Hypervalent iodine(III)-mediated decarboxylative acetoxylation at tertiary and benzylic carbon centers

Article abstract of DOI:10.3762/bjoc.14.92

The decarboxylative acetoxylation of carboxylic acids using a combination of PhI(OAc)₂ and I₂ in a CH₂Cl₂/AcOH mixed solvent is reported. The reaction was successfully applied to two types of carboxylic acids containing an α-quaternary and a benzylic carbon center under mild reaction conditions. The resulting acetates were readily converted into the corresponding alcohols by hydrolysis.

Full text of DOI:10.3762/bjoc.14.92

Hypervalent iodine(III)-mediated decarboxylative
acetoxylation at tertiary and benzylic carbon centers
Kensuke Kiyokawa*, Daichi Okumatsu and Satoshi Minakata*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1046–1050.
Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
doi:10.3762/bjoc.14.92
Received: 14 February 2018
Accepted: 27 April 2018
Published: 15 May 2018
Email:
Kensuke Kiyokawa* - kiyokawa@chem.eng.osaka-u.ac.jp;
Satoshi Minakata* - minakata@chem.eng.osaka-u.ac.jp
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
* Corresponding author
Keywords:
Guest Editor: T. Wirth
acetoxylation; carboxylic acids; decarboxylation; hypervalent iodine;
iodine
© 2018 Kiyokawa et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The decarboxylative acetoxylation of carboxylic acids using a combination of PhI(OAc)2 and I2 in a CH2Cl2/AcOH mixed solvent
is reported. The reaction was successfully applied to two types of carboxylic acids containing an α-quaternary and a benzylic car-
bon center under mild reaction conditions. The resulting acetates were readily converted into the corresponding alcohols by hydro-
lysis.
Introduction
The decarboxylative functionalization of carboxylic acids and stoichiometric amounts of heavy metal oxidants under high-
the derivatives thereof is an important transformation in organic temperature conditions [14,15]. Because these oxidants are typi-
synthesis. In recent years, increasing efforts have been devoted cally highly toxic, their use has remained limited in organic
to the development of decarboxylative transformations [1-13], synthesis. Barton et al. reported on the development of a prac-
especially through radical decarboxylation processes, allowing tical method for the decarboxylative hydroxylation using thio-
an easy access to valuable compounds from readily available hydroxamate esters as substrates [16]. Although the method was
carboxylic acids. However, despite these advances, the oxida- applicable to a broader range of substrates, the preparation of
tive decarboxylation coupled with C–O bond formation has the activated ester is an intrinsic drawback to this procedure.
received considerably less attention, even though it represents a While more convenient and practical methods for decarboxyla-
promising strategy for the synthesis of valuable alcohol deriva- tive oxygenation, in which carboxylic acids are directly used as
tives. One of the classical methods for the decarboxylative C–O a substrate, have recently emerged, these methods have limited
bond formation of aliphatic carboxylic acids involves the use of substrate scope [17-20].
1046

Beilstein J. Org. Chem. 2018, 14, 1046–1050.
A seminal work on decarboxylative functionalization in which a be more effective in producing 2a in moderate yields (Table 1,
combination of PhI(OAc)2 and molecular iodine (I2) are used entries 2–4). The use of nitromethane also resulted in an im-
was reported by Suárez et al. [21]. The method features mild proved yield of 2a of 60% (Table 1, entry 5). Interestingly,
reaction conditions, simple operation, and the use of readily screening of additional solvents revealed that a CH2Cl2/AcOH
available and environmentally friendly oxidants. However, mixed solvent was suitable for this transformation, and a ratio
despite the great potential of this approach with respect to a of 1:1 (v/v) was found to be optimal, with 2a being produced in
decarboxylative C–O bond-forming reaction, the oxidation 73% yield (Table 1, entries 6–8). When the reaction was per-
system was only applied to reactions of uronic acids and formed at a higher concentration, the yield of product remained
α-amino acids [22-24], and further applications have not been the same (Table 1, entry 9). Increasing the amount of oxidants
explored. We recently reported on the decarboxylative Ritter- used had only a slight effect on the product yield, with 2a being
type amination of carboxylic acids containing an α-quaternary
carbon center using a combination of PhI(OAc)2 and I2 to
Table 1: Effect of solvents and reaction parameters on the decarboxyl-
produce the corresponding α-tertiary amine derivatives
(Scheme 1) [25]. Mechanistic investigations indicated that the
reaction proceeds via the formation of an alkyl iodide and the
corresponding iodine(III) species as key intermediates. In this
context, we concluded that the use of such an oxidation system,
combined with the judicious choice of solvent, would enable a
decarboxylative C–O bond forming reaction, namely acetoxyla-
tion, via the oxidative displacement of an iodine atom of the in
situ generated alkyl iodide by PhI(OAc)2 [26]. Herein, we
report on the decarboxylative acetoxylation of carboxylic acids
that contain an α-quaternary carbon center using PhI(OAc)2 and
I2 in a CH2Cl2/AcOH mixed solvent (Scheme 1). In subsequent
experiments, the method was also found to be applicable to the
reaction of benzylic carboxylic acids. The acetates that were
produced in the reaction were readily converted into the corre-
sponding alcohols by hydrolysis.
ative acetoxylation.a
Entry
Solvent
Yield (%)b
1
AcOH
10
48
46
42
60
73
57
65
74
77
75
8
2
CH2Cl2
3
1,2-dichloroethane
chlorobenzene
4
5
CH3NO2
6
CH2Cl2/AcOH (1:1)
CH2Cl2/AcOH (3:1)
CH2Cl2/AcOH (1:3)
CH2Cl2/AcOH (1:1)
CH2Cl2/AcOH (1:1)
CH2Cl2/AcOH (1:1)
CH2Cl2/AcOH (1:1)
CH2Cl2/AcOH (1:1)
CH2Cl2/AcOH (1:1)
7
8
9c
10d
11e
12f
13g
14h
Results and Discussion
We started our investigation by examining the decarboxylative
acetoxylation of 3-(4-bromophenyl)-2,2-dimethylpropanoic acid
(1a) using PhI(OAc)2 and I2 as oxidants. When the reaction was
conducted in AcOH, the corresponding acetate 2a was obtained
in low yield, and substantial amounts of the starting material
were recovered, even though the use of AcOH as the solvent
would be expected to promote the acetoxylation (Table 1, entry
1). Other solvents were then screened in attempts to improve
the yield of the acetate 2a. Halogenated solvents such as
CH2Cl2, 1,2-dichloroethane, and chlorobenzene were found to
0
<5
aReactions were conducted on a 0.2 mmol scale at a 0.2 M concentra-
tion. Unless otherwise noted, reactions were performed on the
benchtop with a fluorescent light on the ceiling. bDetermined by
1H NMR analysis of the crude product using 1,1,2,2-tetrachloroethane
as an internal standard. cThe reaction was conducted at a 0.4 M con-
centration. dPhI(OAc)2 (3 equiv) was used. eI2 (1 equiv) was used.
fI2 (0.1 equiv) was used. gThe reaction was conducted without I2. hThe
reaction was conducted in the dark.
Scheme 1: Decarboxylative functionalization using PhI(OAc)2/I2 system.
1047

Beilstein J. Org. Chem. 2018, 14, 1046–1050.
produced in 77% yield, when 3 equiv of PhI(OAc)2 were used a non-cyclic 2i. Using this protocol, 1-adamantanecarboxylic
(Table 1, entries 10 and 11). The reaction efficiency was signifi- acid was smoothly transformed into the corresponding acetate
cantly decreased with a catalytic amount of I2, and no reaction 2k. In addition to the reaction with respect to tertiary carbon
was observed in the absence of I2 (Table 1, entries 12 and 13). centers, the present method was successfully applied to benzylic
The reaction did not proceed in the dark, and most of the carboxylic acid derivatives. For example, commercially avail-
starting material was recovered (Table 1, entry 14). This result able arylpropanoic acids, which include ibuprofen (1m) and
is consistent with a reaction proceeding via a light-induced loxoprofen (1n), underwent decarboxylative acetoxylation in a
radical decarboxylation process [21,25].
highly efficient manner. It should be noted that, although
benzylic C–H bonds are frequently incompatible with oxidative
We next explored the scope of the decarboxylative acetoxyla- conditions, no products derived from benzylic C–H oxidation
tion reaction (Scheme 2). A variety of carboxylic acids contain- were observed in this reaction system.
ing α-quaternary carbon centers were efficiently converted into
the corresponding acetates under mild reaction conditions [27]. Hydrolysis of the acetates 2c and 2m under basic conditions
Various functional groups, including bromo (2a and 2f), fluoro furnished the corresponding alcohols 3c and 3m, respectively,
(2b), carboxyl (2e), nitro (2g), and ester (2h) groups, were all in nearly quantitative yields (Scheme 3). These results demon-
well tolerated, providing the corresponding products in good strate that the present decarboxylative acetoxylation, followed
yields. Notably, a carboxyl group on the phenyl ring was inert by hydrolysis, offers an efficient and practical method for the
toward decarboxylation under the oxidation conditions used, synthesis of tertiary and benzylic alcohols.
allowing the acetate 2e to be successfully synthesized. The
acetoxylation of a cyclohexane framework was also achieved, The following experiments were performed in attempts to gain
but the yield of the product 2j was somewhat lower than that of insights into the reaction pathway. Monitoring the reaction by
Scheme 2: Substrate scope. Reactions were conducted on a 0.5 mmol scale at a 0.2 or 0.4 M concentration on the benchtop with a fluorescent light
on the ceiling. Yields are for isolated products. aPhI(OAc)2 (3 equiv) was used. bI2 (1 equiv) was used. cI2 (0.75 equiv) was used.
1048

Beilstein J. Org. Chem. 2018, 14, 1046–1050.
the formation of an alkyl iodide and the corresponding tertiary
alkyl-λ3-iodane species as intermediates [25]. To confirm the
participation of these intermediates, the acetoxylation of a sepa-
rately prepared sample of the tertiary alkyl iodide 5 was investi-
gated. When 5 was treated with one equivalent of PhI(OAc)2 in
a CH2Cl2/AcOH mixed solvent at room temperature, the
acetoxylation proceeded efficiently to provide 2c (Scheme 4b).
On the contrary, in the absence of PhI(OAc)2, no products were
formed, and the starting material was recovered. These results
strongly support a reaction pathway involving the formation of
an alkyl iodide, which is oxidized by PhI(OAc)2 to the corre-
sponding hypervalent iodine(III) species that then undergoes
Scheme 3: Hydrolysis of acetates.
1H NMR spectroscopy showed for the reaction of a mixture of acetoxylation.
1a with two equimolar amounts of PhI(OAc)2 in a CD2Cl2/
CD3CO2D (1:1) mixed solvent the formation of a mixture of Based on the experimental results and our previous report [25],
PhI(OAc)2 and 4a in a ratio of 11:1. This result indicates that a proposed reaction pathway is depicted in Scheme 5. At the
ligand exchange between 1a and PhI(OAc)2 was suppressed due beginning of the reaction, PhI(OAc)2 predominantly exists
to the presence of an excess amount of acetic acid (Scheme 4a, rather than 4, as confirmed by NMR analysis. Therefore, in the
see Supporting Information File 1 for details). Based on our initial stage, PhI(OAc)2 preferentially undergoes decomposi-
previous work, we propose that the reaction pathway involves tion with I2 to provide acetyl hypoiodite (AcOI), which partici-
pates in the generation of RCO2I by reacting with a carboxylic
acid 1. Meanwhile, RCO2I is directly generated along with
AcOI when 4 reacts with I2. Subsequently, decarboxylative
iodination of RCO2I under irradiation with visible light affords
an alkyl iodide intermediate, which is then rapidly oxidized by
the remaining PhI(OAc)2 to generate the corresponding alkyl-
λ3-iodane (RI(OAc)2), which then undergoes the acetoxylation
to afford the acetate 2 along with the regeneration of AcOI [28].
Conclusion
In conclusion, the decarboxylative acetoxylation of carboxylic
acids containing α-quaternary and benzylic carbon centers was
achieved by using a combination of PhI(OAc)2 and I2 in a
CH2Cl2/AcOH mixed solvent. The key to the success of the
reaction was the choice of a suitable solvent that enables an oxi-
dative substitution of an alkyl iodide intermediate by
PhI(OAc)2. This operationally simple method under metal-free
Scheme 4: Mechanistic investigations.
and mild reaction conditions can be used to produce a variety of
Scheme 5: Proposed reaction pathway.
1049

Beilstein J. Org. Chem. 2018, 14, 1046–1050.
16.Barton, D. H. R.; Géro, S. D.; Holliday, P.; Quiclet-Sire, B.; Zard, S. Z.
Tetrahedron 1998, 54, 6751–6756.
acetates, which can be efficiently transformed into tertiary and
benzylic alcohols.
doi:10.1016/S0040-4020(98)00337-8
17.Kiyokawa, K.; Yahata, S.; Kojima, T.; Minakata, S. Org. Lett. 2014, 16,
4646–4649. doi:10.1021/ol5022433
Supporting Information
18.Xu, K.; Wang, Z.; Zhang, J.; Yu, L.; Tan, J. Org. Lett. 2015, 17,
4476–4478. doi:10.1021/acs.orglett.5b02142
Supporting Information File 1
Experimental procedures, characterization data, copies of
the 1H, 13C, and 19F NMR spectra.
19.Song, H.-T.; Ding, W.; Zhou, Q.-Q.; Liu, J.; Lu, L.-Q.; Xiao, W.-J.
J. Org. Chem. 2016, 81, 7250–7255. doi:10.1021/acs.joc.6b01360
20.Yuan, Z.; Zhao, T.; Yu, T.; Wang, J.; Wei, H. Asian J. Org. Chem.
2017, 6, 262–264. doi:10.1002/ajoc.201600607
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-92-S1.pdf]
21.Concepción, J. I.; Francisco, C. G.; Freire, R.; Hernández, R.;
Salazar, J. A.; Suárez, E. J. Org. Chem. 1986, 51, 402–404.
doi:10.1021/jo00353a026
22.Francisco, C. G.; González, C. C.; Suárez, E. Tetrahedron Lett. 1997,
38, 4141–4144. doi:10.1016/S0040-4039(97)00805-8
23.Boto, A.; Hernández, R.; Suárez, E. Tetrahedron Lett. 1999, 40,
5945–5948. doi:10.1016/S0040-4039(99)01180-6
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
JP16K17868.
24.Boto, A.; Hernández, R.; Suárez, E. J. Org. Chem. 2000, 65,
4930–4937. doi:10.1021/jo000356t
ORCID® iDs
25.Kiyokawa, K.; Watanabe, T.; Fra, L.; Kojima, T.; Minakata, S.
J. Org. Chem. 2017, 82, 11711–11720. doi:10.1021/acs.joc.7b01202
26.Gallos, J.; Varvoglis, A. J. Chem. Soc., Perkin Trans. 1 1983,
1999–2002. doi:10.1039/p19830001999
Kensuke Kiyokawa - https://orcid.org/0000-0001-6124-2861
Satoshi Minakata - https://orcid.org/0000-0001-9619-445X
References
27.No product was observed when dodecanoic acid was used as a
substrate.
1. Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.;
MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, No. 0052.
doi:10.1038/s41570-017-0052
28.The substitution by an acetate likely proceeds via a cationic
intermediate. However, the detail of the mechanism as well as the
stereochemical course of the step is not clear at this stage.
2. Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117, 8864–8907.
doi:10.1021/acs.chemrev.6b00516
3. Li, Y.; Ge, L.; Muhammad, M. T.; Bao, H. Synthesis 2017, 49,
5263–5284. doi:10.1055/s-0036-1590935
License and Terms
4. Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012,
134, 4258–4263. doi:10.1021/ja210361z
This is an Open Access article under the terms of the
Creative Commons Attribution License
5. Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,
10401–10404. doi:10.1021/ja3048255
6. Liu, C.; Wang, X.; Li, Z.; Cui, L.; Li, C. J. Am. Chem. Soc. 2015, 137,
9820–9823. doi:10.1021/jacs.5b06821
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
7. Candish, L.; Teders, M.; Glorius, F. J. Am. Chem. Soc. 2017, 139,
7440–7443. doi:10.1021/jacs.7b03127
8. Perry, G. J. P.; Quibell, J. M.; Panigrahi, A.; Larrosa, I.
J. Am. Chem. Soc. 2017, 139, 11527–11536.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
doi:10.1021/jacs.7b05155
9. Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc.
2017, 139, 12153–12156. doi:10.1021/jacs.7b07546
10.Wang, D.; Zhu, N.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017,
139, 15632–15635. doi:10.1021/jacs.7b09802
(https://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
11.Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peter, D. S.;
Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan, M.;
Baran, P. S. Science 2017, 356, eaam7355.
doi:10.3762/bjoc.14.92
doi:10.1126/science.aam7355
12.Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.;
Aggarwal, V. K. Science 2017, 357, 283–286.
doi:10.1126/science.aan3679
13.Xue, W.; Oestreich, M. Angew. Chem., Int. Ed. 2017, 56,
11649–11652. doi:10.1002/anie.201706611
14.Mosher, W. A.; Kehr, C. L. J. Am. Chem. Soc. 1953, 75, 3172–3176.
doi:10.1021/ja01109a039
15.Bacha, J. D.; Kochi, J. K. J. Org. Chem. 1968, 33, 83–93.
doi:10.1021/jo01265a016
1050