Remote Oxidation of Aliphatic C-H Bonds in Nitrogen-Containing Molecules

Article abstract of DOI:10.1021/jacs.5b10299

Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Bronsted acid (HBF₄) or an azaphilic Lewis acid (BF₃) to enable remote, non-directed C(sp³)-H oxidations of tertiary, secondary, and primary amine- and pyridine-containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.

Full text of DOI:10.1021/jacs.5b10299

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Communication
Remote Oxidation of Aliphatic C—H Bonds in Nitrogen Containing Molecules
Jennifer M. Howell, Kaibo Feng, Joseph R. Clark, Louis J. Trzepkowski, and M. Christina White
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10299 • Publication Date (Web): 04 Nov 2015
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Journal of the American Chemical Society
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Remote Oxidation of Aliphatic C—H Bonds in Nitrogen Con-
taining Molecules
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Jennifer M. Howell‡, Kaibo Feng‡, Joseph R. Clark, Louis J. Trzepkowski and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United
States
Supporting Information Placeholder
Table 1. Reaction Optimizationa,b
ABSTRACT: Nitrogen heterocycles are ubiquitous in natu-
Me
Me
OH
i. Additive
ii. Fe(PDP) 1c
oxidation
ral products and pharmaceuticals. Herein, we disclose a ni-
trogen complexation strategy that employs a strong Brønsted
acid (HBF4) or an azaphilic Lewis acid (BF3) to enable re-
mote, non-directed C(sp3)—H oxidations of tertiary (3°),
secondary (2°), and primary (1°) amine- and pyridine-
containing molecules with tunable iron catalysts. Imides re-
sist oxidation and promote remote functionalization.
H
Me
Me
Method Ad
piperidine 3a-e
pyridine 4a-b
piperidine 5a-e
pyridine 6a-b
Het
N
Het
N
R2
R2
R1
R1
Additive (equiv)
BF3•OEt2 (1.1)
BF3•OEt2 (1.1)
HBF4•OEt2 (1.1)
F3CCO2H (1.1)
H2SO4 (1.1)
HBF4•H2O (1.1)
HBF4•OEt2 (1.1)
-
Yield (%) (rsm)e
46 (28)
27 (67)
56 (29)
5 (74)
R1
R2
Entry Heterocycle
1
3a
4a
3a
3a
3a
3a
4a
4b
3b
3c
3d
3e
Me
-
-
2
-
3
Me
Me
Me
Me
-
-
4
5f
6g
-
-
0 (76)
-
43 (40)
57 (23)
0 (65)
The development of reactions that selectively oxidize inert
C(sp3)—H bonds while tolerating more electron rich nitro-
gen functionality is a significant, unsolved problem given that
nitrogen is ubiquitous in natural products and medicinal
agents.1 Among the challenges for developing such reactions
are catalyst deactivation via nitrogen binding and direct oxi-
dation of nitrogen to furnish N-oxides. Common electronic
deactivation strategies for 2° and 1° amines (e.g. acylation)
do not disable hyperconjugative activation leading to func-
7
-
8a
9a
10a
11
12a,h
O
-
Boc
TFA
H
-
-
n.d. (37)
n.d. (11)
40 (26)
44 (22)
-
-
-
HBF4•OEt2 (1.1)
-
H
BF3
13a
70 (8)
Fe(PDP) 1c
oxidation
O
N
O
O
N
O
Me
Me
H
OH
glutarimide 3f
glutarimide 5f
Me
Me
tionalization α to the nitrogen (Figure 1).2 Directing group
strategies facilitate oxidation of C(sp3)—H bonds that are
spatially and geometrically accessible from the directing
functional group.3 Remote oxidation of C(sp3)—H bonds in
nitrogen-containing molecules is not currently possible with
ligated transition metal catalysis.
Site-selective and -divergent oxidation of tertiary (3°) and
secondary (2°) C—H bonds has been demonstrated with
small molecule catalysts, Fe(PDP) 1 and Fe(CF3PDP) 2,
respectively.4 Discrimination of C—H bonds can be accom-
plished via catalyst/substrate electronic, steric and stereoe-
lectronic interactions. Inductive effects within a substrate
O
H
H
i. HBF4•OEt2
ii. Fe(CF3PDP) 2c
oxidation
β
δ
Me
Me
γ
Het
N
Het
N
piperidine 3g
pyridine 4c
piperidine 5g
pyridine 6c-d
Method Bi
R
R
Yield (%) (rsm)e
Selectivityj
R
Entry Heterocycle
14
15
3g
4c
Me
-
57 (4)
1:1 δ/mixture
2.6:1 δ/γ
53 (10)
aIterative addition (3x): 5 mol% 1, AcOH (0.5 equiv), H2O2 (1.2 equiv), MeCN (ref 4a).
bSlow addition: 25 mol% 2, AcOH (5.0 equiv), H2O2 (9.0 equiv), MeCN, syringe pump 6
mL/min (ref 4b,c). cCatalyst enantiomers used interchangeably. dMethod A: (i) Additive (1.1
equiv), CH2Cl2, concd in vacuo, (ii) Iterative addition, (iii) 1M NaOH. eIsolated yields, %
recovered starting material (rsm). fNo product observed with H2SO4 (0.55 equiv). gIn situ
addition of HBF4 (1.1 equiv). h2° Piperidine-BF3 complex 3e isolated and purifed. Product
5e isolated/purified as 2° piperidine-BF3 complex. iMethod B: (i) HBF4•OEt2 (1.1 equiv),
j
CH2Cl2, concd in vacuo, (ii) Slow addition, (iii) 1M NaOH. Based on isolation.
(SbF6)2
α C—H
R
functionalization
strongly influence site-selectivity, as highly electrophilic met-
al oxidants (e.g. Fe=O) disfavor oxidation of electron-
deficient C(sp3)—H bonds. Functionalities with positive
charges, such as ammonium cations, or strongly polarized
dative bonds, such as amine-borane adducts, exert a strong
inductive effect on adjacent C—H bonds.5 We hypothesized
that Lewis/Brønsted acid complexation of nitrogen would
afford nitrogen tolerance and remote site-selectivity in iron-
α
N
R'
many examples
R"
N
R
remote
n
NCMe
ref 2
N
N
Fe
H
NCMe
R'
α
remote C—H
functionalization
OH
N
R2N
H
R'
n
this work
R
Het = piperidine
pyridine
1 Fe((R,R)-PDP); R = H
2 Fe((R,R)-CF3PDP);
R = 2,6-diCF3Ar
Het
α
amine
imide
N
R
Figure 1. Heterocycle Functionalization
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Journal of the American Chemical Society
Page 2 of 5
catalyzed C(sp3)—H oxidations. Herein, we describe strate-
Table 2. Basic Aminesa
1
2
3
4
5
6
i. complexation
ii. Fe(PDP) 1b or
Fe(CF3PDP) 2b
gies that enable remote, non-directed aliphatic C—H oxida-
tion in substrates containing prevalent nitrogen functional
groups: amines (3°, 2°, 1°) and pyridines. Imides tolerate
oxidative conditions without complexation and promote
remote C(sp3)—H oxidation.
Me
OH
O
R
or
Me
Me
n
n
n
N
N
R
N
R
oxidation
9a-n
10a-n
R
EtO
O
Me
NC
Me
Tertiary Piperidinesc
OH
OH
Me
Me
Me
OH
We evaluated two strategies to effect nitrogen toler-
ance/remote oxidation: azaphilic, oxidatively stable Lewis
acid complexation with boron trifluoride (BF3) and irre-
versible protonation with tetrafluoroboric acid (HBF4), a
strong Brønsted acid with a weakly coordinating counterion.
Whereas some precedent exists with these strategies for C—
H oxidations,6 olefin oxidations7a-b and metathesis,7c no ex-
amples of remote aliphatic C—H oxidations under ligated
transition metal catalysis are known. In metal complexes
having basic, dative ligands (e.g. PDP), competitive com-
plexation with acid may lead to catalyst deactivation. Explo-
ration of BF3 complexation with both 3° piperidine 3a and
pyridine 4a provided encouraging yields of remotely oxi-
dized products (Table 1, entries 1, 2). HBF4 protonation
afforded remote oxidation products with improved yields for
both 3a and 4a (entries 3, 7). The same protocol with tri-
fluoroacetic acid or sulfuric acid,6c which generate more co-
ordinating counterions, resulted in decreased yield (entry 4,
5). An in situ HBF4 protocol resulted in diminished yield of
5a, suggesting excess acid is not beneficial (entry 6). Oxida-
tion of pyridine N-oxide 4b was unproductive (entry 8).6a
Oxidation of acyl-protected piperidines (3b-c, entries 9,
10) resulted in over-oxidized products, likely via N-
dealkylation pathways. Both HBF4 protonation and BF3
complexation are effective with 2° piperidine 3d (entries 11,
12). The BF3 complexation strategy is preferable for 2° and
1° amines due to facile purification of oxidized amine-BF3
complexes. Additionally, these complexes can be stored
without precaution to exclude atmosphere.8 Despite indis-
criminate oxidation of carbamates and amides, we found that
imides attenuate nitrogen basicity and enable remote oxida-
tion (entry 13).
7
8
9
N
Me
N
N
Me
Me
Me
10a 52% (28%)
10b 55% (20%)
Me
10c 58% (32%)
R =
OH
Me
EtO
O
O
F3C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
10d 50% (41%)
CN
10f 50% (24%)d
46% (28%)f
O
N
N
R
Me
Me
10e 40% (25%)d,e
with Fe(PDP)
Secondary Piperidinesg
EtO
O
Me
NC
Me
OH
OH
Me
Me
Me
OH
N
H
Me
N
H
N
H
BF3
BF3
10i 56% (26%)c with HBF4
43% (22%)h with BF3
O
10g 54% (10%)
10h 60% (21%)
EtO
O
Me
OH
O
Me
10l, R=BF3, 54% (7%)i
10m, 47% (11%)d
with HBF4
10j 65% (31%)
BF3
10k trace
(74%)
N
H
N
H
N
H
BF3
R
Primary Amineg
Me
Me
Fe((S,S)-PDP) 1
oxidation
F3B
H
Me
Me
F3B
H
Me
OH
N
H
N
H
Me
10n 56% (22%)
aIsolated yield is average of two runs, % rsm in parentheses. bCatalyst enantiomers used
interchangeably. cMethod with HBF4•Et2O (1.1 equiv). dMethod B. eStarting material
recycled 1x. fMethod B with 1. gMethod A with BF3•Et2O (1.1 equiv) concd and purified prior to
use. Isolated as BF3-complex, no NaOH workup. hMethod A with BF3•Et2O (1.1 equiv).
iMethod B with BF3•Et2O (1.1 equiv) concd and purified prior to use. Isolated as BF3-complex,
no NaOH workup.
9n
A
Scheme 1. Amine Deprotection Strategies
EtO
Me
Me
O
Me
OH
H
OH
R
OH
20% NaOH
1,4-dioxane, rt
90% yield
CsF
Me
Me
n = 1, 2
Me
2
MeCN, 85 ºC
95% yield
N
H
N
H
N
H
BF3
5d
R = H 5e
R = CO2Et 10g
11
respectively).4a Collectively, these data suggest that
Brønsted/Lewis acid complexation renders basic nitrogen a
strong inductive withdrawing moiety, enabling remote C—
H oxidations often with high site-selectivities.
Me
Me
proximal
Piperidines substituted at N, C4, and C2 are the most
prevalent nitrogen heterocycles in drugs.1a Employing HBF4
protonation, Fe(PDP)-catalyzed tertiary oxidations of N-
methyl or N-alkyl substituted piperidines proceeded uni-
formly in high yields and with excellent site-selectivities to
afford 3° hydroxylated products (Table 2). Notably, piperi-
dine 9a with C2-alkyl substitution was hydroxylated in 52%
yield (10a), showcasing the effectiveness of HBF4 protona-
tion in sterically hindered environments. Piperidines with a
variety of functional groups (esters, nitriles, electron defi-
cient aromatics) perform well under conditions where com-
petitive hydrolysis or oxidation may occur (10b-f). The 4-
phenylpiperidine motif in 10d-e represents a pharmaco-
phore found in opioids such as ketobemidone and haloperi-
dol.9 Improved site-selectivities for Fe(CF3PDP)-catalyzed
remote methylene oxidations were observed in substrates
having more electronic differentiating elements (10e and
10f, 40% and 50%, respectively).
i. HBF4
ii. Fe((R,R)-PDP) 1
oxidation
H
H
distal
(1)
iii. 1M NaOH
Me2N
Me2N
Me
H
OH
51% yield (21% rsm)
>20:1 distal/proximal
Me
Me
Me
7
8
Remote methylene oxidation of piperidine 3g and pyri-
dine 4c with Fe(CF3PDP)4c afforded good overall yields but
with significantly diminished site-selectivities (Table 1, en-
tries 14, 15). In contrast, Fe(PDP) hydroxylation of remote
3° C—H bonds proceeds with high site-selectivity; no ben-
zylic or methylene oxidation products were detected. HBF4
protonation/oxidation of a linear substrate with competing
3° sites proceeded with excellent selectivity (>20:1 dis-
tal/proximal), favoring the site distal from the protonated
amine (eq 1). Electron-withdrawing groups (e.g. Br, F, OAc)
previously evaluated did not afford such strong inductive
deactivation of proximal sites (9:1, 6:1, 5:1 distal/proximal,
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Journal of the American Chemical Society
Analogous 2° piperidine-BF3 complexes worked with equal
facility for remote tertiary and secondary oxidations (Table
Table 3. Pyridinesa
1
2
3
4
5
6
7
8
i. HBF4
Me
Me
OH
O
ii. Fe(PDP) 1b or
H
2). Underscoring the variance in electronics between 3° and
2° C—H bonds, oxidation of 9j delivered 3° alcohol 10j in
65% yield, whereas methylene oxidation of 9k gave trace
product. The BF3 complexation strategy is preferred for oxi-
dation of sterically unencumbered 2° and 1° amines (10n),
where challenges in product isolation with HBF4 protonation
lead to diminished isolated yields (10l vs 10m). Protona-
tion with HBF4 is advantageous in cases where steric hin-
drance at nitrogen retards effective BF3 coordination (10i
56% and 43% yield, respectively). Hydroxylated amine-BF3
complexes are readily converted to the free amine via base-
mediated hydrolysis or exposure to a nucleophilic fluoride
source (Scheme 1). The latter protocol is advantageous for
substrates containing hydrolytically unstable functional
groups, such as 10g.
Pyridines are the most prevalent heteroaromatic in FDA
approved pharmaceuticals.1a Fe(PDP)-catalyzed remote
hydroxylation of 3° sites in 2-alkylpyridines proceeded
smoothly using HBF4 protonation for both mono- and di-
substituted substrates (13a 59%, 13b 61%, Table 3). In
these sterically encumbered substrates, complexation with
BF3 affords diminished yields (32% and 34%, respectively).
Long-chain 3-alkylpyridines, prevalent in natural products,10
are efficiently oxidized (13c 50%). Remote oxidation pro-
ceeds in good yields with electron rich pyridines (6a, 13d)
whereas yield and mass balance are lower with an electron
deficient substrate (13e 34% yield, 29% recovered starting
material (rsm)). Pyridines having less electronically favored
and exposed 3° sites afford modest site-selectivity (13f 52%,
2.7:1). The one carbon shortened analog of 4-pentylpyridine
(4c, Table 1) underwent methylene oxidation with im-
proved site-selectivity (>20:1) but in diminished yield (13g
32% yield). In cyclohexanes4b having bulky, inductive with-
drawing substituents, stereoelectronic preference for oxida-
tion at C3 overrides electronic preference for oxidation at C4
Fe(CF3PDP) 2b
or
Me
Me
Me
n
n
n
N
N
oxidationc
12a-h
13a-h
Me
Me
OH
OH
Me
R
N
Me
N
R = H; 13a 59% (25%) (32%d with BF3)
R = Me; 13b 61% (23%) (34%d with BF3)
13c 50% (30%)
δ
γ
Me
OH
Me
9
OH
Me
Me
X
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X = H; 6a 57% (23%)
X = Me; 13d 57% (26%)
N
X = Cl; 13e 34% (29%)
(+)-13fe 52% (10%),f 2.7:1 γalcohol/δketone
N
g
γ
Me
β
3
4
O
3
N
O
N
13g 32% (24%),h >20:1 γ/βg
13h 42% (5%),h 3.2:1 C3/C4g,i
aIsolated yield is average of two runs, % rsm in parentheses. bCatalyst enantiomers used
interchangeably. cMethod A with HBF4•Et2O (1.1 equiv). dMethod B with BF3•OEt2 (1.1
equiv), catalyst 1 and 20% NaOH workup. e(+)-13f Refers to pure alcohol. fStarting material
recycled 1x. gBased on isolation. hMethod B. 1.6:1 C3/C4 adjusted for number of hydrogens.
i
Table 4. Imidesa,b
O
O
N
O
O
N
O
Fe(PDP) 1c
oxidation
R'
m
or
m
m
R
N
R
R
Me
Me OH
O
n
O
O
Me
14a-i
15a-i
Me
OH
O
Me
Me
OH
O
OH
Me
N
Me
N
Me
Me
N
m
R
n
O
O
O
R
n = 1, m = 1; 15a 66% (18%) R = H; 15c 64% (15%)
n = 2, m = 1; 15b 62% (16%) R = Me; 15d 60% (16%)
15e 57% (9%)
O
O
O
O
m = 3Me
m = 3
N
N
NH
N
OH
Me
OH
Me
O
X
O
O
O
O
Me
15f 57% (10%)d
X = NO2; 15g 58% (18%)
X = H; 15h 46% (17%)
thalidomide analog
15i 54% (17%)
aIsolated yield is average of two runs, % rsm in parentheses. bIterative addition. cCatalyst
enantiomers used interchangeably. dStarting material recycled 1x.
(54%). Imides are oxidatively stable and inductively deac-
tivating motifs that promote remote oxidations.
We evaluated efficacy of the aforementioned nitrogen pro-
tection strategies paired with Fe(PDP) or Fe(CF3PDP) oxi-
dation in late-stage diversification of medicinally important
complex molecules. Dextromethorphan, an antitussive drug
of the morphinan class, contains a basic N-methyl piperidine
moiety, an aromatic ring and a benzylic site, all highly prone
to oxidation (Scheme 2A). We hypothesized that benzylic
deactivation would result from the proximally fused tertiary
piperidine, which as its ammonium BF4 salt would be ren-
dered a strong inductive withdrawing group. Exposure of 16
to HBF4 protonation/Fe((S,S)-CF3PDP) oxidation afforded
remote, non-benzylic oxidation products, ketone 17 and
alcohol 18 in 45% yield with preference for the least sterical-
ly hindered methylene site (2.5:1 ketone/alcohol).
Abiraterone acetate, having a C17-(3-pyridyl) motif, is a
steroidal antiandrogen used in the treatment of prostate can-
cer. Despite a strong preference for oxidation at 3° benzylic
sites (BDE~83 kcal/mol),14 exposure of 19 to HBF4 proto-
nation/Fe((R,R)-CF3PDP) oxidation resulted in a site-
selective remote oxidation at C6 (BDE~98 kcal/mol) of the
steroid core in 42% yield (6:1 alcohol/ketone) (Scheme 2B).
(13h 1.6:1 C3/C4 adjusted for number of hydrogens).
Imides are abundant in biologically active molecules and
serve as synthetic precursors to amines.11 Succinimide 14a
and glutarimide 14b were oxidized in excellent yield, with-
out requirement for Brønsted/Lewis acid complexation, to
afford the corresponding alcohols (Table 4). Cyclopropyl
modified succinimides are tolerated in this C—H oxidation
reaction (15c-d). Spirocyclic glutarimide 14f, a substruc-
ture in anxiolytic agent buspirone,12 underwent site-selective
methylene oxidation in good yield (57%). Analogous to reac-
tivity in enzymatic oxidations,1b we have observed Fe(PDP)
to effect both oxidative N-dealkylation of amines and oxida-
tion of electron neutral or rich aromatics. No N-
demethylation was observed with imide 14e (57%) and
both 4-nitrophthalimide 14g and unsubstituted phthalimide
14h were oxidized in useful yields (15g 58%; 15h 46%).13
Underscoring the medicinal relevance of this reaction, oxida-
tion of thalidomide analog 14i afforded 15i in good yield
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Journal of the American Chemical Society
Page 4 of 5
Scheme 2. Late-Stage Functionalization of Nitrogen Containing Moleculesa
1
2
TfO
O
A.
B.
C.
N
O
OR
NH
H
3
4
5
6
7
8
9
Me
Dextromethorphan
Me
H
O
Derivative (+)-16b
N
Cycloheximide Derivative
(+)-21,b R = C(O)CH2Cl
H
Me
H
Me
HBF4
HBF4
Fe((R,R)-CF3PDP) 2
Me
H
Fe((S,S)-CF3PDP) 2
Fe((S,S)-PDP) 1
oxidation
AcO
oxidation
oxidation
H
TfO
TfO
Abiraterone Acetate
N
O
Analog (+)-19b
Me
O
OR
NH
H
+
Me
H
Me
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
H
H
Me
Me
H
H
HO
(+)-20e
42% yieldf,g
Streptovitacin A, R = H; 22
R = C(O)CH2Cl; (+)-23
50% yieldh
AcO
OH
Me
O
45% yieldc
(+)-17
2.5:1 ketone/alcohold
(+)-18
H
OH
6:1 alcohol/ketoned
aIsolated yield is average of two runs. bSubstrates containing chirality demonstrated matched/mis-matched reactivity with catalyst enantiomers. c(i) HBF4•Et2O (1.1 equiv), CH2Cl2, concd in vacuo, (ii) Slow addition with 2, (iii) 1M
NaOH. dBased on isolation. e(+)-20 Refers to pure alcohol. f(i) HBF4•Et2O (1.1 equiv), CH2Cl2, concd in vacuo, (ii) Iterative addition with 2, (iii) NaHCO3. gStarting material recycled 2x. hIterative addition with 1.
These represent the first examples of transition metal cata-
lyzed remote, aliphatic C—H oxidations on a morphinan
and nitrogen-containing steroid skeletons.
REFERENCES
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Cycloheximide, a readily available natural product with
broad antimicrobial activity but high toxicity is currently
used as a protein synthesis inhibitor. The C4 hydroxylated
analogue, streptovitacin A 22, has shown diminished tox-
icity and has been obtained via an eight step de novo syn-
thesis proceeding in 7% overall yield.15 The direct oxidation
of cycloheximide derivative 21 with Fe((S,S)-PDP) af-
fords streptovitacin A derivative 23 in excellent yield
(50%) (Scheme 2C), underscoring the power of remote
late stage C—H oxidation to streamline synthesis.
We have demonstrated remote Fe(PDP)-catalyzed oxi-
dation in a range of nitrogen heterocycles by employing
Brønsted/Lewis acid complexation strategies. We envision
this will be a highly enabling methodology for the genera-
tion of medicinal agents via late-stage oxidation and for the
evaluation of their metabolites.
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J.; Hamann, L. G.; Patterson, A. W. Chem. Sci. 2014, 5, 2352. Aliphatic
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G.; González-Núñez, M. E.; Bernardini, C. B.; Mello, R.; Adam, W. J. Am.
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ASSOCIATED CONTENT
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mcwhite7@illinois.edu
Author Contributions
‡These authors contributed equally.
(8) Hampe, E. M.; Rudkevich, D. M. Tetrahedron 2003, 59, 9619.
(9) Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong, D. T. Na-
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Funding Sources
Financial support was provided by the NIH/NIGMS (GM
112492).
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ACKNOWLEDGMENT
We thank G. Snapper for initial investigations, J. Griffin, J.
Zhao and T. Osberger for spectra inspection, C. Delaney for
checking procedures, Dr. L. Zhu for assistance with NMR data
analysis, Dr. J. Bertke and Dr. D. Gray for crystallographic data
and analysis. We thank Zoetis for an unrestricted grant to ex-
plore C—H oxidations in pharmaceuticals.
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Fe(PDP)
N
N
1
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remote C—H oxidation
Me
Me
H
H
N
Het
Me
H
Me
H
BF4
H
H
H
AcO
Het = piperidine, pyridine AcO
amine (1º, 2º, 3º)
H
H
H
OH
imide (direct oxidation)
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