Regiodivergent Metal-Catalyzed Rearrangement of 3-Iminocyclopropenes into N-Fused Heterocycles

Abstract

A highly efficient regiodivergent method for the synthesis of N-fused heterocycles via transition-metal-catalyzed rearrangement of 3-iminocyclopropenes has been developed.

Transition-metal-catalyzed chemistry of cyclopropenes¹ benefits from their enormous ring strain.² The highly reactive double bond enjoys a variety of addition³ and cycloaddition⁴ reactions,⁵ while rearrangements allow for construction of various carbo-⁶ and heterocycles.^6c–g,7 Thus, there are several reports on the metal-catalyzed rearrangements of 3-acylcyclopropenes into furans (eq 1).^6c–g,7 However, to the best of our knowledge, an analogous metal-catalyzed construction of N-containing heterocycles has no precedents.⁸ Herein, we wish to report the first example of a regiodivergent Cu- and Rh-catalyzed rearrangement of 3-iminocyclopropenes into N-fused pyrroles, heterocyclic scaffolds endowed with a wide array of important biological properties (eq 2).⁹

(1)

(2)

It deserves mentioning that, until recently, there were no convenient approaches toward C-3 imino-substituted cyclopropenes, potentially useful building blocks for organic chemistry.¹ Recently, we found¹⁰ that 7-halo-substituted N-fused triazoles 1 could be used as surrogates for α-imino diazocompounds¹¹ in the Rh(II)-catalyzed chemoselective reaction with terminal alkynes to produce indolizines 2 or 3-(2-pyridyl)cyclopropenes 3, depending upon catalyst source (eq 3).¹⁰ The presence of the halogen substituent in 1 was crucial, as no reaction occurred with triazoles possessing H or alkyl groups at C-7.¹⁰ Although the direct Rh(II) perfluorobutyrate-catalyzed transannulation of triazoles provided a rapid and convenient approach toward indolizines,¹⁰ it was not without limitations. Thus, only triazoles that possessed strong electron-withdrawing group at C-3 (R² = CO₂R) were efficient in this transannulation reaction. We hypothesized that, potentially, the rearrangement of 3-(2-pyridyl)cyclopropenes 3 could provide alternative routes to indolizines 2 as shown in eq 2.

(3)

To this end, we tested the generality of the Rh₂(S-DOSP)₂-catalyzed cyclopropenation of triazoles with alkynes. To our delight, we found that a variety of pyridyl-containing cyclopropenes can easily be synthesized in good yields via this method (Table 1).¹² Thus, triazoles 1a–d possessing both electron-rich and electron-deficient aryl substituents at C-3 reacted smoothly with various alkyl-, aryl-, and alkenyl-containing alkynes to afford corresponding cyclopropenes 3 chemoselectively (Table 1). Cyclopropenation of 3-carbomethoxytriazole 1e proceeded uneventfully, producing corresponding cyclopropenes 3 in good to excellent yields (entries 9–12, 14).

Table 1.

Rh₂(S-DOSP)₄-Catalyzed Cyclopropenation of Pyridotriazoles with Alkynes

no.	R1	R2		R3		yield,a %
1	Cl	Ph	1a	Ph	3a	81
2	Cl	Ph	1a	p-OMeC6H4	3b	79
3	Cl	Ph	1a	p-CO2MeC6H4	3c	65
4	Br	Ph	1b	Ph	3d	88b
5	Cl	p-OMeC6H4	1c	Ph	3e	67
6	Cl	p-OMeC6H4	1c	o-tolyl	3f	45
7	Cl	p-CF3C6H4	1d	Ph	3g	68
8	Cl	p-CF3C6H4	1d	1-cyclohexenyl	3h	93
9	Cl	CO2Me	1e	p-tolyl	3i	93c
10	Cl	CO2Me	1e	p-OMeC6H4	3j	67
11	Cl	CO2Me	1e	p-CO2MeC6H4	3k	72
12	Cl	CO2Me	1e	m-CO2MeC6H4	3l	87
13	Br	Ph	1b	n-butyl	3m	69
14	Cl	CO2Me	1e	Ph	3n	86d
15	Cl	Ph	1a	(CH2)3Cl	3o	68

^aIsolated yield.

^b8% ee.

^c86% ee.

^d84% ee.

Naturally, having in hand this convenient method for the synthesis of 3-iminocyclopropenes, we evaluated our hypothesis on the cyclopropene into N-fused pyrrole transformation (eq 2). To this end, we tested rearrangement of cyclopropene 3a into indolizines 2a and 4a in the presence of a series of transition-metal catalysts (Table 2). The employment of Pd(II) and Pt(II) chlorides in DMF at room temperature resulted in low yields and moderate regioselectivity of rearrangement (entries 1 and 2). The yield was improved upon switching to Pt(0) complex (entry 3); however, the selectivity remained unsatisfactory. Gratifyingly, we found that the employment of Ir(I) and Rh(I) complexes led to the highly regioselective isomerization of 3a into 2a (entries 6 and 7) in moderate and excellent yields, respectively. Interestingly, when Rh(II) perfluorobutyrate was used as a catalyst, another regioisomer 4a, with the substituent at C-2 position,^14,15 was formed as a single product, though in low yield (entry 8). AgSbF₆ and Au(III) chloride¹⁶ were completely inefficient catalysts for this transformation (entries 9 and 10). However, Cu(I) iodide smoothly isomerized 3a into indolizine 4a in good yield and excellent regioselectivity (entry 11, Table 2).

Table 2.

Metal-Catalyzed Rearrangement of Cyclopropene 3a

no.	Catalyst	T (°C)	2a:4a ratioa	yield,b %
1	PdCl2	rt	2:1	23
2	PtCl2	rt	4:1	38
3	Pt(PPh3)4	60	5:1	86
4	NiCl2	60		0c
5	RuCl2(PPh3)3	60	8:1	32
6	[Ir(cod)py(PCy3)]PF6	60	> 99:1	49
7	RhCl(PPh3)3	rt	> 99:1	92
8	Rh2(pfb)4	rtd	< 1:99	31
9	AgSbF6	60		0c
10	AuCl3	60d		0c
11	CuI	rt	< 1:99	78

^aNMR ratio.

^bCombined NMR yield of both isomers.

^cA mixture of unidentified products formed.

^dDichloroethane used as solvent.

Next, we explored the scope of this novel regiodivergent rearrangement methodology. First, rearrangement of a series of 3-(2-pyridyl)cyclopropenes into 1,3-disubstituted indolizines 2 was tested under Rh(I) catalysis (Table 3). It was found that cyclopropenes possessing both electron-rich and electron-deficient aryl groups¹⁷ at position C-3 and at the double bond underwent clean and regioselective rearrangement into indolizines 2. Notably, 1-alkenyl- (entry 8) and Br-containing (entry 4) substrates were found to be equally efficient in this reaction, as well. Thus, the Rh(I)-catalyzed isomerization of cyclopropenes compliments the direct transannulation protocol,¹⁰ providing access to a wider selection of 1,3-substituted indolizines possessing not only ester but also various aryl groups at C-3. Attempts to perform the analogous transformation with 3-carbomethoxycyclopropene 3n produced only a small amount of the corresponding indolizine 5 together with furan 6 as major product of this reaction (eq 4). Formation of furan 6 in the presence of Wilkinson’s catalyst is consistent with earlier observations (eq 1).^6c–g,7

Table 3.

Rh(I)-Catalyzed Rearrangement of Cyclopropenes

no.	cyclopropene 3		product 2		yielda, %
1		3a		2a	85
2		3b		2b	91
3		3c		2c	79
4		3d		2d	87
5		3e		2e	81
6		3f		2f	93
7		3g		2g	84
8		3h		2h	88

^aIsolated yield.

(4)

After successful synthesis of 1,3-disubstituted indolizines 2 (Table 3), we turned our attention to regioselective formation of valuble^14,15 1,2-subsituted N-fused pyrroles 4 via the Cu(I)-catalyzed rearrangement. To our delight, a variety of 3-carbomethoxy- and 3-arylcyclopropenes reacted smoothly to produce indolizines 4 in good to excellent yields (Table 4). Electron-rich (entries 2 and 3) and electron-deficient (entries 4 and 5) aryl groups and alkyl substituents (entries 7 and 8) at the double bond of cyclopropene were equally well tolerated in this reaction. Gratifyingly, this rearrangement mode worked well with different 3-heteroaryl-cyclopropenes, such as oxazole¹⁸ and isoquinoline¹⁹ derivatives 3p and 3r, giving access to their fused analogues 4j and 4k in good yields (entries 10 and 11).

Table 4.

Cu(I)-Catalyzed Rearrangement of Cyclopropenes

no.	cyclopropene 3		product 4	yielda, %
1	3a			4a	75
2		3i		4b	83
3		3j		4c	95
4		3k		4d	73
5		3l		4e	81
6	3d			4f	78
7		3m		4g	71
8		3n		4h	67
9		3o		4i	73
10		3P		4j	71
11		3r		4k	88

^aIsolated yield.

We propose the following mechanistic rationale for the novel regiodivergent rearrangement of imino cyclopropenes 3 into fused pyrroloheterocycles 2 and 4 (Scheme 1). Cyclopropene 3, in the presence of Rh(I) complex, undergoes ring opening to produce the most substituted carbenoid 5.^6c–e,7c A nucleophilic attack by nitrogen lone pair on carbenoid center leads to the formation of zwitterion 7. A subsequent elimination of the metal furnishes regioisomer 2. In contrast, when Cu(I) catalyst is used, formation of less substituted carbenoid 6 occurs,^6c,f,g,7a cyclization of which via a zwitterion 10 leads to the product 4 selectively. Alternatively, regioisomers 2 and 4 may arise via a reductive elimination of aza metalacycles 8 and 9, respectively, which in turn are formed via a 6π-electrocyclization^6e,20 of carbenoids 5 and 6, or directly from cyclopropene 3, upon regioselective oxidative addition of the metal.^6e,7c It was also proposed that isomeric carbenoids 5 and 6 could interconvert through the cycloaddition/cycloreversion equilibrium.^6d,e We evaluated a possibility of such equilibrium by performing a crossover experiment in the presence of 5 equiv of “external” alkyne. However, no crossover products were detected, thus suggesting independent routes for the formation of 5 and 6.

Scheme 1.

Mechanistic Rationale for Regiodivergent Rearrangement Reactions

In summary, we have developed a highly efficient synthesis of 1,3- and 1,2-disubstituted N-fused pyrroloheterocycles,^9,21 including indolizines, pyrrolooxazole, and pyrroloisoquinoline, via a novel regiodivergent transition-metal-catalyzed rearrangement of 3-iminocyclopropenes. We also demonstrated that the latter can conviniently be synthesized from 1,2,3-triazoles.²³