Synthesis of α-Thiooximes by Addition of Thiols to N, N -Bis(oxy)-enamines: A Comparative Study of S-, N-, and O-Nucleoa-philes in Michael Reaction with Nitrosoalkene Species

Article abstract of DOI:10.1055/s-0036-1591973

Nucleophilic addition of thiols to N, N -bis(oxy)enamines (nitrosoalkene acetals) produce valuable α-thiooximes in a highly efficient manner. The reaction was found to be solvent-dependent, likely because of distinct mechanisms operating in nonpolar and basic solvents (involving either Bronsted acid or Lewis base catalysis). By performing a series of competition experiments, the relative reactivity of S-, N-, and O-nucleophiles in reaction with N, N -bis(oxy)enamines was determined for the first time. Interestingly, the relative nucleophilicity was found to be highly dependent on the solvent, which allows regioselective control of these reactions by using an appropriate medium.

Full text of DOI:10.1055/s-0036-1591973

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
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A
en
Y. A. Naumovich et al.
Letter
Synlett
Synthesis of α-Thiooximes by Addition of Thiols to N,N-Bis(oxy)-
enamines: A Comparative Study of S-, N-, and O-Nucleophiles in
Michael Reaction with Nitrosoalkene Species
Yana A. Naumovicha
TMSO
OTMS
NOH
N
DMF or toluene
Aleksandr O. Kokuevb
Alexey Yu. Sukhorukov*a
Sema L. Ioffea
SR3
R3SH
R1
R1
· broad scope of R1, R2
· R3 = Ar, HetAr, Alk, AlkFG
· stoichiometric
0
0
0
0
0-
0
0
3
4-
4
1
3
9-
4
5
3
R2
R2
16 examples
(24–94%)
· no additives
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky pros-
pect, 47,119991, Moscow, Russian Federation
sukhorukov@ioc.ac.ru
b D. Mendeleev University of Chemical Technology of Russia,
Higher Chemical College, Miusskaya sq., 9, 125047, Moscow,
Russian Federation
Reactivity in DMF:
Reactivity in toluene: ArCOOH
ArSH
ArCOOH
ArOH
ArOH
BnOH
BnOH
>
>
>
>
>
>
ArSH
Received: 09.02.2018
Accepted after revision: 05.03.2018
Published online: 11.04.2018
tion prior the reaction with a nucleophile.3 However, this
procedure is applicable only to sterically demanding tri-
substituted nitrosoalkenes,5a for which polymerization pro-
ceeds slowly under dilute conditions. Furthermore, 2.2
equivalents of S-nucleophile (thiol) are used on the second
stage. Weinreb and co-authors7 successfully utilized TBS-
ethers of α-halooximes as NSA sources in reaction with
thiophenol. This method employs an almost stoichiometric
amount of thiol, however, equimolar amount of tetra-
butylammonium fluoride (TBAF) is needed to generate NSA.
DOI: 10.1055/s-0036-1591973; Art ID: st-2018-v0092-l
Abstract Nucleophilic addition of thiols to N,N-bis(oxy)enamines
(nitrosoalkene acetals) produce valuable α-thiooximes in a highly effi-
cient manner. The reaction was found to be solvent-dependent, likely
because of distinct mechanisms operating in nonpolar and basic sol-
vents (involving either Brønsted acid or Lewis base catalysis). By per-
forming a series of competition experiments, the relative reactivity of
S-, N-, and O-nucleophiles in reaction with N,N-bis(oxy)enamines was
determined for the first time. Interestingly, the relative nucleophilicity
was found to be highly dependent on the solvent, which allows regi-
oselective control of these reactions by using an appropriate medium.
Conventional approach:6
NOH
NOH
R3S cat
(excess)
SR3
α
Hal
R1
Key words thiols, nitrosoalkenes, oximes, Michael addition, solvent
effects
R1
via in situ generation of NSA
R2
R2
1
Coltart et al:3
Michael addition of S-nucleophiles to conjugated nitroso-
alkenes (NSA) is a promising strategy for the synthesis of α-
thiooximes 1 (Scheme 1), which are important bioactive
compounds,1 ligands,2 and precursors of synthetically valu-
able α-thioketones,3 1,2-mercaptoamines,4 and 1,2-mer-
captohydroxylamines.1b However, because of the unstable
and reactive character of most NSA dervatives,5 achieving
successful Michael addition is challenging and depends on
many factors including temperature, concentration, and, es-
pecially, the nature of the NSA precursor.5d–f
R3SH
(2.2 equiv)
O
NOH
NOH
N
NaHCO3
Hal
SR3
R1
R1
R1
R2
R2
R2
1
NSA
isolation in solution
R1, R2 = Alk, –(CH2)n–
Weinreb et al:7
NOH
NOTBS
TBAF, –78 °C, then PhSH
SPh
R1
Hal
R1
via in situ generation of NSA
R2
R2
1
Conventional precursors of NSA are α-halooximes,
which eliminate HHal upon the action of a base.5c Since the
1960s numerous examples of the reaction of S-nucleophiles
with α-halooximes have been reported.6 Although good
yields were generally observed, the reaction required an ex-
cess of thiolate, which also acted as a base to generate the
nitrosoalkene intermediate. In a recent procedure devel-
oped by Coltart et al., NSA were generated in a dilute solu-
This work:
R3SH
TMSO
OTMS
R2
TMSBr
Et3N
NOH
NO2
N
(1 equiv)
SR3
R1
R1
R1
– TMS2O
R2
R2
1
2
- broad scope of R1, R2
- no additives
- stoichiometric
- mild conditions
Scheme 1 Previous and suggested approaches to α-thiooximes 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
Y. A. Naumovich et al.
Letter
Synlett
Recently, we reported that N,N-bis(siloxy)enamines 2,
accessible by double silylation of nitroalkanes,8 serve as
highly efficient equivalents of NSA in reactions with N- and
1, entry 9). A slightly better result (52% yield) was obtained
in the reaction carried out ‘on water’ (entry 10). Recently,
deep eutectic solvents (DES) were demonstrated to be high-
ly efficient for reactions involving nitrosoalkenes.6f In our
reaction, however, the use of urea-choline chloride DES re-
sulted in rather poor yield of α-thiooxime 1a (entry 11).
Surprisingly, the reaction of enamine 2a with less acidic
n-heptanethiol in toluene produced the desired adduct 1b
only in 26% yield (Scheme 2). Switching to DMF, however,
gave product 1b in much higher yield (65%). Further in-
crease in the yield of 1b (up to 86%) was achieved by adding
a solution of n-heptanethiol in DMF to N,N-bis(siloxy)enamine
2a without prior dissolution of the latter. This can be at-
tributed to the previously observed limited stability of
enamines of type 2 in DMF.9c
O-nucleophiles.9 In these reactions,
a stoichiometric
amount of nucleophile is used in H-form, and no special ad-
ditives such as bases or fluoride sources are needed. In this
paper, we report studies on the reaction of enamines 2 with
aromatic and aliphatic thiols, which led to the development
of a highly efficient and general protocol for the synthesis of α-
thiooximes 1. Furthermore, here we report a first comparative
study on the Michael addition of S-, N-, and O-nucleophiles to
nitrosoalkene species.
Initially, interaction of model N,N-bis(siloxy)enamine 2a
with p-thiocresol was explored in different solvents (Table
1). In all tested solvents, except N,N-dimethylformamide
(DMF), formation of the desired α-thiooxime 1a was slow
and a considerable amount of starting material remained
after 2 h (entries 1–3). Prolonged exposure resulted in in-
creased conversion and yield in hexane and toluene (entries
6 and 7). However, in reactions conducted in DMF and CH2Cl2
no substantial increase of yield was observed after 2 h (en-
tries 5 and 8).
solvent
24 h
( )5
S
( )5
(1 equiv)
SH
N
TMSO
OTMS
NOH
2a
1b
solvent, yield:
toluene, 26%
DMF, 65%
DMF, 86%
(without prior dissolution of 2a)
Table 1 Reaction of p-Thiocresol with Enamine 2a: An Optimization
Study
Scheme 2 Reaction of n-heptanethiol with enamine 2a
solvent
time, rt
These model experiments demonstrate that different
media are needed for reactions with aromatic and aliphatic
thiols.10 With the optimized conditions in hand, the sub-
strate scope was studied. As can be seen from Scheme 3,
various bis(oxy)enamines 2 successfully reacted with an
equimolar amount of p-thiocresol in toluene (method 1) to
afford the corresponding α-thiooximes 1 in good yields. Im-
portantly, reactions involve surrogates of highly unstable
mono-substituted nitrosoalkenes or even nitrosoethylene as
intermediates.5a Addition of p-thiocresol to bis(oxy)en-
amines 2 bearing an electron-withdrawing group (R1 = CO2Et)
or internal double bond (R1 = H, R2 = CH3) produced the cor-
responding products 1g and 1h in only moderate yields.
Different thiols reacted with enamines 2 to give the cor-
responding α-thiooximes 1 in good yields (Scheme 3). Reac-
tions with aromatic thiols were conducted in toluene
(method 1), whereas more nucleophilic aliphatic thiols re-
acted smoothly with enamines 2 in DMF solution (method
2). The reaction is well-tolerated by nucleophilic pyridine
and alcohol moieties, as demonstrated by the synthesis of
products 1i and 1l. Protected L-cysteine was also success-
fully oximinoalkylated at the free SH-group (see adduct
1m). Dioxime 1n, prepared from 1,3-propanedithiol, is a
known chelating ligand for Cu(II).2d
SH
S
N
NOH
TMSO
OTMS
(1 equiv)
2a
1a
Entry
Solvent
Time (h)
Yield of 1a (%)a
1
CH2Cl2
hexane
toluene
DMF
2
13b
37c
27
43d
31
77
78
48
43
52
37
2
2
3
2
4
2
5
CH2Cl2
hexane
toluene
DMF
24
24
24
24
24
24
24
6
7
8
9
no solvent
water
10
11
urea/ChCl (2:1)d
a Determined by 1H NMR analysis with internal standard.
b Conversion of 2a: 56%.
c Conversion of 2a: 55%.
d Conversion of 2a: >99%.
d ChCl: choline chloride.
We also attempted the synthesis of product 1a under
green conditions. Thus, solvent-free coupling of p-thiocre-
sol with enamine 2a delivered oxime 1a in 43% yield (Table
Most of the oximes were isolated as dynamic mixtures
of E- and Z-isomers (for details see the Supporting informa-
tion).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
Y. A. Naumovich et al.
Letter
Synlett
The mechanism of thiol addition to bis(oxy)enamines 2
is of particular concern (Scheme 5). Two reaction pathways
can be suggested based on our previous studies with HO-
acids:9c (1) the generation of NSA from enamine 2 upon the
action of Lewis base (LB – solvent or thiolate anion) fol-
lowed by Michael addition of S-nucleophile (elimination-
addition mechanism) or (2) the Brønsted acid promoted SN′
substitution of the OTMS-group with a thiolate-anion in
cation A. Given that thiols are both nucleophiles and Brøn-
sted acids, both pathways can in principle operate. Further-
more, the realization of these pathways may depend on the
solvent. In most reactions carried out in DMF, the appear-
ance of a light-blue color was observed, indicating the gen-
eration of transient NSA.
R2
R2
R1
R1
NOH
method 1 or 2
R3S
R3SH
(1 equiv)
N
TMSO
OTMS
2
1
method 1: toluene, 24 h; method 2: DMF, 24 h
pTol
H
n
pTol
C7H15
S
S
S
NOH
NOH
NOH
1a, 74% (method 1)
1b, 86% (method 2)
1c, 76% (method 1)
pTol
Ph
pTol
pTol
S
CO2Me
S
Ph
S
NOH
NOH
1e, 94% (method 1)
NOH
1d, 85% (method 1)
1f, 80% (method 1)
pTol
CO2Et
NOH
1g, 24% (method 1)
pTol
H
O
N
N
S
S
S
NOH
NOH
R1
1h, 25% (method 1)
1i, 79% (method 1)
R2
NSA
Nu
n
– LB-TMS
– TMSO
n
C7H15
C7H15
Ph
HO
Ph
S
S
S
LB
NOH
NOH
NOH
1j, 69% (method 2)
1k, 77% (method 2)
1l, 91% (method 2)
Lewis base promoted
pathway (1)
O
OTMS
NOE
Si
N
MeO2C
S
S
S
Nu
or
R1
R1
NOH
NOH
NOH
NHBoc
R2
R2
1m, 61% (method 2)
1n, 83% (method 2)
Brønsted acid promoted
pathway (2)
2
1 (E = H or TMS)
Scheme 3 Reaction of thiols with enamines 2: a substrate scope study
H
Nu
SN'
α-Thiooximes 1 are useful precursors of vicinal N,S-con-
taining organic compounds, as shown in Scheme 4. Thus,
model α-thiooximes 1a and 1d were transformed into the
corresponding amines 3 and hydroxylamines 4 by selective
reduction of the oxime group or into sulfones 5 by oxida-
tion of the sulfide moiety. 1-(p-Tolylthio)propan-2-amine
(3a) exhibits antidepressant activity in mice, as described
previously.11
H
O
OTMS
R2
Si
N
– HOTMS
R1
A
Scheme 5 Lewis base and Brønsted acid promoted mechanisms lead-
ing to α-thiooximes 1
To reveal the exact mechanism involved, experiments
with a non-symmetrical en-nitrosoacetals 612 were per-
formed (Scheme 6).
S
LiAlH4
THF
In the reaction of 6a with 1-heptanethiol in DMF
(Scheme 6, reaction 1), only the open-chain product 7a was
formed, suggesting the participation of nitrosoalkene B as
intermediate. In the experiment with p-thiocresol in tolu-
ene (Scheme 6, reaction 2), in addition to open-chain prod-
uct 7b, the cyclic oxime ether 8b was also isolated. The lat-
ter cannot arise from nitrosoalkene B, and is likely to form
through the Brønsted acid promoted SN′ substitution of the
OTMS-group (Scheme 5, pathway (2)). In the case of five-
membered cyclic bis(oxy)enamine 6b, only the isoxazoline
product 8c was isolated. Thus, it can be suggested that, in
DMF, reactions proceed only through the nitrosoalkene
pathway (1), whereas in toluene both pathways (1) and (2)
are realized.
NH2
3
a R1 = Me, R2 = H (31%)
R2
NaBH3CN
AcOH
R2
R1
R1
S
S
HN
4
NOH
OH
1
a R1 = CH3, R2 = H (89%)
d R1 = Bn, R2 = H (80%)
mCPBA
CH2Cl2
S
O
O
NOH
5
a R1 = Me, R2 = H (40%)
Scheme 4 Representative transformations of α-thiooximes 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
Y. A. Naumovich et al.
Letter
Synlett
Low performance of aliphatic thiols in toluene (Scheme
2) can be explained by their lesser acidity compared with
thiophenols and thus an inability to promote pathway (2).
Although many nucleophiles have been involved in re-
action with nitrosoalkenes5b,c and nitrosoacetals 2,9 their
relative reactivity has not been studied before. Therefore,
we conducted a series of competition experiments employ-
ing p-thiocresol, n-heptanethiol, p-ethylphenol, benzoic ac-
id, diethylamine, and benzyl alcohol as reference nucleop-
hiles. In these competition experiments, a pair of nucleop-
hiles was reacted with one equivalent of model enamine 2a
in either DMF or toluene. The distribution of products (av-
erage of two experiments each) is shown in Figure 1.
The overall trend in reactivity of nucleophiles deduced
from these experiments is shown below (Figure 2, lines (1)
and (2)). Benzyl alcohol proved to be the least reactive both
in DMF and toluene. As for other nucleophiles, different
selectivities were observed in DMF and toluene. For exam-
ple, p-thiocresol was found to the most reactive in DMF,
whereas in toluene, benzoic acid reacted with 2a most
readily.
Ph
O
LB
OH
Ph
Si
N
DMF
rt, 24 h
O
( )5
S
(1)
6a
NOH
7a, 91%
( )5
SH
nC7H15
S
Ph
LB - DMF or nC7H15
S
N
O
HO
R1
B
R1
( )n
R2 R2
( )n
pTol
N
R2
TMSO
O
OH
S
R2
6a,b
toluene
rt, 24 h
NOH
67% (7b)
0% (7c)
(2)
SH
H3C
R1
p
Tol
S
( )n
Reactivity in toluene:
N
R2
O
R2
(1) PhCOOH
>
p-CH3C6H4SH
>
Et2NH
>
p-EtC6H4OH
>
BnOH
BnOH
6a, 7a,b, 8b: n = 1, R1 = Ph, R2 = CH3
6b, 7c, 8c: n = 0, R1 = 4-CH3OC6H4–, R2 = H
31% (8b)
62% (8c)
Reactivity in DMF:
Scheme 6 Addition of thiols to non-symmetrical en-nitrosoacetals 6
(2) p-CH3C6H4SH
>
Et2NH
>
PhCOOH
>
p-EtC6H4OH
>
Figure 2 Relative reactivity of S-, N-, and O-nucleophiles
Figure 1 Competition experiments on the addition of various S-, N-, and O-nucleophiles to N,N-bis(oxy)enamine 2a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
Y. A. Naumovich et al.
Letter
Synlett
The observed trends are in line with the hypothesis that
different mechanisms are operating in DMF and toluene. In
toluene, the reactivity generally correlates with the acidity
of the H-form of nucleophile, as can be expected assuming
the protic acid promoted pathway (2). Diethylamine is an
exception, since being a strong nucleophile it initiates the
nitrosoalkene pathway (1) independently of the solvent
used. Interestingly, in the competition experiment with
benzoic acid and diethylamine in toluene (Figure 1 (G), tol-
uene), the addition of diethylamine dominated, in contra-
diction to the trend shown in Figure 2. This is likely because
of the deprotonation of benzoic acid under these conditions
that blocks Brønsted acid promoted pathway (2).
In DMF, the reactivity trend is more complicated. In the
competition experiments conducted in DMF, the addition
of p-thiocresol dominated over the addition of benzoic acid
and diethylamine (cf. data in Figures 1 (A) and (C)). Presum-
ably, the transient nitrosoalkene NSA reacts not with p-thio-
cresol itself, but with its highly nucleophilic anion, which is
reversibly generated upon dissociation of thiol in DMF. For
this reason, p-thiocresol is more reactive than the more nu-
cleophilic diethylamine (Figure 1 (C), DMF). Therefore, for
reactions in DMF both nucleophilicity and acidity of HNu
are important.
In conclusion, a general protocol for the synthesis of α-
thiooximes 1 from nitroalkanes has been developed. The
suggested method is based on the addition of thiols to read-
ily available N,N-bis(oxy)enamines 2 without the need for
additives such as bases or the fluoride anion. The reactivity
of aliphatic and aromatic thiols toward enamines 2 was
found to be somewhat different and solvent dependent,
which was attributed to two distinct mechanisms taking
place. In DMF, thiols were found to be more reactive as
compared to alcohols, phenols, amines, and carboxylic ac-
ids. These results may be helpful in controlling regioselec-
tivity in reactions of nitrosoalkene species with substrates
bearing several nucleophilic sites.
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Funding Information
This work was supported by the Russian Science Foundation (grant
14-50-00126).
R
u
asin
Secince
F
o
u
n
d
oaitn
1(4-50-0
0
1
2
6)
(10) General procedure for the addition of thiophenols to N,N-
bis(oxy)enamines 2 (method 1): To a stirred solution of N,N-
bis(oxy) enamine 2 (1 mmol) in toluene (6 mL) was added p-thio-
cresol (124 mg, 1 mmol) or pyridine-2-thiol (111 mg, 1 mmol).
After keeping for 24 h at room temperature, methanol (5 mL)
was added and the mixture was stirred for 1 h and concentrated
in vacuum (ca. 45 °C). The residue was subjected to column
chromatography on silica gel to give the corresponding α-thioo-
xime 1. Yields are given in Scheme 3 and in the Supporting
information.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591973. Supporting Information
contains experimental procedures, characterization data, copies of
NMR and FT-IR spectra and primary data for Figure 1.
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References and Notes
1-(p-Tolylthio)propan-2-one oxime (1a): White crystals; mp
(1) (a) Abdel-Aziz, H. A.; Al-Rashood, K. A.; ElTahir, K. E. H.; Suddek,
G. M. Eur. J. Med. Chem. 2014, 80, 416. (b) Jiang, B.; Huang, X.;
Yao, H.; Jiang, J.; Wu, X.; Jiang, S.; Wang, Q.; Lu, T.; Xu, J. Org.
81–83°C (pentane–Et2O); Rf
= 0.29 (EtOAc–hexane, 1:1);
dynamic mixture of E/Z-isomers, ratio 3:1. 1H NMR (300 MHz,
CDCl3, E-isomer): δ = 8.35–8.23 (br, 1 H, NOH), 7.31–7.24 (d,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Y. A. Naumovich et al.
Letter
Synlett
J = 8.1 Hz, 2 H, 2 × =CH), 7.09 (d, J = 8.1 Hz, 2 H, 2 × =CH), 3.56 (s,
2 H, CH2), 2.32 (s, 3 H, H3C-Ar), 1.99 (s, 3 H, H3C-C=N). 13C NMR
(50 MHz, DEPT135, CDCl3, E-isomer): δ = 155.09 (C=N), 137.19
(C=C-CH3), 131.39 and 129.84 (4 × =CH), 131.00 (=C-S), 39.93
(CH2), 21.16 (H3C-Ar), 12.89 (H3C-C=N). 1H NMR (300 MHz,
CDCl3, Z-isomer): δ = 8.53–8.38 (br, 1 H, NOH), 7.31 (d, J =
8.1 Hz, 2 H, 2 × =CH), 7.09 (d, J = 8.1 Hz, 2 H, 2 × =CH), 3.79 (s,
2 H, CH2), 2.32 (s, 3 H, H3C-Ar), 1.92 (s, 3 H, H3C-C=N). 13C NMR
(50 MHz, DEPT135, CDCl3, Z-isomer): δ = 154.94 (C=N), 136.84
(C=C-CH3), 131.78 (=C-S), 130.33 and 129.84 (4 × =CH), 30.68
(CH2), 21.19 (H3C-Ar), 19.22 (H3C-C=N). FTIR (KBr): 3239 (s, br),
3104 (s, sh), 3022 (s, sh), 2920 (s), 2870 (s), 1660 (m), 1493 (s),
1448 (s), 1411 (s), 1368 (s), 1270 (m), 1230 (w), 1159 (m), 1091
(m), 1018 (s), 963 (s), 867 (m), 805 (s), 721 (m), 629 (m), 500 (s)
cm–1. HRMS: m/z [M+H]+ calcd. for [C10H14NOS]+: 196.0793;
found: 196.0791.
methanol (5 mL) was added and the mixture was stirred for 1 h
and concentrated in vacuum (ca. 45 °C). The residue was dried
in vacuum (1 Torr, ca. 50 °C) to remove DMF and then subjected
to column chromatography on silica gel to give the correspond-
ing α-thiooxime 1. Yields are given in Scheme 3 and in the Sup-
porting information.
1-(Heptylthio)propan-2-one oxime (1b): Oil; Rf = 0.89 (EtOAc–
hexane, 1:1); single isomer. 1H NMR (300 MHz, CDCl3): δ = 8.25
(s, 1 H, NOH), 3.19 (s, 2 H, CH2C=N), 2.44 (t, J = 7.4 Hz, 2 H,
CH2S), 2.00 (s, 3 H, CH3), 1.61–1.51 and 1.41–1.24 (2 m, 2 H and
8 H, 5 × CH2), 0.89 (t, J = 6.8 Hz, 3 H, CH3). 13C NMR (75 MHz,
CDCl3): δ = 155.72 (C=N), 36.47 (CH2C=N), 31.80, 31.30, 29.27,
28.94, 28.86 and 22.67 (6 × CH2), 14.13 and 12.64 (2 × CH3).
HRMS: m/z [M+Na]+ calcd. for [C10H21NOSNa]+: 226.1239;
found: 226.1236.
(11) Nair, M. D.; David, J.; Nagarajan, K. Ind. J. Chem., Sect. B: Org.
Med. Chem. 1985, 24, 940.
(12) Tishkov, A. A.; Lesiv, A. V.; Khomutova, Y. A.; Strelenko, Y. A.;
Nesterov, I. D.; Antipin, M. Y.; Ioffe, S. L.; Denmark, S. E. J. Org.
Chem. 2003, 68, 9477.
General procedure for the addition of aliphatic thiols to N,N-
bis(oxy)enamines 2 (method 2): A solution of thiol (1 mmol)
in dimethylformamide (1.5 mL) was added to the corresponding
N,N-bis(oxy)enamine 2 (1 mmol; 2 mmol for product 1n) with
vigorous stirring. After keeping for 24 h at room temperature,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F