Use of Aryl Chlorides as Electrophiles in Pd-Catalyzed Alkene Difunctionalization Reactions

Abstract

The development of conditions that allow use of inexpensive aryl chlorides as electrophiles in Pd-catalyzed alkene carboamination and carboetherification reactions is described. A catalyst composed of Pd(OAc)₂ and S-Phos minimizes N-arylation of the substrate and prevents formation of mixtures of regioisomeric products. A number of heterocycles, including pyrrolidines, isoxazolidines, tetrahydrofurans, and pyrazolidines, are efficiently generated with this method.

Over the past several years, our group has developed a new type of cross-coupling reaction in which alkenes bearing pendant aminopropyl groups are transformed to substituted pyrrolidines via Pd-catalyzed carboamination reactions with aryl bromides. These alkene difunctionalization reactions provide a convergent and efficient means to access substituted N-aryl, N-acetyl, or N-Boc pyrrolidines with a high degree of stereocontrol.^1,2 This strategy has also been employed for the generation of several other oxygen- or nitrogen-containing heterocycles.^3,4,5

To further expand the scope and utility of these transformations, we sought to employ inexpensive aryl chlorides as electrophilic coupling partners in these reactions.⁶ In our prior studies we had found that chelating phosphine ligands with wide bite angles, such as Dpe-phos, Xantphos, or dppb, provided optimal results in many transformations of aryl bromides.² However, Pd-catalysts supported by these ligands are not sufficiently active to facilitate transformations of aryl chlorides, which are considerably less reactive than the corresponding aryl bromides. Thus, to achieve our goal, we would need to discover catalysts that both activate aryl chlorides, and also promote the alkene carboamination process.

Due to the significant economic advantages associated with using aryl chlorides in place of aryl bromides, considerable research effort has been expended on the development of ligands for Pd-catalyzed cross-coupling reactions of these relatively unreactive electrophiles.⁷ Many of these ligands are highly effective in Suzuki couplings, N-arylations, and other carbon-carbon or carbon-heteroatom bond-forming processes.^7,8,9 However, our initial efforts to employ these ligands in Pd-catalyzed carboamination reactions of γ–(N-arylamino)alkenes (e.g., 1a) provided unsatisfactory results. Use of Buchwald’s biphenyl(dialkyl)phosphines⁸ led to competing N-arylation of these substrates, and many other electron-rich ligands led to mixtures of regioisomeric products. For example, the Pd/P(^tBu)₂Me-catalyzed reaction of 1a with 2-chloronaphthalene afforded an 11:1:1:3 mixture of 2a:3:4:5 (eq 1).

(1)

After considerable optimization, we discovered that PCy₂Ph provided acceptable results in many Pd-catalyzed carboamination reactions of aryl chlorides with γ-N-(arylamino)alkenes. As shown in Table 1, both electron-donating and electron-withdrawing groups are tolerated on the aryl chloride, and in all cases the major products were formed with ≥ 90% regioselectivity. Transformations involving acyclic internal alkene substrates were unsuccessful, affording complex mixtures of products.¹⁰ However, cyclopentene-derived substrate 1d was converted to bicyclic heterocycles 2f–2g in good yields and with high diastereoselectivities.¹¹

TABLE 1.

Carboamination of γ-(N-Arylamino)alkenes with Aryl Chlorides^a

entry	amine	product	regioselectivityb	yieldc
1	1a	2a	43:3:0:1	79%
2	1a	2b	38:3:0:1	74%
3	1a	2c	27:2:0:1	79%
4	1b	2d	10:1:0:0	66% (>20:1 dr)
5	1c	2e	>20:1	65% (>20:1 dr)d
6	1d	2f	11:1e	70% (>20:1 dr)f
7	1d	2g	12:1e	69% (>20:1 dr)f

^aConditions: amine (1.0 equiv), aryl chloride (1.1–1.4 equiv), NaO^tBu (1.2 equiv), Pd₂(dba)₃ (1 mol %), PCy₂Ph (4 mol %), toluene (0.25 M), 110 °C.

^bDetermined by GC and GC/MS analysis. The minor regioisomers formed are analogous to 3–5 shown in eq 1.

^cIsolated yield (average of two or more experiments).

^dPCy₃•HBF₄ was used in place of PCy₂Ph.

^eThe minor regioisomer was arylated at C4 rather than C5.

^fP(^tBu)₂Me•HBF₄ was used in place of PCy₂Ph.

The mechanism of the carboamination reactions involves the syn-aminopalladation of intermediate I, followed by C–C bond-forming reductive elimination from intermediate II to afford the desired products (Scheme 1).^1,2 Diarylamine side products (III) result from competing C–N bond forming reductive elimination of intermediate I.^12,13 Undesired regioisomers 3–5 are generated through β-hydride elimination of II, followed by a series of hydridopalladation/β-hydride elimination steps.^1,2 In light of this mechanism, the difficulties we encountered during our studies on carboamination reactions between aryl chlorides and γ-(N-arylamino)alkenes can be ascribed to two factors: (a) use of electron-rich ligands slows reductive elimination from II, leading to increased amounts of regioisomers; and (b) use of bulky, electron-rich ligands that facilitate C–C bond forming reductive elimination leads to competing N-arylation via C–N bond-forming reductive elimination from I.

SCHEME 1.

Mechanism and Side Reactions

This mechanistic analysis suggests that transformations of the analogous N-Boc-protected substrates may be less problematic. The electron-withdrawing Boc-group is known to slow the rate of C–N bond-forming reductive elimination that leads to N-arylation.^1b,12 Thus, bulky electron-rich ligands could be used to facilitate the C–C bond-forming reductive elimination from intermediates analogous to II with less concern about competing N-arylation. In addition, the electron-withdrawing Boc-group also disfavors β–hydride elimination pathways that provide regioisomers,^1b which should further aid in the selective formation of a single product.

We have recently illustrated that the electron-rich ligand S-Phos^14,15 provides excellent results in Pd-catalyzed carboetherification reactions between unsaturated alcohols and aryl bromides,¹⁶ and this ligand appeared to be a good candidate for use in alkene difunctionalization reactions between aryl chlorides and substrates containing relatively non-nucleophilic heteroatoms. As such, we examined the Pd-catalyzed coupling of 6a with 4-chlorotoluene and were gratified to find this transformation afforded the desired product 7a in 74% yield (eq 2).

(2)

In order to explore the scope of this method, we examined the coupling of a range of N-Boc-protected γ-aminoalkene derivatives. As shown in Table 2, the transformations are effective with a variety of aryl chlorides, including electron-rich, electron-poor, and ortho-substituted compounds. In addition, satisfactory results were also obtained with the heteroaromatic electrophiles N-benzyl-5-chloroindole, 2-chloropyridine, and 2-chloropyrazine (entries 2, 6, and 8). The synthesis of cis-2,5-disubstituted products was achieved with excellent stereocontrol (entries 12–13), and good to excellent selectivity was obtained in the synthesis of trans-2,3-disubstituted products. In all cases the products were generated with complete regioselectivity.¹⁷ Although substitution at the allylic position of the γ-aminoalkene derivative was tolerated (entries 9–11), efforts to employ substrates bearing internal alkenes were unsuccessful due to competing substrate decomposition.¹⁷

TABLE 2.

Carboamination of γ-(N-Boc)Aminoalkenes with Aryl Chlorides^a

entry	amine	product	yieldb
1	6a	7b	74%
2	6a	7c	66%
3	6a	7d	65%
4	6b	7e	73%
5	6b	7f	81%
6	6b	7g	72%
7	6c	7h	63%
8	6d	7i	56%
9	6e	7j	61% (4:1 dr)
10	6f	7k	64% (> 20:1 dr)
11	6f	7l	63% (> 20:1 dr)
12	6g	7m	71% (> 20:1 dr)
13	6g	7n	69% (> 20:1 dr)

^aConditions: amine (1 equiv), aryl chloride (1.2 equiv), NaO^tBu (1.2 equiv), Pd(OAc)₂ (2 mol %), S-Phos (4 mol %), toluene (0.25 M), 90 °C.

^bIsolated yield (average of two or more experiments).

Following our success with N-Boc-aminopropyl alkenes, we proceeded to examine the utility of the Pd/S-Phos catalyst in carboamination and carboetherification reactions of aryl chlorides that generate other heterocycles. As shown in Table 3, the conversion of urea 8, hydroxylamine 9, and hydrazine 10 to the corresponding imidazolidin-2-one 14, isoxazolidine 15, and pyrazolidine 16 proceeded smoothly. The heterocyclic products were obtained in good chemical yield, and 15 was formed as a single diastereomer. The coupling of tertiary alcohol 11 with 1-chloronaphthalene afforded tetrahydrofuran 17 in 89% yield, although a 13:1 mixture of regioisomers was generated. However, attempts to effect a similar transformation between secondary alcohol 12 and 4-chloroanisole failed to yield the desired tetrahydrofuran product.¹⁸ Instead, oxidation of the alcohol was observed, which suggests that alkene oxypalladation from an intermediate analogous to I is relatively slow with S-Phos as ligand. As a result, β-hydride elimination from this intermediate is the predominant reaction pathway with substrate 12. The conversion of amine 13 to morpholine 19 was also unsuccessful due to competing N-arylation of the substrate.^18,19

TABLE 3.

Synthesis of Other Heterocycles Using Aryl Chlorides as Electrophiles^a

entry	substrate	product	yieldb
1	8	14	77%
2	9	15	81% (20:1 dr)
3	10	16	73%
4	11	17	89%c
5	12	Not observed 18	0%
6	13	19 Not observed	0%

^aConditions: substrate (1 equiv), aryl chloride (1.2 equiv), NaO^tBu (1.2 equiv), Pd(OAc)₂ (2 mol %), S-Phos (4 mol %), toluene (0.25 M), 90 °C or 110 °C.

^bIsolated yield (average of two or more experiments).

^cThis material was obtained as a 13:1 mixture of regioisomers.

In conclusion, we have developed conditions that allow use of inexpensive and readily available aryl chloride electrophiles in many Pd-catalyzed carboamination and carboetherification reactions. These studies significantly expand the scope and utility of this method for heterocycle synthesis and also illustrate several remaining challenges for catalyst development in the field.

Experimental Section

Representative Procedure for Pd-Catalyzed Carboamination Reactions of Aryl Chlorides

(±)-tert-Butyl 2-(4-methylbenzyl)pyrrolidine-1-carboxylate (7a)

A Schlenk tube was evacuated, flame-dried, and backfilled with nitrogen. The tube was charged with Pd(OAc)₂ (2.3 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos, 8.2 mg, 0.02 mmol), and NaO^tBu (57.7 mg, 0.60 mmol). The tube was evacuated and backfilled with nitrogen three times. A solution of tert-butyl pent-4-en-1-ylcarbamate (93 mg, 0.50 mmol) and 4-chlorotoluene (71 μL, 0.60 mmol) in toluene (2 mL) was added to the Schlenk tube via syringe. The mixture was heated in a 90 °C oil bath with stirring until the starting material had been consumed as judged by GC analysis (7 h). The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH₄Cl (2 mL), and diluted with EtOAc (2 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The organic layers were concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel to afford 95 mg (69%) of the title compound as a pale yellow oil. ¹H NMR (400 MHz, C₆D₅CD₃, 100 °C) δ 7.03–6.89 (m, 4 H), 4.03–3.91 (m, 1 H), 3.33–3.23 (m, 1 H), 3.20–3.01 (m, 2 H), 2.51 (dd, J = 8.9, 13.0 Hz, 1 H), 2.13 (s, 3 H), 1.55–1.28 (m, 13 H); ¹³C NMR (100 MHz, C₆D₅CD₃, 100 °C) δ 154.6, 137.1, 135.9, 130.0, 129.6, 78.9, 59.5, 59.4, 47.2, 30.3, 29.1, 23.7, 21.2; IR (film) 1693, 1394, 1172 cm⁻¹; MS (ESI): 298.1779 (298.1783 calcd for C₁₇H₂₅NO₂, M + Na⁺).