Fast and Efficient Continuous Flow Method for the Synthesis of Ynones and Pyrazoles

Article abstract of DOI:10.1002/ejoc.201900468

In this study, we developed a convenient and efficient two-step method for the synthesis of ynones in a flow reactor, through the generation of lithium acetylide and its subsequent reactions with acid chlorides. Using this approach, we obtained the ynones in moderate to good yields at room temperature. Moreover, we transformed the ynones into pyrazole derivatives through coupling with hydrazines. This transition metal-free process, mild reaction conditions, and broad functional group tolerance are all attractive features in comparison with conventional bench-top methods.

Full text of DOI:10.1002/ejoc.201900468

A Journal of
Accepted Article
Title: Fast and efficient continuous flow method for the synthesis of
ynones and pyrazoles
Authors: Mohanraj Kandasamy, Balaji Ganesan, Min-Yuan Hung, and
Wei-Yu Lin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900468
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10.1002/ejoc.201900468
European Journal of Organic Chemistry
FULL PAPER
Fast and efficient continuous flow method for the synthesis of
ynones and pyrazoles
Mohanraj Kandasamy, [a] Balaji Ganesan, [a] Min-Yuan Hung [b] and Wei-Yu Lin*[a,c]
Abstract: In this study, we developed a convenient and efficient
two-step method for the synthesis of ynones in a flow reactor,
through the generation of lithium acetylide and its subsequent
reactions with acid chlorides. Using this approach, we obtained
the ynones in moderate to good yields at room temperature.
Moreover, we transformed the ynones into pyrazole derivatives
through coupling with hydrazines. This transition metal–free
process, mild reaction conditions, and broad functional group
tolerance are all attractive feat in comparison with conventional
bench-top methods.
activities;[11] for example, cyenopyrafen and pyrazolynate are
pesticides[12] and celecoxib is a nonsteroidal anti-inflammatory
agent.[13] The general synthetic method for accessing a pyrazole
ring is through [3+2] cycloaddition of a 1,3-dielectrophile[14]
derivative (an a,b-unsaturated aldehyde/ketone, an allenic ketone,
or a b-alkynyl ketone) with hydrazine.[15] Because of their wide
biological activity,[16] the challenge remains to develop new
synthetic routes for the rapid and regioselective[17] assembly of
substituted pyrazoles from simple and readily available starting
materials.[18] In this context, when compared with batch
techniques, continuous flow chemistry has many attractive
features: enhancing mass- and heat-transfer, minimizing reaction
volumes, and improving the degrees of sample- and reagent-
mixing.[19] Furthermore, the residence time in a micro-reactor can
be controlled precisely to achieve the maximum yield and
reaction-selectivity.[20] These features have made flow-
microreactor systems an excellent alternatives to traditional batch
reaction systems when preparing unstable and highly reactive
Introduction
Ynones are used widely as building blocks in the synthesis of
many bioactive heterocycles and natural products with
pharmaceutical applications.[1] The three main routes[2] that are
commonly used to synthesize ynones are (i) the addition of a
metal acetylide (Li, Zn, Cu, Al, In, Sn, Ag, MgBr, Si)[3] to an
anhydride, aldehyde, or acyl chloride; (ii) the transition metal–
catalyzed cross-coupling of an aryl halide, carbon monoxide, and
an alkyne;[4] and (iii) the direct oxidation of alkynes to ynones
using SeO2/TBHP,[5] CrO3/TBHP,[6] or CuCl2/TBHP.[7] The first of
these methods is typically the simplest because of the ease of
preparation and the broad availability of carbonyl compounds.
Nevertheless, the syntheses of ynones can still require multiple
steps, harsh conditions, or additional additives[8] to prevent over-
addition to the carbonyl group. Thus, it can be challenging to
synthesize ynones in a simple, precise, reagent-controllable,[4c, 9]
and economical manner.
organometallic
intermediates
(e.g.,
aryllithiums,
oxiranyllithiums).[21] In addition, the reaction intermediates can be
trapped through precise control of various reaction parameters
(e.g., residence time, temperature) in a flow-microreactor.[19a]
To date, only a few processes have been reported for the
synthesis of ynones[22] and pyrazoles through flow chemistry.[23]
Ley and co-workers developed a transition metal–catalyzed
process to synthesize ynones and pyrazoles: first coupling a
terminal acetylene with an acyl chloride in the presence of a
palladium catalyst and then reacting the ynone with hydrazine to
afford a pyrazole with overall reaction times of 30 and 60 min,
respectively.[24] The same group subsequently reported a metal-
free multi-step continuous flow process for the generation of N-
aryl pyrazoles using amine-redox chemistry.[25] Recently, Jamison
and co-workers reported[23j, 26] a rapid (within 0.6–60 min) and
modular continuous flow synthesis of therapeutic agents,
containing highly functionalized fluorinate pyrazole units, for the
treatment of measles. Unfortunately, applying their method for the
synthesis of ynones and pyrazoles required specific reagents and
harsh reaction conditions (high temperatures, long reaction times).
Herein, we describe a simple, convenient, and highly efficient
method for the synthesis of ynones and pyrazoles in a continuous
flow reactor. By reacting terminal alkynes with n-butyllithium to
generate unstable lithium-acetylides, and subsequently reacting
them with acid chlorides, we obtained ynones in moderate to good
yields within less than a minute at room temperature. In addition,
we have used the in situ generation of ynones to synthesize 3,5-
di- and 1,3,5-tri-substituted pyrazoles in a sequential manner with
good yields and broad scope within continuous flow reactors.
Ynones are versatile intermediates for the syntheses of many
important N-heterocyclic compounds, including pyrazoles,
quinolones, quinolines, diazepines, triazoles, pyrimidines, indoles,
10]
isoxazoles, oxazepines, and oxazines.[3d,
Pyrazoles five-
membered-ring compounds having two adjacent nitrogen atoms
are particularly interesting because of their wide physiological
[a]
Department of Medicinal and Applied Chemistry, Kaohsiung Medical
University, Kaohsiung 807, Taiwan
Prof. Dr. Wei-Yu Lin; E-mail:wylin@kmu.edu.tw
http://wp.kmu.edu.tw/wylin
[b]
[c]
Centre for Research Resources and Development, Kaohsiung
Medical University, Kaohsiung 807, Taiwan
Department of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan
Supporting information and ORCID from the author(s) for this article
are available on the WWW under https://10.1002/ejoc.201900468
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10.1002/ejoc.201900468
European Journal of Organic Chemistry
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Results and Discussion
that the yield increased upon increasing the residence time (Table
1, entries 1–3). Next, we increased the length of R1 to 25 (126
µL) and 50 cm (251 µL) (Table 1, entries 4–8), and found that the
desired product 3a could be obtained in 83% yield within 9.42 s.
When we performed the reaction at higher temperatures,
P1 = 100 cm
tR1
0. 1 M in THF
R1
M1 = 500 µm
o
including 0 and 20 C, the yields of 3a also improved (Table 1,
n-BuLi
P2 = 50 cm
entries 9–14). At –20 oC, the yield of 3a generally increased upon
M2 = 500 µm
1.6 M in Hexane
3a
o
increasing the reaction time; at 0 or 20 C, however, the yield
P3 = 100 cm
decreased may be due to the aggregation of lithium
0.3 M in THF
[27]
phenylacetylide species over this residence time
(Table 1,
Scheme 1. Optimization of ynones on flow reactor (M1, M2 of 500 µm inner
diameter) and three microtubing reactors (R1(800 µm) and R2(1000 µm))
entries 11 and 14). Our best yield, 94%, was obtained when the
value of T was 20 oC and the value of tR1 was 4.71 s, but the low
flow rate could, in turn, result in channel clogging. Thus, we
considered the conditions in entry 12 (T, 20 oC; tR1, 2.35 s; 90%)
as optimal for further studies. In addition, we did not observe
(through GC–MS analysis) any alcohol products, which would
occur through multiple addition of lithium phenylacetylide, when
using the optimized conditions.
Table 1. Optimization study[a]
Entry
Temp.
(oC)
Length
Volume
of R1
Residence
Time (s)
Flow
Condition
Conv.
Yield(%)
cm (µL)
Scheme 2. Substrate scope for ynone derivatives [a]
1
-20
-20
-20
-20
-20
-20
-20
-20
0
10 (50)
10(50)
0.47
0.94
1.88
1.17
2.35
2.35
4.71
9.42
2.35
4.71
9.42
2.35
4.71
9.42
A
B
C
A
B
A
B
C
A
B
C
A
B
C
34
62
67
66
79
44
73
83
63
91
84
90
94
84
F1 = 6 mL/min
T = 20 o
C
tR1 = 2.35 s
R1 = 50 cm
0. 1 M in THF
2
R1
M1 = 500 µm
F2 = 0.4 mL/min
3
10(50)
n-BuLi
R2
M2 = 500 µm
1.6 M in Hexane
3
F3 = 3 mL/min
4
25(126)
25(126)
50(251)
50(251)
50(251)
50(251)
50(251)
50(251)
50(251)
50(251)
50(251)
0.3 M in THF
5
6
7
8
9
10
11
12
13
14
0
0
20
20
20
a) All the reactions were performed under optimized condition and products was
collected for 1 min. Conversion yield was calculated by gas chromatography.
b) Isolated Yield. c) The yield of isolated product on 3.0 mmol scale. d) The yield
of isolated product on 2.1 mmol scale.
A) F1 = 6.0 mL/min, F2 = 0.4 mL/min, F3 = 3.0 mL/min. B) F1 = 3.0 mL/min,
F2 = 0.2 mL/min, F3 = 1.5 mL/min. C) F1 = 1.5 mL/min, F2 = 0.1 mL/min, F3 =
0.75 mL/min, inner diameters of the tube (R1) 800 µm
Initially, we developed
a
flow setup using two T-shaped
Next, we examined the substrate scope of this method by varying
the structures of the terminal alkynes and acyl chlorides (Scheme
2). Acyl chlorides containing electron-donating (2a–c) and
electron-withdrawing (2d–f) groups reacted with phenylacetylene
(1a) to afforded their desired products (3a–f) in moderate to
excellent yields (59–96%). 2-Furoyl chloride (2g) and cinnamoyl
chloride (2h) coupled smoothly with phenylacetylene to afford
their corresponding ynones (3g and 3h, respectively) in good
yields. Aliphatic acid chlorides also provided their corresponding
products 3i–n in yields of 51–76%. The p-Me– and p-MeO–
substituted aromatic acetylenes 2o and 2p afforded their desired
products (3o and 3p) in yields of 63–83%. The aliphatic terminal
alkynes 2q–s reacted well to give the corresponding ynones 3q–
s in yields of 68–71%. This method was simple to scale-up in the
micromixers (M1, M2), two tubing reactors [R1 (800 µm), R2
(1000 µm)], and a cooling unit (Scheme 1). Our investigation
began with the reaction of phenylacetylene (1) with n-butyllithium
at mixer M1 for the generation of lithium phenylacetylide, which
was then mixed with benzoyl chloride (2) at M2 to afford the
desired ynone 3a. We optimized the reaction by varying the
residence time (tR1) in tubing reactor (R1), the temperature, and
the flow conditions. We used gas chromatography to determine
the conversion yield of the ynone 3a; Table 1 summarizes the
results.
When performing the reaction with three different residence times
o
at –20 C, with the length of R1 set at 10 cm (50 µL), we found
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10.1002/ejoc.201900468
European Journal of Organic Chemistry
FULL PAPER
continuous flow system. For example, we performed the reaction
of 3e in the flow reactor on a 3 mmol scale within 5 min and the
reaction of 3r on a 2.1 mmol scale within 3.5 min, with isolated
yields of 75 and 69%, respectively.
from 54 to 77%. In contrast, the reactions when benzyl or aliphatic
groups were featured at the R2 position gave the corresponding
3,5-disubtituted pyrazoles 5h–k in only moderate yields. As an
alternative to hydrazine monohydrate, we also tested
phenylhydrazine in this reaction system with different substituents
at the R1 and R2 positions, with aryl groups at R1 affording the
corresponding desired 1,3,5-trisubtituted pyrazoles (5b, 5e) in
good yields. X-ray crystallography confirmed the structure of 5e
and suggested that the in situ–generated ynone experienced
Michael addition, followed by intramolecular condensation, to
afford this 1,3,5-trisubstituted pyrazole.[28] Alkyl substituents at R1
position were also tolerated, producing the corresponding
products 5i and 5l. The acetylene derivatives also reacted with
high substrate scope, with p-Me– and p-MeO–substituted
compounds and 1-hexyne providing their desired pyrazoles 5m,
5n, and 5o, respectively.
With our success at preparing ynone derivatives, we applied this
method to the synthesis of pyrazoles. When we introduced the
ynone 3a and hydrazine monohydrate using a two-syringe pump
o
system at 60 C, we obtained the pyrazole product in only 10%
yield (See SI, Table S2, entry 1). To our delight, full conversion of
3a occurred when we used temperatures higher than 70 oC (Table
S2, entries 2 and 3). Considering the results in Tables 1 and S2,
we examined the possibility of synthesizing a pyrazole derivative
from a terminal alkyne, n-butyllithium, benzoyl chloride, and
hydrazine monohydrate in an integrated four-syringe pump
system (Scheme 3).
Scheme 3. Substrate scope for pyrazole derivatives[a]
T = 20 o
C
Conclusions
F1 = 6 mL/min
0. 1 M in THF
t
R1 = 2.35 s
M1 = 500 µm
R1
T = 70 o
C
F2 = 0.4 mL/min
1.6 M in Hexane
t
R2 = 2.50 s
We have developed a convenient and highly efficient method for
the synthesis of substituted ynones through the in situ generation
of lithium acetylide intermediates and their subsequent coupling
with acyl chlorides in an integrated flow microreactor featuring two
T-shaped micromixers and two mictotubular reactors. In parallel,
we also prepared di- and tri-substituted pyrazoles by reacting the
corresponding ynones with hydrazines in this integrated flow
reactor. This transition metal–free process occurred under mild
reaction conditions with good to excellent yields and broad
functional group tolerance, delivering 19 examples of ynones and
15 examples of pyrazoles. Our system was also scalable, and
allowed the syntheses of various heterocyclic derivatives that
cannot be achieved under conventional bench-top reaction
conditions. Thus, this method appears to be a powerful one for
synthesizing ynones and pyrazoles rapidly under transition metal-
free and mild conditions, with simple processing and high reagent
control. We are currently testing further examples of the
transformations of in situ prepared lithium acetylides in flow
reactors in our laboratories.
n-BuLi
R2
M2 = 500 µm
t
R3 = 10.85 s
5
F3 = 3 mL/min
R3
0.3 M in THF
M3 = 500 µm
F4 = 4.5 mL/min
N2H4.H2O
Or
PhNHNH2
0.4 M in THF
a) All the reactions were performed under optimized condition and products was
collected for 1 min. Conversion yield was calculated by gas chromatography.
b) Isolated Yield.
Experimental Section
General Procedure for the preparation of ynone from alkyne and n-
BuLi followed by reaction with acid chlorides; A microreactor system
consist of two T-shaped micromixers (M1 and M2), two microtubes
reaction (R1 and R2) and three precooling units P1 (inner diameter =
800 µm, length L = 100 cm), P2 (inner diameter = 800 µm, length L = 50
cm), and P3 (inner diameter = 800 µm, length L = 100 cm) were used. A
solution of alkyne (0.10 M in THF) (flow rate: 6.0 mL/min) and a solution of
n-BuLi (1.60 M in hexane) (flow rate: 0.4 mL/min) were introduced to M1
(Φ = 0.5 mm) by syringe pumps. The solution was passed through R1 (Φ
= 0.8 mm, L = 50 cm, 251 µL) and was mixed with a solution of acid
chloride (0.3 M in THF) (flow rate: 3.0 mL/min) in M2 (Φ = 0.5 mm). The
resulting solution was passed through R2 (Φ = 1.0 mm, L = 50 cm, 392
µL). After a steady state was reached (after 1 min), the final product
solution was collected for 60 seconds in vial containing saturated solution
of NH4Cl. The reaction mixture was analysed by GC and mixture was
extracted with EA. The organic phase was dried with MgSO4, and solvent
was removed by vacuum. The residue was purified by column
chromatography and product was analysed by 1H, 13C NMR, IR and mass
spectrometer.
When we screened various organic bases (TEA, DIPEA, pyridine)
for addition with hydrazine, we obtained only poor to moderate
yields (See Table S3, entries 1–3). Pleasingly, we achieved a GC
conversion of 73% when performing the reaction without adding
any base (Table S3, entry 4). Under these optimized conditions,
we investigated the scope by reacting various ynone derivatives
with hydrazine monohydrate and phenyl hydrazine in the
integrated flow system featuring four syringe pump reactors
(Scheme 3). The acyl chlorides presenting electron-withdrawing,
electron-donating, and heterocyclic groups at the R2 position all
reacted with lithium acetylide at 20 oC to generate their
corresponding ynones, which were subsequently coupled in situ
with hydrazine monohydrate to afford the desired 3,5-
disubstituted pyrazoles 5a, 5c, 5d, 5f, and 5g, with a residence
time of 15.70 s in 3 tubing reactors and reaction yields ranging
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10.1002/ejoc.201900468
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CCDC1876887 (for 5e) contain the supplementary crystallographic data
for this paper. This data can be obtained free of charge form The
Cambridge Crystallographic Data Centre.
1-phenylundec-1-yn-3-one (3l)[35]
:
1H-NMR (400 MHz, CDCl3): δ 7.58-
7.55 (m, 2H), 7.46-7.35 (m,3H), 2.65 (t, J = 7.6 Hz, 2H), 1.77-1.70 (m, 2H),
1.31-1.22 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 188.4, 133.0, 130.7, 128.6, 120.1, 90.6, 87.9, 45.6, 31.8, 29.3, 29.1, 29.0,
24.2, 22.7, 14.1.
1-phenyldodec-1-yn-3-one(3m)[36]: 1H-NMR (400 MHz, CDCl3): δ 7.56 (d,
J = 6.8 Hz, 2H), 7.46-7.35 (m, 3H), 2.65 (t, J = 7.2 Hz, 2H), 1.77-1.70 (m,
2H), 1.37-1.26 (m, 12H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 188.3, 133.0, 130.7, 128.6, 120.1, 90.6, 87.9, 45.6, 31.9, 29.4,
29.4, 29.3, 29.0, 24.2, 22.7, 14.1.
1,3-diphenylprop-2-yn-1-one (3a)[29] 1H-NMR (400 MHz, CDCl3): δ 8.25-
8.22 (m, 2H), 7.71-7.68 (m,2H), 7.48 (tt, J = 6.4, 1.2 Hz, 1H), 7.54-7.40 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 178.1, 136.9, 134.2, 133.1, 130.9,
129.6, 128.7, 128.7, 120.2, 93.2, 87.0.
3-phenyl-1-(p-tolyl)prop-2-yn-1-one(3b)[30]: 1H-NMR (400 MHz, CDCl3):
δ 8.10 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 7.2 Hz, 2H), 7.48-7.39 (m, 3H), 7.30
(d, J = 8.4 Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 177.8,
145.3, 134.7, 133.1, 130.7, 129.8, 129.4, 128.7, 120.3, 92.6, 87.0, 21.9.
7-bromo-1-phenylhept-1-yn-3-one (3n): Light yellow oily liquid. 1H-NMR
(400 MHz, CDCl3): δ 7.56 (d, 7.6 Hz, 2H), 7.46-7.35 (m, 3H), 3.42 (t, J =
6.4 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 1.93-1.86 (m, 4H). 13C NMR (100
MHz, CDCl3): δ 187.2, 133.1, 130.8, 128.7, 119.9, 91.1, 87.7, 44.4, 33.1,
31.8, 22.7. IR (neat) ν 2958, 2201, 1667, 1489, 1444, 1404, 1358, 1277
cm-1. HRMS (ESI) m/z: calcd for C13H13BrO: 264.0150, found 264.0149.
:
1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one(3c)[30] 1H-NMR (400
MHz, CDCl3): δ 8.18 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.47-
7.38 (m, 3H), 6.97 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 176.7, 164.5, 133.0, 132.0, 130.6, 130.4, 128.7, 120.4, 113.9,
92.3, 87.0, 55.6.
1-phenyl-3-(p-tolyl)prop-2-yn-1-one (3o)[30])
:
1H-NMR (400 MHz,
CDCl3): δ 8.22 (d, J = 6.8 Hz, 2H), 7.63-7.54 (m, 3H), 7.52-7.49 (m, 2H),
7.22 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 178.1,
141.6, 137.0, 134.0, 133.2, 129.6, 129.5, 128.6, 117.1, 93.9, 86.8, 21.8.
3-(4-chlorophenyl)-1-phenylprop-2-yn-1-one(3d)[30]: 1H-NMR (400 MHz,
CDCl3): δ 8.15 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 7.51-7.41 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 176.7, 140.8, 135.4, 133.1, 131.0,
130.9, 129.1, 128.8, 119.9, 93.7, 86.6.
3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-one (3p)[30]
:
1H-NMR (400
MHz, CDCl3): δ 8.21 (d, J = 7.2 Hz, 2H), 7.65-7.59 (m, 3H), 7.50 (t, J = 8.0
Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 178.1, 161.8, 137.1, 135.2, 134.0, 129.5, 128.6, 114.5, 111.9, 94.4, 86.9,
55.5.
1-(2-Iodophenyl)-3-phenylprop-2-yn-1-one(3e)[31] 1H-NMR (400 MHz,
:
CDCl3): δ 8.12 (dd, J = 7.8, 1.4 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.63 (d,
J = 6.8 Hz, 2H), 7.51-7.37 (m, 4H), 7.18 (td, J = 8.0, 2.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 178.0, 142.2, 139.4, 133.5, 133.1, 131.1, 128.8,
128.2, 119.9, 94.4, 92.9, 87.3.
1-phenylhex-2-yn-1-one (3q)[30]: 1H-NMR (400 MHz, CDCl3): δ 8.11 (d, J
= 7.6 Hz, 2H), 7.55 (tt, J = 7.2, 1.6 Hz, 1H), 7.45-7.42 (m, 2H), 2.44 (t, J =
7.2 Hz, 2H), 1.71-1.62 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 178.2, 137.0, 133.9, 129.5, 128.5, 96.7, 79.8, 21.4, 21.2,
13.6.
1-(4-nitrophenyl)-3-phenylprop-2-yn-1-one (3f)[32] 1H-NMR (400 MHz,
:
CDCl3): δ 8.35 (s, 4H), 7.69 (d, J = 7.2 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H),
7.44 (t, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 175.9, 150.9, 141.0,
133.3, 131.5, 130.5, 128.9, 123.9, 119.4, 95.5, 86.6.
1-(4-chlorophenyl)hex-2-yn-1-one(3r): 1H-NMR (400 MHz, CDCl3): δ
8.05 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 2.46 (t, J = 6.8 Hz, 2H),
1.7-1.64 (m,2H), 1.06 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
176.9, 140.5, 135.4, 130.9, 128.9, 97.3, 79.5, 21.4, 21.2, 13.6.
:
1-(Furan-2-yl)-3-phenylprop-2-yn-1-one (3g)[31] 1H-NMR (400 MHz,
CDCl3): δ 7.65-7.59 (m, 3H), 7.45-7.34 (m, 4H), 6.57 (dd, J =3.6, 1.6 Hz
1H). 13C NMR (100 MHz, CDCl3): δ 164.8, 153.2, 148.1, 133.1, 130.9,
128.7, 121.1, 119.8, 112.8, 92.0, 86.3.
1-(p-tolyl)hept-2-yn-1-one (3s)[37]): 1H-NMR (400 MHz, CDCl3): δ 7.99 (d,
J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.38 (s,
3H), 1.66-1.59 (m, 2H), 1.52-1.42 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 178.0, 144.9, 134.7, 129.7, 129.2, 96.3, 79.8,
29.9, 22.1, 21.8, 18.9, 13.5.
:
(E)-1,5-diphenylpent-1-en-4-yn-3-one (3h)[1e] 1H-NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 16 Hz, 1H), 7.65-7.58 (m, 4H), 7.48-7.38 (m, 6H),
6.86 (d, J = 16 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 178.3, 148.4,134.1,
133.0, 131.3, 130.7, 129.2, 128.8, 128.7, 128.6, 120.2, 91.6, 86.7.
General process for the preparation of pyrazole in a sequential flow
microreactor system: A microreactor system consist of three T-shaped
micromixers (M1, M2 and M3), three microtube reactions (R1, R2 and R3)
and three precooling units (P1 (inner diameter = 800µm, length L = 100
cm), P2 (inner diameter = 800 µm, length L = 50 cm), P3 (inner diameter
= 800 µm, length L = 100 cm) and one preheating unit P4 (inner diameter
= 1000 µm, length L = 20 cm) were used. A solution of alkyne (0.10 M in
THF) (flow rate: 6.0 mL/min) and a solution of n-BuLi (1.60 M in hexane)
(flow rate: 0.4 mL/min) were introduced to M1 (Φ = 0.5 mm) using syringe
pumps. The resulting solution was passed through R1 (Φ = 0.8 mm, L =
50 cm, 251 µL) and was mixed with a solution of acid chloride (0.3 M in
THF) (flow rate: 3.0 mL/min) in M2 (Φ = 0.5 mm). The resulting solution
was passed through R2 (Φ = 1.0 mm, L = 50 cm, 393 µL)) and it was mixed
with a solution of hydrazine derivatives (0.4 M in EtOH) (flow rate: 4.0 mL/
min) in M3 (Φ = 0.5 mm). The solution was passed throw preheating unit
1,1-dichloro-4-phenylbut-3-yn-2-one (3i)[33]: 1H-NMR (400 MHz, CDCl3):
δ 7.65 (dd, J = 8.5, 1.1 Hz, 2H), 7.52 (tt, J = 7.6, 1.6 Hz, 1H), 7.42 (t, J =
7.6 Hz, 2H), 5.99 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 168.4, 128.1,
126.3, 123.3, 113.4, 92.4, 77.9, 64.5.
1-Phenylpent-1-yn-3-one (3j)[1e] : 1H-NMR (400 MHz, CDCl3): δ 7.55-7.53
(m, 2H), 7.44-7.32 (m, 3H), 2.67 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 188.6, 133.0, 130.7, 128.6, 120.1, 90.7,
87.7, 38.9, 8.2.
1-phenyldec-1-yn-3-one (3k)[34] : 1H-NMR (400 MHz, CDCl3): δ 7.56-7.54
(m, 2H), 7.45-7.41 (m, 1H),7.37-7.33 (m, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.76-
1.68 (m, 2H), 1.36-1.24 (m, 8H), 0.87 (t, J = 6.8 Hz). 13C NMR (100 MHz,
CDCl3): δ 188.3, 133.0, 130.7, 128.6, 120.1, 90.6, 87.9, 45.6, 31.7, 29.0,
29.0, 24.2, 22.6, 14.1.
o
R3 (Φ = 1.0 mm, L = 500 cm, 2514 µL) at 70 C. After a steady state was
reached (after 1 min), the final product solution was collected for 60
seconds. The reaction mixture was analysed by GC and mixture was
extracted with EA. The organic phase was dried with MgSO4, and solvent
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900468
European Journal of Organic Chemistry
FULL PAPER
was removed by vacuum. The residue was purified by column
chromatography and product was analysed by 1H, 13C NMR, IR and Mass
spectrometer.
(100 MHz, CDCl3): δ 148.8, 137.9, 134.7, 125.4, 123.3, 123.1, 122.8,
122.5, 121.5,119.6, 101.2, 26.3, 24.2, 24.0, 23.6, 22.8, 17.2, 8.6. IR (neat)
ν 2927, 2855, 1597, 1550, 1504, 1458, 1376, 658 cm-1. HRMS (APC1)
calcd for C22H27N2 [M+H]+: 319.2174, found 319.2170.
3,5-diphenyl-1H-pyrazole (5a)[38] 1H-NMR (400 MHz, CDCl3): δ 7.74-
:
7.72 (m, 4H), 7.43-7.32 (m, 6H), 6.84 (s, 1H). 13C NMR (100 MHz, CDCl3):
1,5-diphenyl-3-(p-tolyl)-1H-pyrazole (5m)[39]
:
1H-NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 8.0 Hz, 2H), 7.37-7.22 (m, 12H), 6.79 (s, 1H), 2.38
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 146.5, 138.8, 134.7, 132.3, 125.2,
124.7, 123.8, 123.4, 123.2, 122.9, 122.7, 121.8, 120.2, 119.8, 99.6, 15.8.
δ 148.8, 131.3, 128.9, 128.3, 125.7, 100.2.
1,3,5-triphenyl-1H-pyrazole (5b)[39] : 1H-NMR (400 MHz, CDCl3): δ 7.92
(d, J = 7.3 Hz, 2H), 7.42 (td, J = 6.8, 1.6 Hz, 2H), 7.38-7.26 (m, 11H), 6.82
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 150.9, 143.3, 139.1, 132.0, 129.5,
127.8, 127.7, 127.6, 127.4, 127.2, 126.9, 126.4, 124.7, 124.2, 104.1.
3-(4-methoxyphenyl)-1,5-diphenyl-1H-pyrazole (5n)[46] 1H-NMR (400
:
MHz, CDCl3): δ 7.84 (d, J = 8.4 Hz, 2H), 7.36-7.24 (m, 10H), 6.96 (d, J =
9.2 Hz, 2H), 6.74 (s, 1H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.0,
146.2, 138.7, 134.6, 125.1, 123.2, 123.1, 122.8, 122.6, 121.7, 121.4, 120.2,
119.6, 108.4, 99.2, 49.7.
5-phenyl-3-(p-tolyl)-1H-pyrazole (5c)[40] 1H-NMR (400 MHz, CDCl3): δ
:
7.68 (d, J = 6.8 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.34-7.27 (m, 3H), 7.12
(d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 138.0, 131.6, 129.5, 128.8, 128.3, 128.0, 125.7, 125.5, 99.7, 21.3.
5-butyl-3-phenyl-1H-Pyrazole (5o)[48]: 1H-NMR (400 MHz, CDCl3): δ 9.46
(bs, 1H), 7.63 (d, J = 6.8 Hz, 2H), 7.26-7.15 (m, 3H), 6.24 (s, 1H), 2.47 (t,
J = 7.6 Hz, 2H), 1.49 (quint, J = 7.6 Hz, 2H), 1.24-1.17 (m, 2H), 0.78 (t, J
= 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 144.2, 142.3, 127.1, 123.0,
122.0, 120.1, 95.3, 25.7, 20.4, 16.7, 8.1.
3-(4-chlorophenyl)-5-phenyl-1H-pyrazole (5d)[40]
:
1H-NMR (400 MHz,
CDCl3): δ 7.76 (d, J = 7.2 Hz, 4H), 7.44-7.30 (m, 5H), 6.82 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 127.8, 125.5, 125.2, 123.2, 122.4, 121.2, 119.9,
94.0.
5-(4-chlorophenyl)-1,3-diphenyl-1H-pyrazole (5e)[41]
:
1H-NMR (400
Acknowledgments
MHz, CDCl3): δ 7.92 (dd, J = 7.2, 1.6 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H),
7.36-7.28 (m, 8H), 7.20 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 152.1, 143.2, 139.9, 134.4, 132.9, 130.0, 129.16, 129.1,
128.89, 128.78, 128.21, 127.7, 125.9, 125.4, 105.3.
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST 106-2113-M-037-009-), Taiwan,
Kaohsiung Medical University Research Foundation (KMU-
M108017) and the Center for Research Resources and
Development of Kaohsiung Medical University for Mass and 400
MHz NMR analyses. The authors also thank to Dr. Gopal Chandru
Senadi for technical discussions and for preparation of
manuscript.
3-(4-Nitrophenyl)-5-phenyl-1H-pyrazole (5f)[42]
:
1H-NMR (400 MHz,
CDCl3): δ 8.22 (d, J = 8 Hz, 2H), 7.96 (d, J = 8 Hz, 2H), 7.71 (d, J = 20 Hz,
2H), 7.45-7.28 (m, 3H), 6.88 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 129.0,
128.4, 126.0, 125.6, 124.1, 100.6.
3-(furan-2-yl)-5-phenyl-1H-pyrazole (5g)[43] : 1H-NMR (400 MHz, CDCl3):
δ 11.95-10.86 (bs, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 2H), 7.29-7.21 (m, 4H),
6.62 (s, 1H), 6.51 (d, J = 3.2 Hz, 1H), 6.31 (dd, J = 3.2, 2.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 147.5, 147.2, 141.8, 141.4, 130.6, 128.7, 128.1,
125.6, 111.3, 106.2, 99.1.
Keywords: Continuous flow • Ynone • Pyrazole • Transition
metal free • Lithiation
3-benzyl-5-phenyl-1H-pyrazole(5h)[44]
:
1H-NMR (400 MHz, CDCl3): δ
References
7.64 (d, J = 7.2 Hz, 2H), 7.32-7.17 (m, 8H), 6.29 (s, 1H), 3.93 (s, 2H). 13
C
NMR (100 MHz, CDCl3): δ 149.2, 147.5, 138.6, 132.0, 128.83, 128.81,
[1]
a) H.-L. Cui, H.-Q. Deng, J.-J. Lei, Tetrahedron 2017, 73, 7282-
7290; b) C. G. née Boersch, K. Lutsenko, E. Merkul, W. Frank, T.
J. Müller, Org. Chem. Front. 2016, 3, 887-896; c) W. P. Unsworth,
J. D. Cuthbertson, R. J. Taylor, Org. Lett. 2013, 15, 3306-3309; d)
J. Ciesielski, V. Gandon, A. J. Frontier, J. Org. Chem. 2013, 78,
9541-9552; e) S. Santra, K. Dhara, P. Ranjan, P. Bera, J. Dash, S.
K. Mandal, Green Chem. 2011, 13, 3238-3247.
a) B. H. Xu, G. Kehr, R. Frohlich, B. Wibbeling, B. Schirmer, S.
Grimme, G. Erker, Angew. Chem. Int. Ed. 2011, 50, 7183-7186; b)
R. E. Whittaker, A. Dermenci, G. B. Dong, Synthesis-Stuttgart
2016, 48, 161-183.
a) J. T. DePinto, W. A. deProphetis, J. L. Menke, R. J. McMahon,
J. Am. Chem. Soc. 2007, 129, 2308-2315; b) G. A. Kraus, M. J.
Taschner, J. Am. Chem. Soc. 1980, 102, 1974-1977; c) K.
Wakamatsu, Y. Okuda, K. Oshima, H. Nozaki, Bull. Chem. Soc.
Jpn. 1985, 58, 2425-2426; d) R. E. Whittaker, A. Dermenci, G.
Dong, Synthesis 2016, 48, 161-183; e) M. Schuler, F. Silva, C.
Bobbio, A. Tessier, V. Gouverneur, Angew. Chem. Int. Ed. 2008,
47, 7927-7930.
128.7, 128.0, 126.6, 125.7, 102.1, 33.2. [45]
1
5-benzyl-1,3-diphenyl-1H-pyrazole (5i) [46]: H-NMR (400 MHz, CDCl3):
δ 7.47-7.44 (m, 2H), 7.38-7.32 (m, 8H), 7.25-7.17 (m, 5H), 6.52 (s, 1H),
3.85 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 162.6, 127.8, 127.3, 126.2,
124.18, 124.10, 123.6, 123.4, 123.3, 122.9, 122.8, 122.7, 121.9, 120.2,
116.5, 36.1.
[2]
[3]
3-ethyl-5-phenyl-1H-pyrazole (5j)[44]: 1H-NMR (400 MHz, CDCl3): δ 9.93
(s, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.31 (dt, J = 26.7, 7.3 Hz, 3H), 6.35 (s,
1H), 2.62 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 144.1, 143.8, 127.1, 123.0, 122.0, 120.1, 94.8, 14.0, 7.8.
3-heptyl-5-phenyl-1H-pyrazole (5k)[47] 1H-NMR (400 MHz, CDCl3): δ
:
[4]
a) C.-X. Guo, B. Yu, J.-N. Xie, L.-N. He, Green Chem. 2015, 17,
474-479; b) C. Bai, S. Jian, X. Yao, Y. Li, Cata. Sci. Tech. 2014, 4,
3261-3267; c) K. Wang, L. Yang, W. Zhao, L. Cao, Z. Sun, F.
Zhang, Green Chem. 2017, 19, 1949-1957.
B. Chabaud, K. B. Sharpless, J. Org. Chem. 1979, 44, 4202-4204.
J. Muzart, O. Piva, Tetrahedron Lett. 1988, 29, 2321-2324.
P. Li, W. M. Fong, L. C. F. Chao, S. H. C. Fung, I. D. Williams, J.
Org. Chem. 2001, 66, 4087-4090.
9.86 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.38-7.26 (m, 3H), 6.34 (s, 1H), 2.60
(t, J = 7.8 Hz, 2H), 1.66-1.59 (m, 2H), 1.32-1.25 (m, 8H), 0.87 (t, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 150.1, 147.9, 132.8, 128.7, 127.8,
125.7, 101.0, 31.8, 29.7, 29.3, 29.1, 26.4, 22.7, 14.1.
[5]
[6]
[7]
5-heptyl-1,3-diphenyl-1H-pyrazole (5l): Yellow oily liquid. 1H-NMR (400
MHz, CDCl3): δ 7.31-7.20 (m, 10H), 6.32 (s, 1H), 2.72 (t, J = 8.0 Hz, 2H),
1.77-1.69 (m, 2H), 1.45-1.25 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR
[8]
W. K. Shin, Y. R. Kim, S. H. Im, A. K. Jaladi, S. Gundeti, D. K. An,
Bull. Korean Chem. Soc. 2018, 39, 683-686.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900468
European Journal of Organic Chemistry
FULL PAPER
[9]
S. Kim, S. W. Kang, A. Kim, M. Yusuf, J. C. Park, K. H. Park, RSC
[29]
[30]
[31]
R. E. Whittaker, G. Dong, Org. Lett. 2015, 17, 5504-5507.
Adv. 2018, 8, 6200-6205.
A. Park, K. Park, Y. Kim, S. Lee, Org. Lett. 2011, 13, 944-947.
V. K. Vyas, R. C. Knighton, B. M. Bhanage, M. Wills, Org. Lett.
2018, 20, 975-978.
C. H. Bai, S. P. Jian, X. F. Yao, Y. W. Li, Catal. Sci. Technol. 2014,
4, 3261-3267.
M. A. Ganiek, M. V. Ivanova, B. Martin, P. Knochel, Angew. Chem.
Int. Ed. 2018, 57, 17249-17253.
Y. Sadamitsu, K. Komatsuki, K. Saito, T. Yamada, Org. Lett. 2017,
[10]
a) C. François-Endelmond, T. Carlin, P. Thuery, O. Loreau, F.
Taran, Org. Lett. 2009, 12, 40-42; b) S.-G. Huang, H.-F. Mao, S.-F.
Zhou, J.-P. Zou, W. Zhang, Tetrahedron Lett. 2013, 54, 6178-
6180; c) N. Li, D. Wang, J. Li, W. Shi, C. Li, B. Chen, Tetrahedron
Lett. 2011, 52, 980-982; d) H.-L. Liu, H.-F. Jiang, M. Zhang, W.-J.
Yao, Q.-H. Zhu, Z. Tang, Tetrahedron Lett. 2008, 49, 3805-3809;
e) O. Seppaenen, M. Muuronen, J. Helaja, Eur. J. Org. Chem.
2014, 2014, 4044-4052.
[32]
[33]
[34]
[35]
19, 3191-3194.
[11]
[12]
L. Xiao, X. Y. Lu, D. M. Ruden, Mini Rev. Med. Chem. 2006, 6,
1137-1143.
K. A. Aliferis, S. Jabaji, Pestic. Biochem. Physiol. 2011, 100, 105-
117.
A. Fusano, T. Fukuyama, S. Nishitani, T. Inouye, I. Ryu, Org. Lett.
2010, 12, 2410-2413.
I. E. Marko, J. M. Southern, J. Org. Chem. 1990, 55, 3368-3370.
M. Cai, G. Zheng, G. Ding, Green Chem. 2009, 11, 1687-1693.
M. Tang, W. Zhang, Y. Kong, Org. Biomol. Chem. 2013, 11, 6250-
6254.
X.-W. Fan, T. Lei, C. Zhou, Q.-Y. Meng, B. Chen, C.-H. Tung, L.-Z.
Wu, J. Org. Chem. 2016, 81, 7127-7133.
R. Harigae, K. Moriyama, H. Togo, J. Org. Chem. 2014, 79, 2049-
2058.
B. Willy, T. J. J. Müller, Eur. J. Org. Chem. 2008, 2008, 4157-
4168.
H. L. Zhang, Q. Wei, G. D. Zhu, J. P. Qu, B. M. Wang, Tetrahedron
Lett. 2016, 57, 2633-2637.
S. X. Xu, L. Hao, T. Wang, Z. C. Ding, Z. P. Zhan, Org. Biomol.
Chem. 2013, 11, 294-298.
R. M. Claramunt, P. Cornago, M. D. Santa Maria, V. Torres, E.
Pinilla, M. Torres, J. Elguero, Supramol. Chem. 2006, 18, 349-356.
R. Kinjo, B. Donnadieu, G. Bertrand, Angew. Chem. Int. Ed. 2011,
50, 5560-5563.
S. Kramer, J. L. H. Madsen, M. Rottländer, T. Skrydstrup, Org.
Lett. 2010, 12, 2758-2761.
B. R. Kim, G. H. Sung, K. E. Ryu, S. G. Lee, H. J. Yoon, D. S.
Shin, Y. J. Yoon, Chem. Commun. 2015, 51, 9201-9204.
N. Iranpoor, H. Firouzabadi, E. Etemadi-Davan, Tetrahedron Lett.
2016, 57, 837-840.
[36]
[37]
[38]
[13]
[14]
[15]
A. T. Koki, J. L. Masferrer, Cancer control 2002, 9, 28-35.
M. Zora, A. Kivrak, J. Org. Chem. 2011, 76, 9379-9390.
S. Karabiyikoglu, M. Zora, Appl. Organomet. Chem. 2016, 30, 876-
885.
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[16]
[17]
[18]
[19]
M. M. Bassaco, M. P. Fortes, T. S. Kaufman, C. C. Silveira, Rsc
Adv 2015, 5, 21112-21124.
B. C. Bishop, K. M. J. Brands, A. D. Gibb, D. J. Kennedy,
Synthesis-Stuttgart 2004, 43-52.
A. C. Gotzinger, F. A. Thesseling, C. Hoppe, T. J. J. Muller, J. Org.
Chem. 2016, 81, 10328-10338.
a) J.-i. Yoshida, Y. Takahashi, A. Nagaki, Chem. Commun. 2013,
49, 9896-9904; b) M. Movsisyan, E. Delbeke, J. Berton, C.
Battilocchio, S. Ley, C. Stevens, Chem. Soc. Rev. 2016, 45, 4892-
4928; c) F. Fanelli, G. Parisi, L. Degennaro, R. Luisi, Beilstein J.
Org. Chem. 2017, 13, 520-542; d) B. Gutmann, D. Cantillo, C. O.
Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688-6728; e) R. Porta,
M. Benaglia, A. Puglisi, Org. Process Res. Dev. 2015, 20, 2-25; f)
B. J. Reizman, K. F. Jensen, Acc. Chem. Res. 2016, 49, 1786-
1796; g) I. M. Mándity, S. B. Ötvös, F. Fülöp, ChemistryOpen
2015, 4, 212-223; h) A. Adamo, R. L. Beingessner, M. Behnam, J.
Chen, T. F. Jamison, K. F. Jensen, J.-C. M. Monbaliu, A. S.
Myerson, E. M. Revalor, D. R. Snead, Science 2016, 352, 61-67; i)
A. R. Bogdan, A. W. Dombrowski, J. Med. Chem. 2019; j) S. G.
Koenig, H. F. Sneddon, Green Chem. 2017, 19, 1418-1419; k) M.
B. Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger, Chem. Rev.
2017, 117, 11796-11893; l) M. Baumann, I. R. Baxendale,
Beilstein J. Org. Chem. 2015, 11, 1194-1219.
[20]
[21]
a) S. Kobayashi, Chem. Asian. J. 2016, 11, 425-436; b) I. M.
Mándity, S. B. Ötvös, G. Szőlősi, F. Fülöp, Chem. Rec. 2016, 16,
1018-1033.
a) H. Kim, K.-I. Min, K. Inoue, D.-P. Kim, J.-i. Yoshida, Science
2016, 352, 691-694; b) L. Degennaro, D. Maggiulli, C. Carlucci, F.
Fanelli, G. Romanazzi, R. Luisi, Chem. Commun. 2016, 52, 9554-
9557; c) H. Kim, H. J. Lee, D. P. Kim, Angew. Chem. Int. Ed. 2015,
54, 1877-1880; d) A. Nagaki, K. Imai, S. Ishiuchi, J. i. Yoshida,
Angew. Chem. Int. Ed. 2015, 54, 1914-1918.
[22]
[23]
M. T. Rahman, T. Fukuyama, N. Kamata, M. Sato, I. Ryu, Chem.
Commun. 2006, 2236-2238.
a) J. R. Breen, G. Sandford, D. S. Yufit, J. A. Howard, J. Fray, B.
Patel, Beilstein J. Org. Chem. 2011, 7, 1048; b) J. Comas-Barceló,
D. Blanco-Ania, S. A. van den Broek, P. J. Nieuwland, J. P.
Harrity, F. P. Rutjes, Catal. Sci. Technol. 2016, 6, 4718-4723; c) B.
Li, D. Widlicka, S. Boucher, C. Hayward, J. Lucas, J. C. Murray, B.
T. O’Neil, D. Pfisterer, L. Samp, J. VanAlsten, Org. Process Res.
Dev. 2012, 16, 2031-2035; d) I. R. Baxendale, J. Chem. Technol.
Biotechnol. 2013, 88, 519-552; e) S. Borukhova, T. Noel, B.
Metten, E. de Vos, V. Hessel, Chemsuschem 2013, 6, 2220-2225;
f) K. P. Cole, J. M. Groh, M. D. Johnson, C. L. Burcham, B. M.
Campbell, W. D. Diseroad, M. R. Heller, J. R. Howell, N. J.
Kallman, T. M. Koenig, S. A. May, R. D. Miller, D. Mitchell, D. P.
Myers, S. S. Myers, J. L. Phillips, C. S. Polster, T. D. White, J.
Cashman, D. Hurley, R. Moylan, P. Sheehan, R. D. Spencer, K.
Desmond, P. Desmond, O. Gowran, Science 2017, 356, 1144-
1150; g) C. Battilocchio, B. J. Deadman, N. Nikbin, M. O. Kitching,
I. R. Baxendale, S. V. Ley, Chem. Eur. J. 2013, 19, 7917-7930; h)
S. B. Otvos, A. Georgiades, D. Ozsvar, F. Fulop, Rsc Adv. 2019, 9,
8197-8203; i) C. J. Smith, F. J. Iglesias-Siguenza, I. R. Baxendale,
S. V. Ley, Org. Biomol. Chem. 2007, 5, 2758-2761; j) J. Britton, T.
F. Jamison, Angew. Chem. Int. Ed. 2017, 56, 8823-8827.
I. R. Baxendale, S. C. Schou, J. Sedelmeier, S. V. Ley, Chem. Eur.
J. 2010, 16, 89-94.
[24]
[25]
[26]
[27]
[28]
J.-S. Poh, D. L. Browne, S. V. Ley, React. Chem. Eng. 2016, 1,
101-105.
J. Britton, T. F. Jamison, Eur. J. Org. Chem. 2017, 2017, 6566-
6574.
A. C. Jones, A. W. Sanders, M. J. Bevan, H. J. Reich, J. Am.
Chem. Soc. 2007, 129, 3492-3493.
a) Y. Tu, Z. Zhang, T. Wang, J. Ke, J. Zhao, Org. Lett. 2017, 19,
3466-3469; b) B. Willy, T. J. Mueller, Eur. J. Org. Chem. 2008,
2008, 4157-4168.
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10.1002/ejoc.201900468
European Journal of Organic Chemistry
FULL PAPER
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Key Topic* Continuous flow,
Li
R1
R1
O
Mohanraj Kandasamy, [a] Balaji Ganesan, [a]
Min-Yuan Hung [b] and Wei-Yu Lin*[a,c]
R2
R1
n-BuLi
R3
R2
O
N
N
R1
Page No. – Page No.
Cl
R2
R3 NHNH2
19 examples of ynones
up to 96 yields
15 examples of pyrazoles
up to 77 yields
Fast and efficient continuous flow method for
the synthesis of ynones and pyrazoles
Short reaction time
Mild conditions
Transition metal free conditions
An efficient method for the ynones and polysubstituted pyrazoles in a continuous flow system through the generation of activated lithium acetylide. This process
serves as a powerful strategy for fast, transition metal free, mild conditions, easy process and highly reagent controllable over the benchtop method.
This article is protected by copyright. All rights reserved.