Ritter-type amination of C-H bonds at tertiary carbon centers using iodic acid as an oxidant

Article abstract of DOI:10.1039/c6cc07164c

The Ritter-type amination of a tertiary C-H bond using iodic acid (HIO₃) as an oxidant, in the presence of N-hydroxyphthalimide (NHPI) is reported. This operationally simple method is conducted under metal-free conditions, is scalable, and efficiently provides valuable α-tertiary amine derivatives.

Full text of DOI:10.1039/c6cc07164c

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DOI: 10.1039/C6CC07164C
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Ritter-Type Amination of C–H Bonds at Tertiary Carbon Centers
Using Iodic Acid as an Oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Kensuke Kiyokawa,* Kenta Takemoto, and Satoshi Minakata*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The Ritter-type amination of a tertiary C–H bond using iodic acid intermolecular tertiary C–H amination reactions. However,
(HIO3) as an oxidant, in the presence of N-hydroxyphthalimide only a few oxidation systems have been reported that are
(NHPI) is reported. This operationally simple method is conducted suitable for the reaction, and thus its applications have been
under metal-free conditions, is scalable, and efficiently provides quite limited to date. Early reports were limited to the reaction
of adamantane derivatives.9 Although the amination of
valuable α-tertiary amine derivatives.
benzylic C–H bonds using N-hydroxyphthalimide (NHPI)
Incorporation of an amino functional group into an organic
molecule via the direct conversion of a C(sp3)–H bond to a
C(sp3)–N bond is one of the most powerful and straightforward
strategies for preparing nitrogen-containing organic
compounds.1 The intermolecular, direct amination of C–H
bonds at tertiary carbon centers is a particularly attractive
transformation that produces α-tertiary amine derivatives,
which are potentially useful building blocks for new types of
drugs and in medicinal chemistry.2 In the past decades, the
insertion of a nitrene has evolved to be one of the most
reliable methods for the direct amination of C(sp3)–H bonds.
However, in the case of reactions that involve unactivated
tertiary C–H bonds, a superstoichiometric amount of substrate
is required. As a result, its use in functionalizing valuable
complex molecules has remained undeveloped.3,4 To
overcome these problem, Du Bois et al. recently reported on
an elegant method for selective tertiary C–H amination using
the originally developed rhodium catalyst.5 In this reaction, the
substrate can be used as the limiting reagent. In addition, most
recently, tertiary C–H azidation has also emerged as a
promising approach,6 and these methods were reported to be
applicable to the late stage functionalization of complex
molecules. However, despite these advances, the direct and
site-selective conversion of an unactivated tertiary C–H bond
to a C–N bond, particularly under metal-free conditions,
continues to be a challenging and highly demanding task.7,8
Ritter-type C–H aminations, where nitriles function as the
nitrogen source, are a potentially efficient strategy for
combined with ceric ammonium nitrate (CAN) as an oxidant
was developed by Ishii et al., the reaction with respect to
tertiary C–H bonds, with the exception of adamantane
derivatives, has not been extensively explored.10 Baran et al.
recently developed
a practical Ritter-type tertiary C–H
amination involving a guided C–H oxidation approach using
substoichiometric amounts of copper and zinc salts.11 The
proposed reaction pathway involves the metal-oxidant-
mediated single-electron oxidation of an in-situ generated
alkyl radical species to produce a carbocation intermediate. To
develop a more efficient Ritter-type tertiary C–H amination
that does not involve the use of metal oxidants, we conceived
a new approach using iodine-based oxidants, in which C–H
iodination would be induced to provide tertiary alkyl iodides
and the corresponding iodine(III) species with a higher
oxidation state that could undergo a subsequent substitution
by nitriles (Scheme 1).12 Herein, we report on the Ritter-type
amination of unactivated tertiary C–H bonds using iodic acid
(HIO3) as an oxidant in the presence of NHPI.
I I / III
R3
MeCN
H2O
H
NHAc
R3
R3
R1
R1
R1
R2
R2
R2
C-H iodination
Ritter-type
amination
Scheme 1 Strategy for a Ritter-type C–H amination at a tertiary carbon center.
We began our investigation by screening oxidants for the
amination of isoamyl benzoate (1a), which is used as a limiting
reagent (Table 1).13 On the basis of the reaction conditions
reported by Ishii,10 we first surveyed the effect of several
common oxidants for the reaction in the presence of NHPI in
MeCN at 80
°C for 12 h. When CAN was used, tertiary C−H
amination proceeded to give 2a in low yield (entry 1).
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J. Name., 2013, 00, 1-3 | 1
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Table 1 Survey of oxidants.a
does not require a light-induced process since VtiehweArrtieclaecOtniloinne
proceeded equally well, even in the darkD(OenI:t1r0y.110339)./C6CC07164C
Oxidant (2 equiv)
NHPI (0.4 equiv)
H
NHAc
H
NHAc
OBz
OBz
MeCN, 80 °C, 12 h
HIO3, NHPI
1a
2a
R3
R3
R1
MeCN, 80 °C, 24 h
R1
R2
R2
Yield [%]b
1
2
Entry
Oxidant
CAN
conditions A: HIO3 (0.8 equiv), NHPI (0.2 equiv).
B: HIO3 (2.0 equiv), NHPI (0.8 equiv).
1
2
19
0
C: HIO3 (2.0 equiv), NHPI (0.4 equiv).
Oxone
NHAc
NHAc
NHAc
NHAc
3
4
5c
6c
7c
8c
9d
10d,e
11d,e
12d,e,f
13d,e,g
mCPBA
PhI(OAc)2
CAN
0
OBz
OBz
OBz
OBz
OBz
<5
53
69
65
<5
72
74 (71)
0
2a 71% (A)
71%,a 1.81 g
2b 47% (B)
2c 79% (A)
2d 80% (A)
Oxone
mCPBA
PhI(OAc)2
HIO3
NHAc
NHAc
AcHN
H
OBz
OBz
remote
proximal
2e 84% (C)b
2f 60% (C)b
2g 44% (A)b
(remote/proximal = 4.6:1)c
NHAc
NHAc
NHAc
NHAc
HIO3
CO2Et
CN
NPhth
2k 48% (A)
OAc
none
2h 49% (A)
2i 59% (C)
2j 76% (C)
HIO3
0
NO2
NHAc
AcHN
NPhth
CO2Me
NHAc
HIO3
72
NPhth
2m 54% (C)
O
a Reaction conditions: 1a (0.2 mmol), oxidant (0.4 mmol), NHPI (0.08 mmol),
MeCN (1 mL), 80
C. b Determined by 1H NMR analysis of the crude product
using 1,1,2,2-tetrachloroethane as an internal standard. Yield in
parenthesis is the isolated yield based on the amount of 1a used. I2 (0.5
equiv) was added. Reactions were conducted on a 0.4 mmol scale.
Reactions were conducted using HIO3 (0.8 equiv), NHPI (0.2 equiv), and
MeCN (2 mL) for 24 h. Reaction was conducted without NHPI. Reaction
was conducted under dark.
2l 76% (A)
2n 43% (B)
°
NHAc
NHAc
NHAc
NHAc
c
d
e
NHAc
2o 63% (C)b
2p 51% (C)b
2q 47% (A)
2r 45% (B)
f
g
NHCOEt
NHCOPh
NHAc
OBz
3 46% (C) in EtCN
OBz
4 52% (C) in PhCN
AcHN
Neither Oxone nor m-chloroperbenzoic acid (mCPBA) showed
any reactivity for this reaction (entries 2 and 3), and PhI(OAc)2
gave only a trace amount of 2a (entry 4). Next, to trap the in-
situ generated alkyl radical species, we examined the reaction
using CAN with the addition of 0.5 equiv. of I2, as an iodine
source, and were pleased to find that the amination
proceeded efficiently, affording 2a in 53% yield (entry 5).
Interestingly, when I2 was present in the reaction system, both
Oxone and mCPBA also effectively promoted the amination
(entries 6 and 7) although they were completely inactive when
used as the sole oxidant. Meanwhile, 2a was not produced
when PhI(OAc)2 was used in the reaction (entry 8). These
results prompted us to explore a more effective oxidant for
this reaction. We hypothesized that iodic acid (HIO3) and
iodine pentoxide (I2O5) might be promising oxidants14 since
they are commercially available, low cost, and stable even at
high temperatures and can be reduced in-situ to generate I2
and H2O,14k,14l both of which are requisite components in this
Ritter-type amination. When we examined the use of HIO3, the
amination proceeded efficiently without the need for added I2,
affording 2a in 72% yield (entry 9).15 Furthermore, attempts to
reduce the amount of reagents employed revealed that the
use of HIO3 (0.8 equiv) and NHPI (0.2 equiv) in conjunction
with a longer reaction time of 24 h provided 2a in 74% yield
(entry 10).13 Control experiments in the absence of either HIO3
or NHPI revealed that both reagents were required for this
transformation (entries 11 and 12). In addition, the reaction
2s 61%d
Scheme 2 Substrate scope. Reactions were conducted on a 0.4 mmol scale. Yields are
isolated yields based on the amount of 1 used. Reaction conditions are shown in
parentheses. a Reaction was conducted on a 10 mmol scale. b Reaction was conducted
for 12 h. The ratio was determined by GC analysis of the crude product. HIO3 (1.2
equiv) and NHPI (0.2 equiv) were used. Monoaminated product was obtained in 13%
yield.
c
d
We next investigated the ability and scope of this Ritter-
type C–H amination (Scheme 2). To establish the synthetic
utility of this amination, we carried out the reaction using 1a
on a gram-scale (10 mmol), which resulted in the formation of
2a in 71% yield (1.81 g).13 Electronic effects on the reaction
were evaluated by using a series of substrates bearing a
benzoate group as an electron-withdrawing group (EWG).
Isobutyl benzoate, which contains a tertiary C–H moiety β to
the oxygen atom of the benzoate group, showed a low
reactivity because of the electron deficient character of the C–
H bond, and the product 2b was obtained in a relatively lower
yield than that for 2a. In contrast, a tertiary C–H bond remote
from the benzoate group showed a high reactivity (2c).
Similarly, secondary and tertiary alcohol derivatives as well as
primary alcohols were also suitable for use in this reaction
system, providing 2d and 2e in high yields, respectively. The
replacement of a methyl group with an ethyl group at the
reaction site had a slight effect on the reaction (2f). When a
benzoate derived from 3,7-dimethyl-1-octanol, which has two
2 | J. Name., 2012, 00, 1-3
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tertiary carbon centers, was examined, the tertiary C–H bond irreversible.18 These results are consistent with a reaction
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remote from the benzoate group selectively underwent pathway that involves an alkyl free-radDicOaIl: 1i0n.t1e0r3m9/Ced6CiaCt0e71t6h4aCt
amination over the proximal site, selectively furnishing 2g causes the loss of stereochemical information.7b Although we
(remote/proximal = 4.6:1).13 This selectivity can be attributed considered the possibility that an alkyl iodide could be
to the electronic effect by an EWG, and this trend is consistent generated in-situ as
a
reaction intermediate, the
with previously reported findings on selectivity for the corresponding iodine(I/III) species was not observed in the
oxidation of C–H bonds.6b,16 Substrates bearing functional reaction system. Therefore, to get insights into the nature of
groups, including an acetoxy protected alcohol (2h), an ester the reaction intermediate, several reactions were performed
(
2i), a nitrile (2j), phthaloyl protected amines (2k and 2l), and a employing the separately prepared alkyl iodide
leucine derivative (2m), were also compatible with the whether it is converted into 2a. Stirring a solution of
reaction. The amination of a substrate containing a phenoxy MeCN at 80 while the amination
C failed to give 2a 19
6
to determine
6
in
°
,
moiety,
leading
to
a
medicinally
important proceeded in the presence of HIO3 under otherwise the same
phenoxypropylamine framework, was sluggish because of the conditions to provide 2a even in low yield (9%).13 In the C–H
competitive electrophilic iodination of the aromatic ring. amination under the standard conditions, an alkyl iodide could
Therefore, to prevent this side reaction, the effect of the be generated in-situ catalytically. With this consideration in
incorporation of a nitro group at the para position in the mind, the slow addition of
6 to a suspension of HIO3 in MeCN
phenyl ring was examined, which resulted in the formation of at 80 C was examined, and the yield of 2a was increased to
°
the desired 2n. Furthermore, in this system, cyclic and 56% (Scheme 4c). These results strongly support a reaction
noncyclic hydrocarbons also underwent selective C–H pathway in which an alkyl iodide is generated and oxidized by
amination at tertiary carbon centers (2o–2s). It is noteworthy HIO3 to the corresponding hypervalent iodine species, which
that a double C–H amination was successfully achieved in the then undergoes a Ritter-type amination.20,21
reactions of 2,5-dimethylhexane as well as adamantane (2r
and 2s).13 Finally, the use of propionitrile and benzonitrile as a
(a) KIE measurement
NHAc
solvent instead of acetonitrile provided the corresponding
products and , respectively.
Acid hydrolysis of 2a effectively removed the acetamide
moiety as well as the benzoate moiety to give 1,3-
HIO3, NHPI
3
4
H14/D14
H13/D13
kH/kD = 7.5
MeCN, 80 °C
competitive reaction in the same vessel:
parallel reactions in separate vessels:
kH/kD = 2.5
aminoalcohol
5 as the HCl salt (Scheme 3).
(b) Stereochemical course of the amination
+
−
NHAc
NH3
Cl
HIO3 (2.0 equiv)
NHPI (0.4 equiv)
NHAc
+
OBz
OH
HCl aq. 100 °C, 17 h
OBz
OBz
OBz
MeCN, 80 °C
2a
5 79%
2f 2% ee
(S)-1f
retention
ca. 40% conv.
Scheme 3 Hydrolysis of the acetamide product 2a.
(c) Reaction starting from alkyl iodide
We performed several experiments in attempts to gain
insights into the reaction mechanism (Scheme 4). Initially,
kinetic isotope effects (KIEs) were measured with
methylcyclohexane and methylcyclohexane-d14 for both
competitive reactions in the same vessel and parallel reactions
in separate vessels (Scheme 4a). A significant primary KIE (7.5)
was observed for the competitive reaction in the same vessel,
and a relatively smaller KIE (2.5) was detected when parallel
reactions were carried out in separate vessels. The KIE (2.5)
value in the parallel reactions indicates that C–H bond
cleavage is likely the rate-determining step. In addition, C–H
bond cleavage via hydrogen abstraction by a phthalimide-N-
oxyl (PINO) radical was indicated by the quite large KIE (7.5) for
the reaction in the same vessel.17 The difference in the KIE
values between these two methods suggests that the rate of
oxidation of NHPI to PINO, prior to the rate-determining C–H
bond cleavage step, could affect the overall reaction rate. Next,
to evaluate the stereochemical course for the reaction, the
reaction using an enantiopure (S)-1f was carried out under the
standard conditions (ca. 40% conversion after 6 h), resulting in
the formation of nearly racemic 2f (Scheme 4b). Furthermore,
the starting material was recovered with complete retention
of its stereochemistry, indicating that the C–H bond cleavage is
NHAc
I
HIO3 (0.8 equiv)
MeCN, 80 °C
OBz
(slow addition)
OBz
6
2a 56%
Scheme 4 Mechanistic investigations
H
NHAc
R3
R3
R1
R1
R2
R2
O
I2
N
O
H2O
PINO
O
O
MeCN
H2O
N
OH
HIO3
NHPI
O
III
R2
I
I
I2
HIO3
R3
R3
R1
R1
R3
R1
R2
R2
Scheme 5. Proposed reaction pathway
Based on the experimental results presented herein and
previous reports,17 a proposed reaction pathway is depicted in
Scheme 5. First, NHPI is oxidized to PINO by HIO3, which leads
to the generation of I2 and H2O. Then, the rate determining C–
H bond cleavage by PINO provides an alkyl radical species,
which is rapidly trapped by I2. The resulting alkyl iodide is then
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strong acid medium was reported, see: G. Asensio, M. E.
oxidized by HIO3 to generate an iodine(III) species that
undergoes a Ritter-type amination, thus affording the amide
product.
González-Núñez, C. B. Bernardini, R. Mello, W. VAiedwaAmrtic,leJ.OAnlmine.
DOI: 10.1039/C6CC07164C
Chem. Soc., 1993, 115, 7250.
9
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In conclusion, we report on the development of a new class
of metal-free Ritter-type C–H amination reactions at tertiary
carbon centers using commercially available and easily
handled HIO3 and NHPI. Various α-tertiary amine derivatives
can be prepared by this operationally simple and
environmentally benign method. Preliminary mechanistic
investigations suggest that the reaction proceeds via a unique
reaction pathway that involves the formation of alkyl
iodides(I/III) as reaction intermediates. The present study is an
important example of expanding the utility of HIO3 in organic
synthesis. Further investigations of the mechanism and
applications of this method to the synthesis of more complex
molecules are currently underway.
(e) J. M. Bakke, C. B. Storm, Acta. Chem. Scand., 1989, 43
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13 See the ESI for details.
This work was supported by JSPS KAKENHI Grant Number
JP16K17868.
14 For a review, see: (a) A. G. Choghamarani, Synlett, 2006,
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see: (b) M. J. Cohen, E. McNelis, J. Org. Chem., 1984, 49, 515;
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15 Small amount of the corresponding tertiary alcohol, 3-
hydroxy-3-methylbutyl benzoate, was generated as a by-
product. No amide product 2a was obtained when the
alcohol was exposed to HIO3 in MeCN, indicating that the
alcohol was not an intermediate of the amination.
For selected examples of reactions using a metal nitrenoid,
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18 The retention of stereochemical information of the
recovered starting material was determined by the specific
rotation. See the Supporting Information for details.
5
6
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19 The iodide
6 was hydrolyzed in situ, and benzoic acid was
produced. No product resulting from the amination at the
tertiary carbon center was observed.
7
8
Our group and others reported on radical aminations of
tertiary C−H bonds under metal-free conditions, in which an
excess amount of substrates was required, see: (a) A. A.
Lamar, K. M. Nicholas, J. Org. Chem., 2010, 75, 7644; (b) Y.
Takeda, J. Hayakawa, K. Yano, S. Minakata, Chem. Lett., 2012,
41, 1672; (c) Y. Amaoka, S. Kamijo, T. Hoshikawa, M. Inoue, J.
Org. Chem., 2012, 77, 9959.
20 V. G. Tsypin, M. S. Pevzner, E. L. Golod, Russ. J. Org. Chem.,
2001, 37, 1762.
21 The substitution by a nitrile 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.
Hydroxylation followed by Ritter amination of tertiary C–H
bonds of alkylamines by methyl(trifluoromethyl)dioxirane in
4 | J. Name., 2012, 00, 1-3
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