Effective oxidation of secondary amines to nitrones with alkyl hydroperoxides catalysed by (Trialkanolaminato)titanium(IV) complexes

Article abstract of DOI:10.1002/ejoc.200900867

The effective catalytic oxidation of secondary amines to nitrones with, alkyl hydroperoxides as the primary oxidants is described. The titanium, alkoxi.de catalysts are protected. from the water co-product by the combined use of a tightly binding trialkanolamine ligand and molecular sieves. Nitrones can be obtained in high yields (up to 98%) under homogeneous, anhydrous conditions and even in the absence of solvent. The reactions are fast (2-7 h) and good selectivity and complete conversion can be achieved with as little as 1 % catalyst.

Full text of DOI:10.1002/ejoc.200900867

FULL PAPER
DOI: 10.1002/ejoc.200900867
Effective Oxidation of Secondary Amines to Nitrones with Alkyl
Hydroperoxides Catalysed by (Trialkanolaminato)titanium(IV) Complexes
Massimiliano Forcato,[a] Miriam Mba,[a] William A. Nugent,[b] and Giulia Licini*[a]
Keywords: Nitrones / Amines / Oxidation / Titanium / Trialkanolamines
The effective catalytic oxidation of secondary amines to
nitrones with alkyl hydroperoxides as the primary oxidants
is described. The titanium alkoxide catalysts are protected
from the water co-product by the combined use of a tightly
binding trialkanolamine ligand and molecular sieves. Nitro-
nes can be obtained in high yields (up to 98%) under homo-
geneous, anhydrous conditions and even in the absence of
solvent. The reactions are fast (2–7 h) and good selectivity
and complete conversion can be achieved with as little as
1% catalyst.
ated reduction of nitroalkanes or nitroarenes in the pres-
ence of aldehydes.[9] Another important synthetic procedure
consists of the oxidation of secondary amines,[10] hydroxyl-
amines[11] or imines.[12]
In principle, the catalytic oxidative approach provides the
most direct and general method of synthesis.[13] Hydrogen
peroxide (2–7 equiv.), for example, has been employed as a
stoichiometric oxidant in the presence of catalysts (1–
10mol-%) such as Na2MoO4 or Na2WO4,[10,14] MeReO3,[15]
SeO2,[14] PtII [16] or TiIV.[17] Moreover, dioxygen has been
employed as primary oxidant in the presence of cyclohex-
anone monooxygenase as catalyst.[18]
Introduction
Nitrones (N-alkylidenealkylamine N-oxides)[1] have the
general structure described by the two limit resonance
forms A and B and can be regarded as products originating
from a double oxygen transfer to secondary amines, fol-
lowed by loss of water.[2]
Such oxidations often afford nitrones in high yields. In
some cases, however, the reaction suffers from limited selec-
tivity: for some substrates a significant amount of hydroxyl-
amine is recovered. On the other hand, over-oxidation and
hydrolysis can be a significant problem with highly reactive
nitrones.[19] These problems might be addressable through
the development of a catalytic system that uses a milder
and more selective primary oxidant, such as an alkyl hydro-
peroxide. In this regard we were attracted to the possibility
of a catalyst system based on titanium. Titanium complexes
are inexpensive and non-toxic and are known to activate
alkyl hydroperoxides. However, a challenge in the current
application is that a stoichiometric amount of water is pro-
duced during the course of the oxidation and many tita-
nium complexes are sensitive toward hydrolysis.
In a preliminary communication we reported that the
titanatranes 2[20] (Scheme 1) are able to catalyse the oxi-
dation of secondary amines to nitrones by alkyl hydroper-
oxides.[21,22] In the presence of catalyst 2c (1.0%), for exam-
ple, amine oxidations can be carried out in chloroform at
60 °C in nearly quantitative yields in as little as 1 hour.
The ability of a trialkanolamine ligand such as 1c to sta-
bilize titanium in the presence of water may well have utility
beyond the current application. However, a limitation that
needs to be overcome is the use of a homochiral ligand
The nitrone function resembles the carbonyl group in its
facilitation of the removal of a proton from an adjacent
carbon under basic conditions, as well as in the addition of
organometallic compounds to the unsaturated carbon.[2,3]
The resonance structure B accounts for the reactivity
towards nucleophiles.[4] Moreover, another form of reaction
behaviour characteristic of nitrones arises from the carbon–
nitrogen double bond and N-oxide functionality (structure
A): as a result of their 1,3-dipolar electronic distribution of
this kind, nitrones readily undergo cycloaddition reac-
tions.[5] A variety of heterocycles and natural products have
been synthesized[3,5,6] by exploitation of each of these
modes of reactivity. Cyclic nitrones in particular are of fun-
damental importance for synthetic purposes. Also note-
worthy is the use of nitrones either as spin trap reagents in
EPR spectroscopy[7] or as therapeutic agents.[8]
The synthesis of nitrones is commonly achieved through
condensation of carbonyl compounds with N-monosubsti-
tuted hydroxylamines, N-alkylation of oximes or zinc-medi-
[a] Università di Padova, Dipartimento di Scienze Chimiche,
via Marzolo 1, 35131 Padova, Italy
Fax: +39-049-827-5239
E-mail: giulia.licini@unipd.it
[b] Vertex Pharmaceuticals, Inc.,
130 Waverly Street, Cambridge, MA 02138, U.S.A
740
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Ti(IV)-Catalysed Oxidation of Secondary Amines to Nitrones
Table 1. Effect of the catalyst, alkyl hydroperoxide and molecular
sieves (MS) on the oxidation of dibenzylamine (3a).
Scheme 1. Synthesis of titanatranes 2a–d from the corresponding
trialkanolamines 1a–d.
Cat/ROOH/MS [a]
Time / h Conv.[b] / % 5a[b] / % 6a[b] / %
1
2
3
4
5
6
7
8
9
Ti(OiPr)4/TBHP/5 Å
Ti(OiPr)4/CHP/5 Å
2a/TBHP/5 Å
2a/CHP/5 Å
2b/TBHP/5 Å
2b/CHP/5 Å
2c/TBHP/5 Å
2c/CHP/5 Å
2c/CHP/4 Å
9.0
8.0
21.0
21.0
105.0
6.0
8.0
2.5
2.0
1.5
66
100
6
60
91
6
10
91
Ͼ99
98
Ͼ99
99
Ͼ99
98
3
9
–
–
6
nd
2
nd
1
–
prepared from a relatively expensive enantiopure epoxide.
Consequently, this study had two principal objectives. We
first explored the effect of parameters such as solvent, the
type of molecular sieves and catalyst loading on catalytic
efficiency. Secondly, we extended our studies to the use of
alternative trialkanolamines such as achiral 1d and, espe-
cially, the mixed-ligand system obtained from ammonia and
racemic styrene oxide. Individual diastereomeric and re-
gioisomeric components from this mixed-ligand system
were prepared and tested, revealing unexpected trends in
the reactivities of the corresponding catalysts.
10
100
Ͼ99
100
Ͼ99
100
100
100
100
100
10 2c/CHP/3 Å
11 2d/TBHP/4 Å
12 2d/CHP/4 Å
8.0
2.0
1.0
2
1
2
99
98
13 2c-mix[c]/CHP/4 Å
[a] Conditions: [ROOH]0 = 0.4 , [TiIV]0 = 0.01 , [3a]0 = 0.10 ,
in CDCl3 at 60 °C, molecular sieves (250 mgmmol–1). [b] Deter-
mined by 1H NMR with DCE as internal standard. [c] Ligand pre-
pared from racemic styrene oxide; see text.
Results and Discussion
Effect of Key Reaction Parameters
Encouraged by the results reported in our preliminary
communication, we undertook an investigation of six criti-
cal parameters that would be expected to affect the rate and
selectivity of the reaction. These factors include the choice
of ligand, alkyl hydroperoxide, molecular sieves and sol-
vent, as well as the substrate/catalyst and oxidant/substrate
ratios.
(R = Me). It is unclear whether this is due to electronic
effects (enhanced Lewis acidity) or steric effects (improved
hydrolytic stability) or to some combination of both.
Effect of the Alkyl Hydroperoxide
Influence of the Trialkanolamine Ligand
In all cases in Table 1, CHP is superior to TBHP as
stoichiometric oxidant. This is somewhat unfortunate for
large-scale synthetic applications in terms of separating
side-product alcohol from the nitrone product (tert-butyl
alcohol is volatile whereas cumyl alcohol frequently re-
quires chromatographic separation). The difference between
CHP and TBHP, however, is small when the best catalysts –
2c and 2d – are used. Therefore, from the standpoint of
practicality, TBHP may be the better oxidant for larger-
scale applications.
A series of reactions were performed with either
Ti(OiPr)4 or titanatranes 2 as catalyst and either tert-butyl
hydroperoxide (TBHP) or cumyl hydroperoxide (CHP) as
primary oxidant. A standard set of reaction conditions was
utilized (solvent chloroform, 60 °C, oxidant/substrate/cata-
lyst = 40:10:1). Results are summarized in Table 1 and in-
clude several noteworthy observations.
Under the standard conditions, Ti(OiPr)4 proved to be
a reasonably effective catalyst (Entries 1, 2). However the
reaction is not completely selective and nitrone is obtained
in high yield (91%) only with CHP as stoichiometric oxi-
dant (Entry 2). Interestingly, a titanium complex bearing
the parent triethanolamine ligand 1a (Entries 3, 4) proved
to be a less effective catalyst than Ti(OiPr)4 itself. Reactions
proceeded very slowly, resulting in low levels of conversion
(10% or less after 21 h).[23]
With the best combination of ligand and alkyl hydroper-
oxide (CHP/2c), complete conversion of 3a into 5a could
be achieved in only 1.5 h (Entry 10). Consequently, we fo-
cused on this system in our subsequent studies.
Effect of Molecular Sieves
With regard to the titanatrane complexes 2b and 2c (En-
A set of experiments was carried out in the presence of
tries 5–10), it is evident that α-substitution of the hydroxy- 5 Å, 4 Å and 3 Å molecular sieves (250 mg per mmol of
bearing C atom provides much more effective catalysts. Cat- substrate) under the standard conditions (Figure 1 and
alyst 2c (R = Ph) appears somewhat more effective than 2b Table 1, Entries 8–10).
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M. Forcato, M. Mba, W. A. Nugent, G. Licini
FULL PAPER
t1/2(chloroform) = 27 min] whereas in methanol it is four times
slower [t1/2(methanol) = 105 min]. A major contribution to the
decreased reactivity in methanol is likely to be the competi-
tion between the alcoholic solvent and the alkyl hydroper-
oxide for coordination to the catalyst, which should lower
the concentration of the active TiIV-peroxo complex.
Because of safety considerations, benzene itself is an in-
appropriate choice of solvent for synthetic applications.
However, these results suggest that other non-polar solvents
such as toluene may prove advantageous for this oxidation.
Oxidant/Substrate Ratio
Figure 1. Time-dependence (h) of formation of the nitrone 5a
through the oxidation of dibenzylamine (3a) by CHP catalysed by
(R,R,R)-2c (0.01 ) in CDCl3, at 60 °C in the presence of molecular
sieves (3 Å, 4 Å and 5 Å, 250 mgmmol–1). [3a]0 = 0.10 ; [CHP]0
= 0.40 .
The stoichiometry of the oxidation of a secondary amine
to a nitrone requires a minimum of two molar equivalents
of oxidant for complete conversion. In fact, most of the
reported catalytic methods employ an excess of hydrogen
peroxide (up to 7 equiv.). However, an excess of oxidant can
in some cases have a negative effect on the reaction out-
come. In particular, nitrones formed by oxidation of cyclic
amines tend to be unstable under oxidative conditions and
often undergo further oxidation. In view of the high levels
of conversion achieved with four molar equivalents of alkyl
hydroperoxide, we investigated whether the use of an excess
of oxidant was actually necessary to the process.
A set of reactions was carried out under the standard
catalytic conditions, but with reductions in the amounts of
oxidant to 3 equiv. or 2 equiv. In both cases neither unre-
acted hydroxylamine 4a nor over-oxidation or decomposi-
tion products were detected, indicating that selectivity is not
influenced by the relative amount of alkyl hydroperoxide.
As shown by the kinetic profiles in Figure 3, the reactions
were slower, but nearly complete conversion of dibenzyl-
amine into nitrone 5a was achieved even at an oxidant/sub-
strate ratio of 2:1.
The reaction proceeds more rapidly in the presence of
3 Å or 4 Å molecular sieves than it does with 5 Å sieves:
complete conversion into nitrone 5a is observed in 1.0–1.5 h
in the first two cases, in comparison with 2.5 h in the last.
A much less substantial difference is observed with 3 Å in-
stead of 4 Å molecular sieves and either may be employed.
In addition, a control experiment was carried out under
otherwise identical conditions but with omission of molecu-
lar sieves. The reaction was significantly slower, requiring
4 h for completion; nevertheless, complete conversion of 3a
to 5a had been achieved after that time. In contrast, when
the reaction was run with 4 Å sieves but with omission of
the titanium catalyst, no reaction occurred.
Solvent
The use of solvents other than CDCl3 was briefly investi-
gated. In particular, reactions in the apolar solvent [D6]ben-
zene and in the more polar protic solvent [D4]MeOH were
carried out (Figure 2). Quantitative yields of nitrone were
obtained with all three solvents, although significant differ-
ences in reaction rate were observed. In benzene the reac-
tion is almost twice as fast [t1/2(benzene) = 16 min vs.
Figure 3. Time-dependence of the yields of amine 3a and nitrone
5a in the oxidation of 3a ([3a]0 = 0.10 ) by CHP (2–4 equiv.) cata-
lysed by (R,R,R)-2c (0.01 ) in CDCl3, at 60 °C in the presence of
molecular sieves (4 Å, 250 mgmmol–1).
Substrate/Catalyst Ratio
Catalyst loading is an important consideration for cata-
lytic systems, because it can affect both raw materials cost
and ease of product isolation. The results reported in
Table 2 and Table 3 show the effect of increasing the sub-
Figure 2. Solvent-dependence ([3a]0 = 0.10 ) of the rate of oxi-
dation of amine 3a (dashed lines) to nitrone 5a (solid lines) by CHP
([CHP]0 = 0.40 ) catalysed by (R,R,R)-2c (0.01 ) at 60 °C and in
the presence of molecular sieves (4 Å, 250 mgmmol–1).
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Ti(IV)-Catalysed Oxidation of Secondary Amines to Nitrones
strate/catalyst ratio on the oxidation of dibenzylamine 3c Scope of the Reaction
with CHP. With (R,R,R)-2c as catalyst, 20:1, 100:1 and
A standard protocol based on the above studies was se-
1000:1 ratios were used.
lected to explore the scope of the reaction. These standard
conditions involved the use of a 10% loading of catalyst 2c
with four molar equivalents of cumyl hydroperoxide relative
to the secondary amine substrate. Unless otherwise indi-
cated, the results in Table 4 were obtained in chloroform as
solvent at 60 °C in the presence of molecular sieves (4 Å).
Table 2. Oxidation of dibenzylamine (3a) with CHP (4 equiv.) cata-
lysed by (R,R,R)-2c (0.01 ) in CDCl3, at 60 °C and in the presence
of molecular sieves (4 Å, 250 mgmmol–1 substrate).
[3a]0 / 
3a:(R,R,R)-2c Time / h
5a[a] / %
1
2
3
4
0.1
0.2
1.0
1.0
10:1
20:1
100:1
1000:1
2.5
1.5
1.0
100.0
100
100
100
[b]
68
Table 4. Oxidation of the secondary amines 3a–g by CHP (80% in
cumene) catalysed by (R,R,R)-2c (10%) at 60 °C.[a]
[a] Determined by 1H NMR with DCE as internal standard.
[b] 100% conversion; other products including benzaldehyde (6a,
22%) and N-benzylidenebenzylamine (7a, 10%) were detected.
Table 3. Oxidation of dibenzylamine 3a ([3a]0 = 0.10 ) with CHP
([CHP]0 = 0.40 ) catalysed by (R,R,R)-2c in CDCl3, at 60 °C and
in the presence of molecular sieves (4 Å, 250 mgmmol–1 substrate).
3a/(R,R,R)-2c [2c] / m
Time / h
5a[a] / %
1
2
3
4
10:1
20:1
100:1
1000:1
10.0
5.0
1.0
0.1
2.5
4.0
21.0
71.0
100
100
100
60[b]
[a] Determined by 1H NMR with DCE as internal standard.
[b] 83% conversion; other products including N,N-dibenzylhydrox-
ylamine (4a, 5%), benzaldehyde (6a, 9%) and N-benzylideneben-
zylamine (7a, 9%) were detected.
In the first case (Table 2) the catalyst loading was de-
creased by increasing the substrate concentration (up to
1.0 ), and the CHP concentration accordingly, whereas the
concentration of the catalyst was kept constant ([2c]0
=
0.01 ). In the second set of experiments (Table 3) catalyst
concentration was decreased (0.01–0.0001 ) with a con-
stant substrate concentration ([3a]0 = 0.10 ).
The results reported in Table 2 and Table 3 show that
complete conversion of dibenzylamine and 100% selectivity
for the nitrone could be achieved in the presence of 1% of
catalyst (Entries 3). Faster reaction times were obtained in
the first set of experiments (Table 2) as a result of the in-
creased reactant concentration: it is noteworthy that in or-
der to maintain the catalyst concentration at 0.01  the re-
action corresponding to a substrate/catalyst ratio of 100:1
(Table 2, Entry 3) was performed under essentially neat
conditions. Such high efficiency in the neat reaction would
be a prerequisite for the development of a solvent-free pro-
tocol for a high-performance synthesis of nitrones. Because
the yields of nitrone were quantitative in both cases, 100
turnovers could likewise be obtained under higher-dilution
conditions. When the substrate/catalyst ratio was further in-
creased to 1000:1, which necessarily dropped the catalyst
concentration to 0.001  in the case of Table 3, a substan-
tial decrease in chemical yield as a result of significantly
diminished selectivity was observed (Entries 4). Yields of
nitrone of up to 68%, corresponding to 680 catalytic cycles,
were obtained.
[a] Reaction conditions: [2a]0 = 0.1 ; 3/CHP/Cat = 1:4:0.1, 60 °C.
[b] Based on products isolated after chromatography. Reactions
were carried out on mmol scale. [c] Reaction performed neat ([3a]0
= 1.00 ) in the presence of 2a TYZOR®TE (10%) as catalyst.
[d] Only decomposition products were observed. [e] Reaction was
carried out in the presence of only two equivalents of CHP. [f] Re-
action was carried out at 30 °C.
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M. Forcato, M. Mba, W. A. Nugent, G. Licini
FULL PAPER
The acyclic and cyclic secondary amines 3a–i (Entries 1–9) Alternatives to Enantiopure Trialkanolamines
afforded the corresponding nitrones 5a–i in synthetically use-
Significance of C3 Symmetry
ful yields (63–98%). In the cases of 3g and 3i the systems
proved to be completely regioselective, with exclusive forma-
tion of the regioisomers 5e, originating from benzylic oxi-
dation, and 5i, originating from the tertiary carbon oxidation,
being observed. The C-aldonitrones 5a, 5b, 5d and 5f and the
keto nitrone 5e were found to be quite stable in the oxidative
environment and could be isolated in yields of 90% or higher.
Worthy of note is the synthesis of the enantiopure (R,R)-
nitrone 5h, a valuable intermediate for the synthesis of gly-
cosidase inhibitors and many other natural products,[13]
which could be obtained in good yields without decomposi-
tion or removal of the tert-butyldimethylsilyl protecting
groups (Table 4, Entry 8). This results is superior to those
previously reported in the literature, in which the corre-
sponding hydroxylamine was oxidized to the nitrone with
SeO2 as catalyst.[24] The directed oxidation of the secondary
amine bearing O-MOM protecting groups has been re-
ported as well, but in this case stoichiometric amounts of
the much less “green” HgO were used.[25]
In this study the C3 enantiopure trialkanolamines 2b and
2c were used in reactions in which enantioselectivity was
not an issue. This fact deserves some comment. First of all,
the presence of at least one substituent on each oxygen-
linked trialkanolamine C atom has a crucial role in afford-
ing mononuclear titanatranes, which appear to be better
catalysts for oxidation reactions.[20] In fact, the unsubsti-
tuted titanatrane 2a is known to form polynuclear aggre-
gates in solution and the corresponding peroxo complexes
are very reactive and unstable, resulting in extensive decom-
position of the oxidant over time.[20,26] Furthermore, the
enantiopure trialkanolamines are synthetically much easier
to prepare as pure compounds: the synthesis of (R,R,R)-1c
carried out by addition of ammonia to enantiopure (R)-
styrene oxide affords (R,R,R)-1c as the main component in
80% yield, although a smaller amount of (1S,2ЈR,2ЈЈR)-8
is formed as well, due to incomplete regiocontrol of the
nucleophilic attack on the epoxide. (Scheme 2).[27] Two
other regioisomers – (1S,1ЈS,2ЈЈR)-9 and (1S,1ЈS,1ЈЈS)-10 –
could in principle also be formed, although, presumably as
a result of the steric congestion around the nitrogen atom,
their formation is not observed (Scheme 2).
Another cyclic nitrone 5i, originating from oxidation of
(S)-proline methyl ester (3i), was obtained with complete
regiocontrol and in high yield, much higher than that pre-
viously reported (73% vs. 45%; Table 4, Entry 9).[10a] The
presence of the ester function proved to be totally compati-
ble with the oxidizing system.
Also shown in Entry 1 is an attempt to oxidize dibenzyl-
amine (3a) in the presence of the triethanolamine catalyst
2a (10%) carried out under almost neat conditions ([3a]0 =
1.0 , [CHP]0 = 4.0 ). This resulted in 100% conversion
of the amine after 24 h and a 70% yield of the isolated
nitrone 5a, although the achiral titanatrane 2a had pre-
viously been shown to be far less active than the Cα-substi-
tuted titanatranes 2b–d under dilute conditions (see Table 1
and discussion thereafter). This example is significant be-
cause it suggests that running these reactions at higher con-
centrations may similarly prove beneficial for other catalysts
and substrates.
Scheme 2. Synthesis of (R,R,R)-1c through a threefold ring-open-
ing of (R)-styrene oxide with ammonia.
Under the standard conditions (4 equiv. CHP) the more
reactive cyclic amines 3j and 3k afforded little or none of
the corresponding nitrones (Entries 10 and 11). Such low
yields are a common trend observed in the synthesis of cy-
clic nitrones by oxidation: cyclic nitrones do not survive in
the presence of excess oxidant and are easily further oxid-
ized to oximes or carbonyl compounds.[10,15a] In order to
improve the yields for the oxidation of the cyclic amines
3j and 3k it proved advantageous to modify the reaction
conditions. With only 2 equiv. of oxidant the yields of the
corresponding nitrones were significantly increased, to 45%
for 5j and 85% for 5k. A high yield of 5k (90%) could be
also obtained with 4 equiv. of CHP but with oxidation at
30 °C. It may be noted that nitrone 5k is a chiral molecule
and could in principle be formed stereoselectively with use
Despite these attractive features of the C3 ligand 1c, its
preparation from the relatively expensive optically pure
styrene oxide and the need for chromatographic purifica-
tion of the ligand both represent disadvantages. As an alter-
native, we have noted that useful reaction rates can be
achieved with titanium isopropoxide (Table 1, Entry 2) or
the triethanolamine complex 2a (Table 4, Entry 1) as cata-
lysts under highly concentrated conditions. However, selec-
tivity in nitrone formation, relative to catalyst 2c, is dimin-
ished in both cases. For this reason we investigated ad-
ditional alternatives as described below.
Catalysis with an Achiral Trialkanolamine
1
of an enantiopure catalyst such as (R,R,R)-2c. However H
The achiral ligand 1d is readily prepared from isobutyl-
NMR analysis in the presence of (R)-(–)-1-(9-anthryl)- ene oxide and ammonia. As shown in Table 1, Entry 12, the
2,2,2-trifluoroethanol as chiral solvating agent showed that corresponding titanium complex 2d[28] affords the nitrone
5k was obtained as a racemic mixture.
5a in nearly quantitative yield after 2.0 h with CHP as pri-
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Ti(IV)-Catalysed Oxidation of Secondary Amines to Nitrones
mary oxidant. At least at this relatively high (10%) catalyst the mixed TiIV complexes proved particularly diagnostic for
loading, the performances of catalysts 2c and 2d were vir- determining the ratio of the different trialkanolamines, due
tually indistinguishable. This excellent reactivity may in part to the downfield shift of the benzylic proton upon coordi-
reflect the high stability of titanatrane 2d toward hydrolysis. nation to the metal centre.[30]
In fact, a hydrolysis half-life of more than one year has
The TiIV complex mixture 2c-mix was used in the oxi-
been determined for the corresponding silatrane under con- dation of dibenzylamine (3a) by CHP, under the standard
ditions in which hydrolysis of the unsubstituted silatrane reaction conditions for the oxidation protocol (Table 1, En-
exhibits a half-life of only six minutes.[29]
try 13). The resulting kinetic profile is shown in Figure 4
(curve symbol: black diamond). For comparison, the ki-
netic profile obtained with (2R,2ЈR,2ЈЈR)-2c as catalyst un-
der identical conditions is also reported. We were quite sur-
prised to discover that the catalyst 2c-mix (curve symbol:
black diamond) shows a significantly higher activity than
the homochiral enantiopure (2R,2ЈR,2ЈЈR)-2c (curve sym-
bol: filled circle).
Ligand Preparation from Racemic Styrene Oxide
The ligands (S,S,S)-1b and (R,R,R)-1c both possess C3
symmetry and as such are homochiral. We initially assumed
that such homochirality would enhance catalytic efficiency.
We reasoned that this would promote the formation of a
single catalytic species in the system and avoid destabilizing
interactions between the ligand arms with opposite chirality
in the case of the undesired diastereomers. In order to test
this premise we carried out the addition of ammonia to
racemic styrene oxide in propan-2-ol solution, using a
MW-assisted technique. In contrast with the synthesis of
ligand 1c shown in Scheme 2, the analogous reaction car-
ried out with racemic styrene oxide can also yield dia-
stereomers of the possible four regioisomers, in particular
the diastereomeric trialkanolamine (2R*,2ЈR*,2ЈЈS*)-1cЈ
(Scheme 3).
An ammonia solution in propan-2-ol (2.0 ) was used in
this synthesis in order to avoid the formation of the solvoly-
sis products that had previously been observed in reactions
carried out in methanol.[25] After 4 h at 130 °C (300 W),
68% conversion was observed (determined on the crude
product by 1H NMR). The trialkanolamines were obtained
as a mixture of regio- and diastereoisomers in 62% total
yield after separation from unreacted epoxide by filtration
through silica gel.
Figure 4. Dependence of reaction rate on the nature of the catalyst
(0.01 ) in the oxidation of 3a ([3a]0 = 0.10 ) by CHP ([CHP]0 =
0.40 ) in CDCl3 at 60 °C and in the presence of molecular sieves
(4 Å, 250 mgmmol–1).
The regioisomeric ratio was estimated by 1H NMR to be
The substrate half-conversion time was 10 min in the for-
approximately (1c + 1cЈ)/(8 + 8Ј + 8ЈЈ) = 92:8. No signifi- mer case and 30 min in the latter. Moreover, the typical
cant amounts of the regioisomers 9 and 10 were detected. induction period observed when 2c is used as catalyst (ca.
On the other hand, the diastereomers (2R*,2ЈR*,2ЈЈR*)-1c 10 min) appears to be absent in the reaction profile for 2c-
and (2R*,2ЈR*,2ЈЈS*)-1cЈ were obtained in a 1:2 ratio. The mix. Evidently at least one of the catalysts derived from
mixture of ligands 1c-mix was treated with a stoichiometric Ti(OiPr)4 and the various constituents of 1c-mix is a more
1
amount of Ti(OiPr)4, yielding 2c-mix. H NMR analysis of active catalyst than 2c itself.
Scheme 3. MW-assisted synthesis of the trialkanolamine 1c-mix from racemic styrene oxide.
Eur. J. Org. Chem. 2010, 740–748
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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745

M. Forcato, M. Mba, W. A. Nugent, G. Licini
FULL PAPER
In order to test this premise, the behaviour of the individ- action times with the use of 10% of titanium catalyst. Even
ual trialkanolamines comprising 1c-mix was examined oxidatively sensitive nitrones could be prepared by limiting
separately. The diastereoisomer (2R,2ЈS,2ЈЈS)-1cЈ was pre- the amount of primary oxidant to the two molar equiva-
pared by the procedure shown in Scheme 4.
lents required for the transformation. At least in the case
of dibenzylamine, we have demonstrated that catalyst load-
ing can be diminished to 1% and also that CHP can be
replaced by the more attractive oxidant TBHP, in each case
without significant loss of selectivity. Moreover, the excel-
lent results obtained with catalysts 2d and 2c-mix demon-
strate that this synthetic approach can be used without re-
sorting to relatively expensive enantiopure ligands or ligand
purification by chromatography.
An ideal protocol for the synthesis of sensitive nitrones
such as 5f should proceed rapidly under mild conditions
with only the two molar equivalents of oxidant required by
the stoichiometry. The desire for a high reaction rate is not
merely a matter of convenience; rapid consumption of the
primary oxidant minimizes the exposure of the product
nitrone to the oxidative environment. We have not yet
achieved this ideal situation; however, several observations
during the course of these studies bode well for further pro-
gress toward this goal. The significantly faster reaction ob-
served with catalyst 12 than with our standard catalyst 2c
is noteworthy in this regard and suggests that further im-
provements in catalyst efficiency are achievable. Further-
more, our results indicate that additional increases in the
reaction rates should be attainable either by use of a nonpo-
lar solvent or by running the reaction under highly concen-
trated or neat conditions.
Titanium is an especially attractive transition metal for
applications in organic synthesis because of its low cost and
nontoxic nature; however, hydrolytic instability is a general
problem for many catalytic applications. A remarkable fea-
ture of this chemistry is that a catalytic amount of titanium
complex is utilized in a reaction that produces a stoichio-
metric amount of water. This was accomplished through the
combined use of molecular sieves and a tightly coordinating
trialkanolamine ligand. In that regard, this study appears
to have broader implications beyond its specific application
to nitrone synthesis.
Scheme 4. Synthesis of (2R,2ЈS,2ЈЈS)-1c through a double ring-
opening of (S)-styrene oxide with (R)-11.
(R)-2-Amino-1-phenylethanol [(R)-11] was treated with
enantiopure (S)-styrene oxide (2 equiv.) in methanol, under
microwave irradiation conditions at 130 °C. The compound
(2R,2ЈS,2ЈЈS)-1cЈ was obtained after chromatographic puri-
fication in good yield (60%). The regioisomer
(1S,2ЈR,2ЈЈR)-8 was already available as a co-product of
the synthesis of (R,R,R)-tris(2-phenylethanol)amine (1c)
(Scheme 2).
The TiIV complexes 2cЈ and 12 (Figure 5) were prepared
by the usual protocol and their reactivities were examined
in the oxidation of dibenzylamine [curve symbol ᭡ for
(2R,2ЈS,2ЈЈS)-2cЈ, curve symbol ᭿ for (1S,2ЈR,2ЈЈR)-12
(Figure 4)]. Both new TiIV complexes proved to be more
active than 2c, consistently with the observed increased ac-
tivity of 2c-mix. At least three of the possible isomeric
titanatranes
– (2R,2ЈS,2ЈЈS)-2cЈ, (1R,2ЈS,2ЈЈS)-12 and
(2R,2ЈR,2ЈЈR)-2c – present in 2c-mix thus promote catalytic
activation of alkyl hydroperoxide for the fast and effective
oxidation of secondary amines. In fact, we subsequently
showed that the mixture of trialkanolamines obtained di-
rectly by addition of ammonia to inexpensive racemic
styrene oxide without chromatographic purification of the
single region- and stereoisomers can be used to prepare an
effective TiIV catalyst for oxidation of secondary amines to
nitrones.
Experimental Section
General: All synthetic operations for catalyst preparation were car-
ried out under nitrogen in an MBraun MB 200MOD glove-box,
equipped with a MB 150 G-I gas recycling system (nitrogen work-
ing pressure: 6 bar). 1H NMR kinetics were run by use of the
multi_zgvd (vdlist) sequence on a Bruker Avance DRX 300 instru-
ment. The working temperature was achieved by appropriate ad-
justment of the temperature control units. Molecular sieves (3 Å,
4 Å and 5 Å) both in pellet and in powder form were purchased
from Aldrich and activated before use by overnight heating at 200–
250 °C and cooling under nitrogen. Unless otherwise noted, Fluka
dry-quality solvents were used (water Ͻ0.005–0.010%, stored over
molecular sieves). When necessary, solvents were further purified
or dried by standard techniques, stored over molecular sieves (4 Å)
and degassed prior to use. Distilled water was filtered with a Milli-
pore MILLI-Q system. Microwave-assisted reactions were per-
Figure 5. Titanatranes (2R,2ЈS,2ЈЈS)-2cЈ and (1S,2ЈR,2ЈЈR)-12 ob-
tained from the corresponding trialkanolamines (2R,2ЈS,2ЈЈS)-1cЈ
and (1S,2ЈR,2ЈЈR)-8.
Conclusions
We have developed an effective and selective titanium-
catalysed oxidation of secondary amines to nitrones. Several
nitrones were prepared in synthetically useful yields and re- formed with a Milestone MW Ethos-1600 lab station. Reaction
746 Eur. J. Org. Chem. 2010, 740–748
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Ti(IV)-Catalysed Oxidation of Secondary Amines to Nitrones
mixtures were prepared in 2- or 100-mL reactors (HPR-1000/10S,
Milestone) fitted with pressure and temperature control units. Deu-
mixture was allowed to cool to room temperature and a 68% con-
version of the starting epoxide was obtained. Solvent was then
terated solvents were purchased from Aldrich (CDCl3, 99.8% D; evaporated and crude 1c-mix was separated from unreacted epox-
[D4]MeOH, 99.8% D; [D6]benzene, 99.6% D) and stored over mo-
lecular sieves (4 Å). All chemicals were purchased from Aldrich
and Fluka as high-purity products (Ͼ95%) and were used without
further purification. Ammonia was purchased as solutions (2.0 )
in dry methanol or propan-2-ol. (Triethanolaminato)titanium(IV)
isopropoxide (Aldrich, 80 wt.-% solution in 2-propanol) was dried
prior to use. (R)-(–)-2-Amino-1-phenylethanol (Aldrich, 90%) was
stripped with dry toluene and dried prior to use. (S,S,S)-Tris-2-
propanolamine (1b), (R,R,R)-tris-2-phenylethanolamine (1c), and
tris(2-methyl-propan-2-ol)amine (1d) were prepared by literature
procedures.[25,28] tert-Butyl hydroperoxide (Fluka, 80% solution in
di-tert-butyl peroxide) was distilled under vacuum (bp = 33 °C/
16 Torr) and stored at 4 °C over molecular sieves (4 Å). Cumyl hy-
droperoxide (Fluka, 80% solution in cumene) was stored at 4 °C
over molecular sieves (4 Å). (3S,4S)-3,4-Bis[(tert-butyl)dimethylsil-
yloxy]pyrrolidine (3h) was prepared by a literature method.[30]
ide by radial chromatography (silica gel, petroleum ether/ethyl ace-
tate 95:5), to provide 1c-mix (1.872 g, 4.96 mmol, 62% yield) as
a white solid. The 1c/8 regioisomeric composition in 1c-mix was
determined by H NMR to be approximately 92:8, by integration
of the peaks in the regions δ = 4.95–4.73 ppm (3 H of 1c and 2 H
of 8) and 4.23–3.59 ppm (3 H of 8).
1
(R,R)-Bis(2-phenylethanol)-(S)-(1-phenyl-2-ethanol)amine (8): Com-
pound (1S,2ЈR,2ЈЈR)-8 was obtained by treatment of ammonia with
(R)-styrene oxide by the literature procedure.[27] m.p. 52–53 °C.
1
[α]2D5 = –63.5 (c = 1.02, ethanol). H NMR (CDCl3, 250 MHz): δ
= 7.46–7.14 (m, 15 H, HAr), 4.76 (dd, J = 9.3, 3.5 Hz, 2 H, 2ϫCH),
4.17–3.73 (m, 3 H, 1ϫCH, 1ϫCH2), 2.97 (dd, J = 14.3 and 3.5 Hz,
2 H, 2ϫdiastereotopic CHH–), 2.77 (dd, J = 14.3 and 3.5 Hz, 2
H, 2ϫdiastereotopic CHH) ppm. 13C NMR (CDCl3, 250 MHz): δ
= 142.3, 137.5, 128.6, 128.5, 128.3, 127.9, 127.7, 125.9, 72.9, 69.0,
62.7, 61.5 ppm. C24H27NO3 (377.48): calcd. C 76.36, H 7.21, N
3.71; found C 76.12, H 7.24, N 3.62.
Analysis: Melting points are uncorrected and were determined with
a Reichert Austria apparatus (1 °C precision). 1H NMR spectra
were recorded with a Bruker AC 200 instrument operating at
200.13 MHz or with a Bruker AC 250 (250.18 MHz) or Bruker Av-
ance DRX 300 (300.13 MHz) instrument, with use of the partially
deuterated solvent or TMS as internal references; TMS δ = 0 ppm,
CHCl3 δ = 7.26 ppm, CH3OH δ = 4.78, 3.35 ppm. 1H NMR kinet-
ics (at 28 °C or 60 °C) were recorded with Bruker AC 250
(250.18 MHz) and Bruker Avance DRX 300 (300.13 MHz) spec-
trometers fitted with probe temperature control units. 13C NMR
spectra were recorded with Bruker AC 250 (62.9 MHz) or Bruker
Avance DRX 300 (75.5 MHz) spectrometers in H-decoupled mode,
with use of the solvent carbon resonance as the internal standard:
CHCl3 δ = 77.0 ppm (t). Enantiomeric excesses were determined
In Situ Preparation of Titanatranes 2a–d, 2c-mix, 2cЈ and 12: For
the NMR studies, TiIV/trialkanolamine complexes were prepared
in situ from commercially available Ti(OiPr)4 in CDCl3 as solvent
by the literature procedure.[22,26] The resulting solutions (addition-
ally containing 3 equiv. of 2-propanol released during preparation
of the catalyst) were used directly without purification.
Compound 2d: 1H NMR (CDCl3, 250 MHz): δ = 4.55 (sept, J =
5.8 Hz, 1 H, CH), 3.13 (s, 6 H, 3ϫCH2), 1.32 (d, J = 5.8 Hz, 6 H,
2ϫCH3), 1.31 (s, 18 H, 6ϫCH3) ppm.
Compound (2R,2ЈS,2ЈЈS)-2cЈ: 1H NMR (CDCl3, 250 MHz): δ =
7.48–6.99 (m, 15 H, HAr), 5.97–5.89 (dd, J = 8.8, 5.3 Hz, 1 H, CH),
5.67 (d, J = 7.0 Hz, 1 H, CH), 5.63–5.55 (dd, J = 10.0, 4.3 Hz, 1
H, CH), 4.77 (sept, J = 6.0 Hz, 1 H, CHMe2), 3.43 (dd, J = 12.8,
1.3 Hz, 1 H, 1ϫdiastereotopic CHH), 3.35–3.16 (brm, 3 H), 2.81
(dd, J = 12.3, 4.3 Hz, 1 H, 3 diastereotopic CHH), 2.69 (dd, J =
12.5, 10.3 Hz, 1 H, 1ϫdiastereotopic CHH), 1.46 (d, J = 6.0 Hz,
6 H, 2ϫCH3) ppm.
Compound (1S,2ЈR,2ЈЈR)-12: 1H NMR (CDCl3, 250 MHz): δ =
7.40–7.12 (m, 15 H, HAr), 6.33 (brm, 1 H, CH), 5.56 (t, J = 5.8 Hz,
1 H, CH), 5.17 (t, J = 5.8 Hz, 1 H, diastereotopic CHH), 4.96 (dd,
J = 11.3, 7.5 Hz, 1 H, 1ϫdiastereotopic CHH), 4.80 (sept, J =
6.3 Hz, 1 H, CHMe2), 4.48 (dd, J = 11.8, 5.3 Hz, 1 H, 1ϫdia-
stereotopic CHH), 4.11 (t, J = 7.8 Hz, 1 H, 1ϫdiastereotopic
CHH), 3.72 (dd, J = 13.3, 5.6 Hz, 1 H, 1ϫdiastereotopic CHH),
3.23 (d, J = 5.8 Hz, 1 H, CH), 2.90 (dd, J = 11.8, 5.3 Hz, 1 H,
1ϫdiastereotopic CHH), 1.46 (d, J = 6.0 Hz, 6 H, 2ϫCH3) ppm.
1
by H NMR in the presence of (R)-(–)-(9-anthryl)-2,2,2-trifluoro-
ethanol (Fluka, 98%).
Synthesis of (2R,2ЈS,2ЈЈS)-Tris(2-phenylethanol)amine (1cЈ): (R)-
(–)-2-Amino-1-phenylethanol (500 mg, 3.28 mmol) in dry methanol
(0.80 mL) was placed in a 2 mL screw-cap Teflon® vial. (S)-Styrene
oxide (0.845 mL, 7.24 mmol) was then added and the reaction mix-
ture was irradiated in the microwave apparatus with the following
program: initial power 300 W, target temp. 130 °C, 5 min; working
power 240 W, Tmax = 130 °C, 35 min, after which the reaction mix-
ture was allowed to cool to room temperature. Complete conver-
sion of the starting reagents was observed by TLC [silica gel, tolu-
ene/EtOAc (8:2) with triethylamine (5%)]. The volatile solvent was
evaporated and purification by radial chromatography over silica
gel
(dichloromethane/ethyl
acetate
mixtures)
afforded
Procedure for TiIV-Catalysed Oxidation of Dibenzylamine with
(2R,2ЈS,2ЈЈS)-1cЈ (743 mg, 1.97 mmol, 60% yield) as a low-melting,
yellowish product. m.p. 35–38 °C. [α]2D5 = +12.8 (c = 1.02, ethanol).
1H NMR (CDCl3, 250 MHz): δ = 7.57–7.20 (m, 15 H), 4.85 (dd, J
= 9.3, 5.0 Hz, 1 H, CH), 4.79 (dd, J = 9.3, 4.0 Hz, 2 H, 2ϫCH),
4.09 (brs, 3 H, 3ϫOH), 2.97–2.83 (m, 6 H, 3ϫCH2) ppm. 13C
NMR (CDCl3, 62.9 MHz): δ = 142.1, 141.9, 128.5, 127.7, 126.0,
125.9, 74.2, 72.3, 65.8, 65.6 ppm. C24H27NO3 (377.48): calcd. C
76.36, H 7.21, N 3.71; found C 76.06, H 7.26, N 3.54.
1
TBHP/CHP, Monitored by H NMR: The correct amount of TiIV
catalyst (formed in situ, 0.1  solution in CDCl3) was placed in a
screw-cap NMR tube containing powdered molecular sieves (3 Å,
4 Å or 5 Å, 13 mg). Alkyl hydroperoxide (from a 1.0  solution in
CDCl3) was then added. After 30 min at room temperature the
amine (from a 0.2  solution in CDCl3) was added at 0 °C. Solvent
was added up to a 1.00 mL volume. The consumption of 3a and
formation of 5a were monitored by recording proton NMR spectra
at fixed times with use of 1,2-dichloroethane as internal standard.
Typical Procedure for TiIV-Catalysed Oxidation of Secondary
Amines 3a–g with CHP/(R,R,R)-2c (mmol Scale): A 25 mL screw-
cap vial containing a magnetic stirring bar was charged under ni-
trogen with powdered molecular sieves (4 Å, 250 mg), (R,R,R)-2c
(0.10 mmol), dry chloroform (10 mL) and cumyl hydroperoxide
Synthesis of 1c-mix: Racemic styrene oxide (2.820 mL, 24.0 mmol)
was placed in a 100 mL Teflon®-coated vial and ammonia (2.0 
solution in dry propan-2-ol, 4.0 mL, 8.0 mmol) was added. The vial
was capped and placed in the cavity of a Micro-Wave lab-station. A
heating program was started with the following parameters: initial
power 300 W, target temperature 130 °C, 5 min; working power
240 W, Tmax = 130 °C, 60 min. After four irradiation cycles, the
Eur. J. Org. Chem. 2010, 740–748
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
747

M. Forcato, M. Mba, W. A. Nugent, G. Licini
FULL PAPER
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room temperature for 30 min and was then cooled to 0 °C, after
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capped and the reaction mixture was warmed to 30 °C or 60 °C.
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molecular sieves (4 Å, 500 mg), 2a (TYZOR® TE, 0.300 mL,
1.03 mmol) and cumyl hydroperoxide (7.15 mL, 40.3 mmol) and
the reaction mixture was stirred at room temperature for 30 min.
Dibenzylamine (2.00 mL, 10.1 mmol) was added at 0 °C and the
reaction mixture was stirred overnight at 60 °C. After 18 h quanti-
tative consumption of the substrate was observed by 1H NMR
spectroscopy. Molecular sieves were then filtered from the reaction
mixture. Concentration and chromatographic purification (silica
gel, petroleum ether/diethyl ether 1:1) afforded nitrone 5a (1.486 g,
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Acknowledgments
Funding from the Ministero dell’Università
e della Ricerca
(MIUR) (FIRB-2003 CAMERE-RBNE03JCR5), the Università di
Padova (Assegni di Ricerca 2006) (to M. M.), and the European
Cooperation in Science and Technology (COST) (ACTION D40,
“Innovative Catalysis – New Processes and Selectivities”) is grate-
fully acknowledged.
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Received: July 30, 2009
Published Online: December 17, 2009
748
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 740–748