[3+2]-Annulation of platinum-bound azomethine ylides with distal C=C bonds of N-allenamides

Abstract

A Pt-catalyzed, highly regioselective reaction between N-allenamides and imino-alkynes leading to pyrrolo[1,2-a]indoles is described. This represents the first example of [3+2]-annulation of Pt-bound azomethine ylides with the distal C=C bond of N-allenamides. The mechanism of the reaction was established by computational studies.

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Pyrrolo[1,2-a]indoles and their structural analogues are important structural motifs commonly found in numerous bioactive natural products.¹ The most promising natural products belonging to this catagory are yuremamine,² mitomycins^1b–d and flinderoles³ (Fig. 1). As a consequence, these scaffolds have received considerable attention over the years and many methods for their preparation have been developed in the literature.⁴ Accordingly, a general catalytic method⁵ to access functionalized pyrrolo[1,2-a]indoles is in high demand and would serve to provide a great opportunity to accelerate biological studies of these valuable compounds.⁶

Fig. 1 Some natural products containing the pyrrolo[1,2-a]indole motif.

Over the past decade, gold/platinum-catalyzed annulation reactions have emerged as a powerful technique for rapid access to various ring systems in an extremely efficient and stereoselective manner.⁷ In this context, due to their unique reactivity and ease of accessibility, N-allenamides⁸ have gained much interest in gold catalyzed cascade annulation, leading to synthetically important carbocyclic or heterocyclic scaffolds (Scheme 1). The research groups of González,⁹ Chen,¹⁰ Mascareñas/López¹¹ and Bandini¹² reported gold-catalyzed intermolecular [2+2]-annulation with N-allenamides to obtain cyclobutanes (Scheme 1a, path a). Mascareñas/López,¹³ Vicente¹⁴ and Zhang¹⁵ successfully established gold-catalyzed intermolecular [4+2]-annulation of various diene systems (path b) and alkene-tethered ketones¹⁶ (path c) with N-allenamides. Similarly, Chen and co-workers reported [3+2]-annulation of N-allenamides with nitrones and azomethine imines (path d).¹⁷ Very recently, gold catalyzed regioselective annulation reaction of 2-(1-alkynyl)-2-alken-1-ones with proximal C=C bonds of N-allenamides was developed by Zhang and co-workers (Scheme 1b).¹⁸ Note that Iwasawa and co-workers, in their pioneering work, reported a series of [3+2] cycloaddition reactions of metal bound azomethine ylides with alkenes.¹⁹ Inspired by the above reports and our own interest in the field of π-acid catalysis, we envisioned a scenario wherein annulation of metal-bound azomethine ylides with N-allenamides would lead to pyrrolo[1,2-a]indoles A or Bvia a series of cascade events (Scheme 2). In particular, we became interested in knowing whether the distal bond (path a) or proximal bond (path b) of N-allenamide would participate in the annulation reactions. Herein, we report, for the first time, catalytic [3+2]-annulation of metal-bound azomethine ylides with distal C=C bonds of N-allenamides.

Scheme 1 Annulation reactions of N-allenamides with various partners.

Scheme 2 [3+2]-Annulation of N-allenamides with metal-bound azomethine ylides.

To explore our hypothesis, initial efforts were directed towards finding an appropriate metal catalyst for the proposed reaction using (E)-N-benzylidene-2-(phenylethynyl)aniline (1a) and N-allenamide (2a) as model substrates (Table 1). Unfortunately, the reaction did not occur when AuCl, AuCl₃, Ph₃PAuOTf and Ph₃PAuNTf₂ were used as catalysts (entries 1–4) despite their proven abilities to activate alkynes. Next, the reaction was conducted using PtI₂ as a catalyst (10 mol%) in toluene at 80 °C. Gratifyingly, product 3a was obtained in 51% yield (entry 5). Product 3a was found to be the result of [3+2]-annulation reaction between Pt-bound azomethine ylides and the distal C=C bonds of N-allenamides. The use of the PtBr₂ catalyst gave a slightly better result affording 3a in 54% yield (entry 6). The yield was further improved to 66% with the use of PtCl₂ (entry 7). A Pt(IV) catalyst (e.g. PtCl₄) proved to be inferior and 3a was isolated in 40% yield (entry 8). The reaction was found to be dependent on the solvent used (Table 1, entries 9–13). For instance, in the case of non-polar, non-coordinating solvents such as benzene and m-xylene (entries 9 and 10), the yields of 3a were not much affected; while, in the case of chlorobenzene and fluorobenzene, 3a was obtained in low yields (entries 11 and 12). A drastic reduction in yield was observed when nitrobenzene was used as a solvent (entry 13). Lowering the catalyst loading to 5 mol% resulted in incomplete conversion leading to the isolation of 3a in 38% yield (entry 14). When the temperature of the reaction was decreased to 50 °C, the reaction was not completed and 3a was isolated in 36% yield (entry 15). The use of 5 Å MS was found to be necessary; in its absence, 3a was obtained in only 10% yield (entry 16). The overall optimization studies revealed that the best condition to obtain 3a in acceptable yield is the use of 10 mol% PtCl₂ in the presence of 5 Å MS (50 mg) (entry 7).

Table 1 Optimization studies^a

Entry	Cat. M	Solvent	Yield^b (%)
a Reaction conditions: 0.2 mmol of 1a, 0.4 mmol of 2a, 10 mol% metal catalyst, 5 Å MS (50 mg), toluene (2 mL), 80 °C, 12 h. b Isolated yields. c 5 mol% catalyst loading. d Reaction performed at 50 °C for 24 h. e Reaction was carried out without 5 Å MS.
1	AuCl	Toluene	—
2	AuCl3	Toluene	—
3	PPh3AuOTf	Toluene	—
4	PPh3AuNTf2	Toluene	—
5	PtI2	Toluene	51
6	PtBr2	Toluene	54
7	PtCl2	Toluene	66
8	PtCl4	Toluene	40
9	PtCl2	Benzene	52
10	PtCl2	m-Xylene	55
11	PtCl2	Chlorobenzene	43
12	PtCl2	Fluorobenzene	47
13	PtCl2	Nitrobenzene	16
14	PtCl2	Toluene	38^c
15	PtCl2	Toluene	36^d
16	PtCl2	Toluene	10^e

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With the optimized conditions in hand (Table 1, entry 7), we explored the scope of the reaction using imino-alkyne 1a with various N-allenamides 2 bearing a variety of electron-deficient as well as electron-rich substituents at the aryl rings (Table 2). The reactions proceeded well to give annulated products 3 in good to excellent yields (61–73%). The presence of electron-rich substituents such as 4-Et, 4-OMe, 2-OPh, 3,4-methylene-di-oxy, and 2,4,6-trimethyl in the phenyl ring of N-allenamide gave the corresponding annulated products 3b, 3c, 3g, 3j and 3l in good yields (65–73%). Even the substrates bearing electron-deficient substituents (e.g. 4-Cl, 4-Br, 4-NO₂, 3-CF₃ and 3-Br-4-Me) reacted smoothly to give the respective products (3d–f, 3h and 3i) in 61–71% yields. The reaction also proceeded well when the phenyl ring of N-allenamide was replaced by the –Bn group to afford the corresponding product (3k) in 70% yield. Interestingly, 2-oxazolidinone allenamides, which are frequently used in related cycloaddition reactions (Scheme 1), are found to be inert under the present reaction conditions.

Table 2 Scope of the reaction with various N-allenamides^a,b

a Reaction conditions: 0.2 mmol of 1a, 0.4 mmol of 2, 10 mol% PtCl₂, 5 Å MS (50 mg), toluene (2 mL), 80 °C, 12 h. b Isolated yields.

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Next, we turned our attention to explore the generality of the [3+2]-annulation reaction of various imino-alkynes 1 with N-allenamide 2a (Table 3). A variety of substrates with electron-donating, electron-withdrawing as well as heterocyclic substituents at R¹, R² and R³ positions were examined to understand the scope and limitations. These results showed that the iminoalkyne possessing electron donating aryl groups as R¹ afforded products 3m and 3n in 75 and 76% yields, whereas slightly lower yields were observed in the case of electron withdrawing aryl groups giving 3o and 3p in 60 and 63% yields. The heteroaromatic scaffolds were also well tolerated to give 3q and 3r in 72 and 70% yields, respectively. Next, we were curious to know whether the present strategy is applicable for variation in R². To this end, appropriate precursors consisting of both electron-donating and electron-withdrawing substituents were subjected to the standard reaction conditions. It was observed that the substituents bearing electron-donating groups (4-Me-Ph and 4-OMe-Ph) as R² performed well without hampering the yields of products 3s and 3t (65 and 68%), while in the presence of the electron-withdrawing acetyl group the reaction shuts down without formation of 3u. Furthermore, variation of substituents at R³ of iminoalkynes did not affect the efficiency of the reaction affording the desired products 3v and 3w in 67 and 70% yields, respectively. The X-ray crystallography data for 3a, 3l and 3s have also been obtained which unambiguously confirmed the structure.²⁰ Note that the substrates bearing –H or –alkyl as R² are not viable substrates for the present reactions.

Table 3 Scope of the reaction with various imino-alkynes^a,b

a Reaction conditions: 0.2 mmol of 1, 0.4 mmol of 2a, 10 mol% PtCl₂, 5 Å MS (50 mg), toluene (2 mL), 80 °C, 12 h. b Isolated yields. c Desired product was not obtained.

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Finally, to probe the synthetic utility of the reaction, transformations of 3a were performed (Scheme 3). Initially, the catalytic hydrogenation of 3a with H₂ in the presence of 10% Pd/C led to the formation of aminomethyl-substituted pyrrolo[1,2-a]indole derivative 4 in 83% yield (5 : 1 dr). Next, the treatment of 3a with 12 M HCl in EtOAc as a solvent was performed, and the corresponding aldehyde 5 was obtained in 41% yield (9 : 1 dr). The diastereomer ratio was determined by ¹H NMR analysis.²⁰ Finally, compound 3a was subjected to m-CPBA oxidation to furnish dicarbonyl compound 6 in 68% yield.

Scheme 3 Transformation of 3a.

A plausible mechanism is depicted in Scheme 4. At first, the Pt-catalyst would activate the alkyne moiety of 1a, thereby triggering the attack of imine nitrogen to generate azomethine ylide I. A direct attack of 2a to azomethine intermediate I^19c would then occur to form intermediate II. Next, Pt(II) serves to donate electron density into an electron-deficient iminium ion in a 1,4-fashion (cf.II) to generate III. In short, the Pt(II)-catalyst serves both the roles i.e. activating the alkyne moiety in 1a to form I and donating electron density back to an electron-deficient iminium ion (cf.II). Once intermediate III has been generated, 1,2-aryl migration²¹ would occur to form intermediate IV which subsequently would produce 3a with the regeneration of the Pt-catalyst. Another possibility is that the alkenyl-Pt intermediate V,²² generated in situ from 2a and PtCl₂, would combine with I to form intermediate II (shown as dotted lines) which would follow a similar sequence of events to form 3a. Note that such a kind of dual catalysis employing gold as a catalyst is known.²³ However, this possibility was ruled out based on computational studies.²⁰

Scheme 4 A plausible mechanism (Cl atoms on the Pt-center are omitted for clarity).

In summary, we have demonstrated the first example of intermolecular [3+2]-annulation of Pt-bound azomethine ylides with distal C=C bonds of N-allenamides. The ready availability of the starting materials and the great importance of the pyrrolo[1,2-a]indoles make the current methodology particularly interesting. Mechanistic insights gained through density functional theory suggest that the reaction follows a single substrate activation pathway rather than dual activation.²⁰

Generous financial support from the Department of Science and Technology (DST), New Delhi (Grant No. SB/S1/OC-17/2013), and the Council of Scientific and Industrial Research (CSIR), New Delhi (Grant No. CSC0108 and CSC0130), is gratefully acknowledged. We thank Dr Kumar Vanka and Dr Rahul Banerjee for theoretical studies and X-ray crystallographic structure determination, respectively. I. C. thanks UGC for the award of a Junior Research Fellowship (JRF).

Notes and references

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20. See the ESI† for details.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 1500613, 1500621, 1500652. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6cc07874e

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