A convenient method to construct (Z)-oxazines via 6-exo-dig iodocyclization and synthesis of indolin-3-one

Article abstract of DOI:10.1039/c3ob41272e

An efficient regio-, stereo- and chemo-specific synthesis of 1,3-benzoxazines via 6-exo-dig cyclization to afford the Z-isomer is reported. The structure and connectivity were confirmed unambiguously on the basis of ¹H NMR, NOESY, and ORTEP. Furthermore, DFT studies revealed that the Z-isomer was more stable than the E-isomer. Iodine substituted 1,3-benzoxazines were very useful precursors for cross coupling reactions. Suzuki reaction was carried out successfully and the resulting product was transformed to 1-(4-nitrobenzoyl)-2,2-diphenylindolin-3-one in the presence of a Lewis acid.

Full text of DOI:10.1039/c3ob41272e

Organic &
Biomolecular Chemistry
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A convenient method to construct (Z)-oxazines via
6-exo-dig iodocyclization and synthesis of
indolin-3-one†
Cite this: Org. Biomol. Chem., 2013, 11,
6520
Jaya Kishore Vandavasi,‡a Kung-Kai Kuo,‡b Wan-Ping Hu,c Ho-Chanu Shen,a
Wei-Sheng Loa and Jeh-Jeng Wang*a
An efficient regio-, stereo- and chemo-specific synthesis of 1,3-benzoxazines via 6-exo-dig cyclization to
afford the Z-isomer is reported. The structure and connectivity were confirmed unambiguously on the
basis of 1H NMR, NOESY, and ORTEP. Furthermore, DFT studies revealed that the Z-isomer was more
stable than the E-isomer. Iodine substituted 1,3-benzoxazines were very useful precursors for cross coup-
ling reactions. Suzuki reaction was carried out successfully and the resulting product was transformed to
1-(4-nitrobenzoyl)-2,2-diphenylindolin-3-one in the presence of a Lewis acid.
Received 20th June 2013,
Accepted 26th July 2013
DOI: 10.1039/c3ob41272e
www.rsc.org/obc
In 2011, Saito and co-workers successfully produced 4-alky-
Introduction
lidene-4H-3,1-benzoxazines, eqn (1),10 via 6-exo-dig cyclization
Heterocyclic compounds1 are valuable structural motifs of N-acyl-o-alkynyl anilines. In our previous work we reported
present in many natural products and biologically active mole- an efficient method for the synthesis of 1,3-benzoxazine
cules.2 Among them, nitrogen and oxygen containing derivatives in the presence of iodine, eqn (2).21 Preceding
fused aryl heterocycles occur widely in biologically active results lack iodine substituents, which would be helpful
compounds.2–4 In particular, oxazines5 are generally found in for further diversifications. Considering the importance of
many biologically important molecules6 and their substructure iodine substituted 1,3-oxazines and the drawbacks of the exist-
is a component of naturally occurring active compounds.7 In ing methods, the perusal and development of an alternative
the last decade, great advancements have been made in the method for constructing such an appropriate design is still
synthesis of 1,3-benzoxazines8–14 via halocyclization.15–18 attractive.
However, these methods have some limitations, including
Iodine substituted 1,3-benzoxazines were very useful precur-
harsh conditions, prolonged reaction times and poor selecti- sors for cross coupling reactions. In this aspect, we performed
vity. In this class, the most adorable way has been intramolecu- a Suzuki reaction to afford the desired product from an iodo
lar nucleophilic attack of heteroatoms on C–C multiple bonds derivative. Further, we developed a new strategy to construct
such as alkynes,19–21 alkenes22 and allenes,23 which is one of indolin-3-ones,27–34 in the presence of a Lewis acid as a cata-
the most powerful alterations. Halocyclization of alkyne onto lyst, from compound 5a. Indolin-3-ones also have an impor-
amide involves various challenges such as (i) regioselectivity: tant function in biological and pharmaceutical activities.
nucleophile attack on alkyne follows two approaches such as
exo- or endo-dig cyclization,24 (ii) chemoselectivity: competition
between oxygen and nitrogen as nucleophiles,25 and (iii)
stereospecificity: to obtain
a single geometrical isomer
ð1Þ
ð2Þ
(E or Z).26
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung, Taiwan. E-mail: jjwang@kmu.edu.tw
bDepartment of Surgery, School of Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
cDepartment of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
†Electronic supplementary information (ESI) available. CCDC 834780, 834782,
834785, 834787, 834788, 834789, 837880, 951676 and 951677. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41272e
‡Equally contributed.
ð3Þ
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Table 2 Iodine mediated regio- and stereoselective cyclizationa,b
Recently, we have successfully synthesized a series of oxaza
heterocycles in the presence of a base,19 a Lewis acid20 and
iodine, eqn (2).21 Encouraged by the above results and our
ongoing work on the synthesis of heterocycles by electrophilic
cyclization of alkynes, herein we report a novel synthetic
pathway to synthesize the (Z)-4-(iodo-methylene)-2-aryl-4H-
benzo[d]-[1,3]oxazines, eqn (3).
Results and discussion
In the preliminary investigation, we screened the reaction of
2-alkylidene benzamides
1 in the presence of iodine
(3.0 equiv.), NaHCO3 and toluene at 120 °C (Table 1, entry 1).
Under these conditions the chemoselectivity was at a moderate
level as compound 2 (60%) and compound 3 (24%) yields
(Table 1, entry 1) and the same result was observed in nitro-
methane as a solvent (Table 1, entry 2). Surprisingly high
chemoselectivity was observed in THF and CH3CN, with traces
of compound 3 (Table 1, entries 3 and 5). In acetone, the reac-
tion performance to afford the desired compound was very low
(Table 1, entry 4). With halogenated solvents, the chemo-
selectivity was enriched with 75–80% yield of compound 2 and
11–18% yield of compound 3 (Table 1, entries 6 and 7). In a
polar solvent like DMF, the reaction yield was low (Table 1,
entry 8) and, in terms of protic solvents, the reaction yield was
very low in ethanol (Table 1, entry 10) and cyclization was not
successful in methanol (Table 1, entry 9). Subsequently, some
Table 1 Optimization studiesa,b,c,g
a Stereochemistry was determined on the basis of 1H NMR. b Isolated
yields. c Traces of E-isomer were observed by 1H NMR.
other bases were also evaluated using CH3CN as a solvent;
among them NaHCO3 resulted well (Table 1, entry 18).
Notably, the yield of compound 2 was high in the presence of
I2 (3 equiv.), NaHCO3 (3 equiv.) and CH3CN at 28 °C for 6 h,
which was thus found to be the optimum reaction condition
(Table 1, entry 18).
The scope and generality of this transformation with other
2-alkylidene benzamides were investigated (Table 2). Reactions
were well tolerated with electron-withdrawing and electron-
donating groups on benzene. Z-Isomer was exclusively
obtained in each case without any trace amount of E-isomer,
even when the reaction was performed with aryl or alkyl substi-
tuent (R3). The structures of compounds 2c and 2j were con-
firmed using the ORTEP diagram (Fig. 1).
Entry Solvent
Temp. [°C] Time [h] I2 [eq.] 2 [%] 3 [%]
1
2
3
Toluene 120
MeNO2
THF
24
24
24
24
24
24
24
24
24
24
6
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
5
—
3
60
60
90
30
92
75
80
50
0
30
10
20
90
53
71
91
0
24
21
Traces
12
Traces
18
11
8
0
5
120
80
80
80
60
4
5
6
7
Acetone
MeCN
CH2Cl2
DCE
60
8
9
DMF
MeOH
EtOH
120
100
100
80
10
11d
12e
13f
14
15
16
17
18
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Traces
16
80
6
6
6
6
6
6
80
80
80
80
Traces
Traces
Traces
Traces
0
Stereochemistry was confirmed on the basis of 1H NMR,
NOESY and single crystal X-ray. The two protons are
mentioned in Fig. 2 as the NOE effect. By considering all these
facts, the stereochemistry confirmed that the Z-form was
obtained exclusively, and DFT M06-2x/6-31G* calculations
revealed that the Z-form is more stable than the E-form by
80
28
6
96
0
a Reaction conditions: compound 1 (1 equiv.), iodine, NaHCO3 (3
equiv.) and solvent (5 mL). b Stereochemistry was determined on the
basis of 1H NMR. c Isolated yields. d K2CO3. e Cs2CO3. f Na2CO3.
g Compound 4 was not observed.
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Fig. 3 ORTEP diagram of compounds 5b and 6a.
Fig. 1 ORTEP diagram of compounds 2c and 2j.
presence of a Lewis acid such as FeCl3 also transformed to
1-(4-nitrobenzoyl)-2,2-diphenylindolin-3-one.
Experimental
1
Experimental details: Melting points are uncorrected. H NMR
and 13C NMR spectra were recorded on a 400 MHz instrument
using CDCl3 as a solvent. 1H NMR chemical shifts are refer-
enced to TMS (0 ppm) or CDCl3 (7.26 ppm). 13C NMR was
referenced to CDCl3 (77.0 ppm). Multiplicities were denoted as
s, d, t, and q. Mass spectra and high resolution mass spectra
(HRMS) were measured using the electron-impact (EI, 70 eV)
technique. Flash column chromatography was carried out over
silica gel 60 (230–400 mesh).
Fig. 2 Stereochemistry assignment based on 1H NMR and NOESY of com-
pound 2 (A) and density functional theory M06-2X/6-31G* optimized structures
of Z- and E-form (B and C).
Compound 1
Compound
protocols.21
1 was synthesized using previously reported
General procedure for the synthesis of iodomethylene
benzoxazines 2a–2o
Scheme 1 Suzuki reaction and rearrangement in the presence of FeCl3.
A mixture of the corresponding compound 1 (1.0 mmol),
iodine (3.0 mmol) and NaHCO3 (3.0 mmol) was taken in dry
acetonitrile (10.0 mL) in a flask under an argon atmosphere
and stirred for 6 h at room temperature. The reaction was
monitored by TLC analysis. The formed product was extracted
with ethyl acetate by washing with water, saturated Na2S2O3
solution and brine. The organic layer was separated and con-
centrated under reduced pressure. The crude residue obtained
was chromatographed over silica gel using an ethyl acetate–
hexane mixture as an eluent to obtain title compound 2.
3.5 kcal mol−1 (Fig. 2B and C) and the H–H distance is 3.224 Å
(Fig. 2B).
Further, to study the applications of the desired compound
2, we performed the Suzuki reaction successfully with high
yields to afford compound 5. Interestingly, compound 5a
underwent further transformation in the presence of a Lewis
acid such as FeCl3 to afford compound 6a in 46% yield
(Scheme 1). The structures of compounds 5b and 6a were con-
firmed using the ORTEP diagram (Fig. 3).
4-(Iodo(phenyl)methylene)-2-phenyl-4H-benzo[d][1,3]oxazine
(2a). The title compound 2a was prepared according to the
general procedure and purified by column chromatography to
obtain a yellow solid (96%). Mp = 102–104 °C; 1H NMR (CDCl3,
Conclusion
The reaction was fine tuned with a base to afford the (Z)-4- 400 MHz): δ 8.45 (d, J = 5.6 Hz, 2H), 7.58–7.31 (m, 9H), 7.26
(iodo-methylene)-2-aryl-4H-benzo[d]-[1,3]oxazines in the pres- (td, J = 7.6 Hz and 1.4 Hz, 1H), 6.81 (td, J = 7.6 Hz and 1.4 Hz,
ence of I2 via 6-exo-dig iodocyclization with high stereo-, regio- 1H), 6.56 (dd, J = 8.4 Hz and 1.2 Hz, 1H). 13C NMR (CDCl3,
and chemoselectivity. Stereochemistry of Z-isomer was con- 100 MHz): δ 155.6, 145.4, 141.7, 140.4, 132.0, 130.6, 129.8,
1
firmed by H NMR, NOESY and ORTEP. The DFT calculations 129.3, 128.6, 128.4, 126.7, 126.2, 126.1, 120.2, 75.0. HRMS
M06-2x/6-31G* also revealed that the Z-form is more stable (ESI, m/z) for C21H15INO, calcd: 424.0198, found: 424.0200.
than the E-form by 3.5 kcal mol−1. Iodine substituted mole- Anal. calcd for: C21H14INO; C, 59.59; H, 3.33; N, 3.31; found:
cules have many applications in synthetic chemistry. We have C, 59.37; H, 3.33; N, 3.32.
succeeded with Suzuki reaction, which has afforded the
2-(4-Fluorophenyl)-4-(iodo(phenyl)methylene)-4H-benzo[d]-
desired product in high yields. The Suzuki product in the [1,3]oxazine (2b). The title compound 2b was prepared
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according to the general procedure and purified by column 129.7, 129.5, 129.3, 129.2, 129.1, 128.9, 128.6 (q, J = 16.7 Hz),
chromatography to obtain
a
yellow solid (76%). Mp
=
128.3, 126.5, 123.6 (q, J = 3.7 Hz), 120.5. HRMS (ESI, m/z) for
1
109–111 °C; H NMR (CDCl3, 400 MHz): δ 8.45 (d, J = 5.2 Hz, C22H13ClF3INO [(M + H)+] calcd: 525.9677, found: 525.9679.
2H), 7.41–7.15 (m, 9H), 6.80 (td, J = 8.4 Hz and 1.6 Hz, 1H), Anal. calcd for C22H12ClF3INO; C, 50.26; H, 2.30; N, 2.66;
6.55 (dd, J = 8.0 Hz and 1.2 Hz, 1H). 13C NMR (CDCl3, found: C, 50.20; H, 2.34; N, 2.66.
100 MHz): δ 166.5, 164.0, 154.7, 145.3, 141.6, 140.3, 132.8,
4-(Iodo(phenyl)methylene)-2-(4-nitrophenyl)-6-(trifluoromethyl)-
130.7, 130.6, 129.8, 129.3, 128.6, 126.8 (d, J = 31.0 Hz), 126.7, 4H-benzo[d][1,3]oxazine (2g). The title compound 2g was
126.3, 126.1, 120.1, 115.7, 115.5, 75.2. HRMS (ESI, m/z) for prepared according to the general procedure and purified by
C21H14FINO, calcd: 442.0104, found: 442.0101. Anal. calcd for column chromatography to obtain an orange solid (78%). Mp
C21H13FINO: C, 57.16; H, 2.97; N, 3.17; found: C, 57.15; = 172–174 °C. 1H NMR (CDCl3, 400 MHz): δ 8.61 (d, J = 9.2 Hz,
H, 3.07; N, 3.12.
2H), 8.37 (d, J = 9.2 Hz, 2H), 7.51–7.37 (m, 7H), 6.73 (s, 1H).
2-(4-Chlorophenyl)-4-(iodo(phenyl)methylene)-4H-benzo[d]- 13C NMR (CDCl3, 100 MHz): δ 155.2, 150.1, 143.9, 142.3, 140.3,
[1,3]oxazine (2c). The title compound 2c was prepared accord- 135.8, 129.7, 129.5, 129.4, 129.2, 127.3 (q, J = 3.8 Hz), 124.1
ing to the general procedure and purified by column chrom- (q, J = 270.0 Hz), 123.8 (q, J = 3.8 Hz), 123.7, 120.7, 78.1. HRMS
atography to obtain a yellow solid (74%). Mp = 151–153 °C; (ESI, m/z) for C22H13F3IN2O3, calcd: 536.9923, found: 536.9921.
1H NMR (CDCl3, 400 MHz): δ 8.37 (d, J = 8.8 Hz, 2H), 7.48 (d, Anal. calcd for: C22H12F3IN2O3; C, 49.28; H, 2.26; N, 5.22;
J = 8.8 Hz, 2H), 7.40 (d, J = 4.8 Hz, 4H), 7.37–7.31 (m, 2H), 7.26 found: C, 49.37; H, 2.32; N, 5.28.
(td, J = 8.0 Hz and 1.2 Hz, 1H), 6.81 (td, J = 8.0 Hz and 1.2 Hz,
2-(4-Chlorophenyl)-4-(1-iodopentylidene)-4H-benzo[d][1,3]-
1H), 6.55 (d, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ oxazine (2h). The title compound 2h was prepared according
154.7, 145.2, 141.6, 140.2, 138.2, 130.6, 129.8, 129.7, 129.3, to the general procedure and purified by column chromato-
129.1, 128.8, 128.7, 126.9, 126.3, 126.2, 126.1, 75.3. HRMS graphy to obtain a yellow solid (75%). Mp = 80–82 °C; 1H NMR
(ESI, m/z) calcd for C21H14INO: 457.9809, found: 457.9807. (CDCl3, 400 MHz): δ 8.26 (d, J = 8.8 Hz, 2H), 7.40–7.29 (m, 5H),
Anal. calcd for: C21H13INO; C, 55.24; H, 2.91; N, 3.10; found: 7.19 (t, J = 8.0 Hz, 1H), 2.81 (t, J = 8.0 Hz, 2H), 1.72–1.64 (m,
C, 55.11; H, 2.86; N, 3.06.
2H), 1.45–1.35 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR
4-(Iodo(phenyl)methylene)-2-(4-nitrophenyl)-4H-benzo[d]- (CDCl3, 100 MHz): δ 155.7, 143.7, 140.9, 138.2, 130.5, 129.9,
[1,3]oxazine (2d). The title compound 2d was prepared accord- 129.2, 128.7, 127.0, 125.8, 125.3, 120.8, 87.1, 38.7, 32.0, 21.9,
ing to the general procedure and purified by column 13.9. HRMS (ESI, m/z) calcd for C19H18ClINO: 438.0122, found:
chromatography to obtain
247–249 °C; H NMR (CDCl3, 400 MHz): δ 8.61 (d, J = 8.8 Hz, 3.20; found: C, 52.09; H, 4.05; N, 3.13.
a
yellow solid (87%). Mp
=
438.0119. Anal. calcd for: C19H17ClINO; C, 52.14; H, 3.91; N,
1
2H), 8.37 (d, J = 8.8 Hz, 2H), 7.44–7.26 (m, 7H), 6.87 (td, J =
4-(1-Iodopentylidene)-2-(4-nitrophenyl)-4H-benzo[d][1,3]-
8.4 Hz and 1.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H). 13C NMR oxazine (2i). The title compound 2i was prepared according to
(CDCl3, 100 MHz): δ 154.6, 149.8, 145.0, 141.3, 139.7, 136.4, the general procedure and purified by column chromatography
130.8, 129.7, 129.4, 129.2, 128.8, 127.8, 126.6, 126.4, 123.6, to obtain a yellow solid (77%). Mp = 142–144 °C; 1H NMR
120.3, 76.0. HRMS (ESI, m/z) calcd for
C21H13IN2O3Na: (CDCl3, 400 MHz): δ 8.55 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.8 Hz,
490.9869, found: 490.9865. Anal. calcd for: C21H13IN2O3; 2H), 7.47–7.40 (m, 3H), 7.32 (t, J = 8.0 Hz, 1H), 2.89 (t, J =
C, 55.80; H, 2.84; N, 6.08; found: C, 53.87; H, 2.80; N, 5.98.
8.0 Hz, 2H), 1.79–1.72 (m, 2H), 1.53–1.44 (m, 2H), 1.01 (t, J =
4-(Iodo(phenyl)methylene)-2-phenyl-6-(trifluoromethyl)-4H- 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 154.5, 149.7, 143.4,
benzo[d][1,3]oxazine (2e). The title compound 2e was prepared 140.3, 136.4, 130.6, 129.3, 127.9, 126.3, 125.4, 123.5, 120.9,
according to the general procedure and purified by column 87.7, 38.7, 31.9, 21.9, 13.9. HRMS (ESI, m/z) calcd for
chromatography to obtain
a
yellow solid (81%). Mp
=
C19H18IN2O3: 449.0362, found: 449.0360. Anal. calcd for:
1
139–141 °C. H NMR (CDCl3, 400 MHz): δ 8.44 (d, J = 7.2 Hz, C19H17IN2O3; C, 50.91; H, 3.82; N, 6.25; found: C, 51.05;
2H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.46–7.35 H, 3.77; N, 6.25.
(m, 8H), 6.71 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 157.3,
4-(1-Iodopentylidene)-2-(4-(trifluoromethyl)phenyl)-4H-benzo-
144.4, 143.1, 132.6, 130.1, 129.6, 129.3, 129.2, 129.1, 128.7, [d][1,3]oxazine (2j). The title compound 2j was prepared
128.5, 128.3, 128.2, 127.0 (q, J = 3.8 Hz), 126.5, 123.6 (q, J = according to the general procedure and purified by column
3.8 Hz), 123.2 (q, J = 270.7 Hz), 120.5. HRMS (ESI, m/z) for chromatography to obtain a yellow solid (72%). Mp = 80–82 °C;
C22H14F3INO, calcd: 492.0067, found: 492.0069. Anal. calcd 1H NMR (CDCl3, 400 MHz): δ 8.50 (d, J = 8.8 Hz, 2H), 7.74 (d,
for: C22H13F3INO; C, 53.79; H, 2.67; N, 2.85; found: C, 53.74; J = 8.8 Hz, 2H), 7.45–7.38 (m, 3H), 7.29 (t, J = 8.0 Hz, 1H), 2.89
H, 2.68; N, 2.88.
(t, J = 8.0 Hz, 2H), 1.79–1.72 (m, 2H), 1.53–1.43 (m, 2H),
2-(4-Chlorophenyl)-4-(iodo(phenyl)methylene)-6-(trifluoro- 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ
methyl)-4H-benzo[d][1,3]oxazine (2f). The title compound 2f 155.2, 143.6, 140.6, 134.0, 133.2 (q, J = 33 Hz), 130.5, 128.8,
was prepared according to the general procedure and purified 127.4, 126.1, 125.3 (q, J = 3 Hz), 123.8 (q, J = 270.0 Hz), 120.9,
by column chromatography to obtain a yellow solid (66%). Mp 87.3, 38.4, 32.0, 22.0, 13.9. HRMS (ESI, m/z) calcd for
= 183–184 °C. 1H NMR (CDCl3, 400 MHz): δ 8.36 (d, J = 9.2 Hz, C20H18F3INO: 472.0385, found: 472.0383. Anal. calcd for:
2H), 7.51–7.34 (m, 9H), 6.70 (s, 1H). 13C NMR (CDCl3, C20H17F3INO; C, 50.97; H, 3.64; N, 2.97; found: C, 50.91;
100 MHz): δ 162.8, 156.4, 144.2, 142.9, 140.7, 139.0, 130.0, H, 3.68; N, 2.98.
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4-(Iodo(trimethylsilyl)methylene)-2-(4-nitrophenyl)-4H-benzo- 7.88–7.48 (m, 3H), 7.43–7.22 (m, 4H), 7.13–7.04 (m, 2H),
[d][1,3]oxazine (2k). The title compound 2k was prepared 6.93–6.89 (dt, J = 7.6 Hz and 1.2 Hz, 1H), 6.56 (dd, J = 8.8 Hz
according to the general procedure and purified by column and 1.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 163.8, 161.3,
chromatography to obtain a sticky yellow compound (85%). 1H 155.6, 145.8, 140.5, 137.9, 137.8, 132.0 (d, J = 15.9 Hz), 131.8,
NMR (CDCl3, 400 MHz): δ 8.62 (d, J = 8.8 Hz, 2H), 8.34 (dd, J = 130.8, 130.6, 128.46, 128.45, 126.8, 126.3, 126.1, 116.4 (d, J =
8.8 Hz, 2H), 7.55–7.29 (m, 4H), 0.38 (s, 9H). 13C NMR (CDCl3, 21.9 Hz), 73.5. HRMS (ESI, m/z) for C21H13FINO, calcd:
100 MHz): δ 152.5, 149.7, 140.9, 136.4, 131.9, 129.4, 128.6, 442.0113, found: 442.0110. Anal. calcd for C21H13FINO: C,
127.8, 127.3, 125.7, 123.6, 121.3, 82.4, 2.4. HRMS (ESI, m/z) 57.16; H, 2.97; N, 3.17; found: C, 57.19; H, 2.99; N, 3.16.
calcd for C18H18IN2O3Si [(M + H)+]: 465.0136, found: 465.0133.
Anal. calcd for: C18H17IN2O3Si; C, 46.56; H, 3.69; N, 6.03; oxazine (5a). A mixture of (Z)-4-(iodo(phenyl)methylene)-2-
found: C, 46.29; H, 3.58; N, 6.05. (4-nitrophenyl)-4H-benzo[d][1,3]oxazine (2d) (50 mg, 1.0 mmol),
4-(Diphenylmethylene)-2-(4-nitrophenyl)-4H-benzo[d][1,3]-
2-(4-Chlorophenyl)-4-((4-fluorophenyl)iodomethylene)-4H- Pd(PPh3)4 (12.33 mg, 10 mol%), Cs2CO3 (75.21 mg, 2 equiv.),
benzo[d][1,3]oxazine (2l). The title compound 2l was prepared and phenylboronic acid (15.51 mg, 1.2 equiv.) in acetonitrile–
according to the general procedure and purified by column toluene (1 : 1 mL) in a flask under an argon atmosphere was
chromatography to obtain a sticky yellow compound (83%). 1H stirred for 24 h at 80 °C. The reaction was monitored by TLC
NMR (CDCl3, 400 MHz): δ 8.37 (d, J = 8.4 Hz, 2H), 7.49 (d, J = analysis. After the reaction was complete, the mixture was
8.4 Hz, 2H), 7.41–7.26 (m, 4H), 7.10 (t, J = 8.4 Hz, 2H), 6.86 (dt, poured into ethyl acetate, filtered and evaporated under
J = 8.0 Hz, J = 1.2 Hz, 1H), 6.57 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H). vacuum. The crude mixture was carried to the next reaction,
13C NMR (CDCl3, 100 MHz): δ 163.8, 161.3, 154.7, 145.6, 140.3, crude yield (42.4 mg, 95%).
3
138.4, 137.7, 131 (d, JC–F = 8.3 Hz), 130.9, 129.7, 128.8, 127.1,
2-(4-Nitrophenyl)-4-(phenyl(pyridin-3-yl)methylene)-4H-benzo-
126.2 (d, 2JC–F = 18.9 Hz), 120.0, 116.5 (d, 1JC–F = 21.9 Hz), 73.9. [d][1,3]oxazine (5b). The title compound was prepared accord-
HRMS (ESI, m/z) for C22H13ONClFI [(M + H)+] calcd 475.9717, ing to the procedure for 5a and purified by column chromato-
found: 475.9709. Anal. calcd for C21H12ClFINO C, 53.02; H, graphy to obtain a red solid 5b (91%). Mp = 198–200 °C. 1H
2.54; N, 2.94; found: C, 52.67,H, 2.57; N 2.91.
NMR (CDCl3, 400 MHz): δ 8.79 (s, 1H), 8.56 (d, J = 4 Hz, 1H),
4-((4-Fluorophenyl)iodomethylene)-2-(4-(trifluoromethyl)- 8.20 (td, J = 9.2 Hz and 2.0 Hz, 2H), 8.02 (td, J = 8.8 Hz and
phenyl)-4H-benzo[d][1,3]oxazine (2m). The title compound 2.4 Hz, 2H), 7.64–7.61 (m, 1H), 7.40–7.27 (m, 8H), 6.93–6.89
2m was prepared according to the general procedure and puri- (m, 1H), 6.72 (dd, J = 8.0 Hz and 1.2 Hz, 1H). 13C NMR (CDCl3,
fied by column chromatography to obtain a sticky yellow com- 100 MHz): δ 153.4, 150.6, 149.5, 147.9, 142.3, 140.5, 138.9,
1
pound (82%). H NMR (CDCl3, 400 MHz): δ 8.53 (d, J = 8.0 Hz, 136.9, 136.5, 135.7, 130.7, 130.5, 129.4, 128.6, 128.2, 127.5,
2H), 7.77 (d, J = 8.4 Hz, 2H), 7.43–7.22 (m, 4H), 7.10 (t, J = 127.2, 126.5, 123.5, 123.1, 121.1, 118.1. HRMS (ESI, m/z) for
8.8 Hz, 2H), 6.89 (dt, J = 8.0 Hz and 1.2 Hz, 1H), 6.58 (dd, J = C26H18N3O3, calcd: 420.1348, found: 420.1350.
8.0 Hz and 1.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 163.9,
1-(4-Nitrobenzoyl)-2,2-diphenylindolin-3-one (6a). A crude
161.4, 154.2, 145.5, 140.0, 137.6 (d, J = 3.8 Hz), 134.0, 133.6, mixture of 4-(diphenylmethylene)-2-(4-nitrophenyl)-4H-benzo-
133.3, 131.8 (d, J = 8.3 Hz), 130.9, 128.0, 127.5, 126.6, 126.2, [d][1,3]oxazine (5a) (30 mg, 1.0 mmol) and FeCl3 (1.1 mg,
125.5, 125.4, 125.39, 125.2, 124.1 (q, J = 273.2 Hz), 116.5 (d, J = 10 mol%) in dichloromethane–nitromethane (1 : 0.7 mL) in a
21.2 Hz). HRMS (ESI, m/z) for C22H13ON F4I [(M + H)+] calcd: flask under an argon atmosphere was stirred for 12 h at 60 °C.
508.9987, found 509.9972; Anal. calcd for C22H12F4INO: C, The reaction was monitored by TLC analysis. The formed
51.89; H, 2.38; N, 2.75; found: C, 51.95; H, 2.41; N, 2.79.
product was extracted with ethyl acetate by washing with water
4-((4-Ethylphenyl)iodomethylene)-2-(4-nitrophenyl)-4H-benzo- and brine. The organic layer was separated and concentrated
[d][1,3]oxazine (2n). The title compound 2n was prepared under reduced pressure. The crude residue obtained was
according to the general procedure and purified by column chromatographed over silica gel using an ethyl acetate–
chromatography to obtain an orange solid (68%). Mp = hexane mixture as an eluent to obtain the title compound as a
1
219–221 °C; H NMR (CDCl3, 400 MHz): δ 8.60 (d, J = 8.8 Hz, white solid 6a (46%). Mp = 210–212 °C. 1H NMR (CDCl3,
2H), 8.57 (d, J = 8.8 Hz, 2H), 7.37–7.23 (m, 6H), 6.88 (td, J = 400 MHz): δ 8.04 (d, J = 8.4 Hz, 2H), 7.79 (dd, J = 7.6 Hz and
8.0 Hz and 1.2 Hz, 1H), 6.62 (dd, J = 8.0 Hz and 1.2 Hz, 1H), 0.8 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.37–7.25 (m, 14H).
2.71 (q, 7.6 Hz, 2H), 1.29 (t, 7.6 Hz, 3H). 13C NMR (CDCl3, 13C NMR (CDCl3, 100 MHz): δ 197.9, 152.6, 141.9, 136.9, 136.2,
100 MHz): δ 153.6, 149.8, 145.2, 144.7, 139.6, 138.5, 136.5, 128.7, 128.5, 128.4, 128.1, 125.7, 125.3, 123.5, 122.7, 117.8.
130.7, 129.6, 129.2, 128.9, 127.8, 126.6, 126.3, 123.6, 120.4, HRMS (ESI, m/z) for C27H18N2O4Na, calcd: 457.1164, found:
76.6, 28.6, 15.3. HRMS (ESI, m/z) calcd for C23H18IN2O3: 457.1165.
497.0362, found: 497.0360. Anal. calcd for: C23H17IN2O3; C,
55.44; H, 3.38; N, 5.57; found: C, 55.66; H, 3.45; N, 5.64.
4-((4-Fluorophenyl)iodomethylene)-2-phenyl-4H-benzo[d]-
[1,3]oxazine (2o). The title compound 2o was prepared accord-
Acknowledgements
ing to the general procedure and purified by column We thank the National Science Council of the Republic of
chromatography to obtain a yellow solid (85%). 1H NMR China for financial support. We are thankful to Dr Hsing-Yin
(CDCl3, 400 MHz): δ 8.43 (td, J = 8.8 Hz and 1.6 Hz, 2H), Chen for performing the DFT calculations.
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