Facile, efficient synthesis of polyfunctionalized 2-aminoimidazoles via vinyl azides and cyanamide

Article abstract of DOI:10.1016/j.tet.2014.01.007

A simple and direct synthesis of 2-aminoimidazoles from vinyl azides and cyanamide was developed. An attractive feature of this protocol is that the desired products are generated in a highly efficient and eco-friendly manner without the use of a catalyst. A plausible mechanism has been proposed.

Full text of DOI:10.1016/j.tet.2014.01.007

Tetrahedron 70 (2014) 1418e1421
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Tetrahedron
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Facile, efficient synthesis of polyfunctionalized 2-aminoimidazoles
via vinyl azides and cyanamide
Shen Liu a, Jiaan Shao a, Xiao Guo a, Jing Luo a, Menghao Zhao b, Guolin Zhang a,
,
Yongping Yu a
*
a Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
b School of Biology and Pharmaceutical Engineering Wuhan Polytechnic University, Wuhan 430023, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and direct synthesis of 2-aminoimidazoles from vinyl azides and cyanamide was developed. An
attractive feature of this protocol is that the desired products are generated in a highly efficient and eco-
friendly manner without the use of a catalyst. A plausible mechanism has been proposed.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 30 September 2013
Received in revised form 25 December 2013
Accepted 3 January 2014
Available online 9 January 2014
Keywords:
2-Aminoimidazoles
Vinyl azides
Cyanamide
Direct synthesis
1. Introduction
Herein, we report a novel, facile approach to provide poly-
functionalized 2-aminoimidazoles using vinyl azides and cyana-
2-Aminoimidazoles are one of the most important heterocyclic
motifs in organic chemistry, they are the central feature of alkaloids
and many biologically active substances.1 As a result, the de-
velopment of methods for the preparation of these molecules has
attracted considerable attention. A number of methods have been
developed for the synthesis of 2-aminoimidazoles, such as a cyclo-
condensation between diketones with guanidine followed by cat-
mide. An attractive feature of this protocol is that the desired
product could be generated in a highly efficient and eco-friendly
manner.
2. Results and discussion
alytic hydrogenation;2 the reaction of
acetylguanidine;3 the iminophosphorane-mediated cyclization of
-azido esters;4 the synthesis of 2-aminoimidazoles by the for-
mation of imidazo[1,2- ]pyrimidines followed by cleavage of the
a-halo ketones with N-
Initially, (Z)-2-azido-1,3-diphenylprop-2-en-1-one and cyana-
mide were selected as reagents in order to optimize the reaction
condition. Firstly, a range of solvents were screened (Table 1, entries
1e6). It was determined that ethanol (Table 1, entry 3) was superior
to other aprotic and protic solvents. In order to further improve the
reaction conditions, a range of bases were tested as additives (Table
1, entries 7e13). When an inorganic base, such as Cs2CO3, K2CO3 or
NaOAc was added into the reaction, no significant improvement in
product yields was identified. Moreover, NaOH was found to be
destructive to this reaction (Table 1, entry 10). Conversely the yield
of the desired product was significantly improved when an organic
base like Et3N or DBU was used in this reaction (Table 1, entries 12
and 13). However, when DMAP was used, the yield declined sig-
nificantly (Table 1, entry 11). The reaction was also assessed at
a lower temperature but this resulted in a decrease in the yield
(Table 1, entries 14 and 15). On the basis of this initial study, the
most efficient reaction condition occurred when (Z)-2-azido-1,3-
diphenylprop-2-en-1-one (1 equiv), cyanamide (2 equiv), and
a
a
pyrimidine ring with hydrazine or amines;5 and the ammonolysis
of 2-amino-1,3-oxazol-3-ium salts.6 Some of the common synthetic
approaches either need a prolonged reaction time, difficult exper-
imental procedures, expensive transition metal additives, complex
substrates, or in unsatisfied yields.2e6 Furthermore, polyfunc
tionalized 4,5-disubstututed-2-aminoimidazoles are not readily
available through general methods.
Therefore, the development of improved methods for the syn-
thesis of 2-aminoimidazoles is of importance.
* Corresponding author. Tel./fax: þ86 571 8820 8452; e-mail addresses: yyu@zju.
edu.cn, yyu@tpims.org (Y. Yu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.007

S. Liu et al. / Tetrahedron 70 (2014) 1418e1421
1419
Table 2
Scope of the reaction of vinyl azides and cyanamide under optimal conditionsa
Table 1
Optimization of reaction conditionsa
Entry
Additive
Solvent
T (ꢀC)
Conversion (%)
1
2
3
4
5
6
7
8
d
CH3CN
THF
DMF
90
90
90
90
90
90
90
90
90
90
90
90
90
40
60
53%
34%
Trace
21%
52%
64%
66%
67%
72%
30%
Trace
85%
90%
23%
50%
d
d
d
1,4-Dioxane
Toluene
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
d
d
Cs2CO3
K2CO3
NaOAc
DMAP
NaOH
DBU
Et3N
Et3N
Et3N
9
10
11
12
13
14
15
a
Reaction conditions: (Z)-2-azido-1,3-diphenylprop-2-en-1-one(0.5 mmol,
1.0 equiv), cyanamide (1 mmol, 2 equiv), base (0.5 mmol, 1 equiv), 2 mL of solvent,
6 h, 90 ꢀC. The most efficient entry is highlighted in bold.
Et3N(1 equiv) were mixed in ethanol at 90 ꢀC for 6 h (Table 1, entry
14).
With the optimized reaction condition in hand, the scope of the
reaction was studied using a set of vinyl azides 1 and cyanamide
(Table 2). The
a-azidovinylketones were readily prepared from the
corresponding olefins by successive reaction with bromine then with
sodium azide. And the a-azidovinylesters were prepared from the
corresponding aldehydes with ethyl azidoacetate.7 The result reveals
that various substituted vinyl azides bearing several functional
groups worked well with cyanamide to provide the desired products.
In general,
a-azidovinylketones worked more efficiently in these
conditions when compared to the
a-azidovinylesters (Table 2).
a-
Azidovinylketones with electron-deficient groups at the R1 position
performed slightly better (3e and 3k compared to 3a; 3g compared to
3b; 3h compared to 3m, 3l and 3c). While at the R2 position, relatively
strong electron-donating groups gave slight increases in yields (3g
and 3f compared to 3e; 3b compared to 3a). Not surprisingly, when
a morpholinylcarbonyl group was present at the R2 position (Table 2,
3n) the final yield was lower compared to 3a and 3o.
The structures of the polyfunctionalized 2-aminoimidazoles 3
were characterized by 1H NMR, 13C NMR, and HRMS. Furthermore,
the structure of 3k was confirmed by X-ray crystal structure anal-
ysis as shown in Fig. 1. On the basis of the results above, we pro-
posed the following possible mechanism for this reaction, as shown
in Scheme 1. The likely first step is a Michael additioneelimination
of the cyanamide 2 to the vinyl azides 1 affording an active in-
termediate I, driven by the excellent leaving-group ability of ni-
trogen. Subsequently, the reaction undergoes an intramolecular
condensation to give the desired product 3.
aReaction conditions: vinyl azides (0.4mmol, 1.0equiv), cyanamide(0.8mmol,
2equiv), Et3N(0.4mmol,1 equiv) 2mL of solvent, 6h, 90 oC.Isolated yield.
3. Conclusions
In conclusion, we have developed a facile approach to provide
functionalized 2-aminoimidazoles, which are ubiquitous structural
units in a number of biologically active compounds. The synthesis is
economical both in lost atom count and reaction materials. This
novel reaction provides products in good yields via a domino pro-
cess involving sequential cyclization and intramolecular rear-
rangement. This simple synthesis with the ability to incorporate
multiple functional groups into a desired imidazole ring system
provides an attractive strategy for pharmaceutical building blocks
and medicinal chemistry applications.
Fig. 1. X-ray crystal structure of 3k.

1420
S. Liu et al. / Tetrahedron 70 (2014) 1418e1421
(500 MHz, DMSO):
d
11.07 (s, 1H), 7.37 (m, 2H), 7.22 (m, 5H), 7.11
182.2, 153.4,
(m, 2H), 6.08 (s, 2H); 13C NMR (125 MHz, DMSO):
d
149.9, 138.3, 135.9, 134.7, 131.0, 129.6, 128.1, 128.0, 127.8, 122.3;
HRMSeEI calcd for C16H12ClN3O: 297.0669; Found: 297.0661.
4.2.4. 4-Phenyl-5-(4-nitrobenzoyl)-1H-imidazol-2-amine
Yield: 72%, yellow solid, mp: 205.2e206.9 ꢀC; 1H NMR (500 MHz,
DMSO): 11.19 (s, 1H), 7.94 (m, 2H), 7.55 (m, 2H), 7.12e7.17 (m, 3H),
7.04 (m, 2H), 6.22 (s, 2H); 13C NMR (125 MHz, DMSO):
181.0,
154.1, 151.6, 148.5, 145.6, 134.6, 130.3, 129.7, 128.2, 127.8, 123.3,
(3d).
d
d
122.6; HRMSeEI calcd for
C16H12N4O3: 308.0909; Found:
308.0908.
4.2.5. 4-(4-Bromophenyl)-5-benzoyl-1H-imidazol-2-amine
(3e). Yield: 85%, light yellow solid, mp: 275.2e276.5 ꢀC; 1H NMR
(500 MHz, DMSO):
d
11.07 (s,1H), 7.46 (m, 2H), 7.41 (t, J¼7.8 Hz,1H),
7.36e7.22 (m, 6H), 6.02 (s, 2H). 13C NMR (125 MHz, DMSO):
d
184.0,
Scheme 1. Proposed mechanism for the synthesis of 4,5-disubstituted-2-amino-
imidazoles.
153.0, 139.5, 133.8, 131.4, 130.7, 129.2, 128.5, 128.3, 127.9, 121.1;
HRMSeEI calcd for C16H12BrN3O: 341.0164; Found: 341.0161.
4. Experimental section
4.2.6. 4-(4-Bromophenyl)-5-(4-hydroxybenzoyl)-1H-imidazol-2-
amine (3f). Yield: 88%, white solid, mp: 255.1e255.3 ꢀC; 1H NMR
4.1. General
(500 MHz, DMSO):
6.64 (m, 2H), 5.89 (s, 2H). 13C NMR (125 MHz, DMSO):
161.1, 152.6, 131.9, 131.9, 131.7, 131.7, 131.3, 130.8, 130.2, 120.8,
d
10.97 (s, 1H), 10.03 (s, 1H), 7.35 (m, 6H),
d
180.5,
All solvents were purified according to standard methods prior to
€
use. Melting points were recorded on a BUCHI B-540 melting point
115.0; HRMSeEI calcd for
C16H12BrN3O2: 357.0113; Found:
apparatus. NMR spectra were recorded for 1H NMR at 500 MHz and
357.0111.
13C NMR at 125 MHz. For 1H NMR, tetramethyl-silane (TMS) served
as internal standard (
d
¼0) and data are reported as follows: chemical
4.2.7. 4-(4-Bromophenyl)-5-(4-methylbenzoyl)-1H-imi-dazol-2-
shift, integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
amine (3g). Yield: 87%, light yellow solid, mp: 259.8e261.5 ꢀC; 1H
q¼quartet, m¼multiplet), and coupling constant (s) in Hertz. For 13
C
NMR (500 MHz, DMSO):
d
11.02 (s, 1H), 7.31 (m, 6H), 7.08 (m, 2H),
183.3,
NMR, TMS (
d
¼0) or DMSO ( ¼40.45) was used as internal standard
d
6.02 (s, 2H), 2.29 (s, 3H); 13C NMR (125 MHz, DMSO)
d
and spectra were obtained with complete proton decoupling. LC/MS
and HRMS data was obtained using Agilent Technologies 6224 TOF
LC/MS. The starting material vinyl azides 1a-1s were prepared
according to literature methods.7 The starting material 2 (cyanamide,
50% aqueous solution) was commercially available.
153.1, 147.2, 141.5, 136.8, 134.4, 131.4, 130.7, 129.2, 128.9, 122.4,
121.0, 21.4; HRMSeEI calcd for C17H14BrN3O: 355.0320; Found:
355.0326.
4.2.8. 4-(4-Chlorophenyl)-5-(4-chlorobenzoyl)-1H-imidazol-2-
amine (3h). Yield: 77%, yellow solid, mp: 263.2e265.4 ꢀC; 1H NMR
4.2. General procedure for the synthesis of 2-
aminoimidazoles
(500 MHz, DMSO):
J¼8.2 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H), 7.24 (d, J¼8.3 Hz, 2H), 6.38 (s,
2H). 13C NMR (125 MHz, DMSO):
152.3, 137.8, 136.4, 133.1, 131.6,
131.3, 131.1, 129.2, 128.4, 128.3, 128.0; HRMSeEI calcd for
C16H11Cl2N3O: 331.0279; Found: 331.0275.
d
11.79 (s, 1H), 7.50 (d, J¼7.5 Hz, 2H), 7.36 (d,
d
A
mixture of a-azidovinylester or a-azidovinylketone 1
(0.4 mmol), cyanamide 2 (0.8 mmol), Et3N (0.4 mmol) was stirred in
absolute ethanol 2 mL at 90 ꢀC for 6 h. After the completeness of
the reaction, the reaction was diluted with water and extracted
three times with ethyl acetate. The combined organic extracts were
washed with brine, dried over Na2SO4, concentrated, and purified
by flash chromatography (DCM/MeOH) on silica gel to afford 3a-3s.
4.2.9. 4-(4-Chlorophenyl)-5-(4-nitrobenzoyl)-1H-imidazol-2-amine
(3i). Yield: 70%, yellow solid, mp: 283.4e285.6 ꢀC; 1H NMR
(500 MHz, DMSO):
(m, 2H), 7.34 (m, 2H), 7.20 (m, 2H), 6.57 (m, 2H), 6.17 (s, 2H);
13C NMR (125 MHz, DMSO):
184.3, 163.3, 148.6, 145.5, 133.0, 131.3,
130.4, 127.9, 123.7, 123.3, 118.8, 106.4; HRMSeEI calcd for
16H11ClN4O3: 342.0520; Found: 342.0517.
d
11.24 (s, 1H), 8.06 (d, J¼7.9 Hz, 2H), 7.76e7.58
d
4.2.1. 4-Phenyl-5-benzoyl-1H-imidazol-2-amine (3a). Yield: 82%,
white solid, mp: 245.1e247.3 ꢀC; 1H NMR (500 MHz, DMSO):
C
d
10.98 (s, 1H), 7.40 (d, J¼6.9 Hz, 2H), 7.36e7.31 (m, 1H), 7.26 (d,
J¼6.7 Hz, 2H), 7.21e7.15 (m, 2H), 7.12 (d, J¼6.6 Hz, 1H), 7.07 (d,
4.2.10. 4-(4-Methylphenyl)-5-(4-nitrobenzoyl)-1H-imidazol-2-
J¼6.8 Hz, 2H), 6.02 (s, 2H); 13C NMR (125 MHz, DMSO):
d
183.5,
amine (3j). Yield: 68%, light yellow solid, mp: 296.3e297.1 ꢀC. 1H
153.4, 149.3, 139.5, 135.1, 131.2, 129.6, 129.0, 128.1, 127.8, 127.7,
NMR (500 MHz, DMSO):
7.17 (m, 2H), 6.92 (m, 2H), 6.15 (s, 2H), 2.19 (s, 3H); 13C NMR
(125 MHz, DMSO): 180.8, 154.1, 151.8, 148.4, 145.8, 137.7, 130.26,
130.2, 129.6, 128.5, 128.4, 123.1, 122.5, 21.1; HRMSeEI calcd for
17H14N4O3: 322.1066; Found: 322.1069.
d 11.24 (s, 1H), 8.00 (m, 2H), 7.63 (m, 2H),
122.4; HRMSeEI calcd for C16H13N3O: 263.1059; Found: 263.1054.
d
4.2.2. 4-Phenyl-5-(4-methylbenzoyl)-1H-imidazol-2-amine
(3b). Yield: 85%, light yellow solid, mp: 249.1e249.5 ꢀC; 1H NMR
C
(500 MHz, DMSO):
d
10.94(s,1H), 7.31 (m, 4H), 7.09e7.14 (m, 3H), 7.00
183.3,
(m, 2H), 5.98 (s, 2H), 2.25 (s, 3H); 13C NMR (125 MHz, DMSO):
d
4.2.11. 4-(4-Nitrophenyl)-5-benzoyl-1H-imidazol-2-amine
153.1, 148.6, 141.3, 136.8, 135.1, 129.5, 129.3, 128.7, 127.8, 127.7, 122.3,
(3k). Yield: 85%, light yellow solid, mp: 271.4e272.3 ꢀC; 1H NMR
21.4; HRMSeEI calcd for C17H15N3O: 277.1215; Found: 277.1213.
(500 MHz, DMSO):
d
11.25 (s, 1H), 7.96 (d, J¼8.8 Hz, 2H), 7.96 (d,
J¼8.8 Hz, 2H), 7.62 (d, J¼8.8 Hz, 2H), 7.47 (d, J¼7.2 Hz, 2H), 7.42 (t,
4.2.3. 4-Phenyl-5-(4-chlorobenzoyl)-1H-imidazol-2-amine
J¼7.5 Hz, 1H), 7.26 (t, J¼7.6 Hz, 2H), 6.12 (s, 2H); 13C NMR (125 MHz,
(3c). Yield: 74%, light yellow solid, mp: 253.5e254.4 ꢀC; 1H NMR
DMSO): d 183.7, 153.5, 146.5, 146.1, 141.7, 139.3, 131.7, 130.4, 129.1,

S. Liu et al. / Tetrahedron 70 (2014) 1418e1421
1421
128.4, 123.5, 122.9; HRMSeEI calcd for C16H12N4O3: 308.0909;
DMSO): d 159.6, 152.4, 146.7, 143.4, 141.1, 129.9, 123.3, 113.9, 60.3,
Found: 308.0907.
14.7; HRMSeEI calcd for C12H12N4O4: 276.0859; Found: 276.0858.
4.2.12. 4-(4-(Benzyloxy)phenyl)-5-(4-chlorobenz-oyl)-1H-imidazol-
4.2.19. 4-Phenyl-5-pivaloyl-1H-imidazol-2-amine (3s). Yield: 52%,
2-amine (3l). Yield: 71%, light yellow solid, mp: 243.1e245.2 ꢀC; 1H
white solid, mp: 196.5e197.9 ꢀC; 1H NMR (500 MHz, DMSO):
d
11.20
(s, 1H), 7.57 (d, J¼7.0 Hz, 2H), 7.35 (t, J¼6.5 Hz, 2H), 7.29 (m, 1H),
5.54 (s, 2H), 1.30 (s, 9H). 13C NMR (125 MHz, DMSO):
204.3, 154.0,
NMR (500 MHz, DMSO):
7.29e7.19 (m, 4H), 6.75 (d, J¼8.3 Hz, 2H), 6.05 (s, 2H), 5.05 (s, 2H);
13C NMR (125 MHz, DMSO):
181.7, 158.4, 153.5, 149.9, 138.5, 137.4,
d 10.93 (s, 1H), 7.42e7.33 (m, 7H),
d
d
136.9, 133.8, 132.8, 132.6, 48.5, 32.3.HRMSeEI calcd for C14H17N3O:
135.7, 131.0, 130.8, 128.8, 128.3, 128.2, 127.9, 127.6, 121.9, 114.2, 69.6;
243.1372; Found: 243.1370.
HRMSeEI calcd for C23H18ClN3O2: 403.1088; Found: 403.1085.
Acknowledgements
4.2.13. 4-(4-Methoxyphenyl)-5-(4-chlorobenzoyl)-1H-imidazol-2-
amine (3m). Yield: 73%, light yellow solid, mp: 278.1e280.3 ꢀC; 1H
This research was supported by the National Natural Science
Foundation of China (No. 81273356), Natural Science Foundation of
Zhejiang Province (No. Z2110655), Specialized Research Fund for
the Doctoral Program of Higher Education (No. 20100101110105),
Program for Zhejiang Leading Team of S&T Innovation, Diabetes
National Research Group, USA.
NMR (500 MHz, DMSO):
d 11.00 (s, 1H), 7.47 (m, 2H), 7.28 (m, 4H),
6.71 (d, J¼7.9 Hz, 2H), 6.02 (s, 2H), 3.71 (s, 3H); 13C NMR (125 MHz,
DMSO):
d 172.5, 163.2, 159.3, 152.8, 138.5, 135.8, 131.0, 130.9, 128.2,
118.7, 113.4, 112.9, 55.5; HRMSeEI calcd for
327.0775; Found: 327.0778.
C17H14ClN3O2:
4.2.14. 4-Phenyl-5-(morpholine-4-carbonyl)-1H-imidazol-2-amine
(3n). Yield: 62%, white solid, mp: 176.6e177.8 ꢀC; 1H NMR
Supplementary data
(500 MHz, DMSO):
d
11.02 (s, 1H), 7.48 (d, J¼7.5 Hz, 2H), 7.34 (t,
J¼7.8 Hz, 2H), 7.21 (t, J¼7.3 Hz, 1H), 5.45 (s, 2H), 3.44 (m, 8H); 13C
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra for all products. Supplementary data re-
lated to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.01.007.
NMR (125 MHz, DMSO):
d 164.6, 163.3, 150.5, 132.6, 128.7, 126.8,
126.4, 118.8, 66.5, 45.0; HRMSeEI calcd for C14H16N4O2: 272.1273;
Found: 272.1278.
4.2.15. Ethyl 2-amino-4-phenyl-1H-imidazole-5-carboxylate
(3o). Yield: 65%, light yellow solid, mp: 148.6e150.1 ꢀC; 1H NMR
References and notes
(500 MHz, DMSO):
d
10.89 (s, 1H), 7.90 (d, J¼7.4 Hz, 2H), 7.35 (t,
1. (a) Jung, F.; Olivier, A.; Boucherot, D. Tetrahedron Lett. 1989, 30, 2379; (b) Munk, S. A.;
Harcourt, D. A.; Arasasingham, P. N.; Burke, J. A.; Kharlamb, A. B.; Manlapaz, C. A.;
Padillo, E. U.; Roberts, D.; Runde, E.; Williams, L.; Wheeler, L. A.; Garst, M. E. J. Med.
J¼7.4 Hz, 2H), 7.30 (m, 1H), 5.44 (s, 2H), 4.17 (q, J¼7.1 Hz, 2H),1.24 (t,
J¼7.1 Hz, 3H); 13C NMR (125 MHz, DMSO):
d 172.5, 160.0, 151.6,
ꢀ
Chem.1997, 40,18; (c) Haaksma, E.E. J.; Donne-Op DenKelder, G. M.; Timmerman, H.;
133.7, 130.4, 129.2, 128.2, 127.9, 59.8, 14.7. HRMSeEI calcd for
€
Weinstein, H. New PerspectiVes in Histamine Research; Birkhauser Verlag AG: Basel,
C
12H13N3O2: 231.1008; Found: 231.1009.
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4.2.16. Ethyl 2-amino-4-(4-fluorophenyl)-1H-imidazole-5-
carboxylate (3p). Yield: 73%, white solid, mp: 176.2e179.8 ꢀC; 1H
NMR (500 MHz, DMSO):
d
10.96 (s, 1H),7.97 (dd, J¼8.9, 5.8 Hz, 2H),
7.18 (t, J¼9.0 Hz, 2H), 5.86 (s, 2H), 4.17 (q, J¼7.1 Hz, 2H), 1.24 (t,
J¼7.1 Hz, 3H); 13C NMR (125 MHz, DMSO):
d 184.3, 163.1, 161.1,
160.0, 151.9, 131.2, 131.1, 130.6, 114.8, 114.6, 59.8, 14.7; HRMSeEI
calcd for C12H12FN3O2: 249.0914; Found: 249.0910.
4.2.17. Ethyl 2-amino-4-(4-tert-butylphenyl)-1H-imidazole-5-
carboxylate (3q). Yield: 63%, white solid, mp: 209.8e210.7 ꢀC;
1H NMR (500 MHz, CDCl3):
d
7.63 (d, J¼8.4 Hz, 2H), 7.37 (d, J¼8.5 Hz,
2H), 4.20 (q, J¼7.1 Hz, 2H), 1.31 (s, 9H), 1.22 (t, J¼7.1 Hz, 3H);
13C NMR (125 MHz, DMSO):
160.1, 151.9, 151.8, 150.5, 131.4, 128.9,
2. Nishimura, T.; Kitajima, K. J. Org. Chem. 1979, 44, 818.
3. Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299.
d
4. Molina, P.; Fresneda, P.; Sanz, M. J. Org. Chem. 1999, 64, 2540.
124.6, 112.5, 59.6, 34.7, 31.5, 14.8; HRMSeEI calcd for C16H21N3O2:
287.1634; Found: 287.1635.
5. Casagrande, C.; Ferrini, R.; Miragoli, G.; Ferrari, G. Farmaco, Ed. Sci. 1972, 27, 715;
(b) Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org. Chem. 2008, 73, 6691.
6. Moschny, T.; Hartmann, H. Helv. Chim. Acta 1999, 82, 1981.
7. (a) Gilchrist, T. L.; Mendonca, R. ARKIVOC 2000, 769; (b) Liu, L.; Liebeskind, S. J.
Am. Chem. Soc. 2008, 130, 6918; (c) Khazaei, M. A. Synthesis 2009, 21, 3672; (d)
Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem. 1982, 47, 5088; (e) Chiba, S.;
Wang, Y. F.; Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10, 313; (f) Fardelone, L. C.;
Augusto, J.; Rodrigues, R.; Moran, P. J. S. J. Mol. Catal. B: Enzym. 2004, 29, 41.
4.2.18. Ethyl 2-amino-4-(4-nitrophenyl)-1H-imidazole-5-carboxylate
(3r). Yield: 79%, white solid, mp: 264.1e265.5 ꢀC; 1H NMR
(500 MHz, DMSO):
d
11.14 (s, 1H), 8.24 (q, J¼9.1 Hz, 4H), 5.89 (s, 2H),
4.22 (q, J¼7.1 Hz, 2H), 1.27 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz,