Amine-N-heterocyclic carbene cascade catalysis for the asymmetric synthesis of fused indane derivatives with multiple chiral centres

Article abstract of DOI:10.1039/c3cc42823k

An aminocatalytic asymmetric Diels-Alder reaction of 2,4-dienals and labile 1-indenones in situ generated from 3-bromo-1-indanones was developed, producing highly fused indane products with multiple chiral centres followed by a cascade N-heterocyclic carb

Full text of DOI:10.1039/c3cc42823k

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Amine–N-heterocyclic carbene cascade catalysis for the
asymmetric synthesis of fused indane derivatives with
multiple chiral centres†
Cite this: Chem. Commun., 2013,
49, 5892
Received 17th April 2013,
Accepted 9th May 2013
Zhi-Jun Jia,b Kun Jiang,a Qing-Qing Zhou,b Lin Dongb and Ying-Chun Chen*ab
DOI: 10.1039/c3cc42823k
www.rsc.org/chemcomm
An aminocatalytic asymmetric Diels–Alder reaction of 2,4-dienals and hydrofluorene carbocycles.9 Although these types of electrophiles have
labile 1-indenones in situ generated from 3-bromo-1-indanones was been successfully applied in various catalytic asymmetric reactions,10
developed, producing highly fused indane products with multiple chiral catalytic stereoselective Diels–Alder reaction of 1-indenones has been
centres followed by a cascade N-heterocyclic carbene-mediated benzoin scarcely explored in the literature, probably due to their high tendency
condensation.
for polymerisation.11 In our continuing interest in the application of
2,4-dienals via trienamine activation,7 we envisioned that 1-indenones
The development of multiple catalytic systems for cascade reactions should be used as more reactive dienophiles to react with trienamine
has been provoking increasing interest in organic synthesis in recent intermediates to afford the corresponding Diels–Alder cycloadducts,12
years, owing to their high efficacy in the construction of complex which can be further transformed to fused indane derivatives followed
products from simple starting materials without the need for isolation by an NHC-catalysed intramolecular benzoin condensation. Moreover,
and purification of intermediates.1,2 This strategy appears especially labile 1-indenones could be generated in situ from relatively more
remarkable when some intermediates are unstable. While being stable 3-bromo-1-indanone precursors in the presence of a suitable
efficient and attractive, the examples of such reactions remain base,9g which might be compatible with both secondary amine13 and
relatively limited because of a main challenge of cascade catalysis NHC catalysis. Thus, a highly efficient cascade catalytic process would
that each catalyst must be compatible with not only other catalysts but be developed to produce fused indane compounds with multiple
also all reagents and intermediates during the course of the reaction. stereogenic centres, as outlined in Scheme 1.
Recently, much focus has been placed on cascade reactions with
Based on the above considerations, we initially tested the reaction
multiple organocatalysis, since organocatalysis has emerged as a of 3-bromo-1-indanone 3a and 2,4-dienal 4a in CHCl3 with a catalytic
promising area with unique advantages.3 In particular, the seminal amount of amine14 1a and excess triethylamine that has been
studies by Rovis4 have shown that it is possible to utilise secondary proved to be effective for generating 1-indenone from 3a.9g Unfortu-
amine and N-heterocyclic carbene (NHC) simultaneously to realize nately, no desired Diels–Alder cycloadduct was detected (Table 1,
cascade reactions with the incorporation of multiple catalytic cycles entry 1). The same results were obtained with K2CO3 (entry 2).
in a single procedure. Very recently, Melchiorre5 and our group6 Since an acid is generally necessary for trienamine catalysis,7
independently demonstrated that the newly developed trienamine we turned our attention to some carboxylate salts, which could
catalysis7 could also be effectively combined with NHC catalysis to
access complex chiral products; nevertheless, both reactions have to
be conducted in a sequential catalytic pattern.
Fused indane frameworks have been widely witnessed in a
number of natural products or biologically active materials.8
Apparently, the Diels–Alder reaction of 1-indenones would be one
of the most straightforward methods to construct the related
a College of Pharmacy, Third Military Medical University, Chongqing 400038, China
b Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry, West China School of Pharmacy, and State Key Laboratory of
Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
E-mail: ycchen@scu.edu.cn, ycchenhuaxi@yahoo.com.cn; Fax: +86 28 85502609
† Electronic supplementary information (ESI) available: Experimental procedures,
Scheme 1 A multiple reaction process to access fused indane frameworks via
structural proofs, CIF file of hydrazone of 5a. CCDC 933944. For ESI and crystal-
amine and NHC cascade catalysis.
lographic data in CIF or other electronic format see DOI: 10.1039/c3cc42823k
c
5892 Chem. Commun., 2013, 49, 5892--5894
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Table 1 Screening studies of the cascade reaction of 3-bromo-1-indanone 3a
and 2,4-dienal 4aa
Table 2 Substrate scope and limitationsa,b,c
Entry
1
Solvent
Base
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
CH3CN
Dioxane
CHCl3
CHCl3
CHCl3
CHCl3
NEt3
K2CO3
NaOAc
24
24
6
5
4
5
5
5
4
/
/
32
40
57
40
/
/
/
71
88
88
81
/
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
/
/
9
57
47
47
30
89
91
91
94
10
11
12
5
5
5
a
For entries 1–4, reactions were performed with 3a (0.2 mmol), 4a
(0.1 mmol), 1a (0.02 mmol) and base (0.3 mmol) in CHCl3 (1 mL) at
55 1C. After 4a was consumed, salt 2 (0.02 mmol) was added and the
mixture was stirred at 55 1C for 30 minutes. For entries 5–12, reactions
were performed with 3a (0.2 mmol), 4a (0.1 mmol), 1 (0.02 mmol), salt 2
b
(0.02 mmol) and base (0.3 mmol) in solvent (1 mL) at 55 1C. Isolated
c
yield. Determined by chiral HPLC analysis; dr >19 : 1.
generate the required acids to promote the Diels–Alder reaction after
dehydrobromination. As expected, the corresponding endo-selective
DA adduct could be formed by using NaOAc as the base, but it was
contaminated with the side products resulting from the poly-
merisation of 1-indenone, and slow decomposition was observed
even after purification. It was pleasing that, after adding NHC
precursor 2, a sequential cross benzoin reaction could proceed
smoothly to deliver the highly complex product 5a with excellent
diastereoselectivity and moderate enantioselectivity, albeit in low
yield (entry 3). The DA reaction occurred more rapidly when sodium
benzoate was used. A high ee value was obtained from the benzoin
reaction, but the yield was still unsatisfactory (entry 4).
a
Reactions were performed with 3a (0.2 mmol), 4a (0.1 mmol), 1b
(0.02 mmol), salt 2 (0.02 mmol) and base (0.3 mmol) in CHCl3 (1 mL) at
b
c
55 1C. Isolated yield. ee determined by chiral HPLC analysis; dr
>19 : 1. The absolute configuration of 5a was determined by X-ray
analysis after conversion to 2,4-dinitrobenzenehydrazone, see ESI. The
other products were assigned by analogy.
d
Although our previous attempts to combine amine and NHC
catalysis with 2,4-dienal substrates in a single procedure were
unsuccessful,6 we gratifyingly found that this multiple dehydro- NHC precursor 2 (20 mol%) and 3 equivalent of sodium benzoate. The
bromination–DA cycloaddition–cross benzoin condensation process reactions were conducted at 55 1C in CHCl3 and generally completed
of 3-bromo-1-indanone 3a and 2,4-dienal 4a took place smoothly by within 5 hours. The results are summarised in Table 2. For the reac-
simply combined with excess sodium benzoate and catalytic amount tions with 4-phenyl-2,4-hexadienal 4a, the in situ generated 1-indenones
of amine 1a and NHC precursor 2 together. Product 5a was isolated with electron-withdrawing groups exhibited higher reactivity, and the
after 4 hours in an even higher yield with retained stereoselectivity fused products 5b–5f were obtained in fair to moderate yields and
(entry 5). Subsequently, this cascade catalysis was investigated in with exclusive diastereoselectivity and high enantioselectivity. It was
other solvents. Both yield and enantioselectivity were reduced in noteworthy that the relay NHC catalysis was crucial for the formation of
toluene (entry 6), and the desired product 5a was not obtained these carbocycles. If the reactions were conducted in a sequential
in CH3CN or 1,4-dioxane (entries 7 and 8). Later, we tested other manner, very low yields were observed due to the instability of such
amine catalysts 1b–1e (entries 9–12). Slightly improved ee values DA intermediates. In addition, 1-indenone bearing electron-denoting
were generally observed, while decreased yields were attained with groups also showed good reactivity under the cascade catalysis, and
bulkier catalysts 1c–1e (entries 10–12).
the fused indanes 5g–5j were produced in moderate yields and with
With the optimal conditions in hand, we next explored a series of a similar good stereoselectivity. On the other hand, more 2,4-dienals
3-bromo-1-indanone 3 and 2,4-dienals 4 in the presence of amine 1b, were explored in the reactions with 3-bromo-1-indanone 3a.
c
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´
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adopted to produce fused indane compounds with more structural
diversity. As illustrated in Scheme 2, PCC oxidation of the DA cyclo-
adduct from 3-bromo-1-indanone 3a and 2,4-dienal 4a could give a
lactone product 6 with good diastereoselectivity. More importantly,
a tetrahydropyridine derivative 7 with potential use in medicinal
chemistry could be separated as a single diastereomer after a
domino reductive amination–enamine formation process.13
In conclusion, we have presented an amine–NHC cascade
catalytic reaction of 3-bromo-1-indanones and 2,4-dienals,
which involves a multiple base-promoted dehydrobromination,
asymmetric Diels–Alder reaction via trienamine activation and
the NHC-catalysed intramolecular cross benzoin condensation
process. An array of fused indane derivatives with high molecular
complexity and multiple stereogenic centres were efficiently
produced in a single procedure with high stereoselectivity. More-
over, other selected transformations with the Diels–Alder cyclo-
adducts leading to more diverse and complex scaffolds further
illustrate the synthetic usefulness of this methodology.
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We are grateful for the financial support from the National
Natural Science Foundation of China (21125206 and 21021001)
and Third Military Medical University (2012XZH06).
Notes and references
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c
5894 Chem. Commun., 2013, 49, 5892--5894
This journal is The Royal Society of Chemistry 2013