Straightforward Synthesis of 2-Substituted 3,4-Dihydro-2H-1,4

Ring Opening and Goldberg Coupling Cyclization for the Synthesis of 3,4-Dihydro-2H-1,4-benzoxazines. R. Koteshwar Rao , Ajay B. Naidu and Govindas...
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Ind. Eng. Chem. Res. 2003, 42, 680-686

Straightforward Synthesis of 2-Substituted 3,4-Dihydro-2H-1,4-benzoxazines under Solid-Liquid Phase Transfer Catalysis Conditions Domenico Albanese,* Dario Landini, Vittoria Lupi, and Michele Penso Dipartimento di Chimica Organica e Industriale, Universita` degli Studi di Milano and CNR-ISTM, via Venezian 21, I-20133 Milano, Italia

A straightforward and efficient synthesis of 2-substituted 3,4-dihydro-2H-1,4-benzoxazines 6-9 has been carried out in excellent overall yields through the ring opening of epoxides 1 with arylsulfonamides 2 and 3, followed by cyclization of the hydroysulfonamides 4 and 5 thus obtained. Both steps are carried out under solid-liquid phase transfer catalysis (SL-PTC) conditions using potassium carbonate and sodium hydroxide as bases. The procedure is feasible for the synthesis of non-racemic 2-substituted benzoxazines. Scheme 1a

Introduction 2-Substituted 3,4-dihydro-2H-1,4-benzoxazines have attracted considerable interest because of their potential therapeutic properties as intracellular calcium antagonists, serotonin receptors antagonists, and antibacterial agents.1 The 1,4-benzoxazine skeleton has usually been constructed through cyclocondensation of o-aminophenols with suitable dibromoderivatives such as dibromoalkanes2 or R-halogeno acyl bromides followed by carbonyl reduction with BH33 or through alkylation of o-nitrophenols4 followed by reductive cyclization. However, the scale-up of these procedures is hampered by the use of toxic lachrymatory bromo derivatives and dimethylformamide as a solvent, which is difficult to remove efficiently. Moreover, racemic 2-substituted benzoxazines are obtained, so that additional resolution steps are required to generate enantiomerically pure compounds. Sinou5 and Achiiwa6 independently prepared 2-vinyl-1,4-benzoxazines with enantiomeric excesses of up to 79%, although in moderate yields, by palladium-catalyzed cyclization of N-protected o-aminophenols with (Z)-1,4-bis(methoxycarbonyloxy)but-2-ene. Here, we report that 2-substituted 3,4-dihydro-2H1,4-benzoxazines 6 and 7 can be prepared by the ring opening of epoxides 1 with (2-fluorophenyl)toluene-psulfonamide (2) or (2-fluoro-5-nitrophenyl)toluene-psulfonamide (3) under solid-liquid phase transfer catalysis (SL-PTC) conditions without solvent. The hydroxysulfonamides 4 and 5 thus obtained generate the corresponding benzoxazines 6 and 7 through cyclization under SL-PTC conditions by using 2 molar equiv only of tetrahydrofuran (THF) as the solvent (Scheme 1). Ring Opening of Epoxides. In previous papers, we reported on the ring opening of epoxides with Ntrifluoroacetamide7 and toluene-p-sulfonamide8 under SL-PTC conditions to afford the corresponding hydroxyamides, which were then efficiently converted into amino alcohols and N-sulfonylaziridines. In light of these results and because of the good nucleofugality of the fluoride anion in aromatic nucleophilic substitution, N-(2-fluorophenyl)toluene-p-sulfonamides 2 and 3 were * To whom correspondence should be addressed. Tel.: +39 0250314165. Fax: +39 0250314159. E-mail: [email protected].

a Reagents and conditions: i, K CO 2 3cat, TEBAcat, 90 °C; ii, NaOH, TBABcat, THF, reflux, iii, HBr/AcOH, room temperature.

chosen as the nitrogen nucleophiles incorporating the aromatic moiety of benzoxazine and the leaving group required for the cyclization. When 1,2-epoxy-3-phenoxypropane (1f), chosen as a model compound, was reacted with 2 in the presence of catalytic amounts of solid, anhydrous K2CO3, and triethylbenzylammonium chloride (TEBA) in dioxane at 90 °C, N-(2-fluorophenyl)-N-(2-hydroxy-2-phenoxypropyl)toluene-p-sulfonamide (4f) was obtained in 95% yield after 17 h. Subsequent experiments indicated that the best result, 94% of 4f in only 1 h, can be obtained without any organic solvent, the epoxide behaving as solvent itself. The PTC agent is essential to develop an efficient process, as a reaction time of 56 h was neces-

10.1021/ie020702s CCC: $25.00 © 2003 American Chemical Society Published on Web 01/17/2003

Ind. Eng. Chem. Res., Vol. 42, No. 4, 2003 681 Table 1. Optimization of the Ring Opening of 1fa

Table 3. Hydroxysulfonamides 5a

dioxane (mol/L)

catalyst

t (h)

yield (%)

product

R1

R2

R3

t (h)

yield (%)

2.5 10 -b

TEBA TEBA TEBA TBAB MeBu3N+Br(10)

17 3 1 56 2 2 3

95 85 94 86 89 90 87

5c 5f 5i

H H H

Me CH2OPh COOMe

Me H Me

32 5 3

56b 81 52c

a Reaction conditions: 2 (1.1 molar equiv), catalyst (0.1 molar equiv), K2CO3 (0.1 molar equiv). b 2 (1 molar equiv).

Table 2. Hydroxysulfonamides 4a product

R1

4a 4b 4c 4d 4e 4f (S)-4g 4h 4i 4j

H H H H H H H H H

R2 n-C6H13 Ph Me -(CH2)4CH2OH CH2OPh CH2OBn CH2OTHP COOMe CH2OMs

R3

t (h)

yield (%)

H H Me H H H H H Me H

6 2 12 26 2 1 2 2 2 2.5

90 71b 65c 90 86 94 92 78 91 43

a Reaction conditions: 2 (1.1 molar equiv), TEBA (0.1 molar equiv), K2CO3 (0.1 molar equiv). b Mixture of 4b (56%) and 15% of its regioisomer. c At 50 °C.

sary to generate 86% of the hydroxysulfonamide 4f in the absence of any catalyst. This behavior is clearly to be ascribed to the potassium sulfonamide ion pair reactivity, much lower than that of the quaternary ammonium ion pair generated in situ in the catalyzed reaction. The latter is regenerated through protonation of the intermediate alcoholate deriving from the ring opening by sulfonamides 2 and 3, thus enabling the catalytic process. Comparable results were obtained by using Bu4N+Br- (TBAB) or MeBu3N+Br- instead of TEBA (Table 1). It is worth noting that, when the same reaction is carried out with an ammonium salt partially miscible in water such as n-C14H29Me3N+Cl- (10), the pure hydroxysulfonamide 4f can be isolated in 87% yield by simple filtration of the white solid formed after water dilution. The same precipitation proved to be less efficient in the case of TEBA, as a 67% yield of a sticky compound was obtained. A representative series of epoxides 1 was thus converted into β-hydroxysulfonamides 4 and 5 in excellent yields and short reaction times (Table 2). The ring opening proceeds in a complete regioselective fashion, affording β-hydroxysulfonamides 4 and 5 derived from the nucleophilic attack on the less-substituted carbon atom of the oxirane ring. In the particular case of styrene oxide (1b), a mixture of regioisomers was obtained, probably as a consequence of a mixed SN1/ SN2 pathway. Methyl 2-methyl glycidate (1i) is converted to hydroxysulfonamide 4i without saponification of the ester moiety. On the other hand, the ring opening of O-methanesulfonyl glycidol (1j) affords a complex reaction mixture from which the desired 4j was isolated in only 43% yield. This behavior can be ascribed to the well-known leaving group ability of the methanesulfonyloxy group. In accordance with the observed regiochemistry, nonracemic epoxides generate enantiopure β-hydroxysulfonamides as revealed in the case of (2S)-[(benzyloxy)methyl]oxirane [(S)-(1g)], which affords (2S)-N-(2fluorophenyl)-N-(2-hydroxy-2-benzyloxypropyl)toluenep-sulfonamide [(S)-(4g)] in 92% yield after 2 h.

a Reaction conditions: 2 (1.1 molar equiv), TEBA (0.1 molar equiv), K2CO3 (0.1 molar equiv). b At 50 °C. c Along with 20% of potassium 2-methyl-3,4-dihydro-2H-1,4-benzoxazinyl-2-carboxylate.

Table 4. Synthesis of 6f by Cyclization of 4fa entry

TBAB (%)

T (°C)

t (h)

yield (%)

1 2 3 4 5

10 5 2.5 10

67 67 67 90b 50c

1 8 48 48 35

99 90 95 78 90

a Reaction conditions: NaOH (4 molar equiv), THF (2 molar equiv), reflux. b Dioxane. c With MTBE.

(2-Fluoro-5-nitrophenyl)toluene-p-sulfonamide (3) was also used as a nucleophile, as a nitro group in position 6 of a 2-substituted benzoxazine was found to be an important means of enhancing its bioactivity.9 Moreover, the nitro group was expected to facilitate the fluoride displacement in the cyclization step. Sulfonamide 3 was prepared in good yield through N-tosylation of 2-fluoro-5-nitroaniline and afforded 81% yield of hydroxysulfonamide 5f when reacted with 1f under the previously described SL-PTC conditions (Table 3). In the case of epoxide 1c, sulfonamide 3 afforded results similar to those obtained with sulfonamide 2, whereas, with epoxide 1i, a 52% yield of the expected 5i was isolated, together with 20% of potassium 2-methyl-3,4dihydro-2H-1,4-benzoxazinyl-2-carboxylate (Table 3). Cyclization of Hydroxysulfonamides 4 and 5. The 1,4-benzoxazine ring can be formed by intramolecular aromatic nucleophilic substitution (SNiAr) of fluoride anion promoted by a suitable base, capable of selectively generating the alkoxide anion without direct displacement of the fluoride itself. Only isolated examples have been previously reported concerning SNiAr reactions of fluoride by thiolate10 or phenolate anions,11 taking advantage of the well-known nucleofugality of fluoride anion in SNiAr. Although the task was achieved with a non-nucleophilic strong base such as ButOK in THF at reflux,12 the use of cheaper and environmentally friendly reagents, as well as a simplified procedure for benzoxazines isolation, would be desirable for the economical scale-up of the process. When hydroxysulfonamide 4f, chosen as a model compound, was reacted with an excess of solid K2CO3 in acetonitrile or THF at reflux, in the presence of tetrabutylammonium bromide (TBAB) as a PTC catalyst, only low conversions to benzoxazine 6f were observed after 22 h. On the other hand, ring closure to 6f was complete in only 1 h using an excess of solid NaOH in the presence of 0.1 molar equiv of TBAB along with a minimal amount of THF (2 molar equiv) to enable stirring of the heterogeneous mixture (Table 4). As expected for a PTC mechanism, the cyclization rate decreases gradually with the amount of PT catalyst, but the yield of isolated 6f remains above 90%. The reaction also proceeds without catalyst, although a reaction time of 48 h is necessary to generate 6f in a 78% yield only Table 4. Methyl tert-butyl ether (MTBE) can be suc-

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Table 5. Benzoxazines 6a product

R1

6a 6b 6c 6d 6e 6f 6g 6h 6i

H H H H H H H H

R2 n-C6H13 Ph Me -(CH2)4CH2OH CH2OPh CH2OBn CH2OTHP COOMe

Table 7. N-Deprotection of Benzoxazines 6 and 7 R3

t (h)

yield (%)

product

method

T (°C)

t (h)

yield (%)

H H Me H H H H H Me

2 1 29 0.5 10 0.5 2 0.5 2

90 81 34 99 40 99 90 99 67b

8a 8b 8d 8e 8f 8f 8f (S)-8g (S)-8g 9f

A A A A A B C B C A

25 25 25 25 25 -70 80 -70 80 25

4 1 2 2 2 0.5 12 1 19 23

77 97 84 81b 93 77 81 84 84 93

a Reaction conditions: NaOH (4 molar equiv), TBAB (0.1 molar equiv), THF (2 molar equiv), reflux. b Sodium carboxylate 11 was obtained.

a Method A: 40% HBr in AcOH, PhOH. Method B: Na, naphthalene, DME. Method C: Na(MeOCH2CH2O)2AlH2, toluene. b Yield of 8e recovered from 6h.

Table 6. Benzoxazines 7a product

R1

R2

R3

t (h)

yield (%)

7c 7f

H H

Me CH2OPh

Me H

2 1.5

72 75

Scheme 3

a

a Reaction conditions: NaOH (4 molar equiv), TBAB (0.1 molar equiv), THF (2 molar equiv), reflux.

Scheme 2

a

a Reagents and conditions: i, NaOH (2 molar equiv), TBAB (0.1 molar equiv), THF (2 molar equiv), reflux; ii, NaOH (1 molar equiv), H2O/THF, 25 °C.

cessfully used, although the ring closure is slow because of its lower boiling point (Table 4, entry 5). Under the best reaction conditions (Table 4, entry 1), the cyclizations of hydroxysulfonamides 4 and 5 are usually fast, and benzoxazines 6 and 7 are selectively generated in excellent yields (Tables 5 and 6). The cyclization of hydroxysulfonamides bearing a tertiary hydroxy group is slower, as revealed in the case of compound 4c, which generates benzoxazine 6c in a 34% yield after 29 h. On the other hand, the cyclization of hydroxysulfonamide 4i takes only 2 h, affording 67% yield of benzoxazine 11 deriving from simultaneous saponification of the ester group and cyclization, along with 22% of sulfonamide 2, probably via decarboxylation followed by acetone or propylene oxide elimination. The same result is obtained by cyclization of sodium 3-[(2fluorophenyl)-(toluene-4-sulfonyl)amino]-2-hydroxy-2methylpropionate (12), obtained by saponification of the ester group with an equimolar amount of NaOH at room temperature (Scheme 2). The cyclization of the hydroxymethyl sulfonamide 4e afforded a complex reaction mixture from which 40% of the N-tosyl-2-hydroxymethylbenzoxazine 6e was isolated. This behavior is likely due to competitive reaction pathways involving both hydroxy groups. However, 6e can be obtained in quantitative yields by deprotection of N-tosyl-2-tetrahydropyranyloxybenzoxazine 6h with pyridinium-p-toluensulfonate in methanol at room temperature. Under the PTC conditions employed, no phenols derived from the nucleophilic displacement of the fluoride by hydroxide anion were ever isolated.

a

Reagents and conditions: i, 1f, K2CO3/TEBAcat, 90 °C.

The choice of the catalyst plays a fundamental role in the optimization of the cyclization process, as investigated in the representative cases of hydroxysulfonamides 4f and (S)-4g. In fact, when TBAB was replaced by n-C14H29Me3N+Cl- (10), a catalyst partially soluble in water, the corresponding benzoxazines 6f and (S)6g were isolated in 92 and 90% yields, respectively, after 2 h by simple filtration of the reaction mixture after dilution with water. Deprotection of Benzoxazines 6 and 7. The removal of the N-tosyl protecting group was carried out by treating benzoxazines 6 and 7 with 40% HBr/AcOH at room temperature in the presence of phenol as a bromine scavenger. Benzoxazines 8 and 9 were isolated in excellent yields in short reaction times. On the other hand, good results can also be obtained with alternative methodologies such as Na(MeOCH2CH2O)2AlH2 (RedAl) and Na/naphthalene protocols, that, of course, need to be used in the case of benzoxazines bearing functional groups sensitive to acidic conditions (Table 7). However, 2-hydroxymethylbenzoxazine 8e can be isolated in 81% yield by simultaneous N,O-deprotection of the 2-tetrahydropyranyloxybenzoxazine 6h with HBr/ AcOH. Although benzoxazines 8 and 9 were obtained in high yields by the standard N-detosylation protocols described above, the use of o-nitrobenzensulfonamide as a N-protecting group was investigated. In fact, the o-nitrobenzensulfonyl group (o-Ns) has recently been introduced by Fukuyama as a nitrogen protecting group, removable under very mild conditions, e.g., with potassium benzenthiolate.13 N-(2-Fluorophenyl)-2-nitrobenzensulfonamide (13) was thus reacted with epoxide 1f to generate hydroxysulfonamide 14 in 88% yield after 2 h (Scheme 3). However, the latter afforded complex reaction mixtures when treated with K2CO3 or NaOH under SL-PTC conditions or with t-BuOK in THF to cause ring closure to benzoxazine. Conclusions In conclusion, 2-substituted 3,4-dihydro-2H-1,4-benzoxazines 6-9 can be produced in an efficient and economical manner employing inexpensive, safe, and commercially available reagents under SL-PTC condi-

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tions. Moreover, nonracemic benzoxazines are produced when enantiomerically pure epoxides are used, the stereochemical integrity of the epoxide stereocenter being preserved through the synthetic scheme to benzoxazines. No solvent is required in the ring opening of the epoxides, and a minimal amount was used in the cyclization to benzoxazines. It is worth noting that N-tosyl-benzoxazines 6 and 7 can be isolated by filtration of the reaction mixture after dilution with water to remove n-C14H29Me3N+Cl- (10) and precipitate benzoxazines, thus allowing a high productivity and simplicity of the procedure. Acknowledgment Financial support from MURST (National Project “Stereoselezione in Sintesi Organica, Metodologie e Applicazioni” and FIRB) and CNR is acknowledged. Appendix: Experimental Section General Remarks. Epoxides 1 are all commercially available, except for 1h, which was prepared as reported elsewhere.14 Pellets of NaOH were ground with a mortar before use. K2CO3 was dried by heating at 140 °C in a vacuum (0.05 mmHg) for 6 h. 1H, 19F, and 13C NMR spectra were recorded in CDCl3 at 300.1, 282.4, and 75.5 MHz, respectively, using TMS (1H) and CFCl3 (19F) as external standards and CHCl3 (13C) as an internal standard. The coupling constants are in hertz. IR spectra were recorded on an FT-IR 1725 Perkin-Elmer spectrometer, and frequency values are in wavenumbers. Optical rotations were measured with a PerkinElmer 241 instrument. Melting points are corrected. Experimental Apparatus. The apparatus was a 20-150-mL three-necked jacketed flask fitted with a flat-bladed stirring paddle, reflux condenser, and sampling port. The stirring speed (800 rpm) was determined using a strobe light, and the temperature was checked by a thermostated bath. (2-Fluorophenyl)toluene-p-sulfonamide (2). 2-Fluoroaniline (83 mmol, 9.22 g) was dropwise added to a solution of toluenesulfonyl chloride (83 mmol, 15.82 g) in 20 mL of pyridine at 0 °C, and the mixture was stirred at room temperature for 2 h. The crude was neutralized with 10% HCl, 30 mL of Et2O was added, and the phases were separated. After the organic phase had been dried over MgSO4, the solvent was evaporated in vacuo, and the residue was crystallized from EtOH to give 17.6 g of 2, 86% yield, mp 106-107 °C (lit.15 mp 108-109 °C). 1H NMR (CDCl3): δ 2.37 (s, 3H), 6.67 (bs, 1H), 6.93-7.11 (m, 3H), 7.20 (d, 2H, J ) 8.6 Hz), 7.60 (m, 1H), 7.60 (d, 1H, J ) 8.6 Hz). N-(2-Fluorophenyl)-2-nitrobenzensulfonamide (13). 2-Nitrobenzensulfonyl chloride (20 mmol, 4.43 g) was dropwise added to a solution of 2-fluoroaniline (20 mmol, 2.22 g) in 8 mL of pyridine at 0 °C, and the mixture was stirred at room temperature for 2 h. The crude was neutralized with 10% HCl, 10 mL of Et2O was added, and the phases were separated. After being dried over MgSO4, the solvent was evaporated in vacuo, and the residue was crystallized from AcOEt to give 5.04 g of 13, 85% yield, mp 116-117 °C. 1H NMR (CDCl3): δ 6.99-7.96 (m, 9H). Anal. Calcd for C12H9FN2O4S: C, 48.65; H, 3.06; N, 9.46. Found: C, 48.84, H, 3.21; N, 9.35. (2-Fluoro-5-nitrophenyl)toluene-p-sulfonamide (3). 2-Fluoro-5-nitroaniline (50 mmol, 7.81 g) was drop-

wise added to a solution of toluenesulfonyl chloride (52 mmol, 9.91 g) in 20 mL of pyridine at 0 °C, and the mixture was stirred at room temperature for 3 h. The crude was neutralized with 10% HCl, 30 mL of CH2Cl2 was added, and the phases were separated. After being dried over MgSO4, the solvent was evaporated in vacuo, and the residue was crystallized from AcOEt to give 12.4 g of 3, 80% yield, mp 181-182 °C. 1H NMR (CDCl3): δ 2.41 (s, 3H), 6.95 (bs, 1H), 7.26-7.32 (m, 3H), 7.77 (d, 2H, J ) 12.6 Hz), 7.98 (m, 1H), 8.48 (dd, 1H, J ) 3.9, 10.2 Hz). Anal. Calcd for C13H11FN2O4S: C, 50.32, H; 3.57, N; 9.03. Found: C, 50.49; H, 3.65; N, 8.87. General Method for the Ring Opening of Epoxides 1. Method A. The reactor was charged with sulfonamide 2, 3 (22 mmol), epoxide 1 (20 mmol), K2CO3 (276 mg, 2 mmol), and TEBA (456 mg, 2 mmol), and the resultant heterogeneous mixture was stirred at 90 °C for the time indicated in Tables 2 and 3. Addition of water, extraction with CH2Cl2, drying with MgSO4, filtration and solvent removal in vacuo gave a residue that was purified by column chromatography on silica gel to give hydroxysulfonamides 4 and 5. Yields; chromatographic eluants; and analytical, physical, and spectroscopic data of compounds are the following: N-(2-Fluorophenyl)-N-(2-hydroxyoctyl)toluenep-sulfonamide (4a). 90%, AcOEt/light petroleum (PE, bp 40-60 °C) 1-3, mp 67 °C. 1H NMR (CDCl3): δ 0.84 (t, 3H, J ) 0.64 Hz), 1.23 (bs, 8H), 1.39 (bs, 2H), 2.43 (s, 3H), 3.45-3.58 (m, 3H), 7.06-7.28 (m, 6H), 7.56 (d, 2H). 19F NMR (CDCl3): δ -118.83. Anal. Calcd for C21H28FNO3S: C, 64.10; H, 7.17; N, 3.56. Found: C, 64.35; H, 7.40; N, 3.40. N-(2-Fluorophenyl)-N-(2-hydroxy-2-phenylethyl)toluene-p-sulfonamide (4b). 71%, Et2O/PE 1:2, mp 127-128 °C. 1H NMR (CDCl3): δ 2.41 (s, 3H), 2.95 (d, 1H, J ) 2.9 Hz), 3.59 (dd, 1H, J ) 3.3, 14.4 Hz), 3.78 (dd, 1H, J ) 9.2, 14.4 Hz), 4.81 (dt, 1H, 3.3, 9.2), 7.057.56 (m, 13H). 19F NMR (CDCl3): δ -118.95. Anal. Calcd for C21H20FNO3S: C, 65.44; H, 5.23; N, 3.63. Found: C, 65.62; H, 5.40; N, 3.51. N-(2-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)toluene-p-sulfonamide (4c). 65%, Et2O/PE 1:1. 1H NMR (CDCl ): δ 1.22 (s, 6H), 2.40 (s, 3H), 3.56 (s, 3 2H), 6.98-7.16 (m, 2H), 7.24-7.32 (m, 4H), 7.50 (d, 2H, J ) 8.2 Hz). 19F NMR (CDCl3): δ -117.85.13C NMR (CDCl3, selected data): δ 21.5, 27.3, 61.5, 71.3. Anal. Calcd for C17H20FNO3S: C, 60.51; H, 5.97; N, 4.15. Found: C, 60.70; H, 6.26; N, 3.78. N-(2-Fluorophenyl)-N-(2-hydroxycyclohexyl)toluene-p-sulfonamide (4d). 90%, Et2O/PE 2:3, mp 121122 °C. 1H NMR (CDCl3): δ 0.91 (m, 2H), 1.23 (m, 2H), 1.53 (m, 2H), 1.86 (m, 2H), 2.37 (s, 3H), 2.9 (bs, 1H), 3.15 (m, 1H), 3.80 (m, 1H), 7.10-7.70 (m, 8H).19F NMR (CDCl3): δ -114.9, -118.9. Anal. Calcd for C19H22FNO3S: C, 62.79; H, 6.10; N, 3.85. Found: C, 62.87; H, 6.35; N, 3.80. N-(2-Fluorophenyl)-N-(2,3-dihydroxypropyl)toluene-p-sulfonamide (4e). 86%, Et2O/PE 9:1, mp 9394 °C. 1H NMR (CDCl3): δ 2.30 (bs, 1H), 2.72 (bs, 1H), 2.43 (s, 3H), 3.57-3.72 (m, 5H), 7.03-7.57 (m, 8H).19F NMR (CDCl3): δ -122.37. Anal. Calcd for C16H18FNO4S: C, 56.62; H, 5.35; N, 4.13. Found: C, 56.99; H, 5.59; N, 3.82. N-(2-Fluorophenyl)-N-(2-hydroxy-3-phenoxypropyl)toluene-p-sulfonamide (4f). 94%, Et2O/PE 1:1, mp 91-92 °C. 1H NMR (CDCl3): δ 2.40 (s, 3H), 2.80 (d,

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1H, J ) 4.1 Hz), 3.70-3.80 (m, 2H), 4.00-4.10 (m, 3H), 6.80-7.60 (m, 13H). 13C NMR (CDCl3, selected data): δ 21.6, 53.7, 68.6, 69.2. 19F NMR (CDCl3): δ -118.72. Anal. Calcd for C22H22FNO4S: C, 63.60; H, 5.34; N, 3.37. Found: C, 63.88; H, 5.69; N, 3.31. (S)-N-(2-Fluorophenyl)-N-(2-hydroxy-3-benzyloxypropyl)toluene-p-sulfonamide (4g). 92%, AcOEt/PE 1:1, mp 62 °C, [R]D20 ) -4.2 (c ) 1, CH2Cl2). 1H NMR (CDCl3): δ 2.42 (s, 3H), 2.64 (d, 1H, J ) 4.7 Hz), 3.53 (dd, 1H, J ) 5.4, 9.8 Hz), 3.59 (dd, 1H, J ) 4.3, 9.8 Hz), 3.65 (d, 2H, J ) 6.1 Hz), 3.85 (m, 1H), 4.46 (m, 2H), 6.95-7.56 (m, 13H). 13C NMR (CDCl3, selected data): δ 21.5, 53.6, 68.9, 71.4, 73.4. 19F NMR (CDCl3): δ -118.57. Anal. Calcd for C23H24FNO4S: C, 64.32; H, 5.63; N, 3.27. Found: C, 64.63; H, 5.79; N, 3.12. N-(2-Fluorophenyl)-N-(2-hydroxy-3-tetrahydropyranyloxypropyl)toluene-p-sulfonamide (4h). 78%, Et2O/PE, 2:1, mp 85-86 °C. 1H NMR (CDCl3): δ 1.431.77 (m, 6H), 2.42 (s, 3H), 3.00 (bs, 1H), 3.27 (bs, 1H), 3.47 (m, 1H), 3.57-3.84 (m, 6H), 4.47 (m, 1H), 7.007.57 (m, 8H).19F NMR (CDCl3): δ -118.55, -118.61. Anal. Calcd for C21H26FNO5S: C, 59.56; H, 6.19; N, 3.31. Found: C, 59.90; H, 6.31; N, 3.15. 3-N-(2-Fluorophenyl)-N-(4-methylphenylsulfonyl)2-hydroxy-2-methyl)methyl Propanoate (4i). 91%, AcOET/PE 1:9. mp 67 °C. 1H NMR (CDCl3): δ 1.31 (s, 3H), 2.33 (s, 3H), 3.47 (s, 3H), 3.79 (d, 1H, J ) 14.2 Hz), 3.93 (d, 1H, J ) 14.23 Hz), 6.90 (t, 1H, J ) 10.6 Hz), 7.02 (t, 1H, J ) 7.1 Hz), 7.14-7.21 (m, 4H), 7.40 (d, 2H, J ) 8.4 Hz). 19F NMR (CDCl3): δ -118.18. Anal. Calcd for C18H20FNO5S: C, 56.68; H, 5.29; N, 3.67. Found: C, 57.02; H, 5.48; N, 3.30. N-(2-Fluorophenyl)-N-(2-hydroxy-3-methanesulfonyloxypropyl)toluene-p-sulfonamide (4j). 43%. 1H NMR (CDCl3): δ 2.42 (s, 3H), 3.06 (s, 3H), 3.65 (m, 2H), 3.97 (m, 1H), 3.58 (dd, 1H, J ) 5.2, 6.9 Hz), 4.36 (dd, 1H, J ) 3.6, 3.8 Hz), 7.03-7.37 (m, 6H), 7.53 (d, 2H, J ) 8.3 Hz).19F NMR (CDCl3): δ -118.74. Anal. Calcd for C17H20FNO6S2: C, 48.91; H, 4.83; N, 3.36. Found: C, 49.16; H, 5.10; N, 3.10. N-(2-Fluoro-5-nitrophenyl)-N-(2-hydroxy-2-methylpropyl)toluene-p-sulfonamide (5c). 56%, Et2O/ PE 1:1, mp 98-99 °C. 1H NMR (CDCl3): δ 1.27 (s, 6H), 2.44 (s, 3H), 3.55 (s, 2H), 7.18-7.24 (m, 1H), 7.29 (d, 2H, J ) 8.4 Hz), 7.50 (d, 2H, J ) 8.4 Hz), 7.99-8.03 (m, 1H), 8.17-8.22 (m, 1H).19F NMR (CDCl3): δ -105.84.13C NMR (CDCl3, selected data): δ 22.1, 53.8, 69.0, 69.4. Anal. Calcd for C17H19FN2O5S: C, 53.39; H, 5.01; N, 7.33. Found: C, 53.60; H, 5.20; N, 7.12. N-(2-Fluoro-5-nitrophenyl)-N-(2-hydroxy-3-phenoxypropyl)toluene-p-sulfonamide (5f). 81%, CH2Cl2/PE 3:1. 1H NMR (CDCl3): δ 2.47 (s, 3H), 2.72 (bs, 1H), 3.82 (d, 2H, J ) 6.0 Hz), 4.06 (d, 2H, J ) 5.1 Hz), 4.15 (m, 1H), 6.77 (d, 2H, J ) 7.7 Hz), 6.95 (t, 1H, J ) 7.4 Hz), 7.16-7.28 (m, 3H), 7.33 (d, 2H, J ) 8.2 Hz), 7.59 (d, 2H, J ) 8.2 Hz), 8.08-8.19 (m, 2H). 19F NMR (CDCl3): δ -107.04. Anal. Calcd for C22H21FN2O6S: C, 57.38; H, 4.60; N, 6.08. Found: C, 57.57; H, 4.82; N, 5.87. 3-N-(2-Fluoro-5-nitrophenyl)-N-(4-methylphenylsulfonyl)-2-hydroxy-2-methyl)methyl propanoate (5i). 52%, Et2O/PE 2:1, mp 113-114 °C. 1H NMR (CDCl3): δ 1.41 (s, 3H), 2.44 (s, 3H), 3.29 (s, 1H), 3.70 (d, 1H, J ) 14.5 Hz), 3.77 (s, 3H), 3.99 (d, 1H, J ) 14.5 Hz), 7.18 (t, 1H, J ) 9.2 Hz), 7.29 (d, 2H, J ) 8.1 Hz), 7.49 (d, 2H, J ) 8.1 Hz), 8.01 (m, 1H), 8.20 (m, 1H). 19F NMR (CDCl3): δ -106.29. Anal. Calcd for C18H19-

FN2O7S: C, 50.70; H, 4.49; N, 6.57. Found: C, 50.98; H, 4.62; N, 6.45. Method B. The reactor was charged with sulfonamide 2 (30 mmol, 7.96 g), epoxide 1f (30 mmol, 4.50 g), K2CO3 (3 mmol, 0.42 g), and 10 (3 mmol, 0.88 g), and the heterogeneous mixture thus obtained was stirred at 90 °C for 3 h. After addition of 20 mL of water, the mixture was stirred for 30 min at 25 °C. The white solid being formed was filtered and washed with 5 mL of water to give 10.84 g of 4f, mp 89 °C, with spectroscopic data identical to those previously reported. General Method for the Cyclization of Hydroxysulfonamides 4 and 5 to Benzoxazines 6 and 7. Method A. The reactor was charged with hydroxysulfonamide 4, 5 (20 mmol), solid NaOH (80 mmol, 3.2 g), Bu4N+Br- (2 mmol, 0.64 g), and THF (40 mmol, 3.24 mL), and the heterogeneous mixture thus obtained was stirred at reflux for the time indicated in Tables 5 and 6. Addition of water, extraction with CH2Cl2, drying with Na2SO4, filtration and solvent removal in vacuo gave a residue that was purified by column chromatography on silica gel to give benzoxazine 6 and 7. Yields and analytical and spectroscopic data are the following: N-(Tosyl)-2-(n-hexyl)-3,4-dihydro-2H-1,4-benzoxazine (6a). 90%, AcOEt/PE 1:10. 1H NMR (CDCl3): δ 0.89 (t, 3H), 1.24-1.56 (m, 10H), 2.38 (s, 3H), 3.07 (dd, 1H, J ) 6.7, 9.5 Hz), 3.23 (m, 1H), 4.23 (dd, 1H, J ) 1.5, 9.5 Hz), 6.77-6.80 (m, 1H), 6.87-6.93 (m, 1H), 7.01-7.06 (m, 1H), 7.23 (d, 2H, J ) 4.9 Hz), 7.49 (d, 2H, J ) 5.5 Hz), 7.83 (dd, 1H, J ) 5.5 Hz). Anal. Calcd for C21H27NO3S: C, 67.53; H, 7.29; N, 3.75. Found: C, 67.81; H, 7.45; N, 3.34. N-(Tosyl)-2-phenyl-3,4-dihydro-2H-1,4-benzoxazine (6b). 81%, mp 149-150 °C. 1H NMR (CDCl3): δ 2.43 (s, 3H), 3.27 (dd, 1H, J ) 10.3, 14.6 Hz), 4.24 (dd, 1H, J ) 2.5, 10.3 Hz), 4.40 (dd, 1H, J ) 2.5, 14.6 Hz), 6.96-7.95 (m, 13H). Anal. Calcd for C21H19NO3S: C, 69.02; H, 5.24; N, 3.83. Found: C, 69.10; H, 5.36; N, 3.71. N-(Tosyl)-2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine (6c). 34%, mp 106-108 °C. 1H NMR (CDCl3): δ 1.29 (s, 6H), 2.34 (s, 3H), 3.65 (s, 2H), 6.70-6.76 (m, 2H), 6.83-6.89 (m, 1H), 7.24 (d, 2H, J ) 8.2 Hz), 7.48 (d, 1H, J ) 5.9 Hz), 7.72 (d, 2H, J ) 8.2 Hz). Anal. Calcd for C17H19NO3S: C, 64.33; H, 6.03; N, 4.41. Found: C, 64.30; H, 5.91; N, 4.33. N-(Tosyl)-2,3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (6d). 99%, mp 104-105 °C. 1H NMR (CDCl3): δ 1.30-1.60 (m, 4H), 1.79 (m, 2H), 2.10 (m, 1H), 2.33 (m, 3H), 2.65 (m, 1H), 3.34-3.53 (m, 2H), 6.69 (dd, 1H, J ) 1.9, 7.6 Hz), 6.95-7.11 (m, 4H), 7.25 (d, 2H, J ) 8.2 Hz), 7.79 (dd, 2H, J ) 2.0, 7.8 Hz). 13C NMR (CDCl3, selected data): δ 21.5, 23.9, 24.5, 31.8, 33.4, 65.3, 80.8. Anal. Calcd for C19H21NO3S: C, 66.45; H, 6.16; N, 4.08. Found: C, 66.66; H, 6.34; N, 3.91. N-(Tosyl)-2-hydroxymethyl-3,4-dihydro-2H-1,4benzoxazine (6e). 40%, mp 128-129 °C. 1H NMR (CDCl3): δ 1.80 (t, 1H, J ) 6.5 Hz), 2.38 (s, 3H), 3.37 (dd, 1H, J ) 9.9, 14.3 Hz), 3.55 (m, 1H), 3.75 (m, 2H), 4.26 (dd, 1H, J ) 2.4, 14.3 Hz), 6.84-7.82 (m, 8H). Anal. Calcd for C16H17NO4S: C, 60.17; H, 5.37; N, 4.39. Found: C, 60.57; H, 5.68; N, 4.10. N-(Tosyl)-2-phenoxymethyl-3,4-dihydro-2H-1,4benzoxazine (6f). 99%, mp 114 °C. 1H NMR (CDCl3): δ 2.35 (s, 3H), 3.39 (dd, 1H, J ) 9.9, 14.4 Hz), 3.653.69 (m, 1H), 3.92 (dd, 1H, J ) 6.3, 10.2 Hz), 4.10 (dd, 1H, J ) 4.5, 10.2 Hz), 4.48 (dd, 1H, J ) 4.5, 14.4 Hz),

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6.83-7.11 (m, 6H), 7.14 (d, 2H, J ) 8.1 Hz), 7.25-7.32 (m, 2H), 7.49 (d, 2H, J ) 8.1 Hz), 7.88 (dd, 1H, J ) 1.5, 8.1 Hz). Anal. Calcd for C22H21NO4S: C, 66.82; H, 5.35; N, 3.54. Found: C, 67.12; H, 5.65; N, 3.40. N-(Tosyl)-(2S)-benzyloxymethyl-3,4-dihydro-2H1,4-benzoxazine (6g). 90%, AcOEt/PE 1:7, mp 107107.5 °C, [R]D20 ) -43.0 (c ) 1, CH2Cl2). 1H NMR (CDCl3): δ 2.37 (s, 3H), 3.28 (m, 1H), 3.51 (m, 3H), 4.34 (dd, 1H, J ) 2.0, 14.2 Hz), 4.52 (dd, 2H, J ) 12.4, 14.6 Hz), 6.82 (dd, 1H, J ) 1.6, 8.1 Hz), 6.92 (m, 1H), 7.05 (m, 1H), 7.20 (d, 2H, J ) 8.3 Hz), 7.28-7.38 (m, 5H), 7.50 (d, 2H, J ) 8.3 Hz), 7.83 (dd, 1H, J ) 1.6, 8.3 Hz). 13C NMR (CDCl , selected data): δ 21.5, 46.3, 69.6, 70.7, 3 73.5. Anal. Calcd for C23H23NO4S: C, 67.46; H, 5.66; N, 3.42. Found: C, 67.72; H, 5.98; N, 3.15. N-(Tosyl)-2-tetrahydropyranyloxymethyl-3,4-dihydro-2H-1,4-benzoxazine (6h). 99%. 1H NMR (CDCl3): δ 1.50-1.81 (m, 6H), 2.37 (s, 3H), 3.19-3.54 (m, 4H), 3.67-3.83 (m, 2H), 4.37 (m, 1H), 4.55 (m, 1H), 6.75-7.80 (m, 8H). Anal. Calcd for C21H25NO5S: C, 62.51; H, 6.25; N, 3.47. Found: C, 62.80; H, 6.50; N, 3.23. 2-Methyl-4-(N-tosyl)-3,4-dihydro-2H-1,4-benzoxazin Carboxylic Acid (11). 67%, CH2Cl2/AcOH/MeOH 99:1:1, mp 171 °C. 1H NMR (DMSO-d6): δ 1.56 (s, 3H), 2.38 (s, 3H), 3.52 (d, 1H, J ) 12.6 Hz), 4.60 (d, 1H, J ) 12.6 Hz), 6.75-6.94 (m, 3H), 7.34-7.44 (m, 3H), 7.84 (d, 1H, J ) 8.3 Hz), 13.41 (bs, 1H). Anal. Calcd for C17H17NO5S: C, 58.78; H, 4.93; N, 4.03. Found: C, 59.21; H, 5.23; N, 3.88. N-(Tosyl)-2,2-dimethyl-6-nitro-3,4-dihydro-2H1,4-benzoxazine (7c). 72%, Et2O/PE 2:1, mp 143-144 °C. 1H NMR (CDCl3): δ 1.36 (s, 6H), 2.42 (s, 3H), 3.74 (s, 2H), 6.87 (d, 1H, J ) 9.0 Hz), 7.36 (d, 2H, J ) 8.2 Hz), 7.81-7.86 (m, 3H), 8.53 (d, 1H, J ) 2.5 Hz). Anal. Calcd for C17H18N2O5S: C, 56.34; H, 5.01; N, 7.73. Found: C, 56.62; H, 5.40; N, N-(Tosyl)-2-phenoxymethyl-6-nitro-3,4-dihydro2H-1,4-benzoxazine (7f). 75%, Et2O/PE 1:3, mp 157158 °C. 1H NMR (CDCl3): δ 2.38 (s, 3H), 3.47 (dd, 1H, J ) 9.3, 14.4 Hz), 3.89 (m, 1H), 4.01 (dd, 1H, J ) 5.7, 10.2 Hz), 4.16 (dd, 1H, J ) 4.4, 10.2 Hz), 4.50 (dd, 1H, J ) 2.4, 14.4 Hz), 6.86-7.04 (m, 4H), 7.22 (d, 2H, J ) 8.1 Hz), 7.28-7.34 (m, 3H), 7.59 (d, 2H, J ) 8.1 Hz), 7.96 (dd, 1H, J ) 2.7, 9.0 Hz). Anal. Calcd for C22H20N2O6S: C, 59.99; H, 4.58; N, 6.36. Found: C, 60.36; H, 4.70; N, 6.20. N-(Tosyl)-2-hydroxymethyl-3,4-dihydro-2H-1,4benzoxazine (6e). Pyridinium p-toluensulfonate (0.2 mmol, 0.05 g) was added to a methanolic solution (20 mL) of benzoxazine 6h (2 mmol, 0.80 g). After the mixture had been stirred at room temperature for 2 h, 5 mL of NaHCO3 sat was added, and the mixture was extracted with 20 mL of Et2O. After being dried with MgSO4 and solvent removal in vacuo, the residue was purified by column chromatography on silica gel to give 0.61 g of 6e, yield 95%, whose melting point and 1H NMR spectra are identical to those reported above. Method B. The reactor was charged with hydroxysulfonamide 4f (10 mmol, 4.15 g), solid NaOH (20 mmol, 0.8 g), n-C14H29Me3N+Cl- (1 mmol, 0.29 g), and THF (20 mmol, 1.62 mL), and the heterogeneous mixture thus obtained was stirred at reflux for 2 h. After cooling, 30 mL of water was added, and the mixture was left under stirring for 20 min while a white precipitate was formed. The solid was filtered and washed with water to give benzoxazine 5f in 92% yield. Physical and

spectroscopic data of the compound are identical to those reported previously. General Procedure for N-Detosylation of Benzoxazines 6 and 7. Method A. The reactor was charged with benzoxazine 6, 7 (10 mmol), PhOH (2.82 g, 30 mmol), and 40% HBr/AcOH (40 mL). After being stirred at 25 °C for the time indicated in Table 5, the mixture was neutralized with NaOH 20%, extracted with AcOEt, and dried over MgSO4, and the solvent was removed in vacuo. The residue was purified by column cromatography or crystallized to afford benzoxazines whose yields and physical and spectroscopic data are the following: 2-(n-Hexyl)-3,4-dihydro-2H-1,4-benzoxazine (8a). 77%. 1H NMR (CDCl3): δ 0.90 (t, 3H, J ) 6.6 Hz), 1.281.77 (m, 10H), 3.11 (dd, 1H, J ) 7.9, 11.5 Hz), 3.35 (dd, 1H, J ) 2.4, 11.5 Hz), 4.06 (m, 1H), 6.57-6.80 (m, 4H). Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.39. Found: C, 77.01; H, 9.99; N, 6.02. 2-Phenyl-3,4-dihydro-2H-1,4-benzoxazine (8b). 97%. 1H NMR (CDCl3): δ 3.37 (dd, 1H, J ) 8.7, 11.9 Hz), 3.51 (dd, 1H, J ) 2.5, 11.9 Hz), 3.90 (bs, 1H), 5.09 (dd, 1H, J ) 2.5, 8.6 Hz), 6.65-7.42 (m, 9H). Anal. Calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.93; H, 6.50; N, 6.50. 2,3-Cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (8d). 84%, mp 125-126 °C. 1H NMR (CDCl3): δ 1.261.46 (m, 4H), 1.75 (m, 1H), 1.85 (m, 1H), 1.96 (m, 1H), 2.16 (m, 1H), 2.97 (m, 1H), 3.64 (m, 1H), 6.57-6.80 (m, 4H). Anal. Calcd for C12H15NO: C, 76.16, H, 7.99; N, 7.40. Found: C, 76.58; H, 8.30; N, 7.11. 2-Phenoxymethyl-3,4-dihydro-2H-1,4-benzoxazine (8f). 93%, mp 86-87 °C, Et2O/PE 1:4. 1H NMR (CDCl3): δ 3.39 (dd, 1H, J ) 6.8, 11.6 Hz), 3.56 (dd, 1H, J ) 2.6, 11.6 Hz), 3.76 (bs, 1H), 4.11 (dd, 1H, J ) 6.7, 9.7 Hz), 4.24 (dd, 1H, J ) 4.9, 9.7 Hz), 4.55 (m, 1H), 6.61-6.99 (m, 7H), 7.02-7.32 (m, 2H). Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 75.02; H, 6.59; N, 5.51. 2-Phenoxymethyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (9f). 93%, Et2O/PE 2:3, mp 107-109 °C. 1H NMR (CDCl3): δ 3.45 (dd, 1H, J ) 6.9, 11.9 Hz), 3.61 (dd, 1H, J ) 2.8, 11.9 Hz), 4.13 (dd, 1H, J ) 6.4, 9.9 Hz), 4.25 (dd, 1H, J ) 4.9, 9.9 Hz), 4.61 (m, 1H), 6.867.02 (m, 4H), 7.25-7.33 (m, 2H), 7.51 (d, 1H, J ) 2.6 Hz), 7.59 (dd, 1H, J ) 2.6, 8.8 Hz). 13C NMR (CDCl3, selected data): δ 41.7, 67.2, 73.0. Anal. Calcd for C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found: C, 63.23; H, 5.23; N, 9.54. 2-Hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine (8e). In a round-bottom flask, 6h (2.1 mmol, 0.87 g), and phenol (6.3 mmol, 0.59 g) were dissolved in 10 mL of 40% HBr/AcOH. After the mixture had been stirred at room temperature for 1 h, the pH was made alkaline by dropwise addition of 30% NaOH, and the mixture was heated at 50 °C for 30 min. CH2Cl2 (25 mL) was added, the organic phase was washed with brine and dried over MgSO4, and the solvent was removed in vacuo. The crude thus obtained was purified through column chromatography (Et2O/PE 3:2) to give 0.28 g (81% yield) of 8e, with physical and spectroscopical data identical to those previously reported. Method B. In a two-necked round-bottom flask under nitrogen, sodium (30 mmol, 0.69 g) was added to a naphthalene (30 mmol, 3.84 g) solution in 30 mL of dimethoxyethane (DME), and the mixture thus obtained was stirred at room temperature for 1 h. Sodium

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naphthalenide thus obtained was dropwise added to a solution of benzoxazine 6, 7 (10 mmol) in 30 mL of DME under inert atmosphere and cooled to -70 °C. After being stirred at -70 °C for the time indicated in Table 7, the refrigerating bath was removed, and the mixture was neutralized with saturated NH4Cl solution, extracted with AcOEt, and dried over MgSO4. The benzoxazines 8 and 9 were purified by column chromatography. 2-Phenoxymethyl-3,4-dihydro-2H-1,4-benzoxazine (8f). 77%, mp 87-88 °C. (2S)-Benzyloxymethyl-3,4-dihydro-2H-1,4-benzoxazine (8g). 84%, Et2O/PE 1:4, [R]D20 ) 21.7 (c ) 0.72, CH2Cl2). 1H NMR (CDCl3): δ 3.30 (dd, 1H, J ) 7.3, 11.6 Hz), 3.47 (dd, 1H, J ) 2.6, 11.6 Hz), 3.66 (dd, 1H, J ) 6.0, 10.1 Hz), 3.70 (bs, 1H), 3.77 (dd, 2H, J ) 5.2, 10.1 Hz), 4.38 (m, 1H), 4.63 (s, 2H), 6.58-6.83 (m, 4H), 7.30-7.40 (m, 5H). Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.62; H, 6.96; N, 5.08. Method C. A 65% toluene solution of Na(MeOCH2CH2O)2AlH2 (Red-Al) (40 mmol, 12.1 mL) was added dropwise to a solution of benzoxazine 6 (10 mmol) in 20 mL of toluene, and the mixture was stirred at 80 °C for the time indicated in Table 5. The reaction was quenched with 5% aqueous NH4Cl, the phases were separated, and the organic phase was washed with brine and dried over MgSO4. After removal of the solvent in vacuo, the benzoxazines 8 were purified by column chromatography. 2-Phenoxymethyl-3,4-dihydro-2H-1,4-benzoxazine (8f). 81%. Physical and spectroscopical data identical to those previously reported. (2S)-Benzyloxymethyl-3,4-dihydro-2H-1,4-benzoxazine (8g). 84%. [a]D20 ) 21.1 (c ) 0.75, CH2Cl2). Spectroscopical data identical to those previously reported. Literature Cited (1) (a) Bourlot, A.-S.; Sa´nchez, I.; Dureng, G.; Guillaumet, G.; Massingham, R.; Monteil, A.; Winslow, E.; Pujol, M. D.; Me´rour, J.-Y. New Substituted 1,4-Benzoxazine Derivatives with Potential Intracellular Calcium Activity. J. Med. Chem. 1998, 41, 3142. (b) Combs, D. W.; Rampulla, M. S.;. Bell, S. C.; Klaubert, D. H.; Tobia, A. J.; Falotico, R.; Haertlein, R. B.; Lakas-Weiss, C.; Moore, C. J. B. 6-Benzoxazinylpyridazin-3-ones: Potent, Long-Acting Positive Inotrope and Peripheral Vasodilator Agents. J. Med. Chem. 1990, 33, 380-386. (c) D’Ambra, E. T.; Estep, G. K.; Bell, R. M.; Eissenstat, A. M.; Josef, A. K.; Ward, J. S.; Haycock, A. D.; Baizman, R. E.; Casiano, M. F.; Beblin, C. N.; Chippari, M. S.; Greo, D. J.; Kullnig, K. R.; Daley, T. G. Conformationally Restrained Analogues of Pravadoline: Nanomolar Potent, Enantioselective, (Aminoalkyl)indole Agonists of the Cannabinoid Receptor. J. Med. Chem. 1992, 35, 124-135. (d) Largeron, M.; Dupuy, H.; Fleury, M. B. Novel 1,4-Benzoxazine Derivatives. Tetrahedron 1995, 51, 4953.

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Received for review September 9, 2002 Revised manuscript received November 21, 2002 Accepted November 24, 2002 IE020702S