Highly enantioselective synthesis of 2,3-dihydro-1 H-imidazo[2,1-a isoindol-5(9b H)-ones via catalytic asymmetric intramolecular cascade imidization-nucleophilic addition-lactamization

Article abstract of DOI:10.1021/ol5031603

Highly enantioselective catalytic asymmetric intramolecular cascade imidization-nucleophilic addition-lactamization of N¹-alkylethane-1,2-diamine with methyl 2-formylbenzoate catalyzed by a chiral phosphoric acid represents the first efficient method for the preparation of medicinally interesting chiral 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-ones with high yields and excellent enantioselectivities. This strategy has been shown to be quite general toward various methyl 2-formylbenzoates.

Full text of DOI:10.1021/ol5031603

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Synthesis of 2,3-
Dihydro‑1H‑imidazo[2,1‑a]isoindol-5(9bH)‑ones via Catalytic
Asymmetric Intramolecular Cascade Imidization−Nucleophilic
Addition−Lactamization
Yuwei He,† Chuyu Cheng,† Bin Chen,† Kun Duan,† Yue Zhuang,† Bo Yuan,† Meisan Zhang,†
Yougui Zhou,† Zihong Zhou,† Yu-Jun Su,† Rihui Cao,† and Liqin Qiu*,†,‡,§
†School of Chemistry and Chemical Engineering, Guangdong Engineering Research Center of Chiral Drugs and ‡The Key Laboratory
of Low-carbon Chemistry & Energy Conservation of Guangdong Province, Sun Yat-Sen University, No. 135 Xingangxi Road,
Guangzhou 510275, P. R. China
§Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai, P. R. China
S
* Supporting Information
ABSTRACT: Highly enantioselective catalytic asymmetric intramolecular cascade imidization−nucleophilic addition−
lactamization of N1-alkylethane-1,2-diamine with methyl 2-formylbenzoate catalyzed by a chiral phosphoric acid represents
the first efficient method for the preparation of medicinally interesting chiral 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-
ones with high yields and excellent enantioselectivities. This strategy has been shown to be quite general toward various methyl
2-formylbenzoates.
auxiliary assisted method for this target synthesis.12 To date,
itrogen-containing cyclic compounds with chiral centers
1
Nhave been in synthetic demand in recent years.
In
particular, 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-ones
possess a unique cyclic chiral center, and many compounds
containing this heterocyclic unit in their skeletons have attracted
considerable interest, as they consist of commonly used building
blocks in a wide range of naturally occurring and/or bioactive
substances.2 The biological activities of these compounds have
been well-studied and have shown several promising applica-
tions, including anti-inflammatory agents,3 analgesics,4 blood
pressure lowering agents,5 spasmolytic agents,6 antitussives,7
sedatives, antirheumatics,8 and anorectic agents.9
catalytic asymmetric synthesis of 2,3-dihydro-1H-imidazo[2,1-
a]isoindol-5(9bH)-one still remains a grand challenge. To the
best of our knowledge, there has been no effective related
methodology reported so far. Herein, we disclose the first highly
enantioselective synthesis of 2,3-dihydro-1H-imidazo[2,1-a]-
isoindo l-5(9bH)-ones via asymmetric catalysis (Figure 1).
Chiral phosphoric acids have proven to be efficient catalysts
for many important asymmetric transformations.13 Antilla14
showed that many chiral N,N-aminals, N,O-acetals, N,S-acetals,
Although several methods for the synthesis of racemic 2,3-
dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-ones are available
currently,10 limited approaches to enantioselective synthesis of
the corresponding chiral compounds have been developed. The
first example for the synthesis of chiral 2,3-dihydro-1H-
imidazo[2,1-a]isoindol-5(9bH)-ones was successfully accom-
plished by Katritzky11 et al. via an intramolecular nucleophilic
addition−lactamization cascade between 2-formylbenzoic acid
and chiral 1,2-ethylenediamine under Dean−Stark conditions.
Afterward, Yamada and co-workers reported a chiral sulfonic
Figure 1. Structure of 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-
ones.
Received: October 29, 2014
© XXXX American Chemical Society
A
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Letter
and N,peroxide acetals can be prepared using chiral phosphoric
acids catalysts via nucleophilic addition of imines. The List
group15 and Rueping group16 independently developed
protocols for enantioselective synthesis of the drug molecules
2,3-dihydroquinazolinones bearing a cyclic N,N-aminals struc-
ture via intramolecular amidation between aldehydes and 2-
aminobenzamides. These cyclic aminal compounds were also
successfully synthesized with high enantioselectivities by Tian et
al. and Lin et al.17 Meanwhile, Toste18 and co-workers
established a methodology for the synthesis of similar cyclic
N,N-aminals via cross-dehydrogenative coupling catalyzed by
axially chiral PAs based on BINOL bearing 1,2,3-triazoles at the
3- and 3′-positions. Among the reactions using chiral phosphoric
acid catalysts, most of the nucleophiles were amides, the use of
nonsubstituted alkyl amines instead is rare.19 Inspired by these
pioneer works, attempted investigation of the asymmetric
synthesis of N,N-aminal using nonsubstituted alkylamines as
nucleophiles directly was made by employing chiral phosphoric
acids (Scheme 1).
triisopropylphenyl moiety provided the desired product 3a in
91% yield with 59% ee.
In the optimization of the reaction (Table 1), various solvents
were screened. Nonpolar solvents (entries 1 and 2) allowed the
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
solvent
R1
product
yield (%)
ee (%)
1
PhCH3
C6H6
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
iPr
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
91
88
87
90
87
86
90
94
40
55
88
86
91
82
45
90
88
80
59
55
40
9
2
3
CH2Cl2
CHCl3
Et2O
4
5
37
47
0
6
THF
7
CH3CN
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
8
19
29
77
64
72
90
88
0
Scheme 1. Proposed Pathway for the Preparation of Chiral
2,3-Dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-ones
9
10
11
12
13
Ph2CH
4-iPrBn
2-iPrBn
2,6-di(iPr)Bn
2,6-di(iPr)Bn
2,6-di(iPr)Bn
2,6-di(iPr)Bn
2,6-di(iPr)Bn
2,6-di(iPr)Bn
3g
3g
3g
3g
3g
3g
d
14
e
15
f
16
96
86
70
We started our investigations on the Brønsted acid catalyzed
reaction of methyl 2-formylbenzoate (1.0 equiv) with N1-
benzylethane-1,2-diamine (1.0 equiv). The reaction was carried
out at ambient temperature using a chiral phosphoric acid
derived from 3,3′-phenyl-substituted BINOL ((R)-4a, 10 mol %,
Scheme 2) as the catalyst, toluene as the solvent, and 4 Å MS as a
g
17
h
18
a
Unless otherwise noted, all reactions were run on a 0.1 mmol scale in
b
1.0 mL of solvent with 10 mol % catalyst loading at 25 °C. Isolated
yield. The ee was determined by Chiral HPLC; see the Supporting
Information for details. Reaction was run with 5 mol % catalyst
loading. In the absence of chiral catalyst added. Reaction was run at 0
c
d
e
f
a
Scheme 2. Survey of the Catalysts
g
h
°C. Reaction was run at −10 °C. Reaction was run at −20 °C.
transformation process proceeded with moderate enantioselec-
tivities, while the polar solvents (entries 3−7) resulted in lower
enantioselectivities. The best solvent was toluene for the reaction
system, providing 3a in 59% ee in the trial run (entry 1). It should
be noted that steric hindrance of substrates is an important factor
in the asymmetric catalysis. Substituents R1 on N1-R1-ethane-1,2-
diamine were also explored. The methyl group gave a poor
enantioselectivity with high yield (94% yield, 19% ee) while
introducing a more bulky group such as diphenylmethyl group
was found to be beneficial to the enantioselectivity yet reduced
the product yield (entry 10, 55% yield, 77% ee). The benzyl
group (entries 11−13) provided a high yield (from 86 to 91%),
and the ee value was increased when a more bulky substituent
existed in the ortho-position. The 2,6-diisopropylbenzyl group
was found to be the optimal group for the transformation with
respect to enantioselectivity (entry 13, ee up to 90%). Lower
catalyst loading (5 mol %) showed a slight decrease in
enantioinduction (entry 14, 88% ee). In the absence of acid
catalyst, poor yield for the target product was afforded (entry 15,
45% yield). It is interesting to note that reaction temperature
played a key role in rendering the cascade transformation highly
enantioselective. When the reaction was conducted at 0 °C,
excellent enantioselectivity was observed (entry 16, 96% ee).
Both the yield and ee dropped dramatically when the reaction
was carried out at −10 °C (entry 17, 88% yield, 86% ee) or −20
a
All reactions were run on a 0.1 mmol scale in 1.0 mL of toluene; yield
refers to isolated yield; % ee was determined by chiral HPLC. See the
Supporting Information for details.
desiccant. The intramolecular imidization−nucleophilic addi-
tion−lactamization proceeded smoothly, and the desired
product 1-benzyl-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5-
(9bH)-one was obtained in high yield (89%). However, almost
no enantioselectivity (2% ee) was found in the initial experiment.
Encouraged by the reactivity, we further examined a number of
axially chiral phosphoric acids for the model reaction (Scheme
2). Although most of the tested catalysts aff-orded poor
enantioselectivities, phosphoric acid (R)-4i having a 2,4,6-
B
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Letter
°C (entry 18, 80% yield, 70% ee). Therefore, 0 °C was selected as
the optimal temperature for the balance between the catalyst
activity and product enantioselectivity (entry 16, 90% yield, 96%
ee).
After the optimal conditions were optimized, reaction scope
with regard to variation of the aryl substituent of methyl 2-
formylbenzoate was investigated (Scheme 3). A variety of
respectively). Substrates containing a 4-methyl substituent (1l)
proved viable and gave product 3r with 92% ee. Substrates having
a 4, 5-dimethoxyl substituent (1n) gave product 3t with 88% ee.
An exceptional situation was observed in the reaction of substrate
1q. The poor enantioselectivity (30% ee) is presumably due to
detrimental steric interaction between 3-methoxy and the R1
group.
The absolute stereochemistry of the chiral 2,3-dihydro-1H-
imidazo[2,1-a]isoindol-5(9bH)-one was determined by the
single-crystal X-ray diffraction of 3p (Figure 2). This result
unambiguously shows that the absolute configuration of product
3p to be the (S)-form.
a
Scheme 3. Scope of Substrates 1
Figure 2. Single-crystal X-ray structure of product 3p.
In conclusion, we have successfully developed the first catalytic
asymmetric synthesis of 2,3-dihydro-1H-imidazo[2,1-a]isoindol-
5(9bH)-ones via an intramolecular cascade imidization−
nucleophilic addition−lactamization. This one-pot sequence
using a chiral phosphoric acid as the catalyst provides a simple
and efficient approach to the preparation of various medicinally
important chiral 2,3-dihydro-1H-imidazo[2,1-a]isoindol-5-
(9bH)-ones in high yields with excellent enantiomeric excesses
under mild reaction conditions (up to 94% yield and 96% ee).
Further work will be directed toward the extension of substrate
scope, mechanistic studies, and synthetic application.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Experimental details, characterization data, and NMR spectra of
all new products. This material is available free of charge via the
Internet at http://pubs.acs.org.
All reactions were run on a 0.1 mmol scale in 1.0 mL of toluene; yield
refers to isolated yield; % ee was determined by Chiral HPLC. See the
Supporting Information for details.
AUTHOR INFORMATION
Corresponding Author
substitutions were proven to be successful under this catalytic
system. For instance, substrates bearing halogen at the 4 or 5
position (1b−d,h−j) allowed for excellent enantioselectivities
(92% to 96% ee, 3h−j,n−p). The substrates with an electron-
donating group (methoxyl) at the 4, 5, or 6 position (1f,m,p)
were all excellent for the reaction, giving the corresponding
products with 90−94% ee’s (3l,s,v). Substrates possessing an
electron-withdrawing substituent 5-nitro (1g) or 4-trifluoro-
methyl (1k) provided products 3m and 3q in excellent yields and
enantioselectivities (90% and 91% yields 90% and 91% ees,
■
* E-mail: qiuliqin@mail.sysu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from Special Financial Fund
of Innovative Development of Marine Economic Demonstration
■
C
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Letter
Project (GD2012-D01-001) and Student Innovation Training
Program of Sun Yat-sen University (201401148).
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