Selective Deprotection of N -Tosyl Alkoxyamines Using Bistrifluoromethane Sulfonimide: Formation of Oxime Ethers

Article abstract of DOI:10.1055/s-0037-1610298

The detosylation of N -tosyl alkoxyamines was realized by treatment with benzaldehyde and bistrifluoromethane sulfonimide as the catalyst to afford the corresponding oxime ethers. The reaction is chemoselective as N -tosyl amines are not deprotected. A me

Full text of DOI:10.1055/s-0037-1610298

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
M. S. Azizi, J. Cossy
Letter
Synlett
Selective Deprotection of N-Tosyl Alkoxyamines Using
Bistrifluoromethane Sulfonimide: Formation of Oxime Ethers
Mohamed Salah Azizi
O
O
HNTf2 (10 mol%)
CH2Cl2, 40 °C, 18 h
O
O
O
S
R
N
Janine Cossy*
0
0
0
0
0-
0
0
1
8-
7
4
6
9-
2
3
9
TsOH
+
R
N
+
H
H
40–73%
R'
Laboratory of Organic Chemistry, Institute of Chemistry,
Biology and Innovation (CBI), ESPCI Paris, PSL Research
University, CNRS, 10 Rue Vauquelin, 75231 – Paris Cedex
05, France
R'
metal-free
R' = H, OMe
10 examples
Janine.Cossy@espci.fr
Ph
R =
Received: 24.07.2018
Accepted after revision: 12.09.2018
Published online: 02.10.2018
are notoriously difficult to cleave. A number of methods has
been reported such as electrolysis,1 Li/naphthalene,2 Birch
reduction conditions,3 refluxing in HCl,4 Ni(acac)2/iPrMgCl,5
TiCl4,6 Mg/MeOH,7 Bu3SnH/AIBN,8 Na/K metal on silica,9
Mg/Me3CoLi,10 SmI2/HMPA or SmI2/DMPU,11 SmI2/ROH,12
and SmI2/H2O/amine.13
During our study dealing with the reactivity of N-tosyl
alkoxyamines,14 we observed that, when a N-tosyl alkoxy-
amine was treated with an aromatic aldehyde under acidic
conditions, a detosylation occurred and an oxime ether was
formed (Scheme 1).
DOI: 10.1055/s-0037-1610298; Art ID: st-2018-d0471-l
Abstract The detosylation of N-tosyl alkoxyamines was realized by
treatment with benzaldehyde and bistrifluoromethane sulfonimide as
the catalyst to afford the corresponding oxime ethers. The reaction is
chemoselective as N-tosyl amines are not deprotected. A mechanism is
proposed for this deprotection.
Key words N-detosylation, bistrifluoromethane sulfonimide, N-tosyl-
alkoxyamine, benzaldehyde, oxime ethers
PhCHO
RO
N
Protection and subsequent deprotection of amines are
routine procedures used in multistep synthesis of polyfunc-
tionalized molecules. Among the diverse protecting groups
of amines, the tosyl group is one of the most versatile one.
N-Tosyl amines are readily formed, easy to purify, and
are stable under a variety of conditions. However, the ro-
bustness of N-tosyl amines can be a disadvantage and they
RO NHTs
+
Ph
H
A
B
Scheme 1 One-step N-detosylation/oximation under acidic conditions
Our study started with N-tosyl alkoxyamine 1 (Table 1).
When this N-tosyl alkoxyamine was treated with benzalde-
hyde (PhCHO, 2 equiv) in the presence of different Brønsted
Table 1 Optimization Studies: Effect of the Acid
O
O
O
O
S
O
acid (10 mol%)
N
N
H
H
+
(x equiv)
18 h, 0.25 M
9
1
Entry
Acid
MeCO2H
Solvent
Temp (°C)
x equiv
Conversion (%)
Yield (%)a
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40
40
40
40
40
40
2
2
2
2
1
2
5
13
24
100
60
8
0
0
CF3CO2H
PTSA
18
65
40
0
HNTf2
HNTf2
FeCl3
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
M. S. Azizi, J. Cossy
Letter
Synlett
acids (10 mol%) with increasing acidity such as CH3CO2H,
CF3CO2H, PTSA only a low conversion of 1 was noticed and
no identifiable compounds were formed, except in the pres-
ence of PTSA as 9 was isolated with a yield of 18% (Table 1,
entry 3). By using a very strong Brønsted acid such as bistri-
fluoromethane sulfonimide15 (HNTf2, 10 mol%), in CH2Cl2 at
40 °C, the conversion of 1 was total and oxime 9 was isolat-
ed with a yield of 65% (Table 1, entry 4). By decreasing
benzaldehyde from 2 to 1 equivalent, the conversion of 1
was decreased (60% instead of 100%) and the yield of 9 was
only 40% (Table 1, entry 5). It is worth mentioning that the
use of a Lewis acid such as FeCl3 induced a very low conver-
sion of 1 and 9 was not observed (Table 1, entry 6).
As HNTf2 was revealed to be the best Brønsted acid to
convert 1 into oxime 9,16,17 in the presence of 2 equivalents
of benzaldehyde, a screening of the conditions, e.g., solvent,
temperature, and concentration of 1 was undertaken (Table
2). This screening revealed that CH2Cl2 was the best solvent
(Table 2, entries 1–3) and 40 °C the optimum temperature
(Table 2, entries 4and 5). The best yield of 9 was obtained
when 10 mol% of HNTf2 were used (Table 2, entry 6). In ad-
dition, a decrease in the concentration of 1 led to a decrease
in the yield of 9 (Table 2, entry 7).
were reacted with 1, the conversion of 1 was low and no
traces of the corresponding oxime ethers were detected by
1H NMR analysis of the crude reaction mixtures (Table 3,
entries 5–8).
With the optimized conditions, the scope was further
examined by treating different N-tosyl alkoxyamines with 2
equivalents of benzaldehyde and 10 mol% of HNTf2, at 40 °C
in CH2Cl2. Whatever the nature of the N-tosyl alkoxyamine,
the yields were in the range of 57–73%. The results are re-
ported in Scheme 2.
O
O
O
PhCHO (2 equiv)
HNTf2 (10 mol%)
O
S
R
N
R
N
H
CH2Cl2, 40 °C
18 h
9–16
1–8
O
N
O
N
9 (65%)
10 (66%)
O
N
O
N
11 (71%)
12 (73%)
Having optimized conditions,18 the generalization of the
reaction was studied. N-Tosyl alkoxyamine 1 was applied in
the detosylation/oxime formation with different aldehydes
in the presence of 10 mol% of bistrifluoromethane sul-
fonimide (HNTf2, 10 mol%), and the results are reported in
Table 3.
When electron-rich aromatic aldehydes were used, the
conversion of 1 and the yield in the corresponding oxime
ethers (1719 and 1820) was lower than when using benzal-
dehyde (Table 3, entries 2–4). When aliphatic aldehydes
O
O
N
N
13 (60%)
14 (69%)
16 (57%)
O
N
N
O
15 (62%)
Scheme 2 Scope of the reaction. Isolated yields are given.
Table 2 Optimization Studies: Reaction Conditions
O
O
O
O
S
O
HNTf2 (y mol%)
N
N
H
H
+
(2 equiv)
18 h
9
1
Entry
Solvent
Temp
(°C)
c
(M)
y
Conversion (%)
Yield (%)a
1
2
3
4
5
6
7
CH2Cl2
C2H4Cl2
THF
40
40
40
r.t.
70b
40
40
0.25
10
10
10
10
10
5
100
86
55
52
82
60
60
65
60
37
38
53
40
36
0.25
0.25
0.25
0.25
0.25
0.10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
a Isolated yield.
b With microwave irradiation.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
M. S. Azizi, J. Cossy
Letter
Synlett
Table 3 Optimization Studies: Effect of the Aldehyde
O
O
O
O
S
O
N
HNTf2 (10 mol%)
N
R'
H
+
R'
H
CH2Cl2, 40 °C
18 h
1 (1 equiv)
(2 equiv)
O
O
Entry
1
Yield (%)a
N
R'
R'
H
O
O
O
N
65
H
9
O
H
N
2
3
51
40
17
OMe
OMe
MeO
OMe
O
H
OMe
O
N
18
MeO
HO
O
H
4
5
–
–
0
0
OH
O
H
H
4
O
6
7
–
–
0
0
O
H
a Isolated yield.
It is worth mentioning that the reaction is chemoselec-
tive. When 5 and N-tosyl sulfonamide 19 were treated with
benzaldehyde in the presence of HNTf2, only the N-tosyl
alkoxyamine 5 was transformed into the oxime ether 13,21
and 19 was recovered (Scheme 3).
With this latter result, we can exclude the activation of
the N-tosyl group by HNTf2. Thus, the formation of oxime
ethers B from N-tosyl alkoxyamines A can be explained by
the activation of benzaldehyde by HNTf2, with A being
nucleophilic enough to attack the activated benzaldehyde.
Intermediate C can be produced, which after 1,3-prototro-
py, leads to D. The nucleophilic attack of H2O on D then pro-
duces B and TsOH (Scheme 4).
In summary, the use of bistrifluoromethane sulfonim-
ide in the presence of benzaldehyde allows the chemoselec-
tive N-detosylation/oximation of N-tosyl-alkoxyamines.
This metal-free method can be useful to prepare biological-
ly active oxime ether derivatives.
O
ONHTs
N
Ph
13 (61%)
5
PhCHO
(4 equiv)
+
+
HNTf2
(20 mol%)
CH2Cl2, 40 °C
18 h
Ph
Ts
Ph
Ph
Ts
Ph
H
N
H
N
19 (96%)
19
Scheme 3 Reactivity of N-tosyl alkoxyamine vs N-tosyl amine
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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M. S. Azizi, J. Cossy
Letter
Synlett
(10) Uchiyama, M.; Matsumoto, Y.; Nakamura, S.; Ohwada, T.;
Kobayashi, N.; Yamashita, N.; Matsumiya, A.; Sakamoto, T. J. Am.
Chem. Soc. 2004, 126, 8755.
H
O
O
HNTf2
H
H
H
(11) (a) Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602. (b) Alonso, D.
A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455. (c) Fujihara, H.;
Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055.
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2004, 43, 6125. (e) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.;
Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128. (f) Grach, G.;
Santos, J. S. O.; Lohier, J.; Mojovic, L.; Plé, N.; Turck, A.; Reboul,
V.; Metzner, P. J. Org. Chem. 2006, 71, 9572. (g) Duan, H.; Jia, Y.;
Wang, L.; Zhou, Q. Org. Lett. 2006, 8, 2567.
(12) (a) Knowles, H.; Parsons, A. F.; Pettifer, R. M. Synlett 1997, 271.
(b) Fresneda, P.; Molina, P.; Sanz, M. Tetrahedron Lett. 2001, 42,
851. (c) Wang, S.; Dilley, A.; Poullennec, K.; Romo, D. Tetrahe-
dron 2006, 62, 7155. (d) Trost, B. M.; Dong, G. J. Am. Chem. Soc.
2006, 128, 6054. (e) Moussa, Z.; Romo, D. Synlett 2006, 3294.
(f) Kumar, V.; Ramesh, N. G. Chem. Commun. 2006, 4952.
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(13) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503.
(14) Escudero, J.; Bellosta, V.; Cossy, J. Angew. Chem. Int. Ed. 2018, 57,
574.
N
SO2Ar
RO
A
H
H
O
H
O
1,3-prototropy
H
SO2Ar
N
N
SO2Ar
OR
OR
– H2O
C
D
OR
– TsOH
N
B
Scheme 4 Proposed mechanism
Supporting Information
(15) (a) Mendoza, O.; Rossey, G.; Ghosez, L. Tetrahedron Lett. 2011,
52, 2235; and references therein. (b) Cossy, J.; Lutz, F.; Alauze,
V.; Meyer, C. Synlett 2002, 45.
(16) Compound 9 was isolated as a mixture of E- and Z-isomers in a
ratio 96:4.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610298.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(17) Spectral Data of (E)-9
References and Notes
IR: ν = 2923, 1640, 1446, 1373, 1335, 1210, 1089, 967, 910, 900
cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.60–7.50 (m,
2 H), 7.40–7.30 (m, 3 H), 5.85 (m, 1 H), 5.04 (dqapp, J = 17.0, 1.8
Hz, 1 H), 4.97 (m, 1 H), 4.32 (m, 1 H), 2.18 (m, 2 H), 1.83 (m, 1
H), 1.59 (m, 1 H), 1.30 (d, J = 6.2 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 145.2, 138.4, 130.8, 129.7, 128.4 (2 C), 126.9 (2 C),
114.6, 79.9, 34.8, 29.7, 19.2. MS (EI): m/z = 203 (13) [M+•], 202
(40), 188 (8), 158 (8), 132 (3), 122 (7), 121 (10), 120 (9), 104
(42), 94 (4), 89 (5), 82 (6), 78 (9), 77 (47), 67 (15), 65 (8), 55
(100), 51 (13).
(1) (a) Maia, H. L. S.; Medeiros, M. J.; Montenegro, M. I.; Court, D.;
Pletcher, D. J. Electroanal. Chem. 1984, 164, 347. (b) Civitello, E.
R.; Rapoport, H. J. Org. Chem. 1992, 57, 834. (c) Coeffard, V.;
Thobie-Gautier, C.; Beaudet, I.; Le Grognec, E.; Quintard, J. P.
Eur. J. Org. Chem. 2008, 383.
(2) Alonso, E.; Ramón, D. J.; Yus, M. Tetrahedron 1997, 53, 14355.
(3) (a) Dahlén, A.; Hilmersson, G. Tetrahedron Lett. 2002, 43, 7197.
(b) Dahlén, A.; Hilmersson, G. Chem. Eur. J. 2003, 9, 1123.
(c) Dahlén, A.; Hilmersson, G. Tetrahedron Lett. 2003, 44, 2661.
(d) Dahlén, A.; Hilmersson, G.; Knettle, B. W.; Flowers, R. A. J. Org.
Chem. 2003, 68, 4870. (e) Dahlén, A.; Petersson, A.; Hilmersson, G.
Org. Biomol. Chem. 2003, 1, 2423. (f) Kim, M.; Dahlén, A.;
Hilmersson, G.; Knettle, B. W.; Flowers, R. A. II. Tetrahedron
2003, 59, 10397. (g) Dahlén, A.; Sundgren, A.; Lahmann, M.;
Oscarson, S.; Hilmersson, G. Org. Lett. 2003, 5, 4085. (h) Davis, T.
A.; Chopade, P. R.; Hilmersson, G.; Flowers, R. A. Org. Lett. 2005,
7, 119. (i) Dahlén, A.; Hilmersson, G. J. Am. Chem. Soc. 2005, 127,
8340. (j) Dahlén, A.; Nilsson, Å.; Hilmersson, G. J. Org. Chem.
2006, 71, 1576. (k) Ankner, T.; Hilmersson, G. Tetrahedron Lett.
2007, 48, 5707.
(4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Syn-
thesis; John Wiley and Sons: New York, 2007, 4th ed..
(5) Milburn, R. R.; Snieckus, V. Angew. Chem. Int. Ed. 2004, 43, 892.
(6) Vellemäe, E.; Lebedev, O.; Mäeorg, U. Tetrahedron Lett. 2008, 49,
1373.
(7) (a) Nyasse, B.; Ragnarsson, U. Chem. Commun. 1997, 1017.
(b) Sridhar, M.; Kumar, B. A.; Narender, R. Tetrahedron Lett.
1998, 39, 2847.
(18) General Procedure for the Synthesis of Oxime Ethers from N-
Tosyl Alkoxyamines
In a round-bottom flask, a mixture of a solution of N-tosyl
alkoxyamide (0.2 mmol, 1 equiv) in anhydrous CH2Cl2 (c = 0.25
M), aldehyde (2 equiv), and a solution of HNTf2 (0.1 equiv) in
anhydrous CH2Cl2 was stirred at 40 °C for 18 h. The reaction
mixture was cooled to r.t. and saturated aqueous Na2CO3 was
added. The two phases were separated, and the aqueous layer
was extracted four times with CH2Cl2. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate) to
obtain the desired oxime ether.
(19) Spectroscopic Data for 17
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.52–7.49 (m, 2 H),
6.90–6.70 (m, 2 H), 5.85 (m, 1 H), 5.04 (dqapp, J = 17.1, 1.8 Hz,
1 H), 4.96 (m, 1 H), 4.29 (m, 1 H), 3.82 (s, 3 H), 2.20–2.15 (m, 2
H), 1.81 (m, 1 H), 1.60 (m, 1 H), 1.29 (d, J = 6.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 160.7, 147.5, 138.5, 128.3 (2 C), 125.4,
114.5, 114.1 (2C), 78.7, 55.3, 34.9, 29.7, 19.8. MS (EI): m/z = 233
(22) [M+•], 232 (33), 218 (26), 188 (11), 174 (13), 162 (10), 151
(41), 150 (22), 147 (15), 146 (9), 136 (20), 135 (58), 134 (78),
108 (50), 107 (20), 92 (19), 91 (12), 77 (36), 67 (6), 55 (100), 51
(7). HRMS (ESI): m/z calcd for C14H20NO2 [M + H]+: 234.1489;
found: 234.1485.
(8) Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling, S. Tetrahe-
dron 2000, 56, 979.
(9) Lefenfeld, M.; Dye, J. L.; Nandi, P.; Jackson, J. WO 2007095276,
2007.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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M. S. Azizi, J. Cossy
Letter
Synlett
(20) Spectroscopic Data for (E)-18
(44), 120 (18), 107 (16), 92 (10), 91 (10), 79 (11), 77 (22), 67
(10), 55 (59). HRMS (ESI): m/z calcd for C15H22NO3 [M + H]+:
264.1594; found: 264.1591.
IR: ν = 3077, 2969, 2936, 2838, 1607, 1572, 1504, 1463, 1438,
1418, 1372, 1311, 1283, 1270, 1208, 1159, 1120, 1107, 1068,
1034, 993, 965 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.37 (s, 1
(21) Spectroscopic Data for 13
H), 7.72 (d, J = 8.6 Hz, 1 H), 6.48 (dd, J = 8.6, 0.5 Hz, 1 H), 6.42 (d,
J = 2.3 Hz, 1 H), 5.85 (m, 1 H), 5.03 (dqapp, J = 17.1, 1.8 Hz, 1 H),
4.95 (m, 1 H), 4.28 (m, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 2.17 (m, 2
H), 1.81 (m, 1 H), 1.60 (m, 1 H), 1.29 (d, J = 6.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 162.1, 158.7, 143.9, 138.6, 127.2, 114.4,
114.3, 105.3, 98.2, 78.5, 55.5, 55.4, 34.9, 29.7, 19.8. MS (EI) m/z:
263 (M+., 12), 204 (10), 192 (11), 177 (14), 166 (10), 164 (37),
163 (15), 150 (18), 149 (100), 137 (12), 134 (14), 122 (14), 121
IR: ν = 3073, 2925, 1573, 1448, 1340, 1273, 1210, 1046, 944,
913 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.60–7.55
(m, 2 H), 7.40–7.30 (m, 3 H), 5.87 (m, 1 H), 5.06–5.00 (m, 2 H),
4.04 (s, 2 H), 2.17 (dtapp, J = 7.5 Hz, 0.9 Hz, 2 H), 1.43 (m, 10 H).
13C NMR (100 MHz, CDCl3): δ = 147.7, 134.8, 132.5, 129.5, 128.6
(2 C), 126.8 (2 C), 117.3, 79.5, 40.1, 37.2, 32.7 (2 C), 26.2, 21.4 (2
C). MS (EI): m/z = 257 (14), 256 (36), 132 (5), 122 (62), 106
(100), 104 (58), 95 (30), 93 (12), 81 (64), 79 (20), 69 (13), 55
(30), 51 (13).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E