Organocatalytic [4+1]-annulation approach for the synthesis of densely functionalized pyrazolidine carboxylates

Abstract

A novel one-pot [4+1]-annulation process for the asymmetric synthesis of densely functionalized pyrazolidine carboxylates is described. The in situ generated γ-hydrazino-α,β-unsaturated ester obtained via proline catalysis acts as a four-atom component, and Corey's sulfur ylide or ethyl bromoacetate acts as a one-atom carbon source to construct pyrazolidine carboxylate units in a highly enantio- and diastereoselective fashion.

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The pyrazolidine and pyrazoline moieties are an interesting class of nitrogen-containing heterocyclic structural units found in many complex natural products¹ with significant biological activities (e.g. anticancer,² antidepressant,³ antibacterial,⁴ anticonvulsant,⁵ antiviral,⁶ etc.) and other uses (as an arthropodicidal agent⁷ in agriculture or optical brightening agent).⁸ Furthermore, they can be considered as powerful starting materials for the synthesis of enantiopure azaprolines⁹ and densely functionalized 1,3-diamino derivatives¹⁰ after reductive cleavage of the N–N bond. In particular, recent SAR studies have established that aza-kainic acid derivatives (1) have been proven to exhibit potent neuroexcitatory activity.¹¹

One of the most efficient strategies for the construction of such fused skeletons generally relies on [3+2] cycloadditions of hydrazones to olefins in the presence of Bronsted¹²/Lewis¹³ acids or with strong heating.¹⁴ Their asymmetric synthesis are also reported employing chiral Zr/BINOL,¹⁵ Si-based Lewis acids,¹⁶ transition metal (Pd, Ni, Au)-catalyzed intramolecular annulations¹⁷ including sequential organocatalysis.¹⁸ However, these methods are rather limited due to harsh reaction conditions, complex chiral pool resources, expensive chiral ligands and metal catalysts often involving multistep reaction sequences. To the best of our knowledge, no method has been previously reported for the synthesis of densely substituted pyrazolidine carboxylates in “one-pot” fashion using organocatalysis.

In recent years, proline-catalyzed sequential reactions have gained prominence for the asymmetric synthesis of structurally diverse molecular architectures.^19,20 As part of our program directed towards asymmetric synthesis of bioactive molecules employing organocatalytic sequential reactions,²¹ we envisaged that in situ trapping of γ-hydrazino-α,β-unsaturated ester 6 (ref. 20e) with Corey's sulfur ylide (dimethyloxosulfonium methylide)²² under basic conditions should provide the corresponding highly functionalized cyclopropane carboxylate 3, potent and selective group II metabotropic glutamate receptor (mGluR) antagonists.^3e

Surprisingly, the reaction took a different course to afford the corresponding 3,4-disubstituted pyrazolidine carboxylate 4a as a single diastereomer in 68% yield (Scheme 1).

Scheme 1 In situ trapping of γ-hydrazino-α,β-unsaturated ester 6 with dimethyloxosulfonium methylide.

In this communication, we describe a one-pot sequential procedure for a tandem [4+1] annulation reaction of γ-hydrazino-α,β-unsaturated ester 6 generated in situ with Corey's sulfur ylide or ethyl bromoacetate that proceeds to give densely functionalized chiral pyrazolidine carboxylates 4 & 5 in a highly enantio- and diastereoselective manner (Table 1 and 2).

Table 1 L-Proline catalyzed sequential α-amination/Wittig olefination/Corey–Chaykovsky reaction of aliphatic aldehydes^a

Entry	Aldehyde (2a–k) (R)	Amine (R′)	T (°C)	Products (4a–k)
				Yield^b (%)	ee^c (%)
a Aldehyde (2.5 mmol), amine (R′O2C–N=N–CO2R′) (2.5 mmol), L-proline (10 mol%), Ph3P=CHCO2Et (3.75 mmol), dimethyloxosulfonium methylide (5.0 mmol).b Diastereomeric ratio (dr > 20 : 1) was determined from proton NMR analysis of the crude product.c %ee were determined from chiral HPLC analysis; nd = not determined.
1	Benzyl (2a)	^iPr	0	68	86
2		^iPr	10	75	86
3		^iPr	25	80	86
4		Et	25	79	81
5		^tBu	25	70	86
6	4-Methylbenzyl (2b)	^iPr	25	71	84
7	4-Methoxybenzyl (2c)	^iPr	25	67	87
8	4-Thiomethylbenzyl (2d)	^iPr	25	75	92
9	2-CN-4,5-methylene-dioxybenzyl (2e)	^iPr	25	65	81
10	2-NO2-4,5-methylene-dioxybenzyl (2f)	^iPr	25	69	92
11	2-NO2-4,5-methylene-dioxybenzyl (2f)	^tBu	25	66	94
12	2-Bromo-3,4,5-trimethoxy-benzyl (2g)	^iPr	25	72	94
13	Naphthalene-1-yl-methyl (2h)	^iPr	25	68	90
14	3-Benzyloxypropyl (2i)	^iPr	25	70	92
15	Propyl (2j)	^iPr	25	79	nd
16	Methyl (2k)	^iPr	25	80	nd

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Table 2 L-Proline catalyzed sequential α-amination/Wittig olefination/N-alkylation/Michael addition reaction of aliphatic aldehydes^a

Entry	Aldehyde (2) (R)	Amine (R′)	T (°C)	Products (5a–h)
				Yield^b (%)	ee^c (%)
a Aldehyde (2.5 mmol), amine (R′O2C–N=N–CO2R′) (2.5 mmol), L-proline (10 mol%), Ph3P=CHCO2Et (3.75 mmol), ethyl bromoacetate (3.75 mmol), Cs2CO3 (6.25 mmol).b Isolated yield of products.c %ee were determined from chiral HPLC analysis.d Diastereomeric ratio (dr > 20 : 1) was determined from proton NMR analysis of the crude product.e dr = 7 : 3.f dr = 6 : 1; nd = not determined.
1	Benzyl	^tBu	25	—	—
2		^tBu	50	—	—
3		^tBu	80	50 (5a)^d	86
4		Et	50	72 (5a)^d	96
5	4-Methoxybenzyl	Et	50	77 (5b)^d	96
6	4-F-benzyl	Et	50	64 (5c)^d	95
7	3,4-Dimethylbenzyl	Et	50	75 (5d)^d	94
8	2-NO2-4,5-methyl-enedioxybenzyl	Et	50	64 (5e)^e	88
9	Naphthalene-1-yl-methyl	Et	50	79 (5f)^d	94
10	Pentyl	Et	50	72 (5g)^d	nd
11	Methyl	Et	50	62 (5h)^f	nd

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In order to optimize the reaction conditions, initially the amination/Wittig olefination of hydrocinnamaldehyde 2a was carried out following our amination protocol ^20e that produced the corresponding γ-hydrazino-α,β-unsaturated ester 6 in situ. This was followed by the addition of a solution of dimethyloxosulfonium methylide in DMSO [sulfur ylide (2.0 equiv.), prepared in situ from O=SMe₃I/NaH in DMSO] at 0 °C that gave 4a as a single diastereomer in 68% yield with 86% ee (entry 1). A significant improvement in yield (80%) was, however, realized when the reaction was conducted at 25 °C for 2 h. Increase of temperature (50 °C) resulted in complex reaction mixture. Also, use of other solvents such as CH₂Cl₂ and THF for the tandem protocol resulted in a sluggish reaction with poor yields (<10%). Furthermore, (S)-α,α-diarylprolinol silyl ether as a modified proline catalyst was found to be less effective for the reaction. We then turned our attention to investigate the scope of amine sources, the results of which indicated that diisopropyl was found to be better candidate (Table 1, entry 3). With the optimized reaction condition in hand, we next examined the scope of the reaction. Aldehydes bearing Br, CN, NO₂, OMe, SMe and methylenedioxy groups on the aromatic nucleus, and benzyl ether substitutions in aliphatic compounds were found to be well-tolerated under the reaction condition. For all the cases studied, the products 4a–k were indeed obtained in high yields (65–80%) and excellent enantioselectivities (80–94%) with dr > 20 : 1 (Table 1, entry 6–16).

In order to further extend the scope of [4+1]-annulation strategy, the in situ generated amino ester 6 (R = Bn & R′ = ^tBu) was treated with ethyl bromoacetate (1.5 equiv.) in presence of K₂CO₃ as base at 50 °C and found that the annulation was unsuccessful. However, when Cs₂CO₃ was used as base and heating the mixture at 80 °C, the annulation proceeds smoothly producing the desired pyrazolidine dicarboxylate 5a in 50% yield and 86% ee with dr > 20 : 1. The best results were obtained when the amine source was changed to R′ = Et (72% yield, 96% ee, and dr = 20 : 1 at 50 °C) (entry 4, Table 2). With this optimized reaction conditions, other substrates bearing F, NO₂, Me and OMe substituents on the aromatic nucleus underwent this [4+1] annulations cascade smoothly, affording the corresponding pyrazolidine dicarboxylates 5a–h in high yields with excellent enantio- and diastereoselectivities (Table 2).

The absolute configuration of the newly generated stereogenic centers was assigned on the basis of the previously established configuration of γ-hydazino-α,β-unsaturated ester.^20e The relative stereochemistry in pyrazolidines 4 and 5 is proven unambiguously from X-ray crystallographic analysis²³ (Fig. 1, CCDC 1041539†) as well as COSY and NOESY NMR studies.²⁴

Fig. 1 ORTEP diagram of 4f (R′ = ^tBu).

A probable mechanistic pathway is shown in Scheme 2 in which sulfur ylide adds onto β-carbon of the in situ generated γ-amino-α,β-unsaturated ester 6 to form species A. This in turn is followed by a facile proton exchange²⁵ from the carbamate nitrogen to the basic carbanion A to give the stable species B, which then subsequently undergoes intramolecular cyclization with the removal of DMSO to afford products 4a–k, all occurring sequentially under “one-pot” fashion.

Scheme 2 Probable mechanistic pathway for the formation of 4a–k.

To rationalize the observed high ‘anti’ diastereoselectivity between the two substituents in the formed pyrazolidines 4a–k, Felkin Anh model²⁶ has been proposed (Fig. 2). In this model, nucleophilic attack of the sulfur ylide takes place exclusively at the ‘Si’ face of olefin incorporating Bürgi-Dunitz trajectory²⁷ leading to highly diastereoselective pyrazolidines 4a–k, following transition states (TS-I to TS-III).

Fig. 2 Proposed transition state model (R = alkyl or alkylaryl and R′ = Et, ⁱPr, ^tBu).

In the case of 5a–h, only one diastereomer was obtained predominantly out of four possible diastereomers during Michael addition. This high diastereoselectivity can be explained on the basis of the chelation controlled favorable transition state model.²⁸

To demonstrate its potential applicability, 4a was subjected to reductive cleavage of N–N bond under metal/NH₃ conditions (Na in liquid NH₃, −70 to −40 °C, THF, 1 h) to afford the corresponding anti-1,3-diamino acid 7 (60% yield),²⁹ which are common structural subunits present in many natural products and also useful as chiral ligands (Scheme 3). We have carried out several experiments to deprotect carbamate moieties in 4, 5 and 7 to demonstrate the further utility of this methodology. Unfortunately, we have ended up with complex reaction mixtures in the case of benzyl (Cbz) and tert butyl carbamates (Boc). The deprotection of ethyl carbamate under basic condition was also not successful; starting material was recovered, which may be a limitation of this methodology.³⁰

Scheme 3 Reductive cleavage of N–N bond.

Conclusions

In conclusion, we have described, for the first time, a novel [4+1]-annulation strategy involving a sequential α-amination/Wittig olefination/Corey–Chaykovsky reaction or intramolecular Michael reaction of aldehydes that leads to the synthesis of densely functionalized pyrazolidine carboxylates 4 & 5 containing two to three stereogenic centers with high yields and excellent enantio- and diastereoselectivities. The reductive cleavage of N–N bond in pyrazolidine afforded optically active 2,3-disubstituted 1,3-diamino acid 7. The ready availability of starting materials, milder reaction conditions and the formation of two to three stereogenic centers under “one-pot, metal-free conditions” makes this protocol quite useful in organic synthesis.

Acknowledgements

We sincerely thank CSIR, New Delhi, India (Indus MAGIC project CSC-0123) and DST-SERB (no. SB/S1/OC-42/2014), for financial support. K. G. L and R. D. A thank CSIR, New Delhi, India for senior research fellowships. We thank Dr Rajesh G. Gonnade and Mr Shridhar Thorat (Center for Materials Characterization, CSIR-NCL) for assistance with X-ray crystallography. We also thank Dr B. Senthil Kumar for his initial suggestion and encouragement.

Notes and references

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23. ESI†.
24. The relative stereochemistry of 5g was confirmed by COSY and NOESY studies. A significant NOESY correlation was observed between H₅–H₄ and H₄–H₃ confirming the syn relationship between H₃–H₄–H₅ (see below). .
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28. syn, syn diastereoselectivity obtained during Michael addition can be explained using chelation controlled favorable transition state model as shown below: .
29. Hydrolysis of ester to carboxylic acid was observed during reductive N–N bond cleavage; for detailed experimental procedure see ESI†.
30. Carbamate deprotection in 4, 5 and 7 was unsuccessful with following reaction conditions: (1) R′ = ^tBu; (a) TFA, CH₂Cl₂, 25 °C to 70 °C, 1 h to 12 h; (b) methanolic HCl, 25 °C, 12 h. (2) R′ = Bn; (a) 10% Pd, C/H₂ (1 atm), MeOH; (b) Raney®-Ni, H₂ (60 psi), MeOH. (3) R′ = Et; K₂CO₃, EtOH, 25 °C to 70 °C.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1041539. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra09583b

‡ Both authors contributed equally to this work.

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