α–Aryl-Substituted Allenamides in an Imino-Nazarov Cyclization Cascade Catalyzed by Au(I)

Abstract

An imino-Nazarov cyclization using α–aryl-substituted allenamides is described. This gold(I)-catalyzed cascade is efficient and regioselective in constructing a diverse array of synthetically useful aromatic-ring fused cyclopentenamides. The success in this transformation represents a solution to the challenge in establishing an imino-Nazarov cyclization process.

The Nazarov cyclization¹ has captured an immense amount of interest from the synthetic community in the last three decades.^2,3 This classical pericyclic process proceeds through conrotatory 4π–electron electrocyclic ring-closure of a pentadienyl cation via activation of divinyl ketone 1 or its equivalent, leading to a key oxyallyl cation 2 that can afford cyclopentenone 3 substituted cyclopentanones 4 through trapping [Scheme 1]. Despite a diverse array of innovative structural designs that has been developed,^4–6 one aspect that has received very little attention is an imino version of this cascade with the sole exceptions of Tius’ seminal work on lithiated imino-Nazarov,^7a and recently, with enamine-iminium ions.^7b,c There are examples in which stabilization of the pentadienyl cation is assisted by the presence of an amino or amide substituent, albeit not a formal imino-Nazarov cyclization. Cha’s⁸ earlier work on cephalotaxine synthesis, along with reports by Occhiato/Prandi,⁹ Frontier,¹⁰ Flynn¹¹ employing ynamides, and recently, by West¹² in a clever usage of allenamides represent such elegant cases. The challenge in developing a successful imino-Nazarov cyclization is to overcome the propensity of 2-amino-allyl cation 6 to ring-open in favor of amino-pentadienyl cation 5, which receives a greater stabilization from the amino nitrogen atom.¹³ We wish to communicate here our solution to this challenge through gold(I)-activation of allenamides.

Scheme 1.

Nazarov Cyclizations: Challenge in an Imino-Version.

Our long standing interest in allenamides,^14–16 and in particular, their electrophilic activations,^17,18 led us to explore their potential use in this underdeveloped aspect of the Nazarov cyclization. As shown in Scheme 2, α–vinyl or α–aryl allenamides 7 could be employed in an imino-Nazarov cyclization cascade through Brønsted acid activation.¹⁹ This electrophilic activation could give amido-pentadienyl cation 8, which would undergo an electrocyclization to afford 2-amido-allyl cation 9. It is noteworthy that a distinct advantage in achieving a successful imino-Nazarov cyclization is the synthetically useful enamide functionality²⁰ in the end product 10.

Scheme 2.

An Approach to Imino-Nazarov Cyclization.

We reasoned that unlike amino-pentadienyl cation 5, the electrocyclization of 7 could be more favored given the reduced ability of an N-acyl nitrogen atom to stabilize cations relative to an amino group. Such rationalization would find prevalent support in related chemistry of vinyl N-acyl iminium ions²¹ and aza-Prins cyclizations.²² However, after many attempts, the Brønsted acid activation failed because we were unable to control and overtake the hydrolysis pathway that led to amido ketones 11 through a facile trapping of the initial enone.

Inspired by recent gold-catalysis²³ particularly in the area of Nazarov type process²⁴ with the report by Zhang,^19d we turned our attention to gold catalysts. As shown in Table 1, trivalent gold catalyst was first investigated. Reactions of 12a proceeded smoothly in the presence of catalytic amount of AuCl₃ or cationic AuCl₃/AgSbF₆ (entries 1 and 2), but gave an inseparable mixture of dimers 14 and 15²⁵ with no desired Nazarov cyclization product 13a. Attempts to suppress the dimerization by lowering the concentration (entry 3) or addition of 4 Å MS (entry 4) proved to be fruitless.

Table 1.

Screening for a Suitable Metal Catalyst.

entrya	catalyst	time (h)	conversion (%)b	13a (%)c	14 + 15d (%)c
1	AuCl3	30	>95	–	55
2	AuCl3/AgSbF6	1	>95	–	45
3	AuCl3/AgSbF6e	22	48	–	36
4	AuCl3/AgSbF6f	40	55g	–	36
5	AuCl/AgSbF6	5	>95	–	48
6	AuCl(PPh3)/AgSbF6	60	75g	50h	24
7	JohnphosAuCl/AgSbF6	5	>95	91	–
8	IPrAuCl/AgSbF6	1	>95	97	–
9	IPrAuCl	21	<5	–	–
10	AgSbF6i	20	64	–	24
11	PtCl2	24	<5	–	–
12	PtCl4i	12	>95	–	82j

^aUnless noted, all reactions were carried out at 0.1 mmol scale in 2 mL of CH₂Cl₂ (concn = 0.05 M) at room temperature with the addition of 5 mol % catalyst.

^bConversion determined by ¹H NMR.

^cIsolated yields.

^d14 and 15 could not be separated by column chromatography.

^e20 mL CH₂Cl₂ was used (concn = 0.005 M).

^f35 mg 4 Å MS was added.

^gBased on recovered 12a.

^hInseparable mixture with 12a.

ⁱ10 mol % of catalyst was used.

^jAn inseparable mixture of 14, 15 and unidentified products.

Nevertheless, we were encouraged by dimers 14 and 15 because they imply that the desired imino-Nazarov reaction had taken place possibly post-dimerization through the intermediacy of 14′ [addition of 12a to activated-12a] Gratifyingly with AuCl(PPh₃)/AgSbF₆, 13a was obtained for the first time in 50% yield along with 14/15 mixture in 24% yield. Further optimizations revealed that the best yield was reached when using IPrAuCl/AgSbF₆, leading to 13a in 97% yield (entry 8) with JohnphosAuCl/AgSbF₆ affording 13a in 91% yield. Remarkably, neutral IPrAuCl itself turned out to be completely inactive (entry 9), while AgSbF₆ alone gave 14 and 15, albeit sluggishly (entry 10). Lastly, Pt catalysts were also examined and gave very poor results in this process (entries 11 and 12).

Having established the optimum catalytic system, the scope of the imino-Nazarov process was explored [Table 2]. Notably, for allenamides equipped with more bulky substituents on the nitrogen (n-Bu in 12b and Bn in 12c), reactions were slower, although yields were still excellent (entries 1 and 2). The structure of 13b was unambiguously assigned through its X-ray structure [left in Figure 1]. The cyclization of 12d, bearing a 4-methoxybenzenesulfonyl [MBS] substituent, also worked but at elevated temperature. Lastly, allenamides with different substituents on the aryl ring (entries 4–9) also proved to be quite effective overall with exceptions of 2-MeO and 4-Br substituents (entries 5 and 9). In particular, while the reaction of 12f is very tardy, the cyclization of 12j was completely attenuated. We are not clear of the precise rationale at this point. However, it is noteworthy that the high level of regioselectivity found in cases of 12e and 12k was remarkable. While these two cyclizations appear to favor the less hindered C6-position with no detectable cyclization at C2-position, this preference is likely due to direct donation from the C3-OR group.

Table 2.

An Au(I)-Catalyzed Imino-Nazarov Cyclization.

^aUnless noted, all reactions were carried out at 0.1 mmol scale in 2 mL of CH₂Cl₂ (concn = 0.05 M) at rt with the addition of 5 mol % catalyst.

^bIsolated yields.

^cThe reaction was run at 50 °C in DCE.

^dNo reaction.

Figure 1.

X-Ray Structures of 13b and 20.

To further investigate the regioselectivity issue, allenamides 16 and 19 were subjected to the cyclization condition [Scheme 3]. For allenamide 16 with an α–(2-naphthyl) substituent, cyclization took place selectively at C1 [see 17′], affording 17 exclusively in 97% yield. This regioselectivity is also likely an electronic preference given that cyclization at C1 would involve the cyclohexadiene potion of the naphthyl ring, thereby leading to a greater cation stabilization: Benzylic stabilization in 17′ versus pseudo-benzylic stabilization in 18′ through cyclization from C3. On the other hand, for allenamide 19 with an α–(1-naphthyl) group, a competing 6π-electron cyclization of the reaction intermediate [see 21′] could deliver 1H-phenalene 21. However, the reaction exclusively proceeded through the imino-Nazarov cyclization pathway via 20′, leading to 20 in excellent yield. The structure of 20 was also confirmed by its single crystal X-ray structure [Figure 1]. It is noteworthy that 17 and 20 are structurally almost identical with the difference residing in the position for the respective enamide motif.

Scheme 3.

Regioselective Imino-Nazarov Cyclizations.

Intrigued by this competition, another reaction with potential competing imino-Nazarov’s 4π-electron and 6π-electron electrocyclization was examined using allenamide 22 [Scheme 4]. The reaction of 22 led to 25 and 26 as the only discernable products with latter likely coming from hydrolysis of the initial Nazarov cyclization product 25. This study suggests that while the cationic imino-Nazarov intermediate could exist in two equilibrating conformations 23 and 24 differing only at the ‘s’-marked C–C bond [or being trans- and cis-1-aza-dienes, respectively, shown in green], 6π-electron electrocyclization of 3-aza-triene 24^26,27 was also not competitive in this case.

Scheme 4.

4π– Versus 6π–Electron Electrocyclization.

Lastly, while cyclopentenamides are synthetically useful, we recognized that our imino-Nazarov cyclization could provide a concise approach to indole-fused cyclopentenamides [or cyclopenta[b]indoles],^24a thereby representing an opportunity to develop new strategy for natural product synthesis.²⁸ Consequently, as shown in Scheme 5, under the optimized conditions, cyclizations of α-indolyl-substituted allenamides 28a and 28b proceeded smoothly to afford indole-fused cyclopentenamides 29a and 29b, respectively, in good yields.

Scheme 5.

Synthesis of Indole-Fused Cyclopentenamides.

We have showcased here an imino-Nazarov cyclization using α-aryl-substituted allenamides. This Au(I)-catalyzed cascade represents a successful solution to overcome the challenge in designing an imino-Nazarov cyclization cascade. It is a highly efficient and regioselective transformation in constructing a diverse array of aromatic-ring fused cyclopentenamides. Further mechanistic studies and applications of this cyclization process in total synthesis are currently underway.