Rhodium-Catalyzed Ring Expansion of Cyclopropanes to Seven-membered Rings by 1,5 C–C Bond Migration

Selective cleavage and subsequent elaboration of carbon–carbon σ bonds into complex molecules represents a fundamental challenge in chemistry. The C–C σ bonds of cyclopropanes are activated owing to ring strain, and the ring expansion of cyclopropanes is an attractive route to other ring systems because of the well-documented stereoselective methods for cyclopropanation.^[1] Indeed, ring expansion of cyclopropanes to four- or five-membered rings by 1,2 or 1,3 migration is routinely practiced in organic synthesis [Eq. (1)].^[2] In contrast, ring expansion of cyclopropanes to seven-membered rings by 1,5 C–C bond migration has not been developed as a general method, in spite of the prevalence of cycloheptane skeletons in natural products and pharmaceutical agents.^[3] The 1,5 migration of a cyclopropane C–C bond has been mainly studied in bicyclo-[4.1.0]heptadienes and a few other conformationally constrained bicyclic compounds under thermal conditions.^[4] In fact, it was reported that simple 1,3-dienylcyclopropanes underwent 1,3 C–C bond migration to form vinylcyclopentenes in the presence of Ni or Pd catalysts.^[5]

(1)

The most well-known example of the direct expansion of three-membered rings to seven-membered rings is the [3,3]-sigmatropic Cope rearrangement of divinylcyclopropanes to 1,4-cycloheptadienes.^[6] Although this process requires the double activation of cyclopropanes by two vinyl groups, it is still one of the most important methods for the preparation of seven-membered rings. Methods that can promote ring expansion of cyclopropanes to seven-membered rings with complementary functionalities would be highly desirable. We herein describe the synthesis of functionalized alkylidene cycloheptadiene 3 by a Rh^I-catalyzed tandem isomerization of the monoactivated cyclopropane 1 via an allene intermediate 2 [Eq. (2)].

(2)

Based on the high reactivity of allenes with respect to transition metals,^[7] we hypothesized that a 1,5 migration of a cyclopropane C–C bond in intermediate 2 may become favored over a 1,3 migration, which would generate an allenyl cyclopentene without the participation of the allene. We recently discovered that the [{Rh(CO)₂Cl}₂] catalyst was able to promote 1,3 acyloxy migration of propargyl esters to form allenes;^[8] this transformation was previously realized mainly by π-acidic metal-based catalysts such as silver,^{[9, 10]} copper,^[9–11] platinum,^{[11, 12]} and gold^{[10, 13]} in various cascade reactions.^{[14, 15]} Given this novel reactivity of [{Rh(CO)₂Cl}₂] for the promotion of 1,3 acyloxy migration and its well-known capability to undergo oxidative addition and reductive elimination, we envisioned that alkylidene cycloheptadiene 3 could be prepared directly from readily available cyclopropane 1^[16] in the presence of the [{Rh(CO)₂Cl}₂] catalyst.^[17] The acyloxy substituent on propargyl ester 1 not only eases the preparation of allene 2 but also differentiates the three double bonds in product 3.

To test the proposed transformation in Equation (2), substrate 1a was prepared in four steps from commercially available cyclopropanecarboxaldehyde.^[16] Treatment of cyclopropane 1a with 3 mol% of [{Rh(CO)₂Cl}₂] at 60°C provided a significant amount of product 3a (Table 1, entry 1) after 12 hours and some starting materials were also recovered. Complete conversion was realized after increasing the catalyst loading to 5 mol% (Table 1, entry 2). Under these reaction conditions, however, a small amount of eight-membered-ring product 4a was also observed. Product 4a was isolated in 22% yield when the catalyst loading was increased to 10 mol% (Table 1, entry 3). We speculated that increasing the CO pressure would provide more CO-insertion product 4a. Surprisingly, a complex mixture was observed with more CO (Table 1, entries 4 and 5). No reaction occurred in the presence of several other rhodium catalysts (Table 1, entries 6–8). Changing the solvent from DCE to dioxane led to quantitative production of seven-membered-ring 3a without any eight-membered-ring 4a, as determined by ¹H NMR analysis of the crude product (Table 1, entry 9). The reaction time was shortened from 6 hours to 2.5 hours at higher temperature (Table 1, entry 10). Moreover, π-acidic metal-based catalysts such has Au_I and Pt_II or Brønsted acid catalyst did not provide any desired product 3a (Table 1, entries 11–13).

Table 1.

Screening of catalysts and reaction conditions.

Entry	Catalyst	Conditions	Yield [%]
1	[{Rh(CO)2Cl}2] (3 mol%)	60°C, DCE, 12 h	3 a, 72[a]
2	[{Rh(CO)2Cl}2] (5 mol%)	60°C, DCE, 12 h	3 a, 82[b]
3	[{Rh(CO)2Cl}2] (10 mol%)	60°C, DCE, 12 h	3 a, 70[b] 4 a, 22[b]
4	[{Rh(CO)2Cl}2] (10 mol%)	60°C, DCE, CO (1 atm), 12 h	complex mixture
5	[{Rh(CO)2Cl}2] (5 mol%)	60°C, DCE, CO (5 atm), 12 h	complex mixture
6	[{Rh(CO)2Cl}2] (5 mol%)	60°C, DCE, 3 h	NR
7	[Rh(PPh3)3Cl] (5 mol%)	60 °C, DCE, 3 h	NR
8	[Rh(cod)2]BF4 (5 mol%)	60 °C, DCE, 3 h	NR
9	[{Rh(CO)2Cl}2] (5 mol%)	60°C, dioxane, 6 h	3 a, >95[a]
10	[{Rh(CO)2Cl}2] (5 mol%)	100°C, dioxane, 2.5 h	3 a, >95[a]
11	[AuCl(PPh3)] (5 mol%) AgOTf (5 mol%)	RT, MeCN, 20 h	0
12	PtCl2 (10 mol%)	80°C, DCE, 20 h	0
13	HNTf2 (10 mol%)	RT, CH2Cl2, 20 h	0

^[a]Yields were determined by ¹H NMR spectroscopy using CH₂Br₂ as internal standard.

^[b]Yields of the isolated product. cod=cyclooctadiene, DCE=dichloroethane, NR=No reaction, Piv=pivaloyl.

We then set out to examine the scope of this tandem isomerization process (Table 2). The reaction worked well when the ester was changed from pivalate to acetate (Table 2, entry 2). The gem-dimethyl group on the propargyl ester could be replaced by other alkyl or aryl groups (Table 2, entries 3–5). However, a stereoselectivity issue arises for the exocyclic olefins in these cases. For propargyl ester 3c with a phenyl substituent, we observed a 14:1 Z/E selectivity^[16] (Table 2, entry 3), which is much higher than the selectivity that was obtained in the [5+1] cycloaddition of acyloxy-substituted allenyl cyclopropanes with CO.^[8] Lower selectivity was generally observed for substrates with alkyl groups (Table 2, entries 4 and 5). The 1,1-disubstituted cyclopropane 1f could provide product 3 f, which has an additional substituent on the seven-membered ring (Table 2, entry 6). The Z/E selectivity for the exo cyclic olefins varied slightly with electron-rich or electron-poor aryl substituents (Table 2, entries 7–9).^[18] An aryl group with one ortho substituent significantly lowered the Z/E selectivity (Table 2, entry 10). Various functional groups, such as acetate, free alcohol, and even aldehyde, were tolerated under the reaction conditions (Table 2, entries 11–13). Ring expansion of cyclopropanes 1n and 1o led to 6,7 and 5,7 fused bicyclic systems respectively (Table 2, entries 14 and 15); these fused bicyclic systems are widely present in bioactive natural products.^[19]

Table 2.

Scope of the Rh_I-catalyzed ring expansion.^[a]

Entry	Substrates	Products	Yield [%][b]	Z/E[c]
1	1 a, R =Piv	3 a	83	–
2	1 b, R =Ac	3 b	83	–
3	1 c, R =Ph	3 c	76	14:1
4	1 d, R =nBu	3 d	82	1:1
5	1 e, R =iPr	3 e	93	2:1
6	1 f	3 f	92	–
7	1 g, Ar =Ph	3 g	87	7:1
8	1 h, Ar =4-MeOC6H4	3 h	87	9:1
9	1 i, Ar =4-CF3C6H4	3 i	70	8:1
10	1 j, Ar =2,4-Cl2C6H3	3 j	83	3:1
11	1 k, R =CH2OAc	3 k	95	8:1
12	1 l, R =CH2OH	3 l	81	7:1
13	1 m, R =CHO	3 m	66	5:1
14	1 n	3 n	91	–
15	1 o	3 o	85	–
16	1 p, R =Ph (92% ee)	3p (91% ee)	68	–
17	1 q, R =CH2OTIPS	3 q	99	–
18	1 r, R =CH2OAc	3 r	92	–

^[a]Reaction conditions: [{Rh(CO)₂Cl}₂] (5 mol%), 100°C, dioxane, 2–3 h.

^[b]Yields of the isolated products.

^[c]Estimated by ₁H NMR spectroscopy. TIPS=triisopropylsilyl.

For unsymmetrically substituted cyclopropanes, the cleavage of different cyclopropane C–C σ bonds will lead to isomeric products. Our group^{[8, 20]} and other groups^[21] have found that the regioselectivity for the cleavage of C–C σ bonds in cyclopropanes depends on the stereochemistry of the cyclopropane ring. Only one regioisomer was obtained for aryl- or alkyl-substituted trans cyclopropanes (Table 2, entries 16–18). Interestingly, the corresponding cis cyclopropanes with either aryl or alkyl substituents provided a mixture of seven-membered rings with low regioselectivity under identical reaction conditions.^[16] The chirality in substrate 1p was successfully transferred to the seven-membered-ring product 3p (Table 2, entry 16). This paved the way for the preparation of optically pure seven-membered rings from chiral cyclopropanes.

The mechanism for the ring expansion of cyclopropane 1 to alkylidene cycloheptadiene 3 is proposed in Scheme 1. A Rh^I-catalyzed 1,3 acyloxy migration may occur first and generate allene intermediate 2. Formation of η⁴-(vinylal-lene) rhodium complex 5 can initiate an oxidative cyclization to yield alkylidene metallacyclopentene 6. This transformation has been documented in the rhodium-catalyzed [4+1] cycloaddition of vinylallenes with CO,^[22] and also the corresponding alkylidene metallacyclopentene complexes were isolated and characterized in the absence of CO.^{[23, 24]} Alkylidene metallacyclooctadiene 7 can be obtained by the cleavage of the strained cyclopropane ring in complex 6. Reductive elimination of metallacycle 7 then yields the desired seven-membered-ring 3.^[25] The isolation of the eight-membered-ring product 4a supports the involvement of metallacycle 7, which may undergo carbonylation to form an eight-membered ring.

Scheme 1.

Proposed mechanism and related evidence.

When propargyl ester 1a was treated with catalyst AgSbF₆,^[14] an inseparable mixture of allene 8 and enyne 1a was obtained (ratio=1:1). Submitting this mixture to the standard reaction conditions provided the desired product 3a in 83% yield, thus suggesting that the acyloxy-substituted allene is a plausible intermediate in the ring-expansion reaction.

To gain further insights about the metal-catalyzed 1,5 C–C bond migration, we then prepared 1,3-dienyl cyclopropane 9 and treated it with Rh^I catalyst. In the absence of CO, triene 10 was isolated in 77% yield under the standard reaction conditions in Table 2.^[26] No reaction occurred in the presence of CO.^[27] This confirmed the importance of the allene group in intermediate 2 for the net 1,5 C–C bond migration.

We also prepared allene 11 by treating propargyl ester 1q with excess methyl cuprate reagents.^[28] Under our standard reaction conditions in Table 2, seven-membered-ring product 12 could be obtained in 62% yield from allene 11, thus indicating that the acyloxy substituent in intermediate 2 is not required for the ring expansion. However, the acyloxy substituent is important for differentiating the three double bonds in product 3 for selective functionalization.^[16]

In summary, we developed a novel method for the preparation of highly functionalized seven-membered rings directly from substituted cyclopropanes through a 1,5 C–C migration. This method may provide efficient access to mono-and polycyclic bioactive sesquiterpenoids that contain isopropylidene cycloheptanones.^[29] The π-acidic rhodium catalyst is essential for the conversion of readily available cyclopropanes with propargyl ester group to alkylidene cycloheptadienes with three well-differentiated double bonds. Further studies to understand the details of the 1,5 C–C bond migration and apply this tandem isomerization reaction to the synthesis of bioactive compounds are currently in progress.