Yao
Huang‡
a,
Suchen
Zou‡
a,
Bangkui
Yu
a,
Xuyang
Yan
a,
Song
Liu
*c and
Hanmin
Huang
*ab
aDepartment of Chemistry, School of Chemistry and Material Science, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, 230026, P. R. China. E-mail: hanmin@ustc.edu.cn
bKey Laboratory of Green and Precise Synthetic Chemistry and Applications, Ministry of Education, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
cChongqing Key Laboratory of Environmental Materials and Remediation Technologies, Chongqing University of Arts and Sciences, Chongqing, 402160, P. R. China. E-mail: sliu@cqwu.edu.cn
First published on 2nd February 2022
A ligand-controlled palladium-catalyzed highly regioselective and diastereodivergent aminomethylative annulation of dienyl alcohols with aminals has been established, which allows for producing either cis- or trans-disubstituted isochromans in good yields with complete regioselectivity and good to excellent diastereoselectivity. Moreover, the chiral cis-products were also obtained in good yields with up to 94% ee by using a chiral phosphinamide as the ligand. Mechanistic studies revealed that the hydroxyl group plays a key role in facilitating the Pd-catalyzed Heck insertion regioselectively taking place across the internal CC bond of conjugated dienes.
To address these limitations, we envisioned that once the nucleophile suspended in the diene backbone can complex with an appropriate alkylpalladium species, the chelation between the palladium species and the nucleophile will bring the palladium center close to the internal CC bond of the diene, thus facilitating the formation of the internal alkylated π-allylpalladium intermediate III. It is well known that the hydroxyl group can not only act as a nucleophile for palladium-catalyzed allylic C–O bond formation reactions,5 but also be frequently utilized as a directing group for various metal catalyzed reactions.6,7 However, due to the weak coordination ability of the oxygen atom to the palladium, the hydroxyl group may not act as an effective directing group to make the palladium interact with the internal CC bond of the diene. In this context, we surmised that the directing ability would be enhanced to facilitate the regioselective annulation once the alkylpalladium species interacts with the hydroxyl group like intermediate Bvia hydrogen-bonding. In line with our continuous interest in developing new transformations by using aminomethyl cyclopalladated complex A (Huang-complex) as a leading complex8 and inspired by our recent results on the hydrogen-bonding-assisted alcohol allylation reactions,5h we envisioned that complex A might be a suitable alkylpalladium species to coordinate with the hydroxyl group under the assistance of hydrogen-bonding. Once the diene-tethered benzyl alcohol reacted with complex A, intermediate B might be formed, in which the hydrogen-bonding between the hydroxyl group and the amine moiety would promote the palladium to coordinate with the O-atom of the hydroxyl and facilitate the internal CC bond binding to the palladium. Such interactions would guide the Heck insertion to take place selectively across the internal CC bond of the diene. Herein, we report for the first time a regioselective and diastereodivergent aminomethylative annulation of diene-tethered benzyl alcohols with aminals (Scheme 1B). This transformation offers an unprecedented efficient route for the selective synthesis of both trans- and cis-diastereoisomers of 1,2-disubstituted isochroman derivatives that are pervasive structural motifs omnipresent in myriad natural products and synthetic pharmaceuticals exhibiting an array of biological properties.9
Entry | [Pd] | Ligand | T (°C) | Solvent | Yield (%) | 3aa/4aa | 5aa Yield (%) |
---|---|---|---|---|---|---|---|
3aa + 4aa | |||||||
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), [Pd] (5 mol%), AgOTf (6 mol%), ligand (5 mol%), solvent (1.0 mL), 12 h, isolated yield, the dr value was determined by 1H NMR analysis of the crude reaction mixture. b Ligand (10 mol%). c AgOTf (12 mol%). d 1a (0.36 mmol), 2a (0.30 mmol). e 24 h. | |||||||
1 | [Pd(allyl)Cl]2 | L1 | 80 | Toluene | 40 | 5:1 | 45 |
2b | [Pd(allyl)Cl]2 | PPh3 | 80 | Toluene | 63 | 18:1 | 5 |
3b | [Pd(allyl)Cl]2 | L2 | 80 | Toluene | 59 | >20:1 | Trace |
4b | [Pd(allyl)Cl]2 | L3 | 80 | Toluene | 43 | >20:1 | Trace |
5b,c | PdCl2 | L2 | 80 | Toluene | 48 | >20:1 | Trace |
6b,c | PdBr2 | L2 | 80 | Toluene | 50 | >20:1 | Trace |
7b | [Pd(allyl)Cl]2 | L2 | 80 | CH2Cl2 | 65 | 18:1 | Trace |
8b | [Pd(ally)Cl]2 | L2 | 80 | CH2Cl2/toluene = 3:2 | 67 | >20:1 | Trace |
9b,c | [Pd(allyl)Cl]2 | L2 | 80 | CH2Cl2/toluene = 3:2 | 86 | >20:1 | Trace |
10b,c | [Pd(allyl)Cl]2 | L4 | 80 | CH2Cl2 | 79 | 1:5 | Trace |
11b,c,d | PdBr2 | L4 | 80 | CH2Cl2 | 90 | 1:7 | Trace |
12b,c,d | PdBr2 | L4 | 60 | CH2Cl2 | 84 | 1:9 | Trace |
13b,c,d | PdBr2 | L4 | 40 | CH2Cl2 | 81 | 1:10 | Trace |
14b,c,d | PdBr2 | L4 | rt | CH2Cl2 | 62 | 1:14 | Trace |
15b,c,d,e | PdBr2 | L4 | rt | CH2Cl2 | 89 | 1:14 | Trace |
Having established the highly regioselective and diastereodivergent conditions for the annulation of 1a with 2a as shown above, we then examined the substrate scope with an L2/ or L4/PdBr2/AgOTf catalysis system. Table 2 summarizes the substrates compatible for trans-selective annulation. Aminals derived from benzylamines bearing electron-rich and -deficient substituents worked smoothly with 1a to exclusively give the corresponding trans-products (3aa–3aj) in 60–94% yields with complete regioselectivity. Functional groups such as halides (F, Cl, Br), CF3, and OMe were compatible. Gratifyingly, aminals derived from aliphatic amines, such as dipropylamine and morpholine, could react with 1a to give the corresponding products as well (3ak and 3al) in good yields in the presence of 10 mol% of catalyst. Next, the scope of the diene-tethered benzyl alcohols was also explored under optimized conditions. As shown in Table 2, a variety of substrates bearing electron-donating and -withdrawing functional groups on the phenyl-rings underwent regioselective and diastereoselective annulations to provide the trans-products (3ab–3kb) in good to excellent yields (55–90%). The naphthyl-containing 1l was also compatible, generating the corresponding annulation product 3lb in 52% yield. Meanwhile, the dienes containing a substituent at the benzyl site could also be converted into the desired products with three chiral centers (3mb and 3nb) in good yields. Importantly, substrates containing substituents at C2 or C1 positions also proved to be competent reaction partners to afford the corresponding products (3pb, 3qb and 3ra) in moderate yields with excellent diastereoselectivities and regioselectivities. It is noteworthy that the regio- and diastereoselectivities of this reaction were not affected by the E/Z ratio of the corresponding diene-tethered benzyl alcohols (see the ESI†).
a Reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), [Pd(allyl)Cl]2 (2.5 mol%), AgOTf (6 mol%), L2 (10 mol%), solvent (CH2Cl2:toluene = 3:2, 1.0 mL), 80 °C, 12 h, isolated yields, >20:1 rr, and >20:1 dr in all cases as shown by 1H NMR analysis of the crude reaction mixture, unless otherwise noted. b [Pd(allyl)Cl]2 (5 mol%), AgOTf (12 mol%), L2 (20 mol%). |
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We next focused on exploring the scope of the cis-diastereoselective annulation reaction by using PdBr2/L4/AgOTf as the catalyst. As shown in Table 3, the diastereoselectivity was significantly influenced by the substrates, though the exclusive internal carbo-oxygenation products were observed in all cases. Evaluation of the scope was initiated with the investigation of various aminals. The para-methyl-, t-Bu-substituted benzylamine-derived aminals exhibited high cis-selectivity (15:1 and 14:1, respectively) to give the corresponding cis-annulation products 4ab and 4ac in 69–78% yields. Other benzyl aminals bearing electron-withdrawing substituents showed decreased selectivities (4ae–4aj), among which the lowest was given by aminal 2j containing CF3 (4aj). The substrates 2k and 2l derived from alkyl amines were also compatible, albeit with low to moderate selectivities (4ak and 4al). Next, with 2a as the standard coupling partner, a series of diene-tethered benzyl alcohols were tested. Obviously, the introduction of a substituent on the phenyl ring of the substrate resulted in lower diastereoselectivities, and the lowest cis-selectivity (2:1) was observed when the substrate bore an ortho-fluoro substituent on the phenyl ring (4ia). However, when there was a CF3 at the 5-position, up to >20:1 diastereoselectivity was observed (4ka). In addition, substrate 1l containing naphthalene gave a moderate yield with 11:1 diastereoselectivity (4la). Substrates with substituents at the benzyl carbon bearing the hydroxyl group could also give moderate yields with lower selectivity (4ma–4oa). Nevertheless, the introduction of a methyl group at the C2-position of the diene resulted in no reaction, which might be due to steric hindrance. However, when the methyl group was instead introduced at the C1 position, the desired product could be obtained in 40% yield with excellent selectivity (>20:1 dr) (4qa).
a Reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), PdBr2 (5 mol%), AgOTf (12 mol%), L4 (10 mol%), CH2Cl2 (1.0 mL), rt, 24 h, isolated yield, the dr value was determined by 1H NMR analysis of the crude reaction mixture, >20:1 rr in all cases. |
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To explore the synthetic potential of the present reaction, several transformations of the obtained trans-3aa and cis-4aa were conducted (Scheme 2). One of the benzyl groups in 3aa could be selectively removed to give 6 by treatment with ClCO2CHClCH3.10a To further confirm the structure of the product, the easily crystallizable Ns-protected amide 7 was obtained, whose structure was unambiguously confirmed by an X-ray diffraction analysis. The nucleophilic substitution reaction of 6 with TsCl in the presence of Et3N afforded the sulfamide 8. Oxidation of the sulfamide 8 by using m-CPBA afforded the epoxide 9.10b Highly valuable amino aldehyde 10 was cleanly formed by exposure of 8 to O3 in CH2Cl2/MeOH at −78 °C.10c Similarly, the cis-4aa could also be transformed into sulfonamide 12 in excellent yield via de-benzylation and sulfonation. The structure of 12 was also verified by single-crystal X-ray diffraction.11 The obtained cis-product 11 could be further converted into the ring-fused [6, 6, 5] tricyclic isochroman 13 by a CuBr2-mediated cyclization reaction.10d
To achieve an enantioselective aminomethylative annulation reaction, (S)-L4 was utilized as the chiral ligand. As evident from the results compiled in Table 4, a series of chiral cis-diastereoselective products (4aa–4ac and 4fa–4ka) could be obtained in good yields with moderate to good enantioselectivities under the standard reaction conditions by using PdBr2/(S)-L4/AgOTf as the asymmetric catalysis system. Further optimization of the reaction revealed that the enantioselectivities could be increased when executing the reaction with TsO– as the counter anion of the palladium catalyst. However, although good to excellent enantioselectivities (85–94% ees) could be obtained, the yields of the desired products decreased. Following a two-step derivatization of chiral compound 4aa, the absolute configuration of 4aa was determined to be (3S, 4R) by X-ray diffraction analysis of chiral compound 12 (see the ESI†).
a Reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), PdBr2 (5 mol%), AgOTf (12 mol%), (S)-L4 (12 mol%), CH2Cl2 (1.0 mL), rt, 24 h, isolated yield, the dr value was determined by 1H NMR analysis of the crude reaction mixture, >20:1 rr in all cases, ee values were determined by chiral HPLC analysis. b [Pd(allyl)Cl]2 (2.5 mol%), AgOTs (6 mol%). |
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A series of experiments were conducted to shed light on the mechanism of this transformation. First, the simple diene 1s was subjected to the standard reaction conditions for the generation of trans-products. However, only three major products (14, 15 and 16)8a,b derived from terminal CC bond insertion were observed and none from internal CC bond insertion was detected (Scheme 3-1), showing the importance of the directing-effect of the hydroxyl group. The diene-tethered benzyl methyl ether 1t was prepared and treated with 2a under identical conditions. Although the OMe should be able to coordinate with the palladium, there was no product originating from internal CC bond insertion detected again (Scheme 3-2). This result indicated that the coordination of O to Pd alone could not direct the desired Heck insertion. On the other hand, no desired product but the aldehyde 20 was detected in the reaction with the Li-salt of 1a, which excluded the possibility that the directing effect was furnished via the formation of the Pd–O sigma-bond (Scheme 3-3). In addition, replacing the aminal with PhI led to the recovery of the starting material 1a when the reaction was conducted in the absence of a base. In the presence of a base and at higher temperature, the aldehydes 20 and 21 were generated as major products, and yet gave no desired cyclization product. Besides, we observed an intriguing relationship between the regioselectivity of the reaction and the electronic nature of the substituted aminal. Higher regioselectivity was observed when the aminal contained an electron-rich para-substituent, and the selectivity diminished gradually as the substituent became more electron deficient. The aromatic electronic effect can be represented by a Hammett relationship. The Hammett plot of lg (ratio of regioisomers) against σp shows a linear free-energy relationship (ρ = −1.27, r = 0.969) between regioselectivity and the electronic character of the substituent (see the ESI†).12 These results further confirmed that the formation of hydrogen-bonding was key to furnish the 3,4-difunctionalized annulation. Subjecting the purified cis-4aa to the reaction conditions for producing trans-products resulted in fully recovered cis-4aa (Scheme 3-6). This result ruled out the possibility that C–O bond formation is reversible and the thermodynamically preferred trans-product is generated from the kinetically preferred cis-product in the case of Cphos. Furthermore, no cis-product was detected when a purified trans-product, 3aa, was subject to the reaction conditions for generation of cis-products. On the other hand, the non-linear relationship between the ee value of optically active ligand L4 and the ee value of the cis-4ka (Scheme 3-7) provided evidence that two phosphoramidite ligands and one palladium were involved in the enantioselectivity-determining step.
A tentative mechanism is thus proposed based on the above results and previous reports.8 As depicted in Fig. 1, the cyclopalladated complex A is generated via either oxidative addition of the Pd(0) to the protonated aminal or an SN2-type reductive elimination and oxidative addition process between the aminal and the π-allylpalladium catalyst. The hydroxyl group acts as a directing group to bring the palladium center close to the internal CC double bond, in which the hydrogen-bonding between the aminal moiety of complex A and the hydroxyl group plays a key role in facilitating the formation of intermediate B. The relative free energy of intermediate B is only 2.6 kcal mol−1, when electron-deficient L4 is utilized as the ligand. Subsequently, the migratory insertion of the internal CC bond into the C–Pd bond of complex A takes place to form the π-allylpalladium intermediate C which is exergonic by 11.1 kcal mol−1. The strong π-acceptor ability of the L4 would induce the palladium center to coordinate with the alcohol in intermediate C,13 which undergoes inner-sphere reductive elimination with a free energy barrier of 17.2 kcal mol−1 to afford the cis-diastereoselective product 4 and regenerates the Pd(0) to enter the next catalytic cycle. Notably, there are two phosphoramidite ligands that coordinate with the Pd(II) center in this inner-sphere reductive elimination transition state. The calculated results are consistent with the non-linear relationship. When the electron-rich L2 (Cphos) acts as the ligand,14 the alcohol does not coordinate with the Pd(II) center in π-allylpalladium intermediate E. Then the π-allylpalladium is intramolecularly trapped by the alcohol via the outer-sphere mode with an energy barrier of 21.0 kcal mol−1 to produce the trans-diastereoselective cyclization product 3, and the Pd(0) is regenerated with the assistance of aminal.
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 2111895, 2111898 and 2111899. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc06479g |
‡ Y. H. and S. Z. contributed equally to this work. |
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