A stereospecific route to (Z)-Urocanic acids

Article abstract of DOI:10.1055/s-2008-1067044

(Z)-Urocanic acid and its derivatives can be made stereo-specifically by ring-opening of pyrrolo[l,2-c]imidazol-5-ones in aqueous tetrahydrofuran.

Full text of DOI:10.1055/s-2008-1067044

1676
SHORT PAPER
A Stereospecific Route to (Z)-Urocanic Acids
(Z
)-Urocanic Acid
a
s
vier L. M. Despinoy, Hamish McNab,* Richard G. Tyas
School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
Fax +44(131)6504743; E-mail: H.McNab@ed.ac.uk
Received 4 February 2008
CO2R
Abstract: (Z)-Urocanic acid and its derivatives can be made stereo-
specifically by ring-opening of pyrrolo[1,2-c]imidazol-5-ones in
aqueous tetrahydrofuran.
hν
N
N
CO2R
NH
NH
(Z)-1 R = H
(Z)-2 R = Me
(E)-1 R = H
(E)-2 R = Me
Key words: gas-phase reactions, hydrolyses, heterocycles, lac-
tams, urocanic acids
Scheme 1
R2
(E)-Urocanic acid [(E)-1] is a major chemical component
of the epidermis, formed from histidine by the enzyme
histidase in the stratum corneum.1 Upon ultraviolet irradi-
ation of the skin, trans-urocanic acid [(E)-1] isomerizes to
the cis-form (Z)-1, which is of current biomedical2 and
photophysical3 interest (Scheme 1). In particular, (Z)-uro-
canic acid [(Z)-1] is known to have an immunosuppres-
sive effect in vivo or in vitro and its mode of action has
been recently investigated.4
CO2Me
N
R1
NH
R2
2 R1 = R2 = H
N
N
R1
O
N
R1
N
4a R1 = Me, R2 = H
4b R1 = Me, R2 = Ph
4c R1 = R2 = H
CO2Me
R2
Photoisomerization of the commercially available E-iso-
mer (E)-15 or its methyl ester (E)-26 are the only known
routes to Z-urocanic acid [(Z)-1]. A photostationary equi-
librium between the two isomers is attained (at which the
conversion reaches 70%) and so a chromatographic sepa-
ration is necessary.5,7
3a R1 = Me, R2 = H
3b R1 = Me, R2 = Ph
Scheme 2
In practice, heating 4a–c in aqueous THF (in the absence
of any acidic or basic reagents) for three hours provided
(Z)-urocanic acid [(Z)-1] and its analogues (Z)-5a,b in
high yields (Scheme 3). The progress of the reaction could
be monitored by the disappearance of the characteristic
yellow color of the azapyrrolizinones. For the preparation
of (Z)-1, it is particularly important to minimize decompo-
sition of the azapyrrolizinone 4c by adding the THF–wa-
ter mixture directly to the azapyrrolizinone in the FVP
cold finger trap and carrying out the hydrolysis immedi-
ately after the pyrolysis step. Isolation and manipulation
of the azapyrrolizinone 4c can cause decomposition.
Relatively few derivatives of urocanic acids have been
synthesized, especially as Z-isomers, though fluorinated
analogues provide an interesting exception.8
In this paper, we report a new, stereospecific route to (Z)-
urocanic acid [(Z)-1] and its derivatives, by ring-opening
of the pyrrolo[1,2-c]imidazol-5-one (azapyrrolizinone9–12
)
system 4. These heterocycles are best made by flash vac-
uum pyrolysis (FVP) of (imidazol-4-yl)acrylate esters 2,
by
an
isomerization-elimination-electrocyclization
sequence10 or by FVP of 2-substituted (imidazol-1-
yl)acrylate esters 3, in which directed sigmatropic migra-
tion of the 1-substituent precedes the elimination and cy-
clization steps (Scheme 2).11,12
After the hydrolysis step, the products were isolated sim-
ply by removal of the solvents without the need for chro-
matography. In this way, the Z-urocanic acid [(Z)-1] and
its derivatives (Z)-5a,b were obtained in 72–89% overall
yields based on the pyrolysis precursor. The Z-configura-
tion of the alkene unit of (Z)-1 and (Z)-5a was clear from
their NMR spectra (3J = 12.5–13.0 Hz) and in the case of
(Z)-5b by a NOESY experiment. No isomerization of the
alkene took place under the hydrolysis conditions.
Few reactions of azapyrrolizinones have been published.
However, pyrrolizin-3-ones themselves are readily ring-
opened by treatment with hard nucleophiles7,13 and the
aza-analogues, which have an imidazole unit as a formal
leaving group, would be expected to show greater reactiv-
ity.
Good temperature control of the FVP step is essential.
Thus, on one occasion during optimization of the route to
(Z)-1, 4-ethynylimidazole (7) (15%) was obtained as an
impurity, which could be separated by chromatography
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Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067044; Art ID: P01208SS
© Georg Thieme Verlag Stuttgart · New York
1
after the hydrolysis. Its H-coupled 13C NMR spectrum

SHORT PAPER
(Z)-Urocanic Acids
1677
13C NMR (DMSO-d6): d = 167.24 (q), 144.95 (q), 133.90 (q),
129.98, 122.21, 118.31, 13.27.
R2
R2
H2O–THF
reflux
MS: m/z (%) = 152 (M+, 90), 135 (81), 134 (77), 108 (61), 107 (97),
106 (100), 105 (62), 79 (67).
N
N
N
CO2H
NH
R1
O
R1
HRMS: m/z calcd for C7H8N2O2 (M+): 152.0586; found: 152.0587.
4a R1 = Me, R2 = H
4b R1 = Me, R2 = Ph
4c R1 = R2 = H
(Z)-5a R1 = Me, R2 = H
(Z)-5b R1 = Me, R2 = Ph
(Z)-1 R1 = R2 = H
(Z)-3-(2-Methyl-3H-imidazol-4-yl)-3-phenylacrylic Acid [(Z)-
5b]
FVP of methyl 3-(2-methylimidazol-1-yl)-3-phenylacrylate (3b;
105 mg) (conditions: Tf 875 °C, Ti 160 °C, P 0.010–0.060 Torr, t 15
min) gave solid yellow 3-methyl-7-phenylpyrrolo[1,2-c]imidazol-
5-one (4b).12 The entire crude pyrolysate was dissolved in a mixture
of THF (2 mL) and H2O (10 mL), then transferred to a round-bot-
tomed flask and heated under reflux for 6 h during which time de-
colorization occurred. THF and H2O were removed using a rotary
evaporator and the product was dried under vacuum (oil pump) for
4 h to afford (Z)-5b; yield: 71 mg (72% for the two steps); mp >170
°C (dec. with gas evolution).
Scheme 3
– CO
N
N
N
N
CH
N
N
O
O
6
HN
N
1H NMR (DMSO-d6): d = 7.70–7.62 (5 H, br m), 7.14 (1 H, s), 5.85
(1 H, s), 2.68 (3 H, s).
7
13C NMR (DMSO-d6): d = 167.48 (q), 145.66 (q), 143.51 (q),
141.34 (q), 136.05 (q), 129.57, 129.33 (2 CH), 129.15 (2 CH),
122.57, 121.26, 13.88.
Scheme 4
confirmed the presence of the ethynyl group
(1JC,H = 251.9 Hz). This compound has been reported ex-
perimentally only in the patent literature. The mechanism
of its formation probably involves decarbonylation of the
ring-opened ketene 6 and rearrangement of the resulting
carbene (Scheme 4). Further elution of the column afford-
ed (Z)-urocanic acid [(Z)-1] (46%).
MS: m/z (%) = 228 (M+, 42), 210 (27), 183 (70), 182 (100), 181
(72), 169 (57), 168 (60), 128 (63), 115 (63), 114 (61).
HRMS: m/z calcd for C13H12N2O2 (M+): 228.0898; found:
228.0895.
(Z)-3-(3H-Imidazol-4-yl)acrylic Acid [cis-Urocanic Acid, (Z)-1]
Due to the instability of pyrrolo[1,2-c]imidazol-5-one (4c) in air,
which led to the formation of insoluble material, a preparative
pyrolysis10 of methyl (E)-3-(3H-imidazol-4-yl)acrylate15 [methyl
(E)-urocanate] [(E)-2; 312 mg, 20 mmol] (conditions: Tf 850 °C, Ti
220 °C, P 0.010–0.060 Torr, t 20 min) was performed using a cold-
finger trap (cooled by a mixture of dry-ice and acetone) to collect
the product (cf. ref. 10). The connection between the furnace tube
and the cold-finger was wrapped in aluminum foil, allowing the
product to condense almost exclusively on the cold surface of the
trap. The solid yellow pyrrolo[1,2-c]imidazol-5-one (4c) obtained,
was frozen into a mixture of THF (2 mL) and H2O (10 mL) to min-
imize degradation of 4c. The cold finger was allowed to warm to r.t.
under N2, then the yellow solution of 4c in THF–H2O was trans-
ferred to a round-bottomed flask and heated under reflux for 45 min
during which time the color faded. The solvent was removed using
a rotary evaporator then dried at the oil pump for 3 h to afford (Z)-
1 as an off-white solid; yield: 220 mg (78%); mp 169–171 °C (Lit.16
mp 171–173 °C).
In conclusion, we have described optimized conditions for
the stereospecific synthesis of Z-urocanic acid [(Z)-1] and
its analogues, substituted in either the imidazole ring, or in
the ring and in the alkene side-chain. The route involves
the formation and controlled hydrolysis of ‘dehydrouro-
canic acids’, the pyrrolo[1,2-c]imidazol-5-ones 4.
1H and 13C NMR spectra were recorded at 250 (or 200) MHz and 63
(or 50) MHz, respectively. Chemical shifts are given in ppm relative
to TMS. Mass spectra were recorded under electron impact condi-
tions.
Flash Vacuum pyrolysis (FVP) reactions were carried out by distil-
lation of the substrate in vacuo through an electrically heated silica
furnace tube (35 × 2.5 cm). Unless stated otherwise, products were
trapped in a U-tube situated at the exit point of the furnace and
cooled with liquid N2. Pyrolysis conditions are quoted as follows:
substrate, quantity, furnace temperature (Tf), inlet temperature (Ti),
pressure range (P), pyrolysis time (t), and products.
1H NMR (DMSO-d6): d = 8.16 (1 H, s), 7.67 (1 H, d, J = 0.9 Hz),
6.88 (1 H, d, 3J = 12.9 Hz), 5.68 (1 H, d, 3J = 12.9 Hz).
13C NMR (DMSO-d6): d = 167.26 (q), 136.02, 133.91 (q), 129.90,
123.32, 118.66.
(Z)-3-(2-Methyl-3H-imidazol-4-yl)acrylic Acid [(Z)-5a]
FVP of methyl 3-(2-methylimidazol-1-yl)acrylate (3a; 105 mg)
(conditions: Tf 875 °C, Ti 120 °C, P 0.020–0.065 Torr, t 15 min)
gave a solid yellow pyrolysate of 3-methylpyrrolo[1,2-c]imidazol-
5-one (4a).12 The entire crude pyrolysate was dissolved in a mixture
of THF (2 mL) and H2O (10 mL), then transferred to a round-bot-
tomed flask and heated under reflux for 3 h during which time de-
colorization occurred. THF and H2O were removed using a rotary
evaporator and the product was dried under vacuum (oil pump) for
4 h to afford (Z)-5a; yield: 85 mg (89% for the two steps);7,14 mp
>190 °C (dec. with gas evolution).
4-Ethynylimidazole (7)
In an early reaction carried out under nonoptimized conditions, FVP
of methyl (E)-3-(3H-imidazol-4-yl)acrylate [(E)-2; 518 mg, 3.4
mmol] (conditions: Tf >850 °C, Ti 180–220 °C, P 0.01–0.1 Torr,
t 30 min] was carried out as above. Under N2, the trap was rinsed
with acetone (ca. 50 mL). The solution was poured into a round-bot-
tomed flask and the acetone was removed at the oil pump, keeping
the temperature of the solution below 0 °C. THF (8 mL) and H2O
(45 mL) were added and the mixture was heated at reflux for 3 h.
The solvents were removed using a rotary evaporator successively
under water pump and oil pump pressure. Dry flash chromato-
graphy on silica gel using pure EtOAc as eluent afforded 4-ethy-
1H NMR (DMSO-d6): d = 7.52 (1 H, s), 6.81 (1 H, d, 3J = 12.8 Hz),
5.62 (1 H, d, 3J = 12.8 Hz), 2.39 (3 H, s).
Synthesis 2008, No. 11, 1676–1678 © Thieme Stuttgart · New York

1678
X. L. M. Despinoy et al.
SHORT PAPER
nylimidazole (7) as white crystals; yield: 47 mg (15%). This
1
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McConkey, D. J.; Norval, M.; Ullrich, S. E. Proc. Natl.
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(6) Mohammad, T.; Morrison, H. Org. Prep. Proced. Int. 2000,
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compound has been claimed in a patent,17 but our H NMR spec-
trum is not in agreement with the reported data; mp 100.5–101 °C
(hexane–EtOAc).
1H NMR (acetone-d6): d = 10.05 (1 H, br), 7.74 (1 H, d, 4J = 1.1 Hz),
7.42 (1 H, d, 4J = 1.1 Hz), 3.58 (1 H, s).
13C NMR (acetone-d6): d = 134.95, 122.99, 119.35 (q), 77.49, 76.28
(one quaternary signal not assigned).
MS: m/z (%) = 92 (M+, 100), 65 (32), 41 (43), 38 (40).
(8) (a) Percy, E.; Singh, M.; Takahashi, T.; Takeuchi, Y.; Kirk,
K. L. J. Fluorine Chem. 1998, 91, 5. (b)Dolensky, B.;Kirk,
K. L. J. Org. Chem. 2002, 67, 3468. (c) Fan, F.; Dolensky,
B.; Kim, I. H.; Kirk, K. L. J. Fluorine Chem. 2002, 115, 137.
(9) McNab, H. J. Chem. Soc., Perkin Trans. 1 1987, 653.
(10) McNab, H.; Thornley, C. J. Chem. Soc., Perkin Trans. 1
1997, 2203.
HRMS: m/z calcd for C5H4N2 (M+): 92.0374; found: 92.0375.
Further elution with a mixture of EtOAc–MeOH (4:1) yielded (Z)-
urocanic acid [(Z)-1]; yield: 217 mg (46%); mp 164–166 °C (dec.)
(EtOH–EtOAc) (Lit.16 mp 171–173 °C).
The spectroscopic data were identical with those reported above.
(11) McNab, H.; Parsons, S.; Stevenson, E. J. Chem. Soc., Perkin
Trans. 1 1999, 2047.
Acknowledgment
(12) McNab, H.; Tyas, R. J. Org. Chem. 2007, 72, 8760.
(13) McNab, H.; Thornley, C. Heterocycles 1994, 37, 1977.
(14) E-isomer: Gerlinger, E.; Hull, W. E.; Retey, J. Tetrahedron
1983, 39, 3523.
(15) Kimoto, H.; Jujii, S.; Cohen, L. A. J. Org. Chem. 1984, 49,
1060.
We are grateful to The University of Edinburgh for funding.
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Synthesis 2008, No. 11, 1676–1678 © Thieme Stuttgart · New York