Scalable Multicomponent Synthesis of (Hetero)aryl-Substituted Phenyls: Focus on Metal-Free Halogenated Biaryls, 3-Arylindoles, and Isourolithine A Synthesis

Article abstract of DOI:10.1002/ejoc.201901551

In the context of the growing interest of the scientific community for the development of sustainable synthetic strategies to access aromatic structures, we present a practical and metal-free approach to (hetero)biaryls which exploits the advantages of multicomponent reactions in sustainable solvents. In situ acid-catalysed generation of (hetero)aryl acetoxy dienes from the corresponding (hetero)arylidene acetones in a metal vessel, followed by Diels-Alder reaction using an electron-poor alkyne as dienophile, delivers the expected aromatic products after final oxidation of the cycloadduct. This protocol has been demonstrated as a convenient alternative to the previously reported synthetic strategies, considering its scalability and environmental sustainability and the low cost of substrates and equipment. Moreover, it has been successfully applied to the metal-free regioselective synthesis of (hetero)aryl-substituted-phenyls, 2-unsubstituted-3-aryl-indoles, and to the total synthesis of isourolithine A.

Full text of DOI:10.1002/ejoc.201901551

DOI: 10.1002/ejoc.201901551
Full Paper
Multicomponent Reactions
Scalable Multicomponent Synthesis of (Hetero)aryl-Substituted
Phenyls: Focus on Metal-Free Halogenated Biaryls,
3-Arylindoles, and Isourolithine A Synthesis
Andrea Temperini,*[a] Daniela Lanari,[a] Francesco Colognese,[a] and Francesca Piazzolla[b]
Dedicated to Professor Lucio Minuti on occasion of his retirement.
Abstract: In the context of the growing interest of the scien- ucts after final oxidation of the cycloadduct. This protocol has
tific community for the development of sustainable synthetic been demonstrated as a convenient alternative to the previ-
strategies to access aromatic structures, we present a practical ously reported synthetic strategies, considering its scalability
and metal-free approach to (hetero)biaryls which exploits the and environmental sustainability and the low cost of substrates
advantages of multicomponent reactions in sustainable sol- and equipment. Moreover, it has been successfully applied to
vents. In situ acid-catalysed generation of (hetero)aryl acetoxy the metal-free regioselective synthesis of (hetero)aryl-substi-
dienes from the corresponding (hetero)arylidene acetones in a tuted-phenyls, 2-unsubstituted-3-aryl-indoles, and to the total
metal vessel, followed by Diels-Alder reaction using an electron- synthesis of isourolithine A.
poor alkyne as dienophile, delivers the expected aromatic prod-
Introduction
In current organic chemistry, the synthetic routes to aromatic
targets mostly rely on the use of transition metal catalysts.[1–4]
However, the ever-growing concerns about the transition met-
als exhaustibility[5] and toxicity[6] encouraged the exploration of
efficient metal-free alternatives[7] which are able to meet the
current standards for residual metal traces in pharmaceutical[8]
and electronic[9] industry.
In particular, great attention has been given to the develop-
ment of metal-free approaches to biaryls[7,10] and heterobiaryls,
considering the importance of these scaffolds in several fields,
ranging from their use as ligands in organic synthesis[11–13] to
their predominance in pharmacologically active natural[14–16]
Figure 1. Examples of (hetero)biaryl-containing drugs and functional materi-
als.
and synthetic compounds.[17–20] Moreover, thanks to their elec-
tronic properties, (hetero)biaryls play a key role in current re-
search on electronic materials[21,22] and liquid crystals[23] (Fig-
stituents tolerance, with specific reference to the presence of
extra halogens, strongly contributes to incentive the develop-
ment of alternative methods to prepare halogenated biaryls,
although some sporadic transition metal-catalysed[25–30] and
metal free[7,31] strategies with limited scope have already been
reported.
ure 1).
There is no doubt that the most common strategies to con-
struct a biaryl scaffold involve transition metal-catalysed reac-
tions.[24] However, beyond the above mentioned general
considerations on the use of these catalysts, the limited sub-
Our research group has recently identified high pressure-
promoted Diels-Alder reaction as a key step to accomplish
metal-free synthesis of biaryls, even achieving the total synthe-
sis of biaryl-containing biologically active natural compounds
in a few steps.[32,33] Coupling this strategy with the advantages
of multicomponent reactions to generate in situ an electron-
rich diene, a palette of functionalised aromatics has been pre-
pared under hyperbaric conditions.[34,35]
[a] Dipartimento di Scienze Farmaceutiche, Università di Perugia,
Via del Liceo 1, 06123 Perugia; Italy
[b] School of Chemistry and Biochemistry, University of Geneva,
1211 Geneva, Switzerland
E-mail: andrea.temperini@unipg.it
https://www.unipg.it/personale/andrea.temperini/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901551.
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Unfortunately, the expensive high-pressure apparatus is not field of research under hyperbaric, thermal and microwave acti-
so common in organic chemistry laboratories and it requires vation,[48–50] due to the scarce reactivity of this compound with
properly trained users. In addition, hyperbaric reactions do not consequently unsatisfying yields.[51]
match the growing interest of the scientific community towards
scalable procedures, which are potentially relevant to industrial
applications when enabling the economical, environmentally
Results and Discussion
benign, and safe manufacturing of large amounts of com-
pounds.
A mixture of commercially available (3E)-4-phenyl-but-3-en-2-
one 1a, p-toluenesulfonic acid (pTsOH), isopropenyl acetate
(iPEA), and methyl propiolate was chosen as a model system to
test the efficiency of our synthetic idea. First of all, the reaction
mixture was refluxed in dichloromethane (DCM) using a stan-
dard glassware apparatus for 48 h (Table 1, Entry 1). GC–MS
analysis of the crude mixture showed the presence of unreacted
1a and the corresponding enol acetate intermediate in 1:1 ratio,
as well as traces of 2a. Next, the reaction was carried out under
hyperbaric conditions in a DCM filled Teflon vial (Entry 2) fol-
lowing a previously reported procedure.[34] The substrate was
regioselectively converted into the corresponding 2,5-substi-
tuted cycloadduct which was quickly filtered through a silica
pad and oxidised with 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ)[52] to give biaryl 2a in good yield. Then, the
reaction was performed at 110 °C in a metal vessel using iPEA
as solvent with slightly better results (Entry 3) but decreasing
the amount of alkyne to 1.2 equiv. to improve the reaction
atom economy halved the final yield (Entry 4). Using a combina-
tion of DCM and iPEA (6 equiv.) as co-solvents reported the
average yield of the previous experiments (Entry 5), confirming
the possibility to obtain good results using just a slightly over
stoichiometric amount of alkyne in the right solvent. An at-
tempt to reduce reaction times did not allow the multicompo-
Therefore, we planned a novel synthetic strategy, identifying
an alternative metal-free activation method for the Diels-Alder
reaction in order to avoid the use of a high-pressure apparatus.
Considering that metal-free thermal activation of electron-poor
alkynes in Diels-Alder reactions for biaryls synthesis has already
been demonstrated to be an achievable target,[36–41]a cheap
metal vessel seemed to be a convenient option to export the
advantages of a hyperbaric multicomponent protocol to indus-
trial plants and less equipped laboratories. In contrast with
other systems requiring glass vessels, like microwave and Q-
tube,[42] metal vessels can bear higher pressures and they are
usually equipped with a safety gauge. Indeed, a wide range of
metal vessels with different capability, pressure and tempera-
ture rating, corrosion resistance, and design features are com-
mercially available and in-house construction of pressure ves-
sels for laboratory use is also possible.
We also planned to address the solvent choice concerns to
satisfy the updated green chemistry standards.[43] Balancing the
requirements of polarity and solubility with hazard parameters
and toxicological risks is not always easy but, in general, the
substitution of chlorinated solvents with an environmental sen-
sitive alternative is always considered a wise choice.[44]
Consequently, a systematic screening of the best reaction nent reaction completion even if 1.5 equiv. of alkyne and
conditions to perform a multicomponent acid-catalysed enol- 10 equiv. di iPEA were used (Entry 6). In order to induce the full
acetylation of (hetero)arylidene acetones followed by Diels- conversion of the substrate, the temperature was raised to
Alder reaction with an electron-poor alkyne was performed in 145 °C (oil bath temperature) for 48 h, yielding 2a in good yield
a metal vessel. This involved the in situ generation of an elec- after oxidation with no trace of unreacted 1a (Entry 7). Using
tron-rich acetoxy diene which was then reacted with methyl 1 equiv. of pTsOH did not allow the reaction completion in 24 h,
propiolate in a thermal Diels-Alder reaction. Oxidation of the as unreacted 1a and enol acetate intermediate were detected
resulting cycloadduct allowed to obtain the corresponding in 1:1 ratio (Entry 8). This result confirmed that the Diels-Alder
aromatic products (Scheme 1).Excepting the reports involving reaction is effectively the limiting step of the synthetic se-
dimethyl acetylenedicarboxylate,[45–47] which deliver products quence. Next, we looked for an alternative solvent, in order to
with two identical substituents, the use of methyl propiolate as replace toxic DCM. PhMe did not allow the substrate conversion
dienophile in metal-free Diels-Alder reactions is still a fertile (Entry 9), possibly due to the scarce solubility of pTsOH in this
Scheme 1. Thermal activation of alkynes in multicomponent metal-free synthesis of (hetero)aryl-substituted phenyls in metal vessel.
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Table 1. Optimisation of the multicomponent enolacetylation-cycloaddition sequence in metal vessel. Conditions: 1a, 1 equiv., 0.33
M; pTsOH 0.04 equiv.
Entry
Solvent
iPEA[equiv.]
Methyl
propiolate
[equiv.]
Oil bath
[°C]
t [h]
2a
isolated
yield [%][a]
1
2
3
4
5
6
7
8
DCM
DCM
iPEA
iPEA
DCM
DCM
DCM
DCM
PhMe
Me2CO3
EtOAc
EtOAc
EtOAc
Ac2O
EtOAc
5
5
–
–
3
3
3
85
40
48
68
24
36
24
36
48
48
48
48
48
24
68
68
6
Traces[b,c]
45[d]
53
110
110
110
110
145
145
145
145
145
145
40
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
25
6
48
10
10
10
10
10
10
10
10
–
48[e]
56
Traces[c,f]
0
9
10
11
12
13
14
15
60[g]
54
67[h,i]
42[d,h,i]
50[e,h,i,j]
20[k]
145
145
10
[a] Enolisation-cycloaddition-aromatisation overall yield. [b] Refluxing glassware apparatus. [c] Unreacted 1a and enolacetate intermediate were detected in
1:1 ratio. [d] Teflon vial, 9 kbar. [e] Unreacted 1a was recovered. [f] 1 equiv. of pTsOH was employed. [g] 4:1 Mixture of 2a and its methoxycarbonyl analogue.
[h] 1aConcentration 0.2 M. [i] EtOAc was used as oxidation solvent. [j] Diels-Alder cycloadduct yield calculated by GC–MS. [k] Microwave irradiation 260 watts
in a 10 mL glass vial.
solvent. Me2CO3, instead, delivered an inseparable 4:1 mixture out in a metal vessel equipped with a pressure gauge. In this
of 2a and its corresponding methoxycarbonyl analogue in 60 % way it was possible to assess that the pressure inside the vessel
overall yield (Entry 10). Good results were achieved using EtOAc ranged between 3 and 5 bar during the reaction, thus confirm-
as solvent (Entry 11) and further improvement of the reaction ing the potential dual activation theory but suggesting a scarce
yield was achieved decreasing 1a concentration from 0.33
M
to contribution from the pressure generated inside the vessel.
Unfortunately, any attempt to extend the protocol to disub-
stituted alkynes was not successful. Substrate 1a and methyl
pentynoate did not react at all under hyperbaric conditions de-
scribed in Table 1, Entry 1. The reaction conditions reported in
Table 1, Entry 12 using a metal vessel only lead to the formation
of the enol acetate intermediate and its Diels-Alder reaction
with the alkene moiety of 1a to give the cyclohexene by-prod-
uct, without any participation of the alkyne. In order to pro-
mote the Diels-Alder reaction, the mixture was heated to 195 °C
but complete decomposition of the substrate was observed.
After the reaction conditions screening, we tested the versa-
tility of our protocol using variously functionalised benzylidene
acetones 1 under the conditions reported in (Table 1, Entry
12). Appreciable results were obtained when electron-donating
(Table 2, Entries1–2) or electron-withdrawing (Entries 3–4) sub-
stituents or both (Entry5) were present on the aromatic ring of
the arylidene acetone. Unfortunately, the presence of electron-
withdrawing substituents did not allow the oxidation reaction
to being complete in 24 h in EtOAc but a simple switch to
PhMe allowed to achieve this goal in the desired time. It is
worthy to note that this protocol allowed the synthesis of
0.2 and using EtOAc as solvent also in the oxidation step
M
(Entry 12). To disprove any influence of metal particles leakage
from the metal vessel walls, a Teflon chamber was charged with
the reaction mixture and placed inside the metal vessel, thus
avoiding any contact between the reaction mixture and the
metal walls of the vessel. Interestingly, no substantial change in
2a yield was observed (65 % isolated yield, results not shown).
EtOAc under hyperbaric conditions (Entry 13) did not deliver
better results compared to the same reaction in metal vessel
(Entry 12) and the hyperbaric reaction in DCM (Entry 2). Per-
forming the reaction in acetic anhydride as both acylating
agent and solvent only lead to 50 % conversion of 1a into the
corresponding cycloadduct calculated by GC–MS (Entry 14). In
order to compare autoclave and microwave activation, the reac-
tion was also carried out in a glass vial under microwave irradia-
tion (260 watts for 6 h) (Entry 15). GC–MS analysis of the crude
mixture showed the massive presence of a cyclohexene by-
product derived by Diels-Alder reaction between the enol acet-
ate intermediate and 1a. Moreover, unreacted 1a, enol acetate
intermediate, and the expected cycloadduct 2a (20 % global
yield) were also detected.
Hypothesising a dual contribution to the reaction activation, biaryls bearing every kind of halogens (Entries 6–9) and even
combining thermal and hyperbaric factors due to the heating multiple halogen atoms (Entry 10) or a combination of different
of a solution in a closed vessel, another experiment using the halogens (Entry 11). This objective is not easy to achieve using
reaction conditions described in Table 1, Entry 12 was carried common metal-free synthetic strategies, not to mention the
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chemoselectivity issues arising when using transition-metal me- 6), delivering a scaffold of interest for medicinal chemists due to
diated reactions.
its pharmacological potential.[53–56] Bearing in mind the similar
importance of 2-aryl benzothiophenes in medicinal chemis-
try,[57] also heterobiaryl 2s has been prepared under the opti-
mised reaction conditions in good yield and total regioselecti-
vity (Entry 7).
Table 2. Substrate scope exploration.
Table 3. Application of the protocol to heterobiaryls synthesis in metal vessel.
[a] Enolisation-cycloaddition-aromatisation overall yield. [b] Oxidation was
completed in 45 h.
Moreover, the multigram scale-up of this protocol has been
easily achieved using 15 mmol (2.7 g) of 1h as the substrate in
a 50 mL metal vessel. The expected product 2h was obtained
in 55 % overall isolated yield, thus demonstrating the scalability
of the presented strategy.
The use of heteroarylidene acetones as substrates also gave
satisfying results (Table 3). Firstly, five-membered aromatic rings
bearing a sulfur (Entry 1) or a nitrogen (Entry 2) atom or both
[a] Enolacetylation-cycloaddition-aromatisation overall yield. [b] Calculated
on converted substrate. [c] Multicomponent reaction completed in 72 h.
Further functionalisation of the obtained scaffold can also be
(Entry 3) were tested to replace the phenyl group of 1a. All planned. As proof of concept, we decided to introduce an extra
these substrates gave the expected products with total regio- halogen on the newly constructed ring.[58] To do so, we depro-
selectivity in good yields, although no complete conversion of tected the phenolic moiety of 2a with sodium in dry MeOH.
substrate 1n was achieved under the optimised reaction condi- The resulting phenol 3 was then treated with Br2 solution in
tions. Secondly, the protocol was extended to benzo-fused DCM to give a mixture of mono- and di-brominated phenols 4
five-membered heterocyles. Interestingly, 2-unsubstituted-3- and 5 in 3:1 ratio (Scheme 2). Regioselective iodination of
aryl indoles were easily prepared with this strategy (Entries 4– phenol 3 was attempted by treatment with N-iodosuccinimide
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Scheme 2. Further functionalisation of the biaryl scaffold via phenol halogenation.
Scheme 3. Metal-free total synthesis of isourolithin A.
(NIS) and trifluoroacetic acid (TFA) but an inseparable 1:1 mix- tractive, in addition to the ready availability of equipment and
ture of the two possible mono-ortho-iodinated regioisomers starting materials. The synthetic path tolerates both electron-
was obtained.
withdrawing and electron-donating substituents on the aro-
matic ring of the benzylidene acetone and it can be considered
as a convenient strategy for the synthesis of halogenated bi-
aryls as it is compatible with the presence of halogens on the
starting material or their subsequent introduction on the newly
built ring.
Moreover, its compatibility with heteroarylidene acetones
opens the lead for the efficient metal-free synthesis of hetero-
biaryls with potential applications in pharmaceuticals and elec-
tronics, as highlighted by the selected substrates. The versatility
of this strategy has also allowed accessing the natural com-
pound isourolithin A in a few, high-yielding, metal-free passa-
ges.
Next, we foresaw the opportunity to exploit the presented
method to achieve the metal-free total synthesis of a biaryl-
containing natural product. In particular, we focused on di-
benzo-α-pyrone, which is a common structural motif in biologi-
cally active natural compounds.[59–62]Among all the possibilities,
we were particularly intrigued by the potential use of biaryl 2b
as starting material for the synthesis of isourolithin
(Scheme 3).
A
Firstly, removal of the acetoxy protecting group was
achieved, followed by methoxylation of the phenolic moiety
and basic hydrolysis of the carbomethoxy group without isola-
tion of the intermediates.[52] The resulting biaryl carboxylic acid
6 was converted into dimethyl isourolithin A7 by treatment
Further exploration of other positions to create tetra- and
with NIS in dichloroethane.[63] Deprotection of the phenolic penta-substitution pattern on the newly built ring is currently
substituents[33] delivered the expected natural product 8 in ex- ongoing in our laboratories.
cellent yield.
Experimental Section
Conclusions
Compounds purification by column chromatography was per-
formed on silica gel (Merck 60, 70–230 mesh), and analytical TLC
We have demonstrated that (hetero)aryl-substituted phenyls
was carried out on pre-coated silica gel plates (Merck 60 F254,
synthesis via thermal multicomponent enolacetylation-cyclo-
0.25 mm) using UV light and 0.5 % w/v KMnO4 aqueous solution
addition reaction, followed by cycloadducts oxidation, is possi-
(followed by gentle heating) for visualisation. Melting points were
ble using a simple metal vessel. The use of more sustainable
measured on a hot plate apparatus and are uncorrected. Proton
magnetic resonance (1H-NMR) spectra were recorded at 200 and
reaction solvents as ethyl acetate and toluene, as well as the
rational use of recyclable reagents like iPEA and DDQ,[64]
400 MHz. Carbon magnetic resonance (13C-NMR) spectra were re-
strongly contribute to making this scalable protocol very at- corded at 50.3 and 100.6 MHz. Chemical shifts (δ) are reported in
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parts per million (ppm). The NMR spectra were calibrated using the
proton or carbon signals of residual non-deuterated solvent peaks:
δH = 7.27 and δC7 = 7.0 for CDCl3, δH = 2.54 and δC = 40.4 for
(CD3)2SO. Infrared (IR) spectra were recorded with a FT-IR instru-
ment, using a diffuse reflectance sampling cell. Only significant
absorption maxima (νmax) are reported in wavenumbers (cm–1).
GC–MS analysis were obtained with a gas chromatograph (HP-5MS
(3E)-4-{5-Methoxy-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-
yl}but-3-en-2-one (1r): Eluent EtOAc/Hex, 20:80; white solid (82 %
isolated yield). M.p.58–60 °C. IR (KBr): ν = 3116, 2954, 2837, 1661,
˜
1602, 1438, 1377, 1173, 978, 887, 809 cm–1
.
1H-NMR (200 MHz,
CDCl3): δ = 7.90 (d, 1H,J = 9.1 Hz, ArH); 7.86 (s, 1H, ArH); 7.78 (d,
2H,J = 8.4 Hz, ArH); 7.62 (d, 1H, J = 16.3 Hz, =CH); 7.32–7.16 (m, 3H,
ArH); 7.01 (dd, 1H, J = 9.1, 2.5 Hz, ArH); 6.77 (d, 1H,J = 16.3 Hz, =
capillary column 29.0 m, ID 0.25, film 0.25 μm) equipped with a CH); 3.86 (s, 3H, OCH3); 2.41 (s, 3H, CH3); 2.36 (s, 3H, CH3) ppm. 13C-
mass selective detector at an ionising voltage of 70 eV. Combustion
analyses were carried out on an elemental analyser. Hyperbaric ex-
periments were conducted with a Unipress LV30/16 apparatus while
metal vessel experiments were carried out in a home-made pres-
sure vessel (stainless steel AISI 304). IUPAC names of compounds
were generated with ACD/Name.
NMR (50.3 MHz, CDCl3): δ = 198.2, 156.9, 145.5, 134.5, 134.4, 130.1,
130.0 (2C), 129.1, 129.0, 126.8 (2C), 126.7, 118.0,114.6, 114.3, 103.2,
55.7, 27.5, 21.1ppm.MS: m/z (%) = 369 (64) [M]+, 341 (17), 281 (15),
214 (100), 207 (74), 199 (20), 171 (55), 156 (13), 143 (10), 91 (37), 73
(31). C20H19NO4S (369): calcd. C 65.02, H 5.18, N 3.79; found C 64.90,
H 5.01, N 3.66.
(3E)-4-(1-Benzothien-2-yl)but-3-en-2-one (1s):[68] Eluent Et2O/
Benzylidene acetones 1a, 1g–h and 1k are commercially available.
Benzylidene acetones 1b-d and 1j were prepared by base-catalysed
aldol condensation with acetone from the corresponding alde-
hydes.[34] (Hetero)arylidene acetones 1e–f and 1l–s were prepared
by Wittig reaction with 1-(triphenylphosphoranylidene)propan-2-
one from the corresponding aldehydes.[34] Characterisation
data for (hetero)arylidene acetones 1b,[65] 1c–e,[34] 1i–j,[34] 1m,[34]
1n,[66] and 1o[34] matched the ones previously reported in literature
for these compounds.
Hex, 20:80; light yellow oil (66 % isolated yield). IR (KBr): ν = 3056,
˜
2927, 2867, 1666, 1638, 1612, 1360, 1263, 1144, 955, 818, 751,
727 cm–1 13C-NMR (50.3 MHz, CDCl3): δ = 197.5, 140.1, 139.6, 139.4,
.
136.1, 129.3, 127.7, 126.3, 124.8, 124.3, 122.4, 27.8 ppm. MS: m/z
(%) = 202 (68) [M]+, 187 (100), 159 (24), 115 (57), 89 (10). C12H10OS
(202): calcd. C 71.25, H 4.98; found C 71.47, H 5.19.
General Procedure for Multicomponent Reaction in Metal Ves-
sel and Oxidation Reaction: A solution of (hetero)arylidene acet-
one 1 (1 mmol, 1 equiv.), iPEA (10 mmol, 10 equiv.), pTsOH
(0.04 mmol, 0.04 equiv.) and methyl propiolate (1.5 mmol,
1.5 equiv.) in 4 mL of EtOAc was placed in an 8 mL metal vessel.
The vessel was closed, placed in an oil bath and stirred at 145 °C
for 48 h. The cooled mixture was filtered through a silica pad and
the solvent was evaporated. The crude residue was dissolved in
10 mL of EtOAc or PhMe (see Table 2 and Table 3) and 1.5 mmol
of DDQ (1.5 equiv.) were added. The mixture was stirred under the
conditions reported in Table 2 and Table 3 for the appropriate reac-
tion time. The mixture was poured into a saturated aqueous solu-
tion of Na2HCO3 and extracted twice with EtOAc. The combined
extracts were washed with brine, dried with Na2SO4, and concen-
trated under vacuum. The crude mixture was purified by column
chromatography on silica gel to give pure product 2. Characterisa-
tions data for compounds 2c–e, 2h–j, 2m and 2o matched the ones
previously reported in literature for these compounds.[34]
(3E)-4-(3,5-Dibromo-4-methoxyphenyl)but-3-en-2-one (1f): Elu-
ent EtOAc/Hex, 30:70; light yellow solid (98 % isolated yield), m.p.
99–103 °C. IR (KBr): ν = 2930, 1692, 1665, 1609, 1475, 1261, 979,
˜
1
741 cm–1. H-NMR (200 MHz, CDCl3): δ = 7.68 (s, 2H, ArH); 7.32 (d,
1H, J = 16.2 Hz, =CH); 6.62 (d, 1H, J = 16.2 Hz, =CH); 3.90 (s, 3H,
OCH3); 2.37 (s, 3H, CH3) ppm. 13C-NMR (50.3 MHz, CDCl3): δ = 197.5,
155.5, 139.5, 133.1, 132.1 (2C), 128.2, 118.8 (2C), 60.8, 27.9 ppm. MS:
m/z (%) = 334 (53) [M]+, 319 (81), 353 (26), 238 (71), 195 (15), 167
(30), 116 (38), 101 (22), 88 (33), 74 (29), 62 (35), 43 (100). C11H10Br2O2
(334): calcd. C 39.56, H 3.02; found C 39.29, H 3.13.
(3E)-4-(2-Bromo-4-chlorophenyl)but-3-en-2-one (1l): Eluent
Et2O/Hex, 20:80; colorless oil (89 % isolated yield). IR (KBr): ν = 3089,
˜
2927, 1690, 1466, 1259, 1101, 864, 733 cm–1
.
1H-NMR (200 MHz,
CDCl3): δ = 7.82 (d, 1H,J = 16.3 Hz, =CH); 7.64 (d, 1H, J = 2.2 Hz,
ArH); 7.56 (d, 1H, J = 8.3 Hz, ArH); 7.34 (dd, 1H, J = 8.3, 2.2 Hz, ArH);
6.61 (d, 1H,J = 16.3 Hz, =CH); 2.43 (s, 3H, CH3) ppm. 13C-NMR
(50.3 MHz, CDCl3): δ = 198.0, 140.5, 136.5, 133.0, 132.9, 129.9, 128.3,
128.2, 125.7, 27.3 ppm. MS: m/z (%) = 260 (4) [M]+, 258 (3), 245 (10),
181 (34), 179 (100), 138 (13), 136 (38), 99 (15), 75 (16). C10H8BrClO
(259): calcd. C 46.28, H 3.11; found C 46.50, H 3.34.
Methyl 5-(Acetyloxy)biphenyl-2-carboxylate (2a): Eluent EtOAc/
Hex, 20:80; yellow oil (64 %overall isolated yield). IR (KBr): ν = 3029,
˜
2950, 1765, 1730, 1601, 1286, 1206, 928, 766 cm–1. 1H-NMR (CDCl3):
δ = 7.89 (d, 1H, J = 8.4 Hz, ArH); 7.43–7.28 (m, 5H, ArH); 7.17 (dd,
1H, J = 8.4, 2.4 Hz, ArH); 7.13 (d, 1H, J = 2.4 Hz); 3.62 (s, 3H, OCH3);
2.31 (s, 3H, CH3) ppm. 13C-NMR (50.3 MHz, CDCl3): δ = 168.9, 168.1,
152.5, 144.5, 140.4, 131.4, 128.2 (2C), 128.1, 128.0 (2C), 127.5, 123.8,
120.3, 51.9, 21.1 ppm. MS: m/z (%) = 270 (29) [M]+, 228 (63), 197
(100), 168 (15), 139 (29), 115 (15). C16H14O4 (270): calcd. C 71.10, H
5.22; found C 71.37, H 5.04.
(3E)-4-{1-[(4-Methylphenyl)Sulfonyl]-1H-indol-3-yl}but-3-en-2-
one (1p):[67] IR (KBr): ν = 3113, 3054, 1688, 1605, 1444, 1373, 1174,
˜
1127, 966, 809, 752 cm–1
.
13C-NMR (50.3 MHz, CDCl3):δ = 198.2,
145.6, 135.5, 134.5, 130.1 (2C), 128.8, 127.9, 127.1, 126.9 (2C), 125.5,
124.1, 120.6, 118.1, 113.8, 27.5, 21.6 ppm.
Methyl 5-(Acetyloxy)-4′-methoxybiphenyl-2-carboxylate (2b):
EluentEtOAc/Hex, 30:70; yellow oil (60 % overall isolated yield). IR
(3E)-4-{5-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-
yl}but-3-en-2-one (1q): Eluent EtOAc/Hex, 30:70; light yellow oil
(KBr): ν = 2948, 1765, 1726, 1605, 1434, 1246, 1179, 927, 726 cm–1
.
˜
(63 % isolated yield). IR (KBr): ν = 3136, 3067, 1656, 1435, 1374,
˜
1H-NMR (200 MHz, CDCl3): δ = 7.85 (d, 1H, J = 8.9 Hz, ArH); 7.24 (d,
2H, J = 8.8 Hz, ArH); 7.16 (dd, 1H, J = 8.9, 2.4 Hz, ArH); 7.11 (d, 1H,
J = 2.4 Hz, ArH); 6.96 (d, 2H, J = 8.8 Hz, ArH); 3.85 (s, 3H, OCH3);
3.68 (s, 3H, OCH3); 2.34 (s, 3H, CH3) ppm. 13C-NMR (50.3 MHz, CDCl3):
δ = 168.9, 168.4, 159.1, 152.5, 144.1, 132.7, 131.4, 129.4 (2C), 128.1,
123.8, 119.9, 113.5 (2C), 55.2, 52.0, 21.1 ppm. MS: m/z (%) = 300
(69) [M]+, 258 (100), 227 (97), 184 (16), 155 (11), 128 (10). C17H16O5
(300):calcd. C 67.99, H 5.37; found C 67.80, H 5.51.
1158, 972, 821, 798, 706 cm–1. 1H-NMR (200 MHz, CDCl3): δ = 7.97–
7.85 (m, 3H, ArH); 7.79 (d, 2H,J = 8.4 Hz, ArH); 7.57 (d, 1H, J =
16.4 Hz, =CH); 7.48 (dd, 1H, J = 8.8, 1.8 Hz, ArH); 7.28 (d, 2H, J =
8.4 Hz, ArH); 6.76 (d, 1H,J = 16.4 Hz, =CH); 2.37 (s, 3H, CH3); 2.33 (s,
3H, CH3) ppm. 13C-NMR (50.3 MHz, CDCl3): δ = 198.0, 145.9, 134.2,
134.1, 133.6, 130.2 (2C), 129.6, 129.5, 128.5, 127.3, 126.9 (2C), 123.4,
117.7, 117.3, 115.1, 27.6, 21.6 ppm. MS: m/z (%) = 419 (49) [M]+,
417 (48), 281 (12), 264 (39), 262 (36), 183 (39), 155 (62), 91 (100).
C
19H16BrNO3S (418): calcd. C 54.55, H 3.86, N 3.35; found C 54.69, H
Methyl 5-(Acetyloxy)-3′,5′-dibromo-4′-methoxybiphenyl-2-carb-
oxylate (2f): Eluent EtOAc/Hex, 20:80; yellow oil (40 % overall iso-
4.03, N 3.30.
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lated yield). IR (KBr): ν = 2947, 1734, 1652, 1472, 1205, 1001, 880,
2.37 (s, 3H, CH3); 2.34 (s, 3H, CH3) ppm. 13C-NMR (100.6 MHz, CDCl3):
δ = 168.9, 167.6, 152.9, 145.0, 135.1, 134.7, 134.6, 132.0, 130.2, 129.9
(2C), 128.9, 126.9 (2C), 124.9, 124.5, 124.0, 123.6, 122.7, 121.0, 119.7,
˜
741 cm–1
.
1H-NMR (200 MHz, CDCl3): δ = 7.76 (d, 1H, J = 8.5 Hz,
ArH); 7.35–7.25 (m, 2H, ArH); 7.03 (dd, 1H, J = 8.5, 2.3 Hz); 6.90 (d,
1H, J = 2.3 Hz, ArH); 3.78 (s, 3H, OCH3); 3.58 (s, 3H, OCH3); 2.16 (s, 113.8, 51.9, 21.6, 21.1ppm. HRMS m/z: [M + Na]+, (C25H21NO6SNa)
3H, CH3) ppm. 13C-NMR (50.3 MHz, CDCl3): δ = 168.7, 167.1, 153.4,
152.7, 141.2, 138.8, 132.4 (2C), 132.0, 127.4, 123.9, 121.1, 117.5 (2C),
60.7, 52.2, 21.0 ppm. MS: m/z (%) = 458 (40) [M]+, 416 (100), 385
(28), 306 (28). C17H14Br2O5 (458): calcd. C 44.57, H 3.08; found
C 44.33, H 3.32.
486.09818, found 486.1000.
Methyl 4-(Acetyloxy)-2-{5-bromo-1-[(4-methylphenyl)sulfonyl]-
1H-indol-3-yl}benzoate (2q): Eluent EtOAc/Hex, 30:70; light yellow
solid (61 % overall isolated yield), m.p.145–148 °C. IR (KBr): ν = 3103,
˜
2949, 1765, 1729, 1586, 1463, 1370, 1188, 1115, 965, 803, 751 cm–1
.
1H-NMR (200 MHz, CDCl3): δ = 7.98 (d, 1H, J = 8.5 Hz, ArH); 7.95–
7.87 (m, 1H, ArH); 7.80 (d, 2H, J = 8.4 Hz, ArH); 7.63 (s, 1H, ArH);
7.47–7.38 (m, 2H, ArH); 7.33–7.24 (m, 2H, ArH); 7.22 (d, 1H, J =
2.4 Hz, ArH); 7.17 (d, 1H, J = 2.4 Hz, ArH); 3.49 (s, 3H, OCH3); 2.38 (s,
3H, CH3); 2.35 (s, 3H, CH3) ppm. 13C-NMR (100.6 MHz, CDCl3): δ =
168.8, 167.1, 152.9, 145.3, 134.8, 133.9, 133.3, 132.1, 131.9,130.0 (2C),
128.6, 127.8, 126.8 (2C), 125.2, 124.5, 122.5, 121.7, 121.3, 117.1,
115.2, 52.0, 21.6, 21.1 ppm. HRMS m/z: [M + Na]+, (C25H20BrNO6SNa)
564.00869, found 564.0099.
Methyl 5-(Acetyloxy)-2′-fluorobiphenyl-2-carboxylate (2g): Elu-
ent EtOAc/Hex, 30:70; yellow oil (54 % overall isolated yield). IR
(KBr): ν = 2952, 1764, 1731, 1435, 1290, 1202, 930, 762 cm–1 1H-
.
˜
NMR (200 MHz, CDCl3): δ = 8.1 (d, 1H, J = 8.5 Hz, ArH); 7.41–7.11
(m, 6H, ArH); 3.69 (s, 3H, OCH3); 2.30 (s, 3H, CH3) ppm. 13C-NMR
(50.3 MHz, CDCl3): δ = 168.7, 166.9, 159.1 (d, JC-F = 266.2 Hz), 152.9,
138.4, 131.7, 130.25 (d, JC-F = 3.1 Hz), 129.5 (d, JC-F = 7.8 Hz), 128.4,
128.0, 124.5, 123.95 (d, JC-F= 3.4 Hz), 120.9, 114.9 (d, JC-F = 22.2 Hz),
51.9, 21.0 ppm. MS: m/z (%) = 288 (13) [M]+, 246 (76), 227 (15), 215
(100), 186 (9), 157 (19), 133 (9). C16H13FO4 (288): calcd. C 66.66, H
4.55; found C 66.46, H 4.71.
Methyl 4-(Acetyloxy)-2-{5-methoxy-1-[(4-methylphenyl)sulfon-
yl]-1H-indol-3-yl}benzoate (2r): Eluent EtOAc/Hex, 30:70; yellow
oil (63 % overall isolated yield), m.p. 55–57 °C. IR (KBr): ν = 2950,
˜
Methyl 5-(Acetyloxy)-2′,4′-dichlorobiphenyl-2-carboxylate (2k):
1758, 1717, 1471, 1370, 1175, 1128, 925, 811, 751 cm–1
.
1H-NMR
EluentEtOAc/Hex, 20:80; yellow oil (45 % overall isolated yield). IR
(KBr): ν = 2951, 1772, 1733, 1370, 1287, 1202, 929, 780 cm–1 1H-
.
(200 MHz, CDCl3): δ = 7.99–7.88 (m, 2H, ArH); 7.78 (d, 2H, J = 8.3 Hz,
ArH); 7.59 (s, 1H, ArH); 7.32–7.14 (m, 4H, ArH); 6.94 (dd, 1H, J = 9.0,
2.5 Hz, ArH); 6.75 (d, 1H, J = 2.5 Hz, ArH); 3.74 (s, 3H, OCH3); 3.35 (s,
3H, OCH3); 2.35 (s, 3H, CH3); 2.34 (s, 3H, CH3) ppm. 13C-NMR
(100.6 MHz, CDCl3): δ = 168.9, 167.8, 156.7, 152.9, 144.8, 135.1,
134.5, 132.0, 131.2, 129.8 (2C), 129.3, 128.8, 126.8 (2C), 124.7, 124.4,
122.8, 120.9, 114.7, 114.3, 55.5, 51.2, 21.5, 21.1ppm. HRMS m/z:
[M + Na]+, (C26H23BrNO7SNa) 516.1087, found 516.1099.
˜
NMR (200 MHz, CDCl3): δ = 8.09 (d, 1H, J = 8.6 Hz, ArH); 7.47 (d, 1H,
J = 2.4 Hz, ArH); 7.36–7.17 (m, 3H, ArH); 7.02 (d, 1H, J = 2.4 Hz, ArH);
3.72 (s, 3H, OCH3); 2.33 (s, 3H, CH3) ppm. 13C-NMR (50.3 MHz, CDCl3):
δ = 183.6, 181.1, 168.0, 156.1, 153.2, 148.8, 148.3, 146.9, 144.7, 143.8,
142.3, 141.8, 139.1, 136.2, 67.1, 36.1 ppm. MS: m/z (%) = 303 (69)
[M – Cl]+, 261 (100), 246 (28), 230 (9), 202 (12), 173 (13), 139 (9).
C16H12Cl2O4 (339): calcd. C 56.66, H 3.57; found C 56.89, H 3.42.
Methyl 4-(Acetyloxy)-2-(1-benzothien-2-yl)benzoate (2s): Eluent
Methyl 5-(Acetyloxy)-2′-bromo-4′-chlorobiphenyl-2-carboxylate
EtOAc/Hex, 30:70; yellow oil (59 % overall isolated yield). IR (KBr):
(2l): Eluent EtOAc/Hex, 20:80; yellow oil (57 % overall isolated yield).
ν = 2950, 1762, 1727, 1601, 1251, 1204, 1013, 838, 726 cm–1 1H-
.
1
IR (KBr): ν = 2951, 1765, 1726, 1469, 1369, 1201, 927, 774 cm–1. H-
˜
˜
NMR (200 MHz, CDCl3): δ = 7.91–7.77(m, 3H, ArH); 7.44–7.27 (m, 4H,
ArH); 7.23 (dd, 1H, J = 8.4, 2.3 Hz, ArH); 3.74 (s, 3H, OCH3); 2.35 (s,
3H, CH3) ppm. 13C-NMR (100.6 MHz, CDCl3): δ = 168.8, 167.9,152.3,
141.3, 140.3, 139.8, 136.3, 131.3, 129.1,124.5, 124.1, 123.8, 123.2,
122.1, 121.5, 52.4, 21.1ppm.MS: m/z (%) = 326 (76) [M]+, 284 (100),
253 (82), 224 (14), 195 (16), 181 (12), 152 (15). C18H14O4S (326):
calcd. C 66.24, H 4.32; found C 66.09, H 4.47.
NMR (200 MHz, CDCl3): δ = 8.10 (d, 1H, J = 8.6 Hz, ArH); 7.65 (d, 1H,
J = 2.1 Hz, ArH); 7.36 (dd, 1H, J = 8.2, 2.1 Hz, ArH); 7.27 (dd, 1H, J =
8.6, 2.3 Hz, ArH); 7.19 (d, 1H, J = 8.2 Hz, ArH); 7.00 (d, 1H, J = 2.3 Hz,
ArH); 3.71 (s, 3H, OCH3); 2.36 (s, 3H, CH3) ppm. 13C-NMR (50.3 MHz,
CDCl3): δ = 168.6, 166.0, 153.0, 142.9, 140.3, 133.8, 131.9, 131.8,
130.5, 127.3, 127.1, 124.1, 123.0, 121.3 ppm. MS: m/z (%) = 384 (9)
[M]+, 342 (100), 311 (49), 202 (20) 173 (13), 139 (13). C16H12BrClO4
(383.6): calcd. C 50.09, H 3.15; found C 50.38, H 2.92.
Synthesis of Phenol 3: To a solution of 2a (2.4 mmol, 1 equiv.) in
20 mL of dry MeOH 2.8 mmol (1.2 equiv.) of sodium were added at
r.t. under N2 flow. After 1 h the reaction was quenched with a satu-
rated NH4Cl aqueous solution and extracted twice with EtOAc.The
combined extracts were washed with brine, dried with Na2SO4, and
concentrated under vacuum. The crude mixture was purified by
column chromatography on silica gel to give pure 3.
Methyl 4-(Acetyloxy)-2-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-
2-yl}benzoate (2n): Eluent EtOAc/Hex, 30:70; yellow oil (43 % over-
all isolated yield, a 10 % of the starting heteroarylidene acetone
was also recovered). IR (KBr): ν = 2954, 1766, 1723, 1369, 1291, 1188,
˜
921, 724 cm–1. 1H-NMR (200 MHz, CDCl3): δ = 8.06 (d, 1H, J = 8.6 Hz,
ArH); 7.44 (dd, 1H, J = 3.3, 1.7 Hz, ArH); 7.25–7.10 (m, 5H, ArH); 6.79
(d, 1H, J = 2.4 Hz, ArH); 7.34 (t, 1H, J = 3.3 Hz, ArH); 6.15 (dd, 1H,
J = 3.3, 1.7 Hz, ArH); 3.66 (s, 3H, OCH3); 2.37 (s, 3H, CH3); 2.32 (s, 3H,
CH3) ppm. 13C-NMR (50.3 MHz, CDCl3): δ = 168.5, 165.9, 152.0, 144.6,
135.5, 133.7, 132.4, 131.3, 129.8, 129.5 (2C),127.2 (2C), 126.0, 122.8,
121.7, 114.9, 11.6, 52.0, 21.5, 20.0 ppm. MS: m/z (%) = 413 (89) [M]+,
371 (18), 258 (11), 242 (36), 216 (100), 185 (39), 156 (12), 91 (43).
C21H19NO6S (413): calcd. C 61.01, H 4.63, N 3.39; found C 61.22, H
4.80, N 3.25.
Methyl 5-Hydroxybiphenyl-2-carboxylate (3): Eluent EtOAc/Hex,
20:80; yellow oil (66 % overall isolated yield). IR (KBr): ν = 3387,
˜
2952, 1670, 1436, 1294, 1204, 877, 764 cm–1
.
1H-NMR (CDCl3): δ =
7.79 (dd, 1H, J = 7.2, 1.9 Hz, ArH); 7.38–7.18 (m, 6H, ArH and ArOH);
6.80–6.73 (m, 2H, ArH); 3.63 (s, 3H, OCH3) ppm. 13C-NMR (50.3 MHz,
CDCl3): δ = 169.4, 158.9, 145.6, 141.2, 132.6, 128.1 (2C), 127.9 (2C),
127.2, 121.6, 117.9, 114.2, 52.0ppm. MS: m/z (%) = 228 (60) [M]+,
197 (100), 141 (18), 115 (15). C14H12O3 (228): calcd. C 73.67, H 5.30;
found C 73.50, H 5.53.
Methyl 4-(Acetyloxy)-2-{1-[(4-methylphenyl)sulfonyl]-1H-indol-
3-yl}benzoate (2p): Eluent EtOAc/Hex, 30:70; light yellow solid
Synthesis of Brominated Phenols 4 and 5: To a cooled (–5 °C)
solution of 3 (0.4 mmol, 1 equiv.) in DCM (4.5 mL) a solution of Br2
(64 % overall isolated yield), m.p.58–60 °C. IR (KBr): ν = 2948, 1771,
˜
1721, 1602, 1448, 1368, 1175, 1010, 963, 915, 748 cm–1
.
1H-NMR (0.4 mmol, 1 equiv.) in DCM (2 mL) was added dropwise over
(200 MHz, CDCl3): δ = 8.07–7.93 (m, 2H, ArH); 7.82 (d, 2H, J = 8.3 Hz,
ArH); 7.64 (s, 1H, ArH); 7.40–7.19 (m, 7H, ArH); 3.36 (s, 3H, OCH3);
30 min. After stirring for an extra hour, the mixture was diluted with
EtOAc and the organic layer was washed with water and brine,
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dried with MgSO4, and concentrated in vacuo. Silica gel column
chromatography allowed to isolate 4 and 5 in 85 % overall isolated
yield.
55 equiv.) to which hydrogen iodide (58.8 mmol, 117 equiv.) was
added dropwise. Reaction quenching was achieved after 18 h sim-
ply adding water and washing the mixture with a saturated aque-
ous solution of Na2SO3. After extracting with EtOAc (three times)
the organic phase was washed with brine and dried with Na2SO4.
After evaporation of the organic solvent, the solid residue was tritu-
rated with Et2O to give pure 8 without any further purification.
Methyl 4-Bromo-5-hydroxybiphenyl-2-carboxylate (4): Eluent
Et O/Hex, 30:70; yellow oil (21 % yield). IR (KBr): ν = 3350, 2952,
˜
2
1700, 1591, 1437, 1308, 1253, 1104, 905, 766 cm–1. 1H-NMR (CDCl3):
δ = 8.09 (s, 1H, ArH); 7.41–7.25 (m, 5H, ArH); 6.99 (s, 1H, ArH); 6.05
(br s, 1H, ArOH); 3.65 (s, 3H, OCH3) ppm. 13C-NMR (50.3 MHz, CDCl3):
δ = 166.8, 154.5, 145.0, 140.1, 134.4, 128.0, 127.9 (2C), 127.5 (2C),
123.6, 118.1, 108.6, 51.9 ppm. MS: m/z (%) = 308 (77) [M]+, 306 (76),
277 (99), 275 (100), 196 (75), 168 (37), 139 (52). C14H11BrO3 (307):
calcd. C 54.75, H 3.61; found C 54.49, H 3.90.
Isourolithin A (8):[70] white solid (93 % yield), m.p. 289–290 °C.
Acknowledgments
We gratefully acknowledge the Università degli Studi di Perugia
within financing program “Fondo per la Ricerca di Base 2017”
and Interuniversity Consortium C.I.N.M.P.I.S.
Methyl 4,6-Dibromo-5-hydroxybiphenyl-2-carboxylate (5): Elu-
ent Et2O/Hex, 30:70; yellow oil (64 % yield). IR (KBr): ν = 3355, 2950,
˜
1717, 1432, 1292, 1244, 976, 786 cm–1. 1H-NMR (CDCl3): δ = 8.15 (s,
1H, ArH); 7.46–7.43 (m, 3H, ArH); 7.19–7.14 (m, 2H, ArH); 6.45 (br s,
1H, ArOH); 3.58 (s, 3H, OCH3) ppm. 13C-NMR (50.3 MHz, CDCl3): δ =
165.4, 152.1, 144.1, 139.6, 133.7, 128.3 (2C), 127.9 (2C), 127.8, 125.1,
113.8, 108.0, 52.1 ppm. MS: m/z (%) = 308 (77) [M – Br]+, 306 (76),
277 (99), 275 (100), 196 (75), 168 (37), 139 (52). C14H10Br2O3 (386):
calcd. C 43.56, H 2.61; found C 43.40, H 2.87.
Keywords: Biaryls · Cycloaddition · Cyclization · Enones ·
Multicomponent reactions · Synthetic methods
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Metal-Free Total Synthesis of Isourolithin A (8): To a solution of
2b (1.5 mmol, 1 equiv.) in dry MeOH (20 mL) 1.8 mmol (1.2 equiv.)
of sodium methoxide were added at r.t. under N2 flow. After 1 h
the reaction was quenched with 10 % HCl aqueous solution and
extracted twice with EtOAc. The combined extracts were washed
with brine, dried with Na2SO4, and concentrated under vacuum.
The crude residue was dissolved in dry DMF (15 mL) under N2 at-
mosphere before adding NaH (1.9 mmol, 1.3 equiv.) and stirring for
1 h at r.t. Then, MeI (1.9 mmol, 1.3 equiv.) was added and the reac-
tion mixture was stirred overnight. The reaction was quenched with
10 % HCl aqueous solution and extracted three times with Et2O.
The organic layers were washed with water and brine, dried with
MgSO4, and concentrated in vacuo. The crude residue was dissolved
in MeOH (10 mL) and a solution of KOH (4.5 mmol, 3 equiv.) in
10 mL of water was slowly added. After stirring for 24 h at 95 °C,
the solution was acidified with 10 % HCl aqueous solution and ex-
tracted three times with DCM. The organic phase was washed with
brine, dried with Na2SO4, and concentrated under reduced pressure
to give pure acid 6.
4′,5-Dimethoxybiphenyl-2-carboxylic Acid (6): Yellow solid (97 %
overall isolated yield), m.p.158–160 °C; IR (KBr): ν = 3275, 2921, 1678,
˜
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12.40 (s, 1H, COOH); 7.67 (d, 1H, J = 8.7 Hz, ArH); 7.17 (d, 1H, J =
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Received: October 17, 2019
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Multicomponent Reactions
A. Temperini,* D. Lanari,
F. Colognese, F. Piazzolla .............. 1–10
Scalable Multicomponent Synthesis
of (Hetero)aryl-Substituted Phenyls:
Focus on Metal-Free Halogenated
Biaryls, 3-Arylindoles, and Isouro-
lithine A Synthesis
A
simple, scalable and metal-free in a pressure metal vessel. Aromatiza-
multicomponent enol acetylation of tion of the cycloadduct intermediates
(hetero)arylidene acetones followed yielded the corresponding functional-
by a thermal Diels-Alder reaction with ised (hetero)biaryls.
methyl propiolate was accomplished
DOI: 10.1002/ejoc.201901551
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