An efficient method for the reductive conversion of acyclic esters to ethers via a TMS-protected acetal

Article abstract of DOI:10.1016/j.tetlet.2017.06.043

We report an efficient two step process for the reduction of non-aromatic esters to the corresponding ethers via the intermediate TMS-protected acetal. The acetal formed after the first step can be carried on directly to the subsequent reduction to the ether without purification. The ester reduction step was monitored using in-situ ReactIR for disappearance of the C[dbnd]O peak, allowing for the exact determination of time and equivalents of the reducing agent. Furthermore, use of TMS-imidazole to form the acetal has allowed us to dramatically reduce the overall reaction time required for the two step procedure.

Full text of DOI:10.1016/j.tetlet.2017.06.043

Accepted Manuscript
An efficient method for the reductive conversion of acyclic esters to ethers via
a TMS-protected acetal
Alison Hart, Sarah A. Kelley, Tyler Harless, John A. Hood, Michael Tagert,
Julie A. Pigza
PII:
S0040-4039(17)30774-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.043
TETL 49035
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 May 2017
6 June 2017
13 June 2017
Please cite this article as: Hart, A., Kelley, S.A., Harless, T., Hood, J.A., Tagert, M., Pigza, J.A., An efficient method
for the reductive conversion of acyclic esters to ethers via a TMS-protected acetal, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.06.043
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Tetrahedron Letters
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An efficient method for the reductive conversion of acyclic esters to ethers via a
TMS-protected acetal
Alison Harta , Sarah A. Kelleyb, Tyler Harlessa, John A. Hooda, Michael Tagerta, Julie A. Pigzaa
aUniversity of Southern Mississippi, Department of Chemistry and Biochemistry, 118 College Drive #5043, Hattiesburg, MS 39406, United States
b University of Alabama, Department of Chemistry, 2004 Shelby Hall, Tuscaloosa, AL 35487, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report an efficient two step process for the reduction of non-aromatic esters to the
corresponding ethers via the intermediate TMS-protected acetal. The acetal formed after the first
step can be carried on directly to the subsequent reduction to the ether without purification. The
ester reduction step was monitored using in-situ ReactIR for disappearance of the C=O peak,
allowing for the exact determination of time and equivalents of the reducing agent. Furthermore,
use of TMS-imidazole to form the acetal has allowed us to dramatically reduce the overall
reaction time required for the two step procedure.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Ester reduction
Ether synthesis
Silyl acetal
ReactIR
Introduction
Ethers are commonly observed in pharma, agro, and fine chemicals as they impart desirable steric and electronic properties.1 Ethers
are most commonly synthesized via the Williamson ether synthesis starting from an alkyl halide and a non-bulky alcohol.2 Alternative
methods include the oxymercuration/demercuration of alkenes in an appropriate alcohol solvent,3 coupling of aldehydes or ketones with
alkoxysilanes,4 or acid-catalyzed condensation of alcohols,5 the latter of which is intended for symmetric ethers.
It is desirable to have robust alternative methods for the synthesis of ethers from readily available materials. The direct conversion of
an ester to ether is one such transformation. Esters are easily prepared by condensation reactions between readily available acids and
alcohols. The typical ester reduction proceeds through hydride addition to the carbonyl, resulting in a tetrahedral aluminate acetal
intermediate. Under normal conditions this acetal will collapse, ejecting the ether oxygen and resulting in an aldehyde, which may be
further reduced to the primary alcohol depending on the reducing agent.6 To retain the C-O-C backbone and prevent over-reduction, the
acetal must be trapped or converted to the oxonium ion intermediate.
Several examples exist for the ester to ether conversion using this strategy.7-13 Of the ester→ether methods, each suffers a drawback
such as 1) use of only cyclic examples9,10 (which are free of the complication of over-reduction), 2) no tolerance for branching11,13 or
works only with branching,8 3) over-reduction to the alcohol as a complication,12 or 4) long reaction times while at cold temperatures.7
To effectively develop a practical and efficient method for ester to ether conversion, we monitored the reduction in situ by using an
infrared probe (ReactIR), which is ideal for studying functional group transformations.14
———
 Corresponding author. E-mail address: julie.pigza@usm.edu (J.A. Pigza)

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Results and Discussion
We began with a diverse library of ester substrates, synthesized from the carboxylic acid and alcohol precursors via either an acid
chloride15 or a coupling reagent (EDC).16 Ester 1a was chosen as a model system as it contained a para-substituted aromatic ring to
allow for ready identification by TLC and NMR and a long carbon chain to attenuate volatility of the product. Ester reductions were run
in a 2-necked round bottom flask to be able to accommodate the ReactIR probe. The ReactIR14a generates one IR slice, in units of
absorbance versus wavenumbers, every minute. As time progresses during the reaction, a 3D waterfall plot is generated (time being the
3rd axis).
Fig 1. ReactIR plot of DIBAL reduction of ester 1a.
Using this method, DIBAL (solution in either hexanes or DCM) was added dropwise to ester 1a in DCM at ‒78 °C at varying
equivalents (approximately 1 drop every 3-5 seconds). During this time, the ester carbonyl peak at 1726 cm‒1 was monitored and was
found to decrease from 0.52 to 0.02 absorbance units over a period of 10 minutes (approximate time it takes to add DIBAL, Figure 1).
The decrease in absorbance is due to both C=O reduction and dilution of the reaction through the addition of DIBAL (1 M solution).
The absorbance at 1726 cm‒1 never disappeared completely. At this point, the reaction was quenched with saturated aqueous NH4Cl and
1H NMR showed complete consumption of the starting ester using 1.2 equivalents of DIBAL in only 10 minutes of reaction time.
With proof of concept established for ReactIR monitoring of the ester reduction in place, we then moved forward with finding a
suitable trapping reagent to trap the acetal and prevent breakdown to the aldehyde or over-reduction to the alcohol. We found that TMS-
imidazole15 was a superior reagent to others such as TMSCl or TMSOTf and provided the TMS-acetal 2a in full conversion and short
times (Table 1). In total, conversion of the ester to the TMS-protected acetal took place in 45 min, 10 min for the DIBAL reduction and
35 min for TMS protection (entry 4). This is drastically shorter than reaction times found in the literature for reduction of the ester to an
acetate-protected acetal (12-14 h on average).5 Moreover, we found this reaction could be run at warmer temperatures without
formation of the aldehyde or alcohol (‒40 °C, entry 5). While column chromatography could be performed on the acetal, it was more
advantageous for material throughput to carry on the acetal directly to the ether.
Table 1. Acetal Trapping with Various TMS-Reagentsa
entry
1
TMS-X
base
---
temp
yield
---
TMSOTf
‒78 °C
2
3
4
5
6
TMSCl
TMSCl
pyridine
‒78 °C
‒78 °C
‒78 °C
‒40 °C
0 °C
20%
69%
98%
94%
32%
N-Me-imid
TMS-imid
TMS-imid
TMS-imid
---
---
---
aSee the Supporting Information for conditions. bYields are based on the crude weight after NMR.
We also screened the reduction of acetal 2a to the ether, via oxonium ion 3a, using a combination of Lewis acid and hydride reagents
comparable to those utilized in the literature.4,7,18 Optimal combinations were found when the Lewis acid was added dropwise to a
mixture of the acetal and hydride at ‒78 °C (entry 4, 84%, Et3SiH and TMSOTf). Excess of each reagent had to be used to maintain
high yields (entry 4 versus 5). Lowering the amount of both reagents proved detrimental to the yield (entry 5), as did using a more
nucleophilic hydride source (Bu3SnH, entry 2)
Using the optimal conditions identified in Tables 1 and 2, we exposed a variety of esters 1a-n to this conversion (Table 3). By using
ReactIR to monitor the ester reduction step, we could identify the precise equivalents of DIBAL required to reduce specific substrates to
the acetal (2a-n). As such, we could make some general observations that bulky substituents on the ester – on either the carbonyl (entry
6, 1.6 equiv) or ether oxygen side (entry 4, 1.7 equiv) – require more than the usual 1.2 equivalents to reduce completely. Most notably,
all esters that we attempted were able to be reduced and converted to the TMS-acetal with complete conversion in short time (40 min).
The crude acetal was then subjected to etherification conditions using Et3SiH and TMSOTf to form ethers 4a-n.
Table 2. Acetal Conversion to the Ether via Oxonium Ion Formation and Hydride Reductiona
entry
1
hydride
Bu3SnH
Lewis acid
equivb
2.5
yieldc
59%
BF3•OEt2
2
3
4
5
6
Bu3SnH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
TMSOTf
BF3•OEt2
TMSOTf
TMSOTf
2.5
2.5
2.5
1.2
2.5
47%
46%
84%
50%
0%
MgBr2•OEt2

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3
aSee the Supporting Information for conditions. bEquivalents are the same for both the Lewis acid and hydride. cYields are reported after isolation from silica gel
chromatography.
We have found using this method that esters containing alkyl groups (entries 1, 2, 4, 5), halides (entry 3), or cyclic esters (entry 11)
tend to convert in good yields. Bulky alkyl groups are tolerated on the ether oxygen (entry 4, 73%) but not on the ester carbonyl (entry
6, 0%). Pendant alkenes (entries 7-8) are tolerated in moderate yields and alkynes to a lesser extent (entry 9). If a benzyl group is
attached to the ether oxygen (as the R2 group), the yield of ether is also decreased (entry 10, 1j). We believe that this occurs due to loss
of the benzyl group during oxonium ion formation (3a). To support this hypothesis, we utilized both electron-donating and electron-
withdrawing groups on the benzene ring, 1k and 1l, respectively. As expected, an electron-donating group (p-MeO, 1k), which would
further stabilize the loss of the benzyl group, gave no product, while an electron-withdrawing group (p-CF3, 1l), gave a similar yield as
benzyl. If a phenyl group is directly attached to the ether oxygen (R2), then no acetal is formed and only over-reduction is observed (not
shown in Table 3). The results in Table 3 show some of the limitations of the current method, one of which is that aryl ethers cannot be
synthesized by this method. We have tried additives such as 2,6-di-tert-butylpyridine (DTBP) to counteract the possible formation of
triflic acid during the reaction (TfOH), but this did not improve the yields at all.19
In cases where the yield of the ether product is low, such as entries 9 and 10, we have found that the symmetric ether is forming (9
in Scheme 1). We believe that this occurs through a competing pathway during formation of the oxonium ion. The Lewis acid
(TMSOTf) can bind to either oxygen of the acetal, forming intermediate 5 with the Lewis acid bound to the oxygen resulting from the
carbonyl or intermediate 6 with the Lewis acid bound to the ether oxygen. These two species are likely in equilibrium with only a slight
preference for 5 due to the electron-donating TMS group. Following the desired pathway (Route 1, Scheme 1), collapse of the Lewis-
acid bound acetal will lead to oxonium 3. Reduction with Et3SiH, which is present in the reaction from the beginning, will lead to the
desired ether product 4. If the R2 group is such that it can stabilize a carbocation, such as with the benzyl substituents (Table 3, entry
10), then we would expect that the aldehyde 8 can also form.
Table 3. Ester Substrate Scope for Conversion to the Ethera
entry
ester
DIBAL acetal
(equiv) yieldb
ether
ether
yieldc
1
2
1.2
1.2
98%
98%
84%
82%
3
4
1.6
1.7
81%
97%
94%
73%
5
6
1.5
1.6
91%
89%
59%
0%
7
8
1.2
1.2
95%
65%
56%
55%
9
1.2
92%
39%

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10
1.2
1.2
1.2
93%
95%
98%
36%
0%
30%
11
1.2
1.2
98%
98%
59%
80%
aSee the Supporting Information for conditions. bAcetal yields are based on the weight of the crude material and were of sufficient purity to carry on directly to the ether.
cEther yields are reported after isolation from silica gel chromatography.
The undesired pathway would form an alternative oxonium ion 7, which can then form symmetric ether 9 (via reduction of 7 to the
silyl-protected alcohol, not shown, and coupling with another molecule of oxonium 7),4 aldehyde 8, or the alcohol 10. In most cases, the
alcohol is observed as well when the symmetric ether is observed. The identity of symmetric ether 9 was verified by 1H NMR using an
authentic sample prepared using this method to convert the ester to the ether (Table 3, entry 2). Ether 4b is an example of a substrate
that could not be made using the Williamson ether synthesis, as the main product formed in this case was found to be styrene via an E2
reaction.20 We are currently exploring the use of DFT computations to better understand the two competing pathways involved in
oxonium ion formation with the goal of improving the efficiency of the second step of the reaction involving reduction of the acetal to
the ether.
In conclusion, we have developed an efficient two-step reductive conversion of esters to ethers using ReactIR to monitor the
reduction of the carbonyl peak, which provided the exact equivalents of reducing agent required. We have identified TMS as an ideal
protecting group, allowing us to shorten the time considerably to form the acetal and providing the ether. We have also demonstrated
substrate compatibilities using this method.
Scheme 1. Oxonium-ion formation and two competing pathways
Acknowledgments
The authors gratefully acknowledge the Eppley Foundation for Scientific Research and the University of Southern Mississippi
(Department of Chemistry and Biochemistry and the Vice President for Research) for funding. We also would like to recognize the
funds for acquisition of our 400 MHz Bruker NMR (CHE-0840390). A.H. acknowledges the NSF NRT Interface program (DGE-
1449999) for traineeship support.
References
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Supplementary Material
Supplementary data associated with this article contains general experimental procedures for ester reduction to the acetal and acetal
reduction to the ether as well as characterization data for compounds 1a, 2a, and 4a.

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Highlights
 A non-traditional method for ester reduction to the ether is described
 ReactIR is utilized to determine exact DIBAL equivalents for the reduction
 Reaction times are shortened considerably compared to the literature
 The two-step procedure does not require purification of the intermediate acetal

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Tetrahedron Letters
Graphical Abstract
An Efficient Method for the Reductive
Leave this area blank for abstract info.
Conversion of Acyclic Esters to Ethers via a
TMS-Protected Acetal
Alison P. Hart, Sarah A. Kelley, John A. Hood, Tyler M. Harless, Michael Tagert, Julie A. Pigza*