Thermal Intramolecular [4 + 2] Cycloadditions of Allenamides: A Stereoselective Tandem Propargyl Amide Isomerization–Cycloaddition

Abstract

A stereoselective intramolecular normal demand [4 + 2] cycloaddition of allenamides under thermal conditions without metal assistance is described. This work led to the development of a stereoselective tandem propargyl amide-isomerization–[4 + 2] cycloaddition sequence amenable for rapid assembly of complex nitrogen heterocycles.

We have been embarking on the chemistry of allenamides in the last ten years.^1,2 In particular, allenamides have proven to be an excellent source of nitrogen-stabilized oxyallyl cations^3,4 through DMDO-epoxidation, thereby allowing us to develop highly stereoselective [4 + 3] cycloaddition manifolds^5–7 including intramolecular^8,9 cycloadditions such as using N-tethered allenamide 1⁹ en route to synthetically useful nitrogen heterocycle 3 [Scheme 1]. However, the dependence on DMDO as the key oxidant for the transformation can pose a challenge in terms of scale and operational convenience. Mascareñas’s report¹⁰ intrigued us because of their usage of PtCl₂/CO in catalyzing a [4 + 3] cycloaddition of allenes. More significantly, they also documented that a different catalyst [AuCl] could effectively direct the reactivity toward the competing [4 + 2] cycloaddition instead of the [4 + 3] cycloaddition. Recently, Toste¹¹ revealed a similar divergence in [4 + 2] versus [4 + 3] cycloaddition when using different ligands along with a Au(I) catalyst. Our own efforts in exploring Mascareñas’s PtCl₂ versus AuCl protocol^10,12,13 while adopting allenamides led us to an interesting and different direction than the initially anticipated issues regarding competing [4 + 3] and [4 + 2] cycloadditions [see 4-TS⁴⁺³→6 vs. 4-TS⁴⁺²→7, respectively, in Scheme 1]. We report here a rare normal electron-demand^1,14–17 [4 + 2] cycloaddition involving electron-rich heteroatom-substituted allenes under thermal conditions and a stereoselective tandem propargyl amide isomerization–intramolecular [4 + 2] cycloaddition sequence.

Scheme 1.

Cycloadditions of N-Tethered Allenamides.

To commence our studies, we initially examined an N-Boc- substituted allenamide, but it was not useful for platinum and gold protocols [see footnote 18 for results]. Consequently, N-sulfonyl-allenamide 9¹⁹ was prepared from propargyl amide 8 via our base-promoted isomerization protocol using cat t-BuOK.²⁰ We quickly found that with the exception of AuCl [entries 5–7 in Table 1], platinum catalysts [entries 1–4] and Au(III) catalyst [entry 9] were not useful in generating any cycloaddition types of products. Concentrations did not appear to have any impact, as reactions run at 0.04 M led to the same outcome.

Table 1.

Exploring Conditions for the Cycloaddition.

entry	catalysts	4 Å MS	solvents	temp [°C]	time [h]	yield [%]a
1	PtCl2	√	DCE	65	<12	0
2	PtCl4	√	DCE	65	3	13c
3	PtCl4	√	THF	65	6	15c
4	PtCl4	√	toluene	23	1	11c
5	AuCl	√	DCEb	23	10min	66
6	AuCl	√	THF	65	6	35c
7	AuCl	√	toluene	65	<30 min	42c
8	AuCl/AgSbF6	√	DCE	23	1	16c
9	AuCl3	√	DCE	65	10 min	0
10	AgSbF6	√	DCE	65	6	85c
11	AgBF4	√	DCE	65	6	94
12	AgBF4	√	toluene	65	6	80c
13	AgBF4	√	THF	65	<12	57c
14	CSAd	√	DCE	65	<12	92c
15	PPTSd	√	DCE	65	8	94c
16	No	√	THF	65	30	91c
17	No	No	d8-toluene	110	20	93

^aIsolated yields unless otherwise indicated.

^bDCE: 1,2-Dichloroethane.

^cNMR yields determined with phenanthrene as the internal standard

^d10 mol % was used.

Most intriguingly, the illustration of the corresponding [4 + 2] cycloadduct 10 shown in Table 1 of hindsight after a series of subsequent studies. As shown in Figure 1, although 10 and its regioisomer 11 are readily distinguishable, it is not obvious how to unambiguously distinguish 10 from potential [4 + 3] cycloadduct 12 solely based on the key ¹H NMR resonances. However, as we continued our explorations and began to achieve high yielding reactions with silver salts [entries 10–13], Brønsted acids [entries 14 and 15, and then, ultimately simple thermal conditions with [entry 16] or without 4Å MS [entry 17], we recognized that this did not appear to be a simple [4 + 3] cycloaddition process. Instead, it turned out to be exclusively a [4 + 2] cycloaddition pathway under all conditions after attaining an X-ray crystal structure [vide infra].

Figure 1.

[4 + 2] Versus [4 + 3] Cycloadducts.

δppm: 6.60 (s, H^a); 2.53 (dd, H^b, J = 4.5, 14.0 Hz); 1.91 (d, H^c, J = 14.0 Hz) 5.02 (dd, H^d, J = 1.5, 4.5 Hz); 6.32 (d, H^e, J = 5.5 Hz); 6.04 (d, H^f, J = 5.5 Hz)

The ability to pursue this cycloaddition thermally represents a unique opportunity for two major reasons. Firstly, as shown in Table 2, this thermally driven allenic-[4 + 2] cycloaddition manifold possesses a much broader synthetic potential than previous work.^10,11

Table 2.

Thermal [4 + 2] Cycloaddions of of Allenamides.

entry	allenamidesa	time [h]	cycloadducts	yield [%]b
1	13a: R = p-Ns	12	14a: R = p-Ns	92
2	13b: R = Boc	20	14b: R = Boc	65
3	13c: R = (−)-menthyl	20	14c: R = (−)-menthyl	54c
4	(±)-15a: R = Ph	2	16a: R = Ph	77d
5	(±)-15b: R = Me	30	16b: R = Me	57d
6	17	<12	19	77
7	18	4	20	93
8	21	24	23	95e
9	24	20	25	78

^aUnless otherwise noted, all reactions were carried out in THF at 85 °C at concn = 0.10 M. Reactions in entries 3 and 8 were run in toluene. Entries 4 and 8 were run at 45 °C and 110 °C, respectively.

^bIsolated yields.

^cOnly one isomer by ¹H NMR but absolute configuration unassigned.

^d16a and 16b were found as a ~ 3:1 inseparable isomeric mixture.

^eRegioisomeric ratio of regioisomers 22 and 23 is ~ 4:1.

The substrate scope is comprised of: (1) Different N-substituents [entries 1–3] including carbamates; (2) substitutions at the allenic γ-position [(±)-15a and (±)-15b in entries 4 and 5, respectively] that gave the respective cycloadducts 16a and 16b with the major isomers shown as assigned via nOe experiments [Figure 2]; (3) various furan substitutions [entries 6 and 7]; (4) a longer tethering that led to the regiochemical outcome in favor of the internal olefin of the allenic motif [22 in entry 8], which is found as a single diastereomer;²¹ and also notably in this case, when using 10 mol% of AgBF⁴ and 4Å MS, 22 was isolated in 58% yield as the only regioisomer after heating in toluene at 110 °C for 36 h;²¹ and lastly, (5) a simple butadiene [entry 9].

Figure 2.

nOes Experiments and X-Ray Structure of 14a.

The X-ray structure of cycloadduct 14a unambiguously confirms the [4 + 2] cycloaddition pathway [Figure 2], and it provides a general mechanistic picture for this allenic cycloaddition. Based on the nOe assignments of the respective major isomers for 16a and 16b [dr 3:1], the current mechanistic picture also implies that the furan approaches from the more hindered side with R ≠ H. We are not certain of reasons behind this contra-steric approach.

Secondly and more importantly, we recognized the possibility of developing a tandem sequence consisting of propargyl amide isomerization followed by cycloaddition. As shown in Scheme 2, In the presence of 20 mol% t-BuOK at 65 °C, isomerization of propargyl amide 8 and the ensuing cycloaddition led to 10 in 86% yield over three steps furan [or two steps from commercially available 2-(furan-2-yl)ethanol 26]. Likewise, cycloadduct 29 could be obtained in 68% yield in two steps from furfuryl alcohol. We note here that without t-BuOK, this tandem process does not take place even after heating in toluene at 110 °C for 24 h, thereby suggesting that the tandem sequence proceeds through exclusively the respective allenamide intermediate.

Scheme 2.

A Tandem Propargyl Amide-Isomerization–[4 + 2].

In addition, with platinum or gold catalysts, the reaction proceeded through a very different pathway.^22,23 Moreover, in a related example from Kanemastu’s account,¹⁵ 5.0 equiv of t-BuOK was used and the reaction afforded ring-opened and aromatized products instead of furan-cycloadduct 29. The use of catalytic amount of t-BuOK proves to be the key in accessing these structurally more useful cycloadducts.

Finally, this tandem process is general for a range of propargyl amides [Table 3] including those that are terminally substituted [entries 2–4], thereby also representing first examples of successful based-promoted isomerizations of terminally substituted propargyl amides to allenamides.^20,24 It is noteworthy that all propargyl amides employed here were prepared from respective furyl alcohols featuring a Mitsunobu reaction using N-sulfonylated propargyl amine [see 27 in Scheme 2], allowing this tandem process amenable for facile constructions of complex nitrogen heterocycles from very simple commercially available material.

Table 3.

Tandem Isomerization–[4 + 2] Cycloadditions.

entry	propargyl amidesa	time [h]	cycloadducts	yield [%]b
1	30	24	14a	84
2		24		79c
3		24		42c,e
4		16		25d,e
5	32	14	19	63

^aUnless otherwise noted, all reactions were carried out in THF at concn = 0.10 M with 20 mol % of t-BuOK. For entries 1 and 5: Reaction temp = 65 °C; for entries 3 and 4: temp = 85 °C; and for entry 2: temp = 25 °C.

^bIsolated yields.

^cdr = ~3:1.

^ddr = ~2:1.

^eThe reaction was slower, and also observed was hydrolysis of the starting allenamide.

We have described here a rare normal electron-demand [4 + 2] cycloaddition of N-tethered allenamides under thermal conditions without assistance of any metals. Our efforts also led to the development of an efficient and highly stereoselective tandem propargyl amide-isomerization–[4 + 2] cycloaddition sequence amenable for rapid assembly of highly functionalized nitrogen heterocycles from very simple commercial furyl alcohols. Applications of this method toward constructing isoquinoline, quinoline, or isoindole containing natural products are underway.