Multigram synthesis of a chiral substituted indoline via copper-catalyzed alkene aminooxygenation

Article abstract of DOI:10.1055/s-0031-1289762

(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl) -1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthesis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its N,N-diallylaniline by-product by distillation under reduced pressure.

Full text of DOI:10.1055/s-0031-1289762

SPECIAL TOPIC
▌1481
special topic
Multigram Synthesis of a Chiral Substituted Indoline Via Copper-Catalyzed
Alkene Aminooxygenation
Chiral Substituted Indoline
Fatima C. Sequeira, Michael T. Bovino, Anthony J. Chipre, Sherry R. Chemler*
Department of Chemistry, The State University of New York at Buffalo, Buffalo, NY,
14260, USA
Fax +1(716)6456963; E-mail: schemler@buffalo.edu
PSP
Received: 19.04.2012; Accepted: 22.04.2012
No229
Abstract: (S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was
synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthe-
sis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient
gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its N,N-diallylaniline by-product
by distillation under reduced pressure.
Key words: indoline, aminooxygenation, copper-catalyzed, alkene, TEMPO
F
Cu(OTf)2 (15 mol%)
(4R,5S)-di-Ph-box (3) (18 mol%)
TEMPO, O2 (1 atm)
1) BF3·OEt2
F
F
xylenes, 180 °C
2) TsCl, pyridine
CH2Cl2, r.t.
F
allyl bromide, K2CO3
DMF, 70 °C
toluene, 110 °C
NH
Ts
N
OTEMP
N
then distillation
75%
86–89%
89% ee
(>98% ee after recrystallization)
75% (two steps)
H
Ts
4
NH2
1
2
i-Pr2NH, TMEDA
n-BuLi, MeI, THF
–75 °C to r.t.
O
O
O
O
TEMP = 2,2,6,6-tetramethylpiperidinyl
Ph
Ph
Ph
Ph
N
N
N
N
86%
Ph
Ph
Ph
Ph
3
Scheme 1 Copper-catalyzed enantioselective indoline synthesis
Chiral indolines are found in a number of bioactive com- TEMPO adducts can be reduced with Zn (MeOH, aq
pounds.1 While a number of chiral indoline syntheses ex- NH4Cl, 70 °C) to liberate the free alcohol without dimin-
ist, many involve resolution of racemates or use of ishing enantiopurity (Scheme 2).2a
stoichiometric chiral substrates and auxiliaries.1 We have
recently reported that N-sulfonyl-2-allylanilines react un-
der copper catalysis to provide a range of functionalized
Zn, MeOH, NH4Cl (aq)
80 °C, 24 h
N
O
N
N
OH
chiral indolines where the specific functionalization de-
pends upon the reaction components.2 In 2008, we report-
ed the first catalytic enantioselective intramolecular
alkene aminooxygenation using (2,2,6,6-tetramethyl-
piperdin-1-yl)oxyl (TEMPO) radical as the oxygen
source.2a Herein is reported a four step, five gram synthe-
sis of (S)-5-fluoro-2-(2,2,6,6-tetramethylpiperidin-1-
yloxymethyl)-1-tosylindoline (4) (Scheme 1). This meth-
od makes use of ambient pressure O2 as a green oxidant
and the procedure has been optimized beyond our initial
report2a for reaction scale, catalyst loading, and reaction
time. We have previously shown that the N–O bond of the
73%
Ts
90% ee
Ts
90% ee
Scheme 2 Reduction of the N–O bond gives the alcohol
We were particularly interested in demonstrating the
method starting with a substituted aniline, as the unsubsti-
tuted (S)-(+)-2-indolinemethanol is commercially avail-
able. Our synthesis of N-allyl-4-fluoroaniline (1) required
implementation of a simple vacuum distillation procedure
for its separation from 4-fluoroaniline and its N,N-diallyl-
4-fluoroaniline side product. The separation of mono-, di-,
and trialkylamines can be a challenge3 and we demon-
strate that vacuum distillation can address this challenge
in this instance.
SYNTHESIS 2012, 44, 1481–1484
Advanced online publication: 27.04.2012
0
0
3
9
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7
8
8
1
1
4
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DOI: 10.1055/s-0031-1289762; Art ID: SS-2012-C0376-PSP
© Georg Thieme Verlag Stuttgart · New York

1482
F. C. Sequeira et al.
SPECIAL TOPIC
Table 1 Optimization of the Aminooxygenationa
A larger-scale preparation of the (4R,5S)-di-Ph-box (box =
bisoxazoline) ligand 3 via a simple dialkylation of com-
mercially available 2,2′-methylenebis[(4R,5S)-4,5-diphe-
nyl-2-oxazoline] is also described here.2c,4
Cu(OTf)2
(15 mol%)
(4R,5S)-di-Ph-box (3)
(18 mol%)
F
F
TEMPO, O2 (1 atm)
K2CO3, toluene, 110 °C
Our originally reported catalytic enantioselective intra-
molecular aminooxygenation of N-sulfonyl-2-allylani-
lines provided for the synthesis of a number of substituted
chiral indolines (e.g., 4) with good to excellent yield and
moderate to excellent enantioselectivities.2a N-Tosyl sub-
strates provided higher reactivity, yields, and enantiose-
lectivities than their N-nosyl and N-mesyl counterparts,
and aniline substituents such as F, Cl, OMe, and CN were
all tolerated.2a In that report, the reaction scales were lim-
ited to 40–50 mg (ca. 0.13 mmol) of sulfonamide (e.g., 2)
and TEMPO radical (3 equiv) served as both the oxygen
atom source and the oxidant (Table 1, entry 1).2a It was
subsequently found that upon scale-up to 0.33 mmol the
reactions did not go to completion (Table 1, entry 2). A
N
OTEMP
NH
Ts
Ts
4
2
Entry
2 (mmol)
Time (h)
Yield (%)
ee (%)
1b–d
2b–d
3b
0.131
0.33
0.33
0.33
0.33
3.27
13.9
0.33
0.33
24
24
6
83
45
85
87
87
83
89
88
85
89
nde
91
91
91
91
89
73
93
4
6
5f
6
6f
6
similar reactivity problem with less reactive γ-pentenyl- 7f
6
sulfonamide substrates was solved by introducing an O2
8f,g
24
24
atmosphere (1 atm, balloon) and this was found to be a
general solution to the indoline scale-up problem (Table 9c,f,g
1, entry 3).2a,5 The reaction time was reduced from 24 to 6
a Reaction conditions: Cu(OTf)2 (15 mol%) and (4R,5S)-di-Ph-box 3
(18 mol%) were dissolved in PhMe and heated at 70 °C for 2.5 h. To
the cooled mixture was added sulfonamide 2 (1 equiv), K2CO3 (1
equiv), TEMPO (3 equiv), and additional PhMe (0.08 M final concen-
tration with respect to 2). The reaction was heated with stirring under
O2 (1 atm, balloon). Yields refer to product isolated after flash chro-
matography on silica gel. Enantiomeric excess was determined by
chiral HPLC.
hours and the catalyst loading was lowered from 20 mol%
Cu(OTf)2 to 15 mol% Cu(OTf)2 without diminishing effi-
ciency or selectivity (Table 1, entries 3–7). The presence
of K2CO3 is not needed (Table 1, entries 5–9). Both PhCF3
and PhMe are good solvents for the reaction, so PhMe was
used in the scale-up due to its more common industrial us-
age (Table 1, entries 6 and 7). The use of lower O2 atmo-
sphere was probed by using 10% O2 in N2 and it was
b Reaction was run in PhCF3.
c 20 mol% Cu(OTf)2 and 25 mol% ligand 3 was used.
found that at the 15 mol% Cu(OTf)2 loading, enantiose- d The reaction was run under argon instead of O2.
e nd = not detected.
lectivity was reduced (Table 1, entry 8). At 20 mol%
Cu(OTf)2 loading, the level of enantioselectivity was re-
stored (Table 1, entry 9). For the purposes of this reaction
f No K2CO3 was used in this reaction.
g 10% O2 in N2 (1 atm, balloon) was used.
scale up, minimization of catalyst loading was deemed
more important, so the largest scale (13.9 mmol) reaction
We have observed that the (4R,5S)-diphenylbis(oxazo-
was performed with 100% O2 atmosphere (1 atm, balloon,
line) ligand 3 provides superior reactivity and enantiose-
lectivity, compared to the commercially available (4R)-
Ph-box ligand, in challenging Cu(II)-catalyzed alkene
aminofunctionalization reactions.2 This ligand was key in
enabling the catalyst loading to be reduced from 20 to 15
mol%. The synthesis of this ligand has been reported pre-
viously.4a,b While the published route was sufficient to
produce the ligand, we found that employing a dialkyl-
ation protocol initially introduced by Denmark4c can pro-
vide the ligand directly from commercially available
material.2c In the event, we obtained 1.37 grams (86%
yield) of ligand 3 using this protocol, which is of suffi-
cient quantity to allow for the subsequent large scale ami-
Table 1, entry 7).6
The scaled-up reaction sequence shown in Scheme 1 first
involved N-allylation of 4-fluoroaniline. A 2.5:1 stoichi-
ometry of 4-fluoroaniline to allyl bromide was used to
minimize formation of the N,N-diallyl-4-fluoroaniline
side product, which was harder to separate from N-allyl-
4-fluoroaniline than the parent 4-fluoroaniline. The ratio
of mono to diallylation product is also a function of the an-
iline substituent, so in some cases, for example, aniline, a
stoichiometry closer to 1:1 is sufficient.7 While the crude
mixture generated from this allylation of 4-fluoroaniline
can be separated chromatographically, the separation is
difficult and less practical on a larger scale. Distillation
under vacuum (0.5 mmHg), however, did adequately sep-
arate N-allyl-4-fluoroaniline (1) and proved a very effi-
cient method for isolating nearly pure sample (4.50 g,
75% yield). Subsequent BF3·OEt2 promoted aza-Claisen8
and N-tosylation were uneventful and provided crystal-
line sulfonamide 2 (6.49 g) in 75% yield over two steps.
nooxygenation
reaction.
Thus,
enantioselective
aminooxygenation of 2 under the conditions described in
Table 1, entry 7 provided 5.47–5.69 grams (86–89%) of
indoline 4 in 89% yield. One recrystallization from hex-
anes provided 4.28 grams of indoline 4 in >98% ee as de-
termined by chiral HPLC.
In conclusion, the very promising copper-catalyzed enan-
tioselective intramolecular alkene aminooxygenation
Synthesis 2012, 44, 1481–1484
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Chiral Substituted Indoline
1483
reaction2a has been demonstrated on a multigram scale
and chiral indoline 4 was produced in high enantiomeric
excess. The reaction scale-up study included optimization
of solvent, time, and catalyst loading, and the scale-up
problem (lack of conversion at larger scale) was solved by
introduction of O2 as an environmentally benign oxidant
(1 atm, balloon). Implementation of this method for the
synthesis of chiral indolines is now a practical choice for
synthetic organic chemists.
combined organic phases were washed with brine (2 × 60 mL), fil-
tered, dried (Na2SO4, 65 g), filtered, and concentrated by rotary
evaporation (20 mmHg, 50 °C) to afford a dark red oil. Residual
solvents were removed under vacuum (1 mmHg at 22 °C). The
crude 2-allyl-4-fluoroaniline (4.53 g) was obtained as an oil in suf-
ficient purity for use in the subsequent step. A 250 mL round-bot-
tomed flask containing the crude 2-allyl-4-fluoroaniline (2; 4.50 g,
29.5 mmol, 1 equiv) was equipped with a magnetic stir bar, sealed
with a septum, and purged with argon. The oil was dissolved in
CH2Cl2 (29.0 mL) and treated with pyridine (7.23 mL, 88.7 mmol,
3.0 equiv), both added via syringe. This solution was stirred 10 min
and then treated with TsCl (6.67 g, 34.9 mmol, 1.2 equiv). After stir-
ring for 16 h at r.t., the reaction mixture was washed with aq 1 M
HCl (3 × 60 mL). The combined aqueous layer washes were ex-
tracted with CH2Cl2 (1 × 30 mL). All organic phases were then
combined and washed with brine (2 × 60 mL), dried (Na2SO4, 50 g),
filtered, and concentrated in vacuo (20 mmHg, 35 °C) to afford a
dark red oil. Purification by flash chromatography on silica gel (us-
ing a gradient of 0–15% EtOAc in hexanes) afforded the sulfon-
amide 2 as a pale yellow solid; yield: 6.49 g (75% over two steps);
mp 78 °C.
All reagents were used out of the bottle as purchased from the sup-
plier without further purification, unless otherwise noted. 1H NMR
spectra were recorded in CDCl3 (using 7.26 ppm for reference of re-
sidual CHCl3) at 300, 400, or 500 MHz unless otherwise noted. 13
C
NMR spectra were recorded in CDCl3 (using 77.0 ppm as internal
reference) at 75 MHz, unless otherwise noted. IR spectra were taken
neat using a Nicolet-Impact 420 FTIR. Wave numbers in cm–1 are
reported for characteristic peaks. High-resolution mass spectra were
obtained at SUNY Buffalo’s mass spectrometry facility on a Ther-
moFinnigan MAT XL spectrometer. Optical rotations were ob-
tained using a Rudolph Autopol 1 fitted with a microcell with a 100
mm path length. Melting points are reported as uncorrected.
IR (film): 3263, 1590, 1497, 1167, 1093 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.50–7.48 (dd, J = 8.0, 2.0 Hz, 2
H), 7.20–7.14 (m, 3 H), 6.79 (m, 1 H), 6.73 (dd, J = 2.0, 9.0 Hz, 1
H), 6.56 (br s, 1 H), 5.63 (m, 1 H), 5.02 (dd, J = 1.5, 8.5 Hz, 1 H),
5.85 (dd, 1.5, 17.0 Hz, 1 H), 3.00 (d, J = 6.0 Hz, 2 H), 2.93 (s, 3 H).
N-Allyl-4-fluoroaniline (1)
A 250 mL round-bottomed flask equipped with a magnetic stir bar
was charged with K2CO3 (12.7 g, 91.6 mmol, 1.90 equiv), sealed
with a rubber septum, and purged with argon. The flask was charged
with anhyd DMF (40.0 mL) and 4-fluoroaniline (11.6 mL, 121
mmol, 2.50 equiv) was added via syringe, and the mixture was
stirred for 10 min. Allyl bromide (4.19 mL, 48.2 mmol, 1.0 equiv)
was added via syringe over a period of 5 min. The reaction vessel
was then equipped with a reflux condenser and sealed with a rubber
septum, with a needle outlet exiting through a bubbler to relieve the
pressure. The reaction mixture was then heated for 24 h at 70 °C.
The reaction vessel was allowed to cool to r.t. before H2O (75 mL)
was added and the mixture was stirred for 10 min. The mixture was
extracted with EtOAc (3 × 50 mL) and the combined organic phases
were washed with brine (3 × 50 mL), dried (Na2SO4, 65 g), filtered,
and concentrated by rotary evaporation (20 mmHg, 60 °C) to afford
a dark red oil. Purification of the crude oil by fractional distillation
under vacuum afforded 1 as a colorless oil, isolated as a 28:1 mix-
ture of 1 and the diallylaniline; yield: 4.50 g (75%); bp 50–
58 °C/0.5 mmHg.
13C NMR (75 MHz, CDCl3): δ = 161.0 (d, J = 246.0 Hz), 143.9,
136.5 (d, J = 6.9 Hz), 134.8, 130.4 (d, J = 3.4 Hz), 129.6, 128.2,
127.8 (d, J = 9.2 Hz), 127.0, 117.4, 117.0 (d, J = 23.0 Hz), 114.1 (d,
J = 21.8 Hz), 35.7, 21.5.
HRMS (ESI): m/z calcd for C16H16FNO2S + Na [M + Na]+:
328.0778; found: 328.0772.
2,2-Bis[2-(4R,5S-diphenyl-1,3-oxazolinyl)]propane (3)
An oven-dried 250 mL round-bottomed flask equipped with a stir
bar was charged with 2,2′-methylenebis[(4R,5S)-4,5-diphenyl-2-
oxazoline] (1.50 g, 3.27 mmol, 1 equiv) and the flask was sealed
with a rubber septum, and purged with argon. The compound was
dissolved in anhyd THF (100 mL) and treated with i-Pr2NEt (0.47
mL, 3.33 mmol, 1 equiv) and TMEDA (1.00 mL, 6.67 mmol, 2
equiv), added via syringe. The flask was placed in a –75 °C bath and
the mixture was stirred for 5 min and then treated with aq 1.6 M n-
BuLi in hexanes (4.10 mL, 6.56 mmol, 2 equiv), added dropwise via
syringe. The reaction was then warmed to –20 °C over 15 min.
Once at –20 °C, this temperature was maintained for 30 min, after
which the temperature was lowered to –75 °C and MeI (0.42 mL,
6.73 mmol, 2 equiv) was added via syringe. Upon completion of the
addition, the cold bath was removed and the reaction mixture was
stirred at 22 °C under argon for 16 h. The reaction was quenched
with sat. aq NH4Cl (50 mL) and diluted with H2O (25 mL) to dis-
solve any salts that may form. The mixture was extracted with Et2O
(3 × 100 mL) and the combined organics were washed with brine
(100 mL), dried (MgSO4, 1 g), filtered, and concentrated in vacuo
(20 mmHg, 40 °C). The crude white solid was purified by flash
chromatography on silica gel (50% EtOAc in hexanes) to afford li-
gand 3 as a fluffy white solid; yield: 1.37 g (86%); mp 160 °C;
IR (film): 3426, 1613, 1523, 1313, 1220 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.92–6.87 (m, 2 H), 6.58–6.54 (m,
2 H), 5.92 (m, 1 H), 5.31–5.16 (m, 2 H), 3.74 (dt, J = 1.6, 5.2 Hz, 2
H), 3.65 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 155.6 (d, J = 234.9 Hz), 144.0 (d,
J = 2.3 Hz), 135.3, 116.0 (d, J = 44.9 Hz), 115.4, 113.7 (d, J = 8.1
Hz), 47.0.
HRMS-ESI: m/z [M + H]+ calcd for C9H11FN: 152.0870; found:
152.0865.
N-(2-Allyl-4-fluorophenyl)-4-methylbenzenesulfonamide (2)
An oven-dried 250 mL pressure tube (82.5 mm O.D. × 142 mm)
was equipped with a stir bar, sealed with a rubber septum, and
flushed with argon. The tube was charged with N-allyl-4-fluoroan-
iline (1; 4.50 g, 29.5 mmol, 1.0 equiv) and xylenes (70.0 mL), both
added via syringe. The pressure tube was cooled to –78 °C and the
solution was stirred for 10 min. BF3·OEt2 (4.08 mL, 35.4 mmol, 1.2
equiv) was added via syringe and the solution was stirred for 10 min
at –78 °C, then brought to r.t. The reaction vessel was sealed with a
screw cap, placed in an oil bath, and heated at 180 °C for 10 h. Upon
cooling to r.t., the reaction was quenched with aq 2 M NaOH (52
mL). The mixture was extracted with EtOAc (3 × 60 mL) and the
25
25
[α]D +362.0 (c = 1.0, CH2Cl2) {Lit.4a [α]D +367.0 (c = 1.05,
CH2Cl2)}.
IR (film): 3030, 2931, 1656, 1454, 1143, 1114, 975 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.02 (s, 10 H), 6.96 (s, 10 H), 5.97
(d, J = 10 Hz, 2 H), 5.59 (d, J = 10.4 Hz, 2 H), 1.92 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 170.4, 137.5, 136.2, 127.9, 127.6,
127.4, 126.9, 126.6, 86.3, 73.8, 39.6, 24.8.
HRMS-ESI: m/z [M + H]+ calcd for C33H31N2O2: 487.2374; found:
487.2380.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1481–1484

1484
F. C. Sequeira et al.
SPECIAL TOPIC
(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-
tosylindoline (4)
Acknowledgment
We thank the National Institutes of Health (GM078383) for support
of this research.
An oven-dried, 500 mL, 14/20 neck size, round-bottomed flask
equipped with a magnetic stirring bar was brought into a glove box
under an argon environment, where the flask was charged with
Cu(OTf)2 (0.76 g, 2.1 mmol, 0.15 equiv) and (4R,5S)-diphenyl-
bis(oxazoline) 3 (1.22 g, 2.5 mmol, 0.18 equiv); then the flask was
sealed with a rubber septum. The flask was removed from the glove
box and placed under argon. Freshly dried toluene (78 mL) was add-
ed via syringe and the mixture was heated at 70 °C for 2.5 h. This
catalyst solution was allowed to cool to r.t., then TEMPO (6.51 g,
41.7 mmol, 3.00 equiv) was added as a solid and sulfonamide 2
(4.25 g, 13.9 mmol, 1 equiv) was added via syringe as a solution in
toluene (99 mL). The resulting solution was kept under an O2 atmo-
sphere (1 atm, balloon using a glass 14/20 side arm adapter tapered
to connect to a short rubber vacuum hose connected to the O2 filled
balloon) and was heated at 110 °C (oil bath) for 6 h. The reaction
mixture was cooled to r.t., the stir bar was removed, and the mixture
was concentrated by rotary evaporation (20 mmHg, 50 °C) to afford
a brown oil. The crude oil was purified by flash chromatography on
silica gel (0–30% EtOAc in hexanes gradient), affording indoline 4
as an off-white solid; yield: 5.47–5.69 g (86–89%); mp 87–89 °C;
[α]D22 +92.6 (c = 1.0, CHCl3); ee = 89%, determined by Varian
Prostar High Performance Liquid Chromatography using the
Chiralpak AD-RH: 10% i-PrOH–hexane; 0.4 mL/min; λ = 254 nm;
tR (major) = 9.32 min, tR (minor) = 8.14 min. The optical purity of
indoline 4 was further enriched to >98% ee by recrystallization
from hexanes (4.28 g of optically pure 4).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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IR (film): 2936, 1600, 1480, 1356, 1263, 1163 cm–1.
(5) (a) We believe loss of conversion upon scale-up is due to
self-quenching of the TEMPO radical (disproportionation),
which O2 might prevent. (b) TEMPO reactivity: Vogler, T.;
Studer, A. Synthesis 2008, 1979.
1H NMR (500 MHz, CDCl3): δ = 7.58 (dd, J = 5.0, 3.5 Hz, 1 H),
7.51–7.49 (d, J = 8.0, 2.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 6.87
(dt, J = 9.0 Hz, 1 H), 6.74 (dd, J = 2.5, 5.5 Hz, 1 H), 4.34 (m, 1 H),
3.98–3.93 (m, 2 H), 2.76 (d, J = 16.5 Hz, 1 H), 2.66 (dd, J = 9.5,
16.0 Hz, 1 H), 2.36 (s, 3 H), 1.44–1.38 (m, 5 H), 1.23 (d, J = 10.0
Hz, 1 H), 1.15 (d, J = 7.5 Hz, 6 H), 0.95 (s, 3 H), 0.83 (s, 3 H).
13C NMR (75 Hz, CDCl3): δ = 160.3 (d, J = 243.0 Hz), 143.9, 138.0
(d, J = 2.6 Hz), 135.1 (d, J = 9.2 Hz), 134.8, 129.6, 127.0, 118.2 (d,
J = 9.2 Hz), 113.9 (d, J = 23.1 Hz), 111.8 (d, J = 27.5 Hz), 78.7,
61.4, 59.9, 39.5, 33.1, 31.7, 21.5, 20.0, 19.8, 16.9.
(6) (a) These reactions, as performed (1 atm O2, balloon), are
not expected to pose a fire/explosion hazard, but use of
100% O2 atmosphere with organic solvents can be an
industrial concern. There is precedent for turning a batch
process using O2, balloon, into a continuous flow process
that uses 8% O2 in N2: Ye, X.; Johnson, M. D.; Diao, T.;
Yates, M. H.; Stahl, S. S. Green Chem. 2010, 12, 1180; and
references cited therein. (b) After these studies were
completed, we found that under O2 atmosphere the amount
of TEMPO can be reduced to 1.5 equiv.
HRMS-ESI: m/z [M + 1]+ calcd for C25H34FN2O3S: 461.2275;
found: 461.2274.
Anal. Calcd for C25H33FN2O3S: C, 65.19; H, 7.22; N, 6.09. Found:
C, 65.28, H, 7.09; N, 6.09.
(7) Muniz, K.; Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc.
2008, 130, 763.
(8) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D.
J. Am. Chem. Soc. 2006, 128, 3130.
Synthesis 2012, 44, 1481–1484
© Georg Thieme Verlag Stuttgart · New York