Br?nsted acid-assisted intramolecular aminohydroxylation of N -alkenylsulfonamides under heavy metal-free conditions

Article abstract of DOI:10.1021/jo301523a

The intramolecular aminohydroxylation of N-alkenylsulfonamides proceeded under heavy metal-free conditions to give substituted prolinol derivatives in high yields. Oxone activated by catalytic Br?nsted acid worked well as an electrophilic oxidant for this reaction.

Full text of DOI:10.1021/jo301523a

Note
pubs.acs.org/joc
Brønsted Acid-assisted Intramolecular Aminohydroxylation of
N‑Alkenylsulfonamides under Heavy Metal-free Conditions
Katsuhiko Moriyama,* Yuta Izumisawa, and Hideo Togo*
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: The intramolecular aminohydroxylation of N-
alkenylsulfonamides proceeded under heavy metal-free con-
ditions to give substituted prolinol derivatives in high yields.
Oxone activated by catalytic Brønsted acid worked well as an
electrophilic oxidant for this reaction.
he aminooxygenation of olefins is a very important strategy
to directly provide 1,2-aminoalcohol derivatives that serve
1). The addition of TsOH·H2O as Brønsted acid to activate the
cyclization increased the yield of 2a (entry 2). The use of other
Brønsted acids, such as PhCO2H, (PhO)2P(O)OH, and
(CF3SO2)2NH, decreased the yield of 2a (entries 3−5). The
use of MeNO2, AcOEt, and CH2Cl2 instead of MeCN as organic
solvent was not effective as a organic solvent for the
intramolecular aminohydroxylation (entries 6−8). Under basic
conditions, the reaction with K2CO3 (1.5 equiv) became less
effective, and increasing the amount of K2CO3 to 3.0 equiv had
no effect whatsoever on the transformation of 1a into 2a (entry
9). Raising the temperature of the reaction to 50 °C furnished 2a
in a quantitative yield (entry 10). The use of other oxidants and
changing the ratio of MeCN to H2O as solvent at 50 °C had
negligible effects compared to the use of Oxone in a 1:1 mixture
of MeCN and H2O (entries 11−16). Interestingly, the reaction
in H2O produced a cyclization product in 81% yield (entry 13).
Then, we investigated the scope of the heavy metal-free
intramolecular aminohydroxylation of N-alkenylsulfonamides 1
under the optimized reaction conditions (Table 2). The reaction
of N-alkenylsulfonamides bearing other sulfonyl groups, such as
4-fluorobenzenesulfonyl (1b), 4-nitrobenzenesulfonyl (1c), n-
butanesulfonyl (1d), and (S)-camphorsulfonyl (1e), gave
corresponding products (2b−2e) in high yields (78−97%)
(entries 1−4). When monoalkyl- and dialkyl-substituted
alkenylsulfonamides (1f−1j) were treated with Oxone (1.5 or
2.0 equiv), cyclization products (2f−2j) were obtained in
excellent yields (91−98%) (entries 5−9). The reaction of N-
sulfonyl-2-allylcyclohexylamines (1k and 1l) and N-sulfonyl-2-
allylaniline (1m) with Oxone (2.0 equiv) in a 2:1 mixture of
MeCN and H2O also provided hexahydroindoline derivatives
(2k and 2l) and the indoline derivatives (2m) in high yields (78−
90%), respectively (entries 10−12). π-Electron-rich disubsti-
tuted internal alkenes (1n and 1o) and disubstituted terminal
alkene (1p) were efficiently converted into prolinol derivatives
bearing a secondary alcohol group (2n and 2o) and a quaternary
carbon center (2p), respectively, in high yields (78−91%)
(entries 13−15). Moreover, N-alkenylsulfonamide bearing a
T
as useful bulding blocks in the synthesis of drugs and natural
products.1,2 In particular, the intramolecular aminooxygenation
of N-protected alkenes furnishes nitrogen-containing hetero-
cycles that possess a variety of biological activities.3 Previously,
reported methods required the use of heavy metals, such as Os,4
Pd,5 Cu,6 and Au,7 for the intramolecular aminooxygenation of
N-protected alkenes (Scheme 1, eq 1). Heavy metal-free
Scheme 1. Intramolecular Aminohydroxylation of N-
Protected Alkenes
reactions of N-protected amines with iodine reagents
(phenyliodine(III) bis(trifluoroacetate) (PIFA),8 NIS,9 iodosyl-
benzene,10 and chiral aryliodine(III) diacetate11) were developed
as sustainable strategies. However, the reactions with N-
alkenylamides produced a stoichiometric amount of organic
waste derived from the organic oxidant. We report here a heavy
metal-free intramolecular aminohydroxylation of N-alkenylsul-
fonamides using a Brønsted acid-assisted inorganic oxidant,
which is the simplest aminooxygenation method and produces
no stoichiometric amount of organic waste (Scheme 1, eq 2).
Initially, we optimized the reaction conditions for the
intramolecular aminohydroxylation of N-alkenylsulfonamides
(Table 1). When 1a was treated with Oxone
(2KHSO5·KHSO4·K2SO4) in a mixture of MeCN and H2O
(1:1) at room temperature, 2a was obtained in 74% yield (entry
Received: July 19, 2012
Published: October 10, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
products 3a, 3g, 3i, 3j, and 3k in high yields (80−>99%),
respectively.
Table 1. Screening of Optimal Conditions for Intramolecular
Aminohydroxylation of 1a
Finally, we investigated the possibility of synthesizing of
proline ethyl ester 5a through the cleavage of the sulfonyl groups
of N-sulfonylproline 3a under mild conditions (Scheme 4). 3a
was treated with EtI and K2CO3 to obtain N-tosyl-protected
proline ethyl ester 4a in a quantitative yield. Removal of the tosyl
group in 4a with phenol in aqueous HBr solution and AcOH15
provided desired proline ethyl ester 5a as a hydrobromide salt in
94% yield.
In conclusion, we have developed an intramolecular amino-
hydroxylation of N-alkenylsulfonamides (1) that proceeds under
heavy metal-free conditions. This reaction, which was promoted
by a Brønsted acid catalyst, activated a peroxymonosulfate
complex to obtain N-sulfonyl prolinol derivatives (2). Moreover,
2 were transformed into N-sulfonyl proline derivatives (3) by
oxidation using a DIB/TEMPO system and 3 was, in turn,
converted into proline ethyl ester (5a) by desulfonylation under
mild conditions.
time
(h)
yield of
entry oxidant
additive
conditions
2a (%)
1
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
MeCN:H2O
(1:1), rt
24
24
24
24
24
24
24
24
24
10
10
10
74
2
TsOH·H2O
PhCO2H
MeCN:H2O
(1:1), rt
84
59
68
66
6
3
MeCN:H2O
(1:1), rt
4
(PhO)2P(O)OH
(CF3SO2)2NH
TsOH·H2O
TsOH·H2O
TsOH·H2O
K2CO3
MeCN:H2O
(1:1), rt
5
MeCN:H2O
(1:1), rt
6
MeNO2:H2O
(1:1), rt
7
AcOEt:H2O
(1:1), rt
14
5
EXPERIMENTAL SECTION
■
8
CH2Cl2:H2O
(1:1), rt
1
General Procedure. H NMR spectra were measured on a 400
MHz spectrometer. Chemical shifts were recorded as follows: chemical
shift in ppm from internal tetramethylsilane on the δ scale, multiplicity
(s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br =
broad), coupling constant (Hz), integration, and assignment. 13C NMR
spectra were measured on a 100 MHz spectrometer. Chemical shifts
were recorded in ppm from the solvent resonance employed as the
internal standard (deuterochloroform at 77.0 ppm). High-resolution
mass spectra (HRMS) were performed by orbitrap mass spectrometers.
Characteristic peaks in the Infrared (IR) spectra are recorded in wave
numbers, cm−1. Melting points are reported as uncorrected. Thin-layer
chromatography (TLC) was performed using 0.25 mm silica gel plate
(60F-254). The products were purified by column chromatography on
silica gel 60 (63−200 mesh). Visualization was accomplished by UV
light (254 nm), anisaldehyde, KMnO4, and phosphomolybdic acid. N-
Alkenyl sulfonamides 1a−1e, 1h−1j, and 1n−1p,16a 1f and 1g,16b 1k
and 1l,16c,d 1m,16e and 1q4g were prepared according to the literature
procedure. Spectroscopic data of 2a,6b 2h,17a 2i,6b 2m,6b 2q,4g 3a,17b and
4a17c were in accord with those reported in the literature.
a
b
9
MeCN:H2O
(1:1), rt
44 (0)
>99
92
10
11
12
TsOH·H2O
TsOH·H2O
TsOH·H2O
MeCN:H2O
(1:1), 50 °C
MeCN:H2O
(2:1), 50 °C
MeCN:H2O
(1:2), 50 °C
H2O, 50 °C
MeCN:H2O
(1:1), 50 °C
MeCN:H2O
(1:1), 50 °C
MeCN:H2O
(1:1), 50 °C
91
13
14
Oxone
H2O2
TsOH·H2O
TsOH·H2O
20
20
81
0
15
16
TBHP
TsOH·H2O
TsOH·H2O
20
10
0
t-BuOCl
84
a
Number indicates the yield when the reaction was carried out with
b
K2CO3 (1.5 equiv) and obtained 56% recovery of 1a. Number in
parentheses indicates the yield when the reaction was carried out with
K2CO3 (3.0 equiv) and obtained >99% recovery of 1a.
4-Fluoro-N-(pent-4-en-1-yl)benzenesulfonamide (1b). Colorless
1
oil. H NMR (400 MHz, CDCl3) δ 1.57 (quin, J = 7.1 Hz, 2H), 2.05
(q, J = 6.8 Hz, 2H), 2.96 (q, J = 7.1 Hz, 2H), 4.91 (brs, 1H), 4.92−5.00
(m, 2H), 5.70 (ddt, J = 17.2, 10.5, 6.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H),
7.90 (dd, J = 8.8, 5.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 28.6, 30.5,
42.6, 115.6, 116.3 (d, JC−F = 23.0 Hz) (2C), 129.7 (d, JC−F = 8.6 Hz)
(2C), 136.0 (d, JC−F = 3.8 Hz), 137.0, 165.0 (d, JC−F = 254.8 Hz). IR
(neat) 3286, 2938, 1422, 1328, 1237, 1155 cm−1. MS (ESI) calcd for
C11H15FNO2S [M + H]+ 244.0802, found 244.0801.
hydroxy group (1q) also provided 4-hydroxyprolinol derivative
(2q) in 91% yield (entry 16). Unfortunately, the reaction of
diastereotopic N-alkenyl sulfonamides gave moderate to low
diastereoselectivities (dr = 77:23−54:46).
The proposed reaction mechanism for the Brønsted acid
catalyzed intramolecular aminohydroxylation of N-alkenylsulfo-
namides is depicted in Scheme 2.
N-(Pent-4-en-1-yl)butane-1-sulfonamide (1d). Colorless oil. 1H
NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.4 Hz, 3H), 1.46 (sext, J = 7.4
Hz, 2H), 1.67 (quin, J = 7.2 Hz, 2H), 1.73−1.82 (m, 2H), 2.13 (q, J = 7.1
Hz, 2H), 2.97−3.04 (m, 2H), 3.12 (q, J = 7.2 Hz, 2H), 4.39−4.49 (brm,
1H), 4.99−5.09 (m, 2H), 5.79 (ddt, J = 17.2, 10.3, 7.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ13.6, 21.5, 25.6, 29.4, 30.7, 42.6, 52.3, 115.6,
137.2. IR (neat) 3289, 2962, 1432, 1322, 1144, 1082 cm−1. MS (ESI)
calcd for C9H20NO2S [M + H]+ 206.1209, found 206.1212.
(1S)-10-Camphor-N-(pent-4-en-1-yl)sulfonamide (1e). Colorless
oil. 1H NMR (400 MHz, CDCl3) δ 0.92 (s, 3H), 1.03 (s, 3H), 1.42−1.50
(m, 1H), 1.71 (quin, J = 7.3 Hz, 2H), 1.91−2.09 (m, 3H), 2.10−2.27 (m,
4H), 2.36−2.43 (m, 1H), 2.91 (d, J = 15.2 Hz, 1H), 3.10−3.24 (m, 2H),
3.39 (d, J = 15.2 Hz, 1H), 4.97−5.10 (m, 2H), 5.13−5.20 (brm, 1H),
5.80 (ddt, J = 17.2, 10.5, 6.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
19.5, 19.9, 26.6, 27.0, 29.2, 30.7, 42.8, 42.9, 43.1, 48.8, 49.3, 59.2, 115.4,
137.4, 217.0. IR (neat) 3295, 2959, 1742, 1329, 1146, 1069 cm−1. MS
(ESI) calcd for C15H26NO3S [M + H]+ 300.1628, found 300.1624.
The catalytic Brønsted acid (TsOH or KSO4H) activates
Oxone as an electrophilic oxidant to form activated perox-
ymonosulfate intermediate (A)12 in situ. Intermediate (A)
promotes the intramolecular aminohydroxylation of N-alkenyl-
sulfonamides, particularly electron-poor monosubstituted ole-
fins. This reaction proceeds through a tandem reaction via the
epoxidation of olefins, followed by the exo-selective intra-
molecular amination of epoxides.12,13
Once prolinol derivatives 2 are formed, they are readily
transformed into N-sulfonyl proline derivatives 3 by the
treatment with (diacetoxyiodo)benzene (DIB) (2.2 equiv) and
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) (10 mol %) in a
1:1 mixture of MeCN and H2O at room temperature (Scheme
3).14 The reactions of 2a, 2g, 2i, 2j, and 2k gave corresponding
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Note
Table 2. Intramolecular Aminohydroxylation of N-Alkenylsulfonamides
a
d
b
c
Reaction was carried out at room temperature. Oxone (2.0 equiv) was used. Oxone (2.0 equiv) was used in a 2:1 mixture of MeCN and H2O.
Reaction was carried out without TsOH·H2O at 0 °C.
0.375 mmol) in a 1:1 mixture (1.5 mL) of MeCN and H2O was added
TsOH·H2O (4.8 mg, 0.025 mmol). The solution was stirred at 50 °C for
10 h. Saturated NaHCO3 aqueous solution (10 mL) was added to the
reaction mixture, and the product was extracted with AcOEt (15 mL ×
3). The combined extracts were washed with brine (10 mL) and dried
over Na2SO4. The organic phase was concentrated under reduced
pressure and the crude product was purified by silicagel column
chromatography (eluent: hexane/AcOEt = 2/1) to give desired product
2a (63.8 mg, >99% yield) as a colorless oil.
Scheme 2. Plausible Reaction Mechanism for Intramolecular
Aminohydroxylation of N-Alkenylsulfonamides
( )-(1-((4-Fluorophenyl)sulfonyl)pyrrolidin-2-yl)methanol (2b).
White solid (58.3 mg, 90% yield) mp 69−70 °C. 1H NMR (400
MHz, CDCl3) δ 1.45−1.54 (m, 1H), 1.65−1.77 (m, 2H), 1.77−1.89 (m,
1H), 2.68 (brs, 1H), 3.24 (dt, J = 10.4, 7.1 Hz, 1H), 3.48 (dt, J = 10.4, 6.2
Hz, 1H), 3.59−3.66 (m, 1H), 3.66−3.76 (m, 2H), 7.19−7.28 (m, 2H),
7.85−7.92 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 24.2, 28.9, 50.0,
61.9, 65.7, 116.5 (d, JC−F = 23.0 Hz) (2C), 130.2 (d, JC−F = 9.6 Hz) (2C),
133.0 (d, JC−F = 3.8 Hz), 165.3 (d, JC−F = 256.8 Hz). IR (KBr) 3534,
1493, 1332, 1237, 1155, 1093, 1042 cm−1. MS (ESI) calcd for
C11H14FNNaO3S [M + Na]+ 282.0571, found 282.0567.
General Procedure for the Intramolecular Aminohydroxyla-
tion of N-Alkenyl Sulfonamides (1) (Table 1, entry 10 and Table
2). To a solution of 1a (59.8 mg, 0.25 mmol) and Oxone (230.5 mg,
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Note
(brs, 1H), 3.36 (d, J = 14.6 Hz, 1H), 3.39−3.45 (m, 1H), 3.45−3.56 (m,
1H), 3.57−3.76 (m, 2H), 3.90−3.98 (m, 1H). 13C NMR (100 MHz,
CDCl3) δ 19.9, 20.1, 25.0, 25.4, 27.0, 29.0, 42.7, 42.9, 45.8, 48.0, 49.6,
58.4, 62.1, 65.6, 216.0. IR (neat) 3502, 1743, 1146, 1050 cm−1. MS (ESI)
calcd for C15H26NO4S [M + H]+ 316.1577, found 316.1572.
Scheme 3. Oxidative Transformation of 2 into 3
((5S)-5-Methyl-1-tosylpyrrolidin-2-yl)methanol (2f, Diastereomer
Mixtures). Colorless oil (63.2 mg, 94% yield, dr = 50:50). Major-
diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.17 (d, J = 6.6 Hz, 3H),
1.56−1.66 (m, 1H), 1.79−1.89 (m, 1H), 2.02−2.19 (m, 2H), 2.43 (s,
3H), 2.60 (brs, 1H), 3.58−3.78 (m, 3H), 4.16−4.25 (m, 1H), 7.30 (d, J
= 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
20.2, 21.5, 27.9 31.8, 57.8, 61.3, 65.5, 127.1 (2C), 129.6 (2C), 138.4,
143.2. Minor-diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.34 (d, J =
6.4 Hz, 3H), 1.43−1.54 (m, 2H), 1.55−1.78 (m, 2H), 2.44 (s, 3H), 2.87
(brs, 1H), 3.58−3.67 (m, 2H), 3.67−3.85 (m, 2H), 7.33 (d, J = 8.1 Hz,
2H), 7.74 (d, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5, 23.2,
27.2, 31.7, 58.3, 63.3, 66.1, 127.6 (2C), 129.8 (2C), 134.3, 143.7. IR
(neat) 3512, 1332, 1156, 1095, 1049 cm−1. MS (ESI) calcd for
C13H20NO3S [M + Na]+ 270.1158, found 270.1155.
((5R)-5-Isopropyl-1-tosylpyrrolidin-2-yl)methanol (2g). The dia-
stereomers were separeted by column chromatography. White solid
(67.6 mg, 91% yield, dr = 52:48). Major-diastereomer: 1H NMR (400
MHz, CDCl3) δ 0.92 (d, J = 7.9 Hz, 3H), 1.02 (d, J = 7.9 Hz, 3H), 1.16−
1.27 (m, 1H), 1.50−1.69 (m, 3H), 1.92−2.02 (m, 1H), 2.44 (s, 3H),
3.00 (brs, 1H), 3.49 (td, J = 7.6, 3.9 Hz, 1H), 3.58−3.68 (m, 3H), 7.33
(d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 17.8, 20.1, 21.5, 25.7, 27.1, 31.4, 63.0, 66.0, 68.4, 127.7 (2C),
a
b
2g (dr = 52:48) was used. 2k (dr = 54:46) was used.
1
129.7 (2C), 134.3, 143.7. Minor-diastereomer: H NMR (400 MHz,
Scheme 4. Synthesis of Proline Ethyl Ester 5a by
Desulfonylation of N-Sulfonamide 4a
CDCl3) δ 0.49 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H), 1.68−1.76
(m, 1H), 1.77−2.02 (m, 3H), 2.42 (s, 3H), 2.36−2.46 (m, 1H), 2.61−
2.68 (m, 1H), 3.76−3.85 (m, 3H), 3.94−4.00 (m, 1H), 7.29 (d, J = 8.1
Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 15.6,
19.8, 21.5, 23.8, 29.6, 29.8, 63.0, 65.3, 66.5, 126.8 (2C), 129.5 (2C),
138.5, 143.0. IR (KBr) 3520, 1469, 1328, 1155, 1045 cm−1. MS (ESI)
calcd for C15H24NO3S [M + H]+ 298.1471, found 298.1472.
( )-(2-Tosyl-2-azaspiro[4.5]decan-3-yl)methanol (2j). Colorless
1
oil (79.2 mg, 98% yield). H NMR (400 MHz, CDCl3) δ 0.51−0.59
(m, 1H), 0.66−0.76 (m, 1H), 1.05−1.47 (m, 8H), 1.51 (dd, J = 12.9, 9.7
Hz, 1H), 1.73 (dd, J = 12.9, 7.5 Hz, 1H), 2.44 (s, 3H), 3.16 (d, J = 11.2
Hz, 1H), 3.29 (dd, J = 8.3, 5.1 Hz, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.51−
3.59 (m, 1H), 3.66−3.74 (m, 1H), 3.74−3.83 (m, 1H), 7.33 (d, J = 8.5
Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5,
22.7, 23.7, 25.7, 33.8, 36.2, 40.7, 41.5, 59.6, 61.5, 66.0, 127.5 (2C), 129.7
(2C), 134.0, 143.8. IR (neat) 3500, 1450, 1336, 1157, 1092, 1036 cm−1.
MS (ESI) calcd for C17H26NO3S [M + Na]+ 324.1628, found 324.1624.
( )-(cis-1-Tosyloctahydro-1H-indol-2-yl)methanol (2k, Diaster-
eomer Mixtures). Colorless oil (69.6 mg, 90% yield, dr = 54:46).
( )-(1-((4-Nitrophenyl)sulfonyl)pyrrolidin-2-yl)methanol (2c). Yel-
low solid (55.8 mg, 78% yield) mp 93−94 °C. H NMR (400 MHz,
1
CDCl3) δ 1.50−1.60 (m, 1H), 1.67−1.77 (m, 1H), 1.77−1.96 (m, 2H),
2.51 (brs, 1H), 3.27 (dt, J = 10.6, 7.1 Hz, 1H), 3.53 (dt, J = 10.6, 6.3 Hz,
1H), 3.64−3.78 (m, 3H), 8.06 (d, J = 8.9 Hz, 2H), 8.40 (d, J = 8.9 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 24.2, 28.8, 50.0, 62.1, 65.5, 124.4
(2C), 128.7 (2C), 142.9, 150.2. IR (neat) 3567, 1532, 1349, 1163, 1095
cm−1. MS (ESI) calcd for C11H15N2O5S [M + H]+ 287.0696, found
287.0694.
1
Major-diastereomer: H NMR (400 MHz, CDCl3) δ 0.99−1.02 (m,
1H), 1.02−1.30 (m, 2H), 1.31−1.75 (m, 5H), 1.85−1.88 (m, 1H),
2.21−2.24 (m, 2H), 2.43 (s, 3H), 2.64 (t, J = 6.8 Hz, 1H), 3.62−3.73 (m,
1H), 3.73−3.86 (m, 2H), 3.96 (dt, J = 11.0, 5.8 Hz, 1H), 7.30 (d, J = 8.1
Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 19.8,
21.5, 23.6, 25.8, 27.5, 30.8, 35.6, 59.7, 62.1, 66.6, 127.3 (2C), 129.6 (2C),
( )-(1-(Butylsulfonyl)pyrrolidin-2-yl)methanol (2d). Colorless oil
(53.7 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.6 Hz,
3H), 1.47 (sext, J = 7.6 Hz, 2H), 1.78−1.92 (m, 4H), 1.92−2.00 (m,
1H), 2.01−2.12 (m, 1H), 2.67 (brs, 1H), 2.99 (dd, J = 9.0, 7.1 Hz, 2H),
3.35−3.49 (m, 2H), 3.55−3.69 (m, 2H), 3.82−3.90 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ 13.6, 21.7, 24.8, 25.1, 29.1, 48.9, 49.5, 61.5, 65.8.
IR (neat) 3504, 1327, 1144, 1050 cm−1. MS (ESI) calcd for C9H20NO3S
[M + H]+ 222.1158, found 222.1161.
(1-(1S)-10-Camphorsulfonyl)pyrrolidin-2-yl)methanol (2e, Dia-
stereomer Mixtures). Colorless oil (71.7 mg, 91% yield, dr = 55:45).
Major-diastereomer: 1H NMR (400 MHz, CDCl3) δ 0.90 (s, 3H), 1.14
(s, 3H), 1.38−1.49 (m, 1H), 1.61−1.72 (m, 1H), 1.81−2.16 (m, 7H),
2.34−2.44 (m, 1H), 2.47−2.59 (m, 1H), 2.81 (brs, 1H), 2.83 (d, J = 14.6
Hz, 1H), 3.42 (d, J = 14.6 Hz, 1H), 3.45−3.56 (m, 2H), 3.57−3.76 (m,
2H), 3.82−3.90 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 19.9, 20.1,
24.8, 25.4, 27.0, 29.3, 42.7, 42.9, 44.6, 48.2, 49.9, 58.5, 61.9, 65.8, 215.7.
Minor-diastereomer: 1H NMR (400 MHz, CDCl3) δ 0.90 (s, 3H), 1.13
(s, 3H), 1.38−1.49 (m, 1H), 1.61−1.72 (m, 1H), 1.81−2.16 (m, 7H),
2.34−2.44 (m, 1H), 2.47−2.59 (m, 1H), 2.91 (d, J = 14.6 Hz, 1H), 2.92
1
137.9, 143.2. Minor-diastereomer: H NMR (400 MHz, CDCl3) δ
1.02−1.30 (m, 3H), 1.31−1.75 (m, 7H), 1.92−2.03 (m, 1H), 2.44 (s,
3H), 3.17 (dd, J = 8.2, 4.8 Hz, 1H), 3.52−3.61 (m, 1H), 3.62−3.73 (m,
2H), 3.73−3.86 (m, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 20.1, 21.5, 24.3, 25.6, 30.9, 31.8,
36.0, 61.7, 62.6, 66.3, 127.4 (2C), 129.8 (2C), 134.6, 143.6. IR (neat)
3502, 1335, 1157, 1095, 1049 cm−1. MS (ESI) calcd for C16H24NO3S
[M + H]+ 310.1471, found 310.1465.
( )-(trans-1-Tosyloctahydro-1H-indol-2-yl)methanol (2l, Diaster-
eomer Mixtures). Colorless oil (60.3 mg, 78% yield, dr = 66:34). Major-
1
diastereomer: H NMR (400 MHz, CDCl3) δ 0.84−1.47 (m, 6H),
1.57−1.74 (m, 3H), 1.75−1.88 (m, 2H), 2.35 (td, J = 10.5, 3.4 Hz, 1H),
2.45 (s, 3H), 2.49−2.59 (m, 1H), 3.61−3.77 (m, 3H), 7.35 (d, J = 8.3
Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5,
24.6, 25.2, 29.8, 32.6, 33.1, 43.8, 62.1, 66.9, 67.4, 128.0 (2C), 129.7 (2C),
1
133.0, 143.7. Minor-diastereomer: H NMR (400 MHz, CDCl3) δ
0.84−1.47 (m, 6H), 1.57−1.74 (m, 3H), 1.75−1.88 (m, 2H), 2.05−2.15
9849
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The Journal of Organic Chemistry
Note
(m, 1H), 2.43 (s, 3H), 2.84 (ddd, J = 11.6, 10.5, 3.4 Hz, 1H), 3.04 (brs,
1H), 3.77−3.85 (m, 1H), 4.00−4.08 (m, 1H), 7.29 (d, J = 8.2 Hz, 2H),
7.74 (d, J = 8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5, 25.06,
25.07, 29.5, 29.8, 33.8, 44.7, 62.9, 66.0, 66.6, 127.0 (2C), 129.7 (2C),
139.1, 143.1. IR (neat) 3505, 1340, 1157, 1095, 1045 cm−1. MS (ESI)
calcd for C16H24NO3S [M + H]+ 310.1471, found 310.1468.
134.4, 144.0, 177.2. IR (KBr) 2963, 1729, 1345, 1159, 1093 cm−1. MS
(ESI) calcd for C14H20NO4S [M + H]+ 298.1108, found 298.1104.
( )-2-Tosyl-2-azaspiro[4.5]decane-3-carboxylic acid (3j). Color-
less oil (75.9 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 0.86−0.95
(m, 1H), 0.95−1.05 (m, 1H), 1.14−1.51 (m, 9H), 1.88−1.97 (m, 1H),
1.97−2.06 (m, 1H), 2.44 (s, 3H), 3.22 (d, J = 10.6 Hz, 1H), 3.25 (d, J =
10.6 Hz, 1H), 4.22 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.79 (d, J
= 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5, 22.9, 23.5, 25.6,
34.1, 35.3, 42.2, 42.7, 58.1, 59.8, 127.7 (2C), 129.7 (2C), 134.2, 144.0,
176.8. IR (neat) 3545, 1729, 1346, 1156, 1093, 1056 cm−1. MS (ESI)
calcd for C17H24NO4S [M + H]+ 338.1421, found 338.1411.
( )-syn-1-(1-Tosylpyrrolidin-2-yl)ethanol (2n). White solid (61.2
1
mg, 91% yield, dr = >99:<1) mp 73−74 °C. H NMR (400 MHz,
CDCl3) δ 1.18 (d, J = 6.2 Hz, 3H), 1.28−1.39 (m, 1H), 1.51−1.63 (m,
2H), 1.66−1.77 (m, 1H), 2.44 (s, 3H), 3.32−3.45 (m, 3H), 3.45−3.53
(m, 1H), 3.67−3.76 (m, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1
Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 19.4, 21.5, 24.5, 28.4, 49.8,
66.4, 69.7, 127.6 (2C), 129.8 (2C), 134.2, 143.9. IR (KBr) 3523, 1327,
1153, 1105, 1079 cm−1. MS (ESI) calcd for C13H20NO3S [M + H]+
270.1158, found 270.1158.
( )-cis-1-Tosyloctahydro-1H-indole-2-carboxylic acid (3k, dia-
stereomer mixtures). White solid (80.8 mg, >99% yield, dr = 51:49).
1
Major-diastereomer: H NMR (400 MHz, CDCl3) δ 1.01−1.35 (m,
3H), 1.36−1.72 (m, 4H), 1.72−1.82 (m, 1H), 2.03−2.13 (m, 2H), 2.19
(td, J = 12.6, 8.9 Hz, 1H), 2.45 (s, 3H), 2.54−2.65 (m, 1H), 3.66 (dt, J =
11.0, 6.3 Hz, 1H), 4.20 (t, J = 8.9 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.78
(d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 20.3, 21.5, 23.4,
25.6, 29.5, 32.4, 37.3, 59.1, 60.5, 127.6 (2C), 129.5 (2C), 137.7, 143.4,
178.3. Minor-diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.01−1.35
(m, 3H), 1.36−1.72 (m, 6H), 1.82−1.92 (m, 1H), 1.94 (dd, J = 13.1, 6.3
Hz, 1H), 2.33 (td, J = 13.1, 9.6 Hz, 1H), 2.43 (s, 3H), 3.75−3.86 (m,
1H), 4.40 (d, J = 9.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3
Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 20.1, 21.5, 23.7, 25.6, 28.5,
32.6, 35.8, 59.7, 60.7, 127.6 (2C), 129.8 (2C), 135.0, 143.9, 177.6. IR
(KBr) 2932, 1725, 1340, 1157, 1096 cm−1. MS (ESI) calcd for
C16H22NO4S [M + H]+ 324.1264, found 324.1256.
( )-anti-1-(1-Tosylpyrrolidin-2-yl)ethanol (2o). Colorless oil (55.2
mg, 82% yield, dr =77:23). 1H NMR (400 MHz, CDCl3) δ 1.17 (d, J =
6.4 Hz, 3H), 1.24−1.32 (m, 1H), 1.59−1.69 (m, 1H), 1.69−1.89 (m,
2H), 2.44 (s, 3H), 2.62 (brs, 1H), 3.32−3.43 (m, 2H), 3.48−3.54 (m,
1H), 4.15−4.24 (m, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.5 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 18.3, 21.5, 24.5, 26.0, 50.5, 65.7,
69.0, 127.6 (2C), 129.7 (2C), 133.9, 143.7. IR (KBr) 3506, 1337, 1158,
1092, 999 cm−1. MS (ESI) calcd for C13H19NNaO3S [M + Na]+
292.0978, found 292.0973.
( )-(2-Methyl-1-tosylpyrrolidin-2-yl)methanol (2p). White solid
1
(52.5 mg, 78% yield) mp 64−65 °C. H NMR (400 MHz, CDCl3) δ
1.25 (s, 3H), 1.58−1.68 (m, 1H), 1.71−1.93 (m, 2H), 2.14 (dt, J = 12.4,
7.9 Hz, 1H), 2.43 (s, 3H), 2.66 (brs, 1H), 3.33−3.41 (m, 1H), 3.48 (dt, J
= 9.4, 7.2 Hz, 1H), 3.59 (dd, J = 11.7, 5.4 Hz, 1H), 3.89 (dd, J = 11.7, 3.8
Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 21.5, 22.2, 22.4, 38.1, 50.3, 68.9, 69.1, 127.2 (2C),
129.6 (2C), 137.8, 143.2. IR (KBr) 3527, 1325, 1152, 1094, 1052 cm−1.
MS (ESI) calcd for C13H19NNaO3S [M + Na]+ 292.0978, found
292.0970.
General Procedure for the Transformation of N-Sulfonyl
Prolinol Derivatives (2) into N-Sulfonyl Proline Derivatives (3)
by Oxidation with DIB/TEMPO System (Scheme 3). To a solution
of 2a (63.8 mg, 0.25 mmol) and DIB (177.1 mg, 0.55 mmol) in a 1:1
mixture (1.5 mL) of MeCN and H2O was added TEMPO (3.9 mg, 0.025
mmol), and the solution was stirred at room temperature for 12 h.
Saturated NaHCO3 aqueous solution (10 mL) was added to the reaction
mixture. The product was basified to pH 10 with 1N NaOH aq., and
washed with AcOEt (15 mL × 3). The aqueous layer was acidified to pH
3 with 1N HCl aq., extracted with CHCl3 (15 mL × 3), and dried over
Na2SO4. The organic phase was concentrated under reduced pressure to
give the desired product 3a (59.2 mg, 88% yield) as a white solid without
further purification.
(5R)-5-Isopropyl-1-tosylpyrrolidine-2-carboxylic acid (3g, Diaster-
eomer Mixtures). White solid (72.3 mg, 93% yield, dr = 55:45). Major-
diastereomer: 1H NMR (400 MHz, CDCl3) δ 0.93 (d, J = 6.9 Hz, 3H),
1.00 (d, J = 6.9 Hz, 3H), 1.34−1.45 (m, 1H), 1.71−1.87 (m, 2H), 2.02−
2.17 (m, 2H), 2.45 (s, 3H), 3.53 (dd, J = 11.9, 7.1 Hz, 1H), 4.17 (dd, J =
8.3, 6.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 9.25
(brs, 1H). 13C NMR (100 MHz, CDCl3) δ 17.2, 20.1, 21.6, 26.0, 28.3,
31.1, 62.0, 68.1, 127.7 (2C), 129.9 (2C), 133.8, 144.3, 175.2. Minor-
diastereomer: 1H NMR (400 MHz, CDCl3) δ 0.51 (d, J = 6.9 Hz, 3H),
0.83 (d, J = 6.9 Hz, 3H), 1.70−1.84 (m, 1H), 1.96−2.19 (m, 3H), 2.24−
2.37 (m, 1H), 2.43 (s, 3H), 3.98−4.04 (m, 1H), 4.51 (d, J = 7.3 Hz, 1H),
7.29 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 9.25 (brs, 1H). 13C
NMR (100 MHz, CDCl3) δ 14.8, 19.7, 21.5, 23.7, 29.5, 29.8, 62.3, 64.9,
127.0 (2C), 129.4 (2C), 138.1, 143.2, 178.5. IR (KBr) 2965, 1728, 1344,
1159, 1090, 1019 cm−1. MS (ESI) calcd for C15H22NO4S [M + H]+
312.1264, found 312.1258.
Transformation of N-Tosyl Proline (3a) into Proline Ethyl
Ester (5a) by Detosylation under Mild Conditions (Scheme 4).
The solution of N-tosyl proline (3a) (53.8 mg, 0.20 mmol) and K2CO3
(55.2 mg, 0.40 mmol) in DMF (1.0 mL) was added EtI (24.1 μL, 0.30
mmol). The solution was stirred at room temperature for 14 h under
argon atmosphere. 1N HCl solution (3 mL) was added to the reaction
mixture, and the product was extracted with AcOEt (10 mL × 3). The
combined extracts were washed with brine (10 mL) and dried over
Na2SO4. The organic phase was concentrated under reduced pressure
and the crude product was purified by silicagel column chromatography
(eluent: hexane/AcOEt = 4/1) to give N-tosyl proline ethyl ester (4a)
(59.4 mg, >99% yield) as a white solid.
The solution of N-tosyl proline ethyl ester (4a) (74.3 mg, 0.25 mmol)
and phenol (47.0 mg, 0.50 mmol) and 25% HBr in acetic acid (1 mL)
was stirred at room temperature for 24 h under argon atmosphere. This
reaction mixture was concentrated under reduced pressure to give
proline ethyl ester (5a) (52.6 mg, 94%) as a brown oil.
( )-Ethyl pyrrolidine-2-carboxylate hydrobromide (5a). 1H NMR
(400 MHz, CDCl3) δ 1.34 (t, J = 7.3 Hz, 3H), 2.02−2.27 (m, 3H), 2.41−
2.53 (m, 1H), 3.53−3.69 (m, 2H), 4.32 (q, J = 7.3 Hz, 2H), 4.49−4.60
(m, 1H), 8.52 (brs, 1H), 10.3 (brs, 1H). 13C NMR (100 MHz, CDCl3) δ
14.1, 23.7, 28.8, 46.2, 59.3, 63.3, 168.7. IR (neat) 3427, 1739, 1630,
1241, 1043 cm−1. MS (ESI) calcd for C7H14NO2 [M]+ 144.1019, found
144.1015.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds in the intramolecular
aminohydroxylation, in the oxidation using a DIB/TEMPO
system, and in the derivatization in Scheme 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*moriyama@faculty.chiba-u.jp; togo@faculty.chiba-u.jp
■
Notes
( )-4,4-Dimethyl-1-tosylpyrrolidine-2-carboxylic acid (3i). White
solid (70.6 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 0.74 (s, 3H),
1.09 (s, 3H), 1.91−2.02 (m, 2H), 2.44 (s, 3H), 3.10 (d, J = 10.0 Hz, 1H),
3.21 (t, J = 10.0 Hz, 1H), 4.29 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.3 Hz,
2H), 7.79 (d, J = 8.3 Hz, 2H), 10.43 (brs, 1H). 13C NMR (100 MHz,
CDCl3) δ 21.6, 25.5, 25.7, 38.8, 44.2, 60.4, 60.7, 127.7 (2C), 129.7 (2C),
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. 24750033) from the Ministry of Education,
■
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The Journal of Organic Chemistry
Note
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Iodine Research Project in Chiba University is gratefully
acknowledged.
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