Synthesis, scope, 1H and 13C spectral assignments of isomeric dibenzofuran carboxaldehydes

Article abstract of DOI:10.1007/s11164-016-2698-1

Two isomeric dibenzofuran carboxaldehydes, namely 2-methoxydibenzo[b,d]furan-1-carbaldehyde (4) and 2-methoxydibenzo[b,d]furan-3-carbaldehyde (5), were synthesized. Formylation of 2-methoxydibenzo[b,d]furan (3) with α,α-dichloromethyl methyl ether and tin(IV) chloride gave a mixture of aldehydes 4 and 5 in 95?% yield and in a 35:65 ratio. Their ¹H and ¹³C NMR spectral signals were not sufficiently resolved in CDCl₃ solution to achieve their complete assignment, but this was possible in DMSO-d₆ with the help of 2D-NMR techniques: NOESY for ¹H–¹H interactions and HSQC and HMQC experiments for ¹H–¹³C correlations. These aldehydes were used in the synthesis of novel β-phenylethylamines and NBOMe derivatives, which are undergoing biological evaluation.

Full text of DOI:10.1007/s11164-016-2698-1

Res Chem Intermed
DOI 10.1007/s11164-016-2698-1
1
13
Synthesis, scope, H and C spectral assignments
of isomeric dibenzofuran carboxaldehydes
Thirumal Yempala1
Bruce K. Cassels1
•
Received: 29 February 2016 / Accepted: 9 August 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Two isomeric dibenzofuran carboxaldehydes, namely 2-methoxy-
dibenzo[b,d]furan-1-carbaldehyde (4) and 2-methoxydibenzo[b,d]furan-3-car-
baldehyde (5), were synthesized. Formylation of 2-methoxydibenzo[b,d]furan (3)
with a,a-dichloromethyl methyl ether and tin(IV) chloride gave a mixture of
1
aldehydes 4 and 5 in 95 % yield and in a 35:65 ratio. Their H and 13C NMR
spectral signals were not sufficiently resolved in CDCl3 solution to achieve their
complete assignment, but this was possible in DMSO-d6 with the help of 2D-NMR
techniques: NOESY for 1H–1H interactions and HSQC and HMQC experiments for
1H–13C correlations. These aldehydes were used in the synthesis of novel
b-phenylethylamines and NBOMe derivatives, which are undergoing biological
evaluation.
1
Keywords NMR Á H Á 13C Á 2-Methoxydibenzo[b,d]furan aldehyde regioisomers Á
b-Phenylethylamines and NBOMe derivatives
Introduction
Polycyclic heterocycles with oxygen in a central position constitute an important
class of fused heterocycles found in numerous natural products that have also shown
interesting biological properties. In particular, dibenzo[b,d]furan derivatives have
attracted the interest of natural product and medicinal chemists over the past few
decades because of their characteristic occurrence in lichens and fungi and as
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2698-1)
contains supplementary material, which is available to authorized users.
&
Thirumal Yempala
thirumal.yempala@u.uchile.cl
1
Universidad de Chile, Santiago, Chile
123

T. Yempala, B. K. Cassels
Fig. 1 Some dibenzofuran derivatives reported in the literature (natural and synthetic)
phytoalexins [1]. Dibenzofuran natural products, as well as many synthetic
compounds (Fig. 1) containing this nucleus exhibit a broad variety of promising
biological activities such as antibacterial (including antibiotic-resistant and
antimycobacterial), antifungal, antiproliferative and potentially anticancer, and
anti-inflammatory activities [2–8]. This interesting range of properties and the
possible pharmaceutical applications have stimulated continued effort to obtain new
derivatives incorporating a dibenzofuran unit for their pharmacological evaluation.
Experimental
Chemicals
The reagents required for this study were purchased from Merck S. A., Santiago,
Chile. Commercial solvents used for the reactions were dried as per standard
˚
literature protocols. Silica gel having a pore size of 60 A (70–230 mesh,
63–200 lm) used for column chromatography was purchased from Sigma-Aldrich
Chile. 2-Hydroxydibenzo[b,d]furan (2) was prepared in two steps, according to a
literature procedure [9].
Instrumentation
NMR spectra were recorded in CDCl3 and in DMSO-d6 at 300 K on a Bruker
Avance III HD 400 (9.4 T, 400.13 MHz for 1H, and 100.62 MHz for 13C)
spectrometer with a 5-mm inverse detection Smart Probe equipped with a z-gradient
coil. Chemical shifts (d in parts per million) are referenced to the solvent residual
signals (1H and 13C at 7.26 and 77.16 ppm, respectively, in CDCl3, and 2.50 and
39.52 ppm, respectively, for 13C in DSO–d6) [11]. Coupling constants (J in Hertz)
are accurate to 0.3 Hz for 1H NMR. Typical parameters for 1H NMR spectra were
recorded with a spectral width of 4700 Hz and a pulse width of 10 ls at an
attenuation level of 16.600 W. For 13C NMR spectra, typical values were a spectral
width of 21,000 Hz, a pulse width of 10 ls, an attenuation level of 69.000 W, and a
relaxation delay of 2 s. Waltz16 was used for broad band proton decoupling; the
FIDs were weighted exponentially (lb = 2 Hz) before Fourier transformation. Two-
123

Synthesis, scope, 1H and 13C spectral assignments of…
dimensional 1H–13C gs-HSQC and 1H–13C gs-HMQC experiments were carried out
using standard Bruker software (https://www.bruker.com/products/mr/nmr/
nmrsoftware/software/topspin/overview.html) and in non-phase-sensitive mode.
Gradient selection was achieved through a 5 % sine truncated-shaped pulse gradient
of 1 ms. Selected parameters for gs-HSQC and gs-HMQC experiments were a
1
spectral width of 3649 Hz for H and 18115 Hz for 13C, 1024 9 128 data set, two
scans each for gs-HSQC, and HMQC. The FIDs were processed using zero filling in
the F1 domain, and a sine-bell window function in both dimensions was applied
before the Fourier transformation. In the gs-HMQC experiment, GARP modulation
1
of 13C was used for decoupling. The H–1H NOESY experiments were recorded
with a spectral width of 4.85 kHz in both F2 and F1 domains; 512 9 128 data
points were acquired with four scans per increment and relaxation delays of 2.0 s.
Data processing was performed on a 1024 9 1024 data matrix.
Preparation of 2-methoxydibenzo[b,d]furan (3)
To a solution of compound 2 (1.84 g, 0.01 mol) in dry THF, NaH (0.28 g,
0.012 mol) was added at 0 °C. After stirring the reaction mixture for 10 min, ICH3
(1.70 g, 0.012 mol) was added and stirring was continued at RT for 1 h. After
completion of the reaction (monitored by TLC), the mixture was carefully quenched
with water and extracted with CH2Cl2 (2 9 50 mL). The combined organic layers
were dried with Na2SO4 and the solvent was evaporated under reduced pressure.
Chromatographic purification of the crude reaction mixture (on silica gel using
90:10, hexane:CH2Cl2 as eluent) gave 3 in quantitative yield as a yellow liquid
which upon standing at -10 °C turned into a white solid.
1H NMR (CDCl3, 400 MHz): d 7.92 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.3 Hz,
1H), 7.49–7.41 (multiple peaks, 3H), 7.33 (td, J = 7.3 and 0.7 Hz, 1H), 7.05 (dd,
J = 9.0 and 2.6 Hz, 1H), 3.92 (s, 3H).
1
The H NMR data of compound 3 were in agreement with the literature [10].
Preparation of aldehydes 4 and 5
2-Methoxy[b,d]dibenzofuran (3) (1 g, 0.005 mol) was dissolved in CH2Cl2 (35 mL)
and SnCl4 (1.50 g, 0.006 mol) was added slowly with continuous stirring at RT.
After 10 min, CHCl2OCH3 (0.69 g, 0.006 mol) was added slowly and the resulting
mixture was stirred at RT for another hour. Then the reaction mixture was quenched
with 1 N HCl (15 mL) and the organic phase was treated successively with water,
NaHCO3 solution and finally saturated brine. After drying the organic layer with
anhydrous sodium sulfate, it was concentrated in a rotary evaporator. Silica gel
column chromatography (hexane:CH2Cl2 from 80:20 to 30:70) afforded the pure
aldehydes 4 and 5 in 95 % combined yield in a 35:65 ratio.
2-Methoxydibenzo[b,d]furan-1-carbaldehyde (4)
Light yellow solid; m.p. 150–152 °C. 1H NMR (400 MHz, CDCl3) d 10.80 (s, 1H),
9.05 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.56–7.51 (m, 2H), 7.39–7.34
123

T. Yempala, B. K. Cassels
(m, 1H), 7.10 (d, J = 9.0 Hz, 1H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3) d
190.6, 159.7, 157.8, 150.8, 128.8, 127.1, 123.5, 123.4, 122.5, 119.7, 117.9, 111.0,
110.7, 56.7.
2-Methoxydibenzo[b,d]furan-3-carbaldehyde (5)
White solid; m.p. 139–141 °C. 1H NMR (400 MHz, CDCl3) d 10.56 (s, 1H), 8.00 (s,
1H), 7.95 (d, J = 7.8 Hz, 1H), 7.58–7.46 (m, 2H), 7.38 (s, 1H), 7.36 (dd, J = 7.5
and 6.8 Hz, 1H), 4.05 (s, 3H). 13C NMR (100 MHz, CDCl3) d 189.4, 158.3, 158.1,
150.2, 130.6, 129.0, 124.0, 123.4, 122.9, 121.3, 112.1, 110.6, 102.5, 56.2.
Results and discussion
In this context, we wished to synthesize methoxy substituted dibenzofuran
aldehydes as precursors for new potentially bioactive compounds, starting from
the relatively inexpensive dibenzo[b,d]furan. Although there are literature reports of
ring closure reactions to obtain dibenzofuran analogues [12–14], and functionalized,
but not annulated furan derivatives are the subject of modern synthetic approaches
[15]; a few start from dibenzo[b,d]furan. With this in mind, we chose 2-methoxy-
dibenzo[b,d]furan (3) [10] as the key intermediate and prepared it via the known
2-hydroxydibenzo[b,d]furan (2) [9] according to Scheme 1. Methylation of the
previously described 2 using sodium hydride and methyl iodide gave the required
starting material 3 in quantitative yield as a yellow liquid. The 1H NMR spectrum of
compound 3, 2-methoxydibenzo[b,d]furan, agreed with the published data [10].
2-Methoxydibenzo[b,d]furan-3-carbaldehyde (5) had been described many years
ago as the sole isolated product of the Vilsmeier formylation of 3, and its structure
was then decided convincingly on the basis of further reactions to afford a known
compound [16]. More recently, both 4 and 5 were mentioned as intermediates for a
variant of the Peachmann synthesis leading in these cases to benzofuran annulated
coumarins at the 5,6 and 6,7 positions [17]. In that paper 2-methoxydibenzo[b,d]-
furan was formylated (no details given) using a,a-dichloromethyl methyl ether and
Scheme 1 Synthesis of 2-methoxydibenzo[b,d]furan (3)
123

Synthesis, scope, 1H and 13C spectral assignments of…
titanium(IV) chloride [18], and the products used without any characterization at all
in the successive synthetic reactions [17]. In our hands, the formylation proceeded
in excellent yield (95 %) with a,a-dichloromethyl methyl ether and tin(IV) chloride
giving 2-methoxydibenzo[b,d]furan-1-carbaldehyde (4) and 2-methoxy-
dibenzo[b,d]furan-3-carbaldehyde (5) in 95 % combined yield and in a 35:65 ratio,
which could be separated by chromatography on silica gel (Scheme 2). As these two
compounds were required for further synthetic steps, we decided to characterize
1
them completely by H and 13C NMR and with mass-spectrometry.
Structural elucidation of the synthesized aldehydes 4 and 5 was achieved by
1
routine H and 13C techniques. Nevertheless, for a definitive assignment of all
signals, two-dimensional NMR techniques were used as follows: (1) 2D-HSQC
1
spectra to determine the H–13C correlations for carbons bonded to hydrogen; (2)
2D-HMQC spectra to assign the signals of quaternary carbons via two-bond and
1
three-bond H–13C interactions and (3) 2D-NOESY experiments to determine the
spatial interaction of protons.
1
The H NMR spectrum of 4 in CDCl3 showed the formyl and methoxyl singlets
at d 10.80 and 3.99 ppm, two sharp doublets centered at 7.43 and 7.10 ppm that
could be tentatively assigned to H-4 and H-3, and a broader doublet at 9.05 ppm,
presumably assignable to H-9, but the remaining signals were confusing multiplets,
around 7.62 and 7.36 ppm, that could not be assigned directly. The 13C NMR
spectrum and 2D experiments failed to clarify this situation. Similarly, in the case of
aldehyde 5 the spectra in CDCl3 were unsatisfactory for complete assignment of the
signals, largely because of the near overlap of some multiplets.
Recording the spectra of 4 and 5 in DMSO-d6 this difficulty was overcome, and
the complete assignments for these compounds are shown in Tables 1 and 2. HSQC
experiments done on aldehydes 4 and 5 related the 13C NMR signals to their
attached 1H nuclei. The results obtained from the 2D-HSQC experiments are shown
in Tables 1 and 2.
Using 2D-Heteronuclear Multiple Quantum Coherence (HMQC) NMR experi-
ments, the observed correlations for the aldehydes are represented in Fig. 2. For
compound 4, a distinct correlation between hydrogen (dH) and their corresponding
carbon (dC) was found. For example, the –OCH3 (d 4.00) is in correlation with the 13
C
signal at 159.6 ppm which is assigned to C-2. Similarly the CHO proton (d 10.68) is in
correlation with the 121.9 ppm signal which is assigned to C-11. Also, correlations
between H-3 (d 7.43) and C-1 (d 122.6), C-13 (d 150.0); H-4 (d8.04) and C-2 (d 159.6),
C-11(d121.9);H-3(d7.43) and C-1 (d122.6), C-13 (d 150.0); H-6(d 7.70) and C-10 (d
118.8); H-7 (d 7.61) and C-12 (d 157.0); H-8 (d 7.41) and C-10 (d 118.8); H-9 (d 8.89)
and C-11 (d 121.9), C-12 (d 157.0) were observed. In order to decide the still dubious
Scheme 2 Formylation of 2-methoxydibenzo[b,d]furan (3)
123

T. Yempala, B. K. Cassels
Table 1 1H NMR assignments of compounds 4 and 5 recorded in DMSO-d6 at 300 K
S. no
Aldehyde
1H
Multiplicity
d (ppm)
J (Hz)
1
4
H-3
d(unclear)
7.43
8.04
7.70
7.61
7.41
8.89
4.00
10.68
7.98
7.87
7.69
7.60
7.43
8.23
4.03
10.42
–
2
H-4
d
9.0
3
H-6
d
8.3
4
H-7
t
8.0 and 7.3
5
H-8
t(unclear)
–
6
H-9
d
s
s
s
s
d
t
8.0
7
H-14 (-OCH3)
8
H-15 (-CHO)
9
5
H-1
10
11
12
13
14
15
16
H-4
H-6
8.3
H-7
7.8 and 7.5
7.5 and 7.3
7.8
H-8
t
H-9
d
s
s
H-14 (-OCH3)
H-15 (-CHO)
Table 2 13C NMR assignments
of compounds 4 and 5 recorded
in DMSO-d6 at 300 K
S. no
Aldehyde 4
Aldehyde 5
13C
13C
d (ppm)
d (ppm)
1
C-1
122.6
159.6
122.5
118.8
111.3
129.0
112.3
126.1
118.8
121.9
157.0
150.0
57.0
C-1
109.5
158.0
130.2
104.4
111.8
129.4
123.2
122.3
122.9
123.3
157.3
149.2
56.5
2
C-2
C-2
3
C-3
C-3
4
C-4
C-4
5
C-6
C-6
6
C-7
C-7
7
C-8
C-8
8
C-9
C-9
9
C-10
C-11
C-12
C-13
C-14
C-15
C-10
C-11
C-12
C-13
C-14
C-15
10
11
12
13
14
190.1
188.7
assignments of H-3 (d 7.43) and H-8 (d 7.41), 2D- NOESY experiments were
conducted finding a distinct correlation between the –OCH3 (d 4.00) and H-3 (d 7.43);
and between H-8 (d 7.41) and H-9 (d 8.89) (Fig. 3).
For aldehyde 5, the structural assignments of the proton and carbon chemical shifts
could also be made with the help of 2D-HMQC NMR. The correlations between
123

Synthesis, scope, 1H and 13C spectral assignments of…
Fig. 2 Diagnostic correlations observed from the 2D-HMQC NMR experiments on compounds 4 and 5
in DMSO-d6
Fig. 3 Observed 1H–1H NOESY correlations for compounds 4 and 5
Fig. 4 Atom numbering for aldehydes 4 and 5
-OCH3 (d 4.03) and C-2 (d 158.0); –CHO (d10.42) and C-1 (d 109.5); H-1 (d 7.98)
and C-2 (d 158.0), C-3 (d 130.2), C-13 (d 149.2); H-4 (d 7.87) and C-3 (d 130.2), C-11
(d 123.3), C-15 (d 188.7); H-6 (d 7.69) and C-10 (d 122.9); H-7 (d 7.60) and C-12 (d
157.3); H-8 (d 7.43) and C-10 (d 122.9); H-9 (d 8.23) and C-12 (d 157.3), respectively,
were observed for compound 5 (Fig. 1) in the HMQC experiment. Furthermore, a
good correlation between –OCH3 (d 4.03) and H-1 (d 7.98); H-8 (d 7.43) and H-9 (d
8.23) was found for compound 5 in the 2D-NOESY experiment (Fig. 3).
With the help of the above experimental observations, the complete NMR
assignments for aldehydes 4 and 5 are presented in Tables 1 (1H NMR) and 2 (13C
NMR) according to the numbering shown in Fig. 4.
In view of the potential importance of dibenzofuran derivatives in medicinal
chemistry applications, the following dibenzofuran embedded b-phenethylamines
[19–21] 6 and 7 were synthesized for the first time according to Scheme 3.
123

T. Yempala, B. K. Cassels
Scheme 3 Synthesis of dibenzofuran b-phenylethylamines 6 and 7
Scheme 4 Synthesis of novel dibenzofuran NBOMe derivatives 8 and 9
These dibenzofuran aldehydes were also utilized in synthesizing novel NBOMe
analogues 8 and 9 (Scheme 4) by reaction with 2-(4-bromo-2,5-dimethoxyphenyl)
ethaneamine, an important core unit in serotonin receptor ligands [22, 23].
Conclusions
In conclusion, an efficient protocol for the synthesis of the isomeric 2-methoxy-
dibenzo[b,d]furan-1-carbaldehyde (4) and 2-methoxydibenzo[b,d]furan-3-carbalde-
hyde (5) is described for the first time. These aldehydes were synthesized in good
combined yield (95 %) and in a 35:65 (4:5) ratio starting from 2-methoxy-
dibenzo[b,d]furan (3) using a,a-dichloromethyl methyl ether and tin(IV) chloride.
1
The structures of these aldehydes were assigned unambiguously by H and 13C
123

Synthesis, scope, 1H and 13C spectral assignments of…
NMR spectrometry including 2D-NOESY, 2D-HSQC, and HMQC experiments. It
may be noted that the spectra recorded in CDCl3 could not be completely
interpreted, but this could be done after re-recording them in DMSO-d6. These
findings should be very helpful in ongoing research where the 2-methoxydibenzo-
furan aldehydes are being used as precursors in the synthesis of derivatives for
pharmacological studies. The structure confirmation and biological evaluations of
newly synthesized derivatives 6–9 and some analogues are in progress.
Acknowledgments The authors are thankful to CONICYT for financial assistance through FONDECYT
Postdoctoral Fellowship # 3150474.
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