Addition Reactions of Azoles and Amines
J . Org. Chem., Vol. 61, No. 20, 1996 6827
Sch em e 4
factors. The independence of the concentration shown
in the hydrolysis of the diethyl ester2 suggested an
intramolecular mechanism in which the imidazole was
involved. However, present results would indicate that
intermolecular interactions, probably related with the
translational diffusion of this molecules and water, must
be taken into account to fully explain the influence of both
alcohol moieties.12
Exp er im en ta l Section
Gen er a l P r oced u r es. A description of some analytical
instruments, spectral data formats, and standard calibration
have been previously published.2 GC/MS spectra were re-
corded on a Shimadzu QP-5000 at 70 eV. Phase columm (30
m): nonpolar poly(dimethylsiloxane); variable column tem-
perature from 150 to 250 °C. Products were purchased from
commercial sources. The following compounds were prepared
according to literature procedures: (()-3-(ethoxycarbonyl)-2-
imidazol-1-ylpropanoic acid (20),2 tert-butyl ethyl fumarate
(7).13
P r ep a r a tion of Un sym m etr ica l F u m a r a tes 5 a n d 6 by
Ester ifica tion of Mon oeth yl F u m a r a te. The following
fumarates were prepared according to a slightly modification
of the literature procedure described for 7. A one-necked flask,
equipped with a calcium chloride drying tube, was charged
with monoethyl fumarate (0.2 mol), dry CH2Cl2 (200 mL), the
corresponding alcohol (0.60 mol), and 4-DMAP (0.16 mol). The
solution was stirred and cooled in an ice bath to 0°C while
DCC (0.22 mol) was added over a 5-min period. The solution
was allowed to stir at this temperature for 5 min more, and
then the ice bath was removed and the mixture was stirred
at room temperature for 2 h. After the precipitated dicyclo-
hexylurea was filtered, the Cl2CH2 was evaporated in vacuo
and the residue purified over a silica gel column using hexane:
ethyl acetate, 95:5, as chromatographic eluent to obtain
compounds 5 and 6 as colorless oils that were distilled under
reduced pressure.
homolytic cleavage of R bonds to an amino group.
Regioisomers a and b were easily recognized by the
fragments M - CO2R and M - CO2Et, respectively (Table
5, supporting information).
n -Bu tyl eth yl fu m a r a te (5): bp0.01 54-56 °C; yield 67%;
1H NMR (CDCl3) δ 0.93 (t, 3H, J ) 7.2 Hz), 0.90-1.45 (m,
2H),1.31 (t, 3H, J ) 7.2 Hz), 1.62-1.69 (m, 2H), 4.21 (q, 2H,
J ) 7.1 Hz), 4.26 (t, 2H, J ) 7.1 Hz), 6.84 (s, 2H); 13C NMR
(CDCl3) δ 13.0 (q), 13.5 (q), 18.6 (t), 30.1(t), 60.6 (t), 64.5 (t),
133.0 (d), 133.1 (d), 164.1 (s), 164.2 (s); MS m/ z 155 (26, M -
OCH2CH3), 56 (100); IR (film) ν 1710 (CO) cm-1. Anal. Calcd
for C10H16O4: C, 59.96; H, 8.06. Found: C, 60.20; H, 7.91.
Cycloh exyl eth yl fu m a r a te (6): bp0.01 73-74 °C; yield
Finally, we have investigated the neutral hydrolysis
of isolated compound 8a and of the mixture of regioiso-
mers 8a and 8b with the aim to compare their behavior
with the previously studied 2-imidazol-1-ylsuccinates
(Scheme 4). Considering that in di-n-butyl 2-imidazol-
1-ylsuccinate the acetate-type ester hydrolyzed nearly
three times slower than the corresponding diethyl ester
(100 °C/48 h vs 18 h),2 a slower hydrolysis in 8a with
respect to 8b should be expected. Using this methodol-
ogy, it should be easy to separate 8a from 8b, because
the monoester and the diester present very different
physical properties.2 Thus, a mixture (1:1) of 8a and 8b
was hydrolyzed as described previously for the diethyl
1
66%; H NMR (CDCl3) δ 1.28 (t, 3H, J ) 7.2 Hz), 1.37-1.87
(m, 10H), 4.22 (q, 2H, J ) 7.2 Hz), 4.80-4.90 (m, 1H), 6.79 (s,
1H); 13C NMR (CDCl3) δ 13.7 (q), 23.3 (t), 24.9 (t), 31.1(t), 60.8
(t), 73.2 (d), 133.8 (d), 132.9 (d), 163.9 (s), 164.6 (s); MS m/ z
181 (12, M - OCH2CH3), 67 (100), 55 (95); IR (film) ν 1700
(CO) cm-1
. Anal. Calcd for C12H18O4: C, 63.70; H, 8.02.
1
Found: C, 63.60; H, 7.79.
ester. Surprisingly, the H NMR spectrum in DMSO-d6
ter t-Bu tyl eth yl fu m a r a te (7): bp0.01 42-44 °C (lit.10 bp12
105-107 °C); yield 60%; 13C NMR (CDCl3) δ 13.9 (q), 27.7 (q),
60.9 (d), 81.5 (s), 132.4 (d), 135.3 (d), 163.8 (s), 164.8 (s); MS
m/ z 155 (6, M - OCH2CH3), 57 (100); IR (film) ν 1710 (CO)
of the reaction crude showed the absence of the starting
diesters and the corresponding half esters: 20 and (()-
3-(butoxycarbonyl)-2-imidazol-1-ylpropanoic acid (33) (1:
1) were the major products. Some traces of imidazole
and (()-2-imidazol-1-ylsuccinic acid (34) were observed.
Furthermore, hydrolysis of isolated 8a in the same
conditions yielded the half ester 20 (80%) as shown the
1H NMR spectrum in D2O of the reaction mixture.
These results suggest that the BAC3 mechanism pre-
viously proposed for this hydrolysis,2 on the basis of
analogies with other esters activated with electron-
withdrawing substituents,9-11 may depend on several
cm-1
.
Ad d ition of Azoles 1-4 to Un sym m etr ica l F u m a r a tes
5-7. Gen er a l P r oced u r es. Meth od a . A mixture of azole
(2.5 mmol) and the corresponding fumarate (2.5 mmol) was
heated in an oil bath at 100 °C (120 °C for benzimidazole) and
1
the time shown in Table 1 for each compound. The H NMR
spectra and GC chromatograms of the mixtures are included
as supporting information. Meth od b. A mixture of azole (2.5
mmol) and the corresponding fumaric esters (2.5 mmol) was
located in a 23 mL PARR bomb with a Teflon sample cup. The
reaction mixture was heated in the microwave oven at 300 W
for 3 min. After being cooled at room temperature, the bomb
(9) Euranto, E. K.; Kanerva, L. T.; Cleve, N. J . J . Chem. Soc., Perkin
Trans. 2 1984, 2085.
(10) Neuvonen, H. J . Chem. Soc., Perkin Trans. 2 1986, 1141.
(11) Satchell, D. P. N.; Satchell, R. S. In The chemistry of functional
groups. supplement B: The chemistry of acid derivatives; Patai, S., Ed.;
Wiley: New York, 1992; Vol. 2. Part 1, pp 770-772.
(12) Bu¨rgi, H.-B.; Dunitz, J . D. Structure Correlations; VCH: Wein-
heim, 1994; Vol. 1.
(13) Neises, B.; Steiglich, W. Org. Synth. 1985, 63, 183.