Recent advances in copper-catalyzed propargylic substitution

Tetrahedron Letters 56 (2015) 283–295

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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Digest Paper

Recent advances in copper-catalyzed propargylic substitution De-Yang Zhang, Xiang-Ping Hu ⇑ Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China

a r t i c l e

i n f o

Article history: Received 13 September 2014 Revised 18 November 2014 Accepted 18 November 2014 Available online 1 December 2014 Keywords: Copper Propargylic substitution Asymmetric catalysis N-Nucleophiles C-Nucleophiles

a b s t r a c t The copper-catalyzed propargylic substitution reaction has become a powerful synthetic method to prepare the compounds containing the propargylic subunit. Compared with the other transition-metals applied in the propargylic substitution, copper has many obvious advantages, such as much more inexpensive, easier to handle, milder reaction condition, and higher selectivity. This digest summarizes the recent development in the copper-catalyzed propargylic substitutions with various nitrogen, carbon, oxygen, and sulfur nucleophiles. In addition, the cycloadditions involving the copper-catalyzed propargylic substitution as the key step are included. Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/).

Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic substitution using nitrogen nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic amination of propargylic esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-opening reaction of ethynyl epoxides with amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decarboxylative propargylic amination of propargyl carbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic amination/cyclization tandem reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic substitution using carbon nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ketone enolates or their equivalents as nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic alkylation of enoxysilanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic alkylation of enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decarboxylative propargylic alkylation of propargyl b-ketoesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic alkylation of aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic alkylation of b-dicarbonyl compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic substitution of indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic substitution of terminal alkynes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic trifluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic alkylation/cycloaddition tandem reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propargylic substitution of oxygen and sulfur nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

283 284 284 287 287 287 287 287 287 288 289 290 290 291 291 291 293 294 294 294 294

Introduction

⇑ Corresponding author. Tel.: +86 411 84379276; fax: +86 411 84684746. E-mail addresses: [email protected], [email protected] (X.-P. Hu).

Propargylic compounds are common motifs in many natural products, fine chemicals, and synthetic pharmaceuticals, as well as useful synthetic intermediates in organic synthesis. The presence

http://dx.doi.org/10.1016/j.tetlet.2014.11.112 0040-4039/Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

OLG +

R

R 1

1

H N

R1

CuCl (1-5 mol%)

R2 2 equiv 2

R2 N

50 oC or reflux THF, 2 h

R 3

LG = Ac or PO(OEt)2 Et

OH

Bn

Et N

N

C 5 H11

N C 5H 11

Ph

91% yield

75% yield

85% yield OH

Bn N

N

N

95% yield Ph

OH

N

lic substitution reaction, copper salts display some distinct advantages: (1) low cost, (2) low toxicity, (3) mild reaction condition, (4) operational simplicity, (5) broad substrate scope, (6) excellent selectivity. In particular, recent progress in the Cu-catalyzed asymmetric propargylic substitution further demonstrated its superiority. Although some recent reviews about propargylic substitution have been reported,4 there are no specific reviews focused on the copper-catalyzed propargylic substitution reaction. Herein, we describe recent developments in the emerging field of copper-catalyzed propargylic substitution reactions, classified by the nucleophiles.

HN

Propargylic substitution using nitrogen nucleophiles

C5 H11 60% yield

84% yield

80% yield

85% yield

Scheme 1. Cu-catalyzed propargylic amination.

of the nucleophilic triple bond, accompanied by a fairly acidic terminal acetylenic hydrogen in many cases, make these propargylic compounds highly potential for a wide variety of transformations.1 The Nicholas reaction,2 a well-known substitution reaction of propargylic alcohol derivatives with various nucleophiles, represents one of the most effective methods for the synthesis of a wide range of propargylic compounds. However, this reaction requires a stoichiometric amount of toxic Co2(CO)8, which significantly limited its application. Therefore, the development of a catalytic propargylic substitution becomes a pre-requisite task for organic chemists. In comparison with the transition-metal-catalyzed allylic substitution reaction which is one of the most reliable methods in organic synthesis,3 the catalytic propargylic substitution reaction has been lagging far behind. To date, the catalytic propargylic substitution reaction was mostly limited to work using Pd, Cu, Ti, and Ru catalysts,4 and the first catalytic asymmetric version5 occurred until 2003. Among various catalysts used in the propargy-

OAc +

Ar

R1

Conditions

R1

R2 N H 2.0 equiv

R2

Ar

2

1

N

3 Cl

O

O

N

Ph N

Ph N

Ph

Ph diPh-pybox L1

Conditionsa a b c db e fc g h i j k l a

A A A A A A B B B B B B

Ar

Ph 1-naphthyl 2-pyridyl i Pr Ph Ph Ph 4-BrC 6H 4 4-MeC6 H 4 Ph Ph Ph

MeO MeO

PPh 2 PPh 2

Propargylic amines are versatile building blocks and intermediates for organic synthesis.6 Transition-metal catalyzed propargylic substitution using nitrogen nucleophile is one of the most attractive strategies to synthesize these compounds. In recent years, the copper-catalyzed propargylic substitutions using nitrogen nucleophiles have made great progress. Different kinds of copper-catalyzed propargylic aminations, as well as the cycloadditions with propargylic amination as the key step, have been developed. Propargylic amination of propargylic esters In 1960, Hanzel and co-workers developed a propargylic amination of tertiary propargylic chlorides with various amines.7 It was found that the copper catalyst (CuCl–Cu) was necessary to achieve good yields when the aromatic amines were used as the nucleophiles. The formation of a more reactive copper acetylide species was proposed to be responsible for the improved reactivity. In 1994, Murahashi and co-workers developed a highly effective CuCl-catalyzed propargylic amination of propargylic acetates and phosphates 1 with various amines 2 under mild conditions (Scheme 1).8 The reaction was highly regioselective and no allenylamine byproducts were observed. Additionally, a terminal acetylenic proton was essential for this copper-catalyzed amination, and an internal alkyne did not undergo the amination even under severe conditions. This result suggested a copper–acetylide complex should be formed as the key intermediate. Although still in the racemic series at this stage, this work sets the stage for an enantioselective version. However, it is until 2008, van Maarseveen and Nishibayashi independently reported the first copper-catalyzed asymmetric propargylic amination.9,10 These methods provided an efficient

Cl (R)-Cl-MeO-BIPHEP L2

R1 H H H H H Me Me Me Me Me H

R2

Yield

2-MeOC6 H4 2-MeOC6 H4 2-MeOC6 H4 2-MeOC6 H4 Ph Ph Ph Ph Ph 4-ClC 6 H4 -(CH 2) 5-

97 91 80 27 94 90 96 91 98 96 64 90

Ph

i Pr

2NHEt

Ee of 3 85 85 74 40 87 60 85 85 81 89 80 53

i

Condition A: CuI (10 mol%)/diPh-pybox L1 (12 mol%), Pr2 NEt (4.0 equiv), MeOH, -20 o C. Condition B: CuOTf 1/2C 6 H5 (5 mol%)/ (R)-Cl-MeO-BIPHEP L2 (10 mol%), iPr 2NEt (4.0 equiv), MeOH, 0 o C. b The o c reaction was performed at 40 C. The reaction was performed at rt.

Scheme 2. Cu-catalyzed asymmetric propargylic amination.

i Pr NHEt 2

OAc

i

Ar B

i

Pr 2NEt

Pr2 NEt

CuL* Me

OAc NR 1R 2

O

CuL*

Ar

CuL*

C Ar

i

• •

E

OAc NR 1R 2

1

Pr2 NEt

CuL*

Cu-allenylidene complex Ar

Ar

H

Ar

A

Ar 3

Ar

O

γ D

G *

1 2

CuL

i Pr NEt •AcOH 2

α CuL *

Cu-acetylide complex

NHR R Ar F

β

CuL *

NHR 1 R2 2

Scheme 3. Proposed reaction pathway for Cu-catalyzed propargylic amination.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 pseudo axial

OAc

P

Cu

P

Ph

ArNHR 1 3.0 equiv

+

1

CuOTf 1/2C6 H5 (5 mol%) (R)-BINAP L3 (10 mol%) i Pr NEt (1.2 equiv) 2 MeOH, 0 o C, 96 h

R1

N

Ar

Alkyl

2

3 PPh2 PPh2

(R)-BINAP L3

N

N

50% yield 82% ee

N

Ph Ph 4-CF3C 6H 4 4-MeC6 H 4 2-furyl Ph 4-FC6 H4 4-MeC6 H 4 Ph Ph Bn Cy n Pr Cy

50% yield 83% ee

50% yield 89% ee

OLG ArNH2

+

2.0 equiv

1 LG = Ac or Piv

57% yield 82% ee

CuI (10 mol%) Me-pybox L4 (12 mol%) iPr NEt (4.0 equiv) 2 MeOH, rt, 24-48 h

2

HN

Ar

Alkyl 3

O

O

N N

N

Me-pybox L4 MeO

MeO

HN

HN

77% yield 82% ee

84% yield 67% ee

MeO MeO

Yield (%) ee (%)

Ph H 2-MeOC 6 H4 H 2-MeOC 6 H4 H 2-MeOC 6 H4 H 2-MeOC 6 H4 H Ph Me Ph Me Ph Me Et Et -(CH 2) 5H H Me Me

2-MeOC 6 H4 2-MeOC 6 H4 Ph Ph

85 89 85 84 92 86 90 84 87 77 45 52 76 69

90 93 96 90 89 95 97 92 95 91 78 81 91 93

Scheme 7. Cu-catalyzed asymmetric propargylic amination with chiral P,N,Nligands.

N

Scheme 5. Cu-catalyzed asymmetric propargylic amination of propargylic pentafluorobenzoates with secondary amines.

96% yield 85% ee

A A A A A A A A A A B B B B

R2

a Condition A: CuCl (5 mol%)/(Sc,RP)-L5 (10 mol%), i Pr2 NEt (1.2 equiv), MeOH , 0 oC, 12-24 h. Condition B: Cu(OAc) 2 H 2O (10 mol%)/ (R c)-L6 (12 mol%), i Pr2 NEt (4.0 equiv), MeOH, 0 o C, 60 h. b The reaction o c was performed at -20 C for 48 h. CuOTf 1/2C 6H 6 was used instead of CuCl.

Cl

HN

R

a b c d eb f g h i jc k l m n

N

(R c)-L6 R1

Conditions a b

Alkyl

MeO

N PPh 2

(Sc,R p)-L5

Scheme 4. Model of the transition state of the copper–allenylidene complex bearing (R)-BIPHEP.

Alkyl

3

N

H N

OCOC 6F 5

*

Fe

edge to face interaction

R2

N

R

+

H

R1

Conditions

N

PPh 2

H

re face attack Ph

R2

2

N

Ph (S)

γ

N H

1

pseudo equatorial

α β

+

R

HOMe

R1

HN

59% yield 90% ee

Nishibayashi and co-workers made an exhaustive research on the reaction mechanism and proposed a reaction pathway similar to van Maarseveen’s (Scheme 3).11 The experimental results revealed that the copper–allenylidene complex should be the key intermediate. This conclusion is also supported by density functional theory calculations for the model reaction. Here the attack of the amines to the Cc atom of the copper allenylidene complex D is the key step in determining both the regio- and stereoselectivities. This mechanism explains why the reaction requires the use of propargyl substrates with terminal acetylene. A transition state of the copper–allenylidene complex with the chiral ligand (R)-BIPHEP L2 is proposed to account for high enantioselectivity of the reaction (Scheme 4).11 The re-face of the c-carbon of the copper–allenylidene complex is open to attack by the N-methylaniline. The edge-to-face interaction between the carbonAhydrogen bond of the substrate and the phenyl group at the pseudo-equatorial position of (R)-BIPHEP L2 is considered as an essential factor in achieving high enantioselectivity. In 2011, Nishibayashi and co-workers realized the copper-catalyzed enantioselective propargylic amination of aliphatic propargylic esters 1, a challenging substrate class, with secondary

Scheme 6. Cu-catalyzed asymmetric propargylic amination of propargylic esters with o-anisidines.

OAc Ar

route to prepare optically active propargylic amines 3 in high yields and with good enantioselectivities. The major difference between van Maarseveen’ and Nishibayashi’s methods is the structure of the chiral ligand. In van Maarseveen’s method, a chiral 2,6-bis(oxazolinyl)pyridine-type ligand (diPh-pybox L1) in combination with CuI was used as the catalyst, and primary amines proved to be more suitable nucleophiles (up to 88% ee, Scheme 2). In comparison, Nishibayashi employed the complex of CuOTf1/2C6H5 with an atropisomeric diphosphine ligand (Cl-MeO-BIPHEP L2) as the catalyst and only secondary amines worked as suitable nucleophiles (up to 98% ee, Scheme 2).

1

·

CuOTf 1/2C 6 H6 (5 mol %) R 2 (R)-BICMAP L7 (10 mol %) N + H i Pr 2NEt (1.2 equiv) 1.5 equiv MeOH, -10 o C, 18 h 2 R1

Ar

O O

PPh2 PPh2

(R)-BICMAP L7

a b c d e f g h

R1

R2

Ph Me Ph Ph Me 4-ClC6 H 4 Ph Me 4-MeOC 6H 4 Ph Me 2-MeC6 H 4 4-ClC6 H4 Me Ph Ph Et Ph Ph H Ph Ph Indoline

R1

N

R2

Ar 3 Yield

Ee (%)

68 68 85 68 70 54 83 77

87 87 37 81 90 82 44 70

Scheme 8. Cu-catalyzed asymmetric propargylic amination with (R)-BICMAP.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

CuOTf· 1/2C 6H 6 (5 mol%) (R)-L4 or L8 (10 mol%)

+ O

N Ar

4

O

2

R

L9 Ar = 3,5-t Bu 2-4-MeOC 6 H2 (R)-DTBM-MeO-BIPHEP

Br

L4: 89% yield, 93% ee L8: 89% yield, 96% ee

Ph

N L4: 81% yield, 98% ee L8: 83% yield, 93% ee

Ph

Ph

HO

HN

HO

CuOTf· 1/2C 6 H6 (5 mol%) Ph-pybox L8 (10 mol%) i Pr

2 NEt (2.4 equiv) MeOH, rt, 4 h

1.2 equiv

6

+ PhHN 1.2 equiv

NHPh

CuOTf 1/2C 6 H6 (5 mol%) Ph-pybox L8 (10 mol%) i

Pr 2 NEt (2.4 equiv) MeOH , rt, 20 h

CF3

HN 93% yield 94% ee

tBu

Ph

Ph HN tBu

HO

HN

N

HO

CF3

80% yield 69% ee

91% yield 52% ee

Scheme 11. Cu-catalyzed asymmetric ring-opening reaction of ethynyl epoxides with amines.

*

7 70% yield (meso/dl = 5/1), 75% ee

·

6

* NPh

HO

96% yield 75% ee

87% yield 55% ee

PhNH2

Me

HN

95% yield 79% ee

HO

OAc

10

PAr2 PAr2

MeO

Scheme 9. Cu-catalyzed asymmetric intramolecular propargylic amination of propargylic acetates bearing a secondary amine moiety.

+

NR 1R 2

HO

Pr2 NEt (10 mol%) acteone, -20 o C

MeO

F N

OAc

R

N L4: R = Me L8: R = Ph

N L4: 87% yield, 93% ee L8: 91% yield, 90% ee

i

O

N N

R

9

5

Cu(OTf) 2 (2 mol%) (R)-DTBM-MeO-BIPHEP L9 (5 mol%) R2

1.2 equiv

i

Pr 2NEt (1.2 equiv) MeOH, 0 oC, 8-30 h

H N

R1

O R1 N

O

R2

11

R2

N *

Ar

Et3N (1.2 equiv) MeOH, 0 oC, 12 h

* NPh

3

CuL* O

Cu/N-N-P*

N * Ph

Et3 N

R1

8

O N

R2

68% yield (meso/dl = 8/1), 66% ee

CO2

Ar

Ph N

Scheme 10. Cu-catalyzed sequential inter- and intramolecular double propargylic amination.

PPh2 (S)-L10

amines 2, in which moderate yields with high enantioselectivities were achieved in the presence of 5 mol % CuOTf1/2C6H5/(R)-BINAP L3 complex (up to 90% ee, Scheme 5).12 The introduction of pentafluorobenzoate in place of the acetate group as a leaving group was found to be necessary to promote the amination of aliphatic propargylic esters with secondary amines. However, primary amines were less efficient in this catalytic system. The copper-catalyzed enantioselective amination of non-aromatic propargylic esters 1 with primary amines 2 could be realized with van Maarseveen’s method, in which good yields and high enantioselectivities were achieved by use of 10 mol % CuI with Me-pybox L4 (up to 90% ee, Scheme 6).13 Some secondary amines were also tested, however, only moderate enantioselectivities were achieved. In 2012, Hu and co-workers demonstrated that chiral tridentate P,N,N-ligands, (Sc,Rp)-L5 and (R)-L6, were highly efficient for the Cu-catalyzed asymmetric propargylic amination of propargylic acetates 1.14 In the presence of CuCl/(Sc,Rp)-L5 complex, both primary aromatic amines and secondary amines 2 were found to be suitable nucleophiles, providing the corresponding propargylic amines 3 in high yields and with excellent enantioselectivities (up to 97% ee for secondary amines, and up to 96% ee for primary amines, Scheme 7). Moreover, in the catalysis of Cu(OAc)2H2O/(R)L6 complex, aliphatic propargylic acetates also served well, providing the products with good enantioselectivities (Scheme 7). It was noteworthy that this Cu/P,N,N-ligand catalytic system represents the first successful example in which both primary and secondary

R1

·

Cu(OAc)2 H2 O (5 mol%) (S)-L10 (5.5 mol%)

Ar

•

OAc NHAr

R

R1

•

R1

N

O

O

O

O

N

N

N

N

Cl 96% yield 94% ee

N *

94% yield 91% ee

*

*

*

Me 93% yield 94% ee

N

* S

93% yield 96% ee

N

90% yield 89% ee

HN

*

*

*

92% yield 97% ee

94% yield 95% ee

93% yield 82% ee

Scheme 12. Cu-catalyzed asymmetric decarboxylative propargylic amination of propargyl carbamates.

amines could be used as efficient nucleophiles for the highly enantioselective catalytic propargylic amination of both aliphatic and aromatic propargylic acetates. In 2013, Sakamoto and co-workers reported the copper-catalyzed asymmetric propargylic amination of aromatic propargylic esters 1 with amines 2 using (R)-BICMAP L7 as a chiral ligand, giving the desired products 3 in good yields (up to 85% yield) and with moderate to high enantioselectivities (up to 90% ee, Scheme 8).15

D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

Very recently, Nishibayashi and co-workers disclosed a coppercatalyzed asymmetric intramolecular propargylic amination of propargylic acetates 4 bearing a secondary amine moiety at a suitable position.16 In the catalysis of CuOTf1/2C6H6/Pybox (L4 or L8) complex, a variety of optically active 1-ethynylisoindolines 5 were obtained in good yields and with high enantioselectivities (up to 98% ee, Scheme 9). They also made a preliminary investigation on the sequential inter- and intramolecular double propargylic amination, however, the result was still far from satisfactory (Scheme 10). Ring-opening reaction of ethynyl epoxides with amines In 2009, Nishibayashi and co-workers reported the copper-catalyzed asymmetric ring-opening reaction of ethynyl epoxides 9 with amines 2 catalyzed by Cu(OTf)2/DTBM-MeO-BIPHEP L9 complex. Optically active b-amino alcohols 10 bearing a tertiary carbon at the a-position of the amine were obtained in high yields with high enantioselectivities (up to 94% ee, Scheme 11).17 The catalytic reaction was considered to proceed via copper–allenylidene complexes as the key intermediates. Furthermore, good yields and excellent enantioselectivities were also observed even in the presence of only 0.1 mol % of copper catalyst (84% yield, 94% ee, TON = 840). Decarboxylative propargylic amination of propargyl carbamates Although great advances have been made in propargylic substitution using nitrogen nucleophiles, the development of new strategy for the catalytic synthesis of propargylic amines remains a highly desirable and challenging task. In 2014, Hu and co-workers reported a Cu-catalyzed asymmetric decarboxylative propargylic amination of propargyl carbamates 11 with a tridentate ketimine P,N,N-ligand L10 (Scheme 12).18 The reaction could be performed under very mild condition for a broad range of substrates, providing the corresponding propargylic amines 3 in good yields and with high enantioselectivities (up to 97% ee). In this method, both the nucleophile and the electrophile were formed in situ by the loss of CO2 in catalytic concentration (Scheme 12). This reaction represents a new and complementary strategy for access to optically active propargylic amines. Propargylic amination/cyclization tandem reactions The catalytic sequential reaction using transition metal complexes have attracted much attention due to the advantage of simplicity and facility in the preparation of complex and useful compounds. Recently, some cycloaddition reactions based on the copper-catalyzed propargylic amination have also been developed.

OAc +

Ar

Ph

CuOTf· 1/2C 6H 6 (5 mol%) (R)-L2 (10 mol%) iPr NEt (1.2 equiv) 2

H N 1.2 equiv

MeOH 0 o C, 24 h; then rt, 8h

S

Ph

Ar

Ph

N cis-13

O

Ph N Ph 82% yield cis/trans = 20/1 88% ee (cis)

N

84% yield cis/trans >30/1 90% ee (cis)

Ph

S

Br

N

87% yield cis/trans = 19/1 85% ee (cis)

In 2010, Nishibayashi and co-workers reported the coppercatalyzed asymmetric propargylic amination/[4+2]-cycloaddition tandem reaction of propargylic acetates 1 with N-(E)-penta-2,4dienylaniline 12 to give chiral 1,2-disubstituted tetrahydroisoindole derivatives 13 in high yields and with high diastereo-/enantioselectivities (up to >30/1 dr, up to 90% ee, Scheme 13).19 This work is the first example of the copper-catalyzed diastereo- and enantioselective sequential reaction, in which only a single copper complex worked as a catalyst to promote both the propargylic amination and the intramolecular [4+2] cycloaddition reaction. A proposed reaction pathway is shown in Scheme 14. At first, N(E)-2,4-pentadienylaniline 12 might attack the copper acetylide complex A bearing a cationic c-carbon atom from the re face to give C with high enantioselectivity. Then, the intramolecular [4+2] cycloaddition reaction occurs via the copper acetylide complex D, which is formed from C and the chiral copper complex. The direct transformation from B to D without the formation of C as a reactive intermediate may also be conceivable in the sequential reactions. In 2011, Zhan and co-workers described a Cu(OTf)2-catalyzed tandem reaction of propargylic alcohols 14 with amidine 15 to provide 2,4-disubstituted or 2,4,6-trisubstituted pyrimidines 16 in moderate to good yields (up to 91% yield, Scheme 15), which are important heterocyclic units in pharmaceuticals, agrochemicals, biologically active molecules, and novel materials.20 The reaction is proposed to undergo a propargylation/cyclization/oxidation tandem mechanism (Scheme 16). In the initial step, Cu(OTf)2-induced propargylic amination of propargyl alcohol 14 with benzimidamide leads to C. The intramolecular nucleophilic attack of amidine nitrogen at the Cu-activated triple bond of alkyne produces cyclic dihydropyrimidine intermediate D (6-endo-dig). Then, the dihydropyrimidine D is aromatized to the pyrimidine ring via the oxidation with air. In this reaction, the Cu(OTf)2 acts as a bifunctional catalyst, not only does it assist in the leaving of the hydroxyl group from the propargylic alcohol, furnishing the propargylic cation B, but also activate the triple bond, rendering the cyclization process more facile. Propargylic substitution using carbon nucleophiles The development of new, efficient, and valuable synthetic methodologies for the direct construction of the carbonAcarbon bond is a highly important task in organic chemistry. The propargylic substitution using carbon nucleophile offers a straightforward and efficient route to form the new carbonAcarbon single bond, whereas synthesizes the compound bearing the carbonAcarbon triple bond. In recent years, the copper-catalyzed propargylic substitutions using carbon nucleophiles have attracted much attention, and some related cycloadditions have also been developed. Ketone enolates or their equivalents as nucleophiles

12

1

287

Ph

N

88% yield cis/trans = 17/1 80% ee (cis)

Scheme 13. Cu-catalyzed asymmetric propargylic amination/cycloaddition tandem reaction of propargylic acetates with N-(E)-penta-2,4-dienylaniline.

Propargylic alkylation of enoxysilanes In 2007, Zhan and co-workers reported a very efficient method for the synthesis of b-alkynyl ketones 18 by the substitution reaction of propargylic acetates 1 with enoxysilanes 17 in the catalysis of 1 mol % Cu(OTf)2 (Scheme 17).21 The reaction was completed rapidly within 5 min under the mild condition. It was noticed that the steric bulkiness of side chains (R2) in propargylic acetates 1 had a significant effect on the regioselectivity of the reaction (18 vs 19). Propargylic acetates 1 bearing the terminal or internal alkyne group were also tolerated. Furthermore, the substitution reaction could be followed by a TsOH-catalyzed cyclization without purification of the b-alkynyl ketone intermediates, offering a straightforward synthetic route to polysubstituted furans 20.

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Ph Ph Ph

N

1 13

iPr

OAc

2NEt

[Cu]+

H+

i

Pr 2NEt·AcOH

*LCu Ph

CuL* Ph N

Ph

A

+

E H N

H+

Ph 12

CuL*

CuL*

Ph

Ph N

N+ Ph H

Ph D

B [Cu]+ Ph

H+

N

C

Ph C

Scheme 14. Proposed catalytic cycle for copper-catalyzed sequential reactions.

Ph

Ph

+

R1

Cu(OTf )2 (20 mol%) NH

H 2N

N

Cu(OTf )2 (20 mol%)

N

1

2

R

R

N

PhCl, reflux, air 1.5-24 h

R2 14

16

15

NH

H 2N

+

R1

PhCl, reflux, air 1.5-24 h

R2 14

Ph

OH

Ph

OH

N

aromatization

Ph OMe N N

N

Ph

N

Ph

15

Cu 2+ R1

R1

R2

A N

N

H+

B

N

N

N

6-endo-dig

N

R1

R2

Cu2+

HN

R2

C

Ph

Ph

NH

R1

R2

Ph N

75% yield

Ph HN

+

Ph 79% yield

air

Ph

N HO

R2 = TMS 87% yield 68% yield R2 = H

R2 16

15

Ph Ph

N

R1

D

Scheme 16. Proposed reaction pathway for copper-catalyzed tandem synthesis of pyrimidines.

Ph S R2 = TMS 89% yield R2 = H 69% yield

R2 = TMS 85% yield

73% yield O

R5 OAc

Scheme 15. Cu-catalyzed tandem reactions of propargylic alcohols with amidines. R

R

Propargylic alkylation of enamines In 2009, Hou and co-workers developed the first copper-catalyzed asymmetric propargylic substitution of propargylic acetates 1 with enamines 21 catalyzed by 5 mol % of Cu(CH3CN)4ClO4/(R)Cl-MeO-BIPHEP complex (Scheme 18).22 A series of b-ethynyl ketones 22 were prepared in good yields and with good enantioselectivities (up to 91% ee). The aliphatic enamine derived from cyclohexanone was also examined, providing the product in 33% yield with 10:1 dr and 72% ee when a propargylic benzoate instead of the acetate was used. Very recently, Hu and co-workers reported a highly diastereo-/ enantioselective copper-catalyzed propargylic alkylation of morpholine-derived acyclic ketone enamines 23 with propargylic

R4 Cu(OTf) 2 (1 mol %) +

1 2

OTMS R3 1

MeCN, RT 5 min

3.0 equiv

R5

R1

R2

R3

Ph

H

b

Ph

H

c

Ph

Ph

d

Ph

H

e

Ph

H

Ph

f

Ph

H

H

R3

·

+ R1 R2

R2

R4

R 5 Yield (%, I8:I9)

H

Ph

H

84:0

Ph

Ph

H

88:0

Ph

Ph

H

38:52

H

Me

H

82:0

H Me -(CH2 )4 -

87:0 89:0

g

Ph

H

TMS

-(CH2 )4 -

93:0

h

Ph

Ph

Ph

-(CH2 )4 -

0:87

R4 R5

R3 18

17

a

R1

R4

O

19

TsOH, toluene reflux, 0.5-2 h

R2 = H

R5

R1

20

R3 O

R4

65-85% Yield

Scheme 17. Cu-catalyzed propargylic alkylation of enoxysilanes.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

OAc

NEt2 +

R1

R2 2.0 equiv

1

O

[Cu(CH 3CN) 4]ClO4 (5 mol %) (R)-Cl-MeO-BIPHEP L2 (5 mol %) i

H 3O

O

R2

Pr 2NEt (4.0 equiv) MeOH, -15 o C

R1

R1

21 O

O Ph

Ph

R2

O

Ph O 77% yield 85% ee

95% yield 82% ee

95% yield 73% ee

Ph

80% yield 67% ee

N O

O

Cl

O

O

N

PPh 2 (S)-L10

Ph

NO2 Ph 61% yield 91% ee

Cl 63% yield 82% ee

Ph

N

Ph 85% yield 78% ee

40% yield 84% ee

Scheme 18. Cu-catalyzed asymmetric propargylic alkylation of enamines with propargylic acetates.

a The

R2 22

R1

R2

a

Ph

Ph

96

95

b

2-ClC 6H 4

Ph

65

93

c

4-BrC 6 H4

Ph

95

95

d

4-MeC 6H 4

Ph

93

95

e

4-NO2C 6 H4

Ph

96

94

f

2-naphthyl

Ph

95

96

g

2-thienyl

Ph

91

95

ha

Me

Ph

88

85

i

Ph

4-MeC6 H4

91

89

j

Ph

4-CF3 C 6H 4

96

95

k

Ph

2-naphthyl

94

97

l

Ph

2-thienyl

92

88

O Ph

O R1

Et 3 N (1.2 equiv) toluene, 0 o C, 12 h

25

22 O

Cu(CH 3CN)4 BF 4 (5 mol%) (S)-L10 (5.5 mol%)

O

Yield (%) ee (%)

reaction was performed in MeOH at a catalyst loading of 10 mol%.

Scheme 20. Cu-catalyzed asymmetric decarboxylative propargylic alkylation of propargyl b-ketoesters.

O N OAc

+ R

R1

R3 1.2 equiv 23

1

O

O

Cu(OTf)2 (5 mol%) (S)-L10 (5.5 mol%)

2

R3

H 3O

i Pr NEt 2

R2

Ph

R1

(1.2 equiv) MeOH, -10 o C, 12 h

Ph

O

O

O

O

Ph

O Et3N

O

O

O O

Ph

O

22

24-sy n

Ph CuL *

Ph

Ph Ph

O

93% yield syn/ anti >95/5 99% ee (syn)

F

90% yield sy n/ ant i = 94/6 99% ee (sy n)

O

O

96% yield sy n/ ant i >95/5 97% ee (sy n)

O

O

92% yield sy n/ ant i >95/5 >99% ee (sy n)

Ph

Me 93% yield syn/ anti = 93/7 >99% ee (syn)

Ph 92% yield sy n/ ant i >95/5 >99% ee (sy n)

Ph

Ph

CuL* Ph CO2

Et3 NH

O

O O

O O-

Ph Ph

OH •

H

Ph

Ph

Ph

CuL*

O •

Ph

•

C

O-

O

CuL*

E

Scheme 19. Cu-catalyzed diastereo-/enantioselective propargylic alkylation of acyclic ketone enamines with propargylic acetates.

•

CuL*

D

Scheme 21. Proposed reaction pathway for decarboxylative propargylic alkylation.

O

Decarboxylative propargylic alkylation of propargyl bketoesters Although some ketone enolate equivalents proved to be suitable reagents for catalytic asymmetric propargylic substitutions, the use of simple ketone enolates as nucleophiles is still very limited. In 2014, a breakthrough was made by Hu and co-workers. They developed an intramolecular asymmetric decarboxylative propargylic alkylation of propargyl b-ketoesters 25 by use of Cu(CH3CN)4BF4/(S)-L10 (5 mol %) as the catalyst, in which a variety of b-ethynyl ketones 22 were obtained in good yields and with high enantioselectivities (up to 98% ee) (Scheme 20).24 In this reaction, both the nucleophile and the electrophile were formed in situ in catalytic concentration by the loss of CO2, instead

CuL*

B F

Et3N

60% yield syn/ anti = 81/19 99% ee (sy n)

esters 1 in the presence of a bulky and structurally rigid tridentate ketamine P,N,N-ligand (S)-L10 to forge two vicinal tertiary stereocenters, in which excellent diastereoselectivities (up to >95:5 dr) and perfect enantioselectivities (up to >99% ee) were obtained for a wide range of substrates (Scheme 19).23

Ph

Ph

+

Ph

O

O

S

Cl

O

A 25

94% yield sy n/ ant i >95/5 >99% ee (sy n)

+

Et3 NH

+

Ph

OAc

O

R1

OH

+

Cu(CH 3CN)4 BF 4 (5 mol%) (S)-L10 (5.5 mol%)

R

1.1 equiv 26

Et 3 N (1.2 equiv) MeOH, 0 oC, 12 h

1 Ph N N

PPh2 (S)-L10

O R1

R 22

R1

R

a

Ph

Ph

91

98

b

4-MeC 6H 4

Ph

85

96

c

4-BrC 6H 4

Ph

92

98

d

Me

Ph

65

74

e

Ph

4-FC 6H 4

90

96

f

Ph

2-thienyl

89

93

Yield (%) ee (%)

Scheme 22. Cu-catalyzed asymmetric intermolecular decarboxylative propargylic alkylation of b-keto acids with propargylic esters.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

Ar

CuOTf •1/2C 6H 5 (10 mol%) Chiral amine L11 (20 mol%) Ar r ac-BINAP L3 (20 mol%)

R1 +

O

OCOC6 F5

ClCH 2 CH 2Cl, rt, 1.5-2 h

+

R1

R1 O

2.0 equiv 27

Ar = 1-naphthyl 1

Ar

Ar 1 Ar 1

N H

O 28-anti

28-sy n

OTMS

1

EtOH 0 oC, 1 h

NaBH4

Ar = 3,5-(CF3 )2 C6 H 3 chiral amine (S)-L11

Propargylic alkylation of aldehydes Ar

Ar +

R1

R1 OH 29-sy n

Ar

Ar

Ph

OH 29-anti

Ar

OH

OH

Ar

OH

OH Cl

53% yield syn/ant i = 3.2/1 98% ee (syn) 96% ee (ant i)

52% yield syn/ant i = 3.2/1 97% ee (syn) 98% ee (anti)

58% yield sy n/anti = 3.5/1 83% ee (sy n) 94% ee (anti)

64% yield syn/anti = 3.5/1 84% ee (syn) 94% ee (ant i)

Scheme 23. Cooperative catalytic asymmetric propargylic alkylation of aldehydes.

of the need to prepare preformed enolate equivalents. The nucleophilic attack of the enolate to the c-carbon atom of the copper allenylidene complex should be the key step in determining stereoselectivity (Scheme 21). This work also represents the first successful example of the catalytic asymmetric decarboxylative propargylic alkylation. In addition, the reaction showed to be less sensitive to the nature of the solvent, and the best reaction solvent was toluene in terms of enantioselectivity. This result is different with those observed in the copper-catalyzed enantioselective propargylic substitution, in which only a polar protic solvent such as MeOH proved to be suitable. A copper-catalyzed intermolecular enantioselective decarboxylative propargylic alkylation of propargylic esters 1 with b-keto acids 26 was subsequently developed by the same group.25 A variety of b-keto acids 26 with propargylic esters 1 underwent the decarboxylative propargylic alkylation to give the corresponding

Ar

cat. L11 cat. CuOTf + L

R1 +

O

OCOC 6F5 1

Propargylic alkylation of b-dicarbonyl compounds In 2011, van Maarseveen and co-workers attempted the first copper-catalyzed asymmetric propargylic substitution of 1-phenyl-2-propynyl acetate with 2,2,5-trimethyl-1,3-dioxane-4,6dione, a cyclic derivative of malonate. However, only low enantioselectivity (6% ee) was obtained.13 The development of a catalytic

Cu(CH3 CN)4 BF4 (5 mol%) (R)-L10 (7.5 mol%)

OAc +

+ C 6F5 CO2 H O 28

L11 -H2 O

CuL*

Recently, the combination of distinct catalysts for dual activation of distinct reacting partners has emerged as a new strategy for developing novel and valuable reactions that are difficult or impossible by the use of single catalyst.26 In 2011, Nishibayashi and co-workers reported the asymmetric propargylic alkylation of propargylic pentafluorobenzoate 1 with aldehydes 27 using a CuOTf1/2C6H6/racemic BINAP L3 complex and a chiral secondary amine L11 as the co-catalyst. The reaction gave propargylic alkylation products 29 as a mixture of two diastereoisomers in good yields and with high enantioselectivities (Scheme 23).27 Interestingly, the stereochemistry of BINAP did not affect the enantioselectivity of the alkylation product 29. In this reaction, copper complex (transition metal catalyst) and secondary amine L11 (organocatalyst) activated propargylic esters 1 and aldehydes 27, respectively, and both catalysts worked cooperatively and simultaneously to promote the propargylic alkylation enantioselectively (Scheme 24). This work is an extension of the study of asymmetric propargylic substitution of propargylic alcohols with aldehydes using a thiolate-bridged diruthenium complex and a chiral secondary amine as cocatalysts.28 However, higher diastereoselectivity but lower catalytic activity was observed in the copper-catalyzed propargylic alkylation.

Ar R1

27

b-ethynyl ketones 22 in good yields with excellent enantioselectivities (up to 98% ee, Scheme 22). In comparison to the corresponding intramolecular decarboxylative propargylic alkylation of propargyl b-ketoesters 25, this method displays some significant advantages: (1) more readily available substrates; (2) generally better enantioselectivities; (3) broader substrate scope, especially for aliphatic propargylic esters.

O

R

O

i Pr

R

1.2 equiv 1

2 NEt

31

O

O

O R1 R

30

-CuL* O

O

(2.4 equiv) MeOH, 0 o C, 12 h

1

O O

O

O

O

*

*

CuL

CuL

R1 enamine

Ar OCOC 6F 5

F3 C

Ar 95% yield 98% ee

N R1

85% yield >99% ee

O alkyne complex

alkyne complex -C6 F5CO2 H

O O

H 2O -L11

65% yielda 97% ee

O

O

90% yield 86% ee

O

O O

O

O MeO 2C

L*Cu

Ar

*

L Cu

·α ·β

H

δ γ H Ar

allenylidene complex

L *Cu

· αβ ·

L*Cu

R1

δ H Ar γ

N

N 88% yield 91% ee

Ar R1 acetylide complex

Scheme 24. Proposed reaction pathway for cooperative catalytic propargylic alkylation.

a

83% yield >99% ee

65% yield 97% ee

94% yield anti/sy n = 3.5/1 99% ee (anti)

The reaction was performed at RT under a catalyst loading of 10 mol %.

Scheme 25. Cu-catalyzed asymmetric propargylic alkylation of b-dicarbonyl compounds.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 O

R3

OAc

CO 2R 2

+

R1

i Pr NEt (2.0 equiv) 2 MeOH, 20 oC, 0.5-12 h

O 2.0 equiv 32

R4 1

O

CuBr or Cu(acac) 2 (5 mol%) 3 sec-butyl-pybox L12 (6 mol%) R

R1

O CO R 2 2

R4

33 O

O

N N

N

sec-butyl-pybox L12 Cl

Me

O

O O

O CO Et 2

O CO Et 2

94% yield 98/2 dr 98% ee O

O

90% yield 91/9 dr 92% ee O

Ph

O CO Me 2

91% yield 91/9 dr 94% ee O

Ph

Br

Me

O CO Et 2

91% yield 91/9 dr 94% ee

O CO Et 2

O CO Et 2

93% yield 89/11 dr 78% ee

O CO Et 2

91% yield 90/10 dr 93% ee

O

Ph

Ph

O CO Et 2

MeO

90% yield 91/9 dr 92% ee

79% yield 91/9 dr 88% ee

Scheme 26. Cu-catalyzed diastereo- and enantioselective propargylic alkylation of 2-substituted benzofuran-3(2H)-ones.

R

CuI (10 mol%) pybox ligand L1 (12 mol%)

OAc +

N R 2.0 equiv

Ph

1

N

iPr NEt (4.0 equiv) 2 MeOH, -20 o C, 24 h

N

O

N

Ph N

N

In 2011, van Maarseveen and co-workers reported a copper-catalyzed asymmetric propargylation of propargylic acetates 1 with indoles 34 in the presence of diPh-pybox ligand L1 (Scheme 27).13 Indole and N-methylindole were suitable nucleophiles, giving the 3-propargylindoles 35 in high yields (up to 91% yield) and with excellent enantioselectivities (up to 98% ee). This is different with the Ru-catalyzed asymmetric propargylation of indoles, in which the presence of a bulky group such as triisopropylsilyl at the nitrogen atom of indoles was essential for achieving high enantioselectivity.31 However, the limited scope of the reaction was examined.

35 NH

O

Propargylic substitution of indoles

Propargylic substitution of terminal alkynes

Ph

34

Ph

ketimine P,N,N-ligand (R)-L10. A series of propargylic alkylation products 29 were obtained in high yields and with excellent enantioselectivities (up to >99% ee, Scheme 25).29 The catalytic system was also efficient for cyclic b-ketoesters and cyclic malonate derivatives as nucleophiles. In this reaction, the use of the bulky and structurally rigid chiral ketimine-type P,N,N-ligand (R)-L10 was critical to achieve good performance. Very recently, Wu and co-workers developed a diastereo- and enantioselective propargylic alkylation of 2-substituted benzofuran-3(2H)-ones 32 with propargylic esters in the catalysis of a copper–pybox complex (Scheme 26).30 A series of 2,2-disubstituted benzofuran-3(2H)-ones 33 bearing two vicinal chiral centers and one terminal alkyne functional group were obtained in good to excellent diastereoselectivities (up to 98:2 dr) and enantioselectivities (up to 98% ee).

Ph

Ph diPh-pybox L1

Ph

Ph

71% yield 94% ee

91% yield 98% ee

Scheme 27. Cu-catalyzed asymmetric propargylic alkylation of indoles.

system that could catalyze the asymmetric propargylic substitution in broad substrate spectrum with regard to b-dicarbonyl compounds is therefore highly desirable. Recently, Hu and co-workers reported the first highly enantioselective copper-catalyzed propargylic alkylation of propargylic acetates 1 with b-diketones 30 by employing the chiral tridentate

1,4-Diynes are traditionally obtained by the nucleophilic substitution of propargyl halides or sulfonates with metal acetylides, in which large amounts of salt waste are generated simultaneously.32 In 2011, Zhan and co-workers reported a copper-catalyzed propargylic substitution of propargyl alcohols 14 with terminal alkynes 36 using 10 mol % Cu(OTf)2 as the catalyst.33 The reaction could be finished in 5 min with water as the only byproduct. A range of propargyl alcohols 14 and terminal alkynes 36 were well tolerated, and a variety of 1,4-diynes products 37 were obtained in good yields (up to 87% yield, Scheme 28). Propargylic trifluoromethylation The introduction of a trifluoromethyl (CF3) group into organic molecules has attracted considerable attention since the resulting

R3 OH

Cl + CF SiMe 3 3 R

Cu(OTf) (10 mol%) R3

+

R1 2

° DCE, 4A MS reflux, 5 min

2.0 equiv

R 14

38a

R

37

2

R

R = 1-naphthyl , 86% yield R = Bn, 80% yield CuTC (5 mol%) KF (1.5 equiv)

Ph

Cl + CF3SiMe 3 1.5 equiv

R 38b

Ph Ph Ph 87% yield

72% yield

40

R = 4-MeC6 H 4, 83% yield

Br

OMe

Br

CF3 R

R = 4-CF3 C6 H4 , 75% yield

2

up to 87% yield

R = Aryl, Alkyl; R = Aryl, Alkyl, TMS, H; R3 = Aryl, Alkenyl; R4 = Aryl, Alkyl

THF 60 oC, 20 h

1

36

1

1.5 equiv 39

CuTC (5 mol%) KF (1.5 equiv)

Ph nBu

76% yield

TMS

39

·

R THF 60 oC, 20 h

CF3 41a

R = 4-MeC 6H 4, 79% yield R = 4-ClC 6H 4, 81% yield R = PhCH2 CH 2 , 71% yield

80% yield

Scheme 28. Cu-catalyzed propargylic alkylation of terminal alkynes.

Scheme 29. Cu-catalyzed trifluoromethylation of propargylic chlorides with trifluoromethyltrimethylsilane.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

CF2 Br

O

CF3

CuI (10 mol%) DMEDA (10 mol%) NaO 2CCF2 Br (25 mol%)

O

+

KF, DMF, 50 o C, 14 h activation

R

40

R

·

R

42 CF 3 41b R = 4-MeOC 6H 4, 72% yield, 40/41b = 4.0/1 R = 2-Naphthyl, 57% yield, 40/41b = 3.8/1 R = PhCH 2 CH 2, 70% yield, 40/41b = 1.2/1

Scheme 30. Cu-catalyzed decarboxylative trifluoromethylation of propargyl bromodifluoroacetates.

CF3

O 40

R O

+ R

CF2Br

42

R

· 41b CF 3

O O

CF2Br

NaO L nCuI

Ln Cu

Ln Cu

CF3

KF

KBr+CO2

O

CF2Br

KF

Scheme 31. Proposed catalytic cycle via an activation procedure.

trifluoromethylated compounds are highly promising skeletons in the field of pharmaceuticals, agrochemicals, and materials.34 Recently, Nishibayashi and co-workers reported the reaction of primary and secondary propargylic halides 38a–b with trifluoromethyltrimethylsilane (CF3SiMe3) 39 in the presence of 5 mol % copper(I) thiophene-2-carboxylate (CuTC) to give the corresponding trifluoromethylated products 40 and 41a in good to high yields. This represents the first example on the catalytic trifluoromethylation of propargylic halides by directly using CF3SiMe3 as a trifluoromethylating reagent (Scheme 29).35 The study indicated that the regioselectivity of the reaction was dictated by the substrate, with primary propargyl chlorides providO X

O

Cu(OTf)2 (5 mol %)

O

+

R1

R3

14 or 1

R2

R4

toluene, reflux 0.5-3 h

Scheme 33. Mechanism for propargylic alkylation/cycloisomerization tandem reaction.

ing propargyl trifluoromethanes and secondary propargyl chlorides affording trifluoromethylallenes. The authors proposed that the catalytic reaction should proceed via a pathway involving cationic propargyl/allenyl-copper complexes as reactive intermediates, not via an anti-SN20 pathway. Very recently, Altman and co-workers developed a two-step copper-catalyzed decarboxylative trifluoromethylation of propargyl bromodifluoroacetates 42 into a mixture of propargyl trifluoromethanes 40 and trifluoromethylallenes 41b (Scheme 30).36 In the reaction, an activation procedure and the use of N,N0 -dimethylethylenediamine (DMEDA) as a ligand significantly improved the yield of product. The activation procedure presumably served to convert the pre-catalytic combination of CuI/DMEDA/sodium bromo(difluoro)acetate (NaO2CCF2Br)/KF into the active catalyst, (DMEDA)Cu–CF3 (Scheme 31). Moreover, the activation procedure might circumvent an induction period, during which the substrate could be destroyed via nonproductive pathways. Since NaO2CCF2Br participated only in the activation procedure, it was required just at a substoichiometric amount (25 mol %) in this reaction.

R1

R4 R3

30

O 43

R2 O

OAc

O

R1

X = OH (14) or OAc (1) R1 = Aryl R2 = TMS, H, Ph, nBu R3 = R 4 = -(CH 2) 3-, CH3 ; or R 3 = CH 3, R4 = OEt

OMe

+

R

1.1 equiv 30

EtO Ph

O X = OH 65% yield X = OAc 76% yield

O X = OH 53% yield X = OAc 64% yield Br

N PPh2 (S)-L10

O

O

EtO O X = OH 60% yield X = OAc 78% yield

Scheme 32. Cu-catalyzed tandem reactions of propargylic alcohols or acetates with 1,3-dicarbonyl compounds.

Et3N (1.2 equiv) MeOH, rt, 15 h

MeO2 C

N

a

O

R 44

R1

R

a

Ph

Ph

90

95

b

4-MeOC 6H 4

Ph

81

96

c

4-ClC 6H 4

Ph

86

95

d

2-ClC 6H 4

Ph

89

91

e

2-naphthyl

Ph

84

97

f

2-thienyl

Ph

88

97

g

Me

Ph

90

87

h

Ph

4-FC6 H4

90

96

i

Ph

2-naphthyl

88

92

a

Ph

Me

71

83

ka

Ph

cyclohexyl

65

91

j

Ph

O X = OH 50% yield X = OAc 60% yield

R1

1

O

O

Cu(OTf )2 (5 mol%) (S)-L10 (5.5 mol%)

Yield (%) ee (%)

Corresponding propargylic pentafluorobenzoates were used.

Scheme 34. Cu-catalyzed asymmetric cycloaddition of b-ketoesters with propargylic acetates.

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295

Propargylic alkylation/cycloaddition tandem reaction In 2009, Zhan and co-workers reported a convenient one-pot propargylic alkylation/cycloisomerization tandem process to construct substituted furans derivatives 43 from 1,3-dicarbonyl compounds 30 and propargylic alcohols 14 or acetates 1 catalyzed by copper(II) triflate as a bifunctional catalyst in good yields (up to 93% yield, Scheme 32).37 Increased yields were obtained in all cases when propargylic acetates were used as substrates instead of propargylic alcohols. The authors proposed the mechanism as outlined in Scheme 33. Initially, the ionization of propargylic alcohols 14 would lead to propargylic cation B and the subsequent propargylic substitution of the enol A gives c-alkynyl ketone D. Coordination of cationic copper(II) to the alkyne forms the p–alkyne copper complex E and enhances the electrophilicity of alkyne. Subsequent 5-exodig nucleophilic attack of the hydroxy group on b-carbon of Cu(II)–alkyne complex E would generate the alkenyl-copper derivative F. Protonolysis of F affords dihydrofuran G, which then undergoes isomerization to furan 43. Since dihydrofurans are widely found in many natural products and pharmaceutical molecules, and also serve as attractive precursors for an array of organic transformations.38 If the last isomerization step of alkylene-2,3-dihydrofurans G in Scheme 33 can be efficiently interrupted, it would provide a concise access to synthesize 2-alkylene-2,3-dihydrofurans. Based on this consideration, very recently, Hu and co-workers reported the first copper-catalyzed asymmetric formal [3+2] cycloaddition of b-ketoesters 30 with propargylic esters 1 to generate optically active 2,3-hydrofurans 44 bearing the exocyclic C@C bond in high yields and enantioselectivities (up to 97% ee, Scheme 34).39 Bulky and structurally rigid chiral ketimine-type P,N,N-ligand was critical to achieve good performance. A range of substitution patterns at the b-ketoesters 30 and propargylic acetates 1 were well tolerated. It was noted that the reaction worked well for the aliphatic propargylic substrates when an aliphatic pentafluorobenzoates were used instead of the

NEt 2 OLG +

R

1

Cu(OAc) 2.H 2O (5 mol%) (Rc ,Sp )-L5 (5.5 mol%)

O

O

R

i Pr NEt (1.2 equiv) 2 X 1.2 equiv MeOH, 0-40 oC, 12-60 h

N

38 or 1

a b c d e

X = Cl Yield

X = OCO2 CH3 Yield

X = OCOCF3 Yield

H 4-OMe 4-CN 4-NO2 4-COCH3

69 67 78 81 78

70 70 86 78 86

83 63 86 88 80

Scheme 37. Cu-catalyzed propargylic etherification of propargylic chlorides or esters with phenols.

O

O

86% yield, 95% ee 88% yield, 98% ee 86% yield, 95% ee 58% yield, 97% ee endo/exo >98/2 endo/exo >98/2 endo/exo >98/2 endo/exo >98/2

O

O

Ph

O

+ HO

Cl O

R3

CuI (2 mol%) K2CO3 (2 equiv) KI (1.7 equiv)

R3

a b c d e f g h

DMF, 65 o C 65 oC, 0.5-2 h

R1 R2 48

47 R1

O

48

R

2 equiv 38

(R c,Sp)-L5

O

47

Cl

Fe

O

CH3 CN 0 o C, 5-24 h

HO

R1 R2

PPh 2

O

O

+

exo-46

endo-46 N

R

·

CuCl2 2H 2O (0.1-0.3 mol %) DBU

R

X

X

X

45

LG = Ac or COOEt

R

+

Scheme 36. Proposed mechanism for [3+3] cycloaddition of propargyl ester with cyclic enamine.

R2

Me Me Me Me Me Me Me Me Me Me Me Et Et Et -(CH2 )5 -

3

R

Yield (%)

4-H 4-CN 4-C2 F5 4-Et 2-CN 4-CN 4-CN 4-CN

40 96 72 21 95 100 91 85

PhNEt 2 DMF

140-150 oC 51-90%

R3

R1 O 49

R2

Scheme 38. Cu-catalyzed propargylic etherification of propargylic chlorides with phenols.

O O

O

78% yield, 93% ee 84% yield, 89% ee 76% yield, 89% ee 48% yield, 98% ee endo/exo >98/2 endo/exo >98/ 2 endo/exo >98/2 endo/exo >98/2 trans/cis = 95/5

Scheme 35. Cu-catalyzed asymmetric [3+3] cycloaddition of propargyl esters with cyclic enamines.

corresponding acetates. In addition, the exocyclic double bond can be hydrogenated in a highly diastereoselective fashion to give unusual cis-2,3-dihydrofuran derivatives, which further enhances the scope of this transformation. In 2012, Hu and co-workers developed a new Cu-catalyzed asymmetric [3+3] cycloaddition of propargyl esters 1 with cyclic

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D.-Y. Zhang, X.-P. Hu / Tetrahedron Letters 56 (2015) 283–295 MOMO

OCO2 Me

CuCl2 (1 mol%) DBU (3.0 equiv)

OH

OMOM

O

+ MOMO

CH3 CN 0 oC, 12 h

OMOM

3.0 equiv 1

48

47

OH

O O

O

O

OH

tovophyllin B 50

Scheme 39. Synthesis of the intermediate for tovophyllin B.

OH

CuBr 2 (5 mol%) +

1

R

R2 14

R3

NuH MeNO2 rt, 2-15 h

3.0 equiv 51

Nu R1 R2 52

R1

R2

R3

a

Me

Me

Ph

EtOH

84

b

Me

Me

Ph

BnOH

98

c

Me

Me

Ph

H2 C=CHCH 2OH

57

d

Ph

Ph

Ph

Cl(CH2 )2 OH

54

e

Ph

Ph

H

EtOH

38

f

H

Ph

H

EtOH

74

g

-(CH 2 )5 -(CH 2 )5 -

Ph

EtOH

57

Ph

Cl(CH2 )2 OH

82

h

NuH

Me

Me

Ph

EtSH

96

j

Me

Me

Ph

CySH

78

Ph

EtSH

86

Ph

CySH

38

k l

-(CH 2 )5 -(CH 2 )5 -

R3

Yield (%)

i

the present of 2 mol% CuI to give 1.1-dialkylpropargyl ethers 48 in 21–100% yields (Scheme 38).42 The study indicated that phenols bearing the electron-withdrawing group tended to give higher yields. Moreover, the resulting propargylic ethers could be readily converted into 2H-1-benzopyrans 49. Nicolaou and coworkers applied the copper-catalyzed propargylic etherification in the total synthesis of biologically active compounds 50, tovophyllin B, which possesses a significant inhibitory activity against Mycobacterium tuberculosis (Scheme 39).43 The O-propargylation of the readily available phenol 47 with methyl 2-methyl-3-yn-2-yl carbonate in the presence of DBU and the catalytic amount of CuCl2 proceeded smoothly to afford 1,1-dimethylpropargyl ether 48, a key intermediate in the total synthesis of tovophyllin B 50. In 2008, Huang and co-workers developed a novel copper-catalyzed propargylic etherification reaction of propargylic alcohols 14 with alcohols in the presence of copper(II) bromide with excellent regioselectivity and high yields under very mild conditions (up to 98% yield, Scheme 40).44 Importantly, thiols were also tolerated in the reaction.

Scheme 40. Cu-catalyzed propargylic etherification of propargylic alcohols with alcohols and thiols.

enamines 45 with a combination of Cu(OAc)2H2O and the chiral tridentate ferrocenyl P,N,N-ligand (Rc,Sp)-L5 as the catalyst.40 Under mild conditions, perfect endo selectivities (endo/exo >98:2) and excellent enantioselectivities (up to 98% ee) for endo cycloadducts 46 were achieved for a wide range of substrates (Scheme 35). The mild conditions, broad substrate scope, good yields, and high diastereo- and enantioselectivities make this process highly useful in the synthesis of optically active bicyclo[n.3.1] frameworks. The plausible mechanism is proposed as shown in Scheme 36. The cyclic enamine Cb attacks at the Cc atom of the copper allenylidene complex, which should be the key step for the stereoselection. Then, H atom shifts to Cb of the Cu–acetylide complex to give Cu–vinylidene complex E and subsequent intramolecular nucleophilic attack of the cyclic enamine Cb at the Ca atom of E affords alkenyl complex F. Propargylic substitution of oxygen and sulfur nucleophiles In comparison with N- and C-nucleophiles, less progress has been made with O- and S-nucleophiles. In 1994, Godfrey and coworkers reported the copper-catalyzed propargylic etherification of propargylic chlorides 38 or esters 1 with phenols 47 to give aryl 1.1-dimethylpropargyl ether 48 in good yields under mild conditions (up to 88% yield, Scheme 37).41 Importantly, the reaction proceeded regioselectively and no allenic byproducts were observed. Later, Mann and co-workers also developed the propargylic etherification of dialkylpropargyl chlorides 38 with phenols 47 in

Conclusions and future outlook In summary, significant advances have been achieved in the copper-catalyzed propargylic substitutions over the last two decades. Diverse nucleophiles such as nitrogen, carbon, oxygen, sulfur nucleophiles have been successfully applied in the reaction. Many kinds of propargylic compounds have been prepared in satisfactory yields, regioselectivities, and enantioselectivities under very mild conditions. Especially, some carbo- or heterocyclic scaffolds, that are hard to prepare with conventional methods, could be readily synthesized by copper-catalyzed propargylic substitution/cyclization tandem reactions. Although great progress has been achieved, the Cu-catalyzed propargylic substitution, in particular its asymmetric version, is still in underdeveloped and full of challenges. For instances, only a limited number of chiral ligands are found to be efficient. The scope of the propargylic substrates is narrow, and no successful asymmetric example has been reported for either propargylic esters with an internal alkyne moiety or tertiary propargylic esters. The range of suitable nucleophiles is quite limited, and O- or S-nucleophiles has never been employed in an asymmetric reaction. Moreover, the diastereo- and enantioselective construction of multi-stereogenic centers via the copper-catalyzed asymmetric propargylic substitution remains rarely explored. It is expected, however, that with a deeper understanding of these reactions, new chiral ligands as well as new strategies will be developed, and the scope of both the nucleophiles and the substrates will be expanded in the future. Acknowledgment Financial support from the Dalian Institute of Chemical Physics (CAS) is gratefully acknowledged. References and notes 1. (a) Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1987, 28, 4311; (b) Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D.; Clardy, J. J. Antibiot. 1989, 42, 1449; (c) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937; (d) Wright, J. L.; Gregory, T. F.; Kesten, S. P.; Boxer, P. A.; Serpa, K. A.; Meltzer, L. T.; Wise, L. D.; Espitia, S. A.; Konkoy, C. S.; Whittemore, E. R.; Woodward, R. M. J. Med. Chem. 2000, 43, 3408. 2. For reviews, see: (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207; (b) Caffyn, A. J. M.; Nicholas, K. M. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; vol. 12, p 685; (c) Green, J. R. Curr. Org. Chem. 2001, 5, 809; (d) Müller, T. J. J. Eur. J. Org. Chem. 2001, 2021; (e) Díaz, D. D.; Betancort, J. M.; Martín, V. S. Synlett 2007, 343.

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