Catalytic Generation of Cationic Gold Carbene Complexes From 7‐Alkynylnorbornadienes and Their Intermolecular Cyclopropanation With Alkenes

ABSTRACT

Norbornene derivatives are commonly used in organic chemistry. The development of new norbornene derivatives is important for expanding molecular diversity. In this study, we investigated the cationic gold‐catalyzed cycloisomerization of 7‐alkynylnorbornadienes. The reaction of 7‐alkynylnorbornadienes with an excess of alkenes in the presence of a catalytic amount of [IPrAu(MeCN)]SbF₆ efficiently afforded a new class of norbornene derivatives through intermolecular cyclopropanation of cyclopropyl gold carbene complexes. This reaction exhibited a wide substrate scope, and the product was demonstrated to be applicable to polymer synthesis and click reactions. Furthermore, DFT studies suggested that the developed reaction proceeds via a mechanism involving a gold(III) metallacyclobutane intermediate, which is different from the mechanisms previously reported for cationic gold(I)‐catalyzed styrene cyclopropanation.

Efficient cationic gold(I)‐catalyzed intermolecular cyclopropanation of 7‐alkynylnorbornadiene derivatives has been developed. This methodology offers the synthesis of a new class of norbornene derivatives in high yield with excellent diastereoselectivity. DFT calculations suggest that the developed reaction proceeds via a mechanism involving a gold(III) metallacyclobutane intermediate.

1. Introduction

The development of new types of useful compounds is important in synthetic chemistry. Norbornene and its related compounds are highly useful in materials science and the life sciences. For example, the ring‐opening metathesis polymerization (ROMP) of norbornene derivatives has become a powerful tool for the synthesis of functional polymers (Scheme 1a) [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]. Additionally, the inverse electron‐demand Diels–Alder reaction (IEDDA reaction) between norbornene and tetrazine derivatives has been widely used as a bioorthogonal click reaction in chemical biology (Scheme 1b) [14, 15, 16, 17, 18]. However, most norbornene derivatives used in these reactions are synthesized by the Diels–Alder reaction of cyclopentadiene; therefore, they have a relatively simple structure. From the perspective of molecular diversity, the development of efficient synthetic methods for new classes of norbornene derivatives is crucial. Notably, in click chemistry, faster reaction rates are desirable for biological applications because the concentration of molecules in living cells is very low [16, 17, 18]. Therefore, the synthesis of norbornene derivatives that are more reactive toward tetrazines is desired.

SCHEME 1.

Utility of norbornene derivatives.

SCHEME 2.

Cationic gold‐catalyzed enyne cycloisomerization.

A useful methodology for the synthesis of complex molecular architectures is the transition‐metal‐catalyzed cycloisomerization of enynes [19, 20, 21, 22, 23]. Cationic gold(I) complexes are known to activate alkynes electrophilically through complexation and efficiently catalyze cycloisomerization of enynes [24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]. In general, gold‐catalyzed cycloisomerization is initiated by the formation of cyclopropyl carbene complexes (1, 2, and 3), which, depending on their coordination sphere, may also be described as gold‐coordinated carbocations (Scheme 2a). The carbene complex intermediates then undergo diverse reactions, such as skeletal rearrangement, 1,2‐hydrogen shift, and reactions with nucleophiles. In addition, the carbene complexes can be trapped by alkenes to form another cyclopropane ring [34, 43, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70]. As a quite rare example, direct intermolecular cyclopropanation of cyclopropyl carbene complexes using 1,6‐enyne 4 and alkenes has been previously reported by Echavarren et al. (Scheme 2b) [43]. In this study, to address the existing limitations of the norbornene structure, we sought to develop a cyclization reaction with 7‐alkynylnorbornadiene 5 (Scheme 2c). Endo‐cyclization of the 1,5‐enyne moiety of 5 can generate the cyclopropyl carbene complex 6. We envisioned that the characteristic structure of 6 would prevent a 1,2‐hydrogen shift, which is a common fate of carbene intermediates in 1,5‐enyne cyclizations [35, 39, 71], allowing intermolecular cyclopropanation with alkenes to afford 7. This strategy offers the efficient synthesis of a new type of norbornene derivative.

2. Results and Discussion

Examination of intermolecular cyclopropanation was conducted with 7‐alkynylnorbornadiene 5a and 4 equiv. of styrene in 1,2‐dichloroethane (Table 1). Initially, the reaction with 2 mol% of [JohnPhosAu(MeCN)]SbF₆ was examined at room temperature, and the desired cyclopropanation products (7a + 7a′) were produced in 66% yield with moderate diastereoselectivity (4.2:1; entry 1). The structure of the major isomer 7a was unambiguously determined by x‐ray crystallography, revealing the two phenyl rings located on opposite sides (See Supporting Information) [72]. The reaction at −10°C for 48 h afforded 7a and 7a′ in 73% yield with slightly improved selectivity (5.4:1; entry 2). Then, to improve product yield and selectivity, reactions with other gold catalysts were examined. The use of XPhosAuNTf₂ afforded the desired products in good yields. However, 7a′ was found to be produced as the major product in this case, although the selectivity is modest (entry 3). Reactions with IPr as the ligand afforded 7a with excellent stereoselectivity (entries 4–6). Regarding counter anions, under an in situ cationic catalyst generation system, better results were obtained using NTf₂ ⁻ than SbF₆ ⁻ (entries 4 vs. 5); however, the use of the prepared catalyst [IPrAu(MeCN)]SbF₆ afforded results comparable to those obtained with IPrAuCl + AgNTf₂ (entries 5 vs. 6). Finally, the reaction with [IPrAu(MeCN)]SbF₆ and 8 equiv. of styrene afforded 7a and 7a′ in 79% isolated yield with excellent diastereoselectivity (19:1; entry 7). The reaction using dichloromethane as the solvent afforded a similar result (entry 8). The reaction with toluene improved the yield of 7a and 7a′, but its diastereoselectivity was slightly lower (88%, 14:1; entry 9). The reaction with 1,2‐dichloroethane at room temperature afforded 7a and 7a’ in reasonable yield, albeit with lower diastereoselectivity (76%, 11:1; entry 10).

TABLE 1.

Examination of reaction conditions.

Entry	Catalyst	X	Temp.	Time	Yield of 7a+7a′ a
1	[JohnPhosAu(MeCN)]SbF6	4	r.t.	12 h	66% (4.2:1)
2	[JohnPhosAu(MeCN)]SbF6	4	−10°C	48 h	73% (5.4:1)
3	XPhosAuNTf2	4	−10°C	48 h	60% (1:2.3)
4	IPrAuCl + AgSbF6 (1:1)	4	−10°C	48 h	44% (16:1)
5	IPrAuCl + AgNTf2 (1:1)	4	−10°C	48 h	67% (19:1)
6	[IPrAu(MeCN)]SbF6	4	−10°C	48 h	66% (20:1)
7	[IPrAu(MeCN)]SbF6	8	−10°C	48 h	79% (20:1) 79% (19:1) b
8 c	[IPrAu(MeCN)]SbF6	8	−10°C	48 h	82% (16:1)
9 d	[IPrAu(MeCN)]SbF6	8	−10°C	48 h	88% (14:1) b
10	[IPrAu(MeCN)]SbF6	8	r.t.	24 h	76% (11:1) b

^a Determined by ¹H‐NMR analysis.

^b Isolated yield.

^c The reaction was performed with dichloromethane as the solvent.

^d The reaction was performed with toluene as the solvent.

With the optimal conditions (Table 1, entry 7) in hand, we then examined the generality of the intermolecular cyclopropanation of 7‐alkynylnorbornadiene. First, substituted styrene derivatives were examined using 5a as the substrate (Table 2). When 4‐methylstyrene was subjected to the reaction, the desired cyclopropanation product 7b was obtained in excellent yield (90%) with good diastereoselectivity (16:1; entry 1). Additionally, 4‐tert‐butylstyrene and 3‐methylstyrene afforded similar results, albeit with slightly decreased stereoselectivities (entries 2 and 3). The use of 4‐methoxystyrene afforded the desired product 7e in good yield with a relatively lower diastereomeric ratio (entry 4). The reaction with 4‐fluorostyrene afforded the desired product 7f in good yield with good diastereoselectivity, although 5 mol% of the catalyst was required (entry 5). In the cases with 4‐chloro and 4‐bromostyrenes, due to their lower reactivities, reactions at ambient temperatures were required for reasonable conversion of the starting materials. The reactions over a few days afforded the desired products 7g and 7h in 70% and 65% yields, respectively (entries 6 and 7). However, the reaction with 3‐fluorostyrene afforded the desired product 7i in only 16% yield even after 4 days at room temperature (entry 8); this can be attributed to the low nucleophilicity of 3‐fluorostyrene toward the electrophilic gold carbene complex intermediate 6. In contrast, in the presence of 2 mol% of [JohnPhosAu(MeCN)]SbF₆, the desired reaction proceeded smoothly at −10°C, affording 7i in 47% yield (entry 9); this improvement can be attributed to the more electrophilic nature of JohnPhosAu⁺, which increases the electrophilicity of the gold carbene complex 6 [58].

TABLE 2.

Generality of the reaction (part 1). ^a

Entry	R	Temp.	Time	Yield of 7
1		−10°C	49 h	90%(dr 16:1) (7b)
2		−10°C	48 h	91%(dr 9.4:1) (7c)
3 b		−10°C	48 h	79%(dr 12:1) (7d)
4		−10°C	48 h	83%(dr 5.6:1) (7e)
5 c		−10°C	48 h	79%(dr 14:1) (7f)
6		r.t.	49 h	70%(dr 8:1) (7 g)
7		r.t.	68 h	65%(dr 8.3:1) (7 h)
8		r.t.	96 h	16% d (7i)
9 e		−10°C	48 h	47%(dr 9.2:1) (7i)

^a The reactions were performed using 0.11‐0.17 mmol of 5a.

^b 7.1 equiv. of 3‐methylstyrene were used.

^c 5 mol% of catalyst was used.

^d NMR yield of the major isomer.

^e 2 mol% of [JohnPhosAu(MeCN)]SbF₆ was used.

Next, the substrate scope was examined using other alkenes (Table 3, entries 1–4). 2‐Vinylnaphthalene was also found to be applicable to the cyclopropanation reaction (entry 1). The reaction with α‐methylstyrene proceeded smoothly at −10°C in the same manner as the reaction with styrene, affording 7k in excellent yield with moderate diastereoselectivity (entry 2). Furthermore, aliphatic alkenes reacted with 5a in a similar manner to the styrene derivatives. In the presence of a large excess of 1‐hexene, the reaction of 5a afforded the desired cyclopropanation product 7l in good yield and diastereoselectivity (entry 3). Similarly, the reaction with cyclohexene afforded 7m in good yield. In this case, 7m was obtained as a single isomer (entry 4). The structure of 7m was determined by x‐ray crystallography, revealing a cyclohexane ring positioned on the opposite side of the phenyl group (See Supporting Information) [72].

TABLE 3.

Generality of the reaction (part 2). ^{a .}

Entry	5	Alkene	Temp.	Time	Results
1	5a		r.t.	24 h
2	5a		−10°C	48 h
3 b	5a		−10°C	48 h
4 c	5a		r.t.	21 h
5 d	5b	styrene	r.t.	5.5 h
6 e	5c	styrene	−10°C	41 h
7	5d	styrene	−10°C	48 h
8 f	5d	styrene	−10°C	24 h	7p 87% (dr 12:1) 7q 8% g

^a The reactions were performed using 0.11–0.18 mmol of 5.

^b 6 mol% of catalyst and 20 equiv. of 1‐hexene were used.

^c 3 mol% of catalyst and 15 equiv. of cyclohexene were used.

^d 5 mol% of catalyst was used.

^e 4 mol% of catalyst was used.

^f Styrene (28 equiv.) was used as the solvent.

^g NMR yield.

The generality of the 7‐alkynylnorbornadiene substrate was examined using styrene (Table 3, entries 5–8). When 4‐MeO‐substituted 7‐alkynylnorbornadiene 5b was subjected to the optimal conditions, only 9% of the desired product 7n was observed, and most of 5b was recovered unchanged [73, 74]. However, the reaction with 5 mol% of the catalyst at ambient temperature afforded the desired product 7n in approximately 50% yield with good diastereoselectivity (entry 5). In contrast, the reaction of 4‐CF₃‐substituted 7‐alkynylnorbornadiene 5c proceeded smoothly with 4 mol% of the catalyst, affording the desired product 7o in excellent yield with good diastereoselectivity (entry 6). In the case with 5d, which has an alkyl group at the terminal of alkyne, the reaction under optimal conditions afforded the desired product 7p and the complex polycyclic compound 7q in 46% and 41%, respectively (entry 7). The structure of 7q indicated that the intermolecular cyclopropanation between 7p and the gold‐carbene complex derived from 5d occurred in the reaction. To suppress the undesired side reaction, the reaction with a solvent amount of styrene was examined (entry 8). To our delight, the desired product 7p was obtained in excellent yield with good diastereoselectivity.

To demonstrate the utility of the reaction, we conducted the reaction of 5a with 4‐methylstyrene on a 1.2 mmol scale. As a result, under the conditions described above (Table 2, entry 1), the desired product 7b was obtained in high yield with excellent selectivity (Scheme 3). Although the diastereomers 7b and 7b′ could not be separated by silica gel chromatography, pure 7b was obtained by washing the obtained mixture solid with a small amount of hexane (See Supporting Information).

SCHEME 3.

Semi large‐scale synthesis of 7b.

To demonstrate the feasibility of application to polymer synthesis and chemical biology, which are noted in the introduction, ROMP and IEDDA reactions were examined using 7b. For ROMP, the reaction of 7b with 2 mol% of the second‐generation Grubbs catalyst afforded the desired polymer in good yield (Scheme 4a). For IEDDA reaction, 7b reacted rapidly with tetrazine 8, affording the desired adduct 9 in good yield after oxidation by DDQ (2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone) (Scheme 4b). Furthermore, kinetic studies revealed that 7b reacted with 8 approximately three times faster than 2‐norbornene (see Supporting Information for details). This enhanced reactivity of 7b is advantageous for applications in chemical biology, as noted in the introduction.

SCHEME 4.

ROMP and IEDDA reaction of 7b.

Finally, DFT calculations were performed to elucidate the reaction mechanism. Optimization of the geometries and vibrational analyses were conducted at B3LYP/6‐31G(d) [C, H, N] + SDD [Au], PCM (dichloroethane) (See Supporting Information for details). In this study, reactions of 5a and styrene with IPrAu⁺ were performed without ligand simplification. First, the formation of the cationic gold‐carbene complex (INT0‐2) from the gold‐alkyne complex (INT0‐1) was found to have a reasonable ΔG ^‡ and ΔG (Scheme 5) [75].

SCHEME 5.

DFT calculation for the formation of the gold(I)–carbene complex (INT0‐2). Relative free energies from INT0‐1 in kcal/mol are shown. (B3LYP/6‐31G(d) [C, H, N] +SDD [Au], PCM (dichloroethane)).

Next, we investigated the reaction pathways leading to the formation of 7a from INT0‐2 and styrene. After numerous attempts, two distinct reaction pathways affording 7a were identified. One pathway proceeds via a gold(III) metallacyclobutane intermediate (INT1‐2; metallacyclobutane pathway, Scheme 6a), whereas the other does not involve metallacyclobutane formation (non‐metallacyclobutane pathway, Scheme 6b). In the first metallacyclobutane pathway, the reaction between INT0‐2 and styrene occurs via TS1‐1 to afford the carbocation intermediate INT1‐1 [76]. From INT1‐1, subsequent ring closure with a small barrier (TS1‐2) affords the gold(III) metallacyclobutane intermediate (INT1‐2), which finally affords INT1‐3 through reductive elimination (TS1‐3). This type of mechanism was proposed for an intramolecular cyclopropanation by Echavarren et al., although it was for a disfavored stereoisomer, which was not obtained at all [62]. To the best of our knowledge, calculations for the reductive elimination of a gold(III) metallacyclobutane intermediate have not yet been reported. In contrast, in the latter non‐metallacyclobutane pathway, the carbocation intermediate INT2‐1 is formed via TS2‐1. Owing to the location of the carbocation moiety on the opposite side of the gold atom, INT2‐1 does not undergo metallacyclobutane formation. However, cyclopropanation occurs via TS2‐2 to afford the corner‐aurated cyclopropane INT2‐2. In TS2‐2, formation of the second C─C bond appears to proceed from the back side of the C─Au bond. Similar mechanisms have been proposed for intermolecular cyclopropanation with styrene [58] and cis‐dimethoxyethylene [77]. Overall, because TS2‐1 and TS2‐2 are higher in energies than any geometries in the metallacyclobutane pathway, the metallacyclobutane pathway (Scheme 6a) is the more plausible reaction route. Although some literature proposed concerted mechanisms with styrene derivatives [78, 79], no concerted pathways were identified for the reaction system examined in this study.

SCHEME 6.

(a–d) DFT calculations for the four pathways leading to 7a or 7a′. Relative free energies from INT0‐1 and styrene in kcal/mol are shown. (B3LYP/6‐31G(d) [C, H, N] +SDD [Au], PCM (dichloroethane)). In these schemes, the addition of styrene to the carbene complex occurs from the front of the page. (e,f) Reaction coordinates for the gold‐catalyzed coupling reaction between 5a and styrene. Relative free energies in kcal/mol are shown.

We also examined the reaction pathways leading to the minor stereoisomer 7a′. As shown in Schemes 6c,d, both the metallacyclobutane and non‐metallacyclobutane pathways have higher energies than the pathways for 7a. These calculations are consistent with the experimentally observed high diastereoselectivity.

Owing to the relatively large energy barrier from INT0‐2 to INT1‐1 (24.8 kcal/mol), single‐point calculations were performed using a higher level of theory (B3LYP‐D3/6‐311+G(d,p) [C, H, N] +SDD [Au], PCM (dichloroethane); see Supporting Information for details; Scheme 6e,f). As a result, the energy barrier was calculated to be 8.3 kcal/mol (Scheme 6f). Since the reaction proceeds smoothly at −10°C, the smaller value appears more reasonable [80, 81]. No significant energy changes affecting the favorable pathway were observed after TS1‐1 and TS2‐1. It should be noted that INT1‐1 and TS1‐2 have almost the same energy values, suggesting the possibility of an asynchronous concerted mechanism for the [2+2]‐cycloaddition step.

3. Conclusion

In conclusion, we developed a cationic gold(I)‐catalyzed intermolecular cyclopropanation of 7‐alkynylnorbornadienes, representing a rare example of intermolecular cyclopropanation of cyclopropyl gold(I)–carbene complexes generated from enyne compounds, in line with Echavarren's report [43]. The developed reaction enabled the efficient synthesis of a new type of norbornene derivative. We also demonstrated its applicability in polymer synthesis and click reactions using a product. These results clearly enhance the molecular diversity of norbornene derivatives. In addition, the well‐defined three‐dimensional structure of the cyclopropanation products offers a new rigid scaffold. Since rigid 3D scaffolds have attracted much interest in various fields, especially in medicinal chemistry [82, 83, 84], this synthetic method opens new avenues for innovative applications. Furthermore, DFT studies suggested that the developed gold(I)‐catalyzed reaction proceeded through a metallacyclobutane intermediate (INT1‐2). Because the plausible mechanism of our reaction differs from that previously reported, this study provides new insights into gold carbene chemistry.

Conflicts of Interest

The authors have no conflicts of interest.

Supporting information

Supporting File: The authors have cited additional references within the Supporting Information [85, 86, 87, 88, 89, 90, 91, 92, 93].