Chemoselective arylation of phenols with bromo-nitroarenes: Synthesis of nitro-biaryl-ols and their conversion into benzofurans and carbazoles

Article abstract of DOI:10.1039/c4cc03090g

A series of electron withdrawing or donating group substituted phenols were chemoselectively arylated with various substituted bromo-nitroarenes using KO^tBu at room temperature via an S_NAr pathway. The synthesis of natural alkaloids (carbazoles), dibenzofurans, and a biaryl-indole was achieved from the synthesized nitro-biaryl-ols. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03090g

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Chemoselective arylation of phenols with bromo-
nitroarenes: synthesis of nitro-biaryl-ols and their
conversion into benzofurans and carbazoles†
Cite this: Chem. Commun., 2014,
50, 9481
Received 25th April 2014,
Accepted 2nd June 2014
Amit Kumar, Abhimanyu Yadav, Ajay Verma, Sadhan Jana, Moh. Sattar,
Shailesh Kumar, Ch. Durga Prasad and Sangit Kumar*
DOI: 10.1039/c4cc03090g
www.rsc.org/chemcomm
A series of electron withdrawing or donating group substituted phenols
were chemoselectively arylated with various substituted bromo-
nitroarenes using KOtBu at room temperature via an SNAr pathway.
The synthesis of natural alkaloids (carbazoles), dibenzofurans, and a
biaryl-indole was achieved from the synthesized nitro-biaryl-ols.
Intermolecular cross-coupling reactions for the construction of
carbon–carbon bonds are an interesting area in synthetic
chemistry. The direct functionalization of C–H bonds avoids
the use of pre-functionalized coupling partners, leading to
more atom economical and environment-friendly processes.1
Biaryls, particularly containing nitro/amino and hydroxyl func-
Fig. 1 Biologically active carbazoles and dibenzofurans.
tionalities, are of paramount importance for materials and phenol using aryl iodide in water.6 In order to combine aryl
medicines and are also precursors for natural products.2 Alka- iodides with phenols, the presence of an acidic functionality is
loids with OH and NH2/NO2 groups (e.g. siamenol, mahanim- essential for the binding of the Pd-catalyst with aryl iodide in
bine, mahanimbilol, and carbazomycin B) have numerous benign methodologies. Daugulis and co-workers reported a tran-
biological functions such as antiviral, antifungal, cytotoxic, sition metal free arylation of phenols at 135 1C.7 Nonetheless,
anti-malarial, anti-HIV agents and antibiotics (Fig. 1).3
these methodologies showed limited substrate scope due to
Similarly, pyrrolomycin E, TMC-95-A, benzofurocoumarin, specific binding of the catalyst with the acid/amide functionali-
elbfluorene and NOBIN biaryls possessing 2-OH or 20-NO2/NH2 ties, or they require harsh reaction conditions.
groups have been used as anticancer agents or ligands.4
In continuation of our work on carbon–carbon and carbon–
In this context, a mild method is highly desirable for accessing heteroatom coupling reactions,8 herein, we present a transition
diversely substituted nitro-biaryl-ols. Mild reaction conditions are metal free mild method for the synthesis of nitro-biaryl-ols
required for selective transformations that can tolerate sensitive which tolerates a variety of functional groups. The synthesized
groups such as Br, NH2, CHO, OH, etc., which are advantageous nitro-biaryl-ols were employed for the synthesis of natural
because of their easy transformations at later stages for the alkaloid clausine V and related carbazole analogues. Moreover,
synthesis of functionalized biaryls such as mahanimbine and dibenzofurans can also be obtained from para-substituted
TMC-95-A.3b,4b Although various methods have been reported for phenols and 2-nitrobromobenzene in one pot by the formation
the arylation of phenol making use of transition metal catalysts,5 of C–C and C–O bonds. The synthesis of a biaryl indole was also
most of the methods require protection of the phenolic group. accomplished from the synthesized nitro-biaryl-ol.
The direct arylation of phenol has attracted considerable interest.
Optimization of the reaction conditions was carried out using
Zhou et al. discovered a palladium catalyzed para arylation of phenol and 1-bromo-4-methyl-2-nitrobenzene as coupling part-
ners, Scheme 1 (see also ESI,† Table S1, page S3, for the detailed
optimization of reaction conditions). After screening various bases
Department of Chemistry, IISER Bhopal, Indore By-pass Road, Bhauri, Bhopal,
and solvents, we found that KOtBu in DMSO at room temperature
Madhya Pradesh, India-462 066. E-mail: sangitkumar@iiserb.ac.in
gave nitro-biaryl-ol 1 and 20-nitro-biaryl-4-ol 2 in good yields with
† Electronic supplementary information (ESI) available. CCDC 992291, 993002,
high regioselectivity. The addition of silver acetate as an additive
to the reaction mixture provided 2 exclusively, albeit in a low yield
986893 and 986891. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc03090g
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(6) and other sensitive functional groups such as CHO (7), CN
(8), F (9), Cl (10), Br (11) and NO2 (12) were obtained under the
optimized reaction conditions. Functional groups such as
CHO, CN, Cl, and Br could then be further transformed into
other functionalities.
The reaction with 2-iodo-phenol was noticed to be sluggish,
and isolation of the corresponding iodo-nitro-biaryl-ol was
unsuccessful.
Scheme 1 Optimization of the synthesis of nitro-biaryl-ols. a The reaction
was carried out using 1.0 mmol of bromo-nitrobenzene, 1.2 mmol of
phenol, and 2.5 mmol of KOtBu in DMSO (4 mL) at RT. b AgOAc (1.2 mmol)
was added. c The temperature was raised up to 110 1C for 2 h.
Next, nitro-biaryl-diols 13 and 14 were obtained from resor-
cinol and catechol respectively. Resorcinol gave the single
of 53% (see ESI,† Table S1, entry 13).7 Interestingly, the reaction at regioisomer 13 with a 67% yield, whereas catechol gave a
a higher temperature (110 1C) gave 20-nitro-biaryl-4-ol 2 exclusively mixture of two regioisomers 14a and 14b in an 8 : 2 ratio
in 2 h (see ESI,† Table S1, entry 14).
(67% yield). Further, a-naphthol was used in the coupling
The scope and limitations of this method were further reaction giving a mixture of ortho and para regioisomers 15
studied and the results are summarized in Table 1. para- and 16 in an overall yield of 73% with an 18 : 82 ratio, respectively.
Substituted phenols underwent coupling reactions success- 2,6-Disubstituted phenols were then subjected to the arylation
fully, and yielded nitro-biaryl-ols (3–12) in 41–92% yields. reaction which gave a 74% yield of 20-nitro-biaryl-4-ol 17.
Nitro-biaryl-ols with OCH3 (3), CH3 (4) tert-butyl (5), phenyl On the other hand, the electron withdrawing 2,6-di-chloro
and bromo phenols gave 20-nitro-biaryl-4-ols 18 and 25 in
slightly lower yields. ortho-Methyl, chloro, and nitro substituted
phenols afforded regioisomeric mixtures of ortho and para-
Table 1 The synthesized 20- and 40-nitro-biaryl-olsa
nitro-biaryl-ols 19–23 at room temperature, whereas ortho-
aminophenol gave only 20-nitro-biaryl-4-ol 24. Alternatively,
20-nitro-biaryl-4-ols 20, 22 and 31 (vide supra) were obtained
exclusively by carrying out the reaction at 110 1C. A meta-
substituted phenol gave only regioisomer 34 with a 51% yield.
Highly substituted 2,3,6-trimethyl and 2,3-dimethyl substituted
phenols were also coupled with bromo-nitrobenzene and
yielded 20-nitro-biaryl-4-ols 26 and 27.
Next various bromo-nitroarenes were tested under the opti-
mized reaction conditions. Simple 2-nitro and 4-nitro-bromo-
benzenes were successfully coupled with phenol derivatives
leading to various substituted 20-nitro-biaryl-4-ols 31, 33, and
47, 20-nitro-biaryl-2-ols 30, 32, and 35–37 and 40-nitro-biaryl-4-ol
43. Formation of the respective diaryl ethers was also observed
along with nitro-biaryl-ols 30, 31 and 36 (see ESI,† pages S19
and S21). para-Methoxybromonitrobenzene was noticed to be
an equally efficient substrate as comparable yields of coupled
nitro-biaryl-ols 28, 29, 38–40 and 42 were obtained. Bromo-
nitrobenzenes with electron withdrawing substituents reacted
sluggishly with phenol; however they coupled smoothly with
electron rich 2,6-di-tert-butyl phenol. 2-Nitro-bromoarenes with
Br, CHO, CF3, and COCH3 groups in para positions produced
good yields of 20-nitro-biaryl-4-ols 41, and 44–46, respectively.
Structures of nitro-biaryl-ols 10, 11 and 20-nitro-biaryl-4-ols
27, 33, were established by single crystal X-ray studies (for the
crystal studies, see ESI,† pages S152–S168). Nitro-biaryl-ols 10,
11 were crystallized in chiral space groups structures of and
interestingly, Flack parameter value (ꢀ0.08) for 10 is close to
zero, which suggests that molecule crystallized in one of the
enantiomeric form. Furthermore, the optical rotation value,
[a] = 24.04 ꢁ 0.4 (c = 0.3, CHCl3), of 10, suggests an enantiomeric
pure form in solution.
a
The reactions were carried out using 1.0 mmol of bromo-
Next, the synthesized 20-nitro-biaryl-2-ols were utilized for
nitrobenzene, 1.2 mmol of phenol, and 2.5 mmol of base in DMSO
(4 mL). The ortho and para isomers were not separated. The reaction
was heated at 110 1C.
the preparation of dibenzofurans (Scheme 2).9 Nitro-biaryl-ols
10, 1, 36, and 4 were readily converted into dibenzofurans 48,
b
c
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Here, the addition of KOtBu to phenol generates a phenoxide
ion, which subsequently converts into a carbanion via reso-
nance. The addition of the carbanion to bromonitroarene,
followed by proton abstraction and rearomatization led to the
desired nitro-biaryl-ols 1 and 2 (see ESI,† Scheme S3, page S34).
To sum up, a mild method has been developed for the
construction of nitro-biaryl-ols and 20-nitro-biaryl-4-ols which
tolerates diverse functional groups. The synthesized nitro-
biaryl-ols were converted into important classes of biaryl
heterocycles, dibenzofurans and biaryl-indoles, whereas the
20-nitro-biaryl-4-ols were converted into carbazoles. The devel-
oped methodology is mild and tolerates sensitive functionali-
ties which could be useful for the preparation of highly
functionalized biaryls such as siamenol, mahanimbine, and
carbazomycin B alkaloids. This is currently under investigation
in our laboratory.
Scheme 2 The synthesis of advanced biaryl heterocycles. a The yields
were obtained from nitro-biaryl-ols. b The yields were obtained from
phenols and 2-bromonitrobenzenes using a one pot reaction.
SK thanks DST New Delhi, DRDO New Delhi, DAE-BRNS
Mumbai, and IISER Bhopal for generous funding. Acknowl-
edgement by AK and MS to CSIR-New Delhi, AY and CDP to
UGC-New Delhi, and AV, SK and SJ to IISER Bhopal for
fellowships.
49, 50, and 51, respectively, by using NaH base in HMPA under
heating conditions. Moreover, the synthesis of dibenzofurans
can be accomplished in a single pot from para substituted
phenols and nitrobromobenzene in slightly lower yields com-
pared to the yields obtained from the stepwise reactions. In a
single pot reaction, para-substituted phenols were treated with
ortho-nitrobromobenzenes in DMSO in the presence of KOtBu,
after 4 h NaH and HMPA were added followed by heating at
80 1C, resulting in dibenzofurans. Previously, the synthesis of
dibenzofurans was achieved by diazotization (the Pschorr reac-
tion) and Pd-catalyzed dehydrogenative coupling of diary-
lethers.10 Here dibenzofurans 48, 50 and 51 were obtained in
47–56% yields in one pot from para-substituted phenols and
bromo-nitroarenes. Furthermore, the synthetic utility of the
prepared nitro-biaryl-ol 10 was demonstrated by synthesizing
biaryl-indole 52. For this transformation, first the OH group of
nitro-biaryl-ol 10 was protected as a methyl ether, followed by
the reaction of the nitro group with vinyl-magnesium bromide,
which gave biaryl-indole 52 in a 45% yield.
Next 20-nitro-biaryl-4-ols were converted into carbazoles. The
heating of 20-nitro-biaryl-4-ols 27, 47, 42, and the protected
form of 29 in EtO3P at an elevated temperature provided good
yields of carbazoles 53, 54, 55, and 56.11
Carbazoles are well known for their antioxidant functions
(Fig. 1). Here the synthesis of a fully CH3-substituted phenol
ring, and two tert-butyl substituted carbazoles 54 and 55 was
achieved, which could be efficient antioxidants.12 Also clausine
V, 56, which has anti-HIV properties was obtained in two steps
from 20-nitro-biaryl-4-ol 29, first conversion of the OH group to
a methoxy group using CH3I and K2CO3, followed by C–N
coupling.
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