Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl Chlorides

Abstract

A new family of stereoconvergent cross-couplings of unactivated secondary alkyl electrophiles has been developed, specifically, arylamine-directed alkyl–alkyl Suzuki reactions. This represents the first such investigation to be focused on the use of alkyl chlorides as substrates. Structure-enantioselectivity studies are consistent with the nitrogen, not the aromatic ring, serving as the primary site of coordination of the arylamine to the catalyst. The rate law for this asymmetric cross-coupling is compatible with transmetalation being the turnover-limiting step of the catalytic cycle.

Alkyl–alkyl couplings are among the most challenging of cross-coupling processes, due in part to the potential for intermediates in the catalytic cycle to undergo β-hydride elimination and other undesired reactions.^1,2 The development of highly versatile methods will likely have a substantial impact on organic synthesis,³ particularly if carbon–carbon bond formation can be accomplished enantioselectively. We have recently begun to pursue this objective with both activated and unactivated secondary alkyl electrophiles.^{4,5, 6} Asymmetric cross-couplings of unactivated substrates have proved to be especially difficult, and to date only two families of halides have undergone coupling in good ee (homobenzylic bromides^5a and acylated bromohydrins (and one chlorohydrin)^5b). In each instance, a functional group proximal to the electrophilic site (an aryl substituent or a carbonyl oxygen) is likely interacting with the chiral catalyst in the stereochemistry-determining step of the reaction.⁷

Because a wide array of molecules possess nitrogen-containing functional groups, including bioactive compounds such as alkaloids,⁸ we sought the development of an amine-directed method for the asymmetric alkyl–alkyl cross-coupling of unactivated electrophiles.⁹ In this report, we describe the achievement of this objective, specifically, stereoconvergent Suzuki reactions¹⁰ of racemic secondary alkyl chlorides that bear proximal arylamines (eq 1).

(1)

The potential of β-halo trialkylamines to cyclize (e.g., nitrogen mustards¹¹) led us to focus on arylamines as the directing group¹² and chlorides as the leaving group for our desired asymmetric alkyl–alkyl Suzuki reaction. We recognized that attenuating the nucleophilicity of the amine toward the halide might also diminish the likelihood that the amine would serve as a directing group and that only a single example of an enantioselective cross-coupling of an unactivated secondary alkyl chloride had been described.^5b

When we applied the conditions that we had developed earlier for enantioselective Suzuki reactions of homobenzylic bromides^5a to the cross-coupling of a secondary chloride bearing a pendant arylamine, we obtained a promising lead (eq 2; 70% ee, 58% yield). Optimization of the reaction parameters, primarily through the use of C₂-symmetric 1,2-diamine (1),¹³ provided a method that furnishes the desired alkyl–alkyl coupling product with improved enantioselectivity and yield (Table 1, entry 1).

(2)

Table 1.

Stereoconvergent amine-directed alkyl–alkyl Suzuki reactions of unactivated secondary alkyl chlorides (for the reaction conditions, see eq 1).^a

entry	electrophile	R2	ee (%)	yield (%)b
1		n-Hex	88	84
2c			96	52
3			82	72
4			85	68
5			87	76
6			84	78
7		(CH2)3OTBS	91	63
8			94	86
9			92	70
10			71	82
11			83	70
12			92	57

^aAll data are the average of two experiments.

^bYield of purified product.

^cCatalyst loading: 20% NiBr₂ · diglyme, 24% 1.

Under our optimized conditions, an array of stereoconvergent arylamine-directed alkyl–alkyl Suzuki couplings of unactivated secondary chlorides can be achieved with good enantioselectivity (Table 1).¹⁴ The aromatic ring of the arylamine can be un- (entries 1–3), para- (entries 4–6), meta- (entries 7–9), or ortho-substituted (entry 10). Furthermore, it can be fused to another ring (entries 11 and 12). Suzuki reactions of more hindered electrophiles (e.g., entries 2, 3, and 10) sometimes proceed in moderate ee or yield. Functional groups such as ethers, acetals, and aryl fluorides are compatible with the cross-coupling conditions.¹⁵ Although this method was developed for asymmetric Suzuki couplings of unactivated secondary alkyl chlorides, we have determined that it can be applied without modification to the cross-coupling of an alkyl bromide in good ee and yield (eq 3).

(3)

The spatial relationship between the arylamine and the chloride is important for obtaining good enantioselectivity. Thus, if an additional methylene unit is introduced between the arylamine and the chloride (3), then the cross-coupling product is generated with essentially no ee (<5%). Furthermore, a secondary alkyl chloride that bears a conformationally constrained arylamine (4) couples with only modest enantioselectivity. ¹⁶

We hypothesize that the effective asymmetric induction in the Suzuki cross-couplings illustrated in Table 1 arises from complexation of the arylamine to the chiral nickel catalyst in the stereochemistry-determining step of the catalytic cycle. In order to gain insight into whether this interaction is primarily through the aromatic ring^5a or through the nitrogen¹² of the arylamine, we examined enantioselective Suzuki reactions of arylamines 5 and 6. We determined that these electrophiles undergo cross-coupling with very modest ee (cf. 7), comparable to a substrate that lacks an amino substituent altogether (8).¹⁷ Collectively, these data are consistent with our new Suzuki couplings being nitrogen-directed processes. They therefore complement the only two previous examples of asymmetric cross-couplings of unactivated alkyl electrophiles, which are directed by carbon- (aromatic ring)^5a and oxygen-based (carbonyl)^5b functional groups.

To date, the rate law has not been determined for any enantioselective cross-coupling of an unactivated secondary alkyl halide. For the Suzuki reaction of an arylamine-containing secondary chloride (entry 1 of Table 1), we have established that the rate law is first order in the catalyst and in the organoborane, but zeroth order in the electrophile,¹⁸ which is consistent with a catalytic cycle in which transmetalation is the turnover-limiting step (e.g., Scheme 1¹⁹). In a competition experiment, the catalyst cross-couples an alkyl bromide in preference to a chloride with very high selectivity (eq 4), indicating that, if complexation of the amine to nickel precedes oxidative addition, the complexation is likely reversible vis-à-vis oxidative addition.²⁰ The data illustrated in eq 5 are further consistent with the suggestion that the arylamine does not play a dominant role in determining relative reactivity in these Suzuki couplings of alkyl halides.

(4)

(5)

Scheme 1.

Outline of a Possible Pathway for a Nickel-Catalyzed Cross-Coupling of a Simple Unactivated Alkyl Electrophile.

In summary, a new family of stereoconvergent cross-couplings of unactivated secondary alkyl electrophiles has been developed. These nitrogen-directed enantioselective Suzuki reactions represent the third example of such processes, complementing previous reports of couplings directed by carbon- (arenes) and oxygen-based functional groups, as well as the first investigation focused on the use of unactivated alkyl chlorides as substrates. Structure-enantioselectivity studies indicate that the likely primary site of coordination of the arylamine to the catalyst is the nitrogen, not the aromatic ring. The rate law for an asymmetric cross-coupling of an unactivated alkyl electrophile has been determined for the first time, and the data are consistent with transmetalation being the turnover-limiting step of the catalytic cycle. Additional catalyst-development and mechanistic investigations of enantioselective alkyl–alkyl cross-couplings are underway.