An efficient oxidative lactonization of 1,4-diols catalyzed by Cp*Ru(PN) complexes

Article abstract of DOI:10.1021/ol0706408

An efficient oxidative lactonization of 1,4-diols in acetone is accomplished by the well-defined ruthenium catalyst, whose bifunctional nature underlies the high efficiency as well as unique chemo- and regioselectivity of the reaction which provides a rapid access to γ-butyrolactones including flavor lactones hinokinin, and muricatacin.

Full text of DOI:10.1021/ol0706408

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1821-1824
An Efficient Oxidative Lactonization of
1,4-Diols Catalyzed by Cp*Ru(PN)
Complexes
Masato Ito, Akihide Osaku, Akira Shiibashi, and Takao Ikariya*
Department of Applied Chemistry, Graduate School of Science and Engineering,
Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
tikariya@apc.titech.ac.jp
Received March 23, 2007
ABSTRACT
An efficient oxidative lactonization of 1,4-diols in acetone is accomplished by the well-defined ruthenium catalyst, whose bifunctional nature
underlies the high efficiency as well as unique chemo- and regioselectivity of the reaction which provides a rapid access to
including flavor lactones hinokinin, and muricatacin.
γ-butyrolactones
Functionalized lactones are ubiquitous frameworks in a
variety of biologically active natural products including
antibiotics, lignans, pheromones, antifungal compounds, and
flavor components.1-3 Although a number of methods for
the synthesis of lactones have been reported,1 the oxidation
of diols to lactones is a potentially useful process, and Fe´tizon
oxidation using an excess amount of silver carbonate1e,f has
long been a reliable method owing to its experimental
convenience. Nonetheless, a more environmentally benign
process that generates minimal heavy metal waste would be
highly desirable. Although the metal-catalyzed oxidation of
alcohols with nonhazardous oxidants may offer a practical
solution,4 its application to the oxidative lactonization of diols
is still limited2 mainly due to the intrinsic difficulty in the
selective two-step oxidation of a primary alcoholic group
over another alcoholic groups in the same molecules.5
We have recently developed Cp*Ru(II) catalyst systems
bearing a series of chelating primary amine ligands with
characteristic “NH/metal bifunctional units”6 for highly
effective organic transformations.7 One of the most intriguing
features of the catalyst system Cp*RuCl[Ph2P(CH2)2NH2-
(1) (a) Hudlicky, M. Oxidation in Organic Chemistry; American Chemi-
cal Society: Washington, D.C., 1990. (b) ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7. (c) Seitz,
M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285-292. (d) Collins, I.
J. Chem. Soc., Perkin Trans. 1 1999. 1377-1395. (e) Fe´tizon, M.; Golfier,
M.; Louis, J.-M. Chem. Commun. 1969, 1118-1119. (f) Fe´tizon, M.;
Golfier, M.; Louis, J.-M. Tetrahedron 1975, 31, 171-176.
(2) Metal-catalyzed oxidative lactonization of diols: (a) Blum, Y.; Reshef,
D.; Shvo, Y. Tetrahedron Lett. 1981, 22, 1541-1544. (b) Murahashi, S.-
I.; Ito, K.; Naota, T.; Maeda, Y. Tetrahedron Lett. 1981, 22, 5327-5330.
(c) Shvo, Y.; Blum, Y.; Reshef, D.; Menzin, M. J. Organomet. Chem. 1982,
226, C21-24. (d) Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa,
S. Chem. Lett. 1982, 1179-1182. (e) Ishii, Y.; Osakada, K.; Ikariya, T.;
Saburi, M.; Yoshikawa, S. Tetrahedron Lett. 1983, 24, 2677-2680. (f) Ishii,
Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S. J. Org. Chem. 1986,
51, 2034-2039. (g) Ishii, Y.; Suzuki, K.; Ikariya, T.; Saburi, M.; Yoshikawa,
S. J. Org. Chem. 1986, 51, 2822-2824. (h) Ishii, Y.; Ikariya, T.; Saburi,
M.; Yoshikawa, S. Tetrahedron Lett. 1986, 27, 365-368. (i) Murahashi,
S.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H. J. Org. Chem. 1987, 52, 4319-
4327. (j) Bloch, R.; Brillet, C. Synlett 1991, 829-830. (k) Nozaki, K.;
Yoshida, M.; Takaya, H. J. Organomet. Chem. 1994, 473, 253-256. (l)
Isaac, I.; Aizel, G.; Stasik, I.; Wadouachi, A.; Beaupe´re, D. Synlett 1998,
475-476. (m) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. Org. Lett.
2002, 4, 2361-2363. (n) Miyata, A.; Furukawa, M.; Irie, R.; Katsuki, T.
Tetrahedron Lett. 2002, 43, 3481-3484. (o) Shimizu, H.; Onitsuka, S.;
Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2005, 127, 5396-5413. (p) Zhao,
J.; Hartwig, J. F. Organometallics 2005, 24, 2441-2446.
(3) Recent reviews: (a) Konaklieva, M. I.; Plotkin, B. J. Mini-ReV. Med.
Chem. 2005, 5, 73-95. (b) Wache´, Y.; Aguedo, M.; Nicaud, J.-M.; Belin,
J.-M. Appl. Microbiol. Biotechnol. 2003, 61, 393-404. (c) Koch, S. S. C.;
Chamberlin, A. R. Stud. Nat. Prod. Chem. 1995, 16, 687-725.
(4) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalysed Oxidation of Organic
Compounds; Academic Press: New York, 1981. (b) Sheldon, R. A.; Arends,
I. W. C. E.; Dijksman, A. Catal. Today 2000, 57, 157-166. (c) Sheldon,
R. A.; Arends, I. W. C. E.; Brink, G.-J. T.; Dijksman, A. Acc. Chem. Res.
2002, 35, 774-781.
(5) For a review, see: Arterburn, J. B. Tetrahedron 2001, 57, 9765-
9788.
10.1021/ol0706408 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/05/2007

κ2-P,N] (2a) with KO-t-Bu is its extremely high activity for
the cleavage of R-C-H bonds of sec-alcohols, which may
result from reVersible hydrogen transfer between alcohols
and carbonyls, leading to a rapid racemization of chiral
nonracemic sec-alcohols as illustrated in Scheme 1.7c
ligand to give phthalide (4a) in <1% yield. By contrast,
addition of Ph2P(CH2)2NH2 (1a) brought about the very rapid
reaction to produce 4a in >99% yield under otherwise
identical conditions.9 While Ph2P(CH2)2NH(CH3) (1b) worked
equally well (>99% yield), neither Ph2P(CH2)2N(CH3)2 (1c)
nor Ph2P(CH2)2PPh2 (1d) promoted the reaction (5% and 0%
yields, respectively). These results strongly suggest that the
amino NH group plays a crucial role in the catalysis. Notably,
the conventional Ru catalysts, RuH2(PPh3)42b and Ru3(CO)12,2c
which have been known to effect the same reaction, turned
out to be less efficient, giving 4a in 17% and 0% yield
respectively, under otherwise identical conditions. Oxidative
lactone formation from the diols normally proceeds via lactol
intermediates in equilibrium with one-step oxidized hydroxy-
aldehydes. However, no detectable amount of chemical
species except 3a, 4a, acetone, and 2-propanol was observed
by 1H NMR spectroscopy throughout the reaction of 3a using
the present Cp*Ru-based catalyst system. Accordingly, we
believe that the oxidation of 6a into 4a as well as the
cyclization of 5a into 6a should be much faster than oxidation
of 3a into 5a in the present reaction.10 The possibility of a
Tischenko-type mechanism involving the intermediacy of
dialdehyde 7a was ruled out by a separate experiment using
7a, which resulted in the complete recovery of 7a under
similar conditions. Therefore, the unique metal/NH bifunc-
tionality of the active catalyst shown in Scheme 1 should be
responsible not only for the dehydrogenation from 3a into
5a but also from 6a into 4a, which stands in sharp contrast
Scheme 1. Racemization Catalyzed by 2a and Base System
In addition, we observed a significant rate enhancement
in the catalytic intramolecular H-D scrambling of a prim-
alcohol, benzyl-R,R-d2-alclohol, compared with a sec-alcohol,
1-phenyl-1-d1-ethanol.8 These results led us to explore
oxidative transformations with high preference for primary
alcohols over secondary ones, and now we have found that
a variety of 1,4-diols with a primary hydroxyl at one end
are efficiently dehydrogenated to lactones in acetone,
which contains the catalyst system of 2a and KO-t-Bu
under mild conditions. In this paper, we describe the scope
of this oxidative lactonization using this bifunctional catalyst
system.
2c
with the conventional catalysts RuH2(PPh3)42b,f or Ru3(CO)12
that have been proposed to dehydrogenate alcohols via Ru
alkoxide intermediates.
A variety of 1,4-diols 3b-q (Figure 1) were rapidly
convertible to the γ-butyrolactones 4b-q in acetone (0.5 M)
containing 2a and KO-t-Bu as catalyst (1-3 mol %) at 30
°C within a few hours. The substituents in cis- (3b-k) and
trans-2,3-disubstitued symmetrical diols (3l,m) hardly hinder
the reaction to furnish the corresponding lactones including
hinokinin (4m), one of the biologically important lignans.
Of particular note is the excellent chemoselectivity in the
reaction of diols bearing an olefinic group (3i-k) which
remains intact despite possible saturation via intramolecular
Initial experiments focused on the acceleration effect of
several ligands (1) on the reaction of 1,2-benzenedimethanol
(3a) in acetone (Scheme 2).
Scheme 2. Ligand Effect in Oxidative Lactonization of 3a
(6) (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
(b) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66,
7931-7944. (c) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem.
2006, 4, 393-406.
(7) (a) Ito, M.; Hirakawa, M.; Murata, K.; Ikariya, T. Organometallics
2001, 20, 379-381. (b) Ito, M.; Hirakawa, M.; Osaku, A.; Ikariya, T.
Organometallics 2003, 22, 4190-4192. (c) Ito, M.; Osaku, A.; Kitahara,
S.; Hirakawa, M.; Ikariya, T. Tetrahedron Lett. 2003, 44, 7520-7523. (d)
Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005, 127, 6172-
6173. (e) Ito, M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. J. Am. Chem.
Soc. 2007, 129, 290-291.
(8) For example, 1-phenyl-1-d1-ethanol required 1 h to turn into equimolar
mixtures of PhCH(CH3)OD and PhCD(CH3)OH, whereas benzyl-R,R-d2-
alcohol took only 0.5 h to change into statistical mixtures of PhCHDOH
and PhCD2OH in a toluene solution containing 2a and KO-t-Bu (0.2 mol
%) at 30 °C.
(9) Separate experiments in varying substrate/acetone ratios under
otherwise identical conditions indicated that the TOF of this reaction
(TOF: turnover frequency, h-1) increases with higher substrate concentration
and it exceeds over 1000 TOF at 1.0 M.
The reaction of 3a was carried out in acetone containing
Cp*RuCl(cod) (COD ) 1,5-cyclooctadiene), a ligand, and
KO-t-Bu (3a/Ru/1/KO-t-Bu ) 100:1:1:1, [3a] ) 0.5 M) at
30 °C for 1 h. The reaction hardly proceeded without any
(10) Katsuki’s group reported that RuCl(NO)(salen) catalysts effect a
unique aerobic lactol formation from diols under photoirradiation, in which
the products are not further oxidized to lactones.2n,
°
1822
Org. Lett., Vol. 9, No. 9, 2007

Figure 1. Applicable 1,4-diols (3) and their products (4).
hydrogen transfer. Unsymmetrical 1,4-diols 3n-q with at
least one primary OH group were also oxidized in acetone
to give the lactones 4n-q including flavor lactones 4p and
4q very efficiently. These results indicate that secondary or
tertiary hydroxyl groups in 4n-q only participate in the
lactone formation as nonoxidized alcoholic counterparts. In
fact, the deuterium atom in 3n-d1 (96% atom D) was
completely preserved in the oxidation to give 4n-d1 (96%
atom D). This result clearly indicates that dehydrogenation
of the primary alcohol is much faster than that of the
secondary group or the lactol formation.
OH groups remain intact regardless of whether they are
primary or secondary. It should be noted that no measurable
amount of other isomeric lactones were obtained in these
reactions.
On the other hand, introduction of some tethers, suitable
for cyclization, into a 1,5- or 1,6-diol caused facile lactone
formation. The diol 3v (Figure 2) with a rigid naphthalene
In contrast to the very rapid oxidation of 1,4-diols, 1,5-
diols need a larger amount of acetone and slightly longer
reaction times. For example, the reaction of 1,5-pentanediol
in acetone at a lower concentration (0.05 M, 1 mol %, 30
°C) gave δ-valerolactone in 81% yield only after 4 h.
Moreover, 1,6-hexanediol afforded no ꢀ-caprolactone under
similar conditions, and a substantial amount of the starting
material was recovered. This significant rate difference
becomes synthetically attractive when triols2i are used as the
substrates as shown in Scheme 3.
Figure 2. Applicable 1,5- and 1,6-diols and their products.
Scheme 3. Oxidative Lactonization of Triols
backbone was very rapidly convertible at 30 °C with 1 mol
% of the catalyst into the corresponding δ-lactone 4v (>99%
yield after 1 h), and even diols 3w or 3x with biphenyl
backbone afforded the corresponding ꢀ-lactones 4w and 4x
quantitatively (93% yield after 2 h and >99% yield after 3
h, respectively).
In summary, we have demonstrated that the catalyst system
of 2a and KO-t-Bu is a highly effective catalyst for the
oxidative lactonization of a wide variety of diols in acetone,
in which acetone can be used as a reaction solvent and a
cheap hydrogen acceptor. Due to its high efficiency and
experimental simplicity, the present catalytic method can
provide a powerful and environmentally benign alternative
for Fe´tizon oxidation. Further studies on its application to
stereoselective lactone synthesis are in progress in our
laboratory.
For example, the oxidative lactonization of triols 3r-u
resulted in the exclusive formation of γ-butyrolactones 4r-u
including L-factor (4r) and muricatacin (4s) where the remote
Org. Lett., Vol. 9, No. 9, 2007
1823

Acknowledgment. Support of this research was provided
by the Ministry of Education, Culture, Sports, Science and
Technology of Japan (Nos. 16750073 and 18065017) and
by Taisho Pharmaceutical Co. Ltd. and the Asahi Glass
Foundation (M.I.).
Supporting Information Available: Experimental pro-
cedures, characterization data, and deuterium-labeling experi-
ments. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0706408
1824
Org. Lett., Vol. 9, No. 9, 2007