Reactions of N,N-bis(silyloxy)enamines with sulfur-centered and sulfur-stabilised electrophiles

Article abstract of DOI:10.1070/MC2003v013n02ABEH001720

The coupling of N,N-bis(silyloxy)enamines with arylsulfenyl chlorides and episulfonium cations proceeds as an electrophilic attack at the β-carbon atoms of N,N-bis(silyloxy)enamines and affords functionalised aliphatic compounds.

Full text of DOI:10.1070/MC2003v013n02ABEH001720

, 2003, 13(2), 74–76
Reactions of N,N-bis(silyloxy)enamines with sulfur-centered and sulfur-stabilised
electrophiles†
Aleksei V. Ustinov, Alexander D. Dilman, Sema L. Ioffe,* Yuri A. Strelenko, William A. Smit
and Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5860; e-mail: ioffe@ioc.ac.ru
10.1070/MC2003v013n02ABEH001720
The coupling of N,N-bis(silyloxy)enamines with arylsulfenyl chlorides and episulfonium cations proceeds as an electrophilic
attack at the β-carbon atoms of N,N-bis(silyloxy)enamines and affords functionalised aliphatic compounds.
Doubly silylated derivatives of aliphatic nitro compounds –
N,N-bis(silyloxy)enamines (BENA) 1 – represent a hybrid of
conventional enamines with dialkoxyamines.2 As a conse-
quence, these species are endowed with reactivity toward
coupling with both nucleophiles3,4 and electrophiles.5
Recently, we demonstrated that BENA are much less nucleo-
philic than N,N-dialkylenamines, and are similar in reactivity to
silyl enol ethers.6 Thus, the interaction of BENA with acetals5
and benzhydrilium derivatives6 affords nitro compounds, thereby
resulting in the functionalization of the β-carbon atom of
starting nitro substrates (Scheme 1). Here, we report on an
extension of this methodology by employing sulfur-centered
and sulfur-stabilised electrophiles.
The structures of the obtained products were confirmed by
1H, 13C and 14N NMR spectroscopy,§ and the elemental com-
position was confirmed by microanalysis.
Note that BENA, possessing hydrogen at the α-position
(R1 = H), may be successfully involved in this reaction. Indeed,
previously we could not isolate any products from interaction of
α-unsubstituted BENA with strong carbocationic electrophiles
paired with non-nucleophilic counterion presumably owing to
the extreme reactivity of the unsubstituted iminium ion. In the
present system, the chloride ion suppresses possible side reactions
by the rapid desilylation of the initially formed iminium ion A.
As sulfur stabilised cations, we tested episulfonium ions,
which can be easily generated from alkyl enol ethers, arene-
sulfenyl chloride, and Me3SiOTf (Scheme 2). The reaction of
cations C with BENA occurs at –78 °C.¶ Apparently, the
equilibrium mixture of species A' and B' was first formed. The
subsequent addition of the external chloride ion (BnNEt3+ Cl–)
shifts the equilibrium to the right. Finally, the hydrolysis of
silylnitronate with an NEt3/AcOH mixture affords nitro com-
pounds 4 as a 1:1 mixture of diastereomers.†† The reaction is
applicable only to BENA containing a substituent at the
α-position (R1 ¹ H). Attempts to involve α-unsubstituted enol
i, E+
NO2
N(OSiMe3)2 ii, AcOH/NEt3
iii, MeOH
NO2
Me3SiX
NEt3
E
R1
R1
R1
R2
R2
R2
1a–d
E+ = ArCH(OMe)+ (ref. 5)
Ar2CH+ (ref. 6)
‡
N(OSiMe3)2
SAr
N(O)OSiMe3
All reactions were carried out in an atmosphere of dry argon using
ArSCl
2a,b
– Cl–
Cl–
– Me3SiCl
dry solvents. Starting BENA were obtained by a previously described
SAr
R1
R1
1a–d
procedure.7
R2
R2
General procedure for the preparation of 3a–f. To ArSCl (0.6 mmol)
in toluene (1.5 ml) and CH2Cl2 (0.5 ml) neat Pr2i NEt (0.03 mmol, 5.2 µl)
was added at –78 °C; then, a solution of BENA 1 (0.6 mmol) in toluene
(1 ml) was added dropwise. After stirring for 30 min at –78 °C, the solu-
tions of Et3N (0.72 mmol) in toluene (0.5 ml) and AcOH (1.3 mmol) in
MeOH (0.5 ml) were added successively. The resulting mixture was
warmed to room temperature and stirred for 30 min; then, it was poured
into a two-phase mixture of 20 ml Et2O and 20 ml of H2O; the aqueous
layer was extracted three times with Et2O; the organic phase was washed
with brine, dried over Na2SO4 and concentrated in vacuo. Purification of
the residue using flash chromatography (SiO2; light petroleum–EtOAc,
10:1) gave 1-(4-tolyl)thio-2-nitropropane 3a: Rf 0.16 (light petroleum–
EtOAc, 10:1), oil. Found (%): C, 56.78; H, 6.11; N, 6.48; S 14.99. Calc.
for C10H13NO2S (%): C, 56.85; H, 6.20; N, 6.63; S 15.18.
1-(4-Tolyl)thio-2-nitroethane 3b: Rf 0.45 (light petroleum–EtOAc,
3:1), oil. Found (%): C, 54.77; H, 5.60; N, 7.04; S, 16.01. Calc. for
C9H11NO2S (%): C, 54.80; H, 5.62; N, 7.10; S, 16.26.
1-(4-Chlorophenyl)thio-2-nitropropane 3c. Rf 0.42 (light petroleum–
EtOAc, 3:1), oil. Found (%): C, 46.12; H, 4.39; N, 5.12; S, 13.62; Cl,
15.06. Calc. for C9H10ClNO2S (%): C, 46.65; H, 4.35; N, 6.05; S, 13.84;
Cl, 15.30.
1-(4-Chlorophenyl)thio-2-nitroethane 3d. Rf 0.40 (light petroleum–
EtOAc, 10:1), oil. Found (%): C, 44.16; H, 3.64; N, 6.18; S, 14.72; Cl,
16.27. Calc. for C8H8ClNO2S (%): C, 44.14; H, 3.70; N, 6.43; S, 14.73;
Cl, 16.29.
A
B
NO2
AcOH/NEt3
MeOH
SAr
R1
R2
3a–f
Yield
Product
BENA R1
R2
ArSCl Ar
(%)
1a
1b
1a
1b
1c
1d
Me
H
Me
H
H
H
H
H
2a
2a
2b
2b
p-Tol
p-Tol
3a
3b
82
25
70
77
33
82
p-ClC6H4 3c
p-ClC6H4 3d
p-ClC6H4 3e
p-ClC6H4 3f
H
Me 2b
(CH2)2CO2Me
H
2b
Scheme 1
Arenesulfenyl chlorides rapidly react with BENA at –78 °C
leading to β-arenethio-substituted nitro compounds (Scheme 1).‡
For reproducibility, it is important to use freshly distilled
sulfenyl chlorides and to add 2 mol% Pr2i NEt, which scavenges
acidic impurities into reaction mixture. The reaction proceeds
as an electrophilic attack of sulfenyl chloride on the double
bond followed by the formation of silylnitronate B and Me3SiCl.
1-Nitro-2-(4-chlorophenyl)thiopropane 3e. Rf 0.58 (light petroleum–
EtOAc, 3:1), oil. Found (%): C, 46.77; H, 4.22; N, 6.31; S, 13.71; Cl,
15.22. Calc. for C9H10ClNO2S (%): C, 46.65; H, 4.35; N, 6.05; S, 13.84;
Cl, 15.30.
Methyl 4-nitro-5-(4-chlorophenyl)thiopentanoate 3f. Rf 0.34 (light
petroleum–EtOAc, 3:1), oil. Found (%): C, 47.86; H, 4.72; N, 4.86; S,
9.84; Cl, 10.88. Calc. for C12H14ClNO4S (%): C, 47.75; H, 4.65; N,
4.61; S, 10.56; Cl, 11.67.
†
Chemistry of N,N-bis(silyloxy)enamines. Part 6, previous see ref. 1.
– 74 –

, 2003, 13(2), 74–76
ethers (ethyl vinyl ether, dihydropyrane) in this coupling also
failed: under standard conditions, no reaction takes place. Prob-
ably, less stable unsubstituted episulfonium cations are not
formed at low temperature, while an increase in the temperature
leads to the decomposition of BENA by Me3SiOTf.
R1
SAr
ArSCl
SAr
N(OSiMe3)2
2a,b
TMSOTf
– TMSCl
MeO Cl
MeO
OMe
In summary, we found that sulfur-containing electrophiles
can be used in the functionalization of nitro compounds through
the silylation of the latter.
C
R1
R1
– [Me3Si+]
ArS
ArS
MeO
MeO
This work was performed at the Scientific Educational Centre
for Young Scientists and supported by the Russian Foundation
for Basic Research (grant no. 99-03-32015), the Special Programme
‘Integration’ (project nos. A0082 and B0062) and the US CRDF
(grant no. RC-2 2207).
N(OSiMe3)2
NO2SiMe3
A'
B'
i, BnNEt3+Cl–
ii, AcOH
R1
NO2
ArS
MeO
§
NMR spectra were recorded on a Bruker AM-300 instrument in CDCl3
as a solvent. Chemical shifts were measured relative to internal Me4Si
4a–c
ArSCl Ar
(d = 0; 1H; 13C) or external MeNO2 (d = 0; 14N) standards.
BENA R1
Product Yield (%)
1
3a: H NMR, d: 1.59 (d, 3H, CHMe, J 6.6 Hz), 2.33 (s, 3H, MeAr),
3.07 (dd, 1H, CHAHB, J 6.6, 14.0 Hz), 3.42 (dd, 1H, CHAHB, J 7.4,
14.0 Hz), 4.49–4.61 (m, 1H, CHNO2), 7.13 (d, 2H, J 8.1 Hz) and 7.32
(d, 2H, J 8.1 Hz). 13C NMR, d: 18.7 (MeCH), 21.1 (MeAr), 39.2 (CH2),
82.1 (CHNO2), 129.8 (Ci), 130.1 (2CHAr), 132.1 (2CHAr), 138.1 (Ci).
14N NMR, d: 11.5 (∆n1/2 290 Hz).
1a
1d
1a
Me
2a
p-Tol
(CH2)2CO2Me 2a p-Tol
Me
2b
4a
4b
53
37
57
p-ClC6H4 4c
Scheme 2
3b: 1H NMR, d: 2.34 (s, 3H, MeAr), 3.37 (t, 2H, CH2S, J 7.2 Hz),
4.47 (t, 2H, CH2NO2, J 7.2 Hz), 7.15 (d, 2H, J 8.2 Hz) and 7.34 (d, 2H,
J 8.2 Hz). 13C NMR, d: 21.1 (Me), 31.8 (CH2S), 74.0 (CH2NO2), 129.2
(Ci), 130.2 (2CHAr), 132.3 (2CHAr), 138.3 (Ci). 14N NMR, d: 0.2 (∆n1/2
100 Hz).
References
1 A. V. Lesiv, S. L. Ioffe, Yu. A. Strelenko and V. A. Tartakovskii, Helv.
Chim. Acta, 2002, 85, 3489.
2 A. A. Tishkov, A. D. Dilman, V. I. Faustov, A. A. Birukov, K. A. Lysenko,
P. A. Belyakov, S. L. Ioffe, Yu. A. Strelenko and M. Yu. Antipin, J. Am.
Chem. Soc., 2002, 124, 11358.
3c: 1H NMR, d: 1.60 (d, 3H, CHMe, J 6.6 Hz), 3.13 (dd, 1H, CHAHB,
J 6.6, 14.7 Hz), 3.44 (dd, 1H, CHAHB, J 7.7, 14.7 Hz), 4.51–4.63 (m,
1H, CHNO2), 7.25–7.37 (m, 4H, CHAr). 13C NMR, d: 18.7 (MeCH),
38.7 (CH2), 82.0 (CHNO2), 129.5 (Ci), 132.0 (2CHAr), 132.7 (2CHAr),
133.9 (Ci). 14N NMR, d: 10.7 (∆n1/2 154 Hz).
3 A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko and V. A.
Tartakovsky, Synthesis, 1999, 1767.
1
3d: H NMR, d: 3.40 (t, 2H, CH2S, J 7.0 Hz), 4.48 (t, 2H, CH2NO2,
J 7.0 Hz), 7.26–7.38 (m, 4H, CHAr). 13C NMR, d: 31.3 (CH2S), 73.8
(CH2NO2), 129.6 (2CHAr), 131.5 (Ci), 132.9 (2CHAr), 134.1 (Ci).
14N NMR, d: –0.5 (∆n1/2 133 Hz).
†† 4a. Upper isomer: 1H NMR, d: 1.23 [s, 3H, MeC(OMe)], 1.47 (d, 3H,
CHMe, J 6.6 Hz), 2.02 (dd, 1H, CHAHBCH, J 2.6, 15.1 Hz), 2.33 (s, 3H,
MeAr), 2.48 (dd, 1H, CHAHBCH, J 9.8, 15.1 Hz), 3.05 (d, 1H, CHAHBS,
J 13.1 Hz), 3.14 (s, 3H, OMe), 3.16 (d, 1H, CHAHBS, J 13.1 Hz), 4.68–
4.85 (m, 1H, CHNO2), 7.12 (d, 2H, J 8.2 Hz) and 7.31 (d, 2H, J 8.2 Hz).
13C NMR, d: 21.0, 21.5, 21.6 (all CMe), 41.9, 43.1 (2CH2), 49.6 (OMe),
76.1 (COMe), 79.7 (CHNO2), 129.8 (2CHAr), 130.43 (2CHAr), 132.7
1
3e: H NMR, d: 1.37 (d, 3H, Me, J 6.6 Hz), 3.70–3.86 (m, 1H, CH),
4.26–4.50 (m, 2H, CHAHBNO2), 7.31 (d, 2H, CHAr, J 8.1 Hz), 7.40
(d, 2H, CHAr, J 8.1 Hz). 13C NMR, d: 18.3 (Me), 40.7 (CHS), 79.8
(CH2NO2), 129.5 (2CHAr), 130.0 (Ci), 135.0 (2CHAr), 136.7 (Ci).
14N NMR, d: 7.0 (∆n1/2 152 Hz).
1
(Ci), 136.6 (Ci). Lower isomer: H NMR, d: 1.27 [s, 3H, MeC(OMe)],
3f: 1H NMR, d: 2.15–2.45 (m, 4H, CH2CH2), 3.17 (dd, 1H, CHAS,
J 14.2, 5.5 Hz), 3.39 (dd, 1H, CHBS, J 14.4, 8.2 Hz), 3.65 (s, 3H, OMe),
4.47–4.69 (m, 2H, CHNO2), 7.27 (d, 2H, CHAr, J 8.7 Hz), 7.39 (d, 2H,
CHAr, J 8.7 Hz). 13C NMR, d: 28.0, 29.8 (CH2), 37.6 (CH2S), 52.0
(OMe) 86.1 (CH2NO2), 129.5 (2CHAr), 131.8 (Ci), 133.0 (2CHAr),
134.1 (Ci), 171.9 (C=O). 14N NMR, d: 7.0 (∆n1/2 343 Hz).
1.53 (d, 3H, CHMe, J 6.6 Hz), 1.84 (dd, 1H, CHAHBCH, J 3.6, 15.1 Hz),
2.64 (dd, 1H, CHAHBCH, J 8.5, 15.1 Hz), 2.33 (s, 3H, MeAr), 3.00–3.21
(m, 5H, OMe + CH2S), 4.68–4.85 (m, 1H, CHNO2), 7.10 (d, 2H, J 8.0 Hz)
and 7.29 (d, 2H, J 8.0 Hz). 13C NMR, d: 21.0, 21.4, 21.8 (all CMe),
42.5, 43.2 (2CH2), 49.5 (OMe), 76.0 (COMe), 79.6 (CHNO2), 129.7
(2CHAr), 130.40 (2CHAr), 132.9 (Ci), 136.5 (Ci). 14N NMR, d: 13.9
(∆n1/2 310 Hz).
¶
General preparation procedure for 4a–c. 2-Methoxypropene (1 mmol),
Pr2i NEt (3.5 µl) and a BENA 1 (1 mmol) solution in CH2Cl2 (0.5 ml)
were added successively to a solution of ArSCl (1 mmol) in CH2Cl2
(2.3 ml) at –78 °C. Then, a TMSOTf (1.1 mmol, 0.21 ml) solution in
CH2Cl2 (1 ml) was added dropwise. After stirring for 30 min at –78 °C,
BnNEt3+ Cl– (1.4 mmol) in CH2Cl2 (2 ml), Et3N (2.2 mmol) + AcOH
(2 mmol) in CH2Cl2 (2 ml), and AcOH (2 mmol) in MeOH (2 ml) solu-
tions were added successively. The resulting mixture was warmed to
room temperature and stirred for 30 min; then, it was poured into a two-
phase mixture of 20 ml of Et2O and 20 ml of H2O; the aqueous layer was
extracted three times with Et2O; the organic phase was washed with
brine, dried over Na2SO4 and concentrated in vacuo. Purification of the
residue using flash chromatography (SiO2, light petroleum–EtOAc, 10:1
to 3:1) gave 1-(4-tolyl)thio-2-methoxy-4-nitro-2-methylpentane 4a:
Found (%): C, 59.57; H, 7.39; N, 4.70; S, 11.29. Calc. for C14H21NO3S
(%): C, 59.34; H, 7.47; N, 4.94; S, 11.32. Isomer ratio ca. 1:1. Upper
isomer, Rf 0.42 (light petroleum–EtOAc, 3:1), oil. Lower isomer, Rf 0.38
(light petroleum–EtOAc, 3:1), oil.
1
4b: Upper isomer: H NMR, d: 1.24 [s, 3H, MeC(OMe)], 1.89–2.51
(m, 4H, CH2CH2), 2.33 (s, 3H, MeAr), 2.98–3.27 (m, 2H, CHAHBS),
3.13 (s, 3H, OMe), 3.69 (s, 3H, COOMe), 4.61–4.83 (m, 1H, CHNO2),
7.13 (d, 2H, CHAr, J 7.8 Hz), 7.32 (d, 2H, CHAr, J 7.8 Hz). 13C NMR, d:
20.9, 21.6 (all CMe), 29.8, 30.1, 40.6, 42.9 (all CH2), 49.6 [MeC(OMe)],
51.8 (CO2Me), 76.2 [C(OMe)], 83.5 (CHNO2), 129.8 (2CHAr), 130.6
(2CHAr), 132.6 (Ci), 136.8 (Ci), 172.1 (C=O). Lower isomer: 1H NMR, d:
1.28 [s, 3H, MeC(OMe)], 1.79–2.41 (m, 4H, CH2CH2), 2.32 (s, 3H,
MeAr), 2.53–2.82 and 3.00–3.29 (m, 2H, CHAHBS), 3.11 (s, 3H, OMe),
3.68 (s, 3H, COOMe), 4.57–4.86 (m, 1H, CHNO2), 7.10 (d, 2H, CHAr,
J 7.9 Hz), 7.29 (d, 2H, CHAr, J 7.9 Hz). 13C NMR, d: 21.0, 21.6 (all
CMe), 29.8, 30.3, 41.5, 43.2 (all CH2), 49.6 [MeC(OMe)], 51.8 (CO2Me),
76.1 [C(OMe)], 83.6 (CHNO2), 129.8 (2CHAr), 130.5 (2CHAr), 132.8
(Ci), 136.6 (Ci), 172.2 (C=O). 14N NMR, d: 14.7 (∆n1/2 387 Hz).
4c: Upper isomer: 1H NMR, d: 1.22 [s, 3H, MeC(OMe)], 1.50 (d, 3H,
CHMe, J 7.2 Hz), 1.99 (dd, 1H, CHAHBCH, J 2.3, 15.4 Hz), 2.47 (dd,
1H, CHAHBCH, J 8.9, 15.4 Hz), 2.97–3.18 (m, 2H, CHAHBS), 3.13 (s,
3H, OMe), 4.69–4.87 (m, 1H, CHNO2), 7.18–7.38 (m, 4H, CHAr).
13C NMR, d: 21.5 (2Me), 42.2, 42.8 (2CH2), 49.7 (OMe), 75.8 (COMe),
79.7 (CHNO2), 129.1 (2CHAr), 131.0 (2CHAr), 132.4 (Ci), 135.1 (Ci).
14N NMR, d: 11.4 (∆n1/2 246.2 Hz). Lower isomer: 1H NMR, d: 1.28
[s, 3H, MeC(OMe)], 1.54 (d, 3H, CHMe, J 7.2 Hz), 1.82 (dd, 1H,
CHAHBCH, J 3.6, 15.4 Hz), 2.65 (dd, 1H, CHAHBCH, J 8.5, 15.7 Hz),
3.04 (s, 2H, CHAHBS), 3.12 (s, 3H, OMe), 4.69–4.84 (m, 1H, CHNO2),
7.20–7.33 (m, 4H, CHAr). 13C NMR, d: 21.5, 21.9 (2Me), 42.6, 42.9
(2CH2), 49.7 (OMe), 75.9 (COMe), 79.6 (CHNO2), 129.1 (2CHAr),
131.0 (2CHAr), 132.4 (Ci), 135.2 (Ci). 14N NMR, d: 11.7 (∆n1/2 254.3 Hz).
Methyl 4-nitro-6-methoxy-7-(4-tolyl)thio-6-methylheptanoate 4b: Found
(%): C, 57.58; H, 6.92; N, 3.78; S, 8.77. Calc. for C17H25NO5S (%): C,
57.44; H, 7.09; N, 3.94; S, 9.02. Isomer ratio ca. 1:1. Upper isomer,
Rf 0.31 (light petroleum–EtOAc, 3:1), oil. Lower isomer, Rf 0.26 (light
petroleum–EtOAc, 3:1), oil.
1-(4-Chlorophenyl)thio-2-methoxy-4-nitro-2-methylpentane 4c: Found
(%): C, 51.27; H, 5.94; N, 5.12; S, 10.77; Cl, 11.79. Calc. for
C13H18ClNO3S (%): C, 51.39; H, 5.97; N, 4.61; S, 10.55; Cl, 11.67.
Isomer ratio ca. 1:1. Upper isomer, Rf 0.37 (light petroleum–EtOAc,
3:1), oil. Lower isomer, Rf 0.33 (light petroleum–EtOAc, 3:1), oil.
– 75 –

, 2003, 13(2), 74–76
4 A. V. Ustinov, A. D. Dilman, S. L. Ioffe, P. A. Belyakov and Yu. A.
Strelenko, Izv. Akad. Nauk, Ser. Khim., 2002, 1343 (Russ. Chem. Bull.,
Int. Ed., 2002, 51, 1455).
7 A. D. Dilman, A. A. Tishkov, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko
and V. A. Tartakovsky, Synthesis, 1998, 181.
5 A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko and V. A.
Tartakovsky, J. Org. Chem., 2000, 65, 8826.
6 A. D. Dilman, S. L. Ioffe and H. Mayr, J. Org. Chem., 2001, 66, 3196.
Received: 30th January 2003; Com. 03/2046
– 76 –