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Synthesis 2025; 57(01): 109-114
DOI: 10.1055/a-2349-6944
paper
Special Topic Dedicated to Prof. H. Ila

Annulation Reactions of Isoquinolinium Ylides with Sulfamate-Derived Cyclic Imines toward Polycyclic 1,3-Benzoxazepine Heterocycles

Koushik Patra
,
Sana Mulani
,
Mahiuddin Baidya∗

We gratefully acknowledge the Indian Institute of Technology Madras (IIT Madras) for funding through IOE and ERP projects (RF23241505CYRFER008650 and SB22231237CYETWO008189). K.P. acknowledges funding form the Prime Minister’s Research Fellows (PMRF) scheme from the Ministry of Human Resource Development (MHRD), Ministry of Education, Government of India.
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This article is dedicated to Prof. H. Ila on the occasion of her 80th birthday.

Abstract

A dearomatization-guided and (3+2) cycloaddition-triggered annulation reaction of in situ formed isoquinolinium ylides with sulfamate-derived cyclic imines is reported, offering a cogent synthesis of tetracyclic 1,3-benzoxazepine frameworks in high yields. The protocol features successive ring-forming and ring-breaking events in a cascade fashion and is also scalable.


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Key words

cascade annulation - dearomatization - benzoxazepines - (3+2) cycloaddition - heterocycles

Benzoxazepines are an important class of heterocyclic compounds characterized by a seven-membered oxazepine ring fused to an arene framework. They represent the core structures of various bioactive compounds, which include commercial drugs, for example, loxapine and amoxapine (Figure [1]).[1] Their unique structural features, coupled with a wide range of pharmacological activities, make them highly valuable in medicinal chemistry and drug design. Consequently, devising succinct protocols to access functionalized benzoxazepines is a continuous enterprise in the synthetic community.[2] [3]

Zoom Image
Figure 1 Representative bioactive molecules; Pg = prostaglandin

While benzoxazepines are categorized according to the positions of their nitrogen and oxygen atoms and the point of benzo-fusion within the ring, most synthetic efforts have concentrated on the preparation of 1,4-benzoxazepines and 1,5-benzoxazepines (Scheme [1a]).[3] However, efficient methods for synthesizing structurally related 1,3-benzoxazepine motifs are still limited.[4] In this context, the early work by Daïch et al. on the acid-mediated intramolecular cyclization of suitably adorned α-hydroxylactams and the fluorination-triggered intramolecular domino cyclization of styryl benzamides developed by Gulder et al. are intriguing (Schemes 1b and 1c).[4a] [b] Recently, we showcased an intermolecular cascade annulation reaction of glycine aldimino esters A to prepare 1,3-benzoxazepines in high yields (Scheme [1d]).[4c]

Zoom Image
Scheme 1 Methods for the synthesis of 1,3-benzoxazepines

In continuation of our interest in N,O-heterocycles,[5] and grounded on our previous synthesis,[4c] we surmised that isoquinolinium salt 2 structurally resembles glycine aldimino esters A, and thus, it may facilitate a similar annulation cascade with sulfamate-derived cyclic imine 1 leading to the production of 1,3-benzoxazepine frameworks (Scheme [1e]).[6] However, in contrast to the previous study, this protocol needs to overcome challenges associated with dearomatization of the isoquinoline motif under mild conditions without hampering the necessary bond-forming and bond-breaking cascade events. Nonetheless, if successful, the protocol will offer a route to challenging tetracyclic 1,3-benzoxazepine heterocycles (Scheme [1e]).

Herein, we delineate the development of this approach and demonstrate the intermolecular cascade annulation reaction of sulfamate-derived cyclic imines 1 with readily accessible isoquinolinium salts 2 under basic conditions, affording a range of diversely functionalized tetracyclic 1,3-benzoxazepines in high yields (Scheme [1f]).

We commenced our investigations by examining the model reaction between imine 1a and isoquinolinium salt 2a (Table [1]). When a mixture of 1a and 2a in acetonitrile as the solvent was exposed to sodium carbonate as the base at room temperature, we obtained the desired cascade annulation product 3a in 12% yield (entry 1).

Table 1 Optimization of the Reaction Conditionsa

Entry

Solvent

Base

Temp (°C)

Yield (%)b

1

CH3CN

Na2CO3

rt

12

2

CH3CN

Na2CO3

60

65

3

DCM

Na2CO3

60

68

4

THF

Na2CO3

60

40

5

dioxane

Na2CO3

60

43

6

toluene

Na2CO3

60

23

7

EtOAc

Na2CO3

60

77

8

EtOAc

K2CO3

60

74

9

EtOAc

Li2CO3

60

65

10

EtOAc

Cs2CO3

60

68

11

EtOAc

Et3N

60

53

12

EtOAc

DABCO

60

61

13

EtOAc

Na2CO3

50/70

68/70

14c

EtOAc

Na2CO3

60

42

a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), base (0.6 mmol), solvent (2 mL), nitrogen atmosphere, 24 h.

b Isolated yields are given.

c Reaction with 1.0 equivalent of Na2CO3.

The product formation was significantly improved upon increasing the reaction temperature, delivering 3a in 65% yield at 60 °C (Table [1], entry 2). Encouraged by these results, we examined various aprotic solvents. While the annulation reaction was effective in DCM (CH2Cl2), we observed poor reactivity in THF, dioxane, and toluene (entries 3–6). Interestingly, the cascade annulation proceeded cleanly in ethyl acetate as the solvent, and the desired product 3a was obtained in 77% isolated yield (entry 7). In the presence of K2CO3, the reaction yield marginally decreased, while the reduction was more significant with Li2CO3 and Cs2CO3 (entries 8–10). Organic bases such as triethylamine and DABCO (1,4-diazabicyclo[2.2.2]octane) also resulted in inferior outcomes (entries 11 and 12). Further alterations to the reaction temperature, whether increasing or decreasing, also led to reduced yields of 3a (entry 13). When 1 equivalent of the base was utilized, product 3a was formed in a poor yield (entry 14).

With optimized reaction conditions in hand (Table [1], entry 7), we next explored the substrate scope of this protocol (Scheme [2]). The reaction was quite general for an array of cyclic imines 1 bearing electronically diverse substituents on the phenyl ring. For example, substrates with an electron-donating methyl group and an electron-withdrawing chlorine functionality at the C8 position produced tetracyclic 1,3-benzoxazepines 3b and 3c in 76% and 85% yields, respectively. Similarly, substituents at the C7 position furnished products 3d and 3e in very high yields. The protocol also tolerated synthetically useful bromo (3f) and iodo (3g) functionalities. A sterically bulky dichloro-substituted cyclic sulfamate imine gave product 3h in 84% yield. The protocol was also fruitful for a series of isoquinolinium salts (Scheme [2]). Under the standard conditions, isoquinolinium salts derived from primary (3i), secondary (3j, 3m), tertiary (3k), and allyl (3l) alcohol esters furnished the expected 1,3-benzoxazepine products in very high yields (71–82%). Compound 3l was crystallized and the single-crystal X-ray analysis unambiguously confirmed the product structure and regioselectivity (see also the Supporting Information). In addition, isoquinolinium salts possessing a ketone functionality were also suitable substrates, affording 1,3-benzoxazepines 3n and 3o in 60% and 63% yields, respectively.

Zoom Image
Scheme 2 Exploration of the reaction scope. Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), Na2CO3 (2 equiv), EtOAc (2 mL), nitrogen atmosphere, 24 h.

The ring-substituent patterns in the isoquinolinium salts 2 turned out to be important for this cascade reaction (Figure [2]). The annulation was unproductive in the presence of an electron-rich methoxy group at the C4 position (2i) or a bulky methyl group at the C3 position (2j). Also, under standard reaction conditions, N-benzylisoquinolinium salt 4, without an electron-withdrawing carbonyl functionality, did not participate in this annulation reaction. Further, when quinolinium salt 5 was employed, the desired cascade annulation did not proceed, indicating the reaction specificity towards isoquinolinium salts 2.

Zoom Image
Figure 2 Unsuccessful isoquinolinium salts

To showcase the synthetic utility of this protocol, we performed a gram-scale reaction. Gratifyingly, the efficacy of the small-scale reaction was preserved upon scaling up, where 1,3-benzoxazepine 3a was prepared in 74% isolated yield (Scheme [3a]).

While the exact reaction mechanism must await further investigations, a plausible mechanism is depicted in Scheme [3b]. Initially, the isoquinolinium ylide 2A is formed through deprotonation of isoquinolinium salt 2. This ylide then undergoes dearomative (3+2) annulation with cyclic imine 1, generating intermediate I. In the presence of a base, intermediate I is converted into intermediate II. Subsequent rearrangement via the extrusion of HN=SO2 gives intermediate III, which then readily cyclizes to produce the tetracyclic 1,3-benzoxazepine 3.[7]

Zoom Image
Scheme 3 (a) A gram-scale synthesis. (b) A plausible reaction mechanism.

In conclusion, we have successfully developed an intermolecular cascade annulation that couples sulfamate-derived cyclic imines 1 with in situ generated isoquinolinium ylides, offering functionalized tetracyclic 1,3-benzoxazepine heterocycles in very high yields. The further utilization of isoquinolinium salts for the synthesis of valuable N-heterocycles is currently ongoing in our laboratory.

All reactions were monitored by thin-layer chromatography (TLC) on WhatmanPartisil® K6F TLC plates (silica gel 60 Å, 0.25 mm thickness) and visualized using a UV lamp (366 or 254 nm) or by use of one of the following visualization reagents: PMA: 10 g phosphomolybdic acid/100 mL ethanol; KMnO4: 0.75 g potassium permanganate, 5 g K2CO3­/100 mL water. Products were purified by column chromatography (Merck silica gel 100–200 μm). Yields refer to chromatographically and spectroscopically homogenous materials unless noted otherwise. 13C and 1H NMR spectra were recorded on Bruker 400 or Bruker 500 MHz spectrometers. Mass spectra were recorded using the electrospray ionization (ESI) method on a Q-TOF Micro with a lock spray source. Crystal data were collected and integrated using a BrukerAxs kappa apex2 CCD diffractometer, with graphite monochromated Mo-Kα radiation.


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1,3-Benzoxazepines 3; General Procedure

To an oven-dried reaction tube equipped with a magnetic stir bar were added sulfamate-derived imine 1 (0.3 mmol, 1.0 equiv), isoquinolinium salt 2 (0.36 mmol, 1.2 equiv), and Na2CO3 (2 equiv). Next, EtOAc (1.5 mL) was added and the reaction mixture was stirred at 60 °C under an N2 atmosphere. After 24 h, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (1 → 5%, EtOAc/hexane) to give the pure 1,3-benzoxazepine 3.


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Compound 3a; Gram-Scale Synthesis

A 100 mL oven-dried round-bottom flask equipped with a magnetic stir bar was charged with 1a (5.46 mmol, 1.0 equiv), 2a (6.55 mmol, 1.2 equiv) and Na2CO3 (2 equiv) under an N2 atmosphere. Next, dry EtOAc (20 mL) was added via syringe. The reaction mixture was allowed to stir at 60 °C for 24 h. After completion, the volatiles were removed under reduced pressure and the crude residue was purified by silica gel column chromatography to provide pure product 3a (1.28 g, 74%).

Ethyl (S)-14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3a)

Yield: 74 mg (77%); yellow solid; mp 114 °C; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.3 Hz, 1 H), 7.30–7.23 (m, 4 H), 7.20–7.15 (m, 1 H), 7.06–7.00 (m, 2 H), 6.77 (d, J = 7.5 Hz, 1 H), 5.99 (d, J = 7.6 Hz, 1 H), 5.55 (s, 1 H), 4.38–4.26 (m, 2 H), 1.36 (t, J = 7.1 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.5, 162.0, 134.5, 132.3, 130.9, 130.2, 129.3, 129.3, 128.0, 126.7, 125.7, 125.0, 124.8, 122.9, 122.4, 120.2, 101.3, 86.7, 61.9, 14.4.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C20H18NO3: 320.1281; found: 320.1203.


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Ethyl (S)-13-Methyl-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3b)

Yield: 76 mg (76%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.43–7.39 (m, 1 H), 7.32 (d, J = 7.5 Hz, 2 H), 7.27–7.24 (m, 3 H), 7.12 (d, J = 7.4 Hz, 1 H), 6.99 (t, J = 7.3 Hz, 1 H), 6.82 (d, J = 7.3 Hz, 1 H), 6.01 (d, J = 7.4 Hz, 1 H), 5.51 (s, 1 H), 4.43–4.29 (m, 2 H), 2.15 (s, 3 H), 1.39 (t, J = 7.0 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.7, 160.5, 132.4, 131.9, 130.9, 130.6, 130.2, 129.3, 129.2, 128.0, 127.2, 125.8, 125.1, 124.6, 123.1, 122.1, 101.3, 86.9, 62.0, 167.0, 14.5.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C21H20NO3: 334.1438; found: 334.1352.


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Ethyl (S)-13-Chloro-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3c)

Yield: 89 mg (85%); yellow solid; mp 130 °C; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.41–7.38 (m, 1 H), 7.35–7.28 (m, 2 H), 7.26–7.22 (m, 2 H), 7.19 (d, J = 3.2 Hz, 1 H), 7.03–7.00 (m, 2 H), 6.76 (d, J = 7.1 Hz, 1 H), 6.00 (d, J = 7.3 Hz, 1 H), 5.53 (s, 1 H), 4.39–4.28 (m, 2 H), 1.37–1.33 (m, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.3, 162.3, 135.1, 134.9, 132.5, 130.8, 130.0, 129.6, 128.1, 126.3, 126.0, 125.2, 123.8, 122.9, 121.7, 120.4, 101.6, 87.3, 62.1, 14.4.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C20H17ClNO3: 354.0891; found: 354.0799.


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Ethyl (S)-12-Methyl-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3d)

Yield: 73 mg (73%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.41 (t, J = 7.3 Hz, 1 H), 7.37–7.25 (m, 5 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.86 (s, 1 H), 6.78 (d, J = 7.3 Hz, 1 H), 6.00 (d, J = 7.4 Hz, 1 H), 5.58 (s, 1 H), 4.44–4.27 (m, 2 H), 2.31 (s, 3 H), 1.38 (t, J = 6.7 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.7, 161.9, 140.2, 134.4, 131.5, 131.0, 130.4, 129.3, 128.0, 126.7, 125.7, 125.3, 125.1, 123.6, 120.8, 120.2, 101.1, 86.8, 61.9, 21.3, 14.5.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C21H20NO3: 334.1438; found: 334.1352.


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Ethyl (S)-12-Chloro-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3e)

Yield: 91 mg (86%); yellow solid; mp 142 °C; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.35–7.33 (m, 1 H), 7.30–7.17 (m, 5 H), 7.14 (s, 1 H), 6.92 (t, J = 7.7 Hz, 1 H), 6.74 (d, J = 7.4 Hz, 1 H), 5.97 (d, J = 7.4 Hz, 1 H), 5.44 (s, 1 H), 4.36–4.22 (m, 2 H), 7.36–1.29 (m, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.3, 157.3, 132.8, 132.7, 130.7, 129.6 (2 C), 129.5, 128.4, 126.4, 126.0, 125.4, 125.1, 125.0, 122.8, 122.6, 102.1, 87.8, 62.1, 14.4.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C20H17ClNO3: 354.0891; found: 354.0795.


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Ethyl (S)-12-Bromo-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3f)

Yield: 92 mg (78%); yellow solid; mp 136 °C; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.46–7.39 (m, 1 H), 7.34–7.28 (m, 4 H), 7.24–7.18 (m, 3 H), 6.79 (d, J = 7.5 Hz, 1 H), 6.03 (d, J = 7.7 Hz, 1 H), 5.55 (s, 1 H), 4.41–4.30 (m, 2 H), 1.39 (t, J = 6.7 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.3, 162.3, 135.2, 132.7, 130.8, 129.9, 129.6, 128.1, 126.3, 126.0, 125.8, 125.2, 123.8, 123.4, 123.0, 122.1, 101.7, 87.3, 62.1, 14.4.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C20H17BrNO3: 398.0386; found: 398.0291.


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Ethyl (S)-11-Iodo-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3g)

Yield: 104 mg (79%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.49–7.37 (m, 2 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.28–7.25 (m, 2 H), 7.13 (s, 1 H), 6.80–6.77 (m, 2 H), 6.03 (d, J = 7.5 Hz, 1 H), 5.52 (s, 1 H), 4.44–4.26 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.1, 161.8, 142.3, 137.5, 133.3, 130.8, 129.9, 129.6, 128.1, 126.4, 126.0, 125.5, 125.2, 122.9, 122.3, 101.8, 87.3, 84.7, 62.2, 14.4.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C20H17INO3: 446.0248; found: 446.0137.


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Ethyl (S)-10,13-Dichloro-14aH-benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3h)

Yield: 89 mg (84%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 7.7 Hz, 1 H), 7.31 (s, 1 H), 7.27–7.24 (m, 2 H), 7.21–7.18 (m, 2 H), 7.04 (s, 1 H), 6.75 (d, J = 7.2 Hz, 1 H), 6.00 (d, J = 7.2 Hz, 1 H), 5.40 (s, 1 H), 4.31 (dd, J = 8.1, 4.1 Hz, 2 H), 1.34–1.31 (m, 3 H).

13C NMR (101 MHz, CDCl3): δ = 164.1, 156.1, 133.9, 131.6, 130.6, 129.7, 129.3, 128.9, 128.5, 127.0, 126.3, 126.2, 126.2, 126.0, 125.3, 121.2, 102.6, 88.3, 62.4, 14.4.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C20H16Cl2NO3: 388.0502; found: 388.0408.


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Methyl (S)-14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3i)

Yield: 75 mg (82%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (500 MHz, CDCl3): δ = 7.43–7.40 (m, 1 H), 7.39–7.36 (m, 1 H), 7.30–7.21 (m, 4 H), 7.19–7.16 (m, 1 H), 7.05–6.99 (m, 2 H), 6.75 (dd, J = 7.6, 1.5 Hz, 1 H), 5.99 (d, J = 7.6 Hz, 1 H), 5.55 (d, J = 1.6 Hz, 1 H), 3.85 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 165.0, 162.1, 134.5, 132.2, 131.0, 130.2, 129.4 (2 C), 128.1, 126.8, 125.8, 125.2, 125.1, 122.9, 122.5, 120.3, 101.6, 87.0, 52.8.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C19H16NO3: 306.1152; found: 306.1050.


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Isopropyl (S)-14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3j)

Yield: 72 mg (74%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.7 Hz, 1 H), 7.44–7.41 (m, 1 H), 7.34–7.25 (m, 4 H), 7.24–7.20 (m, 1 H), 7.10–7.03 (m, 2 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.02 (d, J = 7.6 Hz, 1 H), 5.59 (s, 1 H), 5.27–5.18 (m, 1 H), 1.38 (t, J = 6.1 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 164.0, 162.0, 134.5, 132.7, 131.0, 130.3, 129.4, 129.2, 128.1, 126.7, 125.7, 125.1, 124.5, 123.0, 122.4, 120.2, 101.2, 86.8, 69.7, 22.0, 21.9.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C21H20NO3: 334.1438; found: 334.1349.


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tert-Butyl (S)-14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3k)

Yield: 74 mg (71%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.53–7.45 (m, 2 H), 7.39–7.24 (m, 5 H), 7.15–7.08 (m, 2 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.07 (d, J = 7.6 Hz, 1 H), 5.65 (s, 1 H), 1.65 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 163.6, 162.0, 134.4, 133.6, 131.0, 130.4, 129.3, 129.1, 128.1, 126.8, 125.7, 125.1, 124.1, 123.0, 122.4, 120.2, 101.1, 86.8, 82.6, 28.3.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C22H22NO3: 348.1594; found: 348.1512.


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Allyl (S)-14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3l)

Yield: 75 mg (75%); yellow solid; mp 110 °C; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 7.7 Hz, 1 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.25 (t, J = 7.1 Hz, 3 H), 7.21–7.14 (m, 2 H), 7.04–6.98 (m, 2 H), 6.74 (d, J = 7.6 Hz, 1 H), 5.95 (dd, J = 12.0, 6.5 Hz, 2 H), 5.53 (s, 1 H), 5.36 (d, J = 17.2 Hz, 1 H), 5.25 (d, J = 10.4 Hz, 1 H), 4.79–4.68 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ = 164.2, 162.1, 134.6, 132.1, 131.9, 130.9, 130.1, 129.4 (2 C), 128.1, 126.7, 125.8, 125.3, 125.1, 122.9, 122.5, 120.3, 119.0, 101.5, 86.8, 66.5.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C21H18NO3: 332.1281; found: 332.1199.


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Cyclohexyl (S)-14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinoline-8-carboxylate (3m)

Yield: 80 mg (72%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 7.7 Hz, 1 H), 7.41 (t, J = 7.3 Hz, 1 H), 7.32–7.25 (m, 4 H), 7.23–7.18 (m, 1 H), 7.06 (dd, J = 13.3, 5.8 Hz, 2 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.00 (d, J = 7.6 Hz, 1 H), 5.58 (s, 1 H), 5.00–4.96 (m, 1 H), 1.98–1.92 (m, 2 H), 1.81–1.74 (m, 2 H), 1.64–1.48 (m, 4 H), 1.46–1.36 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ = 163.9, 162.0, 134.5, 132.8, 131.0, 130.3, 129.4, 129.2, 128.1, 126.8, 125.7, 125.1, 124.5, 123.0, 122.4, 120.2, 101.2, 86.9, 74.5, 31.7, 31.6, 25.5, 23.9, 23.8.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C24H24NO3: 374.1751; found: 374.1658.


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(S)-(14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinolin-8-yl)(phenyl)methanone (3n)

Yield: 63 mg (60%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.7 Hz, 2 H), 7.62–7.57 (m, 1 H), 7.49–7.44 (m, 2 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.37–7.34 (m, 2 H), 7.31–7.27 (m, 2 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.11–7.05 (m, 2 H), 6.75 (s, 1 H), 6.59 (d, J = 7.5 Hz, 1 H), 5.95 (d, J = 7.5 Hz, 1 H), 5.75 (s, 1 H).

13C NMR (101 MHz, CDCl3): δ = 192.9, 162.1, 140.0, 138.0, 134.3, 133.0, 131.0, 129.8, 129.4, 129.3, 128.7, 128.4, 126.7, 126.3, 126.0, 125.3, 123.5, 122.7, 120.4, 101.9, 87.0.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C24H18NO2: 352.1332; found: 352.1237.


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(S)-(14aH-Benzo[6,7][1,3]oxazepino[2,3-a]isoquinolin-8-yl)(p-to­l­yl)methanone (3o)

Yield: 69 mg (63%); yellow solid; eluent: 5% ethyl acetate in hexane.

1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 7.9 Hz, 2 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.27 (t, J = 7.1 Hz, 2 H), 7.22–7.20 (m, 2 H), 7.18–7.13 (m, 3 H), 7.02–6.97 (m, 2 H), 6.63 (s, 1 H), 6.48 (d, J = 7.6 Hz, 1 H), 5.85 (d, J = 7.5 Hz, 1 H), 5.68 (s, 1 H), 2.35 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 192.5, 162.0, 143.9, 140.2, 135.3, 134.1, 131.0, 130.0, 129.5, 129.4, 129.3, 129.1, 128.4, 126.8, 125.9, 125.3, 125.1, 123.7, 122.7, 120.3, 101.8, 87.0, 21.8.

HRMS (ESI/TOF-Q): m/z [M + H]+ calcd for C25H20NO2: 366.1489; found: 366.1415.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are grateful to the Department of Chemistry and the Sophisticated Analytical Instruments Facility (SAIF), IIT Madras for the instrumental facilities.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2349-6944.
  • Supporting Information

Corresponding Author

Mahiuddin Baidya
Department of Chemistry, Indian Institute of Technology Madras
Chennai 600036
India   

Publication History

Received: 29 May 2024

Accepted after revision: 20 June 2024

Accepted Manuscript online:
20 June 2024

Article published online:
11 July 2024

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Zoom Image
Figure 1 Representative bioactive molecules; Pg = prostaglandin
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Scheme 1 Methods for the synthesis of 1,3-benzoxazepines
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Scheme 2 Exploration of the reaction scope. Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), Na2CO3 (2 equiv), EtOAc (2 mL), nitrogen atmosphere, 24 h.
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Figure 2 Unsuccessful isoquinolinium salts
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Scheme 3 (a) A gram-scale synthesis. (b) A plausible reaction mechanism.