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Article

Synthesis of Substituted Phenyl N-(2-hydroxybenzyl)-N-Methylcarbamates

Department of Organic Chemistry, University of Pardubice, Čs. legií 565, 532 10 Pardubice, Czech Republic
*
Author to whom correspondence should be addressed.
Molecules 2002, 7(2), 200-205; https://doi.org/10.3390/70200200
Submission received: 29 June 2001 / Revised: 29 January 2002 / Accepted: 30 January 2002 / Published: 28 February 2002

Abstract

:
Thirteen previously unreported substituted phenyl N-(2-hydroxybenzyl)-N-methylcarbamates were prepared by the reaction of substituted 2-hydroxybenzyl-N-methylamines with phenyl chlorocarbonates. They were identified by their 1H- and 13C-NMR spectra.

Introduction

Carbamates are widely used nowadays. Apart from the use of polyurethanes in plastics they are also common components of agrochemicals [1] or drugs used for treatment of Alzheimer’s disease [2]. Their ability to cyclise to heterocyclic compounds is widely used in organic syntheses [3]. The aim of this work is to synthesise substituted phenyl N-(2-hydroxybenzyl)-N-methylcarbamates 1 which are to be used for studying kinetics and mechanism of their intramolecular cyclization to 3-methyl-4H-1,3-benzoxazin-2(3H)-ones (Scheme 1)
Scheme 1. Preparation of 3-methyl-4H-1,3-benzoxazin-2(3H)-ones
Scheme 1. Preparation of 3-methyl-4H-1,3-benzoxazin-2(3H)-ones
Molecules 07 00200 g001

Results and Discussion

A report that has been published recently surveys a number of papers concerned with the preparation of carbamates [4]. The selection of methods for preparation of carbamates such as structure 1 is limited both by the methyl group substitution on the nitrogen and by the presence of the nucleophilic hydroxyl group in the aromatic part of the benzylamine molecule. That is the reason why it is not possible to use an isocyanate as an intermediate for the syntheses. Taking into account the presence of the hydroxy group in the desired products, we thus chose to use phenyl chlorocarbonates (Scheme 2) in ether in the presence of TEA for phenoxycarbonylation of the substituted 2-hydroxy-benzyl-N-methyl amines:
Scheme 2.
Scheme 2.
Molecules 07 00200 g002
Table 1.
Table 1.
R1R2R3R4R1R2R3R4
1aHClHH1hHNO2HH
1bHClClH1iHNO2NO2H
1cHClNO2H1jNO2HHH
1dBrHHH1kNO2HHCl
1eBrHHCl1lNO2HClH
1fBrHClH1mNO2HNO2H
1gBrHNO2H
The reaction proceeds at room temperature and its progress can be followed by TLC. The reaction required some 30 minutes for all derivatives 1a-m (see Table 1). The excess of TEA was removed after the saturation of the reaction mixture with hydrogen chloride and filtration of eliminated TEA·HCl. The required carbamates were obtained after the distilling off the solvent. They were purified by crystallisation from the mixture of heptane/propan-2-ol. The identification of compounds 1a-m formed in this way was carried out by means of their elemental analysis and 1H- and 13C-NMR spectra. The carbamates show three characteristic signals in their 13C-NMR spectra: ~ 157 ppm that corresponds to the C-OH carbon; ~ 156 ppm that corresponds to the carbamate carbonyl and ~ 150 ppm that corresponds to the C-10 carbon.

Conclusions

Thirteen previously undescribed substituted phenyl N-(2-hydroxybenzyl)-N-methylcarbamates 1a-m were prepared by the reaction of substituted 2-hydroxylbenzyl-N-methylamines with phenyl chlorocarbonates in ether in the presence of TEA. The structure of the compounds was confirmed by 1H- and 13C-NMR spectra, which are also discussed.

Experimental

General

Melting points were measured on Koffler instrument and they are not corrected 1H- (360 MHz) and 13C-NMR (90.56 MHz) spectra in CDCl3 were recorded using Bruker AMX 360 spectrometer. The 13C-NMR chemical shifts were referred to the solvent signal and this were recalculated in the δ-scale (δ-76.90 ppm). The δ (1H) chemical shifts were referred to the internal hexamethyldisiloxane (δ 0.05) standard. Coupling constants J(H, H) are given in Hz. TLC chromatography was carried out on Silufol UV-254 plates (Kavalier, Czech republic), mobile phase 10:1 chloroform-heptane.

Phenyl N-(2-hydroxybenzyl)-N-methyl carbamates 1 (General method):

Substituted phenyl chlorocarbonate (5 mmol) was dissolved in dry diethyl ether (5 mL) and mixed within 20 minutes with substituted 2-(aminonethyl)phenol (5 mmol) and TEA (6 mmol) in diethyl ether (10 mL) at a temperature of 10 °C. Then the reaction mixture was stirred at the room temperature for 30 min. The mixture was saturated with dry hydrogen chloride and after the cooling (10 °C), the eliminated TEA·HCl was filtered off. Diethyl ether was distilled off under vacuum and the evaporation residue was crystallised from a 4:1 mixture of heptane/propan-2-ol.

Yields and physicochemical properties:

Phenyl N-(4-chloro-2-hydroxybenzyl)carbamate (1a). Yield 61%; m.p. 110.5-112.0oC; Calculated for C15H14ClNO3 (291.2): 61.76 % C, 4.81% H, 4.80% N; found 61.73% C, 4.81% H, 4.95% N; 1H-NMR: 8.93 (br, 1H, OH), 7.35 (m, 2H, H-12), 7.21 (m, 1H, H-13), 7.08 (m, 2H, H-11), 7.05 (d, J=8.1, 1H, H-1), 6.95 (s, 1H, H-4), 6.82 (dd, J=2.1, J=8.0, 1H, H-2), 4.37 (s, 2H, H-7), 3.11 (s, 3H, H-8); 13C-NMR: 157.1 (C-5), 156.7 (C-9), 150.8 (C-10), 135.4 (C-3), 131.8 (C-1), 129.3 (C-12), 125.8 (C-13), 121.4 (C-11), 120.3 (C-6), 119.6 (C-4), 118.0 (C-2), 49.5 (C-7), 34.2 (C-8).
3-Chlorophenyl N-(4-chloro-2-hydroxybenzyl)carbamate (1b). Yield 55%; m.p. 101-103o C; Calculated for C15H13ClNO3 (325.3): 55.24 % C, 4.02% H, 4.29% N; found 55.19% C, 4.10% H, 4.47% N; 1H-NMR: 8.75 (br, 1H, OH), 7.29 (m, 1H, H-14), 7.21 (m, 1H, H-15), 7.14 (m, 1H, H-11), 7.06 (d, J=8.1, 1H, H-1), 7.01 (m, 1H, H-13), 6.96 (s, 1H, H-4), 6.84 (dd, J=1.8, J=8.0, 1H, H-2), 4.38 (s, 2H, H-7), 3.11 (s, 3H, H-8); 13C-NMR: 156.7 (C-5), 156.6 (C-9), 151.2 (C-10), 135.6 (C-12), 134.6 (C-3), 131.9 (C-1), 130.0 (C-14), 126.1 (C-13), 122.1 (C-11), 120.0 (C-6), 119.8 (C-15), 119.8 (C-4), 118.1 (C-2), 49.5 (C-7), 34.3 (C-8).
3-Nitrophenyl N-(4-chloro-2-hydroxybenzyl)carbamate (1c). Yield 81%; m.p. 123-126o C; Calculated for C15H13ClN2O5 (336.3): 53.50 % C, 3.89% H, 8.32% N; found 53.64% C, 3.92% H, 8.31% N; 1H-NMR: 8.53 (br, 1H, OH), 8.08 (d, J = 8.0, 1H, H-13), 8.00 (m, 1H, H-11), 7.54 (m, 1H, H-14), 7.47 (d, J=8.2, 1H, H-15), 7.08 (d, J=8.1, 1H, H-1), 6.91 (d, J=1.4, 1H, H-4), 6.84 (dd, J=2.0, J=8.0, 1H, H-2), 4.41 (s, 2H, H-7), 3.14 (s, 3H, H-8); 13C-NMR: 156.4 (C-5), 156.0 (C-9), 151.0 (C-10), 148.5 (C-12), 135.6 (C-3), 131.9 (C-1), 129.9 (C-14), 127.9 (C-15), 120.6 (C-13 + C-6), 119.9 (C-4), 117.9 (C-2), 117.1 (C-11), 49.5 (C-7), 34.3 (C-8).
Phenyl N-(5-bromo-2-hydroxybenzyl)carbamate (1d). Yield 72%; m.p. 113-115o C; Calculated for C15H14BrNO3 (336.4): 53.61 % C, 4.17% H, 4.17% N; found 53.47% C, 4.20% H, 4.29% N; 1H-NMR: 8.76 (br, 1H, OH), 7.31 (m, 3H, H-3 + H-12 + H-14), 7.24 (s, 1H, H-1), 7.18 (m, 1H, H-13), 7.07 (m, 2H, H-11 + H-15), 6.78 (d, J=8.5, 1H, H-4), 4.33 (s, 2H, H-7), 3.08 (s, 3H, H-8); 13C-NMR (CDCl3): 157.0 (C-5), 155.0 (C-9), 150.8 (C-10), 133.3 (C-3), 132.8 (C-1), 129.3 (C-12 + C-14), 125.8 (C-13), 123.9 (C-6), 121.4 (C-11 + C-15), 119.5 (C-4), 111.2 (C-2), 49.4 (C-2), 29.6 (C-8).
4-Chlorophenyl N-(5-bromo-2-hydroxybenzyl)carbamate (1e). Yield 79%; m.p. 124 - 126o C; Calculated for C15H13BrClNO3 (370.4): 48.62% C, 3.51% H, 3.78% N; found 48.66% C, 3.52% H, 3.77% N; 1H-NMR: 8.65 (br, 1H, OH), 7.32 (m, 3H, H-3 + H-12+ H-14), 7.26 (d, J=2.4, 1H, H-1), 7.04 (m, 2H, H-11 + H-15), 6.83 (d, J=8.6, 1H, H-4), 4.37 (s, 2H, H-7), 3.13 (s, 3H, H-8); 13C-NMR: 156.6 (C-5), 154.9 (C-9), 149.2 (C-10), 133.3 (C-3), 132.9 (C-1), 131.1 (C-13), 129.2 (C-12 + C-14), 123.6 (C-6), 122.7 (C-11 + C-15), 119.5 (C-4), 111.2 (C-2), 49.5 (C-7), 34.4 (C-8).
3-chlorophenyl N-(5-bromo-2-hydroxybenzyl)carbamate (1f). Yield 54%; m.p. 130 -134o C; Calulated for C15H13BrClNO3 (370.4): 48.62% C, 3.51% H, 3.78% N; found 48.38% C, 3.51% H, 3.97% N; 1H-NMR: 8.62 (br, 1H, OH), 7.33 (dd, J=2.3, J=8.7, 1H, H-3), 7.27 (m, 2H, H-14 + H-1), 7.21 (m, 1H, H-15), 7.14 (t, J = 2.00, 1H, H-11), 7.01 (m, 1H, H-13), 6.84 (d, J=8.6, 1H, H-4), 4.37 (s, 2H, H-7), 3.13 (s, 3H, H-8); 13C-NMR: 156.5 (C-5), 155.0 (C-9), 151.2 (C-10), 134.6 (C-12), 133.4 (C-3), 133.1 (C-1), 130.0 (C-14), 126.1 (C-13), 123.5 (C-11), 119.8 (C-15), 119.7 (C-4), 111.2 (C-2), 49.6 (C-7), 34.5 (C-8).
3-Nitrophenyl N-(5-bromo-2-hydroxybenzyl)carbamate (1g). Yield 74%; m.p. 147oC (dec); Calculated for C15H13BrClN2O5 (416.5): 47.27% C, 3.41% H, 7.35% N; found 47.44% C, 3.50% H, 7.26% N; 1H-NMR: 8.41 (br, 1H, OH), 8.11 (m, 1H, H-13), 8.02 (t, J=2.2, 1H, H-11), 7.56 (t, J=8.1, 1H, H-14), 7.49 (m, 1H, H-15), 7.35 (dd, J=2.3, J=8.6, 1H, H-3), 7.29 (d, J=2.4, 1H, H-1), 6.85 (d, J=8.6, 1H, H-4), 4.41 (s, 2H, H-7), 3.18 (s, 3H, H-8); 13C-NMR: 155.0 (C-9), 154.9 (C-5), 150.9 (C-10), 148.5 (C-12), 133.4 (C-3), 133.2 (C-1), 129.9 (C-14), 127.9 (C-15), 123.3 (C-6), 120.7 (C-13), 119.7 (C-4), 117.2 (C-11), 111.4 (C-2), 49.7 (C-7), 34.6 (C-8).
Phenyl N-(4-nitro-2-hydroxybenzyl)carbamate (1h). Yield 49%; m.p. 147.5 – 150 °C; Calulated for C15H14N2O5 (302.3): 59.62% C, 4.63% H, 9.27% N; found 59.44% C, 4.63% H, 9.38% N; 1H-NMR: 9.25 (br, 1H, OH), 7.75 (s, 1H, H-4), 7.70 (d, J=8.2, 1H, H-1), 7.37 (m, 2H, H-12 + H-14), 7.30 (d, J=8.1, 1H, H-2), 7.23 (m, 1H, H-13), 7.10 (m, 2H, H-11 + H-15), 4.96 (s, 2H, H-7), 3.16 (s, 3H, H-8); 13C-NMR: 157.2 (C-5), 156.7 (C-9), 150.8 (C-10), 149.3 (C-3), 131.4 (C-1), 129.4 (C-12 + C-14), 128.6 (C-6), 125.9 (C-13), 121.4 (C-11 + C-15), 114.3 (C-2), 113.0 (C-4), 49.5 (C-7), 34.7 (C-8).
3-Nitrophenyl N-(4-nitro-2-hydroxybenzyl)carbamate (1i). Yield 84%; m.p. 137oC (dec.); Calculated for C15H13N3O7 (347.4): 51.89% C, 3.74% H, 12.11% N; found 51.96% C, 3.76% H, 12.16% N;1H-NMR: 8.95 (br, 1H, OH), 8.13 (d, J=8.1, 1H, H-13), 8.02 (m, 1H, H-11), 7.78 (d, J=1.90, 1H, H-4), 7.73 (dd, J=2.0, J=8.3, 1H, H-2), 7.59 (m, 1H, H-14), 7.49 (dd, J=1.0, J=8.7, 1H, H-15), 7.32 (d, J=8.3, 1H, H-1), 4.53 (s, 2H, H-7), 3.20 (s, 3H, H-8).
Phenyl N-(5-nitro-2-hydroxybenzyl)carbamate (1j). Yield 73%; m.p. 146 (dec.); Calculated for C15H14N2O5 (302.3): 59.62% C, 4.63% H, 9.27% N; found 59.73% C, 4.65% H, 9.43% N; 1H-NMR:9.50 (br, 1H, OH), 8.11 (m, 2H, H-1 + H-3), 7.37 (m, 2H, H-12 + H-14), 7.21 (t, J=7.4, 1H, H-13), 7.10 (m, 2H, H-11 + H-15), 6.97 (d, J=8.8, 1H, H-4), 4.47 (s, 2H, H-7), 3.17 (s, 3H, H-8); 13C-NMR: 162.2 (C-5), 157.5 (C-9), 150.7 (C-10), 140.2 (C-2), 129.4 (C-12 + C-14), 127.2 (C-3), 126.4 (C-1), 126.0 (C-13), 122.0 (C-6), 121.3 (C-11 + C-15), 118.2 (C-4), 49.7 (C-7), 34.5 (C-8).
4-Chlorophenyl N-(5-nitro-2-hydroxybenzyl)carbamate (1k). Yield 88%; m.p. 144.5-147.0o C; Calculated for C15H13ClN2O5 (336.3): 53.50 % C, 3.89% H, 8.32% N; found 53.20% C, 3.86% H, 8.58% N; 1H-NMR: 9.47 (br, 1H, OH), 8.16 (dd, J=2.7, J=9.0, 1H, H-3), 8.11 (d, J=2.7, 1H, H-1), 7.34 (m, 2H, H-12 + H.14), 7.06 (m, 2H, H-11 + H-15), 7.00 (d, J=8.9, 1H, H-4), 4.47 (s, 2H, H-7), 3.18 (s, 3H, H-8).
3-Chlorophenyl N-(5-nitro-2-hydroxybenzyl)carbamate (1l). Yield 71%; m.p. 117-119oC; Calculated for C15H13ClN2O5 (336.3): 53.50 % C, 3.89% H, 8.32% N; found 53.44% C, 3.89% H, 8.44% N; 1H-NMR: 9.54 (br, 1H, OH), 8.09 (m, 2H, H-1 + H-3), 7.28 (t, J=8.1, 1H, H-14), 7.19 (d, J=8.1, 1H, H-13), 7.14 (s, 1H, H-11), 7.02 (d, J=8.0, 1H, H-15), 6.91 (d, J=9.1, 1H, H-4), 4.54 (s, 2H, H-7), 3.15 (s, 3H, H-8); 13C-NMR: 161.9 (C-5), 156.8 (C-9), 150.9 (C-10), 140.1 (C-2), 134.5 (C-12), 130.0 (C-14), 1287.0 (C-13), 127.0 (C-1), 126.4 (C-3), 126.2 (C-11), 121.9 (C-15), 121.7 (C-6), 119.6 (C-4), 49.6 (C-7), 34.5 C-8).
3-Nitrophenyl N-(5-nitro-2-hydroxybenzyl)carbamate (1m). Yield 90%; m.p. 151-154oC; Calculated for C15H13N3O7 (347.4): 51.89% C, 3.74% H, 12.11% N; found 52.18% C, 3.83% H, 12.22% N; 1H-NMR: 9.52 (br, 1H, OH), 8.14 (m, 3H, H-3 + H-1 + H-13), 8.03 (t, J=2.2, 1H, H-11), 7.58 (t, J=8.1, 1H, H-14), 7.50 (m, 1H, H-15), 7.01 (d, J=8.9, 1H, H-4), 4.51 (s, 2H, H-7), 3.23 (s, 3H, H-8); 13C-NMR: 161.9 (C-5), 156.5 (C-9), 150.9 (C-10), 148.6 (C-12), 140.4 (C-2), 130.0 (C-14), 127.8 (C-15), 127.2 (C-1), 126.6 (C-3), 121.6 (C-6), 120.9 (C-13), 118.3 (C-4), 117.2 (C-11), 49.9 (C-7), 34.7 (C-8).

Acknowledgements

The authors would like to thank to the Grant Agency of the Czech Republic for the funds provided (Grant No. 203/01/0227).

References

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  3. Mindl, J.; Hrabík, O.; Štěrba, V.; Kaválek, J. Collect. Czech. Chem. Commun. 2000, 65, 1262.
  4. Mindl, J.; Čegan, A. Sci. Pap. Univ. Pardubice Ser. A5 1999, 129.
  • Sample availability: Available from the authors.

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MDPI and ACS Style

Hrabík, O.; Šimůnek, P.; Mindl, J.; Kaválek, J. Synthesis of Substituted Phenyl N-(2-hydroxybenzyl)-N-Methylcarbamates. Molecules 2002, 7, 200-205. https://doi.org/10.3390/70200200

AMA Style

Hrabík O, Šimůnek P, Mindl J, Kaválek J. Synthesis of Substituted Phenyl N-(2-hydroxybenzyl)-N-Methylcarbamates. Molecules. 2002; 7(2):200-205. https://doi.org/10.3390/70200200

Chicago/Turabian Style

Hrabík, Oldřich, Petr Šimůnek, Jaromír Mindl, and Jaromír Kaválek. 2002. "Synthesis of Substituted Phenyl N-(2-hydroxybenzyl)-N-Methylcarbamates" Molecules 7, no. 2: 200-205. https://doi.org/10.3390/70200200

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