6-endo-dig Cyclization of heteroarylesters to alkynes promoted by Lewis acid catalyst in the presence of Br?nsted acid

Article abstract of DOI:10.1016/j.tetlet.2007.11.020

We report a regiocontrolled 6-endo-dig cyclization of 2-(2-arylethynyl)heteroaryl esters occurred under Br?nsted acidic conditions and in the presence of a catalytic amount of Lewis acids such as Cu(OTf)₂, AuCl₃, or (CF₃CO

Full text of DOI:10.1016/j.tetlet.2007.11.020

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 62–65
6-endo-dig Cyclization of heteroarylesters to alkynes promoted
by Lewis acid catalyst in the presence of Brønsted acid
*
´ ´
Malik Hellal, Jean-Jacques Bourguignon and Frederic J.-J. Bihel
De´partement Pharmacochimie de la Communication Cellulaire, Institut Gilbert-Laustriat UMR 7175 CNRS,
Universite´-Strasbourg I, Faculte´ de Pharmacie, 74 Route du Rhin, BP 60024, 67401 Illkirch Cedex, France
Received 25 September 2007; revised 29 October 2007; accepted 2 November 2007
Available online 7 November 2007
Abstract—We report a regiocontrolled 6-endo-dig cyclization of 2-(2-arylethynyl)heteroaryl esters occurred under Brønsted acidic
conditions and in the presence of a catalytic amount of Lewis acids such as Cu(OTf)2, AuCl3, or (CF3CO2)Ag. A variety of hetero-
cyclic lactones are readily prepared in excellent yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The alkyne is among the most versatile functional
groups in organic chemistry.1 Significant progress has
been made in intramolecular cyclization through alkyne
activation.2 Recently, Uchiyama et al. have reported a
regiocontrolled intramolecular cyclization of carboxylic
acids to carbon–carbon triple bonds mediated by acid
catalyst leading to isocoumarin rings, which constitute
an important class of naturally occurring lactones.3
We report here an efficient Lewis acid-mediated
6-endo-dig cyclization of esters to alkynes leading to iso-
coumarins and their heteroaryl analogs.
(entry 1). Microwave irradiation at 100 ꢁC for 20 min
led to the corresponding lactone 4 in only 18% yield
(entry 2).6 Yao and Larock have reported an efficient
synthesis of isocoumarin and related lactones via an
electrophilic cyclization between alkyne and ester
groups by means of HI at room temperature for 4 days.7
These conditions, applied to nicotinate 3, did not pro-
vide any trace of the corresponding lactone 4, even after
7 days. Recent reports have highlighted the efficacy of
Lewis acids for alkyne activation,2 so various Lewis acid
catalysts were investigated, including derivatives of Cu0,
CuI, CuII, AgI, and AuIII metals (Table 2).
We first focused our attention on the cyclization of
methyl 2-(2-arylethynyl)benzoate 1a–d (Table 1). Previ-
ous theoretical work claimed that under acidic condi-
tions, the electronic bias on both carbons of the triple
bond favors Michael-type (6-endo-dig) cyclization.3 In
good agreement with this report, the reactions of esters
1a–d in trifluoroacetic acid (TFA), as Brønsted acid, at
room temperature led in less than 1 h to the correspond-
ing isocoumarins 2a–d in high yields (Table 1). No
5-exo-dig cyclization was detected.4 Moreover, the pres-
ence of electron-donating groups on the aryl moiety
seems to favor the cyclization (entries 3 and 4). We next
extended this reaction to various heterocyclic esters,
such as ethyl 2-(2-phenylethynyl)nicotinate 3 (Table
2).5 However, the 6-endo-dig cyclization of 3 in TFA
was never detected, even after 12 h at room temperature
Generally speaking, the Lewis acidities of copper de-
pends on its oxidation state and on the counterion. So,
complexes in the CuII oxidation state are more Lewis
acidic, a property which is increased by the electron-
withdrawing capacity of the counterion.8 Consequently,
the cyclization of nicotinate 3 to lactone 4 was carried
out under microwave irradiation using a series of copper
complexes exhibiting varying Lewis acidity (Table 1, en-
tries 3–13 and 17). Surprisingly, even Cu0 as turnings
was able to provide 4 in 47% yield. Moreover, as ex-
pected, CuII complexes turned out to be more efficient
than CuI and Cu0. Cu(OTf)2, bearing the two strongest
electron-withdrawing counterions, appeared to be the
best catalyst providing lactone 4 in 92% yield.9 Reaction
conditions were optimized following a multivariate
screening analysis of the variables involved in this Lewis
acid-promoted cyclization. An increase in the quantity
of copper catalyst did not improve the reaction (entry
14). Moreover, 20 min of microwave irradiation was
*
Corresponding author. Tel.: +33 3 902 44130; fax: +33 3 902
44310; e-mail: frederic.bihel@pharma.u-strasbg.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.020

M. Hellal et al. / Tetrahedron Letters 49 (2008) 62–65
63
Table 1. Acid-promoted isocoumarin cyclizationa
also known to be good Lewis acids.10 However,
CF3CO2AgI as well as AuIIICl3 was not as efficient as
Cu(OTf)2, in providing lactone 4 (entries 21 and 23).
As for copper-mediated catalysis, no 5-exo-dig cycliza-
tion was detected.4 The choice of trifluoroacetic acid
as solvent was critical: use of tetrahydrofuran, dimethyl-
formamide, dichloroethane, or toluene along with TFA
as an additive led to a significantly lower yield (Table 3).
O
CO2Me
TFA, RT
O
R
1
2
R
Entry
1
R
Reaction time (min)
2
Yieldb (%)
1
2
3
4
1a Ph
1b 4-Cl-Ph
1c 4-MeO-Ph
1d 3,4-(MeO)2-Ph 15
60
60
30
2a 83
2b 98
2c 96
2d 97
We next paid our attention to extend this Lewis acid-
promoted cyclization to other heterocyclic esters (5–9),
which were prepared by means of a Sonogashira cou-
pling reaction.11 The cyclizations were carried out in
TFA in the presence of Cu(OTf)2 (5 mol %) under
microwave irradiation (20 min, 100 ꢁC) (Table 4). Ana-
logs of nicotinate 3, bearing electron-donating groups
on the phenyl moiety, led to the corresponding lactones
in excellent yields (entries 1 and 2). Similar results were
obtained starting from pyrimidine 6 (entry 3), indole 7
(entry 4), or tetrahydropyridine 9 (entry 7), providing
the corresponding lactones 11, 12, and 14 in excellent
yields. Surprisingly, under similar conditions, no cycliza-
tion was observed in the case of the imidazopyridine
scaffold (entry 5). However, the saponification of ester
8a into the corresponding carboxylic acid 8b likely
allowed a better nucleophilicity of the carbonyl group,
leading to lactone 13 in 90% yield under Cu(OTf)2-cata-
lyzed cyclization conditions (entry 6). It is noteworthy
that none of these lactones (10–14) was obtained in
the absence of a Lewis acid.
a The reaction was carried out with 1 (1.86 mmol) in TFA (2 mL) as
solvent at rt.
b Yield of isolated product.
Table 2. Lewis acid-catalyzed cyclization of 3 to lactone 4a
O
CO2Me
TFA, Cat.
O
microwave
N
Ph
N
Ph
3
4
Entry Catalyst
Mol % Conditionsb
Yieldc
(%)
nde
1d
2
3
4
5
6
7
8
9
—
—
—
—
5
rt, 12 h
MW (100 ꢁC, 20 min) 18
MW (100 ꢁC, 20 min) 43
MW (100 ꢁC, 20 min) 47
MW (100 ꢁC, 20 min) 74
MW (100 ꢁC, 20 min) 61
MW (100 ꢁC, 20 min) 65
MW (100 ꢁC, 20 min) 74
MW (100 ꢁC, 20 min) 86
MW (100 ꢁC, 20 min) 74
MW (100 ꢁC, 20 min) 68
MW (100 ꢁC, 20 min) 61
MW (100 ꢁC, 20 min) 86
MW (100 ꢁC, 20 min) 83
Cu0 powder
Cu0 turnings 70
CuI2O
5
5
5
5
5
5
5
5
5
10
5
5
5
5
5
5
5
5
CuICl
A plausible mechanism for the present reaction is shown
in Scheme 1. The pyridine ring and heteroaromatic ana-
logs are known to complex Lewis acids such as copper.
However, under strong acidic conditions (TFA as sol-
vent), we observed a protonation of the pyridine ring
by 1H NMR spectroscopy. So the copper catalyst is free
to establish a coordination bond with the triple bond of
3, enhancing the electrophilicity of the alkyne. More-
over, the resulting pyridinium ring acts as an electron-
withdrawing group, leading to an electronic bias on
both carbons of the triple bonds, which favors
Michael-type (6-endo) cyclization. The nucleophilic
attack of the carbonyl oxygen atom on the electron-defi-
cient alkyne provides the cupric ate complex 3B, which,
after a protonolysis step by means of a Brønsted acid
CuIBr
CuII
CuICN
10
CuITcf
11
12
13
14
15
16
17
18
19
20
21
22
23
CuIOAc
CuIICl2
CuII(OAc)2
CuII(OAc)2
CuII(OAc)2
CuII(OAc)2
CuII(OTf)2
CuII(OTf)2
CuII(OTf)2
CF3CO2AgI
CF3CO2AgI
AuIIICl3
AuIIICl3
MW (100 ꢁC, 5 min)
56
MW (100 ꢁC, 30 min) 83
MW (100 ꢁC, 20 min) 92
CH (100 ꢁC, 20 min)
rt, 24 h
45
29
32
rt, 15 h
MW (100 ꢁC, 20 min) 75
rt, 15 h 38
MW (100 ꢁC, 20 min) 83
5
a The reaction was carried out with 3 (0.2 mmol) in TFA (1 mL) as
Table 3. Solvent effect on the Lewis acid-catalyzed cyclization of 3 to
lactone 4a
solvent.
b MW: microwave irradiation; CH: conventional heating.
c Yield of isolated product.
Entry
Solvent
Additive
Equiv
Yieldb (%)
d Ethyl ester was replaced by a methyl ester.
e Not detected.
1
2
3
4
5
6
7
TFA
THF
THF
DMF
DCE
—
92
ndc
36
nd
38
63
61
TFA
TFA
TFA
TFA
TFA
TFA
1
3
3
3
3
6
f Copper(I) thiophene-2-carboxylate.
necessary to complete the reaction, and a longer time did
not improve the yield (entries 13, 15, and 16). Further-
more, cyclization of 3 achieved under conventional heat-
ing for 20 min at 100 ꢁC led to lactone 4 in only 45%
yield, clearly supporting the beneficial effects of micro-
wave irradiation (entry 18). Copper is in the Ib column
of the periodic table, as well as silver and gold, which are
Toluene
Toluene
a The reaction was carried out with 3 (0.2 mmol) in the presence of
Cu(OTf)2 (5 mol %) in solvent (1 mL) under microwave irradiation
(100 ꢁC, 20 min).
b Yield of isolated product.
c Not detected.

64
M. Hellal et al. / Tetrahedron Letters 49 (2008) 62–65
Table 4. Lewis acid-catalyzed cyclization of various heterocyclesa
Entry
Alkyne
R1
R2
Product
Yieldb (%)
CO2R1
O
1
2
5a
5b
Et
Et
4-MeO-Ph
3,4(MeO)2-Ph
10a
10b
98
94
O
N
N
R2
O
R2
CO2R1
N
3
4
6
7
Et
Ph
Ph
11
12
91
83
N
O
MeS
N
R2
R2
MeS
N
O
CO2R1
O
Me
N
R2
N
R2
CO2R1
Bn
Bn
O
N
N
N
N
5c
6
8a
8b
Et
H
Ph
Ph
13
13
ndd
90
O
R2
R2
CO2R1
O
7
9
Et
Ph
14
89
O
N
Bn
N
R2
R2
Bn
a The reaction was carried out with alkyne (0.2 mmol) in the presence of Cu(OTf)2 (5 mol %) under microwave irradiation (100 ꢁC, 20 min) in TFA
(1 mL) as solvent.
b Yield of isolated product.
c CuTc (10 mol %) was used in the place of Cu(OTf)2.
d Not detected.
ciently through a simple and inexpensive copper catalyst
on a wide variety of 2-alkynyl heterocyclic esters.
3A
TFA
OEt
OEt
O
O
TFA
Acknowledgments
N
N
H
3
Ph
Ph
LnCu
´
We thank the ‘Region Alsace’ for financial support. We
also thank C. Antheaume for 2D NMR analysis and P.
Wehrung and P. Buisine for HRMS and MS analysis.
CuLn
CF3CO2H
O
OEt
TFA
3B
TFA
Supplementary data
O
O
N
Ph
N
H
Ph
Experimental details, characterization data, and copies
of 1H, 13C, and NOE NMR spectra for each compound
are available. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.11.020.
H
CuL
4
CF3CO2Et
Scheme 1. Plausible mechanism for copper-catalyzed cyclization under
acidic conditions.
such as trifluoroacetic acid, provides lactone 4, while
regenerating the initial copper catalyst.
References and notes
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In conclusion, an efficient approach to the synthesis of
novel heterocyclic lactones has been developed by
employing an association between a Brønsted acid and
a Lewis acid to catalyze the cyclization of o-alkynylaryl
esters containing nitrogen atoms. It is noteworthy that
this regiocontrolled 6-endo-dig cyclization proceeds effi-

M. Hellal et al. / Tetrahedron Letters 49 (2008) 62–65
65
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6. All the reactions were performed with a self-tuneable
microwave synthesizer (Biotage Initiator EXP microwave
apparatus). The instrument continuously adjusted the
applied wattage to maintain the desired temperature.
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9. 7-Phenyl-5H-pyrano[4,3-b]pyridin-5-one (4): To a solution
of 3 (0.2 mmol) in trifluoroacetic acid (1 mL) was added
Cu(OTf)2 (5 mol %). The solution was irradiated with
microwaves at 100 ꢁC for 20 min. Trifluoroacetic acid was
evaporated under reduced pressure. The residue was
partitioned between CH2Cl2 (10 mL) and water (10 mL).
The organic layer was further washed with brine
(2 · 20 mL), dried (Na2SO4), and concentrated in vacuo.
Purification by chromatography on silica gel R (elution
gradient: EtOAc–heptane 3–7 to 1–1) yielded 4 as a white
1
powder in 92% yield. H NMR (CDCl3, 300 MHz) d 8.91
(dd, 1H, J = 1.3, 4.7 Hz), 8.52 (dd, 1H, J = 1.3, 8.1 Hz),
7.93–7.86 (m, 2H), 7.50–7.45 (m, 3H), 7.40 (dd, 1H,
J = 4.7, 8.1 Hz), 7.20 (s, 1H). 13C NMR (CDCl3, 75 MHz)
d 162.2, 157.4, 156.6, 153.3, 137.8, 131.6, 131.1, 129.3,
125.9, 123.2, 117.2, 104.0. IR (neat, cmÀ1): 3067, 2923,
2853, 2330, 1734, 1633, 1561, 1439, 1280, 1215, 1110, 1079,
774, 752, 688, 530. Mp = 136–137 ꢁC. ESI-HRMS calcd
C14H10NO2 [M+H]+ 224.0706, found 224.0694.
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ings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896;
4. Reaction mixture was analyzed by 1H NMR spectroscopy.
5. Electrophilic cyclization using aqueous sulfuric acid or
polyphosphoric acid was reported to give lactone 4 in
modest yields. See: (a) Sakamoto, T.; An-Naka, M.;
Kondo, Y.; Araki, T.; Yamanaka, H. Chem. Pharm. Bull.
1988, 36, 1890; (b) Sakamoto, T.; Nishiwaki, N.; Koma-
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Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
¨
2007, 46, 3410. For the Ag(I)-mediated activation of
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