A. A. Bazurin et al. / Tetrahedron Letters 45 (2004) 6669–6672
6671
Table 1. trans-4-Alkylcyclohexanecarboxylic acids synthesized in this
work (Scheme 1)
heated under an atmosphere of hydrogen at 140–
150°C and 3.0–4.0MPa for 1h. The catalyst was re-
moved and the reaction mixture was heated at 260–
280°C and 3.0–4.0MPa for an additional 2h. The mix-
ture was cooled to room temperature and acidified with
conc. HCl until pH2. The precipitate formed was fil-
tered off and dried to afford a mixture, which contained
ꢀ75% of the trans-isomer. Pure trans-isomer was sepa-
rated by recrystallization from hexane at ꢁ10°C. The
mother liquor was evaporated to dryness, and the resi-
due was dissolved in 10% aqueous NaOH and subjected
to isomerization. The repeated isomerization–crystalli-
zation cycles afforded trans-4-n-alkylcyclohexanecarb-
oxylic acids 8–14 as white crystals in 80–90% yields.
Compound
R
Yield (%)
8
CH3
90
85
82
88
85
9
C3H7
C4H9
C5H11
C6H13
10
11
12
C3H7
C5H11
13
14
80
80
chlorides and amino acids (Scheme 1, Table 2) as previ-
ously reported.14 All the compounds synthesized were
successfully identified and characterized using 1H
NMR, elemental, and mass-spectral analysis.15
References and notes
1. (a) Brocks, D. R.; Jamali, F. Pharmacotherapy 1995, 15,
551–564; (b) Lemon, A. PharmChem 2003, 2, 27–30.
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Chem. Biol. 2002, 6, 872–877.
3. Phillips, L. S.; Dunning, B. E. Int. J. Clin. Pract. 2003, 57,
535–541.
4. Ayral-Kaloustian, S.; Schow, S. R.; Du, M. T.; Gibbons,
J. J., Jr. U.S. Patent 5,312,831, 1994 Chem. Abstr. 1995,
122, 106538j.
5. Sato, M.; Mukoyama, H.; Kobayashi, J.; Tsuyuki, S.;
Tokutake, Y.; Akaha, S. Japan Patent 2001011037, 2001
Chem. Abstr. 2001, 134, 100592y.
6. Noda, K.; Nakagawa, A.; Yamagata, K.; Hechiya, T.; Ide,
H; Koda, A. U.S. Patent 4,228,304, 1980 Chem. Abstr.
1980, 92, 022815w.
7. (a) Hi Iron, A. J. Am. Chem. Soc. 1949, 71, 81–84(b)
Gavrilovic, D. M. U.S. Patent 4,013,582, 1977; Chem.
Abstr. 1977, 86, 198026e.
In summary, we have described a convenient synthetic
approach to the amino acid derivatives of trans-4-alkyl-
cyclohexanecarboxylic acids, featuring a convenient
RNC-5-catalyzed hydrogenation of 4-alkylbenzoic acids
as the key step. Even in the case of bulky and long-chain
4-alkyl groups, the ruthenium–nickel-catalyzed hydro-
genation followed by alkali-mediated isomerization
provides high yields of pure trans-4-alkylcyclohexane-
carboxylic acids as compared to alternative methods.
Considering the ease of preparation of the initial reac-
tants, convenient synthesis and isolation of products,
and the overall good chemical yields of the described
transformations, this route provides a new valuable
entry to novel stereomerically pure peptidomimetics,
which are of significant interest as promising physiolog-
ically active agents.
8. (a) London, D. T. J. Org. Chem. 1963, 28, 1770–1773; (b)
Levin, R. H.; Pendergrase, I. H. J. Am. Chem. Soc. 1947,
69, 2336–2438.
3. Experimental protocol for the hydrogenation of
4-alkylbenzoic acids
9. Toyoshima, S.; Seto, Y.; Shinkai, H.; Toi, K.; Kumashiro,
I. U.S. Patent 4,816,484, 1989 Chem. Abst. 1987, 106,
85057d.
10. (a) Shubert, H.; Uhlig, V.; Behne, R. Zeitschr. Chem.
1972, 12, 219–220; (b) Kovshev, E. I.; Karamisheva, L. A.;
Geyvandova, T. A. Zhurn. Prikl. Khim. USSR 1983, 56,
2550–2555.
4-Alkylbenzoic acids 1–5 were purchased from Aldrich.
4-(trans-4-Alkylcyclohexyl)benzoic acids 6, 7 were syn-
thesized as reported.16
4-Alkylbenzoic acid (20g), RNC-5 (3g) and 10% aque-
ous NaOH (100mL) were placed in an autoclave
equipped with a high-speed mixer. The mixture was
11. (a) Gurskii, R. N.; Istratova, R. V.; Kirova, A. V.;
Kotlyar, S. A.; Ivanov, O. V.; LukÕyanenko, N. G. J. Org.
Table 2. Amino acid derivatives synthesized in this work (Scheme 1)
Compound
R
R1
R2
Yield from 8–14 (%)
15
16
CH3
CH3
(CH3)2CH
(CH3)2CHCH2
H
H
80
60
17
CH3
62
18
19
20
21
22
C3H7
C4H9
C5H11
C6H13
C6H13
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
CH3S(CH2)2
H
H
H
H
H
65
66
77
60
68
C3H7
23
(CH3)2CH
H
65
C5H11
24
(CH3)2CH
H
68