Efficient nucleophilic substitution reaction of aryl halides with amino acids under focused microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(00)00739-0

The nucleophilic substitution reaction of 2,4-dinitrofluorobenzene with amino acids was complete, under microwave iradiation, within 40 s with yields up to 93%, which are far superior to those obtained under conventional heating. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00739-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8287±8289
Ef®cient Nucleophilic Substitution Reaction of Aryl Halides with
Amino Acids Under Focused Microwave Irradiation
*
Yie-Jia Cherng
Department of Medical Technology, Chung-Tai Institute of Health Science and Technology, Taichung 40605, Taiwan, ROC
Received 4 April 2000; revised 16 August 2000; accepted 17 August 2000
AbstractÐThe nucleophilic substitution reaction of 2,4-dinitro¯uorobenzene with amino acids was complete, under microwave iradiation,
within 40 s with yields up to 93%, which are far superior to those obtained under conventional heating. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
in a monomode microwave reactor (Synthewave 402) for
20 min at 1008C. Unfortunately, no desired product was
detected. We reasoned that the lack of reactivity might be
due to the zwitterionic nature of the amino acid. Therefore,
two equivalents of sodium bicarbonate were added in order
to free the amino group which should increase the nucleo-
philicity of the reactant. Excellent yields (91±93%) of the
N-arylated amino acids were produced under microwave
irradiation at 808C in only 35±40 s (Scheme 1). Our results
are summarized in Table 1.
Aryl halides are characterized by low reactivity toward
nucleophilic reagents like OH2, OR2, NH3, and CN2 that
play an important part in the chemistry of aliphatic-halides.1
Therefore, nucleophilic aromatic substitution is less used in
synthesis than either nucleophilic aliphatic substitution or
electrophilic aromatic substitution.2 The reactivity of aryl
halides is greatly improved by electron-withdrawing groups
such as NO2, ortho and/or para to the aryl halides, however,
long reaction times or vigorous conditions are required to
achieve acceptable yields under conventional heating. The
application of microwaves in promoting organic reactions
has received intense attention recently.3 We wanted to deter-
mine whether the reaction rate of nucleophilic aromatic
substitution can be accelerated under microwave irradiation.
We report herein our studies on the microwave-promoted
reaction of a-amino acids with 2,4-dinitrohalo-benzenes.
To compare the ef®cacy of microwave irradiation with those
of conventional heating, the reaction was heated in an oil
bath (958C bath temperature) for 60 s. No desired product
was detected under these conditions. The results suggested
that improved yields may be due to microwave effect
instead of heating ef®ciency.5
Table 1. Reaction of 2,4-dinitro-1-¯uorobenzene and aminoacids
Results and Discussion
Entry
R
Con®g
Time (s)
Yield (%)
2,4-Dinitro¯uorobenzene (Sanger's reagent) has been used
widely to react with the amino group of amino acids to
afford N-aryl a-amino acids.4 The reaction usually requires
several hours at room temperature to give a satisfactory
yield. In an attempt to develop a more ef®cient process,
glycine was reacted with 2,4-dinitro¯uorobenzene in water
1
2
3
4
5
6
H
Me
i-Pr
i-Bu
Ph
PhCH2
35
35
35
40
35
35
92
93
92
91
93
93
S
S
S
R
S
Scheme 1.
Keywords: microwave irradiation; nucleophilic aromatic substitution.
* Tel.: 1886-4-291647, ext. 1912; fax: 1886-4-2393305; e-mail: yjcherng@chtai.ctc.edu.tw
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00739-0

8288
Y.-J. Cherng / Tetrahedron 56 (2000) 8287±8289
Scheme 2.
Table 2. Reaction of 2,4-dinitro-1-chlorobenzene and aminoacids
under microwave irradiation to achieve high yields in very
short reaction time. Furthermore, our reaction conditions
only required water as the solvent which is more environ-
mentally friendly.
Entry
R
Con®g
Time (min)
Yield (%)
1
2
3
4
5
6
H
Me
i-Pr
i-Bu
Ph
PhCH2
6
7
8
9
7
7
64
60
58
55
61
60
S
S
S
R
S
Experimental
Melting points are uncorrected. Infrared spectra were taken
in KBr solid. 1H NMR (Me4Si as internal standard) and 13
C
NMR (CD3COCD3 at 205.4 ppm as internal standard)
spectra were measured in deuteroacetone solutions on a
Varian Mercury 400. Reactions were monitored by analyti-
cal thin-layer chromatography using silica gel 60 F-254,
layer thickness 0.2 mm. Flash chromatography was carried
out utilizing silica gel 60, 70±230 mesh ASTM. The
Synthewave 402e monomode microwave reactor was
purchased from Prolabo Co.
Table 3. Reaction of 2,4-dinitro-1-bromobenzene and aminoacids
Entry
R
Con®g
Time (min)
Yield (%)
1
2
3
4
5
6
H
Me
i-Pr
i-Bu
Ph
PhCH2
10
11
13
15
11
11
60
57
53
48
56
55
S
S
S
R
S
General procedure for reaction of amino acid and
2,4-dinitrohalobenzene
The in¯uence of the halogen on the ef®ciency of the sub-
stitution reaction was investigated by treating 2,4-dinitro-
chlorobenzene and 2,4-dinitrobromobenzene with amino
acids (Scheme 2). Under SN2 conditions, enhanced reac-
tivity of chloride and bromide over that of the ¯uoride is
expected since they are better leaving groups than the latter.
However, our results revealed that longer reaction times
were required (up to 26 times) to obtain inferior chemical
yields to those of the corresponding ¯uoride (Tables 2 and
3). The order of the reaction yields (F.Cl.Br) suggested
that an SNAr mechanism is operating in which the rate
determining step of the reaction is the attack of the substrate
by the nucleophile that is strongly favored by less hindered
and more electronegative ¯uoride.6 These results are con-
sistent with the literature and that the microwave gives the
same effect and conventional heating, i.e. the ¯uorobenzene
reacts more quickly than the chloro- or bromobenzene.
To a quartz reaction vessel (12 mL) was added a solution of
amino acid (0.3 mmol) and sodium bicarbonate (0.6 mmol,
2 equiv.) in H2O (2 mL) followed by 2,4-dinitrohaloben-
zene (0.3 mmol). The reaction vessel was then placed into
the cavity of a focused monomode microwave reactor
(Synthewave 402) and irradiated for the period listed in
the tables. The reaction temperature was kept by modulating
the power level of the reactor. The desired product precipi-
tates after the addition of 2N HCl (1 mL) to the reaction
mixture. The yellow N-arylated amino acid, collected via
®ltration and washed with water (1 mL£2), required no
further puri®cation to pass elemental analysis. Then was
puri®ed by recrystallization.
N(2,4-Dinitrophenyl)-(s)-glycine. Solid; mp 201±2028C;
IR (KBr) 3355 (NH), 3106 (OH), 1716 (CvO), 1523,
1
1342 cm21; H NMR (400 MHz) 9.01 (d, Jˆ2.8 Hz, 1H),
The yields of the reaction decrease slightly as the steric
bulkness of the side chain on the amino acid increases
from alanine, valine to leucine (Table 1, entries 2±4).
This steric effect is more profound with the less reactive
chloride and the bromide (entries 2±4 of Tables 2 and 3)
presumably as a result of decreasing electronegtivities and
increasing steric demands of the halides.
8.33 (dd, Jˆ9.6, 2.8 Hz, 1H), 7.20 (d, Jˆ9.6 Hz, 1H), 4.46
(m, 2H); 13C NMR (100 MHz) 170.09, 148.55, 137.00,
131.42, 130.62, 124.05, 116.19, 45.13; MS m/z (rel
intensity) 241 (27, M1), 196 (100); Anal. calcd for
C8H7N3O6: C, 39.84; H, 3.93; N, 17.42. Found: C, 39.20;
H, 3.61; N, 17.48.
These results are consistent with the literature and that the
microwaves give the same effect as conventional heating,
i.e. the ¯uorobenzene reacts more quickly than the bromo or
chlorobenzene.
N(2,4-Dinitrophenyl)-(s)-alanine. Solid; mp 173±1748C;
[a]2D5ˆ214.1 (cˆ1.0, acetone); IR (KBr) 3350 (NH),
3114 (OH), 1715 (CvO), 1504, 1361 cm21 1H NMR
;
(400 MHz) 9.01 (d, Jˆ2.8 Hz, 1H), 8.34 (dd, Jˆ9.6,
2.8 Hz, 1H),7.26 (d, Jˆ9.6 Hz, 1H), 4.78 (m, 1H); 1.66
(d, Jˆ7.2 Hz, 3H), 13C NMR (100 MHz) 173.1, 147.89,
137.04, 131.64, 130.85, 124.33, 116.06, 52.05, 18.60; MS
m/z (rel intensity) 255 (16, M1), 210 (100); Anal. calcd for
C9H9N3O6: C, 42.36; H, 3.55; N, 16.47. Found: C, 42.45; H,
3.11; N, 16.93.
Conclusion
We have established an extremely ef®cient substitution
reaction of an aryl ¯uoride by a nitrogen nucleophile

Y.-J. Cherng / Tetrahedron 56 (2000) 8287±8289
8289
N(2,4-Dinitrophenyl)-(s)-valine. Solid; mp 127±1288C;
Acknowledgements
[a]2D5ˆ261.8 (cˆ1.2, acetone); IR (KBr) 3336 (NH),
3110 (OH), 1747 (CvO), 1523, 1340 cm21 1H NMR
;
Yie-Jia Cherng would like to thank Professor Ta-Jung Lu of
Department of Chemistry, National Chung-Hsing Uni-
versity, Taichung, Taiwan, Republic of China for sugges-
tions and discussions. Facility support of the Department of
Chemistry, National Chung-Hsing University is greatly
appreciated.
(400 MHz) 9.02 (d, Jˆ2.8 Hz, 1H), 8.32 (dd, Jˆ9.6,
2.8 Hz, 1H), 7.27 (d, Jˆ9.6 Hz, 1H), 4.61 (dd, Jˆ8.0,
4.4 Hz, 1H), 2.44 (m, 1H), 1.16 (d, Jˆ6.8 Hz, 3H), 1.08
(d, Jˆ6.8 Hz, 3H); 13C NMR (100 MHz) 171.62, 148.60,
137.01, 131.64, 130.81, 124.30, 116.05, 61.53, 32.04,
18.93, 18.49; MS m/z (rel intensity) 283 (17, M1), 240
(15) 238 (100); Anal. calcd for C11H13N3O6: C, 46.65; H,
4.63; N, 14.84. Found: C, 46.17; H, 4.87; N, 14.71.
References
N(2,4-Dinitrophenyl)-(s)-leucine. Solid; mp 90±918C;
[a]2D5ˆ245.3 (cˆ1.0, acetone); IR (KBr) 3347 (NH),
3080 (OH), 1719 (CvO), 1518, 1337 cm21 1H NMR
;
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(400 MHz, acetone) 9.01 (d, Jˆ2.8 Hz, 1H), 8.34 (dd,
Jˆ9.6, 2.8 Hz, 1H), 7.24 (d, Jˆ9.6 Hz, 1H), 4.67 (m, 1H);
2.05 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H), 1.04 (d, Jˆ6.4 Hz,
3H), 0.96 (d, Jˆ6.4 Hz, 3H); 13C NMR (100 MHz, acetone)
172.74, 148.39, 137.39, 131.1, 130.92, 124.33, 124.31,
115.99, 55.38, 41.70, 25.97, 23.14, 22.72; MS m/z (rel
intensity) 27 (21, M1), 252 (100); Anal. calcd for
C12H15N3O6: C, 48.4; H, 5.09; N, 14.14. Found: C, 48.14;
H, 4.42; N, 14.66.
N(2,4-Dinitrophenyl)-(R)-phenylglycine. Solid; mp 203±
2048C; [a]2D5ˆ1183.3 (cˆ1.0, acetone); IR (KBr) 3329
(NH), 3095 (OH), 1726 (CvO), 1523, 1337 cm21 1H
;
NMR (400 MHz) 8.74 (s, 1H), 7.95 (d, Jˆ8.8 Hz, 1H),
7.51±7.15 (m, 5H), 6.66 (d, Jˆ8.8 Hz, 1H); 5.30 (s, 1H);
13C NMR (100 MHz) 172.74, 148.39, 137.39, 131.1,
130.92, 124.33, 124.31, 115.99, 55.38, 41.70, 25.97,
23.14, 22.72; MS m/z (rel intensity) 317 (2, M1), 77
(100); Anal. calcd for C14H11N3O6: C, 53.00; H, 3.49; N,
13.25. Found: C, 53.52; H, 3.26; N, 13.83.
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N(2,4-Dinitrophenyl)-(s)-phenylalnine. Solid; mp185±
1868C; [a]2D5ˆ2103.0 (cˆ1.0, acetone); IR (KBr) 3324
(NH), 3109 (OH), 1748 (CvO), 1521, 1370 cm21 1H
;
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NMR (400 MHz, acetone) 8.98 (d, Jˆ3.2 Hz, 1H), 8.27
(dd, Jˆ9.6, 3.2 Hz, 1H),7.28±7.27 (m, 5H), 7.23 (d,
Jˆ9.6 Hz, 1H) 5.05 (t, Jˆ5.8 Hz, 1H); 3.46 (dd, Jˆ14.0,
5.6 Hz, 1H), 3.36 (dd, Jˆ14.0, 5.6 Hz, 1H); 13C NMR
(100 MHz, acetone) 171.22, 147.61, 136.78, 136.3 131.20,
130.38 2c), 129.02, 127.66, 123.95, 115.82, 57.04, 38.00;
MS m/z (rel intensity) 331 (3, M1), 240 (100); Anal. calcd
for C15H13N3O6: C, 54.38; H, 3.6; N, 12.68. Found: C,
54.42; H, 3.40; N, 12.706.