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Palladium-Catalyzed Amide-Directed Enantioselective Hydrocarbo-functionalization of Unactivated Alkenes Using a Chiral Monodentate Oxazoline Ligand Hao Wang, Zibo Bai, Tangqian Jiao, Zhiqiang Deng, Huarong Tong, Gang He, Qian Peng, and Gong Chen J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00641 • Publication Date (Web): 23 Feb 2018 Downloaded from http://pubs.acs.org on February 23, 2018
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Journal of the American Chemical Society
Palladium-Catalyzed Amide-Directed Enantioselective Hydrocarbofunctionalization of Unactivated Alkenes Using a Chiral Monodentate Oxazoline Ligand Hao Wang1, Zibo Bai1, Tangqian Jiao1, Zhiqiang Deng1, Huarong Tong1, Gang He1,2*, Qian Peng1*, and Gong Chen1,2,3* 1
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China 2 3
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
ABSTRACT. A Pd-catalyzed amide-directed enantioselective hydrocarbofunctionalization of unactivated alkenes with C-H nucleophiles has been developed using a chiral monodentate oxazoline (MOXin) ligand. Various indoles react at C3 position with aminoquinoline-coupled 3-alkenamides to give g addition products in good to excellent yield and enantioselectivity. This study represents an important advance of the development of chiral monodentate oxazoline ligands, which have been underexplored for asymmetric catalysis. Methods for selective addition of carbon functional groups to alkenes would greatly augment the synthetic toolbox for the construction of complex carbon skeletons.1,2 While significant progress has been made in metal-catalyzed carbo-functionalization of activated alkenes substituted by carbonyl or aryl groups, the corresponding transformation of unactivated alkenes, especially in an enantioselective fashion, remains challenging.3-8 Notably, Widenhoefer reported palladium-catalyzed intramolecular addition of 1,3-diones to unactivated alkenes, forming cyclohexanones.5 Sigman developed a series of Pdcatalyzed enantioselective intermolecular Heck arylation reactions of acyclic alkenyl alcohols with chiral pyridine oxazoline (PyOX) ligands using a redox-relay strategy.6 Recently, Engle reported Pd-catalyzed intermolecular hydrocarbofunctionalization of unactivated alkenes with C-H nucleophiles such as indoles using an amide-linked aminoquinoline (AQ) directing group (Scheme 1A).7 Herein, we report the first Pd-catalyzed amide-directed enantioselective hydrocarbofunctionalization of unactivated acyclic internal alkenes using a newly developed monodentate oxazoline ligand (Scheme 1B). Engle has shown that the Pd(II)-catalyzed AQ-directed hydrofunctionalization of unactivated alkenes likely proceeds via regioselective Wacker-type nucleopalladation of alkene/Pd complex 1, forming palladacycle intermediate 2, which readily undergoes protodepalladation to give a g-addition product.7b The use of the AQ directing group is critical to control the regioselectivity of addition and suppress a competing b-H elimination process, which gives an undesired Heck reaction product.9 However, the strong coordination of the N,Nbidentate AQ group makes it a challenging platform for the development of an enantioselective reaction, due to the single ligand binding site left available on Pd for chiral induction.10 In addition to exerting chiral induction, the ligand also needs to accelerate the enantiodetermining nucleopalladation step, thus outcompeting the background non-asymmetric reaction to achieve high enantioselectivity. Encouraged by recent reports on Pd-catalyzed bidentate directing groupmediated asymmetric benzylic C-H arylation using chiral BINOLphosphate ligands,11 we were interested in exploring the AQ-directed enantioselective hydrocarbofunctionalization of alkenes. We commenced our study with Pd-catalyzed reaction of trans-3-pentenamide 3 with N-methylindole 4 (Table 1). We were pleased to find that this reaction proceeded at 60 oC in MeOH with ortho-phenyl benzoic
A) Engle: directed hydrofunctionalization of unactivated alkenes nucleo proto -palladation -depalladation O (AQ)
N
PdII N
O R
O N
N H
L 1
N
+
PdII N Nu
H
O
R γ
L 2
NHAQ
Nu
AcOH or p-OMeC6H 4CO2H (50 mol%), MeCN, 120 oC
Nu−H
B) This work: enantioselective transformation with MOX ligand new MOX ligand for F 3C chiral induction & rate acceleration (unactivated acyclic internal alkenes) O R
O Me
N
N NHAQ
+ Nu(C)−H (unfunctionalized C-nucleophiles)
CF 3
MOXin (20 mol%) Pd(OAc) 2 (10 mol%) o-PhC6H 4CO2H (100 mol%) MeOH, 60 oC
O R γ *
NHAQ
Nu(C) up to 95% yield up to 94% ee
Scheme 1. Pd-catalyzed AQ-directed enantioselective hydrocarbofunctionalization of unactivated acyclic internal alkenes.
acid (oPBA) additive, giving racemic product 5 in moderate yield (entry 1) under milder conditions than the original report (120 oC).7b Previously, oPBA was found to promote a related Pd-catalyzed AQdirected intramolecular methylene C-H arylation reaction with aryl iodides at ambient temperature, possibly due to its facile dissociation from Pd(II) of palladacycle intermediates.12 Various chiral ligands were evaluated for chiral induction and rate acceleration. While most of the common N-heterocyclic carbene, phosphate, and phosphoramidite ligands failed to exert any chiral induction, oxazoline (OX) type ligands gave encouraging results (see Supporting Information for results of additional ligands).13,14 In general, C4-benzyl substituted OX ligands gave higher er than C4-iPr substituted ligands (see L1-L10). While some multidentate OX ligands are effective (see L2 and L4), we found simple mono-dentate 2-methyl OX (MOX) ligands such as L11-L13 gave better er and yield.15 Subsequently, we evaluated a series of MOX ligands bearing a C4-benzyl type substituent.16 As shown by L15-L18, a C2 methyl group is critical for enantioselectivity. As shown by L1920, replacing the phenyl group with larger arenes such as naphthalene or indole further improved the er. Ultimately, our optimization yielded L27, bearing a N-3,5-di-CF3-phenyl substituted indole (MOXin), which gave an er of 93:7 and 95% yield of 5 (entry 5). These MOXin ligands were easily prepared in high yield in three steps from enantiopure tryptophan via reduction, condensation with triethyl orthoacetate, and Cu-catalyzed N-arylation.17 We made several key observations over the course of our optimization campaign. 1) oPBA is necessary to achieve high yield at lower reaction temperature (entries 5-9). 2) While yields of 5 were not affected by the ambient atmosphere (entry 10), we later found that
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Table 1. Development of oxazoline ligands for Pd-catalyzed enantioselective addition of 4 to 3. O N H
ligand (20 mol%) Pd(OAc) 2 (10 mol%)
+
N
N
3
Ph
O *
oBPA (1 equiv) [3]: 0.5 M MeOH, 60 oC, Ar, 48 h standard conditions
4 (2 equiv) Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
N
CO2H NHAQ
5
oPBA
Yield of 5 % (er) a 48 (50:50) 54 (50:50) 80%, >99% ee
a) All screening reactions were carried out in a 8 mL glass vial on a 0.2 mmol scale, yields are based on isolation, er was measured by chiral HPLC. b) MQ: 5-methoxy-8-aminoquinoline, CQ: 5-chloro-8-aminoquinoline, the corresponding modified product were obtained.
ambient atmosphere does diminish the reaction yield with more sterically hindered alkene substrates (see 10 in Scheme 2). 3) The er decreased at higher reaction temperature (entry 11). 4) Alcohol solvents give the best er (see entry 5 vs 13). 5) Substitution on the arene moiety of AQ did not affect the reaction (see MQ and CQ in entries 19 and 20). 6) N-methyl AQ (entry 15) was not effective directing group (see SI). With optimized conditions in hand, we next examined the substrate scope of alkenes using N-methylindole 4 (Scheme 2). Reactions of a variety of trans-3-alkenamides bearing different terminal R groups gave g-indoylated products. In general, substrates with larger R groups gave slightly lower yield and slightly higher er. 14 was obtained with a 97:3 er from a Bn-substituted trans-alkene substrate. Interesting-
ly, reaction of both trans and cis-hexenamide (7E and 7Z) gave the same enantio-enriched product 6 in similar yield and er.18 More sterically hindered alkenes such as 15 (R = iPr) were unreactive. As shown in scheme 3, a variety of indoles generated g-indoylated products in good yield and er under the standard conditions using MOXin L27 ligand. The absolute stereochemistry of 16 was determined via X-ray crystallography. As shown in 21 and 22, cyclic 1,3-dione nucleophiles gave the corresponding g-substituted products in good yield and er.7b As shown in 23, reaction of electron rich phenol proceeded in high yield but with moderate er. As shown in Scheme 4, the AQ group of product 9 can be cleanly removed to give methyl ester 24 without racemization using Ohshima’s Ni(tmhd)2-catalyzed alcoholysis protocol (tmhd:
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Page 3 of 5 Scheme 2. Substrate scope of alkenes
Scheme 4. Removal of AQ
4 (2 equiv) Pd(OAc) 2 (10 mol%) MOXin L27 (20 mol%)
O R
NHAQ trans a
N
O *
oPBA (1.0 equiv) MeOH, 60 oC, Ar, 48 h
NHAQ
N
R
N
Ni(tmhd) 2 (10 mol%)
O
MeOH, 100 oC Ar, 24 h
NHAQ
BnO
24, 85% (95:5 er) OMe
*
O
* O N
O N
NHAQ
O N
NHMQ
1) Boc 2O, DMAP, CH 3CN, rt, 24 h 2) LiOH, H 2O2 THF/H2O, 0 oC, 5 h
9 (95:5 er)
NHAQ
BnO 6 93% (95:5 er) (from trans alkene 7E) 94% (95:5 er) (from cis alkene 7Z)
8, 95% (96:4 er) BnO O
O N
9, 87% (95:5 er)
N
NHAQ
O N
NHAQ
MeO 2C
O N
Ph
A)
N
NHAQ
N
Pd
γ
R
NHAQ
14, 62% (97:3 er)
Pd
L
B)
L R
ΔG
15,
