Europium-Catalyzed Intramolecular Addition of Carboxylic Acid to Nonactivated Alkenes: An Efficient Route to Aryl-Substituted γ-Butyrolactone

Article abstract of DOI:10.1055/s-0040-1707820

Europium(III)triflate has been proved to be an effective catalyst for intramolecular cyclization of aryl-substituted carboxylic acid to afford arylated γ-butyrolactone. Various attractive features, such as broad substrate scope, a wide range of functional

Full text of DOI:10.1055/s-0040-1707820

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
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M. Bandyopadhyay et al.
Letter
Synlett
Europium-Catalyzed Intramolecular Addition of Carboxylic Acid
to Nonactivated Alkenes: An Efficient Route to Aryl-Substituted
-Butyrolactone
Manas Bandyopadhyay
O
OH
Eu(OTf)3
(5 mol%)
Abhijit Nayak
O
O
Mrinal K. Bera*
0
0
0
0-0
0
0
3-4
3
8
2-
6
8
4
1
PhCl, sealed tube
120 °C, 7–12 h
Department of Chemistry, Indian Institute of Engineering
Science and Technology, Shibpur, Howrah-711103, West
Bengal, India
R
R
R = H, alkyl, alkoxy,
halo
13 examples
up to 85% yield
syn:anti ~1:3
complete atom economy
cost and time effective
mrinalkbera26@gmail.com
Received: 07.04.2020
CO2H
Accepted after revision: 06.05.2020
Published online: 16.04.2020
DOI: 10.1055/s-0040-1707820; Art ID: st-2020-u0197-l
O
O
O
O
8
2
(+)-Whisky lactone
(+)-Roccellaric acid
Abstract Europium(III)triflate has been proved to be an effective cata-
lyst for intramolecular cyclization of aryl-substituted carboxylic acid to
afford arylated -butyrolactone. Various attractive features, such as
broad substrate scope, a wide range of functional group tolerance, op-
erational simplicity, complete atom economy, and good-to-excellent
yields have made this new protocol more appealing. Moreover, this
method provides a practical alternative to the existing catalysts.
O
HO
CO2H
O
O
O
2
O
H
(–)-Methylenolactocin
Halenalin
Figure 1 Butyrolactone-containing natural products
Key words -butyrolactones, lanthanide catalyst [Eu(OTf)3], -alke-
noic acid, intramolecular hydroacyloxylation reaction, O-containing
heterocycles
Generally, these atom-economical processes of nonacti-
vated C=C bond functionalization are carried out by various
transition-metal-catalyzed reactions.7 Ag(I) triflate7a and
Cu(II) triflate7b,c have been successfully used for intramolec-
ular cyclization of both alkenoic alcohol and carboxylic acid
leading to the corresponding ether and lactone, respectively
(Scheme 1). Probably, the first example of metal-catalyzed
synthesis of -butyrolactones was reported way back in
19787d (Scheme 1) by Katzenellenbogen et al. They eventu-
ally revealed an efficient method for intramolecular lacton-
ization of 1-pentynoic acid to -methylene--butyrolac-
tone catalyzed by Hg(II) catalyst.
Oxygen heterocycles are important structural units fre-
quently found in various natural products and medicinally
important molecules. Tetrahydrofuran1 and tetrahydropy-
ran2 rings are commonly found in lignin, macrolide, poly-
ether antibiotic, and various food-flavoring agents.3 -Buty-
rolactones decorated with various alkyl substituents and
functional groups are widely observed in natural products,
such as, (+)-whisky lactone, (+)-roccellaric acid, (–)-methyl-
enolactocin, and halenalin (Figure 1); and many of them
show significant biological activities.4,5 -Butyrolactones
are also considered as useful building blocks for many natu-
ral product4a syntheses. As a consequence, the synthesis of
differently substituted -butyrolactone has drawn consid-
erable attention6 from organic chemists; and a variety of
synthetic routes towards -butyrolactone has been report-
ed. Amongst all the existing methods, transition-metal-cat-
alyzed routes to butyrolactone via functionalization of non-
activated alkene are quite significant.7 -Alkenoic acids/al-
cohols and their higher homologues are useful synthetic
intermediates which can undergo intramolecular cycliza-
tion to afford cyclic lactones and ethers, respectively.
Similarly, a wide range of transition metals are known
to promote intramolecular hydroalkoxylation of nonacti-
vated alkenes to afford saturated cyclic ethers. Intramolecu-
lar hydroalkoxylation of - and -hydroxy olefins have been
successfully converted into cyclic ethers via Pt(II)-,8a Sn(IV)-
8b
,
Ru(II)-,8c and Fe(III)-catalyzed8d methods. Even zero-va-
lent gold nanocluster8e and Co(salen)8f complexes have also
been successfully employed for the functionalization of
nonactivated olefins. Recently, Nb-based catalytic systems8g
and Ca(II)8h reagents were found to be efficient to promote
hydrofunctionalization of nonactivated alkene offering var-
ious oxygen heterocycles including lactones.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Bandyopadhyay et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditions
Previous Work:
a) He et al. 20057a
R2
Entry Catalyst
Amount
(mol%)
Time Solventa Temp Yield
(h) (°C)
(%)b
O
R1
Ag(I)
O
R2
OH
O
O
R2
1
2
3
4
5
6c
7
8
9
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Tb(OTf)3
Tb(OTf)3
Eu(OTf)3
Eu(OTf)3
TfOH
2
10
PhH
7 5
ca. 36
b) Hii et al. 20057c
2
22
36
15
15
7
PhCl
PhCl
MeCN
PhCl
PhCl
PhCl
DCM
DCM
PhH
100
120
100
120
120
120
r.t
42
40
45
37
70
51
0
O
Cu(II)
5
OH
O
5
c) Katzenellenbogen et al. 19787d
R
5
R
5
Hg(II)
O
10
500
2
7
O
O
OH
15
24
24
7
This Work:
TfOH
40
0
Me
OH
10
11
TfOH
2
75
<30
<20
0
O
Eu(III)
O
TfOH
5
PhCl
PhCl
PhCl
120
120
120
O
12d,e Eu(OTf)3
13d,f Eu(OTf)3
5
7
R
R
1
2
5
7
0
Scheme 1 Intramolecular hydroacyloxylation reaction leading to buty-
rolactone
a Concentration of all solvents: 2.0 (M).
b Isolated yield.
c Optimized reaction conditions.
d Reactions using additives.
e 2 mol% of dppf.
f 2 mol% of Xantphos.
Unlike the main group transition metals, rare-earth
metals are less famous in the area of organic synthesis.
Among all the rare-earth metals, only samarium9 and scan-
dium10 reagents are widely used in various organic trans-
formations. On the other hand, the synthetic potential of
other lanthanide metal reagents have so far been under-
studied and consequently explored very little.11 The rare-
earth metal like europium (Eu) remains largely unexplored
in organic synthesis; and the reports on its synthetic poten-
tial are still limited.12 Herein, we report the first application
of Eu(III) to mediate the conversion of 3-aryl--alkenoic ac-
ids to -butyrolactone in this publication.
We initially have taken 3-phenyl--alkenoic acid (1a) as
our model compound; and the reaction was carried out in
sealed tube at 120 °C in chlorobenzene as solvent. The cata-
lyst Eu(III) triflate was loaded only with 5 mol%. It was our
delight to see that the intramolecular OH addition to the
terminal double bond to afford 3-phenyl--butyrolactone
(2a, Table 1) went smoothly, and clean conversion was ob-
served, but clearly separable two spots were found on TLC.
We anticipated that the cyclization process may furnish the
mixture of two diastereomers due to the pre-existing aryl
group at the 3-position of -alkenoic acid. The experimen-
tal results proved the anticipation to be true and well-
founded. After separation of two diastereomers on silica gel
column chromatography, we found that the major isomer
was anti oriented, while the minor isomer was found to be
the syn isomer. The ratio of syn/anti isomers for the same
substrate under different reaction conditions was reported
to be either the same or opposite to what we observed.
After reviewing the literature carefully, we have found
that the anti product was the major product in case of Ag(I)
triflate7a catalyzed intramolecular addition of alkenoic acid
to inert olefin, whereas the syn isomer was the major prod-
uct when the same reaction was promoted by Cu(II) tri-
flate.7c Therefore, it could be an interesting issue to study
the stereochemical outcome of this reaction under different
transition-/rare-earth-metal-catalyzed conditions, when
one aryl substituent is present at C-3 of -alkenoic acids.
But surprisingly enough, no detailed study has been con-
ducted till date. Therefore, we executed this reaction with
differently substituted 3-aryl--alkenoic acids under opti-
mized reaction conditions and obtained the anti-oriented
product as the major product in all cases.
Moreover, under this newly developed conditions, the
reaction needed much less time (8–12 h) compared to ex-
isting literature procedures (36–48 h).7c This may be con-
sidered as a major advantage of our newly found reaction
conditions. The reaction was also tried with different tran-
sition-metal triflates which are not reported earlier for this
particular transformation. Sc(III) triflate either in PhH or in
PhCl (Table 1, entries 1–3) gave an incomplete conversion
even after prolonged heating. Other transition-metal tri-
flates like Tb(III) triflate were screened as catalysts in dif-
ferent solvents. The desired product was isolated but with
dissatisfactory yields even after prolonged reaction times
(entries 4 and 5).
Since silver and copper triflates were already reported
in the literature for the similar reaction, we did not pay at-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
M. Bandyopadhyay et al.
Letter
Synlett
tention to them. Best result was obtained by using 5.0 mol%
of Eu(III) triflate heating at 120 °C (Table 1, entry 6). Even
with an increased amount of catalyst loading (10 mol%), the
yield did not improve (entry 7). Triflic acid was also
screened as catalyst for this transformation in different sol-
vents at varying temperature (Table 1, entries 8–11), but it
failed to provide better result. Either no product was de-
tected, or much inferior yield was obtained.
We were also interested to see whether any additives,
like dppf, Xantphos (Table 1, entries 12 and 13), had any
beneficial effect on the reaction. All the additives (2.0 mol%)
were used under the standard reaction conditions, but
none of them was found beneficial.
Table 2 Substrate Scope
O
O
O
Eu(OTf)3 (5 mol%)
PhCl, 120 °C, 7 h
OH
1
2
R
R
Substrate, product
Substrate, product
O
O
O
O
O
O
OH
OH
1a
2a, 70%
syn:anti = 1:2.2
O
O
1i
2i, 79%
syn:anti = 1:2.7
O
O
O
O
O
O
O
O
O
OH
OH
O
1j
2j, 85%
1b
2b, 69%
syn:anti = 1:2.8
syn:anti = 1:2.6
O
O
O
O
O
O
O
O
OH
OH
O
O
1c
2c, 70%
2k, 84%
1k
syn:anti = 1:2.1
syn:anti = 1:2.7
O
O
O
O
O
O
OH
OH
2d, 77%
syn:anti = 1:2.2
2l, 67%
syn:anti = 1:1.9
1l
1d
O
O
O
O
O
O
OH
OH
2m, 70%
1m
2e, 85%
1e
syn:anti = 1:2.4
O
O
O
O
O
O
OH
OH
1n
2n, not detected
Cl
Cl
1f
2f, 78%
syn:anti = 1:2.6
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
M. Bandyopadhyay et al.
Letter
Synlett
Table 2 (continued)
Substrate, product
Substrate, product
O
O
O
O
O
O
OH
OH
S
S
1o
2o, not detected
Br
Br
2g, 85%
syn:anti = 1:2.8
1g
O
O
O
O
O
O
OH
OH
NH
1p
NH
2p, not detected
F
F
1h
2h, 83%
syn:anti = 1:2.8
After having reached the standard reaction conditions
We were in quest for the crystal structure of any one of
the -butyrolactone compounds to confirm the stereo-
chemistry of adjacent aryl and methyl groups present in the
title compounds. We were fortunate enough to obtain a sin-
gle crystal of compound 2j (Figure 2) suitable for crystallo-
graphic analysis. Crystal-structure analysis of the major
component isolated by silica gel column chromatography
established unambiguously the anti relationship between
the adjacent aryl and the methyl group of compound 2j
(Figure 2).
We have proposed a mechanistic pathway of the reac-
tion depicted in Scheme 2. Since lanthanides are oxophilic
in nature, europium(III) is expected to coordinate to the
carboxylic acid group of 1a to form intermediate A (Scheme
2). The triflic acid liberated from metal triflate protonates
terminal olefin to give secondary carbocation B which un-
dergoes C–O bond formation via nucleophilic attack of the
oxygen lone pair to give C. Finally, C decomposes to afford
title compound 2a and Eu(OTf)3 which initiates another
catalytic cycle.
(Table 1, entry 6), we focused our attention to exploring the
substrate scope for this reaction. Differently substituted 3-
aryl--alkenoic acids (Table 2, 1a–m) were subjected to the
optimum reaction conditions. It was observed that all the
substrates (2a–m) were smoothly converted into the prod-
uct -butyrolactones with good-to-excellent yield. It was
also observed that the product ratio was always in favor of
the anti isomer, and the ratio was found to be ca. 3:1 (an-
ti/syn). We also examined the reaction protocol in the ali-
phatic system (1m,n) and observed that alkenoic acid 1m
was smoothly transformed into the corresponding lactone
2m with the yield in line with the literature precedence,
whereas alkenoic acid 1n did not produce any detectable
product 2n (1n). The multiple double bonds present in
alkenoic acid 1n might lead to a complex reaction profile,
and no isolable product was identified.
Though a variety of differently substituted 3-aryl--
alkenoic acids (1a–m) were converted smoothly into 3-
aryl--butyrolactones with consistent yield and stereose-
lectivity, the reaction was found to be unsuccessful for the
-alkenoic acids carrying a heterocycle at 3-position. We
tried to convert -alkenoic acids decorated with thienyl
and indolyl substituents at 3-position (entries 2o,p) to their
corresponding -butyrolactones, but all our efforts were
found to be futile. No detectable product was found in any
cases for some unknown reasons.
OH
O
O
O
Eu(OTf)3
1a
2a
TfOH
Eu(OTf)2
Eu(OTf)2
O
O
O
OTf
O
O
A
O
C
Eu(OTf)2
O
H
Me
O
O
TfOH
O
Me
TfO
B
Figure 2 Single-crystal XRD image (ORTEP diagram) of compound 2j
(CCDC 1849393)
Scheme 2 Plausible reaction mechanism of intramolecular lactonizaton
Thieme. All rights reserved. Synlett 2020, 31, A–E

E
M. Bandyopadhyay et al.
Letter
Synlett
In summary, we have developed a new Eu(III)-catalyzed
intramolecular lactonization reaction of -alkenoic acids
leading to -butyrolactones.13 To the best of our knowledge,
it is the first example to use rare-earth-metal triflate to
achieve functionalization of nonactivated terminal double
bond. A variety of 3-aryl--butyrolactones can be accessible
with good-to-excellent yield. An anti-selective product ori-
entation was observed with consistency in a wide range of
substrates. Operational simplicity, broad substrate range,
good yield, and clean reaction profile made this method
more appealing to the chemists. Moreover, our work may
be considered as a step forward to popularize the use of
rare-earth-metal reagent in organic synthesis.
S.; Mei, H.; Han, J.; Pan, Y. J. Org. Chem. 2017, 82, 9824. (d) Paz
Muñoz, M.; Lloyd-Jones, G. C. Eur. J. Org. Chem. 2009, 516.
(e) Keshavarz, M.; Ahmady, A. Z.; Mostoufi, A.; Mohtasham, N.
Molecules 2017, 22, 1385. (f) Maslak, V.; Matović, R.; Saičić, R. N.
Tetrahedron 2004, 60, 8957.
(7) (a) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7,
4553. (b) Taylor, J. G.; Whittall, N.; Hii, K. K. Chem. Commun.
2005, 5103. (c) Adrio, L. A.; Quek, L. S.; Taylor, J. G.; Hii, K. K. Tet-
rahedron 2009, 65, 10334. (d) Amos, R. A.; Katzenellenbogen, J.
A. J. Org. Chem. 1978, 43, 560.
(8) (a) Qian, H.; Han, X.; Wildenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536. (b) Coulombel, L.; Favier, I.; Dunach, E. Chem.
Commun. 2005, 2286. (c) Oe, Y.; Ohta, T.; Ito, Y. Synlett 2005,
179. (d) Komeyama, K.; Morimoto, T.; Nakayama, Y.; Takaki, K.
Tetrahedron Lett. 2007, 48, 3259. (e) Kamiya, I.; Tsunoyama, H.;
Tsukuda, T.; Sakurai, H. Chem. Lett. 2007, 36, 646. (f) Shigehisa,
H.; Hayashi, M.; Ohkawa, H.; Suzuli, T.; Okayasu, H.; Mukai, M.;
Yamazaki, A.; Kawai, R.; Kikuchi, H.; Satoh, Y.; Fukuyama, A.;
Hiroya, K. J. Am. Chem. Soc. 2016, 138, 10597. (g) Ferrand, L.;
Tang, Y.; Aubert, C.; Fensterbank, L.; Mouriè s-Mansuy, V.; Petit,
M.; Amatore, M. Org. Lett. 2017, 19, 2062. (h) Qi, C.; Yang, S.;
Gandon, V.; Leboeuf, D. Org. Lett. 2019, 21, 7405.
Funding Information
Financial support from Council of Scientific and Industrial Research
(CSIR, Grant No. 02(0270)/16/EMR-II), New Delhi and Department of
Science and Technology, Science and Engineering Research Board
(DST-SERB, Grant No. SB/S1/OC-15/2014), New Delhi are most grate-
(9) (a) For reviews, see: Szostak, M.; Fazakerley, N. J.; Parmar, D.;
Proctor, D. J. Chem. Rev. 2014, 114, 5959; and references cited
therein. (b) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96,
307. (c) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem. Int.
Ed. 2009, 48, 7140.
fully acknowledged.
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i
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eri
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ard(SB/S1/OC-15/2
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Acknowledgment
(10) (a) Kobayashi, S. Eur. J. Org. Chem. 1999, 15. (b) Ishihara, K.;
Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996, 61,
4560. (c) Giuseppone, N.; Schmitt, J.-L.; Schwartz, E.; Lehn, J.-M.
J. Am. Chem. Soc. 2005, 127, 5528.
We sincerely thank Sophisticated Analytical Instruments Facility
(SAIF), IIEST Shibpur for single-crystal X-ray analysis.
(11) For a review, see: Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam,
W. W.-L. Chem. Rev. 2002, 102, 2227; and references cited
therein.
Supporting Information
Supporting information for this article is available online at
(12) (a) Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984, 106,
4294. (b) Castellino, S.; Sims, J. J. Tetrahedron Lett. 1984, 25,
4059. (c) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1983,
105, 3716. (d) Levin, J. I. Tetrahedron Lett. 1989, 30, 2355.
(e) Terada, M.; Nakai, T.; Mikami, K. Inorg. Chim. Acta 1994, 222,
377. (f) Pellissier, H. Coord. Chem. Rev. 2017, 336, 96.
https://doi.org/10.1055/s-0040-1707820.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
(1) For reviews, see: (a) Lorente, A.; Lamariano-Merketegi, J.;
Albericio, F.; Alvarez, M. Chem. Rev. 2013, 113, 4567; and refer-
ences cited therein. (b) Mihovilovic, M. D.; Bianchi, D. A.;
Rudroff, F. Chem. Commun. 2006, 3214. (c) Albertson, A. K. F.;
Lumb, J. P. Angew. Chem. Int. Ed. 2015, 54, 2204. (d) Lin, Y.-S.;
Lin, J.-S.; Chang, C. C.; Lee, S.-S. J. Nat. Prod. 2015, 78, 181.
(2) For a review on oxacyclic macrodiolide natural products, see:
(a) Kang, E. J.; Lee, E. Chem. Rev. 2005, 105, 4348; and the refer-
ences cited therein. (b) Nasir, N. M.; Ermanis, K.; Clarke, P. A.
Org. Biomol. Chem. 2014, 12, 3323. (c) Zaware, N.; LaPorte, M.
G.; Farid, M.; Liu, L.; Wipf, P.; Floreancig, P. E. Molecules 2011,
16, 3648.
(13) Typical Procedure for the Preparation of Reference Com-
pound 5-Methyl-4-phenyldihydrofuran-2(3H)-one (2a)
A chlorobenzene (0.2 M) solution of the 3-phenylpent-4-enoic
acid (1a, 50 mg, 0.284 mmol) was taken in a 10 mL sealed tube,
and Eu(OTf)3 (5 mol%) was added to it. Nitrogen gas was flushed
into it; the tube was closed and placed it in a silicon oil bath.
After 7 h heating the starting material was completely con-
sumed as indicated by TLC, and the reaction was quenched by
adding water. Compound was extracted with ethyl acetate (3 ×
20 mL). Combined organic layer was washed with brine solu-
tion, dried over sodium sulfate, and evaporated to dryness. The
crude product was purified on silica gel (mesh 100–200)
column chromatography using ethyl acetate in petroleum ether
(1:2) as eluent to afford 2a (35 mg, 70%) as yellow oil. IR: 1775
(3) (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309. (b) Cradilo, G.;
Orena, M. Tetrahedron 1990, 46, 3321.
(4) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. 1985, 24,
94. (b) Cava, A.; Cortes, D.; Figureadere, B.; Hocquemiller, R.;
Laprevote, O.; Laurens, A.; Leboeuf, M. In Phytochemical Poten-
tial of Tropical Plants; Downum, K. R.; Romeo, J. T.; Stafford, H.,
Ed.; Plenum Press: New York, 1993, 167.
cm–1 1H NMR (400 MHz, CDCl3):  = 7.39–7.24 (m, 5 H), 4.55
.
(ddd, J = 12, 8.6, 6.2 Hz, 1 H), 3.25 (td, J = 11.2, 6.2 Hz, 1 H), 2.95
(dd, J = 16, 8.4 Hz, 1 H), 2.79 (dd, J = 16, 11.2 Hz, 1 H), 1.42 (d, J =
6.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  = 175.5, 138.2, 129.1,
127.8, 83.2, 49.7, 37.5, 19.2. HRMS: m/z [M + H]+ – H2O calcd for
(5) Lepoittevin, J.-P.; Berl, V.; Giménez-Arnau, E. Chem. Rec. 2009, 9,
258.
C
11H12O2: 159.0837; found: 159.0843.
(6) (a) Mandal, S. K.; Amin, S. R.; Crowe, W. E. J. Am. Chem. Soc.
2001, 123, 6457. (b) Zhu, Y.-L.; Xiang, H.-W.; Wu, G.-S.; Bai, L.;
Li, Y.-W. Chem. Commun. 2002, 254. (c) Sha, W.; Zhang, W.; Ni,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E