A convenient synthetic route to 7,8-fused heterocyclic ring derivatives of (S)-2,3-dihydro-1,4-benzodioxin-2-methanol

Article abstract of DOI:10.1055/s-1999-3526

A much improved synthesis of the dioxino[2,3-e]indolemethanol 9a is described, which is shorter, higher-yielding and less hazardous than the previous synthesis of its racemic form. This novel procedure now allows preparation of multigram quantities of the

Full text of DOI:10.1055/s-1999-3526

PAPER
1181
A Convenient Synthetic Route to 7,8-Fused Heterocyclic Ring Derivatives of
S)-2,3-Dihydro-1,4-benzodioxin-2-methanol
(
Michael Andrew, Alan M. Birch, Paul A. Bradley*
Knoll Pharmaceuticals, Research Department, Pennyfoot Street Campus, Nottingham, NG1 1GF, UK
Fax+44(0)1159124218; E-mail: paul.bradley@knoll.co.uk
Received 5 February 1999
gave a 75% yield of 6a after only 30 minutes. Subsequent
reaction of 6a with aqueous K CO in THF at room tem-
perature furnished the dihydrodioxinoindole 7a. The
Abstract: A much improved synthesis of the dioxino[2,3-e]in-
dolemethanol 9a is described, which is shorter, higher-yielding and
less hazardous than the previous synthesis of its racemic form. This
2
3
novel procedure now allows preparation of multigram quantities of phenolic alkylation described above is of a type known
the enantiomerically pure compound. Application of this methodol- to proceed with retention of configuration at the glycidyl
4
ogy to different 5-hydroxyheterocycles enables access to furo[3,2- asymmetric centre, leading eventually to (S)-(2,3-dihyro-
f][1,4]benzodioxin, thieno[3,2-f][1,4]benzodioxin and 1,4-dioxi-
no[2,3-e]indazole ring systems.
1
,4-benzodioxin-2-yl)methanol derivatives. Hydrolysis of
7
a with lithium hydroxide monohydrate furnished 8a
Key words: 5-hydroxyheterocycles, tricyclic-1,4-benzodioxin-2-
methanols, formylation, Baeyer–Villiger oxidation, decarboxyla-
tion
which was then decarboxylated with copper in quinoline
to afford the key intermediate 9a (Scheme 2). It is worth
noting that decarboxylation of 8a at 257°C following the
1
procedure of Ennis et al produced consistently lower
yields of 9a than the method given above, and that yields
were particularly poor on scale-up.
During the course of our investigations to find a potent,
novel antipyschotic agent, the dioxino[2,3-e]indolemeth-
anol 9a was required as a key intermediate in the synthesis
of a lead compound. The racemic form of 9a had previ-
The formylation procedure described above was then ap-
5
plied to 5-hydroxybenzofuran (1b), 5-hydroxyindazole
6
(
1c) and ethyl 3-chloro-5-hydroxybenzo[b]thiophene-2-
1
ously been prepared by Ennis et al but this process was
7
carboxylate (1d). This successfully furnished the corre-
sponding 4-formyl derivatives 3b, 3c, 3d in varying
long, low-yielding and used hazardous azide for construc-
tion of the indole nucleus. Consequently, an alternative
preparation of the key intermediate 9a was sought. We
now wish to report a novel, shorter, higher-yielding and
less hazardous preparation of the indole 9a which is more
suitable for scale-up (Schemes 1 and 2).
8
yields (see experimental section). Elaboration of these al-
dehydes 3b, 3c, 3d into the desired tricyclic systems was
then achieved by the sequence outlined in Schemes 1 and
2
.
In the furan series, final cyclisation of the formate ester 6b
2
Julia and Lallemand had previously reported that reac-
with aqueous K CO in THF furnished the required dihy-
2
3
tion of ethyl 5-hydroxyindole-2-carboxylate (1a) with 4-
methoxyaniline and triethyl orthoformate at 165°C and
drofuro[3,2-f][1,4]benzodioxinmethanol 7b in 70% yield.
Interestingly, small amounts of the formate 10 were also
isolated from the reaction (no corresponding formates
were observed to form in the other tricyclic systems).
then subsequent acid hydrolysis of the intermediate imine
2
(
2a; R = MeO) gave the aldehyde 3a in 48% yield. How-
ever, when we repeated this reaction a very low yield (9%)
of the imine was isolated. A much more satisfactory prep- Preparation of the indazole 7c proved particularly prob-
aration of the aldehyde 3a was achieved by treating 1a lematical. In the Baeyer–Villiger oxidation of the alde-
hyde 4c with mCPBA at 0°C a very complex reaction
mixture resulted from which no formate ester 6c could be
isolated. However, careful chromatography of this crude
reaction mixture enabled isolation of the desired dihy-
drodioxinoindazole 7c, albeit in only 16% yield, suggest-
ing that any intermediate formate ester 6c may well be a
with commercially available ethyl N-phenylformimidate
followed by hydrolysis of the intermediate imine (2a; R =
H) with 5 M hydrochloric acid. Not suprisingly, formyla-
tion of the much more reactive 5-hydroxyindole using
these conditions produced very complex mixtures from
which no pure product could be isolated. The aldehyde 3a
2
was elaborated to the dioxino[2,3-e]indole 7a by the route very reactive or unstable species.
outlined in Scheme 1. Alkylation of 3a with (R)-glycidyl
tosylate and K CO in DMF at 60°C gave the epoxyether
Baeyer–Villiger oxidation of the benzo[b]thiophene 4d
with mCPBA at room temperature proved to be a very
slow reaction, producing the formate 6d in only 7% yield
after 24 hours reaction. In this case, preferential oxidation
occurred at the benzo[b]thiophene sulfur. However, addi-
tion of one equivalent of TFA at 0°C accelerated the
Baeyer–Villiger reaction such that a 50% yield of 6d
could be isolated after only 1 hour. Cyclisation with aque-
2
3
4
a; small amounts of the bis-alkylated product 5 were also
isolated from the reaction. Treatment of 4a with 3-chlo-
roperoxybenzoic acid (mCPBA) gave a moderate yield
(
47%) of the formate ester 6a. However, it is well known
that trifluoroacetic acid (TFA) can be used to accelerate
3
Baeyer–Villiger oxidations, and to that end addition of
one equivalent of TFA to the oxidation reaction at 0°C
ous K CO3 in THF produced the expected dihy-
2
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York

1
182
M. Andrew et.al
PAPER
Reagents and conditions: (i) D; (ii) 5 M aq HCl, D; (iii) (R)-glycidyl tosylate/K CO /DMF, 60°C; (iv) mCPBA/TFA; (v) aq K CO /THF
2
3
2
3
Scheme 1
drothienobenzodioxin 7d, which was hydrolysed to the In summary, we have established a novel, shorter, higher-
acid 8b and then decarboxylated with copper in quinoline yielding and less hazardous synthesis of the enantiomeri-
to afford the expected 9-chloro derivative 9b in excellent cally pure dihydrodioxino[2,3-e]indole system 9a which
yield (85%) together with a small amount (9%) of the enables the preparation of multigram quantities. This
dechlorinated product 9c.
route was then applied to transform appropriate hydroxy-
heterocycles into the dihydrofuro[3,2-f][1,4]benzodioxin,
dihydrothieno[3,2-f][1,4]benzodioxin and the dihydro-
The stereochemistry at the 2-position in these tricyclic
systems was assigned on the basis of the well-precedented
1
,4-dioxino[2,3-e]indazole ring systems.
S 2 substitution of glycidyl arenesulfonates with
N
4
,9
phenoxides and inversion of the stereochemistry upon
1
0
intramolecular epoxide opening. This was supported by
a comparison of specific rotation and chiral HPLC data paratus and are uncorrected. H and C NMR spectra were recorded
Melting points were determined on a Gallenkamp melting point ap-
1
13
for (S)-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-meth- on a Bruker AC 250 spectrometer and are reported in ppm on the
dscale from internal TMS using CDCl as solvent unless otherwise
stated. IR spectra were obtained using a Mattson-Unicam 3000
FTIR spectrometer. Mass spectra were recorded on a Finnigan
anol 7b and its (R)-enantiomer, which was prepared from
(
3
S)-glycidyl tosylate in an analogous manner.11
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Synthetic Route to (S)-2,3-Dihydro-1,4-benzodioxin-2-methanol
1183
(
i) LiOH•H O/MeOH/H O; (ii) Cu/quinoline, D
2 2
Scheme 2
1
MAT 95S instrument under electron inpact (70 eV) or where indi-
cated, by chemical ionisation (CI). Elemental analyses were deter-
mined by the Physical Chemistry Department (Knoll
Pharmaceuticals, Nottingham). TLC was performed using Merck
Silica gel 60F254 plates. Flash column chromatography was carried
H NMR (DMSO-d ): d = 1.36 (t, 3 H, J = 7 Hz, CH CH ), 4.36 (q,
6
3
2
2 H, J = 7 Hz, CH CH ), 6.93 (d, 1 H, J = 9 Hz, ArH), 7.30 (m, 1 H,
ArH), 7.49 (m, 5 H, ArH), 7.71 (d, 1 H, J = 1.5 Hz, 3-H), 9.45 (s, 1
H, CH = N), 12.01 (br s, 1 H, NH), 13.70 (br s, 1 H, OH).
3
2
Anal. Calcd for C H N O : C, 70.15; H, 5.2; N, 9.1. Found: C,
7
1
8
16
2
3
out on silica 60A. The term ‘dried’ refers to use of anhyd MgSO or
4
0.2; H, 5.2; N, 9.05.
Na SO . Ethyl 5-hydroxyindole-2-carboxylate (1a) and ethyl
2
4
N-phenylformimidate were purchased from Lancaster Synthesis.
Ethyl 3-chloro-5-methoxybenzo[b]thiophene-2-carboxylate was
purchased from Maybridge Chemicals and (R)-glycidyl tosylate
from Aldrich. Petroleum ether used had bp 40–60°C unless other-
wise noted.
Ethyl 4-Formyl-5-hydroxyindole-2-carboxylate (3a)
A stirred suspension of 2a (R = H) (64.0 g, 0.176 mol) in 5 M HCl
2
(1500 mL) was heated at 70°C for 2 h. The mixture was poured into
H O (1500 mL) and extracted with EtOAc (4 × 800 mL). The com-
2
bined extracts were washed with brine (800 mL), dried and evapo-
rated in vacuo to give 3a (40.5 g, 99%) as a pink solid; mp 218–
Ethyl 5-Hydroxy-4-(N-phenyliminomethyl)indole-2-carboxy-
1
2
19°C (Lit. mp 220°C).
late (2a)
–
1
1
2
IR (KBr): n = 3327, 1693, 1637 cm .
A flask containing a mixture of 1a (68.31 g, 0.33 mol) and ethyl
N-phenylformimidate (97%; 54.5g, 0.35 mol) was submerged into
a pre-heated oil bath at 160–180°C and the mixture stirred for 2 h,
by which time all of the EtOH produced in the reaction had been re-
moved. The cooled reaction mixture was dissolved in boiling
MeOH (2000 mL) and the resulting yellow solid collected by filtra-
1
H NMR (DMSO-d ): d = 1.35 (t, 3 H, J = 7 Hz, CH CH ), 4.34 (q,
6
3
2
2
3
1
H, J = 7 Hz, CH CH ), 6.99 (d, 1 H, J = 9 Hz, ArH), 7.63 (s, 1 H,
3 2
-H), 7.66 (d, 1 H, J = 9 Hz, ArH), 10.55 (s, 1 H), 10.64 (s, 1 H),
2.11 (br s, 1 H, OH or NH).
2
Anal. Calcd for C12H11NO : C, 61.8; H, 4.7; N, 6.0. Found: C, 61.7;
4
H, 4.7; N, 6.1.
tion to give 2a (R = H) (44.42 g, 44%)
–
1
IR (KBr): n = 3300, 1694 cm .
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York

1
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M. Andrew et.al
PAPER
Ethyl (R)-5-(2,3-Epoxypropoxy)-4-formylindole-2-carboxylate
4a)
A stirred solution of 3a (1.5 g, 6.44 mmol) in anhyd DMF (40 mL)
(1000 mL) and extracted with EtOAc (4 × 400 mL). The combined
extracts were dried and evaporated in vacuo to give 7a (17.65 g,
89%) as a pale purple solid; mp 152–153°C.
(
under N was treated with K CO (0.89 g, 6.44 mmol). A solution
of (R)-glycidyl tosylate (1.47 g, 6.44 mmol) in anhyd DMF (30 mL)
was then added and the mixture stirred at r.t. for 10 min and then at
–1
2
2
3
IR (KBr): n = 3506, 3293, 1697, 1672 cm .
1
H NMR (DMSO-d ): d = 1.33 (t, 3 H, J = 7 Hz, CH CH ), 3.69 (m,
H), 4.01 (dd, 1 H, J = 11, 7 Hz), 4.26 (m, 2 H), 4.30 (q, 2 H, J = 7
6
3
2
2
6
0°C for 3 h. The mixture was poured into H O (400 mL) and ex-
2
Hz, CH CH O), 5.06 (t, 1 H, J = 6 Hz, CH OH), 6.84 (d, 1 H, J = 9
tracted with EtOAc (3 × 200 mL). The combined extracts were
washed with brine (6 × 200 mL), dried and evaporated in vacuo to
leave a brown oil (2.19 g). Purification by flash column chromato-
graphy on silica gel using a 1:1 mixture of EtOAc and petroleum
ether as eluant gave unreacted starting aldehyde 3a (0.31 g, 20%) as
a yellow solid. Further elution of the column afforded 4a (1.07 g,
3
2
2
Hz, ArH), 6.89 (d, 1 H, J = 9 Hz, ArH), 7.00 (br s, 1 H, 3-H), 11.75
br s, 1 H, NH).
(
+
CI-MS: m/z = 277 (M , 85%).
HRMS: m/z Calc. for C H NO :277.0950. Found:277.0950.
1
4
15
5
5
8%) as an off-white solid; mp 152–154°C.
(
S)-2,3-Dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-e]in-
–
1
IR (KBr): n = 1689, 1667 cm .
dole-8-carboxylic Acid (8a)
A stirred solution of 7a (15.0 g, 0.054 mol) in MeOH (150 mL) un-
der N
in H O (80 mL) and the mixture heated at 60°C for 1 h. The solvent
was evaporated in vacuo and the residue diluted with H O (200
1
H NMR: d = 1.43 (t, 3 H, J = 7 Hz, CH CH ), 2.81 (m, 1 H), 2.95
t, 1 H, J = 4.5 Hz), 3.43 (m, 1 H), 4.12 (m, 1 H), 4.41 (m, 3 H), 7.07
d, 1 H, J = 9 Hz, ArH), 7.63 (d, 1 H, J = 9 Hz, ArH), 7.97 (br s, 1
3
2
(
(
was treated with a solution of LiOH•H O (4.74 g, 0.108 mol)
2 2
2
H, 3-H), 9.25 (br s, 1 H, NH), 10.75 (s, 1 H, CHO).
2
mL). The aqueous solution was adjusted to pH 2 with dil HCl and
the resulting precipitate collected by filtration, washed thoroughly
Anal. Calcd for C H NO : C, 62.3; H, 5.2; N, 4.85. Found: C,
15
15
5
6
2.2; H, 5.2; N, 4.7.
with H O and then dried to leave 8a (12.46 g, 93%) as a pink solid;
2
Further elution of the column gave ethyl 5-[(R)–(2,3-epoxypro-
poxy)]-1-[(R)-(2,3-epoxypropyl)]-4-formylindole-2-carboxylate
mp 216–217°C.
1
H NMR (DMSO-d ): d = 3.69 (m, 2 H), 4.03 (m, 1 H), 4.28 (m, 2
6
(5) (0.20 g, 9%) as a fawn solid.
H), 6.83 (d, 1 H, J = 9 Hz, ArH), 6.89 (d, 1 H, J = 9 Hz, ArH), 6.94
Compound 5
(d, 1 H, J = 2 Hz, 3-H), 11.64 (br s, 1 H, NH), 12.80 (br s, 1 H,
CO H).
Mp 145–147°C.
2
–
1
Anal. Calcd for C H NO 0.9H O: C, 54.3; H, 4.8; N, 5.3. Found:
IR (KBr): n = 1712, 1665 cm .
12 11
5•
2
C,54.05; H, 4.5; N, 5.3.
1
H NMR (DMSO-d ): d = 1.35 (t, 3 H, J = 7 Hz, CH CH ), 2.41 (m,
6
3
2
1
H), 2.63 (m, 1H), 2.68 (m, 1 H), 2.87 (t, 1 H, J = 5 Hz), 3.26 (m, 1
(S)-2,3-Dihydro-7H-1,4-dioxino[2,3-e]indole-2-methanol (9a)
H), 3.43 (m, 1 H), 4.11 (m, 1 H), 4.36 (q, 2 H, J = 7 Hz, MeCH O),
2
A flask containing a mixture of 8a (4.60 g, 18.47 mmol), copper
powder (1.20 g, 18.47 mmol) and quinoline (50 mL) under a N at-
mosphere was submerged into a preheated oil bath at 230°C and
heated at this temperature for 40 min. The mixture was cooled to r.t.,
poured into dil HCl (300 mL) and extracted with EtOAc (3 × 150
mL). The combined extracts were washed with dil HCl (100 mL),
4
.61 (m, 2 H), 5.04 (m, 1 H), 7.34 (d, 1 H, J = 9 Hz, ArH), 7.80 (br
2
s, 1 H, 3-H), 8.00 (d, 1 H, J = 9 Hz, ArH), 10.62 (s, 1 H, CHO).
Anal. Calcd for C H NO 0.4H O: C, 61.35; H, 5.65; N, 3.95.
18
19
6
2
Found: C, 61.7; H, 5.8; N, 3.75
Ethyl (R)-5-(2,3-Epoxypropoxy)-4-formyloxyindole-2-carboxy-
late (6a)
H O (100 mL), dried and evaporated in vacuo to leave a brown oil
2
(3.88 g). Purification by flash column chromatography on silica gel
using a 1:1 mixture of EtOAc and petroleum ether as eluant gave 9a
(2.32 g, 61%) as a fawn solid; mp 51–53°C.
1
A stirred solution of 4a (1.95 g, 6.75 mmol) in CH Cl (40 mL) was
2
2
cooled to 0°C. 3-Chloroperoxybenzoic acid (86%; 1.75 g, 8.43
mmol) was then added, followed by a solution of trifluoroacetic
acid (0.77 g, 6.75 mmol) in CH Cl (10 mL), added portionwise.
H NMR (DMSO-d ): d = 3.68 (m, 2 H), 3.98 (dd, 1 H, J = 11, 7
6
2
2
Hz), 4.19 (m, 1 H), 4.26 (m, 1 H), 5.04 (t, 1 H, J = 5.7 Hz, exchange-
The resulting mixture was stirred at r.t. for 30 min and then diluted
with CH Cl (200 mL), washed with 10% aq NaHSO solution (100
able with D O, OH), 6.31 (br s, 1 H, indole H), 6.44 (d, 1 H, J = 9
2
2
2
3
Hz, ArH), 6.84 (d, 1 H, J = 9 Hz, ArH), 7.19 (br s, 1 H, indole H),
mL), satd aq NaHCO solution (3 × 150 mL), dried and evaporated
3
1
0.90 (br s, 1 H, NH).
in vacuo to leave a pale brown solid (1.98 g). Purification by flash
column chromatography on silica using a 1:1 mixture of EtOAc and
petroleum ether as eluant gave 6a (1.55 g, 75%) as a pale-yellow
crystalline solid; mp 123–125°C.
+
CI-MS: m/z = 205 (M , 100%).
HRMS: m/z Calc. For C H NO :205.0740. Found:205.0740.
1
1
11
3
–
1
2
IR (KBr): n = 3331, 1758, 1699 cm .
1
5-Hydroxy-4-(N-phenyliminomethyl)benzo[b]furan (2b, R =
H)
H NMR: d = 1.41 (t, 3 H, J = 7 Hz, CH CH ), 2.72 (m, 1 H), 2.83
t, 1 H, J = 4 Hz), 3.30 (m, 1 H), 4.01 (m, 1 H), 4.27 (m, 1 H), 4.40
q, 2 H, J = 7 Hz, CH CH O), 7.15 (d, 1 H, J = 9 Hz, ArH), 7.19 (s,
H, 3-H), 7.28 (d, 1 H, J = 9 Hz, ArH), 8.42 (s, 1 H, OCHO), 8.90
3
2
5
A flask containing a mixture of 1b (36.60 g, 0.27 mol) and ethyl N-
(
phenylformimidate (42.50 g, 0.28 mol) was immersed in a pre-
heated oil bath and stirred at 180–190°C for 2 h whilst EtOH pro-
duced in the reaction was removed by distillation. The cooled mix-
ture was then purified by filtration through a flash silica gel pad
using a 1:4 solution of EtOAc and petroleum ether as eluant to give
(
3
2
1
(
br s, 1 H, NH).
Anal. Calcd for C H NO : C, 59.0; H, 4.9; N, 4.6. Found: C, 58.9;
15
15
6
2
H, 4.9; N, 4.4.
2b (R = H) (18.31 g, 29%) as an orange oil.
1
H NMR (DMSO-d ): d = 6.96 (m, 2 H), 7.3–7.6 (m, 6 H), 7.70 (d,
6
Ethyl (S)-2,3-Dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-
e]indole-8-carboxylate (7a)
1
H, J = 2 Hz, ArH), 8.99 (s, 1 H, CH = N), 13.41 (br s, 1 H, OH).
Anal Calcd for C H NO : C, 75.95; H, 4.65; N, 5.90. Found: C,
A stirred solution of 6a (22.0 g, 0.072 mol) in THF (250 mL) was
treated with satd aq K CO solution (200 mL) and the mixture
15 11
2
7
5.8; H, 4.6; N, 6.15.
2
3
stirred vigorously at r.t. for 72 h. The mixture was poured into H O
2
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Synthetic Route to (S)-2,3-Dihydro-1,4-benzodioxin-2-methanol
1185
5
-Hydroxybenzo[b]furan-4-carbaldehyde (3b)
Anal. Calcd for C H O .0.15 EtOAc: C, 63.5; H, 5.1. Found: C,
63.1; H, 5.1.
1
1
10
4
2
A mixture of 2b (R = H) (0.19 g, 0.80 mmol) and 5 M HCl (20 mL)
was heated with stirring at 50–60°C for 30 min. The mixture was
then poured into H O (100 mL) and extracted with CH Cl (2 × 80
mL). The combined extracts were washed with H O (80 mL), dried
and evaporated in vacuo to give 3b (130 mg, ca 100%) as a yellow
Compound 10
2
2
2
–
1
IR (KBr): n = 1726 cm .
2
1
H NMR: d = 4.14 (m, 2 H), 4.33 (m, 1 H), 4.51 (m, 2 H), 6.80 (d,
8
solid; mp 80–81°C (Lit. mp 83°C).
1
H, J = 2 Hz, ArH), 6.85 (d, 1 H, J = 9 Hz, ArH), 7.01 (d, 1 H, J = 9
–
1
Hz, ArH), 7.53 (d, 1 H, J = 2 Hz, ArH), 8.14 (s, 1 H, OCHO).
IR (KBr): n = 1639cm .
1
3
1
C NMR (62.9 MHz): d = 160.4 (OCHO), 151.0 (qauternary),
H NMR: d = 6.90 (d, 1 H, J = 9 Hz, ArH), 7.08 (d, 1 H, J = 2 Hz,
1
44.8 (CH), 137.7 (quaternary), 135.1 (quaternary), 117.8 (quater-
ArH), 7.64 (d, 1 H, J = 9 Hz, ArH), 7.77 (d, 1 H, J = 2 Hz, ArH),
nary), 114.2 (CH), 104.5 (CH), 103.6 (CH), 71.0 (OCH), 64.9
OCH ), 61.9 (OCH ). Anal. Calcd for C H O : C, 61.55; H, 4.25.
1
0.32 (s, 1 H, CHO), 11.40 (br s, 1 H, OH).
(
2
2
12 10
5
Anal Calcd for C H O : C, 66.65; H, 3.7. Found: C, 66.9; H, 3.8
9
6
3
Found: C, 61.9; H, 4.3.
(
R)-5-(2,3-Epoxypropoxy)benzo[b]furan-4-carbaldehyde (4b)
Ethyl 3- Chloro-5-hydroxybenzo[b]thiophene-2-carboxylate
1d)
A stirred solution of ethyl 3-chloro-5-methoxybenzo[b]thiophene-
A stirred solution of 3b (3.04 g, 18.77 mmol) in anhyd DMF (30
mL) was treated with solid K CO (2.85 g, 20.63 mmol) and then a
solution of (R)-glycidyl tosylate (4.50 g, 19.70 mmol) in anhyd
DMF (10 mL) added. The mixture was heated at 60°C for 2 h and
then poured into ice (200 g) and diluted with H O (300 mL). The
mixture was extracted with CH Cl (3 × 300 mL) and the combined
extracts washed with H O (8 × 200 mL), dried and evaporated in
vacuo to leave a red oil (4.61 g). Purification by flash column chro-
matography on silica using a 3:7 mixture of EtOAc and petroleum
ether as eluant gave 4b (3.11 g, 76%) as a yellow oil which crystal-
lised on standing; mp 64–65°C.
(
2
3
2
-carboxylate (20.0 g, 0.084 mol) in CH Cl (80 mL) was cooled to
2 2
–
20°C under a N atmosphere. BBr (1 M solution in CH Cl ; 90
2 3 2 2
2
mL, 0.09 mol) was then added portionwise and the mixture allowed
to warm to r.t. After stirring for 2 h at r.t. the mixture was poured
into EtOH (400 mL), left to stand for 10 min and then evaporated in
vacuo. The residue was dissolved in EtOAc (500 mL), washed with
2
2
2
H O (300 mL), dried and evaporated in vacuo to give 1d (18.68 g,
2
9
9%) as an off-white solid; mp 160–161 °C
1
H NMR: d = 1.34 (t, 3 H, J = 7 Hz, CH CH ), 4.35 (q, 2 H, J = 7
–
1
3
2
IR (KBr): n = 1668 cm .
1
Hz, CH CH ), 7.15 (dd, 1 H, J = 8 and 2 Hz, ArH), 7.24 (d, 1 H,
3
2
H NMR: d = 2.82 (m, 1 H), 2.95 (m, 1 H), 3.43 (m, 1 H), 4.11 (m,
H), 4.41 (m, 1 H), 6.96 (d, 1 H, J = 9 Hz, ArH), 7.55 (d, 1 H, J = 2
J = 2 Hz, ArH), 7.91 (d, 1H, J = 8 Hz, ArH), 10.03 (s, 1 H, OH).
1
+
CI-MS: m/z = 256 (M , 100%).
Hz, ArH), 7.65 (d, 1 H, J = 9 Hz, ArH), 7.75 (d, 1 H, J = 2 Hz, ArH),
0.69 (s, 1 H, CHO).
3
5
HRMS: m/z Calc. For C H S ClO :255.9966. Required:255.9965.
1
11
9
3
Anal Calcd for C H O : C, 66.05; H, 4.60. Found: C, 65.7; H,
1
2
10
4
Ethyl 3-Chloro-5-hydroxy-4-[N-(4-methoxyphenyliminometh-
yl]benzo[b]thiophene-2-carboxylate (2d; R = OMe)
4
.65.
2
A flask containing a mixture of 1d (6.04 g, 0.024 mol) and ethyl N-
(
R)-5-(2,3-Epoxypropoxy)benzo[b]furan-4-yl Formate (6b)
13
(4-methoxyphenyl)formimidate (4.50 g, 0.024 mol) was im-
A stirred solution of 4b (3.08 g, 14.1 mmol) in CH Cl (40 mL) was
2
2
mersed in a pre-heated oil bath at 160°C and the mixture stirred be-
tween 160 and 180°C for 4 h whilst the EtOH produced in the
reaction was removed by distillation. More ethyl N-(4-methoxyphe-
nyl)formimidate (0.80 g, 4.25 mmol) was then added and the heat-
ing continued at 180–190°C for 1 h. The mixture was cooled to r.t.,
heated in boiling MeOH (100 mL) and the resulting pale brown
crystalline solid collected by filtration, washed with MeOH (10 mL)
treated with 3-chloroperoxybenzoic acid (86%; 3.88 g, 19.5 mmol)
and then a solution of trifluoroacetic acid (1.61 g, 14.1 mmol) in
CH Cl (5 mL) was added. The mixture was then stirred at r.t. for
2
2
3
0 min and poured into a 10% aq NaHSO solution (200 mL). The
3
mixture was extracted with CH Cl (2 × 150 mL) and the combined
extracts washed with satd aq NaHCO solution (3 × 150 mL), dried
and evaporated in vacuo to give 6b (3.10 g, 94%) as a red oil.
2
2
3
2
and dried to give 2d (R = OMe) (4.03 g, 43%); mp 162–163°C
1
H NMR: d = 2.72 (m, 1 H), 2.88 (m, 1 H), 3.34 (m, 1 H), 4.01 (m,
1
H NMR: d = 1.34 (t, 3 H, J = 7 Hz, CH CH ), 3.81 (s, 3 H, OCH ),
3
2
3
1
H), 4.29 (m, 1 H), 6.71 (d, 1 H, J = 2 Hz, ArH), 7.06 (d, 1 H, J = 9
4
.36 (q, 2 H, J = 7 Hz, MeCH ), 7.07 (d, 2 H, J = 8 Hz, ArH), 7.20
2
Hz, ArH), 7.36 (d, 1 H, J = 9 Hz, ArH), 7.62 (d, 1 H, J = 2 Hz, ArH),
.40 (s, 1 H, OCHO).
(d, 1 H, J = 8 Hz, ArH), 7.46 (d, 2 H, J = 8 Hz, ArH), 8.08 (d, 1 H,
8
J = 8 Hz, ArH), 10.26 (s, 1 H, CH = N), 15.85 (br s, 1 H, OH).
Anal. Calcd for C H ClNO S: C, 58.55; H, 4.1; N, 3.6; S, 8.2; Cl,
1
9
16
4
(
S)-2,3-Dihydrofuro[3,2-f][1,4]benzodioxin-2-methanol (7b)
9
.1. Found : C, 58.7; H, 4.0; N, 3.5; S, 8.0; Cl, 9.1.
A solution of 6b (3.09 g, 13.2 mmol) in THF (30 mL) was treated
with aq satd K CO solution (15 mL) and the mixture stirred vigor-
2
3
Ethyl 3-Chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-car-
ously at r.t. for 72 h. The mixture was poured into H O (200 mL)
2
boxylate (3d)
and extracted with EtOAc (2 × 150 mL). The combined extracts
were dried and evaporated in vacuo to leave an orange oil. Purifica-
tion by flash column chromatography on silica using a 2:3 mixture
of EtOAc and petroleum ether as eluant gave 10 (0.22 g, 7%) as a
yellow oil which solidified on standing. Further elution of the col-
umn afforded 7b (1.90g, 70%) as a yellow oil.
2
A stirred mixture of the imine 2d (R = OMe, 3.82 g, 9.86 mmol) in
5
7
M HCl (130 mL) was heated at 50–60°C for 4 h and then at 60–
0°C for 3 h. The mixture was poured into H O (350 mL) and ex-
2
tracted with EtOAc (2 × 250 mL). The combined extracts were
washed with H O (200 mL), dried and evaporated in vacuo to afford
2
3
d (2.80 g, 100%) as a pale green solid; mp 128–130°C
–
1
IR (film): n = 3400 cm .
–
1
IR (KBr): n = 1720, 1629 cm .
1
H NMR: d = 1.95 (t, 1 H, J = 6.4 Hz, CH OH), 3.92 (m, 2 H), 4.16
2
1
H NMR (DMSO-d ): d = 1.35 (t, 3 H, J = 7 Hz, CH CH ), 4.37 (q,
(
m, 1 H), 4.34 (m, 2 H), 6.80 (d, 1 H, J = 2 Hz, ArH), 6.85 (d, 1 H,
6
3
2
2
H, J = 7 Hz, MeCH ), 7.29 (d, 1 H, J = 8 Hz, ArH), 8.31 (d, 1 H,
J = 8 Hz, ArH), 7.02 (d, 1 H, J = 8 Hz, ArH), 7.52 (d, 1 H, J = 2 Hz,
ArH).
2
J = 8 Hz, ArH), 11.27 (s, 1 H, CHO), 12.74 (br s, 1 H, OH).
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York

1
186
M. Andrew et.al
PAPER
1
Ethyl (R)-3-Chloro-5-(2,3-epoxypropoxy)-4-formylbenzo[b]
thiophene-2-carboxylate (4d)
H NMR (DMSO-d ): d = 3.69 (m, 2 H), 4.11 (m, 1 H), 4.31 (m, 1
6
H), 4.40 (m, 1 H), 5.11 (br s, 1 H, OH), 7.18 (d, 1 H, J = 8.5 Hz,
A stirred solution of the aldehyde 3d (4.90 g, 0.017 mol) in anhyd
DMF (50 mL) was treated with solid K CO (2.62 g, 0.018 mol) and
then a solution of (R)-glycidyl tosylate (4.12 g, 0.018 mol) in anhyd
DMF (50 mL) was added. The mixture was then heated at 60°C for
ArH), 7.47 (d, 1 H, J = 8.5 Hz, ArH), 12.0-15.0(br s, 1 H, CO H).
2
2
3
Anal. Calcd for C H ClO S.0.28H O: C, 47.15; H, 3.15; S, 10.50;
1
0
9
5
2
Cl, 11.65. Found: C, 47.3; H, 3.3; S,10.9; Cl, 11.9.
3
h and then poured into H O (1200 mL). The resulting pale green
2
(
S)-9-Chloro-2,3-dihydrothieno[3,2-f][1,4]benzodioxin-2-meth-
solid was collected by filtration, washed with H O (200 mL) and
dried to give 4d (5.15 g, 88%).
2
anol (9b) and (S)-2,3-Dihydrothieno[3,2-f][1,4]benzodioxin-2-
methanol (9c)
–
1
IR (KBr): n = 1721, 1688 cm .
A flask containing a mixture of the carboxylic acid 8b (0.80 g, 2.66
mmol), copper powder (0.17 g, 2.66 mmol) and quinoline (10 mL)
was immersed in a pre-heated oil bath at 190°C and the mixture
heated with stirring at this temperature for 30 min. The cooled mix-
ture was poured into 2 M HCl (300 mL) and extracted with EtOAc
1
1
2
8
H NMR (DMSO-d ): d = 1.34 (t, 3 H, J = 7 Hz, CH CH ), 2.74 (m,
6 3 2
H), 2.85 (m, 1 H), 3.34 (m, 1 H), 4.07 (dd, 1 H, J = 6 Hz), 4.36 (q,
H, J = 7 Hz, CH CH ), 4.51 (m, 1 H), 7.58 (d, 1 H, J = 8 Hz, ArH),
3
2
.25 (d, 1 H, J = 8 Hz, ArH), 10.87 (s, 1H, CHO).
(2 × 150 mL). The combined extracts were washed with 2 M HCl
+
CI-MS m/z = 340 (M , 100%).
(
150 mL), H O (150 mL), dried and evaporated in vacuo to leave a
2
3
5
HRMS: m/z Calc. for C H ClO S:340.0178. Found:340.0177.
dark brown oil (0.78 g). Purification by flash column chromatogra-
phy on silica using a 3:7 mixture of EtOAc in petroleum ether as
eluant gave 9b (0.58 g, 85%) as a fawn solid; mp 92–93 °C.
1
5
13
5
Ethyl (R)-3-Chloro-5-(2,3-epoxypropoxy)-4-(formyloxy)ben-
zo[b] thiophene-2-carboxylate (6d)
A stirred solution of 4d (1.0 g, 2.94 mmol) in CH Cl (20 mL) was
treated with 3-chloroperoxybenzoic acid (70%; 0.75 g, 3.04 mmol)
and the mixture cooled to 0°C. A solution of trifluoroacetic acid
Compound 9b
2
2
1
H NMR: d = 2.10 (t, 1 H, J = 6 Hz, exchangeable with D O,
2
CH OH), 3.92 (m, 2 H), 4.14 (m, 1 H), 4.38 (m, 2 H), 6.98 (d, 1 H,
2
J = 9 Hz, ArH), 7.17 (s, 1 H, ArH), 7.24 (d, 1 H, J = 9 Hz, ArH).
(0.35 g, 3.07 mmol) in CH Cl (5 mL) was then added slowly and
2 2
+
the mixture stirred at 0°C for 5 min and then allowed to warm to r.t.
CI-MS: m/z = 256 (M , 100%).
After 1 h, the mixture was poured into 10% aq NaHSO solution
35
3
HRMS: m/z Calc. for C H ClO S:255.9948. Found:255.9948.
1
1
9
3
(
100 mL) and extracted with CH Cl (2 × 200 mL). The combined
2 2
Further elution of the column gave 9c (50 mg, 9%) as a pale-brown
extracts were washed with satd aq NaHCO solution (2 × 150 mL),
3
oil.
dried and evaporated in vacuo to leave a brown oil (1.06 g). Purifi-
cation by flash column chromatography on silica gel using a 1:1
mixture of EtOAc and petroleum ether as eluant gave 6d (0.52 g,
Compound 9c
1
H NMR (DMSO-d ): d = 3.70 (m, 2 H), 4.06 (m, 1 H), 4.33 (m, 2
H), 5.11 (t, 1 H, J = 5.8 Hz, CH OH), 6.95 (d, 1 H, J = 9 Hz, ArH),
7.35 (d, 1 H, J = 6 Hz, 2-or 3-H), 7.41 (d, 1 H, J = 9 Hz, ArH), 7.67
d, 1 H, J = 6 Hz, 2-or 3-H).
6
5
0%) as a pale yellow solid.
2
1
H NMR: d = 1.42 (t, 3 H, J = 7 Hz, CH CH ), 2.73 (m, 1 H), 2.90
3
2
(
m, 1 H), 3.34 (m, 1 H), 4.08 (m, 1 H), 4.36 (m, 1 H), 4.40 (q, 2 H,
(
J = 7 Hz, CH CH ), 7.33 (d, 1 H, J = 8 Hz, ArH), 7.65 (d, 1 H, J = 8
3
2
CI-MS: m/z = 222 (M+, 100%).
Hz, ArH), 8.40 (s, 1 H, OCHO).
HRMS: m/z Calc. For C H O S:222.0345. Required:222.0346.
1
1
10
3
Ethyl (S)-9-Chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-
f][1,4]benzodioxin-8-carboxylate (7d)
5-Hydroxyindazole-4-carbaldehyde (3c)
6
A stirred solution of 6d (1.85 g, 5.18 mmol) in THF (20 mL) was
treated with satd aq K CO solution (20 mL) and the mixture stirred
A flask containing a mixture of 5-hydroxyindazole (14.0 g, 0.10
mol) and ethyl N-phenylformimidate (17.0 g, 0.10 mol) was im-
mersed in a pre-heated oil bath at 175°C and the EtOH produced in
the reaction was removed by distillation. After 2 h, the mixture was
cooled to r.t. and then triturated with boiling MeOH (100 mL). The
resulting orange solid was collected by filtration and dried to leave
2
3
vigorously at r.t. for 18 h. The mixture was poured into H O (200
2
mL) and extracted with EtOAc (2 × 200 mL). The combined ex-
tracts were dried and evaporated in vacuo to leave a yellow solid
(
1.60 g). Purification by flash column chromatography on silica gel
using a 1:1 mixture of EtOAc and petroleum ether as eluant gave 7d
1.44 g, 85%) as a pale yellow solid; mp 165–166°C.
2
2c (R = H) (15.24 g). The filtrate was evaporated in vacuo and the
(
residue eluted through a silica gel pad using a 2:1 mixture of petro-
–
1
leum ether (bp 60–80°C) and EtOAc to give 2.88 g of product (total
yield:18.12 g, 76%). The intermediate imine (2c; R = H) (18.12 g,
76.4 mmol) was treated with 5 M HCl (300 mL) and heated at 50–
IR (KBr): n = 3520, 1713 cm .
1
2
H NMR: d = 1.41 (t, 3 H, J = 7 Hz, CH CH ), 3.92 (m, 2 H), 4.16
m, 1 H), 4.40 (q, 4 H, J = 7 Hz, MeCH and 2 other H’s), 7.09 (d,
H, J = 8 Hz, ArH), 7.23 (d, 1 H, J = 8 Hz, ArH).
3
2
(
1
2
60°C with stirring for 2 h. The cooled mixture was diluted with H O
2
(400 mL) and extracted with EtOAc (6 × 250 mL). The combined
extracts were washed with H O (300 mL), dried and evaporated in
vacuo to give 3c (11.37 g, 94%) as a yellow solid; 98–99°C.
Anal. Calcd for C H ClO S: C, 51.5; H, 3.95; S, 9.75; Cl, 10.80.
Found: C, 51.45; H, 4.2; S, 9.9; Cl, 10.5.
2
1
4
13
5
–
1
IR (KBr): n = 1639 cm .
Ethyl (S)-9-Chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-
f][1,4]benzodioxin-8-carboxylic Acid (8b)
A stirred solution of the ester 7d (1.30 g, 3.96 mmol) in MeOH (20
1
H NMR (DMSO-d ): d = 7.09 (d, 1 H, J = 9 Hz, ArH), 7.79 (d, 1
6
H, J = 9 Hz, ArH), 8.38 (br s, 1 H, 3-H), 10.54 (s, 1 H, CHO), 10.71
(br s, 1 H, NH or OH), 13.24 (br s, 1 H, NH or OH).
mL) was treated with a solution of LiOH•H O (0.17 g, 3.96 mmol)
2
Anal. Calcd for C H N O : C, 59.25; H, 3.70; N, 17.30. Found: C,
in H O (10 mL) and the mixture heated at 60°C for 1 h. The solvent
8
6
2
2
2
5
9.6; H, 3.9; N, 17.3.
was evaporated in vacuo and the residue dissolved in H O (50 mL).
2
The aqueous solution was acidified with 2 M HCl and the resulting
suspension collected by filtration, washed with H O and dried to
(R)-5-(2,3-Epoxypropoxy)indazole-4-carbaldehyde (4c)
2
give 8b (1.15 g, 97%) as an off-white solid; mp 236–237°C.
A mixture of 3c (3.30 g, 0.02 mol) and (R)-glycidyl tosylate (5.0 g,
–
1
0.02 mol) in anhyd DMF (75 mL) was heated to 50 °C under a N
atmosphere. Solid K CO (2.80 g, 0.02 mol) was then added in por-
2
IR (KBr): n = 3389, 1717 cm .
2
3
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Synthetic Route to (S)-2,3-Dihydro-1,4-benzodioxin-2-methanol
1187
tions over 2 h. The resulting cooled mixture was extracted with
(5) 5-Hydroxybenzofuran was prepared by pyridine
hydrochloride demethylation of 5-methoxybenzofuran
EtOAc (3 × 250 mL) and the combined extracts washed with H O
2
(
200 mL), dried and evaporated in vacuo. The residue was purified
following the procedure of René and Royer; René, L.; Royer.
Bull. Soc. Chim. Fr. 1973, 2355.
(6) Davies, R,R. J. Chem. Soc. 1955, 2412.
by flash column chromatography on silica using a 1:1 mixture of
EtOAc and petroleum ether (bp 60–80 °C) as eluant to give 4c (1.65
g, 39%) as a colourless oil.
(7) Ethyl 3-chloro-5-hydroxybenzo[b]thiophene-2-carboxylate
–
1
(1d) was prepared in excellent yield by BBr demethylation of
3
IR (KBr): n = 1664, 1645 cm .
1
its corresponding 5-methyl ether (see experimental section)
which was purchased from Maybridge Chemicals. If
necessary, this methyl ether could be prepared by the
procedure reported by Higa and Krubsack; Higa, T.;
Krubsack, A, J. J. Org. Chem. 1975, 40, 3037.
H NMR: d = 2.82 (m, 1 H), 2.97 (m, 1 H), 3.44 (m, 1 H), 4.12 (m,
H), 4.49 (m, 1 H), 7.19 (d, 1 H, J = 9 Hz, ArH), 7.73 (d, 1 H, J = 9
Hz, ArH), 8.74 (s, 1 H, 3-H), 10.72 (s, 1 H, CHO), 10.80 (br s, 1 H,
NH).
1
+
(8) Royer, R.; René, L.; Buisson, J.P.; Demerseman, P. Eur. J.
Med. Chem. Chim. Ther. 1978, 13, 213.
9) McClure, D.E.; Arison, B.H.; Baldwin, J. J. J. Am. Chem. Soc.
CI-MS: m/z = 218 (M , 39%)
HRMS: m/z Calc. For C H N O :218.0698. Found:218.0699
1
1
10
2
3
(
1
979, 101, 3666.
(
S)1,4-Dioxino[2,3-e]indazole-5-methanol (7c)
Aigbirhio, F.; Pike, V. W.; Francotte, E.; Waters, S. L.;
Banfield, B.; Jaeggri, K. A.; Drake. A. Tetrahedron Asymm.
2
A stirred solution of the aldehyde 4c (1.65 g, 8.0 mmol) in CH Cl2
(
(
200 mL) at 0 °C was treated with 3-chloroperoxybenzoic acid
50%; 10.0 g, 0.029 mol) and the mixture stirred at 0 °C for 2 h. The
1992, 3, 539.
(
(
10) Delgado, A.; Leclerc, G.; Lobato, M. C.; Mauleon, D.
Tetrahedron Lett. 1988, 29, 3671.
11) (S)-2,3-Dihydro[3,2-f][1,4]benzodixin-2-methanol (7b):
solvent was evaporated in vacuo and the residue dissolved in 2.5 M
aq NaOH solution (200 mL). The resulting blue solution was heated
on a steam bath for 1 h, cooled, diluted with H O (200 mL) and ex-
tracted with EtOAc (3 × 250 mL). The combined extracts were
washed with brine (250 mL), dried and evaporated in vacuo to give
2
[α] –25.7(c = 0.191g/100mL MeOH); HPLC: Chiralpak As,
D
(
1
l = 218 nm, 35°C 300psi/2mL/min, mobile phase :90% CO2/
0% (IPA + 0.2% Et NH): Retention Time(min):5.8 (96% ee)
2
7
c (0.27 g, 16%) as a pale green solid; mp 63–66°C.
(
R)-2,3-Dihydro[3,2-f][1,4]benzodioxin-2-methanol:
[α] +26.5 (c = 0.755g/ 100mL MeOH); HPLC(conditions as
above): Retention time(min): 7.02 (90.3% ee).
1
H NMR (DMSO-d ): d = 3.70 (m, 2 H), 4.02 (m, 1 H), 4.31 (m, 2
D
6
H), 5.11 (t, 1 H, J = 5.7 Hz, CH OH), 6.95 (m, 2 H, ArH), 7.91 (br
2
s, 1 H, 3-H), 12.93 (br s, 1 H, NH).
(12) If necessary, ethyl 5-hydroxyindole-2-carboxylate (1a) could
be prepared in good yield by BBr demethylation of its
3
commercially available (Aldrich) 5-methyl ether.
(13) Ethyl N-(4-methoxyphenyl)formimidate was prepared in good
yield and excellent purity by reaction of 4-methoxyaniline, a
catalytic amount of concentrated hydrochloric acid and
triethyl orthoformate.
References
(
1) Ennis, M.D.; Baze, M.E.; Smith, M.W.; Lawson, C.F.;
McCall, R. B.; Lahti, R. A.; Piercey, M. F. J. Med. Chem.
1992, 35, 3058.
(
(
2) Julia, M.; Lallemand, J. F. Bull. Soc. Chim. Fr. 1973, 2046.
3) Koch, S.S.C.; Chamberlin, A.R. Synth. Commun. 1989, 19,
Article Identifier:
8
29.
4) Klunder, J.M.; Onami, T.; Sharpless, K.B. J. Org. Chem.
989, 54, 1295.
1
437-210X,E;1999,0,07,1181,1187,ftx,en;P00599SS.pdf
(
1
Synthesis 1999, No. 7, 1181–1187 ISSN 0039-7881 © Thieme Stuttgart · New York