Heterobimetallic lanthanide/sodium phenoxides: Efficient catalysts for amidation of aldehydes with amines

Article abstract of DOI:10.1021/jo802617d

Heterobimetallic lanthanide/sodium phenoxides were found to be efficient catalysts for amidation of aldehydes with amines under mild conditions. The reactivity follows the order Nd < Y < Sm for metals and 2,6-(Me) ₂C₆H₃O < 2,6-(ⁱPr) ₂C₆H₃O < 2,6-(Bu)₂C ₆H₃O for phenoxide groups. In comparison with the corresponding monometallic complexes, heterobimetallic complexes show higher activity and a wider range of scope of amines. A cooperation of lanthanide and sodium in this process is proposed to contribute to the high activity of the present catalyst.

Full text of DOI:10.1021/jo802617d

Very recently, homoleptic lanthanide amides Ln[N(SiMe3)2]3
have been reported to be efficient catalysts for amidation of
aldehydes with amines under mild conditions without the use
of peroxide and base.8 But this kind of catalyst is not suitable
for the amidation of aldehydes with secondary cyclic amines.8
Thus, the search of a new class of lanthanide catalysts with a
wider scope of substrates is certanly required in the synthesis
of amides.
Homoleptic lanthanide phenoxides, a class of robust catalysts,
have been extensively used in organic systheses9 as well as ring-
opening polymerization of lactones.10 Heterobimetallic lan-
thanide phenoxides have recently been found to be more active
catalysts for ring-opening polymerization of ε-caprolactone and
copolymerization of ε-caprolactone and cyclocarbonate than the
corresponding monometallic ones.11 Heterobimetallic lantha-
num/lithium phenoxide/pybox has been reported to be an
efficient catalyst for the direct asymmetric Mannich-type
reactions of R-keto anilides reaction.12 These results encouraged
us to test the activity of heterobimetallic lanthanide phenoxides
for amidation of aldehydes with amines. It was found that
heterobimetallic lanthanide phenoxides can serve as efficient
catalysts for amides formation and the catalysts have the
advantages of wide substrate scope including secondary cyclic
amines such as pyrrolidine, piperidine, and morphorline. Here
we reporte the results.
Heterobimetallic yttrium/sodium complexes with various
phenoxides [Y(OAr)4][Na(DME)3] were synthesized by the
metathesis reaction of lanthanide trichloride with sodium salt,
respectively. [Ln(OAr)4][Na(DME)3] (Ln ) Nd and Sm)11 and
the corresponding monometallic complexes13 were also syn-
thesized according to the literature method. The molecular
structure of complex III was determined by X-ray crystal
structure analysis to be the ion pair complex composed of an
anion [Y(OAr)4]- and a cation [Na(DME)3]+, which was
isostructural to those for the analogues of Nd and Sm.11 But
the exact bond angles and bond lengths cannot be calculated
because of the poor data. All the complexes used here are listed
in Scheme 1.
Heterobimetallic Lanthanide/Sodium Phenoxides:
Efficient Catalysts for Amidation of Aldehydes
with Amines
Junmei Li,† Fan Xu,† Yong Zhang,† and Qi Shen*,†,‡
Key Laboratory of Organic Synthesis of Jiangsu ProVince,
Department of Chemistry and Chemical Engineering, Dushu
Lake Campus, Suzhou UniVersity, Suzhou 215123, People’s
Republic of China, and State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
qshen@suda.edu.cn
ReceiVed NoVember 26, 2008
Heterobimetallic lanthanide/sodium phenoxides were found
to be efficient catalysts for amidation of aldehydes with
amines under mild conditions. The reactivity follows the
order Nd < Y < Sm for metals and 2,6-(Me)2C6H3O < 2,6-
(iPr)2C6H3O < 2,6-(tBu)2C6H3O for phenoxide groups. In
comparison with the corresponding monometallic complexes,
heterobimetallic complexes show higher activity and a wider
range of scope of amines. A cooperation of lanthanide and
sodium in this process is proposed to contribute to the high
activity of the present catalyst.
The formation of a C-N bond is one of the most important
reactions in organic syntheses, in which amide bond formation
is a particularly interesting topic, as the amide group is an
essential motif in biological systems as well as in important
molecules in the areas of polymers, natural products, and
pharmaceuticals.1 The direct amidation of aldehydes with amines
is the most desired approach to amides as economical and
available starting materials. Various efficient catalysts have been
explored for this process,2-7 and some of these systems need
to use peroxide,2 heating, or equivalent alkali metal amides.4
With the complexes in hand, the reaction of benzaldehyde
1a with pyrrolidine 2d by using various complexes was first
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Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429–3432.
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(9) (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187–2209.
(b) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem. ReV. 2002,
102, 2227–2302.
(10) (a) Yasuda, H.; Aludin, M. S.; Kitamura, N.; Tanabe, M.; Sirahama, H.
Macromolecules 1999, 32, 6047. (b) Ling, J.; Shen, Z. Q.; Huang, Q. H.
Macromolecules 2001, 34, 7613. (c) Yu, C. P.; Zhang, L. F.; Shen, Z. Q. J.
Mol. Catal. A 2004, 212, 365. (d) Ling, J.; Shen, Z. Q. Macromol. Chem. Phys.
2002, 203, 735. (e) Stevels, W. M.; Ankone, M. J. K.; Dijkstra, P. J.; Feijen, J.
Macromolecules 1996, 29, 3332. (f) Martin, E.; Dubois, P.; Robert, J.
Macromolecules 2000, 33, 1530. (g) Ling, J.; Chen, W.; Shen, Z. Q. J. Polym.
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† Suzhou University.
‡ Chinese Academy of Sciences.
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Trans. 1 1976, 1511–1514. (b) Marko, I. E.; Mekhalfia, A. Tetrahedron Lett.
1990, 31, 7237–7240.
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(4) Zhang, L.; Wang, S.; Zhou, S.; Yang, G.; Sheng, E. J. Org. Chem. 2006,
71, 3149–3153.
(5) (a) Nakagawa, K.; Onoue, H.; Minami, K. Chem. Commun. 1966, 17–
18. (b) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983, 474–476. (c) Naota,
T.; Murahashi, S. Synlett 1991, 693–694. (d) Tillack, A.; Rudloff, I.; Beller, M.
Eur. J. Org. Chem. 2001, 523–528. (e) Yoo, W.; Li, C. J. Am. Chem. Soc. 2006,
128, 13064–13065. (f) Reddy, K. R.; Maheswari, C. U.; Venkateshwar, M.;
Kantam, M. L. Eur. J. Org. Chem. 2008, 3619–3622. (g) Chang, J. W. W.;
Chan, P. W. H. Angew. Chem., Int. Ed. 2008, 47, 1138–1140.
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10.1021/jo802617d CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2575–2577 2575

TABLE 2. Optimization Amidation of 1a with 2d Catalyzed by
Complex IIa
SCHEME 1
molar ratio
(1a:2d)
mol % of
catalystb
time
(h)
yield
(%)c
entry
catalyst
1
2
3
4
1:1
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
II
II
II
II
II
II
II
II
II
3
3
3
3
2
3
3
3
3
3
3
3
2
3
3
3
3
3
43
72
96
83
84
80
88
90
70
TABLE 1. Amidation of 1a with 2d Catalyzed by Various
Complexesa
5
6d
7e
8f
9g
a Amine was first added to the catalyst solution, after 30 min,
aldehyde was added, the solvent was THF. b On the basis of lanthanide
metal. c Isolated yield based on pyrrolidine. d Aldehyde was first added
to the catalyst solution, after 30 min, then amine was added. e Amine
was first added to the catalyst solution, then aldehyde was added. f The
solvent was toluene. g Solvent free.
molar ratio
(1a:2d)
mol % of
catalystb
time
(h)
yield
(%)c
entry
catalyst
1
2
3
4
5
6
7
8
9
10
11
12d
13e
14f
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
I
II
III
IV
V
VI
VII
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
83
96
93
53
24
30
32
27
10
around the metal with four bulky phenoxide groups. Optimiza-
tion experiments were then conducted with II. The results
indicate that an excess of aldehyde (3 equiv) is required for
obtaining a product in high yield (Table 2, entries 1-3), as
aldehyde acts as not only a reactant but also an oxidant. Besides,
a side reaction possibly occurred in this process, namely the
Tishchenko reaction, also needed to consume aldehyde. High
yield can be obtained with the feeding sequence of adding
aldehyde into the mixture of amine and catalyst in comparison
with the feeding sequence of adding amine into the mixture of
aldehyde and catalyst (Table 2, entries 3 and 6) because the
Tishchenko reaction is a competitive reaction against the
amidation. A decrease of catalyst loading resulted in a decrease
in yields (Table 2, entry 5). THF is a better solvent than toluene
(Table 2, entries 3 and 8). The reaction proceeded in solvent
free condition affording 3ad in the lowest yield (Table 2, entry
9) compared to the reaction in THF and toluene.
VIII
IX
X
3
3
3
NaOAr
20
70
98
38
VII + NaOAr
VII + NaOAr
La[N(SiMe3)2]3
3 + 3
3 + 3
5
24
a Amine was first added to the catalyst solution, after 30 min,
aldehyde was added, the solvent was THF. b On the basis of lanthanide
metal. c Isolated yield based on pyrrolidine. d Amine was first added to
the catalyst solution, after 30 min, aldehyde was added. e The catalyst
solution was mixed 12 h, then amine was first added, after 30 min,
aldehyde was added. f Reference 8.
examined at 25 °C with 3 mol % catalyst loading. We are
pleased to find that all the heterobimetallic complexes except
V can serve as catalysts for this transformation yielding the
amide 3ad in good to excellent yields (Table 1 entries 1-5).
The yields are much higher than that obtained by homoleptic
lanthanide amides (Table 1, entry 14). In contrast, the mono-
metallic complexes showed much lower activity (Table 1, entries
6-10). The sodium phenoxide complex NaOAr (Ar ) 2,6-di-
tert-butylphenoxide) was not efficient under the same conditions
providing 3ad in only 20% yield (Table 1, entry 11). A mixted
system of NaOAr and VII afforded 3ad in 70% yield. When
the mixture of NaOAr and VII was stirred for 12 h at room
temperature, then the amine was added and at last the aldehyde
was introduced; the product 3ad was prepared in 98% yield,
which is almost equal to the yield obtained by heterobimetallic
catalyst II (Table 1, entries 3, 12, and 13). These experiments
clearly demonstrated that the differences in activity between
heterobimetallic and monometallic complexes may be attributed
to a cooperation effect resulting from lanthanide and sodium
metal in the amidation reaction. The influence of both central
metals and the phenoxide groups on the activity is observed.
The active sequences are Nd < Y < Sm for metals and 2,6-
(Me)2C6H3O < 2,6-(iPr)2C6H3O < 2,6-(tBu)2C6H3O for phe-
noxide groups (Table 1, entries 1-10). The highest activity for
the most bulky phenoxide may be attributed to the most active
Ln-phenoxide bond caused from the crowd coordination sphere
With the optimizing conditions (Table 2, entry 3), we then
screened various aldehydes and amines to explore the generality
and scope of the reaction (Table 3).
All the reactions proceeded efficiently to afford the corre-
sponding amides in good to excellent yields after 3 h. The
aromatic aldehydes with an electron-withdrawing group at the
para-position on the ring give higher yield relative to the
aldehydes with an electron-donating group (Table 3, entries 1-4
and 9-20). The reaction with primary aromatic amine (aniline)
proceeded smoothly to give the amide in good yield, while the
same reaction with aliphatic aldehyde (cyclohexane carboxal-
dehyde) afforded the product in moderate yield (Table 3, entry
7). However, the reaction with benzylamine afforded the product
3ac in only 60% yield, which may be attributed to catalyst
deactivation by water produced via imine formation. Indeed,
the yield can be improved to 75% when the reaction proceeded
in the presence of molecular sieves 4Å (Table 3, entry 8). It
was noticed that the reactions of 2d with other aromatic
aldehydes also occurred smoothly and yielded the corresponding
amides in good to excellent yields and was completed within
3 h at 25 °C with 3 mol % of II. For example, p-chloroben-
zaldehyde (1c) and p-flourobenzaldehyde (1b) were almost
quantitatively converted to N-(p-chlorobenzoyl)pyrrolidine (3cd)
2576 J. Org. Chem. Vol. 74, No. 6, 2009

TABLE 3. Complex II Catalyzed Amidation of Aldehydes with
Aminesa
SCHEME 2. Proposed Catalytic Cycle for Amidation
entry
aldehyde
amine
amide
yield (%)b
90
94
93
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1a
1b
1c
1d
1a
1b
1e
1a
1a
1b
1c
1d
1f
1g
1h
1a
1b
1c
1d
1f
2a
2a
2a
2a
2b
2b
2b
2c
2d
2d
2d
2d
2d
2d
2d
2e
2e
2e
2e
2e
2f
3aa
3ba
3ca
3da
3ab
3bb
3eb
3ac
3ad
3bd
3cd
3dd
3fd
3gd
3hd
3ae
3be
3ce
3de
3fe
Experimental Section
General Procedure. All manipulations and reactions were
performed under a purified argon atmosphere with standard Schlenk
techniques. Solvents were degassed and distilled from sodium
benzophenone ketyl prior to use. [Ln(OAr)4][Na(DME)3] (Ln )
Nd (I), Sm (II); ArO ) 2,6-di-tert-butylphenoxide) were prepared
according to the literature.11 [Ln(OAr)3][THF]2 (Ln ) Nd (VI),
73
80
82
45
60 (75,c 83d)
96
97
98
72
71
94
92
91
94
97
68
72
92
97
96
90
88
99
88
Sm (VII),
Y (VIII); ArO ) 2,6-di-tert-butylphenoxide),
[Y(OAr′)3][THF]2 (IX) (Ar′O ) 2,6-diisopropylphenoxide), and
[Y(OAr′′)3][THF]2 (X) (Ar′′O ) 2,6-dimethylphenoxide) were
prepared according to the literature.13 All aldehydes and amines
were predried, sublimed, recrystallized, or distilled before use.
Melting points were determined in a sealed Ar-filled capillary tube,
and uncorrected. 1H and 13C NMR spectra were recorded on a Unity
Inova-400 spectrometer. Chemical shifts (δ) were reported in ppm.
HRMS were recorded on a GCT-TOF instrument.
General Procedure for the Synthesis of III-V Complexes
([Y(OAr)4][Na(DME)3], III, as an example). A stirred suspension
of YCl3 (0.59 g, 3 mmol) in THF (20 mL) was treated with NaOAr
(2.74 g, 12 mmol) in THF (15 mL). The reaction mixture was stirred
at room temperature for 24 h, and the solvent was removed in vacuo.
The residue was extracted with toluene (40 mL) and the volume
of the extract was reduced to 10 mL followed by an addition of
DME (1 mL). Cooling to 0 °C afforded III as yellow crystals. Yield
2.53 g (70%), melting point 120-123 °C. Anal. Calcd for
C68H114NaYO10 (MW 1203.52): C, 67.86; H, 9.55; Y, 7.39. Found:
C, 67.12; H, 9.35; Y, 7.01. IR (KBr pellet, cm-1) 3430 (s), 3066
(w), 2934 (s), 2897 (w), 2855 (w), 1595 (s), 1472 (m), 1423 (s),
1346 (m), 1236 (m), 1132 (m), 1106 (m), 1032 (w), 879 (m), 758
(m), 510 (w). 1H NMR (400 MHz, C6D6, 25 °C) δ 7.22-7.24 (br,
12H, Ph), 3.38 (m, 12H, OCH2CH2O), 3.17 (s, 18H, OCH3), 1.40
[s, 72H, C(CH3)3] ppm.
General Procedure for the Synthesis of Amides from
Reaction of Amines with Aldehydes Catalyzed by Complex II
(product N-benzyl-N-methylbenzamide, 3aa, as an example). A 30
mL Schlenk flask was charged with a solution of complex II (3.00
mL, 0.03 mmol). N-Methylbenzylamine was added (0.13 mL, 1.00
mmol), then after 0.5 h of stirring, benzaldehyde was added (0.30
mL, 3.00 mmol). The resulting mixture was stirred at 25 °C for
3 h then filtered through a small plug of silica gel to remove the
catalyst. The crude product was purified by column chromatogra-
phy: (ethyl acetate:petroleum ether ) 1: 5) yielding 203 mg (90%).
1a
1b
1c
1d
1f
1h
1i
3af
3bf
3cf
3df
3ff
3hf
3if
2f
2f
2f
2f
2f
2f
a Starting amine, aldehyde, and II concentrations are identical in each
experiment. b Isolated yield based on amine. c Molecular sieves 4Å was
added. d 5 mol % of II without molecular sieves 4Å.
and N-(p-flourobenzoyl)pyrrolidine (3bd) (Table 3, entries 10
and 11), although electron-rich aromatic aldehydes are less
active and afford the corresponding amides in about 72% yields
(Table 3, entries 12 and 13). We were pleased to find that the
present catalysts can also afford benzoylpiperidines 3ae-3ce,
in 91-97% yields (Table 3, entries 16-18), and benzoylmor-
pholines 3af-3if, in 88-99% yields (Table 3, entries 21-27).
A possible mechanism is proposed according to the mechanism
proposed by Marks’ group8 and the results on the influence of
feeding sequence on the yields of amide. The heterobimetallic
complex reacts first with amine to afford the heterobimetallic
complex [Ln(OAr)3(NHAr)][Na(DME)3], which reacts with
aldehyde affording the active species A (Scheme 2). The active
species A reacts with aldehyde to generate B (Scheme 2), which
might be the active species for the Tishchenko reaction.
In summary, we have developed heterobimetallic lanthanide/
sodium phenoxides as a new class of bimetallic catalysts for
amidation of aldehydes with amines. The new catalysts show
high activity and a wide range of scope to produce amides in
good to excellent yields under mild conditions. A cooperation
effect between lanthanide and alkali metals for high activity is
proposed.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Grant no. 20632040) for financial
support.
Supporting Information Available: Experimental details and
characterization data for all amides. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO802617D
J. Org. Chem. Vol. 74, No. 6, 2009 2577