Asymmetric Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene

  1. Magnus Rueping and
  2. Sadiya Raja

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany

  1. Corresponding author email

This article is part of the Thematic Series "Organocatalysis".

Guest Editor: B. List
Beilstein J. Org. Chem. 2012, 8, 1819–1824.
Received 07 Jul 2012, Accepted 19 Sep 2012, Published 23 Oct 2012


A new chiral Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene has been developed. The reaction provides optically active aza-tetracycles in good yields with high diastereo- and enantioselectivities under mild reaction conditions.

Keywords: BINOL phosphate; [4 + 2] cycloaddition; Diels–Alder reaction; organocatalysis


The enantioselective aza-Diels–Alder reaction is an important method for the construction of optically active, nitrogen-containing, six-membered rings, such as tetrahydroquinolines and piperidines. N-heterocycles are found in a wide range of natural products and many biologically active compounds [1-4]. To date, most aza-asymmetric Diels–Alder reactions have been catalyzed by chiral Lewis acids [5-16]. Recently, chiral Brønsted acids have attracted interest as effective catalysts for a variety of asymmetric transformations involving imine electrophiles [17-23]. Among others, the aza-Diels–Alder reaction of imino-dienophiles has been investigated and it was shown that the reaction between arylimines and dienes, catalyzed by chiral Brønsted acids, proceeds with high levels of enantioselectivity. However, these reactions are limited to electron-rich dienes including Brassard’s and Danishefsky dienes [24-32]. To the best of our knowledge the enantioselective Brønsted acid catalyzed aza-Diels–Alder reaction of imines with less-electron-rich dienes has not been reported. Thus, we decided to examine the unprecedented Brønsted acid catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene providing optically active nitrogen-containing heterocycles (Scheme 1).


Scheme 1: Brønsted acid catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene.

Results and Discussion

Our initial study began with the examination of the the aza-Diels–Alder reaction of cyclic C-acylimine 1 with cyclopentadiene (2) in the presence of BINOL-derived phosphoric acid diesters and N-triflylphosphoramides 4–6 (Table 1) [33-51] as the catalysts. We were delighted to see that the reaction proceeded smoothly at different temperatures and that the product could be obtained with an enantiomeric excess of 8% ee when the reaction was performed in toluene at −60 °C in the presence of catalyst 4a (Table 1, entry 1). A slight increase in enantioselectivity was observed when the reaction was conducted at −78 °C (Table 1, entry 2). Subsequently, different catalysts were applied in the Brønsted acid catalyzed hetero-Diels–Alder reaction. From the different catalysts tested, phosphoric acid diester 4b, with the 2,4,6-triisopropylphenyl substituent in the 3,3’-position of the BINOL backbone, proved to be the best catalyst, and the product was obtained with an encouraging enantiomeric excess of 74% (Table 1, entry 3). To optimize the reaction conditions further we evaluated the catalyst loading and solvent. However, the reduction of catalyst loading from 5 to 1 mol % resulted in a significant decrease in enantioselectivity (Table 1, entries 8 and 9).

Table 1: Optimization of reaction conditionsa.

[Graphic 1]
entry catalyst x mol % solvent t [min] ee [%]b, c
1d 4a 5 toluene 2 8
2 4a 5 toluene 15 16
3 4b 5 toluene 20 74
4 4c 5 toluene 8h 40
5 5 5 toluene 90 16
6 6a 5 toluene 40 20
7 6b 5 toluene 20 60
8 4b 2 toluene 60 60
9 4b 1 toluene 60 43
10 4b 5 toluene:CHCl3
40 13
11 4b 5 toluene:CH2Cl2
10 20
12 4b 5 toluene:hexane
5 h 74
13 4b 5 toluene:hexane
6 h 90
14 4b 5 toluene:hexane
8 h 94
15 4b 5 toluene:hexane
16 h 94

aReaction conditions: Imine 1, cyclopentadiene (2.0 equiv) and catalyst. bEnantiomeric excess was determined by HPLC on a chiral phase. cOnly one diastereomer is formed. dThe reaction was carried out at −60 °C.

In our previous studies in asymmetric Brønsted acid catalysis, we noticed that solvent mixtures can strongly influence both the reactivity and selectivity. Thus, we evaluated different solvent mixtures. When a 1:1 mixture of toluene and CHCl3 was used the enantioselectivity dropped considerably. The same effect was observed when a mixture of toluene and CH2Cl2 was used (Table 1, entries 10 and 11). Hence, the chlorinated solvents were replaced by hexane. Interestingly, use of a 1:1 mixture of toluene and hexane afforded the corresponding product without loss of selectivity, but, as anticipated, the reaction time was longer (Table 1, entry 12). Pleasingly, when the reaction was carried out in a 2:1 mixture of hexane/toluene the product exhibited excellent enantioselectivity (Table 1, entry 13). Further improvement of selectivity was obtained by increasing the hexane/toluene ratio to 3:1, which delivered the product with an excellent enantiomeric excess of 94% (Table 1, entry 14). With the optimal reaction conditions in hand, the substrate scope of the aza-Diels–Alder reaction was examined (Table 2). Various substituted cyclic C-acylimines 1a–i with electron-donating and electron-withdrawing groups, as well as different substitutions patterns, were applied. In all cases the corresponding tetracyclic products were obtained in high yields and with excellent diastereo- and enantioselectivities. However, the use of less reactive dienes including cyclohexadiene or linear 1,3-pentadienes resulted in reduced product formation or provided the desired products with low enantioselectivities [52-55].

Table 2: Scope of the aza-Diels–Alder reactiona.

[Graphic 2]
entry product t [h] yield [%]b ee [%]c, d
1 [Graphic 3]
3 92 89
2 [Graphic 4]
8 86 94
3 [Graphic 5]
2 83 86
4 [Graphic 6]
4 79 90
5 [Graphic 7]
8 73 91
6 [Graphic 8]
3 94 82
7 [Graphic 9]
48 83 84
8 [Graphic 10]
96 79 91
9 [Graphic 11]
96 83 86

aReaction conditions: Imine 1, cyclopentadiene (2.0 equiv) and 5 mol % 4b. bYield of the isolated product after column chromatography. cThe enantiomeric excess was determined by HPLC on a chiral phase. dOnly one diastereomer is formed.


In conclusion, we have developed an enantioselective Brønsted acid catalyzed aza-Diels–Alder reaction of C-acylimines with cyclopentadiene. The corresponding aza-tetracycles were obtained in high yields and with excellent enantio- and diastereoselectivities under mild reaction conditions. The results reported not only show that chiral BINOL derived phosphoric acid diesters can be efficient catalysts for [4 + 2] cycloadditions involving less-electron-rich dienes but additionally demonstrate the high potential of these acidic Brønsted acids in asymmetric catalysis.


The starting materials 1a–i were synthesized according to a known literature procedure [56].

General procedure for the aza-Diels–Alder reaction: In a typical experiment the imine and cyclopentadiene were suspended in a mixture of hexane/toluene (3:1) in a screw-capped test tube and stirred at −78 °C for 10 min. The catalyst (5 mol %) was added to the solution and the mixture was stirred until consumption of the imine. The crude reaction mixture was directly charged on silica gel and purified by column chromatography (hexane/ethyl acetate as eluent) to afford the desired products.

Supporting Information

Supporting Information File 1: Experimental details and characterization of the synthesized compounds.
Format: PDF Size: 2.1 MB Download


Financial support by the DFG priority programme Organocatalysis is gratefully acknowledged.


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