N-Chloro and N-bromosaccharins: valuable reagents for halogenation of electron rich aromatics and cohalogenation of alkenes

SHORT REPORT

N-Chloro and N-bromosaccharins: valuable reagents for halogenation of electron rich aromatics and cohalogenation of alkenes

Soraia P. L. de Souza; Joaquim Fernando M. da Silva^*; Marcio C. S. de Mattos^*

Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68545, 21945-970 Rio de Janeiro - RJ, Brazil

ABSTRACT

N-Chloro- and N-bromosaccharins react with electron rich aromatic compounds (anisole, acetanilide, N,N-dimethylaniline) producing halogenated compounds. The reaction with N-bromosaccharin gives para- substituted compounds only, whereas N-chlorosaccharin produces orto and para mixtures (para isomer predominantly, ca. 4-5 : 1). The reactions of the N-halosaccharins with alkenes (cyclohexene, styrene, a-methylstyrene, and 1-hexene) give the corresponding halohydrins.

Keywords: cohalogenation, aromatic halogenation, N-halosaccharin

RESUMO

N-Cloro e N-bromo-sacarinas reagem com compostos aromáticos ricos em elétrons (anisol, acetanilida, N,N-dimetilanilina) para fornecer os produtos de halogenação do anel. As reações com a N-bromo-sacarina fornecem somente os produtos com substituição na posição para, enquanto que a utilização de N-cloro-sacarina gera mistura de produtos orto e para, com predominância do isômero para (ca. 4-5 : 1). Já as reações das halo-sacarinas com alquenos (cicloexeno, estireno, a-metilestireno e 1-hexeno) em acetona aquosa fornecem as respectivas haloidrinas.

Introduction

Although N-halosaccharins (NXSac, Scheme 1) are more electrophilic than the structurally analogue N-halosuccinimides (NXS), they have found little attention in synthetic organic chemistry.¹ Recently, Dolenc published the reaction of NISac with alkenes and aromatic compounds.¹ On the other hand, NCSac and NBSac are easily prepared from the readily available sodium salt of saccharin² and they are used in mild oxidation reactions,^3-7 analytical chemistry,⁸ and as halogenating reagents for allylic,⁹ benzylic^9,10 and a-carbonylic^10,11 positions. Surprisingly, to the best of our knowledge, there is no description of the reaction of those halosaccharins with alkenes and aromatic compounds and we now present our results on this area.

Results and Discussion

NCSac and NBSac react smoothly and fast with electron rich aromatics and the results are summarized in Table 1. The reactions were performed at room temperature stirring together a solution of NXSac (5 mmol) and the aromatic compound (5 mmol) in acetonitrile. The products were characterized by coinjection with authentic commercial samples in high-resolution gas chromatography (HRGC) and spectroscopic methods.

It was observed that the reactions with NBSac were faster with exclusive formation of 4-substituted bromides, whereas reactions with NCSac produced a mixture of 2- and 4-substituted chlorides (the 4-isomer predominated in all cases by ca. 4-5 : 1). Less reactive substrates such as benzene and toluene did not react after 4 h. On the other hand, durene showed interesting results (Scheme 2). Although the reactions were incomplete after several hours, it was observed that using NCSac it was obtained products arising from the reaction with both aromatic nucleus and methyl group, whereas NBSac produced almost exclusive aromatic bromination.

The formation of halodurenes could be rationalized by a nucleophilic attack of the aromatic ring to the electrophilic halogen in NXSac. On the other hand, the chlorination of the methyl in the reaction of durene with NCSac is probably a radical reaction. The difference between NCSac (electrophilic and radical attack) and NBSac (electrophilic attack only) are in accordance with the fact that NCSac is more efficient than NBSac for benzylic halogenation, whereas NBSac is more efficient than NCSac for electrophilic reactions.^7,9

The cohalogenation (halogenation in the presence of a nucleophilic solvent¹²) of representative alkenes was also easily achieved with NCSac and NBSac. The reactions were performed at room temperature with equimolar amounts of alkene and NXSac in aqueous acetone to produce the corresponding halohydrins and the results are summarized in Table 2. In general, the regioselectivity was very high and no regioisomeric products were detected by the analytical methods employed (HRGC and ¹H and ¹³C NMR). The exception was 1-hexene that afforded a regioisomeric mixture of halohydrins in which the 1-halo-2-alkanols predominated (ca. 3 : 1 by high-resolution GC). The products were characterized by spectroscopic methods and, wherever possible, by coinjection in HRGC with authentic commercial samples or prepared by an alternative route.¹³

In summary, NCSac and NBSac are alternative and attractive reagents to perform halogenation of electron rich aromatic compounds and cohalogenation of alkenes. Furthermore, the reaction conditions are simple, safe and these halosaccharins are easily prepared by commercial sodium saccharin.

Experimental

All chemicals were used without further purification. NCSac and NBSac were prepared by reaction of sodium salt of saccharin with KCl or KBr and oxone^®.²¹H NMR and ¹³C NMR spectra were acquired on a Bruker AC-200 (200 MHz and 50 MHz, respectively) spectrometer in CDCl₃ (otherwise stated) solutions with TMS as internal standard. IR spectra were recorded on a Perkin-Elmer 1600 FT-IR spectrometer (KBr film). MS were obtained on a Hewlett-Packard HP5896-A HRGC-MS using electron impact (70 eV). Analyses by HRGC were performed on a HP-5890-II gas chromatograph with FID by using a 30 m (length), 0.25 mm (ID) and 25 µm (phase thickness) RTX-5 silica capillary column and H₂ (flow rate 50 cm s^-1) as carrier gas (split 1:20).

The reactions were complete when an aliquot did not produce a color change in a wet iodide-starch test paper.

Typical procedure for the chlorination and bromination of aromatics

To a stirred solution of the aromatic compound (5 mmol) in acetonitrile (5 cm³), NXSac (5 mmol) was added at rt. After termination of the reaction, CH₂Cl₂ (20 cm³) was added. The solution was washed with 10 % NaHCO₃ (2 x 10 cm³), 10 % NaHSO₃ (2 x 10 cm³) and then dried (Na₂SO₄). Evaporation of the solvent on a rotatory evaporator gave the haloaromatic compound.

p-chloroanisole.¹H NMR: d 3.70 (s, 3H), 6.74 (d, J 8.98 Hz, 2H), 7.15 (d, J 8.96 Hz, 2H) ppm. ¹³C NMR: d 55.6 (CH₃), 115.4 (C), 125.7 (CH), 129.5 (CH), 158.4 (C) ppm.

o-chloroanisole.¹H NMR: d 3.82 (s, 3H), 6.80 (d, J 7.72 Hz, 2H), 7.20 (d, J 8.51 Hz, 2H) ppm. ¹³C NMR: d 56.2 (CH₃), 112.3 (C), 121.5 (CH), 122.4 (CH), 127.9 (CH), 130.4 (CH), 156.0 (C) ppm.

p-bromoanisole.¹H NMR: d 3.79 (s, 3H), 6.79 (d, J 9.00 Hz, 2H), 7.39 (d, J 9.00 Hz, 2H) ppm. ¹³C NMR: d 55.6 (CH₃), 113.0 (C), 115.9 (CH), 132.4 (CH), 158.9 (C) ppm. IR n_max/cm^-1 : 3094, 3072, 3004, 2958, 2938, 2905, 2837, 1590, 1578, 1489, 1290, 1247, 1033, 822, 804, 792, 601, 507. MS: m/z 50, 62, 63, 64, 77, 79, 92, 117, 119, 143, 145, 171, 173, 186 (M⁺, 100%), 188 (M+2⁺, 100%).

p-chloroacetanilide.¹H NMR: d 2.04 (s, 3H), 7.33 (d, J 8.58 Hz, 2H), 7.61 (d, J 8.40 Hz, 2H), 10.06 (broad s, 1H, NH) ppm. ¹³C NMR: d 24.4 (CH₃), 120.9 (CH), 127.0 (C), 129.0 (CH), 138.7 (C), 168.9 (C) ppm. MS: m/z 43, 63, 73, 92, 99, 127 (100%), 129, 169 (M⁺, 24%), 171 (M+2⁺, 8%).

o-chloroacetanilide.¹H NMR: d 2.09 (s, 3H), 7.18 (d, J 7.74 Hz, 1H), 7.47 (d, J 8.34 Hz, 2H), 7.70 (d, J 7.72 Hz, 1H), 9.51 (broad s, 1H, NH) ppm. ¹³C NMR: d 24.7 (CH₃), 121.8 (CH), 122.7 (CH), 124.6 (CH), 127.6 (CH), 128.9 (CH), 134.6 (C), 168.2 (C) ppm. MS: m/z 43, 65, 73, 92, 99, 127 (100%), 129, 134, 135, 169 (M⁺, 13%), 171 (M+2⁺, 5%).

p-bromoacetanilide.¹H NMR (DMSO-d₆): d 2.04 (s, 3H), 7.45 (d, J 8.34 Hz, 2H), 7.56 (d, J 8.52 Hz, 2H), 10.06 (broad s, 1H, NH) ppm. ¹³C NMR (DMSO-d₆): d 24.4 (CH₃), 114.9 (C), 121.3 (CH), 131.9 (CH), 139.1 (C), 168.9 (C) ppm. IR n_max/cm^-1 : 3293, 3260, 3186, 3115, 3052, 1668, 1644, 1601, 1586, 1532, 1487, 1394, 1309, 1290, 1255, 1007, 831, 819, 740, 687, 504. MS: m/z 43, 63, 65, 92, 171 (100%), 173, 213 (M⁺, 27%), 215 (M+2⁺, 26%).

p-chloro-N,N-dimethylaniline.¹H NMR: d 3.01 (s, 3H), 6.55 (d, J 8.00 Hz, 1H), 7.12 (d, J 8.02 Hz, 1H) ppm. ¹³C NMR: d 43.6 (CH₃), 114.5 (CH), 125.4 (C), 130.1 (CH), 142.6 (C) ppm.

o-chloro-N,N-dimethylaniline.¹H NMR: d 3.05 (s, 3H), 6.83 (d, J 7.80 Hz, 2H), 7.10 (d, 8.89 Hz, 2H) ppm. ¹³C NMR: d 41.1 (CH₃), 114.5 (CH), 118.2 (C), 119.4 (CH), 127.3 (CH), 130.0 (CH), 145.0 (C) ppm.

p-bromo-N,N-dimethylaniline.¹H NMR: d 2.90 (s, 1H), 6.70 (d, J 9.00 Hz, 1H), 7.10 (d, J 9.00 Hz, 1H) ppm. ¹³C NMR: d 40.5 (CH₃), 108.4 (C), 114.0 (CH), 131.6 (CH), 149.4 (C) ppm.

bromodurene.¹H NMR: d 2.30 (s, 6H), 2.39 (s, 6H), 7.27 (s, 1H) ppm. ¹³C NMR: d 20.4 (CH₃), 21,1 (CH₃), 130.5 (CH), 131.2 (C), 134.1 (C), 134.9 (C), 135.2 (C) ppm. MS: m/z 65, 77, 91, 105, 115, 117, 133 (100%), 197, 199, 212 (M⁺, 52%), 214 (M+2⁺, 54%).

Typical procedure for the preparation of chloro- and bromohydrins

To a stirred solution of the alkene (5 mmol) in 10 cm³ of water / acetone (1 : 3, v/v), NXSac (5 mmol) was added at rt. After termination of the reaction, Et₂O (10 cm³) was added. The organic phase was washed with 10 % NaHCO₃ (2 x 8 cm³), 10 % NaHSO₃ (2 x 8 cm³) and then dried (Na₂SO₄). Evaporation of the solvent on a rotatory evaporator gave the halohydrin.

trans-2-chlorocyclohexanol.¹H NMR: d 1.05-2.84 (m, 8H), 2.60 (broad s, 1H, OH), 3.30 (s, 1H), 3.39 (s, 1H) ppm. ¹³C NMR: d 24.0 (CH₂), 25.6 (CH₂), 33.1 (CH₂), 35.1 (CH₂), 67.3 (CH), 75.2 (CH) ppm. MS: m/z 57 (100%), 80, 98, 116, 134 (M⁺, 6%), 136 (M+2⁺, 2%).

trans-2-bromocyclohexanol.¹H NMR: d 1.12-2.50 (m, 8H), 2.63 (broad s, 1H, OH), 3.61 (s, 1H), 3.91 (s, 1H) ppm. ¹³C NMR: d 24.1 (CH₂), 26.6 (CH₂), 33.6 (CH₂), 36.2 (CH₂), 61.6 (CH), 75.2 (CH) ppm.

1-chloro-2-hexanol.¹H NMR: d 0.90 (m, 3H), 1.10-1.80 (m, 6H), 2.25 (broad d, J 4.4 Hz, 1H, OH), 3.50 (dd, J 10.9 Hz and 6.4 Hz, 1H), 3.60 (dd, J 10.9 Hz and 3.2 Hz, 1H), 3.80 (m, 1H) ppm. ¹³C NMR: d 14.0 (CH₃), 22.6 (CH₂), 27.7 (CH₂), 34.0 (CH₂), 50.5 (CH), 71.5 (CH₂) ppm.

1-bromo-2-hexanol.¹H NMR: d 0.93 (m, 3H), 1.22-1.80 (m, 6H), 2.20 (d, J 4.8 Hz, 1H), 3.40 (dd, J 10.2 Hz and 7.0 Hz, 1H), 3.53 (dd, J 10.2 Hz and 3.4 Hz), 3.74 (m, 1H) ppm. ¹³C NMR: d 14.0 (CH₃), 22.6 (CH₂), 27.7 (CH₂), 34.8 (CH₂), 40.3 (CH₂), 71.0 (CH) ppm.

2-chloro-1-phenylethanol.¹H NMR: d 2.64 (broad s, 1H, OH), 3.71 (m, 2H), 4.89 (dd, J 3.50 Hz and 8.38 Hz, 1H), 7.37 (s, 5H) ppm. ¹³C NMR: d 51.0 (CH₂), 74.2 (CH), 126.2 (CH), 128.6 (CH), 128.8 (CH), 140.1 (C) ppm. IR n_max/cm^-1 : 3418, 3088, 3064, 3032, 2976, 2928, 2897, 1704, 1615, 1556, 1454, 1396, 1337, 1248, 1175, 1064, 873, 771, 725, 699, 616, 523. MS: m/z 51, 77, 79, 107 (100%), 156 (M⁺, 4%), 158 (M+2⁺, 1%).

2-bromo-1-phenylethanol.¹H NMR: d 2.73 (broad s, 1H, OH), 3.60 (m, 2H), 4.92 (dd, J 3.50 Hz and 8.60 Hz, 1H), 7.37 (s, 5H) ppm. ¹³C NMR: d 40.3 (CH₂), 74.0 (CH), 126.1 (CH), 128,6 (CH), 128.8 (CH), 140.5 (C) ppm. IR n_max/cm^-1 : 3419, 3087, 3063, 3031, 2963, 2918, 2896, 2850, 1705, 1681, 1614, 1453, 1420, 1336, 1258, 1217, 1198, 1016, 764, 701, 593. MS: m/z 51, 77, 79, 107 (100%), 200 (M⁺, 3%), 202 (M+2⁺, 3%).

1-chloro-2-phenyl-2-propanol.¹H NMR: d 1.63 (s, 3H), 2.63 (broad s, 1H, OH), 3.73 (d, J 11.17 Hz, 1H), 3.83 (d, J 11.17 Hz, 1H), 7.40 (m, 5H) ppm . ¹³C NMR: d 27.5 (CH₃), 55.6 (CH₂), 74.0 (C), 125.1 (CH), 127.7 (CH), 128.6 (CH), 144.3 (C) ppm. IR n_max/cm^-1 : 3445, 3089, 3061, 3029, 2978, 2933, 2851, 1730, 1495, 1447, 1377, 1337, 1290, 1249, 1181, 1070, 769, 966, 580. MS: m/z 43, 51, 77, 91, 121 (100%), 170 (M⁺, 0.2%), 172 (M+2⁺, 0.07%).

1-bromo-2-phenyl-2-propanol.¹H NMR: d 1.67 (s, 3H), 2.91 (broad s, 1H, OH), 3.68 (d, J 10.45 Hz, 1H), 3.76 (d, J 10.63 Hz, 1H), 7.37 (m, 5H) ppm. ¹³C NMR: d 28.2 (CH₃), 46.4 (CH₂), 73.3 (C), 125.0 (CH), 127.7 (CH), 128.6 (CH), 144.3 (C) ppm. IR n_max/cm^-1: 3436, 3088, 3060, 3028, 2977, 2932, 2897, 1731, 1494, 1447, 1375, 1337, 1180, 1069, 1050, 766, 701, 591. MS: m/z 43, 51, 77, 78, 91, 105, 121 (100%), 214 (M⁺, 0.3%), 216 (M+2⁺, 0.2%).

Acknowledgements

S.P.L.S. thanks CNPq for fellowship.

References

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Received: October 28, 2002

Published on the web: September 24, 2003

Publication Dates

• Publication in this collection
  04 Feb 2004
• Date of issue
  Oct 2003

History

• Received
  28 Oct 2002
• Accepted
  24 Sept 2003