Nickel(0)-Catalyzed [3+2]-Cycloadditions of Bis(alkylidenecyclopropanes) with Diazenes: A Facile Synthesis of Functionalized ­Pyrazolidine-1,2-dicarboxylates

Keywords

bisalkylidenecyclopropanes - diazenes - pyrazolidine­dicarboxylates - [3+2]-cycloaddition - nickel catalysis

Metal-catalyzed [m+n] cycloaddition reactions are effective tools for the synthesis of carbo- and heterocyclic systems.[1] Functionalized cyclopropanes have been exploited in metal-catalyzed [m+n]-cycloadditions for the synthesis of monocyclic or condensed carbocycles.[2] [3] [4] There are also reports on cycloadditions of activated cyclopropanes with heterodienophiles for the synthesis of monocyclic or condensed carbo- and heterocycles.[2–4] De Meijere and co-workers explored the Lewis acid-catalyzed [3+2] cycloadditions of 2-arylcyclopropane-1,1-dicarboxylates with di­azenes to afford functionalized pyrazolidines.[5] However, [m+n] cycloadditions of functionalized nonactivated cyclopropanes, especially with heterodienophiles, have rarely been reported in the literature.[2c] [d] [6] [7]

Pyrazolidines have been evaluated as antibacterial, antifungal, anticancer, antidepressant, antiinflammatory, antituberculosis, antioxidant, and antiviral agents in various pharmacological studies.[8] Several pyrazolidine-based drugs have been marketed, including the antiinflammatory drug celecoxib, rimonabant for the treatment of obesity, fomepizole as an effective alcohol dehydrogenase inhibitor, and sildenafil as a phosphodiesterase inhibitor.[9] Pyrazolidines are also useful as chiral auxiliaries and as synthetic reagents in multicomponent reactions.[10] In addition, natural products containing pyrazolidine moieties have been shown to have pharmacological properties.[11]

Conventional approaches, such as the condensation of 1,3-dicarbonyl compounds with hydrazines or [3+2] cycloadditions of 1,3-dipoles have been used in syntheses of simple pyrazolines.[12] However, there are few reports on synthesis of functionalized pyrazolidines. Chaudhry et al. recently reported acid-catalyzed cyclizations using allylic hydrazines for the synthesis of pyrazolidines.[13]

In view of these results and our ongoing interest in the cycloaddition chemistry of functionalized cyclopropanes, we wish to report an extension of our nickel(0)-catalyzed [3+2]-cycloadditions of bis(alkylidenecyclopropanes) to the preparation of pyrazolidines by using diazenes (Scheme [1]).[7]

Scheme 1 [3+2]-Cycloadditions of bis(alkylidenecyclopropanes)

In the present work, we examined the [3+2] cycloadditions of bis(alkylidenecyclopropanes) with diazenes such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) as dienophiles (Scheme [1]). The reaction ­resulted in the formation of functionalized cyclopropane-tethered pyrazolidine-1,2-dicarboxylates in good yields.

The bis(alkylidenecyclopropane) reactants 1a–c were synthesized by treating the appropriate dialkyl malonates with 1-vinylcyclopropyl tosylate by using the reported procedure.[14] We examined the cycloaddition reactions of the bis(alkylidenecyclopropanes) 1a–c with azodienophiles in the presence of nickel(0) complexes as catalysts. Importantly, the cycloaddition reactions with the diazenes DIAD and DEAD resulted in the formation of [3+2] cycloadducts, and no competitive [3+2+2] or [3+3+2] cycloadditions were observed.[15] The [3+2] cycloadditions occurred by preferential ring opening at the allylic position of one of the methylenecyclopropane groups of the 2,2-bis(2-cyclopropylideneethyl)malonates 1a–c to afford the corresponding pyrazolidinene-1,2-dicarboxylates 3a–f in good yields.

Treatment of dimethyl bis(2-cyclopropylideneethyl)malonate (1a) with DEAD (2a) in toluene at various temperatures did not result in cycloaddition, and the starting material was recovered (Table [1], entries 1 and 2). The [3+2] cycloaddition of 1a with DEAD (2a) was then examined in the presence of Ni(COD)₂ as catalyst under various conditions (entries 3–13). The reaction proceeded smoothly leading to the formation of diethyl (3E)-3-(5-cyclopropylidene-3,3-bis(methoxycarbonyl)pentylidene)pyrazolidine-1,2-dicarboxylate (3a) in good yields (entries 4–10). However, the [3+2] cycloaddition did not occur in the presence of the ligands PPh₃, DPPE, or P(OEt)₃ when Ni(COD)₂ was used as the catalyst (entries 11–13). The use of fewer equivalents of DEAD led to lower yields due to nonproductive decomposition of DEAD (entries 4 and 5). Poor yields were observed in the polar aprotic solvent DMF, as well as in dichloroethane (DCE) or 1,4-dioxane (entries 8–10). Optimal conversion was obtained by using 10 equivalents of DEAD[16] at 90 °C with toluene as solvent (entry 6).

Table 1 Optimization of the Reaction Conditions for the [3+2] Cycloaddition of Dimethyl 2,2-Bis(2-cyclopropylideneethyl)malonate (1a) with Diethyl Azodicarboxylate (2a)

Entry	Catalyst	Ligand (1 equiv)	DEAD (equiv)	Solvent	Temp (°C)	Time (h)	Yielda (%)
1	–	–	10	toluene	40	24	0b
2	–	–	10	toluene	120	24	0b
3	Ni(COD)2	–	10	toluene	40	24c	10
4	Ni(COD)2	–	1	toluene	90	16	15
5	Ni(COD)2	–	5	toluene	90	16	34
6	Ni(COD)2	–	10	toluene	90	16	72
7	Ni(COD)2	–	10	toluene	120	16	69
8	Ni(COD)2	–	10	1,4-dioxane	90	20	48
9	Ni(COD)2	–	10	DMF	110	24	22
10	Ni(COD)2	–	10	DCE	70	24	24
11	Ni(COD)2	PPh3	10	toluene	120	24	0
12	Ni(COD)2	DPPE	10	toluene	120	24	0
13	Ni(COD)2	P(OEt)3	10	toluene	120	24	0

^a Isolated yield after purification.

^b The starting material was recovered.

^c Incomplete reaction.

After optimization of the reaction conditions, the [3+2]-cycloadditions of various dialkyl 2,2-bis(2-cyclopropylideneethyl)malonates with diazodienophiles using Ni(COD)₂ were explored (Scheme [2]). These reactions resulted in the formation of functionalized pyrazolidine-1,2-dicarboxylates 3a–f in moderate to good yields (Table [2]).[17] No significant change in the yield of the reaction was observed on changing the substrate or the dienophile.

Scheme 2 Nickel-catalyzed [3+2]-cycloaddition of bis(alkylidenecyclopropanes) 1a–c with dialkyl azodicarboxylates 2a and 2b

Table 2 Nickel-Catalyzed [3+2]-Cycloaddition Reactions of Bis­(alkylidenecyclopropanes) 1a–c with Dialkyl Azodicarboxylates^a

Entry	R1	R2	Product	Yieldb (%)
1	Me	Et	3a	72
2	Et	Et	3b	70
3	i-Pr	Et	3c	61
4	Me	i-Pr	3d	68
5	Et	i-Pr	3e	67
6	i-Pr	i-Pr	3f	68

^a Reaction in toluene at 90 °C for 16 h.

^b Isolated yield after purification.

The resulting [3+2] products were characterized by spectroscopic analysis.[18] Diethyl (3E)-3-[5-cyclopropylidene-3,3-bis(isopropoxycarbonyl)pentylidene]pyrazolidine-1,2-dicarboxylate (3c), for example, showed an [M + H]⁺ ion at m/z 495.3 in its mass spectrum. The ¹H NMR (300 MHz) spectrum showed two characteristic multiplets at 5.61 and 5.57 ppm, corresponding to protons H₂ and H₃ respectively (Figure [1]). A characteristic multiplet at 3.70 ppm corresponded to H₁ and two doublets of doublets at 1.05 ppm (J = 4.5 Hz) and 1.02 ppm (J = 4.5 Hz) were assigned to the H₄ and H₅ protons of the cyclopropyl ring, respectively. The ¹³C NMR spectrum showed the presence of two carbonyl carbons at 170.6 and 156.4 ppm corresponding to the isopropyl ester carbonyl and carbamate ester carbonyl, respectively. The ¹³C NMR spectrum also showed the presence of two olefinic carbons at 115.7 and 111.9 ppm, corresponding to C2 and C3, respectively, and two aliphatic carbons at 2.8 and 2 ppm, corresponding to C4 and C5, respectively (Figure [1]).

Figure 1 Diethyl (3E)-3-[5-cyclopropylidene-3,3-bis(isopropoxycarbonyl)pentylidene]pyrazolidine-1,2-dicarboxylate (3c)

A plausible mechanism for the metal-catalyzed cycloaddition involves an initial oxidative addition of the metal complex to the proximal bond of one of the methylene cyclopropanes of 1 to afford metallacyclobutane 4. This is followed by oxidative insertion of the dialkyl azodicarboxylate to afford metallacycle 5. The intermediates 4 and 5 are stabilized by coordination of the π-electrons of neighboring alkylidenecyclopropane moiety with the metal in a metallacyclobutane. The coordination of the metal in the metallacyclobutanes 4 and 5 with the neighboring cyclopropane alkene bond is deemed critical for the formation of functionalized pyrazolidine product 3. Finally, intermediate 5, upon reductive elimination, furnishes the [3+2]-cyclo­adduct product 3 (Scheme [3]).

Scheme 3 Plausible mechanism for the formation of 3

Evidence that the presence of the second alkylidenecyclopropane is crucial for the success of these [3+2] cycloadditions came from the observation that the monoalkylidene compound 6 did not react in this manner, and no bisadducts were obtained (Scheme [4]).

Scheme 4

In conclusion, we have developed an intermolecular [3+2] cycloaddition of previously unexplored bis­(alkylidenecyclopropanes) with diazenes mediated by a nickel(0) catalyst. The diazenes DIAD and DEAD were used in these intermolecular [3+2]-cycloaddition reactions, resulting in the formation of functionalized pyrazolidine-1,2-dicarboxylates in moderate to good yields. Further work ­exploring the application of transition metals in [m+n] ­cycloadditions of bis(alkylidenecyclopropanes) is in progress.

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• 16 An excess of the azodienophile is used to compensate for its thermal decomposition during the reaction.
• 17 [3+2]-Cycloadducts 3a–f; General Procedure Dialkyl azodicarboxylate 2 (2 mmol, 10 equiv) was added to a solution of the appropriate bis(alkylidenecyclopropane) 1 (0.2 mmol, 1 equiv) in toluene (4 mL), and the mixture was degassed for 10 min under argon. Ni(COD)₂ (5 mol%) was added, and the mixture was heated to 90 °C for 16 h. After completion of the reaction, the mixture was cooled to r.t., directly loaded onto a column without evaporation, and purified by flash chromatography [silica gel (100–200 mesh), EtOAc–hexanes].
• 18 Diethyl (3E)-3-[5-Cyclopropylidene-3,3-bis(methoxycarbonyl)pentylidene]pyrazolidine-1,2-dicarboxylate (3a) Colorless liquid; yield: 119 mg (72%). ¹H NMR (300 MHz, CDCl₃): δ = 5.71 (m, 1 H), 5.48 (m, 1 H), 4.13–4.20 (m, 4 H), 3.71 (s, 6 H), 3.65 (m, 2 H), 2.75 (d, J = 9, Hz, 2 H), 2.49 (br s, 2 H), 2.01 (m, 2 H), 1.22–1.27 (m, 6 H), 0.99 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.1, 156.3, 137.7, 126.9, 116.0, 112.3, 61.5, 57.7, 52.1, 46.7, 37.0, 35.5, 29.3, 14.6, 2.6, 2.0. LRMS (ESI): m/z = 439.2 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₃₁N₂O₈: 439.2080; found: 439.2067. Diethyl (3E)-3-[5-Cyclopropylidene-3,3-bis(isopropoxycarbonyl)pentylidene]pyrazolidine-1,2-dicarboxylate (3c) Pale-yellow liquid; yield: 94 mg (61%). ¹H NMR (300 MHz, CDCl₃): δ = 5.61 (m, 1 H), 5.57 (m, 1 H), 5.03 (m, 2 H), 4.19 (m, 4 H), 3.70 (m, 2 H), 2.76 (d, J = 7.2 Hz, 2 H), 2.66 (bs, 2 H), 1.78 (m, 2 H), 1.20–1.32 (m, 18 H), 1.05 (t, J = 4.5 Hz, 2 H), 1.02 (t, J = 4.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.4, 155.6, 137.7, 126.2, 115.5, 112.1, 69.0, 62.4, 57.0, 46.1, 37.8, 35.8, 29.6, 21.5, 14.5, 2.8, 2.0. LRMS (ESI): m/z = 495.3 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₃₉N₂O₈: 495.2706; found: 495.2718.