Axially chiral 3,3′-bi(1-benzothiophene)-2,2′-dicarboxylic acid and its derivatives

Article abstract of DOI:10.1135/cccc20031020

Ullmann dimerization of substituted methyl 3-X-1-benzothiophene-2-carboxylates 1-7 (X = Cl, Br) gave rise to the corresponding dimeric 3,3′-bi(1-benzothiophene) esters 8-13. Resolution of the title acid 20 by fractional crystallization of its mono- and bisquininium salt afforded pure (R)- and (S)-enantiomers, the optical purity and absolute configuration of which was confirmed by CD spectrometry and by X-ray crystallography. Ullmann dimerization of chiral oxazolines 23 and 24 derived from 2 proceeded without any diastereodifferentiation. Reduction of (R)- and (S)-20 afforded the corresponding (R)- and (S)-diols 29, which served as chiral ligands in a model enantioselective reduction of acetophenone. (R)- and (S)-1-phenylethan-1-ol were formed in 28 and 29% e.e., respectively.

Full text of DOI:10.1135/cccc20031020

1020
Mézlová et al.:
AXIALLY CHIRAL 3,3′-BI(1-BENZOTHIOPHENE)-2,2′-DICARBOXYLIC
ACID AND ITS DERIVATIVES
b
c
a2
Marie MÉZLOVÁa1, Hana PETŘÍČKOVÁ , Petr MALOŇ , Václav KOZMÍK and
a3,
Jiří SVOBODA
*
a
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5,
CZ-166 28 Prague 6, Czech Republic; e-mail: majova@centrum.cz, vaclav.kozmik@vscht.cz,
1
2
3
jiri.svoboda@vscht.cz
b
c
Department of Solid State Chemistry, Institute of Chemical Technology, Prague, Technická 5,
CZ-166 28 Prague 6, Czech Republic; e-mail: hana.petrickova@vscht.cz
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo nám. 2, CZ-160 10 Prague 6, Czech Republic; e-mail: malon@uochb.cas.cz
Received Decem ber 5, 2002
Accepted February 26, 2003
Dedicated to the memory of Professor Otakar Červinka.
Ullm an n dim erization of substituted m eth yl 3-X-1-ben zoth ioph en e-2-carboxylates 1–7 (X =
Cl, Br) gave rise to th e correspon din g dim eric 3,3′-bi(1-ben zoth ioph en e) esters 8–13. Resolu-
tion of th e title acid 20 by fraction al crystallization of its m on o- an d bisquin in ium salt af-
forded pure (R)- an d (S)-en an tiom ers, th e optical purity an d absolute con figuration of wh ich
was con firm ed by CD spectrom etry an d by X-ray crystallograph y. Ullm an n dim erization of
ch iral oxazolin es 23 an d 24 derived from 2 proceeded with out an y diastereodifferen tiation .
Reduction of (R)- an d (S)-20 afforded th e correspon din g (R)- an d (S)-diols 29, wh ich served
as ch iral ligan ds in a m odel en an tioselective reduction of acetoph en on e. (R)- an d (S)-
1-ph en yleth an -1-ol were form ed in 28 an d 29% e.e., respectively.
Keyw ord s: Ullm an n reaction ; Hom ocouplin gs; Ben zoth ioph en es; Bi(1-ben zoth ioph en e); Res-
olution ; Stereoselective reduction ; Biaryls; Axial ch irality; CD spectroscopy.
Calam itic liquid crystals1 are ch aracterized by th e presen ce of a rigid core in
th eir m olecules, often represen ted by a biph en yl residue. To in duce ferro-
electricity2 in sm ectic C ph ase, ch iral elem en t is n ecessary to be presen t in
th e liquid-crystallin e m olecule. Th is requirem en t is fulfilled in m ost studied
com poun ds, wh ich possess a carbon stereogen ic cen ter in on e of th e alkyl
ch ain s elon gatin g th e structure. On th e oth er h an d, th is cen ter can also be
replaced by an axially ch iral structural un it located in th e lon g axis of th e
m olecule, e.g. by 1,1′-bin apth alen e-2,2′-diol3, substituted allen e4,5, alkyl-
iden ecycloalkan e6,7, an d biph en yl derivatives8–10. In addition , a h etero-
Collect. Czech. Chem. Commun. (Vol. 68) (2003)
doi:10.1135/cccc20031020

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1021
cyclic un it in th e core supports form ation of th e ch iral sm ectic C ph ase
(Sm C*) in a broad tem perature ran ge. Recen tly we in troduced11–13 n ovel
h eterocyclic system s based on th ien o[3,2-b][1]ben zofuran , th ien o[3,2-b][1]-
ben zoth ioph en e an d [1]ben zoth ien o[3,2-b][1]ben zoth ioph en e to liquid
crystal cores to create n ew liquid-crystallin e m aterials exh ibitin g switch able
m esoph ases.
Axially ch iral biaryls sh ow14 wide application as ch iral tem plates for
stoich iom etric an d asym m etric catalytic reaction s. In particular th e tran si-
tion m etal-catalyzed syn th esis, e.g. asym m etric h ydrogen ation of proch iral
organ ic substrates with biden tate ph osph orus ligan ds such as BINAP or re-
lated system s h as foun d wide use15. Recen tly axially ch iral diph osph in e lig-
an ds of 3,3′-bith ioph en e an d 3,3′-bi(1-ben zoth ioph en e) (BITIANP) were
described16. It h as been foun d16,17 th at Ru(II) com plexed with BITIANP
sh ows excellen t stereodifferen tiation com parable with BINAP in reduction s
of α- an d β-oxo esters to th e correspon din g h ydroxy esters.
Earlier we applied substituted 3-ch loro-1-ben zoth ioph en e-2-carboxylic
acid derivatives18,19 for syn th esis of n ew lipoxygen ase in h ibitors. Easy ac-
cessibility of th is structural m otif in spired us to utilize such type of com -
poun ds for syn th esis of n ovel atropoisom eric bi(1-ben zoth ioph en e)
com poun ds, wh ich can be used in design in g of n ew types of liquid crystals
an d ch iral auxiliaries for various stereoselective syn th eses. In th e presen t
paper we report results of th e syn th esis of th e title bi(1-ben zoth ioph en e)
derivatives, resolution an d ch aracterization of en an tiom ers an d prelim in ary
results of th eir application in stereoselective reduction s.
Form ation of an aryl–aryl bon d can be accom plish ed by various tran sition -
m etal-catalyzed couplin g reaction s of h aloaren es20–22. Sym m etrical biaryls
are accessible by th e copper-m ediated h om ocouplin g of aryl h alides
(Ullm an n reaction 23). In troducin g a ch iral oxazolin e m oiety to th e h alo-
aren e m olecule substan tially in fluen ced th e Ullm an n reaction diastereo-
selectivity10,24–26. To study th e Ullm an n dim erization of 3-h alo-1-ben zo-
th ioph en e-2-carboxylic acid derivatives, m odel com poun ds 1–7 were ch o-
sen . Alth ough reactivity of ch loroaren es in th e Ullm an n reaction is gen er-
ally low23, we expected th at due to th e lower arom aticity of th e th ioph en e
rin g (in com parison with ben zen e), it would be h igh en ough for th em to
en ter th e couplin g reaction . Neverth eless, dim erization of th e related bro-
m o ester 1 was also con sidered. A m eth yl group was also in troduced in po-
sition 4 (ester 3) with respect to requirem en t for even tual in fluen cin g th e
barrier to rotation about th e 3,3′-bon d of th e axially ch iral m olecule. In ad-
dition , m eth oxy group, fluorin e an d ch lorin e atom s in 4–7 are typical lat-
eral substituen ts affectin g m esom orph ic properties of liquid crystals. Th e
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1022
Mézlová et al.:
startin g m eth yl esters were prepared by kn own procedures described else-
wh ere18,27–29
.
Hom ocouplin g was ach ieved by h eatin g esters 1–7 with activated copper
bron ze in N,N-dim eth ylform am ide to 170 °C (Sch em e 1). Un der optim ized
con dition s (4 h for 1, 16 h for th e oth er esters), correspon din g diesters 8–13
were obtain ed in good yields (66–86%) alon g with a sm all portion of h alo-
gen e reduction products – esters 14–19 (yield 6–13%). From m ixtures of
products, th e dim eric esters were easily isolated by a sin gle crystallization .
Th e sh ort reaction tim e for brom o ester 1 con firm ed th e kn own tren d of
h aloaren e reactivity in Ullm an n reaction . An attem pted dim erization of
ester 2 un der Ni(0) catalysis30,31 afforded th e desired diester 8 on ly in 9%
yield.
R3
S
R2
COOCH3
R1
R1
R2
COOCH3
S
R1
R2
R3
X
Cu
8-13
R3
DMF
COOCH3
S
R1
R2
R3
1-7
COOCH3
S
14-19
In formulae 1 X = Br; 2-7 X = Cl; 1, 2, 8, 14 R1-R3 = H; 3, 9, 15 R1 = CH3, R2, R3 = H;
4, 10, 16 R1, R3 = H, R2 = CH3O; 5, 11, 17 R1, R2 = H, R3 = F; 6, 12, 18 R1, R2 = H,
R3 = Cl; 7, 13, 19 R1, R2 = H, R3= CH3O
SCHEME 1
To obtain an d ch aracterize en an tiom ers of th e form ed racem ic dim ers
8–13, th e represen tative ester 8 was h ydrolyzed to diacid 20. Resolution of
th e diacid was attem pted with various ch iral bases, th e best results bein g
obtain ed with quin in e. Triple crystallization of th e m on oquin in ium salt of
S
COOH
20
COOH
S
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1023
20 provided a pure diastereom eric salt, from wh ich th e (+)-20 was liberated
([α ]2D3 +75). Due to its very low solubility in com m on solven ts, optical pu-
rity of (+)-20 was determ in ed by HPLC an alysis of its dim eth yl ester, wh ich
was obtain ed by esterification of (+)-20 with diazom eth an e. It was foun d
th at purity of (+)-20 is h igh er th an 99% e.e. Th e overall preparative yield of
(+)-20 reach ed 15%.
Acid 20 en rich ed with th e (–)-isom er sh owed on ly 79% optical purity. To
obtain th e en an tiom erically pure (–)-isom er, it was subsequen tly fraction -
ally crystallized with cin ch on in e. However, n o separation of th e diastereo-
m eric cin ch on in ium salt proceeded. Surprisin gly, we foun d th at fraction al
crystallization of th e bisquin in ium salt of 20 led to separation of a dia-
stereom eric salt, wh ich after liberation from th e salt afforded th e (–)-20
([α ]2D3 –72), also in a h igh optical purity (97.5% e.e.) an d in overall 18%
yield. Optical purity of both th e en an tiom ers was also con firm ed by th eir
CD spectra (Fig. 1). Th e spectra sh ow n early textbook perfect m irror im age
like ch aracteristics. Th ere are two couplets of CD ban ds cen tered on sin gle
absorption features, th e m ost in ten se of wh ich is th e sh ort wavelen gth cou-
plet at 201 an d 211 n m cen tered on th e absorption feature at 206 n m . Th e
m uch less in ten se couplet is foun d at th e lon g wavelen gth en d of th e spec-
tra. It in volves CD ban ds 314 an d 336 n m an d it is cen tered on absorption
ban d at 326 n m . A sin gle CD ban d correspon ds to th e absorption feature at
286 n m an d several low in ten sity CD ban ds are foun d in th e region be-
tween 220 an d 260 n m . Th e spectra m igh t be in terpretable usin g coupled
oscillator th eory, on ce th e direction s of tran sition m om en ts with in th e sub-
stituted 1-ben zoth ioph en e ch rom oph ores are establish ed.
200
∆ε
0
–200
200
250
300
350
400
λ, nm
FIG. 1
CD spectra of (R)- (––––) an d (S)-20 (·······) in aceton itrile
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1024
Mézlová et al.:
Th e couplet like ch aracteristics of th e CD spectra suggest presen ce of m o-
lecular exciton s an d an in terpretation of th e relation between CD ban ds
sign s an d absolute con figuration of 20 m igh t be attem pted, for th e in ten se
CD couplet cen tered at 206 n m . If we assum e th at th e tran sition m om en t
for th is rath er in ten se tran sition is orien ted alon g th e lon g axis of th e
ben zoth ioph en e ch rom oph ore th en for th e (–)-R con figuration an d th e
orien tation of th e two ben zoth ioph en e un its accordin g to X-ray result th e
exciton m ech an ism suggests th at th e lon ger wavelen gth lobe of th e CD
couplet (th e ban d at 211 n m ) sh ould be of positive sign in accord with ex-
perim en tal data. Validity of such an in terpretation of course assum es th at
th e two ben zoth ioph en e un its in th e m olecule of 20 are on ly weakly elec-
tron ically coupled.
Sin gle crystals of (–)-20 suitable for X-ray diffraction were obtain ed from
eth yl acetate. By X-ray diffraction an alysis, absolute con figuration of (–)-20
was foun d to be (R) (Fig. 2). Th e value of Flack en an tiopole param eter32, F =
0.03(1), proved th e expected absolute con figuration . Con form ation of th e
(R)-20 m olecule is ch aracterized by two torsion an gles: C2–C3–C3′–C2′ =
–121.7(2)° an d C3a–C3–C3′–C3a′ = –109.3(2)°. Two 1-ben zoth ioph en e pla-
n ar un its con tain an an gle of 113.2(3)°. A m olecule of eth yl acetate is built
in to th e crystal structure th rough two h ydrogen bon ds (in tram olecular:
O2–H1···O3 an d in term olecular: O2′–H1′···O3 (–x – 1, +y – 1/2, –z – 1),
wh ich leads to th e form ation of in terestin g ch ain s with th e m olecule of 20
C7′
C7a′
S1′
C6′
C5
O1′
C5′
C3a′
C2′
C6
C4
C4′
C3a
C8′
C3′
C7
C3
C7a
O2′
O2
C8
C2
S1
O1
FIG. 2
ORTEP drawin g of 20, sh owin g th e n um berin g sch em e. Th erm al ellipsoids are drawn at 50%
probability
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1025
in y→0 direction (Fig. 3). Sm all ch an n els can be also foun d in th e structure
from th e y→0 poin t of view (Fig. 4). Th e program ORTEP 33 vas used for
visualisation an d program PARST 34 for furth er calculation s.
For th e plan n ed application of th e en an tiom ers of acid 20, a racem ization
study was furth er accom plish ed. We foun d th at even at lon g term h eatin g
FIG. 3
ORTEP drawin g, in term olecular ch ain s in crystal structure of 20 in 0→y direction , viewin g
0→x direction . Th erm al ellipsoids are drawn at 50% probability
FIG. 4
ORTEP drawin g, sm all ch an n els form ed by eth yl acetate an d m olecule of 20, viewin g 0→z di-
rection . Th erm al ellipsoids are drawn at 50% probability
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1026
Mézlová et al.:
to 100 °C in diglym e, optical rotation of (R)-20 did n ot ch an ge at all. On ly
h eatin g to h igh er tem peratures led to a slow racem ization . On th e basis of
th e very h igh value of th e determ in ed rotation barrier (∆G‡ ≈ 130 kJ/m ol at
128 °C), it can be em ph asized th at en an tiom ers of 20 do n ot practically
racem ize at room tem perature. Th ese results seem surprisin g wh en con sid-
erin g a substan tial differen t bon din g relation in 3,3′-bi(1-ben zoth ioph en e)s
in com parison with th ose in 2,2′-disubstitued 1,1′-bin aph th alen es.
Because preparative yields of (R)- an d (S)-20 were relatively low, we at-
tem pted to exten d th e con cept of th e en an tioselective Ullm an n syn th esis
to 3,3′-bith ioph en e derivatives. Acylation of ch loride 21 with L-valin ol af-
forded th e correspon din g am ido alcoh ol 22, wh ich was in th e subsequen t
step cyclized by m eth an esulfon yl ch loride to oxazolin e derivative 23 in
overall yield 83% (Sch em e 2). We also attem pted to m odify th e reactivity of
Cl
Cl
L-valinol
H
N
OH
COCl
S
S
O
21
22
MsCl, Et3N
I
Cl
O
1. t-BuLi
O
N
2. I2
5´
S
2´
S
N
4´
24
23
Cu, DMF
S
N
O
O
+
S
O
N
26
N
S
25
MsCl, Et3N
S
S
O
S
S
COCl
COCl
OH
OH
L-valinol
N
H
H
N
O
27
28
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1027
23 by substitution of th e ch lorin e atom by iodin e: lith iation of 23 with
t-BuLi afforded th e correspon din g lith ium salt, wh ich was trapped with io-
din e to produce iodooxazolin e 24 in 81% yield. Hom ocouplin g of ch loro-
oxazolin e 23 was perform ed with copper bron ze in DMF un der th e sam e
con dition s as for esters 2–7. However, dim er 25 was isolated on ly in a very
low yield (24%); th e m ajor product was th e dech lorin ated oxazolin e 26
(yield 34%) (Sch em e 2). An alogous reaction with th e iodooxazolin e af-
1
forded th e bisoxazolin e 26 in 62% yield. An alysis of H NMR spectra of 26
sh owed th at n o diastereoselectivity of dim erization was ach ieved an d both
diastereom ers of 26 were form ed in th e 1:1 ratio. In addition , we were n ot
able to separate th e correspon din g diastereom ers of 26 by ch rom atograph ic
m eth ods. We also used an oth er approach to obtain bisoxazolin e 26.
Racem ic acid 20 was tran sform ed with th ion yl ch loride to dich loride 27.
Acylation of L-valin ol with dich loride 27 afforded bis(am idoalcoh ol) 28,
wh ose diastereom ers could n ot be separated by ch rom atograph y. Fin ally,
cyclization of 28 was ach ieved in a very slow reaction with m eth an e-
sulfon yl ch loride an d bisoxazolin e 26 was isolated in a good yield. To in -
duce a diastereoselective course of dim erization , Ullm an n reaction of
oxazolin es 23 an d 24 was also perform ed un der very m ild con dition s35.
However, reaction of 23 an d 24 catalyzed with copper(I) th ioph en e-2-carb-
oxylate was un successful.
Ch irality tran sfer from various 1,1′-bin aph th alen e derivatives to pro-
ch iral m olecules was sh own to be essen tial, e.g. by reduction of m ultiple
bon ds with BINAP-com plexed Rh (I) an d Ru(II) 15,36,37 an d by reduction of
keton es with BINAL-H 38,39. To ach ieve satisfactory en an tiodifferen tiation ,
oth er h ydride agen ts were also m odified with a broad scale of ch iral lig-
an ds. An alogously, we attem pted to utilize th e acid 20 en atiom ers for for-
m ulation of a ch iral reducin g agen t for a m odel en an tioselective reduction
of acetoph en on e. Reduction of (R)-20 an d (S)-20 with DIBAH afforded th e
correspon din g (R)- an d (S)-dim eth an ol 29 in h igh yield an d optical purity
(Sch em e 3). From th e values of rotation al barrier to racem ization of diol 29
en an tiom ers (∆G‡ ≈ 112 kJ/m ol at 53 °C an d 81 kJ/m ol at 100 °C), it is evi-
den t, th at steric requirem en ts of th e h ydroxym eth yl groups in 29 are sub-
stan tially lower th an th at of th e rigid carboxylic group in 20. On th e oth er
h an d, th e determ in ed values are h igh en ough to preven t racem ization of
ch iral dim eth an ol 29 at room tem perature. An alogously to BINAL-H, lith -
ium alum in ium h ydride was th en derivatized with (R)- an d (S)-dim eth an ol
29, respectively, an d an equivalen t of eth an ol to form th e structure 30 of
th e reducin g agen t. Reduction of acetoph en on e with (R)- an d (S)-30 was
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1028
Mézlová et al.:
perform ed in eth er at room tem perature an d (R)- an d (S)-1-ph en yleth an ol
(31) were obtain ed with low optical purities of 28 an d 29% e.e., respectively.
S
S
COOH
COOH
CH2OH
CH2OH
DIBAH
S
S
20
29
1. LiAlH4
2. CH3CH2OH
S
O
Al
O
OCH2CH3
-
H
+
Li
S
30
SCHEME 3
1
Structures of all n ew com poun ds were con firm ed by IR an d H NMR spec-
tra, an d elem en tal an alyses. Th e stron g m utual sh ieldin g of both th e aro-
m atic system s in diesters 8–13 leads to substan tial ch an ges in ch em ical
sh ifts of arom atic proton s in com parison with ch loro esters 2–7 an d th eir
reduced an alogues 14–19 (Table I). Wh ile th e H-4 an d H-5 proton s an d pro-
ton s of 4-m eth yl, 5-m eth oxy an d th e ester m eth oxy groups exh ibit a stron g
up-field sh ift, th e H-7 proton s are sh ifted to lower fields. In Table II, com -
parison of 13C NMR spectra of th e pairs ester 2/dim er 24 an d oxazolin e
23/dim er 25 with th e open ch ain am ido alcoh ol 22 is sh own . Dim erization
of 2 leads to a stron g down -field sh ift of th e ben zoth ioph en e C-3,3′ atom s
(127.4 vs 140.3 ppm ) in dim er 24 an d to sligh t sh ifts of th e n earest carbon
atom s (C-2,2′, C-3a,3′a). Th e sam e is for th e pair 23 an d 25. In addition ,
form ation of an equim olar m ixture of diasteroisom ers in 25 leads to dupli-
cation of m ost of th e carbon atom sign als in th e spectrum .
In con clusion , th e Ullm an n reaction of 3-h alo-1-ben zoth ioph en e-
2-carboxylic esters provides a con ven ien t syn th etic route for preparation of
th e correspon din g 3,3′-bi(1-ben zoth ioph en e) derivatives. Racem ic diacid 20
was separated by fraction al crystallization of th e correspon din g m on o- an d
bisquin in ium salts yieldin g optically pure (R)- an d (S)-diacid 20, wh ose ab-
solute con figuration was determ in ed by X-ray crystallograph y. No dia-
stereodifferen tiation was observed by th e attem pted oxazolin e Ullm an n
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1029
reaction . A n ew axially ch iral reducin g agen t based on (R)- an d (S)-
dim eth an ol 29 was form ulated for en an tioselective reduction of aceto-
ph en on e, wh ich proceeded with 28 an d 29% e.e. Th is prelim in ary results of
proch iral acetoph en on e reduction support th e poten tial applicability of
3,3′-bi(1-ben zoth ioph en e) derivatives in various en an tioselective reaction s,
wh ich will be th e object of future research .
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Leica VM TG block an d are un corrected. Elem en tal
an alyses were carried out on a Perkin –Elm er 2400. IR spectra (ν, cm –1) were recorded on a
Nicolet 740 FT-IR spectrom eter in ch loroform or KBr. NMR spectra (δ, ppm ; J, Hz) were
recorded on a Varian Gem in i 300 HC (300 MHz for 1H an d 100 MHz for 13C), deu-
terioch loroform or DMSO-d6 was used as solven t an d sign als of th e solven ts served as in ter-
TABLE I
Ch em ical sh ifts of arom atic proton s in 1H NMR spectra of 2–19
Com poun d
Substituen t H-4
H-5
H-6
H-7
OCH3
2
14
8
–
7.96
7.53
7.46
7.47
7.18
7.18
7.08
–
7.49
7.40
7.50
7.36
7.35
7.37
7.17
7.11
7.15
–
7.81
7.85
7.94
7.65
7.69
7.78
7.67
7.72
7.80
7.51
7.54
7.61
7.82
7.85
7.93
7.22
7.28
7.34
3.97
–
7.88
3.85
–
7.28
3.69
3
4-Me
4-Me
4-Me
5-Me
5-Me
5-Me
6-F
2.93 (CH3)
2.63 (CH3)
1.89 (CH3)
7.32
3.95
15
9
3.95
3.68
4
3.91, 3.95
3.88, 3.94
3.65, 3.69
3.97
16
10
5
7.28
–
6.65
–
7.94
7.25
7.17
7.05
7.46
7.37
7.26
7.09
7.02
6.90
17
11
6
6-F
7.83
–
3.94
6-F
7.22
–
3.70
6-Cl
6-Cl
6-Cl
6-MeO
6-MeO
6-MeO
7.89
–
3.96
18
12
7
7.79
–
3.95
7.17
–
3.70
7.83
–
3.90, 3.95
3.89, 3.92
3.68, 3.90
19
13
7.74
–
7.16
–
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

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Mézlová et al.:
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1031
n al stan dards. HPLC an alyses were perform ed on Ch iralcel OD-H, elution with h exan e/
propan -2-ol 90:10 v/v. CD spectra of (R)- an d (S)-20 were m easured on a Jobin Yvon Mark VI
in strum en t in aceton itrile solution (≈1.3 × 10–3 m ol l–1). Th e spectra were m easured in
quartz cells with th e path -len gth of 0.5 an d 1.0 m m an d represen t com puter averages of
th ree con secutive scan s each . Optical rotation s are given in 10–1 deg cm 2 g–1
Meth yl ester 1 (m .p. 69–70.5 °C, ref.40 m .p. 71.5 °C) was prepared by a th ree-step route
startin g from 1-ben zoth ioph en e accordin g to refs40–42 1H NMR: 3.97 s, 3 H (OCH3); 7.51 m ,
.
.
1 H (arom .); 7.53 m , 1 H (arom .); 7.84 dd, 1 H, J1 = 8.0, J2 = 2.2 (H-7); 7.99 dd, 1 H, J1 = 8.0,
J2 = 2.2 (H-4).
Meth yl 3-Ch loro-4-m eth yl-1-ben zoth ioph en e-2-carboxylate (3)
A m ixture of 3-ch loro-4-m eth yl-1-ben zoth ioph en e-2-carbon yl ch loride43 (8.50 g, 34.7 m m ol)
an d m eth an ol (50 m l) was h eated to boilin g for 1 h . After coolin g, th e precipitated product
was filtered off an d wash ed with cold m eth an ol. An am oun t of 7.29 g (87%) of 3 was ob-
tain ed, m .p. 79–81 °C. For C11H9ClO2S (240.7) calculated: 54.89% C, 3.77% H, 14.73% Cl,
13.32% S; foun d: 54.76% C, 3.59% H, 14.54% Cl, 13.11% S. IR: 1725 (C=O). 1H NMR:
2.93 s, 3 H (CH3); 3.95 s, 3 H (OCH3); 7.18 d, 1 H, J = 7.1 (H-5); 7.36 t, 1 H, J = 7.7 (H-6);
7.65 d, 1 H (H-7).
An alogously, m eth yl esters 2, 4–7 were obtain ed from th e correspon din g substituted
3-ch loro-1-ben zoth ioph en e-2-carbon yl ch lorides. Ester 2, m .p. 79–80 °C (m eth an ol), ref.29
m .p. 81.3 °C. 1H NMR: 3.97 s, 3 H (OCH3); 7.49 dt, 1 H, J1 = 7.7, J2 = 2.0 (H-6); 7.53 dt, 1 H
(H-5); 7.81 dd, 1 H, J1 = 8.0 (H-7); 7.96 dd, 1 H, J1 = 8.0, J2 = 2.2 (H-4). Ester 4, m .p.
115–116 °C (m eth an ol), ref.44 m .p. 116 °C. 1H NMR: 3.91 s, 3 H (OCH3); 3.95 s, 3 H (OCH3);
7.17 dd, 1 H, J1 = 8.8, J2 = 2.2 (H-6); 7.32 d, 1 H (H-4); 7.67 d, 1 H, J = 9.0 (H-7). Ester 5,
m .p. 119–120 °C (m eth an ol), ref.28 m .p. 119–121 °C. 1H NMR: 3.97 s, 3 H (OCH3); 7.25 ddd,
3
3
4
3
4
1 H, JHH = 8.9, JHF = 8.9, JHH = 2.5 (H-5); 7.51 dd, 1 H, JHF = 8.5, JHH = 2.2 (H-7); 7.94 dd,
3
4
1 H, JHH = 9.0, JHF = 4.5. Ester 6, m .p. 133–134 °C (m eth an ol), ref.28 m .p. 131–133 °C.
1H NMR: 3.96 s, 3 H (OCH3); 7.46 dd, 1 H, J1 = 8.8, J2 = 2.0 (H-5); 7.82 d, 1 H (H-7); 7.89 d,
1 H (H-4). Ester 7, m .p. 139–141 °C (m eth an ol), ref.27 m .p. 138–138.5 °C. 1H NMR: 3.90 s, 3 H
(OCH3); 3.95 s, 3 H (OCH3); 7.09 dd, 1 H, J1 = 8.8, J2 = 2.5 (H-5); 7.22 d, 1 H, J = 2.5 (H-7);
7.83 d, 1 H, J = 8.8 (H-4).
Dim eth yl 3,3′-Bi(1-ben zoth ioph en e)-2,2′-dicarboxylates 8–13
A m ixture of ester 1–7 (15 m m ol), activated copper bron ze (3.81 g, 60 m m ol) an d dry DMF
(12 m l) was h eated un der stirrin g in n itrogen atm osph ere at 170 °C (bath tem perature) for
4 h (com poun d 1) or 16 h (com poun ds 2–7). Th e m ixture was diluted with ch loroform
(100 m l) an d th e in organ ic m aterial was filtered off. Th e organ ic solution was evaporated to
dryn ess, dissolved in ch loroform (150 m l), wash ed with brin e an d dried with an h ydrous
m agn esium sulfate. After evaporation of th e solven t, m eth an ol (50 m l) was added to th e res-
idue; th e h eterogen ous m ixture was h eated to boilin g for 5 m in , allowed to cool to room
tem perature an d th e precipitated crude product 8–13 was filtered off an d wash ed with m eth -
an ol. Pure com poun ds 8–13 were fin ally obtain ed by crystallization . From m eth an olic
m oth er liquors, deh alogen ated products 14–19 were isolated by colum n ch rom atograph y
(silica gel, eluen t toluen e).
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

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Mézlová et al.:
Dimethyl 3,3′-bi(1-benzothiophene)-2,2′-dicarboxylate (8). Yield 86% (from 1), 63% (from 2),
m .p. 209–211 °C (eth an ol). For C20H14O4S2 (382.5) calculated: 62.81% C, 3.70% H, 16.73% S;
foun d: 62.48% C, 3.93% H, 16.53% S. IR: 1722 (C=O). 1H NMR: 3.69 s, 6 H (OCH3); 7.28dd,
2 H, J1 = 7.7, J2 = 2.3 (H-4, H-4′); 7.47 m , 2 H (H-5, H-5′); 7.50 m , 2 H (H-6, H-6′); 7.94 d,
2 H, J = 8.2 (H-7, H-7′).
Dimethyl 4,4′-dimethyl-3,3′-bi(1-benzo[b]thiophene)-2,2′-dicarboxylate (9). Yield 74%, m .p.
205–207 °C (eth an ol). For C22H18O4S2 (410.5) calculated: 64.37% C, 4.42% H, 15.62% S;
foun d: 64.52% C, 4.69% H, 15.55% S. IR: 1723 (C=O). 1H NMR: 1.89 s, 6 H (CH3); 3.68 s,
6 H (OCH3); 7.08 d, 2 H, J = 7.1 (H-5, H-5′); 7.37 t, 2 H, J = 7.2 (H-6, H-6′); 7.78 d, 2 H, J =
8.2 (H-7, H-7′).
Dimethyl 5,5′-dimethoxy-3,3′-bi(1-benzothiophene)-2,2′-dicarboxylate (10). Yield 66%, m .p.
203–204 °C (eth an ol/toluen e). For C22H18O6S2 (442.5) calculated: 59.71% C, 4.10% H,
21.69% S; foun d: 59.74% C, 4.12% H, 21.41% S. IR: 1723 (C=O). 1H NMR: 3.65 s, 6 H
(OCH3); 3.69 s, 6 H (OCH3); 6.65 d, 2 H, J = 2.5 (H-4, H-4′); 7.15 dd, 2 H, J1 = 9.0, J2= 2.5
(H-6, H-6′); 7.80 d, 1 H (H-7, H-7′).
Dimethyl 6,6′-difluoro-3,3′-bi(1-benzothiophene)-2,2′-dicarboxylate (11). Yield 67%, m .p.
189–191 °C (eth an ol). For C20H12F2O4S2 (418.4) calculated: 57.41% C, 2.89% H, 15.33% S;
foun d: 57.23% C, 2.56% H, 15.18% S. IR: 1721 (C=O). 1H NMR: 3.70 s, 6 H (OCH3); 7.05
3
3
4
3
4
ddd, 2 H, JHH = 8.8, JHF = 8.8, JHH = 2.2 (H-5, H-5′); 7.22 dd, 2 H, JHH = 8.8, JHF = 5.5
3
4
(H-4, H-4′); 7.61 dd, 2 H, JHF = 8.5, JHH = 2.2 (H-7, H-7′).
Dimethyl 6,6′-dichloro-3,3′-bi(1-benzothiophene)-2,2′-dicarboxylate (12). Yield 66%, m .p.
238–240 °C (eth an ol/toluen e). For C20H12Cl2O4S2 (451.4) calculated: 53.22% C, 2.68% H,
15.71% Cl, 14.21% S; foun d: 53.09% C, 2.63% H, 15.34% Cl, 14.12% S. IR: 1722 (C=O).
1H NMR: 3.70 s, 6 H (OCH3); 7.17 d, 2 H, J = 8.8 (H-4, H-4′); 7.26 dd, 2 H, J1 = 8.8, J2 = 1.9
(H-5, H-5′); 7.93 d, 2 H (H-7, H-7′).
Dimethyl 6,6′-dimethoxy-3,3′-bi(1-benzothiophene)-2,2′-dicarboxylate (13). Yield 67%, m .p.
180–182 °C (eth an ol). For C22H18O6S2 (442.5) calculated: 59.71% C, 4.10% H, 21.69% S;
foun d: 59.65% C, 3.98% H, 21.46% S. IR: 1723 (C=O). 1H NMR: 3.68 s, 6 H (OCH3); 3.90 s,
6 H (OCH3); 6.90 dd, 2 H, J1 = 8.8, J2 = 1.9 (H-5, H-5′); 7.16 d, 2 H (H-4, H-4′); 7.34 d, 2 H,
J = 2.2 (H-7, H-7′).
Methyl 1-benzothiophene-2-carboxylate (14). Yield 18% (from 1) an d 11% (from 2), m .p. 71–
72 °C (m eth an ol), ref.45 m .p. 71–72 °C. IR: 1714 (C=O). 1H NMR: 3.85 s, 3 H (OCH3); 7.40 m ,
1 H (H-6); 7.46 m , 1 H (H-5); 7.85 dd, 1 H, J1 = 8.8, J2 = 2.2 (H-7); 7.88 dd, 1 H, J1 = 8.8, J2
=
2.2 (H-4); 8.06 s, 1 H (H-3).
Methyl 4-methyl-1-benzothiophene-2-carboxylate (15). Yield 13%, m .p. 51–53 °C (m eth an ol).
For C11H10O2S (206.3) calculated: 64.05% C, 4.89% H, 15.55% S; foun d: 63.90% C, 5.03% H,
15.59% S. IR: 1721 (C=O). 1H NMR: 2.63 s, 3 H (CH3); 3.95 s, 3 H (OCH3); 7.18 d, 1 H, J =
7.1 (H-5); 7.35 t, 1 H, J = 7.7 (H-6); 7.69 d, 1 H, J = 8.2 (H-7); 8.15 s, 1 H (H-3).
Methyl 5-methoxy-1-benzothiophene-2-carboxylate (16). Yield 6%, m .p. 102–104 °C (m eth a-
n ol), ref.44 m .p. 102.5–103.5 °C. For C11H10O3S (222.3) calculated: 59.44% C, 4.54% H,
14.43% S; foun d: 59.27% C, 4.51% H, 14.33% S. IR: 1720 (C=O). 1H NMR: 3.88 s, 3 H
(OCH3); 3.94 s, 3 H (OCH3); 7.11 dd, 1 H, J1 = 8.8, J2 = 2.2 (H-6); 7.28 d, 1 H (H-4); 7.72 d,
1 H, J = 8.8 (H-7); 7.98 s, 1 H (H-3).
Methyl 6-fluoro-1-benzothiophene-2-carboxylate (17). Yield 12%, m .p. 84.5–86 °C (m eth an ol).
For C10H7FO2S (210.2) calculated: 57.13% C, 3.36% H, 15.25% S; foun d: 57.02% C, 3.07% H,
3
3
15.33% S. IR: 1721 (C=O). 1H NMR: 3.94 s, 3 H (OCH3); 7.17 ddd, 1 H, JHH = 8.9, JHF = 8.9,
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1033
3
4
3
4
4JHH = 2.2 (H-5); 7.54 dd, 1 H, JHF = 8.5, JHH = 2.2 (H-7); 7.83 dd, 1 H, JHH = 8.8, JHF = 5.2
(H-4); 8.02 s, 1 H (H-3).
Methyl 6-chloro-1-benzothiophene-2-carboxylate (18). Yield 14%, m .p. 104–106 °C (m eth a-
n ol). For C10H7ClO2S (226.7) calculated: 52.99% C, 3.11% H, 15.64% Cl, 14.14% S; foun d:
52.67% C, 2.98% H, 15.44% Cl, 15.11% S. IR: 1721 (C=O). 1H NMR: 3.95 s, 3 H (OCH3);
7.37 dd, 1 H, J1 = 8.8, J2 = 2.2 (H-5); 7.79 d, 1 H, J = 8.5 (H-4); 7.85 d, 1 H, J = 2.2 (H-7);
8.02 s, 1 H (H-3).
Methyl 6-methoxy-1-benzothiophene-2-carboxylate (19). Yield 8%, m .p. 119–120 °C (m eth a-
n ol). For C11H10O3S (222.3) calculated: 59.44% C, 4.54% H, 14.43% S; foun d: 59.18% C,
4.67% H, 14.26% S. IR: 1717 (C=O). 1H NMR: 3.89 s, 3 H (OCH3); 3.92 s, 3 H (OCH3);
7.02 dd, 1 H, J1 = 8.8, J2 = 2.2 (H-5); 7.28 d, 1 H, J = 2.4 (H-7); 7.74 d, 1 H (H-4); 7.97 s, 1 H
(H-3).
3,3′-Bi(1-ben zoth ioph en e)-2,2′-dicarboxylic Acid (20)
A m ixture of diester 8 (10.4 g, 27.3 m m ol), sodium h ydroxide (6.7 g, 168 m m ol) an d 50%
aqueous eth an ol (180 m l) was h eated un der stirrin g to reflux for 2 h . After coolin g to th e
room tem perature, it was acidified with dilute h ydroch loric acid (1:1) to pH 2. Th e precipi-
tate was filtered a wash ed with water. Crystallization of th e product from acetic acid af-
forded 8.79 g (91%) of diacid 20, m .p. 273–275 °C. For C18H10O4S2 (354.4) calculated:
59.38% C, 3.48% H, 16.10% S; foun d: 59.44% C, 3.64% H, 16.10% S. IR (KBr): 3415 (OH),
1721 (C=O). 1H NMR (DMSO): 7.14 d, 2 H, J = 8.2 (H-4, H-4′); 7.34 t, 2 H, J1 = 7.2, J2 = 7.7
(H-5, H-5′); 7.54 t, 2 H (H-6, H-6′); 8.13 d, 2 H, J = 8.2 (H-7, H-7′).
Resolution of Diacid 20
Method A. Diacid 20 (3.11 g, 8.8 m m ol) was dissolved in aceton e (30 m l) by h eatin g. To
th e solution , quin in e (2.84 g, 8.8 m m ol) was added an d th e m ixture was h eated to reflux for
45 m in . After coolin g, th e precipitated crystals were filtered off an d wash ed with cold ace-
ton e. An am oun t of 3.47 g (58%) of m on oquin in ium salt of diacid 20 was obtain ed, wh ich
after two crystallization s from aceton e, afforded 1.01 g (17%) of pure diastereom eric salt,
m .p. 182–183 °C, [α ]2D3 –91.0 (c 0.85, DMF). For C38H34N2O6S2 (678.8) calculated: 67.24% C,
5.05% H, 4.13% N; foun d: 67.04% C, 5.10% H, 4.01% N.
Th e salt was dissolved in water (100 m l) an d con cen trated h ydroch loric acid (4 m l) was
added un der stirrin g. Th e liberated acid was filtered off, wash ed th orough ly with water an d
dried in vacuo. An am oun t of 0.467 g (1.32 m m ol) of (R)-(+)-acid 20 was obtain ed (overall
yield 15%), m .p. 187–189 °C, [α ]2D3 +75.0 (c 0.54, diglym e). Optical purity of (R)-(+)-acid 20
was determ in ed by HPLC an alysis (Ch iralcel OD-H) of th e correspon din g (+)-m eth yl ester
obtain ed by esterification of (R)-20 with eth ereal diazom eth an e.
X-Ray data for (–)-20: C18H10O2S2·C4H8O2, M = 441.493, m on oclin ic system , space group
P1211 (No. 4)46, a = 8.626(2) Å, b = 14.079(3) Å, c = 8.634(1) Å, β = 90.32 (1)°, V = 1048.5(4) Å3,
Z = 2, Dc = 1.3983 g cm –3, µ(CuKα) = 26.232 cm –1, crystal dim en sion s 0.6 × 0.8 × 0.9 m m .
Data were m easured at 293 K on an En raf–Non ius CAD4 diffractom eter with graph ite
m on och rom atized CuKα radiation . Th e structure was solved by direct m eth ods47 an d
an isotropically refin ed by full m atrix least-squares on F values48 to fin al R = 0.0560, Rw
0.0413 an d S = 1.0135 with 329 param eters usin g 3769 in depen den t reflection s (θran ge
=
=
3.14–67.90°). Hydrogen atom s lin ked to carbon atom s were located from th e expected geom -
etry an d were n ot refin ed. Th e acid h ydrogen atom s H1 an d H11 were foun d from Fourier
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1034
Mézlová et al.:
differen ce electron den sity m ap an d th eir position s were refin ed. Ψ-scan was used for ab-
sorption correction .
CCDC 196033 con tain s th e supplem en tary crystallograph ic data for th is paper. Th ese data
can be obtain ed free of ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from th e
Cam bridge Crystallograph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax:
+44 1223 336033; or deposit@ccdc.cam .ac.uk).
Method B. From th e origin al m oth er liquor, diacid 20 (1.21 g, 3.42 m m ol) en rich ed with
th e (S)-en an tiom er was obtain ed (78% e.e.). Its crystallization with quin in e (2.25 g, 7.0
m m ol) in aceton e (40 m m ol) by m eth od A afforded 2.64 g (77%) of th e crude bisquin in ium
salt. After th ree crystallization s from aceton e, 0.686 g (20%) of th e pure bisquin in ium salt
was obtain ed, m .p. 182–184.5 °C, [α ]2D3 +219.9 (c 1.61, DMF). For C58H58N4O8S2 (1003.3) cal-
culated: 69.44% C, 5.83% H, 5.58% N; foun d: 69.03% C, 5.92% H, 5.32% N.
Th e (S)-(–)-acid 20 (0.224 g, 0.63 m m ol) (overall yield 18%), m .p. 188–190 °C, [α ]2D3 –72.0
(c 0.47, diglym e). Optical purity (97.5% e.e.) was determ in ed an alogously to th e (R)-acid.
N-[(S)-1-(Hydroxym eth yl)-2-(m eth ylpropyl)]-3-ch loro-1-ben zoth ioph en e-
2-carboxam ide (22)
A solution of ch loride18 21 (7.4 g, 32 m m ol) in dich lorom eth an e (50 m l) was dropwise
added to a solution of (S)-valin ol49 (3.7 g, 35.9 m m ol) an d trieth ylam in e (20 m l) in di-
ch lorom eth an e (100 m l) at 0 °C in n itrogen atm osph ere. After stirrin g at room tem perature
for 2 h , th e m ixture was successively wash ed with water (100 m l), 5% aqueous h ydroch loric
acid (50 m l) an d water (100 m l), an d dried with an h ydrous m agn esium sulfate. Evaporation
of th e solven t left a residue, wh ich on crystallization from toluen e afforded th e 8.71 g (91%)
of am ide 22, m .p. 154–155 °C, [α ]D23 –36.5 (c 1, CHCl3). For C14H16ClNO2S (297.8) calculated:
56.46% C, 5.42% H, 11.90% Cl, 4.70% N; foun d: 56.70% C, 5.31% H, 11.89% Cl, 4.70% N.
IR: 3422 (OH), 1640 (C=O). 1H NMR: 1.071 d, 3 H, J = 6.6 (CH3); 1.073 d, 3 H, J = 6.6 (CH3);
2.09 m , 1 H (CH); 2.57 t, 1 H, J = 5.5 (OH); 3.84 dd, 2 H, J1 = 7.7, J2 = 4.4 (CH2); 4.04 m ,
1 H (CH); 7.38 d, 1 H (NH); 7.49 m , 2 H (H-5, H-6); 7.84 m , 2 H (H-4, H-7).
(S)-2-(3-Ch loro-1-ben zoth ioph en -2-yl)-4-isopropyl-4,5-dih ydrooxazole (23)
A solution of am ide 22 (1.20 g, 4 m m ol) an d trieth ylam in e (2.25 m l) in dich lorom eth an e
(30 m l) was cooled to 0 °C in n itrogen atm osph ere. Meth an esulfon yl ch loride (0.5 m l,
6.5 m m ol) was added dropwise an d th e m ixture was stirred at room tem perature for 3 h ,
wash ed with water (50 m l) an d brin e, an d dried with an h ydrous m agn esium sulfate. Th e res-
idue after evaporation was purified by colum n ch rom atograph y (silica gel, ch loroform ) an d
0.98 g (87%) of th e title com poun d 23 was obtain ed, m .p. 84–86 °C, [α ]2D3 –50.1 (c 0.51,
CHCl3). For C14H14ClNOS (279.8) calculated: 60.10% C, 5.04% H, 12.67% Cl, 5.01% N;
foun d: 60.31% C, 5.05% H, 12.50% Cl, 4.85% N. IR: 1638 (C=N). 1H NMR: 0.96 d, 3 H, J =
6.6 (CH3); 1.05 d, 3 H (CH3); 1.91 m , 1 H (CH); 4.21 m , 2 H (CH + 1 H of CH2); 4.48 dd,
1 H, J1 = 6.6, J2 = 6.2 (1 H of CH2); 7.48 m , 2 H (H-5, H-6); 7.92 m , 2 H (H-4, H-7).
(S)-2-(3-Iodo-1-ben zoth ioph en -2-yl)-4-isopropyl-4,5-dih ydrooxazole (24)
tert-Butyllith ium (5.3 m l of a 1.7 M solution in pen tan e) was added dropwise to a solution of
oxazolin e 23 (1.78 g, 6.36 m m ol) in dry tetrah ydrofuran (20 m l) un der stirrin g at –78 °C in
n itrogen atm osph ere. Th e m ixture was stirred for 2 h an d th e form ed lith ium salt was
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1035
trapped by addition of an iodin e (2.42 g, 9.54 m m ol) solution in tetrah ydrofuran (5 m l).
Th e coolin g bath was rem oved an d th e m ixture was stirred at room tem perature for 1 h ,
added to a 5% aqueous solution of sodium th iosulfate (200 m l) an d wash ed with ch loroform
(100 m l). Th e organ ic layer was wash ed with water (50 m l), dried with an h ydrous m agn e-
sium sulfate an d evaporated. Colum n ch rom atograph y (silica gel, toluen e) of th e residue af-
forded 1.92
g (81%) of iodo derivative 24, m .p. 59–61 °C. For C14H14INOS (371.2)
calculated: 45.30% C, 3.80% H, 34.18% I, 3.77% N; foun d: 44.88% C, 3.93% H, 33.82% I,
3.57% N. IR: 1634 (C=N). 1H NMR: 0.99 d, 3 H, J = 6.6 (CH3); 1.08 d, 3 H (CH3); 1.92 m ,
1 H (CH); 4.22 m , 2 H (CH + 1 H of CH2); 4.49 dd, 1 H, J1 = 6.6, J2 = 6.2 (1 H of CH2); 7.45 m ,
2 H (H-5, H-6); 7.79 m , 1 H; 7.89 m , 1 H.
2,2′-Bis[(S)-4-isopropyl-4,5-dih ydrooxazol-2-yl]-3,3′-bi(1-ben zoth ioph en e) (25)
Method A. Com poun d 23 (1.30 g, 4.64 m m ol), activated copper bron ze (2.3 g, 36.2 m m ol)
an d dry DMF (20 m l) were h eated to 170 °C (bath tem perature) in n itrogen atm osph ere for
20 h . Th e m ixture was diluted with ch loroform (50 m l) an d th e in organ ic m aterial was fil-
tered off. Th e organ ic solution was evaporated to dryn ess, dissolved in ch loroform (100 m l),
wash ed with water (50 m l) an d dried with an h ydrous m agn esium sulfate. Th e residue after
evaporation was separated by colum n ch rom atograph y (silica gel, ch loroform /m eth an ol
99.5:0.5 v/v). An am oun t of 0.27 g (24%) of 25 as an equim olar diastereom eric m ixture an d
0.39 g (34%) of dech lorin ated com poun d 26 were isolated.
Method B. By th e sam e procedure as in m eth od A, com poun d 24 (360 m g, 0.96 m m ol), ac-
tivated copper bron ze (0.5 g, 7.8 m m ol) an d DMF (8 m l) afforded 145 m g (62%) of a dia-
stereom eric m ixture of 25 an d 38 m g (16%) of deiodo product 26.
Method C. A solution of com poun d 23 (300 m g, 1.07 m m ol) in dry THF (5 m l) was treated
with tert-butyllith ium (0.67 m l of a 1.7 M solution in pen tan e, 1.14 m m ol) at –78 °C in n i-
trogen atm osph ere for 1 h . An h ydrous copper ch loride (0.3 g, 2.23 m m ol) was added an d
th e m ixture was stirred at room tem perature for 4 h an d h eated to reflux for 1 h . Th e reac-
tion m ixture was worked up as in m eth od A an d 110 m g (0.45 m m ol) of dech loro product
26 was isolated.
Method D. By th e sam e procedure as for 23, diam ide 28 (4.09 g, 7.79 m m ol), m eth an e-
sulfon yl ch loride (1.32 m l, 17.1 m m ol) in th e presen ce of trieth ylam in e (6.5 m l, 46.7 m m ol)
in ch loroform (70 m l) afforded after stirrin g at room tem perature for 14 days an d subse-
quen t aqueous workup 2.16 g (57%) of a 1:1 diastereom eric m ixture of com poun d 23.
2,2′-Bis[(S)-4-isopropyl-4,5-dihydrooxazol-2-yl]-3,3′-bi(1-benzothiophene) (25). For C28H28N2O2S2
(488.7) calculated: 68.82% C, 5.78% H, 5.73% N; foun d 69.13% C, 6.05% H, 5.80% N. IR:
1637 (C=N). 1H NMR: 0.64 d, 3 H, J = 6.5 (CH3); 0.68 d, 3 H, J = 6.5 (CH3); 0.74 d, 3 H, J =
6.5 (CH3); 0.80 d, 3 H, J = 6.5 (CH3); 1.45 m , 2 H (CH); 1.56 m , 2 H (CH); 3.65 dd, 2 H, J1
=
16.1, J2 = 8.1 (1 H of CH2); 3.77–3.94 m , 8 H (CH2); 4.03 dd, 2 H, J1 = 17.9, J2 = 9.0 (1 H of
CH2); 7.15–7.22 m , 8 H (arom .); 7.33 m , 4 H (arom .); 7.82 d, 4 H, J = 8.1 (arom .).
(S)-2-(1-Benzothiophen-2-yl)-4-isopropyl-4,5-dihydrooxazole (26). M.p. 83–85 °C. For C14H15NOS
(245.4) calculated: 68.54% C, 6.16% H, 5.71% N; foun d: 68.35% C, 5.89% H, 5.42% N. IR:
1648 (C=N). 1H NMR: 0.94 d, 3 H, J = 7.1 (CH3); 1.04 d, 3 H, J = 6.6 (CH3); 1.92 m , 1 H
(CH); 4.18 m , 2 H (CH + 1 H of CH2); 4.45 m , 1 H (1 H of CH2); 7.38 m , 2 H (arom .); 7.82 s,
1 H (H-3); 7.79–7.86 m , 2 H (arom .).
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Mézlová et al.:
3,3′-Bi(1-ben zoth ioph en e)-2,2′-bis(carbon yl ch loride) (27)
To a slurry of diacid 20 (5.0, 14.1 m m ol) in toluen e (50 m l), th ion yl ch loride (5.1 m l,
71 m m ol) was added dropwise an d th e m ixture was h eated to reflux 3 h an d evaporated to
dryn ess. Crystallization of th e form ed solid from h eptan e afforded 3.97 g (73%) of ch loride
27, m .p. 206–208 °C. For C18H8Cl2O2S2 (391.3) calculated: 55.25% C, 2.06% H, 18.12% Cl,
16.39% S; foun d: 55.52% C, 1.99% H, 17.91% Cl, 16.55% S. IR: 1749 (C=O). 1H NMR:
7.28 d, 2 H, J = 8.8 (H-4, H-4′); 7.36 dt, 2 H, J1 = 8.2, J2 = 1.3 (H-5, H-5′); 7.59 dt, 2 H (H-6,
H-6′); 7.97 dd, 2 H, J1 = 8.2, J2 = 1.3 (H-7, H-7′).
N,N′-Bis[(S)-1-(h ydroxym eth yl)-2-m eth ylpropyl]-3,3′-bi(1-ben zoben zoth ioph en e)-
2,2′-dicarboxam ide (28)
By th e sam e m eth od as for 22, acylation of dich loride 27 (3.49 g, 9.0 m m ol) with (S)-valin ol
(2.23 g, 21.6 m m ol) in th e presen ce of trieth ylam in e (15 m l) an d dich lorom eth an e (25 m l)
afforded, after aqueous workup, 4.51 g (96%) of oily dicarboxam ide 28. For C28H32N2O4S2
(524.7) calculated: 64.10% C, 6.15% H, 5.34% N, 12.22% S; foun d: 64.01% C, 6.31% H,
5.08% N, 12.06% S. IR: 3409 (NH), 1642 (C=O). 1H NMR of a m ixture of diastereoisom ers:
0.56 d, 6 H, J = 7.1 (CH3); 0.68 d, 6 H, J = 7.2 (CH3); 0.84 d, 6 H, J = 7.2 (CH3); 0.98 d, 3 H,
J = 7.1 (CH3); 1.33 m , 2 H (CH); 1.55 m , 2 H (CH); 3.17 dd, 4 H, J1 = 5.5, J2 = 3.9 (CH2);
3.33 dd, 2 H, J1 = 11.5, J2 = 5.5 (1 H of CH2); 3.58 dd, 2 H, J1 = 8.2, J2 = 2.8 (1 H of CH2);
3.72 m , 4 H (CH); 5.93 d, 4 H, J = 8.2 (NH); 7.16–7.38 m , 8 H (arom .); 7.52 m , 4 H (arom .);
8.00 d, 4 H, J = 8.3 (arom .).
(R)-3,3′-Bi(1-ben zoth ioph en e)-2,2′-dim eth an ol (29)
A slurry of (R)-20 (300 m g, 0.85 m m ol) in dry THF (50 m l) was cooled to –78 °C an d diiso-
butylalum n ium h ydride (10.2 m l of a 1 M solution in h exan es, 10.2 m m ol) was added
dropwise un der n itrogen atm osph ere in 10 m in . Th e stirrin g was con tin ued for 30 m in , th e
coolin g bath was rem oved an d th e m ixture was stirred at room tem perature for 6 h . Th e re-
action was quen ch ed with m eth an ol (2 m l) at –70 °C an d subsequen tly decom posed with
water (5.5 m l) at 0 °C. Th e m ixture was filtered an d th e solid was wash ed with ch loroform
(50 m l). Th e filtrate was wash ed subsequen tly with water (3 × 30 m l), brin e an d dried with
an h ydrous m agn esium sulfate. After rem ovin g th e solven t, 170 m g (62%) of pure (R)-29 was
obtain ed, m .p. 177–179 °C, [α ]2D3 +38.0 (c 0.76, CHCl3), purity >99% e.e. (Ch iralcel OD-H).
For C18H14O2S2 (326.4) calculated: 66.23% C, 4.32% H, 19.64% S; foun d: 65.97% C, 4.25% H,
19.47% S. IR: 3392 (OH). 1H NMR: 2.96 dd, 2 H, J1 = 12.4, J2 = 6.3 (OH); 4.62 dd, 2 H (CH2);
7.24 m , 4 H (arom .); 7.38 t, 2 H, J = 7.4 (arom .); 7.92 d, 2 H, J = 8.0 (H-7, H-7′).
In th e sam e way, reduction of (S)-20 afforded (S)-29 in 75% yield, m .p. 176–178 °C, [α ]D23
–37.0 (c 0.65, CHCl3), purity 97.4% e.e.
Reduction of Acetoph en on e with LiAlH4/(R)-29 an d LiAlH4/(S)-29
A solution of (R)-29 (254 m g, 0.78 m m ol) in dry eth er (5 m l) was cooled to 0 °C, an d solu-
tion of lith ium alum in ium h ydride (3.90 m l of a 0.2 M solution in eth er, 0.78 m m ol) was
added with in 15 m in . After 15 m in stirrin g, eth an ol (45 µl, 0.78 m m ol) was added an d th e
m ixture stirred for an oth er 1 h . Acetoph en on e was added (0.91 m l, 0.78 m m ol) an d stirrin g
was con tin ued at 0 °C for 3 h an d at room tem perature for 16 h . Th e reaction was stopped
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

3,3′-Bi(1-benzothiophene)-2,2′-dicarboxylic Acid
1037
with 4% aqueous sodium h ydroxide (0.2 m l) an d th e precipitated salts rem oved by filtra-
tion . Th e eth ereal solution was dried with an h ydrous m agn esium sulfate, evaporated to dry-
n ess an d th e residue separated by colum n ch rom atograph y (silica gel, toluen e) afforded 76 m g
(81%) of (R)-1-ph en yleth an -1-ol (30) with 28% e.e. an d 228 m g (90%) of (R)-29 was recov-
ered with 98.2% e.e.
By th e sam e procedure, reduction of acetoph en on e with LiAlH4/(S)-diol 29 afforded
(S)-1-ph en yleth an -1-ol (85%) with 29% e.e an d (S)-29 (88%) with 96.2% e.e.
Financial support of the Grant Agency of the Czech Republic (project No. 106/00/0580 and
No. 202/02/0840) and of the Ministry of Education, Youth and Sports (project No. MSM 223100001)
is gratefully acknowledged.
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