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Ring opening of benzothiazoles with allylic grignard reagents
Tetrahedron Letters,Vol.25,No.l9,np Printed in Great Britain
RING OPENING
OF BENZOTHIAZOLES
F. Babudria , G. Bartolib,
0040-4039/84 $3.00 + .OO 01984 Pergamon Press Ltd.
2047-2050,1984
WITH ALLYLIC
F. Ciminalea,
GRIGNARD
S. Florioa*
REAGENTS
and G. Ingrosso'
a Dipartimento di Chimica, Universita, Via Amendola 173, 70126 Bari, Italy b Istituto di Chimica Organica, Viale Risorgimento 4, 40136 Bologna, Italy ' Corso di Laurea
Summary:Anovel
in Scienze
ring opening
1icGrignard
The reactions better understand B1'
years.
the chemistry
thio- benzothiazoles:
with organolithium4
nitrobenzothiazoles
ring opening
A possible
have attracted activated
reagents,
for alkylbenzothiazoles
in order either to
is active site of the Vitamine
Frignard
with cuprates
is presented.
planned
considerable
3
Italy
system with ally-
mechanism
system, which
Lecce,
attention
reagents
over the past ten
for halogenoland
for halogenobenzothiazoles,
and alkylation
in the benzene
alkylme-
ring5 for
have been reported.
To our knowledge moted
of the thiazole
halogen exchange
Via Monteroni,
of the benzothiazole
with organometallic
with Ni-complex
metal
Universita,
is reported.
new derivatives,
Thus, cross-coupling
tallation
reaction
reagents
of benzothiazoles
and to synthesize
Biologiche,
there has not been published
reactions
of the benzothiazole
any paper dealing with organometallic
pro-
system.
It has only been shown that cleavage -6 , amines or MeO-/DMSO* of the thiazole ring can be effected under basic conditions for OH 9 andin non basic conditions by metal coordination. As part of our continuing by using organometallic
with allylic Grignard The addition benzothiazole chloride mental
interest directed
reagents,
10
we report here a novel reaction
analysis
reactions
of heterocycles
of some benzothiazoles
reagents.
of 2-methyl-Z-propenylmagnesium
12 (1 mole) at room temperature
afforded
to the ring opening
chloride
2' (2.2 mole) to a THF solution
and subsequent
very high yield of the ring opened product
and IR, NMR and Mass spectroscopy.
when a I:1 molar ratio between with 2-propenylmagnesium
2,b (2.2 mole) gave compound
l_e and 12 reacted with 2-methyl-Z-propenylmagnesium 11 3f and 3g respectively (see Table). n, N 2047
chloride
with aqueous
of l,a
the reaction
by ele-
was not complete of l,a (1 mole)
3J and benzothiazoles 2," to furnish
of
ammonium
32 that was characterised
The conversion
l,a and 2," was used. Similarly,
bromide
quenching
l,b, tc, Id, c N
compounds
%,3_6, 3e,
2048
+
=I a
R' MgX
s4 R “: H
CH I3 2," R'= CH2-C=CH2,
l_aR=H l,b R = CH3
-f-
R'
R CH
I 3
X = Cl
2b R'= CH2-CH=CH2, Iy
3," R = H, R' = Ct$-C=CH2 3,b R = H, R' = Ct$-CH=CH2
X = Br
CH I," R = C2H5
I 3 3,c R = CH3, R'= CH2-C=CH2
I, R = Ph
3,d R = C2H5, R'=
'
I,' R = CH2Ph
3_e R = Ph, R'=
'
I$ R = CH2CH2CH3
Lf R = CH2Ph,
R' =
3,s R = CH2CH2CH3,
Table.
Ring opened reagents
products
32-2 from reaction
of benzothiazoles
at room temperature. Benzothiazole
' R'=
12-z with allylic
II
Grignard
---____-Grignard
Solvent
Product
(yield %ja
Reagent
THF
2,”
3,” (89)
2,bb
ether
3$(73)
2b
ether
3,b (98)
2:
THF
3," (86)
THF
3,d (47)
THF
3," (83)
THF
3,f (92)
THF
3,9 (8&j
2," 2," 2a
b aYield determined on isolated purified products. Reaction carried out at -50°C and quenched with sat NH4C'1 after Ih. 'Yield based on converted starting material.
The present gnard reagents mixture
ring opening
as no reaction
of many products
liar behaviour such reagents
exhibited
reaction
of benzothiazoles
,I_seems to be specific
took place when 12 was treated with n-BuMgBr
characterised by the allylic
the reaction
of 1," with PhMgBr and PhCH2MgBr.
Grignard may tentatively
may interact with the thiazole
sium on the aza group, to give a six-membered
system,
of allylic
be ascribed
viaa preliminary
cyclic transition
Gri-
and an intractable The pecu-
to the fact that
coordination
of magne-
state of the kind 2, as shown
2049 According
in the scheme.
to this scheme, a benzothiazoline
and the final ring opened product $night Grignard
reagent L (path b) or via the Schiff's
of the postulated a I:1 reactants
intermediate
2 by carrying
from 2 either directly
by reaction
base ,6 (path a). However,
out a reaction
of 1,"with z
Work is in progress reaction
to get more
of benzothiazoles
stress that the reaction venient and high yield
insights of the mechanism
described
here. However,
is quite useful from the synthetic
way to 2-monoalkylaminothiophenols
considered
very important
containing
heterocyclic
Acknowlegements.
12(35%),derived
intermediate:
building
13
from;
which
whatever
trapping
at -50" C and using $
we have been
(R = C2H5, R'= CH3).
is operating
in the ring
the mechanism,
viewpoint
we wish to
as it opens an easy,con-
(as disulfides)
blocks for the construction
with the
attempted
molar ratio failed. Only in the case of Z-ethylbenzothiazole
able to trap the benzothiazoline
opening
derive
2 would form as an intermediate
of N-alkyl
which are to be
nitrogen
and sulfur
systems.
We thank CNR and Minister0
Pubblica
Istruzione
(Rome) for financial
support.
References 1) F. Babudri,
S. Florio,
2) H. Takei, M. Miura, 3) F. Babudri,
L. Ronzini
H. Sagimura
L. Di Nunno,
and M. Aresta,
and H. Okamura,
S. Florio,
G. Marchese
Tetrahedron, ---Chem.Lett.,
2,
1515 (1983).
1447 (1979).
and F. Naso, J. Organometallic __--___
Chem., _, 166
265 (1979). 4) E.J. Corey and D.L. Boger, Tetrahedron 5) G. Bartoli,
R. Leardini,
M. Lelli and G. Rosini, J.Chem.Soc. ---
6) P. Haake and J.M. Duclos, Tetrahedron 7) A.O. Ilvespaa,
Lett., 5 (1978).
Helv.Chim.Acta,
Lett.,
Perkin
I, 884 (1977).
461 (1970) and refs. therein.
5l_, 1723 (1968).
2050
8)
G. Bartoli,
F. Ciminale
F. Ciminale,
9)
M. Fiorentino
and P.E. Todesco,
M. Aresta and F. Ciminale,
J.Chem.Soc.Dalton,
101 F. 11)
and P.E. Todesco, --__l___ J.Chem.Soc.
Babudri,
Typical l&ion
S. Florio,
experimental
G. Indelicati
conditions
of 12 (3.7 mmol)
dropwise
and then the red mixture removal
that was purified following
J.Chem.Soc..Chem.Comn --------I'
and G. Trapani,
at room temperature
was quenched
by crystallisation 59-61°C
4H), 3.5(m,
lH), 4.9(bs,
104°C (ethanol).
with aqueous under reduced
J.Org.Chem,,
48, 4082 (1983).
for the reaction
pressure
(ether/petrol).
(ether/petrol).
IR (CH2C12): 3.65(m,
4H), 4.75(s,
with ether,dry-ing
New compounds
3400 and 1650 cm -’
2H), 5.4-6.1(m,
2H), 6.3-7.4(m,
product had the
. 'HNMR
4.8(s, 4H), 6.3-
4H). s,
2H), 4.8(bs,
2H), 5.2(bs,
IH), 6.1-7.2(m,
4.75(s,
2H), 4.9(s,
m.p. 102-
3410 and 1655 cm-'. 'HNMR
2H), 6.15-7.5(m,
9H). Lf,oil.
’ HNMR(CDC13,D20):6
4H).
$,thick
3H), 1.75(s, 6H), 1.82
2H), 6.5-7.4(m,
4H). 3$, m.p. 46-48°C
(CDC13, D20):6 1.43(s, IR(neat):3380
6H), 2.9(s,
and 1640 cm -I. 'HNMR
1.8(~,6H),2.5(bs,4H),3.15(~,2H),4.9(bs,4H),6.3-7.5(m,9H).
3395 and 1645 cm-'.
of Ih
3400, 1650 cm -'. 'HNMR (CDC13): 6 1.35(s, 3H), 1.75(s, 6H),
4H, AB system),
2H), 4.94(s,
(CDC13,D20):6
in THF
was continued
IH, J 7.5Hz),
aso-
IR (neat): 3400 and 1650 cm -'. 'HNMR (CDC13, D20): 6 2.2(t,
4.68(bs,
IR (CH2C12):
(8.1 mmol)
gave the ring opened
oil. IR (neat): 3410 and 1665 cm -'. 'HNMR (CDC13, D20): 6 0.95(t, (q, 2H), 2.5(dd,
of 1,"with s.To
sat NH4C1. Extraction
or by column chromatography.
2H), 5.l(bs,
IR (CH2C12):
2.5(dd, 4H, AB system),
732 (1974).
under nitrogen.Stirring
(CDC13, D20): 6 1.73(s, 6H), 2.2(d, 4H, J 7.5Hz), 7.3(m, 4H). Mt2= 246. 3b, oil.
G. Bartoli,
1520 (1981) and refs. therein.
were those described
of the solvent
data.3,m.p.
1472 (1975);
in 10 ml of dry THF was added a solution of 2
and with stirring
over MgS04and
Perk. II,
0.9(t,3H),1.75(m,lOH),2.5(dd,4H,AB
3Ng,oil. IR(neat): system),4.7(bs,
2H),4.85(bs,2H),6.3-7.4(m,4H).
12)
Benzothiazoline!
shows: oil. IR(neat):3395
(s,3H),1.95(q,2H),2.7(dd,2H,AB
and 1655 cm -I. 'HNMR(CDCI,):S
system),4.2(bs,lH,
exchange
1.05(t,3H),1.9
with D20),4.8(s,lH),5.0(s,1H),
6.6-7.l(m,4H). 13) The only known procedure de reductive
to 2-monoisoalkylaminothiophenols
ring opening of benzothiazolines.
is the lithium aluminum
W.Mueller,Eur.Pat.App1.,~,469(1981);
hydriC.A.
~,132>70n(1981). 14) Disulfides
3 could actually
cf the corresponding (Received
in
UK
thiols 27
originate
during
initially
formed.
February
1984)
the workup
following
upon an easy oxidation
RING OPENING
OF BENZOTHIAZOLES
F. Babudria , G. Bartolib,
0040-4039/84 $3.00 + .OO 01984 Pergamon Press Ltd.
2047-2050,1984
WITH ALLYLIC
F. Ciminalea,
GRIGNARD
S. Florioa*
REAGENTS
and G. Ingrosso'
a Dipartimento di Chimica, Universita, Via Amendola 173, 70126 Bari, Italy b Istituto di Chimica Organica, Viale Risorgimento 4, 40136 Bologna, Italy ' Corso di Laurea
Summary:Anovel
in Scienze
ring opening
1icGrignard
The reactions better understand B1'
years.
the chemistry
thio- benzothiazoles:
with organolithium4
nitrobenzothiazoles
ring opening
A possible
have attracted activated
reagents,
for alkylbenzothiazoles
in order either to
is active site of the Vitamine
Frignard
with cuprates
is presented.
planned
considerable
3
Italy
system with ally-
mechanism
system, which
Lecce,
attention
reagents
over the past ten
for halogenoland
for halogenobenzothiazoles,
and alkylation
in the benzene
alkylme-
ring5 for
have been reported.
To our knowledge moted
of the thiazole
halogen exchange
Via Monteroni,
of the benzothiazole
with organometallic
with Ni-complex
metal
Universita,
is reported.
new derivatives,
Thus, cross-coupling
tallation
reaction
reagents
of benzothiazoles
and to synthesize
Biologiche,
there has not been published
reactions
of the benzothiazole
any paper dealing with organometallic
pro-
system.
It has only been shown that cleavage -6 , amines or MeO-/DMSO* of the thiazole ring can be effected under basic conditions for OH 9 andin non basic conditions by metal coordination. As part of our continuing by using organometallic
with allylic Grignard The addition benzothiazole chloride mental
interest directed
reagents,
10
we report here a novel reaction
analysis
reactions
of heterocycles
of some benzothiazoles
reagents.
of 2-methyl-Z-propenylmagnesium
12 (1 mole) at room temperature
afforded
to the ring opening
chloride
2' (2.2 mole) to a THF solution
and subsequent
very high yield of the ring opened product
and IR, NMR and Mass spectroscopy.
when a I:1 molar ratio between with 2-propenylmagnesium
2,b (2.2 mole) gave compound
l_e and 12 reacted with 2-methyl-Z-propenylmagnesium 11 3f and 3g respectively (see Table). n, N 2047
chloride
with aqueous
of l,a
the reaction
by ele-
was not complete of l,a (1 mole)
3J and benzothiazoles 2," to furnish
of
ammonium
32 that was characterised
The conversion
l,a and 2," was used. Similarly,
bromide
quenching
l,b, tc, Id, c N
compounds
%,3_6, 3e,
2048
+
=I a
R' MgX
s4 R “: H
CH I3 2," R'= CH2-C=CH2,
l_aR=H l,b R = CH3
-f-
R'
R CH
I 3
X = Cl
2b R'= CH2-CH=CH2, Iy
3," R = H, R' = Ct$-C=CH2 3,b R = H, R' = Ct$-CH=CH2
X = Br
CH I," R = C2H5
I 3 3,c R = CH3, R'= CH2-C=CH2
I, R = Ph
3,d R = C2H5, R'=
'
I,' R = CH2Ph
3_e R = Ph, R'=
'
I$ R = CH2CH2CH3
Lf R = CH2Ph,
R' =
3,s R = CH2CH2CH3,
Table.
Ring opened reagents
products
32-2 from reaction
of benzothiazoles
at room temperature. Benzothiazole
' R'=
12-z with allylic
II
Grignard
---____-Grignard
Solvent
Product
(yield %ja
Reagent
THF
2,”
3,” (89)
2,bb
ether
3$(73)
2b
ether
3,b (98)
2:
THF
3," (86)
THF
3,d (47)
THF
3," (83)
THF
3,f (92)
THF
3,9 (8&j
2," 2," 2a
b aYield determined on isolated purified products. Reaction carried out at -50°C and quenched with sat NH4C'1 after Ih. 'Yield based on converted starting material.
The present gnard reagents mixture
ring opening
as no reaction
of many products
liar behaviour such reagents
exhibited
reaction
of benzothiazoles
,I_seems to be specific
took place when 12 was treated with n-BuMgBr
characterised by the allylic
the reaction
of 1," with PhMgBr and PhCH2MgBr.
Grignard may tentatively
may interact with the thiazole
sium on the aza group, to give a six-membered
system,
of allylic
be ascribed
viaa preliminary
cyclic transition
Gri-
and an intractable The pecu-
to the fact that
coordination
of magne-
state of the kind 2, as shown
2049 According
in the scheme.
to this scheme, a benzothiazoline
and the final ring opened product $night Grignard
reagent L (path b) or via the Schiff's
of the postulated a I:1 reactants
intermediate
2 by carrying
from 2 either directly
by reaction
base ,6 (path a). However,
out a reaction
of 1,"with z
Work is in progress reaction
to get more
of benzothiazoles
stress that the reaction venient and high yield
insights of the mechanism
described
here. However,
is quite useful from the synthetic
way to 2-monoalkylaminothiophenols
considered
very important
containing
heterocyclic
Acknowlegements.
12(35%),derived
intermediate:
building
13
from;
which
whatever
trapping
at -50" C and using $
we have been
(R = C2H5, R'= CH3).
is operating
in the ring
the mechanism,
viewpoint
we wish to
as it opens an easy,con-
(as disulfides)
blocks for the construction
with the
attempted
molar ratio failed. Only in the case of Z-ethylbenzothiazole
able to trap the benzothiazoline
opening
derive
2 would form as an intermediate
of N-alkyl
which are to be
nitrogen
and sulfur
systems.
We thank CNR and Minister0
Pubblica
Istruzione
(Rome) for financial
support.
References 1) F. Babudri,
S. Florio,
2) H. Takei, M. Miura, 3) F. Babudri,
L. Ronzini
H. Sagimura
L. Di Nunno,
and M. Aresta,
and H. Okamura,
S. Florio,
G. Marchese
Tetrahedron, ---Chem.Lett.,
2,
1515 (1983).
1447 (1979).
and F. Naso, J. Organometallic __--___
Chem., _, 166
265 (1979). 4) E.J. Corey and D.L. Boger, Tetrahedron 5) G. Bartoli,
R. Leardini,
M. Lelli and G. Rosini, J.Chem.Soc. ---
6) P. Haake and J.M. Duclos, Tetrahedron 7) A.O. Ilvespaa,
Lett., 5 (1978).
Helv.Chim.Acta,
Lett.,
Perkin
I, 884 (1977).
461 (1970) and refs. therein.
5l_, 1723 (1968).
2050
8)
G. Bartoli,
F. Ciminale
F. Ciminale,
9)
M. Fiorentino
and P.E. Todesco,
M. Aresta and F. Ciminale,
J.Chem.Soc.Dalton,
101 F. 11)
and P.E. Todesco, --__l___ J.Chem.Soc.
Babudri,
Typical l&ion
S. Florio,
experimental
G. Indelicati
conditions
of 12 (3.7 mmol)
dropwise
and then the red mixture removal
that was purified following
J.Chem.Soc..Chem.Comn --------I'
and G. Trapani,
at room temperature
was quenched
by crystallisation 59-61°C
4H), 3.5(m,
lH), 4.9(bs,
104°C (ethanol).
with aqueous under reduced
J.Org.Chem,,
48, 4082 (1983).
for the reaction
pressure
(ether/petrol).
(ether/petrol).
IR (CH2C12): 3.65(m,
4H), 4.75(s,
with ether,dry-ing
New compounds
3400 and 1650 cm -’
2H), 5.4-6.1(m,
2H), 6.3-7.4(m,
product had the
. 'HNMR
4.8(s, 4H), 6.3-
4H). s,
2H), 4.8(bs,
2H), 5.2(bs,
IH), 6.1-7.2(m,
4.75(s,
2H), 4.9(s,
m.p. 102-
3410 and 1655 cm-'. 'HNMR
2H), 6.15-7.5(m,
9H). Lf,oil.
’ HNMR(CDC13,D20):6
4H).
$,thick
3H), 1.75(s, 6H), 1.82
2H), 6.5-7.4(m,
4H). 3$, m.p. 46-48°C
(CDC13, D20):6 1.43(s, IR(neat):3380
6H), 2.9(s,
and 1640 cm -I. 'HNMR
1.8(~,6H),2.5(bs,4H),3.15(~,2H),4.9(bs,4H),6.3-7.5(m,9H).
3395 and 1645 cm-'.
of Ih
3400, 1650 cm -'. 'HNMR (CDC13): 6 1.35(s, 3H), 1.75(s, 6H),
4H, AB system),
2H), 4.94(s,
(CDC13,D20):6
in THF
was continued
IH, J 7.5Hz),
aso-
IR (neat): 3400 and 1650 cm -'. 'HNMR (CDC13, D20): 6 2.2(t,
4.68(bs,
IR (CH2C12):
(8.1 mmol)
gave the ring opened
oil. IR (neat): 3410 and 1665 cm -'. 'HNMR (CDC13, D20): 6 0.95(t, (q, 2H), 2.5(dd,
of 1,"with s.To
sat NH4C1. Extraction
or by column chromatography.
2H), 5.l(bs,
IR (CH2C12):
2.5(dd, 4H, AB system),
732 (1974).
under nitrogen.Stirring
(CDC13, D20): 6 1.73(s, 6H), 2.2(d, 4H, J 7.5Hz), 7.3(m, 4H). Mt2= 246. 3b, oil.
G. Bartoli,
1520 (1981) and refs. therein.
were those described
of the solvent
data.3,m.p.
1472 (1975);
in 10 ml of dry THF was added a solution of 2
and with stirring
over MgS04and
Perk. II,
0.9(t,3H),1.75(m,lOH),2.5(dd,4H,AB
3Ng,oil. IR(neat): system),4.7(bs,
2H),4.85(bs,2H),6.3-7.4(m,4H).
12)
Benzothiazoline!
shows: oil. IR(neat):3395
(s,3H),1.95(q,2H),2.7(dd,2H,AB
and 1655 cm -I. 'HNMR(CDCI,):S
system),4.2(bs,lH,
exchange
1.05(t,3H),1.9
with D20),4.8(s,lH),5.0(s,1H),
6.6-7.l(m,4H). 13) The only known procedure de reductive
to 2-monoisoalkylaminothiophenols
ring opening of benzothiazolines.
is the lithium aluminum
W.Mueller,Eur.Pat.App1.,~,469(1981);
hydriC.A.
~,132>70n(1981). 14) Disulfides
3 could actually
cf the corresponding (Received
in
UK
thiols 27
originate
during
initially
formed.
February
1984)
the workup
following
upon an easy oxidation