Dehydrogenative lactonization of diols in aqueous media catalyzed by a water-soluble iridium complex bearing a functional bipyridine ligand

Article abstract of DOI:10.1002/cctc.201300717

A new catalytic system for the dehydrogenative lactonization of a variety of benzylic and aliphatic diols in aqueous media was developed. By using a water-soluble, dicationic iridium catalyst bearing 6,6′-dihydroxy-2, 2′-bipyridine as a functional ligand, highly atom economical and environmentally benign synthesis of various lactones was achieved in good to excellent yields. Recovery and reuse of the catalyst were also accomplished by a simple phase separation and the recovered catalyst maintained its high activity at least until the fifth run. Copyright

Full text of DOI:10.1002/cctc.201300717

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DOI: 10.1002/cctc.201300717
Dehydrogenative Lactonization of Diols in Aqueous Media
Catalyzed by a Water-Soluble Iridium Complex Bearing
a Functional Bipyridine Ligand
Ken-ichi Fujita,* Wataru Ito, and Ryohei Yamaguchi*[a]
A new catalytic system for the dehydrogenative lactonization
of a variety of benzylic and aliphatic diols in aqueous media
was developed. By using a water-soluble, dicationic iridium
catalyst bearing 6,6’-dihydroxy-2,2’-bipyridine as a functional
ligand, highly atom economical and environmentally benign
synthesis of various lactones was achieved in good to excellent
yields. Recovery and reuse of the catalyst were also accom-
plished by a simple phase separation and the recovered cata-
lyst maintained its high activity at least until the fifth run.
enable the oxidant-free lactonization of diols (Scheme 1b)
have attracted much attention and have been extensively
studied.[7,8] In these catalytic systems, the lactonization pro-
ceeds without any oxidant with the accompanying evolution
of H2, which minimizes the environmental hazard and maximiz-
es the atom efficiency. However, these reactions have to be
performed in an organic solvent under reflux (>110 8C) or sol-
vent-free conditions at a very high temperature (>2008C).
Meanwhile, we have continuously investigated the dehydro-
genative reactions of alcohols[9] and cyclic amines[10] by using Ir
catalysts bearing a functional ligand. In the course of our stud-
ies, we have developed a water-soluble Cp*Ir catalyst 1a (Cp*:
pentamethylcyclopentadienyl) bearing 6,6’-dihydroxy-2,2’-bi-
pyridine as a functional ligand, which exhibits a high catalytic
performance for the dehydrogenation of primary and secon-
dary alcohols to give carbonyl products in aqueous media.[9c]
Inspired by these findings, we started to develop a new envi-
ronmentally benign catalytic system for the dehydrogenative
lactonization of diols that can be performed under reflux in
water. The structures of the Cp*Ir catalysts used in this study
are illustrated in Scheme 2.[11]
Introduction
Lactones are an important class of compounds in organic, bio-
organic, and natural product chemistry. There are many meth-
ods for the synthesis of lactones that include the intramolecu-
lar esterification of hydroxy acids,[1] intramolecular hydroacylox-
ylation of olefinic acids,[2] and Baeyer–Villiger reaction of cyclic
ketones.[3] The oxidative lactonization of diols (Scheme 1a) is
Scheme 2. Cp*Ir catalysts bearing a functional ligand used in the lactoniza-
tion of diols in aqueous media.
Scheme 1. Previously reported catalytic lactonization of diols.
Results and Discussion
another important method for the production of lactones, and
a number of catalytic systems have been studied that use envi-
ronmentally acceptable oxidants such as oxygen,[4] hydrogen
peroxide,[5] or acetone.[6] Very recently, catalytic systems that
Firstly, reactions of 1,2-benzenedimethanol (3a) under various
conditions were conducted to find the optimum conditions
(Table 1). The dehydrogenative lactonization of 3a did not
occur in the absence of catalyst (entry 1). Water-insoluble
[Cp*IrCl2]2 and water-soluble [Cp*Ir(H2O)3][OTf]2 bearing no
functional ligand showed no catalytic activity (entries 2 and 3).
If the solution of 3a in water was heated to reflux for 6 h in
the presence of catalyst 1a (1.0 mol%), phthalide 4a was ob-
tained in 98% yield with high selectivity (entry 4). The evolu-
tion of H2 was confirmed by analysis of the gas phase by using
a hydrogen sensor. Additionally, the volume of H2 was mea-
sured with a gas burette to give a 95% yield of H2 (footnote [c]
[a] Dr. K.-i. Fujita, W. Ito, Prof. Dr. R. Yamaguchi
Graduate School of Human and Environmental Studies
Kyoto University
Sakyo-ku Kyoto 606-8501 (Japan)
Fax: (+81)75-753-6634
E-mail: fujita.kenichi.6a@kyoto-u.ac.jp
yamaguchi.ryohei.75s@st.kyoto-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300717.
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in entry 4). Analogous catalysts 1b and 1c showed
a lower activity than 1a, which indicates that the a-
hydroxy group in the functional ligand is indispensa-
ble for high catalytic performance (entries 5 and 6).
Our previous catalyst 2,[9a] which has a monodentate
functional ligand, showed no activity (entry 7). Reac-
tions with smaller amount of catalyst 1a (entry 8), at
a lower temperature (entry 9), and for a shorter reac-
tion time (entry 10) resulted in lower yields of 4a
compared to that under the optimum conditions
(entry 4).
Table 1. Dehydrogenative lactonization of 3a in aqueous media under various condi-
tions.[a]
Entry
Catalyst [mol%]
T [8C]
t [h]
Conversion [%][b]
Yield [%][b]
1
2
3
4[c]
5
6
7
8
9
–
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
808C
6
6
6
6
6
6
6
6
6
1
0
0
3
100
47
45
0
89
10
41
0
0
0
98
3
41
0
86
10
41
[Cp*IrCl2]2 (1.0)
[Cp*Ir(H2O)3][OTf]2 (1.0)
1a (1.0)
1b (1.0)
1c (1.0)
2 (1.0)
1a (0.2)
1a (1.0)
1a (1.0)
To obtain reliable experimental evidence that the
evolved gas in the lactonization of 3a is H2, we per-
formed the following dual reactions (Scheme 3). The
reaction of 3a with catalyst 1a was conducted in
a flask that was connected by a rubber tube to an-
other flask in which 1-decene and a catalytic amount
of RhCl(PPh3)3 in benzene were placed. When the de-
hydrogenative lactonization of 3a was almost com-
pleted, decane was produced in 82% yield in the
latter flask, which demonstrates that the H2 generat-
10
reflux
[a] The reaction was performed with 3a (1.0 mmol) and catalyst (1.0 or 0.2 mol%) in
water (1.5 mL) under reflux. [b] Determined by 1H NMR spectroscopy. [c] The yield of
H2 was 95% if the reaction was performed with 3a (2.0 mmol) in water (3.0 mL).
ed in the first flask was pure enough to reduce the 1-decene
in the second flask.
To evaluate the scope of this catalytic system, the reactions
of various diols were conducted (Table 2). If the reactions of
1,2-benzenedimethanol derivatives 3b–3e bearing an ortho,
para-directing substituent at the 4-position were performed
under reflux in water for 6 h in the presence of 1a (1.0 mol%),
isomeric mixtures of phthalide derivatives 4ba–4ea and 4bb–
4eb were obtained in good to high yields. In these cases, the
isomers with a substituent at the 5-position (4ba–4ea) were
formed as major products (entries 2–5).[12] However, the reac-
tion of 3 f that has a nitro group required a longer reaction
time to give the product in a moderate yield with the selectivi-
ty opposite to that above (entry 6).[12] Reactions of 3g and 3h
bearing a substituent at the 3-position gave phthalides 4ga
and 4ha, respectively, predominantly in high yields (entries 7
and 8). The reactions of other benzylic diols 3i–3l also gave
five-, six-, and seven-membered lactones 4i–4l in good to ex-
cellent yields (entries 9–12). The dehydrogenative lactonization
of unsymmetrical diol 3m proceeded well to give isomers
Scheme 3. Dual reactions that involve the dehydrogenative lactonization of
3a and the hydrogenation of 1-decene.
Scheme 4. Reuse of 1a.
Scheme 5. A plausible mechanism for the dehydrogenative lactonization of 3a catalyzed by 1a.
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4ma and 4mb in a ratio of 86:14 (entry 13).[12] The
addition of a catalytic amount of base (NaHCO3) was
effective to give lactones selectively in the reactions
of diols that have a secondary alcoholic moiety (en-
tries 14, 15, 18, and 20).[13] Not only aromatic diols,
but also aliphatic ones could be used as substrates in
the present catalytic system (entries 16–22), although
the yields of lactones were relatively low in some
cases.[14]
Table 2. Dehydrogenative lactonization of various diols in aqueous media catalyzed
by 1a.[a]
Entry Diol
t [h] Product
Selectivity[b] Yield [%][c]
1
2
3
4
5
6[e]
R=H
3a
3b
3c
3d
3e
6
6
6
6
6
4a
97
92
63[d]
93
94
57
To demonstrate the advantages of the present cat-
alytic system in aqueous media, the recovery and
reuse of the catalyst were investigated (Scheme 4).[15]
After the dehydrogenative lactonization of 3l cata-
lyzed by 1a in water, the product 4l could be isolat-
ed by simple extraction with an organic solvent. Cat-
alyst 1a could be recovered in the aqueous phase
and reused for the next run. Notably, the recovered
catalyst maintained its high activity at least until the
fifth run.
R=Me
R=OMe
R=Br
R=F
R=NO2
4ba
4ca
4da
4ea
4 fa
4bb
4cb
4 db
4eb
4 fb
55:45
77:23
53:47
67:33
38:62
3 f 20
7
8
R=Me
R=F
3g
3h 20
6
4ga
4ha
4gb
4hb
93:7
81:19
95
89
9[f]
3i 20
4i
4j
92
78
A plausible mechanism for the present dehydro-
genative lactonization of diols catalyzed by 1a is
shown in Scheme 5. The mechanism is closely related
to that of the dehydrogenative oxidation of alcohols
catalyzed by 1a, which we have previously propo-
sed.[9c] The initial step of the reaction would involve
elimination of a proton (H+) and aquo ligand from
the dicationic catalyst 1a to afford a monocationic
unsaturated species A bearing an a-pyridonate-based
functional ligand (cycle A). Then, the cooperative acti-
vation of one of the alcohol moieties in a diol could
proceed to give an alkoxo species B. b-Hydrogen
elimination in B would occur to afford a hydrido iridi-
um species C and a hydroxyaldehyde intermediate E,
which would be cyclized intramolecularly into
a lactol F. The lactol F could be again activated and
dehydrogenated by the active species A to give a lac-
tone as the product (cycle B). Finally, the hydride in C
would react with the hydroxyl proton on the func-
tional ligand (ligand-promoted dehydrogenation) to
release H2 accompanied by the regeneration of the
active species A (cycles A and B).
10[f]
3j
6
6
11[f]
12
3k
4k
4l
74
98
3l
6
13
3m 20
86:14
88
97
4ma
4mb
4n
14[g]
3n
3o
6
6
15[g]
16
4o
4p
91
68
3p 40
17[g]
3q 20
3r 20
4q
4r
67[d]
70
18[e,h]
19
3s 20
3t 20
3u 20
60:40
45:55
64
65
93
Conclusion
4sa
4ua
4sb
4t
20[e,h]
21
We have developed a new catalytic system for the
dehydrogenative lactonization of diols in aqueous
media. By using a water-soluble Cp*Ir catalyst 1a
(Cp*: pentamethylcyclopentadienyl), the highly atom-
economical and environmentally benign synthesis of
a variety of lactones was achieved. The recovery and
reuse of the catalyst by a simple procedure were also
accomplished. To the best of our knowledge, the
present system is the first example of the dehydro-
genative lactonization of diols in aqueous media.
4ub
4v
22
3v 20
52
[a] The reaction was performed with diol (1.0 mmol) and catalyst 1a (1.0 mol%) in
water (1.5 mL) under reflux. [b] The ratio of two isomers was determined by 1H NMR
1
spectroscopy of the crude products. [c] Isolated yield. [d] Determined by H NMR spec-
troscopy. [e] 3.0 mol% of catalyst 1a was used. [f] 3.0 mL of water was used.
[g] 5.0 mol% of NaHCO3 was added. [h] 15.0 mol% of NaHCO3 was added.
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2011, 50, 3533–3537; d) J. Zhang, E. Balaraman, G. Leitus, D. Milstein,
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Experimental Section
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Dehydrogenative lactonization of diols in aqueous media
catalyzed by 1a
General procedure: Under an atmosphere of argon, 1a (1.0 or
3.0 mol%), water (1.5 or 3.0 mL), and diol (1.0 mmol) were placed
in a flask. The mixture was stirred under reflux for 6–40 h. After the
evaporation of the water under vacuum, the crude mixture was an-
1
alyzed by H NMR spectroscopy. Then, the product was isolated by
column chromatography on silica gel (eluent: ethyl acetate/
hexane).
Acknowledgements
This work was supported by KAKENHI (No. 19750075 and
25105732). We thank Masato Kobayashi, Ryuichi Tamura, and
Shoichi Furukawa for their valuable technical assistance.
[11] Cp* iridium complexes bearing similar functional ligands have been
also reported by other research groups; a) W.-H. Wang, J. T. Muckerman,
E. Fujita, Y. Himeda, ACS Catal. 2013, 3, 856–860; b) J. F. Hull, Y. Himeda,
W.-H. Wang, B. Hashiguchi, R. Periana, D. J. Szalda, J. T. Muckerman, E.
Fujita, Nat. Chem. 2012, 4, 383–388.
Keywords: alcohols
catalysis · iridium · lactones
·
dehydrogenation
·
homogeneous
[12] A possible explanation for these selectivities is proposed in Schemes S2,
S3, and S4 in the Supporting Information.
[13] If the reaction of 3n was performed in the absence of base (NaHCO3),
4n was obtained in 76% yield along with 24% of cyclic ether (1,3-dihy-
dro-1-phenylisobenzofuran), which would be formed by the proton-
mediated dehydration of 3n via a secondary carbocation intermediate.
This result suggests that the role of base is as an acceptor of the
proton formed in the initial step of the catalytic mechanism (see
Scheme 5).
[14] To study the tolerance of a C=C bond, the reaction of 3a was examined
in the presence of styrene, which is susceptible to hydrogenation. If the
reaction of 3a (1.0 mmol) was conducted in the presence of 1a
(1.0 mol%) and styrene (1.0 mmol) under reflux in H2O for 6 h, 4a was
obtained in 66% yield along with recovered styrene (90%) and ethyl-
benzene (10%). This result suggests that the C=C bond would be
mostly tolerated in the dehydrogenative lactonization catalyzed by 1a,
although the reaction was slightly slowed.
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[15] The reuse of catalyst 1a in the dehydrogenative lactonization of 3i is
also shown in Scheme S1 in the Supporting Information.
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Received: August 27, 2013
Revised: October 15, 2013
Published online on November 24, 2013
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