Novel and efficient one-pot synthesis of (aminophenyl)carbamic acid esters

Article abstract of DOI:10.1080/00397911.2010.494818

A novel and efficient protocol is developed for the synthesis of various (aminophenyl) carbamic acid esters from the reduction and condensation of nitrophenyl isocyanate derivatives. The reaction takes place in various hydroxy derivatives such as alcohols or phenols under a hydrogen atmosphere using Raney nickel as catalyst. Products are obtained by a convenient one-pot synthesis with excellent yields and short reaction times.

Full text of DOI:10.1080/00397911.2010.494818

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Novel and Efficient One-Pot Synthesis of
(Aminophenyl)carbamic Acid Esters
Antonio Garofalo a b , Laurence Goossens a b , Perrine Six a b
Nicolas Lebegue a c & Patrick Depreux a b
,
a Univ. Lille Nord de France , Lille, France
b UDSL, ICPAL, EA 4481 , Lille, France
c UDSL, UFR de Pharmacie, EA 4481, Laboratoire de Chimie
Thérapeutique , Lille, France
Published online: 02 May 2011.
To cite this article: Antonio Garofalo , Laurence Goossens , Perrine Six , Nicolas Lebegue & Patrick
Depreux (2011) Novel and Efficient One-Pot Synthesis of (Aminophenyl)carbamic Acid Esters,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:13, 2007-2016, DOI: 10.1080/00397911.2010.494818
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Synthetic Communications1, 41: 2007–2016, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.494818
NOVEL AND EFFICIENT ONE-POT SYNTHESIS OF
(AMINOPHENYL)CARBAMIC ACID ESTERS
Antonio Garofalo,1,2 Laurence Goossens,1,2 Perrine Six,1,2
Nicolas Lebegue,1,3 and Patrick Depreux1,2
1Univ. Lille Nord de France, Lille, France
2UDSL, ICPAL, EA 4481, Lille, France
3UDSL, UFR de Pharmacie, EA 4481, Laboratoire de Chimie
´
Therapeutique, Lille, France
GRAPHICAL ABSTRACT
Abstract A novel and efficient protocol is developed for the synthesis of various (aminophe-
nyl)carbamic acid esters from the reduction and condensation of nitrophenyl isocyanate
derivatives. The reaction takes place in various hydroxy derivatives such as alcohols or phe-
nols under a hydrogen atmosphere using Raney nickel as catalyst. Products are obtained by
a convenient one–pot synthesis with excellent yields and short reaction times.
Keywords Carbamic acid ester; hydrogenation; isocyanate
INTRODUCTION
Carbamic acid esters are useful organic functionnal groups for the synthesis of
a large range of biologically and pharmacologically active molecules such as agro-
chemical fungicide,[1] insecticide (Methiocarb, 1),[2] and opioid (URB597, 2).[3] They
are also used as intermediates in combinatorial chemistry[4] and as leaving groups in
prodrugs (prodrug of CI–994, 3)[5] (Fig. 1).
The presence of CO and NH groups generate acceptor–donor hydrogen bond
interaction by recognition of biological systems as receptors or enzymes. So, replace-
ment of amine or urea moieties by carbamic acid ester functions may improve the
physicochemical and pharmacological properties and therefore offer better affinity
with the binding site.
Received January 28, 2010.
Address correspondence to Laurence Goossens, Institut de Chimie Pharmaceutique Albert
´
Lespagnol, Universite de Lille 2, 3 rue du Professeur Laguesse, B.P.83 59006, Lille, France. E-mail:
laurence.goossens@univ–lille2.fr
2007

2008
A. GAROFALO ET AL.
Figure 1. Structure of compounds containing carbamic acid esters.
The main activity of our group consists in the synthesis of potential anticancer-
ous 4-aminophenylquinazoline derivatives bearing acetamide or ureas as donor=
acceptor functionalities. Along with these investigations, efforts have been made
to realize a new series of compounds containing carbamic acid ester to better explore
the structure–activity relationship (SAR) of the envisaged target. (Aminophenyl)car-
bamic acid esters derivatives are usually prepared using a two-step procedure start-
ing with (nitrophenyl)isocyanate. The carbamate moiety is first synthesized under
alkaline conditions in an alcohol=dichloromethane, tetrahydrofuran (THF), dioxane,
or benzene mixture.[6] Catalytic hydrogenation of the isolated nitrocarbamate[7] with
Pd=C or Raney nickel as catalysts then affords the desired (aminophenyl)carbamic
acid esters derivatives. Other approaches[8] by acylation of 1,4-phenylenediamine
in THF may be employed, but this generates side reactions due to free amino
functionalities.
RESULTS AND DISCUSSION
Herein, we report a novel approach to synthesize (3- or 4-aminophenyl)
carbamic acid esters derivatives by a high-yielding, one-pot, quick procedure from
corresponding (nitrophenyl)isocyanate (Scheme 1).
Scheme 1. Original route for the preparation of (4-aminophenyl)carbamic acid methyl ester.

SYNTHESIS OF CARBAMIC ACID ESTERS
2009
During the course of this study, catalytic hydrogenation of 4-nitrophenyliso-
cyanate in the presence of methanol generated the (4-aminophenyl)carbamic acid
methyl ester isolated with 85% yield. The presence of alcohol in large excess involved
the condensation with corresponding isocyanate, and the simultaneous reduction of
nitro entity to give aniline engaged in substitution reaction.
This one-pot procedure is successful for a variety of nitrophenylisocyanate
derivatives substituted on phenyl core with chloro (entries 11, 12, 15, and 16,
Table 1) or methyl groups (entries 9, 10, 13, and 14, Table 1). The specificity
of the ester substituent appears to be dependent on the nature of the
alcohol.
Synthesis of carbamic acid methyl or ethyl ester was then carried out in
the same conditions in the presence of a dichloromethane=methanol or ethanol
mixture to obtain the desired compounds 4, 5, and 9–16 (method A). The
respectively isopropyl, n-butyl, and phenyl carbamates derivatives 6–8 were pre-
pared in good yields from 4-nitrophenylisocyanate in a dichloromethane=tetra-
hydrofuran (THF) solution with 10 molar equiv. of the corresponding alcohols
(2-propanol, 1-butanol) and phenol (method B). The presence of THF is neces-
sary to dissolve the starting material.
Synthesis of compounds 4 and 5 was realized under typical procedures[9,10]
to prove the use of our methodology. From (4-nitrophenyl)isocyanate, a two-step
procedure has been performed. Formation of carbamate moiety was realized in a
mixture of alcohol=dichloromethane at room temperature during 4 h. After con-
centration and washing with petroleum ether, a white solid was obtained,
catalytic hydrogenation of which with Pd=C as catalysts in THF anhydride
afforded the desired (aminophenyl)carbamic acid esters 4 (64% of global yield)
and 5 (67% of global yield) after purification by column chromatography on silica
gel. This procedure features short reaction time, generally excellent yields, easily
available starting materials, and operational simplicity. All of these elements sug-
gest that our method is an attractive alternative to existing methodologies
(Table 2).
The synthesis of heterocyclic derivatives of potential biological interest
such as potency kinase inhibitors 17 and 18 (Fig. 2) was also performed. These
drugs are obtained by nucleophilic substitution in 2-propanol with chloride
intermediates previously synthesized in our laboratory according to described
procedures (Scheme 2).[14,15] Target products were obtained as chlorhydrate
with good yields and were crystallized from various solvents. Using these
(anilino)carbamic acid esters, we have realized a library of compound from
chloride derivatives.[16]

2010
A. GAROFALO ET AL.
Table 1. (Aminophenyl)carbamic acid esters derivatives 4–16
Entry
4[9]
Alcohol
Methanol
Ethanol
Products
Methoda
Yield (%)b
A
A
B
B
B
85
86
78
77
74
5[10]
6[11]
7[11]
8[12]
Propan-2-ol
Butan-1-ol
Phenol
9[13]
Methanol
Ethanol
A
A
86
85
10[13]
11
12
Methanol
Ethanol
A
A
84
84
13
14
15
Methanol
Ethanol
A
A
A
81
83
87
Methanol
16
Ethanol
A
79
aMethod A: (nitrophenyl)isocyanate derivates (6.0 mmol) were dissolved in dichloromethane=methanol
or ethanol mixture (40 ml) under a hydrogen atmosphere with Raney nickel as catalyst. Method B: (nitro-
phenyl)isocyanate derivatives (6.0 mmol) were dissolved in a dichloromethane=THF mixture (40 ml), and
alcohol (10 eq.) was added. The mixture was realized under a hydrogen atmosphere with Raney nickel as
catalyst.
bThe structures of all compounds were determinated by IR and 1H NMR (300-MHz) spectroscopy.
Product purity was confirmed by LC-MS analysis.

SYNTHESIS OF CARBAMIC ACID ESTERS
2011
Table 2. Yield of (aminophenyl)carbamic acid esters derivatives 4 and 5 obtained by two methods
New methodology (method A) yield Existing methodology global yield
(%) (one step)
Entry
4[9]
Products
(%) (two steps)
85
86
64
67
5[10]
Figure 2. Kinase inhibitors synthesized 17 and 18.
Scheme 2. Synthetic route for final products 17 and 18.
CONCLUSION
In summary, we have developed a general, simple, and effective one-pot pro-
cedure for the synthesis of (3- or 4-aminophenyl)carbamic acid ester derivatives by
simultaneous alcohol or phenol condensation and catalytic hydrogenation on the
corresponding nitro-phenylisocyanates. The mild reaction conditions and the toler-
ance of the alcohol nature make this method an attractive alternative to existing
methodologies. This procedure has several advantages such as minimizing the
number of reaction steps, rapid transformations, and the occurrence of two bond-
forming reactions under identical reaction conditions.

2012
A. GAROFALO ET AL.
EXPERIMENTAL
Melting points were determined in open capillary tubes on a Buchi reference
¨
B–530 digital melting-point apparatus and are uncorrected. Kieselgel 60 F-254 com-
mercial plates were used for analytical thin-layer chromatography (TLC) as well as
ultraviolet (UV) light and=or with iodine to follow the course of the reaction. Silica-gel
Kieselgel Si 60, 0.063–0.200 mm (Merck), was used for column chromatography. The
structures of all compounds were supported by IR (using a Bruker Vector 22 instru-
1
ment) H NMR (300-MHz) and 13C NMR (50-MHZ) spectra were recorded on a
Bruker AC300P NMR spectrometer in dimethylsulfoxide (DMSO–[d6]) at room tem-
perature. Chemical shifts (d) are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS). J values are in hertz, and the splitting patterns are designed
as follows: s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet. APCIþ (atmos-
pheric pressure chemical ionization) mass spectra were obtained on a liquid chroma-
tography (LC)–MS system Thermo Electon Surveyor MSQ.
Typical Procedure for the One-Pot Synthesis of N-(4-Aminophenyl)
and N-(3-Aminophenyl)carbamic Acid Ester Derivatives (4, 5, 9–16)
4-nitrophenyl or 3-nitrophenyl isocyanate (1.0 g, 6.0 mmol) was dissolved in a
mixture of dichloromethane=methanol or ethanol (40 mL), and Raney nickel
(400 mg) was added. The mixture was stirred under a hydrogen atmosphere at room
temperature for 16 h. The product was filtered through a plug of celite before being
concentrated and purified by column chromatography on silica gel, eluting with
CH2Cl2=ethyl acetate (9=1).
Data for Compounds 4, 5, and 9–16
N-(4-Aminophenyl)carbamic acid methyl ester (4). Yield 85%; white
solid; mp 89–91 ꢀC (91–93 ꢀC, lit.[9]) (recryst. petroleum ether). IR (n, cmꢁ1): 3382
1
(NH2), 1710 (CO), 1265 (N-CO-O). H NMR (DMSO): d 9.41 (s, 1H, NH), 7.61
(d, J ¼ 8.10 Hz, 2H, ArH), 7.15 (d, J ¼ 8.10 Hz, 2H, ArH), 5.78 (s, 2H, NH2), 3.67
(s, 3H, OCH3). LC=MS (APCIþ) calcd. for C8H10N2O2, m=z: 167 (M þ H)þ.
N-(4-Aminophenyl)carbamic acid ethyl ester (5). Yield 86%; white solid;
mp 72–74 ꢀC (73–74 ꢀC, lit.[10]) (recryst. water). IR (n, cmꢁ1): 3380 (NH2), 1711
1
(CO), 1264 (N-CO-O). H NMR (DMSO): d 9.02 (s, 1H, NH), 7.07 (d, J ¼ 8.40 Hz,
Hz, 2H, ArH), 6.51 (d, J ¼ 8.40 Hz, 2H, ArH), 4.76 (s, 2H, NH2), 4.03 (q,
J ¼ 7.20 Hz, 2H, CH2CH3), 1.27 (t, J ¼ 7.20 Hz, 3H, CH2CH3). LC=MS (APCIþ)
calcd. for C9H12N2O2, m=z: 181 (M þ H)þ.
N-(4-Amino-2-methylphenyl)carbamic acid methyl ester (9). Yield 86%;
white solid; mp 95–97 ꢀC (101–103 ꢀC, lit.[13]) (recryst. heptane). IR (n, cmꢁ1): 3382
(NH2), 1710 (CO), 1265 (N-CO-O). 1H NMR (DMSO): d 8.47 (s, 1H, NH), 6.82 (d,
J ¼ 8.40 Hz, 1H, ArH), 6.38 (d, J ¼ 2.40 Hz, 1H, ArH), 6.30–6.35 (m, J ¼ 2.40 and
8.40 Hz, 1H, ArH), 4.86 (s, 2H, NH2), 3.55 (s, 3H, OCH3), 2.03 (s, 3H, CH3).
LC=MS (APCIþ) calcd. for C9H12N2O2, m=z: 181 (M þ H)þ.

SYNTHESIS OF CARBAMIC ACID ESTERS
2013
N-(4-Amino-2-methylphenyl)carbamic acid ethyl ester (10). Yield 85%;
white solid; mp 240–242 ꢀC (237–240 ꢀC, lit.[13]) (recryst. heptane). IR (n, cmꢁ1):
3382 (NH2), 1710 (CO), 1265 (N-CO-O). 1H NMR (DMSO): d 10.28 (s, 2H,
NH2), 8.92 (s, 1H, NH), 7.47 (d, J ¼ 9.00 Hz, 1H, ArH), 7.13 (m, 2H, ArH), 4.11
(q, J ¼ 7.30 Hz, 2H, CH2CH3), 2.19 (s, 3H, CH3), 1.21 (t, J ¼ 7.30 Hz, 3H, CH2CH3).
LC=MS (APCIþ) calcd. for C10H14N2O2, m=z: 195 (M þ H)þ.
N-(4-Amino-2-chlorophenyl)carbamic acid methyl ester (11). Yield 84%;
white solid; mp 81–83 ꢀC (recryst. heptane). IR (n, cmꢁ1): 3382 (NH2), 1708 (CO),
1265 (N-CO-O), 1085 (C-Cl). 1H NMR (DMSO): 8.57 (s, 1H, NH), 6.97 (d,
J ¼ 8.40 Hz, 1H, ArH), 6.61 (d, J ¼ 2.30 Hz, 1H, ArH), 6.45 (m, J ¼ 2.30 and
8.40 Hz, 1H, ArH), 5.28 (s, 2H, NH2), 3.57 (s, 3H, OCH3).13C NMR (50 MHz,
DMSO) d 52.1, 113.2, 113.9, 123.2, 129.6, 148.8, 155.9, 158.4. LC=MS (APCIþ)
calcd. for C8H9ClN2O2, m=z: 201 (M þ H)þ and 203 (M þ 2 þ H)þ.
N-(4-Amino-2-chlorophenyl)carbamic acid ethyl ester (12). Yield 84%;
white solid; mp 109–111 ꢀC (recryst. heptane). IR (n, cmꢁ1): 3382 (NH2), 1710
1
(CO), 1264 (N-CO-O), 1085 (C-Cl). H NMR (DMSO): d 8.51 (s, 1H, NH), 6.95
(d, J ¼ 8.40 Hz, 1H, ArH), 6.61 (d, J ¼ 2.60 Hz, 1H, ArH), 6.48 (m, J ¼ 2.60 and
8.40 Hz, 1H, ArH), 5.29 (s, 2H, NH2), 4.02 (q, J ¼ 7.30 Hz, 2H, CH2CH3), 1.21
(t, J ¼ 7.30 Hz, 3H, CH2CH3). 13C NMR (50 MHz, DMSO) d 15.1, 60.5, 113.2,
113.9, 123.2, 129.6, 148.6, 155.4, 158.4. LC=MS (APCIþ) calcd. for C9H11ClN2O2,
m=z: 215 (M þ H)þ and 217 (M þ 2 þ H)þ.
N-(5-Amino-2-methylphenyl)carbamic acid methyl ester (13). Yield
81%; white solid; mp 117–118 ꢀC (recryst. heptane). IR (n, cmꢁ1): 3382 (NH2),
1711 (CO), 1265 (N-CO-O). 1H NMR (DMSO): d 8.42 (s, 1H, NH), 6.77 (d,
J ¼ 8.20 Hz, 1H, ArH), 6.58 (d, J ¼ 2.30 Hz, 1H, ArH), 6.31 (m, J ¼ 2.30 and
8.20 Hz, 1H, ArH), 4.87 (s, 2H, NH2), 3.61 (s, 3H, OCH3), 2.02 (s, 3H, CH3).
13C NMR (50 MHz, DMSO) d 17.22, 51.9, 111.2, 111.6, 130.7, 136.8, 147.1, 155.2,
158.1. LC=MS (APCIþ) calcd. for C9H12N2O2, m=z: 181 (M þ H)þ.
N-(5-Amino-2-methylphenyl)carbamic acid ethyl ester (14). Yield 83%;
white solid; mp 91–92 ꢀC (recryst. heptane). IR (n, cmꢁ1): 3381 (NH2), 1711 (CO),
1
1265 (N-CO-O). H NMR (DMSO): d 8.48 (s, 1H, NH), 6.78 (d, J ¼ 8.20 Hz, 1H,
ArH), 6.61 (d, J ¼ 2.30 Hz, 1H, ArH), 6.21 (m, J ¼ 2.30 and 8.20 Hz, 1H, ArH),
4.82 (s, 2H, NH2), 4.05 (q, J ¼ 7.30 Hz, 2H, CH2CH3), 1.22 (t, J ¼ 7.30 Hz, 3H,
CH2CH3). 13C NMR (50 MHz, DMSO) d 15.1, 17.22, 60.6, 111.7, 112.1, 129.9,
136.3, 147.3, 154.9, 157.6. LC=MS (APCIþ) calcd. for C10H14N2O2, m=z: 195
(M þ H)þ.
N-(5-Amino-2-chlorophenyl)carbamic acid methyl ester (15). Yield 87%;
white solid; mp 117–118 ꢀC (recryst. heptane). IR (n, cmꢁ1): 3382 (NH2), 1712 (CO),
1
1265 (N-CO-O), 1085 (C-Cl). H NMR (DMSO): d 8.67 (s, 1H, NH), 7.03 (d,
J ¼ 8.40 Hz, 1H, ArH), 6.81 (d, J ¼ 2.00 Hz, 1H, ArH), 6.38 (m, J ¼ 2.00 and
8.40 Hz, 1H, ArH), 5.33 (s, 2H, NH2), 3.63 (s, 3H, OCH3).13C NMR (50 MHz,
DMSO) d 52.1, 113.1, 113.8, 123.1, 129.6, 148.5, 155.9, 158.5. LC=MS (APCIþ)
calcd. for C8H9ClN2O2, m=z: 201 (M þ H)þ and 203 (M þ 2 þ H)þ.

2014
A. GAROFALO ET AL.
N-(5-Amino-2-chlorophenyl)carbamic acid ethyl ester (16). Yield 79%;
white solid; mp 115–171 ꢀC (recryst. heptane). IR (n, cmꢁ1): 3382 (NH2), 1710
1
(CO), 1265 (N-CO-O), 1086 (C-Cl). H NMR (DMSO): d 8.48 (s, 1H, NH), 6.78
(d, J ¼ 8.20 Hz, 1H, ArH), 6.61 (d, J ¼ 2.30 Hz, 1H, ArH), 6.21 (m, J ¼ 2.30 and
8.20 Hz, 1H, ArH), 4.82 (s, 2H, NH2), 4.05 (q, J ¼ 7.30 Hz, 2H, CH2CH3), 1.22
(t, J ¼ 7.30 Hz, 3H, CH2CH3). 13C NMR (50 MHz, DMSO) d 15.2, 60.3, 111.1,
112.4, 128.9, 135.1, 147.5, 154.9, 158.4. LC=MS (APCIþ) calcd. for C9H11ClN2O2,
m=z: 215 (M þ H)þ and 217 (M þ 2 þ H)þ.
Typical Procedure for the One-Pot Synthesis of
N-(4-Aminophenyl)carbamic Acid Ester Derivatives (6–8)
4-Nitrophenyl isocyanate (1.0 g, 6.0 mmol) was dissolved in a mixture of
dichloromethane=THF (60 mL) and alcohol or phenol (60 mmol) with Raney nickel
(400 mg). The mixture was stirred under a hydrogen atmosphere at room tempera-
ture for 16 h. The product was filtered through a plug of celite before being concen-
trated and purified by column chromatography on silica gel, eluting with CH2Cl2=
ethyl acetate (9=1).
Data for Compounds 6–8
N-(4-Aminophenyl)carbamic acid isopropyl ester (6). Yield 78%; white
solid; mp 80–81 ꢀC (83–84 ꢀC, lit.[11]) (recryst. heptane). IR (n, cmꢁ1): 3380 (NH2),
1711 (CO), 1265 (N-CO-O). 1H NMR (DMSO): d 8.95 (s, 1H, NH), 7.02
(d, J ¼ 8.40 Hz, 2H, ArH), 6.47 (d, J ¼ 8.40 Hz, 2H, ArH), 4.81 (m, 1H, CH), 4.71
(s, 2H, NH2), 1.21 (d, 6H, CH3). LC=MS (APCIþ) calcd. for C10H14N2O2, m=z:
195 (M þ H)þ.
N-(4-Aminophenyl)carbamic acid butyl ester (7). Yield 77%; white solid;
mp 41–42 ꢀC (45–46 ꢀC, lit.[11]) (recryst. heptane). IR (n, cmꢁ1): 3382 (NH2), 1711
1
(CO), 1265 (N-CO-O). H NMR (DMSO): d 9.01 (s, 1H, NH), 7.03 (d, J ¼ 8.20 Hz,
Hz, 2H, ArH), 6.49 (d, J ¼ 8.20 Hz, 2H, ArH), 4.72 (s, 2H, NH2), 4.01 (t, 2H,
J ¼ 4.40 Hz, OCH2CH2), 1.62 (m, 2H, OCH2CH2), 1.31 (m, 2H, CH2CH3), 0.91 (t,
J ¼ 7.40 Hz, 3H, CH2CH3). LC=MS (APCIþ) calcd. for C11H16N2O2, m=z: 209
(M þ H)þ.
N-(4-Aminophenyl)carbamic acid phenyl ester (8). Yield 74%; white
solid; mp 132–134 ꢀC (134–135 ꢀC, lit.[12]) (recryst. toluene). IR (n, cmꢁ1): 3382
1
(NH2), 1710 (CO), 1264 (N-CO-O). H NMR (DMSO): d 9.65 (s, 1H, NH), 7.41
(t, 1H, ArH), 7.10–7.25 (m, 6H, ArH), 6.51 (d, J ¼ 8.20 Hz, 2H, ArH), 4.81 (s, 2H,
NH2). LC=MS (APCIþ) calcd. for C13H12N2O2, m=z: 229 (M þ H)þ.
Typical Procedure for Compounds 17 and 18
Chloride intermediates was dissolved in 2-propanol refluxing (10 mL) and N-
(4-aminophenyl)carbamic acid ester derivatives (1.2 eq.) was added. The mixture
was refluxed for 3 h. Final products were obtained either by filtration or washing
2-propanol and diethyl ether and recrystallization.

SYNTHESIS OF CARBAMIC ACID ESTERS
2015
Data for Compounds 17 and 18
N-f4-[6-(3,4-Dimethoxyphenyl)pyrimidino]phenylgcarbamic
acid
methyl ester (17). Yield 59%; white solid; mp 206–208 ꢀC (recryst. toluene). IR
(n, cmꢁ1): 3212 (NH), 1712 (CO), 1264 (N-CO-O), 1076 (C-O-C). 1H NMR
(DMSO): d 9.53 (s, 1H, NH), 8.62 (s, 1H, ArH), 7.45–7.55 (m, 4H, ArH), 7.41
(d, 2H, J ¼ 8.70 Hz, ArH), 7.14 (s, 1H, ArH), 7.11 (d, 1H, J ¼ 8.40 Hz, ArH), 3.85
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.68 (s, 3H, OCH3). 13C NMR (50 MHz,
DMSO) d 52.1, 57.1, 119.2, 123.1, 127.8, 129.9, 131.1, 132.2, 132.7, 137.1, 153.4,
153.7, 154.5, 155.3, 161.7. LC=MS (APCIþ) calcd. for C20H20N4O4, m=z: 381
(M þ H)þ.
N-f4-([1,3]Dioxolo[4,5-g]quinazolin-8-ylamino)-2-methylphenylgcarbamic
arbamic acid ethyl ester (18). Yield 41%; white solid; mp > 250 ꢀC (recryst. etha-
1
nol 95%). IR (n, cmꢁ1): 3214 (NH), 1711 (CO), 1264 (N-CO-O), 924 (O-C-O). H
NMR (DMSO): d 8.97 (s, 1H, NH), 8.81 (s, 1H, ArH), 8.32 (s, 1H, ArH),
7.35–7.50 (m, 4H, ArH), 6.41 (s, 2H, CH2), 4.11 (q, 2H, J ¼ 7.40 Hz, CH2CH3),
2.21 (s, 3H, CH3), 1.28 (t, J ¼ 7.40 Hz, 3H, CH2CH3). 13C NMR (50 MHz, DMSO)
d 15.2, 18.5, 60.8, 69.8, 97.9, 101.4, 104.3, 107.8, 109.1, 122.9, 125.1, 127.1, 132.3,
133.7, 135.1, 137.6, 149.5, 155.1, 159.1. LC=MS (APCIþ) calcd. for C19H18N4O4,
m=z: 367 (M þ H)þ.
ACKNOWLEDGMENT
The authors are grateful to the Ligue Nationale Contre le Cancer (Committee
of Pas-de-Calais-France) for its financial support.
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