Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones

Article abstract of DOI:10.1021/acs.oprd.6b00306

A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

Full text of DOI:10.1021/acs.oprd.6b00306

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Communication
Microwave Heated Continuous Flow Palladium(II)-
Catalyzed Desulfitative Synthesis of Aryl Ketones
Bobo Skillinghaug, Jonas Rydfjord, Jonas Savmarker, and Mats Larhed
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00306 • Publication Date (Web): 27 Oct 2016
Downloaded from http://pubs.acs.org on October 30, 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 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Microwave Heated Continuous Flow Palladium(II)ꢀ
Catalyzed Desulfitative Synthesis of Aryl Ketones
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
Bobo Skillinghaug,† Jonas Rydfjord,† Jonas Sävmarker‡ and Mats Larhed§,*
† Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, Uppsala
Biomedical Center, Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
‡ The Beijer Laboratory for Drug Discovery, Department of Medicinal Chemistry, Uppsala
Biomedical Center, Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
§ Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala Biomedical Center,
Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 27
1
2
3
4
5
6
TOC
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
ACS Paragon Plus Environment
2

Page 3 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
ABSTRACT
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 protocol for Pd(II)ꢀcatalyzed desulfitative synthesis of aryl ketones from sodium aryl
sulfinates and nitriles in continuous flow has been developed. The reactions proceed with
microwave heating using microwave transparent tube reactors, affording the desired aryl ketones
in fair to good yields. Microwave transparent aluminium oxide reactors were identified as a safe
and thermostable alternative to borosilicate glass reactors.
Keywords: Flow synthesis, Aluminium oxide, Borosilicate glass, Silicon carbide, Microwave,
Aryl sulfonate
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 27
1
2
3
4
INTRODUCTION
5
6
7
8
Dedicated instruments for smallꢀscale batch synthesis employing microwave (MW) heating are
now routinely used in chemistry labs, both due to their design that enables safe processing at
elevated temperatures and pressures, and because of the speed of MW heating.1–5 Thus, MW
synthesizers were early combined with flow technology, both using stopꢀflow and continuousꢀ
flow (CF) approaches.6–14 These systems were often modified commercial MW batch
instruments.8–12,14 We recently reported on a dedicated system for CF synthesis utilizing nonꢀ
resonant MW heating and 200 mm long, øi 2ꢀ6 mm, MW transparent borosilicate glass (BSG)
tube reactors.15,16 Since BSG is a MW transparent material17 the reaction mixture is heated
directly with this type of reactor. In contrast, silicon carbide (SiC) reactors are MW absorbing
and heat the reaction mixture in a more conventional manner.18 Due to their ability to withstand
the stress caused by MW induced hotꢀspots at higher temperature that may form if metal is
deposited on the internal surface of the reactor, SiC reactors have been identified as a safe and
useful alternative for MW heated metalꢀcatalyzed flow reactions.19
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
Aluminum oxide (AlOx) is a complementary MW transparent and highly thermostable ceramic
material ꢀ properties which make it especially interesting in the case of continuous flow MW
assisted organic synthesis (CFꢀMAOS). Though AlOx is a common material used in standard
flow chemistry applications20–23, to our knowledge this material has not previously been
evaluated as a reactor material for CFꢀMAOS.
Our group’s interest in Pdꢀcatalyzed reactions has prompted us to develop CFꢀMAOS
protocols for reactions such as the SuzukiꢀMiyaura reaction15,19,24, the MizorokiꢀHeck reaction19,
an oxidative Heck vinylation reaction15, and a decarboxylative Pd(II)ꢀcatalyzed 1,2ꢀaddition
reaction producing amidines25.
ACS Paragon Plus Environment
4

Page 5 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
In parallel, we have with great interest followed and participated in the development of sodium
arylsulfinates as arylꢀPd precursors. These substrates have recently emerged as useful
alternatives to benzoic acids as arylating agents in Pd(II)ꢀcatalyzed crossꢀcouplings since they
are not limited to electronꢀrich, sterically congested, orthoꢀsubstituted moieties.25–27 The first
synthesis of aryl ketones from aryl sulfinates by Pd(II)ꢀcatalyzed 1,2ꢀaddition to nitriles were
independently reported by Wang28, Deng29 and ourselves30,31, and has since then been followed
by other oxidative applications such as biaryl synthesis32–37, Heckꢀtype reactions38–41, conjugate
addition reactions42,43, hydroarylations44, arylations through CꢀH activation45–47 and ring opening
addition to oxabicyclic alkenes48.
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 this report we further investigate desulfitative reactions by developing a CFꢀMAOS protocol
for the Pd(II)ꢀcatalyzed synthesis of aryl ketones from sodium aryl sulfinates and nitriles.
RESULTS AND DISCUSSION
Based on our previous work in batch,30,31 we envisioned an adapted protocol for a continuous
flow MW assisted organic synthesis (CFꢀMAOS) of aryl ketones using the instrument setup
presented in Figure 1. The selected model reaction between sodium 4ꢀmethylbenzenesulfinate
(1a) and benzyl cyanide (2a) depicted in Table 1 constitutes a challenging system for use in CFꢀ
MAOS as the use of hydrophobic nitriles such as benzyl cyanide results in a biphasic reaction
mixture. After initial attempts we decided to use a simplified reaction setup with one stock
solution rather than separating the reaction components as we found that vigorous stirring
produced an emulsion which could be pumped into the reactor in a controlled fashion (see Figure
2).
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 27
1
2
3
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
a)
b)
Figure 1. a) Setup for CFꢀMAOS showing pump (left), generator with MW applicator on top
(middle) and fraction collector (right). b) Closeꢀup of MW applicator with the front piece
unmounted and a borosilicate glass (BSG) tube reactor inside the helical antenna.
ACS Paragon Plus Environment
6

Page 7 of 27
Organic Process Research & Development
1
2
3
4
a)
b)
c)
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
Figure 2. a) Biphasic reaction mixture without stirring. b) Reaction mixture with vigorous
stirring. c) Reaction mixture in reactor with applied MW heating.
Thus, a stock solution with 75 mM 1a (1.0 equiv), Pd(O2CCF3)2 (8%), 6ꢀmethylꢀ2,2’ꢀbipyridyl
(12%), 2a (5.0 equiv) and TFA (10 equiv) in H2O/THF (1:1) was pumped through a 200 mm, øi
3 mm, BSG tube reactor with an applied axial MW field covering 120 mm of the reactor to
determine suitable reaction temperature and time. The use of MW radiation provides fast heating
and allows for rapid screening of reaction temperatures. However, conventional methods like
thermocouples and mercury thermometers for measuring the temperature of the reaction mixture
are affected by the electromagnetic field in the reactor.49–51 Consequently, the available options
for accurate monitoring the reaction temperature are limited and made us opt for an Optris
CSmicro 3M IR sensor which has previously been shown to provide an accurate estimation of
the temperature of the reaction mixture (correlated to measurements by a fiberꢀoptic sensor).52
This sensor has a spectral response that allows measurement of reaction temperatures through
BSG. For the outcome of the optimization work, see Table 1.
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 27
1
2
3
4
5
6
Table 1. Optimization of Reaction Temperature for CF-MAOS Using a Borosilicate Glass
(BSG) Tube Reactor
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
Entry Temperature a Flow rate
Residence time b Yield c
1
2
3
4
5
6
80 °C
1 mL/min
1 mL/min
50 s
50 s
Tracec
78%
66%
79%
74%
53%
100 °C
120 °C
120 °C
120 °C
140 °C
0.5 mL/min 100 s
1 mL/min
2 mL/min
1 mL/min
50 s
25 s
50 s
The borosilicate glass (BSG) reactor was 200 mm long øi 3 mm and the axial MW field
covered 120 mm of the reactor. a The temperature was measured using an Optris CSmicro 3M IR
b
sensor. Calculated as the time the reaction mixture stays in the irradiated zone of the reactor,
corresponding to the width of the MW field. c Isolated yield. >95% purity according to 1H NMR.
c Determined by GCꢀMS.
When pumped through the system the emulsion quickly separated into a segmented flow but
the reaction seems to occur even though mixing between the phases is limited at the beginning of
the tube reactor (Figure 2). The best yield of 3aa was obtained at 120 °C and at a flow rate of 1
mL/min, corresponding to 50 s in the MW field (Table 1, Entry 4). A lower flow rate of 0.5
mL/min and thus a longer residence time of the reaction mixture in the heated zone of the reactor
gave a lower yield (Entry 3). The reaction temperature also proved more difficult to control at
0.5 mL/min, probably due to the different MW absorbing characteristics of the heterogenous
system, which had more impact at a lower flow rate. Increasing the flow rate to 2 mL/min
ACS Paragon Plus Environment
8

Page 9 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
resulted in somewhat reduced yield (Entry 5). The conditions presented in Entry 4, Table 1, were
thus chosen for investigation of the scope of the protocol, providing a good balance between
process control, production rate and product yield. With these parameters the processing time
was 8 minutes for a reaction at 0.6 mmol scale and the aryl ketone 3aa could be produced at a
rate of 4.3 mmol/h.
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)
b)
100
80
60
40
20
0
Silicon carbide (SiC)
Borosilicate glass (BSG)
Aluminium oxide (AlOx)
0
60
120
180
Time (s)
Figure 3. a) Tube reactors of different materials employed for the Pd(II)ꢀcatalyzed desulfitative
addition of sodium aryl sulfinates to nitriles. Silicon carbide, SiC, (left), borosilicate glass, BSG,
(middle), and aluminum oxide, AlOx (right). All the reactors are of 200 mm length and øi 3 mm.
b) Temperature profiles for heating benzene at 1 mL/min flow rate using different reactor
materials. The temperature was measured using an Optris CSmicro 3M IR sensor for the BSG
reactor, and an Optris CT IR sensor with a LT22 sensing head for the AlOx and SiC reactors.
Next, we decided to investigate the use of other reactor materials (see Figure 3a). Like BSG,
AlOx is a MW transparent material while SiC absorbs MWs. AlOx reactors may serve as a safer
alternative to BSG reactors as they are more thermostable (maximum operating temperature
1950 °C compared to 500 °C, see Supporting Information). The behavior of these reactor
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 27
1
2
3
4
5
6
7
8
9
materials under MW irradiation is illustrated by the heating profiles in Figure 3b. The
temperature for the BSG tube reactor is measured using a sensor designed for measurement of
the temperature of the solvent (Optris CSmicro 3M), while for the AlOx and SiC reactors a
different sensor which measures the outside temperature of the reactor is used (Optris CT with a
LT22 sensing head). The measured temperature increases slowly for MW transparent reactors
(BSG and AlOx) as benzene absorbs very little of the MW radiation due to the low dissipation
factor (tan δ = 1.4×10ꢀ3)53, while the SiC reactor is quickly heated by absorbing the MWs. AlOX
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
(tan δ = 3.8×10ꢀ4) is more MW transparent than BSG (tan δ = 37×10ꢀ4) which may contribute to a
slower heating rate of benzene. Further, the measured temperature for the AlOx reactor probably
also increases more slowly compared to the BSG reactor due to the fact that the outside
temperature of the reactor is measured and not the reaction mixture which is heated directly by
the MWs. Despite the heterogeneous reaction mixture, the temperature readꢀout was stable under
MW processing for all three reactor materials.
The reaction between 1a and 2a was chosen as the model reaction for the study of the different
reactor materials. The reactions were performed at different temperatures (100 °C, 120 °C and
140 °C) and the isolated yields of the most productive conditions (as determined by GCꢀMS) are
shown in Table 2.
ACS Paragon Plus Environment
10

Page 11 of 27
Organic Process Research & Development
1
2
3
4
5
6
Table 2. Pd(II)-Catalyzed Desulfitative Addition Reactions of Sodium Aryl Sulfinates to
Nitriles using Tube Reactors of Different Materials
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
Entry Reactor
Temperature a Heating zone b Residence time c Yield d
1
2
3
Borosilicate glass (BSG) 120 °C
Aluminium oxide (AlOx) 120 °C
Silicon carbide (SiC) 100 °C
120 mm
120 mm
200 mm
50 s
50 s
84 s
79%
78%
74%
The reactors were 200 mm long øi 3 mm and the axial MW field covered 120 mm of the
a
reactor. The temperature was measured using an Optris CSmicro 3M IR sensor for the BSG
b
reactor, and an Optris CT IR sensor with a LT22 sensing head for the AlOx and SiC reactors.
The heated zone corresponds to: the width of the MW field for the BSG and AlOx reactors, or to
c
the full length of the reactor for the SiC reactor. Calculated as the time the reaction mixture
stays in the heated zone of the reactor. d Isolated yield. >95% purity according to 1H NMR.
The BSG and AlOx reactors provided equally satisfactory yields of 3aa at 120 °C in the
model reaction (Entries 1 and 2, Table 2), although metal precipitation on the surface as well as
particle buildꢀup complicated the use of the AlOx reactor. In the BSG reactor we observed no
metal precipitation on the glass, however, some particle buildꢀup was present.
A possible advantage with the use of the CFꢀMAOS methodology with nonꢀhomogeneous
reaction systems is that it has been suggested that MW heating may lead to a specific MW effect
and assist in the creation of an active interface and promote transport processes between liquid
interfaces.54–56 By using a SiC reactor (Figure 3) and taking advantage of the fact that SiC
absorbs MW irradiation18 we could mimic conventional heating and thus comment on a potential
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 27
1
2
MW activated liquid interface55,56. The silicon carbide reactor gave 74% yield of 3aa at 100 °C
(Entry 3). This yield is comparable to the results obtained for the other reactor materials (78% ꢀ
79%), providing no support for a nonꢀthermal beneficial MW effect for this process57. However,
this indicates that the conventional heating option is viable for this reaction.
3
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
Next, we initiated a study of the scope and limitations of the CFꢀMAOS protocol by
investigating the reaction of different nitriles with sodium benzenesulfinate (1b) utilizing both
BSG and AlOx reactors. The reaction with benzonitrile (2a) furnished 3ba in 53% and 50%
isolated yield using a BSG and AlOx reactor, respectively (Table 3, Entry 1).58 Reaction with an
alkylnitrile, butyronitrile (2b) gave ketone 3bb with a good yield of 71% / 54% (Entry 2), and
the reaction with benzyl cyanide (2c) furnished 79% / 63% yield of 3bc (Entry 3). A heterocyclic
functionality could be introduced by employing 3ꢀthiophenecarbonitrile (2d) which gave a
satisfying 66% / 58% yield of 3bd (Entry 4). 4ꢀBromobenzonitrile (2e) gave only 47% / 56%
isolated yield of 3be with the CFꢀMAOS protocol (Entry 5) but no traces of byproducts from
Pd(0)ꢀcatalyzed activation of the phenyl bromide functionality was observed. All entries except
for the reaction with benzyl cyanide (2c) as the nitrile substrate resulted in lower yield than for
the reported batch protocol.31 However, batch reactions of 1b with 2a and 2e performed at the
same diluted concentrations used for flow applications and resulted in identical outcome as the
CFꢀMAOS protocol (see Supporting Information for details). The yields in Table 3 using the
AlOx reactor are generally slightly lower compared to the results obtained using the BSG
reactor. Importantly, although no problems with reactor failure resulting from MW induced
superheating due to metal precipitation was observed in this study, regardless of reactor material.
ACS Paragon Plus Environment
12

Page 13 of 27
Organic Process Research & Development
1
2
3
4
5
6
BSG reactors have previously been reported to undergo thermal cracking under MW
processing.59
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
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 27
1
2
3
4
5
6
Table 3. Pd(II)-Catalyzed Desulfitative Addition Reactions of Sodium Benzenesulfinate to
Different Nitriles
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
Entry Nitrile
Product
Yielda
BSG: 53%
AlOx: 50%
1
2a
3ba
BSG: 71%
AlOx: 54%
2
2b
3bb
BSG: 79%
AlOx: 63%
3
2c
3bc
3bd
BSG: 66%
AlOx: 58%
4
2d
BSG: 47%
AlOx: 56%
5
2e
3be
All reactions were carried out at 100 °C, 120 °C and 140 °C. The highest yielding reaction
temperature according to GCꢀMS was in all cases 120 °C. The temperature was measured using
an Optris CSmicro 3M IR sensor for the borosilicate glass (BSG) reactor, and an Optris CT IR
ACS Paragon Plus Environment
14

Page 15 of 27
Organic Process Research & Development
1
2
sensor with a LT22 sensing head for the aluminium oxide (AlOx) reactor. a Isolated yield. >95%
purity according to 1H NMR.
3
4
5
6
7
8
9
After the screening of nitrile substrates we decided to evaluate the scope of sodium sulfinates
with acetonitrile (2f) as the nitrile partner. Aryl sulfinates 1a, 1b and 1c afforded yields of
55%/50%, 61%/58% and 68%/62%, respectively, of the corresponding products 3af, 3bf and 3cf
with CFꢀMAOS processing (Table 4, Entries 1ꢀ3). Sodium 4ꢀacetamidobenzenesulfinate (1d)
gave the corresponding aryl ketone product 3df in 60%/56% yield (Entry 4) with no trace of the
corresponding hydrolyzed product. The short reaction time of the CFꢀMAOS protocol may
explain the results with the more electronꢀpoor sodium 4ꢀbromobenzenesulfinate 1e which only
afforded trace amounts of 3ef (Entry 5). The same trend with slightly lower yields for reactions
carried out in the AlOx reactor was observed.
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
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 27
1
2
3
4
5
6
Table 4. Pd(II)-Catalyzed Desulfitative Addition Reactions of different Sodium Aryl
Sulfinates to Acetonitrile
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
Entry Sodium sulfinate
Product
Yielda
BSG: 55%
AlOx: 50%
1
1a
3af
BSG: 61%b
AlOx: 58%b
2
1b
3bf
BSG: 68%
AlOx: 62%
3
1c
3cf
BSG: 60%
AlOx: 56%
4
1d
3df
3ef
BSG: Tracec
AlOx: Tracec
5
1e
All reactions were carried out at 100 °C, 120 °C and 140 °C. The highest yielding reaction
temperature according to GCꢀMS was in all cases 120 °C except for entry 2. The temperature
was measured using an Optris CSmicro 3M IR sensor for the borosilicate glass (BSG) reactor,
ACS Paragon Plus Environment
16

Page 17 of 27
Organic Process Research & Development
1
2
and an Optris CT IR sensor with a LT22 sensing head for the aluminium oxide (AlOx) reactor. a
Isolated yield. >95% purity according to H NMR. Reaction run at 140 °C. According to GCꢀ
MS.
3
4
5
6
1
b
c
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
A protocol for CFꢀMAOS of aryl ketones by Pd(II)ꢀcatalyzed addition of sodium aryl
sulfinates to nitriles, with a production capacity of up to 4.3 mmol/h, was developed. Though
reaction mixtures were biphasic, acceptable to good yields of the desired products were obtained.
MW transparent BSG reactors performed well and AlOx reactors were identified as safe
alternatives as they are more thermostable and resilient to MW induced superheating due to
metal precipitation. The use of a MW absorbing silicon carbide reactor gave comparable results
– indicating that no specific MW interaction with the interface between the two phases of the
reaction mixture was present.
EXPERIMENTAL SECTION
General information
Palladium catalysts were purchased from Strem Chemicals. All reagents and solvents are
commercially available and were used as received. The sodium salts of 4ꢀmethylbenzenesulfinic
acid (1a), benzenesulfinic acid (1e) and 4ꢀacetamidobenzenesulfinic acid (1d) are commercially
available. The other sodium arylsulfinates are known compounds and were prepared using
modified literature procedures.60,61 All products are known compounds and are commercially
available. GC–MS analyses were performed with a CPꢀSIL 8 CB Low Bleed (30 m × 0.25 mm)
capillary column using a 70–300 °C temperature gradient or and EI ionization at 70 eV. Nuclear
1
magnetic resonance (NMR) spectra were recorded on an NMR spectrometer at 400 MHz for H
and at 100.5 MHz for 13C. Chemical shifts are reported in parts per million and referenced
ACS Paragon Plus Environment
17

Organic Process Research & Development
Page 18 of 27
1
2
indirectly to TMS via the residual solvent signals (1H, CDCl3 at 7.26 ppm or methanolꢀd4 at 3.31
3
4
5
6
13
ppm; C, CDCl3 at 77.16 ppm or methanolꢀd4 at 49.00 ppm). All final compounds were >95%
7
8
9
pure as determined by NMR. For detailed information regarding the CFꢀMAOS setup, see
Supporting Information.
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
General procedure
Pd(O2CCF3)2 and 6ꢀmethylꢀ2,2’ꢀbipyridyl were weighed and dissolved in THF:H2O (1:1) to a
volume corresponding to approximately 20% of the total reaction volume. Sonication was used
to effect dissolution of the catalyst followed by filtration through a 0.45 µm syringe filter to
remove any particulates. The aryl sulfinate (1, 75 mM), nitrile (2, 5 equiv) and internal standard
(2ꢀmethylnaphthalene, 1.0 equiv) were weighed and dissolved in THF:H2O (1:1) to a volume
corresponding to approximately 40% of the total reaction volume, sonicated and added via a 0.45
µm syringe filter to the catalyst solution. TFA (10 equiv) was added and the reaction mixture
was diluted in a measuring cylinder to the desired reaction volume (typically 50 mL) by addition
of THF:H2O (1:1). The reaction mixture was stirred vigorously and pumped at a flow rate of 1
mL/min into the MW heated 200 mm long øi 3 mm reactor at a pressure of approximately 40 bar
maintained by an adjustable back pressure regulator. After approximately 10 minutes of
equilibration, the microwave processed product mixture was collected manually. The collected
product mixture was stirred vigorously and 8 mL were quickly measured out by syringe and
poured into 30 mL of 2 M NaOH and extracted with 3×50 ml DCM. The organic layers were
combined, dried over MgSO4 and concentrated in vacuo. The crude product was purified by
column chromatography.
ACS Paragon Plus Environment
18

Page 19 of 27
Organic Process Research & Development
1
2
3
4
4’-Methyl-2-phenylacetophenone (3aa). Synthesized from 1a and 2a according to the general
5
6
procedure.
Purification
was
performed
by
column
chromatography
using
7
8
9
1
pentane/dichloromethane as the solvent to give 3aa as a white solid (100 mg; 79%); H NMR
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
13
(400 MHz, CDCl3) δ = 8.09 – 7.82 (m, 2H), 7.51 – 7.13 (m, 7H), 4.26 (s, 2H), 2.40 (s, 3H). C
NMR (101 MHz, CDCl3) δ = 197.4, 144.1, 134.9, 134.3, 129.6, 129.5, 128.9, 128.8, 126.9, 45.6,
21.8.
Benzophenone (3ba): Synthesized from 1b and 2a according to the general procedure.
Purification was performed by column chromatography using pentane/dichloromethane as the
solvent to give 3ba as a colorless oil (58 mg; 53%); 1H NMR (400 MHz, CDCl3) δ = 7.86 – 7.77
13
(m, 4H), 7.63 – 7.56 (m, 2H), 7.53 – 7.44 (m, 4H). C NMR (101 MHz, CDCl3) δ = 196.8,
137.7, 132.5, 130.2, 128.4.
Butyrophenone (3bb): Synthesized from 1b and 2b according to the general procedure.
Purification was performed by column chromatography using pentane/dichloromethane as the
solvent to give 3bb as a colorless oil (63 mg; 71%); 1H NMR (400 MHz, CDCl3) δ = 8.01 – 7.91
(m, 2H), 7.59 – 7.52 (m, 1H), 7.49 – 7.41 (m, 2H), 2.98 – 2.92 (m, 2H), 1.77 (h, J = 7.4 Hz, 2H),
13
1.01 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ = 200.5, 137.2, 133.0, 128.7, 128.2,
40.7, 17.9, 14.0.
Phenyl(thiophen-3-yl)methanone (3bd): Synthesized from 1b and 2d according to the general
procedure.
Purification
was
performed
by
column
chromatography
using
1
pentane/dichloromethane as the solvent to give 3bd as a colorless oil (75 mg; 66%); H NMR
(400 MHz, CDCl3) δ = 7.92 (ddd, J = 2.9, 1.3, 0.5 Hz, 1H), 7.87 – 7.80 (m, 2H), 7.63 – 7.54 (m,
2H), 7.53 – 7.44 (m, 2H), 7.37 (ddd, J = 5.1, 2.9, 0.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ =
190.0, 141.4, 138.7, 134.0, 132.4, 129.4, 128.7, 128.5, 126.3.
ACS Paragon Plus Environment
19

Organic Process Research & Development
Page 20 of 27
1
2
3
4
2-Phenylacetophenone (3bc): Synthesized from 1b and 2c according to the general procedure.
5
6
Purification was performed by column chromatography using pentane/dichloromethane as the
7
8
9
1
solvent to give 3bc as a white solid (93 mg; 79%); H NMR (400 MHz, CDCl3) δ = 8.08 – 7.99
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
13
(m, 2H), 7.61 – 7.52 (m, 1H), 7.52 – 7.42 (m, 2H), 7.39 – 7.22 (m, 5H), 4.30 (s, 2H). C NMR
(101 MHz, CDCl3) δ = 197.6, 136.6, 134.5, 133.1, 129.4, 128.6, 128.6, 128.6, 126.8, 45.5.
4-Bromobenzophenone (3be): Synthesized from 1b and 2e according to the general procedure.
Purification was performed by column chromatography using pentane/dichloromethane as the
1
solvent to give 3be as a white solid (74 mg; 47%); H NMR (400 MHz, CDCl3) δ = 7.81 – 7.74
13
(m, 2H), 7.71 – 7.57 (m, 5H), 7.55 – 7.45 (m, 2H). C NMR (101 MHz, CDCl3) δ = 195.7,
137.3, 136.4, 133.5, 132.8, 131.7, 131.7, 130.1, 128.5, 127.6.
4'-Methylacetophenone (4af): Synthesized from 1a and 2f according to the general procedure.
Purification was performed by column chromatography using pentane/dichloromethane as the
1
solvent to give 4af as a colorless liquid (40 mg; 55%); H NMR (400 MHz, CDCl3) δ = 7.87 –
13
7.83 (m, 2H), 7.27 – 7.23 (m, 2H), 2.56 (s, 4H), 2.40 (s, 3H). C NMR (101 MHz, CDCl3) δ =
197.8, 143.8, 134.7, 129.2, 128.4, 26.5, 21.6.
Acetophenone (3bf): Synthesized from 1b and 2f according to the general procedure.
Purification was performed by column chromatography using pentane/dichloromethane as the
solvent to give 3bf as a colorless oil (49 mg; 61%); 1H NMR (400 MHz, CDCl3) δ = 8.08 – 7.84
(m, 2H), 7.57 – 7.52 (m, 1H), 7.48 – 7.41 (m, 2H), 2.59 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
= 198.2, 137.2, 133.2, 128.6, 128.4, 26.7.
ACS Paragon Plus Environment
20

Page 21 of 27
Organic Process Research & Development
1
2
3
4
4-Methoxy-acetophenone (3cf): Synthesized from 1c and 2f according to the general
5
6
procedure.
Purification
was
performed
by
column
chromatography
using
7
8
9
1
pentane/dichloromethane as the solvent to give 3cf as a colorless oil (61 mg; 68%); H NMR
(400 MHz, CDCl3) δ = 8.11 – 7.71 (m, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H), 2.55 (s, 3H).
13C NMR (101 MHz, CDCl3) δ = 196.9, 163.6, 130.7, 113.8, 55.6, 26.5.
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’-Acetamidoacetophenone (3df): Synthesized from 1d and 2f according to the general
procedure. Purification was performed by column chromatography using
pentane/dichloromethane as the solvent to give 3df as a white solid (63 mg; 60%); 1H NMR (400
MHz, Methanolꢀd4) δ = 7.96 – 7.90 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.53 (s, 1H), 2.57 (s, 3H),
2.22 (s, 3H). 13C NMR (101 MHz, Methanolꢀd4) δ = 199.4, 171.9, 144.8, 133.7, 130.7, 120.1,
26.4, 24.0.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
Detailed continuous flow instrument setup and reactor parameters, heating profiles, 1H NMR and
13C NMR spectra for products.
AUTHOR INFORMATION
Corresponding Author
* Mats Larhed: mats.larhed@orgfarm.uu.se
ACS Paragon Plus Environment
21

Organic Process Research & Development
Page 22 of 27
1
2
3
4
Author Contributions
5
6
7
8
9
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
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
Funding Sources
This research was supported by Uppsala University and the Kjell and Märta Beijer Foundation.
ACKNOWLEDGMENT
We are grateful for the support from Uppsala University and The Kjell and Märta Beijer
Foundation.
ABBREVIATIONS
AlOx, aluminium oxide; BSG, borosilicate glass; CF, continuous flow; CFꢀMAOS, continuous
flow microwave assisted organic synthesis; MW, microwave; Pd, palladium; SiC, silicon
carbide.
ACS Paragon Plus Environment
22

Page 23 of 27
Organic Process Research & Development
1
2
3
4
REFERENCES
5
6
7
8
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
Oliver Kappe, C. Chem. Soc. Rev. 2008, 37, 1127–1139.
Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325–3355.
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
Gising, J.; Odell, L. R.; Larhed, M. Org. Biomol. Chem. 2012, 10, 2713.
Sadler, S.; Moeller, A. R.; Jones, G. B. Expert Opin. Drug Discov. 2012, 441, 1–22.
Larhed, M.; Hallberg, A. Drug Discov. Today 2001, 6, 406–416.
Strauss, C.; Trainor, R. Aust. J. Chem. 1995, 48, 1665–1692.
Chen, S.ꢀT.; Chiou, S.ꢀH.; Wang, K.ꢀT. J. Chem. Soc. Chem. Commun. 1990, 807–809.
He, P.; Haswell, S. J.; Fletcher, P. D. I. Appl. Catal. A Gen. 2004, 274, 111–114.
Wilson, N. S.; Sarko, C. R.; Roth, G. P. Org. Process Res. Dev. 2004, 8, 535–538.
(10) Comer, E.; Organ, M. G. J. Am. Chem. Soc. 2005, 127, 8160–8167.
(11) Bagley, M. C.; Jenkins, R. L.; Lubinu, M. C.; Mason, C.; Wood, R. J. Org. Chem. 2005,
70, 7003–7006.
(12) Smith, C. J.; IglesiasꢀSigüenza, F. J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem.
2007, 5, 2758–2761.
(13) Barnard, T. M.; Leadbeater, N. E.; Boucher, M. B.; Stencel, L. M.; Wilhite, B. A. Energy
and Fuels 2007, 21, 1777–1781.
(14) R. Baxendale, I.; J. Hayward, J.; V. Ley, S. Comb. Chem. High Throughput Screen. 2007,
10, 802–836.
(15) Öhrngren, P.; Fardost, A.; Russo, F.; Schanche, J. S.; Fagrell, M.; Larhed, M. Org.
Process Res. Dev. 2012, 16, 1053–1063.
ACS Paragon Plus Environment
23

Organic Process Research & Development
Page 24 of 27
1
2
3
4
5
6
(16) Fardost, A.; Russo, F.; Larhed, M. Chim. Oggi 2012, 30, 14–16.
(17) Kappe, C. O. Angew. Chemie - Int. Ed. 2004, 43, 6250–6284.
7
8
9
(18) Obermayer, D.; Gutmann, B.; Oliver Kappe, C. Angew. Chemie - Int. Ed. 2009, 48, 8321–
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
8324.
(19) Konda, V.; Rydfjord, J.; Sävmarker, J.; Larhed, M. Org. Process Res. Dev. 2014, 18,
1413–1418.
(20) Cho, S.ꢀH.; Walther, N. D.; Nguyen, S. T.; Hupp, J. T. Chem. Commun. 2005, 5331–5333.
(21) Duque, R.; Pogorzelec, P. J.; ColeꢀHamilton, D. J. Angew. Chemie - Int. Ed. 2013, 52,
9805–9807.
(22) Aellig, C.; Jenny, F.; Scholz, D.; Wolf, P.; Giovinazzo, I.; Kollhoff, F.; Hermans, I. Catal.
Sci. Technol. 2014, 4, 2326.
(23) Amara, Z.; Poliakoff, M.; Duque, R.; Geier, D.; Franciò, G.; Gordon, C. M.; Meadows, R.
E.; Woodward, R.; Leitner, W. Org. Process Res. Dev. 2016, 20, 1321–1327.
(24) Engen, K.; Sävmarker, J.; Rosenström, U.; Wannberg, J.; Lundbäck, T.; JenmalmꢀJensen,
A.; Larhed, M. Org. Process Res. Dev. 2014, 18, 1582–1588.
(25) Rydfjord, J.; Svensson, F.; Trejos, A.; Sjöberg, P. J. R.; Sköld, C.; Sävmarker, J.; Odell, L.
R.; Larhed, M. Chem. A Eur. J. 2013, 19, 13803–13810.
(26) Rodríguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030–5048.
(27) Svensson, F.; Mane, R.; Sävmarker, J.; Larhed, M.; Sköld, C. Organometallics 2013, 7, 1–
8.
(28) Miao, T.; Wang, G.ꢀW. Chem. Commun. 2011, 47, 9501–9503.
(29) Liu, J.; Zhou, X.; Rao, H.; Xiao, F.; Li, C.ꢀJ.; Deng, G.ꢀJ. Chem. - A Eur. J. 2011, 17,
7996–7999.
ACS Paragon Plus Environment
24

Page 25 of 27
Organic Process Research & Development
1
2
3
4
5
(30) Behrends, M.; Sävmarker, J.; Sjöberg, P. J. R.; Larhed, M. ACS Catal. 2011, 1, 1455–
1459.
6
7
8
(31) Skillinghaug, B.; Sköld, C.; Rydfjord, J.; Fredrik, S.; Behrends, M.; Jonas, S.; Per J. R.,
9
S.; Larhed, M. J. Org. Chem. 2014, 79, 12018–12032.
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
(32) Rao, B.; Zhang, W.; Hu, L.; Luo, M. Green Chem. 2012, 14, 3436–3440.
(33) Ortgies, D.; Forgione, P. Synlett 2013, 24, 1715–1721.
(34) Ortgies, D.; Barthelme, A.; Aly, S.; Desharnais, B.; Rioux, S.; Forgione, P. Synthesis
2013, 45, 694–702.
(35) Colomb, J.; Billard, T. Tetrahedron Lett. 2013, 54, 1471–1474.
(36) Zhou, C.; Liu, Q.; Li, Y.; Zhang, R.; Fu, X.; Duan, C. J. Org. Chem. 2012, 77, 10468–
10472.
(37) Gund, S. H.; Balsane, K. E.; Nagarkar, J. M. Tetrahedron 2016, 72, 5051–5056.
(38) Wang, G.ꢀW.; Miao, T. Chem. - A Eur. J. 2011, 17, 5787–5790.
(39) Zhou, X.; Luo, J.; Liu, J.; Peng, S.; Deng, G.ꢀJ. Org. Lett. 2011, 13, 1432–1435.
(40) Hu, S.; Xia, P.; Cheng, K.; Qi, C. Appl. Organomet. Chem. 2013, 27, 188–190.
(41) Bal Raju, K.; Mari, V.; Nagaiah, K. Synthesis 2013, 45, 2867–2874.
(42) Wang, H.; Li, Y.; Zhang, R.; Jin, K.; Zhao, D.; Duan, C. J. Org. Chem. 2012, 77, 4849–
4853.
(43) Chen, W.; Zhou, X.; Xiao, F.; Luo, J.; Deng, G.ꢀJ. Tetrahedron Lett. 2012, 53, 4347–
4350.
(44) Liu, S.; Bai, Y.; Cao, X.; Xiao, F.; Deng, G.ꢀJ. Chem. Commun. 2013, 49, 7501–7503.
ACS Paragon Plus Environment
25

Organic Process Research & Development
Page 26 of 27
1
2
3
4
5
6
(45) Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, J. Chem. - A Eur. J. 2011, 17, 13415–13419.
(46) Miao, T.; Wang, L. Adv. Synth. Catal. 2014, 356, 429–436.
7
8
9
(47) Wang, C.; Jia, H.; Li, Z.; Zhang, H.; Zhao, B. RSC Adv. 2016, 6, 21814–21821.
(48) Li, Y.; Yang, W.; Cheng, G.; Yang, D. J. Org. Chem. 2016, 81, 4744–4750.
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
(49) Langa, F.; de la Cruz, P.; de la Hoz, A.; DíazꢀOrtiz, A.; DíezꢀBarra, E. Contemp. Org.
Synth. 1997, 4, 373–386.
(50) Mingos, D. M. P.; Whittaker, A. G. In Chemistry Under Extreme and Non-Classical
Conditions; van Eldik, R., Hubbard, C. D., Eds.; John Wiley & Sons, Ltd, 1997; pp 479–
514.
(51) Kappe, C. O. Chem. Soc. Rev. 2013, 42, 4977–4990.
(52) Rydfjord, J.; Svensson, F.; Fagrell, M.; Sävmarker, J.; Thulin, M.; Larhed, M. Beilstein J.
Org. Chem. 2013, 9, 2079–2087.
(53) Jansen, K. In In Verified Syntheses of Zeolitic Materials; Robson, H. E., Ed.; Elsevier,
2001; pp 39–43.
(54) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1–47.
(55) Smidovnik, A.; Kobe, J.; Leskovsek, S.; Koloini, T. J. Am. Oil Chem. Soc. 1994, 71, 507–
511.
(56) Olofsson, K.; Kim, S. Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org. Chem. 1999, 64,
4539–4541.
(57) Kappe, C. O.; Pieber, B.; Dallinger, D. Angew. Chemie - Int. Ed. 2013, 52, 1088–1194.
(58) The reaction was also conducted in the presence of 20 mol% tetrabutylammonium
hydrogen sulfate as phase transfer catalyst to facilitate transport between the phases.
Unfortunately, the GCꢀMS yield of 3ba was found to be below 50% using 2ꢀ
methylnaphthalene as the internal standard.
ACS Paragon Plus Environment
26

Page 27 of 27
Organic Process Research & Development
1
2
3
4
5
6
(59) Kaiser, N. F. K.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2002, 4, 109–111.
7
8
9
(60) Curti, C.; Laget, M.; Ortiz Carle, A.; Gellis, A.; Vanelle, P. Eur. J. Med. Chem. 2007, 42,
880–884.
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
(61) Skillinghaug, B.; Rydfjord, J.; Odell, L. R. Tetrahedron Lett. 2016, 57, 533–536.
ACS Paragon Plus Environment
27