Suzuki–Miyaura coupling of quinazolines containing an unprotected NH2 group: Synthesis and biological testing of quinazoline derivatives

Article abstract of DOI:10.1080/00397911.2017.1315672

A robust approach to 4-amino quinazoline bi-aryl compounds was developed through Suzuki–Miyaura coupling reaction of quinazoline containing an unprotected NH₂ group and arylboronic acids. Pd(dcpf)Cl₂ was found to be an efficient catalyst for the reaction. All the compounds were evaluated for antimicrobial activity against gram-positive and gram-negative bacteria and fungi. One of the compounds, 3l, found to be more active against Candida albicans than the standard Miconazole.

Full text of DOI:10.1080/00397911.2017.1315672

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An International Journal for Rapid Communication of Synthetic Organic
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Suzuki-Miyaura Coupling of Quinazolines
Containing an Unprotected NH2 Group: Synthesis
and Biological Testing of Quinazoline Derivatives
Yadagiri Pulipati, Venkateshwarlu Gurram, S. Vijaya Laxmi, Yennam
Satyanarayana, Karan Singh, Vinod Kumar, Somesh Sharma, Narender
Pottabathini & Vijaya Bhaskara Reddy Iska
To cite this article: Yadagiri Pulipati, Venkateshwarlu Gurram, S. Vijaya Laxmi, Yennam
Satyanarayana, Karan Singh, Vinod Kumar, Somesh Sharma, Narender Pottabathini &
Vijaya Bhaskara Reddy Iska (2017): Suzuki-Miyaura Coupling of Quinazolines Containing an
Unprotected NH2 Group: Synthesis and Biological Testing of Quinazoline Derivatives, Synthetic
Communications, DOI: 10.1080/00397911.2017.1315672
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1315672
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Date: 12 April 2017, At: 10:30

Suzuki-Miyaura Coupling of Quinazolines Containing an Unprotected NH2 group:
Synthesis and Biological Testing of Quinazoline Derivatives
Yadagiri Pulipati1,2, Venkateshwarlu Gurram1, S. Vijaya Laxmi2, Yennam
Satyanarayana1, Karan Singh3, Vinod Kumar3, Somesh Sharma1, Narender Pottabathini1
,
Vijaya Bhaskara Reddy Iska1
1Medicinal Chemistry Division, GVK Biosciences Pvt. Ltd, Hyderabad, India, 2KL
University, Guntur, Andhra Pradesh, India, 3Akal College of Engineering and
Technology, Eternal Univeristy, Himachal Pradesh, India
Corresponding Author: Vijaya Bhaskara Reddy Iska, Medicinal Chemistry Division,
GVK Biosciences Pvt. Ltd, Plot 28A, IDA Nacharam, Hyderabad, India. Email:
vijayabhaskara.iska@gvkbio.com
Abstract
A robust approach to 4-amino quinazoline bi-aryl compounds was developed via Suzuki–
Miyaura coupling reaction of quinazoline containing an unprotected NH2 group and
arylboronic acids. Pd(dcpf)Cl2 was found to be an efficient catalyst for the reaction. All
the compounds were evaluated for antimicrobial activity against Gram-positive and
Gram-negative bacteria and fungi. One of the compounds, 3l, found to be more active
against C.albicans than the standard Miconazole.
Graphical Abstract
1

INTRODUCTION
Quinazoline derivatives have proven to be an important class of heterocyclic compounds
found in biologically and pharmacologically active compounds, natural compounds and
functional materials1,2. Among various quinazoline derivatives 4-amino quinazolines
drew less attention in finding their applications. There are only a limited number of
literature reports on biological activity of 4-amino-2-arylquinazoline derivatives.
However, from the known set of 4-amino quinazolines, it has been found that these
molecules are useful as fungicides3,4 and as anti-inflammatory5,6, anti-cancer7,8, anti-
microbial9,10 and anti-hypertensive agents11.
Despite the interest in pharmacological activity of 4-amino-2-aryl quinazolines
almost no general synthetic method has been reported. All the literature reports to
synthesize 4-amino-2-arylquinazolines follow classical methods12-15 involving ring
construction approach. Thus there is a need to improve the synthesis of these compounds
using modern synthetic methodologies.
Synthesis of quinazolines and finding their biological applications has been an
active area of research in our group. We developed different C-C and C-N bond forming
methods to construct quinazoline derivatives with therapeutic activity16,17,18. Direct
synthesis of substituted aryl compounds containing an unprotected NH2 group via
palladium- and nickel-catalysed cross-coupling strategy has been developed by different
research groups during the past two decades19,20. In this article we report a robust Suzuki-
Miyaura coupling procedure to obtain a variety of 2-aryl quinazolines with unprotected
2

NH2 group at 2-position of quinazoline by reacting 4-amino-2-chloro quinazolne with
aryl boronic acids. In 2005, Itoh et al, reported21 synthesis of hetero-biaryl compounds
containing an unprotected NH2 group via Suzuki-Miyaura reaction. To demonstrate the
applicability of their catalytic system 6,7-dimethoxy-3-phenylnaphthalen-1-amine was
synthesized as the only example of such kind. Apart from this one single report and to the
best of our knowledge, there is no other literature evidence to synthesize 2-aryl-4-amino
quinazolines following a direct catalytic method.
RESULTS AND DISCUSSION
Chemistry
In search of a suitable synthetic approach towards C-2 arylation of 4-
aminoquinazoline, we were interested in finding an optimised Suzuki coupling reaction
conditions. Itoh et. al, reported hetero-biaryl synthesis via Suzuki-Miyaura reaction. They
found that Pd(OAc)2/D-t-BPF catalyst is an applicable method for the cross-coupling of
NH2-unprotected hetero-aryl chlorides with phenylboronic acid21. We took the same
catalyst system as a bench mark reference to develop Suzuki-Miyaura cross-coupling of
4-amino-2-chloro quinazoline with different boronic acids. When we applied Itoh et. al,
conditions to react 2-chloro-6,7-dimethoxyquinazolin-4-amine (1) with phenyl boronic
acid, we observed complete conversion of starting material to provide the corresponding
product in 85% yield. However, under the same conditions, 1 reacted with naphthyl
boronic acid and thienylboronic acid only with 45% and 51% conversions respectively
(Table 1). Hence, optimisation of a suitable catalytic system, which can be applicable to
couple 4-amino-2-chloro quinazoline with a variety of boronic acids is required.
3

The effects of the catalyst, base, solvent, and temperature on the cross-coupling reaction
of 4-amino-2-chloro quinazoline with phenyl boronic acid are summarised in Table 2.
Initially a quick survey of catalysts: Pd(PPh3)4, Pd2(dba)3/S-Phos, Pd(OAc)2/CyJhon-
Phos, Pd-118, Pd(dcpf)Cl2 and Pd(amphos)2Cl2 revealed that the reaction is very
sensitive and the reactivity varies significantly from each catalyst. To understand the
sensitivity of the reaction to water, the same reaction was performed under aqueous and
non-aqueous conditions. Pd(PPh3)4 provided the product 5 with moderate yield (49%,
entry 1) under non-aqueous conditions and with poor yield (19%, entry 2) under aqueous
conditions. Hence all the subsequent reactions were performed only under non-aqueous
conditions. Pd2(dba)3/S-Phos, Pd(OAc)2/Cyjhon-Phos, Pd-118, Pd(dcpf)Cl2, and
Pd(amphos)2Cl2 provided product 2 with moderate yields 40%, 22%, 18%, 70% and 13%
respectively (entries 3 – 7). From these initial results we chose Pd(dcpf)Cl2 to study
further due to its easy handling.
Next, we examined the role of base (Table 3) by keeping 10 mol% Pd(dcpf)Cl2 loading. 3
equiv of K3PO4 provided 82% product (Entry 1). Whereas 3 equiv each of K2CO3 and
Cs2CO3 provided 59% and 70% product respectively (Entries 2 and 3). Thus, by keeping
the base (K3PO4), solvent (1,4-dioxane), temperature (100 °C) and reaction time (16 h)
fixed, we decided to optimise the catalyst loading. 1 mol% Pd(dcpf)Cl2 provided 22%
product with 52% of starting material remain unreacted (Entry 4). Upon increasing the
catalyst load to 4 mol%, 6 mol% and 8 mol% the yields improved to 64%, 74% and 92%
respectively (Entries 5, 6, 7). Increase of catalyst load more than 8 mol% found to have
4

no impact on the conversion as well as on the reaction rate. Thus, keeping the catalyst
load to 8 mol%, we changed the solvents to DME (Entry-8), THF (Entry-9) and THP
(Entry-10). However, the reaction seems to work better in 1,4-dioxane solvent.
After optimising the best reaction conditions for Suzuki coupling of 4-amino-2-chloro
quinazoline and phenyl boronic acid, we were interested to test the applicability of the
reaction conditions by coupling with different boronic acids (Table 4). 6,7-Dimethoxy-4-
amino-2-chloro quinazoline is coupled with variety of aryl boronic acids including bi-
phenyl, naphthyl, tolyl boronic acids to get the Suzuki products in 50% to 82% yields
(Entries 1-4). Substituents including methoxy, nitrile, ester, nitro, trimethyl silyl, trifluoro
methyl shows no effect on the reaction while being stable under these conditions (Entries
5-11). However, hetero aryl boronic acids provided mixed results. Indole, dibenzofuran,
thiophene and furan boronic acids provided 3n, 3o, 3c, and 3p in good to excellent yields
62%, 57%, 82% and 70% respectively (Entries 12-15), whereas pyridine and pyrimidine
boronic acids found not to couple with 1 under this condition (Entries 16-19). Alkyl
boronic acids aka isobutyl and cyclohexyl boronic acids did not react with 1 to provide
3v and 3w under this catalytic condition (Entries 21-22). However, methyl boronic acid
reacted with 1 to provide 3q with excellent yield (Entry 23).
Biology
The MIC is the lowest concentration of an antimicrobial, which inhibits microbial growth
and is a routine assay to determine antimicrobial property of test compounds by a
comparison with known antimicrobial agents. In this study, the antibacterial activity of all
5

the test compounds (3a-w) is measured against various Gram-positive and Gram-negative
bacteria and against fungi. The best antibacterial activity was shown by compound 3d
(Two fold and four fold less compound was required for inhibition of B. cereus over 3b
and 3l, respectively). Y. enterocolitica inhibition was observed at same concentration of
test compounds. Antifungal activity was best reported in case of test compound 3l (Two
fold and four fold lead compound was required for inhibition of C. albicans over 3b and
3d, respectively). The antifungal property of test compounds 3l (MIC = 31.25) and 3b
(MIC = 62.5) found to be better than standard antifungal agent ‘Miconazole’ (MIC =
>78.1). Antibacterial activity (MIC) of standard antibiotic ‘Ampicillin’ was better than all
test compounds and might need further modifications to make them more efficient
antibacterial agent. Results are shown in Table 5.
CONCLUSIONS
In summary we have developed a convenient Suzuki condition with 8 mol% Pd(dcpf)Cl2.
This catalyst performs the Suzuki coupling of a variety of boronic acids and quinazoline
with unprotected amino group. The conditions previously reported for similar Suzuki
coupling are not suitable for many aryl and hetero aryl boronic acids. Our modified,
robust, and simple protocol exhibits a broad substrate scope.
EXPERIMENTAL SECTION
Key starting materials and solvents were obtained from commercial sources and used
without further purification. 1H and 13C NMR spectra were recorded on either BRUKER
400 MHz or on VARIAN 300 MHz. NMR measurements were carried out in CDCl3 or
6

DMSO-d6 as NMR solvents. All chemical shifts were reported in parts per million (∂)
with reference to the signal of Si(CH3)4. High resolution mass spectrometry was
performed at the Mass Spectrometry Laboratory at GVK Biosciences Pvt Ltd.
General Procedure For Suzuki-Miyaura Coupling
Procedure For 2-Phenylquinazolin-4-Amine (5)
2-Chloroquinazolin-4-amine (4) (100 mg, 1.0 eq and 0.558 mmol), phenyl boronic acid
(150 mol%), and K3PO4 (300 mol%) in anhydrous 1,4-dioxane (4 mL) were added in a
dry screw-capped vial that was equipped with a stirring bar. The vial was flushed with
argon gas for a few minutes and [PdCl2(dcpf)] (0.08 eq, 8 mol%) was added. The vial
was sealed with a teflon-lined cap and the mixture was heated at 100 °C with stirring for
16h. The mixture was cooled; filter through celite pad, the solvent was evaporated under
reduced pressure and dried under high vacuum. Resulted crude compd was dissolved in
ethyl acetate, washed with water, brine solution and dried over anhydrous Na2SO4. The
organic layer was concentrated under reduced pressure. The crude product, which was
loaded into a silica column packed in CH2Cl2. Sequential elution with pet-ether, followed
by 2-5% MeOH in CH2Cl2, afforded 5 as off-white solid (Yield: 113 mg, 92%). Rf: (5%
MeOH in CH2Cl2) = 0.20; 1H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 8.1 Hz, 2H), 7.96
(d, J = 8.4 Hz, 1H), 7.79–7.73 (m, 2H), 7.49–7.44 (m, 4H), 5.66 (s, 2H), 13C NMR (100
MHz, CDCl3): δ 161.4, 160.9, 151.1, 138.6, 133.2, 130.1, 129.0, 128.4, 125.7, 121.5,
113.1, HRMS (ESI): m/z calcd for C14 H12 N3 [M + H]+ 222.1026; found 222.1025.
7

ACKNOWLEDGEMENTS
The authors are grateful to GVK Biosciences Pvt. Ltd., for the financial support and
infrastructure. We thank Dr. Sudhir Kumar Singh, President, Discovery and Development
Services, GVK Biosciences Pvt. Ltd., for his invaluable support and motivation.
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9

Table 1: Coupling of NH2-unprotected aminochloropyrimidines with phenylboronic acid
Entry
R
Product
Yield
1
45%
2
51%
10

Table 2: Suitable Pd-catalyst screening for coupling of NH2-unprotected
aminochloropyrimidines with phenylboronic acid
Entry Catalyst
Ligand
Base (3 equiv) Solvent
Yield
49%
19%
1
2
3
5 mol% Pd(PPh3)4
--
K3PO4
toluene
toluene
5 mol% Pd(PPh3)4
5 mol% Pd2(dba)3
--
2 M K3PO4
K3PO4
10 mol%
1,4-dioxane 40%
S-Phos
4
5 mol% Pd(OAc)2
10 mol% of
K3PO4
1,4-dioxane 22%
Cyjhon-Phos
5
6
7
5 mol% Pd-118
5 mol% Pd(dcpf)Cl2
10 mol%
--
--
--
Na2CO3
1,4-dioxane 18%
1,4-dioxane 70%
K3PO4
2M Na2CO3
toluene
13%
Pd(AMPHOS)2Cl2
11

Table 3: Optimisation of Pd-catalyst condition for coupling of NH2-unprotected
aminochloropyrimidines with phenylboronic acid
Entry
Catalyst
Base (3 equiv)
K3PO4
Solvent
Yield
82%
59%
70%
22%
64%
74%
92%
78%
66%
86%
1
2
3
4
5
6
7
8
9
10
10 mol% Pd(dcpf)Cl2
10 mol% Pd(dcpf)Cl2
10 mol% Pd(dcpf)Cl2
1 mol% Pd(dcpf)Cl2
4 mol% Pd(dcpf)Cl2
6 mol% Pd(dcpf)Cl2
8 mol% Pd(dcpf)Cl2
8 mol% Pd(dcpf)Cl2
8 mol% Pd(dcpf)Cl2
8 mol% Pd(dcpf)Cl2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DME
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
K3PO4
THP
12

Table 4: Application of Pd-catalysis condition for coupling of NH2-unprotected
aminochloropyrimidines with phenylboronic acid
Entry
1
R
Product
Yield
70%
2
3
70%
50%
4
5
82%
96%
6
73%
13

7
45%
8
9
62%
95%
10
11
12
13
54%
79%
62%
57%
14
82%
14

15
16
70%
NA
17
18
NA
NA
19
NA
NA
20
21
22
NA
85%
15

Table 5: Antibacterial nature of 3b, 3d and 3l
Compound Code/Name
Concentration (µg/mL)
B. cereus
>500
>250
>125
-
E. coli
>125
>250
>125
-
Y. enterocolitica
C. albicans
>31.25
>62.5
>125
3l
>125
>125
>125
-
3b
3d
>78.1
-
Miconazole
Ampicillin
>39
>78.1
>39
16