Intermolecular Hydroamination of 1,3-Dienes to Generate Homoallylic Amines

Abstract

We report a Rh-catalyzed hydroamination of 1,3-dienes to generate homoallylic amines. Our work showcases the first case of anti-Markovnikov selectivity in the intermolecular coupling of amines and 1,3-dienes. By tuning the ligand properties and Brensted acid additive, we find that a combination of rac-BINAP and mandelic acid is critical for achieving anti-Markovni- kov selectivity.

Graphical Abstract:

Coined in the 19^th century, the concept of Markovnikov selectivity¹ remains relevant today in classifying and developing regiose-lective transformations of olefins, including hydroamination.² While hydroamination of alkenes typically furnishes the Markov-nikov product,³ there have been breakthroughs in reversing the re-gioselectivity to obtain the anti-Markovnikov isomer.⁴ However, the intermolecular hydroamination of 1,3-dienes⁵ has been limited to producing allylic amines through 1,2-addition or 1,4-addition, presumably due to the intermediacy of a stabilized π-allyl-metal (Figure 1A, top).⁶ Homoallylic amines are valuable synthetic building blocks that are typically generated by coupling imines to organ-ometallic reagents (Figure 1B).⁷ As a complement to using stoichiometric organometallics, we aimed to use simple dienes by developing a catalytic and regioselective hydroamination (Figure 1A, bottom). Herein, we disclose the first intermolecular hydroamination of 1,3-dienes to proceed with anti-Markovnikov selectivity.^8,9 Our Rh-catalyst transforms conjugated dienes into homoallylic amines with high regiocontrol and atom economy.¹⁰

Figure 1.

Inspiration for anti-Markovnikov hydroamination of 1,3-dienes for synthesis of homoallylic amines

Our laboratory recently rendered the hydroamination of 1,3-dienes enantio- and regioselective. In this previous study, we generated allylic amines by using a [Rh(COD)OMe]2/JoSPOphos catalyst and triphenylacetic acid additive. ^6m,11 In this communication, we focused on achieving a 1,2-anti-Markovnikov addition for the synthesis of homoallylic amines.

To begin this study, we chose indoline and isoprene as coupling partners. Isoprene, a common building block for polymers,¹² derives from thermal cracking of naphtha/oil and biosynthesis by many organisms.¹³ We aimed to transform this feedstock into the corresponding homoallylic amine by studying the effects of biden-tate phosphine ligand and acid combinations. Table 1 summarizes our most relevant findings. Due to its use in alkyne hydroamination, phthalic acid was chosen as the initial acid for screening different bisphosphine ligands.¹⁴ When using dppm, a small bite angle ligand,¹⁵ we observe 1,2-Markovnikov addition product A as the major product (entry 1). Increasing the bite angle of the ligand decreases the reactivity and regioselectivity, leading to mixtures of A, B, C, and D (entries 2–4). Switching to a ferrocene-backbone ligand, dppf, we observed homoallylic amine C as the major product in 33% NMR yield (entry 5). When using rac-BINAP as ligand, the yield and regioselectivity of homoallylic amine C increases to 74% and 19:1 rr by ¹H NMR analysis (entry 6). Rh(COD)₂SbF₆ and [Rh(COD)OMe]₂ pre-catalyst give similar results with [Rh(COD)Cl]₂ (entry 7 and 8). In accordance with Hartwig’s observations, the use of palladium as the catalyst yields 1,4-addition product D as the major isomer (entry 9).^6b These results showcase an intermolecular hydroamination of isoprene where regioselectiv-ity is controlled by catalyst choice.¹⁶

Table 1.

Catalyst and Acid Effects on Regioselective Hydroamination of Isoprene^a

entry	pre-catalyst	ligand	acidb	yield (%)c	rr(A:B:C:D)d
1	[Rh(COD)CI]2	dppm	A2	71	15:<1:<1:1
2	[Rh(COD)CI]2	dppe	A2	20	2:2:1:4
3	[Rh(COD)CI]2	dppp	A2	14	2:1:1:3
4	[Rh(COD)CI]2	dppb	A2	<10	ND
5	[Rh(COD)CI]2	dppf	A2	33	<1:<1:5:1
6	[Rh(COO)CI]2	rac-BINAP	A2	74	<1:<1:19:1
7	Rh(COD)2SbF6	rac-BINAP	A2	71	1:1:>20:1
8	[Rh(COD)OMe]2	rac-BINAP	A2	69	1:1:>20:1
9	Pd(PPh3)4	none	A2	84	1:1:1:>20
10	[Rh(COD)Cl]2	rac-BINAP	none	NR	ND
11	[Rh(COD)Cl]2	rac-BINAP	A1	17	1:1:>20:1
12	[Rh(COD)CI]2	rac-BINAP	A3	81	1:1:>20:1
13	[Rh(COD)Cl]2	rac-BINAP	A4	79	<1:<1:13:1

^aReaction conditions: indoline (0.1 mmol), isoprene (0.5 mmol), [M] (5 mol%), ligand (5 mol%), acid (50 mol%), DCE (0.2 mL), 24 h.

^bpK_a in DCE and pK_a in water in parenthesis.

^c1H NMR yields of major isomer using 1,3,5-trimethoxybenzene as the internal standard.

^dRegioselectivity determined by ¹H NMR analysis of reaction mixture.

With the optimal ligand in hand, we investigated the effect of the acid additive. No product was observed in the absence of acid (entry 10). Diphenyl phosphate was successfully used to form C-C bonds in the hydrofunctionalization of alkynes.¹⁷ Therefore acids with similar pK_a to diphenyl phosphate and phthalic acid were examined. As pK_a values are solvent dependent,¹⁸ the pK_a of the acids in DCE were determined using UV-vis spectroscopy.^19,20a In general, higher yields are obtained with stronger acids (entries 11–13); mandelic acid (A3) gives 81 % yield and the best regioselectivity.^20b

With this protocol, we examined the coupling of various 1,3-dienes 1 with indoline 2a (Table 2). In general, the hydroamination proceeds with 18:1 to >20:1 regioselectivities and 52–83% yields for various 2-aryl-1,3-butadienes (3aa-3ia). Substrates with an electron-donating group on the aryl ring show slightly higher reactivity than those with an electron-withdrawing group. When the aryl ring is ortho-substituted, the yield is lowered to 60% (3ba). In the case where the aryl ring contains an electron-withdrawing tri-fluoromethyl group (3ha), the regioselectivity is 18:1 rr. The transformation also proceeds with alkyl substituted dienes. 2-Cyclo- hexyl-1,3-butadiene undergoes hydroamination with 73% yield (3ja). Myrcene, a readily available monoterpene, furnishes the homoallylic amine (3ka) in 78% yield and >20:1 rr. The hydroamination proceeds efficiently for substrates bearing ether and amide groups and provides the corresponding products in 74% yield (3la) and 87% yield (3ma) with >20:1 regioselectivities.

Table 2.

Anti-Markovnikov Hydroamination of Various 1,3-Dienes^a

^aReaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), [Rh(COD)Cl]₂ (2.5 mol%), rac-BINAP (5 mol%), A3 (50 mol%), DCE (0.4 mL), 80 °C, 15 h. Isolated yields. Regioselectivity ratio (rr) is the ratio of 3 to 4, which is determined by ¹H NMR analysis of reaction mixture.

^bUsing Rh(COD)₂SbF₆ (5.0 mol%) instead of [Rh(COD)Cl]₂.

Transformations of 1,2-disubstituted dienes also proceed well. Hydroamination of the fused ring substrates provide the homoallylic amines in 70% and 73% yields (3na and 3oa) with >20:1 regioselectivities. In addition, we obtain the homoallylic amines 3pa and 3qa from acyclic 1,2-disubstituted dienes in 53% and 73% yields with >20:1 regioselectivities by using Rh(COD)₂SbF₆ as precatalyst. When using the mixture of (Z)- and (E)-β-ocimene isomers, we observe that only the (E)-β-ocimene is transformed to give homoallylic amine (3ra) in 51% yield (7 equivalents diene used); (Z)-β-ocimene is unreacted (eq 1).

(1)

Next, we examined the hydroamination of 2-phenyl-1,3-butadi-ene 1a with different amines 2 (Table 3). Indolines provide the hydroamination products (3ab-3ai) with 62–89% yield and 8:1 to >20:1 anti-Markovnikov selectivity. Indolines with electron-donating groups show higher regioselectivities than those with electron-withdrawing groups. The hydroamination of sterically hindered 2-methyl-indoline gives homoallylic amine (3ab) in 62% yield and 10:1 regioselectivity. Anilines bearing either electron-donating or electron-withdrawing groups both undergo hydroamination with 40–63% yields (3aj-3al). Hydroamination of the acyclic amine N-methylaniline yields the product 3am in 47% yield with 3:1 regioselectivity. 1,2,3,4-tetrahydroquinoline can be used for hydroamination with 45% yield and 4:1 selectivity for the anfi-Mar-kovnikov product (3an). Under our hydroamination conditions, morpholine is an effective amine partner and provides the homoal-lylic amine 3ao in 79% yield with >20:1 rr. Identifying a catalyst that can enable coupling with more challenging amines (such as primary alkyl amines and acyclic dialkyl amines) is still an ongoing challenge that needs to be solved.^20c

Table 3.

Anti-Markovnikov Hydroamination Using Various Amines^a

^aReaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), [Rh(COD)Cl]₂ (2.5 mol%), rac-BINAP (5 mol%), A3 (50 mol%), DCE (0.4 mL), 80 °C, 15 h. Isolated yields. Regioselectivity ratio (rr) is the ratio of 3 to 4, which is determined by ¹H NMR analysis of reaction mixture.

^bUsing Rh(COD)₂SbF₆ (5 mol%) instead of [Rh(COD)Cl]₂.

We reason that the anti-Markovnikov selectivity results from a synergy between the substrate and catalyst structure. To probe the mechanism, we studied the kinetic profile for coupling 1,3-diene 1a and indoline 2a. When using [Rh(COD)Cl]₂ pre-catalyst, we observed a half order dependence on rhodium pre-catalyst, which suggests that breaking up the Rh-dimer is a slow step under our optimal conditions. Because this catalyst resting state is off-cycle, we switched to using monomeric Rh(COD)₂SbF₆ pre-catalyst to probe the mechanism further.

On the basis of both literature precedence and the following mechanistic studies, we propose the mechanism depicted in Figure 2. Rhodium pre-catalyst reacts with BINAP ligand to form the active catalyst I, which is the resting state as determined by ¹H and ³¹P NMR. The amine and acid undergo proton transfer to form ammonium-ion 5 and carboxylate anion (X^-). Using HypNMR,²¹ the equilibrium constant for this process was measured to be K_eq=10.5.¹⁸ Ligand exchange of COD with carboxylate anion results in complex II. In the turnover-limiting step, the ammoniumion 5 oxidatively adds to the Rh(I)-complex II to generate Rh(III)-hydride III. In support of the proposed turnover-limiting step, we observe a first order dependence on the Rh-catalyst and a first order dependence on the ammonium-ion 5. Moreover, we see a zeroth order dependence on the diene, which means its involvement occurs after the turnover limiting step.^20d

Figure 2.

Proposed mechanism for anti-Markovnikov selectivity

The 1,3-diene can exchange with the amine to form η⁴-Rh-hy-dride intermediate IV, which is analogous to a Co-hydride intermediate implicated in the hydrovinylation of 1,3-dienes.²² Because (E)-β-ocimene (and not the Z isomer) undergoes hydroamination (eq 1), we propose that s-cis conformation of the 1,3-diene is necessary for coordination to the catalyst.²³ Due to the steric clash between the R substituent and the catalyst, the hydride insertion is disfavored. In line with this idea, we observe only Markovnikov addition using substrates bearing hydrogen at the 2-position, regardless of the catalyst used (eq 2). When the hydroamination was performed with deuterated indoline d-2a, the deuterium is incorporated into the 3-position of product 3, not the recovered diene (eq 3). This isotopic labeling result helps us rule out mechanisms that involve reversible diene insertion into the Rh-hydride.

(2)

(3)

In accordance with anti-Markovnikov hydroamination of al-kenes using directing groups,²⁴ we imagine that the amine attacks the activated 1,3-diene from the less substituted position to generate Rh-π-allyl intermediate V. Reductive elimination of V at the 3-position gives homoallylic amine 3. This step is related to Rh-catalyzed alkyne or allene hydrofunctionalizations, which tend to favor the branched product after reductive elimination.^14,17,25 We reason that electron rich amines improve regioselectivity by promoting reductive elimination at the 3-position rather than 1-position.

Hydroamination of conjugated dienes represents an attractive way to transform dienes into amine building blocks, but achieving regioselective hydroamination is challenging given the extended π-system. To date, there are few reports of functionalizing the terminal carbon of 1,3-dienes through 1,2-hydrofunctionalization.^5b Modification of the substrate structure has been used to achieve challenging transformations, such as the regiodivergent arylboration of 1,3-dienes.²⁶ Through key interactions between the catalyst and the 2-substitution of the substrate, we were able to achieve a 1,2-anti-Markonvikov hydroamination of dienes to access homoal-lylic amines. Future studies are warranted to better understand the origin of this regiocontrol. Insights from this communication will guide the invention of new diene hydrofunctionalizations.