Yunlei Hou‡
,
Mingze Qin‡,
Xiuxiu Yang,
Qi Shen,
Yanfang Zhao,
Yajing Liu* and
Ping Gong*
Key Laboratory of Structure-based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China. E-mail: gongpinggp@126.com; lyjpharm@126.com
First published on 23rd January 2017
An efficient three-component tandem cyclization reaction for the synthesis of highly substituted oxazolidines was achieved through the Pd0-catalyzed cyclization of buta-2,3-dien-1-ol with aryl iodides and imines. A range of R1 and R2 functional groups is well-tolerated while affording cyclization products in moderate yields and with moderate to high diastereoselectivities.
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Fig. 1 Representative medicinally relevant agents, natural products, and chiral agents containing oxazolidines. |
For instance, the anticancer drug doxorubicin (Fig. 1, V) could be transformed into the oxazolidine prodrug VI to increase tumor response and minimize side effects, especially the treatment-limiting cardiotoxicity associated with doxorubicin therapy.6 Accordingly, the development of new methodologies for the synthesis of oxazolidines has garnered considerable attention.
Recently, Yoon et al. developed an efficient method for synthesizing oxazolidines through the iron- or copper-catalyzed aminohydroxylation of olefins (Scheme 1, Eq (1)).7 Jarvo further demonstrated the stereoselective and stereospecific syntheses of oxazolidines using catalysts with differing rates of allylmetal isomerization (Scheme 1, Eq (2)).8 Zhang investigated the [3 + 2] cycloaddition of azomethine ylides with carbonyl compounds for the synthesis of oxazolidines (Scheme 1, Eq (3)).9 More recently, Zhang explored a new organocatalytic strategy to synthesize oxazolidines through the Pd-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates (VECs) with imines in the presence of chiral ligands (Scheme 1, Eq (4)).10 Therefore, the development of operationally simple and efficient synthetic approaches towards oxazolidines using readily available and stable starting materials is desired.
Multi-component reactions (MCRs) involving domino processes have emerged as powerful tools for the synthesis of molecules, including heterocyclic compounds, with efficiency, atom-economy, and diversity from simple substrates.11 In addition, functionalized allenes have been shown to be efficient starting materials for the synthesis of potentially useful carbo- and heterocycles.12 Inspired by the synthesis of 1,3-oxazolidines from the cycloaddition of imines and vinyl epoxides (Scheme 1, Eq (2)) or VECs (Scheme 1, Eq (4)), we hypothesized that other substrates, such as terminal β-allenols instead of vinyl epoxides or VECs, could be involved in the Pd0-catalyzed reaction of organic halides and imines without the necessity of a chiral ligand, which would allow for the formation of oxazolidine derivatives (Scheme 1, Eq (5)). Towards that end, we developed a novel and efficient route towards 1,3-oxazolidines via the cycloaddition of buta-2,3-dien-1-ol (1a) with aryl iodides and imines by varying the reaction conditions.
Entry | Base | Additive | Solvent | Temp (°C) | Time (h) | Yieldb (%) | drc (cis/trans) |
---|---|---|---|---|---|---|---|
a Reaction conditions: under a N2 atmosphere, 1a (0.35 mmol, 1 equiv.), 2a (0.42 mmol, 1.2 equiv.), 3a (0.42 mmol, 1.2 equiv.), [Pd(PPh3)4] (0.018 mmol, 5 mol%), base (1 mmol, 3 equiv.), solvent (3.0 mL).b Isolated yield.c Determined by 1H NMR.d A = n-Bu4NBr (5 mol%), B = Cu(OTf)2 (5 mol%).e Imine 3a (3.0 equiv.) was used.f [Pd(PPh3)4] (20 mol% or 50 mol%) was used. | |||||||
1 | K2CO3 | — | THF | Reflux | 15 | 23 | 3![]() ![]() |
2e | K2CO3 | — | THF | Reflux | 15 | 25 | 3![]() ![]() |
3 | Na2CO3 | — | THF | Reflux | 15 | Trace | — |
4 | Cs2CO3 | — | THF | Reflux | 12 | 38 | 10![]() ![]() |
5 | CsF | — | THF | Reflux | 10 | 50 | 15![]() ![]() |
6 | CsF | — | CH3CN | Reflux | 10 | 48 | 20![]() ![]() |
7 | CsF | — | Toluene | 80 | 10 | 18 | 8![]() ![]() |
8 | Cs2CO3 | Dioxane | 80 | 12 | 41 | >30![]() ![]() |
|
9 | CsF | — | DMSO | 80 | 12 | 43 | 25![]() ![]() |
10 | CsF | — | Dioxane | 80 | 10 | 50 | >30![]() ![]() |
11 | CsF | — | DMF | 80 | 10 | 45 | 25![]() ![]() |
12 | CsF | Ad | Dioxane | 80 | 10 | 48 | >30![]() ![]() |
13 | CsF | Bd | Dioxane | 80 | 10 | 50 | 10![]() ![]() |
14 | CsF | — | Dioxane | 40 | 48 | 10 | — |
15 | CsF | — | Dioxane | 100 | 8 | 45 | >30![]() ![]() |
16e | CsF | — | Dioxane | 80 | 10 | 49 | >30![]() ![]() |
17f | CsF | — | Dioxane | 80 | 10 | 49 | >30![]() ![]() |
Under the optimized reaction conditions, the scope and limitations of the transformation were evaluated for the reaction of 1a with various imines 3; the results are listed in Table 2. Tandem reactions with imines derived from arylaldehydes with different steric and electronic features proceeded smoothly to afford the corresponding oxazolidines 4 in moderate yields and diastereoselectivities (Table 2, entries 1–14). The position of the substituents on the aryl ring affected the reactivity. For example, p-fluorophenyl-substituted 3f afforded the desired cycloaddition product 4af in 48% yield with a dr of 10:
1 under the optimized conditions (Table 2, entry 6). In contrast, o-fluorophenyl-substituted 3g exhibited a decreased conversion with low diastereoselectivity, indicating that o-substitution on the aryl ring is unfavorable (Table 2, entry 7). The reaction efficiency and diastereomeric ratio decreased dramatically when multiple-halogen atoms were present on the aryl ring, implying that stereospecific blockade groups have a negative effect on the cycloaddition reaction (Table 2, entries 10 and 11). Imines 3l and 3m, derived from 2-formylthiofuran and furfural, were also suitable substrates for the cycloaddition and furnished the corresponding oxazolidines in 47% and 43% yields, respectively (Table 2, entries 12–13). However, imine 3o (R1 = 2-pyrrolyl) gave the product 4ao in only a trace yield, indicating that it was significantly less reactive than 3l (R1 = 2-thienyl) and 3m (R1 = 2-furyl). Gratifyingly, (E)-N-mesyl imine 3n was a viable substrate in this transformation, affording the product in 45% isolated yield under the standard conditions. When using imines 3p with phenyl or p-methoxyl phenyl groups at nitrogen, the target product was not detected, which suggesting that imines with electron-withdrawing groups at nitrogen was necessary in this reaction. The structures and relative stereochemistries of the products were established by X-ray crystallography analysis of 4aa as the 2,4-cis-isomer (Fig. 2), and those of the other products were assigned by analogy.
Entry | 3 | 4 | Yieldb (%) | drc (cis/trans) |
---|---|---|---|---|
a Reaction conditions: under a N2 atmosphere, 1a (0.35 mmol, 1 equiv.), 2a (0.42 mmol, 1.2 equiv.), 3a (0.42 mmol, 1.2 equiv.), [Pd(PPh3)4] (0.018 mmol, 5 mol%), CsF (1 mmol, 3 equiv.), dioxane (3.0 mL).b Isolated yield.c Determined by 1H NMR. The absolute configuration of 4aa was determined by X-ray crystallography (see Fig. 2); those of the other products were assigned by analogy.d 3n = (E)-N-benzylidenemethanesulfonamide.e 3p = (E)-N,1-diphenylmethanimine or (E)-N-(4-methoxyphenyl)-1-phenylmethanimine. | ||||
1 | 3a (R1 = Ph) | 4aa | 50 | >30![]() ![]() |
2 | 3b (R1 = p-MeC6H4) | 4ab | 55 | 15![]() ![]() |
3 | 3c (R1 = p-MeOC6H4) | 4ac | 52 | >30![]() ![]() |
4 | 3d (R1 = m-MeC6H4) | 4ad | 45 | 10![]() ![]() |
5 | 3e (R1 = p-ClC6H4) | 4ae | 51 | 8![]() ![]() |
6 | 3f (R1 = p-FC6H4) | 4af | 48 | 10![]() ![]() |
7 | 3g (R1 = o-FC6H4) | 4ag | 30 | 3![]() ![]() |
8 | 3h (R1 = o-ClC6H4) | 4ah | 28 | 5![]() ![]() |
9 | 3i (R1 = p-BrC6H4) | 4ai | 54 | 4![]() ![]() |
10 | 3j (R1 = 2,4-(F)2-C6H4) | 4aj | 25 | 3![]() ![]() |
11 | 3k (R1 = 2-Cl,4-F-C6H4) | 4ak | 18 | 2![]() ![]() |
12 | 3l (R1 = 2-thienyl) | 4al | 47 | 4![]() ![]() |
13 | 3m (R1 = 2-furyl) | 4am | 43 | 2![]() ![]() |
14 | 3n (R1 = Ph)d | 4an | 45 | 4![]() ![]() |
15 | 3o (R1 = 2-pyrrolyl) | 4ao | Trace | — |
16 | 3p (R1 = Ph)e | 4ap | Trace | — |
After the successful cycloaddition of 1a and iodobenzene 2a with various imines, we subsequently turned our attention toward the cycloaddition of 1a and (E)-N-benzylidenetosylamide 3a with various aryl iodides; the results are summarized in Table 3. In general, aryl iodides bearing electron-withdrawing (Table 3, entries 4–5) or electron-donating groups (Table 3, entries 2–3) afforded the corresponding oxazolidines in moderate yields and diastereoselectivities under identical conditions. Furthermore, the incorporation of multiple-halogens or strong EWGs on the phenyl ring decreased the reaction efficiency, which suggested that the electron density of the phenyl ring played a role in the reaction efficiency (Table 3, entries 4–5, 7–8, 28–40%). Notably, when a heteroaryl iodide was employed as a substrate (Table 3, entry 9, 43%), the product yield was slightly affected, which was attributed to the electronic property of the thiophene ring. In order to investigate the limitations of aryl halides with different carbon–halogen bonds, phenyl bromide and phenyl chloride were tested. As presented in Table 3 (entries 10 vs. 1), only the carbon–iodine bond was cleaved, suggesting that aryl iodides resulted in higher efficiencies. Interestingly, compounds 4aa–4ia (dr > 10:
1) in Table 3 gave a higher diastereomeric ratio than compounds 4ad–4an (dr = 2
:
1–10
:
1) in Table 2, which indicated that R2 has a more general substrate scope.
Entry | 2 | 4 | Yieldb (%) | drc (cis/trans) |
---|---|---|---|---|
a Reaction conditions: under a N2 atmosphere, 1a (0.35 mmol, 1 equiv.), 2a (0.42 mmol, 1.2 equiv.), 3a (0.42 mmol, 1.2 equiv.), [Pd(PPh3)4] (0.018 mmol, 5 mol%), CsF (1 mmol, 3 equiv.), dioxane (3.0 mL).b Isolated yield.c Determined by 1H NMR.d 2j = phenyl bromide or phenyl chloride. | ||||
1 | 2a (R2 = Ph) | 4aa | 50 | >30![]() ![]() |
2 | 2b (R2 = p-MeC6H4) | 4ba | 55 | 11![]() ![]() |
3 | 2c (R2 = p-MeOC6H4) | 4ca | 53 | 10![]() ![]() |
4 | 2d (R2 = p-MeO2CC6H4) | 4da | 40 | 10![]() ![]() |
5 | 2e (R2 = p-NO2C6H4) | 4ea | 38 | 12![]() ![]() |
6 | 2f (R2 = p-FC6H4) | 4fa | 46 | 16![]() ![]() |
7 | 2g (R2 = 3-Cl,4-F-C6H4) | 4ga | 33 | >30![]() ![]() |
8 | 2h (R2 = 3,4-(F)2-C6H4) | 4ha | 28 | >30![]() ![]() |
9 | 2i (R2 = 2-thienyl) | 4ia | 43 | 22![]() ![]() |
10 | 2jd | 4ja | Trace | — |
Based on previous studies,15 a plausible mechanism for the cross-coupling reaction is proposed in Scheme 2. The carbopalladation of PhPdI, which is formed in situ from the oxidative addition of Pd0 to iodobenzene, with buta-2,3-dien-1-ol (1a) at the center carbon atom forms the π-allylic palladium complex B. Subsequent nucleophilic attack of the oxygen nucleophile of B on the imines 3 leads to the intermediate C. Finally, the resulting intermediate C undergoes an intramolecular nucleophilic attack on the inner π-allylic carbon atom to produce the cyclized products 4, along with the regeneration of the Pd0 catalyst D.
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 1516742. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra27993g |
‡ These authors contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2017 |