO2, SeO2etc.).18 We obtained good yields of 2-aryl nitrobenzenes with 5 equiv. MnO2 at 80 °C (Scheme 9). This strategy allows the three-step synthesis of 2-nitrobiaryls.

image file: c4ob00913d-s9.tif
Scheme 9 Three-step synthesis of 2-nitrobiaryls.

The reduction of a nitro function to a primary amine is an especially useful manipulation.19 Application of such selective manipulation of one substituent of our three-component cycloadducts renders an expedient access to carbocyclic 1,2-trans-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.13

image file: c4ob00913d-s10.tif
Scheme 10 Two-step synthesis of trans-1,2-diaminocyclohexenes.

The 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.5,6 The 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–NO2 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.13 The initial amide/aldehyde condensation required elevated temperature (100 °C). The trans,trans-N-acyl-6-nitrocyclohex-2-enyl amines were formed as minor stereoisomers.
image file: c4ob00913d-s11.tif
Scheme 11 Endo-selective Diels–Alder mechanism with carboxamides.
Table 4 Three-component synthesis of cis-nitrocyclohexenyl amidesa

image file: c4ob00913d-u21.tif

Major isomer Substituents   dr Yield [%]
a Amide, aldehyde, β-nitrostyrene (each 3 mmol) in PhMe, 100 °C, 24 h.
image file: c4ob00913d-u22.tif R′′′ = Ph 51 18[thin space (1/6-em)]:[thin space (1/6-em)]1 66
2,6-Cl2–C6H3 52 50[thin space (1/6-em)]:[thin space (1/6-em)]1 67
2,4-Cl2–C6H3 53 28[thin space (1/6-em)]:[thin space (1/6-em)]1 57
2-F–C6H4 54 15[thin space (1/6-em)]:[thin space (1/6-em)]1 44
image file: c4ob00913d-u23.tif R′′ = H 55 8[thin space (1/6-em)]:[thin space (1/6-em)]1 75
4-Me 56 50[thin space (1/6-em)]:[thin space (1/6-em)]1 39
2,4-Me2 57 40[thin space (1/6-em)]:[thin space (1/6-em)]1 74
image file: c4ob00913d-u24.tif R′′′ = H 58 26[thin space (1/6-em)]:[thin space (1/6-em)]1 56
3-Me 59 32[thin space (1/6-em)]:[thin space (1/6-em)]1 79
2,4-Me2 60 13[thin space (1/6-em)]:[thin space (1/6-em)]1 18

The relative configurations were assigned based on the 3JHH coupling constants from 1H-NMR spectra. Crystal structure analyses of cis,trans-51 and trans,trans-51 confirmed the relative configurations of the substituents (Fig. 3).

image file: c4ob00913d-f3.tif
Fig. 3 Crystal structures of cis,trans-51 (left) and trans,trans-51 (right).

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 MnO2 proceeded with good selectivity (Scheme 12).15 However, the related C3-substituted cyclohexenyl amines 51, 53 and 54 exhibited poor dehydrogenation selectivity. Competing NO2-elimination was observed which resulted in mixtures of nitro-acetanilides (62–64) and benzoxazoles (65–67, Scheme 13).20
image file: c4ob00913d-s12.tif
Scheme 12 Two-step synthesis of substituted 2-nitro acetanilide.

image file: c4ob00913d-s13.tif
Scheme 13 Oxidative formation of acetanilides and benzoxazoles.

We 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 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.

image file: c4ob00913d-s14.tif
Scheme 14 Synthesis of cis-1,2-diaminocyclohexenes.


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 reactions12 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.6 Reduction 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.9 In the presence of enantiopure prolinols, one enantiomerically pure set of diastereomers was formed.21 Acid-mediated amine eliminations resulted in the formation of chiral cyclohexadienes. Oxidative aromatisations proceeded with MnO2 to give 2-nitrobiaryls. It is important to note that the presence of two chemically orthogonal N-based substituents (NHR, NO2) allows various selective manipulations of the general structure. Likewise, the electronic polarisation (push–pull substitution) is of high relevance to photoactive materials.

Experimental section


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. 1H and 13C NMR spectra were recorded on a Bruker Avance II 600 (600.20 and 150.94 MHz), a Bruker DRX 500 (500.13 and 125.77 MHz) and a Bruker Avance 300 (300.13 and 75.48 MHz) at 298 K. Chemical shifts (δ in ppm) are referenced to tetramethylsilane (TMS). Abbreviations for 1H-NMR data: s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), q* (apparent quartet), m* (apparent multiplet). Peaks were assigned based on H,H-COSY, H,C-HMQC, and H,C-HMBC. IR-ATR spectroscopy was performed on a Perkin-Elmer 100 Paragon FT-IR. ESI-MS were measured with a Finnigan MAT 900S and an Agilent LC/MSD VL G1956A, respectively. EI-MS were measured with a Finnigan Incos 50 Galaxy and a Finnigan MAT 95, respectively (ionisation 70 eV). Exact masses (HR-MS) were determined by peak matching method. GC-MS analyses were performed on a 6890N Agilent system with 5975 MS detector on an HP-5MS column (30 m × 0.25 mm i.d. × 0.25 μm film thickness) with 5% phenylmethyl siloxane from Macherey-Nagel. H2 was the mobile phase. Standard method 50–300 M: 50 °C (2 min hold), +25 °C min−1→300 °C (5 min hold). Determination of enantiomeric excesses (ee) were performed on a HP6890 GC-FID with chiral BGB 176 column (30 m, 0.25 mm i.d., 0.25 μm film thickness). Helium was the mobile phase. Standard method: 50 °C (2 min hold), 3 °C min−1→150 °C, 1 °C min−1→180 °C. 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).22
Table 5 Crystal structure data for compounds 24, 35, syn-51, trans-51
Compound 24 35 syn-51 trans-51
CCDC number 973119 973120 973121 973122
Formula C37H34Cl2F12N2O3Si C30H30Cl2N2O3 C15H18N2O3 C15H18N2O3
Formula mass 881.65 537.46 274.31 274.31
Crystal system Orthorhombic Orthorhombic Monoclinic Monoclinic
a 10.8393(5) 8.9169(13) 19.3984(10) 19.0719(12)
b 16.7856(3) 17.351(3) 9.6352(5) 5.2738(3)
c 42.689(2) 17.602(3) 16.2688(9) 27.2994(14)
α 90.00 90.00 90.00 90.00
β 90.00 90.00 108.737(2) 90.632(4)°
γ 90.00 90.00 90.00 90.00
Unit cell vol./Å3 7767.0(5) 2723.2(8) 2879.6(3) 2745.6(3)
Temperature/K 100(2) 100(2) 100(2) 100(2)
Space group C2221 P212121 P21/c C2/c
Formula units/cell, Z 8 4 8 8
Reflections measured 13[thin space (1/6-em)]598 12[thin space (1/6-em)]769 13[thin space (1/6-em)]657 7864
Independent refl. 6278 5633 5758 3000
R int 0.0651 0.0783 0.0667 0.0540
R 1 (I > 2σ(I)) 0.0658 0.0630 0.1537 0.0540
wR(F2) (I > 2σ(I)) 0.1413 0.1281 0.0713 0.1300
R 1 (all data) 0.1379 0.1520 0.1482 0.0948
wR(F2) (all data) 0.1657 0.1519 0.1851 0.1456

General 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 SiO2 flash column chromatography (ethyl acetate (ea)/cyclohexane (ch)) or crystallised from solution (for details see below).
1-(5-(2,4-Dichlorophenyl)-3-methyl-6-nitrocyclohex-2-enyl) pyrrolidine (9). TLC (ch–ea 5/1): Rf 0.25. Yield: 90%; dr (trans,trans/cis,trans) 15/1. Mp. 137 °C. 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 1H), 7.21 (m, 2H), 5.50 (s, 1H), 4.95 (t, 10.7 Hz, 1H), 4.26 (d, 8.1 Hz, 1H), 4.21–4.11 (m, 1H), 3.14–2.90 (m, 1H), 2.81 (d, 6.5 Hz, 3H), 2.75–2.61 (m, 2H), 1.84–1.69 (m, 7H). 13C NMR (75 MHz, CDCl3): δ 136.3 (2C), 135.6, 129.8, 129.0, 128.2, 127.7, 118.8, 89.2, 61.3, 47.6 (2C), 40.3, 38.0, 24.7 (2C), 24.1. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 2963 (m), 2912 (m), 2847 (m), 1668 (w), 1551 (s), 1474 (s), 1437 (w), 1368 (m), 1326 (w), 1277 (w), 1172 (w), 1125 (w), 1103 (m), 1046 (w), 910 (w), 865 (m), 823 (s), 764 (w), 744 (m), 732 (m). LR-MS (EI, 70 eV): m/z 354, 308, 272, 256, 152, 137, 122. HR-MS (ESI): calcd [M + H]+ 355.0974, found 355.0977.
N,N-Diallyl-3-methyl-6-nitro-5-phenylcyclohex-2-enyl-1-amine (21). TLC (ch–ea 5/1): Rf 0.3. Yield: 93%; dr (trans,trans/cis,trans) 35/1. Pale yellow solid. Mp. 128 °C. 1H NMR (300 MHz, CDCl3): δ 7.43–6.97 (m, 5H), 5.83–5.74 (m, 1H), 5.74–5.66 (m, 1H), 5.43 (s, 1H), 5.19 (m, 1H), 5.13 (s, 2H), 5.10 (s, 1H), 4.86 (dd, 11.8, 9.8 Hz, 1H), 4.25–4.13 (m, 1H), 3.45 (ddd, 11.8, 9.4, 7.7 Hz, 1H), 3.33–3.28 (m, 1H), 3.28–3.22 (m, 1H), 3.04 (d, 7.7 Hz, 1H), 2.99 (d, 7.7 Hz, 1H), 2.32 (d, 7.7 Hz, 2H), 1.74 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 132.4, 131.3, 130.8, 94.9, 66.2, 64.4, 56.8, 48.8, 41.9, 26.2. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 2968, 2920, 2831, 2806, 1643, 1548, 1495, 1418, 1373, 1315, 1261, 1176, 1109, 1086, 996, 936, 913, 860, 816, 763, 698, 655, 621, 596, 541, 460, 438. HR-MS (EI): calcd [M]+ 312.1838, found 312.1843.
1-[5-(2,4-Dichlorophenyl)-3-methyl-6-nitrocyclohex-2-enyl]-2-(S)-[di-(3,5-bis(trifluoromethyl)phenyl) (trimethylsilyloxy)-methyl]pyrrolidine (24). TLC (ch–ea 20/1): Rf 0.4. Yield: 82%; dr (trans,trans/cis,trans) 19/1. 1H NMR (300 MHz, CDCl3): δ 7.94 (s, 4H), 7.87 (s, 2H), 7.40 (s, 1H), 7.19 (d, 13.9 Hz, 2H), 5.17 (s, 1H), 5.09 (s, 1H), 4.60 (s, 1H), 4.10 (d, 8.9 Hz, 1H), 3.49 (s, 1H), 2.83 (dd, 16.2, 8.5 Hz, 1H), 2.45–2.25 (m, 2H), 2.08–1.82 (m, 3H), 1.69 (s, 3H), 1.65–1.55 (m, 1H), 0.25–0.10 (m, 1H), −0.15 (d, 3.1 Hz, 9H). 13C NMR (75 MHz, CDCl3): δ 145.1, 143.7, 135.7, 135.2, 135.0, 133.8, 131.4, 131.2, 131.0, 130.8, 130.1, 129.5, 128.7, 127.7, 127.2, 125.0, 123.8, 122.0, 121.4, 117.8, 84.8, 83.7, 67.5, 62.3, 40.0, 37.4, 29.1, 23.3, 22.3, 1.5. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 3094 (w), 2956 (m), 2917 (m), 2855 (w), 1676 (w), 1620 (w), 1588 (w), 1547 (s), 1474 (s), 1446 (w), 1368 (s), 1337 (m), 1316 (m), 1275 (s), 1170 (s), 1125 (s), 1047 (m), 1014 (w), 983 (w), 934 (m), 905 (s), 870 (s), 840 (s), 761 (m), 753 (m), 709 (s), 681 (s). LR-MS (EI, 70 eV): m/z 881, 875, 873, 871. HR-MS (ESI): [M + H]+ calcd 881.1596, found 881.1592.
Acid-mediated elimination to give nitrocyclohexadienes. A 10 mL flask was charged with the aminocyclohexene (1 mmol) in dichloromethane (4 mL). Then, trifluoroacetic acid (3 mmol) was added (or 2 mmol benzoic acid in case of small amine substituents). After 10–16 h at room temperature, all volatiles were removed in vacuum and the crude product subjected to SiO2 flash chromatography (ethyl acetate/cyclohexane).
2,4-Dichloro-1-(5-methyl-2-nitrocyclohexa-2,4-dienyl)-benzene (39). From 24 (with TFA): TLC (ch–ea 12/1): Rf = 0.25. Yield: 60%; 93% ee (HPLC). 1H NMR (300 MHz, CDCl3): δ 7.72 (d, 6.3 Hz, 1H), 7.44 (d, 2.3 Hz, 1H), 7.11 (d, 8.4 Hz, 1H), 6.99 (d, 8.4 Hz, 1H), 5.97 (d, 7.2 Hz, 1H), 4.81 (d, 11.1 Hz, 1H), 3.05 (dd, 18.5, 11.3 Hz, 1H), 2.46 (d, 18.0 Hz, 1H), 1.83 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 147.4, 145.0, 135.8, 133.5, 133.5, 131.9, 130.1, 128.0, 127.3, 117.3, 37.2, 33.4, 23.9. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 3067 (w), 2870 (w), 2666 (w), 2544 (w), 1688 (s), 1602 (m), 1583 (s), 1558 (w), 1503 (s), 1466 (m), 1450 (w), 1426 8 m), 1316 (s), 1289 (m), 1269 (w), 1103 (w), 1085 (w), 1050 (w), 1025 (w), 938 (w), 866 (w), 841 (m), 812 (m), 711 (s), 663 (m). LR-MS (EI, 70 eV): m/z 283, 266, 148, 236, 216, 202, 183, 165. HR-MS (EI, 70 eV): calcd 283.0167, found 283.018.
MnO2-mediated oxidation to nitrobiaryls. The nitrocyclohexadiene (1 mmol, 1 equiv.), MnO2 (85%, 5 equiv.) and toluene (5 mL) were combined in a reaction tube. The tube was sealed with a septum and the reaction stirred at 80 °C. After 6 h, the solvent and other volatile compounds were removed by oil pump vacuum. Silica gel flash chromatography (ethyl acetate/cyclohexane) gave the aromatic product in analytically pure form.
2,4-Dichloro-5′-methyl-2′-nitrobiphenyl (47). TLC (ch–ea 10/1): Rf 0.2. Yield: 48%. 1H NMR (300 MHz, CDCl3): δ 8.05 (d, 8.4 Hz, 1H), 7.46 (s, 1H), 7.40–7.30 (m, 2H), 7.19 (d, 8.0 Hz, 1H), 7.11 (s, 1H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 146.1, 144.6, 136.2, 134.5, 133.6, 133.4, 132.7, 131.0, 130.5, 130.0, 129.8, 129.2, 128.2, 127.5, 127.3, 124.8, 115.8, 21.4. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 2922 (w), 1609 (w), 1586 (m), 1519 (s), 1466 (m), 1377 (w), 1342 (s), 1100 (m), 1066 (w), 1025 (w), 888 (w), 866 (w), 837 (s), 790 (s), 759 (m), 688 (w). LR-MS (EI, 70 eV): m/z 248, 246 [M − Cl]+, 216, 165, 154, 127, 97, 81, 69, 57, 55.
Zn/HCl-mediated reduction of cyclohexenyl amines19b. The 6-nitrocyclohexenyl amine (0.4 mmol, 1.0 equiv.) was dissolved in ethanol (3.0 mL) and aqueous HCl (6 N, 2.2 mL) was added. Zinc powder (262 mg, 4.0 mmol, 10 equiv.) was added in small portions and the reaction mixture was stirred for 2 h at room temperature. After addition of saturated aqueous NaHCO3 (20 mL), the solution was extracted with CH2Cl2 (3 × 20 mL), the combined organic layers were dried Na2SO4) and concentrated under reduced pressure to give the diamine in >95% purity and yield.
N2,N2-Diallyl-3-methyl-5-phenylcyclohex-2-ene-1,2-diamine (50). Yield: 99%. Mp. 100 °C. 1H NMR (300 MHz, CDCl3): δ 7.39–7.24 (m, 5H), 6.27–6.07 (m, 2H), 5.64–5.40 (m, 1H), 5.32–5.20 (m, 4H), 3.73 (d, 10.5 Hz, 1H), 3.58–3.51 (m, 2H), 3.47–3.24 (m, 3H), 3.13–2.98 (m, 2H), 2.46–2.14 (m, 2H), 1.77 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 139.8, 139.6, 129.7, 128.1, 121.9, 116.1, 77.4, 54.5, 38.6, 23.3. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 2912, 1600, 1454, 1150, 1098, 1065, 998, 965, 814, 760, 701, 645, 604, 574, 526, 461. HR-MS (EI): calcd [M]+ 282.2096; found 282.20976.
Three-component cyclisation with carboxamides. A 50 mL pressure tube was charged with the carboxamide, unsaturated aldehyde, and nitroalkene (each 3 mmol) and toluene (20 mL) and heated to 100 °C in an oil bath. After 16 h, the volatile components were removed by vacuum distillation. The viscous residue was treated with cold diethylether (15 mL) upon which a white precipitate formed. The solids were collected and dried in vacuum.
N-3-Methyl-(6-nitro-5-phenylcyclohex-2-enyl) acetamide (51). TLC (ch–ea 1/3): Rf 0.3. Yield: 66%; dr (cis,trans/trans,trans) 18/1. Mp. 205 °C. 1H NMR (300 MHz, CDCl3): δ 7.41–7.09 (m, 5H), 5.93 (d, 9.0 Hz, 1H), 5.47 (d, 3.3 Hz, 1H), 5.34–5.21 (m, 1H), 5.13 (dd, 11.1, 4.9 Hz, 1H), 3.53 (td, 10.3, 6.1 Hz, 1H), 2.45 (dd, 18.4, 6.0 Hz, 1H), 2.24 (dd, 18.5, 10.0 Hz, 1H), 1.98 (s, 3H), 1.77 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.7, 140.0, 138.1, 129.0 (2C), 127.6, 127.1 (2C), 118.8, 88.0, 45.6, 39.9, 37.6, 23.1, 22.8. FT-IR (ATR): [small nu, Greek, tilde] [cm−1] 3271 (w), 3030 (w), 2970 (w), 2912 (w), 1732 (w), 1654 (s), 1549 (s), 1455 (w), 1438 (w), 1369 (m), 1281 (w), 1246 (w), 1055 (w), 1029 (w), 975 (w), 832 (w), 802 (w), 785 (w), 758 (m), 699 (m). LR-MS (EI, 70 eV): m/z 274 [M]+, 227 [M − NO2]+. HR-MS (ESI): calcd [M + Na]+ 297.1215, found 297.121.
N-(2,4-Dimethyl-6-nitro-5-phenylcyclohex-2-enyl) acetamide (57). TLC (ch–ea 1/1): Rf 0.2. Yield: 74%; dr (cis,trans/trans,trans) 40/1. Mp 203 °C. 1H NMR (300 MHz, CDCl3): δ 7.26–7.19 (m, 5H), 5.64 (d, 1H, 9.6 Hz), 5.52 (s, 1H), 5.26 (m, 1H), 5.22 (dd, 1H, 12.3/4.9 Hz), 2.81 (dd, 1H, 12.3/10.3 Hz), 2.36 (m, 1H), 2.02 (s, 3H), 1.80 (s, 3H), 0.91 (d, 3H, 6.9 Hz). 13C NMR (75 MHz, APT, CDCl3): δ 170.3, 138.9, 131.5, 130.3, 128.9, 128.0, 127.7 (5C), 89.0, 49.3, 46.7, 38.1, 23.2, 20.6, 19.5. IR (ATR): [small nu, Greek, tilde] [cm−1] 3271 (w), 2970 (w), 1733 (m), 1653 (s), 1550 (s), 1454 (m), 1371 (s), 1241 (s), 1042 (m), 913 (w), 725 (m). LR-MS (ESI, MeOH/CH2Cl2): m/z 289 [M + H]+, 242 [M − NO2]+, 200, 183, 157. HR-MS (ESI): calcd [M + H]+ 289.1552, found 289.154.
MnO2-mediated oxidation to nitroanilides. As above, but 10 equiv. MnO2 were used and reactions heated to 100 °C for 12 h.
N-(4,6-Dimethyl-2-nitrobiphen-3-yl) acetamide (61). TLC (ch–ea 1/1): Rf 0.6. Yield: 71%. 1H NMR (500 MHz, MeOH-d4): δ 7.46–7.35 (m, 5H), 7.08 (s, 1H), 2.54 (s, 3H), 2.52 and 2.27 (2s, 6H), NH resonance obscured. 13C NMR (125 MHz, APT, MeOH-d4): δ 165.1, 150.5, 138.9, 136.4, 133.5, 131.0, 129.4, 128.7, 128.6, 128.5, 123.7, 19.8, 16.3, 14.1. IR (ATR): [small nu, Greek, tilde] [cm−1] 2920 (m), 2860 (w), 1720 (w), 1607 (m), 1486 (m), 1441 (m), 1383 (m), 1250 (m), 1223 (s), 1061 (s), 926 (m), 759 (s), 700 (s). LR-MS (ESI, MeOH): m/z 238 [M − NO2]+, 223 [M − NO2 − Me]+, 213, 186, 137, 129, 105.
Zn/HCl-mediated reduction of cyclohexenyl amides19b. As above, but methanol was used instead of ethanol. N-(6-Amino-2,4-dimethyl-5-phenylcyclohex-2-enyl) acetamide (70): Yield: 72%. Mp. 67 °C. 1H NMR (300 MHz, CDCl3): δ 7.33–7.21 (m, 5H), 5.59 (s, 1H, 9.4 Hz, NH), 5.48 (s, 1H), 4.60 (q*, 1H, 4.69 Hz), 3.36 (dd, 1H, 11.5/4.7 Hz), 2.34 (m, 1H), 2.15 (br m, 3H), 2.10 (s, 3H), 1.76 (s, 3H), 0.81 (d, 3H, 6.8 Hz). 13C NMR (75 MHz, APT, CDCl3): δ 171.4 (CO), 141.4, 131.7, 131.5, 128.8, 128.7, 127.0, 54.2, 51.4 (2C), 38.2, 23.7, 21.0, 19.8. IR (ATR): [small nu, Greek, tilde] [cm−1] 3256 (w), 3027, (w), 2963 (w), 1643 (s), 1536 (s), 1493 (m), 1452 (m), 1370 (m), 1285 (w), 1092 (w), 1092 (w), 1036 (w), 907 (m), 755 (s), 727 (s), 700 (s). LR-MS (EI, 70 eV): m/z 258 [M]+, 199 [M − AcNH]+, 184, 167, 139, 119, 108. HR-MS (ESI): calcd [M + Na]+ 281.1624, found 281.162.


This work was financed by the 7th European framework program (Cataflu.Or).

Notes and references

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Electronic supplementary information (ESI) available: Experimental procedures, analytical data of all new compounds. CCDC 973119–973122. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00913d

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