Efficient new synthesis of N-arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and their benzo[b]thieno[3,2-d]pyrimidin-4-amine analogues via a microwave-assisted Dimroth rearrangement

Article abstract of DOI:10.1002/jhet.1716

A useful and rapid access to libraries of N-arylbenzo[b]furo[3,2-d] pyrimidin-4-amines (1) and their novel benzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) was investigated for the first time. Title compounds were obtained via microwave-accelerated co

Full text of DOI:10.1002/jhet.1716

September 2013 Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and
Their Benzo[b]thieno[3,2-d]pyrimidin-4-amine Analogues via a
Microwave-Assisted Dimroth Rearrangement
1187
Yvonnick Loidreau,a Carole Dubouilh-Benard,a Pascal Marchand,b Marie-Renée Nourrisson,b Muriel Duflos,b
c
c
a
*
Catherine Buquet, Cécile Corbière, and Thierry Besson
aUniversité de Rouen, CNRS UMR 6014 – C.O.B.R.A. & FR3038, Equipe Hétérocycles, Institut de Recherche en Chimie
Organique Fine (I.R.C.O.F.), rue Tesnière, 76130 Mont Saint-Aignan, France
bUniversité de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des
Infections, de l’Immunité et du Cancer, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques et Biologiques,
1 rue Gaston Veil, 44035 Nantes, France
cUniversité de Rouen, EA 3829, UFR Médecine-Pharmacie, 22 Boulevard Gambetta, 76183 Rouen cedex 1, France
*
E-mail: thierry.besson@univ-rouen.fr
Received November 10, 2011
DOI 10.1002/jhet.1716
Published online 27 August 2013 in Wiley Online Library (wileyonlinelibrary.com).
A useful and rapid access to libraries of N-arylbenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their novel
benzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) was investigated for the first time. Title compounds
were obtained via microwave-accelerated condensation and Dimroth rearrangement of suitable anilines with
N0-(2-cyanaryl)-N,N-dimethylformimidamides obtained by reaction of benzo[b]furane and benzo[b]thiophene
precursors with N,N-dimethylformamide dimethyl acetal. This work also demonstrates that well-controlled
parameters offer comfortable use of microwave technology and are both safe and beneficial to the environment.
Some products obtained in this article exhibit interesting in vitro antiproliferative effects.
J. Heterocyclic Chem., 50, 1187 (2013).
INTRODUCTION
method for varying the aromatic amines that can be added to
these tricyclic homologues of the basic 4-anilinopyrimidine
pharmacophore. We decided to adapt the possibilities offered
by the Dimroth rearrangement [5,6]. A survey of literature
revealed that the synthesis of two examples of benzofuro
[3,2-d]pyrimidines 1 was only described 30 years ago via this
thermally sensitive method [7]. We considered that it would
be an interesting challenge to explore microwave-assisted
reaction conditions that may allow efficient synthesis of the
target molecules for which usual methods require forcing
conditions or prolonged reaction times. This article
describes the development of a reliable and simple method
that allows extending of the list of potential precursors to
various bioactive molecules.
Phosphorylation of serine, threonine, and tyrosine resi-
dues by cellular protein kinases plays an important role
in the regulation of various cellular processes. These
enzymes are involved in major human diseases, including
cancer, neurodegenerative disorders (Alzheimer and Down
Syndrome), diabetes, and cardiovascular diseases. A part of
the research activities of our groups concerns the synthesis
of heterocyclic moieties containing nitrogen and sulfur atoms
as kinase inhibitors [1,2]. Our investment in the search of
efficient synthetic procedures allowed us to investigate the
possibility to perform in short time and with good yields
the synthesis of various tricyclic N-arylbenzo[b]furo[3,2-d]
pyrimidin-4-amines and their benzo[b]thieno[3,2-d]pyrimi-
din-4-amine analogues (Scheme 1). In comparison with their
pyrimido[5,4-b]indole isoster and its pyrimido[4,5-b]indole
isomer, these 6,5,6-fused tricycles were only quite recently
studied for their interest as kinases inhibitors [3].
Considering the literature and the scale of research
investment in pyrimidine rings associated with various
heterocyclic skeletons, it appears that derivatives substituted
by an amino group on position 4 of the pyrimidine moiety
have received most attention, accounting for a large part for
the registered compounds cited in papers and patents [4].
Taking into account all of these facts, we decided to
explore the possibility of obtaining a rapid and efficient
RESULTS AND DISCUSSION
The target molecules of our study were benzo[b]furo
[3,2-d]pyrimidines (1) and their thieno analogues (2)
substituted in position 4 of the pyrimidine ring by an
aromatic amine. The synthetic routes mainly described in
literature [3] included three-step reactions from the
starting methyl (or ethyl) 3-aminobenzofurane- or 3-ami-
nobenzothiophene-2-carboxylates. These were cyclized with
formamide via Niementowski reaction to give tricyclic
benzo[b]furo- or benzo[b]thieno[3,2-d]pyrimidin-4-ones
© 2013 HeteroCorporation

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Y. Loidreau, C. Dubouilh-Benard, P. Marchand, M.-R. Nourrisson, M. Duflos,
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C. Buquet, C. Corbière, and T. Besson
Scheme 1. General structures of the target benzofuro[3,2-d]pyrimidines (1) and benzothieno[3,2-d]pyrimidines (2).
followed by a treatment using thionyl chloride, phospho-
ryl chloride, or oxalyl chloride to afford 4-chlorobenzo
[b]furo- or benzo[b]thieno[3,2-d]pyrimidines. Condensation
with a variety of aliphatic and aromatic amines gave the tar-
get compounds (see top of Scheme 2).
of dimethylformamide dimethyl acetal (DMF-DMA) under
microwaves (Scheme 2).
The two benzofurane and benzothiophene precursors
(3 and 4) were obtained by methods previously
described in the literature [8–10]. Subsequently, 3-
amino-2-cyanobenzofurane 3 was prepared by treatment
of 2-hydroxybenzonitrile with bromoacetonitrile in
dimethylformamide. Ring closure of the cyanomethyl
ether intermediate (not isolated) was performed in the pres-
ence of potassium carbonate (K2CO3) as base, which gave
the target product in a good yield (63%) (Scheme 4) [8]. Its
thiophenic analogue 4 was obtained in a similar procedure
from 2-nitrobenzonitrile, 3-mercaptopropionitrile [9], and
aqueous potassium hydroxide in DMF at 0ꢀC, followed by
addition of the alkylating agent. In this case, the cyanomethyl
thioether intermediate was cyclized in the presence of
potassium hydroxide (KOH) to the expected product in
a very good yield (89%) [10] (Scheme 4).
One of the major drawbacks of these processes is the
instability of the very reactive 4-chloro intermediates, which
may decompose under storage and sometimes during the long
heating times required for completion of the reactions. To over-
come this problem and in connection with our work on the ap-
plication of microwave irradiations in organic and medicinal
chemistry, we decided to perform a short synthesis of the
expected tricycles via a Dimroth rearrangement (Scheme 3).
This “ancestral” transformation consists of a transloca-
tion of exocyclic and endocyclic heteroatoms present in
both five- and six-membered heterocycles [5,6]. As shown
in Scheme 3, the reaction generally leads to one of the two
possible isomers, and the thermodynamic stability of the
final compound is the driving force for its formation. For
these reasons, the amount of heat supplied to the starting
mixture will influence the final result.
Our study started with the synthesis of the N0-(2-
cyanobenzofuran-3-yl)-N,N-dimethylformimidamide 5 and
N0-(2-cyanobenzothiophen-3-yl)-N,N-dimethylformimida-
mide 6. After optimization of the microwave conditions by
varying reaction time, power input, temperature, and pres-
sure, we were able to obtain in 15min the expected N,N-
dimethylformimidamides (5 and 6) in quantitative yields
(99% after purification) (Scheme 5). Some comments can
Taking into account all these parameters, the retrosyn-
thetic pathway chosen involved the synthesis of interme-
diate N,N-dimethylformamidine derivatives obtained by
transformation of the starting 3-aminobenzo[b]furane- or
3-aminobenzo[b]thiophene-2-carbonitrile in the presence
Scheme 2. Usual three-step pathway [3] and our retrosynthetic pathway of the target benzo[b]furo[3,2-d]pyrimidines (1) and benzo[b]thieno[3,2-d]
pyrimidines (2).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2013 Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]
thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement
1189
Scheme 3. General pathway of the Dimroth translocation, in the case of quinazolines from anthranilonitriles [5].
Scheme 4. Synthesis of benzofurane and benzothiophene precursors 3 and 4.
Scheme 5. Microwave-assisted (mw) syntheses of benzo[b]furo- and benzo[b]thieno[3,2-d]pyrimidin-4-amines; for reaction times and yields, see Table 1.
be made in comparison with previous works on various anthra-
nilonitrile derivatives [5]. In the case of 2-aminobenzofuran-3-
carbonitrile (3) and 2-aminobenzothiophene-3-carbonitrile 4,
the temperature used for a rapid and convenient production
of compounds 5 and 6 must be increased from 70ꢀC to
90ꢀC, and the time of the synthesis of 10 min was also
extended for an average irradiation time of 15 min (instead of
5 min for anthranilonitriles). The microwave heating was
performed at atmospheric pressure in order to avoid hydrolysis
of the final product or generation of by-products, which can
occur when heating for too long or if microwave heating is
combined with high pressure [5g].
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C. Buquet, C. Corbière, and T. Besson
The second step of the synthesis consisted of heating
acetamide derivatives as by-products [5g]. As described in
various applications of this rearrangement, reaction time
and yields depend on the nucleophilicity of the aniline and
also on steric hindrance of the substituents [5,6]. The
presence of large atoms or groups on the ortho-position of
the aromatic amine (e.g., 4-bromo-2-fluoroaniline in Table 1)
involved an increase of reaction time and slight decrease
of the yields. Heating at higher temperatures in order to
compensate this effect did not give the expected compound.
No traces of 3-arylbenzo[b]furo[3,2-d]pyrimidin-4-
imine isomers (e.g., 7 in Scheme 5) were detected, except
when the condensed aniline was substituted by a strong
electron withdrawing group such as a nitro group. In that
case, we observed initial condensation of the amine and
ring closure into the 4-imino-isomer (7 in Scheme 5), but
the microwave heating was not sufficient to allow this
kinetic intermediate to rearrange into the thermodynamic
product substituted in position 4.
different anilines with 5 or 6 in the presence of acetic acid
(AcOH). The choice of AcOH was guided by the fact that
this carboxylic acid is a good solvent for heating under
microwaves (tan d = 0.174 at 2.45 GHz) [11]. The reactions
were monitored by thin-layer chromatography to obtain
the required reaction for a complete disappearance of the
starting material (Table 1).
After various trials to optimize reaction parameters
(time, temperature, and microwave power) and starting
from 5, we were able to obtain, in short times, excellent
yields (87–99%) of the expected N-arylbenzo[b]furo[3,2-d]
pyrimidin-4-amines (1a–j) (Scheme 5).
It should be noticed that the quantity of amine (1 equiv
only) introduced into the reaction vial must be monitored.
When an excess of aniline was used in the reaction mixture,
the condensation of a part of the starting aromatic amine
with acetic acid was observed and gave the corresponding
Table 1
Synthesis of N-arylbenzo[b]furo[3,2-d]pyrimidin-4-amines (1a–j) and N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines (2a–j).
R
Product
Time (min)
5
Yield (%)a
99
Product
Time (min)
15
Yield (%)
77
1a
2a
1b
1c
5
5
99
98
2b
2c
20
20
61
99
1d
1e
1f
90
15
10
88
82
97
2d
2e
2f
210
45
76
81
84
30
1g
5
77
2g
15
80
1h
1i
15
10
94
98
2h
2i
30
30
68
84
1j
15
89
2j
30
66
Reactions were performed under microwave (mw) at 400 W on a 0.5-mmol scale from 3 or 4 with 1 equiv of aniline (MultiSYNTHTM from Milestone S.r.l. Italy).
aYield of isolated product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2013 Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]
thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement
1191
A library of novel N-arylbenzo[b]thieno[3,2-d]pyrimidin-
4-amines (2a–j) was prepared using similar experimental
conditions and substituted anilines. We observed that the
average time of the reactions needed to be at least three times
increased compared with the corresponding benzofurane
analogues. The most important observation was the slight
decrease of the yields obtained for sulfur five-membered
heterocycles (2a–j, Table 1). In this case, the nucleophilicity
of condensed aniline was not the limiting factor. Long
irradiation time seemed to overcome the difficulty for starting
attack of aniline on the carbon of N,N-dimethylformimidamide
6. Microwave irradiation at higher temperatures (180ꢀC)
decreased slightly the reaction times, but it involved
diminished yields.
The last part of this work concerns the synthesis of benzo
[b]furo[3,2-d]pyrimidin-4-amine (8) [7] and benzo[b]thieno
[3,2-d]pyrimidin-4-amine 9 as sulfur analogue [12]. The
synthesis of such compounds was realized in good yields
by using high microwave heating to decompose formamide
as material for introduction of nitrogen atoms in heterocyclic
rings (Scheme 5) [13].
In this process, the use of dimethylformimidamides 5
and 6 showed to be an attractive method that allowed a
short reaction time (30 min) associated to a convenient
temperature of 170ꢀC to avoid the in situ hydrogen cyanide
formation, which is traditionally produced by thermal
decomposition of formamide at higher temperatures
(200–220ꢀC) [14,15]. Considering these facts, we confirmed
that our method constitutes an interesting and safe alternative
to the harsh conditions usually described in the literature [3].
In a preliminary experiment, the antiproliferative effect
of molecules (1a–e) and (2a–e), each one tested at three
concentrations (0.001, 0.1, and 10 mM), was studied on
Caco-2 and HT-29 cells during 24, 48, and 72 h (1e and
2a were not soluble in the conditions used). Proliferation
of Caco-2 and HT-29 cells was not modified with molecules
1a–d and 2b (data not shown). Table 2 describes the results
of the two promising compounds (2c and 2d). Compounds
2c and 2d showed any effect on HT-29 proliferation (data
not shown), whereas a weak inhibitory effect was observed
in Caco-2 cells.
Indeed, a slight but significant proliferation inhibition of
the Caco-2 colon cancer cells was noticed after 24 h of
treatment with 0.1 or 10.0 mM of compound (2c) (about
10% and 15% inhibition, respectively, p < 0.05) (Table 2).
This inhibitory effect on Caco-2 proliferation was no
longer observed after 24 h incubation. As assessed by
MTT assays, compound 2d inhibited Caco-2 cell growth
at 10 mM after 24 h of treatment (15% inhibition approxi-
mately), and a quite similar inhibitory effect (about 20%)
was observed at 0.1 mM after 72 h incubation (Table 2).
Concentration below 0.1 mM did not affect Caco-2 cell
growth compared with untreated cells (data not shown).
In comparison, the positive control, LY294002 (50 mM),
inhibited Caco-2 cell growth at 24, 48, and 72 h with an
inhibitory effect of 20%, 35%, and 47%, respectively.
Considering the results obtained on HT29 cells with
compounds 2c and 2d, we have not tested the molecule
2e on these cells. In Caco-2 cells, it seems that molecule
2e inhibited cell proliferation at a concentration of 10 mM
in a time-dependent manner: 24% growth inhibition at
48 h and 35% growth inhibition at 72 h (proliferation of
76.0 ꢁ 3.8% and 64.8 ꢁ 1.4%, respectively, compared
with solvent control). Concentrations of 0.1 mM and
1 nM inhibited slightly Caco-2 proliferation at 72 h:
about 9% and 6% inhibition, respectively (proliferation
of 91.4 ꢁ 0.9% and 93.6 ꢁ 0.5%, respectively, compared
with solvent control).
It is well known that HT-29 and Caco-2 colorectal
cancer cell lines contain different p53 mutations [16].
TP53 plays an important role in regulating cell survival.
Mutation inducing a loss of p53 function could explain that
molecules have proliferation effect on Caco-2 cells but not
on HT-29. Compounds 2c and 2d showed a weak inhibi-
tory effect on Caco-2 cells at concentration of 10 mM; this
effect appears to be transient, whereas compound 2e at
10 mM seems to inhibit proliferation in a time-dependent
manner. Compared with other compounds tested (data not
Table 2
Proliferation of Caco-2 cells (mean ꢁ SD in percentage) treated with compounds 2c and 2d after 24, 48, and 72 h treatment.
Time of treatment (h)
Drug concentrations (mM)
24
48
72
LY294002 (50)
2c (10)
2c (0.1)
2d (10)
2d (0.1)
78.0 ꢁ 5.2*
86.4 ꢁ 6.7*
91.5 ꢁ 7.2*
83.4 ꢁ 11.3*
88.1 ꢁ 13.7
64.8 ꢁ 3.1*
100.0 ꢁ 14.7
103.3 ꢁ 10.6
96.7 ꢁ 13.5
98.9 ꢁ 9.0
53.5 ꢁ 7.4*
86.1 ꢁ 12.0
90.8 ꢁ 9.3
85.1 ꢁ 24.0
76.5 ꢁ 17.8*
LY294002 was used as a positive control for growth inhibition.
*p < 0.05.
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C. Buquet, C. Corbière, and T. Besson
plate located below the floor of the microwave cavity and a
Teflon-coated magnetic stir bar inside the vessel. Temperature,
pressure, and power profiles were monitored in both cases through
the EASY-Control software provided by the manufacturer.
shown), these compounds have structure that seems to
interfere with proliferation signaling.
Multi SYNTH (Milestone S.r.l. Italy) is a novel dedicated micro-
wave system for synthetic applications. It allows a fast reaction
optimization, providing high energy density in a single-mode such
as configuration and an efficient scale-up (maximum working vol-
ume 300mL) through parallel synthesis in a multimode configura-
tion. The instrument features a special shaking system that ensures
high homogeneity of the reaction mixtures. It is equipped with an
indirect pressure control through precalibrated springs at the bottom
of the vessel shields and with both contact-less infrared pyrometer
(IRT) and fiber-optic contact thermometer (FO) for accurate temper-
ature measurement. It is noteworthy that the IRT can be calibrated
directly on the temperature read by the FO to ensure the highest
accuracy and reproducibility.
3-Amino-2-cyanobenzo[b]furane (3). To a suspension of 2-
hydroxybenzonitrile (4.00 g, 33.6 mmol) and K2CO3 (10.21 g,
73.9 mmol) in DMF (80 mL), bromoacetonitrile (2.57 mL,
36.9 mmol) was added at room temperature with stirring. The
reaction mixture was heated at 50ꢀC for 16 h. The mixture was
poured into water and extracted with dichloromethane. The organic
layer was washed with brine, then dried, and evaporated to give a
pale brown powder, which was purified by chromatography on
silica gel using dichloromethane as eluent. The desired product (3)
was isolated as a white powder (3.35 g, 63%); mp 160–161ꢀC (lit.
[8]: 162–163ꢀC); IR (KBr) nmax (cmꢂ1): 3445, 3356, 2199 (CN),
1637, 1619, 1607, 1584, 1489, 1449, 1419, 1337, 1251, 1156,
1106, 1008, 885, 848, 761, 735, 648; 1H NMR (400 MHz, DMSO-
d6): d 7.94 (d, J=7.6Hz, 1H), 7.49–7.57 (m, 2H), 7.34 (td,
J1 =1.2Hz, J2 = 7.9 Hz, 1H), 6.70 (br s, 2H); 13C NMR (100 MHz,
DMSO-d6): d 154.3, 142.6, 129.3, 122.8, 121.5, 121.1, 114.6,
112.0, 106.5; MS (ESI) m/z (%): 158.9 [(M + H)+, 100].
CONCLUSION
The synthesis of a library of N-arylbenzo[b]furo[3,2-d]
pyrimidin-4-amines was realized for the first time under
microwaves via an accelerated Dimroth rearrangement
from the corresponding 3-amino-2-cyanobenzofurane
precursor. Good control of the reaction parameters offer
comfortable use of microwave technology with safe and
environmental benefits. It allowed an efficient heating of
the reaction mixture, resulting in short time of reaction
and very good yields. This very useful and rapid procedure
was also successfully applied to the synthesis of novel
N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines analogues
taking into account the necessity to add more heat to the
reaction mixture. The information given in this article is a
further example that microwave heating can be a very
powerful tool for chemists. Further investigations extending
the families of heterocyclic precursors and the nature of the
aromatic amines are underway in the hope to increase the
interesting in vitro antiproliferative effects observed.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography
with silica gel 60 F254 precoated aluminum plates (0.25mm).
Melting points of solid compounds were measured on an Electro-
thermal IA 9000 melting point apparatus (compounds 3 and 4) or
a STUART apparatus advanced SMP3 with a precision of
ꢁ0.5ꢀC (compounds 1, 2, 5–9) and are uncorrected. IR spectra
were recorded on a PerkinElmer Spectrum 100 Series FTIR
spectrometer. Liquids and solids were applied on the Single
Reflection Attenuated Total Reflectance (ATR) Accessories.
3-Amino-2-cyanobenzo[b]thiophene (4).
A solution of
potassium hydroxide (3.8 g, 67.7 mmol) in water (12 mL) was
added dropwise under vigorous magnetic stirring to a cooled
(ice bath) solution of 2-nitrobenzonitrile (3.40 g, 22.9 mmol) and
3-mercaptopropionitrile (2.40 g, 27.5 mmol) in DMF (45 mL).
The cold mixture was stirred for 15 min, and bromoacetonitrile
(2.30 mL, 33.0 mmol) was added dropwise. After 2 h at 0ꢀC, the
mixture was poured into ice water. The crude product was
collected by filtration and purified with silica gel column
chromatography using 100% dichloromethane. The desired
product (4) was isolated as a white powder (3.56 g, 89%); mp
156–157ꢀC (lit. [10]: 155–156ꢀC); IR (KBr) nmax (cmꢂ1): 3319,
2210 (CN), 1644, 1571, 1532, 1467, 1432, 1399, 1326, 1270,
1198, 1150, 1132, 1059, 1022, 754, 721, 680, 644; 1H NMR
(400 MHz, DMSO-d6): d 8.14 (d, J = 8.0 Hz, 1H), 7.91 (d,
J = 8.0 Hz, 1H), 7.58 (td, J1 = 0.6 Hz, J2 = 7.6 Hz, 1H), 7.48
(td, J1 =0.6 Hz, J2 = 7.7 Hz, 1H), 7.18 (br s, 2H); 13C NMR
(100MHz, DMSO-d6): d 152.4, 139.1, 130.4, 128.8, 128.7, 124.7,
123.3, 123.0, 116.4; MS (ESI) m/z (%): 174.9 [(M + H)+, 100].
(E)-N0-(2-Cyanobenzo[b]furan-3-yl)-N,N-dimethylformimida-
Absorption bands are given in cmꢂ1
.
1H, 13C, and 19F NMR spectra were recorded on an AVANCE
400 MHz spectrometer (compounds 3 and 4) or on a Bruker DXP 300
spectrometer at 300, 75, and 282 MHz respectively (compounds 1, 2,
5–9). Abbreviations used for peak multiplicities are as follows: s,
singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet and br (broad).
Coupling constants J are given in hertz (Hz), and chemical shifts are
given in parts per million (d) and calibrated with DMSO-d6 or D2O
(residual solvent signals). Mass spectra analysis was performed by
the Mass Spectrometry Laboratory of the University of Rouen. Mass
spectra (EI) were recorded with a Waters ZQ 2000 and Waters LCP
1er XR spectrometers.
Microwave experiments were conducted in two commercial
microwave reactors especially designed for synthetic chemistry.
Start SYNTH (Milestone S.r.l. Italy) is a multimode cavity with
a microwave power delivery system ranging from 0 to 1200 W.
Open vessel experiments were carried out in a 250-mL round
bottom flask fitted with a reflux condenser. The temperature was
monitored via a fiber-optic contact thermometer protected in a
Teflon-coated ceramic well inserted directly in the reaction
mixture or via contact-less infrared pyrometer. The vessel
contents were stirred by means of an adjustable rotating magnetic
mide (5).
A mixture of 3-aminobenzofurane-2-carbonitrile (3)
(0.5g, 3.16 mmol) and DMF DMA (4.4mL, 31.60 mmol) was
irradiated at 90ꢀC (800W) for 15min. The final solution was
cooled to room temperature, and cold water was added. The solid
was filtered off, washed with cold water, and dried over
magnesium sulfate. Purification by column chromatography over
silica gel using dichloromethane/petroleum ether (5:5, v/v) as the
eluent gave the desired compound (5) as a pale yellow powder
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2013 Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]
thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement
1193
(671 mg; 99%); mp 107–108ꢀC; IR (KBr) nmax (cmꢂ1): 2210 (CN),
1623, 1588, 1568, 1447, 1435, 1384, 1334, 1244, 1192, 1165,
1115, 1095, 1067, 1021, 936, 742, 672, 661; 1H NMR (300 MHz,
DMSO-d6): d 8.31 (s, 1H, NCHN), 7.88 (dd, 1H, J1 = 1 Hz,
J2 = 7 Hz, H-7), 7.55 (m, 2H, J1 = 1 Hz, J2 = 2 Hz, H-5 and H-6),
7.36 (td, 1H, J1 = 2 Hz, J2 =7 Hz, H-4), 3.13 (s, 3H, NCH3), 3.04
(s, 3H, NCH3); 13C NMR (75MHz, DMSO-d6): d 156.2 (NCN),
154.7 (C-3a), 145.9 (C-1), 128.8 (C-2), 123.6 (C-5), 122.6 (C-7a),
121.8 (C-6), 114.6 (CN), 113.9 (C-7), 112.2 (C-4), 33.9 (N(CH3)
2); HRMS calcd for C12H11N3O [M + H]+ 214.0980, found
214.0972.
814, 743, 693; 1H NMR (300 MHz, DMSO-d6): d 10.02 (s, 1H,
NH), 8.59 (s, 1H, H-2), 8.13 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9),
7.85–7.70 (m, 4H, H-ar, H-8 and H-7), 7.52 (td, 1H, J1 = 1 Hz,
J2 = 7 Hz, H-6), 6.95 (td, 2H, J1 = 2 Hz, J2 = 8 Hz, H-ar), 3.76 (s,
3H, OCH3); 13C NMR (75 MHz, DMSO-d6): d 155.7 (C-4),
155.4 (C-14), 153.0 (C-2), 146.6 (C-5a), 145.4 (C-4a), 134.6
(C-7), 132.0 (C-11), 130.3 (C-8), 124.1 (C-9), 122.6 (C-13),
122.3 (C-9a), 121.3 (C-6), 113.8 (C-12), 112.7 (C-9b), 55.2
(OCH3); HRMS calcd for C17H14N3O2 [M + H]+ 292.1086,
found 292.1073.
N-(3,4-Dimethoxyphenyl)benzo[b]furo[3,2-d]pyrimidin-4-amine
(1c). Yield: 98%; gray powder; mp 173–174ꢀC; IR (KBr) nmax
(cmꢂ1): 3448, 2828, 1637, 1509, 1481, 1450, 1423, 1268, 1233,
1201, 1173, 1141, 1034, 987, 838, 830, 778, 761, 748, 700, 611;
1H NMR (300 MHz, DMSO-d6): d 10.05 (s, 1H, NH), 8.66 (s,
1H, H-2), 8.19 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 7.89 (dd, 1H,
J1 = 1 Hz, J2 = 7 Hz, H-6), 7.77 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-7),
7.63–7.52 (m, 3H, H-ar and H-8), 7.01 (dd, 1H, J1 = 1 Hz,
J2 = 8 Hz, H-ar), 3.82 (s, 3H, OCH3), 3.81 (s, 3H, OCH3); 13C
NMR (75 MHz, DMSO-d6): d 155.7 (C-4), 153.0 (C-2), 148.4
(C-13), 146.6 (C-5a), 145.4 (C-4a), 144.9 (C-14), 134.7 (C-7),
132.5 (C-11), 130.3 (C-8), 124.2 (C-9), 122.3 (C-9a), 121.3
(C-6), 113.0 (C-15), 112.6 (C-9b), 111.9 (C-16), 106.3 (C-12),
55.7 (OCH3), 55.4 (OCH3); HRMS calcd for C18H16N3O3
[M+ H]+ 322.1192, found 322.1183.
(E)-N0-(2-Cyanobenzo[b]thiophen-3-yl)-N,N-dimethylformimi-
damide (6). A mixture of 3-aminobenzothiophen-2-carbonitrile (4)
(0.5 g; 2.87 mmol) and DMF DMA (3.9 mL; 28.70 mmol) was
irradiated at 90ꢀC (800 W) for 15 min. The solution was cooled to
room temperature, and the mixture was extracted with ethyl acetate.
The organic layers were washed with cold water, dried over
Na2SO4, filtered, and evaporated in vacuo. Purification by column
chromatography over silica gel using dichloromethane/petroleum
ether (5:5, v/v) as the eluent gave the desired compound (6) as a
yellow powder (655 mg; 99%); mp 88–89ꢀC; IR (KBr) nmax
(cmꢂ1): 2196 (CN), 1614, 1591, 1558, 1501, 1481, 1462, 1438,
1
1427, 1415, 1371, 1314, 111, 1043, 972, 768, 732, 663; H NMR
(300 MHz, DMSO-d6): d 8.18 (s, 1H, NCHN), 7.98 (dd, 1H,
J1 =1Hz, J2 = 8 Hz, H-7), 7.85 (dd, 1H, J1 =1Hz, J2 = 8 Hz, H-4),
7.59 (td, 1H, J1 =1Hz, J2 = 8 Hz, H-6), 7.47 (td, 1H, J1 =1Hz,
J2 = 8 Hz, H-5), 3.12 (s, 3H, NCH3), 3.08 (s, 3H, NCH3); 13C NMR
(75 MHz, DMSO-d6): d 157.2 (C-3a), 156.0 (NCN), 138.7 (C-7a),
134.1 (C-1), 128.5 (C-5), 125.1 (C-6), 123.6 (C-7), 123.2 (C-4),
116.4 (C-2), 85.8 (CN), 34.1 (N(CH3)2); HRMS calcd for
C12H11N3S [M+H]+ 230.0752, found 230.0749.
N-(4-Bromo-2-fluorophenyl)benzo[b]furo[3,2-d]pyrimidin-4-
amine (1d). Yield: 88%; pale yellow powder; mp 174–175ꢀC;
IR (KBr) nmax (cmꢂ1): 3432, 1632, 1519, 1486, 1473, 1466,
1408, 1395, 1310, 1185, 1142, 1107, 1087, 967, 873, 848, 826,
1
799, 746, 741; H NMR (300 MHz, DMSO-d6): d 10.02 (s, 1H,
NH), 8.57 (s, 1H, H-2), 8.15 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9),
7.84 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-6), 7.78–7.45 (m, 5H, H-ar;
H-8 and H-7), 13C NMR (75 MHz, DMSO-d6): d 156.0 (C-4),
154.5 (C-12), 153.0 (C-2), 146.7 (C-5a), 146.4 (C-4a), 134.7
(C-7), 130.7 (C-8), 128.6 (C-11), 127.5 (C-15), 124.3 (C-9),
121.9 (C-9a), 121.5 (C-6), 119.5 (C-13), 119.2 (C-16), 117.4
(C-14), 112.8 (C-9b); HRMS calcd for C16H10N3OBrF
[M+ H]+ 357.9991, found 357.9981.
General procedure for the synthesis of N-arylbenzo[b]furo
[3,2-d]pyrimidin-4-amines (1a–j).
A mixture of (E)-N0-(2-
cyanobenzo[b]furan-3-yl)-N,N-dimethylformimidamide 5 (0.1 g,
0.47 mmol) and appropriate aniline (1.0 equiv) in acetic acid
(2 mL) was irradiated at 118ꢀC (400 W). On completion
(followed by thin-layer chromatography), the reaction was
cooled to room temperature, and water was added. The solid
was filtered off, washed with water, and dried. The crude solid
was purified by column chromatography over silica gel using a
stepwise gradient of petroleum ether/ethyl acetate (100:0 to
0:100, v/v) as the eluent to give the desired compounds.
N-(3-Chloro-4-fluorophenyl)benzo[b]furo[3,2-d]pyrimidin-4-
amine (1e).
Yield: 82%; white powder; mp 221–222ꢀC; IR
(KBr) nmax (cmꢂ1): 1635, 1618, 1489, 1414, 1358, 1309, 1266,
1212, 1198, 1092, 976, 817, 794, 746, 692, 577, 564, 502, 435,
1
428; H NMR (300 MHz, DMSO-d6): d 10.38 (s, 1H, NH), 8.71
N-Phenylbenzo[b]furo[3,2-d]pyrimidin-4-amine (1a). Yield:
99%; pale yellow powder; mp 201ꢂ202ꢀC (lit. [11]: 190ꢀC); IR
(KBr) nmax (cmꢂ1): 3457, 1585, 1566, 1513, 1477, 1437, 1406,
1360, 1308, 1279, 1273, 1158, 1133, 969, 743, 734, 684, 647,
(s, 1H, H-2), 8.30 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 8.17 (d,
1H, J1 = 7 Hz, H-ar), 7.89–7.87 (m, 2H, H-8 and H-ar), 7.78 (td,
1H, J1 = 1 Hz, J2 = 7 Hz, H-7), 7.53 (td, 1H, J1 = 1 Hz, J2 = 7 Hz,
H-6), 7.41 (td, 2H, J1 = 1 Hz, J2 = 8 Hz, H-ar); 13C NMR
(75 MHz, DMSO-d6): d 155.9 (C-4), 152.8 (C-2), 146.1 (C-5a),
146.0 (C-4a), 136.6 (C-14), 134.6 (C-7), 130.7 (C-8), 124.3
(C-9), 122.1 (C-9a), 121.7 (C-11), 121.5 (C-6), 120.8 (C-13),
118.8 (C-16), 116.9 (C-12), 116.6 (C-15), 112.7 (C-9b);
HRMS calcd for C16H10N3OClF [M + H]+ 314.0491, found
314.0496.
N-(3,5-Dimethoxyphenyl)benzo[b]furo[3,2-d]pyrimidin-4-amine
(1f). Yield: 97%; creamy powder; mp 206–207ꢀC; IR (KBr) nmax
(cmꢂ1): 3451, 1609, 1585, 1566, 1480, 1446, 1424, 1303, 1192,
1161, 1090, 1071, 845, 830, 754, 742, 679, 619, 542, 430; 1H
NMR (300 MHz, DMSO-d6): d 10.10 (s, 1H, NH), 8.69 (s, 1H,
H-2), 8.15 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9), 7.86 (dd, 1H,
J1 =1Hz, J2 = 7 Hz, H-6), 7.76 (td, 1H, J1 =1Hz, J2 =7Hz, H-7),
7.55 (td, 1H, J1 =1Hz, J2 = 7 Hz, H-8), 7.28 (s, 2H, H-ar), 6.26
(s, 1H, H-ar), 3.76 (s, 6H, (OCH3)2); 13C NMR (75MHz,
1
617; H NMR (300MHz, DMSO-d6): d 10.18 (s, 1H, NH), 8.66
(s, 1H, H-2), 8.17 (dd, 1H, J1 = 1 Hz, J2 =7 Hz, H-9), 7.94 (dd,
2H, J1 = 2 Hz, J2 = 8 Hz, H-ar), 7.86 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz,
H-8), 7.75 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-7), 7.54 (td, 1H,
J1 = 1 Hz, J2 = 7 Hz, H-6), 7.48 (td, 2H, J1 = 2 Hz, J2 = 8 Hz, H-ar),
7.09 (td, 1H, J1 = 2 Hz, J2 = 8 Hz, H-ar); 13C NMR (75 MHz,
DMSO-d6): d 155.8 (C-4), 152.9 (C-2), 146.5 (C-5a), 145.9
(C-4a), 139.2 (C-11), 134.7 (C-7), 130.5 (C-8), 128.6 (C-13),
124.2 (C-9), 123.0 (C-14), 122.2 (C-9a), 121.4 (C-6), 120.7
(C-12), 112.7 (C-9b); HRMS calcd for C16H12N3O [M+ H]+
262.0980, found 262.0968.
N-(4-Methoxyphenyl)benzo[b]furo[3,2-d]pyrimidin-4-amine
(1b). Yield: 99%; brown powder; mp 158–159ꢀC; IR (KBr)
nmax (cmꢂ1): 3446, 1634, 1612, 1589, 1506, 1489, 1417, 1307,
1295, 1251, 1229, 1200, 1158, 1146, 1134, 1090, 1040, 971,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1194
Y. Loidreau, C. Dubouilh-Benard, P. Marchand, M.-R. Nourrisson, M. Duflos,
Vol 50
C. Buquet, C. Corbière, and T. Besson
DMSO-d6): d 160.4 (C-13), 155.8 (C-4), 152.8 (C-2), 146.4
(C-5a), 145.9 (C-4a), 140.9 (C-11), 134.8 (C-7), 130.5 (C-8),
124.3 (C-9), 122.2 (C-9a), 121.4 (C-6), 112.7 (C-9b), 99.0
(C-12), 94.7 (C-14), 55.1 ((OCH3)2); HRMS calcd for
C18H16N3O3 [M + H]+ 322.1192, found 322.1180.
128.6 (C-16), 124.3 (C-9), 122.1 (C-9a), 121.4 (C-6), 119.4 (C-15),
116.3 (C-12), 112.7 (C-9b); HRMS calcd for C16H11N4O4 [M + H]+
323.0780, found 323.0771.
3-(4-Nitrophenyl)benzo[b]furo[3,2-d]pyrimidin-4(3H)-imine
(7). Yield: 16%; white powder; mp 282–283ꢀC; IR (KBr) nmax
(cmꢂ1): 1644, 1595, 1567, 1509, 1496, 1411, 1341, 1305, 1241,
N-(3,4,5-Trimethoxyphenyl)benzo[b]furo[3,2-d]pyrimidin-4-
amine (1g). Yield: 77%; pale brown powder; mp 183–184ꢀC;
IR (KBr) nmax (cmꢂ1): 3447, 1638, 1585, 1567, 1504, 1473,
1445, 1416, 1231, 1182, 1128, 1090, 999, 805, 736, 627, 609,
594, 574, 528, 422; 1H NMR (300 MHz, DMSO-d6): d 10.05 (s,
1H, NH), 8.67 (s, 1H, H-2), 8.15 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz,
H-9), 7.85 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-6), 7.75 (td, 1H,
J1 = 1 Hz, J2 = 7 Hz, H-7), 7.56 (td, 1H, J1 = 2 Hz, J2 = 7 Hz,
H-8), 7.39 (s, 2H, H-ar), 3.80 (s, 6H, (OCH3)2), 3.66 (s, 3H;
OCH3); 13C NMR (75 MHz, DMSO-d6): d 155.8 (C-4), 152.9
(C-13), 152.8 (C-2), 146.4 (C-5a), 145.7 (C-4a), 135.3 (C-15),
134.7 (C-7), 133.5 (C-11), 130.5 (C-8), 124.2 (C-9), 122.2
(C-9a), 121.4 (C-6), 112.7 (C-9b), 98.7 (C-12), 60.1 (OCH3),
55.1 ((OCH3)2); HRMS calcd for C19H18N3O4 [M + H]+
352.1297, found 352.1297.
1
1182, 1149, 1093, 970, 863, 853, 831, 745, 706, 660; H NMR
(300 MHz, DMSO-d6): d 8.82 (s, 1H, H-2), 8.27 (s, 4H, H-ar),
8.20 (dd, 1H, J1 = 1 Hz, J2 =7 Hz, H-9), 7.90 (dd, 1H, J1 = 1 Hz,
J2 = 8 Hz, H-8), 7.77 (td, 1H, J1 = 2 Hz, J2 =7 Hz, H-7), 7.56 (td,
1H, J1 = 1 Hz, J2 = 8 Hz, H-6); 13C NMR (75 MHz, DMSO-d6): d
157.9 (C-14), 156.2 (C-4), 152.6 (C-2), 147.1 (C-5a), 146.0 (C-
4a), 145.5 (C-11), 141.4 (C-9b), 131.1 (C-7), 124.9 (C-12), 124.5
(C-9a), 121.9 (C-8), 121.6 (C-9), 119.4 (C-13), 112.8 (C-6);
HRMS calcd for C16H11N4O3 [M + H]+ 307.0831, found 307.0829.
General procedure for the synthesis of N-arylbenzo[b]
thieno[3,2-d]pyrimidin-4-amines (2a–j).
A mixture of (E)-
N0-(2-cyanobenzo[b]thiophen-3-yl)-N,N-dimethylformimidamide
6 (0.1 g, 0.43 mmol) and appropriate aniline (1.0 equiv) in acetic
acid (2 mL) was irradiated at 118ꢀC (400 W). On completion
(followed by thin-layer chromatography), the reaction was
cooled to room temperature, and water was added. The solid
was filtered off, washed with water, and dried. The crude solid
was purified by column chromatography over silica gel using a
gradient of petroleum ether/ethyl acetate (100:0 to 0:100, v/v) as
the eluent to give the desired compounds.
N-(Benzo[d][1,3]dioxol-5-yl)benzofuro[3,2-d]pyrimidin-4-amine
(1h). Yield: 94%; brown powder; mp 218–219ꢀC; IR (KBr) nmax
(cmꢂ1): 1641, 1609, 1480, 1448, 1262, 1190, 1140, 1035, 927, 845,
1
789, 782, 748, 697, 648, 634, 600, 571, 502; H NMR (300 MHz,
DMSO-d6): d 10.07 (s, 1H, NH), 8.62 (s, 1H, H-2), 8.14 (dd, 1H,
J1 =1Hz, J2 = 7 Hz, H-9), 7.85 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-6),
7.74 (td, 1H, J1 =1Hz, J2 = 7 Hz, H-7), 7.58–7.51 (m, 2H,
J1 =2Hz, J2 = 8 Hz, H-8 and H-ar), 7.33 (dd, 1H, J1 =1Hz,
J2 =8Hz, H-ar), 6.93 (dd, 1H, J1 =1Hz, J2 = 8 Hz, H-ar), 6.03 (s,
2H, H-18); 13C NMR (75 MHz, DMSO-d6): d 155.7 (C-4), 152.9
(C-2), 146.9 (C-13), 146.5 (C-5a), 145.5 (C-4a), 143.0 (C-14),
134.6 (C-7), 133.3 (C-11), 130.4 (C-8), 124.2 (C-9), 122.2 (C-9a),
121.4 (C-6), 113.9 (C-16), 112.7 (C-9b), 107.9 (C-15), 103.2
(C-12), 101.0 (C-18); HRMS calcd for C17H12N3O3 [M + H]+
306.0879, found 306.0888.
N-Phenylbenzo[b]thieno[3,2-d]pyrimidin-4-amine (2a). Yield:
77%; white powder; mp 272–273ꢀC; IR (KBr) nmax (cmꢂ1): 1610,
1561, 1531, 1495, 1472, 1453, 1432, 1382, 1313, 1297, 1259,
1251, 1227, 1056, 759, 744, 723, 709, 688, 617; 1H NMR
(300 MHz, DMSO-d6): d 9.82 (s, 1H, NH), 8.74 (s, 1H, H-2), 8.35
(dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9), 8.19 (dd, 1H, J1 =1Hz,
J2 = 7 Hz, H-8), 7.80 (dd, 2H, J1 =1Hz, J2 = 7 Hz, H-H-ar), 7.72
(td, 1H, J1 =1Hz, J2 = 7 Hz, H-7), 7.61 (td, 1H, J1 =1Hz, J2 =7Hz,
H-6), 7.42 (td, 2H, J1 =1Hz, J2 =7Hz, H-ar), 7.12 (td, 1H,
J1 =1Hz, J2 =7Hz, H-ar); 13C NMR (75 MHz, DMSO-d6): d 156.2
(C-4), 155.4 (C-2), 154.4 (C-5a), 139.7 (C-4a), 138.4 (C-11), 133.6
(C-7), 129.8 (C-8), 128.5 (C-13), 125.4 (C-9), 123.8 (C-14), 123.7
(C-9a), 123.0 (C-6), 122.4 (C-12), 115.1 (C-9b); HRMS calcd for
C16H12N3S [M+H]+ 278.0752, found 278.0759.
N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)benzofuro[3,2-d]
pyrimidin-4-amine (1i).
Yield: 98%; pale brown powder; mp
212–213ꢀC; IR (KBr) nmax (cmꢂ1): 1648, 1617, 1501, 1479, 1433,
1416, 1304, 1278, 1265, 1257, 1244, 1200, 1166, 1068, 885, 793,
1
759, 742, 576, 431; H NMR (300 MHz, DMSO-d6): d 10.00 (s,
1H, NH), 8.61 (s, 1H, H-2), 8.14 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9),
7.85 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-6), 7.74 (td, 1H, J1 =1Hz,
J2 = 7 Hz, H-7), 7.56–7.52 (m, 2H, J1 =2Hz, J2 =8Hz, H-8 and H-
ar), 7.34 (dd, 1H, J1 =1Hz, J2 = 8 Hz, H-ar), 6.85 (dd, 1H, J1 =1Hz,
J2 = 8 Hz, H-ar), 4.25 (br s, 4H, H-ar); 13C NMR (75 MHz, DMSO-
d6): d 155.6 (C-4), 152.9 (C-2), 146.4 (C-5a), 145.5 (C-4a), 142.8
(C-13), 139.4 (C-14), 134.7 (C-7), 132.6 (C-11), 130.4 (C-8), 124.2
(C-9), 122.2 (C-9a), 121.3 (C-6), 116.6 (C-15), 114.2 (C-16), 112.7
(C-9b), 110.0 (C-12), 64.2 (C-18), 64.0 (C-19); HRMS calcd for
C18H14N3O3 [M + H]+ 320.1035, found 320.1028.
N-(4-Methoxyphenyl)benzo[b]thieno[3,2-d]pyrimidin-4-amine
(2b). Yield: 61%; yellow powder; mp 221–222ꢀC; IR (KBr) nmax
(cmꢂ1): 1599, 1571, 1560, 1504, 1473, 1451, 1435, 1415, 1251,
1
1228, 1172, 1059, 1030, 831, 749, 733, 726, 711, 697, 626; H
NMR (300 MHz, DMSO-d6): d 9.64 (s, 1H, NH), 8.66 (s, 1H,
H-2), 8.33 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 8.15 (dd, 1H,
J1 = 1 Hz, J2 = 7 Hz, H-8), 7.72 (td, 1H, J1 = 1 Hz, J2 = 7 Hz,
H-7), 7.69–7.58 (m, 3H, H-ar and H-6), 6.98 (dd, 2H,
J1 = 1 Hz, J2 = 7 Hz, H-ar), 3.79 (s, 3H, OCH3); 13C NMR
(75 MHz, DMSO-d6): d 156.2 (C-4), 156.0 (C-2), 154.5 (C-5a),
150.2 (C-14), 139.7 (C-4a), 133.6 (C-7), 131.3 (C-11), 129.7
(C-8), 125.3 (C-9), 125.1 (C-13), 123.6 (C-9a), 123.0 (C-6),
114.5 (C-9b), 113.7 (C-12), 55.2 (OCH3); HRMS calcd for
C17H14N3OS [M + H]+ 308.0858, found 308.0846.
4-(Benzofuro[3,2-d]pyrimidin-4-ylamino)-2-nitrophenol
(1j).
Yield: 89%; white powder; mp 262–263ꢀC; IR (KBr) nmax
(cmꢂ1): 3289, 1643, 1591, 1551, 1518, 1486, 1306, 1269, 1253,
1
1180, 1151, 1091, 1035, 978, 833, 759, 677, 584, 570, 552; H
NMR (300 MHz, DMSO-d6): d 10.31 (s, 1H, NH), 8.67 (s, 1H,
H-2), 8.66 (d, 1H, J= 2 Hz, H-ar), 8.15 (dd, 1H, J1 =1Hz,
J2 = 7 Hz, H-9), 8.02 (dd, 1H, J1 =2Hz, J2 =7Hz, H-ar), 7.87
(dd, 1H, J1 =1Hz, J2 = 7 Hz, H-6), 7.74 (td, 1H, J1 =1Hz,
J2 = 7 Hz, H-7), 7.54 (td, 2H, J1 =1Hz, J2 = 7 Hz, H-8), 7.18 (d,
1H, J= 7 Hz, H-ar), 6.03 (s, 2H, H-ar); 13C NMR (75MHz,
DMSO-d6): d 155.8 (C-4), 152.9 (C-2), 148.3 (C-14), 146.2 (C-5a),
145.9 (C-4a), 135.7 (C-13), 134.6 (C-7), 131.0 (C-11), 130.5 (C-8),
N-(3,4-Dimethoxyphenyl)benzo[b]thieno[3,2-d]pyrimidin-
4-amine (2c).
Yield: 99%; gray powder; mp 203–204ꢀC; IR
(KBr) nmax (cmꢂ1): 1574, 1562, 1509, 1503, 1469, 1453, 1445,
1434, 1401, 1266, 1247, 1231, 1201, 1143, 1053, 1020, 978, 744,
730; 1H NMR (300MHz, DMSO-d6): d 9.63 (s, 1H, NH), 8.69 (s,
1H, H-2), 8.34 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 8.15 (dd, 1H,
J1 = 1 Hz, J2 = 7 Hz, H-6), 7.70 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-7),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2013 Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]
thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement
1195
7.64 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-8), 7.30 (dd, 1H, J1 = 1 Hz,
J2 = 8 Hz, H-ar), 6.98 (dd, 1H, J1 = 1 Hz, J2 = 8 Hz, H-ar), 3.78 (s,
3H, OCH3), 3.77 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6):
d 156.0 (C-4), 155.8 (C-2), 154.5 (C-5a), 148.4 (C-13), 145.9
(C-14), 139.8 (C-4a), 133.6 (C-7), 131.7 (C-11), 129.7 (C-8), 125.3
(C-9), 123.6 (C-9a), 123.0 (C-6), 115.8 (C-15), 114.6 (C-9b), 111.6
(C-16), 108.4 (C-12) 55.7 (OCH3), 55.5 (OCH3); HRMS calcd for
C18H16N3O2S[M + H]+ 338.0963, found 338.0956.
N-(Benzo[d][1,3]dioxol-5-yl)benzo[4,5]thieno[3,2-d]pyrimidin-
4-amine (2h). Yield: 68%; brown powder; mp 237–238ꢀC; IR
(KBr) nmax (cmꢂ1): 1571, 1500, 1485, 1472, 1453, 1436, 1393,
1264, 1236, 1186, 1034, 1020, 936, 853, 803, 745, 715, 709, 597,
1
570, 421; H NMR (300MHz, DMSO-d6): d 9.65 (s, 1H, NH),
8.69 (s, 1H, H-2), 8.34 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 8.17
(dd, 1H, J1 = 1 Hz, J2 = 7Hz, H-6), 7.71 (td, 1H, J1 =1 Hz,
J2 = 7 Hz, H-7), 7.63 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-8), 7.37
(d, 1H, J =2 Hz, H-ar), 7.12 (dd, 1H, J1 = 2 Hz, J2 =8 Hz, H-ar),
6.97 (d, 1H, J = 8 Hz, H-ar), 6.06 (s, 2H, H-ar); 13C NMR
(75 MHz, DMSO-d6): d 156.1 (C-4), 155.7 (C-2), 154.4 (C-5a),
147.0 (C-13), 144.0 (C-14), 139.7 (C-4a), 133.6 (C-7), 132.6
(C-11), 129.7 (C-8), 125.3 (C-9), 123.6 (C-9a), 123.0 (C-6),
116.4 (C-16), 114.6 (C-9b), 107.8 (C-15), 105.4 (C-12), 101.2
(C-18); HRMS calcd for C17H12N3O2S[M + H]+ 322.0650,
found 322.0640.
N-(4-Bromo-2-fluorophenyl)benzo[b]thieno[3,2-d]pyrimidin-
4-amine (2d).
Yield: 76%; yellow powder; mp 201–202ꢀC; IR
(KBr) nmax (cmꢂ1): 3417, 1683, 1597, 1562, 1524, 1508, 1469,
1444, 1429, 1411, 1273, 1249, 1180, 1105, 1053, 959, 862, 855,
818, 740, 726, 708; 1H NMR (300 MHz, DMSO-d6): d 9.81 (s, 1H,
NH), 8.66 (s, 1H, H-2), 8.37 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9), 8.20
(dd, 1H, J1 =1Hz, J2 = 7 Hz, H-6), 7.75–7.47 (m, 5H, H-ar, H-8 and
H-7), 13C NMR (75 MHz, DMSO-d6): d 155.8 (C-4), 154.5 (C-2),
152.3 (C-5a), 148.3 (C-12), 146.2 (C-15), 142.6 (C-11), 139.9 (C-
4a), 133.4 (C-7), 129.8 (C-8), 127.7 (C-13), 125.5 (C-9), 123.8 (C-
9a), 123.2 (C-6), 119.7 (C-16), 119.1 (C-14), 114.7 (C-9b); HRMS
calcd for C16H10N3SBrF [M + H]+ 373.9763, found 373.9773.
N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)benzo[4,5]thieno
[3,2-d]pyrimidin-4-amine (2i).
Yield: 84%; gray powder; mp
254–255ꢀC; IR (KBr) nmax (cmꢂ1): 1573, 1563, 1534, 1495, 1472,
1451, 1435, 1420, 1308, 1283, 1203, 1168, 1068, 1059, 862, 745,
730, 709, 576, 421; 1H NMR (300 MHz, DMSO-d6): d 9.59 (s, 1H,
NH), 8.69 (s, 1H, H-2), 8.34 (dd, 1H, J1 =1Hz, J2 =7Hz, H-9),
8.17 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-6), 7.71 (td, 1H, J1 =1Hz,
J2 = 7 Hz, H-7), 7.63 (td, 1H, J1 =1Hz, J2 = 7 Hz, H-8), 7.34 (d,
1H, J= 2 Hz, H-ar), 7.16 (dd, 1H, J1 =2Hz, J2 =8Hz, H-ar), 6.87
(d, 1H, J= 8 Hz, H-ar), 4.26 (br. s, 4H, H-ar); 13C NMR (75MHz,
DMSO-d6): d 156.0 (C-4), 155.5 (C-2), 154.4 (C-5a), 142.7 (C-13),
140.1 (C-14), 139.7 (C-4a), 133.6 (C-7), 132.0 (C-11), 129.7 (C-8),
125.3 (C-9), 123.6 (C-9a), 123.0 (C-6), 116.6 (C-16), 116.2 (C-15),
114.6 (C-9b), 112.1 (C-12), 64.1 (C-18), 64.2 (C-19); HRMS calcd
for C18H14N3O2S[M + H]+ 336.0807, found 336.0801.
N-(3-Chloro-4-fluorophenyl)benzo[b]thieno[3,2-d]pyrimidin-
4-amine (2e). Yield: 81%; white powder; mp 241–242ꢀC; IR
(KBr) nmax (cmꢂ1): 1614, 1563, 1491, 1473, 1449, 1433, 1396,
1264, 1200, 1057, 962, 879, 809, 779, 746, 728, 710, 692, 574;
1H NMR (300 MHz, DMSO-d6): d 9.90 (s, 1H, NH), 8.79 (s,
1H, H-2), 8.38 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 8.22 (d, 1H,
J1 = 7 Hz, H-ar), 8.17 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-8), 7.82–7.72
(m, 2H, H-7 and H-ar), 7.63 (td, 1H, J1 =1 Hz, J2 =7Hz, H-6),
7.45 (td, 2H, J1 =1Hz, J2 = 7 Hz, H-ar); 13C NMR (75 MHz,
DMSO-d6): d 156.3 (C-4), 155.0 (C-2), 154.3 (C-5a), 139.8
(C-4a), 136.3 (C-14), 133.5 (C-7), 130.0 (C-8), 125.5 (C-9),
123.7 (C-9a), 123.1 (C-6), 122.3 (C-11), 119.0 (C-13), 118.7
(C-16), 116.8 (C-12), 116.5 (C-15), 115.3 (C-9b); HRMS
calcd for C16H10N3SClF [M + H]+ 330.0256, found 330.0250.
N-(3,5-Dimethoxyphenyl)benzo[b]thieno[3,2-d]pyrimidin-4-
amine (2f). Yield: 84%; gray powder; mp 194–195ꢀC; IR (KBr)
4-(Benzo[4,5]thieno[3,2-d]pyrimidin-4-ylamino)-2-nitrophenol
(2j).
Yield: 66%; red powder; mp 256–257ꢀC; IR (KBr) nmax
(cmꢂ1): 3360, 1529, 1503, 1473, 1449, 1434, 1328, 1312, 1235,
1216, 1171, 1135, 1056, 969, 825, 753, 708, 684, 576, 555, 425; 1H
NMR (300 MHz, DMSO-d6): d 9.87 (s, 1H, NH), 8.75 (s, 1H, H-2),
8.44 (d, 1H, J= 2 Hz, H-ar), 8.37 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9),
8.21 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-6), 7.97 (d, 1H, J= 8 Hz, H-ar),
7.72 (td, 1H, J1 =1Hz, J2 = 7 Hz, H-7), 7.64 (td, 1H, J1 =1Hz,
J2 = 7 Hz, H-8), 7.18 (dd, 1H, J1 =2Hz, J2 = 8 Hz, H-ar); 13C NMR
(75 MHz, DMSO-d6): d 156.1 (C-4), 155.2 (C-2), 154.3 (C-5a),
139.7 (C-4a), 139.7 (C-14), 135.7 (C-13), 133.6 (C-7), 131.8
(C-11), 130.5 (C-16), 129.9 (C-8), 125.4 (C-9), 123.7 (C-9a),
123.0 (C-6), 119.3 (C-15), 118.2 (C-12), 114.6 (C-9b); HRMS
calcd for C16H11N4O3S[M + H]+ 339.0552, found 339.0547.
n
max (cmꢂ1): 1584, 1568, 1533, 1513, 1487, 1463, 1441, 1415, 1194,
1
1146, 1064, 1009, 821, 744, 712, 669, 620, 595, 441; H NMR
(300 MHz, DMSO-d6): d 9.68 (s, 1H, NH), 8.78 (s, 1H, H-2), 8.36
(dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9), 8.20 (dd, 1H, J1 =1Hz,
J2 = 7 Hz, H-6), 7.73 (td, 1H, J1 =1Hz, J2 = 7 Hz, H-7), 7.64 (td,
1H, J1 =1Hz, J2 = 7 Hz, H-8), 7.13 (s, 2H, H-ar), 6.30 (s, 1H, H-ar),
3.76 (s, 3H, OCH3), 3.35 (s, 3H, OCH3); 13C NMR (75MHz,
DMSO-d6): d 156.0 (C-4), 155.8 (C-2), 154.5 (C-5a), 148.4 (C-13),
145.9 (C-14), 139.8 (C-4a), 133.6 (C-7), 131.7 (C-11), 129.7 (C-8),
125.3 (C-9), 123.6 (C-9a), 123.0 (C-6), 115.8 (C-9b), 114.6 (C-15),
111.6 (C-16), 108.4 (C-12) 55.7 (OCH3), 55.5 (OCH3); HRMS
calcd for C18H16N3O2S[M + H]+ 338.0963, found 338.0956.
Benzo[b]furo[3,2-d]pyrimidin-4-amine (8).
Formamide
(2mL) was added to (E)-N0-(2-cyanobenzo[b]furan-3-yl)-N,N-
dimethylformimidamide (5) (0.1 g, 0.47 mmol). The mixture was
irradiated at 170ꢀC (200W) for 30 min. On completion (followed
by GC–MS chromatography), the reaction was cooled to room
temperature, and water was added. The solid was filtered off,
washed with water, and dried. The crude solid was purified by
column chromatography over silica gel using petroleum ether/
ethyl acetate (100:0 to 0:100, v/v) as the eluent to give the desired
compound (8) (0.076 g, 89%) as a white powder; mp 273–274ꢀC
(lit. [7]: 258ꢀC); IR (KBr) nmax (cmꢂ1): 3308, 3124, 1655, 1628,
1598, 1554, 1446, 1418, 1327, 1296, 1274, 1185, 1155, 1097,
1052, 964, 827, 751, 741, 644, 616; 1H NMR (300MHz, DMSO-
d6): d 8.42 (s, 1H, H-2), 8.09 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9),
7.78 (dd, 2H, J1 = 2 Hz, J2 = 7 Hz, H-8), 7.62 (td, 1H, J1 = 2 Hz,
J2 = 7 Hz, H-7), 7.57 (s, 2H, NH2), 7.49 (td, 1H, J1 = 1 Hz,
J2 = 8 Hz, H-6); 13C NMR (75 MHz, DMSO-d6): d 155.6 (C-4),
N-(3,4,5-Trimethoxyphenyl)benzo[b]thieno[3,2-d]pyrimidin-4-
amine (2g).
Yield: 80%; white powder; mp 198–199ꢀC; IR
(KBr) nmax (cmꢂ1): 1551, 1500, 1458, 1438, 1426, 1413, 1242,
1228, 1124, 1056, 1008, 1001, 747, 728, 708, 675, 631, 595, 520;
1H NMR (300 MHz, DMSO-d6): d 9.68 (s, 1H, NH), 8.74 (s, 1H,
H-2), 8.36 (dd, 1H, J1 = 1 Hz, J2 = 7 Hz, H-9), 8.19 (dd, 1H,
J1 = 1 Hz, J2 = 7 Hz, H-6), 7.72 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-7),
7.61 (td, 1H, J1 = 1 Hz, J2 = 7 Hz, H-8), 7.21 (s, 2H, H-AR), 3.80
(s, 6H, (OCH3)2), 3.68 (s, 3H, OCH3); 13C NMR (75MHz,
DMSO-d6): d 156.1 (C-4), 155.7 (C-2), 154.6 (C-5a), 152.5
(C-13), 139.7 (C-4a), 134.8 (C-14), 134.0 (C-11), 133.6 (C-7),
129.8 (C-8), 125.4 (C-9), 123.6 (C-9a), 123.0 (C-6), 115.0 (C-9b),
100.5 (C-12), 60.1 ((OCH3)2), 55.8 (OCH3); HRMS calcd for
C19H18N3O3S[M + H]+ 368.1069, found 368.1060.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1196
Y. Loidreau, C. Dubouilh-Benard, P. Marchand, M.-R. Nourrisson, M. Duflos,
Vol 50
C. Buquet, C. Corbière, and T. Besson
153.5 (C-5a), 150.3 (C-2), 145.3 (C-4a), 134.3 (C-9a), 130.1
(C-7), 123.9 (C-8), 122.3 (C-9b), 121.3 (C-9), 113.7 (C-6);
HRMS calcd for C10H8N3O [M + H]+ 186.0667, found
186.0657.
Acknowledgments. This work was supported by a PhD grant
from the Région Haute-Normandie (YL) and the ISCE-
CHEM program. We acknowledge Milestone S.r.l. (Italy)
for providing the microwave reactors and financial and
technical support.
Benzo[b]thieno [3,2-d]pyrimidin-4-amine (9). Formamide
(2 mL) was added to (E)-N0-(2-cyanobenzo[b]thiophen-3-yl)-N,N-
dimethylformimidamide (6) (0.1 g, 0.43 mmol). The mixture was
irradiated at 170ꢀC (200W) for 90 min. On completion (followed
by GC–MS chromatography), the reaction was cooled to room ,
temperature and water was added. The solid was filtered off,
washed with water, and dried. The crude solid was purified by
column chromatography over silica gel using petroleum ether/ethyl
acetate (100:0 to 0:100, v/v) as the eluent to give the desired
compound (9) (0.062 g, 71%) as a brown powder; mp 301–302ꢀC
(lit. [12]: 280ꢀC) IR (KBr) nmax (cmꢂ1): 3298, 3117, 1666, 1572,
1523, 1435, 1403, 1344, 1315, 1277, 1142, 1062, 1030, 958, 938,
REFERENCES AND NOTES
[1] (a) Testard, A.; Picot, L.; Lozach, O.; Blairvac, M.; Meijer, L.;
Murillo, L.; Piot, J.-M.; Thiéry, V.; Besson, T. J. Enz Inhib Med Chem
2005, 20, 557.; (b) Testard, A.; Logé, C.; Léger, B.; Robert, J.-M.; Lozach,
O.; Blairvacq, M.; Meijer, L.; Thiéry, V.; Besson, T. Bioorg Med Chem Lett
2006, 16, 4319.; (c) Logé, C.; Testard, A.; Thiéry, V.; Lozach, O.; Blairvacq,
M.; Robert, J.-M.; Meijer, L.; Besson T. Eur J Med Chem 2008, 43, 1469.
[2] (a) Bretéché, A.; Marchand, P.; Nourrisson, M.-R.; De
Nanteuil, G.; Duflos, M. Tetrahedron 2010, 66, 4490; (b) Antoine, M.;
Czech, M.; Gerlach, M.; Günther, E.; Schuster, T.; Marchand, P. Synthesis
2011, 5, 794; (c) Bretéché, A.; Marchand, P.; Nourrisson, M.-R.; Hautefaye,
P.; De Nanteuil, G.; Duflos, M. Tetrahedron 2011, 67, 4767.
[3] Hurley, L. H.; Mahadevan, D.; Han, H.; Bearss, D. J.;
Vankayalapati, H.; Bashyam, S.; Munoz, R. M.; Warner, S. L.; Della
Croce, K.; Von Hoff, D. D.; Grand, C. L.; Welsh, J. (a) US Patent 0
099 165 A1, 2009; Chem Abstr 2009, 150, 414245; (b) US Patent 0
143 399 A1, 2009; Chem Abstr 2009, 151, 8539.
1
812, 787, 740, 719, 674, 651, 609; H NMR (300 MHz, DMSO-
d6): d 8.52 (s, 1H, H-2), 8.30 (dd, 1H, J1 =1Hz, J2 = 7 Hz, H-9),
8.14 (dd, 2H, J1 =2Hz, J2 = 7 Hz, H-8), 7.68 (td, 1H, J1 =2Hz,
J2 = 7 Hz, H-7), 7.57 (s, 2H, NH2), 7.57 (td, 1H, J1 =1Hz,
J2 =8Hz, H-6); 13C NMR (75 MHz, DMSO-d6): d 158.6 (C-4),
155.5 (C-5a), 155.1 (C-2), 140.5 (C-4a), 133.9 (C-9a), 129.4 (C-7),
125.1 (C-8), 123.7 (C-9b), 123.0 (C-9), 113.3 (C-6); HRMS calcd
for C10H8N3S [M+H]+ 202.0439, found 202.0427.
[4] Harris, C. S.; Hennequin, L.; Morgentin, R.; Pasquet, G. In Targets
in Heterocyclic Systems – Chemistry and Properties; Attanasi O. A., Spinelli
D., Eds.; Italian Society of Chemistry: Roma, 2010; Vol. 14, p 315.
[5] (a) Dimroth, O. Liebigs Ann Chem 1909, 364, 183. This paper
is considered as the first paper of Otto Dimroth reporting the translocation
of endocyclic and exocyclic nitrogen atoms with certain 1,2,3-triazoles.
Since the work of Tsou and his co-workers [5b] in 2001, this reaction
becomes very popular in medicinal chemistry[5c–h], e.g. for the synthesis
of 4-substituted bioactive quinazolines (References [5c,g,h] are also
focused on microwave-assisted methods): (b) Tsou, H. R.; Mamuya, N.;
Johnson, B. D.; Reich, M. F.; Gruber, B. C.; Ye, F.; Nilakantan, R.; Shen,
R.; Discafani, C.; DeBlanc, R.; Davis, R.; Koehn, R. E.; Greenberger, L.
M.; Wang, Y. F.; Wissner, A. J. Med Chem 2001, 44, 2719; (c) Yoon, D.
S.; Han, H.; Stark, T. M.; Haber, J. C.; Gregg, B. T.; Stankovich, S. B.
Org Lett 2004, 6, 4775; (d) Domarkas, J.; Dudouit, F.; Williams, C.; Qiyu,
Q.; Banerjee, R.; Brahimi, F.; Jean-Claude, B. J. J. Med Chem 2006, 49,
3544; (e) Chandregowda, V. C.; Rao, C. G.; Reddy, G. C. Org Process
Res Dev 2007, 11, 813; (f) Rachid, Z.; MacPhee, M.; Williams, C.;
Torodova, M.; Jean-Claude, B. J. Bioorg Med Chem Lett 2009, 19,
5505; (g) Foucourt, A; Dubouilh-Benard, C.; Chosen, E.; Corbière, C.;
Buquet, C.; Iannelli, M.; Leblond, B.; Marsais, F.; Besson, T. Tetrahedron
2010, 66, 4495; h) Han, Y.; Binger, K.; Vandevier, L. E.; Maloney, J. W.;
Nirschl, D. S.; Weller, H. N. Tetrahedron Lett 2010, 51, 629.
[6] For two very complete reviews on Dimroth rearrangement, see
(a) El Ashry, E. S. H.; Nadeem, S.; Raza Shah M.; El Kilany, Y.; Adv
Heterocycl Chem 2010, 101, 161; (b) El Ashry, E. S. H.; El Kilany, Y.;
Rashed, N.; Assafir, H. Adv Heterocycl Chem 1999, 75, 79.
[7] Sangapure, S. S.; Agasimundin, Y. S. Indian J Chem B 1980,
19B, 115. This paper described the synthesis of 1a and 8 using a Dimroth
rearrangement form 3-(ethoxymethylene)amino-2-benzo[b]furocarbonitrile.
Only one other aromatic aniline (p-chloro) derivative was also described.
[8] Ando, K.; Tsuji, E.; Ando, Y.; Kuwata, N.; Kunitomo, J.-I.;
Yamashita, M.; Ohta, S.; Kohno, S.; Ohishi, Y. Org Biomol Chem
2004, 2, 625.
General procedure for antiproliferative activity.
Cell
culture. Human HT-29 and Caco-2 colorectal adenocarcinoma
cells were purchased from American Type Culture Collection
(Manassas, VA, USA). HT-29 and Caco-2 colorectal cancer cell
lines possess different p53 mutations. HT29 contains mutation at
codon 273 resulting in an Arg
!
His substitution and
overproduction of p53, whereas Caco2 contains a deletion and a
termination signal at codon 204, which impaired p53 function
[16]. The cells were grown in Dulbecco’s modified Eagle’s
medium supplemented with 20% fetal bovine serum (Invitrogen,
France), 2 mM L-glutamine (Invitrogen) and penicillin (10 U/mL)/
streptomycin (10mg/mL) at 37ꢀC with 5% CO2 and 90% relative
humidity.
MTT proliferation assay.
HT-29 and Caco-2 cells were
seeded at a density of 8000 cells/well in 96-well microplates. Cells
were treated the next day and let to proliferate for 96 h with or
without molecules. Compounds 1a–e and 2a–e were dissolved in
DMSO (Sigma-Aldrich, France) to obtain a concentration of
100 mmol/L and further diluted to the indicated concentrations in
medium immediately before performing each experiment.
Molecules 1e and 2a were not tested because of their poor
solubility in solvent. MTT test was carried out daily after treatment
(24, 48, or 72 h) as previously described [17]. The final
concentration of DMSO in culture medium was maintained at
0.1%. LY294002 (Sigma-Aldrich), a PI3K inhibitor, was used as a
positive control for growth inhibition.
Statistical analysis. Data are presented as mean ꢁ SD from at
least three independent experiments for molecules 2c and 2d and two
independent experiments for molecule 2e. At least six different
replicates were conducted for each compound. For molecules 2c
and 2d, statistical analysis was performed with nonparametric test
(Mann–Whitney U-test between two groups) using SigmaStat
software. Differences were considered statistically significant at a
p-value < 0.05. First, the two controls were compared, control
without and control with solvent, and no effect of the solvent
was seen. Then, the control with the solvent was compared with
the treated cells.
[9] For a synthesis of this reactant, see Klose, J.; Reese, C. B.;
Song, Q. Tetrahedron 1997, 53, 14411.
[10] Beck, J. R.; Yahner, J. A. J. Org Chem 1974, 39, 3440.
[11] Lost dissipation factor (tan d) expresses the capacity of a
molecule or a material to transform electromagnetic energy into thermal
energy. A high susceptibility to microwaves is characterized by a high
value of tan d. In the case of acetic acid, it is similar to the value of water
(0.123 at 2.45 GHz), allowing convenient heating. For more details, see
Gabriel, C. Gabriel, S. Grant, E. J. Halstead, B. S. Mingos, D. M. P. Chem
Soc Rev 1998, 27, 213.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2013 Efficient New Synthesis of N-Arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and Their Benzo[b]
thieno[3,2-d]pyrimidin-4-amine Analogues via a Microwave-Assisted Dimroth Rearrangement
1197
[12] The synthesis of this product was described via another route in
Robba, M.; Touzot, P.; El-Kashef, H. J Heterocyclic Chem 1980, 17, 923.
[13] (a) Kostakis, I. K.; Elomri, H.; Seguin, E.; Iannelli, M.; Besson
T. Tetrahedron Lett 2007, 48, 6609; (b) Nouira, I.; Kostakis, I. K.;
Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T. Tetrahedron Lett
2008, 49, 7033; (c) Grosjean, S.; Triki, S.; Meslin, J.-C.; Julienne, D.;
Deniaud, D. Tetrahedron 2010, 66, 9912.
[14] Cataldo, F.; Patane, G.; Compagnoni, G. J. Macromol. Sci.,
Part A: Pure Appl. Chem. 2009, 46, 1039.
[15] Loidreau, Y.; Besson, T. Tetrahedron 2011, 67, 4852.
[16] Lin-Lee, Y.C.; Tatebe, S.; Savaraj, N.; Ishikawa, T.; Tien Kuo,
M. Biochem Pharmacol 2001, 61, 555.
[17] Corbiere, C.; Liagre, B.; Bianchi, A.; Bordji, K.; Dauça, M.;
Netter, P.; Beneytout, J. L. Int J Oncol 2003, 22, 899.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet