Synthesis of 2-acetamido-5,6-dihalophenyl acetates

Article abstract of DOI:10.1007/s007060050027

2-Acetamido-5,6-dihalophenyl acetates were synthesized as intermediates for the preparation of 6, 7-dihalo-8-quinolinols via the Skraup procedure.

Full text of DOI:10.1007/s007060050027

Monatshefte fuÈr Chemie 131, 795±798 (2000)
Synthesis of 2-Acetamido-5,6-dihalophenyl
Acetates
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Donald D. Clarke , Herman Gershon, and John J. McMahon
Department of Chemistry, Fordham University, Bronx, NY 10458, USA
Summary. 2-Acetamido-5,6-dihalophenyl acetates were synthesized as intermediates for the
preparation of 6, 7-dihalo-8-quinolinols via the Skraup procedure.
Keywords. 6-Chloro-2-acetamidophenyl acetate; 6-Bromo-2-acetamidophenyul acetate; 5,6-
Dichloro-2-acetamidophenyl acetate; 5,6-Dibromo-2-acetamidophenyl acetate.
Introduction
A recent part of our study on structure vs. antifungal activity relationships of
8-quinolinol and its substituted analogues involved preparation of a series dihalo-8-
quinolinols [1]. While these could be prepared generally from monohalo-8-
quinolinols using suitable blocking agents when needed, 6,7-dihalo derivatives
caused extra problems. The more reactive 5-position of 6-halo-8-quinolinol was
blocked by sulfonation. On halogenation of 6-halo-8-quinolinol-5-sulfonic acid,
the sulfonic acid was replaced in part, leading to a mixture of 6,7-dihalo-8-
quinolinol-5-sulfonic acid and a by-product of 5,6,7-trihalo-8-quinolinol [1]. The
separation of the two compounds was accomplished by washing the mixture with
warm acetone, leaving the sulfonic acid as a residue on the ®lter. The sulfonic acid
was subsequently desulfonated to yield 6,7-dihalo-8-quinolinol. Yields of the
desired product were thus diminished [1].
Another route to 6,7-dihalo-8-quinolinols was considered: a Skraup ring
closure reaction on 2-amino-5,6-dihalophenol. The required intermediates seemed
to present dif®cult synthetic problems, since they contained four contiguous o, p-
directing groups which appeared to present problematic synthetic tasks in adjusting
the directive in¯uences of the groups already on the ring as well as steric
hindrance. Based on experience with the preparation of 6-halo-8-quinolinols [2]
and our work with 6-halo-2-nitro-phenols [3,4,5], facile syntheses of the desired
6,7-dihalo-8-quinolinols were achieved by Skraup reactions using acetylated 2-
amino-5,6-dihalophenols. Preparation of the 2-acetamido-5,6-dihalophenyl acetates
is reported here.
Ã
Corresponding author

796
D. D. Clarke et al.
Scheme 1
Results and Discussion
The synthetic approach to the 2-acetamido-5,6-dihalophenyl acetates is outlined in
Scheme 1. Nitration of o-halophenols directs the entering nitro group primarily in
the ortho-position to the phenolic hydroxyl group. Furthermore, the product can be
puri®ed by steam distillation which takes advantage of the strong intramolecular
hydrogen bonding of the substituted o-nitrophenol. Reductive acetylation of the
nitro group was done by catalytic hydrogenation in a mixture of acetic acid and
acetic anhydride. The resulting 6-halo-2-acetamidophenyl acetate was reacted with
N-halosuccinimide (NXS) to yield the title compounds. Since no entering group is
directed between two others already present in a molecule, the problem of steric
hindrance is minimal.
That acetamido is a stronger o,p-director than the acetoxy group has been
established by Theilacker in 1938 [6], and we took advantage of this in an earlier
synthesis of 6-halo-8-quinolinol [2]. When o-aminophenol was heated with acetic
anhydride under re¯ux, a triacetyl deivative was formed which cannot be
halogenated with NXS in acetic acid. The diacetyl derivative as described by
Theilacker [6] is amenable to halogenation [7].
Experimental
Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. The
purity of samples was established by 1H and 13C NMR spectroscopy at 300 and 75 MHz,
respectively, with a Bruker DPX-300 spectrometer using DMSO-d6 as solvent and TMS as internal
standard. Mass spectra of the new compounds 2a,b and 3a,b were obtained using a Fisons VG7070E
double-focusing sector mass spectrometer with a resolution of 3000 (Valley) and per¯uorokerosene
(Lancaster) as a calibration standard.
2-Acetamido-6-chlorophenyl acetate (2a; C10H10ClNO3)
A mixture of 1a (8.7 g, 0.05 mol) [3], 1.5 g of 10% palladium on characoal, 50 cm3 of acetic acid, and
50 cm3 of acetic anhydride were shaken in a Parr hydrogenator under three atmospheres of hydrogen
until the theoretical amount of hydrogen was consumed. The catalyst was removed by ®ltration, and
the solution was stirred overnight, after which it was poured onto ice and stirred until the residual
acetic anhydride was hydrolyzed and complete crystallization of 2a took place. The product was

Synthesis of 2-Acetamido-5,6-dihalophenyl Acetates
797
recovered by ®ltration, washed with water, and dried at 50ꢀC. The yield of compound was 8.7 g
(76%), m.p.: 124ꢀC. A pure sample recrystallized from ethanol melted at 127ꢀC.
1H NMR (300 MHz, ꢀ, DMSO-d6): 9.58 (s, NH), 7.95 (d, J34 ˆ 7.5 Hz, H-3), 7.29 (dd,
J35 ˆ 1.8 Hz, J45 ˆ 8.0 Hz, H-5), 7.24 (t, H-4), 2.36 (s, CH3CONH), 2.10 (s, CH3COO) ppm;
13C NMR (75 MHz, ꢀ, DMSO-d6): 168.77 (C=ONH), 167.88 (C=OO), 137.74 (C-1), 132.95 (C-2),
126.63 (C-4), 126.44 (C-6), 124.54 (C-4), 122.14 (C-3), 23.60 (CH3CONH), 20.69 (CH3COO) ppm;
m/z: calcd. for C10H1035ClNO3: 227.03492, found: 227.03438.
2-Acetamido-6-bromophenyl acetate (2b; C10H10BrNO3)
Compound 2b was prepared from 1b [4] in the same manner as 2a was obtained from 1a. A
0.055 mol run yielded 25.3% of product, m.p.: 122±124ꢀC. A pure sample recrystallized from
aqueous ethanol melted at 127±128ꢀC.
1H NMR (300 MHz, ꢀ, DMSO-d6): 9.56(s, NH), 7.97 (d, J34 ˆ 8.0 Hz, H-3), 7.42 (d, H-5), 7.18 (t,
J45 ˆ 8.2 Hz, H-4) 2.38 (s, CH3COO), 2.10 (s, CH3CONH) ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6):
169.46 (C=ONH), 168.58 (C=OO), 139.08 (C-1), 133.01 (C-2), 127.56 (C-5), 127.12 (C-4), 122.80
(C-3), 116.37 (C-6), 23.59 (CH3CONH), 20.90 (CH3COO) ppm; m/z: calcd. for C10H1079BrNO3:
270.98440, found: 270.98329.
2-Acetamido-5,6-dichlorophenyl acetate (3a; C10H9Cl2NO3)
A mixture of 2a (13.6 g, 0.06 mol) and NCS (8.0 g, 0.06 mol) in 70 cm3 of acetic acid was stirred at
50ꢀC overnight until a negative starch iodide test was obtained. The solution was poured into 5
volumes of water and stirred for 0.5 h. The product was recovered by ®ltration, washed with water,
and dried at 50ꢀC. The yield of compound was 11.4 g (76.2%), m.p.: 147±150ꢀC. A pure sample
crystallized from aqueous ethanol melted at 171±172ꢀC.
1H NMR (300 MHz, ꢀ, DMSO-d6): 9.68 (s, NH), 8.03 (d, H-3), 7.53 (d, J34 ˆ 9.0 Hz, H-4), 2.40
(s, CH3COO), 2.12 (s, CH3CONH) ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6): 168.98 (C=ONH),
167.79 (C=OO), 138.81 (C-1), 131.96 (C-2), 127.05 (C-4), 126.17 (C-5), 125.48 (C-6), 122.26 (C-3),
23.66 (CH3CONH), 20.75 (CH3COO) ppm; m/z: calcd. for C10H935Cl2NO3: 260.99595, found:
260.99586.
2-Acetamido-5,6-dibromophenyl acetate (3b; C10H9Br2NO3)
Compound 3b was prepared from 2b as 3a from 2a. A 0.01 mol run yielded 77.2% of product, m.p.:
158±160ꢀC. A pure sample crystallized from aqueous ethanol melted at 177±178ꢀC.
1H NMR (300 MHz, ꢀ, DMSO-d6: 9.64 (s, NH), 7.98 (d, J34 ˆ 8.95 Hz, H-3), 7.64 (d, H-4), 2.38
(s, CH3COO), 2.10 (s, CH3CONH) ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6: 168.92 (C=ONH), 167.81
(C=OO), 140.05 (C-1), 132.11 (C-2), 130.24 (C-4), 123.34 (C-5), 119.65 (C-5), 118.25 (C-6), 23.64
(CH3CONH), 21.00 (CH3COO); m/z: calcd. for C10H979Br2NO3: 348.89492, found: 348.89536.
6,7-Dichloro-8-quinolinol
To 24 g sulfuric acid, 10.2 cm3 H2O, 12 g sodium m-nitrobenzenesulfonate, 11.2 g glycerol, and
10.0 g (0.038 mol) 3a were added. The mixture was stirred vigorously and heated to re¯ux slowly.
After 3 h the mixture was allowed to cool to 80ꢀC and poured into 1 dm3 of water. The insoluble
material was removed by ®ltration, the pH of the ®ltrate was adjusted to 7 with NH4OH, and the
solution was steam distilled. A volatile product (0.4 g) melting at 177±178ꢀC was not identi®ed. The
residue after steam distillation was recovered and dried at 50ꢀC; yield: 6.33 g (77.5%), m.p: 182±
184ꢀC. Upon sublimation, washing with a little acetone, and crystallization from acetonitrile the

798
D. D. Clarke et al.: Synthesis of 2-Acetamido-5,6-dihalophenyl Acetates
product melted at 190±191ꢀC (Ref. [1]: m.p.: 191±192ꢀC). A mixed melting point with an authentic
1
sample showed no depression, and the H NMR spectra of both samples were identical.
1H NMR (300 MHz, ꢀ, DMSO-d6): 8.94 (dd, J23 ˆ 4.12 Hz, J24 ˆ 1.41 Hz, H-2), 8.36 (dd, H-4),
7.74 (dd, J34 ˆ 8.7 Hz, H-3), 10.8 (s, OH); ppm; 13C NMR (75 MHz, ꢀ DMSO-d6): 151.3 (C-8), 149.3
(C-2), 137.1 (C-8a), 135.6 (C-4), 130.2 (C-6), 126.9 (C-4a), 123.0 (C-3), 117.5 (C-5), 114.9 (C-7);
m/z: calcd. for C9H535Cl2NO: 212.97482, found: 212.97461.
Acknowledgment
This work was supported in part by a grant from the National Science Foundation (DUE #9650684)
to allow purchase of an NMR spectrometer.
References
[1] Gershon H, Clarke DD, Gershon M (1999) Monatsh Chem 130: 653
[2] Gershon H, Clarke DD (1991) Monatsh Chem 122: 935
[3] Poirier JM, Vottero C (1989) Tetrahedron 45: 1415
[4] Meldola R, Streat®eld FH (1898) J Chem Soc 73: 681
[5] Gershon H, Clarke DD, Gershon M (1995) Monatsh Chem 126: 1161
[6] Theilacker W (1938) Chem Ber 71: 2065
[7] Gershon H, Clarke DD, Gershon M (1993) Monatsh Chem 124: 367
Received January 24, 2000. Accepted February 12, 2000