Syntheses of furo[3,4-c]coumarins and related furyl coumarin derivatives via intramolecular Wittig reactions

Article abstract of DOI:10.1039/c1ob06571h

A new and general strategy for highly functional furo[3,4-c]coumarins and related furyl coumarin derivatives has been developed, which is based on an extraordinarily facile intramolecular Wittig reaction, starting from α,β-unsaturated ketones, tributylpho

Full text of DOI:10.1039/c1ob06571h

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Syntheses of furo[3,4-c]coumarins and related furyl coumarin derivatives via
intramolecular Wittig reactions†
Yeong-Jiunn Jang, Siang-en Syu, Yu-Jhang Chen, Mei-Chun Yang and Wenwei Lin*
Received 14th September 2011, Accepted 14th October 2011
DOI: 10.1039/c1ob06571h
A new and general strategy for highly functional furo[3,4-c]coumarins and related furyl coumarin
derivatives has been developed, which is based on an extraordinarily facile intramolecular Wittig
reaction, starting from a,b-unsaturated ketones, tributylphosphine, and acyl chlorides. The phosphorus
ylides were proposed to be the key intermediates for constructing the crucial furan ring, leading to a
wide variety of substituted furyl coumarins in one step.
Introduction
Coumarin derivatives form a valuable group of compounds in
nature, which belong to the flavonoid class of plant secondary
metabolites and are well known to possess multiple biological
activities. In recent years they have attracted strong scientific
interest stemming from their broad spectrum of pharmacological
activities, including antioxidant, antiinflammatory, antibacterial,
and antiviral activities. Therefore, the coumarin unit can be found
not only in many natural products but also in synthetic drug
molecules.1
Similarly, as an important class of heterocyclic fused coumarin
derivatives, furocoumarins also have attracted considerable atten-
tion due to their photochemical, photophysical and photobio-
logical properties.2 They are photosensitizers of plant origin and
increase the sensitivity of biological objects to UVA radiation.
These properties have rendered them useful in a variety of
applications such as useful molecular probes, and skin and
autoimmune disease drugs. Consequently, much effort has been
directed towards the synthesis of this class of compounds.3
Fig. 1 Some representative furocoumarin core structures.
the demethylation–cyclization of 3-aryl-4-ethoxycarbonyl furans,
which were prepared from b-methyl-b-nitrostyrenes through Nef
reactions. However, their application has been limited due to
difficulties in tolerating a broad range of functional groups, which
is a result of high temperatures and harsh reaction conditions.
In addition, the preparation of 3-aryl-4-ethoxycarbonyl furans
from substituted benzaldehydes via b-methyl-b-nitrostyrenes is
laborious and low yielding, even though the protocol is general and
well-known. Therefore, the efficient synthesis of functionalized
furo[3,4-c]coumarins for various pharmacological purposes is still
a challenging endeavor.
Recently, we have reported an efficient and convenient synthetic
route to highly substituted furans5 via an intramolecular Wittig
reaction.6 During the course of this research, we have found that
enones can serve as strong acceptors of phosphines and can be
smoothly converted into furans by using phosphorus ylides as
intermediates. On the basis of these findings, we reasoned that the
readily available enones, with the coumarin core structure, might
also undergo a similar one-step reaction through ylide interme-
diates to give furo[3,4-c]coumarins (Fig. 2A). Our retrosynthetic
Among a large variety of furan fused coumarins (Fig.1), one can
easily imagine there are two major groups which differ in the posi-
tion of fusion between the furan and coumarin unit. Compared to
derivatives with a fused furan on the lactone ring, coumarins with
a fused furan on the aromatic ring are broadly studied because of
their abundance in nature. Furthermore, among the three possible
structural isomers with furan fused on the lactone ring, only one
report to the best of our knowledge is published for the syntheses
of furo[3,4-c]coumarins.4 In 2006, Brahmbhatt4 and co-workers
demonstrated that furo[3,4-c]coumarins could be synthesized by
Department of Chemistry, National Taiwan Normal University, 88, Section
4, Tingchow Road, Taipei, 11677, Taiwan, Republic of China. E-mail:
wenweilin@ntnu.edu.tw; Fax: (+886) 02 29354249
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of substrates 1, 3, 4, 5, 6, 7, and 8; and X-ray crystallographic
data (CCDC numbers: 805741 (3cag) and 833192 (6p)). For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06571h
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Table 1 Optimization of the reaction conditions for the formation of 3caa
from 1ca via the intramolecular Wittig reactiona
Bu3P
(equiv.)
PhCOCl (2a)
(equiv.)
Et3N
(equiv.)
Yield of 3caa
Entry
(%)b
1
2
3
4
5
1.1
1.3
1.5
1.5
1.5
2
2
2
1.5
1.1
2.2
2.2
2.2
1.7
1.3
69
68
79 (71)c
68
Fig. 2 Proposed new reaction pattern and retrosynthetic analysis.
45
analysis of furo[3,4-c]coumarins has led to a strategy involving just
two consecutive reactions; an intramolecular Wittig reaction from
the phosphorus ylides, which should be obtained by a Michael
reaction from Bu3P and the readily available enones (Fig. 2B).
In continuation of our previous work, aiming at the synthesis of
different highly functionalized furans, we are now focused on furo-
coumarins with novel structures which have not been thoroughly
investigated before. Therefore, we would like to report an efficient
and mild approach for the synthesis of furo[3,4-c]coumarin deriva-
tives. In addition, other than fused furocoumarins, several types
of derivatives with furan moieties outside the coumarin core are
prepared for investigating the chemoselective, regioselective, and
photoluminescence properties. It is envisaged that the compounds
containing both these moieties in a single molecule may show
enhanced biological and optical properties.
a Reactions were carried out with 1ca (1 mmol) in THF (5 mL) under
nitrogen at rt. b NMR yields with triphenylmethane as the internal
standard. c Yield of isolated product.
Table 2 Preparation of highly functionalized furocoumarins 3 from
benzoyl chloride (2a) and 1a
1
Entry
R1
R2
Time (h)
Yield of 3 (%)b
1
2
3
4
5
6
7
8
9
H
C6H5
C6H5
C6H5
C6H5
1aa
1ba
1ca
1da
1ea
1cb
1cc
1cd
1ce
24
4
2.5
1.5
3
8
6
3aaa, 38(63)c
3baa, 66
Results and discussion
6-Cl
6-Br
6-NO2
6,8-Cl2
6-Br
6-Br
6-Br
6-Br
3caa, 71
With the above-mentioned hypotheses in mind, 3-benzoyl-6-
bromocoumarin (1ca) was proposed as a test substrate and
prepared according to the literature.7 We began our study by
examining the reaction of 1ca and benzoyl chloride (2a) under
different reaction conditions (Table 1).
3daa, 89
C6H5
3eaa, 69
3-NO2C6H4
4-NO2C6H4
4-MeOC6H4
CH3
3cba, 73
3cca, 86
24
2
3cda, 24(76)c
3cea, 55
Initially, the Michael acceptor 1ca, Bu3P (1.1 equiv.), 2a (2
equiv.), and Et3N (2.2 equiv.) reacted smoothly in anhydrous THF
at room temperature for 2.5 h, providing the desired furo[3,4-
c]coumarin 3caa in 69% NMR yield (Table 1, entry 1). Encouraged
by this important result, different amounts of each reagent were
screened under the same conditions (Table 1). Finally, we were
pleased to find that using Bu3P (1.5 equiv.), 2a (2 equiv.), and
Et3N (2.2 equiv.) were the best conditions, giving 3caa in 71%
isolated yield (Table 1, entry 3).
With the optimal conditions in hand, we turned our attention
to the reaction scope of this transformation by changing the
enone 1. In order to investigate the syntheses of different furo[3,4-
c]coumarins and to explore the effects of different substitutent
groups (Table 2). Various electron-withdrawing and electron-
donating R1 and R2 substituents of enone 1 were all well-tolerated
when reacting with benzoyl chloride (2a). In general, electron-
withdrawing R1 substituents at the 6-position of enone 1 were
uniformly of great benefit with regard to both the time required
for the reaction and the yield produced (Table 2, entries 2–5 vs. 1),
but it had little impact on the yield while electron-withdrawing R1
a Reactions were carried out with 1 (0.5 mmol) in THF (2.5 mL) under
nitrogen at 27 ◦C. b Yields of isolated products. c Recovered yields.
substituents were at the 8-position (Table 2, entry 2 vs. 5). Similarly,
the reaction proceeded acceptably when electron-withdrawing and
-donating groups were used at the R2 position (Table 2, entries
6–8). The presence of electron-withdrawing or -donating groups
on the R2 substituents also followed the general trend mentioned
above which was generated by R1. Remarkably, substituents at R1
can have a larger influence on the yield and reaction time than
those at R2 (Table 2, entries 3–4 vs. 7). Not only an aromatic
substituent but also an aliphatic substituent was introduced as R2,
and it was compatible with this transformation (Table 2, entry 9).
To thoroughly investigate the generality of this transformation,
many other acid chlorides 2 were tested and the results are
summarized in Table 3. To our delight, a wide variety of multi-
substituted furo[3,4-c]coumarins were constructed in medium
to good yields without difficulty. Similarly, higher yields and
shorter reaction times were facilitated by electron-withdrawing R3
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Table 3 Preparation of highly functionalized furocoumarins 3ca and 3da
from 1ca and 1da with different acid chlorides 2a
As mentioned before, owing to their attractive applications
in material science8 and diverse pharmacological properties,
coumarins have recently received intense interest. On the other
hand, chalcones form another important class of natural com-
pounds, which display interesting biological activities including
anti-inflammatory, antioxidant, antimalarial, antibacterial and
anticancer. In the recent design of new materials or drugs, research
suggests that the development of hybrid compounds through
the combination of different chromophores or pharmacophores
may lead to molecules with interesting profiles. Based on our
previous reports, chalcones can be easily transformed to highly
substituted furans by our protocol.5 Therefore, we were especially
interested in molecules with these two moieties together, both for
investigating their reactivities in our method and for examining
the photophysical properties of the generated furans.
Entry
R1 (1)
R3 (2)
Time (h)
Yield of 3 (%)b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
C6H5 (2a)
2.5
3
5
30 min
4
10 min
24
1
1.5
3caa, 71
3cab, 77
3cac, 93
3cad, 95
3cae, 57
3caf, 86
3cag, 64
3cah, 65
3daa, 89
3dad, 91
3dag, 62
2-ClC6H4 (2b)
3-ClC6H4 (2c)
4-ClC6H4 (2d)
2-BrC6H4 (2e)
4-NO2C6H4 (2f)
4-MeOC6H4 (2g)
Cyclohexyl (2h)
C6H5 (2a)
Inspired by these proposals, we have designed and prepared a
series of novel compounds that have both coumarin and chalcone
entities together (Fig. 4) and have reacted them with Bu3P and
benzoyl chloride (2a) (Table 4 and Schemes 1–2).
9
10
11
NO2
NO2
NO2
4-ClC6H4 (2d)
4-MeOC6H4 (2g)
30 min
24
a Reactions were carried out with 1ca or 1da (0.5 mmol) in THF (2.5 mL)
under nitrogen at 27 ◦C. b Yields of isolated products.
substituents of the acid chlorides 2 (Table 3, entries 2–4 and 6 vs.
7), and both aromatic and aliphatic R3 substituents could be used
for this transformation (Table 3, entry 8). In addition, three points
were noteworthy: [1] steric effects were observed when substituents
were introduced at the ortho-position of R3; for example, 2b (R3
= 2-ClC6H4) reacted with 1ca to give 3cab (77%) in a lower yield
than the 3cad (95%) produced from 2d (R3 = 4-ClC6H4) (Table 3,
entry 2 vs. 4), [2] EWG substituents at R3 had a greater impact on
the yield and reaction time than at R2 (Table 3, entry 6 vs. Table 2,
entry 7), and [3] not only 6-Br, but also 6-NO2 can be introduced
at R1, and both of them had high reactivities with acid chlorides
in similar reaction patterns and behavior (Table 3, entries 9–11).
The inspiring results obtained so far prompted us to study
further the synthetic application associated with the introduction
and construction of more functionalities on the coumarin core
structures. It would be unquestionably desirable to extend our
method to conjugated carbonyl compounds in addition to enones.
For this purpose, five compounds as depicted in Fig. 3 were
prepared and tested in a reaction with Bu3P and benzoyl chloride
(2a) under typical conditions. However, no product could be
observed in the reactions and these five starting substrates were
almost completely recovered, even though the structures of the
first two thiocoumarin derivatives (Fig. 3A–B) were very similar
to our previous substrates. From these results, it seemed that the
enone functionality was crucial to this transformation while the
conjugated lactone group also played an important role in the
reaction.
Fig. 4 Novel hybrid molecules through the combination of coumarin and
chalcone.
With this proposal in mind, we firstly focused on the Michael
additions of 3-aryl-1-(3-coumarinyl)propen-1-ones 4 (of the type
shown in Fig. 4A ) which were synthesized by the reaction of
3-acetyl-6-bromocoumarin 1ce and various substituted aromatic
Table 4 Preparation of highly functionalized 6-bromo-3-(2-furyl)-
coumarins 5 from benzoyl chloride (2a) and various coumarin–chalcone
hybrids 4 based on the idea in Fig. 4Aa
Entry
R4 (4)
Time (h)
Yield of 5 (%)b
1
2
3
4
5
6
7
8
C6H5 (4a)
1.5
1
2
4
5a, 81
5b, 83
5c, 70
5d, 68
5e, 71
5f, 75
5g, 24
5h, 87
5i, 74
5j, 86
5k, 51
5l, 65
4-BrC6H4 (4b)
(Z)-2-MeOC6H4 (4c)
(Z)-4-MeOC6H4 (4d)
Piperonyl (4e)
4-MeSC6H4 (4f)
(E)-2-MeC6H4 (4g)
4-MeC6H4 (4h)
2-Furyl (4i)
(E)-2-Thiophenyl (4j)
(Z)-3-Pyridinyl (4k)
2-Naphthyl (4l)
3
30 min
1
2
30 min
30 min
30 min
30 min
9
10
11
12
a Reactions were carried out with 4 (0.2 mmol) in THF (1 mL) under
nitrogen at rt. b Yields of isolated products.
Fig. 3 The five conjugated carbonyl compounds tested for the trans-
formation.
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of the Michael addition of Bu3P (Scheme 1, 4n–p vs. Table 4
entries 1–12).
The scope of the work was further extended to 3-(3-
coumarinyl)propen-1-ones 710 (the type shown in Fig. 4B) as
the conjugated acceptor with Bu3P. To study which position
was predominately chosen by the Bu3P-conjugate addition, the
coumarin–chalcone hybrids 7 were treated with Bu3P, 2a and
triethylamine under similar conditions, the reactions gave 3-(3-
furyl)-coumarins 8 as the only regioselective isomer in medium
yields without any g-addition (Scheme 2). In addition, it was worth
mentioning that such highly functional 3-(3-furyl)-coumarins 8
were conveniently generated for the first time within only one step
compared to methods in the literature.11
The preceding results showed that the intermolecular Bu3P
addition of conjugated enones with coumarin and chalcone
moieties generally led to attack at the b¢-carbon of Fig. 4A
and b-carbon of Fig. 4B systems, respectively, with excellent
regioselectivity.
Scheme 1 Regioselective preparation of highly functionalized furyl
coumarin derivatives 5 and/or 6 from benzoyl chloride (2a) and various
coumarin–chalcone hybrids 4m–q.a
Conclusions
In summary, we have developed a mild and efficient protocol for
the syntheses of furo[3,4-c]coumarins and related furyl coumarin
derivatives from readily available substrates. This set of conditions
nicely compliments our previous work, and provides facile access
to highly functionalized furo[3,4-c]coumarins which are not easily
synthesized via known methods. Ease of operation, mild reaction
conditions, possibilities for the large scale synthesis, and a wide
functional-group tolerance are severalmerits of this highly efficient
protocol. Most of the compounds reported in the present work are
novel, and therefore further investigations by our group to extend
the scope of this reaction, as well as biological evaluation of these
compounds, are currently underway.
Scheme 2 Preparation of highly functionalized 6-bromo-3-(3-furyl)-
coumarins 8 from benzoyl chloride (2a) and various coumarin–chalcone
hybrids 7 based on the idea in Fig. 4B.a
aldehydes in the presence of piperidine in ethanol under reflux
(Table 4).
Based on our previous reports5 and the present work, the
Michael addition of Bu3P with 4 could in principle lead to the
following results, (1) addition at the b-position or (2) addition at
b¢-position. However, the addition selectively took place at the b¢-
carbon of the coumarinyl chalcone to give 5 as the sole product
even though the b-carbon possessed an electron-withdrawing
activating group (coumarinyl lactone) and the b¢-carbon had
electron-donating deactivating substituents (Table 4, entries 3–5
and 7–8). This surprising and striking regioselectivity suggested
that the coumarinyl lactone was too weak an activating group to
govern the selective addition of Bu3P. Therefore, the steric effect
played a key role in the determination of the regiochemistry of the
Michael addition, and Bu3P selectively attacked the less hindered
chalcony b¢-carbon. As a result, a variety of polysubstituted 3-
(2-furyl)-coumarins 5 were constructed in medium to high yields
in similar reaction patterns and behavior to those in Tables 2–3.
Thus, better yields and faster reaction rates were promoted by
electron-withdrawing R4 substituents of the coumarinyl chalcones
4, and vice versa (Table 4, entries 1–2 and 10 vs. others).9
Experimental
Representative preparation of furo[3,4-c]coumarin: 3caa
In a dry, nitrogen-flushed Schlenk flask equipped with a septum
and a magnetic stirrer bar, compound 1ca (164.6 mg, 0.50 mmol)
was dissolved in dry THF (2.5 mL) and stirred. After 5 min
of stirring, tributylphosphine (187.3 mL, 0.75 mmol), benzoyl
chloride (2a) (116.1 mL, 1.0 mmol), and Et3N (152.9 mL, 1.1
mmol◦) were successively added. The resulting solution was stirred
at 27 C until the reaction was complete (monitoring by NMR).
After completion (2.5 h), the solvent was removed in vacuo, and
the crude product was purified by flash chromatography (silica
gel; hexane/ethyl acetate, 10 : 1) to yield the desired product
3caa (147.5 mg, 71%) as a white solid. M.p. 259.5–259.9 ◦C;
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 8.39 (d, J = 7.3 Hz,
2 H), 8.00 (d, J = 2.0 Hz, 1 H), 7.78 (d, J = 7.0 Hz, 2 H),
7.65–7.41 (m, 7H), 7.19 (d, J = 8.8 Hz, 1 H); 13C NMR (100
MHz, CDCl3, 25 ◦C): d = 158.0, 157.2, 150.3, 147.5, 132.2, 130.5,
130.1, 129.7, 129.1, 128.6, 128.2, 128.1, 125.7, 119.3, 116.9, 116.8,
116.2, 107.5; IR (KBr): n-1 = 1742 (s), 1266 (s), 1178 (s), 570
(w) cm-1; MS (20 eV, EI): m/z (%): 418 (M + 2, 100), 416 (M+,
87); HRMS (MALDI) for (C23H1379BrO3 + H)+: 417.0126, found:
417.0137.
Furthermore, the interesting results mentioned above inspired
us to investigate the origin of the steric effects and regioselectivity.
First of all, we examined the Michael addition of Bu3P with 4,
which possessed different sterically sized alkoxy substituents at
the ortho-position of the chalcony 3-benzene ring. (Scheme 1,
4m–p). As expected, due to the steric hindrance coming from
R4, the products contained two regioisomers 5 and 6 when
R4 became bulkier so that the addition of Bu3P towards 4
took place less selectively (Scheme 1, 4m vs. 4n–p). It could be
assumed that the R4 substituent served as a blocking group for
b¢-addition, but a small R4 had little effect on the regiocontrol
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2004, pp. 1–17; (b) A. Abell, D. M. K. Edmonds, Organophosphorus
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9 Besides, we were interested not only in preparing heteroaromatic
derivatives but also especially in the photophysical properties of these
highly functional furyl cumarins 5. Therefore, based on the present
works, UV-vis absorption and fluorescence spectra of some selected
coumarin derivatives were measured and given in Figure SI-1-2 in the
supporting information†.
10 Substrates 7a and 7c were prepared via Wittig reactions from com-
mercial available triphenyl phosphonium ylides of the corresponding
ketones and 6-bromo-3-formylcoumarin which was synthesized ac-
cording to the following reported procedure: (a) L. Rene, J. Poncet
and G. Auzou, Synthesis, 1986, (05), 419; (b) G. Auzou and L. Rene,
J. Heterocycl. Chem., 1986, 23, 955; (c) L. Rene, A. Lefebvre and G.
Auzou, Synthesis, 1986, (07), 567. On the other hand, 7b was obtained
from the reaction of 6-bromo-3-formylcoumarin and cyclohexane
through an aldol condensation.
Acknowledgements
The authors thank the National Science Council of the Republic
of China (NSC Grant No. 99-2113-M-003-004-MY2) and the
National Taiwan Normal University (Grant 99T3030-6) for
financial support.
Notes and references
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3 For metal-catalyzed synthetic examples of furocoumarins, see: (a) L.
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4 D. I. Brahmbhatt, J. M. Gajera, C. N. Patel, V. P. Pandya and U. R.
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