Mechanistic analysis and optimization of the copper-catalyzed enantioselective intramolecular alkene aminooxygenation

Article abstract of DOI:10.1021/jo3023632

The catalytic asymmetric aminooxygenation of alkenes provides an efficient and straightforward approach to prepare chiral vicinal amino alcohols. We have reported a copper(II)-catalyzed enantioselective intramolecular alkene aminooxygenation, using (2,2,6

Full text of DOI:10.1021/jo3023632

Article
pubs.acs.org/joc
Mechanistic Analysis and Optimization of the Copper-Catalyzed
Enantioselective Intramolecular Alkene Aminooxygenation
Monissa C. Paderes, Jerome B. Keister, and Sherry R. Chemler*
University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: The catalytic asymmetric aminooxygenation of
alkenes provides an efficient and straightforward approach to
prepare chiral vicinal amino alcohols. We have reported a
copper(II)-catalyzed enantioselective intramolecular alkene
aminooxygenation, using (2,2,6,6-tetramethylpiperidin-1-yl)-
oxyl (TEMPO) as the oxygen source, which results in the
synthesis of chiral indolines and pyrrolidines. Herein we
disclose that kinetics studies indicate the reaction is first order
both in substrate and the [Cu(R,R)-Ph-bis(oxazoline)]OTf2 catalyst and zero order in TEMPO. Furthermore, kinetic isotope
effect studies support that the cis-aminocupration step, the addition of N−Cu across the alkene, is the rate-limiting step.
Subsequent formation of a carbon radical intermediate and direct carbon radical trapping with TEMPO is the indicated
mechanism for the C−O bond formation as suggested by a deuterium labeling experiment. A ligand screen revealed that C(4)-
phenyl substitution on the bis(oxazoline) is optimal for high asymmetric induction. The size of the substrate’s N-sulfonyl group
also influences the enantioselectivity of the reaction. The preparative-scale catalytic aminooxygenation reaction (gram scale) was
demonstrated, and an unexpected dependence on reaction temperature was uncovered on the larger scale reaction.
oxygenation reaction provides direct access to 2-(hydroxy-
methyl)indoline and pyrrolidine derivatives with very good
levels of enantioselectivity (eqs 1 and 2). We have subsequently
INTRODUCTION
■
The catalytic asymmetric aminooxygenation of alkenes provides
straightforward access to chiral vicinal amino alcohols, which
are valuable intermediates used in the synthesis of catalysts and
ligands as well as biologically active molecules.1 Sharpless and
co-workers reported the first catalytic enantioselective inter-
molecular aminohydroxylation, catalyzed by osmium, which has
proven to be an extremely useful method, as exemplified by its
use in numerous syntheses of biologically active compounds.2
More recently, Yoon and co-workers have developed copper-3
and iron-catalyzed4 protocols for the enantioselective inter-
molecular aminooxygenation of styrenes and dienes as less
expensive and less toxic transition-metal-catalyst alternatives.
Enantioselective aminooxygenation of α,β-unsaturated alde-
hydes catalyzed by chiral pyrrolidines has also been reported
recently.5 The development of catalytic enantioselective
intramolecular alkene aminooxygenation protocols, however,
has been more rare.
A number of regio- and diastereoselective intramolecular
transition-metal-6−11 and nonmetal-promoted12 olefin amino-
oxygenation reactions have been reported over the years. In
2008, our group reported the first catalytic enantioselective
intramolecular alkene aminooxygenation.10a,b Our method
makes use of (2,2,6,6-tetramethylpiperdin-1-yl)oxyl
(TEMPO) as both the oxidant and oxygen source. A
preliminary report of a new enantioselective copper-catalyzed
reaction that uses PhI(OAc)2 as both the stoichiometric oxidant
and oxygen source has since appeared.11b A stoichiometric
chiral hypervalent iodine-promoted aminooxygenation reaction
has also been reported.12g Our copper-catalyzed amino-
demonstrated that the chiral indoline-forming reaction could be
further optimized for catalyst loading and conducted on a
multigram scale (eq 3).10b We found, however, that we were
not immediately able to scale-up the pyrrolidine-forming
reaction (eq 2) using our published method10a and the lessons
we had learned in the indoline synthesis scale-up study (eq
Received: October 26, 2012
Published: December 17, 2012
© 2012 American Chemical Society
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3).10b Herein we report our successful optimization and scale-
up of the chiral pyrrolidine-forming aminooxygenation reaction,
which draws on knowledge we gleaned during a detailed
mechanistic analysis of the enantioselective reaction. We report
herein a mechanistic analysis of the enantioselective reaction
using kinetics, kinetic isotope effects, and isotopic labeling
experiments.
efficiently without using a slight excess of the (R,R)-Ph-Box
ligand, relative to Cu(OTf)2 (Table 1, entry 6). We
hypothesized that [(R,R)-Ph-Box)Cu](OTf)2 is the active
catalyst species in the aminooxygenation reaction; thus, in
order to keep an accurate 1:1 ratio between the Cu and the
(R,R)-Ph-Box ligand we ran the kinetics experiments using the
reaction conditions in Table 1, entry 6. Small-scale reactions
with 2-allylaniline derived substrates such as 1a [<70 mg (ca.
0.240 mmol) 1a] do not require the use of O2 for copper
turnover; the soluble TEMPO radical serves both as copper
oxidant and oxygen atom source (vide infra). This simplified
our kinetics study by reducing a reagent (O2) to monitor. On
larger scale and with less reactive substrates, O2 (1 atm), is
necessary for copper turnover as the reactions do not go to
completion without it.10a,b
Kinetic Order of the Reaction. We determined the kinetic
order of the aminooxygenation reaction by monitoring the
disappearance of substrate 1a using high performance liquid
chromatography (see the Experimental Section for details). The
kinetic order of substrate 1a was established under pseudo-first-
order conditions (excess TEMPO). Loss of 1a showed a linear
decrease of the natural logarithm of its concentration with time,
indicating first-order rate dependence (Figure 1).
RESULTS AND DISCUSSION
■
Experimental Mechanistic Study. Reaction Kinetics. Our
previously reported copper(II)-catalyzed enantioselective intra-
molecular alkene aminooxygenation conditions involved use of
a slight excess of the (4R,5S)-Bis-Ph-Box ligand and K2CO3 as
base (Table 1, entry 1).10a We reexamined the reaction
a
Table 1. Conditions for Reaction Kinetics Optimization
b
c
yield
ee
entry
1
ligand
base
(%)
(%)
(4R,5S)-Bis-Ph-
K2CO3
97
90
Box
2
3
4
(R,R)-Ph-Box
(R,R)-Ph-Box
(R,R)-Ph-Box
K2CO3
90
98
75
88
<5
87
NBu4OAc
2,6-di-tert-butyl-4-methyl-
pyridine
5
(R,R)-Ph-Box
(R,R)-Ph-Box
87
88
88
87
d
6
a
Cu(OTf)2 (20 mol %), (R,R)-Ph-Box (25 mol %) and PhCF3 (0.07
M w/r to 1a) were combined in a pressure tube and heated to 60 °C
for 2 h. Substrate 1a (1 equiv, 0.139 mmol), TEMPO (3 equiv), and
K2CO3 (1 equiv) were added. The reaction mixture was heated to 110
b
°C for 24 h. Yield (%) refers to amount of isolated 2a after
c
purification by flash chromatography on SiO2. Enantiomeric excesses
were determined by chiral HPLC analysis. The reaction was run
using 20 mol % of (R,R)-Ph-Box. OTf = trifluoromethanesulfonyl.
d
Figure 1. Plot of ln[1a] (mM) versus time (min) showing first-order
kinetics in substrate 1a.
conditions to identify an optimal protocol for reaction kinetics.
Because of the low solubility of K2CO3 in CF3Ph, we needed to
find an alternative base to enable optimal reaction kinetics
studies. We also reexamined use of the commercially available
(R,R)-Ph-Box ligand for further protocol simplification.
Gratifyingly, we found that the use of the (R,R)-Ph-Box ligand
gave us comparable yield and enantioselectivity (Table 1, entry
2). In screening soluble bases, we found that use of NBu4OAc
gave high yield but no enantioselectivity (<5%, Table 1, entry
3). This base was previously used in our study of the reaction
kinetics of the copper(II) 2-ethylhexanoate promoted intra-
molecular alkene aminooxygenation reaction.13 Use of 2,6-di-
tert-butyl-4-methylpyridine as base provided the indoline 2a in
87% ee and 75% yield (Table 1, entry 4). We next ran the
reaction in the absence of additional base and found that
sulfonamide 1a cyclized efficiently to form 2a in 87% yield and
88% ee (entry 5). We also found that the reaction proceeds
After we established the order in substrate 1a, we determined
the dependence in the catalyst (Cu−L) and TEMPO
concentration. We obtained the observed rate constant, kobs
from plots of ln[1a] against time at varying catalyst (2.5−20.4
mM) and TEMPO (150 and 300 mM) concentrations. We
found that at constant Cu−L concentration, no significant
change in kobs was observed when the TEMPO concentration
was doubled (see the Experimental Section for the kinetic
data). Thus, we concluded that the aminooxygenation reaction
has zero order kinetic dependence in TEMPO.
To determine the order in catalyst, we plotted ln(kobs
)
against ln[Cu−L] (Figure 2). The plot gave a linear
relationship with slope equal to the order of the catalyst,
which is found to be 0.99 0.02, consistent with first-order
kinetic behavior. In these experiments, reactions were run up to
80−90% conversion for higher catalyst loadings (20−40 mol %
or 10−20 mM). We observed that at low catalyst loadings (5−
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proposed active catalyst species that coordinates with substrate
1a to form the nitrogen−copper(II) intermediate 3. The
existence of an analogous R2N−Cu(II) intermediate has been
previously supported by electron paramagnetic resonance
spectroscopy (EPR)13a and is reasonably invoked in this
reaction mechanism as a heteroatom such as R2NH should
readily displace a triflate anion from a copper(II) complexe. It is
noteworthy that the TEMPO anion [the result of the
reoxidation of copper(I)] or trace TEMPOH14 from excess
TEMPO can also serve as a base to sequester the triflic acid
formed during substrate-catalyst complexation (hence the
realization that K2CO3 is not always necessary). This complex
then undergoes cis-aminocupration via transition state A to give
rise to the alkylorganocopper(II) species 4. In the proposed
transition state A, the substrate’s N-substituent is trans to the
nearest phenyl group of the oxazoline. This proposed transition
state is consistent with the observed first-order dependence on
both substrate 1a and catalyst. The cis-aminocupration
mechanism for this catalytic reaction is further invoked in
analogy to that of the copper(II)-carboxylate promoted
aminooxygenation that gives similar diastereoselectivity trends
in 2,5-disubstituted pyrrolidine-forming reactions.10c,d,13 The
alkyl organocopper(II) species 4 readily homolyzes to provide
the carbon radical intermediate 5, giving off copper(I). The
carbon radical species is quickly trapped by TEMPO to form
the enantiomerically enriched aminooxygenation product 2a.
Copper(I) is then reoxidized by TEMPO to form the reactive
copper(II) species and complete the catalytic cycle.
Figure 2. Plot of ln(kobs) against ln[Cu−L] showing first-order
dependence on the catalyst concentration. The order in Cu−L was
obtained from the slope of the plot, 0.99 0.02.
10 mol % or 2.5−5 mM) the reaction tails off at 40−60%
conversion, presumably due to catalyst decomposition, there-
fore, initial reaction rates were measured for these catalyst
loadings (see the Supporting Information for details).
On the basis of the observed rate law (−d[1a]/dt = kobs
[1a][Cu−L]), we proposed the catalytic cycle shown in
Scheme 1. The [(R,R)-Ph-Box)Cu](OTf)2 complex is the
Kinetic Isotope Effects (KIE). For the rate-limiting step
analysis, we investigated primary and secondary kinetic isotope
effects (kH/kD). We determined the primary kinetic isotope
effect by treating substrates 1a and 1a-1-[D] with our catalytic
Scheme 1. Proposed Mechanism for the Copper(Ii)-Catalyzed Enantioselective Intramolecular Aminooxygenation of Alkenes
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reaction conditions and comparing the rate constants of each
reaction (see the Supporting Information for details). The
primary kinetic isotope effect that was observed (kH/kD = 0.96
0.2) is not significant compared to the maximum theoretical
KIE of 8.5 based on νNH of 3100 cm−1 (25 °C) (eqs 4 and
5).15,16 This result implies that the amine deprotonation in the
conversion of 1a to 3, Scheme 1, is not rate-limiting.
from organomercury hydrides.19 It would have been difficult to
predict the observed relative reactivity using independently
determined rate constants reported for the reaction of carbon
radicals with TEMPO and O2, respectively.18b,c It is likely the
concentration of O2 at 110 °C in PhCF3 is very low,
contributing to the result.
Based on these labeling studies, we were also able to
eliminate other mechanistic alternatives such as the potential
formation of alkyl copper(III) complex via oxidation of an alkyl
copper(II) with TEMPO followed by reductive elimination.
Concerted reaction processes were also ruled out as possible
mechanisms for this transformation. For example, a TEMPO-
coordinated copper complex could facilitate a concerted two-
electron electrophilic addition22,23 and cyclization of the
sulfonamide amine to the alkene, forming an alkylcopper(III)
intermediate which could subsequently undergo reductive
elimination. Alternatively, an oxoammonium ion [ONR2]+
formed from oxidation of TEMPO by CuII could also initiate a
concerted electrophilic addition/cyclization mechanism. In
these other mechanistic possibilities, however, one diaster-
eomer of 7-[D] would be expected.
Effect of Ligand Substituent on Enantioselectivity.
The effect of the ligand substituents on the reaction
enantioselectivity was next examined. An early screen of the
bis(oxazoline) ligands revealed that cis-diphenyl substitutions
on the 4- and 5-positions gave optimal ee.10a,b We found that
commercially available ligands with alkyl substituents [e.g.,
(S,S)-t-Bu-Box, (S,S)-iPr-Box, and (R,R)-Bn-Box] were less
reactive and gave lower enantioselectivity (Table 2, entries 1−
3). We also investigated the effect of adding a substituent on
the phenyl group of the bis(oxazoline). Electron-donating
groups such as -OMe on the 4-position of the phenyl ring gave
comparable yield and % ee to the parent phenyl substituent
(Table 2, compare entry 4 to entry 9), while electron-
withdrawing groups (i.e., −CF3) gave a slightly lower yield and
a significant decrease in % ee (entry 5). 3,5-Dimethylphenyl
substitution rendered the catalyst much less reactive as seen by
the lower yield, and the selectivity was also diminished (entry
6). 4-tert-Butylphenyl substitution, however, gave comparable
yield and % ee (entry 7).
We determined the secondary kinetic isotope effect by
subjecting a mixture of substrates 1a and alkene labeled 1a-2-
[D] to the catalytic conditions under partial conversion and by
analyzing the isotopic ratio before and after the reaction (see
the Supporting Information for details). An inverse secondary
kinetic isotope effect was observed (kH/kD = 0.90 0.04) (eq
6).17 An inverse secondary kinetic isotope effect is consistent
with a change from C(sp2) to C(sp3) in the rate-determining
step of a reaction.17 This result is consistent with the inverse
kinetic isotope effect we observed in the analogous copper(II)
carboxylate promoted intramolecular aminooxygenation of 1a
(kH/kD = 0.90
0.03).13 These studies support the cis-
aminocupration step as the enantioselectivity-determining step
of the reaction.
We further optimized the reaction with the optimal ligand as
shown in Table 2, entries 8−14. When the copper and ligand
[(4R,5S)-Bis-Ph-Box] loadings were further lowered to 15 and
18 mol %, respectively, the starting alkene 1a was recovered
(entry 12). However, in the presence of O2 the reaction goes to
completion (Table 2, entries 8, 13, and 14). Advances in
transition-metal-catalyzed reactions that use O2 as an oxidant
have been reported recently.24 O2 has been recognized as an
attractive oxidant both in academic and industry due to its low
expense and environmental impact. We next found that the
reaction time could be reduced from 24 to 6 h (entries 8, 13,
and 14).10b Our kinetics experiments indicated that the
aminooxygenation of 1a using the [Cu(R,R)-Ph-Box]OTf2
catalyst (20 mol %) was almost complete after 12 h (see the
Supporting Information, Figure S-2). That we were able to
reduce the reaction time even further in Table 2, entry 9,
indicates that the reaction goes even faster in the presence of
O2 (1 atm) and K2CO3. We observed that at the lower catalyst
loading the (4R,5S)-Bis-Ph-Box ligand gave higher yield and %
ee than the (R,R)-Ph-Box ligand (compare entries 10 and 13).
Finally, since we were no longer using TEMPO as the sole
oxidant, we were also able to reduce the TEMPO loading to 1.5
equiv (entry 14). We believe O2 serves as the terminal oxidant
Mechanism for C−O Bond Formation. When we treated
the deuterioalkene 6-[D] with the catalytic aminooxygenation
reaction conditions under partial conversion, 79% of the 1:1
mixture of diastereomers of the aminooxygenation product 7-
[D] and 15% of the starting alkene with retained alkene
geometry were isolated (eq 7). Based on these observations, we
concluded that the reaction most likely proceeds via direct
capture of an sp2-hybridized carbon radical intermediate with
TEMPO18−21 (Scheme 1). The complete retention of the
geometry of the isolated alkene indicates that the N−C bond
formation is not reversible after C−Cu homolysis in this
reaction. It is interesting to note that TEMPO completely out-
competes O2 as the carbon radical trapping agent in this
reaction. Similar relative reactivity, however, has been
previously observed in reactions of carbon radicals generated
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use of bulky substituents both with the 2-allylaniline-derived
substrates (up to 92%, Table 3, entries 3 and 4) and the 4-
Table 2. Ligand Screening, Optimization with Time,
TEMPO and Catalyst Loading
a
a
Table 3. Effect of N-Substituent on Enantioselectivity
b
c
entry
ligand
yield (%)
ee (%) (config)
d
1
2
3
4
5
6
7
(S,S)-t-Bu-Box
30
11 (R)
72 (R)
62 (S)
86 (R)
<5
d
(S,S)-iPr-Box
57
d
(R,R)-Bn-Box
20
(S,S)-4-MeOPh-Box
(R,R)-4-CF3Ph-Box
(S,S)-3,5-di-Me-Ph-Box
(S,S)-4-t-Bu-Ph-Box
(S,S)-4-t-Bu-Ph-Box
(R,R)-Ph-Box
85
75
d
51
81 (R)
91 (R)
90 (R)
88 (S)
83 (S)
90 (S)
86 (S)
91 (S)
90 (S)
85
95
90
e
8
f
9
e
d
10
(R,R)-Ph-Box
82
f
11
(4R,5S)-Bis-Ph-Box
(4R,5S)-Bis-Ph-Box
(4R,5S)-Bis-Ph-Box
(4R,5S)-Bis-Ph-Box
97
g
d
a
12
80
Conditions: Cu(OTf)2 (20 mol %), (R,R)-Ph-Box (25 mol %),
e
13
95
92
TEMPO (3 equiv), K2CO3, PhCF3 (0.07 M wrt substrate), 110 °C, 6
e,
h
b
14
h. Yield (%) refers to amount of isolated 2 after purification by flash
c
a
chromatography on SiO2. Enantiomeric excesses were determined by
Conditions: Cu(OTf)2 (20 mol %), bis(oxazoline) ligand (25 mol
d
chiral HPLC analysis. The remainder of the material is the starting
%), TEMPO (3 equiv), K2CO3, PhCF3 (0.07 M wrt 1a), 110 °C, 24 h.
e
b
olefin 1b. Reaction was run under O2 (1 atm, balloon).
Yield (%) refers to amount of isolated 2a after purification by flash
c
chromatography on SiO2. Enantiomeric excesses were determined by
chiral HPLC analysis. The remainder of the material is the starting
olefin 1a. The reaction was run using 15 mol % of Cu(OTf)2 and 18
mol % of ligand under O2 (1 atm) for 6 h. The reaction was run for 6
h. The reaction was run using 15 mol % of Cu(OTf)2 and 18 mol %
of ligand for 6 h. 1.5 equiv of TEMPO was used.
d
pentenylamine-derived substrates (up to 97%, Table 3, entries 6
and 7). We have previously reported that use of the more easily
removable nosyl group in this reaction led to a decrease in
reactivity and selectivity.10a We found the enantioselective
aminooxygenation reaction efficiency and selectivity to be
highest with substrates that have carbon chain alkyl substitution
(mono or bis) as the parent N-tosyl-4-pentenylamine reacts
poorly in this reaction (yield typically is <50%, substrate can
suffer decomposition, not shown).
Enantiomeric excess for each product was determined by
chiral HPLC. In the cases of products 2c, 7b, and 7c, the
enantiomers were inseparable by chiral HPLC. Reduction of
the O−N bond of each product with zinc in the presence of
saturated aqueous NH4Cl and methanol at 90 °C furnished the
respective alcohols 8 and 9, whose enantiomeric ratios could be
determined by chiral HPLC (eqs 8 and 9).
e
f
g
h
when it is present, oxidizing TEMPO-H back to TEMPO
radical in the presence of K2CO3.25 TEMPO radical is the
oxidant of [Cu(I)] to [Cu(II)] in all cases, and little reaction
occurs in the absence of TEMPO under O2 atmosphere under
catalytic conditions (not shown). We have observed that the
presence of O2 (1 atm) is necessary for the aminooxygenation
reaction to go to completion when it is performed on larger
scale10b and when using the less reactive N-pentenylsulfona-
mide substrates,10a even at lower scale. The need for O2 appears
to be tied to the reactivity of the substrate, and we speculate
that if the aminooxygenation reaction does not occur relatively
rapidly, a competitive process that diminishes the amount of
TEMPO radical (e.g., autoxidation, 2TEMPO + H+ → [R2N
O]+ + TEMPOH) can occur,25 thereby impeding a productive
reaction.
Effect of N-Substituent on Enantioselectivity. We next
examined the effect of the size of the N-sulfonyl group on the
level of enantioselectivity of the reaction. We have previously
shown in catalytic desymmetrization reactions of meso β-
substituted 4-pentenyl sulfonamides that the use of a sterically
demanding aryl sulfonyl group (i.e., 3,5-di-tert-butylbenzene-
sulfonyl) increases the reaction selectivity.10c (Substitution
ortho to the sulfonyl decreases reactivity and selectivity, not
shown.) Similarly, we obtained high enantioselectivity in our
catalytic enantioselective aminooxygenation reaction with the
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Scale-up of the Pyrrolidine-Forming Aminooxygena-
tion Reaction. We next sought to establish if the
enantioselective alkene aminooxygenation reaction of a 4-
pentenylamine-derived sulfonamide could be performed on
gram scale. We recently demonstrated that the catalytic
enantioselective aminooxygenation reaction of N-tosyl-2-allyl-
4-fluoroaniline could be run on multigram scale using 15 mol %
of Cu(OTf)2, 18 mol % of (4R,5S)-Bis-Ph-Box, and 3 equiv of
TEMPO and heating the reaction in PhCF3 to 110 °C under
O2 (1 atm) for 6 h (vide supra, eq 3).10b The chiral indoline
product was prepared on a 5 g scale and with high
enantioselectivity. In that study, use of the (4R,5S)-Bis-Ph-
Box ligand was essential for enabling catalyst loading reduction
to 15 mol %.10b In the process of scaling up the reaction of 2,2-
dimethyl-4-pentenylsulfonamide 6a, we found that the protocol
we reported in 2008 for the enantioselective aminooxygenation
of this substrate10a was significantly less efficient on a larger
scale (250 mg, 19% yield, Table 4, entry 1). When we lowered
With the current optimized conditions in hand, we ran a
gram-scale reaction using substrate 6c since it gave us the
highest enantioselectivity (Table 3, entry 7). Sulfonamide 6c
cyclized efficiently on gram scale to form the pyrrolidine 7c in
good yield and excellent ee (Table 4, entry 5). We have
demonstrated that the TEMPO adducts 7 can be reduced to
the corresponding alcohol or oxidized to the corresponding
aldehyde without erosion of enantiopurity.10
CONCLUSIONS
■
We have reported a mechanistic study of the copper(II)-
catalyzed enantioselective intramolecular aminooxygenation of
alkenes which involved reaction kinetics, kinetic isotope effects
and deuterium-labeling studies. The reaction kinetics showed
first-order dependence in the sulfonamide substrate and the
copper−bis(oxazoline) complex and zero order in TEMPO.
We also observe a secondary kinetic isotope effect for the
alkene addition step. The reactions kinetics and observed
secondary kinetic isotope effect are consistent with the cis-
aminocupration being the rate-limiting step. Isotopic labeling
studies indicate that the C−O bond formation occurs via direct
carbon radical trapping with TEMPO. This deuterium labeling
study also helps rule out other possible concerted reaction
processes. This study is distinct from our previous study of the
copper(II) 2-ethylhexanoate promoted aminooxygenation
reaction where 1/2 order kinetics in both substrate and
[copper] was observed.13 The different kinetics are explained
by the structure of the starting copper complexes: a
[Cu(bisoxazoline)]OTf2 complex is monomeric while Cu(II)
2-ethylhexanoate exists initially as a dimer. The copper-
catalyzed enantioselective aminooxygenation mechanism
(Scheme 1) also shares a number of similarities with the
copper(II) carboxylate promoted aminooxygenation reaction.13
In both cases, the cis-aminocupration was the most likely rate-
determining step, and the C−O bond formation was
determined to occur via direct carbon radical trap. These
mechanistic studies will serve as the experimental basis for
follow up molecular modeling calculations that can shed light
on the detailed three-dimensional transition states that
determine the reaction enantioselectivity.
Table 4. Scaling-up of the Catalytic Aminooxygenation
Reaction of Aliphatic Substrates
a
b
amount substrate
(mg, mmol)
yield
ee
entry
substrate
6a, R = Ts
(%)
(%)
c
1
50, 0.19
97
88
85
86
90
95
c
d
1
6a, R = Ts
6a, R = Ts
6a, R = Ts
250, 0.93
250, 0.93
250, 0.93
300, 0.76
19
e
f
2
88
3
4
95
89
6c, R = 3,5-di-t-Bu-4-
MeOC6H2SO2
5
6c, R =3,5-di-t-Bu-4-
MeOC6H2SO2
1000, 2.53
88
97
a
Yield (%) refers to amount of isolated 7 after purification by flash
b
chromatography on SiO2. Enantiomeric excesses were determined by
chiral HPLC analysis. The reaction was run at 120 °C using 3 equiv of
TEMPO. 80% of the starting alkene 6a was recovered. The reaction
was run at 110 °C using 3 equiv of TEMPO. 9% of the starting alkene
6a was recovered.
c
d
e
f
In this study, we were able to improve the enantioselectivity
of the aminooxygenation reaction (up to 97% ee) with the use
of a bulky N-substituent (i.e., 3,5-di-t-Bu-4-MeOC6H2SO2). We
have shown that the reaction can be efficiently catalyzed with
the use of several chiral bis(oxazoline) ligands [(S,S)-4-t-Bu-Ph-
Box, (R,R)-Ph-Box, (4R,5S)-Bis-Ph-Box]. Our newly optimized
reaction conditions require lower catalyst (15 mol % Cu(OTf)2
and 18 mol % bisoxazoline ligand) and TEMPO (1.5 equiv)
loadings, less time (6 h), lower temperature, and use of
environmentally benign O2 as the stoichiometric oxidant. The
practicality of this protocol was further demonstrated on a gram
scale reaction. This study should aid in the practical application
of this useful copper-catalyzed enantioselective alkene amino-
oxygenation reaction in organic synthesis and drug discovery.
the temperature to 110 °C, a substantial increase in isolated
yield was observed (entry 2). The isolated yield of 7a was
further improved when the TEMPO loading was decreased to
1.5 equiv (entries 3 and 4). We believe the temperature effect is
related to a catalyst decomposition process that can occur
under the reaction conditions. We believe TEMPO may be
involved in the catalyst decomposition process and also the
decomposition of some substrates (e.g., the less reactive N-
tosyl-4-pentenylamine, see the Discussion). When [Cu(4R,5S)-
Bis-Ph-Box]OTf2 was subjected to heating in the presence of
TEMPO and O2 but absence of substrate, a new compound,
1
clearly derived from the ligand, appeared in the H NMR
EXPERIMENTAL SECTION
spectrum of the crude mixture (see the Supporting Information
for spectra). We speculate that the ligand may undergo
oxidation at its benzylic positions. Attempted isolation/
purification of the ligand mixture, unfortunately, failed. We
believe, however, that the development of a more stable ligand
for this aminooxygenation reaction could enable further
lowering of the catalyst loading in future investigations.
■
General Experimental Information. Reagents were used out of
the bottle as purchased from the supplier without further purification
unless otherwise specified. Solvents were purified using a commercial
solvent filtration system. PhCF3 can generally be used out of the bottle
1
as supplied but can be further dried by distillation over CaH2. H
NMR spectra were recorded in CDCl3 at 500 MHz. 13C NMR spectra
were recorded in CDCl3 at 75 MHz. Spectra are reported in ppm
511
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Article
relative to residual chloroform (7.26 ppm for 1H NMRs and 77.0 ppm
for 13C NMRs). IR spectra were obtained neat, and characteristic
peaks are reported in wavenumbers, cm−1. High-resolution mass
spectra were obtained using ESI (double-focusing magnetic sector).
Optical rotations were obtained using a polarimeter fitted with a micro
cell with a 100 mm path length. Melting points are reported as
uncorrected. Cu(OTf)2 was used as purchased but handled in a dry
atmosphere (glovebox). Moisture can lower % yield and % ee.
Sulfonamides 1a−d were synthesized as previously reported.10,26
Characterization data for indolines 2a and 2b have been previously
reported.10a Sulfonamides 6a and 6b were synthesized as previously
reported.10,27 Characterization data for pyrrolidine 7a has been
reported.10a The synthesis of sulfonamide 6-[D] and the character-
ization data for indolines 7-[D] have been reported.10a,13
Chiral Bis(oxazoline) Ligands. The (R,R)-Ph-Box, (S,S)-t-Bu-
Box, (S,S)-i-Pr-Box, and (R,R)-Bn-Box ligands were purchased from
commercial sources. The (4R,5S)-di-Ph-Box ligand was synthesized as
previously reported.10b The remaining ligands were synthesized from
their respective chiral amino alcohols using the procedure reported by
Evans and co-workers.28,29 The amino alcohols were prepared either
from the reduction of the commercially available amino acid30 or
following Sharpless’ asymmetric aminohydroxylation method31,32 from
the corresponding substituted styrene. The substituted styrene was
either commercially available or was readily prepared using the
procedure reported by Denmark and Butler.33,34 The synthesis and
characterization data of the (R,R)-4-t-Bu-Ph-Box, (R,R)-4-MeO-Ph-
Box, and (S,S)-4-CF3-Ph-Box ligands have been reported.35,36
a SiO2 plug (with Et2O washing) and removal of the solvent in vacuo
afforded the crude product. Purification via flash chromatography on
silica gel (0−5% Et2O in hexanes gradient) gave the TEMPO adduct
2c (50 mg, 89% yield) as a white solid: mp 100−105 °C; [α]19D = 66.0
(c = 1.15, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz,
1H), 7.51 (s, 1H), 7.40 (s, 2H), 7.20 (m, 1H), 7.00 (d, J = 5.0 Hz,
2H), 4.25 (m, 1H), 3.99 (dd, J = 9.0 Hz, 3.5 Hz, 1H), 3.93 (dd, J = 8.0
Hz, 6.5 Hz, 1H), 2.72 (d, J = 15.5 Hz, 1H), 2.49 (dd, J = 15.5 Hz, 10.0
Hz, 1H), 1.22−1.38 (m, 6H), 1.18 (s, 18H), 1.14 (s, 3H), 1.10 (s,
3H), 0.96 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.8,
142.3, 136.8, 133.1, 127.2, 126.6, 124.8, 124.4, 121.0, 117.8, 78.8, 60.9,
59.9, 39.5, 35.0, 33.0, 31.6, 31.2, 31.0, 19.9, 19.7, 17.0; IR (neat, thin
film) ν 2965, 2870, 1598, 1478, 1461, 1360, 1360, 1314, 1247, 1170,
1024, 788, 758, 705, 622, 600 cm−1; HRMS (ESI) calcd for [M + H]+
C32H49O3N2S1 541.3458, found 541.3461.
(S)-(1-((3,5-Di-tert-butylphenyl)sulfonyl)indolin-2-yl)methanol
(8). The enantiomers of the TEMPO adduct 2c were inseparable so
the enantiomeric excess was determined using the free alcohol 8.
Following the reported procedure for the reduction of TEMPO,10 2c
(30 mg, 0.06 mmol, 1 equiv) was stirred in methanol (1.5 mL) in a
pressure tube, and then aqueous NH4Cl (1.5 mL) was added followed
by Zn dust (157 mg, 2.4 mmol, 40 equiv). The reaction mixture was
heated to 90 °C for 24 h and was then cooled to room temperature
and filtered through Celite. Purification of the crude product via flash
chromatography (20% ethyl acetate in hexanes) gave 82% yield of N-
protected amino alcohol 8 (18.0 mg) which is a white solid: mp 40−45
°C; [α]19D = 140.6 (c = 1.35, CHCl3), ee = 91%, determined by HPLC
[Regis (S,S) Whelk, 5% IPA/hexane, 1.0 mL/min, λ = 254 nm,
(S,S)-3,5-Di-Me-Ph-Box. The known (2S)-2-amino-2-[3,5-
(dimethyl)phenyl]ethan-1-ol precursor was obtained using Sharpless’
method31 (96% ee). The amino alcohol was converted to the (S,S)-
3,5-di-Me-Ph-Box ligand,28,29 which was obtained as a colorless oil:36
1H NMR (500 MHz, CDCl3) δ 6.89 (s, 2H), 6.86 (s, 4H), 5.16 (dd, J
1
t(major) = 15.00 min, t(minor) = 13.33 min]; H NMR (500 MHz,
CDCl3) δ 7.75 (d, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.39 (s, 2H), 7.24 (d,
J = 6.5 Hz, 1H), 7.03 (m, 2H), 4.23 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H),
2.55 (d, J = 9.5 Hz, 2H), 2.17 (s, 1H), 1.22 (s, 18H); 13C NMR (75
MHz, CDCl3) δ 152.0, 141.5, 136.2, 132.5, 127.7, 127.0, 125.3, 124.9,
121.1, 118.3, 65.3, 63.5, 35.0, 31.1, 31.0; IR (neat, thin film) ν 3541,
2963, 2869, 1593, 1476, 1461, 1349, 1243, 1171, 1095, 1039, 958, 760
cm−1; HRMS (ESI) calcd for [M + Na]+ C23H31O3N1Na1S1 424.1917,
found 424.1925.
= 10.0, 8.0 Hz, 2H), 4.63 (dd, J = 10.0, 8.5 Hz, 2H), 4.16 (t, J = 7.5
Hz, 2H), 2.26 (s, 12H), 1.68 (s, 6H).
N-(2-Allylphenyl)-3,5-di-tert-butylbenzenesulfonamide (1c). o-
Allylaniline37 (120 mg, 0.90 mmol, 1 equiv) was dissolved in dry
CH2Cl2 (4.5 mL), and the solution was treated with 3,5-di-tert-
butylbenzene sulfonyl chloride38,39 (286 mg, 0.99 mmol, 1.1 equiv)
and Et3N (0.38 mL, 2.7 mmol, 3 equiv). The mixture was stirred at
room temperature overnight, washed with 1 N HCl (5.0 mL), and
extracted with CH2Cl2 (3 × 8 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
Flash chromatography of the resulting crude product on SiO2 (0−5%
EtOAc in hexanes) afforded sulfonamide 1c (200 mg, 58% yield)
which matches the previously reported characterization data:27 1H
NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H),
7.43 (s, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (d,
J = 7.5, 1H), 6.41 (s, 1H), 5.66 (m, 1H), 5.06 (dd, J = 10.0 Hz, 1.5 Hz,
1H), 4.87 (dd, J = 17.5 Hz, 1.5 Hz, 1H), 2.73 (d, J = 6.5 Hz, 2H), 1.25
(s, 18H).
(S)-1-((3,5-Di-tert-butyl-4-methoxyphenyl)sulfonyl)-2-(((2,2,6,6-
tetramethylpiperidin-1-yl)oxy)methyl)indoline (2d). Sulfonamide 1d
was converted to indoline 2d using the procedure described for the
aminooxygenation reaction of 1c to 2c. The TEMPO adduct 2d was
obtained as a white solid (46 mg, 85% yield): mp 80−83 °C; [α]20
=
D
66.8 (c = 2.0, CHCl3); ee = 92%, determined by HPLC [Regis (S,S)
Whelk, 0.4% IPA/hexane, 0.5 mL/min, λ = 254 nm, t(major) = 30.56
min, t(minor) = 24.74 min]; 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J
= 8.0 Hz, 1H), 7.45 (s, 2H), 7.19 (t, J = 7.0 Hz, 1H), 7.02 (m, 2H),
4.25 (m, 1H), 4.00 (m, 1H), 3.92 (m, 1H), 3.62 (s, 3H), 2.77 (d, J =
15.5 Hz, 1H), 2.55 (dd, J = 15.5 Hz, 9.0 Hz, 1H), 1.38−145 (m, 6H),
1.26 (s, 18H), 1.16 (s, 3H), 1.13 (s, 3H), 0.95 (s, 3H), 0.85 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 163.4, 144.8, 142.4, 133.1, 131.5, 127.3,
125.5, 124.8, 124.4, 117.8, 78.8, 64.5, 60.8, 59.9, 39.5, 35.9, 33.1, 31.7,
31.6, 29.6, 19.8, 17.0; IR (neat, thin film) ν 2966, 2871, 1603, 1479,
1462, 1406, 1359, 1256, 1227, 1170, 1128, 1007, 883, 794, 759, 707,
665 cm−1; HRMS (ESI) calcd for [M + H]+ C33H51O4N2S1 571.3564,
found 571.3583.
N-(2-Allylphenyl)-3,5-di-tert-butyl-4-methoxybenzenesulfona-
mide (1d). The procedure for the synthesis of 1c was followed except
that 3,5-di-tert-butyl-4-methoxybenzenesulfonyl chloride38,39 was
used.26 Sulfonamide 1d was obtained as a white solid (310 mg, 60%
yield). Its spectral properties matched the reported values:26 1H NMR
(500 MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 1H), 7.48 (s, 2H), 7.25 (t, J
= 7.5, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.40 (s,
1H), 5.66 (m, 1H), 5.06 (dd, J = 10.5 Hz, 1.5 Hz, 1H), 4.90 (dd, J =
17.0 Hz, 1.5 Hz, 1H), 3.66 (s, 3H), 2.80 (d, J = 6.5 Hz, 2H), 1.31 (s,
18H).
(S)-1-((3,5-Di-tert-butylphenyl)sulfonyl)-2-(((2,2,6,6-tetramethyl-
piperidin-1-yl)oxy)methyl)indoline (2c). Cu(OTf)2 (7.5 mg, 0.021
mmol, 0.2 equiv) and (R,R)-Ph-Box (0.32 mL of 0.08 M solution,
0.026 mmol, 0.25 equiv) were combined and stirred in CF3Ph (0.48
mL) under Ar for 2 h at 60 °C in a 100 mL round-bottom flask
equipped with magnetic stir bar. The blue-green solution was cooled
to rt and was treated with sulfonamide 1c (40 mg, 0.104 mmol, 1
equiv), TEMPO (48.6 mg, 0.311 mmol, 3 equiv), K2CO3 (14.3 mg,
0.104 mmol, 1 equiv), and CF3Ph (0.70 mL). The reaction mixture
was heated to 110 °C for 6 h. Filtration of the cooled solution through
3,5-Di-tert-Butyl-N-(2,2-dimethylpent-4-en-1-yl)benzenesulfon-
amide (6b). 2,2-Dimethylpent-4-en-1-amine41,42 (250 mg, 2.2 mmol, 1
equiv) was stirred in dry CH2Cl2 (12 mL), and 3,5-di-tert-butylsulfonyl
chloride38,39 (770 mg, 2.4 mmol, 1.1 equiv) was added followed by
Et3N (0.93 mL, 6.6 mmol, 3 equiv). The reaction mixture was stirred
at room temperature overnight, washed with 1 N HCl (10 mL), and
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Purification by flash chromatography of the resulting crude
product on SiO2 (0−5% EtOAc in hexanes) gave sulfonamide 6c (480
mg, 53% yield) as a colorless oil:27 1H NMR (500 MHz, CDCl3) δ
7.70 (s, 2H), 7.59 (s, 1H), 5.66 (m, 1H), 4.91−4.96 (m, 2H), 2.69 (d,
J = 6.5 Hz, 2H), 1.93 (d, J = 7.5 Hz, 2H), 1.31 (s, 18H), 0.84 (s, 3H);
13C NMR (75 Hz, CDCl3) δ 152.0, 139.1, 134.2, 126.5, 121.0, 117.7,
52.7, 44.0, 35.1, 34.0, 31.2, 24.7; IR (neat) ν 3279, 3076, 2964, 2873,
512
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1639, 1598, 1466, 1410, 1359, 1324, 1313, 1247, 1161, 1070, 993, 922,
876, 831, 749, 704, 592 cm−1; HRMS (ESI) calcd for [M + Na]+
C21H35O2N1Na1S1 388.2281, found 388.2275.
2H), 4.24 (dd, J = 12.5 Hz, 3.0 Hz, 1H), 3.84 (t, J = 8.0 Hz, 1H), 3.67
(s, 3H), 3.63 (m, 1H), 3.12 (AB quartet, J = 10.5 Hz, Δν = 20.6 Hz,
2H), 1.74 (m, 2H), 1.50−1.58 (m, 6H), 1.43 (s, 18H), 1.15 (s, 3H),
1.06 (s, 6H), 1.04 (s, 3H), 0.41 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 163.2, 144.8, 131.6, 125.9, 79.9, 64.6, 61.5, 59.7, 58.1, 44.5, 39.6,
37.4, 36.0, 33.2, 31.7, 26.4, 25.7, 20.0, 17.1; IR (neat, thin film) ν 2955,
2874, 1471, 1453, 1405, 1349, 1253, 1225, 1165, 1125, 1042, 1008,
967, 920, 885, 812, 757, 710, 632, 595 cm−1; HRMS (ESI) calcd for
[M + H]+ C31H55O4N2S1 551.3877, found 551.3887.
3,5-Di-tert-butyl-N-(2,2-dimethylpent-4-en-1-yl)-4-methoxyben-
zenesulfonamide (6c). 2,2-Dimethyl-4-pentenamine (1.00 g, 8.83
mmol) was dissolved in CH2Cl2 (44 mL) and was treated with 3,5-di-
tert-butyl-4-methoxybenzenesulfonyl chloride38,40 (2.95 g, 9.27 mmol)
and Et3N (3.7 mL, 26.5 mmol). The solution was stirred for 2 days at
rt and then was quenched with H2O and extracted with CH2Cl2 (2×).
The combined organic extracts were washed with 1 N HCl and brine
and then were dried over MgSO4. The solution was filtered, and the
volatiles were removed in vacuo. Chromatography on silica gel (0−
10% EtOAc in hexanes gradient) afforded sulfonamide 6c as a white
solid (2.5 g, 72% yield): mp 95−98 °C; 1H NMR (500 MHz, CDCl3)
δ 7.71 (s, 2H), 5.68 (m, 1H), 4.96−5.01 (m, 2H), 4.37 (s, 1H), 3.70
(s, 3H), 2.73 (d, J = 6.5 Hz, 2H), 1.93 (d, J = 7.0 Hz, 2H), 1.43 (s,
18H), 0.85 (s, 6H); 13C NMR (75 Hz, CDCl3) δ 163.2, 145.1, 134.2,
133.6, 125.6, 117.8, 64.5, 52.7, 44.1, 36.1, 34.0, 31.7, 24.8; IR (neat) ν
3266, 2963, 2871, 1639, 1453, 1407, 1327, 1255, 1227, 1163, 1116,
1066, 1004, 928, 886, 756, 710, 592 cm−1; HRMS (ESI) calcd for [M
+ H]+ C22H38O3N1S1 396.2567, found 396.2569.
(S)-(1-((3,5-Di-tert-butyl-4-methoxyphenyl)sulfonyl)-4,4-dime-
thylpyrrolidin-2-yl)methanol (9c). The enantiomeric excess of 7c was
determined using the free alcohol. Compound 9c was obtained as
colorless oil using the same procedure as in the conversion of 2c to 8
(16 mg, 73% yield): [α]22 = −19.3 (c = 1.0, CHCl3), ee =97%,
D
determined by HPLC [Chiralpak AD-RH, 40% H2O/CH3CN, 0.75
mL/min, λ = 254 nm, t(major) = 9.61 min, t(minor) = 8.35 min]; 1H
NMR (500 MHz, CDCl3) δ 7.71 (s, 2H), 3.80 (dd, J = 12.0 Hz, 3.0
Hz, 1H), 3.69 (m, 1H), 3.67 (s, 3H), 3.58 (m, 1H), 3.19 (AB quartet, J
= 11.0 Hz, Δν = 24.4 Hz, 2H), 1.60−1.63 (m, 2H), 1.44 (s, 18H), 1.00
(s, 3H), 0.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 145.2,
130.9, 125.9, 65.8, 64.6, 62.4, 62.2, 43.3, 36.9, 36.0, 31.7, 29.6, 26.0,
25.3; IR (neat, thin film) ν 3503, 2961, 2873, 1576, 1465, 1406, 1337,
1254, 1226, 1162, 1123, 1065, 1034, 1006, 967, 885, 795, 756, 632,
596 cm−1; HRMS (ESI) calcd for [M + H]+ C22H38O4N1S1 412.2516,
found 412.2517.
(S)-1-((1-((3,5-Di-tert-butylphenyl)sulfonyl)-4,4-dimethylpyrroli-
din-2-yl)methoxy)-2,2,6,6-tetramethylpiperidine (7b). In a 100 mL
round-bottom flask equipped with magnetic stir bar were added
Cu(OTf)2 (7.9 mg, 0.022 mmol, 0.2 equiv), (R,R)-Ph-Box (0.34 mL of
0.08 M solution, 0.027 mmol, 0.25 equiv), and CF3Ph (0.46 mL). The
mixture was heated and stirred under Ar for 2 h at 60 °C. The blue-
green solution was then cooled to room temperature, and sulfonamide
6b (40 mg, 0.109 mmol, 1 equiv), TEMPO (48.6 mg, 0.327 mmol, 3
equiv), K2CO3 (14.3 mg, 0.109 mmol, 1 equiv), and CF3Ph (0.8 mL)
were added. The flask was then fitted with a glass side arm adapter
tapered to connect a short rubber vacuum hose through which the O2
balloon was connected. The reaction mixture was heated to 110 °C for
6 h and then was cooled to room temperature and filtered through a
SiO2 plug (with Et2O washing). The solvent was removed in vacuo to
afford the crude product which was then purification by flash
chromatography on silica gel (0−5% Et2O in hexanes gradient). The
(S)-1-((1-((3,5-Di-tert-butyl-4-methoxyphenyl)sulfonyl)-4,4-dime-
thylpyrrolidin-2-yl)methoxy)-2,2,6,6-tetramethylpiperidine (7c)
(Gram Scale). To an oven-dried 250 mL round-bottom flask equipped
with magnetic stir bar were added Cu(OTf)2 (137 mg, 0.38 mmol,
0.15 equiv), (4R,5S)-Bis-Ph-Box (222 mg, 0.46 mmol, 0.18 equiv), and
CF3Ph (30.0 mL). The solution was heated and stirred for 2 h at 60
°C under Ar atmosphere. The blue-green solution was cooled to room
temperature and was treated with sulfonamide 6c (1.0 g, 2.53 mmol, 1
equiv), TEMPO (593 mg, 3.8 mmol, 1.5 equiv), K2CO3 (349 mg, 2.53
mmol, 1 equiv), and an additional 6.0 mL of CF3Ph. The reaction
mixture was heated to 110 °C for 6 h under O2 (1 atm) and was then
cooled to room temperature and filtered through a SiO2 plug (with
Et2O washing). Removal of the solvent in vacuo afforded the crude
product. Purification via flash chromatography on SiO2 (0−5% Et2O in
hexanes) gave the TEMPO adduct 7c (1.23 g, 88% yield).
Enantioselectivity (97% ee) was determined using the amino alcohol
9c.
TEMPO adduct 7b was obtained as a white solid (52.1 mg, 92%
1
yield): mp 90−95 °C; [α]21 = −68.4 (c = 1.0, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.65 (s, 2H), 7.60 (s, 1H), 4.25 (dd, J = 8.5 Hz,
4.0 Hz, 1H), 3.86 (t, J = 8.5 Hz, 1H), 3.62 (m, 1H), 3.14 (AB quartet,
J = 10.5 Hz, Δν = 20.6 Hz, 2H), 1.73 (d, J = 7.5 Hz, 2H), 1.46 (m,
6H), 1.34 (s, 18H), 1.25 (s, 3H), 1.14 (s, 3H), 1.06 (s, 6H), 1.04 (s,
3H), 0.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.9, 137.0, 126.4,
121.5, 79.8, 61.6, 59.7, 58.0, 44.4, 39.6, 37.4, 35.0, 33.0, 31.2, 26.4,
25.8, 20.1, 17.1; IR (neat, thin film) ν 2963, 2873, 1598, 1466, 1351,
1246, 1165, 1110, 1039, 755, 704, 625 cm−1; HRMS (ESI) calcd for
[M + H]+ C30H53O3N2S1 521.3771, found 521.3784.
Mechanistic Analysis of C−O Bond Formation.
(S)-(1-((3,5-Di-tert-butylphenyl)sulfonyl)-4,4-dimethylpyrrolidin-
2-yl)methanol (9b). The enantiomeric excess of 7b was determined
using the free alcohol. Compound 9b was obtained as a colorless oil
using the same method as in the conversion of 2c to 8 (17 mg, 68%
Cu(OTf)2 (5.4 mg, 0.015 mmol, 0.20 equiv) and (R,R)-Ph-Box (0.20
mL of 0.08 M solution, 0.016 mmol, 0.20 equiv) were heated and
stirred in CF3Ph (0.31 mL) for 2 h at 60 °C in a 100 mL round-
bottom flask equipped with magnetic stir bar. Upon being cooled to
room temperature, the reaction mixture was treated with deuterated
substrate 6-[D]13b (20 mg, 0.075 mmol, 1 equiv), TEMPO (35.2 mg,
0.23 mmol, 3 equiv), and CF3Ph (0.60 mL). An O2 balloon was
connected to the flask with the use of a glass side arm adapter
connected to a short rubber vacuum hose. The reaction mixture was
heated in an oil bath at 110 °C for 2 h and then was cooled to room
temperature, diluted with Et2O, and filtered through a plug of silica gel
with Et2O. Removal of the solvent in vacuo afforded the crude
product. Purification by flash chromatography on silica gel (5−10%
EtOAc in hexanes) gave compound 7-[D] (22 mg, 70% yield) and the
unscrambled starting material (4.5 mg, 22% yield). The crude 1H
NMR spectrum showed two −CHD-OTEMP protons at 4.20 and 3.87
ppm, respectively, each integrating as 0.5 H, which indicates the
presence of a 1:1 mixture of diastereomers. This result is consistent
with the analysis of the previously reported C−O bond formation of
the copper(II)-promoted aminooxygenation reaction of alkene.13 Data
yield): [α]22 = −20.6 (c = 1.25, CHCl3), ee =96%, determined by
D
HPLC [Chiralpak AD-RH, 50% H2O/CH3CN, 0.5 mL/min, λ = 254
1
nm, t(major) = 20.58 min, t(minor) = 17.82 min]; H NMR (500
MHz, CDCl3) δ 7.67 (s, 2H), 7.63 (s, 1H), 3.80 (dd, J = 12.0 Hz, 3.0
Hz, 1H), 3.69 (dd, J = 12.0 Hz, 4.5 Hz, 1H), 3.57 (m, 1H), 3.16 (AB
quartet, J = 10.5 Hz, Δν = 22.7 Hz, 2H), 1.61 (dd, J = 7.5 Hz, 1.5 Hz,
2H), 1.34 (s, 18H), 0.99 (s, 3H), 0.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 152.2, 136.3, 126.8, 121.5, 65.8, 62.3, 62.2, 43.3, 36.9, 35.1,
31.2, 26.0, 25.3; IR (neat, thin film) ν 3504, 2961, 2873, 1598, 1466,
1340, 1247, 1162, 1114, 1066, 1036, 968, 791, 756, 707, 631, 592
cm−1; HRMS (ESI) calcd for [M + Na]+ C21H35O3N1Na1S1 404.2230,
found 404.2226.
(S)-1-((1-((3,5-Di-tert-butyl-4-methoxyphenyl)sulfonyl)-4,4-dime-
thylpyrrolidin-2-yl)methoxy)-2,2,6,6-tetramethylpiperidine (7c). Sul-
fonamide 6c was converted to pyrrolidine 7c using the procedure
described for the conversion of 6b to 7b. The TEMPO adduct 7c was
obtained as a white solid (52 mg, 94% yield): mp 140−145 °C; [α]21
D
1
= −64.1 (c = 2.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.70 (s,
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Article
for compound 7-[D] matches the previously reported character-
ization:10a,13 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H),
7.30 (d, J = 8.0 Hz, 2H), 4.17 (m, 0.5H), 3.85 (m, 0.5H), 3.68 (m,
1H), 3.13 (ABq, ΔνAB = 18.5 Hz, J = 10.4 Hz, 2H), 2.43 (s, 3H),
1.78−1.75 (m, 2H), 1.45−1.42 (m, 4H), 1.20 (s, 3H), 1.16 (s, 3H),
1.08 (s, 3H), 1.06 (s, 6H), 0.55 (s, 3H).
Catalyst Decomposition Study. Three separate solutions were
prepared following the procedure below. Cu(OTf)2 (10 mg, 0.028
mmol, 1 equiv) and (4R,5S)-Bis-PhBox (16 mg, 0.033 mmol, 1.2
equiv) were heated and stirred in CF3Ph (2.7 mL) for 2 h at 60 °C in a
10 mL round-bottom flask equipped with magnetic stir bar. The
solution was cooled to room temperature and was treated with
TEMPO (88 mg, 0.56 mmol, 20 equiv). The first solution was stirred
at room temperature for about 15 min, the second and third solutions
were heated to 110 and 120 °C for 6 h, respectively. The cooled
solution was filtered through Celite (with Et2O washing), and the
filtrate was washed with saturated aqueous Na2EDTA (2 × 3 mL). The
organic layer was dried with Na2SO4, filtered, and concentrated in
vacuo to afford the crude product. 1H NMR spectra of the three crude
materials were obtained.
General Procedure for Kinetics Experiments. Cu(OTf)2 and
(R,R)-Ph-Box were heated and stirred in CF3Ph under argon for 2 h at
60 °C in an oven-dried 10 mL round-bottom flask equipped with
magnetic stir bar and sealed with septa. The solution was cooled to rt
and treated with substrate 1a and TEMPO. The reaction mixture was
heated to 110 °C using a temperature regulated oil bath. It was taken
out of the oil bath every hour and a 20 μL aliquot was collected using a
gastight syringe. The aliquots collected were dried under vacuum and
the residue was dissolved in 200 μL acetonitrile. The samples were
analyzed using HPLC in a Microsorb-MV 100 C8 column by gradient
elution (65−100% CH3CN in H2O). Calibration plots for substrate 1a
and the TEMPO adduct 2a were used to calculate the concentrations
of 1a and 2a as a function of time.
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Reactions were run up to 80−90% conversion for higher catalyst
loading (20−40 mol % or 10−20 mM). We observed that at low
catalyst loading (5−10 mol % or 2.5−5 mM) reactions do not go to
completion, and the rate tails off at 40−60% conversion presumably
due to catalyst decomposition. Therefore, initial reaction rates were
measured for these catalyst loadings.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, kinetic studies, kinetic isotope effect
■
S
studies, and characterization data for all reactions and products,
1
including H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: schemler@buffalo.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) (a) Paderes, M. C.; Belding, L.; Fanovic, B.; Dudding, T.;
Keister, J. B.; Chemler, S. R. Chem.Eur. J. 2012, 18, 1711−1726.
(b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem.
2007, 72, 3896−3905.
(14) Rappoport, Z., Liebman, J. F., Eds. The Chemistry of
Hydroxylamines, Oximes and Hydroxamic Acids, Part 1; John Wiley &
Sons Ltd.: New York, 2009.
Financial support for this work was provided by the National
Institutes of Health, NIGMS (GM-078383). We are also
grateful to Dr. Alice Bergmann and Ying Long for assistance
with mass spectrometry.
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NOTE ADDED AFTER ASAP PUBLICATION
■
Figure 1 was incorrect in the version published ASAP on
December 28, 2012; the correct version reposted on January 3,
2013.
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