Gold-catalyzed three-component spirocyclization: a one-pot approach to functionalized pyrazolidines

Abstract

An efficient, highly atom economic synthesis of hitherto unknown spirocyclic pyrazolidines in a one-pot process was developed. The gold-catalyzed three-component coupling of alkynols, hydrazines and aldehydes or ketones likely proceeds via cycloisomerization of the alkynol to an exocyclic enol ether and subsequent [3 + 2]-cycloaddition of an azomethine ylide. A library of 29 derivatives with a wide range of functional groups was synthesized in up to 97% yield. With this new method, every position in the final product can be substituted which renders the method ideal for applications in combinatorial or medicinal chemistry.

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Introduction

Heterocycles are a pivotal structural element of a large number of pharmaceuticals. Hence, in order to tackle new challenges in medicinal chemistry, there is a growing demand for novel types of heterocycles with tailored pharmacological properties.¹ From the preparative point of view, extensive structural variation of the heterocyclic target molecules is required using the full arsenal of modern synthetic methodology, e.g., catalytic processes utilizing transition metals or organocatalysts,² C–H activation,³ and multicomponent reactions (MCRs).⁴

The use of homogeneous gold catalysts in multicomponent reactions holds great promise. Due to their high reactivity towards π-systems (in particular alkynes), gold catalysts allow a distinctive control of selectivity, as well as, wide tolerance towards reactive functional groups.⁵ Combining this with the advantages of MCRs (rapid assembly of complex structural motifs from small molecules with high atom economy) renders the method highly valuable in combinatorial and medicinal chemistry. Since the first publication of a gold-catalyzed coupling of aldehydes, secondary amines and alkynes by Li et al.,⁶ the number of MCRs catalyzed by gold is continuously rising.⁷ Recently, one of us (H.O.) has developed a new approach to dihydropyrazoles by gold-catalyzed three-component annulation of alkynes with hydrazines and aldehydes or ketones, a method that was applied to the one-pot synthesis of dihydroindazoles,⁸ as well as, pyrazolo[4,3-b]indoles.⁹ We now report a conceptually new gold-catalyzed three-component spirocyclization of acetylenic alcohols, hydrazines, and aldehydes or ketones which provides a diversity-oriented access to previously unknown spirocyclic pyrazolidines (Scheme 1).

Scheme 1 Gold-catalyzed three-component annulation vs. spirocyclization.

Many natural products contain spiroacetals as characteristic scaffold (Fig. 1). Prominent examples are the marine toxines okadaic acid, isolated from the sponge Halichondria okadai, and azaspiracid-1, obtained from blue mussels (Mytilus edulis).¹⁰

Fig. 1 Natural products containing [O,O]- and [N,O]-spiroacetals.

Synthetic approaches to the most common [O,O]-spiroacetals are well developed and normally take advantage of Lewis acid, Brønsted acid, or transition metal catalysts for the spirocyclization of prefunctionalized substrates.¹¹ Recent examples involve an efficient gold- or palladium-catalyzed cyclization of monopropargylic triols or ketoallylic diols reported by Aponick and co-workers,¹² the first asymmetric Brønsted acid-catalyzed cyclization of enol ethers with chiral phosphoric acids developed by List and Nagorny,¹³ as well as, the enantioselective synthesis of spiroacetals in a multicomponent approach disclosed by Fañanás, Rodríguez, and Gong.¹⁴ In contrast to this, other heterocyclic spirocompounds have been relegated to a niche existence.¹⁵ A rare exception is the recent report by Xu et al.¹⁶ on the synthesis of spiroaminals and spiroketals by bimetallic relay catalysis involving a gold-catalyzed cycloisomerization of a functionalized alkyne followed by a transition metal-catalyzed hetero-Diels–Alder reaction.

Results and discussion

Crucial to our approach towards spirocyclic pyrazolidines is the use of an acetylenic alcohol instead of a simple alkyne in the three-component reaction with a hydrazine and an aldehyde or ketone. We anticipated that the alkynol would undergo a facile cyclization in the presence of a gold catalyst¹⁷ to afford the ether ring of the desired spiroacetal. We started our investigation with pent-4-yn-1-ol 1, isobutyraldehyde 2 and the protected hydrazine 3⁸ in 1,2-dichloroethane with 5 mol% of Ph₃PAuCl/AgOTf as catalyst at room temperature (Table 1, entry 1). After 22 h, the spiroacetal 4a was isolated with 41% yield. A brief screening showed THF to be the best solvent (52% yield after 16 h at rt; entries 2–4). Increasing the reaction temperature to 50 °C improved the reactivity and afforded 4a with 40% yield after only 3 h (entry 5). A change of the silver salt revealed AgSbF₆ to the best choice (69% yield; entries 5–7), indicating the importance of the counteranion.^5h,i

Table 1 Optimization of the gold-catalyzed spirocyclization^a

Entry	Catalyst	Solvent	Time^b	Yield^c
a Reactions performed on a 0.45 mmol scale (0.15 M solution) with 1.2 equiv. each of 1 and 2 + 1.0 equiv. of 3. Product 4a was obtained with dr = 58 : 42 in all cases. b Time required to reach completion. c Isolated yield. d At rt. e Incomplete conversion. f With 1.5 equiv. each of 1 and 2 + 1.0 equiv. of 3. g With 2.0 equiv. each of 1 and 2 + 1.0 equiv. of 3. h With 2 mol% catalyst. i With 1 mol% catalyst. j With 10 mol% catalyst.
1^d	Ph3PAuCl/AgOTf	1,2-DCE	22 h^e	41%
2^d	Ph3PAuCl/AgOTf	Toluene	16 h^e	37%
3^d	Ph3PAuCl/AgOTf	DCM	16 h^e	43%
4^d	Ph3PAuCl/AgOTf	THF	16 h	52%
5	Ph3PAuCl/AgOTf	THF	3 h	40%
6	Ph3PAuCl/AgBF4	THF	3 h	58%
7	Ph3PAuCl/AgSbF6	THF	3 h	69%
8	AuCl	THF	7 h^e	Traces
9	AuCl3	THF	7 h^e	Traces
10	Ph3PAuNTf2	THF	4 h	75%
11	A	THF	4 h	65%
12	B/AgSbF6	THF	4 h	77%
13	B/AgSbF6 ^f	THF	4 h	89%
14	B/AgSbF6 ^g	THF	4 h	97%
15	B/AgSbF6 ^g^,^h	THF	4 h	85%
16	B/AgSbF6 ^g^,^i	THF	6 h	84%
17	AgSbF6	THF	4 h^e	Traces
18	CuBr^j	THF	14 d^e	Traces
19	PtCl2 ^j	THF	24 h	57%

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The use of neutral gold salts AuCl and AuCl₃ resulted in poor conversion and formation of a gold mirror (entries 8 & 9). In contrast, cationic gold catalysts Ph₃PAuNTf₂ and A furnished good yields of 4a (entries 10 & 11). The best results were obtained with phosphite gold complex B in the presence of AgSbF₆ (entries 12–16). By increasing the amount of alkyne 1 and aldehyde 2 from 1.2 to 2.0 equiv., the yield of spiroacetal 4a could be raised up to 97% (entries 13 & 14). Under these conditions, the catalyst loading could be reduced from 5 to 1 mol%, resulting only in a slight decrease of reactivity and product yield (entries 15 & 16). The silver salt alone does not catalyze the spirocyclization (entry 17); the same is true for CuBr (entry 18). In contrast, PtCl₂ is a competent catalyst, albeit not as efficient as cationic gold (entry 19).

With the optimized conditions (Table 1, entry 14) in hand, we investigated the scope of the gold-catalyzed three-component spirocyclization (Scheme 2). A wide variety of aliphatic (4a–c), aromatic (4d–k), and heteroaromatic aldehydes (4l/m) is tolerated. With butyraldehyde, extensive enolization took place, resulting in a diminished yield (46%) of product 4c. Aromatic aldehydes bearing various substituents (including nitro groups) afforded the spirocyclic pyrazolidines 4d–k with high yield (71–89%). Notably, fluorinated aryl groups (4j/k), as well as, bromide (4h/i) can be introduced without difficulty, the latter offering a handle for further functionalization. Whereas heteroaromatic aldehydes work exceptionally well (products 4l/m), cinnamic aldehyde afforded product 4n with only 33% yield. Attempts to extend this method to ketones revealed a pronounced reactivity issue. With an excess of cyclohexanone in the presence of 4 Å molecular sieves, bis-spirocycle 4o was isolated with only 7% yield. This could be improved to 35% by adding Yb(OTf)₃ as Lewis-acidic activator of the ketone.

Scheme 2 Scope of the gold-catalyzed three-component spirocyclization. Conditions according to Table 1, entry 14. Diastereomeric ratios determined by ¹H-NMR. Moc = methoxycarbonyl. ^a With 8 equiv. of cyclohexanone, 10 mol% of Yb(OTf)₃ and 4 Å molecular sieves. ^b Only two diastereomers observed.

Structural variations of the alkynol 1 were rewarding as well. Introduction of substituents at the tether connecting triple bond and hydroxy gave products 4p–r. Interestingly, only two diastereomers were formed in the case of the richly functionalized 6-oxa-1,2-diazaspiro[4.4]nonane 4r. Extension of the tether by one carbon atom allowed the smooth formation of the 6-oxa-1,2-diazaspiro[4.5]decane 4s with good yield of 75%. Nicely, the spirocyclization is not restricted to terminal alkynols; use of internal acetylenic alcohols furnished the products 4t/u with a fully substituted pyrazole ring, albeit with reduced yield (46/52%). Analogous to 4r, only two of four possible diastereomers were obtained. Finally, variation of the protecting groups at the hydrazine 3 is also possible. For a successful three-component transformation, the hydrazine has to bear an electron-rich and an electron-deficient group.^8,18 The former can be benzyl or p-methoxybenzyl (product 4b); for the latter, various carbamates can be employed: Boc, Cbz (spirocycles 4u–v, 4x–z), or Moc (products 4w, 4aa–ac). This opens up different options for further transformation of the spirocycles. For example, hydrogenative debenzylation of 4a furnished the monoprotected pyrazolidine 5 with almost quantitative yield (Scheme 3). In contrast, removal of the Boc group under acidic conditions led to a mixture containing 50% of the ring-opened product 6. Obviously, the presence of a protecting group at the hemiaminal nitrogen is important for the stability of the spirocyclic pyrazolidine.

Scheme 3 Deprotection of spiroacetal 4a.

In most cases, the spirocyclic pyrazolidines 4 were formed with diastereomeric ratios between 2 : 1 and 3 : 1. Generally, aromatic and heteroaromatic aldehydes give higher diasteroselectivites (up to 4 : 1) than their aliphatic counterparts (Scheme 2). The catalyst did not have an impact on the diastereoselectivity. The relative configuration of the major diastereomer of product 4h was determined by X-ray crystal structure to be (3RS,5SR). The diastereoselectivities and the configuration of the major isomer are analogous to those observed previously in the gold- and Brønsted acid-catalyzed three-component coupling of alkynols, anilines, and glyoxalic acid.^14a

From the mechanistic point of view, there appear be exist two possible pathways for the formation of the spirocyclic pyrazolidines 4 from the components 1–3 which differ in the order of events. Following the proposal made previously by one of us (H.O.) for the gold-catalyzed three-component annulation to dihydropyrazoles, a Mannich-type coupling of the aldehyde with the hydrazine would afford a propargyl hydrazine; cyclization to a dihydropyrazole would then be followed by an intramolecular hydroalkoxylation to give the spiroacetal.⁸ Alternatively, the reaction might be initiated by gold-catalyzed cyclization of the alkynol to an exocyclic enol ether¹⁷ which then undergoes a [3 + 2]-cycloaddition with an azomethine ylide formed from the hydrazine and the aldehyde. Following the reaction of by ¹H-NMR spectroscopy revealed a rapid consumption of the alkynol within 5 min whereas the hydrazine is consumed at a slower rate (Fig. 2). Moreover, an intermediate was observed in the ¹H-NMR at δ ∼3.5 which may be attributed to an enol ether.

Fig. 2 Kinetic ¹H-NMR study of the gold-catalyzed three-component coupling.

Accordingly, we assume that the transformation starts with the gold-catalyzed cycloisomerization of alkynol 1 to enol ether IIIvia intermediates I and II (Scheme 4).^14a,17 The subsequent [3 + 2]-cycloaddition with azomethine ylide IV may follow a stepwise (via intermediate Va) or concerted pathway (via transition state Vb). There is a limited number of examples for gold-catalyzed [3 + 2]-cycloadditions involving azomethine ylides;^14a,19 thus, the gold catalyst may be involved also in the final step towards spirocycles 4. Unfortunately, attempts to perform the [3 + 2]-cycloaddition with preformed enol ethers have failed due to the instability of these substrates.^17b

Scheme 4 Proposed mechanism for the gold-catalyzed three-component spirocyclization.

Conclusions and outlook

We have developed an efficient, highly atom economic and general synthesis of hitherto unknown spirocyclic pyrazolidines in a one-pot fashion based on simple starting materials. The gold-catalyzed three-component coupling of alkynols, hydrazines and aldehydes or ketones likely proceeds via cycloisomerization of the alkynol to an exocyclic enol ether and subsequent [3 + 2]-cycloaddition of an azomethine ylide. We have synthesized a library of 29 derivatives with a wide range of functional groups in up to 97% yield. With this new method, every position in the final product can be substituted as required for applications in combinatorial or medicinal chemistry. Further work devoted to a better mechanistic understanding, as well as, to an improved substrate scope, reactivity, sustainability, and stereoselectivity of the three-component spirocyclization is in progress. Gratifyingly, initial experiments to perform the reaction in micelles with water as bulk solvent were successful.²⁰ Reaction of isobutyraldehyde, pent-4-yn-1-ol, and benzyl/Cbz-protected hydrazine with cationic gold catalyst A in an aqueous medium containing 5% polyoxyethanyl α-tocopheryl sebacate (PTS) and 3 M NaCl afforded spiroacetal 4v with 35% yield after 20 h at 50 °C (Scheme 5). Even though further optimization is required, this result demonstrates that even highly demanding multicomponent reactions can be carried out under the challenging conditions of micellar catalysis.

Scheme 5 Gold-catalyzed three-component spirocyclization in micelles (PTS = polyoxyethanyl α-tocopheryl sebacate).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for all new compounds. See DOI: 10.1039/c5ob02453f

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