Synthesis of enantiopure chiral perhydrobenzimidazole and hexahydroquinoxaline derivatives

Article abstract of DOI:10.1007/s007060070038

Starting from 2-anilino-2-ethoxy-3-oxothiobutyric acid anilides and (R,R)-or (S,S)-trans-1,2-diaminocyclohexane, chiral C2-disubstituted perhydrobenzimidazole and trans-4a,5,6,7,8,8a-hexahydroquinoxaline derivatives were obtained depending on the polarity

Full text of DOI:10.1007/s007060070038

Monatshefte fuÈr Chemie 131, 1061±1066 (2000)
Synthesis of Enantiopure Chiral
Perhydrobenzimidazole and
Hexahydroquinoxaline Derivatives
Ã
Barbara Zaleska and Robert Socha
Department of Organic Chemistry, Jagiellonian University, PL 30060 Cracow, Poland
Summary. Starting from 2-anilino-2-ethoxy-3-oxothiobutyric acid anilides and (R,R)-or (S,S)-trans-
1,2-diaminocyclohexane, chiral C2-disubstituted perhydrobenzimidazole and trans-4a,5,6,7,8,8a-
hexahydroquinoxaline derivatives were obtained depending on the polarity of the solvent.
Keywords. Perhydrobenzimidazole; Hexahydroquinoxaline; 1,2-Diaminocyclohexane.
Introduction
1,2-Diaminocyclohexane [1] has long been recognized as a reagent for the
construction of cyclic compounds with C2 chirality. The resulting strongly basic
optically active C2-chiral diamines, e.g 1,3-diacylbenzimidazoline-2-thione, 2-one
[2], or -amidine [3], have served as auxiliary compounds for the NMR analysis of
enantiomeric mixtures of weakly acidic compounds. Some chiral Schiff bases of 1,2-
diaminocyclohexane are among the most effective chiral catalysts [4]. Moreover,
these cyclic diamines are very attractive bifunctional auxiliaries for asymmetric
syntheses.
Some of the compounds have found application due to their biological activity. In
particular, some perhydrobenzimidazole derivatives show anti-HIV-1 activity [5, 6],
whereas hexahydroquinoxaline derivatives show DNA strand breakage activity [7].
Moreover, they are used as components in photographic development [8]. These very
interesting applications have increased our interest in their synthesis.
Results and Discussion
In this paper we report a novel methodology for the synthesis of hitherto unknown
chiral C2-disubstituted, derivatives of perhydrobenzimidazole (3) and hexahydro-
quinoxaline (4) (Scheme 2) starting from 2-anilino-2-ethoxy-3-oxothiobutyric acid
anilides 1a±d and trans-1,2-diaminocyclohexane (2). The 3-oxoacid derivatives
1a±d themselves were obtained from 3-oxothiobutyric acid anilides and nitroso-
Ã
Corresponding author

1062
B. Zaleska and R. Socha
Scheme 1
Scheme 2
benzene in ethanol at room temperature (Scheme 1) according to the procedure
described for the 1e [9].
The polyfunctional building block 1 offers several advantages including its
stereoselectivity and chemoselectivity when undergoing cyclization with diamine
2. We ®rst examined the reaction of the readily available isomeric mixture of 1,2-
diaminocyclohexane with 1. In principle, this reaction could give a mixture of two
possible products 3 and 4 (Scheme 2).
However, we found that the procedure is chemoselective and the outcome
depends on the reaction conditions such as solvent and stoichiometry, giving
exclusively trans-perhydrobenzimidazole as evidenced by H,H- and C,H-COSY
experiments on compound 3a. In the 13C NMR spectra of 3a, the presence of a
carbonyl group is observed at 172.4 ppm, whereas the thiocarbonyl signal was
observed at 200.5 ppm. The diagnostic C2 carbon of the imidazolidine ring appears
at 68.22 ppm; aliphatic carbons are found at 23.63 (C6), 24.6 (C5), 30.9 (C7), 31.49
(C4), 56.29 (C3a), and 56.61 (C7a) ppm. Additional evidence came from the IR
1
spectra which displayed a peak characteristic for the C=O group at 1684 cm and
1
for the NH moiety in the range of 3170±3360 cm . EIMS con®rmed the structure of

EPC Synthesis of Benzimidazole and Quinoxaline Derivatives
1063
‡
3a; the diagnostic peak at m/z ˆ MH is present in all spectra. The most intense
‡
(100%) peak is formed via loss of phenyl isothiocyanate (M-PhNCS) .
The spectra for hexahydroquinoxaline 4a indicated the difference in the structure
compared to 3a. The 1H NMR spectra of this compound showed the speci®c features
due to the presence of cyclohexane ring, whereas the two trans protons at positions
4a and 8a of 4a appeared as a multiplet in the range of 2.62±2.74ppm with
JHH ˆ 4:25 Hz. The singlet of the CH3 group at 2.37 ppm was shifted down®eld
relative to the perhydrobenzimidazole derivative 3a. 13C NMR data revealed
differences in the range of aliphatic carbons; a signal characteristic for a sp3 carbon
(C2) of perhydrobenzimidazole at 68.22 ppm was not present as well as that of C=O
of the acetyl moiety. C2 and C3 appeared at 157.76 and 157.97 ppm. In the IR
1
spectra, two bands at 1605 and 1624 cm corresponding to a vibration the C=N
group of the quinoxaline skeleton were observed. A very important proof came from
‡
the mass spectra where a characteristic M peak con®rmed the presence of the
hexahydroquinoxaline system.
In conclusion, it should be pointed out that the presented methodology for the
synthesis of perhydrobenzimidazole derivatives 3a±e and the hexahydroquinoxaline
derivatives 4a±c opens a new straightforward entry to a variety of heterocyclic
compounds. Moreover, the products 3a±e represent fundamental compounds which
can be used for the construction of new chiral heterocyclic systems. The new chiral
bases 3 and 4 can be conveniently converted into metal complexes. We have
successfully prepared the Cu(II), Ni(II), Mn(III) complexes by reaction of the ligands
with the corresponding metal salts. The investigation of their asymmetric catalytic
properties is currently in progress.
Experimental
Melting points were determined on an electrothermal IA9000 digital melting point apparatus and are
uncorrected. Column chromatographic separations were performed using Silica gel 60 (35±70 mesh
ASTM). Rotatory chromatography was performed on a Chromatotron apparatus using a 2 mm
sorbent layer (silica gel 60 PF-254) with visualization by UV light. The IR spectra were obtained on
1
a Bruker IFS 48 spectrometer at room temperature. H and 13C NMR spectra were recorded with a
Bruker AMX 500 NMR spectrometer using TMS as internal standard. Chemical shifts are reported in
ppm down®eld from TMS. The elemental analyses (C, H, N, S) agreed favourably with the calculated
values.
General procedure for the preparation of 3
A solution of 0.55 cm3 trans-(Æ)-1,2-diaminocyclohexane (2, 4.58 mmol) and 3.06 mmol of the
corresponding anilide of 2-anilino-2-ethoxy-3-oxothiobutyric acid 1a±d in 20 cm3 anhydrous ethanol
was re¯uxed for 5 min. Removal of the solvent gave a dark residue which was puri®ed by crystal-
lization from benzene.
(Æ)-2-Acetyl-2-phenylthiocarbamoyl-(3a,7a)-trans-perhydrobenzimidazole (3a; C16H21N3OS)
Yield: 54%; m.p.: 220ꢀC (white needles); IR (KBr): ꢀ ˆ 3366 (NH amide), 3177 (NH amine), 1684
(C=O), 1110 (C=S) cm 1; 1H NMR (CDCl3, ꢁ, 500 MHz): 11.86 (s, 1H, NH amide), 7.81 (d, 2H, CH
aromat.), 7.41 (t, 2H, CH aromat.), 7.25 (t, 1H, CH aromat.) 6.08 (s, 1H, NH amine), 2.95 (d,

1064
B. Zaleska and R. Socha
J ˆ 6:78 Hz, 1H, NH amine), 3.03 (m, 1H, 7a-H), 2.75 (m, 1H, 3a-H), 2.01 (m, 1H, 4-H), 1.87 (m,
1H, 7-H), 1.86 (m, 1H, 5-H), 1.78 (m, 1H, 6-H), 1.38 (t, 2H, 5-H, 4-H), 1.26 (t, 2H, 6-H, 7-H), 1.78
(s, 3H, CH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 29.12 (CH3), 23.63, 24.6, 30.99, 31.49, 56.29,
56.61, 68.22 (C aliphat.) 122.28, 126.57, 128.86, 138.76 (C aromat.) 172.39 (C=O), 200.5 (C=S)
‡
‡
ppm; MS:m/z (%) ˆ 304 (MH , 0.96), 167 (M -PhNCS, 100), 135 (PhNCS, 4), 43 (CH3CO, 3.3).
(‡)-(3aR,7aR)-2-Acetyl-2-phenylthiocarbamoyl-(3a,7a)-trans-perhydrobenzimidazole (3a0)
Yield: 40%; m.p.: 186ꢀC; [ꢂ] ˆ ‡160 (c ˆ 1, ethanol).
20
546
( )-(3aS,7aS)-2-Acetyl-2-phenylthiocarbamoyl-(3a-7a)-trans-perhydrobenzimidazole (3a00)
20
546
Yield: 40%; m.p.: 186ꢀC; [ꢂ]
ˆ
160 (c ˆ 1, ethanol).
(Æ)-2-Acetyl-2-(4-methylphenylthiocarbamoyl)-(3a,7a)-trans-perhydrobenzimidazole
(3b; C17H23N3OS)
Yield: 77%; m.p.: 223ꢀC (white needles); IR (KBr): ꢀ ˆ 3366 (NH amide), 3190 (NH amine), 1685
(C=O), 1112 (C=S) cm 1; 1H NMR (CDCl3, ꢁ, 500 MHz): 11.76 (s, 1H, NH amide), 7.65 (d, 2H, CH
aromat.), 7.20 (d, 2H, CH aromat.) 6.28 (s, 1H, NH amine), 2.96 (d, J ˆ 6:83 Hz, 1H, NH amine),
3.01 (m, 1H, 7a-H), 2.74 (m, 1H, 3a-H), 2.01 (m, 1H, 4-H), 1.87 (m, 1H, 7-H), 1.82 (m, 1H, 5-H),
1.77 (m, 1H, 6-H), 1.37 (t, 2H, 5-H, 4-H), 1.27 (t, 2H, 6-H, 7-H), 1.77 (s, 3H, CH3CO), 2.36 (s, 3H,
CH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 29.07 (CH3CO), 21.09 (CH3), 23.63, 24.6, 30.97, 31.57,
56.24, 56.66, 68.06 (C aliphat.) 122.76, 129.38, 136.26, 136.49 (C aromat.), 172.46 (C=O), 200.3
(C=S) ppm.
(Æ)-2-Acetyl-2-(4-methoxyphenylthiocarbamoyl)-(3a,7a)-trans-perhydrobenzimidazole
(3c; C17H23N3O2S)
Yield: 13%; mp.: 222ꢀC (white needles); IR (KBr): ꢀ ˆ 3362 (NH amide), 3193 (NH amine), 1674
(C=O), 1110 (C=S) cm 1; 1H NMR (CDCl3, ꢁ, 500 MHz): 11.71 (s, 1H, NH amide), 7.67 (d, 2H, CH
aromat.), 6.91 (d, 2H, CH aromat.) 6.03 (s, 1H, NH amine), 2.96 (d, J ˆ 6:83 Hz, 1H, NH amine),
3.02 (m, 1H, 7a-H), 2.75 (m, 1H, 3a-H), 2.01 (m, 1H, 4-H), 1.86 (m, 1H, 7-H), 1.83 (m, 1H, 5-H),
1.78 (m, 1H, 6-H), 1.37 (t, 2H, 5-H, 4-H), 1.28 (t, 2H, 6-H, 7-H), 1.78 (s, 3H, CH3CO), 3.82 (s, 3H,
OCH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 29.21 (CH3CO), 55.45 (OCH3) 23.65, 24.6, 31.5,
32.11, 56.14, 56.87, 67.85 (7C aliphat.), 113.98, 124.53, 131.92, 157.9 (C aromat.) 172.49 (C=O),
200.09 (C=S) ppm.
(Æ)-2-Acetyl-2-(4-chlorophenylthiocarbamoyl)-(3a,7a)-trans-perhydrobenzimidazole
(3d; C16H20N3OSCl)
Yield: 54%; mp.: 223ꢀC (white needles); IR (KBr): ꢀ ˆ 3362 (NH amide), 3180 (NH amine), 1687
(C=O), 1113 (C=S) cm 1; 1H NMR (CDCl3, ꢁ, 500 MHz): 11.94 (s, 1H, NH amide), 7.77 (d, 2H, CH
aromat.) 7.37 (d, 2H, CH aromat.), 6.29 (s, 1H, NH amine), 2.92 (d, J ˆ 6:83 Hz, 1H, NH amine),
3.02 (m, 1H, 7a-H), 2.75 (m, 1H, 3a-H), 2.01 (m, 1H, 4-H), 1.87 (m, 1H, 7-H), 1.85 (m, 1H, 5-H),
1.77 (m, 1H, 6-H), 1.38 (t, 2H, 5-H, 4-H), 1.28 (t, 2H, 6-H, 7-H), 1.77 (s, 3H, CH3) ppm; 13C NMR
(CDCl3, ꢁ, 125 MHz): 29.29 (CH3), 23.63, 24.57, 30.9, 31.48, 56.05, 56.89, 68.08 (C aliphat.)
124.08, 128.92, 131.56, 137.27 (C aromat.) 172.38 (C=O), 200.85 (C=S) ppm.

EPC Synthesis of Benzimidazole and Quinoxaline Derivatives
1065
(Æ)-2-Acetyl-2-phenylcarbamoyl-(3a,7a)-trans-perhydrobenzimidazole
(3e; C16H21N3O2)
A solution of 0.38 cm3 trans-(Æ)-1,2-diaminocyclohexane (2, 3.21 mmol) and 1 g anilide of 2-
anilino-2-ethoxy-3-oxobutyric acid 1e (3.21 mmol) in 20 cm3 anhydrous ethanol was re¯uxed for
15 min. Removal of the solvent gave an orange oil which was puri®ed by rotatory chromatography
eluting with a gradient solvent of CHCl3/CH3COCH3 (1:1) through 60% CH3COCH3/CHCl3. The
last fraction was concentrated giving a white residue.
Yield: 12%; mp.: 245ꢀC (white needles); IR (KBr): ꢀ ˆ 3287 (NH amide), 3174 (NH amine),
1
1684 (C=O), 1645 (C=O) cm 1; H NMR (CDCl3, ꢁ, 500 MHz): 9.86 (s, 1H, NH amide), 7.56 (d,
2H, CH aromat.), 7.31 (t, 2H, CH aromat.), 7.09 (t, 1H, CH aromat.), 6.31 (s, 1H, NH amine), 2.41
(s, 1H, NH amine), 3.03 (m, 1H, 7a-H), 2.67 (m, 1H, 3a-H), 1.93 (m, 1H, 4-H), 1.82 (m, 1H, 7-H),
1.78 (m, 1H, 5-H), 1.72 (m, 1H, 6-H), 1.39 (t, 2H, 5-H, 4-H), 1.30 (t, 2H, 6-H, 7-H), 1.74 (s, 3H,
CH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 26.87 (CH3), 23.69, 24.7, 30.8, 31.11, 54.47, 58.37,
63.94 (C aliphat.), 119.76, 124.18, 128.9, 137.8 (C aromat.) 168.94 (C=O), 172.23 (C=O) ppm; MS:
‡
‡
m/z (%); ˆ 288 (MH , 16), 167 (M -PhNCS, 100), 119 (PhNCO, 5).
General procedure for the preparation of 4
A solution of 0.35 g trans-(Æ)-1,2-diaminocyclohexane (2, 3.06mmol) and 3.06 mmol of the
corresponding anilide of 2-anilino-2-ethoxy-3-oxothiobutyric acid 1a±c in 20cm3 benzene was
re¯uxed for 1 min. Removal of the solvent gave a dark oil which was puri®ed by column
chromatography eluting with a gradient solvent of CHCl3 through 40% CH3COCH3/CHCl3. The last
fraction gave a yellow oil on concentrating which was puri®ed by rotatory chromatography eluting
with a gradient solvent of CHCl3 through 10% CH3COCH3/CHCl3. The last fraction was concentrated
giving yellow residue.
(Æ)-2-Methyl-3-phenylthiocarbamoyl-trans-4a,5,6,7,8,8a-hexahydroquinoxaline (4a; C16H19N3S)
Yield: 14%; mp.: 89±90ꢀC (yellow needles); IR (KBr): ꢀ ˆ 3469 (NH amide), 2935, 2854 (CH
1
aliphat), 1624, 1605 (C=N) cm 1; H NMR (CDCl3, ꢁ, 500 MHz): 10.44 (1H, NH amide), 7.88 (d,
2H, CH aromat.), 7.39 (t, 2H, CH aromat.) 7.26 (t, 1H, CH aromat.) 2.62±2.74 (m, 2H, CHN), 2.27±
2.4 (m, 2H, CH aliphat.), 1.86±1.88 (m, 2H, CH aliphat.), 1.47±1.57 (m, 2H, CH aliphat.), 1.32±1.39
(m, 2H, CH aliphat.), 2.37 (s, 3H, CH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 23.34 (CH3), 25.06,
25.38, 32.81, 33.21, 58.73, 59.69 (6C aliphat.), 122.23, 126.92, 128.98, 138.18 (6C aromat.) 157.76,
‡
157.97 (C=N), 189.18 (C=S) ppm; MS: m/z (%) ˆ 285 (M , 100%), 135 (PhNCS, 4.1%).
( )-(4aR,8aR)-2-Methyl-3-phenylthiocarbamoyl-trans-4a,5,6,7,8,8a-hexahydroquinoxaline (4a0)
20
546
Yield: 20%; m.p.: 102ꢀC; [ꢂ]
ˆ
563 (c ˆ 1, ethanol).
(‡)-(4aS,8aS)-2-Methyl-3-phenylthiocarbamoyl-trans-4a,5,6,7,8,8a-hexahydroquinoxaline (4a00)
Yield: 20%; m.p.: 102ꢀC; [ꢂ] ˆ ‡563 (c ˆ 1, ethanol).
20
546
(Æ)-2-Methyl-3-(4-methylphenylthiocarbamoyl)-trans-4a,5,6,7,8,8a-hexahydroquinoxaline
(4b; C17H21N3S)
Yield: 13%; mp.: 83ꢀC (yellow needles); IR (KBr): ꢀ ˆ 3431 (NH amide), 2929, 2854 (CH aliphat.),
1
1625, 1604 (C=N) cm 1; H NMR (CDCl3, ꢁ, 500 MHz): 10.49 (1H, NH amide), 7.76 (d, 2H, CH

1066
B. Zaleska and R. Socha: EPC Synthesis of Benzimidazole
aromat.), 7.21 (d, 2H, CH aromat.), 2.63±2.68 (m, 2H, CHN), 2.29±2.32 (m, 2H, CH aliphat.), 1.85±
1.86 (m, 2H, CH aliphat.), 1.49±1.5 (m, 2H, CH aliphat.) 1.35±1.37 (m, 2H, CH aliphat.), 2.35 (s,
3H, CH3), 2.38 (s, 3H, CH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 23.6 (CH3), 21.13 (CH3), 25.1,
25.42, 32.85, 33.25, 58.73, 59.76 (6C aliphat.), 122.38, 129.5, 135.65, 136.95 (6C aromat.), 157.77,
158 (C=N), 188.9 (C=S) ppm.
(Æ)-2-Methyl-3-(4-methoxyphenylthiocarbamoyl)-trans-4a,5,6,7,8,8a-hexahydroquinoxaline
(4c; C17H21N3OS)
Yield: 14%; mp.: 84ꢀC (yellow needles); IR (KBr): ꢀ ˆ 3437 (NH amide), 2929, 2854 (CH aliphat.),
1
1625, 1605 (C=N) cm 1; H NMR (CDCl3 ꢁ, 500 MHz): 10.56 (1H, NH amide), 7.78 (d, 2H, CH
aromat.) 7.67 (d, 2H, CH aromat.), 2.65±2.68 (m, 2H, CHN), 2.27±2.3 (m, 2H, CH aliphat.), 1.85±
1.86 (m, 2H, CH aliphat.), 1.49±1.5 (m, 2H, CH aliphat.), 1.34±1.36 (m, 2H, CH aliphat.), 2.37 (s,
3H, CH3), 3.81 (s, 3H, OCH3) ppm; 13C NMR (CDCl3, ꢁ, 125 MHz): 23.5 (CH3), 55.47 (OCH3),
25.1, 25.38, 32.82, 33.21, 58.69, 59.68 (6C aliphat.), 114.09, 124, 131.2, 157.77 (6C aromat.),
158.07, 158,15 (C=N), 188.6 (C=S) ppm.
References
[1] Bennani YL, Hannessian S (1997) Chem Rev 97: 3161
[2] Davies SG, Evans GH, Mortlock AA (1994) Tetrahedron Asymm 5: 585
[3] Dauwe C, Buddrus J (1995) Synthesis 171
[4] Jacobsen EN, Zhang W, Muci AR, Ecker JR, Deng L (1991) J Am Chem Soc 113: 7063
[5] El-Ella DA (1997) Bull Far Pharm 35: 1
[6] Young SD, Amblard MC, Brichter SF, Grey VE, Lumma WC, Tran LO, Huff JR, Schleif WA,
Emini EE (1995) Bioorg Med Chem Lett 5: 491
[7] Yamaguchi T, Kashige N, Mishiro N, Miake F, Watanabe K (1996) Biol Pharm Bull 19: 1261
[8] Hayakawa H, Morimoto K, Fujimoto H (1994) JP 06, 148, 840 [94,148,840]; Chem Abstr (1995)
122: 29700 s
[9] Mirek J, Moskal A, Moskal J (1972) Rocz Chem Ann Soc Chim Polonorum 46: 2233
Received April 10, 2000. Accepted May 2, 2000