Synthesis of Functionalized Aliphatic Acid Esters via the Generation of Alkyl Radicals from Silylperoxyacetals

Article abstract of DOI:10.1002/asia.202100723

We describe a catalytic method for the synthesis of a variety of functionalized aliphatic acid esters using silylperoxyacetals, which are versatile alkyl radical precursors with a terminal ester moiety. In the presence of an appropriate transition-metal catalyst, the in situ generation of alkyl radicals and the subsequent bond-forming process proceeds smoothly to afford synthetically valuable aliphatic acid derivatives. The present method can be applied to the efficient synthesis of a pharmaceutically important 1,1-diarylalkane motif. In addition, a novel strategy for the synthesis of structurally diverse hydroxy acid derivatives via a C?O bond formation process that utilizes TEMPO has been developed.

Full text of DOI:10.1002/asia.202100723

doi.org/10.1002/asia.202100723
Communication
Synthesis of Functionalized Aliphatic Acid Esters via the
Generation of Alkyl Radicals from Silylperoxyacetals
Akira Matsumoto,*[a] Yoko Shiozaki,[b] Shunya Sakurai,[b] and Keiji Maruoka*[a, b, c]
Abstract: We describe a catalytic method for the synthesis
of a variety of functionalized aliphatic acid esters using
silylperoxyacetals, which are versatile alkyl radical precur-
sors with a terminal ester moiety. In the presence of an
appropriate transition-metal catalyst, the in situ generation
of alkyl radicals and the subsequent bond-forming process
proceeds smoothly to afford synthetically valuable aliphatic
acid derivatives. The present method can be applied to the
efficient synthesis of a pharmaceutically important 1,1-
Figure 1. Selected examples of functionalized aliphatic acid derivatives.
diarylalkane motif. In addition, a novel strategy for the
synthesis of structurally diverse hydroxy acid derivatives via
a CÀ O bond formation process that utilizes TEMPO has
been developed.
ester moiety (Scheme 1a).[4] While this process was successfully
merged with further transformations such as dimerization,
chlorination, or radical conjugate addition to provide function-
alized aliphatic acid esters, the same strategy could not be
applied to other hemiacetal species, probably due to their
unstable nature and the lack of strain energy required to
promote the ring-opening process.[5]
Recently, synthetic methods for the generation of alkyl
radicals from alkylsilyl peroxides via β-scission and subsequent
functionalization in the presence of transition-metal catalyst
have been developed.[6] Using these methods, a variety of
functional groups can be introduced to the in situ generated
alkyl radicals, which have a terminal keto group, to provide the
corresponding aliphatic ketone derivatives. In addition, we have
prepared acetal-derived alkylsilyl peroxides from sugar
derivatives.[6f] These compounds can be transformed into
polyoxygenated linear formyl esters via an iron-catalyzed CÀ C
bond cleavage/CÀ C bond formation sequence. As part of these
ongoing studies, we herein report a practical approach for the
synthesis of functionalized aliphatic acid esters via a radical
process (Scheme 1b). This method uses silylperoxyacetals, an
underexplored class of alkylsilyl peroxides prepared from readily
Aliphatic acids and their derivatives are ubiquitous fundamental
structural motifs that have found a variety of applications, from
biologically active molecules[1] to monomer units in material
science (Figure 1).[2] Since most of these compounds contain
various functional groups on their aliphatic carbon chains, the
development of a universal strategy for the synthesis of
functionalized aliphatic acid derivatives is of great importance.
Thus, given the outstanding ability of radical species to serve in
diverse carbon–carbon or carbon–heteroatom bond-forming
reactions, the generation and functionalization of alkyl radical
intermediates may potentially represent an attractive solution
to this problem.[3] Although many protocols that use well-
designed precursors for the generation of alkyl radicals have
been developed so far, very few of these precursors lead to
alkyl radicals with terminal carboxy or ester groups. For
example, Schaafsma and coworkers have reported that a single-
electron oxidation of a cyclopropanone hemiacetal affords a
transient alkoxy radical that immediately induces a strain-
releasing ring-opening via β-scission to generate a terminal
[a] Dr. A. Matsumoto, Prof. Dr. K. Maruoka
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo, 606-8501 Kyoto (Japan)
E-mail: matsumoto.akira.3c@kyoto-u.ac.jp
maruoka.keiji.4w@kyoto-u.ac.jp
[b] Y. Shiozaki, Dr. S. Sakurai, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, 606-8502 Kyoto (Japan)
[c] Prof. Dr. K. Maruoka
School of Chemical Engineering and Light Industry
Guangdong University of Technology
510006 Guangzhou (P. R. China)
Scheme 1. Synthesis of aliphatic acid esters via radical functinoalization
(FG=functional group).
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100723
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available cyclic ketones. The versatility of these compounds as a
precursor for aliphatic acid esters was investigated by applying
them in a series of radical functionalizations.[7] Furthermore, the
synthesis of hydroxy acid derivatives via the iron-catalyzed
aminooxygenation of the in situ generated alkyl radicals was
also demonstrated.
arylated ester 8 under mild reaction conditions. In addition to
copper catalysts, the iron salt FeCl3 was also found to facilitate
the generation of an alkyl radical from 1a, and the subsequent
addition to diphenylethylene furnished 9 in good yield.
One of the products 9 can be regarded as a precursor of an
aliphatic acid with a 1,1-diarylalkane structure, an important
We commenced our study using silylperoxyacetal 1a
(Scheme 2), which is prepared from cyclohexanone in three
steps (for details, see the Supporting Information). First, the
applicability of 1a as an alkyl radical precursor in a variety of
transition-metal-catalyzed radical functionalizations was eval-
uated. As shown in Scheme 2, 1a could be used in a variety of
bond-forming reactions (CÀ N, CÀ O, CÀ C, CÀ B, and CÀ Si
bonds).[6] The reaction of 1a with benzamide using a CuI/1,10-
phenanthroline (L1) catalytic system furnished the correspond-
ing amide product 2 in high yield. The formation of a CÀ O
bond was also possible via the coupling with a benzoic acid
derivative or a phenol derivative to afford 3 and 4, respectively.
An arylacetylene could also be used as a coupling partner
resulting in the formation of a Csp3À Csp bond and providing
alkynylated ester 5 in 44% yield. In addition, radical borylation
and silylation reactions furnished the corresponding products 6
and 7, albeit in moderate yields. The copper-catalyzed forma-
tion of a Csp3À Csp2 bond using phenylboronic acid afforded
motif that exists in
a
number of biologically active
compounds.[8] Thus, we attempted to construct the substructure
of a potent thromboxane A2 (TXA2)-receptor antagonist (Fig-
ure 1) using an iron-catalyzed radical addition to the corre-
sponding diarylethylene (Scheme 3).[6f] Starting from a silylper-
oxyacetal containing a five-membered ring (1b), the reaction
with diarylethylene 10 in the presence of a catalytic amount of
FeCl3 gave the desired alkene 11 in good yield as a mixture of E
and Z isomers. The isomers were reduced efficiently using a
catalytic amount of palladium on carbon under an atmosphere
of hydrogen gas to furnish 1,1-diarylalkane 12. The subsequent
deprotection of the para-substituent on the aryl ring of 12
resulted in the formation of 13. Mesylation of 13, followed by
the nucleophilic substitution with sulfonamide 14, afforded 15,
which is an ethyl ester derivative of a TXA2-receptor antagonist.
These results demonstrate that various functionalized aliphatic
acid esters, including a pharmaceutically relevant motif, can be
efficiently synthesized by our method using silylperoxyacetals.
Having confirmed the utility of silylperoxyacetals as pre-
cursors for aliphatic acids, we next investigated expanding the
scope of valuable aliphatic acid derivatives that can be created
using our method. Hydroxy acids are an attractive synthetic
target due to the crucial roles they play in the metabolic system
and in functional materials such as surfactants or biodegradable
plastics.[9] While the previously described methods for the
formation of CÀ O bonds using 1a can provide the correspond-
ing hydroxy acid derivatives such as 3 and 4 (Scheme 2), these
products present a potential problem for further transforma-
tions as it is challenging to selectively deprotect the benzoyl or
aryl groups while keeping the ester moiety intact. Thus, the
introduction of an alternative oxygen source that can be
selectively and flexibly transformed would be preferrable. In
this regard, we focused on the formation of a CÀ O bond via the
reaction of alkyl radicals with 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO).[10] As outlined in Scheme 4, a single-electron
transfer (SET) from a suitable transition-metal catalyst to
silylperoxyacetal 1a would form alkoxy radical I. The subse-
quent ring-opening of I via β-scission would generate alkyl
Scheme 2. Transition-metal-catalyzed functionalizations using silylperoxya-
cetal 1a. For detailed reaction conditions, see the Supporting Information.
Scheme 3. Synthesis of TXA2-receptor antagonist derivative 15.
Scheme 4. Proposed mechanism for the reaction of 1a with TEMPO.
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radical II, which can react with TEMPO to furnish the desired
product 16a. In this catalytic system, TEMPO can also act as a
reducing reagent for the transition-metal catalyst. We also
thought that the weak NÀ O bond of the resulting TEMPO
adduct could be selectively cleaved giving access to various
oxygen functionalities (hydroxy, formyl, or carboxyl groups)
depending on the reaction conditions used.[10b,f]
The optimization of the reaction conditions was carried out
using silylperoxyacetal 1a and 2.0 equivalents of TEMPO. The
screening of transition-metal catalysts, ligands, and solvents
revealed that FeCl3 efficiently promotes the desired reaction in
addition, silylperoxyacetals 1g and 1h, derived from 2-
indanone and 2-adamantanone, respectively, gave structurally
unique hydroxy acid derivatives 16g and 16h.
Subsequently, we conducted the reactions using acyclic
silylperoxyacetals 1j–1l (Table 2). When 1j, derived from
isopentyl methyl ketone, was used isopentyl-substituted alkoxy-
amine 16j was selectively obtained in 43% yield. Moreover,
silylperoxyacetals prepared from aliphatic aldehydes could also
be applied to this transformation. For example, the reaction of
citronellal-derived peroxyacetal 1k successfully furnished the
corresponding TEMPO adduct 16k without affecting the
terminal olefin moiety. Notably, a deoxyribose-derivative 1l,
which contains both a silyl-protected acetal and a free hydroxy
moiety, could be transformed into erythritol derivative 16l in
moderate yield, indicating that our method has the potential to
be applied to the functionalization of complex molecules.
Depending on the CÀ C bond that is cleaved via the β-
scission of the alkoxy radical intermediate, two possible
products are potentially formed during the reactions that use
unsymmetric silylperoxyacetals 1m–1o (Scheme 5). In these
cases, we observed that the cleavage of the CÀ C bond occurs in
a highly regioselective manner. Specifically, the reaction of 2-
°
DMSO at 80 C without the need for an external ligand,
affording TEMPO adduct 16a in high yield within an hour. It
should be noted that the use of FeCl2 instead of FeCl3 also gave
16a in a good yield (see S26 in the Supporting Information).
These results indicate that both Fe(II) and Fe(III) species would
be involved in the catalytic cycle, which is consistent with the
proposed mechanism described in Scheme 4. Under the
optimal conditions, the reactivity of a series of cyclic silylperox-
yacetals was investigated (Table 1). In general, the reactions
proceed smoothly to furnish the corresponding TEMPO adducts
16 as hydroxy acid derivatives in good to high yields. Not only
was six-membered cyclic silylperoxyacetal 1a reactive under
these conditions, but five- and seven-membered derivatives 1b
and 1c were also active. The desired products 16a–c were
obtained in good yield regardless of the difference in the strain
energy of the ring systems. The reaction of silylperoxyacetal 1d
also worked well to give the corresponding phenyl-substituted
product 16d. Several functional groups such as cyclic ether
(1e), N-tert-butoxycarbonyl amine (1f), and cyclic acetal (1i)
moieties were well tolerated, and the corresponding products
16e, 16f, and 16i were obtained in good to high yields. In
Table 2. Scope with respect to acyclic silylperoxyacetals.[a]
Table 1. Scope with respect to cyclic silylperoxyacetals.[a]
[a] Reaction conditions: 1 (0.10 mmol), TEMPO (0.20 mmol), and FeCl3
°
(20 mol%) in DMSO (1.0 mL) at 80 C for 1 h under N2 atmosphere. Yields
of isolated product are shown.
[a] Reaction conditions: 1 (0.10 mmol), TEMPO (0.20 mmol), and FeCl3
°
(20 mol%) in DMSO (1.0 mL) at 80 C for 1 h under N2 atmosphere. Yields
of isolated products are shown. [b] 1.1 g of 1a was used. [c] The reaction
was quenched with [nBu4N]F, followed by the addition of MeI.
Scheme 5. Reactions of unsymmetric silylperoxyacetals with TEMPO.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: CÀ C bond cleavage · β-scission · alkyl radicals ·
silylperoxyacetals · iron-catalysis · hydroxy acids
[1] Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochem-
icals (Eds.: C. Lamberth, J. Dinges), Wiley-VCH, Weinheim, 2016.
[2] a) A. Köckritz in Liquid Phase Aerobic Oxidation Catalysis: Industrial
Applications and Academic Perspectives (Eds.: S. S. Stahl, P. L. Alsters),
Wiley-VCH: Weinheim, 2016; pp. 331–348; b) E. A. Rainbolt, K. E. Wash-
ington, M. C. Biewer, M. C. Stefan, Polym. Chem. 2015, 6, 2369–2381;
c) N. G. Ricapito, C. Ghobril, H. Zhang, M. W. Grinstaff, D. Putnam, Chem.
Rev. 2016, 116, 2664–2704.
[3] a) Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi), Wiley-VCH,
2001; b) Encyclopedia of Radicals in Chemistry, Biology and Materials
(Eds.: C. Chatgilialoglu, A. Studer), John Wiley & Sons, Ltd, Chichester,
UK, 2012; c) S. Z. Zard, Radical Reactions in Organic Synthesis; Oxford
University Press, Oxford, 2003; d) M. Yan, J. C. Lo, J. T. Edwards, P. S.
Baran, J. Am. Chem. Soc. 2016, 138, 12692–12724; e) A. Studer, D. P.
Curran, Angew. Chem. Int. Ed. 2016, 55, 58–102; Angew. Chem. 2016,
128, 58–106.
Scheme 6. Subsequent transformations of the TEMPO adducts 16a and 16i.
methyl-substituted silylperoxyacetal 1m selectively afforded
16m because the CÀ C bond cleavage occurs at the more
substituted bond of the acetal center. An aryl-fused silylperox-
yacetal 1n also showed high regioselectivity, furnishing 16n via
the trapping of TEMPO at the benzylic position. It is also
noteworthy that the reaction of 1o, which contains an electron-
withdrawing methoxycarbonyl group at the 2-position, also
proceeded smoothly via the selective cleavage of the CÀ C bond
at the more substituted bond of the acetal center affording
16o in a good yield.
[4] a) S. E. Schaafsma, H. Steinberg, T. J. de Boer, Recl. Trav. Chim. Pays-Bas
1966, 85,70–72; b) S. E. Schaafsma, R. Jorritsma, H. Steinberg, T. J.
de Boer, Tetrahedron Lett. 1973, 11, 827–830.
[5] M. Murakami, N. Ishida, Chem. Lett. 2017, 46, 1692–1700.
[6] a) R. Sakamoto, S. Sakurai, K. Maruoka, Chem. Eur. J. 2017, 23, 9030–
9033; b) R. Sakamoto, T. Kato, S. Sakurai, K. Maruoka, Org. Lett. 2018, 20,
1400–1403; c) S. Sakurai, T. Kato, R. Sakamoto, K. Maruoka, Tetrahedron
2019, 75, 172–179; d) T. Seihara, S. Sakurai, T. Kato, R. Sakamoto, K.
Maruoka, Org. Lett. 2019, 21, 2477–2481; e) J.-C. Yang, L. Chen, F. Yang,
P. Li, L.-N. Guo, Org. Chem. Front. 2019, 6, 2792–2795; f) Y. Shiozaki, S.
Sakurai, R. Sakamoto, A. Matsumoto, K. Maruoka, Chem. Asian J. 2020,
15, 573–576; g) S. Sakurai, S. Tsuzuki, R. Sakamoto, K. Maruoka, J. Org.
Chem. 2020, 85, 3973–3980; h) L. Chen, J.-C. Yang, P. Xu, J.-J. Zhang, X.-
H. Duan, L.–N. Guo, J. Org. Chem. 2020, 85, 7515–7525; i) M.-T. Suo, S.
Yang, J.-C. Yang, Z.-Y. Liu, J.-J. Zhang, L.-N. Guo, Org. Chem. Front. 2020,
7, 2414–2418; j) S. Sakurai, A. Matsumoto, T. Kano, K. Maruoka, J. Am.
Chem. Soc. 2020, 142, 19017–19022; k) S. Yang, P. Gao, M.-T. Suo, S.-X.
Gao, X.-H. Duan, L.-N. Guo, Chem. Commun. 2020, 56, 10714–10717; l) S.
Sakurai, T. Kano, K. Maruoka, Chem. Commun. 2021, 57, 81–84; m) W.
Xu, Y. Liu, T. Kato, K. Maruoka, Org. Lett. 2021, 23, 1809–1813. For a
review, see; n) A. Matsumoto, K. Maruoka, Bull. Chem. Soc. Jpn. 2020, 94,
513–524.
[7] Recently, only one example of the use of silylperoxyacetal as an alkyl
radical precursor has been reported. See ref [6k].
[8] a) R. Soyka, A. Heckel, J. Nickl, W. Eisert, T. H. Müller, H. Weisenberger, J.
Med. Chem. 1994, 37, 26–39; b) X. Zhu, M. Su, Q. Zhang, Y. Lui, H. Bao,
Org. Lett. 2020, 22, 620–625.
[9] a) N. G. Ricapito, C. Ghobril, H. Zhang, M. W. Grinstaff, D. Putnam, Chem.
Rev. 2016, 116, 2664–2704; b) E. A. Rainbolt, K. E. Washington, M. C.
Biewer, M. C. Stefan, Polym. Chem. 2015, 6, 2369–2381.
Finally, we conducted transformations of the obtained
TEMPO adducts to demonstrate their synthetic utility
(Scheme 6). As expected, the NÀ O bond of the product could
be cleaved under both reductive and oxidative conditions,
affording the corresponding alcohols 17a and 17i or aldehyde
18 without affecting the terminal ester moiety. In addition, the
conversion of the ester moiety via a Grignard reaction without
removing the NÀ O bond of the TEMPO moiety was also
possible. The subsequent oxidative cleavage of the NÀ O bond
furnished hydroxy acid 19, which bears a tertiary alcohol
moiety. These results demonstrate the general utility of our
method for the synthesis of a broad range of hydroxy acid
derivatives.
In conclusion, we have presented a method for the
synthesis of functionalized aliphatic acid esters. Using silylper-
oxyacetals, i.e., alkyl radical precursors that bear an ester
moiety, a broad range of functionalized aliphatic acid esters
were efficiently synthesized via the transition-metal-catalyzed
generation and subsequent functionalization of alkyl radicals.
As a practical application of the present method, the synthesis
of a pharmaceutically relevant molecule containing a 1,1-
diarylalkane structure was demonstrated. In addition, the
development of an iron-catalyzed aminooxygenation of the
in situ generated alkyl radicals allowed for the synthesis of
structurally diverse hydroxy acid derivatives.
[10] a) M. P. Sibi, M. Hasegawa, J. Am. Chem. Soc. 2007, 129, 4124–4125;
b) P. H. Fuller, J.-W. Kim, S. R. Chemler, J. Am. Chem. Soc. 2008, 130,
17638–17639; c) T. Koike, M. Akita, Chem. Lett. 2009, 38, 166–167; d) J. F.
Van Humbeck, S. P. Simonovich, R. R. Knowles, D. W. C. MacMillan, J. Am.
Chem. Soc. 2010, 132, 10012–10014; e) T. Tagami, Y. Arakawa, K.
Minagawa, Y. Imada, Org. Lett. 2019, 21, 6978–6982; f) J.-W. Zhang, Y.-R.
Wang, J.-H. Pan, Y.-H. He, W. Yu, B. Han, Angew. Chem. Int. Ed. 2020, 59,
3900–3904; Angew. Chem. 2020, 132, 3928–3932.
Acknowledgements
Manuscript received: June 30, 2021
Revised manuscript received: July 16, 2021
Accepted manuscript online: July 18, 2021
Version of record online: ■■■, ■■■■
This work was supported by JSPS KAKENHI grants JP26220803,
JP17H06450 (Hybrid Catalysis), and JP21H05026.
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COMMUNICATION
Dr. A. Matsumoto*, Y. Shiozaki, Dr. S.
Sakurai, Prof. Dr. K. Maruoka*
1 – 5
Synthesis of Functionalized
Aliphatic Acid Esters via the Gen-
eration of Alkyl Radicals from Si-
lylperoxyacetals
A catalytic method to access func-
tionalized aliphatic acid esters using
silylperoxyacetals as alkyl radical pre-
cursors with a terminal ester moiety is
described. The reaction proceeds via
the in situ generation and subsequent
functionalization of alkyl radicals,
affording synthetically valuable
aliphatic acid derivatives. A novel
strategy for the synthesis of hydroxy
acid derivatives via a CÀ O bond
formation process is also developed.