Simple and efficient synthesis of various dibenzofuran carbaldehydes

Article abstract of DOI:10.1080/00397911.2016.1235201

We herein report simple and efficient methods for the synthesis of various formyl derivatives of dibenzofuran. The aldehydes reported are prepared in at most three steps and in yields greater than 60% from commercially available dibenzofuran, with one exception where isomers must be separated. The protocols described involve either formylation of previously functionalized dibenzofuran derivatives or the initial introduction of the formyl group and subsequent further functionalization under standard reaction conditions as described. We have also reported an efficient and simple method for the synthesis of key methoxydibenzofurans in high yield (65% overall for two steps).

Full text of DOI:10.1080/00397911.2016.1235201

Simple and Efficient Synthesis of Various Dibenzofuran Carbaldehydes
1
1
Thirumal Yempala , Bruce K. Cassels
1
Departamento de Química, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
Corresponding author: Thirumal Yempala, Email: thirumal.yempala@u.uchile.cl
Abstract
We herein report simple and efficient methods for the synthesis of various formyl
derivatives of dibenzofuran. The aldehydes reported are prepared in at most three steps
and in yields greater than 60% from commercially available dibenzofuran, with one
exception where isomers must be separated. The protocols described involve either
formylation of previously functionalized dibenzofuran derivatives or the initial
introduction of the formyl group and subsequent further functionalization under standard
reaction conditions as described. We have also reported an efficient and simple method
for the synthesis of key methoxydibenzofurans in high yield (65% overall for two steps).
Graphical Abstract:
1

KEYWORDS: Dibenzofuran carbaldehydes, efficient protocols, formylation, methoxy
derivatives, bromo derivatives.
INTRODUCTION
Dibenzo[b,d]furan (1) is a tricyclic heterocyclic compound consisting of two benzene
rings fused to one central furan ring. Dibenzofuran is a minor but relatively inexpensive
constituent of coal tar and also a structural unit which is not widespread in nature, but
seems to be largely confined to particular groups of organisms such as lichens, fungi and
[
1]
some higher plants. Although several literature studies have revealed the synthesis of
substituted furans and few dibenzofuran derivatives using various cyclization processes,
[
2]
these require costly metal catalysts. The chemistry of dibenzofuran has attracted the
interest of scientists over the past decade because of its promising applications in various
areas like biological and medicinal chemistry, and materials science. Many natural and
[
3]
synthetic dibenzofuran derivatives have been tested for various activities, such as
antibacterial, antifungal, antiviral and cytotoxic, and some have proved to be quite potent.
[
4]
In organic chemistry the synthesis of molecules having aldehyde functional groups is
vital because of the significant involvement of this functionality in various chemical
transformations. The applications of aldehydes are central in many named reactions and
not limited to Wolff–Kishner reduction, oxo-Diels–Alder reaction, Wittig reaction, Takai
reaction, hydroacylation, Corey–Fuchs reactions, Ohira–Bestmann reaction, Johnson–
[
5]
Corey–Chaykovsky reaction, decarbonylation, etc. All these chemical modifications are
used for the synthesis of numerous active molecules and for various applications, making
2

the introduction of a formyl group on a complex moiety a pivotal step in modern organic
synthesis. The literature reports a limited number of aldehydic dibenzofuran-containing
[
6]
[7]
natural products (e.g. hypostrepsilic acid, penioflavin, ) (Figure 1). Although the
introduction of a formyl group on the dibenzofuran skeleton would seem to be a
straightforward proposition, only dibenzofuran 2-carbaldehyde (2) and dibenzofuran 4-
carbaldehyde (3) have been reported as products of the application of efficient,
[
8,9]
regioselective synthetic procedures with moderate to good yields.
Thus, electrophilic
attack of the bulky dichloromethyl methyl ether – Lewis acid complex occurs
preferentially at the less hindered C-2, para to the dibenzofuran oxygen atom, while
lithiation with n-butyl lithium shows a strong preference for C-4, ortho to the directing
group. In view of the significance of the aldehyde functional group in organic chemistry
and also considering the growing interest of the dibenzofuran nucleus over the past few
years, we decided to synthesize various dibenzofuran carbaldehydes as intermediates for
use in a range of chemical modifications.
RESULTS AND DISCUSSION
Our present approach started with the formylation of the dibenzofuran nucleus in which
one or two electron-donating oxygen atoms had already been introduced. Thus, 2-
methoxy and 2,8-dimethoxydibenzofuran (8 and 9) were prepared from the previously
reported 2-bromo and 2,8-dibromo dibenzofuran (6 and 7). The bromo derivatives were
[
10]
synthesized according to the literature procedures
and used without further
purification. The required methoxy derivatives were then conveniently prepared from the
corresponding bromo derivatives by reaction with NaOMe in the presence of CuBr
3

(Scheme 1). These methoxy derivatives, 8 and 9, were purified by silica gel
1
13
chromatography and characterized by H and C NMR spectral analysis. Although the
synthesis of key intermediate 2-methoxy dibenzofuran (8) was reported in an earlier
communication starting from dibenzofuran (1) via the synthesis of dibenzofuran-2-
[
11]
carbaldehyde (2) and dibenzofuran-2-ol (10), it involved three column purifications
resulting in a relatively low yield. Here we report an efficient and simple synthesis of
compound 8 from 2-bromodibenzofuran (6) (in 65% overall yield) which only required a
single chromatographic purification. Efficient syntheses of 8 were reported recently by
ring closure of 2-(4-methoxy)phenoxyphenol tosylate or mesylate, but an expensive
[
12]
catalyst was necessary and the precursors had to be prepared. A similar synthesis of 9
[
13]
only achieved 65% yield from 2-(2-chloro-4-methoxy)phenoxybenzonitrile.
Formylation of 2-methoxy dibenzofuran (8) with α,α-dichloromethyl methyl ether and
SnCl has already been shown to afford dibenzofuran carbaldehydes 4 and 5 in 92%
4
yield, in a 35:65 ratio. Aldehydes 4 and 5 were separated chromatographically and fully
[
14]
characterized by their standard analytical data.
A set of new dibenzofuran aldehydes 11, 12 and 13 were synthesized according to the
[9]
previous literature protocol, using n-BuLi and dry DMF (Scheme 2). Under these
reaction conditions, aldehydes 11, and 12 were obtained in moderate yields starting from
the dibenzofuran derivatives 8, and 9 respectively. Phenolic aldehyde 13 was synthesized
[
10]
from dibenzofuran-2-ol (10), using a larger excess of n-BuLi (3 equivalents). All these
1
13
derivatives were properly characterized by using H and C NMR and mass spectral
analysis.
4

As expected, an aldehyde group deactivates the ring that bears it towards electrophilic
substitution. However, in the case of dibenzofuran-4-carbaldehyde, the other aromatic
ring is sufficiently reactive for facile bromination or iodination at C-8, para to the
dibenzofuran oxygen. Thus, the halo derivatives (14 and 15) of aldehyde 3 were obtained
in good yields (75% and 70% isolated after recrystallization, respectively) by treatment
with bromine or with iodine monochloride in acetic acid (Scheme 3). Unexpectedly,
attempts to obtain aldehyde 15 using N-iodosuccinimide were not fruitful. These halo
aldehydes were fully characterized with their spectral data.
Several attempts were made to synthesize 2-cyanodibenzofuran-6-carbaldehyde starting
from the bromo derivative 14 according to protocols described in the literature for
halogen substitution using CuCN, and Zn(CN) as CN group sources, even in presence of
2
Pd catalysts. In contrast, the iodo derivative 15 underwent ready substitution with CuCN
(Scheme 4). The structure of aldehyde 16 was confirmed by its spectral data. An
[
15]
alternative approach, via lithiation of 2-cyanodibenzofuran (17), prepared from 2-
bromodibenzofuran (4), proved unsuccessful.
2
-Bromodibenzofuran-6-carbaldehyde 14 was inert to substitution of the bromine atom
by different amines such as ethylamine, morpholine or imidazole, even after modifying
the aldehyde functional group to an acetal. However, aldehyde 11 could be obtained from
aldehyde 14 after derivatizing the formyl group with trimethyl orthoformate, followed by
methoxylation with NaOMe (Scheme 5).
5

CONCLUSION
We have succeeded in developing useful and efficient protocols for the synthesis of new
substituted dibenzofuran carbaldehydes starting from reported analogues. Thus, in
addition to the previously reported dibenzofuran-2- and 4-carbaldehydes (2 and 3) and 2-
methoxy-1- and 3-carbaldehydes (4 and 5), methoxy, dimethoxy and hydroxyl
dibenzofurans were formylated efficiently to yield different new aldehydes. Also,
dibenzofuran-4-carbaldehyde was halogenated and its bromo and iodo derivatives were
subjected to further modifications. These one- or two-step processes led to the reported
aldehydes in good to excellent yields. We have also developed a novel method for the
preparation of 2-methoxydibenzofuran (8) and 2,8-dimethoxydibenzofuran (9) starting
from dibenzofuran, in satisfactory yields and using cheap, readily available reagents. All
the new analogues are in the process of further utilization for the synthesis of novel,
potentially bioactive molecules.
EXPERIMENTAL SECTION
General Remarks: Dibenzofuran and α,α-dichloromethyl methylether were purchased
from Merck Chile, and n-BuLi, NaOMe and SnCl were from Sigma Aldrich. Solvents
4
were purchased commercially and dried prior to use according to the standard protocols.
Melting points were measured with a Stuart SMP 10 melting point apparatus and are
uncorrected. NMR spectra were recorded on 300 (Bruker), 400 (Bruker) and 500 MHz
(Varian) spectrometers in appropriate solvents using TMS as internal standard and the
chemical shifts are shown in the δ scale. High-resolution mass spectra was obtained by EI
ionization for compound 14 and ESI-MS High resolution mass spectrometer Exactive™
6

Plus Orbitrap, Thermo Fisher Scientific (Bremen, Germany) was used for the other
dibenzofuran formyl derivatives. IR spectra were recorded in KBr pellets and the wave
-1
numbers are shown in cm . All the experiments were monitored by analytical thin layer
chromatography (TLC) performed on silica gel GF254 pre-coated plates and silica gel
finer than 200 mesh was used for column chromatography. Yields refer to
chromatographically and spectroscopically homogeneous materials unless otherwise
stated.
Procedure for the synthesis of methoxy dibenzofurans 8 and 9: To a solution of
compound 6 or 7 (1 eq.) in dry toluene, an excess of NaOMe (25% v/v in MeOH) (>10
eq.), CuBr (1.2 eq.) and a small volume of ethyl acetate was added at RT to improve
solubility. Then the deep blue colored solution was refluxed overnight under a nitrogen
atmosphere. After completion of the reaction (TLC), water was carefully added and the
reaction mixture extracted with dichloromethane. The combined organic layers were
dried with anhydrous sodium sulfate and the solvent was evaporated under reduced
pressure. Purification of the crude reaction mixture (using hexane/dichloromethane
mixtures as eluent) afforded the title compounds 8 and 9 in good yields. Usually the pure
products were isolated along with other methoxy derivatives (mono-/di-) and
dibenzofuran in smaller quantities (<5%).
Procedure for the synthesis of aldehydes 11-13: To a solution of compound 8/9/10 (20
mmol) in dry THF (15 mL) n-BuLi (2.0 M in hexane, 30 mmol or 60 mmol in the case of
compound 10) was added at 0 °C and stirring was continued at RT for 3 h. Afterwards,
7

dry DMF (~5 mL) was added at 0 °C and stirring was continued further at RT for 2 h.
After completion of the reaction, it was quenched with 1M HCl carefully at 0 °C and then
the reaction mixture was extracted with CH Cl and water. The combined organic layer
2
2
was then treated with brine, dried over anhydrous Na SO and the solvent was evaporated
2
4
under reduced pressure. Purification of this crude material over silica gel (EtOAc:hexane,
various ratios not exceeding 30:70) afforded the new dibenzofuran 4-carbaldehydes with
good yields.
ACKNOWLEDGEMENTS
Authors (TY and BKC) are grateful to CONICYT (Chile) for providing funds through
FONDECYT postdoctoral grant 3150474.
SUPPORTING INFORMATION
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Full experimental detail, including the analytical data and copies of H and C NMR
spectra, ESI-HRMS were included. This material can be found via the “Supplementary
Content” section of this article’s webpage.
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Scheme 1. Preparation of 2-methoxy- and 2,8-dimethoxydibenzofurans 8 and 9.
Reagents and Conditions: (a) Br , AcOH, RT. (b) NaOMe (25% v/v in MeOH), toluene,
2
EtOAc (small amounts), CuBr, reflux, 16h, overall yield 65% for compound 8 and 70%
for compound 9. (c) SnCl , α,α-dichloromethyl methyl ether, DCM, RT, 2 h, 92% yield
4
with 35:65 ratio of aldehydes 4 and 5.
1
1

Scheme 2. Synthesis of 2-methoxy, 2,8-dimethoxy and 8–hydroxy dibenzofuran-4-
carbaldehydes 11, 12 and 13. Reagents and Conditions: (a) n-BuLi/THF, 0 °C to RT (3
h), DMF at 0 °C to RT, 2 h, 65% for 11, 68% for 12, 60% for 13.
1
2

Scheme 3. Synthesis of 8-halo dibenzofuran-4-carbaldehydes 14 and 15.
1
3

Scheme 4. Synthesis of 8-cyano dibenzofuran-4-carbaldehyde 16.
1
4

Scheme 5. Alternative method for the synthesis of 8-methoxy-4-carbaldehyde 11.
Reagents and Conditions: (a) CH(OMe) , acetone, RT, overnight. (b) NaOMe (25% v/v
3
in MeOH), CuBr, EtOAc (small amounts), toluene, reflux, 16 h. (c) p-TSA, acetone,
reflux, 3 h, 45% (overall yield).
1
5

Figure 1. Examples of natural dibenzofurans with aldehyde functional group and
previously reported dibenzofuran aldehydes.
1
6