Preparation of N(π)-alkyl- histamine and histidine derivatives through efficient alkylation followed by deprotection using activated silica gel

Article abstract of DOI:10.1016/S0040-4039(00)01792-5

Efficient N(π)-alkylation of L-histidine and histamine derivatives through employment of N(τ)-tritylprotection was achieved and regioselective removal of the N(τ)-trityl group in the presence of either Bocor trityl-protected primary amine was effected bas

Full text of DOI:10.1016/S0040-4039(00)01792-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10031–10034
Preparation of N(p)-alkyl- histamine and histidine
derivatives through efficient alkylation followed by
deprotection using activated silica gel
B. Moon Kim,* Joon Shik Park and Jong Hyun Cho
School of Chemistry & Molecular Engineering and Center for Molecular Catalysis, Seoul National University,
Seoul 151-747, South Korea
Received 20 September 2000; accepted 13 October 2000
Abstract
Efficient N(p)-alkylation of
L
-histidine and histamine derivatives through employment of N(t)-trityl-
protection was achieved and regioselective removal of the N(t)-trityl group in the presence of either Boc-
or trityl-protected primary amine was effected based on a mild hydrolysis mediated by activated silica gel
with 0.1–0.2% trifluoroacetic acid. © 2000 Elsevier Science Ltd. All rights reserved.
Substituted histamine and histidine derivatives are often core constituents in biologically
active compounds.1–3 Both histidine and histamine have two common functional groups, i.e. an
imidazole ring and a primary amine. The imidazole ring can be used as a useful scaffold for the
construction of compounds possessing a conformational constraint such as a turn or extended
structural motif, thus selective introduction of N(t)- or N(p)-substituent in the imidazole ring is
of considerable importance in preparing peptidomimetic structures. However, methods for
general and efficient construction of N(p)-alkylated histamine or histidine derivatives have not
been widely available. Some of the known methods of alkylation have been limited to the
purpose of installing a blocking group which protects the N(p)-position against racemization of
histidine at the a-carbon center in peptide synthesis.4 During the course of a solution-phase
combinatorial library synthesis of histidine and histamine derivatives, we needed a general and
highly efficient alkylation method at the N(p)-position and selective removal of the N(t)-protec-
tion in the presence of N-(tert-butyloxycarbonyl)- (Boc-) or N-triphenylmethyl- (Trt-) protected
primary amine. Herein we wish to report such alkylation through employment of N(t)-Trt-pro-
tected histamine or histidine derivatives and regioselective removal of N(t)-trityl group in the
presence of either Boc- or trityl-protected primary amine based on a mild hydrolysis mediated
by activated silica gel.
* Corresponding author. E-mail: kimbm@snu.ac.kr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01792-5

10032
Introduction of various alkyl groups such as phenylacyl-, t-butoxymethyl-, benzyloxymethyl-,
or benzyl groups at the N(p)-position of histidine derivatives equipped with Boc-, Cbz-, Trt-, or
Fmoc-protecting groups at the N(t)-position of the imidazole ring and primary amine has been
reported.5–9 However, several drawbacks have been associated with some of these methods.
Bis-acylated histidines at the N(t)- and primary amine positions have low nucleophilicity
towards alkylating agents. On the other hand, N(t)-trityl histidine derivatives with the primary
amine protected with Boc, Cbz, or Trt group exhibited higher nucleophilicity and allowed for
the use of a wide variety of alkylating agents. However, various basic and acidic deprotecting
conditions for the trityl group from the imidazolium salt intermediate afforded only moderate
yields of the desired products. Also, selective removal of Boc and Trt groups at the N(t)-posi-
tion in the presence of those at the primary amine-position of histidine derivatives under acidic
conditions has been troublesome.4 In particular, selective deprotection the N(t)-trityl group of
histidine and histamine intermediate salts (2) with Boc or Trt group at the primary amine under
acidic conditions has not been reported. In this communication we disclose an easy and
convenient strategy for the synthesis of N(p)-alkylated histidine and histamine derivatives
protected at the primary amine position with Boc or Trt group under extremely mild conditions
(Scheme 1).
R
N
R
N
NHProt
R1
NHProt
R1
NHProt
R1
N
RX, Et3N, DMF
rt or 50 oC
silica gel
N
Trt
N
Trt
Method A or B
N
1
2
3
R1 = H or CO2Me
Prot: = Boc or Trt
Scheme 1. Alkylation and deprotection of histamine or histidine derivatives
The histidine and histamine derivatives protected at the N(t)- and the primary amine with Trt
or Boc group were synthesized by following the literature procedure.10,11 Products obtained
through this procedure exhibited purities higher than 95% according to HPLC analyses.
Alkylation at the nitrogen of the N(p)-position of histidine and histamine derivatives (1)
proceeded smoothly with many commercially available aryl bromides (room temperature), allyl
bromide or n-hexyl iodide (5.0 equiv., 50°C) in DMF over a period of 24–48 h (Table 1). It is
noteworthy that the introduction of n-hexyl group was accomplished in high yields under these
conditions. Benzyl or alkyl chloride was found to be unreactive towards the N(t)-Trt histidine
and histamine derivatives, which is consistent with the literature report.9
In the course of removing excess alkylating agents, we found that the resulting trityl group of
the imidazolium salt intermediates was partially cleaved when eluted with 5% methanolic
dichloromethane on silica gel columns to give a small amount of N(p)-alkylated derivatives (3).
Recently it was also reported that N(t)- and amino-Boc histidine was selectively removed on
pre-activated silica gel.12 On the basis of these results, we tested deprotection of N(t)-trityl group
on the salt intermediates using activated silica gel. The salt intermediates of histidine and
histamine after alkylation were adsorbed onto silica gel which had been activated under reduced
pressure at 50°C for 12 h, and a 5% methanolic methylene chloride solution (2 mL g−1 of silica
gel) was added to the silica gel. The silica gel slurry was allowed to stir slowly for a period of
3 days at room temperature, when complete deprotection was observed by TLC (Method A). In

10033
Table 1
Preparation of N(p)-alkylated histidine and histamine derivatives
Entry
R1
Prot
Boc
Trt
RX
Alkylation
Deprotection
Method Time (h)
Yield (%) a
Time (h)
Temp. (°C)
1
2
3
4
5
6
7
8
9
4-NO2-C6H4CH2Br
4-Br-C6H4CH2Br
4-CN-C6H4CH2Br
3-CH3-C6H4CH2Br
C6H5CH2Br
4-NO2-C6H4CH2Br
4-CN-C6H4CH2Br
n-C6H11I
24
24
24
24
24
24
24
18
24
Rt
Rt
Rt
Rt
Rt
Rt
Rt
50
50
A
A
A
A
A
B
B
B
B
72
72
72
72
72
24
24
24
24
90
88
95
95
94
90
88
97
92
H
Allyl bromide
10
11
12
13
14
15
4-CN-C6H4CH2Br
4-NO2-C6H4CH2Br
4-CN-C6H4CH2Br
4-NO2-C6H4CH2Br
n-C6H11I
24
24
24
24
24
24
Rt
Rt
Rt
Rt
50
50
A
A
B
B
B
B
72
72
24
24
24
24
88
87
89
87
93
83
Allyl bromide
16
17
18
4-NO2-C6H4CH2Br
n-C6H11I
Allyl bromide
48
48
48
Rt
50
50
B
B
B
24
24
24
95
91
83
Boc
Trt
19
20
21
22
CO2Me
4-NO2-C6H4CH2Br
n-C6H11I
Allyl bromide
Benzyl bromide
36
24
48
24
Rt
50
50
50
B
B
B
B
24
24
24
12
83
85
82
80
a Isolated yields after two steps.
order to speed up the reaction, a small amount of trifluoroacetic acid (TFA) was added to the
slurry otherwise under the same conditions. Thus by employing 0.1–0.2% of TFA in methanol,
the deprotection of the N(t)-trityl group on the salt intermediate was complete within 24 h to
furnish only N(p)-alkylated histamine and histidine derivatives in excellent yields (Method B).13
However, when more than 0.5% TFA was employed, a partial cleavage of the Boc or Trt group
at the primary amine was observed through HPLC analysis.
In order to investigate the stereochemical integrity of the alkylation/selective deprotection
process, we have examined the enantiomeric purity of an -histidine methyl ester derivative by
L
comparing with a racemic derivative. Chiral HPLC analyses of both derivatives (Daicel Chiracel
OD column; eluent: hexane/2-propanol 93:7; 0.5 mL min−1) clearly indicated no epimerization at
the a-center of the -histidine derivative.
L
In summary, a general and efficient alkylation strategy has been developed at the N(p)-posi-
tion of the imidazole moiety of histamine or histidine, and selective removal of the N(t)-trityl
group at imidazolium salt intermediate was achieved through the use of a pre-activated silica gel
with methanolic methylene chloride solution containing 0.1–0.2% of TFA to give N(p)-alkylated
histamine and histidine derivatives. This method has been successfully exploited in a solution-

10034
phase combinatorial synthesis of biologically active compounds containing the histidine and
histamine cores and the result will be reported in due course.
Acknowledgements
This work was supported by grants from the Korea Science and Engineering Foundation
through Center for Molecular Catalysis. J.S.P. and J.H.C. thank the Brain Korea 21 Program
of the Ministry of Education, Korea for their BK21 fellowships.
References
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13. General procedure: To a stirred solution of N(a)-Trt-N(t)-Trt-L-histidine methyl ester (0.10 g, 0.15 mmol) in 0.50
mL of DMF was added benzyl bromide (0.13 g, 0.77 mmol). The reaction mixture was allowed to stir for 48 h
at 50°C. When the reaction was complete (monitored by HPLC), the solvent was removed under reduced
pressure. Excess benzyl bromide was removed by filtering through a pad of silica gel (5% methanol in CH2Cl2).
The crude product was dissolved in 5% methanol in CH2Cl2 (6.0 mL). To the solution was added a 0.01 M TFA
solution in CH2Cl2 (0.02 mL, 0.15 mol%) and activated silica gel (2.0 g, preactivated under 0.1 mPa at 50°C for
12 h). The slurry was allowed to stir for 24 h at room temperature. The reaction mixture was filtered and washed
with 5% methanolic methylene chloride solution (15 mL×5). The combined filtrate was concentrated and purified
on silica gel chromatography (from CH2Cl2 to CH2Cl2:MeOH=95:5) to give N(a)-Trt-N(p)-benzyl-L-histidine
1
methyl ester (0.060 g, 0.12 mmol, 80% yield). Rf=0.60 (CH2Cl2:MeOH=95:5); H NMR (500 MHz, CDCl3) l
7.33 (s, 1H), 7.22–7.02 (m, 20H), 6.76 (s, 1H), 4.92 (s, 2H), 3.20 (m, 1H), 2.88 (s, 3H), 2.72 (m, 2H), 1.47 (br, 1H);
13C NMR (75 MHz, CDCl3) l 174.51, 145.58, 138.11, 136.04, 128.98, 127.95, 127.86, 126.75, 126.54, 126.48,
77.21, 71.03, 56.81, 51.49, 48.49, 30.31; IR (KBr, neat) 3358, 3057, 2927, 1731, 1684, 1599, 1486, 1448, 1373,
1250, 1207, 1169, 1113, 1033, 706 cm−1; LCMS (m/z) 502.7 (M+H)+ for C33H31N3O; HRFABMS (M+1)+ calcd
for C33H31N3O2 502.2416, found 502.2478.
.
.