Efficient preparation of urocanic acid derivatives from histidine

Article abstract of DOI:10.3987/COM-09-S(S)127

Urocanic acid derivatives have served as useful starting materials in several total synthesis endeavors in our lab. This paper describes a convenient, large-scale synthesis of several derivatives of urocanic acid via the net elimination of ammonia from hi

Full text of DOI:10.3987/COM-09-S(S)127

HETEROCYCLES, Vol. 80, No. 2, 2010
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HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1353 - 1358. © The Japan Institute of Heterocyclic Chemistry
Received, 4th September, 2009, Accepted, 3rd December, 2009, Published online, 3rd December, 2009
DOI: 10.3987/COM-09-S(S)127
EFFICIENT PREPARATION OF UROCANIC ACID DERIVATIVES
FROM HISTIDINE1
Carl J. Lovely,* Rasapalli Sivappa, Sabuj Mukherjee, Thomas Doundoulakis,
Heather M. Lima, and Muhammed Yousufuddin
Department of Chemistry and Biochemistry, The University of Texas at Arlington,
TX 76019, USA. lovely@uta.edu
Abstract – Urocanic acid derivatives have served as useful starting materials in
several total synthesis endeavors in our lab. This paper describes a convenient,
large-scale synthesis of several derivatives of urocanic acid via the net elimination
of ammonia from histidine.
INTRODUCTION
Inspired by the structural complexity presented by several members of the oriodin alkaloids,1 e.g.
ageliferin (3),2-4 we have initiated a number of total synthesis programs which feature the Diels-Alder
reaction of 4-vinylimidazoles prominently.5-9 The requisite 4-vinylimidazoles were prepared either from
the corresponding 4-iodoimidazole derivative through a Stille cross-coupling reaction or from
commercially available urocanic acid.5, 7, 10 From time-to-time, we were unable to obtain urocanic acid
from commercial sources, and as a result we have developed a method for its preparation (as the methyl
ester) from histidine through a net elimination of ammonia.11, 12 In this submission, we describe this
chemistry along with the selective N-protection of the methyl ester.
NH2
H
HN
O
N
N
HN
O
H
N
Br
Br
N
OR
H2N
N
H
N
N
H
HN
O
1: R = H, urocanoic acid
2: R = Me, methyl urocanoate
3: ageliferin
Figure 1. Urocanic acid and its relation to ageliferin
1
This manuscript is dedicated to Professor Akira Suzuki on the occasion of his 80th birthday.

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RESULTS AND DISCUSSION
Although there are methods in the literature for the preparation of urocanic acid derivatives, these involve
Wittig-like processes13-17 or cross-coupling processes18-21 which suffer from scalability or efficiency
issues; therefore, we sought an alternative approach. Our attention was drawn immediately to histidine as
it already contains the requisite carbon skeleton and just requires the introduction of unsaturation. A
number of possibilities exist for effecting this transformation, but we elected to convert the amino group
into a chloro group through diazotization in the presence of chloride ion, providing the -chloro acid 5 in
good yield.22 This material was immediately converted to the methyl ester by a Fischer esterification to
afford the –chloro ester 6 (Scheme 1). After some experimentation it was found that heating a DMF
solution of the ester and triethylamine at 70 C for 48 h provided the methyl ester of urocanic acid 2 in
60% yield.
NH
NH
O
O
N
N
O
O
N
N
OMe
N
OMe
Et3N, DMF
NaH, THF
MeOH, H2SO4
OH
OMe
70 C, 60%
then BnCl,
60 C, 75%
reflux, 90%
N
H
NH2
Cl
6
Ph
NaNO2,
HCl
4: X = NH2
5: X = Cl
2
7
Me2NSO2Cl,
NaH, THF,
87%
O
N
N
N
N
OMe
OMe
O
O
S
S
O
O
O
Me2N
Me2N
8
9
Scheme 1
In most of our total synthesis endeavors we have employed protected urocanoate esters specifically the
benzyl- and dimethylsulfamoyl derivatives 8 and 9 respectively (Scheme 1). These can be prepared in a
selective fashion by treatment of ester 2 with either BnCl or DMASCl under equilibrating conditions
from which the least hindered nitrogen is protected.7, 23 On larger scales, when we used the crude
product directly from the elimination reaction, we found that if the reactions were not heated a second
compound was produced in yields of up to 10%. X-Ray crystallography24 of this derivative
demonstrated that it was the regioisomeric product in which the DMAS group was attached to the more
hindered nitrogen atom. We have found previously that with other protecting groups (e.g., PG = Bn,
MOM, SEM) that mixtures of regioisomers are formed initially, but if the reaction mixture contains a
small excess of the corresponding protecting group donor (BnCl, MOMCl, SEMCl) and is heated,
isomerization occurs to provide predominantly the 4-isomer.23

HETEROCYCLES, Vol. 80, No. 2, 2010
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Figure 2. X-Ray crystal structure of the minor urocanoate ester 9
EXPERIMENTAL
1H and 13C NMR spectra were recorded as CDCl3 solutions unless otherwise indicated.25
Methyl 3-(Imidazol-4(5)-yl)-2-chloropropanoate (6):22 L-Histidine (10.0 g, 0.06 mol) was dissolved in
conc. HCl (75 mL) and cooled in an ice-bath with stirring. NaNO2 (10.0 g, 0.14 mol) in H2O (20 mL) was
added dropwise to the reaction mixture, maintaining the temperature between 0-5 C. The mixture was
stirred until the temperature reaches 0 C, then for another 1-1.5 h at room temperature. The solution was
filtered through a sintered-glass funnel to remove the precipitated NaCl, which was washed with MeOH
and the filtrate was evaporated under vacuum. To the remaining thick yellow liquid MeOH was added
and the NaCl ppt was also washed with MeOH. The combined MeOH solutions were evaporated under
vacuum. The residual -chloro urocanic acid was dissolved in anhydrous MeOH (150 mL), and then
anhydrous Na2SO4 (2.0 g) and concentrated sulfuric acid (8 mL) was added. The solution was heated at
reflux for 15 h. The MeOH was evaporated under vacuum and the resulting thick liquid was dissolved
in a small quantity of water and neutralized with saturated aqueous NaHCO3 solution until the evolution
of CO2 ceased. The cloudy aqueous layer was extracted repeatedly with CH2Cl2, the organic layer was
dried over Na2SO4 and the solvent was removed by rotary evaporation to provide 6 as a thick yellow
liquid (10.9 g, 90%) which was used directly in the next step without further purification.22 1H NMR:
δ 9.67 (b, 1H), 7.58 (s, 1H), 6.89 (s, 1H), 4.53 (t, J = 6.9 Hz, 3H), 3.70 (s, 3H), 3.30 (dd, J = 7.6, 14.5 Hz,
1H), 3.14 (dd, J = 7.6 Hz, 14.8 Hz, 1H). 13C NMR: δ 170.1, 135.3, 133.2, 117.2, 56.1, 53.1, 33.3.
Methyl 3-(Imidazol-4(5)-yl)-2-propenoate (2): Ester 6 (10.0 g, 0.05 mol) was dissolved in anhydrous
DMF (30 mL) and the reaction mixture was cooled to 0 C, then Et3N (20.8 mL, 0.15 mol, 3 equiv.) was

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added slowly. The mixture was allowed to come to room temperature and then heated to 70 C for 48 h.
The mixture was cooled to room temperature and precipitated solids were filtered and washed with ethyl
acetate. The ethyl acetate was removed under vacuum and the DMF was distilled off under vacuum. The
resulting residue was purified by column chromatography (EtOAc) from which a white solid was
obtained (4.84 g, 60%). Mp 92-94 C.26 1H NMR: δ 7.70 (s, 1H), 7.59 (d, J = 15.6 Hz, 1H), 7.28 (s,
1H), 6.45 (d, J = 15.6 Hz, 1H), 3.77 (s, 3H).
Methyl 3-(1-Benzylimidazol-4-yl)-2-propenoate (7): Ester 2 (20.0 g, 0.13 mol) was dissolved in THF
(300 mL) under an N2 atmosphere. The reaction mixture was cooled to 0 C and NaH (6.3 g, 0.16 mol,
60% in mineral oil) was added portionwise. The reaction mixture was allowed to come to room
temperature for 1.5 h, then again cooled to 0 C and neat benzyl chloride (19.6 ml, 0.17 mol) was added
dropwise. The resulting solution was stirred at 60 C for 10 h. After quenching with water (5 ml), the
solvent was removed under vacuum and the resulting solid was dissolved in CH2Cl2. The organic solution
was separated and aqueous layer was extracted repeatedly with additional portions of CH2Cl2. The
combined organic solutions were dried over anhydrous Na2SO4 and concentrated. The residue was
triturated with hexane to provide the benzyl protected methyl ester (24.0 g, 75%) as a colorless solid
which exhibited analytical data matching material prepared previously.7
Methyl 3-(1-(N,N-Dimethylsulfamoyl)imidazol-4-yl)-2-propenoate (8): Methyl ester 2 (20.0 g, 0.13
mol) was dissolved in THF (300 mL) under N2 atmosphere. The reaction mixture was cooled to 0 C and
NaH (5.5 g, 0.14 mol, 60% in mineral oil) was added portionwise. The reaction mixture was allowed to
come to room temperature for 1 h, then again cooled to 0 C and neat N,N-dimethylsulfamoyl chloride
(15.4 ml, 0.14 mol) was added dropwise. The reaction mixture was allowed to warm up to room
temperature and stirred overnight. After quenching with water (5 ml), the solvent was removed under
vacuum. The resulting solid was dissolved with CH2Cl2 and washed with water, brine, dried over
anhydrous Na2SO4 and concentrated.
Finally it was triturated with hexane to obtain pure
N,N-dimethylsulfamoyl protected methyl ester 8 (29.5 g, 87%) as colorless solid.7 In some cases, the
crude reaction mixture was purified by chromatography (CH2Cl2/ethyl acetate, 7:31:1) providing the 8
(30.0 g) and 9 (2.0 g) the latter as a colorless solid.
1
Methyl (2E)-3-(1-(N,N-Dimethylsulfamoyl)imidazol-5-yl)-2-propenoate (9): Mp: 150.5 °C. H
NMR (CDCl3):  = 7.99 (s, 1H), 7.87 (d, J = 16.0 Hz, 1H), 7.47 (s, 1H), 6.35 (d, J = 16.0 Hz, 1H), 3.78 (s,
3H), 2.87 (s, 6H); 13C NMR (CDCl3):  = 166.5, 140.8, 131.9, 129.7, 128.5, 52.0, 38.2; FT-IR (KBr,

HETEROCYCLES, Vol. 80, No. 2, 2010
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cm-1): 3113, 2952, 1699, 1626, 1385, 1353, 1314, 1241, 1096. Anal. Calcd for C9H13N3O4S: C, 41.69;
H, 5.05; N, 16.21. Found: C, 41.37; H, 4.98; N, 16.22.
X-Ray Crystallography:
Diffraction data were collected on a colorless prismatic crystal (approximate dimensions 0.35 x 0.15 x 0.05
mm3) at low temperature (T = -173 °C) on a Bruker SMART APEX CCD diffractometer with
graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The cell parameters for the organic complex
were obtained from the least-squares refinement of the spots (from 60 collected frames) using the SMART
program. A hemisphere of the crystal data was collected up to a resolution of 0.75 Å, and the intensity data
were processed using the Saint Plus program. All calculations for structure determination were carried out
using the SHELXTL package (version 6.1).24 Initial atomic positions were located by direct methods using
XS, and the structure was refined by least-squares methods using SHELX with 2615 independent
reflections and within the range of Θ = 1.98-28.27 (completeness 92.7%). Calculated hydrogen positions
were input and refined in a riding manner along with the attached carbons. CCDC 746411 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGEMENTS
We are grateful for the financial support of the Robert A. Welch Foundation (Y-1362), the National
Institutes of Health (GM066503) and the NSF (CHE-9601771, CHE-0234811) for provision of funding
for the NMR spectrometers used in this work. The X-ray crystallographic work was performed in the
Center for Nanostructured Materials at the University of Texas at Arlington.
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