C2-Symmetric nitroxides and their potential as enantioselective oxidants

Article abstract of DOI:10.1016/j.tetasy.2005.09.016

The synthesis and evaluation of four C₂-symmetric nitroxides are presented. The nitroxides were evaluated for their ability to mediate the oxidation of several alcohols and found to have good catalytic activity. One enantioenriched nitroxide was found to kinetically resolve selected secondary alcohols with very modest selectivities.

Full text of DOI:10.1016/j.tetasy.2005.09.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3584–3598
C2-Symmetric nitroxides and their potential as
enantioselective oxidants
Benjamin Graetz, Scott Rychnovsky,* Wen-Hao Leu, Patrick Farmer* and Rong Lin
Department of Chemistry, University of California, Irvine, 516 Rowland Hall, Irvine, CA 92697-2025, USA
Received 20 July 2005; accepted 9 September 2005
Available online 10 November 2005
Abstract—The synthesis and evaluation of four C2-symmetric nitroxides are presented. The nitroxides were evaluated for their abil-
ity to mediate the oxidation of several alcohols and found to have good catalytic activity. One enantioenriched nitroxide was found
to kinetically resolve selected secondary alcohols with very modest selectivities.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
O
O
N
O
N
MeO
N
Nitroxyl radical catalyzed enantioselective oxidations of
alcohols have great potential for synthetic utility due to
the ubiquitous need for enantiomerically pure secondary
alcohols. One of the difficult challenges facing nitroxide
mediated enantioselective oxidations is generating a
nitroxide that has both good catalytic activity and high
enantioselectivity. The design and rationale for selectiv-
ity in nitroxide mediated oxidations has been established
in several literature reports.1 Many categories of nitrox-
ides have been used in oxidation chemistry, such as aze-
pines,1d pyrrolidines,2 piperidines,3 morpholines,4
piperazinones,4 piperazines,4 and isoindoles.5 One com-
mon theme among these synthetic efforts centers around
nitroxides with bis(tetralkyl) substituents a to the nitro-
gen. This constraint for bis(tetralklyl) substituents is due
to rapid disproportionation to produce a nitrone and a
N-hydroxylamine, which generally occurs when hydro-
gens a to the nitrogen are present.
MeO
OMe
OMe
1
2
3
4
Figure 1. Synthesized nitroxides.
to investigate the preparation, stability, and utility of
chiral bridgehead nitroxides (Fig. 1) as enantioselective
oxidation catalysts, and the results of this investigation
are described herein.
2. Results and discussion
2.1. Synthesis of nitroxides
The synthesis of 1 is based on the work of Zhang et al.
and Halterman et al. with slight modifications to their
procedures.8 Synthesis of 1 began with a Birch reduction
of para-xylene9 with lithium in liquid ammonia in the
presence of methanol to give 6 in 45% yield, with the
remaining 55% as unreacted starting material (Scheme
1). The low yield in this step may be due to the poor
solubility of para-xylene in liquid ammonia, making
reduction of the precipitate by lithium difficult. How-
ever, attempts to enhance solvation of para-xylene by
the addition of THF did not improve the yield. Com-
pound 6 could not be separated from para-xylene
and was used as a mixture. Enantiomerically pure iso-
pinocampheylborane (IpcBH2) was prepared according
There are examples, however, of bicyclic nitroxide sys-
tems in which the nitrogen resides at the bridgehead of
the bicyclic system.6 These bridgehead nitroxides, while
containing a-hydrogens, will still obey Bredtꢀs rule,7
thereby reducing or eliminating rapid decomposition
of the nitroxide to a nitrone with a bridgehead olefin.
Most of the reported bridgehead nitroxides were achiral,
and none of the chiral bridgehead nitroxides were pre-
pared in enantiomerically enriched form. We decided
*
Corresponding authors. Tel.: +1 949 824 8292; fax: +1 949 824
6379; e-mail: srychnov@uci.edu
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.016

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3585
i) 2.2 equiv IpcBH2
from (+)-α-pinene
Lio, MeOH, NH3 (l)
45% (55% RSM)
ii) H2O2, NaOH
58%, 90% ee
5
6
2.3 equiv CH3SO2Cl,
Et3N, CH2Cl2
1.3 equiv. NaN3
OH
OMs
DMF
HO
97%, 90% ee
47%
MsO
7
8
X
H
H
N
N3
i) Ph3P, THF
MsO
ii) HBr or HCl (aq)
10 (free base amine)
10a: X = Br, 86%
10b: X = Cl, 94%
9
X
H
O
N
H
N
i) 0.1 N NaOH
ii)
m-CPBA
10a orb
1
Unable to isolate neat due to decomposition -
Confirmed presence by EPR and MS
Scheme 1. Synthesis of [2.2.1] nitroxide 1.
to a Brown procedure10 using (+)-a-pinene. Treatment
of 6 with IpcBH2 followed by oxidation with alkaline
hydrogen peroxide gave a mixture of C2- and Ci-sym-
metric diols in a 3:1 ratio. Separation of the diols by
flash chromatography gave the C2-symmetric diol 7 in
58% yield with 90% ee, as determined by the specific
rotation.8b The diol was treated with methanesulfonyl
chloride and triethylamine in CH2Cl2, to provide
bis(methanesulfonate) ester 8 in 97% yield. Monodis-
placement with sodium azide in DMF11 afforded 9 in
47% yield. Treatment of 9 with triphenylphosphine12
effectively reduced the azide with concomitant cycliza-
tion to the bicyclic [2.2.1] secondary amine 10, which
was isolated as the amine salt with aqueous HBr or
HCl, providing 10a and 10b in 86% and 94% yield,
respectively. Isolation of the free amine 10 was difficult
due to its apparent low boiling point but it could be
generated in a solution of CH2Cl2 as needed by treat-
ment of 10a or 10b with 0.1 M NaOH and extraction
with CH2Cl2. The free-based amine was used to generate
nitroxide 1 by treatment with m-CPBA. The isolation of
the nitroxide itself was not possible due to its apparent
instability (vide infra); however, oxidations with nitr-
oxide 1 could be carried out if the nitroxide was gener-
ated immediately before use in the oxidation studies.
OH
i) 2.2 eq IpcBH2
from (+)-α-pinene
TMSCl, Et3N,
CH2Cl2
ii) H2O2, NaOH
48%, 89% ee
45%
(49% recov. S.M.)
HO
11
12
OTMS
OTMS
MsCl, Et3N,
CH2Cl2
NaN3, DMF,
2 d, 70 oC
25%
47%
HO
MsO
13
14
OMs
OH
MsCl, Et3N,
CH2Cl2
Ph3P, THF
41%
74%
N3
16
N3
15
H
O
N
m
-CPBA, CH2Cl2
67%
N
We set out to synthesize the analogous [3.3.1] nitroxide 2
in the same fashion as 1; however, the reaction sequence
used for 1 could not be directly applied. The successful
synthesis is outlined in Scheme 2. The initial strategy
2
17
Scheme 2. Synthesis of [3.3.1] nitroxide 2.

3586
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
translated onto this substrate well with an asymmetric
hydroboration of commercially available 1,5-dimethyl-
1,5-cyclooctadiene using Brownꢀs IpcBH2 to produce
diol 12 in 48% yield and 89% ee, determined by specific
rotation (Scheme 2).13 The remaining sequence, how-
ever, required a stepwise approach. Starting with diol
12, protection of one of the alcohols with TMSCl pro-
vided silyl ether 13 in 45% with the remaining material
recovered as unreacted starting material. Alcohol 13
was treated with methanesulfonyl chloride and provided
a separable mixture of two products. One product was
the TMS ether 14, isolated in 25% yield. The remaining
isolated material (61%) arose from deprotection of the
labile TMS ether during the work up. Each product
was separately treated with sodium azide in DMF to
provide azide 15 by removal of any remaining TMS
ether in the acidic workup. Azide 15 was converted to
methanesulfonate 16 in 74% yield. Treatment of 16 with
triphenylphosphine12 effectively reduced the azide with
concomitant cyclization to the bicyclic [3.3.1] secondary
amine 17 in 41% yield. While amine 17 was higher in
molecular weight than amine 10, the volatility of amine
17 accounted for the modest yield in the reduction. A
stable and isolable nitroxide 2 was produced in 67%
yield when amine 17 was treated with m-CPBA.
A racemic C2-symmetric aza-adamantyl amine was
synthesized as a precursor to nitroxide 3 (Scheme 3).
The synthesis of amine 24 began with the preparation
of Meerweinꢀs ester14 by a condensation reaction of
dimethyl-malonate and formaldehyde in refluxing ben-
zene while removing water with a Dean Stark trap.
The crude intermediate tetraester was decarboxylated
in refluxing acetic acid, hydrochloric acid, and water
to produce dione 18.15 Grignard addition to the dione
gave 47% of isolated C2-symmetric diol, which when
treated with BF3ÆOEt2, gave diene 19. If the crude diol
from the Grignard reaction was treated with BF3ÆOEt2,
the yield for the two steps could be improved to 89%.
From the 13C NMR spectrum of the crude intermediate
diol, several alcohol bearing carbon atoms were
observed, suggesting multiple diastereomers were pres-
ent. Each of the diastereomers would eliminate to pro-
duce diene 19, accounting for the improved yield.
Treatment of 19 with m-CPBA gave 41% of the racemic,
C2-symmetric bis-epoxide 20. Other epoxide diastereo-
mers were produced in the reaction but were separated
during chromatography. Heating 20 in methanol satu-
rated with ammonia provided 21, the aza-adamantyl
core in 95% yield.16 Protection of the amine with triflu-
oroacetic anhydride gave a peracylated intermediate
O
i) (CH2O)n, PhH,
i) MeMgBr
Piperidine (cat), ∆
O
O
O
O
ii) BF3•OEt2,
CH2Cl2
89% (2 steps)
ii) AcOH, HCl, H2O
36%
O
18
O
m-CPBA,
NH3/MeOH
95%
HO
NH
CH2Cl2
41%
O
19
OH
20
21
O
i) (CF3CO)2O,
Et3N, CH2Cl2
NaH, MeI
HO
N
CF3
THF
99%
ii) K2CO3, MeOH
97%
22 OH
O
MeO
MeO
MeO
NH
NaBH4
Resolve with
L-tartaric acid
to 93% ee
N
CF3
EtOH, 60 ˚C
98%
OMe
OMe
23
( )-24
O
MeO
NH
m
-CPBA
N
CH2Cl2
OMe
OMe
24
3
Unable to isolate neat due to decomposition -
Confirmed presence by EPR and MS
Scheme 3. Synthesis of nitroxide 3.

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3587
that could be deprotected selectively by treatment with
potassium carbonate in methanol to provide trifluoro-
acetamide 22 in 97% yield. Diol 22 was converted to
the dimethyl ether in 99% yield by treatment with
sodium hydride and methyl iodide. Deprotection of
the amine with sodium borohydride in refluxing ethanol
cleanly afforded racemic amine 24 in 98% yield.
tection of the amine was removed by hydrogen reduction
with palladium on carbon in 91% yield to provide amine
28. Racemic amine 28 was used to generate nitroxide 4 by
treatment with m-CPBA. The isolation of the nitroxide
itself was not possible due to its apparent instability (vide
infra); however, oxidations with nitroxide 4 could be car-
ried out if the nitroxide was generated immediately
before use in oxidation studies.
Amine 24 could be resolved by complexation with L-tar-
trate and an unoptimized recrystallization from ethanol
and ether to provide a low yield of a white precipitate.
These crystals were treated with 0.1 M NaOH, and anal-
ysis of the remaining amine by GC on a chiral column
indicated an enantiomeric excess of 93%.
2.2. EPR analysis for nitroxide conformation
Only nitroxide 2 was stable enough to be isolated. To
evaluate each of the nitroxides ability to catalyze the
oxidation of alcohols, it became imperative to establish
that a nitroxide was in fact generated from each amine
precursor. The remaining nitroxides gave fleeting evi-
dence for their formation, such as turning a solution
of CH2Cl2 red or pink upon the addition of m-CPBA.
This color change would fade over minutes to hours
depending on the nitroxide. While this was supportive
evidence, it was hardly diagnostic. NMR spectroscopy
could not be used to observe any transient nitroxide
present, due to the paramagnetic broadening of the
NMR signals. Electron paramagnetic resonance (EPR)
spectroscopy is a direct method to observe nitroxides.
The EPR of a typical nitroxide is characterized by three
sharp lines that are separated by 13–15 Gauss. We set
out to study nitroxides 1–4 by EPR spectroscopy.
Amine 24 was used to generate nitroxide 3 by treatment
with m-CPBA. The isolation of the nitroxide itself was
not possible due to its apparent instability (vide infra);
however, oxidations with nitroxide 3 could be carried
out if the nitroxide was generated immediately before
use in the oxidation studies.
A final synthesis of a second [3.3.1] bicyclic system was
undertaken. It was believed that the [3.3.1] nitroxide sys-
tem may impart some unusual stability that allowed for
the isolation of nitroxides such as 2. A facile synthetic
entry into such a [3.3.1] system, amine 26, was reported
by Michel and Rassat.17
The synthesis began with a rhenium catalyzed hydrogen
peroxide oxidation of 1,5-cyclooctadiene to provide the
syn-bis-epoxide 25 in 50% yield with the remaining mate-
rial as the mono-epoxide (Scheme 4). Simple refluxing of
25 with benzylamine in water provided the [3.3.1] bicyclic
amine core in 91% yield. The resultant diol 26 was con-
verted to dimethyl ether 27 in 68% yield by treatment
with sodium hydride and methyl iodide. The benzyl pro-
When each of the amine precursors was dissolved in
CH2Cl2, placed in an EPR tube, and treated with
m-CPBA, a nitroxide signal was immediately observed
(Fig. 2). These EPR experiments were carried out at
room temperature. Control experiments with m-CPBA
in CH2Cl2 or the amine in CH2Cl2 gave no observable
EPR signal. The nitroxide signals were then observed
over time to determine the lifetimes of nitroxides 1–4.
O
Bn
H2O2, Pyridine
CH3ReO3 (cat)
Benzylamine,
N
H2O, ∆
CH2Cl2
50%
91%
HO
OH
O
26
25
Bn
H
H2, 500 psi
EtOH, 12 h
NaH, MeI
THF
N
N
68%
10% Pd/C (cat)
91%
MeO
MeO
OMe
OMe
27
( )-28
H
O
N
N
m
-CPBA
CH2Cl2
MeO
MeO
OMe
OMe
4
28
Unable to isolate neat due to decomposition -
Confirmed presence by EPR and MS
Scheme 4. Synthesis of [3.3.1] nitroxide 4.

3588
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
Figure 2. EPR spectra of nitroxides 1–4 over time.
As can be seen in Figure 2, the characteristic triplet of a
nitroxide was observed for structure 1. After 30 min
from the time of addition of m-CPBA, the triplet signal
had already decreased significantly in strength. By
70 min from the time of addition of m-CPBA, almost
all evidence of a nitroxide signal had faded into the
noise.
with approximately the same intensity. Nitroxide 2
was indefinitely stable at reduced temperature.
Azaadamantyl nitroxide 3 presents a strong EPR signal
that diminished slowly over several hours at room
temperature. After 30 min, the characteristic triplet
remained as a strong signal but diminished somewhat
from its previous high intensity. After 90 min, the signal
had decreased to approximately half of its original
intensity. The signal, however, remained for several
additional hours and at 4 h is still quite clear. After
about 7 h the signal was completely lost, diminishing
into background noise.
The fate of nitroxide 2 is quite different from that of the
other nitroxides. Upon addition of m-CPBA to amine
17, a strong EPR signal was observed. After 6 h this sig-
nal remained unchanged with essentially the same in
intensity. Two days later, the same characteristic triplet
was observed with no loss of intensity. The sample was
then stored in a freezer (ꢀ15 ꢁC) for five weeks. After
warming back to room temperature and observing the
EPR signal, again a characteristic triplet was observed
The final [3.3.1] nitroxide 4, presented an interesting
contrast to structure 2, the other [3.3.1] nitroxide
reported. A strong triplet was immediately observed

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3589
upon the addition of m-CPBA to amine 24. This signal,
however, faded rapidly at room temperature. Within
20 min the signal had decreased to approximately 20%
of its original intensity, and by 30 min, the signal had
almost completely disappeared. This [3.3.1] nitroxide
represented the least stable of the four synthesized
nitroxides. There are two major differences between nitr-
oxide 2 and nitroxide 4. The methyl ether substituents
on nitroxide 4 are oriented equatorially, while the
methyl substituents of nitroxide 2 are axial. In addition,
the methyl ethers are electron withdrawing substituents
compared to the methyl substituents of nitroxide 2.
However, these structural and electronic differences do
not provide an obvious explanation for the disparity in
stability between 2 and 4.
Anelliꢀs procedure is a useful and widely used TEMPO
catalyzed oxidation of alcohols. Anelliꢀs conditions18
for the oxidation of alcohols utilized a nitroxide cata-
lyst, an alcohol, KBr, and a buffered bleach solution
(pH ꢁ 8.6) as the bulk oxidant. m-CPBA has also been
used as a bulk oxidant in TEMPO oxidations. Previous
research by Rychnovsky et al. evaluated the role of
halide ions in TEMPO catalyzed oxidation of alcohols
using m-CPBA as the bulk oxidant.19 These studies dem-
onstrated that redox-active counterions have a signifi-
cant effect on the oxidation reaction. The counterion
could, in some systems, increase the amount of oxida-
tion observed. A procedure was then developed using
the hydrobromide salt of 2,2,6,6-tetramethylpiperidine
(TMPÆHBr).19 An alcohol mixed with 1 equiv of
m-CPBA as the bulk oxidant and catalytic TMPÆHBr
(1 mol %) converted the alcohol to its corresponding
ketone. Additionally, a phase transfer catalyst, such as
Bu4NBr, could be used to facilitate the biphasic reac-
tion. An adaptation of this procedure, using m-CPBA
as the bulk oxidant, was selected to evaluate nitroxide
1 as an oxidation catalyst.
Since the intensity of the EPR signal is proportional
to the concentration of nitroxide, we can estimate a
half-life for each of the nitroxides in solution at room
temperature. Nitroxide 1 had a half-life of ca. 20 min.
Nitroxide 3 had a half-life of ca. 90 min. Nitroxide 4
had a half-life of ca. 7 min.
With confirmation that each of the four nitroxides was
in fact capable of being generated, even if for limited
times, it was appropriate to evaluate whether these nitr-
oxides would act as catalysts in the oxidations of alco-
hols. If the compound showed catalytic activity, the
enantiopurity of the remaining alcohol would be deter-
mined, thereby evaluating each nitroxide for both cata-
lytic efficiency and enantioselectivity.
Since nitroxide 1 was generated from HCl or HBr salts
of the amine precursor, this method of starting from
the HCl and HBr salts seemed ideal for evaluating nitr-
oxide 1. Following the reported procedure, nitroxide salt
10a or 10b was dissolved in CH2Cl2 and added to a solu-
tion of an alcohol and m-CPBA (Table 1). Control
experiments in Table 1 (entries 1, 4, 5, 10, 11, and 14)
have the catalyst and/or the additive omitted to identify
any background oxidation.
2.3. Oxidation of alcohols usingnitroxide catalysts
From Table 1, several general trends appear. First, the
addition of 1 or 10a as a catalyst increases the amount
of oxidation compared to m-CPBA alone. This suggests
the catalyst is acting in some fashion to mediate the oxi-
dation, and in the case of entries 12and 13, the catalyst
is resolving alcohol 31 with minimal selectivity. There is
no increase in resolution or conversion when increasing
Nitroxide catalyst,
Bulk Oxidant
OH
R2
OH
R2
O
+
R1
R1
R1
R2
ð1Þ
Oxidations were carried out under kinetic resolution
conditions (Eq. 1), in which the progress of the oxida-
tion is controlled by the limiting reagent, in this case
the bulk oxidant. A series of secondary alcohols were
required as test substrates for oxidations. Four alcohols
were chosen based on availability and ease of separation
of the enantiomers by GC on a chiral column. Separa-
tion of the oxidized ketone product from the remaining
alcohol by GC also was a requisite. Commercially avail-
able sec-phenylethanol 29 and 2-octanol 30 were chosen.
Additionally, 20-chloro-sec-phenylethanol 31 and 20-
methyl-sec-phenylethanol 32 were synthesized by simple
LiAlH4 reduction of commercially available 20-chloro-
acetophenone and 20-methylacetophenone (Fig. 3).
Table 1. Oxidation of alcohols with m-CPBA, 1% catalyst, and
additive
Entry Alcohol Catalyst Additive
%
% ee
Conversiona alcohol
1
2
3
4
5
6
7
8
29
29
29
30
30
30
30
30
30
31
31
31
31
32
32
None
1
None
None
Bu4NBr 53
14
34
—
0
0
1
None
None
None
1
None
12—
Bu4NBr 10
t-BuOHb 14
Bu4NBr 40
Bu4NBr 36
None
Bu4NBr 15
BHT 17
Bu4NBr 30
Bu4NBr 33
Bu4NBr 15
Bu4NBr 40
—
—
0
0
0
—
—
9
9
—
0
10a
10a
9
35
10
11
12
13
14
15
None
None
10a
10ac
None
10a
OH
Cl
OH
CH3 OH
OH
a Conversion determined by GC.
b 0.5 equiv of t-BuOH.
c 2.5% Catalyst.
29
30
31
32
Figure 3. Alcohols used in oxidations.

3590
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
Table 3. Oxidation of alcohols with 0.5 equiv BAIB and 1% cat. at
0 ꢁC
Entry Alcohol Catalyst % Conversiona % ee S-Value
the catalyst from 1% to 2.5% (cf. entry 12 vs 13). It is
also apparent from Table 1 that m-CPBA alone provides
significant background oxidation (entries 1 and 4).
Minisci et al. have shown that m-CPBA will also oxidize
simple alcohols, such as cyclohexanol and 2-heptanol, in
up to 83% yield at elevated temperatures (40 ꢁC, 24 h).20
Minisci et al. was able to suppress the oxidation using
t-BuOH as solvent; however, entry 6 shows that with
0.5 equiv of t-BuOH, background oxidation persisted
in this system. Minisci proposed a radical mechanism
for the oxidations of alcohols by m-CPBA; however,
addition of the radical inhibitor 2,6-di-tert-butyl-4-
methylphenol (BHT) also failed to inhibit background
oxidation (entry 11). The high background oxidation
observed with m-CPBA and Bu4NBr or m-CPBA alone
makes it difficult to determine the true amount of oxida-
tion mediated by the nitroxide; therefore, another
method for one evaluation of the oxidation ability of
the nitroxides was needed.
1
2
3
4
5
6
7
8
31
31
31
32
32
29
29
30
None
10
0
0
46
0
50
0
43
41
—
—
22
—
7
—
4
0
—
—
2.1
—
1.2
—
1
None
1
None
1
1
1.2
—
a Conversion determined by GC.
amine 10 was oxidized with m-CPBA to the nitroxide
since BAIB was not reported to generate a nitroxide
from an amine.24 This hypothesis was tested and con-
firmed by the use of amine 10 (entry 2), in which no oxi-
dation was observed. The nitroxide solution was then
added to the alcohol mixture, and the oxidation of the
alcohol monitored. Without nitroxide (entries 1, 2, 4,
and 6), oxidation did not occur, indicating that there
was no background oxidation. Therefore, the choice of
BAIB as a bulk oxidant should help elucidate oxidations
that are directly mediated by the nitroxide catalyst with-
out contamination by background oxidations. Each of
the alcohols was oxidized to high conversion of the the-
oretical 50% possible based on 0.5 equiv of BAIB, sug-
gesting 1 is an efficient oxidation catalyst. A small
amount of kinetic resolution occurred as indicated by
the % ee of the recovered alcohols and the very modest
calculated S-values in entries 3, 5, and 7.
A bulk oxidant that gave minimal background oxida-
tion was required to elucidate the catalytic activities of
1–4 and better determine their abilities to resolve alco-
hols. Procedures are known that generate a nitroxide
from an amine or amine hydrobromide salt such as oxi-
dation with basic peroxide,21 sodium tungstate,22 or
in situ generation of dimethyl dioxirane from Oxoneꢂ
and acetone.23 Each of these methods was attempted
(Table 2). While there was little or no background oxi-
dation for each of these methods in the absence of 10,
there was also no oxidation of the alcohol observed
when 10 was added. Presumably, these reaction condi-
tions failed to further oxidize any nitroxide generated
to N-oxoammonium salt, the active oxidizing species,
even though the literature reported isolation of the
N-oxoammonium salt in selected cases.21,22 The redox-
active halogen counterion appears to be oxidizing the
alcohol, as reported by Rychnovsky and Vaidyana-
than,19 in the case of entries 8 and 9 since there was
no significant oxidation observed without the counter-
ion present (cf. entries 6 vs 8 and 7 vs 9).
With the proper choice of bulk oxidant now realized,
screening the remaining catalysts was a straightforward
process (Table 4). To be consistent in the evaluation of
the alcohols, the same method of preparation presented
earlier was utilized. Specifically, various alcohols were
dissolved in CH2Cl2 with 0.5 equiv of BAIB at 0 ꢁC.
In a separate flask, the amine precursor to the nitroxide
was oxidized with m-CPBA, generating the nitroxide.
The nitroxide was then transferred to the alcohol solu-
tion to initiate oxidation at 0 ꢁC.
Margarita et al.24 developed a method using a hyper-
valent iodide species to mediate the oxidation of alcohols
to carbonyl compounds. The procedure uses catalytic
TEMPO in combination with [bis(acetoxy)iodo]benzene
(BAIB) as the bulk oxidant. Following this precedent,
various alcohols were dissolved in CH2Cl2 with one half
an equivalent of BAIB (Table 3). In a separate flask,
The long lived [3.3.1] nitroxide 2 (entries 1–4) displays
good catalytic activity with yields ranging from 78% to
Table 4. Oxidation of alcohols with 0.5 equiv BAIB, 1% cat. at 0 ꢁC
Entry
Alcohol
Catalyst
% Conversiona
% ee alcohol
1
2
3
4
5
6
7
8
29
30
31
32
29
30
31
32
29
30
31
32
2
2
2
2
3
3
3
3
4
4
4
4
46
39
43
46
48
44
47
49
30
19
2
0
0
0
0
0
0
0
0
—
—
8
8
Table 2. Oxidation of 31 with various bulk oxidants
Entry
Bulk oxidant
Catalyst
% Conversiona
1
2
3
4
5
6
7
8
9
H2O2/NaOH
H2O2/NaOH
None
10
0
0
0
0
0
Na2WO4Æ2H2O
Na2WO4Æ2H2O
Oxone/acetone
Oxone/acetone
Oxone/acetone
Oxone/acetone
Oxone/acetone
None
10
None
10
3
0
9
TMP
10a
10
11
12
40
43
—
—
TMPÆHBr
2
a Conversion determined by GC.
a Conversion determined by GC.

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3591
94% based on 0.5 equiv of BAIB, the limiting reagent;
however, no kinetic resolution was observed. The enan-
tioenriched azaadamantyl nitroxide 3, which had been
resolved to 93% ee by crystallization with L-tartaric acid,
consistently shows the best conversions compared to the
other nitroxides with a lowest yield for 2-octanol at 88%
of theory (entries 5–8). Unfortunately, again, no kinetic
resolution was observed for any of the alcohols. Finally,
the racemic [3.3.1] nitroxide 4 showed moderate cata-
lytic activity with yields from 40 to 60%. This is presum-
ably due to the shorter lifetime of the nitroxide as shown
by the EPR studies (Fig. 2). While nitroxides 1, 3, and 4
all had lifetimes ranging from hours to weeks, nitroxide
4 lasted for only about 30 min. These oxidation reac-
tions, while fast, are run for 30–45 min, a length of time
long enough for the decay of 4 to become a factor.
an unexpected result, azaadamatyl nitroxide 4, which
was previously shown to have the best catalytic activity,
was an inefficient catalyst at low temperature (entries
7–9). Additionally, no kinetic resolution was observed
for nitroxide 4. Racemic 4 was then evaluated at higher
catalyst loading (2%) to determine if 0.5% was an insuf-
ficient amount. Conversions with 2% catalyst loading
remained effectively unchanged as seen from entries
7–9. When the temperature was lowered to ꢀ55 ꢁC,
the only tested nitroxide, 1, showed no increase in
enantioselectivity compared to the results at ꢀ35 ꢁC.
2.4. Oxidative stability cyclic voltammetry
Electrochemical characterization of the nitroxides by
cyclic voltammetry yielded information on both the oxi-
dation potential and stability of the catalytically active
N-oxo ammonium salts. The voltammograms of nitrox-
ides 1–4, Figure 4, showed that while the nitroxides vary
in little in oxidation potential, there is large variation in
the stability of their corresponding N-oxo ammonium
species. A measure of the stability of the oxidized forms
were obtained by comparison of the reversibility (or
symmetry) of the voltammometric scans under identical
conditions; a loss of current in the reverse scan, mea-
sured by the ratio of the cathodic and anodic peak cur-
rents, ipa/ipc, indicates that the oxo ammonium ion is
being depleted via a competing pathway before it can
be reduced back to the nitroxide.
In 2000, Tanaka et al. reported a strong temperature
dependence in the kinetic resolution of alcohols.25 In
Tanakaꢀs work, an electro-oxidative kinetic resolution
of sec-alcohols mediated with a catalytic amount of a
nitroxide was performed by use of an undivided cell
under constant current conditions. The S-values
increased markedly when the reaction was performed
at lower temperatures. Varying the temperature from
room temperature to ꢀ15 ꢁC produced S-values increas-
ing from 1.6 (room temperature), to 6.3 (ꢀ5 ꢁC), to 16.4
(ꢀ15 ꢁC). Tanakaꢀs work was limited to ꢀ15 ꢁC because
of the aqueous biphasic experimental design. Tempera-
tures below ꢀ15 ꢁC solidified the aqueous phase.
The same nitroxides that were observed to decay over
time by EPR 1, 3, and 4 also showed enhanced irrevers-
ibility by cyclic voltammetry. The implication is that in
each of these cases 1, 3, and 4, both the nitroxide and
the oxo-ammonium appear to decay by pathways that
have not been elucidated. In the case of nitroxide 2, a
reversible CV was observed with a reversibility factor
ipa/ipc = 1.06 or nearly unity.
This low temperature enhancement of kinetic resolution
seemed ideal for our nitroxides, as BAIB in CH2Cl2
should be amenable to low temperature oxidations.
Herein, only the enantioenriched catalysts 1, 2, and 4
were evaluated (Table 5). The catalyst loading was
reduced to 0.5%, and the amount of BAIB was increased
to 0.6 equiv (0.8 equiv in the case of 2). The temperature
was lowered to ꢀ35 ꢁC. Nitroxide 1 continued to display
good catalytic activity even at the lower catalyst loading
(entries 1–3). Additionally, a nominal increase in the
kinetic resolution was observed with S-values increasing
slightly. Nitroxide 2 also showed high catalytic activity
at the lower temperature; however, no resolution of
the remaining alcohol was observed (entries 4–6). In
We have previously evaluated a series of nitroxide cata-
lysts under Alleliꢀs conditions and shown that effective
nitroxide catalysts have oxidation potentials between
638 and 807 mV, whereas the ineffective catalysts have
oxidation potentials above 852mV. 26 The oxidation
potential of 2 (Eꢁ) obtained by voltammetry (Eꢁ =
(Epa + Epc)/2) is 657 mV. It has already been demon-
strated that nitroxides 1, 3, and 4 are catalytically active
suggesting they are turning over through a redox cycle
to oxidize alcohols. Although electrochemically irrevers-
ible, the oxidation potentials of these nitroxides can be
estimated from the potential of the initial anodic cur-
rent peak, and are approximated as: 1 ꢂ 700 mV, 3 ꢂ
550 mV, and 4 ꢂ 650 mV. It is noteworthy that all of
these potentials are similar to TEMPO at ca. 640 mV.
Interestingly, the stability of the N-oxo ammonium
species does not correlate with the catalytic efficiency
or the enantioselectivity of these catalysts.
Table 5. Oxidation of alcohols with 0.6 equiv BAIB, 0.5% cat. at
ꢀ35 ꢁC
Entry Alcohol Catalyst
%
% ee
S-Value
Conversiona alcohol
1
2
3
4
5
6
7
8
9
29
31
32
29
31
32
29
31
32
1
45
56
48
74b
71b
61b
10
5
27
30
16
0
0
0
0
0
0
2.5
2.1
1.6
—
—
—
—
—
—
1
1
2
2
2
4c
4c
4c
3
3. Conclusions
a Conversion determined by GC.
b 0.8 equiv of BAIB used.
c Additional attempts with 2% catalysts did not improve conversions.
We have prepared a number of bicyclic nitroxides with a-
hydrogens and explored their utility as enantioselective

3592
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
Figure 4. Cyclic voltammograms of nitroxides 1–4.
alcohol oxidation catalyst. Nitroxide 2 was indefinitely
stable, but the other three nitroxides showed lifetimes
of 40 min to 7 h at room temperature in CH2Cl2. Three
of the nitroxides, 1, 2, and 3, showed high efficiency
and good turnover as catalysts for the oxidation of alco-
hols. Only catalyst 1 showed any enantioselectivity in the
oxidation of alcohols, and the selectivities were modest.
The rationale for poor selectivity is not obvious at this
time but could be attributed to the simply alkyl methyl
substituents around the nitroxide not providing enough
steric interaction to induce selectivity. This is the first
report of the synthesis of enantiomerically active bicyclic
nitroxides, and the first example of a-hydrogen nitroxide
as catalyst for alcohol oxidations. Considering the wide
variety of nitroxides that are not effective catalysts for
the oxidation of alcohols, it is remarkable that three of
the four bicyclic nitroxides prepared in our study showed
very good catalytic efficiency.
gas. Reaction solvents were distilled or obtained from
alumina filtration system when necessary. Thin layer
chromatography was performed on Whatman silica gel
PE SIL G/UV plates. Concentration in vacuo was per-
formed using a Buchi rotary evaporator. Flash chroma-
¨
tography was performed on EM Science 230–400 mesh
silica gel. Melting points were determined using an Elec-
trothermal apparatus and are uncorrected. Infrared
spectra were recorded on a MIDAC Grams/Prospect
FT-IR. NMR spectra were recorded on a Bruker
¨
GN500, a Bruker Omega 500, and a Bruker DRX
¨
¨
400 MHz FTNMR instruments. Proton NMR spectra
were obtained using CDCl3 as solvent, unless otherwise
noted, and referenced to residual protiated solvent (d
7.26 ppm) or to a TMS standard (d 0.0 ppm). Carbon
NMR spectra were recorded in ppm relative to the resid-
ual solvent signal: CDCl3 (d 77.00 ppm). Mass spectra
were determined on an AE2-MS 30, a PG 7070E-HF,
a CG Analytical 7070E, or a Fisions autospec spectro-
meter. Optical rotations were measured with a Jasco
DIP-370 digital polarimeter. Tetrahydrofuran, diethyle-
ther, toluene, and methylene chloride were dried by fil-
tration through alumina according to the procedure by
Grubbs.27 Capillary GC analysis was performed on a
Hewlett Packard Model 6890 instrument equipped with
a FID detector. Chiral capillary GC analysis was per-
formed on a Hewlett Packard Model 5890 instrument
4. Experimental
4.1. General procedures
All moisture- and air-sensitive reactions were carried
out in flame- or oven-dried glassware using magnetic
stirring under a positive pressure of nitrogen or argon

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3593
equipped with a FID detector and beta-cyclodextrin
permethylated hydroxypropyl column. All cyclic voltam-
metry studies were performed in the laboratories of
Professor Patrick Farmer, at UC, Irvine. A BAS 100W
electrochemistry system was used for CV. The three-
electrode cell employed a Pt wire counter electrode.
All CV experiments were performed at room tempera-
ture. The electrodes were immersed in dichloromethane
solutions containing 0.1 M tetrabutyl-ammonium hexa-
fluorophosphate. Scan rates were 100 mV/s. Electron
paramagnetic resonance experiments were performed
Two layers were separated after cooling. The aqueous
layer was extracted with diethyl ether (3 · 20 mL). The
combined organic phases were dried over MgSO4 and
concentrated in vacuo to give ca. 4 g of an unpurified
oil. Purification on silica gel (2% hexane/ethyl acetate)
removed the nonpolar pinanol and provided a mixture
of the C2 and Ci-symmetric diols. Further purification
on silica gel (diethyl ether) provided diol 7 as a white
23
solid (0.63 g, 58%): mp 121 ꢁC; ½aŠ ¼ þ29:7 (c 0.51,
D
CH2Cl2); IR (neat) 3280, 2930, 2860, 1450, 1420, 1256,
1
1094, 1064, 659 cmꢀ1; H NMR (500 MHz, CDCl3) d
on a Bruker ESP 300 E. All reagents were purchased
¨
3.54 (m, 2H), 1.88 (ddd, J = 13.2, 6.7, 6.6 Hz, 2H),
1.74 (ddd, J = 13.4, 7.2, 4.5 Hz, 2H), 1.54 (ddd,
J = 13.5, 7.4, 3.4 Hz, 2H), 1.32 (d, J = 4.5 Hz, 2H),
1.00 (d, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d 71.4, 35.5, 35.2, 17.9. Anal. Calcd for C8H16O2: C,
66.63; H, 11.18. Found: C, 66.53; H, 10.97.
from Aldrich Chemical Co. or Acros and were used as
received, unless otherwise stated. Elemental analyses
were performed by M-H-W Laboratories (Phoenix,
AZ).
4.2. 1,4-Dimethylcylohexa-1,4-diene 6
4.4. (1S,2S,4S,5S)-(+)-2,5-Dimethylcyclohexane-1,4-diol
bis(methanesulfonate) 8
Compound 6 was prepared using a modified Kwart pro-
cedure.9 A solution of methanol (6.87 g, 214 mmol) and
p-xylene (25.0 mL, 204 mmol) in 500 mL of ammonia
was cooled to ꢀ78 ꢁC, and lithium wire (3.54 g,
510 mmol) was added in five portions over 1 h. After
stirring for 24 h, the ammonia was allowed to evaporate.
Methanol (250 mL) was slowly added to the resulting
residue, while the flask was immersed in a 0 ꢁC bath.
The solution was warmed to room temperature and
water (150 mL) was added. The aqueous layer was
extracted with hexane (4 · 120 mL). The combined
organic phases were dried over anhydrous MgSO4 and
concentrated in vacuo to give 20.8 g of an unpurified
oil, as a mixture of 1,4-dimethylcylohexa-1,4-diene 6
and p-xylene (45:55). The oil was taken on as a mixture:
To a solution of diol 7 (0.48 g, 3.1 mmol) and dry trieth-
ylamine (0.65 g, 6.4 mmol) in CH2Cl2 (20 mL) at 0 ꢁC
was added dropwise a solution of methanesulfonyl chlo-
ride (0.73 g, 6.4 mmol) in CH2Cl2 (5 mL). The mixture
was stirred at 0 ꢁC for 30 min and then at room temper-
ature for 1 h. The reaction mixture was quenched by
addition of saturated aqueous NaHCO3 solution
(20 mL). The aqueous layer was extracted with CH2Cl2
(3 · 10 mL). The combined organic phases were washed
with brine (15 mL), dried over MgSO4, and concen-
trated in vacuo to give 0.935 g of an unpurified oil. Puri-
fication on silica gel (diethyl ether) provided 8 as a white
23
solid (0.903 g, 97%): mp 68–82 ꢁC; ½aŠ ¼ þ29:8 (c
D
IR (neat) 2965, 2818, 1517, 1458, 1385, 948, 795 cmꢀ1
;
1.025, CH2Cl2); IR (neat) 3020, 2950, 1460, 1330,
1
1H NMR (500 MHz, CDCl3) d 5.40 (s, 2H), 2.56 (s,
4H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3) d
131.2, 118.6, 31.7, 20.9.
1119, 996, 890, 850 cmꢀ1; H NMR (500 MHz, CDCl3)
d 4.57 (m, 2H), 3.04 (s, 6H), 2.22 (ddd, J = 14.0, 7.0,
3.5 Hz, 2H), 2.07 (ddd, J = 14.0, 7.1, 4.5 Hz, 2H), 1.81
(ddd, J = 13.9, 7.2, 3.4 Hz, 2H), 1.08 (d, J = 7.0 Hz,
6H); 13C NMR (125 MHz, CDCl3) d 81.5, 38.8, 33.9,
33.2, 17.4; HRMS (CI/isobutane) m/z calcd for
C10H21O6S2 [M+H]+ 301.0781, found: 301.0778. Anal.
Calcd for C9H20O6S2: C, 39.99; H, 6.71. Found: C,
40.05; H, 6.85.
4.3. (1S,2S,4S,5S)-(+)-2,5-Dimethylcyclohexane-
1,4-diol 7
Compound 7 was prepared according to Haltermanꢀs
procedure.8b To
a
solution of 2IpcBH2ÆTMED
(16.6 mL, 0.47 M, 7.8 mmol) in THF was added
BF3ÆOEt2 (2.1 mL, 17 mmol) dropwise. The flask was
swirled to mix the solution, then allowed to stand for
3 h undisturbed, during which time a translucent precip-
itate of 2BF3ÆTMED was formed. The supernatant was
collected in a separate flask by anhydrous filtration of
the precipitate followed by washing the precipitate with
cold THF (3 · 8 mL). The collected supernatant
containing (+)-IpcBH2 was cooled to ꢀ78 ꢁC, and the
1,4-dimethylcylohexa-1,4-diene and p-xylene mixture
(1.81 g of diene/p-xylene, 45:55, 7.5 mmol of 6) was
added slowly. The mixture was placed in a refrigerator
at 5 ꢁC for ca. 30 h, then cooled with an ice bath and
treated with 1 mL of methanol dropwise (H2 was
evolved). The solution of organoboranes was oxidized
by successive slow addition of aqueous sodium hydr-
oxide (4.0 M, 13.4 mL, 54 mmol) and hydrogen peroxide
(30% in water, 5.96 g, 54 mmol). The solution was
warmed to 35 ꢁC for 4 h to ensure complete oxidation.
4.5. Azide 9
To a solution of 8 (2.5 g, 8.2 mmol) in DMF (15 mL)
was added sodium azide (701 mg, 10.8 mmol). The mix-
ture was heated to 85 ꢁC and stirred for 9 h, then
allowed to cool to room temperature. Water (10 mL)
and saturated aqueous NaHCO3 solution (10 mL) were
added. The aqueous layer was extracted with CH2Cl2
(4 · 15 mL). The combined organic phases were washed
with brine (10 mL), dried over MgSO4, and concen-
trated in vacuo to give 1.5 g of an unpurified oil. Purifi-
cation on silica gel (8% ethyl acetate/hexane) provided 9
23
D
(955 mg, 47%) as a white solid: mp 52 ꢁC; ½aŠ ¼ þ27:6
(c 2.30, CH2Cl2); IR (neat) 2944, 2867, 2100, 1350, 1172,
1258, 1080, 963, 890 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 4.49 (ddd, J = 9.3, 9.3, 4.1 Hz, 1H), 3.67 (ddd,
J = 10.4, 4.4, 4.4 Hz, 1H), 2.69 (m, 1H), 2.10 (ddd,
J = 13.4, 4.4, 4.4 Hz, 1H), 1.90 (ddd, J = 13.6, 3.3,

3594
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3.3 Hz, 1H), 1.83 (m, 1H), 1.76 (ddd, J = 14.0, 10.0,
4.4 Hz, 1H), 1.54 (ddd, J = 10.3, 10.3, 3.3 Hz, 1H),
1.12(d, J = 6.7 Hz, 3H), 1.02(d, J = 7.2Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 82.4, 61.3, 38.7, 35.8, 35.6,
31.9, 29.7, 18.3, 13.5; HRMS (CI/isobutane) m/z calcd
for C9H16NO3S [Mꢀ2N+H]+ 220.1007, found:
220.1010. Anal. Calcd for C9H17N3O3S: C, 43.71; H,
6.93. Found: C, 43.92; H, 6.88.
(3.96 g, 29.1 mmol) was added slowly. The mixture
was placed in a freezer at ꢀ15 ꢁC for 4 d then cooled
with an ice bath and treated with 4 mL of methanol
dropwise (H2 evolved). The solution of organoboranes
was oxidized by successive slow addition of aqueous
sodium hydroxide (4.0 M, 30 mL, 120 mmol) and
hydrogen peroxide (30% in water, 8.0 mL, 71 mmol).
The solution was warmed to 35 ꢁC for 4 h to ensure
complete oxidation. Two layers were separated after
cooling. The aqueous layer was extracted with diethyl
ether (4 · 75 mL). The combined organic phases were
dried over MgSO4 and concentrated in vacuo to give
ca. 14 g of an unpurified oil. Purification on silica gel
(2% hexane/ethyl acetate) removed the less polar pina-
nol and provided a mixture of the C2 and Ci-symmetric
diols. Further purification on silica gel (diethyl ether)
4.6. Amine 10a
To a solution of 9 (190 mg, 0.77 mmol) in THF (10 mL)
was added triphenylphosphine (227 mg, 0.87 mmol).
The mixture was stirred at room temperature for 2d,
then aqueous 2M NaOH (5 mL) was added. The aque-
ous layer was extracted with diethyl ether (3 · 3 mL).
The combined organic phases were extracted with aque-
ous 2N HBr (4 · 4 mL). The aqueous acid was washed
consecutively with CH2Cl2 (2 · 6 mL) then toluene
(2 · 6 mL). The aqueous acid was concentrated in vacuo
to give ca. 150 mg of crude crystals. The crystals were
provided diol 12 as a white solid (1.96 g, 48%): mp
23
130–132 ꢁC; ½aŠ ¼ þ8:1 (c 0.15, THF); IR (neat)
D
3280, 2996, 2881, 2819, 1450, 1420, 1093, 947,
708 cmꢀ1 1H NMR (500 MHz, CDCl3) d 3.35 (dt,
;
J = 10.9, 8.6 Hz, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.40
(s, 2H), 1.35 (m, 2H), 1.04 (d, J = 6.7 Hz, 6H); 13C
NMR (125 MHz, CDCl3) d 78.0, 40.7, 34.4, 29.0, 20.4;
HRMS (EI) m/z calcd for C10H19O [MꢀOH]+
155.1436, found: 155.1436. Anal. Calcd for C10H20O2:
C, 69.72; H, 11.70. Found: C, 69.53; H, 11.62.
recrystallized from THF to give 10a (136 mg, 86%) as
23
white crystals: ½aŠ ¼ þ17:0 (c 0.705, MeOH); IR (neat)
D
2870, 1610, 1600, 1195, 947, 820, 805, 776 cmꢀ1
;
1H
NMR (500 MHz, CDCl3) d 8.99 (br s, 2H), 3.90 (d,
J = 4.5 Hz, 2H), 1.93 (m, 4H), 1.78 (ddd, J = 12.4, 4.6,
4.6 Hz, 2H), 1.30 (d, J = 6.9 Hz, 6H); 13C NMR
(125 MHz, CDCl3) d 65.1, 36.8, 34.5, 20.2. HRMS
(EI) m/z calcd for C8H15N [MꢀHBr]+ 125.1204, found:
125.1207.
4.9. Alcohol 13
To a solution of diol 12 (0.172g, 1.00 mmol) and dry tri-
ethylamine (0.142g, 1.40 mmol) in CH 2Cl2 (5 mL) at
0 ꢁC was added dropwise a solution of trimethylsilyl
chloride (0.108 g, 1.00 mmol) in CH2Cl2 (2mL). The
mixture was warmed to room temperature and stirred
for 5 h. The reaction mixture was quenched by addition
of saturated aqueous NaHCO3 solution (5 mL). The
aqueous layer was extracted with CH2Cl2 (4 · 5 mL).
The combined organic phases dried over MgSO4, and
concentrated in vacuo to give 110 mg of an unpurified
oil. Purification on silica gel (10% ethyl acetate/hexane)
provided 13 as a clear oil (111 mg, 45%) and recovered
12 (85 mg, 49%); IR (neat) 3260, 2994, 2965, 2886,
4.7. Amine 10b
To a solution of 9 (133 mg, 0.54 mmol) in THF (8 mL)
was added triphenylphosphine (161 mg, 0.62mmol).
The mixture was stirred at room temperature for 3 d,
then aqueous 2N NaOH (5 mL) was added. The aque-
ous layer was extracted with diethyl ether (3 · 3 mL).
The combined organic phases were extracted with aque-
ous 2M HCl (4 · 4 mL). The aqueous acid was washed
consecutively with CH2Cl2 (2 · 6 mL) and then toluene
(2 · 6 mL). The aqueous acid was concentrated in vacuo
to give ca. 100 mg crude crystals. The crystals were
1
1420, 1268, 1121, 940, 772 cmꢀ1; H NMR (500 MHz,
recrystallized from THF to give 10b (82mg, 94%) as
CDCl3) d 3.32 (m, 2H), 2.93 (m, 1H), 1.80 (m, 4H),
1.68 (m, 4H), 1.44 (s, 1H), 1.30 (m, 2H), 1.47 (m, 2H),
1.05 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.13
(s, 9H); 13C NMR (125 MHz, CDCl3) d 79.0, 78.4,
41.1, 41.0, 35.1, 34.9, 29.8, 29.3, 21.1, 20.8, 0.7.
23
white crystals: ½aŠ ¼ þ32:1 (c 0.570, MeOH); IR (neat)
D
2870, 1610, 1600, 1190, 942, 846, 808, 770 cmꢀ1
;
1H
NMR (500 MHz, CDCl3) d 9.55 (br s, 2H), 3.85 (d,
J = 4.5 Hz, 2H), 1.92 (m, 4H), 1.73 (ddd, J = 12.4, 4.6,
4.6 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3) d 64.8, 37.0, 34.6, 20.0.
4.10. Methanesulfonate 14
4.8. Diol 12
To a solution of alcohol 13 (640 mg, 2.62 mmol) and dry
triethylamine (1 mL) in CH2Cl2 (20 mL) at 0 ꢁC was
added dropwise a solution of methanesulfonyl chloride
(363 mg, 3.17 mmol) in CH2Cl2 (5 mL). The mixture
was allowed to warm to room temperature and stirred
overnight. The reaction mixture was quenched by addi-
tion of saturated aqueous NaHCO3 solution (20 mL).
The aqueous layer was extracted with CH2Cl2
(3 · 10 mL). The combined organics were dried over
MgSO4, and concentrated in vacuo to give 880 mg of
an unpurified oil. Purification on silica gel (5–50% ethyl
acetate/hexanes) provided 14 as a clear oil (212 mg,
To a solution of 2IpcBH2ÆTMED (50.0 mL, 0.47 M,
23.5 mmol) in THF was added BF3ÆOEt2 (3.0 mL,
24 mmol) dropwise. The flask was swirled to mix the
solution, then allowed to stand for 3 h undisturbed, dur-
ing which time a translucent precipitate of 2BF3ÆTMED
formed. The supernatant was collected in a separate
flask by anhydrous filtration of the precipitate followed
by washing the precipitate with cold THF (3 · 20 mL).
The collected supernatant containing (+)-IpcBH2 was
cooled to ꢀ78 ꢁC, and 1,5-dimethylcyloocta-1,5-diene

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3595
25%); IR (neat) 3020, 2950, 1480, 1456, 1374, 1330,
aqueous 4 M NaOH. The basic aqueous layer was
extracted with CH2Cl2 (3 · 8 mL). The combined organ-
ic phases were dried over MgSO4, and concentrated in
vacuo to give 78 mg of an unpurified oil. Purification
of the oil by Kugelrohl distillation provided 17 as a clear
oil (40 mg, 41%): IR (neat) 3424, 3057, 2936, 2874, 1438,
1
1258, 1123, 1025, 892, 825 cmꢀ1; H NMR (500 MHz,
CDCl3) d 4.42(dt, J = 9.0, 2.5 Hz, 1H), 3.30 (dt,
J = 8.0, 2.0 Hz, 1H), 2.97 (s, 3H), 2.05 (m, 1H), 1.94
(m, 2H), 1.78 (m, 3H), 1.65 (m, 2H), 1.31 (m, 2H),
1.01 (d, J = 6.5 Hz, 3H), 0.92(d, J = 6.5 Hz, 3H), 0.08
(s, 9H); 13C NMR (125 MHz, CDCl3) d 89.4, 77.8,
39.8, 38.7, 37.7, 33.3, 32.1, 28.4, 28.2, 20.6, 20.2, 0.3.
1345, 1191, 1119, 1070, 1040, 997, 905, 756, 772cm ꢀ1
;
1H NMR (500 MHz, CDCl3) d 2.68 (br s, 2H), 2.50
(br s, 1H), 2.08 (ddd, J = 22.0, 12.0, 5.0 Hz, 2H), 1.98
(ddd, J = 22.0, 12.0, 5.0 Hz, 2H), 1.65 (br s, 2H), 1.34
(m, 2H), 1.30 (m, 2H), 1.11 (d, J = 7.2Hz, 6H); 13C
NMR (125 MHz, CDCl3) d 52.4, 32.4, 27.1, 25.2, 20.4.
HRMS (CI/isobutane) m/z calcd for C10H20N
[M+H]+ 154.1597, found: 154.1591.
4.11. Azide 15
To a solution of 14 (212 mg, 0.657 mmol) in DMF
(5 mL) was added sodium azide (53 mg, 0.82mmol).
The mixture was heated to 70 ꢁC and was stirred for
48 h, then allowed to cool to room temperature. Water
(2mL) and saturated aqueous NaHCO 3 solution
(2mL) were added. The aqueous layer was extracted
with CH2Cl2 (3 · 2mL). The combined organic phases
were dried over MgSO4, and concentrated in vacuo to
give an unpurified oil. Purification on silica gel (5–10%
4.14. Diene 19
To a solution of methyl magnesium bromide (3 M,
30 mL, 90 mmol) in diethyl ether was added dropwise
dione 1815,16 (3.515 g, 23.10 mmol) dissolved in THF
(100 mL). The mixture was heated at reflux for 24 h,
then cooled to 0 ꢁC. The cooled reaction mixture was
quenched by slow addition of saturated aqueous ammo-
nium chloride (100 mL) and water (100 mL). The aque-
ous layer was extracted with ethyl acetate (4 · 150 mL).
The combined organic phases were washed with brine
(2 · 20 mL), dried over MgSO4, and concentrated in
vacuo to give ca. 4.5 g of an unpurified solid. The unpu-
rified solid was dissolved in CH2Cl2 (100 mL) and
cooled to 0 ꢁC. To the solution was added dropwise
BF3ÆOEt2 (9.0 mL, 73 mmol). The mixture was allowed
to stir for 1 h. The reaction mixture was quenched by
addition of saturated aqueous NaHCO3 solution
(50 mL) and water (20 mL). The aqueous layer was
extracted with CH2Cl2 (3 · 40 mL). The combined
organic phases were dried over MgSO4, and concen-
trated in vacuo to give ca. 4 g of an unpurified oil. Puri-
fication on silica gel (hexane) provided 19 as a clear oil
(3.03 g, 89%); IR (neat) 3000, 2961, 2910, 2832, 1670,
ethyl acetate/hexane) provided 15 as a clear oil (87 mg,
23
47%): ½aŠ ¼ þ25:6 (c 0.31, CH2Cl2); IR (neat) 3375,
D
2926, 2871, 2094, 1480, 1456, 1373, 1278, 1191, 1011,
952, 772 cmꢀ1 1H NMR (500 MHz, CDCl3) d 3.81
;
(dt, J = 9.5, 3.5 Hz, 1H), 3.28 (dt, J = 9.0, 3.5 Hz,
1H), 2.04 (m, 2H), 1.86 (m, 1H), 1.74 (m, 2H), 1.58
(m, 4H), 1.41 (m, 2H), 1.07 (d, J = 6.0 Hz, 3H), 0.97
(d, J = 6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
77.9, 63.7, 38.5, 36.0, 33.1, 28.9, 28.4, 28.0, 21.7, 17.7.
ESMS m/z calcd for C10H19N3ONa [M+Na]+ 220.15
found 220.09.
4.12. Azidemethanesulfonate 16
To a solution of alcohol 15 (87 mg, 0.35 mmol) and dry
triethylamine (200 lL) in CH2Cl2 (10 mL) at 0 ꢁC was
added dropwise a solution of methanesulfonyl chloride
(49 mg, 0.43 mmol) in CH2Cl2 (0.5 mL). The mixture
was allowed to warm to room temperature and stirred
for 2d. The reaction mixture was quenched by the addi-
tion of saturated aqueous NaHCO3 solution (10 mL).
The aqueous layer was extracted with CH2Cl2
(2 · 8 mL). The combined organic were dried over
MgSO4, and concentrated in vacuo to give an unpurified
oil. Purification on silica gel (10% ethyl acetate/hexanes)
provided 16 as a clear oil (70 mg, 74%); IR (neat) 2988,
2940, 2876, 2101, 1353, 1170, 1254, 1087, 966, 891, 777,
1443, 1377, 1198, 1143, 1012, 803 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 5.32(q, J = 1.5 Hz, 2H), 2.23 (m,
1H), 2.19 (m, 3H), 1.96 (m, 1H), 1.92 (m, 1H), 1.69 (q,
J = 1.4 Hz, 6H), 1.66 (t, J = 7.9 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 137.3, 119.2, 32.4, 30.4, 29.6, 22.4.
4.15. Bisepoxide 20
709 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 4.46 (dt,
To a solution of m-CPBA (1.03 g (70 wt %), 4.18 mmol)
in CH2Cl2 (25 mL) at 0 ꢁC was added dropwise a solu-
tion of 19 (204 mg, 1.38 mmol) in CH2Cl2 (5 mL). The
mixture was warmed to room temperature and allowed
to stir for 9 h. The reaction mixture was diluted in
diethyl ether (50 mL) and sequentially washed with
NaHSO3 (10% aqueous, 3 · 20 mL), saturated aqueous
NaHCO3 solution (20 mL), water (10 mL), and brine
(10 mL). The organic phase was dried over MgSO4,
and concentrated in vacuo to give 208 mg of an unpuri-
fied oil. Purification on silica gel treated with 2% trieth-
ylamine (10% ethyl acetate/hexane) provided 20 as a
white solid (99 mg, 41%): mp 44–45 ꢁC; IR (neat)
J = 8.0, 2.0 Hz, 1H), 3.75 (dt, J = 8.0, 3.0 Hz, 1H),
3.00 (s, 3H), 2.50 (tt, J = 13.6, 2.5 Hz, 1H), 2.09 (m,
1H), 1.95–1.88 (m, 3H), 1.79–1.70 (m, 2H), 1.58–1.47
(m, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz,
3H).
4.13. Amine 17
To a solution of 16 (177 mg, 0.64 mmol) in THF
(10 mL) was added triphenylphosphine (200 mg,
0.76 mmol). The mixture was stirred at room tempera-
ture overnight, then warmed to 45 ꢁC for 2d. The reac-
tion mixture then had 2M HCl (aq) (10 mL) added and
the organic layer separated. The aqueous layer was
washed with CH2Cl2 (3 · 5 mL), then made basic with
1
2980, 2890, 1435, 1379, 1097, 1006, 848, 834 cmꢀ1; H
NMR (500 MHz, CDCl3) d 2.96 (d, J = 4.1 Hz, 2H),
2.12 (dd, J = 16.0, 6.6 Hz, 2H), 2.06 (dd, J = 16.2,

3596
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3.3 Hz, 2H), 1.89 (s, 2H), 1.54 (s, 2H), 1.33 (s, 6H); 13C
NMR (125 MHz, CDCl3) d 59.7, 57.4, 29.5, 26.5, 21.3,
21.3. HRMS (FAB) m/z calcd for C11H17O2 [M+H]+
181.1228, found: 181.1222.
The aqueous layer was extracted with CH2Cl2
(3 · 7 mL). The combined organic phases were dried
over MgSO4, and concentrated in vacuo to give an
unpurified oil. Purification on silica gel (5% ethyl ace-
tate/hexane) provided 23 as a clear oil (186 mg, 99%):
IR (neat) 2940, 2909, 2831, 1690, 1450, 1221, 1199,
4.16. Aminediol 21
1
1137, 1073, 1010, 916, 703 cmꢀ1; H NMR (500 MHz,
To a solution of bisepoxide 20 (176 mg, 0.976 mmol) in
MeOH (1 mL) was added ammonia saturated MeOH
(3 mL) in a sealed tube. The tube was heated to
120 ꢁC for 36 h. The reaction mixture was concentrated
in vacuo to give 194 mg of an unpurified solid. Recrys-
tallization from acetone provided 21 as a brown solid
(182mg, 95%): mp 162 ꢁC; IR (neat) 3440, 3370, 2885,
CDCl3) (mixture of rotamers) d 4.54 (s, 1H), 3.81 (s,
1H), 3.23 (s, 3H), 3.22 (s, 3H), 2.34 (dt, J = 13.4,
1.0 Hz, 1H), 2.27 (dt, J = 13.4, 1.0 Hz, 1H), 1.93 (m,
2H), 1.88 (m, 2H), 1.71 (dt, J = 13.4, 3.4 Hz, 1H), 1.65
(dt, J = 13.4, 3.4 Hz, 1H), 1.23 (s, 3H), 1.18 (s, 3H);
13C NMR (125 MHz, CDCl3) d 155.7 (q, J = 35.0 Hz),
116.7 (q, J = 287 Hz), 74.3, 74.0, 55.8, 55.8, 51.9, 48.3,
48.3, 33.4, 32.1, 29.7, 27.6, 25.9, 25.6, 19.2, 18.6. HRMS
(FAB) m/z calcd for C15H23F3NO3 [M+H]+ 322.1629,
found: 322.1623.
1
1445, 1105, 1034, 989, 931, 900, 607 cmꢀ1; H NMR
(500 MHz, CDCl3) d 3.48 (s, 1H), 2.63 (s, 2H), 2.30
(dq, J = 16.5, 2.5 Hz, 2H), 2.06 (t, J = 3.5 Hz, 2H),
1.85 (d, J = 16.5 Hz, 2H), 1.70 (s, 2H), 1.44 (s, 6H);
13C NMR (125 MHz, CDCl3) d 71.3, 55.3, 37.5, 29.9,
27.2, 26.6. HRMS (FAB) m/z calcd for C11H20NO2
[M+H]+ 198.1494, found: 198.1489.
4.19. Aminediether 24
To a solution of amidediether 23 (186 mg, 0.522 mmol)
in ethanol (10 mL) was added sodium borohydride
(80 mg, 2.11 mmol). The mixture heated to 60 ꢁC and
allowed to stir for 8 h. The reaction mixture was concen-
trated in vacuo to ca. 1 mL and quenched by addition of
water added (15 mL). The aqueous layer was extracted
with CH2Cl2 (3 · 10 mL). The combined organic phases
were dried over MgSO4, and concentrated in vacuo to
give 24 (121 mg, 98%): IR (neat) 3345, 2900, 2819,
4.17. Amidediol 22
To a solution of aminediol 21 (154 mg, 0.78 mmol) and
triethylamine (730 mg, 7.26 mmol) in CH2Cl2 (20 mL) at
0 ꢁC was added trifluoroacetic anhydride (604 mg,
2.88 mmol). The mixture was allowed to warm to room
temperature and stirred for 2h. The reaction mixture
was quenched by addition of water (20 mL). The aque-
ous layer was extracted with CH2Cl2 (4 · 7 mL). The
combined organic phases were dried over MgSO4, and
concentrated in vacuo to give ca. 0.5 g of an unpurified
oil. The unpurified oil was dissolved in MeOH (8 mL)
and had ca. 250 mg K2CO3 added. The mixture was stir-
red at room temperature for 30 min, then diluted with
ethyl acetate (10 mL), and water (8 mL). The aqueous
layer was extracted with CH2Cl2 (4 · 5 mL). The com-
bined organic phases were dried over MgSO4, and con-
centrated in vacuo to give an unpurified oil. Purification
on silica gel (30% ethyl acetate/hexane) provided 22 as a
white solid (222 mg, 97%): mp 172–174 ꢁC; IR (neat)
3423, 2999, 2881, 1675, 1460, 1197, 1145, 1099, 923,
1
1451, 1374, 1351, 1186, 1097, 957, 889 cmꢀ1; H NMR
(500 MHz, CDCl3) d 3.19 (s, 6H), 2.70 (s, 2H), 2.21
(dt, J = 10.9, 2.1 Hz, 1H), 1.86 (m, 5H), 1.73 (dt,
J = 10.9, 2.0 Hz, 1H), 1.36 (s, 6H); 13C NMR
(125 MHz, CDCl3) d 74.7, 53.7, 47.7, 33.3, 29.0, 26.6,
19.8. HRMS (FAB) m/z calcd for C13H24NO3
[M+H]+ 226.1807, found: 226.1812.
4.20. Aminediether 27
To a suspension of hexanes washed (15 mL) sodium
hydride (317 mg, 13.2mmol) in THF (50 mL) cooled to
0 ꢁC was added dropwise a solution of amidediol 2617
(1.487 g, 6.01 mmol) in THF (15 mL). The reaction mix-
ture was stirred at 0 ꢁC for 30 min, then to the reaction
mixture was added iodomethane (1.87 g, 13.1 mmol).
The mixture was allowed to stir overnight at room tem-
perature. The reaction mixture was cooled to 0 ꢁC and
quenched by addition of methanol dropwise until H2
evolution stopped then water was added (30 mL). The
aqueous layer was extracted with CH2Cl2 (3 · 20 mL).
The combined organic phases were dried over MgSO4,
and concentrated in vacuo to give an unpurified oil.
Purification on silica gel (10% ethyl acetate/hexane) pro-
vided 27 as a clear oil (1.125 g, 68%): IR (neat) 3054,
2935, 2874, 1490, 1450, 1438, 1190, 1038, 996,
1
906, 707 cmꢀ1; H NMR (500 MHz, CD3OD) (mixture
of rotamers) d 4.31 (s, 1H), 3.73 (s, 1H), 3.33 (s, OH),
2.38 (t, J = 14.8 Hz, 2H), 2.09 (s, 2H), 1.75 (t,
J = 14.9 Hz, 2H), 1.68 (s, 2H), 1.24 (s, 3H), 1.19 (s,
3H); 13C NMR (125 MHz, CD3OD) d 156.8 (q,
J = 35.0 Hz), 118.2(q, J = 285 Hz), 71.1, 70.7, 58.6,
55.3, 38.0, 37.7, 28.9, 27.2, 27.0, 25.7. HRMS (FAB)
m/z calcd for C13H19F3NO3 [M+H]+ 294.1317, found:
294.1306.
4.18. Amidediether 23
To a solution of amidediol 22 (153 mg, 0.522 mmol) in
THF (10 mL) was added sodium hydride (89 mg,
3.71 mmol), which was washed with hexanes (5 mL).
To the reaction mixture was added iodomethane
(340 mg, 2.4 mmol). The mixture was allowed to stir
for 5 h. The reaction mixture was cooled to 0 ꢁC and
quenched by the addition of methanol dropwise until
H2 evolution stopped and then water added (10 mL).
758 cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.35 (d,
;
J = 7.2, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.2,
1H), 3.94 (q, J = 13.9, 2H), 3.64 (ddd, J = 11.0, 11.0,
5.3 Hz, 2H), 3.27 (s, 6H), 2.88 (t, J = 4.9 Hz, 2H), 2.00
(ddd, J = 13.0, 13.0, 6.4 Hz, 2H), 1.90 (dd, J = 14.0,
6.9 Hz, 2H), 1.81 (ddd, J = 14.0, 13.4, 6.4 Hz, 2H),
1.65 (ddd, J = 14.0, 13.4, 6.4 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 139.9, 128.2, 127.9, 126.8, 76.5,

B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
3597
56.6, 55.7, 51.9, 27.1, 20.2. HRMS (CI/isobutane) m/z
calcd for C17H25NO2 [M+H]+ 276.1965, found:
276.1973.
4.23. General procedures for oxidation of alcohols using
m-CPBA as the bulk oxidant
The m-CPBA used was first purified according to stan-
dard protocol.28 A solution of the alcohol (1 mmol) in
CH2Cl2 (0.5 mL) and any additive and/or catalyst
(0.01 mmol) was cooled to 0 ꢁC. A solution of m-CPBA
(0.5 mmol) in CH2Cl2 (1.5 mL) cooled to 0 ꢁC was
added dropwise over a few minutes. The reaction mix-
ture was stirred at 0 ꢁC for 20 min, then was allowed
to warm to room temperature and stirred for another
30 min. The reaction mixture was quenched by addition
of saturated aqueous NaHCO3 (3 mL), and the layers
separated. The aqueous layer was extracted with CH2Cl2
(3 · 1 mL). The combined organic phases were dried
over MgSO4 and concentrated in vacuo. The resulting
oil was analyzed by GC and NMR for any oxidation
and enantiomeric excess of unreacted alcohol.
4.21. Amine 28
Argon was bubbled through a solution of 27 (515 mg,
1.87 mmol), acetic acid (470 lL, 8.25 mmol), and 10%
palladium on carbon (130 mg) in ethanol (3 mL) in a
Parr bomb. The resultant suspension was pressurized
with hydrogen (500 psi) and stirred at room temperature
overnight. After filtration through Celite, the solution
was taken up in CH2Cl2 (15 mL). The organic layer
was washed with 1 M NaOH (10 mL), the organic layer
was separated, dried over MgSO4, and concentrated
in vacuo to give an unpurified oil. The unpurified amine
was diluted with CH2Cl2 (10 mL) and extracted with
2M HCl (10 mL). The aqueous layer was washed with
CH2Cl2 (2 · 8 mL), and then made basic with 4 M
NaOH. The basic aqueous layer was extracted with
CH2Cl2 (4 · 10 mL). The combined organic phases
were dried over MgSO4, and concentrated in vacuo to
give 28 as a clear oil (317 mg, 91%). IR (neat) 3283,
2933, 2819, 1451, 1374, 1351, 1186, 1097, 957,
4.24. General procedures for oxidation of alcohols using
H2O2/NaOH as the bulk oxidant
A solution of the alcohol (1 mmol) in 0.5 mL of THF
and catalyst (0.01 mmol) was cooled to 0 ꢁC. A solution
of H2O2 (30% in water, 0.5 mmol) and aqueous 1 M
NaOH in THF (1.5 mL) cooled to 0 ꢁC was added drop-
wise over a few minutes. The reaction mixture was stir-
red at room temperature for 1 d. The reaction mixture
was quenched by addition of saturated aqueous NaH-
CO3 (3 mL), and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3 · 1 mL). The com-
bined organic phases were dried over MgSO4 and con-
centrated in vacuo. The resulting oil was analyzed by
GC and NMR for any oxidation and enantiomeric
excess of unreacted alcohol.
889 cmꢀ1 1H NMR (500 MHz, CDCl3) d 3.46 (ddd,
;
J = 11.1, 11.1, 5.5 Hz, 2H), 3.35 (s, 6H), 3.09 (t, J =
4.8, 2H), 2.05 (dd, J = 12.8, 4.6 Hz 2H), 1.98 (q, J =
6.7 Hz, 2H), 1.72–1.60 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 79.7, 56.0, 47.6, 27.3, 23.8. HRMS (CI/iso-
butane) m/z calcd for C10H20NO2 [M+H]+ 186.1495,
found: 186.1499.
4.22. General procedures used in oxidations
Catalyst 10 was prepared according to the following
procedure: To 10b dissolved in CH2Cl2 (1 mL) was
added aqueous 0.1 N NaOH (1.5 mL). The aqueous
layer was extracted with CH2Cl2 (3 · 0.5 mL). The com-
bined organic phases were dried over MgSO4 and added
to reactions calling for 10.
4.25. General procedures for oxidation of alcohols using
Na2WO4Æ2H2O, H2O2 as the bulk oxidant
A solution of the alcohol (1 mmol) in CH2Cl2 (0.5 mL)
and catalyst (0.01 mmol) was cooled to 0 ꢁC. A solution
at 0 ꢁC of Na2WO4Æ2H2O (0.2mmol), H 2O2 (0.5 mmol)
in CH2Cl2 (1.5 mL), and Bu4NHSO4 (0.04 mmol), as a
phase transfer catalyst, was added dropwise over a few
minutes. The reaction mixture was stirred at room tem-
perature for 1 d. The reaction mixture was quenched by
addition of saturated aqueous NaHCO3 (3 mL), and the
layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 · 1 mL). The combined organic phases
were dried over MgSO4 and concentrated in vacuo.
The resulting oil was analyzed by GC and NMR for
any oxidation and enantiomeric excess of unreacted
alcohol.
Catalyst 1, 2, 3, and 4 were prepared according to the
following procedure:10 was made as described above.
To 10, 17, 24, or 28 was added 1 equiv of m-CPBA in
CH2Cl2 (ꢁ0.1 M). The solution was stirred for 15 min,
during which time it turned faint red. This solution
was added to reactions calling for 1, 2, 3, or 4.
Alcohols were resolved by chiral GC using a Hewlett
Packard Model 5890 instrument equipped with a FID
detector and b-cyclodextrin permethylated hydroxy-
propyl column. sec-Phenethyl alcohol (2): Initial
temperature—65 ꢁC (5 min), rate—0.7ꢁ/min, final
temperature—150 ꢁC (25 min). Retention times: 26.01,
29.66 min. 2-Ocatanol 30: Initial temperature—60 ꢁC
(5 min), rate—0.5ꢁ/min, final temperature—150 ꢁC
(25 min). Retention times: 15.35, 17.22 min. 20-Chloro-
sec-phenethyl alcohol 31: Initial temperature—90 ꢁC
(5 min), rate—1.3ꢁ/min, final temperature—150 ꢁC
(25 min). Retention times: 38.22, 40.80 min. 20-Methyl-
sec-phenethyl alcohol 32: Initial temperature—80 ꢁC
(5 min), rate—1.0ꢁ/min, final temperature—150 ꢁC
(25 min). Retention times: 41.84, 44.23 min.
4.26. General procedures for oxidation of alcohols using
Oxoneꢂ/acetone as the bulk oxidant
A solution of the alcohol (1 mmol) in CH2Cl2 (0.5 mL),
catalyst (0.01 mmol), and Bu4NHSO4 (0.06 mmol), as a
phase transfer catalyst was cooled to 0 ꢁC. A solution at
0 ꢁC of phosphate buffer (1 mL, pH 8.0), acetone
(1 mL), Oxoneꢂ (0.5 mmol), in water (1.5 mL) was
added dropwise over a few minutes. The reaction

3598
B. Graetz et al. / Tetrahedron: Asymmetry 16 (2005) 3584–3598
F.; Olive, G.; Tordo, P. J. Phys. Chem. A 1997, 101, 7965–
7970.
mixture was stirred at room temperature for 1 d. The
reaction mixture was quenched by addition of saturated
NaHCO3 (3 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 · 1 mL).
The combined organic phases were dried over MgSO4
and concentrated in vacuo. The resulting oil was ana-
lyzed by GC and NMR for any oxidation and enantio-
meric excess of unreacted alcohol.
3. (a) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Durif, A.;
Averbuch, M.-T.; Pierre, J.-L. Tetrahedron Lett. 1998, 39,
2565–2568; (b) Einhorn, J.; Einhorn, C.; Ratajczak, F.;
Pierre, J.-L. J. Chem. Soc., Chem. Commun. 1995, 1029–
1030.
4. Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.;
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Chem. 1982, 47, 5074–5083.
11. Bates, R. B.; Gangwar, S. Tetrahedron: Asymmetry 1993,
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J. Org. Chem. 1989, 45, 3292–3303.
13. (a) Langrand, G.; Secchi, M.; Buono, G.; Baratti, J.;
Triantaphylides, C. Tetrahedron Lett. 1985, 26, 1857–
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2655–2659.
4.27. General procedures for oxidation of alcohols using
BAIB as the bulk oxidant
A solution of the alcohol (1 mmol) in CH2Cl2 (0.5 mL)
and catalyst (0.01 mmol) was cooled to 0 ꢁC. A solution
at 0 ꢁC of BAIB in CH2Cl2 (1 mL) was added dropwise
over a few minutes. The reaction mixture was stirred at
0 ꢁC for 3 h. The reaction mixture was quenched by
addition of saturated aqueous NaHCO3 (3 mL), and the
layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 · 1 mL). The combined organic phases
were dried over MgSO4 and concentrated in vacuo.
The resulting oil was analyzed by GC and NMR for
any oxidation and enantiomeric excess of unreacted
alcohol.
4.28. General procedure for electrochemical character-
ization of nitroxides
The experiments were performed in CH2Cl2, using SCE
as the reference electrode.29 Therefore, all potentials
reported are in reference to SCE. Tetrabutylammonium
hexafluoro-phosphate was used as the supporting elec-
trolyte. The potentials were recorded at a scan rate of
100 mV/s.
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Support was provided by the Schering-Plough Research
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