Proton-Catalyzed Hydroamination and Hydroarylation Reactions of Anilines and Alkenes

Acid-catalyzed additions of amines to alkenes are generally unsuccessful due to the buffering effect of the amine substrate.¹ Friedel—Crafts alkylations of arylamines are hindered by coordination of the amine to the Lewis acid catalyst.² A recent communication by Hartwig et al. reports that several common Brønsted acids catalyze the intramolecular hydroamination of tosyl-protected amino olefins.³ Beller and co-workers have reported that alkylations of electron-rich anilines with styrene are promoted with HBF₄·Et₂O.^2b,4 Herein we report the first homogeneous⁵ acid catalyst that promotes both hydroamination and hydroarylation reactions of anilines and alkenes, including simple cyclic alkenes and dienes. These transformations are air- and moisture-tolerant and can be controlled to favor either N—H or Ar—H addition products based on reaction conditions and aniline substitution pattern. The key to the activity of this system is that the acid counteranion has a dramatic effect on reaction efficiency.

In the course of our studies on metal-catalyzed hydroamination reactions,⁶ we found that Ph₃CB(C₆F₅)₄ (1) catalyzes the reaction of norbornene with aniline. Both hydroamination (2) and ortho-hydroarylation (3) products are formed using 5 mol % of 1 (eq 1).⁷

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To determine the role of the trityl cation, the above reaction was run in the presence of several trapping reagents. The addition of radical traps, such as 2,6-di-tert-butylphenol and 1,4-cyclohexadiene, did not affect the outcome of the reaction. In contrast, the addition of one catalytic equivalent of NEt₃ completely inhibited both hydroamination and hydroarylation, suggesting that the reaction is acid-catalyzed.

We anticipated that the strongest acid in the reaction solution would be an anilinium salt.⁸ Accordingly, PhNH₃B(C₆F₅)₄·Et₂O(4) was synthesized and shown to be as competent as 1, affording an identical product distribution (Table 1, entry 2). As shown in Table 1, several other anilinium salts and strong acids were screened as catalysts for the addition of aniline to norbornene. It was assumed that the acids in entries 3, 4, and 6 would rapidly react with aniline in the reaction mixture to form the corresponding anilinium salts. As expected, HOTf provided a yield similar to that observed with anilinium triflate. Analogous reactivity was anticipated for H(Et₂O)_2.5B(C₆F₅)₄ (5) and 4; however, a significant decrease in reactivity was observed for 5. This discrepancy may be caused by the additional 1.5 equiv of ether associated with 5 and coincides with a lack of reactivity of these catalysts in donor solvents.⁹ The trend in reactivity is an increase in catalytic efficiency with decreasing anion coordination ability (BPh₄^- < OTf^- < NTf₂^- < B(C₆F₅)₄^-).¹⁰ This suggests that the effective acidity of the anilinium salt in benzene increases with decreasing anion coordination ability and thereby facilitates protonation of the alkene.¹¹ It has previously been shown that TFA does not catalyze the hydroamination of styrene with aniline. These results are consistent with our observations assuming that trifluoroacetate is a more strongly coordinating anion than OTf^-.^1b

Table 1.

Acid Catalysts for the Hydroamination and Hydroarylation of Norbornene

entry	catalyst	%yielda	2:3a
1	Ph3CB(C6F5)4 (1)	58	1:1
2	PhNH3B(C6F5)4·Et2O(4)	60	1:1
3	H(Et2O)2.5B(C6F5)4 (5)	33	1:1
4	HNTf2	35	1:1
5	PhNH3OTf	19	1:1
6	HOTf	13	1:1
7	PhNH3BPh4	0

^aCombined yield of 2 and 3. Yields and product ratios were determined by GC.

After determining that 4 was the optimal catalyst for the hydroamination/hydroarylation reaction, a variety of substituted anilines were evaluated to probe steric and electronic effects on product distribution. As shown in Table 2, the addition reaction tolerates substitution on the nitrogen as well as the aromatic ring of the aniline. The ortho-addition is favored for the hydroarylation products unless the ortho-positions of the aniline substrate are blocked. Electron-withdrawing substituents on the aniline increase the overall yield of the reaction and favor formation of the hydroamination product.^7b Surprisingly, using aniline as a solvent does not affect the product ratio but decreases the overall yield of the transformation.

Table 2.

Effect of Aniline Substitution on Hydroamination and Hydroarylation Product Ratios

entry	X	% yielda	6:7
1	H	84	1:1
2	4-Cl	56 (55b)	only 6
3	4-OMe	34	1:2
4	2,6-Me2	50c	2:3d,e
5	N-Me	55b	1:4d
6	3,5-CF3	80	only 6

^aCombined yield of 6 and 7.

^bWith 5 mol % of 3, 72 h.

^cGC yield.

^dGC ratio of isomers.

^e7 is the p-hydroarylation product.

Compound 4 also catalyzes the hydroamination and hydroarylation reactions of substituted styrenes (Table 3).¹² Notably, these transformations require lower temperatures and shorter reaction times than the norbornene reactions and are facilitated by electron-donating substituents on the styrene substrate (OMe vs Cl) and electron-withdrawing substituents on the aniline (OMe vs Cl or CF₃). The para-substituted hydroarylation products are favored for these styrene substrates unless the para-position is blocked. These observations are consistent with the intermediacy of a stabilized carbocation and suggest that these transformations proceed along a reaction pathway similar to that of acid-catalyzed hydration, where either the heteroatom or the aromatic ring can act as the nucleophile (Scheme 1).¹³ The difference in the ortho—para selectivity between norbornene and styrene hydroarylation products may be caused by differences in the stabilities of protonated intermediates.¹³

Table 3.

Hydroamination and Hydroarylation Reactions of Vinyl Arenes (Unless noted, yields are % yields determined by ¹H NMR)

entry	R	X	T (°C)	t (h)	yield	8:9:10
1a	OMe	H	45	1	34	87:3:10
2a	OMe	H	45	4	83	57:8:35
3	OMe	H	45	8	72b	25:10:65
4	OMe	H	75	4	93	4:22:74
5	OMe	4-OMe	45	51	82b	90:10:0
6	OMe	4-OMe	75	24	85b	20:80:0
7a	Cl	4-Cl	105	1	89	50:50:0
8a	Cl	4-Cl	105	4	99	25:75:0
9a	Cl	3,5-CF3	45	3	52	100:0:0
10	Cl	3,5-CF3	45	24	63b	100:0:0
11	OMe	3-Cl	25	5	82b	40:60:0
12	OMe	3-Cl	45	12	71b	0:100:0

^aTime points from single NMR tube experiments.

^bCombined % yields of isolated products.

Scheme 1.

Proposed Mechanism

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The most notable trend in Table 3 is that N—H addition dominates at short reaction times, and Ar—H addition is the major product at longer reaction times and higher temperatures (Table 3, entries 1–4). Specifically, the yield of the hydroarylation product increases at the expense of the hydroamination product as the reaction proceeds. A control experiment demonstrated that isolated 11 undergoes a Hofmann—Martius rearrangement¹⁴ in the presence of 5 mol % of 4 to afford 12 (eq 5).^4,12 This observed conversion of hydroamination to hydroarylation products allows for preferential generation of either the kinetic or the thermodynamic product based on reaction time and temperature.

Cyclic alkenes and dienes undergo analogous addition reactions (Table 4). These substrates give primarily hydroarylation products when treated with aniline; however, electron-poor anilines provide hydroamination products. Although these reactions are unoptimized, they illustrate the potential scope of this proton-catalyzed transformation.

Table 4.

Hydroamination and Hydroarylation Reactions of Other Unsaturated Substrates

entry	alkene	X	T (°C)	% yield	13:14
1a	cyclopentene	H	135	39	0:1
2a	cis-cyclooctene	H	135	45c	1:3
3b	cyclohexadiene	H	105	56	0:1
4b	cyclohexadiene	3,5-CF3	75	20	1:0

^aAlkene:aniline (1:1), chlorobenzene, 7 days.

^bAlkene:aniline (1:2), benzene, 12 h.

^cNMR yield of 13 and 14.

In conclusion, PhNH₃B(C₆F₅)₄ has been identified as a new catalyst for the hydroamination and hydroarylation of several activated alkenes with anilines. We are currently investigating the details of the mechanism of this transformation and how to further control the selectivity for N—H and Ar—H additions. The control experiment used to identify this catalyst should also serve as a reminder that acid catalysis exists as a possibility in many metal-catalyzed systems and should always be investigated.