Iridium-catalyzed reaction of enones with alcohols affording 1,3-diketones

Article abstract of DOI:10.1039/c2cc32787b

An iridium-catalyzed coupling reaction of alcohols with enones has been successfully developed providing access to 1,3-diketones with high selectivity in good yields. This reaction provides an atom-economical route to 1,3-diketones from readily available

Full text of DOI:10.1039/c2cc32787b

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COMMUNICATION
Iridium-catalyzed reaction of enones with alcohols affording
1,3-diketonesw
Yasushi Obora,* Kazuhiro Nakamura and Shintaro Hatanaka
Received 19th April 2012, Accepted 11th May 2012
DOI: 10.1039/c2cc32787b
An iridium-catalyzed coupling reaction of alcohols with enones
has been successfully developed providing access to 1,3-diketones
with high selectivity in good yields. This reaction provides an
atom-economical route to 1,3-diketones from readily available
alcohols.
atom-economical organic synthetic method using easily acces-
sible starting materials.
1,3-Diketones are an important class of compounds in organic
synthesis and are widely employed as building blocks for the
synthesis of a variety of heterocyclic compounds.1 Classically,
1,3-diketones are prepared by the oxidation of aldol-type
compounds, which are prepared from the reaction of the
corresponding enolates with aldehydes2 or by the acylation
of acid chlorides/esters with ketone enolates.3
ð1Þ
The reaction of cyclohexenone (1a) and benzyl alcohol (2a)
was employed as a model reaction and carried out under a
variety of reaction conditions (Table 1). In one example, 1a
Table 1 Ir-catalyzed reaction of cyclohexenone (1a) with benzyl
alcohol (2a)a
In contrast, Rh-catalyzed reductive aldol coupling reactions
involving the hydrogenation of enones/enals to give b-hydroxy-
ketones have attracted a great deal of interest and have been
studied in great detail by Krische and coworkers.4
Furthermore, Ryu and coworkers have reported the
Ru-catalyzed reaction of enals with alcohols leading to the
formation of b-hydroxyketones as products.5 In a recent
publication, the same group reported the synthesis of
1,3-diketones by the Ru-catalyzed reaction of enals with
aldehydes.6
Yieldb/%
3a
Entry Ir-catalyst
Ligand (mol%) Base (mol%)
1
2
3
4
5
6
7
8
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(coe)2]2
[Ir(OH)(cod)]2
P(n-Oct)3 (20)
None
P(n-Bu)3 (20)
PPh3 (20)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
None
82 (70)
n.d.c
78
It is well known that Ir and Ru complexes serve as efficient
catalysts for hydrogen-transfer (also named as borrowing
hydrogen) from alcohols to aldehydes.7 To date, intense
research efforts have been focused on both a-alkylation8 and
b-alkylation9 reactions using alcohols as alkylating agents.
The hydrogen-transfer methodology is also utilized in coupling
reactions of alcohols and 2-alkynes to give homoallylic alcohols
and a,b-enones by our group.10 During the course of our
own investigations into Ir-catalyzed transfer hydrogenation
reactions using alcohols, we discovered an unprecedented
route to 1,3-diketones by the reaction of enones (1) with
alcohols (2) in the presence of an iridium complex catalyst
(eqn (1)). This catalytic coupling process represents a highly
73
P(OPh)3 (20)
P(n-Oct)3 (10)
P(n-Oct)3 (30)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
P(n-Oct)3 (20)
Trace
Trace
70
71
9
NaHCO3 (40) 67
10
11
12d
13e
14f
15
16
17
18
Na2SO3 (20)
t-BuOK (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
Na2SO3 (40)
72
n.d.c
12
21
46
39
7 (trace)g
Trace
n.d.c
[Ir(OMe)(cod)]2 P(n-Oct)3 (20)
[Cp*IrCl2]2 P(n-Oct)3 (20)
a
Conditions: a mixture of 1a (5 mmol) and 2a (1 mmol) was reacted in
the presence of an Ir-catalyst (0.2 mmol, 5 mol% based on 2a), ligand
(10–30 mol%), base (20–40 mol%), i-PrOH (3 mmol) and p-xylene
Department of Chemistry and Materials Engineering,
Faculty of Chemistry, Materials and Bioengineering, Kansai
University, Suita, Osaka 564-8680, Japan.
E-mail: obora@kansai-u.ac.jp; Fax: +81-6-6339-4026;
Tel: +81-6-6368-0876
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data (1H NMR, 13C
NMR). See DOI: 10.1039/c2cc32787b
b
(1 mL) at 120 1C for 15 h. Yields were determined by GC based on
the amount of 2a used. The numbers in parentheses refer to isolated
c
yields. Not detected by GC. 1a (1 mmol) was used. 1a (2 mmol)
d
e
f
was used. The reaction was performed without i-PrOH. The reaction
g
was performed in the absence of base.
c
6720 Chem. Commun., 2012, 48, 6720–6722
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(5 mmol) was reacted with 2a (1 mmol) in the presence of a
combination of [IrCl(cod)]2 (0.05 mmol, 5 mol% based on 1a),
tri(n-octyl)phosphine (0.20 mmol) and isopropanol (3 mmol)
in p-xylene (1 mL) at 120 1C for 15 h, providing 2-benzoyl
cyclohexanone (3a) in 82% yield (entry 1). The addition of a
phosphine ligand was found to be critical for the success of
the reaction. Thus, in the absence of a phosphine ligand
(entry 2), no 3a was observed. With regard to the phosphine
ligand, trialkylphosphines such as tri(n-octyl)phosphine and
tri(n-butyl)phosphine were found to be the most suitable
ligands (entries 1 and 3). Triphenyl phosphine showed
comparable activity, whereas the use of triphenyl phosphite
revealed low catalytic activity (entries 4 and 5, respectively).
The optimized Ir : P ratio was determined to be 2. Smaller or
larger amounts of tri(n-octyl)phosphine (10 mol%, Ir : P = 1 : 1
or 30 mol%, Ir : P = 1 : 3, respectively) resulted in lower yields of
3a (entry 1 vs. entries 6 and 7). The reaction was found to
proceed in substantial yield in the absence of a base (71%,
entry 8). However, the addition of Na2SO3 (40 mol%, based
on the amount of 2a) increased the yield of 3a to 82% (entry 1).
The use of a weak base (NaHCO3) or a smaller amount of
Na2SO3 (20 mol%) did not reveal any additive effect (entries 9
and 10). In contrast, the use of a strong base, such as t-BuOK,
completely deteriorated the catalytic activity and subsequent
yield of 3a (entry 11).
Table 2 Ir-catalyzed reactions of enones (1) with alcohols (2)a
Entry Enone (1)
Alcohol (2)
Product (3)/yieldb (%)
1
2
3
4
1a
1a
1a
1a
R = H (2a)
R = CH3 (2b)
70 (3a)
77 (3b)
R = OCH3 (2c) 72 (3c)
R = Cl (2d)
80 (3d)
5
6
7
8
1a
2a
2a
2a
The reaction of an excess of 1a (5 equiv.) with 2a led to
higher yield of 3a (entry 1), owing to the formation of
cyclohexanone from 1a, which serves as a hydrogen acceptor
in this reaction. Thus, the reaction of equimolar amounts of 1a
and 2a under these conditions resulted in a decrease in the
yield of 3a (12%, entry 12). The addition of isopropanol
(3 equiv.) to the reaction system effectively enhanced the reaction
yield (entry 1 vs. entry 14). This result reveals that isopropanol
serves as an external hydrogen atom donor for the iridium
complex, assisting in the efficient formation of an iridium-hydride
which is a key intermediate in this reaction (vide infra, eqn (2)).
Furthermore, the reaction of 1a with benzaldehyde did not lead
to the formation of any 1,3-diketone (3a) under these conditions.
With regard to the iridium complex, [IrCl(cod)]2 showed the
best results and other selected iridium complexes, such as
[IrCl(coe)2]2, [Ir(OH)(cod)]2, [Ir(OMe)(cod)]2 and [Cp*IrCl2]2
which are known to function as efficient transfer hydrogenation
catalysts, showed limited or no catalytic activities (entries 15–18).
The reaction at 100 1C under these conditions gave 3a in 45% yield.
Needless to say, no 3a was formed in the absence of an Ir complex.
The use of a [RhCl(cod)]2 complex in place of [IrCl(cod)]2 under the
conditions of entry 1, Table 1, did not afford 3a at all.
9
2a
10
2a
2a
11
a
Conditions: 1 (5 mmol) was allowed to react with 2a (1 mmol) in the
presence of [IrCl(cod)]2 (0.05 mmol) combined with P(n-Oct)3
(0.2 mmol), Na2SO3 (0.4 mmol) and i-PrOH (3 mmol) in p-xylene
In the present reaction, various solvents were tolerated.
According to the reaction conditions given in Table 1, the
conditions associated with entry 1 in particular produced 3a in
a variety of yields depending upon the solvent used. Thus,
toluene, 1,4-dioxane, mesitylene, DMF and DMSO gave
yields of 74%, 72%, 56%, 44% and 40%, respectively.
The reactions of various enones (1) and alcohols (2a) were
carried out under the optimized reaction conditions. The
results are listed in Table 2. Various benzyl alcohol derivatives
(2a–2d) and 2-thiophenemethanol (2e) were reacted with 1a to
give the corresponding 1,3-ketones (3a–3e) in good yields
(entries 1–5). With regard to the enones, cyclopentenone (1b)
b
(1 mL) at 120 1C for 15 h. Isolated yields.
and cycloheptenone (1c) were well tolerated under the reaction
conditions (entries 6 and 7). In addition to cyclic enones, a
variety of acyclic enones were also employed in the reaction,
affording the corresponding products (entries 8–11).
Unfortunately, the use of aliphatic alcohols proved to be
sluggish, providing the desired 1,3-diketones in less than 10%
yield under the optimized conditions. The reaction with cinnamyl
alcohol led to an intractable mixture under these conditions.
c
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Strategic Project to Support the Formation of Research Bases
at Private Universities (2010–2014), matching fund subsidy
from the Ministry of Education, Culture, Sports, Science and
Technology.
Notes and references
1 (a) M. A. P. Martins, S. Brondani, V. L. Leidens, D. C. Flores,
S. Moura, N. Zanatta, M. Horner and A. F. C. Flores, Can. J. Chem.,
2005, 83, 1171; (b) C. P. Felix, N. Khatimi and A. J. Laurant, J. Org.
Chem., 1995, 60, 3907; (c) A. L. Baumstark, A. Choudhary,
P. C. Vasquez and M. Dotrong, J. Heterocycl. Chem., 1990, 27, 291.
2 For the recent work on the synthesis of 1,3-diketones, see:
(a) S. Kamijo and G. B. Dudley, Org. Lett., 2006, 8, 175;
(b) V. Fargeas, M. M. Baalouch, E. Metay, J. Baffreau, D. Menard,
P. Gosselin, J.-P. Berge, C. Barthomeuf and J. Lebreton, Tetrahedron,
2004, 60, 10359.
3 For example, (a) Y. Nishimura, Y. Miyake, R. Amemiya and
M. Yamaguchi, Org. Lett., 2006, 8, 5077; (b) D. Lim, F. Fang,
G. Zhou and D. M. Coltart, Org. Lett., 2007, 9, 4139; (c) K. Sato,
S. Yamazoe, R. Yamamoto, S. Ohata, A. Tarui, M. Omote,
I. Kumadaki and A. Ando, Org. Lett., 2008, 10, 2405.
4 (a) M.-Y. Ngai, J.-R. Kong and M. J. Krische, J. Org. Chem.,
2007, 72, 1063; (b) C.-K. Jung, S. A. Garner and M. J. Krische,
Org. Lett., 2006, 8, 519; (c) C. Bee, S. B. Han, A. Hassan, H. Iida
and M. J. Krische, J. Am. Chem. Soc., 2008, 130, 2746;
(d) G. A. Marriner, S. A. Garner, H.-Y. Jang and M. J. Krische,
J. Org. Chem., 2004, 69, 1380; (e) P. K. Koech and M. J. Krische, Org.
Lett., 2004, 6, 691; (f) R. R. Huddleston, D. F. Cauble and M. J.
Krische, J. Org. Chem., 2003, 68, 11; (g) H.-Y. Jang, R. R. Huddleston
and M. J. Krische, J. Am. Chem. Soc., 2002, 124, 15156.
Fig. 1 A possible reaction pathway for the Ir-catalyzed formation of
1,3-diketones.
To further investigate the reaction mechanism, a deuterium
labeling experiment was carried out. Thus, 1a and benzalde-
hyde were reacted in the presence of isopropanol-d8 under the
conditions of entry 1 as documented in Table 1 (eqn (2)).
Consequently, deuterium incorporation was observed at the
b-alkenyl position of the product. The deuterium incorporation
ratio at the b-alkenyl position was estimated to be 50% based
5 Reaction of enones with aldehydes to obtain 1,3-diketones,
T. Fukuyama, T. Doi, S. Minamino, S. Omura and I. Ryu, Angew.
Chem., Int. Ed., 2007, 46, 5559.
1
on H-NMR measurement.
This result strongly suggested that isopropanol serves as an
effective hydrogen atom source for the formation of iridium-
hydride.7
6 Reaction of enals with alcohols to obtain 2-hydroxymethyl ketones,
A. Denichoux, T. Fukuyama, T. Doi, J. Horiguchi and I. Ryu,
Org. Lett., 2010, 12, 1.
7 For example, (a) S. Ourida and J. M. J. Williams, Top. Organomet.
Chem., 2011, 34, 77; (b) J. Zhang, G. Leitus, Y. Ben-David and
D. Milstein, J. Am. Chem. Soc., 2005, 127, 10840; (c) Y. Obora
and Y. Ishii, Synlett, 2011, 30; (d) F. Hanasaka, K. Fujita and
R. Yamaguchi, Organometallics, 2004, 23, 1490; (e) G. Guillena,
D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2007, 46, 2358;
(f) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv.
Synth. Catal., 2007, 349, 1555; (g) T. D. Nixon, M. K. Whittlesey
and J. M. J. Williams, Dalton Trans., 2009, 753; (h) J. F. Bower,
I. S. Kim, R. L. Patman and M. J. Krische, Angew. Chem., Int. Ed.,
2009, 48, 34; (i) G. Guillena, D. J. Ramon and M. Yus, Chem.
Rev., 2010, 110, 1611; (j) G. E. Debereiner and R. H. Crabtree,
Chem. Rev., 2010, 110, 681.
ð2Þ
Based on these experimental results, the following reaction
pathway was proposed as depicted in Fig. 1. The reaction is
initiated by the formation of an iridium hydride (A) and an
aldehyde (B) via hydrogen transfer from the alcohol to the iridium
catalyst. Then enone (1) was inserted by an Ir–H bond of A to
form the hydridooxa(p-allyl)iridium (C) as a key intermediate.5
Subsequently, C reacts with aldehyde (B) to afford 1,3-diketones.
In conclusion, we have successfully developed an atom-
economical synthesis for 1,3-diketones by the reaction of enones
with alcohols in the presence of an Ir-catalyst. Further experi-
mental investigations aimed at expanding the scope of this
reaction are currently underway.
8 For example, (a) K. Taniguchi, H. Nakagawa, T. Hirabayashi,
S. Sakaguchi and Y. Ishii, J. Am. Chem. Soc., 2004, 126, 72;
(b) K. Maeda, Y. Obora, S. Sakaguchi and Y. Ishii, Bull. Chem.
Soc. Jpn., 2008, 81, 689; (c) Y. Iuchi, Y. Obora and Y. Ishii, J. Am.
Chem. Soc., 2010, 132, 2536; (d) C. S. Cho, B. T. Kim, T.-J. Kim
and S. C. Shim, J. Org. Chem., 2001, 66, 9020.
9 For example, (a) Y. Obora, Y. Anno, R. Okamoto, T. Matsu-ura
and Y. Ishii, Angew. Chem., Int. Ed., 2011, 50, 8618; (b) E. F. Pratt
and D. G. Kubler, J. Am. Chem. Soc., 1954, 76, 52; (c) A. S. Ndou,
N. Plint and N. J. Coville, Appl. Catal., A, 2003, 251, 337;
(d) C. S. Cho, B. T. Kim, H.-S. Kim, T.-J. Kim and S. C. Shim,
Organometallics, 2003, 22, 3608; (e) R. Martınez, D. J. Ramon and
´ ´
M. Yus, Tetrahedron, 2006, 62, 8982; (f) T. Matsu-ura,
S. Sakaguchi, Y. Obora and Y. Ishii, J. Org. Chem., 2006,
71, 8306; (g) K. Koda, T. Matsu-ura, Y. Obora and Y. Ishii,
Chem. Lett., 2009, 838; (h) K. Fujita, C. Asai, T. Yamaguchi,
F. Hanasaka and R. Yamaguchi, Org. Lett., 2005, 7, 4017.
10 (a) Y. Obora, S. Hatanaka and Y. Ishii, Org. Lett., 2009, 11, 3510;
(b) S. Hatanaka, Y. Obora and Y. Ishii, Chem.–Eur. J., 2010,
16, 1883.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, the Kansai University Research Grants:
Grant-in-Aid for Encouragement of Scientists, 2011, and the
c
6722 Chem. Commun., 2012, 48, 6720–6722
This journal is The Royal Society of Chemistry 2012