A Visible-Light-Driven, Metal-free Route to Aromatic Amides via Radical Arylation of Isonitriles

Article abstract of DOI:10.1002/adsc.201700619

The photochemical metal-free carboamidation of aryl radicals has been exploited for the preparation of aromatic amides, including hetero- and polyaromatic derivatives, under visible light irradiation of arylazo sulfones in the presence of isocyanides in aqueous acetonitrile. The process was useful for the smooth preparation of the antidepressant moclobemide. (Figure presented.).

Full text of DOI:10.1002/adsc.201700619

Title: A visible light driven, metal-free route to aromatic amides via
radical arylation of isonitriles.
Authors: Marco Alberto Malacarne, Stefano Protti, and Maurizio
Fagnoni
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10.1002/adsc.201700619
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Visible-Light-Driven, Metal-free Route to Aromatic Amides
via Radical Arylation of Isonitriles
Marco Malacarne,a Stefano Protti,a* Maurizio Fagnonia
a
PhotoGreen Lab, Department of Chemistry, University of Pavia, V.le Taramelli 12, 27100 Pavia, Italy.
Email: stefano.protti@unipv.it
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######.((Please
delete if not appropriate))
Aryl radicals could be also generated under visible
Abstract. The photochemical metal-free carboamidation of
aryl radicals has been exploited for the preparation of
aromatic amides, including hetero- and polyaromatic
derivatives, under visible light irradiation of arylazo
sulfones in the presence of isocyanides in aqueous
acetonitrile. The process was useful for the smooth
preparation of the antidepressant moclobemide.
light photoredox catalyzed reactions of arene
+ [12]
diazonium salts (Ar-N2 )
or aryl halides (mainly
iodides, Ar-I).[13] The aromatics underwent here a
photocatalyzed SET and the desired Ar• were formed
•
upon fragmentation of the Ar-N bond in ArN2 or of
the Ar-I bond in ArI•- (Scheme 1a, paths a, b).[14]
The presence of a redox active moiety is
mandatory to allow the SET between the
photoexcited catalyst (PC*, in the role of reductant)
and the starting substrate.[15] Despite the impressive
advancements reported in this field, to the best of our
knowledge, a photoredox carboamidation process of
aromatics is still limited.[16]
Keywords: benzamides; metal-free arylation; aryl radicals;
visible light; arylazo sulfones.
Due to the widespread presence of the arylamide
moiety in both natural- and non-natural bioactive
compounds[1,2] including anticancer,[3] antiviral
agent[4] and antidepressant,[5] the introduction of the
amide group onto an aromatic ring is a challenge in
organic synthesis.[6]
We recently introduced a new class of substrates
namely arylazo sulfones as suitable precursors of aryl
radicals[17] under visible light irradiation. Such
compounds could be smoothly prepared in two steps
(Scheme 1b, paths a') starting from colorless and
stable anilines, via diazotization and treatment of the
Apart from the activation of aromatic acids (or
their derivatives) in the presence of amines under
either homogeneous[7] or heterogeneous[8] conditions,
other approaches are based on the formation of an Ar-
C bond, such as the transition metal catalyzed
aminocarbonylation of (hetero)aryl halides (mainly
iodides),[9] and sulfonates.[10] More recently, the
metal-free coupling of aryl diazonium salts with
isonitriles has been described by the groups of
Grimaud[11a] and Zhu.[11b] In the proposed mechanism,
an aryl radical was thermally generated and then
trapped by the isocyanide to form an aryl imidoyl
radical[11b] that, in turn, underwent single electron
transfer (SET) reaction and hydration of the resulting
imidoyl cation.[11b]
obtained
diazonium
salt
with
sodium
methanesulfinate (see experimental section and
supporting information for further details). The amino
group is then converted into a colored, bench stable
but yet photolabile moiety (-N2SO2CH3).[17] We
propose now that such structural motif that imparts
both color and photoreactivity is dubbed as
dyedauxiliary group, in analogy to the electro-
auxiliary groups.[14] Arylazo sulfones were recently
applied to the metal- and photocatalyst-free synthesis
of (hetero)biaryls.[17] We thus reasoned that arylazo
sulfones are the ideal substrates to develop an
uncatalyzed, metal-free radical route to benzamides,
via arylation of isonitriles (Scheme 1b).
Excellent
results
were
obtained
with
arenediazonium salts bearing electron withdrawing
substituents,[11] and in one case a strategy involving
the in situ formation of the diazonium salts have been
tested.[11a]
1
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10.1002/adsc.201700619
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions. [a]
Products
(%yield)
1aH, 18
Entry
1
Solvent
CH2Cl2
Conditions
1a (1 mmol),
tBuNC (4 equiv.)
SolarBox[b]
2
3
CH3COOEt 1a (1 mmol),
tBuNC (4 equiv.)
SolarBox[b]
1aH, 4;
2a, 3
CH3CN
1a (1 mmol),
tBuNC (4 equiv.)
SolarBox[b]
1aH, 30;
2a, 6
4
CH3CN/H2O 1a (1 mmol),
1aH, 14;
2a, 20
9:1
tBuNC (4 equiv.)
Scheme 1. a) Visible light photoredox generation of aryl
radicals from redox active Ar-X; b) Photocatalyst-free,
visible light generation of aryl radicals from arylazo
sulfones bearing a dyedauxiliary group.
SolarBox[b]
5
Acetone/H2O 1a (1 mmol),
9:1 tBuNC (4 equiv. )
SolarBox[b]
CH3CN/H2O 1a (2 mmol),
1aH, 18;
2a, 11
6
1aH, 14;
2a, 5
9:1
tBuNC (2 equiv)
With this aim, the photoreactivity of a model
SolarBox[b]
compound,
1-(methylsulfonyl)-2-(4-
7
CH3CN/H2O 1a (2 mmol),
1aH, 20;
2a, 27
acetylphenyl)diazene 1a was tested in the presence of
tert-butyl isocyanide and the results are depicted in
Table 1. Early experiments were carried out in a solar
simulator equipped with a 500 W Xenon lamp.
Irradiation in non-anhydrous CH2Cl2 (entry 1) led
exclusively to the photoreduced acetophenone 1aH.
Shifting to ethyl acetate, 1aH was again observed in
small amounts, along with traces of the desired
benzamide 2a (entry 2).
Similar results were obtained in neat acetonitrile,
1aH remaining predominant, along with a 6% yield
of 2a (entry 3). However, when replacing part of the
organic solvent with water, the yield of acetophenone
1aH was halved, in favor of 2a that became the major
product though obtained in a low yield (20%, entry 4).
Less satisfactory results were observed in
acetone/water 9:1 mixture (entry 5). Doubling the
concentration of 1a resulted in a lowering of the
arylation efficiency (2a isolated in only 5% yield,
entry 6). Gratifyingly, the addition of 2 equiv. of a
buffering agent (NaHCO3) to the reaction mixture
resulted in a significant increase of the benzamide
yield, though the amount of 1aH was still significant
(entry 7). Higher amounts of isocyanide (up to 5
equiv., 0.5 M) gave 2a in 51% yield (entry 8). We
then investigated the role of the light source. Low
pressure Hg lamps emitting in the UV region (310
and 366 nm, entries 9,10) were used, and 2a was
obtained in 44% and 33% yield, respectively.
9:1
tBuNC (2 equiv.)
NaHCO3[c],SolarBox[b]
8
CH3CN/H2O 1a (2 mmol),
1aH, 5;
2a, 51
9:1
tBuNC (5 equiv.)
NaHCO3[c],SolarBox[b]
9
CH3CN/H2O 1a (2 mmol),
1aH, 13;
2a, 33
9:1
tBuNC (5 equiv.)
NaHCO3[c],366 nm[d]
10
11
12
13[h]
14
CH3CN/H2O 1a (2 mmol),
9:1 tBuNC (5 equiv.),
NaHCO3[c],310 nm[e]
CH3CN/H2O 1a (2 mmol),
1aH, 12;
2a, 44
1aH, 12;
2a, 55
9:1
tBuNC (5 equiv.)
NaHCO3[c],410 nm[f]
CH3CN/H2O 1a (2 mmol),
1aH, 12;
2a, 68
9:1
tBuNC (5 equiv.)
NaHCO3[c],450 nm[g]
CH3CN/H2O 1a (2 mmol),
-
9:1
tBuNC (5 equiv.)
NaHCO3
[c]
CH3CN/H2O 1a (2 mmol),
1aH, 60
9:1
NaHCO3[c], 450 nm[g]
[a] Reaction conditions. 1a (1-2 mmol), tBuNC (2-5 equiv)
in the chosen solvent (2 mL). A 100% consumption of 1a
was observed in all cases. [b]Irradiation was carried out by
using a solar simulator equipped with a 500 W Xenon
lamp, outdoor + IR filter. tirr = 16 h. [c] 2 equiv. [d]15 W Hg
phosphor coated lamp, tirr = 24 h; [e]15 W Hg phosphor
coated lamp, tirr = 24 h; [f]1 W LED, em = 410 nm, tirr = 24
h; [g]1 W LED, em = 450 nm, tirr = 24 h.
Blank
[h]
experiment in the absence of light.
2
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10.1002/adsc.201700619
Advanced Synthesis & Catalysis
Interestingly, when moving to visible light sources
by using a 410 nm LED (tert-butylbenzene 1eH was
also found as side product). The parent phenylazo
sulfone 1j afforded the corresponding amide 2j in a
poor yield (29%). Ortho- and meta- substituted
the arylated product was formed in satisfactory
amounts, especially with a 1W 450 nm LED (entry
12). No arylation took place in the absence of light
(entry 13). Finally, irradiation of 1a in the absence of
tBuNC exclusively led to 1aH (entry 14).
The conditions described in entry 12 were thus
adopted to investigate the synthetic scope of the
reaction. A set of arylazo sulfones (1a-s) was then
synthesized in variable yields (see supporting
information for further details) and irradiated in the
presence of tert-butyl isocyanide.
benzamides 2k-m,o-p
as well as 2,3-
difluorobenzamide 2q were isolated in satisfactory
amounts, but the reaction was unsuccessful with 2-
nitrophenylazo sulfone 2n. Finally, 1-naphthyl (2r)
and 3-pyridyl (2s) derivatives were likewise obtained
in discrete yields (48 and 46% respectively) upon 410
nm LED irradiation. We then extended the scope of
the reaction to other isocyanides. Arylation of
cyclohexyl isocyanide took place efficiently when
using electron poor substrates 1a-c, and also 3-cyano
derivative 3k was isolated in a modest yield. On
contrast, the synthesis of 3d was not clean. The
process was finally applied to the synthesis of the
antidepressive moclobemide (4f) and its analogues
(4a,b and 4g)[18] (Scheme 2), that were obtained in
discrete yields (34-45%) from the corresponding
aromatic precursors and commercially available 2-
morpholinoethyl isocyanide.
Table 2. Photochemical synthesis of N-alkyl arylamides
2,3.[a]
Scheme 2. Photochemical synthesis of moclobemide 4f
and its analogues 4a,b and 4g.
The photochemistry of arylazo sulfones was
investigated in details by our research group.[17] In
particular, the selective generation of aryl radicals
and aryl cations has been demonstrated by simply
tuning the irradiation wavelength (visible light for the
former ones and UVA light for the latter ones).
Accordingly, excitation of substrates 1a-s at 450 or
410 nm promoted the substrate to its singlet n*
excited state, which underwent homolysis of the N-S
bond to give, after N2 loss, aryl radicals I (Scheme 3,
paths a, b) that were subsequently trapped by the
chosen isocyanide to give imidoyl radical II. The
chemistry of aryl radicals has been deeply studied in
the past.[19] Thus, when generated in the presence of a
hydrogen donor, homolytic hydrogen atom transfer
(path c'). is favored (see Table 1, entry 14). However,
under the optimized conditions, trapping of I by the
isonitrile moiety took place faster than hydrogen
abstraction, and reduced 1a-sH were observed only
as the minor products. Replacing part of the organic
solvent having labile C-H bonds with water was
As depicted in Table 2, para- substituted N-tert-
butylbenzamides 2a-i were mainly obtained in highly
satisfactory amounts from the corresponding arylazo
sulfones, except for aminoderivative 2i isolated in
38% yield along with a significant amount of N,N-
dimethylaniline 1iH (15%). When using 4-tert-
butylphenylazo sulfone 1e, best results were obtained
3
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10.1002/adsc.201700619
Advanced Synthesis & Catalysis
beneficial for the process. Oxidation of II,[20] by a
SET reaction has been reported as feasible[21] and we
propose that methanesulfonyl radical acts here as
oxidant in the formation of the nitrilium ion III[22]
responsible for the formation of the desired
benzamides 2-4 upon water addition (paths d, e).[23]
Methanesulfinic acid generated during the
process,[17] can likewise act as hydrogen donor.[24]
The presence of NaHCO3, however, was probably
able to prevent the formation of this acid and thus
limiting the formation of products 1a-sH.
In order to deepen the mechanism involved, the
reaction of 1b with tBuNC was conducted in the
presence of 2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO)[11b, 13d] as a radical trap. Notably, arylation
was suppressed in favor of the formation of adduct 5b
(16% yield, path c'').
Experimental Section
Synthesis of arylazo sulfones 1a-s. Diazonium salts were
prepared just before use from the corresponding anilines[25]
and purified by dissolving in acetone and precipitation by
adding cold diethyl ether. To a cooled (0 °C) suspension of
the appropriate diazonium salt (1 equiv, 0.3 M) in CH2Cl2
was added sodium methanesulfinate (1 equiv. except
where indicated see Supporting Information for further
details) in one portion. The temperature was allowed to
rise to room temperature and the suspension stirred
overnight. The resulting mixture was then filtered and the
solvent evaporated under vacuo from the resulting solution.
The raw product was purified by dissolution in cold
CH2Cl2 and precipitation by adding n-hexane.
General Procedure for the synthesis of benzamides 2-4.
To a solution (5 mL) of aryl azosulfone 1a-s (0.5 mmol,
0.1 M) and the isocyanide (2.5 mmol, 0.5 M) in
MeCN−H2O 9:1 The resulting solution was divided were
in two portion and poured into two Pyrex vials. 2 Equiv. of
NaHCO3 were then added and the mixture purged for 2
min with nitrogen and irradiated at 450 nm for 24 h. The
course of the reaction has been followed by both GC and
HPLC analyses. The photolyzed solution was then
concentrated and the crude residue purified by column
chromatography (eluant, cyclohexane/ethyl acetate
mixture).
Acknowledgements
The authors thank Dr. C. Raviola, Dr. D. Ravelli, and Dr. S.
Crespi (University of Pavia) for fruitful discussions. The work
has been funded by Cariplo Foundation, Italy, project 2015-0756
“Visible Light Generation of Reactive Intermediates from
Azosulfones”.
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5
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10.1002/adsc.201700619
Advanced Synthesis & Catalysis
COMMUNICATION
A Visible-Light-Driven, Metal-free Route to
Aromatic Amides via Radical Arylation of
Isonitriles
Adv. Synth. Catal. Year, Volume, Page – Page
M. Malacarne, S. Protti,* M. Fagnoni
6
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