Neutral flavins: Green and robust organocatalysts for aerobic hydrogenation of olefins

Article abstract of DOI:10.1021/ol902393p

"Chemical Equation Presented" Various olefins can be hydrogenated quantitatively with neutral flavin 2 catalysts in the presence of 1 -2 equiv of hydrazine under 1 atm of O₂. Vitamin B₂ derivative 2g acts as a highly efficient and robust catalyst for the present environmentally benign process producing water and nitrogen gas as the only waste products

Full text of DOI:10.1021/ol902393p

ORGANIC
LETTERS
2010
Vol. 12, No. 1
32-35
Neutral Flavins: Green and Robust
Organocatalysts for Aerobic
Hydrogenation of Olefins
Yasushi Imada,* Takahiro Kitagawa, Takashi Ohno, Hiroki Iida, and
Takeshi Naota*
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity,
Machikaneyama, Toyonaka, Osaka 560-8531, Japan
imada@chem.es.osaka-u.ac.jp; naota@chem.es.osaka-u.ac.jp
Received October 16, 2009
ABSTRACT
Various olefins can be hydrogenated quantitatively with neutral flavin 2 catalysts in the presence of 1-2 equiv of hydrazine under 1 atm of
O2. Vitamin B2 derivative 2g acts as a highly efficient and robust catalyst for the present environmentally benign process producing water and
nitrogen gas as the only waste products.
Flavins, simple model compounds of various flavin-contain-
ing oxidases1 and monooxygenases,2 attract much attention
Scheme 1. Redox Process for Oxidative Transformations with
as a very rare class of organocatalysts that can perform
aerobic oxidative transformations of organic compounds
under mild conditions.3-5 Most aerobic oxidative transfor-
mations with flavoenzymes and synthetic flavin catalysts
proceed via substantially similar catalytic cycles, which
include the following: (i) hydrogen transfer from reductants
(AH2) to oxidized flavin (Flox); (ii) O2 incorporation into the
resulting reduced flavin (Flred) to afford 4a-hydroperoxyflavin
(FlOOH); and (iii) oxygen transfer to substrates S followed
by dehydration of FlOH or dissociation of H2O2 to regenerate
Flavoenzymes and Synthetic Flavin Catalysts
(1) Fitzpatrick, P. F. Acc. Chem. Res. 2001, 34, 299–307.
(2) (a) van Berkel, W. J. H.; Kamerbeek, N. M.; Fraaije, M. W.
J. Biotechnol. 2006, 124, 670–689. (b) Ballou, D. P. In FlaVins and
FlaVoproteins; Massey, V., Williams, C. H., Eds.; Elsevier: New York,
1982; pp 301-310.
Flox (Scheme 1). Reductases and oxidases use the first
dehydrogenation process as a crucial step for oxidative
transformation.1 Simulation of these enzymatic functions with
flavins, isoalloxazines, provides catalytic dehydrogenative
oxidations of alcohols,6 primary and secondary amines,7 and
thiols8 under O2 atmosphere. Monooxygenases promote the
third process, employing FlOOH as the active species for
oxygen transfer to the substrates.2 Various heteroatom
(3) Reviews on flavin-catalyzed oxidations: (a) Gelalcha, F. G. Chem.
ReV. 2007, 107, 3338–3361. (b) Imada, Y.; Naota, T. Chem. Rec. 2007, 7,
354–361
.
(4) Ishii, Y.; Sakaguchi, S. In Modern Oxidation Methods; Ba¨ckvall,
J.-E., Ed.; Wiley-VCH: Weinheim, Germany, 2004; pp 119-163.
(5) (a) Ohkubo, K.; Suga, K.; Morikawa, K.; Fukuzumi, S. J. Am. Chem.
Soc. 2003, 125, 12850–12859. (b) Ohkubo, K.; Nanjo, T.; Fukuzumi, S.
Bull. Chem. Soc. Jpn. 2006, 79, 1489–1500. (c) Ohkubo, K.; Suga, K.;
Fukuzumi, S. Chem. Commun. 2006, 2018–2020
.
10.1021/ol902393p  2010 American Chemical Society
Published on Web 12/01/2009

compounds such as tertiary amines,9 sulfides,9 and ketones10
undergo aerobic oxidations with 5-ethylflavinium perchlorate
catalysts in the presence of reductants.3
Scheme 2
. Catalytic Activities for Aerobic Hydrogenation of
Styrene to Ethylbenzene with Various Flavin Compoundsa
Recently, we found that diimide (HNdNH), a powerful
reducing agent for a variety of unsaturated bonds,11 can be
generated by aerobic oxidation of hydrazine with flavin
catalyst 1 through both dehydrogenation and oxygenation
processes of the above redox system. This method can be
applied to a new type of “aerobic hydrogenation” of olefins,
performing efficiently under 1 atm of molecular oxygen or
air (eq 1).12 The method provides an alternative, convenient
method for the catalytic hydrogenation of olefins, which
proceeds without transition metals and dangerous oxidants,
producing water and nitrogen gas as waste products. This is
rare for organocatalytic hydrogenation reactions.13
In this paper we describe 5-unsubstituted isoalloxazines
2, which act as highly efficient and robust catalysts for this
new type of reduction. 5-Unsubstituted isoalloxazines 2 are
inexpensive, safe, and common materials, and are widely
used as medicines, cosmetics, and health supplements.14
Compared to cationic flavin species FlEt+·ClO4- 13,9,10 and
its reduced form FlEtH,15,16 this class of compounds is
considerably safer and easier to prepare, handle, and store,
thus the development of general methods for oxidative
transformations with 2 catalysts is highly desired from
synthetic, industrial, and environmental viewpoints. However,
the catalytic use of 2 for molecular transformations has been
limited to just a few reactions,6,8,17 mainly due to the lower
stability of FlOOH. The present finding adds further synthetic
utility to this new environmentally benign process. A recent
a The experimental conditions are described in the text.
paper on a similar type of reaction with a much more unstable
reduced flavin catalyst16 prompted us to report our new
results.
The catalytic activity of various flavin compounds (1 mol
%) (Scheme 2) was examined for the hydrogenation of
styrene (0.1 mmol) with NH2NH2·H2O (0.12 mmol) in
CH3CN (0.4 mL) at 30 °C under O2 (1 atm). Yields of
ethylbenzene were evaluated by GLC analysis after stirring
for 8 h. While flavinium perchlorate 1 showed the highest
catalytic activity among the catalysts examined,12 a series
of 5-unsubstituted neutral flavins 2a-c showed comparably
high activities. This is in contrast to the fact that compounds
(6) (a) Fukuzumi, S.; Kuroda, S.; Tanaka, T. J. Am. Chem. Soc. 1985,
107, 3020–3027. (b) Shinkai, S.; Kameoka, K.; Ueda, K.; Manabe, O. J. Am.
Chem. Soc. 1987, 109, 923–924. (c) Svoboda, J.; Schmaderer, H.; Ko¨nig,
B. Chem.sEur. J. 2008, 14, 1854–1865.
(7) (a) Hoegy, S. E.; Mariano, P. S. Tetrahedron 1997, 53, 5027–5046.
(b) Li, W.-S.; Zhang, N.; Sayre, L. M. Tetrahedron 2001, 57, 4507–4522.
(8) Yano, Y.; Ohshima, M.; Yatsu, I.; Sutoh, S.; Vasquez, R. E.; Kitani,
A.; Sasaki, K. J. Chem. Soc., Perkin Trans. 2 1985, 753–758.
(9) (a) Imada, Y.; Iida, H.; Ono, S.; Murahashi, S.-I. J. Am. Chem. Soc.
2003, 125, 2868–2869. (b) Imada, Y.; Iida, H.; Ono, S.; Masui, Y.;
Murahashi, S.-I. Chem. Asian J. 2006, 1, 136–147.
2 gave unsatisfactory results for catalytic oxidations of
9,10
amines and sulfides with O2
and H2O2.18 Vitamin B2
derivatives 2e-g also showed high activities, while unpro-
tected vitamin B2 (2d) gave unsatisfactory results due to its
low solubility in organic solvents. Bisflavin 319 had decreased
activity owing to intramolecular electron transfer. The flavin
analogue, 1,3-dimethylalloxazine (4), exhibited much lower
catalytic activity in this case, while its 5-ethyl-1,5-dihydro
(10) Imada, Y.; Iida, H.; Murahashi, S.-I.; Naota, T. Angew. Chem., Int.
Ed. 2005, 44, 1704–1706.
(11) For reviews, see: (a) Hu¨nig, S.; Mu¨ller, H. R.; Thier, W. Angew.
Chem., Int. Ed. Engl. 1965, 4, 271–280. (b) Pasto, D. J.; Taylor, R. T. Org.
React. 1991, 40, 91–155.
(12) Imada, Y.; Iida, H.; Naota, T. J. Am. Chem. Soc. 2005, 127, 14544–
14545.
(13) Organocatalytic transfer hydrogenations :(a) Yoneda, F.; Kuroda,
K.; Tanaka, K. J. Chem. Soc., Chem. Commun. 1984, 1194–1195. (b) Yang,
J. W.; Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43, 6660–
6662. (c) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 32–33.
(17) (a) Tamao, K.; Hayashi, T.; Ito, Y. J. Chem. Soc., Chem. Commun.
1988, 795–797. (b) Akiyama, T.; Simeno, F.; Murakami, M.; Yoneda, F.
J. Am. Chem. Soc. 1992, 114, 6613–6620.
(18) (a) Murahashi, S.-I.; Oda, T.; Masui, Y. J. Am. Chem. Soc. 1989,
111, 5002–5003. (b) Mazzini, C.; Lebreton, J.; Furstoss, R. J. Org. Chem.
1996, 61, 8–9. (c) Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem., Int.
Ed. 2002, 41, 2366–2368. (d) Imada, Y.; Ohno, T.; Naota, T. Tetrahedron
Lett. 2007, 48, 937–939.
(14) Powers, H. J. Am. J. Clin. Nutr. 2003, 77, 1352–1360.
(15) (a) Bergstad, K.; Ba¨ckvall, J.-E. J. Org. Chem. 1998, 63, 6650–
6655. (b) Linde´n, A. A.; Kru¨ger, L.; Ba¨ckvall, J.-E. J. Org. Chem. 2003,
68, 5890–5896
.
(16) Smit, C.; Fraaije, M. W.; Minnaard, A. J. J. Org. Chem. 2008, 73,
(19) Imada, Y.; Ohno, T.; Naota, T. Tetrahedron Lett. 2008, 49, 2523–
2526.
9482–9485
.
Org. Lett., Vol. 12, No. 1, 2010
33

Table 1. Aerobic Hydrogenation with Neutral Flavin Catalysta
Scheme 3. Synthesis of 2g
conditions,20 remain intact under the present reaction condi-
tions (entries 5, 6, and 12). Another synthetic utility of the
present method is illustrated by the highly efficient reduction
of sulfur-containing olefins (entries 13-16), which are
negligibly reduced by conventional hydrogenation with
transition metal catalysts.
One important advantage of the present reaction is the
availability of the catalysts. A series of neutral flavin 2
catalysts can be prepared much more easily than cat-
ionic9,12,18 or reduced forms.16 Neutral flavin 2a can be
prepared readily by a conventional process including reduc-
tion of o-nitroaniline, condensation with alloxane, and
subsequent N-methylation, while cationic flavin 1 requires
subsequent reductive amination and oxidation, both of which
are synthetically difficult.9b Vitamin B2 2d is an inexpensive
mass-produced material, and its derivatives 2e and 2f are
also commercially available. 3-Methyl-2′,4′:3′,5′-di-O-me-
thylenedioxyriboflavin (DMRFl) 2g can be readily derived
from 2d by a conventional process (Scheme 3). Also, neutral
flavins 2 can be purified readily, and preserved for a long
time under ambient atmosphere. This is in contrast to less
stable, cationic flavins which cannot be purified by ordinary
experimental procedures such as extraction, chromatographic
separation, and recrystallization. Preparation and treatment
of reduced flavins require much more sophisticated tech-
niques to prevent spontaneous incorporation of O2.
Another feature of the present method is the high reus-
ability of the catalysts arising from their thermal and
chemical stabilities. DMRFl 2g has proven to be the most
robust catalyst among those examined. Table 2 shows typical
recycling use of catalyst 2g in the hydrogenation of 1-tet-
radecene (5) and 4-tert-butylstyrene (6). The product alkanes
7 and 8 can be obtained quantitatively upon simple extraction
with hexane. After the reaction, the resulting CH3CN phase
including 2g can be stored for a long time, and reused
repeatedly for subsequent runs without loss of efficiency.
Vitamin B2 derivative 2f also exhibited comparably higher
reusability for the present aerobic hydrogenations, although
the yield in the second run decreased (8: 64%) due to
deactivation by slow hydrolysis of the catalyst. Cationic
flavins are not robust toward such a tough recycling use.
a The reaction was carried out in CH3CN in the presence of 2f (2.0 mol
%), and NH2NH2·H2O (2.0 equiv) at 30 °C for 24 h under O2 (1 atm).
b Isolated yield. c 2a was used instead of 2f. d 2g was used instead of 2f.
e 2e was used instead of 2f. f NH2NH2·H2O (1.5 equiv) was used at 25 °C.
g NH2NH2·H2O (4.0 equiv) was used. After 24 h, additional NH2NH2·H2O
(1.0 equiv) was added, and the mixture was stirred another 6 h. h NH2NH2·H2O
(2.4 equiv) was used at 50 °C.
analogue can be used as an efficient catalyst for oxidations
of amines and sulfides with H2O2.15
Table 1 shows representative results for the neutral flavin-
catalyzed aerobic hydrogenation of olefins. A variety of linear
and cyclic olefins were converted to the corresponding
hydrogenated products when the reaction was performed in
CH3CN with neutral flavin catalyst 2 and 2 equiv of
hydrazine at ambient temperature under O2 (1 atm). In
addition to 2a, vitamin B2 derivatives 2e-g can be used as
efficient catalysts for quantitative hydrogenation. Conve-
niently, there is no significant difference in product yields
between cationic flavin 1 and neutral 2 under the present
conditions, although control experiments with 1 equiv of
hydrazine showed that the catalytic activity of 1 is higher
than those with 2. Monosubstituted olefins are hydrogenated
chemoselectively in the presence of trisubstituted ones (entry
10). Alkynes can be converted to the corresponding alkanes
with 5 equiv of hydrazine (entry 11). Various heteroatom-
containing substituents such as alkoxy, epoxy, acyloxy,
hydroxy, and amido groups are tolerated by the reaction
(entries 5-12). Noteworthy is that benzyloxy and carboben-
zyloxy groups, highly labile protecting groups under reducing
(20) Wuts, P. G.; Greene, T. W. ProtectiVe Groups in Organic Synthesis,
4th ed.; John Wiley & Sons: New York, 2006.
34
Org. Lett., Vol. 12, No. 1, 2010

Table 2. Aerobic Hydrogenation of 5 and 6 with 2g Catalyst
Scheme 4
.
Proposed Catalytic Cycle for Aerobic Hydrogenation
of Olefins with Neutral Flavin Catalyst 2
isolated yield (%)
run
tetradecane (7)
4-tert-butylethylbenzene (8)
complex 10 reacts with olefins to afford the hydrogenated
products and molecular nitrogen. Incorporation of O2 to the
liberated FlH2 9 gives 4a-hydrodioxyflavin FlHOOH 11. The
second hydrazine undergoes fast oxygen transfer directly
from 11 to afford the Fl·HNdNH complex 12. An alternative
pathway for the formation of 12 is elimination of H2O2 from
11 and subsequent oxidation of hydrazine with the resulting
Fl·H2O2 complex 13. Similar hydrogenation of a second
olefin with 12 generates 2 to complete the catalytic cycle.
The stoichiometry of reduction of 2 equiv of olefins with 1
equiv of O2, depicted in eq 1, was confirmed experimentally,
with 0.027 mmol of O2 being consumed in the hydrogenation
of 0.058 mmol of 9-decen-1-ol under standard conditions
with neutral flavin catalyst 2g. Efforts are currently underway
to investigate the full scope of the reaction.
1a
2b
3b
98
97
96
93
94
94
a The reaction of 1-tetradecene (5) or 4-tert-butylstyrene (6) was carried
out in CH3CN in the presence of 2g (2.0 mol %), and NH2NH2·H2O (2.0
equiv) at 30 °C for 24 h under O2 (1 atm). b The acetonitrile solution from
the previous run was reused instead of a recharged catalyst.
The yield of 8 did not exceed 40% after the second run with
recycled 1 catalyst.
The present catalytic reaction can be rationalized by the
consecutive anaerobic and aerobic processes as shown in
Scheme 4.12 Although neutral flavin 2 is less reactive than
cationic 1, it undergoes smooth nucleophilic attack of
hydrazine due to the high nucleophilic properties of hydrazine
arising from the R-nitrogen effect.21 Subsequent 1,3-
hydrogen shift generates reduced flavin FlH2 (9) and diim-
ide.7 FlH2 9 and diimide then form the H-bonded
FlH2·HNdNH complex 10, which prevents the problematic
self-disproportionation reaction of the diimide, which pro-
duces hydrazine and molecular nitrogen.11 The diimide in
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) (a) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84,
16–24. (b) Hoz, S. J. Org. Chem. 1982, 47, 3545–3547.
OL902393P
Org. Lett., Vol. 12, No. 1, 2010
35