Key words
γ-butyrolactones - lanthanide catalyst [Eu(OTf)
3] - ω-alkenoic acid - intramolecular hydroacyloxylation reaction - O-containing heterocycles
Oxygen heterocycles are important structural units frequently found in various natural
products and medicinally important molecules. Tetrahydrofuran[1] and tetrahydropyran[2] rings are commonly found in lignin, macrolide, polyether antibiotic, and various
food-flavoring agents.[3] γ-Butyrolactones decorated with various alkyl substituents and functional groups
are widely observed in natural products, such as, (+)-whisky lactone, (+)-roccellaric
acid, (–)-methylenolactocin, and halenalin (Figure [1]); and many of them show significant biological activities.[4]
[5] γ-Butyrolactones are also considered as useful building blocks for many natural
product[4a] syntheses. As a consequence, the synthesis of differently substituted γ-butyrolactone
has drawn considerable attention[6] from organic chemists; and a variety of synthetic routes towards γ-butyrolactone
has been reported. Amongst all the existing methods, transition-metal-catalyzed routes
to butyrolactone via functionalization of nonactivated alkene are quite significant.[7] ω-Alkenoic acids/alcohols and their higher homologues are useful synthetic intermediates
which can undergo intramolecular cyclization to afford cyclic lactones and ethers,
respectively.
Figure 1 Butyrolactone-containing natural products
Generally, these atom-economical processes of nonactivated C=C bond functionalization
are carried out by various transition-metal-catalyzed reactions.[7] Ag(I) triflate[7a] and Cu(II) triflate[7b]
[c] have been successfully used for intramolecular 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 γ-butyrolactones was
reported way back in 1978[7d] (Scheme [1]) by Katzenellenbogen et al. They eventually revealed an efficient method for intramolecular
lactonization of 1-pentynoic acid to γ-methylene-γ-butyrolactone catalyzed by Hg(II)
catalyst.
Similarly, a wide range of transition metals are known to promote intramolecular hydroalkoxylation
of nonactivated alkenes to afford saturated cyclic ethers. Intramolecular hydroalkoxylation
of γ- and δ-hydroxy olefins have been successfully converted into cyclic ethers via
Pt(II)-,[8a] Sn(IV)-,[8b] Ru(II)-,[8c] and Fe(III)-catalyzed[8d] methods. Even zero-valent gold nanocluster[8e] and Co(salen)[8f] complexes have also been successfully employed for the functionalization of nonactivated
olefins. Recently, Nb-based catalytic systems[8g] and Ca(II)[8h] reagents were found to be efficient to promote hydrofunctionalization of nonactivated
alkene offering various oxygen heterocycles including lactones.
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 samarium[9] and scandium[10] reagents are widely used in various organic transformations. On the other hand,
the synthetic potential of other lanthanide metal reagents have so far been understudied
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 potential are still limited.[12] Herein, we report the first application of Eu(III) to mediate the conversion of
3-aryl-ω-alkenoic acids to γ-butyrolactone in this publication.
Scheme 1 Intramolecular hydroacyloxylation reaction leading to butyrolactone
We initially have taken 3-phenyl-ω-alkenoic acid (1a) as our model compound; and the reaction was carried out in sealed tube at 120 °C
in chlorobenzene as solvent. The catalyst 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-γ-butyrolactone (2a, Table [1]) went smoothly, and clean conversion was observed, 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 ω-alkenoic
acid. The experimental 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.
Table 1 Optimization of the Reaction Conditions
|
Entry
|
Catalyst
|
Amount (mol%)
|
Time (h)
|
Solventa
|
Temp (°C)
|
Yield (%)b
|
|
1
|
Sc(OTf)3
|
2
|
10
|
PhH
|
7 5
|
ca. 36
|
|
2
|
Sc(OTf)3
|
2
|
22
|
PhCl
|
100
|
42
|
|
3
|
Sc(OTf)3
|
5
|
36
|
PhCl
|
120
|
40
|
|
4
|
Tb(OTf)3
|
5
|
15
|
MeCN
|
100
|
45
|
|
5
|
Tb(OTf)3
|
5
|
15
|
PhCl
|
120
|
37
|
|
6c
|
Eu(OTf)3
|
5
|
7
|
PhCl
|
120
|
70
|
|
7
|
Eu(OTf)3
|
10
|
7
|
PhCl
|
120
|
51
|
|
8
|
TfOH
|
500
|
15
|
DCM
|
r.t
|
0
|
|
9
|
TfOH
|
2
|
24
|
DCM
|
40
|
0
|
|
10
|
TfOH
|
2
|
24
|
PhH
|
75
|
<30
|
|
11
|
TfOH
|
5
|
7
|
PhCl
|
120
|
<20
|
|
12d,e
|
Eu(OTf)3
|
5
|
7
|
PhCl
|
120
|
0
|
|
13d,f
|
Eu(OTf)3
|
5
|
7
|
PhCl
|
120
|
0
|
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.
After reviewing the literature carefully, we have found that the anti product was the major product in case of Ag(I) triflate[7a] catalyzed intramolecular addition of alkenoic acid to inert olefin, whereas the
syn isomer was the major product when the same reaction was promoted by Cu(II) triflate.[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 ω-alkenoic acids. But surprisingly
enough, no detailed study has been conducted till date. Therefore, we executed this
reaction with differently substituted 3-aryl-ω-alkenoic acids under optimized 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 existing literature procedures (36–48 h).[7c] This may be considered as a major advantage of our newly found reaction conditions.
The reaction was also tried with different transition-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 triflates like Tb(III) triflate were screened as catalysts in different
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 attention 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 solvents at varying temperature (Table [1], entries 8–11), but it failed to provide better result. Either no product was detected,
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.
After having reached the standard reaction conditions (Table [1], entry 6), we focused our attention to exploring the substrate scope for this reaction.
Differently substituted 3-aryl-ω-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 product γ-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 (anti/syn). We also examined the reaction protocol in the aliphatic 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.
Figure 2 Single-crystal XRD image (ORTEP diagram) of compound 2j (CCDC 1849393)
Though a variety of differently substituted 3-aryl-ω-alkenoic acids (1a–m) were converted smoothly into 3-aryl-γ-butyrolactones with consistent yield and stereoselectivity,
the reaction was found to be unsuccessful for the ω-alkenoic acids carrying a heterocycle
at 3-position. We tried to convert ω-alkenoic acids decorated with thienyl and indolyl
substituents at 3-position (entries 2o,p) to their corresponding γ-butyrolactones, but all our efforts were found to be futile.
No detectable product was found in any cases for some unknown reasons.
We were in quest for the crystal structure of any one of the γ-butyrolactone compounds
to confirm the stereochemistry of adjacent aryl and methyl groups present in the title
compounds. We were fortunate enough to obtain a single crystal of compound 2j (Figure [2]) suitable for crystallographic 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 reaction 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 undergoes 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.
Scheme 2 Plausible reaction mechanism of intramolecular lactonizaton
In summary, we have developed a new Eu(III)-catalyzed intramolecular lactonization
reaction of ω-alkenoic acids leading to γ-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-γ-butyrolactones
can be accessible with good-to-excellent yield. An anti-selective product orientation 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.
