Palladium-catalyzed three-component tandem cyclization of buta-2,3-dien-1-ol, aryl iodides, and imines: an efficient protocol for the synthesis of oxazolidine derivatives

Abstract

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.

---

Introduction

Multifunctional heterocyclic compounds play an essential role in organic and medicinal chemistry, as well as in drug discovery. Notably, nearly 70% of marketed drugs contain heterocycles.¹ Oxazolidine rings are common pharmacophores that comprise potent antitumor tetrahydroisoquinoline-based natural products including quinocarcin (Fig. 1, I) and tetrazomine (Fig. 1, II).² In addition, chiral oxazolidines are used as chiral auxiliaries (Fig. 1, III)³ and chiral ligands (Fig. 1, IV)⁴ in a variety of asymmetric transformations. Oxazolidines are also commonly utilized as prodrugs for improving the pharmacokinetic profile of certain β-amino alcohol pharmacophores.⁵

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.

Scheme 1 Strategies for the construction of oxazolidines.

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.

Results and discussion

Based on literature precedent,^13,14 we set out to test the model reaction of buta-2,3-dien-1-ol (1a) with iodobenzene (2a) and imine (3a) in the presence of 5 mol% of [Pd(PPh₃)₄] at 80 °C, as shown in Table 1. The reaction in THF with K₂CO₃ as the base afforded oxazolidine 4aa in 23% yield with a dr of 3 : 1 (Table 1, entry 1). In order to improve the yield and stereoselectivity, different bases, solvents, and additives were tested. Among the tested bases, CsF and Cs₂CO₃ resulted in higher efficiencies with 50% and 38% yields, respectively (Table 1, entries 4–5), while Na₂CO₃ only gave the product in a trace yield (Table 1, entry 3). Polar solvents such as DMSO and DMF resulted in moderate stereoselectivity with a >25 : 1 dr (Table 1, entries 9 and 11). Less polar solvents such as toluene decreased the diastereoselectivity to 8 : 1 and resulted in an 18% yield (Table 1, entry 7). When the reaction was conducted in dioxane, 4aa was obtained in 50% yield with a >30 : 1 dr (Table 1, entry 10). Next, the reaction temperature was examined. Upon lowering the temperature to 40 °C, the conversion dramatically dropped to only 10%, even when the reaction time was extended to 48 h. Higher temperatures (100 °C) accelerated the reaction rate without any increase in the yield (Table 1, entries 10 and 15). On the basis of previous studies, various additives were tested (Table 1, entries 12–13). Among them, the phase-transfer catalyst n-Bu₄NBr had no dramatic effect on the stereoselectivity. The Lewis acid Cu(OTf)₂ did not improve the yields, but the cis/trans ratio decreased to 10 : 1. An increase in the molar amount of imine 3a from 1.2 to 3.0 equiv. also gave a similar result (Table 1, entries 1 vs. 2, 15 vs. 16). Higher palladium concentrations (from 5 mol% to 50 mol%) was tried in order to improve the yield, but the yield did not increased (Table 1, entry 17). Overall, the best results were obtained when 3.0 equiv. of CsF was used as the base in the presence of 5 mol% [Pd(PPh₃)₄] in dioxane at 80 °C.

Table 1 The effect of different reaction conditions on the Pd⁰-catalyzed three-component tandem cyclization reaction of 1a, 2a, and 3a^a

Entry	Base	Additive	Solvent	Temp (°C)	Time (h)	Yield^b (%)	dr^c (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 : 1
2^e	K2CO3	—	THF	Reflux	15	25	3 : 1
3	Na2CO3	—	THF	Reflux	15	Trace	—
4	Cs2CO3	—	THF	Reflux	12	38	10 : 1
5	CsF	—	THF	Reflux	10	50	15 : 1
6	CsF	—	CH3CN	Reflux	10	48	20 : 1
7	CsF	—	Toluene	80	10	18	8 : 1
8	Cs2CO3		Dioxane	80	12	41	>30 : 1
9	CsF	—	DMSO	80	12	43	25 : 1
10	CsF	—	Dioxane	80	10	50	>30 : 1
11	CsF	—	DMF	80	10	45	25 : 1
12	CsF	A^d	Dioxane	80	10	48	>30 : 1
13	CsF	B^d	Dioxane	80	10	50	10 : 1
14	CsF	—	Dioxane	40	48	10	—
15	CsF	—	Dioxane	100	8	45	>30 : 1
16^e	CsF	—	Dioxane	80	10	49	>30 : 1
17^f	CsF	—	Dioxane	80	10	49	>30 : 1

---

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.

Table 2 The Pd⁰-catalyzed three-component tandem cyclization reaction of 1a, iodobenzene 2a, and different imines^a

Entry	3	4	Yield^b (%)	dr^c (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 (R^1 = Ph)	4aa	50	>30 : 1
2	3b (R^1 = p-MeC6H4)	4ab	55	15 : 1
3	3c (R^1 = p-MeOC6H4)	4ac	52	>30 : 1
4	3d (R^1 = m-MeC6H4)	4ad	45	10 : 1
5	3e (R^1 = p-ClC6H4)	4ae	51	8 : 1
6	3f (R^1 = p-FC6H4)	4af	48	10 : 1
7	3g (R^1 = o-FC6H4)	4ag	30	3 : 1
8	3h (R^1 = o-ClC6H4)	4ah	28	5 : 1
9	3i (R^1 = p-BrC6H4)	4ai	54	4 : 1
10	3j (R^1 = 2,4-(F)2-C6H4)	4aj	25	3 : 1
11	3k (R^1 = 2-Cl,4-F-C6H4)	4ak	18	2 : 1
12	3l (R^1 = 2-thienyl)	4al	47	4 : 1
13	3m (R^1 = 2-furyl)	4am	43	2 : 1
14	3n (R^1 = Ph)^d	4an	45	4 : 1
15	3o (R^1 = 2-pyrrolyl)	4ao	Trace	—
16	3p (R^1 = Ph)^e	4ap	Trace	—

---

Fig. 2 X-ray crystal structure of compound 4aa.

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.

Table 3 The Pd⁰-catalyzed three-component tandem cyclization reaction of 1a, imine 3a, and different aryl iodides^a

Entry	2	4	Yield^b (%)	dr^c (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 (R^2 = Ph)	4aa	50	>30 : 1
2	2b (R^2 = p-MeC6H4)	4ba	55	11 : 1
3	2c (R^2 = p-MeOC6H4)	4ca	53	10 : 1
4	2d (R^2 = p-MeO2CC6H4)	4da	40	10 : 1
5	2e (R^2 = p-NO2C6H4)	4ea	38	12 : 1
6	2f (R^2 = p-FC6H4)	4fa	46	16 : 1
7	2g (R^2 = 3-Cl,4-F-C6H4)	4ga	33	>30 : 1
8	2h (R^2 = 3,4-(F)2-C6H4)	4ha	28	>30 : 1
9	2i (R^2 = 2-thienyl)	4ia	43	22 : 1
10	2j^d	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.

Scheme 2 Plausible reaction mechanism.

Conclusions

In conclusion, we have developed an efficient Pd⁰-catalyzed MCR for the synthesis of polysubstituted oxazolidine derivatives from buta-2,3-dien-1-ol, aryl iodides, and imines. Because of the three-component reaction concept, this cyclization could provide multiple points for diversity with excellent diastereoselectivity. As all three building blocks are readily available, this study will advance the transition-metal-catalyzed chemistry of allenes. Further studies regarding the scope and synthetic applications of this reaction are being pursued in our laboratory and will be reported in due course.

Acknowledgements

We are grateful for the financial support from the Program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative Research Team in University (IRT1073).

References

1. A. Barghi-Lish, S. Farzaneh and M. Mamaghani, Synth. Commun., 2016, 46, 1209.
2. (a) J. D. Scott and R. M. Williams, Chem. Rev., 2002, 102, 1669; (b) R. M. Williams, T. Glinka, M. E. Flanagan, R. Gallegos, H. Coffman and D. Pei, J. Am. Chem. Soc., 1992, 114, 733; (c) F. Tomita, K. Takahashi and T. Tamaoki, Antibiotics, 1984, 37, 1268; (d) Y.-C. Wu, M. Liron and J. Zhu, J. Am. Chem. Soc., 2008, 130, 7148; (e) M. Yotsu-Yamashita, Y. H. Kim, S. C. Dudley Jr, G. Choudhary, A. Pfahnl, Y. Oshima and J. W. Daly, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 4346.
3. (a) A. Pastor, W. Adam, T. Wirth and G. Tóth, Eur. J. Org. Chem., 2005, 14, 3075; (b) I. Hoppe, H. Hoffmann, I. Grtner, T. Krettek and D. Hoppe, Synthesis, 1991, 12, 1157; (c) C. Scolastico, Pure Appl. Chem., 1988, 60, 1689; (d) D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc., 1982, 104, 1737; (e) S. Kanemasa and K. Onimura, Tetrahedron, 1992, 48, 8631; (f) N. Hiroto, O. Yuko and K. Eunsang, Heterocycles, 2014, 89, 1.
4. (a) C. Wolf and H. Xu, Chem. Commun., 2011, 47, 3339; (b) C. Agami and F. Couty, Eur. J. Org. Chem., 2004, 4, 677; (c) A. Tessier, N. Lahmar, J. Pytkowicz and T. Brigaud, J. Org. Chem., 2008, 73, 3970; (d) C. A. Caputoand and N. D. Jones, Dalton Trans., 2007, 41, 4627–4640.
5. (a) G. P. Moloney, D. J. Craik, M. N. Iskander and T. L. Nero, J. Chem. Soc., Perkin Trans. 2, 1998, 2, 199; (b) J. Danielsson, L. Toomand and P. Somfai, Eur. J. Org. Chem., 2011, 3, 607; (c) B. Seashore-Ludlowand and P. Somfai, Eur. J. Org. Chem., 2010, 20, 3927; (d) T. H. Fife and L. Hagopian, J. Am. Chem. Soc., 1968, 90, 10074; (e) F. Gosselin, A. Roy, P. D. O'Shea, C. Chen and R. P. Volante, Org. Lett., 2004, 6, 641.
6. (a) G. C. Post, B. L. Barthel, D. J. Burkhart, J. R. Hagadorn and T. H. Koch, J. Med. Chem., 2005, 48, 7648; (b) D. J. Burkhart, B. L. Barthel, G. C. Post, B. T. Kalet, J. W. Nafie, R. K. Shoemaker and T. H. Koch, J. Med. Chem., 2006, 49, 7002; (c) G. Minotti, P. Menna, E. Salvatorelli, G. Cairo and L. Gianni, Pharmacol. Rev., 2004, 56, 185; (d) D. A. Gewirtz, Biochem. Pharmacol., 1999, 57, 727.
7. (a) D. J. Michaelis, C. J. Shaffer and T. P. Yoon, J. Am. Chem. Soc., 2007, 129, 1866–1867; (b) D. J. Michaelis, M. A. Ischay and T. P. Yoon, J. Am. Chem. Soc., 2008, 130, 6610–6615; (c) K. S. Williamson and T. P. Yoon, J. Am. Chem. Soc., 2010, 132, 4570–4571.
8. M. B. Shaghafi, R. E. Grote and E. R. Jarvo, Org. Lett., 2011, 13, 5188.
9. X. Wu, L. Li and J. Zhang, Chem. Commun., 2011, 47, 7824.
10. L. Yang, A. Khan, R. Zheng, L. Y. Jin and Y. J. Zhang, Org. Lett., 2015, 17, 6230.
11. (a) X. Chu, X. Xu and S. Ji, Chem.–Eur. J., 2016, 22, 14181; (b) M. Ghorbani, B. Mohammadi, M. Saraii, B. Masoumi, M. Abbasian, A. Ramazani, K. Slepokura and T. Lis, Org. Lett., 2016, 18, 4759; (c) L. G. Voskressensky, T. N. Borisova, M. D. Matveeva, V. N. Khrustalev, A. V. Aksenov, A. A. Titov, A. E. Vartanova and A. V. Varlamova, RSC Adv., 2016, 6, 74068; (d) H. Dong, L. Xu, S. Li, L. Wang, C. Shao and J. Xiao, ACS Comb. Sci., 2016, 18, 604; (e) X. Lian, J. Meng and Z. Han, Org. Lett., 2016, 18, 4270; (f) J. Chu, B. Hu, Z. Liao and X. Zhang, J. Org. Chem., 2016, 81, 8647.
12. (a) B. Miao, S. Li, G. Li and S. Ma, Org. Lett., 2016, 18, 2556; (b) T. Cao and S. Ma, Org. Lett., 2016, 18, 1510; (c) W. Yuan and S. Ma, Org. Lett., 2014, 16, 193; (d) J. Ye and S. Ma, Acc. Chem. Res., 2014, 47, 989; (e) X. Huang, W. Wu, S. Song, C. Fu and S. Ma, Adv. Synth. Catal., 2016, 358, 2791; (f) Y. Shigeo, K. Yasuaki, O. Yuta and M. Chisato, Chem.–Eur. J., 2016, 22, 12181; (g) T. Aurelien, B. Aurelie, N. W. Vijay and L. Benjamin, Angew. Chem., Int. Ed., 2016, 55, 8962; (h) G. Charlotte, M. Veronique and T. Y. Patrick, Org. Lett., 2016, 18, 676.
13. S. Ma and N. Jiao, Angew. Chem., Int. Ed., 2002, 41, 4737.
14. X. Cheng and S. Ma, Angew. Chem., Int. Ed., 2008, 47, 4581.
15. (a) A. Khan, J. Xing, J. Zhao, Y. Kan, W. Zhang and Y. Zhang, Chem.–Eur. J., 2015, 21, 120; (b) J. Cheng, X. Jiang, C. Zhu and S. Ma, Org. Lett., 2011, 353, 1676; (c) J. Ye and S. Ma, Acc. Chem. Res., 2014, 47, 989; (d) Q. Xiao, B. Wang, L. Tian, Y. Yang, J. Ma, Y. Zhang, S. Chen and J. Wang, Angew. Chem., Int. Ed., 2013, 52, 9305; (e) P. Miao, H. Wang, L. Liu, W. Chang and J. Li, Asian J. Org. Chem., 2015, 4, 1050; (f) J. Le Bras and J. Muzart, Chem. Soc. Rev., 2014, 43, 3003; (g) R. W. Bates and V. atcharoen, Chem. Soc. Rev., 2002, 31, 12.

---

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.

---