Baeckvall J.-E. (ed.) Modern Oxidation Methods

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employing iodosylbenzene as the terminal oxidant. In sharp contrast, the epoxidation

of trans-alkenes showed moderate selectivities (ee <60%); however, the enantio-

selectivities could be improved by the introduction of additional chiral groups at the

3,3

-positions of the phenolate part of the ligand. For the conversion of trans-stilbene,

enantioselectivities of up to 80% have been reported using these modiﬁed salen

ligands [73].

The oxidizing species in this catalytic epoxidation is proposed to be a Mn

-oxo

intermediate [74d,e] similar to that observed in the Mn-porphyrin-catalyzed epox-

idation, as based on electrospray ionization mass spectrometry [75]. An extensive

discussion of the stereoselectivity, mechanism, and scope of this asymmetric

epoxidation [73] using the preferred oxidant iodosylbenzene is beyond the scope

of this chapter, although several mechanistic features apply to epoxidation with

. Despite the fact that there is consensus on the nature of the active species

(i.e., a Mn

-oxo intermediate), some controversy remains on the exact mechanism

by which enantioselection is achieved. Three key issues can be distinguished: (i) the

catalyst structure (i.e., whether the salen ligand is planar, bent, or twisted), (ii) the

trajectory of approach of the reacting alkene, and (iii) the mode of oxygen transfer

from the salen Mn

¼ O to the alkene (involving a concerted pathway, a stepwise

radical pathway, or a metallaoxetane intermediate) [47, 73, 76]. Cumulative exper-

imental evidence indicates that, in addition to the catalyst structure being either

planar or twisted, the substituents at the C

-symmetric diimine bridge and bulky

substituents at the 3,3

-positions play an important role in governing the trajectory of

the side-on approach of the alkene and, as a consequence, the asymmetric induction.

With the ﬁve-membered chelate ring, consisting of the ethylenediamine and the

-ion, being non-planar, the approach of the alkene over the downwardly bent

benzene ring of the salen ligand along one of the MnN bonds can be envisioned

(Scheme 11.7). The largest substituent of the alkene is then pointing away from the

3,3

-substituents, and this would then govern the stereochemical outcome of the

reaction between the Mn

-oxo intermediate and the alkene [73].

Although high enantioselectivities are obtained for a wide range of substrates,

the stability of the Mn-salen complexes is often a severe problem, and turnover

numbers are usually in the range 40–200. More recently, a robust salen catalyst, was

introduced by Katsuki and coworkers [77] based on ligand 15 with a carboxylic acid

functionality attached to the diamine bridge (Figure 11.4). With this catalyst,

Scheme 11.7 Model rationalizing the stereocontrol achieved in Mn-salen-catalyzed

epoxidation [73c].

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

383

2,2-dimethylchromene was converted to the corresponding epoxide in 99% ee with

iodosylbenzene as oxidant. Turnover numbers as high as 9200 after 6 h were reached,

but results with H

as the terminal oxidant have not been reported to date [77].

While iodosylbenzene and hypochlorite are the most common oxidants, consid-

erable effort has been devoted to the use of H

in epoxidations with Mn-salen

catalysts. Promising results have been reported for certain substrates (see below),

although low turnover numbers (generally up to 20–50) were obtained with H

the terminal oxidant for a limited scope of substrates. Employing H

as the oxidant,

the manganese-salen systems were found to be only catalytically active in the

presence of additives such as imidazole and derivatives thereof or carboxylates

[49b, 78, 79, 80]. The role of these additives is considered to be in inhibiting OO

bond homolysis, which leads to radical pathways and destruction of the catalyst, as

has been discussed for the Mn-porphyrin based catalysts (see above).

Berkessel and coworkers have designed a chiral dihydrosalen ligand with a

covalently attached imidazole group. This salen complex (16) was used to convert

1,2-dihydronaphthalene to the corresponding epoxide in 72% yield and with prom-

ising enantioselectivities (up to 64%; Table 11.3) using a dilute (1%) aqueous solution

of H

as oxidant. An important feature of this system is that epoxidation reactions

can be performed in the absence of the additives usually employed [49b].

Using Mn-salen 17 together with N-methylimidazole as an axial ligand, Katsuki

and coworkers obtained up to 96% ee in the epoxidation of a substituted chromene

with 30% aqueous H

as oxidant, although the yield of the epoxide was only 17%.

With excess of H

(10 equiv.) and increased concentration of the reactants, the yield

was increased to 98%, with only a slight decrease in the enantioselectivity to 95%

(Table 11.3) [79]. Although only a limited number of substrates were tested, these

excellent results (ee 88–98%) demonstrate that full enantioselectivity with H

can

be achieved.

Pietik

€

ainen reported that, in the presence of carboxylate salts, 30% aqueous H

could be used as an oxidant for asymmetric epoxidation with chiral Mn-salen

catalysts (64–96% ee, Table 11.3) [80b]. Furthermore it was shown that the use of

in situ prepared peroxycarboxylic acids, from the corresponding anhydrides and

anhydrous H

, gives improved enantioselectivity in the epoxidation of alkenes

compared with the use of aqueous H

in the presence of a carboxylate salt [81]. In

particular, good results are obtained with maleic anhydride and UHP (urea-H

)in

combination with Mn(III)-salen complex 18a together with the additive N-methyl-

morpholine N-oxide (NMO). Although the substrate scope tested is again limited, in

general 3–5% higher enantioselectivities were obtained, and the reaction time was

reduced under these conditions. The use of urea-H

for the Mn(III)-salen

catalyzed epoxidation of alkenes has also been described by Kureshy and cow-

orkers [82]. Although for styrene only 39% ee was obtained, moderate to excellent

enantioselectivities were reported for chromene derivatives (55–99%) in the presence

of ammonium acetate.

Recently, immobilization of salen-based catalysts has been demonstrated both on

solid supports [83] and on dendritic molecular frameworks, which allow for en-

antioselective catalysis with good to excellent ee over several cycles [84].

384

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

11.4.4

Tri- and Tetra-azacycloalkane Derivatives

Over the last two decades several groups have focused attention on tri- and tetra-

azacycloalkane-based manganese complexes in the catalyzed oxidation of organic

Table 11.3 Epoxidation of alkenes by Mn(III)-salen complexes employing H

as oxidant.

Ph*

Ph* = 4-t-butylphenyl

PhPh

a R = Me

b R = CH

N(C

)

Substrate Mn-salen Oxidant (equiv.) Epoxide yield (%) ee (%) Ref.

16 1% H

(10) 72 64 [49b]

18a 30% H

(1.5) 74 69 [81]

18a Urea.H

/maleic

anhydride (1.5)

70 73 [81]

13 30% H

(4) 84 96 [80b]

cNH

17 30% H

(1) 17 96 [79]

cNH

17 30% H

(10) 98 95 [79]

18b Urea.H

(2) >99 >99 [82b]

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

385

substrates including alkanes, alkenes, alcohols, aldehydes, and sulﬁdes, albeit with

the majority of studies focusing on alkene epoxidation [6, 10].

11.4.4.1 Tetra-azacyloalkane Derivatives

Busch and coworkers have reported a number of catalytic and mechanistic studies

on the manganese complexes formed with the ligand 4,11-dimethyl-1,4,8,11-tetra-

azabicyclo[6.6.2]hexadecane (Me

EBC) [85–89] and related ligands [90]. The ligand

EBC is designed speciﬁcally to preclude formation of manganese di- and multi-

nuclear complexes and allowed for the isolation of an Mn

III

-(OH)

complex such as

that shown in Figure 11.5.

The complex could achieve up to 45 turnovers in the oxidation of alkenes

(Table 11.4); however, despite its low activity relative to other systems, it serves as

an excellent platform for mechanistic studies given the relative stabilities of the

higher-oxidation-state manganese complexes formed and isolated using this ligand.

Haras and Ziegler have recently proposed, based on DFTcalculations, that the mode

of action of these complexes is via the Mn

-OOH adduct, with oxygen transfer of the

Figure 11.5 X-Ray crystallographic structure of [(Me

EBC)Mn

III

(OH)

]

. Reproduced from

Ref. [86] with permission. Copyright ACS 2006.

Table 11.4 Epoxidation of alkenes with H

catalyzed by Mn(Me

EBC)Cl

Substrate Product Yield (%)

Cyclohexene Cyclohexene oxide 18.0

Cyclohexen-1-one 13.3

Styrene Styrene oxide 45.5

Benzaldehyde 2.8

Norbornylene Norbornylene oxide 32.0

cis-Stilbene cis-Stilbene oxide 17.5

trans-Stilbene oxide 2.0

Benzaldehyde 2.6

a) Reaction conditions: acetone/water (4 : 1), catalyst (1 mM), alkene (0.1 M), 50% H

(1 mL),

added stepwise by 0.2 mL/0.5 h, rt, yield determined by GC with internal standard. From

Ref. [86].

386

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

distal oxygen to the alkene substrate, that is, via a classic inorganic peracid oxidation-

type mechanism [91]. This mechanism places this class of complex in sharp contrast

with the salen- and porphyrin-based systems discussed above, in which Mn

¼ O

and Mn

¼ O species are widely accepted to be the oxygen transfer agents.

11.4.4.2 Triazacyclononane Derivatives

Manganese complexes such as 6 ([Mn

(tmtacn)

](PF

)

, Figure 11.2), 19

([Mn(OMe)

(tmtacn)] and 20 [Mn

O(OAc)

(tmtacn)

](PF

)

based on the N,N

trimethyl-1,4,7-triazacyclononane ligand (4, tmtacn, Figure 11.1) were developed by

Wieghardt and coworkers in the late 1980s and 1990s as functional models for biotic

manganese systems [10, 37], in particular, dinuclear manganese-based catalase

enzymes [92, 93] and PSII [19]. The activity of these complexes as oxidation catalysts

with H

in both aqueous [40] and nonaqueous [94] media have, however, made this

family of complexes the focus of considerable interest for a broad range of oxidative

transformations including textile stain bleaching [6], benzyl alcohol oxidation [94c],

CH bond activation [94f], sulfoxidation [95] and the cis-dihydroxylation, and

epoxidation of alkenes [94, 117].

Epoxidation with H

In combination with H

, the dinuclear manganese

complex 6 was found to be a highly active and selective epoxidation catalyst

[40,94g,96]. High turnover numbers (>400) were obtained in the oxidation of styrene

and vinylbenzoic acid. In methanol carbonate-buffered solutions, conversions of 99%

were reached without notable catalyst degradation [94g,96]. The scope for epoxidation

reactions was considerably expanded by De Vos and Bein through the use of acetone as

the solvent [94b,97]. Although the procedure is not suitable for the epoxidation of

electron-deﬁcient alkenes, high turnover numbers of up to 1000 have been reported

for the conversion of a range of alkenes to their corresponding epoxides using Mn-

tmtacn complexes prepared in situ with MnSO

and tmtacn (Table 11.5). For example,

with styrene, complete conversion with 98% epoxide selectivity is achieved at 0



Cin

acetone with 2 equiv. of H

(Scheme 11.8)[97].It should be notedthat cleavage of the

double bond was not observed, although some cis/trans isomerization was observed in

the oxidation of cis-alkenes. Furthermore, with alkenes such as cyclohexene only

minor amounts of allylic oxidation products are obtained.

Table 11.5 Oxidation of selected alkenes with Mn-tmtacn [94b].

Substrate Turnover number

Selectivity (%)

Cyclohexene 290 87

Styrene 1000 >98

cis-2-Hexene 540 >98

1-Hexene 270 >98

trans-b-Methylstyrene 850 90

a) In acetone (0.6 g), alkene (1 mmol), tmtacn (1.5 mmol), Mn

2 þ

(1 mmol). H

(2 mmol 30%

diluted in acetone 3 times) was added over 1h at room temperature. Turnover number in moles

product per mole catalyst (after 3 h).

b) Selectivity: moles of epoxide per mole of converted substrate.

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

387

The turnover numbers for this reaction are high; however, there remains a need to

develop catalytic systems that employ H

efﬁciently. With many Mn or Fe catalysts,

decomposition of H

is a signiﬁcant secondary, if not primary, process, and hence

often a large excess of H

is required to reach full conversion [34]. Supression of

catalase-type activity is indeed possible by performing the oxidation reactions in

acetone at subambient temperatures. In contrast, the use of other solvents results

in rapid competitive oxidant decomposition. The oxidation characteristics of the

Mn-tmtacn complexes in acetone compared with other solvents were rationalized

by a mechanism involving the nucleophilic addition of H

to acetone, resulting

in the formation of 2-hydroperoxy-2-hydroxypropane (hhpp, 21) as depicted in

Scheme 11.9 [98]. Most probably, due to the reduction of the H

concentration

in acetone, the epoxidation reaction is favored over oxidant decomposition. It was

proposed that at low temperature hhpp serves as an oxidant reservoir, which gradually

releases H

and maintains a low steady-state oxidant concentration [97b], although

direct involvement of peroxide 21 in the epoxidation pathway was not excluded.

However, the combination of acetone and H

can also result in the formation of

potentially explosive cyclic peroxides, and therefore this solvent is not acceptable for

industrial applications involving H

Hydrogen peroxide decomposition by Mn-tmtacn complexes in CH

CN was

shown to be suppressed effectively by addition of oxalate [94d] or ascorbic acid

[94a] as co-catalysts. Indeed the addition of these additives even in co-catalytic

amounts resulted in a dramatic enhancement in the epoxidation activity of the

in situ prepared Mn-tmtacn complex [94d]. In general, full conversion was reached

with less than 1 mol% of catalyst within 1 h. In addition to oxalic acid, several other

bi- or polydentate additives, for example, diketones or diacids, in combination with

Mn-tmtacn and H

were found to favor alkene epoxidation over oxidant decom-

position [94d]. Employing this mixed catalytic system, allylic alkenes (e.g., allyl

HO OOH

(hhpp)

Scheme 11.9 Reaction of acetone with H

0.1 mol% MnSO

0.15 mol% tmtacn

2 equiv. H

(aq. 30%)

acetone, 0

98%

Scheme 11.8 Oxidation of styrene catalyzed by an in-situ-formed manganese complex in

acetone [97].

388

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

acetate) and especially terminal alkenes (e.g., 1-hexene, see Scheme 11.10 and

Table 11.6) could be converted to their corresponding epoxides in high yields with

only 1.5 equiv. of H

[94d].

Importantly, the isomerization of cis- and trans-alkenes is suppressed in the

presence of oxalate. The epoxidation of 2-hexene was found to be completely

stereospeciﬁc(>98%) using only 1.5 equiv. of the oxidant, in contrast to the reaction

in acetone [97], in which the Mn-tmtacn catalyst produced as much as 34% trans-

epoxide from cis-2-hexene. Furthermore, several functional groups, including

CH

OH, CH

OR, COR, and CO

R, are tolerated. Despite the high reactivity

Table 11.6 Representative examples of epoxidation of terminal and deactivated alkenes with the

Mn-tmtacn/oxalate system [94d].

Substrate Epoxide yield (%) Epoxide selectivity (%)

>99 >99

35 >98 (trans)

72 >98 (cis)

83 92

66 96

OEt

55 94

88 91

89 91 (diepoxide)

8 (monoepoxide)

a) Selectivity: moles of epoxide/moles of converted substrate.

0.1 mol% MnSO

0.15 mol% tmtacn

0.3 mol% oxalate buffer

1.5 eq. H

(35% aq.)

MeCN, 0

> 99%

Scheme 11.10 Selective epoxidation of 1-hexene by Mn-tmtacn using H

in the presence of

oxalate [94d].

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

389

of the catalytic system, epoxidation is preferred over alcohol oxidation in the case of

alkenes bearing alcohol moieties. This procedure is also suitable for the oxidation

of dienes resulting in bis-epoxidation. For example, 4-vinylcyclohexene yields the

corresponding bis-epoxide.

Although the precise role of the oxalate co-catalyst remains unclear (see below), the

formation of a Mn-tmtacn/oxalate species (22, Figure 11.6) [99], related to known

2 þ

- and Cr

3 þ

-structures [100], has been proposed. It has been suggested that the

addition of a catalytic amount of the bidentate oxalate impedes the formation of the

m-peroxo-bridged dimer 23, and as a result the catalase-type decomposition of H

typical of dinuclear complexes, is suppressed [34].

Nevertheless, the system of De Vos and coworkers based on the use of oxalate

buffer represented a major advance in the application of this catalyst and stimulated

the search for other additives that could further improve the reactivity of this system.

Subsequently, additives such as ascorbic acid (Scheme 11.11) and squaric acid

facilitated extension in the epoxidation activity of the Mn-tmtacn complex with

[94a]. Although only a limited number of substrates were examined, nearly

[Mn(OTf)

(

)]

Figure 11.7 Ligand 24 used in the catalyzed oxidation of alkenes with H

and acetic acid

[101, 102].

MnN

IV IV

2+ 2+

62322

Figure 11.6 Dinuclear Mn-tmtacn complexes 6 and 23, and the proposed structure for the

Mn-tmtacn/oxalate oxidation catalyst 22 (X ¼ activated O to be transferred [99].

390

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

quantitative yields of epoxides with retention of alkene conﬁguration were found

employing catalyst loadings as low as 0.03 mol%. The electron-deﬁcient methyl

acrylate and the terminal alkene 1-octene were converted to the corresponding

epoxides with yields of 97% and 83%, respectively. Typical conditions are shown

in Scheme 11.11. Importantly, the H

efﬁciency with this Mn catalytic system was

one of the highest reported thus far.

Recently, Costas and coworkers reported a modiﬁed manganese-tmtacn system

for the epoxidation of alkenes that has shown to be particularly effective where

the terminal oxidant is a peracetic acid (0.1 mol% catalyst, 500–1000 t.o.n.,

Table 11.7) [101]. This system is based on a tmtacn-type ligand in which one of the

methyl groups is replaced by a pyridyl group (24, Figure 11.7) and shows a broad

substrate scope including cyclic, aromatic, and allylic cis- and trans-alkenes and

terminal alkenes. Isotope labeling studies indicated that the incorporated oxygen was

derived solely from the peracid. This system was subsequently found to be highly

effective when H

was employed as terminal oxidant also, and, importantly, the key

to its success was found to be the addition of excess acetic acid. As in the case of the

related Mn-tmtacn based systems, the acetic acid suppresses the catalase activity of

the complex, allowing epoxidation to compete effectively [102]. Under these condi-

tions, normally acid-sensitive substrates such as stilbenes and 1-phenylcyclohexene

could be epoxidised effectively (Table 11.7), which was not possible with peracetic

acid. This difference has been ascribed to the presence of traces of strong acid

impurities such as H

in commercial peracetic acid. From a mechanistic

perspective, the absence of cis-dihydroxylation (see below) indicates that this system,

although structurally similar to Mn-tmtacn, represents a new class of manganese

oxidation catalysts. Importantly, the addition of the pyridyl groups results in distinct

chemoselectivity, which allows, for example, for selective monoepoxidation of dienes.

As noted by Costas and coworkers, a key point in understanding the increase in

efﬁciency in the case of acid-sensitive substrates, seen upon switching from peracetic

acid to acetic acid/H

, highlights the point that commercial peracetic acid contains

substantial levels of H

and is considerably more acidic.

HOH

0.03 mol% Mn(OAc)

.4H

0.04 mol% tmtacn

0.2-0.3 mol% ascorbic acid

2.equiv. H

(30% aq.)

MeCN, 0

97%

ascorbic acid

Scheme 11.11 Epoxidation promoted by ascorbic acid [94a].

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

391

Table 11.7 Epoxidation of alkenes with H

/CH

HinCH

CN catalyzed by [Mn(OTf)

(L)]

L ¼ 24 Conv. (yield) L ¼ 37 Conv. (yield)

100 (94) 89 (77)

91 (91) —

100 (94) 31 (31)

100 (92) 83 (78)

Ph Ph

100 (86) 26 (26)

100 (95) 36 (28)

100 (83) 100 (97)

96 (81) 95 (75)

90 (90) 95 (70)

84 (84) 89 (89)

87 (87) 61 (53)

100 (89) 100 (87)

100 (90) 59 (51)

97 (83) —

100 (92) —

95 (86) —

a) Typical reaction conditions: alkene (1.66 mmol), catalyst (1.66 mmol), acetic acid 14 equiv.

(23.3 mmol), CH

CN (15 mL), 1.1–1.4 equiv. H

added over 30 min at 0



392

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide