In Situ Generation of Alkynylzinc and Its Subsequent Negishi Reaction in a Flow Reactor

Article abstract of DOI:10.1002/ejoc.201900471

A highly efficient and convenient Negishi cross-coupling reaction has been developed for the synthesis of unsymmetrical alkynes and enynes in a continuous-flow process. The reaction proceeds through an in situ generated alkynylzinc reagent by the reaction of lithium acetylide with zinc halide at room temperature followed by a cross-coupling reaction with aryl or vinyl iodides. The notable features of this work compared to the conventional benchtop method are mild reaction conditions, good to excellent yields, broad functional-group compatibility, short residence time (73 sec) and especially desilylation of TMS group with the residence time of only 10.5 sec.

Full text of DOI:10.1002/ejoc.201900471

A Journal of
Accepted Article
Title: In situ generation of alkynylzinc and its subsequent cross-
coupling reaction in a flow reactor
Authors: Mohanraj Kandasamy, Yu- Hsuan Huang, Balaji Ganesan,
Gopal Chandru Senadi, and Wei-Yu Lin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900471
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900471
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10.1002/ejoc.201900471
European Journal of Organic Chemistry
FULL PAPER
In situ generation of alkynylzinc and its subsequent cross-
coupling reaction in a flow reactor
Mohanraj Kandasamy, [a] Yu- Hsuan Huang, [a] Balaji Ganesan,[a] Gopal Chandru Senadi[c] and Wei-Yu
Lin*[a, b]
Abstract: A highly efficient and convenient Negishi cross-coupling
reaction has been developed for the synthesis of unsymmetrical
alkynes and enynes in a continuous-flow process. The reaction
proceeds through an in situ generated alkynylzinc reagent by the
reaction of lithium acetylide with zinc halide at room temperature
followed by a cross-coupling with aryl or vinyl iodides. The notable
features of this work over the conventional benchtop method are mild
reaction conditions, good to excellent yields, broad functional group
compatibility, short residence time (73 sec) and especially desilylation
of TMS group with the residence time of only 10.5 sec.
yield (STY) of 20.4 g/Lh,[8] by Sonogashira cross-coupling
reaction. Similarly, James et al reported the drug-like 3-
aminoindolizine derivatives with STY of 1.6 g/Lh[9] from milligram
to gram scale.[8-10] Despite these significant advancements, some
of the methods require copper as co-catalyst that may lead to the
undesired homocoupled product (Glaser coupling), stoichiometric
bases, high temperatures and long reaction times. To overcome
the drawbacks, modified catalytic conditions has been reported in
the literature,[4]but, those reagents are expensive or need to be
prepared in the laboratories which may hamper the practicality in
the large scale.
On the other hand, the formation of C(sp2)-C(sp) and C(sp3)-
C(sp3) bonds via the Negishi reaction using palladium- or nickel-
catalyzed coupling of organozinc compounds with various
halides[11] have been extensively studied because of its mild
conditions and low toxicity of zinc salts.[12] However, the high
reactivity and sensitivity of organozinc reagents to air/moisture
makes it difficult to prepare under cryogenic conditions.[13] To date,
only a few methodologies have been reported for the in situ
generation of organozinc and its subsequent use in cross-
coupling or electrophilic reactions in flow chemistry.[14] Knochel
and co-workers demonstrated the in situ zincations of
functionalized arenes and heteroarenes using (Cy2N)2Zn·2LiCl in
a continuous flow system followed by a batch process.[14a]
Buchwald and co-workers[15] reported the synthesis of aryloxirane
derivatives via an in situ generated organozinc reagents followed
by Negishi cross-coupling. Recently, Alcázar and co-workers
reported the photoinduced[16] Pd or Ni catalyzed Negishi cross-
couplings in a flow reactor using the zinc metal. Nevertheless,
applying these methods for the preparation of organozinc by a
lithium base still demands a low temperature conditions nor
further transformation in a batch reactor and excessive amount of
starting materials. By considering the above facts and our
continuing interest in lithium acetylide chemistry[17] Herein, we
designed an alternative approach for the synthesis of internal
alkynes and enynes via Negishi cross-coupling between an in situ
generated alkynylzinc reagents and aryl or vinyl iodides in a
simple and robust flow system using commercial catalyst and
ligand that can enable the gram scale synthesis.
Introduction
Alkynes are valuable building blocks because of their versatile
use in natural products, pharmaceuticals, and material
sciences.[1] In this context, the alkynylation of aryl halides by
Sonogashira reaction[2] has gained significant attention for the
synthesis of functionalized alkynes.[3] However, the production of
these alkynes on an industrial scale using the conventional
method still remains a potential challenge.[4]
Continuous-flow mediated transition-metal catalysis has gained
much attention in recent years as an alternative for benchtop
chemistry because of the key benefits like enhanced mass and
heat transfer, reduced reaction volumes, improved sample and
reagents mixing.[5] Thus, the development of new synthetic
methods under flow technology that could deliver the desired
compounds in an environmentally benign manner on a larger
scale with ease of operation is an essential area of research in
the scientific community.
The pioneering work developed by Yoshida and co-workers on
organolithium flash-chemistry has created a bench mark for the
researchers to do synthetic transformations from in situ generated
organolithium in the flow-process.[6] For instances, Buchwald and
Yoshida independently developed the continuous-flow synthesis
of biaryls enabled by multistep lithiation / borylation / Suzuki–
Miyaura cross-coupling sequence.[7] Ryu et al developed the
synthesis of metalloproteinase inhibitor having a high space time
Results and Discussion
[a]
Department of Medicinal and Applied Chemistry, Kaohsiung Medical
University, Kaohsiung 807, Taiwan
A flow setup has been made using three T-shaped micromixers
(M1, M2 and M3), three tubing reactors [(R1 (800 µm), R2 (1000
µm) and R3 (1000 µm), and a heating unit as presented in
Scheme 1. We began our preliminary investigation by choosing
phenylacetylene 1a and iodobenzene 2a as the model substrate
for Negishi cross-coupling reaction. The active lithium
phenylacetylide was generated according to our previous
reported literature [17] using 1a with n-butyllithium at mixer M1 at
Prof. Dr. Wei-Yu Lin; E-mail:wylin@kmu.edu.tw
http://wp.kmu.edu.tw/wylin
Department of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan
Department of Chemistry, Faculty of Engineering and Technology,
SRM Institute of Science and Technology, Kattankulathur, Chennai -
603203, India.
[b]
[c]
Supporting information and ORCID from the author(s) for this article
are available on the WWW under https://10.1002/ejoc.201900471R1
.
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10.1002/ejoc.201900471
European Journal of Organic Chemistry
FULL PAPER
20 °C with the residence time (tR1). Subsequent reaction of the
lithium phenylacetylide with ZnBr2 at M2 provided the
corresponding alkynylzinc in reactor R2 with the residence time
(tR2) at 20 °C. The in situ generated alkynylzinc reagent was
reacted with iodobenzene 2a in the presence of 5 mol% Pd(OAc)2
and 10 mol % of PPh3 at M3 to afford the desired cross-coupling
product 3aa in reactor R3 with the residence time of (tR3). Further
optimization studies were done by varying the residence (tR2) in
R2, cross-coupling temperature and the flow parameters.
Li
T1 = 20 oC
R1
P1 = 100 cm
M1
T2 oC
tR1
M2
n-BuLi
tR2
P2 = 25 cm
M3
ZnBr2
At room temperature, the conversion of the desired product 3aa
by GC was found to be 24% without any traces of Glaser coupled
product (Table 1, entry 1). When the temperature (T2) was
gradually increased from 50 °C to 80 °C (Table 1, entries 2-5), the
conversion of 3aa was improved to 99% with an isolated yield of
92% (Table 1, entry 5). Changing to other zinc halides like ZnCl2
and ZnI2 ended up in low yields (Table 1, entries 6-7). Reducing
the catalyst/ligand loading to 2.5 mol% and 5 mol% also
decreased the yield of 3aa (Table 1, entry 8). Equivalents studies
of ZnBr2 (Table 1, entries 9-11) revealed that the maximum yield
of 3aa can be achieved using 2.0 equiv. of ZnBr2 (Table 1, entry
5).
tR3
P3 = 25 cm
Catalyst
+
ligand
P4 = 20 cm
Scheme 1. Optimization of Negishi cross coupling on flow reactor
(M1, M2 and M3: 1000 µm of inner diameter) and three
microtubing reactors (R1(1000 µm), R2(1000 µm) and R3(1000
µm)
Table 1. Optimization study [a]
Entry
R1
Catalyst
ZnBr2
T2
(oC)
Yield
[b]
(%)
(x, mol%)
(equiv.)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(2.5)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(5.0)
Pd(OAc)2(1.0)
Pd(OAc)2(0.5)
Ni(OAc)2(5.0)
NiCl2(5.0)
2.0
2.0
2.0
2.0
2.0
2.0[d]
2.0[e]
2.0
1.5
1.25
1.0
2.0
2.0
1.5
1.5
2.0
2.0
2.0
2.0
20
50
60
70
80
80
80
80
80
80
80
50
80
80
80
80
80
80
80
24
Scheme 2. Substrate scope for alkyne derivatives. [a]
T1 = 20 o
C
2
48
F1 = 1.125 mL/min
P1 = 100 cm
0. 4 M in THF
tR1 = 10.58 s
3
63
M1 = 1000 µm
tR2 = 10.83 s
M2 = 1000 µm
T2 = 80 oC
F2 = 0.3 mL/min
P2 = 25 cm
n-BuLi
1.6 M in Hexane
tR3 = 50.76 s
F3 = 0.75 mL/min
P3 = 25 cm
ZnBr2
0. 6 M in THF
4
77
M3 = 1000 µm
F4 = 1.0 mL/min
P4 = 20 cm
Pd(OAc)2
+
5
99 (92)[c]
68
PPh3
0. 3 M in THF
6
R
7
77
MeO
Bu
Bu
R
3aa, R = H, 99, 92%[b]
3ca, R = H, 99, 85%[b,d]
3cb, R = 4- Me, 76%[b]
3cc, R = 4-OMe, 97, 87%[b]
3cd, R = 3-OMe, 25%
3ce, R = 2-OMe, 99%
71[f]
96
3ba, 70%
8
3ab, R = 4- Me, 83,77%[b]
3ag, R = 4-Cl, 68%[b]
3ah, R = 4-Br, 66%[b]
R
9
3cj, R = 4- CN, 62%
3ck, R = 4- CF3, 68 (64b)%
O
R
10
11
12
13
14
15
16
17
18
19
89
Bu
Bu
CH3
3cf, R = 4-F, 81%[b]
3cg, R = 4- Cl, 75%
3ch, R = 4-Br, 79 %
3ci, R = 3-Br, 74%[b]
S
3cl, 90%[b]
81
Bu
3cn, 71%[b]
41
Bu
Bu
Bu
I
83
3cp, 62%
3cm, 62% + 3cm' 25%
N
99[g,h]
87[g,i]
N.R
N.R
N.R
N.R
3co, 53%[b]
Pr
Hex
3ea, R = H, 98%
R
TMS
R
3da, R = H, 69%
3fa, R = H, 94%[b]
3eb, R = 4- Me, 83%[b]
3ec, R = 4-OMe, 65%[b]
3eg, R = 4-Cl, 99 %
3fc, R = 4-OMe, 99, 91%[b]
3fh, R = Br, 94%[c]
3eh, R = 4-Br, 82%[b]
OMe
Co(OAc)2(5.0)
Co(acac)2(5.0)
N
3gc, 43%
3hb, 56%[b]
[a] Reaction conditions: Flow condition-A (alkyne, ZnBr2 = 2.0 equiv, n-BuLi
=2.16 equiv), residence time 20.34 s, catalyst (x mol %), PPh3 (10 mol %) were
maintained unless otherwise noted. [b] GC conversion yield. [c] Yields in the
brackets corresponds to the isolated yields. [d] ZnCl2. [e] ZnI2. [f] PPh3 = 5
mol %. [g] Flow condition-B (alkyne, ZnBr2 =1.5 equiv, n-BuLi =1.6 equiv),
residence time 72.17 s. [h] PPh3 = 2 mol %. [i] PPh3 = 1 mol %. phenylacetylene:
1a, hexyne 1c. Inner diameters of the tube (R1) 800 µm. N.R. = No Reaction.
[a] Flow condition: (Alkyne, ZnBr2 =1.5 equiv, n-BuLi =1.6 equiv), residence time
= 72.17 s, GC conversion yield. [b] Isolated Yield. [c] 3.0 mmol scale reaction
(10 min). [d] 8.4 mmol scale reaction (28 min).
Based on the skeletal importance of alkyl substituted alkynes in
natural product synthesis,[18] we next examined hexyne 1c as a
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10.1002/ejoc.201900471
European Journal of Organic Chemistry
FULL PAPER
coupling partner with 2a using 5 mol% of Pd catalyst, 10 mol% of
PPh3 and 2.0 equiv. of ZnBr2 at 50 °C (T2). Unfortunately, the
conversion of the expected compound was less (Table 1, entry
12), whereas at an elevated temperature the conversion of the
product was drastically improved to 83% (Table 1, entry 13). To
our surprise, quantitative conversion was obtained by decreasing
the catalytic quantity to 1.0 mol% and increasing the residence
time in order to increase the mixing efficiency, and the quantitative
yield was almost observed (Table 1, entry 14). When the catalytic
amount was reduced to 0.5 mol%, yield also dropped to 87%. The
reaction was attempted with other catalysts, such as Ni(OAc)2,
NiCl2, Co(OAc)2 and Co(acac)2, but failed to provide the desired
product (Table 1, entries 16-19). Eventually, applying the same
strategy to the Sonogashira cross-coupling resulted in
heterogeneous solution and thereby leading to channel clogging.
The probable reason for this observation could arise from the use
of CuI catalyst.
desired 1,3-enyne (Z)-5aa was obtained in 98% yield with full
retention of stereochemistry. Further expansion of the scope with
Scheme 3. Substrate scope for enyne derivatives. [a]
T1 = 20 o
C
F1 = 1.125 mL/min
P1 = 100 cm
0. 4 M in THF
tR1 = 10.58 s
M1 = 1000 µm
tR2 = 10.83 s
M2 = 1000 µm
T2 = 80 oC
F2 = 0.3 mL/min
P2 = 25 cm
n-BuLi
1.6 M in Hexane
tR3 = 50.76 s
F3 = 0.75 mL/min
P3 = 25 cm
ZnBr2
0. 6 M in THF
M3 = 1000 µm
F4 = 1.0 mL/min
P4 = 20 cm
Pd(OAc)2
+
PPh3
0. 3 M in THF
Bu
Pr
Hex
EtOOC
EtOOC
EtOOC
EtOOC
5ca, 96,74%[b] 5da, 93,92%[b]
5aa, 98%
5ea, 94%
92 %[c], 79%[b,c]
With the optimized reaction conditions in hand for the synthesis
of internal alkynes, the scope of the reaction was examined with
different terminal alkynes and aryl iodides as presented in
Scheme 2. The electron-donating substituents such as p-Me (2b),
p-Cl (2g) and p-Br (2h) iodobenzenes reacted with 1a to afford
the desired products (3ab-3ah) in good to excellent yields.
Similarly, p-Methoxyphenylacetylene (1b) also underwent smooth
conversion with 2a to give 3ba in 70% yield. The reaction of
electron-donating aryl iodides (2b-e) with aliphatic alkyne such as
1-hexyne (1c) gave the required internal alkyne scaffolds 3cb-3ce
in excellent yields except in the case of m-iodoanisole (2d). The
practicality of the reaction was demonstrated on an 8.4 mmol
scale to beget compound 3ca within 28 minutes over 90%
conversion and an isolated yield of 85% with a space time yield
of 27.1 g/Lh (See Table S1). Whereas, the space time yield range
is only 2.1 [19] to 6.2 [20] g/Lh in a commercial batch reactor for the
synthesis alkynyl derivatives, suggesting that the flow system
enables a 12.3 fold increase in throughput for a given reactor
volume.
Ph
Bn
TMS
N
Bn N
N
EtOOC
EtOOC
EtOOC
5ha, 100, 99%[b]
5ia, 96,84%[b]
EtOOC
5ja, 96,77%[b]
5fa, 98%
Bu
Bu
Cl
O
O
O2N
5cc, 96, 65%[b]
5cb, 92%
[a] Flow condition: (Acetylene, ZnBr2 =1.5 equiv, n-BuLi =1.6 equiv), residence
time = 72.17 s, GC conversion. [b] Isolated Yield. [c] 3.0 mmol scale reaction
(10 min): 427 mg (79 %) of desired product.
different alkyl acetylenes such as 1-hexyne (1c), 1-pentyne (1d),
1-octyne (1e), TMS (1f), N-propargyl carbazole (1h), N-methyl-N-
propargylaniline (1i) and N,N-dibenzylpropargylamine (1j) with 4a
gave the corresponding products in good yields. The practicality
of the reaction was demonstrated on a 3.0 mmol scale under the
standard condition for 10 min and obtained 427 mg of 5ca (79%).
Next, we also investigated the feasibility of the reaction by
changing the vinyl iodide derivatives such as (Z)-2-iodo-vinyl
phenyl vinyl ether (3-Cl, 4b) and (4-NO2, 4c) with 1b; both were
tolerated in this process, affording the corresponding (Z)-5ab and
(Z)-5ac in good yield.
Electron-deficient groups such as -CN, and -CF3 as well as
halo- functional groups (2f-2k) were tolerated well to give the
corresponding products 3cf-3ck. Interestingly, when the di-iodo
compound 2m was employed, the desired mono- alkynylated
3cm was obtained as a major product with a 62% yield, and di-
alkynylated 3cm’ was observed with a 25% yield, which illustrated
the precise control of reagent over the batch conditions.[21]
Notably, acetyl functional groups, hetero aryl iodides and bulky
substituents (2l, 2n-2p) were proceeded smoothly and the cross-
coupling products 3cl, 3cn-3cp were obtained in moderate to
excellent yields. In addition, 1-pentyne (1d), 1-octyne (1e), TMS
acetylene (1f), cyclic enyne (1g) and N-propargyl carbazole (1h)
were efficiently coupled with various aryl iodides under these
reaction conditions to afford the desired alkynes in moderate to
excellent yields (49-99%).
ꢀꢁꢂ
n-BuLi
Work up
ZnBr2
Br
I
T1 = 20 o
tR1 = 10 s
C
Flow system 1
F1 = 4.0 mL/min
M1 = 500 µm
K2CO3
F2 = 2 mL/min
Flow system 2
0. 3 M in H2
O
With the successful outcome of alkyne derivatives, we applied
this methodology for the synthesis of various enynes, which are
versatile building blocks in organic synthesis.[22] The reaction of
1a with 4a (ethyl cis-3-iodoacrylate) was performed under the
standard conditions as presented in Scheme 3. Interestingly, the
Scheme 4. Two flow microreactor systems for the stepwise Negishi cross-
coupling and deprotection.
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10.1002/ejoc.201900471
European Journal of Organic Chemistry
FULL PAPER
solution was passed through R2 (Φ = 1.0 mm, L = 50 cm, 392 µL) and
introduced M3 (Φ = 1.0 mm). A solution of aryl iodide or vinyl iodide,
palladium acetate (1 mol %) and triphenyl phosphine (2 mol %) and
introduced in M3. The resulting final solution passed through R3 (Φ = 1.0
mm, L = 350 cm, 2749 µL) at 80 oC. 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. The crude mixture was diluted with EA and water, organic phase
was separated and the aqueous phase extracted twice with EA (2 × 20
mL). The combined organic layer was dried over MgSO4, and purified by
column chromatography and product was analysed by 1H, 13C NMR, IR
and mass spectrometer.
To show a broader application of this process, the deprotection
of TMS protected alkynes was investigated by reacting alkyne 3fa
with K2CO3 as base using one T-shaped micromixer (M1), one
tubing reactor [R1(800 µm)] at room temperature. The reaction
underwent complete desilylation with a residence time of 10.5 s
(See SI, Table S2, entry 1-3). With this success, two flow systems
(Scheme 4 and see SI) were used to demonstrate the stepwise
Negishi cross-coupling of TMS-protected alkyne and the
deprotection of the corresponding TMS-alkyne. In this regards,
compound 3fh was synthesized in a 3 mmol scale using the first
flow system and the resulting solution was worked up, re-
dissolved in THF/MeOH to react with an aqueous solution of
K2CO3 in the second flow system. This two-step reaction worked
well to get the desired terminal alkyne 3fh’ in 92% yield (496 mg,
2.75 mmol).
1,2-diphenylethyne (3aa)[24]: 49 mg, 92% yield. 1H NMR (400 MHz,
CDCl3): δ 7.57-7.55 (m, 2H), 7.36-7.35 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ 131.7, 128.4, 128.3, 123.3, 89.5.
1-methyl-4-(phenylethynyl)benzene (3ab)[24]: 44 mg, 77% yield. 1H
NMR (400 MHz, CDCl3): δ 7.56-7.54 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H),
7.38-7.34 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 138.4, 132.5, 131.5, 129.1, 128.3, 128.0, 123.4, 120.2,
89.5, 88.7, 21.5.
Conclusions
In summary, we have successfully developed a C(sp)-C(sp2)
Negishi cross-coupling reaction in a continuous flow system using
three T-shaped micromixers and three microtubular reactors. The
reaction proceeds via an in situ generated alkynylzinc reagent
from lithium acetylide and zinc bromide followed by a Pd-
catalyzed cross-coupling with aryl iodides to form internal alkynes
in good to excellent yields. The key advantages of this flow
protocol are low catalyst/ligand, excellent conversion, short
reaction time, highly controllable, broad substrate scope and
desilylation of alkynes. Moreover, the synthesis of 1,3-enynes
were achieved with retention of configuration using vinyl halides
as the coupling partners.
1-chloro-4-(phenylethynyl)benzene (3ag)[24]: 43 mg, 68% yield. 1H NMR
(400 MHz, CDCl3): δ 7.45-7.43 (m, 2H), 7.39-7.37 (m, 2H), 7.29-7.23 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 134.3, 132.8, 131.6, 128.7, 128.5,
128.4, 123.0, 121.8, 90.3, 88.32.
1-bromo-4-(phenylethynyl)benzene (3ah)[24]: 51 mg, 66% yield. 1H NMR
(400 MHz, CDCl3): δ 7.46-7.43 (m, 2H), 7.41-7.39 (m, 2H), 7.32-7.26 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 133.1, 131.7, 133.6, 128.5, 128.4,
122.9, 122.5, 122.3, 90.5, 88.3.
1-methoxy-4-(phenylethynyl)benzene (3ba)[25]
:
1H NMR (400 MHz,
CDCl3): δ 7.52-7.50 (m, 2H), 7.47 (d, J = 8.8Hz, 2H), 7.35-7.30 (m, 3H),
6.88 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.7,
133.1, 131.5, 128.4, 128.0, 123.6, 115.4, 114.1, 89.4, 88.1, 55.3.
Experimental Section
hex-1-yn-1-ylbenzene (3ca)[26]: 42 mg, 89% yield. 1H NMR (400 MHz,
CDCl3): δ 7.40-7.37 (m, 2H), 7.27-7.24 (m, 3H), 2.40 (t, J = 7.2 Hz, 2H),
1.60-1.55 (m, 2H), 1.50-1.44 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 131.6, 128.2, 127.5, 124.1, 90.5, 80.6, 30.9, 22.1,
19.1, 13.7.
General information
Dry THF was freshly distilled under a nitrogen atmosphere over sodium
and used for the reaction. All the compounds were commercially available
and used without further purification unless otherwise noted. Compounds
1b, 1g, 1h, 1i, 1j, 2o, 2p, 4a, 4b and 4c were prepared according to
previous literature report.[23] n-BuLi was purchased from Rockwood
Lithium company and ZnBr2 was purchased from Alfa Aesar. ZnBr2
solution (0.60 M in THF) was prepared by drying ZnBr2 (8.10 g, 36 mmol)
in a Schlenk-flask under flame dried for 5 minutes. After cooling to 25 oC,
dry THF (60 mL) was added and stirred until the salts were dissolved.
Micro mixture 500 µm was purchased from Sanko Seiki company,
stainless tube and peek were purchased from Idex health & science.
Harvard syringe pump model-11 elite were used for the reaction.
1-(hex-1-yn-1-yl)-4-methylbenzene (3cb)[24]:39 mg, 76% yield. 1H NMR
(400 MHz, CDCl3): δ 7.28 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 2.40
(t, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.60-1.58 (m, 2H), 1.50-1.43 (m, 2H), 0.94
(t, J= 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 137.4, 131.4, 128.9,
120.9, 89.6, 80.5, 30.9, 22.0, 21.4, 19.1, 13.6.
1-(hex-1-yn-1-yl)-4-methoxybenzene (3cc)[26]: 49 mg, 87% yield. 1H
NMR (400 MHz, CDCl3): δ 7.25 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz,
2H), 3.71 (s, 3H), 2.31 (t, J = 6.8 Hz, 2H), 1.52-1.46 (m, 2H), 1.42-1.36 (m,
2H), 0.86 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.0, 132.9,
116.3, 113.8, 88.8, 80.2, 55.3, 31.0, 22.1, 19.1, 13.7.
General procedure for synthesis of aromatic internal alkynes and 1,3-
enynes: A microreactor system consist of three T-shaped micromixers
(M1, M2 and M3), three tubing reactors (R1, R2 and R3) and two
precooling units P1 (inner diameter = 800 µm, length L = 50 cm), P2 (inner
diameter = 1000 µm, length L= 50 cm), and one preheating unit P3 (inner
diameter = 1000 µm, length L = 342 cm)) were used. A solution of terminal
alkyne (0.40 M in THF) (flow rate: 1.125 mL/min) and a solution of n-BuLi
(1.60 M in Hexane) (flow rate: 0.3 mL/min) were introduced into M1 (Φ =
1.0 mm) by 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 a ZnBr2
(0.60 M in THF) (flow rate: 0.75 mL/min) at M2 (Φ = 1.0 mm). The resulting
1-(hex-1-yn-1-yl)-3-methoxybenzene (3cd)[27]
:
1H NMR (400 MHz,
CDCl3): δ 7.09 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.85-6.84 (m,
1H), 6.73 (m, 1H), 3.69 (s, 3H), 2.32 (t, J = 6.8 Hz, 2H), 1.52-1.37 (m, 4H),
0.86 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.3, 129.3, 125.1,
124.1, 116.4, 114.1, 90.3, 80.5, 55.2, 30.9, 22.1, 19.1, 13.7.
1-(hex-1-yn-1-yl)-2-methoxybenzene (3ce)[27]
:
1H NMR (400 MHz,
CDCl3): δ 7.29 (d, J = 7.2, 1.2 Hz, 1H), 7.17-7.12 (m, 1H), 6.81-6.75 (m,
2H), 3.78 (s, 3H), 2.39 (t, J = 6.8 Hz, 2H), 1.57-1.49 (m, 2H), 1.46-1.38 (m,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900471
European Journal of Organic Chemistry
FULL PAPER
2H), 0.86 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.8, 133.7,
7.1 Hz, 2H), 1.65-1.44 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 152.6, 146.5, 138.0, 129.6, 129.3, 127.4, 127.1, 118.3,
94.1, 77.9, 30.7, 22.1, 19.3, 13.7.
128.9, 120.4, 113.2, 110.5, 94.7, 76.6, 55.8, 31.0, 22.1, 19.5, 13.7.
1-fluoro-4-(hex-1-yn-1-yl) benzene (3cf)[26]: 43 mg, 81% yield. 1H NMR
(400 MHz, CDCl3): δ 7.30-7.27 (m, 2H), 6.91-6.87 (m, 2H), 2.31 (t, J = 7.2
Hz, 2H), 1.52-1.37 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 162.0 (d, J = 246 Hz), 133.3 (d, J = 7.7 Hz), 120.2, 115.4 (d, J =
21.9 Hz), 90.0, 79.5, 30.8, 22.1, 19.0, 13.7.
4,4',4''-((4-(hex-1-yn-1-yl)phenyl)methanetriyl)tris(methylbenzene)
(3cp):
Brown solid. m.p: 146-148 oC. 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J =
8.0 Hz, 2H), 7.19-7.07 (m, 2H), 2.43 (t, J= 6.8 Hz, 2H), 2.35 (s, 9H), 1.63-
1.59 (m, 2H), 1.54-1.48 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 146.8, 143.9, 135.3, 132.9, 130.5, 128.1, 127.3, 121.3,
90.2, 80.4, 63.8, 30.8, 21.9, 20.9, 19.1, 13.6. HRMS (EI) calcd for
C34H34[M]+442.2661, found for 442.2668.
1-chloro-4-(hex-1-yn-1-yl) benzene (3cg)[27]: 1H NMR (400 MHz, CDCl3):
δ 7.30 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 2.38 (t, J = 7.0 Hz, 2H),
1.61-1.54 (m, 2H), 1.50-1.41 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 133.3, 132.7, 128.4, 122.6, 91.5, 79.5, 30.7, 22.0,
19.1, 13.6.
pent-1-yn-1-ylbenzene (3da)[32]: 1H NMR (400 MHz, CDCl3): δ 7.33-7.31
(m, 2H), 7.21-7.18 (m, 3H), 2.31 (t, J = 7.2 Hz, 2H), 1.60-1.51 (m, 2H), 0.97
(t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 131.6, 128.2, 127.5,
124.1, 90.3, 80.7, 22.3, 21.4, 13.6.
1-bromo-4-(hex-1-yn-1-yl)benzene (3ch)[27]: 1H NMR (400 MHz, CDCl3):
δ 7.38 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H),
1.58-1.53 (m, 2H), 1.48-1.43 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 133.1, 131.4, 123.1, 121.6, 91.8, 79.6, 30.7, 22.1,
19.2, 13.7.
oct-1-yn-1-ylbenzene (3ea)[34] 1H NMR (400 MHz, CDCl3): δ 7.39-7.36
:
(m, 2H), 7.27-7.23 (m, 3H), 2.38 (t, J = 7.6 Hz, 2H), 1.62-1.54 (m, 2H),
1.47-1.40 (m, 2H), 1.34-1.28 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 131.6, 128.2, 127.5, 124.1, 90.5, 80.6, 31.4, 28.8,
28.7, 22.6, 19.5, 14.1.
1-bromo-3-(hex-1-yn-1-yl)benzene (3ci) : 53 mg, 74% yield. 1H NMR
(400 MHz, CDCl3): δ 7.54 (t, J = 1.6 Hz, 1H), 7.41-7.35 (m, 1H), 7.31 (d, J
= 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 2.40 (t, J = 7.2 Hz, 2H), 1.62-1.41
(m, 4H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 134.4,
130.6, 130.1, 129.2, 126.2, 12.0, 92.1, 79.2, 30.7, 22.0, 19.1, 13.7.
1-methyl-4-(oct-1-yn-1-yl)benzene (3eb) [34]: 53 mg, 83% yield. 1H NMR
(400 MHz, CDCl3): δ 7.29 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 2.39
(t, J = 6.8 Hz, 2H), 2.33 (s, 3H), 1.62-1.55 (m, 2H), 1.49-1.41 (m, 4H), 1.35-
1.30 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 137.
4, 131.4, 129.0, 121.1, 89.7, 80.6, 31.5, 28.9, 28.7, 22.6, 21.4, 19.5, 14.1.
4-(hex-1-yn-1-yl)benzonitrile (3cj)[28]: 1H NMR (400 MHz, CDCl3): δ 7.48
(d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 2.35 (t, J = 6.8 Hz, 2H), 1.54-
1.48 (m, 2H), 1.42-1.37(m, 2H), 0.87 (t, J = 7.6 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 132.1, 131.9, 129.2, 118.7, 110.8, 95.7, 79.5, 30.5, 22.1,
19.2, 13.6.
1-methoxy-4-(oct-1-yn-1-yl)benzene (3ec)[35]: 45 mg, 65% yield 1H NMR
(400 MHz, CDCl3): δ 7.25 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 3.72
(s, 3H), 2.30 (t, J = 7.2 Hz, 2H), 1.55-1.48 (m, 2H), 1.40-1.35 (m, 2H), 1.28-
1.22 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.0,
132.9, 116.3, 113.8, 88.9, 80.2, 55.3, 31.4, 28.9, 28.7, 22.6, 19.5, 14.1.
1-(hex-1-yn-1-yl)-4-(trifluoromethyl)benzene (3ck)[29]: 43 mg, 64% yield.
1H NMR (400 MHz, CDCl3): 7.45 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz,
2H), 2.35 (t, J = 6.8 Hz, 2H), 1.54-1.49 (m, 2H), 1.45-1.37 (m, 2H), 0.88 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): 131.8, 129.3 (d, J = 33 Hz),
128.0, 125.4, 125.1 (d, J = 4 Hz), 93.3, 79.5, 30.6, 22.1, 19.2, 13.7.
1-(4-chlorophenyl)oct-1-yn-3-one (3eg)[34] 1H NMR (400 MHz, CDCl3):
:
δ 7.29 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H),
1.61-1.54 (m, 2H), 1.46-1.38 (m, 2H), 1.34-1.23 (m, 4H), 0.88 (t, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 133.4, 132.8, 128.5, 122.6, 91.6,
79.5, 31.4, 29.7, 28.7, 22.6, 19.4, 14.1.
1-(4-(hex-1-yn-1-yl)phenyl)ethan-1-one (3cl)[30]: 54 mg, 90% yield. 1H
NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz,
2H), 2.54 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.60-1.52 (m, 2H), 1.49-1.41 (m,
2H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.4, 135.6,
131.7, 129.2, 128.2, 94.4, 80.1, 30.7, 26.6, 22.1, 19.2, 13.7.
1-(4-chlorophenyl)oct-1-yn-3-one (3eh)[36]: 69 mg, 82% yield. 1H NMR
(400 MHz, CDCl3): δ 7.33 (dt, J = 8.4, 2.0 Hz, 2H), 7.17 (dt, J = 9.2, 2.0
Hz, 2H), 2.30 (t, J = 6.8 Hz, 2H), 1.55- 1.48 (m, 2H), 1.40-1.18 (m, 6H),
0.83 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 133.0, 131.4, 123.1,
121.5, 91.8, 79.6, 31.4, 29.7, 28.6, 22.6, 19.5, 14.1.
1-(hex-1-yn-1-yl)-4-iodobenzene (3cm): 1H NMR (400 MHz, CDCl3): δ
7.60 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 2.39 (t, J = 7.0 Hz, 2H),
1.54-1.62 (m, 2H), 1.40-1.50 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 137.3, 133.1, 123.6, 93.0, 92.0, 79.7, 30.7, 22.0, 19.1,
13.6.
trimethyl(phenylethynyl)silane (3fa)[37]: 49 mg, 94% yield. 1H NMR (400
MHz, CDCl3): δ 7.48-7.46 (m, 2H), 7.32-7.29 (m, 3H), 0.25 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 131.9, 128.5, 128.2, 123.1, 105.1, 94.1, -0.04.
1,4-di(hex-1-yn-1-yl)benzene (3cm’)[31] 1H NMR (400 MHz, CDCl3): δ
:
7.22 (s, 4H), 2.33 (t, J = 6.8 Hz, 4H), 1.53-1.47 (m, 4H), 1.44-1.36 (m, 4H),
0.87 (t, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 131.4, 123.2, 91.9,
80.4, 30.8, 22.1, 19.2, 13.7.
((4-methoxyphenyl)ethynyl)trimethylsilane (3fc)[37]: 56 mg, 91% yield.
1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 9.2 Hz, 2H), 6.74 (d, J = 9.2 Hz,
2H), 3.72 (s, 3H), 0.16 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 159.8, 133.6,
115.3, 113.9, 105.3, 92.5, 55.3, 0.2.
2-(hex-1-yn-1-yl)thiophene (3cn)[32]: 35 mg, 71% yield. 1H NMR (400
MHz, CDCl3): δ 7.07 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 6.84 (dd,
J = 4.8, 4.0 Hz, 1H), 2.34 (t, J = 7.2 Hz, 2H), 1.54-1.47 (m, 2H), 1.43-1.35
(m, 2H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 130.9,
126.8, 125.9, 124.3, 94.5, 73.7, 30.7, 22.1, 19.4, 13.7.
((4-bromophenyl)ethynyl)trimethylsilane (3fh)[37]: 714 mg, 94% yield.
1H NMR (400 MHz, CDCl3): δ 7.41(d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.4 Hz,
2H), 0.23 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 133.4, 131.5, 122.8, 122.1,
103.9, 95.6, -0.03.
3-(hex-1-yn-1-yl)quinoline (3co)[33] 1H NMR (400 MHz, CDCl3): δ 8.85
:
1-(cyclohex-1-en-1-ylethynyl)-4-methoxybenzene (3gc)[25]
(400 MHz, CDCl3): δ 7.28 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H),
:
1H NMR
(d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4
Hz, 1H), 7.66 (td, J = 7.8, 1.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 2.46 (t, J =
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900471
European Journal of Organic Chemistry
FULL PAPER
6.10-6.08 (m, 1H), 3.72 (s, 3H), 2.16-2.04 (m, 4H), 1.63-1.50 (m, 4H). 13
C
7.29 (m, 4H), 7.26-7.22 (m, 2H), 6.22 (dt, J = 11.6, 2.0 Hz, 1H), 6.11 (d, J
= 11.6 Hz, 1H), 4.24 (q, J = 7.6 Hz, 2H), 3.75 (s, 3H), 3.48 (d, J = 1.6 Hz,
2H), 1.30 (t, J = 7. 2Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.7, 138.9,
129.1, 128.4, 128.3, 127.1, 123.0, 98.2, 82.6, 60.4, 57.6, 42.5, 14.3. IR
(neat) ν 3029, 1723, 1608, 1495, 1454, 1410 cm-1. HRMS (APCI) calcd for
C22H23NO2 [M+H]+: 334.1807, found 334.1800.
NMR (100 MHz, CDCl3): δ 159.2, 134.5, 132.9, 120.9, 115.9, 113.9, 89.9,
86.7, 55.3, 29.4, 25.8, 22.4, 21.6.
9-(3-(p-tolyl)prop-2-yn-1-yl)-9H-carbazole (3hb): Pale yellow solid. 50
mg, 56% yield. m.p: 114-116 oC.1H NMR (400 MHz, CDCl3): δ 8.12 (d, J =
8.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.51 (td, J = 7.7, 1.2 Hz, 2H), 7.30-
7.24 (m, 4H), 7.05 (d, J = 7.6 Hz, 2H), 5.25 (s, 2H), 2.30 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 140.1, 138.6, 131.7, 129.0, 125.9, 123.3, 120.4,
119.4, 119.3, 109.0, 84.2, 82.6, 33.3, 21.5. IR (KBr) ν 1698, 1598, 1508,
1484, 1454, 1327, 1259, 1207, 1150 cm-1. HRMS (APCI) calcd for
C22H17N [M+H]+: 296.1439, found 296.1436.
(Z)-1-chloro-3-((1-phenyloct-1-en-3-yn-1-yl)oxy)benzene (5cb): Yellow
oily liquid. 1H NMR (400 MHz, CDCl3): δ 7.51-7.48 (m, 2H), 7.34-7.30 (m,
3H), 7.15 (t, J = 8.0 Hz, 1H), 7.04-7.02 (m, 1H), 6.95 (d, J = 1.2 Hz, 1H),
6.90-6.87 (m, 1H), 5.92 (q, J = 2.0, 4.4 Hz, 1H), 2.24 (t, J = 7.2 Hz, 2H),
1.30-1.21 (m, 4H), 0.82 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
157.9, 157.8, 134.8, 134.0, 130.2, 129.3, 128.8, 125.2, 122.2, 116.7, 114.4,
99.5, 97.5, 75.4, 30.6, 21.8, 19.5, 13.6. IR (neat) ν 3065, 2958, 2871, 2218,
1737, 1590, 1519, 1473, 1343, 1239,1165 cm-1. HRMS (APCI) calcd for
C20H19ClO [M+H]+: 311.1203, found 311.1206.
ethyl (Z)-5-phenylpent-2-en-4-ynoate (5aa)[38]
:
1H NMR (400 MHz,
CDCl3): δ 7.52-7.50 (m, 2H), 7.33-7.30 (m, 3H), 6.33 (d, J = 11.4 Hz, 1H),
6.11 (d, J = 11.4 Hz, 1H), 4.24 (q, J = 6.8 Hz, 1H), 1.30 (t, J = 7.6 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 164.9, 132.1, 129.2, 128.4, 128.3, 122.9,
122.7, 101.2, 86.4, 60.5, 14.3. IR (neat) ν 2982, 2204, 1721, 1609, 1490,
1443, 1412, 1180 cm-1.
(Z)-1-nitro-4-((1-phenyloct-1-en-3-yn-1-yl)oxy)benzene(5cc):
Light
yellow liquid. 63 mg, 65% yield. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J =
9.2 Hz, 2H), 7.49-7.46 (m, 2H), 7.33-7.32 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H),
6.00 (t, J = 2.4 Hz, 1H), 2.20 (td, J = 2.0, 6.8 Hz, 2H), 1.30-1.17 (m, 4H),
0.76 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 162.2, 157.1, 142.4,
133.2, 129.7, 128.9, 125.9, 124.9, 116.1, 100.4, 98.2, 75.0, 30.5, 21.7,
19.4, 13.5. IR (neat) ν 3081, 2958, 2871, 2217, 1737, 1591, 1518, 1447,
1343, 1238, 1165, 1111 cm-1. HRMS (APCI) calcd for C20H19NO3 [M]+:
321.1365, found 321.1363.
ethyl (Z)-non-2-en-4-ynoate (5ca)[39]: 427 mg, 79% yield. 1H NMR (400
MHz, CDCl3): δ 6.12 (dt, J = 11.3, 2.5 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H),
4.20 (q, J = 6.8 Hz, 2H), 2.43 (td, J = 7.1, 2.3 Hz, 2H), 1.62-1.37 (m, 4H),
1.28 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 165.0, 127.4, 124.0, 104.2, 77.7, 60.3, 30.5, 22.0, 22.0, 19.8,
14.3, 13.6.
1-bromo-4-ethynylbenzene (3fh’): 496 mg, 92% yield. 1H NMR (400 MHz,
CDCl3): δ 7.20 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 2.86 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 133.6, 131.6, 123.2, 121.1, 82.6, 78.4.
ethyl (Z)-oct-2-en-4-ynoate (5da): Colourless liquid. 46 mg, 92% yield.
1H NMR (400 MHz, CDCl3): δ 5.92 (dt, J = 11.2, 2.4 Hz, 1H), 5.79 (d, J =
11.6 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 2.19 (td, J = 6.8, 2.4 Hz, 2H), 1.39
(sex, J = 6.8 Hz, 2H), 1.07 (t, J = 7.6 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H). 13
C
NMR (100 MHz, CDCl3): δ 164.9, 127.4, 123.9, 104.0, 77.8, 60.2, 22.0,
21.9, 14.2, 13.5. IR (neat) ν 2965, 2935, 2905, 2873, 2208, 1726, 1608
cm-1. HRMS (EI) calcd for C22H23NO2 [M+Na]+: 189.0627, found 189.0623.
Acknowledgments
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.
ethyl (Z)-6-oxoundec-2-en-4-ynoate (5ea)[38]
:
1H NMR (400 MHz,
CDCl3): δ 6.11 (dt, J = 11.2, 2.4 Hz, 1H), 5.79 (d, J = 11.2 Hz, 1H), 4.18 (q,
J = 6.8 Hz, 2H), 2.41 (td, J = 7.2, 2.4 Hz, 2H), 1.55 (q, J = 7.2 Hz, 2H),
1.42-1.35 (m, 2H), 1.31-1.23 (m, 7H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 165.0, 127.4, 124.0, 104.3, 77.7, 60.3, 31.3, 28.7,
28.4, 22.5, 20.1, 14.3, 14.1.
ethyl (Z)-5-(trimethylsilyl)pent-2-en-4-ynoate (5fa)[40] 1H NMR (400
:
Keywords: Continuous flow, Alkynyl zinc, Cross-coupling,
MHz, CDCl3): δ 6.11 (d, J =11.2 Hz, 1H), 6.04 (d, J =11.2 Hz, 1H), 4.20 (q,
J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 2H), 0.20 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 164.6, 129.5, 122.4, 108.1, 100.7, 60.6, 14.3, -0.2.
Internal alkyne, enyne
ethyl (Z)-6-(9H-carbazol-9-yl)hex-2-en-4-ynoate (5ha): Red oily liquid.
86 mg, 99% yield. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.6 Hz, 2H),
7.36 (d, J = 3.6 Hz, 4H), 7.17-7.10 (m, 2H), 5.92 (d, J = 12.0 Hz, 1H), 5.87
(dt, J = 12.0, 2.0 Hz, 1H), 5.10 (s, 2H), 3.98 (q, J = 6.8 Hz, 2H), 1.03 (t, J
= 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.7, 139.9, 129.5, 126.0,
123.3, 122.2, 120.5, 119.6, 108.9, 95.6, 80.5, 60.6, 33.4, 14.2. IR (neat) ν
3053, 2982, 1722, 1613, 1486, 1456, 1330, 1189 cm-1. HRMS (APCI)
calcd for C22H23NO2 [M+H]+: 303.1338, found 304.1335.
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Entry for the Table of Contents
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Key Topic*
Mohanraj Kandasamy, Yu- Hsuan
Huang, Balaji Ganesan Gopal Chandru
Senadi and Wei-Yu Lin*
Page No. – Page No.
Title
In situ generation of alkynylzinc and its
subsequent cross-coupling reaction in a
flow reactor
* Mild and highly efficient method for synthesis of internal alkynes or 1,3-enynes was achieved in a continuous flow system through the generation of alkynylzinc reagent from
lithium acetylide and zinc bromide followed by a Pd-catalyzed cross-coupling with aryl or vinyl iodides.
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