Hypervalent Iodine(III)-Mediated Decarboxylative Ritter-Type Amination Leading to the Production of α-Tertiary Amine Derivatives

Article abstract of DOI:10.1021/acs.joc.7b01202

α-Tertiary amines (ATAs) are attractive structural motifs that are frequently found in biologically active molecules. Therefore, the development of an efficient method for the synthesis of ATAs represents an important research topic in the field of medicinal chemistry as well as organic chemistry. Although the Ritter reaction is a reliable approach for preparing α-tertiary amine derivatives via intermolecular amination reactions, the typical methods suffer from disadvantages such as harsh reaction conditions and the use of strong acids. Because of this, it has been of limited use in the synthesis of ATAs. We report here on the decarboxylative Ritter-type amination of carboxylic acids bearing an α-quaternary carbon center using a combination of PhI(OAc)₂ and molecular iodine (I₂) to produce the corresponding α-tertiary amine derivatives. This reaction proceeded at ambient temperature on the benchtop with a fluorescent light. Mechanistic investigations suggest that the reaction proceeds via the formation of an alkyl iodide and a higher oxidation state iodine(III) species as key intermediates. Similarly, a stepwise protocol for the Ritter-type amination of alcohols via the formation of oxalic acid monoalkyl esters was also achieved. The present methods represent a useful tool for the synthesis of ATAs that are difficult to prepare by conventional methods.

Full text of DOI:10.1021/acs.joc.7b01202

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Article
Hypervalent Iodine(III)-Mediated Decarboxylative Ritter-Type
Amination Leading to the Production of #-Tertiary Amine Derivatives
Kensuke Kiyokawa, Tomoki Watanabe, Laura Fra, Takumi Kojima, and Satoshi Minakata
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Jun 2017
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Page 1 of 32
The Journal of Organic Chemistry
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Hypervalent Iodine(III)-Mediated Decarboxylative
Ritter-Type Amination Leading to the Production of α-
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Tertiary Amine Derivatives
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Kensuke Kiyokawa,* Tomoki Watanabe, Laura Fra, Takumi Kojima, and Satoshi Minakata*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
kiyokawa@chem.eng.osaka-u.ac.jp, minakata@chem.eng.osaka-u.ac.jp
ABSTRACT: α-Tertiary amines (ATAs) are attractive structural motifs that are frequently found in
biologically active molecules. Therefore, the development of an efficient method for the synthesis of
ATAs represents an important research topic in the field of medicinal chemistry as well as organic
chemistry. Although the Ritter reaction is a reliable approach for preparing α-tertiary amine
derivatives via intermolecular amination reactions, the typical methods suffer from disadvantages
such as harsh reaction conditions and the use of strong acids. Because of this, it has been of limited
use in the synthesis of ATAs. We report here on the decarboxylative Ritter-type amination of carboxylic
acids bearing an α-quaternary carbon center using a combination of PhI(OAc)2 and molecular iodine
(I2), to produce the corresponding α-tertiary amine derivatives. This reaction proceeded at ambient
temperature on the benchtop with a fluorescent light. Mechanistic investigations suggest that the
reaction proceeds via the formation of an alkyl iodide and a higher oxidation state iodine(III) species
as key intermediates. Similarly, a stepwise protocol for the Ritter-type amination of alcohols via the
formation of oxalic acid monoalkyl esters was also achieved. The present methods represent a useful
tool for the synthesis of ATAs that are difficult to prepare by conventional methods.
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Page 2 of 32
INTRODUCTION
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α-Tertiary amines (ATAs), which consist of a tetrasubstituted carbon atom surrounded by
three carbons and one nitrogen functionality, are attractive structural motifs that are frequently found
in biologically active molecules (Figure 1).1 In addition, ATAs are recognized as useful building
blocks in drug discovery, since sterically demanding tertiary alkyl substituents can improve the
lipophilicity and metabolic stability of a drug.2 Therefore, the development of efficient methods for
the synthesis of ATAs has been an important research topic in the field of organic synthesis and
medicinal chemistry. Among the methods for preparing α-tertiary amine derivatives, introducing an
amino functional group into a tertiary carbon centers, i.e. the formation of a C–N bond at a tertiary
carbon center, has been recognized as one of the most straightforward approaches,1f and has attracted
considerable attention in the past decades. In this context, efficient synthetic methods for amination at
a tertiary carbon center,3 including radical C–H amination3a,c,d and C–H amination by an imino-λ3-
bromane3b and a metal nitrenoid3f, have recently been developed. Most recently, the azidation of
tertiary carbon centers4 and the hydroamination of alkenes5 have also emerged as powerful and useful
methods. However, despite these advances, novel synthetic strategies for preparing ATAs from readily
available starting materials, especially under mild and environmentally benign conditions, continue to
be highly desirable in terms of expanding the scope of accessible ATAs.
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NH2
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NH2
Cl
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HN
Ketamine
O
Phentermine
Memantine
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N
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OH
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Cl
O
H
N
H2N
OH
Cl
Clenbuterol
O
N
Olodaterol
O
O
CN
H
N
N
H
N
OH
NH2
Fingolimod
N
HO
Anagliptin
N
Figure 1. Representative biologically active molecules containing an α-tertiary amine moiety.
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The Ritter reaction, in which nitriles function as a nitrogen source, would be a reliable
method for producing amides via an intermolecular amination reaction.6 Since the reaction proceeds
through the generation of a carbocation intermediate that is trapped by a nitrile, the method could be
used in the amination of tertiary carbon centers. The classical Ritter reaction employs alkenes and
alcohols as starting materials and, when α-tertiary amine derivatives are being prepared, strong
Brønsted/Lewis acids and high temperatures are needed.7 Because of this, its use has remained limited
in scope. The Ritter-type C–H amination of a tertiary carbon center has recently emerged as a
promising approach for the synthesis of ATAs.8,9 Our group has also developed the Ritter-type
amination of tertiary C–H bonds using iodic acid (HIO3) as an oxidant, and mechanistic investigations
suggest that the reaction proceeds via a unique reaction pathway that involves the formation of tertiary
alkyl iodides and the corresponding iodine(III) species as reaction intermediates (Scheme 1).10 On the
basis of these results and our ongoing interest in iodine-mediated decarboxylative amination
reactions,11 we hypothesized that a method involving a decarboxylative iodination process12 to
generate tertiary alkyl-λ3-iodanes, followed by the Ritter-type amination, would be a useful new
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approach to producing ATAs from carboxylic acids (Scheme 1).13 Herein, we report on the
decarboxylative Ritter-type amination of carboxylic acids bearing an α-quaternary carbon center,
mediated by a hypervalent iodine(III)/molecular iodine system. The starting carboxylic acids can be
readily prepared, and the reaction effectively proceeds at ambient temperature to afford α-tertiary
amine derivatives.14 In addition, a series of mechanistic experiments were performed to reveal the
reaction pathway.
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Scheme 1. Strategies for the Ritter-Type Amination at Tertiary Carbon Centers Using Iodine
Oxidants
O
N OH
Previous work
O
NHPI (cat.)
H
HIO3,
R3
R1
C–H iodination
R2
MeCN
H2O
I I / III
NHAc
R3
R3
Ritter-type
amination
R1
R1
R2
R2
CO2H
PhI(OAc)2 / I2
R3
decarboxylative
iodination
R1
R2
This work
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RESULTS AND DISCUSSION
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We began our investigation by examining the decarboxylative Ritter-type amination of 2,2-
dimethyl-3-phenylpropanoic acid (1a) using a combination of PhI(OAc)2 and I2 as oxidants.12a After
optimizing the reaction parameters, including the amount of oxidants required, temperature, and time,
we found that, when 1a was treated with PhI(OAc)2 (2 equiv) and I2 (0.5 equiv) in acetonitrile at
ambient temperature for 16 h on the benchtop in the presence of a fluorescent light on the ceiling, the
decarboxylative amination proceeded effectively, thus affording the corresponding amide 2a in 79%
yield (Table 1, entry 1).15 It is noteworthy that no products derived from oxidation at the benzylic
position were detected. Control experiments in the absence of either PhI(OAc)2 or I2 revealed that both
reagents are required for this transformation to proceed (entries 2 and 3). Decreasing the amount of
PhI(OAc)2 from two equivalents to one equivalent resulted in lower yields of 2a (entries 4 and 5). The
addition of one equivalent of iodine did not improve the product yield, and no reaction was observed,
when a catalytic amount of iodine was used (entries 6 and 7). Investigation of the effect of other
hypervalent iodine(III) reagents revealed that PhI(OAc)2 was the most suitable oxidant for this
amination, while PhIO, PhI(Ot-Bu)2, and PhI(OCOCF3)2 resulted in very low yields (entries 8–10). In
addition, simple iodine(V) oxidants such as HIO3 and I2O5 failed to provide 2a, even though they were
found to be efficient oxidants in our previous work on tertiary C–H amination (entries 11 and 12).10 It
should also be noted that N-iodosuccinimide (NIS) and tert-butyl hypoiodite (t-BuOI), both of which
can induce decarboxylative iodination,12b-d were not effective for this decarboxylative amination
(entries 13 and 14). These results demonstrate the superiority of hypervalent iodine reagents in this
transformation and imply that the formation of a tertiary alkyl-λ3-iodane as a reaction intermediate
appears to be crucial for the success of this reaction. The fact that the reaction did not proceed in the
dark clearly indicates that this transformation involves a light-induced process (entry 15). However,
irradiation with a 32 W compact fluorescent lamp or a high-pressure mercury lamp failed to improve
the yield of 2a (entries 16 and 17).
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Table 1. Effect of Oxidant and Reaction Parameters on the Decarboxylative Ritter-Type
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3
Aminationa
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5
6
7
8
oxidant (x equiv)
I2 (y equiv)
CO2H
NHAc
Ph
Ph
MeCN (2 mL), rt, 16 h
fluorescent light
9
1a (0.2 mmol)
2a
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entry
1
oxidant (x equiv)
I2 (equiv)
yield (%)b
PhI(OAc)2 (2 equiv)
none
0.5
0.5
0
79
0
2
3
PhI(OAc)2 (2 equiv)
PhI(OAc)2 (1.5 equiv)
PhI(OAc)2 (1 equiv)
PhI(OAc)2 (2 equiv)
PhI(OAc)2 (2 equiv)
PhIO (2 equiv)
0
4
0.5
0.5
1.0
0.1
0.5
0.5
0.5
0.5
0.5
0
77
64
70
0
5
6
7
8c
9c
23
18
0
PhI(Ot-Bu)2 (2 equiv)
PhI(OCOCF3)2 (2 equiv)
HIO3 (2 equiv)
10c
11c
12c
13c
14c
15d
16e
17c,f
<5
<5
8
I2O5 (1 equiv)
NIS (1 equiv)
t-BuOI (1 equiv)
PhI(OAc)2 (2 equiv)
PhI(OAc)2 (2 equiv)
PhI(OAc)2 (2 equiv)
0
<5
0
0.5
0.5
0.5
79
73
a
Reactions were performed on a 0.2 mmol scale. Unless otherwise noted, reactions were performed on the
b
1
benchtop in the presence of a fluorescent light on the ceiling. Determined by H NMR analysis of the crude
c
d
product using 1,1,2,2-tetrachloroethane as an internal standard. Reaction was run for 6 h. Reaction was
e
conducted under dark. Reaction was conducted under irradiation with a 32 W compact fluorescent lamp.
fReaction was conducted under irradiation with high-pressure mercury lamp
.
It would be expected that the Ritter-type C–H amination would preferably occur at the
benzylic position over the tertiary carbon center.9 Indeed, when the C–H amination of (2-
methylpropyl)benzene using HIO3 (1 equiv) and N-hydroxyphthalimide (NHPI) (0.2 equiv) in
acetonitrile was carried out based on our previous work,10 the benzylic position was preferably
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oxidized, resulting in the formation of a very low yield of 2 (Scheme 2). This result clearly
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demonstrates the synthetic usefulness of the present method using carboxylic acids.
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Scheme 2. The Ritter-Type C–H Amination of (2-Methylpropyl)benzene Using HIO3 as an
Oxidant
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NHAc
O
HIO3 (1 equiv)
NHPI (0.2 equiv)
NHAc
Ph
+
+
Ph
Ph
Ph
(12%)a
MeCN (2 mL)
70 °C, 4 h
(0.4 mmol)
47%
2a 4%
a Determined by 1H NMR analysis of the crude product
.
We next explored the scope of the decarboxylative Ritter-type amination (Scheme 3). In this
amination, a variety of carboxylic acids bearing an α-quaternary carbon center were efficiently
converted into the corresponding amides under mild reaction conditions. Functional groups on the
phenyl ring, such as methyl (2b), fluoro (2c), bromo (2d and 2f), and nitro (2g) groups were all well
tolerated. In addition, a carboxyl group on the phenyl ring was found to be inert toward
decarboxylation under the oxidation conditions employed, therefore permitting the amide 2e to be
successfully synthesized. These products containing α,α-dimethylphenethylamine motifs would be
useful building blocks for the synthesis of pharmaceutical agents. Using this protocol, 3-
phenylpropylamine (2h) and γ-amino acid (2i) derivatives, which are also important structural motifs
that are found in many biologically active compounds, were easily prepared. The amination of
aliphatic cyclic systems such as cyclohexane and cyclopentane frameworks was also achieved, thus
furnishing cyclohexyl (2j and 2k) and cyclopentyl (2l) amine derivatives, respectively. Furthermore,
this Ritter-type amination provides an efficient synthetic route to the simple aliphatic amide 2m as
well as 1-acetamidoadamantane (2n). Unfortunately, attempts to use carboxylic acids containing an
α-tertiary carbon center, leading to α-secondary amine derivatives, resulted in very low yields (data
not shown).
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Scheme 3. Scope of Carboxylic Acidsa
1
2
3
4
5
6
7
PhI(OAc)2 (2 equiv)
I2 (0.5 equiv)
CO2H
R3
NHAc
R3
R1
R1
R2
R2
MeCN (5 mL), rt
fluorescent light
1 (0.5 mmol)
2
8
9
81% (16 h)
73% (16 h)b
75% (16 h)b
78% (16 h)b
66% (16 h)b
2a X = H
2b X = Me
2c X = F
2d X = Br
2e X = CO2H
NHAc
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X
NHAc
NHAc
O2N
Ph
NHAc
NHAc
Br
2f 76% (16 h)b
2g 78% (16 h)
2h 78% (16 h)
NHAc
Ph
MeO2C
NHAc
2i 68% (24 h)c
Ph NHAc
2j 70% (16 h)c
2k 71% (16 h)d
NHAc
NHAc
2l 55% (16 h)b
2m 45% (7 h)c,e
2n 73% (6 h)
aUnless otherwise noted, reaction conditions: 1 (0.5 mmol), PhI(OAc)2 (1 mmol), I2 (0.25 mmol), MeCN (5 mL), room
temperature. Reaction time is shown in parentheses. bPhI(OAc)2 (1.5 equiv) was used. cPhI(OAc)2 (2.5 equiv) was used.
dMeCN (2.5 mL) was used. eReaction was conducted under irradiation with a 32 W compact fluorescent lamp.
To further investigate the property of this amination, the following reactions were examined
(Scheme 4). In the reaction of a substrate bearing an electron-rich phenoxy moiety (1o) under the
standard reaction conditions, decarboxylative amination did not occur, and the phenyl ring was
iodinated exclusively at the para-position. After a brief screening of reaction parameters, irradiation
with a compact fluorescent lamp (CFL) was found to promote the decarboxylative amination. Finally,
when the amounts of oxidants were increased, decarboxylative amination together with the iodination
of the aromatic ring effectively proceeded to provide 2o-I in 63% yield. Disappointingly, the presence
of an alkene moiety was incompatible with these oxidative reaction conditions. For example, when
the carboxylic acid 1p was employed as a substrate, the predominant iodolactonization provided
lactone 3.
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The Journal of Organic Chemistry
1
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3
Scheme 4. Reactions of Substrates Bearing Pphenoxy (1o) and Olefin (1p) Moieties
4
5
6
PhI(OAc)2 (3 equiv)
I2 (1 equiv)
O
O
7
8
9
CO2H
NHAc
MeCN, rt, 16 h
with 32 W CFL
I
1o
2o-I 63%
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O
O
PhI(OAc)2 (2 equiv)
I2 (0.5 equiv)
CO2H
MeCN, rt, 3 h
I
1p
3 82%
In situ 1H NMR monitoring experiments were performed to gain insights into the reaction
pathway. The reaction of 1a with two equimolar amounts of PhI(OAc)2 in acetonitrile at room
temperature immediately gave a mixture of PhI(OAc)2, 4a, and 5a in a ratio of 63:30:7, as determined
by 1H NMR analysis (Scheme 5 and Figure 2i).16 By monitoring of the progress of the reaction after
the addition of 0.5 equivalents of I2 to the reaction mixture, the hypervalent iodine species 4a and 5a
were consumed, with the formation of amide 2a and imide 2a’ (Figure 2ii). These results strongly
suggest that the in situ generated hypervalent iodine species derived from the starting carboxylic acids
participate in the decarboxylative Ritter-type amination in the presence of I2, thus affording amides.
Interestingly, after a prolonged reaction time, the imide 2a’ was gradually consumed, and the yield of
2a was increased (Figure 2iii), indicating that 2a’ is one of the intermediates that leads to the formation
of 2a. In addition, during the course of the reaction, MeI, which was likely generated form AcOI via
decarboxylative iodination, was produced as a byproduct.
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Scheme 5. 1H NMR Monitoring of a Reaction Mixture of PhI(OAc)2 and 1a
1
2
3
4
5
6
7
8
9
OAc
I
OCOR
OCOR
+ 1a
+
Ph
Ph
Ph
I
I
Ph
R =
CD3CN, rt
5 min
OAc
OAc
OCOR
(2 equiv)
4a
5a
PhI(OAc)2 : 4a : 5a = 63/30/7
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PhI(OAc)2
(2 equiv)
I2
(0.5 equiv)
NHAc
NAc2
CO2H
+
Ph
Ph
Ph
CD3CN, rt
1a
2a
2a'
i) 1a + PhI(OAc)2
4a + 5a
1a
2a
2a
2a'
MeI
ii) 3 h after addition of I2
2a
2a'
MeI
iii) 21 h after addition of I2
2a
2a'
Figure 2. 1H NMR spectra in CD3CN. i) A mixture of 1a and 2 equivalents of PhI(OAc)2. ii) Spectrum
obtained 3 h after the addition of I2. iii) Spectrum obtained 21 h after the addition of I2.
To further probe the reaction pathway, additional mechanistic experiments were performed.
Initially, upon treating imide 2a’ with acetic acid in acetonitrile, amide 2a was formed quantitatively
(Scheme 6i). The Ritter-type amination of 1a was next conducted in CD3CN. Interestingly, the non-
deuterated amide 2a as well as 2a-d3 were produced (Scheme 6ii). This result also strongly supports
the conclusion that the imide 2a’-d3 participates in the reaction as an intermediate in this reaction.
Based on our previous work and related literature precedents,10 we propose that the reaction pathway
involves the formation of tertiary alkyl-λ3-iodanes as intermediates. However, neither the
corresponding iodine(III) species nor the alkyl iodide was observed in the NMR study described above.
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Therefore, to confirm that these intermediates participate, we examined the Ritter-type amination of
the separately prepared alkyl iodide 6. When a solution of 6 was stirred in acetonitrile at room
temperature, no aminated products were formed, and the starting material was recovered (Scheme 6iii).
However. the amination proceeded smoothly in the presence of one equivalent of PhI(OAc)2 to
provide 2a and 2a’. These results are consistent with a reaction pathway involving the formation of
an alkyl iodide intermediate which is oxidized by PhI(OAc)2 to the corresponding hypervalent
iodine(III) species that then participates in the Ritter-type amination.10,17
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Scheme 6. Mechanistic Investigations
i) Exposure of imide 2a' to acetic acid
NAc2
NHAc
2a 95%
AcOH (2 equiv)
MeCN, rt, 6 h
Ph
Ph
2a'
ii) Reaction conducted in CD3CN
PhI(OAc)2 (2 equiv)
H
I2 (0.5 equiv)
CO2H
N
X
Ph
Ph
CD3CN, rt, 6 h
fluorescent light
O
1a
2a-d3 X = CD3
2a X = CH3
49%
27%
O
CD3
CH3
N
Ph
O
2a'-d3
iii) Ritter-type amination of tertiary alkyl iodide 6
NHAc
NAc2
I
+
Ph
Ph
Ph
MeCN, rt
<30 min
6
2a
2a'
0%
30%
0%
67%
with PhI(OAc)2 (1 equiv)
Based on the experimental results and previous reports,10 a proposed reaction pathway is
depicted in Scheme 7. Initially, ligand exchange between the carboxylic acid 1 and PhI(OAc)2 occurs
immediately. The resulting hypervalent iodine species 4, 5, and the remaining PhI(OAc)2 undergo
decomposition with I2 to provide acyl hypoiodite (RCO2I) and acetyl hypoiodite (AcOI) species. The
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generated AcOI is predicted to participate in the generation of RCO2I by reacting with 1.
Decarboxylative iodination of RCO2I under visible light irradiation subsequently affords a tertiary
alkyl iodide intermediate, which is then rapidly oxidized by remaining PhI(OAc)2 to generate the
corresponding tertiary alkyl-λ3-iodane (RI(OAc)2), which then undergoes the Ritter-type amination,
thus furnishing the amide 2 along with the regeneration of AcOI.18 During the course of the amination,
the generated nitrilium ion could be trapped by an acetate instead of water. The resulting imide 2’ via
rearrangement, reacts with in situ generated acetic acid to give 2. In this reaction system, AcOI
undergoes decarboxylation to generate MeI, the formation of which was observed by in situ NMR
monitoring (vide supra, Figure 1). Iodine is consumed in this process, implying that a stoichiometric
amount of I2 is required to complete the reaction.
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Scheme 7. Plausible Reaction Pathway
RCO2H
OAc
I
OCOR
OCOR
I2
(1)
+
Ph
Ph
Ph
I
I
OAc
OAc
4
OCOR
5
PhI
1
AcOI
hν
AcOH
CO2
OAc
I
+
H2O
CH3CN
MeI
RCO2I
R NHAc
R N
R
+
OAc
2
OAc
−
Ac2O
hν
AcOH
PhI
R
I
CO2
PhI(OAc)2
OAc
R
Ac
N
R
N
Ac
2'
To expand the utility of this method, an oxalic acid monoalkyl ester, which is easy to prepare
from the corresponding alcohol in one step, was used in the Ritter-type amination (Scheme 8).
Gratifyingly, the amination of 7 with PhI(OAc)2 (2 equiv) and I2 (0.75 equiv) in acetonitrile effectively
proceeded to afford 2h in good yield through a double decarboxylation.19 However, it should be noted
that oxalic acid monoalkyl esters derived from tertiary alcohols are somewhat unstable and should be
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The Journal of Organic Chemistry
stored carefully due to disproportionation into the corresponding dialkyl oxalate and oxalic acid. Thus,
we next examined a sequential stepwise process, in which an alcohol as a starting material is treated
with oxalyl chloride, and the resulting oxalic acid monoalkyl ester is used for the next Ritter-type
amination in succession without a purification step (Scheme 9). When 2-methyl-4-phenylbutan-2-ol
was employed as a starting material for the sequential method, the amide 2h was produced in 65%
yield in two steps. Similarly, 1-methylcyclohexanol was also converted into the corrsponding amide
2j in satisfactory yield. Notably, this method was found to be applicable to a secondary alcohol albeit
the product yield was relatively low (2q). Although overall yields are moderate, this operationally
simple method, which employs mild reaction condtions offers an efficient alternative to the
conventional Ritter reaction in which alcohols are used as starting materials.6
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Scheme 8. The Ritter-Type Amination of Oxalic Acid Monoalkyl Ester 7
PhI(OAc)2 (2 equiv)
I2 (0.75 equiv)
Ph
OCOCO2H
Ph
NHAc
MeCN (5 mL), rt, 6 h
fluorescent light
2h 72%
7 (0.5 mmol)
Scheme 9. Sequential Stepwise Approach for the Ritter-Type Amination of Alcohols via the
Formation of Oxalic Acid Monoalkyl Esters
a
(COCl)2
(2 equiv)
PhI(OAc)2 (2 equiv)
I2 (0.75 equiv)
OH
OCOCO2H
R3
NHAc
R3
R3
R1
R1
R1
MeCN (10 mL), rt, 6 h
fluorescent light
Et2O
R2
(1 mmol)
R2
R2
w/o purification
2
NHAc
NHAc
Ph
NHAc
2h 65%a
aYield in two steps based on the amount of alcohols used.
2j 54%a
2q 32%a
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CONCLUSION
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9
In conclusion, we report on a new type of synthetic method for preparing α-tertiary amine
derivatives by decarboxylative Ritter-type amination using a combination of PhI(OAc)2 and I2, both
of which are commercially available and easily handled. The present reaction effectively proceeded
at ambient temperature on the benchtop with a fluorescent light. Mechanistic investigations suggest
that the reaction pathway involves the formation of alkyl iodides and the corresponding alkyl-λ3-
iodanes as reaction intermediates. In addition, this strategy was successfully applied to the
decarboxylative amination of oxalic acid monoalkyl esters that are easily prepared from alcohols. The
methods presented herein are operationally simple and environmentally benign, thus offering a useful
tool for the synthesis of ATAs that are difficult to prepare by conventional methods.
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EXPERIMENTAL SECTION
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19
General Information. New compounds were characterized by H, C, F, IR, MS, and HRMS.
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19
1H, C, and F NMR spectra were recorded on a JEOL JMTC-400/54/SS spectrometer (1H NMR,
13
1
400 MHz; C NMR, 100 MHz; 19F NMR, 377 MHz). H NMR chemical shifts were determined
relative to Me4Si (0.00 ppm) or residual undeuterated solvent signal (DMSO-d6 at 2.50 ppm) as an
internal standard. 13C NMR chemical shifts were determined relative to solvent signal (CDCl3 at 77.0
ppm or DMSO-d6 at 39.5 ppm) as an internal standard. 19F NMR chemical shifts were determined
relative to C6F6 (−164.9 ppm) as an external standard. Infrared spectra were recorded on a
SHIMADZU IRAffinity-1 FT-IR Spectrometer. Mass spectra were obtained on a SHIMADZU
GCMS-QP2010 and a JEOL JMS-700 mass spectrometer. High-resolution mass spectra were obtained
on a JEOL JMS-700 mass spectrometer (magnetic sector type mass spectrometer). Melting points
were determined on a Stanford Research Systems MPA100 OptiMelt Automated Melting Point
System. All reactions were carried out under nitrogen. Otherwise noted, reactions were performed on
the benchtop with a fluorescent light on the ceiling. Products were purified by chromatography on
silica gel BW-300 (Fuji Silysia Chemical Ltd.) or Chromatorex NH (Fuji Silysia Chemical Ltd.).
Analytical thin-layer chromatography (TLC) was performed on pre-coated silica gel glass plates
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The Journal of Organic Chemistry
(Merck silica gel 60 F254 and Fuji Silysia Chromatorex NH, 0.25 mm thickness). Compounds were
visualized with UV lamp or treatment with an ethanolic solution of phosphomolybdic acid followed
by heating.
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Materials. Dehydrated acetonitrile was used from a solvent purification system. Starting materials
1a,20 1h,20 1p,21 and 722 were prepared according to literature procedures. Analytical data for 1h23 and
1p24 were in excellent agreement with reported data. Starting materials 1j and 1n were purchased and
used as obtained. All other solvents and reagents were purchased and used as obtained.
Typical Procedure for the Preparation of Carboxylic Acids. A heat-gun-dried round bottom
flask containing a magnetic stir bar was charged with dry THF (30 mL) and cooled to −78 °C.
Diisopropylamine (11 mmol) and n-BuLi (1.6 M in hexane, 9.4 mmol) were added, and the solution
was allowed to stir at −78 °C for 30 min. Methyl ester (7.9 mmol) was then added, and the solution
was stirred an additional 30 min. Bromide (9.4 mmol) in THF (6 mL) was added dropwise over 10
min, and the reaction mixture was stirred at this temperature for 8 h, and then allowed to warm up to
room temperature. The mixture was stir for 12 h before quenching with water (30 mL). The aqueous
layer was extracted with Et2O (3 x 30 mL), and the combined organic layers were dried over Na2SO4.
The solution was concentrated under reduced pressure to give the crude product, which was directly
used for the next step. The crude product was dissolved in the mixture of MeOH (30 mL) and NaOH
aq. (2 M, 70 mL), and the solution was stirred at 80 ºC for 24 h. Then the solution was concentrated
under reduced pressure, and the resulting aqueous layer was extracted with Et2O (3 x 30 mL) to remove
impurities and acidified with 2 M HCl. The aqueous layer was extracted with Et2O (3 x 70 mL), and
the combined organic layers were dried over Na2SO4. The solution was concentrated under reduced
pressure to give the crude product, which was purified by flash column chromatography on silica gel
(hexane/EtOAc = 70:30) to give the product.
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2,2-dimethyl-3-(4-methylphenyl)propanoic acid (1b). Following the typical procedure, the reaction
using diisopropylamine (1.06 g, 11 mmol), n-BuLi (1.6 M in hexane, 5.9 mL, 9.4 mmol), methyl
isobutyrate (0.81 g, 7.9 mmol), and 4-methylbenzyl bromide (1.74 g, 9.4 mmol) provided 1b as a
1
white solid (1.37 g, 90% yield). mp: 56.6–57.6 ºC; H NMR: (400 MHz, CDCl3) δ 11.90 (brs, 1H),
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7.15–6.97 (m, 4H), 2.85 (s, 2H), 2.32 (s, 3H), 1.19 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 184.8,
136.0, 134.4, 130.1, 128.7, 45.5, 43.4, 24.6, 21.0; IR: (ATR) 2970, 2932, 1694, 1512, 1470, 1283, 930,
814 cm-1; MS: (EI) m/z 192 (M+, 14), 105 (100); HRMS: (EI) calcd for (C12H16O2) 192.1150 (M+),
found m/z 192.1151.
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3-(4-fluorophenyl)-2,2-dimethylpropanoic acid (1c). Following the typical procedure, the reaction
using diisopropylamine (1.06 g, 11 mmol), n-BuLi (1.6 M in hexane, 5.9 mL, 9.4 mmol), methyl
isobutyrate (0.81 g, 7.9 mmol), and 4-fluorobenzyl bromide (1.78 g, 9.4 mmol) provided 1c as a white
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1
solid (1.50 g, 97% yield). mp: 39.7–40.2 ºC; H NMR: (400 MHz, CDCl3) δ 12.00 (brs, 1H), 7.17–
13
7.08 (m, 2H), 7.02–6.91 (m, 2H), 2.86 (s, 2H), 1.20 (s, 6H); C{1H} NMR: (100 MHz, CDCl3) δ
184.1, 161.8 (d, JCF = 243.7 Hz), 133.1 (d, JCF = 3.3 Hz), 131.6 (d, JCF = 7.4 Hz), 114.9 (d, JCF = 20.6
19
Hz), 45.0, 43.4, 24.6; F NMR: (377 MHz, CDCl3) δ −119.7; IR: (ATR) 2986, 2941, 1695, 1506,
1290, 1217, 945, 827 cm-1; MS: (EI) m/z 196 (M+, 9), 109 (100); HRMS: (EI) calcd for (C11H13FO2)
196.0900 (M+), found m/z 196.0900.
3-(4-bromophenyl)-2,2-dimethylpropanoic acid (1d). Following the typical procedure, the reaction
using diisopropylamine (1.06 g, 11 mmol), n-BuLi (1.6 M in hexane, 5.9 mL, 9.4 mmol), methyl
isobutyrate (0.81 g, 7.9 mmol), and 4-bromobenzyl bromide (2.35 g, 9.4 mmol) provided 1d as a white
solid (1.21 g, 60% yield). mp: 118.4–119.0 ºC; 1H NMR: (400 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz,
2H), 7.04 (d, J = 8.4 Hz, 2H), 2.84 (s, 2H), 1.20 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 184.0,
136.5, 131.9, 131.2, 120.6, 45.2, 43.3, 24.7; IR: (ATR) 2970, 2947, 1692, 1489, 1288, 1011, 945, 833
cm-1; MS: (EI) m/z 258 ([M+2]+, 16), 256 (M+, 17), 171 (95), 169 (100), 90 (35), 89 (25); HRMS: (EI)
calcd for (C11H13BrO2) 256.0099 (M+), found m/z 256.0100.
3-(4-carboxyphenyl)-2,2-dimethylpropanoic acid (1e). Following the typical procedure, the
reaction using diisopropylamine (1.11 g, 11 mmol), n-BuLi (1.6 M in hexane, 6.9 mL, 11 mmol),
methyl isobutyrate (1.02 g, 10 mmol), and 4-methoxycarbonylbenzyl bromide (2.52 g, 11 mmol) was
conducted. The crude product was purified by recrystallization from EtOAc to give 1e as a white solid
(0.91 g, 41% yield). mp: 205.1–207.8 °C; 1H NMR: (400 MHz, DMSO-d6) δ 12.58 (brs, 2H), 7.83 (d,
J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 2.85 (s, 2H), 1.07 (s, 6H); 13C{1H} NMR: (100 MHz, DMSO-
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d6) δ 178.1, 167.3, 143.4, 130.2, 129.0, 128.9, 45.2, 42.6, 24.8; IR: (ATR) 2808, 1678, 1649, 1427,
1416, 1319, 1298, 943, 920 cm-1; MS: (EI) m/z 222 (M+, 9), 135 (100), 107 (36), 91 (20); HRMS: (EI)
calcd for (C12H14O4) 222.0892 (M+), found m/z 222.0891.
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3-(2-bromophenyl)-2,2-dimethylpropanoic acid (1f). Following the typical procedure, the reaction
using diisopropylamine (1.06 g, 11 mmol), n-BuLi (1.6 M in hexane, 5.9 mL, 9.4 mmol), methyl
isobutyrate (0.81 g, 7.9 mmol), and 2-bromobenzyl bromide (2.35 g, 9.4 mmol) provided 1f as a white
solid (1.72 g, 85% yield). 86.5–86.9 °C;1H NMR: (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.29–
7.17 (m, 2H), 7.11–7.05 (m, 1H), 3.17 (s, 2H), 1.27 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ
184.3, 137.5, 133.1, 131.6, 128.2, 127.1, 126.1, 44.0, 43.8, 24.6; IR: (ATR) 2984, 1697, 1474, 1294,
1157, 912, 880, 750 cm-1; MS: (CI) m/z 259 ([M+2+H]+, 95), 257 ([M+H]+, 100); HRMS: (EI) calcd
for (C11H13BrO2) 256.0099 (M+), found m/z 256.0100.
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2,2-dimethyl-3-(3-nitrophenyl)propanoic acid (1g). Following the typical procedure, the reaction
using diisopropylamine (1.11 g, 11 mmol), n-BuLi (1.6 M in hexane, 6.9 mL, 11 mmol), methyl
isobutyrate (1.02 g, 10 mmol), and 3-nitrobenzyl bromide (2.38 g, 11 mmol) provided 1g as a white
solid (1.23 g, 55% yield). mp: 81.4–82.3 °C; 1H NMR: (400 MHz, CDCl3) δ 11.63 (brs, 1H), 8.11 (d,
J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.58–7.41 (m, 2H), 3.01 (s, 2H), 1.25 (s, 6H);13C{1H} NMR: (100 MHz,
CDCl3) δ 183.6, 148.1, 139.6, 136.4, 129.0, 124.9, 121.8, 45.3, 43.5, 24.7; IR: (ATR) 2936, 1694,
1524, 1476, 1352, 1296, 1223, 1130, 914, 733 cm-1; MS: (EI) m/z 223 (M+, 2), 205 (35), 137 (26), 136
(100), 120 (32), 91 (25), 90 (62), 89 (29), 59 (20); HRMS: (EI) calcd for (C11H13NO4) 223.0845 (M+),
found m/z 223.0846.
4-methoxycarbonyl-2,2-dimethylbutanoic acid (1i). A heat-gun-dried round bottom flask containing
a magnetic stir bar was charged with a solution of 2,2-dimethylglutaric anhydride (1.42 g, 10 mmol)
in MeOH (10 mL). The solution was stirred at 50 ºC for 30 min then allowed to warm up to 100 ºC.
Then the solution was stirred an additional 1 h. The solution was concentrated under reduced pressure
to give the crude product as a yellow oil. The crude product was dissolved in EtOAc (5 mL), and
cyclohexylamine (0.99 g, 10 mmol) was added. The white solid that formed immediately was collected
and recrystallized twice from acetone to give the cyclohexylammonium salt. The salt was dissolved
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in 2 M HCl and extracted with Et2O. The organic layer was dried over Na2SO4. The solution was
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3
1
concentrated under reduced pressure to give the product as a colorless oil (0.75 g, 47% yield). H
4
5
6
7
8
9
NMR: (400 MHz, CDCl3) δ 3.68 (s, 3H), 2.40–2.31 (m, 2H), 1.96–1.87 (m, 2H), 1.22 (s, 6H); 13C{1H}
NMR: (100 MHz, CDCl3) δ 183.9, 173.8, 51.7, 41.5, 34.8, 29.9, 24.8; IR: (ATR) 2982, 1738, 1697,
1477, 1437, 1373, 1204, 1132, 939 cm-1; MS: (CI) m/z 175 ([M+H]+, 54); HRMS: (CI) calcd for
(C8H15O4) 175.0970 ([M+H]+), found m/z 175.0969.
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1-(2-phenylethyl)cyclohexanecarboxylic acid (1k). Following the typical procedure, the reaction
using diisopropylamine (1.45 g, 14 mmol), n-BuLi (1.6 M in hexane, 9.0 mL, 14 mmol), methyl
cyclohexanecarboxylate (1.85 g, 13 mmol), and (2-bromoethyl)benzene (3.61 g, 20 mmol) provided
1k as a white solid (2.52 g, 85% yield). mp: 91.5–92.5 °C; 1H NMR: (400 MHz, CDCl3) δ 12.23 (brs,
1H), 7.35–7.05 (m, 5H), 2.65–2.53 (m, 2H), 2.20–2.08 (m, 2H), 1.92–1.73 (m, 2H), 1.70–1.16 (m,
13
8H); C{1H} NMR: (100 MHz, CDCl3) δ 183.9, 142.1, 128.4, 128.3, 125.8, 46.9, 42.0, 33.8, 30.6,
25.8, 23.1; IR: (ATR) 2936, 2922, 2859, 1688, 1454, 1244, 1207, 930, 756, 741 cm-1; MS: (EI) m/z
232 (M+, 3), 128 (100), 91 (34); HRMS: (CI) calcd for (C15H21O2) 233.1542 ([M+H]+), found m/z
233.1540.
1-(2-phenylethyl)cyclopentanecarboxylic acid (1l). Following the typical procedure, the reaction
using diisopropylamine (1.06 g, 11 mmol), n-BuLi (1.6 M in hexane, 5.9 mL, 9.4 mmol), methyl
cyclopentanecarboxylate (1.01 g, 7.9 mmol), and (2-bromoethyl)benzene (1.74 g, 9.4 mmol) provided
1
1l as a white solid (1.12 g, 65% yield). mp: 100.4–101.4 °C; H NMR: (400 MHz, CDCl3) δ 11.95
(brs, 1H), 7.38–7.10 (m, 5H), 2.70–2.53 (m, 2H), 2.32–2.14 (m, 2H), 2.06–1.88 (m, 2H), 1.80–1.50
(m, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 184.3, 142.1, 128.34, 128.32, 125.8, 53.8, 41.0, 36.2,
32.4, 25.1; IR: (ATR) 2945, 1688, 1452, 1267, 1215, 947, 745 cm-1; MS: (EI) m/z 218 (M+, 2), 114
(100), 91 (43), 86 (21), 73 (21); HRMS: (CI) calcd for (C14H19O2) 219.1385 ([M+H]+), found m/z
219.1382.
2,2,4-trimethylpentanoic acid (1m). Following the typical procedure, the reaction using
diisopropylamine (5.56 g, 55 mmol), n-BuLi (1.6 M in hexane, 34.0 mL, 55 mmol), methyl isobutyrate
(5.10 g, 50 mmol), and isobutyl bromide (7.54 g, 55 mmol) provided 1m as a pale yellow oil (2.15 g,
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30% yield). 1H NMR: (400 MHz, CDCl3) δ 1.76–1.65 (m, 1H), 1.53 (d, J = 6.8 Hz, 2H), 1.20 (s, 6H),
0.88 (d, J = 6.8 Hz, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 184.8, 49.1, 41.7, 25.7, 25.2, 23.7; IR:
(ATR) 2961, 1697, 1476, 1248, 1182, 941 cm-1; MS: (CI) m/z 145 ([M+H]+, 100); HRMS: (CI) calcd
for (C8H17O2) 145.1229 ([M+H]+), found m/z 145.1230.
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2,2-dimethyl-4-phenoxybutanoic acid (1o). Following the typical procedure, the reaction using
diisopropylamine (1.06 g, 11 mmol), n-BuLi (1.6 M in hexane, 5.9 mL, 9.4 mmol), methyl isobutyrate
(0.81 g, 7.9 mmol), and (2-bromoethoxy)benzene (1.89 g, 9.4 mmol) provided 1o as a white solid
(1.16 g, 70% yield). mp: 87.3–87.7 ºC; 1H NMR: (400 MHz, CDCl3) δ 11.95 (brs, 1H), 7.25 (dd, J =
8.4, 7.2 Hz, 2H), 6.92 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 2.10 (t, J
= 6.8 Hz, 2H), 1.30 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 184.3, 158.7, 129.4, 120.7, 114.4,
64.4, 40.7, 39.0, 25.3; IR: (ATR) 2982, 1692, 1474, 1246, 1225, 1036, 930, 754 cm-1; MS: (EI) m/z
208 (M+, 3), 115 (27), 94 (100), 59 (25); HRMS: (EI) calcd for (C12H16O3) 208.1099 (M+), found m/z
208.1099.
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(2-iodo-2-methylpropyl)benzene (6). A heat-gun-dried round bottom flask containing a magnetic
stir bar was charged with 2-methyl-1-phenylpropan-2-ol (0.78 g, 5.2 mmol), sodium iodide (1.51 g,
10 mmol), and MeCN (25 mL). The solution was cooled to 0 °C, and methanesulfonic acid (0.65 mL,
10 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and
stirred at the same temperature for 2 h. Then, the mixture was diluted with Et2O, washed with water,
sat. NaHCO3 aq., 1 M Na2S2O3 aq., and brine. The organic layer was dried over Na2SO4, and
concentrated under reduced pressure to give the product as a yellow oil (1.20 g, 88% yield). 1H NMR:
(400 MHz, CDCl3) δ 7.35–7.21 (m, 5H), 3.22 (s, 2H), 1.96 (s, 6H); 13C{1H} NMR:
(100 MHz, CDCl3) δ 137.6, 130.7, 127.9, 126.9, 56.2, 49.9, 37.4; IR: (ATR) 2976, 2959, 2920, 1452,
1096 cm-1; MS: (CI) m/z 261 ([M+H]+, 1); HRMS: (EI) calcd for (C10H13I) 260.0062 (M+), found m/z
260.0058.
Typical Procedure for the Decarboxylative Ritter-Type Amination. Otherwise noted, reactions
were performed on the benchtop with a fluorescent light on the ceiling. A heat-gun-dried two-necked
reaction flask containing a magnetic stir bar was charged with carboxylic acid 1 (0.5 mmol),
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PhI(OAc)2 (0.75, 1.0, or 1.25 mmol), and MeCN (5 mL). To the mixture, I2 (0.25 mmol) was added,
and the reaction mixture was stirred at room temperature for the indicated time. The reaction was
quenched by Na2S2O3 aq. (1 M, 10 mL), and extracted with Et2O (3 x 20 mL). Collected organic layers
were dried over Na2SO4. The solution was concentrated under reduced pressure to give the crude
product, which was analyzed by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal
standard. Purification by flash column chromatography on silica gel (hexane/EtOAc) gave the pure
product.
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N-(1,1-dimethyl-2-phenylethyl)acetamide (2a). According to the typical procedure, the reaction
using 2,2-dimethyl-3-phenylpropanoic acid (1a) (89.5 mg, 0.50 mmol), PhI(OAc)2 (321.7 mg, 1.0
mmol), MeCN (5 mL), and I2 (63.3 mg, 0.25 mmol) was conducted at room temperature for 16 h.
Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product
as a white solid (77.0 mg, 81% yield). The analytical data for this compound were in excellent
agreement with the reported data.25
N-[1,1-dimethyl-2-(4-methylphenyl)ethyl]acetamide (2b). According to the typical procedure, the
reaction using 2,2-dimethyl-3-(4-methylphenyl)propanoic acid (1b) (96.4 mg, 0.50 mmol), PhI(OAc)2
(241.9 mg, 0.75 mmol), MeCN (5 mL), and I2 (63.6 mg, 0.25 mmol) was conducted at room
temperature for 16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc =
70:30) gave the product as a white solid (75.1 mg, 73% yield). mp: 72.2–72.6 °C; 1H NMR: (400 MHz,
CDCl3) δ 7.10 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 5.05 (brs, 1H), 3.00 (s, 2H), 2.33 (s, 3H),
1.90 (s, 3H), 1.32 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 169.8, 135.8, 134.9, 130.4, 128.7, 54.0,
44.1, 27.3, 24.6, 21.0; IR: (ATR) 3254, 3078, 2961, 1638, 1566, 1514, 1445, 1362, 758 cm-1; MS:
(CI) m/z 206 ([M+H]+, 100); HRMS: (EI) calcd for (C13H19NO) 205.1467 (M+), found m/z 205.1468.
N-[2-(4-fluorophenyl)-1,1-dimethylethyl]acetamide (2c). According to the typical procedure, the
reaction using 3-(4-fluorophenyl)-2,2-dimethylpropanoic acid (1c) (98.5 mg, 0.50 mmol), PhI(OAc)2
(241.2 mg, 0.75 mmol), MeCN (5 mL), and I2 (63.1 mg, 0.25 mmol) was conducted at room
temperature for 16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc =
70:30) gave the product as a white solid (78.0 mg, 75% yield). mp: 96.2–97.4 °C; 1H NMR: (400 MHz,
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CDCl3) δ 7.16–7.04 (m, 2H), 7.03–6.90 (m, 2H), 5.02 (brs, 1H), 3.04 (s, 2H), 1.91 (s, 3H), 1.30 (s,
6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 169.8, 161.6 (d, JCF = 242.9 Hz), 133.7 (d, JCF = 3.2 Hz),
131.7 (d, JCF = 7.4 Hz), 114.7 (d, JCF = 20.6 Hz), 53.9, 43.3, 27.3, 24.5; 19F NMR: (377 MHz, CDCl3)
δ −120.2; IR: (ATR) 3281, 2959, 2922, 1641, 1564, 1508, 1443, 1362, 1229, 706 cm-1; MS: (CI) m/z
210 ([M+H]+, 100); HRMS: (CI) calcd for (C12H17FNO) 210.1294 ([M+H]+), found m/z 210.1294.
N-[2-(4-bromophenyl)-1,1-dimethylethyl]acetamide (2d). According to the typical procedure, the
reaction using 3-(4-bromophenyl)-2,2-dimethylpropanoic acid (1d) (128.1 mg, 0.50 mmol),
PhI(OAc)2 (241.3 mg, 0.75 mmol), MeCN (5 mL), and I2 (63.2 mg, 0.25 mmol) was conducted at
room temperature for 16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc
= 70:30) gave the product as a white solid (104.9 mg, 78% yield). mp: 119.7–120.1 °C; 1H NMR: (400
MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 5.05 (brs, 1H), 3.03 (s, 2H), 1.90
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(s, 3H), 1.30 (s, 6H); C{1H} NMR: (100 MHz, CDCl3) δ 169.8, 137.1, 132.1, 131.0, 120.3, 53.9,
43.5, 27.4, 24.5; IR: (ATR) 3281, 3080, 2965, 1641, 1555, 1489, 1433, 1371, 1013, 841 cm-1; MS:
(CI) m/z 272 ([M+2+H]+, 94), 270 ([M+H]+, 100); HRMS: (CI) calcd for (C12H17BrNO) 270.0494
([M+H]+), found m/z 270.0494.
N-[2-(4-carboxyphenyl)-1,1-dimethylethyl]acetamide (2e). According to the typical procedure, the
reaction using 3-(4-carboxyphenyl)-2,2-dimethylpropanoic acid (1e) (111.5 mg, 0.50 mmol),
PhI(OAc)2 (241.2 mg, 0.75 mmol), MeCN (5 mL), and I2 (63.4 mg, 0.25 mmol) was conducted at
room temperature for 16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc
= 50:50) gave the product as a white solid (77.8 mg, 66% yield). mp: 242.6–243.8 °C; 1H NMR: (400
MHz, DMSO-d6) δ 7.84 (d, J = 8.0 Hz, 2H), 7.23 (brs, 1H), 7.20 (d, J = 8.0 Hz, 2H), 3.04 (s, 2H),
1.77 (s, 3H), 1.18 (s, 6H); 13C{1H} NMR: (100 MHz, DMSO-d6) δ 169.4, 167.3, 143.8, 130.4, 128.8,
128.6, 52.9, 43.3, 27.0, 23.6; IR: (ATR) 3319, 2926, 1678, 1649, 1555, 1423, 1288, 750, 702 cm-1;
MS: (CI) m/z 236 ([M+H]+, 100); HRMS: (CI) calcd for (C13H18NO3) 236.1287 ([M+H]+), found m/z
236.1285.
N-[2-(2-bromophenyl)-1,1-dimethylethyl]acetamide (2f). According to the typical procedure, the
reaction using 3-(2-bromophenyl)-2,2-dimethylpropanoic acid (1f) (128.0 mg, 0.50 mmol), PhI(OAc)2
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(241.6 mg, 0.75 mmol), MeCN (5 mL), and I2 (63.2 mg, 0.25 mmol) was conducted at room
temperature for 16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc =
50:50) gave the product as a white solid (103.1 mg, 76% yield). mp: 124.1–124.7 °C; 1H NMR: (400
MHz, CDCl3) δ 7.58–7.52 (m, 1H), 7.28–7.16 (m, 2H), 7.13–7.03 (m, 1H), 5.30 (brs, 1H), 3.27 (s,
2H), 1.94 (s, 3H), 1.38 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 169.8, 137.8, 133.0, 132.5, 128.0,
127.0, 126.0, 55.2, 43.1, 27.3, 24.7; IR: (ATR) 3273, 2965, 2928, 1638, 1557, 1433, 1373, 1024, 748,
729 cm-1; MS: (CI) m/z 272 ([M+2+H]+, 97), 270 ([M+H]+, 100); HRMS: (CI) calcd for (C12H17BrNO)
270.0494 ([M+H]+), found m/z 270.0493.
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N-[1,1-dimethyl-2-(3-nitorophenyl)ethyl]acetamide (2g). According to the typical procedure, the
reaction using 2,2-dimethyl-3-(3-nitrophenyl)propanoic acid (1g) (111.8 mg, 0.50 mmol), PhI(OAc)2
(321.9 mg, 1.0 mmol), MeCN (5 mL), and I2 (63.8 mg, 0.25 mmol) was conducted at room temperature
for 16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the
product as a white solid (92.1 mg, 78% yield). mp: 171.3–171.7 °C; 1H NMR: (400 MHz, CDCl3) δ
8.12–8.03 (m, 1H), 7.98 (s, 1H), 7.53–7.40 (m, 2H), 5.22 (brs, 1H), 3.22 (s, 2H), 1.94 (s, 3H), 1.32 (s,
6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 170.1, 148.0, 140.3, 136.6, 128.7, 124.9, 121.4, 53.8, 43.4,
27.4, 24.3; IR: (ATR) 3254, 3073, 2965, 1638, 1566, 1514, 1445, 1373, 758 cm-1; MS: (CI) m/z 237
([M+H]+, 100); HRMS: (CI) calcd for (C12H17N2O3) 237.1239 ([M+H]+), found m/z 237.1241.
N-[1,1-dimethyl-3-phenylpropyl]acetamide (2h). According to the typical procedure, the reaction
using 2,2-dimethyl-4-phenylbutanoic acid (1h) (96.3 mg, 0.50 mmol), PhI(OAc)2 (322.4 mg, 1.0
mmol), MeCN (5 mL), and I2 (63.5 mg, 0.25 mmol) was conducted at room temperature for 16 h.
Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product
as a white solid (79.8 mg, 78% yield). mp: 62.0–63.0 °C; 1H NMR: (400 MHz, CDCl3) δ 7.32–7.23
(m, 2H), 7.23–7.13 (m, 3H), 5.28 (brs, 1H), 2.62–2.54 (m, 2H), 2.08–2.01 (m, 2H), 1.88 (s, 3H), 1.36
(s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 169.4, 142.2, 128.4, 128.3, 125.7, 53.7, 41.6, 30.7, 27.1,
24.4; IR: (ATR) 3273, 3084, 1643, 1562, 746 cm-1; MS: (EI) m/z 205 (M+, 34), 148 (26), 146 (60),
131 (100), 101 (60), 100 (31), 91 (64), 60 (22), 58 (86); HRMS: (EI) calcd for (C13H19NO) 205.1467
(M+), found m/z 205.1468.
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4-(acetylamino)-4-methylpentanoic acid methyl ester (2i). According to the typical procedure, the
reaction using 4-methoxycarbonyl-2,2-dimethylbutanoic acid (1i) (87.1 mg, 0.50 mmol), PhI(OAc)2
(402.6 mg, 1.25 mmol), MeCN (5 mL), and I2 (63.6 mg, 0.25 mmol) was conducted at room
temperature for 24 h. Purification by flash column chromatography on silica gel (hexane/EtOAc =
50:50) gave the product as a white solid (63.5 mg, 68% yield). mp: 76.8–77.8 °C; 1H NMR: (400 MHz,
CDCl3) δ 5.76 (brs, 1H), 3.67 (s, 3H), 2.38–2.28 (m, 2H), 2.11–1.99 (m, 2H), 1.92 (s, 3H), 1.32 (s,
6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 174.5, 169.6, 53.1, 51.8, 34.7, 29.3, 26.7, 24.4; IR: (ATR)
3279, 2961, 1728, 1641, 1555, 1435, 1364, 1287, 1209, 1134, 729 cm-1; MS: (CI) m/z 188 ([M+H]+,
100); HRMS: (CI) calcd for (C9H18NO3) 188.1287 ([M+H]+), found m/z 188.1286
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N-(1-methylcyclohexyl)acetamide (2j). According to the typical procedure, the reaction using 1-
methylcyclohexanecarboxylic acid (1j) (71.4 mg, 0.50 mmol), PhI(OAc)2 (402.2 mg, 1.25 mmol),
MeCN (5 mL), and I2 (63.9 mg, 0.25 mmol) was was conducted at room temperature for 16 h.
Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product
as a white solid (54.3 mg, 70% yield). The analytical data for this compound were in excellent
agreement with the reported data.10
N-[1-(2-phenylethyl)cyclohexyl]acetamide (2k). According to the typical procedure, the reaction
using 1-(2-phenylethyl)cyclohexanecarboxylic acid (1k) (116.3 mg, 0.50 mmol), PhI(OAc)2 (322.1
mg, 1.0 mmol), MeCN (2.5 mL), and I2 (63.5 mg, 0.25 mmol) was conducted at room temperature for
16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the
product as a white solid (86.9 mg, 71% yield). mp: 154.8–155.3 °C; 1H NMR: (400 MHz, CDCl3) δ
7.36–7.08 (m, 5H), 5.07 (brs, 1H), 2.61–2.49 (m, 2H), 2.18–1.96 (m, 4H), 1.94 (s, 3H), 1.65–1.18 (m,
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8H); C{1H} NMR: (100 MHz, CDCl3) δ 169.4, 142.6, 128.4, 128.3, 125.6, 55.9, 39.6, 34.9, 29.9,
25.7, 24.4, 21.7; IR: (ATR) 3300, 2930, 1647, 1555, 1447, 1373, 1302, 745, 702 cm-1; MS: (EI) m/z
245 (M+, 15), 186 (37), 141 (29), 140 (35), 104 (84), 98 (100), 95 (20), 91 (62), 60 (81); HRMS: (EI)
calcd for (C16H23NO) 245.1780 (M+), found m/z 245.1781.
N-[1-(2-phenylethyl)cyclopentyl]acetamide (2l). According to the typical procedure, the reaction
using 1-(2-phenylethyl)cyclopentanecarboxylic acid (1l) (109.2 mg, 0.50 mmol), PhI(OAc)2 (241.4
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mg, 0.75 mmol), MeCN (5 mL), and I2 (63.1 mg, 0.25 mmol) was conducted at room temperature for
16 h. Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the
product as a white solid (63.1 mg, 55% yield). mp: 131.1–132.1 °C; 1H NMR: (400 MHz, CDCl3) δ
7.31–7.10 (m, 5H), 5.47 (brs, 1H), 2.64–2.51 (m, 2H), 2.22–2.10 (m, 2H), 2.06–1.93 (m, 2H), 1.89 (s,
3H), 1.77–1.57 (m, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 169.6, 142.4, 128.3, 128.2, 125.6, 64.6,
38.7, 38.0, 31.6, 24.1, 23.5; IR: (ATR) 3275, 2947, 1641, 1551, 1452, 1366, 729 cm-1; MS: (EI) m/z
231 (M+, 6), 172 (28), 127 (34), 126 (29), 104 (55), 91 (70), 84 (86), 81 (21), 60 (100); HRMS: (CI)
calcd for (C15H22NO) 232.1701 ([M+H]+), found m/z 232.1699.
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N-(1,1,3-trimethylbutyl)acetamide (2m). According to the typical procedure, the reaction using
2,2,4-trimethylpentanoic acid (1m) (72.4 mg, 0.50 mmol), PhI(OAc)2 (402.6 mg, 1.25 mmol), MeCN
(5 mL), and I2 (63.7 mg, 0.25 mmol) was conducted under irradiation with a 32 W compact fluorescent
lamp at room temperature for 7 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 70:30) gave the product as a white solid (35.5 mg, 45% yield). mp: 56.4–57.0 °C;
1H NMR: (400 MHz, CDCl3) δ 5.35 (brs, 1H), 1.91 (s, 3H), 1.86–1.58 (m, 3H), 1.33 (s, 6H), 0.94 (d,
13
J = 6.0 Hz, 6H); C{1H} NMR: (100 MHz, CDCl3) δ 169.3, 54.0, 48.1, 27.5, 24.6, 24.5, 24.4; IR:
(ATR) 3277, 2965, 1641, 1564, 1433, 1371, 1312, 1190, 737 cm-1; MS: (CI) m/z 158 ([M+H]+, 100);
HRMS: (CI) calcd for (C9H20NO) 158.1545 ([M+H]+), found m/z 158.1543.
N-(adamantan-1-yl)acetamide (2n). According to the typical procedure, the reaction using 1-
adamantancarboxylic acid (1n) (90.1 mg, 0.50 mmol), PhI(OAc)2 (322.1 mg, 1.0 mmol), MeCN (5
mL), and I2 (63.5 mg, 0.25 mmol) was conducted at room temperature for 6 h. Purification by flash
column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product as a white solid (70.9
mg, 73% yield). The analytical data for this compound were in excellent agreement with the reported
data.26
N-[3-(4-iodophenoxy)-1,1-dimethylpropyl]acetamide (2o-I). According to the typical procedure,
the reaction using 2,2-dimethyl-4-phenoxybutanoic acid (1o) (104.1 mg, 0.50 mmol), PhI(OAc)2
(482.7 mg, 1.50 mmol), MeCN (5 mL), and I2 (126.9 mg, 0.50 mmol) was conducted under irradiation
with a 32 W compact fluorescent lamp at room temperature for 16 h. Purification by flash column
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chromatography on silica gel (hexane/EtOAc = 70:30) gave the product as a white solid (109.6 mg,
63% yield). mp: 114.8–116.2 °C; 1H NMR: (400 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 2H), 6.66 (d, J
= 8.8 Hz, 2H), 5.68 (brs, 1H), 4.06–4.00 (m, 2H), 2.23–2.14 (m, 2H), 1.92 (s, 3H), 1.41 (s, 6H);
13C{1H} NMR: (100 MHz, CDCl3) δ 169.6, 158.4, 138.3, 116.7, 82.9, 65.0, 53.1, 38.9, 27.3, 24.5; IR:
(ATR) 3292, 2930, 1636, 1551, 1487, 1474, 1435, 1362, 1285, 1242, 1227, 1180, 1026, 997, 820, 716
cm-1; MS: (CI) m/z 348 ([M+H]+, 100); HRMS: (EI) calcd for (C13H18INO2) 347.0382 (M+), found
m/z 347.0379.
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tetrahydro-6-(iodomethyl)-3,3-dimethyl-2H-pyran-2-one (3). According to the typical procedure,
the reaction using 2,2-dimethyl-5-hexenoic acid (1p) (71.3 mg, 0.50 mmol), PhI(OAc)2 (322.2 mg,
1.0 mmol), MeCN (5 mL), and I2 (63.9 mg, 0.25 mmol) was conducted at room temperature for 3 h.
Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product
as a yellow oil (109.3 mg, 82% yield). 1H NMR: (400 MHz, CDCl3) δ 4.30–4.19 (m, 1H), 3.43–3.30
13
(m, 2H), 2.11–1.99 (m, 1H), 1.92–1.68 (m, 3H), 1.31 (s, 6H); C{1H} NMR: (100 MHz, CDCl3) δ
176.3, 79.1, 37.7, 33.7, 27.6, 27.4, 26.0, 8.4; IR: (ATR) 2965, 2932, 1730, 1387, 1285, 1136, 1117,
1011, 993 cm-1; MS: (EI) m/z 268 (M+, 5), 97 (48), 55 (100); HRMS: (CI) calcd for (C8H14IO2)
269.0038 ([M+H]+), found m/z 269.0036.
N-acetyl-N-(1,1-dimethyl-2-phenylethyl)acetamide (2a’). White solid. mp: 88.9–89.3°C; 1H NMR:
(400 MHz, CDCl3) δ 7.35–7.16 (m, 5H), 3.29 (s, 2H), 1.90 (s, 6H), 1.43 (s, 6H); 13C{1H} NMR: (100
MHz, CDCl3) δ 174.3, 138.1, 130.6, 128.0, 126.6, 60.7, 44.2, 27.7, 27.1; IR: (ATR) 1730, 1651, 1325,
1312, 1211, 1190, 1165, 1123, 974, 750, 710 cm-1; HRMS: (CI) calcd for (C14H20NO2) 234.1494
([M+H]+), found m/z 234.1495.
Experimental Procedure for 1H NMR Monitoring of a Reaction Mixture of PhI(OAc)2 and 1a.
The mixture of PhI(OAc)2 (32.2 mg, 0.10 mmol) and 2,2-dimethyl-3-phenylpropanoic acid (1a) (8.9
mg, 0.05 mmol) in CD3CN (0.50 mL) was prepared. After mixing for 5 min at room temperature, the
mixture was transferred into NMR tube.
Experimental Procedure for the Ritter-Type Amination of Alkyl Iodide 6. A heat-gun-dried
two-necked reaction flask containing a magnetic stir bar was charged with (2-iodo-2-
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methylpropyl)benzene (6) (52.2 mg, 0.20 mmol), PhI(OAc)2 (64.2 mg, 0.20 mmol) and MeCN (2 mL).
The reaction mixture was stirred for 5 min at room temperature. The reaction was quenched by
Na2S2O3 aq. (1 M, 5 mL), and extracted with Et2O (3 x 10 mL). Collected organic layers were dried
over Na2SO4. The solution was concentrated under reduced pressure to give the crude product, which
was analyzed by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
The Ritter-Type Amination of Oxalic Acid Monoalkyl Ester 7. The reaction was performed on
the benchtop with a fluorescent light on the ceiling. A heat-gun-dried two-necked reaction flask
containing a magnetic stir bar was charged with oxalic acid monoalkyl ester 7 (118.0 mg, 0.50 mmol),
PhI(OAc)2 (321.8 mg, 1.0 mmol), and MeCN (5 mL). To the mixture, I2 (94.9 mg, 0.374 mmol) was
added, and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched
by Na2S2O3 aq. (1 M, 10 mL), and extracted with Et2O (3 x 20 mL). Collected organic layers were
dried over Na2SO4. The solution was concentrated under reduced pressure to give the crude product,
which was analyzed by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product
as a white solid (67.4 mg, 72% yield).
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Typical Procedure for the Ritter-Type Amination of Alcohols via the Formation of Oxalic
Acid Monoalkyl Esters. Reactions were performed on the benchtop with a fluorescent light on the
ceiling. A heat-gun-dried round bottom flask containing a magnetic stir bar was charged with alcohol
(1.0 mmol) and dry Et2O (5 mL), and the resulting solution was cooled to 0 °C. To the mixture, oxalyl
chloride (2.0 mmol) was added dropwise over 10 min, and the reaction mixture was allowed to warm
up to room temperature and stirred for 18 h. The reaction mixture was cooled to 0 °C and quenched
by slow addition of water (10 mL). The aqueous layer was extracted with Et2O (3 x 10 mL), and the
combined organic layers were dried over Na2SO4. The solution was concentrated under reduced
pressure to give the crude product, which was directly used for the next step. The crude product was
dissolved in MeCN (10 mL). To the solution, PhI(OAc)2 (2.0 mmol) and I2 (0.75 mmol) were added,
and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched by
Na2S2O3 aq. (1 M, 20 mL), and extracted with Et2O (3 x 20 mL). Collected organic layers were dried
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over Na2SO4. The solution was concentrated under reduced pressure to give the crude product, which
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was analyzed by H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
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Purification by flash column chromatography on silica gel (hexane/EtOAc) gave the product.
N-[1,1-dimethyl-3-phenylpropyl]acetamide (2h). According to the typical procedure, the reactions
using 2-methyl-4-phenylbutan-2-ol (165.1 mg, 1.0 mmol), dry Et2O (5 mL), oxalyl chloride (253.4
mg, 2.0 mmol), MeCN (10 mL), PhI(OAc)2 (644.4 mg, 2.0 mmol), and I2 (190.4 mg, 0.75 mmol) were
conducted. Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave
the product as a white solid (134.2 mg, 65% yield).
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N-(1-methylcyclohexyl)acetamide (2j). According to the typical procedure, the reactions using 1-
methylcyclohexanol (117.6 mg, 1.0 mmol), dry Et2O (5 mL), oxalyl chloride (253.8 mg, 2.0 mmol),
MeCN (10 mL), PhI(OAc)2 (664.2 mg, 2.1 mmol), and I2 (190.1 mg, 0.75 mmol) were conducted.
Purification by flash column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product
as a white solid (87.1 mg, 54% yield).
N-cyclohexylacetamide (2q). According to the typical procedure, the reactions using cyclohexanol
(103.5 mg, 1.0 mmol), dry Et2O (5 mL), oxalyl chloride (253.6 mg, 2.0 mmol), MeCN (10 mL),
PhI(OAc)2 (644.6 mg, 2.0 mmol), and I2 (190.9 mg, 0.75 mmol) were conducted. Purification by flash
column chromatography on silica gel (hexane/EtOAc = 70:30) gave the product as a white solid (46.1
mg, 32% yield). The analytical data for this compound were in excellent agreement with the reported
data.27
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Number JP16K17868.
Supporting Information. Copies of 1H, 13C, and 19F NMR spectra.
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