Alumina-supported Cu(II), A versatile and recyclable catalyst for regioselective ring opening of aziridines and epoxides and subsequent cyclization to functionalized 1,4-benzoxazines and 1,4-benzodioxanes

Article abstract of DOI:10.1021/jo101916e

An easily accessible catalyst, alumina-supported copper(II), efficiently catalyzes the ring opening of aziridines and epoxides followed by cyclization of the corresponding intermediate to produce a variety of functionalized 1,4-benzoxazines and 1,4-benzodioxanes, respectively, in one pot without any ligand in high yields. The ring cleavages of aziridines and epoxides are highly regioselective. The catalyst is inexpensive, non-air-sensitive, environmentally friendly, and recyclable. The function of the catalyst and the reaction pathway are postulated. This protocol is successfully utilized for the formation of three carbon-heteroatom bonds, namely, C-O, C-N, and C-S, in one pot.

Full text of DOI:10.1021/jo101916e

pubs.acs.org/joc
Alumina-Supported Cu(II), A Versatile and Recyclable Catalyst for
Regioselective Ring Opening of Aziridines and Epoxides and Subsequent
Cyclization to Functionalized 1,4-Benzoxazines and 1,4-Benzodioxanes
Sukalyan Bhadra,† Laksmikanta Adak,† Subhas Samanta,‡ A. K. M. Maidul Islam,§
Manabendra Mukherjee,§ and Brindaban C. Ranu*,†
†Department of Organic Chemistry, and ‡Department of Inorganic Chemistry, Indian Association for the
Cultivation of science, Jadavpur, Kolkata-700031, India, and Surface Physics Division,
Saha Institute of Nuclear Physics, Kolkata-700067, India
§
ocbcr@iacs.res.in
Received September 29, 2010
An easily accessible catalyst, alumina-supported copper(II), efficiently catalyzes the ring opening of
aziridines and epoxides followed by cyclization of the corresponding intermediate to produce a
variety of functionalized 1,4-benzoxazines and 1,4-benzodioxanes, respectively, in one pot without
any ligand in high yields. The ring cleavages of aziridines and epoxides are highly regioselective. The
catalyst is inexpensive, non-air-sensitive, environmentally friendly, and recyclable. The function of
the catalyst and the reaction pathway are postulated. This protocol is successfully utilized for the
formation of three carbon-heteroatom bonds, namely, C-O, C-N, and C-S, in one pot.
Introduction
reversible and irreversible antagonists at adrenergic receptor.5
They are also found in a variety of natural products.6
The molecules containing 1,4-benzoxazines and 1,4-benzo-
dioxanes moieties have attracted considerable interest in recent
times because of their potential therapeutic properties.1,2 Flu-
mioxazin 1 and thidiazimin 2 (Figure 1) have been successfully
used as effective herbicides with protoporphyrinogen oxidase
inhibiting action in chlorophyll biosynthetic pathway.3 2-Ary-
lidine-4-aminoalkyl-2H-1,4-benoxazin-(4H)-ones and related
compounds were found to exhibit significant CNS (central
nervous system) depression.4 On the other hand 2-N,N-diethy-
laminomethyl-1,4-benzodioxane 4and its derivatives are used as
Thus, the synthesis of these heterocyclic units have re-
ceived renewed interest. Several protocols for the synthesis of
benzoxazines, such as cyclo-condensation of aminophenols
with R-halogeno acyl bromides followed by carbonyl reduc-
tion using BH3,7 alkylation of o-nitrophenol with haloester
and subsequent reductive cyclization,8 and epoxide ring
opening with o-fluorosulfonamides followed by cyclization
under solid-liquid phase transfer catalysis9 in neat, are
noteworthy among others.10 On the other hand, the most
common method for the synthesis of 1,4-benzodioxanes are
(1) (a) Combs, D. W.; Rampulla, M. S.; Bell, S. C.; Klaubert, D. H.;
Tobia, A. J.; Falotico, R.; Hertlein, R. B.; Lakas-Weiss, C.; Morre, C. J. B.
ꢀ
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Merour, J.-Y. J. Med. Chem. 1998, 41, 3142–3158. (c) Largeron, M.; Dupuy,
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J. Chem. Soc., Chem. Commun. 1979, 695–695. (b) Willard, A. K.; Smith,
R. L.; Cragoe, E. J., Jr. J. Org. Chem. 1981, 46, 3846–3852.
(3) Huang, M.-Z.; Luo, F.-X.; Mo, H.-B.; Ren, Y.-G.; Wang, X.-G.; Ou,
X.-M.; Lei, M.-X.; Liu, A.-P.; Huang, L.; Xu, M.-C. J. Agric. Food Chem.
2009, 57, 9585–9592.
(5) Avner, B. P.; Triggle, D. J. J. Med. Chem. 1974, 17, 197–200.
(6) Chu, D. T. W.; Maleczka, R. E., Jr. J. Heterocycl. Chem. 1987, 24,
453–456.
(7) Butler, R.; Chapleo, C. B.; Myers, P. L.; Welbourn, A. P. J. Hetero-
cycl. Chem. 1985, 177–181.
(8) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.; Yoden,
T.; Uchida, W.; Asano, M.; Fujita, S.; Yanagisawa, I.; Fujikura, T. Chem.
Pharm. Bull. 1996, 44, 103–114.
(9) Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Ind. Eng. Chem. Res.
2003, 42, 680–686.
(10) (a) Kuroita, T.; Sakamori, M.; Kawakita, T. Chem. Pharm. Bull.
1996, 44, 756–764. (b) Chen, D.; Shen, G.; Bao, W. Org. Biomol. Chem. 2009,
7, 4067–4073. (c) Brown, D. W.; Ninan, A.; Sainsbury, M. Synthesis 1997,
895–898.
(4) Turk, C. F.; Krapcho, J.; Michel, I. M.; Weinryb, I. J. Med. Chem.
1977, 20, 729–732.
DOI: 10.1021/jo101916e
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Published on Web 11/11/2010
J. Org. Chem. 2010, 75, 8533–8541 8533
2010 American Chemical Society

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SCHEME 1. Copper-Catalyzed Ring Opening-Cyclization Using
2-Iodophenols
TABLE 1. Optimization of Reaction Conditionsa
FIGURE 1. Some biologically important compounds.
based on the reaction of catechol with epoxides or R-haloalk-
enes or similar substrates.11 A Pd-catalyzed intramolecular
etherification of R-halo alcohols leading to 1,4-benzodiox-
anes is also reported.12 However, despite the availability of
these multistep procedures a more efficient one-pot process is
highly desirable.
entry
X
solvent
base
temp (ꢀC) time (h) yield (%)
1
2
3
4
5
6
7
8
NTs THF
K2CO3
toluene K2CO3
H2O
DMF
DMF
DMF
DMF
DMF
THF
70
110
100
100
100
100
100
100
70
110
100
100
100
100
100
100
16
16
16
8
8
8
16
16
16
16
16
8
37
19
0
93
0b
85
55
46
30
tr
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
NaOH
K2CO3
The domino reaction is a useful and attractive tool in organic
synthesis as it provides a cost- and energy-effective process.13
Recently, Sekar et al. reported a synthesis of trans-3,4-dihydra-
2H-1,4-benzoxazine by CuI/ethylenediamine-catalyzed domi-
no aziridine ring opening with o-iodophenol followed by cycli-
zation.14 However, this method employed only cycloalkane
fused aziridines, and not a single reaction with noncycloalkane
fused aziridine was addressed. Earlier, Bao et al. described a
similar approach for the synthesis of 1,4-benzodioxanes involv-
ing ring opening of epoxides and cyclization catalyzed by
Cu2O/1,10-phenanthroline.15 Although this method covers a
wide range of epoxides, in several reactions regioselectivity of
epoxide ring cleavage is not controlled. Considering the great
potential of 1,4-benzoxazines and 1,4-benzodioxanes, we be-
came interested to develop a general protocol for access to both
molecules. Recently we introduced a stable alumina-supported
Cu(II) catalyst for the coupling of thiols with aryl halides16a and
electrophilic substitution by PhSeBr in organoboranes, orga-
nosilanes, and organostannanes.16b We report here another
novel application of this unique catalyst for the ring opening of
aziridines and epoxides by 2-iodophenols and simultaneous
cyclization to produce the 1,4-benzoxazines and 1,4-benzodiox-
anes, respectively (Scheme 1)
9
O
10
11
12
13
14
15
16
toluene K2CO3
H2O
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K3PO4
NaOH
0
DMF
DMF
DMF
DMF
DMF
20
81
0b
35
51
8
8
16
16
aReactions were carried out in the presence of 4 mol % of Cu/Al2O3
catalyst unless otherwise stated. bReactions were carried out in the
absence of Cu/Al2O3 catalyst.
parameters such as solvent, base, temperature, etc. for a
representative reaction of 2-iodophenol and 2-phenyl-N-
tosyl aziridine/styrene oxide in the presence of Cu/Al2O3
catalyst. The results are summarized in Table 1. Among the
various solvents investigated DMF was found to perform
better at 100 ꢀC for both the reactions. Potassium carbonate
was found to give the best yields in aziridine reactions
(Table 1, entry 4), whereas the reactions of epoxides needed
cesium carbonate (Table 1, entry 13). The amount of catalyst
was optimized to 4 mol %. Nevertheless, the reactions did
not proceed at all in the absence of catalyst (Table 1, entries 5
and 14).
Results and Discussion
Thus, in a typical experimental procedure, a mixture of
aziridine/epoxide and 2-iodophenol in DMF was heated at
100 ꢀC in the presence of Cu/Al2O3 and a base, K2CO3/
Cs2CO3, for a certain period of time (TLC). Standard work-
up and purification by column chromatography provided
the product.
A series of diversely functionalized 1,4-benzoxazines were
synthesized by this procedure using a variety of substituted
N-tosyl aziridines. The results are reported in Table 2. This
reaction is equally effective for the participation of 2-phenyl-
substituted, 2,3-dialkyl-disubstituted, and cycloalkane fused
aziridines. The reactions of 2-substituted and 2,3-disubsti-
tuted aziridines were not addressed earlier.14 However, these
reactions are of much interest because of the issue of the
To optimize the reaction conditions, a series of experi-
ments were carried out with variation of different reaction
(11) (a) Koo, J.; Avakian, S.; Martin, G. J. J. Am. Chem. Soc. 1955, 77,
5373–5375. (b) Willard, A. K.; Smith, R. L.; Cragoe, E. J., Jr. J. Org. Chem.
1981, 46, 3846–3852. (c) Massacret, M.; Lhoste, P.; Lakhmiri, R.; Parella, T.;
Sinou, D. Eur. J. Org. Chem. 1999, 2665–2673.
(12) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202–12206.
(13) (a) Grondal, C.; Jeanty, M.; Enders, D. Nat.. Chem. 2010, 2, 167–
178. (b) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.;Eur. J. 2009, 15,
12168–12179. (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996,
96, 195–206. (d) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341–5378.
(14) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11, 1923–1926.
(15) Bao, W.; Liu, Y.; Lv, X.; Qian, W. Org. Lett. 2008, 10, 3899–3902.
(16) (a) Bhadra, S.; Sreedhar, B.; Ranu, B. C. Adv. Synth. Catal. 2009,
351, 2369–2378. (b) Bhadra, S.; Saha, A.; Ranu, B. C. J. Org. Chem. 2010, 75,
4864–4867.
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TABLE 2. Copper-Catalyzed Synthesis of 1,4-Benzoxazines
entries 1-4) are highly regioselective, ending up with only
one regioisomer using Cu/Al2O3 catalyst. The identity of the
product (Table 2, entry 1) was unequivocally established as
3,4-dihydro-2-phenyl-4-tosyl-(2H)benzo[b][1,4]oxazine by
X-ray crystal data (Figure 2, 2a).17a By analogy, the other
products (Table 2, entries 2-5) were also characterized as the
corresponding 2-phenyl/hexyl benzoxazine by comparison
of their spectral data (IR, 1H and 13C NMR) with those of
product in entry 1, Table 2. To investigate the regioselectivity
of cleavage of aziridine and epoxide rings a few control
experiments were carried out. The reaction of 2-phenyl-N-
tosyl aziridine with phenol in the presence of Cu/Al2O3 and
K2CO3 provided only one product by the cleavage at 2-posi-
tion adjacent to the Ph ring possibly because of stabilization
of carbocation by phenyl ring (Scheme 2). The same reaction
with K2CO3 only or Al2O3/K2CO3 provided a mixture of two
regioisomers together with unreacted aziridines. This indi-
cates a decisive role of Cu/Al2O3 catalyst in aziridine ring
cleavage leading to only one isomer (Scheme 2). Very inter-
estingly, for comparison, when this reaction was performed
with CuI/ethylenediamine,14 no benzoxazine was obtained.
Moreover, the reaction of 2-iodophenol with cyclooctane
fused N-tosyl aziridine, which gave 48% yield in an earlier
procedure,14 furnished 89% yield by our procedure. This
demonstrates the superiority of our catalyst over CuI/
ethylenediamine.14 In fact, the reaction of 2-iodophenols
with all cycloalkane-fused aziridines provided high yields
of corresponding benzoxazines. The ring junction stereo-
chemistry of the products in entries 8-10 of Table 2 is found
1
to be trans as determined by the H NMR spectroscopic
data, which are in good agreement with the values of the
reported compounds.14 The X-ray crystal structures of the
products in entries 8 and 15 (Table 2) also confirmed the
trans stereochemistry (Figure 2, 2h, 2o).17b,c The formation
of one single regioisomeric product from the reaction of
2-iodophenol and indene-fused aziridine is also very note-
worthy. The structure of this product was also confirmed by
X-ray crystal data (Figure 2, 2p).17d Thus all the reactions
(aziridine cleavage þ cyclization) using this Cu/Al2O3 cata-
lyst are highly regio- and stereoselective. Several substituted
2-iodophenols (Table 2, entries 2, 3, 4, 7, 12, 13, and 14)
participated in this reaction without any difficulty, produc-
ing highly functionalized 1,4-benzoxazines that are of much
potential for pharmaceutical uses.
SCHEME 2. Cu-Catalyzed Regioselective Aziridine Ring Opening
Similarly, the reactions of 2-iodophenols with epoxides
produced corresponding 1,4-benzodioxanes via epoxide ring
aIsolated yield of pure product.
(17) (a) CCDC no. for the compound 2a, 786009. (b) CCDC no. for the
compound 2h, 786010. (c) CCDC no. for the compound 2o, 786008.
(d) CCDC no. for the compound 2p, 786006. (e) CCDC no. for the
compound 3f, 786007.
regioselectivity in the ring opening of aziridine and hence
formation of product. We have found that the ring open-
ing of the 2-substituted aziridines and cyclization (Table 2,
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FIGURE 2. ORTEP diagram of some functionalized 1,4-benzoxazines and 1,4-benzodioxanes.
opening followed by cyclization. The results are reported in
Table 3. These reactions are also highly regioselective, pro-
ducing only one regioisomeric set of products in contrast to
the formation of a mixture of regioisomers using Cu2O/1,10-
phenanthroline.15 Very interestingly the minor product ob-
served using Cu2O/1,10-phenanthroline was obtained as the
sole product in our procedure using Cu/Al2O3 as shown in
Table 3, entries 3 and 5. The regioisomeric identities of the
products are established by comparison of their spectro-
scopic data (1H and 13C NMR) with those reported earlier.15
In one case (Table 3, entry 6), the structure was also con-
firmed by X-ray crystal data (Figure 2, 3f).17e
In general, the reactions of both aziridines and epoxides are
very clean and high-yielding compared to other methods. The
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TABLE 3. Copper-Catalyzed Synthesis of 1,4-Benzodioxanes
SCHEME 3. Cu-Catalyzed One-Pot Synthesis of 1,4-Benzoxazine
Thioethers and 1,4-Benzoxazine Amines
aIsolated yield of pure product.
procedure is compatible with a variety of functional groups
such as CHO, Cl, Br, CO2Et, OMe, etc. present in 2-iodophenol
and differently substituted aziridines and epoxides.
The Cu/Al2O3 catalyst was recovered and reused for 7
subsequent reactions without any appreciable loss of efficiency.
No significant leaching of the catalyst in the reaction mixture
was observed (0.497 mmol g-1 after seventh cycle compared
to 0.517 mmol g-1 as determined by ICP-MS). A remarkable
application of this protocol is demonstrated by the consecutive
formation of three carbon-heteroatom bonds, namely, C-O,
C-N and C-S, in one stroke leading to the synthesis of 1,4-
benzoxazine thioethers and amines (Scheme 3). These com-
pounds (4a, 4b, 4c, and 4d) are of much importance as poten-
tial herbicides and are usually synthesized through a multistep
process.3
the 2p3/2 lines at 934.7 and 933.7 eV, respectively, with char-
acteristic shakeup features (Figure 3a and c).19
This clearly indicates that Cu is in a þ2 oxidation state
before and after the reaction (a slightly higher value in the
binding energy of Cu2þ in the fresh catalyst is due to a com-
bined contribution of CuSO4 and Cu(OH)2 on the surface of
alumina). On the other hand, the X-band EPR spectrum of
the fresh catalyst shows four well-defined hyperfine lines for
a solid sample at 77 K resulting from the coupling of the
unpaired electron with the nuclear spin of Cu(II) (Figure 4).
The regenerated catalyst also shows a very similar EPR
To investigate the mechanism, a series of experiments were
conducted. The X-ray photo electron spectroscopic (XPS)
study of the fresh and used catalyst at the Cu 2p level shows
(19) (a) Chary, K.V. R.; Sagar, G. V.; Srikanth, C. S.; Rao, V. V. J. Phys.
Chem. B. 2007, 111, 543–550. (b) Choudary, B. M.; Sridhar, C.; Kantam,
M. L.; Venkanna, G. T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948–
9949. (c) Adolphi, B.; Berger, O.; Fischer, W.-J. Appl. Surf. Sci. 2001, 179,
102–108. (d) Handbook for X-ray Photoelectron Spectroscopy; Chastain, J.,
Roger, C. K., Jr., Eds.; Physical Electronics Inc.: Eden Prairie, MN, 1995.
(18) Saxena, A. K.; Ram, S.; Saxena, M.; Singh, N.; Prathipati, P.;
Jain, P. C.; Singh, H. K.; Anand, N. Bioorg. Med. Chem. 2003, 11, 2085–
2090.
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FIGURE 3. XPS of Cu 2p3/2 for (a) fresh catalyst, (b) Cu(II)-intermediate complex, and (c) used catalyst; (d) XPS of N 1s for Cu(II)-
intermediate complex.
SCHEME 4. Probable Mechanistic Pathway
FIGURE 4. X-band EPR spectral pattern of Cu2þ in (a) fresh
catalyst, (b) used catalyst, and (c) intermediate complex B.
spectrum as observed in the fresh catalyst. The g values of the
fresh catalyst are g =2.41367, 2.5408 and g^=2.1406, and those
of the used catalyst are g = 2.3940, 2.5296 and g^ = 2.0741,
indicating a tetragonally distorted octahedral geometry for
Cu(II).20 The regioselective formation of 1,4-benzoxazine and
1,4-benzodioxane from the corresponding aziridines and epox-
ides indicates a Cu(II)-catalyzed regioselective ring opening21
followed by C-N or C-O coupling leading to the product.
Thus the copper catalyst shows a dual role in ring opening
(20) (a) Matsuoka, M.; Ju, W.-S.; Takahashi, K.; Yamashita, H.; Anpo,
as well as cross-coupling steps. To understand the cross-
M. J. Phys. Chem. B 2000, 104, 4911–4915. (b) Kantam, M. L.; Chakravarti,
coupling pathway via C-N bond formation, cyclopentane-
R.; Neelima, B.; Arundhati, R.; Sreedhar, B. Appl. Catal., A 2007, 333, 136–142.
(21) (a) Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013–
7022. (b) Hong, D.; Lin, X.; Zhu, Y.; Lei, M.; Wang, Y. Org. Lett. 2009, 11,
fused aziridine was chosen as a model substrate as the corre-
sponding ring-opened product was easily prepared on treatment
with 2-iodophenol using K2CO3 alone. On the other hand,
ꢀ
5678–5681. (c) Barluenga, J.; Vazquez-villa, H.; Ballesteros, A.; Gonzalez,
J. M. Org. Lett. 2002, 4, 2817–2819.
ꢀ
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a styrene aziridine provided a mixture of products on similar
treatment. Thus, when the fresh catalyst was treated with the
ring-opened product of cyclopentane-fused aziridine with
2-iodophenol, a dirty white complex B was formed. The EPR
spectral pattern of this intermediate complex B exhibited
a dramatic change from the earlier g values now at 2.212 with
g =2.41276, 2.4840 and g^=2.04, 2.124, which is indicative
of an even more distorted octahedral environment with an
axial distortion at the metal center. The formation of these
type of intermediate is also not unprecedented.19b,22 The
XPS of Cu 2p3/2 and N 1s lines appear at 935.6 and 401.8 eV,
respectively, which is assigned for Cu-N bonds (the larger
peak at 933.2 is due to Cu-O bond) (Figure 3b and d). The
atom ratio of Cu:N was found to be 0.5, indicating two
N-atoms are associated with each Cu(II) unit. Thus the
formation of Cu(II)-intermediate complex B is proposed.
Although we were not being able to isolate any further
intermediate complex, we speculate that a Cu-assisted nu-
cleophilic displacement of I- of the arene19b,23 by the N of the
aziridine residue took place via the transients C and D. The
elimination of the suitable benzoxazine or benzodioxane from
the coordination sphere of Cu(II) regenerates the catalyst,
which initiates the next cycle. Thus, on the basis of these results
of model study with cyclopentane-fused aziridine, we suggest a
possible general reaction pathway as outlined in Scheme 4.
recorded at 300 and 500 MHz for 1H NMR and at 75 and 125
MHz for 13C NMR in CDCl3 solutions. XPS measurements
were performed with a spectrometer fitted with an EA125 hemi-
spherical analyzer and a monochromatized Al KR (1486.6 eV)
source. X-band EPR measurements were carried out at 77 K.
The Cu/Al2O3 was prepared following our procedure reported
earlier.16a
General Experimental Procedure for the Synthesis of 1,4-Ben-
zoxazines. Representative Procedure for the Synthesis of 2-Phen-
yl-4-(toluene-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(Table 2, entry 1). To a solution of 2-iodophenol (264 mg,
1.2 mmol) and 2-phenyl-1-(toluene-4-sulfonyl)-aziridine
(274 mg, 1 mmol) in DMF (4 mL) were added K2CO3 (276 mg,
2 mmol) and Cu/Al2O3 catalyst (80 mg, 4 mol %), and the mixture
was heated at 100 ꢀC (oil bath) for 8 h. The reaction mixture was
allowed to cool, extracted with EtOAc (3 ꢀ 20 mL), and washed
with dilute NaOH solution (5%) and brine. The organic phase was
dried (Na2SO4) and evaporated to leave the crude product, which
was purified by column chromatography over silica gel (hexane/
EtOAc=90:10) to provide pure 2-phenyl-4-(toluene-4-sulfonyl)-
3,4-dihydro-2H-benzo[1,4]oxazine as a yellow solid (340 mg, 93%)
mp 146 ꢀC; IR (KBr) 3018, 2928, 2864, 1915, 1799, 1726, 1597,
1583, 1489, 1450, 1356, 1215, 1166, 1057, 927, 754 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.42 (s, 3H), 3.26 (dd, J1 = 10.35 Hz, J2 =
14.4 Hz, 1H), 4.21-4.25 (m, 1H), 4.36-4.42 (m, 1H), 6.93-7.03
(m, 2H), 7.11-7.13 (m, 1H), 7.21-7.23 (m, 2H), 7.30 (d, J =
8.02 Hz, 2H), 7.35-7.39 (m, 3H), 7.59 (d, J = 8.02, 2H) 7.94 (d, J =
8.193, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 21.7, 50.4, 73.3,
117.8, 121.2, 123.5, 124.9, 126.0 (2C), 126.5, 127.5 (2C), 128.9 (3C),
130.1 (2C), 135.6, 137.2, 144.6, 147.5 ppm. HRMS: m/z calcd for
C21H19NO3S [M þ Naþ ] 388.2833; found 388.0983.
Conclusion
In summary, we have developed a very powerful tool for
the synthesis of 1,4-benzoxazines and 1,4-benzodioxanes by
a sequential one-pot ring opening/cyclization of aziridines
and epoxides, respectively, using a heterogeneous Al2O3-
supported Cu(II) catalyst. This protocol has also been used
for a one-pot synthesis of 1,4-benzoxazine thioethers and
amines demonstrating formation of the consecutive three
bonds C-O, C-N, and C-S in one stroke. These 1,4-benzox-
azine thioethers and amines are of high potential as herbicides.
In addition this Cu/Al2O3-catalyzed procedure offers signifi-
cant advantages over other methods because of its high yields,
excellent regioselectivity in aziridine and epoxide ring opening,
generality (applicable to aziridines and epoxides), versatility
(compatibility with a wide variety of substrates), and reusa-
bility of the catalyst . To the best of our knowledge, this is the
first report of control of regioselectivity in Cu-catalyzed
domino ring opening/cyclization mediated synthesis of 1,4-
benzoxazines and 1,4-benzodioxanes. It is likely that solid
alumina surface acts as a microligand and promotes creation
of a stable active site that provides unique catalytic function
providing better control over regio- and stereoselectivity.24
Nevertheless, this demonstrates the potential of our alumina-
supported Cu(II) catalyst for a variety of organic reactions.
After workup the residual catalyst was washed with water
(5 ꢀ 3 mL), EtOAc (3 ꢀ 4 mL), and acetone (3 ꢀ 4 mL). The
solid was then dried at 100 ꢀC for 8 h for further use. The catalyst
was recycled 7 times without appreciable loss of activity.
General Experimental Procedure for the Synthesis of 1,4-
Benzodioxanes. Representative Procedure for the Synthesis of
2-Phenyl-2,3-dihydro-benzo[1,4]dioxane (Table 3, entry 1). To a
solution of 2-iodophenol (264 mg, 1.2 mmol) and styrene oxide
(180 mg, 1.5 mmol) in DMF (4 mL) were added Cs2CO3
(650 mg, 2 mmol) and Cu/Al2O3 catalyst (80 mg, 4 mol %), and
the mixture was heated at 100 ꢀC (oil bath) for 8 h. The reaction
mixture was allowed to cool, extracted with EtOAc (3 ꢀ 20 mL),
and washed with dilute NaOH solution (5%) and brine. The
organic phase was dried (Na2SO4) and evaporated to leave the
crude product, which was purified by column chromatography
over silica gel (hexane/EtOAc = 90:10) to provide pure 2-phen-
yl-2,3-dihydro-benzo[1,4]dioxane as a colorless liquid (172 mg,
81%). The spectroscopic data (1H NMR and 13C NMR) of
this product are in good agreement with those of an authentic
sample.15
Preparation of Complex B. A mixture of Cu/Al2O3 catalyst
(100 mg, 5 mol %) and the ring-opened product of cyclopentene-
fused N-tosyl aziridine by 2-iodo phenol (458 mg, 1 mmol) in
DMF (3 mL) was heated at 100 ꢀC for 8 h. The mixture was
cooled to room temperature, the supernatant liquid was filtered
off, and the dirty white residue was thoroughly washed with
water, ethylacetate, and acetone and dried to get the complex B.
Recyclability of the Catalyst. The catalyst was recycled up to a
seventh run without appreciable loss of efficiency for the rep-
resentative reaction of 2-phenyl-N-tosyl aziridine and 2-iodo-
phenol (Figure 5). The copper loading of the catalyst after
seventh cycle was found to be 0.497 mmol g-1 compared to
0.517 mmol g-1 in the fresh catalyst (as detected by ICP-MS).
Although the representative procedure is based on a 1 mmol
scale reaction, it has been scaled up to 5 g scale with reproducible
results. The compounds are of high purity as checked by 13C
NMR.
Experimental Section
General. IR spectra were taken as thin films for liquid
compounds and as KBr pellets for solids. NMR spectra were
(22) Choudary, B. M.; Madhi, S.; Kantam, M. L.; Sreedhar, B.; Iwasawa,
Y. J. Am. Chem. Soc. 2004, 126, 2292–2293.
(23) Lindley, J. Tetrahedron 1984, 40, 1433–1456. (b) Suzuki, H.; Abe, H.
Tetrahedron Lett. 1995, 36, 6239–6242.
(24) (a) Mori, K.; Yamaguchi, K.; Hara, T.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2002, 124, 11572–11573. (b) Mori, K.; Hara,
T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2003, 125,
11460–11461.
J. Org. Chem. Vol. 75, No. 24, 2010 8539

Bhadra et al.
JOCArticle
1597, 1579, 1487, 1346, 1251, 1170, 1089, 945, 896, 812, 759,
1
684 cm-1; H NMR (300 MHz, CDCl3) δ 0.80-0.91 (m, 6H),
1.28-1.36 (m, 6H), 1.47-1.56 (m, 2H), 2.33 (s, 3H), 3.06-3.09
(m, 1H), 4.10-4.16 (m, 1H), 6.76 (d, J = 9 Hz, 1H), 6.92 (t, J =
8.4 Hz, 1H), 7.02 (t, J = 6.67 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H),
7.45 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 9.0 Hz, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 13.8 (2C), 18.5, 18.9, 21.6, 26.7, 33.8,
55.5, 73.6, 117.1, 120.9, 121.6, 126.1, 126.2, 127.3 (2C), 129.9 (2C),
135.9, 144.1, 147.4 ppm. HRMS: m/z calcd for C21H27NO3S [M þ
Naþ ] 396.1607; found 396.1609.
3,4-Dihydro-6-methyl-2,3-dipropyl-4-tosyl-2H-benzo[b][1,4]oxa-
zine (Table 2, entry 7). White solid (mp 121 ꢀC); IR (KBr) 3031,
2956, 2934, 2874, 1596, 1499, 1467, 1349, 1237, 1170, 955, 809,
FIGURE 5. Recyclability of the Cu/Al2O3 catalyst.
1
687 cm-1; H NMR (300 MHz, CDCl3) δ 0.78-0.91 (m, 6H),
1.16-1.27 (m, 6H), 1.28-1.50 (m, 2H), 2.29 (s, 3H), 2.33 (s, 3H),
3.01-3.04 (m, 1H), 4.06-4.11 (m, 1H), 6.64 (d, J = 8.3 Hz, 1H),
6.83-6.86 (m, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz,
2H), 7.72 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.6, 13.7,
18.4, 18.7, 20.8, 21.4, 26.6, 33.7, 55.4, 73.3, 116.5, 121.1, 126.2,
126.9, 127.2 (2C), 129.7 (2C), 130.1, 135.8, 143.9, 145.0 ppm.
HRMS: m/z calcd for C22H29NO3S [M þ Naþ ] 410.1768; found
410.1766.
The known compounds were identified by comparison of
their spectra with those of authentic samples (see references in
Tables 2 and 3). The unknown compounds were properly char-
acterized by their spectroscopic data (IR, 1H and 13C NMR, and
HRMS or elemental analysis), which are provided below in
order of their entries in the respective tables.
6-Bromo-3,4-dihydro-2-phenyl-4-tosyl-2H-benzo[b][1,4]oxa-
zine (Table 2, entry 2). Yellow solid (mp 160 ꢀC); IR (KBr) 3107,
2922, 2852, 1919, 1595, 1481, 1357, 1246, 1167, 1062, 927, 813,
752, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.24 (s, 3H), 3.02
(dd, J1=10.21 Hz, J2=15.0 Hz, 1H), 3.97-4.01 (m, 1H), 4.13-4.18
(m, 1H), 6.62 (d, J=8.736 Hz, 1H), 6.98-7.04 (m, 3H), 7.12-7.19
Ethyl-9-tosyl-[1,2,3,3a,9,9a]-hexahydrobenzo[b]cyclopenta[e]-
[1,4]oxazine-6-carboxylate (Table 2, entry 12). White solid (mp
132 ꢀC); IR (KBr) 3394, 3001, 2985, 2964, 1705, 1597, 1568,
1494, 1464, 1357, 1300, 1269, 1172, 1120, 881, 763, 661 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.57-1.61
(m, 1H), 1.76-1.88 (m, 3H), 1.94-2.01 (m, 1H), 2.26 (s, 3H),
2.49 (m, 1H), 3.29-3.32 (m, 1H), 3.81-3.87 (m, 1H), 4.23 (q,
J = 7.1 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.36-7.42 (m, 3H),
7.51 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.79, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 14.3, 18.3, 21.5, 25.3, 28.4, 60.9, 62.8, 80.7,
119.3, 122.1, 122.9, 127.1, 127.6 (2C), 129.7 (2C), 131.6, 133.8,
144.5, 148.6, 165.7 ppm. HRMS: m/z calcd for C21H23NO5S
[M þ Hþ ] 402.1370; found 402.1406.
(m, 5H), 7.42 (d, J=8.27 Hz, 2H), 7.90-7.91 (m, 1H) ppm; 13
C
NMR (75 MHz, CDCl3) δ 21.6, 49.9, 73.3, 112.9, 119.1, 124.6,
125.9 (2C), 127.0, 127.4 (2C), 128.8 (2C), 128.9, 129.1, 130.1 (2C),
135.1, 136.6, 144.8, 146.4 ppm. HRMS: m/z calcd for C21H18Br-
NO3S [M þ Naþ ] 466.0101; found 466.0088.
3,4-Dihydro-6-iodo-2-phenyl-4-tosyl-2H-benzo[b][1,4]oxazine
(Table 2, entry 3). Yellow solid (mp 172 ꢀC); IR (KBr) 3117,
2925, 2860, 1918, 1597, 1483, 1367, 1266, 1170, 1064, 925, 811,
748, 695 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3H), 3.12
(dd, J1 = 10.24 Hz, J2 = 15.0 Hz, 1H), 4.09-4.13 (m, 1H),
4.24-4.29 (m, 1H), 6.62 (d, J = 8.61 Hz, 1H), 7.13-7.10 (m,
2H), 7.21-7.34 (m, 6H), 7.54 (d, J=8.23 Hz, 2H), 8.18-8.19 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3) δ 21.7, 49.9, 73.4, 82.7,
119.7, 125.7, 125.9 (2C), 127.4 (2C), 128.8 (2C), 128.9, 130.1,
130.3 (2C), 133.0, 135.1, 136.6, 144.9, 147.3 ppm. HRMS: m/z
calcd for C21H18INO3S [M þ Naþ ] 513.9831; found 513.995.
3,4-Dihydro-8-methoxy-2-phenyl-4-tosyl-2H-benzo[b][1,4]oxa-
zine-5-carbaldehyde (Table 2, entry 4). Orange solid (mp 185 ꢀC); IR
(KBr) 3650, 3355, 3064, 2943, 2865, 2254, 1687, 1589, 1500, 1445,
1357, 1278, 1257, 1166, 1046, 912, 814, 732, 669 cm-1; 1H NMR
(500 MHz, CDCl3) δ2.40 (s, 3H), 3.26 (dd, J1 = 11.5 Hz, J2 = 15.5
Hz, 1H), 3.89 (s, 3H), 4.25-4.28 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H),
7.11-7.13 (m, 2H), 7.29-7.34 (m, 6H), 7.49 (d, J = 8.5 Hz, 1H),
7.68 (d, J = 8.5 Hz, 1H), 10.18 (s,1H) ppm; 13C NMR (125 MHz,
CDCl3) δ 21.6, 49.8, 56.3, 72.9, 109.2, 121.1, 125.0, 125.8 (2C),
126.5, 128.2 (2C), 128.8 (2C), 128.9, 130.4 (2C), 134.3, 136.7, 139.0,
145.5, 152.8, 187.6 ppm. HRMS: m/z calcd for C23H21NO5S [M þ
Naþ ] 446.1038; found 446.1038.
8-Phenyl-10-tosyl-2,3,4,4a,10,10a-hexahydro-1H-phenoxazine
(Table 2, entry 13). White solid (mp 121 ꢀC); IR (KBr) 3446,
3032, 2937, 2862, 1483, 1357, 1276, 1168, 1055, 812, 759, 665,
1
570 cm-1; H NMR (300 MHz, CDCl3) δ 1.30-1.65 (m, 4H),
1.82-1.86 (m, 2H), 2.16-2.19 (m, 1H), 2,35 (s, 3H), 2.72-2.76
(m, 1H), 3.45-3.50 (m, 1H), 3.55-3.62 (m, 1H), 6.81 (d, J = 8.3
Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H),7.30-7.36 (m, 4H), 7.47 (t, J =
7.7 Hz, 2H), 7.67 (d, J = 7.1 Hz, 2H), 8.13 (s, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 21.6, 24.0, 24.6, 31.9, 33.5, 65.3, 80.9,
117.4, 124.6, 124.7, 126.6, 126.8 (2C), 127.1, 127.5 (2C), 128.8 (2C),
129.4 (2C),133.6, 135.1, 140.2, 143.9, 152.1 ppm. HRMS: m/z,
calcd for C25H25NO3S [M þ Naþ ] 442.1452; found 442.1453.
2-Methyl-11-tosyl-5a,6,7,8,9,10,10a,11-octahydrobenzo[b]cy-
clohepta[e][1,4]oxazine (Table 2, entry 14).White solid (mp 129 ꢀC);
IR (KBr) 3057, 2929, 2858, 1940, 1595, 1502, 1454, 1348, 1259, 1165,
1
1064, 1008, 958, 819, 713, 669, 567 cm-1; H NMR (300 MHz,
CDCl3) δ 1.41-1.55 (m, 6H), 1.57-1.67 (m, 3H), 2.05-2.06
(m, 1H), 2.35 (s, 6H), 3.45-3.52 (m, 1H), 3.99-4.05 (m, 1H),
6.60 (d, J = 8.1 Hz, 1H), 6.85-6.88 (m,1H), 7.10 (d, J = 10.7 Hz,
2H), 7.26 (d, J = 8.1 Hz, 2H), 7.47-7.49 (m, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 20.9, 21.6, 23.7, 24.7, 25.0, 33.5, 34.0, 64.7,
83.7, 116.6, 127.2 (2C), 127.4, 127.5, 127.8, 129.2 (2C), 132.1, 134.6,
143.5, 151.3 ppm. HRMS: m/z calcd for C21H25NO3S [M þ Naþ ]
394.1454; found 394.1453.
2-Hexyl-3,4-dihydro-4-tosyl-2H-benzo[b][1,4]oxazine (Table 2,
entry 5). Colorless liquid; IR (neat) 2953, 2929, 2858, 1599, 1583,
1489, 1354, 1247, 1166, 1089, 813, 754, 680 cm-1; 1H NMR (300
MHz, CDCl3) δ0.84-0.92 (m, 3H), 1.19-1.41 (m, 7H), 1.46-1.58
(m, 3H), 2.37 (s, 3H), 3.04-3.26 (m, 1H), 3.87 (d, J = 11.1 Hz,
1H), 4.23-4.28 (m, 1H), 6.70-6.81 (m, 1H), 6.95-6.98 (m, 1H),
7.05-7.07 (m, 1H), 7.18-7.23 (m, 2H), 7.44-7.53 (m, 2H),
7.89-7.92 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 14.0,
21.5, 22.6, 24.5, 25.8, 28.8, 30.1, 52.7, 64.7, 117.4, 120.9, 126.0,
126.3, 127.2 (2C), 129.8 (2C), 135.5, 144.1, 144.2, 146.3 ppm.
HRMS: m/z calcd for C21H27NO3S [M þ Naþ] 396.1604; found
396.1609.
(Table 2, entry 15). White solid (mp 155 ꢀC); IR (KBr) 3041,
2902, 2872, 2355, 1921, 1597, 1485, 1357, 1284, 1242, 1168, 1084,
1
1020, 945, 923, 815, 750, 665, 576 cm-1; H NMR (300 MHz,
CDCl3) δ 1.37-1.40 (m, 2H), 1.5-1.7 (m, 4H), 2.28 (s, 3H), 2.45
(s, 1H), 2.71-2.73 (m, 1H), 3.13 (s, 1H), 3.52-3.54 (m, 1H),
6.73-6.76 (m, 1H), 6.84-6.88 (m, 2H), 7.13 (d, J = 7.8 Hz, 2H),
7.50 (d, J = 7.8 Hz, 2H), 8.19 (d, J = 7.98 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 20.7, 21.6, 31.4, 37.1, 38.6, 41.8, 69.7, 86.1,
119.1, 120.9, 121.7, 125.0, 126.4, 127.7 (2C), 129.7 (2C), 133.2,
3,4-Dihydro-2,3-dipropyl-4-tosyl-2H-benzo[b][1,4]oxazine (Table 2,
entry 6). White solid (mp 119 ꢀC); IR (KBr) 3045, 2956, 2870,
8540 J. Org. Chem. Vol. 75, No. 24, 2010

Bhadra et al.
JOCArticle
144.3, 149.0 ppm. HRMS: m/z calcd for C20H21NO3S [M þ Naþ ]
378.1146; found 378.1140.
1.19-1.27 (m, 2H), 1.28-1.49 (m, 4H), 1.78-1.82 (m, 2H),
2.36 (s, 3H), 3.42-3.58 (m, 2H), 6.70 (d, J = 8.4 Hz, 1H),
7.09-7.11 (m, 3H), 7.15-7.29 (m, 6H), 7.88 (s, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 21.6, 23.9, 24.6, 31.8, 33.3, 65.0, 80.8,
118.1, 126.7, 127.5 (2C), 128.7, 129.2 (2C), 129.5 (2C), 130.4,
130.8, 130.9 (2C), 132.5, 133.8, 136.0, 144.1, 152.4 ppm. HRMS:
m/z calcd for C25H24ClNO3S2 [M þ Naþ] 508.0785; found
508.0784.
10-Tosyl-4b,10,10a,11-tetrahydrobenzo[b]indeno[2,1-e][1,4]oxa-
zine (Table 2, entry 16). White solid (mp 160 ꢀC); IR (KBr) 3030,
2920, 2856, 1483, 1359, 1242, 1170, 1087, 812, 756, 665 cm-1; 1H
NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 3.37-3.42 (m, 1H),
3.59-3.69 (m, 2H), 4.98 (d, J = 8.6 Hz, 1H), 6.98-7.09 (m, 3H),
7.16 (d, J = 8.3 Hz, 2H), 7.30-7.32 (m, 3H), 7.39-7.41 (m, 1H),
7.49 (d, J = 8.3 Hz, 2H), 8.18-8.21 (m, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ21.6, 35.7, 64.8, 81.5, 118.7, 122.0, 122.6, 123.6,
125.5, 125.9, 127.3, 127.6, 127.8 (2C), 128.8, 129.8 (2C), 133.9,
137.5, 139.0, 144.4, 148.6 ppm. HRMS: m/z calcd for C22H19NO3S
[M þ Naþ ] 400.0984; found 400.0983.
6-(Benzo[d]thiazol-2-ylthio)-3,4-dihydro-2-phenyl-4-tosyl-2H-
benzo[b][1,4]oxazine (Scheme 2, 4b). Yellow solid (mp 152 ꢀC);
IR (KBr) 3103, 3034, 2922, 1595, 1479, 1454, 1346, 1244, 1161,
1003, 920, 812, 748, 677 cm-1; 1H NMR (500 MHz, CDCl3) δ
2.41 (s, 3H), 3.27-3.29 (m, 1H), 4.34-4.45 (m, 2H), 7.05 (d, J =
8.5 Hz, 1H), 7.25 (d, J = 7 Hz, 2H), 7.29 (d, J = 8.5 Hz, 3H),
7.38-7.47 (m, 5H), 7.64-7.69 (m, 3H), 7.89 (d, J = 8.0 Hz, 1H),
8.34 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 21.7, 49.9,
73.9, 119.3, 120.8, 121.0, 121.8, 124.3, 124.7, 125.9 (2C), 126.2,
127.5 (2C), 128.9 (2C), 129.1, 130.2 (2C), 131.8, 133.5, 135.1,
135.4, 136.4, 144.9, 149.3, 153.9, 170.8 ppm. HRMS: m/z calcd
for C28H22N2O3S3 [M þ Hþ] 531.0864; found 531.0865.
1,2,3,4,4a,10,10a-Heptahydro-8-morpholino-10-tosyl-10H-phe-
noxazine (Scheme 2, 4c). Brown gummy liquid; IR (neat) 2941,
2,3-Dihydro-2,6-diphenylbenzo[b][1,4]dioxine (Table 3, entry 2).
White solid (mp 118 ꢀC); IR (KBr) 3059, 2926,, 1587, 1518, 1485,
1313, 1267, 1234, 1126, 1057, 895, 819, 752, 700 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.09 (dd, J1 = 8.9 Hz, J2 = 11.4 Hz, 1H),
4.39-4.43 (m, 1H), 5.17-5.21 (m, 1H), 7.04-7.09 (m, 1H),
7.14-7.18 (m, 1H), 7.25-7.27 (m, 1H), 7.28-7.32 (m, 1H),
7.40-7.46 (m, 7H), 7.56-7.59 (m, 2H) ppm; 13C NMR (75
MHz, CDCl3) δ 69.6, 75.4, 116.2, 117.5, 117.9, 120.4, 126.7 (2C),
126.9 (3C), 128.7 (2C), 128.8 (2C), 135.1, 136.5, 140.7, 142.7, 144.1
ppm. HRMS: m/z calcd. for C20H16O2 [M þ Hþ] 289.1226; found
289.1223.
2864, 1494, 1357, 1273, 1168, 1051, 813, 754, 665 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 1.37-1.39 (m, 2H), 1.39-1.43
(m, 3H), 1.51-1.53 (m, 1H), 1.77-1.78 (m, 3H), 2.07-2.10
(m, 1H), 2.33 (s, 3H), 3.07-3.15 (m, 3H), 3.33-3.36 (m, 1H),
3.44-3.49 (m, 1H), 3.85-3.87 (m, 3H), 6.62 (s, 2H), 7.11 (d, J =
8 Hz, 3H), 7.25 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H) ppm; 13C NMR
(125 MHz, CDCl3) δ 21.7, 24.1, 24.7, 32.0, 33.7, 50.6 (2C), 65.5,
67.0 (2C), 81.2, 114.2, 114.6, 117.2, 127.6 (2C), 128.3, 129.4(2C),
133.6, 143.9, 146.7, 146.8 ppm. HRMS: m/z calcd for C23H28-
N2O4S [M þ Hþ] 429.1842; found 429.1875.
2-[(4-Methoxyphenoxy)methyl]-2,3-dihydrobenzo[b][1,4]diox-
ine (Table 3, entry 4). Colorless liquid; IR (neat) 3043, 2997,
2931, 2833, 1593, 1508, 1494, 1267, 1230, 1107, 1043, 823, 750
cm-1; 1H NMR (300 MHz, CDCl3) δ 3.81 (s, 3H), 4.11-4.16 (m,
1H), 4.21-4.27 (m, 2H), 4.41-4.46 (m, 1H), 4.56-4.60 (m, 1H),
6.87-6.97 (m, 8H) ppm; 13C NMR (75 MHz, CDCl3) δ 55.7,
65.4, 67.1, 71.5, 114.7 (2C), 115.7 (2C), 117.3, 117.5, 121.6,
121.8, 143.0, 143.2, 152.5, 154.3 ppm. HRMS: m/z calcd for
C16H16O4 [M þ Naþ ] 295.0945; found 295.0946.
7-(Pyrrolidin-1-yl)-9-tosyl-1,2,3,3a,9,9a-hexahydrobenzo[e]cy-
clopenta[b][1,4]oxazine (Scheme 2, 4d). Brown gummy liquid; IR
(neat) 2958, 2924, 2883, 1739, 1492, 1359, 1168, 1087, 813, 754,
2-[(4-Methoxyphenoxy)methyl]-6-bromo-2,3-dihydrobenzo-
[b][1,4]dioxine (Table 3, entry 6). White solid (mp 90 ꢀC); IR (KBr)
3061, 2962, 2935, 2835, 1585, 1487, 1479, 1271, 1232, 1055, 821,
665 cm-1; H NMR (500 MHz, CDCl3) δ 1.04-1.05 (m, 1H),
1
800, 740 cm-1; H NMR (300 MHz, CDCl3) δ 3.78 (s, 3H),
1.41-1.43 (m, 2H), 1.60-1.68 (m, 3H), 1.71-1.82 (m, 4H), 2.12
(s, 3H), 2.32-2.35 (m, 1H), 3.04-3.15 (m, 4H), 3.61-3.65 (m,
1H); 6.07 (d, J = 7.4 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 6.96 (d, J =
1
4.05-4.10 (m, 1H), 4.16-4.21 (m, 2H), 4.36-4.40 (m, 1H),
4.50-4.52 (m, 1H), 6.76-6.82 (m, 1H), 6.83-6.88 (m, 4H),
6.94-6.98 (m, 1H), 7.07-7.08 (m, 1H) ppm; 13C NMR (75
MHz, CDCl3) δ 55.7, 65.3, 67.0, 71.5, 113.2, 114.8 (2C), 115.7
(2C), 118.6, 120.3, 124.4, 142.5, 143.8, 152.4, 154.5 ppm. HRMS: m/z
calcd for C16H15BrO4 [M þ Naþ ] = 373.0051; found 373.0051.
2-Hexyl-2,3-dihydrobenzo[b][1,4]dioxine (Table 3, entry 7).
Colorless liquid; IR (neat) 3043, 2955, 2928, 2858, 1593, 1494,
8.3 Hz, 2H), 7.13-7.22 (m, 1H), 7.28 (d, J = 8.3 Hz, 2H) ppm; 13
C
NMR (75 MHz, CDCl3) δ 18.3, 21.5, 25.3, 25.4, 28.2, 28.5, 48.4
(2C), 63.2, 80.3, 106.5, 109.2, 118.0, 127.8 (2C), 129.5 (2C), 131.2,
133.6, 133.8, 143.2, 143.9 ppm. HRMS: m/zcalcd. for C22H26N2O3S
[M þ Hþ] 399.1736; found 399.1719.
1465, 1267, 1255, 1045, 906, 746 cm-1; H NMR (300 MHz,
1
Acknowledgment. We are pleased to acknowledge finan-
cial support from CSIR, New Delhi by Grant No. 01(2365)/
10/EMR-II. S.B. and L.A. are thankful to CSIR for their
fellowships.
CDCl3) δ 0.89-0.93 (m, 3H), 1.27-1.42 (m, 6H), 1.55-1.71
(m, 4H), 3.86 (dd, J1 = 7.7 Hz, J2 = 11.1 Hz, 1H), 4.07-4.15
(m, 1H), 4.21-4.23 (m, 1H), 6.82-6.88 (m, 4H) ppm; 13C NMR
(75 MHz, CDCl3) δ 14.2, 22.7, 25.0, 29.3, 31.1, 31.8, 68.2, 73.2,
117.0, 117.4, 121.2, 121.5, 143.6, 143.4 ppm. HRMS: m/z calcd
for C14H20O2 [M þ Hþ] 221.1535; found 221.1536.
1
Supporting Information Available: Copies of H and 13C
NMR spectra of all products listed in Tables 2 and 3 and
Scheme 3 and crystallographic data of compounds 2a, 2h, 2o,
and 2p in Table 2 and 3f in Table 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
8-(4-Chlorophenylthio)-1,2,3,4,4a,10,10a-heptahydro-10-tosyl-
10H-phenoxazine (Scheme 2, 4a). Yellow gummy liquid; IR
(neat) 3064, 2941, 2886, 1597, 1475, 1359, 1267, 1168, 1089,
1047, 813, 754, 677 cm-1 1H NMR (300 MHz, CDCl3) δ
;
J. Org. Chem. Vol. 75, No. 24, 2010 8541