Gold‐Catalyzed Intramolecular Cyclizations of Cyclopropenes with Propargylic Esters

Abstract

Homogeneous gold catalysts are interesting as they can act as potent carbophilic Lewis acids to activate the π bonds of alkynes, allenes, and alkenes. Many impressive applications for the formation of C−C or C−heteroatom bonds have been found due to the excellent functional group compatibility of these catalysts and the air and moisture tolerance of their reactions. Here, we have developed gold‐catalyzed novel intramolecular cycloisomerizations of nitrogen or oxygen‐tethered cyclopropenes with propargylic esters. The reaction proceeded through different pathways according to different substituent styles, affording 5‐azaspiro[2.5]oct‐7‐enes and bicyclo[4.1.0]heptanes.

Homogeneous gold catalysis has been a hot topic over the last decade. Such catalysts act as potent carbophilic Lewis acids to activate the π bonds of alkynes, allenes, and alkenes. Many impressive applications for the formation of C−C or C−heteroatom bonds have been found due to the excellent functional group compatibility of these catalysts and the air and moisture tolerance of their reactions.1 In the presence of gold catalysts, propargylic esters readily undergo 1,2‐ or 1,3‐acyloxy migration, resulting in different cascade reactions.2 Indeed, many groups including ours have made numerous contributions in this research area.3

On the other hand, cyclopropenes are highly strained but readily prepared compounds that can serve as useful building blocks in organic synthesis.4 In the presence of a gold(I) catalyst, activated cyclopropene undergoes a ring‐opening process to give a vinyl gold carbene or gold‐stabilized allylic carbocation which can be regarded as a pair of resonant structures.1e, 5 Such a carbenoid can readily accept a nucleophilic attack from many kinds of nucleophiles, such as alcohols, arenes, and carbonyl groups. For instance, Lee and colleagues reported the addition of alcohols to cyclopropenes in the presence of a gold catalyst (Scheme 1 a). Besides being the precursor of vinyl carbene, cyclopropenes can also serve as nucleophiles to attack other functional groups which have been activated by a gold(I) catalyst. In 2010, Wang's group reported the intramolecular cycloisomerization of cyclopropene‐ynes catalyzed by a gold complex, in which cyclopropene served as a nucleophile to attack the gold‐activated alkynes (Scheme 1 b).6 Considering that both propargylic ester and cyclopropene can serve as good π donors, we envisaged that a substrate which combined these two components could exhibit versatile reactivities under gold catalysis. Herein, we wish to report a novel cycloisomerization of cyclopropenyl propargylic esters, which afford an efficient access to multifunctionalized 5‐azaspiro[2.5]oct‐7‐enes 2 and bicyclo[4.1.0]heptanes 4. The reaction outcomes are controlled by the substituent on cyclopropene. When the substituent R is not a hydrogen atom, there are two possible reaction pathways yielding products. The syn‐addition of the C−Au bond with cyclopropene takes place, or the cyclopropane cation derived from the activation by gold(I) catalyst is attacked by the in‐situ‐generated allene moiety, giving the corresponding cis‐substituted cyclopropanes 2. If R=H, the cyclopropanation of allene by the in‐situ‐generated carbene species delivers the corresponding products 4.

Scheme 1.

General reactivity of cyclopropenes in the presence of gold catalysts.

Initially, we commenced our studies using propargylic acetate cyclopropene 1 a as model substrate to optimize the reaction conditions. The results are summarized in Table 1. We found an interesting six‐membered spiro‐heterocyclic product 2 a, which was formed in 55 % yield upon treating 1 a with tBuXPhosAu(NCMe)SbF₆ in toluene at 100 °C (Table 1, entry 1). Various gold(I) catalysts were first examined, such as PPh₃AuNTf₂, JackiePhosAuNTf₂, Me₄ tBuXPhosAuOTf, CyJohnPhosAu(NCMe)SbF₆, and SPhosAuNTf₂, giving inferior results (Table 1, entries 2–6). IPrAuNTf₂ was also used as the catalyst to carry out the reaction under the standard conditions, giving the desired product 2 a in 51 % yield (Table 1, entry 7). The combination of tBuXPhosAuCl (5 mol %) with different silver(I) salts (5 mol %), for instance, AgOTf, AgSbF₆, or AgNTf₂, did not give better results either (Table 1, entries 8–10). Increasing catalyst loading to 10 mol % delivered 2 a in a decreased yield of only 49 % (Table 1, entry 11). Fine‐tuning catalyst loading to 2.5 mol % gave 2 a in a moderate yield of 53 %, indicating that only a small amount of the catalyst can maintain the catalytic cycle (Table 1, entry 12).

Table 1.

Optimal reaction conditions for the intramolecular cycloisomerizations.

Entry	Catalyst [mol %]	T [°C]	Solvent	Yield [%][a]
1	tBuXPhosAu(NCMe)SbF6 [5]	100	toluene	55
2	PPh3 AuNTf2 [5]	100	toluene	27
3	JackiePhosAuNTf2 [5]	100	toluene	45
4	Me4 tBuXPhosAuOTf [5]	100	toluene	39
5	CyJohnPhosAu(NCMe)SbF6 [5]	100	toluene	43
6	SPhosAuNTf2 [5]	100	toluene	43
7	IPrAuNTf2 [5]	100	toluene	51
8	tBuXPhosAuCl/AgOTf [5]	100	toluene	41
9	tBuXPhosAuCl/AgSbF6 [5]	100	toluene	35
10	tBuXPhosAuCl/AgNTf2 [5]	100	toluene	43
11	tBuXphosAu(NCMe)SbF6 [10]	100	toluene	49
12	tBuXphosAu(NCMe)SbF6 [2.5]	100	toluene	53
13	tBuXphosAu(NCMe)SbF6 [5]	100	THF	ND
14	tBuXphosAu(NCMe)SbF6 [5]	100	MeCN	53
15	tBuXphosAu(NCMe)SbF6 [5]	100	DCE	59
16	tBuXphosAu(NCMe)SbF6 (5]	80	DCE	49
17	tBuXphosAu(NCMe)SbF6 [5]	120	DCE	56
18	tBuXPhosAuOTf [5]	100	DCE	69 (73[b])

All reactions were carried out using 1 a (0.1 mmol) in the presence of catalyst (x mol %) in various solvents (1.0 mL); [a] Yield of isolated product; [b] 4 Å MS (100 mg) were added to the reaction mixtures.

The solvent effect was also evaluated. No product was formed in tetrahydrofuran (THF) (Table 1, entry 13). Changing the solvent to acetonitrile gave the desired product 2 a in 53 % yield (Table 1, entry 14). Finally we found that 1,2‐dichloroethane (DCE) was the best solvent in this transformation, giving 2 a in 59 % yield (Table 1, entry 15). Decreasing the reaction temperature to 80 °C or elevating the temperature to 120 °C did not improve the reaction outcome either, giving the corresponding product 2 a in 49 % and 56 % yields, respectively (Table 1, entries 16 and 17). Different coordination anions of the gold(I) catalyst were also tested. The use of tBuXPhosAuOTf turned out to be very effective in the reaction, giving the desired product 2 a in 69 % yield in DCE and in 73 % yield with 4 Å molecular sieves (MS) in the reaction mixture (Table 1, entry 18) (for more detailed information, see Table S1 in the Supporting Information).

With the optimized reaction conditions in hand, we set out to explore the substrate scope (Table 2). Aromatic rings (R³) bearing electron‐withdrawing groups (fluorine and bromine) or electron‐donating groups (3,5‐di‐methyl) were all tolerated in this reaction, giving the spirocyclic products 2 b–d in moderate to good yields, and electron‐donating groups were proved to improve the efficiency of the reaction. With a change of R³ to an alkyl substituent such as methyl, cyclopropyl, and isopropyl groups, the reactions delivered the corresponding products 2 e–g in good yields. Various propargylic esters were then examined. For cycloalkyl‐group‐substituted propargylic esters, the reactions proceeded smoothly to give the desired products 2 h–j in 56–81 % yields. Interestingly, larger ring sizes resulted in better yields. When R¹ was replaced by linear alkyl substituents such as ethyl, n‐propyl, and n‐butyl groups, the reactions delivered the corresponding products 2 k–m as Z/E isomeric mixtures. Next, several sulfonyl amides such as p‐bromobenzenesulfonyl (Bs) and p‐nitrobenzenesulfonyl (Ns) were tested, and products 2 n–o were obtained in excellent yields. The structure of 2 o was confirmed by X‐ray diffraction.7 A substrate with a pivaloyl (Piv) group in place of an acyl (Ac) group produced the diene product 2 p in 86 % yield. When a substrate with an oxygen linker was employed, the corresponding product 2 q was afforded in 47 % yield in the presence of AgOTf. In general, AgOTf could catalyze this reaction as well, but only afforded the corresponding product in low yield. The structure of 2 q was also determined by X‐ray diffraction studies.7

Table 2.

Substrate scope of the intramolecular cycloisomerization.

Entry	Substrate	Product and yield
1		2 b, R3=4‐FC6H4, 54 % yield 2 c, R3=4‐BrC6H4, 71 % yield 2 d, R3=3, 5‐di‐Me‐C6H3, 90 % yield 2 e, R3=Me, R4=Et, 72 % yield 2 f, R3=cyclopropyl, R4=Me, 67 % yield 2 g, R3=iPr, R4=Me, 84 % yield
2		2 h, n=1, 56 % yield 2 i, n=2, 68 % yield 2 j, n=3, 81 % yield
3		2 k, R1=Et, R1′=Me, 53 % yield, E/Z=1:1 2 l, R1=n‐Pr, R1′=Et, 81 % yield, E/Z=1:1 2 m, R1=nBu, R1′=n‐Pr, 97 % yield, E/Z=1:1
4		2 n, X=BsN, 99 % yield 2 o, X=NsN, 84 % yield (X‐ray)
5		2 p, 86 % yield
6		2 q, 47 % yield[b] (X‐ray)

[a] 100 mg of 4 Å molecular sieves (MS) were added to the reaction mixtures. [b] Catalyzed by AgOTf at 120 °C in a sealed tube.

Surprisingly, when substituent R³ was a proton instead of an aromatic or alkyl substituent, bicyclo[4.1.0]heptane products 4 a–c were obtained in moderate yields (Scheme 2). The structure of 4 c was determined by X‐ray diffraction.7

Scheme 2.

Intramolecular cycloisomerization of proton‐substituted cyclopropenes 3. Reagents and conditions: a) t‐BuXPhosAuOTf (5 mol %), 4 Å MS, DCE, 100 °C, 2 h, 4 a: 59 %, 4 b: 43 %, 4 c: 41 % (X‐ray).

To elucidate the mechanism, deuterium labeling experiments were performed as shown in Scheme 3. Carrying out the reaction of [D]‐1 a in the presence of gold catalyst, product [D]‐2 a was produced in 52 % yield with 99 % D content at the phenyl‐substituted carbon, indicating that a syn‐addition might occur instead of the nucleophilic attack from the back side of the gold‐activated alkene.

Scheme 3.

Deuterium labeling experiment. Reagents and conditions: a) t‐BuXPhosAuOTf (5 mol %), 4 Å MS, DCE, 100 °C, 2 h, 52 %.

Plausible mechanisms8 for the formation of 2 and 4 are outlined in Scheme 4. The cationic gold(I) complex first coordinates with the alkyne moiety of [D]‐1 a to give intermediate A. Then gold‐catalyzed [3,3]‐sigmatropic rearrangement takes place to deliver the corresponding carboxyallene intermediate B. The following activation of allene by gold affords vinyl gold intermediate C, which then results in the cyclopropyl gold intermediate D after syn‐addition of C−Au bond to cyclopropane (path a). Alternatively, the gold(I) catalyst can activate the cyclopropene moiety (intermediate E) to form the corresponding cyclopropane cationic intermediate F. Due to the steric hindrance between the phosphine ligand and the ester group, the coordination of the gold(I) catalyst with the cyclopropene should be on the opposite face from where the ester group is placed. This would force the phenyl group to go to the same face with the ester group. Then cationic intermediate F underwent nucleophilic attack by the allene to give the intermediate D (path b). Finally, the desired product [D]‐2 a is formed after protodeauration. Due to the bukyl phosphine ligand of gold catalyst, the cis‐addition to cyclopropene from the back side of the ester group is favored (Scheme 4 a). On the other hand, for the synthesis of 4, substrate 3 c is first transformed to intermediate G upon coordination. The [3,3]‐sigmatropic rearrangement delivers the allenic intermediate H, which is activated by the gold catalyst. The following ring opening of cyclopropene furnishes gold carbene I, which is trapped by the double bond of carboxyallene, furnishing the final product 4 c (Scheme 4 b).

Scheme 4.

Plausible mechanisms for the formation of 2 and 4.

To further demonstrate the versatile reactivity of cyclopropene, we also examined the performance of 1 a in the presence of FeCl₃ (1.2 equiv), but the reaction of 1 a gave a new triene derivative 5 a in 40 % yield. Upon coordination of the ester group with FeCl₃, the nucleophilic addition of the cyclopropene to the alkyne along with acyloxy group departure affords carbocation J, which gives rise to intermediate K after isomerization. Subsequent chlorination delivers the final product 5 a (Scheme 5). The structure of 5 a was determined by X‐ray diffraction.7

Scheme 5.

FeCl₃‐mediated intramolecular cycloisomerization. Reagents and conditions: a) FeCl₃ (1.2 eq), DCE, rt, 3 d, 40 %.

In conclusion, we have developed a highly efficient gold‐catalyzed intramolecular cycloisomerization of propargylic esters with cyclopropenes. By varying the substituents on the cyclopropenes (R³ as a proton or not), two types of products could be obtained. The reaction mechanism is proposed on the basis of deuterium labeling experiments and previous literature. Substrate 1 a can also undergo cycloisomerization in the presence of FeCl₃, affording a new triene product 5 a after a tandem ring‐opening process. Further applications of cyclopropene chemistry are underway in our laboratory.

Supporting information

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Supplementary

P.-L. Zhu, X.-Y. Tang, M. Shi, ChemistryOpen 2016, 5, 33.