Regiospecific synthesis of 2,3-disubstituted-L-histidines and histamines

Article abstract of DOI:10.1016/S0960-894X(01)00154-8

Regiospecific synthesis of 2,3-disubstituted-L-histidines and 2,3-disubstituted histamines starting from L-histidine methyl ester and histamine is reported. The key step involves homolytic free radical alkylation via silver catalyzed oxidative decarboxyla

Full text of DOI:10.1016/S0960-894X(01)00154-8

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1133–1136
Regiospecific Synthesis of 2,3-Disubstituted-L-Histidines and
Histaminesy
Sanju Narayanan, Suryanarayana Vangapandu and Rahul Jain*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67,
S.A.S. Nagar-160 062, Punjab, India
Received 20 December 2000; accepted 24 February 2001
Dedicated to the memory of Dr. Louis A. Cohen
Abstract—Regiospecific synthesis of 2,3-disubstituted-l-histidines and 2,3-disubstituted histamines starting from l-histidine methyl
ester and histamine is reported. The key step involves homolytic free radical alkylation via silver catalyzed oxidative decarboxyl-
ation of alkylcarboxylic acids with ammonium persulfate. # 2001Elsevier Science Ltd. All rights reserved.
With the increasing importance of enzymes and peptide
hormones as targets for biological intervention, the
synthetic derivatization of the genetically coded amino
acids and their incorporation into peptides has become
one of the attractive strategies for the preparation of
hormone agonist/antagonists and enzyme inhibitors of
pharmacological importance.1 These synthetic building
blocks of complex peptides are much more versatile for
drug development. For example, they can circumvent
the enzymatic degradation due to proteolysis, and
thereby enhance the transport and absorption of
peptide drugs.
Synthetic design of ring-substituted bioimidazoles, such
as histidine and histamine is an arduous task that
depends on the targeted ring position, and of these, the
C-2 position presents the greatest challenge. Direct
introduction of the alkyl group at the C-2 position of
histidine or histamine by electrophilic substitution is not
possible, because all electrophiles react preferentially at
the C-5 position of the imidazole ring. Nucleophilic
substitution on the imidazole ring is likewise a problem,
requiring activation of the ring through placement of an
electron withdrawing group on the ring. At the same
time, the NH group of the ring requires selective pro-
tection, as the nucleophile would abstract the proton.
On account of their implications in many physiological
responses, histidine and histamine consisting of the aza
aromatic imidazole ring are referred to collectively as
bioimidazoles. Histidine is often an important amino
acid at the active site of numerous enzymes, and
appears to be essential for the recognition of peptide
hormones by their receptors.2 It is also known, for
example, that the derivatized histidine containing pep-
tides have a significant role in drug discovery.3 On the
other hand, involvement of histamine in a wide variety
of physiological responses4 including that for allergic
and gastric manifestations have stimulated immense
interest in the development of new synthetic methodo-
logies for these novel bioimidazole derivatives.
One of the major efforts of our laboratory has been the
design and synthesis of novel ring-substituted-l-histi-
dines for the purpose of obtaining highly potent thyro-
tropin-releasing hormone (TRH) analogues. Towards
this end, we have previously reported general regio-
specific synthetic routes to N(1)t-alkyl-l-histidines and
N(1)t-alkyl histamines,5 2-substituted-l-histidines and
2-substituted histamines,6 1,2-disubstituted-l-histidines
and 1,2-disubstituted histamines,7 and more recently, an
efficient and practical synthesis of ring-halogenated-l-
histidines and ring-halogenated histamines.8 We have
demonstrated, as evident from reports,6,7 that the
synthesis of 2-alkyl and 1,2-dialkyl bioimidazoles could
be efficiently achieved by direct regiospecific alkylation
at the C-2 position of suitably protected histidine and
histamine via silver catalyzed radical oxidative
decarboxylation of alkylcarboxylic acids by ammonium
persulfate in 10% H2SO4 as solvent based upon the
*Corresponding author. Tel.: +91-172-214682; fax: +91-172-214692;
e-mail: rahuljain@mailmetoday.com
yNIPER Communication no. 87.
0960-894X/01/$ - see front matter # 2001Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00154-8

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S. Narayanan et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1133–1136
modifications of the procedures described by Minisci et
al.9 for the alkylation of aza heteroaromatics. As
observed by us earlier, the method fails for more stable
and less nucleophilic radicals such as aryl, heteroaryl
and benzyl. However, it is the only method available for
the direct regiospecific introduction of primary, secondary
and tertiary alkyl groups of varying sizes at the C-2 posi-
tion of the histidine and histamine. This communication
describes the extension of these methodologies to include
the first general route to hitherto unknown chiral 2,3-di-
alkyl-l-histidines and 2,3-dialkylhistamines (15 and 16).
and 8) on treatment with methyl iodide or benzyl bro-
mide in acetonitrile at reflux temperature for 24 h gave
the 1,3-dialkylated imidazolium quaternary compounds
(9 and 10). No attempts were made to purify com-
pounds 9 and 10 due to their extremely hygroscopic
nature. However, crude 9 and 10 obtained by dropwise
addition of their solutions in acetonitrile to vigorously
stirred anhydrous ether, on treatment with glacial acetic
acid/methanol (1:1) and zinc dust under ultra-sonication
conditions provided 3-alkyl-N-a-carbomethoxy-l-histi-
dines (11) and 3-alkyl-N-a-carbomethoxyhistamines (12)
in 70–90% yield after column chromatography (EtOAc/
CH3OH, 95:5) (Scheme 1).
Key intermediates 3-alkyl-a-carbomethoxy-l-histidines
(11) and 3-alkyl-a-carbomethoxyhistamines (12)
required for the synthesis of 2,3-disubstituted-l-histi-
dines and 2,3-disubstituted histamines are synthesized
according to Scheme 1.10 Thus, 5,6,7,8-tetrahydro-5-
oxoimidazo[1,5-c]pyrimidines (3, 4), obtained by react-
ing 1 and 2 with 1,10-carbonyl-diimidazole in DMF at
60 ꢀC for 5–8 h, led to 2-phenacyl substituted qua-
ternary salts 5 and 6, on treatment with phenacyl bro-
mide in acetonitrile under reflux conditions.5,10
Compounds 5 and 6 on refluxing with methanol in the
presence of N,N-diisopropylethylamine for 5 days gave
fully protected 1-phencyl-N-a-carbomethoxy-l-histidine
methyl ester (7) and 1-phencyl-N-a-carbomethoxy-
histamine (8) (Scheme 1).5,10,11 The latter compounds (7
Homolytic radical alkylation of 3-alkyl-N-a-carbo-
methoxy-l-histidines (11) and 3-alkyl-N-a-carbo-
methoxyhistamines (12) with various commercially
available alkylcarboxylic acids in the presence of
ammonium persulfate and catalytic silver nitrate in 10%
H2SO4 at 70 ꢀC for 15 min readily provided protected
2,3-dialkyl bioimidazoles 13 and 14 in 12–45% yield
(Table 1, Scheme 2).12,13 Representative biologically
important groups like tert-butyl, isopropyl, cyclohexyl
and adamantyl were easily introduced at the C-2 position
of the imidazole ring. As reported earlier, reaction is
highly regiospecific in nature, with no apparent alkyla-
tion observed at the C-5 position of the imidazole ring.5
Scheme 1.
Table 1. C-2 alkylation of protected 3-alkyl-l-histidines and histamines
R1
R2
% Yield
% Yield
[a]2D5 (15)
13
14
1516
a) CH3
b) CH3
c) CH2C6H5
d) CH2C6H5
e) CH2C6H5
f) CH2C6H5
c-C6H11
C(CH3)3
Adamantyl
c-C6H11
CH(CH3)2
C(CH3)3
43
45
12
40
42
45
nda
nd
15
42
44
43
80
85
95
87
82
85
nd
nd
89
83
91
90
ꢁ15.2ꢀ (c=1.0, H2O)
ꢁ23.7ꢀ (c=1.2, H2O)
ꢁ10.4ꢀ (c=1.1, H2O)
ꢁ7.9ꢀ (c=1.25, H2O)
ꢁ8.8ꢀ (c=1, CH3OH)
ꢁ11.2ꢀ (c=1, CH3OH)
and (not done).

S. Narayanan et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1133–1136
1135
Scheme 2.
Compounds 13 and 14 were smoothly deprotected by
reaction with 6 N HCl at reflux temperature to provide
dihydrochloride salts of 2,3-dialkyl-l-histidines (15)14,15
and 2,3-dialkylhistamines (16).16 In the case of 2,3-di-
alkylhistidines the free amino acids were obtained by
ion-exchange chromatography (Dowex, 50ꢂ2-200, H+
form) after eluting the column with 15% NH4OH,
whereas the histamine derivatives were directly obtained
by evaporation after acid hydrolysis.
G.; Cohen, L. A.; Labroo, V. M. Eur. J. Pharmacol. 1989, 164,
77.
4. (a) Goot, H.; Timmerman, H. Eur. J. Med. Chem. 2000, 35,
5. (b) Scozzafava, A.; Supuran, C. T. Eur. J. Med. Chem.
2000, 35, 31. (c) Elz, S.; Kramer, K.; Leschke, C.; Schunack,
W. Eur. J. Med. Chem. 2000, 35, 41. (d) Elz, S.; Kramer, K.;
Pertz, H. H.; Detert, H.; Laak, A. M.; Kuhne, R.; Schunack,
¨
W. J. Med. Chem. 2000, 43, 1071.
5. Jain, R.; Cohen, L. A. Tetrahedron 1996, 52, 5363.
6. Jain, R.; Cohen, L. A.; El-Kadi, N. A.; King, M. M. Tet-
rahedron 1997, 53, 2365.
7. Jain, R.; Cohen, L. A.; King, M. M. Tetrahedron 1997, 53,
4539.
8. Jain, R.; Avramovitch, B.; Cohen, L. A. Tetrahedron 1998,
54, 3235.
Typical procedure for homolytic radical alkylation
A freshly prepared solution of ammonium persulfate
(3 mmol) in water (10 mL) was added dropwise to a pre-
heated (70 ꢀC) mixture of 11 or 12 (1mmol), silver
nitrate (0.6 mmol) and alkylcarboxylic acid (2.5 mmol)
in 10% H2SO4 (20 mL) during 10 min. The heating
source was then removed and reaction proceeded with
evolution of carbon dioxide. After 10 min, the reaction
mixture was poured onto ice, and the resulting mixture
was made alkaline with addition of 30% NH4OH. This
was extracted with ethyl acetate (4ꢂ50 mL), and the
combined extracts were washed with NaCl solution
(2ꢂ10 mL), dried over Na2SO4, and the solvent
removed in vacuo to afford oil, which on flash column
chromatography [EtOAc/CH3OH, 95:5] over silica gel
(230–400 mesh) gave 13 or 14 (Table 1).
9. (a) For mechanistic aspects of the homolytic radical reac-
tion, please see: Minisci, F.; Bernardi, R.; Bertini, F.; Galli,
R.; Perchinummo, M. Tetrahedron 1971, 27, 3575. (b) Minisci,
F.; Visamara, E.; Fontana, F.; Morini, G.; Serravalle, M.;
Giordano, C. J. Org. Chem. 1987, 52, 730. (c) Giordano, C.;
Minisci, F.; Visamara, E.; Levi, S. J. Org. Chem. 1986, 51, 536.
(d) Visamara, E.; Serravalle, M.; Minisci, F. Tetrahedron Lett.
1986, 27, 3187. (e) Anderson, J. M.; Kochi, J. K. J. Am. Chem.
Soc. 1970, 92, 1651. (f) Minisci, F. Synthesis 1973, 1. (g) Minisci,
F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489.
10. Chivikas, C. J.; Hodges, J. C. J. Org. Chem. 1987, 52,
3591.
11. Gonzalez, F. B.; Baz, J. P.; Santinelli, F.; Real, F. M. Bull.
Chem. Soc. Jpn. 1991, 64, 674.
12. Spectral data for N-carbomethoxy-2-tert-butyl-3-benzyl-
l-histidine methyl ester (13f): mp 97–99 ꢀC; IR (KBr), 3418,
2955, 1715, 1562, 1263; 1H NMR (CDCl3) d 1.36 (s, 9H,
3ꢂCH3), 2.78 (t, 2H, CH2, J=5.9 Hz), 3.64 (s, 3H, OCH3),
3.69 (s, 3H, OCH3), 4.48 (m, 1H, CH), 5.24 (bs, 1H, NH), 6.78
(s, 1H, 5-Ar-H), 6.86 (m, 2H, Ar-H), 7.29 (m, 3H, Ar-H); ana-
lysis for C20H27N3O4 (373.5), calcd C, 64.32; H, 7.29; N, 11.25;
found C, 64.32; H, 7.25; N, 11.33; HRMS m/z 374 (M+1).
13. Spectral data for N-carbomethoxy-2-cyclohexyl-3-benzyl-
histamine (14d): mp 86–88 ꢀC; IR (KBr), 3443, 2932, 2854,
The results summarized now establish the first direct
regiospecific synthesis of previously inaccessible 2,3-di-
substituted-l-histidines and 2,3-disubstituted hista-
mines. The key to the synthesis is the free radical
alkylation of the protonated 3-substituted bioimidazoles
via silver catalyzed oxidative decarboxylation of acids
with peroxydisulfate.
1
1711, 1217, 756; H NMR (CDCl3) d 1.24 (m, 4H, 2ꢂCH2),
1.73 (m, 6H, 3ꢂCH2), 2.52 (m, 2H, CH), 2.58 (m, 2H, CH2),
3.62 (s, 3H, OCH3), 5.80 (bs, 1H, NH), 5.08 (s, 2H, CH2), 6.82
(s, 1H, 5-Ar-H), 6.88 (m, 2H, Ar-H), 7.30 (m, 3H, Ar-H); ana-
lysis for C20H27N3O2 (341.5), calcd C, 70.35; H, 7.97; N, 12.31;
found C, 70.22; H, 7.65; N, 12.37; MS (EI) m/z 341(M +).
14. Spectral data for 2-tert-butyl-3-benzyl-l-histidine (15f):
mp 217–219 ꢀC (dec.); IR (KBr), 3387, 2981, 1738, 1409, 736;
References and Notes
1. (a) Hocart, S. J.; Jain, R.; Murphy, W. A.; Taylor, J. E.;
Morgan, B.; Coy, D. H. J. Med. Chem. 1998, 41, 1146. (b)
Hocart, S. J.; Jain, R.; Murphy, W. A.; Taylor, J. E.; Coy,
D. H. J. Med. Chem. 1999, 42, 1863.
2. (a) Timmermans, P. B. M. W. M.; Smith, R. D. In Burger’s
Medicinal Chemistry and DrugDiscovery: Therapeutic Agents ,
5th ed.; Wolff, M. F., Eds.; Wiley-Interscience: New York,
1996; Vol. 2, pp 265–321. (b) Perlman, J. H.; Colson, A.-O.;
Jain, R.; Czyzewski, B.; Cohen, L. A.; Osman, R.; Ger-
shengorn, M. C. Biochemistry 1997, 36, 15670.
1H NMR (D2O) d 0.79 (m, 9H, 3ꢂCH3), 2.41(m, 2H, CH ),
2
3.28 (m, 1H, CH), 4.98 (s, 2H, CH2), 6.38 (d, 2H, Ar-H), 6.72
(m, 2H, Ar-H), 6.78 (s, 1H, 5-Ar-H); analysis for C17H23N3O2
(301.4), calcd C, 67.75; H, 7.69; N, 13.94; found C, 67.80; H,
7.55; N, 13.50; HRMS m/z 302 (M+1); [a]2D5 ꢁ11.2ꢀ (c=1,
CH3OH). TLC system A (nBuOH/AcOH/H2O, 2:1:1), Rf=0.6
(one spot); TLC system
2:1:1:1), Rf=0.55 (one spot).
B (EtOAc/nBuOH/AcOH/H2O,
3. (a) Faden, A. I.; Labroo, V. M.; Cohen, L. A. J. Neuro-
trauma 1993, 10, 101. (b) Vanhof, S.; Paakkari, I.; Feuerstein,
15. The optical purity of modified histidine analogues were
assessed on HPLC using CHIRALPAK WH chiral column

1136
S. Narayanan et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1133–1136
(ID 0.46 cm, particle size 10 mm), and results indicate presence
of 40.8% of the d-enantiomer in all cases.
16. Spectral data for 2-cyclohexyl-3-benzylhistamine dihy-
CH2, J=7.4 Hz), 2.23 (m, 2H, CH2), 4.55 (s, 2H, CH2), 6.19
(d, 2H, Ar-H), 6.73 (m, 3H, Ar-H), 6.82 (s, 1H, 5-Ar-H); ana-
.
lysis for C18H25N3 2HCl (356.3), calcd C, 60.67; H, 7.63; N,
drochloride (16d): mp 203–205 ꢀC (dec.); IR (KBr), 3390,
11.79; found C, 60.88; H, 7.67; N, 12.01; HRMS m/z 284
(M+1).
1
1405; H NMR (D2O) d 0.59 (m, 10H, 5ꢂCH2), 2.08 (t, 2H,