The iron(II) complex [Fe(CF3SO3)2(mcp)] as a convenient, readily available catalyst for the selective oxidation of methylenic sites in alkanes

Article abstract of DOI:10.1002/adsc.201300923

The efficient and selective oxidation of secondary C-H sites of alkanes is achieved by using low catalyst loadings of a non-expensive, readily available iron catalyst [Fe(II)(CF₃SO₃)₂(mcp)], {Fe-mcp, [mcp=N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)cyclohexane-trans-1,2-diamine]}, and hydrogen peroxide (H₂O₂) as oxidant, via a simple reaction protocol. Natural products are selectively oxidized and isolated in synthetically amenable yields. The easy access to large quantities of the catalyst and the simplicity of the C-H oxidation procedure make this system a particularly convenient tool to carry out alkane C-H oxidation reactions on the preparative scale, and in short reaction times.

Full text of DOI:10.1002/adsc.201300923

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DOI: 10.1002/adsc.201300923
The Iron(II) Complex [Fe
N
U
Readily Available Catalyst for the Selective Oxidation of
Methylenic Sites in Alkanes
Mercꢀ Canta,a David Font,a Laura Gꢁmez,a Xavi Ribas,a and Miquel Costasa,*
a
QBIS-CAT Research Group, Institut de Quꢂmica Computacional i Catꢃlisi (IQCC) and Departament de Quꢂmica,
Universitat de Girona, Campus Montilivi, E-17071 Girona, Catalonia, Spain
Fax : (+34)-972-418-150; e-mail: miquel.costas@udg.edu
Received: October 16, 2013; Revised: December 19, 2013; Published online: February 6, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300923.
Abstract: The efficient and selective oxidation of easy access to large quantities of the catalyst and the
À
À
secondary C H sites of alkanes is achieved by using simplicity of the C H oxidation procedure make this
low catalyst loadings of a non-expensive, readily system a particularly convenient tool to carry out
À
available iron catalyst [Fe(II)
G
(mcp)], {Fe- alkane C H oxidation reactions on the preparative
mcp,
[mcp=N,N’-dimethyl-N,N’-bis(2-pyridylme- scale, and in short reaction times.
thyl)cyclohexane-trans-1,2-diamine]}, and hydrogen
peroxide (H2O2) as oxidant, via a simple reaction
protocol. Natural products are selectively oxidized Keywords: catalysis; C H oxidation; hydrogen per-
À
and isolated in synthetically amenable yields. The oxide; iron; natural products; selectivity
Introduction
tions but present limited stability and most commonly
their manipulation requires special care.[3] Indeed,
À
Oxidized hydrocarbons constitute a basic structural a general problem of alkane C H oxidation reactions
motif in organic molecules and, because of that, meth- is that the scale-up is not obvious because of the lim-
À
À
odologies for site selective oxidation of alkyl C H ited stability and high reactivity of most C H oxidiz-
bonds are highly desirable.[1] Methods for selective ing reagents. All of these aspects call for the develop-
À
late stage C H oxidation will permit the rapid synthe- ment of novel synthetic methodologies that can target
À
sis of libraries of structurally diverse compounds shar- C H bonds in a selective manner and could be suita-
ing a common structural core, especially suitable for ble for practical organic synthesis.[4–8]
structure-activity relationship studies, which could
Fe-based complexes represent powerful oxidants
lead to the discovery and development of new drugs for the hydroxylation of not only tertiary but also sec-
and materials.[2] However, most often alkyl C H bond ondary sites.[4] Porphyrinic iron complexes are models
À
functionalization occurs early within a multi-step syn- of heme oxygenases and have been explored for
thesis and is applied to very simple substrates, mainly decades.[1d,5] More recently, non-heme complexes have
because it is one of the most difficult transformations emerged as a promising alternative.[6] While the com-
in synthetic chemistry. This is so due to the kinetic bination of iron compounds and hydrogen peroxide
À
stability of C H bonds and their ubiquitous presence finds wide precedent in the literature and could be
in organic molecules, which make site selectivity a for- dated back to Fenton chemistry,[7] iron catalysts for
À
À
midable challenge. Oxidation of alkyl C H bonds has selective alkane C H oxidation that could yield prep-
traditionally required the use of highly oxidizing, non- aratively useful quantities of oxidation products have
selective reagents, which are often incompatible with not been described until recently, and are still scarce.
other functional groups. Moreover, the reagents that This class of catalysts presents very attractive features,
perform these reactions often rely on heavy and toxic such as the environmentally benign nature of the
metal oxides, which exhibit poor atom economy in metal and their use of H2O2 as oxidant.[8] The most
their reactions.[1e,f] Organic peroxides such as dioxir- relevant examples in the literature are summarized in
anes constitute valuable alternatives because they Figure 1. These include [Fe(II)
ACHUTGTNERN(NUG pdp)CAHTUNGTREN(NUGN CH3CN)2]
show excellent selectivity and efficiency in their reac- (SbF6)2, Fe-pdp [pdp=N,N’-bis(2-pyridylmethyl)-2,2’-
AHCTUNGTRENNUNG
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The Iron(II) Complex [FeACTHNUTRGENN(UG CF3SO3)2ACHTUNTGREN(NUGN mcp)]
Figure 1. Iron catalysts for methylenic site oxidations.
bipyrrolidine], which was described as a selective and
predictable catalyst for tertiary and secondary alkyl
À
C H oxidation with H2O2, but required the use of
high 15–>25 mol% catalyst loadings.[9] Improved ac-
tivity was obtained with pinene-derivatized catalysts
[Fe(II)
methyl-N,N’-bis{[(R)-4,5-pinenepyridin-2-yl]-methyl}-
cyclohexane-1,2-diamine)[10] and [Fe(II)
(CF3SO3)2
ACHTUNGTRENNUNG(CF3SO3)2ACHTUNGTRENNUNG(mcpp)], Fe-mcpp (mcpp=N,N’-di-
AHCTUNGTRENNUNG
Figure 2. ACTHNUGTRNEUNG(S,S)- and (R,R)-Fe-mcp catalysts.
ACHTUNGTRENNUNG(pdpp)], Fe-pdpp {pdpp=N,N’-bis[(R)-4,5-pinenepyri-
din-2-yl]methyl-2,2’-bipyrrolidine},[11] the enhanced
stability of which allows for efficient operation at sig-
nificantly lower catalyst loadings (1–3 mol%), and providing oxidized products with synthetically amena-
they introduce modulation of the regioselectivity on ble yields and exhibiting remarkable selectivity
À
C H oxidation of complex organic molecules. High among secondary sites. This catalyst can be readily
activity has also been described with the tacn-based prepared in multigram amounts from inexpensive,
catalyst
[Fe(II)
Me,MePytacn=1-(6-methyl-2-pyridyl- odology described herein allows the performance of
alkane oxidation reactions in comparable yields to
(CF3SO3)2(Me,MePytacn)], commercially available reagents. The catalytic meth-
ACHTUNGTRENNUNG
Fe-Me,MePytacn
[
methyl)-4,7-dimethyl-1,4,7-triazacyclononane],[12]
which shows a remarkable preference towards meth- those reported for more complex and expensive iron
ylene oxidation in comparison to Fe-pdp, Fe-mcpp, catalysts, but requires substantially lower catalyst
and
[Fe(II)
G
(ClO4)2,
Fe-qpy
(qpy=2, loadings than Fe-pdp. However, the most important
2’:6’,2’’:6’’,2’’’:6’’’,2’’’’-quinquepyridine), which uses aspect of the work is that reactions can be conven-
Oxoneꢅ as oxidant.[13] Nevertheless, these catalysts iently performed on a gram scale, following experi-
share a major drawback in the fact that they all con- mentally simple and safe protocols. These methodo-
tain highly elaborated and rather expensive ligands logical aspects, in combination with the readily acces-
that limit scale-up of the reactions. Therefore there is sible nature and cost of the catalyst, make it a very
still a need for the development of straightforward convenient tool for synthetic purposes.
methodologies that use simpler, readily available,
non-expensive iron catalysts for performing selective
C H oxidation on a preparative scale.
À
Results and Discussion
Towards this end, in this work we show that the
mononuclear iron complex [Fe(II)ACHTUNGTRENNUG(CF3SO3)2ACHTUTGNREN(NUGN mcp)], Multigram Scale Preparation of the Fe-mcp Catalyst
Fe-mcp [mcp=N,N’-dimethyl-N,N’-bis(2-pyridylme-
thyl)cyclohexane-trans-1,2-diamine, Figure 2] is an ef- The preparation of [Fe(II)ACTHNUTRGENN(UG CF3SO3)2ACHUTNGTRENN(UGN mcp)], Fe-mcp
ficient catalyst for the oxidation of alkanes with H2O2, on the mg scale was previously described,[14] but in
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Mercꢀ Canta et al.
À
Table 1. Optimization of reaction conditions for tertiary C H bond oxidation with (S,S)-Fe-mcp.
Entry
Cat:Subst:H2O2:AcOH [%]
Conversion [%][a]
Yield [%] [2/3][a]
1
2
3
4
5
6
7
8
1:100:200:150
51
55
54
54
46
31
54
68
71
81
84
62
36 [92/8]
41 [93/7]
43 [91/9]
41 [93/7]
36 [92/8]
25 [92/8]
44 [89/11]
51 [92/8]
54 [91/9]
57 [90/10]
54 [90/10]
47 [95/5]
3:100:200:150
1(ꢆ3):100:120(ꢆ3):100(ꢆ3)[c]
5:100:200:150
15:100:200:150
15:100:200:150[d]
3:100:360:150
3:100:200:1000
9
3:100:360:1000
10
11[b]
12[f]
3(ꢆ2):100:200(ꢆ2):500(ꢆ2)[e]
3(ꢆ2):100:200(ꢆ2):500(ꢆ2)[e]
3(ꢆ2):100:200(ꢆ2):500(ꢆ2)[e]
[a]
Substrate conversion and product yield based on GC analysis.
Using Fe-mcp-SbF6 as catalyst.
Iterative addition protocol with slow addition of catalyst.
[b]
[c]
[d]
[e]
[f]
Slow addition protocol.
Iterative addition protocol with direct addition of catalyst (see the Experimental Section for details).
Using Fe-mep as catalyst.
À
order to illustrate the ready accessibility of this cata- Optimization of Catalytic C H Oxidation Reactions
lyst, a multigram scale preparation was performed.
À
Starting from 26.8 g of (+/À)-trans-diaminocyclohex- The activity of Fe-mcp as alkane C H oxidation cata-
ane, the racemic diamine was resolved using (À)-d- lyst employing H2O2 was optimized using cis-4-
tartaric acid, obtaining the desired (S,S)-diaminocy- methyl-1-cyclohexylpivalate (1, Table 1) and 1,1-dime-
clohexane in 99% yield with ꢀ99% enantiomeric thylcyclohexane (4, Table 2), as model substrates. Oxi-
purity as confirmed by chiral GC, without the need of dation of the latter was also studied with the set of
recrystallization. Note that for non-chiral substrates, catalysts [Fe(II)
this step is not required and the racemic diamine can N,N’-dimethyl-N,N’-bis(2-pyridylmethyl)ethylenediam-
be directly used. 10 g of this diamine were used to ine] and {Fe(II)(CF3SO3)2A[(R,R)-pdp]}, Fe-pdp-OTf in
(mep)], Fe-mep[15] [mep=
ACHTUTGNRENNUG(CF3SO3)2ACHUTNGTRENNGUN
A
R
CHTUNGTRENNUNG
synthesize the ligand by performing a reductive ami- order to investigate possible changes in the regiose-
nation with 2-picolylaldehyde, followed by an lectivity of the oxidations responding to the catalyst
Eschweiler–Clarke methylation with formaldehyde nature. {Fe(II)CAHTNUGTREN[NNUG (S,S)-mcp]ACHTUNRGTEG(NNUN CH3CN)2}ACHTUNGRTNE(NUGN SbF6)2 Fe-mcp-
and formic acid. The ligand was purified by flash SbF6 was also used to study the possible effect of the
silica gel chromatography yielding 9.9 g of enantio- anion on the catalytic performance.
merically pure mcp ligand with 81% overall yield in 3
Table 1 and Table 2 collect results obtained in the
synthetic steps that can be performed in 2 days. 2.5 g optimization of the oxidation of 1 and 4, respectively.
À
of this ligand were reacted with FeCl2 under an N2 at- Oxidation of 1 occurs preferentially at the tertiary C
mosphere for 3 h and immediately after, without any H bond in a stereospecific (ꢀ96%) manner, yielding
work-up, with AgOTf (2 equiv.) for another 3 h. After the corresponding tertiary alcohol with retention of
filtration to remove precipitated AgCl, the complex the configuration. Aside from that, minor amounts (<
was crystallized in CH2Cl2/Et2O yielding 4.2 g of 6%) of ketone 3 were also detected. On the other
bright yellow crystals (grown after 3 days of diethyl hand, oxidation of 4 results in the formation of ke-
ether diffusion) corresponding to Fe-mcp (75% yield). tones 5, 6, and 7 (Table 2), which relative ratios
This complex should be stored under an inert atmos- depend on the nature of the catalyst (vide infra). The
phere but can be easily manipulated under air for experimental parameters of the reactions were opti-
short periods of time.
mized with regard to catalyst loading (from 1 to
15%), amount of hydrogen peroxide (H2O2, from 2 to
4.2 equivalents), acetic acid (AcOH, as additive be-
tween 1.5 and 10 equivalents) and the number of ad-
ditions of the reagents (H2O2, AcOH and Fe-mcp).
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The Iron(II) Complex [FeACTHNUTRGENN(UG CF3SO3)2ACHTUNTGREN(NUGN mcp)]
À
Table 2. Optimization of reaction conditions for secondary C H bond oxidation with (S,S)-Fe-mcp.
Entry
Cat:Subst:H2O2:AcOH [%]
Conversion [%][a]
Yield [%] [5/6/7][a]
1
2
3
4
5
6
7
8
1:100:280:150
76
64
94
84
71
60
78
90
87
95
98
97
78
47 [21/55/24]
49 [22/53/25]
67 [19/57/24]
52 [21/57/23]
45 [24/53/24]
35 [23/51/26]
54 [20/56/24]
59 [20/56/24]
64 [20/56/24]
71 [19/58/23]
73 [20/58/22]
65 [35/45/20]
59 [34/46/20]
3:100:280:150
1(ꢆ3):100:120(ꢆ3):100(ꢆ3)[e]
5:100:280:150
15:100:280:150
15:100:280:150[f]
3:100:420:150
3:100:280:1000
3:100:420:1000
9
10
11[b]
12[c]
13[d]
3(ꢆ2):100:280(ꢆ2):500(ꢆ2)[g]
3(ꢆ2):100:280(ꢆ2):500(ꢆ2)[g]
3(ꢆ2):100:280(ꢆ2):500(ꢆ2)[g]
3(ꢆ2):100:280(ꢆ2):500(ꢆ2)[g]
[a]
Based on GC analysis.
Using Fe-mcp-SbF6 as catalyst.
Using Fe-pdp-OTf as catalyst.
Using Fe-mep as catalyst.
Iterative addition protocol with slow addition of catalyst.
Slow addition protocol.
Iterative addition protocol with direct addition of catalyst (see the Experimental Section for details).
[b]
[c]
[d]
[e]
[f]
[g]
Catalyst loading was first interrogated. The use of 4.2 equiv. (from 49% to 54% yield, entries 2 and 7,
1 mol% Fe-mcp afforded a combined 36% yield of Table 2). Acetic acid is commonly used as a beneficial
(2+3) (entry 1, Table 1) and 47% yield of (5+6+7) additive in iron-catalyzed oxidation reactions,[16] and
(entry 1, Table 2). Yields were slightly increased by the effect of the amount used was also studied. In-
the use of 3 mol% (entry 2, Table 1 and Table 2), and crease of the amount of acetic acid from 1.5 to
the best results were obtained when the catalyst, 10 equivalents resulted in a systematic improvement
acetic acid, and peroxide were delivered to the reac- of ~10% in product yields both for 1 (compare en-
tion mixture in three consecutive additions. Under tries 2 and 8, and also 7 and 9 in Table 1) and 4 (com-
these conditions, 1 and 4 were oxidized in 43% and pare entries 2 and 8, and also 7 and 9 in Table 2). Fi-
67% respective combined yields (entry 3, Table 1 and nally we observed a further improvement of the reac-
Table 2). Further increase of the catalyst loading did tion yields by following an experimental protocol that
not result in higher yields (entries 4–6, Table 1 and involved two consecutive additions of catalyst, oxi-
Table 2); instead, the use of 15 mol% of Fe-mcp re- dant and acetic acid. Using this protocol, high sub-
sulted in low product yields (entry 5, Table 1 and strate conversion was noticed and we achieved the
Table 2), and the same happened when the catalyst highest yields of all tested conditions, obtaining 57%
was delivered via syringe pump (entry 6, Table 1 and yield for the oxidation of 1 (entry 10, Table 1) and
Table 2). The next parameter evaluated was the 71% yield for the oxidation of 4 (entry 10, Table 2).
amount of oxidant (H2O2). In this case, for simplicity
For comparison, we performed the oxidation of
reasons, a single addition of 3 mol% catalyst was em- 1 under optimized conditions using Fe-mep as catalyst
ployed. Optimization was initiated by using 2 and (entry 12, Table 1). Recent work by Bermejo and co-
2.8 equivalents of H2O2 to oxidize 1 and 4, respective- workers has shown that this simple catalyst can be
ly, because alcohols (2 eÀ oxidation products) are used for the oxidation of organic molecules and natu-
mainly obtained in the oxidation of 1 and ketones ral products.[15b] However, a substantially poorer yield
(4 eÀ oxidation products) are the products of the oxi- was obtained (47% vs. 57%, compare entries 10 and
dation of 4. Increase of the H2O2 loading led to 12, Table 1), indicating that Fe-mcp is a more active
a minor improvement in the oxidation of 1 (from and suitable catalyst to perform such transformations.
41% to 44% yield using 3.6 equiv., entries 2 and 7,
It is worth noticing that the selectivity patterns ob-
Table 1), but a moderate improvement was obtained served in the oxidation of 1 and 4 with catalyst Fe-
in the oxidation of 4 when increasing from 2.8 to mcp remain virtually the same regardless of the cata-
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Mercꢀ Canta et al.
lytic conditions used. Alcohol 2 is the major oxidation ketone and alcohol products during the course of the
product of 1 in all cases, obtained with ca. 90% selec- reaction, or during GC analysis.[17] In order to confirm
tivity vs. ketone 3 (Table 1). In the oxidation of 4, that formation of alkyl peroxides did not occur in the
ketone 6 is the major product (from 51% to 58% se- course of the catalysis, the final reaction mixtures
lectivity, entries 1–10, Table 2) ketones 5 and 7 being from oxidation of substrates 1 and 4 were treated
the minor products, obtained in ca. 20% selectivity with triphenylphosphine. No changes were observed
each (note that the statistically expected selectivity in terms of yield or alcohol/ketone ratio with respect
ratio would be [40/40/20] according to the number of to these determined before adding PPh3 (see the Sup-
À
C H bonds present in the molecule). These results in- porting Information, Table S2). Those results exclude
dicate that Fe-mcp is able to discriminate among the the presence of alkyl peroxides among the oxidation
three methylenic sites of 4. The preferred oxidation products.
site leading to 6 should be understood as a compro-
mise between steric accessibility (7>6>5) and elec-
tron richness of the oxidized methylene site (7<6< Scope and Selectivity Bases for C H Oxidation
5). Since the relative amount of 5, which results from
À
oxidation at the most sterically impeded methylene Once the best reaction conditions had been estab-
site, is substantially lower than the 40% statistically lished, the oxidation of structurally more complex
expected value, we conclude that steric interactions substrates containing multiple secondary and tertiary
À
with Fe-mcp are the most decisive aspect in defining C H bonds was evaluated. A comparison between
the overall regioselectivity in these reactions. This oxidation of cis-4-methyl-1-cyclohexyl pivalate versus
conclusion will have further support in the following its trans isomer 8 (entries 1–3, Table 3) is informative
lines. To further strengthen this point the performance as it reflects the importance of subtle aspects in defin-
of Fe-mcp under optimized conditions was then com- ing the regioselectivity of the oxidation. As already
pared with that of related catalysts that have previ- discussed, while oxidation of 1 occurs preferentially at
ously proven effective in alkane oxidation, or that C-1 with high regioselectivity (91%, entry 2, Table 3),
differ in the nature of the anion.[9d,e,15b] In first place, the oxidation of trans-4-methyl-1-cyclohexyl pivalate
Fe-mcp-SbF6 and Fe-mcp showed virtually identical exhibits a slightly different selectivity, and the corre-
results in terms of yield and selectivity (entry 10 vs. sponding ketone resulting from oxidation at C-2 is ob-
entry 11, ÀTable 1 and Table 2), indicating that triflate tained in ~30% relative ratio. This difference between
and SbF6 could be indistinctly used, plus the benefit cis- and trans-4-methyl-1-cyclohexyl pivalate arises
À
of the triflate being less expensive. On the other from the position of the C H bond to be attacked in
hand, under identical experimental conditions, oxida- the chair conformation. The trans substrate 8 has the
À
tion of 4 with the structurally related catalysts Fe- tertiary C H to be oxidized in axial position, but the
pdp-OTf and Fe-mep proceed with lower yields (65% same tertiary site in 1 is in equatorial position. Break-
À
for Fe-pdp-OTf, entry 12, and 59% for Fe-mep, age of equatorial C H bonds is facilitated in terms of
entry 13; Table 2), than for Fe-mcp. More interesting stereoelectronic effects and strain release, and be-
is the observation that the regioselectivity in the oxi- cause of that, formation of 2 is favored.[1b,10] The im-
À
dation of 4 with Fe-pdp-OTf and Fe-mep is distinct portance of electronic effects in defining C H site se-
from that obtained with Fe-mcp, the formers being lectivity is evidenced in the oxidation of substrates
close to the statistically expected ratio on the basis of containing electron-withdrawing moieties. For exam-
À
the number of C H bonds (40/40/20). As observed ple, oxidation of 3,7-dimethyloctyl acetate 9 (entries 4
for substrate 1, the oxidation of 4 by Fe-mep is not as and 5, Table 3) occurs at the more distal position
efficient as when performed with Fe-mcp (71% vs. from the acetate deactivating group showing that the
59% yield, compare entries 10 and 13, Table 2).
The mass balance in these reactions is not complete
(see Table 1 and Table 2). Attempts to increase the tate 11 are menthol derivatives with multiple and
substrate conversion did not result in higher product chemically distinct C H bonds and therefore consti-
yields, presumably due to the formation of multiple tute interesting, non-trivial substrate platforms to
oxidizing species have electrophilic character.
(À)-Menthyl acetate 10 and (+)-neomenthyl ace-
À
À
overoxidized products. Unfortunately, we were not evaluate C H regioselectivity exhibited by the cata-
able to isolate the multiple side products, due to the lyst. As these substrates are also chiral, matching-mis-
small amounts in which they are formed (<5% matching effects with the chirality of the catalyst can
yield). Illustrative chromatograms are shown in the be also interrogated. Oxidation of 10 with (S,S)-Fe-
Supporting Information (Figure S1).
mcp affords selectively the tertiary alcohol resulting
It is well established that the oxidation of alkanes from stereospecific oxidation at C-1, and minor
mediated by iron catalysts in the presence of H2O2 amounts of ketone from oxidation at C-2 (entry 6,
can give rise to the formation of alkyl peroxides, Table 3) in a combined 63% isolated yield. However,
which can decompose to form the corresponding when 10 is oxidized with the (R,R)-Fe-mcp enantio-
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The Iron(II) Complex [FeACTHNUTRGENN(UG CF3SO3)2ACHTUNTGREN(NUGN mcp)]
À
Table 3. Oxidation of tertiary and secondary C H bonds with (S,S)-Fe-mcp. Unless otherwise stated, catalytic conditions are
2ꢆ (3 mol% catalyst, 200 mol% H2O2, 500 mol% AcOH).
Substrate
Entry
Conversion [%][a]
Yield [%][a]
Selectivity [C-1/C-2/C-3][a]
1
81
81
57
53
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1
8
2[b]
3
66
57
ACHTUNGTRNE[NUNG 70/30]
4
74
76
42
45
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
5[c]
6
86
77
63d)
44
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
10
7[e]
8
79
67
47
49
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
11
9[e]
12
13
10[f]
11[b]
67
37
50
26
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
12[g,h]
13[h,i]
99
87
99
99
99
37
51
60
41
58
14
15
14[h,i,j]
15[e,h]
16[e,h,i]
17[k]
86
79
74
75
69
96
56
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
18[k,l]
19[e,k]
20[b,k]
21[k,l,m]
22[n]
49
64 (60d))
55
55
50
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
[b]
[c]
[d]
[e]
[f]
Based on GC analysis.
Using rac-Fe-mcp.
Using 1.5 equiv. of AcOH per addition.
Isolated yield.
Using (R,R)-Fe-mcp.
Using 3.2 equiv. of H2O2.
Using 2.6 equiv. of H2O2.
Reaction at room temperature.
Using 1.8 equiv. of H2O2.
One addition.
[g]
[h]
[i]
[j]
[k]
[l]
Using 3.4 equiv. of H2O2.
Using 15 mol% catalyst.
4.5 mM catalyst.
[m]
[n]
Using 25 mol% catalyst with protocol described by White et al.[9e]
mer catalyst, the selectivity for C-1 site is reduced ferred when using (S,S)-Fe-mcp (55% selectivity, 47%
(71%), and a more modest 44% combined yield is ob- combined yield); instead, (R,R)-Fe-mcp favors oxida-
tained (entry 7, Table 3). In the case of (+)-neo- tion at C-2 yielding the ketone as major product
menthyl acetate 11, the acetate group provides steric (49% combined yield, with 62% selectivity for C-2
À
hindrance to the axially oriented tertiary C-3 H bond site; entry 9, Table 3). These results show that the re-
À
in the chair. Consequently, competitive C H oxida- gioselectivity in the oxidation of these chiral sub-
tion is expected to occur at the methylenic site C-2 strates is sensitive to the relative chirality of the cata-
and at the isopropyl group (C-1). Entry 8 in Table 3 lyst.[11]
shows that the tertiary alcohol is only slightly pre-
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Table 4. Oxidation of cyclohexane derivatives with (S,S)-Fe-mcp. Catalytic conditions are 3 mol% catalyst, 200 mol% H2O2,
500 mol% AcOH.
Substrate
Entry
1
Conversion [%][a]
83
Yield [%][a]
68
Selectivity [C-1/C-2/C-3][a]
ACHTUNGTRENNUNG
[81/19[b]]
16
17
18
19
2
3
4
86
81
76
49
46
56
ACHTUNGTRENUN[NG 67/17/16]
AHCTUNGTRENNG[UN 20/27/53]
AHCTUNGTRENN[GUN 4/37/59]
[a]
[b]
Based on GC analysis.
C-2+C-3 oxidation products.
Oxidation of methylene sites with Fe-mcp can also yields (entry 20, Table 3), and the same happened
be accomplished in good yields, and reactions exhibit when the catalyst loading was increased (entries 18
analogous selectivity patterns to those observed in the and 22, Table 3). In all cases, the same selectivity pat-
À
oxidation of tertiary C H bonds. The role of steric ef- tern is maintained regardless of the protocol em-
fects in dictating regioselectivity has been already dis- ployed. Of particular interest is the observation that
cussed in the oxidation of 4 and these effects are also selectivity towards C-2 appears to be superior to
seen in the oxidation of the linear alkane n-heptane those obtained with Fe-mcpp, Fe-pdpp and Fe-pdp-
12, where no major electronic effects interplay. Oxi- OTf.[11]
dation of n-heptane yielded ketones resulting from
oxidation at methylene sites C-1, C-2, and C-3 (50%
yield, entry 10, Table 3) with a modest but remarkable Comparative Regioselectivity between Iron Catalysts
À
selectivity for the less sterically crowded site (49% se- in C H Oxidation Reactions
lectivity, entry 10, Table 3. Note that the statistically
expected product ratio would be (40/40/20). On the Cyclohexanes constitute common basic frameworks in
other hand, the electrophilic nature of the oxidizing organic molecules and, because of that, their selective
species becomes obvious when oxidizing substrates oxidation is an interesting issue in organic synthesis.
that contain electron-withdrawing groups. In this case, Furthermore, substituted cyclohexanes are also infor-
À
proximal positions are deactivated. For example, oxi- mative substrate probes to interrogate C H regiose-
dation of 13 takes place at the more distal positions lectivity preferences between different catalysts. Re-
from the deactivating group (entry 11, Table 3), albeit sults from the oxidation of cyclohexane derivatives
at a reduced yield.
catalyzed by (S,S)-Fe-mcp are collected in Table 4.
The hyperconjugative effect of ethers in activating cis-1,2-Dimethylcyclohexane 16 (cis-DMCH) and cis-
À
adjacent C H bonds can be also used to direct site se- decalin 17 were oxidized in good to moderate yields
lectivity in the oxidation of complex molecules. For (68% and 49%, respectively) and selectivity for the
example, (À)-ambroxide 14 was oxidized to (+)-sclar- tertiary site (81% and 67%, respectively) with
eolide 15 in up to 60% yield (entries 12–16, Table 3). 3 mol% (S,S)-Fe-mcp (entries 1 and 2, Table 4). Oxi-
In this case the best results are obtained with lower dations are stereospecific and only the alcohol with
amounts of hydrogen peroxide (1.8 equivalents) and retention of the configuration was obtained. Preferen-
a single addition of catalyst, H2O2 and acetic acid, to tial oxidation of these tertiary sites was indeed ex-
limit overoxidation of the product.
pected because of their equatorial position, as break-
Further oxidation of (+)-sclareolide 15 can be age of these bonds is facilitated by strain release. In
À
achieved in good yields and preferential selectivity to- contrast, the tertiary C H site in trans-1,2-dimethylcy-
wards the less sterically hindered C-2 site (up to 64% clohexane 18 (trans-DMCH) and trans-decalin 19 are
yield and 72% selectivity, entries 17–22, Table 3). Use in the axial position. Consequently, strain release is
À
of the racemic form of the catalyst elicited lower not contributing to the activation of these C H
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The Iron(II) Complex [FeACTHNUTRGENN(UG CF3SO3)2ACHTUNTGREN(NUGN mcp)]
2 and C-3 sites is highly dependent on the nature of
the catalyst. Thus only Fe-mcpp[11] and Fe-mcp oxidize
preferentially C-3, while the rest of the catalysts have
basically no preference for any of the two sites. Con-
sidering that methylene site C-3 is the sterically least
congested, we conclude that cyclohexyl-based cata-
lysts Fe-mcpp and Fe-mcp are the most sensitive to
steric factors when the substrate contains multiple
and distinct methylene sites. Indeed, this conclusion is
further reinforced when the same analysis is per-
formed in the oxidation of 1,1-dimethylcyclohexane 4
(Table 2). The important conclusion of this compara-
tive analysis is that the nature of the diamine back-
bone in this class of catalysts appears to be more deci-
sive than building the structure of the pyridines in
À
order to modulate C H selectivity among multiple
methylene sites. Therefore,
a rather structurally
simple catalyst such as Fe-mcp not only oxidizes al-
AHCTUNGTRENNUNG
lectivity among multiple methylenic sites on the basis
of steric arguments.
Figure 3. Oxidation of trans-DMCH and trans-decalin with
3% of (S,S)-Fe-mcp (current work), Fe-pdp-OTf,[11] and
Fe-Me,MePytacn.[12]
Oxidation of Elaborated Substrates
The ability of Fe-mcp to discriminate among multiple
À
bonds, and in addition, for 17 and 19, their bridgehead C H sites in simple organic molecules hints at the
situation confers them with some additional steric possibility of using this catalyst in the oxidation natu-
protection. Not unexpectedly, oxidation of trans- ral products. Towards this end, (S,S)-Fe-mcp and
DMCH and trans-decalin occurs preferentially at the (R,R)-Fe-mcp were used in the oxidation of andros-
methylenic sites, providing the corresponding ketones terone derivatives 20, 21 and 22 (see the Supporting
as the major products (entries 3 and 4, Table 4). Most Information for 22). These molecules are steroids, and
interesting is the observation that oxidation occurs se- it is well known that biosynthesis and biological deg-
lectively at the most sterically accessible methylenic radation of steroidal hormones in living organisms in-
site (C-3) of both trans-DMCH and trans-decalin.
volves oxidation by P450 enzymes.[18] Therefore, their
In order to substantiate this trend, regioselectivities oxidation can present biological interest.[19] In addi-
in the oxidation of cycloalkanes obtained with Fe-mcp tion, these substrates are structurally complex, with
À
can be compared with analogous parameters obtained multiple and distinct C H bonds, and because of that
under analogous conditions with non-heme iron cata- they constitute excellent platforms for studying selec-
[20]
lysts Fe-pdp, Fe-Me,MePytacn, and Fe-mcpp previously tivity in C H oxidation.
À
described in the literature (Figure 3).
trans- (20) and cis-androsterone acetate (21) con-
Oxidation of cis-DMCH and cis-decalin (see Fig- tain 3 primary C H sites, 9 secondary C H sites and
ure S2 in the Supporting Information) show little dif- 5 tertiary C H bonds potentially susceptible of being
ferences among the series of catalysts. The tertiary al- oxidized. Since rings A and D contain electron-with-
À
À
À
À
cohol is the dominant product in both cases with a se- drawing groups, it was envisioned that C H bonds at
lectivity that ranges from 85% with Fe-pdp (current rings B and C would be more prone to oxidation. Fur-
work) to 75% with Fe-Me,MePytacn,[12] for cis-DMCH, thermore, considering the low reactivity of the terti-
À
and from 80% with Fe-pdp to 67% with Fe-mcp for ary bridgehead tertiary C H bonds at trans-decaline
cis-decalin (current work).
(Table 4), it was also presumed that tertiary sites C-8
More remarkable is the oxidation of trans-DMCH and C-9 would also be disfavored. Indeed, when sub-
and trans-decalin, which is shown in a graphical jected to the standard experimental conditions, oxida-
manner in Figure 3. Irrespective of the iron catalyst tion of 20 and 21 proceeds with good product conver-
employed, oxidation of these substrates occurs prefer- sion (82–90%), and three major oxidation products
entially at the secondary sites, Fe-Me,MePytacn and Fe- are obtained resulting from oxidation at three differ-
mcp being the ones for which this selectivity is most ent methylenic sites (C-7, C-6 and C-12, Table 5), all
enhanced. But the most interesting aspect is the ob- of them belonging to rings B and C. Although a clear
servation that discrimination between oxidation at C- rationale for the lack of oxidation at C-11 could not
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Table 5. Oxidation of androsterone derivatives with Fe-mcp. Unless stated otherwise, catalytic conditions are 2ꢆ (3 mol%
catalyst), 200 mol% H2O2, 500 mol% AcOH.
Substrate
Entry
Conversion [%][a]
Yield [%][a]
Selectivity[a]
AHCTUNGTRENNUNG
[C-6[b]/C-7/C-12/C-14]
20
1[c]
2[d]
3[e]
4[f]
5[h]
82
85
76
71
73
59
67
45
48
45
[50/32/17/0]
[52/13/35/0]
[38/37/16/9]
[32/32/13/23]
[44/32/11/13]
[C-6/C-7/C-12]
21
6[c]
7[d]
8[g]
9[e]
10[f]
86
90
90
82
84
52
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
55
53 (45)[i]
38
35
AHCTUNGTRENNUNG
[a]
Based on GC analysis.
[b]
[c]
[d]
[e]
[f]
Sum of ketone and a-alcohol.
Using (S,S)-Fe-mcp as catalyst.
Using (R,R)-Fe-mcp as catalyst.
Using (R,R)-Fe-pdp-OTf as catalyst, 1 addition.
Using (S,S)-Fe-pdp-OTf as catalyst, 1 addition.
Using rac-Fe-mcp as catalyst.
Using Fe-mep as catalyst.
[g]
[h]
[i]
Isolated yield.
be discerned, it may be speculated that steric hin- Fe-pdp-OTf (entry 3, Table 5), and 32% relative selec-
drance caused by ring A and the methyl group C-19 tivity for (S,S)-Fe-pdp-OTf, (entry 4, Table 5)]. For
protect this site. Mass balance in these reactions (R,R)-Fe-pdp-OTf the ketone resulting from oxida-
ranges from 60–80%, which should be regarded as tion at C-12 remains as the third major product (16%
good considering the complexity of the substrates and normalized selectivity, entry 3, Table 5), but the alco-
the difficulty of the reaction. Ketone at C-6 is the hol resulting from hydroxylation at the tertiary posi-
dominant product when (S,S)-Fe-mcp or (R,R)-Fe- tion C-14 is detected in significant amounts (9% rela-
mcp are used as catalyst, accounting for 50–52% of tive selectivity, entry 3, Table 5). On the other hand,
the products in the oxidation of 20, and up to 71% the relative selectivity between C-12 and C-14 oxida-
for 21. Ketones arising from oxidation at C-7 and C- tion products is reversed using (S,S)-Fe-pdp-OTf, in
12 are also obtained in the oxidation of 20, and the favor of the C-14 tertiary alcohol (23% relative selec-
relative proportion of the two products depends on tivity, entry 4, Table 5). This product is interesting
the chirality of the catalyst [C-7/C-12; 32/17 for (S,S)- since it is only observed when using the Fe-pdp-OTf
Fe-mcp; entry 1, Table 5, vs. 13/35 for (R,R)-Fe-mcp, catalysts, showing again the preference of the Fe-mcp
entry 2, Table 5].
systems for methylenic sites.
Reduced product yields and a different selectivity
For comparison, Fe-mep was tested under the same
pattern are observed for Fe-pdp-OTf catalysts in the reaction conditions, appearing as a less active catalyst
oxidation of 20. In this case, a second addition of the than Fe-mcp (67% vs. 45% yield, compare entries 2
reagents increased product convcersion, but reduced and 5, Table 5).
product yields were obtained due to severe overoxida-
When the Fe-pdp-based catalysts are tested in the
tion reactions. In this case, oxidation at C-6 and C-7 is oxidation of 21, product yields are again lower than
obtained in virtually identical relative yields [38% the ones obtained with the Fe-mcp systems. Oxidation
and 37% relative selectivity, respectively, for (R,R)- at C-6 appears as the major product for both catalyst
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The Iron(II) Complex [FeACTHNUTRGENN(UG CF3SO3)2ACHTUNTGREN(NUGN mcp)]
Figure 4. Gram-scale oxidation of (+)-sclareolide (15).
enantiomers with ~50% relative selectivity (entries 9 tained. Despite the low yield of 23, its isolation can
and 10, Table 5). However, the second major product be regarded as significant since it had only been syn-
is dependent on the catalyst used. While (R,R)-Fe- thesized by means of biological methods,[21] which re-
pdp-OTf affords oxidation at C-12 with 30% relative quire high reaction times, and with Fe-pdpp[11] under
selectivity (entry 9, Table 5), (S,S)-Fe-pdp-OTf yields very low temperature catalytic conditions.
C-7 oxidized product in 28% relative selectivity
Overall, the mass balance of the reaction is moder-
(entry 10, Table 5). Finally, by using racemic catalysts, ate (~64%), but it should be considered as quite good
À
we obtained oxidation products with intermediate for a C H oxidation reaction of a complex molecule.
product ratios between those attained with the chiral Most importantly, product yields and regioselectivities
form of the catalysts. These results indicate that regio- obtained in this large-scale reaction are in reasonably
selectivity is dependent on the chirality of the cata- good agreement with that obtained from small-scale
lysts, and both enantiomers have equal contribution reactions (entry 17, Table 3, 56% combined product
to the overall reaction.
yields, with normalized [C-1/C-2/C-3]=[7:64:29],
compared with 50% combined yield, and normalized
[C-1/C-2/C-3]=[5:69:26] for the large-scale reaction),
highlighting the straightforward translation of the re-
action from small to relatively large scales.
Multigram Scale Oxidation of Elaborated Molecules
À
Most commonly, C H oxidation reactions are not
Further illustrating the practical aplicability of the
straightforward to scale-up because of the cost and Fe-mcp catalyst in the large-scale oxidation of com-
sensitive nature of the reagents. In this regard, in plex organic molecules, a multigram scale oxidation
order to illustrate the utility of the Fe-mcp catalysts in of steroid 20 (Figure 5) was also performed with cata-
À
C H oxidation reactions with preparative value, the lyst (S,S)-Fe-mcp following the same standard proce-
oxidation of natural products (+)-sclareolide (15) and dure as employed in the oxidation of 15. As observed
trans-androsterone acetate (20) was performed on in the small scale oxidations, oxidation of position 6
a multigram scale. Figure 4 collects results from the was largely favored, obtaining 834 mg of ketone 26-K,
oxidation of 2.5 g (9.8 mmol) of (+)-sclareolide (15). along with 130 mg of 26-a-OH (29% combined yield).
The reaction was performed in acetonitrile solvent Ketones arising from oxidation at C-7 (27) and C-12
(100 mL) at 08C during 17 min, using 3 mol% of (28) were also obtained in 16% (545 mg) and 12%
(S,S)-Fe-mcp catalyst, 5 equiv. of AcOH diluted in (393 mg) respective yields, which all together account
acetonitrile (8.7 mM) and 3.4 equiv. of H2O2 diluted for 57% combined yield. In addition, 598 mg of un-
in acetonitrile (1.8M), that was added by syringe reacted starting material (18%) were recovered. Mass
pump. After 10 min, a second addition of catalyst, balance of the reaction is ~75% and yield and regio-
À
AcOH and H2O2 via syringe pump over 17 min was selectivity of the C H oxidation reaction is also in
performed. The reaction was complete in 55 min. reasonably good agreement with that obtained in
After work-up, chromatographic separation afforded analogous small-scale oxidations (compare entry 1,
352 mg of unreacted starting material (14%) and two Table 5, 59% yield and normalized ratio [C-6:C-7:C-
major oxidation products. 865 mg of pure ketone 24 12]=[50:32:18], with 57% yield and normalized ratio
resulting from oxidation at the spatially more exposed [C-6:C-7:C-12]=[51:28:21] for the large-scale reac-
site were isolated (34% yield), along with 324 mg of tion). The most important difference arises from the
ketone 25 (13% yield). In addition, 62 mg of 23 (2.4% isolation of small amounts (4%) of alcohol 26-a-OH
yield) resulting from oxidation at C-2 are also ob- in the large-scale reactions, and that was observed
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Mercꢀ Canta et al.
Figure 5. Gram-scale oxidation of trans-androsterone acetate (20).
only in trace amounts in the small-scale reactions. It access to large amounts of catalyst, and the simplicity
is important to notice that no signs of the correspond- of the methodology, multigram scale oxidation of nat-
ing diastereoisomeric alcohol resulting from hydroxyl- ural products can be conveniently performed in short
À
ation at the equatorial C-6 C H bond could be de- reaction times, and product yields and selectivities are
tected. This suggests that formation of 26-a-OH may reliably predicted from small scale reactions.
correspond to a diastereoselective methylene hydrox-
ylation reaction.
À
Summarizing, large-scale C H oxidation reactions Experimental Section
of natural products can be conveniently performed
with the Fe-mcp catalyst, and product yields and se- Sample Analysis
lectivities can be reasonably inferred from small-scale
reactions.
GC analyses of the reaction mixtures provided substrate
conversions and product yields relative to the internal stan-
dard integration. Calibration curves were obtained from
commercial products when available or from pure isolated
samples obtained from catalytic reactions.[11] Cyclohexanone,
n-heptanones, 1-decalone, 2-decalone, and gem-dimethylcy-
clohexanones were purchased from Aldrich or TCI Ameri-
ca. For non-commercially available products, pure samples
were synthesized, isolated and characterized following the
experimental procedures in the literature.[10,11]
Conclusions
The present work shows that Fe-mcp is a very conven-
À
ient catalyst for C H oxidation reactions employing
H2O2 as terminal oxidant. This complex operates at
low catalyst loadings (1–6 mol%) at 08C and short re-
action times, leading to oxidation of non-activated ter-
À
tiary and secondary alkyl C H bonds of organic mol-
Catalytic Conditions
ecules in preparative useful yields. Preparation of the
catalyst on a multigram scale can be done from
simple and inexpensive reagents, which constitutes an
Single addition protocol: In entries 1–2, 4–5, and 7–9 from
Table 1 and Table 2, the single addition protocol is used.[11]
In this protocol, a 5-mL vial was charged with the proper
amounts of catalyst, substrate (1 equiv.) and CH3CN to
obtain a 1.5 mM solution of catalyst (see Supporting Infor-
mation, Table S3 for detailed amounts of reagents). The vial
was placed on an ice bath and stirred. A 1.74M CH3COOH
solution in CH3CN was added and a 1.5M H2O2 solution
À
important advantage with regard to other C H oxida-
tion reagents described so far, including Fe-based cat-
alysts. The catalyst exhibits predictable site selectivity;
it generates electrophilic species upon reaction with
H2O2 that appear sensitive to the structural properties
of the substrate, and this results in remarkable site-se- (diluted from a 35% H2O2 aqueous solution) were delivered
by syringe pump over 17 min at 08C. After syringe pump
addition, the solution was stirred for 10 min at 08C. At this
point, 12.5 mmol of internal standard were added and the so-
lution was then filtered through a silica plug to remove the
catalyst and eluted with 2 mL of AcOEt. The sample was
then submitted to GC analysis.
Slow addition protocol: In entry 6 of Table 1 and Table 2,
the single addition protocol is used. In this case, the catalyst
was delivered via syringe pump over 17 min, simultaneously
with the H2O2 solution. The substrate (1 equiv., 27 mmol)
lectivity properties that can be used to direct oxida-
tion in substrates where multiple methylene sites are
available, obtaining remarkable selectivity for oxida-
tion products of the less sterically hindered methylen-
ic sites. This has been demonstrated to be useful in
the oxidation of complex molecules such as natural
products. Site selectivity in these reactions is distinct
from that attained with other iron catalysts previously
À
described, offering new alternatives for selective C H
functionalization. Most remarkably, given the easy was dissolved in 250 mL of CH3CN in a 5-mL vial and stirred
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The Iron(II) Complex [FeACTHNUTRGENN(UG CF3SO3)2ACHTUNTGREN(NUGN mcp)]
in an ice bath. The catalyst (15 mol%, 4 mmol) was dissolved
in 2.42 mL of CH3CN and a 1.74M CH3COOH solution in
CH3CN was added (1.5 equiv., 40 mmol). This catalyst solu-
tion was delivered to the substrate solution via syringe
pump over 17 min, simultaneously with a 1.5M H2O2 solu-
tion (diluted from a 35% H2O2 aqueous solution, 2 equiv.,
53 mmol for Table 1; 2.8 equiv., 75 mmol for Table 2). After
syringe pump addition, the solution was stirred for 10 min at
08C. At this point, 12.5 mmol of internal standard were
added and the solution was then filtered through a silica
plug to remove the catalyst and eluted with 2 mL of AcOEt.
The sample was then submitted to GC analysis.
catalyst and eluted with 2 mL of AcOEt. The sample was
then submitted to GC analysis
Procedure for Gram Scale Oxidations
A 250-mL round-bottom flask was charged with (S,S)-Fe-
mcp (0.29 mmol, 3 mol%), alkane (9.7 mmol, 1 equiv.),
CH3CN (100 mL, 3 mM solution with respect to catalyst)
and a magnetic stir bar. A 8.73M CH3COOH solution in
CH3CN was added (48 mmol, 500 mol%) and the mixture
was placed on an ice bath and stirred. The necessary
amount of a 1.5M H2O2 solution [diluted from a 30% H2O2
aqueous solution, 3.4 equiv. for (+)-sclareolide, 2 equiv. for
trans-androsterone acetate] was delivered by syringe pump
over 17 min at 08C. After syringe pump addition, the solu-
tion was stirred for 10 min at 08C. A second addition was
performed according to the aforementioned iterative addi-
tion protocol. When the catalysis was finished, the iron com-
plex was removed by passing the solution through a short
path of silica followed by elution with 2 mL of AcOEt. Sol-
vent was removed under reduced pressure and the resulting
residue was purified by flash chromatography on silica gel.
Full characterization data are given in the Supporting In-
formation.
Iterative addition protocol: In entries 3, 10, and 11 from
Table 1 and entries 3, 10–13 from Table 2, the iterative addi-
tion protocol is used.[11]
Iterative addition protocol with slow addition of cata-
lyst: For the three-addition protocol (entry 3), a 5-mL vial
was charged with catalyst (1 mmol, 1 mol%), the substrate
(100 mmol, 1 equiv.) and CH3CN (0.67 mL). The vial was
placed on an ice bath and stirred. 100 mmol of CH3COOH
from a 1.74M solution in CH3CN were added and the
proper amount of a 1.5M H2O2 solution (diluted from
a 35% H2O2 aqueous solution, 1.2 equiv., 120 mmol, see Sup-
porting Information, Table S4) was delivered by syringe
pump over 6 min at 08C. After syringe pump addition, the
solution was stirred for 10 min at 08C. Then a solution of
catalyst (1 mmol, 1 mol%), CH3CN (0.67 mL) and
CH3COOH (100 mmol, 5 equiv.) was added simultaneously
with 1.2 equiv. of a 1.5M (120 mmol) H2O2 solution via sy-
ringe pump over 6 min. After syringe pump addition the re-
sulting solution was stirred for another 10 min. Finally,
a third addition was performed by adding a solution of cata-
lyst (1 mmol, 1 mol%), CH3CN (0.67 mL) and CH3COOH
(100 mmol, 5 equiv.) simultaneously with 1.2 equiv, of a 1.5M
(120 mmol) H2O2 solution via syringe pump over 6 min.
After syringe pump addition the resulting solution was
stirred for another 10 min. At this point, 12.5 mmol of inter-
nal standard were added and the solution was then filtered
through a silica plug to remove the catalyst and eluted with
2 mL of AcOEt. The sample was then submitted to GC
analysis.
Iterative addition protocol with direct addition of cata-
lyst: For the two-addition protocol (entries 10 and 11 in
Table 1, entries 10–13 in Table 2), a 5-mL vial was charged
with catalyst (1 mmol, 3 mol%), the substrate (100 mmol,
1 equiv.) and CH3CN (0.67 mL). The vial was placed on an
ice bath and stirred. 167 mmol of CH3COOH from a 1.74M
solution in CH3CN were added and the proper amount of
a 1.5M H2O2 solution (diluted from a 35% H2O2 aqueous
solution, 2 or 2.8 equiv., see the Supporting Information,
Table S3) was delivered by syringe pump over 17 min at
08C. After syringe pump addition, the solution was stirred
for 10 min at 08C and a solution of catalyst (1 mmol,
3 mol%), CH3CN (0.67 mL) and CH3COOH (167 mmol,
5 equiv.) were added all at once to the reaction mixture. An-
other addition of a 1.5M H2O2 solution (2 or 2.8 equiv., see
the Supporting Information, Table S2) was performed via sy-
ringe pump over 17 min at 08C. After syringe pump addi-
tion, the solution was stirred for 10 min at 08C. At this
point, 12.5 mmol of internal standard were added and the so-
lution was then filtered through a silica plug to remove the
Acknowledgements
We would like to thank European Research Foundation for
Project ERC-2009-StG-239910, MICINN for projects
CTQ2012-37420-C02-01/BQU and CSD2010-00065. General-
itat de Catalunya for an ICREA Academia Award (X.R. and
M.C.) and PhD grant (M.Canta). X.R. thanks financial sup-
port from INNPLANTA project INP-2011-0059-PCT-
420000-ACT1.
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