Direct C-H Bond Imidation with Benzoyl Peroxide as Both Mild Oxidant

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Direct C-H Bond Imidation with Benzoyl Peroxide as Both Mild Oxidant and Reagent Tobias Brandhofer, Andrea Gini, Sebastian Stockerl, Dariusz G. Piekarski, and Olga Garcia Mancheno J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01765 • Publication Date (Web): 28 Aug 2019 Downloaded from pubs.acs.org on August 29, 2019

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The Journal of Organic Chemistry

Direct C-H Bond Imidation with Benzoyl Peroxide as Both Mild Oxidant and Reagent Tobias Brandhofer,a,b Andrea Gini,b Sebastian Stockerl,a Dariusz G. Piekarski,a Olga García Mancheñoa* a

Institute of Organic Chemistry, University of Münster, 48149 Münster

b

Institute for Organic Chemistry, University of Regensburg, 93053 Regensburg

Phone: +49 251 83 36514, Fax: +49 251 83 36503, e-mail: [email protected] Table of Contents/Abstract Graphic

Abstract A simple and mild Cu-catalyzed oxidative three-component oxidative Ugi-type method for the synthesis of a variety of substituted imides has been developed. In this direct imidation approach, benzoyl peroxide serves as both the oxidant and carboxylate source, allowing not only the functionalization of C(sp3)-H bonds in alpha position to an amine, but also benzylic substrates. This procedure presents a wide substrate-type and functional group tolerance. Moreover, the mildness of the method permitted to extend its applicability to the late stage functionalization of complex natural products such as the alkaloids Brucine and Strychnine, leading to interesting highly functionalized imide derivatives. Based on experimental and computational studies, a plausible mechanism has been proposed.

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Introduction Imides are an important class of compounds present in natural products and with a wide application spectrum in the polymer, agrochemical and pharmaceutical industry.1 Although they are structurally related to anhydrides, imides are more resistant toward hydrolysis, which makes them highly interesting for the development of new drug targets less susceptible to fast biodegradation (Figure 1). Thus, besides the more acknowledged cyclic imides, such as Lenalidomide (I)2 or Amonafine (II)3 with anti-cancer properties, acyclic imide-containing compounds have recently awakened high interest due their rich potential in medical applications.1,4 In particular, they present interesting activities as antibiotic (e.g. natural product Fumaramidmycin) (III)),5 anti-cancer (e.g. PI3K inhibitor IV)6 or pulmonary hypertension treatment (e.g. endothelin antagonist V)7 agents. O

O

O

H N

N

H 2N

O

I Lenalidomide multiple myeloma treatment

N N N

O

O

N

IV PI3K inhibitor anti-cancer agent

NH 2

H 2N

O

O N H

III Fumaramidmycin antibiotic

MeO

O H 2N

O

N

N

O O

N

II Amonafide Leukemia treatment

N N

NH 2

O

OH

O N nPr

N

O

O V endothelin antagonists pulmonary hypertension treatment

Figure 1. Selected representative bioactive imides. Considering the high applicability of imides, several approaches for their synthesis, such as by Nalkylation, reaction of amines with the corresponding cyclic imides, amide -oxidation, and Nacylation or C-N oxidative coupling of amides, have been developed (Scheme 1, a).8 Another important approach relies on the variant of the Ugi multicomponent reaction with secondary amines.9 However, new straightforward methods based on C-H bond functionalization of readily available ACS Paragon Plus Environment

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substrates are still highly desirable.10 In this regard, the oxidative Ugi-type reaction between amines, isocyanides and carboxylic acids has been recently introduced as a powerful alternative (Scheme 1, b).11 Nevertheless, the methods are restricted to amine substrates with activated -C-H bonds, leading to bis-amides11 or imides11l depending on the substitution at the nitrogen atom.

Scheme 1. Synthesis of imides and the oxidative Ugi-type approach. Continuing our research program on mild, selective oxidative C-H functionalization,12 and aiming at overcoming some of the current restrains, we have recently developed a method, in which benzylic substrates such as acridanes 1 could now be imidated (Scheme 2).13 Thus, we have established an original approach for the preparation of an innovative family of acridinium photocatalysts 3 based on a Cu-catalyzed oxidative Ugi-type strategy using benzoyl peroxide (BPO) as key step.



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Scheme 2. Oxidative Ugi-type conditions for the synthesis of acridinium photocatalysts.

Herein, we present the applicability, scope and mechanism of our novel approach using benzoyl peroxide as both mild oxidant and carboxylate reagent in oxidative Ugi-type reactions (Scheme 1, c). This mild and robust procedure allows not only the functionalization of classical substrates with C-H bonds in alpha position to a N-atom, but also benzylic derivatives, as well as complex alkaloid natural products. Results and Discussion To test the feasibility of the method for a broad substrate scope, we decided to start our study with the barely explored dibenzylic substrates in oxidative Ugi-reactions (Table 1). Following the initial optimized conditions for N-methyl acridane (1a),13 several acridanes and xanthenes were subjected to the oxidative Ugi-reaction with cyclohexyl isocynanide (2a). Thus, the reactions were carried out using 10 mol% of Cu(OTf)2 as catalyst and 30 mol% of the 2,2’-bipyridine (bpy) ligand, in combination with 1.2 equivalents of BPO and 2.0 equivalents of the isocyanide reagent at room temperature. The reaction tolerated well various N-alkylic (1a, Me and 1b, Bn) and arylic (1c, Ph) substituted acridanes, providing to the corresponding imides 3a-c in good yields (66-70%). It is worthy to note that in the case of the N-alkyl substituted derivatives 1a and 1b, a selective addition to the benzylic position occurred, without any substitution at the -alkyl group of the amine. Similarly, the reaction of xanthene (1d) with 2a delivered the desired imide 3d, however the yield was significantly lower compared to its parent nitrogen-derivative 1a (21% vs. 66%). This could be explained due to the fact that acridanes are electron richer heterocycles than xanthenes. Therefore,


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methoxy substituted derivatives were next reacted under the standard conditions, leading to the corresponding imides 3e and 3f in good yields (58 and 67%, respectively).

Table 1. Reaction with dibenzylic substratesa),b)

a)

Substrate 1 (0.2 mmol, 1.0 eq.), isocyanide 2a (2.0 eq.), benzoyl peroxide (1.2 equiv.), Cu(OTf)2

(10 mol%) and 2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube under N2 atmosphere. b) Isolated yields.

Encouraged by these results, we continued our investigations with N-aryl tetrahydroisoquinolines (THIQs) as typical substrates in oxidative Csp3-H functionalization (Table 2).10 We found out that the reaction of this type of cyclic heterocycles was highly effective, allowing reducing the amount of the isocyanide reagent from 2.0 to 1.2. equivalents and the easy scaling up of the reaction of the prototypical N-phenyl THIQ 4a with 2a from 0.2 and 0.4 to 1 mmol (5a, 68, 85 and 74%, respectively). Moreover, in this case other isocyanide with alkylic (2b, tBu and 2c, nBu), arylic (2d,



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2-naphtyl), benzylic (2e) or ethylacetate rests (2f) provided the corresponding imides 5b-f in good to excellent yields (66-92%). Finally, the effect on the reactivity of various substituents at the THIQ core or N-aryl group were explored (5g-k). Electron rich THIQs provided the products in excellent yields (5g), while electron deficient derivatives were not efficiently enrolled in the reaction (e.g. 4h). Conversely, both electron donating (OMe) and withdrawing (CN, F) groups at the N-aryl moiety were well tolerated, giving consistent high yields. Table 2. Oxidative Ugi-reaction with THIQs 4a),b)

a)

THIQ 4 (0.2 – 1.0 mmol, 1.0 eq.), 2 (1.2 eq.), benzoyl peroxide (1.2 eq.), Cu(OTf)2 (10 mol%) and

2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube under N2 atmosphere. b) Isolated yield. ACS Paragon Plus Environment

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The methodology was next extended to N,N-dimethyl anilines. It turned out that this type of compounds reacts sluggish under the conditions given above for THIQs. Therefore, a short reoptimization of the reaction of N,N-dimethyl aniline (6a) with isocyanide 2a was first carried out (Table 3). While an excess of the isocyanide was crucial (entries 1-5), an increase of the amount of peroxide (entry 6) or the use of higher concentrations (from 0.1 to 0.2 and 0.4 M, entries 7 and 8) did not improve the yield. As a result, the best yield (entry 4, 50%) was obtained when employing 2 equivalents of 2a, as in the initial conditions for the benzylic derivatives (see Table 1). Table 3. Re-optimization of the reaction for N,N-dimethyl anilinea)

a)

Entry 2a (eq.) BPO (eq.) [M] Yield (%)b) 1 1.2 1.2 0.1 36 2 1.6 1.2 0.1 42 3 1.8 1.2 0.1 45 4 2.0 1.2 0.1 50 5 2.4 1.2 0.1 47 6 2.0 1.4 0.1 46 7 2.0 1.2 0.2 35 8 2.0 1.2 0.4 32 N,N-Dimethyl aniline (6a) (0.2 mmol, 1.0 eq.), isocyanide 2a, benzoyl peroxide, Cu(OTf)2

(10 mol%) and 2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube under N2 atmosphere. b) Isolated yield.

The scope of the reaction with anilines 6 was then investigated (Table 4). Although in systematically inferior conversions than the THIQs 4, N,N-dimethyl anilines 6 also did react with a variety of aryl and alkyl-substituted isocyanides 2 to form the imides 7b-f. However, the best results were obtained with the cyclohexyl and 2-naphthyl isocyanides (50 and 59% yield; 7a and 7b, respectively). Consequently, they were next employed in the reaction with differently para-substituted anilines. The



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4-methyl and methoxy derivatives 7g-k were obtained in good yields (60-67%), while the anilines bearing halogen atoms (such as bromo or fluoro) gave the products 7l-m in moderate yields. It is also important to note that not only benzoyl peroxide but also other substituted derivatives such as lauroyl peroxide could be used as both oxidant and carboxylic reagent, providing the imide 7h with a C11alkylic chain product in 45% yield. Moreover, more demanding bio-derivatives such as the N,Ndimethyl coumarin 6n could also be enrolled, forming the imide 7n in a 38% yield. Furthermore, the reaction with 6a and 6b as representative substrates could be efficiently carried out up to a gram-scale (6b, 7 mmol), leading to 7a and 7g in similar good yields. Table 4. Scope of the reaction with N,N-dimethyl anilines 6a),b)

a)

N,N-Dimethyl aniline 6 (0.2 mmol, 1.0 eq.), isocyanide 2 (2.0 eq.), peroxide (1.2 equiv.), Cu(OTf)2

(10 mol%) and 2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube under N2 atmosphere. b) Isolated yield. c) 0.5 mmol scale. d) 3 mmol scale. e) 7 mmol scale.


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Finally, we challenged our method with more complex molecules such as the natural products brucine and strychnine, possessing two reactive allylic C-H bonds in alpha position to nitrogen (blue) or oxygen (red) (Figure 2). We were delighted to observe the imidation of these alkaloids in good to high yields (54-76%) and in a high regioselectivity towards the allylic position in alpha to the N-atom (8 and 8’) vs. to the O-atom14 (8#) (e.g. 8a:8a’:8a# in a 3.5:1.0:1.2 ratio, and with a 78:22 d.r. for 8a/8a‘, see Exp. Sect. and S.I.). Furthermore, the Tröger’s base selectively reacted as well, delivering the corresponding mono-imide 9 in a moderate 30% yield.

Figure 2. C-H bond imidation of natural products.

Moreover, we probed that the imide unit could be transformed into the corresponding amide by acylgroup elimination upon treatment with hydrazine. This was illustrated with the model THIQ-imide product 5a, which undergoes a mild benzoyl deprotection leading to the amide 10 in a good 87% yield (Scheme 3).

Scheme 3. Representative N-benzoyl deprotection of the imide group to the corresponding amide.



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In order to shed some light into the mechanism of this oxidative Ugi-type reaction with benzoyl peroxide, the role of the Cu-catalyst was studied. Thus, the reaction of 6b in the absence of the CuOTf2/bpy catalytic system under heating conditions (80 °C) for promoting the thermal homolytic cleavage of the BPO oxidant required for the first step led to a 54% yield of the Ugi-product 7g.15 This shows that the Cu-catalyst only plays a key role in the activation of the oxidant. Moreover, a competition experiment with 6a and 1 equivalent of BPO in the presence of 3 equivalents of p-toluic acid was performed (Scheme 4). Then, the products 7a and 7o were obtained in a statistical 2:3 ratio in a 46% yield, which indicates the in situ formation of 2 equivalents of benzoate from BPO during the course of the reaction. Based on these experimental observations and previous reports,10,12b,16 the initial oxidation of the substrate should proceed through a CuI-catalyzed homolytic cleavage of BPO to benzoyl radical, which upon a single electron transfer (SET) forms the radical cation I (or corresponding benzylic radical for substrates 1) and one equivalent of benzoate. Subsequently, I suffers a second oxidation with the generated CuII-carboxylate to provide the iminium intermediate II that further reacts with the isocyanide and free carboxylate.


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Scheme 4. Mechanistic studies and proposed first-step Cu-catalyzed C-H oxidation mechanism.

Assuming the in situ formation of the cationic iminium intermediates and carboxylate as described above, a density functional theory (DFT) mechanistic study was next carried out. The reaction profile with N,N-dimethyl aniline (6a) as model substrate was analyzed computationally starting with the iminium intermediate II as initial point (Figure 3). The calculations were performed at DFT level of theory using the M06-2X functional17 with the 6-31++G(d,p)18 basis set within the Gaussian 09 software.19 The relative Gibbs free energies were calculated including entropic effects at 298.15K and a 1 M concentration with corrections for low vibration modes (

Direct C-H Bond Imidation with Benzoyl Peroxide as Both Mild Oxidant

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