Continuous Flow Chlorination of Alkenyl Iodides Promoted by Copper Tubing

Article abstract of DOI:10.1055/s-0037-1610398

A simple continuous flow synthesis of alkenyl chlorides from the corresponding readily available alkenyl iodides in copper reactor tubing is described. A variety of alkenyl chlorides were obtained in good to excellent yields with full retention of the dou

Full text of DOI:10.1055/s-0037-1610398

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
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en
A. Nitelet et al.
Feature
Synthesis
Continuous Flow Chlorination of Alkenyl Iodides Promoted by
Copper Tubing
Antoine Niteleta
Vanessa Kairouzb
Hélène Lebel*b
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André B. Charette*b
Gwilherm Evano*a
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a Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie
Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt
50, CP160/06, 1050 Brussels, Belgium
Gwilherm.Evano@ulb.be
b Centre in Green Chemistry and Catalysis, Faculty of Arts and Sciences,
Department of Chemistry, Université de Montréal, P.O. Box 6128,
Station Downtown, Montréal, Québec, H3C 3J7, Canada
andre.charette@umontreal.ca
helene.lebel@umontreal.ca
Received: 25.10.2018
Accepted: 05.11.2018
Published online: 30.11.2018
DOI: 10.1055/s-0037-1610398; Art ID: ss-2018-z0718-fa
Despite these advantages, the halogen exchange typical-
ly requires 48 hours of reaction time to reach full conver-
sion, which represents the main limitation of the process.
Furthermore, any remaining traces of starting material sig-
nificantly increases the level of difficulty of the purification
step as it is quite challenging to separate the starting mate-
rial from the desired product. A significant reduction in the
reaction time would undeniably greatly improve the effi-
ciency of this method. This goal should be achievable by
transposing this reaction to continuous flow. Continuous
flow chemistry has recently emerged as a powerful tech-
nology that increases mass and heat transfer, thus acceler-
ating reaction processes considerably.5 Furthermore, the
use of copper reactors for in situ generation of copper cata-
lysts has been successfully reported for a number of trans-
formations, including alkyne–azide cycloaddition, Ullmann
condensation, Sonogashira coupling, decarboxylation reac-
tions, and hydroxylation of aryl iodides.6 Inspired by
Buchwald’s copper-catalyzed aromatic Finkelstein reaction
in continuous flow7 and on the basis of our combined inter-
est in copper catalysis4a,8 and flow chemistry,9 we report
herein a continuous flow synthesis of alkenyl chlorides
from alkenyl iodides using a copper reactor.
The copper-catalyzed vinylic retro-Finkelstein reaction
was studied using β-iodo-styrene (1a) as the model sub-
strate. The reaction occurred when a heated PFA reactor coil
in ethanol was used in the presence of an 8 bar back-pres-
sure regulator (BPR). Aliquat 336® (n-Octyl3MeNCl) was iden-
tified as a soluble chloride source in replacement of Me4NCl
(used in the previously reported batch method) in combina-
tion with copper(I) iodide (10 mol%) and trans-N,N′-di-
methylcyclohexane-1,2-diamine (20 mol%) in ethanol to af-
ford the chlorinated alkenyl iodide (Scheme 2). Conversion
was low when the reactor coil was heated at 110 °C with a
residence time of 120 minutes. Increasing the temperature
did not lead to fruitful results, as extensive substrate degra-
dation was observed when heating the reactor coil at 130 °C
License terms:
Abstract A simple continuous flow synthesis of alkenyl chlorides from
the corresponding readily available alkenyl iodides in copper reactor
tubing is described. A variety of alkenyl chlorides were obtained in good
to excellent yields with full retention of the double bond geometry. The
reaction time was reduced by a factor of 24–48 compared to the batch
process.
Key words copper catalysis, heterogeneous catalysis, halogen ex-
change, Finkelstein reaction, continuous flow process
Alkenyl chlorides are commonly found in natural prod-
ucts and pharmaceutical and agrochemical compounds. In
comparison to the related alkenyl iodides, which can be
readily prepared through a range of efficient processes,1
there are only a limited number of known methods to pro-
duce alkenyl chlorides in high yield and stereoselectivity.2
Among them, the copper-catalyzed retro-Finkelstein3 reac-
tion we recently reported enables an easy synthesis of a
wide variety of alkenyl chlorides from the corresponding
iodides in high yields and with full retention of the double
bond geometry (Scheme 1).4 This process was shown to be
especially efficient and broadly applicable, even with sensi-
tive and/or complex substrates.
Me4NCl
CuI (10 mol%)
(
)
R1
R1
NH HN
(20 mol%)
R2
R2
I
Cl
EtOH, 110 °C, 48 h
50–92%
R3
R3
1
2
Scheme 1 Copper-catalyzed chlorination of alkenyl iodides in batch
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
A. Nitelet et al.
Feature
Synthesis
Biographical sketches
Antoine Nitelet was born in Bel-
gium in 1990 and studied chemis-
try at the Université libre de
Bruxelles. In 2013, he received his
Master’s degree under the supervi-
sion of Prof. Gwilherm Evano, fo-
cusing on the development of new
copper-mediated transformations.
After obtaining an F.R.I.A fellow-
ship in 2013, he pursued a Ph.D. in
the same group, where his re-
search focused on copper-cata-
lyzed transformations, notably the
development of a vinylic version of
the Finkelstein reaction, and their
use in natural product synthesis.
Within the framework of a joint
project between Profs. Lebel, Cha-
rette, and Evano, he went twice to
the Université de Montréal to de-
velop the vinylic Finkelstein reac-
tion in continuous flow. After
graduating in December 2017, he
then moved to INSA Rouen in Nor-
mandie (France) as a postdoctoral
fellow in the group of Prof. Xavier
Pannecoucke.
Vanessa Kairouz obtained both
her B.Sc. (2011) and M.Sc. (2014;
well as the NSERC CREATE Program
in Continuous Flow Science located
at the Université de Montréal. Her
versatile educational background
in supramolecular chemistry, catal-
ysis, green chemistry, biochemis-
try, and microfluidics, in addition
to her extensive experience in
training students enables her to
understand and anticipate stu-
dents’ needs when it comes to us-
research
director:
Andreea
Schmitzer) in chemistry from the
Université de Montréal. She is the
scientific coordinator of the Center
for Continuous Flow Synthesis, as
ing
and
maintaining
flow
infrastructure.
Hélène Lebel received her PhD
from the Université de Montréal
under the supervision of Prof. An-
dré B. Charette in 1998. She then
joined the group of Eric N. Jacob-
sen at Harvard University as an
NSERC postdoctoral fellow. She be-
gan her independent academic ca-
reer at the Université de Montréal
as an assistant professor in 1999,
under an NSERC University Faculty
Award. She was promoted to the
rank of associate professor in 2005,
and full professor in 2010. The
quality of her research has been
recognized with many awards, in-
cluding the Enantioselective Syn-
thetic Chemistry Research Award
in 2005, the Johnson & Johnson Fo-
cused Funding Grant Award in
2008, the Merck Frosst Centre for
Therapeutic Research Award in
2009, and the Clara Benson Award
in 2014. She held the Canada Re-
search Chair in Organometallic Ca-
talysis (tier II) from 2006 to 2016.
She has been the author of more
than 60 publications as an inde-
pendent researcher and has con-
tributed to numerous book
chapters. Her research program
addresses the development of nov-
el catalytic green processes and
the discovery of recyclable re-
agents. More recently, her research
program has included the study of
novel, innovative continuous flow
processes.
André B. Charette received his
B.Sc. in 1983 from the Université
de Montréal. He then moved south
of the border to the University of
Rochester to pursue graduate
studies under the supervision of
Robert K. Boeckman Jr. (M.Sc. in
1985 and Ph.D. in 1987). Following
an NSERC postdoctoral fellowship
at Harvard University with David A.
Evans, he began his academic ca-
reer, first at Université Laval
(1989–1992) then at his alma ma-
ter, Université de Montréal, where
was promoted to the rank of full
professor in 1998 and where he
currently serves as holder of a Can-
ada Research Chair in Stereoselec-
novel and practical approaches to
the design of catalysts and reac-
tions for the synthesis of cyclopro-
panes, heterocyclic derivatives,
and greener functional group
transformations using continuous
flow synthesis. In addition, he has
received more than twenty inter-
national awards, including the CIC
Medal (2018), a doctorate honoris
causa from INSA-Rouen (2015), the
CSC Alfred Bader Award (2009),
the Marie Victorin Award (2008),
and an Arthur C. Cope Award
(2007).
tive
Synthesis
of
Bioactive
Molecules (2005–), co-director of
the FRQNT Centre in Green Chem-
istry and Catalysis (2009–), co-di-
rector of the NSERC CREATE
Program in Continuous Flow Sci-
ence, and director of his Depart-
ment of Chemistry (2014–). With a
publication record that encom-
passes well over 220 articles in in-
ternational journals, he has
achieved worldwide recognition in
the area of organic synthesis. He is
widely recognized for conceptually
Gwilherm Evano was born in Paris
in 1977 and studied chemistry at
the Ecole Normale Supérieure. He
received his Ph.D. from the Univer-
sité Pierre et Marie Curie in 2002
under the supervision of Profs.
François Couty and Claude Agami.
After postdoctoral studies with
Prof. James S. Panek at Boston Uni-
versity, he joined the CNRS as asso-
ciate professor in 2004. He then
moved to the Université libre de
Bruxelles, where he has been the
head of the Laboratory of Organic
Chemistry since 2012. His research
program currently focuses on nat-
ural/bioactive product synthesis,
copper catalysis, and the chemis-
try of heteroatom-substituted
alkynes and reactive intermedi-
ates. He has published more than
120 articles and 10 book chapters
and has received several awards,
the latest one being the 2017 Tri-
ennial Prize of the Belgian Royal So-
ciety of Chemistry.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
A. Nitelet et al.
Feature
Synthesis
for 120 minutes of residence time. To improve the catalyst
solubility, dioxane was introduced as a co-solvent, but this
did not lead to any significant improvement.
Table 1 Optimization of the Continuous Flow Chlorination of Alkenyl
Iodides Promoted by Copper Tubing
Ph
I
Ph
1a
I
+
1a
n-Octyl3MeNCl
(2 equiv)
+
Cu tubing
+
BPR
n-Octyl3MeNCl
(2 equiv)
PFA
tubing
Ph
Cl
8 bar
+
2a
BPR
10 mL
T (°C), tR
CuI (10 mol%)
+
Ph
( )
Cl
8 bar
NH HN
(20 mol%)
in EtOH
2a
10 mL
(
)
110 °C, tR : 120 min, 8% (1a: 66%)
130 °C, tR : 120 min, 12% (1a: 26%)
NH HN
(20 mol%)
in EtOH
Yield (%)a
t
R (min)
Entry
Temp (°C)
EtOH/dioxane (7:3)
110 °C, tR : 60 min, 13% (1a: 85%)
1
110
110
110
110
110
130
130
150
120
60
60
60
60
30
40
30
43
Scheme 2 Copper-catalyzed chlorination of alkenyl iodides in continu-
ous flow using PFA reactor tubing
2
72
3b
4c
5d
6
70
0
Facing little success using a PFA reactor coil, we then re-
sorted to using a copper reactor coil. These reactors are
known to be more resistant to high pressures and tempera-
tures in addition to enabling in situ generation of the cop-
per catalyst6 without the need of an external source of cop-
per(I) iodide (Table 1). Full conversion was observed after
60 minutes of residence time without CuI (entries 1–3). The
diamine ligand was, however, essential for obtaining the de-
sired product (entry 4). Optimization with substrate 1a
showed that the maximum yield was obtained at 130 °C
and with 40 minutes residence time. Under these reaction
conditions, a yield of 84% of 2a was achieved (entry 7). Im-
portantly, the exact same yield was obtained when the re-
action was scaled up to afford 3.5 g of product 2a as a single
stereoisomer.
The optimized reaction conditions were then applied to
the transformation of other substrates; representative ex-
amples are shown in Scheme 3. In most cases, the yields ob-
tained in continuous flow were similar or superior to those
obtained in batch, but with a significant reduction in the re-
action time.4 With E-iodo-substituted alkenes, the maxi-
mum yields were achieved at 110 °C with a residence time
of 60 minutes. In the case of products 2b, 2c, 2e, and 2h,
DMSO was used as the solvent to favor a homogeneous sys-
tem. In the case of more sterically hindered Z-iodo-substi-
tuted alkenes, it was necessary to heat the reaction at
120 °C for 120 minutes of residence time. Under these con-
ditions, the corresponding Z-chloro-substituted alkenes 2i–
l were obtained in good to excellent yields and, most impor-
tantly, without detectable presence of isomerization prod-
ucts. The chlorination was found to proceed equally well
with aryl- and alkyl-substituted alkenyl iodides and was
shown to tolerate electron-withdrawing (2c) and electron-
donating (2e) groups, as well as acetal (2l), silyl ether (2g,
2m), and phthalimide (2h) protecting groups. Notably, a la-
bile allylic PMP ether (2k) remained untouched under these
80
83
7
84 (84e, 84f)
72
8
a Yields determined by NMR; DMF used as internal standard.
b Using EtOH/dioxane, 7:3.
c Without the diamine ligand.
d Using diamine ligand (40 mol%).
e Isolated yield.
f Isolated yield on a 3.5 g scale.
reaction conditions. As previously reported in batch, only
moderate yields were obtained for the α-substituted chlo-
roalkene 2m. When using continuous flow techniques, the
temperature had to be increased to 130 °C to achieve full
conversion in 120 minutes (47% isolated yield). However,
significant substrate decomposition was observed. This re-
sult is not surprising, as it has been stated that higher tem-
peratures lead to the decomposition of the starting materi-
al.
The advantages of the continuous flow chlorination of
alkenyl iodides promoted by copper tubing compared to
our original procedure in batch are fairly evident when
looking at the most important reaction parameters summa-
rized in Table 2. Indeed, slightly higher yields (average yield
of 78% in flow vs 74% in batch) are obtained in flow with
significantly reduced reaction time (1–2 h in flow vs 24–48
h in batch) without the use of an external source of copper.
Moreover, the reaction is more easily scaled up in flow
compared to the batch process without any loss in yield. Fi-
nally, it should be mentioned that the optimized conditions
require the reaction to be performed at temperatures ex-
ceeding the boiling point of the solvent (110–130 °C in eth-
anol); while this procedure is easily possible in continuous
flow by using the copper reactor coil and an 8 bar back-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
A. Nitelet et al.
Feature
Synthesis
copper-catalyzed chlorination of alkenyl iodides features
several advantages compared to the batch process: these in-
clude the in situ generation of the copper catalyst from the
copper tubing, an easy scale-up, slightly higher yields, oper-
ational simplicity when performing the halogen exchange
above the boiling point of the solvent, and reduction in re-
action times by a factor of 24–48. Further applications of
this vinylic retro-Finkelstein reaction are under study and
will be reported in due time.
R1
R2
I
R3
1
Cu tubing
R1
+
n-Octyl3MeNCl
(2 equiv)
+
BPR
8 bar
R2
Cl
R3
10 mL
110–130 °C
60–120 min
2
(
)
NH HN
(20 mol%)
in EtOH or DMSO
F3C
Cl
The chlorination reactions were performed using a Vapourtec R-se-
ries continuous flow system equipped with a 10 mL heated copper re-
actor coil (1.00 mm I.D., 1.59 mm O.D.) and an 8 bar back-pressure
regulator. All solvents were reagent grade. DMSO and dioxane over
molecular sieves in AcroSeal® bottles were bought from Acros Organ-
ics and used as supplied. CuI (99.999% purity) was purchased from Al-
drich and used as supplied. All other reagents were used as supplied.
Analytical TLC was performed by using 0.25 mm silica gel 60-F plates.
Visualization of the developed chromatogram was performed by us-
ing UV absorbance or aq KMnO4. Flash chromatography and filtra-
tions were performed with silica gel (230–400 mesh). Yields refer to
chromatographically and spectroscopically pure compounds, unless
otherwise stated. 1H NMR spectra were recorded using an internal
deuterium lock at ambient temperature on Bruker 300 and JEOL 400
MHz spectrometers (internal reference, δH = 7.26, CDCl3, relative to
Cl
Cl
Cl
Cl
Cl
2b, 88%a,b
2c, 62%a,b
2d, 65%b
MeO
C8H17
2f, 81%b
TBDPSO
2g, 91%b
Cl
2e, 75%a,b
Cl
O
Cl
N
Cl
O
2h, 85%a,b
2i, 79%c
2j, 86%c
TBDPSO
δ
TMS = 0). Resonances that are either partially or fully obscured are de-
noted obscured (obs). 13C NMR spectra were recorded at 75 MHz us-
ing CDCl3 (δC = 77.16) as internal reference. 19F NMR spectra were re-
corded at 377 MHz using C6F6 (δF = –164.92) as external reference.
Melting points were recorded on a Stuart Scientific Analogue SMP11.
IR spectra were recorded on a Bruker Alpha Spectrophotometer (ATR).
High-resolution mass spectra were obtained on a Waters QTof API US,
a Thermo Finnigan MAT 95XP, or a Waters XevoQTof spectrometer.
Cl
Cl
PMPO
2k, 88%c
THPO
2l, 80%c
Cl
2m, 47%d
Scheme 3 Scope of the continuous flow chlorination of alkenyl iodides
promoted by copper tubing. a In DMSO; b 110 °C, 60 min; c 120 °C, 120
min; d 130 °C, 120 min.
(E)-(2-Chlorovinyl)benzene (2a)
pressure regulator, performing the reaction under the same
conditions in batch requires a pressurized tube, which can
be quite challenging and hazardous on a larger scale.
In an oven-dried 10 mL flask, (E)-(2-iodovinyl)benzene (115 mg, 0.50
mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (16 μL, 0.10
mmol), and Aliquat 336® (457 μL, 1.00 mmol) were premixed in EtOH
(1 mL) for 5 min. The resulting reaction mixture was pumped into the
copper reactor at 130 °C for 40 min with a flow rate of 0.25 mL/min.
Upon exiting the copper reactor, the reaction stream passed through a
back-pressure regulator (8 bar) before being collected into a flask. The
crude reaction mixture was diluted with EtOAc, filtered through a
plug of silica gel and concentrated. The crude residue was finally puri-
fied by flash column chromatography (silica gel, pentane) to afford
2a.
Table 2 Comparison of the Copper-Catalyzed Chlorination of Alkenyl
Iodides in Continuous Flow and in Batch
Average
yield
Reaction Exogenous Pressure
Scale-up
time
copper
handling
copper
tubing
identical
yield
78%
74%
1–2 h
none
Yield: 58 mg (0.42 mmol, 84%); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.28 (m, 5 H), 6.85 (d, J = 13.5 Hz,
1 H), 6.64 (d, J = 13.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 135.0, 133.4, 128.9, 128.3, 126.3, 118.8.
The spectroscopic data correspond to those previously reported.2d
pressure
tube
reduced
yield
24–48 h CuI
(E)-2-(2-Chlorovinyl)naphthalene (2b)
In conclusion, we have reported an easily accessible
continuous flow synthesis of alkenyl chlorides from the
corresponding readily available alkenyl iodides. The proce-
dure was shown to be broadly applicable and compatible
with a range of functional groups. The continuous flow
In an oven-dried 10 mL flask, (E)-2-(2-iodovinyl)naphthalene (140
mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine
(16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00 mmol) were pre-
mixed in DMSO (1 mL) for 5 min. The resulting reaction mixture was
pumped into the copper reactor at 110 °C for 60 min with a flow rate
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
A. Nitelet et al.
Feature
Synthesis
of 0.166 mL/min. Upon exiting the fourth flow reactor, the reaction
stream passed through a back-pressure regulator (8 bar) before being
collected into a flask. The crude reaction mixture was diluted with
H2O and extracted with Et2O (2×); the combined organic layers were
dried (MgSO4), filtered, and concentrated. The crude residue was fi-
nally purified by flash column chromatography (silica gel, pentane) to
afford 2b.
(E)-(2-Chlorovinyl)-4-methoxybenzene (2e)
In an oven-dried 10 mL flask, (E)-(2-iodovinyl)-4-methoxybenzene
(130 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-di-
amine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00 mmol)
were premixed in DMSO (1 mL) for 5 min. The resulting reaction mix-
ture was pumped into the copper reactor at 110 °C for 60 min with a
flow rate of 0.166 mL/min. Upon exiting the fourth flow reactor, the
reaction stream passed through a back-pressure regulator (8 bar) be-
fore being collected into a flask. The crude reaction mixture was di-
luted with H2O and extracted with Et2O (2×); the combined organic
layers were dried (MgSO4), filtered, and concentrated. The crude resi-
due was finally purified by flash column chromatography (silica gel,
hexane–EtOAc, 95:5) to afford 2e.
Yield: 83 mg (0.44 mmol, 88%); white solid; mp 75 °C.
1H NMR (300 MHz, CDCl3): δ = 7.90–7.75 (m, 3 H), 7.70 (s, 1 H), 7.56–
7.41 (m, 3 H), 7.02 (d, J = 13.5 Hz, 1 H), 7.79 (d, J = 13.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 133.8, 133.5, 132.7, 128.9, 128.4, 128.1,
127.0, 126.7, 126.6, 123.4, 119.4.
The spectroscopic data correspond to those previously reported.10
Yield: 63 mg (0.32 mmol, 75%); light yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.7
Hz, 2 H), 6.77 (d, J = 13.8 Hz, 1 H), 6.50 (d, J = 13.5 Hz, 1 H), 3.80 (s, 1
(E)-1-(2-Chlorovinyl)-4-(trifluoromethyl)benzene (2c)
In an oven-dried 10 mL flask, (E)-1-(2-iodovinyl)-4-(trifluorometh-
yl)benzene (149 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohex-
ane-1,2-diamine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00
mmol) were premixed in DMSO (1 mL) for 5 min. The resulting reac-
tion mixture was pumped into the copper reactor at 110 °C for 60 min
with a flow rate of 0.166 mL/min. Upon exiting the fourth flow reac-
tor, the reaction stream passed through a back-pressure regulator (8
bar) before being collected into a flask. The crude reaction mixture
was diluted with H2O and extracted with Et2O (2×); the combined or-
ganic layers were dried (MgSO4), filtered, and concentrated. The crude
residue was finally purified by flash column chromatography (silica
gel, pentane) to afford 2c.
H).
13C NMR (75 MHz, CDCl3): δ = 160.0, 133.1, 128.0, 127.7, 116.8, 114.6,
55.7.
The spectroscopic data correspond to those previously reported.2c
(E)-1-Chlorodec-1-ene (2f)
In an oven-dried 10 mL flask, (E)-1-iododec-1-ene (133 mg, 0.50
mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (16 μL, 0.10
mmol), and Aliquat 336® (457 μL, 1.00 mmol) were premixed in EtOH
(1 mL) for 5 min. The resulting reaction mixture was pumped into the
copper reactor at 110 °C for 60 min with a flow rate of 0.166 mL/min.
Upon exiting the fourth flow reactor, the reaction stream passed
through a back-pressure regulator (8 bar) before being collected into a
flask. The crude reaction mixture was diluted with EtOAc, filtered
through a plug of silica gel and concentrated. The crude residue was
finally purified by flash column chromatography (silica gel, pentane)
to afford 2f.
Yield: 64 mg (0.31 mmol, 62%); light yellow oil.
IR (ATR): 3074, 1614, 1412, 1324, 1165, 1123, 1109, 1067, 1017, 931,
845, 823, 795, 755, 728 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 8.1 Hz, 2 H), 7.40 (d, J = 8.1
Hz, 2 H), 6.86 (d, J = 13.5 Hz, 1 H), 6.75 (d, J = 13.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.4, 132.2, 130.1 (q, J = 32.3 Hz),
126.4, 125.9 (q, J = 3.8 Hz), 124.1 (q, J = 270.4 Hz), 121.6.
19F NMR (377 MHz, CDCl3): δ = –65.8 (s).
HRMS (EI): m/z [M]+ calcd for C9H635ClF3: 206.0105; found: 206.0106.
Yield: 71 mg (0.41 mmol, 81%); colorless oil.
IR (ATR): 2956, 2925, 2855, 1457, 1377, 931, 805, 721 cm–1
1H NMR (300 MHz, CDCl3): δ = 5.96–5.84 (m, 2 H), 2.04 (app qd, J =
7.2, 1.2 Hz, 2 H), 1.41–1.20 (m, 12 H), 0.88 (t, J = 6.9 Hz, 3 H).
.
13C NMR (75 MHz, CDCl3): δ = 134.2, 116.7, 32.0, 31.0, 29.5, 29.4, 29.1,
29.0, 22.8, 14.2.
(E)-1-Chloro-4-(2-chlorovinyl)benzene (2d)
In an oven-dried 10 mL flask, (E)-1-chloro-4-(2-iodovinyl)benzene
(132 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-di-
amine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00 mmol)
were premixed in EtOH (1 mL) for 5 min. The resulting reaction mix-
ture was pumped into the copper reactor at 110 °C for 60 min with a
flow rate of 0.16 mL/min. Upon exiting the fourth flow reactor, the re-
action stream passed through a back-pressure regulator (8 bar) before
being collected into a flask. The crude reaction mixture was diluted
with EtOAc, filtered through a plug of silica gel and concentrated. The
crude residue was finally purified by flash column chromatography
(silica gel, pentane) to afford 2d.
HRMS (EI): m/z [M]+ calcd for C10H1935Cl: 174.1170; found: 174.1178.
(E)-3-(tert-Butyldiphenylsiloxy)-1-chloroprop-1-ene (2g)
In an oven-dried 10 mL flask, (E)-3-(tert-butyldiphenylsiloxy)-1-io-
doprop-1-ene (211 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclo-
hexane-1,2-diamine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL,
1.00 mmol) were premixed in EtOH (1 mL) for 5 min. The resulting
reaction mixture was pumped into the copper reactor at 110 °C for 60
min with a flow rate of 0.166 mL/min. Upon exiting the fourth flow
reactor, the reaction stream passed through a back-pressure regulator
(8 bar) before being collected into a flask. The crude reaction mixture
was diluted with EtOAc, filtered through a plug of silica gel, and con-
centrated. The crude residue was finally purified by flash column
chromatography (silica gel, hexane–EtOAc, 98:2) to afford 2g.
Yield: 56 mg (0.33 mmol, 65%); white solid; mp 33 °C.
IR (ATR): 1488, 1403, 1090, 1012, 944, 927, 832, 818 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.29 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.4
Hz, 2 H), 6.77 (d, J = 13.8 Hz, 1 H), 6.62 (d, J = 13.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 134.0, 133.2, 132.2, 129.1, 127.4, 119.5.
HRMS (EI): m/z [M]+ calcd for C8H635Cl2: 171.9841; found: 171.9851.
Yield: 150 mg (0.45 mmol, 91%); colorless oil.
IR (ATR): 2930, 2857, 1471, 1376, 1111, 1067, 1007, 962, 926, 822,
767, 738, 700, 614 cm–1
.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
A. Nitelet et al.
Feature
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.71 (d, J = 7.5 Hz, 4 H), 7.50–7.38 (m, 6
H), 6.27 (dt, J = 12.9, 1.8 Hz, 1 H), 6.03 (dt, J = 13.2, 4.8 Hz, 1 H), 4.20
(dd, J = 4.8, 1.5 Hz, 2 H), 1.10 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 135.6, 133.3, 132.3, 129.9, 127.9, 119.0,
62.7, 26.9, 19.3.
flow rate of 0.083 mL/min. Upon exiting the fourth flow reactor, the
reaction stream passed through a back-pressure regulator (8 bar) be-
fore being collected into a flask. The crude reaction mixture was di-
luted with EtOAc, filtered through a plug of silica gel, and concentrat-
ed. The crude residue was finally purified by flash column chroma-
tography (silica gel, pentane) to afford 2j.
HRMS (EI): m/z [M]+ calcd for C19H2335ClOSi: 330.1201; found:
330.1205.
Yield: 66 mg (0.43 mmol, 86%); colorless oil.
IR (ATR): 2922, 1615, 1509, 1448, 1344, 1173, 1120, 856, 821, 786,
730, 694, 621 cm–1
.
(E)-1-Chloro-3-phthalimidoprop-1-ene (2h)
1H NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 8.1 Hz, 2 H), 7.18 (d, J = 8.1
Hz, 2 H), 6.60 (d, J = 8.1 Hz, 1 H), 6.21 (d, J = 8.1 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 138.3, 131.5, 129.3, 129.3, 129.1, 116.8,
In an oven-dried 10 mL flask, (E)-1-iodo-3-phthalimidoprop-1-ene
(156 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-di-
amine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00 mmol)
were premixed in DMSO (1 mL) for 5 min. The resulting reaction mix-
ture was pumped into the copper reactor at 110 °C for 60 min with a
flow rate of 0.166 mL/min. Upon exiting the fourth flow reactor, the
reaction stream passed through a back-pressure regulator (8 bar) be-
fore being collected into a flask. The crude reaction mixture was di-
luted with H2O and extracted with Et2O (2×); the combined organic
layers were dried (MgSO4), filtered, and concentrated. The crude resi-
due was finally purified by flash column chromatography (silica gel,
hexane–EtOAc, 80:20) to afford 2h.
21.5.
HRMS (EI): m/z [M]+ calcd for C9H935Cl: 152.0387; found: 152.0393.
(Z)-1-Chloro-3-(4-methoxyphenoxy)prop-1-ene (2k)
In an oven-dried 10 mL flask, (Z)-1-iodo-3-(4-methoxy)phenyloxy-
prop-1-ene (152 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohex-
ane-1,2-diamine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00
mmol) were premixed in EtOH (1 mL) for 5 min. The resulting reac-
tion mixture was pumped into the copper reactor at 120 °C for 120
min with a flow rate of 0.083 mL/min. Upon exiting the fourth flow
reactor, the reaction stream passed through a back-pressure regulator
(8 bar) before being collected into a flask. The crude reaction mixture
was diluted with EtOAc, filtered through a plug of silica gel, and con-
centrated. The crude residue was finally purified by flash column
chromatography (silica gel, pentane–Et2O, 98:2) to afford 2k.
Yield: 95 mg (0.42 mmol, 85%); white solid; mp 102 °C.
IR (ATR): 3078, 1703, 1429, 1393, 1345, 1120, 1044, 941, 798, 717,
614 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.85 (dd, J = 5.4, 3 Hz, 2 H), 7.72 (dd, J =
5.7, 3 Hz, 2 H), 6.35 (d, J = 13.5 Hz, 1 H), 6.00 (dt, J = 13.2, 7.2 Hz, 1 H),
4.26 (dd, J = 6.3, 0.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 167.7, 134.3, 132.1, 126.9, 123.6, 123.5,
Yield: 94 mg (0.44 mmol, 88%); colorless oil.
37.4.
IR (ATR): 2833, 1506, 1462, 1227, 1181, 1107, 1039, 823, 751, 700 cm–1
1H NMR (300 MHz, CDCl3): δ = 6.85 (s, 4 H), 6.23 (dt, J = 7.2, 1.8 Hz, 1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H935ClNO2: 222.0316; found:
222.0318.
H), 6.05 (dt, J = 7.2, 1.5 Hz, 1 H), 4.72 (dd, J = 5.7, 1.8 Hz, 2 H), 3.77 (s, 3
H).
(Z)-(2-Chlorovinyl)benzene (2i)
13C NMR (75 MHz, CDCl3): δ = 154.3, 152.4, 128.4, 120.7, 115.8, 114.8,
64.4, 55.7.
HRMS (EI): m/z [M]+ calcd for C10H1135ClO2: 198.0442; found:
198.0452.
In an oven-dried 10 mL flask, (Z)-(2-iodovinyl)benzene (115 mg, 0.50
mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (16 μL, 0.10
mmol), and Aliquat 336® (457 μL, 1.00 mmol) were premixed in EtOH
(1 mL) for 5 min. The resulting reaction mixture was pumped into the
copper reactor at 120 °C for 120 min with a flow rate of 0.083
mL/min. Upon exiting the fourth flow reactor, the reaction stream
passed through a back-pressure regulator (8 bar) before being collect-
ed into a flask. The crude reaction mixture was diluted with EtOAc,
filtered through a plug of silica gel, and concentrated. The crude resi-
due was finally purified by flash column chromatography (silica gel,
pentane) to afford 2i.
(Z)-1-Chloro-3-(tetrahydropyran-2-yloxy)prop-1-ene (2l)
In an oven-dried 10 mL flask, (Z)-1-iodo-3-(tetrahydropyran-2-
yloxy)prop-1-ene (134 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcy-
clohexane-1,2-diamine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL,
1.00 mmol) were premixed in EtOH (1 mL) for 5 min. The resulting
reaction mixture was pumped into the copper reactor at 120 °C for
120 min with a flow rate of 0.083 mL/min. Upon exiting the fourth
flow reactor, the reaction stream passed through a back-pressure reg-
ulator (8 bar) before being collected into a flask. The crude reaction
mixture was diluted with EtOAc, filtered through a plug of silica gel
and concentrated. The crude residue was finally purified by flash col-
umn chromatography (silica gel, pentane–Et2O, 80:20) to afford 2l.
Yield: 54 mg (0.39 mmol, 79%); colorless oil.
IR (ATR): 3025, 1617, 1491, 1445, 1346, 926, 846, 772, 722, 689, 658
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 7.2 Hz, 2 H), 7.41–7.29 (m, 3
H), 6.64 (d, J = 8.1 Hz, 1 H), 6.27 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 134.3, 129.4, 129.3, 128.4, 128.3, 117.7.
HRMS (EI): m/z [M]+ calcd for C8H735Cl: 138.0231; found: 138.0239.
Yield: 71 mg (0.40 mmol, 80%); brown oil.
IR (ATR): 2942, 1634, 1454, 1351, 1201, 1156, 1120, 1070, 1029, 964,
906, 870, 815, 733, 683 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.15 (dt, J = 7.2, 1.8 Hz, 1 H), 5.98 (app
dd, J = 12.9, 6.3 Hz, 1 H), 4.65 (t, J = 3.6 Hz, 1 H), 4.41 (A of ABXY sys-
tem, J = 13.3, 5.6, 1.7 Hz, 1 H), 4.26 (B of ABXY system, J = 13.3, 6.4, 1.6
Hz, 1 H), 3.88 (m, 1 H), 3.53 (m, 1 H), 1.88–1.47 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 129.0, 120.1, 98.7, 62.9, 62.5, 30.7, 25.5,
19.6.
(Z)-1-(2-Chlorovinyl)-4-methylbenzene (2j)
In an oven-dried 10 mL flask, (Z)-(2-iodovinyl)-4-methylbenzene
(122 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-di-
amine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00 mmol)
were premixed in EtOH (1 mL) for 5 min. The resulting reaction mix-
ture was pumped into the copper reactor at 120 °C for 120 min with a
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
A. Nitelet et al.
Feature
Synthesis
HRMS (ESI): m/z [M]+ calcd for C8H1335ClO2: 176.0599; found:
176.0609.
2012, 68, 654. (j) Das, J. P.; Sujit, R. J. Org. Chem. 2002, 67, 7861.
(k) Kulbitski, K.; Nisnevich, G.; Gandelman, M. Adv. Synth. Catal.
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(2) For representative examples, see: (a) Williams, D. R.; Nishitani,
K.; Bennett, W.; Sit, S. Y. Tetrahedron Lett. 1981, 22, 3745.
(b) Miller, R. B.; McGarvey, G. J. Org. Chem. 1978, 43, 4424.
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(3) For recent reviews on aromatic and vinylic Finkelstein reac-
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(b) Evano, G.; Nitelet, A.; Thilmany, P.; Dewez, D. F. Front. Chem.
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1-(tert-Butyldiphenylsiloxy)-2-chloroprop-2-ene (2m)
In an oven-dried 10 mL flask, 1-(tert-butyldiphenylsiloxy)-2-iodo-
prop-2-ene (211 mg, 0.50 mmol), (±)-trans-N,N′-dimethylcyclohex-
ane-1,2-diamine (16 μL, 0.10 mmol), and Aliquat 336® (457 μL, 1.00
mmol) were premixed in DMSO (1 mL) for 5 min. The resulting reac-
tion mixture was pumped into the copper reactor at 130 °C for 120
min with a flow rate of 0.083 mL/min. Upon exiting the fourth flow
reactor, the reaction stream passed through a back-pressure regulator
(8 bar) before being collected into a flask. The crude reaction mixture
was diluted with H2O and extracted with Et2O (2×); the combined or-
ganic layers were dried (MgSO4), filtered, and concentrated. The crude
residue was finally purified by flash column chromatography (silica
gel, pentane) to afford 2m.
(4) (a) Nitelet, A.; Evano, G. Org. Lett. 2016, 18, 1904. (b) Nitelet, A.;
Jouvin, K.; Evano, G. Tetrahedron 2016, 72, 5972.
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(c) Morse, P. D.; Beingessner, R. L.; Jamison, T. F. Isr. J. Chem.
2017, 57, 218. (d) Plutschack, M. B.; Pieber, B.; Gilmore, K.;
Seeberger, P. H. Chem. Rev. 2017, 117, 11796. (e) Wirth, T.
Angew. Chem. Int. Ed. 2017, 56, 682.
(6) (a) Bogdan, A. R.; Sach, N. W. Adv. Synth. Catal. 2009, 351, 849.
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X.; Hendra; Kwan, W. L.; Lee, C.-L. K. Org. Lett. 2013, 15, 65.
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Tranmer, G. K. Chem. Commun. 2015, 51, 3037. (h) Nuyts, K.;
Ceulemans, M.; Parac-Vogt, T. N.; Bultynck, G.; De Borggraeve,
W. M. Tetrahedron Lett. 2015, 56, 1687.
Yield: 76 mg (0.23 mmol, 47%); colorless oil.
IR (ATR): 2931, 2857, 1647, 1472, 1427, 1111, 1089, 885, 824, 738,
700, 613 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.71–7.64 (m, 4 H), 7.49–7.36 (m, 6 H),
5.66 (d, J = 1.5 Hz, 1 H), 5.34 (d, J = 1.5 Hz, 1 H), 4.18 (t, J = 1.5 Hz, 2 H),
1.09 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 140.0, 135.6, 133.1, 130.1, 128.0, 110.9,
66.3, 26.9, 19.4.
HRMS (EI): m/z [M]+ calcd for C19H2335ClOSi: 330.1201; found:
330.1211.
Funding Information
This research was supported by the Fonds pour la formation ̀a la Re-
cherche dans l’Industrie et dans l’Agriculture (F.R.I.A., graduate fel-
lowship to A.N.), the Natural Science and Engineering Research
Council of Canada (NSERC) under the CREATE Training Program in
Continuous Flow Science (CREATE 449307-2014), and the ‘G-3 des
(7) Chen, M.; Ichikawa, S.; Buchwald, S. L. Angew. Chem. Int. Ed.
2015, 54, 263.
(8) For representative contributions, see: (a) Coste, A.; Karthikeyan,
G.; Couty, F.; Evano, G. Angew. Chem. Int. Ed. 2009, 48, 4381.
(b) Coste, A.; Couty, F.; Evano, G. Org. Lett. 2009, 11, 4454.
(c) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272.
(d) Evano, G.; Tadiparthi, K.; Couty, F. Chem. Commun. 2011, 47,
179. (e) Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrot, J.;
Couty, F.; Evano, G. Org. Lett. 2012, 14, 6. (f) Jouvin, K.; Bayle, A.;
Legrand, F.; Evano, G. Org. Lett. 2012, 14, 1652. (g) Pradal, A.;
Evano, G. Chem. Commun. 2014, 50, 11907. (h) Theunissen, C.;
Wang, J.; Evano, G. Chem. Sci. 2017, 8, 3465.
(9) For representative contributions, see: (a) Lebel, H.; Piras, H.;
Borduy, M. ACS Catal. 2016, 6, 1109. (b) Rullière, P.; Cyr, P.;
Charette, A. B. Org. Lett. 2016, 18, 1988. (c) Audubert, C.;
Gamboa Marin, O. J.; Lebel, H. Angew. Chem. Int. Ed. 2017, 56,
6294. (d) Audubert, C.; Lebel, H. Org. Lett. 2017, 19, 4407.
(e) Lévesque, E.; Laporte, S. T.; Charette, A. B. Angew. Chem. Int.
Ed. 2017, 56, 837. (f) Rullière, P.; Benoit, G.; Allouche, E. M. D.;
Charette, A. B. Angew. Chem. Int. Ed. 2018, 57, 5777. (g) Sayes,
M.; Benoit, G.; Charette, A. B. Angew. Chem. Int. Ed. 2018, 57,
13514.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G