Hg(OTf)₂ Catalyzed Intramolecular 1,4-Addition of Donor–Acceptor Cyclopropenes to Arenes

Abstract

A Hg(OTf)₂ catalyzed intramolecular arene 1,4-addition reaction of N-benzyl donor–acceptor cyclo-propenecarboxamides was developed to synthesize a series of [3.2.2]nonatriene derivatives. This novel reaction is also observed with silver(I) catalysts known to form metal carbene intermediates in competition with the Buchner reaction.

Graphical abstract

In our efforts to broaden the scope of transition metal complexes suitable for catalysis in metal carbene reactions of diazo compounds, we have investigated and compared reactivities and selectivities of transition metal complexes, especially those of dirhodium(II), copper, and silver, capable of forming metal carbene intermediates from diazoesters.¹ These efforts have prompted us to investigate reactions with diazo compounds of those transition metals having limited evidence for the formation of metal carbene intermediates. Mercury(II) is one such candidate having both a rich history as a π-acceptor electrophilic catalyst² and recent developments in metal-NHC chemistry,³ but limited evidence for the intermediate formation of a reactive mercury-carbene intermediate.^4,5 The most relevant indicator for a mercury carbene in reactions of a diazo compound is that of mercury(II) catalyzed cyclo-propanation reactions of diazooxindoles which was reported in this journal by Zhou and co-workers.⁵ We have recently described intramolecular C–H insertion reactions of N-benzyl-enoldiazoacetamides at the benzyl C–H bond to form β-lactams that occur in competition with the Buchner reaction at the aromatic ring of the benzyl group;^1a since these reactions occur in high yields with dirhodium(II), copper, and silver catalysts, we thought that C–H insertion/aromatic cyclo-addition of N-benzyl-enoldiazoacetamides could be a good indicator for the involvement of metal carbene intermediates. However, the use of highly electrophilic mercury(II) compounds with N-benzyl-enoldiazoacetamides has surprised us with its complexity and has led us to a novel Hg(OTf)₂ catalyzed intramolecular 1,4-addition reaction across the benzyl aromatic ring to form bicyclononatriene derivatives in high yield (Scheme 1).

Scheme 1.

Divergent Pathways for Intramolecular Reactions of Enoldiazoacetamide and Donor–Acceptor Cyclopropenes

In our initial survey to evaluate mercury(II) activity, we selected reactions of N-tert-butyl-N-(4-chlorobenzyl)enoldiazo-acetamide 1a and expected products from either C–H insertion or aromatic cycloaddition.^1a However, the highly electrophilic mercuric triflate catalyzed dinitrogen loss with the formation of a product mixture dominated by the enol-silyl ether hydrolysis product 2a (Scheme 2). Enol-silyl ether hydrolysis products were also dominant in Hg(OTf)₂ catalyzed reactions with other enoldiazoacetamides and enoldiazoacetates. Neither the careful drying of reagents and solvents nor the use of molecular sieves could substantially reduce interference from this reaction. However, thorough examination of the reaction mixture from the reaction of 1a with mercuric triflate in dichloromethane following exposure to water for hydrolysis provided evidence for two reaction products formed with the loss of dinitrogen. One was the product expected from the Buchner reaction⁶ following hydrolysis of the vinyl-OTBS group (3a), and the other one was bicyclo[3.2.2]nonatriene 4a which formally results from 1,4-addition across the benzene ring of the N-benzyl group. The β-lactam C–H functionalization product was not detected (Scheme 2). The structure of bicyclo[3.2.2]nona-triene 4a was confirmed by single-crystal X-ray diffraction (Figure 1).⁷

Scheme 2.

Hg(OTf)₂ Catalyzed Reaction of N-tert-Butyl-N-(4-chlorobenzyl)enoldiazoacetamide 1a

Figure 1.

X-ray crystal structure of 2-(ter-butyl)-6-chloro-8-hydroxy-2,3,6,7-tetrahydro-1H-3a,6-ethenocyclohepta[c]pyrrol-1-one 4a.

To avoid the dominant hydrolysis observed in Hg(OTf)₂-catalyzed reactions of enoldiazoacetamides, we considered that their corresponding donor–acceptor cyclopropenes might be suitable alternatives that minimized this side reaction. Donor–acceptor cyclopropenes can be thermally generated from enoldiazoacetates and enoldiazoacetamides in quantitative yield⁸ and are known to be capable of metal carbene formation in catalytic reactions.^1a,b,9 When cyclopropene 5a was used in place of 1a in the Hg(OTf)₂-catalyzed reaction, the combined yield of the 1,4-addition product 4a and the Buchner reaction product 3a was improved to 58% (entry 1, Table 1). Since some hydrolysis of the initially formed silyl ether products was observed, trifluoroacetic acid was added to produce a more homogeneous mixture. The reaction solvent was varied to further increase the combined yield of 3a and 4a and, perhaps, to influence their product ratio; this study revealed that acetonitrile solvent significantly increased product yield and the 4a:3a product ratio (entry 7). The uses of HgCl₂ or Hg(OAc)₂ were also examined as catalysts in acetonitrile; however, lower product yields were obtained with these mercury(II) compounds. Further improvement of yield and chemo-selectivity was achieved when BINOL-derived phosphoric acid 6 was added as an additive to the reaction. The combination of a metal catalyst and BINOL-derived phosphoric acids has been exploited in organic transformations to enhance activity/selectivity.¹⁰ An NMR study of the combination of Hg(OTf)₂ and 6 indicated a possible association between the Hg salt and the phosphoric acid (see Supporting Information), but their precise role in this transformation remains unknown.

Table 1.

Optimization of Reaction Conditions^a

entry	catalyst	solvent	time/h	3a:4ab	yieldc/% 3a+4a
1	Hg(OTf)2	DCM	12	52:48	58
2	Hg(OTf)2	CHCl3	8	58:42	65
3	Hg(OTf)2	DCE	12	56:44	61
4	Hg(OTf)2	toluene	24	66:33	55
5	Hg(OTf)2	1,4-dioxane	24	55:45	40
6	Hg(OTf)2	hexanes	12	80:20	31
7	Hg(OTf)2	CH3CN	8	38:62	69
8	HgCl2	CH3CN	16	42:58	39
9	Hg(OAc)2	CH3CN	16	40:60	50
10d	Hg(OTf)2/6	CH3CN	6	30:70	85

^aReactions were performed on a 0.2 mmol scale: 0.2 mmol of 5a was quantitatively generated from 1a using the reported procedure;⁶ 0.2 mmol of 5a, 5 mol % Hg catalyst, in 2 mL of solvent.

^bThe ratios of 3a to 4a were determined by ¹H NMR analysis of the reaction mixture before treatment with TFA.

^cIsolated yield.

^d5 mol % 6 was added with 5 mol % Hg(OTf)₂.

The scope of intramolecular 1,4-addition reactions of enoldiazoacetamides was then investigated with Hg(OTf)₂ catalysis under the optimized conditions established for 5a (Table 1, entry 10). As indicated in Table 2, the substituent on the aromatic ring and its placement are the primary determinants of the observed selectivity. With chloride at either the meta or para positions, cogeneration of Buchner and 1,4-addition products occurs in 30:70 and 37:63 ratios (Table 2, entries 1 and 2). However, with chloride in the ortho position (5d) only the 1,4-addition product 3d was obtained (entry 4). Ortho-substitution of the benzyl group in cyclopropene reactants produced only the 1,4-addition reaction product in good yields (entries 5–7), but so did the unsubstituted 5h and the p-methyl substituted 5i (entries 8 and 9), indicating the electronic influence of substituents on the 3:4 ratio. With the p-MeO substituent, however, decomposition of the cyclopropene reactant occurred without formation of either 3 or 4. The steric effect of R¹ was also examined. As indicated by the reactions of 5j (R¹ = Me) and 5k (R¹ = Et), formation of the 1,4-addition product remained the sole process but in lower yields reflecting the size of R¹ (entries 10 and 11). However, no product was obtained from the electron-withdrawing 4-nitroaryl substituted cyclopropene reactant (R² = NO₂).

Table 2.

Substrate Scope^a

entry	5	R1	R2	3:4b	yieldc/% 3 + 4
1	5a	H	4-Cl	30:70	85
2	5b	H	3-Cl	37:63	59
3	5c	H	4-Br	46:54	71
4	5d	H	2-Cl	<5:95	83
5	5e	H	2-Br	<5:95	68
6	5f	H	2-CH3	<5:95	81
7	5g	H	2,3-benzo	<5:95	66
8	5h	H	H	<5:95	75
9	5i	H	4-CH3	<5:95	61
10	5j	CH3	2-Cl	<5:95	53
11	5k	C2H5	2-Cl	<5:95	38

^aReactions were performed on a 0.3 mmol scale: 0.3 mmol of 5a, 5 mol % Hg(OTf)₂, 5 mol % 6, in 2 mL of acetonitrile.

^bThe ratios of 3 to 4 were determined by ¹H NMR analysis of reaction mixture before treatment with 1.0 equiv of TFA.

^cIsolated yield after treatment with TFA.

Recently bicyclo[3.2.2]nonatriene derivatives were reported to be formed from benzyl enoldiazoacetates via a dirhodium(II) catalyzed Buchner reaction and subsequent Cope rearrangement.¹¹ Initially, we thought that the 1,4-addition product in the Hg(OTf)₂-catalyzed reactions also originated from the Buchner product after Cope rearrangement, but the influence of the ortho-substituted aryl group in forming only the product from 1,4-addition led us to question this interpretation. We predicted that ortho-halide substitution would inhibit the Buchner reaction but would have little or no influence on a subsequent Cope rearrangement.¹² Furthermore, the Buchner reaction product formed from benzyl enoldiazoacetates undergoes Cope rearrangement only at elevated temperatures, whereas 1,4-addition products formed in the Hg(OTf)₂-catalyzed reactions are generated at room temperature. In order to examine if the Buchner reaction and subsequent Cope rearrangement was the cause for the formation of compound 4 in this Hg(OTf)₂ catalyzed process, reaction of 5a was performed in the presence of molecular sieves for prolonged reaction times. As shown in Scheme 3, the silyl ether conserved products 7a and 8a were obtained with the same selectivity as were the desilylated products from the reaction reported in Table 2. Furthermore, under prolonged reaction times up to 24 h, no conversion between 7a and 8a was observed. Additionally, no 1,4-addition product 8a was detected from the isolated Buchner reaction product 7a under the optimized reaction conditions obtained using molecular sieves to inhibit hydrolysis. These results exclude the Buchner reaction/Cope rearrangement pathway to bicyclo[3.2.2]nonatriene compounds in the Hg(OTf)₂ catalyzed reaction of donor–acceptor cyclopropenes.

Scheme 3.

Control Experiments to Determine if Cope Rearrangement Accompanied the Buchner Reaction

Hg(OTf)₂ has been developed as a powerful catalyst in organic transformations including hydration of terminal alkynes and the cyclization of enyne, arylyne, and yne-en-aryl substrates, utilizing its ability to associate with olefins and alkynes.² Based on this knowledge and on our experimental observations, a plausible mechanism for this Hg(OTf)₂ catalyzed 1,4-addition reaction is proposed in Scheme 4. Intermediate I is generated by π-complexation of Hg(OTf)₂ with the cyclopropene, and this coordination occurs on the side opposite to R¹. The bulky tert-butyl attachment to the amide nitrogen facilitates the proper orientation of the amide to realize nucleophilic attack by the aromatic ring to the Hg(OTf)₂-activated cyclopropene. Consistent with our experimental results (Table 2, entries 10 and 11), bulkier substituted groups R¹ hinder the intramolecular reaction (I→II) due to their steric conflict with the aromatic ring with the result that lower yields of 1,4-addition products are obtained (entries 10 and 11, Table 2). The bicyclo[3.2.2]nonatriene product is obtained following intramolecular nucleophilic addition to the para position of the aromatic ring that occurs with the release of the Hg(II) catalyst. The formation of the formal Buchner reaction product can also be explained with this mechanism by nucleophilic addition to the ortho position of the aromatic ring.

Scheme 4.

Plausible Mechanism of Hg(OTf)₂ Catalyzed 1,4-Addition Reaction of Donor–Acceptor Cyclopropenes

We wondered if this 1,4-addition reaction also existed in other well-studied metal catalyzed transformations, such as with Ag, Cu, and Rh catalysts. With this aim in mind, a catalyst screening was performed with donor–acceptor cyclopropene 5c, and the results are shown in Table 3. The 1,4-addition product 8c was obtained, albeit as a minor product, from various Ag catalyzed reactions (Table 3, entries 1–4), but not with the other catalysts surveyed. Both Cu and Rh catalysts produced β-lactam 9c, but this C–H insertion product was not observed in Ag(I)-catalyzed reactions, and the Buchner addition product 7c was a minor product in copper catalyzed reactions. No reaction occurred with Lewis acid catalysts Sc(OTf)₃, La(OTf)₃, and In(OTf)₃. The 1,4-addition process found with Hg(II) and Ag(I) catalysts may be more broadly applicable, but the pathway for its formation which is also linked to 1,2-addition suggests that Buchner addition products may not always be derived from a metal carbene process involving aromatic cycloaddition.

Table 3.

Catalyst Screening^a

entry	catalyst	time/h	7c/%b	8c/%b	9c/%b
1	AgSbF6	4	62	6	<5
2	AgBF4	12	67	14	<5
3	AgClO4	12	57	11	<5
4	AgOTf	12	68	6	<5
5	Cu(MeCN)4PF6	6	8	<5	69
6	Cu(MeCN)4BF4	8	18	<5	51
7	Cu(OTf)2	12	15	<5	38
8	Rh2(OAc)4c	6	<5	<5	82
9	Sc(OTf)3	12	<5	<5	<5
10	La(OTf)3	12	<5	<5	<5
11	In(OTf)3	12	<5	<5	<5

^aReactions were performed on a 0.2 mmol scale: 0.2 mmol of 2c, 5 mol % catalyst, in 2 mL of acetonitrile at room temperature.

^bThe yields of 7c, 8c, and 9 were determined by ¹H NMR analysis of reaction mixture using an internal standard.

^c2 mol % Rh₂(OAc)₄ was used.

In summary, an intramolecular Hg(OTf)₂ catalyzed arene 1,4-addition reaction of donor–acceptor cyclopropenes generated from enoldiazoacetamides has been developed. Through the 1,4-addition reaction, a series of novel bicyclo[3.2.2]nona-triene compounds have been synthesized. Additionally, the 1,4-addition reaction is not unique to Hg(OTf)₂ but is also observed in silver(I) catalyzed reactions, and the general features of these mercury(II) and silver(I) reactions with donor–acceptor cyclopropenes open new synthetic approaches to multicyclic structures.