Gold-Catalyzed [3+3]-Annulation of Azomethine Imines with Propargyl Esters

The reactions of alkenyl Fischer carbenes 1 with 1,3-dipoles typically proceed via a concerted-asynchronous [3+2] cycloaddition (eq 1). Considering the orbitals involved in these transformations, the isolobal analogy allows the comparison of the reactivity of 1 to that of Lewis-acid complexed acrylates.¹ In contrast, the LUMO of alkenyl metal-carbenoids of type 2 may be approximated as singlet vinylcarbenes (eq 2).^2,3 Given this analogy, a [3+3]-cycloaddition between 1,3-dipoles and carbenoids of type 2 would be predicted. Unfortunately, free electrophilic vinylcarbenes undergo rapid rearrangement to cyclopropenes and intermolecular cycloadditions of these species are typically low yielding.^4,5 This problem has been circumvented through the use of alkenyl metal-carbenoids 2, which are typically generated in situ from metal-catalyzed diazo decomposition;⁶ however, cycloaddition reactions of 1,3-dipoles with carbenoids⁷ of type 2 have yet to be reported. We report herein a gold(III)-catalyzed [3+3]-cycloaddition⁸ of propargyl esters and azomethine imines, which is proposed to proceed via stepwise cycloaddition with a gold(III)-carbenoid intermediate of type 2.^9,10,11

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Beginning with our previously optimized reaction conditions,^9d we were delighted to find that bicyclic [3+3] cycloadduct 5a was formed in 90% yield and with 6:1 cis:trans diastereoselectivity in the Au(III)-catalyzed reaction of ylide 4a with propargyl ester 3a (Table 1, entry 1).^12,13 While varying the solvent failed to provide an increase in the diastereoselectivity (entries 2–4), lowering the temperature to 0 °C improved the ratio of cis:trans to 8:1 (entry 5).¹⁴ Other Au(III)-chloride salts also catalyzed the reaction with only slightly diminished yields (entries 6–7); however, Au(III) bromide and various Au(I) catalysts failed to provide any of the desired product (entries 8–9).¹⁵

Table 1.

Reaction optimization.

entry	catalyst	solvent	temp.	conversion	yielda	dr (cis:trans)
1	PicAuCl2 (6)b	CD2Cl2	rt	100%	90%	(6:1)
2c	6	MeCN	rt	48%	44%	(6:1)
3c	6	NO2Me	rt	71%	61%	(5:1)
4	6	C6D6	rt	--d	49%	(3:1)
5c	6	CD2Cl2	0 °C	100%	89% (79%e)	(8:1)
6	NaAuCl4	CD2Cl2	rt	100%	73%	(6:1)
7	AuCl3	CD2Cl2	rt	100%	85%	(6:1)
8	AuBr3	CD2Cl2	rt	20%	<5%	--
9	Ph3PAuCl/AgSbF6	CD2Cl2	rt	<5%	<5%	--

^aYield and diastereomeric ratio determined by ¹H-NMR versus an internal standard.

^bPic = 2-picolinic acid

^cReaction time was 4 hours.

^dThe starting ylide was partially insoluble in 0.3M C₆D₆

^eIsolated yield of analytically pure cis 5a.

With optimal conditions in hand (entry 5), the substrate scope of the gold-catalyzed [3+3]-cycloaddition reaction was examined. As demonstrated in the reaction of β-phenyl substituted azomethine imine 4a, substitution of the β-position of the pyrazolidinone generally provides bicyclic product 5a with high cis selectivity (vida infra). Alkyl substituents are also tolerated at this position (Table 2, entries 1–2), with larger substituents giving increased selectivity (20:1 for tert-butyl versus 8:1 for methyl). Remarkably, even an alkynyl substituent is sufficient to provide high selectivity (7:1, entry 3). Moreover, this reaction was readily extended to the synthesis of tetracycle (eq 3). Following the initial [3 + 3] cycloaddition of azomethine imine 4p, the alkyne was deprotected with TBAF and subjected to Au(I)-catalyzed hydroarylation conditions to deliver 7.¹⁶

Table 2.

Azomethine imine scope.

entry		product	yield (cis:trans)
1		5b R=Me	98% (8:1)
2		5c R = tBu	92% (20:1)
3		5d R=C ≡ CTIPS	96% (7:1)
4		5e (R=H)	94% (1.3:1)
5		5f (R=Me)	83% (10:1)
6		5g	90% (>20:1)
7		5h R=R′=H	82%a
8		5i R = Me, R′= H	82%a,b
9		5j R = H, R′ = Me	88%a
10		5k R = Ph, R′ = 3,4,5-(MeO)3-C6H2	80% (6:1)
11		5l R=Ph, R′=4-CN-C6H4	94% (5:1)
12		5m R=Ph, R′ = 3-pyridyl-2-cl	98% (1.7:1)
13		5n R=Me, R; = 2-I-C6H4	72% (1.8:1)
14		5o R = Ph, R′ = cyclopropyl	41%a (2.8:1)

^aReaction performed at room temperature.

^b2 mmol scale.

The azomethine imine can also be substituted at the α-position, although in this case the product (5e) was formed with 1.3:1 cis:trans diastereoselectivity (entry 4). On the other hand, the cycloaddition of azomethine imine 4f, having both α- and β-substituents, remained highly selective (10:1, entry 5). Finally, the backbone need not be substituted (entry 7), but can also accommodate quaternary carbons in either position (entries 8–9).

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The aldehyde-derived substituent of the azomethine imine can also be varied. Both electron-rich and electron-deficient aryl groups are well tolerated in the gold(III)-catalyzed cycloaddition (entries 10–11). Ortho-substituted aryl groups are also accommodated (entries 12–13), but provide the cycloadducts with significantly lower diastereoselectivity. Finally, the cycloaddition reaction of ylides derived from aliphatic aldehydes generally proceeded in lower yield (entry 14).

An additional stereocenter is generated when secondary propargyl esters are employed (eqs 4, 5). In this case, regardless of whether the cycloaddition is concerted or stepwise (as depicted),¹⁷ the high 1,2-cis diastereoselectivity can be rationalized as resulting from the cis-imine geometry and the preferred trans geometry of the proposed gold-carbenoid intermediate.^9d,18 To gain further insight into the origin of the 1,2-cis stereoselectivity, secondary propargyl ester 8c was reacted with tert-butyl substituted azomethine imine 4c (eq 5).¹⁹ In this case, a 2:1 mixture of diastereomers with respect to the pyrazolidinone substituent, and favoring the 1,3-trans isomer of 9c, was formed.²⁰ Furthermore, the high diastereoselectivity in the gold-catalyzed reactions of 3a can be rationalized by minimization of unfavorable steric interactions between the propargyl ester methyl groups and the β-substituent in the ring closing transition state (eq 6). These result suggests that the diastereoselectivity is determined during ring closing, rather than in the formation of allylgold intermediate 10.¹³

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In conclusion, we have developed a gold(III)-catalyzed synthesis of diazabicycles from readily available starting materials.²¹ This report represents the first example of a formal cycloaddition between alkenyl metal carbenoids and 1,3-dipoles. In contrast to the previously reported cycloadditions,^9d,10f this reaction highlights the difference in the reactivity of alkenyl Fischer carbenes and the alkenyl Au-carbenoids generated from the rearrangement of propargyl esters. Further studies exploring and exploiting this difference are ongoing and will be reported in due course.