Fe(PyTACN)-catalyzed cis-dihydroxylation of olefins with hydrogen peroxide

Article abstract of DOI:10.1002/adsc.201200938

A family of iron complexes with general formula [Fe(II)( ^R,Y,XPyTACN)(CF₃SO₃)₂], where ^R,Y,XPyTACN=1-[2′-(4-Y-6-X-pyridyl)methyl]-4,7-dialkyl-1,4, 7-triazacyclononane, X and Y refer to the groups at positions 4 and 6 of the pyridine, respectively, and R refers to the alkyl substitution at N-4 and N-7 of the triazacyclononane ring, are shown to be catalysts for efficient and selective alkene oxidation (epoxidation and cis-dihydroxylation) employing hydrogen peroxide as oxidant. Complex [Fe(II)(^Me,Me,HPyTACN)(CF ₃SO₃)₂] (7), was identified as the most efficient and selective cis-dihydroxylation catalyst among the family. The high activity of 7 allows the oxidation of alkenes to proceed rapidly (30 min) at room temperature and under conditions where the olefin is not used in large amounts but instead is the limiting reagent. In the presence of 3 mol% of 7, 2 equiv. of H₂O₂ as oxidant and 15 equiv. of water, in acetonitrile solution, alkenes are cis-dihydroxylated reaching yields that might be interesting for synthetic purposes. Competition experiments show that 7 exhibits preferential selectivity towards the oxidation of cis olefins over the trans analogues, and also affords better yields and high [syn-diol]/[epoxide] ratios when cis olefins are oxidized. For aliphatic substrates, reaction yields attained with the present system compare favourably with state of the art Fe-catalyzed cis-dihydroxylation systems, and it can be regarded as an attractive complement to the iron and manganese systems described recently and which show optimum activity against electron-deficient and aromatic olefins. Copyright

Full text of DOI:10.1002/adsc.201200938

FULL PAPERS
DOI: 10.1002/adsc.201200938
Fe
N
Irene Prat,a David Font,a Anna Company,a Kathrin Junge,b Xavi Ribas,a
Matthias Beller,b,* and Miquel Costasa,*
a
QBIS Group, Department of Chemistry and Institute of Computatioinal Chemsity and Catalysis (IQCC), University of
Girona, Campus Montilivi, 17071 Girona, Catalonia, Spain
Fax : (+34)-97-241-8150; e-mail: miquel.costas@udg.edu
Leibniz-Institute for Catalysis at the University of Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
b
Fax : (+49)-381-1281-51113; e-mail: matthias.beller@catalysis.de
Received: November 12, 2012; Revised: January 7, 2013; Published online: March 15, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200938.
Abstract: A family of iron complexes with general 15 equiv. of water, in acetonitrile solution, alkenes
formula [Fe(II)(R,Y,XPyTACN)
ACHTUNGTRENNUNG
alkyl-1,4,7-triazacyclononane, X and Y refer to the periments show that 7 exhibits preferential selectivity
groups at positions 4 and 6 of the pyridine, respec- towards the oxidation of cis olefins over the trans an-
tively, and R refers to the alkyl substitution at N-4 alogues, and also affords better yields and high [syn-
and N-7 of the triazacyclononane ring, are shown to diol]/ACHTUNTRGNEUNG[epoxide] ratios when cis olefins are oxidized.
be catalysts for efficient and selective alkene oxida- For aliphatic substrates, reaction yields attained with
tion (epoxidation and cis-dihydroxylation) employing the present system compare favourably with state of
hydrogen as
peroxide
oxidant.
Complex the art Fe-catalyzed cis-dihydroxylation systems, and
[Fe(II)(Me,Me,HPyTACN)
ACHTUNGTENRN(NUG CF3SO3)2] (7), was identified it can be regarded as an attractive complement to
as the most efficient and selective cis-dihydroxyla- the iron and manganese systems described recently
tion catalyst among the family. The high activity of 7 and which show optimum activity against electron-
allows the oxidation of alkenes to proceed rapidly deficient and aromatic olefins.
(30 min) at room temperature and under conditions
where the olefin is not used in large amounts but in-
stead is the limiting reagent. In the presence of Keywords: alkenes; cis-dihydroxylation; homogene-
3 mol% of 7, 2 equiv. of H2O2 as oxidant and ous catalysis; hydrogen peroxide; iron
Introduction
drawbacks to the practical applicability of these reac-
tions. Because of that, more convenient alternatives
Olefin cis-dihydroxylation is an important reaction are actively pursued. Methodologies that employ cata-
for organic synthesis because syn-diols are very useful lytic amounts of OsO4 in combination with sacrificial
synthons for a number of organic transformations. oxidants have been successfully developed,[5] and less
Notably, olefins constitute convenient feedstocks be- toxic Ru[6–12] and Pd[13–19] catalyst-based methods have
cause of their readily availability from petroleum re- been studied, but obviously the most attractive solu-
sources.[1,2] cis-Dihydroxylation reactions are com- tion will be to discover heavy-metal free reac-
monlyÀ performed with stoichiometric amounts of tions.[20–26] Towards this end, organic peroxides have
MnO4 , and heavy metal oxides such as RuO4 and been recently explored with promising results. In ad-
OsO4. Particularly reliable in terms of yields and se- dition, a particularly appealing alternative is the de-
lectivity are methodologies that rely on the latter velopment of catalytic methodologies that make use
metal. Outstanding and predictable stereoselectivities of first-row transition metal catalysts, and convenient
and yields can be routinely attained by using well-es- oxidants such as peroxides. Along this line, selected
tablished Cinchona alkaloid ligands.[3,4] However, the Mn complexes have been recently described as highly
toxicity and significant cost of OsO4 pose serious active cis-dihydroxylation catalysts in combination
Adv. Synth. Catal. 2013, 355, 947 – 956
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
947

Irene Prat et al.
FULL PAPERS
with H2O2 and Oxone.[27–31] Despite their obvious in- triad donor set present in the enzyme,[32,45] have been
terest, so far these reactions have a rather limited also explored (Scheme 1).[46–48]
substrate scope, and provide best yields and selectivi-
The major drawback of these bioinspired catalysts
ty in the cis-dihydroxylation of electron-deficient ole- is that they require the use of a large excess of sub-
fins. Excellent enantioselectivities have been also very strate, and provide very modest turnover numbers
recently obtained in selected cases, by employing (TONs) and substrate conversion. Therefore, an im-
Oxone as oxidant.[30]
portant goal in the field of bioinspired oxidation cat-
The family of Rieske oxygenases is a versatile alysis remains in the design of catalysts for perform-
group of bacterial iron-dependent enzymes that cata- ing cis-dihydroxylation reactions in a more practical
lyze a wide array of oxidation reactions,[32–36] but their manner. Research towards this target has been at-
biotechnological interest remains in their capacity for tempted with tpa-based systems with moderate to
catalyzing stereo- and enantioselective cis-dihydroxy- good yields and moderate selectivity towards cis-dihy-
lation of arenes and olefins. The activity of these en- droxylation vs. epoxidation.[49] In terms of yields and
zymes constitutes a source of inspiration for the de- selectivities, state of the art Fe-catalyzed olefin cis-di-
velopment of synthetic methodologies and iron cata- hydroxylations were reported recently by Che and co-
lysts that are able to mediate the cis-dihydroxylation workers, who described a chemically robust complex
of olefins.[37] Inspired by these enzymes, the ability of [Fe
iron complexes to catalyze these reactions was first combination with Oxone as oxidant (Scheme 1). By
described for the [Fe(II)(tpa)] family of com- using 0.7–3.5 mol% of catalyst loading, and Oxone
plexes,[38–40] and rapidly extended to a series of iron (2 equivalents) as terminal oxidant, a range of alkenes
(III)(Cl)2(c-Py2NMe2)]+ as an efficient catalyst in
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
complexes
containing
N-based
ligands was oxidized at room temperature with moderate to
(Scheme 1).[41–44] Iron catalysts which contain ligands good yields and high chemoselectivities. Best yields
that combine N and O donor sites, and that are more were obtained in the cis-dihydroxylation of electron-
closely related to the actual His2Carboxylate-facial poor alkenes.[50]
We have previously described a family of iron com-
plexes based on a triazacyclononane ligand, [Fe(II)-
AHCTUNGTRENNUNG
(CF3SO3)2(R,Y,HPyTACN)] (where R=Me, i-Pr, Y=H,
Me, 1, 7, 10 and 11, Scheme 2) as models for non-
heme iron-dependent oxygenases.[44,51] In the presence
of a large excess of substrate with respect to the oxi-
dant (10–100 milliequiv. H2O2 per equiv. of substrate)
these complexes make an efficient use of the peroxide
to mediate alkane and alkene oxidation reactions,
suggesting that they are promising candidates to de-
velop bioinspired oxidation catalysts with synthetic
value.
Scheme 1. Representation of ligands used to prepared mon-
onuclear iron (II) complexes to perform olefin oxidation. A)
Complexes based on N4 ligands and B) complexes based on
N,N,O ligands.
Scheme 2. Family of [Fe
studied as cis-dihydroxylation catalysts.
(CF3SO3)2(R,Y,XPyTACN)] complexes
ACHTUNGTRENNUNG
948
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 947 – 956

FeACHTUNGTRENNUNG(PyTACN)-Catalyzed cis-Dihydroxylation of Olefins with Hydrogen Peroxide
Table 1. Oxidation of cis-cyclooctene (S1) with H2O2
catalyzed by the family of complexes
[Fe(II)
(CF3SO3)2(Me,X,YPyTACN)].[a]
Herein, we describe the development of the family
of [Fe(II)
(CF3SO3)2(Me,Y,XPyTACN)] (Scheme 2) com-
plexes as catalysts for the cis-dihydroxylation of ole-
fins in yields that may be amenable for synthetic pur-
poses, employing H2O2 as oxidant.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Results and Discussion
Catalyst H2O2 (milliequiv.)
(TON)[b] 1D+1E[c] 1D/1E[d]
ACHTUNGTRENNUNG
Catalyst Screening
1
2
3
4
5
6
7
8
9
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
8
99
9
85
9
85
8
50
8
69
7
73
7
86
8
63
8
1.0
1.0
2.6
1.0
1.5
2.1
1.5
1.1
2.3
1.4
0.8
1.0
5.5
6.2
2.5
4.7
3.6
3.5
Our
ACHTUNGTRENNUNG
previous
studies
with
[Fe(II)-
(CF3SO3)2(Me,Y,XPyTACN)] complexes have shown
that N-methyl substituted TACN rings give rise to
more active catalysts than those containing N-i-Pr
substitutions.[44] Further optimization of this family of
catalysts was devised by introducing modifications in
the positions 4 and 6 of the pyridine ligand. Groups
with different electronic properties were inserted in
position 4 of the pyridine in order to study putative
electronic effects in the catalytic activity. On the
other hand, modifications in position 6 were pre-
sumed to mainly introduce steric effects, because this
position is in close spatial proximity to the cis-avail-
able coordination sites, initially occupied by labile tri-
flate ligands, and where oxidation of the substrate
takes place. Taking these premises into consideration,
the series of complexes shown in Scheme 2 was tested
as catalysts in olefin oxidation. A first screening was
performed by using a large excess of olefin (cis-cyclo-
octene (S1), (1 equiv.), and reduced amount of oxi-
dant H2O2 (10–100 milliequiv.) added via syringe
pump (30 min) to an acetonitrile solution of the cata-
lyst (0.1 mol%). These conditions are commonly em-
ployed in the literature for iron-catalyzed cis-dihy-
droxylation reactions, and allow a fair comparison
with our family of catalysts.[37] Under these conditions,
the current set of iron complexes catalyzes the oxida-
100
81
[a]
1 equiv. of substrate was employed, catalyst concentra-
tion 1 mM (0.1 mol%). The reaction was performed by
slow syringe pump addition over 30 min, of an acetoni-
trile solution of H2O2 into a solution of catalyst and sub-
strate at room temperature.
TON=turnover number (mol product/mol catalyst).
1D stands for syn-cyclooctane-1,2-diol, and 1E for cyclo-
octene epoxide.
[b]
[c]
[d]
1D/1E=mols of diol/mols of epoxide.
tion of the model substrate cis-cyclooctene to give lectivity to ratios D/E 2.3–2.6 (see catalysts 2 and 5).
a mixture of cyclooctene epoxide (1E) and cis-1,2-cy- These differences are lost at higher peroxide concen-
clooctanediol (1D) (Table 1, Scheme 2). The full trations, and catalysts 1, 2 and 4, 5 uniformly provide
family of complexes provides good to excellent con- nearly equimolar mixtures of epoxide and diol. Com-
version of the oxidant into the different olefin oxida- plex 3 appears to be an exception, showing a slight
tion products (50 to 99%). Efficiencies attained by preference towards cis-dihydroxylation. On the other
these complexes are among the highest reached with hand, a more substantial increase in the chemoselec-
any non-heme iron catalyst under analogous condi- tivity towards the syn-diol product is observed both at
tions.[37,39–50,52–56]
low and high peroxide concentrations when the
The results on the catalytic activity of the series of proton in the position 6 of the pyridine ligand is re-
complexes where substitution is introduced at position placed by bulkier groups such as Me (7 and 9), or Cl
4 of the pyridine (1–5) shows that the chemoselectivi- (8). Fluorine-substituted complex 6 gives an equimo-
ty towards epoxidation vs. cis-dihydroxylation is gov- lar mixture of epoxide and syn-diol. Most remarkable
erned only to a minor extent by electronic effects im- among the full series of complexes, catalyst 7 exhibit-
posed by the pyridine ring. The simplest catalyst ed a high chemoselectivity towards the formation of
1 yields an equimolar mixture of epoxide and syn- the syn-diol product, while retaining a high efficiency
diol. The catalysts with electron-withdrawing groups in the use of H2O2. These results prompted us to in-
NO2 and Cl (3, 4) slightly favour the cis-dihydroxyla- vestigate conditions where the substrate was the limit-
tion, while electron-donating groups enhance this se- ing reagent by using complex 7.
Adv. Synth. Catal. 2013, 355, 947 – 956
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
949

Irene Prat et al.
Oxidant
FULL PAPERS
Table 2. Oxidation of cis-cyclooctene (S1) using catalyst 7: optimization of reaction conditions.[a]
Entry
Cat. (mol%):Oxidant (equiv.):H2O (equiv.)
1D [%]
1E [%]
1D/1E
Conv[b] [%]
1
2
3
4
5
6
7
8
3:2:0
3:1.2:15
3:1.6:15
3:2.5:15
3:2:0
24
42
47
46
2
37
9
0.6
4.7
3.9
3.3
0.1
–
99
75
81
87
>99
46
13
35
99
99
H2O2
H2O2
H2O2
12
14
64
31
9
3.5
17
13
15
10
H2O2
H2O2/AcOH[c]
peracetic acid
Oxone
TBHP
3:2:0
0
0
1:2:[d]
–
3:2:15
3:2:5
3:2:10
3:2:15
3:2:20
0.5
31
41
56
28
0.14
1.9
3.3
3.6
3.3
9
H2O2
H2O2
H2O2
H2O2
10
11
12
90
86
[a]
1 equiv. refers to substrate, catalyst concentration 1 mM. The reaction was performed by slow syringe pump addition
(15 min) of H2O2 to a solution of the catalyst (700 mM solution in CH3CN), the substrate and water when required at
08C. Yield obtained by GC.
Conv=substrate conversion.
In the presence of 150 equiv. of acetic acid.
[b]
[c]
[d]
Solvent used MeCN:H2O (1:1) and the addition of 300 equiv. of NaHCO3.
By employing 3 mol% of catalyst 7, and 2 equiv. of Table 3. Oxidation of cis-cyclooctene (S1) applying different
catalysts.[a]
H2O2 with respect to substrate (Table 2), cis-cyclooc-
tene was converted into epoxide and diol in a com-
bined 61% yield, with epoxide being the main prod-
uct (37%). Other oxidants such as peracetic acid,
TBHP and Oxone were also tested under analogous
conditions, but none of them provided better yields.
The combination of H2O2 and acetic acid provided
the epoxide in 64% yield and only minor amounts of
the diol. Because of that, H2O2 was retained as the
oxidant of choice.
Catalyst
Yield 1D+1E [%]
1D/1E
Conversion [%]
1
3
6
7
8
9
46
56
60
71
57
64
0.56
0.42
0.42
3.6
3.4
3.3
99
99
95
90
95
91
[a]
All reactions were performed using 3 mol% of catalyst,
1 equiv. of substrate, 2 equiv. of H2O2 and 15 equiv. of
water. Yield obtained by GC.
Interestingly, addition of water has a significant
beneficial effect on the chemoselectivity of the reac-
tion favouring syn-diol formation. When water was
added, the ratio [diol]/ACTHNUGRTNEUNG[epoxide] increased considera- hand, complexes 1, 3 and 6 give comparable or slight-
bly, and the syn-diol product 1D was obtained with ly inferior yields, (46–60%), but low diol/epoxide
good yields (Table 2, entries 9–12). The optimum con- ratios (0.4–0.6) (Table 3).
centration of water necessary for cis-dihydroxylation
was screened by using from 5 to 20 equiv. of water.
The best catalytic results were obtained when Substrate Scope
15 equiv. were used. Under these optimized condi-
tions, cis-cyclooctene was oxidized to corresponding Next, the substrate scope of the catalytic cis-dihydrox-
syn-diol 1D (56%) and epoxide 1E (15%).
ylation was investigated under the optimized condi-
By using these conditions (Table 2, entry 11), tions in the presence of complex 7. Best yields were
3 mol% of catalyst, 2 equiv. of H2O2 with respect to obtained when terminal or cis aliphatic olefins were
the substrate, and 15 equiv. of water, in acetonitrile used as substrates (Table 4, substrates S1, S2, S5–S8).
solution, some of the complexes were tested for the In these cases the syn-diol product was obtained in
oxidation of cis-cyclooctene. Catalyst 7 remained as 25–56% yield, and diol/epoxide ratios range from 1.8
the most efficient for this type of reactions. Moreover, to 3.6. On the other hand, when the system was ap-
this screening confirmed our initial hypothesis that plied in the oxidation of trans olefins such as trans-2-
the only complexes that provide high chemoselectivity octene (S3), trans-4-octene (S4), and the 1,1-disubsti-
towards cis-dihydroxylation are those that have tuted olefin 2-methyl-heptene (S9), the epoxide prod-
a bulky group in the 6 position of the pyridine; com- uct was obtained preferentially. Noteworthy, besides
plexes 8 and 9 give moderate yields 57–64%, and che- epoxide and diol, 2-hydroxy ketone products were
moselectivity towards syn-diol as shown by diol/epox- also identified as oxidation products in some of the
ide ratios of 3.4 and 3.3, respectively. On the other reactions. The latter products are most likely originat-
950
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 947 – 956

FeACHTUNGTRENNUNG(PyTACN)-Catalyzed cis-Dihydroxylation of Olefins with Hydrogen Peroxide
Table 4. Substrate scope.[a]
Substrate
Conversion
Yield [%]
D/E
Yield [%]
D
56
56
E
S1
S2
94[b]
92[b]
15
26
3.6
2.2
71
82
S3
S4
S5
S6
S7
S8
80
66
85
68
56
51
9
4
35
37
35
33
25
17
20
14
12
12
0.4
0.2
1.8
2.6
2.9
2.8
34
21
55
51
47
46
S9
66
68
-.
7
39
21
26
0.2
49
42
48
S10
S11
21
22
1
0.9
S12
S13
75[c]
77
25
13
1.8
3.4
38
40
31; 25[d]
9; 3[d]
S14
S15
89
80
43
34
23
22
2.0
1.5
66
56
S16
S17
80
76
9
35
0.3
1.7
44
60
38; 38[d]
22; 22[d]
[a]
1 equiv. of substrate, 3 mol% catalyst (1 mM). The reaction was performed by slow syringe pump addition (15 min) of
2 equiv. of H2O2 (700 mM solution in CH3CN) to a solution of the catalyst, the substrate and 15 equiv. of H2O at 08C.
Hydroxy ketone yields for substrates cis-cyclooctene (S1) and cis-2-octene (S2) are 6% and 5%, respectively; in the other
cases are <5%.
Alcohol product resulting from deprotection is obtained in 20% yield.
Isolated yields.
[b]
[c]
[d]
ing from overoxidation of the originally formed syn- oxidation species involved. In the case of the
diol. On the other hand, aromatic olefins are not suit- [Fe complex, cis-
(III)(Cl)2(c-Py2NMe2)]+
A
a
able substrates for the system. Oxidation of cis-b- Fe(V)(O)(OH) and/or cis-Fe(V)(O)2 is proposed to
methylstyrene gives a mixture of products, and the be the active catalytic species.[50] The oxidizing species
same occurs when an aromatic enone such as methyl proposed for catalyst 7 on the basis of isotopic label-
cinnamate was employed as substrate. The latter sub- ling analysis is described as Fe(V)(O)(OH).[44] At
strate is oxidized very efficiently and selectively by present it is not possible to ascertain the basis for the
the [FeACHTUNGTRENNUNG
(III)(Cl)2(c-Py2NMe2)]+ system recently de- distinct electronic preference exhibited by both spe-
scribed by Che et al.[50] Moreover, this catalyst can ox- cies. On the other hand, precedents for electrophilic
idize the diester dimethyl fumarate giving 99% of and nucleophilic preferences in iron-based cis-dihy-
syn-diol product, but our catalyst 7 is not capable of droxylation catalysis has been previously documented
oxidizing this olefin, presumably because it is deacti- for the Fe
vated by the two ester groups. Because of this differ- they may arise from distinct spin states.[57]
ent catalytic behaviour it is very likely that both sys- Functional groups are tolerated to a different
tems differ fundamentally in the nature of the active extent. Olefins containing epoxide (S13) and siloxane
ACHTUNGTRENUN(NG TPA) family of complexes, suggesting that
Adv. Synth. Catal. 2013, 355, 947 – 956
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
951

Irene Prat et al.
FULL PAPERS
(S12) functionalities are oxidized towards the corre-
cis- and trans-olefins behave quite differently in
sponding syn-diol in yields close to 30%. When the these catalytic reactions. Hence, further information
olefin substrate contains an ester moiety, the yields to explain this difference was sought by means of
depend on the distance between the olefin and the competition experiments. Competitive oxidation of an
ester group. Moderate yields (approx 45%) are ob- equimolar mixture of cis-2-octene (S2) and trans-2-
tained when the olefin is distant to the ester group octene (S3) led to quantitative conversion of the cis-
(S14), but drops to 34% as the ester is closer to the isomer, while 50% of the trans-isomer remained un-
olefinic sites (S15). Nevertheless, chemoselectivity to- reacted. Moreover, cis-2-octene oxidation occurred
wards cis-dihydroxylation appears to be highly depen- preferentially towards the diol product (2D) (diol/ep-
dent on the nature of the substrate; norbornene-2-yl oxide ratio=3), while trans-2-octene oxidation afford-
acetate (S16) is oxidized with a poor chemoselectivity ed only minor amounts of the diol (3D) (4%). The re-
towards the diol, yielding a low D/E ratio (Table 4). action exhibited a poor mass balance, and epoxide
A halide moiety is reasonably tolerated, hence 1- (3E) was obtained in modest 14% yield (Scheme 4,
chloro-cis-non-9-ene (S17) was oxidized in 59% com- A).
bined yield (38% diol and 22% epoxide). Terminal
A second competitive experiment was performed
olefins in linear alkenes afford relatively good yields with the substrate trans-trans-cis-1,5,9-cyclododeca-
of cis-diol. The possibility that part of this diol will triene (S19) where trans- and cis-olefin sites are pres-
originate from epoxide ring opening was therefore in- ent in the same substrate in a relative 2:1 ratio. cis-
vestigated. When 1,2-octene epoxide was submitted to Dihydroxylation took place preferably in the cis-
catalytic
conditions,
catalyst:epoxide:H2O2:H2O olefin, giving a 39% of the syn-diol product (19D),
(3:100:200:150), the epoxide product was recovered and only 11% of syn-diol resulting from cis-dihydrox-
in 80% yield and no formation of syn-diol product ylation at the trans-olefin site (19D’). However, the
was observed. Because of that we concluded that the epoxidation occurred with similar relative reactivity.
diol also comes exclusively from a cis-dihydroxylation Interestingly, oxidation of this substrate gave an ex-
reaction for these classes of substrates.
cellent overall ratio diol/epoxide=5 (Scheme 4, B).
Oxidation of (2E,6Z)-nona-2,6-dienyl acetate (S20)
A cautious note is that the mass balance shows sub-
stantial losses in some of the reactions. In the case of further underlines the preference of the catalyst to
the most volatile olefins, this may be an important oxidize cis-double bounds. In this case we also have
contributing factor, but in the case of substrates such to take into account that the trans-olefin is deactivat-
as 1-tert-butyldimethylsilyloxy-5-hexene (S12) and ed because of the proximity to the electron-withdraw-
1,5-cyclododecadiene-9,10-oxide (S13), mass loss is in- ing acetate group. The corresponding syn-diol result-
dicative of important, unidentified side reactions. ing from selective cis-dihydroxylation at the remote
Indeed GC-MS analysis of crude reaction mixtures re- cis-site was obtained in 50% yield (20D), along with
vealed the presence of multiple oxidation products in 13% of the corresponding epoxide (20E). Products
small amounts, preventing proper characterization.
arising from oxidation of the proximal trans-olefinic
Carboxylic acids are not compatible with the cis-di- site were not formed (Scheme 4, C).
hydroxylation activity of a terminal olefin. In the oxi-
An interesting target for selective cis-dihydroxyla-
dation of the pentanoic acid (S18), as observed in the tion represents the natural product cis-jasmone (S21),
presence of acetic acid, the formation of the syn-diol which was oxidized in relatively good yield (21D)
product was precluded, and the oxidation was di- (44%). In this case, the side product obtained was the
verged towards formation of the epoxide, which anti-diol 19% (21E), originating from the opening of
under the catalytic conditions provided the corre- the epoxide ring during work-up (Scheme 5).
sponding lactone 5-(hydroxymethyl)dihydrofuran-
2(3H)-one (18E), in 55% yield (Scheme 3).
Time Course Analysis
The selectivity towards the syn-diol product in reac-
tions where the substrate is the limiting reagent is
substantially smaller than that obtained with small
amounts of H2O2 and large excess of substrate. To
shed light onto this difference, a time course analysis
of the oxidation of cis-cyclooctene was performed.
The study shows that the syn-diol is formed with very
high selectivity within the first 20 min of the reaction
(Table 5). In this period, epoxide is obtained in minor
amounts and syn-diol/epoxide ratios are high (6.5–
Scheme 3. Catalytic oxidation of 3-pentenoic acid (S18).
8.3), comparable to the ratios observed under condi-
952
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 947 – 956

FeACHTUNGTRENNUNG(PyTACN)-Catalyzed cis-Dihydroxylation of Olefins with Hydrogen Peroxide
Scheme 4. Competitive oxidation experiments. Yields obtained by GC.
Table 5. Time course analysis using cis-cyclooctene.[a]
Time (min)
1D [%]
1E [%]
1D/1E
10
20
30
25
47
51
3
7
16
8.3
6.5
3.2
[a]
1 equiv. of cis-cyclooctene, catalyst concentration 1 mM
and oxidant concentration 700 mM. The reaction was
performed by slow syringe pump addition (30 min) of
H2O2 to a solution of the catalyst and the substrate at
room temperature. Samples were taken every 10 min.
centration of cis-diol would then block the iron site,
shutting down the cis-dihydroxylation reactivity. In
favour of this interpretation, product release appears
also to be the rate-determining step in the catalytic
Scheme 5. Catalytic oxidation of cis-jasmone (S21).
tions of limiting amounts of H2O2. After 30 min, the cycle of naphthalene dioxygenase, an enzyme of the
reaction slowed down and the epoxidation reaction Rieske oxygenase family that catalyzes the cis-dihy-
became more important, erasing the 1D/1E ratio.
droxylation of naphthalene.[58] In our catalytic system,
Based on these observations, we assume that syn- the excess of H2O2 in the absence of two available cis
diol products can reversibly bind to the iron site, be- sites at the iron catalyst may lead to epoxidation reac-
cause of the formation of a five-membered chelate tions, for which multiple paths may exist,[39,56] but also
iron glycolate (or hydrogen glycolate species). Previ- results in oxidation of the metal-bound diol towards
ous studies have shown that two cis-labile sites are re- the corresponding 2-hydroxy ketone. In order to test
quired for Fe-catalyzed efficient cis-dihydroxylation this idea, we performed the oxidation of cis-cyclooc-
reactivity. In agreement with this an increased con- tene (S1) in the presence of different amounts of syn-
Adv. Synth. Catal. 2013, 355, 947 – 956
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
953

Irene Prat et al.
Table 6. Catalytic oxidation of cis-cyclooctene S1 in the presence of different equivalents of syn-cyclooctane-1,2-diol.[a]
FULL PAPERS
Olefin [equiv.]:syn-diol [equiv.]
1D[b] [%]
1E [%]
1H [%]
1D/1E
1:0
0.7:0.3
0.5:0.5
56
37
0
15
18
22
6
12
29
3.6
2
–
[a]
The reaction was performed by slow syringe pump addition (15 min) of H2O2 to a solution of the catalyst, the substrate
and syn-diol at 08C.
Difference yield of syn-diol expressed as the difference D[1D]=[1D]after reactionÀY[1D]0.
[b]
cyclooctane-1,2-diol 1D (Table 6). Indeed, when a mix-
Under these conditions, aliphatic olefins are oxi-
ture of 70 equiv. of cis-cyclooctene and 30 equiv of dized towards the corresponding cis-diols in improved
the syn-diol 1D was subjected to standard oxidation yields ranging from 19 to 60% and diol/epoxide ratios
conditions, only a minor increase of the syn-diol was between 1 and 6.7. To the best of our knowledge for
observed (37%) but epoxide 1E and 2-hydroxy all the substrates collected in Table 7, these numbers
ketone 1H products were formed in larger amount represent the most efficient iron-based system in
(18 and 12%, respectively). Even more revealing was terms of syn-diol product yield described to date.
the oxidation of an equimolar mixture of cis-cyclooc-
tene (S1) and syn-diol 1D. The reaction resulted in no
further increase in the concentration of diol, but ep- Conclusions
oxide 1E and hydroxy ketone 1H products were
formed in 22 and 29% relative yields. In conclusion, The present work describes an active and selective
product release from the ferric glycolate species rep- iron catalyst that performs the cis-dihydroxylation of
resents most likely the rate-determining step of the aliphatic olefins in yields that become interesting for
reactions. Interestingly, this interpretation also offers synthetic purposes simply by using H2O2 as green oxi-
a reasonable interpretation for the beneficial role of dant. The selectivity towards syn-diol product ob-
water in the chemoselectivity towards the cis-dihy- tained with our catalyst is determined by the nature
droxylation reaction. Water may enhance product re- of the alkene. Best yields and selectivities are ob-
lease by favouring the hydrolytic cleavage of the tained when cis-olefins are oxidized. On the other
ferric glycolate species, thus disfavouring epoxidation hand, trans-olefins are oxidized with comparable ep-
and diol-bound over-oxidation paths. Based on this oxide:diol ratios. Notably, small differences among
conclusion, we had the idea to improve the cis-dihy- the structures of the active iron complexes can dra-
droxylation by removing the syn-diol from the reac- matically change the selectivity of the oxidations.
tion mixture.
Pure electronic modifications in the electron-donating
nature of the PyTACN ligand result in catalysts exhib-
iting quite similar chemoselectivities in olefin oxida-
tion. On the other hand, the introduction of a bulky
group at position 6 of the pyridine reverses the selec-
Iterative Catalytic Oxidation
To our delight, an improved methodology in terms of tivity towards the preferential formation of the syn-
product yields and selectivity could be derived by per- diol product.
forming the oxidation reaction at substoichiometric
For aliphatic substrates, reaction yields attained
conversion levels, and separating the diol product with the present system compare favourably with
from the reaction mixture. After the first peroxide ad- those of state of the art Fe-catalyzed cis-dihydroxyla-
dition, the catalytic solution was loaded onto a silica tion systems, and because of that it can be regarded
gel column, and the syn-diol product was removed as an attractive complement. That is not the case for
from the solution. The recovered substrate was sub- electron-deficient and aromatic olefins, which are
jected to a second addition of catalyst and H2O2. This most conveniently oxidized with the highly active sys-
allows us to substantially increase the product yields tems recently described by Che.[50] This somewhat dif-
and in some cases also to improve the ratio of diol/ep- ferent substrate scope is surprising given the similari-
oxide (Table 7).
ties of the first coordination sphere FeN4 of both cata-
954
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 947 – 956

FeACHTUNGTRENNUNG(PyTACN)-Catalyzed cis-Dihydroxylation of Olefins with Hydrogen Peroxide
Table 7. Catalysis using two iterative catalytic oxidations.
Substrate
Conversion
Yield [%]
D/E
Yield [%]
71
D
E
S1[a]
96
60
11
5.7
S6[a]
S2[a]
73
98
53
56
20
26
2.7
2.2
73
82
S3[a]
69
75
19
40
19
16
1
2.6
38
56
S7[a]
S13[b]
94
33
5[a]
–
38
S19[b]
S20[b]
96
88
53
56
21
17
2.5
3.3
73
73
S21[b]
90
45
7[c]
6.7
52
[a]
[b]
[c]
GC yield.
Isolated yields.
trans-Diol product originated from the ring opening of the epoxide product.
lysts, but at the same time it hints at the possibility of Acknowledgements
developing novel catalysts with alternative substrate
scope. Efforts towards this goal are currently being
undertaken in our laboratory.
Financial support by ERC-29910, MCYT of Spain through
project CTQ2009-08464/BQU to MC. IP, and MC thank
MICINN and Generalitat de Catalunya, respectively for PhD
grants. MC and XR thank Generalitat de Catalunya for
2009SGR637 and ICREA Acadꢀmia Awards. XR is grateful
for finanical support from INNPLANTA project IPN-2011-
0059-PCT-42000-ACT1.
Experimental Section
Typical Catalytic Oxidation Procedure
A 15-mL vial was charged with catalyst (1.5 mmol, 3 mol%),
alkene (50 mmol, 1 equiv.), CH3CN (1.5 mL) and a magnetic References
stir bar. The vial was placed on an ice bath and stirred.
13.5 mL of water were added (750 mmol, 1500 mol%) and
143 mL of a 700 mM (100 mmol, 2 equiv.) H2O2 solution (di-
luted in acetonitrile from a 35% H2O2 aqueous solution)
were delivered by syringe pump over 15 min at 08C. After
syringe pump addition, the solution was stirred for 30 min at
08C.
An internal standard was added at this point. The iron
complex was removed by passing the solution through
a short path of silica followed by elution with 2 mL of
AcOEt. Finally, the solution was subjected to GC analysis.
Full experimental details of iterative addition protocol
and products characterization are collected in the Support-
ing Information.
[1] J.-E. Bꢁckvall, Modern oxidation Methods, Wiley-VCH,
Weinheim, 2004.
[2] C. J. R. Bataille, T. J. Donohoe, Chem. Soc. Rev. 2011,
40, 114–128.
[3] R. A. Johnson, K. B. Sharpless, in: Catalytic Asymmet-
ric Synthesis, 2nd edn., (Ed.: I. Ojima), Wiley-VCH,
New York, 2000, pp 357–398.
[4] H. C. V. Kolb, M. S. Nieuwenhze, K. B. Sharpless,
Chem. Rev. 1994, 94, 2483–2547.
[5] C. Dçbler, G. M. Mehltretter, U. Sundermeier, M.
Beller, J. Am. Chem. Soc. 2000, 122, 10289–10297.
[6] W.-P. Yip, C.-M. Ho, N. Zhu, T.-C. Lau, C.-M. Che,
Chem. Asian J. 2008, 3, 70–77.
Adv. Synth. Catal. 2013, 355, 947 – 956
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
955

Irene Prat et al.
FULL PAPERS
[7] C. M. Ho, W. Y. Yu, C. M. Che, Angew. Chem. 2004,
116, 3365–3369; Angew. Chem. Int. Ed. 2004, 43, 3303–
3307.
[33] D. T. Gibson, R. E. Parales, Curr. Opin. Biotechnol.
2000, 11, 236–243.
[34] T. Hudlicky, D. Gonzalez, D. T. Gibson, Aldrichimica
[8] W. P. Yip, W. Y. Yu, N. Y. Zhu, C. M. Che, J. Am.
Chem. Soc. 2005, 127, 14239–14249.
[9] N. M. Neisius, B. Plietker, J. Org. Chem. 2008, 73,
3218–3227.
Acta 1999, 32, 35–62.
[35] B. Kauppi, K. Lee, E. Carredano, R. E. Parales, D. T.
Gibson, H. Eklund, S. Ramaswamy, Structure 1998, 6,
571–586.
[10] B. Plietker, M. Niggemann, J. Org. Chem. 2005, 70,
2402–2405.
[11] B. Plietker, M. Niggemann, A. Pollrich, Org. Biomol.
Chem. 2004, 2, 1116–1124.
[36] D. T. Gibson, V. Subramanian, in: Microbial Degrada-
tion of Aromatic Hydrocarbons, (Ed.: D. T. Gibson),
Marcel Dekker, New York, 1984, pp 181–251.
[37] L. Que, W. B. Tolman, Nature 2008, 455, 333–340.
[38] K. Chen, L. Que Jr, Angew. Chem. 1999, 111, 2365–
2368; Angew. Chem. Int. Ed. 1999, 38, 2227–2229.
[39] K. Chen, M. Costas, J. Kim, A. K. Tipton, L. Que Jr, J.
Am. Chem. Soc. 2002, 124, 3026–3035.
[12] B. Plietker, M. Niggemann, Org. Biomol. Chem. 2004,
2, 2403–2407.
[13] Y. Li, D. Song, V. M. Dong, J. Am. Chem. Soc. 2008,
130, 2962–2964.
[14] A. Wang, H. Jiang, H. Chen, J. Am. Chem. Soc. 2009,
131, 3846–3847.
[40] Y. Feng, C. Y. Ke, G. Xue, L. Que Jr, Chem. Commun.
2009, 50–52.
[15] W. Wang, F. Wang, M. Shi, Organometallics 2010, 29,
928–933.
[16] C. P. Park, J. H. Lee, K. S. Yoo, K. W. Jung, Org. Lett.
2010, 12, 2450–2452.
[41] M. Costas, L. Que Jr, Angew. Chem. 2002, 114, 2283–
2285; Angew. Chem. Int. Ed. 2002, 41, 2179–2181.
[42] K. Suzuki, P. D. Oldenburg, L. Que Jr, Angew. Chem.
2008, 120, 1913–1915; Angew. Chem. Int. Ed. 2008, 47,
1887–1889.
[17] M.-K. Zhu, J.-F. Zhao, T.-P. Loh, J. Am. Chem. Soc.
2010, 132, 6284–6285.
[43] J. Bautz, P. Comba, C. L. d. Laorden, M. Menzel, G.
Rajaraman, Angew. Chem. 2007, 119, 8213–8216;
Angew. Chem. Int. Ed. 2007, 46, 8067–8070.
[18] A. Wang, H. Jiang, J. Org. Chem. 2010, 75, 2321–2326.
[19] Y.-B. Kang, L. H. Gade, J. Am. Chem. Soc. 2011, 133,
3658–3667.
[44] A. Company, L. Gꢂmez, X. Fontrodona, X. Ribas, M.
[20] B. C. Giglio, V. A. Schmidt, E. J. Alexanian, J. Am.
Chem. Soc. 2011, 133, 13320–13322.
[21] L. Emmanuvel, T. M. A. Shaikh, A. Sudalai, Org. Lett.
Costas, Chem. Eur. J. 2008, 14, 5727–5731.
[45] P. C. A. Bruijnincx, G. van Koten, R. J. M. K. Gebbink,
Chem. Soc. Rev. 2008, 37, 2716–2744.
2005, 7, 5071–5074.
[22] W. Zhong, S. Liu, J. Yang, X. Meng, Z. Li, Org. Lett.
2012, 14, 3336–3339.
[23] J. C. Griffith, K. M. Jones, S. Picon, M. J. Rawling,
B. M. Kariuki, M. Campbell, N. C. O. Tomkinson, J.
Am. Chem. Soc. 2010, 132, 14409–14411.
[24] C. Yuan, A. Axelrod, M. Varela, L. Danysh, D. Siegel,
Tetrahedron Lett. 2011, 52, 2540–2542.
[46] P. D. Oldenburg, Y. Feng, I. Pryjomska-Ray, D. Ness, L.
Que Jr, J. Am. Chem. Soc. 2010, 132, 17713–17723.
[47] P. C. A. Bruijnincx, I. L. C. Buurmans, S. Gosiewska,
M. A. H. Moelands, M. Lutz, A. L. Spek, G. van Koten,
R. J. M. K. Gebbink, Chem. Eur. J. 2008, 14, 1228–1237.
[48] P. D. Oldenburg, C.-Y. Ke, A. A. Tipton, A. A. Shtein-
man, L. Que Jr, Angew. Chem. 2006, 118, 8143–8146;
Angew Chem. Int. Ed. 2006, 45, 7975–7978.
[25] K. M. Jones, N. C. O. Tomkinson, J. Org. Chem. 2012,
77, 921–928.
[49] J. Y. Ryu, J. Kim, M. Costas, K. Chen, W. Nam, L. Que
Jr, Chem. Commun. 2002, 12, 1288–1289.
[26] M. Schwarz, O. Reiser, Angew. Chem. 2011, 123,
10679–10681; Angew. Chem. Int. Ed. 2011, 50, 10495–
10497.
[50] T. W.-S. Chow, E. L.-M. Wong, Z. Guo, Y. Liu, J.-S.
Huang, C.-M. Che, J. Am. Chem. Soc. 2010, 132,
13229–13239.
[27] P. Saisaha, D. Pijper, R. P. v. Summerren, R. Hoen, C.
Smit, J. W. de Boer, R. Hage, P. L. Alsters, B. L. Ferin-
ga, W. R. Browne, Org. Biomol. Chem. 2010, 8, 4444–
4450.
[28] J. W. de Boer, W. R. Browne, J. Brinksma, P. L. Alsters,
R. Hage, B. L. Feringa, Inorg. Chem. 2007, 46, 6353–
6372.
[29] J. W. de Boer, J. Brinksma, W. R. Browne, A. Meetsma,
P. L. Alsters, R. Hage, B. L. Feringa, J. Am. Chem. Soc.
2005, 127, 7990–7991.
[51] I. Prat, J. S. Mathieson, M. Gꢃell, X. Ribas, J. M. Luis,
L. Cronin, M. Costas, Nat. Chem. 2011, 3, 788–793.
[52] K. Chen, L. Que Jr, Angew. Chem. 1999, 111, 2365–
2368; Angew. Chem. Int. Ed. 1999, 38, 2227–2229.
[53] M. Costas, A. K. Tipton, K. Chen, D.-H. Jo, L. QueJr,
J. Am. Chem. Soc. 2001, 123, 6722–6723.
[54] M. Klopstra, G. Roelfes, R. Hage, R. M. Kellogg, B. L.
Feringa, Eur. J. Inorg. Chem. 2004, 4, 846–856.
[55] P. D. Oldenburg, A. A. Shteinman, L. Que Jr, J. Am.
Chem. Soc. 2005, 127, 15672–15673.
[30] T. W.-S. Chow, Y. Liu, C.-M. Che, Chem. Commun.
[56] M. R. Bukowski, P. Comba, A. Lienke, C. Limberg,
C. L. de Laorden, R. Mas-Balleste, M. Merz, L. Que,
Angew. Chem. 2006, 118, 3524–3528; Angew. Chem.
Int. Ed. 2006, 45, 3446–3449.
2011, 47, 11204–11206.
[31] J. Brinksma, L. Schmieder, G. van Vliet, R. Boaron, R.
Hage, D. E. De Vos, P. L. Alsters, B. L. Feringa, Tetra-
hedron Lett. 2002, 43, 2619–2622.
[57] M. Fujita, M. Costas, L. Que Jr, J. Am. Chem. Soc.
[32] A. Karlsson, J. V. Parales, R. E. Parales, D. T. Gibson,
H. Eklund, S. Ramaswamy, Science 2003, 299, 1039–
1042.
2003, 125, 9912–9913.
[58] M. D. Wolfe, J. V. Parales, D. T. Gibson, J. D. Lipscomb,
J. Biol. Chem. 2001, 276, 1945–1953.
956
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 947 – 956