Continuous Flow Synthesis of Carbonylated Heterocycles via Pd-Catalyzed Oxidative Carbonylation Using CO and O2 at Elevated Temperatures and Pressures

Article abstract of DOI:10.1021/acs.oprd.7b00217

A continuous-flow Pd-catalyzed oxidative carbonylation protocol utilizing CO and O₂ gas for the synthesis of carbonylated heterocycles is described. The optimization of temperature, pressure, CO/O₂ ratio, catalyst loading, and reaction time resulted in process intensified conditions for this transformation. The optimized continuous flow conditions (120 °C, 20 bar pressure, 24 min residence time) were used to prepare a number of benzoxazolone, 2-benzoxazolidinone, and other biologically and synthetically important five- and six-membered carbonylated heterocycles in good overall yield and purity (14 examples). The continuous-flow process enables the safe and scalable oxidative carbonylation using CO/O₂ under elevated pressures and temperatures.

Full text of DOI:10.1021/acs.oprd.7b00217

Subscriber access provided by EAST TENNESSEE STATE UNIV
Full Paper
Continuous Flow Synthesis of Carbonylated Heterocycles
via Pd-Catalyzed Oxidative Carbonylation Using
CO and O2 at Elevated Temperature and Pressure
Yuesu Chen, Christopher A. Hone, Bernhard Gutmann, and C. Oliver Kappe
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00217 • Publication Date (Web): 28 Jun 2017
Downloaded from http://pubs.acs.org on June 28, 2017
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 24
Organic Process Research & Development
1
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
Continuous Flow Synthesis of Carbonylated
Heterocycles via PdꢀCatalyzed Oxidative
Carbonylation Using CO and O2 at Elevated
Temperature and Pressure
Yuesu Chen,† Christopher A. Hone, †,‡ Bernhard Gutmann†,‡ and C. Oliver
Kappe*,†,‡
† Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Aꢀ8010 Graz, Austria
‡ Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
* C. Oliver Kappe. Eꢀmail: oliver.kappe@uniꢀgraz.at.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 24
2
1
2
3
4
5
6
TABLE OF CONTENTS GRAPHICS
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

Page 3 of 24
Organic Process Research & Development
3
1
2
3
4
5
6
7
8
9
ABSTRACT: A continuousꢀflow Pdꢀcatalyzed oxidative carbonylation protocol utilizing CO
and O2 gas for the synthesis of carbonylated heterocycles is described. Optimization of
temperature, pressure, CO/O2 ratio, catalyst loading and reaction time resulted in process
intensified conditions for this transformation. The optimized continuous flow conditions (120
°C, 20 bar pressure, 24 min residence time) were used to prepare a number of benzoxazolone,
2ꢀbenzoxazolidinone and other biologically and synthetically important fiveꢀ and sixꢀ
membered carbonylated heterocycles in good overall yield and purity (14 examples). The
continuousꢀflow process enables the safe and scalable oxidative carbonylation using CO/O2
under elevated pressure and temperatures.
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: carbon monoxide; continuousꢀflow; microreactor; oxygen; palladium
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 24
4
1
2
INTRODUCTION
3
4
5
6
7
8
Carbon monoxide is a cheap and synthetically useful C1 building block in organic
chemistry, and CO is readily available in large quantities from the bulk chemical industry.1,2
Since the development of a highꢀpressure technique in the early 20th century, a large number
of carbon monoxide reactions were discovered and rapidly found their application in the
chemical industry, among them carbonylation reactions.2,3 The carbonyl group is a key
component in aldehydes, ketones, carboxylic acids and their derivatives, and also appears in
biologically active compounds, natural products and a broad spectrum of fine chemicals.4
Carbonylation has become a straightforward approach for the introduction of such linkage
into organic molecules. For synthetic chemists, Pdꢀcatalyzed carbonylation reactions in
particular provide an alternative strategy for the atom economic preparation of several classes
of organic molecules that are otherwise not easily accessible.5 Pdꢀcatalyzed carbonylations
have become a powerful methodology in organic synthesis given its diverse chemistry,
mildness and atom efficiency compared to classical oxidations, such as FriedelꢀCrafts
acylation, and other carbonyl forming reactions.5b Pdꢀcatalyzed carbonylations are particularly
important for the formation of 5ꢀ and 6ꢀmembered rings containing carbonyl groups.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
Carbonylated heterocycles are of key biological and synthetic significance.
Benzoxazolone derivatives for example have shown promising bioactivity, including for antiꢀ
cancer,6a antiꢀmycobacterial6a and antiꢀconvulsant applications.6bꢀc In addition, the pure
enantiomers of substituted 2ꢀoxazolidinones are valuable Evans’ chiral auxiliaries.7 The
classical approach for the synthesis of benzoxazolone and 2ꢀoxazolidinone is through the
condensation of 2ꢀaminophenol and 2ꢀaminoalcohols with carbonic acid derivatives, such as
phosgene,8 carbonates9 or urea (Figure 1).10 Alternatively, carbonylated heterocycles are also
accessible via Pdꢀcatalyzed oxidative carbonylation reactions using CO and O2 as reagent.11
The PdI2/KI system developed by Gabriele and coꢀworkers is highly efficient for the
conversion of 2ꢀaminophenol11a and 2ꢀaminoalcohols.11eꢀf Compared to most of the traditional
condensation reactions, oxidative carbonylation methods do not rely on corrosive reagents
such as phosgene and are cheaper and more atomꢀeconomic than condensation with urea and
carbonates, because the only byproduct is water.
ACS Paragon Plus Environment

Page 5 of 24
Organic Process Research & Development
5
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
Figure 1. Different strategies for the synthesis of carbonylated heterocycles.
Oxidative carbonylation provides a carbonylative coupling of two donor (nucleophilic)
groups,12d which in many ways is complimentary to classical donorꢀacceptor carbonylation
chemistry.12 The mechanism of oxidative carbonylation is generally considered to be a
palladium redox cycle.12 The conversion of the substrate molecule to the product involves the
removal of two electrons, via the reduction of Pd(II) to Pd(0).12 Correspondingly, the
regeneration of the Pd(II) catalyst necessitates the use of an external oxidant to complete the
catalytic cycle (Figure 2a).12 Liquid phase oxidants, such as metal salts,13 peroxides14 and
benzoquinone15 have been utilized for the reoxidation of Pd(0), but this is inherently atom
inefficient due to the generation of a stoichiometric quantity of waste. Molecular oxygen is a
highly abundant, cheap and a suitable green alternative to existing oxidizing agents. In the
catalytic cycle, O2 is reduced to environmentally benign water, which does not complicate
product isolation. O2 cannot reoxidize Pd(0) directly in the liquid phase, thus a cocatalyst
(iodide11aꢀh or copper salt11i) is introduced to serve as electron carrier (Figure 2b). However,
utilization of O2 in the presence of an organic solvent as a fuel and an ignition source often
results in a potentially flammable mixture. In practice, the reaction is most commonly
performed in glass flasks fitted with gas balloons17a at atmospheric pressure or in highꢀ
pressure autoclaves. A strategy to improve the operational safety is to dilute the mixture either
11f
with an inert gas (e.g. N2)16 or with a large excess of either CO11bꢀe,17 or O2 to deviate the
composition from the range of the explosive limit18 (15.5 – 93.9 vol % CO in O2).19 However,
the use of pure gases without dilution typically provides higher reaction rates and process
efficiency.22b For the case of oxidative carbonylation, a technique which enables the safe
handling of highly flammable mixtures of CO, solvent vapor and pure O2 is clearly required.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 24
6
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
Figure 2. Pdꢀcatalyzed oxidative carbonylation reaction: (a) general sketch and (b) the role of
the cocatalyst when O2 is used as oxidant.
Over the past decade, continuousꢀflow technology has received significant attention from
organic and process chemists,20ꢀ22 especially those working with hazardous reagents21 and
gaseous feedstocks.22 The characteristic features of flow reactors (i.e., fast heat and mass
transfer, precise control over reaction time, easiness of scaleꢀup etc.) facilitate operation under
extreme conditions (especially high T, p, high concentrations of reactive and explosive
intermediates) with the presence of minimum amount of hazard.21 In microreactors, the mass
transfer effects are reduced for a gasꢀliquid reaction, because a segmented flow pattern inside
the reactor channel provides a high interfacial area between the gas and liquid phases. The
high interfacial area significantly accelerates the dissolution of the gases into the liquid
phase.22 The safety of the operation is guaranteed,23 even for a worst case scenario, since a
properly designed metallic microreactor is able to sustain an explosion event for a mixture of
flammable gases and O2.22b,23 By virtue of these advantages, a large variety of gasꢀliquid
reactions using hazardous reagents have been performed in continuousꢀflow reactors.21,22
Based on previous research and our experience in safely handling molecular oxygen24 and
ACS Paragon Plus Environment

Page 7 of 24
Organic Process Research & Development
7
1
2
3
4
5
6
7
8
CO25ꢀ26 in flow reactors, we herein present a continuousꢀflow oxidative carbonylation
protocol utilizing molecular oxygen and CO for the synthesis of carbonylated heterocycles.
To the best of our knowledge, this is the first example of liquidꢀphase oxidative carbonylation
chemistry performed under continuousꢀflow conditions.27,28
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
RESULTS AND DISCUSSION
Design and Construction of the Microreactor. We were inspired by the work of Gabriele
and coꢀworkers using a PdI2/KI catalyst system for the oxidative carbonylation of amines, βꢀ
amino alcohols, and 2ꢀaminophenols in batch (1 mol% PdI2, 10 mol% KI, 32 bar CO + 8 bar
air).11a We commenced our investigation with the synthesis of 2a via the oxidative
carbonylation of 2ꢀaminophenol (1a) using a palladium/iodide catalyst system, but both PdI2
and KI proved poorly soluble in organic solvents. We wanted to obtain homogeneous feed
solutions to make the chemistry more amenable for continuous processing. Pd(OAc)2 and
tetrabutylammonium iodide (n
ꢀBu4N+Iꢀ,TBAI) were used as catalyst and cocatalyst
respectively, because of their good solubility in organic solvents. Acetonitrile was selected as
solvent and provided good solubility for all reactants and products. Moreover, we observed
that 1a and Pd(OAc)2 form a precipitate within a few minutes of mixing,29 therefore the Pd
catalyst and substrate were introduced as two separate feed streams.
Based on the above considerations, a continuousꢀflow setup was constructed as
outlined in Figure 3. A stainless steel coil (R) (internal volume
V = 20 mL, inner diameter 1.0
mm) fitted with a temperature control unit was utilized as the reactor. The entrance of the
reactor coil was connected to a fourꢀway mixer (M) to introduce the feed streams (catalyst,
substrate, CO and O2). A backꢀpressure regulator (BPR) was installed downstream of the
reactor to control the system pressure. The outlet of R and the inlet of BPR were connected
with a piece of transparent PFA tubing (L0) for the observation of flow pattern and color
changes. The solution of Pd(II) catalyst in MeCN (stream 1), the solution of 1a and TBAI in
MeCN (stream 2), CO (stream 3) and O2 (stream 4) were directed into M; the resulting gasꢀ
liquid mixture then entered the reaction coil (R), where the oxidative carbonylation took
place. After the reaction, the reaction mixture containing the product exited the reactor
through the outlet of the BPR, and was finally collected in a test tube. The two liquid feeds
were injected through injection loops (L1 and L2). The flow rates of the gas streams were
monitored using calibrated Bronkhorst mass flow controllers (MFCs) (for more details of the
setup, see the Supporting Information)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 24
8
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
Figure 3. Construction of the microreactor for the oxidative carbonylation
Optimization of the Reaction Conditions. Initially, the influence of temperature, pressure
and gas flow rate were investigated to identify the optimal reaction conditions for the
continuousꢀflow oxidative carbonylation of 2ꢀaminophenol (1a) (Figure 4). For this
preliminary optimization, CO and O2 were fed in excess at equal flow rates, whilst the
concentration of 1a in the feed stream was 0.10 M. Under 15 bar pressure, the conversion
reached a plateau at 90 °C (curve a). When higher pressure (20 bar) was exerted for those
experiments above 90 °C (curve b), the molar fraction (area % by GC) of benzoxazolone (2a)
reached 97% at 120 °C within 17 min residence time. Doubling the gas flow rates resulted in
a decrease in conversion, probably from the reduced reaction time (curve c).
ACS Paragon Plus Environment

Page 9 of 24
Organic Process Research & Development
9
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
Figure 4. Influence of the reaction temperature, pressure and the gas flow rate. (a) 15 bar, FCO
= FO = 4.40 mLN/min, residence time tR = 15 min; (b) 20 bar, FCO = FO = 4.40 mLN/min, tR =
2
2
17 min; (c) 15 bar, FCO = FO = 8.80 mLN/min, tR = 8 – 10 min. (Concentration of 1a in feed
2
stream 0.10 M, corresponding to 0.05 M within the reactor; liquid flow rates 0.50 mL/min for
each stream; analyzed by GCꢀFID. Subscript “N” denotes volume under STP (273.15 K, 1 bar)
condition.)
During the optimization studies, we discovered that the internal surface of the reactor
coil became coated with some of the Pd catalyst over time. A control run without the addition
of Pd within the feed demonstrated that the residual Pd on the coil still retained some activity
and was catalyzing the reaction, albeit at lower levels (Table 1, entry 1). This phenomenon
was also observed by us in the Pd catalyzed continuousꢀflow Mizoroki–Heck coupling30 and
by some other researchers.31 In organic solvent under high temperature, the Pd(II) catalyst
will be rapidly converted into Pd(0) colloids/nanoparticles, from which Pd black is formed.32
The Pd deposited on the reactor coil can be reꢀoxidized by I2 (from TBAI) to reꢀform the
active Pd(II) catalyst.33,11g To guarantee the reproducibility of our results, the residual Pd
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 24
10
1
2
3
4
5
black inside the reactor was removed after each experiment by washing the reactor with 20%
HNO3 (aq) at 70 °C.
6
7
8
9
The subsequent optimization of the catalyst type and catalyst loading was carried out
under double the substrate feed concentration (0.20 M) and halved liquid flow rate. Under
these conditions, good conversions were obtained when using 5.0 mol% Pd(OAc)2 and
Pd(TFA)2 (Table 1, entries 2 and 3). Reducing the catalyst loading also resulted in a decrease
in conversion (Table 1, entries 4 and 5). The increase of residence time for 1.0 mol% catalyst
loading failed to improve the conversion any further, instead a large amount of oxidation
product (7a) was formed11e presumably via a sequential oxidation/1,4ꢀaddition mechanism
(Table 1, entry 6).34 In the control experiment without catalyst, only oxidation of the substrate
took place (Table 1, entry 7). Furthermore, 20 mol% cocatalyst was found to be necessary to
obtain high substrate conversion in a residence time appropriate to flow processing (Table 1
entry 8).
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. Optimization of Catalyst Type and Loading.
b
flow rate (mLN/min)
molar fraction c (%)
cocatalyst
(TBAI)
tR
entry
catalyst
(min)
F1
F2
FCO
4.40
4.40
4.40
4.40
4.40
2.20
4.40
4.40
FO2
4.40
4.40
4.40
4.40
4.40
2.20
4.40
4.40
1a
2a
46
94
91
87
68
48
0
7a d
1
2
3
4
5
6
7
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
10 mol%
reactor not cleaned
Pd(OAc)2 5.0 mol%
Pd(TFA)2 5.0 mol%
Pd(OAc)2 2.5 mol%
Pd(OAc)2 1.0 mol%
Pd(OAc)2 1.0 mol%
no catalyst
0.25
0.25
0.25
0.25
0.25
0.12
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.12
0.25
0.25
24
24
24
24
24
48
24
24
36
4
18
2
5
4
9
4
24
23
74
12
8
29
26
5
8
Pd(OAc)2 5.0 mol%
83
a
Conditions: 0.20 M concentration of 1a in feed, corresponding to 0.10 M within the reactor, cocatalyst TBAI
20 mol%, 120 °C, 20 bar. Reactor was washed with HNO3 before each experiment (unless otherwise mentioned).
b
Residence time measured by a stop watch. c Determined by GCꢀFID. d Byproduct stemmed from the oxidation
of 1a.
ACS Paragon Plus Environment

Page 11 of 24
Organic Process Research & Development
11
1
2
3
4
5
6
7
8
9
The influence of the CO/O2 ratio on the reaction was also investigated (Figure 5). The
experiments under 15 bar and 20 bar indicated that CO/O2 = 1.0 is the optimal gas phase
composition. A high CO concentration is favored by the carbonylation. However the presence
of too much CO can also cause faster deactivation of the Pd(II) catalyst by reduction to Pd(0).
A higher O2 concentration is necessary to maintain the presence of iodine, which reoxidizes
Pd(0) to Pd(II) in the liquid phase;33 whereas pure O2 can slowly oxidize the substrate at high
temperature and long residence time11e (Table 1, entries 5 and 6). The contradictory effects of
CO and O2 finally led to the optimum ratio CO/O2 (1:1), under which the best conversion of
1a is achieved. Since potentially explosive gas mixtures can be safely handled in flow, it is
permitted that the gas composition could be further optimized to conditions that are within the
explosive regime without the use of dilution gases, whereas heating a pressurized explosive
mixture of CO and O2 in an autoclave is strictly forbidden.
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 5. Influence of CO/O2 ratio on product formation. (a) 90 °C, 15 bar, tR = 15 min; concentration
of 1a in feed stream 0.10 M, corresponding to 0.05 M within the reactor. (b) 120 °C, 20 bar, tR = 17
min, concentration of 1a in feed stream 0.20 M. (liquid flow rates F1 = F2 = 0.50 mL/min; total gas
flow rate FCO + FO2 = 8.80 mLN/min; analyzed by GCꢀFID.)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 24
12
1
2
3
4
A mechanism based on earlier reports11,12 and our experiments is proposed for the
oxidative carbonylation of 1a (Figure 6). Substrate 1a is a bidentate ligand which is present in
large excess with respect to palladium, therefore the formation of chelates 3a and 6a are
thermodynamically favored. However, in the absence of a strong base, the insoluble complex
6a forms rather slowly.29 Thus, this allows electronꢀdeficient (14e) precursor 3a, which may
also exist as a dimer, to coordinate with CO for the subsequent migratory insertion and the
reductive elimination, giving 2a and Pd(0). The Pd(0) species is present in the form of Pd
nanoparticles, Pd black suspension (and ultimately deposited on the reactor wall) in the
reaction system. These Pd(0) species are then reoxidized by I2 (generated by the oxidation of
iodide) forming Pd(II) for the next catalytic cycle.33,11h
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 6. A proposed mechanism for the oxidative carbonylation of 1a.
Using the optimized reaction conditions (Table 1, entry 1), an array of five and sixꢀmembered
carbonylated heterocycles (2) were prepared from their corresponding precursors (1) (Figure
7). Most of the compounds were isolated in good yield after purification by flash
chromatography. The only exceptions were the precursors which are readily oxidized (1d and
ACS Paragon Plus Environment

Page 13 of 24
Organic Process Research & Development
13
1
2
3
4
5
6
7
8
9
1l) or less reactive to achieve complete conversion (1k and 1n). Alkyl substituted 2ꢀ
aminophenols (1b and 1c) and alkyl substituted catechol (1m) gave higher yields than their
unsubstituted counterparts (1a and 1l respectively), since the alkyl substituents resist
oxidative dimerization34 by steric hindrance without making the aromatic ring too electronꢀ
rich. Amino group and phenolic hydroxyl group interact stronger with Pd(II) than alcoholic
hydroxyl groups. For the conformational flexible 1j and 1k, a stronger linkage with Pd atom
is necessary to stabilize the intermediates containing sixꢀ(3 and 4) and sevenꢀ(5) membered
palladacycles; as a result, 1j (with phenolic OH) was converted completely to afford 2j,
whereas 1k (with alcoholic OH) reacted rather slowly. Glycol 1n bears only two alcoholic
OHꢀgroups, failed to achieve complete conversion within the given residence time.
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 7. Synthesis of carbonylated heterocycles via oxidative carbonylation. (Reported
values refer to isolated yields, for more details see Experimental Section).
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 24
14
1
2
3
4
5
6
7
8
Among the molecules in the scope, there are some structures of medicinal and synthetic
significance. 5ꢀtꢀButylꢀbenzoxazolone (2c) exhibits cytotoxicity against cancer cells.6a Chiral
oxazolidinones 2e and 2f served as chiral auxiliaries for stereoselective synthesis35 and the
preparation of highly isotactic, optically active polymers.36 The enantiomers of 4ꢀ
benzyloxazolidinꢀ2ꢀone (2g and 2h) are a pair of Evans chiral auxiliaries used in asymmetric
synthesis;37 their precursors (1g and 1h) are prepared from the reduction of phenylalanine.38
All chiral oxazolidinones (2e-h) are obtained with excellent enantiopurity (e.e. > 99.5%), no
racemization occurred during the course of the conversion. (For the analysis of their purity,
see Experimental section).
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
As we have mentioned in the Introduction part before, compounds in the scope (2)
have been synthesized from their precursors (1) by the condensation with carbonic acid
derivatives8ꢀ10 and the oxidative carbonylation in batch.11 Compared to traditional
condensation procedures, the use of corrosive reagent (phosgene) and the formation of
hazardous waste (HCl and NH3) are avoided in the oxidative carbonylation. In the continuousꢀ
flow oxidative carbonylation described above, the safe use of the optimal CO/O2 ratio in the
explosive regime is permitted and therefore allows the reaction time to be shortened from 24
hours11a to merely 24 min. For the reaction in a segmented gasꢀliquid flow pattern, only a
small excess of CO (4 equiv.) and O2 (8 equiv.) is needed, whereas the reaction in an
autoclave requires much more (ca. 127 equiv. CO, 13 equiv. O2).11a Although the catalyst
loading is relatively high, the continuousꢀflow operation has made this reaction more scalable
than the batch alternatives. Similar to the classical carbonylation reactions22a and the
oxidation using molecular oxygen22 in microreactors, the oxidative carbonylation in flow took
advantage of the intensified mass transfer and the pressure resistance of microchannels. Even
24f
though, the simplicity of some devices for the homogeneous catalyzed reactions using O2
and CO25c is maintained.
CONCLUSION
A continuousꢀflow protocol for the synthesis of carbonylated heterocycles via a liquid
phase palladium catalyzed oxidative carbonylation is developed. The continuousꢀflow
operation in a stainless steel capillary enables safe manipulation of pressurized CO/O2
mixture within the explosive regime. The flow reaction uses pure gases as feedstock to
ACS Paragon Plus Environment

Page 15 of 24
Organic Process Research & Development
15
1
2
3
4
5
6
7
8
generate gasꢀliquid segmented flow patterns allows the reaction to be completed within 24
min residence time with much smaller excess (4 equiv. CO, 8 equiv. O2) of gases than batch.
Fourteen examples have been prepared proving the applicability of this protocol to the
synthesis of fiveꢀ and sixꢀmembered carbonylated heterocycles.
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
EXPERIMENTAL SECTION
General Methods. NMR spectra were recorded on a 300 MHz instrument (75 MHz
13
for C). Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard.
The letters s, d, t, q and m stand for singlet, doublet, triplet, quadruplet and multiplet. GCꢀFID
analysis was performed using a HP5 column (30 m × 0.250 mm × 0.025 ꢁm). After 1 min at
50 °C the temperature was increased in 2 °C minꢀ1 stepped up to 80 °C, then in 25 °C minꢀ1
stepped up to 300 °C and kept at 300 °C for 4 minutes. The detector gas for the flame
ionization is H2 and compressed air (5.0 quality). GC−MS spectra were recorded using a HP5ꢀ
MS column (30 m × 0.250 mm × 0.25 ꢁm) with helium as carrier gas (1 mL/min constant
flow) coupled with a mass spectrometer (EI, 70 eV). After 1 min at 50
°C, the temperature was
increased in 25 C/min steps up to 300 C and kept at 300 C for 1 min. Chiral HPLC was
°
°
°
performed using a chiral column (250 mm × 4.6 mm, particle size 5 ꢁm) using heptane/iꢀ
PrOH = 90:10 as mobile phase; flow rate 1.0 mL/min; column temperature 30 °C; injection
volume 5 µL. All solvents and chemicals were obtained from standard commercial vendors
and were used without any further purification. Products were characterized by H and 13C
1
NMR and identified by comparison of the spectra with those reported in the literature. All
compounds synthesized herein are known in the literature. Proof of purity was obtained by 1H
NMR spectroscopy.
CAUTION: Risk of explosion and CO poisoning! CO is an odorless, toxic and flammable
gas; its mixture under certain conditions with air or oxygen is potentially explosive. All the
experiments must be performed in a wellꢀventilated fume cupboard with a fitted CO detector.
A thorough safety assessment should be made before conducting any experiments.
Oxidative Carbonylation Reaction. The solution of 0.01 M palladium salt in MeCN
(5.50 mL) (stream 1) and the solution of 0.20 M substrate (1) and 0.04 M nꢀBu4N+Iꢀ in MeCN
(5.00 mL) (stream 2) were loaded into their corresponding injection loops. The flow rates of
the gas streams (streams 3 and 4) were measured and controlled by two mass flow controllers
(MFCs) (gas flow rates FCO = FO2 = 4.40 mLN/min). The reaction temperature and the flow
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 24
16
1
2
3
4
5
6
7
8
9
rates of the liquid streams (liquid flow rates F1 = F2 = 0.25 mL/min) were measured and
monitored by the control platform of the pumping system. After the temperature (120 °C) and
the pressure (20 bar) became stable and a biphasic flow appeared in the observation loop (L0),
the injection of the liquid reagents and timing were started. When colored reaction mixture
appeared in L0 (residence time tR = 24 min), timing was ceased and product collection was
started by directing the discharge into a glass test tube. When no colored solution was coming
out from the outlet, collecting was stopped. The collected solution was analyzed by GCꢀFID
and GCꢀMS thereafter.
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
Workup and Product Isolation. The collected reaction mixture was concentrated
in vacuo, dissolved in ethyl acetate and then washed with 1 M HCl (aq) (3 × 10 mL) and
distilled water (1 × 10 mL) (2l, 2m, 2n were washed with 3 × 10 mL distilled water; no HCl
wash was needed). The combined organic phase was dried over anhydrous Na2SO4, filtered
and the solvent removed under reduced pressure. Subsequently the reaction mixture was
purified by silica gel flash chromatography using hexane and ethyl acetate (gradient: 5 – 90%
EtOAc over 15 CV, and then maintained at 90% EtOAc for another 10 CV) as eluent to afford
the product (2).
Benzo[d]oxazol-2(3H)-one (2a): 98.0 mg (73%); pale yellow crystals; mp 140.5 –
1
141.5 °C (lit.6a 134 – 136 °C); H NMR (300 MHz, CDCl3) δ 9.90 (s, 1H), 7.26 – 7.09 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 156.3, 143.9, 129.4, 124.2, 122.8, 110.3, 110.2.
4-Methylbenzo[d]oxazol-2(3H)-one (2b): 119.0 mg (80%); light brown crystals; mp
1
171.3 – 172.5 °C (lit.39a 156 – 158 °C); H NMR (300 MHz, CDCl3) δ 10.44 (s, 1H), 7.13 –
13
6.95 (m, 3H), 2.42 (s, 3H); C NMR (75 MHz, CDCl3) δ 156.9, 143.6, 128.6, 125.4, 122.5,
120.6, 107.6, 16.1 (lit.39b).
5-(tert-Butyl)benzo[d]oxazol-2(3H)-one (2c): 169.3 mg (88%); grey crystals; mp
135.5 – 136.0 °C C (lit.39c 146 – 147 °C); 1H NMR (300 MHz, CDCl3) δ 10.11 (s, 1H), 7.23 –
13
7.09 (m, 3H), 1.34 (s, 9H); C NMR (75 MHz, CDCl3) δ 157.0, 148.0, 141.8, 129.3, 119.6,
109.3, 107.7, 34.9, 31.6 (lit.39d).
5-Methoxybenzo[d]oxazol-2(3H)-one (2d): 79.0 mg (48%); orange crystals; mp
162.3 – 163.0 °C (lit.39e 168 – 170 °C); 1H NMR (300 MHz, CDCl3) δ 9.63 (s, 1H), 7.12 (d, J
= 8.8 Hz, 1H), 6.77 – 6.58 (m, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.9, 156.6,
138.0, 130.0, 110.5, 107.9, 96.8, 56.0 (lit.39f).
ACS Paragon Plus Environment

Page 17 of 24
Organic Process Research & Development
17
1
2
3
(S)-4-Phenyloxazolidin-2-one (2e): 106.5 mg (65%); pale yellow crystals; mp 128.6
4
5
6
7
– 129.8 °C (lit.39g 128 – 130 °C); 1H NMR (300 MHz, CDCl3) δ 7.47 – 7.29 (m, 5H), 6.70 (s,
13
1H), 5.02 – 4.91 (m, 1H), 4.72 (t, J = 8.7 Hz, 1H), 4.16 (dd, J = 8.5, 6.9 Hz, 1H); C NMR
(75 MHz, CDCl3) δ 160.2, 139.6, 129.1, 128.7, 126.0, 72.6, 56.4 (lit. 39h); e.e. = 99.63%.
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
(R)-4-Phenyloxazolidin-2-one (2f): 94.4 mg (58%); white crystals; mp 130.1 °C
(lit.11a 128 – 130 °C); 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.25 (m, 5H), 6.73 (s, 1H), 5.02 –
13
4.90 (m, 1H), 4.71 (t, J = 8.7 Hz, 1H), 4.15 (dd, J = 8.5, 6.9 Hz, 1H); C NMR (75 MHz,
CDCl3) δ 160.2, 139.6, 129.1, 128.7, 126.0, 72.5, 56.4 (lit.11a); e.e. = 100.00%.
(S)-4-Benzyloxazolidin-2-one (2g): 123.0 mg (69%); white crystals; mp 86.7 – 87.4
1
°C (lit. 39i 89 – 90 °C); H NMR (300 MHz, CDCl3) δ 7.41 – 7.24 (m, 3H), 7.24 – 7.14 (m,
13
2H), 6.04 (s, 1H), 4.51 – 4.37 (m, 1H), 4.21 – 4.03 (m, 2H), 2.97 – 2.79 (m, 1H); C NMR
(75 MHz, CDCl3) δ 159.6, 135.9, 129.0, 129.0, 127.2, 69.6, 53.8, 41.4 (lit. 39j); e.e. =
100.00%.
(R)-4-Benzyloxazolidin-2-one (2h): 126.0 mg (77%); white crystals; mp 88.1 – 88.5
1
°C (lit. 39j 86 °C); H NMR (300 MHz, CDCl3) δ 7.40 – 7.24 (m, 3H), 7.23 – 7.12 (m, 2H),
13
6.41 (s, 1H), 4.50 – 4.30 (m, 1H), 4.22 – 4.01 (m, 2H), 3.02 – 2.70 (m, 2H); C NMR (75
MHz, CDCl3) δ 159.9, 136.0, 129.1, 128.9, 127.2, 69.5, 53.8, 41.3 (lit. 39j); e.e. = 99.96%.
5-Phenyloxazolidin-2-one (2i): 120.0 mg (77%); white crystals; mp 88.5 – 89.5 °C
1
(lit. 39i 88 – 90 °C); H NMR (300 MHz, CDCl3) δ 7.47 – 7.33 (m, 5H), 6.75 (s, 1H), 5.66 –
13
5.58 (m, 1H), 3.99 (t, J = 8.8 Hz, 1H), 3.55 (dd, J = 8.8, 7.7 Hz, 1H); C NMR (75 MHz,
CDCl3) δ 160.4, 138.5, 128.9, 125.7, 78.00, 48.4 (lit. 39k).
3,4-Dihydro-2H-benzo[e][1,3]oxazin-2-one (2j): 49.1 mg (33%); white crystals;
1
mp 190.0 – 191.0 °C (lit. 39l 185 °C, lit. 39m 193 °C); H NMR (300 MHz, CDCl3) δ 7.35 –
13
7.23 (m, 1H), 7.20 – 7.10 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 4.57 (s, 2H); C
NMR (75 MHz, CDCl3) δ 151.8, 149.7, 128.9, 125.8, 124.5, 116.7, 116.6, 42.4 (lit. 39m).
1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one (2k): 79.8 mg (54%); pale yellow
1
crystals; mp 116.3 – 118.5 °C (lit. 39n 118 – 119 °C); H NMR (300 MHz, CDCl3) δ 9.55 (s,
13
1H), 7.30 – 7.21 (m, 1H), 7.14 – 7.00 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 5.33 (s, 2H); C
NMR (75 MHz, CDCl3) δ 154.2, 135.6, 129.2, 124.1, 123.3, 117.8, 114.4, 68.8 (lit. 39n).
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 24
18
1
2
3
Benzo[d][1,3]dioxol-2-one (2l): 35.5 mg (26%); colorless crystals; mp 116.5 – 117.0
4
5
6
7
1
°C (lit. 39o 119 – 120 °C, lit. 39p 118 °C); H NMR (300 MHz, CDCl3) δ 7.36 – 7.16 (m, 4H)
(lit. 39p); 13C NMR (75 MHz, CDCl3) δ 151.2, 143.3, 124.9, 110.5 (lit. 39q).
8
9
5-(tert-Butyl)benzo[d][1,3]dioxol-2-one (2m): 128.5 mg (67%); pale yellow
crystals; mp 42.7 – 44.1 °C; 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.22 (m, 2H), 7.17 (d, J =
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
8.4 Hz, 1H), 1.35 (s, 9H); C NMR (75 MHz, CDCl3) δ 151.7, 149.0, 143.2, 141.0), 121.5,
109.6, 107.7, 35.2, 31.5.
1
4-Phenyl-1,3-dioxolan-2-one (2n): 43.5 mg (26%); colorless liquid; H NMR (300
MHz, CDCl3) δ 7.51 – 7.34 (m, 1H), 5.70 (t, J = 8.0 Hz, 1H), 4.82 (t, J = 8.4 Hz, 1H), 4.36
13
(dd, J = 8.6, 7.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 154.9, 135.8, 129.7, 129.2, 125.9,
78.0, 71.2 (lit.37r).
Supporting Information Available. More details of the microreactor setup, copies of 1H and
13C NMR spectra of all compounds and HPLC chromatograms of all chiral compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEGMENT
We thank Dr. Michael Fuchs (University of Graz) for the measurement of chiral purity
of compounds 2e, 2f, 2g and 2h.
REFERENCE
(1) Green, M. M.; Wittcoff, H. A. Organic Chemistry Principles and Industrial Practice;
WileyꢀVCH: Weinheim, 2003
(2) Arpe, H.ꢀJ. Industrial Organic Chemistry, 5th ed.; VCH: Weinheim, 2010.
(3) Falbe, J. Synthesen mit Kohlenmonoxyd, Springer: Berlin Heidelberg, 1967.
(4) (a) Wu, X.ꢀF.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1. (b) Cupido, T.; Tullaꢀ
Puche, J.; Spengler, J.; Albericio, F. Curr. Opin. Drug Discov. Devel. 2006, 9, 765. (c) Bode,
J. W. Curr. Opin. Drug Discov. Devel. 2006, 9, 765. (d) Graul, A.; Castaner, J. Drugs Future
1997, 22, 956.
ACS Paragon Plus Environment

Page 19 of 24
Organic Process Research & Development
19
1
2
3
4
5
6
7
8
9
(5) (a) Fang, W.; Zhu, H.; Deng, Q.; Liu, S.; Liu, X.; Shen, Y.; Tu, T. Synthesis 2014, 46,
1689. (b) Brennführer, A.; Neumann, H.; Beller, M., ChemCatChem 2009, 1, 28. (c) Heck, R.
F. Palladium Reagents in Organic Synthesis; Academic Press Ltd.: San Diego, 1985 (d)
Barnard, C. F. J. Organometallics, 2008, 27, 5402. (e) Bai, Y.; Davisand, D. C.; Dai, M. J.
Org. Chem., 2017, 82, 2319.
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
(6) (a) Reddy, K. I.; Aruna, C.; Babu, S. K.; Vijayakumar, V.; Manisha, M.; Sridevi, J. P.;
Yogeeswarie, P.; Srirame, D. RSC Adv., 2014, 4, 59594. (b) Ucar, H.; Van derpoorten, K.;
Cacciaguerra, S.; Spampinato, S.; Stables, J. P.; Depovere, P.; Isa, M.; Masereel, B.; Delarge
J.; Poupaert, J. H. J. Med. Chem. 1998, 41, 3102. (c) Ucar, H.; Van derpoorten, K.;
Cacciaguerra, S.; Spampinato, S.; Stables, J. P.; Depovere, P.; Isa, M.; Masereel, B.; Delarge
J.; Poupaert, J. H. J. Med. Chem. 1998, 41, 1138.
(7) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. (b) Evans, D.
A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737. (c) Evans, D. A.;
Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1984, 106, 4261.
(8) (a) Ceccarellia, S. M.; Jaeschkea, G.; Buettelmanna, B.; Huwylerb, J.; Kolczewskia, S.;
Petersa, J.ꢀU.; Prinssena, E.; Portera, R.; Spoorena, W.; Vieiraa, E. Bioorg. Med. Chem. Lett.
2007, 17, 1302. (b) Vo, L.; Ciula, J.; Gooding, O. W. Org. Process Res. Dev. 2003, 7, 514. (c)
Akiba, T.; Tamura, O.; Terashima; S. Org. Synth. 1998, 75, 45. (d) Musser, J. H.; Jones, H.;
Sciortino, S.; Bailey, K.; Coutts, S. M.; Khandwala, A.; SonninoꢀGoldman, P.; Leibowitz, M.;
Wolf, P.; Neiss, E. S. J. Med. Chem. 1985, 28, 1255. (e) Hanslick, R. S.; Bruce, W. F.;
Mascitti, A. Org. Syn. 1953, 33, 74. (f) Close, W. J.; Tiffany, B. D.; Spielman, M. A. J. Am.
Chem. Soc. 1949, 71, 1265.
(9) (a) Guidi, S.; Calmanti, R.; Noè, M.; Perosa, A.; Selva, M. ACS Sustainable Chem. Eng.
2016, 4, 6144. (b) Pulla, S.; Unnikrishnan, V.; Ramidi, P.; Sullivan, S. Z.; Ghosh, A.; Dallas,
J. L.; Munshi, P. J. Mol. Catal. A: Chem., 2011, 338, 33. (c) Kim, S.; Ko, Y. K. Heterocycles
1986, 24, 1625.
(10) (a) PeÇaꢀLýpez, M.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2016, 55, 7826. (b)
Bala, M.; Verma, P. K.; Sharma, D.; Kumar, N.; Singh, B. Mol. Divers. 2015. 19. 263. (c)
Bhanage, B. M.; Fujita, S.ꢀi.; Ikushima, Y.; Arai M. Green Chem., 2004, 6, 78.
(11) (a) Mancuso, R.; Raut, D. S.; Ca‘, N. D.; Fini, F.; Carfagna, C.; Gabriele, B.
ChemSusChem 2015, 8, 2204. (b) Peng, X.; Li Fu.; Hu, X.; Xia, C.; Sandoval, C. A. Chin. J.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 24
20
1
2
3
4
5
6
7
8
9
Catal. 2008, 29, 638. (c) Li, F.; Xia, C. Tetrahedron Lett. 2007, 48, 4845. (d) Li, F.; Peng, X.;
Xia, C.; Hu, B. Chin. J. Chem. 2005, 23, 643. (e) Gabriele, B.; Mancuso, R.; Salerno, G.;
Costa, M. J. Org. Chem. 2003, 68, 601. (f) Gabriele, B.; Salemo, G.; Brindisi, D.; Costa, M.;
Chiusoli, G. P. Org. Lett. 2000, 5, 625. (g) Li, F.ꢀW.; Xia, C.ꢀG. J. Catal. 2004, 227, 542. (h)
Giannoccaro, P.; Ferragina, C.; Gargano, M.; Quaranta, E. Appl. Catal., A 2010, 375, 78. (i)
Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.; Murahashi, S.ꢀI. Bull. Chem. Soc. Jpn. 1996,
69, 2079.
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
(12) (a) Gadge, S. T.; Bhanage, B. M., RSC Adv. 2014, 4, 10367. (b) Wu, X.ꢀF.; Neumann,
H.; Beller, M., ChemSusChem 2013, 6, 229. (c) Gabriele, B.; Mancuso, R.; Salerno, G. Eur. J.
Org. Chem. 2012, 6825. (d) Liu, Q.; Zhang, H.; Lei. A., Angew. Chem. Int. Ed. 2011, 50,
10788. (e) Díaz, D. J.; Darko, A. K.; McElweeꢀWhite, L. Eur. J. Org. Chem. 2007, 4453. (f)
Q. Xing, F. Li, Top. Heterocycl. Chem. 2015, 156, 121.
(13) (a) Chen, M.; Ren, Z.ꢀH.; Wang, Y.ꢀY.; Guan, Z.ꢀH. J. Org. Chem. 2015, 80, 1258. (b)
Li, J.; Jiang, H.; Chen, M. Synth. Commun. 2001, 31, 199. (c) Tsuji, J.; Takahashi, M.;
Takahashi, T. Tetrahedron Lett. 1980, 21, 849. (d) Orito, K.; Miyazawa, M.; Nakamura, T.;
Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda,
M. J. Org. Chem. 2006, 71, 5951. (e) Tam, W. J. Org. Chem. 1986, 51, 2977.
(14) (a) Wen, J.; Tang, S.; Zhang, S.; Shi, R.; Lei, A. Org. Lett. 2017, 19, 94. (b) Xie, P.; Xie,
Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 9902. (c) Zhang, H.;
Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang, Q.; Lei, A. Angew. Chem. Int. Ed. 2012, 51, 5204.
(15) (a) Lu, L.; Shi, R.; Liu, L.; Yan, J.; Lu, F.; Lei, A. Chem. – Eur. J. 2016, 22, 14484. (b)
Zhu, C.; Yang, B.; Bäckvall, J.ꢀE. J. Am. Chem. Soc. 2015, 137, 11868. (c) Xu, T.; Alper, H.
Org. Lett. 2015, 17, 4526.
(16) (a) Hughes, N. L.; Brown, C. L.; Irwin, A. A.; Cao, Q.; Muldoon, M. J., ChemSusChem
2017, 10, 675. (b) Cao, Q.; Hughes, N. L.; Muldoon, M. J., Chem. Eur.ꢀJ. 2016, 22, 11982.
(17) (a) Liu, K.; Zou, M.; Lei, A., J. Org. Chem. 2016, 81, 7088. (b) Gadge, S. T.; Bhanage,
B. M., J. Org. Chem. 2013, 78, 6793.
(18) Weast, R. C. CRC Handbook of Chemistry and Physics, 65th ed.; CRC Press Inc.: Boca
Raton, Florida, 1984
ACS Paragon Plus Environment

Page 21 of 24
Organic Process Research & Development
21
1
2
3
4
5
6
7
(19) Only in a few cases oxidative carbonylations have been performed in an explosive
regime under atmospheric conditions: (a) Zhao, H.; Han, W. Eur. J. Org. Chem. 2016, 4279.
(b) Izawa, Y.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2004, 77, 2033.
8
9
(20) Selected reviews on general flow chemistry: (a) Jensen, K. F.; Reizmana, B. J.; Newman,
S. G. Lab Chip 2014, 14, 3206. (b) Baxendale, I. R.; Brocken, L.; Mallia, C. J. Green Process
Synth. 2013, 2, 211. (c) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38. (d) Anderson, N. G.
Org. Process Res. Dev. 2012, 16, 852. (e) Plutschack, M. B.; Pieber, B.; Gilmore, K.;
Seeberger, P. H. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00183
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
(21) Selected reviews on flow chemistry handling hazardous transformations: (a) Gemoets, H.
P. L.; Su, Y.; Shang, M.; Hassel, V.; Luque, R.; Noël, T. Chem. Soc. Rev. 2016, 45, 83. (b)
Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens,
C. V. Chem. Soc. Rev. 2016, 45, 4892. (c) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew.
Chem. Int. Ed. 2015, 54, 6688. (d) Poechlauer, P.; Braune, S.; Dielemans, B.; Kaptein, B.;
Obermüller, R.; Thathagar, M. Chim. Oggi/Chem. Today 2013, 30, 51.
(22) Selected reviews on flow chemistry handling gaseous feedstock: (a) Mallia, C. J.;
Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 327. For selected reviews on flow
chemistry handling molecular oxygen, see: (b) Hone, C. A.; Roberge, D.; Kappe, C. O.
ChemSusChem 2017, 10, 32. (c) Pieber, B.; Kappe, C. O. Top. Organometal. Chem. 2016, 57,
97. (d) Pieber, B.; Kappe, C. O. Chim. Oggi/Chem. Today 2016, 34, 38.
(23) A review on the safety accessment of flow process: Kockmann, N.; Thenée, P.;
FleischerꢀTrebes, C.; Laudadioc, G.; Noël, T. React. Chem. Eng. 2017, DOI:
10.1039/C7RE00021A
(24) For recent publications on O2 oxidation in flow, see: (a) Gutmann, B.; Cantillo, D.;
Weigl, U.; Cox, D. P.; Kappe, C. O. Eur. J. Org. Chem. 2017, 914. (b) Gutmann, B.; Elsner,
P.; Cox, D. P.; Weigl, U.; Roberge, D. M.; Kappe, C. O. ACS Sust. Chem. Eng. 2016, 4, 6048.
(c) Gutmann, B.; Weigl, U.; Cox, D. P.; Kappe, C. O. Chem.ꢀEur. J. 2016, 22, 10393. (d)
Pieber, B.; Cox, D. P.; Kappe, C. O. Org. Process Res. Dev. 2016, 20, 376. (e) Hone, C.;
O’KearneyꢀMcMullan, A.; Munday, R.; Kappe, C. O. ChemCatChem 2017, 9, DOI:
10.1002/cctc.201700671 (f) Erdmann, N.; Su, Y.; Bosmans, B.; Hessel, V.; Noël, T. Org.
Process Res. Dev. 2016, 20, 831.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 24
22
1
2
3
4
5
6
7
8
9
(25) For continuousꢀflow CO reactions in tubular reactors, see: (a) Glotz, G.; Gutmann, B.;
Hanselmann, P.; Kulesza, A.; Roberge, D.; Kappe, C. O. RSC Adv. 2017, 7, 10469. (b)
Alonso, N.; Munoz, J. de M.; Egle, B.; Vrijdag, J. L.; De Borggraeve, W. M.; de la Hoz, A.;
DiazꢀOrtiz, A.; Alcazar, J. J. Flow Chem. 2014, 4, 105. (c) Kelly, C. B.; Lee, C.; Mercadante,
M. A.; Leadbeater, N. E. Org. Process Res. Dev. 2011, 15, 717. Multiple setep reaction: (d)
Fukuyama, T.; Totoki, T.; Ryu, I. Org. Lett. 2014, 16, 5632. (e) Gong, X.; Miller, P. W.; Gee,
A. D.; Long, N. J.; de Mello, A. J.; Vilar, R. Chem. ꢀ Eur. J. 2012, 18, 2768. (f) Miller, P. W.;
Jennings, L. E.; de Mello, A. J.; Gee, A. D.; Long N. J.; Vilar, R. Adv. Synth. Catal. 2009,
351, 3260. (g) Miller, P. W.; Long, N. J.; de Mello, A. J.; Vilar, R.; Audrain, H.; Bender, D.;
Passchier, J.; Gee, A.; Angew. Chem., Int. Ed. 2007, 46, 2875. (h) Rahman, Md. T.;
Fukuyama, T.; Kamata, N.; Sato, M.; Ryu, I. Chem. Commun. 2006, 2236. (i) Miller, P. W.;
Long, N. J.; de Mello, A. J.; Vilar, R.; Passchier, J.; Gee, A. Chem. Commun. 2006, 546. (e)
Gong, X.; Miller, P. W.; Gee, A. D.; Long, N. J.; de Mello, A. J.; Vilar, R. Chem. ꢀ Eur. J.
2012, 18, 2768.
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
(26) For continuousꢀflow CO reactions in tubeꢀinꢀtube reactors, see: (a) Hansen, S. V. F.;
Wilson, Z. E.; Ulven, T.; Ley, S. V. React. Chem.Eng. 2016, 1, 28. (b) Mallia, C. J.; Walter,
G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2016, 12, 1503. (c) Gross, U.; Koos, P.;
O'Brien, M.; Polyzos, A.; Ley, S. V. Eur. J. Org. Chem. 2014, 6418. (d) Brancour, C.;
Fukuyama, T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org. Lett. 2013, 15, 2794. (e) M. A.
Mercadante and N. E. Leadbeater, Org. Biomol. Chem. 2011, 9, 6575; (f) T. Fukuyama, Y.
Mukai and I. Ryu, Beilstein J. Org. Chem. 2011, 7, 1288;
(27) For a review on the synthesis of dialkyl carbonates, see: Huang, S.; Yan, B.; Wang S.;
Ma, X. Chem. Soc. Rev. 2015, 44, 3079.
(28) Selected examples of vaporꢀphase continuousꢀflow oxidative carbonylation: (a) Zheng,
H.ꢀY.; Wang, JiaꢀZhen; Li, Z.; Yana, L.ꢀF.; Wen, J. Z. Fuel Process Technol. 2016, 152, 367.
(b) Liu, T.ꢀC.; Chang, C.ꢀS. Applied Catalysis, A: General 2006, 304, 72. (c) Yang, P.; Cao,
Y.; Hu, J.ꢀC.; Dai, WeiꢀLin; Fan, K.ꢀN. Appl. Catal., A. 2003, 241, 363. (d) Han, M. S.; Lee,
B. G.; Ahn, B. S.; Kim, H. S.; Moon, D. J.; Hong, S. I. J. Mol. Catal. A: Chem. 2003, 203,
137. (e) Han, M. S.; Lee, B. G.; Suh, I.; Kim, H. S.; Ahn, B. S.; Hong, S. I. J. Mol. Catal. A:
Chem. 2001, 170, 225.
(29) (a) Watt, G. W.; Knifton, J. F. Inorg. Chem. 1968, 7, 1443. (b)Tanaka, K.; Tasaka, M.;
Cao, H.; Shionoya, M. Supramol. Chem. 2002 14, 255.
ACS Paragon Plus Environment

Page 23 of 24
Organic Process Research & Development
23
1
2
3
(30) Gutmann, B.; Glasnov, T. N.; Razzaq, T.; Goessler, W.; Roberge; D. M.; Kappe; C. O.
4
5
Beilstein J. Org. Chem. 2011, 7, 503.
6
7
8
9
(31) (a) Shore, G.; Morin, S.; Organ, M. G. Angew. Chem., Int. Ed. 2006, 45, 2761. (b) Shore,
G.; Yoo, W. J.; Li, C. J.; Organ, M. G. Chem.–Eur. J. 2010, 16, 126.
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) (a) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559. (b) Phan, N. T. S.; Van der
Sluys, M.; Jones, C. W. Adv. Synth. Catal. 2006, 348, 609.
(33) de Vries, A. H. M. ;Parlevliet, F. J.; Schmiederꢀvan de Vondervoort, L.; Mommers, J. H.
M.; Henderickx, H. J. W.; Walet, M. A. M.; de Vries, J. G. Adv. Synth. Catal. 2002, 344, 996.
(34) Jawale, D.V.; Gravel, E.; Geertsen, V.; Li, H.; Shah, N.; Namboothiri, I. N. N.; Doris, E.
ChemCatChem 2014, 6, 719.
(35) (a) Boyce, G. R.; Johnson, J. S. J. Org. Chem. 2016, 81, 1712. (b) Xu, Y.ꢀS.; Tang, Y.;
Feng, H.ꢀJ.; Liu, J.ꢀT.; Hsung, R. P. Org. Lett. 2015, 17, 572.
(36) Miyake, G. M.; DiRocco, D. A.; Liu, Q.; Oberg, K. M.; Bayram, E.; Finke, R. G.; Rovis,
T.; Chen, E. Y.ꢀX. Macromolecules 2010, 43, 7504.
(37) (a) Nickerson, L. A.; Huynh, V.; Balmond, E. I.; Cramer, S. P.; Shaw, J. T. J. Org.
Chem. 2016, 81, 11404. (b) Balasubramanian, N.; Mandal, T.; Cook, G. R. Org. Lett. 2015,
17, 314.
(38) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58, 3568.
(39) (a) Atkinson, R. S.; Judkins, B. D. J. Chem. Soc., Perkin Trans. 2 1981, 509. (b) Bach,
A.; Pizzirani, D.; Realini, N.; Vozella, V.; Russo, D.; Penna, I.; Melzig, L.; Rita, S.; Piomelli,
D. J. Med. Chem. 2015, 58, 9258. (c) Clark, R. L.; Pessolano, A. A. J. Am. Chem. Soc. 1958,
80, 1662. (d) Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei, A. Angew. Chem. Int.
Ed. 2012, 51, 4666. (e) Ryu, K. E.; Kim, B. R.; Sung, G. H.; Yoon, H. J.; Yoon, Y. J. Synlett
2015, 26, 1985. (f) Singh, R.; Nagesh, K.; Parameshwar, M. ACS Catal. 2016, 6, 6520. (g)
Nicolas, E.; Russell, K. C.; Hruby V. J. J. Org. Chem. 1993, 58, 766. (h) MacNevin, C. J.;
Moore, R. L.; Liotta, D. C. J. Org. Chem. 2008, 73, 1264. (i) Orito, K.; Miyazawa, M.;
Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.;
Tokuda, M. J. Org. Chem. 2006, 71, 5951. (j) af Gennäs, G. B.; Talman, V.; Aitio, O.; Ekokoski,
E.; Finel, M.; Tuominen, R. K.; YliꢀKauhaluoma, J. J. Med. Chem. 2009, 52, 3969. (k) Du,
Y.; Wu, Y.; Liu, A.ꢀH.; He, L.ꢀN. J. Org. Chem. 2008, 73, 4709. (l) Lindemann, H.;
ACS Paragon Plus Environment

Organic Process Research & Development
Page 24 of 24
24
1
2
3
4
5
6
7
8
9
Schultheis, W. Justus Liebigs Ann. Chem. 1928, 464, 237. (m) Suchocki, J. A.; Sneden, A. T.
J. Org. Chem. 1988, 53, 4116. (n) Wang, X.; Lin, G.; Xue, Y.; Lu, X. Eur. J. Org. Chem.
2005, 1675. (o) Hanslick, R. S.; Bruce, W. F.; Mascitti, A. Org. Synth. 1953, 33, 74. (p)
Kaupp, G.; Boy, J.; Schmeyers, J. J. Prakt. Chem. 1998, 340, 1521. (q) Olah, G. A.; Grant, G.
L. J. Org. Chem. 1977, 42, 2237. (r) Jiang, J.ꢀL.; Gao, F.; Hua, R. Qiu, X. J. Org. Chem.
2005, 70, 38.
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