Unexpected detection of 3-aroylbenzofuran side products in the preparation of 2-arylbenzofurans: Identification, characterization, and comparison with chalcone's fragmentation patterns using EI/MSn

Article abstract of DOI:10.1002/jms.4425

A gas chromatography-mass spectrometry study of the intramolecular Wittig reaction revealed, together with the expected 2-phenylbenzofuran, the formation of an unexpected side product that has not been reported until now. This study reports the identification of the by-product, ie, the 3-benzoyl-2-phenylbenzofuran, on the base of its mass spectrometric behaviour using a combination of electron ionization, exact mass measurement, multiple stage mass spectrometry, and labelled compounds. This study reports the common fragmentation pathways and discusses possible fragment structures of characteristic ions from a series of 3-aroyl-2-arylbenzofuran derivatives obtained as by-product under Wittig conditions. Emphasis is laid on the formation and structure investigation of the [M-H]⁺ and [M-OH]⁺ ions. Our results showed interesting analogies with the mass spectrometric behaviour of chalcones.

Full text of DOI:10.1002/jms.4425

Begala Michela (Orcid ID: 0000-0002-8213-2335)
Unexpected detection of 3-aroylbenzofuran side products in
the preparation of 2-arylbenzofurans: identification,
characterization
and
comparison
with
chalcone’s
fragmentation patterns using EI/MSn
*
Michela Begala and Giovanna Lucia Delogu
Department of Life and Environmental Sciences, Unit of Drug Sciences, University of
Cagliari, via Ospedale 72, 09124 Cagliari, Italy
*Correspondence to Michela Begala, Department of Life and Environmental Sciences,
University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy. Email: michelabegala@unica.it
+
+
Running title: unexpected [M-H] and [M-OH] from 3-aroyl-2-arylbenzofurans
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/jms.4425
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Abstract
A gas chromatography-mass spectrometry study of the intramolecular Wittig reaction
revealed, together with the expected 2-phenylbenzofuran, the formation of an unexpected
side product that has not been reported until now. This study reports the identification of the
by-product, i.e. the 3-benzoyl-2-phenylbenzofuran, on the base of its mass spectrometric
behaviour using a combination of electron ionization (EI), exact mass measurement, multiple
stage mass spectrometry and labelled compounds. This study reports the common
fragmentation pathways and discusses possible fragment structures of characteristic ions from
a series of 3-aroyl-2-arylbenzofuran derivatives obtained as by-product under Wittig
+
conditions. Emphasis is laid on the formation and structure investigation of the [M-H] and
+
[
M-OH] ions. Our results showed interesting analogies with the mass spectrometric behavior
of chalcones.
KEYWORDS
n
+
Intramolecular Wittig reaction, 3-aroylbenzofurans, MS , [M-OH] , chalcone-like
fragmentations
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1
INTRODUCTION
2
-Phenyl[b]benzofurans serve as core structures of many natural and artificial compounds of
1
biological and medical importance. In the course of a program directed towards the synthesis
of novel monoamine oxidase (MAO) and butyrylcholinesterase (BChE) inhibitors,2,3 we
planned to synthesize 2-phenylbenzofurans using an intramolecular Wittig procedure due to
the accessibility and simplicity of this methodology.4,5 In particular, compounds 4a-g were
prepared from the appropriate triphenylphosphonium salt 2 and the commercially available
aroyl chlorides 3a-g (Scheme 1).
The reaction mixtures were analysed by gas chromatography coupled with mass
spectrometry because the reaction products are susceptible to analysis by GC for their
volatility and thermal stability. However, while developing this procedure, GC/MS analysis
of the reaction mixture, obtained from the salt 2 and the benzoyl chloride 3a, revealed that,
together with the desired product of cyclization 4a, the unexpected side-product 5a was
present. The same trend was observed in the crude reaction mixtures of the main products 4b-
g, obtained from the reaction of 2 with a variety of aroyl chlorides (3b-g). Although the
Wittig reaction has been described in several papers regarding the preparation of 2-
arylbenzofuran derivatives, the formation of secondary products was not mentioned.4,5
Identification of unknown peaks is useful to permit discovery of novel or unexpected
reaction products and play an important role in comprehending the reaction mechanism by
which this reaction evolves. However, isolation and purification of sufficiently large
quantities of by-product compounds for their unambiguous identification and characterization
by different instrumental techniques, such as infrared spectroscopy (IR) and nuclear magnetic
resonance (NMR), is a very complex and time-consuming process. Nowadays, GC-MS
n
coupled to multiple stage mass spectrometry (MS ) is an invaluable tool for the rapid
identification and structural characterization of unknown compounds, especially when low
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amount of analyte or not very pure samples are available for the analysis. Hence, we have
undertaken a detailed investigation on the unknown side products aimed to identify their
structure and to elucidate their mass spectrometric behaviour. To this aim, EI-MSn
experiments were performed using a quadrupole ion trap analyser (IT) as it is a very efficient
multiple-stage mass spectrometers.6
2
2
EXPERIMENTAL
.1 MS analysis
All experiments were performed with a Varian Saturn 2000 ion trap mass spectrometer
ITMS), operating under EI conditions (electron energy 70 eV, emission current 20 mA, ion-
trap temperature 200°C, manifold temperature 80°C, automatic gain control (AGC) target
1.000) with the ion trap operating in scan mode (scan range from m/z 40-400 at a scan rate
(
2
of 1 scan/s), coupled with a Varian 3800 gas chromatograph (Varian, Walnut Creek, CA).
Collision-induced dissociations (CIDs) experiments were carried out by using helium as
n
the collision gas (gas purity (He) was 99.9999%). For MS experiments the supplementary rf
voltage (45-55V) was varied in such a way that the relative abundance of the surviving
precursor ions was 5-15 %. An isolation time of 10 msec, excitation time of 40 msec and an
isolation width of 3 m/z for the precursor ion were used. Each MS/MS spectrum was an
average of 5 scans.
-5
Compounds 5a-g (1 μL aliquots of 1.0 x 10 M solutions in dichloromethane) were
introduced into the gas chromatographer inlet. An Agilent J&W VF-5ms Low-bleed/MS GC
capillary column (30 m, 0.25 mm i.d., 0.25 mm film thickness) (Agilent Technologies Inc.,
Wilmington, DE, USA) was used. The oven temperature was programmed from 150°C (held
for 2 min) to 310°C at 30°C/min (held for 2 min). The temperature was then ramped to 350 at
This article is protected by copyright. All rights reserved.

2
2
0°C/min. The transfer line was maintained at 180°C and the injector port (30:1 split) at
90°C.
HRMS: MS analyses were performed on a Agilent 6520 LC-ESI(+)-QTOF-MS operated
in the positive ion mode. Compounds (1 mg) were dissolved in acetonitrile (CH CN, 0.5 ml)
3
and after injection mass spectral data were acquired in the range m/z of 100-1,500 with an
acquisition rate of 1.35 spectra/s, averaging 10,000 transients. The source parameters were
adjusted as follows: drying gas temperature 250 °C, drying gas flow rate 5 L/min, nebulizer
pressure 45 psi, and fragmentor voltage 150 V.
2
.2 Materials and reagents
All reagents and solvents were purchased from Sigma-Aldrich (Sigma‐Aldrich Srl, Milan,
Italy) and Alfa Aesar (Thermo Fisher, Kandel, Germany) and used without further
purification.
Compounds 4a and 5a were obtained by 2-benzyloxy-benzyl triphenyl phosphomium
bromide 2 (1.1 mmol) and benzoyl chlorides (1.1 mmol) in the presence of Et
using the Wittig methodology described by Hercouet and Le Corre.4,5 Compounds 4b-g and
b-g were prepared using an adaptation of this procedure.7
3
N in toluene
5
2
-(Hydroxyldideuterium-methyl) phenol 1d was prepared starting from the methyl 2-
2
hydroxybenzoate in THF at 0ºC using lithium aluminum deuteride, as described in literature.8
The reference compound 3-benzoyl-2-phenyl-benzofuran was prepared by direct Friedel-
Craft acylation of the 2-phenylbenzofuran 4a with benzoyl chloride using AlCl as Lewis acid
3
in anhydrous dichloromethane.9
3
-Benzoyl-2-phenyl-d
5
-benzofuran 5ad
5
was synthesized in the same way as 3-benzoyl-2-
4ad
phenyl-benzofuran starting from 2-phenylbenzofuran-d
5
5
.
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2
-Phenylbenzofuran-d
5
4ad
5
and 3-benzoyl-d
5
-2-phenyl-d -benzofuran 5ad10 were
5
prepared starting from 2-benzyloxy-benzyl triphenyl phosphomium bromide 2 and benzoyl
N using the procedure reported elsewhere.7
chloride-d
5
in toluene and Et
3
3
-Phenyl-4H-chromen-4-one 6 (isoflavone) was prepared by Suzuki-Miyaura Cross-
Coupling of 3-iodochromone with benzenboronic acid catalyzed by Pd(0)/C.10,11
3
3
RESULTS AND DISCUSSION
.1 Identification of the by-product 5a
A typical gas chromatogram of the reaction mixture from the triphenylphosphonium salt of 2-
hydroxybenzyl alcohol and the benzoyl chloride is presented in Figure 1. As can be seen,
together with the desired 2-phenylbenzofuran 4a (T
oxide (T 12.5 min), one further peak is present at higher retention time (T
corresponding to the unexpected product 5a.
R
9.2 min) and the triphenylposphine
R
R
12.6 min),
By comparing the data obtained from the EI mass spectra of compounds 4a and 5a (Figure
and Figure 2A), it was enabled to define which part of the molecule of 2-phenylbenzofuran
a was also present in the structure of the unknown compound 5a. In particularly, we focused
1
4
our attention on the diagnostic ion at m/z 193 in the mass spectrum of 5a (Figure 2A). This
ion most likely corresponds to the intact 2-phenylbenzofuran molecule deprived of a H atom.
In fact, under MS/MS experiments m/z 193 exhibits the loss of CO typical of the benzofuran
nucleus to give the ion at m/z 165, which is also observed in the EI and MS/MS mass spectra
+
.
12-14
of the 2-phenylbenzofuran 4a (M m/z 194).
As the sum of m/z value of the fragment
+
.
ions at m/z 193 and m/z 105, absent in the mass spectrum of 4a, is equal to m/z M (m/z 298),
these two ions could be complementary ions, representing two parts of the molecule; the rest
of the structure was determined by comparison of the data achieved from the identification of
the ion at m/z 105, with that from accurate mass measurement of the unknown compound 5a.
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Under CID experiments, the m/z 105 ion decomposes into ions at m/z 77 and 51 thus
1
5
indicating the presence of a benzoyl group (C
6
H
5
CO) in the structure of 5a. Accordingly,
(calc. 299.1066 exp.
99.1066) composition, showing that the mass difference between 5a and the 2-
accurate mass measurement for the side product 5a reveals a C21
H
14
O
2
2
phenylbenzofuran 4a (C14H10O) was in seven carbon atoms, four hydrogen atoms and one
oxygen (104 Da) suggesting the addition of a benzoyl group to the main product 4a.
Even more, when the reaction was performed using the labeled benzoyl chloride-d
5
3ad
5
in place of the benzoyl chloride 3a, we found that the molecular ion shifted from m/z 298, for
compound 5a, to m/z 308, for the labeled compound 5ad10, thus confirming that two
molecules of the labeled acyl chloride contribute to the structure of the side product (Figure
2
B). The general structure of acylated 2-phenylbenzofuran was than proposed for the
unknown compound 5a.
The position of the acyl group was then investigated using the 2-hydroxybenzyl alcohol-d
2
1
2
d as starting reagent. The Wittig reaction so performed, leads to the unlabelled acyl
benzofuran 5a at m/z 298. These data clearly show the lack of methine hydrogen in the furan
ring of compound 5a, thus demonstrating that the benzoyl group is attached to the C-3
position of the benzofuran nucleus. Our results indicate, therefore, that the side products 5a
most likely have the 3-aroylbenzofuran structure depicted in Scheme 1. The model 3-
benzoyl-2-phenylbenzofuran was prepared by Friedel-Craft acylation of the 2-
phenylbenzofuran 4a and was analysed by MS, as a final confirmation of the proposed
structure for 5a. A detailed study aimed to provide a much deeper insight into the reaction
mechanism that lead to the 3-aroyl derivative have been reported elsewhere.7
These findings are of particular interest since the 3-aroyl-2-arylbenzofuran scaffold
constitutes the core of many pharmaceutical drug candidates such as amiodarone,16 LY
3
20135,17 benzbromarone 18 and SKF-64346.19 Moreover, from synthetic viewpoint this
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procedure represents a new regioselective and versatile synthetic approach to 3-acyl
7
derivatives. However, to the best of our knowledge, mass spectrometric investigation of 3-
aroylbenzofurans has received only little attention with most of the emphasis devoted to the
plasma and urine detection of few biologically active compounds i.e. amiodarone,
benziodarone, desethylamiodarone20,21 and benzbromarone.22
A detailed study dealing with the fragmentation of aroyl benzofurans have also appeared,
however it only covered the ESI MS/MS behavior of 2-aroyl derivatives.23
Therefore, as a material for further investigations, we present a systematic and detailed
study on the EI induced fragmentation of 3-benzoyl-2-phenylbenzofurans. To this aim, we
selected several ring substituted 3-acyl derivatives obtained by our procedure, and subjected
n
them to EI MS experiments using an IT mass spectrometer.
3
.2 Fragmentation typical for 3-aroyl-2-arylbenzofurans
The EI mass spectra of compounds 5a-g are depicted in Table 1. We divided the structure
into three parts: the benzofuran scaffold, the aryl group (ring A) and the aroyl group (ring B)
(See Scheme 2 referred to compound 5a, Ar = C
6
5
H ). Two sets of acylium ions were
observed resulting from the two competing α-cleavages next to the carbonyl group, i.e. the
+
+
[
M-Ar] ions a and the ArC=O ions b. Both type of acylium ions under MS/MS conditions
undergo the typical loss of CO to generate, respectively, the 2-phenylbenzofuran fragment
ions c (complementary to ion b) and the phenylium ions d (complementary to ion a) which,
therefore, allow an easy identification of the original intact molecule (vide supra). The only
exception to this trend was observed for the nitro derivatives 5b. Under CID experiments,
+
each of the acylium ions from 5b, i.e. the [M-Ar] ion of m/z 266 and the 4-
nitrobenzoylcation of m/z 150, does not show the direct losses of CO. Instead, they both form
characteristic fragment ions at m/z 236 and 220 and at m/z 120 and 104, respectively, due to
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.
., which only subsequently lose CO molecule (See
the losses of NO and of NO
2
supplementary material).24
We also examined how the intensity of ions b is influenced by substituents on rings B or
by heteroaromatic rings, for instance furyl and thienyl moieties. Concerning compounds 5b-e,
we found that the intensity of the acylium ions b is strongly influenced by the nature of the
substituent on the benzoyl group (Table 1). In the mass spectrum of compound 5e, bearing
the methoxy group on the ring B, the p-methoxybenzoyl cation (m/z 135) is particularly
intense (relative abundance, R.A. 36%). This behavior can be explained with the ability of the
p-methoxy group to exert resonance stabilization of the p-methoxybenzoyl cation. The mass
+
spectra of the heteroaryl compounds 5f and 5g exhibit the ArC=O ions rather intense (R.A.
4
4 and 37%) reasonably because the 2-furyl and 2-thienyl substituents have electronic effect
comparable with that of p-anisyl group, well recognized as an overall electron-donating
system.
In the case of compounds 5b-d bearing electron withdrawing groups, NO
2
, CN and CF ,
3
+
the formation of the ArC=O ions is strongly suppressed (R.A. 4-16%) in favor of the [M-
+
Ar] ions (R.A. 34-63%). Moreover, the stronger the electron-withdrawing effect on the ring
B, the lower is the relative abundance of the benzoyl cation b.
+
The [M-Ar] acylium ions a constitute the most prominent fragment ions in the mass
spectra of all compounds (R.A. 34-66%), with the only exception of compounds 5e-g, for
which the formation of ion b is the most favored process (vide supra). A possible
+
representations of the [M-Ar] ions is the resonance-stabilized oxonium structure j depicted
in Scheme 2, which could account for the high intensities observed. We therefore thought of
+
interest to compare the CID mass spectrum of the [M-Ar] ions from 5a with that of the
2
5
oxonium ion at m/z 221 formed in the EI mass spectrum of isoflavone 6 (m/z 222), used as
reference ion (Figure 3). As can be seen, the CID mass spectra are very similar, proving that
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the cyclization to structure j occurs to some extents. There is, however, a difference in the
relative intensity of the m/z 193 ion. This ion that we assign to the CO loss, is more abundant
for the compound 5a (45% vs 4%). These data can be rationalized by the fact that part of the
m/z 221 ions population of 5a posses the open structure a, which undergoes easier this
fragmentation.
In addition to the α-cleavages, characteristic for carbonyl compounds, some further
interesting losses were observed under EI-MS and MS/MS experiments i.e. the losses of H.
.
and of OH radicals from the molecular ion.
3
.3 Elimination of a hydrogen radical
+
The EI mass spectra of the 3-benzoyl-benzofurans 5a-e show intense [M-H] ions (Table 1).
.
In the MS/MS spectra the H loss was even more pronounced (Figure 4). Only for compounds
.
5
b and 5e, the H loss occurred together with the loss of the substituent or of part of it as they
show the total loss of 47 and 16 amu from the molecular ion. We suggest that the first step is
.
.
the loss of a hydrogen atom and that NO
2
or CH
3
are lost from the even-electron ion so
formed. Thus, the high abundant ions at m/z 341 and m/z 342 were attributed to the [M-H-
+.
]+. for compounds 5b and 5e, respectively (Figure 4B and 4E).
NO
2
] and the [M-H-CH
3
+
To get insight into the structure of the [M-H] specie, we first investigated the origin of the
.
H lost. To this aim the MS/MS spectrum of the unsubstituted compound 5a (m/z 298. Figure
A) was compared with that of its deuterium labelled analogue 5ad10 (rings A and B = C
m/z 308. Figure 2C). Under this condition 5a formed the stable ion at m/z 297, with a R.A. of
4
6
5
D ;
1
00%. The loss of 2 amu (m/z 306) from the molecular ion of the labelled derivatives 5ad10
.
(
m/z 308), clearly indicates that the source of the H eliminated is the phenyl group in position
2
(ring A) and/or the aroyl group in position 3 (ring B). MS/MS experiments on the 3-
benzoyl-2-phenyl-d -benzofuran 5ad (Figure 5B), has helped to further elucidate the origin
5
5
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.
2
of the H loss. Under MS experiments the molecular ion of the labelled derivative 5ad
5
(ring
A = C ; m/z 303) shows the preferential loss of deuterium radical from the ring A (m/z 301
6
D
5
.
RA 100%), rather than the loss of H from the benzoyl group (ring B; m/z 302 R.A. 25%).
This result indicates that the former process requires less energy than the latter and
n
consequently is more favoured. In fact, MS experiments performed using an ion trap,
2
6
privilege processes with the lowest critical energies. Accordingly, a different trend was
observed in the full scan EI mass spectrum of 5ad , which displayed the ions at m/z 302 and
01 with similar intensities (R.A. 29 and 34%. Figure 5A).
We supposed that the driving force for the loss of the aromatic hydrogen radical
5
3
preferentially from ring A, lay in the formation of a highly resonance-stabilized ion, i.e. the
oxonium ion k reported in Scheme 3. A possible mechanism consists in an intramolecular
aromatic substitution reaction; this might occur through the interaction of the carbonyl group
’
with the 2 position of the phenyl ring A to form a six membered ring and consequent
hydrogen radical loss, that would result in restoration of aromaticity to ring A. Analogous
2
7
rearrangement process was also postulated to occur by Ronayne and co-workers and by Van
2
8
de Sande and co-workers for chalcones and led to the formation of an oxonium ion. In fact,
-benzoyl-2-phenylbenzofurans can be considered as benzofuran-chalcones hybrids where
3
the C2-C3 double bond of the benzofuran nucleus fixes in the cis disposition the chalcones-
type double bond (bold part of the ions in Scheme 3). It must be point out that the aromatic
oxonium ion k could further rearrange to the structure k
1
, as demonstrated to occur in
2
9
chalcones and 3-flavene by Traldi and co-workers. Unfortunately, unlike chalcones, CID
+
.
experiments on the [M-H] ion lead to the losses of CHO and CO that agree with both
structures k and k
1
.
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3
.4 Elimination of hydroxyl radical. 3-Aroyl-2-aylbenzofurans vs calchones
All compounds under investigation exhibit unusual and fairly small [M-17] peaks (Table 1).
With the only exception of compounds 5a, 5c and 5d, this behavior is somewhat increased in
intensity under MS/MS conditions (R.A. 2-30%. Figure 4). The deuterium labeling results
using the simplest 3-benzoyl-benzofuran 5a indicate that a deuterium was involved in this
process. As can be seen, in the mass spectrum the deuterated analogue 5ad10 (Figure 2B),
.
ions at m/z 281 shifted to m/z 290 reflecting the loss of OD from the molecular ion. The most
.
reasonable inference is that the oxygen involved in the OH loss arises from the carbonyl
group. In fact, compounds 5a, as well as compounds 5f and 5g, have no additional
+
substituents, which could themselves produce [M-OH] ion. To the best of our knowledge,
only few papers have been reported on the involvement of a carbonyl oxygen atom in the
formation of dehydroxylated ions. Bowie and White described the formation of [M-H
O]+.
2
+
and [M-OH] ions in the mass spectra of aromatic carbonyl compounds which contain an
30
ortho (or peri) methoxy-substituent. More recently, Zenchevich and Pushkareva reported
that compounds bearing -CO-CH=CH-N(CH
3
)
2
structural fragments exhibit unusual peaks of
+
31
[
M-OH] ions formed by a rearrangement with the migration of a hydrogen atom.
+
To get insight into the mechanism of formation of the [M-OH] ion, further experiments
were performed on the labeled compound 5ad
5
. In the MS/MS mass spectrum of 5ad the
5
+
formation of ion at m/z 285 [M-OD] clearly indicates that the hydrogen lost derives from
ring A (Figure 5B).
One of the possible mechanisms rationalizing these results is reported in Scheme 4. The
carbonyl undergoes loss of a hydroxyl radical after abstraction of the hydrogen from ring A
3
2
by McLafferty type rearrangement; the ionic species so generated is plausibly represented
as the ion with the structure y, which contains a new five-membered ring.
In the case of p-nitro-derivative 5b, some considerations have to be done. Compound 5b
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has two nitro groups in the para positions of ring-A and B, respectively, which may be
.
themselves involved in a M-OH process. The OH loss is commonly observed in nitro-
aromatic derivatives, due to an ortho effect.33-37 However, the proximity effect described in
these studies occurs between aromatic nitro function and a group in its proximity i.e. in ortho
or peri positions, and, therefore, appears unlikely for p-nitro-compound 5b where the
distances between the NO substituents and the phenyl rings are rather much greater.
2
Interestingly, Baldas and Porter38 reported that the spectra of 3- and 4-nitrocalchones
display the loss of hydroxyl radical, and that this fragmentation is initiated by the transfer of a
hydrogen atom from the 2-position of the phenyl ring to the nitro group via a cyclized
intermediate.
Considering the striking analogy between chalcone and 5a (vide supra), we expected, for
3
8
p-NO derivative 5b, a similar mechanism to that reported for nitrochalcones, that involves
2
the nitro group rather than the carbonyl. A chalcone-like mechanism was therefore proposed
for compound 5b (Scheme 5).
This behavior is in agreement with the collisional experiments performed on compound 5b
3
+
.
(
Figure 6). Under MS experiments the [M-OH] ion (m/z 371) loses NO to form the m/z
4
3
2
41. MS experiments reveal that the m/z 341 ion fragments by the loss of a nitro radical (m/z
95) and of NO (m/z 311). However, the sequential loses of NO and NO
from the [M-OH]+
.
.
.
2
ion is also consistent with the mechanism that involves the carbonyl group (Scheme 4),
which, therefore, cannot be ruled out for the nitro derivative 5b.
4
CONCLUSIONS
Electron ionization and collision induced dissociation tandem mass spectrometry have proved
to be highly effective for a complete structure assignment of 3-benzoyl-2-phenylbenzofuran,
a side product formed in the preparation of 2-phenylbenzofurans under Wittig conditions.
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Our study showed that beside the alfa cleavages typical of carbonyl compounds, the unusual
.
.
losses of H and of OH constitute diagnostic fragmentations. These losses were attributed to
the interaction between the carbonyl of the 3-acyl group and the 2-phenyl ring, thus reflecting
their proximity in the structure of the benzofuran nucleus. We also evidenced that 3-aroyl-2-
aylbenzofurans can be considered as benzofuran-calchones hybrids and that their EI
fragmentation routes have strong similarities compared with those of chalcones. However,
.
some differences were also underlined. In particular, we found that the OH loss from the
molecular ion of 3-aroyl-2-arylbenzofurans, involves the carbonyl group in position 3. Only
+
nitro-chalcones were reported to show the [M-OH] ion, and it was suggested that the source
.
of the OH loss was exclusively the nitro group. In the case of the analogous 3-benzoyl-2-
n
phenylbenzofuran derivatives bearing the NO
2
group, MS experiments demonstrated that a
nitro-chalcone-like mechanism cannot be excluded.
Supporting Information
Additional Supporting Information may be found online in the supporting information tab for
this article.
Acknoledgments
The present work was partially supported by Fondo integrativo per la ricerca (Fir) - Annualità
2
018 – University of Cagliari. The authors thank Professor Pierluigi Caboni from the
Department of Life and Environmental Sciences, University of Cagliari, for the accurate mass
measurements.
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Table 1. EI (70 eV) mass spectra of compounds 5a-g
5
a
5ad10
5ad
5
5b
5c
5d
5e
5f
5g
M+.
298 (100) 308 (100) 303 (100) 388 (100) 348 (100) 434 (100) 358 (100) 278 (100) 310 (100)
297 (53)
+
+
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
M-H]
M-D]
M-CH
M-H-CH
M-OH]
M-OD]
M-F]
M-CO]
M-NO]
M-SH]
M-CH
M-H-NO
M-CO-CHO]
M-CF
M-Ar] a
a-CO] c
a-NO]
a-CH CO]
a-NO
307(20)
306 (44)
302 (29)
301 (34)
387 (18)
347 (40)
433 (44)
357 (2)
277 (3)
309 (6)
]+
343 (5)
342 (10)
341 (4)
3
]+.
3
+
281 (5)
371 (5)
331 (2)
417 (3)
415 (7)
261 (5)
293 (5)
+
290 (4)
285 (3)
+
+.
250 (55)
282 (9)
281 (6)
277 (18)
+
358 (5)
+
+
3
-CO]
315 (5)
+.
2
]
341 (17)
+
221 (55)
+
3
+
]
365 (12)
289 (63)
261 (2)
221 (56)
193 (5)
226 (66)
198 (5)
226 (62)
198 (3)
266 (34)
-
236 (20)
246 (54)
218 (2)
251 (14)
223 (3)
211 (7)
183 (2)
227 (11)
199 (2)
+
+
.
+.
3
208 (4)
+.
2
+
]
220 (5)
-
150 (4)
c-CO]
165 (20)
105 (24)
170 (21)
170 (20)
105 (25)
190 (15)
130 (12)
233 (8)
173 (16)
195 (9)
135 (36)
155 (12)
95 (44)
171 (6)
111 (37)
+
ArCO b
+
C
6
D
5
CO b
110 (25)
82 (37)
+
[
[
[
b-CO] d
b-NO]
b-NO
77 (31)
77 (38)
-
102 (20)
145 (19)
107 (13)
67 (2)
83 (7)
+.
120 (7)
104 (5)
]+.
2
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Figure 1. GC-MS analysis of the reaction mixture along with the mass spectrum of the 2-
phenylbenzofurane 4a (9.36 min)
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Figure 2. EI mass spectra of compounds A) 5a (m/z 298) and B) the labelled 5ad10 (m/z 308). C) CID of
ad10
5
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Figure 3. A) EI mass spectrum of isoflavone 6. CID of the m/z 221 ions of
B) isoflavone 6 and C) compound 5a
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2
2
Figure 4. MS/MS of compunds 5a-g. A) MS of 5a (m/z 298); (B) MS of 5b (m/z 388); (C)
2
2
2
2
MS of 5c (m/z 348); (D) MS of 5d (m/z 434); (E) MS of 5e (m/z 358); (F) MS of 5f (m/z
2
2
78); (G) MS of 5g (m/z 310)
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2
Figure 5. (A) MS and (B) MS/MS of compound 5ad (m/z 303)
5
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2
3
4
+
Figure 6. A) MS , B) MS and C) MS of the M . ion of compound 5c (m/z
3
88)
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Scheme 1. Synthetic route towards 2-phenylbenzofurans 4a-g and 3-benzoyl-2-phenylbenzofurans 5a-g
2
3
Scheme 2. Main proposed fragmentation pathways for compound 5a on the basis of MS and MS spectra.
Possible structures for ions at m/z 221
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Scheme 3. Proposed mechanism of radical H. loss from compound 5a and similarity with chalcone (bold
part of the structures)
Scheme 4. Proposed mechanism of OH. loss for 5a
Scheme 5. Chalcones-like mechanism of OH. loss for 3-benzoyl-2-phenylbenzofurans (benzofuran–
calchones hybrids)
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