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

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droxylation activity, however, a change in the UV-vis absorption spectrum is observed,

and ultimately the characteristic absorption spectrum of a [Mn

III

O(m-O)(m-RCO

)

(tmtacn)

]

2 þ

-type complex appears. Notably, further addition of oxalic acid at the

point where the selectivity of the system changes suppresses cis-dihydroxylation

completely, and only epoxidation is observed. These studies demonstrate that it is not

necessarily the case that a single mechanism is in operation for all additives studied.

It is clear that systems containing ascorbic or oxalic acid are more complex, and while

insight gained with one additive/[Mn

(m-O)

(tmtacn)

]

2 þ

combination is relevant

to other similar systems, it must be recognized that distinctly different catalytically

active species can be generated with different additives. The occurrence of different

catalytic mechanisms implies that it may be possible to tune the activity of 6 further

through the use of other additive classes than those tested to date.

Asymmetric cis-dihydroxylation of Alkenes with Mn-tmtacn Although readily acces-

sible through the osmium-based catalytic methods developed by Sharpless and

coworkers [114, 124, 125], asymmetric cis-dihydroxylation (AD) of alkenes still poses

a key challenge industrially because of the cost and toxicity of the osmium-based

AD systems, which has precluded their widespread industrial application [126]. This

has provided a strong driving force behind the identiﬁcation and development of

economically viable and environmentally benign methods based on ﬁrst-row tran-

sition metals and H

. Despite considerable effort over the past two decades the

search for ﬁrst-row transition metal-catalyzed alkene cis-dihydroxylation methods

themselves remains a key challenge. Recent success in using iron-based systems by

Que and coworkers [127] demonstrated that the challenge may yet be met. Recently,

Feringa and coworkers demonstrated [128] that the Mn-tmtacn based catalytic system

employing carboxylic acids can be used for asymmetric cis-dihydroxylation of an

electron-rich cis-alkene – ironically a notably challenging substrate in the case of the

osmium-based systems. Importantly, the manganese-based catalytic system for AD

of alkenes developed employs H

as the oxidant. With 0.4 mol% catalyst loading,

the enantioselective cis-dihydroxylation of 2,2

-dimethylchromene proceeds with full

conversion and high selectivity toward the cis-diol product with an enantiomeric

excess of up to 54% (Scheme 11.16). In contrast to previous efforts to achieve

enantioselectivity with tmtacn-type catalysts by modifying the tmtacn ligand, in this

approach chiral carboxylato ligands were employed allowing for rapid screening of a

large library of potential chiral ligands.

Although the reactivity and selectivity is readily tunable by variation in the

carboxylic acid employed, the preference of this system toward electron-rich cis-

alkenes limits its scope. Nevertheless, the high turnover numbers and efﬁciency

achieved, the tunablity of the system, and its use of H

as the terminal oxidant

demonstrate that a sustainable and synthetically useful method for ﬁrst-row tran-

sition metal-catalyzed AD is realizable.

11.4.4.3 Manganese Complexes for Alkene Oxidation Based on Pyridyl Ligands

A drawback associated with the 1,4,7-trimethyl-1,4,7-triazacyclononane based

catalyst is the often tedious procedure to achieve modiﬁcations of the ligand

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

403

structure [129]. In view of the excellent catalytic activity of the Mn-tmtacn systems, a

major challenge is therefore the design of novel dinucleating ligands featuring the

three-N-donor facial coordinating set (as for the tmtacn ligand) for each manganese

site [131] while retaining the high oxidation activity. Stack, Chan, and coworkers have

employed pyridyl-amine based manganese complexes as highly efﬁcient catalysts in

the epoxidation of alkenes using peracetic acid and isobutyraldehyde/O

, respec-

tively [130]. The development of equally effective catalysts employing H

, however,

is a major challenge.

High epoxidation activity was found for manganese complexes based on dinu-

cleating ligand N,N,N

-tetrakis(2-pyridylmethyl)-1,3-propanediamine (tptn) [132].

The ligand contains a three-carbon spacer between the three-N-donor sets. This type

of ligand is readily accessible, and facile modiﬁcation of the ligand structure can be

achieved. Complexes of this type have also been reported as mimics for PSII [131].

Complex 34 [(Mn

O(OAc)

tptn)]

2 þ

is able to catalyze the oxidation of a range of

alkenes including styrene, cyclohexene, and trans-2-octene to the corresponding

epoxides in good yields and turnovers up to 870 (Scheme 11.17). In sharp contrast,

CN/H

0.4 mol% Mn-dimer

4.0 mol% R-CO

up to 54% ee

III

O O

Scheme 11.16 Asymmetric cis-dihydroxylation (AD) of 2,2-dimethylchromene with H

catalyzed

by the system 6/R-CO

H(¼acetyl-D-phenylglycine) [128].

O O

(0.1 mol%)

(aq 30%)

acetone, 0

868 t.o.n. (87%)

n=1

35 n= 0

(ClO

)

Scheme 11.17 Epoxidation with Mn-tptn catalyst and structures of manganese complexes [132].

404

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

complex 35 based on N,N,N

-tetrakis(2-pyridylmethyl)-1,2-ethylenediamine

(tpen), featuring a two-carbon spacer between the three-N-donor sets in the ligand,

was unreactive in epoxidation reactions [132].

High selectivity was observed in the epoxidation of cyclic alkenes (especially

cyclohexene) with the important feature that allylic oxidation products were not

obtained. Excellent results are reported for internal alkenes, for example, trans-2-

octene and trans-4-octene, whereas terminal linear alkenes give slightly lower yields.

The oxidation of cis-b-methylstyrene with H

in the presence of [Mn

(OAc)

tptn]

2 þ

catalyst (34) provides in addition to the corresponding cis-epoxide

also a considerable amount of trans-epoxide. Cis/trans isomerization has been

frequently observed in mechanistic studies using porphyrin and manganese salen

catalysts and is usually attributed to the formation of a radical intermediate

(a, Scheme 11.18) with a lifetime sufﬁcient for internal rotation before ring closure

via reaction path B occurs to give the thermodynamically more stable trans-epoxide

(b) [133]. In the event of a rapid collapse of the radical intermediate (via reaction path

A) retention of conﬁguration will be observed. The Mn-39-based catalyst [34] provides

a viable alternative to the Mn-tmtacn and Mn-salen systems, with high activity for

epoxidation and the distinct advantage that ligand variation for further catalyst ﬁne-

tuning is readily accomplished.



A very recent study has identiﬁed that fort a

wide range of ligands containing the (pyridin-

2-yl)methyl unit, decomposition to pyridine-

2-carboxylic acid occurs in the presence

of hydrogen peroxide and acetone. It is the

pyridine-2-carboxylic acid thus formed that is

responsible for the activity observed. See Pijper

et al. (2010) Dalton, DOI:10.1039/

C0DT00452A and Saisaha et al. (2010) Org.

Biomol. Chem., in press.

R R'

III

Path A

Path B

Scheme 11.18 Radical-type pathways to epoxidation of alkenes [133].

11.4 Epoxidation and cis-Dihydroxylation of Alkenes

405

Costas and coworkers have shown recently that manganese complexes based on

BPMEN-type ligands (where BPMEN is bis((pyridin-2-yl)methyl)ethylene-1,2-

diamine, Figure 11.11) show enhanced activity in the epoxidation of alkenes with

in the presence of excess acetic acid, albeit with lower activity and with a

narrower substrate scope than for the pyridyl-tmtacn based systems reported in the

same study (see above, Table 11.7) [102].

Recently, Zhong et al. have reported a series of quinolin-8-ol-based manganese

catalysts which show remarkably high efﬁciency in the epoxidation of a wide range

of alkenes with H

in acetone/water [134]. A key ﬁnding in this study is that

the activity was highly pH dependent and the reaction could be controlled by

regulating pH.

11.5

Manganese Catalysts for the Oxidation of Alkanes, Alcohols, and Aldehydes

11.5.1

Oxidation of Alkanes

From an industrial perspective, alkanes represent one of the most challenging and

one of the most important classes of substrates with regard to oxidation catalysis.

CH activation with manganese-based catalysts is an area of continuing interest,

with considerable attention being given to systems employing peracetic acid [135]

and iodosylarenes [136]. Nevertheless, several groups have demonstrated that H

can also be employed to effect alkane oxidation with the help of Mn catalysts [137] and

Fe catalysts [138].

In general, the focus on alkane oxidation has been on CH activation of standard

alkane substrates; however, recently focus has shifted toward selective reactions on

real synthetic targets. An impressive example of this can be seen in the report of Chen

and White employing an iron-based catalyst and H

as the terminal oxidant [139].

More recently, Macleod et al. have used the Jacobsen salen catalyst to achieve selective

OTf

Figure 11.11 BPMEN type ligands 36 and 37 employed by Costas and coworkers for the

epoxidation of alkenes with H

/acetic acid [102].

406

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

CH activation of pharmaceutical intermediates including phenylethylmalondia-

mide, primidone, and phenobarbital [140].

Although focused on the oxidation of alkenes, de Boer et al. [117] noted in their

report from 2005 that [Mn

(m-O)

(tmtacn)

]

2 þ

together with 1 mol% of CCl

was moderately effective in the oxidation of linear and cyclic alkanes with H

for example, with cyclooctane: 50% conversion to cyclooctanone with 1.3 equiv.

. Unfortunately, the high activity of this class of complex for alcohol oxidation

precludes selective CH oxidation to the alcohol (see below).

11.5.2

Oxidation of Alcohols and Aldehydes

In the common repertoire of synthetic methods, the selective oxidation of alcohols to

aldehydes holds a prominent position. A number of catalytic procedures have been

introduced in recent years, and the Ley-Grifﬁth system employing [NBu

][RuO

N-methylmorpholine oxide has proven to be particularly valuable in synthetic

applications [141]. Selective catalytic aldehyde formation using H

as terminal

oxidant is highly warranted, however. The Mn-tmtacn [94c] catalysts and several

in situ prepared complexes [142] of Mn(OAc)

with tptn-type ligands (Scheme 11.19)

have been shown to be selective catalysts for the oxidation of benzyl alcohols as well as

secondary alcohols to the corresponding aldehydes and ketones. In the case of

oxidation of alcohols with Mn-tmtacn-based catalysts, aldehydes are formed initially,

but the reaction continues with formation of the corresponding carboxylic acids [117].

Mn complexes based on ligands 39–43 (Scheme 11.19), show high activity and

selectivity (t.o.n. up to 850, Table 11.9), depending on the ligand structure. Ligands 40

and 41, containing a two-carbon or three-carbon spacer and lacking one pyridine

compared to tptn, were found to form only moderately active catalysts, however, with

as longer induction periods observed than the case of 6.

0.1-0.2 mol% Mn(OAc)

0.1 mol% Ligand 38-43

acetone

aq. H

(30%)

40 n = 1

41 n = 2

( )n

42 n = 1

43 n = 2

( )n

38 n = 1

39 n = 2

( )n

Scheme 11.19 Ligands used for the manganese-catalyzed alcohol oxidation at ambient

temperature [142].

11.5 Manganese Catalysts for the Oxidation of Alkanes, Alcohols, and Aldehydes

407

Using in situ prepared complexes based on ortho-methyl-substituted ligands 42

and 43, excellent results were found, and, remarkably, the induction period was

strongly reduced. A strong 16-line EPR signal was observed immediately after mixing

ligand 43 with Mn(OAc)

, and substrate, which points to the involvement of

dinuclear species in the oxidation reaction. The catalyst based on the ligands with the

three-carbon spacers show in all cases much higher reactivity (shorter induction

period) than the two-carbon spacer analogs, which is likely to be a result of faster

formation of the dinuclear species in the former case. The primary kinetic isotope

effects (k

) for the Mn-catalyzed oxidation of benzyl alcohol and benzyl-d

alcohol

observed are in the range of 2.2–4.3. These values strongly indicate that cleavage of

the benzylic CH bond is involved in the rate-determing step [143]. It has been

concluded on the basis of these data that hydroxyl radicals are not involved in these

processes, as, owing to the high reactivity of these radicals, a much lower isotopic

effect would be expected [144]. Accordingly, no indication of hydroxylation of

aromatic rings was observed for any of the substrates. At this point it has not been

established which active species (e.g., high-valent Mn ¼ OorMnOOH) is involved

in the selective aldehyde formation.

11.5.3

Sulfides, Sulfoxides, and Sulfones

Although suﬁdes are among the most straightforward of substrates to oxidize, the

selective oxidation of sulﬁdes to sulfoxides and to a lesser extent sulfones is often

challenging for substrates other than simple dialkyl-, diaryl-, and alkylaryl-sulﬁdes.

In transition metal-catalyzed oxidations the relatively low reactivity of electron-

deﬁcient sulﬁdes and their insolubility in polar solvents is problematic when

is employed as the terminal oxidant.

Table 11.9 Oxidation of selected alcohols with in-situ-prepared Mn catalysts based on ligands 39

and 43 [142].

Substrate T.o.n.

Selectivity (%)

T.o.n.

Selectivity (%)

39 43

Benzyl alcohol 326 95 303 99

4-Methoxybenzyl alcohol 201 80 291 75

4-Chlorobenzyl alcohol 449 99 414 99

4-Triﬂuoromethylbenzyl alcohol 329 70 258 70

4-Fluorobenzyl alcohol 233 90 248 70

2,5-Dimethoxybenzyl alcohol 90 99 63 99

Cyclohexanol 363 95 593 80

Cycloheptanol 849 85 688 99

1-Octanol 108 85 46 90

2-Octanol 680 95 480 95

sec-Phenylethyl alcohol 657 90 715 95

a) Turnover numbers (t.o.n.) after 4 h and selectivity (%) with ligands 39 and 43.

408

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

The selective catalytic oxidation of sulﬁdes to sulfoxides has been a challenge for

many years, not unexpectedly in view of the importance of sulfoxides as intermedi-

ates in organic synthesis [145]. The undesired sulfone is a common by-product in

sulﬁde oxidation using H

as oxidant, and its formation must be suppressed in any

system intended for widespread application. Recently, Bagherzadeh et al. have

reported the selective oxidation of sulﬁdes to sulfoxides using a manganese(III)

complex based on bidentate oxazoline ligands [146]. In this system, a water-free

source of H

was employed (UHP) in methanol/dichloromethane. Notably the

selectivity toward oxidation to the sulfoxide or sulfone was determined both by the

solvent employed and by the nature of the axial ligand added (e.g., imidazole).

The use of aqueous H

is, however, advantageous because of the reduction in the

waste products that need to be dealt with. In addition, considerable effort has been

devoted to the development of catalytic methods for the preparation of optically active

sulfoxides [145]. Jacobsen and coworkers have applied manganese(III) salen com-

plexes to sulﬁ de oxidation [71a]. The high reactivity encountered with sodium

hypochlorite precluded the selective oxidation of sulﬁdes. With iodosylbenzene, by

contrast, complete selective oxidation to sulfoxide could be achieved [147]. As with

hypochlorite and UHP, iodosylbenzene shows poor solubility and low atom efﬁ-

ciency, while it is costly in large-scale applications. Suprisingly, with H

high yields

and identical enantioselectivities (34–68% ee) compared with iodosylbenzene could

be achieved [147]. In acetonitrile, 2–3 mol% of catalyst and 6 equiv. of oxidant resulted

in minimum formation of the sulfone [147]. Ligands with bulky substituents at the

3,3

- and 5,5

-positions yielded the highest enantioselectivities (Scheme 11.20). The

enantioselectivity for sulfoxidation was found to be generally lower than that observed

for epoxidation using the same catalysts. Para-tert-butyl-substituted salen 44 (R ¼

Bu, Scheme 11.20) was the most selective for a range of substrates. Mn complexes

derived from ligands with electron-withdrawing substituents showed lower

(R,R)-catalyst

44-45 (2-3 mol%)

6equivH

64-90% yield

up to 47% e.e.

Ph Ph

Scheme 11.20 Manganese(III)-salen complexes for sulfide oxidation introduced by Jacobsen

and coworkers [147].

11.5 Manganese Catalysts for the Oxidation of Alkanes, Alcohols, and Aldehydes

409

enantioselectivities, and, in the case of the para-nitro-substituted complex 44 (R ¼

), asymmetric sulﬁde oxidation was not observed.

Katsuki and coworkers have employed the related chiral manganese salen com-

plexes, in particular the so-called second-generation Mn(salen) 46, in sulﬁde oxida-

tion [148]. This complex was found to serve as an efﬁcient catalyst in asymmetric

sulfoxidation, albeit the less atom-efﬁcient iodosylbenzene was required as oxidant

(Scheme 11.21).

Katsuki and Saito reported that di-m-oxo titanium complexes of chiral salen ligands

serve as efﬁcient catalysts for asymmetric oxidation of a range of sulﬁdes using H

or UHP as terminal oxidants [149]. Enantioselectivities as high as 94% were

achieved [149]. A monomeric peroxo titanium species was proposed as the active

oxidant based on MS and NMR studies [150].

Mn catalysts that show activity in alkene or alcohol oxidation with H

are

potentially active in the oxidation of sulﬁdes also. The Mn-tmtacn catalysts and a

number of in-situ-formed complexes employing ligands such as 39 are examples

of such catalysts (see above). These complexes were found to be highly active in the

oxidation of sulﬁdes to sulfoxides. For example, the dinuclear manganese complex

based on tmtacn (6) performs efﬁciently in the oxidation of aryl alkyl sulﬁdes and

generally results in full conversion within 1 h. Unfortunately, as is often the case, in

2mol%

2.0 equivPhIO

OCH

+PF

94% ee, 90%

Scheme 11.21 Mn(III)-salen complexes for asymmetric sulfide oxidation reported by Katsuki and

coworkers [148c].

410

11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide

addition to the desired sulfoxide, the sulfone was also formed. Similar reactivity

patterns were observed with manganese complexes based on tpen (38) and tptn (39).

With ligand 47 (Scheme 11.22), however, only slight over-oxidation to sulfone was

observed [151]. Ligand 47 combines structural features of both tptn and salen ligands.

With ligand 48, a chiral version of ligand 47, the Mn-catalyzed conversion of sulﬁdes

to sulfoxides with H

proceeded in yields ranging from 48 to 55%, albeit with low

enantioselectivities (<18%) [152]. Schoumacker et al. have employed manganese

complexes of chiral bis-pyridyl-cyclohexane-1,2-diamine-based ligands in the asym-

metric oxidation of several aryl alkyl sulﬁdes using H

as the terminal oxidant [153].

Importantly, although the enantiomeric excess achieved was modest (ee <34%), the

presence or absence of acetylacetonate in the reaction determined which sulfoxide

enantiomer was formed. This is an indication that, as for epoxidation, the combi-

nation of metal and ligand is not the only factor that must be considered in catalyst

design. Other components may either act as additional ligands or affect the

coordination mode of the ligand to the metal, thereby in ﬂuencing the reactivity of

the catalyst as has been observed in the Mn-tmtacn based systems, vide supra.

11.6

Conclusions

Hydrogen peroxide is a particularly attractive oxidant and holds a prominent

position in the development of benign catalytic oxidation procedures. In recent

years a number of highly versatile catalytic oxidation methods based on, for example,

polyoxometalates [154], methyltrioxorhenium [155] or tungstate [4, 156] complexes

in the presence of phase transfer catalysts, all using hydrogen peroxide as the

terminal oxidant, have been introduced. Mn-catalyzed epoxidations, aldehyde

R Ar

0.2 mol% Ligand 47/48

0.2 mol% Mn(OAc)

.2H

Acetone

Scheme 11.22 Nitrogen- and oxygen-based donor ligands used in sulfide oxidation by Feringa and

coworkers [152].

11.6 Conclusions

411

formation, and sulfoxidation with H

have emerged as effective and practical

alternatives. In particular, recently developed epoxidation catalysts based on a

combination of Mn-tmtacn and additives show high activity and excellent selectivity

in the epoxidation of a wide range of alkenes. Despite considerable progress in

enantioselective epoxidation with Mn-salen systems using H

as the oxidant, a

general catalytic epoxidation method based on chiral Mn complexes remains a

highly warranted goal. Particularly promising are the ﬁndings that signiﬁcant cis-

dihydroxylation can be achieved with Mn catalysts. These studies could provide

guiding principles for the design of Mn catalysts as an alternative to current

Os-based chiral cis-dihydroxylation systems. For industrial application, further

improvement with respect to hydrogen peroxide efﬁciency and catalytic activity is

needed for most of the Mn systems developed so far. The delicate balance between

oxygen transfer to the substrate and hydrogen peroxide decomposition remains a

critical issue in all these systems. Other challenges include determination of the

nature of the Mn complexes in solution and identiﬁcation of the actual active species

involved in oxygen transfer and the mechanisms of the Mn-catalyzed oxidations with

hydrogen peroxide, and elucidation of the key role of the additives in several cases. It

is likely that detailed insight into these aspects of the catalytic systems developed

recently will bring major breakthroughs in Mn-catalyzed oxidations with hydrogen

peroxide in the near future.

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11 Manganese-Catalyzed Oxidation with Hydrogen Peroxide