Novel synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones via decarboxylative cyclization reaction of α-amino acids and α-ketoamides

Article abstract of DOI:10.1016/j.tetlet.2016.12.079

An efficient and practical method was developed for the synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones based on the decarboxylative cyclization reaction of α-ketoamides and proline. In most cases, tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones were obtained with perfect diastereoselectivity to give trans-isomer in excellent yield.

Full text of DOI:10.1016/j.tetlet.2016.12.079

Accepted Manuscript
Novel Synthesis of Tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones via Decar-
boxylative Cyclization reaction of α-Amino Acids and α-Ketoamides
Jia-shou Wu, Hua-jiang Jiang, Jian-guo Yang, Zheng-neng Jin, Ding-ben Chen
PII:
S0040-4039(16)31734-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.079
TETL 48491
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 November 2016
23 December 2016
26 December 2016
Please cite this article as: Wu, J-s., Jiang, H-j., Yang, J-g., Jin, Z-n., Chen, D-b., Novel Synthesis of
Tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones via Decarboxylative Cyclization reaction of α-Amino Acids and α-
Ketoamides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.079
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Novel Synthesis of Tetrahydro-1H-
pyrrolo[1,2-a]imidazol-2-ones via
Decarboxylative Cyclization reaction of α-
Amino Acids and α-Ketoamides
Leave this area blank for abstract info.
Jia-shou Wua,  , Hua-jiang Jiang a , Jian-guo Yang a, Zheng-neng Jina and Ding-ben Chen a

1
Tetrahedron Letters
Novel Synthesis of Tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones via
Decarboxylative Cyclization reaction of α-Amino Acids and α-Ketoamides
Jia-shou Wua,  , Hua-jiang Jiang a , Jian-guo Yang a, Zheng-neng Jina and Ding-ben Chen a
a School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, Zhejiang, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and practical method was developed for the synthesis of tetrahydro-1H-pyrrolo[1,2-
a]imidazol-2-ones based on the decarboxylative cyclization reaction of α-ketoamides and
proline. In most cases, tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones were obtained with perfect
diastereoselectivity to give trans-isomer in excellent yield.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
α-Ketoamide
α-Amino acid
Azomethine ylide
Decarboxylative cyclization
Tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones
Tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones
are
an
and captured by suitable nucleophile to give addition product.3
Considering the bicyclic N,N-acetal ring system of
tetrahydro[1,2-a]imidazol-2-one, we envisioned that it could be
important class of compounds as a result of their occurrence in
many natural products and biologically active molecules.1 There
are a few reported synthetic methods to tetrahydro-1H-
pyrrolo[1,2-a]imidazol-2-ones.2 An overview of the most
important methods is outlined in Scheme 1. Tsuge et al. found
that the reaction of ketenimines 1 with cyclic nitrones 2 could
form tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones,2a but this
method suffers from drawbacks of using highly reactive
ketenimine and limited substrate scope. An intramolecular
oxidative cyclization route to tetrahydro-1H-pyrrolo[1,2-
a]imidazol-2-ones was developed with 2-pyrrolidinyl substituted
amides as substrates (Scheme 1, eq. 2),2b but this oxidative
reaction requires excess amount of mercuric acetate, potassium
hexacyanoferrate(III), or potassium permanganate. More recently,
Wong and co-workers reported a catalytic version of this
transformation, but still with the drawback of using expensive
and less available enzyme catalysts (eq. 3).2cThe group of
Katritzky has reported a multistep approach to 3-substituted-
tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones with moderate
yields from N-Boc-α-aminoamides.1b However, a one-step, atom-
economic route to tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones
is more attractive. So, development of an efficient and practical
route to prepare tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones is
still of highly desirable.
α-Amino acids are readily available natural compounds.
Therefore, the use of α-amino acids as the nitrogen-containing
motifs in organic synthesis is very attractive. The
decarboxylation reaction of α-amino acid with aldehyde or
Scheme 1. Previous approaches to the synthesis of tetrahydro-
1H-pyrrolo[1,2-a]imidazol-2-ones
ketone leads to azomethine ylide, which then can be protonated
———
 Corresponding author. Tel./ fax: +86 576 886 60177; e-mail: jsw79@tzc.edu.cn

2
Tetrahedron
10
i-PrOH
90
75
81
accessed via an intramolecular nucleophilic addition reaction of
azomethine ylide intermediate formed from the decarboxylation
reaction of ketoamide with proline (Scheme 2). In continuation
of our ongoing research interests in the decarboxylation reactions
of α-amino acids,4 we’d like to describe herein a novel, efficient,
atom-economic
a]imidazol-2-ones.
11
n-BuOH
110
a Reaction conditions: 3aa (0.50 mmol), 4a (0.55 mmol), solvent (1.5 mL), 10
h.
b With 0.2 equiv. of DIPEA.
c Isolated yield.
approach
to
tetrahydro-1H-pyrrolo[1,2-
d With 0.50 mmol of 4a.
Initially, the reaction of ketoamide 3aa with proline was
performed in toluene at 130 oC in a sealed tube (Table 1). As
Having the optimized reaction conditions in hand (Table 1,
entry 7), decarboxylative cyclization reaction of proline with
various α-ketoamides was examined, and the results are
summarized in Table 2. N-Phenyl-substituted α-ketoamides
having various functional groups in the aniline part reacted
smoothly with proline to give the corresponding tetrahydro-1H-
pyrrolo[1,2-a]imidazol-2-ones. In general, high yields (70-98%)
were obtained irrespective of the electronic or steric variation of
the N-phenyl ring (5ab-aq).
When dichloro-substituted
ketoamide was employed, the desired product 5aq formed in
relatively lower yield. N-naphthyl-substituted α-ketoamide was
applicable affording the expected tetrahydro-1H-pyrrolo[1,2-
a]imidazol-2-one 5ar in 88% isolated yield. N-alkyl and N-
unsubtituted α-ketoamide also worked well, and excellent yields
were obtained (5as-av). Various 2-aryl substituted ketoamides
were well tolerated (5ba-bf). Heterocyclic ketoamide was also
reactive giving 5bg in 63% yield. When 2-oxo-N-(p-
tolyl)propanamide was used, 5bh was isolated as a 10:1 mixture
of diastereomers in 56% yield.
Scheme 2. A proposed route for the synthesis of tetrahydro-
1H-pyrrolo[1,2-a]imidazol-2-ones
expected, tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-one 5aa was
obtained in 66% isolated yield as a single diastereomer (entry 1).
The structure of 5aa was characterized by NMR spectra, and the
NOE experiments indicated that the relationship between the two
methine hydrogens adjacent to the nitrogen atom was trans (see
supporting information). Addition of base had little effect on
yield (entry 2). A significant improvement in efficiency was
observed when DMF was used as the solvent (entry 3). Other
solvents such as DMSO, 1,4-dioxane and 2-ethoxyethanol also
gave good results (entries 4-6). i-PrOH proved to be the solvent
Table 2. Synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-
2-ones via decarboxylative cyclization reaction of proline
with α-ketoamides a
o
of choice giving 5aa in 94% isolated yield after 10 h at 110 C
Entry
1
3
Product
Yield
(%) b
(entry 7). Lowering the amount of 4a from 1.1 to 1.0 equiv led to
a slight drop in yield (entry 8). Decreasing the reaction
temperature was found to be detrimental (entries 9-10). As
comparison, when n-butanol was employed as the solvent, the
yield decreased to 81% (entry 11).
89
3ab
3ac
Table 1. Optimization of the reaction conditions a
5ab
5ac
2
3
90
91
Entry
Solvent
Temp (°C)
130
Yield (%) c
1
2b
3
4
5
6
7
8
9
toluene
66
63
85
92
91
92
94
92d
80
toluene
130
DMF
130
3ad
3ae
5ad
5ae
DMSO
130
4
97
1,4-dioxane
2-ethoxyethanol
i-PrOH
130
130
110
i-PrOH
110
i-PrOH
100

3
5
95
16
17
18
19
20
21
22
23
70
3af
3aq
3ar
5aq
5ar
5as
5at
88
91
92
86
93
92
93
5af
6
7
86
95
3ag
5ag
3as
3at
3ah
3ai
5ah
5ai
5aj
8
9
96
87
3au
3av
3ba
5au
5av
5ba
3aj
10
93
5ak
3ak
3al
11
12
92
95
3bb
3bc
5bb
5bc
5bd
24
25
26
96
97
91
5al
3bd
3be
5am
3am
3an
13
95
5be
5bf
5bg
5an
27
92
63
14
15
98
92
3bf
28
29
3ao
3ap
5ao
5ap
3bg
56,
10:1
dr
3bh

4
Tetrahedron
5bh
Acknowledgments
a Reaction conditions: 3 (0.50 mmol), 4a (0.55 mmol), i-PrOH (1.5 mL),
110oC, 10 h.
We are grateful to the Natural Science Foundation of China
(21402137 and 21302135) and the Chemical Engineering &
Technology of Zhejiang Province First-Class Discipline (Taizhou
University) for financial support.
b Isolated yield.
References and notes
1.
2.
3.
(a) Yamada, S.; Takahashi, Y. Tetrahedron Lett. 2009, 50, 5395-
5398. (b) Katritzky, A. R.; He, H.-Y.; Wang, J. J. Org. Chem.
2002, 67, 4951-4956. (c) Bell, S. C.; Gochman, C. U.S. Patent 3
631 061, 1971; d) Bell, S. C.; Gochman, C. U.S. Patent 3 423
459, 1969.
(a) Tsuge, O.; Watanabe, H.; Masuda, K.; Yousif, M. M. J. Org.
Chem. 1979, 44, 4543-4547. (b) Vasvari-Debreczy, L.; Beckett, A.
H.; Vutthikongsirigool, W. Tetrahedron 1981, 37, 4337-4342. (c)
Ren, X.; O’Hanlon, J. A.; Morris, M.; Robertson, J.; Wong, L. L.
ACS Catal. 2016, 6, 6833-6837.
(a) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10,
889-892. (b) Bi, H.-P.; Teng, Q.; Guan, M.; Chen, W.-W.; Liang,
Y.-M.; Yao, X.; Li, C.-J. J. Org. Chem. 2010, 75, 783-788. (c)
Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798-1799. (d)
Das, D.; Richers, M. T.; Ma, L.; Seidel, D. Org. Lett. 2011, 13,
6584-6587. (e) Zhang, C.; Das, D.; Seidel, D. Chem. Sci. 2011, 2,
233-236. (f) Yang, D.; Zhao, D.; Mao, L.; Wang, L.; Wang, R. J.
Org. Chem. 2011, 76, 6426-6431. (g) Firouzabadi, H.; Iranpoor,
N.; Ghaderi, A.; Ghavami, M. Tetrahedron Lett. 2012, 53, 5515-
5518. (h) Dighe, S. U.; Kumar K. S., A.; Srivastava, S.; Shukla, P.;
Singh, S.; Dikshit, M.; Batra, S. J. Org. Chem. 2015, 80, 99-108.
(a) Wu, J.; Jiang, H.; Chen, D.; Shen, J.; Zhao, D.; Xiang, J.;
Zhou, Q. Synlett 2014, 25, 539-542. (b) Jin, Z.; Jiang, H.; Wu, J.;
Gong, W.; Cheng, Y.; Xiang, J.; Zhou, Q. Tetrahedron Lett. 2015,
56, 2720-2723.
Scheme 3. Decarboxylation reaction of 3aa with α-amino
acids
4.
As a comparison, the reaction of ketoamide 3aa with
thioproline 4b failed to afford any product even at an elevated
reaction temperature (Scheme 3). While the reaction of 4-
hydroxy proline with 3aa gave a pyrrole derivative 6 instead of
the desired cyclization product. When acyclic amino acid N-
methylglycine was used, the desired decarboxylative cyclization
product 7 was isolated in 33% yield. However, the reaction of
3aa with N-benzylglycine was rather complex.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
In conclusion, we have developed an efficient and practical
method for the synthesis of tetrahydro-1H-pyrrolo[1,2-
a]imidazol-2-ones from readily available starting materials based
on the decarboxylative cyclization reaction of α-ketoamides and
proline. In most cases, the reaction proceeded with perfect
diastereoselectivity to give trans-isomer in excellent yield.
Click here to remove instruction text...

5
Research highlights

An efficient and practical approach to tetrahydro-1H-
pyrrolo[1,2-a]imidazol-2-ones.


Two C-N bonds are formed in one step.
In most cases, high yields and perfect
diastereoselectivity were obtained.