An Efficient Synthesis of 3,3′,4,4′-Tetrahydro-4,4a -bibenzo[e][1,3]oxazine-2,2a -dione Derivatives with the Aid of Low-valent Titanium

Article abstract of DOI:10.1002/cjoc.201180418

Synthesis of 3,3′,4,4a′-tetrahydro-4,4′-bibenzo[e][1,3] oxazine-2,2′-diones via reaction of salicylidendphenylhydrazone and triphosgene with the aid of low-valent titanium reagent is described. This method has the advantages of accessible starting materials, good yields and short reaction time.

Full text of DOI:10.1002/cjoc.201180418

FULL PAPER
An Efficient Synthesis of 3,3',4,4'-Tetrahydro-4,4'-bibenzo-
[e][1,3]oxazine-2,2'-dione Derivatives with the Aid of
Low-valent Titanium
Dou, Guolana,b(窦国兰)
Sun, Fanga(孙芳)
Zhao, Xuana(赵玄)
Shi, Daqing*,a(史达清)
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123, China
b School of Safety Engineering, China University of Mining &Technology, Xuzhou, Jiangsu 221116, China
Synthesis of 3,3',4,4'-tetrahydro-4,4'-bibenzo[e][1,3]oxazine-2,2'-diones via reaction of salicylidendphenylhy-
drazone and triphosgene with the aid of low-valent titanium reagent is described. This method has the advantages of
accessible starting materials, good yields and short reaction time.
Keywords synthesis design, benzo[e][1,3]oxazine-2,2'-diones, low-valent titanium reagent, radical reactions
Introduction
condensation of 1-menthone with salicylamide followed
by isomerization of the adduct with 1,8-diazabicyclo-
[5,4,0]undec-7-ene (DBU),12 and salicylamideacetylene-
dicarboxylate reactions as a route to benzoxazinones.13
However, scarce general routes are known for the
preparation of bibenzo[e][1,3]oxazine-2,2'-diones so far,
therefore, a novel and general approach would be desir-
able and of high value.
Recent years we have witnessed a phenomenal
growth in the application of low-valent titanium re-
agent.14-16 The application of low-valent titanium re-
agent in organic synthesis provides some chemical
processes with attributes such as enhanced reaction rates,
higher yields of products and easier workup. Thus, this
reagent should become popular.
Efavirenz (Sustiva) (Figure 1), a benzoxazinone de-
rivative, is a nonnucleoside reverse transcriptase inhibi-
tor that has been approved by the FDA (September 17,
1998) and is presently in clinical use for the treatment of
AIDS. The fight against HIV, by developing more effi-
cacious drugs than Efavirenz, has been the prime driving
force for benzoxazinone derivatisation which has re-
ceived considerable attention.1-6
Results and discussion
Considering the above reports and in pursuing our
work on new reductive cyclization procedures,17-21 we
wanted to study the synthesis of compound 3a using
salicylidendphenylhydrazone (1a) and triphosgene 2 as
starting materials. To our surprise, 1H,1'H-1,1'-binaph-
tho[1,2-e][1,3]oxazine-3,3'(2H,2'H)-dione (4a) was ob-
tained as our final product (Scheme 1), while the ex-
pected product 3a, was not detected.
Figure 1 Structure of Sustiva.
Partly due to the biological implications, much atten-
tion has been paid to the development of efficient
methods for preparation of substituted benzoxazinones.
They include such strategies as CO2 incorporation reac-
tion based upon three-component assembly by the use of
arynes and imines,7 salicylaldehyde-based mineral sup-
ported expeditious synthesis of benzoxazin-2-ones,8,9
one-pot montmorillonite K-10 clay supported three-
component reactions of substituted salicylaldehydes,
ribosyl/deoxyribosylureas and ammonium acetate via
cycloisomerisation of an aldimine intermediate under
solvent-free irradiation conditions,10 solution-phase par-
allel synthesis using complementary molecular reactiv-
ity and molecular recognition purification technology,11
The IR spectrum of 4a showed intense peaks at 3233,
3148 cm－ for secondary amine (NH) and 1733, 1705
1
cm－ for carbonyl (C＝O). H NMR spectra of 4a
showed two singlets at δ 5.34 and 5.35 for the methyne
proton. The structure of 4a was confirmed by sin-
gle-crystal X-ray analysis (Figure 2).22 The crystallo-
graphic data are shown in Table 1.
1
1
*
E-mail: dqshi@suda.edu.cn
Received April 11, 2011; revised June 22, 2011; accepted July 12, 2011.
Project supported by the National Natural Science Foundation of China (No. 21072144) and the Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions (No. 10KJA150049).
Chin. J. Chem. 2011, 29, 2465— 2470
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Dou et al.
FULL PAPER
Scheme 1
Table 1 Crystallographic data of compound 4a
Empirical formula
C24H14N2O4
394.37
Formula weight
Temperature
223(2) K
0.71073 Å
Triclinic
P-1
Wavelength
Crystal system
Space group
Unit cell dimensions
a＝7.5307(15) Å, α＝100.47(3)°
b＝11.066(2) Å, β＝96.25(3)°
c＝12.088(2) Å, γ＝105.58(3)°
Volume
940.9(3) Å3
Z
2
Density (calculated)
Absorption coefficient
F(000)
1.392 Mg/m3
0.096 mm－
1
408
Crystal size
0.45 mm×0.40 mm×0.20 mm
Theta range for data collection
Limiting indices
3.40 to 27.50°
－9≤h≤9, －11≤k≤14, －15≤l≤14
8440
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I＞2σ(I)]
R indices (all data)
Largest diff. peak and hole
4070 [R(int)＝0.0284]
4070/0/272
1.270
R1＝0.0857, wR2＝0.2359
R1＝0.1140, wR2＝0.3151
0.677 and －0.647 e•Å－
3
Then we performed the reaction of a variety of sali-
cylidendphenylhydrazones 1 and triphosgene 2 via low-
valent titanium reagent (TiCl4/Sm) (Scheme 2). It was
particularly noteworthy that the method could be ap-
plied to substituted salicylals with either electron-
donating groups (such as alkyl, alkoxyl groups) or elec-
tron-withdrawing groups (such as halide groups), which
highlighted the wide scope of the reaction. The results
are summarized in Table 2.
Considering atom economy, we then study the reac-
tions of triphosgene 2 and salicylaldhydrazone under
Figure 2 Molecular structure of product 4a.
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Chin. J. Chem. 2011, 29, 2465— 2470

Synthesis of 3,3',4,4'-Tetrahydro-4,4'-bibenzo[e][1,3]oxazine-2,2'-dione Derivatives
Table 2 Synthesis of products 4a
Entry
Salicylidendphenylhydrazone
Product
Yield/%
1
89
4a
4b
2
90
3
90
4c
4
85
4d
5
88
4e
Chin. J. Chem. 2011, 29, 2465— 2470
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Dou et al.
FULL PAPER
Continued
Entry
Salicylidendphenylhydrazone
Product
Yield/%
6
7
8
92
87
96
4f
4g
4g
a All the products were characterized by 1H NMR, IR spectra and HRMS.
the same conditions. However, the reactions were com-
plex, only trace of the desired products were detected.
Although the mechanism of the reaction has not yet
been established, a possible explanation is proposed in
Scheme 2. TiCl4 is reduced by Sm dust to give low-
valent titanium species. First, an electron is transferred
from low-valent titanium to salicylidendphenylhydra-
zone 1 to give a radical anion A. The two molecules of
radical anion A couples each other to give B. Under the
low-valent titanium reagent, N—N bond in B was
cracked to form C. Then intermediate C cyclized to
triphosgene to give the products 4.
Scheme 2 Proposed mechanism
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Chin. J. Chem. 2011, 29, 2465— 2470

Synthesis of 3,3',4,4'-Tetrahydro-4,4'-bibenzo[e][1,3]oxazine-2,2'-dione Derivatives
In summary, the present method provides a useful
preparation of 3,3',4,4'-tetrahydro-4,4'-bibenzo[e][1,3]-
oxazine-2,2'-dione derivatives which cannot be prepared
otherwise. A series of 3,3',4,4'-tetrahydro-2H,2'H-4,4'-
bibenzo[e][1,3]oxazine-2,2'-diones were synthesized by
the reaction of various salicylidendphenylhydrazones
and triphosgene induced by low-valent titanium reagent
(TiCl4/Sm). A variety of substrates can participate in the
process with good yields. Importantly, all the products
we synthesized are new compounds. Our approach fea-
tures the first successful reductive coupling of sali-
cylidendphenylhydrazones and triphosgene, possessing
the advantages of accessible starting materials, good
yields and short reaction time. Thus, we developed a
novel versatile method for the synthesis of 3,3',4,4'-
tetrahydro-4,4'-bibenzo[e][1,3]oxazine-2,2'-diones and
hence offering easy access to a diverse array of
N-heterocyclic compounds.
1587, 1518, 1466, 1439, 1399, 1379, 1300, 1223, 1181,
－1
1161, 1112, 994, 914, 80＋8, 747 cm ; HRMS (ESI) calcd
for C24H17N2O4 [M＋H] 311.1032, found 311.1040.
3,3',4,4'-Tetrahydro-2H,2'H-4,4'-bibenzo[e][1,3]-
oxazine-2,2'-dione (4b): m.p. ＞ 300 ℃ ; 1H NMR
(DMSO-d6, 400 MHz) δ: 4.64 (s, 2H, 2×CH), 6.62 (d,
J＝7.6 Hz, 1H, ArH), 6.82 (d, J＝8.4 Hz, 1H, ArH),
6.94 (d, J＝8.0 Hz, 1H, ArH), 7.03 (t, J＝7.6 Hz, 1H,
ArH), 7.12—7.16 (m, 1H, ArH), 7.28—7.35 (m, 3H,
ArH), 8.35 (s, 1H, NH), 8.47 (s, 1H, NH); IR (KBr) ν:
3243, 3144, 2940, 2360, 2341, 1733, 1618, 1594, 1460,
1406, 1317, 1250, 1225, 1190, 1099, 1030, 939, 911,
－1
782, 750 cm ; HRMS (ESI) calcd for C16H12N2O4Na
[M＋Na]＋ 319.0695, found 319.0697.
6,6'-Dichloro-3,3',4,4'-tetrahydro-2H,2'H-4,4'-
bibenzo[e][1,3]oxazine-2,2'-dione (4c): m.p.＞300 ℃;
1H NMR (DMSO-d6, 400 MHz) δ: 4.68 (s, 2H, 2×CH),
6.72 (s, 1H, ArH), 6.98—7.02 (m, 2H, ArH), 7.39—7.40
(m, 2H, ArH), 7.56—7.57 (m, 1H, ArH), 8.27 (s, 1H,
NH), 8.63 (s, 1H, NH); IR (KBr) ν: 3239, 3149, 3042,
2945, 1733, 1613, 1589, 1493, 1475, 1421, 1378, 1286,
1261, 1241, 1210, 1185, 1105, 1082, 933, 913, 905, 822,
Experimental
THF was distilled from sodium-benzophenone imme-
diately prior to use. All the reactions were conducted un-
der N2 atmosphere. Melting points are uncorrected. IR
spectra were recorded on a Tensor 27 spectrometer in
－1
761 cm ; HRMS (ESI) calcd for C16H10Cl2N2O4Na
[M＋Na]＋ 386.9916, found 386.9910.
6,6'-Dibromo-3,3',4,4'-tetrahydro-2H,2'H-4,4'-
bibenzo[e][1,3]oxazine-2,2'-dione (4d): m.p.＞300 ℃;
1H NMR (DMSO-d6, 400 MHz) δ: 4.68 (s, 2H, 2×CH),
6.84 (s, 2H, ArH), 6.92—6.96 (m, 2H, ArH), 7.52—7.54
(m, 2H, ArH), 8.63 (s, 2H, 2×NH); IR (KBr) ν: 3244,
3151, 2942, 1717, 1652, 1613, 1585, 1558, 1490, 1463,
1381, 1285, 1265, 1244, 1223, 1184, 1125, 1098, 1073,
－1
1
KBr with absorptions in cm . H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Bruker
DPX 400 MHz spectrometer in DMSO-d6 solution with
TMS as internal standard. HRMS were obtained on a mi-
croma GCT-TOF instrument. X-Ray diffractions were
recorded on a Siemens P4 diffractometer.
－1
940, 904, 885, 823, 769 cm ; HRMS (ESI) calcd for
General procedure for the synthesis of bibenzo[e]-
[1,3]oxazine-2,2'-diones 4
C16H10Br2N2O4Na [M＋Na]＋ 474.8905, found 474.8929.
6,6,8,8'-Tetrachloro-3,3'4,4'-tetrahydro-2H,2'H-4,4'-
bibenzo[e][1,3]oxazine-2,2'-dione (4e): m.p.＞300 ℃;
1H NMR (DMSO-d6, 400 MHz) δ: 4.72 (s, 2H, 2×CH),
6.76 (s, 2H, ArH), 7.74—7.75 (m, 2H, ArH), 8.86 (s, 2H,
2×NH); IR (KBr) ν: 3264, 3160, 2929, 1755, 1735,
1670, 1458, 1376, 1320, 1292, 1206, 1183, 1088, 980,
TiCl4 (0.5 mL, 4 mmol) was added dropwise using a
syringe to a stirred suspension of samarium powder (0.6
g, 4 mmol) in freshly distilled anhydrous THF (10 mL)
at room temperature under a dry N2 atmosphere. After
completion of the addition, the mixture was refluxed for
2 h. The suspension of the low-valent titanium reagent
formed was cooled to temperature and a solution of
salicylidendphenylhydrazones (1 mmol) and triphosgene
(1 mmol) in THF (5 mL) was added dropwise. The reac-
tion mixture was then refluxed for 2 h under N2 atmos-
phere. After this period, the TLC analysis of the mixture
showed the completion of this reaction. The mixture
was then quenched with 5% HCl (30 mL) and extracted
with ClCH2CH2Cl (50 mL × 3). The extracts were
washed with water (50 mL×3) and dried over anhy-
drous Na2SO4. After evaporation of the solvent under
reduced pressure, the crude products were purified by
recrystallization from 95% ethanol and DMF.
－ 1
939, 871, 837, 752 cm ＋ ; HRMS (ESI) calcd for
C16H8Cl4N2O4Na [M＋Na] 454.9136, found 454.9153.
6,6,8,8'-Tetrabromo-3,3'4,4'-tetrahydro-2H,2'H-4,4'-
bibenzo[e][1,3]oxazine-2,2'-dione (4f): m.p.＞300 ℃;
1H NMR (DMSO-d6, 400 MHz) δ: 4.70 (s, 2H, 2×CH),
6.88 (s, 2H, ArH), 7.93 (s, 2H, ArH), 8.84 (s, 2H, 2×
NH); IR (KBr) ν: 3245, 3160, 2949, 1717, 1607, 1418,
－1
1381, 1285, 1223, 1125, 1088, 940, 909, 823, 769 cm ;
HRMS (ESI) calcd for C16H8Br4N2O4Na [M＋Na]＋
630.7116, found 630.7131.
7,7'-Dimethoxy-3,3',4,4'-tetrahydro-2H,2'H-4,4'-
bibenzo[e][1,3]oxazine-2,2'-dione (4g): m.p.＞300 ℃;
1H NMR (DMSO-d6, 400 MHz) δ: 3.58 (s, 6H, 2×
CH3O), 4.62 (s, 2H, 2×CH), 6.20 (s, 2H, ArH), 6.88 (s,
4H, ArH), 8.36 (s, 2H, 2×NH); IR (KBr) ν: 3233, 3142,
2938, 1734, 1629, 1596, 1515, 1444, 1403, 1302, 1187,
1H,1'H-1,1'-Binaphtho[1,2-e][1,3]oxazine-3,3'(2H,
1
2'H)dione (4a): m.p.＞300 ℃; H NMR (DMSO-d6,
400 MHz) δ: 5.34 (s, 1H, CH), 5.35 (s, 1H, CH), 6.84 (d,
J＝12.0 Hz, 2H, ArH), 7.08—7.09 (m, 4H, ArH), 7.36—
7.39 (m, 2H, ArH), 7.82 (d, J＝8.0 Hz, 2H, ArH), 7.79
(d, J＝8.0 Hz, 2H, ArH), 8.77 (s, 1H, NH), 8.78 (s, 1H,
NH); IR (KBr) ν: 3233, 3148, 2941, 1754, 1655, 1633,
－1
1158, 1131, 1113, 1030, 830, 798, 752 cm ; HRMS
(ESI) calcd for C18H16N2O6Na [M＋Na]＋ 379.0906,
found 379.0922.
Chin. J. Chem. 2011, 29, 2465— 2470
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Dou et al.
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FULL PAPER
6,6'-Dimethyl-3,3',4,4'-tetrahydro-2H,2'H-4,4'-bi-
benzo[e][1,3]oxazine-2,2'-dione (4h): m.p.＞300 ℃; 1H
NMR (DMSO-d6, 400 MHz) δ: 2.14 (s, 6H, 2×CH3),
4.54 (s, 1H, CH), 4.55 (s, 1H, CH), 6.36 (s, 2H, ArH),
6.81 (d, J＝8.0 Hz, 2H, ArH), 7.12 (d, J＝8.0 Hz, 2H,
ArH), 8.40 (s, 1H, NH), 8.41 (s, 1H, NH); IR (KBr) ν:
3238, 3151, 3029, 2945, 2920, 1723, 1618, 1605, 1504,
1478, 1377, 1304, 1268, 1255, 1157, 1120, 1098, 927,
－ 1
842, 811, 766, 724 cm ; HRMS (ESI) calcd for
C18H16N2O4Na [M＋Na]＋ 347.1008, found 347.1017.
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