Copper–Catalyzed Propargylation of Nitroalkanes

Abstract

Using a commercially available, inexpensive, and abundant copper catalyst system, an efficient α–functionalization of nitroalkanes with propargyl bromides is now established. This mild and robust method is highly functional group tolerant and provides straightforward access to complex secondary and tertiary homopropargylic nitroalkanes. Moreover, the utility of these α-propargylated nitroalkanes is demonstrated through downstream functionalization to biologically relevant, five-membered N-heterocycles such as pyrroles and 2-pyrrolines.

Graphical Abstract

Nitroalkanes are versatile intermediates in organic synthesis. Not only do they serve as precursors to a wide variety of functional groups (including amines, oximes, hydroxylamines, carbonyls, olefins, nitriles, and alkanes) and participate in various C–C bond forming reactions (including Henry and nitro-Mannich reactions, Michael additions, and Pd-catalyzed arylation and allylation),^1,2 they are also valuable precursors to numerous types of heterocycles. The latter includes lactones, lactams, spi-rocyclic acetals, cyclic amines, cyclic nitrones, isoxazolines, and isoxazoles,³ all of which are prevalent motifs in both bioactive compounds and natural products. Homopropargylic nitroalkanes are of particular interest in the formation of heterocycles.⁴ The versatile, and often orthogonal, reactivity of the nitro and the alkynyl functionalities presents many opportunities to forge heterocycles from these intermediates.

Several routes to homopropargylic nitroalkanes have been previously described. Nucleophilic nitration of homopropargyl halides,⁴ Henry reactions of ynones,⁵ and methods based on Michael additions to nitroalkenes or other electrophiles have been reported.⁶ For the latter methods, elegant asymmetric examples have also been established. However, all of these methods require relatively complex starting materials and have limited generality.

A potentially simpler and more general approach to homopropargylic nitroalkanes is the propargylation of nitroalkanes using propargylic electrophiles. However, such methods have not been well developed. No doubt owning to the propensity of nitronate anions to undergo alkylation at oxygen,⁷ S_N2 propargylations are limited to the use of nitroesters.⁸ Importantly, S_N2 propargylation of simple (less stabilized) nitroalkanes remains unknown (Fig 1a).⁹ Further, while propargylations of nitroalkanes via S_RN1 or S_N1 mechanisms are known,^10,11 these pathways severely limit the useful electrophiles to those with significant electronic bias that are capable of supporting either electron transfer or the formation of cationic intermediates (respectively, Fig 1b).¹² Thus, the development of a general method for nitroalkane propargylation remains an important goal.

Figure 1.

Propargylation of Nitroalkanes

Recently, we have shown that Cu catalysis can overcome the inherent preference of nitroalkanes to undergo O-alkylation when treated with alkyl electrophiles bearing radical-stabilizing groups.¹³ To date, we have reported alkylation reactions with benzylic bromides, as well as α-bromo-carbonyl and α-bromonitrile electrophiles. However, the use of propargylic electrophiles has not been investigated. We hypothesized that alkynes could be exploited as an adjacent stabilizing group and pave a new way to prepare diverse homopropargylic nitroalkanes. Herein, we disclose a novel Cu-catalyzed method for the propargylation of nitroalkanes. The method uses a simple Cu catalyst, which is made in situ from inexpensive and commercially available materials. The method is robust, highly functional group tolerant, and provides straightforward access to complex secondary and tertiary homopropargylic nitroalkanes. Furthermore, to showcase the synthetic utility, we report conditions to form 2,3,5-trisubstituted pyrroles and 2-pyrrolines using the products of these reactions.

Our investigation began by studying the coupling between propargyl bromide 1a (R = SiMe₃) and nitroalkane 2 (Table 1). Control experiments revealed no background reaction and confirmed the need for a catalyst to obtain the desired reaction (entry 1). Our previous reports have employed diketimine 6 as the optimal ligand.¹³ Encouragingly, adding catalytic CuBr and 6 to the model reaction led to detectable levels of desired product 3a. However, the yield was surprisingly low, and the bis-propargylated byproduct 4a was also detected (entry 2). Recently, we reported the use of N,N’-dibenzylcyclohexanediamine ligands in a Ni-catalyzed nitroalkane alkylation.¹⁴ We were pleased to find that with the use of ligand 7 in this copper-catalyzed reaction, a significant improvement in the yield of 3a was observed (entry 3). Attempts to further improve the yield of desired product 3a by tuning the electronic and steric properties of the aromatic groups on the ligand proved unsuccessful (entries 4–5).¹⁵ In contrast, by switching the diamine backbone to the less conformationally restricted ethylenediamine ligand 10, both an increase in the yield of desired product 3a and less of byproduct 4a were observed (entry 6).

Table 1.

Reaction Optimization

Entry	R	mol % CuBr	Ligand [mol %]	Yield [%]a
				3	4	5
1	SiMe3	—	—	0	0	—
2	SiMe3	20	6 [25]	34	6	—
3	SiMe3	20	7 [25]	65	7	—
4	SiMe3	20	8 [25]	60	7	—
5	SiMe3	20	9 [25]	65	8	—
6	SiMe3	20	10 [25]	73	3	—
7b	Me	22	10 [23]	39	1	25
8b	Me	22	11 [23]	53	0	9
9b	Me	22	12 [23]	54	3	4
10c	Me	10	12 [30]	53	7	0

^aDetermined via ¹H NMR against internal standard.

^b1.05 equiv KO^tBu, 70 °C, 4 h.

^c1.15 equiv 1, 1.05 equiv KO^tBu, rt, 4 h.

With these results in hand, we anticipated that ligand 10 would be the optimal ligand for the general transformation. Unfortunately, as we began to investigate its use with a variety of other substrates, a new and unanticipated byproduct emerged. For example, with the simpler propargyl bromide 1b (R = Me) only 39% of desired product 3b was obtained (entry 7), and a major byproduct corresponding to β-allenyl nitroalkane 5b was observed (entry 7). We postulated that the formation of the competing allene product might be due to the smaller steric nature of the substrate. This line of thinking led us to investigate the use of larger ligands as a possible means to gain selectivity for the desired homopropargylic product. Indeed, when the benzyl groups of 10 were replaced with the bulkier (R)-2-phenethyl groups (11), both suppression of the allenic product and increase in the formation of desired homopropargylic product 3b were observed (entry 8). Although promising, ligand 11 is fairly expensive to prepare due to its enantioenriched nature. As it also did not provide significant levels of enantioselectivity in the reaction,¹⁵ we sought a more practical analogue. Fortunately, the use of commercially available, highly inexpensive, and achiral N,N’-diisopropylethylenediamine (12) as ligand proved similarly effective.^16,17 Using this ligand, good yield of 3b with minimal byproduct formation was observed (entry 9). We were further pleased to find that this reaction could be performed at room temperature under reduced CuBr loading, and that by adjusting the ligand to metal ratio, the allene byproduct formation could be suppressed (entry 10).

With these optimal conditions in hand, the substrate scope was evaluated. Encouragingly, many combinations of nitroalkanes and propargyl bromides provided even higher yield of product than was observed with the model system. As shown in Scheme 1, a wide range of both primary (3a-20) and secondary (21–30) nitroalkanes participated in the reaction. Primary (3b-17, 21–28) and secondary (18, 19, 29, 30) propargyl bromides were well tolerated, as well as tertiary propargyl bromides (20) (albeit with somewhat suppressed yield). A wide range of functional groups were also compatible with the reaction; these include aryl groups with varying electronic properties (14, 19, 21, 22, 24), alkyl bromides (30), esters (3a-b, 20), olefins (15,16), amides (23), ketones (24, 25), protected alcohols (13), and amines (18, 19). Heterocycles such as pyrimidine (15), indole (16), and thiophene (28) could also be incorporated without issue. In cases where the yield was limited, the mass balance was largely starting material, along with traces of bis-propargylation. Attempts to increase catalysts loading or reaction time did not improve conversion in these cases. One limitation we noted with respect to functional group compatibility is with the use of nitrile groups (17), which while tolerated, seem to suppress the yield of the reaction (3a vs 17). We hypothesize this is due to competitive binding of the nitrile to the metal center.

Scheme 1.

Synthesis of Secondary and Tertiary Homopropargylic Nitroalkanes

^a20 h. ^b 20 mol % CuBr. ^c 20 mol % CuBr, 20 h.

To showcase the utility of homopropargylic nitroalkanes, the synthesis of nitrogen-containing heterocycles was explored. First we were inspired by Dixon’s nitro-Mannich/Au-catalyzed hydroamination sequence that converts primary homopropargylic nitroalkanes to pyrroles.⁴ Although the one-pot conditions reported by Dixon did not prove applicable to secondary homopropargylic nitroalkanes, we were able to develop a slightly modified two-step procedure. Accordingly, we found that a sequential DMSO/4Å MS promoted nitro-Mannich reaction,¹⁸ followed by a PPh₃AuCl/AgPF₆ catalyzed cyclization reaction resulted in the formation of 2,3,5-trisubstituted pyrroles (Scheme 2). These processes enabled the formation of pyrroles containing ester (33a), protected alcohol (33b), olefin (33c), and indole (33c) in reasonable yields.

Scheme 2.

Pyrroles Synthesis Using Modification of Dixon’s Protocol.

^a4Å MS, DMSO. ^b10 mol % PPh₃AuCl/AgPF₆, PhMe, 110 °C.

In addition to pyrroles, we also envisioned that our tertiary nitroalkane products could be transformed into 2-pyrrolines via a sequential reduction, amine protection, and 5-endo-dig cyclization process. As shown in Scheme 3, both the reduction and benzoyl protection proceeded smoothly under mild conditions. Treatment of the resulting amine product with catalytic PPh₃AuCl/AgOTf resulted in the formation of 2-pyrroline heterocycles in good yields.¹⁹ Notably, aryl groups (35a-b) and heterocycles such as 1,3-benzodioxole and thiophene (35c) were tolerated under these conditions.

Scheme 3.

Preparation of 2-Pyrrolines from Homopropargylic Nitroalkanes

^aZn dust, AcOH. ^bBzCl, Et₃N, DCM. ^c10 mol % PPh₃AuCl/AgOTf, PhMe, 110 °C. ^d Yield over 2-steps.

In conclusion, we have developed a mild and commercially available Cu catalyst system for converting nitroalkanes to homopropargylic nitroalkanes using propargyl bromides. This reaction allows both primary and secondary nitroalkanes to be utilized as starting materials despite the imposing steric limitation surrounding the C–C bond formation. Moreover, this method proved to be highly functional group tolerant, enabling the synthesis of complex homopropargylic nitroalkane products. We have also demonstrated that the nitroalkane products can be converted to valuable, nitrogen-containing heterocycles such as pyrroles and 2-pyrrolines.