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

Article abstract of DOI:10.1039/c4ob00913d

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).

Full text of DOI:10.1039/c4ob00913d

Organic &
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Modular synthesis of cyclic cis- and
trans-1,2-diamine derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 5267
Anna K. Weber,a Josef Schachtner,b Robert Fichtler,a Timo M. Leermann,a
Jörg M. Neudörfla and Axel Jacobi von Wangelin*a,b
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, conju-
gate addition, and nitro-Mannich cyclisation. Upon employment of less nucleophilic carboxamides, a
concerted Diels–Alder cycloaddition mechanism operated to give the corresponding cis,trans-nitrocyclo-
hexenyl amides. Both types of substituted carbocycles offer ample opportunities for chemical manipula-
tions 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).
Received 4th May 2014,
Accepted 6th June 2014
DOI: 10.1039/c4ob00913d
www.rsc.org/obc
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 pat-
terns. The majority of syntheses involve functionalisation of
already cyclic precursors whereas de-novo-syntheses of functio-
nalised 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 reac-
tions 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 develop-
ments, syntheses of pharmaceutically active molecules, natural
products and materials (Scheme 1).5
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
aDepartment of Chemistry, University of Cologne, Germany
bInstitute of Organic Chemistry, University of Regensburg, Germany.
E-mail: axel.jacobi@ur.de; Fax: +49 (0)941 943 4617; Tel: +49 (0)941 943 4802
†Electronic supplementary information (ESI) available: Experimental proce-
dures, 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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Table 1 Selected optimisation experimentsa
Entry Conditions
Yieldb [%]
1
2
3
4
5
6
7
8
CH3CN
CH2Cl2
DMF
PhMe
27 (40)c
58
72
76
68
PhMe, 2 equiv. aldehyde
PhMe, 2 equiv. amine
29
PhMe, slow addition (∼2 h) of 1.2 equiv. aldehyde 90 (19/1)d,e
As entry 8, but with pyrrolidine/benzoic acid (1/1) 64 (18/1)d
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.
Scheme 2 Applications of trans- (top) and cis-1,2-diaminocyclohexanes.
component cyclisation of secondary amines, α,β-unsaturated
aldehydes and nitroalkenes. We chose pyrrolidine, croton-
aldehyde 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
Rapid aldehyde addition resulted in oligomer formation.
The three-component cycloadduct 1-(6-nitro-5-phenylcyclo-
hex-2-enyl)pyrrolidine (1) was obtained with high thermodynamic
stereocontrol (trans,trans/cis,trans = 19/1). The minor dia-
stereomer 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
Scheme 3 The stereoselectivity switch: amines vs. N-acyl amines.
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
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 dieno-
philes.6 Here, we report the viability of controlling the reac-
tion mechanism and stereoselectivity by the employment of
secondary amines (R1 = EDG) or less nucleophilic acylamines
(R1 = EWG) in three-component cyclisations with α,β-unsatu-
rated aldehydes and nitroalkenes to give trans- or cis-1,2-diamino-
cyclohexenes (Scheme 3).
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- Scheme 4 Nitro-Mannich mechanism with secondary amines.
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We extended the reaction conditions to various other coupling constants of 10–12 Hz. Employment of morpholine
amines, aldehydes and nitroolefins (Table 2).13 The trans,trans- gave lower dr values (13, 14). Products with substituents in the
isomers were preferentially formed in diastereomeric ratios of 2-position formed rather slowly (15, 18, 19), possibly due to
>10/1.10 Diastereomeric ratios (dr) were assigned based on steric congestion with the amine substituent in the planar
high-resolution 1H-NMR spectra. The trans-configurations of aminodiene species. Similarly, crotonaldehydes bearing γ-sub-
the vicinal amino/nitro and nitro/aryl groups, respectively, at stituents reacted very slow due to steric inhibition of the
the cyclohexene result in dihedral angles of 170–180° and 3JHH Michael-type attack onto β-nitrostyrenes (14, 19). The latter
Table 2 Three-component synthesis of trans,trans-nitrocyclohexenyl aminesa
Major isomer
Substituents
dr
Yieldb [%] Major isomer
Substituents
dr
Yieldb [%]
82e
R″ = Ph
1
2
3
4
19 : 1
15 : 1
34 : 1
30 : 1c
83
69
59
66
20
21
6 : 1
2,3-(MeO)2–C6H3
3,4-(OCH2O)–C6H3
2,6-Cl2–C6H3
R″ = Ph
5
6
7
8
9
28 : 1
14 : 1
34 : 1
18 : 1
15 : 1
94
62
78
91
90
90
91
90
70
53
35 : 1
93
46
2,3-(MeO)2–C6H3
3,4-(OCH2O)–C6H3
2-F–C6H4
2,4-Cl2–C6H3
2-NO2–C6H4
2,6-Cl2–C6H3
2-Furyl
10 5 : 1
11 10 : 1c
12 12 : 1
13 13 : 1
14 7 : 2 : 1d
R′ = 3-Me
R′ = 4-Me
22
10 : 1
15 2 : 1
38
R″ = Ph
23f 28 : 1 : 1 86
2,4-Cl2–C6H3
24f 19 : 1
82
75
69
74
96
3,4-(OCH2O)–C6H3 25f 27 : 1
2-Furyl
2-NO2–C6H4
2-F–C6H4
26f 11 : 1
27f 2 : 1
28
11 : 1
16 6 : 1
17 50 : 1
18 3 : 1d
72
90
16
29f 15 : 1
68
R″ = Ph
2,4-Cl2–C6H3
30
31
40 : 1
6 : 1
82
82
R′ = H
Me
R″ = Ph
2-F–C6H4
2,4-Cl2–C6H3
32
33
34
14 : 9 : 1 63
1.5 : 1
4 : 3 : 1
19 28 : 6 : 1d 39
69
62
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.
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Scheme 5 Rate of aldehyde addition governs selectivity.
Scheme 6 Kinetic cis,trans-35 and thermodynamic trans,trans-35.
Fig. 1 Crystal structure of trans,trans-24.
trend allowed selective conversion of citral to the 3-alkyl cyclo-
adduct 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
Fig. 2 Crystal structure of the kinetic product cis,trans-35.
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. Consist-
ently, the trans,trans-isomers were formed preferentially. Crystal
structure analysis confirmed the absolute and relative configur-
ation of 24 (Fig. 1). However, bulky 1-nitro-2-(2′,6′-dichloro-
phenyl)ethylene preferentially gave cis,trans-35 (cis,trans : trans,trans
5 : 1). Slow epimerisation at C-1 occurred during work-up (SiO2)
or in the presence of acid (wet CDCl3, HCl) to give the thermo-
dynamic trans,trans-35 (cis,trans : trans,trans ∼1 : 1) possibly via
elimination of the axial amine group (Scheme 6, Fig. 2).13
Scheme 7 Core and peripheral reactions to dienes, arenes and
diamines.
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 nitrocyclo-
hexadienes (Scheme 8). Stronger acids (HCl, TFA) allowed elimi-
nation 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 nitro-
alkenes gave low selectivities.13,17
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 (MnO2) resulted in unselective decomposition invol-
ving 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
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
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Scheme 8 Acid-mediated elimination of pyrrolidine.
Table 3 Acid-mediated elimination of chiral prolinols
Scheme 9 Three-step synthesis of 2-nitrobiaryls.
Cyclohexenyl amine Cyclohexadiene
eea [%] Yieldb [%]
R′′′ = Ph
36c 94
37c 85
39c 93
41c 82
54
29
60
29
2-F–C6H4
2,4-Cl2–C6H3
2-Furyl
39
92
55
Scheme 10 Two-step synthesis of trans-1,2-diaminocyclohexenes.
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 posi-
tion. 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
a Enantiomeric excess (ee) determined by chiral HPLC. b Isolated
yields. c Ar = 3,5-bis(trifluoromethyl)phenyl.
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, SeO2 etc.).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.
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
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 initial amide/aldehyde condensation required elevated
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Fig. 3 Crystal structures of cis,trans-51 (left) and trans,trans-51 (right).
Scheme 11 Endo-selective Diels–Alder mechanism with carboxamides.
Table 4 Three-component synthesis of cis-nitrocyclohexenyl amidesa
Scheme 12 Two-step synthesis of substituted 2-nitro acetanilide.
Major isomer
Substituents
dr
Yield [%]
R′′′ = Ph
51
52
53
54
18 : 1
50 : 1
28 : 1
15 : 1
66
67
57
44
2,6-Cl2–C6H3
2,4-Cl2–C6H3
2-F–C6H4
R″ = H
4-Me
2,4-Me2
55
56
57
8 : 1
50 : 1
40 : 1
75
39
74
Scheme 13 Oxidative formation of acetanilides and benzoxazoles.
R′′′ = H
3-Me
2,4-Me2
58
59
60
26 : 1
32 : 1
13 : 1
56
79
18
a Amide, aldehyde, β-nitrostyrene (each 3 mmol) in PhMe, 100 °C,
24 h.
temperature (100 °C). The trans,trans-N-acyl-6-nitrocyclohex-2-
enyl amines were formed as minor stereoisomers.
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 rela-
tive configurations of the substituents (Fig. 3).
Scheme 14 Synthesis of cis-1,2-diaminocyclohexenes.
Reactions of cis-nitrocyclohexenyl amides
NO2-elimination was observed which resulted in mixtures of
nitro-acetanilides (62–64) and benzoxazoles (65–67, Scheme 13).20
We have also applied the Zn/HCl reduction protocol to the
cycloaddition products.19b Clean reduction of the nitro substi-
tuents gave the corresponding cis-diamines in excellent yields
with retention of stereochemistry (Scheme 14). The overall
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
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synthetic strategy allows the straight-forward preparation of m* (apparent multiplet). Peaks were assigned based on H,
carbocyclic 1,2-diamine derivatives with high cis-stereocontrol H-COSY, H,C-HMQC, and H,C-HMBC. IR-ATR spectroscopy
in a modular manner starting from simple amide, aldehyde, was performed on a Perkin-Elmer 100 Paragon FT-IR. ESI-MS
and nitroethylene precursors.
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
Conclusions
We have applied an operationally simple one-pot protocol to 6890N Agilent system with 5975 MS detector on an HP-5MS
the synthesis of multi-substituted carbocycles upon three-com- column (30 m × 0.25 mm i.d. × 0.25 µm film thickness) with
ponent reaction of amines, aldehydes, and nitroalkenes. The 5% phenylmethyl siloxane from Macherey-Nagel. H2 was the
synthesis is highly modular, operates under practical reaction mobile phase. Standard method 50–300 M: 50 °C (2 min hold),
conditions with cheap starting materials (20–100 °C, toluene +25 °C min−1→300 °C (5 min hold). Determination of enantio-
as solvent), and tolerates ester, ether, chloro, fluoro, thioether, meric excesses (ee) were performed on a HP6890 GC-FID with
and carbamate substituents. Upon wide variations of the start- chiral BGB 176 column (30 m, 0.25 mm i.d., 0.25 µm film
ing materials, the synthesis allows the access to diverse thickness). Helium was the mobile phase. Standard method:
cycloadducts in combinatorial fashion. The electronic pro- 50 °C (2 min hold), 3 °C min−1→150 °C, 1 °C min−1→180 °C.
perties of the employed amine component dictate the reaction Chiral HPLC spectra were recorded on a Merck Hitachi HPLC
mechanism and product stereochemistry. Reactions with sec- with D-6000 interface, L-4000A UV-detector, L-6200A intelligent
ondary amines proceed via reversible Michael/nitro-Mannich pump, and a Merck differential refractometer RI-71. Mixtures
reactions12 to give trans,trans-6-nitrocyclohex-2-enyl amines. of n-hexane and 2-propanol were used as mobile phase. Crystal
The less nucleophilic carboxamides trigger a Diels–Alder-type structure data were collected on a Nonius Kappa CCD diffracto-
mechanism toward N-acyl cis,trans-6-nitrocyclo-hex-2-enyl meter using monochromated Mo-Kα radiation, structures
amines.6 Reduction with Zn/HCl afforded the corresponding refined by shelxs97 and shelxl97 (Table 5).22
1,2-diamine derivatives. The tri-, tetra-, and penta-substituted
carbocycles constitute derivatives of cis- and trans-1,2-diamino-
General procedures (selected examples)13
cyclo-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 dia-
stereomers 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 rele-
vance to photoactive materials.
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 com-
pounds 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) pyrro-
lidine (9). TLC (ch–ea 5/1): Rf 0.25. Yield: 90%; dr (trans,trans/
1
cis,trans) 15/1. Mp. 137 °C. H 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): ˜ν [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.
Experimental section
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 chemi-
cals were purchased from commercial suppliers and used
without further purification unless otherwise noted. Solvents
were dried and distilled before use. H and 13C NMR spectra
1
N,N-Diallyl-3-methyl-6-nitro-5-phenylcyclohex-2-enyl-1-amine
were recorded on
a Bruker Avance II 600 (600.20 and (21). TLC (ch–ea 5/1): Rf 0.3. Yield: 93%; dr (trans,trans/cis,
1
150.94 MHz), a Bruker DRX 500 (500.13 and 125.77 MHz) and trans) 35/1. Pale yellow solid. Mp. 128 °C. H NMR (300 MHz,
a Bruker Avance 300 (300.13 and 75.48 MHz) at 298 K. Chemical CDCl3): δ 7.43–6.97 (m, 5H), 5.83–5.74 (m, 1H), 5.74–5.66 (m,
shifts (δ in ppm) are referenced to tetramethylsilane (TMS). 1H), 5.43 (s, 1H), 5.19 (m, 1H), 5.13 (s, 2H), 5.10 (s, 1H), 4.86
Abbreviations for 1H-NMR data: s (singlet), d (doublet), t (triplet), (dd, 11.8, 9.8 Hz, 1H), 4.25–4.13 (m, 1H), 3.45 (ddd, 11.8,
q (quartet), sept (septet), m (multiplet), q* (apparent quartet), 9.4, 7.7 Hz, 1H), 3.33–3.28 (m, 1H), 3.28–3.22 (m, 1H),
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Table 5 Crystal structure data for compounds 24, 35, syn-51, trans-51
Compound
24
35
syn-51
trans-51
CCDC number
Formula
Formula mass
Crystal system
973119
973120
C30H30Cl2N2O3
537.46
973121
C15H18N2O3
274.31
973122
C15H18N2O3
274.31
C
37H34Cl2F12N2O3Si
881.65
Orthorhombic
Orthorhombic
Monoclinic
Monoclinic
a/Å
b/Å
c/Å
α/°
10.8393(5)
16.7856(3)
42.689(2)
90.00
8.9169(13)
17.351(3)
17.602(3)
90.00
19.3984(10)
9.6352(5)
16.2688(9)
90.00
19.0719(12)
5.2738(3)
27.2994(14)
90.00
β/°
γ/°
90.00
90.00
7767.0(5)
100(2)
C2221
90.00
90.00
108.737(2)
90.00
2879.6(3)
100(2)
P21/c
8
13 657
5758
0.0667
0.1537
0.0713
0.1482
0.1851
90.632(4)°
90.00
2745.6(3)
100(2)
C2/c
8
7864
3000
0.0540
0.0540
0.1300
0.0948
0.1456
Unit cell vol./Å3
Temperature/K
Space group
Formula units/cell, Z
Reflections measured
Independent refl.
Rint
2723.2(8)
100(2)
P212121
4
12 769
5633
0.0783
0.0630
0.1281
0.1520
0.1519
8
13 598
6278
0.0651
0.0658
0.1413
0.1379
0.1657
R1 (I > 2σ(I))
wR(F2) (I > 2σ(I))
R1 (all data)
wR(F2) (all data)
3.04 (d, 7.7 Hz, 1H), 2.99 (d, 7.7 Hz, 1H), 2.32 (d, 7.7 Hz, 2H), (d, 6.3 Hz, 1H), 7.44 (d, 2.3 Hz, 1H), 7.11 (d, 8.4 Hz, 1H), 6.99
1.74 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 132.4, 131.3, 130.8, (d, 8.4 Hz, 1H), 5.97 (d, 7.2 Hz, 1H), 4.81 (d, 11.1 Hz, 1H), 3.05
94.9, 66.2, 64.4, 56.8, 48.8, 41.9, 26.2. FT-IR (ATR): ˜ν [cm−1] 2968, (dd, 18.5, 11.3 Hz, 1H), 2.46 (d, 18.0 Hz, 1H), 1.83 (s, 3H).
2920, 2831, 2806, 1643, 1548, 1495, 1418, 1373, 1315, 1261, 1176, 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):
˜ν [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 nitro-
cyclohexadiene (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.
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]pyrro-
lidine (24). TLC (ch–ea 20/1): Rf 0.4. Yield: 82%; dr (trans,trans/
1
cis,trans) 19/1. H 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): ˜ν [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
2,4-Dichloro-5′-methyl-2′-nitrobiphenyl (47). TLC (ch–ea 10/1):
(s), 1170 (s), 1125 (s), 1047 (m), 1014 (w), 983 (w), 934 (m), Rf 0.2. Yield: 48%. 1H NMR (300 MHz, CDCl3): δ 8.05
905 (s), 870 (s), 840 (s), 761 (m), 753 (m), 709 (s), 681 (s). (d, 8.4 Hz, 1H), 7.46 (s, 1H), 7.40–7.30 (m, 2H), 7.19 (d, 8.0 Hz,
LR-MS (EI, 70 eV): m/z 881, 875, 873, 871. HR-MS (ESI): 1H), 7.11 (s, 1H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3):
[M + H]+ calcd 881.1596, found 881.1592.
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): ˜ν [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.
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).
Zn/HCl-mediated reduction of cyclohexenyl amines.19b 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.
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: Zinc powder (262 mg, 4.0 mmol, 10 equiv.) was added in small
60%; 93% ee (HPLC). 1H NMR (300 MHz, CDCl3): δ 7.72 portions and the reaction mixture was stirred for 2 h at room
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temperature. After addition of saturated aqueous NaHCO3 128.7, 128.6, 128.5, 123.7, 19.8, 16.3, 14.1. IR (ATR): ˜ν [cm−1
]
(20 mL), the solution was extracted with CH2Cl2 (3 × 20 mL), 2920 (m), 2860 (w), 1720 (w), 1607 (m), 1486 (m), 1441 (m),
the combined organic layers were dried Na2SO4) and concen- 1383 (m), 1250 (m), 1223 (s), 1061 (s), 926 (m), 759 (s), 700 (s).
trated under reduced pressure to give the diamine in >95% LR-MS (ESI, MeOH): m/z 238 [M − NO2]+, 223 [M − NO2 − Me]+,
purity and yield.
213, 186, 137, 129, 105.
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,
Zn/HCl-mediated reduction of cyclohexenyl amides.19b As
above, but methanol was used instead of ethanol. N-(6-Amino-
2,4-dimethyl-5-phenylcyclohex-2-enyl) acetamide (70): Yield:
1
72%. Mp. 67 °C. H 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):
˜ν [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.
121.9, 116.1, 77.4, 54.5, 38.6, 23.3. FT-IR (ATR): ˜ν [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.
Acknowledgements
N-3-Methyl-(6-nitro-5-phenylcyclohex-2-enyl) acetamide (51). This work was financed by the 7th European framework
TLC (ch–ea 1/3): Rf 0.3. Yield: 66%; dr (cis,trans/trans,trans) program (Cataflu.Or).
1
18/1. Mp. 205 °C. H 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),
Notes and references
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,
1 (a) M. J. Palframan and A. F. Parsons, in Science of
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ations, ed. H. Hiemstra, Thieme, Stuttgart, 2009, vol. 48,
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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): ˜ν [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): ˜ν [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.
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1
(ch–ea 1/1): Rf 0.6. Yield: 71%. H NMR (500 MHz, MeOH-d4):
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(2s, 6H), NH resonance obscured. 13C NMR (125 MHz, APT,
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