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Reductive asymmetric ring-opening reaction of azabenzonorbornadienes has been demonstrated under the co-catalytic system of palladium and silver. Various tertiary amines were successfully used as the hydrogen source. A wide range of azabenzonorbornadienes with both electron donating and electron withdrawing substituents performed well in the developed protocol resulting in the 1,2-dihydronaphthalen-1-amine derivatives in excellent yields and good to high enantioselectivities.
Asymmetric catalysis is one of the most important transformations in modern synthetic chemistry because it requires only catalytic amount of chiral catalysts for the formation of enantiopure compounds.[1] The transition metal catalyzed asymmetric ring-opening (ARO) reactions of aza/oxabenzonorbornadienes has remained as an important method for the generation of optically active substituted hydronaphthalenes which are present in compounds with biological activities.[2] Some bioactive compounds with hydronaphthalene cores are shown in figure 1.
Lautens and co-workers have extensively studied the ARO reactions of aza/oxabicyclicalkenes, and many catalytic systems have been developed for the ARO reactions.[3] Various nucleophiles, including amines,[4] alcohols,[5] phenols[6] have been successfully used for the ARO reactions of aza/oxabenzonorbornadienes.
Our group has been working on the ARO reactions of aza/oxabicyclicalkenes to develop new asymmetric catalytic systems for the ARO reactions.[7] Although many studies have been reported on the ARO of azabenzonorbornadienes using nucleophiles, transfer hydrogenation of azabicyclicalkenes leading to the reductive ARO product has not received due attention.[8]
Transfer hydrogenation (TH) has emerged as a convincing alternative to direct hydrogenation,[9,10] while asymmetric transfer hydrogenation (ATH) has become one of the most important transformations due to its broad substrate scope, operational simplicity and outstanding selectivity.[11] Some of the frequently used hydrogen sources are alcohols, acids and amines.[12] Many groups have studied the ATH,[10a,11c,13] including our group’s new co-catalytic system of palladium and zinc for the ATH of aza/oxabenzonorbornadienes by alcohols.[14] In addition, photocatalytic system has been reported for the transfer hydrogenation of imines using triethylamine as the hydrogen source.[15]
Further expanding the scope, ruthenium catalyzed asymmetric TH of ring-substituted β-amino ketones by HCOOH/Et3N as hydrogen source has been developed recently.[16] We also have demonstrated the transfer hydrogenation of azabicyclicalkenes using secondary amines as hydrogen source in a co-catalytic system of silver and palladium with the formation of the corresponding imines.[17] In continuation, in this study, we report the successful application of tertiary amines as the hydrogen source in the reductive asymmetric transfer hydrogenation of azabenzonorbornadienes.
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In the TH reactions of aza/oxabenzonorbornadienes reported earlier,[14],[17] the hydrogen sources were transformed into C=O and C=N bonds. The novelty of our present work is the dehydrogenation of the tertiary amines and generation of C=C bonds which is less explored transformation.[18]
The reductive ARO of N-boc-azabenzonorbornadiene 1a was attempted by reacting with the easily available tertiary amine 2a in presence of Pd(OAc)2 as catalyst, AgBF4 as co-catalyst, (R)-MONOPHOS as the chiralligand, and benzoic acid as additive. This reaction resulted in ARO product 3a with R configuration in low yield with 10% ee, and the corresponding N,N-diethylethenamine. Further, different ligands were screened to check whether the reaction yield and enantioselectivity could be improved (Table 1).
Table 1. Screening of Different Ligands for the Reaction of 1a with Triethylamine[a],[b]
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (0.01 mmol), AgBF4 (0.02 mmol), PhCOOH (0.4 mmol), chiralligand (0.012 mmol) in toluene (2 mL) at 90 oC. [b] Yield determined by 1H NMR spectroscopy.
Among the tested ligands, (R,R)-DIOP produced better yield (54%), but the ee was negligible. To our delight, use of (R,R)-BDPP as chiralligand increased the reaction yield to 94%, but failed to improve the enantioselectivity. This may be because of the smaller size of (R,R)-BDPP causing less steric hindrance and hence less stereo selectivity. Following this, we tested a more hindered ligand (R)-P-Phos and as expected, appreciable improvement in the enantioselectivity (85%) was observed with average yield. In the next attempt, more sterically crowded (R)-SEGPHOS resulted in excellent yield and high enantioselectivity. Other ligands such as (R)-MeO-BIPHEP, (R)-Cl-MeO-BIPHEP, (R)-Synphos and (R)-Tol-BINAP also afforded the expected transfer hydrogenation product 3a in very high yields and high enantioselectivities. Highest yield and best ee was observed when (R)-BINAP was used as the chiralligand. The absolute configuration of all the products were confirmed with HPLC and NMR profiles, which were in agreement with the data reported earlier.[14a]
In order to attain the optimized reaction conditions, we screened different Lewis acids and carboxylic acids using Pd(OAc)2 as catalyst and (R)-BINAP as the chiralligand in toluene at 90 oC. Initially, various Lewis acids were tested using benzoic acid as additive. On using AgBF4 and CuBr, the expected R-isomer 3a was produced in excellent yields and high enantioselectivities (Table 2, entries 1 and 2), while Bu4NI drastically decreased the reaction yield and the enantioselectivity was also lowered to 60% (Table 2, entry 3). ZnI2 failed to promote the reaction of 1a with triethylamine 2a (Table 2, entry 4). Notably, triflates such as CuOTf, Cu(OTf)2, Zn(OTf)2, Fe(OTf)3, Fe(OTf)2, Al(OTf)3 and AgOTf also led to formation of the expected product in excellent yields with good to high enantioselectivities (Table 2, entries 5-11). The results of CuOTf and AgOTf were same, but AgOTf is more economically viable, so we opted AgOTf for the present transformation. Among the tested Lewis acids, other comparative performers to that of AgOTf in the reaction included AgSbF6 and AgPF6 (Table 2, entries 12 and 13). Low yield and very poor enantioselectivity was observed when the reaction was carried out in absence of Lewis acid (Table 2, entry 14). This result indicates that Lewis acid is required in the observed ARO transformation involving tertiary amine as reductant.
Next, the effect of carboxylic acids, including benzoic acid as additive, was studied in the reductive ARO reaction of 1a with triehtylamine (2a) in presence of AgOTf. Among the acids, additive effect of p-bromobenzoic acid was negligible as the product formed was only 23% with 95% ee (Table 2, entry 15). However, when p-methoxybenzoic acid was used as the additive, the reaction was completed in lesser time giving the expected product 3a in 96% yield with 96% enantioselectivity (Table 2, entry 16). Other additives like p-methylbenzoic acid, Potassium benzoate, CF3COOH and CH3COOH also resulted into the corresponding hydrogenated product in excellent yields with average to high enantioselectivities (Table 2, entries 17-20). Contrastingly, there was poor enantioselectivity when the reaction was done using only AgOTf in absence of additives showing that carboxylic acids and their salts such as potassium benzoate are essential in the tested reaction conditions for the resolution of the ARO product (Table 2, entry 21).
| entry | Lewis acid | additive | Time (h) | Yield (%)[b] | ee (%) |
|---|---|---|---|---|---|
| 1 | AgBF4 | PhCOOH | 72 | 94 | 96 |
| 2 | CuBr | PhCOOH | 48 | 91 | 90 |
| 3 | Bu4NI | PhCOOH | 72 | 60 | NR |
| 4 | ZnI2 | PhCOOH | NR | / | / |
| 5 | CuOTf | PhCOOH | 47 | 96 | 96 |
| 6 | Cu(OTf)2 | PhCOOH | 72 | 95 | 94 |
| 7 | Zn(OTf)2 | PhCOOH | 72 | 94 | 93 |
| 8 | Fe(OTf)3 | PhCOOH | 72 | 95 | 73 |
| 9 | Fe(OTf)2 | PhCOOH | 72 | 95 | 87 |
| 10 | Al(OTf)3 | PhCOOH | 39 | 93 | 91 |
| 11 | AgOTf | PhCOOH | 58 | 96 | 96 |
| 12 | AgSbF6 | PhCOOH | 24 | 96 | 84 |
| 13 | AgPF6 | PhCOOH | 24 | 96 | 90 |
| 14 | - | PhCOOH | 72 | 10 | 30 |
| 15 | AgOTf | p-Br-C6H4COOH | 72 | 23 | 95 |
| 16 | AgOTf | p-MeO-C6H4COOH | 24 | 96 | 96 |
| 17 | AgOTf | p-Me-C6H4COOH | 40 | 95 | 96 |
| 18 | AgOTf | PhCOOK | 72 | 93 | 81 |
| 19 | AgOTf | CF3COOH | 72 | 96 | 91 |
| 20 | AgOTf | CH3COOH | 36 | 95 | 95 |
| 21 | AgOTf | - | 72 | 83 | 23 |
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (0.01 mmol), Lewis acid (0.02 mmol), additive (0.4 mmol), (R)-BINAP (0.012 mmol) in toluene (2 mL) at 90 oC. [b] Yield determined by 1H NMR spectroscopy.
Having known that para-methoxybenzoic acid is the most efficient additive, we screened the reaction of 1a and triethylamine 2a using different concentrations of para-methoxybenzoic acid under the same reaction conditions. It was observed that one equivalent is the most ideal concentration of para-methoxybenzoic acid for the desired transformation (Table 3). In order to further improve the reaction yield and ee, we investigated the effect of different solvents on the present transfer hydrogenation reaction. The reaction of 1a with triethylamine 2a in THF produced 3a in excellent yield with 84% ee (Table 3, entry 5). Similarly, using of 1,4-dioxane and DME also resulted in the formation of the product 3a in high yields and very good enantioselectivities (Table 3, entries 6 and 7). MTBE and DCE gave inferior performance as they furnished 3a in reduced yields with 87% and 16% ees respectively (Table 3, entries 8 and 9). However, the reaction in toluene produced better yield and enantioselectivity as compared to other aforementioned solvents indicating that the reaction needs solvent with high boiling point. The reaction was carried out in toluene at 80 oC and 100 oC also, but there was no improvement in the results (Table 3, entries 10 and 11).
Further, the reaction of 1a was studied by changing the concentration of triethylamine 2a (Table 3, entries 12-14). Unfortunately, the desired effect was not observed neither in yield nor the enantioselectivity when 1, 2 or 5 equivalents of 2a were used in the reaction. Although, on using 5 equivalent of triethylamine, the reaction took lesser time, the yield was less as compared to the use of 3 equivalents (Table 3, entry 14).
| entry | p-MeO-C6H4COOH (equiv) | solvent | Et3N (equiv) | Time (h) | Yield (%)[b] | ee (%) |
|---|---|---|---|---|---|---|
| 1 | 2 | Toluene | 3 | 24 | 96 | 96 |
| 2 | 1 | Toluene | 3 | 24 | 97 | 96 |
| 3 | 0.5 | Toluene | 3 | 26 | 96 | 93 |
| 4 | 0.2 | Toluene | 3 | 40 | 96 | 85 |
| 5 | 1 | THF | 3 | 36 | 96 | 84 |
| 6 | 1 | 1,4-dioxane | 3 | 36 | 95 | 85 |
| 7 | 1 | DME | 3 | 18 | 93 | 87 |
| 8 | 1 | MTBE | 3 | 72 | 61 | 87 |
| 9 | 1 | DCE | 3 | 72 | 34 | 16 |
| 10[c] | 1 | Toluene | 3 | 53 | 95 | 95 |
| 11[d] | 1 | Toluene | 3 | 10 | 95 | 93 |
| 12 | 1 | Toluene | 1 | 72 | 97 | 87 |
| 13 | 1 | Toluene | 2 | 29 | 96 | 93 |
| 14 | 1 | Toluene | 5 | 20 | 95 | 95 |
[a] Reaction conditions: 1a (0.2 mmol), 2a (as indicated in the table), Pd(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), p-MeO-C6H4COOH (as indicated in the table), (R)-BINAP (0.012 mmol) in solvent (2 mL) at 90 oC. [b] Yield determined by 1H NMR spectroscopy.[c] Reaction temperature was 80 oC.[d] Reaction temperature was 100 oC.
With the optimized reaction conditions in place, we investigated the ability of different amines to function as hydrogen source under the developed protocol (Table 4). Other aliphatic tertiary amines 2b, 2c, 2d and 2e also performed well as the hydrogen source and gave the corresponding product 3a in high yields and very good ees (Table 4, entries 2-5). Substituted anilines 2f and 2g resulted into the corresponding TH product 3a′ with S configuration in moderate yields and low enantioselectivities (Table 4, entries 6 and 7). The reason for this observation may be attributed to the steric effect of substituents of the tertiary amines. N-benzyl-N-ethylethanamine 2h and N,N-diethyl-2-phenylethan-1-amine 2i also performed well and gave the ARO product in excellent yields and high enantioselectivities (Table 4, entries 8 and 9). N,N-diethyl-2-(4-fluorophenyl)ethan-1-amine 2j and N,N-diethyl-2-(p-tolyl)ethan-1-amine 2k also gave the expected product 3a in excellent yields and high enantioselectivity (Table 4, entries 10 and 11).
Unfortunately, N,N-dimethyl-2-phenylethan-1-amine 2l gave the corresponding product 3a in poor yield and reduced ee (Table 4, entry 12). N-methyl-N-phenethyl-2-phenylethan-1-amine 2m resulted in the expected product 3a in excellent yield with 52% ee (Table 4, entry 13). Triphenethylamine 2n delivered the ATH product in very high yield but we could not obtain either of the enantioenriched products (Table 4, entry 14). Secondary amine diethylamine 2o resulted into lowering of yield with high ee (Table 4, entry 15). On using dibenzyl amine 2p as the hydrogen source, we could get the desired product 3a in excellent yield and moderate ee along with the corresponding imine under the developed reaction conditions (Table 4, entry 16). Primary amine benzylamine 2q resulted into diminished yield and average enantioselectivity (Table 4, entry 17). From this study, it has been observed that the reaction results into good to high yield and high enantioselectivity on using tertiary amines which can form the corresponding enamines more readily.
| Entry | Time (h) | Yield (%)[b] | ee (%) | R/S |
|---|---|---|---|---|
| 1 | 24 | 97 | 96 | R |
| 2 | 41 | 92 | 91 | R |
| 3 | 72 | 90 | 86 | R |
| 4 | 53 | 95 | 95 | R |
| 5 | 24 | 94 | 89 | R |
| 6 | 72 | 81 | 43 | S |
| 7 | 72 | 74 | 61 | S |
| 8 | 40 | 95 | 86 | R |
| 9 | 24 | 97 | 90 | R |
| 10 | 24 | 96 | 85 | R |
| 11 | 40 | 97 | 88 | R |
| 12 | 72 | 31 | 69 | R |
| 13 | 15 | 95 | 52 | R |
| 14 | 15 | 94 | / | |
| 15 | 72 | 53 | 91 | R |
| 16 | 39 | 96 | 60 | R |
| 17 | 72 | 12 | 52 | R |
[a] Reaction conditions: 1a (0.2 mmol), 2a-q (0.6 mmol), Pd(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), p-MeO-C6H4COOH (0.2 mmol), (R)-BINAP (0.012 mmol) in toluene (2 mL) at 90 oC. [b] Yield determined by 1H NMR spectroscopy.
In continuation of our investigation, we intended to study the substrate scope of the reaction with respect to different bicyclicalkenes under the optimized reaction conditions. N-bocazabenzonorbornadienes containing electron donating substituents performed well in the reaction giving high yields with very good enantioselectivities (Scheme 1, 3b, 3c, 3d and 3e). Dibromo substituted azabenzonorbornadiene was also well accepted giving the transfer hydrogenation product 3f in moderate yield with 94% ee. Further, high yield and excellent ee (98%) was observed when difluoro substituted azabenzonorbornadiene was subjected to ATH reaction under the developed reaction condition (Scheme 1, 3g). Cbz-protected azaobenzonorbornadiene also resulted in the formation of the desired product 3h in excellent yield with 90% ee. Unsubstitutedoxabenzonorbornadiene also took part in asymmetric transfer hydrogenation giving the desired product 3i in 61% yield and 45% ee. Hence, the developed methodology provides a new route for the synthesis of biologically important dihydronaphthalene skeleton.
Scheme 1. Substrate Scope of Various BicyclicAlkenes. Reaction conditions: 1a-i (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), p-MeO-C6H4COOH (0.2 mmol), (R)-BINAP (0.012 mmol) in toluene (2 mL) at 90 oC. Yield determined by 1H NMR spectroscopy.[a] Reaction conditions: 1f (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (0.02 mmol), AgOTf (0.04 mmol), p-MeO-C6H4COOH (0.4 mmol), (R)-BINAP (0.024 mmol) in toluene (2 mL) at 110 oC.[b] Reaction conditions: 1h (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2 (0.015 mmol), AgOTf (0.03 mmol), p-MeO- C6H4COOH (0.3 mmol), (R)-BINAP (0.018 mmol) in toluene (2 mL) at 80 oC.
In accordance with the plausible mechanism that we have hypothesized recently for similar reaction,[17] we have proposed a mechanism for the present transformation (Scheme 2). Initially, the chiral complex combines with the amine-acid complex A to form the intermediate B which further coordinates with C giving the complex D. Then addition of one hydrogen atom into the carbon-carbon double bond takes place resulting into complex E which rearranges into F and it finally afforded the product 3a in high yield and excellent ee along with the corresponding enamine.
We have successfully demonstrated the ATH of azabenzonorbornadienes using tertiary amines as the hydrogen sources. The reaction was catalyzed by palladium and silver co-catalytic system with (R)-BINAP as the chiralligand and para-anisic acid as additive. The reaction resulted into the reductive ARO product. A wide range of tertiary amines performed well as the hydrogen source. Various substituted azabenzonorbornadienes took part in the transfer hydrogenation giving the corresponding ARO product in excellent yields with good to high enantioselectivities paving a way for the synthesis of 1,2-dihydronaphthalene derivatives.
Typical procedure for the asymmetric transfer hydrogenation reaction of Azabenzonorbornadienes: Pd(OAc)2 (2.3 mg, 0.01 mmol), (R)-BINAP (7.5 mg, 0.012 mmol) and 1.0 mL toluene were added to a Schlenk tube under argon atmosphere. The resulting solution was stirred at room temperature for 30 minutes, then AgOTf (5.1 mg, 0.02 mmol) was added and stirred for an additional 10 minutes, then a solution of N-Boc-azabenzonorbornadiene 1a (48.6 mg, 0.2 mmol), p-anisic acid (30.5 mg, 0.2 mmol) in toluene (1.0 mL) were added, and the mixture was stirred for additional 10 min. After the addition of trimethylamine 2a (83 μL, 0.6 mmol), the mixture was stirred at 90 oC under argon atmosphere with TLC monitoring until the complete consumption of 1a. The residue was purified by chromatography on a silica gel column to afford the desired product (47.5 mg, 97% yield).
Tertiary Amine-Mediated Reductive Asymmetric Ring-Opening of Azabenzonorbornadienes: Palladium-Silver Co-Catalytic System. (2024, Feb 22). Retrieved from https://studymoose.com/document/tertiary-amine-mediated-reductive-asymmetric-ring-opening-of-azabenzonorbornadienes-palladium-silver-co-catalytic-system
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