Integrated Synthesis Using Isothiocyanate-Substituted Aryllithiums by Flow Chemistry

Article abstract of DOI:10.1055/s-0040-1707251

The isothiocyanate (NCS) group is an attractive functional group in the field of organic and pharmaceutical chemistry. It can be transformed into other heteroatomic functional groups. It usually acts as the inductive group of biological activity and has also been traditionally used as the fluorescent-labeling reagent. However, it is not compatible with strong bases. When the NCS group is at para position in halobenzenes, it generally undergoes nucleophilic additions upon reaction with strong bases. To the best of our knowledge, there is currently no general methodology for the formation and reactions of NCS-functionalized aryllithiums for meta and para substituents. Herein, we report the continuous-flow generation of NCS-substituted aryllithiums from the corresponding haloarenes via a selective halogen-lithium exchange reaction and its reaction with various electrophiles to yield NCS-containing products. We also achieved an integrated synthesis through sequential reactions of the NCS-containing compounds with additional nucleophiles using the continuous-flow reactors.

Full text of DOI:10.1055/s-0040-1707251

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
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H.-J. Lee et al.
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Integrated Synthesis Using Isothiocyanate-Substituted Aryllithi-
ums by Flow Chemistry
Hyune-Jea Leea
Integrated Flow Synthesis via Sequential Reactions
Daiki Toriib
Yongju Jeona
Jun-ichi Yoshida*b,c
Heejin Kim*a,b
H
NCS
within 6 s of reaction time
N
Nu
X
E
S
X = I or Br
- 3-step integrated
- continuous and rapid
RLi
E+
Nu–
a Department of Chemistry, Korea University, 145 Anam-ro,
Seongbuk-gu, Seoul 02841, Korea
heejinkim@korea.ac.kr
b Department of Synthetic Chemistry and Biological Chemistry,
Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
c National Institute of Technology, Suzuka College, Shiroko-cho,
Suzuka, Mie 510-0294, Japan
Dedicated to Prof. Jun-ichi Yoshida (1952–2019) for his
pioneering work on flow chemistry
Published as part of the Cluster Integrated Synthesis Using
Continuous-Flow Technologies
Received: 23.06.2020
Accepted after revision: 21.07.2020
Published online: 21.08.2019
hiles, such as organolithium and organomagnesium re-
agents.4 For example, many reports describe the reactions
of halobenzenes bearing the NCS group with various basic
reagents that result in nucleophilic addition to the NCS
group (Scheme 1, a). The previous reports have only de-
scribed the generation of ortho-NCS-substituted phenyl-
lithium, which could be generated under very low tempera-
ture within short reaction time (1 min of lithiation) in a
flask, because the ortho-substituted intermediate is rela-
tively stable due to the ortho-directing effect.5 We also re-
ported that the o-NCS-substituted aryllithium could be ef-
fectively generated and reacted with various electrophiles
to synthesize bioactive heterocycles using flow microreac-
tors even at room temperature.6 However, to the best of our
knowledge, there are no reports concerning the generation
of m- or p-NCS-substituted aryllithium and their reactions,
presumably because of their high instability.
DOI: 10.1055/s-0040-1707251; Art ID: st-2020-u0365-c
Abstract The isothiocyanate (NCS) group is an attractive functional
group in the field of organic and pharmaceutical chemistry. It can be
transformed into other heteroatomic functional groups. It usually acts
as the inductive group of biological activity and has also been tradition-
ally used as the fluorescent-labeling reagent. However, it is not compat-
ible with strong bases. When the NCS group is at para position in halo-
benzenes, it generally undergoes nucleophilic additions upon reaction
with strong bases. To the best of our knowledge, there is currently no
general methodology for the formation and reactions of NCS-function-
alized aryllithiums for meta and para substituents. Herein, we report
the continuous-flow generation of NCS-substituted aryllithiums from
the corresponding haloarenes via a selective halogen–lithium exchange
reaction and its reaction with various electrophiles to yield NCS-con-
taining products. We also achieved an integrated synthesis through se-
quential reactions of the NCS-containing compounds with additional
nucleophiles using the continuous-flow reactors.
S
S
Key words isothiocyanate, organolithium, flow chemistry, microreac-
tor, integrated synthesis
HN
Nu
NCS
HN
R2
Nu:
nucleophile
R1-X
R2-Li
R'Li
flask
(a)
reported work
integrated flow system
The isothiocyanate (NCS) group plays an important role
in the construction of useful heteroatomic skeletons in or-
ganic synthesis. Due to its strong electrophilic nature, it can
be readily converted into thioamide, thiourea, and carba-
mothiolate by the reaction with various nucleophiles.1 It is
also important for the biological activity of various druglike
molecules2 and can be used as the traditional fluorescent-
labeling reagent called fluorescein isothiocyanate (FITC).3
The strategy to synthesize NCS-containing molecules,
however, has been limited, because of its strong reactivity.
It is well known to be incompatible with strong nucleop-
X
R1
X
(b)
this work
X: Br or I
Scheme 1 Comparative synthetic methods using halobenzene bearing
an isothiocyanate (NCS) group. (a) Nucleophilic addition to the NCS
group. (b) A halogen–lithium exchange reaction followed by sequential
reactions using flow reactors.
In recent years, we have reported that highly reactive
organolithiums can be effectively generated and used under
mild conditions in flow microreactors.7 Flow microreactors
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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H.-J. Lee et al.
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afford many advantages including fast mixing, effective
temperature control, and short residence time control,
which lead to increased yield and selectivity.8 In this con-
text, we envisaged that the generation of aryllithiums bear-
ing the NCS group at meta or para position followed by re-
action with an electrophile and sequential reaction with a
nucleophile could be achieved using flow microreactors
(Scheme 1, b).
First, we examined the substrates suitable for achieving
the selective generation of NCS-substituted aryllithium in-
termediates, without the nucleophilic additions of organo-
lithium reagents to the NCS group. In preliminary studies,
we performed flask reactions of p-halophenyl isothiocya-
nate with n-BuLi or PhLi, followed by the trapping with
methyl chloroformate (for details, see the Supporting Infor-
mation). Then, we could not get the desired product at all,
because of not only unwanted nucleophilic addition of or-
ganolithium to NCS group, but also the overreaction of gen-
erated NCS-substituted aryllithiums with the NCS group.
Therefore, we decided to use a flow reaction platform to
optimize the starting substrate and organolithium.
product in poor yield (entry 1), the reaction using s- or n-
BuLi gave the desired product 2a in moderate yields (63–
78%; entries 2 and 3). The use of PhLi did not give the prod-
uct 2a at all, because of the unwanted nucleophilic addition
to NCS group to give the byproduct (entry 4). We then ex-
amined the reactions of iodophenyl isothiocyanate with or-
ganolithiums (entries 5–8), and the best result was ob-
tained in the reaction with PhLi to resulted in 84% yield of
desired product (entry 8). These results clearly indicate that
the selectivity on the halogen–lithium exchange versus nu-
cleophilic addition to NCS group is highly dependent to the
substrate as well as the organolithium reagent. For selective
Br–Li exchange, reactive alkyllithiums were effective,
whereas in the case of I–Li exchange reaction, PhLi was bet-
ter than the alkyllithiums in terms of conversions and
yields.
Next, we examined the effects of temperature and reac-
tion time using m- and p-iodophenyl isothiocyanates with
PhLi. The flow reactions were carried out at various tem-
peratures (–40 °C to 20 °C) and residence time in flow reac-
tor, R1 (0.014–6.3 s). The results are summarized in Figure
1. The results stipulate that the generated intermediate is
We used a flow reaction system for the reaction of halo-
benzenes bearing the NCS group at para position with sev-
eral organolithium reagents. The flow reaction system con-
tains T-shaped mixers (diameter: 0.25 or 0.50 mm) and
stainless-steel tubing as shown in Table 1. Although the
flow reaction of bromoarene 1 with MeLi gave the desired
Table 1 The Halogen–Lithium Exchange Reaction of p-Halophenyl Iso-
thiocyanates and Organolithium Reagents Followed by Reaction with
Tributyltin Chloride Using Flow Reactorsa
Entry
X
RLi
MeLi
Conversion of 1 (%)b Yield of 2a (%)b
1
2
3
4
5
6
7
8
Br
74
100
100
100
100
89
9
63
78
0
Br
Br
Br
I
s-BuLi
n-BuLi
PhLi
MeLi
50
16
73
84
Figure 1 Optimization of the I–Li exchange reactions of iodophenyl
isothiocyanates by using the flow reactors under various reaction con-
ditions. (a) The flow reaction system for the I–Li exchange reaction of
m- or p-phenyl isothiocyanate. (b) Effects of temperature and reaction
time in R1 on the yield of p-iodophenyl isothiocyanate (1a). (c) Effects
of temperature and reaction time in R1 on the yield of m-iodophenyl
isothiocyanate (1b).
I
s-BuLi
n-BuLi
PhLi
I
100
100
I
a The reaction was conducted with 1.1 equiv of RLi and 1.5 equiv of tribut-
yltin chloride.
b The conversion and yield were determined by GC.
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H.-J. Lee et al.
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unstable. Therefore, the intermediate is rapidly decom-
posed within a few seconds at a relatively high temperature
(–20 °C to 20 °C). However, we found that the reaction of p-
iodophenyl isothiocyanate (1a) or m-iodophenyl isothiocy-
anate (1b) proceeded effectively to give the corresponding
desired product in high yield (>84%) at relatively low tem-
perature (–40 °C) with short residence time (0.014 s). Fig-
ure 1 also shows the similar stabilities between m- and p-
NCS-substituted phenyllithium.
Under the optimized condition, the selective I–Li ex-
change reactions of m- or p-iodophenyl isothiocyanates,
followed by reactions with various electrophiles such as
trimethylsilyl triflate, methyl chloroformate, methyl tri-
flate, diethyl oxalate, and N-fluorobenzenesulfonimide (NF-
SI) lead to the formation of desired products in good yields
(63–97%, Table 2).
Yield (%)a
91
Substrate
Electrophile
MeOTf
Product
NCS
3d
Me
NCS
O
OEt
69
63
EtO
O
O
O
3e
OEt
NCS
NFSI
3f
F
a Isolated yield.
The optimized reaction conditions for the generation of
m- or p-NCS-substituted aryllithium and the subsequent
reaction with electrophiles were applied to a three-step in-
tegrated flow synthesis (Scheme 2). The m- or p-methyl, si-
lyl, or benzyl alcoholic functionalized phenyl isothiocya-
nates were synthesized in situ in flow and sequentially re-
acted with organolithiums. In the integrated flow system,
various thioamide compounds were synthesized within
6.11 s of total reaction time in high yields (73–95%; Scheme
2). In cases of reactions with n-BuLi as a nucleophile to
form product 4b and 5b, bromophenyl isothiocyanate and
n-BuLi were used, because the use of iodoarene and PhLi
leads to the formation of iodobenzene that undesirably fur-
ther react with n-BuLi in the third reaction step.
Table 2 The Optimized Iodine–Lithium Exchange Reaction of Io-
dophenyl Isothiocyanate Followed by Reaction with an Electrophile
NCS
NCS
E
I
Yield (%)a
81
Substrate
Electrophile
Bu3SnCl
Product
NCS
NCS
1a
2a
Bu3Sn
Me3Si
MeO2C
Me
I
NCS
Me3SiOTf
ClCO2Me
97
85
66
2b
H
NCS
NCS
N
Nu
X
E
S
2c
NCS
H
MeOTf
H
N
H
N
H
N
Ph
Ph
Ph
Ph
N
n-Bu
2d
S
S
S
S
Me3Si
Me
Me
NCS
O
OH
O
4a, 88%
4b, 79 %
4c, 82%
4d, 85%
OEt
65
65
81
EtO
EtO
O
2e
O
H
H
N
H
N
H
N
N
Ph
Ph
Ph
n-Bu
NCS
NFSI
S
S
S
S
2f
F
SiMe3
5c, 87%
Me
5a, 95%
Me
5b, 73%
HO
Ph
NCS
NCS
5d, 74%
Bu3SnCl
Scheme 2 Three-step integrated flow reaction of the meta- and para-
substituted phenyl isothiocyanate with organolithium
1b
SnBu3 3a
I
NCS
Me3SiOTf
ClCO2Me
82
78
Furthermore, we conducted a flow-assisted synthesis
by combining with the flask reaction and synthesized de-
rivatives of biologically active compounds 6a and 6b in high
yields (66% and 74%, respectively; Scheme 3). p-Fluorophe-
nyl isothiocyanate (2f) was synthesized in the flow reactors
and it reacted with functional amines in the flask (for de-
3b
SiMe3
NCS
3c
CO2Me
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H.-J. Lee et al.
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tails, see the Supporting Information). Notably, compound
6a is known as an antimitotic agents,9 and compound 6b
can be used as an intermediate of fluorine-containing ne-
crostatin-5.10
Falconer, S. B.; Wildenhain, J.; Coombes, B. K.; Tyers, M.; Brown,
E. D.; Wright, G. D. Nat. Chem. Biol. 2011, 7, 348. (c) Lee, C.-M.;
Lee, D.-S.; Jung, W.-K.; Yoo, J. S.; Yim, M.-J.; Choi, Y. H.; Park, S.;
Seo, S.-K.; Choi, J. S.; Lee, Y.-M.; Park, W. S.; Choi, I.-W. Int. J. Mol.
Med. 2016, 38, 912. (d) Stone, L. K.; Baym, M.; Lieberman, T. D.;
Chait, R.; Clardy, J.; Kishony, R. Nat. Chem. Biol. 2016, 12, 902.
(e) Kjaerulff, L.; Sikandar, A.; Zaburannyi, N.; Adam, S.;
Herrmann, J.; Koehnke, J.; Müller, R. ACS Chem. Biol. 2017, 12,
2837.
H
O
N
S
N
NCNH2
BnBr
F
NH2
NCS
NCS
t-BuOK
(3) (a) Coons, A. H.; Creech, H. J.; Jones, R. N.; Berliner, E. J. Immunol.
1942, 45, 159. (b) The, T. H.; Feltkamp, T. E. W. Immunology
1970, 18, 875. (c) Christensen, P. J.; Goodman, R. E.; Pastoriza,
L.; Moore, B.; Toews, G. B. Am. J. Pathol. 1999, 155, 1773.
(d) Hermanson, G. T. Bioconjugate Techniques, 3rd ed. 2013; 395.
(4) (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300.
(b) Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39, 2053.
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(5) Kim, H.; Lee, H.-J.; Kim, D.-P. Angew. Chem. Int. Ed. 2015, 54,
1877.
6a, 74%
I
F
flow
H
H
2f
S
N
N
S
H2N
EtO2C
S
F
EtO2C
6b, 66%
Scheme 3 The synthesis of fluorine-containing intermediate com-
pounds of bioactive molecules
(6) (a) Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem. Int. Ed. 2008, 47,
7833. (b) Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem. Int. Ed.
2009, 48, 8063. (c) Nagaki, A.; Kim, H.; Usutani, H.; Matsuo, C.;
Yoshida, J. Org. Biomol. Chem. 2010, 8, 1212. (d) Nagaki, A.; Kim,
H.; Moriwaki, Y.; Matsuo, C.; Yoshida, J. Chem. Eur. J. 2010, 16,
11167. (e) Kim, H.; Nagaki, A.; Yoshida, J. Nat. Commun. 2011, 2,
264. (f) Yoshida, J.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4,
331. (g) Ren, W.; Kim, H.; Lee, H.-J.; Wang, J.; Wang, H.; Kim, D.-
P. Lab Chip 2014, 14, 4263.
(7) (a) Kim, H.; Lee, H.-J.; Kim, D.-P. Angew. Chem. Int. Ed. 2016, 55,
1422. (b) Kim, H.; Min, K.-I.; Inoue, K.; Im, D. J.; Kim, D.-P.;
Yoshida, J. Science 2016, 352, 691. (c) Kim, H.; Inoue, K.; Yoshida,
J. Angew. Chem. Int. Ed. 2017, 56, 7863. (d) Lee, H.-J.; Kim, H.;
Yoshida, J.; Kim, D.-P. Chem. Commun. 2018, 54, 547. (e) Kim, H.;
Yonekura, Y.; Yoshida, J. Angew. Chem. Int. Ed. 2018, 57, 4063.
(f) Kim, H.; Yin, Z.; Sakurai, H.; Yoshida, J. React. Chem. Eng.
2018, 3, 635. (g) Lee, H.-J.; Kim, H.; Kim, D.-P. Chem. Eur. J. 2019,
25, 11641. (h) Lee, H.-J.; Roberts, R. C.; Im, D. J.; Yim, S.-J.; Kim,
H.; Kim, J. T.; Kim, D.-P. Small 2019, 15, 1905005.
(8) (a) Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456.
(b) Pastor, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42,
8849. (c) Fukuyama, T.; Totoki, T.; Ryu, I. Green Chem. 2014, 16,
2042. (d) Ley, S. V.; Fitzpatrick, D. E.; Myers, R. M.; Battilocchio,
C.; Inham, R. J. Angew. Chem. Int. Ed. 2015, 54, 10122.
(e) Kobayashi, S. Chem. Asian J. 2016, 11, 425. (f) Cambié, D.;
Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noel, T. Chem. Rev.
2016, 116, 10276. (g) Plutschack, M. B.; Pieber, B.; Gilmore, K.;
Seeberger, P. H. Chem. Rev. 2017, 117, 11796. (h) Shen, G.;
Osako, T.; Nagaosa, M.; Uozumi, Y. J. Org. Chem. 2018, 83, 7380.
(i) Arakawa, Y.; Ueta, S.; Okamoto, T.; Minagawa, K.; Imda, Y.
Synlett 2020, 31, 866.
In conclusion, we have demonstrated the integrated
flow synthesis through the sequential reactions from
haloarenes bearing the NCS group at meta or para position.
The generation and subsequent reaction of the NCS-substi-
tuted aryllithiums were optimized by control of residence
time and temperature in the flow reaction system. Various
electrophiles were introduced to the NCS-substituted aryl-
lithiums in high yields of 63–97%. Moreover, the integrated
flow synthesis of various thioamides was achieved by the
sequential nucleophilic additions of organolithiums to the
remaining NCS groups of meta- and para-functionalized
phenyl isothiocyanates. The flow reaction was also com-
bined with the flask reaction to result in the synthesis of bi-
ologically active compounds in high yields.
Funding Information
We acknowledge the National Research Foundation of Korea (NRF)
grants funded by the Korea government (MSIP) (No.
2019R1G1A1100681 and No. 2020R1C1C1014408).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707251.
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