Cu-Catalyzed Stereoselective Î³-Alkylation of Enones - Journal of the

Subscriber access provided by ORTA DOGU TEKNIK UNIVERSITESI KUTUPHANESI

Communication

Cu-Catalyzed Stereoselective #-Alkylation of Enones Xiaohong Chen, Xiaoguang Liu, and Justin T Mohr J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02565 • Publication Date (Web): 09 May 2016 Downloaded from http://pubs.acs.org on May 10, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Cu-Catalyzed Stereoselective γ-Alkylation of Enones Xiaohong Chen, Xiaoguang Liu, and Justin T. Mohr* Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States Supporting Information Placeholder ABSTRACT: A general regio- and stereoselective γ-C–C

bond formation is achieved using α-halocarbonyl compounds and dienol ethers via Cu(II) catalysis. This method constitutes a novel approach to the challenging 1,6dioxygenation motif. A range of γ-substituted enones, including many bearing all-carbon quaternary centers, are available through a simple protocol under mild reaction conditions with superb functional group compatiblity. Excellent stereoinduction is observed providing controlled access to challenging stereochemical arrays.

The carbonyl group is arguably the most important and versatile functional group in synthetic chemistry. This moiety is valuable not only for the useful electrophilic character of the carbonyl carbon, but also due to the ability to manipulate the surrounding atoms to construct new bonds.1 Utilizing these features of carbonyl reactivity in combination, powerful strategies for synthesizing dicarbonyl compounds have been developed. Claisen condensation, enolate alkylation with αhalocarbonyl electrophiles, and Michael addition protocols are robust classical platforms for generating 1,3-, 1,4-, and 1,5-dicarbonyl compounds. The homologous 1,6-dicarbonyl motif is considerably more challenging, however. Dienolate derivatives of enones posit a potential solution,2 but such hypothetical reactions are often complicated by the decreased electron density at the distant γ-site, and most electrophiles are found to react preferentially at the more nucleophilic α-C (Scheme 1, path A).3 As a result, it has been necessary to rely on antithetical disconnections such as oxidative cleavage of cyclohexenes, but these methods have substantial scope limitations (path B). The need for a direct γ-C–C bond formation technique is therefore quite significant. Our research program has aimed to develop robust systems for bond formation at γ-sites that are directly applicable to the synthesis of valuable target molecules bearing substitutions at this location.4 One potential strategy involves the addition of radical intermediates to dienol ethers which are, in turn, readily available enone derivatives (Scheme 1, path C).4b,c This design is based on the hypothesis that site selectivity in bond formation will be controlled through a preference for the stabilized oxyallyl radical that is only accessible

Scheme 1. Strategies for 1,6-dicarbonyl synthesis O O

1,6-dicarbonyl motif antithetical step (limited scope)

B

A conventional disconnection

α γ

(not generally feasible)

α alkylation favored

O

O O

O α

C OR O

radical addition to diene

α

OR

γ

γ

(this work)

O

OTBS

X

O

practical feedstocks

through the γ-addition pathway. Seminal reports by Kim and co-workers suggested the viability of this design using specialized substrates such as hydroxamic acids, but a general application of this strategy to common ketone synthesis has not been reported.3h,i We have therefore sought a system to resolve the significant and long-standing problem of γ-C–C bond formation in simple enone systems. In this communication we disclose the first regio- and stereoselective γalkylation protocol that enables direct synthesis of 1,6dicarbonyl compounds from simple enones and readily available α-halocarbonyl compounds using Cu catalysis. At the outset, we were attracted to recent reports of Cu catalysts capable of activating α-haloesters toward addition to π-systems.5 Although the mechanism of these Table 1. Optimization of radical coupling conditionsa

O

OTBS

O Br

EtO

2a

1a entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Cu catalyst (mol %) none Cu(OTf)2 (10) Cu(OTf)2 (10) Cu(OTf)2 (10) Cu(OTf)2 (10) CuI (10) CuCl2 (10) CuBr•SMe2 (10) CuCO 3 (10) none Cu(OTf)2 (10) Cu(OTf)2 (10) Cu(OTf)2 (10) Cu(OTf)2 (10) Cu(OTf) 2 (7.5)

a

Cu catalyst ligand solvent NaHCO 3 80 °C, 24 h ligand (mol %) none none bipy (20) TMEDA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (20) PMDTA (15)

3a EtO 2C solvent

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene CH3CN THF 1,4-dioxane DCE DCE

% yield 0 0 0 16 58 16 12 49 42 0 73 77 86 92 94

Isolated yield from reaction of of dienol ether 1a (0.25 mmol), α-haloester 2a (1.5 equiv), NaHCO3 (1.0 equiv), Cu catalyst, and ligand in 1 mL of solvent at 80 °C for 24 h.

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

transformations have not been rigorously supported, we hypothesized that a C-centered radical may be key intermediate that is potentially useful in our proposed coupling.6 We selected readily available, stable TBS dienol ether 1a4b,c and commercially available α-haloester 2a to examine the γalkylation with a range of Cu catalysts in toluene solvent with heterogeneous base (Table 1).7 We quickly learned that the supporting ligand is critical to reactivity: unligated Cu(II) and the bipy complex each fail to catalyze the coupling. Tertiary amine Cu complexes are catalytically active, and commercially available pentamethyldiethylenetriamine (PMDTA) is particularly effective (entries 1–5).5 Other Cu salts were inferior to Cu(OTf)2 and Cu is necessary for reaction to occur (entries 6–10). A solvent survey found 1,2dichloroethane (DCE) to be the optimal solvent (entries 11– 14). Reduction of the catalyst loading to 7.5 mol % resulted in isolation of the γ-alkylation product 3a in 94% yield.8 We have observed that a variety of dienol ethers are viable substrates for the γ-alkylation reaction (Table 2). These dienol ethers are prepared by straightforward enolization/silylation under basic conditions or through soft Table 2. Scope of siloxydiene coupling partner

O

OTBS EtO 2C

R

1 entry

2 3

7.5 mol% Cu(OTf)2 15 mol% PMDTA

Br

2a

OTBS R

4 5

1a 1b 1c 1d 1e

R =H

R

R = Me

O

3a 3b 3c 3d 3e

O

OTBS

OTBS

siloxydiene

1

1a 1a 1a 1a

3 4 5b

R1

1k

entry

1a

7

1a 1a

R2

2b 2c Br 2d 2e

O Y

2f

Br

EtO

Y = OPropargyl Y = OCH2CH2OH Y = NEt 2

9d

1a

Y

R =H

EtO 2C

t-Bu O

1k

OEt

Br

>20:1 dr 68

71

3j

64

3o O

R

80 84 93 77 97

3p

85

3q

93

3r

90

3s

82

3t

74

3u

65

3v

83

O

Br 2j

MeO

>20:1 dr 72

3i

O

Y = SC18H 37

Ph

O

1k

13 e

14 e

Ph O

O

O

2m O

O

2n

Br

O

O

1k

OEt

O

Cl

1k

O

2l

O 12 e

t-Bu

O

O

1k

MeO 2C O

2k

O

CO2Et

3k 3l 3m 3n

O

>20:1 dr 64

75

% yield

O

Br

3h

R1

product Y = OAllyl

2h R = CO2Et 2i

R

O

R2

Y

2g Y = H O

3

NaHCO 3 DCE, 80 °C

halocarbonyl

O

Ph

3w 57

O

2o

Ph 3x

72

3y N Ph

85

Br

O

OTBS


2

1a

6

11 e

CO2Et

1i

9b

1a

2

X

Y

CO2Et

O

O

>20:1 dr 88

3g >20:1 dr 76

1h

8b

94 >20:1 dr 82

EtO 2C O

1g

7

OTBS or

10 e

3f

OTBS

O OTBS

% yield

R = Allyl EtO 2C

Table 3. Scope of α-halo coupling partnera

8c

R = Bn R = CH2CO2t-Bu

enolization techniques.4b,c When the enone precursor contained an α-substituent, we observed exceptional stereoselectivity in the alkylation reaction, delivering the 1,6-dicarbonyl products in high yield as a single detectable diastereomer (entries 2–5). This stereoinduction was maintained with βsubstituted enones as well, delivering the anti stereodiads as a single isolated diastereomer (entries 6–7). Dienols containing an exocyclic reactive site also proved to be very good substrates for the coupling reaction (entries 8–10). Modification of the α-halocarbonyl coupling partner

EtO 2C

1f

6

3

product

OTBS

10 b

R

NaHCO 3 DCE, 80 °C

siloxydiene

1

a

Page 2 of 5

O

1j CO2Et

O 15 e,f

1k

Br

a

Isolated yield (average of two runs) from reaction of of dienol ether 1a (0.25 mmol), α-haloester 2a (1.5 equiv), NaHCO3 (1.0 equiv), 7.5 mol% Cu(OTf)2, and 15 mol% PMDTA in 1 mL of DCE at 80 °C for 24 h. b Isolated yield over two steps from the corresponding enone.

O

a

N

O

2p N Ph

Ph

O

N

Ph

Isolated yields. See Table 2 for reaction conditions. b Reaction in EtOH solvent. c 1:1 dr. d 1.4:1 dr. e Isolated yield over two steps from the corresponding enone. f Reaction at 22 °C.


Page 3 of 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


provided a test of functional group tolerance (Table 3). We were delighted to discover that alkenes, alkynes, unprotected hydroxyl groups, amides, thioesters, and even aldehydes are compatible with our protocol (entries 1–6). Use of an αbromomalonate, an α-bromopropionate, a neopentyl bromide, or a benzylic bromide each provided excellent results, indicating both steric and electronic flexibility in the halide component (entries 7–10). Isophorone-derived dienol ether 1k was readily alkylated with either cyclic or acyclic αhalocarbonyls to generate tertiary or all-carbon quaternary centers in high isolated yields (entries 10–15). Notably, αchlorocyclohexanone (2m) performed well under our standard conditions and the use of a brominated derivative of the commercialized antiinflammatory agent phenylbutazone (2p) delivered the coupling product in very good yield when the reaction was conducted at 22 °C. Seeking to test the limits of our method for preparing sterically congested systems, we examined γ-alkylated dienol ether 1l (eq 1). Although this substrate was unreactive with OTBS

Br

EtO

1l

O


O

4

NaHCO 3 DCE, 80 °C 54% yield, 1.3:1 dr

2i

(1)

EtO 2C

tertiary α-halo esters (e.g., 2a), vicinal quaternary and tertiary carbon centers could be accessed using ethyl 2bromopropionate (2i) under our standard conditions, thereby demonstrating the ability to generate sterically challenging C–C bonds with relative ease.

Table 4. α-Polyhalo coupling partnersa TBSO R

X2

EtO

entry

2 siloxydiene

1a

O

1a

3 R

EtO

EtO

1a R = H 1c R = Bn

4

Cl

Cl

EtO 2C

2q

Cl Cl

Cl

O EtO

Br F

3aa

EtO 2C

F

2r

Cl

R

TBSO

O

1f

EtO

F O

F

F

3ac

>20:1 dr

3ad

>20:1 dr

F F

90

F

Isolated yields. See Table 2 for reaction conditions.

2u

O 1. TFA CH2Cl2

Cu cat.

OTBS

1a

71

Boc NBn

3af

Boc

O

3ag CO2Me

O2N

HO

H

O

H

2. 2 N HCl

H N Cl

Cl

Chloramphenicol (2w) antibiotic


O OH

1k O

TBSO

Cu(OTf)2 (7.5%) PMDTA (15%) NaHCO 3 EtOH, 80 °C, 6h; DBU, 20 min

O

H

CO2Me

OH

63

71% NBn overall 1:1 dr

1. MeLi THF 0 → 22 °C

Cu cat.

8

H

2. TsOH PhH, ∆

O

Cl

2v

7

91% single diastereomer

EtO 2C

O

d)

6 (95%)

O

H O

NBn

OH

H

Cl

1a

e)

Br 2r EtO 2C

a

3ab

Cu cat.

2t

Br

O

O

OTBS

59

O

2r

O

1a

3.9:1 dr

Ph O

EtO

c)

5 (84%) O

3ae

88

Cl Cl

Ph

(80%, 1.1:1 dr)

OTBS

O

O

DBU THF

Cl

Cl

b)

Zn (1 equiv) AcOH

Ph

Cl

2s

O

O

Cu cat.

O Ph

% yield

3z

EtO 2C

5

X1

2q

Cl

O

(3.05 equiv)

TBSO

X1

product

O 2

3

O

TBSO 1

1a

EtO 2C

α-halo compound

OTBS

R

NaHCO 3 DCE, 80 °C

X1 X1

1

a) O


O

In further examining the scope of the halocarbonyl component, we observed that ethyl trichloroacetate (2q, Table 4, entry 1) furnished the coupled product 3z in excellent yield. Adjustment of reagent stoichiometry led to formation of the 2:1 coupling product 3aa as the major product, although the final chloride proved reluctant to couple further even under forcing conditions (entry 2). In addition to chlorinated compounds, ethyl bromodifluoroacetate (2r) was found to provide desirable difluoracetate derivatives efficiently (entries 3–5). The exceptional diastereoselectivity was maintained with these less sterically demanding substrates. Although primary α-halo compounds were unreactive under our standard reactions conditions, we discovered that dihalocarbonyl compounds served as viable synthons for the parent coupling partners. α,α-Dichloroacetophenone (2s) coupled with dienol ether 1a in 80% yield, and the initial coupling product was readily reduced with Zn0 in AcOH to enone 5 in 84% yield (Scheme 2a). Alternatively, the initial coupling product (3ae) eliminates under basic conditions to furnish the formal α-arylation product 6 in 95% yield. To explore the prospect of heterocycle synthesis, we employed haloacetoacetate 2t in our transformation and obtained hexahydrobenzofuran 7, the product of a formal [3+2] cycloaddition, in excellent yield (Scheme 2b).4c Toward N-heterocycles, we employed propionimide 2u in our coupling and after cleavage of the Boc group and acidcatalyzed conjugate addition, lactam 8 was formed in 71% Scheme 2. Synthetic applications of coupling products

O2N

10 (82%)

HO

O

wine lactone (9) 37% overall

H N

O


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

overall yield (Scheme 2c). Through a similar strategy, dienol ether 1a was coupled with propionate 2v and after subsequent chemoselective addition of MeLi and acid treatment, the natural product wine lactone (9) was isolated in 37% overall yield (Scheme 2d). As a final application, the unprotected broad-spectrum antibiotic chloramphenicol (2w) was coupled to dienol ether 1k with concomitant elimination to acrylamide 10 in high overall yield (Scheme 2e). To conclude, we have developed a robust, general, Cucatalyzed technology for γ-alkylation of enones via readily available dienol ether derivatives and α-halo compounds. The transformation proceeds in excellent yield, exhibits complete regiocontrol, tolerates sterically demanding coupling partners, and is highly diastereoselective. This method enables the synthesis of 1,6-dicarbonyl compounds that have largely eluded conventional bond formation strategies. The excellent functional group compatibility of this transformation ensures broad applicability to a variety of highly functionalized target molecules. A S S O C I AT E D C O N T E N T The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data (PDF) Copies of NMR spectra (PDF)

A U T H O R I N F O R M AT I O N Corresponding Author

* E-mail: [email protected]

A C K N O WL E D G M E N T Funding was provided by the UIC Department of Chemistry. We thank Profs. Vladimir Gevorgyan, Duncan Wardrop, Tom Driver, Laura Anderson, Daesung Lee, and Neal Mankad (UIC) for helpful discussions and use of reagents and equipment.

REFERENCES 1. (a) Stoltz, B. M.; Mohr, J. T. Protonation, Alkylation, Arylation, and Vinylation of Enolates. In Science of Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 3, pp 615–674. (b) MacMillan, D. W. C.; Watson, A. J. B. α-Functionalization of Carbonyl Compounds. In Science of Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 3, pp 675–745. (c) Nguyen, B. N.; Hii, K. K.; Szymanski, W.; Janssen, D. B. Conjugate Addition Reactions. In Science of Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 1, pp 571–688. 2. The γ-dienolate is lower in energy than the isomeric α-dienolate, see: Bartmess, J. E.; Kiplinger, J. P. J. Org. Chem. 1986, 51, 2173–2176.

Page 4 of 5

3. For selected examples of γ-functionalization of carbonyl compounds, see: (a) Katzenellenbogen, J. A.; Crumrine, A. L. J. Am. Chem. Soc. 1974, 96, 5662–5663. (b) Bryson, T. A.; Gammill, R. B. Tetrahedron Lett. 1974, 15, 3963–3966. (c) Fleming, I.; Goldhill, J.; Paterson, I. Tetrahedron Lett. 1979, 20, 3209–3212. (d) Majewski, M.; Mpango, G. B.; Thomas, M. T.; Wu, A.; Snieckus, V. J. Org. Chem. 1981, 46, 2029–2045. (e) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 813– 814. (f) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998, 39, 6203–6206. (g) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800–7801. (h) Kim, S.; Lim, C. J. Angew. Chem., Int. Ed. 2004, 43, 5378–5380. (i) Lee, J. Y.; Kim, S. Synlett 2008, 49–54. (j) Hyde, A. M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 177–180. (k) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756–2757. (l) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131, 14231–14233. (m) Huang, D. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49, 5757–5761. (n) Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 15362–15364. (o) Li, S.; Zhu, R.-Y.; Xiao, K.-J.; Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 4317–4321. (p) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A. Y.; Tran, K.; Stoltz, B. M. J. Am. Chem. Soc. 2016, 138, 5234–5237. (q) Fu, L.; Guptill, D. M.; Davies, H. M. L. J. Am. Chem. Soc. ASAP. DOI: 10.1021/jacs.6b01941. (r) Gurak, J. A., Jr.; Yang, K. S.; Liu, Z.; Engle, K. M. L. J. Am. Chem. Soc. ASAP. DOI: 10.1021/jacs.6b02718. (s) For an alternative β,β-coupling approach, see: Hu, X.-H.; Zhang, J.; Yang, X.-F.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 3169–3172. 4. (a) Chen, X.; Martinez, J. S.; Mohr, J. T. Org. Lett. 2015, 17, 378–381. (b) Liu, X.; Chen, X.; Mohr, J. T. Org. Lett. 2015, 17, 3572–3575. (c) Liu, X.; Chen, X.; Mohr, J. T. Chem.–Eur. J. 2016, 22, 2274–2277. (d) Chen, X.; Liu, X.; Mohr, J. T. Org. Lett. 2016, 18, 716–719. (e) Chen, X.; Liu, X.; Martinez, J. S.; Mohr, J. T. Tetrahedron 2016, 72, in press. DOI: 10.1016/j.tet.2016.02.006 5. (a) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 3638–3641. (b) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc. 2013, 135, 16372–16375. (c) Gietter, A. A. S.; Gildner, P. G.; Cinderella, A. P.; Watson, D. A. Org. Lett. 2014, 16, 3166–3169. (d) Xu, T.; Hu, X. Angew. Chem., Int. Ed. 2015, 54, 1307–1311. (e) Fisher, D. J.; Burnett, G. L.; Velasco, R.; Read de Alaniz, J. J. Am. Chem. Soc. 2015, 137, 11614–11617. 6. (a) Nagashima, H.; Wakamatsu, H.; Itoh, K.; Tomo, Y.; Tsuji, J. Tetrahedron Lett. 1983, 24, 2395–2398. (b) Pirrung, F. O. H.; Steeman, W. J. M.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Boesten, W. H. J.; Schoemaker, H. E.; Kamphuis, J. Tetrahedron Lett. 1992, 33, 5141–5144. (c) Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J. Org. Chem. 1993, 58, 464–470. For selected reviews featuring Cumediated radical reactions, see: (d) Minisci, F. Acc. Chem. Res. 1975, 8, 165–171. (e) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519– 564. (f) Gossage, R. A.; van de Kuil, L. A.; van Koten, G. Acc. Chem. Res. 1998, 31, 423–431. (g) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464–3484. (h) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234–6458. (i) Guo, X.-X.; Gu, D.W.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115, 1622–1651. (j) Anastaski, A.; Nikolaou, V.; Nurumbetov, G.; Wilson, P.; Kempe, K.; Quinn, J. F.; Davis, T. P.; Whittaker, M. R.; Haddleton, D.M. Chem. Rev. 2016, 116, 835–877. 7. The base is important to overall reactivity, although several bases were found to be competent. See the Supporting Information for details. 8. The reaction proceeds with lower catalyst loadings but achieving high yield requires long reaction time. A reaction with 1 mol % Cu(OTf)2 for 48 h delivered 77% yield although conversion was incomplete.


Page 5 of 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


OTBS

γ Br

α

R1 O

R2 R3 practical feedstocks

O

Cu-catalyzed α, γ-coupling

R1

α

γ R2

R3

O

– new γ-C–C bond – regioselective – stereoselective – 1,6-dicarbonyl moiety – quaternary centers – functional group tolerant – 36 examples


5

Cu-Catalyzed Stereoselective Î³-Alkylation of Enones - Journal of the

Recommend Documents