Efficient transposition of the sandmeyer reaction from batch to continuous process

Article abstract of DOI:10.1021/acs.oprd.6b00318

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

Full text of DOI:10.1021/acs.oprd.6b00318

Subscriber access provided by Macquarie University
Full Paper
Efficient transposition of the Sandmeyer
reaction from batch to continuous process
Joseph D'Attoma, Titi Camara, Pierre-Louis Brun, Yves
Robin, Stephane Bostyn, Frédéric Buron, and Sylvain Routier
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00318 • Publication Date (Web): 30 Nov 2016
Downloaded from http://pubs.acs.org on December 2, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Efficient transposition of the Sandmeyer reaction
from batch to continuous process.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Joseph D’Attoma,† Titi Camara,‡ Pierre Louis Brun,‡ Yves Robin,‡ Stéphane Bostyn,§*
Frédéric Buron†* and Sylvain Routier †*
†
Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, rue de
Chartres, BP 6759, 45067 Orléans Cedex 2, France.
‡ ISOCHEM, 4 rue Marc Sangnier, BP 16729, 45300 Pithiviers, France.
§ Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, avenue
de la recherche scientifique, 45071 Orléans cedex 2, France.
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 25
1
2
3
4
TABLE OF CONTENTS GRAPHIC
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
ACS Paragon Plus Environment

Page 3 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT. The transposition of Sandmeyer chlorination from a batch to a safe continuous
flow process was investigated. Our initial approach was to develop a cascade method using
flow chemistry which involved the generation of a diazonium salt and its quenching with
copper chloride. To achieve this safe continuous process diazotation, a chemometric approach
(Simplex method) was used and extrapolated to establish a fully continuous flow method. The
reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation
and scaleꢀup of the process were also performed. A higher productivity was obtained with
increased safety.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: Continuous process, Diazonium, Chlorination, Simplex, Scaleꢀup.
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 25
1
2
3
4
INTRODUCTION
5
6
7
8
Diazonium salts are very versatile intermediates and reagents in organic synthesis and their
chemical nature makes them an excellent leaving group in Sandmeyer,1ꢀ3 Meerwein,4,5 Balzꢀ
Schiemann6,7 and palladoꢀcatalyzed coupling chemistry.8ꢀ10 Diazonium salts are highly
energetic and sensitive compounds. They react strongly to heat, light, shock, or static
electricity which can lead to rapid, uncontrollable decomposition and explosion.11ꢀ14 Salt
handling requires precautionary measures in the laboratory and is thus less widely used for
industrial scaleꢀup phases.15ꢀ17 However, their increasing usefulness in organic synthesis has
contributed to the development of safe preparation methods .18ꢀ20
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Continuous flow chemistry, which has been rapidly adopted in academic, pharmaceutical
and fine chemistry laboratories. One of the main reasons for its emergence and popularity is
the ability to significantly improve the safety of batch reactions.29 Improved reagent mixing,
heat and mass transfer but also increased reproducibility, scaleꢀup and automated synthetic
operations explain the growing interest in this field.21ꢀ28 Sensitive and toxic reaction
intermediates can be generated and directly consumed in a single process without
intermediate handling or hazardous material storage.
The earliest example of continuous chloroꢀdediazotation was demonstrated by the de Mello
group in 2002 on a microfluidic chip reactor. During the past decade several studies have
investigated the transposition of diazonium salt formation from batch to continuous processes
but only regarding sulfonylation or hydrazine formation.30ꢀ35 Surprisingly, to the best of our
knowledge, no study has yet reported the optimization of chloroꢀdediazotation under a
continuous mesoꢀscale process.
In this study we first present transposition of the Sandmeyer chlorination reaction into a semiꢀ
continuous process using a Simplex optimization method. Starting from anilines, diazonium
salts were formed under flow conditions prior to trapping this unstable intermediate and
4
ACS Paragon Plus Environment

Page 5 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
forming the desired chlorinated aryl derivative. We then investigated the implantation of a
fully continuous process, including the generation and consumption of the diazonium entities.
The scope and limitations of the process were explored using conventional substituted aryl
anilines and amino heterocycles. The challenges encountered during the investigation as well
as the scaleꢀup phase are disclosed and the results discussed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
1. Switch from batch to continuous-flow diazotation. Typically, the batch reaction is
performed in concentrated hydrochloric and acetic acids with aqueous NaNO2.1 These
experimental conditions were considered too harsh for use in a flow reactor due to the
presence of corrosive reagents and strongly acidic conditions which can induce interference
with chemical functions or scaffolds. However, Indeed, these conditions generate a biphasic
system which interferes with the limiting factor, the solubility of organic starting materials.
To work around this issue, we decided to use a homogenous system considering alkyl nitrites
as universal organic diazotizing agents. Additionally, this strategy avoids acidic conditions
and stabilizes the intermediate salt.36 This alternative requires the use of acetonitrile as
solvent, which limits the direct transposition of the classical batch method to a flow process
due to the low solubility of copper chloride.
In order to avoid the risk of clogging the reactor, we conducted an initial inspection to
develop a semiꢀcontinuous process involving first the synthesis of diazonium salt in
continuous flow followed by the substitution of the diazo group in a flask with a
heterogeneous copper chloride solution. The formation of the diazonium salt was carried out
with a commercial flow chemistry device from Uniqsis®. A solution A containing 1 (1.32
mmol) in MeCN (2 mL) was introduced at 1.25 mL.minꢀ1 and mixed using a standard Tꢀ
junction with a second solution B of tertꢀbutyl nitrite 2 (1.44 mmol, 1.1 equiv.) in acetonitrile
(2 mL) pumped at the same flow rate. The combined solution was then passed through a
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 25
1
2
3
4
5
6
7
8
9
tubular 2.5 mL reactor (1 mm internal diameter, PTFE). The mixing Tꢀjunction and the coil
were both submerged in a thermostatic bath to control the temperature. To determine the best
experimental conditions able to quantitatively furnish the diazonium salt, the reactor outlet
containing the diazo species was immediately poured into a well stirred suspension of CuCl2
in acetonitrile at 65 °C (Scheme 1) in a 250 mL roundꢀbottom flask equipped with a
condenser. In order to quantify the efficiency of the continuous process during step 1, the
formation of the diazonium salt at the reactor outlet was followed by TLC. This cascade
procedure offers an advantage in pressure management. The nitrogen gas production during
the second step is not problematic as the final reactor is open and the flow system is not
pressurized.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Sandmeyer reaction under semiꢀcontinuous processing mode.
2. Flow parameter optimization. The first parameter considered to generate the diazonium
salt of 1 was the reaction temperature T1. Due to the instability of these species, the flow
reactor was placed at 0 °C in a thermostated bath. Under these conditions and with an
arbitrarily chosen 10 min. residence time, the desired compound 3 was isolated in a
satisfactory 60 % yield (Table 1, entry 1). A residence time study indicated that 1 minute was
a good compromise as 30 seconds led to a slight decrease in yield (entries 2, 3). To verify
whether an increase in temperature would adversely affect the intermediate, the reactor was
placed at 20 °C. The yield of 3 increased to 77% (entry 4) with a 1 minute holding time.
6
ACS Paragon Plus Environment

Page 7 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Finally, the quantity of nitrite was adjusted and after several assays 3 was prepared in an
excellent 84% yield (entry 5), in spite of the near stoichiometric quantity of tertꢀbutylnitrite.
In conclusion, with an equimolar amount of reagents and after only one minute at room
temperature we were now able to induce a full conversion of aniline 1 into its diazo
equivalent under a flow process. Further consumption of the intermediate was achieved in a
flask with a very slight excess of copper chloride and the chlorinated derivative 3 was purified
and quantified as the sole reaction product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Parameters for the first diazonium formation.
Entry
Equiv. of
tert-butyl nitrite 2
T1 (°C) t1 (min) Yield of 3
(%)
1
2
3
4
6
1.5 equiv.
1.5 equiv.
1.5 equiv.
1.5 equiv.
1.1 equiv.
0
0
10
1
60
74
68
77
84
0
0.5
1
20
20
1
3. Simplex optimization of the semi-continuous process for step 2. Having in hand an
optimized diazonium generation flow process leading to the chloro derivative 3 from 1, we
then considered creating a full flow system including both synthesis and displacement of the
diazo group by a chlorine atom. In order to achieve this goal, it was necessary to optimize
each of the parameters involved in the twoꢀstep reaction. The Simplex method is an
evolutionary operation technique in which a series of experiments is built in such a manner
that the reaction conditions for a given experiment are controlled by the results of the
preceding experiments in the series 37ꢀ39
The parameters retained for optimization were
.
temperature, and two parameters to define the reaction, namely the amount of CuCl2 and the
reaction time (Table 2).
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 25
1
2
3
Table 2. Initial simplex in reduced coordinates and in real coordinates.
4
5
6
7
Reduced coordinate matrix
Real coordinate matrix
Experiment
number
T
CuCl2
t
Xi,1
Xi,2
Xi,3
(°C)
(equiv.)
(min)
8
9
0
1
2
3
0
0
0
0
21
65
43
43
1.2
1.2
30
30
30
39
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
0
0.5
0.5
0.866
0.289
0
1.55
1.32
0.817
Our three dimensional simplex had four vertices represented by a tetrahedron. The
experiments which constituted the first simplex were deliberately chosen within the boundary
of the experimental domain in order to progress inside the domain. After the initial
experiments of the first simplex, the method evolved sequentially with the addition of a new
experiment, performed in the opposite direction to the worst point (w). The reduced
coordinates of the new point were calculated with the following equation:
xi,j = x0,j + Xi,j ×ꢀxj
(1)
where i corresponds to the simplex points from 0 to k, j corresponds to the variable from 1 to
k, x0,j is the real coordinate for the variable j at the center of the domain studied, Xi,j
corresponds to the reduced coordinate for the variable j at the point i, and ꢀxj corresponds to
the step size for the variable j. The step sizes and the values of the domain center are reported
in Table 3 for each variable.
Table 3. The control variable values at the center of the domain and their step sizes.
Control variable
xi,1 (Temperature)
xi,2 (CuCl2)
Value of the domain center
Step size
44
Unit
°C
21
1.2
0.4
equiv.
xi,3 (Time)
30
10
min.
8
ACS Paragon Plus Environment

Page 9 of 25
Organic Process Research & Development
1
2
3
4
5
For the simplex evolution, calculation of the new point coordinate was based on the
following equation:
6
7
8
Xr,j = Xg,j + α(Xg,j - Xw,j)
(2)
9
where Xr,j is the reduced coordinate of the new point for the variable j; Xg,j is the centroid of
the remaining face/hyperface (i.e. the average levels for the remaining trials), and Xw,j is a
rejected trial.40 Therefore, this method allowed a certain leeway in the choice of the initial
step sizes that were sometimes difficult to define due to the lack of experiments at the
beginning of the study.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Relation between yields and experiment number during simplex optimization (w
corresponds to the worst point of the simplex and b to the best point of the simplex).
Experiment
number
T
CuCl2
t
Yield
(%)
Number of simplex
(°C)
(equiv.)
(min)
1
2
3
0
21
1.2
30
54
4 (w)
1
2
3
4
5
65
43
43
80
82
1.2
1.5
1.3
1,5
1,1
30
30
39
36
39
70
57
59
82
86
1 (b)
2
3
3
2
4 (w)
3
4
2
1 (b)
1 (b)
The first simplex in table 4 showed that the best experiment was number 1 with a yield of
70 %. Experiment 0 was the worst with a yield of only 54 % of chlorinated product 3. This
assay was therefore eliminated in the simplex process and the new coordinates for experiment
4 were the projection relative to this point. In the second simplex, experiment 2 was the worst
with 57 % of the chlorinated product; the best result achieved was 82 % yield. Finally, a third
simplex was applied, and showed that the best experiment had an 86 % yield. As the
calculated temperature (108 °C) of the next simplex projection, with respect to point 5, was
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 25
1
2
3
4
5
6
7
8
9
outside the feasible region (Teb ACN = 82 °C at atmospheric pressure), we decided to end the
simplex evolution since: i) the temperature of the next point would be above the boiling point
of the solvent; ii) the yield of 86 % was judged to correspond to the maximum yield obtained
in the batch mode. To conclude, using this optimization method the yield was drastically
increased from 52 % to 86 % in only five experiments.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. Full Sandmeyer continuous process. In order to furnish a fully continuous process,
the CuCl2 solubility problem had to be circumvented. Several batch assays were undertaken to
identify a coꢀsolvent to increase this solubility. Ethylene glycol (EG) was identified as an
excellent coꢀsolvent, since only 0.25 equivalent of EG increased the solubility of copper (II)
chloride up to 202 g/L in acetonitrile.41 This addition of coꢀsolvent did not interfere with the
diazonium trapping step under the previously described semiꢀcontinuous process and the
desired product 3 was isolated with a similar efficiency (83% yield).
Consequently, a real fully continuous process was now achievable. A third pump containing
a solution of CuCl2/ethylene glycol in MeCN (0.36 mol.Lꢀ1; solution C) was placed after
reactor 1, using both a second standard Tꢀjunction and reactor (20 mL, 1 mm internal
diameter, PTFE) (Scheme 2). With this modification, the holding time of reactor 2 was 4 min
due to the total flowrate imposed by the sum of each individual throughput (solution A: 0.66
mol/l, 1.25 mL.minꢀ1; solution B: 0.72 mol/l, 1.25 mL.minꢀ1; solution C: 0.36 mol/l, 2.5
mL.minꢀ1) and gave a continuous process in 5 minutes as total holding time. Additionally, the
desired product 3 was isolated in an unprecedented 87 % yield, after only 5 minutes (versus
30 min in batch mode). Both of these improvements increase the attractiveness of the
technology. To regulate the internal pressure in the second reactor due to the solvent heating
(82 °C) and the nitrogen release, a 100 psi back pressure regulator was fitted prior to the
collection flask. Further scaleꢀup will depend on our ability to manage the pressure.
10
ACS Paragon Plus Environment

Page 11 of 25
Organic Process Research & Development
1
2
3
Scheme 2. Sandmeyer reaction under the fully continuous process.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5. Extending the chemical scope. Having in hand this 3ꢀinlet flow setꢀup as depicted in
Scheme 2, we extended the scope of aniline derivatives to formally establish the considerable
advantage of such a continuous flow process. The first tests were conducted with anilines 1ꢀ8
bearing an electroꢀattracting group (Table 5). The reaction efficiency was preserved,
especially for acetyl compound 5 which was isolated in a quantitative yield and for nitro
compound 7 in a 91 % yield.36 Nevertheless, the reaction appeared to be sensitive to the
presence of an acidic function as 15 was isolated in only 50% yield (entry 7). Efficiency was
partially restored with a cyano group. Yields increased again with methyl or ethyl esters to
reach around 80 % in the final chloro derivatives 11 and 13.
Anilines substituted with electronꢀdonating groups such as CH3 or OMe in para position
caused problems and only degradation was observed. However with additionalnitro
substitution of the aromatic ring, 21 (entry 9) was isolated in 66% yield. This further
confirmed that the electronic character of the aryl drives the Sandmeyer chlorination under
our flow process. The less donating methyl sulfur partially restored the efficiency as 23 was
isolated in average yield (entry 10).
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 25
1
2
3
Table 5. Scope of the Sandmeyer reaction in aryl chlorines under continuous mode.
4
5
6
7
8
Entry
Reactant
Product
Yield (%)
87
1
1
4
3
5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
quant.
2
91
75
81
3
4
5
6
8
7
9
10
11
80
50
6
7
8
12
14
16
13
15
17
ND
ND
66
9
18
20
19
21
10
46
11
22
23
ND: Not detected.
To expand the scope and identify other limits, the behavior of several amino
heteroaromatic systems was investigated (Table 6). The pyridine moieties demonstrated a
moderate reactivity and products 25 and 27 were isolated in 47 % and 44 % yield,
respectively. Next, the procedure was tried with benzothiazole and benzoxazole rings and the
reaction was fully efficient with the sulfur heterocycle 29 (entry 3), but appeared to be
partially inhibited in presence of the electron rich oxygen atom (entries 4, 5). The instability
12
ACS Paragon Plus Environment

Page 13 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
of the diazonium salt from 2ꢀaminopyrimidine was observed and adduct 37 was formed in
only 20% yield (entry 7). A strong limitation occurred as starting amino derivative 38 was
fully insoluble in acetonitrile. To solve this compatibility with the flow technology, we started
from the benzyl protected nitrogen derivative 40. This protection significantly increased the
solubility in acetonitrile and reactivity was partially restored. Product 41 was synthesized in
26 % yield. With an electron withdrawing Nꢀprotecting group such as a phenylsulfonyl
moiety, the same behavior was observed and derivative 42 was isolated in a 23% yield (entry
9ꢀ10).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. Scope of the Sandmeyer reaction in Hetaryl chlorine under continuous mode.
Entry
Reactant
Product
Yield (%)
47
1
24
26
25
27
44
2
74
33
25
3
4
5
28
30
32
29
31
33
54
20
6
7
34
36
35
37
0a
8
38
39
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 25
1
2
3
4
5
6
7
8
26
23
9
40
42
41
10
43
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a) Only starting material was recovered.
6. Validation process and scale-up of the fully continuous process. To investigate
the stability of the reaction process, a validation with aniline was performed during
1
30 minutes. This step is necessary to evaluate the compatibility of the flow procedure
with a large scale setup. However, as already mentioned, during the assay the
generation of large quantities of nitrogen gas caused a serious breach in back pressure
regulation and residence time control. In order to solve this problem, a Liquid/Gas
separator vessel was designed and built.42 The reactor 2 output was collected in an
external flask fitted with a screw cap GL45 with four ports (Scheme 3).
Scheme 3. Liquid/gas separator vessel.
BPR 100 psi
N2
N2 pressurization
Output
Input
Evacuation
valve
14
ACS Paragon Plus Environment

Page 15 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
This homeꢀmade system was connected to a back pressure regulation of 100 psi and
pressurized with nitrogen. An evacuation valve was added to stabilize the system
pressure, the flowꢀrate and the volume in the Liquid/Gas separator (Scheme 4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Fully continuous process with L/G separator.
With this additional tool, pressure spikes were totally eliminated and the system was
fully stabilized during 30 minutes (Scheme 5). The throughput rate of chlorinated
product
3 was up to 5.61 g/h. Temperature monitoring in reactor 1 showed no
exothermicity during the formation of the diazonium salt. This system will be very
useful to design a safe, semiꢀindustrial diazonium flow process, since the diazonium
salt intermediate can be generated and directly consumed in a single oneꢀpot continuous
sequence without intermediate handling or storage of hazardous material.
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 25
1
2
3
Scheme 5. System pressure with the Liquid/Gas separator.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
This study has shown that the transfer of the Sandmeyer reaction from batch mode to an
efficient and safe continuous process is possible. First, chemometric approaches enabled the
development of an efficient semiꢀcontinuous process. The implementation of the 3ꢀinlet flow
setꢀup made it possible to overcome the cascade step for chlorination. This continuous process
also demonstrated its effectiveness with the generation of unstable diazonium salts in the
synthesis of chlorinated compounds on a large scale. This scaleꢀup also exhibited the limits of
using a mechanical Backꢀpressure reactor (BPR), requiring us to create an online Liquid/Gas
separator vessel which helped to increase the quantity of product formed while ensuring a safe
process. The efficiency of the reaction was proven during 30 min without any observed
exothermicity. This new fully flow procedure will undoubtedly have a major impact on the
use of a safe Sandmeyer reaction in R&D research.
16
ACS Paragon Plus Environment

Page 17 of 25
Organic Process Research & Development
1
2
3
4
EXPERIMENTAL PART
5
6
7
8
13
General Information. 1H NMR and C NMR spectra were recorded on a Bruker
DPX 250 MHz or 400 MHz instrument using CDCl3 or DMSOꢀ 6. The chemical shifts
are reported in parts per million (δ scale) and all coupling constant ( ) values are in
d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
Hertz (Hz). The following abbreviations were used to explain the multiplicities: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and dd (doublet doublet).
Melting points are uncorrected. IR absorption spectra were obtained on a Perkin Elmer
PARAGON 1000 PC and values are reported in cmꢀ1. HRMS were recorded on a
Bruker maXis mass spectrometer by the “Fédération de Recherche” ICOA/CBM
(FR2708) platform. Monitoring of the reactions was performed using silica gel TLC
plates (silica Merck 60 F254). Spots were visualized by UV light at 254 nm and 356
nm. Column chromatography was performed using silica gel 60 (0.063–0.200 mm,
Merck).
Experimental procedure of the semi-continuous process. A solution A of aniline
derivative (1.0 equiv) in MeCN (2 mL) was flowed at 1.25 ml.minꢀ1 and mixed with a second
solution B containing t
BuONO (1.1 equiv.) in MeCN (2 mL) also pumped at 1.25 ml.minꢀ1.
The combined solution was then passed through a 2.5 mL linear reactor (1 mm internal
diameter, PTFE). After a residence time of one minute, the solution was poured directly into a
250 mL roundꢀbottom flask with a condenser containing a suspension of CuCl2 in acetonitrile
at 65 ° C. After the flow reaction was complete, the reaction mixture was stirred for another
39 min. The entire output from the reactor was then collected and concentrated under reduced
pressure, (rotary evaporator; T = 40 ◦C). The resulting mixture was extracted three times with
EE (3x20 mL), dried under MgSO4, filtered and the solvents were evaporated under vacuum.
The residue was purified by flash chromatography on silica gel.
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 25
1
2
3
4
5
6
7
8
Experimental procedure of the fully continuous process. A solution A of aniline
derivative (1.0 equiv; C = 0.66 mol.Lꢀ1 in MeCN for procedure A; C = 0.33 mol.Lꢀ1 in MeCN
for procedure B and C = 0.33 mol.Lꢀ1 in DMF for procedure C) was flowed at 1.25 ml.minꢀ1
9
and mixed using a standard Tꢀpiece with a second solution B containing tBuONO (1.1 equiv.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
in MeCN (2 mL) also pumped at 1.25 ml.minꢀ1. The combined solution was then passed
through a 2.5 mL linear reactor with a residence time of one minute at room temperature. A
solution C containing the CuCl2/ethylene glycol in MeCN (0.36 mol.Lꢀ1; solution C) was
introduced with a third pump after reactor 1 at 2.5 ml.minꢀ1 using a standard Tꢀpiece
connected to a second reactor (20 mL, 1 mm internal diameter, PTFE). The residence time
was 4 min and the temperature 82°C. The entire output from the reactor was collected and
◦
concentrated under reduced pressure, (rotary evaporator; T = 40 C). The resulting mixture
was extracted three times with EE (3x20 mL), dried under MgSO4, filtered and the solvents
were evaporated under vacuum. The residue was purified by flash chromatography on silica
gel.
4-Chloro-3-nitrotoluene (3). The reaction was carried out as described in general
procedure A using 4ꢀmethylꢀ2ꢀnitroaniline (200 mg, 1.31 mmol). After purification with silica
flash chromatography (EP/EE 98/2), the product was isolated as a yellow oil (195 mg, 87%).
1
CAS number 89ꢀ60ꢀ1. H NMR (250 MHz, Chloroformꢀd) δ 7.66 (d,
J
= 1.7 Hz, 1H, Har),
7.41 (d,
J
= 8.3 Hz, 1H, Har), 7.31 (ddd,
J
= 8.2, 2.1, 0.6 Hz, 1H, Har), 2.40 (s, 3H, CH3).
Conform to the literature.43
4’-Chloro-benzophenone (5). The reaction was carried out as described in general
procedure A using 4′ꢀaminoacetophenone (177 mg, 1.31 mmol). After purification with silica
flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (201 mg, 99%).
1
CAS number 99ꢀ91ꢀ2. H NMR (250 MHz, Chloroformꢀd) δ 7.83 (d,
J = 8.8 Hz, 2H, Har),
7.37 (d, J
= 8.8 Hz, 2H, Har), 2.53 (s, 3H, CH3). Conform to the literature.44
18
ACS Paragon Plus Environment

Page 19 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
4-Chloro-nitrobenzene (7). The reaction was carried out as described in general
procedure A using 4ꢀnitroaniline (200 mg, 1.44 mmol). After purification with silica flash
chromatography (EP/EE 90/10), the product was isolated as a yellow oil (208 mg, 91%). CAS
9
number 100ꢀ00ꢀ5. 1H NMR (250 MHz, Chloroformꢀd) δ 8.15 (d,
= 9.2 Hz, 2H, Har). Conform to the literature.45
J = 9.0 Hz, 2H, Har), 7.49 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
4-Chlorobenzonitrile (9). The reaction was carried out as described in general procedure
A using 4ꢀaminobenzonitrile (171 mg, 1.44 mmol). After purification with silica flash
chromatography (EP/AE 90/10), the product was isolated as a yellow oil (148 mg, 75%). CAS
number 623ꢀ03ꢀ0. 1H NMR (250 MHz, Chloroformꢀd) δ 7.61 (d,
= 8.9 Hz, 2H, Har). Conform to the literature.46
J = 8.9 Hz, 2H, Har), 7.47
(d,
J
Methyl 4-chlorobenzoate (11). The reaction was carried out as described in general
procedure A using methyl 4ꢀaminobenzoate (196 mg, 1.31 mmol). After purification with
silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (180 mg,
1
81%). CAS number 1126ꢀ46ꢀ1. H NMR (250 MHz, Chloroformꢀd) δ 7.95 (s, 2H, Har), 7.40
(d,
J
= 8.4 Hz, 2H, Har), 3.91 (s, 3H, CH3). Conform to the literature.47
Ethyl 4-chlorobenzoate (13). The reaction was carried out as described in general
procedure A using ethyl 4ꢀaminobenzoate (212 mg, 1.31 mmol). After purification with silica
flash chromatography (EP/EE 95/5), the product was isolated as a yellow oil (193 mg, 80%).
CAS number 7335ꢀ27ꢀ5. 1H NMR (250 MHz, Chloroformꢀd) δ 7.97 (d,
J
= 8.8 Hz, 2H, Har),
7.40 (d,
Conform to the literature.48
J = 8.8 Hz, 2H, Har), 4.37 (q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1 Hz, 3H, CH3).
4-Chlorobenzoic acid (15). The reaction was carried out as described in general procedure
A using 4ꢀaminobenzoic acid (180 mg, 1.31 mmol). After acidification with HCl and
trituration in EP, the product was filtered to afford a white solid (101 mg, 50%). CAS number
19
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 25
1
2
3
4
5
74ꢀ11ꢀ3. 1H NMR (250 MHz, DMSOꢀd6) δ 7.93 (d,
2H, Har). Conform to the literature.49
J = 8.1 Hz, 2H, Har), 7.55 (d, J = 8.0 Hz,
6
7
8
4-Chloro-3-nitroanisole (21). The reaction was carried out as described in general
9
procedure A using 4ꢀmethoxyꢀ2ꢀnitroaniline (221 mg, 1.31 mmol). After purification with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (160 mg,
1
66%). CAS number 10298ꢀ80ꢀ3. H NMR (250 MHz, Chloroformꢀd) δ 7.41 (d,
J
= 8.9 Hz,
1H), 7.36 (d,
literature.50
J
= 3.0 Hz, 1H), 7.05 (dd,
J
= 8.9, 3.0 Hz, 1H), 3.85 (s, 3H). Conform to the
4-Chlorothioanisole (23). The reaction was carried out as described in general procedure
A using 4ꢀ(methylthio)aniline (182 mg, 1.31 mmol). After purification with silica flash
chromatography (EP/EE 95/5), the product was isolated as a yellow oil (94 mg, 46%). CAS
number 123ꢀ09ꢀ1. 1H NMR (250 MHz, Chloroformꢀd) δ 7.24 (d,
= 8.9 Hz, 2H, Har), 2.45 (s, 3H, CH3). Conform to the literature.51
J = 8.8 Hz, 2H, Har), 7.16 (d,
J
4-Chloropyridinium chloride (25). The reaction was carried out as described in general
procedure B using 4ꢀaminopyridine (124 mg, 1.31 mmol). After purification with silica flash
chromatography (EP/AE 90/10), the product was isolated as an amorphous white solid (69
1
mg, 47%). CAS number 626ꢀ61ꢀ9. H NMR (250 MHz, Deuterium Oxide) δ 8.76 (d,
J = 6.2
Hz, 2H, Har), 8.15 (d, J
= 6.3 Hz, 2H, Har). Conform to the literature.52
3-Chloro-2-nitropyridine (27). The reaction was carried out as described in general
procedure C using 3ꢀaminoꢀ2ꢀnitropyridine (91 mg, 0.66 mmol). After purification with silica
flash chromatography (EP/AE 80/20), the product was isolated as a yellow oil (45 mg, 44%).
CAS number 54231ꢀ32ꢀ2. 1H NMR (400 MHz, Chloroformꢀd) δ 8.44 (dd,
J
= 4.6, 1.5 Hz, 1H,
Har), 8.00 (dd,
literature.53
J = 8.0, 1.5 Hz, 1H, Har), 7.55 (dd, J = 8.1, 4.6 Hz, 1H, Har). Conform to the
20
ACS Paragon Plus Environment

Page 21 of 25
Organic Process Research & Development
1
2
3
2-Chlorobenzothiazole (29). The reaction was carried out as described in general
4
5
6
procedure A using 2ꢀaminobenzothiazole (197 mg, 1.31 mmol). After purification with silica
7
8
flash chromatography (EP/AE 90/10), the product was isolated as a yellow oil (165 mg, 74%).
9
1
CAS number 615ꢀ20ꢀ3. H NMR (250 MHz, Chloroformꢀd) δ 7.93 (ddd,
J = 8.0, 1.4, 0.7 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H, Har), 7.75 (ddd,
literature.54
J = 7.7, 1.5, 0.7 Hz, 1H, Har), 7.50 – 7.32 (m, 2H, Har). Conform to the
2-Chlorobenzoxazole (31). The reaction was carried out as described in general procedure
A using 2ꢀaminobenzoxazole (176 mg, 1.31 mmol). After purification with silica flash
chromatography (EP/DCM 90/10), the product was isolated as a yellow oil (66 mg, 33%).
CAS number 615ꢀ18ꢀ9. 1H NMR (250 MHz, Chloroformꢀd) δ 7.73 – 7.61 (m, 1H, Har), 7.56 –
7.44 (m, 1H, Har), 7.43 – 7.28 (m, 2H, Har). Conform to the literature.55
2,5-Dichloro-1,3-benzoxazole (33). The reaction was carried out as described in general
procedure B using 2ꢀAminoꢀ5ꢀchlorobenzoxazole (221 mg, 1.31 mmol). After purification
with silica flash chromatography (EP 100%), the product was isolated as a yellow oil (62 mg,
1
25%). CAS number 3621ꢀ81ꢀ6. H NMR (250 MHz, Chloroformꢀd) δ 7.65 (dd,
J
= 2.1, 0.6
Hz, 1H, Har), 7.42 (dd,
J
= 8.7, 0.6 Hz, 1H, Har), 7.32 (dd,
J
= 8.7, 2.0 Hz, 1H, Har). 13C NMR
(101 MHz, Chloroformꢀd) δ 152.27 (C), 150.12 (C), 142.06 (C), 130.79 (C), 125.85 (CH),
119.78 (CH), 111.16 (CH). HRMS [M+H]+ (EI) calcd. for C7H4Cl2NO : 187.9664 , found:
187.9663.
Methyl 3-chlorothiophene-2-carboxylate (35). The reaction was carried out as described
in general procedure A using methyl 3ꢀaminoꢀ2ꢀthiophenecarboxylate (206 mg, 1.31 mmol).
After purification with silica flash chromatography (EP/AE 95/5), the product was isolated as
1
a yellow oil (125 mg, 54%). CAS number 88105ꢀ17ꢀ3. H NMR (250 MHz, Chloroformꢀd) δ
7.46 (d,
J = 5.3 Hz, 2H, Har), 7.00 (d, J = 5.3 Hz, 2H, Har), 3.88 (s, 3H, CH3). Conform to the
literature.56
21
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 25
1
2
3
4
5
6
7
8
2,4,6-Trichloropyrimidine (37). The reaction was carried out as described in general
procedure C using 2ꢀaminoꢀ4,6ꢀdichloropyrimidine (107 mg, 0.66 mmol). After purification
with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (24
9
1
mg, 20%). CAS number 3764ꢀ01ꢀ0. H NMR (250 MHz, Chloroformꢀd) δ 7.38 (s, 1H, Har).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conform to the literature.57
1-Benzyl-2-chloro-1H-benzoimidazole (41). The reaction was carried out as described in
general procedure A using 2ꢀaminoꢀ1ꢀbenzylbenzimidazole (293 mg, 1.31 mmol). After
purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a
1
yellow oil (82 mg, 26%). CAS number 43181ꢀ78ꢀ8. H NMR (250 MHz, Chloroformꢀd) δ
7.73 – 7.65 (m, 1H, Har), 7.31 – 7.11 (m, 8H, Har), 5.36 (s, 2H, CH2). Conform to the
literature.58
1-Benzyl-2-chloro-1H-benzoimidazole (42). The reaction was carried out as described in
general procedure B using 2ꢀaminoꢀ1ꢀbenzylbenzimidazole (179 mg, 0.66 mmol). After
purification with silica flash chromatography (EP/AE 80/20), the product was isolated as a
yellow oil (44 mg, 23%). 1H NMR (400 MHz, Chloroformꢀd) δ 8.13 (d,
J = 8.2 Hz, 1H), 8.03
(d, = 7.5 Hz, 2H), 7.65 (dd, = 7.5, 7.5 Hz, 2H), 7.54 (dd, = 7.9, 7.9 Hz, 2H), 7.45 – 7.40
J
J
J
(m, 1H), 7.39 – 7.33 (m, 1H). 13C NMR (101 MHz, Chloroformꢀd) δ 140.91 , 138.33 , 137.61
, 135.15 , 133.79 , 129.68 , 127.50 , 125.74 , 125.26 , 119.94 , 113.86 . HRMS [M+H]+ (EI)
calcd. for C13H10ClN2O2S : 293.0145, found: 293.0145.
SUPPORTING INFORMATION.
Additional 1H and 13C NMR spectra for products are available in the supporting information.
AUTHOR INFORMATION
Corresponding Author
22
ACS Paragon Plus Environment

Page 23 of 25
Organic Process Research & Development
1
2
3
4
5
* Eꢀmail: frederic.buron@univꢀorleans.fr, sylvain.routier@univꢀorleans.fr and
stephane.bostyn@univꢀorleans.fr.
6
7
8
9
ACKNOWLEDGMENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ICOA and ISOCHEM thank the Région CentreꢀVal de Loire “Flowsyn program” for
supporting their collaboration. The ICOA team thanks the COMI FEDER and the IRON
LABEX programs (ANRꢀ11ꢀLABXꢀ0018ꢀ01) for their financial support.
ABBREVIATIONS
BPR : Back Pressure Regulation
EtOAc : ethyl acetate
EE : diethylether
vs : versus
mg : milligram
Satd : saturated
MeCN : acetonitrile
MW : microwave
DMF : dimethylformamide
EtOH : ethanol
23
ACS Paragon Plus Environment

Organic Process Research & Development
Page 24 of 25
1
2
3
4
5
6
REFERENCES
7
8
9
(1) Meerwein, H.; Dittmar, G.; Göllner, R.; Hafner, K.; Mensch, F.; Steinfort, O. Chem. Ber.
1957, 90, 841ꢀ852.
(2) Galli, C. Chem. Rev. 1988, 88, 765ꢀ792.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) Browne, D. L. Angew. Chem., Int. Ed. 2014, 53, 1482ꢀ1484.
(4) Meerwein, H.; Büchner, E.; van Emster, K. J. Prakt. Chem. 1939, 152, 237ꢀ266.
(5) PrasadꢀHari, D.; Hering, T.; König, B. Angew. Chem., Int. Ed. 2014, 53, 725ꢀ728.
(6) Balz, G.; Schiemann, G. Ber. Dtsch. Chem. Ges. 1927, 60, 1186ꢀ1190.
(7) Abele, S.; Schmidt, G.; Fleming, M. J.; Steiner, H. Org. Process Res. Dev. 2014, 18, 993ꢀ
1001.
(8) Roglans, A.; PlaꢀQuintana, A.; MorenoꢀMañas, M. Chem. Rev. 2006, 106, 4622ꢀ4643.
(9) Kikukawa, K.; Matsuda, T. Chem. Lett. 1977, 6, 159ꢀ162.
(10) Okazaki, T.; Laali, K. K.; Bunge, S. D.; Adas, S. K. Eur. J. Org. Chem. 2014, 2014, 1630ꢀ
1644.
(11) Sheng, M.; Frurip, D.; Gorman, D. J. Loss Prev. Process Ind. 2015, 38, 114ꢀ118.
(12) Ullrich, R.; Grewer, T. Thermochim. Acta 1993, 225, 201ꢀ211.
(13) Shaw, R., Thermochemistry of diazo compounds and organic azides. In Diazonium and Diazo
Groups (1978), John Wiley & Sons, Ltd.2010; pp 137ꢀ147.
(14) Klamann, D.; Editor, Methods of Organic Chemistry, Vol. E 16a: Organic Nitrogen
Compounds I (with N-Alkyl, N-Aryl, and N-Hetaryl Bonds). Georg Thieme Verlag1990; p 1576 pp.
(15) Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chem. Eur. J. 2015, 21, 2298ꢀ2308.
(16) Anderson, N. G. Org. Process Res. Dev. 2001, 5, 613ꢀ621.
(17) Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Process Res. Dev. 2004, 8, 1059ꢀ1064.
(18) Filimonov, V. D.; Trusova, M.; Postnikov, P.; Krasnokutskaya, E. A.; Lee, Y. M.; Hwang, H.
Y.; Kim, H.; Chi, K.ꢀW. Org. Lett. 2008, 10, 3961ꢀ3964.
(19) Callonnec, F. L.; Fouquet, E.; Felpin, F.ꢀX. Org. Lett. 2011, 13, 2646ꢀ2649.
(20) D'Attoma, J.; Cozien, G.; Brun, P. L.; Robin, Y.; Bostyn, S.; Buron, F.; Routier, S.
ChemistrySelect 2016, 1, 338ꢀ342.
(21) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17ꢀ57.
(22) Barrow, D.; Taylor, S.; Morgan, A.; Giles, L., Properties and Use of Microreactors. In
Microreactors in Organic Chemistry and Catalysis, WileyꢀVCH Verlag GmbH & Co. KGaA2013; pp
1ꢀ33.
(23) Baxendale Ian, R.; Brocken, L.; Mallia Carl, J. Green Processing and Synthesis 2013; Vol. 2,
p 211.
(24) Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849ꢀ8869.
(25) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675ꢀ680.
(26) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384ꢀ6389.
(27) Glasnov, T. N.; Kappe, C. O. Chem. Eur. J. 2011, 17, 11956ꢀ11968.
(28) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50, 7502ꢀ7519.
(29) Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456ꢀ1472.
(30) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Lab Chip 2002, 2, 5ꢀ7.
(31) Fortt, R.; Wootton, R. C. R.; de Mello, A. J. Org. Process Res. Dev. 2003, 7, 762ꢀ768.
(32) Jacq, J.; Pasau, P. Chem. Eur. J. 2014, 20, 12223ꢀ12233.
(33) Yu, Z.; Tong, G.; Xie, X.; Zhou, P.; Lv, Y.; Su, W. Org. Process Res. Dev. 2015, 19, 892ꢀ896.
(34) Yu, Z.; Lv, Y.; Yu, C. Org. Process Res. Dev. 2012, 16, 1669ꢀ1672.
(35) Hu, T.; Baxendale, I.; Baumann, M. Molecules 2016, 21, 918.
(36) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem. 1977, 42, 2426ꢀ2431.
(37) Spendley, W.; Hext, G. R.; Himsworth, F. R. Technometrics 1962, 4, 441ꢀ461.
(38) Fourdinier, M.; Bostyn, S.; Delépée, R.; Fauduet, H. Talanta 2010, 81, 1281ꢀ1287.
(39) Bostyn, S.; Cagnon, B.; Fauduet, H. Talanta 2009, 80, 1ꢀ7.
(40) Caqueret, V.; Bostyn, S.; Porte, C.; Fauduet, H. Chem. Eng. J. 2008, 145, 203ꢀ210.
24
ACS Paragon Plus Environment

Page 25 of 25
Organic Process Research & Development
1
2
3
4
(41) MaletꢀSanz, L.; Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324ꢀ
5332.
(42) Karney, M. J.; Porter, K. A.; Barnhardt, E. K.; Vanier, G. S. RSC Adv. 2013, 3, 7106ꢀ7111.
(43) Fu, Z.; Li, Z.; Song, Y.; Yang, R.; Liu, Y.; Cai, H. J. Org. Chem. 2016, 81, 2794ꢀ2803.
(44) Chaudhari, D. A.; Fernandes, R. A. J. Org. Chem. 2016, 81, 2113ꢀ2121.
(45) Aridoss, G.; Laali, K. K. J. Org. Chem. 2011, 76, 8088ꢀ8094.
(46) Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908ꢀ9917.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(47) McNulty, J.; Capretta, A.; Laritchev, V.; Dyck, J.; Robertson, A. J. J. Org. Chem. 2003, 68,
1597ꢀ1600.
(48) Hu, Y.; Liu, J.; Lü, Z.; Luo, X.; Zhang, H.; Lan, Y.; Lei, A. J. Am. Chem. Soc. 2010, 132,
3153ꢀ3158.
(49) Cacchi, S.; Cotet, C. L.; Fabrizi, G.; Forte, G.; Goggiamani, A.; Martín, L.; Martínez, S.;
Molins, E.; MorenoꢀMañas, M.; Petrucci, F.; Roig, A.; Vallribera, A. Tetrahedron 2007, 63, 2519ꢀ
2523.
(50) Lee, Y. M.; Moon, M. E.; Vajpayee, V.; Filimonov, V. D.; Chi, K.ꢀW. Tetrahedron 2010, 66,
7418ꢀ7422.
(51) Luo, F.; Pan, C.; Li, L.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47, 5304ꢀ5306.
(52) Giger, W.; Simon, W. Helv. Chim. Acta 1970, 53, 1609ꢀ1611.
(53) Yao, J.; Blake, P. R.; Yang, J. Heterocycles 2005, 65.
(54) Popov, I.; Do, H.ꢀQ. J. Org. Chem. 2009, 74, 8309ꢀ8313.
(55) Boga, C.; Del Vecchio, E.; Forlani, L.; Milanesi, L.; Edgardo Todesco, P. J. Organomet.
Chem. 1999, 588, 155ꢀ159.
(56) Satonaka, H. Bull. Chem. Soc. Jpn. 1983, 56, 2463ꢀ2468.
(57) PuigꢀdeꢀlaꢀBellacasa, R.; Giménez, L.; Pettersson, S.; Pascual, R.; Gonzalo, E.; Esté, J. A.;
Clotet, B.; Borrell, J. I.; Teixidó, J. Eur. J. Med. Chem. 2012, 54, 159ꢀ174.
(58) Luo, Y.; Xiao, F.; Qian, S.; Lu, W.; Yang, B. Eur. J. Med. Chem. 2011, 46, 417ꢀ422.
25
ACS Paragon Plus Environment