Reductive Amination/Cyclization of Keto Acids Using a Hydrosilane for Selective Production of Lactams versus Cyclic Amines by Switching of the Indium Catalyst

Article abstract of DOI:10.1002/anie.201509465

Described herein is that the catalytic construction of N-substituted five- and six-membered lactams from keto acids with primary amines by reductive amination, using an indium/silane combination. This relatively benign and safe catalyst/reductant system tolerates the use of a variety of functional groups, especially ones that are reduction-sensitive. A direct switch from synthesizing lactams to synthesizing cyclic amines is achieved by changing the catalyst from In(OAc)₃ to InI₃. This conversion occurs by further reduction of the lactam using the indium/silane pair.

Full text of DOI:10.1002/anie.201509465

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Chemie
International Edition: DOI: 10.1002/anie.201509465
German Edition: DOI: 10.1002/ange.201509465
Cyclizations
Reductive Amination/Cyclization of Keto Acids Using a Hydrosilane
for Selective Production of Lactams versus Cyclic Amines by Switching
of the Indium Catalyst
Yohei Ogiwara, Takuya Uchiyama, and Norio Sakai*
Abstract: Described herein is that the catalytic construction of
N-substituted five- and six-membered lactams from keto acids
with primary amines by reductive amination, using an indium/
silane combination. This relatively benign and safe catalyst/
reductant system tolerates the use of a variety of functional
groups, especially ones that are reduction-sensitive. A direct
switch from synthesizing lactams to synthesizing cyclic amines
is achieved by changing the catalyst from In(OAc)3 to InI3. This
conversion occurs by further reduction of the lactam using the
indium/silane pair.
S
ince N-substituted lactams are important core structural
units in many research fields such as organic and pharma-
ceutical chemistry, an efficient and versatile method for the
construction of valuable lactam skeletons from simple and
inexpensive substrates would be desirable. The combination
of a reductive amination of keto acids and a subsequent
cyclization is one of the most attractive approaches to these
ring structures, because the starting keto acids are easily
acquired compounds. Levulinic acid (1; 4-oxopentanoic acid)
is accessible from lignocellulosic biomass, and the other
starting compounds are primary amines which readily intro-
duce a variety of N-substituents to the ring skeleton. In this
context, several catalytic or catalyst-free preparations of N-
substituted lactams using keto acids and primary amines
through reductive amination have been reported, but the
reducing reagents are limited to relatively active ones, such as
H2 or formic acid (Scheme 1a).[1] In terms of functional-group
tolerance and chemoselectivity for the production of fine
chemicals, hydrosilanes are mild and highly selective reducing
agents which are considered alternative reductants for
achieving this concept, even though siloxane waste is an
unavoidable byproduct.[2,3] Although several synthetic proce-
dures, such as hydrosilane reductive amination of keto-
amides[4] and 2-carboxybenzaldehyde,5] for the synthesis of
N-substituted lactams have been reported (Scheme 1b), to
the best of our knowledge, the use of keto acids as a substrate
in this type of conversion remains unexplored.
Scheme 1. Reductive amination strategies for the synthesis of lactams.
amines by a reductive amination strategy using PhSiH3 as
a mild reductant (Scheme 1c). A large variety of aromatic and
aliphatic amines are readily available for this reaction, which
gives N-substituted lactams and transforms 2-carboxybenz-
aldehyde into N-arylisoindolinone derivatives.
Also, we disclose a divergent synthesis for cyclic amines,
such as pyrrolidine and piperidine, from the reaction of keto
acids with amines in the presence of the InI3 (Scheme 2). InI3
has a stronger Lewis acidity than In(OAc)3, and thus results in
an over-reduction of the lactam to give N-substituted
pyrrolidines and piperidines.[6]
Scheme 2. Selective production of lactams and cyclic amines (this
work).
We report herein a one-pot In(OAc)3-catalyzed prepara-
tion of N-substituted lactams from keto acids and primary
Initially, we conducted the reaction of levulinic acid (1)
with 1 equivalent of 4-methylaniline (2a) in the presence of
an indium catalyst and a hydrosilane. After several screenings
of the reaction conditions,[7] 1 mol % of In(OAc)3 with
1 equivalent of PhSiH3 in toluene at 1208C was found to be
the best catalytic system, thus giving the desired g-lactam 3a
in a 98% yield upon isolation [Eq. (1)].
The use of other primary amines (2) as a nitrogen source
for the lactam skeleton was explored with the In(OAc)3/
PhSiH3 system (Scheme 3). A variety of aromatic amines, 2b–
u, were applicable in this reaction and formed the corre-
[*] Dr. Y. Ogiwara, T. Uchiyama, Prof. Dr. N. Sakai
Department of Pure and Applied Chemistry, Faculty of Science and
Technology, Tokyo University of Science
2641 Yamazaki, Noda, Chiba 278-8510 (Japan)
E-mail: sakachem@rs.noda.tus.ac.jp
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201509465.
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To construct the d-lactam skeleton, an annulation of 4-
acetylbutyric acid (6) with various aniline derivatives (2) was
next conducted (Table 1). The reactions of the methyl-
substituted anilines 2a–c and aniline (2d), as well as 4- and
2-methoxy anilines (2e and 2 f) afforded the N-aryl d-lactams
Table 1: Substrate scope for d-lactams.[a]
Entry
Ar
t [h]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-MeC6H4 (2a)
3-MeC6H4 (2b)
2-MeC6H4 (2c)
Ph (2d)
4-MeOC6H4 (2e)
2-MeOC6H4 (2 f)
4-ClC6H4 (2g)
3-ClC6H4 (2h)
2-ClC6H4 (2i)
4-BrC6H4 (2j)
4-FC6H4 (2k)
4-NCC6H4 (2m)
4-EtOC(O)C6H4 (2p)
3,4-Me2C6H3 (2t)
3,4-Cl2C6H3 (2z)
1
1
1
3
1
1
3
3
3
5
2
5
5
1
3
7a
7b
7c
7d
7e
7 f
7g
7h
7i
91
94
92
88
91
90
94
90
92
91
96
89
91
94
87
7j
7k
7m
7p
7t
7z
[a] Reaction conditions: 6 (1 mmol), 2 (1 mmol), In(OAc)3 (0.01 mmol),
and PhSiH3 (1 mmol) in toluene (2 mL) at 1208C. [b] Yield of isolated
product.
Scheme 3. Substrate scope for g-lactams. Reaction conditions: 1 or 4
(1 mmol), 2 (1 mmol), In(OAc)3 (0.01 mmol), and PhSiH3 (1 mmol) in
toluene (2 mL) at 1208C. Yields of isolated 3 and 5 are shown.
7a–f in excellent yields (entries 1–6). Anilines bearing
a halogen atom (2g–k), a cyano group (2m), and an
ethoxycarbonyl group (2p) also provided the corresponding
products 7g–p without the loss of those functional groups. In
the cases with disubstituted anilines, the six-membered
lactams 7t and 7z were isolated in 94 and 87% yields,
respectively (entries 14 and 15).
One of the most advantageous features of the present
reaction is that complete conversion into the lactam can be
achieved by using a small quantity of the catalyst with only
1 equivalent of each of the substrates, a keto acid, an amine,
and a silane. Hence, the siloxane which is generated during
the reaction is the sole organic byproduct and enables facile
isolation of the N-substituted lactam in its pure form by
a simple workup. Indeed, after a gram-scale reaction of
1 (10 mmol), 2a (10 mmol), and PhSiH3 (10 mmol) with
0.05 mol% In(OAc)3 in toluene for 48 hours, the desired
lactam 3a was isolated in a 94% yield (1.78 g) by the addition
of methanol, filtration of the precipitate derived from the
siloxane, and silica gel column chromatography. The turnover
number (TON) was 1880 and 3a was isolated in analytically
pure form (as determined by 1H NMR spectroscopy).[7]
The use of a substrate other than a keto acid for this
transformation was next investigated (Scheme 4). Conversion
of 2-carboxybenzaldehyde (8) using the anilines 2a, 2j, and 2s
proceeded to provide the corresponding N-arylisoindolinone
derivatives 9a, 9j, and 9s in 38–93% yields. Isoindolinone
sponding N-aryl g-lactams 3b–u in excellent yields. The
benzylic amines 2v–x and alkyl amine 2y were also converted
into the corresponding N-benzyl (3v–3x) and alkyl (3y) g-
lactams, respectively, in good yields, although the process
required a 24 hour reaction time. When 3-benzoylpropionic
acid (4) was used as a substrate, the reactivity was slightly
decreased compared with that of 1, but the corresponding 5-
phenyl-substituted N-aryl g-lactams 5a, 5d, and 5j were
obtained in good yields. A noteworthy feature of these
examples is that functional groups such as a cyano, nitro, acyl,
ethoxycarbonyl, amide, hydroxy, and vinyl group, which are
sensitive to the conventional reductive amination conditions,
were well-tolerated under our reaction conditions. These
results proved that an In(OAc)3/PhSiH3 system functions as
a relatively mild reducing system.
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Table 2: InI3-catalyzed reductive transformation for cyclic amines.[a]
Entry
n
Substrate
Ar
Product
Yield [%][b]
1
2
3
4
5
6
1
2
1
2
1
2
1
6
1
6
1
6
4-MeC6H4 (2a)
4-MeC6H4
Ph (2d)
10a
11a
10d
11d
10k
11k
91
85
92
89
86
84
Ph
Scheme 4. Applications for isoindolinone derivatives.
4-FC6H4 (2k)
4-FC6H4
[a] Reaction conditions: 1 or 6 (1 mmol), 2 (1 mmol), InI3 (0.01 mmol),
and PhSiH3 (3 mmol) in toluene (2 mL) at 1208C for 24 h. [b] Yield of
isolated product.
skeletons have been found in many important biologically
active compounds such as indoprofen, which is used as
a nonsteroidal anti-inflammatory drug.[8] The carbon–bro-
mine bond in 9j and a vinyl functional group in 9s makes both
of them good reaction sites for further transformations, and
these products are considered precursor compounds for
indoprofen.[9]
During the screening of a series of indium catalysts for
reductive amination/cyclization [Eq. (1)], the N-aryl pyrroli-
dine derivative 10a was generated when InI3, which is known
as a stronger Lewis acid than In(OAc)3, was used as
a catalyst.[7] The pyrrolidine 10a was also obtained by
reduction of 3a using an InI3/PhSiH3 system. In contrast,
the reduction was not observed in case of In(OAc)3
(Scheme 5).
series (see Figure S2 in the Supporting Information). It can be
considered that the rate-determining step would exist in the
initial stage of all processes in this reaction. When using
a mixture of 1, In(OAc)3, and PhSiH3 (the conditions without
2d), no reaction proceeded after 4 hours (see Figure S3). In
contrast, when the reaction of 1, 2d, and In(OAc)3 (conditions
without PhSiH3) was carried out for 24 hours, several weak
signals, which presumably correspond to the imine and/or
ketoamide derivatives, appeared. Therefore, when PhSiH3
was added into the mixture, both the formation of the desired
lactam 3d and the disappearance of the imine and/or
ketoamide derivative signals were observed, thus confirming
the stepwise reaction (see Figure S4). Although additional
detailed information about the intermediates have not been
obtained at this stage, we propose a possible mechanism
through a reductive amination at the carbonyl group of a keto
acid (Scheme 6). First, the condensation of a ketone with
Scheme 5. Formation of the cyclic amine 10a by reduction of the
lactam 3a.
Since 10 would be formed by the further reduction of 3
after the reductive amination/cyclization, an InI3-catalyzed
formation of 10 was examined with an excess of PhSiH3
(3 equiv; Table 2). The reaction of 1 with 2a provided 10a
as the sole product in a 91% yield (entry 1), and annulation of
6 with 2a successfully produced the N-aryl piperidine 11a in
a 85% yield (entry 2). The anilines 2d and 2k also provided
the corresponding five- and six-membered cyclic amines (10
and 11) selectively without any lactams as byproducts
(entries 3–6).
Scheme 6. A plausible mechanism.
a primary amine occurs to form a ketimine. This step is
estimated to be the rate-determining step. Then, a silyl ester
forms through dehydrogenative silylation of a carboxylic acid
[10]
with concomitant generation of H2 and hydrosilylation of
To gain some insight into the mechanism of this reaction,
several spectroscopic investigations were conducted by using
1H NMR analysis.[7] The reaction of the keto acid 1 and 2d
with In(OAc)3/PhSiH3 in [D8]toluene at 1208C for 3 hours
afforded a new singlet, ascribed to H2 (d = 4.51 ppm), with the
signals for the lactam product 3d. It was implied that there
was formation of a silyl ester from 1 and PhSiH3 with the
generation of H2. However, no other new signals, including
those of the silyl ester, were observed during this reaction
the imine. Subsequently, the cyclization affords the N-
substituted lactams with the release of the indium catalyst
and the siloxane. In contrast, another pathway through the
cyclization/hydrogenation from a ketoamide is also possible.[4]
In the case of InI3, an over-reduction of the carbonyl group of
the lactam occurs to produce the corresponding pyrrolidine or
piperidine skeleton.[11]
In summary, we demonstrated an efficient and straight-
forward annulation to N-substituted g- and d-lactams through
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reaction conditions. The major byproduct, a siloxane, derived
from PhSiH3 can be removed as a precipitate by the simple
addition of methanol, and therefore, the desired lactams were
obtained easily in a pure form and could even be synthesized
on gram-scale. When the reaction was conducted in the
presence of InI3, instead of In(OAc)3, and 3 equivalents of
PhSiH3 an over-reduction of the lactam occurred to generate
five- and six-membered cyclic amines as the sole products.
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Acknowledgments
This work was partially supported by a Grant-in-Aid for
Scientific Research (C) (No. 25410120) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
and by the Sasakawa Scientific Research Grant from The
Japan Science Society. We deeply thank Shin-Etsu Chemical
Co., Ltd., for the gift of silanes. We are grateful to Minoru
Gibu, Dr. Yuki Yamaguchi, and Prof. Kenjiro Fujimoto
(Tokyo University of Science) for the ICP analysis.
Keywords: amines · cyclizations · indium · lactams · silanes
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1864–1867
Angew. Chem. 2016, 128, 1896–1899
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[9] Syntheses of indoprofen from either 9j or 9s are now in progress.
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salts as unimportant for the observed reactivity. See the
Supporting Information for the details (Figure S1).
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Received: October 9, 2015
Revised: November 14, 2015
Published online: December 21, 2015
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