Flavin Catalysis Employing an N(5)-Adduct: an Application in the Aerobic Organocatalytic Mitsunobu Reaction

Article abstract of DOI:10.1002/ejoc.201900397

An artificial flavin system has been firstly proved to employ an N(5)-adduct for a catalytic transformation. This mode of catalysis occurs in some flavoenzymes but it is unknown in chemocatalysis, still exclusively using only C(4a)-adducts. In our report, an ethylene-bridged biomimetic flavin has been shown to participate in the Mitsunobu esterification reaction as an alternative to dialkyl azodicarboxylate. The reaction occurs via a flavin N(5)-triphenylphosphane adduct and is catalytic from the point of view of the flavin, which is regenerated by oxygen. This approach distinguishes from other catalytic Mitsunobu reaction procedures which require an extra catalytic system.

Full text of DOI:10.1002/ejoc.201900397

A Journal of
Accepted Article
Title: Flavin Catalysis Employing an N(5)-Adduct: An Application in the
Aerobic Organocatalytic Mitsunobu Reaction
Authors: Michal März, Martin Babor, and Radek Cibulka
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900397
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900397
Supported by

10.1002/ejoc.201900397
European Journal of Organic Chemistry
COMMUNICATION
Flavin Catalysis Employing an N(5)-Adduct: An Application in the
Aerobic Organocatalytic Mitsunobu Reaction
Michal März,[a] Martin Babor,[b] and Radek Cibulka*[a]
Abstract: An artificial flavin system has been firstly proved to
employ an N(5)-adduct for a catalytic transformation. This mode of
catalysis occurs in some flavoenzymes but it is unknown in
chemocatalysis, still exclusively using only C(4a)-adducts. In our
report, an ethylene-bridged biomimetic flavin has been shown to
participate in the Mitsunobu esterification reaction as an alternative
to dialkyl azodicarboxylate. The reaction occurs via a flavin N(5)-
triphenylphosphine adduct and is catalytic from the point of view of
the flavin, which is regenerated by oxygen. This approach
distinguishes from other catalytic Mitsunobu reaction procedures
which always need an extra catalytic system.
position have been described to occur exclusively through their
corresponding 10a-adduct (Figure 1).9a,10 The only artificial flavin
N(5) adduct reported to date is 2a-PPh3, which was reported by
Müller and shown to be reversibly formed from 2a and
triphenylphosphine (Ph3P).11
Herein, we report the unprecedented application of a flavin
N(5)-adduct in artificial catalysis. Specifically, the N(5)-adduct of
2 and triphenylphosphine was shown to activate alcohol during
the esterification of a carboxylic acid to provide its corresponding
ester in an analogous manner to the Mitsunobu reaction. It
should be noted that the conventional Mitsunobu esterification
protocol
needs
stoichiometric
amounts
of
both
triphenylphosphine and dialkyl azodicarboxylate, and produces a
large quantity of the triphenylphosphine oxide and dialkyl
hydrazine dicarboxylate by-products.12 This fact together with
the explosive character of dialkyl azodicarboxylates are
disadvantages of the Mitsunobu reaction in large-scale. In our
protocol, the conventional stoichiometric dialkyl azodicarboxylate
reagent was replaced by a catalytic amount of a biomimetic
flavin, which is regenerated in situ by oxygen (Scheme 1A). To
the best of our knowledge, our procedure is the first
organocatalytic Mitsunobu reaction protocol in which the
Mitsunobu reagent is regenerated directly with oxygen without
the need of any additional reagents. A few catalytic procedures
with either dialkyl azodicarboxylate or phosphine regeneration
have been previously reported.13,14 However, they require at
least an extra catalyst or even a sacrificial oxidizing (other than
oxygen) or reducing agent (Scheme 1A, left).
There are over a thousand flavoenzymes recognized today and
a large number of them have been evaluated in terms of their
structure and/or mechanism of action.1,2 In flavoenzymes, the
flavin co-factors (FMN or FAD) participate in one- or two-electron
redox processes via an electron transfer. In addition, covalent
adducts of the flavin species with the substrate and/or reagent
play an essential role in many transformations.2a,3 In particular,
the adducts formed at the C(4a) position of the flavin (Fl) core
are important intermediates (see Figure 1). For example, flavin-
4a-hydroperoxide is a versatile agent in monooxygenases4 and
the corresponding thiol adduct is an intermediate of glutathione
reductase.5 The N(5) position of the flavins is also important in
enzymatic processes; however, it is mainly involved in hydrogen
atom transfer. According to the current literature, the formation
of an adduct at the N(5) position with species other than hydride
is limited to the carbanions in nitroalkane oxidase6 and acyl
dihydroxyacetone-P synthase, respectively.7
Artificial systems using flavinium salts 1 or 2 have been used
to mimic the functions of flavin co-factors as well as to help to
understand the mechanism of the transformations occurring in
flavoenzymes.8,9 Moreover, some catalytic processes based on
flavinium salts have been established as valuable tools in
organic synthesis.8,9 In contrast to flavoenzymes, only the C(4a)
adducts have been described in these artificial catalytic systems.
This is natural for 5-alkylflavinium salts 1 with a covalently
blocked N(5) position.4,8a,b However, also catalytic processes
using ethylene-bridged flavinium salts 2 bearing a free N(5)
[a]
M.Sc. Michal März, Prof. Dr. Radek Cibulka*
Department of Organic Chemistry
University of Chemistry and Technology, Prague
Technická 5, 166 28 Prague 6, Czech Republic
E-mail: cibulkar@vscht.cz;
URL: https://uoch.vscht.cz/research-groups/cibulka-en
M.Sc. Martin Babor
Department of Solid State Chemistry
University of Chemistry and Technology, Prague
Technická 5, 166 28 Prague 6, Czech Republic
[b]
Figure 1. Structure of flavin cofactors (Fl; e.g. R = ribityl for riboflavin, R =
ribitol-5-phosphate for flavinmononucleotide) and flavinium salts 1 and 2 and
schematic formation of adducts with nucleophiles (Nu). The artificial flavin
N(5)-adduct11 (in box).
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900397
European Journal of Organic Chemistry
COMMUNICATION
reaction. This could be eventually eliminated using a flavinium
catalyst containing a non-nucleophilic anion, e.g., flavinium
triflate 2d or perchlorate 2e (Entries 8-9). Importantly, the
formation of ester 5a was not observed in the blank experiment
(i.e. in the absence of either 2 or triphenylphosphine) (Table 1,
Entries 11 and 12). In addition, the reaction did not occur when a
neutral flavin, 3-methyl tetraacetyl riboflavin (7), was used
instead of flavinium salt 2 (Entry 10), which was attributed to the
weak interactions between 7 and Ph3P.16
Table 1. Looking for conditions for aerial catalytic Mitsunobu reaction
mediated by flavins.[a]
Scheme 1. Mitsunobu reaction (M.R.) procedure with catalytic amount of
dialkyl azodicarboxylate regenerated by oxidation catalysed by C (A, left) and
flavin-catalysed esterification presented in this work (A, right). Intermediates
are shown in (B).
Entry
Flavin
Time
[h]
Ph3P
[equiv]
Temp.
[°C]
Yield[b] [%]
5a
6a
The structure of complex 2-PPh3 is remarkably similar to the
1
2
3
4
5
6
7
8
9
10
11
12
13
14[d]
2b
2c
2c
2c
2c
2c
2c
2d
2e
7
24
24
24
48
24
48
48
48
48
24
24
24
24
24
2
2
2
2
2
2.5
3
2
2
2
25
25
50
50
60
50
50
50
50
50
50
50
50
50
13
31
39
49
31
62
59
43
40
0
3
5
6
6
4
6
7
0
0
0
0
0
5
0
Morrison-Brunn-Huisgen
intermediate
formed
during
conventional Mitsunobu reaction from dialkyl azodicarboxylate
and triphenylphosphine (Scheme 1B). Therefore, we envisage
its use in the catalytic Mitsunobu reaction. In such procedure, 2-
PPh3 would react with alcohol to give the corresponding alkoxy
triphenylphosphonium intermediate (i.e., the alcohol hydroxyl
group is activated towards the nucleophilic substitution reaction)
and dihydroflavin 2-H2. Consequently, dihydroflavin 2-H2 would
be oxidized using molecular oxygen to regenerate flavinium salt
2 for the next catalytic cycle (cf. Scheme 2).15 We have proven
this concept using the model reaction between benzyl alcohol 3a
and benzoic acid 4a. Using 10 mol% of flavin 2b (the chloride
salt of 7,8-dimethylflavinium used by Müller) and 2.0 equivalents
of Ph3P, ester 5a was formed in 13% conversion (Table 1, Entry
1). We hypothesized the electron density on the flavin subunit
will affect the formation and reactivity of the adduct. Indeed, the
use of 7-trifluoromethylflavinium chloride 2c significantly
increased the yield of the target ester (Table 1, Entry 2). Further
optimization was focused on the structure of phosphines.
However, reactions with triarylphosphines possessing an
electron-donating ((4-MeOPh)3P) or an electron-withdrawing
group ((4-ClPh)3P) gave significantly lower amount of ester
compared to those with Ph3P. Reaction with aliphatic
phosphines (tributyl- and tricyclohexylphosphine) does not
provide ester at all (see Supporting Information). It should be
noted that changing the solvent did not improve the reaction
yield (see Supporting Information). On the other hand, an
excess of Ph3P, elevated temperature and longer reaction time
increased the amount of ester formed in our catalytic procedure
(Table 1, Entries 3-7). Molecular sieves (MS) were essential in
the reaction (Table 1, Entry 14) as decomposed the hydrogen
peroxide formed from oxygen during the regeneration of the
flavin catalyst. It was proved by an independent experiment with
classical Mitsunobu reaction which does not proceed when
hydrogen peroxide (1 equiv.) is added. On the other hand,
esterification started immediately after addition of MS to the
reaction mixture containing hydrogen peroxide. Notably, a small
amount of chloride 6a was formed from the alcohol involving the
anion of the flavinium catalyst via a nucleophilic substitution
-
2
-
2.5
2
0
0
61
0
2c
2c[c]
2c
[a] Reaction conditions: 3a (75 µmol), flavin (7.5 µmol), 4a (90 µmol), MS
4Å (150 mg), oxygen (balloon). [b] Conversion was determined by 1H NMR.
[c] Added in the form of 2c-PPh3 adduct. [d] No MS.
Using the optimal conditions in regards to the amount of
ester formed, we investigated the substrate scope from the point
of view of both the carboxylic acid and alcohol (Table 2).
Chloride 2c can be used as the catalyst as by-product 6 was
found to be separable by column chromatography during the
purification of the final ester product 5. The ester products were
formed in moderate to good yield with all the benzoic acid
studied including unsubstituted substrates (5a and 5b) and
those substituted with electron-withdrawing (5c-p) or electron-
donating (5q) groups. Various benzyl alcohols were also
transformed into their corresponding esters irrespective of the
type (5b-i and 5n) and position (5k vs 5l vs 5m) of the
substituent. Importantly, significant yields of the desired esters
were formed in the case of aliphatic (5u and 5v) and
unsaturated acids (5t). The yields and conversions of the esters
derived from aliphatic alcohols (5r and 5s) were relatively small,
but nevertheless, still sufficient to confirm the regeneration of the
flavin catalyst. Unfortunately, we did not succeed with our
attempt to prepare ester 5w using 1-phenylethanol, which was
attributed to the steric hindrance of the secondary alcohol.17 It
should be noted that esterification with 1 mmol of 4-chlorobenzyl
alcohol (3b) and 1.2 mmol 4a afforded ester 5b in the yield 58%
confirming the procedure is useful on preparative scale.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900397
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Substrate scope for esterification mediated by 2c catalyst and Ph3P.[a]
[a] Reaction conditions: alcohol 3 (150 µmol), 2c (15 µmol), acid 4 (180 µmol),
Ph3P (375 µmol), MS 4Å (300 mg), oxygen (balloon), 50 °C, 48h.
[b] Determined by 1H NMR.
Importantly, when monitoring the model esterification
reaction of trifluorobenzoic acid and methanol in the presence of
a substoichiometric amount of 2c (0.25 equiv.) and PPh3 (0.5
equiv.) using 31P NMR spectroscopy, we observed a new signal
at  = 47.3 ppm corresponding to the signal of 2c-PPh3 prepared
in an independent experiment (Figure 3). This signal was
located in the area typical for the Morrison-Brunn-Huisgen
intermediate.18 Moreover, another signal at  = 63.5 ppm was
present in the spectrum, which corresponded to the signal of a
methoxytriphenylphosphonium species,19 an intermediate of the
Mitsunobu reaction (Figure 3). Notably, when adding 2c-PPh3
(prepared in advance) into the catalytic esterification instead of
2c, almost the same conversion of 3a to 5a was observed (see
Table 1, entries 6 and 13).
Next, we turned our attention to the reaction mechanism,
which is outlined in Scheme 2. Initially, we confirmed the
formation of the adduct formed upon mixing flavinium salt 2c
and triphenylphosphine using 1H NMR spectroscopy (see Figure
2). The stepwise addition of triphenylphosphine to a solution of
2c in acetonitrile resulted in the decrease of the signals
corresponding to 2c, which completely disappeared when an
excess of Ph3P was present (2c:Ph3P = 1:2). New signals
corresponding to the flavin moiety appeared and were shifted in
the direction of the signals observed for 2-H2, which indicated
the “reduced” form of the flavin was present in the adduct. In
addition, new signals of bound Ph3P appeared in the spectrum
and their chemical shift indicated a positive charge was present
on the phosphorus atom. The structure of complex 2c-PPh3 was
further confirmed by HR-MS and the NOE observed between the
ortho-hydrogen atoms on the phenyl ring in Ph3P and the
hydrogen atom at C(6) on the flavin moiety (see Scheme and
Supporting Information). The adduct was also isolated as a solid.
Figure 2. 1H NMR spectrum of flavinium salt 2c (5 mg) in the absence
(spectrum A) and in the presence of PPh3 (B-D) in CD3CN (1 mL ). Spectra of
Ph3P (E) in CD3CN and reduced flavin 2c-H2 (F) in DMSO-d6 are given for
comparison.
Scheme 2. The proposed mechanism of esterification mediated by 2c catalyst
and Ph3P. Anion is omitted for clarity.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900397
European Journal of Organic Chemistry
COMMUNICATION
We also used 31P NMR spectroscopy to explain why the
conversions of the alcohols to their corresponding esters was
not quantitative. In standard experiments with catalytic amount
of 2c, triphenylphosphine oxide and the remaining
triphenylphosphine, which was used in excess, were observed
after 48 h of reaction. However, we never observed the signal
corresponding to the 2c-PPh3 adduct after finishing the reaction.
This adduct should be detectable if 2c is present along with
PPh3 in the reaction mixture (when considering the ease of
adduct formation in the presence of Ph3P). This indicated that
the flavinium catalyst underwent an undesired decomposition
pathway and the esterification reaction was stopped before
achieving quantitative conversion. After the addition of another
dose of catalyst 2c after 48h, higher conversion (80%) of ester
was formed according to an independent experiment.
nitrobenzoic acid with 1-phenylethan-1-ol using catalytic
procedure. Thus, we performed this esterification with
stoichiometric amount of flavin 2c. Interestingly, we isolated (S)-
5w with the yield 28% and ee = 95% starting from (S)-1-
phenylethan-1-ol. The observed retention can be explained that
SNAc pathway predominates in the reaction with secondary
alcohols preferring activation of less sterically demanding (and
more acidic) carboxylic group.
In conclusion, first catalytic system which employ N(5)-
adduct to flavin species was developed in artificial catalysis. It
confirms that this mode of flavin-based activation is possible
also outside enzymes.
Flavinium salt 2c was shown to
participate in the Mitsunobu esterification reaction as an
alternative to dialkyl azodicarboxylate. In the presence of
triphenylphosphine, 2c forms the N(5) adduct, which is able to
activate alcohols towards the esterification reaction with various
carboxylic acids. Our procedure is catalytic from the point of
view of the flavin and it is distinguishable from other catalytic
Mitsunobu protocols13,14 due to the direct regeneration of the
Mitsunobu reagent by oxygen without the need of an additional
catalytic system or sacrificial oxidant. Despite some limitations in
substrate scope, this example clearly shows that the toxic and
explosive dialkyl azodicarboxylates usually used in the
Mitsunobu reaction could be replaced by environmentally benign
biomimetic flavins. The structural modification of these flavin
derivatives to improve their efficiency and substrate scope in this
procedure is currently under investigation in our laboratory.
Experimental Section
See Supporting Information for experimental details.
Figure 3. Selected 31P NMR spectrum of model esterification of methanol
(0.15 mmol) with 3-trifluoromethylbenzoic acid (0.15 mmol) in the presence of
Ph3P (0.075 mmol), 2c (0.0375 mmol) and activated MS 4 Å (50 mg) in
CD3CN (1 mL) under oxygen after 7h heating at 50 °C (spectrum A). 31P NMR
spectrum of adduct 2c-PPh3 (B), betain formed from DIAD and Ph3P with
signal of Ph3P=O usually formed after mixing DIAD and Ph3P (C), and Ph3P=O
(D) are given for comparison.
Acknowledgements
This project was supported by the Czech Science Foundation
(Grant No. 16-09436S).
Keywords: Flavoenzymes • Organocatalysis • Flavins •
Esterification • Mechanism
The Mitsunobu reaction is known to proceed via an SN2
reaction on the activated alcohol by the triphenylphosphonium
species. Nevertheless, the alkoxyphosphonium is often in an
equilibrium with the acyloxyphosphonium species in the
presence of the carboxylic acid.12b,20 Thus, the carboxylic acid
group could be activated towards the acyl substitution reaction.
The contribution of both pathways was estimated to be 73:27 for
the SN2 vs SNAc reaction in our case using the model
esterification reaction between isotopically-labelled benzoic acid
and benzyl alcohol (see Supporting Information). For
comparison, the same transformation with stoichiometric amount
of diisopropyl azodicarboxylate afforded exclusively product of
SN2 reaction.
[1]
[2]
[3]
R. Hille, S. Miller, B. Palfey, Volume 1 Oxidases, Dehydrogenases and
Related Systems, 2012.
a) C. T. Walsh, T. A. Wencewicz, Nat. Prod. Rep. 2013, 30, 175-199 ;
b) L. De Colibus, A. Mattevi, Curr. Opin. Struct. Biol. 2006, 16, 722-728.
a) E. Romero, J. R. Gómez Castellanos, G. Gadda, M. W. Fraaije, A.
Mattevi, Chem. Rev. 2018, 118, 1742-1769; b) V. Piano, B. A. Palfey, A.
Mattevi, Trends Biochem. Sci. 2017, 42, 457-469; c) S. Ghisla, V.
Massey, Eur. J. Biochem. 1989, 181, 1-17.
[4]
[5]
F. G. Gelalcha, Chem. Rev. 2007, 107, 3338-3361.
R. L. Fagan, B. A. Palfey, in Comprehensive Natural Products II (Eds.:
H.-W. Liu, L. Mander), Elsevier, Oxford, 2010, pp. 37-113.
H. L. Holland, Nat. Prod. Rep. 2001, 18, 171-181.
[6]
[7]
A. Razeto, F. Mattiroli, E. Carpanelli, A. Aliverti, V. Pandini, A. Coda, A.
Mattevi, Structure 2007, 15, 683-692.
Participation of SN2 and SNAc reaction pathway can be also
recognized monitoring stereochemistry of esterification of chiral
secondary alcohols. Unfortunately, as mentioned above (Table
2), we observed only traces of 5w after esterification of 3-
[8]
a) H. Iida, Y. Imada, S. I. Murahashi, Org. Biomol. Chem. 2015, 13,
7599-7613; b) R. Cibulka, Eur. J. Org. Chem. 2015, 915-932; c) G. de
Gonzalo, M. W. Fraaije, ChemCatChem 2013, 5, 403-415.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900397
European Journal of Organic Chemistry
COMMUNICATION
[9]
a) J. Zelenka, E. Svobodová, J. Tarábek, I. Hoskovcová, V.
Boguschová, S. Bailly, M. Sikorski, J. Roithová, R. Cibulka, Org. Lett.
2019, 21, 114-119; b) T. Sakai, T. Kumoi, T. Ishikawa, T. Nitta, H. Iida,
Org. Biomol. Chem. 2018, 16, 3999-4007; c) T. Hartman, R. Cibulka,
Org. Lett. 2016, 18, 3710-3713; d) S. Murahashi, D. Zhang, H. Iida, T.
Miyawaki, M. Uenaka, K. Murano, K. Meguro, Chem. Comm. 2014, 50,
10295-10298; e) Y. Imada, H. Iida, S.-I. Murahashi, T. Naota, Angew.
Chem. Int. Ed. 2005, 44, 1704-1706; f) Y. Imada, H. Iida, S. Ono, S.-I.
Murahashi, J. Am. Chem. Soc. 2003, 125, 2868-2869; g) S. Murahashi,
T. Oda, Y. Masui, J. Am. Chem. Soc. 1989, 111, 5002-5003.
[13] R. H. Beddoe, H. F. Sneddon, R. M. Denton, Org. Biomol. Chem. 2018,
16, 7774-7781.
[14] a) D. Hirose, M. Gazvoda, J. Košmrlj, T. Taniguchi, Chem. Sci. 2016, 7,
5148-5159; b) D. Hirose, M. Gazvoda, J. Kosmrlj, T. Taniguchi, Org.
Lett. 2016, 18, 4036-4039; c) J. A. Buonomo, C. C. Aldrich, Angew.
Chem. Int. Ed. 2015, 54, 13041-13044; d) D. Hirose, T. Taniguchi, H.
Ishibashi, Angew. Chem. Int. Ed. 2013, 52, 4613-4617; e) T. Y. S. But,
P. H. Toy, J. Am. Chem. Soc. 2006, 128, 9636-9637; f) M. März, J.
Chudoba, M. Kohout, R. Cibulka, Org. Biomol. Chem. 2017, 15, 1970-
1975.
[10] a) J. Žurek, E. Svobodová, J. Šturala, H. Dvořáková, J. Svoboda, R.
Cibulka, Tetrahedron: Asymmetry 2017, 28, 1780-1791; b) A. T. Murray,
M. J. Dowley, F. Pradaux-Caggiano, A. Baldansuren, A. J. Fielding, F.
Tuna, C. H. Hendon, A. Walsh, G. C. Lloyd-Jones, M. P. John, D. R.
Carbery, Angew. Chem. Int. Ed. 2015, 54, 8997-9000; c) A. T. Murray,
P. Matton, N. W. G. Fairhurst, M. P. John, D. R. Carbery, Org. Lett.
2012, 14, 3656-3659; d) J. Žurek, R. Cibulka, H. Dvořáková, J.
Svoboda, Tetrahedron Lett. 2010, 51, 1083-1086; e) B. J. Marsh, D. R.
Carbery, Tetrahedron Lett. 2010, 51, 2362-2365; f) W.-S. Li, L. M.
Sayre, Tetrahedron 2001, 57, 4523-4536.
[15] Regeneration of 2 from its reduced form by oxygen was proved in
various catalytic systems, see ref. 10.
[16] Stability of the Ph3P complex with 2a is by 1 order of magnitude lower
than that with the corresponding “neutral” flavin, see ref.11.
[17] a) D. Liu, L. P. Sanow, C. Zhang, Tetrahedron Lett. 2014, 55, 3090-
3092; b) J. An, R. M. Denton, T. H. Lambert, E. D. Nacsa, Org. Biomol.
Chem. 2014, 12, 2993-3003.
[18] K. E. Elson, I. D. Jenkins, W. A. Loughlin, Org. Biomol. Chem. 2003, 1,
2958-2965.
[19] H. Maeda, T. Koide, T. Maki, H. Ohmori, Chem. Pharm. Bull. 1995, 43,
1076-1080.
[11] F. Müller, Zeitschrift für Naturforschung B, 1972, 1023-1026.
[12] a) S. Fletcher, Org. Chem. Front. 2015, 2, 739-752; b) K. C. K. Swamy,
N. N. B. Kumar, E. Balaraman, K. V. P. P. Kumar, Chem. Rev. 2009,
109, 2551-2651; c) M. Oyo, Y. Masaaki, Bull. Chem. Soc. Jpn. 1967, 40,
2380-2382.
[20] a) S. Schenk, J. Weston, E. Anders, J. Am. Chem. Soc. 2005, 127,
12566-12576; b) J. McNulty, A. Capretta, V. Laritchev, J. Dyck, A. J.
Robertson, Angew. Chem. Int. Ed. 2003, 42, 4051-4054.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900397
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Key topic: Biomimetic organocatalysis
Layout 2:
COMMUNICATION
März M., Babor, M., Cibulka R*
Page No. – Page No.
Flavin Catalysis Employing an N(5)-
Adduct: An Application in the Aerobic
Organocatalytic Mitsunobu Reaction
Text for T
An N(5)-flavin adduct was firstly utilized in artificial catalysis! Adduct of a flavin
derivative with triphenylphosphine provides catalytic Mitsunobu reaction in which
flavin acts as Mitsunobu reagent instead of dialkyl azodicarboxylate. Flavin is used
in catalytic amount only as it is regenerated by dioxygen.
This article is protected by copyright. All rights reserved.