Salicylic Acid-Catalyzed Arylation of Enol Acetates with Anilines

Article abstract of DOI:10.1002/adsc.201800427

α-Aryl ketones are both structure moieties commonly found in bioactive compounds and versatile synthetic intermediates for the preparation of drug-like molecules. An operationally simple and scalable protocol has been developed to prepare α-aryl ketones from readily available aromatic amines and enol acetates (or silyl enol ethers). This metal-free methodology features the use of salicylic acid as a convenient catalyst to promote the formation of aryl radicals from in-situ generated aryl diazonium salts, without demanding thermal or photochemical activation. The mild reaction conditions used are compatible with anilines substituted with diverse functionalities. Structural elaboration of some prepared α-aryl ketones was accomplished to illustrate their usefulness as building blocks. (Figure presented.).

Full text of DOI:10.1002/adsc.201800427

Title: Salicylic Acid-Catalyzed Arylation of Enol Acetates with Anilines
Authors: Diego Felipe-Blanco and Jose Gonzalez-Gomez
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Advanced Synthesis & Catalysis
10.1002/adsc.201800427
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Salicylic Acid-Catalyzed Arylation of Enol Acetates with
Anilines
a
a
Diego Felipe-Blanco and Jose C. Gonzalez-Gomez *
a
Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain
E-mail: josecarlos.gonzalez@ua.es
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. α-Aryl ketones are both structure moieties commonly found in bioactive compounds and versatile synthetic
intermediates for the preparation of drug-like molecules. An operationally simple and scalable protocol has been developed
to prepare α-aryl ketones from readily available aromatic amines and enol acetates (or silyl enol ethers). This metal-free
methodology features the use of salicylic acid as a convenient catalyst to promote the formation of aryl radicals from in-situ
generated aryl diazonium salts, without demanding thermal or photochemical activation. The mild reaction conditions used
are compatible with anilines substituted with diverse functionalities. Structural elaboration of some prepared α-aryl ketones
was accomplished to illustrate their usefulness as building blocks.
Keywords: α-aryl ketone; salicylic acid; aryl radicals; aniline; enol acetates
Introduction
The importance of the α-aryl ketone motif is
evidenced by its occurrence among natural products
and pharmaceuticals. This moiety is an important
pharmacophore for a number of bioactive molecules,
as illustrated in Figure 1. Moreover, the
straightforward transformation of these compounds
into a plethora of functionalities facilitates the
construction of diverse heterocycles, which, in turn,
are common scaffolds of drug molecules.[
1]
Intensive investigation on the α-arylation of
ketones during the last two decades has allowed the
development of appealing protocols for the transition-
metal catalyzed coupling of enolates with aryl
halides,[ including those with C-H activation.
2]
[3]
Copper-mediated reaction of lithium enolates with
[4]
indoles and pyrroles have also been reported. Also
recently, important efforts have been devoted to
implement transition-metal-free arylation protocols.
Among them, those involving diaryliodonium salts
Figure 1. Selected bioactive molecules bearing the α-aryl
ketone moiety.
[5]
provide a good synthetic alternative. Elegant
methods based on the triflic acid-mediated hydrative
arylation of alkynes, or the reaction of electron-rich
Aryldiazonium salts are ideal starting materials in
organic synthesis because they can be prepared in one
[6]
[8]
step from cost-effective anilines, and can be easily
aromatic compounds with in-situ [ generated
º
[9]
reduced ( 퐸
~ + 0 V vs Ag/AgCl) to the
푟푒푑
7]
enolonium species (umpolung reactivity), have also
corresponding highly reactive aryl radical. This
reactivity has been largely exploited in fundamental
been developed.
[
10]
transformations such as the Sandmeyer reaction,
[11]
the Meerwein arylation
and the intramolecular
Pschorr reaction. It is noteworthy that in all these
[12]
reactions N
2
is released as a traceless and inert by-
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201800427
product that does not affect the reactivity of the aryl
radical. In particular, aryldiazonium salts have been
also used as aryl radical sources which, after
interception with enol acetates, have furnished α-aryl
ketones. Selected examples illustrating the
implementation of this strategy are: (a) the α-
arylation of methyl ketones promoted by
inexpensive, harmless and a renewable feedstock, it
could be an ideal catalyst to generate aryl radicals;
therefore, we decided to elaborate this concept for the
α-arylation of enol acetates. In our previous work, we
proposed that the in-situ formed diazonium salts (A)
could undergo a nucleophilic addition of salicylic
acid to form the aryl diazobenzoate B (not
[13]
[21]
stoichiometric amounts of KOAc (Scheme 1a); (b)
isolated), which upon N-O bond homolysis, would
the visible-light induced transformation with
generate N , the aryl radical (D) and the H-bond
2
2
+
[14]
[
Ru(bpy)
the use of hydrazines as organocatalysts (Scheme
c). Closely related methods for the oxidative
3
] as photocatalyst
(Scheme 1b); and (c)
stabilized salicyloyl radical (C). Given the intrinsic
electrophilic character of aryl radicals, we envisioned
that reaction with nucleophilic enol acetate 2a would
afford α-oxyradical E, which after single electron
transfer to radical C would lead to carbocation F,
regenerating the SA. Alternatively, the diazonium salt
A can also act as an oxidant of radical E in a typical
radical polar crossover to propagate the radical chain
reaction. Hydrolysis of cation F would lead to the
final ketone (3), generating acetic acid as by-product
(Scheme 2).
[15]
1
arylation of vinyl arenes with aryl diazonium salts
have also been developed, employing stoichiometric
[16]
amounts of ascorbic acid as promoter
or visible-
light photoredox catalysis[17]. However, the latter
strategy is limited to the synthesis of 2-
arylacetophenones, while benzyl alkyl ketones are not
accessible. Herein, we describe the in-situ generation
of aryl diazonium salts from anilines and tert-
butylnitrite, and their salicylic acid (SA)- catalyzed
reaction with enol acetates (or silyl enol ethers) at 20
ºC, to afford the corresponding α-aryl ketones
(
Scheme 1d).
Scheme 2. Plausible mechanism.
In order to validate our proposal, we conducted the
reaction of p-nitroaniline (1a) with isopropenyl
acetate (2a) in the presence of tert-butylnitrite and 10
mol-% of salicylic acid at 20 ºC (Table 1). After
screening different solvent systems (entries 1-9), we
were pleased to obtain product 3a in good yield when
a 2:1 mixture of CH
only 1.5 equivalents of 2a (entry 5). Interestingly, the
presence of H O as a minor component of the solvent
3
CN / H O was used, even with
2
Scheme 1. α-Arylation of enol acetates with aryl
diazonium salts.
2
mixture was well tolerated, even affording slightly
better results (entries 5 and 9 vs 4). Furthermore,
increasing the amount of 2a up to 10 equivalents
Results and Discussion
(
entries 10-12), while keeping the concentration of 1a
The group of Carrillo has reported that aryl radicals
can be conveniently generated at room temperature,
by reduction of the corresponding diazonium ions
in 0.20 M, resulted in an optimal reaction yield (entry
12). Control experiments revealed that the ambient
[22]
light was not promoting the reaction (entry 13),
[18]
[19]
catalyzed by ascorbic acid
or gallic acid
.
whereas significantly lower yields of 3a were
Inspired by their work, we have recently developed
obtained in the absence of salicylic acid, even at 60
[23]
the hydrodeamination of in-situ formed diazonium
ºC (entries 14 and 15). It is worth noting that in
some related reactions with preformed aryldiazonium
salts, slow addition and high temperatures are
salts, catalyzed by salicylic acid (SA) and using THF
as the hydrogen donor.[
20]
Given that SA is
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201800427
required to avoid the attack of the aryl radicals onto
unconverted diazonium ions.[24] Our protocol is
operationally very simple and easy to reproduce
because the reaction is conducted at room
temperature (20 ºC of a water bath) and slow addition
is not required for any reagent. Presumably, since
tert-butylnitrite is the last reactant added to the
reaction mixture, decomposition of the diazonium salt
might occur immediately after its formation,
minimizing the concentration of the latter species.
This metal-free procedure allows the direct formation
of α-aryl acetones, from inexpensive and bench stable
anilines, without photochemical or thermal activation,
under mild acidic conditions (pH ~ 3-4).
the desired product in a reasonable yield. Aryl-
substituted enol acetates were also found to be good
reaction partners, furnishing the desired products (3p
to 3w) in moderate-to-good yields. Moreover, the
present protocol was also compatible with
heteroaromatic enol acetates, as demonstrated by
obtaining compound 3x in a reasonable 50% yield. It
is worthwhile mentioning that the standard procedure
could be easily extended to a gram scale, as
exemplified for the functionalized product 3v.
Table 2. Substrate scope with enol acetates[a]
Table 1. Optimization of the reaction conditions.
Entry Deviation from above
Yield (%)[a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
in DMF
in DMSO
in Acetone
19
21
37
61
69 (65)
54
53
51
63
in CH
none
3
CN
2
in 2:1 Acetone/H O
in 1:1 CH
in 1:2 CH
in 5:1 CH
5 equiv. of 2a
[1a] = 0.10 M, 10 equiv. of 2a
10 equiv. of 2a
3
3
3
CN/H
CN/H
CN/H
2
O
O
O
2
2
0
1
2
3
4
80
56
86 (84)
10 equiv. of 2a, protected from light 84
Without S.A.
0 equiv. of 2a, without SA and
heating to 60 ºC
16
1
1
5
39
[
a]
Determined by GC, using adamantane as the internal
[
a]
Yields are reported for isolated products in 0.50 mmol
standard. In parentheses are the yields of isolated pure 3a.
[
b]
scale, unless otherwise indicated.
1.336 g of 3v were
obtained from 5 mmol of 1n.
With suitable reaction conditions in hand (entry 12,
Table 1), the scope of the α-arylation of different enol
acetates was examined for various anilines. As
depicted in Table 2, different acceptor substituted
anilines reacted with isopropenyl acetate 2a,
affording the corresponding α-aryl acetones (3a to
The reactions of p-anisidine or p-toluidine with
isopropenyl acetate under the previously optimized
conditions were complicated by the formation of
several side-products, from which acetanilides and
the hydrodeamination products were identified by
GC-MS (especially for p-anisidine). To avoid the
formation of acetanilides and minimizes the
hydrodeamination reaction we decided to explore the
performance of trimethylsilyl enol ethers in the
reaction with electron-richer anilines, under
otherwise similar conditions. As shown in Table 3,
the corresponding products were obtained in
moderate yields. The electron-donating methyl and
methoxy groups at the para- position of anilines were
well tolerated with aliphatic (products 5a-5c) and
aromatic (products 5d and 5e) silyl enol ethers. In
3
o) in synthetically useful yields (42-85%). A wide
range of functionalities tolerate the mild reaction
conditions used, including electron-withdrawing ones
at different positions, such as nitro, ester, halogens,
ketones, nitriles and the trifluoromethyl group.
Remarkably, iodine-bearing anilines were well
tolerated and products 3n and 3v were obtained in
[25]
high yields, without significant deiodination.
While unsubstituted aniline afforded the expected
product (3i) in a moderate yield (54%), electron-
richer anilines (Me or MeO-substituted) failed to give
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201800427
addition, ortho-methoxy aniline gave the expected
product in a modest 40% yield (5f), whereas no
reaction took place when introducing a methyl group
at ortho-position (5g), most likely because of the
increased steric hindrance.
transformed easily into other drug-like aromatic
heterocycles. Additionally, when compound 3k was
heated at 120 ºC under mildly basic conditions,
isocoumarin 12 was obtained in good yield. Finally,
when the iodo derivative 3v was treated with an
[29]
excess of K
2
CO under microwave activation, the
3
Table 3. Reaction with trimethylsilyl enol ethers.
intramolecular biaryl coupling took place, giving rise
to the phenanthrene 13 in a non-optimized 47%
[30]
yield.
In order to support the mechanism proposed in
Scheme 2, we conducted some control experiments
(
Scheme 3). The detrimental effect of O in the
2
reaction yield was evident, increasing from 23% in
the presence of air to 85% yield under an Ar
atmosphere (eq 1). This result is in accordance with
the in-situ formation of aryl radicals that can be
intercepted by the persistent O
when 3 equivalents of TEMPO (2,2,6,6-tetramethyl-
-piperidinyloxy) were added to the reaction mixture,
the formation of compound 3a was completely
inhibited and p-NO Ph-TEMPO (6) was isolated in
2
diradical. Actually,
1
2
5
6% yield (eq 2). In addition, when 1,1-
Scheme 3. Control experiments.
diphenylethylene was used as the radical scavenger,
instead of 2a, compounds 7 and 8 were obtained in
7
5% overall yield (eq 3). The latter result might
Conclusion
involve the intermediacy of radical I which, after
being oxidized to the carbocation II, could lose a
proton to form compound 7 or undergo water
addition from the reaction media to obtain 8.
Moreover, when aryl diazonium salt A1 was allowed
to react with 2a in the presence of SA, the expected
compound 3a was obtained in good yield after
purification (eq 4). All these results support that SA
catalyzes the transformation of aryl diazonium salts
In summary, α-aryl ketones can be obtained from
readily available anilines and enol acetates through
the in-situ formation of diazonium salts with tert-
butylnitrite and using salicylic acid as catalyst (10
mol-%), without thermal (20 ºC) or photochemical
activation. The mild conditions used enabled the
reaction of a wide range of anilines with enol acetates
in moderate-to-good yields. It must be highlighted
that the protocol is operationally very simple, and the
target compounds can be obtained in gram quantities
with similar yield. Moreover, the methodology can
include anilines with electron-donating groups by
using trimethylsilyl enol ethers instead of enol
acetates. The utility of the prepared α-aryl ketones as
synthetic intermediates was exemplified with five
different follow-up reactions. This work demonstrates
the potential benefits of the use of salicylic acid as
cheap and green catalyst for the generation of aryl
radicals from anilines.
(
in-situ formed) into the corresponding aryl radicals,
[26]
as proposed in Scheme 2.
The high tolerance of the method herein described
for the preparation of α-aryl ketones to the presence
of diverse functionalities, provided a range of useful
compounds ready for further structural elaborations,
as illustrated for some examples in Scheme 4.
Regioselective chlorination at the benzylic position of
compound 3a was easily accomplished using FeCl
3
and PIDA, to obtain compound 9 in excellent yield
eq 1).[27]
(
The aerobic oxidation of ketone 3t was
efficiently promoted under the reported reaction
conditions to obtain diketone 10 (eq 2) or, in the
presence of o-phenylenediamine (eq 3), quinoxaline
[28]
1
1. We must underline that diketone 10 can be also
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201800427
adding water (10 mL) and the mixture was extracted with
2
Et O (3 x 15 mL). The organic layers were collected, dried
4
over anhydrous MgSO and filtered. The residue was
purified by flash column chromatography on silica gel, to
give the desired product.
Acknowledgements
This work was generously supported by the Spanish Ministerio de
Economía y Competitividad (MINECO; grant no. CTQ2017-
8
8171-P), the Generalitat Valenciana (GV; grant no.
AICO/2017/007), and the Institute of Organic Synthesis (ISO).
The authors thank Prof. F. Alonso for helpful discussion and the
revision of this manuscript.
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21] All attempts to isolate intermediate
B were
unsuccessful. However, we concluded that both
hydroxyl groups of the salicylic acid need to be free,
because poor aryl radical formation was observed with
methyl salicylate or O-acetyl salicylic acid (see
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201800427
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Salicylic Acid-Catalyzed Arylation of Enol
Acetates with Anilines
Adv. Synth. Catal. Year, Volume, Page – Page
Diego Felipe-Blanco, Jose C. Gonzalez-Gomez*
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