Vinyl selenones: Annulation agents for the synthesis of six-membered benzo-1,4-heterocyclic compounds

Article abstract of DOI:10.1016/j.tet.2012.11.036

A novel and general approach to six-membered bicyclic benzo fused 1,4-heterocycles is described. The addition-cyclization cascade of benzo 1,2-diols, 1,2-thiols and 2-(benzylamino)phenols with stable and easily available vinyl selenones affords differently substituted 2,3-dihydro-1,4- benzodioxines, benzodithiines and 3,4-dihydro-2H-1,4-benzoxazines in good yields. The same procedure has been extended to the synthesis of 1,2,3,4-tetrahydroquinoxalines. All of these heterocycles are present in a variety of biologically active compounds.

Full text of DOI:10.1016/j.tet.2012.11.036

Tetrahedron 69 (2013) 481e486
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Vinyl selenones: annulation agents for the synthesis of six-membered
benzo-1,4-heterocyclic compounds
*
Luana Bagnoli , Sara Casini, Francesca Marini, Claudio Santi, Lorenzo Testaferri
ꢀ
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universita di Perugia, Via del Liceo 1, 06134 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2012
Received in revised form 17 October 2012
Accepted 7 November 2012
Available online 14 November 2012
A novel and general approach to six-membered bicyclic benzo fused 1,4-heterocycles is described. The
additionecyclization cascade of benzo 1,2-diols, 1,2-thiols and 2-(benzylamino)phenols with stable and
easily available vinyl selenones affords differently substituted 2,3-dihydro-1,4-benzodioxines, benzodi-
thiines and 3,4-dihydro-2H-1,4-benzoxazines in good yields. The same procedure has been extended to
the synthesis of 1,2,3,4-tetrahydroquinoxalines. All of these heterocycles are present in a variety of bi-
ologically active compounds.
Dedicated to the memory of Professor
Marcello Tiecco
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl selenones
MIRC reaction
1,4-Benzodioxines
1,4-Benzothiines
1,4-Benzoxazines
1. Introduction
Development of new synthetic methods for the construction of
six-membered bicyclic benzo fused 1,4-heterocycles is particularly
important because these are the core structures in many natural
products and biologically active medicinally significant compounds.1
Fig.
1
shows
a
variety of important pharmaceutical 1,4-
-adrenergic block-
benzodioxine derivatives such as piperoxan, an
a
ing agent, fluparoxan, a potent antidepressant, and americanol A, that
has interesting neurotrophic properties.2 A simple 2,3-dihydro-1,4-
benzodioxine is present in isovanillyl sweetening agents, that are
500 times sweeter than sucrose2b,c (Fig.1). Furthermore, this nucleus
exists in many natural products, such as silybin, isosilybin, haedoxan
A, eusiderin, and so on.
Fig. 1. Examples of biologically active 1,4-benzodioxine derivatives.
In particular the six-membered bicyclic fused heterocycles con-
taining nitrogen neighboring an aromatic ring, like the 3,4-dihydro-
2H-1,4-benzoxazines, have received considerable attention due to
their wide range of biological and therapeutic properties.3 For ex-
ample, in Fig. 2 are reported a precursor of a human URAT-1 (urate
transporter-1) inhibitor,3c and another 1,4-benzoxazine that pos-
sesses peroxisome proliferator-activated receptor
a (PPARa) and
* Corresponding author. Tel./fax: þ39 (0)75 585 5116; e-mail address: bagnoli@
unipg.it (L. Bagnoli).
Fig. 2. Selected biologically active 3,4-dihydro-2H-1,4-benzoxazines.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.036

482
L. Bagnoli et al. / Tetrahedron 69 (2013) 481e486
PPAR
g
agonist activity, potentially used in the treatment of diabetes,
in the presence of base initially gives the carbanions 4aee, which
hyperlipidemia, and other diabetic complications.3b
after a proton transfer form oxygen anions 5aee. The subsequent
intramolecular displacement of the phenylselenonyl group affords
the 2,3-dihydro-1,4-benzodioxines 3aee (Scheme 2). As showed in
Table 2, starting from substituted vinyl selenones 1b,c (Table 2,
entries 3e5) sodium hydride was used as base to complete the
reaction, in the case of selenone 1c the solution in tetrahydrofuran
was refluxed. Only 2,3-dihydro-1,4-benzodioxines 3aec were ob-
tained using selenones 1a,b, while starting from selenone 1c the
2,3-dihydro-1,4-benzodioxines 3d,e and the 2,2-disubstituted-1,3-
benzodioxoles 7d,e were isolated after column chromatography.
As observed in previous works,9,10 the oxygen anions 5d,e behave
as bases rather than as nucleophiles and give the alkenes 6d,e, which
were rapidly converted into the 1,3-benzodioxoles 7d,e through
purification by column chromatography on silica gel (Scheme 3).
A variety of naturally bioactive compounds such as piperine,
sesamol, and justicidin are known to possess a 1,3-benzodioxole
scaffold.11
Encouraged by these good results we carried out a similar MIRC
procedure for the preparation of 2,3-dihydro-1,4-benzodithiines
9aed, using commercial available benzene-1,2-dithiols 8a,b (Table
3). The one-pot Michael addition/cyclization sequence should pro-
ceed with the same mechanism illustrated in Scheme 2 for the syn-
thesis of the 2,3-dihydro-1,4-benzodioxines. In the case of the sulfur
nucleophile the base of choice was triethylamine. Different
substituted 2,3-dihydro-1,4-benzodithiines can be obtained in mod-
erateyieldssimplychangingtheselenones(entries2and3,Table 3)or
varying the substituents on the aromatic nucleus (entry 4, Table 3).
Finally we extended the method to the synthesis of nitrogen
containing heterocycles. Starting from 2-(benzylamino)phenols
10aec, preparedusingstandardprocedures,12 wehavesynthesized4-
benzyl-3,4-dihydro-2H-benzo-1,4-oxazines 14aec (Table 4). As ob-
served in previous work,9 the initial formation of an oxygen anion,
Considering their remarkable biological relevance, several
methods for the synthesis of this type of benzo fused heterocycles
have been developed in recent years.2e6 However some of these
procedures have limitations such as the availability of the starting
materials, the high costs of the catalysts,2,4a,b,6a or the use of mul-
tistep sequences.1,3b,d Moreover, most of the methods reported
target the synthesis of specific benzo fused compounds and lack
generality. Thus it is important to develop general and straight-
forward approaches for their construction. Cascade or tandem re-
actions can be useful economical and environmentally friendly
tools for the rapid assembly of heterocycles.7 Previously8 vinyl
selenones were shown to be valuable and versatile substrates to
realize these types of reactions. They were employed for the one-
pot synthesis of cyclopropanes8a or aziridines8b through Michael
initiated ring closure (MIRC) reactions. The vinyl selenone plays
a dual role as activating group in the conjugate addition and as
leaving group in the following cyclization. Very recently we also
described a cascade reaction for the one-pot synthesis of enantio-
pure morpholines, thiomorpholines, and piperazines through an
MIRC reaction starting from readily available enantiopure amino-
alcohols/thiols/amines and vinyl selenones.9
Herein we describe the simple and novel use of MIRC reactions
to obtain, in one step and in good yields, six-membered 1,4-
heterocycles fused to an aromatic group from commercially avail-
able benzene 1,2-diols, 1,2-thiols, 1,2-aminoalcohols or 1,2-
diamines using vinyl selenones as Michael acceptors.
2. Results and discussion
The vinyl selenones necessary for the present investigation were
easily synthesized through oxidation of the corresponding vinyl sel-
enides.9 We began our investigation by examining the reaction of
pyrocatechol 2a with simple vinyl selenone 1a (Scheme 1). As shown
in Table 1, the choice of base was important, and the reaction did not
take place in its absence (Table 1, entry 1). The reactions proceeded in
good yields using sodium hydride and cesium carbonate (Table 1,
entries 2 and 3), while using organic bases such as triethylamine, DBU
(1,8-diazabicyclo[5,4,0]undec-7-ene), and DABCO (1,4-diazabicyclo
[2.2.2]octane) (Table 1, entries 4e6) lower yields were obtained.
We then synthesized different 2,3-dihydro-1,4-benzodioxines
3aee employing vinyl selenones 1aec and the commercially
available pyrocatechol 2a and naphthalene-2,3-diol 2b. The reaction
conditions, the reaction products, and the yields are reported in
Table 2 and the plausible mechanism is reported in Scheme 2.
On the basis of the accepted mechanism for Michael initiated
ring closure (MIRC) reactions it can be proposed that the reactions
of the selenones 1aec with the commercial benzene-1,2-diols 2a,b
which effects the conjugate addition atthe b-position of the selenone,
followed by the intramolecular displacement of the phenylselenonyl
group by the nitrogen atom is likely. As showed in Table 4, electron-
rich substituents and electron-deficient substituents on the aryl
ring (entries 2 and 3) were employed and the corresponding het-
erocycles 14aec were obtained in moderate to good yields. The pos-
sibility of removing the protecting group, according to the procedure
reported in the literature,13 increases the importance of the present
method for the synthesis of 3,4-dihydro-2H-benzo-1,4-oxazines.
The reactivity of N,N’-1,2-phenylenebis(4-methyl benzene-
sulfonamide) 15 was also investigated. Using sodium hydride
(1.2 equiv) as base, we have obtained 1,4-bis[(4-methylphenyl)
sulfonyl]-1,2,3,4-tetrahydroquinoxaline 16 (58% yield) (Scheme 4).
This heterocyclic core is present in many bioactive compounds.
Several 1,2,3,4-tetrahydroquinoxalines have found applications
as prostaglandin D2 receptor antagonists, vasopresin V2 receptor
antagonists, and potent cholesteryl ester transfer protein
inhibitors.14
3. Conclusion
Scheme 1. Reaction of vinyl selenone with pyrocatechol.
In the present investigation we have reported a novel and
simple approach for the synthesis of benzo fused heterocyclic rings
through an MIRC reaction from vinyl selenones and benzene 1,2-bis
nucleophiles. Various biologically and pharmaceutically important
nuclei such as 2,3-dihydro-1,4-benzodioxines,2 2,3-dihydro-1,4-
Table 1
Optimization of the reaction conditions
Entry
Base
equiv
Reaction conditions
Yield (%)
benzodithiines,
4-benzyl-3,4-dihydro-2H-benzo-1,4-oxazines,3
1
2
3
4
5
6
d
d
1.2
1.2
2
2
2
CH2Cl2, rt, 36 h
d
and 1,2,3,4-tetrahydroquinoxaline14 were obtained in one pot and
in good yields. The wide applicability of this method, the easy
availability, and low cost of the starting materials confirm the po-
tential of vinyl selenones as valuable substrates for cascade re-
actions. Further applications of this strategy for the synthesis of
NaH
CH2Cl2, 0 ꢀC to rt, t¼5 h
CH2Cl2, rt, t¼24 h
CH2Cl2, rt, t¼18 h
CH2Cl2, rt, t¼18 h
CH2Cl2, rt, t¼36 h
53
80
38
40
35
Cs2CO3
Et3N
DBU
DABCO

L. Bagnoli et al. / Tetrahedron 69 (2013) 481e486
483
Table 2
Synthesis of 2,3-dihydro-1,4-benzodioxines
Entry
1
Selenones 1aec
Substrates 2aeb
Bꢁ
equiv
1.2
Reaction conditions
Products 5aee, 7dee
Yield (%)
1a
1a
1b
2a
2b
2a
Cs2CO3
CH2Cl2, 0 ꢀC to rt, 24 h
3a
3b
3c
80
73a
60
2
3
Cs2CO3
1.2
1.2
CH2Cl2, 0 ꢀC to rt, 36 h
NaH
CH2Cl2, 0 ꢀC to rt, 36 h
3d
7d
35
35
4
1c
2a
NaH
1.2
THF, 0 ꢀC to reflux, 72 h
3e
7e
35
61
5
1c
2b
NaH
1.2
THF, 0 ꢀC to reflux, 72 h
a
Employing 1 equiv of NaH, the yields of the products 3a and 3b were 53% and 43%, respectively.
more complex benzo fused heterocycles are currently underway in
our laboratory.
4. Experimental section
4.1. General
All new compounds were characterized by GCeMS, 1H and 13C
NMR spectra. 1H and 13C NMR spectra were recorded at 400 and
100.62 MHz, respectively, on a Bruker DRX 400 instrument. The
chemical shifts (d
) are referred to internal standard TMS (1H NMR)
and the residual signals of the solvent (CDCl3d77.0 ppm for 13C
NMR). J values are given in hertz. The following abbreviations are
used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q,
quartet; sept, septet; m, multiplet; br, broad signal. GC analyses and
MS spectra were carried out with an HP 6890 gas chromatograph
(25 m dimethyl silicone capillary column) equipped with an HP
5973 Mass Selective Detector at an ionizing voltage of 70 eV. For the
ions containing selenium, only the peaks arising from the
selenium-80 isotope are given. FTIR spectra were recorded with
a Jasco model 410 spectrometer equipped with a diffuse reflectance
accessory. Elemental analyses were carried out on a Carlo Erba 1106
Elemental Analyzer. The melting points are uncorrected. Thin layer
chromatography (TLC) was performed on silica gel 60 F254 (Merck).
Purification of reaction products was carried out by chromatogra-
phy on silica gel Merck 60 (70e230 mesh).
Scheme 2. Proposed mechanism for the synthesis of 2,3-dihydro-1,4-benzodioxines.
The vinyl selenones 1aec were prepared according to the pro-
cedure reported in the literature.8,9 Benzo-1,2-diols 2a,b, benzo-1,2-
thiols 8a,b are commercially available. The 2-(benzylamino)phenols
Scheme 3. Synthesis of acetals 7d,e.

484
L. Bagnoli et al. / Tetrahedron 69 (2013) 481e486
Table 3
Synthesis of 2,3-dihydro-1,4-benzodithiines
Entry
1
Selenones 1aec
Substrates 8a,b
Base
Et3N
Equiv
3.0
Reaction conditions
CH2Cl2, rt, 48 h
Products 9aed
Yield (%)
85a
1a
1b
8a
8a
9a
9b
2
3
Et3N
Et3N
5.0
5.0
CH2Cl2, rt, 72 h
63
58
1c
1a
8a
8b
THF reflux, 48 h
9c
4
Et3N
3
CH2Cl2, rt, 48 h
9d
57
a
Employing 1 equiv of Cs2CO3, the yield of the product 9a was 67%.
Table 4
Synthesis of 4-benzyl-3,4-dihydro-2H-benzo-1,4-oxazines
Entry
Selenone 1a
Substrates 10aec
Bꢁ
equiv
1.2
Reaction conditions
Products 14aec
Yield (%)
68a
1
1a
1a
10a
10b
NaH
CH2Cl2, 0 ꢀC to rt, 48 h
14a
14b
2
NaH
NaH
1.2
1.2
CH2Cl2, 0 ꢀC to rt, 48 h
CH2Cl2, 0 ꢀC to rt, 48 h
70
60
3
1a
10c
14c
a
Employing 1 equiv of Cs2CO3 the product 14a was obtained with 50% yield.
(0.6 mmol) at room temperature in the case of simple selenone 1a
or NaH (0.6 mmol) at 0 ꢀC to room temperature in the cases of
substituted selenones 1b,c. After 10 min a solution of vinyl sele-
nones 1aec (0.5 mmol) was added and the reaction mixture was
stirred for the times and at the temperature indicated in Table 2.
The progress of the reactions was monitored by TLC. The reaction
mixtures were poured into aqueous ammonium chloride solution
and extracted with CH2Cl2, washed with water and brine, dried
over Na2SO4, filtered, and evaporated under vacuum. Reaction
products 3aee and 7d,e were obtained in a pure form after column
chromatography of the residue on silica gel. Physical and
spectral data of the 2,3-dihydro-1,4-benzodioxine (3a),4b 2,3-
dihydronaphtho[2,3-b][1,4]dioxine (3b),4c 2-phenyl-2,3-dihydro-
1,4-benzodioxine (3d),2b and 2-methyl-2-phenyl-1,3-benzodioxole
(7d)11 are identical to those reported in the literature. Physical
and spectral data of the 2,3-dihydro-1,4-benzodioxines 3c,e and the
acetal 7e are reported below.
Scheme 4. Synthesis of 1,4-bis[(4-methylphenyl) sulfonyl]-1,2,3,4-tetrahydroquin-
oxaline 16.
10aec12 and N,N0-1,2-phenylenebis(4-methyl benzenesulfonamide)
1515 were prepared according to the procedure described in the
literature. Physical and spectral data of o-(benzylamino)phenol
10a,16 2-benzylamino-4-chlorophenol 10c,12 and the N,N0-1,2-
phenylenebis(4-methyl benzenesulfonamide) 1515 are identical to
those reported in the literature. Physical and spectral data of the 2-
(benzylamino)-4-methylphenol 10b are reported below.
2-(Benzylamino)-4-methylphenol (10b): colorless solid; mp
106e109 ꢀC [lit.17 mp 110e111 ꢀC]; 1H NMR (400 MHz, CDCl3, 25 ꢀC,
TMS):
d
¼7.42e7.30 (m, 5H, AreH), 6.65e6.46 (m, 3H, AreH),
4.38e4.36 (m, 4H, CH2Ph, OH, NH), 2.26 (s, 3H). Anal. Calcd for
C14H15NO: C, 78.48; H, 7.09; N, 6.57. Found: C, 78.16; H, 6.93; N,
6.36.
4.2.1. 2-Hexyl-2,3-dihydro-1,4-benzodioxine (3c). Purification by
column chromatography (EE/EP from 2:98 to 10:90). Yield 60%; oil;
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d
¼6.90e6.82 (m, 4H, AreH),
4.25 (dd, 2J(H,H)¼11.2 Hz, 3J(H,H)¼2.1 Hz, 1H, CH2O), 4.16e4.09 (m,
1H, CHO), 3.90 (dd, 2J(H,H)¼11.2 Hz, 3J(H,H)¼7.8 Hz, 1H, CH2O),
1.77e1.23 (m, 10H, 5CH2), 0.92 (t, 3J(H,H)¼6.6 Hz, 3H, CH3); 13C
4.2. General procedure for the synthesis of 2,3-dihydro-1,4-
benzodioxines, 5aee and 2-methyl-2-phenyl-1,3-
benzodioxoles, 5d,e
NMR (100 MHz, CDCl3, 25 ꢀC):
d
¼143.5 (Cipso), 143.3 (Cipso), 121.4
(CH, Ar), 121.1 (CH, Ar), 117.3 (CH, Ar), 116.9 (CH, Ar), 73.0 (CHO),
68.1 (CH2O), 31.6, 31.0, 29.1, 24.9, 22.5 (5CH2),14.0 (CH3); MS (70 eV,
EI): m/z (rel int.): 220 (100) [Mþ], 135 (32), 121 (66), 110 (97), 81
A stirred solution of benzene-1,2-diols 2a,b (0.5 mmol) in
CH2Cl2 (3 mL) or THF was treated under argon with Cs2CO3

L. Bagnoli et al. / Tetrahedron 69 (2013) 481e486
485
(23), 69 (54), 55 (33). FTIR (KBr): nmax, cmꢁ1 2959, 2930, 2869, 1591,
1461, 1283, 1055, 747. Anal. Calcd for C14H20O2: C, 76.33; H, 9.15.
Found: C, 76.21; H, 9.01.
Yield 58%; oil; 1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d
¼7.43e7.31
(m, 5H, AreH), 7.28e7.25 (m, 1H, AreH), 7.22e7.18 (m, 1H, AreH),
7.07e7.03 (m, 2H, AreH), 4.64 (dd, 3J(H,H)¼10.1 Hz, 3J(H,H)¼3.4 Hz,
1H, CHS), 3.44 (dd, 2J(H,H)¼13.0 Hz, 3J(H,H)¼10.1 Hz, 1H, CH2S),
3.35 (dd, 2J(H,H)¼13.0 Hz, 3J(H,H)¼3.4 Hz, 1H, CH2S); 13C NMR
4.2.2. 2-Phenyl-2,3-dihydronaphtho[2,3-b][1,4]dioxine
(3e). Purifi-
cation by flash column chromatography on silica gel (from EP to EE/
(100 MHz, CDCl3, 25 ꢀC):
d
¼140.1 (Cipso), 133.2 (Cipso), 130.6
EP 3:97). Yield 35%; colorless solid; mp 77e80 ꢀC; 1H NMR (400 MHz,
(Cipso), 128.9 (2CH, Ar),128.6 (CH, Ar),128.2 (CH, Ar), 128.1 (CH, Ar),
127.6 (2CH, Ar), 125.3 (CH, Ar), 125.1 (CH, Ar), 48.1 (CHS), 35.6
(CH2S); MS (70 eV, EI): m/z (rel int.): 244 (50) [Mþ], 229 (100), 167
(35), 152 (10), 103 (20). FTIR (KBr): nmax, cmꢁ1 3055, 2917, 1558,
1489, 1453, 1422, 744, 697. Anal. Calcd for C14H12S2: C, 66.81; H,
4.95. Found: C, 66.37; H, 4.62.
CDCl3, 25 ꢀC, TMS):
d
¼7.72e7.70 (m, 2H, AreH), 7.53e7.24 (m, 9H,
AreH), 5.29 (dd, 3J(H,H)¼9.0 Hz, 3J(H,H)¼2.4 Hz, 1H, CHO), 4.47 (dd,
2J(H,H)¼11.5 Hz, 3J (H,H)¼2.4 Hz,1H, CH2O), 4.18 (dd, 2J(H,H)¼11.5 Hz,
3J(H,H)¼9.0 Hz, 1H, CH2O); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d¼144.2 (Cipso), 143.9 (Cipso), 136.4 (Cipso), 130.3 (2 Cipso), 128.9
(CH), 128.8 (2CH, Ar), 126.6 (2CH, Ar), 126.5 (CH, Ar), 126.4 (CH, Ar),
124.3 (CH, Ar), 124.2 (CH, Ar), 112.8 (CH, Ar), 112.4 (CH, Ar), 75.3
(CHO), 69.4 (CH2O); MS (70 eV, EI): m/z (rel int.): 262 (28) [Mþ], 171
(100), 102 (27), 77 (11). FTIR (KBr): nmax, cmꢁ1 3059, 2930, 1509, 1471,
1439, 1271, 1239, 1169, 1021, 747, 699. Anal. Calcd for C18H14O2: C,
82.42; H, 5.38. Found: C, 82.21; H, 5.15.
4.3.3. 6-Methyl-2,3-dihydro-1,4-benzodithiine (9d). Purification by
column chromatography (from EP to EtOAc/EP 1:99). Yield 57%; oil;
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d
¼7.07 (d, 3J(H,H)¼8.0 Hz,
1H, AreH), 7.03e7.0 (m, 1H, AreH), 6.86e6.83 (m, 1H, ArH),
3.28e3.26 (m, 4H, 2CH2S), 2.26 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3, 25 ꢀC):
d
¼137.6 (Cipso),136.7 (Cipso),131.3 (Cipso), 129.2 (CH,
4.2.3. 2-Methyl-2-phenylnaphtho[2,3-d][1,3]dioxole (7e). Purification
by flash column chromatography on silica gel (from EP to EE/EP 3:97).
Ar), 128.7 (CH, Ar), 126.3 (CH, ArH), 29.4 (2CH2S), 21.0 (CH3); MS
(70 eV, EI): m/z (rel int.): 182 (11) [Mþ], 167 (100), 153 (45), 134 (7),
121 (14). FTIR (KBr): nmax, cmꢁ1 3044, 2916, 1653, 1583, 1457, 815,
735, 687. Anal. Calcd for C9H10S2: C, 59.29; H, 5.53. Found: C, 59.10;
H, 5,45.
Yield 61%; oil; 1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d¼7.67e7.62
(m, 4H, AreH), 7.43e7.35 (m, 3H, AreH), 7.32e7.30 (m, 2H, AreH),
7.13e7.12 (m, 2H, AreH), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3,
25 ꢀC):
d
¼147.6 (2Cipso), 141.3 (Cipso), 130.4 (2Cipso, Ar), 128.9 (CH,
Ar), 128.4 (2CH, Ar), 126.8 (2CH, Ar), 124.9 (2CH, Ar), 124.1 (2CH, Ar),
4.4. General procedure for the synthesis of 4-benzyl-3,4-
dihydro-2H-1,4-benzoxazines, 14aec and 1,4-bis[(4-
methylphenyl)sulfonyl]-1,2,3,4-tetrahydroquinoxaline, 16
116.7 (Cquat), 103.8 (2CH, Ar), 27.0 (CH3). MS (70 eV, El): m/z (rel int.):
262 (40) [Mþ], 247 (21), 160 (100), 103 (57), 77 (27). FTIR (KBr): nmax
,
cmꢁ1 3047, 2926, 1653, 1559, 1465, 1250, 1193, 926, 862, 751, 702.
Anal. Calcd for C18H14O2: C, 82.42; H, 5.38. Found: C, 82.21; H, 5.15.
A stirred solution of 2-(benzylamino)phenols 10aec (0.5 mmol)
or
(0.5 mmol) in CH2Cl2 (3 mL) was treated with NaH (0.6 mmol) at
0
ꢀC under argon. After 10 min, a solution of vinyl selenone 1a
N,N0-1,2-phenylenebis(4-methylbenzenesulfonamide)
15
4.3. General procedure for the synthesis of 2,3-dihydro-1,4-
benzodithiines, 9aed
(0.5 mmol) in CH2Cl2 (3 mL) was added and the reaction mixture
was allowed to warm at room temperature and stirred for the times
indicated in Table 4 and in Scheme 4. The progress of the reactions
was monitored by TLC. The reaction mixtures were poured into
aqueous ammonium chloride solution and extracted with CH2Cl2,
washed with water and brine, dried over Na2SO4, filtered, and
evaporated under vacuum. Reaction products 14aec and 16 were
obtained in a pure form after column chromatography of the resi-
due on silica gel. Physical and spectral data of the 4-benzyl-3,4-
dihydro-2H-1,4-benzoxazine 14a are identical to those reported
in the literature.6a Physical and spectral data of the 6-substituted-4-
benzyl-3,4-dihydro-2H-1,4-benzoxazines 14b,c and 1,4-bis[(4-
methylphenyl)sulfonyl]-1,2,3,4-tetrahydroquinoxaline 16 are re-
ported below.
A stirred solution of benzene-1,2-dithiols 8a,b (0.5 mmol) in
CH2Cl2 (3 mL) was treated with Et3N (1.5 mmol) at room temper-
ature under argon. After 10 min, a solution of vinyl selenones 1aec
(0.6 mmol) in CH2Cl2 (3 mL) or THF was stirred for the times in-
dicated in Table 3. The progress of the reactions was monitored by
TLC. The reaction mixtures were poured into aqueous ammonium
chloride solution and extracted with CH2Cl2, washed with water
and brine, dried over Na2SO4, filtered, and evaporated under vac-
uum. Reaction products 9aed were obtained in a pure form and in
satisfactory yields after column chromatography of the residue on
silica gel. Physical and spectral data of the 2,3-dihydro-1,4-
benzodithiine, 9a are identical to those reported in literature.5a
Physical and spectral data of the 2,3-dihydro-1,4-benzodithiines
9bed are reported below.
4.4.1. 4-Benzyl-6-methyl-3,4-dihydro-2H-1,4-benzoxazine (14b). Puri-
fication by flash column chromatography on silica gel (EE/EP 15:85).
4.3.1. 2-Hexyl-2,3-dihydro-1,4-benzodithiine (9b). Purification by
column chromatography on silica gel (from EP to EtOAc/EP 3:97).
Yield 70%; oil; 1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d¼7.39e7.28
Yield 63%; oil; 1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d¼7.20e7.16
(m, 5H), 6.74 (d, 3J¼8.0 Hz, 1H, AreH), 6.54 (d, 4J¼2.0 Hz, 1H, AreH),
6.47 (dd, 4J¼8.0 Hz, 3J¼2.0 Hz, 1H, AreH), 4.46 (s, 2H, NCH2),
4.27e4.24 (m, 2H, CH2O), 3.36e3.34 (m, 2H, CH2N), 2.23 (s, 3H, CH3);
(m, 2H, AreH), 7.05e6.98 (m, 2H, AreH), 3.52e3.45 (m, 1H, CHS),
3.24 (dd, 2J(H,H)¼13.0 Hz, 3J(H,H)¼3.2 Hz, 1H, CH2S), 3.0 (dd,
2J(H,H)¼13.0 Hz, 3J(H,H)¼8.3 Hz, 1H, CH2S), 1.76 (q, J¼7.0 Hz, 2H,
CH2),1.58e1.30 (m, 8H, 4ꢂCH2), 0.89 (t, 3H, J¼7.0 Hz, CH3); 13C NMR
13C NMR (100 MHz, CDCl3, 25 ꢀC):
d¼141.7 (Cipso),138.1 (Cipso), 135.3
(Cipso), 130.9 (Cipso), 128.6 (2CH, Ar), 127.1 (2CH, Ar), 127.0 (CH, Ar),
118.1 (CH, Ar), 116.0 (CH, Ar), 113.9 (CH, Ar), 64.5 (CH2O), 54.8
(PhCH2N), 47.2 (CH2N), 21.1 (CH3). MS (70 eV, EI): m/z (rel int.): 239
(100) [Mþ], 148 (67), 120 (31), 91 (96), 77 (20), 65 (29). FTIR (KBr):
nmax, cmꢁ1 3030, 2868, 1610, 1512, 1451, 1341, 1306, 1213, 1050, 799,
696. Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
80.12; H, 7.01; N, 5.76.
(100 MHz, CDCl3, 25 ꢀC):
d
¼131.9 (Cipso), 131.2 (Cipso), 128.6 (CH,
Ar),128.5 (CH, Ar),125.3 (CH, Ar),124.8 (CH, AreH), 43.4 (CHS), 35.7
(CH2S), 34.4 (CH2), 31.6 (CH2), 29.7 (CH2), 26.7 (CH2), 22.6 (CH2),
14.1 (CH3); MS (70 eV, EI): m/z (rel int.): 252 (50), 167 (44), 153 (43),
142 (30), 140 (12), 135 (10), 134 (100). FTIR (KBr): nmax, cmꢁ1 3050,
2968, 2845, 1650, 1453, 761. Anal. Calcd for C14H20S2: C, 66.61; H,
7.99. Found: C, 66.31; H, 7.29.
4.4.2. 4-Benzyl-6-chloro-3,4-dihydro-2H-1,4-benzoxazine (14c). Puri-
4.3.2. 2-Phenyl-2,3-dihydro-1,4-benzodithiine (9c). Purification by
column chromatography on silica gel (from EP to EtOAc/EP 3:97).
fication by flash column chromatography on silica gel (EE/EP 15:85).
1
Yield 60%; oil; H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d¼7.39e7.28

486
L. Bagnoli et al. / Tetrahedron 69 (2013) 481e486
(m, 5H, AreH), 6.74 (d, 3J¼8.4 Hz, 1H, AreH), 6.66 (d, 4J¼2.3 Hz, 1H,
AreH), 6.59 (dd, 4J¼2.3 Hz, 3J¼8.4 Hz, 1H, AreH), 4.45 (s, 2H, NCH2),
4.27e4.24 (m, 2H, CH2O), 3.40e3.35 (m, 2H, CH2N); 13C NMR
3509e3519; (c) Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg, E. J. Chem. Soc., Perkin
Trans. 2 1991, 1399e1406.
3. (a) Zhang, Y. R.; Xie, J. W.; Huang, X. J.; Zhu, W. D. Org. Biomol. Chem. 2012, 10,
6554e6561; (b) Ilas, J.; Anderluh, S. P.; Dolenc, M. S.; Kikelj, D. Tetrahedron
2005, 61, 7325e7348 and references cited therein; (c) Cho, H.; Iwama, Y.; Su-
gimoto, K.; Mori, S.; Tokuyama, H. J. Org. Chem. 2010, 75, 627e636; (d) Mat-
suoka, H.; Ohi, N.; Mihara, M.; Suzuki, H.; Miyamoto, K.; Maruyama, N.; Tsuji,
K.; Kato, N.; Akimoto, T.; Taketa, Y.; Yano, K.; Kuroki, T. J. Med. Chem. 1997, 40,
105e111.
4. For the synthesis of the 2,3-dihydro-1,4-benzodioxines, see: (a) Kuwabe, S. I.;
Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202e12206; (b)
Torraca, K. E.; Kuwabe, S. I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
12907e12908; (c) Clavier, S.; Khouili, M.; Bouyssou, P.; Coudert, G. Tetrahe-
dron 2002, 58, 1533e1540; (d) Eynde, J. J. V.; Mailleux, I. Synth. Commun.
2001, 31, 1e7; (e) Harrak, Y.; Guillaumet, G.; Pujol, M. D. Synlett 2003,
813e816.
(100 MHz, CDCl3, 25 ꢀC):
d¼142.4 (Cipso), 137.2 (Cipso), 136.4 (Cipso),
128.7 (2CH, Ar), 127.3 (CH, Ar), 127.0 (2CH, Ar), 126.4 (Cipso), 117.0
(2CH, Ar), 111.9 (CH, Ar), 64.4 (CH2O), 54.6 (NCH2Ph), 46.8 (CH2N). MS
(70 eV, EI): m/z (rel int.): 261 (10) [Mþþ2], 259 (28) [Mþ], 168 (7), 91
(100), 65 (10). FTIR (KBr): nmax, cmꢁ1 3075, 2976, 2843, 1600, 1501,
1453, 1313, 1228, 1199, 915, 904, 838, 807, 761, 736, 700. Anal. Calcd
for C15H14ClNO: C, 69.36; H, 5.43; N, 5.39. Found: C, 69.19; H, 5.18; N,
5.07.
4.4.3. 1,4-Bis[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydroquinoxaline
(16). Purification by column chromatography (MeOH/CH2Cl2 3:97).
Yield 58%; colorless solid; mp 165e168 ꢀC [lit.18 mp 162 ꢀC]; 1H NMR
5. For the synthesis of the 2,3-dihydro-1,4-benzodithiine, see: (a) Harrison, D. J.;
Fekl, U. Chem. Commun. 2009, 7572e7574; (b) Parham, W. E.; Roder, T. M.;
Hasek, W. R. J. Am. Chem. Soc. 1953, 75, 1647e1651; (c) Pierini, A. B.; Baum-
gartner, M. T.; Rossi, R. A. J. Org. Chem. 1987, 52, 1089e1092.
6. For the synthesis of the 3,4-dihydro-2H-1,4-benzoxazines, see: (a) Omar-Am-
rani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5,
2311e2314; (b) Mizar, P.; Myrboh, B. Tetrahedron Lett. 2006, 47, 7823e7826; (c)
Albanese, D.; Donghi, A.; Landini, D.; Lupi, V.; Penso, M. Green Chem. 2003, 5,
367e369; (d) Buon, C.; Chacun-Lefevre, L.; Rabot, R.; Bouyssou, P.; Coudert, G.
Tetrahedron 2000, 56, 605e614.
7. (a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257e260; (b)
Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2008, 47,
3784e3786; (c) Du, Z.; Zhou, C.; Gao, Y.; Ren, Q.; Zhang, K.; Cheng, H.; Wang,
W.; Wang, J. Org. Biomol. Chem. 2012, 10, 36e39; (d) Wang, J.; Xie, H.; Li, H.; Zu,
L.; Wang, W. Angew. Chem., Int. Ed. 2008, 47, 4177e4179.
8. (a) Bagnoli, L.; Scarponi, C.; Testaferri, L.; Tiecco, M. Tetrahedron: Asymmetry
2009, 20, 1506e1514; (b) Sternativo, S.; Marini, F.; Del Verme, F.; Calandriello,
A.; Testaferri, L.; Tiecco, M. Tetrahedron 2010, 66, 6851e6857.
9. Bagnoli, L.; Scarponi, C.; Rossi, M. G.; Testaferri, L.; Tiecco, M. Chem.dEur. J.
2011, 17, 993e999.
(400 MHz, CDCl3, 25 ꢀC, TMS):
d
¼7.86e7.81 (m, 2H, AreH), 7.42 (d,
J¼8Hz, 4H, AreH), 7.22(d,J¼8Hz, 4H, AreH), 7.16e7.11 (m, 2H, AreH),
3.51 (s, 4H, 2CH2), 2.42(s, 6H, 2CH3); 13C NMR (100 MHz, CDCl3, 25ꢀC):
d
¼144.3 (2Cipso), 135.6 (2Cipso), 129.8 (4CH, Ar), 128.2 (2Cipso), 127.0
(4CH, Ar), 124.9 (2CH, AreH), 123.6 (2CH, AreH), 43.3 (2CH2), 21.5
(2CH3). MS (70 eV, EI): m/z (rel int.). Anal. Calcd for C22H22N2O4S2: C,
59.71; H, 5.01; N, 6.33. Found: C, 59.59; H, 4.91; N, 6.06.
Acknowledgements
ꢀ
Financial support from M.I.U.R. (Ministero Italiano Universita e
Ricerca), National Projects PRIN2007, University of Perugia and
Consorzio CINMPIS and Fondazione Cassa di Risparmio: Project
‘Processi ecosostenibili per la produzione e l’analisi di molecole di
interesse farmaceutico’ 2012.0114.021, is gratefully acknowledged.
10. Tiecco, M.; Chianelli, D.; Tingoli, M.; Testaferri, L.; Bartoli, D. Tetrahedron 1986,
42, 4897e4906.
11. Li, M.; Hua, R. J. Org. Chem. 2008, 73, 8658e8660 and references cited therein.
12. Feng, G.; Wu, J.; Dai, W. M. Tetrahedron 2006, 62, 4635e4642.
13. Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Tetrahedron 1980, 36,
409e415.
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