Substituent effects on the catalytic activity of bipyrrolidine-based iron complexes

Article abstract of DOI:10.1021/jo4020744

The catalytic activity and the selectivity of the new bipyrrolidine-based Fe(II) complexes 2·Fe(OTf)₂ and 3·Fe(OTf)₂ in the oxidation of a series of alkyl and alkenyl hydrocarbons as well as of an aromatic sulfide with H₂O₂ were tested and compared with the catalytic efficiency of White's parent complex 1·Fe(OTf)₂ in order to evaluate the sensitivity of the reaction to electronic effects.

Full text of DOI:10.1021/jo4020744

Article
pubs.acs.org/joc
Substituent Effects on the Catalytic Activity of Bipyrrolidine-Based
Iron Complexes
Giorgio Olivo, Osvaldo Lanzalunga, Luigi Mandolini, and Stefano Di Stefano*
Dipartimento di Chimica and Istituto CNR di Metodologie Chimiche (IMC-CNR), Sezione Meccanismi di Reazione, c/o
Dipartimento di Chimica, Sapienza Universita di Roma, P.le A. Moro, 5, I-00185 Rome, Italy
̀
S
* Supporting Information
ABSTRACT: The catalytic activity and the selectivity of the
new bipyrrolidine-based Fe(II) complexes 2·Fe(OTf)2 and 3·
Fe(OTf)2 in the oxidation of a series of alkyl and alkenyl
hydrocarbons as well as of an aromatic sulfide with H2O2 were
tested and compared with the catalytic efficiency of White’s
parent complex 1·Fe(OTf)2 in order to evaluate the sensitivity
of the reaction to electronic effects.
substituents on pyridine rings may exert some influence on
the catalytic oxidation, whose effectiveness depends on
substrate nature.
INTRODUCTION
■
Iron(II) or -(III) nonheme complexes have emerged in the last
10 years as the most promising tools to oxidize nonactivated
C−H bonds.1 This chemical transformation remained elusive to
synthetic chemists until recently, because of the inertness of
aliphatic C−H bonds, coupled with the difficulty of a selective
transformation into the desired oxygenated product. However,
a number of high-valent nonheme iron complexes have been
recently demonstrated to act as good promoters or catalysts of
hydrocarbon oxidation. These complexes usually have simple
structures, high catalytic efficiencies, good selectivities and
require environmentally friendly and cheap oxidants such as
hydrogen peroxide.2,1d
The past decade has witnessed a growing quest for new and
more effective iron(II) catalysts. Among them, the complex 1·
Fe(SbF6)2, developed by White and co-workers,7 has certainly
reached the degree of ripeness for use in laboratory-scale
syntheses in terms of efficiency and selectivity. For instance, it
was successfully used in the regio- and stereoselective oxidation
of the less hindered tertiary C−H bond in substrates containing
different tertiary C−H bonds.
The reaction mechanisms of the catalytic processes are still a
subject of debate. Nevertheless, it is very likely that in many
cases a FeIII−OOH intermediate is involved which, in turn,
evolves into the oxoferryl active species FeIVO or FeVO
generated from homolysis or heterolysis of the O−O bond,
respectively.3 The nature of the ligand influences the
decomposition pathway of the intermediate. Acid additives
were also shown to exert a great influence on the reaction,4
enhancing both the yield and selectivity of C−H oxidation. The
active oxidant is most likely an electrophilic species, as electron-
rich C−H bonds, such as tertiary bonds, are the most easily
oxidized.
Efforts devoted to elucidation of the features that make a
ligand more active than another pointed out that, among other
ligands, those based on tetradentate or pentadentate pyridine or
tertiary amine N-donors give the most satisfactory results.
Furthermore, a high degree of rigidity in the iron complex was
found to slow down catalyst degradation. As expected, steric
hindrance around the metal ion makes the catalyst more
selective toward the oxidation of the most accessible, least
sterically encumbered C−H bonds.5 Rather surprisingly, the
effects of the presence of substituents with different electronic
properties on the ligands have been far less studied. There are
only a few previous investigations6,5a which show that
In spite of the high efficiency shown by 1·Fe (SbF6)2 in the
oxidation of aliphatic C−H bonds no systematic studies of
substituent effects on its catalytic activity have been carried out.
Thus, in order to acquire a deeper knowledge of this catalytic
system, we considered it worthwhile to investigate the
electronic effect of pyridine ring substituents on the catalytic
efficiency and selectivity of 1·Fe(SbF6)2. In this paper we report
on the results of the oxidations of a series of substrates
catalyzed by iron(II) complexes of ligands 1−3, with the new
complexes of 2 and 3 differing from that of 1 for the presence
of a methoxy (ERG) and an ethoxycarbonyl (EWG) group,
respectively, in the γ position of the pyridine rings. The
substrates selected in this study have been chosen in order to
compare the catalytic efficiency and selectivity of the three iron
complexes in the oxidation of several types of C−H bonds. In
Received: September 19, 2013
Published: October 15, 2013
© 2013 American Chemical Society
11508
dx.doi.org/10.1021/jo4020744 | J. Org. Chem. 2013, 78, 11508−11512

The Journal of Organic Chemistry
Article
particular, we focused on reactivity toward secondary C−H
bonds in the case of cyclohexane, tertiary/secondary selectivity
in the case of adamantane, and selectivity toward different kinds
of tertiary C−H bonds in the case of d-menthyl acetate. In
order to widen the scope of this study, we included also the
oxidation of the double bond of cyclooctene and the sulfur
atom of 4-bromophenyl methyl sulfide.
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Complexes. The
new ligands 2 and 3 were prepared by double N,N′ alkylation
of (S,S′)-2,2′-bipyrrolidine tartrate with 4-methoxy- and 4-
ethoxycarbonyl-2-picolyl chloride, respectively, using White’s
procedure7 as depicted in Scheme 1. Ligands 2 and 3 were
1
characterized by H and 13C NMR, ESI-TOF exact mass, and
Figure 2. Titration of 0.20 mM ligand 1 with Fe(OTf)2 in CH3CN at
25 °C.
UV−vis spectroscopy.
Scheme 1. Syntheses of Ligands 2 and 3
observed during the titrations of all the ligands. It was
attributed to the probable formation of complexes with
different stoichiometries formed by a defect of iron(II),
which completely disappear when the equivalence is reached.
Oxidation Experiments. In all oxidation experiments the
catalyst loading was fixed at 5% molar equiv. The substrate was
used at high concentration (0.48−0.66 M), with the sole
exception of adamantane, for which a concentration as low as
0.025 M was used due to its low solubility. Catalyst and additive
(acetic acid, 0.5 molar equiv) were added to the acetonitrile
substrate solution in one shot at the beginning of the reaction,
while hydrogen peroxide (1.2 mol equiv) was added over a
period of 2 min through a syringe pump. The reaction mixture
was then stirred at room temperature for an additional 28 min.
The complexes 1·Fe(OTf)2, 2·Fe(OTf)2, and 3·Fe(OTf)2
were prepared in situ by adding equimolar amounts of the
ligand and iron(II) triflate (Fe(OTf)2) in acetonitrile solution.
In Figure 1 the UV−vis spectra of ligand 3 and of the complex
1
After workup, the crude mixture was analyzed by GC or H
NMR. All results are the average from three independent runs.
In the original procedure reported by White,7a catalyst, acid,
and oxidant were added three times during the reaction course.
The simplified procedure adopted in this work was aimed at
maximizing reproducibility in oxidation experiments.
The oxidation of cyclohexane affords a mixture of cyclo-
hexanol and cyclohexanone (Scheme 2).8 The results are
Scheme 2. Oxidation of Cyclohexane to Cyclohexanol (A)
and Cyclohexanone (K)
Figure 1. UV−vis spectra of 0.20 mM 3 and 0.20 mM complex 3·
Fe(OTf)2 in CH3CN at 25 °C. Inset: increase of absorbance at λmax
450 nm vs time recorded after the addition of Fe(OTf)2 to a solution
of 3.
shown in Table 1. It appears that all three catalysts are much
more effective than iron(II) triflate, for which low reactivity and
3·Fe(OTf)2 are reported (UV−vis spectra of ligands 1 and 2
and of the corresponding complexes are reported in the
Supporting Information). As reported in the inset of Figure 1,
the complexation reaction between ligand 3 and Fe(OTf)2 was
fast and binding was complete within 2 min from the addition
of the components. Complex formation for ligands 1 and 2 was
even faster.
Figure 2 reports as an example the saturation profile obtained
in the titration of ligand 1 with Fe(OTf)2 in acetonitrile. The
limiting value for the absorbance recorded at λmax 377 nm is
attained exactly when 1 equiv of the iron salt is added, as
expected for a strong 1:1 binding between ligand and metal ion
(K ≥ 106 M−1). A nonlinear increase in absorbance was
Table 1. Oxidation of Cyclohexane
a
a
catalyst
A
K
A + K
A/K
Fe(OTf)2
3.1 0.1
6.5 0.5
7.5 0.5
8.0 0.5
3.5 0.5
7
60
64
30
ca. 1
0.11
0.13
0.36
1·Fe(OTf)2
2·Fe(OTf)2
3·Fe(OTf)2
53
56
22
1
1
1
a
GC yields defined as (mol of product)/(mol of substrate) × 100.
Reactants: cyclohexane (0.66 M), hydrogen peroxide (0.86 M), acetic
acid (0.33 M), catalyst (0.033 M). Average of three determinations.
11509
dx.doi.org/10.1021/jo4020744 | J. Org. Chem. 2013, 78, 11508−11512

The Journal of Organic Chemistry
Article
no selectivity are observed. The catalysts 1·Fe(OTf)2 and 2·
Fe(OTf)2 display similar catalytic efficiencies in terms of both
yield and selectivity, while the catalyst 3·Fe(OTf)2 is less
effective. Thus, while negligible effects on the reaction yield and
selectivity are observed in the presence of an electron-releasing
group, a significantly lower efficiency is observed in the
presence of an electron-withdrawing group. In the case of
iron(II) triflate the formation of similar amounts of cyclo-
hexanol and cyclohexanone with low yields is a typical clue of a
free radical process, while a completely different scenario is
observed for all three PDP-based catalysts.9 In these cases the
low A/K values, comparable with those previously reported by
White7 and Costas,5b suggest that the oxidant is not a freely
diffusing hydroxyl radical but more probably a metal-based
oxidant.
Table 3. Oxidation of d-Menthyl Acetate
a
a
b
S
catalyst
T1
T2
2.0 0.5
total
T2/T1
Fe(OTf)2
1.0 0.5
2.0 0.2
2.0 0.2
ca. 3
13
89
84
74
82
2
1·Fe(OTf)2
2·Fe(OTf)2
3·Fe(OTf)2
11
22
12
1
1
1
6
2
1
1
24
11
3
1
15
ca. 4
a
1H NMR yields defined as (mol of product)/(mol of substrate) ×
b
100. Experimental conditions as in Table 1. Yield of recovered
substrate, in percent.
Scheme 4. Oxidation of d-Menthyl Acetate to Tertiary
Alcohols T1 and T2
In Table 2 the results related to the oxidation of adamantane
(Scheme 3) are reported together with those obtained in the
Table 2. Oxidation of Adamantane
calculations to be also the more electron-rich C−H bond.7a The
C5 carbon atom configuration is retained during hydroxylation,
as shown by a comparison of the H NMR spectra (see Figure
a
a
b
c
catalyst
A1
A2 + K
total tert/sec
S
Fe(OTf)2
12.0 0.5
25.5 0.5
6.1 0.2
6.0 0.2
18
31
40
39
26
6
13
9
57
61
49
53
66
2
1
2
2
2
1
1·Fe(SbF6)2
1·Fe(OTf)2
2·Fe(OTf)2
3·Fe(OTf)2
SI 11 in the Supporting Information) with those reported in the
literature,10 pointing to the probable involvement of a metal-
based oxidant. The addition of iron(II) triflate gives practically
no reaction, indicating again that a PDP ligand is required for
an effective process. The catalysts 1·Fe(OTf)2 and 3·Fe(OTf)2
display similar catalytic efficiencies, while the complex 2·
Fe(OTf)2 appears to be the most efficient, with a significantly
higher conversion of the substrate into the reaction products.
As in the case of adamantane, the catalyst 2·Fe(OTf)2 results to
be more selective than 1·Fe(OTf)2 (T2/T1 ratio 11/6) toward
tertiary C−H bond oxidation. In this case we see an appreciable
substituent effect, with the methoxy group enhancing both yield
and selectivity.
30
34
21
1
1
1
10
1
5.1 0.1
21
13
5
1
a
GC yields defined as (mol of product)/(mol of substrate) × 100.
Reactants: adamantane (0.025 M), hydrogen peroxide (0.030 M),
acetic acid (0.012 M), catalyst (0.0012 M). Average of three
b
determinations. Normalized tertiary/secondary ratio defined as 3 ×
c
[A1/(A2 + K)]. Yield of recovered substrate, in percent.
Scheme 3. Oxidation of Adamantane to 1-Adamantol (A1),
2-Adamantol (A2), and Adamantone (K)
In Table 4 the results related to the oxidation of cyclooctene
(Scheme 5) are reported. A good material balance was observed
Table 4. Oxidation of Cyclooctene
a
a
b
catalyst
A
E
total
E/A
S
Fe(OTf)2
2.5 0.5
4.0 0.5
3.5 0.5
4.5 0.5
18
2
20.5
96.5
98.5
87.5
8.2
23
64
1
presence of iron(II) triflate and the White’s commercially
available complex 1·Fe(SbF6)2. A good material balance
(>97%) was observed in all experiments. As found in the
oxidation of cyclohexane, all three complexes are much better
catalysts than iron(II) triflate. The catalysts 1·Fe(OTf)2 and 2·
Fe(OTf)2 have again very similar efficiencies in terms of total
yields, while 3·Fe(OTf)2 is characterized by a lower efficiency.
The oxidation catalyzed by 2·Fe(OTf)2 exhibits a higher
selectivity toward tertiary C−H bonds than 1·Fe(OTf)2. The
catalyst 1·Fe(OTf)2 appears to be more efficient than 1·
Fe(SbF6)2, indicating that the catalytic process can be affected
to some extent by the nature of the counterion. Moreover, all
complexes show a tertiary/secondary ratio within the range
10−30 (see Table 2), indicating again the involvement of a
metal-based oxidant.6b
Table 3 reports results related to d-menthyl acetate oxidation
(Scheme 4). The material balance was again satisfactory
(>92%). In this case only two out of three tertiary carbon
atoms are oxidized, since the third atom is deactivated by the
proximal acetoxy group.5b,7a The main product T2 is obtained
by attack of the oxidant on the less hindered tertiary C−H
bond at the C5 position, which has been shown by DFT
1·Fe(OTf)2
2·Fe(OTf)2
3·Fe(OTf)2
92.5 0.5
95.0 0.5
<1
<1
<1
27
83
1
18
a
GC yields defined as (mol of product)/(mol of substrate) × 100.
Experimental conditions as in Table 1. Yield of recovered substrate,
in percent.
b
in the reactions promoted by 1·Fe(OTf)2 and 2·Fe(OTf)2
(>97%) but not in the reactions promoted by iron(II) triflate
and 3·Fe(OTf)2 (<90%). This result can be likely attributed to
the formation of other unidentified oxidation products. A
Scheme 5. Oxidation of Cyclooctene to 3-
Hydroxycyclooctene (A) and Cyclooctene Oxide (E)
11510
dx.doi.org/10.1021/jo4020744 | J. Org. Chem. 2013, 78, 11508−11512

The Journal of Organic Chemistry
Article
marked preference for epoxidation over allylic oxidation is
shown by all three catalysts, in line with the outcome of other
nonheme-catalyzed alkene oxidation processes.1d It should be
noted that, under the same experimental conditions adopted for
the aliphatic C−H oxidation, iron(II) PDP systems display a
very high catalytic efficiency in cyclooctene oxidation with an
almost quantitative conversion of the alkene into the
corresponding epoxide.
In view of the particularly high conversion only small
differences should be expected when reactivity data of the three
catalytic systems are compared. A slight steady increase of
reaction yield and selectivity is indeed observed by enhancing
the electron-donating power of the pyridine substituents.
The three iron(II) complexes were also tested in the
oxidation of 4-bromophenyl methyl sulfide (Scheme 6). Table
group a significant destabilization of the active species probably
leads to its faster degradation. Further investigations are
certainly needed in order to rationalize the PDP Fe(II)
substituent effects in a mechanistic framework.
In conclusion, however, in light of the results presented in
this report and in other investigations,6,5a even considering the
slightly higher catalytic efficiency shown by the methoxy-
substituted complex, the introduction of a substituent in the γ
position of pyridine rings does not seem the right key to
improve to a very significant extent the catalytic activity and
selectivity of iron(II) nonheme catalysts.
EXPERIMENTAL SECTION
■
Instruments and General Methods. NMR spectra were
recorded on either a 300 or 200 MHz spectrometer. The spectra
were internally referenced to the residual proton solvent signal. HR-
ESI mass spectra were obtained on an ESI-TOF spectrometer. UV−vis
spectra were registered by a double-ray spectrophotometer. GC
analyses were carried out on a gas chromatograph equipped with a
capillary methylsilicone column (30 m × 0.25 mm × 25 μm),
Chrompack CP-Sil 5 CB. GC-MS analyses were performed with a
mass detector (EI at 70 eV) coupled with a gas chromatograph
equipped with a melted silica capillary column (30 m × 0.2 mm × 25
μm) covered with a methylsilicone film (5% phenylsilicone, OV5).
Materials. All reagents and solvents were purchased at the highest
commercial quality and were used without further purification unless
otherwise stated.
Scheme 6. Oxidation of 4-Bromophenyl Methyl Sulfide to
the Corresponding Sulfoxide and Sulfone
4-Methoxy-2-chloromethylpyridine hydrochloride was prepared in
several steps following literature procedures (see the synthetic scheme
in the Supporting Information). Commercially available 2-picoline was
first oxidized to its N-oxide,11 which was subsequently reacted with a
HNO3/H2SO4 mixture to obtain 4-nitro-2-picoline N-oxide.12 This
compound was then reacted with methanol in the presence of
potassium tert-butoxide to give 4-methoxy-2-picoline N-oxide.13
Reaction of the latter with trifluoroacetic anhydride and subsequent
hydrolysis provided us 4-methoxy-2-hydroxymethylpyridine,14 which
was finally transformed into 4-methoxy-2-chloromethylpyridine hydro-
chloride by reaction with thionyl chloride. 4-Ethoxycarbonyl-2-
chloromethylpyridine hydrochloride was prepared from pyridine-2,4-
dicarboxylic acid following a literature procedure (see the synthetic
scheme in the Supporting Information).15 The above chloromethyl
derivatives were used as alkylating agents for the preparations of
ligands 2 and 3 using White’s protocol.7a The complex 1·Fe(SbF6)2
was purchased from Aldrich and used as such without further
purification. Ligand 1 was purchased from Aldrich as a hydrochloride
salt. The related base was obtained by extraction of a basic aqueous
solution (1 M NaOH) with dichloromethane.
2-({(S)-2-[(S)-1-(4-Methoxypyridin-2-ylmethyl)pyrrolidin-2-
yl]pyrrolidin-1-yl}methyl)-4-methoxypyridine (Ligand 2).
(S,S′)-2,2′-Bipyrrolidine tartrate trihydrate (500 mg, 1.45 mmol) and
NaOH (550 mg, 13.8 mmol) were dissolved in a biphasic mixture of
CH2Cl2 (4.6 mL) and water (4.6 mL). Then, 4-methoxy-2-
chloromethylpyridine hydrochloride (680 mg, 3.50 mmol) was
added and the reaction mixture was stirred for 46 h. The resulting
mixture was diluted with 1 M NaOH and extracted with CH2Cl2 (6 ×
20 mL). The organic layers were combined, dried over MgSO4, and
filtered, and the solvent was removed. Purification by column
chromatography was carried out on the crude product (SiO2,
CH2Cl2 MeOH 1% NH4OH 0.5%). Fractions containing the desired
product were washed with 1 M NaOH and dried over Na2SO4. After
evaporation the procedure yielded pure ligand 2 as a yellow oil (340
mg, 0.89 mmol, 62% yield). 1H NMR (300 MHz, CDCl3): δ 1.73 (m,
6H), 1.87 (m, 2H), 2.32 (m, 2H), 2.88 (m, 2H), 3.04 (m, 2H), 3.58
(d, 2H, J = 15 Hz), 3.79 (s, 6H), 4.19 (d, 2H, J = 15 Hz), 6.63 (m,
2H), 6.98 (s, 2H), 8.29 (m, 2H). 13C NMR (300 MHz, CDCl3): δ
23.7, 24.4, 55.0, 55.1, 61.1, 65.9, 108.29, 108.34, 150.0 166.2. HRMS
(ESI-TOF): calcd for C22H31N4O2 383.2447 (M + H+), found
383.2426. UV−vis: λmax 260 nm, shoulder (ε = 1465 L mol−1 cm−1).
Table 5. Oxidation of 4-Bromophenyl Methyl Sulfide
a
a
b
catalyst
none
SO
1.5 0.5
51
SO2
total
S
0.6 0.1
2.5 0.5
3.0 0.2
5.1 0.1
2.0 0.1
ca. 2
53.5
90.5
94
98
46
1
1
Fe(OTf)2
1
1·Fe(OTf)2
2·Fe(OTf)2
3·Fe(OTf)2
87.5 1.5
89.1 0.2
7.0 0.5
5.7 0.5
85
1
87
12
1
a
GC yields defined as (mol of product)/(mol of substrate) × 100.
Reactants: 4-bromophenyl methyl sulfide (0.48 M), hydrogen peroxide
b
(0.58 M), acetic acid (0.24 M), catalyst (0.024 M). Yield of recovered
substrate, in percent.
5 shows that all three complexes are very efficient catalysts in
the sulfide oxidation process. 4-Bromophenyl methyl sulfoxide
is formed as the main product, accompanied by much lower
amounts of 4-bromophenyl methyl sulfone, and a good material
balance (>97%) was observed in all experiments. As found in
cyclooctene oxidation, total yields slightly increase on
increasing the electron-donating power of the pyridine
substituent, in the order 3·Fe(OTf)2 < 1·Fe(OTf)2 < 2·
Fe(OTf)2.
To sum up, in this study we have reported the synthesis and
characterization of two new PDP-type Fe(II) catalysts for the
oxidation of unactivated hydrocarbons. The methoxylated
complex 2·Fe(OTf)2 displayed catalytic efficiency and
selectivity that are generally higher than or comparable to,
depending on the substrate, those of the parent complex 1·
Fe(OTf)2. On the other hand, a significant decrease in the
catalytic efficiency and reaction selectivity has been generally
observed in the presence of the electron-withdrawing CO2Et
substituent. The beneficial effect on the catalytic process
deriving from the introduction of a methoxy substituent in the
ligand pyridine ring would suggest that the stabilization of the
electrophilic active species by the electron-releasing methoxy
group is more important than the decrease of its electrophilic
character. In the presence of the electron-withdrawing CO2Et
11511
dx.doi.org/10.1021/jo4020744 | J. Org. Chem. 2013, 78, 11508−11512

The Journal of Organic Chemistry
Article
2-({(S)-2-[(S)-1-(4-Ethoxycarbonylpyridin-2-ylmethyl)-
pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)-4-ethoxycarbonylpyri-
dine (Ligand 3). (S,S)-2,2′-Bipyrrolidine tartrate trihydrate (430 mg,
1.26 mmol) and NaOH (370 mg, 9.2 mmol) were dissolved in a
biphasic mixture of CH2Cl2 (3.3 mL) and water (3.3 mL). To this
mixture was added 4-ethoxycarbonyl-2-chloromethylpyridine hydro-
chloride (710 mg, 3.03 mmol), and the reaction mixture was stirred for
46 h. The resulting mixture was diluted with 1 M NaOH and extracted
with CH2Cl2 (6 × 20 mL). The organic layers were combined, dried
over MgSO4, and filtered, and the solvent was removed. Purification by
column chromatography was carried out on the crude product (SiO2,
CH3CN/MeOH 1/1). After evaporation of the selected fractions
ligand 3 was obtained as a yellow oil (210 mg, 0.45 mmol, 36% yield).
1H NMR (300 MHz, CDCl3, containing a trace of trifluoroacetic acid):
δ 1.40 (t, J = 6 Hz, 6H), 1.76−1.84 (m, 2H), 1.92−1.99 (m, 4H), 2.19
(m, 2H), 3.03 (m, 2H), 3.41 (m, 2H), 3.6 (m, 2H), 4.41 (q, J = 6 Hz,
4H), 4.50 (d, J = 15 Hz, 2H), 4.63 (d, J = 15 Hz, 2H), 7.82 (d, J = 3
Hz, 2H), 8.06 (s, 2H), 8.73 (d, J = 3 Hz, 2H). 13C NMR (300 MHz,
CDCl3, in the presence of a trace of trifluoroacetic acid): δ 14.1, 23.5,
27.8, 54.0, 59.2, 62.0, 66.8, 122.3, 123.8, 138.8, 150.0, 156.3, 164.7.
HRMS (ESI-TOF): calcd for C26H35N4O4 467.2658 (M + H+), found
467.2686. UV−vis: λmax 279 nm (ε = 5095 L mol−1 cm−1).
Oxidation Procedure. In the oxidation of cyclohexane, d-menthyl
acetate, cyclooctene, and 4-bromophenyl methyl sulfide, the complexes
1·Fe(OTf)2, 2·Fe(OTf)2 and 3·Fe(OTf)2 were prepared in situ by
dissolving 2.3 mg (7 μmol) of iron(II) triflate in an acetonitrile
solution (0.066 M) of the given ligand (100 μL, 7 μmol). After 2 min,
to the resulting solutions were added the following: (i) 30 μL of
acetonitrile, 4 μL of AcOH (66 μmol, 50 mol %), 7 μL of PhNO2 used
as an internal standard (66 μmol, 50 mol %), and 12 μL of
cyclohexane (134 μmol, 100 mol %); (ii) 37 μL of acetonitrile, 4 μL of
AcOH (66 μmol, 50 mol %), and 26 mg of d-menthyl acetate (136
μmol, 100 mol %); (iii) 25 μL of acetonitrile, 4 μL of AcOH (66 μmol,
50 mol %), 7 μL of PhNO2 as an internal standard (66 μmol, 50 mol
%), and 17 μL of cyclooctene (134 μmol, 100 mol %); (iv) 4 μL of
AcOH (66 μmol, 50 mol %), 7 μL of PhNO2 as an internal standard
(66 μmol, 50 mol %), and 100 μL of a 1.33 M solution of 4-
bromophenyl methyl sulfide (134 μmol, 100 mol %).
After the addition of the above reagents, 70 μL of a 2.4 M solution
of H2O2 in acetonitrile freshly prepared from commercial 30% aqueous
H2O2 was added by a syringe pump over a period of 2 min, and the
reaction mixture was stirred for an additional 28 min. Then 1.0 mL of
a saturated NaHCO3 solution was added and the mixture was
extracted with Et2O. The organic layer was dried over Na2SO4, filtered,
and analyzed by GC chromatography.
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.D.S.: stefano.distefano@uniroma1.it.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Thanks are due to the Ministero dell’Istruzione, dell’Universita
e della Ricerca (MIUR, PRIN 2010CX2TLM), and the
Consiglio Nazionale delle Ricerche (CNR) for financial
support. This work was also partially supported by the
Dipartimento di Chimica, Sapienza Universita
through the Supporting Research Initiative 2013.
̀
̀
di Roma,
REFERENCES
■
(1) (a) Kaizer, J.; Klinker, E. J.; Oh, N. Y.; Rohde, J.-U.; Song, W. J.;
Stubna, A.; Kim, J.; Munck, E.; Nam, W.; Que, L., Jr. J. Am. Chem. Soc.
̈
2004, 126, 472−473. (b) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev.
2011, 111, 1293−1314. (c) White, M. C. Science 2012, 335, 807−809.
(d) Talsi, E. P.; Bryliakov, K. P. Coord. Chem. Rev. 2012, 256, 1418−
1434.
(2) (a) Que, L., Jr. Acc. Chem. Res. 2007, 40, 493−500. (b) Que, L.,
Jr.; Tolman, W. B. Nature 2008, 455, 333−340.
(3) (a) Fujita, M.; Costas, M.; Que, L., Jr. J. Am. Chem. Soc. 2003,
125, 9912−9913. (b) Nam, W. Acc. Chem. Res. 2007, 40, 522−531.
(c) Yoon, J.; Wilson, S. A.; Yu, K. J.; Seo, M. S.; Nehru, K.; Hedma
Hodgson, K. O.; Bill, E.; Solomon, E. I.; Nam, W. Angew. Chem., Int.
Ed. 2009, 48, 1257−1260. (d) Klinker, E. J.; Shaik, S.; Hirao, H.; Que,
L., Jr. Angew. Chem., Int. Ed. 2009, 48, 1291−1295.
́
(4) (a) Mas-Balleste, R.; Que, L., Jr. J. Am. Chem. Soc. 2007, 129,
15964−15972. (b) White, M. C.; Doyle, A. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2001, 123, 7194−7195. (c) Wang, Y.; Janardanen, D.;
Usharani, D.; Han, K.; Que, L., Jr.; Shaik, S. ACS Catal. 2013, 3,
1334−1341.
(5) (a) England, J.; Gondhia, R.; Bigorra-Lopez, L.; Petersen, A. R.;
White, A. J. P.; Britovsek, G. J. P. Dalton Trans. 2009, 5319−5334.
́
(b) Gomez, L.; Garcia-Bosch, I.; Company, A.; Benet-Buchholz, J.;
Polo, A.; Sala, X.; Ribas, X.; Costas, M. Angew. Chem., Int. Ed. 2009, 48,
5720−5723.
(6) (a) Hitomi, Y.; Furukawa, S.; Higuchi, M.; Shishido, T.; Tanaka,
T. J. Mol. Catal. A 2008, 288, 83−86. (b) Prat, I.; Company, A.;
Postils, V.; Ribas, X.; Que, L., Jr.; Luis, J. M.; Costas, M. Chem. Eur. J.
2013, 19, 6724−6738. (c) Prat, I.; Font, D.; Company, A.; Junge, K.;
Ribas, X.; Beller, M.; Costas, M. Adv. Synth. Catal. 2013, 355, 947−
956.
In the case of adamantane oxidation, the complexes 1·Fe(OTf)2, 2·
Fe(OTf)2, and 3·Fe(OTf)2 were prepared in situ by dissolving 0.18
mg of iron(II) trifluoromethanesulfonate (0.51 μmol) in an
acetonitrile solution (0.066 M) of the given ligand (7.5 μL, 0.51
μmol). To the resulting solutions were added the following: 10 μL of a
0.5 M AcOH solution in acetonitrile (5 μmol, 50 mol %) and 330 μL
of a 0.033 M solution of adamantane (10 μmol, 100 mol %). After the
addition of the above reagents, 40 μL of a 0.30 M solution of H2O2 in
acetonitrile was added by a syringe pump over a period of 2 min, and
the reaction mixture was stirred for 28 min. Then 10 μL of a 0.50 M
PhCl solution (as an internal standard, 5 μmol, 50 mol %) and 1 mL of
a saturated NaHCO3 were added, and the mixture was extracted with
Et2O. The organic layer was dried over Na2SO4, filtered, and analyzed
by GC chromatography.
(7) (a) Chen, M. S.; White, M. C. Science 2007, 318, 783−787.
(b) Chen, M. S.; White, M. C. Science 2010, 327, 566−571.
(8) Quantitative analysis of the unreacted substrate was problematic
due to the close proximity of cyclohexane and solvent chromato-
graphic peaks.
(9) PDP is the acronym for 2-({(S)-2-[(S)-1-(pyridin-2-ylmethyl)
pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)pyridine.
(10) Asakawa, Y.; Matsuda, R.; Tori, M.; Hashimoto, T.
Phytochemistry 1988, 27, 3861−3869.
(11) (a) Shuman, R. T.; Ornstein, P. L.; Paschal, J. W.; Gesellchen, P.
D. J. Org. Chem. 1990, 55, 738−741. (b) Ochiai, E. J. Org. Chem. 1953,
18, 534−551.
(12) Hom, R. K.; Chi, D. Y.; Katzenellenbogen, J. A. J. Org. Chem.
1996, 61, 2624−2631.
ASSOCIATED CONTENT
■
(13) Kuhler, T. C.; Swanson, M.; Shcherbuchin, V.; Larsson, H.;
̈
S
* Supporting Information
Mellgard, B.; Sjostrom, J.-E. J. Med. Chem. 1998, 41, 1777−1788.
̈
̈
Figures giving the synthetic scheme followed in 2-chlorome-
(14) (a) Zaman, N.; Guillot, R.; Sen
́ ́
echal-David, K.; Boillot, M.-L.
1
thylpyridine derivatives preparation, H and 13C NMR and
Tetrahedron Lett. 2008, 49, 7274−7275.
UV−vis spectra of the new ligands, GC chromatograms and 1H
NMR spectra of selected crude products of some oxidation
reactions. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Kojima, T.; Hayashi, K.-I.; Iizuka, S.-Y.; Tani, F.; Naruta, Y.;
Kawano, M.; Ohashi, Y.; Hirai, Y.; Ohkubo, K.; Matsuda, Y.;
Fukuzumi, S. Chem. Eur. J. 2007, 13, 8212−8222.
11512
dx.doi.org/10.1021/jo4020744 | J. Org. Chem. 2013, 78, 11508−11512