A calcium catalysed regioselective (5-exo dig) tandem process for the synthesis of fully substituted furans

Article abstract of DOI:10.1039/c6ra03042d

An efficient and highly regio-selective synthesis of fused & substituted furans has been described using Ca(OTf)₂ as the catalyst. This tandem process involves alkylation, 5-exo dig cyclisation and isomerization to furnish densely substituted f

Full text of DOI:10.1039/c6ra03042d

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A calcium catalysed regioselective (5-exo dig)
tandem process for the synthesis of fully
substituted furans†‡
Cite this: RSC Adv., 2016, 6, 28865
Received 2nd February 2016
Accepted 9th March 2016
*
Srinivasarao Yaragorla, Ravikrishna Dada, Abhishek Pareek and Garima Singh
DOI: 10.1039/c6ra03042d
www.rsc.org/advances
An efficient and highly regio-selective synthesis of fused & substituted benzylpyrazolyl coumarins,10c and sp3 C–H functionalization of
furans has been described using Ca(OTf)2 as the catalyst. This tandem methyl azaarenes.10d–f In continuation of our research aimed
process involves alkylation, 5-exo dig cyclisation and isomerization to towards the synthesis of medicinally relevant molecules
furnish densely substituted furans under solvent free conditions. A through a sustainable catalysis,10 herein we report a cascade
case study of regioselectivity has been demonstrated.
calcium catalyzed regioselective synthesis of 2,3-disubstituted
benzofurans under solvent free conditions.
Fig. 2 represents the conceptualization of our strategy
towards the regioselective synthesis of furan derivatives over the
pyran derivatives. 3-Benzylated coumarin [I] may undergo two
possible intramolecular oxacyclisations (i) 5-exo dig cyclisation
to form furan moiety (ii) 6-endo dig cyclisation to form pyran
moiety. Since the intermediate compound [I] is prone to
undergo cyclisation in both ways, we propose that if –R group is
an electron withdrawing group then b-carbon will be more
electron decient and hence it provokes the intramolecular
nucleophilic attack by a 5-exo dig oxacyclisation pathway to
furnish the regioselective furan derivatives. We began to
implement our idea by reuxing ethyl 4-hydroxy-4-phenylbut-2-
ynoate (1a, 1 equiv.) with 4-hydroxy coumarin (1.1 equiv.) in
dichloromethane at 55 ꢀC in presence of Ca(OTf)2 and Bu4NPF6
(10 mol%) and isolated the proposed furan compound 3a in
35% aer 5 h (Table 1, entry 1). Continuing the reaction
furthermore could not help in increasing the yields of the
product. Various other solvents were studied for enhancing the
product yield as showed in Table 1.
Furan derivatives are important 5-membered oxygen containing
aromatic heterocyclics present in many of the biologically
important natural products (Fig. 1) and synthetic molecules.1
Particularly, fused and 2,3-disubstituted furans have received
special attention due to their structural features and biological
activities such as antifungal, antiviral, antidiabetic, antipara-
sitic activities and pharmaceutical applications.2,3 Therefore
these scaffolds have become synthetically intriguing and chal-
lenging for chemists and hence the need to come up with novel
synthetic methodologies for their synthesis.4–7 Although viable
synthetic methods are available for their synthesis, most of
them suffer from multistep synthesis, regioselectivity, usage of
nonavailable starting materials, expensive transition metal
catalysts, strong bases or acids.4–7 Therefore, it is highly desir-
able to develop a regioselective, solvent free, step and atom
economic synthesis of 2,3-disubstituted benzofurans.
One-pot cascade reactions offer many advantages in terms of
economic and environmental point of view.8 In the recent years
calcium salts proved as an alternative Lewis acids due to their
abundance and stability towards moisture and air.9 Our group
has also showed the utility of Ca(OTf)2 as a green catalyst in
many of the organic transformations during the synthesis of
small heterocyclic molecules using the Ritter reaction,10a
tandem synthesis of pyranocoumarins,10b benzo[b]pyrans &
SY-Organic & Medicinal Chemistry Laboratory, Department of Chemistry, Central
University of Rajasthan, NH-8, Bandersindri, Ajmer-distt, 305817, India. E-mail:
srinivasarao@curaj.ac.in; ysriict@gmail.com
† This work is dedicated to Prof. Goverdhan Mehta for his contributions in the
area of organic chemistry.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra03042d
Fig. 1 Representatives of biologically important natural products with
benzofuran moiety.
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73% only and in the absence of both we only could observe trace
of product and hence we concluded that the reaction yields
better only when 10 mol% catalyst and additive was used under
solvent free conditions (Table 1, entry 6).
Having optimum conditions set for the regioselective
synthesis of 2,3-disubstituted furocoumarins,11 we were inter-
ested to check the scope of various other propargylic alcohols as
the electrophilic counter parts against 4-hydroxy coumarin
(Table 2).
Ethyl 4-hydroxy-4-(p-tolyl)but-2-ynoate gave 80% furo-
coumarin 3b aer
3 h. Similarly ethyl 4-hydroxy-4-(4-
methoxyphenyl)but-2-ynoate yielded 83% of 3c in 2.5 h only.
Other propargylic alcohols (1) bearing p-halo substitutions on
the phenyl ring like bromo, chloro and uoro yielded the
respective furocoumarins 3d, 3e and 3f in 85%, 78% and 80%
yields. Methyl 4-hydroxy-4-phenylbut-2-ynoate and its 4-methyl
and 4-methoxy derivatives furnished the furan derivatives 3g, 3h
and 3i in 93%, 95% and 90% yields respectively. Aer
describing the scope of electrophilic partners in the furan
synthesis, we further investigated the scope of nucleophilic
partners other than 4-hydroxy coumarin (Table 3). We choose
5,5-dimethyl-cyclohexane 1,3-dione (4a) and cyclohexane 1,3-
dione (4b) as the nucleophilic partners because they can
undergo further cyclization through enolic –OH group. As
planned 5,5-dimethyl-cyclohexane 1,3-dione (4a) was treated
with ethyl 4-hydroxy-4-phenylbut-2-ynoate (1a) at 120 ꢀC for 4 h
and isolated the benzofuran 5a in 78% yield. para-Phenyl
derivatives of 1a such as p-methyl, methoxy, bromo and uoro
compounds furnished the corresponding 2,3-disubstituted
benzofurans 5b, 5c, 5d and 5e in good yields (Table 3). Similar
way methyl 4-hydroxy-4-phenylbut-2-ynoate and its para-phenyl
derivatives yielded benzofurans 5f, 5g and 5h in good yields.
Third nucleophilic counterpart cyclohexane-1,3-dione (4b) was
equally competent and reacted with variety of propargylic
Fig. 2 Conceptualization of highly regioselective synthesis of furan
derivatives.
When the same reaction was repeated in THF, acetonitrile,
and toluene the product was isolated in 25%, 30% and 40%
respectively (Table 1, entries 2–4). Water gave only 5% conver-
sion even aer 15 h under reux. However we were glad to
isolate 91% of benzofuran 3a under solvent free conditions
(Table 1, entry 6). Aer optimizing the solvent case in the
reaction we were interested in looking at the catalyst loading.
When the reaction was performed in the absence of additive the
yield was found to be 45% (Table 1, entry 7) nevertheless we
were surprised to notice that when additive alone was used
under neat conditions the yield was better 57% (Table 1, entry 8)
than the previous case. Therefore we performed the reaction
using 20 mol% of additive alone and noticed that the yield was
increased to a small extent (Table 1, entries 8 and 9). In case of 5
mol% of catalyst and additive loading the isolated yield was
Table 1 Optimization studies for the synthesis of 2,3-disubstituted furocoumarin 3a
Entry
Ca(OTf)2 (mol%)
Bu4NPF6 (mol%)
Solvent
Temperature (ꢀC)
Time (h)
Yielda (%)
1
2
3
4
10
10
10
10
10
10
10
—
—
5
10
10
10
10
10
10
—
10
20
5
CH2Cl2
THF
CH3CN
PhCH3
H2O
Neat
Neat
Neat
Neat
50
90
90
5
5
6
5
15
3
6
5
5
5
8
35
25
30
40
5
91
45
57
61
73
Trace
120
100
120
120
120
120
120
120
5
6b
7
8
9
10
11
Neat
Neat
—
—
a
Isolated yields. b Optimum conditions.
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Table 2 Scope of propargylic alcohols as the electrophilic counter Table 3 Substrate scope of 2,3-disubstituted benzofuransa
parts against 4-hydroxy coumarin in the synthesis of 2,3-disubstituted
furocoumarins (3)a
a
All reactions were carried out using alkyne 1 (1 mmol) and coumarin 2
(1.1 mmol) with catalytic amount of Ca(OTf)2 and Bu4NPF6 (10 mol%)
each under solvent free condition. At 120 ꢀC.
systems and furnished the respective benzofurans in good to
excellent yields (Table 3, 5i–5o).
A plausible mechanism for the Ca(II) catalyzed regioselective
synthesis of furan derivatives is described in the Scheme 1.
Initially, propargylic alcohol reacts with calcium triate and
generates the carbocation then nucleophilic substitution takes
place through a carbocation intermediate [A] to form alkyl
substituted compound [B]. In the next stage a regioselective oxa-
cyclization takes place through a 5-exo dig passion to form the
intermediate [E], because of having electron withdrawing group
(–CO2Et) attached to alkyne the b-carbon become more elec-
a
All reactions were carried out using 1 (1 mmol) and 4 (1.1 mmol) with
catalytic amount of Ca(OTf)2 and Bu4NPF6 (10 mol%) each under
trophilic and hence it drives to the formation of ve membered
cyclization in preference to the six membered. Finally
compound [E] isomerizes to yield the thermodynamically stable
furan compound [5].
When we tried a reaction with 1-phenyl-3-(trimethylsilyl)
prop-2-yn-1-ol along with cyclohexane 1,3-dione under the
same reaction conditions we could isolate the 2-methyl-
benzofuran 10a in 78% aer 6 h (Scheme 2). Surprisingly the
TMS group was cleaved during the process and this could be
due to the presence of uoride ions in the reaction in the form
of additive. When another propargyl alcohol with a terminal
alkyne 1-phenylprop-2-yn-1-ol was used we still got the same
benzofuran product as expected (10a).12
solvent free condition.
In order to validate the conceptualization proposed in the
Fig. 2, we choose 1,3-diphenylprop-2-yn-1-ol (9a) as the elec-
trophilic partner instead of methyl 4-hydroxy-4-phenylbut-2-
ynoate (1a) against 4-hydroxy coumarin and subjected under
same reaction conditions. Aer 2 h, we could isolate the mixture
of both furan and pyran (6a/7a)13 in 1 : 9.08 ratios with an
overall yield of 93%. Similarly when 3-phenyl-1-(p-tolyl)prop-2-
yn-1-ol (9b) treated with 4-hydroxy coumarin we observed the
mixture of furan and pyran (6b/7b) in 1 : 8 ratios. It is true with
1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-ol (9c) also and
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Table 4 1,3-Diphenylprop-2-yn-1-ol and its derivatives in the regio-
selective synthesis of benzofurans
over the pyrans. For example the ratios of furan/pyran for 8a, 8b,
8c & 8d are 1/0.06, 1/0.05, 1/0.04 & 1/0.03 respectively. Never-
theless this observation still supports our conceptualization
(Fig. 2), probably aromatic and non-aromatic nature of nucle-
ophilic enols (4-hydroxycoumarin and cyclohexane 1,3-dione)
could be deciding the ratios.
Scheme 1 Plausible mechanism for the Ca(II) catalyzed regioselective
synthesis of densely substituted furans.
Conclusions
In summary, we are successful in developing a one-pot cascade
synthesis of fully functionalized furans under solvent free
conditions using eco-friendly & highly abundant calcium cata-
lyst. Step economy & atom economy of the methodology are
delineated as the advantages compared to the two-step
syntheses reported earlier. Regioselectivity, substrate scope
and high yields are proved this methodology as one of the
Scheme 2 Reaction of cyclohexane 1,3-dione with silyl and terminal
alkynes.
yielded 85% of 6c/7c in 1 : 13.3 ratios as described in the remarkable in the furans synthesis. Application this strategy for
Scheme 3.7b,c Which is strongly supporting our conceptualiza- the synthesis of novel related heterocyclics is currently under
tion that if there is a powerful electron withdrawing group a-to progress in our laboratory.
the alkyne that drives the reaction through a 5-exo dig pathway
in preference to the 6-endo dig pathway. Probably that could be
the main reason why we got only furan compounds with the
Acknowledgements
propargylic ester 1 (Tables 2 and 3).
DST-India is acknowledged for the nancial support under Fast
When the same regioselective study was performed with Track Young Scientist Scheme (SB/FT/CS-149/2012). RD, AP and
dione 4 and propargylic alcohols 9a, 9b and 9c (Table 4) it is still GS thank Central University of Rajasthan for their fellowships.
evidenced the same observation. But in this case we observed
the furans as the major isomers and the selectivity is very high
Notes and references
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11 General experimental procedure for the Ca(II)-catalysed
synthesis of fully substituted furans: suitable propargylic
alcohol (1mmol) and 4-hydroxycoumarin (1.1 mmol) were
heated at 120 ꢀC in presence of Ca(OTf)2 (10 mol%) and
nBu4NPF6. Aer completion (reaction progress was
monitored by TLC), reaction mixture was brought to room
temperature diluted with water and extracted into ethyl
acetate thrice. Combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. Finally the crude mass
was puried through column chromatography using
petroleum ether and ethyl acetate as the eluents to obtain
112.6, 109.6, 61.7, 32.9, 21.3, 14.2 ppm; HRMS (ESI) m/z
calcd for C22H19O6 [M + H]+ 379.1176; found 379.1194;
ethyl 2-(3-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-c]chromene-
2-yl)acetate (3c): yellow solid, mp 109.2 ꢀC, 67.6 mg, 83%
yield, (eluent: petroleum ether : EtOAc 88 : 12); 1H NMR
(500 MHz, CDCl3): d 7.91 (dd, J ¼ 7.5 Hz, J ¼ 7.5 Hz, 1H),
7.53–7.44 (m, 4H), 7.37–7.34 (m, 1H), 7.03–7.01 (m, 2H),
4.26 (q, J ¼ 7 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 2H), 1.32 (t, J ¼
7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): d 168.8, 159.6,
157.1, 152.5, 146.9, 131.0, 130.7, 124.4, 123.2, 121.3, 120.9,
117.1, 113.9, 112.7, 109.6, 61.7, 55.3, 32.9, 14.2 ppm;
HRMS (ESI) m/z calcd for C22H18NaO5 [M + Na]+ 385.1046;
found 385.1062; ethyl 2-(3-(4-methoxyphenyl)-6,6-dimethyl-
4-oxo-4,5,6,7-tetrahydrobenzofuran-2-yl) acetate (5c): yellow
liquid, 72.5 mg, 89% yield; (eluent: petroleum
ether : EtOAc 80 : 20); 1H NMR (500 MHz, CDCl3): d 7.37
(d, J ¼ 8.5 Hz, 2H), 6.94 (d, J ¼ 8 Hz, 2H) ppm; 13C NMR
(125 MHz, CDCl3): d 193.5, 169.4, 165.8, 159.0, 144.5,
130.9, 123.0, 121.7, 118.5, 113.5, 61.4, 55.2, 52.9, 37.6, 34.8,
32.5, 28.6, 14.1 ppm; HRMS (ESI) m/z calcd for C21H24O5
[M
+
H]+ 365.1364; found 365.1348; ethyl 2-(3-(4-
methylphenyl)-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-yl)acetate
(5k): brown liquid, 51.6 mg, 73% yield; (eluent: petroleum
ether : EtOAc 80 : 20); 1H NMR (500 MHz, CDCl3): d 7.34
(d, J ¼ 9 Hz, 2H), 6.92 (d, J ¼ 9 Hz, 2H), 4.20 (q, J ¼ 7.25
Hz, 2H), 3.83 (s, 3H), 3.63 (s, 2H), 2.91 (t, J ¼ 6 Hz, 2H),
2.49 (t, J ¼ 7 Hz, 2H), 2.19 (t, J ¼ 6.5 Hz, 2H), 1.29–1.25
(m, 3H) ppm; 13C NMR (125 MHz, CDCl3): d 194.0, 169.5,
166.6, 159.0, 144.2, 130.8, 123.1, 121.9, 119.7, 113.5, 61.4,
55.2, 38.6, 32.4, 23.7, 22.4, 14.1 ppm; HRMS (ESI) m/z calcd
for C19H20NaO5 [M + Na]+ 351.1208; found 351.1262.
the desired furan
compounds: ethyl
3
&
5. Spectral data of selected
2-(4-oxo-3-(p-tolyl)-4H-furo[3,2-c]
chromene-2-yl)acetate (3b): brown solid, mp 107 ꢀC, 66.4
mg, 80% yield, (eluent: petroleum ether : EtOAc 88 : 12);
1H NMR (500 MHz, CDCl3): d 7.91 (d, J ¼ 8 Hz, 1H), 7.52–
7.50 (m, 1H), 7.46–7.43 (m, 3H), 7.35 (t, J ¼ 7.5 Hz, 1H), 12 We thank one of the reviewers for suggesting to make this
7.30 (d, J ¼ 8 Hz, 2H), 4.26 (q, J ¼ 7.25 Hz, 2H), 3.87 (s,
example.
2H), 2.43 (s, 3H), 1.32 (t, J ¼ 7.25 Hz, 3H) ppm; 13C NMR 13 The isomeric ratio was taken based on 1H NMR recorded for
(125 MHz, CDCl3): d 168.8, 157.6, 157.1, 152.5, 147.1,
the crude reaction mixture.
138.2, 130.7, 129.6, 129.1, 126.2, 124.4, 123.4, 120.9, 117.1,
28870 | RSC Adv., 2016, 6, 28865–28870
This journal is © The Royal Society of Chemistry 2016