Trityl-directed regiospecific synthesis of 2,3-disubstituted bioimidazoles

Article abstract of DOI:10.1081/SCC-120022183

We report an efficient trityl-directed regiospecific synthesis of 2,3-disubstituted-L-histdines and 2,3-disubstituted histamines starting from α-N-trifluoroacetyl-L-histidine methyl ester and α-N-trifluoroacetylhistamine respectively in five steps.

Full text of DOI:10.1081/SCC-120022183

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Trityl-Directed Regiospecific Synthesis of 2,3-
Disubstituted Bioimidazoles
Pooja Chandana a , Amit Nayyar a & Rahul Jain a
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research, S.A.S. Nagar, Punjab, India
Published online: 19 Aug 2006.
To cite this article: Pooja Chandana , Amit Nayyar & Rahul Jain (2003) Trityl-Directed Regiospecific Synthesis of 2,3-
Disubstituted Bioimidazoles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:16, 2925-2933, DOI: 10.1081/SCC-120022183
To link to this article: http://dx.doi.org/10.1081/SCC-120022183
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 16, pp. 2925–2933, 2003
Trityl-Directed Regiospecific Synthesis of
2,3-Disubstituted Bioimidazoles#
*
Pooja Chandana, Amit Nayyar, and Rahul Jain
Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and
Research, S.A.S. Nagar, Punjab, India
ABSTRACT
We report an efficient trityl-directed regiospecific synthesis of 2,3-
disubstituted-L-histdines and 2,3-disubstituted histamines starting
from a-N-trifluoroacetyl-L-histidine methyl ester and a-N-trifluoro-
acetylhistamine respectively in five steps.
Key Words: Bioimidazoles; Homolytic free-radical reaction; Trityl.
#NIPER Communication no. 162.
*Correspondence: Rahul Jain, Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar,
Punjab, 160 062, India; Fax: 91-172-214692; E-mail: rahuljain@niper.ac.in.
2925
DOI: 10.1081/SCC-120022183
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2926
Chandana, Nayyar, and Jain
INTRODUCTION
The continuing interest in design, synthesis, and use of non-
proteinogenic a-amino acids as building blocks in the design and synth-
esis of bioactive peptides and peptidomimetics has led to intense efforts
aimed at discovering new synthetic methodologies for these compounds.
The use of the ring-substituted histidines as substrate for the synthesis
of bioactive peptides,[1] and diverse biological activities of ring-substituted
histamines[2] has appealed to several research groups including our own.
However, to a large extent, the access to these important classes of
compounds are restricted due to lack to credible synthetic method-
ologies. Over the years, the research efforts of our group are directed
towards this end, and we have successfully reported synthesis of
several novel ring-substituted bioimidazoles such as histidine and
histamine.[3–6]
RESULTS AND DISCUSSION
We have recently utilized phenacyl group as the protection for N-1(t)
position of the imidazole ring, and that resulted in the first synthesis of
2,3-disubstituted L-histidines and histamines.[7] This synthetic strategy
consists of phencayl-directed regiospecific N-3(p) alkylation to provide
protected 3-substituted L-histidines and histamines, which upon homo-
lytic free radical alkylation led to successful realization of 2,3-disubsti-
tuted L-histidines and histamines. The protection of N-1(t) position of
the imidazole nucleus was required, because ring exists in two tautomeric
forms, and it is commonly known that direct ring alkylation almost
always results in a mixture of t(1) and p(3) derivatives. Although, the
t derivative is often the major product, it is rarely exclusive. Only two
classes of reagents, the halonitrobenzenes[8] and triarylmethyl halides[9–10]
are found to give exclusively t products. This clearly indicates that spe-
cific alkylation at the p nitrogen requires protection of the t nitrogen, in
addition to that of the side-chain functions.
Although, we have reported the first and only report on the synthesis
of 2,3-disubstituted L-histidines and histamines, we conclude that this
methodology suffers due to following disadvantages: (a) selective
N-1(t) protection of the imidazole ring by phenacyl group was achieved
in three steps that also requires use of expensive 1,10-carbonyl-diimid-
azole; (b) the intermediate imidazolium quaternary compounds were
found to be highly hygroscopic, and attempts towards their isolation

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2,3-Disubstituted Bioimidazoles
2927
and purification were not successful; (c) regiospecific N-3(p) alkylation of
the imidazole ring was achieved in five steps; (d) and finally, this seven-
step methodology had provided low-overall yield of the desired histidine
and histamine analogues.[7]
As a continuation of our search for easy availability of novel ring-
substituted bioimidazoles, this article describes an efficient and practical
synthetic route to 2,3-disubstituted L-histidines and histamines in five
steps. This alternate shorter strategy involves successful utilization of
triphenylmethyl group (trityl, Trt) for the protection of the N-1(t) nitro-
gen of the imidazole ring. In addition to the easy introduction in one step
in excellent yield, the trityl group was efficiently and cleanly removed
from t nitrogen of the imidazole ring under very mild conditions using
glacial acetic acid at ambient temperature.[10] However, the most impor-
tant aspect of the use of trityl protection was the realization of
the regiospecific N-3 substitution in three steps (Sch. 1) as compared
to five-steps in the case of phenacyl-directed N-3 substitution of the
imidazole ring.[7]
Thus, a-N-trifluoroacetyl-L-histidine methyl ester (1) and a-N-tri-
fluoroacetylhistamine (2) on reaction with triphenylmethyl chloride and
triethylamine in anhydrous benzene at reflux temperature for 1 h pro-
vided the exclusive N-1(t)-trityl group protected analogues (3 and 4) in
excellent yield (Sch. 1). The latter compounds 3–4 on treatment with
various commercially available alkyl halides in chloroform at
R
R
R
ii
i
N
N
NHCOCF3
N
N
NHCOCF3
HN
N
NHCOCF3
Ph3C
Ph3C
R1
X-
5. R=CO2CH3
6. R=H
3. R=CO2CH3
4. R=H
1. R=CO2CH3
2. R=H
iii
R
R
R
NHCOCF3
v
iv
N
N
NH2
N
N
NHCOCF3
N
N
R1
R1
R1
R2
R2
7a. R=CO2CH3, R1=CH2C6H5
7b. R=CO2CH3, R1=CH3
7c. R=CO2CH3, R1=C2H5
8a. R=H, R1=CH3
11. R=CO2H
12. R=H
9. R=CO2CH3
10. R=H
Scheme 1. Reagents and conditions: (i) Ph3CCl, NEt3, C6H6, reflux; (ii) R1X,
CHCl3, rt, 20 h; (iii) AgOAc, HOAc, 24–48 h; (iv) R2CO2H, AgNO3, (NH4)2S2O8,
10% H2SO4, 70ꢀC; (v) 6 N HCl, reflux, 8 h.

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2928
Chandana, Nayyar, and Jain
Table 1. Yields and [a]D of 2,3-dialkylated bioimidazole derivatives.
Yield (%)
Yield (%)
25
½aŠ (11)
No.
R1
R2
9
10
11
12
D
a
b
c
d
e
f
CH2C6H5 C(CH3)3
CH2C6H5 c-C5H9
CH2C6H5 c-C4H7
CH2C6H5 c-C3H5
48
44
39
21
45
38
95[7]
90
88[7] À11.9ꢀ (c ¼ 1, H2O)
90
92
95
nd
nd
nd
À8.5ꢀ (c ¼ 1, H2O)
À10.4ꢀ (c ¼ 1, H2O)
À7.2ꢀ (c ¼ 1, H2O)
À9.7ꢀ (c ¼ 1, H2O)
À19.8ꢀ (c ¼ 1.1, H2O)
À22.3ꢀ (c ¼ 1.2, H2O)
35
85
19
88
CH2C6H5 CH(CH3)2 35
nda
nd
nd
95[7]
88
CH3
C2H5
c-C5H9
c-C5H9
47
42
g
85
aNd (notdone).
ambient temperature for 20 h afforded corresponding imidazolium qua-
ternary salts (5–6). These imidazolium salts (5–6) were found to be highly
hygroscopic and every attempt towards their isolation proved to be
unsuccessful. Thus, crude salts 5–6 upon deprotection with glacial
acetic acid in the presence of silver acetate for 24–48 h provided a-N-
trifluoroacetyl-3-alkyl-L-histidine methyl ester (7) and a-N-trifluoroace-
tyl-3-alkylhistamine (8) in 60–88% yield. Compounds 7–8 on homolytic
free radical reaction with various commercially available alkylcarboxylic
acids in the presence of ammonium persulfate and silver nitrate in 10%
H2SO4 readily provided fully protected a-N-trifluoroacetyl-2,3-dialkyl-L-
histidine methyl esters (9) and a-N-trifluoroacetyl-2,3-dialkylhistamines
[4,5,7]
(10). As described by Jain etal. earlier,
the reaction proceeds
via silver catalyzed free radical oxidative decarboxylation of alkylcar-
boxylic acids by ammonium persulfate in 10% sulfuric acid as solvent.
Reaction is highly regiospecific,[11] and groups such as cyclopropyl, cyclo-
pentyl, and tert-butyl are easily introduced in 19–48% yields (Table 1). In
all cases, the 2,3-dialkyl-L-histidines (11) and 2,3-dialkylhistamines (12)
were obtained by the deprotection of 9 and 10 with refluxing 6 N HCl,
followed by ion-exchange chromatography (Dowex, 50 Â 2–200, Hþ
form) for the amino acids; whereas, histamine derivatives were isolated
as their hydrochloride salts by evaporation of the acid hydrolysis
solution.
In conclusion, this communication describes a facile trityl-directed
synthesis for 2,3-disubstituted bioimidazoles in five-step, each of which in
good yields, and that is more efficient and affordable compared to
phenacyl-directed approach for 2,3-disubstituted bioimidazoles reported
by us earlier.

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2,3-Disubstituted Bioimidazoles
EXPERIMENTAL
2929
Melting points were determined with a capillary apparatus and are
1
uncorrected. H NMR spectra were obtained on Bruker Avance DPX
(300 MHz) spectrometer using TMS as internal reference. Chemical
Ionization (CI) mass spectra were recorded on Shimadsu GCMS-QP
5000 spectrometer using methane as carrier reagent gas. Electron Spray
Ionization (ESI) spectra were recorded on a LCMS Finnigan Mat LCQ
spectrometer. Optical rotations were recorded on a Perkin–Elmer 241
MC Polarimeter. Elemental analyses were recorded on Elementar Vario
EL spectrometer. All chromatographic purification was performed with
silica gel 60 (230–400 mesh), whereas all TLC (silica gel) developmentwas
performed on silica gel coated (Merck Kiesel 60 F254, 0.2 mm thickness)
sheets.
Synthesis of a-N-Trifluoroacetyl-1-trityl-L-histidine
Methyl Ester (3) and a-N-Trifluoroacetyl-1-tritylhistamine (4)
A mixture of triphenylmethyl chloride (10 mmol), a-N-trifluoroace-
tyl-L-histidine methyl ester (1, 10 mmol) or a-N-trifluoroacetylhistamine
(2, 10 mmol), and triethylamine (10 mmol) in anhydrous benzene (50 mL)
was heated at reflux for 1 h. Reaction mixture was cooled, filtered, and
the solvent was evaporated to yield compounds (3–4) as off white solid.
a-N-Trifluoroacetyl-1-trityl-L-histidine methyl ester (3). Yield: 92%;
m.p. 102–104ꢀC. H NMR (CDCl3): ꢀ 3.15 (m, 2H, CH2), 3.67 (s, 3H,
1
CH3), 4.83 (m, 1H, CH), 6.65 (s, 1H, 5-Ar-H), 7.21 (m, 15H, Ar-H), 7.56
(s, 1H, 2-Ar-H). Anal. calcd.: C, 66.27; H, 4.77; N, 8.28. Found: C, 66.22;
H, 4.77; N, 8.25. ESIMS: m/z 508 (M þ 1).
a-N-Trifluoroacetyl-1-tritylhistamine (4). Yield: 95%; m.p. 120–123ꢀC.
1H NMR (CDCl3): ꢀ 2.78 (m, 2H, CH2), 3.66 (m, 2H, CH2), 6.61
(s, 1H, 5-Ar-H), 7.24 (m, 15H, Ar-H), 7.39 (s, 1H, 2-Ar-H). Anal. calcd.:
C, 69.48; H, 4.93; N, 9.35. Found: C, 69.44; H, 4.90; N, 9.29. ESIMS: m/z
450 (M þ 1).
General Procedure for the Synthesis of
a-N-Trifluoroacetyl-3-alkyl-L-histidine Methyl Esters (7)
and a-N-Trifluoroacetyl-3-alkylhistamines (8)
A mixture of a-N-trifluoroacetyl-1-trityl-L-histidine methyl ester (3,
1 mmol) or a-N-trifluoroacetyl-1-tritylhistamine (4, 1 mmol) and alkyl

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2930
Chandana, Nayyar, and Jain
halide (1.2 mol) in chloroform (2 mL) was stirred at room temperature for
20 h. The solvent was evaporated and residue was added to cold vigor-
ously stirred diethyl ether (25 mL). The solvent removed by filtration to
yield the imidazolium quaternary salts 5–6. To the solution of the imid-
azolium salt( 5–6) in glacial acetic acid (10 mL) was added silver acetate
(1 mmol) and reaction mixture was stirred for 24–48 h at ambient tem-
perature. Filtered, solvent was evaporated, and the resulting residue was
basified with 10% aqueous sodium carbonate solution. Extracted with
CH2Cl2 (2 Â 25 mL), dried (Na2SO4), and solventremoved in vacuo. The
resulting residue upon purification by column chromatography provided
compounds (7–8).
a-N-Trifluoroacetyl-3-benzyl-L-histidine methyl ester (7a). Yield:
75%; m.p. 130–135ꢀC. H NMR (CDCl3): ꢀ 3.17 (m, 2H, CH2), 3.79 (s,
1
3H, CH3), 4.69 (m, 1H, CH), 5.15 (s, 2H, CH2), 6.94 (s, 1H, 5-Ar-H), 7.11
(m, 2H, Ar-H), 7.37 (m, 3H, Ar-H), 7.52 (s, 1H, 2-Ar-H). Anal. calcd.: C,
54.09; H, 4.54; N, 11.83. Found: C, 54.13; H, 4.60; N, 11.77. ESIMS: m/z
356 (M þ 1).
a-N-Trifluoroacetyl-3-methyl-L-histidine methyl ester (7b). Yield:
65%; m.p. 98–99ꢀC. H NMR (CDCl3): ꢀ 3.10 (m, 2H, CH2), 3.63 (s,
1
3H, CH3), 3.80 (s, 3H, CH3), 4.81 (m, 1H, CH), 6.67 (s, 1H, 5-Ar-H),
7.39 (s, 1H, 2-Ar-H). Anal. calcd.: C, 43.02; H, 4.33; N, 15.05. Found: C,
43.20; H, 4.55; N, 14.89. ESIMS: m/z 280 (M þ 1).
a-N-Trifluoroacetyl-3-ethyl-L-histidine methyl ester (7c). Yield: 60%;
m.p. 88–90ꢀC. 1H NMR (CDCl3): ꢀ 1.50 (t, 3H, CH3), 3.15 (m, 2H, CH2),
3.82 (s, 3H, CH3), 3.99 (t, 2H, CH2), 4.75 (m, 1H, CH), 6.68 (s, 1H, 5-Ar-
H), 7.38 (s, 1H, 2-Ar-H). Anal. calcd.: C, 45.05; H, 4.81; N, 14.33. Found:
C, 45.27; H, 4.59; N, 14.21. ESIMS: m/z 294 (M þ 1).
a-N-Trifluoroacetyl-3-benzylhistamine (8a). Yield: 88%; m.p.
111–113ꢀC. 1H NMR (CDCl3): ꢀ 2.75 (m, 2H, CH2), 3.58 (m, 2H,
CH2), 4.77 (m, 1H, CH), 4.99 (s, 2H, CH2), 6.96 (s, 1H, 5-Ar-H), 7.07
(m, 3H, Ar-H), 7.14 (m, 2H, Ar-H), 7.32 (s, 1H, 2-Ar-H). Anal. calcd.: C,
56.56; H, 4.75; N, 14.14. Found: C, 56.44; H, 4.67; N, 14.33. ESIMS: m/z
298 (M þ 1).
Typical Procedure for the Synthesis of
2,3-Dialkyl-L-histidines (11) and 2,3-Dialkylhistamines (12)
a-N-Trifluoroacetyl-3-alkyl-L-histidine methyl ester (7, 1 mmol) or
a-N-trifluoroacetyl-3-alkylhistamine (8, 1 mmol), was added to a mixture
of silver nitrate (0.6 mmol) and alkylcarboxylic acid (2.5 mmol) in 10%
H2SO4 (10 mL), and the reaction mixture was heated at 70ꢀC. A freshly

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2,3-Disubstituted Bioimidazoles
2931
prepared solution of ammonium persulfate (3 mmol) in water (5 mL) was
added drop wise over 15 min. The heating source was removed and the
reaction proceeded with evolution of carbon dioxide. After 15 min, the
reaction was terminated by pouring it onto ice. The resulting mixture was
made alkaline with 25% NH4OH solution and extracted with ethyl
acetate (3 Â 25 mL). The combined extracts were washed with brine
(2 Â 5 mL) and dried (Na2SO4). The solventwas removed in vacuo ot
afford oil, which on chromatography over silica [ethyl acetate/hexanes
(8:2)] provided compounds (9–10) in 19–48% yield (Table 1). A solution
of 9 or 10 (1 mmol) in 6 N HCl (10 mL) was heated at reflux for 8 h. The
dihydrochloride salts of the 2,3-dialkyl-L-histidines (11) and 2, 3-dialkyl-
histamines (12) were obtained directly by evaporation of the acid hydro-
lysis solutions. A solution of the 2,3-dialkyl-L-histidine dihydrochloride
(11) in water (5 mL) was applied to an ion-exchange column (Dowex
50 Â 2–200, Hþ form). The column was eluted with water until neutral
to pH paper. The amino acid was eluted with 10% NH4OH solution.
Evaporation of solvent afforded the free crystalline amino acids 11.[12]
2-Cyclopentyl-3-benzyl-L-histidine (11b). M.p. 212–214ꢀC. H NMR
1
(D2O): ꢀ 1.73 (s, 4H, CH2), 2.14 (m, 4H, CH2), 2.48 (m, 1H, CH), 3.01
(m, 2H, CH2), 4.18 (m, 1H, CH), 5.49 (s, 2H, CH2), 7.03 (s, 1H, 5-Ar-H),
7.29 (m, 3H, Ar-H), 7.46 (m, 2H, Ar-H). Anal. calcd.: C, 68.98; H, 7.40;
N, 13.41. Found: C, 67.00; N, 7.53; N, 13.22. CIMS: m/z 314 (M þ 1).
2-Cyclobutyl-3-benzyl-L-histidine (11c). M.p. 205–209ꢀC. 1H NMR
(D2O): ꢀ 1.83 (m, 6H, CH2), 2.31 (m, 1H, CH), 2.94 (m, 2H, CH2),
4.21 (m, 1H, CH), 5.29 (s, 2H, CH2), 6.88 (s, 1H, 5-Ar-H), 7.09 (m,
3H, Ar-H), 7.36 (m, 2H, Ar-H). Anal. calcd.: C, 68.20; H, 7.07; N,
14.04. Found: C, 68.12; N, 7.30; N, 13.88. CIMS: m/z 300 (M þ 1).
2-Cyclopropyl-3-benzyl-L-histidine (11d). M.p. 199–202ꢀC. H NMR
1
(D2O): ꢀ 1.56 (m, 4H, CH2), 2.66 (s, 1H, CH), 3.15 (m, 2H, CH2), 4.10
(m, 1H, CH), 5.51 (s, 2H, CH2), 7.14 (s, 1H, 5-Ar-H), 7.34 (m, 3H, Ar-H),
7.52 (s, 2H, Ar-H). Anal. calcd.: C, 67.35; H, 6.71; N, 14.73. Found: C,
67.25; N, 7.85; N, 14.99. CIMS: m/z 386 (M þ 1).
2-Cyclopentyl-3-methyl-L-histidine (11e). M.p. 216–219ꢀC. H NMR
1
(D2O): ꢀ 1.53 (m, 4H, CH2), 1.83 (m, 4H, CH2), 2.82 (m, 1H, CH), 2.95
(m, 2H, CH2), 3.67 (s, 3H, CH3), 3.88 (m, 1H, CH), 6.99 (s, 1H, 5-Ar-H).
Anal. calcd.: C, 60.74; H, 8.07; N, 17.71. Found: C, 60.55; N, 7.99; N,
17.92. CIMS: m/z 238 (M þ 1).
2-Cyclopentyl-3-ethyl-L-histidine (11f ). M.p. 202–205ꢀC. 1H NMR
(D2O): ꢀ 1.55 (m, 7H, CH3, CH2), 1.85 (m, 4H, CH2), 2.75 (m, 1H,
CH), 2.93 (m, 2H, CH2), 3.89 (q, 2H, CH2), 3.99 (m, 1H, CH), 6.87 (s,
1H, 5-Ar-H). Anal. calcd.: C, 61.13; H, 8.42; N, 16.72. Found: C, 61.42;
N, 8.67; N, 16.99. CIMS: m/z 252 (Mþ1).

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2932
Chandana, Nayyar, and Jain
2-Cyclopentyl-3-benzylhistamine dihydrochloride (12b). M.p. 188–
191ꢀC. H NMR (D2O): ꢀ 1.89 (m, 8H, CH2), 2.54 (m, 2H, CH2), 2.83
(m, 3H, CH2 and CH), 5.21 (s, 2H, CH2), 6.88 (s, 1H, 5-Ar-H), 7.31 (m,
3H, Ar-H), 7.56 (m, 2H, Ar-H). Anal. calcd.: C, 59.65; H, 7.36; N, 12.28.
Found: C, 59.33; H, 7.09; N, 12.44. ESIMS: m/z 270 (M þ 1).
1
2-Cyclobutyl-3-benzylhistamine dihydrochloride (12c). M.p. 185–
189ꢀC. H NMR (D2O): ꢀ 1.99 (m, 6H, CH2), 2.64 (m, 2H, CH2), 2.97
1
(m, 3H, CH2 and CH), 5.17 (s, 2H, CH2), 6.93 (s, 1H, 5-Ar-H), 7.33(m,
3H, Ar-H), 7.52 (m, 2H, Ar-H). Anal. calcd.: C, 58.54; H, 7.06; N; 12.80.
Found: C, 58.55; H, 7.17; N, 12.89. ESIMS: m/z 256 (M þ 1).
2-Cyclopropyl-3-benzylhistamine dihydrochloride (12d). M.p. 182–
184ꢀC. H NMR (D2O): ꢀ 1.96 (m, 4H, CH2), 2.57 (m, 2H, CH2), 2.99
1
(m, 3H, CH2 and CH), 5.09 (s, 2H, CH2), 6.83 (s, 1H, 5-Ar-H), 7.37 (m,
3H, Ar-H), 7.59 (m, 2H, Ar-H). Anal. calcd.: C, 57.33; H, 6.74; N; 13.37.
Found: C, 57.54; H, 7.03; N, 13.55. ESIMS: m/z 242 (M þ 1).
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2933
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Received in the UK November 19, 2002

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