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Synthesis of Nonracemic 1,4-Benzoxazines via Ring Opening/Cyclization of Activated Aziridines with 2-Halophenols: Formal Synthesis of Levofloxacin Abhijit Mal, Imtiyaz Ahmad Wani, Gaurav Goswami, and Manas K. Ghorai J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Jun 2018 Downloaded from http://pubs.acs.org on June 4, 2018

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The Journal of Organic Chemistry

Synthesis of Nonracemic 1,4-Benzoxazines via Ring Opening/Cyclization of Activated Aziridines with 2Halophenols: Formal Synthesis of Levofloxacin Abhijit Mal, Imtiyaz Ahmad Wani, Gaurav Goswami and Manas K. Ghorai* Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India Fax: (+91)-512-2597436; Phone: (+91)-512-2597518; email: [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

ABSTRACT. Novel 3,4-dihydro-1,4-benzoxazine derivatives have been synthesized by an efficient and simple method in excellent enantio- and diastereospecificity (ee >99%, de >99%). The reaction proceeds via Lewis acid catalyzed SN2-type ring opening of activated aziridines with 2-halophenols followed by Cu(I) catalyzed intramolecular C–N cyclization in a stepwise fashion under one-pot condition to furnish the 3,4-dihydro-1,4-benzoxazine derivatives in

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excellent yields (up to 95%). The strategy offers a short and efficient synthesis to (S)-3-methyl1,4-benzoxazine (S)-3v, a late stage intermediate in the synthesis of levofloxacin.

INTRODUCTION Benzoxazines are an important class of heterocyclic compounds of biological and pharmacological significance (Figure 1).1 They exhibit a wide range of biological activities e.g. dopamine agonist, calcium antagonist, potassium channel modulators, antirheumatic and antihypertensive agents etc.2 Benzoxazine derivatives are also used as powerful drugs.3 A popular example is levofloxacin which has been shown as a antibacterial agent against a number of diseases.4 1,4-Benzoxazines also serve as synthetic building blocks for the construction of more complex molecular structures useful for medical and industrial applications.5 H N

O

N

O

O N O

N R

Cl

A Azasetron (serotonin 3 antagonist) R O

R

R

HO

O

H

B (5aR)-2,3,5a,6,6,11,11,12-Octamethyl-6,11, 11a,12-tetrahydro-5aH-benzo[b]phenoxazine (potential chain-breaking antioxidant)

O N O

F N

R

O

H N N

R R

N R

O

C 3,4-Dihydro-2H-1,4-benzooxazine derivatives (potassium channel activator)

N

NH O

D Bemoradan (vasodilator agent)

E Levofloxacin (antibiotic)

Figure 1. Some biologically and pharmacologically important compounds


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Although, several interesting strategies have been developed for the synthesis of 1,4benzoxazines,6 efficient routes for their enantioselective synthesis are still limited.7 Some of them are I2/K2CO3-catalyzed ring cyclization via dehydrohalogenation of o-aminophenols and αhaloketones,6f copper-catalyzed coupling of o-halophenols and 2-halo-amides,6g opening of epoxide with o-halosulfonamides followed by cyclization under SL-PTC6i and asymmetric organocatalytic hydrosilylation of 1,4-benzoxazines etc.7b Aziridines8,9 have also been exploited for the synthesis of 1,4-benzoxazines.10 Earlier Sekar et al. has revealed an efficient strategy for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine via copper-catalyzed domino aziridine ring opening with o-iodophenols followed by intramolecular C‒N coupling in excellent yields.10c Ranu and coworkers have used alumina-supported Cu(II) as a versatile and recyclable catalyst for the ring opening of aziridine and epoxide with o-iodophenols to synthesize 1,4-benzoxazine and 1,4-benzodioxane respectively.10b Although these strategies are attractive, most of them are of limited substrate scope and deal with only racemic examples. In continuation of our research interest in the area of LA-catalyzed SN2-type ring opening of activated aziridines/azetidines11,12 and based on our recent findings on the synthesis of tetrahydroquinoxalines11f and dihydrobenzothiazines,11d we have developed a simple strategy for the synthesis of highly substituted 3,4-dihydro-2H-benzo[b][1,4]oxazines with excellent enantioand diastereospecificity (ee >99%, de >99%) via Lewis acid catalyzed SN2-type ring opening of activated aziridines with 2-halophenols followed by Cu(I) catalyzed intramolecular C–N cyclization in a stepwise fashion in excellent yields (up to 95%). Herein, we report our results as an article.


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RESULTS AND DISCUSSION Our study began with the reaction of 2-phenyl-N-tosylaziridine 1a with 2-bromophenol 2a in the presence of LiClO4 as the Lewis acid (LA) in acetonitrile at 85 °C11b–c,d,f followed by treatment of CuI, K2CO3 in DMF at 120 °C for overnight (10 h) in the same pot to afford the corresponding cyclized product 2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 3a in 87% yield exclusively (Scheme 1, Table 1, entry 1). The reaction conditions were optimized for one-pot ring-opening cyclization process as shown in Table 1 and the best result was obtained in the presence of 0.3 equiv. LiClO4 as the LA in acetonitrile at 85 °C for 2 h followed by the addition of 0.5 equiv. of CuI, 2.0 equiv. of K2CO3, and DMF at 120 °C for 10 h with quantitative conversion (Table 1, entry 6).

Scheme 1. One-pot synthesis of dihydro-1,4-benzoxazine 3a Table 1. Optimization studies for one-pot ring-opening cyclization processa

entry

reaction conditions

yield (%)b

1

i) LiClO4 (0.3 equiv.), CH3CN, 85 °C, 2 h ii) CuI (1 equiv.), K2CO3 (2 equiv.), DMF, 120 °C, 10 h

87

2

i) LiClO4 (1 equiv.), CH3CN, 85 °C, 1.5 h ii) CuI (1 equiv.), K2CO3 (2 equiv.), DMF, 120 °C, 10 h

76


4

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3

i) LiClO4 (0.3 equiv.), CH3CN, 85 °C, 2 h ii) CuI (0.2 equiv.), (±)-trans-1,2-diaminocyclohexane (0.5 equiv.), K2CO3 (2 equiv.), DMF, 120 °C, 10 h

73

4

i) LiClO4 (0.3 equiv.), CH3CN, 85 °C, 2 h ii) Cu-powder (2 equiv.), DMF, 120 °C, 10 h

51

5

i) LiClO4 (0.3 equiv.), CH3CN, 85 °C, 2 h ii) CuI (1 equiv.), Na2CO3 (2 equiv.), DMF, 120 °C, 10 h

64

6

i) LiClO4 (0.3 equiv.), CH3CN, 85 °C, 2 h ii) CuI (0.5 equiv.), K2CO3 (2 equiv.), DMF, 120 °C, 10 h

89

7

i) LiClO4 (0.3 equiv.), CH3CN, 85 °C, 2 h ii) CuI (0.2 equiv.), K2CO3 (2 equiv.), DMF, 140 °C, 10 h

57

a

All reactions were carried out with 1a (1 equiv.) and 2a (1.1 equiv.). bYields of isolated products. To generalize our approach a number of substituted aziridines were investigated under the optimized conditions. To our delight, the reactions were found to be successful in all the cases and the results are shown in Table 2. Interestingly, the halo substituted aziridines were successfully converted directly into target products (Table 2, entries 1‒2, 4‒6) in good to excellent yields (79‒89%), which could be further functionalized. Furthermore, aziridines with different arylsulphonyl protecting groups on the nitrogen such as phenyl or 2-pyridyl groups were also found to be suitable substrates for this transformation (3i‒j, 92% and 79%). The structure of 3b was confirmed by X-ray crystallographic analysis.13 Table 2. Substrate scope of aziridinesa


5


entry

aziridine (1)

2-halophenol (2)

1,4-benzoxazine (3)

Br

1

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time (h)

yield (%)b

1.5

79

OH 2a

2

2a

1.5

84

3

2a

3.0

87

4

2a

2.5

89

5

2a

2.0

88

6

2a

2.0

88

7

2a

2.5

85


6

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8

2a

SO2Ph N O

1.5

92

2.0

79

Ph

3i

9

a

2a

All reactions were carried out with 1 (1 equiv.) and 2a (1.1 equiv.). bYields of isolated products.

We then examined the scope of our protocol with different 2-halophenols. The reaction worked well with the electron-donating groups attached to the phenyl ring of 2 (Table 3, entry 2 and 4). In the case of electron-withdrawing groups at the ortho/para position of the phenyl ring, the products were obtained with reduced yields (Table 3, entry 1,3,5 and 6). When we have replaced the 2-bromophenols coupling partner by 2-chlorophenol 2h and 2-iodophenol 2i, the reaction with 2-phenyl-N-tosylaziridine 1a proceeded smoothly to afford the corresponding product 2phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 3a in 83% and 88% yield, respectively (Table 3, entry 7 and 8). Table 3. Substrate scope of 2-bromophenolsa


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entry

aziridine (1)

2-halophenol (2)

Ph

1,4-benzoxazine (3)

Br

Ts N

1

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time (h)

yield (%)b

3.0

82

OH

1a NO2 2b

2

1a

1.5

94

3

1a

2.5

83

4

1a

2.0

92

5

1a

2.5

85

6

1a

3.0

82

7

1a

2.5

83

Ts N O

Ph

3a


8

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8

1a

2.0

Ts N O

88

Ph

3a a

All reactions were carried out with 1a (1 equiv.) and 2 (1.1 equiv.). bYields of isolated products.

To demonstrate the effectiveness of our protocol for the synthesis of highly substituted dihydro-1,4-benzoxazine derivatives, the ring-opening/cyclization of trans-disubstituted aziridine 1k with the oxygen nucleophile 2a was studied. When trans-2-methyl-3-phenyl-1tosylaziridine 1k was treated with 2a followed by cyclization under one-pot reaction conditions, the corresponding cis-dihydro-1,4-benzoxazine 3q was obtained as a single diastereomer in excellent yield (95%, Scheme 2).

Scheme 2. Synthesis of highly substituted dihydro-1,4-benzoxazine 3q To extend the scope of the methodology further by accommodating additional functionality in the products, 2-vinyl-N-tosylaziridine 1l was employed as the substrate. When 1l was treated with 2a under the optimized reaction conditions, the corresponding vinyl-substituted 3,4dihydro-2H-benzo[b][1,4]oxazine derivative 3r was formed as a single regioisomer in 75% yield (Scheme 3). The structure of 3r was confirmed by X-ray crystallographic analysis.13


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Scheme 3. Synthesis of vinyl-substituted dihydro-1,4-benzoxazine 3r To enhance the potential and applicability of the 3,4-dihydro-2H-benzo[b][1,4]oxazine derivatives as synthesized by us in medicinal chemistry,14 we attempted the deprotection of the tosyl group. As a representative example, detosylation of 3a was accomplished with excess magnesium in methanol at rt and the corresponding 3,4-dihydro-2H-benzo[b][1,4]oxazine derivative 4a with a free NH group was obtained in excellent yield (91%, Scheme 4).

Scheme 4. Deprotection of tosyl group of 3a Next, the synthetic significance of the strategy was demonstrated by the synthesis of nonracemic dihydro-1,4-benzoxazine derivatives. When enantiopure (R)-1a was reacted with 2a under the optimized reaction conditions (Table 1, entry 6), the corresponding product (S)-3a was obtained with moderate enantioselectivity (ee 78%, Table 4, entry 1). Surprisingly when the reaction was carried out without any LA, the reaction took long time for completion and 3a was obtained in racemic form (Table 4, entry 3). Probably because of high temperature and long reaction time in acidic medium (in the presence of 2a), the strating (R)-1a got racemized leading to the formation of racemic 3a. Based on our earlier observation11e when we attempted to improve the ee of the product 3a using tetrabutylammonium hydrogen sulfate (TBAHS) as a quaternary ammonium salt along with the optimized reaction conditions, the corresponding product (S)-3a was formed in good yield, although with reduced enantiomeric excess (ee 60%,


10

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Table 4, entry 2). In order to control the racemization of the starting enantiopure aziridine (R)-1a and thus to obtain the product 3a with higher ee, we intended to enhance the nucleophilicity of 2a by converting it to the corresponding phenoxide ion. When the reaction was carried out employing NaH as the base, gratifyingly, the ring-opening reaction was completed within 1 h and 3,4-dihydro-2H-benzo[b][1,4]oxazine (S)-3a was obtained in 80% yield with excellent enantioselectivity (ee >99%) (Table 4, entry 4). Performing the reaction with half (0.1 equiv.) of the catalyst loading, the efficiency of the reaction could not improved further (Table 4, entry 5). Table 4. Optimization studies to increase the enantiomeric excessa

entry

reaction conditions

time (h)

yield (%)b

ee (%)c

1

LiClO4 (0.3 equiv.), CH3CN, 85 °C

2.0

85

78

2

LiClO4 (0.3 equiv.), TBAHS (2 equiv.), CH3CN, 85 °C

2.0

83

60

3

CH3CN, 85 °C

12.0

54

0

4

LiClO4 (0.2 equiv.), NaH (1.5 equiv.), CH3CN, 85 °C

1.0

80

>99

5

LiClO4 (0.1 equiv.), NaH (1.5 equiv.), CH3CN, 85 °C

1.5

72

nd

a

All reactions were carried out with (R)-1a (1 equiv.) and 2a (1.1 equiv.). bYields of isolated products. cee was determined by chiral HPLC analysis.

Successive efforts were invested to synthesize 1,4-benzoxazine heterocycles in nonracemic forms by employing enantiopure activated aziridines as the substrate. When activated aziridines (R)-1a,i–j (ee >99%) underwent one-pot ring-opening cyclization reaction with 2-bromophnols


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2a,c–e,j in above reaction conditions (Table 4, entry 4), the corresponding 1,4-benzoxazine derivatives (S)-3i–j,l–n,s respectively, were obtained in good yields as single enantiomers (Table 5, entry 1–6). To get the other enantiomer of the product, (S)-2-(2-chlorophenyl)-1-tosylaziridine (83% ee) was treated with 2-iodophenol under optimized reaction conditions and the desired nonracemic 1,4-benzoxazine (R)-3t was obtained in good yield (75%) without loss of any enantiomeric excess (83% ee, Table 5, entry 7). Table 5. Substrate scope of nonracemic 1,4-benzoxazinesa

entry

aziridine (1)

2-bromophenol (2)

1,4-benzoxazine (3)

Br

1

time (h)

yield (%)b

ee (%)c

1.0

82

>99

1.5

81

>99

1.0

84

>99

OH 2a

2a

2

3

Ts N Ph (R)-1a


12

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4

(R)-1a

1.5

78

>99

5

(R)-1a

1.0

87

>99

6

(R)-1a

2.0

80

>99

1.5

75

83d

7

Ts N

Cl (S)-1m a

All reactions were carried out with (R)-1,(S)-1m (1 equiv.) and 2 (1.1 equiv.). bYields of

isolated products. cee was determined by chiral HPLC analysis. dee of the corresponding starting aziridine (S)-1m was 83%.

Next, to widen scope of the strategy we engaged 2-alkyl substituted aziridine as the substrate. 2-Methyl-1-tosylaziridine 1n failed to undergo ring-opening with 2a under our optimized reaction conditions (Table 1, entry 6) probably due to weak nucleophilicity of 2-bromophenol to react with comparatively less reactive alkyl aziridine. To enhance the nucleophilicity of 2a, it was converted to the corresponding phenoxide ion using NaH as the base. The reaction proceeded smoothly with the ring-opening at the terminal side of 1n to afford the 3,4-dihydro2H-benzo[b][1,4]oxazine 3u in 79% yield. Further, desulfonation of compound 3u was


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performed under mild conditions using Mg powder in methanol to furnish the corresponding dihydro-1,4-benzoxazine 4b with a free –NH group in 86% yield (Scheme 5).

Scheme 5. Reaction with alkyl aziridine 1n and further desulfonation of compound 3u Encouraged by our successful results for the synthesis of 3-methyl-3,4-dihydro-2Hbenzo[b][1,4]oxazine, we next explored the formal synthesis of a valuable precursor of the antimicrobial agent, levofloxacin.4 The synthetic route is described in Scheme 6 starting from enantiopure aziridine (S)-1n and commercially available 2,3-difluorophenol 5. First, a selective o-bromination of the aromatic ring was performed using NBS and iso-propylamine in dichloromethane at low temperature, yielding the 2-bromo-5,6-difluorophenol 2k in 80% yield. Treatment of 2k with enantiopure 2-methyl-1-tosylaziridine (S)-1n under similar reaction conditions afforded the corresponding 1,4-benzoxazine derivative (S)-3v in 75% yield in enantiopure form. From this key precursor (S)-3v, levofloxacin could be synthesized in four steps following literature report.15


14

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Scheme 6. Synthesis of (S)-7,8-difluoro-3-methyl-4-tosyl-3,4-dihydro-2Hbenzo[b][1,4]oxazine (S)-3v

MECHANISM Based on our experimental observations we reasoned that the reaction proceeds via an SN2-type ring opening of aziridines 1 with 2-halophenols 2 to generate the corresponding intermediate ring-opened products 6 that further undergo a well documented CuI mediated C‒N cyclization11c to furnish the final products 3 (Figure 2).


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Figure 2. Plausible mechanistic pathway to 1,4-benzoxazine

CONCLUSION In conclusion, we have developed a simple protocol for the synthesis of a wide range of racemic and nonracemic dihydro-1,4-benzoxazines in excellent yields and stereoseletivities. The reaction proceeds through Lewis acid catalyzed SN2-type ring-opening of N-activated aziridines with 2-halophenols followed by Cu(I) catalyzed intramolecular C‒N bond formation in one-pot process. This methodology has been utilized for an efficient synthesis of the valuable levofloxacin precursor from readily available starting materials.

Experimental Section Analytical thin layer chromatography (TLC) was carried out using silica gel 60 F254 pre-coated plates. Visualization was accomplished with UV lamp or I2 stain. Silica gel 230−400 mesh size was used for flash column chromatography using the combination of ethyl acetate and petroleum ether as eluent. Unless noted, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen/argon using anhydrous solvents. Where appropriate, all reagents were


16

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purified prior to use following the guidelines of Perrin, Armerego16 and Vogel.17 The monosubstituted N-Ts aziridines were prepared from different styrene derivatives following a reported procedure.18 Chiral monosubstituted N-Ts aziridines were prepared from the corresponding amino alcohol following a reported procedure.19 All commercial reagents were used as received. Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 400 MHz/500 MHz. Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethyl silane (δ 0.00). 1H NMR splitting patterns are designated as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet (m) etc. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded at 100 MHz/125 MHz. HRMS were obtained using an (ESI) mass spectrometer (TOF). IR spectra were recorded in KBr for solids. Melting points were determined using a hot stage apparatus and are uncorrected. Optical rotations were measured using a 6.0 mL cell with a 1.0 dm path length and are reported as [α]25D (c in g per 100 mL solvent) at 25 °C. Enantiomeric excess were determined by HPLC using chiralpak Cellulose 2, OJ-H analytical columns (detection at 254 nm). General Procedure for one-pot synthesis of 3,4-dihydro-1,4-benzoxazine: Method A: Aziridine (1.0 equiv.), 2-halophenol (1.1 equiv.) and LiClO4 (0.3 equiv.) were taken in two neck RB flask then CH3CN (0.1 mL) was added to reaction mixture and stirred for appropriate time at 85 °C under argon atmosphere. The completion of the reaction was confirmed by monitoring the TLC using 20% ethyl acetate in petroleum ether as the eluent. After completion of the ring-opening reaction CuI (0.5 equiv.), K2CO3 (2.0 equiv.) and DMF (1.0 mL) were added to the reaction mixture and stirred at 120 °C for 10 h. After the completion of the reaction (monitored by TLC using 10% ethyl acetate in petroleum ether as the eluent) the reaction mixture was extracted with ethyl acetate (3×5.0 mL). The combined organic layer was


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washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 3% ethyl acetate in petroleum ether as the eluent. Method B: To suspension of NaH (1.5 equiv.) in CH3CN (0.5 mL), 2-bromophenol (1.1 equiv.) (if 2-bromophenol is solid, then dissolving in CH3CN) was added at room temperature under nitrogen atmosphere. Subsequently solutions of aziridine (1.0 equiv.) and LiClO4 (0.2 or 0.3 equiv.) in CH3CN (0.5 mL) was added to the reaction mixture and stirred at 85 °C for appropriate time. The completion of the reaction was confirmed by monitoring the TLC using 20% ethyl acetate in petroleum ether as the eluent. After completion of the ring-opening reaction CuI (0.5 equiv.), K2CO3 (2.0 equiv.) and DMF (1.0 mL) were added to the reaction mixture and stirred for 10 h at 120 °C. After the completion of the reaction (monitored by TLC using 10% ethyl acetate in petroleum ether as the eluent) the reaction mixture was extracted with ethyl acetate (3×5.0 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 3% ethyl acetate in petroleum ether as the eluent. General Procedure for desulfonylation of 3,4-dihydro-1,4-benzoxazine: Method C: A solution of 3 (1.0 equiv.) in dry methanol (2.0 mL) was added to Mg powder (10.0 equiv.) at rt. The reaction mixture was stirred for appropriate time under a nitrogen atmosphere until the substrate disappeared by TLC (using 20% ethyl acetate in petroleum ether as the eluent). To the reaction mixture equal volumes of diethyl ether and saturated aqueous NH4Cl were added and the whole mixture was stirred for another 1 hr. The organic layer was separated and the aqueous layer washed with ether. The combined organic layers were dried over


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anhydrous sodium sulfate. The organic mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 6% ethyl acetate in petroleum ether as the eluent. 2-Phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3a):10a,b The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2bromophenol 2a (24 µL, 0.207 mmol) in presence of LiClO4 (6 mg, 0.056 mmol) at 85 °C for 2 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3a was obtained as a colourless solid, mp 107‒108 °C in 89% (59.5 mg, 0.163 mmol) yield. Rf 0.32 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3035, 2924, 2853, 1740, 1597, 1487, 1454, 1357, 1308, 1264, 1244, 1215, 1167, 1123, 1091, 1057; 1H NMR (500 MHz, CDCl3) δ 2.41 (s, 3H), 3.25 (dd, J = 14.6, 10.3 Hz, 1H), 4.21 (dd, J = 10.3, 2.5 Hz, 1H), 4.37 (dd, J = 14.8, 2.5 Hz, 1H), 6.93 (dd, J = 8.2, 1.6 Hz, 1H), 7.0 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.19–7.22 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.34–7.40 (m, 3H), 7.58 (d, J = 6.6 Hz, 2H), 7.92 (dd, J = 8.2, 1.6 Hz, 1H);

13

C{1H} NMR (100 MHz,

CDCl3) δ 21.7, 50.3, 73.2, 117.7, 121.2, 123.4, 125.0, 126.0, 126.4, 127.5, 128.9, 129.8, 130.1, 135.6, 137.1, 144.6, 147.4; HRMS (ESI-TOF) calculated for C21H20NO3S [M+H]+ 366.1164 found 366.1163. 2-(2-Fluorophenyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3b): The general method A described above was followed when 2-(2-fluorophenyl)-1-tosylaziridine 1b (50 mg, 0.172 mmol) was reacted with 2-bromophenol 2a (22 µL, 0.190 mmol) in presence of LiClO4 (5.5 mg, 0.052 mmol) at 85 °C for 1.5 h followed by addition of CuI (16.4 mg, 0.086 mmol) and K2CO3 (47.5 mg, 0.344 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3b was obtained as a colourless solid, mp 153‒154 °C in 79% (52.1 mg, 0.136 mmol) yield. Rf 0.37 (10% ethyl acetate in


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petroleum ether); IR ν̃max (KBr, cm-1) 3434, 2925, 1585, 1488, 1458, 1357, 1318, 1268, 1247, 1210, 1185, 1168, 1125, 1106, 1089, 1063, 1035; 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 3.19 (dd, J = 15.1, 10.5 Hz, 1H), 4.52 (dt, J = 12.4, 2.5 Hz, 2H), 6.92 (dd, J = 8.0, 1.4 Hz, 1H), 6.99–7.09 (m, 2H), 7.11–7.19 (m, 2H), 7.24–7.26 (m, 2H), 7.29–7.39 (m, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.97 (dd, J = 8.2, 1.6 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 49.0, 67.4,

115.4, 115.6, 117.7, 121.3, 123.4, 124.4, 124.6, 124.7, 125.3, 126.6, 127.4, 127.5, 130.1, 130.2, 130.3, 135.4, 144.5, 147.1, 159.5 (d, 1JC-F = 247.0 Hz); HRMS (ESI-TOF) calculated for C21H19FNO3S [M+H]+ 384.1070 found 384.1070. 2-(3-Fluorophenyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3c): The general method A described above was followed when 2-(3-fluorophenyl)-1-tosylaziridine 1c (50 mg, 0.172 mmol) was reacted with 2-bromophenol 2a (22 µL, 0.190 mmol) in presence of LiClO4 (5.5 mg, 0.052 mmol) at 85 °C for 1.5 h followed by addition of CuI (16.4 mg, 0.086 mmol) and K2CO3 (47.5 mg, 0.344 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3c was obtained as a colourless solid, mp 135‒136 °C in 84% (55.4 mg, 0.144 mmol) yield. Rf 0.32 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2924, 1618, 1595, 1487, 1450, 1357, 1315, 1269, 1244, 1210, 1185, 1168, 1121, 1090, 1064; 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.21 (dd, J = 14.9, 10.4 Hz, 1H), 4.20 (dd, J = 10.2, 2.7 Hz, 1H), 4.37 (dd, J = 14.7, 2.7 Hz, 1H), 6.93–7.06 (m, 5H), 7.13 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.35 (dt, J = 13.6, 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.91 (dd, J = 8.1, 1.4 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7,

50.2, 72.6, 113.0, 113.2, 115.6, 115.9, 117.7, 121.4, 121.6, 123.4, 125.0, 126.5, 127.4, 130.2, 130.5, 130.5, 135.5, 139.6, 139.7, 144.7, 147.1, 163.0 (d, 1JC-F = 248.0 Hz); HRMS (ESI-TOF) calculated for C21H22FN2O3S [M+NH4]+ 401.1335 found 401.1337.


20

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2-(m-Tolyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3d): The general method A described above was followed when 2-m-tolyl-1-tosylaziridine 1d (50 mg, 0.174 mmol) was reacted with 2-bromophenol 2a (22 µL, 0.190 mmol) in presence of LiClO4 (5.5 mg, 0.052 mmol) at 85 °C for 3 h followed by addition of CuI (16.6 mg, 0.087 mmol) and K2CO3 (48.1 mg, 0.348 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3d was obtained as a colourless solid, mp 150‒151 °C in 87% (57.4 mg, 0.151 mmol) yield. Rf 0.50 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3031, 2924, 2855, 1738, 1597, 1583, 1487, 1462, 1357, 1316, 1290, 1267, 1245, 1211, 1185, 1167, 1122, 1090, 1060, 1036; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.40 (s, 3H) 3.22 (dd, J = 14.6, 10.5 Hz, 1H), 4.16 (dd, J = 10.0, 2.3 Hz, 1H), 4.35 (dd, J = 14.6, 2.3 Hz, 1H), 6.93 (dt, J = 11.9, 1.4 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 7.08–7.15 (m, 2H), 7.23–7.29 (m, 3H), 7.57 (d, J = 8.2 Hz, 2H), 7.91 (dd, J = 8.2, 1.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 21.6, 21.7, 50.3, 73.3, 117.8, 121.1, 123.1, 123.4, 125.0, 126.4, 126.6, 127.5, 128.7, 129.6, 130.1, 135.6, 137.1, 138.7, 144.6, 147.5; HRMS (ESI-TOF) calculated for C22H22NO3S [M+H]+ 380.1320 found 380.1321. 2-(4-Fluorophenyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3e): The general method A described above was followed when 2-(4-fluorophenyl)-1-tosylaziridine 1e (50 mg, 0.172 mmol) was reacted with 2-bromophenol 2a (22 µL, 0.190 mmol) in presence of LiClO4 (5.5 mg, 0.052 mmol) at 85 °C for 2.5 h followed by addition of CuI (16.4 mg, 0.086 mmol) and K2CO3 (47.5 mg, 0.344 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3e was obtained as a colourless solid, mp 153‒154 °C in 89% (58.7 mg, 0.153 mmol) yield. Rf 0.36 (10% ethyl acetate and petroleum ether); IR ν̃max (KBr, cm-1) 3435, 2924, 1603, 1511, 1487, 1460, 1357, 1317, 1263, 1245, 1226, 1185, 1167, 1123, 1090, 1061; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.22 (dd, J = 14.8, 10.3 Hz, 1H), 4.20 (dd, J = 10.3, 2.9 Hz, 1H), 4.34 (dd, J = 14.3, 2.3 Hz, 1H), 6.92 (dd,


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J = 8.0, 1.1 Hz, 1H), 7.0 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 7.17–7.19 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.91 (dd, J = 8.6, 1.7 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.3, 73.2, 117.7, 121.2, 123.4, 125.0, 126.0,

126.4, 127.5, 128.9, 129.8, 130.1, 135.6, 137.1, 144.6, 147.4, 159.9 (d, 1JC-F = 247.0 Hz); HRMS (ESI-TOF) calculated for C21H22FN2O3S [M+NH4]+ 401.1335 found 401.1333. 2-(4-Chlorophenyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3f): The general method A described above was followed when 2-(4-chlorophenyl)-1-tosylaziridine 1f (50 mg, 0.162 mmol) was reacted with 2-bromophenol 2a (21 µL, 0.181 mmol) in presence of LiClO4 (5.2 mg, 0.049 mmol) at 85 °C for 2 h followed by addition of CuI (15.4 mg, 0.081 mmol) and K2CO3 (44.8 mg, 0.324 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3f was obtained as a colourless solid, mp 157‒158 °C in 88% (57.0 mg, 0.142 mmol) yield. Rf 0.32 (10% ethyl acetate and petroleum ether); IR ν̃max (KBr, cm-1) 3066, 2922, 1910, 1597, 1584, 1488, 1459, 1407, 1357, 1317, 1304, 1263, 1244, 1214, 1185, 1167, 1123, 1089, 1061, 1036, 1014; 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.20 (dd, J = 14.6, 10.1 Hz, 1H), 4.20 (dd, J = 10.1, 2.3 Hz, 1H), 4.33 (dd, J = 14.6, 2.3 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.97–7.01 (m, 1H), 7.09–7.15 (m, 3H), 7.28 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.89 (dd, J = 8.2, 1.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.2, 72.6, 117.7, 121.4, 123.4, 124.9, 126.5, 127.4, 127.4, 129.1, 130.1, 134.7, 135.5, 135.7, 144.7, 147.1; HRMS (ESI-TOF) calculated for C21H19ClNO3S [M+H]+ 400.0774 found 400.0775. 2-(4-Bromophenyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3g): The general method A described above was followed when 2-(4-bromophenyl)-1-tosylaziridine 1g (50 mg, 0.142 mmol) was reacted with 2-bromophenol 2a (19 µL, 0.164 mmol) in presence of LiClO4 (4.5 mg, 0.042 mmol) at 85 °C for 2 h followed by addition of CuI (13.5 mg, 0.071 mmol) and K2CO3


22

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(39.2 mg, 0.284 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3g was obtained as a colourless solid, mp 143‒144 °C in 88% (55.5 mg, 0.125 mmol) yield. Rf 0.28 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2923, 2852, 1725, 1596, 1488, 1461, 1404, 1358, 1317, 1304, 1263, 1244, 1213, 1185, 1167, 1123, 1090, 1070, 1010; 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.20 (dd, J = 14.6, 10.5 Hz, 1H), 4.20 (dd, J = 10.1, 2.3 Hz, 1H), 4.33 (dd, J = 14.6, 2.7 Hz, 1H), 6.92 (dd, J = 8.2, 1.4 Hz, 1H), 7.0 (t, J = 7.3 Hz, 1H), 7.07–7.01 (m, 3H), 7.28 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 7.3 Hz, 1H); 13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.1, 72.7, 117.7, 121.4, 122.8, 123.4, 124.9, 126.5,

127.4, 127.6, 130.1, 132.0, 135.5, 136.2, 144.7, 147.1; HRMS (ESI-TOF) calculated for C21H18BrNNaO3S [M+Na]+ 466.0088 found 466.0086. 4-Tosyl-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (3h): The general method A described above was followed when 1-tosyl-2-(4-(trifluoromethyl)phenyl)aziridine 1h (50 mg, 0.146 mmol) was reacted with 2-bromophenol 2a (19 µL, 0.164 mmol) in presence of LiClO4 (4.6 mg, 0.043 mmol) at 85 °C for 2.5 h followed by addition of CuI (13.9 mg, 0.073 mmol) and K2CO3 (40.3 mg, 0.291 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3h was obtained as a colourless solid, mp 107‒108 °C in 85% (53.8 mg, 0.124 mmol) yield. Rf 0.26 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3467, 3065, 2923, 2851, 1598, 1584, 1487, 1462, 1428, 1358, 1315, 1244, 1213, 1185, 1167, 1124, 1089, 1066, 1036, 1018; 1H NMR (500 MHz, CDCl3) δ 2.41 (s, 3H), 3.23 (dd, J = 14.6, 10.2 Hz, 1H), 4.30 (dd, J = 10.2, 2.3 Hz, 1H), 4.38 (dd, J = 14.6, 2.4 Hz, 1H), 6.95 (dd, J = 8.2, 1.4 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 8.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.90 (dd, J = 8.3, 1.4 Hz, 1H);

13

C{1H} NMR (125 MHz, CDCl3) δ

21.6, 50.1, 72.7, 117.6, 121.4, 123.4, 124.8, 125.7, 125.8, 126.3, 126.4, 127.4, 130.1, 131.1,


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135.6, 141.0, 144.6, 146.9; 19F NMR (372.5 MHz, CDCl3) δ ‒62.6; HRMS (ESI-TOF) calculated for C22H19F3NO3S [M+H]+ 434.1038 found 434.1044. 2-Phenyl-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (3i): The general method A described above was followed when 2-phenyl-1-(phenylsulfonyl)aziridine 1i (50 mg, 0.193 mmol) was reacted with 2-bromophenol 2a (25 µL, 0.215 mmol) in presence of LiClO4 (6.1 mg, 0.057 mmol) at 85 °C for 1.5 h followed by addition of CuI (18.4 mg, 0.097 mmol) and K2CO3 (53.3 mg, 0.386 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3i was obtained as a colourless solid, mp 99‒100 °C in 92% (62.4 mg, 0.177 mmol) yield. Rf 0.31 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2955, 2924, 2854, 1740, 1582, 1487, 1447, 1360, 1309, 1264, 1244, 1216, 1170, 1123, 1091; 1H NMR (400 MHz, CDCl3) δ 3.19–3.29 (m, 1H), 4.10– 4.17 (m, 1H), 4.30–4.38 (m, 1H), 6.88–7.01 (m, 2H), 7.06–7.19 (m, 3H), 7.31–7.38 (m, 3H), 7.44–7.52 (m, 2H), 7.55–7.62 (m, 1H), 7.65–7.71 (m, 2H), 7.86–7.93 (m, 1H);

13

C{1H} NMR

(100 MHz, CDCl3) δ 50.3, 73.3, 117.8, 121.2, 123.3, 124.9, 126.0, 126.5, 127.4, 128.8, 128.9, 129.5, 133.6, 137.0, 138.5, 147.4; HRMS (ESI-TOF) calculated for C20H21N2O3S [M+NH4]+ 369.1273 found 369.1278. 2-Phenyl-4-(pyridin-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

(3j):

The

general

method A described above was followed when 2-(2-phenylaziridin-1-ylsulfonyl)pyridine 1j (50 mg, 0.192 mmol) was reacted with 2-bromophenol 2a (25 µL, 0.215 mmol) in presence of LiClO4 (6.1 mg, 0.057 mmol) at 85 °C for 2 h followed by addition of CuI (18.3 mg, 0.096 mmol) and K2CO3 (53.1 mg, 0.384 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3j was obtained as a colourless solid, mp 100‒101 °C in 79% (53.4 mg, 0.151 mmol) yield. Rf 0.36 (30% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2954, 2923, 2853, 1739, 1579, 1489, 1462, 1376, 1308, 1246, 1215, 1180, 1125, 1085; 1H NMR (400 MHz, CDCl3) δ 3.42 (dd, J =


24

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14.2, 10.0 Hz, 1H), 4.73 (dd, J = 14.2, 2.3 Hz, 1H), 5.06 (dd, J = 10.0, 2.7 Hz, 1H), 6.86–6.93 (m, 2H), 7.02 (t, J = 6.9 Hz, 1H), 7.36–7.41 (m, 5H), 7.45–7.49 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 8.71 (d, J = 4.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 50.9, 75.0, 117.8, 121.0, 122.9, 123.4, 123.6, 125.9, 126.2, 127.3, 128.8, 137.3, 138.2, 147.1, 150.4, 156.4; HRMS (ESI-TOF) calculated for C19H17N2O3S [M+H]+ 353.0960 found 353.0965. 8-Nitro-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3k): The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-bromo-6-nitrophenol 2b (43.9 mg, 0.201 mmol) in presence of LiClO4 (5.8 mg, 0.054 mmol) at 85 °C for 3 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3k was obtained as a yellow solid, mp 147‒148 °C in 82% (61.6 mg, 0.150 mmol) yield. Rf 0.54 (25% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3064, 2924, 2854, 1734, 1595, 1574, 1538, 1493, 1468, 1454, 1361, 1314, 1269, 1252, 1237, 1213, 1185, 1167, 1093, 1053; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 3.21 (dd, J = 15.1, 10.5 Hz, 1H), 3.91 (dd, J = 15.1, 3.2 Hz, 1H), 4.82 (d, J = 10.8 Hz, 1H), 7.21–7.24 (m, 3H), 7.29 (t, J = 8.2 Hz, 1H), 7.35–7.40 (m, 5H), 7.53 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.8, 48.8, 74.0,

115.8, 118.0, 122.1, 126.1, 126.7, 128.6, 129.0, 129.2, 130.3, 133.8, 136.5, 145.5, 146.7, 150.3; HRMS (ESI-TOF) calculated for C21H19N2O5S [M+H]+ 411.1015 found 411.1012. 6-Methoxy-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3l): The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-methoxyphenol 2c (40.9 mg, 0.201 mmol) in presence of LiClO4 (5.8 mg, 0.054 mmol) at 85 °C for 1.5 h followed by addition of CuI (17.4 mg, 0.091 mmol) and


25


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K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3l was obtained as a colourless solid, mp 115‒116 °C in 94% (68.0 mg, 0.172 mmol) yield. Rf 0.36 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2924, 2854, 1731, 1597, 1500, 1454, 1355, 1292, 1275, 1221, 1167, 1092, 1054, 1035; 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.22 (dd, J = 14.6, 10.5 Hz, 1H), 3.82 (s, 3H), 4.12 (dd, J = 10.0, 2.3 Hz, 1H), 4.34 (dd, J = 14.2, 2.3 Hz, 1H), 6.70 (dd, J = 9.2, 2.7 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 7.18–7.20 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.33–7.39 (m, 3H), 7.51 (d, J = 3.2, 1H), 7.59 (d, J = 8.2 Hz, 2H);

13

C{1H} NMR (100 MHz,

CDCl3) δ 21.7, 50.5, 55.9, 73.0, 108.9, 113.5, 118.2, 123.5, 126.0, 127.5, 128.7, 128.8, 130.1, 135.4, 137.3, 141.4, 144.7, 153.7; HRMS (ESI-TOF) calculated for C22H21NNaO4S [M+Na]+ 418.1089 found 418.1089. 6-Chloro-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3m):10a The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-chlorophenol 2d (41.7 mg, 0.201 mmol) in presence of LiClO4 (5.8 mg, 0.054 mmol) at 85 °C for 2.5 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3m was obtained as a colourless solid, mp 165‒166 °C in 83% (60.8 mg, 0.152 mmol) yield. Rf 0.40 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3065, 3032, 2956, 2924, 2853, 1737, 1597, 1574, 1484, 1454, 1414, 1360, 1307, 1292, 1247, 1214, 1185, 1168, 1126, 1090, 1028, 1018; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.20 (dd, J = 14.6, 10.1 Hz, 1H), 4.16 (dd, J = 10.1, 2.3 Hz, 1H), 4.34 (dd, J = 14.6, 2.3 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 7.06 (dd, J = 8.7, 2.3 Hz, 1H), 7.17– 7.19 (m, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.34–7.40 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 2.7 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.1, 73.4, 118.8, 124.3, 124.4, 126.0,


26

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126.4, 127.5, 128.9, 129.0, 130.3, 135.2, 136.7, 144.9, 145.9; HRMS (ESI-TOF) calculated for C21H19ClNO3S [M+H]+ 400.0774 found 400.0771. 6-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3n): The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-methylphenol 2e (25 µL, 0.207 mmol) in presence of LiClO4 (5.8 mg, 0.054 mmol) at 85 °C for 2 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3n was obtained as a colourless solid, mp 117‒118 °C in 92% (63.9 mg, 0.168 mmol) yield. Rf 0.48 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2954, 2923, 2853, 1738, 1597, 1502, 1455, 1361, 1322, 1308, 1262, 1247, 1225, 1185, 1168, 1132, 1092; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.40 (s, 3H), 3.20 (dd, J = 14.6, 10.5 Hz, 1H), 4.13 (dd, J = 10.5, 2.3 Hz, 1H), 4.32 (dd, J = 14.6, 2.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 8.7, 1.8 Hz, 1H), 7.17–7.19 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.32–7.38 (m, 3H), 7.57 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 1.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 21.0, 21.7, 50.4, 73.0, 117.3, 123.0, 125.2, 126.0, 127.3, 127.5, 128.9, 130.1, 130.7, 135.6, 137.3, 144.5, 145.3; HRMS (ESI-TOF) calculated for C22H21NNaO3S [M+Na]+ 402.1140 found 402.1148. 6-Fluoro-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3o): The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-fluorophenol 2f (38.4 mg, 0.201 mmol) in presence of LiClO4 (5.8 mg, 0.054 mmol) at 85 °C for 2.5 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3o was obtained as a colourless solid, mp 142‒143 °C in 85% (59.6 mg, 0.155 mmol) yield. Rf 0.38 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2954, 2924, 2854, 1740, 1598, 1496, 1462, 1376, 1261,


27


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1246, 1215, 1170, 1091; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.22 (dd, J = 14.6, 10.1 Hz, 1H), 4.16 (dd, J = 10.1, 2.3 Hz, 1H), 4.36 (dd, J = 14.6, 2.3 Hz, 1H), 6.80–6.89 (m, 2H), 7.18– 7.21 (m, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.34–7.40 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.72 (dd, J = 10.5, 2.7 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.2, 73.3, 110.9, 111.2, 113.1,

113.3, 118.3, 118.4, 123.8, 123.9, 126.0, 127.4, 128.9, 129.0, 130.2, 135.2, 136.9, 143.4, 144.9, 156.7 (d, 1JC-F = 238.7 Hz); HRMS (ESI-TOF) calculated for C21H18FNNaO3S [M+Na]+ 406.0889 found 406.0889. 6-Nitro-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3p): The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-nitrophenol 2g (43.9 mg, 0.201 mmol) in presence of LiClO4 (5.8 mg, 0.054 mmol) at 85 °C for 3 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3p was obtained as a yellow solid, mp 153‒154 °C in 82% (61.6 mg, 0.150 mmol) yield. Rf 0.57 (25% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2955, 2924, 2854, 1741, 1583, 1520, 1462, 1376, 1343, 1273, 1249, 1168, 1089; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 3.28 (dd, J = 15.4, 10.4 Hz, 1H), 4.40–4.46 (m, 2H), 7.04 (d, J = 9.1 Hz, 1H), 7.21–7.23 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.39–7.44 (m, 3H), 7.65 (d, J = 8.1 Hz, 2H), 8.01 (dd, J = 9.1, 2.7 Hz, 1H), 8.83 (d, J = 2.7 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 49.6, 74.7, 118.2, 120.4, 121.6, 123.7, 126.0,

127.6, 129.1, 129.4, 130.4, 135.0, 135.8, 141.7, 145.3, 152.2; HRMS (ESI-TOF) calculated for C21H22N3O5S [M+NH4]+ 428.1280 found 428.1286. 2-Phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3a):10a,b (Table 3, entry 7) The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-chlorophenol 2h (21 µL, 0.206 mmol) in presence of LiClO4 (6 mg, 0.056


28

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mmol) at 85 °C for 2.5 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3a was obtained as a colourless solid, mp 107‒108 °C in 83% (55.5 mg, 0.152 mmol) yield. Rf 0.32 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3035, 2924, 2853, 1740, 1597, 1487, 1454, 1357, 1308, 1264, 1244, 1215, 1167, 1123, 1091, 1057; 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.24 (dd, J = 14.6, 10.4 Hz, 1H), 4.20 (dd, J = 10.4, 2.4 Hz, 1H), 4.37 (dd, J = 14.6, 2.4 Hz, 1H), 6.93 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (t, J = 6.7 Hz, 1H), 7.12 (t, J = 6.7 Hz, 1H), 7.19–7.21 (m, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.34–7.40 (m, 3H), 7.58 (d, J = 7.9 Hz, 2H), 7.92 (dd, J = 8.5, 1.8 Hz, 1H); 13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.3, 73.2, 117.7, 121.2, 123.4, 125.0, 126.0, 126.4,

127.5, 128.9, 129.8, 130.1, 135.6, 137.1, 144.6, 147.4; HRMS (ESI-TOF) calculated for C21H20NO3S [M+H]+ 366.1164 found 366.1163. 2-Phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3a):10a,b (Table 3, entry 8) The general method A described above was followed when 2-phenyl-1-tosylaziridine 1a (50 mg, 0.183 mmol) was reacted with 2-iodophenol 2i (44.3 mg, 0.201 mmol) in presence of LiClO4 (6 mg, 0.056 mmol) at 85 °C for 2 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3a was obtained as a colourless solid, mp 107‒108 °C in 88% (58.8 mg, 0.161 mmol) yield. Rf 0.32 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3035, 2924, 2853, 1740, 1597, 1487, 1454, 1357, 1308, 1264, 1244, 1215, 1167, 1123, 1091, 1057; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.24 (dd, J = 14.6, 10.4 Hz, 1H), 4.20 (dd, J = 10.4, 2.4 Hz, 1H), 4.37 (dd, J = 14.6, 2.4 Hz, 1H), 6.93 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (t, J = 6.7 Hz, 1H), 7.11 (t, J = 6.7 Hz, 1H), 7.18–7.21 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.34–7.40 (m, 3H), 7.57 (d, J = 7.9 Hz, 2H), 7.92 (dd, J = 8.5, 1.8 Hz, 1H);

13

C{1H}

NMR (100 MHz, CDCl3) δ 21.7, 50.3, 73.2, 117.7, 121.2, 123.4, 125.0, 126.0, 126.4, 127.5,


29


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128.9, 129.8, 130.1, 135.6, 137.1, 144.6, 147.4; HRMS (ESI-TOF) calculated for C21H20NO3S [M+H]+ 366.1164 found 366.1163. (Z)-3-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3q): The general method A described above was followed when trans-2-methyl-3-phenyl-1-tosylaziridine 1k (63 mg, 0.219 mmol) was reacted with 2-bromophenol 2a (28 µL, 0.241 mmol) in presence of LiClO4 (7 mg, 0.066 mmol) at 85 °C for 2 h followed by addition of CuI (20.8 mg, 0.109 mmol) and K2CO3 (60.5 mg, 0.438 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3q was obtained as a colourless solid, mp 129‒130 °C in 95% (78.9 mg, 0.208 mmol) yield. Rf 0.42 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3030, 2955, 2925, 2854, 1741, 1598, 1583, 1488, 1452, 1356, 1305, 1256, 1214, 1198, 1170, 1122, 1082, 1042,1007; 1H NMR (400 MHz, CDCl3) δ 0.86 (d, J = 7.2 Hz, 3H), 2.37 (s, 3H), 4.16 (d, J = 2.4 Hz, 1H), 4.48–4.53 (m, 1H), 6.96 (d, J = 8.2 Hz, 1H), 7.01 (dt, J = 8.5, 1.2 Hz, 1H), 7.12–7.16 (m, 1H), 7.20 (d, J = 7.2 Hz, 2H), 7.26–7.30 (m, 3H), 7.36 (t, J = 7.2 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.2 Hz, 1H);

13

C{1H}

NMR (100 MHz, CDCl3) δ 11.7, 21.6, 53.3, 74.6, 117.3, 121.4, 121.5, 125.4, 126.0, 126.2, 127.3, 128.0, 128.5, 130.0, 135.5, 137.2, 144.3, 146.5; HRMS (ESI-TOF) calculated for C22H22NO3S [M+H]+ 380.1320 found 380.1319. 4-Tosyl-2-vinyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3r): The general method A described above was followed when 1-tosyl-2-vinylaziridine 1l (50 mg, 0.224 mmol) was reacted with 2bromophenol 2a (29 µL, 0.250 mmol) in presence of LiClO4 (7.1 mg, 0.067 mmol) at 85 °C for 2.5 h followed by addition of CuI (21.3 mg, 0.112 mmol) and K2CO3 (61.9 mg, 0.448 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3r was obtained as a white solid, mp 135‒136 °C in 75% (53.0 mg, 0.168 mmol) yield. Rf 0.38 (15% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2922, 2851, 1651, 1598, 1488, 1463, 1409, 1348, 1316, 1265, 1245, 1213, 1185, 1164,


30

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1120, 1089, 1074, 1037, 1017; 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 3.14 (dd, J = 14.6, 10.1 Hz, 1H), 3.73–3.77 (m, 1H), 4.25 (dd, J = 14.2, 2.3 Hz, 1H), 5.26–5.31 (m, 2H), 5.69–5.77 (m, 1H), 6.84 (dd, J = 8.2, 1.8 Hz, 1H), 6.91–6.95 (m, 1H), 7.04–7.08 (m, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 8.2, 1.4 Hz, 1H);

13

C{1H} NMR (100 MHz,

CDCl3) δ 21.7, 48.4, 72.2, 117.6, 118.9, 121.1, 123.5, 124.7, 126.4, 127.3, 130.0, 133.3, 135.6, 144.4, 146.9; HRMS (ESI-TOF) calculated for C17H17NNaO3S [M+Na]+ 338.0827 found 338.0822. 2-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4a): The general method C described above was followed when 2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 3a (50.0 mg, 0.137 mmol) in dry methanol (2.0 mL) was reacted with Mg powder (34.0 mg, 1.4 mmol) at rt for 1 h, 4a was obtained as a white solid, mp 97‒98 °C in 91% (26.4 mg, 0.125 mmol) yield. Rf 0.27 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3388, 2955, 2924, 2854, 1741, 1609, 1590, 1500, 1454, 1377, 1345, 1262, 1210, 1114, 1093, 1042; 1H NMR (400 MHz, CDCl3) δ 3.34–3.40 (m, 1H), 3.50 (dd, J = 12.1, 2.4 Hz, 1H), 3.89 (bs, 1H), 5.09 (dd, J = 8.5, 2.4 Hz, 1H), 6.66–6.70 (m, 1H), 6.73 (dd, J = 7.9, 1.8 Hz, 1H), 6.80–6.85 (m, 1H), 6.93 (dd, J = 7.9, 1.2 Hz, 1H), 7.33–7.44 (m, 5H);

13

C{1H} NMR (100 MHz, CDCl3) δ 47.9, 76.1, 115.7, 117.2, 119.2,

121.6, 126.4, 128.4, 128.7, 132.9, 139.1, 144.8; HRMS (ESI-TOF) calculated for C14H14NO [M+H]+ 212.1075 found 212.1079. (S)-2-Phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (S)-3a: The general method B described above was followed when (R)-2-phenyl-1-tosylaziridine (R)-1a (50 mg, 0.183 mmol) was reacted with 2-bromophenol 2a (24 µL, 0.207 mmol) in presence of NaH (6.6 mg, 0.275 mmol) and LiClO4 (4 mg, 0.037 mmol) at 85 °C for 1 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-


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3a was obtained as a white solid, mp 109‒110 °C in 80% (53.5 mg, 0.146 mmol) yield. Rf 0.32 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3035, 2924, 2853, 1740, 1597, 1487, 1454, 1357, 1308, 1264, 1244, 1215, 1167, 1123, 1091, 1057; 1H NMR (500 MHz, CDCl3) δ 2.40 (s, 3H), 3.23 (dd, J = 14.9, 10.4 Hz, 1H), 4.20 (d, J = 10.4 Hz, 1H), 4.36 (d, J = 14.5 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.33–7.38 (m, 3H), 7.56–7.58 (m, 2H), 7.91 (d, J = 8.2 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.3, 73.2, 117.7, 121.2, 123.4, 125.0, 126.0,

126.4, 127.5, 128.9, 129.8, 130.1, 135.6, 137.1, 144.6, 147.4; HRMS (ESI-TOF) calcd for C21H20NO3S [M+H]+ 366.1164 found 366.1163. [α]D25 = 36.1 (c 0.17, CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 98:2, flow rate = 0.5 mL/min, tR (1) = 38.83 min. (S)-2-Phenyl-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

(S)-3i:

The

general

method B described above was followed when (R)-2-phenyl-1-(phenylsulfonyl)aziridine (R)-1i (50 mg, 0.193 mmol) was reacted with 2-bromophenol 2a (25 µL, 0.215 mmol) in presence of NaH (6.9 mg, 0.287 mmol) and LiClO4 (4.1 mg, 0.038 mmol) at 85 °C for 1 h followed by addition of CuI (18.4 mg, 0.097 mmol) and K2CO3 (53.3 mg, 0.386 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3i was obtained as a white solid, mp 99‒100 °C in 82% (55.6 mg, 0.158 mmol) yield. Rf 0.31 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2955, 2924, 2854, 1740, 1582, 1487, 1447, 1360, 1309, 1264, 1244, 1216, 1170, 1123, 1091; 1H NMR (500 MHz, CDCl3) δ 3.27 (dd, J = 14.7, 10.4 Hz, 1H), 4.17 (dd, J = 10.2, 1.9 Hz, 1H), 4.37 (dd, J = 14.6, 2.3 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 7.0 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 6.6 Hz, 2H), 7.34–7.39 (m, 3H), 7.51 (t, J = 7.7 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.92 (d, J = 7.2 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 50.3,


32

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73.3, 117.8, 121.2, 123.3, 124.9, 126.0, 126.5, 127.4, 128.8, 128.9, 129.5, 133.6, 137.0, 138.5, 147.4; HRMS (ESI-TOF) calculated for C20H21N2O3S [M+NH4]+ 369.1273 found 369.1278. [α]D25 = 83.1 (c 0.07, CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 14.37 min. (S)-2-Phenyl-4-(pyridin-2-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (S)-3j: The general method B described above was followed when (R)-2-(2-phenylaziridin-1-ylsulfonyl)pyridine (R)1j (50 mg, 0.192 mmol) was reacted with 2-bromophenol 2a (25 µL, 0.215 mmol) in presence of NaH (6.9 mg, 0.287 mmol) and LiClO4 (4.1 mg, 0.038 mmol) at 85 °C for 1.5 h followed by addition of CuI (18.3 mg, 0.096 mmol) and K2CO3 (53.1 mg, 0.384 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3j was obtained as a white solid, mp 100‒101 °C in 81% (54.8 mg, 0.155 mmol) yield. Rf 0.36 (30% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2954, 2923, 2853, 1739, 1579, 1489, 1462, 1376, 1308, 1246, 1215, 1180, 1125, 1085; 1H NMR (500 MHz, CDCl3) δ 3.43 (dd, J = 14.2, 10.0 Hz, 1H), 4.73 (dd, J = 14.2, 2.3 Hz, 1H), 5.07 (dd, J = 10.0, 2.7 Hz, 1H), 6.87–6.94 (m, 2H), 7.03 (t, J = 6.9 Hz, 1H), 7.35–7.43 (m, 5H), 7.48 (dd, J = 7.3, 4.6 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 8.72 (d, J = 4.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 50.9, 75.0, 117.8, 121.0, 122.9, 123.4, 123.6, 125.9, 126.2, 127.3, 128.8, 137.3, 138.2, 147.1, 150.4, 156.4; HRMS (ESI-TOF) calculated for C19H17N2O3S [M+H]+ 353.0960 found 353.0965. [α]D25 = 22.0 (c 0.23, CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 57.93 min. (S)-6-Methoxy-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

(S)-3l:

The

general

method B described above was followed when (R)-2-phenyl-1-tosylaziridine (R)-1a (50 mg,


33


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0.183 mmol) was reacted with 2-bromo-4-methoxyphenol 2c (40.9 mg, 0.201 mmol) in presence of NaH (6.6 mg, 0.275 mmol) and LiClO4 (4 mg, 0.037 mmol) at 85 °C for 1.0 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3l was obtained as a white solid, mp 115‒116 °C in 84% (60.8 mg, 0.154 mmol) yield. Rf 0.36 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2924, 2854, 1731, 1597, 1500, 1454, 1355, 1292, 1275, 1221, 1167, 1092, 1054, 1035; 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.22 (dd, J = 14.2, 10.1 Hz, 1H), 3.82 (s, 3H), 4.12 (dd, J = 10.1, 2.3 Hz, 1H), 4.34 (dd, J = 14.6, 2.7 Hz, 1H), 6.70 (dd, J = 9.2, 3.2 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 7.17–7.19 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.33–7.38 (m, 3H), 7.51 (d, J = 3.2, 1H), 7.59 (d, J = 8.7 Hz, 2H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.5, 55.9, 73.0, 108.9, 113.5,

118.2, 123.5, 126.0, 127.5, 128.7, 128.8, 130.1, 135.4, 137.3, 141.4, 144.7, 153.7; HRMS (ESITOF) calculated for C22H21NNaO4S [M+Na]+ 418.1089 found 418.1089. [α]D25 = 118.9 (c 0.13, CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 19.92 min. (S)-6-Chloro-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

(S)-3m:

The

general

method B described above was followed when (R)-2-phenyl-1-tosylaziridine (R)-1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-chlorophenol 2d (41.7 mg, 0.201 mmol) in presence of NaH (6.6 mg, 0.275 mmol) and LiClO4 (4 mg, 0.037 mmol) at 85 °C for 1.5 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3m was obtained as a white solid, mp 165‒166 °C in 78% (57.1 mg, 0.143 mmol) yield. Rf 0.40 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3065, 3032, 2956, 2924, 2853, 1737, 1597, 1574, 1484, 1454, 1414, 1360, 1307, 1292, 1247, 1214,


34

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1185, 1168, 1126, 1090, 1028, 1018; 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.21 (dd, J = 14.6, 10.1 Hz, 1H), 4.17 (dd, J = 10.1, 2.3 Hz, 1H), 4.35 (dd, J = 14.6, 2.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 7.07 (dd, J = 8.7, 2.3 Hz, 1H), 7.18–7.20 (m, 2H), 7.32–7.41 (m, 5H), 7.61 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 2.7 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 50.1, 73.4,

118.8, 124.3, 124.4, 126.0, 126.4, 127.5, 128.9, 129.0, 130.3, 135.2, 136.7, 144.9, 145.9; HRMS (ESI-TOF) calculated for C21H19ClNO3S [M+H]+ 400.0774 found 400.0771. [α]D25 = 142.2 (c 0.1, CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 15.71 min. (S)-6-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (S)-3n: The general method B described above was followed when (R)-2-phenyl-1-tosylaziridine (R)-1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-methylphenol 2e (25 µL, 0.207 mmol) in presence of NaH (6.6 mg, 0.275 mmol) and LiClO4 (4 mg, 0.037 mmol) at 85 °C for 1.0 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3n was obtained as a white solid, mp 117‒118 °C in 87% (60.4 mg, 0.159 mmol) yield. Rf 0.48 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2954, 2923, 2853, 1738, 1597, 1502, 1455, 1361, 1322, 1308, 1262, 1247, 1225, 1185, 1168, 1132, 1092; 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.41 (s, 3H), 3.21 (dd, J = 14.6, 10.5 Hz, 1H), 4.14 (dd, J = 10.5, 2.3 Hz, 1H), 4.33 (dd, J = 14.6, 2.7 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.7, 1.8 Hz, 1H), 7.18–7.20 (m, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.33–7.39 (m, 3H), 7.58 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 1.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 21.0, 21.7, 50.4, 73.0, 117.3, 123.0, 125.2, 126.0, 127.3, 127.5, 128.9, 130.1, 130.7, 135.6, 137.3, 144.5, 145.3; HRMS (ESITOF) calculated for C22H21NNaO3S [M+Na]+ 402.1140 found 402.1148. [α]D25 = 79.5 (c 0.1,


35


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CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 23.66 min. (S)-2-Phenyl-4-tosyl-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

(S)-3s:

The

general method B described above was followed when (R)-2-phenyl-1-tosylaziridine (R)-1a (50 mg, 0.183 mmol) was reacted with 2-bromo-4-(trifluoromethyl)phenol 2j (28 µL, 0.203 mmol) in presence of NaH (6.6 mg, 0.275 mmol) and LiClO4 (4 mg, 0.037 mmol) at 85 °C for 2.0 h followed by addition of CuI (17.4 mg, 0.091 mmol) and K2CO3 (50.6 mg, 0.366 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3s was obtained as a white solid, mp 110‒111 °C in 80% (63.4 mg, 0.146 mmol) yield. Rf 0.28 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2923, 2852, 1359, 1333, 1271, 1250, 1168, 1121, 1073; 1H NMR (500 MHz, CDCl3) δ 2.43 (s, 3H), 3.24 (dd, J = 14.7, 10.3 Hz, 1H), 4.27 (dd, J = 10.2, 1.9 Hz, 1H), 4.40 (dd, J = 14.7, 2.3 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 6.4 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.35–7.41 (m, 4H), 7.59 (d, J = 8.2 Hz, 2H), 8.21 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 21.6, 49.8, 73.8, 118.1, 122.2, 122.2, 123.0, 123.1, 123.6, 125.9, 127.4, 128.9, 129.1, 130.2, 135.0, 136.3, 145.0, 149.6; 19F NMR (372.5 MHz, CDCl3) δ ‒61.5; HRMS (ESI-TOF) calculated for C22H22F3N2O3S [M+NH4]+ 451.1303 found 451.1304. [α]D25 = 39.5 (c 0.1, CHCl3) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), nhexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 48.71 min. (R)-2-(2-Chlorophenyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

(R)-3t:

The

general

method B described above was followed when (S)-2-(2-chlorophenyl)-1-tosylaziridine (S)-1m (83% ee, 50 mg, 0.162 mmol) was reacted with 2-iodophenol 2i (39.2 mg, 0.178 mmol) in presence of NaH (5.8 mg, 0.242 mmol) and LiClO4 (3.4 mg, 0.032 mmol) at 85 °C for 1.5 h


36

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followed by addition of CuI (15.4 mg, 0.081 mmol) and K2CO3 (44.8 mg, 0.324 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (R)-3t was obtained as a white solid, mp 151‒152 °C in 75% (48.6 mg, 0.121 mmol) yield. Rf 0.33 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2924, 2854, 1489, 1316, 1357, 1246, 1214, 1167, 1065, 1091; 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 3.09 (dd, J = 14.6, 10.4 Hz, 1H), 4.63 (dd, J = 14.6, 2.4 Hz, 1H), 4.83 (dd, J = 10.4, 2.4 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 7.13 (t, J = 6.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.25–7.31 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.96 (d, J = 7.9 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 21.7, 48.4, 70.5,

117.6, 121.3, 123.5, 124.9, 126.6, 127.5, 127.6, 127.7, 129.7, 129.8, 129.9, 131.7, 135.0, 135.8, 144.4, 147.2; HRMS (ESI-TOF) calculated for C21H19ClNO3S [M+H]+ 400.0774 found 400.0779. [α]D25 = ‒100.0 (c 0.1, CHCl3) for a 83% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak Cellulose 2 column), n-hexane/i-propanol = 95:5, flow rate = 1.0 mL/min, tR (1) = 88.85 min (minor), tR (2) = 107.78 min (major). 3-Methyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (3u):15a The general method B described above was followed when 2-methyl-1-tosylaziridine 1n (50 mg, 0.237 mmol) was reacted with 2-bromophenol 2a (31 µL, 0.267 mmol) in presence of NaH (8.5 mg, 0.354 mmol) and LiClO4 (7.6 mg, 0.071 mmol) at 85 °C for 2 h followed by addition of CuI (22.6 mg, 0.119 mmol) and K2CO3 (65.5 mg, 0.474 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, 3u was obtained as a white solid, mp 140‒141 °C in 79% (56.8 mg, 0.187 mmol) yield. Rf 0.36 (20% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 2925, 1737, 1598, 1582, 1488, 1454, 1349, 1321, 1306, 1291, 1266, 1244, 1213, 1185, 1168, 1131, 1116, 1091, 1071, 1043, 1014; 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J = 6.8 Hz, 3H), 2.37 (s, 3H), 3.20 (dd, J = 10.9, 2.3 Hz, 1H), 3.79 (dd, J = 10.9, 1.4 Hz, 1H), 4.41–4.46 (m, 1H), 6.80 (dd, J = 8.1, 1.4 Hz, 1H), 6.93–6.97 (m, 1H), 7.07 (td,


37


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J = 8.6, 1.4 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.88 (dd, J = 8.1, 1.4 Hz, 1H);

13

C{1H} NMR (100 MHz, CDCl3) δ 17.1, 21.6, 48.6, 66.1, 117.2, 121.2, 122.0, 126.0,

126.2, 127.3, 129.9, 135.4, 144.2, 146.1; HRMS (ESI-TOF) calcd for C16H18NO3S [M+H]+ 304.1007 found 304.1009. 3-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4b):15a The general method C described above was followed when 3-methyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 3u (50.0 mg, 0.165 mmol) in dry methanol (2.0 mL) was reacted with Mg powder (39.6 mg, 1.65 mmol) at rt for 1 h, 4b was obtained as a brown oil in 86% (21.2 mg, 0.142 mmol) yield. Rf 0.48 (30% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm-1) 3374, 2957, 2924, 2853, 1732, 1608, 1590, 1500, 1460, 1428, 1379, 1345, 1308, 1279, 1209, 1173, 1121, 1083, 1045, 1022; 1H NMR (400 MHz, CDCl3) δ 1.17 (d, J = 6.2 Hz, 3H), 3.51–3.55 (m, 1H), 3.76 (dd, J = 10.3, 8.2 Hz, 1H), 4.18 (dd, J = 10.3, 3.1 Hz, 1H), 6.58 (dd, J = 7.7, 2.1 Hz, 1H), 6.65 (td, J = 7.7, 1.5 Hz, 1H), 6.73–6.79 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 17.9, 45.2, 70.8, 115.5, 116.5, 118.9, 121.4, 133.5, 143.7; HRMS (ESI-TOF) calculated for C9H12NO [M+H]+ 150.0919 found 150.0911. 6-Bromo-2,3-difluorophenol (2k):15b To a solution of 2,3-difluorophenol (0.10 g, 0.769 mmol) and isopropylamine (67.0 µL, 0.780 mmol) in dry DCM (7.0 mL) was added NBS (136.0 mg, 0.764 mmol) portionwise at ‒ 30 °C. The mixture was stirred at that temperature for 30 min and then allowed to reach rt. The reaction mixture was then diluted with HCl (1 N in H2O) and extracted with DCM (3×5.0 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 3% ethyl acetate in petroleum ether as the eluent. The desired fractions were collected and the solvent was removed under reduced pressure to yield 6-bromo-2,3-difluorophenol 2k as a colorless liquid in 80%


38

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(127.7 mg, 0.611 mmol) yield. Rf 0.49 (10% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm1

) 2922, 2851, 1738, 1463; 1H NMR (400 MHz, CDCl3) δ 6.68 (td, J = 9.9, 7.6 Hz, 1H), 7.19

(ddd, J = 9.9, 4.6, 2.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 105.3, 105.4, 109.3, 109.5, 126.1, 126.1, 126.2, 126.2, 140.3 (dd, 1JC-F = 248.9 Hz, 2JC-F = 15.6 Hz), 142.9, 143.1, 150.7 (dd, 1

JC-F = 248.3 Hz, 2JC-F = 10.8 Hz); HRMS (ESI-TOF) calculated for C6H2BrF2O [M‒H]+

206.9257 found 206.9251. (S)-7,8-Difluoro-3-methyl-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (S)-3v:15a The general method B described above was followed when (S)-2-methyl-1-tosylaziridine (S)-1n (100 mg, 0.473 mmol) was reacted with 6-bromo-2,3-difluorophenol 2k (109.0 mg, 0.521 mmol) in presence of NaH (15.7 mg, 0.654 mmol) and LiClO4 (13.9 mg, 0.131 mmol) at 85 °C for 2 h followed by addition of CuI (41.6 mg, 0.218 mmol) and K2CO3 (130.7 mg, 0.946 mmol) in DMF (1.0 mL) heated at 120 °C for 10 h, (S)-3v was obtained as a white solid, mp 120‒121 °C in 75% (120.4 mg, 0.355 mmol) yield. Rf 0.32 (20% ethyl acetate in petroleum ether); IR ν̃max (KBr, cm1

) 2924, 2853, 1736, 1632, 1598, 1507, 1483, 1355, 1306, 1265, 1233, 1183, 1165, 1135, 1113,

1088, 1037; 1H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.7 Hz, 3H), 2.39 (s, 3H), 3.16 (dd, J = 11.0, 2.6 Hz, 1H), 3.91 (dd, J = 11.0, 1.1 Hz, 1H), 4.43–4.48 (m, 1H), 6.77 (td, J = 9.6, 7.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.63 (ddd, J = 9.6, 5.1, 2.4 Hz, 1H); 13

C{1H} NMR (100 MHz, CDCl3) δ 16.8, 21.6, 48.2, 66.2, 108.1, 108.2, 119.2, 120.2, 120.2,

120.2, 120.3, 127.2, 130.1, 134.8, 136.6, 139.9 (dd, 1JC-F = 247.7 Hz, 2JC-F = 15.6 Hz), 144.6, 148.5 (dd, 1JC-F = 245.9 Hz, 2JC-F = 10.8 Hz); HRMS (ESI-TOF) calcd for C16H15F2NNaO3S [M+Na]+ 362.0638 found 362.0633. [α]D25 = ‒186.0 (c 0.14, EtOH) for a >99% ee sample. The enantiomeric excess was determined by chiral HPLC analysis (chiralpak OJ-H column), nhexane/i-propanol = 90:10, flow rate = 0.8 mL/min, tR (2) = 27.43 min.


39


Page 40 of 47

Supporting Information Copies of

1

H and

13

C NMR spectra of the compounds, HPLC chromatograms for ee

determination and crystal structures. This material is available free of charge via the internet at http://pubs.acs.org.

ACKNOWLEDGEMENTS M.K.G. is grateful to IIT-Kanpur and CSIR, India for financial support. A.M. thanks to CSIR, India and I.A.W. and G.G. thank UGC, India for research fellowships. M.K.G thanks Mr. Indresh Verma for helpful discussions to solve X-ray crystal structures.

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Enamides:

(Z)-3-Arylidene-4-acetyl-3,4-dihydro-2H-1,4-

benzoxazines. J. Org. Chem. 2015, 70, 1679‒1683. (b) Liu, X.-W.; Wang, C.; Yan, Y.; Wang, Y.-Q.; Sun, J. An Organocatalyst Bearing Stereogenic Carbon and Sulfur Centers as an Efficient Promoter for Enantioselective Hydrosilylation of 1,4-Benzooxazines. J. Org. Chem. 2013, 78, 6276−6280. (c) Wang, Y.-Q.; Zhang, Y.; Pan, K.; You, J.; Zhao, J. Direct Organocatalytic Asymmetric

Mannich

Addition

of

3-Substituted-2H-1,4-Benzoxazines:

Access

to

Tetrasubstituted Carbon Stereocenters. Adv. Synth. Catal. 2013, 355, 3381−3386.


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8.

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For reviews on aziridines see: (a) Couty, F.; David, O. R. P. Ring Expansions of

Nonactivated Aziridines and Azetidines. Top. Heterocycl. Chem. 2016, 41, 1–48. (b) Ghorai, M. K.; Bhattacharyya, A.; Das, S.; Chauhan, N. Ring Expansions of Activated Aziridines and Azetidines. Top. Heterocycl. Chem. 2016, 41, 49‒142. (c) Ghorai, M. K.; Shahi, C. K.; Bhattacharyya, A.; Sayyad, M.; Mal, A.; Wani, I. A.; Chauhan, N. Syntheses of Tetrahydrobenzodiazepines via SN2-Type Ring-Opening of Activated Aziridines with 2Bromobenzylamine Followed by Copper-Powder-Mediated C–N Bond Formation. Asian J. Org. Chem. 2015, 4, 1103‒1111 and references cited therein. (d) Callebaut, G.; Meiresonne, T.; Kimpe, N. D.; Mangelinckx, S. Synthesis and Reactivity of 2-(Carboxymethyl)aziridine Derivatives. Chem. Rev. 2014, 114, 7954‒8015 and references cited therein. 9.

For some representative examples on aziridine chemistry see: (a) Hao, W.; Wu, X.; Sun,

J. Z.; Siu, J. C.; Macmillan, S. N.; Lin, S. Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes. J. Am. Chem. Soc. 2017, 139, 12141–12144. (b) Lin, T.-Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Divergent Access to Functionalized Pyrrolidines and Pyrrolines via Iridium-Catalyzed Domino-Ring-Opening Cyclization of Vinyl Aziridines with β-Ketocarbonyls. Org. Lett. 2017, 19, 6526‒6529. (c) Li, K.; Weber, A. E.; Tseng, L.; Malcolmson, S. J. Diastereoselective and Enantiospecific Synthesis of 1,3-Diamines via 2Azaallyl Anion Benzylic Ring-Opening of Aziridines. Org. Lett. 2017, 19, 4239‒4242. (d) Wang, Y.-N.; Li, T.-R.; Zhang, M.-M.; Cheng, B.-Y.; Lu, L.-Q.; Xiao, W.-J. Formal [3 + 2] Cycloadditions via Indole Activation: A Route to Pyrroloindolines and Furoindolines. J. Org. Chem. 2016, 81, 10491‒10498. (e) Dolfen, J.; Vervisch, K.; Kimpe, N. D.; Dʹhooghe, M. LiAlH4‐Induced

Selective

Ring

Rearrangement

of

2‐(2‐Cyanoethyl)aziridines

toward

2‐(Aminomethyl)pyrrolidines and 3‐Aminopiperidines as Eligible Heterocyclic Building Blocks.


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