NIS-mediated intramolecular oxidative α-functionalization of tertiary amines: transition metal-free synthesis of 1,2-dihydro-(4H)-3,1-benzoxazin-4-one derivatives

Abstract

A novel method for direct α-functionalization of tertiary amines via NIS-mediated oxidative C–O bond formation, where NIS serves as both an oxidant and an iodination reagent, has been developed. The method provides easy access to either iodinated or non-iodinated 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones, depending on the nature of the reactant, via a regioselective transition metal-free approach.

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Introduction

Cross-dehydrogenative coupling (CDC) reactions, which spare pre-functionalization of the substrates, boast high synthetic efficiency and atom economy; and have, hence, attracted much attention in recent decades.¹ Among the CDC reactions, selective functionalization of sp³ C–H bonds adjacent to a nitrogen atom in simple amines is of fundamental significance in organic chemistry for the synthesis of nitrogen-containing compounds.² Classical strategies to realize such transformations have been achieved by utilizing transition-metals such as Ru,³ Fe,⁴ Cu,⁵ V,⁶ etc., with co-oxidant to afford an iminium cationic species, which subsequently reacts with various nucleophiles to form a C–C or C-heteroatom bond for the functionalization of the C–H bond adjacent to the nitrogen. As one of the most important branches of CDC reactions, direct C–O bond formation accomplished via selective sp³ C–H bond functionalization of tertiary amines has been intensively studied for many years.⁷ In 2006, a novel Pd-catalyzed highly selective acetoxylation of Boc-protected N-methylamines using IOAc as the oxidant and involving a Boc-directed C–H activation process, was developed by Yu and co-workers⁸ (Scheme 1, path a). In 2013, Maycock^7a group reported a copper-catalyzed regioselective intramolecular α-functionalization of tertiary amines to synthesize dihydro-1,3-oxazines via C–O bond formation. Similar works have also been achieved in 2014 by Jana^7b and Maiti^5f employing stoichiometric Ag₂O or catalytic amount of CuCl₂·H₂O under air, respectively (Scheme 1, path b). Lately, we reported a hypervalent iodine-mediated synthesis of 1,2-dihydro-(4H)-3,1-benzoxazin-4-one derivatives and 1,2-dihydro-(4H)-3,1-benzoxazine derivatives through intramolecular functionalization of sp³ C–H bond of diaryl amines,^7c an attractive metal-free protocol to functionalize sp³ C–H bond adjacent to the nitrogen (Scheme 1, path c). Despite the significant progress made in this area in recent years,⁹ there is still much to be improved notably in the reaction selectivity, the expansion of substrate scope as well as the variety of the products.

Scheme 1 Direct C–O bond formation via activation of the C–H bond adjacent to nitrogen in a tertiary amine.

Benzoxazin-4-one derivatives¹⁰ are an important class of heterocyclic compounds, which exhibit a wide range of biological activities including anti-inflammatory effects,¹¹ inhibitor of human leukocyte elastase,¹² HSV-1 protase,¹³ and have been used as potent inhibitors of chymotrypsin.¹⁴ Iodinated 1H-benzoxazin-4-(H)-one derivatives can not only be readily functionalized by various coupling reactions for further application, but also be reported as inhibitors of MEK for the treatment of a variety of proliferative disease.¹⁵ The importance of these benzoxazinones also resides in their occurrence in natural products and the application as precursors for the preparation of other heterocyclic compounds.¹⁶ Traditionally, the general method for the synthesis of benzoxazin-4-one derivatives involves the condensation between an aromatic aldehyde and an anthranilic acid in the presence of an anhydride.¹⁷ Kunai reported a straightforward access to benzoxazinones by CO₂ incorporation with a zwitterion arising from nucleophilic addition of imines to arynes.¹⁸ However, efficient approaches to construct these molecules are still limited in number. On the other hand, N-halosuccinimides, aside from serving as halogenation reagents, have also been widely adopted as an oxidant to realize oxidative cyclization reactions in recent years.¹⁹ We herein disclose a novel N-iodosuccinimide (NIS)-mediated protocol to access 1,2- dihydro-(4H)-3,1-benzoxazin-4-one derivatives via α-functionalization of sp³ C–H bond adjacent to the nitrogen of tertiary amines. To our knowledge, this is an unusual reported instance to form benzoxazinones or regioseletively iodinated benzoxazinones where NIS serves both as an oxidant and an iodination reagent (Scheme 1).

Results and discussion

Initially, we postulated that treating N-methyl-N-phenylanthranilic acid 1a with NIS would probably generate an iminum intermediate which could be attacked by the neighboring carboxylic acid group to afford the aminal 2a′. However, only 15% yield of 2a′ was formed as the minor product, along with the major product of iodinated 1H-benzoxazin-4(H)-one 2a formed in 65% yield. This result suggested a regioselective iodo- aromatic substitution occurred in addition to the expected oxidative annulation.

Following up with the initial result, we set out to explore the reaction conditions in hopes to enhance the chemoselectivity of the reaction, the main research interest of ours in identifying metal-free methods for the preparation of heterocycles.²⁰ The first study was on the effect of the oxidant amount. The results, with the amount of oxidant varying between 1.0 and 3.0 equiv., showed that compound 2a was consistently the major product while 2a′, the minor product (not shown). The solvent effect study showed that acetonitrile was the most effective in comparison to all the other solvents including DCE, ethyl acetate, TFE and DMF (Table 1, entries 1–6). None of the solvents, however, showed any significant influence on the chemoselectivity of the reaction. Further studies revealed that a basic additive could dramatically improve the selectivity as well as the yield (Table 1, entries 7–10), as we were able to isolate compound 2a as the single product with a yield of 93% when Na₂CO₃ was applied as an additive (Table 1, entries 8). Additional bases such as K₂CO₃, Li₂CO₃ and pyridine were also examined, but no further enhancement of the yield was observed (not shown). Finally, molecular iodine was tested as a possible oxidant, yet only 10% yield of 2a was isolated (Table 1, entries 11–12). Other N-halosuccinimides, NBS and NCS, were also investigated. When NBS was used as the oxidant, neither the corresponding annulated/brominated product nor 2a′ was observed. In contrast, when NCS was employed, the reaction proceeded smoothly to give the non-halogenated 2a′ in moderate 47% yield (not shown).

Table 1 Optimization of reaction conditions^a

Entry	Oxidant (equiv.)	Solvent	Additive (equiv.)	Yield^b (%) of 2a′	Yield^b (%) of 2a
a All reactions were carried out with 1a (0.4 mmol) and oxidant in the specific solvent (c = 0.05 M).b Isolated yield.c 15% of the starting material was recovered. ND = no desired product.
1^c	NIS (2.0)	CH3CN	—	15%	67
2	NIS (3.0)	CH3CN	—	15%	73
3	NIS (3.0)	DCE	—	20%	68
4	NIS (3.0)	EA	—	17%	70
5	NIS (3.0)	THF	—	23%	65
6	NIS (3.0)	DMF	—	18%	45
7	NIS (3.0)	CH3CN	NaHCO3 (2.0)	<5	85
8	NIS (3.0)	CH3CN	Na2CO3 (2.0)	—	93
9	NIS (3.0)	CH3CN	NaOAc (2.0)	<5	79
10	NIS (3.0)	CH3CN	TEA (2.0)	Trace	Trace
11	I2 (2.0)	CH3CN	—	ND	ND
12	I2 (2.0)	CH3CN	Na2CO3 (2.0)	Trace	10

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To evaluate the efficiency and generality of the newly established method, various substituted diaryl tertiary amines were examined under the optimized conditions (Table 1, entry 8). As shown in Table 2, the corresponding 1,2-dihydro-(4H)-3,1- benzoxazin-4-ones bearing a wide range of substitutions could be obtained in moderate to excellent yields. The substituent effect of R¹ proved to be minimal, with well tolerated both electron-withdrawing and -donating R¹ groups to give satisfactory yields (Table 2, entries 1–6). Larger alkyl groups of various sizes, such as benzyl, ethyl and hexyl were used to replace the methyl group as R³. While the yields all remained unwaveringly high (Table 2, entries 7–9), the stability of the generated product decreased dramatically in those containing a long-chained alkyl group, as 2h and 2i were found to decompose readily during purification. Drastically different from the cases of R¹ and R³, the substituent effect of R² was more pronounced. For substrates bearing one or more electron-donating groups on the B ring, diiodination occurred and diiodinated/annulated products were formed in moderate to good yields (Table 2, entries 10–12).

Table 2 Scope of the oxidative annulation and iodination reaction^a

Entry	Substrate	Product	Yield^b (%)
a All reactions were carried out with 1 (0.4 mmol) in the presence of NIS (3.0 equiv.) and Na2CO3 (2.0 equiv.) in CH3CN (c = 0.05 M).b Isolated yield.c NMR yield employing mesitylene as the internal standard.
1			93
2			75
3			90
4			77
5			81
6			76
7			95
8			88^c
9			87^c
10			63
11			68
12			41

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For substrates bearing an electron-withdrawing R² group, no iodination occurred but oxidative annulation proceeded smoothly (Table 3, entries 1–5). Electron-withdrawing R² groups such as halogens, NO₂ and CF₃ were all tolerated and the non-iodinated products were all obtained in great yields (Table 3, entries 1–4), including one case where there was an electron-donating –CH₃ group on the A ring (Table 3, entry 5). The dibenzylic substituted tertiary amine 1r was also accessible and afforded the annulated product 2r in a relatively low yield of 43%. To our disappointment, for N-methyl amines bearing protecting groups such as Ac or Ts, no desired reaction took place (not shown).

Table 3 Oxidative annulation of tertiary amines^a

Entry	Substrate	Product	Yield^b (%)
a All reactions were carried out with 1 (0.4 mmol) in the presence of NIS (2.0 equiv.) and Na2CO3 (2.0 equiv.) in CH3CN (c = 0.05 M).b Isolated yield.c The reaction mixture was heated to 60 °C.
1			91
2			85
3^c			81
4^c			73
5			75
6			43

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Attempts to expand the carboxylic acid functional group to a larger range of nucleophilic moieties for the same transformation turned out to be unsuccessful. As shown in Scheme 2, subjecting 3, where the carboxylic acid in 1a was replaced by an NH–OMe amide, to the same reaction under optimized conditions, a high yield of 1,4-benzodiazepine derivative 4²⁰ was afforded instead. When the acid moiety was switched to an alcohol, no annulation took place but only para iodination which yielded amine 6 as the final product.

Scheme 2 Further investigation of scope of the reaction.

To gain more insight into the reaction mechanism, some control experiments were carried out. Treatment of the cyclized compound 2a′ with NIS in the presence of Na₂CO₃ under the optimized conditions led to a completely recovery of the starting material, and this suggested that iodination occurs prior to cyclization. The hypothesis was supported by the successful conversion of substrates 1m and 1n to the corresponding annulated product in 91% and 85% yields, respectively. Another control experiment was to carry out the experiment in the presence of 2 equiv. of a radical scavenger TEMPO. The unaffected high yield of the expected product excluded a radical process during the transformation.

On the basis of all the experiment results, we postulate a mechanistic pathway. Illustrated in Scheme 3, deprotonation of the acid resulted in the benzoate A, which underwent a typical electrophilic substitution reaction of aromatic ring to form C. Oxidation with the second equiv. of NIS resulted in the formation ammonium D which was subsequently transformed into the corresponding iminum intermediate E. Finally, intramolecular annulation led to the ultimate formation of product 2a. The regioselectivity of preferred para-substitution can be straightforwardly explained by the structure of the cationic B, which carries the electronic advantage over the meta-substituted counterparts and the stereo advantage over the ortho-substituted one. Finally, the electrophilic substitution mechanism for the iodination effectively explains the negative effect of an electron-withdrawing R² group on the formation of the iodinated product, as well as the observation of multiple substitutions with an electron-donating R² group.

Scheme 3 Proposed mechanism.

Conclusions

In conclusion, we have developed a novel NIS-mediated intramolecular α-functionalization reaction of tertiary amines via C–O bond formation to access synthetically and biologically interesting iodinated or non-iodinated 1,2-dihydro-(4H)-3,1-benzoxazin-4-one derivatives. Besides its novelty as a CDC reaction, the one-pot procedure, mild reaction conditions, and transition metal-free feature render it a useful alternative to the existing methods for the preparation of benzoxazin-4-one derivatives.

Experimental section

All reactions were carried out at room temperature under air unless otherwise noted. ¹H (600 MHz or 400 MHz) and ¹³C (150 MHz or 100 MHz) NMR spectra were recorded at 25 °C. The chemical shifts (δ) are reported in ppm with reference to TMS (0 ppm) and coupling constants (J) are given in Hz. High resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro spectro meter. Melting points were determined with a Micro Melting point apparatus without corrections. Organic solutions were concentrated by rotary evaporation below 40 °C in vacuum.

General procedure for the synthesis of substrate 1

To a solution of 2-iodobenzoic acid or 2-bromobenzoic acid derivative (10 mmol) in 1,4-dioxane (c = 0.3 M) was added Cu₂O (0.5 equiv.), N-methylmorpholine (1.5 equiv.), and aniline (1.5 equiv.) or its derivative. The resulting mixture was refluxed under N₂ until the completion of the reaction. The mixture was filtered, and aqueous KOH solution (0.5 N, 2.5 equiv.) was added to the residue and filtered. The filtrate was extracted with DCM to remove the impurities and the pH value of the water phase was adjusted to 4 using conc. HCl. The solid generated was filtered and dried. And the crude product was used directly without further purification.

To a solution of the crude product in DMF (c = 0.3 M) was slowly added NaH (2.5 equiv.) at 0 °C. And the mixture was stirred for 30 min, followed by the addition of methyl iodide (4.0 equiv.) or the corresponding haloalkane. The reaction was allowed to stir at room temperature overnight. The mixture was poured into water and extracted with EA (3 × 80 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give the corresponding esters.

To a solution of the ester in MeOH/H₂O (5 : 1, c = 0.6 M) was added KOH (2.0 equiv.), and the resulting mixture was allowed to heat to reflux. Upon completion monitored by TLC, the mixture was concentrated and poured into water. The solution was acidified with conc. HCl, and the solid was filtered to give the desired product. If no precipitation, the reaction mixture was extracted with EA (3 × 60 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column chromatography on silica gel to give the product.

Known substrates 1a,²² le,^7c 1f,^7c 1g,²³ 1h,²¹ 1k,²⁰ 1m–q,^7c 1r,^7c 3²⁰ and 5^7c were prepared according to the literature procedures.

5-Methyl-2-(methyl(phenyl)amino)benzoic acid (1b). Yellowish solid (1.08 g), yield: 45% (over three steps), mp. 84–86 °C. ¹H NMR (600 MHz, CDCl₃) δ 14.10 (s, 1H), 8.18 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.33–7.25 (m, 2H), 7.10–7.04 (m, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 7.5 Hz, 2H), 3.19 (s, 3H), 2.42 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.4, 148.3, 148.2, 138.1, 135.8, 132.6, 129.3, 126.7, 125.6, 123.1, 118.6, 42.0, 21.0. HRMS (ESI) calcd for C₁₅H₁₆NO₂⁺ [M + H⁺] 242.1176, found 242.1171.

5-Methoxy-2-(methyl(phenyl)amino)benzoic acid (1c). Yellow solid (1.36 g), yield: 53% (over three steps), mp. 123–125 °C. ¹H NMR (600 MHz, CDCl₃) δ 14.55 (brs, 1H), 7.84 (d, J = 2.9 Hz, 1H), 7.29 (t, J = 7.9 Hz, 2H), 7.11 (dd, J = 8.8, 3.0 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.1 Hz, 2H), 3.88 (s, 3H), 3.20 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.2, 158.6, 148.4, 143.4, 129.3, 128.0, 127.1, 123.1, 122.5, 118.5, 114.5, 55.9, 42.0. HRMS (ESI) calcd for C₁₅H₁₆NO₃⁺ [M + H⁺] 258.1125, found 258.1123.

3,4,5-Trimethoxy-2-(methyl(phenyl)amino)benzoic acid (1d). Brown solid (0.98 g), yield: 31% (over three steps), mp. 117–119 °C. ¹H NMR (600 MHz, CDCl₃) δ 14.58 (brs, 1H), 7.67 (s, 1H), 7.32–7.26 (m, 2H), 7.03 (t, J = 7.1 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.26 (s, 3H), 3.23 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.1, 153.1, 150.9, 148.8, 147.7, 136.1, 129.1, 122.5, 121.8, 117.2, 108.7, 60.8, 60.1, 56.2, 39.5. HRMS (ESI) calcd for C₁₇H₂₀NO₅⁺ [M + H⁺] 318.1336, found 318.1335.

2-(Hexyl(phenyl)amino)benzoic acid (1i). Yellow oil (1.1 g), yield: 37% (over three steps). ¹H NMR (600 MHz, CDCl₃) δ 14.82 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.13 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.1 Hz, 1H), 6.97 (d, J = 7.8 Hz, 2H), 3.52 (s, 2H), 1.65–1.52 (m, 2H), 1.36–1.21 (m, 6H), 0.91–0.79 (d, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.4, 149.2, 147.6, 134.7, 132.3, 129.4, 127.8, 127.5, 127.1, 123.7, 119.9, 54.6, 31.4, 26.9, 26.8, 22.5, 14.0. HRMS (ESI) calcd for C₁₉H₂₄NO₂⁺ [M + H⁺] 298.1802, found 298.1805.

2-(Methyl(o-tolyl)amino)benzoic acid (1j). Pale white solid (1.04 g), yield: 43% (over three steps), mp. 108–110 °C. ¹H NMR (600 MHz, CDCl₃) δ 14.53 (brs, 1H), 8.30 (dd, J = 7.8, 1.3 Hz, 1H), 7.45 (td, J = 7.9, 1.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.36–7.30 (m, 2H), 7.18–7.13 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 3.20 (s, 3H), 1.93 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.6, 151.5, 146.4, 134.5, 132.7, 132.5, 132.0, 127.0, 126.4, 125.5, 124.7, 124.5, 120.4, 45.1, 19.0. HRMS (ESI) calcd for C₁₅H₁₆NO₂⁺ [M + H⁺] 242.1176, found 242.1172.

2-((3,5-Dimethoxyphenyl) (methyl)amino)benzoic acid (1l). Yellow solid (1.32 g), yield: 46% (over three steps), mp. 88–90 °C. ¹H NMR (600 MHz, CDCl₃) δ 14.15 (brs, 1H), 8.35 (d, J = 6.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 6.04 (s, 2H), 3.72 (s, 6H), 3.18 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 166.1, 161.4, 150.4, 150.2, 135.0, 132.5, 128.0, 127.1, 126.0, 100.0, 97.8, 94.4, 55.4, 42.1. HRMS (ESI) calcd for C₁₆H₁₈NO₄⁺ [M + H⁺] 288.1230, found 288.1231.

General procedure for the synthesis of compounds 2, 4 and 6

To a solution of N-alkyl-N-aryl anthranilic acids 1 (0.4 mmol) in CH₃CN (8 mL) was added NIS (1.2 mmol) followed by the addition of Na₂CO₃ (0.8 mmol) at ambient temperature. The reaction mixture was maintained at room temperature and monitored by TLC. Upon completion, the mixture was poured into sat. aqueous solution of Na₂S₂O₃ (30 mL) and extracted by ethyl acetate (3 × 50 mL). The combined organic phase was washed with brine (1 × 80 mL). Dried over anhydrous Na₂SO₄, evaporation of the solvent under reduced pressure and purification of the crude residue by flash column chromatography on silica gel (EA/PE with 5‰TEA) afforded the desired products. For the synthesis of compounds 2m–r, 2.0 equiv. of NIS was used following the similar procedure mentioned above.

4-(4-Iodophenyl)isochroman-1-one (2a). White solid (131 mg), yield: 93%, mp. 129–131 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.09 (dd, J = 7.9, 1.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.50–7.44 (m, 1H), 7.17–7.11 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 5.52 (s, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 163.5, 146.0, 143.8, 138.8, 134.8, 131.1, 124.7, 123.1, 118.5, 117.3, 88.9, 80.5. HRMS (ESI) calcd for C₁₄H₁₁¹²⁷INO₂⁺ [M + H⁺] 351.9829, found 351.9823.

1-(4-Iodophenyl)-6-methyl-1H-benzo[d][1,3]oxazin-4(2H)-one (2b). White solid (109.5 mg), yield: 75%, mp. 150–152 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.89 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.30 (dd, J = 8.3, 1.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 5.51 (s, 2H), 2.37 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 163.8, 144.4, 143.5, 138.7, 136.0, 133.4, 130.8, 124.2, 119.2, 117.7, 88.3, 80.7, 20.7. HRMS (ESI) calcd for C₁₅H₁₃¹²⁷INO₂⁺ [M + H⁺] 365.9985, found 365.9985.

1-(4-Iodophenyl)-6-methoxy-1H-benzo[d][1,3]oxazin-4(2H)-one (2c). White solid (137.1 mg), yield: 90%, mp. 141–143 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 2.9 Hz, 1H), 7.11 (dd, J = 8.9, 2.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 5.54 (s, 2H), 3.86 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 163.7, 156.1, 145.0, 139.2, 138.6, 124.0, 123.8, 121.9, 119.3, 111.8, 87.9, 81.2, 55.9. HRMS (ESI) calcd for C₁₅H₁₃¹²⁷INO₃⁺ [M + H⁺] 381.9935, found 381.9937.

1-(4-Iodophenyl)-6,7,8-trimethoxy-1H-benzo[d][1,3]oxazin-4(2H)-one (2d). Brown solid (135.8 mg), yield: 77%, mp. 57–59 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.60 (d, J = 8.7 Hz, 2H), 7.38 (s, 1H), 6.75 (d, J = 8.7 Hz, 2H), 5.54 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.63 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 163.6, 151.5, 148.3, 145.8, 145.5, 138.2, 133.2, 123.5, 115.7, 107.0, 88.0, 82.9, 61.2, 60.5, 56.3. HRMS (ESI) calcd for C₁₇H₁₇¹²⁷INO₅⁺ [M + H⁺] 442.0146, found 442.0140.

7-Chloro-1-(4-iodophenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2e). White solid (124.7 mg), yield: 81%, mp. 152–154 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.03–7.98 (m, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J = 8.5 Hz, 2H), 5.50 (s, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 162.8, 147.1, 142.7, 141.5, 139.1, 132.5, 125.3, 123.3, 117.5, 114.8, 90.1, 80.3. HRMS (ESI) calcd for C₁₄H₁₀³⁵Cl¹²⁷INO₂⁺ [M + H⁺] 385.9439, found 385.9435.

6-Fluoro-1-(4-iodophenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2f). Pale solid (112.1 mg), yield: 76%, mp. 126–128 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.76 (dd, J = 7.9, 2.3 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.23 (td, J = 8.4, 3.0 Hz, 1H), 7.04 (dd, J = 9.0, 4.3 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 5.53 (s, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 162.6, 158.4 (d, J_C–F = 243.7 Hz), 144.2, 142.2 (d, J_C–F = 2.2 Hz) 138.9, 124.4, 122.8 (d, J_C–F = 23.9 Hz), 121.3 (d, J_C–F = 7.5 Hz), 119.0 (d, J_C–F = 7.7 Hz), 116.5 (d, J_C–F = 23.5 Hz), 88.9, 81.0. HRMS (ESI) calcd for C₁₄H₁₀F¹²⁷INO₂⁺ [M + H+] 369.9735, found 369.9731.

1-(4-Iodophenyl)-2-phenyl-1H-benzo[d][1,3]oxazin-4(2H)-one (2g). White solid (162.3 mg), yield: 95%, mp. 141–143 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.92 (dd, J = 7.9, 1.0 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.49–7.46 (m, 2H), 7.46–7.41 (m, 1H), 7.34–7.28 (m, 3H), 7.09 (d, J = 8.3 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.72 (s, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 162.6, 144.6, 144.4, 138.8, 137.1, 135.1, 130.7, 129.2, 128.8, 127.2, 124.9, 122.6, 119.2, 117.9, 90.9, 88.8. HRMS (ESI) calcd for C₂₀H₁₅¹²⁷INO₂⁺ [M + H⁺] 428.0142, found 428.0145.

1-(4-Iodophenyl)-2-methyl-1H-benzo[d][1,3]oxazin-4(2H)-one (2h). 88% yield based on crude NMR within mesitylene as internal standard. ¹H NMR (600 MHz, CDCl₃) δ 7.97 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.3 Hz, 1H), 5.69 (dd, J = 12.0, 6.0 Hz, 1H), 1.49 (d, J = 6.0 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 163.7, 146.6, 142.4, 139.0, 135.1, 130.7, 128.5, 121.9, 118.4, 116.1, 91.2, 87.4, 19.9. HRMS (ESI) calcd for C₁₅H₁₃¹²⁷INO₂⁺ [M + H⁺] 365.9985, found 365.9981.

1-(4-Iodophenyl)-2-pentyl-1H-benzo[d][1,3]oxazin-4(2H)-one (2i). 87% yield based on crude NMR within mesitylene as internal standard. ¹H NMR (600 MHz, CDCl₃) δ 8.06 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.2 Hz, 1H), 5.60 (t, J = 6.7 Hz, 1H), 2.0–1.9 (m, 1H), 1.86–1.79 (m, 1H), 1.60–1.54 (m, 1H), 1.51–1.45 (m, 1H), 1.32–1.26 (m, 3H), 0.83–0.89 (m, 5H). ¹³C NMR (150 MHz, CDCl₃) δ 163.2, 145.3, 144.3, 138.8, 135.0, 130.5, 126.7, 122.6, 119.8, 117.4, 91.7, 89.8, 33.3, 31.2, 24.6, 22.5, 13.9. HRMS (ESI) calcd for C₁₉H₂₁¹²⁷INO₂⁺ [M + H⁺] 422.0611, found 422.0610.

1-(2,4-Diiodo-6-methylphenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2j). White solid (123.7 mg), yield: 63%, mp. 147–149 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.36 (d, J = 1.9 Hz, 1H), 7.71 (s, 1H), 7.63 (dd, J = 8.7, 2.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 8.6 Hz, 1H), 5.37 (s, 2H), 2.19 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 162.4, 147.1, 143.6, 140.8, 140.2, 139.6, 138.2, 136.9, 128.9, 117.8, 116.3, 93.3, 82.9, 79.8, 17.9. HRMS (ESI) calcd for C₁₅H₁₂¹²⁷I₂NO₂⁺ [M + H⁺] 491.8952, found 491.8956.

1-(2,4-Diiodo-5-methoxyphenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2k). White solid (137.9 mg), yield: 68%, mp. 166–168 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.29 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.48–7.40 (m, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.59 (s, 1H), 5.55 (s, 1H), 5.38 (s, 1H), 3.76 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 163.9, 159.8, 148.5, 147.2, 146.8, 135.2, 131.1, 122.4, 117.7, 116.0, 111.2, 87.5, 86.2, 80.3, 56.8. HRMS (ESI) calcd for C₁₅H₁₂¹²⁷I₂NO₃⁺ [M + H⁺] 507.8901, found 507.8906.

1-(2,4-Diiodo-3,5-dimethoxyphenyl)-1H-benzo[d][1,3]oxa-zin-4(2H)-one (2l). Brown oil (88 mg), yield: 41%. ¹H NMR (600 MHz, CDCl₃) δ 8.10 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.45 (s, 1H), 5.59 (s, 1H), 5.39 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 3.77 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 164.0, 161.5, 160.7, 146.9, 135.2, 131.1, 122.4, 117.9, 116.0, 107.2, 85.2, 82.7, 80.5, 60.8, 57.1. HRMS (ESI) calcd for C₁₆H₁₄¹²⁷I₂NO₄⁺ [M + H⁺] 537.9007, found 537.9009.

1-(4-Fluorophenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2m)^7c. Yellow solid (88.5 mg), yield: 91%, mp. 76–78 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.08 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.17–7.03 (m, 5H), 6.93 (d, J = 8.3 Hz, 1H), 5.51 (s, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 163.9, 160.3 (d, J_C–F = 244.4 Hz), 147.0, 139.9, 135.0, 131.1, 125.5 (d, J_C–F = 8.4 Hz), 122.5, 117.9, 116.7 (d, J_C–F = 22.6 Hz), 116.5, 80.9.

1-(4-Bromophenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2n)^7c. Yellow solid (103 mg), yield: 85%, mp. 110–112 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.09 (d, J = 7.7 Hz, 1H), 7.54–7.44 (m, 3H), 7.15 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.0 Hz, 3H), 5.54 (s, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 163.7, 146.1, 143.0, 135.0, 132.9, 131.1, 124.5, 123.1, 118.5, 118.3, 117.2, 80.6.

1-(3-(Trifluoromethyl)phenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2o)^7c. Following the general procedure, the reaction mixture was heated to 60 °C. 2o was obtained as pale solid (99.6 mg), yield: 81%, mp. 68–69 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 7.1 Hz, 1H), 7.51 (t, J = 8.4 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.60 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 163.5, 145.7, 144.7, 135.0, 132.4 (q, J_C–F = 32.4 Hz), 131.2, 130.4, 125.7, 123.6, 123.5 (q, J_C–F = 270.9 Hz), 121.8 (q, J_C–F = 3.7 Hz), 119.2 (q, J_C–F = 3.7 Hz), 118.7, 117.7, 80.6.

1-(3-Nitrophenyl)-1H-benzo[d][1,3]oxazin-4(2H)-one (2p)^7c. Following the general procedure, the reaction mixture was heated to 60 °C. 2p was obtained as a yellow solid (79 mg), yield: 73%, mp. 131–133 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.14 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.48 (d, J = 7.5 Hz, 1H), 7.29–7.26 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 5.66 (s, 2H). ¹³C NMR (150 MHz, CDCl₃) δ 163.3, 149.2, 145.5, 144.9, 135.2, 131.4, 130.7, 127.6, 124.4, 119.4, 119.2, 118.2, 116.6, 80.5.

1-(4-Chlorophenyl)-6-methyl-1H-benzo[d][1,3]oxazin-4(2H)-one (2q)^7c. White solid (82 mg), yield: 75%, mp. 109–111 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.89 (s, 1H), 7.35–7.29 (m, 3H), 7.04 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.3 Hz, 1H), 5.52 (s, 2H), 2.37 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 164.0, 143.7, 143.2, 136.1, 133.3, 130.7, 130.2, 129.8, 123.8, 119.1, 117.5, 80.9, 20.8.

1-Benzyl-2-phenyl-1H-benzo[d][1,3]oxazin-4(2H)-one (2r)^7c. Yellow oil (54 mg), yield: 43%. ¹H NMR (600 MHz, CDCl₃) δ 7.97 (dd, J = 7.8, 1.3 Hz, 1H), 7.46–7.40 (m, 3H), 7.34–7.29 (m, 5H), 7.28–7.24 (m, 3H), 6.95 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.33 (s, 1H), 4.63 (d, J = 16.1 Hz, 1H), 4.41 (d, J = 16.1 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 163.9, 148.3, 136.9, 136.0, 135.4, 130.9, 129.4, 128.8, 128.9, 127.9, 127.5, 127.2, 120.8, 116.4, 116.0, 90.5, 53.3.

10-Methoxy-5-methyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (4)²¹. White solid (89 mg), yield: 88%, mp. 125–127 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.90 (dd, J = 7.6, 1.1 Hz, 1H), 7.49 (dd, J = 8.3, 1.4 Hz, 1H), 7.41 (td, J = 8.1, 1.6 Hz, 1H), 7.20–7.16 (m, 1H), 7.15–7.03 (m, 4H), 3.87 (s, 3H), 3.35 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 165.0, 153.0, 145.8, 133.9, 132.8, 132.1, 126.4, 125.6, 124.4, 123.1, 121.1, 118.5, 116.7, 62.3, 37.7.

(2-((4-Iodophenyl) (methyl)amino)phenyl)methanol (6). Yellow oil (96.3 mg), yield: 71%. ¹H NMR (600 MHz, CDCl₃) δ 7.53 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 7.35 (td, J = 7.5, 1.7 Hz, 1H), 7.31 (td, J = 7.4, 1.3 Hz, 1H), 7.12–7.09 (m, 1H), 6.32 (t, J = 6.0 Hz, 2H), 4.54 (s, 2H), 3.18 (s, 3H), 2.03 (s, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 149.1, 145.6, 139.0, 137.7, 129.5, 129.1, 128.1, 127.3, 115.7, 79.0, 61.8, 39.9. HRMS (ESI) calcd for C₁₄H₁₅¹²⁷INO⁺ [M + H⁺] 340.0193, found 340.0195.

Acknowledgements

We acknowledge the National Science Foundation of China (#21472136) and the National Basic Research Project (2014CB932201) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: NMR spectra for all new compounds, See DOI: 10.1039/c5ra03882k

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