Synthesis and analgesic activity of some 1-benzofurans, 1-benzothiophenes and indoles

Article abstract of DOI:10.1135/cccc20000280

3-Unsubstituted 1-benzofurans 1e and 1f, 3-methyl-1-benzofurans 1a-1d, and 3-amino-1-benzofurans 2a-21, as well as 3-amino-1-benzothiophenes 3a, 3b and 3-aminoindoles 4a-4f, 11a, and 11b were prepared and tested as analgesics. The 3-amino-1-benzofurans 2 were prepared from the corresponding 2-hydroxybenzonitriles 5 and phenacyl bromides 6 via intermediates 7. Similar treatment of 2-sulfanylbenzonitrile (8) provided 3-amino-1-benzothiophenes 3. Appropriately substituted 2-aminobenzonitriles 9 then provided N-substituted 3-aminoindoles 4. 1-(Ethoxycarbonyl)indoles 4e and 4f were successfully deprotected giving indoles 11a and 11b, respectively.

Full text of DOI:10.1135/cccc20000280

280
Rádl, Hezký, Urbánková, Váchal, Krejčí:
SYNTHESIS AND ANALGESIC ACTIVITY OF SOME 1-BENZOFURANS,
1-BENZOTHIOPHENES AND INDOLES
a
b
b
Stanislav RÁDLa1,*, Petr HEZKÝ , Jitka URBÁNKOVÁ , Petr VÁCHAL
a
andIvan K REJČÍ
a
Research Institute of Pharmacy and Biochemistry, Kouřimská 17, 130 60 Prague 3,
Czech Republic; e-mail: radl@vufb.cz
Department of Organic Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6,
Czech Republic
1
b
Received Novem ber 29, 1999
Accepted Jan uary 19, 2000
3-Un substituted 1-ben zofuran s 1e an d 1f, 3-m eth yl-1-ben zofuran s 1a–1d , an d 3-am in o-
1-ben zofuran s 2a–2l, as well as 3-am in o-1-ben zoth ioph en es 3a, 3b an d 3-am in oin doles
4a–4f, 11a, an d 11b were prepared an d tested as an algesics. Th e 3-am in o-1-ben zofuran s 2
were prepared from th e correspon din g 2-h ydroxyben zon itriles 5 an d ph en acyl brom ides 6
via in term ediates 7. Sim ilar treatm en t of 2-sulfan ylben zon itrile (8) provided
3-am in o-1-ben zoth ioph en es 3. Appropriately substituted 2-am in oben zon itriles 9 th en pro-
vided N-substituted 3-am in oin doles 4. 1-(Eth oxycarbon yl)in doles 4e an d 4f were success-
fully deprotected givin g in doles 11a an d 11b, respectively.
Key w ord s: Ben zofuran s; Ben zoth ioph en es; In doles; Xan th oxylin e an alogs; An algesics.
An tin ociceptive activity of 2-(4-brom oben zoyl)-4,6-dim eth oxy-3-m eth yl-
1-ben zofuran (1a) h as recen tly been reported1,2. Th is com poun d, wh ich
was prepared from n aturally occurrin g 1-(2-h ydroxy-4,6-dim eth oxy-
ph en yl)eth an -1-on e (xan th oxylin e), represen ts a n ew structural type exert-
in g an algesic effect. Quite un usually, n o oth er 1-ben zofuran derivative of
th e active com poun d 1a was m en tion ed an d th erefore we decided to pre-
pare th e com poun d itself an d also its derivatives 1b–1f.
Th ere are several well-docum en ted m eth ods of preparation of
3-un substituted an d 3-m eth yl-2-ben zoyl-1-ben zofuran s3. Syn th esis of com -
poun d 1d from th e correspon din g 6-h ydroxy derivative h as been pub-
lish ed4. A low yield of com poun d 1f was form ed, in addition to several
oth er products, durin g form ylation of 2-(3,5-dim eth oxyph en oxy)-
1-ph en yleth an -1-on e5. We decided to prepare all th e com poun ds 1 from
appropriate 2-h ydroxyacetoph en on es or 2-h ydroxyben zaldeh ydes an d
2-brom o-1-ph en yleth an -1-on es by a m odification of th e publish ed proce-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles
281
dure6. First we decided to prepare 1a to prove th e reported activity. Th e de-
scribed m eth ods of preparation of xan th oxylin e are m ostly n on selective
an d in clude th e Friedel–Crafts acetylation of 3,5-dim eth oxyph en ole7 or
m eth ylation of 1-(2,4,6-trih ydroxyph en yl)eth an -1-on e8,9 un der various
con dition s. Dem eth ylation of 1-(2,4,6-trim eth oxyph en yl)eth an -1-on e with
alum in um ch loride is also n on selective providin g a m ixture of all possible
m on o-, di-, an d trih ydroxy derivatives10. We applied a publish ed proce-
dure11 of selective dem eth ylation of ortho-m eth oxy arom atic keton es. Th is
procedure m on odem eth ylated 1-(2,4,6-trim eth oxyph en yl)eth an -1-on e to
give acceptable yields of xan th oxylin e. Th is com poun d treated with
2-brom o-1-(4-brom oph en yl)eth an -1-on e in th e presen ce of potassium h y-
droxide provided 1a. Sin ce th e reported an algesic activity of 1a was proved,
com poun ds 1b–1d were prepared from th e correspon din g 1-(2-h ydroxy-
ph en yl)eth an -1-on es by th e sam e procedure. Sim ilarly, startin g from
2-h ydroxy-4,6-dim eth oxyben zaldeh yde an d th e correspon din g 2-brom o-
1-phenylethan-1-ones, com pounds 1e and 1f were prepared. In this case, th e
use of potassium carbon ate in butan -2-on e un der reflux was sufficien t for a
sm ooth reaction .
An algesic screen in g foun d com poun d 1a th e m ost active of th e series.
However, all th ese com poun ds were foun d active on ly for i.p. or s.c. appli-
cation an d on ly sligh tly active or in active after p.o. application . In order to
obtain com poun ds with better ph arm acological profile, we decided to pre-
pare som e m ore differen t an alogs of 1a. First we decided to prepare
3-am in o-substituted 1-ben zofuran s 2, 1-ben zoth ioph en es 3, an d in doles 4,
sin ce we expected th at th ese com poun ds could form water-soluble salts.
R1
R3
R2
NH2
NH2
R
O
O
O
X
O
MeO
O
1
R1 R2 R3
Br Me MeO
2, X = O
3, X = S
4, X = NR
12
a
b
R
Me
OEt
a
b
c
d
e
f
H
Me MeO
Br Me
H
H
Br
H
Me
H
H
H
MeO
MeO
Syn th esis of 1-ben zofuran 2a startin g from 2-h ydroxyben zon itrile (5a)
an d 6a h as been described12,13. Wh en th e reaction was don e with sodium
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

282
Rádl, Hezký, Urbánková, Váchal, Krejčí:
h ydroxide in 2-m eth oxyeth an -1-ol, th e in term ediate ben zoylm eth oxy de-
rivative 7a was isolated an d ch aracterized12. Usin g potassium carbon ate in
aceton e led directly to 1-ben zofuran 2a. We usually prepared 1-ben zofuran
derivatives 2a–2l from th e appropriate ben zon itrile 5 an d brom o derivative
6 via th e correspon din g ben zoylm eth oxy derivatives 7, basically as de-
scribed12 for 2a. We used sodium h ydroxide in 2-m eth oxyeth an -1-ol or so-
dium h ydrogen carbon ate in DMF at room tem perature to get com poun ds 7,
wh ich were after isolation cyclized with sodium m eth oxide or potassium
tert-butoxide in m eth an ol at room tem perature to give good yields of com -
poun ds 2 (Sch em e 1). Startin g 2-h ydroxy-3-m eth oxyben zon itrile (5b) an d
2-h ydroxy-4,6-dim eth oxyben zon itrile (5c) were prepared from th e appro-
priate com m ercially available ben zaldeh ydes via th e correspon din g oxim es,
wh ich were deh ydrated in situ with form ic acid to th e required ben zo-
n itriles14.
R1
R4
CN
R1
R1
NH2
CN
R4
R2
OH
O
R3
5
R2
O
R2
O
O
+
R3
O
R3
R3
H
H
H
H
MeO
MeO Br
MeO Ph
Br
7
2
2, 7
a
b
c
d
e
f
g
h
i
R1
H
H
H
H
H
H
H
H
R2
R4
H
Br
Ph
R4
6
H
H
H
H
H
H
H
H
R4
H
Br
Ph
6
a
b
c
d
5
a
b
c
R1
R2
H
H
R3
H
MeO
2,4-F2C6H3
H
H
H
MeO MeO H
2,4-F2C6H3
MeO 2,4-F2C6H3
MeO MeO
MeO MeO
MeO MeO
MeO MeO
H
H
H
H
H
Br
Ph
j
k
l
2,4-F2C6H3
SCHEME 1
Form ation of 3a from 2-sulfan ylben zon itrile (8) an d 2-ch loro-1-ph en yl-
eth an -1-on e in an aqueous sodium h ydroxide solution h as been reported
with out an y experim en tal details15. We prepared 1-ben zoth ioph en e deriva-
tives 3 un der an alogous con dition s described above for th e preparation of
1-ben zofuran s 2. Th e reaction of 2-fluoroben zon itrile with ph en yl-
m eth an eth iol provided in good yield startin g 2-(ben zylsulfan yl)ben zo-
n itrile. Sim ilar preparation of th is com poun d from 2-n itroben zon itrile h as
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles
283
been publish ed16. Th e required 2-sulfan ylben zon itrile (8) was prepared by
deben zylation of th is com poun d with alum in um ch loride. In our h an ds,
th is m eth od provided purer product, wh ich did n ot require distillation ,
th an th e described m eth od17 startin g from 2-brom oben zon itrile an d eth yl
3-sulfan ylpropion ate. In th e case of 1-ben zoth ioph en es, th e expected open
in term ediates can n ot be isolated an d th e target com poun ds 3a an d 3b were
directly form ed un der th e used con dition s (Sch em e 2).
O
CN
S
R
CN
SH
Br
+
R
O
6
a
b
R
H
Br
R
8
NH2
3
a
b
R
H
Br
S
O
SCHEME 2
Th e use of addition of an activated CH2 group to a n itrile fun ction ality
for th e syn th esis of 3-am in oin doles is rare18. Our attem pts to use
N-un substituted 2-am in oben zon itrile for sim ilar preparation of in dole de-
rivatives failed. Th e reaction with 2-brom o-1-(4-brom oph en yl)eth an -1-on e
un der m ilder con dition s did n ot proceed; un der m ore h arsh con dition s, it
provided com plex m ixtures. Th erefore, we prepared N-activated derivatives
9a–9d as suitable startin g com poun ds. Reaction of 9a or 9b with brom o de-
rivatives 6a or 6b provided sm ooth ly in term ediates 10, togeth er with sm all
am oun ts of th e correspon din g in doles 4. Th e sam e treatm en t of 9c pro-
vided directly in doles 4e an d 4f, respectively. On th e oth er h an d, th e sam e
reaction of acetyl derivative 9d un der differen t con dition s provided com -
plex m ixtures. Com poun ds 10 were purified by crystallization an d th en
cyclized in to in doles 4 with sodium m eth oxide. With com poun ds 10c an d
10d , th e use of trieth ylam in e in eth an ol provided clean er reaction m ixtures
an d h igh er yields of in doles 4c an d 4d , respectively. We tried to deprotect
com poun ds 4 to get th e correspon din g N-un substituted in doles un der vari-
ous con dition s. After several failures we succeeded in deprotection of
N-eth oxycarbon yl derivatives 4e an d 4f by alkalin e h ydrolysis to yield
N-un substituted in doles 11a an d 11b, respectively (Sch em e 3).
An alogously to com poun ds 2, th e kn own 2-acetyl-3-am in o-1-ben zofuran
(12a) an d eth yl 3-am in o-1-ben zofuran -2-carboxylate (12b) were prepared
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

284
Rádl, Hezký, Urbánková, Váchal, Krejčí:
from 2-h ydroxyben zon itrile (5a) an d ch loroaceton e or eth yl brom oacetate,
by m odification s of th e publish ed procedures12,13
.
O
R2
CN
CN
Br
+
NH
R1
N
R1
R2
R1
MeSO2
MeSO2
4-Me-C6H4SO2
4-Me-C6H4SO2
CO2Et
O
4,10
R2
H
Br
H
Br
H
Br
10
9
a
b
c
d
R1
MeSO2
6
a
b
R2
H
Br
a
b
c
d
e
f
4-Me-C6H4SO2
CO2Et
MeCO
R2
R
NH2
NH2
CO2Et
11
a
b
R
H
Br
N
R1
O
N
4
O
H
SCHEME 3
Structures of all n ew com poun ds were proved by elem en tal an alysis an d
NMR spectroscopy. IR an d UV spectra of selected com poun ds were also
m easured. In th ese cases, IR spectra sh owed ch aracteristic vibration s of th e
fun ction al groups presen t. UV spectra of all m easured 1-ben zofuran s,
1-ben zoth ioph en es, an d in doles were foun d to exh ibit sim ilar pattern s.
All th e prepared target com poun ds, i.e. 1-ben zofuran s 1, 2, an d 12,
1-ben zoth ioph en es 3 as well as in doles 4 an d 11, were evaluated for th eir
an tin ociceptive activity in two basic tests, th e h ot-plate test an d
in traperiton eal writh in g test in m ice. Selected com poun ds were tested also
in th e tail-flick test in rats. An algesic activity of com poun ds h avin g at least
in on e of th e tests activity h igh er th an 30% is sh own in Table I. It is evi-
den t th at th e m odel com poun d 1a is h igh ly active after subcutan eous ap-
plication an d on ly sligh tly active after oral application . Th e sam e pattern is
observed also with oth er com poun ds 1. In th is subset, on ly com poun ds
h avin g th e 4,6-dim eth oxy substituen ts are fairly active. No such pattern
can be seen in th e group of 3-am in o-1-ben zofuran s 2, wh ere th e good an al-
gesic activity after subcutan eous application was foun d in com poun d 2a, as
well as in 7-m eth oxy derivative 2e an d 4,6-dim eth oxy derivative 2k. Both
tested com poun ds 12a an d 12b, wh ich do n ot con tain th e 2-ben zoyl group,
were foun d on ly sligh tly active. Also both tested 1-ben zoth ioph en es 3a an d
3b were on ly sligh tly active. No im provem en t in th e an algesic activity was
foun d also in in doles 4, com poun d 4f bein g th e on ly active N-substituted
in dole of th is group. On th e oth er h an d, both N-un substituted in doles 11
were active. However, th eir activity was n ot quite con vin cin g.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles
285
In con clusion , a series of n ew 1-ben zofuran s, 1-ben zoth ioph en es, an d
in doles were syn th esized an d tested as an algesics. Som e of th em , e.g., com -
poun ds 2a, 2k, 4f, 11a, an d 11b, are in doses of 30 m g/kg active in th e used
an algesic m odels. However, th eir activity is n ot h igh en ough to justify th eir
furth er developm en t as an algesic agen ts.
EXPERIMENTAL
Meltin g poin ts were m easured on a Kofler block an d are un corrected. 1H NMR spectra were
recorded on a Bruker in strum en t (250 MHz). Ch em ical sh ifts are given in ppm (δ-scale), cou-
plin g con stan ts (J) in Hz. IR spectra (KBr) were recorded on a Un icam SP 2006 spectrom eter,
waven um bers are given in cm –1. UV spectra were m easured on a Sh im adzu UV-260 spec-
trom eter in eth an ol, wavelen gth s are given in n m . Flash ch rom atograph y was don e on silica
gel 60 (230–400 m esh ) an d preparative TLC on pre-coated PLC plates (silica gel 60) from EM
Scien ce.
Th e followin g startin g com poun ds were prepared by th e previously described m eth ods:
1-(biph en yl-4-yl)-2-brom oeth an -1-on e19 (6c), 2-brom o-1-(2′,4′-difluorobiph en yl-4-yl)eth an -
1-on e20 (6d ), N-(2-cyan oph en yl)m eth an esulfon am ide21 (9a), N-(2-cyan oph en yl)-4-m eth yl
ben zen esulfon am ide22 (9b ), eth yl N-(2-cyan oph en yl)carbam ate23 (9c), an d N-(2-cyan o-
ph en yl)acetam ide24 (9d ). Th e kn own 1-ben zofuran s 12a an d 12b were prepared an alogously
as described in th e literature12,13
.
TABLE I
An algesic activitya of active com poun ds 1–4, 11
Com poun d
Hot plate, %
Writh in g, %
Tail flick, %
1a
1e
–/63
–/27
–/7
22/–
1/–
–/47
–/32
–/45
–/52
–/–
1f
15/–
7/37
33/–
–/70
33/–
32/–
31/–
2a
14/39
5/44
–/44
–/29
–/27
18/17
2e
2k
–/–
4f
1/93
10/–
3/–
11a
11b
a
– p.o./s.c., 30 m g/kg.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

286
Rádl, Hezký, Urbánková, Váchal, Krejčí:
1-(2-Hydroxy-4,6-dim eth oxyph en yl)eth an -1-on e
Butyllith ium (10 m l of a 2.5 M solution in h exan es, 25 m m ol) was added to a toluen e solu-
tion (25 m l) of 1-m eth ylpiperazin e (2.5 g, 25 m m ol) un der argon at 0 °C an d th e m ixture
was stirred at room tem perature for 20 m in . Th e m ixture was cooled to 0 °C an d a solution
of 1-(2,4,6-trim eth oxyph en yl)eth an -1-on e (4.2 g, 20 m m ol) in toluen e (50 m l) was added
dropwise keepin g th e tem perature below 15 °C. After addition of butyllith ium (10 m l of a
2.5 M solution in h exan es, 25 m m ol), th e m ixture was stirred at room tem perature for 30
m in an d th en at 80 °C for 10 h . Th e cold m ixture was quen ch ed with 5% h ydroch loric acid
(20 m l) an d th e aqueous layer was extracted with dieth yl eth er. Th e com bin ed organ ic ex-
tracts were dried with m agn esium sulfate, th e residue after evaporation (2.7 g) was crystal-
lized twice from h exan e to give th e required product (2.7 g, 71%) as wh ite crystals; m .p.
84–85 °C (ref.25 87 °C). 1H NMR (CDCl3): 2.61 s, 3 H (CH3); 3.82 s, 3 H (CH3O); 3.85 s, 3 H
(CH3O); 5.92 d, 1 H, J = 2.5 (H-5); 6.06 d, 1 H, J = 2.5 (H-3); 14.01 s, 1 H (OH).
Preparation of 2-Ben zoyl-3-m eth yl-1-ben zofuran s 1a–1d . Gen eral Procedure
A solution of an appropriate 2-brom o-1-ph en yleth an -1-on e (10 m m ol) in eth an ol (20 m l)
was added to a stirred solution of 1-(2-h ydroxyph en yl)eth an -1-on e (10 m m ol) an d potas-
sium h ydroxide (1 g, 18 m m ol) in eth an ol (30 m l) an d th e m ixture was stirred overn igh t.
Th e in soluble portion was filtered off an d crystallized from eth an ol (ch arcoal) to give 1.
2-(4-Bromobenzoyl)-4,6-dimethoxy-3-methyl-1-benzofuran (1a). Yield 82%; m .p. 180–184 °C
(ref.2 185 °C). For C 18H15BrO4 (375.2) calculated: 57.62% C, 4.03% H, 21.30% Br; foun d:
57.67% C, 4.54% H, 21.62% Br. 1H NMR (CDCl3): 2.75 s, 3 H (CH3); 3.86 s, 3 H (CH3O);
3.90 s, 3 H (CH3O); 6.29 d, 1 H, J = 1.9 (H-5); 6.56 d, 1 H, J = 1.9 (H-7); 7.63 dt, 2 H, J = 8.7,
2.2 (ben zoyl); 7.91 dt, 2 H, J = 8.7, 2.2 (ben zoyl).
2-Benzoyl-4,6-dimethoxy-3-methyl-1-benzofuran (1b ). Yield 88%; m .p. 123–126 °C. For
C
18H16O4 (296.3) calculated: 72.96% C, 5.44% H; foun d: 73.27% C, 5.55% H. 1H NMR
(CDCl3): 2.74 s, 3 H (CH3); 3.85 s, 3 H (CH3O); 3.90 s, 3 H (CH3O); 6.29 d, 1 H, J = 1.9
(H-5); 6.58 d, 1 H, J = 1.9 (H-7); 7.38–7.63 m , 3 H (ben zoyl); 8.01 m , 2 H (ben zoyl).
2-(4-Bromobenzoyl)-6-methoxy-3-methyl-1-benzofuran (1c). Yield 90%; m .p. 117–119 °C. For
C
17H13BrO3 (345.2) calculated: 59.15% C, 3.80% H, 23.15% Br; foun d: 58.88% C, 3.70% H,
22.66% Br. UV, λ (log ε): 205 (4.51), 244 (4.00), 264 (4.11), 349 (4.40). 1H NMR (CDCl3):
2.63 s, 3 H (CH3); 3.88 s, 3 H (CH3O); 6.93–7.03 m , 2 H (H-5, H-7); 7.55 dd, 1 H, J = 8.3, 0.9
(H-4); 7.65 dt, 2 H, J = 8.6, 1.9 (ben zoyl); 7.96 dt, 2 H, J = 8.6, 1.9 (ben zoyl).
2-Benzoyl-6-methoxy-3-methyl-1-benzofuran (1d ). Yield 54%; m .p. 74–75 °C (ref. 4 76 °C). For
C
17H14O3 (266.3) calculated: 76.68% C, 5.30% H; foun d: 76.34% C, 4.92% H. IR (KBr): 1 621
(C=O). UV, λ (log ε): 205 (4.42), 241 (4.03), 256 (4.11), 344 (4.33). 1H NMR (CDCl3): 2.61 s,
3 H (CH3); 3.88 s, 3 H (CH3O); 6.94 m , 2 H (H-5, H-7); 7.46–7.63 m , 4 H (H-4, ben zoyl);
8.02 m , 2 H (ben zoyl).
Preparation of 2-Ben zoyl-1-ben zofuran s 1e, 1f. Gen eral Procedure
A m ixture of 2-h ydroxy-4,6-dim eth oxyben zaldeh yde (1.8 g, 10 m m ol), an appropriate
2-brom o-1-ph en yleth an -1-on e (10 m m ol), potassium carbon ate (2 g, 14 m m ol) an d
butan -2-on e (50 m l) was refluxed for 6 h . Th e in soluble portion was filtered off, th e filtrate
was evaporated an d crystallized twice from eth an ol (ch arcoal) to give th e required product.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1-Benzofurans, 1-Benzothiophenes, Indoles
287
2-(4-Bromobenzoyl)-4,6-dimethoxy-1-benzofuran (1e). Yield 53%; m .p. 179–181 °C. For
C
17H13BrO4 (361.2) calculated: 56.53% C, 3.63% H, 22.12% Br; foun d: 56.72% C, 3.52% H,
21.78% Br. UV, λ (log ε): 207 (4.56), 230 (3.92), 255 (4.04), 286 (3.89). 1H NMR (CDCl3):
3.87 s, 3 H (CH3O); 3.91 s, 3 H (CH3O); 6.34 d, 1 H, J = 1.9 (H-5); 6.69 dd, 1 H, J = 1.9, 1.0
(H-7); 7.52 d, 1 H, J = 1.0 (H-3); 7.64 dt, 2 H, J = 8.8, 2.0 (ben zoyl); 7.88 dt, 2 H, J = 8.8, 2.0
(ben zoyl).
2-Benzoyl-4,6-dimethoxy-1-benzofuran (1f). Yield 57%; m .p. 135–136 °C (ref.5 140–141 °C).
For C17H14O4 (282.3) calculated: 72.33% C, 5.00% H; foun d: 72.50% C, 5.33% H. IR (KBr):
1 631 (C=O). UV, λ (log ε): 205 (4.44), 254 (4.14), 352 (4.28). 1H NMR (CDCl3): 3.87 s, 3 H
(CH3O); 3.91 s, 3 H (CH3O); 6.34 d, 1 H, J = 1.9 (H-5); 6.70 dd, 1 H, J = 1.9, 0.9 (H-7);
7.50 m , 3 H (ben zoyl); 7.54 d, 1 H, J = 0.9 (H-3); 7.94 m , 2 H (ben zoyl).
2-Hydroxy-3-m eth oxyben zon itrile (5b)
A m ixture of 2-h ydroxy-3-m eth oxyben zaldeh yde (7.6 g, 50 m m ol), h ydroxylam in e h ydro-
ch loride (4.4 g, 63 m m ol), dry sodium acetate (4.5 g, 55 m m ol), an d an h ydrous form ic acid
(60 m l) was refluxed un der n itrogen for 3 h . Th e m ixture was evaporated un der reduced
pressure, th e residue was poured in to water, th e m ixture was extracted with eth er, th e or-
gan ic layer was wash ed with brin e an d dried with m agn esium sulfate. Th e residue was puri-
fied by flash ch rom atograph y (petroleum eth er–aceton e, from 20 : 1 to 8 : 2) followed by
crystallization from h exan e to give 5.6 g (75%) of wh ite crystals, m .p. 56–57 °C (ref. 14
47–48 °C; ref.26 59 °C). For C 8H7NO2 (149.1) calculated: 64.42% C, 4.73% H, 9.39% N;
foun d: 64.03% C, 4.83% H, 9.24% N. 1H NMR (CDCl3): 3.93 s, 3 H (CH3); 6.63 bs, 1 H (OH);
6.89 dd, 1 H, J = 8.4, 7.8 (H-5); 7.05 m , 2 H (H-4, H-6).
2-Hydroxy-4,6-dim eth oxyben zon itrile (5c)
A m ixture of 2-h ydroxy-4,6-dim eth oxyben zaldeh yde (10 g, 55 m m ol), h ydroxylam in e h y-
droch loride (4.4 g, 63 m m ol), dry sodium acetate (4.5 g, 55 m m ol), an d an h ydrous form ic
acid (40 m l) was refluxed un der n itrogen for 3 h . Th e m ixture was worked up as above an d
purified by flash ch rom atograph y (petroleum eth er–aceton e, 20 : 1) to give 3.35 g (33.5%)
of th e startin g aldeh yde an d 4.0 g (40%) of wh ite crystals, m .p. 203–206 °C (eth an ol–water,
1 : 1). For C9H9NO3 (179.2) calculated: 60.33% C, 5.06% H, 7.82% N; foun d: 60.12% C,
5.28% H, 7.56% N. 1H NMR (CDCl3): 3.87 s, 3 H (CH3); 3.95 s, 3 H (CH3); 6.05 d, 1 H, J =
2.0 (H-3 or H-5); 6.08 d, 1 H, J = 2.0 (H-3 or H-5); 10.95 bs, 1 H (OH). 13C NMR (CDCl3):
55.54 (CH3), 56.12 (CH3), 88.88 (C-1), 90.20 (C-5), 93.46 (C-3), 114.85 (CN), 162.52 (C-2),
163.01 (C-4), 164.73 (C-6).
Preparation of 2-(2-Oxo-2-ph en yleth oxy)ben zon itriles 7. Gen eral Procedure
Method A. A solution of sodium h ydroxide (1 g, 25 m m ol) in water (2 m l) was added to a
stirred m ixture of an appropriate 2-h ydroxyben zon itrile 5 (25 m m ol) an d a 2-brom o-
1-ph en yleth an -1-on e 6 (10 m m ol) in 2-m eth oxyeth an -1-ol (20 m l) an d th e m ixture was
refluxed for 15 m in . Th en th e m ixture was cooled, th e in soluble portion was filtered an d
crystallized from eth an ol to give 7.
Method B.
A m ixture of 2-h ydroxyben zon itrile 5 (10 m m ol), 2-brom o-1-ph en yl-
eth an -1-on e 6 (11 m m ol), an d potassium carbon ate (1.5 g, 15 m m ol) in DMF (20 m l) was
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stirred at room tem perature for 2 h . Th e m ixture was poured in to water (100 m l), th e in solu-
ble portion was filtered off, wash ed with water an d crystallized from eth an ol to give pure 7.
2-(2-Oxo-2-phenylethoxy)benzonitrile (7a). Yield 83% (Meth od A), 79% (Meth od B); wh ite
crystals, m .p. 147–148 °C (ref.12 148–149 °C). For C 15H11NO2 (237.3) calculated: 75.94% C,
4.67% H, 5.90% N; foun d: 75.57% C, 4.74% H, 6.01% N. 1H NMR (CDCl3): 5.43 s, 2 H
(CH2); 6.83 d, 1 H, J = 8.5 (H-3); 7.03 dt, 1 H, J = 7.5, 1.0 (H-5); 7.54 m , 5 H (H-4, H-6, H-3′,
H-4′, H-5′); 8.01 bd, 2 H (H-2′, H-6′).
2-[2-(4-Bromophenyl)-2-oxoethoxy]benzonitrile (7b). Yield 57% (Meth od A); wh ite crystals,
m .p. 141–150 °C (ref. 12 164–165 °C; crystallized from CHCl 3–CCl4). For C15H10BrNO2
(316.1) calculated: 56.99% C, 3.19% H, 25.27% Br, 4.43% N; foun d: 56.67% C, 3.44% H,
24.89% Br, 4.57% N. IR (KBr): 1 692 (C=O), 2 223 (CN).
2-[2-(Biphenyl-4-yl)-2-oxoethoxy]benzonitrile (7c). Yield 82% (Meth od A); wh ite crystals,
m .p. 148–151 °C. For C 21H15NO2 (313.4) calculated: 80.49% C, 4.82% H, 4.47% N; foun d:
80.19% C, 5.01% H, 4.43% N. IR (KBr): 1 688 (C=O), 2 226 (CN). UV, λ (log ε): 207 (4.72),
291 (4.52). 1H NMR (CDCl3): 5.44 s, 2 H (CH2); 6.85 d, 1 H, J = 7.8 (H-3); 7.02 dt, 1 H, J =
7.8, 1.6 (H-4); 7.46 m , 4 H (H-5, H-2′′, H-4′′, H-6′′); 7.57 dd, 1 H, J = 7.5, 1.6 (H-6); 7.62 bd,
2 H (H-3′′, H-5′′); 7.72 d, 2 H, J = 8.5 (H-3′, H-5′); 8.08 d, 2 H, J = 8.5 (H-2′, H-6′).
2-[2-(2′,4′-Difluorobiphenyl-4-yl)-2-oxoethoxy]benzonitrile (7d ). Yield 49% (Meth od B); wh ite
crystals, m .p. 141–143 °C. For C 21H13F2NO2 (349.3) calculated: 72.20% C, 3.75% H, 10.88% F,
4.01% N; foun d: 72.13% C, 4.09% H, 10.57% F, 3.57% N. 1H NMR (CDCl3): 5.44 s, 2 H
(CH2); 6.86 d, 1 H, J = 8.5 (H-3); 6.99 m , 3 H (H-5, H-3′′, H-5′′); 7.46 m , 2 H (H-4, H-6′′);
7.59 dd, 1 H, J = 7.9, 1.9 (H-6); 7.65 dd, 2 H, J = 8.5, 1.6 (H-3′, H-5′); 8.09 d, 2 H, J = 8.5
(H-2′, H-6′). 19F NMR (CDCl3): –109.68 (F-2′′), –113.21 (F-4′′).
3-Methoxy-2-(2-oxo-2-phenylethoxy)benzonitrile (7e). Yield 67% (Meth od B); wh ite crystals,
m .p. 83–84 °C. For C 16H13NO3 (267.3) calculated: 71.90% C, 4.90% H, 5.24% N; foun d:
71.66% C, 4.68% H, 5.02% N. 1H NMR (CDCl3): 3.77 s, 3 H (CH3); 5.50 s, 2 H (CH2);
7.09–7.17 m , 3 H (H-4, H-5, H-6); 7.49 m , 2 H (H-3′, H-5′); 7.60 m , 1 H (H-4′); 7.97 m , 2 H
(H-2′, H-6′).
3-Methoxy-2-[2-(4-bromophenyl)ethoxy-2-oxo]benzonitrile (7f). Yield 79% (Meth od B); wh ite
crystals, m .p. 132–133 °C. For C 16H12BrNO3 (346.2) calculated: 55.51% C, 3.49% H, 23.08%
Br, 4.05% N; foun d: 55.49% C, 3.68% H, 23.55% Br, 3.60% N. 1H NMR (CDCl3): 3.78 s, 3 H
(CH3); 5.41 s, 2 H (CH2); 7.09–7.17 m , 3 H (H-4, H-5, H-6); 7.63 d, 2 H, J = 8.7 (H-3′, H-5′);
7.86 d, 2 H, J = 8.7 (H-2′, H-6′).
2-[2-(Biphenyl-4-yl)-2-oxoethoxy]-3-methoxybenzonitrile (7g). Yield 87% (Meth od B); wh ite
crystals, m .p. 122–125 °C. For C 22H17NO3 (343.4) calculated: 76.95% C, 4.99% H, 4.08% N;
foun d: 76.82% C, 5.33% H, 3.71% N. IR (KBr): 1 693 (C=O), 2 231 (CN). UV, λ (log ε): 208
(4.68), 289 (4.41). 1H NMR (CDCl3): 3.79 s, 3 H (CH3); 5.52 s, 2 H (CH2); 7.09–7.18 m , 3 H
(H-4, H-5, H-6); 7.45 m , 3 H (H-3′′, H-4′′, H-5′′); 7.63 m , 2 H (H-2′′, H-6′′); 7.71 d, 2 H, J =
8.3 (H-3′, H-5′); 8.06 d, 2 H, J = 8.3 (H-2′, H-6′).
2-[2-(2′,4′-Difluorobiphenyl-4-yl)-2-oxoethoxy]-3-methoxybenzonitrile (7h ). Yield 77% (Meth od B);
wh ite crystals, m .p. 126–128 °C. For C 22H15F2NO3 (379.4) calculated: 69.65% C, 3.99% H,
10.02% F, 3.69% N; foun d: 69.57% C, 4.24% H, 9.67% F, 3.51% N. IR (KBr): 1 674 (C=O),
232 (CN). UV, λ (log ε): 209 (4.72), 282 (4.30). 1H NMR (CDCl3): 3.80 s, 3 H (CH3); 5.51 s,
2 H (CH2); 6.97 m , 2 H (H-3′′, H-5′′); 7.10–7.18 m , 3 H (H-4, H-5, H-6); 7.44 m , 1 H (H-6′′);
7.63 dd, 2 H, J = 8.8, 1.6 (H-3′, H-5′); 8.06 d, 2 H, J = 8.8 (H-2′, H-6′). 19F NMR (CDCl3):
–109.76 (F-2′′), –113.19 (F-4′′).
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4,6-Dimethoxy-2-(2-oxo-2-phenylethoxy)benzonitrile (7i). Yield 95% (Meth od B); wh ite crys-
tals, m .p. 148–150 °C. For C 17H15NO4 (297.3) calculated: 68.68% C, 5.09% H, 4.71% N;
foun d: 68.86% C, 5.24% H, 4.62% N. IR (KBr): 1 701 (C=O), 2 220 (CN). UV, λ (log ε): 205
(4.57), 216 (4.60), 250 (4.44). 1H NMR (CDCl3): 3.78 s, 3 H (CH3O); 3.87 s, 3 H (CH3O);
5.33 s, 2 H (CH2); 5.96 d, 1 H, J = 1.9 (H-3 or H-5); 6.08 d, 1 H, J = 1.9 (H-3 or H-5); 7.50 bt,
2 H (H-3′, H-5′); 7.62 bt, 1 H (H-4′); 8.01 bd, 2 H (H-2′, H-6′).
2-[2-(4-Bromophenyl)-2-oxoethoxy]-4,6-dimethoxybenzonitrile (7j). Yield 99% (Meth od B);
wh ite crystals, m .p. 191–192 °C. For C 17H14BrNO4 (376.2) calculated: 54.28% C, 3.75% H,
21.24% Br, 3.72% N; foun d: 54.59% C, 3.84% H, 21.09% Br, 3.59% N. IR (KBr): 1 694
(C=O), 2 217 (CN). UV, λ (log ε): 205 (4.44), 216 (4.62), 258 (4.52). 1H NMR (CDCl3): 3.79 s,
3 H (CH3); 3.87 s, 3 H (CH3); 5.26 s, 2 H (CH2); 5.96 d, 1 H, J = 2.2 (H-3 or H-5); 6.08 d,
1 H, J = 2.2 (H-3 or H-5); 7.65 d, 2 H, J = 8.5 (H-3′, H-5′); 7.90 d, 2 H, J = 8.5 (H-2′, H-6′).
2-[2-(Biphenyl-4-yl)-2-oxoethoxy]-4,6-dimethoxybenzonitrile (7k ). Yield 29% (Meth od B);
cream y crystals, m .p. 142–143 °C. For C 23H19NO4 (373.4) calculated: 73.98% C, 5.13% H,
3.75% N; foun d: 73.65% C, 5.20% H, 3.94% N. IR (KBr): 1 688 (C=O), 2 219 (CN). 1H NMR
(CDCl3): 3.79 s, 3 H (CH3); 3.87 s, 3 H (CH3); 5.35 s, 2 H (CH2); 5.99 d, 1 H, J = 2.2 (H-3 or
H-5); 6.08 d, 1 H, J = 2.2 (H-3 or H-5); 7.44 m , 3 H (H-3′′, H-4′′, H-5′′); 7.63 m , 2 H (H-2′′,
H-6′′); 7.72 d, 2 H, J = 8.2 (H-3′, H-5′); 8.10 d, 2 H, J = 8.2 (H-2′, H-6′).
2-[2-(2′,4′-Difluorobiphenyl-4-yl)-2-oxoethoxy]-4,6-dimethoxybenzonitrile (7l). Yield 44%
(Meth od B); cream y crystals, m .p. 142–146 °C. For C 23H17F2NO4 (409.4) calculated: 67.48%
C, 4.19% H, 9.28% F, 3.42% N; foun d: 67.66% C, 4.34% H, 8.92% F, 3.25% N. IR (KBr):
1 689 (C=O), 2 215 (CN). UV, λ (log ε): 217 (4.67), 260 (4.41). 1H NMR (CDCl3): 3.79 s, 3 H
(CH3); 3.87 s, 3 H (CH3); 5.35 s, 2 H (CH2); 5.99 d, 1 H, J = 1.9 (H-3 or H-5); 6.08 d, 1 H, J =
1.9 (H-3 or H-5); 6.96 m , 2 H (H-3′′, H-5′′); 7.44 m , 1 H (H-6′′); 7.64 dd, 2 H, J = 8.5, 1.6
(H-3′, H-5′); 8.09 d, 2 H, J = 8.5 (H-2′, H-6′). 19F NMR (CDCl3): –109.80 (F-2′′), –113.18
(F-4′′).
Preparation of 2-Ben zoyl-1-ben zofuran -3-am in es 2. Gen eral Procedure
Sodium m eth oxide (0.55 g, 10 m m ol) was added to a stirred solution of 7 (10 m m ol) in
m eth an ol (20 m l) an d th e m ixture was stirred at room tem perature for 30 m in . Th e m ixture
was poured in to water (25 m l), th e in soluble portion was filtered off, wash ed with water an d
crystallized from eth an ol to give 2.
2-Benzoyl-1-benzofuran-3-amine (2a). Yield 89%; yellow crystals, m .p. 124–126 °C (ref. 12
125–126 °C). For C 15H11NO2 (237.3) calculated: 75.94% C, 4.67% H, 5.90% N; foun d:
76.11% C, 4.53% H, 5.97% N. IR (KBr): 1 621 (C=O); 3 296, 3 422 (NH2). UV, λ (log ε): 208
(4.13), 252 (4.23), 312 (3.99), 380 (4.26).
2-(4-Bromobenzoyl)-1-benzofuran-3-amine (2b). Yield 90%; yellow crystals, m .p. 198–200°C
(ref.12 203–204 °C). For C 15H10BrNO2 (316.1) calculated: 56.99% C, 3.19% H, 25.27% Br,
4.43% N; foun d: 56.90% C, 3.26% H, 24.88% Br, 4.03% N. IR (KBr): 1 613 (C=O); 3 297,
3 420 (NH2). UV, λ (log ε): 203 (4.32), 221 (4.10), 357 (4.28), 314 (3.98), 385 (4.33). 1H NMR
(CDCl3, 60 °C): 5.83 bs, 2 H (NH2); 7.30 m , 1 H (H-5); 7.47 m , 1 H (H-7); 7.56 m , 1 H (H-6);
7.65 m , 1 H (H-4); 7.69 d, 2 H, J = 8.8 (ben zoyl); 8.17 d, 2 H, J = 8.8 (ben zoyl).
2-(Biphenyl-4-ylcarbonyl)-1-benzofuran-3-amine (2c). Yield 87%; yellow crystals, m .p.
167–169 °C. For C 21H15NO2 (313.4) calculated: 80.49% C, 4.82% H, 4.47% N; foun d: 80.38% C,
5.00% H, 4.29% N. IR (KBr): 1 615 (C=O); 3 316, 3 418 (NH2). UV, λ (log ε): 206 (4.56), 226
(4.19), 249 (4.12), 295 (4.22), 387 (4.31). 1H NMR (CDCl3, 60 °C): 6.01 bs, 2 H (NH2);
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7.22 m , 1 H (H-5); 7.41 m , 4 H (H-6, H-7, H-3′′, H-4′′, H-5′′); 7.61 m , 3 H (H-4, H-2′′, H-6′′);
7.72 d, 2 H, J = 8.2 (H-3′, H-5′); 8.33 d, 2 H, J = 8.2 (H-2′, H-6′).
2-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]-1-benzofuran-3-amine (2d ). Yield 51%; yellow crys-
tals, m .p. 173–176 °C. For C 21H13F2NO2 (349.3) calculated: 72.20% C, 3.75% H, 10.88% F,
4.01% N; foun d: 72.13% C, 4.02% H, 10.98% F, 3.75% N. IR (KBr): 1 613 (C=O); 3 304,
3 406 (NH2). UV, λ (log ε): 204 (4.57), 224 (4.22), 258 (4.24), 284 (4.18), 386 (4.33). 1H NMR
(CDCl3, 60 °C): 6.03 bs, 2 H (NH2); 6.94 m , 2 H (H-3′′, H-5′′); 7.24 bt, 1 H (H-5); 7.46 m , 3 H
(H-6, H-7, H-6′′); 7.63 m , 3 H (H-4, H-3′, H-5′); 8.33 d, 2 H, J = 8.2 (H-2′, H-6′). 19F NMR
(CDCl3): –110.91 (F-2′′), –113.06 (F-4′′).
2-Benzoyl-7-methoxy-1-benzofuran-3-amine (2e). Yield 75%; yellow crystals, m .p. 166–168 °C.
For C16H13NO3 (267.3) calculated: 71.90% C, 4.90% H, 5.24% N; foun d: 71.99% C, 5.01% H,
5.26% N. IR (KBr): 1 621 (C=O); 3 316, 3 442 (NH2). UV, λ (log ε): 204 (4.39), 251 (4.34),
319 (3.90), 380 (4.25). 1H NMR (CDCl3): 3.99 s, 3 H (CH3); 6.01 bs, 2 H (NH2); 6.96 dd, 1 H,
J = 6.8, 2.0 (H-6); 7.16 m , 2 H (H-4, H-5); 7.49 dd, 3 H, J = 5.2, 1.9 (H-3′, H-5′); 8.27 m , 2 H
(H-2′, H-6′).
2-(4-Bromobenzoyl)-7-methoxy-1-benzofuran-3-amine (2f). Yield 64%; yellow crystals, m .p.
201–204°C. For C 16H12BrNO3 (346.2) calculated: 55.51% C, 3.49% H, 23.08% Br, 4.05% N;
foun d: 55.30% C, 3.60% H, 23.27% Br, 3.88% N. IR (KBr): 1 620 (C=O); 3 322, 3 440 (NH2).
1H NMR (CDCl3, 60 °C): 4.01 s, 3 H (CH3); 5.94 bs, 2 H (NH2); 6.98 m , 1 H (H-6); 7.18 m , 2 H
(H-4, H-5); 7.65 d, 2 H, J = 7.9 (H-3′, H-5′); 8.16 d, 2 H, J = 7.9 (H-2′, H-6′).
2-(Biphenyl-4-ylcarbonyl)-7-methoxy-1-benzofuran-3-amine (2g). Yield 92%; yellow crystals,
m .p. 208–210 °C. For C 22H17NO3 (343.4) calculated: 76.95% C, 4.99% H, 4.08% N; foun d:
77.27% C, 5.39% H, 3.92% N. 1H NMR (CDCl3): 4.03 s, 3 H (CH3); 5.99 bs, 2 H (NH2); 7.00 m ,
1 H (H-6); 7.20 m , 2 H (H-4, H-5); 7.39 tt, 1 H (H-4′′); 7.48 m , 2 H (H-3′′, H-5′′); 7.68 m , 2 H
(H-2′′, H-6′′); 7.76 bd, 2 H, J = 8.6 (H-3′, H-5′); 8.37 bd, 2 H, J = 8.6 (H-2′, H-6′).
2-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]-7-methoxy-1-benzofuran-3-amine (2h ). Yield 97%; yel-
low crystals, m .p. 178–180 °C. For C 22H15F2NO3 (379.4) calculated: 69.65% C, 3.99% H,
10.02% F, 3.69% N; foun d: 69.27% C, 4.22% H, 9.79% F, 3.49% N. IR (KBr): 1 617 (C=O);
3 348, 3 449 (NH2). UV, λ (log ε): 204 (4.58), 253 (4.22), 281 (4.22), 321 (3.92), 387 (4.34).
1H NMR (CDCl3, 60 °C): 4.03 s, 3 H (CH3); 6.02 bs, 2 H (NH2); 6.96 m , 2 H (H-3′′, H-5′′);
7.00 m , 1 H (H-6); 7.20 m , 2 H (H-4, H-5); 7.48 m , 1 H (H-6′′); 7.67 bdd, 2 H, J = 8.5, 1.6
(H-3′, H-5′); 8.36 bd, 2 H, J = 8.5 (H-2′, H-6′). 19F NMR (CDCl3): –110.98 (F-2′′), –113.28
(F-4′′).
2-Benzoyl-4,6-dimethoxy-1-benzofuran-3-amine (2i). Yield 92%; yellow crystals, m .p.
112–113 °C. For C 17H15NO4 (297.3) calculated: 68.68% C, 5.09% H, 4.71% N; 68.54% C,
5.27% H, 4.73% N. IR (KBr): 1 624 (C=O); 3 333, 3 435 (NH2). UV, λ (log ε): 204 (4.44), 255
(4.20), 311 (3.90), 384 (4.41). 1H NMR (CDCl3, 60 °C): 3.83 s, 3 H (CH3O); 3.92 s, 3 H
(CH3O); 6.20 d, 1 H, J = 1.6 (H-5); 6.39 bs, 2 H (NH2); 6.47 d, 1 H, J = 1.6 (H-7); 7.47 m , 3 H
(ben zoyl); 8.17 m , 2 H (ben zoyl).
2-(4-Bromobenzoyl)-4,6-dimethoxy-1-benzofuran-3-amine (2j). Yield 95%; yellow crystals,
m .p. 225–226 °C. For C 17H14BrNO4 (376.2) calculated: 54.28% C, 3.75% H, 21.24% Br,
3.72% N; foun d: 54.56% C, 3.85% H, 21.06% Br, 3.66% N. IR (KBr): 1 624 (C=O); 3 331,
3 452 (NH2). UV, λ (log ε): 204 (4.37), 259 (4.17), 312 (3.84), 388 (4.35). 1H NMR (CDCl3):
3.84 s, 3 H (CH3); 3.92 s, 3 H (CH3); 6.20 d, 1 H, J = 1.9 (H-5); 6.42 bs, 2 H (NH2); 6.46 d,
1 H, J = 1.9 (H-7); 7.60 d, 2 H, J = 8.5 (H-3′, H-5′); 8.06 d, 2 H, J = 8.5 (H-2′, H-6′).
2-(Biphenyl-4-ylcarbonyl)-4,6-dimethoxy-1-benzofuran-3-amine (2k). Yield 75%; yellow crys-
tals, m .p. 177–183 °C. For C 23H19NO4 (373.4) calculated: 73.98% C, 5.13% H, 3.75% N;
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foun d: 73.94% C, 5.20% H, 4.02% N. IR (KBr): 1 624 (C=O); 3 333, 3 456 (NH2). UV, λ (log ε):
205 (4.77), 224 (4.29), 260 (4.20), 285 (4.35), 391 (4.37). 1H NMR (CDCl3, 60 °C): 3.86 s, 3 H
(CH3); 3.98 s, 3 H (CH3); 6.20 d, 1 H, J = 1.8 (H-5); 6.44 bs, 2 H (NH2); 6.50 d, 1 H, J = 1.8
(H-7); 7.34–7.52 m , 3 H (H-3′, H-5′, H-4′′); 7.65–7.82 m , 4 H (H-2′′, H-3′′, H-5′′, H-6′′);
8.28 bd, 2 H, J = 8.4 (H-2′, H-6′).
2-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]-4,6-dimethoxy-1-benzofuran-3-amine (2l). Yield 55%;
yellow crystals, m .p. 199–201 °C. For C 23H17F2NO4 (409.4) calculated: 67.48% C, 4.19% H,
9.28% F, 3.42% N; foun d: 67.18% C, 4.15% H, 9.26% F, 3.10% N. IR (KBr): 1 628 (C=O);
3 326, 3 428 (NH2). UV, λ (log ε): 205 (4.55), 261 (4.28), 278 (4.28), 390 (4.42). 1H NMR
(CDCl3, 60 °C): 3.85 s, 3 H (CH3); 3.94 s, 3 H (CH3); 6.43 bs, 2 H (NH2); 6.22 d, 1 H, J = 1.9
(H-5); 6.49 d, 1 H, J = 1.9 (H-7); 6.94 m , 2 H (H-3′′, H-5′′); 7.45 m , 1 H (H-6′′); 7.61 dd, 2 H,
J = 8.2, 1.6 (H-3′, H-5′); 8.26 d, 2 H, J = 8.2 (H-2′, H-6′). 19F NMR (CDCl3): –111.30 (F-2′′),
–113.17 (F-4′′).
2-(Ben zylsulfan yl)ben zon itrile
A m ixture of 2-fluoroben zon itrile (12 g, 0.1 m ol), ph en ylm eth an eth iol (13.7 g, 0.11 m m ol),
potassium carbon ate (35 g, 0.25 m ol), an d butan -2-on e (125 m l) was stirred at room tem per-
ature un der n itrogen . Th e in soluble portion was filtered off, th e filtrate was evaporated to
dryn ess an d purified twice by flash ch rom atograph y (silica gel, petroleum eth er–aceton e,
from 40 : 1 to 10 : 1) followed by crystallization from h exan e to give 5.45 g (24%) of th e title
com poun d; m .p. 59–61 °C (ref.27 57–58 °C; ref.16 62–64 °C). For C 14H11NS (225.3) calcu-
lated: 74.63% C, 4.93% H, 6.22% N, 14.23% S; foun d: 74.92% C, 5.24% H, 6.37% N,
14.17% S.
2-Sulfan ylben zon itrile (8)
A solution of 2-(ben zylsulfan yl)ben zon itrile (6.45 g, 28.6 m m ol) in ben zen e (50 m l) was
added dropwise to a suspen sion of alum in um ch loride (5.8 g, 43 m m ol) in ben zen e (50 m l)
stirred un der argon an d th e m ixture was stirred at room tem perature for 30 h . Th e m ixture
was poured in to cold water (150 m l) an d th e organ ic layer was wash ed with 5% solution of
sodium h ydroxide (2 × 50 m l). Th e com bin ed aqueous solution was acidified with 10%
h ydroch loric acid an d th e m ixture was extracted with eth er (2 × 60 m l, 2 × 30 m l). Th e organ ic
extract was dried with an h ydrous m agn esium sulfate to give 3.6 g (93%) of th e title com -
poun d, wh ich was used for furth er reaction s with out purification .
Preparation of 2-Ben zoyl-1-ben zoth ioph en -3-am in es 3. Gen eral Procedure
Sodium h ydride (0.5 g, 50% dispersion in m in eral oil, 10 m m ol) was added to a solution of
2-sulfan ylben zon itrile (8) (10 m m ol) in DMF (30 m l) an d th e m ixture was stirred un der ar-
gon for 1 h . Th en a solution of an appropriate 2-brom o-1-ph en yleth an -1-on e 6 (10 m m ol)
was added an d th e m ixture was stirred at room tem perature for 24 h . Th e m ixture was
poured in to water (250 m l), th e in soluble portion was filtered off, wash ed with water an d
crystallized from eth an ol.
2-Benzoyl-1-benzothiophen-3-amine (3a). Yield 52%; yellow crystals, m .p. 124–125 °C (ref.15
gives a differen t m .p. 103–104 °C). For C 15H11NOS (253.3) calculated: 71.12% C, 4.38% H,
5.53% N, 12.66% S; foun d: 71.28% C, 4.77% H, 5.47% N, 12.49% S. IR (KBr): 1 598 (C=O);
3 321, 3 433 (NH2). UV, λ (log ε): 204 (4.40), 279 (4.18), 310 (3.84), 319 (3.92), 404 (4.00).
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Rádl, Hezký, Urbánková, Váchal, Krejčí:
1H NMR (CDCl3): 7.04 bs, 2 H (NH2); 7.35 td, 1 H, J = 7.3, 1.2 (H-4′); 7.43–7.53 m , 4 H
(H-2′, H-3′, H-5′, H-6′); 7.70 m , 2 H (H-5, H-6); 7.98 dd, 2 H, J = 7.3, 1.5 (H-4, H-7).
2-(4-Bromobenzoyl)-1-benzothiophen-3-amine (3b). Yield 41%; yellow crystals, m .p. 119–124 °C.
For C15H10BrNOS (332.2) calculated: 54.23% C, 3.03% H, 24.05% Br, 4.22% N, 9.65% S;
foun d: 54.55% C, 3.17% H, 24.48% Br, 4.07% N, 9.58% S. IR (KBr): 1 602 (C=O); 3 318,
3 430 (NH2). UV, λ (log ε): 205 (4.33), 274 (4.11), 322 (3.82), 404 (4.12). 1H NMR (CDCl3):
7.05 bs, 2 H (NH2); 7.37–7.50 m , 2 H (H-2′, H-6′); 7.60–7.69 m , 4 H (arom . H, H-3′, H-5′);
7.75 m , 2 H (arom . H).
Preparation of Ben zon itriles 10. Gen eral Procedure
Sodium h ydride (0.5 g, 50% dispersion in m in eral oil, 10 m m ol) was added to a stirred
N-substituted 2-am in oben zon itrile 9 (10 m m ol) in DMF (30 m l) an d th e m ixture was stirred
for 1 h . Th en a solution of an appropriate 2-brom o-1-ph en yleth an -1-on e 6 (10 m m ol) was
added an d th e m ixture was stirred at room tem perature for 2–24 h (TLC). Th e m ixture was
poured in to water (250 m l), th e in soluble portion was filtered off, wash ed with water an d
crystallized from a suitable solven t.
N-(2-Cyanophenyl)-N-(2-oxo-2-phenylethyl)methanesulfonamide (10a). Yield 86%; wh ite crys-
tals, m .p. 189–192 °C (eth an ol). For C 16H14N2O3S (314.4) calculated: 61.13% C, 4.49% H,
8.91% N, 10.20% S; foun d: 61.55% C, 4.32% H, 8.68% N, 9.92% S. IR (KBr): 1 153, 1 340 (SO2);
1 709 (C=O); 2 237 (CN). UV, λ (log ε): 204 (4.52), 243 (4.18). 1H NMR (CDCl3): 3.25 s, 3 H
(CH3); 5.28 s, 2 H (CH2); 7.48 m , 3 H (arom . H); 7.62–7.75 m , 3 H (arom . H); 7.93 d, 2 H, J =
7.5 (H-2, H-6, ben zoyl); 8.00 d, 1 H, J = 8.5 (H-3, cyan oph en yl).
N-[2-(4-Bromophenyl)-2-oxoethyl]- N-(2-cyanophenyl)methanesulfonamide (10b). Yield 88%;
wh ite crystals, m .p. 154-159 °C (eth an ol). For C 16H13BrN2O3S (393.2) calculated: 48.87% C,
3.33% H, 20.32% Br, 7.12% N, 8.15% S; foun d: 48.44% C, 3.21% H, 20.72% Br, 6.87% N,
7.76% S. IR (KBr): 1 158, 1 345 (SO2); 1 733 (C=O); 2 241 (CN). UV, λ (log ε): 205 (4.44),
248 (4.02). 1H NMR (CDCl3, 60 °C): 3.21 s, 3 H (CH 3); 5.20 s, 2 H (CH2); 7.46 dt, 1 H, J =
7.5, 1.3 (H-4, cyan oph en yl); 7.61 d, 2 H, J = 8.8 (H-3, H-5, ben zoyl); 7.67 m , 2 H (H-5, H-6,
cyan oph en yl); 7.78 d, 2 H, J = 8.8 (H-2, H-6, ben zoyl); 7.94 bd, 1 H (H-3, cyan oph en yl).
N-(2-Cyanophenyl)-N-(2-oxo-2-phenylethyl)-4-methylbenzene-1-sulfonamide (10c). Yield 44%;
wh ite crystals, m .p. 146–148 °C (m eth an ol). For C 22H18N2O3S (390.5) calculated: 67.68% C,
4.65% H, 7.17% N, 8.21% S; foun d: 67.33% C, 4.91% H, 7.03% N, 8.05% S. IR (KBr): 1 162,
1 345 (SO2); 1 697 (C=O); 2 229 (CN). 1H NMR (CDCl3): 2.44 s, 3 H (CH3); 5.24 s, 2 H
(CH2); 7.30 d, 2 H, J = 8.05 (H-3, H-5); 7.40 m , 1 H (H-5, cyan oph en yl); 7.48 d, 2 H, J = 8.05
(H-2, H-6); 7.60 m , 5 H (H-4, H-6, cyan oph en yl; H-3, H-4, H-5, ben zoyl); 7.79 dd, 1 H (H-3,
cyan oph en yl); 7.92 m , 2 H (H-2, H-6, ben zoyl).
N-[2-(4-Bromophenyl)-2-oxoethyl]-N-(2-cyanophenyl)-4-methylbenzenene-1-sulfonamide (10d ).
Yield 40%; wh ite crystals, m .p. 162-166 °C (eth an ol). For C 22H17BrN2O3S (469.3) calculated:
56.30% C, 3.65% H, 17.02% Br, 5.97% N, 6.83% S; foun d: 55.99% C, 3.72% H, 16.85% Br,
5.86% N, 7.03% S. IR (KBr): 1 145, 1 352 (SO2); 1 694 (C=O); 2 235 (CN). 1H NMR (CDCl3):
2.44 s, 3 H (CH3); 5.17 s, 2 H (CH2); 7.26 m , 2 H (H-3, H-5); 7.31 t, 1 H, J = 7.8 (H-5,
cyan oph en yl); 7.61 m , 6 H (H-2, H-6, H-3, H-4, cyan oph en yl; H-2, H-6, ben zoyl); 7.80 m ,
3 H (H-6, cyan oph en yl; H-3, H-5, ben zoyl).
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Preparation of N-(Alkan esulfon yl)-2-ben zoylin dol-3-am in es 4a–4d . Gen eral Procedure
Method A. Sodium m eth oxide (55 m g, 1 m m ol) was added to a stirred solution of 10 (1
m m ol) in eth an ol (5–20 m l) an d th e m ixture was stirred at room tem perature for 10 h . Th e
m ixture was poured in to water (25 m l), th e in soluble portion was filtered off, wash ed with
water an d crystallized from eth an ol to give 4.
Method B. Trieth ylam in e (0.2 g, 2 m m ol) was added to a stirred solution of 10 (1 m m ol)
in eth an ol (5–20 m l) an d th e m ixture was stirred at room tem perature for 10 h . Th e m ixture
was evaporated to dryn ess an d crystallized from eth an ol to give 4.
2-Benzoyl-1-(methanesulfonyl)indol-3-amine (4a). Yield 45% (Meth od A); yellow crystals,
m .p. 190–191 °C. For C 16H14N2O3S (314.4) calculated: 61.13% C, 4.49% H, 8.91% N, 10.20% S;
foun d: 60.68% C, 4.74% H, 8.57% N, 9.85% S. IR (KBr): 1 144, 1 339 (SO2); 1 631 (C=O); 3 333,
3 449 (NH2). UV, λ (log ε): 203 (4.44), 259 (4.08), 308 (3.67), 368 (4.13). 1H NMR (CDCl3):
2.43 s, 3 H (CH3); 6.01 bs, 2 H (NH2); 7.44 m , 4 H (H-4, H-5, H-6, H-4′); 7.62 m , 2 H (H-3′,
H-5′); 7.93 dd, 2 H, J = 7.6, 1.9 (H-2′, H-6′); 8.04 d, 1 H, J = 8.2 (H-7).
2-(4-Bromobenzoyl)-1-(methanesulfonyl)indol-3-amine (4b). Yield 59% (Meth od A); yellow
crystals, m .p. 208–212 °C. For C 16H13BrN2O3S (393.2) calculated: 48.87% C, 3.33% H,
20.32% Br, 7.12% N, 8.15% S; foun d: 48.43% C, 3.11% H, 19.87% Br, 7.36% N, 8.43% S. IR
(KBr): 1 164, 1 345 (SO2); 1 620 (C=O); 3 349, 3 461 (NH2). UV, λ (log ε): 213 (4.41), 263
(4.24), 308 (3.80), 370 (4.19). 1H NMR (DMSO-d6): 2.51 s, 3 H (CH3); 7.16 bs, 2 H (NH2);
7.45 ddd, 1 H, J = 8.0, 7.3, 1.0 (H-6); 7.60 d, 2 H, J = 8.7 (H-3′, H-5′); 7.63 ddd, 1 H, J = 8.3,
7.3, 1.2 (H-5); 7.71 d, 2 H, J = 8.7 (H-2′, H-6′); 7.86 dt, 1 H, J = 8.3, 0.8 (H-4); 8.08 ddd, 1 H,
J = 8.0, 1.2, 0.8 (H-7).
2-Benzoyl-1-(4-methylbenzene-1-sulfonyl)indol-3-amine (4c). Yield 46% (Meth od A), 85%
(Meth od B); yellow crystals, m .p. 189–191 °C. For C 22H18N2O3S (390.5) calculated: 67.68% C,
4.65% H, 7.17% N, 8.21% S; foun d: 67.38% C, 4.84% H, 7.13% N, 8.08% S. IR (KBr): 1 172,
1 350 (SO2); 1 626 (C=O); 3 339, 3 449 (NH2). UV, λ (log ε): 203 (4.46), 257 (4.22), 308
(3.82), 372 (4.11). 1H NMR (CDCl3): 2.22 s, 3 H (CH3); 5.90 bs, 2 H (NH2); 6.96 d, 2 H, J = 8.0
(H-3, H-5, tosyl); 7.29 m , 4 H (H-4, H-5, H-2, H-6, tosyl); 7.49 m , 4 H (H-6, H-3′, H-4′, H-5′);
8.05 m , 2 H (H-2′, H-6′); 8.14 d, 1 H, J = 8.3 (H-7).
2-(4-Bromobenzoyl)-1-(4-methylbenzene-1-sulfonyl)indol-3-amine (4d). Yield 66% (Meth od A),
82% (Meth od B); yellow crystals, m .p. 187–195 °C. For C 22H17BrN2O3S (469.3) calculated:
56.30% C, 3.65% H, 17.02% Br, 5.97% N, 6.83% S; foun d: 55.87% C, 3.85% H, 16.77% Br,
5.77% N, 7.11% S. IR (KBr): 1 174, 1 355 (SO2); 1 623 (C=O); 3 333, 3 442 (NH2). UV, λ (log ε):
203 (4.56), 264 (4.31), 308 (3.71), 375 (4.10). 1H NMR (CDCl3): 2.23 s, 3 H (CH3); 5.93 bs,
2 H (NH2); 6.97 bd, 2 H, J = 8.3 (H-3, H-5, tosyl); 7.22–7.36 m , 4 H (H-5, H-6, H-2, H-6,
tosyl); 7.60 m , 3 H (H-7, H-3′, H-5′); 7.93 dt, 2 H, J = 8.6, 2.3 (H-2′, H-6′); 8.14 d, 1 H, J = 8.2
(H-7).
Preparation of 2-Ben zoyl-1-(eth oxycarbon yl)in dole-3-am in es 4e, 4f. Gen eral Procedure
Sodium h ydride (0.5 g, 50% dispersion in m in eral oil, 10 m m ol) was added to a solution of
2-am in oben zon itrile 9 (10 m m ol) in DMF (30 m l) an d th e m ixture was stirred for 1 h . Th en
a solution of an appropriate 2-bromo-1-phenylethan-1-one 6 (10 mmol) was added and the mixture
was stirred at room tem perature for 24 h . Th e m ixture was poured in to water (250 m l), th e in -
soluble portion was filtered off, wash ed with water an d crystallized from eth an ol.
2-Benzoyl-1-(ethoxycarbonyl)indol-3-amine (4e). Yield 68%; yellow crystals, m .p. 129–131 °C
(ref.18 131–133 °C). For C 18H16N2O3 (308.3) calculated: 70.12% C, 5.23% H, 9.09% N;
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Rádl, Hezký, Urbánková, Váchal, Krejčí:
foun d: 69.98% C, 5.14% H, 8.68% N. IR (KBr): 1 612 (C=O); 1 726 (COO); 3 349, 3 467
(NH2). 1H NMR (CDCl3): 0.84 t, 3 H, J = 7.2 (CH3); 3.73 q, 2 H, J = 7.2 (CH2); 5.19 bs, 2 H
(NH2); 7.31 ddd, 1 H, J = 7.8, 7.2, 0.9 (H-4′); 7.38–7.48 m , 3 H (H-5, H-3′, H-5′); 7.55 ddd,
1 H, J = 8.4, 7.2, 1.2 (H-6); 7.62 ddd, 1 H, J = 7.8, 1.2, 0.8 (H-4); 7.76 m , 2 H (H-2′, H-6′);
8.21 dt, 1 H, J = 8.4, 0.8 (H-7).
2-(4-Bromobenzoyl)-1-(ethoxycarbonyl)indol-3-amine (4f).Yield 67%; yellow crystals, m .p.
118–120 °C. For C 18H15BrN2O3 (387.2) calculated: 55.83% C, 3.90% H, 20.63% Br, 7.23% N;
foun d: 55.52% C, 4.15% H, 21.17% Br, 6.93% N. IR (KBr): 1 612 (C=O); 1 722 (COO); 3 350,
3 390 (NH2). UV, λ (log ε): 213 (4.40), 263 (4.53), 308 (3.79), 370 (4.19). 1H NMR (CDCl3, 60 °C):
0.93 t, 3 H, J = 7.1 (CH3); 3.84 q, 2 H, J = 7.1 (CH2); 5.78 bs, 2 H (NH2); 7.31 bt, 1 H, J = 7.4
(H-5); 7.56 m , 6 H (H-4, H-6, ben zoyl); 8.20 d, 1 H, J = 8.3 (H-7).
2-Ben zoylin dol-3-am in e (11a)
A solution of sodium h ydroxide (0.4 g, 10 m m ol) in water (2 m l) was added to a stirred so-
lution of 4e (0.31 g, 1 m m ol) in eth an ol (3 m l) an d th e m ixture was refluxed for 10 m in .
Th e m ixture was evaporated to dryn ess, th e residue was triturated with water (5 m l) an d ex-
tracted with dich lorom eth an e (2 x 5 m l). Th e extract was wash ed with water to n eutral reac-
tion of th e aqueous layer an d dried with m agn esium sulfate. Th e residue after evaporation
was crystallized th ree tim es from h exan e to give 11a as a brown solid (0.15 g, 63%); m .p.
51–52 °C. Th e com poun d darken s on ligh t. For C 15H12N2O (236.3) calculated: 76.25% C,
5.12% H, 11.86% N; foun d: 76.26% C, 5.49% H, 11.45% N. 1H NMR (CDCl3): 5.57 bs, 2 H
(NH2); 7.06 dt, 1 H (H-7); 7.21 bd, 1 H, J = 8.4 (H-4); 7.35 dt, 1 H (H-5); 7.45–7.60 m , 5 H
(H-1, H-6, ben zoyl); 7.82 m , 2 H (ben zoyl).
2-(4-Brom oben zoyl)in dol-3-am in e (11b)
Accordin g to th e procedure described for com poun d 11a, com poun d 11b was obtain ed from
4f as a brown solid (51%); m . p. 44–46 °C (cycloh exan e). Th e com poun d darken s on ligh t.
For C15H11BrN2O (315.2) calculated: 57.16% C, 3.52% H, 25.35% Br, 8.89% N; foun d:
57.55% C, 3.64% H, 24.97% Br, 8.63% N. IR (KBr): 1 599 (C=O); 3 319, 3 435 (NH2). UV, λ (log ε):
204 (4.74), 228 (4.23), 264 (4.29), 333 (4.20), 426 (3.91). 1H NMR (CDCl3): 5.53 bs, 2 H
(NH2); 7.04 dt, 1 H, J = 8.0, 0.8 (H-7); 7.22 m , 1 H (H-4); 7.35 dt, 1 H, J = 8.1, 0.8 (H-5);
7.55–7.70 m , 6 H (H-1, H-6, ben zoyl).
Biological Evaluation
Hot-Plate Test
Th e h ot-plate test was used to m easure th e respon se laten cies accordin g to th e m eth od de-
scribed earlier28, with m in or m odification s. All an im als (m ale NMRI m ice) were selected on
th e basis of th eir reactivity in th e m odel. Th e selected an im als were placed in to a glass cyl-
in der an d th e plate tem perature was m ain tain ed at 54 °C. Th e tim e n ecessary to in duce th e
lickin g reflex of th e forepaws or jum pin g was recorded. Th e m easurem en t was don e 30 an d
60 m in after adm in istration of 30 m g/kg of th e tested com poun d an d th e results were ex-
pressed as prolon gation of th e lickin g laten cies (%).
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Acetic Acid-Induced Writhing
Writh in g was in duced by in traperiton eal in jection of 0.2 m l of 0.7% solution of acetic acid
to m ale NMRI m ice 30 m in after th e adm in istration of 30 m g/kg of th e tested com poun d29
Writh in gs were coun ted for 20 m in , com pared with th e con trol an d expressed as decrease in
th e stretch in g m ovem en ts (%).
.
Tail-Flick Test
A sligh tly m odified m eth od of D’Am our an d Sm ith 30 was used. Th e an im als (m ale
Wistar–Han n over rats) were placed in a Ugo Basile (Varese, Italy) apparatus an d th e predrug
laten cy to rem oval of th e tail from a radian t h eat source (ligh t beam focused 3 cm from th e
en d of th e tail) was determ in ed twice for each rat. Th e an im als were th en adm in istered th e
appropriate tested com poun d (30 m g/kg) an d were placed in th e h oldin g apparatus. Th irty
an d sixty m in utes later, a postdrug laten cy was m easured. A postdrug laten cy was expressed
as a decrease in laten cy of th e con trol (%).
The authors are indebted to T. Pilarčík and M. Bartůněk for the NMR, and Ms M. Švorčíková for the
UV and IR measurements. This work was supported by the Grant Agency of the Ministry of Industry
and Trade of the Czech Republic (grant No. PP-Z1/08) and by Léčiva Co. Praha.
REFERENCES
1. Vaz Z. R., Cechinel-Filho V., Yunes R. A., Calixto J. B.: J. Pharmacol. Exp. Ther. 1996, 278,
304.
2. Cechinel-Filho V., Vaz Z. R., Zunino L., Calixto J. B., Yunes R. A.: Eur. J. Med. Chem.
1996, 31, 833.
3. Livingstone R. in: Rodd’s Chemistry of Carbon Compounds (S. Coffey, Ed.), Vol. IV, Part A,
p. 83. Elsevier, Amsterdam 1973.
4. Mackenzie J. B. D., Robertson A., Bushra A., Towcis R.: J. Chem. Soc. 1949, 2057.
5. Hirota T., Fujita H., Sasaki K., Namba T., Hayakawa S.: Heterocycles 1986, 24, 771.
6. Bisagni M., Buu-Hoi N. P., Royer R.: J. Chem. Soc. 1955, 3693.
7. Sonn A., Bülow W.: Chem. Ber. 1925, 58, 1691.
8. Dean F. M., Robertson A.: J. Chem. Soc. 1953, 1241.
9. Srivastava S. D., Srivastava S. K.: Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1987, 26, 57.
10. Malterud K. E., Undheim J., Erdal J. E.: Tetrahedron Lett. 1985, 26, 4807.
11. Gillies I., Loft M.: Synth. Commun. 1988, 18, 191.
12. Gewald K., Jansch H.-J.: J. Prakt. Chem. 1973, 315, 779.
13. Vaidya V. P., Mahajan S. B., Agasimundin Y. S. : Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1981, 20, 391.
14. Rahman L. K. A., Scrowton R. M.: J. Chem. Soc., Perkin Trans. 1 1983, 2973.
15. Carrington D. E. L., Clarke K., Scrowston R. M.: J. Chem. Soc. C 1971, 3903.
16. Beck J. R.: J. Heterocycl. Chem. 1978, 15, 513.
17. Beugelmans R., Bois-Choussy M., Boudet B.: Tetrahedron 1983, 39, 4153.
18. Garcia E. E., Benjamin L. E., Fryer R. I.: J. Heterocycl. Chem. 1973, 10, 51.
19. Pirkle W. H., Simmons K. A.: J. Org. Chem. 1983, 48, 2520.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

296
Rádl, Hezký, Urbánková, Váchal, Krejčí:
20. Fišnerová L., Brůnová B., Kocfeldová Z., Tíkalová J., Matunová E., Grimová J.: Collect.
Czech. Chem. Commun. 1991, 56, 2373.
21. Abramovitch R. A., Knaus G. N., Uma V.: J. Org. Chem. 1974, 39, 1101.
22. Auwers K.: Chem. Ber. 1925, 58, 2081.
23. Schroeder H. E., Rigby G. W.: J. Am. Chem. Soc. 1949, 71, 2205.
24. Auwers K., Frese E.: Justus Liebigs Ann. Chem. 1926, 450, 273.
25. Brandt E. V., Ferreira D., Roux D. G.: J. Chem. Soc., Perkin Trans. 1 1981, 514.
26. Borsche W., Hahn-Weinheimer P.: Justus Liebigs Ann. Chem. 1950, 570.
27. Bates D. K.: J. Org. Chem. 1977, 42, 3452.
28. Eddy N. B., Leimbach D.: J. Pharmacol. Exp. Ther. 1953, 80, 385.
29. Koster R., Anderson M., De Beer J.: Fed. Proc. 1959, 18, 412.
30. D’Amour F. E., Smith D. L. J.: Pharmacol. Exp. Ther. 1941, 72, 74.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)