Al(OTf)3-Catalyzed Preparation of 4-Hydroxy-3-propargylic Coumarins and Subsequent Regioselective Cyclization towards Furo- or Pyrano[3,2-c]coumarins

Article abstract of DOI:10.1055/s-0034-1379971

An efficient and economical approach to functionalized furo[3,2-c]coumarin and pyrano[3,2-c]coumarin derivatives has been developed from 4-hydroxy-3-(prop-2-ynyl)coumarin derivatives through organocatalysis or metallo-organocatalysis. Selective '5-exo-dig

Full text of DOI:10.1055/s-0034-1379971

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, A–F
letter
A
S. Ponra et al.
Letter
Synlett
Al(OTf)3-Catalyzed Preparation of 4-Hydroxy-3-propargylic
Coumarins and Subsequent Regioselective Cyclization towards
Furo- or Pyrano[3,2-c]coumarins
R3
Sudipta Ponra
R2
R3
R2
OH
Mukut Gohain
R1
O
O
O
catalyst
Johannes H. van Tonder
Barend C. B. Bezuidenhoudt*
HO
R1
or R1
+
R2
R3
two steps
O
O
O
O
O
Department of Chemistry, University of the Free
State, PO Box 339, Bloemfontein, 9300, South Africa
bezuidbc@ufs.ac.za
Received: 03.11.2014
Accepted after revision: 12.12.2014
Published online: 05.02.2015
tive, antithrombotic, antiviral, and anticarcinogenic activi-
ties.18,19 Furthermore they have found relevance as plant
growth hormones, growth regulators, in control of respira-
tion, photosynthesis, defense against infection, as well as
additives to food and cosmetics and optical brightening
agents.18,19,23 The furan ring is a common structural motif in
several important natural products, including furanoflavo-
noids, furanolactones, furanocoumarins, and many natural
terpenoids. Furthermore, the chromane skeleton is found in
numerous medicinally important compounds that have ex-
tensive biological activities.24–30 Dihydropyranones, for ex-
ample, occur widely as the key structural subunit in numer-
ous natural products such as obolactone,31,32 cyclocurcum-
in,33,34 and have also been reported as a synthetic precursor
for hypocholesterometic compounds.35,36 Although there
are several procedures available for the synthesis of couma-
rin-fused furan or pyran derivatives, the search for new
methodologies proceeding via more efficient routes and in-
volving readily available starting materials still remains an
active area of research.
DOI: 10.1055/s-0034-1379971; Art ID: st-2014-d0916-l
Abstract An efficient and economical approach to functionalized fu-
ro[3,2-c]coumarin and pyrano[3,2-c]coumarin derivatives has been de-
veloped from 4-hydroxy-3-(prop-2-ynyl)coumarin derivatives through
organocatalysis or metallo-organocatalysis. Selective ‘5-exo-dig’ or
‘6-endo-dig’ cyclization of the 4-hydroxy-3-(prop-2-ynyl)coumarin sub-
strates could be achieved under organocatalytic {1,8-diazabicyc-
lo[5.4.0]undec-7-ene} or metallo-organocatalytic (N-methylmorpho-
line/CuBr) conditions, respectively, to yield potentially bioactive
heterocycles in excellent yields.
Key words furo[3,2-c]coumarin, pyrano[3,2-c]coumarin, Al(OTf)3,
DBU, NMM, propargylic alcohol
Carbon–carbon and carbon–heteroatom bond-forming
reactions play a vital role in the efficacy of chemical trans-
formations in synthetic organic chemistry. Due to selectivi-
ty, environmental friendliness, and mild reaction condi-
tions, organocatalytic processes have achieved considerable
attention as one of the main branches of enantioselective
synthesis next to metal and biocatalysis. Small organic mol-
ecules can act as powerful organocatalysts to introduce
multiple carbon–carbon or carbon–heteroatom bonds in a
single operation.1–8 More recently metallo-organocatalysts
have been demonstrated to act as synthetic entities for dual
activation of both the electrophilic and nucleophilic centers
in reactions.9–13 Dual activation is usually the combination
of two separate catalysts in one system, that is, the combi-
nation of a metal catalyst and either a stoichiometric or cat-
alytic amount of an organocatalyst. These two-component
activation systems have been successfully employed in vari-
ous reactions.14–17
In 2006, Cardierno et al.37 reported a catalytic system
involving a 16-electron allyl-ruthenium(II) complex [Ru(η3-
2-C3H4Me)(CO)(dppf)][SbF6] [dppf = 1,1′-bis(diphenylphos-
phino)ferrocene] and trifluoroacetic acid (TFA) to promote
coupling between activated secondary propargylic alcohols
and cyclic 1,3-diketones for the synthesis of either pyran or
furan structures. This one-pot protocol, however, involved
the use of an expensive metal complex and corrosive acid.
Furthermore, the ring size of the resulting products was
found to be dependent on the nature of the dicarbonyl com-
pound. Herein we report on the preparation 4-hydroxy-3-
(prop-2-ynyl)coumarin derivatives 3 (Scheme 1) and the
organocatalytic or metallo-organocatalytic cyclization of
these compounds to either furo[3,2-c]coumarin or pyra-
no[3,2-c]coumarin derivatives 4 and 5, respectively, as a re-
sult of ‘5-exo-dig’ or ‘6-endo-dig’ cyclization.
Coumarins are important oxygen-containing fused het-
erocycles that display interesting biological activities.18,19 In
addition to their vital effects in plant biochemistry and
physiology, these compounds can be used as drugs,20 dyes,
antioxidants, enzyme inhibitors,21,22 and as precursors to
lethal substances.18,19 Coumarin derivatives also possess
anti-inflammatory, antioxidant, antiallergic, hepatoprotec-
Recently, our group has reported the Al(OTf)3-catalyzed
alkylation of indoles using secondary/tertiary propargylic
alcohols to produce 3-propargylated indoles in excellent
yields and high selectivity.38 The current investigation is a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–F

B
S. Ponra et al.
Letter
Synlett
R3
R2
O
R1
DBU
R3
O
O
CH2Cl2, r.t.
OH R2
OH
O
4
R1
R1
Al(OTf)3
MeCN
R3
+
R3
HO
R2
O
O
O
O
O
R1
3
1
2
CuBr, NMM
CH2Cl2, r.t.
R2
O
5
Scheme 1 Synthesis of 4-hydroxy-3-(prop-2-ynyl)coumarin, furo[3,2-c]coumarin, and pyrano[3,2-c]coumarin derivatives 3–5
continuation of this work, and the aforementioned protocol
was extended to the preparation of 4-hydroxy-3-(prop-2-
ynyl)coumarin derivatives 3 from propargylic alcohols 2
and 4-hydroxycoumarins 1. Preliminary studies with 4-hy-
droxycoumarin 1a and 1,3-diphenylprop-2-yn-1-ol (2a) es-
tablished the optimized reaction conditions as refluxing
MeCN for five hours in the presence of 10 mol% Al(OTf)3.
This protocol43 was then applied to the preparation of a va-
riety of 4-hydroxy-3-(prop-2-ynyl)coumarins (3, Table 1)
producing comparable yields with both electron-donating
(1b, Table 1, entry 13 vs. entry 2) and electron-withdrawing
(1c, Table 1, entry 14 vs. entry 3) substituents in the 6-posi-
tion of the coumarin moiety. Similarly, the reaction condi-
tions were found tolerant towards electron-donating and
electron-withdrawing phenyl substituents on the propar-
gylic alcohol 2b–f producing the substituted coumarins 3 in
Table 1 Synthesis of 4-Hydroxy-3-(prop-2-ynyl)coumarin Derivatives 3a
R3
OH
OH
OH
R1
R1
Al(OTf)3 (10 mol%)
R2
R2
+
R3
MeCN, reflux, 5 h
O
O
O
O
1
2
3
Entry
Substrates
Substituents
Product
Yield (%)b
1
2
1a, 2a
1a, 2b
1a, 2c
1a, 2d
1a, 2e
1a, 2f
1a, 2g
1a, 2h
1a, 2i
1a, 2j
1a, 2k
1a, 2l
1b, 2b
1c, 2c
R1 = H; R2 = R3 = Ph
3a
3b
3c
3d
3e
3f
91
85
91
90
87
88
81
72
75
93
94
96
92
89
R1 = H; R2 = 4-MeC6H4; R3 = Ph
R1 = H; R2 = 4-MeOC6H4; R3 = Ph
R1 = H; R2 = 2-MeC6H4; R3 = Ph
R1 = H; R2 = 4-ClC6H4; R3 = Ph
R1 = H; R2 = 4-BrC6H4; R3 = Ph
R1 = H; R2 = Me; R3 = Ph
3
4
5
6
7
3g
3h
3i
8
R1 = R2 = R3 = H
9
R1 = H; R2 = 2-SC4H4; R3 = Ph
R1 = H; R2 = 4-MeOC6H4; R3 = t-Bu
R1 = H; R2 = 4-ClC6H4; R3 = i-Pr
R1 = H; R2 = 4-MeC6H4; R3 = C5H11
R1 = Me; R2 = 4-MeC6H4; R3 = Ph
R1 = Cl; R2 = 4-MeOC6H4; R3 = Ph
10
11
12
13
14
3j
3k
3l
3m
3n
a Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), Al(OTf)3 (0.1 mmol), MeCN (3 mL), reflux, 5 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–F

C
S. Ponra et al.
Letter
Synlett
high to excellent yields (Table 1, entries 2–6). Aliphatic (2g)
and heterocyclic (2i) 1-substituted propargylic alcohols
could be coupled in high yields under the optimized condi-
tions (Table 1, entries 7 and 9). Good to excellent yields
were also obtained for propargylic alcohols 2h (R2 = R3 = H;
Table 1, entry 8) and 2j–l (R2 = aromatic, R3 = aliphatic; Ta-
ble 1, entries 10–12) demonstrating the wide scope of this
protocol.
With the propargyl-substituted coumarin substrates 3
in hand, attention was turned towards producing the de-
sired cyclic analogues. Reaction of substituted coumarin 3a
with a stoichiometric amount of N-methylmorpholine
(NMM) in CH2Cl2 resulted in the exclusive formation of the
‘5-exo-dig’ product, furo[3,2-c]coumarin 4a, albeit in mod-
erate yield (Table 2, entry 1). Reducing the NMM to catalytic
quantities (10 mol%), however, led to a severe drop in yield
to only 20% (Table 2, entry 2). When the NMM and CH2Cl2
were replaced with DBU (10 mol%), a base with profound
importance in various organic transformations,39–42 and
acetonitrile as solvent, the furo[3,2-c]coumarin 4a was ob-
tained in 55% yield (Table 2, entry 3). The presence of DBU
proved to be crucial in this result as reactions in the ab-
sence of the catalyst revealed no product formation at all
(Table 2, entry 12).
Optimization of the reaction conditions revealed CH2Cl2
to be the solvent of choice (Table 2, entry 5) for the reaction
with DBU as well and led to the yield being increased to
96%. While a decrease in DBU concentration from 10 mol%
to 5 mol% resulted in diminished product yield (Table 2, en-
try 9), higher loadings (20 mol%) gave comparable results
(Table 2, entry 8). Although a decrease in reaction time
from four to three hours had a detrimental effect on prod-
uct yield (Table 2, entry 10), an increase in reaction time
exhibited no improvement (Table 2, entry 11). Optimized
conditions for the cyclization reaction were thus estab-
lished as 10 mol% DBU in CH2Cl2 for four hours at room
temperature (Table 2, entry 5).43
The optimum conditions were subsequently applied to
the cyclization of the remaining propargyl-substituted cou-
marin substrates (Table 3). The substrates containing diaryl
substituted propargylic units, (3a–e,m,n) including thio-
phene 3i, all gave excellent yields of their respective fu-
ro[2,3-c]coumarin derivatives. The substrate with a 2-
methylphenyl unit in the 1-position of the propargyl moi-
ety (3d, Table 3, entry 4), however, did not lead to any ob-
servable product, probably due to steric interference by the
2-methyl group as the 4-methyl analogue (3b, Table 3, en-
try 2) gave the product 4b in excellent yield (96%). The reac-
Table 3 Synthesis of Furo[3,2-c]coumarin Derivatives 4a
Table 2 Optimization of DBU-Catalyzed Cyclization Reaction Condi-
tionsa
R3
R3
R2
Ph
OH
O
O
Ph
R1
R1
DBU (10 mol%)
CH2Cl2, r.t., 4 h
R2
OH
O
O
Ph
Ph
O
O
O
catalyst/base
solvent, r.t.
3
4
O
O
O
3a
Entry
4a
Time (h)
Entry Substrate Substituents
Product Yield (%)b
Catalyst/base (mol%)
NMM (100)
NMM (10)
DBU (10)
DBU (20)
DBU (10)
DBU (10)
DBU (10)
DBU (20)
DBU (5)
Solvent
CH2Cl2
CH2Cl2
MeCN
MeCN
CH2Cl2
THF
Yield (%)b
72
1
2
3a
3b
3c
3d
3e
3f
R1 = H; R2 = R3 = Ph
4a
4b
4c
4d
4e
4f
96
96
95
0
1
2
4
4
R1 = H; R2 = 4-MeC6H4; R3 = Ph
R1 = H; R2 = 4-MeOC6H4; R3 = Ph
R1 = H; R2 = 2-MeC6H4; R3 = Ph
R1 = H; R2 = 4-ClC6H4; R3 = Ph
R1 = H; R2 = 4-BrC6H4; R3 = Ph
R1 = H; R2 = Me; R3 = Ph
20
3
3
4
55
4
4
4
55
5
94
98
0
5
4
96
6
6
4
41
7
3g
3h
3i
4g
4h
4i
7
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
4
55
8
R1 = H; R2 = R3 = H
0
8
4
96
9
R1 = H; R2 = 2-SC4H4; R3 = Ph
R1 = H; R2 = 4-MeOC6H4; R3 = t-Bu
R1 = H; R2 = 4-ClC6H4; R3 = i-Pr
R1 = H; R2 = 4-MeC6H4; R3 = C5H11
R1 = Me; R2 = 4-MeC6H4; R3 = Ph
R1 = Cl; R2 = 4-MeOC6H4; R3 = Ph
97
0
9
4
82
10
11
12
13
14
3j
4j
10
11
12
DBU (10)
DBU (10)
–
3
78
3k
3l
4k
4l
0
6
96
0
10
0
3m
3n
4m
4n
94
91
a Reaction conditions: 3a (1 mmol), catalyst/base, solvent (2 mL), r.t.
b Isolated yield.
a Reaction conditions: 3 (1 mmol), DBU (0.1 mmol), CH2Cl2 (2 mL), r.t., 4 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–F

D
S. Ponra et al.
Letter
Synlett
tion was also unsuccessful for substrates containing only
hydrogen (3h, Table 3, entry 8) or alkyl substituents (3g,3j–
l) attached to the propargyl unit (R2 and/or R3 = H or alkyl,
Table 3, entries 7, 10–12).
system, a 4-methyl substituent on R3 did not prevent cy-
clization (Table 5, entry 5). Furthermore, all of the aliphatic-
substituted propargylic derivatives (Table 5, entry 7, entries
10–12) were readily converted into their respective pyra-
no[3,2-c]coumarins 5g,j–l. Similarly to the DBU system, no
product formation could be observed in the absence of any
R2 and R3 substituents (3h, Table 5, entry 8). The presence
of either an electron-donating (3m) or electron-withdraw-
ing group (3n) in the 9-position of the coumarin skeleton
did not reflect any significant influence on the outcome of
the reaction (Table 5, entries 13 and 14).
The formation of the furo[3,2-c]coumarin and pyra-
no[3,2-c]coumarin derivatives 4 and 5 is probably explica-
ble in terms of two mechanistic routes (Scheme 2). In the
presence of DBU, compound 3 undergoes ‘5-exo-dig’ mode
of cyclization to give the intermediate A that undergoes
isomerization of the olefinic double bond to introduce the
aromatic system in the furan moiety of 4. In the presence of
the Lewis acidic copper salt, the alkyne may be activated by
π-complex formation (intermediate B) that then undergoes
‘6-endo-dig’ cyclization to produce 5. This hypothesis was
confirmed by introducing 1 mol% CuBr along with 10 mol%
DBU which produced both the furo[3,2-c]coumarin and
pyrano[3,2-c]coumarin derivatives 4 and 5. Upon removal
of the DBU, in presence of only CuBr, the reaction was found
to be slow requiring extended reaction times to reach com-
pletion. In the presence of NMM, however, the reaction
times were reduced to only three hours.
In an effort to shift the cyclization mode to ‘6-endo-dig’
and pyrano[3,2-c]coumarin formation, the cyclization of
the substituted coumarin 3a was repeated with NMM in
the presence of CuBr and the desired product (5a) obtained
in 91% yield (Table 4, entry 1).43 Consequently, CuI (Table 4,
entry 2) and Cu(OTf)2 (Table 4, entry 3) were also evaluated
with 3a as model substrate but CuBr produced the highest
conversion and selectivity toward 5a. The reaction time
was then shortened to three hours (Table 4, entry 4) which
yielded results similar to those of the four-hour reaction. A
further shortening of the reaction time to two hours (Table
4, entry 5) had a detrimental effect on product yield (71%)
as conversion was significantly lower. Different CuBr load-
ings were next investigated, of which 20 mol% (Table 4, en-
try 6) exhibited no improvement over 10 mol% (Table 4, en-
try 4). A significant loss in regioselectivity was, however,
observed upon lowering of the CuBr loading to 5 mol% (Ta-
ble 4, entry 7). Other polar solvents, that is, MeCN and
MeOH, were also tested, but gave inferior results with re-
spect to conversion (Table 4, entries 8 and 9).
The scope of this protocol was investigated by subject-
ing the previously prepared propargyl-substituted couma-
rins 3 to the optimized conditions (Table 5). Similarly to the
DBU system, excellent yields were obtained when both R2
and R3 were aromatic groups (Table 5, entries 1–6) and R2
being heterocyclic (Table 5, entry 9). In contrast to the DBU
Table 4 Optimization of Metallo-Organocatalyst-Mediated Cyclization Reaction Conditionsa
Ph
Ph
Ph
Ph
O
O
OH
O
O
NMM
Ph
Ph
+
catalyst, r.t.
O
O
O
O
3a
4a
5a
Entry
Catalyst (mol%)
Solvent
Time (h)
Yield of 4a/5a (%)b
1
2
3
4
5
6
7
8
9
CuBr (10)
CuI (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeOH
4
4
4
3
2
3
3
3
3
5:91
5:86
7:84
5:91
3:71
5:91
19:63
3:56
2:52
Cu(OTf)2 (10)
CuBr (10)
CuBr (10)
CuBr (20)
CuBr (5)
CuBr (10)
CuBr (10)
a Reaction conditions: 3a (1 mmol), NMM (1 mmol), catalyst, solvent (2 mL), r.t.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–F

E
S. Ponra et al.
Letter
Synlett
Table 5 Synthesis of Pyrano[3,2-c]coumarin Derivatives 5a
organocatalytic (DBU) or metallo-organocatalytic (CuBr/
NMM) cyclization of 4-hydroxy-3-(prop-2-ynyl)coumarins
3. The latter is readily accessible through Al(OTf)3-catalyzed
substitution of propargylic alcohols 2 with 4-hydroxycou-
marins 1. The protocols reported herein are quick and sim-
ple to perform and utilize readily available, cost-effective
materials that are converted into the desired products in
high to excellent yields. As a result of affordability and op-
erational simplicity these methods can thus be applied to-
ward the synthesis of a large number of naturally occurring
and pharmaceutically important compounds.
R3
R3
O
OH
O
R1
R1
CuBr (10 mol%)
R2
R2
NMM, CH2Cl2, r.t., 3 h
O
O
O
3
5
Entry Substrate Substituents
Product Yield (%)b
1
2
3a
3b
3c
3d
3e
3f
R1 = H; R2 = R3 = Ph
5a
5b
5c
5d
5e
5f
91
92
90
88
89
81
76
0
R1 = H; R2 = 4-MeC6H4; R3 = Ph
R1 = H; R2 = 4-MeOC6H4; R3 = Ph
R1 = H; R2 = 2-MeC6H4; R3 = Ph
R1 = H; R2 = 4-ClC6H4; R3 = Ph
R1 = H; R2 = 4-BrC6H4; R3 = Ph
R1 = H; R2 = Me; R3 = Ph
Acknowledgment
3
Financial support by SASOL Ltd is gratefully acknowledged.
4
5
Supporting Information
6
7
3g
3h
3i
5g
5h
5i
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379971.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
8
R1 = H; R2 = R3 = H
9
R1 = H; R2 = 2-SC4H4; R3 = Ph
R1 = H; R2 = 4-MeOC6H4; R3 = t-Bu
R1 = H; R2 = 4-ClC6H4; R3 = i-Pr
R1 = H; R2 = 4-MeC6H4; R3 = C5H11
R1 = Me; R2 = 4-MeC6H4; R3 = Ph
R1 = Cl; R2 = 4-MeOC6H4; R3 = Ph
90
94
94
92
93
88
References and Notes
10
11
12
13
14
3j
5j
3k
3l
5k
5l
(1) Domino Reactions in Organic Synthesis; Tietze, L. F.; Gordon, B.;
Kersten, G. M., Eds.; Wiley-VCH: Weinheim, 2006.
(2) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed.
2007, 46, 1570.
(3) Chen, S.; Salo, E. C.; Kerrigan, N. J. In Asymmetric Organocataly-
sis 1: Lewis Base and Acid Catalysts; List, B., Ed.; Georg Thieme:
Stuttgart, 2012, 455.
(4) Singh, R. P.; Deng, L. Asymmetric Organocatalysis 2: Brønsted
Base and Acid Catalysts and Additional Topics, In Science of Syn-
thesis; Maruoka, K., Ed.; Georg Thieme: Stuttgart, 2012, 41.
(5) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541.
(6) De Jong, S.; Nosal, D. G.; Wardrop, D. J. Tetrahedron 2012, 68,
4067.
3m
3n
5m
5n
a Reaction conditions: 3 (1 mmol), CuBr (0.1 mmol), NMM (1 mmol), CH2Cl2
(2 mL), r.t., 3 h.
b Isolated yield.
In conclusion, practical strategies have been developed
to access potentially bioactive furo[3,2-c]coumarin or pyra-
no[3,2-c]coumarin derivatives 4 and 5 in high yield via
R2
R2
R2
R1
OH
O
O
H
R1
R1
DBU
isomerization
O
O
O
O
O
O
5-exo-dig
A
3
4
CuBr
R2
R2
R2
CuBr
R1
CuBr
R1
O
O
O
O
OH
NMMH+
– CuBr
NMM
R1
6-endo-dig
O
O
O
O
C
B
5
Scheme 2 Proposed pathway for the cyclization of 4-hydroxy-3-(prop-2-ynyl)coumarin to furo[3,2-c]coumarin and pyrano[3,2-c]coumarin derivatives
3 to 4 and 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–F

F
S. Ponra et al.
Letter
Synlett
(7) Fraile, A.; Parra, A.; Tortosa, M.; Aleman, J. Tetrahedron 2014, 70,
9145.
(43) Typical Procedures
4-Hydroxy-3-(prop-2-ynyl)coumarins 3a–n
(8) Mahrwald, R. Drug Discovery Today: Technol. 2013, 10, 29.
(9) Ma, J.; Cahard, D. Angew. Chem. Int. Ed. 2004, 43, 4566.
(10) Gröger, H. Chem. Eur. J. 2001, 7, 5246.
Substituted 4-hydroxycoumarin derivatives (1 mmol) were dis-
solved in MeCN (3 mL), and the solution was stirred at r.t. for 5
min before the substituted propargyl alcohol (1.2 mmol) was
added and stirring continued for an additional 5 min. After sub-
sequent addition of Al(OTf)3 (0.1 mmol) the mixture was heated
to reflux for 5 h. Upon completion of the reaction (TLC) the
solvent was removed in vacuo, H2O was added (25 mL), and the
crude product was extracted into CH2Cl2 (3 × 25 mL). The
organic phases were combined, washed with brine (4 × 25 mL),
and dried over anhydrous Na2SO4. After filtration and removal
of the solvent, the pure products 3 were obtained by column
chromatography (hexane–EtOAc, 4:1).
(11) Hodgson, D. M.; Charlton, A. Tetrahedron 2014, 70, 2207.
(12) Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761.
(13) Gryko, D.; Zimnicka, M.; Lipinski, R. J. Org. Chem. 2007, 72, 964.
(14) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726.
(15) Jusseau, X.; Chabaud, L.; Guillou, C. Tetrahedron 2014, 70, 2595.
(16) Duthaler, R. O. Angew. Chem. Int. Ed. 2003, 42, 975.
(17) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(18) Murray, R. D. H.; Méndez, J.; Brown, S. A. The Natural Couma-
rins: Occurrence, Chemistry, and Biochemistry; 1982.
(19) Coumarins: Biology, Applications and Mode of Action;
O’Kennedy, R.; Thornes, R. D., Eds.; Wiley: Chichester, 1997.
(20) Silvan, A. M.; Abad, M. J.; Bermejo, P.; Sollhuber, M.; Villar, A.
J. Nat. Prod. 1996, 59, 1183.
(21) Romines, K. R.; Morris, J. K.; Howe, W. J.; Tomich, P. K.; Horng,
M.-M.; Chong, K.-T.; Hinshaw, R. R.; Anderson, D. J.; Strohbach, J.
W.; Turner, S.-R.; Miszak, S. A. J. Med. Chem. 1996, 39, 4125.
(22) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa,
H.; Takahashi, D.; Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem.
Lett. 2000, 10, 59.
Furo[3,2-c]coumarins 4a–n
To a stirring solution of compound 3 (1 mmol) in CH2Cl2 (2 mL)
was added DBU (0.1 mmol), and the mixture was stirred for 4 h.
Upon completion of the reaction (TLC) H2O (25 mL) was added,
and the product was extracted into CH2Cl2 (3 × 25 mL). The
combined organic phases were washed with brine (4 × 25 mL),
and dried over anhydrous Na2SO4. After filtration, the solvent
was removed by distillation and the crude product purified by
column chromatography (hexane–EtOAc, 6:1).
Pyrano-[3,2-c]coumarins 5a–n
(23) Zahradnik, M. The Production and Application of Fluorescent
Brightening Agents; John Wiley and Sons: New York, 1992.
(24) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864.
(25) Gowrisankar, S.; Lee, K.-Y.; Kim, J.-N. Bull. Korean Chem. Soc.
2007, 28, 624.
(26) Ibrahim, M. A.; Ali, T. E.; Alnamer, Y. A.; Gabr, Y. A. ARKIVOC
2010, (i), 98.
(27) Khadem, S.; Marles, R. J. Molecules 2012, 17, 191.
(28) Patil, R. B.; Sawant, S. D.; Thombare, P. A. Int. J. Pharm. Tech. Res.
2012, 4, 375.
To a stirred solution of 4-hydroxy-3-(prop-2-ynyl)coumarin 3
(1 mmol) in CH2Cl2 (2 mL) at r.t. were added NMM (1 mmol) and
CuBr (0.1 mmol), and stirring was continued for 4 h. Upon com-
pletion of the reaction (TLC) the mixture was filtered to remove
excess solid CuBr, H2O (25 mL) was added, and the product was
extracted into CH2Cl2 (3 × 25 mL). The combined organic phases
were washed with brine (4 × 25 mL), and dried over anhydrous
Na2SO4. Filtration of the extract and removal of the solvent by
distillation followed by column chromatography (hexane–
EtOAc, 5:1) gave the desired product 5.
(29) Corradini, E.; Foglia, P.; Giansanti, P.; Gubbiotti, R.; Samperi, R.;
Laganà, A. Nat. Prod. Res. 2011, 25, 469.
Representative Analytical Data
4-Hydroxy-3-(prop-2-ynyl)-coumarin (3m)
(30) Verma, A. K.; Pratap, R. Tetrahedron 2012, 68, 8523.
(31) Dumontet, V.; Van H, N.; Adeline, M. T.; Riche, C.; Chiaroni, A.;
Sévenet, T.; Guéritte, F. J. Nat. Prod. 2004, 67, 858.
(32) Zhang, J.-Y.; Li, Y.; Wang, W.-K.; She, X.-G.; Pan, X.-F. J. Org.
Chem. 2006, 71, 2918.
1H NMR (300 MHz, CDCl3): δ = 2.25 (s, 3 H), 2.31 (s, 3 H), 5.67 (s,
1 H), 7.10 (m, 3 H), 7.24–7.29 (m, 4 H), 7.41–7.44 (m, 4 H), 7.56
(br d, 1 H, J = 2.3 Hz), 8.25 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ =
20.9, 21.1, 33.0, 86.8, 87.6, 105.0, 115.6, 116.3, 121.5, 123.1,
127.0, 128.5, 129.1, 129.7, 131.8, 133.4, 133.8, 135.6, 137.5,
150.8, 161.1, 162.8. ESI-HRMS: m/z calcd for C26H20O3 [M + Na]+:
403.1310; found: 403.1320.
(33) Kiuchi, F.; Goto, Y.; Sugimoto, Y.; Akao, N.; Kondo, K.; Tsuda, Y.
Chem. Pharm. Bull. 1993, 41, 1640.
(34) Yamada, K.; Subeki Nabeta, K.; Yamasaki, M.; Katakura, K.;
Matsuura, H. Biosci. Biotechnol. Biochem. 2009, 73, 776.
(35) Danishefsky, S.; Kerwin, J. F. Jr.; Kobayashi, S. J. Am. Chem. Soc.
1982, 104, 358.
(36) Danishefsky, S.; Kato, N.; Askin, D.; Kerwin, J. F. Jr. J. Am. Chem.
Soc. 1982, 104, 360.
Furo[3,2-c]coumarin (4m)
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H), 2.35 (s, 3 H), 4.08 (s,
2 H), 7.15–7.25 (m, 9 H), 7.34 (d, 2 H, J = 9.0 Hz), 7.55 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.9, 21.4, 32.5, 109.5, 112.5,
116.9, 120.6, 121.8, 126.8, 127.6, 128.4, 128.8, 129.1, 129.7,
131.5, 134.1, 137.4, 137.9, 150.7, 152.7, 157.0, 158.0. ESI-HRMS:
m/z calcd for C26H20O3 [M + Na]+: 403.1310; found: 403.1324.
Pyrano[3,2-c]coumarin (5m)
(37) Cadierno, V.; Díez, J.; Gimeno, J.; Nebra, N. J. Org. Chem. 2008,
73, 5852.
(38) Gohain, M.; Marais, C.; Bezuidenhoudt, B. C. B. Tetrahedron Lett.
2012, 53, 4704.
(39) Muthusamy, S.; Srinivasarao, A. B.; Chidambaram, G. Synth.
Commun. 2002, 32, 3247.
(40) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, H. A. J. Am. Chem. Soc.
2004, 126, 2314.
(41) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125,
8432.
Mp 172–174 °C. 1H NMR (300 MHz, CDCl3): δ = 2.25 (s, 3 H),
2.43 (s, 3 H), 5.19 (s, 1 H), 5.62 (s, 1 H), 7.09 (d, 2 H, J = 6.0 Hz),
7.13–7.22 (m, 3 H), 7.22 (d, 1 H, J = 6.0 Hz), 7.28–7.38 (m, 3 H),
7.52–7.58 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ = 21.0, 21.2,
49.8, 106.5, 107.6, 111.3, 117.0, 122.3, 127.1, 127.8, 128.5,
128.6, 129.7, 134.0, 134.1, 134.2, 136.8, 137.5, 153.5, 158.0,
158.8, 164.2. ESI-HRMS: m/z calcd for C26H20O3 [M + Na]+:
403.1310; found: 403.1319.
(42) Rhee, H.; Kim, J. Y. Tetrahedron Lett. 1998, 39, 1365.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–F