C3-symmetric titanium(IV) triphenolate amino complexes for a fast and effective oxidation of secondary amines to nitrones with hydrogen peroxide

Article abstract of DOI:10.1002/adsc.200800494

The efficient catalytic oxidation of secondary amines to nitrones using hydrogen peroxide as primary oxidant is described. The titanium(IV) complex 2 bearing a C₃-symmetrical triphenolate amino ligand has proved to be an air- and water-tolerant complex that efficiently catalyzes secondary amine oxidations at 60°C without previous activation [catalyst loading as low as 0.01%, yields up to 99%, turnover numbers (TONs) up to 8000 and turnover frequencies (TOFs) up to 11000 h^-1).

Full text of DOI:10.1002/adsc.200800494

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DOI: 10.1002/adsc.200800494
C3-Symmetric Titanium(IV) Triphenolate Amino Complexes for a
Fast and Effective Oxidation of Secondary Amines to Nitrones
with Hydrogen Peroxide
Cristiano Zonta,a Elisa Cazzola,a Miriam Mba,a and Giulia Licinia,*
a
Universitꢀ di Padova, Dipartimento di Scienze Chimiche, via Marzolo 1, 35131, Padova, Italy
Fax : (+34)-049-827-5239; e-mail: giulia.licini@unipd.it
Received: August 7, 2008; Published online: November 4, 2008
Abstract: The efficient catalytic oxidation of secon-
dary amines to nitrones using hydrogen peroxide as
primary oxidant is described. The titanium(IV)
complex 2 bearing a C3-symmetrical triphenolate
amino ligand has proved to be an air- and water-tol-
erant complex that efficiently catalyzes secondary
amine oxidations at 608C without previous activa-
tion [catalyst loading as low as 0.01%, yields up to
99%, turnover numbers (TONs) up to 8000 and
turnover frequencies (TOFs) up to 11000 hÀ1).
Recently we have shown the possibility to use the
titanium alkoxide catalyst 1 for this reaction using
alkyl hydroperoxides as primary oxidants.[9] Nitrones
are obtained in high yield (up to 98%) under homo-
geneous conditions and even in the absence of sol-
vent. The reactions are fast (2–7 h) and good selectivi-
ty can be achieved with as little as 1% catalyst. The
catalyst is protected from co-product water by the ad-
dition of molecular sieves. The high stability of 1
allows the incorporation of the catalysts in polyvinyli-
dene difluoride (PVFD) membranes without affecting
their performance even after 5-fold recycling of the
catalytic membrane.[11]
Keywords: homogeneous catalysis; hydrogen per-
ACHTUNGTRENNUNG
A
More recently we have been interested in the study
of coordination chemistry and catalytic activity of C3-
symmetrical triphenolate amino complexes of
Ti(IV).[12] In particular we have shown that the in situ
prepared Ti(IV) triphenolate amino complex
2
Nitrones are valuable synthetic intermediates for the (Figure 1), is able to activate hydrogen peroxide and
synthesis of biologically active compounds,[1] as effec- catalyze the oxidation of sulfides, with catalyst load-
tive spin trap reagents[2] and as therapeutic agents.[3] ings down to 0.01%, TONs up to 8000 and TOFs up
Usually, they are synthesized either via condensation to 1700 hÀ1.[12b] The Ti(IV)-tri(phenolate) amino com-
of carbonyl compounds with N-monosubstituted hy- plex 2 is structurally very similar to 1 when consider-
droxylamines, N-alkylation of oximes and zinc-medi- ing the trigonal bipyramidal coordination geometry of
ated reduction of nitroalkanes and nitroarenes, in the Ti(IV) and the number and type of donor atoms. The
presence of aldehydes.[4] Another important synthetic higher acidity of phenol compared to alcohol has a
procedure consists of the oxidation of secondary beneficial effect on the stability of 2 with respect to 1
amines,[5] hydroxylamines[6] or imines.[7]
and thus allows higher TONs on the oxidation of sul-
In principle, the oxidative approach, using hydro- fides. Moreover, as shown in the previous works, the
gen peroxide (or urea hydrogen peroxide) or alkyl hy- presence of the tert-butyl groups on the periphery
droperoxide starting from corresponding secondary (upper rim) of the ligand is essential for the stability
amines, provides the most direct and general method of the complex in the presence of water.
for preparing nitrones.[8,9] Hydrogen peroxide (2–
7 equiv.) is used as primary oxidant in the presence of
a catalyst (1–8% mol) such as Na2MoO4, Na2WO4,
CH3ReO3 or SeO2. Good yields have been obtained
for the catalytic oxidation of certain amines. Howev-
er, other cases suffer from limited chemoselectivity
such that a significant amount of hydroxylamine is re-
covered or overoxidation can be observed and hydrol-
ysis of the products can be a significant problem.[5b,10]
Figure 1. Titanatranes from C3-symmetrical tris(2-phenyl
ethanolate amino (1) and triphenolate amino (2) ligands.
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Cristiano Zonta et al.
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Herein we report that the in situ prepared Ti(IV)
The preferential imine 7a formation could originate
triphenolate amino complex 2 is a very stable and from the degradation of CHP which initiates radical
highly efficient catalyst for the oxidation of secondary processes under the reaction conditions.[13] The use of
amines to nitrones. The catalyst is highly active in the tert-butyl hydroperoxide as primary oxidant did not
competitive solvent MeOH using aqueous hydrogen improve significantly the system, allowing the recover
peroxide as the primary oxidant. These reaction con- of only 20% of nitrone 5a (Table 1, entry 2) .
ditions are unprecedented for these kinds of catalysts
and make them far superior to the titanatrane 1.
Despite the modest results in chloroform with alkyl
hydroperoxides, we decided to investigate the catalyt-
Triphenolamine has been prepared with a new syn- ic activity of the complex using aqueous hydrogen
thetic strategy, recently developed by us, based on a peroxide (70%) in methanol or acetonitrile (Table 1,
three-fold reductive amination of the corresponding entries 3–5). Interestingly, in both cases complete con-
substituted salicyl aldehyde,[12a] followed by a reaction version of the amine 3a in few hours with high yields
of the triphenolamine with TiACHTUNTGRNEUNG(O-i-Pr)4 in CHCl3 in nitrone 5a was observed. Among the two solvents
under nitrogen furnishing the corresponding mononu- that allow us to work under homogeneous conditions,
clear, C3-symmetric Ti(IV) complex 2. The formation methanol gave the best result in terms of reactivity
of the complexes is fast and quantitative, as confirmed and selectivity (Table 1, entry 4). The detailed analysis
by 1H NMR spectra recorded a few minutes after of the reaction course clearly showed the formation
mixing of the reagents.[12b]
of the hydroxylamine intermediate 4a that is subse-
Stimulated by the remarkable stability of complex 2 quently oxidized to the corresponding nitrone 5a
even in the presence of large excesses of water, we (Figure 2).
decided to study also the catalytic activity of 2 in the
As in the case of the titanatranes 1, along the
oxidation of secondary amines using aqueous hydro- course of the reaction we observe the formation of
gen peroxide as oxidant. The use of hydrogen perox- the benzaldehyde 6a. This product is arising from the
ide is highly advantageous, since it is non-toxic and hydrolysis/overoxidation of nitrone 5a. In order to im-
environmentally friendly, producing only water as by- prove the yields we decided to perform multiple addi-
product.
tions of hydrogen peroxide at time intervals. Indeed,
In an initial study, dibenzylamine 3a was used as the addition of one equivalent of hydrogen peroxide
model substrate and the optimized conditions from every 30 min effected a decrease of the aldehyde 6a
our previous studies with catalyst 1 were utilized [1% formation in favour of the corresponding nitrone 5a
catalyst , 4 equiv. of cumyl hydroperoxide (CHP), in (96% in 8 h).
CDCl3). However, under these reaction conditions a
The effect of substrate concentration and catalyst
rather slow conversion of the reagent occurred and loading was further studied to determine the catalytic
the corresponding imine 7a was obtained as main efficiency of the system. Table 2 shows the effect of
product. (Table 1, entry 1).
increasing the substrate to catalyst ratio on the oxida-
tion of dibenzyl amine 3a. Good substrate conversion
with high selectivity for the nitrone 5a were obtained
even at a substrate to catalyst ratio up to 10,000 for
total 8000 TONs and a very high TOF (11,000 hÀ1)
(table 2, entry 4). Interestingly, further decreasing the
catalyst loading (0.01%), which necessarily drops the
catalyst concentration to 0.01 mM, did not affect sen-
sibly the chemoselectivity and slow down the reac-
tion.
Table 1. Oxidation of dibenzylamine 3a catalyzed by 2 at
608C. Effect of the oxidant and solvent.[a]
The scope of the reaction was explored under the
conditions reported in Table 2, entry 1, catalyst load-
ing 5%. Table 3 reports isolated yields for a series of
nitrones prepared under these conditions on a 1.0-
mmol scale . The nitrones were readily isolated via re-
moval of the solvent under vacuum followed by chro-
matography over silica gel.
All the nitrones were obtained in synthetically
useful yields (73–98%). In the case of less hindered
amines (3a, b, e, f) the oxidation occurs in short reac-
tion times while more hindered amines (3c, d) require
longer reaction times, up to 45 h. Interestingly the
chemoselectivity of the reaction remains high because
of the high stability of the catalyst under turnover
ROOH Solvent Time [h] Conv.[b] [%] 4a:5a:6a:7a
1
2
3
4
5
CHP
TBHP CDCl3
H2O2
H2O2[c] CD3OD
H2O2 CD3OD
CDCl3
24
12
76
36
83
98
3:0:21:76
0:25:20:55
16:75:9:0
1:92:7:0
CD3CN 18
8
8
>99
0:96:4:0
[a]
[b]
[c]
Reaction conditions: [3a]0 =0.1M; 3a:oxidant:2=1:4:0.01,
608C.
Based on the substrate, determined via 1H NMR using
DCE as internal standard.
Reaction carried out using multiple additions of hydro-
gen peroxide: one equivalent every half hour.
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C3-Symmetric Titanium(IV) Triphenolate Amino Complexes
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~
~
*
Figure 2. Dependence of the yields of nitrone ( , 5a), hydroxylamine ( , 4a) and benzaldehyde ( , 6a) on the time (min)
*
for the oxidation of dibenzylamine ( , 3a) [0.1M] with aqueous H2O2 (70%) [0.4M] catalyzed by 2 [0.001M] in CD3OD at
608C.
Table 2. Oxidation of dibenzylamine 3a catalyzed by 2 at
608C with aqueous H2O2 (70%). Effect of concentration
and catalyst loading.[a,b]
Table 3. Oxidation of secondary amines 3a–f by aqueous
H2O2 (70%) catalyzed by 2 (5%) at 608C.[a]
Substrate
Product
Time [h] Yield[b] [%]
[c]
[3a]0
[M]
2
t1/2
5a[d]
TON TOF[e]
[hÀ1]
[%] [min]
[%][c]
1
2
2.0
3.5
92
97
1 0.1
2 0.1
3 1
5
1
10
31
17
92
90
84
80
18
90
80
3180
0.1
0.01 26
840 3200
8000 11000
4 1
3
4
5
6
45.0
45.0
0.5
73
92
99
76
[a]
Reaction conditions: 3a: oxidant=1:4, aqueous H2O2
(70%), 608C in CD3OD.
[b]
[c]
[d]
Uncatalyzed reaction yields 25% of 5a after 15 h.
Time for 50% decrease of [3a]o.
Based on the substrate, determined via 1H NMR using
DCE as internal standard. In the final reaction mixture
unreacted 3a and 4a intermediates are the other com-
pounds present.
[e]
Determined at 20% conversion.
3.0
[a]
[b]
Reaction conditions: [3a]0 =1M; 3a: H2O2: 2=1:4:0.05,
608C.
Based on the substrate, determined via H NMR.
conditions and of hydrogen peroxide, that does not
decompose. In the case of substrate 3e (Table 3,
entry 5) a single nitrone was obtained, consistent with
the regioselectivity already observed with other oxi-
dizing systems.[8,9]
1
In summary, we have reported that the C3-symmet- 0.01%, high selectivity for the nitrone production,
rical Ti(IV) complex 2 is an effective catalyst for the reaching TONs up to 8000 and fast reactions (TOFs
oxidation of secondary amines to nitrones. Thanks to up to 11,000). More detailed studies on the use of dif-
the high stability of the complex 2, the inexpensive ferent oxidants and on the mechanism of the reaction
and ꢀgreenꢁ aqueous hydrogen peroxide can be used and the characterization of the species involved in the
as primary oxidant, with catalyst loadings down to process are currently in progress.
Adv. Synth. Catal. 2008, 350, 2503 – 2506
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Experimental Section
Typical Oxidation Procedure with Ti(IV)/2 Catalysis
In a 25-mL screw-cap vial, under nitrogen, the in situ
formed complex in CDCl3 catalyst (0.05 mmol) was dis-
solved in 10 mL of MeOH, followed by H2O2 (4.0 mmol,
70% in water) and, after 30 min, by the substrate
(1.0 mmol). The solution was heated at 608C and the reac-
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1
tion course was monitored via TLC, GC-MS and H NMR.
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1
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