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M H. H. (c) Alkyne-mediated allylic alkylation of unactivated ketones. O. *. O. Ar. Me. Ar. O. Ar .... Isolated yield. f exo-2a' was obtained with 11%...
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Pd-Catalyzed Intramolecular #-Allylic Alkylation of Ketones with Alkynes: Rapid and Stereodivergent Construction of [3.2.1] Bicycles Pengfei Zheng, Chengpeng Wang, Ying-Chun Chen, and Guangbin Dong ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00997 • Publication Date (Web): 07 May 2019 Downloaded from http://pubs.acs.org on May 7, 2019

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ACS Catalysis

Pd-Catalyzed Intramolecular α-Allylic Alkylation of Ketones with Alkynes: Rapid and Stereodivergent Construction of [3.2.1] Bicycles Pengfei Zheng†,‡, Chengpeng Wang‡, Ying-Chun Chen† and Guangbin Dong*‡ †College

of Pharmacy, Third Military Medical University, Chongqing 400038, China.

‡Department

of Chemistry, University of Chicago, Chicago, Illinois 60637, United States.

ABSTRACT: Here we describe a palladium-catalyzed intramolecular α-allylic alkylation of unactivated ketones with alkynes. The reaction proceeds in the absence of any amine cocatalyst; both endo and exo-bridged cyclohexanone bicycles can be obtained diastereoselectively. The stereodivergency is controlled by the ligand and acid additive used. Specifically, the monodentate DTBMPP ligand favors forming the endo isomer, while the bidentate DIOP ligand prefers to give the exo isomer. A broad range of functional groups are tolerated, which provides a chemoselective approach to access [3.2.1] bicyclic skeletons. Further deuterium labeling studies support a pathway involving an alkyne/allene isomerization and Pd-π-allyl complex formation. KEYWORDS: cyclization, palladium catalysis, alkynes, stereodivergent, bridged rings

Intramolecular ketone/alkyne couplings, also known as the alkynyl Conia-Ene reaction, represent a highly important approach for constructing bridged and fused bicyclic rings (Scheme 1a), which have been frequently utilized in complex natural product syntheses.1,2 This reaction is typically catalyzed by a π-acidic metal, and a new C−C bond is formed between the α-position of the ketone and the proximal alkynyl carbon. Given the easy access to alkyne-tethered ketones, one intriguing question is whether the C−C bond forming event could occur at the propargylic position instead, which, in turn, should lead to a different bridged structure along with two vicinal stereocenters. Terminal and methyl alkynes are well known to serve as allene surrogates that can undergo hydrometalation to generate electrophilic metal π-allyl species (Scheme 1b).3 Seminal reports by Trost4 and Yamamoto5 demonstrated the feasibility of alkyne-mediated allylic substitutions using a Pd catalyst. Elegant work by Breit6 and later Dong7 showed that branched selectivity can be achieved with Rh catalysis. In terms of the C−C forming reactions, while the use of activated methylene compounds as nucleophiles in the alkyne-based allylic alkylation has been known since 1998,5a direct employment of simple, unactivated ketones was not reported until the recent work by Lin,8 which utilized the amine/palladium cooperative catalysis to generate a nucleophilic enamine intermediate in situ (Scheme 1c). The enantioselective transformation of the reaction was realized by the Zhao group in 2018.9 Both reports were focused on intermolecular reactions with methyl alkynes as the coupling partner. To the best of our knowledge, intramolecular α-allylic alkylation of unactivated ketones with alkynes remained an unknown transformation. Herein, we describe an accidental discovery of a Pdcatalyzed intramolecular allylic alkylation of cyclic ketones with internal alkynes in the absence of amine cocatalysts (Scheme 1d). This method enables a rapid and stereodivergent synthesis of a unique [3.2.1] bicyclic skeleton, which is often found in biologically important and structurally fascinating natural products (Figure 1).10

(a) Intramoleular ketone alkyne couplings X

X

-acidic metal cat. O

O

[3.3.1]

R

X

R

Conia-Ene

X

cat. O

O

?

[3.2.1]

(b) Alkyne serving as an allylic electrophile M

M H

R

R

(Pd or Rh)

R'

Nu

Nu-H

R'

R

H

R'

(c) Alkyne-mediated allylic alkylation of unactivated ketones 

O

O

N

Ar

Me

Ar



[Pd]/amine dual catalyst

Lin (2016); Zhao (2018)

(d) This work O

O

O H

Ar

H

Pd DTBMPP

X endo

Ar X

Ar

Pd X exo

()-DIOP

X = O, NR X O

H

Ar

stereodivergent two vicinal stereocenters byproduct free amine co-catalyst free

X O

Ar

H

Scheme 1. Transition-Metal-Catalyzed Alkyne/Ketone Couplings

ACS Paragon Plus Environment

ACS Catalysis Me Me

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HO H

O Me

Me Me

Me

Me Me

aegicerin antimycobacterial H

Me Me

Me O

miliusane XIX anticancer

O

H O

O

Me

O

HO

endo-2a

O Me MeO Me

H

O

O

Ph

dioxane (0.1 M) N2, 110 °C, 12 h

Entry

()-hexacyclinol antiproliferative COOMe

O

H

DTBMPP (20 mol %) Pd(OPiv)2 (10 mol %) CsOPiv (10 mol %) HFIP (200 mol %)

O

O

O

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O O

N

()-securinine (CNS) stimulant

Figure 1. Representative natural products or pharmaceuticals containing a [3.2.1] bicyclic skeleton.

During our ongoing efforts on developing ketone/unsaturate coupling reactions,11 a pair of unexpected allylic alkylation products (2a and 2a’) was observed when using ketone 1a as the substrate. Intrigued by the unique scaffolds of these annulation products, the reaction was carefully optimized to achieve good yields and satisfactory diastereoselectivities for each product (Table 1 and Supporting Information). Ultimately, complementary conditions (A and B) were identified. When Pd(OPiv)2 and a monodentate electron-rich phosphine were used as the metal/ligand combination, the endo-diastereoisomer 2a was selectively formed in good yields (entries 1−3, Table 1). For the choice of ligand, tris(3,5-di-tert-butyl-4-methoxyphenyl)phosphine (DTBMPP) proved to be superior to P(Cy)3 and less sterically hindered tris(3,5-dimethyl-4methoxyphenyl)phosphine (DMMPP). Different palladium precatalysts have also been examined: while Pd(OAc)2 gave a comparable yield, the diastereoselectivity was significantly worse than that of Pd(OPiv)2 (entry 4, Table 1). Surprisingly, Pd(TFA)2 and Pd(COD)Br2 give no conversion, which may suggest the importance of having a basic X ligand on Pd for deprotonation of the ketone αC−H bond during the reaction (entries 5 and 6, Table 1). A catalytic amount of CsOPiv is critical to the reactivity (entry 7, Table 1), which further supports the role of the basic X ligand. Other inorganic bases were also effective albeit with somewhat lower diastereoselectivity (entry 8, Table 1 and Supporting Information). In addition, adding mildly acidic HFIP (pKa 9.3 in H2O) as an additive was another key factor for the enhanced endo selectivity (entry 9, Table 1), though the exact reason is unclear. Other sterically hindered HFIP analogues displayed similar reactivity but the reactions were less stereoselective. Slightly lower reaction temperature reduced the conversion, though improving the diastereoselectivity (entry 10, Table 1).

()-DIOP (10 mol %) [Pd(allyl)Cl]2 (5 mol %) CsOPiv (100 mol %) PhCOOH (50 mol %)

Ph

O O

dioxane (0.067 M) N2, 130 °C, 7 h

"standard conditions A"

"standard conditions B"

1a

endo:exo ratioc

Variations from the "standard conditions"

Ph

H exo-2a'

Yield (%)d

1

standard conditions Aa

8:1

80 (78e)

2

P(Cy)3 instead of DTBMPP

4.7:1

81

3

DMMPP instead of DTBMPP

3:1

68

4

Pd(OAc)2 instead of Pd(OPiv)2

2.4:1

70

5

Pd(TFA)2 instead of Pd(OPiv)2

/

6

Pd(COD)Br2 instead of Pd(OPiv)2

/

/

7

w/o CsOPiv

/