Efficient synthesis of novel 3-(het)arylanthranilic acids via a suzuki cross-coupling reaction of 7-iodoisatin with (het)arylboronic acids in water

Full text of DOI:10.1021/jo991948i

J . Org. Chem. 2000, 65, 4193-4194
4193
Sch em e 1
Efficien t Syn th esis of Novel
3-(Het)a r yla n th r a n ilic Acid s via a Su zu k i
Cr oss-Cou p lin g Rea ction of 7-Iod oisa tin
w ith (Het)a r ylbor on ic Acid s in Wa ter
Vincent Lisowski,† Max Robba,‡ and Sylvain Rault*,†
Centre d’Etudes et de Recherche sur le Me´dicament de
Normandie, UFR des Sciences Pharmaceutiques, 5, rue
Vaube´nard, 14032 Caen Cedex, France, and SYNTHEVAL
S.A., Esplanade de la Paix, Universite´ de Caen, 14032 Caen
Cedex, France
Received December 20, 1999
In contrast with anthranilic acid derivatives, which
have been extensively used as building blocks in medici-
nal chemistry, few studies have addressed their biphenyl
analogues. In looking for novel and versatile scaffolds,
of use in combinatorial chemistry, we focused on the
synthesis of 3-arylanthranilic acids of type 2. An in depth
survey of the literature shows only one description of
3-phenylanthranilic acid itself (2, R ) H) obtained as a
byproduct of ammonolysis of phenyloxazepinone,1 one
recent synthesis of 2 (R ) H) via isatin 3 (R ) H),2
and one palladium-catalyzed cross-coupling of mono-
organozinc halides with 3-iodoanthranilonitriles.3 This
situation prompted us to investigate a general method
to prepare compounds of type 2 based on the development
of Suzuki-type cross-coupling reactions.4
boronic acids. Unexpectedly our first results indicated
clearly that the cross-coupling was gradually effective,
but as might have been anticipated, it was concomitant
with the cleavage of the isatin ring, leading to an
unworkable mixture at the end of the reaction.
These observations prompted us to study in depth the
experimental conditions of this cross-coupling reaction.
A long-lasting reaction (more than 40 h at reflux tem-
perature in DME) was the major deleterious fact; we tried
to shorten this reaction time by modifying the nature of
the base (NaHCO3, TEA, NaOH), as well as the type and
the quantity of Pd(0) catalyst (5-20%), but none of these
modifications was efficient. To improve the reactivity of
the partners, we increased the solubility by adding more
water, until a highly diluted and homogeneous reaction
mixture was obtained.6 These modifications allowed a
rapid coupling reaction without cleavage of the iodoisatin
6, and finally, the optimal conditions were found to be 6,
1 mmol; ArB(OH)2, 1.1 equiv; NaHCO3, 2 equiv; Pd-
(PPh3)4, 0.05 equiv; DME/H2O v/v, 60 mL; 85 °C; 5 h to
give arylisatins 3a -f with 55-70% yield. Oxidative
cleavage of 3 was then readily performed in an alkaline
medium in the presence of hydrogen peroxide to give the
desired anthranilic acid 2a -f in a 70-75% yield.7
In conclusion, the methodology we have developed
allows the chemistry of arylisatins and arylanthranilic
acids. The presence of an aromatic substitution fails to
alter the reactivity of the anthranilic moiety, and for
example, reactive species such as 8-arylisatoic anhydrides
or 3-aryl-2-aminophe´nylglyoxylic acids were readily ob-
tained following standard methods8 and will be published
elsewhere.
Resu lts a n d Discu ssion
At the initiation of this project, three routes were
envisaged starting from 2-iodoaniline, as depicted in
Scheme 1.
The first, route A, was a cross-coupling reaction of
o-iodoaniline with various boronic acids, followed by
cyclization of isatin and oxidative cleavage of this latter
according to the method previously described by Marvel
and Hiers.5 This route was unsatisfactory. Although the
first step gave reasonable results, the second failed
totally, and in our hands, no cyclization of isatin occurred
with substituted biphenylamine 4.
The second, route B, was the synthesis of 3-iodoan-
thranilic acid 5, via 7-iodoisatin 6, and a cross-coupling
reaction at the final step. While the hitherto unknown 5
was prepared with a reasonable yield (30% from 2-io-
doaniline), the cross-coupling reaction was completely
ineffective; the unprotected amino acid was always
recovered unchanged at the end of the reaction. On the
basis of the above and considering 7-iodoisatin 6 as a
biprotected precursor of anthranilic acid, we investigated
the route C (the most improbable as a result of the
fragility of isatins), the cross-coupling reaction of 6 with
† Centre d’Etudes et de Recherche sur le Me´dicament de Normandie.
‡ SYNTHEVAL S.A..
(1) Troshchenko, A. T.; Lobanova, T. P. Russ. J . Org. Chem. 1967,
3, 480; Zh. Org. Khim. 1967, 3, 501.
(2) Batt, D. G.; J ones, D. G.; Greca, S. J . Org. Chem. 1991, 56, 6704-
6708.
(6) Beletskaya, I. P.; Cheprakov, A. V. In Organic Synthesis in
Water; Blackie A&P Thomson Sciences: London, 1998; pp 141-222
(200 refs).
(7) Baker, B. R.; Shaub, R. E.; J oseph, J . P.; McEvoy, F. J .; Williams,
J . H. J . Org. Chem. 1952, 17, 141 and 164-176.
(8) Coppola, G. M. Synthesis 1980, 505-536 (213 refs).
(3) Campbell, J . B.; Firor, J . W.; Davenport, T. W. Synth. Commun.
1989, 19, 2265-2272.
(4) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(5) Marvel, C. S.; Hiers, G. S. Organic Syntheses; Wiley: New York,
1932, Collect. Vol. 1, pp 327-330.
10.1021/jo991948i CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/26/2000

4194 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
7-(F u r -2-yl)isa tin (3d ): red solid, 65%, mp 220 °C; 1H NMR
(CDCl3) δ 8.88 (br s, 1H), 7.74 (d, J ) 7.8 Hz, 1H), 7.59 (s, 1H),
7.55 (d, J ) 7.2 Hz, 1H), 7.15 (m, 1H), 6.77 (m, 1H), 6.58 (m,
1H); IR (KBr)λmax 3246 (NH), 1741 (CO), 1739 (CO). Anal. Calcd
for C12H7N1O3: C, 67.60; H, 3.30; N, 6.57. Found: C, 67.42; H,
3.11; N, 6.35.
7-(Th ien -2-yl)isa tin (3e): orange solid, 65%, mp 170-171
°C; 1H NMR (CDCl3) δ 8.13 (br s, 1H), 7.66 (d, J ) 7.8 Hz, 1H),
7.61 (d, J ) 7.3 Hz, 1H), 7.47 (m, 1H), 7.20-7.18 (m, 3H); IR-
(KBr)λmax 3276 (NH), 1739 (CO). Anal. Calcd for C12H7N1O2S1:
C, 62.87; H, 3.07; N, 6.10. Found: C, 62.42; H, 3.03; N, 5.92.
7-(3,5-Dich lor op h en yl)isa tin (3f): red solid, 60%, mp >220
°C; 1H NMR (CDCl3) δ 9.66 (br s, 1H), 7.59 (d, J ) 8.4 Hz, 1H),
7.51 (m, 1H), 7.47 (m, 1H), 7.41 (br s, 1H), 7.34 (br s, 2H), 7.16
(m, 1H); IR(KBr)λmax 3442 (NH), 1739 (CO). Anal. Calcd for
Exp er im en ta l Section
7-Iod oisa tin (6). In a 250 mL flask is placed chloral hydrate
(1.81 g, 0.011 mol) in H2O (24 mL). To this solution are then
added, in order, crystallized sodium sulfate (25.56 g, 0.18 mol),
2-iodoaniline (2.19 g, 0.01 mol) in H2O (36 mL), hydrochloric acid
(1.35 mL, 0.03 mol), and finally, a solution of hydroxylamine
hydrochloride (2.1 g, 0.03 mol) in H2O (10 mL). The mixture is
stirred and heated to 80 °C for 1 h and then cooled to room
temperature. The precipitate corresponding to 2-iodohydroxy-
iminoacetanilide is filtered and dried under vacuum to give a
1
white solid (2.19 g, 76%): mp 157-158 °C; H NMR (CDCl3) δ
8.98 (br s, 1H), 8.77 (s, 1H), 8.29 (d, J ) 8.0 Hz, 1H), 7.79 (d, J
) 9.5 Hz, 1H), 7.60 (s, 1H), 7.37 (m, 1H), 6.87 (m, 1H);
IR(KBr)λmax 3434 (OH), 3309 (NH), 1660 (CO). Anal. Calcd for
C8H7N2O2I: C, 33.12; H, 2.43; N, 9.65. Found: C, 33.38; H, 2.59;
N, 9.87. Then, concentrated sulfuric acid (15 mL) is warmed to
50 °C in a 100 mL flask fitted with an efficient stirrer, and to
this is added dry 2-iodohydroxyiminoacetanilide (2.19 g, 7.5
mmol) at the rate necessary to keep the temperature between
60-70 °C. After the addition of the isonitroso compound is
finished, the solution is heated to 80 °C and kept at this
temperature for about 15 min to complete the reaction. Then
the reaction mixture is cooled to room temperature and poured
into cracked ice with continual stirring. After 1 h, the 7-iodoi-
satin 6 is filtered, washed several times with cold water, and
then dried under vacuum to give a crude red product (1.02 g,
50%) 6: mp 208 °C; 1H NMR (CDCl3) δ 8.26 (s, 1H), 7.89 (d, J )
7.9 Hz, 1H), 7.59 (d, J ) 8.4 Hz, 1H), 6.95 (dd, J ) 8.4 Hz, J )
7.9 Hz, 1H); 13C NMR (CDCl3) δ 183.16, 158.4, 151.3, 146.6,
125.6, 125.2, 119.5, 77.9; IR(KBr)λmax 3410 (NH), 1740 (CO).
Anal. Calcd for C8H4NO2I: C, 35.19; H, 1.47; N, 5.13. Found: C,
35.46; H, 1.68; N, 5.38.
C
14H7N1O2Cl2: C, 57.56; H, 2.41; N, 4.79. Found: C, 57.32; H,
2.33; N, 4.61.
3-Ar yla n th r a n ilic Acid s (2). Gen er a l P r oced u r e. To a
stirred suspension of 7-arylisatin 3 (1 mmol) in 5% sodium
hydroxide (5 mL) is added 30% hydrogen peroxide (5 mL)
dropwise. The reaction mixture is stirred at 50 °C for 30 min
and then allowed to reach room temperature. The filtered
solution is acidified to pH 4 with 1 M hydrochloric acid, and the
solid product 2 is collected by filtration.
3-P h en yla n th r a n ilic a cid (2a ): beige solid, 72%, mp 146
°C (lit 148-149 °C); 1H NMR (DMSO) δ 7.84 (m, 1H), 7.54-
7.45 (m, 5H), 7.22 (m, 1H), 6.70 (m, 1H); IR(KBr)λmax 3488, 3367
(NH2), 1661 (CO). Anal. Calcd for C13H11N1O2: C, 73.22; H, 5.20;
N, 6.57. Found: C, 72.95; H, 5.03; N, 6.66.
3-(4-Meth oxyp h en yl)a n th r a n ilic a cid (2b): white solid,
70%, mp 158 °C;1H NMR (CDCl3) δ 7.94 (d, J ) 7.7 Hz, 1H),
7.34 (d, J ) 8.3 Hz, 2H), 7.25 (d, J ) 7.9 Hz, 1H), 7.00 (d, J )
8.3 Hz, 2H), 6.71 (m, 1H), 3.86 (s, 3H); IR(KBr)λmax 3470, 3362
(NH2), 1655 (CO). Anal. Calcd for C14H13N1O3: C, 69.12; H, 5.38;
N, 5.75. Found: C, 68.97; H, 5.13; N, 5.59.
7-Ar ylisa tin s (3). Gen er a l P r oced u r e. To a mixture of
7-iodoisatin 6 (272.9 mg, 1 mmol) and Pd(PPh3)4 (58 mg, 0.05
mmol) in DME (30 mL) is added the corresponding arylboronic
acid (1.1 mmol), followed by the addition of sodium hydrogen
carbonate (168 mg, 2.0 mmol) in H2O (30 mL). The reaction
mixture is refluxed with vigorous stirring, and the rate of the
reaction is followed by TLC. After the starting aryl halide was
consumed (5 h), the organic solvent is removed under reduced
pressure. The residue, partially soluble in H2O, is extracted with
CH2Cl2 (30 mL), and then the organic layer is dried (CaCl2) and
evaporated. The crude products are purified by column chro-
matography (CH2Cl2/MeOH, 97.5/2.5).
7-P h en ylisa tin (3a ): orange solid, 55%, mp 185-186 °C; 1H
NMR (CDCl3) δ 7.83 (br s, 1H), 7.51 (m, 7H), 7.21 (m, 1H); IR-
(KBr)λmax 3406 (NH), 1745 (CO), 1741 (CO). Anal. Calcd for
14H9N1O2: C, 75.32; H, 4.06; N, 6.27. Found: C, 75.52; H, 4.28;
N, 6.48.
7-(4-Meth oxyp h en yl)isa tin (3b): orange solid, 70%, mp
3-(4-Meth ylp h en yl)a n th r a n ilic a cid (2c): beige solid, 75%,
1
mp 160 °C; H NMR (DMSO) δ 10.24 (br s, 1H), 7.74 (m, 1H),
7.60 (m, 1H), 7.25-7.11 (m, 4H), 6.61 (m, 1H); IR(KBr)λmax 3492,
3376 (NH2), 1653 (CO). Anal. Calcd for C14H13N1O2: C, 73.99;
H, 5.76; N, 6.16. Found: C, 73.78; H, 5.53; N, 5.91.
3-(F u r -2-yl)a n th r a n ilic a cid (2d ): salmon solid, 82%, mp
137 °C; 1H NMR (CDCl3) δ 7.97 (m, 1H), 7.57 (m, 2H), 6.61 (m,
3H); IR(KBr)λmax 3488, 3371 (NH2), 1671 (CO). Anal. Calcd for
C
11H9N1O3: C, 65.02; H, 4.46; N, 6.89. Found: C, 65.12; H, 4.51;
N, 6.71.
3-(Th ien -2-yl)a n th r a n ilic a cid (2e): beige solid, 77%, mp
138 °C; 1H NMR (CDCl3) δ 7.98 (d, J ) 7.9 Hz, 1H), 7.40 (m,
2H), 7.19 (m, 1H), 7.15 (m, 1H), 6.70 (m, 1H), 6.29 (br s, 2H);
IR(KBr)λmax 3459, 3350 (NH2), 1667 (CO). Anal. Calcd for
C
C
11H9N1O2S1: C, 60.25; H, 4.13; N, 6.38. Found: C, 59.95; H, 3.97;
N, 6.21.
3-(3,5-Dich lor op h en yl)a n th r a n ilic a cid (2f): white solid,
>200 °C; 1H NMR (CDCl3) δ 7.80 (br s, 1H), 7.59 (d, J ) 7.6 Hz,
1H), 7.54 (d, J ) 7.8 Hz, 1H), 7.33 (d, J ) 8.6 Hz, 2H), 7.20 (m,
1H), 7.04 (d, J ) 8.6 Hz, 2H), 3.87 (s, 3H); IR(KBr)λmax 3448
(NH), 1742 (CO), 1730 (CO). Anal. Calcd for C15H8N1O3: C, 71.99;
H, 3.22; N, 5.59. Found: C, 72.27; H, 3.33; N, 5.72.
7-(4-Meth ylp h en yl)isa tin (3c): orange solid, 55%, mp 178
°C; 1H NMR (CDCl3) δ 7.79 (br s, 1H), 7.60 (d, J ) 7.4 Hz, 1H),
7.56 (d, J ) 7.4 Hz, 1H), 7.35-7.28 (m, 4H), 7.19 (m, 1H), 2.43
(s, 3H); IR(KBr)λmax 3448 (NH), 1740 (CO). Anal. Calcd for
C15H8N1O2: C, 76.91; H, 3.44; N, 5.97. Found: C, 77.15; H, 3.68;
N, 6.18.
76%, mp 196-198 °C; 1H NMR (CDCl3) δ 8.00 (d, J ) 7.1 Hz,
1H), 7.40 (br s, 1H), 7.33 (br s, 2H), 7.22 (d, J ) 7.1 Hz, 1H),
6.74 (m, 1H); IR(KBr)λmax 3489, 3362 (NH2), 1666 (CO). Anal.
Calcd for C13H9N1O2Cl2: C, 55.34; H, 3.22; N, 4.96. Found: C,
55.47; H, 3.18; N, 4.72.
Ack n ow led gm en t. This work was supported by
FEDER (Fond Europe´en de De´veloppement Economique
Re´gional).
J O991948I