Nickel-Catalyzed Acylation of Aryl Bromides with Acyl Imidazoles Junming Zhuo,†,‡,¶ Yong Zhang,‡,¶ Xiaoxia Zhao,‡ Zijian Li,‡ Chao Li*,†,‡,§

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†Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China ‡National Institute of Biological Sciences (NIBS), Beijing, 102206, China §Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China

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ABSTRACT: Alkyl imidazolides, underexplored yet eas- A. Representative radical acylation reaction 2 O O CO, ArB(OH)2/ArBr ArX , [Ir]/[Ni], BLED ily prepared and flexible species derived from abundant Alk-I Alk• [Pd]/hυ, [Ni] or [Cu]/[Mn] 1 • X = H or CO2H Alk Alk X1 alkyl carboxylic acids, were herein found to be viable [Suzuki, Miyaura, [Macmillan] coupling partners for the Ni-catalyzed acylation of aryl Ryu, Weix, Mankad, Odell] O bromides. This cross-coupling reaction features a broad [Gong] Alkyl Ar [Ohmiya, Baran, Weix] ArCOX2 substrate scope and can be performed in an extremely ArCOCl, ArCOSPy O X2 = OCOR, Cl [Ni], Zn cost-efficient fashion. Mechanistically, formation of acyl Alk-X1 Alk• Alk• [Ni], Zn or ArCHO, NHC Alk NHPI radicals via reduction of imidazolides represents a major B. Traditional utility of acyl imidazoles departure from other reported radical acylation reactions. O O O [+ Nu-] R1 1 Nu Of particular note, extensive studies revealed an intri- R R2 OH N N nucleophilic 3 R2 R guing radical chain mechanism and a remarkable CO- 3 substitution amides, esters, R N N extrusion-recombination phenomenon. Finally, the prac- CDI ketones etc. O OH ticality of this cross-coupling was demonstrated with a - 1 CDI R1 [+ H ] R H N gram-scale reaction for the synthesis of a furan diterpe- R2 N reduction R2 H - imidazole; - CO2 R3 R3 noid natural product. alcohols or aldehydes ✦ inexpensive feedstock CDI ✦ innocuous waste ✦ easily handled products ✦ easy preparation (mild conditions, no coupling agents, no chromatography) C. This Work: carbonyl radical derived from alkyl carboxylic acids Synthetic methods to obtain alkyl aryl ketones, com- O O O 1 CO R1 R1 ArBr, Ni/L R • • R1 mon and essential moieties present in both natural prod- N 2 Ar 2 N R2 R 2 1-3 R Zn, ZnBr2 3 R3 R ucts and drugs, have been studied extensively. Tradi- R3 R R3 CO-extrusion-recombination tionally, nucleophilc substitution of acyl derivatives and Friedel-Crafts acylation have been widely used with a Figure 1. (A) Representative alkyl-aryl ketone formation via very broad range of substrates. However, the harsh reac- a radical acylation reaction. (B) Traditional utility of acyl tion conditions—sensitive and strong basic organometal- imidazoles. (C) Nickel-catalyzed cross-coupling of acyl im- lics or strong Lewis acids—and the resulting restricted idazoles with aryl bromides. window of chemoselectivity, prevents use of such meth- Macmillan group developed two novel methods for ods with certain functional groups. Recently, transition ketone synthesis via merging photoredox and nickel metal-catalyzed radical carbonylation and acylation reac- catalysis, and they chose to derive their alkyl carbonyl tions have emerged as an attractive choice for alkyl-aryl radicals from aldehydes or keto acids.11 Redox-active ketone synthesis due to their relatively mild reaction esters (RAEs) prepared from abundant carboxylic acids conditions and good functional group tolerance.4 Studies are currently popular alkyl radical donors, three excellent in this area have focused on three-component related methods were recently reported by the Ohmiya, carbonylative cross-coupling reactions, which were Baran, and Weix groups.12-14 Notably, in each case, the pioneered by Suzuki and Miyaura and later elaborated by carbonyl groups were derived from aryl side. Ryn, Weix, and Mankad et al. (Figure 1A).5-9 Gong later developed reductive coupling of alkyl halides with acyl Acyl imidazole, an easily handled and relatively stable anhydrides and acyl chlorides.10 A notable commonality species compared to acyl chlorides and anhydrides, can for both of these reaction strategies is their exploitation of be easily prepared from reactions between abundant radicals generated from alkyl halides. Very recently, the carboxylic acids and inexpensive feedstock N, N´- carbonyldiimidazole (CDI) (Figure 1B).15 Since no dehydrating agent is needed in this process and the Besides strained cyclopropane and cyclobutane ring byproducts are simply the innocuous CO2 and water- systems (13, 19), a series of functional groups such as soluble imidazole, purification of acyl imidazole products olefins (5, 8, 12), esters (10, 25, 26), ethers (12, 18, 21, can be easily achieved via simple extraction. 25), carbamates (15, 16, 23), even a silyl ether (31) could Traditionally, acyl imidazoles have been widely used be tolerated in this reaction condition. Of partcular note, because they can be flexibly converted into a myriad of we found that densely functionalized natural products (10, related functional groups such as esters, amides, ketones, 21, 25) could still serve as competent substrates, enabling aldehydes, or alcohols via nucleophilic substitution or access to the desired products in moderate-to-high yields. reduction.15b In this Communication, we report a novel Moreover, the stereochemical orientation of 28 was nickel-catalyzed radical acylation reaction in which the retained completely in this cross-coupling reaction. It was radicals are derived from ubiquitous alkyl carboxylic also interesting to note that the common byprouduct of acids via the formation of acyl imidazoles (Figure 1C). this cross-coupling of different acyl imidazoles with PhBr Table 1. Reaction Optimizationa (2) was identified as benzophenone (32), the carbonyl group of which was presumably derived from the acyl O O imidazoles (vide infra). While a variety of acyl Br 10 mol% NiI2 N 15 mol% bpy (L1) N + imidazoles were demonstrated to be viable in these Zn (3.0 equiv.) reaction conditions, limitations in scope should be noted: 1 2 ZnBr2 (2.5 equiv.) 3 (1.0 equiv.) (2.0 equiv.) DMF, 60 ℃, 20 h 83%b, 85%c acyl imidazoles derived from a-heteromaton acids (33,

entry deviation from above yield (%)b entry deviation from above yield (%)b 34) and phenylacetic acid (35) were low yielding.

1 w/o NiI2 0 8 w/o ZnBr2 73 Next, we examined the reaction scope for aryl bromides

2 NiBr2 instead of NiI2 67 9 LiBr instead of ZnBr2 49 and found it to be remarkably broad (Table 2). First, both

3 w/o L1 0 10 5 mol%NiI2/7.5 mol% L1 79 electron-rich and electron-deficient phenyl bromides with 4 L2 instead of L1 51 11 ZnBr2 (1.0 equiv.) 80 variety of functional groups were demonstrated to be 5 L3 instead of L1 79 12 Zn (1.5 eq) 77 viable coupling partners (36-43). Second, a series of 6 w/o Zn 0 13 PhI instead PhBr 74 medicinally relevent heterocycles including benzofurans 7 Mn instead of Zn 43 14 PhOTf instead of PhBr 62 (44-47), furans (48, 49), indoles (50-52), a pyrrolo[2,3- tBu tBu b]pyridine (53), a pyrimidine (54), and a pyridine (55) N were examined, and the desired products were N N N N N N successfully afforded in good-to-excellent yields. Of L1 L2 L3 particular note: a vinyl bromide (56) was viable in this a0.2 mmol. bYield determined by GC/MS with dodecane cross-coupling as well, although this required slight as internal standard. cIsolated yield. modification of the reaction conditions and the product, obtained in moderate yield, was an interesting a, b- Table 1 illustrates the optimal reaction parameters unsaturated ketone. along with an abbreviated picture of the optimization for the reaction between imidazolide 1 and phenylbromide 2 Our detection of common byproducts—diaryl ke- (see SI for further details). Notably, the desired ketone 3 tones—in these cross-coupling reactions mechanistically indicated that a radical decarbonylative pathway appar- could be provied in excellent yield with extremely cost 4c,16 efficient reagents and conditions. Specifically, we used ently underlies this process. Further mechanistic in- the inexpensive NiI as the catalyst, unmodified bipy (L1) vestigation is depicted in Figure 2. For the acyl imidaz- 2 oles derived from primary and secondary acids, the pres- as the ligand, Zn powder as the reductant, as well as ZnBr2 as an additive, each of which was found to be required to ence of a carbon monoxide (CO)-extrusion- obtain 3 in high yield (entries 1-9). Although 10 mol% of recombination pathway via radical intermediates was ev- catalyst, 3.0 equiv. of Zn powder and 2.5 equiv. of idenced by three radical clock experiments: a cyclopro- additive (ZnBr ) were used in standard conditions, pane-opened product, 58, that was generated from imid- 2 azolide 57 (Figure 2A, eq. 1); a 5-exo-trig cyclization lowering the equivalent of nickel catalyst, Zn, and ZnBr2 also delivered the desired product in satisfactory yields product 7 generated from imidazolide 60 (Figure 2A, eq. (entries 10-12). Moreover, PhI and PhOTf were found to 2); and a transannular 5-exo-trig cyclization product 63 be a viable coupling partners as well, although the product generated from imidazolide 62. The uncyclized products 3 was afforded in slightly lower yields (entries 13 and 14). 61 and 64 were also obtained from imidazolide 60, prob- ably due to a solvent cage effect. Interestingly, our obser- With optimized reaction conditions in hand, we vation that modulating the level of nickel catalyst loading examined the scope of this nickel-catalyzed cross- predictably altered the product ratio of 7 to 61 suggested coupling reaction. As shown in Table 2, over thirty a potential radical chain mechanism (Figure 2A, eq. 3).13, examples of acyl imidazoles derived from structrually 17, 18 More precisely, we detected a direct linear relation- diverse alkyl carboxylic acids were explored initailly, and ship between the nickel catalyst concentration and for- the reaction appears to be general for the imidazolides of mation of cyclized 7, indicating that a nickel species primary, secondary, and sterically hindered tertiary acids.

Table 2. Scope of the Ni-Catalyzed Reductive Cross-Coupling of Acyl imidazoles with Aryl Bromidesa

> 50 examples R1 R1 10 mol% NiI2, 15 mol% bpy (L1) ♦ R3 CDI, CH Cl 3 O 2 2 R Zn (3.0 equiv.), ZnBr2 (2.5 equiv.) ♦ inexpensive catalyst, ligand, and additive OH imi Ar Ar R2 R2 + Br ♦ primary, secondary, and tertiary acids 3 no column DMF, 60 ℃, 20 h R ♦ functional group tolerance O O 1 2 > 80% standard conditions R R ♦ natural products (1.0 equiv.) (2.0 equiv.) heteroaromatic bromides Carboxylic Acid Scope ♦ A. Primary acids B. Secondary acids Ph Ph O 3, X = CH2, 85% Me O Me O Ph O Ph Me Ph Me O 14, X = CF2, 81% Me Me O 15, X = NBoc, 65% Ph n-Bu Me Ph O O 16, X = NCbz, 67% Me Ph Et 4, 71% 5, 73% 6, 54% 7, 82% Me 17, X = NTs, 87% X O OMe 18, X = O, 82% 13, 80% 19, 80% 20, 68%b Ph 8, 47% Me O Ph OAc Me 9 Me OMe Me O O H 11, 73% myristic acid Me H OMe Me H O H H Ph H H Me 7 5 O AcO 21, 84% H O 9, 84% 10, 46% 12, 75% (from elaidic acid) (from 3-keto-4-etiocholenic acid) X-ray of 21 C. Tertiary acids O O O OMe Me Ph Me H Me Ph AcO H Me X O H 22, X = CH2, 79% Me Me 23, X = NBoc, 85% 24, 75% Me Me X-ray of 25 25, 91% (from enoxolone) O D. Major byproduct and current limitations O Ph O Me Boc O N O O Ph O Ph R Ph Ph Ph O O Ph Me Me 29, R = Ph, 40% Ph MeO C b Ph 2 28 30, R = H, 37% b 26, 65% 27, 47% ndo:exo = 8:1 31, R = OTBS, 46% 32, major byproduct 33, 20% 34, < 1% 35, < 1% Aryl Bromide Scope c-Hex O c-Hex O O O O OMe O O O c-Hex c-Hex c-Hex c-Hex c-Hex

CO Me MeO OMe O OMe NMe2 CO2Me CN 2 36, 70% 37, 77% 38, 80% 39, 89% 40, 63% 41, 61% 42, 83% O O O O c-Hex c-Hex O c-Hex c-Hex c-Hex c-Hex O c-Hex O O O O O OCF3 O O 43, 79% 44, 89% 45, 71% 46, 80% 47, 75% 48, 90% 49, 78%b c-Hex O O O O O O

c-Hex c-Hex c-Hex N c-Hex c-Hex N c-Hex N Boc N N N N OMe N OMe Boc O Me Boc 50, 90% 51, 90% 52, 89% 53, 72% 54, 84% 55, 73% 56, 60%b aReactions were conducted on 0.2 mmol scale in 1 mL DMF. Yield of isolated products are indicated in each case. bL3, LiBr (1.0 equiv.), and ZnCl2 (1.0 equiv.) were used. may be trapped with CO prior to its reaction with the acyl (pathway a). At this point, combination of the alkyl radi- and alkyl radicals. Consistent with this idea, adding yet cal species X and Ni(II) complex III renders the for- more nickel catalyst both promoted the extrusion of CO mation of Ni(III) intermediate IV which, after reductive and concomitantly prolonged the lifetime of the alkyl rad- elimination, affords the desired acylated product and ical, thereby increasing the proportion of the cyclized Ni(I) complex V.7 Ni(I) complex V then acts as a reduc- product from the reaction (Figure 2A, eq. 3). ing reagent that gives an electron to imidazolide VII via Based on these lines of evidence, a postulated mecha- a single electron transfer (SET), thus generating Ni(II) nism for this transformation is depicted in Figure 2B. Re- complex VI and radical anion VIII. The ZnBr2 additive duction of a Ni pre-catalyst affords Ni(0) complex I, and may interact with the carbonyl group or the imidazole after oxidative addition of aryl bromide, the resulting moiety of imidazolide VII, strengthening the oxidative 13 Ni(II) complex II traps a CO derived from the fragmen- ability of VII. Imidazolide Ni(II) complex VI can then tation of an acyl radical to from acyl Ni(II) complex III be further reduced by Zn powder, regenerating Ni(0) complex I. In the meantime, fragmentation of radical

A. Radical clocks on primary and secondary imidazolides periment (Figure 2C) and is also consistent with the afore- O O O PhBr mentioned retention of 28's stereochemical orientation. + (1) imi standard Ph Ph Additionally, it is noteworthy that this special radical 57 conditions 58, 60% 59, 0% mechanism enabled “carbonyl transfer reaction”, which O delivered substrates 58, 7, and 63 (Figure 2A), represents PhBr Ph (2) imi + Ph a major difference from other acylation reactions. standard O conditions O To showcase the scalability and practicality of this 60 7 47%, 1.6 : 1 61 radical cyclization as a function of catalyst loading cross-coupling strategy, a gram-scale reaction was exam- 2.5 ined for the synthesis of a furan diterpenoid natural product (67) that was initially isolated and characterized from 2.0 Baccharis santelicis.20 As shown in Scheme 1, treatment 61 / 7 1.5 of sclareol (68), an inexpensive terpene feestock, with (3) RuCl3 and NaIO4 afforded acid 69 in 64% yield via a tan- ratio of ratio 1 dem oxidative degradation.21 Exposure of acid 69 to CDI

0.5 and subjection of the resulting acyl imidazole to our 0 5 10 15 20 standard reaction conditions with 3-bromofuran (70) at NiI2 loading (mol%, NiI2/L1 = 1:1.5) O H O O gram scale provided the desire ketone 71 in 68% yield PhBr H over two steps. The structure of 71 was confirmed by X- imi standard H Ph + Ph (4) conditions ray crystallographic analysis. Finally, the natural furan 62 63 23% 1:1 64 diterpenoid 67 was afforded after a facile deprotection of B. Proposed mechanism acetate. ZnBr(imi) ArBr N Scheme 1. Nickel-Catalyzed Acylation Performed on Ni0 Zn N Gram Scale for Furan Diterpenoid Synthesis. I

O N Br N Ar Me NiII VI pathway b NiII N N OH imi Br Me Me Me Me II OH 1. RuCl •3H O, NaIO CO 3 2 4 OH O imi O pathway a H H H H OAc CCl /CH CN/H O + 4 3 2 Alkyl Alkyl 64% Me Me Me Me Alkyl VIII SET IX sclareol, 68 69 X 2. CDI, CH2Cl2 gram scale O imi Ar O 3. N O Br NiIII XI 68% over N N Alkyl I N II Ar 2 steps VII Ni Br Br Alkyl Ni O 70 N N Br standard conditions V III X-ray of 71 71 O Alkyl N O O O NiIII Ar Alkyl N Br Ar IV Me Me Me Me C. Enantiopurity retention on tertiary imidazolides O 4. t-BuOK, THF O H H OH H H OAc O O 88% imi PhBr Ph Me Me Me Me Et Me Et Me 67 71 standard conditions 65, 90% ee 66, 34%, 91% ee In conclusion, we developed a new nickel-catalyzed reductive cross-coupling reaction, which enables the effi- Figure 2. Mechanistic investigation and possible reaction cient synthesis of alkyl-aryl ketones from easily prepared mechanism. and handled alkyl imidazolides and aryl bromides. To our anion VIII gives rise to an acyl radical IX that can either knowledge, this is the first time alkyl imidazolides have undergo CO extrusion (pathway a) or combine with Ni(II) been used to achieve a radical cross-coupling reaction. complex II to form Ni(III) intermediate XI to provide the Mechanistically, our evidence supports a striking radical desired product after reductive elimination (pathway b). chain process alongside an intriguing CO-extrusion- The diaryl ketone byproducts might be generated from re- recombination phenomenon. We anticipate that this cross- action between nickel complexes II and III.19 Moreover, coupling strategy will serve as a powerful and flexible pathway b is likely responsible for any imidazolides de- complementary radical acylation reaction that is likely to rived from untethered tertiary carboxylic acids (e.g., 29- find broad application on account of its ease-of-use and 31) because of potential low reactivity between sterically the ubiquity of its essential building blocks: alkyl carbox- hindered tertiary radicals and nickel complex III. This ylic acids and aryl bromides. Finally, our illustration of its hypothesis (pathway b) concerning tertiary imidazolides application for complex natural product synthesis at gram is supported by data from an enantiopurity retention ex- scale reinforces the practicality of the approach. Studies focused on uncovering further details of the reaction mechanism and on expanding the reaction scope to in- Chem. Commun. 2015, 51, 5089–5092. 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O O Easily handled acyl imidazole R1 R1 OH Radical chain mechanism Ar R2 R2 R R 3 Natural product synthesis 3 CDI

CO-extrusion-recombination O O ArBr, [Ni] CO R R1 R1 1 N • • N R R2 R2 Zn, ZnBr2 2 R R3 R3 3