A new synthesis of chloroheterocycles via metal-halogen exchange between trichloroacetyl derivatives and heteroaromatic lithium and Grignard reagents

Article abstract of DOI:10.1016/S0022-328X(99)00363-0

The reaction between 2-lithio derivatives of aromatic azaheterocycles and trichlorocetyl derivatives rapidly produces the corresponding 2-chloro derivatives in high yields through a metal-halogen exchange mechanism. The use of ethyl trichloroacetate can give better results with respect to those obtained with trichloroacetyl chloride, which probably involves dichloroketene formation. The reaction with Grignard reagents is more complex: in fact, 2-benzothiazolylmagnesium chloride with ethyl trichloroacetate or trichloroacetyl chloride gives 2-chlorobenzothiazole together with considerable amounts of ethyl 1,3-benzothiazole-2-carboxylate or 2-benzothiazolyl dichloromethyl ketone, respectively.

Full text of DOI:10.1016/S0022-328X(99)00363-0

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 588 (1999) 155–159
A new synthesis of chloroheterocycles via metalꢀhalogen exchange
between trichloroacetyl derivatives and heteroaromatic lithium and
Grignard reagents
Carla Boga *, Erminia Del Vecchio, Luciano Forlani, Lilia Milanesi,
Paolo Edgardo Todesco
Dipartimento di Chimica Organica ‘A. Mangini’, V. le Risorgimento 4, I-40136 Bologna, Italy
Received 15 April 1999
Abstract
The reaction between 2-lithio derivatives of aromatic azaheterocycles and trichlorocetyl derivatives rapidly produces the
corresponding 2-chloro derivatives in high yields through a metalꢀhalogen exchange mechanism. The use of ethyl trichloroacetate
can give better results with respect to those obtained with trichloroacetyl chloride, which probably involves dichloroketene
formation. The reaction with Grignard reagents is more complex: in fact, 2-benzothiazolylmagnesium chloride with ethyl
trichloroacetate or trichloroacetyl chloride gives 2-chlorobenzothiazole together with considerable amounts of ethyl 1,3-benzo-
thiazole-2-carboxylate or 2-benzothiazolyl dichloromethyl ketone, respectively. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Chlorination; Trichloroacetyl chloride; Grignard reagents; Lithium compounds; Aromatic heterocycles; Metalꢀhalogen exchange
have been obtained after treatment with electrophiles,
but very few examples of synthesis of chloroderivatives
via metalꢀchlorine exchange from lithium compounds
or Grignard reagents have been reported so far [3].
In the literature, some reactions involving
metalꢀhalogen exchange in which trichloroacetyl
derivatives were used as ‘positive chloro ion’ donors
have been reported: the reaction between isopropyl-
magnesium chloride and ethyl trichloroacetate was ex-
ploited to produce, in high yield, the corresponding
dichloroacetyl enolate [4], whereas 2-thienyl-lithium re-
acts with trichloroacetonitrile to give 2-chlorothiophene
in 40% yield [5].
These findings prompted us to perform the reaction
between lithium and Grignard derivatives of some
azaaromatics and trichloroacetyl derivatives, in order to
check if it was possible to obtain the corresponding
chloroheterocycles by a simple and direct procedure.
Here we report the obtained results which, in the case
of the reaction between 2-benzothiazolylmagnesium
chloride and trichloroacetyl derivatives, are unexpected
and allow us to propose a reaction mechanism.
1. Introduction
Haloderivatives of heterocycles like thiazoles, oxa-
zoles, imidazoles and their benzoderivatives are inter-
esting compounds as useful intermediates for the
preparation of a wide number of substances, most of
these of biological interest. Classical methods to obtain
these compounds [1], such as the Sandmeyer reaction
on aminoprecursors or the direct halogenation under
drastic conditions, are often laborious and limited in
yield and, in the latter case, in regioselectivity. For
example, 1,3-imidazoles, 1,3-oxazoles and 1,3-thiazoles
suffer electrophilic attack at either the 5 or a combina-
tion of both 4 and 5 positions, whereas benzimidazoles
and benzothiazoles also undergo electrophilic substitu-
tion in the benzenoid moiety of the molecule [1,2].
Alternatively, the metalation of these compounds oc-
curs exclusively in position 2 and several derivatives
* Corresponding author. Tel.: +39-51-2093616; fax: +39-51-
2093654.
E-mail address: boga@ms.fci.unibo.it (C. Boga)
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00363-0

156
C. Boga et al. / Journal of Organometallic Chemistry 588 (1999) 155–159
carbonyl group. The ‘positive chloro ion’ extraction
2. Results and discussion
might occur through a pathway involving the formation
of dichloroketene, favored by the departure of a good
leaving group such as the chloride ion (Scheme 3).
The presence of 7 in the reaction mixture supports
this mechanism because the dichloroketene could react
with the remaining Grignard reagent 2 to give an
enolate that, after quenching, tautomerizes to the stable
form 7. Since 4 and 7 can also arise from a halo-
genꢀmetal exchange between 2 and 8, we performed the
reaction between these reagents in THF at 0°C, but we
found neither 4 nor 7 in the reaction mixture: this result
agrees with the proposed mechanism of Scheme 3.
The reaction depicted in Scheme 2 was carried out in
THF under different experimental conditions; the re-
sults obtained are collected in Table 1.
Reactions carried out at 0°C and at room tempera-
ture were immediate and gave mixtures of products
with prevalence of 4. At room temperature, only 2-
chlorobenzothiazole (4) and ketone 7 were recovered.
When an excess of organometallic reagent was used
(entry 3), a small amount of bis(2-benzothiazole) (9)
was detected.
The reaction (Scheme 1) between 2-benzothiazolyl-
magnesium chloride (2) (prepared from benzothiazole
(1) and ethylmagnesium chloride) and ethyl trichloroac-
etate (3) (1:1 molar ratio) afforded a mixture of prod-
ucts, with prevalence of 2-chlorobenzothiazole (4)
(57%) and ethyl 1,3-benzothiazole-2-carboxylate (5)
(25%), coming from an attack to carboxylic carbon
followed by elimination of trichloromethyl anion.
This fact allowed us to perform the reaction between
2 and trichloroacetyl chloride (6), bearing a better
leaving group than 3, in order to increase the yield of 4.
The reaction (Scheme 2) was carried out at 0°C with
equimolar amount of 2 respect to 6 (Table 1, entry 1).
After about 10 min, the GC–MS analysis of the
reaction mixture revealed the presence of several prod-
ucts, some of them identified as 4 (62%), 2-benzothia-
zolyl dichloromethyl ketone (7) (18%) and
2-benzothiazolyl trichloromethyl ketone 8 (20%). The
structure of products was ascertained by spectroscopic
analyses of isolated compounds and/or by comparison
with authentic samples (see Section 3).
The recovery of both 4 and 8 is due to the competi-
Lowering the reaction temperature to −70°C, a low
reactivity and an increase in the yield of addition
product 8, with respect to 4 and 7, were observed (entry
4); after 24 h, the temperature being allowed to stand,
many unidentified by-products were present in the reac-
tion mixture.
tion between the two reactive groups
—
trichloromethyl and carbonyl — present on 6: 2-
chlorobenzothiazole (4) arises from a halogenꢀmetal
exchange reaction between 2 and the trichloromethyl
group, whereas 8 comes from the usual 1,2 attack to
Scheme 1.
Scheme 2.
Table 1
Reaction between 2 and 6
Entry
Molar ratio
Reaction
Productsa
2:6
Temperature (°C)
Time
1
4
7
8
9
1
2
3
4
1:1
1:1
2:1
2:1
0
r.t.
10 min
10 min
30 min
4 h
–
–
–
62
62
75
69
16
18
25
16
4
20
–
3
–
–
6
tr.
0 to r.t.
−70 to −10
18
a Relative ratio from GC–MS analysis.

C. Boga et al. / Journal of Organometallic Chemistry 588 (1999) 155–159
157
Scheme 3.
These data clearly indicate that the temperature plays
an important role in driving the regiochemistry of the
attack towards the 1,2 addition to carbonyl group or
the metalꢀhalogen interchange. In addition, the data
reported above show that the reactions between the
Grignard reagent 2 and trichloroacetyl derivatives were
unpredictable: it should be noted that the use of the
ester or of the acyl chloride generates different behav-
iors, with formation of different by-products.
This fact prompted us to perform the reaction be-
tween trichloroacetyl derivatives and 2-lithio deriva-
tives, to increase the yield of metalꢀhalogen interchange
product and to avoid side reactions (Scheme 4).
Reactions between 2-lithiobenzothiazole (10) and
trichloroacetyl derivatives were carried out in THF at
−70°C, with different molar ratios of the reagents. The
obtained results are shown in Table 2, together with
those from the reactions between lithium derivatives of
heterocycles 11, 13, 15, 17 and trichloroacetylchloride.
The reactions gave, after a few minutes, 2-chlorohete-
rocycles in satisfactory yield: this chlorinating method
is better than classical methods [1].
2-Lithiobenzothiazole (10) gave quantitatively the
metalꢀchlorine exchange product 4, also using the
trichloroester 3 or the trichloroacetic anhydride (entries
1–3). The better result obtained using ethyl trichloroac-
etate with respect to the use of trichloroacetyl chloride
can be explained considering that, with the latter
reagent, the formation of the very reactive
dichloroketene may interfere. Consequently, the behav-
ior of ethyl trichloroacetate could be generalized, mak-
ing it an easy reagent for synthetic purposes. When an
excess of 10 was used (entries 4, 5), 4 was obtained
together with a considerable amount of 9 and only
traces of 7, detectable in GC–MS analysis.
For comparison, we also performed the reaction
between 2-lithiobenzothiazole (10) and N-chlorosuccin-
imide: after 1 h at −70°C the GC–MS analysis of the
reaction mixture showed conversion to 4 in 68% yield.
In the case of N-methylimidazole (17) the reaction
afforded the corresponding chloroderivative in better
yield with respect to that reported in a similar reaction
with N-chlorosuccinimide as chlorinating agent [6]. The
low yield obtained in the case of 2-chlorobenzoxazole
(14) is probably due to the low stability of the 2-lithio
precursor, which is in equilibrium with its opened form
[7].
In conclusion, the reaction between the Grignard
reagent 2 and trichloroacetyl derivatives gave a mixture
of products from different reaction pathways, whereas
using the corresponding lithium derivative 10 a com-
plete regioselectivity toward the ‘positive halogen ion’
extraction was observed. This reaction was also ex-
tended to other heterocycles, giving the corresponding
chloroderivatives in good yields. This method can be
considered an efficient non-classical halogenation route
to chloroheterocycles.
3. Experimental
3.1. General
1H- and 13C-NMR spectra were recorded on a Varian
Gemini spectrometer at 300 and 75.46 MHz, respec-
1
tively, in CDCl3 (l=7.27 ppm for H-NMR and 77.20
ppm for 13C-NMR). J values are given in Hz. IR
spectra were recorded on a Perkin–Elmer model 1600
FT-IR spectrophotometer. MS spectra were recorded at
Scheme 4.

158
C. Boga et al. / Journal of Organometallic Chemistry 588 (1999) 155–159
Table 2
Reactions between lithio heterocycles and Cl3CCOZa
Entry
Heterocycle
Cl3CCOZ
Molar ratio
Reaction time
Product (yield %)
1
2
3
4
5
6
7
8
9
1
1
1
1
Cl3CCOOEt
(Cl3CCO)2O
Cl3CCOCl
Cl3CCOCl
Cl3CCOCl
Cl3CCOCl
Cl3CCOCl
Cl3CCOCl
Cl3CCOCl
1/1
1/1
1/1
2/1
3/1
1/1
1/1
1/1
1/1
30 min
30 min
30 min
20 min
180 min
30 min
72 h
4 (94b,c
4 (95b,c
)
)
4 (75d, 82b,c
4 (50d)
)
1
4 (50c,e
)
11
13
15
17
12 (87f)
14 (20c, 15d)
16 (90d)
30 min
30 min
18 (70c,f
)
a Reactions carried out in anhydrous THF, at −70°C.
b Conversion.
c Yield from GC–MS.
d Yield from FC.
e In this case also 30% of bis(2-benzothiazole) (9) was recovered.
f Conversion calculated from 1H-NMR spectra.
an ionization voltage of 70 eV on a VG 7070 E
spectrometer. GC–MS analyses were performed on an
HP-5890 gas chromatograph equipped with a methyl
silicone capillary column and an HP-5970 mass detec-
tor. Chromatographic purifications were carried out on
columns packed with silica gel Kieselgel (Merck, 230–
400 mesh) at medium pressure. Thin-layer chromatog-
The solvents were removed in vacuum. Flash-chro-
matography of the residue (eluant: 4:1 light petroleum–
diethyl
ether)
gave
0.241
g
(57%)
of
2-chlorobenzothiazole (4), and 0.130 g (25%) of ethyl
1,3-benzothiazole-2-carboxylate (5).
3.3. Reactions between 2-lithio heterocycles and
trichloroacetyl deri6ati6es: typical procedure
raphy was performed on Merck Kieselgel 60 F254
.
Melting points were measured with a Bu¨chi apparatus
and are uncorrected. THF was distilled from sodium
benzophenone ketyl. All the reagents were commercial
samples (Aldrich). Ethylmagnesium chloride was from
Aldrich and was titrated immediately before use by
standard methods [8]. All the reactions were performed
in a flame-dried apparatus under a static atmosphere of
dry nitrogen. 2-Benzothiazolylmagnesium chloride 2
was prepared according to the procedure [9] described
for the preparation of 2-thiazolylmagnesium bromide.
2-Lithio derivatives were prepared as in ref. [2].
Authentic samples of 2-benzothiazolyl dichloromethyl
ketone (7) and 2-benzothiazolyl trichloromethyl ketone
(8) were synthesized from 2-(trimethylsilyl)-benzothi-
azole and the respective acyl chloride, according to
literature procedures [10,11].
To a solution of 0.35 ml (5.0 mmol) of thiazole (11)
in 5 ml of THF, at −70°C, 2.5 ml of n-BuLi (2.5 M in
n-hexane, diluted with 3.0 ml of THF), were added.
After 15 min, 0.56 ml (5.0 mmol) of 6 in 3 ml of THF
were dropped into the orange solution.
After 30 min the reaction was quenched in saturated
aqueous solution of NH4Cl. After extraction with Et2O
the organic layer was washed with brine, dried over
Na2SO4 and concentrated at reduced pressure. 1H-
NMR spectra of the residue showed the presence of 11
and 12 in 13:87 relative ratio.
3.4. Characteristics of obtained compounds
3.4.1. 2-chlorobenzothiazole (4)
1H-NMR (CDCl3), l 7.91 (dd, 1H, J=8.0 Hz, J=
0.6 Hz, 4-H), 7.71 (dd, 1H, J=8.0 Hz, J=0.7 Hz,
7-H), 7.44 (t, 1H, 5-H), 7.38 (t, 1H, 6-H); 13C-NMR
(CDCl3), l 153.0, 150.7, 135.9, 126.4, 125.5, 122.8,
120.9; MS: (m/e) 171, 169, 134.
3.2. Reactions between 2 and trichloroacetyl
deri6ati6es: typical procedure
To a solution of 2 (2.5 mmol in 10 ml of THF),
cooled at 0°C, a solution of ethyl trichloroacetate (3)
(2.5 mmol in 5 ml of THF) was added. The reaction
was monitored by TLC and GC–MS analyses. When
the spot (or the peak) corresponding to benzothiazole
(1) disappeared, the reaction mixture was treated with
saturated aqueous solution of NH4Cl. After extractions
with diethyl ether and CH2Cl2, the organic layers were
washed with brine and dried over anhydrous Na2SO4
3.4.2. Ethyl 1,3-benzothiazole-2-carboxylate (5)
M.p.:70–71°C (from methanol), lit. [12]: 71°C; H-
1
NMR (CDCl3), l 8.30–8.25 (m, 1H, 4-H or 7-H),
8.02–7.97 (m, 1H, 4-H or 7-H), 7.60 (td, 1H, J=7.2
Hz, J=1.6 Hz, 5-H or 6-H), 7.55 (td, 1H, J=7.2 Hz,
J=1.4 Hz, 5-H or 6-H), 4.58 (q, 2H, J=7.1 Hz, CH2),
1.50 (t, 3H, CH3). 13C-NMR (CDCl3), l 160.6, 158.5,

C. Boga et al. / Journal of Organometallic Chemistry 588 (1999) 155–159
159
153.2, 136.7, 127.5, 127.0, 125.5, 122.0, 63.1, 14.3.
123.0, 122.5, 119.2, 109.2, 30.4. MS (m/e): 168, 166,
131, 129.
MS: (m/e) 207 [M+], 162, 135. IR(CHCl3) w: 1735
cm−1
.
3.4.9. 2-Chloro-1-methyl imidazole (18)
1H-NMR (CDCl3), l: 6.94 (d, 1H, J=1.4 Hz), 6.86
(d, 1H, J=1.4 Hz), 3.57 (s, 3H, CH3). 13C-NMR
(CDCl3), l: 131.0, 126.7, 121.4, 32.3. MS (m/e): 118,
116, 89.
3.4.3. 2-Benzothiazolyl dichloromethyl ketone (7)
M.p.: 117–118°C (from methanol); lit. [10]: 118°C.
1H-NMR (CDCl3), l 8.25–8.21 (m, 1H, 4-H or 7-H),
8.04–8.00 (m, 1H, 4-H or 7-H), 7.67–7.58 (m, 2H, 5-H
and 6-H), 7.44 (s, 1H, CHCl2). 13C-NMR (CDCl3), l
181.1, 161.0, 153.3, 138.2, 128.9, 127.8, 126.2, 122.7,
66.1. MS (m/e): 245, 247, 162, 134. IR (CHCl3): 1720
Acknowledgements
cm−1
.
Investigation supported by University of Bologna
(funds for selected research topics AA. 1997–99), Min-
istero dell’Universita` e della Ricerca Scientifica e Tec-
nologica (MURST, Roma) and Consiglio Nazionale
delle Ricerche (CNR, Roma).
3.4.4. 2-Benzothiazolyl trichloromethyl ketone (8)
M.p.: 84.5–86.6°C (from methanol). 1H-NMR
(CDCl3), l: 8.33–8.29 (m, 1H, 4-H or 7-H), 8.06–8.02
(m, 1H, 4-H or 7-H), 7.67–7.61 (m, 2H, 5-H and 6-H).
13C-NMR (CDCl3), l 175.4, 157.8, 153.4, 137.6, 128.8,
127.6, 126.4, 122.1, 93.5; HRMS: C9H4Cl3NOS requires
278.9072; found: m/e 278.9079; IR (CHCl3) w: 1712
References
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3.4.5. Bis(2-benzothiazole) (9)
1H-NMR (CDCl3), l: 8.90 (d, 2H, J=8.8 Hz), 8.00
(d, 2H, J =7.2 Hz), 7.60–7.42 (m, 4H). MS (m/e): 268
[M+], 134, 108.
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3.4.6. 2-Chlorothiazole (12)
1H-NMR (CDCl3), l: 7.59 (d, 1H, J=3.7 Hz, H-4),
7.28 (d, 1H, J=3.7 Hz, H-5). 13C-NMR (CDCl3), l:
151.9, 141.5, 121.3. MS (m/e): 121, 119, 84.
3.4.7. 2-Chlorobenzoxazole (14)
1H-NMR (CDCl3), l: 7.67 (dd, 1H, J=6.1 Hz,
J=3.2 Hz), 7.50 (dd, 1H, J=6.1 Hz, J=3.6 Hz),
7.40–7.33 (m, 2H). 13C-NMR (CDCl3), l: 151.8, 151.1,
141.3, 125.6, 125.2, 119.9, 110.5. MS (m/e): 155, 153,
125, 90, 63.
3.4.8. 2-Chloro-1-methyl benzimidazole (16)
M.p.: 115–116°C (from light petroleum); lit. [13]:
114–116°C. 1H-NMR (CDCl3), l 7.70–7.60 (m, 1H,
4-H), 7.30–7.18 (m, 3H, 5-H, 6-H, 7-H), 3.73 (s, 3H,
NCH3). 13C-NMR (CDCl3), l 141.5, 140.8, 135.5,
.