Copper-Catalyzed Three-Component Synthesis of Highly Substituted Morpholines

Abstract

Unprotected, highly substituted morpholines were obtained through a copper-catalyzed three-component reaction utilizing amino alcohols, aldehydes, and diazomalonates. The transformation was effective for diversely substituted aldehydes and for a broad range of readily available vicinal amino alcohols, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids. Epimerization of morpholines using light-mediated stereochemical editing was demonstrated, and the unprotected morpholine products were readily elaborated through efficient transformations.

Graphical Abstract

Morpholines are an important class of saturated nitrogen heterocycles that are increasingly being incorporated in drugs and clinical candidates.¹ Morpholines with diverse substitution patterns are present in molecules with a wide range of biological activities, including analgesic, anti-inflammatory, antioxidant, antibiotic, antimicrobial, and anticancer activities. The development of robust synthetic methods to access these compounds has been extensively pursued, but efficient approaches to highly substituted derivatives are not yet well developed.²

Most synthetic routes for the preparation of unprotected, substituted morpholines rely on amino alcohol inputs.^2–5 One important approach relies on vicinal amino alcohols and α-halo acid chlorides as the two reactants, an approach that has been implemented on larger scales (Scheme 1a).³ Bode and co-workers have also developed SnAP and SLAP reagents, in which reactive functionality is appended to the oxygen of the amino alcohol thereby enabling single-step annulations to morpholines utilizing readily available carbonyl compounds (Scheme 1b and 1c).⁴ Although the starting SnAP/SLAP reagents often require multistep syntheses, a variety of the reagents are now commercially available to further enhance the practicality of these methods. We sought to capitalize on the wide commercial availability of both amino alcohols and aldehydes to develop a one-step approach for the synthesis of morpholines. Herein, we report a copper-catalyzed three-component synthesis of unprotected highly substituted morpholines using amino alcohols, aldehydes, and diazomalonates (Scheme 1). We further demonstrate that the unprotected morpholine products can readily be elaborated to useful derivatives through efficient and high yield transformations, including epimerization, nitrogen functionalization, ester reduction, and decarboxylation.

Scheme 1.

Multicomponent Synthesis of Morpholines

We first explored this transformation using Rh₂(OAc)₄, a catalyst commonly used for metallocarbene formation with diazo compounds; however, the yield of the desired morpholine product was low, and with further optimization, we discovered that much more earth abundant Cu(I) catalysts are more effective (Table 1, Table S1–S4 in the Supporting Information).^6,7 Under the optimized conditions, reaction of 2-amino-2-methylpropan-1-ol (1a), p-tolualdehyde (2a), and diethyl 2-diazomalonate (3a) as the limiting reagent in toluene at 90 °C gave morpholine 4a in 70% yield (entry 1). A lower reaction temperature did not affect the yield significantly (entry 2), but a higher reaction temperature resulted in a lower yield (entry 3). When the concentration of the reaction was halved (entry 4) or doubled (entry 5), a slight reduction in the yield of 4a was observed. DCE as the solvent resulted in a lower yield (entry 6), and MeCN proved to be detrimental (entry 7). Other Cu(I) catalysts were also evaluated. No formation of morpholine 4a was observed when CuCl was employed as the catalyst (entry 8). Other commercially available Cu(I) sources such as CuOTf (entry 9) and Cu(MeCN)₄PF₆ (entry 10) provided morpholine 4a, albeit in lower yield, perhaps because these catalysts have lower solubility in toluene than Cu(MeCN)₄B(C₆F₅)₄. An in situ formation of the active catalyst using CuI and AgB(C₆F₅)₄ resulted in a lower yield compared to using the preformed catalyst (entry 11). Lastly, increasing the amount of Cu(I) catalyst did not increase the yield (entry 12).

Table 1.

Optimization of Reaction Conditions^a

Entry	Variation from standard conditions	Yield (%)b
1	None	70
2	80 °C	69
3	100 °C	55
4	0.1 M	59
5	0.4 M	60
6	DCE as solvent	59
7	MeCN as solvent	36
8	CuCl as catalyst	0
9	CuOTf as catalyst	31
10	Cu(MeCN)4PF6 as catalyst	48
11	CuI + AgB(C6F5)4 as catalyst	44
12	20 mol % of Cu(MeCN)4B(C6F5)4	68

^aConditions: 0.2 mmol of 1a, 0.3 mmol of 2a, and 0.1 mmol of 3a.

^bYields determined by ¹H NMR relative to 1,3,5-trimethoxybenzene as a standard.

We next explored the scope for the three-component morpholine synthesis (Scheme 2). Morpholine 4a was obtained with 2-amino-2-methylpropan-1-ol (1a) as the amino alcohol in 65% isolated yield, at both 0.2 and 1 mmol scales. Other amino alcohols with different substitution patterns were evaluated to give the desired morpholine product in yields ranging from 46% to 50% (4b–4d). Notably, amino alcohols derived from chiral amino acids were shown to be effective substrates, providing 4e (from (±)-alaninol) in 70% yield and 4f (from l-valinol) in 47% yield, albeit with only modest diastereoselectivity.

Scheme 2.

Morpholine Synthesis Scope^a

^aConditions: 0.4 mmol of 1, 0.6 mmol of 2, and 0.2 mmol of 3. Isolated yields of pure product after chromatography. ^bReaction performed at 70 °C.

Application of the approach to the preparation of thiomorpholine 4g was not successful, with reaction between 2-aminoethane-1-thiol and 4-tolualdehyde resulting in the thiazolidine adduct as the only product. The synthesis of benzomorpholine 4h also was not successful.

Commercially available aldehydes provided rapid access to morpholines 4 with different substituents. Morpholine 4i was obtained in a moderate 46% yield employing the electron-deficient 4-trifluoromethylbenzaldehyde. More electron-rich aldehydes provided 4j and 4k in comparable yield to when p-tolualdehyde was employed. The reaction gives 4l in 41% yield with an ortho-substituted benzaldehyde, though a lower reaction temperature of 70 °C proved to be optimal. Halogen substituents were next investigated because they provide a useful handle for further synthetic elaboration, with chloro-and bromo-substituted benzaldehydes providing the desired morpholines 4m-4o, respectively, in good yields. Morpholine 4p was also obtained in reasonable yield using 4-fluorobenzaldehyde. Different heterocyclic aldehydes were next evaluated, giving morpholines 4q-4s in yields ranging from 46% to 68%. Finally, alkyl-substituted morpholine 4t was also obtained from isobutyraldehyde, albeit in a much lower yield, perhaps because it is susceptible to competitive enolization. Methyl and tert-butyl diazomalonates were also explored, giving the desired morpholines 4u and 4v in 50% and 59% yields, respectively.

Based on existing literature involving Cu(I) catalysts and diazo compounds,^6,7 we propose the mechanism depicted in Scheme 3 for the three-component synthesis of morpholines. First, diazo ester 3 reacts with the catalyst to provide the copper carbenoid I. Reaction of imino alcohol II, which is formed in situ by condensation of amino alcohol 1 and aldehyde 2, then generates the insertion product III. Lastly, nucleophilic attack of the malonate enolate to the iminium group furnishes morpholine 4 and regenerates the copper catalyst.

Scheme 3.

Proposed Mechanism

As depicted in Scheme 2, chiral amino alcohols were effective substrates for morpholine synthesis, though with low diastereoselectivity. However, our group had previously developed a light-mediated reversible hydrogen atom transfer (HAT) approach for the epimerization of substituted morpholines to provide a ratio of diastereomers that correlated with their relative stability.⁸ We therefore applied this strategy to the light-mediated epimerization of morpholine 4e, which had been obtained in a 57:43 anti/syn ratio. Under the optimized conditions for epimerization using methyl thioglycolate as the HAT reagent and [Ir(dtbbpy)(ppy)₂]PF₆ as the photocatalyst, 4e-anti was obtained as the major isomer in 71% isolated yield. Morpholine 4e-syn was also obtained in 16% yield (Scheme 4a).

Scheme 4.

Light-Mediated Epimerization of 4e

^aIsolated yields of pure product after chromatography. ^bYields and dr determined by ¹H NMR relative to 1,3,5-trimethoxybenzene as a standard.

A deuterium labeling experiment was performed and resulted in extensive deuterium incorporation at both positions alpha to the amine consistent with a reversible HAT mechanism (Scheme 4b).⁸ Additionally, the complete equilibration of 4e under the reaction conditions was demonstrated through the epimerization of diastereomerically pure 4e-anti and 4e-syn, with both providing approximately the same 4e-anti/4e-syn diastereomer ratio (Scheme 4c). Finally, the relative stereochemistry for 4e-anti was rigorously assigned by X-ray structural analysis.

Morpholine 4e-anti was further functionalized using a variety of different transformations (Scheme 5). First, N-benzylation of 4e-anti with benzyl iodide afforded 5 in good yield. Reduction of 5 with lithium aluminum hydride provided morpholine 6 containing a tetrasubstituted carbon and alcohol groups as useful handles for further elaboration. Other methods for N-functionalization were also successful. Acetylation to give morpholine 7 and reductive amination with formaldehyde to provide N-methyl morpholine 8 both proceeded in high yields.

Scheme 5.

Product Diversification^a

^aIsolated yields of pure product after chromatography.

Decarboxylation of 8 was achieved through a two-step sequence of saponification and then heating the mono acid in acidic ethanol. In the base treatment step, only one ester group was saponified. Moreover, decarboxylation and protonation of the resultant enol proceeded with high diastereoselectivity to provide the ester-substituted morpholine 9 as a single diastereomer. The relative stereochemistry of 9 was determined using J-coupling constants determined by ¹H NMR as well as 2D NMR experiments (HSQC, HMBC, COSY, and NOESY) and was further confirmed by X-ray structural analysis (see Supporting Information).

In conclusion, an efficient three-component copper-catalyzed synthesis of unprotected, highly substituted morpholines has been developed. The transformation utilizes commercially available amino alcohols and aldehydes along with easily accessible diazomalonates as the starting materials. Morpholines with more than one chiral center are accessible using chiral amino alcohols, and although they are obtained with poor diastereoselectivity, a higher diastereomeric ratio can be obtained by light-mediated, reversible epimerization. Lastly, the synthetic versatility of the morpholines were demonstrated through a variety of product diversifications, including N-functionalization and ester reduction and decarboxylation.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.