Synthesis of Functionalized Dihydrofurocoumarin Derivatives from 3-Aminoalkyl-4-hydroxycoumarin

Article abstract of DOI:10.1080/00397911.2015.1027405

(Chemical Presented). Some dihydrofuro-fused coumarin derivatives were synthesized from 3-aminoalkyl-4-hydroxycoumarin via in situ generation of N-ylide. The 3-aminoalkylated 4-hydroxycoumarin derivatives were synthesized from one-pot, three-component reaction of 4-hydroxycoumarin, aryl aldehydes, and secondary amines in ethanol at room temperature. Again, when salicylaldehyde was employed instead of benzaldehyde, interestingly pyranocoumarins were obtained. The reaction protocol can be further explored toward the synthesis of many other heterocyclic fused dihydrofurans.

Full text of DOI:10.1080/00397911.2015.1027405

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Synthesis of Functionalized
Dihydrofurocoumarin Derivatives from 3-
Aminoalkyl-4-hydroxycoumarin
Pallabi Boraha, P. Seetham Naidua & Pulak J. Bhuyana
a Medicinal Chemistry Division, Council of Scientific and Industrial
Research, North East Institute of Science and Technology, Jorhat,
Assam, India
Accepted author version posted online: 16 Mar 2015.Published
online: 16 Mar 2015.
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To cite this article: Pallabi Borah, P. Seetham Naidu & Pulak J. Bhuyan (2015): Synthesis of
Functionalized Dihydrofurocoumarin Derivatives from 3-Aminoalkyl-4-hydroxycoumarin, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2015.1027405
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Synthetic Communications1, 0: 1–8, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1027405
SYNTHESIS OF FUNCTIONALIZED
DIHYDROFUROCOUMARIN DERIVATIVES FROM
3-AMINOALKYL-4-HYDROXYCOUMARIN
Pallabi Borah, P. Seetham Naidu, and Pulak J. Bhuyan
Medicinal Chemistry Division, Council of Scientific and Industrial Research,
North East Institute of Science and Technology, Jorhat, Assam, India
GRAPHICAL ABSTRACT
Abstract Some dihydrofuro-fused coumarin derivatives were synthesized from
3-aminoalkyl-4-hydroxycoumarin via in situ generation of N-ylide. The 3-aminoalkylated
4-hydroxycoumarin derivatives were synthesized from one-pot, three-component reaction
of 4-hydroxycoumarin, aryl aldehydes, and secondary amines in ethanol at room
temperature. Again, when salicylaldehyde was employed instead of benzaldehyde,
interestingly pyranocoumarins were obtained. The reaction protocol can be further
explored toward the synthesis of many other heterocyclic fused dihydrofurans.
Keywords Aryl aldehyde; dihydrofurocoumarins; 4-hydroxycoumarin; pyrano[3,2-c]-
coumarins; ylides
INTRODUCTION
Fused coumarin system, in particular furocoumarins, are secondary metabo-
lites found in some higher plants such as celery (Apium graveolens), parsnip (Pasti-
naca sativa), and carrot (Daucus carota).[1] Naturally occurring furocoumarins
exist either in the linear form where the furan is attached at the C(6) and C(7) or
in the angular form, carrying the substituent at C(7) and C(8). The most abundant
Received November 13, 2014.
Address correspondence to Pallabi Borah or Pulak J. Bhuyan, Medicinal Chemistry Division,
Council of Scientific and Industrial Research, North East Institute of Science and Technology, Jorhat
785006, Assam, India. E-mail: pallabibora0123@gmail.com; pulak_jyoti@yahoo.com
1

2
P. BORAH, P. S. NAIDU, AND P. J. BHUYAN
Figure 1. Linear and angular isomers for furocoumarins.
Figure 2. Some bioactive furocoumarins.
linear furocoumarins are psoralen, xanthotoxin, and bergapten, whereas the angular
form is mostly represented by angelicin, sphondin, and pimpinellin (Fig. 1).
Furocoumarin derivatives possess diverse biological activities such as antifun-
gicidal,[2] insecticidal,[3] insect antifeedant,[4] anti-HIV,[5] and anticancer activities.[6]
They have also attracted considerable attention because of their photochemical,
photophysical, and photobiological activities.[7] Furocoumarins are photosensitizers
of plant origin and increase the sensitivity of biological objects to UVA radiation.
Because of these properties, furocoumarins have a wide range of applications as
drugs for skin and autoimmune disease and thus are useful for molecular manipu-
lation.[8] Some of the biologically important furocoumarins are shown in Fig. 2.
As a part of our continuing efforts toward the synthesis of various heterocyclic
compounds,[9] particularly annelated coumarins of biological importance,[10] we
report here the synthesis of some functionalized dihydrofurocoumarin derivatives
7 from the reaction of 3-aminoalkyl-4-hydroxycoumarin 6 and pyridinium salt 3 in
the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
acetonitrile under refluxing condition (Scheme 2).
DISCUSSION
We initiated our study with the three-component reaction of 4-hydroxycou-
marin 1a, benzaldehyde 2a, and pyridinium salt 3a under refluxing conditions in
acetonitrile in the presence of DBU (Scheme 1). Unfortunately, the reaction
produced simply biscoumarin compounds 4a instead of the expected furocoumar-
ins.[11] This might be because of the highly reactive 4-hydroxycoumarin, which
undergoes Michael addition to the Knoeveagal condensed product [A] before the

SYNTHESIS OF DIHYDROFUROCOUMARIN DERIVATIVES
3
Scheme 1. Formation of biscoumarin derivatives.
expected attack of the pyridinium ylide forms in the reaction process (Scheme 1). In
fact, formation of such biscoumarin is well precedented.[12]
Then, we planned to utilize 3-aminoalkyl-4-hydroxycoumarins 6 with
pyridinium salts 3 to achieve the furan fused coumarin derivatives 7 (Scheme 2).
The 3-aminoalkyl-4-hydroxycoumarin derivative 6a was first prepared from one-
pot, three-component reaction of 4-hydroxycoumarin 1, benzaldehyde 2a, and
pyrrolidine 5a in ethanol at room temperature following the reported method.[13]
Interestingly, when the compound 6a so obtained was reacted with pyridinium salt
3a in the presence of a catalytic amount of DBU in ethanol under refluxing con-
ditions, it afforded the dihydrofuro[2,3-c]coumarin derivative 7a in very good yield
(Scheme 2). The structure of the compound was ascertained from the spectroscopic
data and elemental analysis. The 1H NMR spectra showed the absence of the singlet
peak at d 5.23 and presence of two doublets at d 4.72 (J ¼ 4.86 Hz) and d 6.10
(J ¼ 6.96 Hz), which indicate the formation of cyclized dihydro furan fused product.
The coupling constants of the 1H NMR spectra of these two protons further indicate
Scheme 2. Synthesis of dihydrofurocoumarins.

4
P. BORAH, P. S. NAIDU, AND P. J. BHUYAN
the formation of the thermodynamicly stable trans isomer of the product. The mass
spectra showed a sharp molecular ion peak at 369.3 (M þ H)þ. Then, we utilized a
number of 3-aminoalkyl-4-hydroxy-coumarins 6 with various pyridinium salts
bearing COPh, CN, and COOEt groups and synthesized a large number of dihydro-
furo[2,3-c]coumarin derivatives 7b–i. All the new products obtained were character-
ized from their spectroscopic data and elemental analysis. Our observations are
recorded in Table 1.
The reaction was also studied in some other solvents, for example, ethanol,
tetrahydrofuran (THF), dimethylformamide (DMF), and toluene, but acetonitrile
was found as the best solvent for the reaction. DBU was used as base in the reaction
process for its nonnucleophilic nature. We studied the reaction by utilizing various
aryl aldehydes possessing electron-withdrawing as well as electron-donating groups
at the aromatic ring. It was observed that the reactions were smooth in all the cases.
However, the aldehyde having the electron-withdrawing substituent produced the
product in shorter time with better yield in comparison to the aldehyde with elec-
tron-donating substituent. Further increase in the reaction time did not improve
the yield of the products.
It was very interesting to note that when salicylaldehyde 8a was used with
4-hydroxycoumarin 1a and pyrolidine 5a, we obtained the cyclized pyrano[2,3-c]cou-
marin derivative 9a instead of 3-aminoalkyl-4-hydroxycoumarins 6, in good yield
(Scheme 3). Notably, pyran-fused coumarins are very important class of naturally
occurring bioactive molecules.[14] The structure of the compound was ascertained
from spectroscopic data and elemental analysis. Although the formation of a pyran
ring was obvious because of the presence of two suitably located hydroxyl groups,
notable point is that the cyclization occurred at very mild condition. Subsequently,
a series of pyrano[3,2-c]coumarins 9b–l were synthesized by utilizing different substi-
tuted salicylaldehydes 8a–c with 4-hydroxycoumarin 1a,b and 5a,b and character-
ized. The number of generalizations is shown in Table 2. However, unlike the
previous reaction, we have not observed any significant effect of substituent in the
aromatic ring of the aldehyde in this reaction in terms of yield and reaction time.
The possible mechanism which could account for the formation of products 7a
and 9a is depicted in Schemes 4 and 5.
The compound 6a under thermal condition produces the intermediate [A] by
eliminating pyrrolidine molecule, and on the other hand, the pyridinium ylide [B]
Table 1. Synthesis of compound 7 catalyzed by DBU
Product
R1
R4
Time (h)
Yield (%)
7a
7b
7c
7d
7e
7f
7 g
7 h
7i
H
H
H
Cl
Cl
COPh
CN
COOEt
COPh
CN
COOEt
COPh
CN
3
3
3
2.5
2.5
2.5
3
3
3
81
78
80
82
79
81
80
77
78
Cl
Me
Me
Me
COOEt

SYNTHESIS OF DIHYDROFUROCOUMARIN DERIVATIVES
5
Scheme 3. Synthesis of pyranocoumarins 9.
Table 2. Synthesis of compound 9 via one-pot, three-component reaction
Product
R1
R2
[CH2]n
Time (h)
Yield (%)
9a
9b
9c
9d
9e
9f
9 g
9 h
9i
H
H
H
H
H
H
H
[CH2]1
[CH2]2
[CH2]1
[CH2]2
[CH2]1
[CH2]2
[CH2]1
[CH2]2
[CH2]1
[CH2]2
[CH2]1
[CH2]2
3
3
73
76
75
79
74
77
73
76
73
78
79
81
Br
Br
Me
Me
H
2.5
2.5
3.5
3.5
3.5
3.5
3
3
4
4
H
Me
Me
Me
Me
Me
Me
H
Br
Br
Me
Me
9j
9k
9 l
Scheme 4. Mechanism for the formation of compound 7.

6
P. BORAH, P. S. NAIDU, AND P. J. BHUYAN
Scheme 5. Mechanism for the formation of compound 9.
forms in situ from N-phenacylpyridinium bromide 3a in presence of DBU. The
pyridinium ylide [B] then undergoes Michael addition to intermediate [A] to afford
the pyridinium enolate [C]. The enolate [C] is not isolable, which cyclizes instantly
by eliminating pyridine to give the dihydrofurocoumarin derivative 7a.
For the formation of compound 9a, the reaction occurs via an initial reaction
between salicylaldehyde 8a and pyrrolidine 5a in the presence of protic solvent to
give the intermediate [D], which subsequently suffers a nucleophilic attack by 4-
hydroxycoumarin 1a to give compound [E]. Finally, the intermediate [E] eliminates
water molecule to afford the pyrano[3,2-c]coumarin 9a.
In conclusion, we have reported an efficient method for the synthesis of dihydro-
furocoumarin derivatives starting from the reaction of 3-aminoalkyl-4-hydroxycou-
marin and pyridinium ylides generated in situ from pyridinium salt. Moreover, a
series of novel pyrano[3,2-c]-coumarin derivatives were synthesized via one-pot, three-
component reaction of 4-hydroxycoumarin, aryl aldehydes, and secondary amines at
room temperature. This reaction protocol can be explored for the synthesis of some
other furan-fused heterocyclic compounds.
EXPERIMENTAL
Representative Procedure for the Synthesis of Compound 7
A
mixture of 4-hydroxy-3-(phenyl-pyrrolidin-1-yl-methyl)coumarin 6a
(321 mg, 1 mmol), pyridinium salt 3a (278 mg, 1 mmol), and DBU (152 mg, 1 mmol)
in acetonitrile (10 ml) under N2 atmosphere was refluxed for 3 h. After completion of
the reaction (monitored by thin-layer chromatography, TLC), the solvent was
removed under reduced pressure. The product was purified by silica-gel column
chromatography by using 8:2 petroleum ether (PE) and ethylacetate as eluent. The
product was ascertained as 7a from various spectroscopic data. Similarly other com-
pounds 7b–i were synthesized and characterized.
Compound 7a: Yield: 298 mg (81%); mp 167 °C; IR (CHCl3): nmax 1711, 1745,
2868 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 4.72 (d, J ¼ 4.86 Hz, 1H), 6.10 (d, J ¼ 6.96
Hz, 1H), 7.19–7.96 (m, 14H); 13C NMR (75 MHz, CDCl3): d 38.17, 81.67, 93.49,
121.31, 125.24, 125.91, 126.32, 127.49 (2C), 127.81, 128.10, 128.76 (2C), 128.84
(4C), 132.66, 138.69, 140.22, 146.69, 161.91, 167.23, 186.43; MS (m=z): 369.3
[MþH]þ. Anal. calcd. for C24H16O4: C, 78.25; H, 4.38%. Found: C, 78.21; H, 4.29%.
Representative Procedure for the Synthesis of Compound 9
A mixture of 4-hydroxycoumarin 1a (162mg, 1 mmol), salicylaldehyde 8a
(122mg, 1 mmol), and pyrrolidine 5a (70 mg, 1 mmol) was taken in a round-bottomed

SYNTHESIS OF DIHYDROFUROCOUMARIN DERIVATIVES
7
flask containing ethanol. Then the reaction mixture was stirred vigorously at room
temperature for 3 h. After completion of the reaction (monitored by TLC), the solid
compound was filtered off and crude products were recrystallized from ethanol. The
product 9a was obtained in 73% yield. The structure of the compound was ascertained
from the spectroscopic data and elemental analysis. Similarly, other compounds 9b–l
were synthesized and characterized.
Compound 9a: Yield: 240 mg (75%); mp 209 °C; IR (CHCl3): nmax 1221,
1
1745.1, 2884.3 cmꢀ1; H NMR (300 MHz, CDCl3): d 2.12 (br s, 4H), 2.93 (br s,
1H), 3.24 (br s, 1H), 3.70 (br s, 1H), 3.96 (br s, 1H), 5.31 (s, 1H), 7.26–8.08 (m,
8H); 13C NMR (75 MHz, CDCl3): d 22.79 (2C), 45.63 (2C), 50.93, 97.31, 119.38,
121.47, 122.32, 124.68, 125.21, 126.37, 127.73, 127.91, 128.11, 129.35, 149.39,
153.63, 160.09, 164.69; MS (m=z): 320.7 [MþH]þ. Anal. calcd. for C20H17NO3: C,
75.22; H, 5.37; N, 4.39%. Found: C, 75.09; H, 5.18; N, 4.31%.
FUNDING
The authors thank the Department of Science and Technology (DST) and the
Council for Scientific and Industrial Research (CSIR), New Delhi, for financial sup-
port (Project No. SR=S1=OC-24=2012 and Project CAAF-NE respectively). P. S. N.
thanks the University Grants Commission for financial support.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra of 7a, 7b, 7c, and 9a
can be accessed on the publisher’s website.
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