Palladium-catalyzed direct C–H allylation of arenes without directing groups

Abstract

A palladium-catalyzed direct C–H allylation of simple arenes without directing groups was developed for allyl arene synthesis. The use of bidentate monoanionic nitrogen ligands enabled the progress of initial C–H activation of arenes, as well as the subsequent insertion and β-OAc elimination.

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Allylic substitution is a process that has been widely studied over the past few decades.¹ Several nucleophiles have been employed with good regioselectivity and stereoselectivity. Aryl metal reagents are mainly used in relation to aryl nucleophiles (Scheme 1a).² From the viewpoint of economical processes, using accessible prefunctionalized materials is attractive. Reported examples mostly relied on the highly active electron-rich arenes³ or arene-bearing directing groups (DGs)⁴ (Scheme 1b and 1c) that facilitate C–H functionalization⁵ at the ortho position. By contrast, electron-neutral or electron-deficient arenes without DGs have not been analyzed because of difficulty in cleaving inert C–H bonds, except polyfluoroarenes and heteroarenes, which both bear highly acidic C–H bonds.⁶ We reported a palladium-catalyzed C–H allylation of simple arenes that efficiently yielded a series of allyl arenes (Scheme 1d).

Scheme 1 Synthetic routes for allylarenes.

We previously described a palladium/2-OH-1,10-phenanthroline(phen)-catalyzed Fujiwara–Moritani reaction⁷ of simple arenes,⁸ in which bidentate monoanionic nitrogen ligands accelerated the C–H activation of various arenes smoothly.^9,10 We speculated that the generated aryl–palladium intermediate could react with allylic acetate through insertion and subsequent β-OAc/β-H competing elimination procedures for allyl arene synthesis.¹¹ Bidentate characteristics of the employed ligand also inhibit the β-H elimination pathway because these characteristics reduce the available number of free coordinate sites on the palladium center, which is a prerequisite for the progress of β-H elimination.¹²

This study began with the reaction of allylic acetate 2 with benzene in the presence of nitrogen ligands and various additives. Screening additives indicated that copper acetate and silver salts yielded the desired coupling products (Table 1, entries 1–3). Optimal amounts of silver carbonate were found, and adding 4 Å molecular sieves was beneficial to the product yield (Table 1, entries 4 and 6). The use of cesium carbonate or cesium acetate did not form the product (Table 1, entries 12 and 13). A series of ligands was tested to examine the effects on this reaction. Mono-hydroxy-bipyridine 5 also exhibited a certain activity (Table 1, entry 15). By contrast, 2,9-OH-1,10-phen, 2-methoxy-1,10-phen, N-acetyl-8-amino-quinoline, and 1,10-phen showed no activities (Table 1, entries 16–19). Monopyridine ligands (e.g., ethyl nicotinoate^13a and ortho-disubstituted pyridine^13b developed by Yu et al.) were also examined, which exhibited relatively low product yields (Table 1, entries 20 and 21). Protected amino acids, which had important functions in promoting Pd-catalyzed C–H activation reactions,⁹ also showed no activity (Table 1, entry 22).

Table 1 Palladium-catalyzed reactions of benzene with allylic acetates^a

Entry	Substrate	Ligand	Additive (equiv.)	Yield^b	Ratio of E/Z isomers^c
a All the reactions were conducted with 0.20 mmol of allylic acetates in 1.0 mL of arenes unless specifically noted. b Yields were determined by ^1H NMR analysis of the crude product using CH2Br2 as the internal standard. c The E/Z ratio was determined by ^1H NMR analysis of the crude product. d Isolated yield.
1	2a	4	Cu(OAc)2 (1.0)	62%	1.3/1
2	2a	4	AgOAc (0.5)	21%	1.3/1
3	2a	4	Ag2CO3 (0.5)	40%	1.3/1
4	2a	4	Ag2CO3 (0.5)/4 Å MS	82%^d	1.3/1
5	2b	4	Ag2CO3 (0.5)	55	1.4/1
6	2b	4	Ag2CO3 (0.5)/4 Å MS	61	1.4/1
7	2b	4	Cu(OAc)2 (1.0)	12	1.6/1
8	2b	4	Ag2O (0.5)	50	1.4/1
9	2b	4	AgBF4 (0.5)	0	—
10	2b	4	Ag2SO4 (0.5)	0	—
11	2b	4	Ag3PO4 (0.5)	0	—
12	2b	4	Cs2CO3 (0.5)	0	—
13	2b	4	CsOAc (0.5)	0	—
14	2a	No ligand	Ag2CO3 (0.5)/4 Å MS	4	—
15	2a	5	Ag2CO3 (0.5)/4 Å MS	68	1.6/1
16	2a	6	Ag2CO3 (0.5)/4 Å MS	0	—
17	2a	7	Ag2CO3 (0.5)/4 Å MS	0	—
18	2a	8	Ag2CO3 (0.5)/4 Å MS	0	—
19	2a	1,10-Phen	Ag2CO3 (0.5)/4 Å MS	0	—
20	2a	9	Ag2CO3 (0.5)/4 Å MS	26%	E only
21	2a	10	Ag2CO3 (0.5)/4 Å MS	12%	E only
22	2a	Boc-L-valine	Ag2CO3 (0.5)/4 Å MS	3	—

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The scope of allylic acetates was subsequently examined with the optimal conditions obtained. The electron-rich or electron-deficient substituent groups at ortho, meta, or para positions were found to be suitable electrophiles and yielded corresponding products with moderate to good yields (Table 2). The alkyl-substituted groups were also examined, and the product was generated with the formation of a double addition product (Table 2, entry 10: 3ka′, 15% yield). Bis-substituted allylic acetates were tested under the same conditions to obtain substituted products with 65% and 70% yields (Table 2, entries 11 and 12: 3la and 3ma). Table 3 summarizes the results of substituted arenes with allylic acetates. 1,4-Difluorobenzene and 1,4-dichlorobenzene are suitable aryl donors with yields of 70% and 78%, respectively. The allyl moiety was selectively installed at the less hindered position for 4-chloro-trifluorobenzene. Tetrafluorobenzene was also examined to obtain a 65% product yield, which was not described in the reported catalytic system⁶ because of the higher pK_a of the C–H bond compared with that of pentafluorobenzene. Electron-rich arenes were also investigated; 1,3-dimethoxybenzene was functionalized only at the meta-position, which suggested that ligand 4 had a key function in determining regioselectivity.¹⁴ Naphthalene also exhibited relatively good regioselecitivty¹⁵ because of the steric effects.

Table 2 Palladium-catalyzed allylation of benzene with allylic acetates^a

Entry	Product^b^,^c (%)	Entry	Product^b^,^c (%)
a All the reactions were conducted with 0.20 mmol of allylic acetates in 1.0 mL of arenes unless specifically noted. b Isolated yields. c The E/Z ratio was determined by ^1H NMR analysis of the isolated product.
1		2
3		4
5		6
7		8
9		10
11		12

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Table 3 Palladium-catalyzed allylation of arenes with allylic acetates^a

Entry	Product^b^,^c (%)	Entry	Product^b^,^c (%)
a All the reactions were conducted with 0.20 mmol of allylic acetates in 1.0 mL of arenes unless specifically noted. b Isolated yields. c The E/Z ratio was determined by ^1H NMR analysis of the isolated product. d 1 g of arenes in 1 mL of 1,4-dioxane.
1		2^d
3		4
5		6
7^d
8^d
9

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To further understand the reaction, we conducted a reaction of deuterated benzene with 2a under identical conditions and obtained K_H/K_D = 2.9, indicating that C–H bond cleavage was involved in the rate-limiting step (Scheme 2).¹⁶ The use of homoallylic alcohol acetate yielded a functionalized allylic acetate as the β-H elimination product (eqn (1)). The use of cinnamic acetate as the substrate did not yield the allylation product (eqn (2)), which ruled out the involvement of a π-allylic palladium intermediate. The use of phenylboronic acid as a nucleophile instead of benzene also generated a mixture of E/Z products (eqn (3)). The enantio-enriched allylic acetate (R)-2l (78% ee) reacted with benzene, (S)-trans-alkene was isolated in 72% ee, and (R)-cis-alkene was obtained in 65% ee (eqn (4)).¹⁷ On the basis of the above results, a possible stereochemical pathway was proposed for the current reaction in Scheme 3. The C–H cleavage of benzene enabled by palladium ligated with ligand 4 generated a palladium–aryl intermediate. A facial selective insertion of alkene into the aryl–palladium bond produced two alkyl palladium intermediates. Finally, cis-β-OAc elimination yielded the (E) and (Z)-products.

Scheme 2 Experiments with isotopically labelled compounds.

Scheme 3 Proposed stereochemical pathway.

In summary, we have reported a palladium-catalyzed C–H allylation of simple arenes without directing groups with allylic acetates, which yielded the corresponding allyl arenes with moderate to good yields. The bidentate monoanionic ligand framework has a significant effect on the success of C–H activation and subsequent β-OAc elimination.

We thank the National Basic Research Program of China (973 Program; 2010CB833300), the NSFC (20902099 and 21172238), and SIOC for funding this work. We thank Prof. Shi-Kai Tian for kindly donating an authentic sample of (S)-(E)-3la.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical data for all new compounds. See DOI: 10.1039/c4qo00097h

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