The Fe(PDP)-catalyzed aliphatic C-H oxidation: a slow addition protocol

Article abstract of DOI:10.1016/j.tet.2008.11.082

This report describes a slow addition protocol for the Fe(PDP)-catalyzed aliphatic C-H oxidation reaction. Under this protocol, the reaction can be productively driven to higher conversions without decreasing site-selectivity or chemoselectivity. The operational advantages of this procedure are highlighted in the oxidation of two complex natural product derivatives. Hydroxylated products can be obtained in high isolated yields without the need for recycling recovered starting materials.

Full text of DOI:10.1016/j.tet.2008.11.082

Tetrahedron 65 (2009) 3078–3084
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The Fe(PDP)-catalyzed aliphatic C–H oxidation: a slow addition protocol
*
Nicolaas A. Vermeulen, Mark S. Chen, M. Christina White
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2008
Received in revised form 14 November 2008
Accepted 25 November 2008
Available online 30 November 2008
This report describes a slow addition protocol for the Fe(PDP)-catalyzed aliphatic C–H oxidation reaction.
Under this protocol, the reaction can be productively driven to higher conversions without decreasing
site-selectivity or chemoselectivity. The operational advantages of this procedure are highlighted in the
oxidation of two complex natural product derivatives. Hydroxylated products can be obtained in high
isolated yields without the need for recycling recovered starting materials.
Ó 2008 Published by Elsevier Ltd.
Dedicated to Professor Justin Du Bois in
celebration of his receiving the Tetrahedron
Young Investigator Award
1. Introduction
required, carboxylic acids may serve as directing groups to furnish
five-membered ring lactones.11
Modern synthetic planning relies on the manipulation of oxi-
dized functionality, often ignoring ubiquitous and inert C–H bonds
in organic scaffolds. Methods that directly transform C–H bonds
into C–O, C–N, or C–C bonds enable the construction of oxidized
materials through an orthogonal strategy,1 often leading to sim-
plified synthetic routes. For example, we have developed methods
that allow oxygen, nitrogen, and carbon functionalities to be in-
stalled directly from allylic C–H bonds2 and demonstrated that
strategically employing such oxidations late in synthetic sequences
markedly reduces unproductive chemical manipulations (i.e.,
oxidation state changes, protection–deprotections, functional
group transformations).3 Importantly, for these reactions to be
applied at late stages of synthetic routes, they must proceed with
predictable and high selectivities. Selective C–H functionalization
reactions on complex substrates have been primarily accomplished
2. Results
While the Fe(PDP) aliphatic C–H oxidation reaction enables for
the first time the selective oxidation of complex substrates at
unactivated, isolated C–H bonds with preparatively useful isolated
yields (43–57%), important challenges remain; these include
improving catalyst turnovers and productive substrate conversions.
Currently, three iterative additions of Fe(PDP) catalyst 1 (5 mol %),
hydrogen peroxide oxidant (H2O2, 1.2 equiv), and acetic acid addi-
tive (AcOH, 0.5 equiv) in 10–15 min intervals are utilized to obtain
maximum product yields (Table 1, entry 5, Table 2). Adding more
oxidant alone does not alter product yield (Table 1, entry 2),
indicating that catalyst decomposition, not inefficient use of H2O2,
is responsible for the modest yields observed. Significantly, with
a single addition, increasing the catalyst loading to 15 mol % with or
without increasing the amount of oxidant affords no significant
improvement in yield and diminishes the selectivity for the 3ꢀ
hydroxylated product 3 (Table 1, entry 1 vs entries 3 and 4). These
results suggest that increased catalyst concentrations are deleteri-
ous to catalyst productivity.
Although new catalyst and reagents (1/H2O2/AcOH) are in-
troduced during each cycle of the iterative addition protocol, the
third addition fails to significantly promote product formation due
to deteriorating catalyst reactivity and selectivity in the reaction
mixture (Table 1, entry 5). Notably, a fourth addition of 1/H2O2/
AcOH is ineffective at catalyzing desired product formation (Table 1,
entry 5; Table 2, entries 2 and 4). In cases where valuable starting
material remains, conversion to product can be achieved using
a ‘recycling protocol’ that consists of physically separating (via
column chromatography) the starting material from the reaction
for activated C–H bonds (i.e.,
p
-system2–4 or adjacent to a hetero-
atom5) or via the use of substrate directing groups.6 In contrast to
this, we recently disclosed an iron (Fe)-based small molecule cat-
alyst, Fe(PDP) 1 [[Fe(II)(PDP)(CH3CN)2](SbF6)2]7 that catalyzes the
oxidation of isolated, unactivated sp3 C–H bonds in complex mo-
lecular settings with predictable and high levels of selectivity and
without the requirement for directing groups.8–10 Selectivity for oxi-
dation of 3ꢀ C–H bonds with 1 can be predicted using a series of
simple rules based on the electronic and steric properties of the
C–H bonds (vide infra). Moreover, in all cases examined when the
3ꢀ C–H bond is part of a stereogenic center, hydroxylation occurs
with complete retention of stereochemistry.8 Although not
* Corresponding author.
E-mail address: white@scs.uiuc.edu (M. Christina White).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.11.082

N.A. Vermeulen et al. / Tetrahedron 65 (2009) 3078–3084
3079
Table 1
Table 2
Reaction optimization
Comparison of iterative addition protocol to slow addition protocol
Entry Hydroxylation product
Isolated % yielda (rSMb)
Iterative additionc Slow addition
5 mol %ꢂ3
15 mol %d 20 mol %
1
2
46 (26)
51 (27)
44 (35)
61 (0)
49 (15)e
3
4
43 (33)
54 (23)
45 (23)e
5
6
60 (18)
53 (43)
61 (21)
67 (30)
66 (0)
72 (0)
Entry
Fe(PDP) 1
(mol %)
Yielda
(%)
Conv.a
(%)
Select.a
(%)
1
2
3
4
5
5
32
32
28
40
35
42
33
56
91
76
85
71
5b
7
8
43 (42)
33 (67)
48 (22)
45 (32)
40 (59)
56 (18)
50 (19)
46 (50)
15
15c
Iteratived
5
33
36
92
10 (5)e
15 (5)e
20 (5)e
15% (slow)g
52 (19)e
57 (5)e
57 (0)e
60
70 (34)e
89 (19)e
96 (7)e
95
74 (56)f
64 (26)f
59 (0)f
63
6
a
Determined by GC. The stereoretentive nature of the oxidation reaction was
determined by GC (average of 9 runs). Oxidation of cis-2 (>98% cis) afforded cis-3
(99.58%ꢁ0.05% cis).
9
61 (9)
b
H2O2 (1.2 equiv) added after one iteration.
H2O2 (3.6 equiv), 1.5 equiv AcOH, 0.67 M CH3CN.
Iterative addition of 5 mol % 1, AcOH (0.5 equiv), H2O2 (1.2 equiv) every 10–
c
d
15 min (see Section 4).
e
For increases in catalyst loading, yield or conversion relative to previous itera-
39 (32)
9:1 [C7:C3]
43 (20)
10:1 [C7:C3]
10
41 (22)
54 (16)
tion, see values in parentheses.
f
Selectivity for iteration is noted in parentheses.
Slow addition of 15 mol % 1 (0.15 M in CH3CN) and 3 equiv H2O2 (0.4 M in
g
50 (11)
55 (4)
CH3CN) via syringe pump over 45 min into a CH3CN solution (0.5 M) of 2 (1 equiv)
11:1 [C1:C8]
11:1 [C1:C8]
and AcOH (0.5 equiv).
11
mixture and re-submitting it to oxidation (Eqs. 1 and 2). These
results imply that catalyst decomposition products forming during
the course of the reaction are interfering with productive oxida-
tions with 1.
a
Yields of isolated hydroxylated products (0.5 mmol substrate) are an average of
two runs.
b
rSM¼Recovered starting material.
c
Yields for iterative addition are from Ref. 7.
d
Slow addition of 15 mol % 1 (0.15 M in CH3CN) and 3 equiv H2O2 (0.4 M in
In order to investigate if catalyst decomposition proceeds via
ligand oxidation, we performed the aliphatic C–H oxidation of 4-
methylvaleric acid catalyzed by Fe(PDP) 1 under the standard
iterative addition protocol and recovered the ligand. We obtained
48% isolated yield of the volatile lactone product and recovered 95%
of the (S,S)-PDP ligand unoxidized (see Section 4). Collectively,
these experimental observations suggested to us that catalyst de-
composition is occurring via bi- or multimolecular reactions at the
metal center to furnish species that inhibit productive oxidations.
We hypothesized that slow addition of both the catalyst and
oxidant over an extended period of time could disfavor these
decomposition pathways and improve overall catalyst productivity.
Herein we report a slow addition protocol for aliphatic C–H
oxidations with 1 that generally results in higher isolated yields
of hydroxylated products and, for two representative complex
CH3CN) via syringe pump over 45 min into a CH3CN solution (0.5 M) of 2 (1 equiv)
and AcOH (0.5 equiv).
e
Four iterative additions of 1 (5 mol %), AcOH (0.5 equiv), H2O2 (1.2 equiv).
substrates, eliminates the need for recycling starting materials to
obtain high yields.
We developed a slow addition protocol in which separate so-
lutions of catalyst 1 (15 or 20 mol %, 0.2 M CH3CN) and H2O2
(50 wt % in H2O, 3 or 4 equiv, 0.4 M CH3CN) were simultaneously
added over 45 or 60 min via syringe pump to a stirring solution of
substrate (1.0 equiv, 0.5 M CH3CN) and AcOH (0.5 equiv). The re-
sults in Table 2 are presented with comparison to those obtained
using the iterative addition protocol. At comparable catalyst and

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(1)
(2)
oxidant loadings (15 mol % 1, 3 equiv H2O2) the slow addition pro-
tocol provides only modest improvements in yields with similar
amounts of recovered starting material relative to the iterative
addition protocol (Table 1, entry 6; Table 2). However, in cases
where large amounts of starting material (>20%) were previously
observed, the slow addition protocol, performed with slightly
increased catalyst and oxidant loadings (20 mol % 1, 4 equiv H2O2),
afforded significant increases (11–19%) in isolated yields of hy-
droxylated products (Table 2, entries 1, 3, 6, 8, 9). In contrast, when
the iterative addition protocol is performed with comparable
increases in catalyst and oxidant loadings, as previously shown in
Table 1, no significant improvement in yield is observed (Table 1,
entry 5; Table 2, entries 2 and 4). Importantly, beyond the excellent
yields recorded in Table 2 for these highly challenging trans-
formations, the Fe(PDP) aliphatic C–H oxidation reaction is opera-
tionally simple to perform. Catalyst 1 exists as a purple solid that is
indefinitely stable under air when refrigerated at 0 ꢀC.12 Moreover,
with both the iterative and slow addition protocols, reactions are
run open to air without excluding moisture under a single set of
experimental conditions.
Importantly, the predictable site-selectivities and high chemo-
selectivities in oxidations catalyzed by 1 are not altered under the
slightly more forcing conditions of increased catalyst and oxidant
loadings used in the slow addition protocol (Table 2, entries 10 and
11). In molecules containing two electronically distinct 3ꢀ C–H
bonds, as in (þ)-11, electrophilic catalyst 1 maintains its selectivity
for oxidation of the most electron rich C–H bond (C7). In cases
where two 3ꢀ C–H bonds are electronically equivalent, as in
substrate (ꢃ)-12, bulky catalyst 1 persists in oxidizing with high
selectivity at the C–H bond that is less sterically hindered. It is
important to note, however, that in cases like these where con-
versions are high or the substrate is robust toward oxidation under
the iterative addition protocol, the slow addition protocol does not
significantly improve yields. The Fe(PDP) aliphatic C–H oxidation
reaction performed under the slow addition protocol remains tol-
erant of a wide range of functionalities such as halides, esters,
carbonates, and electron-deficient amides (Table 2, entries 1–8, 10–
11). Consistent with the observation that electron-deficient func-
tionality is compatible with these oxidative conditions, we now
report that aromatic functionality substituted with an electron-
withdrawing nitro group is also well tolerated (Table 2, entry 9). In
general, we have observed that the presence of electron-with-
drawing groups on aromatic rings is crucial for deactivating them
toward oxidation.
products. For example, we previously reported that the antimalarial
compound (þ)-artemisinin 13 could be oxidized with 1 under
iterative addition conditions to afford (þ)-10
b-hydroxyartemisinin
14 in 34% yield with 41% recovered starting material (Eq. 1). By
recycling recovered (þ)-13 through the reaction twice (three
column chromatographic purifications), a total of 54% isolated yield
of (þ)-14 could be obtained. Using the slow addition protocol with
20 mol % 1 and 4 equiv H2O2 (0.5 equiv AcOH), (þ)-14 can now be
furnished in 51% isolated yield after only one chromatographic
purification (Eq. 1). It is significant to note that this reaction pro-
ceeds with extraordinary site-selectivity and chemoselectivity.
Specifically, (þ)-artemisinin 13 is predictably oxidized preferen-
tially at one of five 3ꢀ C–H bonds based on electronic considerations
and the sensitive endoperoxide moiety is maintained with both
oxidation protocols.
Consistent with our hypothesis that the AcOH additive is acting
as an ancillary ligand for the active Fe catalyst, we have demon-
strated that chiral carboxylic acids may direct highly diaster-
eoselective C–H oxidations of 2ꢀ C–H bonds with 1. For example,
tetrahydrogibberellic acid analog (þ)-15 was previously oxidized
with 1 under the iterative addition protocol to afford lactone (þ)-16
as a single diastereomer in 37% isolated yield with 40% recovered
starting material (Eq. 2). By recycling recovered (þ)-15 through the
reaction once (two chromatographic purifications), a total of 52%
isolated yield of (þ)-16 could be obtained. Using the slow addition
protocol with 25 mol % 1 and 5 equiv H2O2 (no AcOH), (þ)-16 can be
now furnished directly in 51% isolated yield after only one chro-
matographic purification (Eq. 2). It is significant to note that with
complex substrates the Fe(PDP) aliphatic C–H oxidation represents
an especially powerful late stage oxidation. In considering potential
alternative synthetic routes toward natural product analogs such as
(þ)-14 and (þ)-16, state-of-the-art methods would require lengthy
de novo syntheses.
3. Summary and conclusions
The Fe(PDP) 1 aliphatic C–H oxidation has demonstrated for the
first time that, using a highly electrophilic and sterically bulky
catalyst, isolated and inert C–H bonds can be selectively oxidized in
a predictable fashion based on subtle differences in their electronic
and steric properties. In this report we disclose a slow addition
protocol that enables increasing the catalyst and oxidant loadings
to productively drive the aliphatic C–H oxidation reaction to higher
conversions without sacrificing site-selectivity or chemoselectivity.
The operational advantages of this new procedure are demon-
strated by the ability to eliminate the recycling of recovered start-
ing materials in the oxidation of two complex natural product
The most significant simplifying feature of the slow addition
protocol is the ability to eliminate the recycling of valuable starting
materials while still obtaining comparable yields of oxidized

N.A. Vermeulen et al. / Tetrahedron 65 (2009) 3078–3084
3081
derivatives while obtaining comparable isolated yields. The
increased catalyst productivity with the slow addition protocol,
together with the complete recovery of PDP ligand, suggests bi- or
multimolecular catalyst decomposition pathways occur at the iron
center. Future studies are directed toward identifying the precise
structures of these decomposition products, elucidating the
mechanism by which they inhibit oxidation, and developing
chemical strategies for preventing their formation.
4. Experimental
4.1. General information
The following commercially obtained reagents for the C–H ox-
idation reaction were used as received: H2O2 (50 wt % in H2O,
Sigma–Aldrich), AcOH (Mallinckrodt), CH3CN (Sigma–Aldrich). All
oxidation reactions were run under air with no precautions taken
to exclude moisture. Fe(S,S-PDP) 1 catalyst was prepared as de-
scribed in Ref. 8. Supplementary crystallographic data for Fe(S,S-
PDP) 1 can be obtained from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif on quoting regis-
try no. CCDC-661933. Achiral gas chromatographic (GC) analyses
were performed on Agilent Technologies 6890N Series instruments
equipped with FID detectors using a HP-5 (5%-phenyl)-methyl-
Figure 1. Photograph of slow addition setup.
temperature while open to ambient atmosphere. A 1.0 mL glass
syringe was charged with a solution of Fe(S,S-PDP) 1 catalyst
(93.1 mg, 0.1 mmol, 20 mol %) in CH3CN (0.5 mL, 0.2 M) and loaded
into a syringe pump set with an addition rate of 0.5 mL/1 h
(0.0083 mL/min). A 10 mL glass syringe was charged with a solu-
polysiloxane column (30 m, 0.32 mm, 0.25
was performed on an Agilent 5890 Series instruments equipped
with FID detectors using a J&W cyclodex- column (30 m, 0.25 mm,
0.25 m). Thin-layer chromatography (TLC) was conducted with E.
mm). Chiral GC analysis
tion of H2O2 (50 wt % in H2O, 136 mL, 2.0 mmol, 4.0 equiv) in CH3CN
b
(5.0 mL, 0.4 M) and loaded into a syringe pump set with an addition
rate of 5 mL/1 h (0.083 mL/min). Both syringes were equipped with
26G needles and directed into the center of the uncapped vial;
precautions should be taken not to touch the sides (Fig. 1). The two
additions were initiated simultaneously and both Fe(S,S-PDP) 1
catalyst and H2O2 were added to the reaction vial over the course of
1 h. The crude mixture was concentrated via rotary evaporation to
a minimal amount of CH3CN. Et2O was added until a brown pre-
cipitate formed. The mixture was filtered through a short plug of
Celite, concentrated by rotary evaporation and purified by flash
chromatography.
m
Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized
with UV, potassium permanganate, ceric ammonium molybdate, or
vanillin staining. Slow addition protocols were performed using
a New Era Pump Systems NE-300 syringe pump. Flash silica gel and
reverse-phase silica gel column chromatography were performed
using EM reagent silica gel 60 (230–400 mesh) and Versaflash
spherical C18 bonded flash silica gel (45–75 mm, 70 Å), respectively.
1H NMR spectra were recorded on a Varian Unity-400 (400 MHz) or
Varian Unity-500 (500 MHz) spectrometer and are reported in
parts per million using solvent as an internal standard (CDCl3 at
7.26 ppm). Data reported as: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad, app¼apparent; coupling con-
stant(s) in hertz; integration. Proton-decoupled 13C NMR spectra
were recorded on a Varian Unity-400 (100 MHz) or Varian Unity-
500 (125 MHz) spectrometer and are reported in parts per million
using solvent as an internal standard (CDCl3 at 77.0 ppm). Mass
spectra were obtained through the Mass Spectrometry Laboratory,
School of Chemical Sciences, University of Illinois. Chemical ioni-
zation (CI) spectra were collected on a Waters 70-VSE spectrometer
using methane as the carrier gas. Electrospray ionization (ESI)
spectra were performed on a Waters Q-Tof Ultima spectrometer. IR
spectra were recorded as thin films on NaCl plates on a Mattson
Galaxy Series FTIR 5000 and are reported in frequency of absorp-
tion (cmꢃ1). Optical rotations were measured using a 1 mL cell with
a 1 dm path length on a Perkin–Elmer 341 polarimeter or using
a 1 mL cell with a 5 cm path length on a Jasco DIP-360 digital
4.2.2. Slow addition protocol (15 mol % 1)
Slow addition protocol for oxidation of substrate (0.5 mmol,
1.0 equiv), AcOH (15.0 mg, 0.25 mmol, 0.5 equiv) in 1.0 mL CH3CN
with one addition of H2O2 (50 wt %, 102.0 mL, 1.5 mmol, 3.0 equiv,
0.4 M) in 3.75 mL CH3CN in a 10 mL glass syringe was added at the
rate of 5 mL/1 h (0.083 mL/min) over the course of 45 min. Addition
of 1 (69.9 mg, 0.075 mmol, 15 mol %, 0.2 M) in 0.375 mL CH3CN in a
1.0 mL glass syringe was added at a rate of 0.5 mL/h (0.0083 mL/min)
over the course of 45 min.
4.3. General procedure for iterative addition protocol
A 40 mL screwtop vial was charged with the following: Fe(S,S-
PDP)
1 catalyst (23.3 mg, 0.025 mmol, 5 mol %), substrate
(0.5 mmol,1.0 equiv), CH3CN (0.75 mL, 0.67 M), and AcOH (15.0 mg,
0.25 mmol, 0.5 equiv) and a magnetic stir bar. The vial was placed
on a stir plate and stirred vigorously at room temperature. A so-
polarimeter. Optical rotations were obtained with a sodium lamp
TꢀC
and are reported as follows: [
a
]
(c¼g/100 mL, solvent). UV–vis
l
spectra were taken on a Shimadzu PharmaSpec UV-1700 UV–vis
spectrophotometer with 1 cm quartz cuvettes.
lution of H2O2 (50 wt %, 36.8 mL, 0.6 mmol, 1.2 equiv) in CH3CN
(4.5 mL, 0.13 M) was added dropwise via syringe over ca. 45–75 s.
The first drop of peroxide solution instantly changed the reaction
mixture from a reddish-purple color to a yellow, which quickly
dissipated to an orange/purple. Subsequent drops of peroxide
continued this fluctuating pattern until an amber color was reached
and maintained. When no further color changes were observed, the
dropwise addition rate of peroxide was increased so that the
addition was completed within 45–75 s. Significant decreases in
yield were noted when the peroxide solution was added rapidly. After
4.2. General procedure for slow addition protocol
4.2.1. Slow addition protocol (20 mol % 1)
A 40 mL screwtop vial was charged with the following: sub-
strate (0.5 mmol, 1.0 equiv), CH3CN (1.0 mL, 0.5 M), and AcOH
(15.0 mg, 0.25 mmol, 0.5 equiv) and a magnetic stir bar. The vial
was placed on
a stir plate and stirred vigorously at room

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N.A. Vermeulen et al. / Tetrahedron 65 (2009) 3078–3084
ca. 10 min,
a
solution of Fe(S,S-PDP)
1
catalyst (23.3 mg,
4.5. Comparison of iterative and slow addition protocols for
0.025 mmol, 5 mol %), AcOH (15 mg, 0.25 mmol, 0.5 equiv), in
CH3CN (0.5 mL) was added via glass pipette. This was followed by
C–H oxidation (Table 2, Eqs. 1 and 2)
H2O2 (50 wt %, 36.8
m
L, 0.6 mmol, 1.2 equiv) in CH3CN (4.5 mL)
All reactions were performed on 0.5 mmol scale and are
reported as the average of two runs. Yields from iterative addition
protocol, purification and full characterization of oxidation prod-
ucts 4–7, (þ)-8, (ꢃ)-9, (þ)-11, (ꢃ)-12 in Table 2 and (þ)-14 and
(þ)-16 in Eqs. 2 and 3 are available in Ref. 8. The purification of
(þ)-14 was modified from the previously reported procedure so
that it was now purified by flash reverse-phase silica gel chroma-
tography (20% CH3CN/H2O). All isolated products were compared
with previously obtained 1H NMR, 13C NMR, ESI-MS data and were
found to be identical.
Table 2, compound 4. Slow addition protocol using 1-bromo-5-
methylhexane (89.6 mg, 0.5 mmol, 1.0 equiv) as substrate. Purifi-
cation by flash silica gel chromatography (30% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (59.1 mg, 0.303 mmol, 61%), run
2 (58.2 mg, 0.298 mmol, 60%). Average: 61%. Recovered starting
material (rSM): run 1 and run 2 (0 mg, 0 mmol, 0%). Average re-
covered starting material: 0%.
15 mol % catalyst loading: run 1 (50.7 mg, 0.259 mmol, 52%), run
2 (47.7 mg, 0.244 mmol, 49%). Average: 51%. Recovered starting
material (rSM): run 1 (25.0 mg, 0.140 mmol, 28%), run 2 (22.4 mg,
0.125 mmol, 25%). Average recovered starting material: 27%.
Table 2, compound 5. Slow addition protocol using 2,2,2-tri-
fluoro-N-(6-methylheptan-2-yl)acetamide (112.3 mg, 0.5 mmol,
1.0 equiv) as substrate. Purification by flash silica gel chromato-
graphy (30% EtOAc/hexanes).
added dropwise over ca. 45–75 s. A third addition was performed in
the same manner for a total of 15 mol % 1, 1.5 equiv AcOH, and
3.6 equiv H2O2. Each addition was allowed to stir for 10 min, for
a total reaction time of 30 min.
4.4. General procedure for reaction optimization (Table 1)
Oxidation of cis-4-methylcyclohexyl pivalate (2) was performed
on 0.1 mmol scale (19.8 mg, 1.0 equiv). The general procedure un-
der ‘iterative addition protocol’ was followed for entries 1–5, with
the vials in entries 1, 3, and 4 receiving only one (1) addition of
catalyst 1/AcOH and H2O2 oxidant. The vial in entry 2 received
a second addition of only H2O2 oxidant. H2O2 solutions were added
over a period of ca. 45 s, unless specified otherwise. An aliquot was
removed from the reaction mixture 10 min after the final addition
of H2O2 (unless otherwise specified), and diluted with Et2O, filtered
through a SiO2 plug and analyzed by GC. All product yields reported
are calibrated for response factors, rounded to the nearest whole
number and reported as the average (mean) of two runs.
Table 1, entry 1. H2O2 (50 wt %, 7.4 mL, 0.12 mmol, 1.2 equiv) in
0.9 mL CH3CN was added to 1 (4.7 mg, 0.005 mmol, 5 mol %), 2
(19.8 mg, 0.1 mmol, 1.0 equiv), AcOH (3.0 mg, 0.05 mmol,
0.5 equiv), in 0.15 mL CH3CN.
Table 1, entry 2. H2O2 (50 wt %, 7.4 mL, 0.12 mmol, 1.2 equiv) in
0.9 mL CH3CN was added to 1 (4.7 mg, 0.005 mmol, 5 mol %), 2
(19.8 mg, 0.1 mmol, 1.0 equiv), AcOH (3.0 mg, 0.05 mmol,
0.5 equiv), in 0.15 mL CH3CN. After stirring for 10 min with the first
addition of H2O2, a second addition of H2O2 (50 wt %, 7.4 mL,
0.12 mmol, 1.2 equiv) in CH3CN (0.9 mL) was added to the reaction
mixture.
20 mol % catalyst loading: run 1 (63.9 mg, 0.265 mmol, 53%), run
2 (65.1 mg, 0.269 mmol, 54%). Average: 54%. Recovered starting
material (rSM): run 1 (28.1 mg, 0.125 mmol, 25%), run 2 (22.5 mg,
0.100 mmol, 20%). Average recovered starting material: 23%.
15 mol % catalyst loading: run 1 (54.2 mg, 0.225 mmol, 45%), run
2 (51.7 mg, 0.210 mmol, 43%). Average: 44%. Recovered starting
material (rSM): run 1 (38.2 mg, 0.170 mmol, 34%), run 2 (40.3 mg,
0.180 mmol, 36%). Average recovered starting material: 35%.
Table 2, compound 6. Slow addition protocol using methyl
6-methylheptanoate (79.1 mg, 0.5 mmol, 1.0 equiv) as substrate.
Purification by flash silica gelchromatography (30% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (59.2 mg, 0.340 mmol, 68%), run
2 (55.7 mg, 0.320 mmol, 64%). Average: 66%. Recovered starting
material (rSM): run 1 and run 2 (0 mg, 0%). Average recovered
starting material: 0%.
15 mol % catalyst loading: run 1 (54.0 mg, 0.310 mmol, 62%), run
2 (52.3 mg, 0.300 mmol, 60%). Average: 61%. Recovered starting
material (rSM): run 1 (15.8 mg, 0.100 mmol, 20%), run 2 (16.6 mg,
0.105 mmol, 21%). Average recovered starting material: 21%.
Table 2, compound 7. Slow addition protocol using 5-methyl-
hexyl acetate (79.1 mg, 0.5 mmol, 1.0 equiv) as substrate. Purifica-
tion by flash silica gel chromatography (30% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (63.2 mg, 0.363 mmol, 73%), run
2 (62.1 mg, 0.356 mmol, 71%). Average: 72%. Recovered starting
material (rSM): run 1 and run 2 (0 mg, 0 mmol, 0%). Average re-
covered starting material: 0%.
15 mol % catalyst loading: run 1 (59.3 mg, 0.340 mmol, 68%), run
2 (57.4 mg, 0.329 mmol, 66%). Average: 67%. Recovered starting
material (rSM): run 1 (25.9 mg, 0.164 mmol, 33%), run 2 (20.7 mg,
0.138 mmol, 26%). Average recovered starting material: 30%.
Table 2, compound (þ)-8. Slow addition protocol using (S)-5-
((R)-5,5-dimethyl-2-oxo-1,3-dioxolan-4-yl)-3-methylpentyl ace-
tate (129.2 mg, 0.5 mmol, 1.0 equiv) as substrate. Purification by
flash silica gel chromatography (40% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (69.9 mg, 0.255 mmol, 51%), run
2 (67.2 mg, 0.245 mmol, 49%). Average: 50%. Recovered starting
material (rSM): run 1 (25.8 mg, 0.100 mmol, 20%), run 2 (21.8 mg,
0.084 mmol, 17%). Average recovered starting material: 19%.
Table 1, entry 3. H2O2 (50 wt %, 7.4 mL, 0.12 mmol, 1.2 equiv) in
0.9 mL CH3CN was added to 1 (14.0 mg, 0.015 mmol, 15 mol %), 2
(19.8 mg, 0.1 mmol, 1.0 equiv), AcOH (3.0 mg, 0.05 mmol,
0.5 equiv), in 0.15 mL CH3CN.
Table 1, entry 4. H2O2 (50 wt %, 22.2 mL, 0.36 mmol, 3.6 equiv) in
0.9 mL CH3CN was added to 1 (14.0 mg, 0.015 mmol, 15 mol %), 2
(19.8 mg, 0.1 mmol, 1.0 equiv), AcOH (9.0 mg, 0.15 mmol, 1.5 equiv),
in 0.15 mL CH3CN.
Table 1, entry 5. Iterative addition protocol for oxidation of 2
(19.8 mg, 0.1 mmol, 1.0 equiv) in 0.15 mL CH3CN. A fourth addition
of 1 (4.7 mg, 0.005 mmol, 5 mol %), AcOH (3.0 mg, 0.05 mmol,
0.5 equiv), in 0.10 mL CH3CN and H2O2 (50 wt %, 7.4 mL, 0.12 mmol,
1.2 equiv) in 0.9 mL CH3CN was added. Aliquots for GC analysis
were taken 10 min after each H2O2 addition, immediately before
the next solution of 1/AcOH was added.
Table 1, entry 6. Slow addition protocol for oxidation of 2
(99.1 mg, 0.5 mmol, 1.0 equiv), AcOH (15.0 mg, 0.25 mmol,
0.5 equiv) in 1.0 mL CH3CN with one addition of H2O2 (50 wt %,
102.0 mL, 1.5 mmol, 3.0 equiv) in 3.75 mL CH3CN was added at the
rate of 5 mL/1 h (0.083 mL/min) over the course of 45 min. Addition
of 1 (69.9 mg, 0.075 mmol, 15 mol %) in 0.375 mL CH3CN was added
at a rate of 0.5 mL/h (0.0083 mL/min) over the course of 45 min.
The stereoretentive nature of the Fe(PDP) 1 catalyzed oxidation
of cis-2 (>98% cis, Alfa Aesar) to cis-3 was determined by GC
analysis of crude reaction mixtures from two individual reactions.
Authentic samples of cis-3 and trans-3 were used as GC standards
to determine retention times. The average cis:trans ratio of 3
was found to be 242:1 (reaction 1, injection 1: cis:trans¼218:1,
injection 2¼223:1, injection 3¼197:1, injection 4¼247:1; reaction
2, injection 1: cis:trans¼237:1, injection 2¼259:1, injection
3¼258:1, injection 4¼265:1, injection 5¼273:1) corresponding to
99.58%ꢁ0.05% cis-3.

N.A. Vermeulen et al. / Tetrahedron 65 (2009) 3078–3084
3083
15 mol % catalyst loading: run 1 (61.8 mg, 0.225 mmol, 45%), run
2 (62.0 mg, 0.226 mmol, 45%). Average: 45%. Recovered starting
material (rSM): run 1 (41.3 mg, 0.160 mmol, 32%), run 2 (40.8 mg,
0.158 mmol, 32%). Average recovered starting material: 32%.
Table 2, compound (ꢃ)-9. Slow addition protocol using (S)-4-
Eq. 1, compound (þ)-14. Iterative addition protocol for the oxi-
dation of (þ)-artemisinin ((þ)-13) (0.5 mmol, 141.2 mg, 0.5 mmol,
1.0 equiv) is similar to the general procedure with the exception
that only 3.0 mg AcOH (0.05 mmol, 10 mol %) was added to the
reaction and the starting material was initially solvated in 2.25 mL
CH3CN (0.22 M). The subsequent two additions of 1 (5 mol %)/AcOH
(10 mol %) in 0.50 mL CH3CN and H2O2 (1.2 equiv) in 4.5 mL CH3CN
were added without modification from the previously described
procedure. Immediately upon completion, the reaction was
quenched with a solution of saturated NaHCO3, extracted with Et2O
(3ꢂ30 mL), dried on MgSO4, filtered, and purified by flash silica gel
column chromatography (25% EtOAc/hexanes). Upon re-isolation of
starting material via chromatography, the oxidation was setup
again according to the iterative addition protocol described above
with identical reagent stoichiometries (based on equivalents of
recovered (þ)-13). Altogether, this process of recycling recovered
starting material was done twice.
methyl-2-(2,2,2-trifluoroacetamido)pentyl
acetate
(127.6 mg,
0.5 mmol, 1.0 equiv) as substrate. Purification by flash silica gel
chromatography (40% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (63.7 mg, 0.235 mmol, 47%), run
2 (61.0 mg, 0.225 mmol, 45%). Average: 46%. Recovered starting
material (rSM): run 1 (65.1 mg, 0.255 mmol, 51%), run 2 (62.5 mg,
0.245 mmol, 49%). Average recovered starting material: 50%.
15 mol % catalyst loading: run 1 (54.2 mg, 0.200 mmol, 40%) run 2
(52.8 mg, 0.195 mmol, 39%). Average: 40%. Recovered starting ma-
terial (rSM): run 1 (74.0 mg, 0.290 mmol, 58%), run 2 (75.1 mg,
0.295 mmol, 59%). Average recovered starting material: 59%.
Table 2, compound 10. Slow addition protocol using 2-nitro-p-
cymene (99.6 mg, 0.5 mmol, 90% purity) as substrate. Purification
by flash silica gel chromatography (20% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (59.6 mg, 0.305 mmol, 61%), run
2 (58.9 mg, 0.302 mmol, 60%). Average: 61%. Recovered starting
material (rSM): run 1 (8.1 mg, 0.045 mmol, 9%), run 2 (7.2 mg,
0.040 mmol, 8%). Average recovered starting material: 9%.
15 mol % catalyst loading: run 1 (54.6 mg 0.280 mmol, 56%), run 2
(53.7 mg, 0.275 mmol, 55%). Average: 56%. Recovered starting
material (rSM): run 1 (16.7 mg 0.093 mmol, 19%), run 2 (15.0 mg,
0.084 mmol, 17%). Average recovered starting material: 18%.
Iterative addition protocol: run 1 (47.6 mg, 0.244 mmol, 49%), run
2 (45.5 mg, 0.235 mmol, 47%). Average: 48%. Recovered starting
material (rSM): run 1 (19.7 mg, 0.110 mmol, 22%), run 2 (18.8 mg,
0.105 mmol, 21%). Average: 22%.
Slow addition protocol for the oxidation of (þ)-13 (0.5 mmol,
141.2 mg, 1.0 equiv) was performed identically as described in the
general procedure with a single addition of H2O2 (50 wt %, 136.0 mL,
2.0 mmol, 4.0 equiv) in 5.0 mL and a single addition of 1 (93.1 mg,
0.1 mmol, 20 mol %) in 0.5 mL CH3CN was added over the course of
60 min to
a
solution of (þ)-13, AcOH (15.0 mg, 0.25 mmol,
0.5 equiv) in 1.0 mL CH3CN. The substrate was not fully soluble
initially, but reached full dissolution by the end of the reaction.
Upon reaction completion the crude mixture was concentrated via
rotary evaporation to a brown residue and purified by flash reverse-
phase silica gel column chromatography (20% CH3CN/H2O). Note:
with slow addition protocol there is no recycling of starting
material.
20 mol % catalyst loading: run 1 (74.4 mg, 0.249 mmol, 50%), run
2 (77.6 mg, 0.260 mmol, 52%). Average: 51%. Recovered starting
material (rSM): run 1 (2.7 mg, 0.010 mmol, 2%), run 2 (5.6 mg,
0.02 mmol, 4%). Average recovered starting material: 3%.
15 mol % catalyst loading: run 1 (71.6 mg, 0.240 mmol, 48%).
Recovered starting material (rSM): run 1 (20.3 mg, 0.072 mmol,
14%).
1H NMR (500 MHz, CDCl3)
d
8.09 (d, J¼1.5 Hz, 1H), 7.62 (dd, J¼2,
8 Hz, 1H), 7.31 (d, J¼8 Hz, 1H), 2.58 (s, 3H), 1.60 (s, 6H). 13C NMR
(125 MHz, CDCl3)
d 148.6, 132.7, 131.8, 129.2, 120.8, 72.1, 31.7, 20.0.
IR (film, cmꢃ1): (neat, cmꢃ1) 2980.4, 2934.1, 2361.1, 2344.2, 1527.4,
1345.4. HRMS (EI) m/z calcd C10H14O3N [MþH]þ: 196.09737, found:
196.09745.
Table 2, compound (þ)-11. Slow addition protocol using (S)-1-
bromo-3,7-dimethyloctane (110.6 mg, 0.5 mmol, 1.0 equiv) as sub-
strate. Regioselectivity was determined by 1H NMR analysis of the
crude reaction mixture.8 Purification by flash silica gel chroma-
tography (10% EtOAc/hexanes).
20 mol % catalyst loading: run 1 (50.9 mg, 0.215 mmol, 43%, C7
oxidation; 4.9 mg, 0.021 mmol, 4%, C3 oxidation), run 2 (49.6 mg,
0.210 mmol, 42%, C7 oxidation). Average C7 oxidation: 43%.
Recovered starting material (rSM): run 1 (22.1 mg, 0.100 mmol,
20%), run 2 (20.9 mg, 0.095 mmol, 19%). Average recovered starting
material: 20%.
15 mol % catalyst loading: run 1 (47.4 mg, 0.200 mmol, 40%), run
2 (48.6 mg, 0.205 mmol, 41%). Average C7 oxidation: 41%. Re-
covered starting material (rSM): run 1 (24.2 mg, 0.110 mmol, 22%),
run 2 (23.3 mg, 0.105 mmol, 21%). Average recovered starting
material: 22%.
Table 2, compound (ꢃ)-12. Slow addition protocol using (1R)-
menthyl acetate (99.1 mg, 0.5 mmol, 1.0 equiv) as substrate.
Regioselectivity was determined by 1H NMR analysis of the crude
reaction mixture.8 Purification by flash silica gel chromatography
(20% EtOAc/hexanes).
Eq. 2, compound (þ)-16. Iterative addition protocol for the oxi-
dation of 16
b
-tetrahydrogibberellate diacetate [(þ)-15] (108.6 mg,
0.25 mmol, 1.0 equiv) is similar to the general procedure with the
exception that 0.25 mmol of starting material was initially solvated
in 1.50 mL CH3CN (0.17 M) and no AcOH was added to the reaction.
The subsequent two additions of 1 (5 mol %) in 0.50 mL CH3CN and
H2O2 (1.2 equiv) in 2.25 mL CH3CN were added without modifica-
tion from the previously described procedure. The crude mixture
was concentrated via rotary evaporation to a brown residue and
immediately purified by flash silica gel column chromatography
(30:70:1 EtOAc/hexanes/AcOH). Upon re-isolation of starting ma-
terial via chromatography, the oxidation was setup again according
to the iterative addition protocol described above with identical
reagent stoichiometries (based on equivalents of recovered (þ)-15).
This process of recycling recovered starting material was done once.
Slow addition protocol for the oxidation of (þ)-15 (217.2 mg,
0.5 mmol, 1.0 equiv) was performed similarly to the general pro-
cedure with the exception that AcOH was not added to the reaction
mixture. A single addition of H2O2 (50 wt %, 170.0 mL, 2.5 mmol,
5.0 equiv) in 6.25 mL CH3CN and a single addition of 1 (116.5 mg,
0.125 mmol, 25 mol %) in 0.625 mL CH3CN were added over the
course of 75 min to (þ)-15 in 1.0 mL CH3CN. Upon reaction
completion the crude mixture was concentrated via rotary evapo-
ration to a brown residue and purified by flash silica gel column
chromatography (30:70:1 EtOAc/hexanes/AcOH). Note: with slow
addition protocol there is no recycling of starting material.
15 mol % catalyst loading: run 1 (86.4 mg, 0.200 mmol, 40%).
Recovered starting material (rSM): run 1 (84.6 mg, 0.195 mmol,
39%).
20 mol % catalyst loading: run 1 (57.9 mg, 0.270 mmol, 54%), run
2 (59.8 mg, 0.280 mmol, 56%). Average: 55%. Recovered starting
material (rSM): run 1 (2.0 mg, 0.010 mmol, 2%), run 2 (5.2 mg,
0.026 mmol, 5%). Average recovered starting material: 4%.
15 mol % catalyst loading: run 1 (58.7 mg, 0.274 mmol, 55%), run
2 (55.7 mg, 0.260 mmol, 52%). Average: 54%. Recovered starting
material (rSM): run 1 (17.7 mg, 0.089 mmol, 18%), run 2 (12.9 mg,
0.065 mmol, 13%). Average recovered starting material: 16%.

3084
N.A. Vermeulen et al. / Tetrahedron 65 (2009) 3078–3084
20 mol % catalyst loading: run 1 (104.0 mg, 0.240 mmol, 48%).
Recovered starting material (rSM): run 1 (54.2 mg, 0.125 mmol,
25%).
25 mol % catalyst loading: run 1 (110.3 mg, 0.255 mmol, 51%), run
2 (109.0 mg, 0.250 mmol, 50%). Average: 51%. Recovered starting
material (rSM): run 1 (41.0 mg, 0.095 mmol, 19%), run 2 (39.0 mg,
0.090 mmol, 18%). Average recovered starting material: 19%.
fellowship. M.S.C. is a Harvard University graduate student com-
pleting doctoral work with M.C.W. at the University of Illinois at
Urbana-Champaign. M.S.C. gratefully acknowledges Bristol-Myers
Squibb for a graduate fellowship. We thank M.A. Bigi for performing
the oxidative lactonization of 4-methylvaleric acid, and E.M. Stang
for verifying the hydroxylation results of artemisinin. Both M.A.B.
and E.M.S. are thanked for helpful discussions in the writing of this
manuscript.
4.6. Lactonization of 4-methylvaleric acid and recovery of
free (S,S)-PDP ligand after oxidation
References and notes
Iterative addition protocol for the oxidation of 4-methylvaleric
acid (58.1 mg, 0.5 mmol, 1.0 equiv) was performed similarly to the
general procedure with the exception that no AcOH was added to
1. For some recent reviews on C–H bond functionalizations: (a) Muller, P.; Fruit, C.
Chem. Rev. 2003, 103, 2905; (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62,
2439; (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417; (d) Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013; (e) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
2. Allylic C–H to C–O: (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126,
1346; (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem.
Soc. 2005, 127, 6970; (c) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White,
M. C. J. Am. Chem. Soc. 2006, 128, 9032; (d) Delcamp, J. D.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 15076; Allylic C–H to C–N: (e) Fraunhoffer, K. J.; White,
M. C. J. Am. Chem. Soc. 2007, 129, 7274; (f) Reed, S. A.; White, M. C. J. Am. Chem.
Soc. 2008, 130, 3316; Allylic C–H to C–C: (g) Young, A. J.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 14090.
the reaction. The subsequent two additions of
0.025 mmol, 5 mol %) in 0.50 mL CH3CN (0.05 M) and H2O2
(50 wt %, 36.8 L, 0.6 mmol, 1.2 equiv) in 4.5 mL CH3CN (0.13 M)
1 (23.3 mg,
m
were added without modification from the previously described
procedure. The reaction was run with two different workups; one
workup was designed to isolate lactone product and a second
workup was designed to isolate (S,S)-PDP ligand.13
3. (a) Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223; (b)
Covell, D. J.; Vermeulen, N. A.; Labenz, N. A.; White, M. C. Angew. Chem., Int. Ed.
2006, 45, 8217; For an excellent review see: (c) Hoffman, R. W. Synthesis 2006,
21, 3531.
4.6.1. Isolation of the lactone product
The reaction was quenched with a solution of saturated NaHCO3.
The aqueous layer was extracted with Et2O (3ꢂ30 mL) and the
organic layers were combined, dried over MgSO4, filtered, and
concentrated carefully by rotary evaporation at 0 ꢀC to prevent loss
of volatile product. The crude product was purified by flash silica
gel column chromatography (30% EtOAc/hexanes). The product 5,5-
dimethyldihydrofuran-2(3H)-one14 was obtained in 27.5 mg (run 1,
0.241 mmol, 48%) and 26.9 mg (run 2, 0.236 mmol, 47%). Average:
48%.
4. For some elegant examples of SeO2 allylic oxidations in natural products syn-
thesis, see: (a) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy,
R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorenson,
E. J. Nature 1994, 367, 630; (b) Wender, P. A.; Jesudason, C. D.; Nakahira, H.;
Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976.
5. For some recent examples, see: (a) Lee, S.; Fuchs, P. L. J. Am. Chem. Soc. 2002,
124, 13978; (b) Wender, P. A.; Hilinski, M. K.; Mayweg, A. V. W. Org. Lett. 2005, 7,
79; (c) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485.
6. For some selected examples, see: (a) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 7190; (b) Lafrance, M.; Blaquiere, N.; Fagnou, K. Eur.
J. Org. Chem. 2007, 811; (c) Das, S.; Incarvito, C. D.; Crabtree, R. H.; Brudvig, G. W.
Science 2006, 312, 1941; (d) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496; (e) Hinman, A.; Du Bois, J. J. Am.
Chem. Soc. 2003, 125, 11510; (f) Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.;
Liu, S.; Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251; (g) Shevi, R. A.; Guerrero,
C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241.
7. PDP indicates 2-({(S)-2-[(S)-1-(pyridin-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-
1-yl}methyl)pyridine].
4.6.2. Isolation of (S,S-PDP) ligand
The crude reaction was quenched with concentrated NH4OH
and concentrated via rotary evaporation at 35 ꢀC to dryness in order
to remove volatile lactone product. The brown residue was filtered
through a SiO2 plug with EtOAc as eluent to obtain free (S,S)-PDP
ligand: run 1, 23.1 mg, 0.072 mmol, 95%; run 2, 22.8 mg,
0.071 mmol, 94%; based on 15 mol % (0.075 mmol) 1.
8. Chen, M. S.; White, M. C. Science 2007, 318, 783.
9. For the first report of a related non-heme iron(mep) complex [mep¼N,N0-
dimethyl-N,N0-bis(2-pyridylmethyl)-ethane, 1,2-diamine] and its oxidation
reactivity see: (a) Okuno, T.; Ito, S.; Ohba, S.; Nishida, Y. J. Chem. Soc., Dalton
Trans. 1997, 3547; For mechanistic studies on Fe(mep) oxidations see: (b) Chen,
K.; Que, L., Jr. Chem. Commun. 1999, 1375; For the first demonstration of
1H NMR (400 MHz, CDCl3)
d
8.49 (dd, J¼0.8, 4.8 Hz, 2H), 7.60 (dt,
J¼2.0, 7.8 Hz, 2H), 7.39 (d, J¼7.6 Hz, 2H), 7.11 (dd, J¼5.2, 6.0 Hz, 2H),
4.19 (d, J¼14.0 Hz, 2H), 3.49 (d, J¼14.4 Hz, 2H), 2.99 (p, J¼4.4 Hz,
2H), 2.79 (m, 2H), 2.22 (appq, J¼8.4 Hz, 2H), 1.77–1.64 (m, 8H). 13C
a
preparatively useful non-heme iron system see the Fe(mep) catalyzed
epoxidation: (c) White, M. C.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2001,
123, 7194.
NMR (100 MHz, CDCl3)
d 160.4, 148.8, 136.3, 122.7, 121.6, 65.3, 61.1,
55.3, 25.9, 23.5. IR (film, cmꢃ1): 2960, 2920, 2872, 2806, 1588, 1570,
1474, 1431, 1366, 1212, 1150, 1120, 1046, 993, 931, 897, 759. HRMS
(ESI) m/z calcd C20H27N4 [MþH]þ: 323.2236, found: 323.2239.
10. For some examples of non-directed aliphatic C–H oxidation reactions with
simple hydrocarbon substrates see: (a) Murray, R. W.; Jeyaraman, R.; Mohan, L.
J. Am. Chem. Soc. 1986, 108, 2470; (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R.
J. Am. Chem. Soc. 1989, 111, 6749; (c) DesMarteau, D. D.; Donadelli, A.; Montanari,
V.; Petrov, V. A.; Resnati, G. J. Am. Chem. Soc. 1993, 115, 4897; (d) Labinger, J. A.;
Bercaw, J. E. Nature 2002, 417, 507 and references therein; (e) Brodsky, B. H.; Du
Bois, J. J. Am. Chem. Soc. 2005, 127, 15391; (f) Ref. 5a.; (g) Ref. 9a.
11. For the first demonstration of the importance of carboxylic acid additives in
non-heme iron catalyzed oxidations, see Ref. 9c.
Acknowledgements
We are grateful to the A.P Sloan Foundation, the Camille and
Henry Dreyfus Foundation, Bristol-Myers Squibb, Pfizer, Amgen, Eli
Lilly, Merck Research Laboratories, Abbott Laboratories, AstraZe-
neca, and the University of Illinois for financial support and gen-
erous gifts. N.A.V. gratefully acknowledges Pfizer for a graduate
12. We have not observed decreases in catalyst 1 hydroxylation activity after ca. 1
year storage at 0 ꢀC.
13. Jensen, M. P.; Mehn, M. P.; Que, L., Jr. Angew. Chem., Int. Ed. 2003, 42, 4357.
14. For full characterization see: Martin, D. D.; Marcos, I. S.; Basabe, P.; Romero,
R. E.; Moro, R. F.; Lumeras, W.; Rodriguez, L.; Urones, J. G. Synthesis 2001, 7, 1013.