Synthesis of Substituted Pyrido-oxazine through Tandem S_N2 and S_NAr Reaction

Abstract

Pyrido-oxazine derivatives have been synthesized by employing tandem S_N2 and S_NAr reaction between 2,4,6-tribromo-3-(2-bromoethoxy)pyridine or 2,4,6-tribromo-3-(3-bromopropoxy)pyridine and a variety of primary amines. Moderate to good regioselectivity in favor of cyclization at the 2-position is observed. Pyrido-oxazine products thus generated are converted into biarylated pyrido-oxazine and terpyridine ligands.

Key words

pyridine - terpyridine - pyrido-oxazines - Suzuki coupling - Stille coupling

Pyridine is an important heterocycle that is frequently encountered in natural products, bioactive molecules, and therapeutic drugs and serves also as a common synthetic building block.[1] There is a demand for reactions that allow direct functionalization of pyridine. Phenanthroline, bipyridine, terpyridine (Figure [1]) and their derivatives have been extensively used as organic ligands with a variety of metals to perform important synthetic transformations.[2] Pyrido-oxazines are a class of heterocycles in which one of the carbon atoms in benzoxazine is replaced with nitrogen, and such compounds have shown promising biological activity.[3] Halo-pyridines are important building blocks in organic synthesis because they easily react with various nucleo­philes. This reactive nature can be attributed to the high electronegativity of the halogen atom, which makes carbon–halogen bonds prone to nucleophilic aromatic substitutions (S_NAr). In general, substituted 2- and 4-halopyridines are attractive intermediates in synthetic and medicinal chemistry and they are extensively used for the construction of various pyridine-based heterocycles including N-fused heterocycles.[4] This electrophilic character of halopyridines has also been used in pyrido-oxazines syntheses.[5] Several other synthetic protocols are also available in the literature.[6] However there is a need to develop alternative methods in view of the importance of these scaffolds. In a continuation of our ongoing program of synthesizing brominated marine natural product and their analogues,[7] we wish to report a simple strategy for the synthesis of functionalized pyrido-oxazines by employing a tandem S_N2 and S_NAr reaction.

We have recently reported a synthesis of dihydrobenzoxazines and tetrahydrobenzoxazepines by employing complementary ambiphile pairing (CAP) and complementary pairing (CP) method through an interesting N-dealkylative S_NAr substitution reaction with activated aromatic halides.[8] We thought of extending the same protocol for the synthesis of pyrido-oxazines. Unlike our previous work,[8] the pyridine moiety does not require an EWG activating group and therefore 2,4,6-tribromopyridin-3-ol (1) and 3-chloro-N,N-dimethylpropan-1-amino hydrochloride (1ab) appeared to be a suitable substrate pair for this study.

Figure 1 The important pyridine motif

Accordingly, when 1 was treated with 1ab, we observed the formation of regioisomeric seven-membered N-demethylative products 1a and 1b in 44% overall yield. Similarly, treatment of 1 with 2-chloro-N,N-dimethylethanamino hydrochloride (2ab) gave 2a and 2b in 54% overall yield (Scheme [1]).

Scheme 1 N-Dealkylative cyclization

Alternatively, transformation of 1 into 6a and 6b would furnish bis-electrophilic species, which, upon treatment with primary amines, would provide the corresponding products, without a N-demethylative pathway.[8] Phenol 1, on treatment with 1,2-dibromoethane, gave bis-electrophile 6a in 54% yield, and similar treatment of 1,3-dibromopropane gave 6b in 85% yield (Scheme [2]). When 6a was subjected to aqueous methylamine (2ba) in DMF at ambient temperature, cyclized products 2a and 2b were obtained in 80% overall yield (Scheme [3]). To check the scope of the reaction, 6a was then subjected to a variety of primary amines. This methodology tolerates functional groups including allyl (2c, 2d), cyclopropyl (2g, 2h), and benzyl (2o, 2p) (Scheme [3]). Interestingly the use of a chiral amine afforded the cyclic products 2k, 2l in good yield. 2-(Aminomethyl)aniline 2qr, which has two free NH₂ groups, reacted selectively at the benzyl amino group to give the products 2q and 2r in good yield. Biologically important indole derivatives 2u and 2v were prepared in good yield. This methodology has also been used to prepare seven-membered pyrido-oxazine derivatives 1a–d in good yield.

Scheme 2 Synthesis of bis-electrophilic intermediates 6a and 6b

Scheme 3 Cyclization with primary amines

The structural assignment of the two regioisomeric (2- or 4-cyclized) products was based on the characteristic ¹³C NMR values of methine carbon shifts in the pyridine ring of the two isomers. As depicted in Figure [2], for the 2-cyclized isomer the methine carbon appears in the range δ = 119.6–117.6 ppm and the signal for the 4-cyclized isomer resonates between δ = 110.4–108.1 ppm. An unambiguous confirmation was obtained by single- crystal X-ray analysis of 2p (Figure [2]). A similar difference, δ = 119.8–121.5 ppm for 2-cyclized isomer and δ = 112.4–114.3 ppm for 4-cyclized isomer, allowed assignment of the seven-membered derivatives.

Figure 2 Characteristic ¹³C NMR shifts of the 2- and 4-isomer and single-crystal X-ray structure of compound 2p (CCDC 1584958)

With pyrido-oxazine products in hand, we thought of utilizing bromine atoms at the 2,6- or 4,6-positions for further functionalization through standard procedures. Application of Suzuki–Miyaura reaction furnished biarylated pyrido-oxazine 7a–g in good yield (Scheme [4]). Similarly, Stille coupling between pyrido-oxazine 2b and 2-(tributylstannyl)pyridine 8 in the presence of Pd(PPh₃)₄ gave terpyridine ligand 8a in good yield (Scheme [5]). This reaction was then extended to 1a, 2l, 2k, 2c, 2g to obtain terpyridine ligands 8b–f in good yield.

Scheme 4 Synthesis of biarylated pyrido-oxazine

Scheme 5 Synthesis of terpyridine ligand

In conclusion, we have developed a method for the synthesis of pyrido-oxazine through tandem S_N2 and S_NAr reaction in good yield. We were also able to functionalize pyrido-oxazine to form biarylated pyrido-oxazine and terpyridines using Suzuki and Stille coupling reactions in moderate to good yield.

All starting material and reagents were purchased from standard commercial sources or were prepared in the laboratory. All the glassware were cleaned with soap water followed by acetone and dried in a hot air oven at 100 °C for 2 h. Solvents were distilled prior to use. IR spectra were recorded with a Bruker Tensor 37 (FTIR) spectrophotometer.¹H NMR spectra were recorded with a Bruker Avance 400 (400 MHz) spectrometer at 295 K in CDCl₃; chemical shifts (δ, ppm) and coupling constants (Hz) are reported with reference to either tetramethylsilane (TMS) (δ = 0.00 ppm ppm) or CHCl₃ (δ = 7.26 ppm). ¹³C NMR spectra were recorded with a Bruker Avance 400 (100 MHz) spectrometer at 298 K in CDCl₃; chemical shifts (δ, ppm) are reported relative to CHCl₃ (δ = 77.00 ppm; central line of triplet). For ¹³C NMR analysis, the nature of the carbon atoms (C, CH, CH₂, and CH₃) was determined by recording DEPT-135 spectra. In ¹H NMR data, the following abbreviations are used throughout: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, and br. s = broad singlet. The assignment of the signals was confirmed by ¹H, ¹³C and DEPT spectra. High-resolution mass spectra (HRMS) were recorded with an Agilent 6538 UHD Q-TOF using multimode source in +ESI method at the Department of Chemistry, Indian Institute of Technology Hyderabad, India. Reactions were monitored by TLC on silica gel (254 mesh) using a combination of hexane and EtOAc as eluents.

2,4,6-Tribromopyridin-3-ol (1)

To a solution of 3-hydroxypyridine (5 g, 52.5 mmol) in H₂O (60 mL) was added bromine (10.84 mL, 210 mmol) at 0 °C and the reaction mixture was stirred at r.t. for 12 h. The formed solid was filtered through suction filter. Solid product 1 was collected and used without further purification.

Yield: 12 g (69%); yellow solid; mp 74–76 °C; R_f = 0.5 (60%, EtOAc/hexane).

IR (neat): 3743, 3677, 3617, 1698, 1540, 1516, 1459 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.60 (s, 1 H), 6.02 (s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.4, 131.1, 129.7, 128.6, 120.8.

HRMS (ESI+): m/z [M]⁺ calcd for C₅H₂Br₃NO: 330.7666; found: 330.775.

Typical Procedure and Spectral Data for 1a, 1b, 2a, 2b Obtained through N-Dealkylative Cyclization

To a stirred suspension of K₂CO₃ (167 mg, 1.208 mmol) in DMF (1 mL) was added 2,4,6-tribromopyridin-3-ol (1; 100 mg, 0.302 mmol) and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (1ab; 86 mg, 0.604 mmol) and, after stirring for 10 h at 120 °C, water (3 mL) was added. The mixture was extracted with EtOAc (8 × 3 mL) and the organic layer was washed with water (3 mL) and brine (3 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified over silica gel chromatography (20%, EtOAc­/hexane) to give 1a (38 mg, 39%) and 1b (5 mg, 5%) as colorless solids.

7,9-Dibromo-5-methyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (1a)

Yield: 38 mg (39%); white solid; mp 92–94 °C; R_f = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2922, 1562, 1522, 1416, 1363, 1192, 1042, 962, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.91 (s, 1 H), 4.24 (t, J = 6.4 Hz, 2 H), 3.56–3.48 (m, 2 H), 3.06 (s, 3 H), 2.19–2.04 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.3, 140.5, 131.4, 125.1, 119.8, 70.3, 50.0, 39.5, 28.0.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₉H₁₁Br₂N₂O: 322.9218; found: 322.9201.

6,8-Dibromo-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepine (1b)

Yield: 5 mg (5%); white solid; mp 98–100 °C; R_f = 0.5 (10%, EtOAc/hexane).

¹H NMR (400 MHz, CDCl₃): δ = 6.57 (s, 1 H), 4.31–4.22 (m, 2 H), 3.62–3.53 (m, 2 H), 2.99–2.90 (m, 3 H), 2.21–2.09 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 151.7, 141.2, 134.0, 133.9, 112.5, 70.2, 51.9, 40.8, 28.0.

IR (neat): 2925, 1564, 1511, 1426, 1382, 1264, 1196, 1040 cm^–1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₉H₁₁Br₂N₂O: 322.9218; found: 322.9202.

6,8-Dibromo-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2a)

Yield: 38 mg (41%); white solid; mp 82–84 °C; R_f = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2939, 2892, 1580, 1531, 1510, 1451, 1415, 1357, 1302, 1211, 1051, 922, 778, 695 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.84 (s, 1 H), 4.3 (t, J = 4.4 Hz, 2 H), 3.48 (t, J = 4.4 Hz, 2 H), 3.11 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.8, 136.4, 129.7, 118.6, 117.9, 64.4, 47.7, 36.2.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₈H₉Br₂N₂O: 308.9061; found: 308.9053.

5,7-Dibromo-1-methyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2b)

Yield: 12 mg (36%); white solid; mp 138–140 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2945, 2882, 1581, 1509, 1461, 1426, 1352, 1290, 1249, 1217, 1119, 1052, 926, 822, 790 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.56 (s, 1 H), 4.31 (t, J = 4.4 Hz, 2 H), 3.43 (t, J =4.4 Hz, 2 H), 2.97 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 136.8, 131.6, 126.9, 108.5, 64.1, 48.0, 37.9.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₇H₁₆Br₂N₃O: 308.9061; found: 308.9053.

2,4,6-Tribromo-3-(2-bromoethoxy)pyridine (6a)

To a stirred suspension of K₂CO₃ (4.99 g, 36.15 mmol) in DMF (35 mL) was added 2,4,6-tribromopyridin-3-ol (1; 4 g, 12.05 mmol) and the mixture was stirred at 0 °C for 0.5 h. 1,2-Dibromoethane (11.32 g, 60.25 mmol) was added and, after stirring for 12 h at 80 °C, water (100 mL) was added. The mixture was extracted with EtOAc (80 × 2 mL) and the organic layer was washed with water (12 × 3 mL) and brine (20 × 2 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified over silica gel chromatography (10%, EtOAc/hexane) to give 2,4,6-tribromo-3-(2-bromoethoxy)pyridine 6a.

Yield: 2.45 g, 46%); colorless solid; mp 60–62 °C; R_f = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2924, 1516, 1412, 1310, 985, 742 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.66 (s, 1 H), 4.35 (t, J = 6.5 Hz, 2 H), 3.72 (t, J = 6.5 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.2, 136.7, 134.8, 131.5, 129.7, 72.9, 28.6.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₇H₆Br₄NO: 439.7142; found: 439.7134.

2,4,6-Tribromo-3-(3-bromopropoxy)pyridine (6b)

To a stirred suspension of K₂CO₃ (2.5 g, 18.12 mmol) in DMF (20 mL) was added 2,4,6-tribromopyridin-3-ol (1; 2 g, 6.02 mmol) and the mixture was stirred at 0 °C for 0.5 h. 1,3-Dibromopropane (6.08 g, 30.1 mmol) was added and after stirring for 4 h at 80 °C, water (40 mL) was added. The mixture was extracted with EtOAc (30 × 2 mL) and the organic layer was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified over silica gel chromatography (20%, EtOAc/hexane) to give 2,4,6-tribromo-3-(3-bromopropoxy)pyridine 6b.

Yield: 1.67 g (61%); colorless solid; mp 40–42 °C; R_f = 0.7 (20%, EtOAc­/hexane).

IR (neat): 2950, 1517, 1416, 1311, 996, 742 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.65 (s, 1 H), 4.18 (t, J = 5.6 Hz, 2 H), 3.70 (t, J = 6.4 Hz, 2 H), 2.41 (quin, J = 6.4, 5.7 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.5, 136.9, 134.4, 131.5, 129.8, 71.4, 33.17, 29.5.

HRMS (ESI+): m/z [M]⁺ calcd for C₈H₇Br₄NO: 452.7220; found: 452.7368.

Typical Procedure and Spectral Data for 2c–x

To a solution of 2,4,6-tribromo-3-(2-bromoethoxy)pyridine (6a; 100 mg, 0.228 mmol) in DMF (1 mL) was added benzyl amine (73 mg, 0.684 mmol) and the reaction mixture was stirred at r.t. for 36 h. Water (3 mL) was then added and the mixture was extracted with EtOAc (12 × 3 mL). The combined organic phases were washed with water (3 mL), brine (3 mL), dried over Na₂SO₄ and concentrated in vacuo The resulting crude residue was purified over silica gel column chromatography (10–20%, EtOAc/hexane) to afford product 2o (52 mg, 59%) and 2p (26 mg, 30%).

4-Allyl-6,8-dibromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2c)

Yield: 45 mg (59%); white solid; mp 54–56 °C; R_f = 0.6 (10%, EtOAc­/hexane).

IR (neat); 3093, 2939, 1578, 1534, 1502, 1449, 1418, 1357, 1305, 1255, 1213, 1094, 1040, 992, 925, 806, 673 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.85 (s, 1 H), 5.89–5.72 (m, 1 H), 5.27–5.16 (m, 2 H), 4.27 (t, J = 4.4 Hz, 2 H), 4.21 (d, J = 5.9 Hz, 2 H), 3.44 (t, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.8, 135.1, 131.7, 128.5, 117.6, 117.2, 117.1, 63.4, 49.1, 43.5.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₁Br₂N₂O: 334.9218; found: 334.9212.

1-Allyl-5,7-dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2d)

Yield: 26 mg (34%); white solid; mp 78–80 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 3086, 2874, 1576, 1528, 1503, 1454, 1402, 1352, 1287, 1246, 1211, 1167, 1070, 1035, 925, 822, 796, 700, 662 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.58 (s, 1 H), 5.78 (tdd, J = 5.0, 10.4, 17.2 Hz, 1 H), 5.33–5.11 (m, 2 H), 4.3 (t, J = 4.4 Hz, 2 H), 3.91 (td, J = 1.7, 5.0 Hz, 2 H), 3.46 (t, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.1, 136.7, 131.7, 130.2, 127.5, 118.1, 108.7, 64.0, 52.8, 46.3.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₁Br₂N₂O: 334.9218; found: 334.9212.

6,8-Dibromo-4-ethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2e)

Yield: 42 mg (57%); white solid; mp 82–84 °C; R_f = 0.6 (10%, EtOAc/hexane).

IR (neat): 2932, 1578, 15051443, 1358, 1209, 1058, 930, 767 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.82 (s, 1 H), 4.31–4.23 (m, 2 H), 3.64 (q, J = 7.2 Hz, 2 H), 3.53–3.44 (m, 2 H), 1.17 (t, J = 7.1 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.9, 136.1, 129.7, 118.0, 117.9, 64.3, 44.7, 42.7, 11.7.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₉H₁₁Br₂N₂O: 322.9218; found: 322.9209.

5,7-Dibromo-1-ethyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2f)

Yield: 22 mg (30%); white solid; mp 78–80 °C; R_f = 0.2 (10%, EtOAc/hexane).

IR (neat): 2932, 1578, 1505, 1423, 1358, 1209, 1058, 930, 767 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.59 (s, 1 H), 4.32–4.24 (m, 2 H), 3.46–3.42 (m, 2 H), 3.36 (q, J = 7.3 Hz, 2 H), 1.27–1.12 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.8, 136.8, 131.7, 127.4, 108.1, 63.9, 45.5, 45.0, 10.9.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₉H₁₁Br₂N₂O: 322.9218; found: 322.9209.

6,8-Dibromo-4-cyclopropyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2g)

Yield: 30 mg (39%); white solid; mp 91–93 °C; R_f = 0.5 (10%, EtOAc­/hexane).

IR (neat): 2979, 1575, 1485, 1443, 1354, 1219, 1118, 1023 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.93 (s, 1 H), 4.31–4.23 (m, 2 H), 3.51–3.43 (m, 2 H), 2.68 (tt, J = 3.5, 7.0 Hz, 1 H), 0.93–0.82 (m, 2 H), 0.68–0.58 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.0, 136.6, 129.5, 119.6, 117.9, 65.3, 45.7, 30.5, 7.6.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₁Br₂N₂O: 334.9218; found: 334.9214.

5,7-Dibromo-1-cyclopropyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2h)

Yield: 33 mg (43%); white solid; mp 142–144 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2958, 1574, 1487, 1451, 1348, 1251, 1116, 1026, 823 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.05 (s, 1 H), 4.28 (br. s., 2 H), 3.42 (br. s., 2 H), 2.48 (br. s., 1 H), 0.99–0.88 (m, 2 H), 0.69 (br. s., 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.4, 137.2, 131.1, 127.1, 110.4, 64.9, 45.7, 31.1, 8.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₁Br₂N₂O: 334.9218; found: 334.9211.

6,8-Dibromo-4-propyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2i)

Yield: 41 mg (54%); gummy solid; R_f = 0.5 (10%, EtOAc/hexane).

IR (neat): 2927, 1578, 1504, 1423, 1357, 1300, 1211, 1061, 938, 746.

¹H NMR (400 MHz, CDCl₃): δ = 6.81 (s, 1 H), 4.29–4.22 (m, 2 H), 3.59–3.43 (m, 4 H), 1.70–1.55 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.1, 135.8, 131.5, 129.6, 117.9, 64.3, 49.6, 45.5, 20.1, 11.4.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₃Br₂N₂O: 336.9374; found: 336.9365.

5,7-Dibromo-1-propyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2j)

Yield: 24 mg (31%); white solid; mp 67–69 °C; R_f = 0.2 (10%, EtOAc/hexane).

IR (neat): 2933, 1505, 1403, 1065, 939, 797 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.57 (s, 1 H), 4.32–4.23 (m, 2 H), 3.49–3.42 (m, 2 H), 3.28–3.19 (m, 2 H), 1.65 (sext, J = 7.4 Hz, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, 400 MHz, CDCl₃): δ = 143.1, 136.6, 131.7, 127.4, 108.1, 63.8, 52.3, 46.5, 19.5, 11.4.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₃Br₂N₂O: 336.9374; found: 336.9383.

(S)-6,8-Dibromo-4-(1-phenylethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2k)

Yield: 47 mg (52%); gummy solid; R_f = 0.2 (10%, EtOAc/hexane).

IR (neat): 2938, 1574, 1488, 1415, 1353, 1211, 1064, 775, 699 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.23 (m, 5 H), 6.87 (s, 1 H), 6.20 (q, J = 7.0 Hz, 1 H), 4.25–4.16 (m, 1 H), 4.03 (ddd, J = 2.9, 7.5, 10.6 Hz, 1 H), 3.32 (ddd, J = 3.2, 7.5, 12.8 Hz, 1 H), 3.04 (ddd, J = 2.7, 4.5, 12.8 Hz, 1 H), 1.61–1.50 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.7, 140.2, 136.0, 131.5, 129.5, 128.5, 127.5, 127.4, 118.3, 72.9, 64.6, 51.0, 39.3, 28.6, 15.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₅Br₂N₂O: 398.9531; found: 398.9521.

(S)-5,7-Dibromo-1-(1-phenylethyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2l)

Yield: 24 mg (26%); white solid; mp 106–108 °C; R_f = 0.3 (10%, EtOAc/hexane).

IR (neat): 2938, 1574, 1488, 1415, 1353, 1211, 1064, 775, 699 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.21 (m, 5 H), 6.80 (s, 1 H), 5.08 (q, J = 6.8 Hz, 1 H), 4.31–4.21 (m, 1 H), 4.09 (ddd, J = 2.9, 7.7, 10.9 Hz, 1 H), 3.30 (ddd, J = 3.2, 7.5, 12.8 Hz, 1 H), 3.17–3.04 (m, 1 H), 1.68–1.52 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.2, 139.0, 136.8, 131.8, 129.0, 128.1, 127.9, 126.8, 108.5, 64.2, 55.0, 40.1, 15.8.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₅Br₂N₂O: 398.9531; found: 398.952.

4-Benzyl-6,8-dibromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2o)

Yield: 52 mg (59%); gummy solid; R_f = 0.3 (10%, EtOAc/hexane).

IR (neat): 2836, 2899, 1576, 1533, 1500, 1445, 1417, 1356, 1298, 1210, 1048, 915, 737, 697 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.25 (m, 5 H), 6.88 (s, 1 H), 4.80 (s, 2 H), 4.21 (t, J = 4.4 Hz, 2 H), 3.37 (t, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.0, 136.9, 136.0, 129.5, 128.7, 128.2, 127.6, 118.8, 118.5, 64.4, 50.9, 44.5.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₃Br₂N₂O: 384.9374; found: 384.9364.

1-Benzyl-5,7-dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2p)

Yield: 26 mg (30%); white solid; mp 142–144 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2931, 2874, 1574, 1528, 1501, 1453, 1352, 1246, 1072, 922, 799, 733, 697 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.29 (m, 3 H), 7.24–7.14 (m, 2 H), 6.65 (s, 1 H), 4.51 (s, 2 H), 4.31 (t, J = 4.4 Hz, 2 H), 3.48 (t, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.4, 136.7, 135.0, 131.8, 129.2, 128.1, 127.7, 126.8, 108.7, 64.1, 53.9, 46.5.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₃Br₂N₂O: 384.9374; found: 384.9365.

2-((6,8-Dibromo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl)aniline (2q)

Yield: 48 mg (53%); white solid; mp 81–83 °C; R_f = 0.7 (10%, EtOAc­/hexane).

¹H NMR (400 MHz, CDCl₃): δ = 7.18–7.04 (m, 2 H), 6.87 (s, 1 H), 6.74–6.63 (m, 2 H), 4.68 (s, 2 H), 4.55 (br. s., 2 H), 4.21 (t, J = 4.4 Hz, 2 H), 3.45 (t, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.9, 146.2, 136.2, 131.5, 129.4, 129.2, 119.8, 118.7, 118.6, 117.4, 115.9, 64.3, 49.0, 44.5.

IR (neat): 3450, 3339, 3220, 3010, 2895, 1631, 1575, 1502, 1443, 1354, 1298, 1251, 1206, 1162, 1111, 1041, 908, 747 cm^–1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₄Br₂N₃O: 399.9483; found: 399.9473.

2-((5,7-Dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)methyl)aniline (2r)

Yield: 23 mg (25%); white solid; mp 164–166 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 3743, 2929, 1572, 1504, 1456, 1401, 1354, 1247 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.19 (dt, J = 1.2, 7.7 Hz, 1 H), 7.01 (d, J = 7.3 Hz, 1 H), 6.82–6.72 (m, 3 H), 4.34 (s, 2 H), 4.3 (t, J = 4.4 Hz, 2 H), 3.71 (br. s., 2 H), 3.29 (t, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 143.6, 137.2, 131.7, 129.5, 129.1, 127.7, 119.0, 118.3, 116.4, 109.0, 64.5, 50.9, 44.5.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₄Br₂N₃O: 399.9483; found: 399.9476.

tert-Butyl 3-(6,8-Dibromo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)propylcarbamate (2s)

Yield: 40 mg (39%); gummy solid; R_f = 0.3 (25%, EtOAc/hexane).

IR (neat): 3743, 3616, 3346, 2929, 1698, 1577, 1518, 1360, 1167, 1067 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.83 (s, 1 H), 5.56 (br. s., 1 H), 4.25 (t, J = 4.4 Hz, 2 H), 3.64 (t, J = 6.4 Hz, 2 H), 3.48 (t, J = 4.4 Hz, 2 H), 3.10 (q, J = 6.4 Hz, 2 H), 1.74 (quin, J = 6.1 Hz, 2 H), 1.48–1.40 (m, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.2, 147.3, 135.9, 129.5, 118.4, 78.9, 64.2, 45.5, 45.0, 36.0, 28.5, 27.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₅H₂₁Br₂N₃NaO₃: 473.9827; found: 473.9779.

tert-Butyl 3-(5,7-Dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-1-yl)propylcarbamate (2t)

Yield: 27 mg (26%); white solid; mp 121–123 °C; R_f = 0.2 (25%, EtOAc­/hexane).

IR (neat): 3343, 2773, 2933, 1694, 1577, 1520, 1459, 1401, 1359, 1281, 1248, 1167, 1065, 930, 796 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.55 (s, 1 H), 4.70 (br. s, 1 H), 4.27 (t, J = 4.4 Hz, 2 H), 3.45 (t, J = 4.4 Hz, 2 H), 3.33 (t, J = 7.3 Hz, 2 H), 3.22–3.15 (m, 2 H), 1.80 (quin, J = 7.0 Hz, 2 H), 1.48–1.37 (m, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.1, 142.9, 136.8, 131.6, 127.5, 108.1, 79.7, 63.9, 48.1, 46.5, 38.0, 28.4 (3×CH₃), 27.0.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₂₂Br₂N₃O₃: 452.0007; found: 451.9996.

4-(2-(1H-Indol-3-yl)ethyl)-6,8-dibromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2u)

Yield: 57 mg (57%); white solid; mp 62–64 °C; R_f = 0.3 (25%, EtOAc­/hexane).

IR (neat): 3413, 2932, 1577, 1532, 1504, 1450, 1421, 1357, 1258, 1210, 1088, 1041, 927, 742 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (br. s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 7.8 Hz, 1 H), 7.16–7.03 (m, 2 H), 6.88 (d, J = 2.0 Hz, 1 H), 6.77 (s, 1 H), 4.02–3.93 (m, 2 H), 3.75 (t, J = 7.3 Hz, 2 H), 3.27–3.19 (m, 2 H), 2.97 (t, J = 7.8 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.8, 136.3, 136.0, 129.9, 127.5, 122.2, 122.0, 119.5, 119.2, 118.1, 117.9, 113.3, 111.2, 64.3, 49.3, 46.3, 22.9.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₇H₁₆Br₂N₃O: 437.9640; found: 437.9628.

1-(3-(1H-Indol-3-yl)propyl)-5,7-dibromo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2v)

Yield: 30 mg (30%); gummy solid; R_f = 0.1 (25%, EtOAc/hexane).

IR (neat): 3400, 1658, 1578, 1523, 1355, 1247, 1021, 999, 822, 759, 620 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.85 (br. s, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.08 (dt, J = 1.2, 7.5 Hz, 1 H), 7.02–6.94 (m, 1 H), 6.74 (s, 1 H), 4.11 (t, J = 4.4 Hz, 2 H), 3.64 (t, J = 7.1 Hz, 2 H), 3.37–3.32 (m, 2 H), 2.96 (t, J = 7.1 Hz, 2 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 143.3, 136.2, 136.1, 130.8, 127.0, 126.1, 123.3, 121.0, 118.4, 118.0, 111.5, 110.8, 107.8, 63.5, 50.4, 45.8, 21.4.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₇H₁₆Br₂N₃O: 437.9640; found: 437.9631.

6,8-Dibromo-4-butyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2w)

Yield: 47 mg (59%); gummy solid; R_f = 0.4 (10%, EtOAc/hexane).

IR (neat): 2925, 1694, 1513, 1460, 1211 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.81 (s, 1 H), 4.26 (t, J = 4.4 Hz, 2 H), 3.58 (t, J = 7.1 Hz, 2 H), 3.49 (t, J = 4.4 Hz, 2 H), 1.58 (quin, J = 7.1, 15 Hz, 2 H), 1.35 (qd, J = 7.2, 15.0 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.1, 135.9, 131.5, 129.7, 117.9, 64.3, 47.6, 45.4, 29.0, 20.1, 13.9.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₁H₁₅Br₂N₂O: 350.9531; found: 350.9516.

5,7-Dibromo-1-butyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2x)

Yield: 24 mg (30%); white solid; mp 47–49 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 2956, 2868, 1577, 1505, 1459, 1403, 1354, 1246, 1210, 1066, 920, 818, 698 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.56 (s, 1 H), 4.26 (t, J = 4.4 Hz, 2 H), 3.44 (t, J = 4.4 Hz, 2 H), 3.27 (t, J = 7.8 Hz, 2 H), 1.59 (quin, J = 7.3 Hz, 2 H), 1.45–1.29 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.1, 136.6, 131.7, 127.4, 108.1, 63.8, 50.5, 46.5, 28.2, 20.2, 13.9.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₁H₁₅Br₂N₂O: 350.9531; found: 350.952.

7,9-Dibromo-5-cyclopropyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (1c)

Yield: 25 mg (33%); white solid; mp 60–62 °C; R_f = 0.6 (10%, EtOAc­/hexane).

IR (neat): 1559, 1526, 1467, 1434, 1370, 1349, 1308, 1278, 1203, 1094, 1061, 1023, 949, 878, 820, 777, 689 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.05 (s, 1 H), 4.16 (t, J = 6.1 Hz, 2 H), 3.61–3.52 (m, 2 H), 2.80 (tt, J = 3.5, 7.0 Hz, 1 H), 2.01 (quin, J = 6.0 Hz, 2 H), 0.87–0.76 (m, 2 H), 0.57–0.48 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.1, 141.3, 131.2, 125.1, 121.5, 70.3, 50.2, 33.8, 29.5, 8.3.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₁H₁₃Br₂N₂O: 348.9374; found: 348.9365.

6,8-Dibromo-1-cyclopropyl-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepine (1d)

Yield: 23 mg (36%); white solid; mp 106–108 °C; R_f = 0.2 (10%, EtOAc­/hexane).

IR (neat): 3086, 2956, 1562, 1518, 1444, 1385, 1336, 1281, 1234, 1062, 1025, 990, 951, 836, 689 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.01 (s, 1 H), 4.18 (t, J = 5.8 Hz, 2 H), 3.64 (t, J = 5.8 Hz, 2 H), 2.55 (tt, J = 3.3, 6.7 Hz, 1 H), 2.05 (quin, J = 6.0 Hz, 2 H), 0.94–0.83 (m, 2 H), 0.67–0.58 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.1, 141.5, 133.7, 133.2, 114.3, 70.2, 51.4, 34.0, 29.5, 9.0.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₁H₁₃Br₂N₂O: 348.9374; found: 348.9366.

Typical Procedure and Spectral Data for 7a–g

To solution of 5,7-dibromo-1-methyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2b; 40 mg, 0.129 mmol) in dioxane (1 mL) was added Pd(PPh₃)₄ (14 mg, 0.0129 mmol), o-tolylboronic acid and aq 2 M K₂CO_3­ (0.2 mL). The reaction mixture was stirred for 8 h at 80 °C. Water (4 mL) was added and the mixture was extracted with EtOAc (12 × 3 mL). The combined organic phases were washed with brine (3 mL), dried over Na₂SO₄ and concentrated in vacuo. The resulting crude material was purified over silica gel column chromatography (10%, EtOAc­/hexane) to afford product 7g (32 mg, 74%).

4-Benzyl-6,8-diphenyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7a)

Synthesized from 2o (11 mg).

Yield: 9 mg (82%); white solid; mp 144–146 °C; R_f = 0.5 (10%, EtOAc­/hexane).

IR (neat): 1693, 1648, 1515, 1462, 756 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.05–7.97 (m, 2 H), 7.63 (dd, J = 1.2, 8.6 Hz, 2 H), 7.51–7.23 (m, 11 H), 7.12 (s, 1 H), 5.07 (s, 2 H), 4.26–4.18 (m, 2 H), 3.51–3.42 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.9, 146.8, 139.7, 138.6, 135.6, 135.0, 129.2, 128.6, 128.4, 128.2, 127.9, 127.7, 127.2, 126.2, 111.1, 64.3, 51.0, 45.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₆H₂₃N₂O: 379.1810; found: 379.1796.

1-Methyl-5,7-diphenyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (7b)

Yield: 23 mg (59%); white solid; mp 130–132 °C; R_f = 0.4 (10%, EtOAc­/hexane).

IR (neat): 2930, 1589, 1507, 1235, 774, 696 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 7.8 Hz, 4 H), 7.42 (t, J = 7.3 Hz, 4 H), 7.34 (d, J = 4.4 Hz, 2 H), 6.91 (s, 1 H), 4.26 (br. s, 2 H), 3.41 (br. s, 2 H), 3.02 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.4, 144.1, 142.9, 140.5, 138.4, 129.6, 128.5, 128.0, 128.0, 127.9, 126.8, 102.4, 64.0, 48.5, 38.2.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₀H₁₉N₂O: 303.1497; found: 303.149.

4-Benzyl-6,8-di(naphthalen-1-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7c)

Synthesized from 2o (62 mg).

Yield: 52 mg (68%); white solid; mp 170–172 °C; R_f = 0.7 (10%, EtOAc­/hexane).

IR (neat): 3051, 1546, 1454, 1358, 1046, 778 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 8.8 Hz, 1 H), 7.93–7.74 (m, 5 H), 7.69–7.61 (m, 1 H), 7.58–7.21 (m, 12 H), 6.95–6.87 (m, 1 H), 5.10–5.00 (m, 1 H), 4.97–4.85 (m, 1 H), 4.16–4.03 (m, 2 H), 3.50–3.33 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.9, 146.7, 138.9, 138.5, 135.9, 134.9, 134.2, 134.1, 133.6, 131.5, 131.4, 128.6, 128.4, 128.4, 128.3, 128.2, 127.3, 127.2, 126.7, 126.3, 126.2, 125.9, 125.9, 125.6, 125.4, 125.4, 117.4, 64.2, 51.0, 45.4.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₃₄H₂₇N₂O: 479.2123; found: 479.213.

5-Methyl-7,9-diphenyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (7d)

Synthesized from 1a (50 mg).

Yield: 47 mg (96%); white solid; mp 89–91 °C; R_f = 0.7 (10%, EtOAc­/hexane).

IR (neat): 2950, 1544, 1497, 1370, 1202, 1036, 952, 762, 696 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.07–8.00 (m, 2 H), 7.58–7.53 (m, 2 H), 7.49–7.33 (m, 6 H), 7.17 (s, 1 H), 4.20 (t, J = 6.1 Hz, 2 H), 3.60–3.49 (m, 2 H), 3.31–3.19 (m, 3 H), 2.18–2.06 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.4, 148.1, 141.2, 140.6, 139.5, 137.5, 129.2, 128.5, 128.1, 128.0, 127.9, 127.7, 126.4, 126.3, 112.6, 70.3, 50.6, 40.0, 29.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₁H₂₁N₂O: 317.1654; found: 317.1635.

(S)-6,8-Diphenyl-4-(1-phenylethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7e)

Synthesized from 2k (70 mg).

Yield: 63 mg (91%); white solid; mp 116–118 °C; R_f = 0.5 (15%, EtOAc­/hexane).

IR (neat): 2932, 1594, 1484, 1440, 1358, 1207, 1029, 771, 744, 695 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.90 (m, 2 H), 7.55–7.50 (m, 2 H), 7.38–7.13 (m, 11 H), 7.00 (s, 1 H), 6.56 (q, J = 6.8 Hz, 1 H), 4.11–4.04 (m, 1 H), 3.95 (ddd, J = 2.9, 7.6, 10.5 Hz, 1 H), 3.30 (ddd, J = 2.9, 7.7, 12.3 Hz, 1 H), 3.03–2.97 (m, 1 H), 1.54 (d, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.7, 146.5, 141.8, 139.8, 136.9, 135.6, 134.9, 129.2, 128.4, 128.4, 128.2, 127.8, 127.7, 127.5, 127.0, 126.2, 110.7, 64.4, 50.4, 39.5, 15.0.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₇H₂₅N₂O: 393.1967; found: 393.1956.

1-Cyclopropyl-5,7-diphenyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (7f)

Synthesized from 2h (35 mg).

Yield: 16 mg (47%); white solid; mp 55–57 °C; R_f = 0.4 (15%, EtOAc­/hexane).

IR (neat): 2929, 1583, 1546, 1505, 1358, 1231, 1023, 1023, 776 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.07–7.96 (m, 4 H), 7.50–7.41 (m, 5 H), 7.39–7.32 (m, 2 H), 4.38–4.19 (m, 2 H), 3.53–3.38 (m, 2 H), 2.60–2.45 (m, 1 H), 1.03–0.89 (m, 2 H), 0.83–0.66 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.0, 144.3, 143.0, 140.5, 138.4, 137.8, 129.6, 128.5, 127.9, 127.9, 127.8, 126.7, 115.3, 104.0, 64.8, 46.1, 31.3, 8.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₂H₂₁N₂O: 329.1654; found: 329.1647.

4-Methyl-6,8-di-o-tolyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (7g)

Yield: 32 mg (74%); white solid; mp 44–46 °C; R_f = 0.8 (10%, EtOAc­/hexane).

IR (neat): 2926, 1601, 1454, 1359, 1206, 1036, 759 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.43 (m, 1 H), 7.29–7.18 (m, 7 H), 6.55 (s, 1 H), 4.27–4.20 (m, 2 H), 3.50–3.42 (m, 2 H), 3.18 (s, 3 H), 2.50 (s, 3 H), 2.25 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.4, 147.1, 140.7, 136.7, 136.3, 136.1, 135.5, 134.6, 130.8, 129.9, 129.7, 129.5, 127.9, 127.4, 125.7, 125.6, 115.5, 64.2, 48.2, 36.3, 21.1, 20.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₂H₂₃N₂O: 331.1810; found: 331.1802.

Typical Procedure and Spectral Data for 8a–f

To a solution of (S)-5,7-dibromo-1-(1-phenylethyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (2l; 85 mg, 0.213 mmol) in toluene (2 mL) was added Pd(PPh₃)₄ (24 mg, 0.0213 mmol), 2-(tributylstannyl)pyridine 8 and, after degassing under argon, the reaction mixture was stirred for 16 h at reflux. After completion of reaction, which was checked by TLC, the reaction mixture was filtered through a short pad of Celite and concentrated in vacuo. The resulting crude material was purified over 5% KF + silica gel column chromatography with 10% MeOH in CH₂Cl₂, which afforded product 8c (52 mg, 61%).

1-Methyl-5,7-di(pyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (8a)

Synthesized from 2b (60 mg).

Yield: 55 mg (92%); white solid; mp 102–104 °C; R_f = 0.2 (80%, EtOAc­/hexane).

IR (neat): 2934, 1560, 1501, 1433, 1364, 1203, 1050, 791, 607 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.76–8.68 (m, 1 H), 8.63–8.56 (m, 1 H), 8.35–8.28 (m, 1 H), 8.11 (s, 1 H), 7.82–7.78 (m, 1 H), 7.71 (dtd, J = 2.0, 7.7, 11.4 Hz, 2 H), 7.24–7.14 (m, 2 H), 4.33–4.26 (m, 2 H), 3.55–3.46 (m, 2 H), 3.25 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 154.7, 149.5, 148.9, 147.6, 145.8, 138.1, 136.4, 135.8, 133.1, 124.9, 122.4, 122.3, 120.2, 112.0, 64.4, 47.8, 36.3.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₈H₁₇N₄O: 305.1402; found: 305.1391.

5-Methyl-7,9-di(pyridin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (8b)

Synthesized from 1b (48 mg).

Yield: 46 mg (92%); white solid; mp 98–100 °C; R_f = 0.2 (25%, EtOAc­/hexane).

¹H NMR (400 MHz, CDCl₃): δ = 8.72 (td, J = 1.3, 4.8 Hz, 1 H), 8.64–8.57 (m, 1 H), 8.37–8.29 (m, 1 H), 8.11 (s, 1 H), 7.78–7.68 (m, 3 H), 7.28–7.16 (m, 2 H), 4.22 (t, J = 6.1 Hz, 2 H), 3.55 (dd, J = 5.1, 6.6 Hz, 2 H), 3.23 (s, 3 H), 2.15–2.08 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.6, 155.4, 154.3, 149.4, 148.9, 147.3, 142.9, 139.4, 136.5, 135.8, 125.0, 122.6, 122.4, 120.5, 113.4, 70.3, 50.5, 40.0, 28.8.

IR (neat): 2951, 1699, 1547, 1488, 1428, 1371, 1263, 1198, 1043, 792 cm^–1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₉H₁₉N₄O: 319.1559; found: 319.1547.

(S)-1-(1-Phenylethyl)-5,7-di(pyridin-2-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (8c)

Yield: 52 mg (61%); white solid; mp 100–102 °C; R_f = 0.2 (5%, MeOH/CH₂Cl₂).

IR (neat): 1693, 1648, 1515, 1462, 754 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.79–8.73 (m, 1 H), 8.62–8.58 (m, 1 H), 8.47 (d, J = 8.3 Hz, 1 H), 8.07 (d, J = 1.0 Hz, 1 H), 7.93–7.89 (m, 1 H), 7.82–7.70 (m, 2 H), 7.41–7.32 (m, 4 H), 7.31–7.25 (m, 2 H), 7.21 (ddd, J = 1.0, 4.9, 7.3 Hz, 1 H), 5.57 (q, J = 6.8 Hz, 1 H), 4.25–4.17 (m, 1 H), 4.08 (ddd, J = 2.9, 7.5, 10.6 Hz, 1 H), 3.36 (ddd, J = 2.9, 7.6, 12.5 Hz, 1 H), 3.14–3.03 (m, 1 H), 1.66 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.3, 156.7, 149.3, 148.9, 148.6, 144.1, 142.2, 140.1, 139.4, 136.6, 136.0, 128.7, 127.6, 127.2, 124.9, 122.8, 122.5, 121.2, 103.1, 64.2, 54.0, 39.8, 15.2;

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₅H₂₃N₄O: 395.1872; found: 395.1867.

(S)-4-(1-Phenylethyl)-6,8-di(pyridin-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (8d)

Yield: 78 mg (91%); white solid; mp 118–120 °C; R_f = 0.2 (30%, EtOAc­/hexane).

IR (neat): 2931, 1698, 1300, 1254, 1174, 1060, 789 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.75–8.71 (m, 1 H), 8.60 (td, J = 1.0, 4.9 Hz, 1 H), 8.31 (d, J = 8.3 Hz, 1 H), 8.11 (s, 1 H), 7.82–7.77 (m, 1 H), 7.71 (tt, J = 1.8, 7.8 Hz, 2 H), 7.46–7.41 (m, 2 H), 7.37–7.30 (m, 2 H), 7.28–7.20 (m, 2 H), 7.17 (ddd, J = 1.0, 4.9, 7.3 Hz, 1 H), 6.61 (q, J = 6.8 Hz, 1 H), 4.25–4.17 (m, 1 H), 4.09 (ddd, J = 2.9, 7.5, 10.6 Hz, 1 H), 3.42 (ddd, J = 3.2, 7.3, 12.5 Hz, 1 H), 3.15–3.08 (m, 1 H), 1.63 (d, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.8, 154.9, 149.5, 148.9, 146.4, 145.7, 141.6, 137.7, 136.5, 135.9, 133.7, 128.5, 127.4, 127.1, 124.9, 122.5, 122.4, 120.3, 111.7, 64.6, 50.7, 39.3, 15.0.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₅H₂₃N₄O: 395.1872; found: 395.1865.

4-Benzyl-6,8-di(pyridin-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (8e)

Synthesized from 2o (96 mg).

Yield: 63 mg (67%); white solid; mp 150–152 °C; R_f = 0.2 (35%, EtOAc­/hexane).

IR (neat): 2928, 1560, 1497, 1436, 1362, 1204, 1043, 747 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.77–8.69 (m, 1 H), 8.63–8.56 (m, 1 H), 8.30–8.23 (m, 1 H), 8.14 (s, 1 H), 7.83–7.78 (m, 1 H), 7.69 (dtd, J = 2.0, 7.8, 11.7 Hz, 2 H), 7.40–7.35 (m, 2 H), 7.34–7.29 (m, 2 H), 7.28–7.20 (m, 2 H), 7.15 (ddd, J = 1.0, 4.8, 7.5 Hz, 1 H), 5.04 (s, 2 H), 4.31–4.17 (m, 2 H), 3.52–3.38 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 154.8, 149.5, 148.9, 146.8, 145.8, 138.4, 137.7, 136.5, 135.9, 133.8, 128.6, 128.1, 127.2, 124.9, 122.5, 122.4, 120.3, 112.1, 64.4, 51.2, 45.0;

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₄H₂₁N₄O: 381.1715; found: 381.1703.

4-Cyclopropyl-6,8-di(pyridin-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (8f)

Synthesized from 2g (50 mg).

Yield: 44 mg (89%); white solid; mp 118–120 °C; R_f = 0.3 (40%, EtOAc­/hexane).

IR (neat): 2951, 1517, 1416, 1375, 1311, 1247, 997, 742 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.75–8.71 (m, 1 H), 8.60 (td, J = 1.2, 5.0 Hz, 1 H), 8.43–8.38 (m, 1 H), 8.18 (s, 1 H), 7.82–7.68 (m, 3 H), 7.25–7.14 (m, 2 H), 4.37–4.19 (m, 2 H), 3.60–3.43 (m, 2 H), 2.80–2.63 (m, 1 H), 1.03–0.87 (m, 2 H), 0.78–0.65 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.9, 154.8, 149.5, 148.8, 147.9, 145.7, 138.3, 136.5, 135.8, 133.3, 124.9, 122.4, 122.3, 120.3, 112.9, 65.4, 46.0, 31.0, 7.8.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₀H₁₉N₄O: 331.1559; found: 331.1546.

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