Cobalt(II)-Catalyzed Alkoxycarbonylation of Aliphatic Amines via C–N

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Cobalt(II)-Catalyzed Alkoxycarbonylation of Aliphatic Amines via C−N Bond Activation Chong-Liang Li,†,‡,∇ Xuan Jiang,§,∇ Liang-Qiu Lu,*,§ Wen-Jing Xiao,§ and Xiao-Feng Wu*,†,‡ †

Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany § Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China Downloaded via NOTTINGHAM TRENT UNIV on August 15, 2019 at 00:07:07 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: The first cobalt-catalyzed deaminative alkoxycarbonylation reaction was described for the conversion of readily available primary alkyl amines to synthetically versatile esters with moderate to high yields. This transformation shows good functional group compatibility and can serve as a powerful tool for the modification of alkyl amine-containing complex natural products and drug molecules.

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salts with alkenes.5b Under blue-light irradiation and 80 bar of CO pressure, good yields of the desired enones can be obtained. In the above deaminative cross-coupling reactions, the key alkyl radical species is mainly generated from pyridinium salts by using transition-metal-catalyzed or photoinduced single electron transfer (SET) pathways. On the other hand, transition-metal-catalyzed carbonylation has been widely used in organic chemistry for the preparation of carbonyl-containing organic compounds over the past decades.9 By using alcohol as the nucleophile, various esters can be easily prepared through alkoxycarbonylation. In more detail, arenes and aryl halides can be easily transformed to the corresponding benzoates in good yields in the presence of catalysts (Scheme 1, eq a). For the alkoxycarbonylation of unactivated alkyl halides or alkanes, several catalytic systems

lkyl amines are prevalent organic molecules in nature and are important building blocks that are widely used in pharmaceutical synthetic chemistry (see Figure 1).1 Among

Figure 1. Examples of important primary alkyl amine pharmaceuticals.

Scheme 1. Alkoxycarbonylation Strategies

them, primary alkyl amines are readily available, inexpensive, and abundant reagents. However, methods for their activation are still very limited, especially in comparison with their aromatic amine analogues and benzylic amines, which can be activated by the formation of diazonium salts and πcoordinated intermediate. In 2017, a group of researchers led by Watson trailblazed the use of pyridinium salts2 (“Katritzky salts”) that are derived from primary alkyl amines as significant surrogates of alkyl halides, carboxylic acids, sulfonates, oxalates, and organometallics in nickel-catalyzed deaminative cross-coupling reactions.3 Later, studies showed the great potential of pyridinium salts in cross-coupling reactions, including C(sp3)−C(sp3),4 C(sp2)−C(sp3),5 and C(sp3)−C(sp)6 reactions. Exploration of the formation of deaminative carbon− heteroatom bonds, particularly C−X (X = N, O, S)7 and C− B,8 have also been reported. Notably, some of us recently developed a novel carbonylative Heck coupling of pyridinium © XXXX American Chemical Society

Received: July 20, 2019

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DOI: 10.1021/acs.orglett.9b02534 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

KH2PO4, and K2CO3, led to a significant decrease in the reaction efficiency (Table 1, entries 10 and 11; see the Supporting Information for more details). Notably, the exclusion of DMF essentially shut down the reaction (Table 1, entry 12) and when DMF was substituted by THF or CH3CN, this seemingly trivial change slightly diminished the yield (Table 1, entries 13 and 14). With the optimized conditions in hand, the scope of this cobalt-catalyzed deaminative alkoxycarbonylation methodology was explored (see Figure 2). A variety of aryl-substituted

also have been established (Scheme 1, eq b). However, challenges that are due to the inherent presence of π-acidic CO (which decreases the electron density on the metal center) and fast subsequent β-hydride elimination still exist.10 For alcohols, aromatic alcohols can be activated by triflate while aliphatic alcohols can be transformed to the corresponding alkyl halides and then easily carbonylated to give the desired esters (Scheme 1, eq c). However, carbonylation procedures that are able to use alkyl amine as the electrophile are still very rarely reported. In order to solve the challenges mentioned, and also as our continuing efforts in developing new metal-catalyzed carbonylation reactions,11 we herein describe a cobalt-catalyzed deaminative carbonylation of activated primary amines with alcohols, providing a versatile method for the transformation of alkyl amino groups into ester products (Scheme 1, eq d). We initiated our investigations by studying the alkoxycarbonylation between phenethylpyridinium salt (1a) and CH3OH (2a) in N,N-dimethylformamide (DMF). After screening various reaction parameters, using a CoII(acac)2 catalyst with the addition of 4,7-dihydroxy-1,10-phenanthroline (L5) and 2.0 equiv of potassium bicarbonate was found to be critical to achieve excellent yields of the desired product (Table 1, entry Table 1. Optimization of the Reaction Conditionsa

entry

deviation from standard conditions

yieldb [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14

none L1 instead of L5 L2 instead of L5 L3 instead of L5 L4 instead of L5 L6 instead of L5 L7 instead of L5 L8 instead of L5 L9 instead of L5 DABCO instead of KHCO3 K2CO3 instead of KHCO3 no DMF, CH3OH (1.5 mL) THF instead of DMF CH3CN instead of DMF

91 [86]c 0 0 0 10 23 trace trace 20 trace 17 0 80 76

Figure 2. Scope of pyridinium salts for the alkoxycarbonylation. Reaction conditions: 1a (0.25 mmol), 2a (10 mmol), Co(acac)2 (10 mol %), L5 (10 mol %), KHCO3 (2.0 equiv), CO (20 bar), DMF (1.1 mL), 100 °C, 12 h, isolated yield.

alkylpyridinium salts provided the corresponding esters in moderate to excellent yields. Both 3- and 4-phenyl-substituted pyridinium salts can deliver excellent yields of the corresponding esters (3ba and 3ca). Versatile functional groups appended to the aromatic ring, such as methyl, methoxy, fluoride, chloride, and bromide, were well-tolerated (3fa to 3ja). However, when electron-deficient functional groups substituted for other groups, such as the nitro and acetylamino groups, the reactions in this chemistry failed (see the Supporting Information for more details). Remarkably, secondary alkyl amine substrate could also give the corresponding ester product in 95% yield (3ka). Indolesubstituted alkyl amine gives a moderate yield as well (3la). Furthermore, Alogliptin, which is a commercially available antidiabetic drug,12 could be easily modified by this novel transformation and give the desired product in 92% yield (3ma). This fact supports the synthetic potential of natural or drug molecule modification in the future. Subsequently, the generality of this method, with respect to the alcohol partner, was explored (Figure 3). Both ethanol and methoxyethanol can deliver the desired esters smoothly, in yields of 74% and 75%, respectively (4ab and 4ac). Here, because of the low boiling point of the alcohols, 10 equiv of alcohols are still needed. However, when 2-(phenylthio)-

a

Reaction conditions: 1a (0.25 mmol), 2a (10 mmol), Co(acac)2 (10 mol %), L5 (10 mol %), KHCO3 (2.0 equiv), CO (20 bar), DMF (1.1 mL), 100 °C, 12 h. bGC yields, using n-hexadecane as an internal standard. cIsolated yield.

1). Numerous N-ligands were screened and it was found that the 1,10-phenanthroline-4,7-diol (L5), an electron-rich aromatic diol ligand, providing the best outcomes (Table 1, entries 2−9). Both steric and electron-deficient phenanthroline-ligands lowered the yield significantly (Table 1, entries 7− 9). Next, we found that other bases, such as DBU, DABCO, B

DOI: 10.1021/acs.orglett.9b02534 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Mechanistic Experiments

Scheme 3. Proposed Mechanism

Figure 3. Scope of alcohols for the alkoxycarbonylation. Reaction conditions: 1 (0.25 mmol), 2 (1.25 mmol), Co(acac)2 (10 mol %), L5 (10 mol %), KHCO3 (2.0 equiv), CO (20 bar), DMF (1.5 mL), 100 °C, 12 h, isolated yield. For 4ab and 4ac, 2 (10 mmol) and DMF (1.1 mL) were used.

ethanol was used as the nucleophile, only a 43% yield was obtained (4ad). Notably, both allyl and propargyl alcohol can deliver the corresponding products in 63% and 61%, respectively (4ae, 4af). Then, electron-rich benzyl alcohols (4aj to 4ai, 4ag) can give good yields of the target esters as well, compared to the −CF3 group, which only gives 65% yield (4aj to 4ai). Notably, our newly developed protocol could also be readily extended to complex molecules derived from natural product or pharmaceutical molecules. A highly efficient intramolecular deaminative spirocyclization reaction was performed; 81% yield of the target product (4ok) was isolated.13 Moreover, 7-(2-hydroxyethyl)theophylline,14 could be transformed to the corresponding product in 70% yield as well (4al). To investigate the reaction mechanism, a radical-clock experiment was performed by using a cyclopropylpyridinium salt 1p under standard reaction conditions (see Scheme 2). Instead of normal carbonylative product 5pg, a ring-opened product 5p′g was detected and isolated in 39% yield from the reaction mixture. In addition, when this reaction was added with a radical trapping reagent TEMPO (2,2,6,6-tetramethyl-1piperidinyloxy), this transformation was suppressed and no desired carbonylative product (5pg) was detected. These results suggest that deaminative alkoxycarbonylation follows a radical-mediated pathway. Based on these studies and literature, a plausible mechanism of the deaminative carbonylation is proposed and shown in Scheme 3. Initially, Katritzky salt 1 undergoes a single-electron transfer (SET) pathway with a Co0Ln intermediate (A) to deliver a pyridinyl radical 2. The pyridinyl radical 2 then fragments and delivers alkyl radical 4, which recombines with

CoILn intermediate (B) to give alkyl-CoIILn species (C). The coordination and insertion of CO to the alkyl-cobalt intermediate (C) would form an (alkyl)acyl cobalt(II) intermediate (IV). Finally, alcohol reacts with the acyl cobalt(II) (D) and produces the desired esters via reductive elimination. Catalytic active Co0Ln (A) is regenerated in this step and used for the next cycle. In summary, the first cobalt-catalyzed deaminative alkoxycarbonylation reaction for the conversion of readily available primary alkyl amines to synthetically versatile esters has been developed. This transformation shows good functional group compatibility and efficiency and can serve as a powerful tool for the modification of alkyl amine-containing complex natural products and drug molecules. The involvement of alkyl radicals in this process also has been supported.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02534. General comments, general procedure, optimization details, analytic data, and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (L.-Q. Lu). C

DOI: 10.1021/acs.orglett.9b02534 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters *E-mail: [email protected] (X.-F. Wu).

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ORCID

Liang-Qiu Lu: 0000-0003-2177-4729 Wen-Jing Xiao: 0000-0002-9318-6021 Xiao-Feng Wu: 0000-0001-6622-3328 Author Contributions ∇

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Chinese Scholarship Council for financial support. We also thank the Analytical Services Department of Leibniz-Institute for Catalysis at the University of Rostock for their excellent analytical service.

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REFERENCES

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