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Aerobic Copper-Catalyzed Alkene Oxyamination for Amino Lactone Synthesis Fan Wu, Scott Stewart, Jeewani Poornima Ariyarathna, and Wei Li ACS Catal., Just Accepted Manuscript • Publication Date (Web): 29 Jan 2018 Downloaded from http://pubs.acs.org on January 29, 2018
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ACS Catalysis
Aerobic Copper-Catalyzed Alkene Oxyamination for Amino Lactone Synthesis Fan Wu, Scott Stewart, Jeewani Poornima Ariyarathna, and Wei Li* Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States Copper catalysis, Aerobic oxidation, Alkene oxyamination, Amino lactone, Electron-rich amines ABSTRACT: A convenient alkene oxyamination compatible with a wide range of alkenoic acids and electron-rich amines is accomplished via aerobic copper catalysis. The synthetic value of this protocol is highlighted with the stereoselective formation of complex amino lactone products. In addition, product derivatizations to privileged nitrogen heterocycles have also been demonstrated via simple reduction methods. The reaction is proposed to proceed through a copper-catalyzed iodolactonization process.
Alkene difunctionalization is an important and fundamental strategy for the rapid and efficient assembly of molecular complexity. In particular, an alkene oxyamination process simultaneously installs both a C–O and a C–N bond, important motifs in a number of chemical fields, across simple alkene structures, to afford useful 1,2-amino alcohol derivatives.1 In this regard, a number of powerful transition-metal-catalyzed strategies utilizing osmium,2 palladium,3 copper,4 gold,5 platinum,6 rhodium,7 etc.,8 have been developed to accomplish the alkene oxyamination coupling (Scheme 1a). However, the nitrogen and/or oxygen coupling components employed in these reactions are often electrophilic reagents that require prior synthesis and can be sensitive for handling. Consequently, development of procedures utilizing unadorned amines and acids as the coupling partners, in alkene oxyamination reactions, represents an attractive alternative and complement to the existing technologies.9 However, an initial examination of the desired reaction reveals that the overall process is a challenging oxidative coupling, requiring an external oxidant. With the identity of the oxidant often guiding the practicality of the overall oxidative couplings, the utilization of molecular oxygen as a terminal oxidant is ideal for being environmentally friendly and atom economical.10 In this context, copper catalysts are versatile and inexpensive catalysts known to engage in a range of aerobic oxidative coupling reactions.11 With these considerations in mind, we have developed a simple and practical aerobic copper-catalyzed oxyamination process, to furnish amino lactone structures. As a result of their prevalent appearances in natural products and pharmaceuticals, amino lactones are an important class of functionalized lactones.12 In addition, these molecules can serve as exceptional gateway compounds to other useful functional entities, such as 1,2-amino alcohol derivatives.13 Given their importance, rapid and efficient synthetic access to these molecules are highly desired. However, a dearth of such methods often prompts the adoption of laborious multistep procedures, impeding the timely exploration of these useful compounds in pivotal biological studies.14 Recently, an elegant copper-catalyzed strategy, utilizing an electrophilic amine
source, O-benzoylhydroxylamine, was developed by the Wang group to achieve the amino lactonization (Scheme 1b).15 The dual role of the O-benzoylhydroxylamines as both an oxidant and electron-rich amine source is particularly noteworthy; nonetheless, the pregeneration of these compounds is an essential requirement.16 Scheme 1. Transition-metal-catalyzed alkene oxyamination
As part of our program to directly convert simple chemical feedstock into heterocycles, we are interested in the design of strategies for amino lactone synthesis utilizing alkenes (Scheme 1c).17 Although our initial attempts at the proposed transformation were not successful, we fortuitously discovered that the simple addition of an iodide salt as an additive, could produce the desired amino lactone product in good yields via copper catalysis. Therefore, we initiated our optimization studies with alkenoic acid 1 and N-benzylmethylamine 2. A combination of copper(II) triflate, lithium iodide (LiI), and acetonitrile (ACN) and methanol (MeOH) at 60 °C, gratifying-
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ly, afforded the desired amino lactone 3 in 82% yield (Table 1, entry 1). Screening of copper catalysts and halides revealed that Cu(OTf)2 and potassium iodide (KI) were the optimal combination (Table 1, entries 2-6). In addition, copper(I) salt such as copper iodide also effectively produced the desired amino lactone product in reasonable yield (Table 1, entry 7). Solvent optimization indicated that MeOH alone could function as a viable alternative to achieve high efficiency (Table 1, entry 8). Lowering the temperature from 60 °C to rt, resulted in only 20% of desired product (Table 1, entry 9). Decreasing the copper catalyst loading to 5 mol%, afforded the product in a slightly diminished yield of 76% (Table 1, entry 10). Finally, we settled on the optimized conditions as entry 3 in Table 1 with an 82% isolated yield of the amino lactone product. Table 1. Reaction optimizationsa
entry
Cu catalyst (%)
halide
solvent ratio (1:1)
yield (%)b
1
Cu(OTf)2 (10)
LiI
ACN/MeOH
82
2
Cu(OTf)2 (10)
NaI
ACN/MeOH
78
3
Cu(OTf)2 (10)
KI
ACN/MeOH
86(82)
4
CuBr2 (10)
KI
ACN/MeOH
67
5
CuCl2 (10)
KI
ACN/MeOH
65
6
Cu(OAc)2 (10)
KI
ACN/MeOH
65
7
CuI (10)
KI
ACN/MeOH
78
8
Cu(OTf)2 (10)
KI
MeOH
80
c
Cu(OTf)2 (10)
KI
ACN/MeOH
20
10
Cu(OTf)2 (5)
KI
ACN/MeOH
76
11
Cu(OTf)2 (10)
-
ACN/MeOH
0
12
-
KI
ACN/MeOH
0
13d
Cu(OTf)2 (10)
KI
ACN/MeOH
26
9
a
Reaction conditions: alkenoic acid 1 (0.5 mmol), amine 2 (1.0 mmol), copper catalyst (10 mol%), halide salt (0.5 mmol), solvent (1 mL), 60 ºC, 16 h. bYields were determined by crude 1H NMR using 1,3-benzodioxole as the internal standard. Yield shown in parenthesis was isolated yield. crt. dAir was used instead of an oxygen balloon.
With the optimized conditions in hand, we ventured to explore the alkenoic acid substrate scope (Table 2). 4-Pentenoic acid proceeded smoothly to afford the amino lactone 4 in 72% yield (Table 2, product 4). Similarly, mono- or di-methyl substituted α-pentenoic acids also resulted in product formation with high yields (Table 2, products 5 and 6). Interestingly, a range of spirocyclic lactone structures containing carbo- or heterocyclic motifs, were generated with great efficiencies, with the exception of the cyclopropane substrate in diminished yield (Table 2, products 7-11). In addition, N-Boc α-amino lactone 12 was produced with a reasonable 50% yield. Moreover, sterically congested carbon centers were established, from a number of 4,4-disubstituted pentenoic acids, in the amino lactone products (Table 2, products 13-16).18 A benzene backbone in the lactone ring was also tolerated with high efficiency (Table 2, product 17). Finally, product 18 highlighted
the sturdy formation of the 5-membered lactone, as the installation of an electronically biased phenyl group to favor the 6membered lactone, still resulted in only 5-membered amino lactone (Table 2, product 18). Table 2. Alkenoic acid substrate scopea
a Standard reaction conditions. b15% Lactone ring opening product was also observed. cMeOH was used as the solvent, 36 h. d CH3CN/MeOH (1 M), amine (2.5 mmol), 36 h. eAmine (2.5 mmol), 36 h.
Satisfied with the range of lactone architectures, we turned our attention to the amine substrate scope. In this case, we were delighted to observe that a number of acyclic and aliphatic secondary amines, containing alkyl, benzyl, amide, and cyano functionalities, readily participated towards product formations (Table 3, products 19-24). Remarkably, even a primary amine, (R)-(+)-α-benzylmethylamine, afforded the desired product (Table 3, product 25). Furthermore, a number of 6- and 7-membered nitrogen heterocycles including piperidine, piperazine, morpholine, azepane, and diazepane, all proceeded in good yields (Table 3, products 26-32). In the case of piperazine, simple Boc- and Cbz-protecting groups were compatible. Notably, dimethyl- and dibenzyl N-Boc 1,2diamines, challenging substrates in copper-catalyzed reactions often due to catalyst inhibition, generated the lactone products in exceptional yields (Table 3, products 33 and 34). With both substrate scopes in good standing, we decided to probe the synthetic capability of this reaction by pursuing more complex amino lactone structures containing fused or bridged bicycles.19 Thus, three products 35, 36, and 37 were synthesized from the respective alkenoic acids under the standard reaction conditions (Figure 1). Notably, all three products were obtained as a single diastereomer, illustrating
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ACS Catalysis great potential of stereocontrol in complex amino lactone syntheses. More specifically, both the 5,6-fused 35 and the 5,5fused 36 amino lactones were produced with great yields of 83% and 94%, respectively. The bridged bicyclic lactone was also formed, followed by in situ ring opening with methanol to produce 37. These examples demonstrated the synthetic capability of this simple reaction protocol for the stereoselctive formation of complex amino lactone structures. Table 3. Amine substrate scopea Figure 2. Derivatizations to nitrogen heterocycles.
To probe the reaction mechanism, we had conducted a series of control experiments (Table 1, entries 11-13). As expected, the absence of either Cu(OTf)2 or KI resulted in complete reaction inhibition. Switching the oxidant from an oxygen balloon to air was detrimental to the reaction yields. Anaerobic condition with nitrogen gas afforded
