One-pot synthesis of epoxides from benzyl alcohols and aldehydes

Article abstract of DOI:10.3762/bjoc.14.205

A one-pot synthesis of epoxides from commercially available benzyl alcohols and aldehydes is described. The reaction proceeds through in situ generation of sulfonium salts from benzyl alcohols and their subsequent deprotonation for use in Corey–Chaykovsky epoxidation of aldehydes. The generality of the method is exemplified by the synthesis of 34 epoxides that were made from an array of electronically and sterically varied alcohols and aldehydes.

Full text of DOI:10.3762/bjoc.14.205

One-pot synthesis of epoxides from benzyl alcohols
and aldehydes
Edwin Alfonzo, Jesse W. L. Mendoza and Aaron B. Beeler*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2308–2312.
Department of Chemistry, Boston University, Boston, Massachusetts
02215, United States
doi:10.3762/bjoc.14.205
Received: 09 July 2018
Email:
Accepted: 21 August 2018
Published: 03 September 2018
Aaron B. Beeler* - beelera@bu.edu
* Corresponding author
Associate Editor: D. Y.-K. Chen
Keywords:
© 2018 Alfonzo et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Corey–Chaykovsky; epoxide; heterocycle; one-pot; ylide
Abstract
A one-pot synthesis of epoxides from commercially available benzyl alcohols and aldehydes is described. The reaction proceeds
through in situ generation of sulfonium salts from benzyl alcohols and their subsequent deprotonation for use in Corey–Chaykovsky
epoxidation of aldehydes. The generality of the method is exemplified by the synthesis of 34 epoxides that were made from an array
of electronically and sterically varied alcohols and aldehydes.
Introduction
Epoxides have historically served as strategic functional groups tion has seen major advancement since its original disclosure,
in target-oriented synthesis [1-4]. Common examples of their particular in the area of asymmetric synthesis [22-24]. Other
utility include stereospecific ring opening [5-7], rearrange- notable advancements include the expansion of its scope by
ments into carbonyls [8-17], and application to cascade or using organic bases and a one-pot oxidation/epoxidation se-
domino reactions [18,19]. More recently, our group has used quence of benzyl alcohols with manganese dioxide and an
benzyl epoxides for the photoredox generation of carbonyl exogenous sulfonium salt [25,26]. Despite these efforts, the
ylides which are leveraged in the synthesis of cyclic ethers [20]. synthesis of epoxides using this powerful transformation still
This work has led us to search for a general and operationally often requires multiple steps due to the need to independently
simple method to generate benzyl epoxides. One of the most synthesize the sulfonium salt. Typically, the salt is synthesized
powerful methods to access epoxides is through the from nucleophilic displacement of benzyl halides but the work
Corey–Chaykovsky reaction [21] which uses sulfonium ylides by Aggarwal and co-workers [27] has demonstrated that these
and their subsequent reaction with carbonyl groups. This reac- can be generated from inexpensive benzyl alcohols in the pres-
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Beilstein J. Org. Chem. 2018, 14, 2308–2312.
ence of tetrafluoroboric acid and a thio-trapping agent. Unfortu- 21 performed well providing synthetically useful quantities of
nately, isolation of the salt was still required for use in epoxida- the desired epoxides. Finally, epoxides containing electron-defi-
tion of carbonyl groups.
cient aryl groups are also available with this method, as exem-
plified by the synthesis of compounds 22 and 23, which were
Inspired by these aforementioned precedents, we hypothesized obtained in good yields on a 10 mmol scale. With respect to the
that a process, using commercially available starting materials, reactivity of the benzyl alcohols, electron-rich alcohol 4 showed
wherein the sulfonium salt could be generated in situ from faster reaction rates and yields, presumably due to faster and
benzyl alcohols and deprotonated would provide an efficient more efficient formation of the sulfonium salt through a
protocol for the synthesis of epoxides in a single reaction. para-quinonemethide (p-QM) intermediate. Furthermore, the
Herein, we describe the realization of this methodology and its lower diastereomeric ratios (dr) observed for benzyl alcohol
use in the synthesis of epoxides that are often unattainable by 4 may be due to competing p-QM formation at the betaine
standard epoxidation methods.
intermediate prior to epoxide formation through displacement
of THT. This is supported by example 9 which contained
a para-methoxy group at the aldehyde component but was
Results and Discussion
After evaluating numerous approaches toward the proposed isolated as a single diastereomer [28]. Functional groups
reaction and subsequent optimization, we found that the sulfo- that are not compatible with this method include phenols, esters,
nium salt 2 (Scheme 1) could be generated in situ from benzyl and ketones (Figure 1). The latter is most likely due to
alcohol (1) in the presence of slight excess of tetrafluoroboric competing enolization of the ketone leading to undesired reac-
acid in diethyl ether (HBF4·Et2O) and tetrahydrothiophene tivity [29].
(THT). Notably, the use of acetonitrile (MeCN) as a solvent
was critical for maintaining a homogeneous reaction and a Many of the epoxides that are of interest to us are highly
successful outcome. We also observed that sodium hydride oxygenated on the aryl rings and can be used for the synthesis
(NaH) was the only base that successfully afforded the desired of numerous bioactive molecules [27,30-34]. Attempts at
epoxide 3, typically in excellent and reproducible yields synthesizing one of these epoxides with the standard mCPBA
(other bases screened included KOt-Bu, LiHMDS, TBD epoxidation (Scheme 2) led exclusively to rearranged aldehyde
[25], and KOH). Furthermore, diluting the reaction after forma- 24, presumably promoted by the carboxylic acid byproduct of
tion of the sulfonium salt, and cooling it in an ice bath, mCPBA. Unfortunately, attempts to remedy this by using
proved essential to control the exotherm caused by the depro- buffered conditions only led to an mCPBA-epoxide adduct 25
tonation.
[35].
Having established a robust method, we then turned our atten- However, the one-pot reaction was highly successful with three
tion to evaluating the scope of the reaction using three electroni- electron-rich benzyl alcohols 26, 27, and 28 all bearing multiple
cally varied benzyl alcohols 1, 4, and 5 (Figure 1) on a prepara- oxygenation and with a large panel of electron-rich aldehydes
tive scale (3 mmol, 5 mmol, 10 mmol). A range of aryl alde- (Figure 2). The reaction was highly successful even when
hydes worked well including para-nitro (7), ortho-methyl (8), both partners were poly-oxygenated (29–32). Other notable
and para-methoxy groups (9). Other notable examples include functionalities include heteroaromatics 34, alkenes 36,
heterocycles, such as basic pyridines, thiophenes, and furans halides 33 and 37, and a benzyl protected alcohol 38.
16–18. Additionally, aliphatic 13 and 20 and alkenyl aldehydes Furthermore, electron-donating groups were tolerated
Scheme 1: One-pot synthesis of epoxides from benzyl alcohols and aldehydes.
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Beilstein J. Org. Chem. 2018, 14, 2308–2312.
Figure 1: Scope of the one-pot synthesis of epoxides from benzyl alcohols and aldehydes.
Scheme 2: mCPBA epoxidation of electron-rich stilbene derivatives.
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Beilstein J. Org. Chem. 2018, 14, 2308–2312.
Figure 2: Scope of the reaction with electron-rich alcohols and aldehydes.
in all positions on the aryl groups (41–44). Although the
Corey–Chaykovsky reaction has been well studied, nearly all
the examples shown in Figure 2 represent new compounds and
an extension to this methodology.
Supporting Information
Supporting Information File 1
Experimental procedures and characterization for all new
compounds described herein.
Conclusion
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-205-S1.pdf]
In conclusion, we have developed a general and simple method
to access benzylic epoxides through the Corey–Chaykovsky
reaction between benzyl alcohols and aldehydes. This method
provides expedient access to epoxides from commercially avail-
able materials in a step and time economical fashion. In particu-
lar, we have demonstrated its applicability to the synthesis of
epoxides that were generally unattainable using the standard
mCPBA epoxidation.
Acknowledgements
Financial support from Boston University and National Science
Foundation (ABB CHE-1555300) is gratefully acknowledged.
We thank Dr. Norman Lee (Boston University) for high-resolu-
tion mass spectrometry data. NMR (CHE-0619339) and MS
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Beilstein J. Org. Chem. 2018, 14, 2308–2312.
24.Illa, O.; Namutebi, M.; Saha, C.; Ostovar, M.; Chen, C. C.;
(CHE0443618) facilities at Boston University are supported by
the NSF.
Haddow, M. F.; Nocquet-Thibault, S.; Lusi, M.; McGarrigle, E. M.;
Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 11951–11966.
doi:10.1021/ja405073w
ORCID® iDs
Jesse W. L. Mendoza - https://orcid.org/0000-0002-6690-7639
25.Phillips, D. J.; Graham, A. E. Synlett 2010, 769–773.
doi:10.1055/s-0029-1219359
Aaron B. Beeler - https://orcid.org/0000-0002-2447-0651
26.Phillips, D. J.; Kean, J. L.; Graham, A. E. Tetrahedron 2013, 69,
6196–6202. doi:10.1016/j.tet.2013.05.036
27.Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T.
Angew. Chem., Int. Ed. 2003, 42, 3274–3278.
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