SNAr reaction in aqueous medium in the presence of mixed organic and inorganic bases

Article abstract of DOI:10.1039/c5ra03510d

N-Arylation of amines with fluorobenzonitriles in aqueous medium is described. A mixture of N,N-diisopropylethyl amine and Na₂CO₃ (1:1) is found to achieve maximum conversion by refluxing for 3 hours in water. The product can be easily isolated by solvent extraction.

Full text of DOI:10.1039/c5ra03510d

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SNAr reaction in aqueous medium in the presence
of mixed organic and inorganic bases†
Cite this: RSC Adv., 2015, 5, 31226
a
a
a
b
a
*
Nilesh B. Shelke, Ramrao Ghorpade, Ajay Pratap, Vijay Tak and B. N. Acharya
Received 26th February 2015
Accepted 25th March 2015
DOI: 10.1039/c5ra03510d
www.rsc.org/advances
N-Arylation of amines with fluorobenzonitriles in aqueous medium is quinazolones are bioactive molecules also part of various
described. A mixture of N,N-diisopropylethyl amine and Na2CO3 (1 : 1) natural products and drugs.7 Among the quinazolines, 2,4-dia-
is found to achieve maximum conversion by refluxing for 3 hours in minoquinazolines are very important pharmacophore present
water. The product can be easily isolated by solvent extraction.
in many marketed drugs such as prazosin,8a methotrexate,8b
trimetrexate,8c and piritrexim.8d They have shown signicant
biological activities such as anticancer,9a SMN2 promoter,9b
dihydrofolate reductase (DHFR) inhibitor,9c kinase inhibitor
and opioid receptor like-1 (ORL1) antagonists.9d
Traditionally, 2,4-diaminoquinazolines are synthesized by
reacting 2-uorobenzonitrile with guanidine carbonate at
elevated temperature via aromatic SNAr reaction.10 Alternatively,
they can also be synthesized by Cu-catalyzed Ullmann type
N-arylation of 2-bromobenzonitrile with guanidine.11
The reaction was optimized using 2-uorobenzonitrile as
substrate and guanidine carbonate as nucleophile. The rst
reaction was carried out with reference to a reported method in
N,N-dimethylacetamide (DMA) at reux condition with
moderate yield12 (Table 1, entry a). With the introduction of a
base, the yield of the reaction improved signicantly (entry b).
However this reaction was not feasible at lower temperature
(entry c). Several inorganic and organic bases were tried at
elevated temperature from which Na2CO3 and diisopropyle-
thylamine (DIPEA) were found to give good yield. Reaction in
presence of DIPEA was carried out at 125 ꢀC. The yield was
found slightly less than the same reaction carried out in pres-
ence of Na2CO3 (entry l). Then we thought to use a mixture of
Na2CO3 and DIPEA in order to see the effect on yield (entry m to
q). A very signicant improvement in yield was observed when
both the bases were used in 1 : 1 mole ratio (entry o). With this
encouraging result, we tried to explore the greener aspect of this
reaction by replacing DMA with water. To our disappointment
the reaction didn't proceed even at reux condition (entry r).
The reason may be attributed to the very high water solubility of
guanidine carbonate and poor water solubility of 2-uo-
robenzonitrile. This solubility difference may keep these two
reactants in immiscible phases due to which the reaction didn't
occur at all even in presence of tetrabutylammoniumbromide
(TBAB), a phase transfer catalyst (PTC).
N-Arylation of amines is an important C–N bond forming
process in pharmaceutical research.1 Usually these compounds
are synthesized via aromatic nucleophilic substitution reaction
(SNAr) of amines2 with aryl halides or via transition metal
mediated cross-coupling reaction.3 Transition metal catalyzed
N-arylation has some drawbacks in industrial applications as
the metal catalysts are expensive, oxygen sensitive, and toxic.
Hence metal catalyst free SNAr should be the reaction of choice.
But electron rich aromatic compounds are generally unreactive
toward nucleophilic substitution. Hence electron poor aryl
electrophiles with one or more strong electron withdrawing
groups have been the substrates of choice.4a–f Fluorobenzoni-
triles are widely used substrates for SNAr, but reported methods
have several draw backs including low yield, use of high boiling
organic solvents and reaction at elevated temperature.4g–i In our
recent attempts to develop new green protocols5 and to improve
arylation of amines,6 we used mixed organic and inorganic
bases for SNAr reaction. Herein we describe a simple, high
yielding, metal catalyst free N-arylation reaction in water in
which uorine is replaced from uorobenzonitriles by using
mixed organic and inorganic bases in presence of a phase
transfer catalyst (PTC).
During the course of our ongoing research activity on
bioactive compounds, we were exploring suitable protocols to
synthesize
2,4-diaminoquinazolines.
Quinazolines
and
aProcess Technology Development Division, Defence R & D Establishment, Jhansi Road,
Gwalior-474002, MP, India. E-mail: bnacharya@drde.drdo.in; bnacharya@yahoo.
com
bVertox Laboratory, Defence R & D Establishment, Jhansi Road, Gwalior-474002, MP,
India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra03510d
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Table 1 Varying reaction conditions for quinazoline synthesisa
To check the feasibility of above protocol for SNAr, a batch
reaction was carried out in water using 2-uorobenzonitrile as
substrate and piperidine as nucleophile in place of guanidine
carbonate. Around 40% yield was observed (Table 2, entry a).
When the same reaction was carried out in DMA at 100 ꢀC
surprisingly 88% yield was recorded (entry b). Choices of
solvent and base are crucial for catalyst free SNAr reactions.
Both the reactants are insoluble in water while both Na2CO3
and DIPEA are highly water soluble. Probably they are not
available in the reaction due to phase separation. All the
reactants and bases are soluble in DMA which is leading for a
very good conversion. With the introduction of TBAB, a
signicant improvement in yield was observed in water (entry
c and d). Couple of reactions were carried out with reference
to a reported method in DMA by using Cs2CO3 as base.2a
Moderate yield of product was observed (entry e). As the
Reactn
code
Inorganic base
(mol%)
Organic base
(mol%)
Temp.
(ꢀC)
Time
(hrs)
Yieldb
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
rc
0
140
140
60
140
140
60
100
140
140
125
125
125
125
125
125
125
125
100
8
8
8
8
8
8
8
8
8
8
8
8
3
3
3
3
3
8
37
72
0
25
55
0
Na2CO3 (100)
Na2CO3 (100)
K2CO3 (100)
NaHCO3 (100)
DBU (100)
DBU (100)
DBU (100)
DBN (100)
TEA (100)
DIPEA (100)
0
31
22
0
reaction was carried out in
a conventional laboratory
assembled reactor, some part of piperidine (bp 106 ꢀC) might
have been lost to give moderate yield (entry e). At lower
temperature the yield was found even lower (entry f). Most
63
10
45
48
79
63
55
0
Na2CO3 (100)
Na2CO3 (90)
Na2CO3 (70)
Na2CO3 (50)
Na2CO3 (30)
Na2CO3 (10)
Na2CO3 (50)
DIPEA (10)
DIPEA (30)
DIPEA (50)
DIPEA (70)
DIPEA (90)
DIPEA (50)
Table 3 Synthesis of 2,4-diaminoquinazolinesa
a
Reaction conditions: 2-uorobenzonitrile (1 mmol), guanidine
carbonate (1 mmol), base (2 equiv.; organic/inorganic), DMA (3 mL),
reaction time
3
h. DMA: N,N-dimethylacetamide, DIPEA:
diisopropylethylamine, DBU: 1,8-diazabicyclo[5.4.0]undec-8-ene, DBN:
b
1,5-diazabicyclo[4.3.0]non-5-ene, TEA: triethylamine. Isolated yield.
c
Reaction medium: water.
Entry
a
ArX (1)
Product (3)
Yieldb
79
Table 2 Varying reaction conditions for SNAr reactiona
b
88
c
52
48
25
Temp.
(ꢀC)
Organic
base
Inorganic
base
TBAB
(mol%)
Yieldb
[%]
Entry
Solvent
a
b
c
d
e
f
Water
DMA
Water
Water
DMA
100
100
100
100
140
100
100
100
30
DIPEA
DIPEA
DIPEA
DIPEA
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
Cs2CO3
0
0
5
10
0
0
10
10
10
10
10
10
40
88
66
83
61
35
40
30
0
d
e
DMA
g
h
i
j
k
l
Water
Water
Water
Water
Water
Water
DIPEA
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
f
44
19
DIPEA
DBU
DBN
TEA
100
100
100
65
58
71
g
a
Reaction conditions: 2-uorobenzonitrile (1 mmol), piperidine
(1 mmol), base (2 equiv.; organic/inorganic 1 : 1), solvent (3 mL),
reaction time
diisopropylethylamine, DBU: 1,8-diazabicyclo[5.4.0]undec-8-ene, DBN:
1,5-diazabicyclo[4.3.0]non-5-ene, TEA: triethylamine, TBAB:
tetrabutylammoniumbromide. b Isolated yield.
3
h. DMA: N,N-dimethylacetamide, DIPEA:
a
Protocol 1: 2-uorobenzonitrile (1 mmol), guanidine carbonate
(1 mmol), base (2 equiv.; DIPEA/Na2CO3 1 : 1), solvent DMA (3 mL),
reaction time 3 h at 125 ꢀC.15 DMA: N,N-dimethylacetamide, DIPEA:
diisopropylethylamine. b Isolated yield.
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interestingly yield was reduced, when the reaction was carried and are presented in Tables 3 and 4 respectively. As shown in
out in absence of either inorganic (entry g) or organic base the Table 3, the desired 2,4-diaminoquinazolines were obtained
(entry h). This indicated that both organic and inorganic in good to excellent yields (entries a–e). The protocol is not
bases are required whether the reaction was carried out either found effective for 2-chlorobenzonitrile (entry g).
in DMA or in water. No conversion was observed when the
Protocol 2 was carried out in water to check the feasibility of
reaction was carried out at room temperature (entry i). the green aspect. Various substrates including uorobenzoni-
Organic bases like DBU, DBN, and TEA also showed triles, dinitrochlorobenzene. Excellent yields were recorded in
promising yields (entries j and k) but DIPEA gave maximum all cases (Table 4, entries a–e). Incase of uoroquinazolines no
yield among them.
conversion was observed.
From these optimization experiments we have standardized
Excellent yield for 2,4-dinitrochlorobenzene was also
two protocols for the synthesis of 2,4-diaminoquinazolines observed (entry f). 2,5-Diurobenzonitrile (entry g) showed good
(protocol 1, Table 3) and derivatization of uorobenzonitriles conversion only aer extended reaction time. This shows pres-
(protocol 2, Table 4). The latter one can be carried out in both ence of electron withdrawing groups at 2 and 4 position are
DMA and water. To study the general applicability of the present benecial where as at 5 position it is not benecial for product
developed methods, the standardized reaction conditions were yield. This indicates that the reaction mechanism is following
attempted with different halobenzonitriles with various amines
Table 4 Arylation of amines with fluorobenzonitrilesa
Entry
a
ArX (1)
Amine (2)
Time
3
Yieldb
83
b
(2a)
3
87
c
(2a)
(2a)
3
3
82
76
d
Scheme 1
e
(2a)
3
81
f
(2a)
(2a)
3
8
79
75
g
h
i
(1a)
(1b)
3
5
85
79
j
(1b)
3
72
a
Protocol 2: 2-uorobenzonitrile (1 mmol), piperidine (1 mmol), base
Fig.
1
Relative energy of starting material, transition states and
(2 equiv.; DIPEA/Na2CO3 1 : 1), water (3 mL), TBAB 10 mol%, reaction
b
time 3 h at reux.16 Isolated yield.
intermediates with respect to products in presence (solid line) and
absence (dotted line) of DIPEA.
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SNAr pathway. Other nitrogen containing nucleophiles also
witnessed good yield with this protocol (entries h to j). The
products were isolated by simple solvent extraction with ethyl-
acetate and puried by ash chromatography.
The most important nding of this study is the effect of the
mixture of organic and inorganic bases on yield. A plausible
mechanism is attempted in Scheme 1 on the basis of experi-
mental observations, semiempirical calculations and literature
report.13
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2-Fluorobenzonitrile and piperidine react with each other to
form a transition state (TS1) in the organic phase. TBAB helps
the transport of amine (piperidine) as well as DIPEA from
aqueous phase to organic phase and thus plays a signicant role
to enhance the rate of reaction. TS1 converts to an intermediate
(IM) aer migration of hydrogen from amine to nitrile group. At
the same time the organic base DIPEA forms a strong hydrogen
bonding with the intermediate and forms another transition
state (TS2). The energy of transition state in presence and
absence of DIPEA was calculated by semiempirical method AM1
(Fig. 1).14 Transition state 2 (TS2) and IM are stabilized by
DIPEA. The difference in transition state energy of TS2 clearly
indicates the involvement of DIPEA for facilitation of the reac-
tion. This was also reected in the % yield of product (Table 2,
entry d and entry h). As uorine is a better leaving group in SNAr
reaction, it leaves the ring with pair of electron. Simultaneously
base abstracts the hydrogen and a pair of electron is available to
satisfy aromaticity. The product remains in the organic phase
and the uoride anion is sequestered out from the organic
phase to aqueous phase by the cation of DIPEA. The organic
base was regenerated in aqueous phase by the inorganic base
Na2CO3 and again comes to organic phase. Thus the mixture of
organic and inorganic bases enhances the yield through above
mechanism.
From this study we may conclude that a mixed organic and
inorganic base system is useful to achieve better yield in
N-arylation of amine through SNAr mechanism. The reaction
may be carried out in aqueous medium. The inorganic base will
remain in the aqueous phase to regenerate the organic base due
to which the yield will increase.
M.
Graffner-Nordberg,
K.
Kolmodin,
J.
Aqvist,
Acknowledgements
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We thank Director, DRDE, Gwalior for his keen interest and
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0.001 mole of Na2CO3. Reaction was carried out at 125 ꢀC
in an oil bath. Aer 3 hours, reaction was stopped by
cooling the reaction mixture. The product was precipitated
out by adding 1 mL dicloromethane followed by excess
hexane on an ice bath. Precipitates were separated, washed
with 3 mL water and recrystalized from methanol to achive
the pure product.
12 B. Chao, X.-K. Tong, W. Tang, D.-W. Li, P.-L. He, J.-M. Garcia,
L.-M. Zeng, A.-H. Gao, L. Yang, J. Li, F.-J. Nan, M. Jacobs,
R. Altmeyer, J.-P. Zuo and Y.-H. Hu, J. Med. Chem., 2012, 16 General procedure for protocol 2: synthesis of 2-
55, 3135.
piperidinylbenzonitrile: in a round bottom ask add 3 mL
water, 0.001 mole of 2-uorobenzonitrile, 0.001 mole of
piperidine, 0.001 mole of N,N-diisopropylethylamine
(DIPEA), 0.0001 mole of tetrabutylammoniumbromide
(TBAB) and 0.001 mole of Na2CO3. Reaction was carried
out at reux for 3 hours. Then reaction mixture was cooled
and extracted with ethyl acetate. The products were
puried by ash chromatography on silica by using
hexane–ethylacetate mobile phase.
13 X. Wang, E. J. Salaski, D. M. Berger and D. Powell, Org. Lett.,
2009, 11, 5662.
14 Spectral data and AM1 calculation availabe in ESI.†
15 General procedure for protocol 1: synthesis of 2,4-
diaminoquinazoline: in a round bottom ask add 3 mL
N,N-dimethylacetamide (DMA), 0.001 mole of 2-
uorobenzonitrile, 0.001 mole of guanidine carbonate,
0.001 mole of N,N-diisopropylethylamine (DIPEA) and
31230 | RSC Adv., 2015, 5, 31226–31230
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