Photoinduced Synthesis of Dibenzofurans: Intramolecular and Intermolecular Comparative Methodologies

Article abstract of DOI:10.1021/acs.joc.8b00742

The S_RN1 reaction has been used as a powerful tool for the synthesis of heterocycles, and only a few studies about photoinduced intramolecular cyclization to generate a new C-O bond by a radical pathway have been reported. This work introduces two strategies for the synthesis of substituted dibenzofurans by electron transfer (eT) reactions. The first one is a three-step process that comprises bromination of o-arylphenols, Suzuki-Miyaura cross-coupling and photoinduced cyclization in order to obtain the above-mentioned products. The second one is a metal-free procedure and does not require any photocatalyst. Different solvents were tested, and the yields ranged from low to moderate. A comparison was established between both methodologies, showing that the second one is the most suitable for the synthesis of dibenzofurans.

Full text of DOI:10.1021/acs.joc.8b00742

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Article
Photoinduced Synthesis of Dibenzofurans. Intramolecular
and Intermolecular Comparative Methodologies.
Patricia Camargo Solórzano, Federico Brigante, Adriana Beatriz Pierini, and Liliana Beatriz Jimenez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00742 • Publication Date (Web): 01 Jun 2018
Downloaded from http://pubs.acs.org on June 1, 2018
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Photoinduced Synthesis of Dibenzofurans.
Intramolecular and Intermolecular
Comparative Methodologies
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†
Patricia Camargo Solórzano, Federico Brigante, Adriana B. Pierini,
Liliana B. Jimenez*
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional
de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
CORRESPONDING AUTHOR FOOTNOTE (Phone number: (+54) 351ꢀ5353867 int.53330, eꢀmail:
ljimenez@fcq.unc.edu.ar)
†
Prof. Adriana B. Pierini deceased on 29th of July, 2016
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GRAPHICAL ABSTRACT
B(OH)2
Cl
R2
R3
OH
I
OH
R3
R3
Br
O
Br
R3
OH
R1
h , eT
h , eT
R1
Cl
+
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step 2
step 3
Suzuki-Miyaura
coupling
R2
R2
R1
R2
step 1
3
R1
2
1
5
4
Method B
Method A
ABSTRACT
The S 1 reaction has been used as a powerful tool for the synthesis of heterocycles, only few
RN
studies about photoinduced intramolecular cyclization to generate a new CꢀO bond by a radical
pathway have been reported. This work introduces two strategies for the synthesis of substituted
dibenzofurans by electron transfer (eT) reactions. The first one is a threeꢀstep process that comprises
bromination of oꢀarylphenols, SuzukiꢀMiyaura crossꢀcoupling and photoinduced cyclization in order to
obtain the aboveꢀmentioned products. The second one is a metalꢀfree procedure and does not require
any photocatalyst. Different solvents were tested and the yields ranged from low to moderate. A
comparison was established between both methodologies showing the second one is the most suitable
for the synthesis of dibenzofurans.
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INTRODUCTION
The dibenzofuran nucleus provides chemical characteristics that enable it to position itself as a
versatile molecule in different fields of chemical research. Different potential applications have been
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studied such as anticancer, antioxidant, antibacterial and as enzyme inhibitors. In addition,
1
0
substituted dibenzofurans have been used in the development of OLED.
Due to its promising activity in the development of optoelectronic materials and their intriguing
biological properties, in the last decade, the chemical synthetic community has focused on improving
the methodologies that allow to access to the substituted dibenzofuran nucleus. The synthetic
approaches to prepare dibenzofurans can be classified into two main categories. One involves the
1
1ꢀ13
construction of the dibenzofuran from diaryl ethers.
the new CꢀC bond proceeds through three sequential steps, in the presence of Pd,
The second category refers to the intramolecular oꢀarylation of 2ꢀarylphenols. This method is mainly
The mechanism proposed for the formation of
1
4,15
16
17
Rh or Ag.
1
8ꢀ21
22
based on the activation of CꢀH bonds catalyzed by Pd
or Cu and a subsequent intramolecular
2
3,24
etherification. The last step can also be achieved by starting from 2'ꢀhaloꢀarylphenols.
Moreover, a
few examples are reported where dibenzofurans are generated from 2'ꢀhaloꢀarylphenols in metalꢀfree
conditions, employing light or high temperatures. An example is the synthesis of naphtho[1,2ꢀ
25
b]benzofuran, which was reported by photocyclization of 1ꢀ(2ꢀchlorophenoxy)naphthalene.
Furthermore, intramolecular Oꢀ/Nꢀarylations afford dibenzofurans and carbazoles respectively by a
20
typical S Ar pathway, in presence of potassiumꢀtertꢀbutoxide and high temperatures. Recently, a
N
combination of in situ diazotization and a later photocatalytic process promoted by a photosensitizer
was reported for the synthesis of dibenzofurans from 2ꢀ(2’ꢀaminoaryl)phenols. These substrates were
26
synthetized previously by CꢀH bond activation mainly, using metal catalysts as Pd or Ni.
In the last years, a third approach has emerged, in which the synthesis of dibenzofurans is planned
from simpler substrates and all together react in a oneꢀpot methodology. This is the case of a Michaelꢀ
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oxidationꢀoxaꢀMichael reaction sequence to obtain dibenzo[b,d]furan scaffolds from the binding of
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substituted phenols and oꢀbenzoquinones. The construction of dibenzofuran from 6ꢀdiazoꢀ2ꢀ
cyclohexenone and oꢀhaloiodobenzene in a oneꢀpot synthesis has also been developed. In this case, the
2
8
process involves two metalꢀcatalyzed crossꢀcoupling reactions.
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However, up to now the great majority of the synthetic methods used present drawbacks such as
high temperatures, use of transition metals, tedious procedures and extensive reaction times.
On the other hand, radical synthesis has proved to be an advantageous alternative in comparison
with other mechanisms due to shorter reaction times, simpler methodologies and also involves a
29
synthetic route free of heavy metals. In particular, the radical nucleophilic substitution mechanism
3
0,31
(SRN1) is a chain process that involves radicals and radical anions as intermediates.
The initiation
step is an electron transfer (eT) from a suitable donor (e.g., the nucleophile) to afford the radical anion
of the substrate (ArX)•− as shown in Scheme 1.
Scheme 1. S 1 mechanism
RN
This process can be induced by light, inorganic salts, electrochemically, by solvated electrons or
thermally (spontaneous reactions). The S 1 mechanism offers the possibility of achieving substitution
RN
in compounds that are nonꢀreactive under classical nucleophilic substitutions, is also compatible with
many substituents and in addition, several nucleophiles such as carbanions and heteroatomic anions can
be used to form new CꢀC or Cꢀheteroatom bonds with good yields respectively. The scope of this
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process has increased considerably and currently serves as an important synthetic route for different
30,31
types of compounds.
3
2
The S 1 mechanism has clearly manifested to be useful for obtaining heterocyclic compounds.
RN
Recently, the S 1 reaction was applied to form new CꢀC bonds in the synthesis of heterocycles such
RN
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as phenanthridines and benzophenanthridines,
phenanthrolines,
1ꢀphenylꢀ1ꢀoxazolylꢀindane
35
36
37,38
derivatives, cyclopentaꢀoxazoloꢀisoquinolinꢀ6ꢀones carbazoles and carbolines,
pyrrole, indole,
3
9
and pyrazole fused azaheterocycles. The formation of Cꢀheteroatom bonds is also reported as a
4
0
consequence of an intramolecular cyclization to generate compounds such as 9Hꢀcarbazoles, among
others. Although, the intramolecular reaction S 1 has been shown to be a powerful tool for the
RN
synthesis of heterocycles, only few reports about photoinduced intramolecular cyclization to generate a
new CꢀO bond by a radical pathway have been found. Benzoxazoles from pyrroleꢀ2ꢀcarboxamide or
41
indoleꢀ2ꢀcarboxamide, naphtho[2,1ꢀb]benzofurans from the photostimulated reaction between oꢀ
4
2
bromoiodobenzene and the 2ꢀnaphthoxide ion and phenanthro[9,10ꢀb]benzofuran from the oꢀ
4
3
dihalobenzene and the anion of phenanthrenꢀ9ꢀol.
Therefore, we were interested in developing a complementary approach to have access to the
dibenzofuran framework by photostimulated eT reactions. Two synthetic pathways were studied to
obtain the same substituted dibenzofuran. In the first one, substituted oꢀarylphenols were used and, in
the second pathway, substituted phenols and oꢀdihalobenzene react in a oneꢀpot method for the
synthesis of dibenzofurans.
In the present work we first carried out the construction of 2'ꢀchloroꢀ3ꢀR ꢀ5ꢀR ꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀol
3
2
(2, R: substituent), which both, leaving group and nucleophile, are located within the same molecule
step 1, Method A in Scheme 2). In a second phase, the formation of a new CꢀO bond by a
(
photoinduced intramolecular reaction of 2, to give the corresponding substituted dibenzofurans (1) was
studied as a key step (step 2, Method A in Scheme 2). On the other hand, the development of a oneꢀpot
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methodology involving the photoinduced S 1 process to obtain 1 was also studied. This is the reaction
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between 2ꢀbromoꢀ1ꢀiodoꢀ4ꢀR benzene (5) and the substituted phenol 4 (step 3, Method B in Scheme 2).
1
B(OH)2
Cl
R2
Cl
R3
OH
I
OH
R3
R3
Br
O
Br
R3
OH
R1
h , eT
0
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h , eT
R1
+
step 2
step 3
Suzuki-Miyaura
coupling
R2
R2
R1
R2
step 1
3
R1
2
1
5
4
Method B
Method A
Scheme 2. Synthesis of substituted dibenzofurans by electron transfer reactions.
RESULTS AND DISCUSSION
Method A:
1
. Synthesis of substituted 2'-chloro-3-R -5-R -[1,1'-biphenyl]-2-ol (2) compounds (step 1, Method A)
3 2
4
4ꢀ46
Substituted 2ꢀhaloꢀphenylphenols were prepared by a crossꢀcoupling SuzukiꢀMiyaura reaction
from 2ꢀchlorophenylboronic acid and p-substituted o-brominated phenols (3) as substrates. Compounds
47ꢀ49
2
a-d were synthetized employing PPh as ligand
and a palladium source such as Pd(OAc) or
2
3
Pd(dba) . Instead, Pd/C was used for the synthesis of compounds 2e-h and no ligand was taken into
2
account (Table 1). It is noteworthy that several reaction conditions were carried out changing the
solvent, ligands or bases with the objective of improving yields of the SuzukiꢀMiyaura cross coupling
products.
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Scheme 3. Representation of the SuzukiꢀMiyaura crossꢀcoupling reaction between substituted oꢀ
bromophenols (3) and oꢀchlorophenylboronic acids.
Table 1. SuzukiꢀMiyaura crossꢀcoupling reactions for the synthesis of substituted 2'ꢀchloroꢀ3ꢀR ꢀ5ꢀ
3
a
R ꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀol (2).
2
2
Entry
3
Method
Time (h)
(% isolated yield)
b
Method with Pd-PPh3
Pd (%)
PPh (%)
3
c
2
3
a
1
2
4
0.25
0.5
2a (58)
2b (67)
Pd(OAc) 2
(
R = R = H)
2 3
3
3
b
15
30
(
R = CH , R = H)
2
Pd(OAc) 2
3
3
c
3
5
3
4
10
10
0.5
0.5
2c (15)
2d (10)
(
R = OCH , R = H)
Pd(dba)2
2
3
3
d
5
(
R = F, R = H)
Pd(dba)2
2
3
d
Method with Pd-C
Pd/C (%)
2
CsF (eq)
4
3
e
5
6
7
2.5
120
3
2e (40)
2f (20)
(
R = C(CH ) , R = H)
2 3 3 3
3
f
6
12
4
(
R = R = C(CH ) )
2 3 3 3
3
g
10
10
2g (<10)
2h (25)
(R = CN, R = H)
2
3
e
3b
8
4
3
(R = CH , R = H)
2
3
3
a
Ratio of 3:chlorophenylboronic acid was 1:1.3. Isolated yields are given in parenthese and are with respect
b
to initial substrate added. For the method A: solvent: dioxane: H O mixture in 4:1 ratio and 3 equiv of
2
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0,51
c
K PO were added. Heating was performed by MW
at 150°C for the specific time in atmosphere of N . 1
3
4
2
d
equiv of oꢀiodophenol was used as substrate. For the method B: solvent: H O (5 mL). It was used a 6% of
NBu Br. T= 80 ° C. It was used 2ꢀchloroꢀ4ꢀmethylphenylboronic acid (R =CH ).
2
e
4
1
3
Regardless of the methodology used, 2,2'ꢀdichloroꢀ1,1'ꢀbiphenyl was observed as a byproduct from
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the homocoupling of boronic acid.
oꢀBromophenols with electron withdrawing groups (EWG) as
substituents, such as 3d and 3g (Table 1, entries 4 and 7), gave the lowest yields of this set of reactions,
2d and 2g respectively.
On the other hand, substituted phenols with electron donating groups (EDG) showed better yields
such as products 2b and 2e (Table 1, entries 2 and 5). The exceptions are products 2c and 2f, which
were obtained with low yields.
In many cases, the electronic effects have been used to rationalize different reactivity of haloarenes
in crossꢀcoupling reactions, such as the SuzukiꢀMiyaura one, which is important for the regioselective
53ꢀ56
57
transformations of polyhalogenated aromatic compounds.
On the other hand, Fauvarque et al.
proposed an analogy between aromatic nucleophilic substitution (S Ar) and the oxidative addition of
N
transition metals to the Cꢀhalogen bond of haloarenes. They postulated that brominated phenols would
behave as nucleophiles, and that their performance would be determined by the inductive effect, charge
effect or steric hindrance that each substituent could contribute on the molecule.
For the phenol 3c, the presence of the methoxy group could generate an inductive effect on the
molecule, converting it into a deficient substrate (analogy with a weak nucleophile) to the oxidative
addition step with palladium. Otherwise, the presence of the two tꢀbutyl groups in 3f, would generate a
difficulty to the oxidative addition step by steric hindrance, decreasing the yield of 2f.
Product 2g was evidenced by GCꢀMS in the reaction mixture. It was isolated in very low quantity,
enough just to characterize it by NMR.
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2. Synthesis of substituted dibenzofurans (1) by photoinduced intramolecular reaction (step 2, method
A)
The substrates (2a-h) were then engaged in the S 1 reaction in order to achieve the synthesis of
RN
1
1
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3
4
5
6
7
8
9
0
the substituted dibenzofurans was further explored (Scheme 4). The results are presented in Table 2.
Scheme 4. Photostimulated intramolecular reaction of substituted 2'ꢀchloroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀols
(2).
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1
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. Photostimulated intramolecular reaction of substituted 2'ꢀchloroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀol (2) in
a
DMSO.
1
Conversion
(%)
Entry
2
(
% isolated yield)
b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2a (R = R = R = H)
1a (89)
1a (84)
1a (38)
1a --
93
88
55
--
1
2
3
2
2a (R = R = R = H)
1 2 3
c
3
2a (R = R = R = H)
1 2 3
d
4
2a (R = R = R = H)
1 2 3
e
5
2a (R = R = R = H)
1a --
--
1
2
3
f
6
2a (R = R = R = H)
1a (53)
1b (51)
1c (49)
1d (60)
1e (67)
1f (50)
1h (78)
60
90
73
92
84
84
79
1
2
3
7
8
9
2b (R =H, R = CH , R = H)
1 2 3 3
2c ( R =H, R = OCH , R = H )
1
2
3
3
2d ( R =H, R = F, R = H )
1
2
3
1
0
2e (R = H, R = C(CH ) , R = H)
1 2 3 3 3
11
2f (R = H, R = R = C(CH ) )
1 2 3 3 3
1
2
2h (R = R = CH , R = H)
1 2 3 3
a
[2]= 50 mM, [KOBuꢀt]= 0.1 M. Irradiation time= 3 h, N atmosphere. Conversion was
2
b
determined potentiometrically by titration of chloride anions with AgNO . The reaction was
carried out in 60 mL of NH (l) (−33 °C), [2a]= 4 mM, [KOBuꢀt]= 8 mM Irradiation time= 2
3
c
3
d
e
f
h. Absence of light. In the absence of KOBuꢀt. Addition of 30 mol% of mꢀDNB respect to
a.
2
After 180 min of irradiation, the reaction of 2'ꢀchloroꢀ[1,1'ꢀbifenil]ꢀ2ꢀol (1a) in liquid ammonia
with excess of KOBuꢀt (2 equiv) afforded the dibenzofuran (1a) in 89% yield (Table 2, entry 1). A
similar result was obtained in DMSO as solvent (Table 2, entry 2). As the yields of 1a have no
significant difference with the change of the solvent, DMSO was preferred to simplify the experimental
setꢀup.
Monosubstituted and disubstituted dibenzofurans 1b-h were obtained in moderate to good yields
using 2b-2h. Quantification of chloride ion informs about the conversion of the substrate. The reduced
product was evidenced only in traces in some of the reactions, which is obtained from the hydrogen
●
atom abstraction by the radical (2a ), usually from the solvent. In general, the conversions are very
good for all substrates studied.
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4
There was no reaction under dark conditions (in absence of light), which excludes a benzyne
mechanism (Table 2, entry 4). The effect of the base was evaluated by carrying out the photostimulated
reaction in the absence of KOBuꢀt (Table 2, entry 5) and no product 2a was observed. It is necessary to
have the anion form of the substrate for the mechanism success. Also, the photostimulated reaction was
partially inhibited when adding 30 mol% of mꢀdinitrobenzene (mꢀDNB), a strong electronꢀacceptor
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Table 2, entry 6), which would indicate the presence of radical anions in the reaction mechanism.
The results suggest that the formation of the new CꢀO bond occurs through eT reactions with
radicals and radical anions as intermediates. The formation of the dibenzofuran 1a via the nucleophilic
radical substitution mechanism S 1 (scheme 5).
RN
Scheme 5. Mechanism proposed for the synthesis of dibenzofuran 1a by a photoinduced intramolecular
SRN1 reaction.
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Method B:
-
Synthesis of substituted dibenzofurans by photoinduced intermolecular reaction
In order to explore deeper the synthesis of dibenzofurans by reactions that are free of heavy metals,
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a oneꢀpot methodology was proposed to obtain substituted dibenzofurans following a bimolecular
coupling between pꢀsubstituted phenols and 2ꢀbromoꢀ1ꢀiodoꢀ4ꢀR benzene under S 1 conditions
1
RN
(scheme 6).
Scheme 6. Synthesis of substituted dibenzofurans (1) by photostimulated nucleophilic substitution of 2ꢀ
bromoꢀ1ꢀiodoꢀ4ꢀR benzene (5) with substituted phenols (4).
1
58
The reaction conditions and optimization were explored with 4e as a model substrate. When
reaction of 4e with 2ꢀbromoiodobenzene (5a) was carried out for 3 hours, in liquid ammonia as solvent,
the corresponding dibenzofuran 1e (15% yield) was obtained. When the irradiation time has increased
to 6 h, the yield of 1e was improved (55%, Table 3, entry 5). Both results obtained for the yield of 1e
are similar in DMSO and NH , 52% and 55% respectively, (Table 3, entries 1 and 5).
3
(l)
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Aromatic or benzyne mechanisms were discarded because no reaction took place in absence of
light. The yield of 1e was lower when 30 mol% of mꢀDNB was added (18%, Table 3, entries 2 and 4)
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
suggesting the participation of radical anions as intermediates. These last experiments are good
evidence of a S 1 type mechanism.
RN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Photostimulated nucleophilic substitution of pꢀsubstituted phenols (4) with 2ꢀbromoꢀ1ꢀiodoꢀ4ꢀ
a
R benzene (5).
1
ꢀ
ꢀ
Reaction
time (h)
I
Br
Entry
1
5
4
(%)
(%)
1
(
% isolated yield)
5a (R = H)
4e (R = C(CH ) , R = H)
6
6
6
2
6
4
6
4
7
6
8
6
6
6
6
1e (52)
ꢀꢀ
75
ꢀꢀ
69
ꢀꢀ
1
2
3 3
3
b
2
4e (R = C(CH ) , R = H)
2 3 3 3
c
3
4e (R = C(CH ) , R = H)
ꢀꢀ
ꢀꢀ
ꢀꢀ
2
3 3
3
d
4
4e (R = C(CH ) , R =H)
1e (18)
1e (55)
1a (20)
1b (57)
1c (40)
1d (15)
1f (40)
1g (31)
1i (47)
1j (64)
1k (43)
1l (48)
77
79
93
88
99
20
98
65
92
99
87
81
20
76
74
69
96
15
70
32
49
92
80
54
2
3 3
3
e
5
4e (R = C(CH ) , R = H)
2 3 3 3
f
6
4a (R = R = H)
2 3
7
8
4b (R = CH , R = H)
2 3 3
4c (R = OCH , R = H)
2
3
3
9
4d (R = F, R =H)
2 3
10
4f (R = R = C(CH ) )
2 3 3 3
1
1
4g (R = CN, R = H)
2 3
12
4i (R = R = CH )
2 3 3
e
1
3
5b (R = CH )
4d (R = F, R = H)
2 3
1
3
1
4
4e (R = C(CH ) , R = H)
2 3 3 3
e
1
5
a
5c (R = OCF )
4c (R = OCH , R = H)
2 3 3
1
3
[5]= 50 mM, [4]= 0.15 M, [KOBuꢀt]= 0.15 M, N atmosphere. Halide ions were determined potentiometrically
2
by titration with AgNO . Bromobenzene, benzene and 2ꢀbromoiodobenzene were found as byproducts but they
3
b
c
d
e
were not quantified. Absence of light. In the absence of KOBuꢀt. 30 mol % of mꢀDNB was added. NH (l) as
solvent, [5]= 2 mM, [4]= 6 mM, [KOBuꢀt]= 6 mM. Traces of [1,1'ꢀbiphenyl]ꢀ4ꢀol was detected by CGꢀMS.
3
f
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5
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6
The mechanism proposed for the synthesis of products 1 by the bimolecular pathway is shown in
Scheme 7. As can be seen, the 2ꢀbromophenyl radical generated in step 1’ may couple at the orthoꢀC
respecting to the CꢀO bond of the substituted phenolate ion to finally generate the monosubstituted
product with retention of the bromine atom 6 (step 2’). On the other hand, fragmentation of the CꢀBr
bond by intramolecular eT (intraꢀeT) and later deprotonation affords the radical anion intermediate 2•−,
which by an intramolecular cyclization finally produces the substituted dibenzofuran 1 (step 3’).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Mechanism proposed to obtain dibenzofurans by a bimolecular mechanism type S 1.
RN
The aim to extend this oneꢀpot methodology for the synthesis of monosubstituted dibenzofurans
was evaluated using different pꢀsubstituted phenols (4) with 2ꢀbromoꢀ1ꢀiodobenzene (5a), (Table 3,
entry 5ꢀ9 and 11). The yields ranged from low to moderate. It was observed that reactions with phenols
4
d and 4g, having a EWG as substituent, give lower yields of their products 1d and 1g respectively,
than the phenols with EDG substituents employed. This is in agreement with previous studies where it
was shown that, under electrochemical or photostimulated initiation, the substitution yields on arylated
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2
2
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substrates increase when the phenoxy ion has electron donor groups as substituents such as pꢀOCH or
3
59ꢀ62
2
,4ꢀdiꢀC(CH ) .
3 3
In the same way, it can be assumed that EWG located at the para position in the phenol generates a
lower reactivity of the phenoxy anion by converting it into a less reactive nucleophile. For this type of
phenols, the coupling reaction between the nucleophile and the substrate radical and the eT from the
radical anion of the substitution product towards the substrate become the crucial steps. When these
steps are not efficient, the chain will be short or even nonꢀexistent and the scope of substitution will
0
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0
1
2
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9
0
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0
1
2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
0
fail. Therefore, for these cases it is necessary that the chain restarts constantly; which means longer
irradiation times. This was also observed experimentally, products 1d and 1g required higher times of
photostimulation.
ꢀ
The quantification of I indicates the generation of the radical anion of substrate 5a and its
subsequent mesolytic fragmentation and it seems to be efficient under this methodology. This is also
confirmed because the main byproducts found were benzene and bromobenzene for all reactions
(compounds resulting from H atom abstraction).
The monosubstitution compound with the second halogen retention was not observed as a
byproduct, except in the reaction of phenol 4d (traces) and 4g. For this last particular case, 1g and 6g
were found as reaction products. This can be explained by an intermolecular eT after the first
substitution (step 2’, scheme 7) competing with the intramolecular eT to give the final cyclized product
(step 3’, scheme 7). The ratio between monosubstituted and cyclized product depends on the relative
3
0,63
rate constants for both intraꢀeT and interꢀeT pathways.
It was observed the 2'ꢀbromoꢀ6ꢀhydroxyꢀ
[1,1'ꢀbiphenyl]ꢀ3ꢀcarbonitrile (6g) compound as an intermediate in the formation of the cyclized
64
product 1g (scheme 8).
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1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
By the other hand, the intraꢀeT could also occur simultaneously and lead to the formation of 1g
through the intermediary of (2g)•−.
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8. Mechanism proposed for the formation of the compound dibenzo[b,d]furanꢀ2ꢀ
carbonitrile 1g.
Phenols 4f and 4i generate disubstituted dibenzofurans 1f and 1i in moderate yields, 40 and 47 %
respectively. Moreover, the disubstitution in the dibenzofuran can be in both aromatic rings by
changing the substrate to a substituted oꢀdihalobenzene. Dibenzofurans 1j-l were obtained in moderate
yields following the same experimental procedure, from substrates 5b and 5c (Table 3, entries 13ꢀ15).
The versatility of this methodology is also demonstrated by the use of an oꢀdihaloheterocycle as
substrate. 6ꢀ(tertꢀButyl)benzofuro[2,3ꢀb]pyridine (7) was obtained in 25 % isolated yield when the
reaction between 3ꢀbromoꢀ2ꢀchloropyridine and 4ꢀ(tert-butyl)phenol (4e) was carried out as shown in
Scheme 9.
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 9. Synthesis of 6ꢀ(tertꢀButyl)benzofuro[2,3ꢀb]pyridine (7) by photostimulated nucleophilic
substitution of 3ꢀbromoꢀ2ꢀchloropyridine with 4e.
Finally, a comparison of the yields, for the substituted dibenzofurans synthetized by eT reactions in
a oneꢀpot methodology (bimolecular reactions from pꢀsubstituted phenols) and those obtained from the
methodology involving SuzukiꢀMiyaura reactions plus intramolecular eT reactions, are presented in
Table 4.
Table 4. Dibenzofuran yields from the two different pathways.
Total yield of 1 from 2'ꢀchloroꢀ
1,1'ꢀbiphenyl]ꢀ2ꢀols synthesis
plus photoinduced eT cyclization
%)
Yield of the oneꢀpot
[
bimolecular
eT reactions
Entry
1
(
(%)
20
57
40
15
52
40
31
ꢀꢀ
47
64
43
48
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
49
34
7
6
27
10
ꢀꢀ
20
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
10
1j
1k
1l
1
1
1
2
It is clear from Table 4 that global yields of the SuzukiꢀS 1 reactions are lower than the yields of
RN
the oneꢀpot pathway, with exception of product 1a. In general, the synthesis of 2'ꢀchloroꢀ[1,1'ꢀ
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1
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
biphenyl]ꢀ2ꢀols presented several experimental difficulties, mainly due to the presence of the
unprotected hydroxyl group. Also, each SuzukiꢀMiyaura reaction that was carried out, showed different
behavior among the phenols used, so it was impossible to make only one procedure for all phenols
employed. On the other hand, the bimolecular synthesis pathway is metalꢀfree and, in general, does not
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
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7
8
9
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1
2
3
4
5
6
7
8
9
0
have big changes in the experimental conditions, only irradiation time and solvent (NH (l) or DMSO)
3
were the parameters to be considered. The same behavior was observed for the reactions when
substrates 5b and 5c were employed.
CONCLUSIONS
This work has developed a novel oneꢀpot strategy for the synthesis of substituted dibenzofurans by
eT reactions. The oneꢀpot synthetic route, which is free of transition metals, is carried out from
commercial reagents, such as pꢀsubstituted phenols and 2ꢀbromoiodobenzene, under photostimulated
conditions and exhibits moderate yields, but they are very good considering those substituted
dibenzofurans obtained from procedures which use photocatalyzers or transition metals. Moreover, the
bimolecular procedure is a more efficient option than the pathway involving SuzukiꢀMiyaura coupling
reactions for the formation of halogenated aryl phenols as substrates, and then, the intramolecular
photoinduced
eT
reaction.
Compounds
as
2ꢀmethyldibenzo[b,d]furan
(1b),
2ꢀ
methoxydibenzo[b,d]furan (1c) and 2ꢀfluorodibenzo[b,d]furan (1d) are examples of the efficiency of
2
6
the oneꢀpot synthesis since they were obtained in similar yields to those reported recently. This
methodology shows the versatility of the reaction to obtain a wide range of substituted dibenzofurans.
Different substituents could be present in pꢀsubstituted phenols and/or substituted oꢀdihalobenzenes.
This point was demonstrated by the synthesis of 5 novel dibenzofurans (1f, 1i, 1j, 1k and 1l).
EXPERIMENTAL SECTION
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Phenols, KOBuꢀt, boronic acids, dimethoxyethane, NBS, acetonitrile, ammonium acetate,
palladium (II) acetate, Pd(dba) , triphenylphosphine, bases used in Suzukiꢀmiyaura reactions, 2ꢀ
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bromoiodobenzene and 3ꢀbromoꢀ2ꢀchloropyridine were obtained from SigmaꢀAldrich and used as
received. 2ꢀbromoꢀ1ꢀiodoꢀ4ꢀmethylbenzene (5b) and 2ꢀbromoꢀ1ꢀiodoꢀ4ꢀ(trifluoromethoxy)benzene
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(5c) were synthetized from their respective oꢀbromoaniline derivatives following the procedure of the
65
Sandmeyer reaction. Dimethylformamide and dimethylsulfoxide are Carlo Erba and were stored
under molecular sieves (4Å). Dimethoxyethane (Aldrich) was used as received. Photoirradiation was
performed in a reactor equipped with two 400 W lamps (Philips model Master HPIꢀT Plus, airꢀ and
waterꢀcooled). The Figure S1 in SI shows the spectrum of the lamps. Microwave monomode CEMꢀ
Discovery reactor was employed for SuzukiꢀMiyaura reactions showed in Table 1 described by method
A. Reactions were performed in a single mode instrument equipped with a noncontact infrared
temperature sensor, direct pressure control system for measuring the pressure of the reaction sealed
vessel contents and a cooling system by compressed air. The sample vessels reach the selected
temperature in about 30 s. Although, the maximum microwave power was set at 150 W, after the initial
heating pulse of maximum 100 W for 30 s, the average applied power was about 1 W to keep the
selected temperature. After 10 min of irradiation the device cooled the tube to 50 ºC with compressed
air above 1 min. The average pressure in the vessel was 1.7 atm during the reaction time. After
completion of the reaction, the vessel was removed from the microwave cavity and opened to the
atmosphere for extraction of the crude. HPLC analysis were carried out on a Waters 1525 Binary
HPLC Pump connected to a Waters 2998 Photodiodo Array Detector, and employing an Agilent
Zorbax Eclipse XDBꢀC18 Analytical column (4.6 x 150 mm, 5 ꢀm) and RxꢀSil Analytical column (4.6
x 150 mm, 5 ꢀm). Gas chromatographic analysis was performed on a Varian GC with a flame
1
ionization detector, and equipped with a VFꢀ5ms, 30 m x 0.25 mm x 0.25 mm column. H NMR and
1
3
C NMR were recorded on a 400 MHz Bruker nuclear magnetic resonance spectrometer. HRꢀMS were
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recorded on a Bruker, MicroTOF Q II equipment, operated with an ESI source in (positive/negative)
mode, using nitrogen as nebulizing and drying gas and sodium formiate 10 mM as internal standard.
Gas Chromatographic/Mass Spectrometer analysis were carried out on a Shimadzu GCꢀMS QP 5050
spectrometer equipped with a VFꢀ5ms, 30 m x 0.25 mm x 0.25 mm column. Potentiometric titration of
halide ions was performed with a pH meter (Orion) using an Ag/AgCl electrode.
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General procedures for the synthesis of brominated phenols (3a-g).
The synthesis of pꢀRꢀoꢀbromophenols was carried out following different procedures and they were
6
6ꢀ68
slightly modified.
The bromophenols were identified by GCꢀMS.
Synthesis of 3b, 3f and 3g. 3 mL of acetonitrile and 1 mmol of a corresponding phenol (4b, 4f and 4g)
were added to a 25 mL roundꢀbottomed flask with a magnetic stirrer. After a few minutes, 0.1 eq. of
CH COONH was added to the mixture. Finally, a solution of 1.05 eq. of NBS dissolved in 2 mL of
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acetonitrile was added. It was stirred until no substrate was observed. 3b: 55% yield (102.3 mg), 3f:
8% yield (165 mg) and 3g: 60% yield (118 mg).
5
Synthesis of 3c and 3d. The reaction was carried out under inert atmosphere. The phenol (1 mmol, 4c
and 4d) was dissolved in 4 mL of acetonitrile and cooled to 0 ºC. The NBS solution (1.05 eq. of NBS
dissolved in 2 mL of CH CN) was added dropwise. After total addition of NBS, the mixture was stirred
3
at room temperature until total conversion of the phenol. 3c: 64% yield (129 mg) and 3d: 70% yield
(133 mg).
Synthesis of 3e. The reaction was carried out under inert atmosphere. The phenol (1 mmol, 4e and 4h)
was dissolved in 1 mL of acetonitrile and cooled to ꢀ20 ºC. CF₃SO₃H (1.2 eq.) was added to the
mixture and, then, a NBS solution (1.05 eq. of NBS dissolved in 2 mL of CH CN) was also added, both
3
dropwise. After total addition of NBS, the mixture was stirred at room temperature until total
conversion of the phenol. 3e: 76% yield (173 mg).
For all the methodologies described above, the reactions were quenched by addition of NaHCO to
3
reach a pH=7. Extractions were carried out employing CH Cl and H O (x3). The organic extracts were
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dried with Na SO , filtered, and evaporated under reduced pressure. The crudes were analyzed by GCꢀ
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MS and the products were purified by column chromatography using as eluent pentane / ethyl acetate
80/20).
General procedures for the synthesis of 2'-chloro-3-R -5-R -[1,1'-biphenyl]-2-ol (2).
(
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Method with PdꢀPPh (synthesis of 2aꢀd): Palladium (II) acetate or Pd(dba) , triphenylphosphine
3
2
(the equivalents and Pd source are shown in Table 1) and 4 mL of dioxane were added to a microwave
sealed tube and stirred for 10 minutes. Then, the corresponding brominated phenol (1 eq, 1 mmol), 2ꢀ
chlorophenylboronic acid (1.5 eq., 1.5 mmol), K PO (3 eq., 3 mmol) and 1 mL of water were added.
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The tube was sealed and irradiated in the MW oven at 150°C for 15 minutes.
Method with Pd/C (synthesis of 2e-h): brominated phenol (1 eq., 0.25 mmol) and 2ꢀ
chlorophenylboronic acid (1.1 eq., 0.275 mmol) were added to a Schlenk tube with 5 mL of distilled
+
ꢀ
water. Then, (nꢀBu) N Br (6% eq.), CsF, and Pd/C (the equivalents used are indicated in Table 1) were
4
added to the mixture and stirred for the time indicated in Table 1. The system was heated to 80°C.
Products were first identified by GC and GCꢀMS. Isolated by column chromatography using
pentane and ethyl acetate. 2d and 2c were isolated by semiꢀpreparative reversedꢀphase HPLC using
acetonitrile and water as HPLC grade eluents.
General procedure for photostimulated intramolecular reaction of compounds 2.
A solution of compound 2 (1 eq., 0.245 mmol) and KOBuꢀt (2 eq., 0.5 mmol) in DMSO (5 mL) is
stirred in a previously vacuum dried Schlenk tube, under N atmosphere. The mixture is irradiated
2
under UV light for 3 h, then quenched by the addition of NH NO and deionized water. In dark
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3
reactions (without irradiation), the reaction flask was protected from light with aluminum foil and kept
under N atmosphere. For the extraction process, CH Cl (3 x 20 mL) was used. The organic extract
2
2
2
was washed until no residual of DMSO remained, then dried with Na SO , filtered, and evaporated
2
4
under reduced pressure.
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General procedure for the synthesis of substituted dibenzofurans by photoinduced
intermolecular reaction of phenols (4) and substrates (5).
Into a previously dried 20 mL Schlenkꢀtype flask (Pyrex) equipped with nitrogen inlet and magnetic
stirrer, 7 mL of dried DMSO stored under molecular sieves (4Å) was added. The solvent was degassed
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three times under vacuum and stirring, interspersed with N . Afterwards, KOBuꢀt (3.3 eq., 1.2 mmol)
2
and the corresponding phenol (3 eq., 1 mmol) were added. Five minutes later, substrate (5) (1 eq., 0.35
mmol) was added. The mixture was irradiated for 180 min then quenched by the addition of NH NO ,
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and deionized water. In dark reactions (without irradiation), the reaction flask was protected from light
with aluminum foil and keep under N atmosphere. For the extraction process, CH Cl (3 x 20 mL) was
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used. The organic extract was washed until no residual of DMSO remained, then dried with Na SO ,
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filtered, and evaporated under reduced pressure.
General procedure for the synthesis of substituted dibenzofurans by photoinduced eT reaction in
liquid ammonia.
The following procedure is representative for all reactions in NH3(l) as solvent (T= ꢀ33 ºC). The
equipment used is a closed system, composed by a 100 mL threeꢀnecked roundꢀbottomed pyrexꢀflask
with a Dewar condenser, N inlet and NH inlet (see Figure S2, SIꢀsection 1.2). The system was dried
2
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under vacuum. Liquid ammonia (100 mL), previously dried over Na metal (See Figure S3 in SI), was
distilled into the flask under nitrogen atmosphere. (See Figures S4 and S5 in SI). KOBuꢀtert and then
the precursor of the nucleophile (the substituted phenol for photoinduced bimolecular substitution)
were added to the distilled ammonia. After 15 min, the substrate (5a, 5b or 5c) was added to the
mixture (or substrates 2, SuzukiꢀMiyaura products, in the case of photoinduced unimolecular
substitution). The reaction mixture was irradiated for the time indicated in Table 3. In dark reactions
(without irradiation), the reaction flask was protected from light with aluminum foil and kept under N2
atmosphere. After 3 hours, the mixture was quenched with an excess of NH NO . The ammonia was
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allowed to evaporate, and deionized water (50 mL) with diluted sulphuric acid (until pH = 5) were
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added to the residue and extracted twice with CH Cl (30 mL). The organic extract was dried (Na SO )
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and filtered. The solvent was removed under reduced pressure and product was purified either by
column chromatography or semipreparative TLC or HPLC.
Spectroscopical information of compounds synthetized. Spectra are in Supplementary
Information Section.
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Dibenzo[b,d]furan (1a). Isolated as a white solid by semiꢀpreparative TLC, employing as eluent a
mixture pentane/CH Cl 90:10. Yield: 89% (37 mg) in step 2, 20 % (12 mg) in step 3. M.p.: 80ꢀ83 °C.
2
2
1
H NMR (400 MHz, (CD ) CO) δ 8.11 (d, 2H, J= 7.8 Hz); 7.64 (d, 2H, J= 8.2 Hz); 7.52 (t, 2H, J= 7.8
3
2
13
Hz); 7.39 (t, 1H, J= 7.5 Hz). C NMR (100 MHz, (CD ) CO) δ 157.0 (q, 2C, CꢀO); 128.3 (2C, CꢀH);
3
2
125.0 (q, 2C); 123.8 (2C, CꢀH); 121.7 (2C, CꢀH); 112.4 (2C, CꢀH).
1
3,16,69
2
-Methyldibenzo[b,d]furan (1b).
Isolated as a white solid by semiꢀpreparative TLC, employing
as eluent a mixture pentane/CH Cl 90:10. Yield: 51% (23 mg) in step 2, 57% (36 mg) in step 3. M.p.:
2
2
1
4
2ꢀ44 °C. H NMR (400 MHz, (CD ) CO) δ 8.05 (d, 1H, J= 8.0 Hz); 7.88 (s, 1H); 7.60 (d, 1H, J= 8.0
3 2
1
3
Hz); 7.51ꢀ7.47 (m, 2H); 7.39ꢀ7.31 (m, 2H); 2.48 (s, 3H, CH3). C NMR (100 MHz, (CD ) CO) δ
3 2
1
1
2
57.2 (q, CꢀO); 155.3 (q, CꢀO);133.3 (q); 129.3 (CꢀH); 128.1 (CꢀH); 125.0 (q); 124.9 (q); 123.7 (CꢀH);
21.6 (2C, CꢀH); 112.3 (CꢀH); 111.9 (CꢀH); 21.3 (CH3).
1
3,16
-Methoxydibenzo[b,d]furan (1c).
Isolated as a white solid by semiꢀpreparative TLC, employing
as eluent a mixture pentane/CH Cl 90:10. Yield: 49% (24 mg) in step 2, 40 % (28 mg) in step 3. M.p.:
2
2
1
4
5ꢀ47 °C. H NMR (400 MHz, (CD ) CO) δ 8.07 (d, 1H, J= 7.7 Hz); 7.65 (sd, 1H, J= 2.6 Hz); 7.59 (d,
3 2
1H, J= 8.8 Hz); 7.54ꢀ7.47 (m, 2H); 7.36 (t, 1H, J= 7.4 Hz); 7.10 (dd, 1H, J= 8.9 Hz, 2.6 Hz); 3.90 (s,
13
3
H, CH ). C NMR (100 MHz, (CD ) CO) δ 157.7 (q, CꢀO); 157.2 (q, CꢀO); 151.6 (q, CꢀO);128.2 (Cꢀ
3
3 2
H); 125.5 (q); 125.4 (q); 123.5 (CꢀH); 121.8 (CꢀH); 116.3 (CꢀH); 112.9 (CꢀH); 112.4 (CꢀH); 104.8 (Cꢀ
H); 56.3 (CH3).
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2-Fluorodibenzo[b,d]furan (1d).
Isolated as a white solid by semiꢀpreparative TLC, employing as
eluent a mixture pentane/CH Cl 90:10. Yield: 60% (27 mg) in step 2, 15 % (10 mg) in step 3. M.p.:
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7ꢀ89 °C. H NMR (400 MHz, (CD ) CO) δ 8.11 (d, 1H, J= 7.7 Hz); 7.86 (dd, 1H, J= 8.4 Hz, J= 2.7
3 2
Hz); 7.65ꢀ7.62 (m, 2H); 7.55 (td, 1H, J= 7.8 Hz, J= 1.3 Hz); 7.40 (t, 1H, J= 7.7 Hz); 7.29 (td, 1H, J=
0
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.0 Hz, 2.7 Hz). C NMR (100 MHz, (CD ) CO) δ 160.0 (d, q, CꢀF, J = 236.2 Hz); 158.1 (q, CꢀO);
3
2
CꢀF
53.1 (q, CꢀO); 129.0 (CꢀH); 126.05 (d, q, JCꢀF = 10.5 Hz); 124.7 (q); 123.9 (CꢀH); 122.2 (CꢀH); 115.4
(d, CꢀH, JCꢀF = 26.0 Hz); 113.4 (d, CꢀH, JCꢀF = 9.3 Hz); 112.6 (CꢀH); 107.7 (d, CꢀH, JCꢀF = 25.4 Hz).
7
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-(tert-Butyl)dibenzo[b,d]furan (1e). The product was isolated and purified as a white solid by semiꢀ
preparative TLC, employing as eluent a mixture pentane/CH Cl 90:10. Yield: 67% (37 mg) in step 2,
2
2
1
52 % (41 mg) in step 3. H NMR (400 MHz, (CD ) CO) δ 8.16 (sd, 1H, J= 1.6 Hz); 8.12 (d, 1H, J= 7.6
3
2
1
3
Hz); 7.62ꢀ7.59 (m, 2H); 7.55ꢀ7.47 (m, 2H); 7.37 (t, 1H, J= 7.5 Hz); 1.43 (s, 9H). C NMR (100 MHz,
(
CD ) CO) δ 157.4 (q, CꢀO); 155.2 (q, CꢀO); 147.0 (q); 128.0 (C ꢀH); 126.0 (C ꢀH); 125.4 (q); 124.6
3
2
Ar
Ar
(q); 123.6 (C ꢀH); 121.6 (C ꢀH); 118.1 (C ꢀH); 112.3 (C ꢀH); 111.7 (C ꢀH); 35.5 (q); 32.2 (3C,
Ar
Ar
Ar
Ar
Ar
CH3).
,4-di-tert-Butyldibenzo[b,d]furan (1f). The product was isolated and purified as an oil by semiꢀ
preparative TLC, employing as eluent a mixture pentane/CH Cl 90:10. Yield: 50% (34 mg) in step 2,
2
2
2
1
4
1
0% (39 mg) in step 3. H NMR (400 MHz, (CD ) CO) δ 8.09 (d, 1H, J= 7.6 Hz); 8.00 (s, 1H); 7.64 (d,
3 2
13
H, J= 8.2 Hz); 7.52ꢀ7.46 (m, 2H); 7.35 (t, 1H, J= 7.4 Hz); 1.58 (s, 9H); 1.43 (s, 9H). C NMR (100
MHz, (CD ) CO) δ 156.9 (q, CꢀO); 153.4 (q, CꢀO); 146.7 (q); 134.8 (q); 127.7 (C ꢀH); 125.4 (q);
3 2
Ar
1
25.0 (q); 123.5 (C ꢀH); 122.6 (C ꢀH); 121.4 (C ꢀH); 115.9 (C ꢀH); 112.3 (C ꢀH); 35.6 (q); 35.3
Ar Ar Ar Ar Ar
+
(
q); 32.2 (3C, CH ); 30.2 (3C, CH ). HRMS (ESIꢀTOF) m/z: [M+H] Calcd. for C H O: 281.1900;
3 3 20 25
Found: 281.1910.
1
9
Dibenzo[b,d]furan-2-carbonitrile (1g). The product was isolated and purified as a solid by semiꢀ
preparative TLC, employing as eluent a mixture pentane/CH Cl 90:10. Yield: 31% (21 mg). M. p.:
2
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139ꢀ141 ºC. H NMR (400 MHz, (CD ) CO) δ 8.61 (sd, 1H, J = 1.2 Hz), 8.23 (d, J = 8.0 Hz, 1H), 7.92
3 2
(
dd, 1H, J = 8.4 Hz, J = 1.6 Hz), 7.85 (d, 1H, J = 8.4 Hz), 7.73 (d, 1H, J = 8.4 Hz); 7.64 (td, 1H, J =
13
7
.2 Hz, J = 1.2 Hz); 7.50 (td, 1H, J = 8.0 Hz, J = 0.8 Hz). C NMR (100 MHz, (CD ) CO) δ 158.8 (Cꢀ
3
2
O), 157.6 (CꢀO), 132.1 (CꢀH), 129.9 (CꢀH), 126.8 (CꢀH), 126.1 (q), 124.8 (CꢀH), 123.5 (q), 122.5 (Cꢀ
H), 119.6 (q), 111.9 (CꢀH), 113.0 (CꢀH), 107.7 (q, C≡N).
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,7-Dimethyldibenzo[b,d]furan (1h). The product was isolated and purified as a solid by semiꢀ
preparative TLC, employing as eluent a mixture pentane/CH Cl 90:10. Yield: 78% (37 mg), step 2. M.
2
2
1
p.: 72ꢀ74 ºC. H NMR (400 MHz, (CD ) CO) δ 7.91 (d, 1H, J = 7.8 Hz), 7.81 (s, 1H), 7.46 (d, 1H, J =
3
2
8
.4 Hz), 7.41 (s, 1H), 7.28 (d, 1H, J = 8.4 Hz), 7.19 (d, 1H, J = 7.9 Hz); 2.40 (s, 3H); 2.47 (s, 3H).
2,4-Dimethyldibenzo[b,d]furan (1i). The product was isolated and purified as a colorless oil by semiꢀ
1
preparative TLC, employing as eluent a mixture pentane/CH Cl 70:30. Yield: 47% (32 mg). H NMR
2
2
(400 MHz, (CD ) CO) δ 8.03 (d, 1H, J= 7.6 Hz); 7.69 (s, 1H); 7.61 (d, 1H, J= 8.2 Hz); 7.48 (dt, 1H,
3 2
1
3
J = 8.3 Hz, J = 1.1 Hz); 7.35 (t, 1H, J= 7.3 Hz); 7.14 (s, 1H); 2.53 (s, 3H); 2.45 (s, 3H). C NMR (100
1
2
MHz, (CD ) CO) δ 157.2 (q, CꢀO); 154.2 (q, CꢀO); 133.2 (q); 130.3 (C ꢀH); 127.9 (C ꢀH); 125.4 (q);
3
2
Ar
Ar
1
24.5 (q); 123.6 (C ꢀH); 122.0 (C ꢀH); 121.7 (C ꢀH); 119.0 (C ꢀH); 112.4 (C ꢀH); 21.3 (CH ); 15.1
Ar Ar Ar Ar Ar 3
+
(CH ). HRMS (ESIꢀTOF) m/z: [M+H] Calcd. for C H O: 197.0961; Found: 197.0972.
3 14 13
2
-Fluoro-7-methyldibenzo[b,d]furan (1j). The product was isolated and purified as a white solid by
semiꢀpreparative TLC, employing as eluent a mixture pentane/CH Cl 75:25. M. p.: 127ꢀ130 ºC. Yield:
2
2
1
6
4% (52 mg). H NMR (400 MHz, (CD ) CO) δ 7.97 (d, 1H, J= 7.9 Hz); 7.81 (dd, 1H, J = 8.4 Hz, J=
3 2 1
1
3
2.6 Hz); 7.60 (dd, 1H, J = 8.8 Hz, J= 2.0 Hz); 7.46 (s, 1H); 7.27ꢀ7.22 (m, 2H); 2.52 (s, 3H). C NMR
1
(100 MHz, (CD ) CO) δ 160.0 (q, CꢀF, J = 235.9 Hz); 158.6 (q, CꢀO); 153.1 (q, CꢀO); 139.7 (q, Cꢀ
3
2
1
CH ); 126.3 (q, J = 10.4 Hz ); 125.2 (C ꢀH); 122.2 (q); 121.7 (C ꢀH); 114.7 (C ꢀH, J = 26.0 Hz );
3
3
Ar
Ar
Ar
2
113.3 (C ꢀH, J = 9.4 Hz); 112.7 (C ꢀH); 107.4 (C ꢀH, J = 25.4 Hz); 21.4 (CH ). HRMS (ESIꢀTOF)
Ar
3
Ar
Ar
2
3
+
m/z: [M+H] Calcd. for C H FO: 201.0710; Found: 201.0720.
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2-(tert-Butyl)-7-methyldibenzo[b,d]furan (1k). The product was isolated and purified as a white solid
by semiꢀpreparative TLC, employing as eluent a mixture pentane/CH Cl 90:10. M. p.: 120ꢀ122 ºC.
2
2
1
Yield: 43% (34 mg). H NMR (400 MHz, (CD ) CO) δ 8.09 (ds, 1H, J= 1.6 Hz); 7.97 (d, 1H, J= 7.9
3
2
Hz); 7.56 (dd, 1H, J= 8.8 Hz, J= 1.6 Hz); 7.49 (d, 1H, J= 8.7 Hz); 7.42 (s, 1H); 7.20 (d, 1H, J= 7.9 Hz);
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
2
.50 (s, 3H); 1.42 (s, 9H). C NMR (100 MHz, (CD ) CO) δ 157.8 (q, CꢀO); 155.2 (q, CꢀO); 146.8
3
2
(
q); 138.4 (q); 125.4 (C ꢀH); 124.8 (C ꢀH); 124.7 (q); 122.8 (q); 121.2 (C ꢀH); 117.8 (C ꢀH); 112.5
Ar Ar Ar Ar
(C ꢀH); 111.5 (C ꢀH); 35.4 (q, C(CH ) ); 32.2 (CꢀH, 3C, CH ); 21.9 (CH ). HRMS (ESIꢀTOF) m/z:
Ar
Ar
3 3
3
3
+
[
M+H] Calcd. for C H O: 239.1430; Found: 239.1422.
17 19
2
-Methoxy-7-(trifluoromethoxy)dibenzo[b,d]furan (1l). The product was isolated and purified as a
white solid by semiꢀpreparative TLC, employing as eluent a mixture pentane/CH Cl 80:20. M. p.: 148ꢀ
2
2
1
1
51 ºC. Yield: 48% (54 mg). H NMR (400 MHz, (CD ) CO) δ 8.19 (d, 1H, J= 8.5 Hz); 7.70 (ds, 1H,
3 2
J= 2.6 Hz); 7.62 (s, 1H); 7.57 (d, 1H, J= 9.0 Hz); 7.35 (d, 1H, J= 7.7 Hz); 7.14 (dd, 1H, J= 9.0 Hz, J=
1
3
2.6 Hz); 3.51 (s, 3H). C NMR (100 MHz, (CD ) CO) δ 157.6 (q, CꢀO); 157.4 (q, CꢀO); 152.5 (q, Cꢀ
3
2
3
O); 148.9 (q, C ꢀOꢀCF , J= 1.9 Hz); 124.6 (q); 124.6 (q); 122.7 (C ꢀH); 121.6 (q, (125.4, 122.18,
Ar
3
Ar
1
20.3, 117.7), CF ); 117.0 (C ꢀH); 116.9 (C ꢀH); 113.1 (C ꢀH); 106.2 (C ꢀH); 105.0 (C ꢀH); 56.3
3 Ar Ar Ar Ar Ar
+
(
CH ). HRMS (ESIꢀTOF) m/z: [M+H] Calcd. for C H F O : 283.0577; Found: 283.0571.
3 14 10 3 3
2
4
2
'-Chloro-[1,1'-biphenyl]-2-ol (2a). The compound was isolated from the crude by column
chromatography as an oil, employing a linear gradient of eluent composed by pentane and ethyl
1
acetate, from 100 % pentane to 90%. Yield: 58% (118 mg). H NMR (400 MHz, (CD ) CO) δ 8.28 (s,
3 2
1
2
1
1H, OH); 7.48 (m, 1H); 7.36ꢀ7.34 (m, 3H); 7.235 (td, 1H, J= 7.4 Hz, J= 1.6 Hz); 7.12 (dd, 1H, J=
2
1
2
1
2
13
7
.6 Hz, J= 1.6 Hz); 6.97 (dd, 1H, J= 8.0 Hz, J= 0.8 Hz); 6.91 (td, 1H, J= 7.4 Hz, J= 0.8 Hz). C
NMR (100 MHz, (CD ) CO) δ 155.1 (q, CꢀOH); 138.6 (q, CꢀCl); 134.3 (q); 132.8 (CꢀH); 131.6 (CꢀH);
3
2
129.91 (CꢀH); 129.88 (CꢀH); 129.4 (CꢀH); 127.3 (CꢀH); 127.3 (q); 120.0 (CꢀH); 116.4 (CꢀH).
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2'-Chloro-5-methyl-[1,1'-biphenyl]-2-ol (2b). The compound was isolated from the crude by
column chromatography as a solid, employing a linear gradient of eluent composed by pentane and
1
ethyl acetate, from 100 % pentane to 90%. Yield: 67% (37 mg). M. p.: 163ꢀ165 ºC. H NMR (400
1
2
MHz, (CD ) CO) δ 8.04 (s, 1H, OH); 7.47 (m, 1H); 7.34ꢀ7.33 (m, 3H); 7.04 (dd, 1H, J= 8.2 Hz, J=
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
13
1
.6 Hz); 6.93 (sd, 1H, J= 1.6 Hz); 6.86 (d, 1H, J= 8.0 Hz); 2.27 (s, 3H, CH ). C NMR (100 MHz,
3
(
CD ) CO) δ 153.1 (q, CꢀOH); 139.05 (q, CꢀCl); 134.6 (q); 132.9 (CꢀH); 132.1 (CꢀH); 130.49 (CꢀH);
3
2
130.1 (CꢀH); 129.5 (CꢀH); 128.9 (q); 127.5 (CꢀH); 127.3 (q); 116. (CꢀH); 20.5 (CH3).
'-Chloro-5-methoxy-[1,1'-biphenyl]-2-ol (2c). The product was isolated and purified as an oil by
2
semiꢀpreparative HPLC, employing as eluent a gradient from 50:50 to 90:10 of a mixture
1
acetonitrile/water and a constant flow of 2 mL/min. Yield: 15% (35 mg). H NMR (400 MHz,
1
(
CD ) CO) δ 7.83 (s, 1H, OH); 7.49ꢀ7.43 (m, 1H); 7.37ꢀ7.33 (m, 3H); 6.90 (d, 1H, J= 8.2 Hz); 6.83
3
2
1
2
1
13
(
dd, 1H, J= 8.0 Hz, J= 2.8 Hz); 6.706 (d, 1H, J= 8.0 Hz); 3.75 (s, 3H, CH ). C NMR (100 MHz,
3
(CD ) CO) δ 153.6 (q, CꢀOH); 149.2 (q, CꢀO); 138.8 (q, CꢀCl); 134.4 (q); 132.9 (C ꢀH); 130.1 (C ꢀ
3
2
Ar
Ar
H); 129.6 (C ꢀH); 127.9 (q); 127.5 (C ꢀH); 117.3 (C ꢀH); 116.8 (C ꢀH); 115.4 (C ꢀH); 55.9 (CH ).
Ar
Ar
Ar
Ar
Ar
3
+
HRMS (ESIꢀTOF) m/z: [M+Na] Calcd. for C H ClO Na: 257.0340; Found: 257.0319.
1
3
11
2
2
'-Chloro-5-fluoro-[1,1'-biphenyl]-2-ol (2d). The product was isolated and purified as an oil by semiꢀ
preparative HPLC, employing as eluent a gradient from 70:30 to 90:10 of a mixture acetonitrile/water
1
and a constant flow of 2 mL/min. Yield: 10% (22 mg). H NMR (400 MHz, (CD ) CO) δ 8.27 (s, 1H,
3
2
1
2
OH); 7.51ꢀ7.49 (m, 1H); 7.38ꢀ7.37 (m, 3H); 7.04ꢀ6.95 (m, 2H); 6.91 (dd, 1H, J= 9.0 Hz, J= 2.9 Hz).
1
3
1
C NMR (100 MHz, (CD ) CO) δ 156.9 (q, CꢀF, d, J = 234.0 Hz); 151.7 (q, CꢀOH); 137.8 (q);
3
2
FꢀC
3
1
34.4 (q, CꢀCl); 132.9 (C ꢀH); 130.3 (C ꢀH); 130.0 (C ꢀH); 128.7 (q, d, J = 7.8 Hz); 127.7 (C ꢀ
Ar Ar Ar FꢀC Ar
2
3
2
H); 117.9 (C ꢀH, d, J = 23.1 Hz); 117.6 (C ꢀH, d, J = 8.1 Hz); 116.2 (C ꢀH, d, J = 22.7 Hz).
Ar
FꢀC
Ar
FꢀC
Ar
FꢀC
ꢀ
HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd. for C H ClFO: 221.0175; Found: 221.0171.
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5-(tert-Butyl)-2'-chloro-[1,1'-biphenyl]-2-ol (2e). The compound was isolated from the crude by
column chromatography as a pale yellow oil, employing a linear gradient of eluent composed by
1
pentane and CH Cl , from a ratio 90:10 to a 50:50. Yield: 40% (52 mg). H NMR (400 MHz,
2
2
1
2
(CD ) CO) δ 8.04 (s, 1H, OH); 7.49ꢀ7.47 (m, 1H); 7.36ꢀ7.31 (m, 3H); 7.28 (dd, 1H, J= 8.4 Hz, J= 2.4
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
13
Hz); 7.17 (sd, 1H, J= 2.4 Hz); 6.90 (d, 1H, J= 8.4 Hz); 1.31 (s, 9H, 3xCH ). C NMR (100 MHz,
3
(
CD ) CO) δ 153.0 (q, CꢀOH); 142.5 (q, CꢀCl); 139.3 (q); 134.6 (q); 133.2 (CꢀH); 130.2 (CꢀH); 129.4
3
2
(CꢀH); 128.7 (CꢀH); 127.4 (CꢀH); 126.8 (CꢀH); 116.2 (CꢀH); 116.1 (q); 34.6 (q); 31.9 (3C, CH3).
ꢀ
HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd. for C H ClO: 259.0884; Found: 259.0886.
1
6
16
3
,5-di-tert-Butyl-2'-chloro-[1,1'-biphenyl]-2-ol (2f). The compound was isolated from the crude by
column chromatography as a colourless oil, employing a linear gradient of eluent composed by pentane
1
and ethyl acetate, from 100 % pentane to 95%. Yield: 20% (32 mg). H NMR (400 MHz, (CD ) CO) δ
3
2
2
7
.52ꢀ7.49 (m, 1H); 7.38ꢀ7.37 (m, 4H); 6.7 (sd, 1H, J= 2.4 Hz); 6.85 (s, 1H, OH); 1.46 (s, 9H, 3xCH );
3
1
3
1.31 (s, 9H, 3xCH ). C NMR (100 MHz, (CD ) CO) δ 150.9 (q, CꢀOH); 142.0 (q, CꢀCl); 138.4 (q);
3
3 2
1
1
36.8 (q); 135.1 (q); 133.6 (CꢀH); 130.7 (CꢀH); 130.1 (CꢀH); 128.1 (CꢀH); 127.5 (q); 126.0 (CꢀH);
ꢀ
24.4 (CꢀH); 35.8 (q); 34.8 (q); 32.0 (3C, CH ); 30.2 (3C, CH ). HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd.
3
3
for C H ClO: 315.1510; Found: 315.1504.
20 24
2
'-Chloro-4',5-dimethyl-[1,1'-biphenyl]-2-ol (2h). The compound was isolated from the crude by
column chromatography as an oil, employing a linear gradient of eluent composed by pentane and ethyl
1
acetate, from 100 % pentane to 97%. Yield: 25% (29 mg). H NMR (400 MHz, (CD ) CO) δ 7.97 (s,
3 2
1
1
2
1H, OH); 7.29 (s, 1H); 7.20 (d, 1H, J= 8.0 Hz); 7.15 (d, 1H, J= 7.6 Hz); 7.02 (dd, 1H, J= 8.4 Hz, J=
13
2
.0 Hz); 6.90 (s, 1H); 6.84 (d, 1H, J= 8.0 Hz); 2.56 (s, 3H, CH ); 2.36 (s, 3H, CH ). C NMR (100
3
3
MHz, (CD ) CO) δ 153.2 (q, CꢀOH); 139.5 (q, CꢀCl); 135.9 (q); 134.2 (q); 132.7 (CꢀH); 132.2 (CꢀH);
3
2
130.5 (CꢀH); 130.3 (CꢀH); 128.8 (q); 128.2 (CꢀH); 127.2 (q); 116.4 (CꢀH); 20.8 (CH ); 20.5 (CH ).
3
3
ꢀ
HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd. for C H ClO: 231.0582; Found: 231.0576.
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6-(tert-Butyl)benzofuro[2,3-b]pyridine (7). The product was isolated and purified as a white solid by
semiꢀpreparative TLC, employing as eluent a mixture pentane/CH Cl 95:5. M. p.: 105ꢀ108 ºC. Yield:
2
2
1
2
5% (23 mg). H NMR (400 MHz, (CD ) CO) δ 8.62 (d, 1H, J= 4.5 Hz); 8.21 (ds, 1H, J= 1.6 Hz); 7.99
3 2
(d, 1H, J= 8.3 Hz); 7.74 (d, 1H, J= 8.8 Hz); 7.61 (d, 1H, J= 8.8 Hz); 7.51ꢀ7.47 (m, 1H); 1.45 (s, 9H).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
C NMR (100 MHz, (CD ) CO) δ 156.5 (q, CꢀO); 150.9 (q, CꢀO); 147.8 (q, C ꢀC(CH ) ); 146.1 (C ꢀ
3
2
Ar
3 3
Ar
H); 145.1 (q); 128.1 (C ꢀH); 123.8 (q); 122.4 (C ꢀH); 119.4 (C ꢀH); 117.9 (C ꢀH); 112.4 (C ꢀH);
Ar
Ar
Ar
Ar
Ar
+
35.5 (q, C(CH ) ); 32.0 (3C, CH ). HRMS (ESIꢀTOF) m/z: [M+H] Calcd. for C H NO: 226.1226;
3
3
3
15 16
Found: 226.1218.
Acknowledgments. This work was partly supported by the Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET), Secretaría de Ciencia y Tecnología, Universidad Nacional de
Córdoba (SECyT), and the Agencia Nacional de Promoción Científica y Técnica (ANPCyT). P. C. S.
gratefully acknowledges a fellowship from CONICET.
1
13
Supporting Information Available. H NMR, C NMR and 2D NMR spectra are in SI.
References
(1)
Takahashi, S.; Suda, Y.; Nakamura, T.; Matsuoka, K.; Koshino, H. Total Synthesis of
Kehokorins A–E, Cytotoxic pꢀTerphenyls. J. Org. Chem. 2017, 82, 3159.
(2) Watanabe, K.; Ohtsuki, T.; Yamamoto, Y.; Ishibashi, M. New Kehokorins and Trichiols from
the Myxomycete Trichia favoginea. Heterocycles 2007, 71, 1807.
3) Ye, Y. Q.; Negishi, C.; Hongo, Y.; Koshino, H.; Onose, J.; Abe, N.; Takahashi, S. Structural
elucidation and synthesis of vialinin C, a new inhibitor of TNFꢀα production. Bioorg. Med. Chem.
014, 22, 2242.
4) Ye, Y. Q.; Koshino, H.; Yoshikawa, K.; Onose, J.; Abe, N.; Takahashi, S. Expeditious
(
2
(
Synthesis of Vialinin B, an Extremely Potent Inhibitor of TNFꢀα Production. Org. Lett. 2009, 11, 5074.
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