Highly efficient and versatile synthesis of lactams and N -heterocycles via Al(OTf)3-catalyzed cascade cyclization and ionic hydrogenation reactions

Article abstract of DOI:10.1021/ol403173x

The discovery and development of an efficient and versatile method for the synthesis of N-substituted lactams is described. Pyrrolindinones, piperidones, and structurally related heterocycles were formed by Al(OTf)₃- catalyzed cascade cyclizati

Full text of DOI:10.1021/ol403173x

Letter
pubs.acs.org/OrgLett
Highly Efficient and Versatile Synthesis of Lactams and
N‑Heterocycles via Al(OTf)3‑Catalyzed Cascade Cyclization and Ionic
Hydrogenation Reactions
Jianguo Qi,†,§ Chenbin Sun,‡,§ Yulin Tian,† Xiaojian Wang,*,†,‡ Gang Li,† Qiong Xiao,‡ and Dali Yin*,†,‡
†State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P.R. China
‡Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of
Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P.R. China
S
* Supporting Information
ABSTRACT: The discovery and development of an efficient and
versatile method for the synthesis of N-substituted lactams is
described. Pyrrolindinones, piperidones, and structurally related
heterocycles were formed by Al(OTf)3-catalyzed cascade cyclization
and ionic hydrogenation reactions of corresponding nitrogen
substituted ketoamides in good yields.
N-Substituted lactams constitute an important class of chemical
structures that have found widespread applications in agro-
chemicals, pharmaceuticals (Figure1), and other industries.1
Scheme 1. Strategies for the Synthesis of Pyrrolidinones and
Piperidones
Figure 1. Pharmacologically active nitrogen substituted lactams.
Because lactam derivatives have great influence in their
properties, efficient methods for the preparation of this
structural unit are highly desirable. In the past few decades,
several approaches to lactams have been developed (Scheme
1). Nicolaou and Li et al. reported that pyrrolidinones could be
formed by unactivated alkenes via a radical mechanism.2,3 Che
et al. and Hartwig also used alkenes as starting material to
afford pyrrolidinones by a hydroamination method.4,5 Baudoin
and co-workers reported a novel method for preparing N-
arylated lactams that relied on the Pd-catalyzed coupling
reaction.6 In addition, transition-metal-catalyzed reductive
amination methods were developed to convert levulinic acid
to pyrrolidinones in one pot.7 During studies on the
methodology of the construction of heterocycles, we discovered
that Al(OTf)3-catalyzed cascade cyclization and ionic hydro-
genation reactions could generate five- and six-membered
heterocycles with substitution of various groups in good yields
under conventional conditions.
such a combination might be utilized though Lewis acid
catalyzed cyclization and ionic hydrogenation to provide
pyrrolidinones from N-substituted γ-ketoamides. 4-Oxo-N-
phenylpentanamide 1a was initially employed as a substrate
with the TiCl4 /Et3SiH/CH2Cl2 system in our investigation.
Hydroxyamide 1c was detected as the major product while only
10% N-phenyl pyrrolidinone (1b) was obtained (Table1, entry
1). Further study was performed to investigate the effects of
different solvent systems and various Lewis or Brønsted acid
catalysts for intramolecular cyclization of γ-ketoamide 1a. As
shown in Table 1, CH3CN proved to be superior and resulted
in a 30% yield among the solvents tested (Table 1, entries 1−
The idea was based on our recent finding that tetralins could
be obtained from arene-1,4-diones with a combination of
TiCl4/Et3SiH.8 Encouraged by this result, we conceived that
Received: November 3, 2013
Published: December 6, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Table 2. Assembly of N-Substituted Pyrrolidinones and
a
Piperidinones from Ketoamides
b
yield (%)
entry
catalyst (equiv)
solvent
time (h)
1b
1c
1
2
TiCl4 (2.0)
CH2Cl2
THF
5
5
4
5
4
4
3
1
1
1
1
1
2
10
25
30
0
65
30
45
50
50
69
0
TiCl4 (2.0)
3
TiCl4 (2.0)
CH3CN
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
4
TiCl4 (2.0)
5
SnCl4 (2.0)
8
6
AlCl3 (2.0)
29
76
97
98
98
80
45
85
7
CF3COOH (2.0)
Al(OTf)3 (2.0)
Al(OTf)3 (1)
Al(OTf)3 (0.5)
Al(OTf)3 (0.5)
Al(OTf)3 (0.5)
Al(OTf)3 (0.2)
8
0
9
0
10
0
c
11
0
d
12
0
13
0
a
All reactions were performed at reflux for 1−5 h with 1.0 mmol of 1a,
the indicated amount of Lewis or Brønsted acid, and 2.0 equiv of
b
c
Et3SiH in 5.0 mL of the indicated solvent. Isolated yields. 1.5 equiv
of Et3SiH. 1.0 equiv of Et3SiH.
d
4). Then, attention was turned to screen various Lewis or
Brønsted acids (Table 1, entries 5−8) to facilitate the
cyclization step. Notably, Al(OTf)3 (Table 1, entry 8) was
found to be more generally effective than other agents. The
yield of 1b was significantly increased to 97% with 2 equiv of
Al(OTf)3 after only 1 h. To further optimize the reaction
parameters, the catalyst loadings were reduced to 1, 0.5, and 0.2
equiv, leading to 98%, 98%, and 85% yields, respectively (Table
1, entries 9, 10, and 13). The amount of Et3SiH was also
observed to affect the yield of 1b (Table 1, entries 10−12). The
best result was found that 1a was added into CH3CN with
Al(OTf)3 (0.5 equiv)/Et3SiH (2 equiv) and refluxed for 1 h to
afford 1b in 98% yield.
After the optimized reaction conditions were established, we
examined the scope and limitation of this cascade process for
the assembly of 5-methyl-N-(aryl,alkyl)-2-pyrrolidinones. Both
amides from anilines or alkylamines were used to explore the
scope of the reaction. To our delight, the reaction was unbiased
to aryl (Table 2, entries 1−12) or alkyl (Table 2, entries 13−
16) substitution on the nitrogen atom. It was found that all
compounds with electron-donating groups (Table 2, entry 6),
electron-withdrawing groups (Table 2, entries 1, 7−9, and 11),
and halides(Table 2, entries 1−3, 10, and 11) situated at the
ortho, meta, or para position at the aniline phenyl ring
proceeded smoothly and in good yields. It was noteworthy that
the nitro group substituted compound (Table 2, entry 8) was
converted into the corresponding product in good yield, which
was reported as being difficult to prepare under normal
conditions.2 The heterocycle substituted ketoamides (Table 2,
entries 17 and 18) were also found to work well in the current
reaction system. In addition, structure diverse pyrrolidinones
(Table 2, entries 19−23) had also been obtained in moderate
to good yields. Encouraged by the results above, the generality
of this catalytic system was further tested in the reaction of δ-
ketoamides. Corresponding piperidones (Table 2, entries 24−
28) had been achieved, which represented another class of
a
Reaction conditions: All reactions were performed at reflux for 1−4 h
with 1.0 mmol of 1a, 0.5 equiv of Al(OTf)3, and 2.0 equiv of Et3SiH in
b
5.0 mL of dry acetonitrile. Yield of isolated product.
important heterocycle compounds of significant bioactive
interest.9
This Al(OTf)3-catalyzed cascade cyclization and ionic
hydrogenation reaction was considered to provide an efficient
alternative method for the formation of the C−N bond, which
might enable the construction of structure diverse lactams from
a vast array of building blocks. Remarkably, isoindolinones,
oxazolidinone, and dihydroquinazolinone were readily as-
sembled from the corresponding N-aryl amides, carbamates,
and open-chain ureas, respectively, with good yields (Table 3).
The X-ray crystal structure of representative target molecule
20b (CCDC 969129) was elucidated (Figure 2), showing that
the desired intramolecular cyclization of ketoamide had been
achieved by this protocol.
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Organic Letters
Letter
Table 3. Assembly of Isoindolinones, Oxazolidinone, and
Dihydroquinazolinone Catalyzed by Al(OTf)3
AUTHOR INFORMATION
Corresponding Authors
■
a
*E-mail: wangxiaojian@imm.ac.cn.
*E-mail: yindali@imm.ac.cn.
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (NSFC No. 81102322), PUMC
Youth Fund (No. 3332013072), and the Fundamental Research
Funds for the Central Universities.
REFERENCES
■
(1) (a) Brickner, S. J.; Barbachyn, M. R.; Hutchinson, D. K.;
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a
Reaction conditions: All reactions were performed at reflux for 1−4 h
with 1.0 mmol of 1a, 0.5 equiv of Al(OTf)3, and 2.0 equiv of Et3SiH in
5.0 mL of dry acetonitrile. Yield of isolated product.
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Figure 2. X-ray crystal structure of compound 20b.
In conclusion, we have developed an efficient and verstaile
Al(OTf)3-catalyzed cascade cyclization and ionic hydrogenation
method for N-substituted lactams preparation. The reaction is
applicable to a wide range of substrates with various functional
groups to afford the corresponding pyrrolidinones, piperidones,
and structure related heterocycles in moderate to good yields.
The ease of preparation of the nitrogen substituted precursors,
the mild reaction conditions, and the efficiency of this reaction
that enable cyclization and hydrogenation to be attainable in
one step make this protocol an attractive methodology in
organic synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
compounds and X-ray crystal structure data (CIF) for
compound 20b. This material is available free of charge via
the Internet at http://pubs.acs.org.
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dx.doi.org/10.1021/ol403173x | Org. Lett. 2014, 16, 190−192