Ortho-selective nucleophilic aromatic substitution reactions of polyhaloanilines with potassium/sodium O-ethyl xanthate: A convenient access to halogenated 2(3H)-benzothiazolethiones

Article abstract of DOI:10.1021/jo049056s

Polyhaloanilines bearing an ortho halogen atom undergo smooth nucleophilic aromatic substitution reactions with anionic sulfur nucleophiles at relatively mild temperatures (95-120 °C). These reactions are very efficient and highly ortho-selective. With potassium/sodium O-ethyl xanthate as a nucleophile, subsequent cyclization follows to afford halogenated 2(3H)-benzothiazolethiones (2-mercaptobenzothiazoles) in high yields.

Full text of DOI:10.1021/jo049056s

TABLE 1. Rea ction s of 2-Ha lo-4-flu or oa n ilin es w ith
P ota ssiu m /Sod iu m O-Eth yl Xa n th a te
Or th o-Selective Nu cleop h ilic Ar om a tic
Su bstitu tion Rea ction s of P olyh a loa n ilin es
w ith P ota ssiu m /Sod iu m O-Eth yl Xa n th a te:
A Con ven ien t Access to Ha logen a ted
2
(3H)-Ben zoth ia zoleth ion es
Lei Zhu* and Mingbao Zhang*
entry aniline
X
R
M
temp (°C) time (h) yield (%)a
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1c
1c
1c
1d
1d
F
F
H
H
H
H
H
H
H
Me
K
K
K
K
K
K
Na
K
80
95
4
4
3
3
3
3
4
3
3
NRb
Department of Chemistry Research, Bayer Research Center,
3a , 91
3a , 99
4
00 Morgan Lane, West Haven, Connecticut 06516
Br
Cl
Cl
Cl
Cl
F
105
100
120
100
100
100
100
b
NR
c
c
mingbao.zhang.b@bayer.com
Received J une 4, 2004
3a , 55
3a , 94
3a , 96
3d , 15
3d , 70
d
F
Me Na
Abstr a ct: Polyhaloanilines bearing an ortho halogen atom
undergo smooth nucleophilic aromatic substitution reactions
with anionic sulfur nucleophiles at relatively mild temper-
atures (95-120 °C). These reactions are very efficient and
highly ortho-selective. With potassium/sodium O-ethyl xan-
thate as a nucleophile, subsequent cyclization follows to
afford halogenated 2(3H)-benzothiazolethiones (2-mercap-
tobenzothiazoles) in high yields.
a
Isolated yield. b No reaction; starting aniline was recovered.
c 1
H NMR yield, calculated on the basis of integration data of
product and starting material peaks. d Also present was 2.2 equiv
of 18-crown-6.
SCHEME 1
Simple halogenated anilines are considered poor sub-
strates for aromatic nucleophilic halogen substitution
reactions due to strong deactivating effects of the amino
group.1 Nonetheless, under certain conditions such as
metal mediation, simple haloanilines have been shown
to undergo halogen displacement reactions with alkyl and
,2
zothiazolethiones (6-substituted 2-mercaptobenzothia-
zoles). While the potential mechanism for the benzothia-
zolethione formation was not discussed in the article, it
is conceivable that the reaction proceeded via a nucleo-
philic halogen substitution reaction with the xanthate
anion followed by a subsequent cyclization step (Scheme
6
3
aryl thiolates. In one instance, simply heating di- and
trichloroanilines with potassium phenyl thiolate at high
temperature (140-190 °C) is sufficient to effect such a
substitution reaction to afford bis- and tris(phenylthio)-
4
anilines in low to moderate yields. While these reactions
1
). We were intrigued by the possibility of an ortho-
are useful in providing ready access to alkyl and aryl-
thioanilines, the necessity of using heavy metal reagents
or the unusually high reaction temperatures coupled with
the lack of regioselectivity have prompted us to explore
alternate reagents/conditions for halogen displacements
in reactions with polyhaloanilines. We are primarily
interested in regioselective halogen displacement in these
reactions under relatively mild conditions.
selective halogen displacement by the xanthate salt in
polyhaloanilines, which would provide a ready access to
halogentaed 2-mercaptobenzothiazoles. In this paper, we
report that polyhaloanilines bearing an ortho halogen
atom undergo smooth ortho-selective nucleophilic halogen
substitution reactions with potassium/sodium O-ethyl
xanthate at relatively mild temperatures (95-120 °C) to
produce halogenated 2-mercaptobenzothiazoles in high
yields.
Potassium/sodium O-ethyl xanthates have received
5
little attention as anionic sulfur nucleophiles in nucleo-
We initially explored reactions of several 2-halo-4-
fluoroanilines 1 with potassium/sodium O-ethyl xanthate
in N,N-dimethylformamide (DMF) under various condi-
tions. The results are summarized in Table 1. With 2,4-
difluoroaniline 1a , no reaction was observed after a
period of 4 h at 80 °C, as the starting aniline was
completely recovered (entry 1, Table 1). However, at 95
°C, after a similar period of time, near complete reaction
was achieved, resulting in the isolation of the cyclized
product benzothiazolethione 3a in 91% yield, in analyti-
cally pure form (entry 2, Table 1). With potassium ethyl
xanthate, 2-bromo-4-fluoroaniline afforded the same ben-
zothiazole product 3a in 99% isolated yield, although at
a slightly higher temperature (105 °C) (entry 3, Table
philic aromatic substitution reactions compared to the
more widely studied thiolates. In one study, heating
4
-alkyl- and alkoxy-2-bromo/chloroanilines with potas-
sium O-ethyl xanthate in DMF at reflux (160 °C) af-
forded, respectively, 6-alkyl- and 6-alkoxy-2(3H)-ben-
(1) For leading references on nucleophilic aromatic substitution
reactions, see: (a) March, J . Advanced Organic Chemistry, 4th ed.;
Wiley: New York, 1992; Chapter 13. (b) Bunnett, J . F.; Zahler, R. E.
Chem. Rev. 1951, 49, 273-412.
(
2) Berliner, E.; Monack, L. C. J . Am. Chem. Soc. 1952, 74, 1574-
1
579.
3) (a) Adams, R.; Reifschneider, W.; Nair, M. D. Croatica Chem.
Acta 1957, 29, 277. (b) Adams, R.; Ferretti, A. J . Am. Chem. Soc. 1959,
(
8
5
2
1, 4927.
(4) Caruso, A. J .; Colley, A. M.; Bryant, G. L. J . Org. Chem. 1991,
6, 862-865.
(
5) (a) Scully, F. E., J r.; Ortega, T. J . Org. Chem. 1989, 54, 2978-
980. (b) Creary, X. Tetrahedron. Lett. 1999, 40, 29-32.
(6) Chaudhuri, N. C. Synth. Commun. 1996, 26, 3783-3790.
1
0.1021/jo049056s CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/10/2004
J . Org. Chem. 2004, 69, 7371-7374
7371

TABLE 2. Rea ctivity Or d er of F , Br , a n d Cl a s Lea vin g Ha logen Atom s
SCHEME 2
1
2
). The 2-chloro analogue is less reactive than both the
-fluoro and 2-bromo substrates. With potassium xan-
thate salt, after 3 h, no reaction at 100 °C and only ca.
0% reaction at 120 °C were observed (entries 4 and 5).
5
However, the reaction was substantially faster (complete
in 3 h at 100 °C) when 2.2 equiv of 18-crown-6 was
present, reaching a level of reactivity comparable to that
of the 2-fluoro analogue (entry 6, Table 1). This same
level of reactivity, with the 2-chloro analogue, can also
be achieved by replacing the potassium salt with the
difluoroaniline with 2.2 equiv of sodium ethanethiolate
in DMF at 90-100 °C afforded the corresponding 2-(eth-
ylthio)-4-fluoroaniline 7 in 98% isolated yield. Its regio-
isomer 8 was not detected. This experiment suggests
that the cyclization step in the xanthate case played no
role in bringing about the ortho selectivity.
9
7
corresponding sodium salt (entry 7, Table 1). Signifi-
cantly, under the same reaction conditions, N-methylated
2
,4-difluoroaniline afforded exclusively, in good yield, the
To establish the scope of the aniline substrates, we
investigated polyhaloanilines with and without an ortho
halogen (9b-j). The reaction was carried out with potas-
sium O-ethyl xanthate in DMF at 120 °C, and the results
are summarized in Table 3. While polyfluoroanilines
bearing an ortho halogen reacted efficiently and ortho-
selectively to produce the corresponding benzothiazole-
thiones 10 (entries 4, 7-11, Table 3), aniline substrates
lacking an ortho-halogen failed to react under the same
conditions (entries 1-3, Table 3). In sharp contrast to
N-methylated benzothiazolethione 3d (entry 9, Table 1).
This result is in sharp contrast to that of the conventional
alkylation method of benzothiazolethione, which yields
a mixture of N- and S-alkylation products, with the latter
being the predominant product. No 4-F displacement
products were observed in any of the reactions in Table
8
1
.
The relative reactivity order of the leaving halogen
atoms was established with 2,4,6-trihaloanilines 4a -c
with both ortho positions occupied by different halogens
2
,4-difluoroaniline, which reacted smoothly with potas-
(
Table 2). The reactivity ratios (F/Br 13:1, F/Cl 100:0, and
Br/Cl 12:1) were estimated by product ratios of 5a /6a ,
b/6a , and 5b/5a , which were calculated on the basis of
sium O-ethyl xanthate at the ortho position (entry 2,
Table 1), the 2,5-difluoro analogue reacted very sluggishly
under similar conditions (entry 5, Table 3). 2,3-Dichlo-
roaniline also reacted at a much slower rate, albeit
cleanly at the ortho position (entry 10, Table 3).
The origin of the regioselectivity is not entirely clear
at this point. It is plausible that precoordination of the
sulfur nucleophile to the amino group of the aniline via
hydrogen bonding is responsible for delivering the nu-
cleophile to the ortho position.10 Hydrogen bonding
between a sulfur anion and the N-H group has been
extensively documented.11 This explanation is reasonable,
particularly as the experimental data have ruled out an
5
1
H NMR integration.
The exclusive ortho selectivity of the nucleophilic
aromatic substitution reactions of polyhaloanilines is not
limited to xanthate salts as nucleophiles where subse-
quent cyclization ensues. Similarly, high ortho selectivity
was also observed when sodium ethanethiolate (NaSEt)
was used as a nucleophile (Scheme 2). Treatment of 2,4-
(
7) The sodium salt is more reactive than the potassium salt in
+
+
this case because Na is a harder Lewis acid compared to K ; thus,
there is more mismatch between Na /S (a soft Lewis base) compared
to K /S . As a result, the S is more exposed for nucleophilic attack,
similar to the crown ether effect.
+
-
+
-
-
(
8) Radha Rani, B.; Bhalerao, U. T.; Rahman, M. F. Synth. Commun.
(9) Small amount of the rearrangement product 2-mercapto-4-fluoro-
N-ethylaniline was also present (<5% estimated by H NMR).
1
1
990, 20, 3045-3052.
7
372 J . Org. Chem., Vol. 69, No. 21, 2004

TABLE 3. Rea ction s of P olyh a loa n ilin es w ith P ota ssiu m O-Eth yl Xa n th a te in DMF
a
1
H NMR yields, calculated on the basis of integration data of product and starting material peaks. Isolated yields are in parentheses.
The isolation procedure was not optimized. No reaction; starting aniline was recovered. c Run at 110 °C with sodium O-ethyl xanthate.
b
initial reaction of the xanthate with the amino group
followed by a cyclization onto the ortho position.12
In summary, we have demonstrated that polyhaloge-
nated anilines bearing an ortho halogen can be good
substrates for nucleophilic aromatic substitution reac-
tions with excellent regioselectivity and efficiency. With
appropriate nucleophiles (e.g., xanthate salts), intramo-
lecular cyclization with the amino group can ensue to
form important heterocycles in high yields.
(10) Precoordination of reactants via noncovalent forces can have
dramatic effects on reactivity by bringing the reactive sites in close
proximity. For a recent example, see: Gatti, F, G.; Leigh, D. A.;
Nepogodiev, S. A.; Slawin, A. M. Z.; Teat, S. J .; Wong, J . K. J . Am.
Chem. Soc. 2001, 123, 5983-5989.
J . Org. Chem, Vol. 69, No. 21, 2004 7373

Exp er im en ta l Section
was stirred for 30 min and filtered under vacuum. The wet cake
was rinsed with water twice and dried to obtain 6-fluoro-1,3-
benzothiazole-2(3H)-thione (3a ) as an off-white solid (19.5 g,
Typ ica l P r oced u r e for Ben zoth ia zole-2(3H)-th ion e F or -
m a tion a s Illu str a ted by th e P r ep a r a tion of 6-F lu or o-1,3-
ben zoth ia zole-2(3H)-th ion e (3a ). 2,4-Difluoroaniline (15.0 g,
1
9
7
2
1
1%): H NMR (DMSO-d
6
) δ 13.80 (s, 1H), 7.65 (d, J ) 8.0, 1H),
) δ 188.78, 158.21 (d, J C-F
38), 137.28, 129.58 (d, J ) 10.9), 114.18 (d, J ) 24.2), 112.86,
.28 (m, 2H); 13C NMR (DMSO-d
)
6
1
2
16.2 mmol, 1.0 equiv) and potassium O-ethyl xanthate (41.0 g,
55.6 mmol, 2.2 equiv) were heated in anhydrous DMF (75 mL)
1
9
08.40 (d, J ) 27.3); F NMR (DMSO-d
MS m/z (MH ) 186. Anal. Calcd for C
6
) δ -118.50 (m). ESI-
at 95 °C (internal temperature) for 4 h under nitrogen. The
reaction mixture was then cooled to room temperature, diluted
with water (150 mL), and acidified to pH 3-4 by adding 1 N
HCl solution (200 mL). The suspension formed on acidification
+
7
H
4
FNS : C, 45.39; H, 2.18;
2
N, 7.56. Found: C, 45.40; H, 2.25, N, 7.54.
Ack n ow led gm en t. We thank Laszlo Musza and J eff
Chin for assistance in NMR analysis and Miao Dai for
providing some experimental help.
(
11) (a) Letcher, T. M.; Bricknell, B. C. J . Chem. Eng. Data 1996,
1, 166-169. (b) Krepps, M. K.; Parkin, S.; Atwood, D. A. Cryst. Growth
Des. 2001, 4, 291-297, and references cited therein.
12) Formation of the benzothiazole heterocycle could also be
expected if the NH group somehow reacted first with the xanthate to
4
(
2
form a dithiocarbamate intermediate that then cyclized onto the ortho
position. To rule out this possibility, aniline and sodium O-ethyl
xanthate was heated in DMF-d at 120 °C in an NMR tube and
7
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information and complete characterization data for com-
pounds 3d , 5a ,b, 6a , 7, and 10d -j. This material is available
free of charge via the Internet at http://pubs.acs.org.
monitored by 1H NMR. No reaction between the aniline and the
xanthate was observed after 6 h (in the absence of a reaction with
aniline, sodium O-ethyl xanthate undergoes slow decomposition under
these conditions). This observation is consistent with the fact that
aniline substrates lacking an ortho halogen were recovered under the
reaction conditions (entries 1-3, Table 3).
J O049056S
7
374 J . Org. Chem., Vol. 69, No. 21, 2004