Methyl ketone break-and-rebuild: A strategy for full α-heterofunctionalization of acetophenones

Article abstract of DOI:10.1039/c7gc02558k

The Willgerodt reaction under iron-catalyzed aerobic conditions was found to be an excellent tool for full α-heterofunctionalization of acetophenones with sulfur and amines. Via this break-and rebuild strategy, a wide range of thioglyoxamides was synthesi

Full text of DOI:10.1039/c7gc02558k

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Methyl ketone break-and-rebuild: a strategy for full α-
heterofunctionalization of acetophenones
Thanh binh Nguyen,a and Pascal Retailleaua
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Willgerodt reaction under iron-catalyzed aerobic conditions was approaches relied on stoichiometric use of oxidants other than
found to be an excellent tool for fully α-heterofunctionalization of dioxygen.4
acetophenones with sulfur and amines. Via this break-and rebuild
strategy, a wide range of thioglyoxamides was synthesized in a
four-component, highly atom-, step- and redox- economical
manner with water as the only by-product.
Fully
α-heterosubstituted carbonyl motifs A are widely
present among pharmaceutically active compounds as well as
natural products.1 Classical strategies to such scaffolds based
on readily available methyl ketone
Scheme 1. The first approach consists of an activation of the
-halide1a/sulfonate2
methyl moiety via followed by
nucleophilic displacement to introduce the first
heterosubstituent. The sequence activation/displacement
could be repeated to provide . In the second approach,
intermediate glyoxal B was Scheme 1. Fully α-heterosubstituted carbonyl motifs A from methyl ketone B
obtained from a 4e- oxidation of
B are summarized in
α
C,
A
D
subjected to nucleophilic attack and 2e- oxidation. In both
approaches, stoichiometric use of activating/oxidizing agents
and multistep syntheses are required.
In this context, the direct formation of thioglyoxamides from
an acetophenone , elemental sulfur and an amine with
1
To simplify the transformation, one-pot protocols involving
activating agents and nucleophiles were proposed. For
example, thioglyoxamide 3a could be obtained via one-pot
reaction of acetophenone 1a with morpholine 2a and hydrated
NaSH as nucleophiles and I2/DMSO as oxidants, which implies
that dimethyl sulfide, a volatile compound with unpleasant
odor even at quite low concentrations, is among the by-
products.3 Moreover, the scope of aliphatic amines of the
method is limited to the method is limited to six-membered
ring amines such as morpholine, piperidine, cyclohexylamine
oxygen as oxidizing agent would be an excellent and highly
desirable solution, which exemplifies the principle of atom-,
step- and redox economy (Scheme 2).
and piperazine motifs. Although the global transformation B →
is simply a displacement of three hydrogen atoms by one
A
sulfur atom and one amino group, all the above-mentioned
Scheme 2. Design of iron-catalyzed of oxidative Willgerodt reactions via break-and-
rebuild strategy
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The expected reaction is similar to a typical Willgerodt-Kindler5 acetophenone 3a. Adding FeCl2•4H2O (5 mol %) to the
reaction in the starting material, except for the presence of reaction mixture did not lead to any significant change in
oxygen. In a classical Willgerodt-Kindler6 reaction involving product ratio (entry 2). When the reaction was performed
methyl ketone
function is reduced to the methylene group, its terminal dramatically improved and 3a could be isolated in good yield
methyl group is oxidized to thioamide function in (“break” (entry 3). These aerobic conditions were found to be much less
1 as the ketone substrate, while its carbonyl under an atmosphere of oxygen, the formation of 3a was
4
step). If the reaction is performed under aerobic conditions in efficient to deliver 3a in the absence of iron catalyst (entry 4).
the presence of an appropriate catalyst, the methylene moiety Indeed, most of acetophenone was oxidized into benzoate and
of
4, thanks to its benzylic position, will be readily oxidized to the yield of thioglyoxamides 3a was low. The system Fe/O2/S8
regenerate the ketone function in
3
(“rebuild” step). was shown to be more efficient at 80 °C (entry 5), even with
The choice of catalyst determines the success or failure of the lower catalyst loading (entry 6). Lower the reaction
transformation as the oxidation of the thioamide function in temperature to 60 °C resulted in a slower conversion of
both
Moreover, due to high complexing capacity of both amine
and sulfide species (generated in the mixture of elemental comparable ratio of product and pleasingly, the yield is
sulfur and amine ), a metal catalyst involving in this reaction improved to 78% (entry 6). Finally, 3a could also be formed in
should be compatible. lower yields when either sulfur content or iron catalyst loading
3
and
4
as well as of amine
2
must be taken into account. acetophenone 1a (entry 5 vs 3). Interestingly, we found that
2
the reaction performed with 5 mol % of iron salt leads to
2
As iron-sulfur clusters7 are ubiquitous in living systems and was lowered (entries 7 and 8). We noted that thioamide 3a
responsible for a wide range of chemical transformations that could be readily oxidized into thioglyoxamide 4a when 3a was
sustain many fundamental life processes, iron was our first stirred with sulfur (1 equiv), FeCl2•4H2O (1 mol %) and
choice. The complexity of these catalytic systems complicates dibutylamine 2a (1 equiv) under an atmosphere of oxygen.
the synthesis, the study of their properties and the application The optimized conditions were next applied to a range of
in organic synthesis. We wondered if the addition of simple acetophenone derivatives and dibutylamine 2a (Scheme 3).
iron salt could perform this expected transformation,
especially under aerobic conditions, which were known to be
incompatible with iron-sulfur cluster.8
To address this question, we set up a model reaction of
acetophenone 1a with dibutylamine 2a in the presence of
elemental sulfur under solvent-free conditions (Table 1).
Table 1. Optimisation of reaction conditions
entrya temp (°C)
n
4
4
2
2
2
2
2
2
x
0
p
0
0
1
1
1
1
1
1
1a:3a:4a ratiob
0:5:95
yield of 3a (%)c
1
2
3
4
5
6
7
8
100
100
100
100
80
ndd
ndd
70
25
75
78
59
70
10
10
0
0:5:95
5:95:0
5:95:0
10
5
5:95:0
80
5:95:0
60
5
30:70:0
10:90:0
80
2
a
Reaction conditions unless otherwise noted: 1a (1 mmol), 2a (2 mmol), S (n
b
mmol, 32 mg.mmol-1), oxygen (p atm), FeCl2•4H2O (x mol %). Determined by
1H NMR of the crude reaction mixture. c Isolated yield. d Not determined.
The classical Willgerodt-Kindler conditions in the absence of
both oxygen and iron catalyst was capable of transforming
totally ketone 1a efficiently the expected phenylthioacetamide
4a along with a small amount of thioglyoxamide 3a (entry 1).
The reaction mixture was however unclean due to the
oxidation of 2a into N-butylthiobutyramide. Because oxygen
was excluded from the reaction mixture, the oxygen atom of
3a in this case was obviously issued from the starting
Scheme 3. Reaction scope with open chain aliphatic amines
Although this kind of open chain secondary amine has never
been tested under previously described oxidative conditions,3a
it was found to be an excellent amine substrate. Halogen and
phenoxy substituted products 3b-d, including o-substituted
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one 3c
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,
were also obtained without any difficulty. although the phenol function is known to coordinate strongly
Polyaromatic (such as acetonaphthones) and heteroaromatic with iron(III).
(acetylpyridines, acetylthiophene) ketone substrates also
underwent the aerobic oxidative condensation to afford the
corresponding thioglyoxamides 3e
-i
.
Highly lipophilic
thioglyoxamide 3k bearing two long chains could be
synthesized by our strategy.
We next attempted the reaction conditions to primary amines.
The expected secondary thioamides 3l
-p were formed in
acceptable yields, including thioglyoxamide 3l derived from
low boiling butylamine and thioglyoxamide 3o with
a
protected aldehyde function.
Scheme 5. Selected reactions with diethylamine
Morpholine as well as other cyclic analogs such as piperidine,
pyrrolidine and hexamethyleneimine were also competent
amine substrates (Scheme 4). In all cases tested, the
corresponding thioglyoxamides were obtained in moderate to
good yields. The halogen substituents are potentially useful for
further functionalization. We noted that due to high
nucleophilicity of pyrrolidine (bp 89 °C), its reactions with
acetophenones could be performed at temperature as low as
Conclusions
In conclusion, a simple but effective and green synthesis of
thioglyoxamides based on Willgerodt reaction under iron-
catalyzed aerobic conditions has been described. This ketone
break-and-rebuild strategy complements nicely the existing
methods based on one-pot
α-functionalization of methyl
70 °C and gave rise to the corresponding thioamides 3i-j in
ketones followed by sulfuration and amination. It is likely that
the catalytic activities of Fe/S system may be applied to other
heterofunctionalizations, even under aerobic conditions, and
such investigations are in progress in our laboratory.
high yields. Compared to the previously reported
methods3,4c,6b in which the temperatures were in the range
100-130 °C, our strategy provided a first direct access to
pyrrolidine derived thioglyoxamides under mild conditions.
O
S
O2 (1 atm)
R
HN
+
+
S
Me
N
X
R
FeCl2•4H2O
(5 mol %)
O
X
Conflicts of interest
80 ºC, 16 h
1
2h-k (2 equiv)
2 equiv
3
There are no conflicts to declare.
R
X
S
S
N
N
Notes and references
O
O
O
O
R = H, 3q, 76%
R = Me, 3r, 73%
X = Cl, 3s, 69%
X = Br, 3t, 67%
X-ray structure of 3q
MeO
1
For selected examples, see: (a) S. Ravez, C. Corbet, Q. Spillier,
A. Dutu, A. D. Robin, E. Mullarky, L. C. Cantley, O. Feron and
R. Frédérick, J. Med. Chem. 2017, 60, 1591. (b) C. N.
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MeO
MeO
S
S
N
S
N
N
O
O
O
O
O
3u, 68%
3v, 70%
3w, 76%
MeO
S
S
S
N
N
N
O
O
O
3x, 6 h, 74%
3y, 73% at 70 ºC
3z, 70% at 70 ºC
Scheme 4. Reaction scope with cyclic secondary amines
Finally, with a highly volatile amine such as diethylamine (bp
55.5 °C), the reaction could be carried out at temperature as
low as 60 °C (Scheme 5). To compensate the loss of
diethylamine due to its volatility, the reaction was performed
with 3 equiv of this amine. Interestingly, good yields of
2
3
O. R. S. John, N. M. Killeen, D. A. Knowles, S. C. Yau, M. C.
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representative substrates. To fully functionalize 1,4-
diacetylbenzene, mixture of sulfur (5 equiv) and
(3ac-3aa) were obtained for all three
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4
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a
diethylamine (5 equiv) was used with the same iron catalyst
loading and oxygen pressure. Our conditions were found to be
efficient also to provide phenolic thioglyoxamides 3ac
,
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