Kinetic Resolution by Lithiation: Highly Enantioselective Synthesis of Substituted Dihydrobenzoxazines and Tetrahydroquinoxalines

Abstract

Kinetic resolution provided a highly enantioselective method to access a range of 3-aryl-3,4-dihydro-2H-1,4-benzoxazines using n-butyllithium and the chiral ligand sparteine. The enantioenrichment remained high on removing the tert-butoxycarbonyl (Boc) protecting group. The intermediate organolithium undergoes ring opening to an enamine. The kinetic resolution was extended to give enantiomerically enriched substituted 1,2,3,4-tetrahydroquinoxalines and was applied to the synthesis of an analogue of the antibiotic levofloxacin that was screened for its activity against the human pathogen Streptococcus pneumoniae.

Biographical Sketches

From left to right: Joshua Priest obtained his Masters degree from the University of Loughborough (UK) in 2012 and his PhD from the University of Birmingham (UK) in 2017 under the supervision of Dr Paul Davies­. He carried out postdoctoral research in the group of Prof. Coldham at the University of Sheffield (UK) from 2018–2019.

Soneni Ndlovu obtained her Masters degree from the University of Sheffield (UK) in 2020. She is now working towards her PhD under the supervision of Prof. Paul Wright at the University of St Andrews (UK).

Song-Hee (Jennifer) Yeo obtained her Masters degree from the University of Sheffield (UK) in 2018. She continued her research in the group of Prof. Coldham in Sheffield and is working towards her PhD.

Anthony Choi obtained his PhD in the group of Prof. Coldham at the University of Sheffield (UK) in 2019. He is currently a postdoctoral research associate in Sheffield that includes a collaboration with Liverpool ChiroChem.

Iain Coldham obtained his PhD from the University of Cambridge (UK) in 1989 working under the supervision of Dr Stuart Warren­. After postdoctoral research in the USA with Prof. Phil Magnus, he returned to the UK to a Lectureship at the University of Exeter. He moved to the University of Sheffield (UK) in 2003 and was promoted to Professor in 2008.

Ashraf El-Tunsi obtained his Masters degree from the University of Benghazi (Libya) in 2008 and his PhD from the University of Sheffield (UK) in 2020.

Nick Carter obtained his PhD from the University of Sheffield (UK) in 2017 working under the supervision of Prof. Coldham. He moved to Manchester Metropolitan University (UK) for a postdoctoral position under the supervision of Dr Macia Ruiz, followed by work as a Technical Specialist at Nottingham Trent University (UK).

Andrew Fenton completed his PhD studies at the University of Nottingham (UK) under the supervision of Prof. Liz Sockett. After this, he worked at the Centre for Bacterial Cell Biology in Newcastle (UK) before working at Harvard Medical School (USA) under the supervision of Prof. Tom Bernhardt and Prof. David Rudner. Currently, he leads a research group studying cell wall biology, host–pathogen interactions, and antimicrobial resistance in Streptococcus pneumoniae at the Florey Institute within the University of Sheffield (UK).

Carolin Kobras received her PhD in microbiology from the University of Bath (UK) in 2019. She then joined the group of Dr Andrew Fenton at the University of Sheffield (UK) as a postdoctoral research associate to investigate antimicrobial resistance in the human pathogen Streptococcus pneumoniae.

Ilaria Proietti Silvestri is Head of R&D at Liverpool ChiroChem (LCC). She did doctoral work at Sapienza University of Rome and had postdoctoral research fellowships at the University of Copenhagen and at Politecnico of Milan. In 2015 Ilaria moved to the UK to join RedX Pharma and in 2017 she joined LCC, where she is currently leading the R&D team investigating the design and synthesis of novel 3D-rich N-heterocycles specifically designed for leading applications in drug discovery.

Nitrogen-containing heterocycles are extremely common in pharmaceutical and agrochemical compounds. One class of such heterocycles are 3,4-dihydro-2H-1,4-benzoxazines that are represented in several important bioactive compounds including the antibiotic levofloxacin,[1] and in other compounds with a variety of activities such as androgen receptor modulators,[2] anti-arrhythmic agents,[3] and together with various 1,2,3,4-tetrahydroquinoxaline compounds as cholesteryl ester transfer protein inhibitors (Figure [1]).[4]

The ability to prepare enantiomerically pure substituted 3,4-dihydro-2H-1,4-benzoxazines is therefore of importance and the development of methods to access such chiral derivatives is of interest in medicinal chemistry.[5] The most common approaches involve asymmetric reduction of 2H-1,4-benzoxazines using transition-metal catalysts, organocatalysts, or enzymes,[6] or transition-metal-catalysed cyclisation reactions with concomitant generation of a new stereocentre.[7] An alternative method involves kinetic resolution of the racemic dihydro-2H-1,4-benzoxazine on reaction with a chiral acid chloride,[8] or with an imine and a chiral phosphoric acid.[9]

In a continuation of our work on the kinetic resolution of 2-arylpiperidines,[10] 2-aryltetrahydroquinolines,[11] and 2-arylindolines,[12] we considered the possibility that this chemistry could be exploited for the formation of enantiomerically enriched 3,4-dihydro-2H-1,4-benzoxazines, particularly derivatives with an aryl group at the 3-position (adjacent to the nitrogen atom). Recently, we demonstrated that one enantiomer of N-Boc-2-aryltetrahydroquinolines preferentially undergoes lithiation in the presence of n-BuLi and the chiral ligand (+)-sparteine.[11] [13] This provided high enantioselectivities (selectivity factor, S = 20)[14] to give the recovered starting material with enantiomer ratio (er) up to 98:2, together with the 2,2-disubstituted tetrahydroquinoline products from electrophilic quench (Scheme [1]). Here we describe our work with the related N-Boc-3-aryl-3,4-dihydro-2H-1,4-benzoxazines (X = O, Scheme [1]) that has similarly led to very high enantiomer ratios through a kinetic resolution process. In addition, we have extended the chemistry to 2-aryl-1,2,3,4-tetrahydroquinoxalines (X = N-Boc, Scheme [1]).

The racemic N-Boc-3-aryl-3,4-dihydro-2H-1,4-benzoxazines 1a–h with a variety of substituents were prepared from the corresponding 2-aminophenol by addition of the relevant 2-bromoketone followed by reduction of the imine with sodium borohydride and Boc protection of the nitrogen atom (Scheme [2]).[15]

Treatment of benzoxazine 1a with n-BuLi in THF followed by addition of MeOH, AcOH, or NaHCO₃ resulted in decomposition, presumably as the intermediate organolithium undergoes elimination to an unstable enaminophenol.[16] However, trapping with a chloroformate was successful and we found that addition of ethyl chloroformate gave the ethyl carbonate product 2a that was easier to purify than the corresponding methyl carbonate. Therefore, EtOCOCl­ was used in the subsequent kinetic resolution experiments. We anticipated that lithiation would lead to the ring-opened products 2 but the recovered starting material would be enantioenriched due to the slower reaction of one enantiomer of the racemic benzoxazines 1 with the chiral base n-BuLi/sparteine.

Optimisation of the yield and enantiomer ratio for the recovered benzoxazine 1 led to the following reaction conditions in which, typically, 1.0 equivalent of n-BuLi was added to a mixture of the racemic benzoxazine 1 and 1.0–1.3 equivalents of the chiral ligand (+)-sparteine in toluene at –78 °C. After about 1 hour, ethyl chloroformate was added and the mixture was warmed to room temperature and ethanol was added. The alkene products 2 were readily separable from the recovered benzoxazines 1 by column chromatography. These conditions gave about 40% yield of the benzoxazines 1 with high enantiomer ratios (Scheme [2]). The parent benzoxazine 1a (Ar = Ph) gave either enantiomer with excellent selectivity (er ≈ 99:1, S ≈ 20) on using (+)-sparteine or (–)-sparteine. Electron-withdrawing or electron-donating substituents on the 3-aryl ring were tolerated to give (R)-1b or (R)-1c and the absolute configurations of these two recovered benzoxazines were verified by single crystal X-ray analyses (Figure [2]).[17] The stereochemistry matches that expected for the use of (+)-sparteine in comparison to the use of this enantiomer for other lithiations.[10] [11] [18] The 7-chloro derivative 1d and the 3-(2-naphthyl) derivative 1e were both suitable substrates. The 3-(2-chlorophenyl) derivative 1f gave lower selectivities although good enantioselectivity of recovered 1f was possible at higher conversion. In addition, heteroaryl derivatives 1g and 1h resulted in lower selectivities of the recovered benzoxazines, perhaps due to coordination of the heteroatom in the heteroaryl group with the n-BuLi.

Removal of the N-Boc group was achieved under acidic conditions to give the amines 3a–e (Scheme [3]). In each case there was no loss of enantiopurity (see experimental), as determined by chiral stationary phase HPLC. The absolute configurations of the 3-aryl-3,4-dihydro-2H-1,4-benzoxazines 3a–e matched those reported in the literature.[19]

We then prepared 1,2,3,4-tetrahydroquinoxaline 4a by reduction of 2-phenylquinoxaline with sodium borohydride,[20] followed by double N-Boc protection. Kinetic resolution was carried out by addition of n-BuLi to a mixture of the racemic 2-phenyl-1,2,3,4-tetrahydroquinoxaline 4a and (+)-sparteine in toluene, followed by electrophilic quench with methyl chloroformate (Scheme [4]). The recovered (R)-2-phenyl-1,2,3,4-tetrahydroquinoxaline 4a was isolated with high enantiomer ratio. The absolute configuration of the recovered tetrahydroquinoxaline (R)-4a was verified by single crystal X-ray analysis (Figure [3]).[17] In the same way as the benzoxazines, the side product (5a) was the ring-opened compound. Likewise, kinetic resolution was carried out with the 4-fluoro derivative 4b, which gave the recovered (R)-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline 4b with high enantioselectivity.

The antibiotic levofloxacin contains a 3,4-dihydro-2H-1,4-benzoxazine in which a methyl group is located at position C-3 (see Figure [1]). The (S)-(–)-enantiomer is more active than the racemic compound (ofloxacin).[21] We were intrigued by the possibility that our methodology could provide access to the (S)-enantiomer of analogues of levofloxacin with an aryl group at C-3. The racemic benzoxazine 6 was prepared from the known aminophenol and its kinetic resolution was tested (Scheme [5]).[22] Treatment of (±)-6 with n-BuLi and (–)-sparteine gave the desired recovered (S)-6 (49% yield, er 85:15) that was recrystallised from CH₂Cl₂–hexane to give the recovered (S)-6 in 38% yield and excellent enantiomer ratio (er 98:2). Removal of the Boc group gave amine 8 with only a small loss of enantiopurity. Amine (S)-8 was converted into diester 9 and hence ketone (S)-10. Hydrolysis of the ester and S_NAr reaction gave the analogue (S)-11 of levofloxacin.[23] We were not able to determine the enantiomer ratio of products 9–11 but the desired analogue 11 had a specific rotation, [α]_D ²³ –68 (c 0.2, DMSO).

Levofloxacin together with the phenyl analogues (S)-11 and (±)-11 were tested for their bioactivity using a strain of Streptococcus pneumoniae (D39 Δcps).[24] The compounds (10 mg·mL^–1 in DMSO) were added to a culture of the cells (final concentration 10 µg·mL^–1) and incubated at 37 °C. The number of viable cells remaining after treatment was measured at regular intervals in comparison to a control, in which the respective volume of DMSO solvent was used. In this assay, levofloxacin gave a significant (~10⁵-fold) reduction in cell viability after 5 hours of treatment (Figure [4]), which was consistent with previous findings.[24e] In contrast, analogues (S)-11 and (±)-11 had a similar profile to the solvent only control and did not show reduced cell viability after­ treatment. Very similar results were obtained on incubation­ at a higher concentration of these compounds (100 µg·mL^–1, see the Supporting Information). These experiments suggest the presence of a phenyl group (rather than a methyl group) at C-3 of the benzoxazine was detrimental­ to antibiotic activity, likely the result of a poorer fit in the active site of the target enzyme (possibly DNA gyrase).[25]

In conclusion, kinetic resolution of racemic N-Boc-3-aryl-3,4-dihydro-2H-1,4-benzoxazines and N-Boc-2-aryl-1,2,3,4-tetrahydroquinoxalines can be achieved by addition of the chiral ligand sparteine and the base n-butyllithium, followed by electrophilic quench with a chloroformate. This provides the recovered dihydro-1,4-benzoxazines and tetrahydroquinoxalines with very high levels of enantiopurity in yields approaching the optimum 50% (relative rate of reaction of the enantiomers, S ≈ 20). The side product from these reactions is the achiral N-Boc enamine formed by ring opening of the organolithium intermediate. Removal of the Boc group from the enantioenriched N-Boc-3-aryl-3,4-dihydro-2H-1,4-benzoxazines results in little or no loss of enantiopurity. The chemistry provides access to highly enantioenriched substituted dihydrobenzoxazines and tetrahydroquinoxalines that could be exploited for the synthesis of chiral drug compounds, as illustrated by the preparation of an analogue of levofloxacin.

All reagents were obtained from commercial suppliers and were used without further purification unless otherwise specified. Solvents were purified using a Grubbs dry solvent system. TLC analysis was performed on Merck silica gel 60 F₂₅₄ plates and visualised by UV irradiation at 254 nm or by staining with an alkaline KMnO₄ dip. Flash column chromatography was carried out on VWR silica gel (40–63 μm mesh). Petrol refers to petroleum ether, bp 40–60 °C. IR spectra were recorded on a Perkin-Elmer Spectrum RX FT-IR system. Only selected peaks are reported and absorption maxima are given in cm^–1. Melting points were recorded using a Gallenkamp hot stage apparatus. ¹H NMR spectra were recorded in CDCl₃ or DMSO-d ₆ on a Bruker AC400 (400 MHz) instrument. All chemical shifts are expressed in parts per million (ppm) with respect to the residual solvent peaks. Coupling constants (J) are given in Hz to the nearest 0.5 Hz. The following abbreviations are used singularly or in combination to indicate the multiplicity of signals: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. ¹³C NMR spectra were recorded on the same instrument above at 100 MHz. ¹⁹F NMR were recorded on the same instrument above at 377 MHz. High-resolution (accurate mass) mass spectra were recorded on a Waters LCT instrument using electrospray (ES) ionisation.

(±)-tert-Butyl 3-Phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1a)[15b]

K₂CO₃ (38 g, 275 mmol) in H₂O–CH₂Cl₂ (1:1) was added to 2-aminophenol (5.0 g, 45.8 mmol) and Bu₄NHSO₄ (0.4 g, 1.1 mmol), then 2-bromoacetophenone (9.1 g, 45.8 mmol) was added. After 16 h, the layers were separated, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄) and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave the imine (7.0 g, 72%) as an amorphous solid; mp 106–108 °C (Lit.[19e] 113 °C); ¹H NMR (400 MHz, CDCl₃): δ = 7.98–7.92 (m, 2 H), 7.54–7.45 (m, 4 H), 7.19 (td, J = 7.5, 1.5 Hz, 1 H), 7.07 (td, J = 7.5, 1.5 Hz, 1 H), 6.96 (dd, J = 8.0, 1.5 Hz, 1 H), 5.10 (s, 2 H). Data consistent with the literature.[19e]

NaBH₄ (2.5 g, 65 mmol) was added to this imine (6.8 g, 32.4 mmol) in EtOH–H₂O (4:1) and the mixture was heated at 90 °C. After 3 h, the solvent was removed under reduced pressure. The crude mixture was partitioned between CH₂Cl₂ and H₂O and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄) and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave racemic dihydrobenzoxazine 3a (5.9 g, 85%) as an oil; ¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.36 (m, 5 H), 6.94–6.90 (m, 1 H), 6.88 (td, J = 7.5, 1.5 Hz, 1 H), 6.76 (td, J = 7.5, 1.5 Hz, 1 H), 6.72 (dd, J = 7.5, 1.5 Hz, 1 H), 4.55 (ddd, J = 8.5, 3.0, 1.0 Hz, 1 H), 4.37–4.30 (m, 1 H), 4.08–4.00 (m, 2 H). Data consistent with the literature.[19e]

n-BuLi (1.51 mL, 3.78 mmol, 2.5 M in hexanes) was added to racemic dihydrobenzoxazine 3a (0.73 g, 3.44 mmol) in THF (8 mL) at –78 °C. After 30 min, Boc₂O (0.75 g, 3.44 mmol) in THF (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with 10% NaHCO₃ solution and was extracted with Et₂O. The combined organic layers were dried (MgSO₄) and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave racemic carbamate 1a (0.56 g, 52%) as an amorphous solid; mp 81–83 °C (no lit. mp reported).[15b]

¹H NMR (400 MHz, CDCl₃): δ = 8.16–8.03 (m, 1 H), 7.35–7.22 (m, 5 H), 7.01–6.93 (m, 2 H), 6.92–6.85 (m, 1 H), 5.63 (t, J = 2.5 Hz, 1 H), 4.57 (dd, J = 11.0, 2.5 Hz, 1 H), 4.39 (dd, J = 11.0, 3.0 Hz, 1 H), 1.50 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.7, 146.1, 139.0, 128.5, 127.4, 126.4, 126.2, 123.8, 123.0, 121.2, 117.1, 81.9, 68.5, 55.0, 28.2.

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₉H₂₁NO₃Na: 334.1414; found: 334.1413.

Anal. Calcd for C₁₉H₂₁NO₃: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.29; H, 6.85; N, 4.39.

Resolution between the enantiomers of carbamate 1a was achieved using a Beckman system fitted with a Lux Cellulose-2 column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.5:0.5 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 8.9 and 10.0 min. Alternatively, resolution was achieved using a Lux Cellulose-1, 5 μm column [n-hexane–i-PrOH (95:5 v/v)] at 1 mL·min^–1 with the components eluting at 5.2 and 5.9 min. Alternatively, resolution was achieved using a Daicel Chiralcel OJ column [n-hexane–i-PrOH (99:1 v/v)] at 1 mL·min^–1 with the components eluting at 10.9 and 14.5 min.

(R)-tert-Butyl 3-Phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1a)[15b] and 2-[(tert-Butoxycarbonyl)(1-phenylethenyl)amino]phenyl Ethyl Carbonate (2a)

n-BuLi (0.17 mL, 0.34 mmol, 2 M in hexanes) was added to (+)-sparteine (80 mg, 0.34 mmol) and racemic carbamate 1a (105 mg, 0.34 mmol) in anhydrous PhMe (8 mL) at –78 °C. After 30 min, ethyl chloroformate (0.11 mL, 1.15 mmol) was added, the mixture was allowed to warm to room temperature, ethanol (1 mL) was added and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave carbamate (R)-1a (41 mg, 39%); mp 97–98 °C (no lit. mp reported^[15b)^]; data as above; the enantiomeric ratio (er) was determined to be 98:2 by CSP-HPLC (Cellulose-1 column, major component eluted at 5.2 min); [α]_D ²⁴ –87.4 (c 1.0, CHCl₃) {Lit.[15b] [α]_D ²⁰ –61.1 (c 0.4, CHCl₃)}.

Carbonate 2a (79 mg, 61%) as an oil was also isolated:

IR (neat): 2979, 2933, 1763, 1713, 1624, 1496, 1454, 1368, 1348, 1298, 1239, 1202, 1162, 1140, 1086, 1059, 995, 899, 856, 768, 712, 695 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.60–7.55 (m, 2 H), 7.39–7.31 (m, 4 H), 7.31–7.24 (m, 2 H), 7.24–7.18 (m, 1 H), 5.24 (s, 1 H), 4.90 (s, 1 H), 4.23 (q, J = 7 Hz, 2 H), 1.26 (t, J = 7 Hz, 3 H), 1.20 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 153.2, 153.0, 149.0, 146.3, 135.5, 128.4, 128.3, 128.2, 127.4, 126.6, 126.0, 123.5, 110.1, 81.5, 64.9, 27.8, 14.2.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₂H₂₅NO₅Na: 406.1625; found: 406.1632.

(S)-tert-Butyl 3-Phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1a)

n-BuLi (0.175 mL, 0.35 mmol, 2 M in hexanes) was added to (–)-sparteine (81 mg, 0.35 mmol) and racemic carbamate 1a (104 mg, 0.34 mmol) in anhydrous PhMe (8 mL) at –78 °C. After 30 min, ethyl chloroformate (0.11 mL, 1.15 mmol) was added, the mixture was allowed to warm to room temperature, ethanol (1 mL) was added and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave carbamate (S)-1a (39 mg, 38%); mp 98–99 °C; data as above; the er was determined to be 99:1 by CSP-HPLC (Cellulose-1 column, major component eluted at 5.9 min); [α]_D ²⁴ +91.3 (c 0.9, CHCl₃).

Carbonate 2a (79 mg, 62%) as an oil was also isolated; data as above.

(±)-tert-Butyl 3-(4-Fluorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1b)

In the same way as 1a, K₂CO₃ (30 g, 220 mmol), 2-aminophenol (4.0 g, 36.7 mmol), 4-fluorophenacyl bromide (8.0 g, 36.7 mmol), and Bu₄NHSO₄ (0.3 g, 0.9 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), the imine (6.7 g, 80%) as an amorphous solid; mp 130–131 °C; ¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.92 (m, 2 H), 7.45 (dd, J = 7.5, 1.5 Hz, 1 H), 7.22–7.14 (m, 3 H), 7.06 (td, J = 7.5, 1.5 Hz, 1 H), 6.95 (dd, J = 8.0, 1.5 Hz, 1 H), 5.06 (s, 2 H). Data consistent with the literature.[19e]

This imine (6.6 g, 29.1 mmol) and NaBH₄ (2.2 g, 59 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic dihydrobenzoxazine 3b (6.3 g, 94%) as an amorphous solid; mp 61–63 °C (Lit.[19a] 70–72 °C for er 94:6); ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.38 (m, 2 H), 7.17–7.09 (m, 2 H), 6.94–6.84 (m, 2 H), 6.77 (td, J = 7.5, 1.5 Hz, 1 H), 6.73 (dd, J = 8.0, 1.5 Hz, 1 H), 4.52 (dd, J = 8.5, 1.5 Hz, 1 H), 4.33–4.26 (m, 1 H), 4.06–3.96 (m, 2 H); ¹⁹F NMR (377 MHz, CDCl₃): δ = –113.8. Data consistent with the literature.[19a]

Racemic dihydrobenzoxazine 3b (1.07 g, 4.66 mmol), n-BuLi (2.05 mL, 5.12 mmol, 2.5 M in hexanes), and Boc₂O (1.02 g, 4.66 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic carbamate 1b (1.47 g, 95%) as an amorphous solid; mp 85–87 °C.

IR (neat): 3130, 3045, 2990, 2980, 2880, 1700, 1605, 1585, 1510, 1490, 1330, 1215, 1140, 1000, 830, 755 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.04 (d, J = 7.0 Hz, 1 H), 7.30–7.22 (m, 2 H), 7.02–6.92 (m, 4 H), 6.91–6.86 (m, 1 H), 5.61 (t, J = 2.0 Hz, 1 H), 4.54 (dd, J = 11.5, 2.0 Hz, 1 H), 4.37 (dd, J = 11.5, 2.0 Hz, 1 H), 1.50 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 162.0 (d, J = 245.5 Hz), 152.7, 145.8, 134.6 (d, J = 3.0 Hz), 128.2 (d, J = 8.0 Hz), 125.8, 124.0, 123.0, 121.2, 117.1, 115.4 (d, J = 21.5 Hz), 82.1, 68.3, 54.2, 28.2.

¹⁹F NMR (377 MHz, CDCl₃): δ = –115.1.

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₉H₂₀FNO₃Na: 352.1319; found: 352.1325.

Resolution between the enantiomers of carbamate 1b was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.3:0.7 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 9.1 and 12.4 min.

(R)-tert-Butyl 3-(4-Fluorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1b) and 2-[(tert-Butoxycarbonyl)[1-(4-fluorophenyl)ethenyl]amino]phenyl Ethyl Carbonate (2b)

In the same way as (R)-1a, n-BuLi (0.17 mL, 0.34 mmol, 2 M in hexanes), (+)-sparteine (80 mg, 0.34 mmol), racemic carbamate 1b (113 mg, 0.34 mmol), and ethyl chloroformate (0.10 mL, 1.1 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (R)-1b (45 mg, 40%) as an amorphous solid; mp 106–107 °C; data as above; the er was determined to be 97:3 by CSP-HPLC (major component eluted at 11.6 min); [α]_D ²⁴ –56.5 (c 0.9, CHCl₃).

Carbonate 2b (82 mg, 60%) as an amorphous solid was also isolated; mp 73–75 °C:

IR (neat): 3010, 2995, 2985, 1755, 1720, 1705, 1630, 1600, 1500, 1350, 1245, 1160, 1075, 900, 845, 770, 725 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.62–7.54 (m, 2 H), 7.38–7.21 (m, 4 H), 7.11–7.03 (m, 2 H), 5.22–5.18 (m, 1 H), 4.92–4.88 (m, 1 H), 4.29–4.20 (m, 2 H), 1.31–1.21 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 162.0 (d, J = 245.5 Hz), 153.0, 152.8, 147.8, 146.1, 135.1, 128.2, 128.2 (d, J = 8.0 Hz), 127.4, 126.5, 123.4, 115.4 (d, J = 21.5 Hz), 109.8, 81.5, 64.8, 27.7, 14.1.

¹⁹F NMR (377 MHz, CDCl₃): δ = –114.0.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₂H₂₄FNO₅Na: 424.1531; found: 424.1539.

(±)-tert-Butyl 3-(4-Methoxyphenyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1c)

In the same way as 1a, K₂CO₃ (30 g, 220 mmol), 2-aminophenol (4.0 g, 36.7 mmol), 4-methoxyphenacyl bromide (8.4 g, 36.7 mmol), and Bu₄NHSO₄ (0.3 g, 0.9 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), the imine (6.6 g, 75%) as an amorphous solid; mp 124–125 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.89 (m, 2 H), 7.44 (dd, J = 8.0, 1.5 Hz, 1 H), 7.15 (td, J = 8.0, 1.5 Hz, 1 H), 7.08–6.98 (m, 3 H), 6.94 (dd, J = 8.0, 1.5 Hz, 1 H), 5.06 (s, 2 H), 3.89 (s, 3 H). Data consistent with the literature.[19e]

This imine (6.5 g, 27.3 mmol) and NaBH₄ (2.1 g, 55 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic dihydrobenzoxazine 3c (5.7 g, 86%) as an amorphous solid; mp 91–93 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.32 (m, 2 H), 6.99–6.93 (m, 2 H), 6.89 (dd, J = 7.5, 1.5 Hz, 1 H), 6.84 (td, J = 7.5, 1.5 Hz, 1 H), 6.74 (td, J = 7.5, 1.5 Hz, 1 H), 6.70 (dd, J = 7.5, 1.5 Hz, 1 H), 4.48 (dd, J = 8.5, 2.5 Hz, 1 H), 4.32–4.25 (m, 1 H), 4.04–3.96 (m, 2 H), 3.85 (s, 3 H). Data consistent with the literature.[19e] [26]

Racemic dihydrobenzoxazine 3c (1.0 g, 4.2 mmol), n-BuLi (1.8 mL, 4.6 mmol, 2.5 M in hexanes), and Boc₂O (0.91 g, 4.2 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic carbamate 1c (1.16 g, 81%) as an amorphous solid; mp 95–96 °C.

IR (neat): 3125, 3015, 3000, 2985, 2975, 2840, 1705, 1610, 1585, 1510, 1490, 1330, 1245, 1140, 1030, 830, 770 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 7.5 Hz, 1 H), 7.25–7.19 (m, 2 H), 7.01–6.91 (m, 2 H), 6.91–6.86 (m, 1 H), 6.86–6.80 (m, 2 H), 5.60 (t, J = 2.5 Hz, 1 H), 4.56 (dd, J = 11.0, 2.0 Hz, 1 H), 4.37 (dd, J = 11.0, 3.0 Hz, 1 H), 3.77 (s, 3 H), 1.52 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.8, 152.7, 146.0, 130.9, 127.7, 125.9, 123.9, 123.1, 121.1, 117.0, 113.9, 81.8, 68.5, 55.2, 54.1, 28.3.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₀H₂₃NO₄Na: 364.1519; found: 364.1521.

Resolution between the enantiomers of carbamate 1c was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.3:0.7 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 14.4 and 20.5 min.

(R)-tert-Butyl 3-(4-Methoxyphenyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1c) and 2-[(tert-Butoxycarbonyl)[1-(4-methoxyphenyl)ethenyl]amino]phenyl Ethyl Carbonate (2c)

In the same way as (R)-1a, n-BuLi (0.14 mL, 0.36 mmol, 2.5 M in hexanes), (+)-sparteine (84 mg, 0.36 mmol), racemic carbamate 1c (102 mg, 0.30 mmol), and ethyl chloroformate (0.10 mL, 1.1 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (97:3), carbamate (R)-1c (42 mg, 41%) as an amorphous solid; mp 81–83 °C; data as above; the er was determined to be 98:2 by CSP-HPLC (major component eluted at 20.0 min); [α]_D ²⁴ –90.7 (c 0.2, CHCl₃).

Carbonate 2c (70 mg, 56%) as an amorphous solid was also isolated; mp 90–92 °C:

IR (neat): 3070, 3005, 2980, 2935, 2835, 1765, 1700, 1625, 1605, 1505, 1455, 1350, 1300, 1245, 1165, 1025, 975, 885, 770, 725 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.55–7.50 (m, 2 H), 7.37–7.18 (m, 4 H), 6.94–6.88 (m, 2 H), 5.21 (s, 1 H), 4.88 (s, 1 H), 4.27 (q, J = 7.0 Hz, 2 H), 3.84 (s, 3 H), 1.33–1.25 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 153.1, 153.0, 148.4, 146.2, 135.4, 131.4, 128.0, 127.2 (2 × CH), 126.4, 123.3, 113.6, 108.8, 81.2, 64.7, 55.3, 27.8, 14.1.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₃H₂₇NO₆Na: 436.1731; found: 436.1735.

(±)-tert-Butyl 7-Chloro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1d)

In the same way as 1a, K₂CO₃ (40 g, 290 mmol), 2-amino-5-chlorophenol (7.0 g, 49 mmol), 2-bromoacetophenone (9.7 g, 49 mmol), and Bu₄NHSO₄ (3.8 g, 11 mmol) gave, after extraction with CH₂Cl₂ (2 × 100 mL), drying (MgSO₄), and evaporation, the crude imine as an oil, which was used directly in the next step.

This imine (4.5 g, 18 mmol) and NaBH₄ (1.4 g, 37 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (97:3), racemic dihydrobenzoxazine 3d (3.3 g, 74%) as an amorphous solid; mp 61–63 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.30 (m, 5 H), 6.85 (d, J = 2.5 Hz, 1 H), 6.77 (dd, J = 8.5, 2.5 Hz, 1 H), 6.58 (d, J = 8.5 Hz, 1 H), 4.48 (dd, J = 8.5, 3.0 Hz, 1 H), 4.28 (dd, J = 10.5, 3.0 Hz, 1 H), 4.08–3.81 (m, 2 H). Data consistent with the literature.[19b]

Racemic dihydrobenzoxazine 3d (3.0 g, 8.8 mmol), n-BuLi (3.69 mL, 8.8 mmol, 2.4 M in hexanes), and Boc₂O (2.3 g, 10.6 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic carbamate 1d (2.8 g, 93%) as an amorphous solid; mp 118–120 °C.

IR (neat): 2973, 2970, 2930, 1708, 1577, 1492, 1368, 1257, 1140, 1061, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.5 Hz, 1 H), 7.36–7.20 (m, 5 H), 6.97–6.83 (m, 2 H), 5.62 (br s, 1 H), 4.60 (dd, J = 11.0, 2.5 Hz, 1 H), 4.36 (dd, J = 11.0, 3.0 Hz, 1 H), 1.49 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.5, 146.5, 138.4, 128.6, 128.5, 127.5, 126.3, 124.8, 123.9, 121.2, 117.1, 82.3, 68.4, 54.5, 28.2.

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₉H₂₀ ³⁵ClNO₃Na: 368.1024; found: 368.1022.

Resolution between the enantiomers of carbamate 1d was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.3:0.7 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 8.4 and 9.5 min.

(R)-tert-Butyl 7-Chloro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1d) and 2-[(tert-Butoxycarbonyl)(1-phenylethenyl)amino]-5-chlorophenyl Ethyl Carbonate (2d)

In the same way as (R)-1a, n-BuLi (0.12 mL, 0.29 mmol, 2.5 M in hexanes), (+)-sparteine (88 mg, 0.38 mmol), racemic carbamate 1d (100 mg, 0.29 mmol), and ethyl chloroformate (0.09 mL, 0.9 mmol, added after 90 min) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (R)-1d (40 mg, 40%) as an amorphous solid; mp 110–111 °C; data as above; the er was determined to be 98:2 by CSP-HPLC (major component eluted at 9.9 min); [α]_D ²⁷ –15.3 (c 1.5, CHCl₃).

Carbonate 2d (63 mg, 50%) as an oil was also isolated:

IR (neat): 3083, 3060, 3026, 2980, 2933, 1780, 1700 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.58–7.46 (m, 2 H), 7.33–7.25 (m, 4 H), 7.23–7.18 (m, 1 H), 7.13 (dd, J = 8.5, 2.0 Hz, 1 H), 5.21 (br s, 1 H), 4.83 (br s, 1 H), 4.18 (q, J = 7.0 Hz, 2 H), 1.22 (t, J = 7.0 Hz, 3 H), 1.16 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 153.2, 153.0, 149.1, 146.8, 134.5, 132.5, 129.2, 128.8, 128.2, 127.2, 126.3, 124.3, 110.7, 82.1, 65.5, 28.1, 14.5.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₂H₂₄ ³⁵ClNO₅Na: 440.1235; found: 440.1230.

(±)-tert-Butyl 3-(2-Naphthyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1e)

In the same way as 1a, K₂CO₃ (38 g, 276 mmol), 2-aminophenol (5.0 g, 46 mmol), 2-bromo-2′-acetonaphthone (11.5 g, 46 mmol), and Bu₄NHSO₄ (2.2 g, 6.5 mmol) gave, after extraction with CH₂Cl₂ (2 × 100 mL), drying (MgSO₄), and evaporation, the crude imine as an amorphous solid, which was used directly in the next step; mp 140–142 °C (Lit.[19f] 140–145 °C).

This imine (9.8 g, 38 mmol) and NaBH₄ (2.9 g, 76 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic dihydrobenzoxazine 3e (8.0 g, 81%) as an amorphous solid; mp 82–84 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.92–7.80 (m, 4 H), 7.55–7.46 (m, 3 H), 6.92–6.80 (m, 2 H), 6.77–6.69 (m, 2 H), 4.69 (dd, J = 8.5, 3.0 Hz, 1 H), 4.37 (ddd, J = 10.7, 3.0, 2.0 Hz, 1 H), 4.13–4.05 (m, 2 H). Data consistent with the literature.[19f]

Racemic dihydrobenzoxazine 3e (2.5 g, 9.6 mmol), n-BuLi (3.8 mL, 9.6 mmol, 2.5 M in hexanes), and Boc₂O (2.5 g, 11.5 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic carbamate 1e (1.4 g, 40%) as an amorphous solid; mp 100–102 °C.

IR (neat): 3000, 2979, 2930, 1710, 1586, 1493, 1368, 1252, 1140, 1065, 764 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.16–8.04 (m, 1 H), 7.89–7.67 (m, 4 H), 7.51–7.36 (m, 3 H), 7.02–6.91 (s, 2 H), 6.90–6.83 (m, 1 H), 5.79 (m, 1 H), 4.68 (dd, J = 11.0, 2.5 Hz, 1 H), 4.45 (dd, J = 11.0, 2.5 Hz, 1 H), 1.49 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.9, 146.2, 136.3, 133.3, 132.8, 128.5, 128.1, 127.7, 126.2, 126.2, 126.0, 125.5, 124.7, 124.1, 123.2, 121.3, 117.2, 82.1, 68.4, 55.0, 28.4.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₃H₂₃NO₃Na: 384.1576; found: 384.1575.

Resolution between the enantiomers of carbamate 1e was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.6:0.4 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 19.4 and 21.4 min.

(R)-tert-Butyl 3-(2-Naphthyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1e) and 2-[(tert-Butoxycarbonyl)[1-(2-naphthyl)ethenyl]amino]phenyl Ethyl Carbonate (2e)

In the same way as (R)-1a, n-BuLi (0.13 mL, 0.34 mmol, 2.5 M in hexanes), (+)-sparteine (88 mg, 0.38 mmol), racemic carbamate 1e (100 mg, 0.29 mmol), and ethyl chloroformate (0.09 mL, 0.9 mmol, added after 60 min) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (R)-1e (40 mg, 40%) as an amorphous solid; mp 108–109 °C; data as above; the er was determined to be 99:1 by CSP-HPLC (major component eluted at 18.3 min); [α]_D ²⁷ –45.2 (c 0.6, CHCl₃).

Carbonate 2e (52 mg, 43%) as an oil was also isolated:

IR (neat): 3055, 3005, 2975, 2930, 2870, 1775, 1700, 1490, 1320, 1250, 1155, 1010, 815, 750 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.08–8.06 (m, 1 H), 7.90–7.83 (m, 3 H), 7.74 (dd, J = 8.5, 2 Hz, 1 H), 7.54–7.46 (m, 2 H), 7.44 (dd, J = 8, 1.5 Hz, 1 H), 7.37–7.22 (m, 3 H), 5.45 (br s, 1 H), 5.07 (br s, 1 H), 4.24 (q, J = 7 Hz, 2 H), 1.25 (t, J = 7 Hz, 3 H), 1.19 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.1, 153.0, 148.8, 146.3, 136.2, 135.4, 133.3, 133.2, 128.3, 128.1, 127.9, 127.6, 127.3, 126.5, 126.3, 126.1, 124.8, 124.1, 123.4, 110.7, 81.4, 64.8, 27.7, 14.1.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₆H₂₇NO₅Na: 456.1781; found: 456.1794.

(±)-tert-Butyl 3-(2-Chlorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1f)

In the same way as 1a, K₂CO₃ (21.5 g, 156 mmol), 2-aminophenol (2.8 g, 26 mmol), 2-bromo-2′-chloroacetophenone (6.0 g, 26 mmol), and Bu₄NHSO₄ (1.2 g, 3.5 mmol) gave, after extraction with CH₂Cl₂ (2 × 100 mL), drying (MgSO₄), and evaporation, the crude imine as an oil, which was used directly in the next step.

This imine (4.0 g, 16.5 mmol) and NaBH₄ (1.25 g, 33 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic dihydrobenzoxazine 3f (3.0 g, 75%) as an oil; ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (dd, J = 7.5, 2.0 Hz, 1 H), 7.44 (dd, J = 7.5, 2.0 Hz, 1 H), 7.37–7.23 (m, 2 H), 6.93–6.83 (m, 2 H), 6.80–6.70 (m, 2 H), 5.05 (dt, J = 7.0, 3.0 Hz, 1 H), 4.43 (ddd, J = 11.0, 3.0, 1.5 Hz, 1 H), 4.09–3.95 (m, 2 H). Data consistent with the literature.[19d]

Racemic dihydrobenzoxazine 3f (3.0 g, 12 mmol), n-BuLi (6.1 mL, 15 mmol, 2.4 M in hexanes), and Boc₂O (3.0 g, 13 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (97:3), racemic carbamate 1f (3.6 g, 85%) as needles; mp 110–112 °C.

IR (neat): 3065, 3000, 2985, 2875, 1715, 1585, 1510, 1490, 1335, 1145 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.39 (d, J = 7.5 Hz, 1 H), 7.41 (dd, J = 7.5, 2.0 Hz, 1 H), 7.23 (td, J = 7.5, 2.0 Hz, 1 H), 7.18–7.08 (m, 2 H), 7.07–6.98 (m, 2 H), 6.95–6.91 (m, 1 H), 5.91 (t, J = 3.0 Hz, 1 H), 4.39 (dd, J = 11.0, 3.0 Hz, 1 H), 4.30 (dd, J = 11.0, 3.0 Hz, 1 H), 1.37 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.3, 146.4, 137.6, 131.7, 129.6, 128.7, 127.8, 127.4, 127.1, 123.4, 122.0, 121.4, 117.4, 82.0, 67.2, 55.0, 28.0.

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₉H₂₀ ³⁵ClNO₃Na: 368.1024; found: 368.1027.

Resolution between the enantiomers of carbamate 1f was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99:1 v/v) at a flow rate of 0.5 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 5.3 and 7.3 min.

(R)-tert-Butyl 3-(2-Chlorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1f) and 2-[(tert-Butoxycarbonyl)[1-(2-chlorophenyl)ethenyl]amino]phenyl Ethyl Carbonate (2f)

In the same way as (R)-1a, n-BuLi (0.07 mL, 0.17 mmol, 2.5 M in hexanes), (+)-sparteine (80 mg, 0.34 mmol), racemic carbamate 1f (100 mg, 0.29 mmol), and ethyl chloroformate (0.09 mL, 0.9 mmol, added after 60 min) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (97:3), carbamate (R)-1f (41 mg, 41%) as an amorphous solid; mp 89–91 °C; data as above; the er was determined to be 75:25 by CSP-HPLC (major component eluted at 8.0 min); [α]_D ²³ +35.4 (c 1.9, CHCl₃). Alternatively, using n-BuLi (0.8 eq.) and (+)-sparteine (1.1 eq.) gave the carbamate (R)-1f (21%), er 93:7, data as above.

Carbonate 2f (63 mg, 53%) as an oil was also isolated:

IR (neat): 3070, 3000, 2975, 2935, 1765, 1710, 1090, 800 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.58–7.53 (m, 2 H), 7.41–7.36 (m, 1 H), 7.33–7.20 (m, 5 H), 5.00 (br s, 1 H), 4.93 (br s, 1 H), 4.30 (q, J = 7.0 Hz, 2 H), 1.35 (t, J = 7.0 Hz, 3 H), 1.23 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.0, 152.0, 147.0, 145.2, 137.8, 134.5, 132.1, 130.3, 129.9, 128.9, 128.8, 127.8, 126.6, 126.5, 123.1, 110.8, 81.4, 64.8, 27.7, 14.2.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₂H₂₄ ³⁵ClNO₅Na: 440.1235; found: 440.1233.

(±)-tert-Butyl 3-(2-Furanyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1g)

In the same way as 1a, K₂CO₃ (14 g, 101 mmol), 2-aminophenol (1.83 g, 16.8 mmol), 2-bromo-1-(2-furanyl)ethanone (3.17 g, 16.8 mmol), and Bu₄NHSO₄ (0.8 g, 2.4 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), the imine (2.4 g, 72%) as an amorphous solid; mp 81–83 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.65–7.62 (m, 1 Η), 7.45 (dd, J = 7.5, 1.5 Hz, 1 H), 7.14 (td, J = 7.5, 1.5 Hz, 1 H), 7.05–6.99 (m, 2 Η), 6.91 (dd, J = 7.5, 1.5 Hz, 1 H), 6.58 (dd, J = 3.5, 1.5 Hz, 1 H), 4.91 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 145.9, 128.6, 127.8, 122.8, 115.9, 113.8, 112.4, 77.5, 77.2, 76.8, 62.0. Data consistent with the literature.[19d]

This imine (2.4 g, 12 mmol) and NaBH₄ (1.0 g, 24 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic dihydrobenzoxazine 3g (2.0 g, 82%) as an oil; ¹H NMR (400 MHz, CDCl₃): δ = 7.42–7.37 (m, 1 Η), 6.88–6.79 (m, 2 Η), 6.76–6.63 (m, 2 Η), 6.38–6.37 (m, 2 Η), 4.64 (dt, J = 7.0, 3.0 Hz, 1 H), 4.43 (ddd, J = 11.0, 3.0, 1.5 Hz, 1 H), 4.25 (dd, J = 11.0, 7.0 Hz, 1 H), 4.08 (br s, 1 H). Data consistent with the literature.[19d]

Racemic dihydrobenzoxazine 3g (1.68 g, 8.3 mmol), n-BuLi (3.5 mL, 8.3 mmol, 2.4 M in hexanes), and Boc₂O (1.8 g, 8.3 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic carbamate 1g (1.6 g, 64%) as needles; mp 69–71 °C.

IR (neat): 3149, 3119, 2959, 2918, 2856, 1680, 1584, 1491, 1364, 1255, 1152, 1013, 850 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 7.5 Hz, 1 H), 7.32–7.30 (m, 1 H), 7.00–6.93 (m, 1 H), 6.92–6.82 (m, 2 H), 6.23–6.21 (m, 1 H), 6.09–6.07 (m, 1 H), 5.75 (br s, 1 H), 4.67 (dd, J = 11.0, 1.5 Hz, 1 H), 4.29 (dd, J = 11.0, 3.0 Hz, 1 H), 1.55 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.4, 151.1, 145.3, 142.0, 124.8, 124.4, 123.6, 120.8, 117.0, 110.5, 107.7, 82.3, 66.7, 48.9, 28.4.

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₇H₁₉NO₄Na: 324.1206; found: 324.1208.

Resolution between the enantiomers of carbamate 1g was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.6:0.4 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 10.1 and 13.0 min.

(S)-tert-Butyl 3-(2-Furanyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1g) and 2-[(tert-Butoxycarbonyl)[1-(2-furanyl)ethenyl]amino]phenyl Ethyl Carbonate (2g)

In the same way as (R)-1a, n-BuLi (0.09 mL, 0.23 mmol, 2.5 M in hexanes), (+)-sparteine (80 mg, 0.34 mmol), racemic carbamate 1g (100 mg, 0.33 mmol), and ethyl chloroformate (0.10 mL, 1.0 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (S)-1g (43 mg, 43%) as an amorphous solid; mp 71–73 °C; data as above; the er was determined to be 80:20 by CSP-HPLC (major component eluted at 13.0 min); [α]_D ²¹ –20.5 (c 2.0, CHCl₃).

Carbonate 2g (64 mg, 52%) as an oil was also isolated:

IR (neat): 3640, 2985, 2930, 1765, 1700, 1615, 1525, 1200, 1095, 895, 770 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.39 (m, 1 H), 7.37–7.33 (m, 1 H), 7.30–7.26 (m, 2 H), 7.23–7.18 (m, 1 H), 6.51 (d, J = 3.5 Hz, 1 H), 6.43 (dd, J = 3.5, 1.5 Hz, 1 H), 5.25 (s, 1 H), 5.10 (s, 1 H), 4.30 (q, J = 7 Hz, 2 H), 1.41–1.32 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ (two C could not be observed) = 153.1, 152.9, 146.3, 142.2, 138.8, 127.7, 127.4, 126.4, 123.3, 111.4, 110.0, 107.5, 81.3, 64.8, 27.9, 14.2.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₀H₂₃NO₆Na: 396.1418; found: 396.1430.

(±)-tert-Butyl 3-(2-Pyridinyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1h)

In the same way as 1a, K₂CO₃ (18 g, 130 mmol), 2-aminophenol (1.89 g, 17.3 mmol), 2-(2-bromoacetyl)pyridinium bromide[12] (4.93 g, 17.6 mmol), and Bu₄NHSO₄ (0.1 g, 0.3 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (85:15), the imine as an amorphous solid; mp 85–86 °C; ¹H NMR (400 MHz, CDCl₃): δ = 8.63 (ddd, J = 5.0, 1.5, 1.0 Hz, 1 H), 8.37 (dt, J = 8.0, 1.0 Hz, 1 H), 7.81 (td, J = 8.0, 1.5 Hz, 1 H), 7.43 (dd, J = 7.5, 1.5 Hz, 1 H), 7.37 (ddd, J = 8.0, 5.0, 1.0 Hz, 1 H), 7.18 (td, J = 7.5, 1.5 Hz, 1 H), 7.02 (td, J = 7.5, 1.5 Hz, 1 H), 6.93 (dd, J = 7.5, 1.5 Hz, 1 H), 5.34 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 159.5, 153.7, 149.0, 147.2, 136.7, 133.7, 129.5, 128.1, 125.3, 122.3, 121.4, 116.0, 62.6.

This imine (854 mg, 4.1 mmol) and NaBH₄ (333 mg, 8.8 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (4:1), racemic dihydrobenzoxazine 3h (817 mg, 95%) as an oil; ¹H NMR (400 MHz, CDCl₃): δ = 8.60 (d, J = 4.5 Hz, 1 H), 7.69 (td, J = 7.5, 1.5 Hz, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.26–7.21 (m, 1 H), 6.88–6.81 (m, 2 H), 6.76 (dd, J = 7.5, 1.5 Hz, 1 H), 6.71 (td, J = 7.5, 1.5 Hz, 1 H), 4.67 (dd, J = 7.5, 3.0 Hz, 1 H), 4.51 (br s, 1 H), 4.43 (dd, J = 10.5, 3.0 Hz, 1 H), 4.11 (dd, J = 10.5, 7.5 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 158.6, 149.6, 143.9, 137.1, 133.1, 123.0, 121.8, 121.5, 119.1, 116.9, 116.2, 69.1, 55.5.

Racemic dihydrobenzoxazine 3h (0.49 g, 2.3 mmol), n-BuLi (1.3 mL, 2.6 mmol, 2.0 M in hexanes), and Boc₂O (0.63 g, 2.9 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (4:1), racemic carbamate 1h (719 mg, 99%) as an amorphous solid; mp 104–105 °C.

IR (neat): 2987, 2882, 1701, 1587, 1493, 1434, 1364, 1330, 1272, 1252, 1219, 1146, 1122, 1068, 1047, 1004, 933, 823, 751, 663, 606 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.58 (d, J = 4.5 Hz, 1 H), 8.16 (br, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.15–7.07 (m, 2 H), 6.98–6.89 (m, 2 H), 6.83–6.77 (m, 1 H), 5.68 (br s, 1 H), 4.99 (d, J = 10.5 Hz, 1 H), 4.30 (br d, J = 10.5 Hz, 1 H), 1.47 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.0, 152.8, 149.5, 146.0, 136.8, 125.8, 124.0, 122.8, 122.3, 121.2, 120.7, 117.3, 82.2, 67.4, 57.1, 28.3.

HRMS (ES): m/z [M + H]⁺ calcd for C₁₈H₂₁N₂O₃: 313.1547; found: 313.1552.

Resolution between the enantiomers of carbamate 1h was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (98:2 v/v) at a flow rate of 1 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 11.5 and 17.8 min.

(R)-tert-Butyl 3-(2-Pyridinyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1h) and 2-[(tert-Butoxycarbonyl)[1-(2-pyridinyl)ethenyl]amino]phenyl Ethyl Carbonate (2h)

In the same way as (R)-1a, n-BuLi (0.165 mL, 0.33 mmol, 2 M in hexanes), (+)-sparteine (80 mg, 0.34 mmol), racemic carbamate 1h (103 mg, 0.33 mmol), and ethyl chloroformate (0.10 mL, 1.0 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (85:15), carbamate (R)-1h (33.5 mg, 32%) as an amorphous solid; mp 95–96 °C; data as above; the er was determined to be 72:28 by CSP-HPLC (major component eluted at 17.8 min); [α]_D ²¹ –59.7 (c 1.7, CHCl₃).

Carbonate 2h (85 mg, 67%) as an oil was also isolated:

IR (neat): 3065, 2984, 2933, 1753, 1708, 1632, 1589, 1496, 1469, 1367, 1327, 1247, 1203, 1165, 1086, 1059, 1034, 992, 910, 866, 839, 797, 776, 767, 755, 713, 674 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (ddd, J = 4.5, 1.5, 0.8 Hz, 1 H), 7.70 (td, J = 7.5, 1.5 Hz, 1 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.30–7.25 (m, 2 H), 7.25–7.19 (m, 2 H), 5.71 (s, 1 H), 5.14 (s, 1 H), 4.23 (q, J = 7.0 Hz, 2 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.22 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 153.2, 152.8, 149.2, 148.3, 146.4, 136.4, 135.5, 128.3, 127.5, 126.7, 123.3, 122.8, 120.5, 112.9, 81.4, 64.9, 27.8, 14.2.

HRMS (ES): m/z [M + H]⁺ calcd for C₂₁H₂₅N₂O₅: 385.1758; found: 385.1762.

(R)-3-Phenyl-3,4-dihydro-2H-1,4-benzoxazine (3a)[27]

Trifluoroacetic acid (0.20 mL, 2.6 mmol) was added to benzoxazine (R)-1a (32.5 mg, 0.105 mmol, er 98:2) in CH₂Cl₂ (1 mL) at room temperature. After 18 h, the solvent was evaporated and aqueous NaOH (1 M) was added. The mixture was extracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄) and evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave amine (R)-3a (21 mg, 95%) as an oil; data as above; the er was determined to be 98:2 by CSP-HPLC using a Daicel Chiralpak IA column (250 × 4.6 mm i.d.), 15 μL injection volume, hexane–i-PrOH (98:2), components eluting at 13.3 (major) and 11.1 (minor) min; [α]_D ²⁴ –101.6 (c 0.9, CHCl₃) {Lit.[27] [α]_D ²⁰ –118.1 (c 1.0, CHCl₃) for 98% ee}.

(R)-3-(4-Fluorophenyl)-3,4-dihydro-2H-1,4-benzoxazine (3b)[19f]

In the same way as (R)-3a, trifluoroacetic acid (0.20 mL, 2.6 mmol) and benzoxazine (R)-1b (37.5 mg, 0.11 mmol, er 99:1, obtained after recrystallization from hexane–EtOAc) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), amine (R)-3b (25 mg, 96%) as an amorphous solid; mp 69–70 °C (Lit.[19a] 70–72 °C for er 94:6); data as above; the er was determined to be 99:1 by CSP-HPLC using a Daicel Chiralpak IA column (250 × 4.6 mm i.d.), 10 μL injection volume, hexane–i-PrOH (98:2), components eluting at 18.5 (major) and 15.3 (minor) min; [α]_D ²³ –104.3 (c 0.7, CHCl­₃) {Lit.[19f] [α]_D ²⁵ –117.9 (c 1.0, CHCl₃) for 99% ee}.

(R)-3-(4-Methoxyphenyl)-3,4-dihydro-2H-1,4-benzoxazine (3c)[19e]

In the same way as (R)-3a, trifluoroacetic acid (0.07 mL, 0.9 mmol) and benzoxazine (R)-1c (32 mg, 0.09 mmol, er 98:2) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (9:1), amine (R)-3c (16 mg, 71%) as an amorphous solid; mp 92–94 °C; data as above; the er was determined to be 98:2 by CSP-HPLC using a Daicel Chiralpak IA column (250 × 4.6 mm i.d.), 10 μL injection volume, hexane–i-PrOH (9:1), components eluting at 15.1 (major) and 9.5 (minor) min; [α]_D ²² –121.4 (c 0.7, CHCl₃) {Lit.[19e] [α]_D ²⁰ –126.5 (c 1.0, CHCl₃) for 98% ee}.

(R)-7-Chloro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (3d)[19b]

In the same way as (R)-3a, trifluoroacetic acid (0.01 mL, 0.12 mmol) and benzoxazine (R)-1d (41 mg, 0.12 mmol, er 98:2) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (97:3), amine (R)-3d (29 mg, 99%) as needles; mp 55–56 °C; data as above; the er was determined to be 98:2 by CSP-HPLC using a Daicel Chiralcel OJ column (250 × 4.6 mm i.d.), 20 μL injection volume, hexane–i-PrOH (99:1), components eluting at 78.4 (major) and 93.6 (minor) min; [α]_D ²³ –73.2 (c 0.2, CHCl₃) {Lit.[19b] [α]_D ²⁰ –81.3 (c 1.2, CHCl­₃) for 86% ee}.

(R)-3-(2-Naphthyl)-3,4-dihydro-2H-1,4-benzoxazine (3e)[19b]

In the same way as (R)-3a, trifluoroacetic acid (0.04 mL, 0.47 mmol) and benzoxazine (R)-1e (17 mg, 0.05 mmol, er 99:1) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (97:3), amine (R)-3e (13 mg, 99%) as an amorphous solid; mp 70–71 °C; data as above; the er was determined to be 99:1 by CSP-HPLC using a Daicel Chiralpak IA column (250 × 4.6 mm i.d.), 20 μL injection volume, hexane–i-PrOH (99.3:0.7), components eluting at 13.7 (major) and 17.6 (minor) min; [α]_D ²⁷ –106 (c 1.5, CHCl₃) {Lit.[19b] [α]_D ²⁰ –119.6 (c 1.0, CHCl₃) for 85% ee}.

(±)-1,4-Di-tert-butyl 2-Phenyl-1,2,3,4-tetrahydroquinoxaline-1,4-dicarboxylate (4a)

NaBH₄ (1.8 g, 49 mmol) was added portionwise to 2-phenylquinoxaline (2.51 g, 12.2 mmol) in AcOH (75 mL) at 0 °C. After 15 min, H₂O (80 mL) was added and the aqueous layer was extracted with CH₂Cl₂ (50 mL). Aqueous NaOH (50 mL, 5 M) was added and the aqueous layer was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were dried (MgSO₄) and evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave 2-phenyl-1,2,3,4-tetrahydroquinoxaline (1.59 g, 62%) as an amorphous solid; mp 76–77 °C (Lit.[28] 77–78 °C); ¹Η ΝMR (400 MHz, CDCl₃): δ = 7.44–7.28 (m, 5 Η), 6.68–6.61 (m, 2 H), 6.61–6.54 (m, 2 H), 4.49 (dd, J = 8.0, 3.0 Ηz, 1 H), 3.99–3.77 (m, 2 H), 3.47 (dd, J = 11.0, 3.0 Hz, 1 H), 3.36 (dd, J = 11.0, 8.0 Hz, 1 H). Data consistent with the literature.[28]

n-BuLi (7.86 mL, 18.8 mmol, 2.4 M in hexanes) was added to racemic 2-phenyl-1,2,3,4-tetrahydroquinoxaline (1.8 g, 8.6 mmol) in THF (35 mL) at –78 °C. After 20 min, Boc₂O (4.0 g, 18.8 mmol) in THF (10 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with 10% NaHCO₃ solution (20 mL) and was extracted with Et₂O (3 × 15 mL). The combined organic layers were dried (MgSO₄) and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), gave racemic carbamate 4a (2.99 g, 85%) as needles; mp 166–167 °C.

IR (neat): 3010, 2925, 1715, 1600, 1500, 1250, 1140, 1065, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 8.0 Hz, 1 H), 7.52 (br s, 1 H), 7.33–7.20 (m, 5 H), 7.17–7.12 (m, 1 H), 7.08–7.03 (m, 1 H), 5.40 (t, J = 5.0 Hz, 1 H), 4.04–3.75 (m, 2 H), 1.35 (s, 9 H), 1.26 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 153.1, 152.5, 141.8, 132.1, 128.5, 127.2, 125.7, 124.4, 124.1, 123.0, 122.7, 81.5, 81.0, 61.4, 49.4, 28.1, 27.9.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₄H₃₀N₂O₄Na: 433.2098; found: 433.2103.

Resolution between the enantiomers of carbamate 4a was achieved using a Beckman system fitted with a Lux Cellulose-2 column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.4:0.6 v/v) at a flow rate of 0.8 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 11.9 and 15.5 min.

(R)-1,4-Di-tert-butyl 2-Phenyl-1,2,3,4-tetrahydroquinoxaline-1,4-dicarboxylate (4a) and tert-Butyl N-[2-[(tert-Butoxycarbonyl)(methoxycarbonyl)amino]phenyl]-N-(1-phenylethenyl)carbamate (5a)

In the same way as (R)-1a, n-BuLi (0.086 mL, 0.22 mmol, 2.5 M in hexanes), (+)-sparteine (68 mg, 0.29 mmol), racemic carbamate 4a (100 mg, 0.24 mmol), and methyl chloroformate (0.06 mL, 0.7 mmol, added after 60 min) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (R)-4a (48 mg, 48%) as needles; mp 177–178 °C; data as above; the er was determined to be 94:6 by CSP-HPLC (major component eluted at 11.8 min); [α]_D ²³ –8.2 (c 0.9, CHCl₃).

Carbonate 5a (45 mg, 40%) as an oil was also isolated:

IR (neat): 3060, 2980, 2935, 1790, 1760, 1715, 1495, 1345, 1250, 1120, 1025, 855, 770 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.58–7.47 (m, 2 H), 7.39–7.25 (m, 7 H), 5.16 (s, 1 H), 4.92 (s, 1 H), 3.68 (s, 3 H), 1.42 (s, 9 H), 1.17 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.3, 153.0, 151.2, 148.5, 140.5, 139.4, 134.9, 130.8, 129.1, 128.9, 128.2, 128.0, 127.0, 125.9, 109.9, 83.2, 81.4, 53.5, 27.8, 27.7.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₆H₃₂N₂O₆Na: 491.2153; found: 491.2156.

(±)-1,4-Di-tert-butyl 2-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1,4-dicarboxylate (4b)

In the same way as carbamate 4a, NaBH₄ (1.1 g, 28 mmol), 2-(4-fluorophenyl)quinoxaline (1.6 g, 7.1 mmol), and AcOH (40 mL) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), 2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline (1.1 g, 70%) as an amorphous solid; mp 96–98 °C [Lit.[29] 103–104 °C for the (R)-enantiomer]; ¹Η ΝMR (400 MHz, CDCl₃): δ = 7.42–7.34 (m, 2 H), 7.14–7.04 (m, 2 H), 6.71–6.57 (m, 4 H), 4.50 (dd, J = 8.0, 3.0 Ηz, 1 H), 3.89 (br s, 2 H), 3.46 (dd, J = 11.0, 3.0 Hz, 1 H), 3.32 (dd, J = 11.0, 8.0 Hz, 1 H). Data consistent with the literature.[29]

In the same way as carbamate 4a, n-BuLi (4.21 mL, 9.7 mmol, 2.3 M in hexanes), racemic 2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline (1.0 g, 4.4 mmol), and Boc₂O (2.1 g, 9.9 mmol) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), racemic carbamate 4b (1.1 g, 60%) as needles; mp 180–182 °C.

IR (neat): 2970, 1710, 1690, 1500, 1390, 1015, 765 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.09 (d, J = 8.0 Hz, 1 H), 7.51 (br s, 1 H), 7.23–7.11 (m, 3 H), 7.09–6.96 (m, 3 H), 5.46 (t, J = 5.0 Hz, 1 H), 3.99–3.57 (m, 2 H), 1.38 (s, 9 H), 1.30 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 160.8 (d, J = 259 Hz), 153.0, 152.5, 137.6, 131.8, 127.3 (d, J = 8.3 Hz), 124.5, 124.1, 123.0, 122.8, 115.4 (d, J = 21.4 Hz), 81.7, 81.2, 60.7, 49.3, 28.1, 27.9.

¹⁹F NMR (377 MHz, CDCl₃): δ = –115.4.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₄H₂₉FN₂O₄Na: 451.2004; found: 451.2012.

Resolution between the enantiomers of carbamate 4b was achieved using a Beckman system fitted with a Lux Cellulose-4 column (250 × 4.60 mm i.d.) with n-hexane–i-PrOH (99.2:0.8 v/v) at a flow rate of 0.5 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 18.7 and 23.0 min.

(R)-1,4-Di-tert-butyl 2-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1,4-dicarboxylate (4b) and tert-Butyl N-[2-[(tert-Butoxycarbonyl)(ethoxycarbonyl)amino]phenyl]-N-[1-(4-fluorophenyl)ethenyl]carbamate (5b)

In the same way as (R)-1a, n-BuLi (0.09 mL, 0.21 mmol, 2.3 M in hexanes), (+)-sparteine (70 mg, 0.3 mmol), racemic carbamate 4b (100 mg, 0.23 mmol), and ethyl chloroformate (0.06 mL, 0.48 mmol, added after 60 min) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (R)-4b (48 mg, 48%) as needles; mp 179–181 °C; data as above; the er was determined to be 96:4 by CSP-HPLC (major component eluted at 18.7 min); [α]_D ²¹ –19.2 (c 1.3, CHCl₃).

Carbonate 5b (50 mg, 43%) as an oil was also isolated:

IR (neat): 3073, 2992, 2916, 1793, 1750, 1695, 1540, 1218, 842 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.52–7.45 (m, 2 H), 7.40–7.35 (m, 2 H), 7.35–7.25 (m, 2 H), 7.10–7.01 (m, 2 H), 5.09 (s, 1 H), 4.38 (s, 1 H), 4.28–3.99 (m, 2 H), 1.40 (s, 9 H), 1.19 (s, 9 H), 0.97–0.87 (m 3 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 163.0 (d, J = 259 Hz), 153.1, 152.6, 151.1, 147.2, 140.3, 134.8, 130.9, 129.3, 128.0, 127.5 (d, J = 8.1 Hz), 127.1, 115.0 (d, J = 21 Hz), 109.0, 83.1, 81.4, 62.9, 27.8, 27.7, 14.1.

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₇H₃₃FN₂O₆Na: 523.2215; found: 523.2217.

(±)-tert-Butyl 7,8-Difluoro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (6)

n-BuLi (6.2 mL, 15 mmol, 2.4 M in hexane) was added to benzoxazine (±)-8 (3.32 g, 13.4 mmol) in anhydrous THF (34 mL) at –78 °C. After 40 min, Boc₂O (4.28 g, 19.6 mmol) in anhydrous THF (5 mL) was added and the mixture was allowed to warm to room temperature over 16 h. The mixture was diluted with aqueous 10% NaHCO₃ solution (20 mL) and was extracted with Et₂O (3 × 50 mL), and the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (98:2 to 95:5), gave carbamate 6 (4.2 g, 90%) as an amorphous solid; mp 56–58 °C.

IR (neat): 3007, 2979, 2931, 2880, 1704, 1509, 1492, 1368, 1302, 1260, 1230, 1160, 1090, 749 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.82–7.74 (m, 1 H), 7.33–7.24 (m, 5 H), 6.77–6.68 (m, 1 H), 5.69 (t, J = 3.0 Hz, 1 H), 4.79 (dd, J = 11.0, 3.0 Hz, 1 H), 4.41 (dd, J = 11.0, 3.0 Hz, 1 H), 1.51 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.5, 146.9 (dd, J = 244.0, 10.0 Hz), 140.1 (dd, J = 245.5, 15.5 Hz), 137.7, 136.4 (dd, J = 10.5, 3.0 Hz), 128.7, 127.7, 126.4, 123.2, 117.2 (dd, J = 7.0, 4.0 Hz), 107.8 (d, J = 18.0 Hz), 82.5, 68.6, 53.9, 28.2.

¹⁹F NMR (377 MHz, CDCl₃): δ = –142.9 (d, J = 21.0 Hz, 1 F), –159.6 (d, J = 21.0 Hz, 1 F).

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₉H₁₉F₂NO₃Na: 370.1225; found: 370.1225.

Resolution between the enantiomers of carbamate 6 was achieved using a Beckman system fitted with a Lux Cellulose-1 column (250 × 4.6 mm i.d.) with n-hexane–i-PrOH (99:1 v/v) at a flow rate of 1.0 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 8.3 and 9.2 min.

(S)-tert-Butyl 7,8-Difluoro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (6) and 2-[(tert-Butoxycarbonyl)(1-phenylethenyl)amino]-5,6-difluorophenyl Ethyl Carbonate (7)

In the same way as (R)-1a, n-BuLi (0.24 mL, 0.58 mmol, 2.4 M in hexanes), (–)-sparteine (277 mg, 1.2 mmol), racemic carbamate 6 (335 mg, 0.97 mmol), and ethyl chloroformate (0.20 mL, 2 mmol, added after 30 min) gave, after purification by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), carbamate (S)-6 (164 mg, 49%) as an amorphous solid; mp 50–52 °C; data as above; the er was determined to be 85:15 by CSP-HPLC (major component eluted at 8.5 min) and recrystallisation (CH₂Cl₂–hexane) gave (S)-6 (38%, er 98:2); [α]_D ²³ +90 (c 0.3, CHCl₃).

Carbonate 7 (202 mg, 50%) as an oil was also isolated:

IR (neat): 2981, 1779, 1714, 1508, 1298, 1249, 1215, 1161, 1008, 775, 705 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.56 (d, J = 7.0 Hz, 2 H), 7.42–7.30 (m, 3 H), 7.16–7.03 (m, 2 H), 5.30 (s, 1 H), 4.93 (s, 1 H), 4.40–4.15 (m, 2 H), 1.36–1.17 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.7, 151.2, 149.3 (dd, J = 249.5, 11.0 Hz), 148.5, 144.2 (dd, J = 253.0, 15.0 Hz), 138.3, 136.3 (dd, J = 11.0, 2.5 Hz), 133.0 (d, J = 3.5 Hz), 128.4, 128.3, 125.8, 122.3 (dd, J = 7.5, 3.5 Hz), 114.3 (d, J = 18.0 Hz), 110.4, 81.9, 65.7, 27.6, 13.9.

¹⁹F NMR (377 MHz, CDCl₃): δ = –134.0 (d, J = 21.0 Hz, 1 F), –159.6 (d, J = 21.0 Hz, 1 F).

HRMS (ES): m/z [M + Na]⁺ calcd for C₂₂H₂₃F₂NO₅Na: 442.1437; found: 442.1447.

(±)-7,8-Difluoro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (8)

2-Bromoacetophenone (4.84 g, 24.3 mmol) in CH₂Cl₂ (50 mL) was added to a stirred solution of 6-amino-2,3-difluorophenol (3.49 g, 24.0 mmol), Bu₄NHSO₄ (277 mg, 0.814 mmol), and K₂CO₃ (19.0 g, 138 mmol) in H₂O (140 mL) and CH₂Cl₂ (140 mL). After 16 h, the layers were separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 100 mL). The solvent was evaporated and the crude product was purified by column chromatography on silica gel, eluting with petrol–EtOAc (95:5), to give the imine (4.5 g, 76%) as an amorphous solid; mp 114–116 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.90 (m, 2 H), 7.59–7.47 (m, 3 H), 7.20 (ddd, J = 8.5, 5.5, 2.0 Hz, 1 H), 6.83 (ddd, J = 10.0, 8.5, 7.5 Hz, 1 H), 5.15 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 158.2, 150.4 (dd, J = 248.5, 10.5 Hz), 139.5 (dd, J = 250.5, 16.0 Hz), 134.9, 131.6, 131.1 (dd, J = 4.0, 2.0 Hz), 128.9, 126.4, 122.1 (dd, J = 8.0, 3.5 Hz), 109.1 (d, J = 18.5 Hz), 62.6; ¹⁹F NMR (376 MHz, CDCl₃): δ = –135.7 (d, J = 20.0 Hz, 1 F), –160.5 (d, J = 20.0 Hz, 1 F).

NaBH₄ (1.21 g, 31.9 mmol) was added to the imine (3.59 g, 14.4 mmol) in EtOH (50 mL) and H₂O (13 mL) and the mixture was heated at 90 °C for 3 h. After cooling to room temperature, CH₂Cl₂ (100 mL) and H₂O (100 mL) were added. The aqueous phase was extracted with CH₂Cl₂ (2 × 100 mL) and the solvent was evaporated to give benzoxazine 8 (3.4 g, 93%) as an amorphous solid; mp 54–56 °C.

IR (neat): 3369, 3064, 3029, 2956, 2921, 2851, 1612, 1500, 1324, 1255, 1223, 1055, 752 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.56–7.35 (m, 5 H), 6.63 (dt, J = 9.0, 8.0 Hz, 1 H), 6.37 (ddd, J = 9.0, 5.0, 2.0 Hz, 1 H), 4.50 (dd, J = 9.0, 1.5 Hz, 1 H), 4.44–4.37 (m, 1 H), 4.11–3.94 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ (one C could not be observed) = 144.5 (dd, J = 237.5, 10.5 Hz), 140.7 (dd, J = 244.5, 15.5 Hz), 138.2, 131.5 (dd, J = 6.0, 3.5 Hz), 129.0, 128.7, 127.2, 108.4 (dd, J = 7.5, 4.0 Hz), 108.0 (d, J = 18.5 Hz), 71.2, 53.8.

¹⁹F NMR (377 MHz, CDCl₃): δ = –149.7 (d, J = 21.0 Hz, 1 F), –160.4 (d, J = 21.0 Hz, 1 F).

HRMS (ES): m/z [M + H]⁺ calcd for C₁₄H₁₂F₂NO: 248.0881; found: 248.0887.

Resolution between the enantiomers of amine 8 was achieved using a Beckman system fitted with a Daicel Chiralpak IA column (250 × 4.6 mm i.d.) with n-hexane–i-PrOH (99:1 v/v) at a flow rate of 1.0 mL·min^–1; ambient temperature; detection by UV absorbance at 254 nm. Injection volume was 20 μL of the sample in a 2 g·L^–1 solution of the eluent. The components were eluted at 18.2 and 20.8 min.

(S)-7,8-Difluoro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (8)

Trifluoroacetic acid (0.72 mL, 9.4 mmol) was added to carbamate (S)-6 (164 mg, 0.47 mmol, er 98:2) in CH₂Cl₂ (10 mL) at room temperature. After 24 h, the solvent was evaporated. Purification by column chromatography on silica gel, eluting with petrol–EtOAc (96:4), gave amine (S)-8 (103 mg, 88%) as an amorphous solid; data as above; the er was determined to be 95:5 by CSP-HPLC [components eluted at 18.7 (major) and 21.2 (minor) min]; [α]_D ²³ +110 (c 0.1, CHCl₃).

(S)-1,3-Diethyl 2-[(7,8-Difluoro-3-phenyl-3,4-dihydro-2H-1,4-benoxazin-4-yl)methylidene]propanedioate (9)

Diethyl ethoxymethylenemalonate (268 mg, 1.24 mmol) was added to amine (S)-8 (153 mg, 0.62 mmol, er 95:5) and the mixture was heated at 140 °C. After 26 h, the mixture was cooled to room temperature and the solvent was evaporated. Purification by recrystallisation (hexane­–CH₂Cl₂) gave diester 9 (255 mg, 98%) as an oil (racemic compound was an amorphous solid; mp 108–110 °C); [α]_D ²³ +60 (c 0.2, CHCl₃).

IR (neat): 3037, 2986, 1723, 1594, 1564, 1480, 1304, 1250, 1170, 1084, 798, 699, 534 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.99 (s, 1 H), 7.37–7.25 (m, 3 H), 7.15–7.13 (m, 2 H), 7.01–6.96 (m, 1 H), 6.89–6.82 (m, 1 H), 5.31 (br s, 1 H), 4.71 (dd, J = 11.0, 1.5 Hz, 1 H), 4.39 (dd, J = 11.0, 1.5 Hz, 1 H), 4.33–4.16 (m, 2 H), 3.98 (dq, J = 11.0, 7.0 Hz, 1 H), 3.37 (dq, J = 11.0, 7.0 Hz, 1 H), 1.28 (t, J = 7.0 Hz, 3 H), 0.93 (t, J = 7.0 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 166.6, 166.2, 147.6 (dd, J = 245.0, 10.5 Hz), 142.2, 140.4 (dd, J = 248.5, 15.5 Hz), 136.1 (dd, J = 11.5, 3.0 Hz), 135.7, 128.8, 128.1, 126.2, 126.1, 111.4 (dd, J = 7.5, 4.0 Hz), 109.1 (d, J = 19.0 Hz), 103.1, 69.3, 61.4, 61.0, 57.3, 14.3, 13.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –141.4 (d, J = 20.5 Hz, 1 F), –157.5 (d, J = 20.5 Hz, 1 F).

HRMS (ES): m/z [M + H]⁺ calcd for C₂₂H₂₂F₂NO₅: 418.1461; found: 418.1475.

(S)-Ethyl 6,7-Difluoro-10-oxo-2-phenyl-4-oxa-1-azatricyclo[7.3.1.0^5,13]trideca-5(13),6,8,11-tetraene-11-carboxylate (10)

Polyphosphoric acid (2.39 g, 24.5 mmol) was added to diester (S)-9 (255 mg, 0.61 mmol) and the mixture was heated at 140 °C for 4 h. After cooling to room temperature, H₂O (10 mL) was added and the mixture was filtered to collect the crude product that was washed with H₂O to give ketone (S)-10 (169 mg, 74%) as an amorphous solid; mp 190–192 °C; insufficiently soluble to obtain specific rotation and ¹H or ¹³C NMR spectra.

IR (neat): 1725, 1595, 1565, 1483, 1305, 1252, 1172, 1086, 799, 751, 700 cm^–1.

¹⁹F NMR (377 MHz, CDCl₃): δ = –138.6 (d, J = 22.8 Hz, 1 F), –153.6 (d, J = 22.8 Hz, 1 F).

HRMS (ES): m/z [M + H]⁺ calcd for C₂₀H₁₆F₂NO₄: 372.1042; found: 372.1053.

(S)-7-Fluoro-6-(4-methylpiperazin-1-yl)-10-oxo-2-phenyl-4-oxa-1-azatricyclo[7.3.1.0^5,13]trideca-5(13),6,8,11-tetraene-11-carboxylic Acid (11)

Aqueous HCl (1 mL, 12 M) and glacial AcOH (2 mL) were added to ketone (S)-10 (169 mg, 0.46 mmol) in H₂O (1 mL) and the mixture was heated at 90 °C for 16 h. The mixture was cooled to 0 °C for 1 h and was filtered. The crude product was washed with H₂O to give the difluoro carboxylic acid intermediate (140 mg, 89%) as an amorphous solid; mp 274–276 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 14.7 (s, 1 H), 8.94 (s, 1 H), 8.01–7.79 (m, 1 H), 7.45–7.36 (m, 3 H), 7.23–7.14 (m, 2 H), 6.17 (br s, 1 H), 5.02 (br d, J = 11.5 Hz, 1 H), 4.81 (br d, J = 11.5 Hz, 1 H); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.1, 165.9, 149.4 (dd, J = 249.0, 11.5 Hz), 148.0, 142.2 (dd, J = 253.0, 17.0 Hz), 136.7 (dd, J = 11.5, 3.0 Hz), 136.5, 129.6, 129.3, 127.1, 126.9, 121.7 (dd, J = 8.0, 2.0 Hz), 108.6, 104.5 (d, J = 19.5 Hz), 69.7, 61.7; ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –135.6 (d, J = 22.5 Hz, 1 F), –150.6 (d, J = 22.5 Hz, 1 F); HRMS (ES): m/z [M + H]⁺ calcd for C₁₈H₁₂F₂NO₄: 344.0729; found: 344.0730.

1-Methylpiperazine (0.75 mL, 6.8 mmol) was added to the difluoro carboxylic acid intermediate (140 mg, 0.41 mmol) in Et₃N (0.3 mL) and MeCN (0.3 mL) and the mixture was heated at 90 °C for 24 h. The mixture was cooled to room temperature and was filtered. The crude product was washed with MeOH to give amine (S)-11 (34 mg, 20%) as an amorphous solid; mp 252–254 °C (dec) (Lit.[23] 252–253 °C); [α]_D ²³ –68 (c 0.2, DMSO).

IR (neat): 3064, 3032, 2924, 2852, 2793, 1724, 1619, 1520, 1448, 1374, 1291, 1238, 1089, 1005, 805, 744, 699, 449 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.80 (s, 1 H), 7.66 (d, J = 12.5 Hz, 1 H), 7.44–7.34 (m, 3 H), 7.17–7.10 (m, 2 H), 6.06 (br s, 1 H), 4.88 (br d, J = 11.5 Hz, 1 H), 4.68 (br d, J = 11.5 Hz, 1 H), 3.26–3.21 (m, 4 H), 2.43–2.33 (m, 4 H), 2.20 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.1, 166.3, 155.9 (d, J = 246.5 Hz), 147.2, 140.8, 137.3, 132.7, 129.6, 129.1, 127.0, 126.6, 119.8 (d, J = 10.0 Hz), 107.5, 104.1 (d, J = 24.0 Hz), 68.9, 61.6, 55.6, 50.5, 46.5.

¹⁹F NMR (377 MHz, DMSO-d ₆): δ = –120.0 (s, 1 F).

HRMS (ES): m/z [M + H]⁺ calcd for C₂₃H₂₃FN₃O₄: 424.1667; found: 424.1674.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We acknowledge support from the listed funding agencies. In addition, we thank Paul Colbon and Jiwu Ruan at Liverpool ChiroChem for helpful discussions, Craig Robertson for the single crystal X-ray analyses, and the Faculty of Science Mass Spectrometry Centre at the University of Sheffield.

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Corresponding Author

Publication History

Received: 20 August 2021

Accepted: 06 September 2021

Accepted Manuscript online:
06 September 2021

Article published online:
26 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

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• 15a Ten Brink RE, Merchant KM, McCarthy TJ. WO Patent 03/089438A1, 2003
  PubMed

For spectroscopic data for compound 1a, see:
• 15b Jangili P, Kashanna J, Das B. Tetrahedron Lett. 2013; 54: 3453
  CrossrefSearch in Google Scholar

For related ring opening of lithiated intermediates, see:
• 16a Babudri F, Florio S, Reho A, Trapani G. J. Chem. Soc., Perkin Trans. 1 1984; 1949
  Crossref
• 16b Garrido F, Mann A, Wermuth C.-G. Tetrahedron Lett. 1997; 38: 63
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• Supplementary Material