Bicyclic Pyrazolidinone Derivatives from Diastereoselective Catalytic [3 + 3]-Cycloaddition Reactions of Enoldiazoacetates with Azomethine Imines

Abstract

A highly regio- and diastereoselective synthesis of bicyclic pyrazolidinone derivatives by rhodium(II) acetate catalyzed [3+3]-annulation with enoldiazoacetates and azomethine imines has been achieved in high yield. A vinylogous reaction of the metal enol carbene with the azomethine imine initiates [3 + 3]-cycloaddition, whereas reaction at the carbene center effects N-N-cleavage of the azomethine imine.

Recent reports have demonstrated considerable interest in the development of effective methodologies for formal [3 + 3]-cycloaddition transformations¹ catalyzed by transition metal compounds^2,3 or organocatalysts.⁴ Generation of metallo-vinylcarbene-like intermediates has been the key to successes in transition metal catalyzed reactions, as we have recently demonstrated through efficient and highly stereoselective formal [3 + 3]-cycloaddition reactions between hydrazones^3a or nitrones^3b,c and vinylcarbene intermediates derived from vinylogous attack of the electrophilic metal vinylcarbenes on nucleophilic reactants and are completed by intramolecular electrophilic addition that is coupled with catalyst dissociation (Scheme 1). They offer convenient methodologies for the synthesis of a diverse array of heterocyclic compounds in high yields and selectivities. In an effort to broaden the scope of [3 + 3]-cycloaddition reactions with conveniently accessible enoldiazoacetates we have employed azomethine imine reactants,⁵ whose ability to undergo cycloaddition has recently been reported with metal catalyst-derived vinylcarbenes derived from propargyl esters^2c and (2-acetoxymethyl-2-propenyl)trimethylsilane.^2d

Scheme 1.

[3 + 3]-Cycloaddition with Vinylcarbene Intermediates from Enoldiazoacetates and Dipolar Reactants.

Treatment of enoldiazoacetate 1a with azomethine imine 2a in the presence of a catalytic amount of rhodium acetate at room temperature in dichloromethane did not form a cycloaddition product as we had expected. Instead, this combination of reactants and catalyst resulted in the formation of diimine 3a geometrical isomers in an apparent metal carbene-directed nitrogen-nitrogen cleavage reaction (eq 1). Ring fragmentation of a four-membered ring

(1)

azomethine imine has been noted in a gold-catalyzed reaction of a propargyl benzoate,^2c but not in reactions of the five-membered ring azomethine imine analogs. In efforts to moderate this cleavage reaction, different azomethine imines (Fig. 1) were employed with 1a.⁶ Replacement of the phenylimimium ion group in 2a by the trans-styryliminium group did not change the reaction outcome, and different alkyl substituents at the 4- and 5-positions of the azomethine imines (2b-2f) also showed dominant or complete N-N cleavage. However, phenyl substitution at the 5-position facilitated formal [3 + 3]-cycloaddition which occurred in 43% yield with complete diastereocontrol (eq 2) without evidence of N-N cleavage.

(2)

Figure 1.

Azomethine Imines That Underwent Predominant Ring Fragmentation in Rhodium Acetate Catalyzed Reactions with Enoldiazoacetate 1a.

To ascertain the generality of this cycloaddition process, representative copper, silver and gold catalysts were also used, and optimization of reaction conditions was performed (Table 1). Silver triflate gave a complex mixture whose contents were not pursued. Treatment with copper(II) triflate or AuCl₃ only produced the [3+2]-cycloaddition product 5a in high yield,⁷ although with low diastereocontrol in the case of AuCl₃ catalysis. Rhodium(II) acetate formed the [3 + 3]-cycloaddition product 4a as the sole diastereoisomer without evidence for 5a, and optimization was performed with this catalyst. Very low azomethine imine and catalyst solubilities prevented reaction in hexane, and THF coordination with rhodium acetate limited effective catalysis. However, use of 1,2-dichloroethane improved the yield to 69% from 43% obtained in dichloromethane, and a further increase in yield occurred for the reaction performed in toluene. Increasing the reaction temperature to 50 °C favored [3+3]-cycloaddion with an even higher 85% yield without a decrease in diastereocontrol, but a further increase in the reaction temperature gave a slightly lower product yield.

Table 1.

Optimization of the [3 + 3]-Annulation of OTBS-Substituted Enoldiazoacetate 1a and Azomethine Imine 2g.^a

entry	MLn	solvent	tem p (°C)	yield, %b		drc (cis:trans)
				4a	5a
1	AgOTf	CH2Cl2	23	Complex mixture		--
2	Cu(OTf)2	CH2Cl2	23	-	74	> 20:1
3	AuCl3	CH2Cl2	23	-	91	3:2
4	Rh2(OAc)4	CH2Cl2	23	43	-	> 20:1
5	Rh2(OAc)4	CHCl3	23	64	-	> 20:1
6	Rh2(OAc)4	ClCH2CH2Cl	23	69	-	> 20:1
7	Rh2(OAc)4	Toluene	23	74	-	> 20:1
8	Rh2(OAc)4	Toluene	50	85	-	> 20:1
9	Rh2(OAc)4	Toluene	80	81	-	> 20:1

^aReactions were performed by the dropwise addition over 1 h of enol diazoacetate 1a (0.75 mmol) in 1 mL solvent to the mixture of azomethine imine 2g (125 mg, 0.50 mmol), and catalyst (2.0 mol %) in 4 mL of solvent.

^bIsolated yield after column chromatography.

^cDiastereoselectivities were determined by ¹H NMR spectral analyses of the unpurified reaction mixture.

The tolerance of azomethine substituents R¹ to this [3+3] cycloaddition reaction was evaluated under optimized reaction conditions, and the results obtained are summarized in Table 2. In all cases, the reaction proceeded smoothly to give cycloaddition products 4a-j in good to high yields (52%-91%) with exclusive cis diastereoselectivities (>20:1 dr). Use of electron-donating substituents in R¹ resulted in higher yields of the corresponding cycloaddition products than when R¹ had electronic-withdrawing substituents. In addition, R¹ as furyl (entry 8) or styryl (entry 9) did not diminish reactivity or selectivity (>20:1 dr). Notably, R¹ as cyclohexyl (entry 10) also provided the cycloaddition product in moderate yield with a high diastereomeric ratio.

Table 2.

Rhodium(II) Acetate Catalyzed [3 + 3]-Annulation of Enoldiazoacetate 1a and Azomethine Imines 2.^a

entry	R1	R2	4	yield 4, %b	dr 4c (cis:trans)
1	Ph	Ph	a	85%	> 20:1
2	4-BrC6H4	Ph	b	81%	> 20:1
3	4-MeOC6H4	Ph	c	91%	> 20:1
4	4-NO2C6H4	Ph	d	61%	> 20:1
5	4-ClC6H4	Ph	e	83%	> 20:1
6	3-BrC6H4	Ph	f	78%	> 20:1
7	4-MeC6H4	Ph	g	80%	> 20:1
8	trans-styryl	Ph	h	89%	> 20:1
9	2-furyl	Ph	i	88%	> 20:1
10	cyclohexyl	Ph	j	53%	> 20:1
11	Ph	4-BrC6H4	k	82%	> 20:1
12	Ph	4-MeOC6H4	l	87%	> 20:1
13	Ph		m	86%	> 20:1
14	Ph	CO2Me	n	71%	> 20:1

^aReactions were performed by the dropwise addition over 1 h of enoldiazoacetate 1a (0.75 mmol) in 1 mL of toluene to the mixture of azomethine imine 2 (0.50 mmol), and Rh₂(OAc)₄ (2.0 mol %) in 4 mL of toluene at 50 °C.

^bIsolated yield after column chromatography.

^cDiastereoselectivities were determined by ¹H NMR spectral analyses of the unpurified reaction mixture and were greater than 20:1 in all cases.

Changing the substituent R² of the azomethine imime from phenyl to substituted phenyl (entries 11 and 12, Table 2) had no adverse effect on either reactivity or selectivity. Remarkably, the azomethine imine with an alkynyl substituent or even an ester group provided [3 + 3]-annulation products 4m and 4n in good yield with only the cis stereochemistry as confirmed by single-crystal X-ray analysis of 4b (entry 2).⁸ In contrast, ring fragmentation is the outcome with R² = H, Me, and Bn, and the cause for this disparity appears to be linked to subtle steric and/or stereoelectronic factors.

Enoldiazoacetate 1b in which a methyl group has replaced hydrogen in the 4-position, also favored [3+3] cycloaddition; the desired product 6 was obtained in high 81% yield, and only the all-cis isomer was observed (eq 3) as established by NOE experiments. However, phenyl substituted enoldiazoacetate 1c did not undergo reaction with azomethine ylides, presumably because of steric encumbrance.

(3)

The pathway for this formal [3+3] annulation reaction is triggered by Rh(II) catalyzed dinitrogen extrusion from enoldiazoacetate 1 that forms an electrophilic rhodium vinylcarbene which undergoes either carbenic carbon or vinylogous attack on the nucleophilic nitrogen of the azomethine imine to form adducts 7 or 8 (Scheme 2). The formation of 6a is consistent with steric control in the formation of 8. Subsequent ring formation from 8 followed by extrusion of the catalyst give the dinitrogen-fused heterocyclic ring.⁹ The high diastereoselectiviy in this reaction can be rationalized by minimization of unfavorable steric interactions between the dirhodium position and R² in the transition state that accompanys ring closing. Alternatively, the metal-associated ylide 7 preferentially undergoes N-N cleavage to form diimine 3. The discriminition between the pathways leading to intermediates 7 and 8 has its origin in the steric and/or electronic natuure of R², but the precise cause is unknown.

Scheme 2.

Proposed Pathway for Rh(II) Catalyzed [3+3]-Annulation of Electrophilic Vinycarbene and Azomethine Imines.

In summary, we have developed a highly efficient way to prepare N,N-bicyclic pyrazolidinone derivatives by rhodium(II) acetate catalyzed [3+3]-annulation with enoldiazoacetate and azomethine imines that occur in high yield and, to the extent that we can measure, complete regio- and diasterocontrol. The azomethine imines with aryl and polar substituents at the 5-position selectively attack the vinylogous position of the Rh(II)-vinyl carbenes rather than at the carbene center. Research is currently underway to demonstrate the use of this methodology for other [3+3]-cycloaddition reactions.

Figure 2.

X-ray Structure of Bicyclic Pyrazolidinone 4b.