Tandem aza-wittig/carbodiimide-mediated annulation applicable to 1,2-diaza-1,3-dienes for the one-pot synthesis of fully substituted 1,2-diaminoimidazoles

Article abstract of DOI:10.1021/jo301376z

One-pot sequential aza-Michael, Staudinger, and aza-Wittig reactions on 1,2-diaza-1,2-dienes (DDs) can afford fully substituted 1,2-diaminoimidazoles. A plausible mechanism for the imidazole core formation involving an intramolecular ring closure of the c

Full text of DOI:10.1021/jo301376z

Note
pubs.acs.org/joc
Tandem Aza-Wittig/Carbodiimide-Mediated Annulation Applicable
to 1,2-Diaza-1,3-dienes for the One-Pot Synthesis of Fully
Substituted 1,2-Diaminoimidazoles
Orazio A. Attanasi, Silvia Bartoccini, Gianfranco Favi, Paolino Filippone, Francesca Romana Perrulli,
and Stefania Santeusanio*
̀
Dipartimento DiSteVa, Sezione COSON, Universita degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy
S
* Supporting Information
ABSTRACT: One-pot sequential aza-Michael, Staudinger, and aza-Wittig
reactions on 1,2-diaza-1,2-dienes (DDs) can afford fully substituted 1,2-
diaminoimidazoles. A plausible mechanism for the imidazole core formation
involving an intramolecular ring closure of the carbodiimide-derived
phosphazene intermediate is given. The reported strategy has sufficient
flexibility to allow substituted 1,2-diaminoimidazoles with orthogonal nitrogen-
protective groups to be generated from a variety of heterocumulene moieties
linked to the DDs skeleton.
In the course of our continuing interest in the construction
he imidazole ring system is one of the most important
Tsubstructures found in a large number of natural products
and pharmacologically active compounds. For example, the
amino acid histidine, the hypnotic agent etomidate,1 the
antiulcerative agent cimetidine,2 the proton pump inhibitor
omeprazole,3 the fungicide ketoconazole,4 and the benzodiaze-
pine antagonist flumazenil5 are imidazole derivatives. Recent
advances in the imidazole-tailored ionic liquids,6 stable
nucleophilic carbene,7 and organic catalyst8 are other
applications of imidazole derivatives. Consequently, new
methodologies for the preparation of multisubstituted
imidazoles are still desirable in synthetic organic and
pharmaceutical chemistry.
Significantly, the class of 2-aminoimidazoles has a particular
interest due to various biological properties, and among them,
examples of 1-substituted 2-aminoimidazoles have been
reported to possess antiviral9 and anticancer activity10 along
with antagonistic effects against biofilm formation by Salmonella
typhimurium and Pseudomonas aeruginosa.11
Because of these interesting biological activities, numerous
synthetic routes to 2-aminoimidazoles have been reported. The
most common methods for the direct synthesis of polysub-
stituted 2-aminoimidazoles involve condensation of α-amino-
carbonyl compounds with cyanamide,12 isothioureas or their
synthetic equivalents,13 or more recently, cyclocondensation of
2-aminopyrimidines with α-bromocarbonyl compounds fol-
lowed by the hydrazine-mediated cleavage of imidazo[1,2-
a]pyrimidin-1-ium salts.14 Other general applicable strategies
are the iminophosphorane-mediated cyclization of α-azido ester
derivatives.15
of heterocycles based on 1,2-diaza-1,3-dienes (DDs) building
blocks,17 we recently focused our attention on development of
synthetic procedures to obtain the imidazole core.18 Here, we
report a novel one-pot protocol for the synthesis of fully
substituted 1,2-diaminoimidazoles combining sequential azida-
tion, Staudinger and aza-Wittig reactions on 1,2-diaza-1,3-
dienes.
As recent literature has thoroughly discussed,19 phospha-
zenes have been shown to be useful intermediates in organic
synthesis, particularly for the preparation CN-containing
heterocycles, including imidazoles.15,16 Therefore, we envi-
sioned DDs as powerful tools in a synthetic pathway involving a
tandem aza-Wittig/heterocumulene-mediated annulation to
give rise to fully substituted 1,2-diaminoimidazoles.
It is noteworthy that DDs 1 act as efficient partners in the
aza-Michael additions from which arises a large variety of
heterocycles by means of different intramolecular cyclizations
where three atoms (C−CN) of the azo-ene system are
frequently involved.17,18,20
Based on our recent experience in the use of α-
azidohydrazones obtained from DDs as valuable precursors
for the construction of linked small heterocycles,21 we reasoned
that α-azidation reaction of 1 could be represented as the first
step of our strategy. Thus, 1,4-addition of trimethylsililazide
(TMSN3)22,23 2 to DDs 1a−h was carried out in the presence
of a catalytic amount of Cu(OAc)2·H2O in CH2Cl2 at room
temperature (Table 1). After the disappearance of the starting
1a−h (TLC check), the readily available crude α-azidohy-
drazone derivatives21 3a−h were treated with PPh3 for the
Additionally, fully substituted 1,2-diaminoimidazoles with a
distinct substitution pattern at N1 and at the 2-amino function
are scarcely represented,14−16 and new approaches should be
developed for their synthesis.
Received: July 2, 2012
© XXXX American Chemical Society
A
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Note
Table 1. Mechanism Pathway for One-Pot Synthesis of 1,2-Diaminoimidazoles 7a−s
DD 1
R1
heteroallene 5
a
entry
R2
R3
X
1,2-diamino-imidazole 7
time (h)
yield (%)
1
2
1a
1a
1b
1c
1d
1d
1d
1d
1d
1e
1e
1f
CONHPh
CONHPh
CONHPh
CONH2
CO2Me
N(Me)2
N(Me)2
N(Et)2
5a
5b
5a
5a
5c
5d
5e
5f
Ph
S
7a
7b
7c
7d
7e
7f
7
4
65
73
61
70
60
65
78
55
82
88
85
83
68
71
61
67
64
60
84
76
Bn
S
3
Ph
S
7
4
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
Morph
Ph
S
11
7
5
Ph
O
O
O
O
O
O
O
O
O
O
S
6
CO2Me
3-Cl-Ph
Ts
8
7
CO2Me
7g
7h
7i
8
8
CO2Me
n-Bu
4-Cl-Ph
3-Cl-Ph
Ph
7
9
CO2Me
5g
5d
5c
5c
5f
6
10
11
12
13
14
15
16
17
18
19
20
CO2Et
7j
7
CO2Et
7k
7l
6
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
4-NO2−Ph
Ph
5
1f
Morph
n-Bu
Ph
7m
7n
7n
7o
7p
7q
7r
6
1g
1g
1g
1g
1g
1g
1h
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
N(Me)2
5c
5a
5d
5e
5f
6
Ph
5
3-Cl-Ph
Ts
O
O
O
O
S
8
7
n-Bu
4-Cl-Ph
Ph
6
5g
5a
4
7s
11
a
Yield of isolated pure product based on DD 1.
Staudinger reaction to deliver the related iminophosphoranes
4a−h (monitored by TLC).
In view of a sequential one-pot procedure and to be sure of
the hypothesized mechanistic pathway, only 4a was isolated as
crystalline solid (yield 96%) for the characterization of the
phosphazene intermediate.
In all cases, 4a−h were then coupled with the appropriate
heteroallene (isocyanates or isothiocyanates) 5a−g for the aza-
Wittig reaction affording directly fully substituted 1,2-
diaminoimidazoles 7a−s in 55−88% overall yields (Table 1).
Mechanistically, we propose that the conversion 4→7 involves
the formation of the reactive carbodiimide-derived phospha-
zene intermediate 6 which undergoes a spontaneous ring
closure by intramolecular nucleophilic attack of the hydrazone
nitrogen at the central carbon of the heterocumulene moiety of
6. Moreover, the reactions affording 7n by use of isocyanate or
its thio-analogue derivative (entries 14 and 15) were also
performed. By comparison of the yields obtained (Table 1),
phenylisocyanate seemed to be more efficient. This synthetic
strategy, directly provides a precise substitution pattern at 2-
B
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Note
min, the reaction mixture was reported at room temperature and
stirred until the complete formation of the triphenylphosphine oxide
or triphenylphosphine thioxide as byproduct (TLC check). After
removal of the solvent in vacuo, the residue was purified by column
chromatography on silica gel (elution mixture: EtOAc/cyclohexane or
EtOAc/MeOH) to give 1,2-diaminosubstituted imidazoles 7a−s.
Iminophosphorane derivative (4a): yield 516.0 mg (96%); white
powder; mp 112−115 °C (from CH2Cl2/Et2O); IR (Nujol, ν, cm−1)
3198, 3057, 3028, 2024, 1728, 1646, 1604, 1554, 1541, 1505; 1H NMR
(DMSO-d6) δ 1.86 (s, 3H), 2.64 and 2.76 (2 s, 6H), 4.93 (d, 3J = 10.8
Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.46 (d, J =
7.6 Hz, 2H), 7.72−7.84 (m, 15H), 8.61 (s, 1H), 9.83 (s, 1H); 13C
NMR (DMSO-d6) δ 13.2 (q), 35.6 (q), 36.4 (q), 58.8 (d), 119.0 (d),
121.5 (s, 1J = 102.4 Hz), 122.5 (s), 128.8 (d), 129.7 (d, 2J = 12.9 Hz),
amino function of the imidazole ring and constitutes an
improvement over our previous results12b in which the selective
N-alkylation in 2-position of 1,2-diaminoimidazoles, obtained
by reaction of DDs and cyanamide, was uneffective due to
competitive N1-alkylation. Due to the easy access of the
starting materials, the good overall yields without the need to
isolate intermediates, and due to the simplicity of the one-pot
protocol, this synthetic strategy leads to a large variability of the
substitution patterns both at the positions of the ring and at the
2-amino function and favorably implements the existing
approach based on alkyl 2-amino-3-azidoacrylates.16a
In summary, combining sequential azidation, Staudinger and
aza-Wittig reactions on 1,2-diaza-1,3-dienes in a one-pot
protocol, fully substituted 1,2-diaminoimidazoles are directly
accessible in good yields. The imidazole core formation could
result from a spontaneous intramolecular ring closure of the
carbodiimide-derived phosphazene intermediate formed. By
suitable choice of the substituents both of the DD and
heteroallene, selective protected 1,2-diaminoimidazoles can be
obtained from which regioselective N-deprotection could be
conveniently modulated.
3
133.6 (d, J = 10.6 Hz), 134.7 (d), 138.8 (d), 143.9 (s), 152.9 (s),
167.7 (s); MS m/z 537 (M+, 11), 493 (1), 465 (2), 445 (1), 373 (20),
352 (23), 329 (24), 304 (14), 277 (45), 262 (93), 183 (100). Anal.
Calcd for C31H32N5O2P (537.59): C, 69.26; H, 6.00; N, 13.03. Found:
C, 69.10; H, 5.88; N, 13.08.
2-Anilino-1-[(anilinocarbonyl)amino]-N,N,5-trimethyl-1H-imida-
zole-4-carboxamide (7a): yield 245.9 mg (65%); white powder; mp
223−226 °C (from CH2Cl2/light petroleum ether); IR (Nujol, ν,
1
cm−1) 3357, 3282, 3200, 1713, 1622, 1604, 1575, 1550; H NMR
Moreover, the mild reaction conditions, good yields,
accessible starting materials of the synthetic procedure here
discussed, complements the existing routes for the synthesis of
fully substituted 1,2-diaminoimidazoles.16
(DMSO-d6) δ 2.18 (s, 3H), 2.93 and 3.36 (2 br s, 6H), 6.83 (t, J = 7.2
Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 7.21−7.30 (m, 4H), 7.51 (d, J = 8.4
Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 8.63 (s, 1H), 9.16 (1H, s, NH), 9.42
(1H, s, NH); 13C NMR (DMSO-d6) δ 8.9 (q), 35.3 (q), 38.4 (q),
116.2 (d), 118.7 (d), 119.8 (d), 122.3 (d), 124.8 (s), 128.6 (d), 128.7
(d), 129.3 (s), 139.3 (s), 141.3 (s), 142.3 (s), 153.7 (s), 164.8 (s); MS
m/z 378 (M+, 62), 285 (54), 214 (55), 186 (100), 170 (41), 119 (71).
Anal. Calcd for C20H22N6O2 (378.42): C, 63.48; H, 5.86; N, 22.21.
Found: C, 63.32; H, 5.95; N, 22.18.
EXPERIMENTAL SECTION
■
General Methods. All chemicals and solvents were purchased
from commercial suppliers and used as received. 1,2-Diaza-1,3-dienes
(DDs) were prepared as reported17,24 and used as EE/EZ isomer
mixtures. TMSN3,23 Cu(OAc)2·H2O, PPh3, and isocyanate or
isothiocyanate derivatives were commercial materials and were used
without further purification. Melting points were determined in open
capillary tubes and are uncorrected. FT-IR spectra were obtained as
Nujol mulls or neat. Mass spectra (MS) were carried out by electron
impact (EI) at an ionizing voltage of 70 eV. 1H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded in DMSO-d6 or in
1-[(Anilinocarbonyl)amino]-2-(benzylamino)-N,N,5-trimethyl-
1H-imidazole-4-carboxamide (7b): yield 286.4 mg (73%); white
powder; mp 192−195 °C (from MeOH/light petroleum ether); IR
(Nujol, ν, cm−1) 3262, 3208, 3145, 1736, 1680, 1668, 1652, 1612,
1
1571; H NMR (DMSO-d6) δ 2.11 (3H, s), 2.85 and 3.19 (2 br s,
6H), 4.36 (br s, 2H) 6.53 (t, J = 6.0 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H),
7.17−7.50 (m, 9H), 9.05 (s, 1H), 9.28 (s, 1H); 13C NMR (DMSO-d6)
δ 8.9 (q), 35.6 (q), 36.4 (q), 45.5 (t), 118.6 (d), 122.2 (d), 124.5 (d),
126.3 (d), 127.3 (s), 127.6 (d), 128.6 (d), 129.3 (s), 139.3 (s), 140.7
(s), 147.1 (s), 153.6 (s), 165.1 (s); MS m/z 392 (M+, 50), 299 (39),
228 (40), 200 (100), 185 (27), 106 (13). Anal. Calcd for C21H24N6O2
(392.45): C, 64.27; H, 6.16; N, 21.41. Found: C, 64.38; H, 6.28; N,
21.33.
CDCl3 as specified below. Dynamic 1H NMR experiments were
performed between 298−328 K to confirm the existence of a mixture
of conformers for compounds 7a−s. Chemical shifts (δH) and (δC) are
reported in parts per million (ppm), and were referred to solvent
signals as follows: δ = 2.50 ppm for proton (middle peak) and δ =
39.50 ppm for carbon in DMSO; δ = 7.26 ppm for proton and δ =
77.00 ppm for carbon (middle peak) in CDCl3. All coupling constant
(J values) are given in hertz (Hz). The following abbreviations are
used to describe peak patterns where appropriate: s, singlet; d,
doublet; dd, double−doublet; t, triplet; q, quartet; m, multiplet; br,
broad. All the NH exchanged with D2O. Precoated silica gel plates 0.25
mm were employed for analytical thin layer chromatography and silica
gel 35−70 μm for column chromatography. All new compounds
showed satisfactory elemental analysis. The nomenclature was
generated using ACD/IUPACName (version 3.50, 5 Apr. 1998),
Advanced Chemistry Development Inc., Toronto, ON (Canada).
General One-pot procedure for the synthesis of variously
substituted 1,2-diaminoimidazoles 7a−s. In a 25-mL flask, DD
1a−h (1.0 mmol) was dissolved in CH2Cl2 (4 mL) and the TMSN3 2
(1.1 mmol) was added. Catalyst Cu(OAc)2·H2O was then added (0.2
mmol) and the reaction mixture was stirred at room temperature until
the complete formation of organic azide 3a−h (TLC check). The
reaction flask was then immersed in an ice bath (T = 0 °C), and a
cooled solution of triphenylphosphine (1.0 mmol) in CH2Cl2 (1 mL)
was added dropwise. The reaction was reported at room temperature
and stirred until the disappeareance of organic azide 3a−h (monitored
by TLC). The formation of iminophosphorane 4a−h was accom-
panied by the development of nitrogen gas from the reaction mixture.
The reaction mixture was cooled again to 0 °C, and isocyanate or
isothiocyanate derivative 5a−g (1.1 mmol) was slowly added. Within 5
2-Anilino-1-[(anilinocarbonyl)amino]-N,N-diethyl-5-methyl-1H-
imidazole-4-carboxamide (7c): yield 247.9 mg (61%); white powder;
mp 180−183 °C (from EtOAc/light petroleum ether); IR (Nujol, ν,
1
cm−1) 3349, 3298, 3140, 1714, 1609, 1584, 1552, 1540; H NMR
(DMSO-d6) δ 1.12 (br s, 3H), 1.27 (br s, 3H), 2.20 (s, 3H), 3.37 (br s,
2H), 3.79 (br s, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H),
7.20−7.30 (m, 4H), 7.52 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H),
8.62 (s, 1H), 9.15 (s, 1H), 9.38 (s, 1H); 13C NMR (DMSO-d6) δ 9.0
(q), 13.0 (q), 14.8 (q), 40.1 (t), 42.2 (t), 116.2 (d), 118.7 (d), 119.7
(d), 122.3 (d), 125.0 (s), 128.4 (d), 128.7 (d), 129.6 (s), 139.3 (s),
141.2 (s), 142.3 (s), 153.7 (s), 163.9 (s); MS m/z 406 (M+, 15), 313
(6), 307 (17), 241 (10), 214 (23), 200 (100), 170 (11), 119 (24).
Anal. Calcd for C22H26N6O2 (406.48): C, 65.01; H, 6.45; N, 20.68.
Found: C, 65.12; H, 6.35; N, 20.59.
1-[(Aminocarbonyl)amino]-2-anilino-N,N,5-trimethyl-1H-imida-
zole-4-carboxamide (7d): yield 211.6 mg (70%); white powder; mp
234−237 °C (from EtOAc/light petroleum ether); IR (Nujol, ν,
cm−1) 3453, 3254, 3177, 1685, 1653, 1629, 1606, 1574, 1560, 1541;
1H NMR (DMSO-d6) δ 2.13 (s, 3H), 2.90 and 3.34 (2 br s, 6H), 6.39
(s, 2H) 6.80 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 2H), 7.70 (d, J =
7.5 Hz, 2H), 8.44 (s, 1H), 8.91 (s, 1H); 13C NMR (DMSO-d6) δ 8.8
(q), 35.5 (q), 38.4 (q), 116.2 (d), 119.6 (d), 124.7 (s), 128.4 (d),
129.2 (s), 141.3 (s), 142.1 (s), 157.0 (s), 164.8 (s); MS m/z 302 (M+,
80), 285 (10), 214 (27), 200 (35), 186 (100), 170 (30), 119 (21).
C
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Note
Anal. Calcd for C14H18N6O2 (302.33): C, 55.62; H, 6.00; N, 27.80.
Found: C, 55.75; H, 5.92; N, 27.72.
1H); 13C NMR (DMSO-d6) δ 8.6 (q), 14.2 (q), 35.4 (q), 38.2 (q),
61.8 (t), 114.8 (d), 115.6 (d), 119.5 (d), 125.0 (s), 128.8 (s), 130.1
(d), 133.0 (s), 141.2 (s), 142.5 (s), 155.1 (s), 164.4 (s); MS m/z 367
[M+ + 2, (22)], 365 (M+, 71), 322 (8), 294 (46), 248 (36), 220 (100),
203 (42), 153 (15). Anal. Calcd for C16H20ClN5O3 (365.81): C, 52.53;
H, 5.51; N, 19.14. Found: C, 52.41; H, 5.62; N, 19.09.
Methyl 2-anilino-4-[(dimethylamino)carbonyl]-5-methyl-1H-imi-
dazol-1-ylcarbamate (7e): yield 190.4 mg (60%); pale yellow
powder; mp 183−185 °C (from EtOAc/Et2O); IR (Nujol, ν, cm−1)
1
3346, 3318, 1778, 1747, 1731, 1611, 1576, 1551; H NMR (DMSO-
d6) δ 2.14 (s, 3H), 2.92 and 3.33 (2 br s, 6H), 3.75 (s, 3H), 6.84 (t, J =
7.7 Hz, 1H), 7.23 (t, J = 7.7 Hz, 2H), 7.70 (d, J = 7.7 Hz, 2H), 8.69 (s,
1H), 10.38 (s, 1H); 13C NMR (DMSO-d6) δ 8.6 (q), 35.5 (q), 38.2
(q), 52.8 (q), 116.3 (d), 119.9 (d), 124.9 (s), 128.5 (d), 130.0 (s),
141.1 (s), 141.8 (s), 155.6 (s), 164.6 (s); MS m/z 317 (M+, 82), 273
(11), 246 (45), 214 (26), 186 (100), 170 (29). Anal. Calcd for
C15H19N5O3 (317.34): C, 56.77; H, 6.03; N, 22.07. Found: C, 56.65;
H, 6.11; N, 22.14.
Methyl 2-[(3-chlorophenyl)amino]-4-[(dimethylamino)carbonyl]-
5-methyl-1H-imidazol-1-ylcarbamate (7f): yield 228.6 mg (65%);
pale yellow powder; mp 216−218 °C (from EtOAc/Et2O); IR (Nujol,
ν, cm−1) 3303, 3086, 1746, 1620, 1607, 1566, 1550; 1H NMR
(DMSO-d6) δ 2.14 (s, 3H), 2.93 and 3.32 (2 br s, 6H), 3.76 (s, 3H),
6.89 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.96 (s, 1H), 9.00 (s, 1H), 10.45 (s, 1H); 13C NMR (DMSO-d6)
δ 8.6 (q), 35.4 (q), 38.9 (q), 52.9 (q), 114.9 (d), 115.7 (d), 119.5 (d),
124.9 (s), 128.7 (s), 130.2 (d), 133.1 (s), 141.2 (s), 142.4 (s), 155.6
(s), 164.4 (s); MS m/z 353 [M+ + 2, (21)], 351 (M+, 62), 280 (54),
248 (25), 220 (100), 203 (40), 153 (38). Anal. Calcd for
C15H18ClN5O3 (351.78): C, 51.21; H, 5.16; N, 19.91. Found: C,
51.34; H, 5.07; N, 20.02.
Ethyl 2-anilino-4-[(dimethylamino)carbonyl]-5-methyl-1H-imi-
dazol-1-ylcarbamate (7k): yield 281.6 mg (85%); white powder;
mp 176−179 °C (from EtOAc/Et2O); IR (Nujol, ν, cm−1) 3308,
3140, 1733, 1726, 1606, 1581, 1552; 1H NMR (DMSO-d6) δ 1.28 (t, J
= 6.4 Hz, 3H), 2.14 (s, 3H), 2.92 and 3.34 (2 br s, 6H), 4.15−4.17 (m,
2H), 6.84 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 7.70 (d, J = 7.6
Hz, 2H), 8.68 (s, 1H), 10.32 (s, 1H); 13C NMR (DMSO-d6) δ 8.6 (q),
14.3 (q), 35.4 (q), 38.6 (q), 61.7 (t), 116.3 (d), 119.9 (d), 125.0 (s),
128.5 (d), 130.0 (s), 141.1 (s), 141.8 (s), 155.2 (s), 164.6 (s); MS m/z
331 (M+, 56), 288 (6), 260 (28), 214 (29), 186 (100), 169 (38), 119
(14). Anal. Calcd for C16H21N5O3 (331.37): C, 57.99; H, 6.39; N,
21.13. Found: C, 58.07; H, 6.27; N, 21.21.
tert-Butyl [2-anilino-5-methyl-4-(morpholin-4-ylcarbonyl)-1H-
imidazol-1-yl]carbamate (7l): yield 333.2 mg (83%); white powder;
mp 186−189 °C (from MeOH/Et2O/light petroleum ether); IR
(Nujol, ν, cm−1) 3419, 3322, 1746, 1608, 1585, 1551, 1504; 1H NMR
(DMSO-d6) δ 1.48 (s, 9H), 2.15 (s, 3H), 3.63−3.96 (m, 8H), 6.84 (t, J
= 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 8.67
(s, 1H), 10.01 (s, 1H); 13C NMR (DMSO-d6) δ 8.6 (q), 27.8 (q), 42.8
(t), 47.2 (t), 66.4 (t), 81.2 (s), 116.3 (d), 120.0 (d), 124.3 (s), 128.5
(d), 132.0 (s), 141.0 (s), 142.0 (s), 154.1 (s), 163.6 (s); MS m/z 401
(M+, 24), 345 (42), 301 (27), 285 (20), 260 (38), 232 (100), 200
(29), 170 (17), 119 (15). Anal. Calcd for C20H27N5O4 (401.46): C,
59.84; H, 6.78; N, 17.44. Found: C, 59.73; H, 6.88; N, 17.36.
tert-Butyl [2-(butylamino)-5-methyl-4-(morpholin-4-ylcarbonyl)-
1H-imidazol-1-yl]carbamate (7m): yield 259.4 mg (68%); beige
powder; mp 139−141 °C (from EtOAc/Et2O); IR (Nujol, ν, cm−1)
Methyl 4-[(dimethylamino)carbonyl]-5-methyl-2-[[(4-
methylphenyl)sulfonyl]amino]-1H-imidazol-1-ylcarbamate (7g):
yield 308.4 mg (78%); pale yellow powder; mp 169−172 °C (from
EtOAc/Et2O); IR (Nujol, ν, cm−1) 3222, 3163, 1757, 1662, 1618,
1
1587, 1530; H NMR (CDCl3) δ 2.15 (s, 3H), 2.36 (s, 3H), 3.02 (s,
6H), 3.75 (br s, 3H), 7.21 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 7.6 Hz,
2H), 9.40 (br s, 1H), 9.77 (br s, 1H); 13C NMR (CDCl3) δ 9.0 (q),
21.4 (q), 37.2 (q), 53.4 (q), 113.0 (s), 126.1 (d), 128.4 (s), 129.2 (d),
132.0 (s), 139.7 (s), 142.3 (s), 146.5 (s), 155.4 (s), 160.9 (s); MS m/z
395 (M+, 31), 324 (6), 264 (3), 240 (100), 197 (51), 167 (9). Anal.
Calcd for C16H21N5O5S (395.43): C, 48.60; H, 5.35; N, 17.71. Found:
C, 48.49; H, 5.43; N, 17.78.
Methyl 2-(butylamino)-4-[(dimethylamino)carbonyl]-5-methyl-
1H-imidazol-1-ylcarbamate (7h): yield 163.5 mg (55%); pale yellow
crystals; mp 79−82 °C (from EtOAc/light petroleum ether); IR
(Nujol, ν, cm−1) 3263, 3176, 1746, 1732, 1697, 1606; 1H NMR
(DMSO-d6) δ 0.87 (t, J = 7.2 Hz, 3H), 1.26−1.32 (m, 2H), 1.46−1.51
(m, 2H), 2.04 (s, 3H), 2.88−3.31 (m, 8H), 3.69 (s, 3H), 5.95 (br s,
1H), 10.11 (s, 1H); 13C NMR (DMSO-d6) δ 8.7 (q), 13.8 (q), 19.5
(t), 31.3 (t), 35.4 (q), 38.3 (q), 41.8 (t), 52.6 (q), 124.8 (s), 127.7 (s),
147.0 (s), 155.6 (s), 165.1 (s); MS m/z 297 (M+, 72), 253 (16), 224
(42), 194 (10), 166 (100), 152 (21). Anal. Calcd for C13H23N5O3
(297.35): C, 52.51; H, 7.80; N, 23.55. Found: C, 52.60; H, 7.69; N,
23.61.
1
3373, 3206, 1748, 1703, 1605, 1596, 1510; H NMR (DMSO-d6) δ
0.86 (t, J = 7.2 Hz, 3H), 1.25−1.49 (m, 13H), 2.07 (s, 3H), 3.10 (br s,
2H), 3.57−3.77 (m, 8H), 5.87 (br s, 1H), 9.80 (s, 1H); 13C NMR
(DMSO-d6) δ 8.7 (q), 13.7 (q), 19.4 (t), 27.8 (q), 31.2 (t), 41.7 (t),
46.5 (t), 66.4 (t), 80.7 (s), 124.1 (s), 129.0 (s), 147.1 (s), 154.0 (s),
163.7 (s); MS m/z 381 (M+, 18), 325 (39), 281 (19), 265 (22), 240
(41), 212 (100), 195 (30), 168 (53). Anal. Calcd for C18H31N5O4
(381.47): C, 56.67; H, 8.19; N, 18.36. Found: C, 56.79; H, 8.28; N,
18.28.
tert-Butyl [2-anilino-4-[(dimethylamino)carbonyl]-5-methyl-1H-
imidazol-1-yl]carbamate (7n): yield 255.2 mg (71% from 5c);
white powder; mp 176−178 °C (from MeOH/EtOAc/light petroleum
ether); IR (Nujol, ν, cm−1) 3427, 3299, 1752, 1741, 1728, 1604, 1584,
1
1540; H NMR (DMSO-d6) δ 1.48 (s, 9H), 2.13 (s, 3H), 2.92 and
3.32 (2 br s, 6H), 6.83 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.7 Hz, 2H),
7.70 (d, J = 7.7 Hz, 2H), 8.64 (s, 1H), 9.99 (s, 1H); 13C NMR
(DMSO-d6) δ 8.6 (q), 27.8 (q), 35.4 (q), 38.6 (q), 81.1 (s), 116.3 (d),
119.8 (d), 125.0 (s), 128.5 (d), 131.5 (s), 141.2 (s), 141.8 (s), 154.2
(s), 164.7 (s); MS m/z 359 (M+, 27), 303 (59), 259 (24), 244 (28),
200 (23), 186 (100), 119 (11). Anal. Calcd for C18H25N5O3 (359.42):
C, 60.15; H, 7.01; N, 19.49. Found: C, 60.01; H, 7.12; N, 19.53.
tert-Butyl [2-[(3-chlorophenyl)amino]-4-[(dimethylamino)-
carbonyl]-5-methyl-1H-imidazol-1-yl]carbamate (7o). yield 263.9
mg (67%); pale yellow crystals; mp 170−174 °C (from MeOH/light
petroleum ether); IR (Nujol, ν, cm−1) 3275, 3133, 1730, 1623, 1615,
1601, 1579, 1528; 1H NMR (DMSO-d6) δ 1.48 (s, 9H), 2.14 (s, 3H),
2.93 and 3.32 (2 br s, 6H), 6.88 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz,
1H), 7.59 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 8.96 (s, 1H), 10.05 (s,
1H); 13C NMR (DMSO-d6) δ 8.6 (q), 27.8 (q), 35.4 (q), 38.3 (q),
81.3 (s), 114.8 (d), 115.6 (d), 119.4 (d), 125.0 (s), 128.8 (s), 130.1
(d), 133.0 (s), 141.3 (s), 142.6 (s), 154.1 (s), 164.5 (s); MS m/z 395
[M+ + 2 (5)], 393 (M+, 17), 337 (63), 320 (2), 293 (24), 278 (41),
266 (50), 249 (9), 234 (27), 220 (100), 204 (17), 153 (10). Anal.
Calcd for C18H24ClN5O3 (393.86): C, 54.89; H, 6.14; N, 17.78.
Found: C, 55.01; H, 6.05; N, 17.71.
Methyl 2-[(4-chlorophenyl)amino]-4-[(dimethylamino)carbonyl]-
5-methyl-1H-imidazol-1-ylcarbamate (7i): yield 288.4 mg (82%);
white powder; mp 198−200 °C (from EtOAc/Et2O); IR (Nujol, ν,
1
cm−1) 3317, 3087, 1772, 1742, 1607, 1575, 1549, 1503; H NMR
(DMSO-d6) δ 2.13 (s, 3H), 2.92 and 3.30 (2 br s, 6H), 3.75 (s, 3H),
7.29 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 8.92 (s, 1H), 10.43
(s, 1H); 13C NMR (DMSO-d6) δ 8.6 (q), 35.4 (q), 38.3 (q), 52.9 (q),
117.8 (d), 123.4 (s), 125.0 (s), 128.4 (d), 128.5 (s), 140.0 (s), 141.5
(s), 155.6 (s), 164.5 (s); MS m/z 353 [M+ + 2, (22)], 351 (M+, 66),
319 (2), 307 (9), 292 (22), 280 (46), 248 (23), 220 (100), 203 (38),
152 (16), 127 (12). Anal. Calcd for C15H18ClN5O3 (351.78): C, 51.21;
H, 5.16; N, 19.91. Found: C, 51.35; H, 5.24; N, 19.80.
Ethyl 2-[(3-chlorophenyl)amino]-4-[(dimethylamino)carbonyl]-5-
methyl-1H-imidazol-1-ylcarbamate (7j): yield 321.9 mg (88%);
white powder; mp 192−194 °C (from EtOAc/Et2O); IR (Nujol, ν,
1
cm−1) 3328, 3085, 1735, 1618, 1605, 1580, 1574, 1552; H NMR
(DMSO-d6) δ 1.28 (t, J = 6.4 Hz, 3H), 2.15 (s, 3H), 2.93 and 3.33 (2
br s, 6H), 4.15−4.17 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0
Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 8.98 (s, 1H), 10.37 (s,
tert-Butyl (4-[(dimethylamino)carbonyl]-5-methyl-2-[[(4-
methylphenyl)sulfonyl]amino]-1H-imidazol-1-yl)carbamate (7p):
D
dx.doi.org/10.1021/jo301376z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
yield 280.0 mg (64%); pale yellow powder; mp 150−152 °C (from
MeOH/Et2O); IR (Nujol, ν, cm−1) 3608, 3488, 3290, 3118, 1732,
1658, 1627, 1597, 1511; H NMR (CDCl3) δ 1.45 (s, 9H), 2.17 (s,
REFERENCES
■
(1) Wauquier, A.; Van Den Broeck, W. A. E.; Verheyen, J. L.; Janssen,
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1
3H), 2.35 (s, 3H), 3.04 (s, 6H), 7.19 (d, J = 8.0 Hz, 2H), 7.78 (d, J =
8.0 Hz, 2H), 8.31 (s, 1H), 9.74 (s, 1H); 13C NMR (CDCl3) δ 9.1 (q),
21.3 (q), 27.8 (q), 37.2 (q), 82.9 (s), 112.7 (s), 126.0 (d), 127.4 (s),
129.1 (s), 140.1 (s), 142.0 (s), 146.5 (s), 154.1 (s), 161.1 (s); MS m/z
437 (M+, 11), 381 (7), 337 (47), 293 (2), 264 (4), 226 (32), 182
(100), 155 (14). Anal. Calcd for C19H27N5O5S (437.51): C, 52.16; H,
6.22; N, 16.01. Found: C, 52.22; H, 6.12; N, 15.90.
tert-Butyl [2-(butylamino)-4-[(dimethylamino)carbonyl]-5-meth-
yl-1H-imidazol-1-yl]carbamate (7q): yield 203.6 mg (60%); colorless
crystals; mp 115−116 °C (from Et2O); IR (Nujol, ν, cm−1) 3368,
3139, 1740, 1613, 1581, 1517; 1H NMR (DMSO-d6) δ 0.86 (t, J = 7.6
Hz, 3H), 1.26−1.47 (m, 13H), 2.04 (s, 3H), 2.86−3.26 (m, 8H), 5.78
(br s, 1H), 9.76 (s, 1H); 13C NMR (DMSO-d6) δ 8.6 (q), 13.7 (q),
19.4 (t), 27.8 (q), 31.3 (t), 35.3 (q), 38.0 (q), 41.8 (t), 80.7 (s), 124.8
(s), 127.8 (s), 147.0 (s), 154.1 (s), 165.1 (s); MS m/z 339 (M+, 28),
283 (57), 266 (3), 239 (21), 224 (29), 210 (38), 195 (20), 166 (100),
151 (16). Anal. Calcd for C16H29N5O3 (339.43): C, 56.62; H, 8.61; N,
20.63. Found: C, 56.70; H, 8.50; N, 20.56.
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tert-Butyl [2-[(4-chlorophenyl)amino]-4-[(dimethylamino)-
carbonyl]-5-methyl-1H-imidazol-1-yl]carbamate (7r): yield 330.8
mg (84%); white powder; mp 180−184 °C (from THF/light
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́
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1
1700, 1685, 1600, 1576, 1538; H NMR (DMSO-d6) δ 1.48 (s, 9H),
2.13 (s, 3H), 2.92 and 3.29 (2 br s, 6H), 7.27 (d, J = 8.8 Hz, 2H), 7.76
(d, J = 8.8 Hz, 2H), 8.87 (s, 1H), 10.03 (s, 1H); 13C NMR (DMSO-
d6) δ 8.6 (q), 27.8 (q), 35.4 (q), 38.3 (q), 81.2 (s), 117.9 (d), 123.3
(s), 125.0 (s), 128.3 (d), 128.6 (s), 140.1 (s), 141.6 (s), 154.2 (s),
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(31), 278 (33), 266 (49), 234 (31), 220 (100), 204 (19), 153 (11),
126 (9). Anal. Calcd for C18H24ClN5O3 (393.86): C, 54.89; H, 6.14;
N, 17.78. Found: C, 54.76; H, 6.21; N, 17.70.
2-Anilino-N,N,5-trimethyl-1-[(4-nitrophenyl)amino]-1H-imida-
zole-4-carboxamide (7s): yield 289.1 mg (76%); yellow brown
powder; mp 236−239 °C (from EtOAc/Et2O); IR (Nujol, ν, cm−1)
3255, 3097, 1665, 1650, 1618, 1591, 1574, 1558, 1505; 1H NMR
(DMSO-d6) δ 2.10 (s, 3H), 2.94 and 3.38 (2 br s, 6H), 6.62 (d, J = 7.4
Hz, 2H), 6.83 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.71 (d, J =
7.6 Hz, 2H), 8.16 (d, J = 7.4 Hz, 2H), 8.73 (s, 1H), 10.02 (s, 1H); 13C
NMR (DMSO-d6) δ 8.8 (q), 35.4 (q), 38.5 (q), 111.5 (d), 116.4 (d),
120.1 (d), 125.9 (s), 126.1 (d), 128.0 (s), 128.5 (d), 140.0 (s), 140.9
(s), 141.9 (s), 152.6 (s), 164.5 (s); MS m/z 380 (M+, 55), 309 (11),
243 (85), 200 (100), 186 (30), 170 (30), 138 (7). Anal. Calcd for
C19H20N6O3 (380.40): C, 59.99; H, 5.30; N, 22.09. Found: C, 60.13;
H, 5.38; N, 22.01.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of products 4a and 7a−s.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org. Chem. 2008, 73,
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2540.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stefania.santeusanio@uniurb.it.
(16) (a) Molina, P.; Conesa, C.; Velasco, M. D. Synthesis 1996, 1459.
(b) Nie, Y.-B.; Wang, L.; Ding, M-W J. Org. Chem. 2012, 77, 696.
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Bartoccini, S.; Giorgi, G.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S.
Tetrahedron 2010, 66, 5121. (c) Attanasi, O. A.; Bartoccini, S.; Favi,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministero dell’Istruzione, dell’Uni-
versita
̀
e della Ricerca (MIUR)-Roma, and from the University
of Urbino “Carlo Bo” is gratefully acknowledged.
E
dx.doi.org/10.1021/jo301376z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
G.; Giorgi, G.; Perrulli, F. R.; Santeusanio, S. Tetrahedron 2012, 68,
608.
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(22) For use of TMSN3 as versatile reagent in organic synthesis, see:
Jafarzadeh, M. Synlett 2009, 2144.
(23) Attention: The main concern about this one-pot procedure is
that it may pose a serious safety issue. In fact, it is well documented in
the literature that ionic azides react with dichloromethane to form
explosive azidochloromethane and/or diazidomethane. See: (a) Con-
row, R. E.; Dean, W. D. Org. Process Res. Dev. 2008, 12, 1285−1286.
(b) Hassner, A.; Stern, M.; Gottlieb, H. E. J. Org. Chem. 1990, 55,
2304−2306. Luckily, under our reaction conditions (short reaction
times, stoichiometric amount of TMSN3), the possible competitive
nucleophilic substitution on CH2Cl2 is effectively suppressed since the
Michael addition is the favorite and exclusive pathway. Caution:
organic azides are potentially explosive compounds (when dry) and
should be handled with great care. During our experiments we used
TMSN3 and we encountered no problem.
(24) (a) Sommer, S. Tetrahedron Lett. 1977, 18, 117. (b) Attanasi, O.
A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 671.
F
dx.doi.org/10.1021/jo301376z | J. Org. Chem. XXXX, XXX, XXX−XXX