Totally regio- and stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines under palladium catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.03.081

A new, one-pot palladium catalyzed reaction has been developed for the general synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines at room temperature. The reaction procedure tolerates various functional groups. The method is characterized by reg

Full text of DOI:10.1016/j.tetlet.2010.03.081

Tetrahedron Letters 51 (2010) 2859–2861
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Totally regio- and stereoselective synthesis of (E)-3-arylidene-3,4-
dihydro-2H-1,4-benzoxazines under palladium catalyst
*
Chinmay Chowdhury , Kaushik Brahma, Sanjukta Mukherjee, Anup Kumar Sasmal
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, one-pot palladium catalyzed reaction has been developed for the general synthesis of (E)-3-ary-
lidene-3,4-dihydro-2H-1,4-benzoxazines at room temperature. The reaction procedure tolerates various
functional groups. The method is characterized by regio- and stereoselectivity, operational simplicity,
mild reaction conditions, and short reaction time.
Received 12 February 2010
Revised 17 March 2010
Accepted 19 March 2010
Available online 25 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Benzoxazine
Regio- and stereoselective
Synthesis
Palladium catalyst
The development of simplified and efficient reaction protocol
using palladium catalysts for the synthesis of various heterocyclic
scaffolds has attracted a great deal of attention in recent years. To-
wards this end, selection of appropriate catalyst and reaction con-
ditions are two challenging tasks. Heterocyclic compounds,
possessing heteroatoms at C1 and C4 and fused with an aromatic
ring, are important targets because of their wide range of biological
and therapeutical properties.1 Notably, 2H-1,4-benzoxazine repre-
sents an important heterocyclic core, as several of its derivatives
are shown to display a wide range of activities such as anticancer,2a
antihypertensive,2b antirheumatic,2c serotonin-3(5-HT3) receptor
antagonist,2d neuroprotective antioxidant2e and other activities.2f,g
1,4-Benzoxazine structural motif is also found in the secondary
metabolites of gramineous plants and plays a key role in the de-
fense of the germinating stage of maize, wheat and rye against
the attack of insects, fungi, bacteria and other pathogens.3
In particular, the 3-substituted-3,4-dihydro-2H-1,4-benzoxa-
zines have been integral parts of bioactive natural products,4a po-
tent drugs,4b and important building blocks4c,d which are used in
the synthesis of fascinating molecules of therapeutic interests.
The substitution and stereochemistry at C3 position of 3,4-dihy-
dro-2H-1,4-benzoxazines play important role in pharmacological
activities.5 In recent past, a 3-(ylidene)-1,4-benzoxazine derivative
1 (Fig. 1) have been reported as a potential useful agent for treating
the infections caused by Mycobacterium species.6
derivatives, using mostly conventional methods7 and few modern
palladium catalyzed reactions.8 Although there are many reports
about the synthesis of 2H-1,4-benzoxazines, the stereoselective
synthesis of 2- or 3-ylidene-3,4-dihydro-2H-1,4-benzoxazines 2
(Fig. 1), which could provide biologically attractive chiral analogs
(upon asymmetric hydrogenation9a) and other important building
blocks, are only few in numbers.9 Among these, the palladium cat-
alyzed synthesis of the Z-isomers of compound 2 was demon-
strated recently by Kundu9b followed by Zhou9a under multi-step
reactions. However, to the best of our knowledge there is no report
on the general synthesis of the E-isomers of 3-arylidene-3,4-dihy-
dro-2H-1,4-benzoxazines 2 in one-pot under palladium catalyst.
As part of our efforts in the field of palladium catalyzed reac-
tions10 for the development of efficient strategies for accessing
privileged heterocycles, we have reported very recently the syn-
thesis of 1,4-benzoxazine fused with triazoles.10b We envisaged
that the development of straightforward and general method for
the stereoselective synthesis of the (E)-3-arylidene-3,4-dihydro-
O
PG
R
Me
H
N
N
O
H
3
O
O 1
Emergence of such promising results has stimulated investiga-
tions into the synthesis of 1,4-benzoxazines and their various
O
O
Me
Me
R = Aryl /Alkyl
PG = Protecting
Group
2
1
* Corresponding author. Tel.: +91 33 2499 5862; fax: +91 33 2473 0284.
E-mail address: chinmay@iicb.res.in (C. Chowdhury).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.081

2860
C. Chowdhury et al. / Tetrahedron Letters 51 (2010) 2859–2861
to Pd(PPh3)4 diminished the product yield to 50% (Table 1, entry
Ts
NH
Ts
N
H
6). Employment of PdCl2/PPh3 as catalytic system furnished the
product 5a (61%) at elevated temperature (80 °C) only (Table 1,
entry 7). Substituting PdCl2 with Pd/C, used frequently in various
heteroannulations,12 gave low yield of the product 5a (Table 1,
entry 8). Thus, combination of Pd(OAc)2 and PPh3 appeared to be
the catalyst of choice. Screening of a wide range of bases (all are
not shown in Table 1) led to identification of K2CO3 as the best
option. Among the different solvent systems examined, DMF
appeared to be superior to the others. The aforementioned hetero-
annulation proceeded well at room temperature. The tosyl group
attached with amine functionality of 3 was found to be essential
for the reaction to proceed. Neither free nor otherwise protected
Pd(OAc)2 / PPh3
Ar
+ ArI
K2CO3 , Bu4NBr
DMF, rt
O
O
3
4
5
Scheme 1. Palladium catalyzed synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,
4-benzoxazines.
2H-1,4-benzoxazine 5 could be realized through the palladium cat-
alyzed reaction of N-tosyl-2-(prop-20-ynyloxy)aniline 3 and aryl io-
dide 4. The strategy appeared to be viable by choosing appropriate
catalyst and reaction conditions (Scheme 1). We are reporting
herein the preliminary results obtained so far towards this goal.
Encouraged by the remarkable advancement of Sonogashira
coupling11a,b and its spectacular applications in various heteroann-
ulation strategies,11c,d we initially studied the reaction of the read-
ily available acetylenic substrate 3 with phenyl iodide (4a) under
Sonogashira’s catalyst system [Pd(PPh3)2Cl2/CuI], targeting the het-
eroannulated product 5a (Table 1). However, it furnished the de-
sired product 5a only in low yield (14%) along with the acyclic
product 6 with 35% yield (Table 1, entry 1). In order to obtain more
appropriate reaction conditions, we examined a variety of condi-
tions for the reactions of acetylene 3 with phenyl iodide (4a) by
employing different palladium catalysts, bases, solvents and other
parameters. Some selected data are presented in Table 1. Towards
this endeavor, replacing Pd(PPh3)2Cl2 by Pd(OAc)2/PPh3 (Table 1,
entry 2) afforded (56%) only the acyclic product 6, which could
not be converted to the cyclized product 5a even after heating
the reaction mixture at 90 °C for several hours. Realizing that the
formation of acyclic product 6 is occurring through Sonogashira’s
pathway,11a,b we decided to eliminate the CuI from the reaction
mixture. Indeed removal of CuI and also employment of Et3N as
base, suppressed the formation of product 6 but the desired prod-
uct 5a was still isolated with poor (15%) yield (Table 1, entry 3).
Gratifyingly, changing the base to K2CO3 along with phase-transfer
catalyst (Bu4NBr) furnished exclusively the cyclized product 5a
with 69% yield (Table 1, entry 4). However, removal of PPh3
dropped the product yield to 22% (Table 1, entry 5), indicating its
importance in the product formation. Further change of catalyst
Table 2
Substrate scope for the palladium catalyzed synthesis of 3-arylidene-2H-1,4-benzox-
azines 5a
Entry
1
Iodide (ArI) Ar
Timeb
2 h
Productsc
5
Yield (%)
69
5a
4a
4b
2
3 h
5b
71
3
4
5
2.5 h
2 h
5c
5d
5e
70
78
38
N
4c
S
4d
2.5 h
Me
4e
6
7
5 h
5f
51
55
CF3
Me
4f
Table 1
Optimization of reaction conditions for the synthesis of 3aa,b
Ts
NH
2.5 h
5g
Ph
Ts
NH
H
Ts
N
NO2
Pd catalyst
Base
4g
4i
Ph
+
+ PhI
O
O
O
8
9
5 h
5h
5i
58
74
OMe
CO2Me
3
4a
5a
6
4h
Entry
Catalyst
Co-catalyst
Base
Time (h)
Yield (%)
3.5 h
5a
6
1
2
3
4
Pd(PPh3)2Cl2
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2
Pd(PPh3)4
PdCl2/PPh3
Pd/C, PPh3
CuI
CuI
—
—
—
—
—
—
K2CO3
K2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
2
16
2
4
3
14
0
35
56
30
0
0
0
OMe
15
69
22
50
61
14
N
10
5.5 h
5j
68
5
6
N
OMe
7c
8c
5
5
0
0
4j
a
Acetylene 3 (0.5 mmol), iodide 4 (0.57 mmol), Pd(OAc)2 (0.025 mmol), PPh3
(0.1 mmol), K2CO3 (2.0 mmol), Bu4NBr (0.05 mmol) in DMF (4 ml) at room tem-
a
N-Tosyl-2-(prop-20-ynyloxy)aniline 3 (1.0 equiv), phenyl iodide 4a (1.15 equiv),
perature (35–40 °C).
palladium catalyst (0.05 equiv), PPh3 (0.2 equiv), CuI (0.1 equiv, entries 1 and 2
only), Bu4NBr (0.1 equiv), base (4.0 equiv) in dry DMF at rt (except entries 7 and 8).
b
Time indicated the completion of the reaction as monitored through TLC.
Satisfactory spectroscopic and analytical data were obtained for all new
c
b
Rt represents the temperature between 35 and 40 °C.
c
products.
Reaction was heated at 80 °C.

C. Chowdhury et al. / Tetrahedron Letters 51 (2010) 2859–2861
2861
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scope and generality of this transformation (Table 2). To assess the
impact of different structural motifs on the reaction, we examined
various iodides 4 having different functional groups (e.g., nitro, es-
ter, methyl, trifluoromethyl, methoxy, etc.) which were found to be
tolerant to the reaction conditions. Apparently, heteroaryl iodides
afforded better product yields compared to simple aryl iodides.
Similarly, electron-withdrawing groups present in aryl iodide 4
facilitated the reactions compared to electron-donating groups.
This method was found to be completely regio- and stereoselec-
tive. No formation of seven membered ring product via 7-endo-
dig mode or of products with Z-stereochemistry was observed.
The spectral and analytical data13 of products 5 were in accordance
with the assigned structures. In 1H NMR, the olefinic proton ap-
peared in downfield (dH >7 ppm) due to the deshielding effect of
the N-tosyl group, indicating the E-stereochemistry of the exocy-
clic double bond. The chemical shifts (dH) of the olefinic proton
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Floris, C.; Melis, S.; Sotgiu, F.; Cerioni, G. J. Heterocycl. Chem. 1986, 23, 1815.
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2678; (c) Chowdhury, C.; Mandal, S. B.; Achari, B. Tetrahedron Lett. 2005, 46,
8531. and Ref. 7b.
3
came from NOE experiments and JCH coupling constant value be-
tween the vinylic proton and methylenic carbon (OCH2) of 1,4-oxa-
3
zine ring. In literature,14 JCH values less than 5 Hz or more than
7 Hz were attributed to Z- or E-isomer, respectively. In our case,
3JCH values of the isolated products were between 7 and 8 Hz, sup-
porting E-stereochemistry. Finally, single crystal X-ray analysis15 of
product 5d (for ORTEP diagram see Supplementary data) con-
firmed the stereochemistry and structure simultaneously.
The reaction proceeded through activation of the triple bond of
substrate 3 followed by concurrent cyclization leading to the prod-
uct 5 with E-stereochemistry.16
In conclusion, we have developed a general and practical
methodology that provides rapid access to a variety of (E)-3-arylid-
ene-1,4-benzoxazines with moderate to excellent yields at room
temperature. The methodology uses readily available inexpensive
starting materials and is characterized by regio- and stereoselectiv-
ity, operational simplicity, mild reaction conditions and short reac-
tion time. This method may find applications in synthetic organic
chemistry and medicinal chemistry as well.
11. (a) Sonogashira, K.; Tohda, Y.; Haghihara, N. Tetrahedron Lett. 1975, 16, 4467;
(b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46; (c) Zeni, G.; Larock, R. C.
Chem. Rev. 2006, 106, 4644; (d) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
874.
12. Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
13. General procedure for the synthesis of (E)-3-arylidene-4-tosyl-3,4-dihydro-2H-
[1,4]benzoxazine (5): Pd(OAc)2 (4 mg, 5 mol %) and PPh3 (20 mg, 20 mol %) were
dissolved in dry DMF (3 mL) under argon atmosphere and stirred magnetically
for 10 min. Then aryl iodide 4 (0.382 mmol) dissolved in dry DMF (2 mL) was
added slowly to the reaction mixture followed by the addition of K2CO3
(183 mg, 1.329 mmol) and n-Bu4NBr (11 mg, 0.033 mmol). After stirring of
another 10 min, the acetylenic compound 3 (0.332 mmol) was added and the
whole reaction mixture was allowed to stir at room temperature (35–40 °C)
under argon atmosphere. After completion of the reaction (monitored by TLC),
the solvent was removed in vacuum; the crude residue was diluted with water
(10 mL) and extracted with ethyl acetate (3 ꢀ 15 mL). The combined organic
extracts were washed with brine (10 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The resulting residue was
purified through silica gel (100–200 mesh) column chromatography using
ethyl acetate-petroleum ether (2:98 to 30:70, v/v) as eluent to furnish the
desired product 5. (E)-3-[(Naphthalen-1-yl)methylidene]-4-tosyl-3,4-dihydro-
2H-1,4-benzoxazine (5b): Yield: 71%; white solid, mp: 154–156 °C; 1H NMR
(300 MHz, CDCl3) d 2.39 (s, 3H), 4.05 (s, 2H), 6.77 (d, J = 8.1 Hz, 1H), 7.04 (t,
J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.18–7.25 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H),
7.53–7.61 (m, 4H), 7.75 (s, 1H), 7.86 (t, J = 9.1 Hz, 2H), 7.96 (d, J = 7.8 Hz, 1H),
8.10 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 21.58, 61.98, 117.08,
121.16, 124.93, 124.99, 125.16, 125.89, 126.36, 126.44, 126.72, 126.75, 127.71,
128.36, 128.84, 129.78, 129.96, 130.56, 131.42, 131.84, 133.38, 134.51, 144.58,
147.29; IR (KBr, cmꢁ1) 3056, 1591, 1360, 1165; ESI-MS m/z 450.18 [M+Na]+;
Anal. Calcd for C26H21NO3S: C, 73.04; H, 4.95; N, 3.28. Found: C, 73.09; H, 5.01;
N, 3.24.
Acknowledgments
K.B. thanks CSIR, India for the award of fellowship. C.C. thanks
the Director, IICB, Kolkata for his support.
Supplementary data
14. Voegeli, U.; von Philipsborn, W. Org. Magn. Reson. 1975, 7, 617. and see also Ref.
9d.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.081.
15. Product 5d was crystallized by slow evaporation from petroleum ether (bp.
60–80 °C); Crystal data: C20H17NO3S2, M = 383.47, orthorhombic P, space group
0
0
0
0
P2(1)2(1)2(1), a = 6.2186(7) ÅA, b = 14.4311(19) ÅA, c = 20.025(2) ÅA, V = 1797.1(4) ÅA3,
References and notes
Z = 4, Dcalcd = 1.417 mg mꢁ3, T = 296(2) K,
l
= 0.316 mmꢁ1, F(000) = 800, k =
0.71073 Å, processed reflections 4426 and unique reflections 2282, Final R
factor = 0.0463. The crystal data has been deposited at Cambridge
Crystallographic Data Centre [CCDC No. 745154]. Copies of the data can be
obtained free of charge via www.ccdc.ac.uk/conts/retrieving.html or CCDC, 12
union Road, Cambridge CB2 1EZ, UK.
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IV, Six-Membered and Larger Hetero-Rings with Maximum Unsaturation. In
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16. Mechanistically, the stereoselective (E) formation of product 5 can be explained as
described in the following steps: (a) generation of
r-arylpalladium(II) iodide
(ArPdIII) through oxidative addition of aryl iodide 3 to palladium(0) which is
formed in situ from Pd(OAc)2 and PPh3; (b) activation of the triple bond of
substrate 5 through the palladium of ArPdIII; (c) intramolecular nucleophilic
attack of NH-Ts on activated alkyne via 6-exo-dig mode resulting in the
formation of 1,4-benzoxazine ring with exo-methylene (at C3) attached with
PdII-Ar moiety; (d) reductive elimination of palladium regenerates Pd(0) and
affords the product 5 with E-stereochemistry.