Copper(I)-catalyzed intramolecular Caryl-O bond-forming cyclization for the synthesis of 1,4-benzodioxines and its application in the total synthesis of sweetening isovanillins

Article abstract of DOI:10.1055/s-0030-1258206

Various substituted 1,4-benzodioxines were synthesized through an Ullmann-type intramolecular C_aryl-O coupling cyclization reaction using a catalytic amount of BINOL-CuI complex. This methodology was successfully utilized as the key step in the total synthesis of isovanillyl sweetening agents 5-(2,3-dihydro-1,4-benzodioxin-2-yl)-2-methoxyphenol and 5-(2,3-dihydro-1,4-benz-oxathiin-2-yl)-2-methoxyphenol in 15.8% and 14.85% overall yields in five steps from isovanillin. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258206

PAPER
3509
Copper(I)-Catalyzed Intramolecular Caryl–O Bond-Forming Cyclization for
the Synthesis of 1,4-Benzodioxines and Its Application in the Total Synthesis
of Sweetening Isovanillins
S
ynthesis of 1,4-B
j
enzodio
a
xines y B. Naidu, D. Ganapathy, Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu-600 036, India
Fax +91(44)22574202; E-mail: gsekar@iitm.ac.in
Received 15 June 2010; revised 25 June 2010
palladium catalysts, and oxophilicity associated with the
phosphine-based ligands. Therefore, there is a need to de-
velop an efficient catalyst for the synthesis of 1,4-benzo-
Abstract: Various substituted 1,4-benzodioxines were synthesized
through an Ullmann-type intramolecular Caryl–O coupling cycliza-
tion reaction using a catalytic amount of BINOL–CuI complex.
This methodology was successfully utilized as the key step in the to-
tal synthesis of isovanillyl sweetening agents 5-(2,3-dihydro-1,4-
benzodioxin-2-yl)-2-methoxyphenol and 5-(2,3-dihydro-1,4-benz-
oxathiin-2-yl)-2-methoxyphenol in 15.8% and 14.85% overall
yields in five steps from isovanillin.
F
H
O
O
N
NH
O
O
H
Key words: copper catalyst, 1,4-benzodioxines, BINOL ligand,
Ullmann-type coupling, C–O bond formation
1
2
piperoxan
fluparoxan
α-adrenergic blocking agent
potent antidepressant
OH
The 1,4-benzodioxine framework has been noted as
present in a variety of biologically active compounds such
as piperoxan (1) (Figure 1), an a-adrenergic blocking
agent with considerable stimulating activity, used to diag-
nose pheochromocytoma and that also serves as an antihy-
pertension agent.1 Fluparoxan (2) is claimed to have
potent antidepressant properties2 and sinaicitin (3) exhib-
its significant inhibitory activity against the murinelym-
phocytic leukaemia P-338 cell line.3 Americanol A (4)
and isoamericanol A (5) exhibit interesting neurotrophic
properties.4 Silybin (6) is a naturally occurring benzodiox-
ine that has stimulating therapeutic applications.5 Very
important isovanillyl sweetening agents 7a and 7b,6
which are 500 times sweeter than sucrose, also contain the
1,4-benzodioxine moiety. These compounds could also be
used as intermediates for further synthetic transforma-
tions.7
O
HO
O
O
OH
O
OH
3
sinaicitin
against the murinelymphocytic
leukaemia P-338 cell line
OH
OH
O
O
O
CH2OH
CH2OH
OH
OH
HO
O
4
HO
5
General methods for the synthesis of the 1,4-benzodioxine
fragment include cyclocondensation of catechol with vic-
inal dibromide derivative analogues,8 epichlorohydrin,9 or
chloroacrylonitrile.10 Another approach uses the cycload-
dition of a variety of o-quinones with a dienophile, either
directly or through a two-step process involving a hetero-
Diels–Alder reaction followed by [3,3]-sigmatropic rear-
rangement.11 Recently Buchwald et al., reported palladi-
um-catalyzed intramolecular C–O bond formation by
employing a di-tert-butylphosphinobiaryl ligand for the
synthesis of 1,4-benzodioxines.12 However some of these
protocols have some limitations such as the availability of
starting materials, harsh reaction conditions, high cost of
americanol A
isoamericanol A
exhibits neurotrophic properties
O
OH
HO
O
O
OMe
O
OH
OH
OH
6
OMe
OH
silybin
interesting therapeutic applications
O
X
7a X = O
7b X = S
isovanillyl sweetening agents
SYNTHESIS 2010, No. 20, pp 3509–3519
x
x.
x
x
.
2
0
1
0
Advanced online publication: 13.08.2010
DOI: 10.1055/s-0030-1258206; Art ID: Z15310SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Biologically active compounds containing the 1,4-benzo-
dioxine fragment

3510
A. B. Naidu et al.
PAPER
dioxine. In the last decade, several research groups13
including our research group14 have developed an effi-
cient catalyst system for the formation of Caryl–X bonds
(X = N, O, S, etc.) through copper-catalyzed Ullmann-
type coupling between aryl halides and heteroatom-
centered nucleophiles. More recently, the Ullmann cou-
pling was successfully extended to the preparation of
many heterocycles via copper-mediated cyclization.15
Table 1 Ligand Screening for Intramolecular Caryl–O Bond-Form-
ing Cyclizationa
OH
O
L–Cu salt (20 mol%)
Cs2CO3 (2 equiv)
O
MeCN, 110 °C
O
I
8a
9a
Entry
Ligand
Copper salt Time (h) Yieldb (%)
Very recently, we have shown that ethylenediamine–CuI
is an efficient catalyst system for domino aziridine ring
opening followed by Goldberg coupling cyclization in the
synthesis of 3,4-dihydro-2H-1,4-benzoxazines.16 Due to
our continuous interest in this field, herein for the first
time we report an easily available BINOL–CuI complex
catalyzed synthesis of the racemic 1,4-benzodioxine
skeleton 9 through intramolecular Caryl–O bond-forming
cyclization from the corresponding 2-(2-iodoaryloxy)al-
kanol 8 (Scheme 1).
1
2
3
4
5
6
7
8
9
BINAM L1
DIOL L4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
28
27
72
48
28
48
36
36
30
70
74
45
38
86
45
45
38
59
TMEDA L5
(+)-DET L9
BINOL L6
TMHD L7
DBBINAM L2
TMBINAM L3
CHDA L8
OH
O
BINOL-CuI
R
R
MeCN, 110 °C
O
O
a Reactions were carried out in a sealed tube.
b Isolated yield.
n
n
I
9
( )-8
n = 0, 1, 3
up to 86% yield
As anticipated, racemic anthracene-based diol, trans-
9,10-dihydro-9,10-ethanoanthracene-11,12-dimethanol
(L4) gave 9a in 74% isolated yield in 27 hours (entry 2).
Use of BINOL (L6) in the place of diol L4 afforded an ex-
cellent yield of 1,4-benzodioxine 9a with almost the same
reaction time (entry 5). However, replacing ligand L6 by
L5, L7, L8, or L9, reduced the yield of the coupling prod-
uct 9a and the cyclization reaction took much to go to
completion (entries 3, 4, 6, and 9). It must be mentioned
here that when the reaction was carried out only with cop-
per(I) iodide in the absence of a ligand, the reaction did
not provide even a trace amount of coupling product 9a,
which indicates that the ligand is mandatory for the cou-
pling reaction.
Scheme 1
In preliminary studies, 20 mol% of 1,1¢-binaphthyl-2,2¢-
diamine (BINAM, L1; Figure 2) was used as a ligand with
20 mol% of copper(I) iodide for the intramolecular Caryl
–
O coupling cyclization of 2-(2-iodophenoxy)cyclohex-
anol (8a) in acetonitrile at 110 °C in a sealed tube. Work-
up of the reaction after 28 hours furnished 1,4-
benzodioxine 9a in 70% isolated yield (Table 1, entry 1).
When the ligand L1 was replaced by N,N¢-dibenzyl-
BINAM (DBBINAM, L2), and ligand N,N¢-tetramethyl-
BINAM (TMBINAM, L3), the coupling reaction afford-
ed 1,4-benzodioxine 9a in 45% and 38% isolated yields,
respectively (entries 7 and 8).
Then the reaction was screened with several copper salts,
solvents, and bases to optimize the efficiency of the cou-
pling reaction and the results are summarized in Table 2.
OH
OH
NR1R2
NR1R2
NMe2
Although several copper salts catalyzed the reaction, cop-
per(I) iodide was the copper salt of choice based on the
isolated yield of the coupling product (Table 2, entry 1).
When the reaction was carried out in other solvents such
as dioxane, N,N-dimethylformamide, dimethyl sulfoxide,
etc, the reaction either did not take place or gave a lower
yield of 1,4-benzodioxine 9a (entry 1 vs entries 8–11).
Cesium carbonate as base gave the best yields of 9a in
comparison with bases such as tripotassium phosphate
and potassium carbonate (entry 1 vs entries 12 and 13). It
was also observed that lowering the loading of catalyst
BINOL L6–CuI complex from 20 mol% of copper(I) io-
dide and 20 mol% of L6 to 10 mol% of copper(I) iodide
and 10 mol% of L6 reduced the yield drastically (entry
NMe2
L1 = R1 = H, R2 = H
L2 = R1 = H, R2 = Bn
L3 = R1 = Me, R2 = Me
L5
TMEDA
L4
DIOL
t-Bu
t-Bu
NH2
O
O
OH
OH
NH2
L7
TMHD
L6
BINOL
L8
CHDA
Figure 2
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzodioxines
3511
Table 2 Effect of Copper Salts, Solvents, Bases, and Cu/L Ratioa
14) and other copper/BINOL ratios also reduced the
yields (entries 15–17).
OH
O
BINOL–Cu salt
Using these optimized reaction conditions, investigations
were initiated into the scope of the BINOL–CuI-catalyzed
Ullmann-type intramolecular Caryl–O coupling reaction
and the results are summarized in Table 3. Various substi-
tuted 2-(2-iodoaryloxy)alkanols 8 reacted to give the cor-
responding 1,4-benzodioxine skeleton 9 under optimized
reaction conditions. When the coupling reaction was car-
ried out with 2-(2-iodophenoxy)cyclohexanol (8a), it
gave the corresponding 1,4-benzodioxine 9a with the
highest isolated yield of 86% in 28 hours (entry 1). Yields
of substituted 1,4-benzodioxines were reduced when an
iodobenzene bearing an electron-releasing group, such as
a tert-butyl group in 8c, was present (entry 1 vs entry 3).
When the reaction was carried out with a strong electron-
withdrawing group present, such as the nitro group in 8e,
the reaction failed to give the corresponding benzodioxine
(entry 5). However, when the nitro group was replaced
with a weak electron-withdrawing group, such as the
chloro group in 8d, the coupling reaction was successful
and corresponding benzodioxine 9d was obtained in 54%
isolated yield, though the reaction was somewhat sluggish
requiring 40 hours for completion (entry 4).
base (2 equiv)
MeCN,110 °C
O
O
I
8a
9a
Entry Copper salt Ratio Cu/L Solvent
(mol%)
Time
(h)
Yieldb
(%)
1
2
CuI
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
10:10
10:20
5:10
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
28
36
28
28
48
48
48
36
48
28
48
28
28
28
28
28
28
86
52
83
48
44
30
38
42
32
74
52
48c
59d
49
50
38
55e
Cu(OTf)2
CuBr
CuCl
CuCl2
CuSO4
Cu(OAc)2
CuI
3
4
5
6
7
8
9
CuI
toluene
1,4-dioxane
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14
15
16
17
CuI
CuI
When 2-(2-iodophenoxy)cyclohexanol (8a) was replaced
by 2-(2-iodophenoxy)cyclopentanol (8f) or unsaturated
eight-membered (Z)-8-(2-iodophenoxy)cyclooct-4-enol
(8h), the respective benzodioxines 9f and 9h were ob-
tained in 58% and 70% yields, respectively (entry 1 vs en-
tries 6 and 8). Further, alicyclic secondary alcohols 8i and
8j successfully underwent intramolecular Caryl–O cou-
pling cyclization reactions to provide the corresponding
cyclized products 9i and 9j in good yields (entries 9 and
10). It is important to mention that under these optimized
conditions, less reactive bromo precursors 10 also provid-
ed moderate to good yields of the Ullmann-type intramo-
lecular coupling cyclization products 9 without increasing
the catalytic loading and reaction temperature (Table 4).
CuI
CuI
CuI
CuI
CuI
CuI
5:10
a Reactions were carried out in a sealed tube, base was Cs2CO3 with a
reaction temperature of 110 °C, unless otherwise stated.
b Isolated yield.
c K3PO4 was used as base.
d K2CO3 was used as base.
e Reaction was carried out at 82 °C.
Table 3 Scope of Intramolecular Caryl–O Coupling Cyclization for the Synthesis of the 1,4-Benzodioxine Moietya
HO
O
BINOL-CuI (20 mol%)
R
R
Cs2CO3 (2 equiv)
MeCN, 110 °C
O
O
n
n
I
8 n = 0, 1, 3
9
Entry
1
2-(2-Iodoaryloxy)alkanol
1,4-Benzodioxine
Time (h)
28
Yieldb (%)
86
I
O
O
O
OH
9a
8a
Ph
I
Ph
O
O
2
32
83
O
OH
9b
8b
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

3512
A. B. Naidu et al.
PAPER
Table 3 Scope of Intramolecular Caryl–O Coupling Cyclization for the Synthesis of the 1,4-Benzodioxine Moietya (continued)
HO
O
O
BINOL-CuI (20 mol%)
R
R
Cs2CO3 (2 equiv)
MeCN, 110 °C
O
n
n
I
8 n = 0, 1, 3
9
Entry
3
2-(2-Iodoaryloxy)alkanol
1,4-Benzodioxine
Time (h)
36
Yieldb (%)
73
t-Bu
I
t-Bu
O
O
O
OH
9c
8c
Cl
I
Cl
O
O
4
40
54
O
OH
9d
8d
O2N
I
O2N
O
O
5
6
7
48
48
30
00
58
72
O
OH
9e
8e
I
O
O
O
OH
9f
8f
Ph
I
Ph
O
O
O
OH
9g
9h
9i
8g
I
O
O
8
36
70
O
HO
8h
8i
I
O
O
Ph
Ph
9
30
30
74
73
O
OH
I
Ph
O
O
Ph
10
O
OH
9j
8j
a Reactions were carried out in sealed tube.
b Isolated yield.
A possible mechanism for the Ullmann-type intramolecu- zodioxine moiety 9 and regeneration of the catalytically
lar Caryl–O coupling cyclization reaction has been pro- active copper(I) species for the next catalytic cycle
posed as shown in Scheme 2. Copper(I) oxidatively adds (Scheme 2).
across the aryl–halogen bond of 11 to form the aryl–cop-
per(III) species 12. Then a nucleophile–halogen exchange
takes place to give copper(III) species 13. This will be fol-
lowed by reductive elimination of 13 to give the 1,4-ben-
After the development of the BINOL–CuI catalyst for the
synthesis of various substituted 1,4-benzodioxines using
intramolecular Caryl–O coupling cyclization, the same pro-
tocol was successfully applied as a key step for the total
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzodioxines
3513
Table 4 BINOL–CuI Complex Catalyzed Synthesis of 1,4-Benzodioxines from 2-(2-Bromophenoxy)alkanols by Ullmann-Type Intramolec-
ular Couplinga
HO
O
O
BINOL-CuI (20 mol%)
R
R
Cs2CO3 (2 equiv)
MeCN, 110 °C
O
n
n
Br
10 n = 1, 3
9
Entry
1
2-(2-Bromoaryloxy)alkanol
1,4-Benzodioxine
Time (h)
48
Yieldb (%)
58
Br
O
O
OH
O
9a
10a
Br
O
O
2
3
48
48
57
60
O
HO
9h
10b
Br
O
O
Ph
Ph
O
OH
9i
10c
a Reactions were carried out in sealed tube.
b Isolated yield.
sulfur ylide. This synthetic route involves only three steps
from commercially available isovanillin (17) with our
BINOL–CuI-catalyzed intramolecular coupling cycliza-
tion as the key step.
OH
X
O
O
CuII
R
Ln
R
O
n
n
11
9
Readily available isovanillin (17) on acylation using
acetyl chloride with catalytic amount of 4-(dimethylami-
no)pyridine and pyridine in dichloromethane at room tem-
perature gave the corresponding acetylated product 21 in
96% yield (Scheme 5). Attempted conversion of aldehyde
21 into epoxide 19 using a sulfur ylide failed under several
different reaction conditions.
oxidative addition
reductive
elimination
I
III
O
X
CuIII
Cu
Ln
I
OH
Ln
O
O
n
R
R
13
However, the epoxide 19 could be synthesized by an alter-
native route in two steps as shown in Scheme 5. Wittig
olefination of aldehyde 21 gave olefin 18 in 65% isolated
yield. When the epoxidation reaction of terminal olefin 18
with 3-chloroperoxybenzoic acid was carried out, it did
not stop with the epoxide formation stage and the ep-
oxide-opened product 20 was obtained. In this reaction,
epoxide 19 was immediately opened by the byproduct 3-
chlorobenzoic acid (Scheme 4). Several attempts to open
the in situ generated epoxide by nucleophiles 15a,b failed
to give the expected products 22a,b. Finally the Shi epoxi-
dation of terminal olefin 18 gave the epoxide 19 in 68%
isolated yield. The epoxide 19 was opened with 2-io-
dophenol (15a) or 2-iodothiophenol (15b) using cesium
carbonate in N,N-dimethylformamide solvent at 110 °C to
give the required epoxide-opened products 22a and 22b,
which are the required starting materials for the synthesis
of isovanillyl sweeteners 1,4-benzodioxine 7a and 1,4-
benzoxathiine 7b.
12
n
L = BINOL
nucleophile–halogen
exchange
Scheme 2
synthesis of isovanillyl sweetening agents 2,3-dihydro-
1,4-benzodioxine 7a and 2,3-dihydro-1,4-benzoxathiine
7b.
Retrosynthetic analysis for isovanillyl sweeteners 7a,b in-
dicates that they can be synthesized from the secondary
alcohols 14a,b by Ullmann-type intramolecular coupling
reaction through
Caryl–O bond-forming cyclization
(Scheme 3). Compounds 14a,b can be synthesized by SN2
ring opening of epoxide 16 with nucleophiles such as 2-
iodophenol (15a) or 2-iodothiophenol (15b) in the pres-
ence of a base. Epoxide 16 can be obtained from the readi-
ly available starting material isovanillin (17) using a
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

3514
A. B. Naidu et al.
PAPER
X
Y
Ullmann-type intramolecular
(aryl)–O coupling
O
Y
OH
YH
I
C
1,2-diX
OH
+
O
OH
HO
OMe
OMe
15a Y = O
15b Y = S
16
OMe
7a Y = O
7b Y = S
14a Y = O
14b Y = S
sulfur ylide
O
OH
H
OMe
17
isovanillin
Scheme 3 Retrosynthetic analysis of isovanillyl sweeteners 7a,b
O
Cl
O
O
OH
MCPBA
Cl
COOH
NaHCO3, CH2Cl2
74%
OAc
0 °C to r.t.
AcO
OAc
OMe
OMe
OMe
18
19
20
Scheme 4 Epoxidation of olefin with 3-chloroperoxybenzoic acid gives product 20
O
H
O
H
AcCl
MePPh3Br, NaH
benzene, r.t., 14 h
65%
DMAP, pyridine
CH2Cl2, r.t., 3 h
96%
OH
OAc
OAc
OMe
OMe
OMe
17
21
1.
18
I
O
15a
HO
oxone, NaHCO3
acetone–H2O
MeO
I
Cs2CO3, DMF
110 °C, 2 h
r.t., 1 h, 68%
HO
O
2. aq NaOH, 1 h, 55%
OAc
OH
OMe
19
22a
I
BINOL-Cu(I)
(20 mol%)
1.
15b
Ullmann-type coupling
cyclization
HS
Cs2CO3
(2 equiv),
MeCN,
Cs2CO3, DMF
110 °C, 2 h
2. aq NaOH, 1 h, 60%
110 °C
OMe
Ullmann-type coupling
cyclization
O
X
MeO
HO
I
OH
BINOL-Cu(I) (20 mol%)
Cs2CO3 (2 equiv)
MeCN, 110 °C
S
OH
7a X = O; 2,3-dihydro-1,4-benzodioxine 67%a
7b X = S; 2,3-dihydro-1,4-bezoxathiine 63%
22b
Scheme 5 Total synthesis of isovanillyl sweeteners using copper(I)-catalyzed coupling cyclization as the key step
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzodioxines
3515
HRMS: m/z [M + H2O] calcd for C12H17IO3: 336.0222; found:
336.0229.
The final key step through Ullmann-type intramolecular
Caryl–O coupling cyclization was carried out using 20
mol% BINOL–CuI and cesium carbonate as base in ace-
tonitrile solvent at 110 °C and the reaction provided the
target molecule isovanillyl sweetening agents 2,3-dihy-
dro-1,4-benzodioxine 7a and 2,3-dihydro-1,4-benzoxa-
thiine 7b in good yields (Scheme 5). An overall yields of
15.8% and 14.85% were obtained for the synthesis of 7a
and 7b, respectively. It is very important to note that this
is the second and easiest method for the total synthesis of
isovanillyl sweeteners 7a and 7b.
2-(3-Iodobiphenyl-4-yloxy)cyclohexanol (8b)
Light-brown oil; Rf = 0.43 (hexanes–EtOAc, 90:10).
FT-IR (neat): 699, 739, 1022, 1266, 2863, 2939, 2985, 3051, 3587
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.09–1.40 (m, 4 H), 1.60–1.70 (m,
2 H), 1.99–2.10 (m, 2 H), 2.95 (br s, 1 H), 3.71–3.78 (m, 1 H), 3.90–
3.99 (m, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 7.18–7.24 (m, 1 H), 7.29 (t,
J = 7.6 Hz, 2 H), 7.34–7.41 (m, 3 H), 7.88 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.8, 24.0, 29.6, 31.9, 73.2, 84.5,
89.0, 114.7, 126.8, 127.3, 128.1, 128.9, 136.3, 137.9, 139.2, 156.2.
In summary, a new, efficient, experimentally simple, and
economically attractive copper(I)–BINOL catalyzed
Ullmann-type intramolecular Caryl–O bond-forming cou-
pling cyclization has been developed for the synthesis of
a variety of 1,4-benzodioxines from the corresponding 2-
(2-iodoaryloxy)alkanols. Less reactive bromo precursors
were also used for the synthesis of 1,4-benzodioxines un-
der the same reaction conditions without increasing the re-
action temperature and catalyst loading. Using this
protocol as a key step, the second and easiest total synthe-
ses of two important isovanillyl sweeteners 2,3-dihydro-
1,4-benzodioxine 7a and 2,3-dihydro-1,4-benzoxathiine
7b were successfully completed.
HRMS: m/z [M + H2O] calcd for C18H21IO3: 412.0535; found:
412.0539.
2-(4-tert-Butyl-2-iodophenoxy)cyclohexanol (8c)
Colorless oil; Rf = 0.43 (hexanes–EtOAc, 90:10).
FT-IR (neat): 705, 739, 1041, 1203, 2865, 2962, 3049, 3581 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20–1.36 (m, 10 H), 1.36–1.49
(m, 3 H), 1.65–1.76 (m, 2 H), 2.03–2.16 (m, 2 H), 3.41 (br s, 1 H),
3.72–4.10 (m, 2 H), 6.88 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 1
H), 7.76 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.9, 24.1, 29.8, 31.5, 31.9, 34.2,
73.3, 84.7, 88.5, 114.3, 126.5, 136.5, 146.3, 154.6.
2-(4-Chloro-2-iodophenoxy)cyclohexanol (8d)
Colorless oil; Rf = 0.46 (hexanes–EtOAc, 90:10).
FT-IR (neat): 687, 738, 1034, 1240, 2861, 2936, 3237 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.47–1.73 (m, 5 H), 1.93–2.03 (m,
3 H), 3.95 (br s, 1 H), 4.12–4.22 (m, 1 H), 4.31–4.42 (m, 1 H), 6.63–
6.74 (m, 1 H), 7.04–7.09 (m, 1 H), 7.56 (d, J = 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.4, 29.8, 32.8, 77.3, 86.3, 114.1,
116.9, 129.3, 129.4, 137.6, 138.7, 155.0.
All reactions were carried out in sealed tubes under nitrogen atmo-
sphere. All other reagents are commercially available and used
without further purification. o-Iodophenol, o-bromophenol, cyclo-
hexene oxide and cyclopentene oxide were purchased from Sigma-
Aldrich company. 4-Chloro-2-iodophenol, 2-iodo-4-tert-butylphe-
nol, 2-iodo-4-phenylphenol, 2-iodo-4-nitrophenol were prepared by
a literature procedure.17 Thin-layer chromatography (TLC) was per-
formed using precoated silica gel 60 F254 plates (0.25 mm) which
1
were visualized using a UV fluorescent lamp. H and 13C NMR
MS (EI): m/z = 352 (M+).
spectra were recorded on a Bruker 400 MHz instrument. 1H NMR
spectra are reported relative to TMS (d = 0.0 ppm) or residual
CDCl3 (d = 7.26 ppm). 13C NMR spectra are reported relative to
CHCl3 (d = 77.16 ppm). FTIR spectra were recorded on a Nicolet
6700 spectrophotometer and are reported in frequency of absorption
(cm–1). High-resolution mass spectra (HRMS) were recorded on a
Micromass Q-Tof mass spectrometer.
2-(2-Iodophenoxy)cyclopentanol (8f)
Colorless oil; Rf = 0.40 (hexanes–EtOAc, 90:10).
FT-IR (neat): 648, 748, 1017, 1275, 2932, 3359 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.55–1.62 (m, 1 H), 1.71–1.84 (m,
3 H), 2.02–2.15 (m, 2 H), 4.28–4.34 (m, 1 H), 4.46–4.51 (m, 1 H),
6.63 (td, J = 1.6, 7.8, 7.6 Hz, 1 H), 6.82 (dd, J = 1.2, 8.2 Hz, 1 H),
7.18–7.23 (m, 1 H), 7.69 (dd, J = 1.6, 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.4, 29.9, 32.8, 77.4, 86.0, 87.8,
113.9, 122.8, 129.5, 139.7, 156.7.
2-(2-Iodophenoxy)cyclohexanol (8a); Typical Procedure
Cyclohexene oxide (2.43 g, 24 mmol), 2-iodophenol (4.4 g, 20
mmol), and Cs2CO3 (1.9 g, 60 mmol) were added to a 250-mL 2
neck round-bottom flask equipped with a condenser and septum.
DMF (12 mL) was added to the contents of the round-bottom flask
and the mixture was refluxed at 110 °C for 24 h. The mixture was
then allowed to cool to r.t. and washed with EtOAc and H2O. The
organic layer was dried (anhyd Na2SO4) and the solvent was re-
moved under reduced pressure. The crude residue was purified by
column chromatography (silica gel, EtOAc–hexanes) to give 8a
(5.0 g, 80%) as a brown oil; Rf = 0.33 (hexanes–EtOAc, 90:10).
HRMS: m/z [M + Na+] calcd for C11H13INaO2: 326.9858; found:
326.9864.
2-(3-Iodobiphenyl-4-yloxy)cyclopentanol (8g)
Yellow semisolid; Rf = 0.33 (hexanes–EtOAc, 90:10).
FT-IR (neat): 697, 760, 1037, 1245, 2944, 3029, 3055, 3373 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.11–1.20 (m, 1 H), 1.52–1.61 (m,
1 H), 1.70–1.84 (m, 2 H), 2.02–2.14 (m, 2 H), 4.26–4.36 (m, 1 H),
4.50 (dd, J = 3.2, 6.0 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 7.18–7.25
(m, 1 H), 7.27–7.35 (m, 2 H), 7.36–7.47 (m, 3 H), 7.90 (d, J = 2.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.3, 21.4, 32.7, 60.6, 86.0, 88.1,
113.7, 126.8, 127.2, 128.1, 128.9, 135.9, 138.0, 139.3, 156.0.
FT-IR (neat): 648, 748, 1017, 1242, 2861, 2936, 3059, 3399 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25–1.56 (m, 4 H), 1.70–1.90 (m,
2 H), 2.10–2.23 (m, 2 H), 2.97 (br s, 1 H), 3.84–3.92 (m, 1 H), 4.02–
4.10 (m, 1 H), 6.73–6.78 (m, 1 H), 6.93–6.97 (m, 1 H), 7.28–7.33
(m, 1 H), 7.80 (dd, J = 1.6, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.8, 24.0, 29.7, 31.9, 73.3, 84.5,
88.6, 114.8, 123.2, 129.6, 139.5, 156.8.
HRMS: m/z [M + Na+] calcd for C17H17INaO2: 403.0171; found:
403.0178.
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

3516
A. B. Naidu et al.
PAPER
(Z)-8-(2-Iodophenoxy)cyclooct-4-enol (8h)
Colorless oil; Rf = 0.40 (hexanes–EtOAc, 90:10).
FT-IR (neat): 635, 786, 1048, 1240, 2907, 2984, 3538 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64–1.84 (m, 2 H), 2.01–2.27 (m,
4 H), 2.31–2.57 (m, 2 H), 2.93 (br s, 1 H), 4.03–4.12 (m, 1 H), 4.33–
4.41 (m, 1 H), 5.51–5.67 (m, 2 H), 6.64 (td, J = 1.2, 7.6, 7.6 Hz, 1
H), 6.74–6.79 (m, 1 H), 7.18–7.23 (m, 1 H), 7.68 (dd, J = 1.6, 7.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.0, 23.4, 29.1, 31.9, 72.8, 83.2,
88.2, 114.1, 123.1, 128.5, 129.6, 130.0, 139.6, 156.4.
1H NMR (400 MHz, CDCl3): d = 3.07 (br s, 1 H), 3.91 (t, J = 9.2
Hz, 1 H), 4.08 (dd, J = 3.2, 9.6 Hz, 1 H), 5.07 (d, J = 8.4 Hz, 1 H),
6.74–6.80 (m, 2 H), 7.11–7.16 (m, 1 H), 7.21–7.33 (m, 3 H), 7.35–
7.40 (m, 2 H), 7.43–7.48 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 72.4, 74.8, 112.5, 113.9, 122.7,
126.4, 128.3, 128.7, 133.5, 139.4, 154.8.
MS (EI): m/z = 293 (M+).
1,2,3,4,4a,10a-Hexahydrodibenzo[b,e][1,4]dioxine18 (9a); Typi-
cal Procedure
2-(2-Iodophenoxy)cyclohexanol (8, 159 mg, 0.50 mmol), BINOL
(L6, 28.6 mg, 0.1 mmol), CuI (19 mg, 0.1 mmol), and Cs2CO3 (325
mg, 1.0 mmol) were added to a sealed tube and this was equipped
with screw cap. The sealed tube was evacuated and backfilled with
N2. MeCN (2 mL) was added to the mixture at r.t. and the mixture
was heated at 110 °C for 28 h. After complete disappearance of 8
(TLC monitoring), the mixture was allowed to cool to r.t., and the
solvent was removed by evaporation. The crude residue was puri-
fied by column chromatography (silica gel, EtOAc–hexanes) to af-
ford 9a (81.7 mg, 86%) as a white solid; mp 43–45 °C (Lit. 43–44
°C); Rf = 0.8 (hexanes–EtOAc, 95:5).
FT-IR (neat): 659, 735, 1264, 2868, 2946, 3049 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36–1.54 (m, 4 H), 1.79–1.91 (m,
2 H), 2.20–2.29 (m, 2 H), 3.68–3.76 (m, 2 H), 6.80–6.90 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 24.0, 30.3, 76.7, 117.1, 121.4,
144.0.
HRMS: m/z [M + Na+] calcd for C12H14NaO2: 213.0891; found:
213.0886.
HRMS: m/z [M + H+] calcd for C14H18IO2: 345.0352; found:
345.0380.
2-(2-Iodophenoxy)-1-phenylethanol (8i)
Colorless oil; Rf = 0.6 (hexanes–EtOAc, 90:10).
FT-IR (neat): 699, 737, 1018, 1272, 2856, 2923, 3384 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.05 (t, J = 9.2 Hz, 1 H), 4.24 (dd,
J = 3.2, 9.2 Hz, 1 H), 5.24 (dd, J = 3.2, 8.6 Hz, 1 H), 6.76–6.88 (m,
2 H), 7.25–7.59 (m, 6 H), 7.83 (dd, J = 1.6, 7.8, 1 H).
13C NMR (100 MHz, CDCl3): d = 72.5, 74.9, 87.0, 112.8, 123.4,
126.5, 128.4, 128.7, 129.7, 139.3, 139.5, 156.9.
1-(2-Iodophenoxy)-3-phenylpropan-2-ol (8j)
Brown oil; Rf = 0.36 (hexanes–EtOAc, 80:20).
FT-IR (neat): 700, 730, 1017, 1245, 2922, 3412 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.94 (dd, J = 2.4, 6.6 Hz, 2 H),
3.82 (dd, J = 6.0, 9.2 Hz, 1 H), 3.95 (dd, J = 3.6, 9.2 Hz, 1 H), 4.15–
4.24 (m, 1 H), 6.63–6.73 (m, 2 H), 7.12–7.30 (m, 6 H), 7.69 (dd,
J = 1.6, 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 39.9, 71.2, 72.2, 86.9, 112.6,
123.2, 126.8, 128.7, 129.5, 129.7, 137.7, 139.5, 156.9.
7-Phenyl-1,2,3,4,4a,10a-hexahydrodibenzo[b,e][1,4]dioxine
(9b)
White solid; mp 135 °C; Rf = 0.66 (hexanes–EtOAc, 95:5).
FT-IR (neat): 693, 752, 1238, 2862, 2940, 3032 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36–1.59 (m, 4 H), 1.81–1.93 (m,
2 H), 2.23–2.33 (m, 2 H), 3.73–3.82 (m, 2 H), 6.97 (d, J = 8.4 Hz, 1
H), 7.12 (dd, J = 2.4, 8.4 Hz, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 7.32 (t,
J = 7.2 Hz, 1 H), 7.39–7.46 (m, 2 H), 7.54–7.60 (m, 2 H).
HRMS: m/z [M + H+] calcd for C15H16IO2: 355.0195; found:
355.0199.
2-(2-Bromophenoxy)cyclohexanol (10a)
Colorless oil; Rf = 0.36 (hexanes–EtOAc, 90:10).
13C NMR (100 MHz, CDCl3): d = 23.9, 30.2, 76.7, 76.8, 115.6,
FT-IR (neat): 660, 742, 1027, 1242, 2861, 2937, 3406 cm–1.
117.3, 120.1, 126.8, 126.8, 128.5, 128.8, 134.6, 140.8, 143.5, 144.0.
1H NMR (400 MHz, CDCl3): d = 1.08–1.38 (m, 4 H), 1.53–1.68 (m,
2 H), 1.93–2.03 (m, 2 H), 3.14 (br s, 1 H), 3.64–3.73 (m, 1 H), 3.85–
3.94 (m, 1 H), 6.71 (t, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H),
7.10 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.6, 23.8, 29.4, 31.8, 72.9, 84.2,
113.7, 116.2, 122.4, 128.4, 133.3, 154.5.
HRMS: m/z [M + H+] calcd for C18H19O2: 267.1385; found:
267.1381.
7-tert-Butyl-1,2,3,4,4a,10a-hexahydrodiben-
zo[b,e][1,4]dioxine15h (9c)
White solid; mp 132–133 °C (Lit. 130–131 °C); Rf = 0.80 (hexanes–
EtOAc, 95:5).
HRMS: m/z [M + Na+] calcd for C12H15BrNaO2: 293.0153; found:
293.0150.
FT-IR (neat): 704, 733, 1265, 2864, 2947 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.30 (s, 9 H), 1.39–1.50 (m, 4 H),
1.82–1.87 (m, 2 H), 2.20–2.27 (m, 2 H), 3.69–3.76 (m, 2 H), 6.81
(d, J = 8.8 Hz, 1 H), 6.88 (dd, J = 2.4, 8.6 Hz, 1 H), 6.93 (d, J = 2.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.0, 30.3, 31.6, 34.3, 76.6, 76.7,
114.1, 116.4, 118.3, 141.5, 143.1, 144.7.
(Z)-8-(2-Bromophenoxy)cyclooct-4-enol (10b)
Colorless oil; Rf = 0.63 (hexanes–EtOAc, 90:10).
FT-IR (neat): 660, 743, 1022, 1239, 2878, 2929, 3011, 3558 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64–1.86 (m, 2 H), 2.03–2.28 (m,
4 H), 2.31–2.57 (m, 2 H), 4.06 (td, J = 4.0, 8.4, 8.2 Hz, 1 H), 4.35
(td, J = 3.6, 8.4, 8.4 Hz, 1 H), 5.51–5.73 (m, 2 H), 6.70–6.97 (m, 2
H), 7.11–7.22 (m, 1 H), 7.36–7.50 (m, 1 H).
MS (EI): m/z = 246 (M+).
13C NMR (100 MHz, CDCl3): d = 22.9, 23.4, 29.3, 32.0, 72.9, 83.6,
115.6, 116.3, 122.6, 128.7, 129.3, 130.1, 133.6, 155.0.
7-Chloro-1,2,3,4,4a,10a-hexahydrodibenzo[b,e][1,4]dioxine15h
(9d)
White solid; mp 115–118 °C (Lit. 116–118 °C); Rf = 0.80 (hexanes–
EtOAc, 95:5).
FT-IR (neat): 705, 720, 1060, 1275, 2865, 2942, 3052 cm–1.
2-(2-Bromophenoxy)-1-phenylethanol (10c)
Colorless oil; Rf = 0.56 (hexanes–EtOAc, 90:10).
FT-IR (neat): 666, 700, 1053, 1246, 3060, 3574 cm–1.
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzodioxines
3517
1H NMR (400 MHz, CDCl3): d = 1.33–1.52 (m, 4 H), 1.79–1.88 (m,
2 H), 2.18–2.26 (m, 2 H), 3.63–3.73 (m, 2 H), 6.76–6.79 (m, 2 H),
6.85–6.87 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 37.6, 67.0, 73.8, 117.2, 117.5,
121.4, 121.7, 126.9, 128.7, 129.5, 136.5, 143.3, 143.4.
Total Synthesis of Isovanillyl Sweeteners
3-Acetyl-4-methoxybenzaldehyde (21)
13C NMR (100 MHz, CDCl3): d = 23.9, 30.1, 30.2, 76.7, 117.3,
117.9, 121.3, 125.7, 142.8, 144.5.
To a stirred soln of isovanillin (17, 5g, 32.8 mmol, 1 equiv), DMAP
(few crystals), and pyridine (5.3 mL, 65.6 mmol, 2 equiv) in CH2Cl2
at 0 °C was added AcCl (2.35 mL, 32.8 mmol, 1 equiv) dropwise
and the resulting mixture was slowly warmed up to r.t. and stirred
for 3 h. The mixture was then washed with 2 M HCl and the organic
layer was separated, dried (anhyd Na2SO4), and concentrated under
reduced pressure. The crude product was purified by column chro-
matography (silica gel, hexanes–EtOAc,) afford 21 (6.1 g, 96%) as
a white solid; Rf = 0.56 (hexanes–EtOAc, 70:30).
MS (EI): m/z = 224 (M+).
2,3,3a,9a-Tetrahydro-1H-benzo[b]cyclopenta[e][1,4]dioxine
(9f)
White solid; mp 116 °C; Rf = 0.66 (hexanes–EtOAc, 95:5).
FT-IR (neat): 705, 750, 1254, 2880, 2974, 3047 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.67–1.80 (m, 2 H), 1.87–1–97 (m,
2 H), 2.14–2.24 (m, 2 H), 3.92–4.01 (m, 2 H), 6.85–6.95 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 17.0, 24.9, 78.5, 117.9, 121.8,
144.3.
FT-IR (neat): 781, 873, 1264, 1683, 1762, 2859, 3013, 3066 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.27 (s, 3 H), 3.85 (s, 3 H), 7.01
(d, J = 8.4 Hz, 1 H), 7.52 (d, J = 2.0 Hz, 1 H), 7.69 (dd, J = 2.0, 8.4
Hz, 1 H), 9.79 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.7, 56.3, 112.1, 123.5, 130.1,
130.3, 140.3, 156.5, 168.8, 190.2.
HRMS: m/z [M + H+] calcd for C10H11O4: 195.0657; found:
195.0652.
HRMS: m/z [M + Na+] calcd for C11H12NaO2: 199.0735; found:
199.0738.
6-Phenyl-2,3,3a,9a-tetrahydro-1H-benzo[b]cyclopen-
ta[e][1,4]dioxine (9g)
White solid; mp 132 °C; Rf = 0.62 (hexanes–EtOAc, 95:5).
FT-IR (neat): 700, 749, 1265, 2882, 2923, 2984, 3053 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.70–1.83 (m, 2 H), 1.90–1.99 (m,
2 H), 2.18–2.27 (m, 2 H), 3.98–4.07 (m, 2 H), 7.0 (d, J = 8.4 Hz, 1
H), 7.14 (dd, J = 2.0, 8.4 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.29–
7.36 (m, 1 H), 7.39–7.46 (m, 2 H), 7.54–7.59 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 17.0, 24.9, 29.5, 78.6, 78.6, 116.5,
118.2, 120.6, 126.9, 127.0, 128.8, 135.2, 140.6, 143.8, 144.4.
3-Acetyl-4-methoxystyrene (18)
NaH (721.3 mg, 7 equiv) was added to a stirred suspension of
MePh3P+Br– (2.76 g, 3 equiv) in benzene (6 mL). The suspension
was stirred at r.t. for 12 h. To the yellow-colored suspension, 21
(500 mg, 2.57 mmol, 1 equiv) was added and the resulting mixture
was stirred for 2 h. The crude product was extracted with EtOAc
and the organic layer was separated, dried (anhyd Na2SO4), and the
solvent removed under reduced pressure. The crude residue was pu-
rified by column chromatography (silica gel, hexanes–EtOAc,) to
afford 18 (320 mg, 65%) as a pale-yellow solid; Rf = 0.59 (hexanes–
EtOAc, 90:10).
(Z)-5a,6,7,10,11,11a-Hexahydrobenzo[b]cycloocta[e][1,4]diox-
ine (9h)
Colorless oil; Rf = 0.83 (hexanes–EtOAc, 95:5).
FT-IR (neat): 744, 766, 1266, 2833, 2919, 3008, 3044 cm–1.
FT-IR (neat): 788, 817, 1270, 1762, 2850, 2926 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.94–2.04 (m, 2 H), 2.21–2.31 (m,
2 H), 2.42–2.53 (m, 2 H), 2.60–2.72 (m, 2 H), 4.15–4.22 (m, 2 H),
5.59–5.63 (m, 2 H), 6.81–6.92 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 23.9, 29.7, 76.6, 116.7, 121.1,
128.6, 144.1.
HRMS: m/z [M + H+] calcd for C14H17O2: 217.1229; found:
217.1228.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H), 3.83 (s, 3 H), 5.16
(d, J = 10.8 Hz, 1 H), 5.59 (d, J = 17.6 Hz, 1 H), 6.62 (dd, J = 10.8,
17.6 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.13 (s, 1 H), 7.22 (d,
J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.8, 56.1, 112.3, 112.8, 120.3,
125.2, 131.1, 135.7, 139.9, 150.9, 169.2.
HRMS: m/z [M + H+] calcd for C11H13O3: 193.0865; found:
193.0476.
2-Phenyl-2,3-dihydro-1,4-benzodioxine15h (9i)
White solid; mp 55–57 °C (Lit. 54–56 °C); Rf = 0.68 (hexanes–
EtOAc, 95:5).
2-Methoxy-5-(oxiran-2-yl)phenyl Acetate (19)
To a stirred suspension of alkene 18 (500 mg, 2.63 mmol, 1.0
equiv), and NaHCO3 (2.5 g, 31.6 mmol, 12.0 equiv) in acetone (20
mL) at 0 °C was added a soln of Oxone (5 g, 8.42 mmol, 3.2 equiv)
in H2O (20 mL) dropwise over a period of 30 min. The resulting
mixture was stirred at r.t. for 30 min and the mixture was extracted
with Et2O. The organic layer was separated, dried (anhyd Na2SO4),
and the solvent removed under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, hexane–
EtOAc) to afford 19 (368 mg, 68%) as a pale-yellow oil; Rf = 0.46
(hexanes–EtOAc, 70:30).
1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3 H), 2.76 (dd, J = 2.8, 5.4
Hz, 1 H), 3.10 (dd, J = 4.0, 5.2 Hz, 1 H), 3.80 (dd, J = 2.8, 3.8 Hz,
1 H), 3.82 (s, 3 H), 6.91–6.96 (m, 2 H), 7.13 (dd, J = 2.0, 8.4 Hz, 1
H).
FT-IR (neat): 699, 746, 1261, 2866, 2938, 3049 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.01 (dd, J = 9.2, 11.2 Hz, 1 H),
4.33 (dd, J = 2.4, 11.4 Hz, 1 H), 5.11 (dd, J = 2.0, 8.8 Hz, 1 H),
6.85–7.01 (m, 4 H), 7.33–7.44 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 69.5, 75.2, 117.2, 117.7, 121.1,
121.7, 126.6, 127.0, 128.9, 136.6, 143.2, 144.0.
HRMS: m/z [M + H2O] calcd for C14H14O3: 230.0943; found:
230.0949.
2-Benzyl-2,3-dihydro-1,4-benzodioxine (9j)
Colorless oil; Rf = 0.62 (hexanes–EtOAc, 95:5).
FT-IR (neat): 700, 725, 1263, 2929, 3027 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.93 (dd, J = 7.2, 14.0 Hz, 1 H),
3.15 (dd, J = 6.4, 14.0 Hz, 1 H), 3.95 (dd, J = 6.8, 11.2 Hz, 1 H),
4.21 (dd, J = 2.4, 11.4 Hz, 1 H), 4.40 (dq, J = 2.4, 13.8 Hz, 1 H),
6.87–6.98 (m, 4 H), 7.28–7.42 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 20.7, 51.2, 51.9, 56.1, 112.5,
120.1, 124.3, 130.3, 140.0, 151.2, 169.1.
HRMS: m/z [M + H+] calcd for C11H13O4: 209.0814; found:
209.0816.
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

3518
A. B. Naidu et al.
PAPER
5-[1-Hydroxy-2-(2-iodophenoxy)ethyl]-2-methoxyphenol (22a)
Following the typical procedure for 8a gave 22a as a dark-brown
oil; yield: 55%; Rf = 0.42 (hexanes–EtOAc, 65:35).
FT-IR (neat): 705, 750, 1111, 1267, 2844, 2922, 3271 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.77 (dd, J = 3.6, 12.2 Hz, 1 H),
3.85 (s, 3 H), 3.96 (dd, J = 8.4, 12.0 Hz, 1 H), 5.17 (dd, J = 3.2, 8.4
Hz, 1 H), 6.61–6.70 (m, 2 H), 6.79–6.90 (m, 2 H), 6.96 (d, J = 1.6
Hz, 1 H), 7.06–7.14 (m, 1 H), 7.71–7.77 (m, 1 H).
FT-IR (neat): 750, 760, 1266, 1275, 2987 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.05 (dd, J = 1.6, 13.2 Hz, 1 H),
3.27 (dd, J = 9.6, 13.2 Hz, 1 H), 3.91 (s, 3 H), 5.06–5.13 (m, 1 H),
5.70 (br s, 1 H), 6.84–6.95 (m, 4 H), 6.97–7.05 (m, 2 H), 7.08–7.14
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 31.9, 56.2, 76.4, 110.8, 112.5,
117.3, 118.0, 118.9, 121.7, 125.8, 127.3, 133.7, 146.0, 146.8, 152.5.
HRMS: m/z [M + H+] calcd for C15H15O3S: 275.0742; found:
275.0766.
13C NMR (100 MHz, CDCl3): d = 56.1, 67.6, 82.7, 87.5, 111.0,
112.7, 114.4, 118.1, 123.1, 129.5, 130.4, 139.3, 146.1, 146.7, 156.3.
HRMS: m/z [M + Na+] calcd for C15H15INaO4: 408.9991; found:
408.9995.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are the 1H and 13C NMR spectra data for all the compounds.
5-[1-Hydroxy-2-(2-iodophenylthio)ethyl]-2-methoxyphenol
(22b)
Following the typical procedure for 8a gave 22b as a brown oil;
yield: 60%; Rf = 0.35 (hexanes–EtOAc, 70:30).
Acknowledgment
FT-IR (neat): 650, 1168, 1268, 2928, 3392 cm–1.
We thank DST (Project No. SR/S1/OC-06/2008), New Delhi for fi-
nancial support. A.B.N. thanks UGC, New Delhi for SRF and
D.G.P. thanks CSIR New Delhi for JRF. We thank DST, New Delhi
for funding towards the 400 MHz NMR machine to the Department
of Chemistry, IIT-Madras under the IRPHA Scheme and for fun-
ding to the ESI-MS facility under the FIST Programme.
1H NMR (400 MHz, CDCl3): d = 3.11 (dd, J = 9.2, 13.6 Hz, 1 H),
3.27 (dd, J = 4.0, 13.8 Hz, 1 H), 3.87 (s, 3 H), 4.69 (dd, J = 3.6, 9.2
Hz, 1 H), 5.73 (br s, 1 H), 6.79–6.98 (m, 4 H), 7.28–7.40 (m, 2 H),
7.84 (dd, J = 1.2, 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 44.3, 56.1, 71.5, 101.6, 110.7,
112.3, 117.7, 127.8, 128.9, 129.2, 135.5, 139.9, 140.4, 145.8, 146.5.
References
HRMS: m/z [M + Na+] calcd for C15H15INaO3S: 424.9763; found:
424.9759.
(1) Zhou, R.; Luo, G.; Ewing, A. G. J. Neurosci. 1994, 14, 2402.
(2) Pinder, R. M.; Wieringa, J. H. Med. Res. Rev. 1993, 13, 259.
(3) She, X.; Jing, X.; Pan, X.; Chan, A. S. C.; Yang, T. K.
Tetrahedron Lett. 1999, 40, 4567.
5-(2,3-Dihydro-1,4-benzodioxin-2-yl)-2-methoxyphenol19 (7a)
Phenol 22a (193 mg, 0.50 mmol), BINOL (L6, 28.6 mg, 0.1 mmol),
CuI (19 mg, 0.1 mmol), and Cs2CO3 (325 mg, 1.0 mmol) were add-
ed to a sealed tube and equipped with screw cap. The sealed tube
was evacuated and backfilled with N2. MeCN (3 mL) was added to
the mixture at r.t. and the mixture was heated at 110 °C for 36 h. Af-
ter complete disappearance of 22a (TLC monitoring), the mixture
was allowed to cool to r.t. and the solvent was removed by evapo-
ration. The crude residue was purified by column chromatography
(silica gel, EtOAc–hexanes) to afford 7a (86.4 mg, 67%) as a white
solid; mp 96–98 °C (Lit. 98–99 °C); Rf = 0.56 (CH2Cl2–EtOAc,
80:20).
(4) Matsumoto, K.; Takahashi, H.; Miyake, Y.; Fukuyama, Y.
Tetrahedron Lett. 1999, 40, 3185.
(5) Gong, Z. X.; Weng, L. J.; Wanng, F.; Feng, Y. B.; Zhou, C.
X.; Li, H. B.; Wu, Y. H.; Hao, X. J.; Wu, X. M.; Bai, H.;
Stockigt, J.; Zhao, Y. Chin. Chem. Lett. 2006, 17, 465.
(6) Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg, E. J. Chem. Soc.,
Perkin Trans. 1 1993, 1359.
(7) (a) Lee, T. V.; Leigh, A. J.; Chapleo, C. B. Tetrahedron
1990, 46, 921. (b) Mata, E. G.; Suarez, A. G. Synth.
Commun. 1997, 27, 1291. (c) Woo, W. S.; Kang, S. S.;
Wagner, H.; Chari, V. M. Tetrahedron Lett. 1978, 19, 3239.
(d) Woo, W. S.; Kang, S. S.; Seligmann, O.; Chari, V. M.;
Wagner, H. Tetrahedron Lett. 1980, 21, 4255. (e) Chin, Y.
W.; Kim, J. Tetrahedron Lett. 2004, 45, 339.
(8) (a) Martin, A. R.; Mallik, S. K.; Caputo, J. F. J. Org. Chem.
1974, 39, 1808. (b) Koo, J.; Avakian, S.; Martin, G. J. J. Am.
Chem. Soc. 1955, 77, 5373. (c) Chapleo, C. B.; Myers, L. P.
Tetrahedron Lett. 1981, 22, 4839.
(9) Delgado, A.; Lecherc, G.; Lobato, C.; Mauleón, D.
Tetrahedron Lett. 1988, 29, 3671.
FT-IR (neat): 750, 803, 1246, 1267, 2930, 3511 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H), 3.89–3.98 (m, 1 H),
4.24 (dd, J = 1.6, 11.6 Hz, 1 H), 4.95 (d, J = 8.8 Hz, 1 H), 5.63 (br
s, 1 H), 6.77–6.94 (m, 7 H).
13C NMR (100 MHz, CDCl3): d = 56.2, 69.4, 74.9, 110.9, 113.0,
117.2, 117.7, 118.5, 121.6, 121.7, 129.8, 143.2, 144.1, 146.1, 147.0.
HRMS: m/z [M + H+] calcd for C15H15O4: 259.0970; found:
259.0950.
(10) (a) Cook, M. J.; Katritzky, A. R.; Sewell, M. J. J. Chem. Soc.
B 1970, 1207. (b) Guillaumet, G.; Coudert, G.; Ponchant,
M.; Beaucourt, J. P.; Pichat, L. J. Labelled Compd.
Radiopharm. 1982, 21, 161.
(11) (a) Horspool, W. M.; Tedder, J. M.; Din, Z. U. J. Chem. Soc.
C 1969, 1692. (b) Ansell, M. F.; Leslie, V. J. J. Chem. Soc.
C 1971, 1423. (c) Dondoni, A.; Fogagnolo, M.; Mastellari,
A.; Pedrini, P.; Ugozzoli, F. Tetrahedron Lett. 1986, 27,
3915. (d) Takada, M.; Oshima, R.; Yamauchi, Y.;
Kumanotani, J.; Seno, M. J. Org. Chem. 1988, 53, 3073.
(12) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 12202.
5-(2,3-Dihydro-1,4-benzooxathiin-2-yl)-2-methoxyphenol20 (7b)
Thiophenol 22b (201 mg, 0.50 mmol), BINOL (L6, 28.6 mg, 0.1
mmol), CuI (19 mg, 0.1 mmol), and Cs2CO3 (325 mg, 1.0 mmol)
were added to a sealed tube and equipped with screw cap. The
sealed tube was evacuated and backfilled with N2. MeCN (3 mL)
was added to the mixture at r.t. and the mixture was heated at 110
°C for 36 h. After complete disappearance of 22b (TLC monitor-
ing), the mixture was allowed to cool to r.t. and the solvent was re-
moved by evaporation. The crude residue was purified by column
chromatography (silica gel, EtOAc–hexanes) to afford 7b (86.3 mg,
63%) as a yellow solid; mp 127–129 °C (Lit. 128 °C); Rf = 0.43
(CH2Cl2–EtOAc, 80:20).
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzodioxines
3519
(13) For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D.
Synlett 2003, 2428. (b) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400. (c) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.
(d) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005,
973. (e) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed.
2009, 48, 6954.
(14) (a) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009,
74, 3675. (b) Naidu, A. B.; Sekar, G. Tetrahedron Lett.
2008, 49, 3147. (c) Naidu, A. B.; Ragunath, O. R.; Prasad,
D. J. C.; Sekar, G. Tetrahedron Lett. 2008, 49, 1057.
(d) Rao, R. K.; Naidu, A. B.; Jaseer, E. A.; Sekar, G.
Tetrahedron 2009, 65, 4619. (e) Prasad, D. J. C.; Naidu, A.
B.; Sekar, G. Tetrahedron Lett. 2009, 50, 1411. (f) Thakur,
K. G.; Jaseer, E. A.; Naidu, A. B.; Sekar, G. Tetrahedron
Lett. 2009, 50, 2865. (g) Prasad, D. J. C.; Sekar, G. Org.
Biomol. Chem. 2009, 7, 5091. (h) Prasad, D. J. C.; Sekar, G.
Synthesis 2010, 79. (i) Naidu, A. B.; Sekar, G. Synthesis
2010, 579.
G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. (b) Yang, T.; Lin,
C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781.
(c) Evinder, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802.
(d) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
(e) Martin, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L.
Org. Lett. 2007, 9, 3379. (f) Viirre, R. D.; Evindar, G.;
Batey, R. A. J. Org. Chem. 2008, 73, 3452. (g) Chen, Y.;
Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625.
(h) Bao, W.; Liu, Y.; Lv, X.; Qian, W. Org. Lett. 2008, 10,
3899.
(16) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11,
1923.
(17) Edgar, K. J.; Falling, S. N. J. Org. Chem. 1990, 55, 5287.
(18) Mincione, E.; Sirna, A.; Covini, D. J. Org. Chem. 1981, 46,
1010.
(19) Arnoldi, A.; Camarda, L.; Merlini, L. J. Agric. Food Chem.
1986, 34, 339.
(20) Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg, E. J. Chem. Soc.,
Perkin Trans. 1 1993, 1359.
(15) For the latest selected examples, see: (a) Cacchi, S.; Fabrizi,
Synthesis 2010, No. 20, 3509–3519 © Thieme Stuttgart · New York