A new efficient method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines via iodocyclization

Article abstract of DOI:10.1016/j.tetlet.2010.08.016

An efficient approach for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine derivatives is described by molecular iodine- mediated cyclization. The reaction condition is very simple, offers easy isolation, and affords good to excellent yields of the products.

Full text of DOI:10.1016/j.tetlet.2010.08.016

Tetrahedron Letters 51 (2010) 5437–5439
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Tetrahedron Letters
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A new efficient method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines
via iodocyclization
⇑
K. C. Majumdar , Krishanu Ray, Sudipta Ponra
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine derivatives is described by
molecular iodine- mediated cyclization. The reaction condition is very simple, offers easy isolation, and
affords good to excellent yields of the products.
Received 1 July 2010
Revised 31 July 2010
Accepted 5 August 2010
Available online 11 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Dihydro-2H-1,4-benzoxazine
Iodine
1,2,3,4-Tetrahydroquinoloxalines
Heterocycles
Recently organic compounds containing 1,4-benzoxazine deriv-
atives have received great attention in chemical and medicinal re-
search because of their natural occurrence and important
biological activities. Several 3,4-dihydro-2H-1,4-benzoxazine deriv-
atives have been reported as potassium channel openers (PCOs) in
vascular smooth muscle.1 Some 1,4-benzoxazine derivatives are
known to be central nervous system depressants, antipsychotic
agents, calcium antagonists, and antibacterial agents while some
other derivatives are potential drugs for treating neurodegenerative,
inflammatory, autoimmune, cardiovascular, and diabetic disor-
ders.2 For example, levofloxacin used as antibiotics exhibits excel-
lent activities against gram-positive and gram-negative bacteria
contains 3,4-dihydro-2H-1,4-benzoxazine moiety.3 1,4-Benzox-
azine derivatives have also been used as intermediates for the syn-
thesis of other heterocyclic structures of biological importance.4,5
As a consequence several methods have been developed so far for
the synthesis of 3,4-dihydro-2H-1,4-benzoxazine derivatives.2a,6
However, most of the methods reported were multistep procedures
and lacked generality, needed use of toxic and expensive reagents,
and suffered from complex workup and purification procedures.
These difficulties have limited their wider applicability. Moreover
recent publications7 rely on the use of different metal catalysts for
the construction of the 3,4-dihydro-2H-1,4-benzoxazine derivatives
(using palladiumor copper catalysts). The reaction condition also re-
quires the presence of ligands and proceeds under thermal condi-
tions. So there is always a demand for more general, more
economic, environment friendly reaction pathways that proceed
under mild conditions.
In recent years, molecular iodine has received considerable
attention as an inexpensive, non-toxic, readily available reagent
to effect the iodocyclization reactions. The halocyclization of an
unsaturated C–C bond with an intramolecular nucleophilic center
plays an important role in the stereo selective construction of cyc-
lic compounds and functionalization of double bonds.8 Synthesis of
various heterocyclic compounds of biological importance by iodo-
cyclization has been explored with a wide variety of nucleophiles,
including N, O, S, Se etc., and it has become a powerful tool for the
construction of different heterocycles.9
As a part of our ongoing research interest toward the develop-
ment of new methodologies to construct various biologically active
heterocycles,10 we have undertaken a study to synthesize different
3,4-dihydro-2H-1,4-benzoxazines via iodocyclization reactions
and the results are reported here.
We have initiated our investigation with the substrate 1a. Un-
der usual reaction conditions (1.5 equiv I2–2.5 equiv NaHCO3–
CH3CN) the iodocyclization of 1a afforded the desired cyclized
product 2a in 65% yield and the reaction took 10 h to completion.
Increasing the amount of iodine or base did not improve the yield
O
O
(i)
I
Cl
N
Cl
NHTs
Ts
2a
1a
⇑
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
Scheme 1. Reagents and conditions: (i) I2 (1.5 equiv), base (2.5 equiv), CH3CN, rt.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.016

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K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 5437–5439
Table 1
Optimization of iodine mediated reactiona
O
O
DBU
Entry
I2 (equiv)
Baseb
Time (h)
Solvent
Yieldc (%)
I
Toluene
reflux, 24h
97 %
Cl
N
Cl
N
Ts
Ts
1
2
3
4
5
6
7
8
1.5
1.5
6
1.5
1.5
1.5
1.5
1.5
—
24
6
6
10
6
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
THF
NR
88
85
65
82
75
25
<20
3
2a
K2CO3
K2CO3
NaHCO3
Cs2CO3
Na2CO3
K2CO3
K2CO3
Scheme 2.
6
6
Ts
N
Ts
N
(i)
a
b
c
All the reactions are carried out at room temperature.
In all cases 2.5 equiv base is used.
Isolated yield of products.
I
NHTs
N
4
Ts
1g
Scheme 3. Reagents and conditions: (i) I2 (3 equiv), K2CO3 (1.5 equiv), CH3CN, rt,
6h.
of the product. After a survey of basic reagents to improve the
nucleophilicity of the nitrogen atom we found that the reaction
of 1a with a relatively strong base such as K2CO3, Cs2CO3, or
Na2CO3 proceeds to give 2a11 in good yields (Scheme 1). Among
various bases used K2CO3 was found to produce the highest yield
and also reduced the reaction time (6 h) (Table 1, entry 2).
We have also examined the effect of various solvents regarding
the yield of the reaction and CH3CN was found to give the highest
yield (entry 2). Thus the optimal reaction conditions developed so
far include stirring of the substrate with 1.5 equiv of iodine,
2.5 equiv K2CO3 in CH3CN at room temperature for 6 h.
refluxing condition it afforded product 3 which further supported
the formation of the six-membered ring (Scheme 2).
Compounds containing 1,2,3,4-tetrahydroquinoxaline moiety
are found to possess a wide range of biological activities.12,13
Therefore, we have extended the reaction for the synthesis of
1,2,3,4-tetrahydroquinoxaline derivative (4). Thus when 1g was
subjected to iodocyclization it afforded product 4 in 92% yield
(Scheme 3).
In conclusion, we have achieved an efficient and straightfor-
ward method for the construction of 1,4-benzoxazines via iodocyc-
lization. The procedure reported here is more economic than other
applied methods and avoids separation problems. The applicability
of this method for the synthesis of 1,2,3,4-tetrhydroquinoxaline is
also described and further applications toward expanding the sub-
strate scope are underway. Moreover, during the cyclization pro-
cess iodine atom is incorporated in the final compounds, which
Having demonstrated the optimal reaction condition, we ex-
plored the scope and generality of this cyclization protocol with
the substrates 1b–f and on similar treatment substrates 1b–f affor-
ded the products 2b–f in excellent yields (Table 2).
The formation of the product 2a via 6-exo-cyclization mode is in
accordance with the Baldwin’s rules. Initially the structure of 3,4-
dihydro-2H-1,4-benzoxazines was determined from spectral data.
Furthermore when 2a was treated with DBU in toluene under
Table 2
Summarized results of iodocyclization
Entrya
Substrate
Time (h)
6
Product
Yieldb
88
O
O
1
I
Cl
NHTs
Cl
N
1a
Ts
2a
O
O
2
3
6
6
85
87
I
NHTs
N
Ts
1b
2b
O
O
I
Br
NHTs
O
Br
N
Ts
2c
1c
O
4
5
6
6
6
6
90
92
88
I
H3C
NHTs
O
H3C
N
Ts
1d
2d
O
I
t-Bu
NHTs
O
t-Bu
N
Ts
2e
1e
Me
Me
O
I
Cl
NHTs
Cl
N
Ts
1f
2f
a
All the reactions are carried out under optimized reaction conditions.
Isolated yield of product.
b

K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 5437–5439
5439
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