Palladium(II) acetate catalyzed acylative cleavage of cyclic and acyclic ethers under neat conditions

Article abstract of DOI:10.1016/j.tetlet.2017.10.080

During the development of a palladium catalyzed C–H activation cross-coupling reaction involving acyl halides, it was noted that palladium(II) acetate catalyzes the acylative cleavage of tetrahydrofuran (used as a solvent) at room temperature to afford the corresponding 4-chlorobutyl ester derivative. After optimization, the reaction was shown to work well with epoxides, oxetane and tetrahydrofuran, but only barely with oxanes at room temperature. Acyclic ethers systematically failed to react under similar conditions, but underwent complete conversion in a microwave reactor at 100 °C.

Full text of DOI:10.1016/j.tetlet.2017.10.080

Accepted Manuscript
Palladium(II) acetate catalyzed acylative cleavage of cyclic and acyclic ethers
under neat conditions
Jean Fotie, Brandy R. Adolph, Shreya V. Bhatt, Casey C. Grimm
PII:
S0040-4039(17)31393-X
https://doi.org/10.1016/j.tetlet.2017.10.080
TETL 49442
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
18 September 2017
30 October 2017
31 October 2017
Please cite this article as: Fotie, J., Adolph, B.R., Bhatt, S.V., Grimm, C.C., Palladium(II) acetate catalyzed acylative
cleavage of cyclic and acyclic ethers under neat conditions, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/
j.tetlet.2017.10.080
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Palladium(II) acetate catalyzed acylative cleavage of cyclic and acyclic ethers under
neat conditions
Jean Fotie,a* Brandy R. Adolph,a Shreya V. Bhatta and Casey C. Grimmb
aDepartment of Chemistry and Physics, Southeastern Louisiana University, SLU 10878, Hammond, LA
70402-0878, United States
bFood Processing and Sensory Quality Research, United States Department of Agriculture (USDA),
1100 Robert E. Lee Boulevard, Bldg 001 SRRC, New Orleans, LA 70124, United States
 Corresponding author. Phone: +1 985 549 5112; Fax: +1 985 549 5126; e-mail: jean.fotie@selu.edu
Abstract
During the development of a palladium catalyzed C–H activation cross-coupling reaction involving acyl
halides, it was noted that palladium(II) acetate catalyzes the acylative cleavage of tetrahydrofuran
(used as a solvent) at room temperature to afford the corresponding 4-chlorobutyl ester derivative.
After optimization, the reaction was shown to work well with epoxides, oxetane and tetrahydrofuran,
but only barely with oxanes at room temperature. Acyclic ethers systematically failed to react under
similar conditions, but underwent complete conversion in a microwave reactor at 100 oC.
Keywords: Palladium(II) acetate, acylative ether cleavage, haloesters, microwave
1

Introduction
Transition-metal catalysts have evolved as powerful tools in organic synthesis, mainly due to their
involvement in coupling and cross-coupling reactions, including direct C–H activation, with palladium-
catalyzed reactions being among the most prominent.1 Ethers are among the most widely used
solvents for these transformations, mainly because of their high chemical stability, and the ease with
which they are removed from the reaction mixture as a result of their low boiling points. Ethers are
also capable of dissolving both polar and nonpolar molecules, and their cleavage is normally possible
only under acidic or extremely basic conditions. Nevertheless, the cleavage of ethers as a synthetic
strategy, especially in the protection and deprotection of alcohols, is well documented.2 Furthermore,
the synthesis of chloroesters through the deconstruction of cyclic ethers by acyl halides is been known
since the early 1900.3 In recent years, several reports involving the acylative cleavage of cyclic, acyclic,
symmetrical and unsymmetrical ethers have appeared in the chemical literature. These
transformations often require the presence of Lewis acids,4 either alone or in combination with a
metal catalyst.5 In a comparative analysis, Guo and co-workers6 found that MoCl5, WCl6, NbCl5 and
TaCl5 were more efficient for the acylative cleavage of the ether C–O bond than conventional Lewis
acid catalysts such as ZnCl2, AlCl3, SnCl4 and TiCl4. It also should be mentioned that a wide range of
other metals and/or their salts or complexes, including Mg,7 Pt,5d Pd,5e Hg,5f Fe,5a Zn,4i, 8 Co,4b, 4c, 9 Rh,5b,
5c In4e and Bi4d, 4g have been used to catalyze or mediate these types of transformations. With respect
to the palladium catalyzed acylative cleavage of ethers, the only report in the chemical literature, to
the best of our knowledge, was published by Pri-Bar and Stille in 1982,5e utilizing palladium(II)
complexes including PhCH2PdCl(PPh3)2, PhCOPdCl(PPh3)2, and [(π-C3H5)2PdCl]2 in combination with
triphenylphosphine as catalysts.5e However, in order for the reaction to proceed, the addition of
triorganotin halides such as n-Bu3SnCl, Me3SnCl or Me3SnBr was required.5e
2

With the above in mind, upon unexpectedly discovering that palladium(II) acetate can catalyze the
cleavage of tetrahydrofuran in the presence of acyl halides at room temperature without requiring
any additive, it seemed appropriate to further explore the reaction as it could be of interest in organic
synthesis. Furthermore, in addition to developing a new method for the acylative cleavage of ethers,
this study provides some insights into the conditions under which ethers could still be used as a
solvent for palladium catalyzed coupling reactions involving acyl halides without a risk of acylative
cleavage side-products.
Results and Discussion
During the development of a palladium catalyzed cross-coupling reaction involving acyl halides, it was
noted that palladium(II) acetate can catalyze the cleavage of tetrahydrofuran (used as solvent), in the
presence of benzoyl chloride, to produce 4-chlorobutyl benzoate at room temperature after four
hours (Scheme 1). A quick optimization of the reaction conditions was performed, using the initial
reaction conditions as the starting point (Table 1, entry 1).
The percent conversion increased progressively as the catalyst loading was increased from 0.5 to 2
mol%, with the reaction time set to four hours. However, only at 2 mol% catalyst loading did the
reaction proceed to completion within that time frame, producing compound 1 in 98.3% yield as
indicated by GC-MS. When the time was reduced to two hours, the reaction did not reach full
conversion, and only a 87.9% yield was achieved. On the other hand, the reaction failed to produce
any product in the absence of Pd(OAc)2, or when other palladium catalysts such as Pd/C (Entry 7) and
Pd(PPh3)2Cl2 (Entry 8) were used, even upon extending the reaction time to 24 hours. In these cases,
the starting materials were recovered.
3

Scheme 1: Cleavage of THF by benzoyl chloride in the presence of Pd(OAc)2.
Table 1: Optimization of the reaction conditions
Entry Catalyst
Loading (mol%)
Time (h)
Yield 1 (%)a
53.7
1
2
3
4
5
6
7
8
Pd(OAc)2
1
4
Pd(OAc)2
0.5
1
4
39.6
Pd(OAc)2
6
58.0
Pd(OAc)2
1.5
2
4
76.7
Pd(OAc)2
4
98.3
Pd(OAc)2
2
2
87.9
Activated Pd/C
Pd(PPh3)2Cl2
2
24
24
N.R
2
N.R
Reagents and conditions: benzoyl chloride (100 mg, 0.71 mmol), THF (3 mL, 37.0 mmol), catalyst, room temperature.
aYield determined by GC–MS through a calibrated curve using tridecane as an internal standard. bN.R. = No reaction,
starting material was recovered.
4

As a result, the conditions in entry 5 (2 mol% Pd(OAc)2, 4 h) were selected for further exploration of
the reaction scope, and a wide diversity of acyl halides were reacted with THF at room temperature
for four hours (Table 2).
5

Table 2: Cleavage of THF by a series of acyl halides
Acyl halide
Product
Yield (%)a
1a: R = H, 87.4
1b: R = 4-OMe, 67.1
1c: R = 4-Cl, 78.7
1d: R = 3-NO2, 39.5
1e: R = 2-Me, 87.1
2a: R = H, 86.3
2b: R = 4-CH2Br, 80.9
3: 79.7
4: 78.8
5: 81.9
6

6a: n = 4, 87.7
6b: n = 8, 89.4
Reagents and conditions: acyl halide (1 g) in THF (1M), Pd(OAc)2 (2 mol%), 4 h, room temperature. aIsolated yield.
For each of the above reactions, a 1M solution of the acyl halide in THF was used for consistency;
however, the reaction works equally well when 1.2 equivalent of THF is used. The reaction proceeds
with both aliphatic and aromatic acyl chlorides, including diacyl chlorides (adipoyl chloride and
sebacoyl chloride), producing the corresponding product in high yields. Only 3-nitrobenzoyl chloride
resulted in a poor yield (1d, 39.5%), and most of the starting material was recovered at the end of the
reaction. This low yield might be the result of the poor solubility of 3-nitrobenzoyl chloride in the
amount of THF used, as no significant impact of the electronic effects of the aromatic ring substituents
on the reaction was observed. In fact, benzoyl chloride (1a, 87.4%), 2-methylbenzoyl chloride (1e,
87.1%) and 4-chlorobenzoyl chloride (1c, 78.7%) gave very similar isolated yields. The low yield
obtained for 4-methoxybenzoyl chloride (1b, 67.1%) is due to the fact that the reaction proceeded
beyond the deconstruction of only one THF ring, and a side-product corresponding to the addition of
two successive THF rings to the starting material (1ba, 20.8%) was also obtained. This successive
deconstruction reaction was also observed with other starting materials, but at a significantly reduced
rate, making it difficult to isolate these side-products from any of these latter reactions.
Figure 1: Side-product obtained from the addition of two successive THF rings to 4-methoxybenzoyl
chloride
7

Furthermore, acyl bromides (benzoyl bromide and 4-bromomethylbenzoyl bromide) also produced
very good yields (2a: R = H, 86.3%, 2b: R = 4-CH2Br, 80.9 %). The reaction failed when benzoyl cyanide
or methyl benzoate were used as substitutes for the acyl halides.
The acylative cleavage of other cyclic ethers including epoxides, 3,3-dimethyloxetane, 2-
methyltetrahydrofuran and tetrahydropyran were also investigated (Table 3).
8

Table 3: Cleavage of other cyclic ethers by acyl halides
Cyclic ether Acyl halide
Product
Yield (%)a
7a: X = Cl, 72.7
7b: X = Br, 98.3
8: 76.5
9a: X = Cl, 94.4
9b: X = Br, 81.0
10a: X = Cl, 24.5b
10b: X = Br, 18.6b
9

11a: X = Cl, 22.7b
11b: X = Br, 20.9b
Reagents and conditions: acyl halide (1 g), cyclic ether (1 M, unless otherwise indicated in the ESI), Pd(OAc)2 (2 mol%), 4 h, room temperature. aIsolated yield.
bReaction was stirred for 24 h.
10

For non-symmetrical cyclic ethers such as 2-phenyloxirane (7a and 7b), allyl glycidyl ether (8) and
methyltetrahydrofuran (10a and 10b), the ether ring appeared to open from the most substituted
side of the C–O bond, resulting in a product in which the ether oxygen attaches to the carbonyl of the
acyl halide through its less substituted carbon, while the most substituted carbon becomes
halogenated. Although epoxides and 3,3-dimethyloxetane produced very good yields with both
benzoyl chloride and benzoyl bromide, it should be noted that 2-methyltetrahydrofuran and
tetrahydropyran could not be cleaved within 4 hours, and produced only traces of the expected
product as indicated by GC-MS. In fact, even after 24 hours at room temperature, these two cyclic
ethers produced only limited amounts of the expected products (10a 24.5%, 10b 18.6%, 11a 22.7%,
11b 20.9%, Table 3), while acyclic ethers (diethyl ether, dibutyl ether and 2-chloroethyl ether) failed
to produce any product at room temperature, even after 24 hours.
To further explore the limits of this reaction, 2-methyltetrahydrofuran, tetrahydropyran and selected
acyclic ethers were heated at 100 oC under microwave irradiation for two hours in the presence of
Pd(OAc)2 (2 mol%) and an acyl halide (Table 4). Under these conditions, both 2-
methyltetrahydrofuran (10a, 85.1% and 10b, 81.9%, Table 4) and tetrahydropyran (11a, 92.6% and
11b, 83.2%, Table 4) produced the expected products in high yield with both benzoyl chloride and
benzoyl bromide. More importantly, dibutyl ether (12, 92.6%) also produced the expected product in
excellent yield, while diethyl ether and 2-chloroethyl ether failed to produce any product. This failure
might be due to the low boiling point of these two ethers since further studies showed that, when
the reaction temperature was lowered to 60 oC, in the microwave for two hours, even 2-
methyltetrahydrofuran and tetrahydropyran, which gave very good yields at 100 oC, produced only
traces of the desired products.
11

Table 4: Acylative cleavage of tetrahydropyran, 2-(chloromethyl)tetrahydropyran and acyclic ethers
Ethers Acyl halides Products
Yields (%)a
10a: X = Cl, 85.1
10b: X = Br, 81.9
11a: X = Cl, 92.6
11b: X = Br, 83.2
12: 96.1
13: 79.5
14: 95.9
12

15: 38.7
Reagents and conditions: acyl halide (1 g), ether (1 M, unless otherwise indicated in the ESI), Pd(OAc)2 (2 mol%), 2 h, microwave irradiation, 100 oC. aIsolated yield.
13

To explore the reaction selectivity, a series of unsymmetrical acyclic ethers including 2-
(allyloxy)ethyl)benzene, (allyloxymethyl)benzene, allyloxycyclohexane, allyloxybenzene, (2-
propoxyethyl)benzene, (2-butoxyethyl)benzene and (2-(pentyloxy)ethyl)benzene were investigated.
2-(Allyloxy)ethyl)benzene and allyloxycyclohexane, possessing an allyloxy group at one end of the
ether and a phenethyl or cyclohexyl group at the other end, respectively, produced phenethyl
benzoate (13, 79.5%) and cyclohexyl benzoate (14, 95.9%), respectively, in high yields. It is important
to note that in these products, the ethers selectively attached the moiety other than the allyl group
to the carbonyl of the acyl halide. This selectivity is also observed with (allyloxymethyl)benzene (15,
38.7%), and allyloxybenzene for which the purification of the product was impractical due to co-
elution with the starting material, even when 1.2 equivalent of the ether was used. It is possible that
the allyl group, due to its proximity to the ether oxygen, allows a π-type coordination in the transition
state with the palladium catalyst, thus resulting in the observed selectivity. In fact, (2-
propoxyethyl)benzene, (2-butoxyethyl)benzene or (2-(pentyloxy)ethyl)benzene, possessing a
phenethyl group at one end of the ether and n-propyl, n-butyl or n-pentyl at the other end,
respectively, failed to display any selectivity, producing inseparable mixtures of products.
Furthermore, while the proximity of the cyclohexyl ring to the ether oxygen seems to have no effect,
the reaction yield appeared to diminish drastically as the aromatic ring moves closer to the ether
oxygen as illustrated with compound 15. In this case, the proximity of the aromatic ring might also
create the same π-type coordination in the transition state as the allyl group, resulting in the
observed reduced yield. This hypothesis still needs to be further investigated.
14

Conclusion
A palladium(II) acetate catalyzed acylative cleavage of cyclic and acyclic ethers under neat conditions
has been developed. The reaction proceeds well with epoxides, 3,3-dimethyloxetane and
tetrahydrofuran at room temperature using a diversity of acyl halides, while with 2-
methyltetrahydrofuran, tetrahydropyran and open-chain ethers, the reaction mixtures had to be
heated at 100 oC under microwave irradiation for two hours. Furthermore, for asymmetric cyclic
ethers, the ring appeared to open from the most substituted side of the C–O bond in such a way that
the ether oxygen is attached to the carbonyl of the acyl halide through the less substituted side. For
unsymmetrical open-chain ethers possessing an allyloxy group at one end of the ether, the reaction
selectively attaches the side of the ether other than that of the allyloxy group to the carbonyl of the
acyl halide. However, this selectivity appeared to be limited to the allyloxy group, as ethers with
different groups did not display any selectivity. It is expected that this reaction, in addition to
becoming a useful synthetic tool for the preparation of different type of esters, can also help in the
selection of better ethers solvents to be used for any type of palladium(II) acetate catalyzed reaction
involving acyl halides.
Acknowledgements
J.F. acknowledges the financial support from the Louisiana Board of Regents’ Research and
Development Program, Industrial Ties Research Subprogram (ITRS) LEQSF(2015-18)-RD-B-04, while
S.V.B. acknowledges the financial support from the Louisiana Board of Regents’ NSF EPSCoR
Supervised Undergraduate Research Experiences (SURE) program LEQSF-EPS(2017)-SURE-189.
15

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Highlights
 Pd(OAc)2 catalyzed cleavage of cyclic, acyclic, symmetrical and unsymmetrical ethers
 The reaction takes place mostly at room temperature, under neat conditions
 Ethers that could not be cleaved at room temperature were heated at 100 oC in a microwave
reactor
 Some unsymmetrical ethers were cleave in a regioselective manner, but this regioselectivity is
very limited
18

Graphical Abstract
Palladium(II) acetate catalyzed acylative cleavage of cyclic and acyclic
ethers under neat conditions
Leave this area blank for abstract
Jean Fotie,a* Brandy R. Adolph,a Shreya V. Bhatta and Casey C. Grimmb
19