Copper(i)-catalyzed N-H olefination of sulfonamides for: N -sulfonyl enaminone synthesis

Article abstract of DOI:10.1039/c8cc04385j

This communication reports copper-catalyzed N-H olefination of sulfonamides for enaminone synthesis using saturated ketones as olefin sources. With TEMPO derivatives and O₂ as oxidants, this method provided an efficient way to produce various enaminones in good yields. Mechanistic studies helped figure out the stable intermediates and develop novel methodologies for the difunctionalization of saturated ketones.

Full text of DOI:10.1039/c8cc04385j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
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DOI: 10.1039/C8CC04385J
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Copper(I)-Catalyzed N–H Olefination of Sulfonamides for N-
sulfonyl Enaminones Synthesis
a
b
a
c
a
Xiao Liang, Xin Huang, Mingteng Xiong, Kexin Shen and Yuanjiang Pan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
This paper reports copper-catalyzed N–H olefination of few years, increasing novel methodologies for constructing such
5
sulfonamides for enaminones synthesis using saturated ketones as structures have been reported. In 2009, Uneo and Kuwano reported
2
olefin sources. With TEMPO derivatives and O as oxidants, this a method involving the nickel-catalyzed formation of a carbon–
method provided an efficient way to produce various enaminones nitrogen bond at the β-position of propiophenone, highlighting
in good yields. Mechanism studies helped figure out the stable α, β-unsaturated ketone as the key intermediate (Scheme 1, entry
6
intermediates and develop novel methodologies for the 1). In 2017, Hong and co-workers developed Au-catalyzed
difunctionalization of saturated ketones.
chemoselective method for synthesizing N-sulfonyl enaminones,
by employing Au(I) and Au(III) as catalysts to obtain two
different isomers. Recently, they reported another work, in
Enaminones constitute powerful class of significant
a
7
intermediates which are versatile for various chemical
transformations, especially for heterocyclic compounds
synthesis.1 Such enaminone structures exist in both drug
molecules and natural products. Our group has a long-term
interest in the application of such structures, in natural product
synthesis,2 ligand designing,3 gas-phase reactions in mass
spectrometry,4 and so on. Traditionally, the 1, 4-conjugate
addition of nucleophiles to a triple bond was the most
predominating approach for enaminone synthesis. Over the past
which N-heterocyclic carbene was utilized as organocatalyst to
activate isocyanides during transformation (Scheme 1, entry 3).8
In 2013, Zhang et al. developed a step-economical protocol for
the synthesis of enaminones via a three component reaction of
calcium carbide, aryl aldehyde, and amine, demonstrating the
versatility of the acetylide ion, which can bridge both
9
electrophiles and nucleophiles (Scheme 1, entry 2). In 2012, Li
used diethyl azodicarboxylate to synthesize cis-β-enaminones
via transformation of substituted propargylamines.10 In 2014,
Chang and co-workers later described the iridium-catalyzed
direct intermolecular C–H amidation of ester and ketone
1
1
derivatives . However, most of these reported methods suffer
from several limitations, such as inconvenient starting materials,
narrow scope, and special requirement for expensive substrates.
Scheme 1 Representative examples to synthesize
enaminones
Scheme 2 Strategies in
Unlike reported works, we chose propiophenone as the source
of olefination, 4-CH O-TEMPO and O as the oxidants to
synthesize the target compounds via the radical-relay process in
our research. This one-step strategy could modify β-carbon and
β-functionalization of ketone
a.Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, P. R.
China. E-mail: panyuanjiang@zju.edu.cn; Fax: +86 571 87951629;
Tel: +86 571 87951629
3
2
b.
School of Chemistry and Chemical Engineering, Shandong University of
Technology, Zibo 255049, Shandong, P. R. China.
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310027,
c.
Zhejiang, P. R. China.
†Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data and crystallographic data. CCDC 1846064. See
DOI: 10.1039/x0xx00000x
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introduce the unsaturated structure to the compound. The the reaction under O
2
atmosphere produced better results, and 4-
View Article Online
DOI: 10.1039/C8CC04385J
O-TEMPO was the most effective oxidant (entries 6–9).
existence of α, β-disubstituted compounds during the CH
3
transformation also provided the potential to realize the multi- Furthermore, both Cu(I) and Cu(II) salts could function as catalysts,
functionalization of ketones. and CuTC produced the best result (entries 10 and 11). Other catalysts
Since the last century, β-functionalization of saturated ketones has such as Ni and Pd were also tested, but found to be unsuitable for the
been a research hotspot, and various approaches to construct β- condition (entries 12 and 13).
functionalized ketones have been reported.12 In 2016, on the basis of
previous works for synthesizing chalcones and heterocyclic analogues Table 2 Substrate Scope of Ketonesa
(
Scheme 2, entry 1),13 Su reported a copper-catalyzed direct β-
functionalization of saturated ketones, in which the target compounds
were obtained via conjugate addition to α, β-unsaturated ketones
(
Scheme 2, entry 2).14 In 2017, our group reported the direct α-
oxyacylation of ketones with carboxylic acids under air condition to
form an α-carbon radical intermediate that can undergo further
transformation to establish new C–O bond.15 Inspired by the above-
mentioned works, we surmised that the simultaneous
functionalization of α-carbon and β-carbon might be possible. As the
continuation of our previous works, we still focused on the research
on copper-catalyzed functionalization of ketones. In this paper, we
report a novel TEMPO-assisted Cu-catalyzed synthetic strategy to
construct N-sulfonyl enaminones.
Table 1 Optimization of the reaction conditionsa
a
Reaction conditions: 1 (0.9 mmol), 2a (0.3 mmol), CuTC (20
mol%), DMAP(100 mol%), 4-CH O-TEMPO (3 equiv), DMSO (2
mL), 110 °C, O , 24 h.
entry
variation from standard condition
isolated yield
3
1
2
3
4
5
6
7
8
9
none
88
65
2
1,10-phenanthroline instead of DMAP
byp instead of DMAP
42
Under optimized reaction conditions, various aromatic ketones
were investigated to broaden the substrate scope of the model reaction
Cs
pyridine instead of DMAP
atmosphere
TBHP instead of 4-CH
TEMPO instead of 4-CH
2
CO
3
instead of DMAP
trace
79
(Table 2). In general, the yields for most of the tested aromatic ketones
N
2
trace
trace
77
3
O-TEMPO
O-TEMPO
were good, and sometimes even excellent. Ketones with either
electron-donating or electron-withdrawing substituents on the
aromatic ring reacted moderately under the standard condition. In
particular, ketones with weak electron-donating or weak electron-
withdrawing substituents, such as the aliphatic group and halogen
group (3a, 3e, 3g, and 3h), performed much better in the reaction.
Disubstituted substrates were also examined, and different dichloro-
and difluoro- compounds could be obtained at moderate yield (3j, 3k,
and 3l). Notably, electron-donating heterocyclic ketones (3m and 3n)
proceeded well in the reaction, whereas electron-withdrawing
heterocyclic ketones (3o) did not work. Strong electron-donating
3
4-Acetyl-TEMPO instead of 4-CH
3
O-TEMPO
81
1
1
1
1
0
1
2
3
CuI instead of CuTC
78
Cu(OAc)
NiCl instead of CuTC
Pd(OAc) instead of CuTC
2
instead of CuTC
65
2
trace
trace
2
a
Reaction conditions: 1a (0.9 mmol), 2a (0.3 mmol), catalysts (20
mol%), addtives and oxidants were stirred in DMSO (2 mL) at
10 °C under O atmosphere (operating in Schlenk tube) for 24 h.
1
2
Initial trials still focused on the Cu-O
2
catalytic system. With substituents (3i) contributed less to the reaction, leading to a decrease
investigations in screening a variety of metal catalysts, oxidants and in yield. Furthermore, the steric effect had a huge influence on the
additives, optimized reaction conditions were determined as follows: transformation, as isobutyrophenone, n-butyrophenone, and
N-methyl-p-toluene sulfonamide (2a, 0.3mmol), propiophenone (1a, valerophenone did not work under the reaction conditions. Aliphatic
3
equiv), CuTC (copper (I) thiophene-2-carboxylate, 20 mol%), ketones (3q), carboxylic acids, and amides (3r) failed to afford
DMAP (N,N-dimethyl-4-aminopyridine, 1 equiv), 4-CH
O-TEMPO corresponding products.
4-methoxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 3 equiv), DMSO
More sulfonamide derivatives were investigated to expand the
atmosphere utility of this catalytic system. As shown in Table 3, weak electron-
3
(
was used as solvent, and the reaction proceeded under O
2
at 110 °C for 24 h (entry 1). Compared with other additives, DMAP donating and electron-withdrawing groups on the benzene ring (4b
showed prior promotion to the reaction, which might work as a base and 4c) showed good performance, whereas stronger electron-
and the ligand (entries 2–5). Given that the reaction involved the donating and electron-withdrawing substituents demonstrated lower
dehydrogenation process, attempting to enhance the oxidative ability reactivity (4g and 4h), almost similar to the ketone substrates
of the catalytic system by introducing some co-oxidants and operating mentioned above. Steric hindrance did not make considerably
2
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influence to the result, and even the trisubstituted (4m) and reaction samples at various reaction time points (0.5, 1V,i2ew, 3Ar,ti5cl,e7O,n1lin2e,
disubstituted (4k and 4l) substrates could afford corresponding and 18 h) for TLC measurement. The TLC reDsuOlIt:s1i0n.1d0ic3a9t/eCd8CthCa0t4s3o8m5Je
enaminones. Besides, the lengthening of the carbon chain slightly stable key intermediates could appear during the reaction and the
influenced the yield to some extent (4o). In addition, alkyl sulfonyl exact structure of these intermediates could be determined (See ESI†).
amide (4p) and cyclic sulfonyl amide (4q) could proceed smoothly. At the beginning of the reaction, compound C was rapidly generated,
Unfortunately, the primary sulfonamide, formamide (4s), alkyl amine, which may be the precursor of α, β-unsaturated ketone. Almost
and aromatic amine (4r) did not work in the reaction.
simultaneously, α, β-disubstituted compound G was formed. When
the reaction time reached 4 h, the product emerged and gradually
accumulated. After 12 h, compounds C and G were almost gone.
Table 3 Substrate Scope of Sulfonamidesa
Scheme 3 Control experiments
On the basis of the observations, a possible mechanism was
proposed in Scheme 4. Initially, the copper–ketone complex A was
rapidly formed through the deprotonation process. The homolysis of
Cu(II)–C bond in complex A produced Cu(I) species and key radical
a
Reaction conditions: 1a (0.9 mmol), 2 (0.3 mmol), CuTC (20
3
mol%), DMAP (100 mol%), 4-CH O-TEMPO (3 equiv), DMSO (2
mL), 110 °C, O , 24 h.
2
To obtain further insight into the mechanism of the reaction,
several control experiments were conducted (Scheme 3). When
the reaction was conducted under N atmosphere, only trace
2
yield was obtained (Table 1, entry 6). The reaction of α, β-
unsaturated ketone with N-methyl-p-toluene sulfonamide was
investigated under standard conditions, giving the corresponding
enaminone an excellent yield of 86 % (Scheme 3, entry 1).
Therefore, α, β-unsaturated ketone might be an important
intermediate. By utilizing α, β-disubstituted compound
the system, the target molecule was obtained with a yield of more
than 90 % yield indicating that compound might play a crucial
role in the transformation (Scheme 3, entry 2). When the reaction
time was controlled between 1 and 2 h, compounds and
could be produced and separated with the yield at 20 % and 35 Scheme 4 Proposed mechanism
, respectively (Scheme 3, entry 3). Surprisingly, when the
G into
G
G
C
%
intermediate B, which was immediately captured by 4-CH
3
O-TEMPO
reaction temperature was set at 80 °C, only α, β-disubstituted
compound was got instead of the downstream enaminone products
to form compound C.16 The elimination of 4-CH
O-TEMPOH from
3
C gave rise to the formation of α, β-unsaturated ketone D.17 The
sulfonamide was transformed to corresponding radical species E
through the SET process. The radical addition between E and D
produced the radical intermediate F, which subsequently reacted with
(
Scheme 3, entry 4). These results suggested that enaminone
products could be synthesized by further elimination of compound G,
which might be a thermodynamic-controlled step.
Furthermore, monitoring the reaction course through H-NMR was
1
another 4-CH
3
O-TEMPO molecule to construct the α, β-disubstituted
O-TEMPOH from G
difficult due to the excess amounts of TEMPO. Therefore, in situ TLC
detection was conducted to observe the reaction course. We collected
compound G. Finally, the elimination of 4-CH
3
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resulted in the formation of the product.
4. Y. Chai, H. Sun, J. Wan, Y. Pan and C. Sun, AnalyVsite,w2A0rt1ic1le,O1n3lin6e,
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4
DOI: 10.1039/C8CC04385J
On the basis of our mechanistic studies, the reaction was also
applied to synthesize α, β-disubstituted products. According to the
preliminary screening results for the optimization of the reaction
condition, using morpholine as the N-source, TEMPO as the oxidant,
5
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2
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and sulfonamides in good to excellent yields. In situ TLC
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This work was supported by the National Natural Science
Foundation of China (No.21532005) and the National Key R&D
Program of China (No.2016YFF0200503). We thank Prof.
Shenlin Huang and Dr. Quan He and for revision and language
editing.
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Conflicts of interest
There are no conflicts to declare.
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