Green synthesis of new boron-containing quinazolines: Preparation of benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives

Article abstract of DOI:10.1080/00397911.2012.751612

A series of new boron-containing quinazolinones, benzo[d][1,3,2] diazaborinin-4(1H)-one derivatives, were synthesized by the sequential one-pot reaction of isatoic anhydride, amines, and arylboronic acids in the absence of a catalyst and solvent. Heating isotoic anhydride and amines led to the formation of 2-aminobenzamide intermediates, which reacted easily with boronic acids to obtain the title compounds in good yields. Solvent-free conditions provided a unique procedure because the corresponding products were not obtained using various solvents either under reflux conditions or at room temperature.

Full text of DOI:10.1080/00397911.2012.751612

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Green Synthesis of New Boron-Containing Quinazolines:
Preparation of Benzo[d][1,3,2]Diazaborinin-4(1H)-One
Derivatives
Mohammad Mahdavi a , Mehdi Asadi b , Mina Saeedi a , Maryam Hosseinpour Tehrani a ,
Seyedeh Sara Mirfazli a , Abbas Shafiee a & Alireza Foroumadi a c
a Department of Medicinal Chemistry , Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences , Tehran , Iran
b School of Chemistry, University College of Science, University of Tehran , Tehran , Iran
c Kerman Neuroscience Research Center, Kerman University of Medical Sciences , Kerman ,
Iran
Accepted author version posted online: 31 May 2013.
To cite this article: Mohammad Mahdavi , Mehdi Asadi , Mina Saeedi , Maryam Hosseinpour Tehrani , Seyedeh Sara Mirfazli ,
Abbas Shafiee & Alireza Foroumadi (2013): Green Synthesis of New Boron-Containing Quinazolines: Preparation of Benzo[d]
[1,3,2]Diazaborinin-4(1H)-One Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.751612
To link to this article: http://dx.doi.org/10.1080/00397911.2012.751612
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GREEN SYNTHESIS OF NEW BORON-CONTAINING QUINAZOLINES:
PREPARATION OF BENZO[d][1,3,2]DIAZABORININ-4(1H)-ONE
DERIVATIVES
Mohammad Mahdavi1, Mehdi Asadi2, Mina Saeedi1, Maryam Hosseinpour Tehrani1,
Seyedeh Sara Mirfazli1, Abbas Shafiee1, Alireza Foroumadi1,3,
1Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran, Iran, 2School of
Chemistry, University College of Science, University of Tehran, Tehran, Iran, 3Kerman
Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
∗Corresponding author. , , Tel.: +98-21-66954708; fax: +98-21-66461178; E-mail:
aforoumadi@yahoo.com
Abstract
A series of new boron-containing quinazolinones; benzo[d][1,3,2]diazaborinin-4(1H)-one
derivatives were synthesized by the sequential one-pot reaction of isatoic anhydride,
amines and arylboronic acids in the absence of a catalyst and solvent. Heating isotoic
anhydride and amines led to the formation of 2-aminobenzamide intermediates which
reacted easily with boronic acids to obtaine the title compounds in good yields. Solven-
free conditions provided unique procedure since the corresponding products were not
obtained using various solvents neither under reflux conditions nor at room temperature.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
O
O
1)
2)
R NH2
X
2
R
O
N
B
B(OH)2
N
H
1
O
N
H
3
X
4
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KEYWORDS: Boron-containing quinazolines; isatoic anhydride; 2-aminobenzamides;
boronic acids; solvent-free
INTRODUCTION
Increasing interest in organoboron compounds can be referred to the ability of boron to
create important biological properties in the corresponding compounds.[1–3] For instance,
boron-containing derivatives of 2-thiouracil have been introduced as good candidates for
boron neutron-capture therapy of malignant melanoma.[4]
Boron-containing heterocyclic compounds have been the focus of attention due to their
useful biological and medicinal effects. Baker et al. have reported synthesis of various
novel boron-containing antifungal agents.[5] Their studies shows that 5-fluoro-1,3-
dihydro-1-hydroxy-2,1-benzoxaborole derivative possesses significant properties for the
treatment of onychomycosis. Boron heterocycles steroid mimics were provided by
Grogiak as pharmaceutical agents in treatment of estrogen-depended cancers.[6] Also the
mentioned compounds are useful in diagnostic techniques such as magnetic resonance
imaging (MRI) and magnetic resonance spectroscopy (MRS).
N–B–N Bond formation in analogues of quinazoline as one of the important class of
heterocyclic compounds with particular biological activities,[7] is found to be very useful
since these compounds have depicted high inhibitory activity against epidermal growth
factor receptor protein tyrosine kinase [8] and also are useful as an antitumor agent.[9]
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Replacement of carbon in the quinazoline derivatives with a boron atom has been
reported in the literature using different and efficient routes: i) synthesis of boron-
containing analogues of purine, pyrimidine and perimidine derivatives by reaction nitriles
and diboranes and also reaction of amines and boron chloride;[10] ii) synthesis of
benzodiazaborinones using reaction of boronic acids and o-aminobenzamide
intermediates;[11] iii) synthesis of 1,1'-biaryl-4-boronic acid bearing anthranilamide on the
boron atom which subsequently underwent Ru-catalyzed o-silylation.[12]
On the one hand, quinazolines properties; on the other hand, importance of boron-
containing heterocycles directed our research interests in the synthesis of novel
heterocycles[13–15] specially having biological activities[16] to prepare boron-containing
quinazolinones, benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives (Scheme 1). It seems
development of rapid and selective synthetic routes to prepare library of related
compounds is of great importance to both medicinal and organic chemists, and still
constitutes a challenge from organic synthesis points of view.
RESULTS AND DISCUSSION
In this work, we have focused on the reaction of isatoic anhydride 1, amines 2 and
arylboronic acids 3 to synthesize new benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives
4 (Scheme 1).
Our initial investigation began by studying Yale's report in 1979 (Scheme 2).[11] It
indicates that reaction of 2-aminobenzamide or its substituted derivatives 5 and
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arylboronic acids 3 in boiling nonprotic solvents led to the formation of some
benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives 4. Removing the formed water from
the reaction mixture was the most problematic issue which should be isolated
mechanically using Dean-Stark trap, slow distillation through a fractionating column or
drying apparatus with phosphorus pentoxide. It should be noted that in the case of some
derivatives the problem was more remarkable and no product was obtained.
Recently we have successfully developed synthesis of novel 3-alkyl-2-
(alkylamino)quinazolin-4(3H)-one derivatives via the reaction of isatoic anhydride,
amines and N,N'-dialkylcarbodiimes under catalyst- and solvent-free conditions.[14] We
could obtain several 2-aminobenzamide intermediates 5 in situ by heating of equal
stoichiometric amounts of isatoic anhydride and different amines at 150 ºC for 3 h in the
absence of solvent and catalyst. Then, they reacted with N,N'-dialkylcarbodiimes under
the same conditions to obtain corresponding products in good yields. We decided to
apply the same procedure and replace boronic acids 3 instead of N,N'-dialkylcarbodiimes
to solve the above mentioned problem and also prepare novel
benzo[d][1,3,2]diazaborinin-4(1H)-ones.
To clarify more details, the reaction of isatoic anhydride 1 (1 mmol), benzylamine 2a (1
mmol) and phenylboronic acid 3a (1 mmol) was investigated as a model reaction. Isatoic
anhydride underwent ring-opening upon heating with benzyl amine at 150 ºC to produce
2-amino-N-benzylbenzamide after 3 h (5a). Then, phenylboronic acid 3a (1 mmol) was
added to the reaction mixture, stirring continued at the same temperature, and the
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corresponding product 4a (Table 1, Entry 1) was obtained in 50% after 3 h. It was found
that using 1.2 mmol phenylboronic acid gives the product in higher yield (75%). Also the
model reaction was conducted in different solvents such as toluene, methanol, ethanol
and DMF. As we expected no product was obtained either at room temperature or under
reflux condition. Therefore, using solvent-free conditions is essential not only due to
environmentally issues but also it has other advantages.
After confirmation of the structure of 4a and with the optimized conditions in hand, we
next set out to explore the scope of our reaction. To our delight, isatoic anhydride 1,
various amines 2 and arylboronic acids 3 (Scheme 1) produced diverse
benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives 4 in good to high yields. The results
are summarized in Table 1.
Sequences of the formation of benzo[d][1,3,2]diazaborinin-4(1H)-ones 4 are given in
Scheme 3. It is believed that the initial event is the formation of 2-amino-N-
alkylbenzamides 5 from the reaction of isatoic anhydride 1 and amines 2. Then boronic
acid 3 is added to 5. Continuing, cyclization of intermediate by double elimination of
H2O gives compounds 4.
In conclusion, we have developed a practical and environmentally benign protocol to
construct novel benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives via reaction of isatoic
anhydride, various primary amines and arylboronic acids in the absence of a catalyst and
solvent. It is noteworthy that all the reactions proceeded only under solvent-free
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conditions and no products were obtained using various solvents either under reflux
conditions or at room temperature.
EXPERIMENTAL
Melting points was taken on a Kofler hot stage apparatus and were uncorrected. 1H and
13CNMR spectra were recorded on Bruker FT-500, using TMS as an internal standard.
The IR spectra were obtained on a Shimadzu 470 spectrophotometer (in KBr). Mass
spectra were determined on an Agilent Technology (HP) mass spectrometer operating at
an ionization potential of 70 eV. The elemental analysis was performed with an
Elementar Analysensystem GmbH VarioEL CHNS mode.
Synthesis Of Benzo[D][1,3,2]Diazaoborinin-4(1H)-Ones 4
General Procedure
A mixture of isotonic anhydride 1 (1 mmol), appropriate amine 2 (1 mmol) was stirred at
150 °C for 3 h. Then, arylboronic acid derivatives 3 (1.2 mmol) was added to the reaction
mixture and stirring continued at 150 °C for 3 h. After completion of the reaction, it was
cooled to room temperature and the residue was purified by column chromatography
(SiO2, petrolume ether/ethyl acetate = 5/1).
Selected Data
3-(2-Chlorobenzyl)-2,3-Dihydro-2-Phenylbenzo[D][1,3,2]Diazaborinin-4(1H)-One
(4b)
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Yield 80%, white crystals, mp 211-213 ◦C; IR (KBr): 3299, 2920, 2849, 1637, 1616,
1520 cm-1; 1H NMR (CDCl3, 500 MHz): δH = 8.27 (d, J = 7.0 Hz, 1H), 7.54 (dt, J = 7.6,
1.4 Hz, 1H), 7.42-7.40 (m, 3H), 7.36-7.31 (m, 3H), 7.20-7.16 (m, 3H), 7.11-7.08 (m, 2H),
7.04 (s, 1H, NH), 5.05 (s, 2H, NCH2); 13C NMR (CDCl3, 125 MHz): δC = 166.7, 143.5,
136.5, 134.6, 133.7, 132.4, 131.9, 129.7, 129.6, 129.4, 128.8, 128.2, 127.7, 126.9, 126.5,
121.9, 118.7, 117.3, 114.6, 46.0; Anal. Calcd for C20H16BClN2O: C, 69.30; H, 4.65; N,
8.08. Found: C, 69.05; H, 4.88; N, 8.30.
3-Benzyl-2-(4-Chlororophenyl)-2,3-Dihydrobenzo[D][1,3,2]Diazaborinin-4(1H)-One
(4c)
Yield 80%, white crystals, mp 215-218 ◦C; IR (KBr): 3313, 2933, 2854, 1640, 1520 cm-1;
1H NMR (CDCl3, 500 MHz): δH = 8.29 (dd, J = 7.2, 1.5 Hz, 1H), 7.55 (ddd, J = 8.2, 7.2,
1.5 Hz, 1H), 7.38 (dd, J = 6.4, 2.0 Hz, 2H), 7.34 (dd, J = 6.4, 2.0 Hz, 2H), 7.26-7.20 (m,
2H), 7.22-7.18 (m, 2H), 7.12 (d, J = 7.0 Hz, 2H), 7.06 (d, J = 7.2 Hz, 1H), 6.75 (s, 1H,
NH), 4.97 (s, 2H, NCH2); 13C NMR (CDCl3, 125 MHz): δC = 166.6, 143.0, 139.1, 135.8,
133.6, 133.4, 129.7, 128.4, 126.8, 126.6, 122.1, 119.1, 117.1, 47.5; MS m/z (%) = 348
[M+2]+ (33), 346 [M]+ (100), 267 (31), 235 (31), 205 (10), 165 (14), 91 (82), 65 (20);
Anal. Calcd for C20H16BClN2O: C, 69.30; H, 4.65; N, 8.08. Found: C, 69.15; H, 4.77; N,
8.25.
ACKNOWLEDGMENTS
This research was supported by grants from the research council of Tehran University of
Medical Sciences and Iran National Science Foundation (INSF).
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Supporting information: full experimental details, 1H and 13C NMR spectra are available
online.
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Table 1. Synthesis of benzo[d][1,3,2]diazaborinin-4(1H)-ones 4
Product
X in boronic
O
Entry
R in amines 2
Yield (%)a
R
N
B
acids 3
N
H
4
X
CH2
1
2
3
4
5
H
4a[11]
75
80
80
85
70
CH2
Cl
H
4b
4c
4d
4e
CH2
4-Cl
4-F
H
CH2
Cl
CH2
MeO
CH2
6
7
8
9
4-F
H
4f
4g
4h
4i
75
80
85
80
MeO
CH2
OMe
CH2
4-F
H
OMe
MeO
CH2
MeO
O
CH2
10
11
4-F
H
4j
60
80
CH2
4k
aIsolated yields, and compounds 4b-4k are new
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Scheme 1. Synthesis of benzo[d][1,3,2]diazaborinin-4(1H)-one derivatives 4.
R1 NH2
2
1)
O
O
solvent-free, 150 oC
3 h
R
N
B
O
B(OH)
2)
X
2 3
N
H
N
H
O
X
1
4
solvent-free, 150 oC
3 h
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Scheme 2. Reaction of 2-aminobenzamides and boronic acids reported by Yale.[13]
O
O
nonprotic solvents
reflux
R
R
B(OH)2
N
H
N
B
X
+
NH2
N
H
4
X
5
3
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Scheme 3. Mechanism of synthesis of benzo[d][1,3,2]diazaborinin-4(1H)-ne derivatives
4.
X
O
O
B(OH)2
O
NHR
O
R
-CO2
O
N
H
3
+
R NH2
-H2O
N
H
1
O
NH2
5
N
H
O
2
O
O
R
R
-H2O
N
H
N
B
NH
OH
N
H
B
X
4
X
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