Highly active copper-network catalyst for the direct aldol reaction

Article abstract of DOI:10.1002/asia.201100284

The development of a highly active solid-phase catechol-copper network catalyst for direct aldol reaction is described. The catalyst was prepared from an alkyl-chain-linked bis(catechol) and a copper(II) complex. The direct aldol reaction between carbonyl

Full text of DOI:10.1002/asia.201100284

DOI: 10.1002/asia.201100284
Highly Active Copper-Network Catalyst for the Direct Aldol Reaction
Hidetoshi Ohta,[a] Yasuhiro Uozumi,*[a, b] and Yoichi M. A. Yamada*[a]
Abstract: The development of a highly active solid-phase catechol–copper network
catalyst for direct aldol reaction is described. The catalyst was prepared from an
alkyl-chain-linked bisACTHNUTRGNEU(GN catechol) and a copper(II) complex. The direct aldol reac-
Keywords: aldol reaction · copper ·
isocyanoacetates · molecular convo-
lution · solid-phase catalysts
tion between carbonyl compounds (aldehydes and ketones) and methyl isocyanoa-
cetate was carried out using 0.1–1 mol% [Cu] catalyst to give the corresponding
oxazolines at yields of up to 99% and a trans/cis ratio of >99:1. The catalyst was
reused with no loss of catalytic activity. A plausible reaction pathway is also de-
scribed.
Introduction
active insoluble polymer-supported metal catalyst that is re-
cyclable for the direct aldol reaction of aldehydes and ke-
tones.
The development of metal catalysts for the direct aldol reac-
tion of carbonyl compounds, ketone substrates in particular,
is an important pursuit in organic synthesis.[1] Such catalysts
We previously developed a highly active, reusable hetero-
geneous polymeric metal catalyst, also known as molecular
convolution, wherein a soluble linear polymer that has mul-
tiple ligand groups was convoluted with neutral metals,
anionic metals, or cationic metal salts by coordinative- or
ionic complexation.[6–8] We applied this methodology to the
development of a reusable metal–organic catalyst compris-
ing a monomeric C3-trisphosphine ligand as a hub ligand
and a palladium species as a metal connector that efficiently
mediated Suzuki–Miyaura coupling reactions.[9,10] With the
direct aldol reaction in mind, we designed a new copper-net-
À
can promote the formation of new carbon carbon bonds be-
tween the reactants to yield tertiary and quaternary carbon
stereocenters. In addition, these catalysts can be used in the
synthesis of bioactive natural compounds and pharmaceuti-
cal products that have tetrasubstituted carbon centers.[2]
Whilst there is no lack of pioneering work on direct aldol
reactions promoted by homogeneous catalysts, heterogene-
ous switching of the catalytic aldol reaction to meet sustain-
able chemical requirements remains a major challenge.
Moreover, if the low reactivity of the ketone substrates and
the retro-aldol reaction could be overcome,[3–5] and if the
catalysts could be reused through simple manipulation, the
direct aldol reaction system would be more attractive and
applicable. These ideas inspired us to develop a highly
work catalyst using a bisACTHNUGRTENUNG(catechol) framework bearing flexi-
ble alkyl-chain tethers as a hub ligand[10] through Cu O
bonding.[11] Herein, we report the preparation of a novel bis-
À
AHCTUNGTRENNUNG
(catechol)/copper-network catalyst[12] that shows the highest
activity for the direct aldol reaction between carbonyl com-
pounds (aldehydes and ketones) and methyl isocyanoace-
tate. The corresponding oxazolines were provided at yields
of up to 99% and a trans/cis ratio of >99:1.
[a] Dr. H. Ohta, Prof. Dr. Y. Uozumi, Prof. Dr. Y. M. A. Yamada
RIKEN Advanced Science Institute
2-1, Hirosawa, Wako, Saitama 351-0198 (Japan)
Fax : (+81)-48-467-9599
E-mail: ymayamada@riken.jp
Results and Discussion
[b] Prof. Dr. Y. Uozumi
Institute for Molecular Science, and the Graduate University for Ad-
vanced Studies
Myodaiji, Okazaki, Aichi 444-8787 (Japan)
Fax : (+81)564-59-5574
Catechol borate linear polymer 1 was prepared from 1,2-di-
methoxybenzene and dodecanedioyl dichloride in four
steps,[13] and isolated as a white powder that was soluble in
dimethyl sulfoxide (DMSO), N,N-dimethyl formamide
(DMF), methanol, acetonitrile, 1,2-dimethoxyethane, tetra-
hydrofuran, and acetone. The 11B{1H} NMR spectrum of 1 in
E-mail: uo@ims.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100284.
Chem. Asian J. 2011, 6, 2545 – 2549
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FULL PAPERS
[D6]dimethyl sulfoxide showed a broad singlet peak at
14.7 ppm, which was assigned to catechol borate.[14] The
[Cu]-network catalyst 3 was readily formed when a mixture
of 1 and [Cu] species 2 was heated in 1,2-dimethoxyethane/
water at 508C for 24 hours, during which time complete hy-
drolytic transmetalation of boron to copper took place. The
obtained reddish-brown precipitate was hardly soluble in
water, dimethyl sulfoxide, N,N-dimethylformamide, metha-
nol, acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, di-
ethyl ether, chloroform, dichloromethane, toluene, and ace-
tone. The insoluble complex 3 was characterized by XPS,
ICP-AES, and elementary analysis. The XPS spectrum of 3
showed four characteristic peaks for C, O, N, and Cu atoms.
No B 1s binding-energy peak was detected, but broad
copper 2p3/2 binding-energy peaks were observed (Table 1;
also see the Supporting Information, Figure S1). The broad
Figure 1. ATR-IR spectra a) of 3, b) catechol borate polymer 1, and
c) [Cu(bpy)(OAc)2] 2.
N
ACHTUNGTRENNUNG
Table 1. Binding energies of 3, 1, 1·Et3N, and [Cu] references obtained
from XPS spectra in the B 1s and Cu 2p regions.[a]
Sample
B 1s [eV]
[Cu] 2p3/2 [eV]
3
–
935.9, 933.9 (ratio; 3.6:1)
1
193.0
–
1·Et3N
CuO
Cu2O
CuCl2
CuCl
192.4
–
–
–
–
–
934.8
931.8
936.4
933.0
[a] The binding energies were referred to 285.0 eV of the C 1s peak.
Scheme 1. Preparation of copper-network catalyst 3. DME=1,2-dime-
thoxyethane.
peaks at 935.9 and 933.9 eV (ratio 3.6:1) can be assigned to
an electron-poor copper(II) major species and an electron-
rich copper(II) minor species. ICP-AES analysis of 3 re-
vealed loading ratios of 9.60 and <0.1 wt% for Cu and B,
respectively. In the ATR-IR spectra of 1–3, peaks corre-
sponding to the OAc group in the copper salt disappeared,
whilst the catechol peaks became broadened and delocalized
(Figure 1). These results suggested the formation of a
copper-catecholate from the hydrolytic transmetalation of
boron to copper.[15] Although the structure of 3 has not yet
been confirmed, these results, as well as the insolubility of
this compound in various solvents, suggest that it is a cross-
linked supramolecular network complex (Scheme 1).[9,12a,16]
With 3 in hand, we conducted the direct aldol reaction be-
tween various carbonyl compounds (aldehydes and ketones)
and methyl isocyanoacetate (5) to afford their correspond-
ing oxazoline compounds. The direct aldol reaction between
carbonyl compounds and isocyanoacetates is one of the
most-useful methods for preparing b-hydroxy-a-amino-acid
derivatives.[17] Since the first report on the catalytic reaction
of aldehydes with isocyanoacetates[18] and its asymmetric
version,[19] several catalyst systems have been developed by
one of the authors of the present study (Y.U.) and by
others.[20–22] However, there are very few reports on the cata-
lytic direct aldol reaction of ketones with isocyanoacetates,
even under homogeneous conditions.[16,23] In these reactions,
high temperatures (808C) or the use of large amounts of the
catalyst (10 mol%) in the presence of an additional base is
inevitable. Moreover, as far as we know, there is no report
on the direct aldol reaction of ketone substrates under het-
erogeneous conditions.[24]
The reaction of 4a with 5 proceeded readily in the pres-
ence of 1 mol% [Cu] 3 in tetrahydrofuran at 258C, even
without the use of an additional base, and trans,cis-4-me-
thoxycarbonyl-5-phenyl-2-oxazoline 6a was obtained in a
yield of 99% (trans/cis, 88:12) within 1 hour (Table 2,
entry 1). After the reaction, the catalyst was recovered by
centrifugation and reused twice to give 6a in quantitative
yield (Table 2, entries 2 and 3).[25] When using 0.1 mol%
[Cu] 3, the reaction proceeded smoothly within 6 hours to
afford 6a in quantitative yield with a TON of 1000 (Table 2,
entry 4). As far as we know, this is the highest TON ob-
tained to date for the catalytic direct aldol reaction with iso-
cyanoesters. para-/ortho-Tolylaldehydes 4b and 4c, as well
as the sterically hindered 2,4,6-trimethylbenzaldehyde 4d,
were converted into the corresponding oxazoline com-
Abstract in Japanese:
2546
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2545 – 2549

Copper-Network Catalyst for the Direct Aldol Reaction
Table 2. Direct aldol reaction between carbonyls (aldehydes and ke-
tones) and methyl isocyanoacetate.[a]
at a yield of 99% (trans/cis ratio:>99:1); no self-aldol prod-
ucts of the aldehyde were detected in these reactions
(Table 2, entries 11–14).
Encouraged by these results with aldehyde substrates, we
then attempted the direct aldol reaction of ketones. The re-
action of acetophenone 4l with 5 in the presence of 1 mol%
[Cu] 3 at 258C proceeded smoothly within 6 hours to give
oxazoline 6l in a yield of 97% (Table 2, entry 15); the reac-
tion conditions were similar to those for the direct aldol re-
action of aldehydes. Even less-reactive aliphatic and alicyclic
ketones 4m and 4n were readily converted into their corre-
sponding oxazolines 6m and 6n, respectively (99% yield);
self-aldol products of ketones were not formed (Table 2, en-
tries 16–17).
Entry
1
Substrate
t
6
Yield
[%][b]
Trans/cis ratio of
[h]
6[c]
4a
1
6a
99
88:12
2
2nd use of 3
3rd use of 3
4a (0.1 mol% 3)
1
1
6
6a
6a
6a
99
99
99
87:13
82:18
76:24
3
4[d]
Although the reaction pathway has not been confirmed, a
plausible model is shown in Scheme 2, which is based on
Togni and Pastorꢁs gold-catalyzed aldol-reaction pathway.[26]
Thus, copper(II) catalyst 3 reacts with methyl isocyanoace-
tate (5) to give A, where copper acts as a Lewis acid and
catecholate as a Brønsted base.[1c] The reaction of A with
substrate 4 gives two possible transition states, B1 and B2.
Because B1 is more-stable than B2 owing to the larger
steric repulsion in B2, trans-6 is formed as a major product,
and the copper(II) catalyst is regenerated. Therefore, the re-
action of bulky aldehydes 4j–k (R=c-Hex, tBu) should give
6j–k with exclusive trans diastereoselectivity (trans/cis
ratio:>99:1).
5
6
4b
4c
1
1
6b
6c
99
94
87:13
85:15
7
8
4d
4e
1
1
6d
6e
98
97
93:7
88:12
9
4 f
4g
1
1
6 f
6g
99
95
80:20
81:19
Conclusions
10
11
12
4h
4i
1
1
6h
6i
99
99
89:11
87:13
A copper-network catalyst was designed and synthesized.
This catalyst promoted the direct aldol reaction of aldehydes
and ketone substrates with methyl isocyanoacetate under
heterogeneous conditions to afford the corresponding oxa-
zolines in yields of up to 99% and a trans/cis ratio of >99:1.
13
14
4j
1
1
6j
99
99
>99:1
>99:1
4k
6k
15
4l
6
6l
97
56:44
16
17
4m
4n
6
1
6m
6n
99
99
68:32
--
[a] All reactions were carried out using 4 (0.5 mmol), 5 (0.5 mmol), and 3
(1 mol% Cu) in THF (2 mL) at 258C under an Ar atmosphere. [b] Yield
of isolated product. [c] Determined by 1H NMR spectroscopy.
[d] 0.1 mol% [Cu] 3 was used.
pounds 6b–d in yields of 94–99% (Table 2, entries 5–7). The
reaction of electron-rich/poor benzaldehydes 4e–f and the
heteroaryl substrate 4-pyridylaldehyde 4g gave the corre-
sponding oxazolines 6e–g in yields of 95–99% (Table 2, en-
tries 8–10). Primary, secondary, and tertiary aliphatic alde-
hydes 4h–k were also suitable substrates for the direct aldol
reaction and afforded their corresponding oxazolines 6h–k
Scheme 2. Plausible reaction pathway.
Chem. Asian J. 2011, 6, 2545 – 2549
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2547

Y. Uozumi, Y. M. A. Yamada et al.
FULL PAPERS
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Experimental Section
Preparation of Network Copper Catalyst 3
An aqueous solution of 2 (0.025m, 2 mL, 0.05 mmol) was added to a solu-
tion of a 1·DMF adduct (0.10 mmol [B], 47 mg) in dry DME (2 mL) at
508C under Ar. The resulting suspension was stirred at 508C for 24 h
under Ar. After centrifugation, the solvent was removed via syringe.
Then, the residue was washed with dry DME, MeOH, and THF (3ꢂ
4 mL each) and dried under reduced pressure to give 3 as a reddish-
brown solid (25 mg, 75% yield based on Cu loading, 1.47 mmol Cu/g):
Anal. Calcd. For C342H410Cu10N18O42: C 67.55, H 6.80, N 4.15, Cu 10.45.
Found: C 67.48, H 6.73, N 4.63, Cu 9.60.
General Procedure for the Direct Aldol Reaction of Aldehydes and
Ketones with Methyl Isocyanoacetate
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hydes or ketones 4 (0.5 mmol) and 3 (0.1–1 mol% [Cu]) in dry THF
(2 mL) at 258C under an Ar atmosphere. After the reaction was complet-
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the combined organic layer was concentrated. The crude product was dis-
solved in CHCl3/NEt3 (99:1) and passed through a short column of silica
gel to give the oxazoline products 6.
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Acknowledgements
We acknowledge the financial support extended by the JSPS (Grant-in-
Aid for Scientific Research, No. 20655035), MEXT (Science Research on
Priority Areas, No. 460), JST (CREST Project), and METI/NEDO
(Green-Sustainable Chemical Process project). We also thank the
RIKEN Advanced Science Institute Advanced Technology Support Divi-
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Chem. Asian J. 2011, 6, 2545 – 2549

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Received: March 18, 2011
Published online: July 12, 2011
ˇ
Bellus, Helv. Chim. Acta 1981, 64, 2279. Also see Ref. [18b] and
[18c].
Chem. Asian J. 2011, 6, 2545 – 2549
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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