C-H oxygenation at tertiary carbon centers using iodine oxidant

Article abstract of DOI:10.1039/C8CC03735C

An oxidation system in which iodic acid (HIO₃) is used as an oxidant in the presence of N-hydroxyphthalimide (NHPI) permitted the selective hydroxylation of tertiary C-H bonds and the lactonization of carboxylic acids containing a tertiary carbon center. These reactions are operationally simple and proceed under metal-free conditions using commercially available reagents, thus offering an ideal tool for the efficient oxidation of C-H bonds at tertiary carbon centers.

Full text of DOI:10.1039/C8CC03735C

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C–H Oxygenation at Tertiary Carbon Centers Using Iodine Oxidant
Kensuke Kiyokawa,* Ryo Ito, Kenta Takemoto, and Satoshi Minakata*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An oxidation system in which iodic acid (HIO3) is used as an context, a novel synthetic strategy for the efficient and
oxidant in the presence of N-hydroxyphthalimide (NHPI) operationally simple hydroxylation of C(sp3)–H bonds with
permitted the selective hydroxylation of tertiary C–H bonds and readily available reagents would be highly desirable.10,11
the lactonization of carboxylic acids containing a tertiary carbon
H
OH
center. These reactions are operationally simple and proceed
under metal-free conditions using commercially available
reagents, thus offering an ideal tool for the efficient oxidation of
C–H bonds at tertiary carbon centers.
R3
R3
R1
R1
C−H hydroxylation
R2
R2
oxidation reagents:
R3
O
O
O
N O
The selective oxygenation of C(sp3)–H bonds is one of the most
fundamental transformations in organic synthesis because it
permits the straightforward synthesis of valuable oxygen-
containing compounds from simple starting materials.1 Over
the past decades, extensive efforts have been devoted to the
development of new approaches for the direct conversion of a
C(sp3)–H bond to a C(sp3)–O bond (Scheme 1). The most
general method for C(sp3)–H oxygenation in a site-selective
manner has relied on the application of defined transition-
metal-oxo complexes, and significant progress has been made
in C–H hydroxylation at a tertiary carbon center, thus enabling
the functionalization of complex molecules.2,3 Methods that do
not involve the use of transition-metal catalysts, oxidants such
as dioxiranes4,5 and perfluorinated oxaziridines6 have been
widely used, although the preparation of these reagents is
laborious and potentially hazardous. Catalytic methods, in
which organocatalysts are employed with terminal oxidants to
generate active dioxiranes and oxaziridines in situ, have
recently emerged as a promising synthetic tool,7,8 even though
there are still some drawbacks, such as the use of elaborate
catalysts and the relatively low efficiency of such reations.
Most recently, the use of commercially available and
inexpensive persulfate salts for oxidizing such bonds has been
reported but these reagents have only been applied to
substrates bearing a nitrogen-containing functionality.9 In this
[M]
R1
R2
R1
R2
(M = Fe, Ru, etc)
metal-oxo complexes
Scheme 1 Representative examples of C(sp3)−H bond hydroxylaꢀon.
dioxiranes
oxadiridines
N-hydroxyphthalimide (NHPI), which is
a cheap and
commercially available reagent, is widely used as a hydrogen-
atom tranfer (HAT) mediator in C(sp3)–H oxidation.12 However,
despite the great advances, except for adamantane
derivatives, NHPI has rarely been used in the oxidative
functionalization of C–H bonds at tertiary carbon centers. Our
group recently reported on the development of the NHPI-
mediated Ritter-type C–H amination at tertiary carbon centers
using iodic acid (HIO3) as an oxidant (Scheme 2a).13 As part of
our continuing interest in the oxidative functionalization of
C(sp3)–H bonds, we herein report on a new approach to the
site-selective C–H oxygenation at tertiary carbon centers by
employing a NHPI/HIO3 oxidation system.
Based on our previous work on the Ritter-type C–H
amination,13 a possible pathway for C–H hydroxylation using
HIO3 in the presence of NHPI as a catalyst is described (Scheme
2b). In this system, NHPI is initially oxidized to phthalimide N-
oxyl (PINO) by HIO3, which leads to the generation of I2 and
H2O. The site-selective C–H bond cleavage by PINO then
generates a tertairy alkyl radical species, which is rapidly
trapped by I2. The resulting alkyl iodide is oxidized by the
remaining HIO3 to provide an alkyl-λ3-iodane species that
undergoes substitution by the in situ-generated H2O to afford
tertiary alcohols.
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pentavalent ioidne reagents such as NaIO3, NH4IO3, and 2-
iodoxybenzoic acid (IBX), were used.14 Unexpectedly, the
presence of oxygen, which is usually needed to promote NHPI-
catalyzed C(sp3)–H oxidations, had a negative effect on this
hydroxylation (entry 9). The reaction appears to proceed via a
radical process but does not involve a light-induced process,
since the reaction worked equally well, even in the dark (entry
6
vs. 10). Encouraged by the success of the C(sp3)–H
hydroxylation, we next examined use of other oxygen
nucleophiles in the C(sp3)–H oxygenation reaction. When the
reaction was run in methanol, neither the desired methyl
ether product nor 2a (entry 11) were produced. Meanwhile,
when acetic acid was used as a solvent, the predominant
reaction was C(sp3)–H acetoxylation, leading to the production
of the corresponding acetate with the concomitant formation
of the alcohol 2a (entry 12).15
Scheme 2 C(sp3)–H bond functionalization using HIO3 with NHPI.
Table 1 Optimization of reaction conditionsa
HIO3 (0.8 equiv)
NHPI (0.2 equiv)
H2O (5 equiv)
HIO3 (0.8 equiv)
NHPI (0.2 equiv)
H2O (x equiv)
H
OH
OH
R3
MeNO2 (0.2 M)
80 °C
R3
R1
R1
R2
R2
OBz
OBz
solvent (0.2 M)
80 °C, 12 h
1
2
1a
2a
OH
OH
OH
Entry
1
Solvent
H2O
H2O [equiv]
Yieldb [%]
RSMb [%]
>95
40
OBz
OBz
OBz
−
−
0
32
2a 68% (24 h)
2b 55% (24 h)
(73% brsm)
2c 63% (12 h)
(68% brsm)
2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeOH
AcOH
58% (1.21 g)a
3
20
15
10
5
38
52
OH
OH
4
42
47
OBz
OH
5
50
48
OBz
6
7c
62
20
2d 43% (12 h)
(61% brsm)
2e 29% (12 h)
(60% brsm)
2f 45% (12 h)b
(53% brsm)
5
72
<5
8c,d
9e
10f
11
12
5
67
6
X = p-CN 2g 60% (24 h)
o-F 2h 52% (30 h)
o-Cl 2i 60% (24 h)
p-Br 2j 59% (24 h)
OH
O
5
49
32
X
O
5
61
19
p-I
2k 58% (24 h)
−
0
>95
<5
−
15 (47)g
OH
OH
OH
CO2Me
a
Reactions were performed on a 0.4 mmol scale under a nitrogen
atmosphere unless othewise noted. b Yields are based on the amount of 1a
used. Determined by 1H NMR analysis of the crude product using
OAc
2l 44% (12 h)
NPhth
NPhth
2m 57% (12 h)
(75% brsm)
2n 18% (24 h)
(58% brsm)
bromoform as an internal standard. Reaction was conducted for 24 h. d
I2O5 (0.4 equiv) was used instead of HIO3. e Reaction was conducted under
c
Scheme 3 Substrate scope for C–H bond hydroxylation. Reactions were conducted on a
a
f
g
0.4 mmol scale. Yields are isolated yields based on the amount of 1 used. Reaction
O2 (1 atm). Reaction was conducted in the dark. Yield of the C−H
acetoxylated product. RSM = recovered starting material.
b
was conducted on a 10 mmol scale. A mixed solvent of MeNO2/1,2-dichloroethane
(1:1, v/v) was used. brsm = based on recovered starting material.
With this design in mind, we started our investigation by
screening solvents for the C(sp3)–H hydroxylation of isoamyl
We next investigated the utility and scope of the C(sp3)–H
hydroxylation (Scheme 3). To demonstarate the synthetic
utility, the reaction using 1a on a gram-scale (10 mmol) was
carried out, affording 2a in an acceptable yield (58%, 1.21 g).
The effect of an electron-withdrawing benzoate group was
benzoate
(1a) using HIO3 and NHPI under a nitrogen
atmosphere (Table 1). No reaction occurred when the reaction
was conducted in water, due to the low solubility of 1a as well
as NHPI in water (entry 1). Several organic solvents were then
screened, and the hydroxylation was found to proceed,
producing 2a in 32% yield when nitromethane was used as a
solvent (entry 2). The efficiency of the hydroxylation reaction
was improved by the addition of water, and 5 equiv of water
proved to be the most effective, with 2a being formed in 62%
yield, with 20% of 1a being recovered (entries 3–6). Further
investigations revealed that, when the reaction reached
completion after 24 h, the yield of 2a was increased up to 72%
(entry 7). The reactivity of iodine pentoxide (I2O5) was similar
to that of HIO3 (entry 8), while no 2a was detected when other
evaluated by the reaction using substrates 1a–c. Isobutyl
benzoate (1b), in which a tertiary C–H bond is located at the β-
position to the oxygen atom of the benzoate group, showed a
lower reactivity than that of 1a, which is explained by the
electron deficient character of the C–H bond, providing the
product 2b in 55% yield, with 25% (1H NMR) of the starting
material being recovered. In contrast, a tertiary C−H bond
remote from the benzoate group showed a high reactivity, and
the reaction reached completion within 12 h (2c). A secondary
alcohol derivative was also suitable for use in this reaction
2 | J. Name., 2012, 00, 1-3
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system (2d). The replacement of a methyl group with an ethyl methylnonanoic acid also proceeded smoothly to form 4d
group at the reaction site resulted in a low yield of 2e Furthermore, the present reaction could be applied to
probably because of a steric hindrance. Adamantane was also spirolactonization (4e).18 A benzylic C–H bond showed a high
successfully converted into the 1-adamantanol (2f) using a reactivity, and the reaction was therefore conducted at 60
.
,
°C
nitromethane/1,2-dichloroethane mixed solvent.16,17 We next to suppress the competitive formation of a ketone, providing
surveyed the functional group tolerance for this reaction. 4f in moderate yield. In addition to the synthesis of γ-lactones,
Isoamyl benzoate derivatives, which contain cyano (2g), fluoro this reaction system was also successfully applied to the
(
2h), chloro (2i), bromo (2j), and iodo (2k) groups on the synthesis of the δ-lactone 4g. However, disappointingly, a
phenyl ring, all provided the corresponding alcohols without mixture of γ- and δ-lactones was obtained in very low yield
the loss of their functionalities. In addition, an acetyl protected when hexanoic acid, which does not contain a tertiary carbon
alcohol (2l), a phthaloyl protected amine (2m), and a valine center, was used as a substrate. The formal dehydrogenative
derivative (2n) were also compatible with this hydroxylation. lactonization of carboxylic acids is rare and remains
a
The use of a valine derivative resulted in a low yield because of challenging issue.19 The present reaction offers a simple and
the strong electron deficient character of the C–H bond in this powerful tool for the synthesis of lactones from readily
molecule.
available carboxylic acids.
a) Stereochemical course of the hydroxylation
HIO3 (0.8 equiv)
NHPI (0.2 equiv)
H2O (5 equiv)
OH
OBz
OBz
MeNO2 (0.2 M)
80 °C, 24 h
(S)-1e
2e 0% ee
Scheme 4 Lactonization of N-phthaloyl leucine methyl ester 2o.
b) Reaction starting from alkyl iodide
I
OH
additive, H2O (5 equiv)
MeNO2 (0.2 M)
OBz
OBz
5
2a
Yield [%]
Entry Additive [x equiv]
Conditions
1
2
3
4
5
none
80 °C, 10 min
80 °C, 10 min
80 °C, 1 h, slow addition
rt, 10 min
<5
13
34
0
HIO3 (0.8)
HIO3 (0.8)
none
HIO3 (0.8)
rt, 10 min
95
Scheme 6 Mechanistic investigations.
Some additional experiments were performed in attempts
to further investigate the reaction pathway for this
hydroxylation depicted in Scheme 2b. To evaluate the
stereochemical course of the reaction, enantiopure (S)-1e was
subjected to the standard reaction conditions, resulting in the
formation of racemic 2e (Scheme 6a). This result is consistent
with a pathway that proceeds via an alkyl radical intermediate,
which would result in the loss of stereochemical
information.14,20 Based on our previous work,13 we considered
it likely that an alkyl iodide and the corresponding alkyl-λ3-
iodane would be generated in-situ as reaction intermediates in
this hydroxylation. To confirm the reaction pathway, several
reactions were examined employing the separately prepared
Scheme 5 Substrate scope for the lactonization of carboxylic acids. Reactions were
conducted on a 0.4 mmol scale. Yields are isolated yields based on the amount of 3
used. Values in parentheses are yields determined by 1H NMR analysis of the crude
b
c
product. a HIO3 (1.2 equiv) was used. I2O5 (0.8 equiv) was used instead of HIO3. I2O5
(0.4 equiv) was used instead of HIO3. d Reaction was conducted at 60 °C.
When the N-phthaloyl leucine methyl ester 2o was
selected as
a substrate under hydroxylation reaction
alkyl iodide
5 to determine whether it is converted into 2a
conditions, cyclization proceeded to afford the γ-lactone 4c
instead of the corresponding tertiary alcohol (Scheme 4). This
unexpected result and the success in C(sp3)–H acetoxylation
(Table 1, entry 12) encouraged us to investigate the
lactonization of carboxylic acids containing a tertiary carbon
center. To our delight, the NHPI/HIO3 oxidation system was
found to be quite effective for preparing lactones directly from
readily available carboxylic acids (Scheme 5). 4-Methylvaleric
acid underwent smooth lactonization, with the formation of
the corresponding γ-lactone 4a. Lactones containing acetoxy
(Scheme 6b). In the absence of HIO3, only a trace amount of 2a
was formed21 while the hydroxylation proceeded in the
presence of HIO3 under the otherwise same conditions to
provide 2a even in low yield (entries 1 and 2). The slow
addition of
5 to a suspension of HIO3 in MeNO2 at 80 °C
resulted in a slight increase in the yield of 2a to 34% (entry 3).
The necessity of HIO3 for this transformation was more clearly
demonstrated by running the reaction at room temperature.
Although, running the reaction in the absence of HIO3 led to
the full recovery of the starting material, in the presence of
HIO3, 2a was formed quantitatively (entries 4 and 5).22 These
(
4b) and phthalimido (4c) groups were also readily accessed
with this method in good yields. The lactonization of 4-
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7
8
9
(a) B. H. Brodsky and J. Du Bois, J. Am. Chem. Soc., 2005, 127,
results strongly support the reaction pathway shown in
Scheme 2b, in which an alkyl iodide is generated and oxidized
by HIO3 to the corresponding hypervalent iodine species,
which then undergoes hydroxylation.23
15391; (b) N. D. Litvinas, B. H. Brodsky and J. Du Bois, Angew.
Chem., Int. Ed., 2009, 48, 4513; (c) A. M. Adams and J. Du
Bois, Chem. Sci., 2014, 5, 656.
(a) C. J. Pierce and M. K. Hilinski, Org. Lett., 2014, 16, 6504;
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Lett., 2016, 18, 3826; (c) W. G. Shuler, S. L. Johnson and M. K.
Hilinski, Org. Lett., 2017, 19, 4790.
In conclusion, we report on the development of a new class
of metal-free C–H oxygenation reactions at tertiary carbon
centers using commercially available and easily handled HIO3
and NHPI. Various tertiary alcohols as well as lactones can be
prepared by this operationally simple and environmentally
benign method. Further investigations of applications of this
method to the synthesis of more complex molecules are
currently in progress.
(a) X. Li, X. Che, G.-H. Chen, J. Zhang, J.-L. Yan, Y.-F. Zhang, L.-
S. Zhang, C.-P. Hsu, Y. Q. Gao and Z.-J. Shi, Org. Lett., 2016,
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572.
,
10 For selected recent examples, see: (a) G.-X. Li, C. A. Morales-
Rivera, F. Gao, Y. Wang, G. He, P. Liu and G. Chen, Chem. Sci.,
2017, 8, 7180; (b) Y. Kawamata, M. Yan, Z. Liu, D.-H. Bao, J.
,
This work was supported by JSPS KAKENHI Grant Numbers
JP16K17868 and JP18K14217.
Chen, J. T. Starr and P. S. Baran, J. Am. Chem. Soc., 2017, 139
7448.
11 For selected examples by a directing activator method, see:
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Chem. Soc., 1998, 120, 6611; (b) K. Chen, J. M. Richter and P.
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20 Addition of 1 equiv of 2,2,6,6-tetramethylpiperidine 1-oxyl
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described in entry 6 of Table 1 resulted in no reaction, and
1a was fully recovered.
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21 The iodide
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5 was hydrolyzed in situ, and benzoic acid was
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22 An acid-promoted mechanism can be ruled out, since 2a was
not produced in the presence of CF3CO2H instead of HIO3.
23 The lactonization appears to proceed through a similar
reaction pathway, but the details of the mechanism remain
unclear.
6
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DOI: 10.1039/C8CC03735C
An oxidation system which employs iodic acid and N-hydroxyphthalimide permitted effective oxygenation of tertiary C–H bonds.