An improved method for the synthesis of dissymmetric N,N′-disubstituted imidazole-4,5-dicarboxamides

Article abstract of DOI:10.1021/jo025536c

Symmetrically and dissymmetrically disubstituted imidazole-4,5-dicarboxamides (I45DCs) have diverse bioactivities and therefore represent useful small molecules for lead structure identification in drug discovery. For this reason, an improved synthesis was developed as a first step in the preparation of greater numbers of analogues. The method involves the transformation of imidazole-4,5-dicarboxylic acid into dissymmetrically disubstituted I45DCs in four steps and in a minimum yield of 51%. This reflects an overall reduction of one synthetic step and a greater than 30% improvement in yield over the known method.

Full text of DOI:10.1021/jo025536c

biotics.6 Intramolecular hydrogen bonded conformations
of I45DCs are structurally similar to purine bases, and
select I45DCs are known to influence respiration7 as well
as bind to adenosine receptors.8 The ability of some
I45DCs to mimic adenosine is particularly suggestive
that these compounds could have bioactivities at other
signal transduction targets such as G-proteins, ion chan-
nels, or kinases. In addition to their biological signifi-
cance, I45DCs have also been studied in the context of
metal binding9 and as a monomer incorporated into
polyamides.10
An Im p r oved Meth od for th e Syn th esis of
Dissym m etr ic N,N′-Disu bstitu ted
Im id a zole-4,5-d ica r boxa m id es
Alexander V. Wiznycia and Paul W. Baures*,†
Department of Chemistry, Kansas State University,
Manhattan, Kansas, 66506
pbaures@signaturebio.com
Received J anuary 18, 2002
In addition to the previously described syntheses of
I45DCs in the literature,6,9,11 examples of mixed acid-
amide or ester-amide functional group combinations
substituted at the 4- and 5-positions of the imidazole ring
have been reported.6a,11 We report herein an improved
synthesis of the dissymmetrically disubstituted I45DCs
undertaken as part of a research effort to further explore
the structure and function of these compounds. Sym-
metrically disubstituted I45DCs are naturally dissym-
metric both by the tautomeric form of the imidazole ring
as well as by the consequence of an intramolecular
hydrogen bonded conformation that forms preferentially
in these compounds.10,11e,12 However, for the purposes of
this paper, the term dissymmetric refers to the relative
identity of the two carboxamide substitutents.
The literature route to dissymmetric I45DCs utilizes
imidazole-4,5-dicarboxylic acid (1) as the starting mate-
rial to create the pyrazine diacid dichloride (2) in 89%
yield by refluxing with SOCl2 in benzene with catalytic
DMF (Scheme 1).6a Addition of water hydrolyzes the two
acid chlorides to give 3 in 97% yield. Amines are then
added to 3 to open the acyl imidazole bond, thereby
generating 4 in 73% yield. Intermediate 4 is subsequently
cyclized to pyrazine 5 in the presence of SOCl2 and
catalytic DMF in 35% yield. A subsequent pyrazine ring-
opening reaction with a different amine provides the
dissymmetric I45DC (6) in as high as 87% isolated yield.
The maximum overall yield reported for this five-step
synthesis is 19.2%.6a,11e Dissymmetric I45DCs have been
Abstr a ct: Symmetrically and dissymmetrically disubsti-
tuted imidazole-4,5-dicarboxamides (I45DCs) have diverse
bioactivities and therefore represent useful small molecules
for lead structure identification in drug discovery. For this
reason, an improved synthesis was developed as a first step
in the preparation of greater numbers of analogues. The
method involves the transformation of imidazole-4,5-dicar-
boxylic acid into dissymmetrically disubstituted I45DCs in
four steps and in a minimum yield of 51%. This reflects an
overall reduction of one synthetic step and a greater than
30% improvement in yield over the known method.
Imidazole is a common structural unit found in many
biologically active compounds. Substituted imidazoles
have been synthesized by combinatorial fashion on solid-
supports1 as well as in the solution phase2 and are
promising scaffolds for drug design. We have previously
reported the use of symmetric N,N′-disubstituted imida-
zole-4,5-dicarboxamides (I45DCs) in a study on hetero-
cyclic HIV-1 protease inhibitors, finding modest inhibi-
tory activity with this class of compounds.3 The I45DCs
are also known to affect memory,4 to protect embryos
from teratogens,5 and as structural components of anti-
† Current address: Signature Bioscience, Inc., 1240 S. 47th Street,
Richmond, CA 94804-4610.
(1) (a) Zhang, C.; Moran, E. J .; Woiwode, T. F.; Short, K. M.; Mjalli,
A. M. M. Tetrahedron Lett. 1996, 37, 751-754. (b) Sarshar, S.; Siev,
D.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 835-838. (c) Tortolani,
D. R.; Biller, S. A. Tetrahedron Lett. 1996, 37, 5687-5690. (d) Gelens,
E.; Koot, W. J .; Menge, W. M.; Ottenheijm, H. C.; Timmerman, H.
Bioorg. Med. Chem. 2000, 10, 1935-1938. (e) Lee, H. B.; Balasubra-
manian, S. Org. Lett. 2000, 2, 323-326. (f) Saha, A. K.; Liu, L.;
Simoneaux, R. L.; Kukla, M. J .; Marichal, P.; Odds, F. Bioorg. Med.
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P.; Odds, F. Bioorg. Med. Chem. Lett. 2000, 10, 2735-2739. (h)
Newman, M. J .; Rodarte, J . C.; Benbatoul, K. D.; Romano, S. J .; Zhang,
C.; Krane, S.; Moran, E. J .; Uyeda, R. T.; Dixon, R.; Guns, E. S.; Mayer,
L. D. Cancer Res. 2000, 60, 2964-2972. (i) Zhang, C.; Sarshar, S.;
Moran, E. J .; Krane, S.; Rodarte, J . C.; Benbatoul, K. D.; Dixon, R.;
Mjalli, A. M. Bioorg. Med. Chem. Lett. 2000, 10, 2603-2605. (j) Kondo,
Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111-3113.
(2) (a) Blass, B. E.; Huang, C. T.; Kawamoto, R. M.; Li, M.; Liu, S.;
Portlock, D. E.; Rennells, W. M.; Simmons, S. Bioorg. Med. Chem. Lett.
2000, 10, 1543-1545. (b) Boger, D. L.; Dechantsreiter, M. A.; Ishii,
T.; Fink, B. E.; Hedrick, M. P. Bioorg. Med. Chem. Lett. 2000, 10, 2049-
2057. (c) Boger, D. L.; Fink, B. E.; Hedrick, M. P. J . Am. Chem. Soc.
2000, 122, 6382-6394. (d) Hamper, B. C.; J erome, K. D.; Yalamanchili,
G.; Walker, D. M.; Chott, R. C.; Mischke, D. A. Biotechnol. Bioeng.
2000, 71, 28-37.
(5) Bichevaya, N. K.; Chebotar, N. A.; Aleksandrova, I. Y.; Stepanov,
I. I.; Klement’ev, B. I.; Sapronov, N. S. Russ. J . Dev. Biol. 1999, 30,
259-263.
(6) (a) Yasuda, N.; Iwagami, H.; Nakanishi, E.; Nakamiya, T.;
Sasaki, Y.; Murata, T. J . Antibiotics 1983, 36, 242-249. (b) Vostrova,
L. N.; Grenaderova, M. V.; Nedzvetsky, V. S.; Konup, I. P.; Andreyeva,
E. K.; Bondar, A. E. Khim.-Farm. Zh. 1989, 23, 584-587.
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Borodkin, Y. S. Russ. Pharmacol. Toxicol. 1980, 43, 202-207.
(8) Reikhardt, B. A.; Kulikova, O. G. Biochemistry (Mosc.) 1994, 59,
1059-1063.
(9) Nonoyama, K.; Mori, W.; Nonoyama, M. Polyhedron 1994, 13,
891-897.
(10) Bouck, K. J .; Rasmussen, P. G. Macromolecules 1993, 26, 2077-
2084.
(11) (a) Takahashi, K.; Iguma, N.; Kato, N.; Mitsuhashi, K. Nippon
Kagaku Kaishi 1975, 12, 2244-2245. (b) Schubert, H.; Hoffmann, S.;
Uhlig, V.; Polster, H.-E. Z. Chem. 1976, 16, 483-484. (c) Vostrova, L.
N.; Gernega, S. A.; Ivanov, E. I.; Kirichenko, A. M.; Krivopishchenko,
I. I.; Sharbatyan, P. A. Soviet Prog. Chem. 1982, 48, 74-77. (d) Ivanov,
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10.1021/jo025536c CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/04/2002
J . Org. Chem. 2002, 67, 7151-7154
7151

SCHEME 1
SCHEME 3
isolated yields (80-96%) by the addition of a second
amine. This modified synthesis to dissymmetric I45DCs
requires only four steps from 1 and results in overall
yields of analytically pure dissymmetric I45DCs of at
least 51% by the pathway 1f6a -d .
The preparation of 2 was slightly altered in this work
as compared with the literature method,6a including
modified reagent quantitites and the total time of the
reflux. The reactivity of 2 and its relative insolubility in
CDCl3 made routine characterization difficult, as 1H
NMR analysis in DMSO-d6 results in partial hydrolysis
due to the trace water present in the DMSO-d6.
We initially attempted to make 6c directly from 2 by
adding 2 equiv each of benzylamine and diisopropyleth-
ylamine at -78 °C, followed by 2 equiv of n-butylamine
(Scheme 3). However, only mixtures containing the
symmetric I45DCs (9 and 10) and 6c were obtained from
this procedure, and our modified synthesis was chosen
as an alternative method to control the relative reactivity
of the acid chloride versus the acyl imidazole group.
SCHEME 2
The addition of phenol and pyridine to 2 in dichlo-
romethane results in a rapid reaction to yield 7. The
reaction proceeds in apparent quantitative yield as
1
determined by H NMR analysis of a reaction aliquot;
however, the initial solid obtained by filtration often
yields 7 contaminated with trace pyridine. The elemental
analysis of 7 yields CHN ratios consistent with the
presence of 8% of diacid 3, explaining why the initial solid
requires multiple washes to remove trace pyridine.
The conditions for the ring opening of 7 by different
primary amines were first determined by comparing
small-scale reactions at varying temperatures and re-
moving aliquots from these reactions as a function of time
for subsequent 1H NMR analysis. Addition of n-butyl-
amine to 7 was determined to be complete within 30 min
synthesized from analogues of 5 in 34-87% yield for this
step alone.6
1
at -60 °C. We observed phenol displacement in the H
NMR spectrum over the entire range of temperatures
tested (from -60 to 20 °C), although this appeared to be
most significant (∼6%) above -20 °C. Though pyridine
is known as a general acylation catalyst, no difference
in the reactivity of 7 was observed in the absence of
pyridine under otherwise similar conditions.
Our major modification to the known synthesis of
dissymmetric I45DCs is to replace the water in Scheme
1 with phenol, thereby modulating the reactivity of the
acid chloride as compared with the acyl imidazole bond
for subsequent additions of two different primary amines.
Thus, 1 is refluxed with SOCl2 in benzene in the presence
of catalytic DMF to yield 2 that is used without extensive
purification. Addition of phenol and pyridine to 2 yields
7 (92% pure) contaminated with 3 or the partially
hydrolyzed acid-ester combination or both (Scheme 2).
Addition of n-butylamine to crude 7 at -40 °C opens the
acyl imidazole bond to provide purified amide-ester 8a
(84% yield based on available 7), whereas sterically
hindered amines such as tert-butylamine require sub-
stantially longer reaction times at -20 °C for optimal
conversion to ester-amide 8b (45% yield based on avail-
able 7). Either ester-amide (8a or 8b) could then be
converted to the dissymmetric I45DCs (6a -e) in good
The ring opening of 7 by tert-butylamine was expected
to be slower as compared to n-butylamine due to the
steric constraints of the former. Indeed, the reaction was
only 85% complete after 50 h at -20 °C as determined
by the relative integration of signals for 7 vs 8b in the
1H NMR spectrum. There were also signals evident for
competing displacement of the phenyl ester.
The dissymmetrically disubstituted I45DCs are of
interest as a promising drug design scaffold, and this
improved synthetic procedure is an important first step
to the preparation of multiple I45DCs for screening
against a variety of biological targets.
7152 J . Org. Chem., Vol. 67, No. 20, 2002

available 7) after drying: mp 177-178 °C; TLC Rf (85:10:5 CH2-
Cl2/MeOH/AcOH) ) 0.29; 1H NMR (DMSO-d6) δ 13.48 (bs, 1 H),
9.36 (bs, 1 H), 7.91 (s, 1 H), 7.46-7.50 (m, 2 H), 7.27-7.34 (m,
3 H), 1.33 (m, 9 H); 13C NMR (DMSO-d6) δ 163.8, 157.0, 150.3,
137.1, 134.0, 129.7, 128.1, 126.2, 122.0, 50.9, 28.6; FAB MS m/z
288 [M + H]+. Anal. Calcd for C15H17N3O3: C, 62.71; H, 5.96;
N, 14.63. Found: C, 62.92; H, 6.18; N, 14.74.
Exp er im en ta l Section
Gen er a l Meth od s. All apparatus were oven-dried and cooled
in a desiccator. Reagent-grade THF and CH2Cl2 were distilled
from sodium benzophenone ketyl and CaH2, respectively, before
use. All other reagents were purchased from commercial sup-
pliers and used without purification. Thin-layer chromatography
was done on 250 µm silica gel plates containing a fluorescent
indicator and visualized by using UV and I2 as well as ninhydrin
spray for amines. Melting points are uncorrected, and elemental
analyses were done by a contracting lab. 1H and 13C NMR
spectra were measured in DMSO-d6 at 400 and 75.5 MHz,
respectively, and are referenced to DMSO [1H (δ 2.50) and 13C
(δ 39.5)].
5,10-Dioxo-5H,10H-d iim id a zo[1,5-a :1′-5′-d ]p yr a zin e-1,6-
d ica r boxylic Acid Dip h en yl Ester (7). To a dry round-bottom
flask were added 10.01 g of imidazole-4,5-dicarboxylic acid (64.13
mmol) and 50 mL of benzene. To this stirred suspension were
added 28.0 mL of thionyl chloride (384 mmol) and 2.5 mL of
DMF (32 mmol), and the resulting mixture was refluxed for 16
h. After the mixture was cooled to room temperature, the solid
product was collected by vacuum filtration, washed with two 20
mL portions of benzene, and dried under vacuum to yield 9.80
g of crude 2 (98% recovery) as a tan solid. This product was used
without characterization.
4(5)-n -Bu tyla m in oca r bon yl-5(4)-isop r op yla m in oca r bon -
ylim id a zole (6a ). To a dry round-bottom flask were added 8a
(0.862 g, 3.00 mmol) and isopropylamine (0.51 mL, 6.00 mmol)
in 10 mL of THF under N2. The solution was refluxed for 5 h
before concentration of the solution under vacuum to yield an
oil. The oil was dissolved in 20 mL of 9:1 hexane-chloroform.
This solution was extracted with two 50 mL portions of 0.1 M
HCl followed by three 100 mL portions of H2O. The organic
fraction was concentrated and the resulting solid crystallized
from methanol to yield 0.608 g of 6a (80%) after drying: mp
141-143 °C; TLC Rf (85:10:5 CH2Cl2/MeOH/AcOH) ) 0.69. The
1H spectrum indicated the presence of conformers: 1H NMR
(DMSO-d6) δ 13.16 (bs, 1 H), 11.11 (bs, 1 H), 8.53 (bs, 0.6 H),
8.24 (bs, 0.4 H), 7.78 (s, 1 H), 3.95-4.16 (m, 2 H), 3.17-3.30 (m,
2 H), 1.46-1.54 (m, 2 H), 1.32-1.34 (m, 2 H), 1.17 (s, 3.6 H),
1.18 (s, 5.4 H), 0.87-0.91 (m, 3 H); 13C NMR (DMSO-d6) δ 163.3,
157.1, 135.8, 132.7, 128.3, 40.66, 38.33, 31.16, 22.30, 19.64, 13.67;
FAB MS m/z 253 [M + H]+. Anal. Calcd for C12H20N4O2: C,
57.13; H, 7.99; N, 22.21. Found: C, 57.11; H, 8.16; N, 22.30.
4(5)-n -Bu t yla m in oca r b on yl-5(4)-t-b u t yla m in oca r b on -
ylim id a zole (6b). To a dry round-bottom flask were added 8a
(0.862 g, 3.00 mmol) and tert-butylamine (0.63 mL, 6.00 mmol)
in 10 mL of THF under N2. The solution was refluxed for 12 h
before workup as described for 6a . The organic fraction was
concentrated and the resulting oil azeotroped (three times) with
10 mL portions of chloroform to yield 0.716 g of 6b (90%) as an
oil after drying: TLC Rf (85:10:5 CH2Cl2/MeOH/AcOH) ) 0.72.
The 1H and 13C NMR spectrum indicated the presence of
conformers: 1H NMR (DMSO-d6) δ 13.19 (bs, 0.4 H), 13.06 (bs,
0.6 H), 11.49 (bs, 0.6 H), 11.21 (bs, 0.4 H), 8.50 (bs, 1 H), 7.76
(s, 1 H), 3.23-3.42 (m, 2 H), 1.42-1.53 (m, 2 H), 1.38 (s, 9 H),
1.22-1.32 (m, 2 H), 0.87-0.99 (m, 3 H); 13C NMR (DMSO-d6) δ
163.4, 162.9, 157.9, 157.2, 135.5, 133.0, 132.2, 129.1, 128.0, 50.7,
50.2, 31.1, 28.4, 19.6, 13.6; FAB MS m/z 267 [M + H]+. Anal.
Calcd for C13H22N4O2: C, 58.63; H, 8.33; N, 21.04. Found: C,
58.72; H, 8.53; N, 21.07.
To a dry round-bottom flask was added crude 2 (0.524 g, 1.67
mmol) followed by 10 mL of dichloromethane and phenol (0.332
g, 3.53 mmol) under N2. The suspension was cooled to 0 °C, and
285 µL of pyridine (3.53 mmol) was added dropwise over two
min. After 1 h, the solid was collected by vacuum filtration and
washed with two 10 mL portions of dichloromethane. Pyridine
is the most frequent contaminant of this solid as determined by
1H NMR analysis. The pyridine can be completely removed by
suspending the solid in 20 mL of refluxing dichloromethane for
10 min, cooling to room temperature, collecting the solid by
vacuum filtration, rinsing the solid with two 10 mL portions of
dichloromethane, and drying the solid under vacuum. This
procedure yielded 0.612 g of 7 (83% from 1): 1H NMR (DMSO-
d6) δ 9.12 (s, 2 H), 7.52-7.56 (m, 4 H), 7.34-7.40 (m, 6 H); 13C
NMR (DMSO-d6) δ 159.0, 150.0, 148.2, 139.2, 139.0, 129.9, 126.6,
123.3, 121.5; FAB MS m/z 429 [M + H]+. Anal. Calcd for
C
21.04H11.36N4O6 (7, 92%:3, 8%): C, 60.72; H, 2.75; N, 13.47.
Found: C, 60.32; H, 2.64; N, 13.16.
4-P h en oxyca r bon yl-5-n -bu tyla m in oca r bon ylim id a zole
(8a ). To a dry round-bottom flask were added 7 (3.945 g, 9.21
mmol, 92% pure) and 60 mL of THF under N2. To this
suspension at -40 °C was added n-butylamine (1.82 mL, 18.4
mmol) dropwise over 2 min before stirring for 1.5 h. The THF
was removed under vacuum to yield a solid that was crystallized
and subsequently recrystallized from methanol until pure. The
final product was dried under vacuum to yield 4.11 g of 8a (84%
from available 7): mp 142-144 °C; TLC Rf (85:10:5 CH2Cl2/
MeOH/AcOH) ) 0.38; 1H NMR (DMSO-d6) δ 13.52 (bs, 1 H), 9.37
(bs, 1 H), 7.93 (s, 1 H), 7.46-7.50 (m, 2 H), 7.26-7.34 (m, 3 H),
3.26-3.29 (m, 2 H), 1.43-1.49 (m, 2 H), 1.26-1.30 (m, 2 H),
0.81-0.85 (m, 3 H). Carbonyl resonances and one of the
substituted imidazole carbons were observed only as weak and
broad signals in the 13C NMR spectrum recorded in DMSO-d6.
The peak maximum for each is estimated to the nearest whole
ppm: 13C NMR (DMSO-d6) δ 163, 158, 150.2, 137.3, 133, 129.6,
126.1, 121.9, 38.5, 31.0, 19.5, 13.5; FAB MS m/z 288 [M + H]+;
Anal. Calcd for C15H17N3O3: C, 62.71; H, 5.96; N, 14.63. Found:
C, 62.51; H, 5.70; N, 14.59.
4-P h en oxyca r b on yl-5-t-b u t yla m in oca r b on ylim id a zole
(8b). To a dry round-bottom flask were added 7 (3.218 g, 7.51
mmol, 92% pure) and 100 mL of THF under N2. To this
suspension at -20 °C was added tert-butylamine (1.58 mL, 15.0
mmol) dropwise over 2 min, and the reaction was stirred for 50
h. The reaction mixture was diluted with 200 mL of ethyl ether
and filtered to remove solids. Concentration under vacuum
resulted in an oily residue that was redissolved in 10 mL of THF.
Addition of 200 mL of water resulted in precipitation of a light-
yellow solid that was collected by filtration. This solid was
crystallized from methanol to yield 1.792 g of 8b (45% from
4(5)-Ben zyla m in oca r b on yl-5(4)-n -b u t yla m in oca r b on -
ylim id a zole (6c). Meth od A, via Stoich iom etr ic Ad d ition s.
To a dry round-bottom flask was added 2 (1.002 g, 3.19 mmol)
in 100 mL of THF under Ar, and the suspension was cooled to
-78 °C. A solution of benzylamine (698 µL, 6.38 mmol) and
diisopropylethylamine (1.11 mL, 6.38 mmol) in 25 mL of THF
was added dropwise with stirring over 30 min. The solution was
held 24 h at -78 °C before a solution of n-butylamine (0.631
µL, 6.38 mmol) in 20 mL of THF was added dropwise, and the
reaction mixture was stirred for another 8 h at -78 °C and then
allowed to warm to room temperature. After 12 h at room
temperature, the THF was removed under vacuum and the
resulting material partitioned between ethyl acetate and 10%
citric acid. The organic fraction was washed with 1 M NaHCO3,
water, and brine. The solution was dried over MgSO4, filtered,
and concentrated to a solid containing both symmetric I45DCs
and 6c. TLC and 1H NMR analysis of the reaction following
workup indicated the presence of significant quantities (∼25%
of the isolated total) of the symmetric I45DCs 9 and 10 along
with 6c. The three products were separable by column chroma-
tography, although this synthetic method to dissymmetric
I45DCs was not further pursued. TLC: 9, Rf (19:1 CH2Cl2/
MeOH) ) 0.54; 10, Rf (19:1 CH2Cl2/MeOH) ) 0.44; 6c, Rf ( 19:1
CH2Cl2/MeOH) ) 0.58.
Meth od B, via 8a . To a dry round-bottom flask were added
8a (0.863 g, 3.00 mmol) and benzylamine (0.66 mL, 6.00 mmol)
in 10 mL of THF under N2. The solution was refluxed for 5 h
before concentration under vacuum. The solid was suspended
in 50 mL of water, stirred for 10 min, filtered, and washed with
an additional 50 mL of water. Crystallization from methanol
provided 0.559 g of 6c (88%) after drying: mp 126-128 °C; TLC
J . Org. Chem, Vol. 67, No. 20, 2002 7153

Rf (85:10:5 CH2Cl2/MeOH/AcOH) ) 0.75. The 1H and 13C NMR
spectrum indicated the presence of conformers: 1H NMR
(DMSO-d6) δ 13.25 (bs, 1 H), 11.64 (bs, 0.5 H), 11.06 (bs, 0.5 H),
9.16 (bs, 0.5 H), 8.61 (bs, 0.5 H), 7.83 (bs, 1 H), 7.22-7.32 (m, 5
H), 4.47-4.56 (m, 2H), 3.22-3.32 (m, 2 H), 1.45-1.52 (m, 2 H),
1.25-1.37 (m, 2 H), 0.85-0.90 (m, 3 H); 13C NMR (DMSO-d6) δ
163.6, 163.3, 158.2, 157.9, 139.2, 139.0, 136.1, 136.0, 133.0, 132.5,
128.5, 128.3, 127.9, 127.2, 127.0, 126.8, 42.2, 38.7, 31.2, 19.6,
13.6; FAB MS m/z 301 [M + H]+. Anal. Calcd for C16H20N4O2:
C, 63.99; H, 6.71; N, 18.66. Found: C, 63.99; H, 6.45; N, 18.75.
4(5)-(S)-r-Meth ylben zyla m in oca r bon yl-5(4)-n -bu tyla m i-
n oca r bon ylim id a zole (6d ). To a dry round-bottom flask were
added 8a (0.862 g, 3.00 mmol) and (S)-R-methylbenzylamine
(0.77 mL, 6.00 mmol) in 10 mL of THF under N2. The solution
was refluxed for 5 h before workup as described for 6a . The
organic fraction was concentrated and the resulting oil azeo-
troped (three times) with 10 mL portions of chloroform to yield
0.919 g of 6d (96%) as an oil after drying: TLC Rf (85:10:5
CH2Cl2/MeOH/AcOH) ) 0.78. The 1H and 13C NMR spectrum
indicated the presence of conformers: 1H NMR (DMSO-d6) δ
13.18 (bs, 1 H), 11.70 (bs, 0.6 H), 10.97 (bs, 0.4 H), 8.81 (bs, 0.4
H), 8.60 (bs, 0.6 H), 7.81 (bs, 1 H), 7.22-7.40 (m, 5 H), 5.12-
5.14 (m, 2 H), 3.28-3.32 (m, 2 H), 1.45-1.52 (m, 5 H), 1.29-
1.34 (m, 2 H), 0.89-0.91 (m, 3 H). Carbonyl resonances were
only observed as a weak and broad signal near 160 ppm in the
13C NMR in DMSO-d6: 13C NMR (DMSO-d6) δ 144.2, 136.0,
128.4, 126.8, 126.0, 48.2, 38.7, 31.1, 22.6, 19.6, 13.7; 13C NMR
(CDCl3) δ 163.3, 162.6, 158.7, 144.6, 135.1, 133.6, 128.8, 128.2,
127.2, 126.2, 97.4, 50.4, 48.9, 39.4, 31.6, 23.1, 22.4, 20.3, 13.9;
ES MS m/z 315 [M + H]+. Anal. Calcd for C17H22N4O2: C, 64.95;
H, 7.05; N, 17.82. Found: C, 64.55; H, 6.88; N, 17.78.
as described for 6c. Crystallization from methanol provided 0.771
g of 6e (86%) after drying: mp 177-178 °C; TLC Rf (85:10:5
1
CH2Cl2/MeOH/AcOH) ) 0.74. The H NMR spectrum indicated
the presence of conformers: 1H NMR (DMSO-d6) δ 13.13 (bs, 1
H), 11.47 (bs, 0.3 H, N-H), 10.98 (bs, 0.7 H), 9.09 (bs, 1 H), 7.81
(s, 1 H), 7.22-7.37 (m, 5 H), 4.48-4.57 (m, 2 H), 1.38 (s, 9 H);
13C NMR (DMSO-d6) δ 163.6, 157.2, 139.2, 135.8, 132.1, 129.4,
128.4, 127.2, 126.9, 50.4, 42.1, 28.4; FAB MS m/z 301 [M + H]+.
Anal. Calcd for C16H20N4O2: C, 63.99; H, 6.71; N, 18.66. Found:
C, 64.10; H, 6.75; N, 18.73.
Deter m in in g Con d ition s for th e Syn th esis of 8a by 1H
NMR An a lysis. Conditions for the formation of 8a from 7 were
determined by monitoring reactions as a function of temperature
and time. The reactions were set up similar to those described
for the synthesis of 8a but with 0.60 mmol of 7 and 1.2 mmol of
n-butylamine in 10 mL of THF under N2 at the various
temperatures. In addition, pyridine was added (1.2 mmol) to each
reaction as a general acylation catalyst. The reaction was stirred,
and aliquots were removed at 30 min, 1 h, and 2 h. Each aliquot
was concentrated under vacuum and dissolved in DMSO-d6 for
analysis by 1H NMR spectroscopy. The presence or absence of
C2-H/C2′-H from 7 (9.12 ppm) was taken as an indication of the
reaction progress, while the relative integration of the C2-H in
8a (7.92 ppm) along with the phenol signals furthest upfield
(6.73-6.77 ppm) provided an indication of how much product
formed versus how much phenol was displaced under the given
reaction condition.
Ack n ow led gm en t. The synthetic assistance of J er-
emy R. Rush is appreciated. This work was supported
by a NIH-COBRE award 1-P20-RR15563 and matching
support from the state of Kansas.
4(5)-Ben zylam in ocar bon yl-5(4)-t-bu tylam in ocar bon ylim -
id a zole (6e). To a dry round-bottom flask were added 8b (0.863
g, 3.00 mmol) and tert-butylamine (0.66 mL, 6.00 mmol) in 10
mL of THF under N2. The solution was refluxed for 5 h before
J O025536C
7154 J . Org. Chem., Vol. 67, No. 20, 2002