Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow Conditions

Article abstract of DOI:10.1021/acs.oprd.7b00212

Highly efficient and chemoselective singlet oxygen oxidation of unprotected methionine was performed in water using a continuous mesofluidic reactor. Sustainable process engineering and conditions were combined to maximize process efficiency and atom economy, with virtually no waste generation and safe operating conditions. Three water-soluble metal-free photosensitizers [Rose Bengal, Methylene Blue, and tetrakis(4-carboxyphenyl)porphyrin] were assessed. The best results were obtained with Rose Bengal (0.1 mol %) at room temperature under white light irradiation and a slight excess of oxygen. Process and reaction parameters were monitored in real-time with in-line NMR. Other classical organic substrates (α-terpinene and citronellol) were oxidized under similar conditions with excellent performances.

Full text of DOI:10.1021/acs.oprd.7b00212

Subscriber access provided by AUSTRALIAN NATIONAL UNIV
Communication
Scalable Photocatalytic Oxidation of
Methionine under Continuous-Flow Conditions
Noémie Emmanuel, Carlos Mendoza, Marc Winter, Clemens Horn, Alessandra
Vizza, Laurent Dreesen, Benoit Heinrichs, and Jean-Christophe M Monbaliu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00212 • Publication Date (Web): 11 Jul 2017
Downloaded from http://pubs.acs.org on July 12, 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 15
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scalable Photocatalytic Oxidation of Methionine
under ContinuousꢀFlow Conditions
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
Noémie Emmanuel,† Carlos Mendoza,‡ Marc Winter,§ Clemens R. Horn,§ Alessandra Vizza,§
Laurent Dreesen,ǁ,* Benoît Heinrichs,‡,* JeanꢀChristophe M. Monbaliu†,*
† Center for Integrated Technology and Organic Synthesis, Department of Chemistry, University
of Liège, Bꢀ4000 Liège (Sart Tilman), Belgium
‡ Nanomaterials, Catalysis & Electrochemistry ꢀ NCE, Department of Chemical Engineering,
University of Liège, Bꢀ4000 Liège (Sart Tilman), Belgium
§ Corning Reactor Technologies, Corning SAS, 7 bis, Avenue de Valvins CS 70156 Samois sur
Seine, 77215 Avon Cedex ꢀ France
ǁ Biophotonics, Department of Physics, University of Liège, Bꢀ4000 Liège (Sart Tilman),
Belgium
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 15
1
2
3
4
Table of Content
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
ACS Paragon Plus Environment
2

Page 3 of 15
Organic Process Research & Development
1
2
3
4
ABSTRACT
5
6
7
8
Highly efficient and chemoselective singlet oxygen oxidation of unprotected methionine was
performed in water using a continuous mesofluidic reactor. Sustainable process engineering and
conditions were combined to maximize process efficiency and atomꢀeconomy, with virtually no
waste generation and safe operating conditions. Three water soluble metalꢀfree photosensitizers
(Rose Bengal, Methylene Blue, and tetrakis(4ꢀcarboxyphenyl)porphyrin) were assessed. The best
results were obtained with Rose Bengal (0.1 mol%) at room temperature under white light
irradiation and a slight excess of oxygen. Process and reaction parameters were monitored in
realꢀtime with inꢀline NMR. Other classical organic substrates (αꢀterpinene and citronellol) were
oxidized under similar conditions with excellent performances.
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
KEYWORDS
Singlet oxygen, Continuousꢀflow process, Photooxidation, Metalꢀfree photosensitizer,
Sustainable conditions
INTRODUCTION
Oxidation reactions are one of the most ubiquitous chemical transformations in living matter and
chemical labs, and a huge palette of oxidizers, i.e. chemicals prone to extract electrons from
other substrates, are available to the chemist.1 In the context of developing more sustainable
chemical processes, molecular oxygen is most likely the cheapest, the most widely available and
greenest oxidant. Oxidation reactions using ground state triplet oxygen [X3Σg] often require high
pressure and/or coordination complexes, increasing safety and environmental concerns at larger
scale.2 Compared to triplet oxygen, singlet oxygen [a1ꢀg] shows a much higher reactivity that
usually alleviates the use of drastic process conditions, but, on the downside, that could also
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 15
1
2
3
4
5
6
7
8
9
trigger a variety of side reactions if not tamed appropriately. Singlet oxygen is conveniently
generated via an energy transfer to triplet oxygen from catalytic metalꢀfree or metalꢀbased
photosensitizers (PS) upon exposure to UV or visible light. The association of light (in particular
visible light), a widely accessible and environmentally benign gas, a catalyst and mild process
conditions is setting essential foundations whereupon sustainable and green oxidation processes
can be designed.3,4 However, the inherent limitations of catalytic photosensitized oxidations, i.e.
light penetration in macroscopic reaction media, gasꢀliquid mass transfer, solubility of oxygen in
solution and the transient nature of singlet oxygen, impose long irradiation/reaction times,
consequent energy input for active mixing, large excess of oxygen, and the use of noxious
solvents or additives, hence challenging process sustainability and efficiency.3,5 Photochemistry
in continuousꢀflow microreactors is now widely recognized as an enabling combination,6–9
providing major process assets arising from a much improved light penetration and accurate
control of irradiation time, high mass and heat transfer, safe and efficient handling of transient
species, and seamless scalability. Many organic substrates have been successfully oxidized with
singlet oxygen in microfluidic devices.6,10–14 For instance, Alemán et al. reported a microfluidic
procedure utilizing Pt(II) coordination complexes for the visible light photooxidation of various
sulfides.10
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
Sulfoxides are found in many natural products15 and are important organic building blocks
with tremendous applications in organic synthesis, pharmaceutical sciences, biochemistry and
material sciences.16,17 Sulfoxides are traditionally obtained from the oxidation of sulfides with
peroxides,18 peracids19 or periodates,20 with optionally metal catalysts,21 but these methods suffer
from a high risk of overoxidation to sulfones.22 The recent developments in catalytic
photosensitized oxidations have led to robust and chemoselective oxidation procedures, either in
ACS Paragon Plus Environment
4

Page 5 of 15
Organic Process Research & Development
1
2
batch,3,10 or in microfluidic devices.10,23 Methionine sulfoxide 2a (Figure 1), i.e. the sulfoxide of
essential amino acid methionine (1a) has attracted considerable attention over the last few
years.17,24–26 It has numerous applications in studying the pathogenesis of neurodegenerative
diseases,27,28 cell aging and oxidative stress,29 peptide sciences,30–32 material sciences,33,34 and in
organic synthesis.35,36 To date, only one report described the catalytic photooxidation of 1a
methyl ester in D2O using a microfluidic setup in the presence of supported [60]fullerene PS.23
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
1
This process took advantage of O2 longer lifetime and faster oxidation kinetics in deuterated
solvents,26 with a quantitative conversion in 33 s residence time. The output remained, however,
at a slender 0.5 mmol dꢀ1 scale.
In this communication, we report for the first time the development of a scalable continuousꢀ
flow strategy for the photocatalytic oxidation of methionine 1a towards methionine sulfoxide 2a
under mild, chemoselective, atomꢀeconomic, safe and sustainable process conditions (Figure 1).
The best results (1 mol dayꢀ1) were obtained with an extremely low loading of Rose Bengal (0.1
mol%) as photocatalyst, at room temperature under white light irradiation (4000K) and a slight
excess of oxygen (1.1 equiv.). This was enabled by innovative reactor design combining high
mixing and irradiation efficiencies. Other classical organic substrates such as αꢀterpinene 1b and
citronellol 1c were oxidized under similar conditions with excellent performances (Figure 1).
O
OH
O
OH
O2
white LEDs
NH2
NH2
RB (0.1 mol%), H2O
continuous flow
20 °C, 1.4 min
O
S
S
2a
1a
quant.
R'
R
O
O
R'
OH
OH
OH
HOO
R
OOH
2c'
1b
2b
1c
2c
R = Me, R' = iPr
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 15
1
2
3
4
Figure 1. (
L)ꢀmethionine (1a), αꢀterpinene (1b) and citronellol (1c) and the corresponding
5
catalytic photooxidation products (2a-c’) (see Supporting Information for details).
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
EXPERIMENTAL SECTION
Continuous-flow setup
The continuousꢀflow setup (Figure 2) involved a compact commercial glass mesofluidic module
(Corning® Lab ReactorTM, 155 x 125 mm size, 400 µm I.D. reaction path, 2.6 mL internal
volume) integrated with static mixers and sandwiched in a high capacity heatꢀexchanger (2
layers, 22 mL, 1 W mLꢀ1 Kꢀ1). The integrated static mixers were designed to optimize multiphase
mass transfer.37,38 LED panels were mounted on both sides of the fluidic module (40 mm from
the center of the reaction path). Each LED panel was equipped with multiple wavelengths (20
LEDs for each wavelength) and a heat exchanger (T = 10 °C). The continuousꢀflow reactor was
alimented in aqueous 1a through a FLOM® HPLC pump (0.01 – 100 mL minꢀ1) and with
industrial grade oxygen (99.99%, ALPHAGAZ 1, Air Liquide) through a Bronkhorst® mass flow
controller (MFC). A Zaiput Flow Technologies® domeꢀtype backꢀpressure regulator (BPR) was
inserted downstream (set point: 8 barg). Analysis of the reactor effluent was carried out by inꢀ
and offꢀline NMR (Supporting Information).
Feed preparation
The feed solutions of 1a-c were prepared in D.I. water or in methanol containing 0.1 mol% of
PS, and stored in brown bottles.
Typical Run
The HPLC pump used to deliver the aqueous solution of 1a (0.3 M) and RB (0.1 mol%) was set
to 1 mL minꢀ1 and the oxygen flow was set to 7.5 mLN minꢀ1 with the MFC, and both fluids were
ACS Paragon Plus Environment
6

Page 7 of 15
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
conveyed to the continuousꢀflow photoreactor through perfluoroalkoxyalkane (PFA) tubing (1/8”
O.D.). Mixing and irradiation (white LED, 100% intensity) occurred along the entire reaction
channel (2.6 mL internal volume, 1.4 min residence time) under 8 barg of pressure. Conversion:
>99%; selectivity: >99%; Output: 132 g dayꢀ1.
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. Continuousꢀflow setup for the catalyzed photooxidation of 1a. The fluidic module and
the LED panels are integrated with heat exchangers (omitted for clarity).
RESULTS AND DISCUSSION
Waterꢀsoluble metalꢀfree Rose Bengal (RB), Methylene Blue (MB), and tetrakis(4ꢀ
carboxyphenyl)porphyrin (TCPP) sensitizing dyes were selected for dyeꢀsensitized generation of
singlet oxygen.38 These PS are harmless, widely available and can be photodegraded as an
additional postꢀreaction treatment.39,40 Two competitive mechanisms are generally accepted for
photocatalytic oxidations of organic substrates: (a) an oxidative process involving the unique
reactivity of singlet oxygen via an energy transfer and (b) an oxidative process involving radical
intermediates such as the superoxide radical anion.10,26 The prevalence of the singlet oxygen or
the radical mechanism essentially depends on the PS and on the reaction medium.10,26,41 In the
case of sulfides, both mechanisms result in the formation of sulfoxides.41
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 15
1
2
3
4
5
6
7
8
9
Preliminary experiments were designed to set the boundary conditions for the PS effective
concentration (0.1 mol%) and oxygen excess to ensure total conversion within short reaction
times (Supporting Information). Controlled experiments were run in the absence of light, PS or
oxygen, and 2a was not detected in the reactor effluent. The reaction temperature had no notable
effect on the conversion, and the temperature was set at 20 °C for all experiments. The
concentration in 1a of the feed solution had a significant impact on the reaction: at saturation
(0.3 M), completion was obtained within a residence time of 1.4 min, while at lower
concentrations, the residence time to reach completion dropped to 0.6 min (0.1 M), with 0.1
mol% PS and a 1.1:1 O2/1a ratio (Table 1). Upon optimization, the O2/1a ratio was decreased
from 12.9 to 1.1, still affording complete conversion in 1.4 min residence time. The oxygen
excess (equiv.) was thus successfully reduced from 3.8 to 0.1. The best set of conditions
involved a liquid flow of 1 mL minꢀ1 and a gas flow of 7.5 mLN minꢀ1 of oxygen, corresponding
to an estimated residence time of 1.4 min. The consumption of oxygen could be visually
monitored through the glass continuousꢀflow reactor.
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
The light intensity had a profound impact on the conversion (Table 1). With white light LEDs
(4000K) and in the presence of RB (λmax = 550 nm), the conversion was still complete with 80%
intensity, and then dropped to 54% with 20% intensity. The lower conversion observed at lower
irradiation intensity reflects the lower amount of singlet oxygen available in the system.
Changing white LEDs to monochromatic LEDs affected more severely the conversion with 4%
at 622 nm, and 63% at 385 nm, although complete conversion was obtained with blue (405 nm)
LEDs under the same conditions (Table 1).
Table 1. Optimization of the photocatalytic oxidation of 1a under continuousꢀflow conditions in
the presence of Rose Bengal
ACS Paragon Plus Environment
8

Page 9 of 15
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
[1a]
Feed 1
Feed 2
T
Res. time
LEDs
(intensity)
Conv.
(%)
Entry
(M) (mL min-1) (mLN min-1) (°C)
(min)
0.6
1
1.4
0.6
0.6
1
0.1
0.2
0.3
0.1
0.1
0.2
0.2
0.3
0.3
0.3
2.5
1.5
1
2.5
2.5
1.5
1.5
1
15
7.5
7.5
15
rt
rt
rt
10
50
rt
rt
rt
rt
rt
White (100%)
White (100%)
White (100%)
White (100%)
White (100%)
White (50%)
White (20%)
622 nm (100%)
385 nm (100%)
405 nm (100%)
quant.
quant.
quant.
quant.
quant.
89
54
4
63
quant.
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
15
7.5
7.5
7.5
7.5
7.5
1
1.4
1.4
1.4
1
1
10
The nature of the photosensitizer had also a profound impact on the oxidation efficiency. Stock
solutions were prepared with MB and TCPP (0.1 mol% each), and handled as described above.
The optimal conditions for the photooxidation of 1a with RB (1.4 min residence time, 1.1 equiv.
O2, room temperature, white LEDs) only led to partial conversion when the photooxidation was
carried out with MB (λmax = 610 nm)42 as photocatalyst. Shifting to orange LEDs (622 nm)
increased the conversion, but the optimum required a larger excess of oxygen (1.5 equiv.). The
light intensity also impacted the conversion (Supporting Information). At 80 and 50% intensity,
the conversion dropped to 91 and 65%, respectively. Changing the LEDs to 385 nm expectantly
reduced the conversion (13%). TCPP (λmax = 405 nm)43 performed even less under white light
irradiation, with a mere 25% conversion under the optimized conditions with white LEDs.
Adjusting the wavelength to 405 nm together with an increase of the residence time to 1.4 min
and 1.5 equivalent of oxygen led to full conversion. Decreasing light intensity also led to lower
conversions (88% conversion at 50% intensity), similarly to RB.
These results emphasized RB as a superior sensitizer for the photooxidation of 1a under
sustainable process conditions.3 Various production campaigns (8 h runs) emphasized stable
reactor operation and provided consistent results. Decompression after the BPR released the
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 15
1
2
3
4
5
6
7
8
9
excess oxygen. Downstream treatment of reactor effluents included the filtration of the solution
on activated charcoal to remove the PS, concentration of the solution and antisolvent
recrystallization (slow addition of iꢀPrOH), giving 2a in 79% isolated yield (99% purity).
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
Similar conditions were amenable to other organic substrates (Figure 1 and Supporting
information). In particular, αꢀterpinene (1b) and citronellol (1c) are very common model organic
substrates for assessing photocatalytic singlet oxygen process efficiency.27,44 For solubility
reasons, methanol was utilized for these trials. Feed solutions of 1b with concentrations of up to
1 M were submitted to photocatalytic oxidation using white light and a slightly larger excess of
oxygen (1.4 equiv.). Total conversion was observed with 2.2 min of residence time, with no
detectable traces of pꢀcymene, giving a productivity of up to 273 g dꢀ1 (1.6 mol dꢀ1). Quantitative
photocatalytic oxidation of 1c (0.1 M) was obtained within 1 min residence time with 3 equiv. of
oxygen, yielding a 3:2 ratio of peroxides 2c,c’ (Supporting Information).
Outꢀscaling the best conditions for the catalytic photooxidation of 1a with RB (0.3 M, 1.1
equiv. O2, room temperature and residence time of 1.4 min) with a similar light input and surface
to volume ratio in a Corning® Advancedꢀflow G1TM photoreactor would allow to process ca. 72
mL minꢀ1 (daily productivity of 31.1 mol dayꢀ1 or 5.1 kg dayꢀ1). A Corning® Advancedꢀflow G3
reactorTM with similar process conditions would increase the productivity up to 6 T yꢀ1.
In conclusion, we have developed a scalable catalytic photooxidation process for the
production of methionine sulfoxide under sustainable process conditions. By contrast to
previously reported catalytic photooxidation processes where a large excess of oxygen is
required, the integration of static mixers along the reactor path ensured an excellent mass transfer
and, hence, fast oxidation rates despite the moderate solubility of oxygen in the reaction medium.
ACS Paragon Plus Environment
10

Page 11 of 15
Organic Process Research & Development
1
2
3
4
The conditions are amenable to other organic substrates, and provided high productivities within
5
6
short residence time for ascaridole 1b and Rose oxide synthetic intermediates 1c,c’.
7
8
9
ASSOCIATED CONTENT
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
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.oprd. Details of the continuousꢀflow setup, typical runs
and optimizations, and analytical data (1H NMR).
AUTHOR INFORMATION
Corresponding Author
jc.monbaliu@ulg.ac.be (JeanꢀChristophe M. Monbaliu)
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
The research was funded through the ARC grant (iCFlow 15/19ꢀ05) for Concerted Research
Actions, financed by the French Community of Belgium. JCMM gratefully acknowledges
financial support from the University of Liège (WGꢀ13/03).
Notes
The authors declare no competing financial interest. Marc Winter, Clemens R. Horn and
Alessandra Vizza are employees of Corning SAS.
ABBREVIATIONS
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 15
1
2
3
4
5
6
7
8
9
BPR, Back pressure regulator; LED, lightꢀemitting diode; MB, Methylene Blue; NMR, nuclear
magnetic resonance; PS, photosensitizer; RB, Rose Bengal; TCPP, tetrakis(4ꢀ
carboxyphenyl)porphyrin)
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
REFERENCES
(1)
Guo, Z.; Liu, B.; Zhang, Q.; Deng, W.; Wang, Y.; Yang, Y. Chem. Soc. Rev. 2014, 43,
3480–3524.
(2)
(3)
(4)
(5)
Correa, P. E.; Hardy, G.; Riley, D. P. J. Org. Chem. 1988, 53, 1695–1702.
Gu, X.; Li, X.; Chai, Y.; Yang, Q.; Li, P.; Yao, Y. Green Chem. 2013, 15, 357–361.
Alsters, P. L.; Jary, W.; Box, P. O.; Uni, V. Org. Process Res. Dev. 2010, 10, 259–262.
Elvira, K. S.; Wootton, R. C. R.; Reis, N. M.; Mackley, M. R.; DeMello, A. J. ACS
Sustain. Chem. Eng. 2013, 1, 209–213.
(6)
Cambie, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noel, T. Chem. Rev. 2016,
116, 10276–10341.
(7)
(8)
(9)
Levesque, F.; Seeberger, P. H. Org. Lett. 2011, 13, 5008–5011.
Ciriminna, R.; Delisi, R.; Xu, Y.; Pagliaro, M. Org. Process Res. Dev. 2016, 20, 403–408.
Mallia, C. J.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 327–360.
(10) CasadoꢀSánchez, A.; GómezꢀBallesteros, R.; Tato, F.; Soriano, F. J.; PascualꢀCoca, G.;
Cabrera, S.; Alemán, J. Chem. Commun. 2016, 52, 9137–9140.
(11) Heugebaert, T. S. A.; Stevens, C. V.; Kappe, C. O. ChemSusChem 2015, 8, 1648–1651.
ACS Paragon Plus Environment
12

Page 13 of 15
Organic Process Research & Development
1
2
3
4
5
6
(12) Maurya, R. A.; Park, C. P.; Kim, D. P. Beilstein J. Org. Chem. 2011, 7, 1158–1163.
(13) Wootton, R. C. R.; Fortt, R.; De Mello, A. J. Org. Process Res. Dev. 2002, 6, 187–189.
7
8
9
(14) Loponov, K. N.; Lopes, J.; Barlog, M.; Astrova, E. V; Malkov, A. V; Lapkin, A. A. Org.
Process Res. Dev. 2014, 18, 1443–1454.
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
(15) Imae, Y.; Takada, K.; Okada, S.; Ise, Y.; Yoshimura, H.; Morii, Y.; Matsunaga, S. J. Nat.
Prod. 2013, 76, 755–758.
(16) Matsuoka, S.; Mizoguchi, Y.; Itoh, H.; Okura, K.; Shinohara, N.; Inoue, M. Tetrahedron
Lett. 2010, 51, 4644–4647.
(17) Yamada, S.; Ikkyu, K.; Iso, K.; Goto, M.; Endo, T. Polym. Chem. 2015, 6, 1838–1845.
(18) Gan, S.; Yin, J.; Yao, Y.; Liu, Y.; Chang, D.; Zhu, D.; Shi, L. Org. Biomol. Chem. 2017,
15, 2647ꢀ2654.
(19) Mello, R.; Olmos, A.; AlcaldeꢀAragonés, A.; DíazꢀRodríguez, A.; González Núñez, M. E.;
Asensio, G. Eur. J. Org. Chem. 2010, 32, 6200–6206.
(20) Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27, 282ꢀ284.
(21) Arterburn, J. B.; Nelson, S. L. J. Org. Chem. 1996, 61, 2260–2261.
(22) Lazzaro, F.; Crucianelli, M.; De Angelis, F.; Neri, V.; Saladino, R. Tetrahedron Lett.
2004, 45, 9237–9240.
(23) Carofiglio, T.; Donnola, P.; Maggini, M.; Rossetto, M.; Rossi, E. Adv. Synth. Catal. 2008,
350, 2815–2822.
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 15
1
2
3
4
(24) Ng, S.; Lin, E.; Kitov, P. I.; Tjhung, K. F.; Gerlits, O. O.; Deng, L.; Kasper, B.; Sood, A.;
5
6
Paschal, B. M.; Zhang, P.; et al. J. Am. Chem. Soc. 2015, 137, 5248–5251.
7
8
9
(25) Hellwig, M.; Löbmann, K.; Orywol, T.; Voigt, A. J. Agric. Food Chem. 2014, 62, 4425–
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
4433.
(26) Liu, F.; Liu, J. J. Phys. Chem. B 2015, 119, 8001–8012.
(27) Taniguchi, A.; Sasaki, D.; Shiohara, A.; Iwatsubo, T.; Tomita, T.; Sohma, Y.; Kanai, M.
Angew. Chem. Int. Ed. 2014, 53, 1382–1385.
(28) Schöneich, C. Biochim. Biophys. Acta ꢀ Proteins Proteomics 2005, 1703, 111–119.
(29) Gennaris, A.; Ezraty, B.; Henry, C.; Agrebi, R.; Vergnes, A.; Oheix, E.; Bos, J.; Leverrier,
P.; Espinosa, L.; Szewczyk, J.; et al. Nature 2015, 528, 409–412.
(30) Kukowska, M.; KukowskaꢀKaszuba, M.; Dzierzbicka, K. Tetrahedron Lett. 2015, 56,
525–528.
(31) Harris, P. W. R.; Kowalczyk, R.; Yang, S. H.; Williams, G. M.; Brimble, M. A. J. Pept.
Sci. 2014, 20, 186–190.
(32) Zhang, Y.; Li, T.; Li, X. Org. Biomol. Chem. 2013, 11 (34), 5584.
(33) Reddy, S. M. M.; Dorishetty, P.; Deshpande, A. P.; Shanmugam, G. ChemPhysChem
2016, 2170–2180.
(34) Seixas, J. D.; Santos, M. F. A.; Mukhopadhyay, A.; Coelho, A. C.; Reis, P. M.; Veiros, L.
F.; Marques, A. R.; Penacho, N.; Gonçalves, A. M. L.; Romão, M. J.; et al. Dalt. Trans.
2015, 44, 5058–5075.
ACS Paragon Plus Environment
14

Page 15 of 15
Organic Process Research & Development
1
2
3
4
(35) Li, S. G.; PortelaꢀCubillo, F.; Zard, S. Z. Org. Lett. 2016, 18, 1888–1891.
5
6
7
(36) Lamborelle, N.; Simon, J. F.; Luxen, A.; Monbaliu, J.ꢀC. Org. Biomol. Chem. 2015, 13,
8
9
11602ꢀ11606
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
(37) Jeong, H. G.; Choi, M. S. Isr. J. Chem. 2016, 56, 110–118.
(38) Cherfan, D.; Verter, E. E.; Melki, S.; Gisel, T. E.; Doyle, F. J.; Scarcelli, G.; Yun, S. H.;
Redmond, R. W.; Kochevar, I. E. Investig. Ophthalmol. Vis. Sci. 2013, 54, 3426–3433.
(39) Chesneau, E.; Neckers, D. C. J. Photochem. Photobiol. A Chem. 1988, 42, 269–281.
(40) Bonesi, S. M.; Manet, I.; Freccero, M.; Fagnoni, M.; Albini, Chem. Eur. J. 2006, 12,
4844–4857.
(41) Heger, D.; Jirkovský, J.; Klán, P. J. Phys. Chem. A 2005, 109, 6702–6709.
(42) Cherian, S.; Wamser, C. C. J. Phys. Chem. B 2000, 104, 3624–3629.
(43) Ziegenbalg, D.; Wriedt, B.; Kreisel, G.; Kralisch, D. Chem. Eng. Technol. 2016, 39, 123–
134.
(44) Ronzani, F.; Costarramone, N.; Blanc, S.; Benabbou, A. K.; Bechec, M. Le; Pigot, T.;
Oelgemöller, M.; Lacombe, S. J. Catal. 2013, 303, 164–174.
ACS Paragon Plus Environment
15