Manganese(iii) acetate-mediated direct C(sp2)-H-sulfonylation of enamides with sodium and lithium sulfinates

Article abstract of DOI:10.1039/c9ob00825j

A Mn(OAc)₃ mediated oxidative C(sp²)-H sulfonylation of enamides and encarbamates with sodium and lithium sulfinates is reported. This operationally simple transformation provides a straightforward and highly stereoselective access to (E)-β-amidovinyl sulfones in moderate to excellent yields. The reaction proceeds readily under mild conditions at room temperature and tolerates various sensitive functional groups. This process affords exclusively (E)-configurated β-amidovinyl sulfones independent of the starting material configuration. Moreover, a direct transformation of organolithium reagents and sulfur dioxide into β-amidovinyl sulfones is described.

Full text of DOI:10.1039/c9ob00825j

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DOI: 10.1039/C9OB00825J
ARTICLE
Manganese(III) Acetate-Mediated direct C(sp2)-H-Sulfonylation of
Enamides with Sodium and Lithium Sulfinates
Received 00th January 20xx,
Accepted 00th January 20xx
Philipp Kramer, Sara-Cathrin Krieg, Harald Kelm and Georg Manolikakes *
DOI: 10.1039/x0xx00000x
A Mn(OAc)3 mediated oxidative C(sp2)-H sulfonylation of enamides and encarbamates with sodium and lithium sulfinates is
reported. This operationally simple transformation provides a straightforward and highly stereoselective access to (E)-β-
amidovinyl sulfones in moderate to excellent yields. The reaction proceeds readily under mild conditions at room
temperature and tolerates various sensitive functional groups. This process affords exclusively (E)-configurated β-
amidovinyl sulfones independent of the staring material configuration. Moreover, a direct transformation of organolithium
reagents
and
sulfur
dioxide
into
β-amidovinyl
sulfones
is
described.
Among the plethora of different sulfone-containing molecules,
the β-amido sulfone motif represents a particularly interesting
scaffold. β-Amido sulfones are useful building blocks for the
synthesis of amino acids,9 alkaloids10 or carbohydrate
derivatives.11 The β-amido sulfone unit is present in molecules
with attractive biological properties. Selected examples are
depicted in Figure 2: the PDE4 inhibitor apremilast is used for
the treatment of psoarisis;12 LY404039, a glutamate receptor
agonist, is under investigation as potential antipsychotic
agent;13 Sulbactam and Tazobactam are two synthetic β-
lactam antibiotics.14
Introduction
Sulfones have found widespread applications as versatile
synthetic intermediates in organic chemistry and are
frequently found in biologically active molecules.1 Selected
examples of active pharmaceutical ingredients containing a
sulfone functional group include eletriptan, used for the
treatment of migraine,2 the antibiotic dapsone3 or the
anticancer agent bicalutamide4 (Figure 1).
O
S
HO Me
O
N
O
H
O
O
OMe
F3C
N
O
O
S
EtO
S
O
Ph
O
O
O
S
O
H
H
O
N
H2N
NH2
S
S
O
O
N
H
O
N
F
HOOC
N
S
N
N
N
N
O
O
Eletriptan
Bicalutamide
Dapsone
COOH
H2N
COOH
COOH
O
Figure 1 Biologically active sulfones
NHAc
Apremilast
LY404039
Sulbactam
Tazobactam
Commonly, sulfones are prepared from prefunctionalized
molecules containing a sulfur functionality, for example by the
oxidation of sulfides or Friedel-Crafts-type reactions with
sulfonyl chlorides.1,5 In the last ten years, the synthesis of
sulfonyl-group containing molecules via the direct
incorporation of sulfur dioxide has gained increasing
attention.6,7 . At the same time, the development of novel
methods for the construction of sulfones via the direct
functionalization of C-H-bonds has opened a new opportunity
for a more sustainable synthesis of this important functional
useful building block
O
O
O
S
O
O
S
O
R3
O
R3
H
R1
N
*
R2
R1
N
R1
N
H
H
R2
H
R2
Figure 2 Biologically active β-amido sulfones and a synthetic approach to this scaffold
The hydrogenation of the corresponding β-amidovinyl sulfones
represents one of the most attractive approaches for the
construction of the β-amido sulfone scaffold, especially for the
asymmetric synthesis of chiral derivatives.15 Therefore the
development of novel methods for an efficient preparation of
the required enamide-bearing starting materials is highly
desirable. In principle, the direct C(sp2)-H sulfonylation of
simple enamides as readily available building blocks16 provides
a very straightforward and flexible access to β-amidovinyl
sulfones. Thus, several groups have established protocols for
the C-H-sulfonylation of enamides (Scheme 1). The groups of
Loh and Yu have reported Pd- and Ir-catalyzed reactions18, 19
group.8,9
.
Department of Chemistry Technical University Kaiserslautern, Erwin-Schrödinger-
Str. 54, 60438 67663 Kaiserslautern, Germany.
manolikakes@chemie.uni-kl.de
https://www.chemie.uni-kl.de/manolikakes/startseite/
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
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for the direct C-H-functionalization of enamides with sulfonyl
chlorides (Scheme 1a and 1b). Whereas method of Loh is solely
limited to indenyl-derived enamides,18 the reaction of Yu is
compatible with various tertiary enamides and affords
exclusively the corresponding (E)-configured β-amidovinyl
sulfones.19 Zhang and coworkers reported a metal-free, visible-
light induced oxidative C-H-functionalization of secondary
enamides with sodium sulfinates (Scheme 1c).20 The authors
did not observe any stereroselctivity in the case of acyclic
products. More recently, Zhao and Loh described a Cu(OTf)2-
mediated C-H-sulfonylation of tertiary enamides with
incorporation of sulfur dioxide, leading to the corresponding
(E)-amidovinyl sulfones (Scheme 1d).21 Despite these
advances, novel synthetic procedures for the preparation of
sulfonylated enamides with an expanded substrate scope
avoiding the use of expensive catalysts would be highly
desirable. Of particular interest are methods for the
construction of geometrically well-defined acyclic β-amidovinyl
sulfones as well as transformations with secondary enamides
or encarbamates, which would allow a more facile subsequent
modification of the amino-moiety.
Results and Discussion
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In the framework of our studies towardsDnOoI:v1e0l.,10h3ig9h/Cly9OmBo00d8u2l5aJr
procedures for the synthesis of sulfones22 and sulfonamides7c,
,
we were able to identify Mn(OAc)3 in 1,1,1,3,3,3-
hexafluoroisopropan-2-ol (HFIP) as an highly efficient
promoter for the oxidative C-H-sulfonylation of 8-
aminoquinolines,9g anilines,23 or 1,4-dimethoxybenzenes24
with sulfinic acid salts. We envisioned, that this system should
be also capable of mediating an analogous cross-
dehydrogenative coupling with enamides.
To our delight, a first test reaction of the (E)-configured
secondary enamide 1a with two equivalents of sodium p-
toluenesulfinate 2a and Mn(OAc)3 2H2O in HFIP afforded the
.
desired β-amidovinyl sulfone 3a in 78% yield within two hours
at room temperature (Table 1, entry 1).
Table 1 Optimization of the reaction conditions.
O
O
O
Ph
NH
Oxidant
S
Ph
NH
p-Tol
ONa
Me
solvent
rt
O
O
S
Tol-p
Herein we want to report a novel procedure for the direct C-H-
sulfonylation of secondary enamides and encarbamates with
sodium and lithium sulfinates mediated by Mn(OAc)3 as simple
base metal promoter (Scheme 1e). This method affords
synthetically valuable acyclic (E)-β-amidovinyl sulfones in good
yields and excellent stereoselectivities.
Me
2a
1a
3a
Entry
Oxidant (equiv.)
Additiv
(equiv.)
Solvent
Time
(h)
2
2
2
24
24
24
24
24
24
2
2
24
2
Yield[a]
(%)
78
44
55
43
47
67
50
70
64
84
84
-
.
1
2
3
4
5
6
7
8
9
10
11
12
13[b]
14[c]
15
Mn(OAc)3 2 H2O (2.0)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HFIP
HFIP
HFIP
MeCN
acetone
THF
CH2Cl2
DMF
iPrOH
MeOH
EtOH
Water
EtOH
EtOH
EtOH
.
Mn(OAc)3 2 H2O (3.0)
.
Mn(OAc)3 2 H2O (1.0)
a.) Loh et al.
.
Mn(OAc)3 2 H2O (2.0)
NHAc
NHAc
.
Mn(OAc)3 2 H2O (2.0)
O
O
[Pd]
O
S
.
S
O
R
R
120 °C
Mn(OAc)3 2 H2O (2.0)
Ar
Cl
Ar
.
Mn(OAc)3 2 H2O (2.0)
.
b.) Yu et al.
Mn(OAc)3 2 H2O (2.0)
O
.
O
Mn(OAc)3 2 H2O (2.0)
R1
NR3
O
O
[Ir]
.
R1
NR3
Mn(OAc)3 2 H2O (2.0)
R2
R4
S
R4
Cl
h
R2
.
O
O
Mn(OAc)3 2 H2O (2.0)
S
.
Mn(OAc)3 2 H2O (2.0)
E-selective
c.) Zhang et al.
.
Mn(OAc)3 2 H2O (2.0)
72
71
91
NHAc
NHAc O
S
.
O
O
R
Mn(OAc)3 2 H2O (2.0)
2
2
rose bengal
S
.
Mn(OAc)3 2 H2O (2.0)
NaOAc
R
ONa
h
(2.0)
NaOAc
(1.0)
Na2CO3
(2.0)
-
-
not selective
.
16
17
Mn(OAc)3 2 H2O (2.0)
EtOH
EtOH
2
2
85
d.) Zhao & Loh et al.
Ac
Bn
N
Ac
Bn
N
DABSO
Cu(II)
.
Ar2 N2BF4
Mn(OAc)3 2 H2O (2.0)
63
Ar1
O
O
Ar1
S
Ar2
.
18
19
Mn(OAc)2 4 H2O (2.0)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
24
24
24
24
24
24
2
-
10
-
-
-
E-selective
.
Cu(OAc)2 (2.0)
e.) This work
O
O
20
21
22
23
24[d]
NaIO4 (2.0)
K2S2O8 (2.0)
TBHP(2.0)
PIDA (2.0)
-
-
-
-
O
S
R1
NH
Mn(OAc)3
R1
NH
R
OMet
R3
R4
NaOAc
EtOH, RT
O
S
O
-
87
R3
.
Mn(OAc)3 2 H2O (2.0)
NaOAc
(2.0)
1
2
3
E-selective
Scheme 1 C-H-sulfonylation of enamides.
Reaction conditions unless otherwise specified: Oxidant (2.0 equiv.), sulfinate salt
(2.0 equiv.), solvent (2 mL), 2h, rt. [a] Overall isolated yield after column
chromatography; In all cases, the (E)-configured β-amidovinyl sulfone 3a could be
isolated; [b] 1.5 equiv. of the sulfinate salt were used; [c] 1.1 equiv. of the
sulfinate salt were used; [d] degassed, under nitrogen atmosphere.
2 | J. Name., 2012, 00, 1-3
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Interestingly, an exclusive formation of the (E)-configured enamide 4 or enamides 5 and 6, bearing a more bulky tert-
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product was observed.25 Increasing or decreasing the amount butyl- or phenyl-substituent at the alpha carbon, were not
DOI: 10.1039/C9OB00825J
.
of Mn(OAc)3 2 H2O led to significantly lower yields (entries 2 successful. Tertiary enamides, such as 7 or 8, lacking a free N-
and 3). Contrary to our pervious observations, the use of HFIP H, proved to be not suitable for our reaction.
is not crucial for an efficient transformation. The β-amidovinyl
sulfone 3a was obtained in moderate to good yields in various
solvents, such as acetonitrile, acetone, tetrahydrofuran (THF),
O
O
2.0 eq. Mn(OAc)3 2 H2O
O
S
R
NH
CH2Cl2, dimethylformamide (DMF) or 2-propanol (entries 4-9).
However, longer reaction times of 24 hours were needed in all
cases. On the other hand, the use of methanol and ethanol
afforded the desired product in 84% yield after only two hours
reaction time (entries 10 and 11). Water proved to be not a
suitable medium for this transformation (entry 12). For all
further studies EtOH, a recommend solvent from the CHEM21
solvent selection guide,26 was used. Lowering the amount of
sulfinate 3a to 1.5 or 1.1 equivalents afforded the product 3a
in slightly decreased yields of 71-72% (entries 13 and 14). The
yield could be further increased to 91% by the addition of
sodium acetate (entry 15). The weak base NaOAc might serve
as a buffer, thereby suppressing a potential degradation of the
acid-sensitive enamide. On the other hand, decreasing the
amount of NaOAc or addition of stronger bases, such as
Na2CO3, did afford the product 3a in lower isolated yields
(entry 16). No product formation was observed in the
presence of manganese(II) acetate (entry 18). The reaction
with Cu(OAc)2 instead of Mn(OAc)3 afforded the
amidovinylsulfone 3a in only 10% yield (entry 19). Other
oxidants, such as NaIO4, K2S2O8 tert-butylhydroperoxide
(TBHP) or (diacetoxyiodo)benzene (PIDA) did not furnish the
product at all (entries 20-23). In general, the use of other
oxidants did lead to a fast decomposition of the sulfinic acid
salt. In our typical setup, the reaction is performed without
any efforts to exclude air or moisture. However, performing
the reaction under a nitrogen atmosphere did not affect the
isolated yield (entry 24).
R1
2.0 eq. NaOAc
R1
R
N
H
p-Tol
ONa
EtOH, rt
O
S
Tol-p
O
(E) - 1
2
3
O
O
O
O
Tol
O
Tol
O
S
To
S
N
S
N
O
O
H
N
H
O
H
S
R
Et
3b: R = MeO: 83%
3c: R = CN: 80%
3d: R = F: 81%
3e
85%
3f
76 %
O
O
S
O
O
O
O
O
Tol
Tol
Tol
S
S
N
N
tBu
N
Ph
N
H
O
H
O
O
H
3g
86 %
3h
70%
3i
66%
unsuccessful exampes
O
O
O
O
O
Me
Ph
Ph
N
Ph
N
Ph
N
Ph
N
N
H
H
H
Scheme 2 Substrate scope with E-Enamides.
Next we studied the reaction of (Z)-configured enamide 1a
with p-toluene sulfinate 2a. Interestingly, a selective formation
of the (E)-configured amidovinyl sulfone 3a in a comparable
yield of 87% was observed (Scheme 3). The formation of the
same product from both geometrical isomers of an enamide
implies the formation of a common intermediate during the
reaction. Since our preferred method for the synthesis of the
required enamide starting materials,
a nickel-catalyzed
isomerization of the corresponding allylamides,27 usually
affords a mixture of the (E)- and the (Z)-enamide, we
investigated the direct transformation of such a mixture using
our standard conditions. To our delight, an exclusive formation
of the (E)-configured amidovinyl sulfone 3a in 85% yield took
place.
With the optimized conditions at hand, we started to
investigate the substrate scope of this oxidative C-H-
sulfonylation. First, reactions of geometrically defined (E)-
enamides with sodium p-toluene sulfinate were investigated
(Scheme 2). Different benzamide-derived enamides, bearing
an electron-withdrawing or -donating group, afforded the
desired amidovinyl sulfones 3b-d in 80-81% yield. In a similar
manner, reactions of a heterocyclic derivative or an enamide
with an alkyl amide group afforded the expected products 3e
and 3g in 85% and 86% yield. This process is not limited to C-H-
sulfonylation of enamides. Using the standard reaction
conditions the direct sulfonylation of the corresponding
encarbamte or enurea derivatives afforded the aminovinyl
sulfones 3h and 3i in 70 and 66% yield. The direct synthesis of
products bearing different amino-protecting groups could be
highly useful for subsequent transformations. In all cases, the
exclusive formation of the (E)-configured products was
observed. However, this process is sensitive towards structural
modifications of the enamide. Whereas the reaction of an
ethyl-substituted enamide furnished amidovinylsulfone 3f in
76% yield, transformations with the parent, unsubstituted
O
O
O
S
Ph
NH
Mn(OAc)3 2 H2O
Me
Me
Ph
N
H
NaOAc,
EtOH, rt, 2h
p-Tol
ONa
Ts
(E) - 1a
2a
3a
91%
O
O
O
S
Ph
NH
Mn(OAc)3 2 H2O
Me
Ph
N
H
NaOAc,
EtOH, rt, 2h
p-Tol
ONa
Me
Ts
(Z) - 1a
2a
3a
87%
O
O
O
S
Ph
NH
Mn(OAc)3 2 H2O
Me
Me
Ph
N
H
NaOAc,
EtOH, rt, 2h
p-Tol
ONa
Ts
(E/Z) - 1a
E:Z = 77:23
2a
3a
85%
Scheme 3 Sulfonylation of configurational isomers of 1a. Ts = Tosyl.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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As the separation of both isomers of an given enamide can be In parallel with studied the reaction of enamide 1a with
View Article Online
DOI: 10.1039/C9OB00825J
quite cumbersome, we decided to perform a further set of different sulfinic acid sodium salts (Scheme 5). In general
reactions directly with the (E/Z)-mixtures obtained after the arene sulfinates bearing different functional groups, proved to
Ni-catalyzed isomerization (Scheme 4). Also in these cases, the be suitable substrates for our transformation, affording the
amidovinyl sulfones 3p-3x in 55-84% yield. Halogen-
O
2.0 eq. Mn(OAc)3 2 H2O
O
O
substituents, such as a bromo- or fluoro-functionality, were
2.0 eq. NaOAc
EtOH, rt
Ts
S
R
N
R
N
H
well tolerated, thereby providing
a handle for further
p-Tol
ONa
H
manipulations. Only in the case of the very electron-poor p-
nitrobenzene sulfinate 9 no product formation was observed.
Reactions with heterocyclic sulfinic acid salts provided the
sulfonylated enamide 3v and 3w in 46% and 64% yield. Using
sodium methane sulfinate the methylsulfone derivative 3x was
synthesized in 74% yield. Unfortunately, no reaction was
observed with the corresponding trifluoromethyl derivative
10.
(E/Z) - 1
2a
3
O
O
O
MeO
MeO
Ts
Ts
Ts
N
N
Ph
N
H
H
H
F3C
OMe
3l
88%
3k
87%
3j
98%
O
O
Ts
Ts
Ts
FmocNH
N
H
O
N
H
NPhth
In order to expand the scope of our method, we studied the C-
H-sulfonylation with different lithium sulfinates, which can be
easily synthesized from the corresponding organolithium
reagent and sulfur dioxide.28 Thus, two sulfinic acid salts 12a
and 12b were prepared from sulfur dioxide and phenyllithium
11a or n-butyllithium 11b in quantitative yields (Scheme 6).
Gratifyingly, the crude lithium sulfinates are suitable
substrates for our direct C-H-sulfonylation, furnishing the
amidovinyl sulfones 3y and 3z in 36% and 47% yield. In a
similar manner, reaction of lithium p-toluene sulfinate 12c,
prepared in two steps from 4-iodotoluene via lithium-halide
exchange and trapping with sulfur dioxide, afforded the
sulfonylated enamide 3a in 81% yield. Although the isolated
yields are not as high as for the corresponding sodium
sulfinates, these results demonstrate, that β-amidovinyl
sulfones can be directly accessed from simple building blocks
by merging classical organolithium chemistry with our
oxidative coupling procedure.
3n
93%
3o
70%
3m
52%
Scheme 4 Substrate Scope with (E/Z)-mixtures of enamides. Ts = Tosyl, Phth = Phth.
desired sulfonylated enamides 3j-o were formed exclusively as
the (E)-isomer. Again electron-rich or electron-poor benzamide
derived enamides were efficiently sulfonylated.
chemoselective sulfonylation of the more-electron-rich
enamide moiety was observed for substrate 3l. The reaction of
a structurally more complex valine-derived enamide afforded
the amidovinyl sulfone 3m in 52% yield. Interestingly, the
transformations of Boc- and Fmoc-derived encarbamates 1n
and 1o proceeded with similar efficiency, furnishing the N-
protected aminovinyl sulfones 3n and 3o in 95% and 70% yield.
A
O
Ph
2.0 eq. Mn(OAc)3 2 H2O
O
S
Ph
NH
O
NH
2.0 eq. NaOAc
Me
R
EtOH, rt
R
ONa
O
S
a)
O
2.0 eq. Mn(OAc)3 2 H2O
O
1a
2
R
SO2
3
2.0 eq. NaOAc
S
R-Li
R-SO2Li
BzNH
-40 to 25 °C
EtOH, rt
O
R
11a: R = Ph
12a: R = Ph
3y: 47% R = Ph
11b: R = nBu
12b: R = nBu
3z: 36 % R = nBu
O
S
O
HNBz
O
b)
S
2.0 eq. Mn(OAc)3 2 H2O
HNBz
O
O
p-Tol
1.) nBuLi, 0 °C
2.0 eq. NaOAc
S
p-Tol-SO2Li
p-Tol-I
BzNH
EtOH, rt
2.) SO2, -40 °C
O
3p R = Bu: 84%
3q R = Br: 74%
3r R = F: 59%
3s R = CF3: 62%
3t R = OMe: 55%
3u
t
76%
13
12c
3a: 81%
Scheme 6 Synthesis of β-amidovinyl sulfones using organolithium chemistry.
S
O
O
O
S
Since the preparation of the starting enamides as well as the
oxidative C-H-sulfonylation can be performed in the same
solvent (EtOH), we investigated a merger of both reactions
into a one-pot procedure (Scheme 7). Therefore, allylamide 14
was isomerized using an air-stable nickel-precatalyst.27 After
completion of the isomerization, the formed (E/Z)-mixture of
enamide 1a was not isolated. Instead, sulfinate 2a, NaOAc and
Mn(OAc)3 were directly added to the reaction mixture. To our
delight, the nickel-catalyst does not interfere with the
oxidative C-H-sulfonylation and the desired β-amidovinyl
sulfone 3a could be obtained in 87% overall yield. This
HNBz
S
S
N
O
HNBz
HNBz
O
O
3w
3v
3x
74%
64%
46%
O
S
O
S
ONa
F3C
ONa
unsuccessful exampes
O2N
9
10
Scheme 5 Substrate scope with different sodium sulfinates. Bz = Benzoyl.
4 | J. Name., 2012, 00, 1-3
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ARTICLE
operationally simple one-pot procedure offers a very attractive obtained in 14% yield, indicating the formation of sulfonyl
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avenue for the preparation of different amidovinyl sulfones.
radicals. Based on these results and DpOrIe: 1v0io.1u03s9/sCt9uOdBie0s082w5eJ
Finally, we briefly studied the hydrogenation of amidovinyl propose the following reaction mechanism. Single-electron
sulfone 3a as model substrate (scheme 8). In the presence of oxidation of the sulfinate salt 2 with Mn(OAc)3 affords a
10 mol% of Wilkionson’s catalyst a smooth hydrogenation sulfonyl radical I. Addition of this electrophilic radical to the
takes place, furnishing the β-amido sulfone 15 in 85% yield.
nucleophilic alpha-carbon of the enamide 1a leads to the
formation of a radical intermediate I. Single-electron-oxidation
of II with a second equivalent of Mn(OAc)3 furnishes the N-
Acyliminium intermediate III. Finally loss of a proton leads to
the formation of the amidovinyl sulfone product 3.
O
O
O
1.) 5 mol% Ni(PPh3)2[NaphthylBr]
24h, rt
S
N
N
H
O
H
2.) 2.0 eq. Mn(OAc)3 2 H2O
2.0 eq. TolSO2Na
2.0 eq. NaOAc
87 %
3a
MeOH, rt, 2h
14
Scheme 7 Telescoped process for the direct synthesis of amidovinylsulfone 3a from
allylamide 14.
NHBz
Mn(OAc)3
RSO2Na
Mn(OAc)3
Me
NHBz
NHBz
Me
1a
NHBz
Me
Me
RSO2
Since the synthesis of molecules bearing a stereogenic carbon
center directly attached to a sulfonyl group is scarcely studied,
the herein obtained amidovinyl sulfones can provide a new
opportunity for the enantioselective synthesis of such
structural motifs.
-H
SO2R
SO2R
I
SO2R
Mn(OAc)2
Mn(OAc)2
2
II
III
3
Scheme 10. Proposed reaction mechanism.
Conclusions and Outlook
10mol% [RhCl(PPh3)3]
O
O
H2 (20 bar)
O
In summary, we have reported a Mn(OAc)3-promoted C(sp2)-H-
sulfonylation of enamides and encarbamtes with sulfinic acid
salts. This novel method allows a facile preparation of β-
amidovinyl sulfones, important building blocks for
pharmacologically relevant scaffolds, in high yields. The
reaction proceeds at room temperature under mild conditions
and tolerates various functional groups as well as common
carbamte protecting groups on the nitrogen. This process is
highly stereoselective, affording exclusively E-configured
sulfonylated enamides, independent of the configuration of
the starting material. In combination with organolithium
chemistry, amidovinyl sulfones can be accessed in a very
modular manner. Further, we could demonstrate a telescoped
transformation of a readily available allylamide into the
corresponding sulfonylated enamide. Mechanistic studies
support a radical reaction pathway.
O
S
N
S
O
H
MeOH, 60 °C, 24 h
N
O
H
85 %
15
3a
Scheme 8 Hydrogenation of 3a with Wilkinson’s catalyst.
In order to gain more insight into the reaction mechanism, a
series of control experiments were performed. In the presence
of radical inhibitors a marked decrease of the reaction rate
was observed (Scheme 9). Whereas the addition of TEMPO
((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) or DPE
(
1,1-
Diphenylethylene) led to a complete shutdown of the reaction,
amidovinyl sulfone 3a was isolated in 36% yield in the
presence of BHT (2,6-Di-tert-butyl-4-methylphenol).
O
2.0 eq. pTolSO2Na 2a
O
2.0 eq. Mn(OAc)3 2 H2O
Ph
NH
Me
2.0 eq. NaOAc
Ph
N
Me
H
EtOH, rt, 2h
+ 2.0 eq TEMPO
Ts
Conflicts of interest
1a
3a not detected
There are no conflicts to declare.
O
O
tBu
tBu
2.0 eq. pTolSO2Na 2a
O
Ph
NH
2.0 eq. Mn(OAc)3 2 H2O
Me
2.0 eq. NaOAc
+
Ph
N
Me
Acknowledgements
H
EtOH, rt, 2h
Ts
NHBz
+ 2.2 eq BHT
Ts
1a
We would like to thank the Polytechnische Gesellschaft
(Fellowship to P.K.), the DFG (MA 6093/3-1) and COST Action
15106 (C-H Activation in Organic Synthesis) for financial support
and Albemarle (Frankfurt) for the generous donation of chemicals.
Further, we would like to thank Dr. Markus Räschle and Dr.
Frederic Sommer at the Center for MS Analytics, TU
Kaiserslautern for their support with HRMS - measurements.
Me
36 %
16
3a
observed by ESI-MS
O
2.0 eq. PhSO2Na 2k
O
2.0 eq. Mn(OAc)3 2 H2O
SO2Ph
Ph
NH
Me
2.0 eq. NaOAc
Ph
N
Me
SO2Ph
+
H
EtOH, rt, 2h
Ph
Ph
+ 2.0 eq DPE
14 %
17
1a
3a not detected
Scheme 9. Mechanistic studies. Ts = Tosyl, Bz = Benzoyl.
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J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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