Reactivity of 2-aminothiazole and 2- or 6-aminobenzothiazole derivatives towards the triphenylbismuth diacetate/catalytic copper diacetate phenylation system

Article abstract of DOI:10.1002/ejoc.200300656

The copper diacetate catalysed reaction of triphenylbismuth diacetate with 6-aminobenzothiazole compounds afforded selectively the 6-phenylamino derivatives in good to high yields. A similar reaction with 2-aminothiazole or 2-amino-benzothiazole compounds gave mixtures of the monophenylated and diphenylated products 2-phenylaminothiazole and 2-(N-phenylamino)-3-N′- phenylthiazole derivatives, respectively, with the diphenyl product being predominant. Semi-empirical calculations with the SAM1/D and CHAIN methods performed on the evolution of a 2-aminobenzothiazole - copper(III) intermediate were in good qualitative agreement with the experimental results. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300656

FULL PAPER
Reactivity of 2-Aminothiazole and 2- or 6-Aminobenzothiazole Derivatives
Towards the Triphenylbismuth Diacetate/Catalytic Copper Diacetate
Phenylation System
[a]
[a]
[b]
[c]
´
Abdellah Miloudi, Douniazad El-Abed, Gerard Boyer,* Jean Pierre Finet,
Jean Pierre Galy,[b] and Didier Siri[d]
Keywords: Thiazole / Aromatic substitution / Heterocycles / Semi-empirical calculations / X-ray diffraction
The copper diacetate catalysed reaction of triphenylbismuth
diacetate with 6-aminobenzothiazole compounds afforded
selectively the 6-phenylamino derivatives in good to high
ively, with the diphenyl product being predominant. Semi-
empirical calculations with the SAM1/D and CHAIN
methods performed on the evolution of a 2-aminobenzothia-
yields. A similar reaction with 2-aminothiazole or 2-amino- zole − copper(III) intermediate were in good qualitative
benzothiazole compounds gave mixtures of the monophenyl- agreement with the experimental results.
ated and diphenylated products 2-phenylaminothiazole and ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
2-(N-phenylamino)-3-NЈ-phenylthiazole derivatives, respect-
Germany, 2004)
Introduction
Thiazole and benzothiazole derivatives have attracted
continuing interest over the years because of their varied
biological activities.[1,2] Among them, the 2-amino series
was studied in the 1950s as a muscle relaxant acting under
the central nervous system (CNS).[3] Interest in that series
was revived by the recent discoveries of Riluzole (2-amino-
6-trifluoromethoxybenzothiazole), a blocker of excitatory
amino acid-mediated neurotransmission[4,5] and of
R116010, a 2-(para-substituted phenylamino)benzothiazole
which acts as a potent selective inhibitor of all-trans-reti-
noic acid metabolism.[6] (Scheme 1).
Among the various possible routes for the synthesis of
R116010, an attractive approach is the convergent coupling
of 2-aminobenzothiazole with an aryl derivative bearing a
leaving group. However, aromatic nucleophilic substitution
under either Goldberg, basic or palladium-catalysed con-
ditions failed to give satisfactory results.[6]
Scheme 1. Structures of Riluzole and R116010
As an extension of our recent studies on the organobis-
muth-mediated copper-catalysed N-arylation of heterocyclic
amines,[7] we decided to investigate the reaction of various
aminothiazole derivatives with the triarylbismuth diacetate/
copper diacetate system which is one of the mildest for N-
arylation reactions.[8,9] It can be realized by using either the
trivalent triarylbismuth/stoichiometric copper diacetate sys-
tem[10,11] or the pentavalent triarylbismuth/catalytic copper
diacetate system.[12] In view of the oxidizing properties of
copper diacetate, which could lead to a competitive oxidat-
ive degradation of the thiazolic substrate, we selected the
pentavalent triarylbismuth/catalytic copper diacetate sys-
tem. Nucleophilic reactions of 2-aminothiazole derivatives
take place on either the exocyclic or the endocyclic nitrogen
centre, depending on the nature of the electrophile and the
reaction conditions.[13] In nucleophilic aromatic substi-
tution reactions of 2-aminothiazole derivatives with
strongly activated aryl halides, the regiochemistry is gov-
erned essentially by the steric hindrance: the endocyclic ni-
trogen of the non-substituted 2-aminothiazole is the most
[a]
`
´
Laboratoire de Synthese Organique, Departement de Chimie,
´
´
Faculte des Sciences, Universite d’Oran,
B.P. 1524, Oran, Algeria
[b]
Laboratoire de Valorisation de la Chimie Fine, UMR CNRS
´
´ ˆ
6009, Faculte des Sciences St-Jerome,
Case 552, 13397 Marseille, Cedex 20, France
Fax: (internat.) ϩ 33-4-91288323
E-mail: gerard.boyer@univ.u-3mrs.fr
[c]
`
Laboratoire de Chimie Organique de Synthese, UMR CNRS
´
´ ˆ
6517, Faculte des Sciences St-Jerome,
Case 541, 13397 Marseille Cedex 20, France
[d]
´
´
´
´
Laboratoire de Chimie Theorique et Modelisation Moleculaire,
´ ˆ
UMR CNRS 6517, Faculte des Sciences St-Jerome,
Case 521, 13397 Marseille Cedex 20, France
Eur. J. Org. Chem. 2004, 1509Ϫ1516
DOI: 10.1002/ejoc.200300656
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A. Miloudi, D. El-Abed, G. Boyer, J. P. Finet, J. P. Galy, D. Siri
FULL PAPER
reactive.[14] However, in the case of 4-substituted 2-amino- was the expected product of monophenylation of the 2-am-
thiazole and in the 2-aminobenzothiazole series, the ex- ino group (respectively 8, 11 and 14).
ocyclic nitrogen is the most reactive for monoarylation,[15]
The second products were always formed in slightly pre-
the N,NЈ-diaryl derivative being obtained with an excess of
dominant yields. These compounds (respectively 9, 12 and
15), which could have been the 2-diphenylamino derivatives,
were in fact found to be monophenylated on both nitrogen
atoms, the 2-amino group and the endocyclic N-3 atom, as
determined by a detailed NMR study of these compounds.
The aromatic protons for both the mono- and the N,NЈ-
diphenylated compounds were assigned after COSY experi-
ments. The protonated carbon atoms were unambiguously
assigned by HMQC correlation experiments, and the
HMBC technique was used to show the long-range proton-
carbon correlations of the quaternary aromatic carbon
atoms. In the case of the 6-fluoro-3-phenyl-2-phenylimino-
1,3-benzothiazoline 15, NOESY experiments confirmed the
substitution on the N-3 nitrogen atom by occurrence of
cross correlation peaks between the 4-H and 20-H protons,
revealing their direct proximity. The absence of correlation
peaks between the 10-H and 16-H protons of the two phe-
nyl groups is indicative of the anti configuration of the phe-
nyl group present on the N-8 nitrogen atom.
the electrophilic reagent.[16]
Results and Discussion
Phenylation of 6-Aminobenzothiazole Derivatives
In a first series of reactions, the 6-aminobenzothiazole
derivatives 1, 3 and 5 were treated with 1.1 molar equiva-
lents of triphenylbismuth diacetate and 0.1 equivalent of
copper diacetate in dichloromethane at room temperature
(Scheme 2). The three substrates afforded selectively the
corresponding mono N-phenyl derivatives 2, 4 and 6 in
moderate to good yields (39Ϫ70%). In the case of the 2-
methyl derivative 3, the highest yield of the 6-monophenyla-
minobenzothiazole derivative 4 was obtained, even though
the presence of the 2-methyl substituent could induce the
formation of a tautomeric 2-methylenebenzothiazoline iso-
mer leading to the 3-N-phenyl derivative by reaction with
the triphenylbismuth diacetate/catalytic copper diacetate
system.
The structures of 14 and 15 were confirmed by X-ray
crystallography. The ORTEP drawings[17] of the two struc-
tures are shown in Figure 1 and 2 and selected geometrical
parameters are collected in Table 1Ϫ3 with the respective
atom-numbering schemes.
Phenylation of 2-Aminobenzothiazole Derivatives
The copper-catalysed N-phenylation reaction of the 2-
aminobenzothiazole derivatives 7, 10 and 13 led to more
complex results (Scheme 3). Under classical reaction con-
ditions [triphenylbismuth diacetate (1.1 equiv.)/copper di- 1.41Ϫ1.42 A are observed for the bond between the ex-
acetate (0.1 equiv.) in dichloromethane at room tempera- ocyclic nitrogen atom and the ipso carbon atom,
ture], a mixture of two N-phenylation products was always N(22)ϪC(8) in 14 and N(2)ϪC(14) in 15 (Table 2). The dis-
obtained in relatively modest yields. One of the compounds tances between the exocyclic nitrogen atom and the ipso
In the case of the N-phenyl bonds, similar values of
˚
Scheme 2. Phenylation of 6-aminobenzothiazole derivatives 1, 3 and 5
Scheme 3. Phenylation of 2-aminobenzothiazole derivatives 7, 10 and 13
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Triphenylbismuth Diacetate and Copper Diacetate Phenylation System
FULL PAPER
carbon atom of the thiazole moiety are significantly
˚
˚
shorter: 1.3515 A for N(22)ϪC(7) in 14 and 1.2729 A for
N(2)ϪC(13) in 15. The longest N-carbon bond is observed
between the endocyclic nitrogen atom and the ipso carbon
˚
atom of the second phenyl group in 15 [1.4419 A for
N(1)ϪC(7)]. If we consider the dihedral angles between the
planes of the phenyl groups and the thiazole moiety of both
molecules, a value of 134.83° is found for the atoms
C(7)ϪN(22)ϪC(8)ϪC(9) in the case of 14, and a value of
133.55° for the corresponding dihedral angle involving the
atoms C(13)ϪN(2)ϪC(14)ϪC(15) of 15. In this latter case,
the second phenyl ring linked to the endocyclic nitrogen is
twisted with an angle of about 83.37° for the atoms
C(13)ϪN(1)ϪC(7)ϪC(8) (Table 4). It must also be noted
that, in the N,NЈ-diphenyl compound 15, the two phenyl
groups C(14)ϪC(19) and C(7)ϪC(12) represented in Fig-
ure 2, are in an anti position relative to the C(3)ϪN(1)
double bond. Moreover, when the H atoms were treated as
Figure 1. ORTEP view of compound 14
˚
riding with a CϪH distance of 0.96 A and an NϪH dis-
˚
tance of 0.902 A, adjacent molecules of 14 were found to
be linked by a weak NϪH···N hydrogen bond between N(1)
˚
and H(22) [mean distance of 2.111 A between N(1) and
H(22), distance of 3.0085(6) between N(1) and N(22), and
angle of 172.9(5)° for N(22)ϪH(22)ϪN(1)]. A strong con-
˚
tact between H(12) and F(1) [mean distance of 3.2086(7) A
˚
between C(12) and F(1), and mean distance of 2.644 A be-
tween H(12) and F(1)] was also observed.
The modest yields obtained in the phenylation of com-
pounds 7, 10 and 13, combined with the complete disap-
pearance of the aminobenzothiazole substrate, led us to in-
vestigate the influence of the reaction conditions on the
yields of the mono and diphenyl derivatives 14 and 15,
formed in the reaction of the 2-aminobenzothiazole deriva-
tive 13. When the phenylation reaction was performed in
dichloromethane, the amount of copper diacetate used had
only a modest effect on the yields (Table 4, Entries 1 and
2), and a large excess of triphenylbismuth diacetate had to
Figure 2. ORTEP view of compound 15
˚
Table 1. Selected bond lengths (A) for 14 and 15
14
15
N(22)ϪC(7)
N(22)ϪC(8)
S(1)ϪC(7)
F(1)ϪC(3)
1.3515(6)
1.4194(6)
1.7662(5)
1.3632(6)
N(2)ϪC(14)
N(1)ϪC(7)
N(2)ϪC(13)
S(1)ϪC(13)
F(1)ϪC(3)
1.4095(4)
1.4419(4) be used to reach a 40% yield of the diphenyl derivative 15
1.2729(4)
1.7868(3)
(Table 4, Entry 3). A slightly better selectivity was obtained
when the reaction was performed in THF. Although formed
1.3693(4)
in a relatively modest yield (26%), the monophenyl deriva-
tive 14 was obtained as the only product when the reaction
was performed at room temperature with 1.1 equivalents of
the bismuth reagent (Table 4, Entry 6). On the other hand,
39Ϫ40% yields of the diphenyl derivative 15 were obtained
when 2.2 equivalents of the bismuth reagent was used
Table 2. Selected typical angles (°) for 14 and 15
14 15
C(7)ϪN(22)ϪC(8) 126.85(4) C(13)ϪN(2)ϪC(14) 122.95(2)
(Table 4, Entries 7 and 9). However, optimisation of the re-
action conditions failed to increase significantly either the
selectivity or the overall yields due to the sensitivity of the
C(1)ϪS(1)ϪC(7)
88.47(2) C(13)ϪN(1)ϪC(7)
C(1)ϪS(1)ϪC(13)
121.66(2)
91.10(1)
Table 3. Dihedral angles between selected atoms (°) of 14 and 15
14
15
C(7)ϪN(22)ϪC(8)ϪC(13)
C(7)ϪN(22)ϪC(8)ϪC(9)
Ϫ48.31(6)
134.83(7)
C(13)ϪN(2)ϪC(14)ϪC(19)
C(13)ϪN(2)ϪC(14)ϪC(15)
C(13)ϪN(1)ϪC(7)ϪC(8)
C(13)ϪN(1)ϪC(7)ϪC(12)
51.93(3)
Ϫ133.55(4)
83.37(4)
Ϫ96.15(4)
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FULL PAPER
Table 4. Phenylation reactions of 13 with Ph3Bi(OAc)2/Cu(OAc)2
Entry
Solvent
13 (mmol/mL)
Ph3Bi(OAc)2 (equiv.)
Cu(OAc)2 (equiv.)
Reaction conditions
14 [%]
15 [%]
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
THF
0.12
0.1
0.1
0.1
0.1
0.1
0.3
0.3
0.3
1.1
1.1
1.1
2.2
3.3
1.1
2.2
2.2
2.2
0.1
1
room temp./5 h
room temp./5 h
reflux/5 h
room temp./5 h
room temp./5 h
room temp./5 h
room temp./5 h
room temp./24 h
reflux/5 h
15
16
10
15
10
26
12
17
7
22
31
30
33
40
0
39
20
40
0.1
0.1
0.1
0.1
0.1
0.1
0.1
substrate and products towards competitive oxidation reac-
tions.
Phenylation of 2-Aminothiazole
When 2-aminothiazole (16) was treated with triphenylbis-
muth diacetate/catalytic copper diacetate in dichlorometh-
ane at room temperature, a mixture of mono- and di-
phenylated compounds was also obtained. When 1.1 equiv-
alents of the bismuth reagent was used, the monophenyl
derivative 17 was isolated in 33% yield and the diphenyl
derivative 18 in 29% yield. With an excess of the bismuth
reagent (2.2 equivalents), the diphenyl derivative became
predominant (55%) with only 9% of the monophenyl de-
rivative being formed (Scheme 4).
Scheme 5. Enthalpies of formation ∆H0f (kcal·molϪ1) of different
isomers of 14 and 15 after geometry optimisation by AM1 (RHF)
semi-empirical calculations
Semi-Empirical Calculations
various isomers of 14 and 15 were calculated (Scheme 5).
In an attempt to rationalize the regioselectivity of these The 2-(phenylamino)benzothiazole 14 has the lowest en-
diphenylation reactions of either 2-aminothiazole or 2-ami- thalpy of formation, but the difference between 14 and 14a
nobenzothiazole derivatives, semi-empirical calculations is relatively small (∆∆H0f 14a-14 ϭ 1.5 kcal·molϪ1), compared
were performed on various isomers of 14 and 15. The semi- to the 2-imino-3-phenyl-benzothiazoline 14b (∆∆H0f 14b-14 ϭ
empirical calculations were carried out with the Ampac 10.6 kcal·molϪ1). Thus, formation of the 2-(phenylamino)b-
6.55 package[18] with the AM1[19] Hamiltonian at the re- enzothiazole derivatives appears largely favoured. On the
stricted HartreeϪFock (RHF) level on a Silicon Graphics other hand, the difference between the enthalpies of forma-
Origin 200 R10000 workstation. After geometry optimis- tion of the two diphenyl regioisomers 15 and 15a is small
ation by application of the NewtonϪRaphson method (∆∆H0f 15a-15 ϭ 0.7 kcal·molϪ1), but in favour of the ob-
(convergence limit of gradient norm of 4.18 ϫ 10Ϫ3, force served product 15.
calculations performed to ensure that the conformations are
The selective formation of the diphenyl products 9, 12
potential-energy minima), the enthalpies of formation of and 15 could benefit from two effects. The NϭCϪN system
Scheme 4. Phenylation of 2-aminothiazole (16)
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Triphenylbismuth Diacetate and Copper Diacetate Phenylation System
FULL PAPER
Scheme 6. Plausible copper intermediates involved in the ligand-
transfer step
present in the intermediate hypervalent copper species[9,12] intermediate was optimised by NewtonϪRaphson calcu-
can be tridentate with a 1,3-diaza-π-allyl type structure. The lations (convergence limit of gradient norm of 4.18 ϫ 10Ϫ3
,
copper atom can also enter into a π-interaction with the force calculations performed to ensure that the confor-
phenyl group bound to the 2-amino group (Scheme 6). mations are potential-energy minima). Then, the two reac-
These two interactions could lead to a facilitation of the tion pathways were calculated using the CHAIN
formation of the diphenyl derivatives, which are predomi- method.[21] All transition structures were confirmed by fre-
nant over the monophenyl derivatives. Moreover, combi- quency calculations and the corresponding two minima
nation of the difference between the enthalpies of formation were established by tracing the intrinsic reaction coordi-
of 15 and 15a with the smaller steric hindrance around the nates (IRC).[22] The reaction pathways for the second phe-
N-3 nitrogen than around the 2-phenylamino group, which nylation on the endocyclic and the exocyclic nitrogen atoms
can freely rotate around the NϪCipso bond, could be in fav- are depicted in Schemes 8 and 9.
our of the formation of the observed product 15.
However, the mechanism depicted in Scheme 6 implies a
kinetic control of the formation of products, whereas the
enthalpies of formation of the final products are related to
a thermodynamic control. Thus we considered that the en-
thalpies of formation of the copper intermediates should
give a more accurate view, as the evolution of these inter-
mediates should govern the outcome of the overall reaction.
Semi-empirical calculations were performed on a postulated
hypervalent copper() intermediate, with the substrate and
the incoming phenyl group being two of the copper sub-
stituents.[9,12] (Scheme 7).
Scheme 8. Reaction pathway for the formation of 15: second
phenylation on the endocyclic nitrogen atom
Scheme 7. Model copper() intermediate used for the semi-empiri-
cal calculations
The barrier-height values of the transition states are 79.6
Semi-empirical SAM1/D calculations[20] were performed kcal·molϪ1 for the pathway leading to 15 and 82.8
with the Ampac 6.55 package. The SAM1/D method was kcal·molϪ1 for the pathway leading to 15a. Five-membered
preferred because it is the only method parametrized for the metallacyclic transition states are found on both routes. In
copper atom. First, the structure of the model tricoordinate the path leading to 15, the lengths between the copper cen-
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A. Miloudi, D. El-Abed, G. Boyer, J. P. Finet, J. P. Galy, D. Siri
FULL PAPER
alternative to our method, but is unlikely to be useful for
the synthesis of the diphenylated derivatives.
Experimental Section
General Remarks: Melting points were recorded with a Büchi Melt-
1
ing Point Apparatus and are uncorrected. H and 13C NMR spec-
tra were obtained with a Bruker Avance 300 spectrometer operating
at 300 MHz, using [D6]DMSO (δH ϭ 2.48 ppm and δC
ϭ
39.70 ppm) as solvent unless otherwise stated, and J values in
Hertz. Combustion analyses were performed in the ‘‘Laboratoire
de Microanalyse du Centre National de la Recherche Scientifique’’,
Vernaison (France). Column chromatography separations were per-
formed with Merck ‘‘Silicagel 60’’ 60Ϫ230 mesh. Ether refers to
diethyl ether. All solvents were purified by standard techniques.
General Procedure for the Synthesis of Arylamines. Copper Diacet-
ate Catalysed Phenylation with Triphenylbismuth Diacetate: A mix-
Scheme 9. Reaction pathway for the formation of 15a: second
ture of the appropriate aminothiazole (4 mmol,
1 equiv.),
phenylation on the exocyclic nitrogen atom
Ph3Bi(OAc)2 (1.1 equiv.) and Cu(OAc)2 (0.1 equiv.) in dichloro-
methane (10 mL/mmol) was stirred at room temperature during
4 h, unless otherwise stated. The mixture was filtered and the sol-
vent was distilled under reduced pressure to afford an oil which
was purified by chromatography on silica gel to give the N-phe-
nylation products.
˚
tre and the nitrogen atoms are: CuϪN(3) 2.59 A and
˚
CuϪN(8) 2.03 A. In the path leading to 15a, the corre-
˚
sponding lengths are: CuϪN(3) 2.06 A and CuϪN(8) 2.60
˚
˚
A. Moreover, the CipsoϪN distances are 2.0 A [CipsoϪN(3)]
˚
in the transition state to 15 and 2.06 A [CipsoϪN(8)] in the
6-Phenylamino-1,3-benzothiazole (2): Elution with ether/pentane
transition state to 15a. These calculations show that the se-
cond phenylation on the endocyclic nitrogen atom is fav-
oured by a difference of activation energies of 3.8
kcal·molϪ1. The values of the enthalpies of formation of
the products give the same trends (∆∆H0f ϭ 0.8 kcal·molϪ1).
These values of the barrier heights are in good agreement
with the experimental observations, even if they are of only
qualitative value as the actual nature of the key intermedi-
ate still remains a matter of speculation.
1
(1:1); 0.52 g; 58%; m.p. 142 °C: H NMR (CDCl3): δ ϭ 5.89 (s, 1
H, NH), 6.92 (t, J ϭ 7.6 Hz, 1 H, 12-H), 7.04 (d, J ϭ 8 Hz, 2 H,
10-H and 14-H), 7.11 (m, 1 H, 5-H), 7.24 (t, J ϭ 7.7 Hz, 2 H, 11-
H and 13-H), 7.53 (m, 1 H, 7-H), 7.92 (d, J ϭ 8.6 Hz, 1 H, 4-H)
and 8.71 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3): δ ϭ 108.53 (C-7),
118.90 (C-10), 118.90 (C-5), 122.17 (C-12), 124.38 (C-4), 129.89 (C-
11), 135.74 (C-7a), 142.10 (C-6), 143.02 (C-9), 148.41 (C-3a) and
151.48 (C-2) ppm. C13H10N2S (226.30): calcd. C 69.00, H 4.45, N
12.38; found C 68.79, H 4.66, N 12.50.
2-Methyl-6-phenylamino-1,3-benzothiazole (4): Elution with ether/
1
pentane (1:4); 0.67 g; 70%; m.p. 138Ϫ139 °C. H NMR: δ ϭ 2.71
Conclusion
(s, 3 H, Me), 6.84 (t, J ϭ 7.1 Hz, 1 H, 12-H), 7.12 (d, J ϭ 8.3 Hz,
2 H, 10-H and 14-H), 7.14 (m, 1 H, 5-H), 7.24 (t, J ϭ 7.6 Hz, 2
H, 11-H and 13-H), 7.63 (m, 1 H, 7-H), 7.74 (d, J ϭ 8.8 Hz, 1 H,
4-H) and 8.33 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 19.68 (Me), 107.72
(C-7), 117.06 (C-10), 117.36 (C-5), 120.14 (C-12), 122.47 (C-4),
129.42 (C-11), 136.99 (C-7a), 141.12 (C-6), 143.50 (C-9), 147.16 (C-
The reaction of triphenylbismuth diacetate/catalytic cop-
per diacetate with the tautomeric 2-aminothiazole system
shows a unique behaviour: N,NЈ-diphenylation is favoured
over monophenylation of the exocyclic nitrogen atom. This
reactivity is in sharp contrast with all the previously re- 3a) and 163.15 (C-2) ppm. C14H12N2S (240.32): calcd. C 69.97, H
5.03, N 11.66; found C 69.76, H 4.92, N 11.42.
ported reactions using this combination of reagents, in
which either mono- or diphenylation was possible but com-
pletely selective. Moreover, after the first phenylation of the
exocyclic nitrogen atom, the second phenylation takes place
on the endocyclic nitrogen atom. Semi-empirical AM1 cal-
culations were in qualitative agreement with the experimen-
tal regioselectivity. Unfortunately, the overall yields of the
products do not reach the range required for industrial
preparation of derivatives of this type due to competitive
oxidative processes affecting the thiazolic reactants. More-
over, in a recent paper, Knochel et al. reported an interest-
ing alternative approach for the synthesis of 6-(phenylami-
no)benzothiazoles involving the reaction of an arylmagnes-
ium reagent with 6-nitrobenzothiazole.[23] If applicable to 2-
2-Diethylamino-6-phenylamino-1,3-benzothiazole (6): Elution with
ether/pentane (1:4); 0.46 g; 39%; m.p. 150Ϫ151 °C. H NMR: δ ϭ
1
1.18 (t, J ϭ 7 Hz, 6 H, Me), 3.49 (q, J ϭ 7.1 Hz, 4 H, NϪCH2),
6.72 (t, J ϭ 7.2 Hz, 1 H, 12-H), 6.96 (d, J ϭ 7.9 Hz, 2 H, 10-H
and 14-H), 7.00 (m, 1 H, 5-H), 7.16 (t, J ϭ 7.3 Hz, 2 H, 11-H and
13-H), 7.33 (d, J ϭ 8.5 Hz, 1 H, 4-H), 7.45 (m, 1 H, 7-H) and 7.96
(s, 1 H, NH) ppm. 13C NMR: δ ϭ 12.94 (Me), 45.07 (CH2), 110.92
(C-7), 115.36 (C-10), 118.60 (C-12), 129.30 (C-11), 130.80 (C-5),
131.33 (C-4), 136.94 (C-7a), 137.48 (C-6), 145.05 (C-9), 147.78 (C-
3a) and 165.12 (C-2) ppm. C17H19N3S (297.42): calcd. C 68.65, H
6.44, N 14.13; found C 68.81, H 6.67, N 14.27.
6-Methyl-2-phenylamino-1,3-benzothiazole (8) and 6-Methyl-3-phen-
yl-2-phenylimino-1,3-benzothiazoline (9): Elution with ether/pen-
nitrobenzothiazole, this method could also be a valuable tane (1:4) afforded 9 and then 8.
1514  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 1509Ϫ1516

Triphenylbismuth Diacetate and Copper Diacetate Phenylation System
FULL PAPER
1
8: 0.11 g; 12%; m.p. 154Ϫ155 °C. H NMR: δ ϭ 2.37 (s, 3 H, Me),
H, 10-H and 14-H), 7.03 (m, 1 H, 7-H), 7.06 (t, J ϭ 7.4 Hz, 1 H,
7.02 (t, J ϭ 7.3 Hz, 1 H, 12-H), 7.14 (m, 1 H, 5-H), 7.36 (t, J ϭ 12-H), 7.30 (t, J ϭ 7.8 Hz, 2 H, 11-H and 13-H), 7.46 (t, J ϭ 7.7
7.5 Hz, 2 H, 11-H and 13-H), 7.48 (d, J ϭ 8.1 Hz, 1 H, 4-H), 7.55 Hz, 1 H, 18-H), 7.49 (d, J ϭ 7.6 Hz, 2 H, 16-H and 20-H) and
(m, 1 H, 7-H), 7.76 (d, J ϭ 7.8 Hz, 2 H, 10-H and 14-H) and 10.38
7.58 (t, J ϭ 7.7 Hz, 2 H, 17-H and 19-H) ppm. 13C NMR: δ ϭ
109.59 (C-7), 110.80 (C-4), 113.00 (C-5), 121.56 (C-10), 123.95 (C-
(s, 1 H, NH) ppm. 13C NMR: δ ϭ 20.89 (Me), 117.66 (C-10),
118.90 (C-4), 120.93 (C-7), 121.89 (C-12), 126.97 (C-5), 128.99 (C- 7a), 123.95 (C-12), 128.64 (C-16), 128.91 (C-18), 129.53 (C-11),
11), 130.07 (C-7a), 131.57 (C-6), 140.75 (C-9), 150.03 (C-3a) and 130.20 (C-17), 136.86 (C-15), 137.68 (C-3a), 151.53 (C-9), 156.71
160.82 (C-2) ppm. C14H12N2S (240.32): calcd. C 69.97, H 5.03, N
11.66; found C 69.71, H 5.11, N 11.82.
(C-2) and 158.56 (C-6) ppm. C19H13FN2S (320.38): calcd. C 71.23,
H 4.09, N 8.74; found C 70.85, H 3.91, N 8.74.
1
9: 0.19 g; 15%; m.p. 150Ϫ151 °C. H NMR: δ ϭ 2.28 (s, 3 H, Me),
2-Phenylamino-1,3-thiazole (17) and 3-Phenyl-2-phenylimino-1,3-
thiazoline (18): Elution with ether/pentane (1:4) afforded 18 and
then 17, with 1.1 equiv. of Bi reagent.
6.51 (d, J ϭ 8.2 Hz, 1 H, 4-H), 6.95 (d, J ϭ 8.2 Hz, 2 H, 10-H and
14-H), 7.00 (m, 1 H, 5-H), 7.06 (t, J ϭ 7.4 Hz, 1 H, 12-H), 7.33 (t,
J ϭ 7.8 Hz, 2 H, 11-H and 13-H), 7.37 (m, 1 H, 7-H), 7.52 (t, J ϭ
7.4 Hz, 1 H, 18-H), 7.55 (d, J ϭ 7.8 Hz, 2 H, 16-H and 20-H) and
7.63 (t, J ϭ 7.8 Hz, 2 H, 17-H and 19-H) ppm 13C NMR: δ ϭ
20.47 (Me), 109.90 (C-4), 121.03 (C-10), 122.80 (C-7), 122.80 (C-
7a), 123.45 (C-12), 127.17 (C-5), 128.60 (C-16), 128.60 (C-18),
129.54 (C-11), 129.96 (C-17), 131.67 (C-6), 136.69 (C-15), 151.00
(C-9), 138.42 (C-3a) and 156.07 (C-2) ppm. C20H16N2S (316.42):
calcd. C 75.92, H 5.10, N 8.85; found C 75.59, H 4.88, N 8.77.
17: 0.23 g; 33%; m.p. 127Ϫ128 °C ref.[24] 128Ϫ129 °C. 1H NMR:
δ ϭ 7.23 (d, J ϭ 3.6 Hz, 1 H, 4-H), 6.88 (d, J ϭ 3.6 Hz, 1 H, 5-
H), 7.62 (d, J ϭ 7.7 Hz, 2 H, 8-H and 12-H), 7.28 (t, J ϭ 7.5 Hz,
2 H, 9-H and 11-H), 6.91 (t, J ϭ 7.1 Hz, 1 H, 10-H) and 10.15 (s,
1 H, NH) ppm. 13C NMR: δ ϭ 108.32 (C-5), 116.69 (C-8), 120.96
(C-10). 128.88 (C-9), 138.80 (C-4), 141.30 (C-7) and 163.84 (C-2)
ppm. C9H8N2S (176.24): calcd. C 61.33, H 4.58, N 15.90; found C
61.01, H 4.28, N 16.
6-Ethoxy-2-phenylamino-1,3-benzothiazole (11) and 6-Ethoxy-3-phe-
nyl-2-phenylimino-1,3-benzothiazoline (12): Elution with ether/pen-
tane (1:4) afforded 12 and then 11.
1
18: 0.29 g; 29%; m.p. 124Ϫ125 °C. H NMR: δ ϭ 7.24 (d, J ϭ 5.1
Hz, 1 H, 4-H), 6.38 (d, J ϭ 5 Hz, 1 H, 5-H), 6.94 (d, J ϭ 7.4 Hz,
2 H, 8-H and 12-H), 7.31 (t, J ϭ 8.1 Hz, 2 H, 9-H and 11-H), 7.01
(t, J ϭ 7.3 Hz, 1 H, 10-H), 7.64 (d, J ϭ 7.4 Hz, 2 H, 14-H and 18-
H), 7.48 (t, J ϭ 8.1 Hz, 2 H, 15-H and 17-H) and 7.33 (t, J ϭ 7.2
Hz, 1 H, 16-H) ppm. 13C NMR: δ ϭ 99.41 (C-5), 121.10 (C-8),
123.08 (C-10), 125.19 (C-14), 126.92 (C-16), 128.32 (C-4), 129.15
(C-9), 129.68 (C-15), 138.62 (C-13), 151.82 (C-7) and 157.41 (C-2)
ppm. C15H12N2S (252.33): calcd. C 71.40, H 4. 79, N 11.10; found
C 71.29, H 4.68, N 10.90.
1
11: 0.13 g; 13%; m.p. 135 °C. H NMR: δ ϭ 1.36 (t, J ϭ 7 Hz, 3
H, Me), 4.09 (q, J ϭ 7 Hz, 2 H, OϪCH2), 6.93 (m, 1 H, 5-H), 7.02
(t, J ϭ 7.3 Hz, 1 H, 12-H), 7.35 (t, J ϭ 7.4 Hz, 2 H, 11-H and 13-
H), 7.36 (m, 1 H, 7-H), 7.49 (d, J ϭ 8.7 Hz, 1 H, 4-H), 7.73 (d,
J ϭ 7.7 Hz, 2 H, 10-H and 14-H) and 9.90 (s, 1 H, NH) ppm. 13C
NMR: δ ϭ 14.10 (Me), 63.66 (CH2), 106.19 (C-7), 113.92 (C-5),
117.59 (C-10), 119.12 (C-4), 121.37 (C-12), 128.26 (C-11), 130.82
(C-7a), 140.58 (C-9), 145.89 (C-3a), 154.21 (C-6) and 159.78 (C-2)
ppm. C15H14N2OS (270.35): calcd. C 66.64, H 5.22, N 10.36; found
C 66.44, H 5.20, N 9.97.
X-ray Crystallographic Study: The X-ray diffraction data were
measured at room temperature on an BrukerϪNoniusϪKappa
CCD diffractometer with graphite-monochromated Mo-Kα (λ ϭ
1
12: 0.18 g; 14%; m.p. 121 °C. H NMR: δ ϭ 1.28 (t, J ϭ 6.9 Hz, 3
[25]
˚
0.71073 A) radiation.
A set of 90 frames was measured for 14
H, Me), 3.95 (q, J ϭ 7 Hz, 2 H, OCH2), 6.51 (d, J ϭ 8.9 Hz, 1 H,
4-H), 6.75 (m, 1 H, 5-H), 6.94 (d, J ϭ 7.4 Hz, 2 H, 10-H and 14-
H), 7.04 (t, J ϭ 7 Hz, 1 H, 12-H), 7.22 (m, 1 H, 7-H), 7.31 (t, J ϭ
8.1 Hz, 2 H, 11-H and 13-H), 7.45 (t, J ϭ 7.3 Hz, 1 H, 18-H), 7.53
(d, J ϭ 7.5 Hz, 2 H, 16-H and 20-H) and 7.60 (t, J ϭ 7.8 Hz, 2 H,
17-H and 19-H) ppm. 13C NMR: δ ϭ 14.81 (Me), 63.91 (CH2),
109.14 (C-7), 110.74 (C-4), 113.37 (C-5), 121.24 (C-10), 123.55 (C-
12), 128.67 (C-18), 128.74 (C-16), 129.93 (C-11), 130.08 (C-17),
137.14 (C-3a), 151.37 (C-9), 155.31 (C-6), 155.84 (C-2) and 160.16
(C-6) ppm. C21H18N2OS (346.45): calcd. C 72.80, H 5.24, N 8.09;
found C 72.53, H 5.01, N 8.05.
and 15 through a 180° scan in the following conditions: 2° steps,
120 seconds per frame repeated twice. Lorentz and polarisation
corrections were applied to the raw data, which were not corrected
for absorption.[26] The structures were solved by direct methods
using SIR92.[27] All non-hydrogen atoms were refined aniso-
tropically through cycles of full-matrix least-squares using
Maxus.[28]
Crystal Data of 14: White prisms (0.2 ϫ 0.2 ϫ 0.1) of C13H9FN2S,
˚
˚
M ϭ 244.29, triclinic, a ϭ 3.9808(2) A, b ϭ 11.1672(9) A, c ϭ
3
˚
˚
12.545(1) A, β ϭ 94.600(5)°, V ϭ 551.54(7) A , Z ϭ 2, space group:
P
Ϫ1, Dcalcd. ϭ 1.471 gcmϪ3. θmax. ϭ 26.33°. Unique reflections used
6-Fluoro-2-phenylamino-1,3-benzothiazole (14) and 6-Fluoro-3-phe-
nyl-2-phenylimino-1,3-benzothiazoline (15): Elution with ether/pen-
tane (1:9) afforded 15 and then elution with ether/pentane (1:4)
gave 14.
were 2020 with R(F) ϭ 0.035 (1702 refl. Ͼ 3σ(I)], and wR(F2) ϭ
0.048 (w ϭ 1/(σ2(F2o) ϩ 0.03F2o)].
Crystal Data of 15: White prism crystals (0.2 ϫ 0.2 ϫ 0.1) of
˚
1
C19H13FN2S, M ϭ 320.39, monoclinic, a ϭ 22.231(1) A, b ϭ
14: 0.15 g; 15%; m.p. 156 °C. H NMR: δ ϭ 7.04 (t, J ϭ 7.4 Hz, 1
3
˚
˚
˚
5.5046(1) A, c ϭ 26.976(1) A, β 109.684(1)°, V ϭ 3108.2(2) A ,
H, 12-H), 7.13 (m, 1 H, 5-H), 7.36 (t, J ϭ 7.6 Hz, 2 H, 11-H and
13-H), 7.57 (dd, J ϭ 4.8 Hz and 8.3, 1 H, 4-H), 7.63 (m, 1 H, 7-
H), 7.74 (d, J ϭ 7.3 Hz, 2 H, 10-H and 14-H) and 10.08 (s, 1 H,
NH) ppm. 13C NMR: δ ϭ 107.10 (C-7), 112.70 (C-5), 117.90 (C-
10), 119.31 (C-4), 121.81 (C-12), 128.32 (C-11), 130.86 (C-7a),
140.44 (C-9), 148.37 (C-3a), 157.62 (C-6) and 161.44 (C-2) ppm.
C13H9FN2S (244.29): calcd. C 63.92, H 3.71, N 11.47; found C
64.01, H 3.73, N 11.05.
Z ϭ 8, space group: calcd. C2/c, Dcalcd. ϭ 1.369 gcmϪ3. θmax.
ϭ
26.33°. Unique reflections used were 2677 with R(F) ϭ 0.042 [2274
refl. Ͼ 3σ(I)], and wR(F2) ϭ 0.054 [w ϭ 1/(σ2(F2o) ϩ 6F2o)].
CCDC-214417 and -214418 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; Fax: (internat.) ϩ44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk].
1
15: 0.28 g; 22%; m.p. 138 °C. H NMR: δ ϭ 6.56 (dd, J ϭ 4.3 Hz
and 8.8 Hz, 1 H, 4-H), 6.80 (m, 1 H, 5-H), 6.98 (d, J ϭ 7.6 Hz, 2
Eur. J. Org. Chem. 2004, 1509Ϫ1516
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1515

A. Miloudi, D. El-Abed, G. Boyer, J. P. Finet, J. P. Galy, D. Siri
FULL PAPER
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1516
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1509Ϫ1516