Novel route to the synthesis of 4-quinolyl isothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2006.01.119

4-Quinolyl isothiocyanates were synthesized in a regiospecific fashion from the corresponding 4-chloroquinolines and silver thiocyanate in refluxing toluene. The products were isolated in quantitative yield and high purity (>95%) by simple filtration and

Full text of DOI:10.1016/j.tetlet.2006.01.119

Tetrahedron Letters 47 (2006) 2161–2164
Novel route to the synthesis of 4-quinolyl isothiocyanates
*
Boyu Zhong, Rima S. Al-Awar, Chuan Shih, John H. Grimes, Jr.,
Michal Vieth and Chafiq Hamdouchi
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 8 December 2005; accepted 23 January 2006
Abstract—4-Quinolyl isothiocyanates were synthesized in a regiospecific fashion from the corresponding 4-chloroquinolines and sil-
ver thiocyanate in refluxing toluene. The products were isolated in quantitative yield and high purity (>95%) by simple filtration and
concentration. Reactivity and mechanism of the reaction are discussed. The new approach would provide a new mean which had
been lacking for the synthesis of functionalized 4-quinolinyl isothiocyanate.
Ó 2006 Elsevier Ltd. All rights reserved.
Isothiocyanate is a very useful building block in syn-
thetic chemistry, especially for constructing heterocycles
such as thiodiazole, triazole, thiouracil, thioquinazo-
for compounds with pharmacological importance. Our
efforts using reported transformations starting from 4-
aminoquinoline had led to failure. We turned to the di-
rect replacement of the chlorine atom in 4-chloroquino-
lines with inorganic thiocyanates, inspired by the
1
lone, thiopyrimidine, etc. It has been proven to be a
key reagent in Edman peptide sequencing and other bio-
2
8
logical assays of DNA and protein. Due to their syn-
previous work of Kristian. Our use of silver thiocyanate
3
thetic and biological importance, several methods for
turned out to be successful. In a typical reaction, a mix-
ture of 4-chloroquinoline and silver thiocyanate in anhy-
4
,5
the preparation of isothiocyanate have been reported.
9
Although these methods were shown to be highly effec-
tive in alkyl and homocyclic systems, they suffered from
the limited scope such as their applicability to hetero-
cyclic systems. In fact, the synthesis of N-heterocyclic
drous toluene was rapidly stirred at 110 °C for 12 h.
The reaction mixture was filtered and the filtrate was
concentrated under vacuum to provide 4-quinolyl isothio-
1
0
cyanate as an off-white solid in quantitative yield.
5
,6
isothiocyanates has been a very challenging topic, as
they are prone to oligomerize by autocatalysis. As a
result, they are generally generated in situ and trapped
with amines or other reagents. Recently, 2-methyl-4-
Attempts to purify the isothiocyanate on silica gel or
recrystallization resulted in its decomposition. However,
the crude product was sufficiently pure (>95%) for rou-
tine synthetic uses.
7
quinolyl isothiocyanate was synthesized. Although the
overall yield was as high as 80%, it required a two-step
process including the isolation of a thiuronium salt
intermediate, treatment with aqueous sodium hydroxide
solution, and recrystallization in a nucleophilic solvent
of aqueous alcohol. Nevertheless, it is the only 4-quin-
olyl isothiocyanate ever reported.
Representative examples of 4-quinolyl isothiocyanates
that were successfully prepared using our new approach
are listed in Tables 1 and 2. The data illustrate the broad
scope of the reaction. The reaction was compatible with
a variety of functional groups. Interestingly, the elec-
tronic nature of the substitution did not significantly
affect the reaction. For instance, the substrates with
electron withdrawing groups, such as phenyl, fluorine,
bromine, chlorine, trifluoromethyl, and carboxylic ester
groups gave the products in similar yields and purities to
those with electron-donating groups such as methyl,
methoxy, and methylthio. The 4-chlorine is specifically
activated during the reaction with no apparent effect
on the other positions. The availability of these halo-
quinolyl isothiocyanates was found to be valuable
for further chemical transformations. The quantitative
Our ongoing medicinal chemistry effort prompted us to
undertake the synthesis of a variety of 4-quinolinyl
isothiocyanates as key building blocks in the search
Keywords: 4-Quinolyl isothiocyanate; Thiocyanate; Silver thiocyanate.
*
Corresponding author. Tel.: +1 317 277 6024; fax: +1 317 277
652; e-mail: zhong_boyu@lilly.com
3
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.119

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B. Zhong et al. / Tetrahedron Letters 47 (2006) 2161–2164
Table 1. Synthesis of 4-quinolyl isothiocyanates
Table 2. Synthesis of 2- and 8-substituted 4-quinolyl isothiocyanates
reaction, yield, and purity as in Table 1)
(
Cl
N
NCS
N
2
eq AgSCN
Yield: 100%
Entry
Chloride a
Isothicyanate b
Reaction
time (h)
R
toluene, 110 o
12 hr
R
C
Purity: 100% (HPLC-CLND)
>95% (1H NMR)
a
b
Cl
NCS
Entry
1
Chloride a
Isothiocyanate b
11
18
60
60
12
N
N
Cl
NCS
Cl
NCS
N
N
1
1
2
3
N
N
Cl
O
NCS O
2
3
4
5
6
7
8
9
O
O
Cl
N
N
Not detected
Cl
NCS
N
CF3
F
F
Cl
NCS
N
N
Cl
NCS
14
15
Br
CF3
O
Br
N
N
F
F
N
N
Cl
NCS
Cl
NCS
CF3
60
12
N
N
N
N
CF3
CF3
Cl
NCS
Cl
N
NCS
O
1
6
N
N
N
S
S
Cl
NCS
Cl
Br
O
N
Cl
Br
N
Cl
NCS
to entry 11. The high affinity between sulfur atom and
silver cation further suggested participation of silver.
Finally, we noted that silver salt is critical to the reaction.
When the silver salt was replaced with either potassium
thiocyanate or copper(I) thiocyanate, very little or no
product was obtained. Besides the driving force of the
formation of silver chloride, it is worth to note the pos-
sible catalytic role of the silver cation.
N
N
Cl
NCS
N
O
N
Cl
NCS
10
CF3
N
CF3
N
Reactions of silver thiocyanate with 4-chloroquinoline
(entry 1) and 2-methyl-4-chloroquinoline (entry 11) were
monitored by HPLC-CLND. The kinetics of both reac-
tions seemed to be similar with the exception that the
latter was much slower. The outcome of the reaction is
outlined in Figure 1 for entry 11 and a typical stepwise
process. In the first five hours, 52% of the starting mate-
rial was converted exclusively into an intermediate,
which was isolated and found to be 2-methyl-4-quinolyl
thiocyanate (17). When submitted to the same reaction
conditions, intermediate 17 rearranged to isothiocyanate
11b quantitatively. Figure 1 also showed a noticeable
induction period (about two hours) followed by a
chain-like kinetics. When one equimole (to silver thio-
cyanate) of TEMPO was initially added, the reaction
failed to proceed. This observation strongly suggested
the involvement of radical intermediates in the process.
It was not clear however if the silver cation acted as an
electron-transferring agent in this radical reaction. The
details of the reaction mechanism and the role of the sil-
ver cation are currently under investigation and the
results will be published in due course.
nature and regiospecificity of this reaction coupled with
the minimal purification requirements make it an effi-
cient synthesis.
During the course of this study, we noticed an important
effect of the size of the substituents at both positions 2
and 8 on the outcome of the reaction. As shown in Table
2
, with a substituent at 2-position the reaction is much
slower (18 h for methyl and 60 h for phenyl). When a tri-
fluoromethyl group, an isostere of an i-propyl or t-alkyl
1
1
groups, was present at 2-position (entry 13), the chlo-
ride failed to react. The steric effect of groups at 8-posi-
tion was not as pronounced as that at position 2. For
instance, 4-chloro-8-trifluoromethyl quinoline (entry
1
5), a counterpart of entry 13, was converted into isothi-
ocyanate in 60 h. These results suggested that the ring
nitrogen may interact with a silver cation to promote
the aromatic substitution. Interestingly, 8-methylthio
group (entry 16) accelerated the reaction as compared

B. Zhong et al. / Tetrahedron Letters 47 (2006) 2161–2164
2163
Heterocycles 1992, 33, 973; (d) Nedolya, N. A.; Trofimov,
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Cl
N
S
N
CN
NCS
AgSCN
AgSCN
N
1
1a
17
11b
2
3
100
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8
0
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3
5
7
9
11
13
15
-20
Time (hr)
Figure 1. Reaction of 2-methyl-4-chloroquinoline with AgSCN.
1
34, 3121–3126.
4
. (a) Drobnica, L.; Kristian, P.; Augustin, J. In The
Chemistry of Cyanates and their Thio Derivatives; Patai,
S., Ed.; John Wiley & Sons: New York, 1977; Vol. 2, pp
In summary, we have described a novel and practical
approach to the construction of 4-quinolyl isothiocyanates
by reacting 4-chloroquinolines and silver thiocyanate in
refluxing toluene. A stepwise kinetics was illustrated.
The protocol provides a simple and efficient access to
1
5
013–1062; (b) Molina, P.; Arques, A. A. Synthesis 1982,
96; (c) Mazagova, D.; Sabolova, D.; Kristian, P.; Imrich,
J.; Antalik, M.; Podhradsky, D. Collect. Czech. Chem.
Commun. 1994, 59, 203; (d) Adam, W.; Bargon, R. M.;
Bosio, S. G.; Schenk, W. A.; Stalke, D. J. Org. Chem.
4
-quinolyl isothiocyanates in quantitative yield and
excellent purity.
2
002, 67, 7037; (e) Le Count, D. J.; Dewsbury, D. J.;
Grundy, W. Synthesis 1977, 582; (f) Hansen, E. T.;
Petersen, H. J. Synth. Commun. 1984, 14, 537.
. L’abbe, G. Synthesis 1987, 525.
5
6
7
Acknowledgements
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The authors gratefully thank Mr. James M. Gilliam for
the collection of HRMS data, Mr. Darrell S. Coleman
for the gift of compound 16a, Ms. Kathryn Lawrence
and Mr. Thomas J. Mitchell for the assistance in FTIR
experiments, and Dr. Robert C. Anderson for many use-
ful discussions.
8
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1
010.
9
. The rapid stirring was crucial for the success of the
reaction; otherwise, the reaction either progressed very
slowly or completely ceased. A mixture of 4-chloroquino-
line and silver thiocyanate in anhydrous toluene was
stirred at 110 °C for 12 h. The hot reaction mixture was
filtered and washed three times with chloroform. The
filtrate was concentrated under vacuum to afford the 4-
quinolinyl isothiocyanate as an off-white solid. We thank a
reviewer for the suggestion of using regular toluene.
Reactions 1, 5, 7 and 11 were carried out in anhydrous
toluene and regular toluene side by side. No obvious
differences were noted in yields and proton NMR spectra
between the two sets of reactions.
Supplementary data
General experimental procedure and spectroscopic data
1
13
(
H NMR, C NMR, HRMS, FTIR, and melting
point) for all products and intermediate 17 are available.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2
006.01.119.
References and notes
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10. The structure of the product was confirmed by a strong
À1
and broad infrared band in the range of 2000–2130 cm
1
3
1
and a peak around 138–143 ppm (-NCS) on the C NMR
1
2,13
spectrum.
The purity of the product was determined
1
using H NMR spectroscopy and an HPLC coupled with
a Chemiluminescent Nitrogen Detector (CLND) that
linearly responds to the nitrogen content in the sample.
In the H NMR spectrum of the crude product, only trace
amount of impurities (<5%) was observed. In the HPLC-
CLND chromatography, the desired isothiocyanate was
1
4
1

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B. Zhong et al. / Tetrahedron Letters 47 (2006) 2161–2164
the only peak (sample concentration 1 mg/1 mL). The
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1
4
limit of CLND (<25 picomole/5 lL).
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