A challenging Heck reaction of maleimides

Abstract

Maleimides are extremely susceptible to basic hydrolysis and gave poor yields under Heck conditions. The longstanding problem is solved with the use of a weak base KOAc in a carbonate solvent.

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A palladium-catalyzed Heck reaction enables arylation and vinylation of olefins and is commonly used to prepare drugs, fragrance, agrochemicals and advanced materials.¹ Electron-deficient olefins such as enones, acrylates and acrylonitriles are commonly used and they react efficiently with aryl halides and sulfonates.² However, maleimides typically give very poor yields due to fast hydrolysis of the cyclic imides under basic conditions. Pd-catalyzed couplings of halomaleimides were often used as alternative methods.³ In synthesis of drug candidates, copper-catalyzed Meerwein reaction of maleimides and aryldiazonium salts is also used, although yields are often low-to-moderate.⁴ Recently, other metal-catalyzed methods were developed to prepare substituted maleimides, for example carbonylative couplings of alkynes and amines⁵ or isocyanates.⁶

Herein, we report an efficient general Heck reaction of problematic substrates, maleimides using aryl iodides. A weak acetate base KOAc was used to prevent hydrolysis of maleimides and arylated products. The motifs of 3-arylmaleimide and the related arylsuccinimide are present in many bioactive compounds and some drugs (Fig. 1).⁷ For example, phensuximide is an anticonvulsant drug⁸ and another succinimide exhibited both immunostimulatory and anti-inflammatory activities.⁹

Fig. 1 Bioactive arylated maleimides and succinimides.

In a model reaction of the parent maleimide (MI), after many experiments we found that a combination of a weak base KOAc in ethylene carbonate was crucial to obtain good yield at 60 °C after 12 hours (Table 1, entry 3). Notably, a longer reaction time led to diminished yields due to increased hydrolysis of the products. This testified to the challenge associated with this particular olefin. We noticed that many bases including K₂CO₃, Cs₂CO₃, CsF, KF and K₃PO₄ caused hydrolysis of both maleimide and Heck products and led to poor yields (entries 6–11). In addition, trialkylamines also caused fast hydrolysis of the imide linkage (entries 12 and 13).

Table 1 Optimization of bases in a model Heck reaction of maleimide (the GC yield and conversion based on 120% of maleimide)

Entry	Ligand	Conv (% PhI)	Conv (% MI)	Yield (%)
1	LiOAc	25	57	17
2	NaOAc	40	89	31
3	KOAc	100	112	88
4	NaHCO3	91	116	71
5	KHCO3	100	120	80
6	Li2CO3	9	98	5
7	Na2CO3	49	74	41
8	K2CO3	21	120	4
9	Cs2CO3	35	120	0
10	KF	80	120	52
11	K3PO4	88	119	49
12	Et3N	72	119	30
13	i-Pr2NEt	97	119	36

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The choice of solvents was also important (Table 2). For example, in THF, dioxane, toluene and DCE, the yield was only poor-to-moderate (entries 1–5). Notably, in highly polar solvents such as DMF and DMSO (entries 7 and 8), base hydrolysis of the cyclic imide became much faster and gave rise to poor yields. Better solvation of the metal ion in these solvents leaves the acetate ion more exposed and more nucleophilic. However, in ethylene carbonate, good yield was obtained (entry 9).¹⁰ It is a highly polar aprotic solvent with an exceptionally high dielectric constant of 95 at 25 °C.

Table 2 Effect of solvents in a model Heck reaction (the GC yield and conversion based on 120% of maleimide)

Entry	Solvent	Conv (% PhI)	Conv (% MI)	Yield (%)
1	THF	85	92	62
2	1,4-Dioxane	82	85	69
3	Diglyme	97	102	64
4	Toluene	26	35	15
5	DCE	55	56	46
6	DMA	96	108	64
7	DMF	66	120	38
8	DMSO	8	120	0
9	Ethylene carbonate	100	112	88

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Many phosphines can support the Pd catalysis well (Table 3). Good examples of ligands include SPhos, MePhos, Q-Phos, PCy₃, dppe and DPEphos. A ferrocene bisphosphine dppf also afforded good yield and was used for isolations, due to its substrate generality and low cost (entry 10). In the absence of a phosphine, the ligand-free procedure also gave 64% yield, probably via an anionic pathway of [(aryl)PdX₂]⁻ or [(aryl)PdX₃]²⁻ (entry 17).¹¹

Table 3 Effect of phosphine ligands in a model Heck reaction (the GC yield and conversion based on 120% of maleimide)

Entry	Ligand	Conv (% PhI)	Conv (% MI)	Yield (%)
1	Pt-Bu3	69	114	45
2	PCy3	100	120	90
3	PPh3	100	117	60
4	P(2-furyl)3	95	107	73
5	XPhos	99	116	61
6	SPhos	100	111	92
7	DavePhos	50	117	33
8	MePhos	100	112	93
9	Q-Phos	98	106	97
10	dppf	100	112	88
11	dppe	100	116	89
12	dppp	57	119	39
13	dppb	87	116	63
14	Xantphos	96	108	78
15	BINAP	5	80	<5
16	DPEphos	100	105	96
17	No added ligand	85	100	64

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Next, we explored the scope of aryl iodides (Fig. 2a). In a typical procedure, Pd(OAc)₂, dppf, KOAc, ArI and maleimides were mixed in ethylene carbonate under argon (or nitrogen) and heated with stirring at 60 °C for 12 hours. Notably, higher temperatures or a longer reaction time led to decreased yields due to partial hydrolysis of both maleimide and arylated products. The aryl rings can have electron-withdrawing and donating groups. The ortho-substituted aryl iodides led to slightly higher yields than the para ones, because of slower hydrolysis of products. One indolyl iodide also reacted smoothly and the yield was much higher in THF than that in ethylene carbonate. Common aryl bromides remained unreactive under similar conditions. The N-groups can be both alkyl and aryl groups (Fig. 2b). When N-arylmaleimides were used, another bisphosphine DPEphos proved to be a better catalyst. The N-anisylmethyl group in Heck products can be cleaved by treatment of AlCl₃ or CF₃CO₂H.^3b In addition, the Heck reaction of 3-methylmaleimide afforded a product containing an exo-benzylidene unit. This is probably formed via base-induced isomerization of the endocyclic olefin in maleimide (Fig. 2c).¹²

Fig. 2 Examples of the Heck reaction of maleimides (isolated yield on the 0.5 mmol scale unless stated otherwise).

As a side note, we attempted radical arylation by modifying Baran's procedure using PhB(OH)₂ and persulfate.¹³ Unfortunately, the yield was only 61% even after extensive optimization (Fig. 3a). Other arylboronic acids led to very poor yields. In another procedure for radical arylation using FeSO₄ and oxone, only 11% was reported previously by Komeyama et al. (Fig. 3b).¹⁴ These unsatisfactory results confirmed that maleimides are very sensitive to hydrolysis even under very mild conditions.

Fig. 3 Radical arylation methods.

In summary, we report an efficient Heck method for arylation of challenging maleimides, which are prone to undergo facile hydrolysis. A specific combination of KOAc and a carbonate solvent allowed the formation of Heck products in good yields with generality.

We thank the Singapore Ministry of Education Academic Research Fund (MOE2013-T2-2-057 and MOE2014-T1-001-021) and Nanyang Technological University for financial support and Johnson Matthey for palladium salts.

Notes and references

1. Reviews: (a) R. F. Heck, Acc. Chem. Res., 1979, 12, 146; (b) I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009; (c) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4442; (d) S. Bräse and A. de Meijere, in Metal-Catalyzed Cross-coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, 2004, p. 217; (e) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644; (f) The Mizoroki-Heck Reaction, ed. M. Oestreich, Wiley, New York, 2009.
2. A. F. Littke and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 6989.
3. (a) A. I. Roshchin and E. V. Polunin, Mendeleev Commun., 2008, 18, 332; (b) E. Awuah and A. Capretta, J. Org. Chem., 2011, 76, 3122; (c) A review of synthesis: P. S. Deore and N. P. Argade, Synthesis, 2014, 281.
4. (a) C. S. Rondestvedt and O. Vogl, J. Am. Chem. Soc., 1955, 77, 2313; (b) P. T. Izzo, J. Org. Chem., 1963, 28, 1713; (c) C. S. Rondestvedt, M. J. Kalm and O. Vogl, J. Am. Chem. Soc., 1956, 78, 6115.
5. K. M. Driller, H. Klein, R. Jackstell and M. Beller, Angew. Chem., Int. Ed., 2009, 48, 6041.
6. T. Kondo, M. Nomura, Y. Ura, K. Wada and T.-a. Mitsudo, J. Am. Chem. Soc., 2006, 128, 14816.
7. (a) N. Matuszak, G. G. Muccioli, G. Labar and D. M. Lambert, J. Med. Chem., 2009, 52, 7410; (b) C. I. Manley-King, G. Terre'Blanche, N. Castagnoli, J. J. Bergh and J. P. Petzer, Bioorg. Med. Chem., 2009, 17; (c) H. Yuki, T. Yamamoto, Y. Tohira, B. Aoki, T. Kano and T. Yamazaki, Chem. Pharm. Bull., 1967, 15, 1101; (d) A. Kar and N. P. Argade, Synthesis, 2005, 2284.
8. (a) C. A. Miller and L. M. Long, J. Am. Chem. Soc., 1951, 73, 4895; (b) T. C. McKenzie, J. W. Epstein, W. J. Fanshawe, J. S. Dixon, A. C. Osterberg, L. P. Wennogle, B. A. Regan, M. S. Abel and L. R. Meyerson, J. Med. Chem., 1984, 27, 628.
9. S.-C. Chien, M.-L. Chen, H.-T. Kuo, Y.-C. Tsai, B.-F. Lin and Y.-H. Kuo, J. Agric. Food Chem., 2008, 56, 7017.
10. (a) Y. Chernyak, J. Chem. Eng. Data, 2006, 51, 416; (b) R. P. Seward and E. C. Vieira, J. Phys. Chem., 1958, 62, 127.
11. B. P. Carrow and J. F. Hartwig, J. Am. Chem. Soc., 2009, 132, 79.
12. Y. Liu and W. Zhang, Angew. Chem., Int. Ed., 2013, 52, 2203.
13. I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L. Sobel and P. S. Baran, J. Am. Chem. Soc., 2010, 132, 13194.
14. K. Komeyama, T. Kashihara and K. Takaki, Tetrahedron Lett., 2013, 54, 1084.

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Footnote

† Electronic supplementary information (ESI) available: The experimental procedure of the Heck reaction and characterization of compounds. See DOI: 10.1039/c5qo00015g

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