Di-tert-butylsilylene as a protecting group for substituted salicylic acids

Article abstract of DOI:10.1016/j.tetlet.2020.152465

The use of di-tert-butylsilyl bis(trifluoromethanesulfonate) has been used to form cyclic protecting groups for substituted salicylic acids. The reaction works well in the presence of a variety of electron-donating groups (EDG) affording the protected compounds in moderate to excellent yields (70–99%) in most cases. In addition, a handful of electron-withdrawing groups (EWG) also provided the corresponding protected silylene derivatives in good yields (77–83%). However, substrates bearing additional ortho -substitution of the carboxylic acid moiety as well as strongly deactivating groups on the aromatic ring did not undergo reaction.

Full text of DOI:10.1016/j.tetlet.2020.152465

Journal Pre-proofs
Di-tert-butylsilylene as a protecting group for substituted salicylic acids
Gabriel J. Pongdee, Kathryn G. Bell, Peri R. Prestwood, Rongson Pongdee
PII:
S0040-4039(20)30946-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152465
TETL 152465
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 August 2020
10 September 2020
13 September 2020
Please cite this article as: Pongdee, G.J., Bell, K.G., Prestwood, P.R., Pongdee, R., Di-tert-butylsilylene as a
protecting group for substituted salicylic acids, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152465
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Di-tert-butylsilylene as a protecting group for
substituted salicylic acids
Gabriel J. Pongdeea, Kathryn G. Bellb, Peri R. Prestwoodb, and Rongson
Pongdeea,b,‡
*
aVanderbilt University, Department of Chemistry, 7330 Stevenson Center, Station B,
Nashville, TN 37235, USA
bThe University of the South, Department of Chemistry, 735 University Avenue, Sewanee,
TN 37383, USA
‡ ORCID: 0000-0003-4228-6695
1

Complex molecule synthesis oftentimes requires the manipulation of protecting
groups for the successful completion of a target molecule. The chemical literature is
overflowing with reports detailing the development or repurposing of protecting groups for
a wide range of structural motifs.1 Along these lines, silicon-based protecting groups have
garnered significant attention due to their ease of preparation, facility of removal, and their
ability to be incorporated into orthogonal deprotection strategies.2
During the course of our own investigations into developing new medicinal agents
employing natural product scaffolds, we required the desymmetrization of 2,6-
dihydroxybenzoic acid (1) to use as a key building block. To accomplish this endeavor,
we envisioned the conversion of 1 to its isopropylidene derivative 2 as depicted in Scheme
1.3 However, we found the literature precedents for this transformation to be unreliable in
delivering 2 in consistently high-yield even after extensive alterations of the reaction
conditions.
Since a reliable pathway to access sufficient quantities of 2 could not be found, we
began exploring the chemical literature for alternative protecting groups that could be used
to accomplish our goals. The only other protecting group we found that has been used
for 2-hydroxybenzoic acids was to convert them to their corresponding cyclic carbonates.4
Unfortunately, the procedures we found were low-yielding and required the use of the
2

highly poisonous reagent phosgene. After further consideration, we determined that the
use of a silicon-based protecting group would be the most desirable since deprotection
may occur under essentially neutral conditions using fluoride ion. Due to the prodigious
development and use of silicon-based protecting groups over the past few decades, we
were surprised to find no examples in the chemical literature detailing a systematic study
for the use of cyclic silicon-based protecting groups for 2-hydroxybenzoic acids.5 As such,
we viewed this as an opportunity to resolve our own protecting group dilemma while also
providing researchers with an additional tool to use in their own syntheses of complex
molecules. With this in-mind, we set out to explore the feasibility of preparing cyclic silicon-
based protecting groups for salicylic acids.
Our initial efforts focused on determining, and optimizing, a general set of reaction
conditions that could be utilized for a wide array of substrates and are summarized in
Table 1. In each trial, we used di-tert-butylsilyl bis(trifluoromethansulfonate) (4) as the
silylating agent due to its higher reactivity compared to its di-chloro counterpart. We were
pleased to observe that all of the reaction conditions we attempted resulted in formation
of the desired cyclic silicon-protected salicylic acid 5 thus validating the viability of our
proposed protection method. We found that both acetonitrile (CH3CN) and N,N-
dimethylformamide (DMF) worked substantially better than tetrahydrofuran (THF) as a
reaction solvent (entries 2-4). While DMF and CH3CN produced similar yields of 5, we
elected to use acetonitrile as our solvent for technical reasons.6 Increasing the amount of
silylating agent 4 from 1.2 to 2.0 equiv resulted in a minor increase in reaction yield (entries
6 and 7). However, increasing the amount of 4 beyond 2.0 equiv did not translate into
increasingly higher amounts of product 5. An extremely noteworthy finding is that the
amount of base used was crucial to obtaining high yields of the desired silylated product
5 with 4.0 equiv being optimal (entry 7).
3

After completing our initial optimization study, we turned our attention to a
systematic evaluation of the substrate scope for our newly developed method. We sought
to determine the effects of both electron-donating (EDG) and electron-withdrawing (EWG)
groups on the overall efficiency of the reaction. Additionally, we desired to gauge the
impact on the reaction outcome of differences in location of both EDGs and EWGs on the
aromatic ring.
4

As can be seen from Figure 1, use of our optimized reaction conditions led to the
successful conversion of a number of electron-rich salicylic acids to their corresponding
cyclic di-tert-butylsilylenes in high yields. The lone exception to our findings was our
attempt to prepare the silylene derived from 6-methoxysalicylic acid 9 presumably due to
increased steric crowding surrounding the carboxylic acid reaction site. Additionally, we
determined that the silylenes derived from salicylic acids possessing an additional
phenolic functional group, such as 12-14, required the use of 5.0 equiv of 2,6-lutidine as
base for efficient conversion. Furthermore, during our synthesis of 12-14 we observed the
formation of a significant amount of precipitate that hindered the reactions from mixing
efficiently. We were pleased to find that merely switching the reaction solvent to DMF
alleviated this potential issue. An interesting finding was the observation that protection
of 2,3-dihydroxybenzoic acid resulted in the chemoselective formation of the 6-membered
di-tert-butylsilylene 12 as the major product (83%) with the competing 5-membered di-tert-
butylsilylene 13 being formed as the minor product (13%). Both isomers 12 and 13 were
readily separable by column chromatography.
5

After completing our examination of electron-rich salicylic acids, we turned our
attention to studying electron-poor salicylic acids as substrates. As depicted in Figure 2,
silylenes derived from salicylic acids containing halogen substituents 15-17 were readily
protected under our optimized reaction conditions in good to excellent yields. The lone
exception to this trend was the silylene derived from 6-chlorosalicylic acid 18, perhaps
again reflecting increased steric congestion surrounding the carboxylic acid reaction site,
once the ortho-substituent becomes larger than a methyl group. Furthermore, we
encountered significant difficulty in preparing silylenes bearing strongly deactivating
groups. For example, we were unable to synthesize the silylenes 19-21 under our
optimized or refluxing conditions. We believe that the presence of the strongly
6

deactivating nitro group significantly lowers the basicity and nucleophilicity of the C(2)-OH
group rendering it essentially unreactive toward 4. This substantial decrease in
nucleophilicity occurs through inductive effects for 19-21 and is enhanced in 19 and 21
through conjugative deactivation of the ortho-phenol by the nitro groups.7
Once we completed exploring the substrate scope for our newly developed
process, we deemed it prudent to determine the ease of removal for the cyclic silylene
protecting group. To that end, deprotection of di-tert-butylsilylene 5 is depicted in Scheme
2. Treatment of 5 with tetrabutylammonium fluoride (TBAF) in cold THF resulted in rapid,
and efficient, removal of the protecting group affording salicylic acid (3) in good yield.
7

In summary, we have demonstrated a new application for di-tert-butylsilyl
bis(trifluoromethanesulfonate) (3) in the protection of substituted salicylic acids. Our
method works well with activated salicylic acids and moderately deactivated salicylic acids
affording the corresponding cyclic di-tert-butylsilylenes in good to excellent yields.
However, a drawback of our method is sensitivity when a substituent is positioned ortho
to the carboxylic acid moiety. Additionally, the presence of strongly deactivating functional
groups, such as nitro, result in no product formation presumably due to decreased
nucleophilicity of the phenolic moiety of the salicylic acid. Nevertheless, we believe that
our method provides researchers with an attractive tool that they can exploit in synthetic
applications. Our own use of the method described here within the context of complex
molecule synthesis will be reported in due course.
Acknowledgments
We gratefully acknowledge financial support from The University of the South
administered through the Dean’s Office as part of its University Research Grants (URG)
Program. Accurate mass measurements were performed by Dr. William Boggess of the
Mass Spectrometry and Proteomics Facility at the University of Notre Dame.
8

Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/
References and notes
1. (a) Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis, 5th ed.; John
Wiley & Sons, Inc.: Hoboken, NJ, 2014. (b) Jarowicki, K.; Kocienski, P. J. Chem. Soc.,
Perkin Trans. 2001, 1, 2109. (c) Locienski, P. J. Protecting Groups, 3rd ed.: Thieme:
Stuttgart, 1994.
2. (a) Crouch, R. D. Synth. Commun. 2013, 43, 2265. (b) van Look, G.; Simchen, G.;
Heberle, J. Silylating Agents, Fluka Chemie AG, 1995.
3. (a) Weigel, W. K.; Dennis, T. N.; Kang, A. S.; Perry, J. J. P.; Martin, D. B. C. Org. Lett.
2018, 20, 6234. (b) Swamy, M. M. M.; Murai, Y.; Ohno, Y.; Jojima, K.; Kihara, A.;
Mitsutake, S.; Igarashi, Y.; Yu, J.; Yao, M.; Suga, Y.; Anetai, M.; Monde, K. Chem.
Comm. 2018, 54, 12758. (c) Mallampudi, N. A.; Reddy, G. S.; Maity, S.; Mohapatra, D.
K. Org. Lett. 2017, 19, 2074. (d) Yadav, J. S.; Mishra, A. K.; Dachavaram, S. S.;
Ganesh, K. S.; Das, S. Tetrahedron Lett. 2014, 55, 2921. (d) Zhou, J.; Matos, M.-C.;
Murphy, P. V. Org. Lett. 2011, 13, 5716. (e) Uchiyama, M.; Ozawa, H.; Takuma, K.;
Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517.
4. (a) Valgeirsson, J.; Nielsen, E. O.; Peters, D.; Mathiesen, C.; Kristensen, A. S.;
Madsen, U. J. Med. Chem. 2004, 47, 6948. (b) Kaufmann, H. P.; Seher, A.; Hagedorn,
P. Justus Liebigs Annalen der Chemie. 1954, 587, 226.
5. This reference details the gas chromatography mass spectrometry studies of cyclic di-
tert-butylsilyene derivatives of various salicylic acids. However, no experimental
procedures or yields are reported. As a result, we elected to provide the necessary data
to allow researchers to be able to reliably prepare these types of compounds: Brooks, C.
J. W.; Cole, W. J. J. Chromatogr. A. 1988, 441, 13.
6. Due to the tendency for DMF to interfere with reaction monitoring by thin-layer
chromatography and the need for additional work-up procedures, we elected to use
acetonitrile rather than DMF as our reaction solvent.
7. This argument has been used prior in a different context relating to regioselective
addition of a Grignard reagent to juglone: Stork, G.; La Clair, J. J.; Spargo, P.; Nargund,
R. P.; Totah, N. J. Am. Chem. Soc. 1996, 118, 5304.
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• Di-tert-butylsilylene serves as an effective protecting group for substituted salicylic
acids
• Electron-rich salicylic acids are protected in good to excellent yields (70-99%)
• Electron-poor salicylic acids are protected in good yields (77-83%)
• Deprotection occurs readily upon treatment with tetrabutylammonium fluoride
Declaration of interests
☒ The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in
this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
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