introduction to organocatalytic cycloaddition reaction ...€¦ · methods to synthesize carbo‐...

1

Organocatalytic Cycloadditions for Synthesis of Carbo- and Heterocycles, First Edition. Min Shi, Yin Wei, Mei-Xin Zhao, and Jun Zhang. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2018 by Wiley-VCH Verlag GmbH & Co. KGaA.

1

1.1 General Introduction

Carbo‐ and heterocycles as core structures exist in a variety of pharmacological agents and natural products [1]. Therefore, development of novel and efficient methods to synthesize carbo‐ and heterocyclic compounds is a topic of para-mount importance in modern organic synthesis. Although a variety of highly efficient methodologies for the synthesis of various carbo‐ and heterocyclic systems exist, the development of novel strategies involving readily accessible starting materials, reduced numbers of transformation steps and purification procedures, and high selectivities (chemo‐, regio‐, and stereoselectivity) is in continuous demand. Among the synthetic methods to access carbo‐ and hetero-cyclic compounds, cycloaddition reactions catalyzed by utilizing nucleophilic organocatalysts, such as tertiary amines, phosphines, or N‐heterocyclic carbenes (NHCs) represent one of the most commonly used and efficient methods. In general, organocatalytic cycloaddition reactions can be processed based on a zwitterion‐oriented synthetic strategy depicted in Scheme 1.1 in which the addi-tion of a nucleophilic organocatalyst to the electrophilic substrate generates the zwitterion intermediate, which then undergoes the addition with the second electrophilic substrate followed by cyclization and releasing the catalyst to give carbo‐ and heterocyclic products. Taking advantage of the zwitterion‐oriented synthetic strategy, subtle tuning catalysts, substrates, and the reaction conditions can provide divergent synthetic routes to access different carbo‐ and heterocy-clic compounds. Thus, this research field has attracted a lot of attention in recent decades. Many research groups such as Lu’s group [2], Kwon’s group [3], Shi’s group [4], Zhang’s group [5], Guo’s group [6], Huang’s group [7], Tong’s group [8], and so on have contributed a series of research works on organocatalytic

Introduction to Organocatalytic Cycloaddition ReactionYin Wei1 and Min Shi 1,2

1 Chinese Academy of Sciences, University of Chinese Academy of Sciences, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, State Key Laboratory of Organometallic Chemistry, 345 Lingling Road, Shanghai 200032, China2 East China University of Science and Technology, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Key Laboratory for Advanced Materials, 130 Mei Long Road, Shanghai 200237, China

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COPYRIG

HTED M

ATERIAL

1 Introduction to Organocatalytic Cycloaddition Reaction2

cycloaddition reactions, which have enriched the literature on the synthetic methods to access carbo‐ and heterocyclic compounds.

Although several reviews [9] have discussed the progresses of organoamine‐catalyzed, organophosphine‐catalyzed, and NHC‐promoted cycloaddition reac-tions, comprehensive literature fully covering these topics is lacking. We would like to concentrate our discussion and assessment on the following issues: (i) in‐depth investigations of reaction mechanisms for zwitterion‐oriented cycloadditions promoted by organoamines and organophosphines as well as NHCs; (ii) synthesis of different products from the same starting material(s) by subtle choice of different catalysts; (iii) how to control the chemo‐, regio‐, and stereoselectivity; and (iv) synthetic applications of these organocatalytic cycload-dition reactions. We hope that this book will satisfy the expectations of experi-enced researchers and graduated students who are interested in the development of the field and are looking for complete and up‐to‐date information on the chemistry of organocatalytic cycloaddition reactions.

1.2 General Mechanistic Insights into Cycloadditions Catalyzed by Nucleophilic Organocatalysts

Most of organocatalytic cycloaddition reactions are initiated by the conjugate addition of a nucleophilic catalyst to the electrophilic substrate producing a zwitterionic intermediate, which can then go through various cycloaddition pathways depending on the substrates, nature of catalyst, and the reaction con-ditions. The selected examples were depicted to demonstrate the mechanisms for common organocatalytic cycloaddition reactions.

1.2.1 Mechanisms for Common Organoamine‐catalyzed Cycloaddition Reactions

In the early 1980s, Wynberg and Staring began a systematic investigation of the formal [2+2] cycloaddition between ketenes and aldehydes [10]. The reaction

Nucleophilicorganocatalysts

(amines, phosphines, NHCs)

ZwitterionicintermediateIntermediate

Electrophilicsubstrate 1

Electrophilicsubstrate 2

Carbo- and heterocyclicproduct

Scheme 1.1 General mechanism of organocatalytic cycloaddition reaction.

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1.2 eneral Mechanistic Insights into Cycloadditions Catalyyed by ucleoohilic Organocatalysts 3

mechanism was proposed to proceed through the attack of the chiral amine catalyst 1 or 2 on the ketene 3, which leads to the formation of a highly reactive amidonium enolate 4 (Scheme 1.2). This enolate then adds to an electrophilic aldehyde to generate an alkoxide that can close onto the acylammonium ion 5, subsequently releasing the chiral amine catalyst and forming the [2+2] cycload-duct β‐lactone 6. In a classic series of studies, it was shown that both enantiom-ers of the product could be obtained simply through judicious choice of the alkaloid catalyst. Subsequent analysis of the crystal and solution structures of these compounds provides a clear rationale for the factors influencing the stereoselectivity [11]. In the context of organoamine‐catalyzed reactions, it is interesting to note that enhanced nucleophilicity at C2 played a role in the f ormation of the carbon–carbon bond while enhanced electrophilicity at C1 played a role in the final cyclization step.

Shi and co‐workers reported that utilizing DABCO as the catalyst, N‐ tosylimines 7 underwent formal [2+2] cycloadditions with 2,3‐butadien-oates to afford azetidine derivatives 8; however, switching the catalyst to DMAP, the formal [4+2] cycloaddition occurred to give dihydropyridine deriv-atives 9 [12] (Scheme 1.3). The nuclophilicities of organoamines probably affected the reaction pathways. They proposed the plausible mechanisms as shown in Scheme 1.4. The nitrogen Lewis bases (LB) DABCO and DMAP act as a nucleophilic organocatalyst and produce the key intermediate 10, which exists as a resonance‐ stabilized zwitterionic intermediate 10 (enolate) or 11 (allylic carbanion). In the case of DABCO, the allylic carbanion 11 adds to the N‐tosylated imine to give the intermediate 12, which undergoes an intra-molecular nucleophilic attack (Michael type) to give another zwitterionic intermediate 13. The elimination of NR3 from 13 affords product 8 and regen-erates DABCO (Scheme 1.4a). However, in the case of DMAP, the enolate 10 adds to the N‐tosylated imine to afford the intermediate 14, which adds to another N‐tosylated imine to give the intermediate 15. The proton transfer

O

H H

Cat. 2 or 3 (1 mol%)N

OR

RR

1 4

Cl3CCHON

OR

RR

5

O

Cl3CH

O

O

HCl3C

6N

OMe

N

HO

Quinidinecat. 2

N

OMe

N

OH

Quininecat. 3

quinidine: >99% yield, er 99 : 1quinine: >99 yield, er 12 : 88

1

2

Scheme 1.2 The proposed mechanism for the formal [2+2] cycloaddition between ketenes and aldehydes.

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NTs

Ar H

CO2Et

DABCO, C6H6MS 4 Å, 1 h

N

CO2Et

HAr

Ts

7

8

up to 99% yield+

DMAPCH2Cl2, 10 min

N

CO2Et

Ar Ar

Ts

9

up to 60% yield

Scheme 1.3 The formal [2+2] cycloaddition versus [4+2] cycloaddition catalyzed by amines.

CO2Et DABCO

NR3

CO2Et

NR3

CO2Et

ArCH=NTsC

R3N CO2Et

ArNTs

H

ArN NR3

CO2Et

N

CO2Et

HAr

TsTs

CO2Et DABCO

NR3

CO2EtArCH=NTs

NR3

CO2Et

HC Ar

NTsC

NHTsAr

NR3

CO2Et

HC Ar

NTs

ArCH=NTs

NR3

CO2Et

HC Ar

NTsC

NTsAr

HNTs

Ar

CO2EtNR3

TsHN

Ar

NTs

Ar

CO2EtNR3

TsHN

ArNTs

Ar

CO2Et

TsHN

Ar–NH2Ts

NAr Ar

CO2Et

Ts

10 11

(a)

(b)

12 13 8

NR3

10 14

15 16

17 9NR3

Scheme 1.4 Proposed mechanisms for the formal [2+2] cycloaddition versus [4+2] cycloaddition catalyzed by amines.

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produces the intermediate 16, and the subsequent intramolecular Michael addition gives the intermediate 17. Proton shift and NHTs elimination furnish product 9 and regenerate DMAP.

Shi’s group reported another chemoselective [4+2] versus [2+2] cycloaddition between allenoates and dithioesters 18, which can be controlled by switching the nucleophilic amine catalyst to give [4+2] product 19 and [2+2] cycloaddition product 20 [13] (Scheme 1.5). A plausible mechanism is depicted in Scheme 1.6 to account for the selective control. The [4+2] and [2+2] cycloaddition reactions are initiated by the formation of zwitterionic intermediate 21 via the nucleo-philic addition of amine to allenoate. When amine is DABCO, the thiophilic attack of 21 on the sulfur atom of the thiocarbonyl group in 18 generates inter-mediate 22. The subsequent cyclization delivers an intermediate 23, which elim-inates the catalyst to afford product 19. Based on this mechanism, the reaction of dithioesters bearing electron‐deficient R2 group with allenoate is favored because the negative charge in intermediate 22 can be stabilized by delocalization. This is probably why they have better chemoselectivity. When the amine catalyst is 26 or β‐isocupreidine (β‐ICD), the nucleophilic attack of zwitterionic intermediate 21 on the carbon atom of the thiocarbonyl group in 18 is preferred to give an intermediate 24, perhaps due to the observation that the hydrogen‐bonding interaction between the catalyst with its hydrogen‐bonding donor and the sub-strate leads to the chemoselective [2+2] exceeding over [4+2] cycloaddition (Scheme 1.6). Thus, the C–S bond is formed to generate an intermediate 25 and then the catalyst is released to give product 20.

Although the mechanisms for common organoamino‐catalyzed cycloaddition reactions are proposed from time to time, the detailed mechanistic studies are still scarcely reported. Li and Du [14] investigated the mechanism of the DMAP‐ catalyzed [2+4] cycloaddition between γ‐methyl allenoate and phenyl(phenyldiazenyl)methanone by using density functional theory (DFT) calculations for a better understanding of the mechanistic details. They investigated two possible reaction pathways as shown in Scheme 1.7. Mechanism A includes four reaction steps: (i) the nucleophilic attack of catalyst DMAP on 27 forms the zwitterionic adduct 28, (ii) the γ‐addition of 28 to 29 generates an intermediate γ‐30, (iii) the intermediate γ‐30 undergoes an intramolecular Michael addition to afford an intermediate γ‐31, and (iv) the catalyst elimination from γ‐31 yields the final product γ‐32. Mechanism B comprises three steps: (i) the nucleophilic addition of catalyst DMAP to 27 gener-ates a zwitterionic intermediate 28, which is the same as that in mechanism A,

O

R2

S

SR1

+

R3

S

OR2

R1S

R3

SR1S

R2

O

R3

DABCO Chiral amine catalyst

up to 85% yieldup to 94% yield,er 94 : 6

[4+2] [2+2]

initial S-attack initial C-attack

18

19 20

Scheme 1.5 [4+2] versus [2+2] cycloaddition between allenoates and dithioesters.

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(ii) α‐addition of 28 to 29 affords an intermediate α‐33, and (iii) the intermediate α‐33 is transformed to the final product α‐34 via a concerted intramolecular cycli-zation and catalyst elimination process. Through a series of DFT calculations, the calculated results support the proposed mechanism A. In the DMAP‐catalyzed [2+4] cycloaddition between γ‐methyl allenoate and phenyl(phenyldiazenyl)metha-none, catalytic cycle can be characterized by four steps: (i) nucleophilic attack of

CO2BnNR3

CO2BnNR3

S

SMe

O

Ph

O

R3N

S

CO2Bn

SMePh

CO2BnNR3

SMeSPhOC

S

PhOCMeS

CO2Bn

NR3NR3

[4+2] [2+2]

initial S-attack initial C-attack

O

PhS

SMe

SMeS

Ph

O

CO2Bn

S

OPh

MeS

CO2Bn

+ CO2Bn

21

22

23

24

25

NR3 = DABCO NR3 = β-ICD or 26

NN

OH

NH

NH

SNN

OH

OH

26β-ICD

18

19 20

Scheme 1.6 [4+2] versus [2+2] cycloaddition between allenoates and dithioesters.

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CO2Et

Me

+

N

N

DMAP = NR3

NR3Me

CO2Et

Ph NN

Ph

O

Ph NN

Ph

O

MeNR3 CO2Et

Ph NN

Ph

O

Me R3N

CO2Et

Ph NN

Ph

O

Me CO2Et

Mechanism A

γ-addition

H

Me NR3

N

CO2Et

NPh

OPh

N N

OCO2Et

Ph

Ph

Me

NR3

NR3

Mechanism B

α-addition

Mechanism A is supported byDFT calculations

27

28

29

γ-30

γ-31

γ-32

α-33

α-34

Scheme 1.7 Two possible mechanisms for DMAP‐catalyzed [2+4] cycloaddition between γ‐methyl allenoate and phenyl(phenyldiazenyl)methanone.

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DMAP on 27 to form the zwitterionic intermediate 28; (ii) γ‐addition of 28 to 29 leads to intermediate γ‐30, (iii) γ‐2 undergoes an intramolecular Michael addition to form the six‐membered ring intermediate γ‐31, and (iv) elimination of catalyst completes the catalytic cycle and yields the final product γ‐32. The calculated results show that the first step is the rate‐ determining step. The second step is calculated to be both the regio‐ and enantio‐selectivity‐determining step.

Subsequently, investigations were conducted on the mechanisms and stereoselectivities of the [4+2] cycloaddition reaction of methylallenoate with methyleneindolonone 35 catalyzed by DABCO to give product E‐36 (Scheme 1.8a) and by DMAP to afford Z‐36 as major product (Scheme 1.8b) [15]. The reaction mechanisms were examined with DFT (M06‐2X) calcula-tions. Several possible reaction pathways (paths 1a, 1b, and 1c shown in Scheme 1.9 for DABCO‐catalyzed reaction, paths 2a and 2b shown in Scheme 1.10 for DMAP‐catalyzed reaction) were located and compared. The results of their studies reveal that for both reactions, three reaction stages are necessary: nucleophilic addition of the catalyst (DABCO or DMAP) to methy-lallenoate (Stage 1), addition of the other reactant 35 (Stage 2), intramolecular cycloaddition and liberation of the catalyst (DABCO or DMAP) that afforded the final product (Stage 3). For the DABCO‐catalyzed cycloaddition, it was predicted that path 1a leading to product E‐36 is the most energy favorable pathway among the three possible pathways. The energy barrier for carbon–carbon bond formation step is 23.6 kcal mol−1, which is the rate‐determining step. With the DMAP catalyst, the suggested that path 2b is preferred; thus, the same reaction gave Z‐36 as the major product (Scheme 1.10). The barrier for the rate‐determining step (addition of R1 to DMAP) is 25.8 kcal mol−1. The calculated results are in agreement with the experimental findings. Moreover, for both reactions, the analysis of global reactivity indexes has been carried out to demonstrate that the catalyst’s nucleophilicity plays a key role in their cycloaddition reaction. Their theoretical studies provided a general mechanis-tic framework for this kind of organoamine‐catalyzed cycloaddition reaction, and rationalized the stereoselectities.

CO2Et+

NO

EtO2C

Ac

OEtDABCO

THF, rt

DMAP

toluene, 80 °C

NAc

OMeO2C

OEtEtO2C

(a)

E-36

NAc

OMeO2C

OEtEtO2C

NAc

O

OEtEtO2C

+

major minor

CO2Et

(b)

35

Z-36 E-36

Scheme 1.8 [4+2] cycloaddition reaction of methylallenoate with methyleneindolonone.

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CO

2Et

+

NO

EtO

2C

AcO

Et

NR

3 =

DA

BC

O

N Ac

O

OE

tE

tO2C

E

O

OM

eR

3N

NR

3OO

Me

OM

eO

R3H

2N

OE

tE

tO2C

N

O

Ac

NR

3

O

OM

e

NR

3

O

MeO

NR

3

OE

tE

tO2C

NA

c

O

NR

3

N Ac

O

OE

t

Z

OM

eO

+

NR

3 =

DA

BC

O

NR

3

OM

eON

O

EtO

2C

AcO

Et

R3N

OM

eO

NR

3

OM

e

O

OE

tC

O2E

tN

O

Ac

NR

3N A

c

O

OE

tE

tO2C

O

OM

e

OM

e

O

pat

h 1

a

pat

h 1

b

pat

h 1

c

Sche

me

1.9

Poss

ible

mec

hani

sms

for D

ABC

O‐c

atal

yzed

[4+2

] cyc

load

ditio

n re

actio

n of

met

hyla

lleno

ate

with

met

hyle

nein

dolo

none

.

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CO

2Et

+

NO

EtO

2C

AcO

Et

NR

3 =

DM

AP

N Ac

O

OE

tE

tO2C

NR

3OO

Me

OM

eO

R3H

2N

OE

tE

tO2C

N

O

Ac

NR

3

O

MeO

NR

3

OE

tE

tO2C

NA

c

O

NR

3N A

cO

OE

t

Z-3

6

OM

eO

NO

EtO

2C

AcO

Et

OM

e

O

N

OM

eON

Me 2

N

OM

e

O

NM

e 2

Pat

h 2

a

Pat

h 2

b

E-3

6

Sche

me

1.10

Pos

sibl

e m

echa

nism

s fo

r DM

AP‐

cata

lyze

d [4

+2] c

yclo

addi

tion

reac

tion

of m

ethy

lalle

noat

e w

ith m

ethy

lene

indo

lono

ne.

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1.2.2 Mechanisms for Common Organophosphine‐catalyzed Cycloaddition Reactions

The first seminal report of phosphine‐catalyzed [3+2] cycloaddition reaction of allenoate with alkene was published in 1995 by Lu’s group [2a]. They initially explored the reaction of ethyl 2,3‐butadienoate 37 with methyl acrylate 38 in the presence of triphenylphosphine (50 mol%) in dry benzene at room temperature, and two cycloaddition products 39 and 40 were obtained. In this report, they proposed a plausible mechanism for this reaction as shown in Scheme 1.11. In the proposed mechanism, the zwitterionic inermediate 41 is generated readily through addition of phosphine to the 2,3‐butadienoate 37. The zwitterionic inermediate 41 undergoes a [3+2] cycloaddition with an electron‐deficient alk-ene 38 to give phosphrous ylides 42 and 43. Then, an intramolecular [1, 2] pro-ton transfer occurs to convert the phosphorus ylides to intermediates 44 and 45, which, upon elimination of the phosphine catalyst, afford the final cycloadducts 39 and 40.

Although the mechanism for phosphine‐catalyzed [3+2] cycloaddition reaction of allenoate with electron‐deficient alkene was first proposed by Lu’s group (see Scheme 1.11), the detailed mechanism was not systematically inves-tigated for a long time. In 2007, Yu’s group studied the detailed mechanism for this reaction through DFT calculations [16]. Subsequently, Yu’s group contin-ued to investigate the detailed mechanism of the phosphine‐catalyzed [3+2]

CO2Et37PR3

PR3

CO2Et

41

E [3+2]

E

CO2EtR3P CO2EtR3P

E

+

42 43

E

CO2EtR3P CO2EtR3P

E+

44 45

E

CO2Et CO2Et

E+

39 40

38

Proton transfer

Scheme 1.11 The mechanism of phosphine‐catalyzed [3+2] cycloaddition reaction of allenoate with alkene proposed by Lu’s group.

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cycloaddition reactions of allenoates and electron‐deficient alkenes with the aid of DFT calculations and kinetic experiments [17]. They suggested that this reac-tion proceeded via the following consecutive steps: (i) in situ generation of a 1,3‐dipole 46 from nucleophilic addition of phosphine to allenoate; (ii) the first carbon–carbon bond formation to give intermediate 47 and then the second carbon–carbon bond formation occurring to provide [3+2] cycloaddition inter-mediate 48, which takes place in a stepwise manner; (iii) association of a water molecule with the intermediate 48 to give a complex 49, then proton transfer from water to the carbon atom connected with the phosphorus atom occurs to afford a contact ion pair 50, which undergoes another proton transfer to give complex 51; (iv) elimination of water to furnish intermediate 52; and (v) elimina-tion of the phosphine catalyst to afford product 53 (Scheme 1.12). They con-cluded that the phosphine‐catalyzed [3+2] cycloaddition of allenoate with electron‐deficient alkene is a stepwise process, and that the generally accepted intramolecular [1, 2] proton shift in the phosphine‐catalyzed [3+2] cycloaddition of allenoate with electron‐deficient alkene was not possible owing to the very high activation barrier. However, a trace amount of water can assist the [1, 2] proton shift process.

CO2Et PR3

PR3

CO2Et

E

Stepwise [3+2] addition

E

CO2EtR3P

E

CO2EtR3P

E

CO2Et

1,2-H shift with assistant of water

46

48

52

53

E

CO2EtR3P47

HH2O (trace)

E

CO2EtR3P HHO

H

E

CO2EtR3P HHO

H

E

CO2EtR3P HO H

H

O H

H

49

50

51

Scheme 1.12 The detailed mechanism for phosphine‐catalyzed [3+2] cycloadditions proposed by Yu’s group.

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Through computational analysis at the B3LYP/6‐31G(d) level of theory, Dudding and Kwon almost simultaneously investigated phosphine‐catalyzed cycloaddition reactions of acrylates, imines, and aldehydes with allenoates, ver-ified that this phosphine‐catalyzed [3+2] cycloaddition reaction proceeded in a stepwise manner, and provided a rational for the reaction regioselectivity [18]. The reaction started from the addition of phosphine to allenoate to generate the zwitterionic intermediate as commonly suggested step in organo catalytic cycloaddition reaction (Scheme 1.13). It was already established that acrylate 54 and imine 55 could undergo predominant α‐addition to zwitterionic inter-mediate 46 to afford [3+2] cycloaddition products (Scheme 1.13, paths a and b). However, using aldehyde 56 as a substrate, a γ‐selective [2+2+2] cycloaddi-tion reaction took place to afford dioxanylidene (E)‐57 and (Z)‐57 (E:Z > 8 : 1) with exclusive cis‐diastereoselectivity (Scheme 1.13, path c) [3d]. Through extensive DFT calculations, an excellent level of correlation between the calcu-lated regioselectivities and experimental results was observed. Based on the calculation results, they verified that this phosphine‐catalyzed [3+2] cycloaddi-tion reaction proceeded in a stepwise manner, and revealed that Lewis acid acti-vation, strong hydrogen bonding (H‐bonding), and minimization of unfavorable

CO2EtPR3

PR3

CO2Et

+

PR3

CO2Et

OMe

O

PR3

MeO2C MeO2C

CO2Me

PR3

CO2Me

+CO2Me

α-addition γ-addition

CO2Me

MeO2C+

CO2Me

CO2Me

α : γ -product = 85 : 15

N

PhH

Ts

N

Ts

α-addition

Ph

NTs

MeO2C

+

Phdimer

by-product

α-product : γ -dimer = 86 : 14

O

PR3PR3

Ph

CO2Me

γ-addition

O O

Ph

Ph

CO2Me

(E) and (Z)-57via exclusive γ-addition

Path aPath b Path c

O

PhH

46

54 55

56

Scheme 1.13 The proposed mechanisms for phosphine‐catalyzed cycloaddition reactions of acrylates, imines, and aldehydes with allenoates.

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van der Waals contacts were the critical factors that affected the regioselectiv-ity. Subsequently, they also identified the catalytic role of trace water, which played as a proton‐shuttle, for proton transfer step[18a], which agreed with Yu’s work [16].

In 2015, Shi’s group reported regioselectively catalytic asymmetric [3+2] cycloadditions of benzofuranone‐derived olefins 58 with allenoate 59 and substituted allenoates 60 in the catalysis of (R)‐SITCP 63, affording different functionalized 3‐spirocyclopentene benzofuran‐2‐ones 61 and 62 in good yields with high enantioselectivities under mild condition (Scheme 1.14). In the meantime, they also rationalized the regioselectivity affected by the γ‐ substituent of allenoate through DFT calculations [19]. The plausible mechanisms for this phosphine‐catalyzed [3+2] cycloaddition have been proposed in Scheme 1.15. They proposed that the reaction started from the formation of a zwitterionic intermediate 64 between allenoate (59 or 60) and phosphine. Intermediate 64 acts as a 1,3‐dipole and undergoes a [3+2] cycloaddition with benzofuranone 58 to give a phosphrous ylide 65 via a γ‐addition or 66 via α‐addition. For allenoate 59 (R3 = H), γ‐addition is the main pathway. In contrast, allenoate 60 (R3 = aryl or alkyl group) mainly undergoes α‐addition. Then an intramolecular [1, 2] pro-ton transfer is speculated to convert the phosphorus ylide 65 or 66 to another zwitterionic intermediate 67 or 68, which, upon elimination of the phosphine catalyst, gives rise to the final cycloadduct 61 or 62. Through DFT calculations, they verified the proposed mechanism, and revealed that the allenoate having

γ

+

CO2R2

63 (10 mol%)

toluene, rt, 24 hOO

R1

OO

R3

R1

R3

R2O2C

1

2

3

4

5

+

COR2

63 (10 mol%)

4 Å MS, toluene/DCM, rtOO

R1

OO

COR2

R1 1

2

3

45

R1 = Aryl, alkyl

R1 = Aryl, alkyl

up to 99% yield,99% ee, >99 : 1 rr

R2 = OBn, OEt, Me

R2 = Bn, Et, tBu

R3 = Ph, Me

P

63

γ-addition

α-addition

α

α

γ

up to 96% yield,99% ee, >99 : 1 rr

58

58

59

60

61

62

Scheme 1.14 Chiral phosphine‐catalyzed tunable cycloaddition reactions of allenoates with benzofuranone derived olefins.

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γ‐substituent preferred to undergo α‐ addition mode due to the steric hindrance between the R3 substituents and benzofuranone in γ‐addition mode.

The idea of employing acetate/tert‐butylcarbonate‐protected β‐hydroxym-ethylacrylates in phosphine catalysis was first introduced by Lu’s group in 2003 [20]. By using Morita–Baylis–Hillman alcohol derivatives (MBHAD) as sub-strates, novel phosphonium species were accessed in the presence of phos-phines through new pathways, which subsequently underwent cycloadditions with electron‐ deficient alkenes to give cycloaddition products. The mechanism proceeds with conjugate addition to the MBHAD 69 with the ejection of the β‐ leaving group, forming the phosphonium species 70 (Scheme 1.16). The expelled acetate or tert‐butoxide acts as a base to activate and generate the phosphonium ylide 71. In the presence of an activated alkene, the following [3+2] cycloaddition reaction occurs to yield a mixture of the cyclopentenes 72 and 73.

In 2003, the formal [4+2]‐cycloadditions of Ts‐imines and α‐substituted alle-noates were first reported by Kwon and co‐workers [3a]. They also proposed a plausible mechanism as shown in Scheme 1.17. The [4+2] cycloaddition begins with the initial addition of phosphine to the α‐alkyl‐2,3‐butadienoate 74 to give the phosphonium dienolate 75. Unlike phosphine‐catalyzed [3+2] cycloaddition, addition at the α‐position is prohibited by the steric bulkiness; therefore, initial addition occurs only at the γ‐position. In the presence of an imine 76, the zwit-terion 77 is subsequently generated. Proton transfer provides the vinyl phospho-nium ylide 78, which is converted to the more stable phosphonium amide

CO2R2

PR3

59 or 60

58

H-shift

64

OO

R1

OO

CO2R2

R1PR3

R3

PR3

OR2

OR3

+

58O

O

R1

OO

CO2R2

R1PR3

OO

CO2R2

R1

R3 = H

61

OO

R3

R1PR3

R2O2C

H-shiftR3 = aryl or alkyl

OO

R3

R1PR3

R2O2COO

R3

R1

R2O2C

62

α

γ

γ -additionα-addition

65

66

67

68

Scheme 1.15 Plausible mechanism for phosphine‐catalyzed [3+2] cycloaddition of allenoates with benzofuranone derived olefins.

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EPR3

PR3

E

70

PR3R3

E

X

X

XHPR3

ER2

R1

R3

R2

R1

R3

ER2

R1

R3

ER2

R1

+

X = OAc, OBoc

69

71

72 73

Scheme 1.16 Proposed mechanism for [3+2] cycloaddition of MBHAD and alkene.

zwitterion 79. The final nitrogen–carbon bond is formed upon the Michael addition of the amide anion, followed by extrusion of the phosphine catalyst to provide the final product tetrahydropyridine 80.

Although phosphine‐catalyzed [4+2] cycloaddition reactions have been developed very well, it is rare to see reports on the studies of the detailed reac-tion mechanism. In 2012, Han and co‐worker investigated phosphine‐catalyzed [4+2] cycloadditions between allenoates and electron‐poor trifluoromethyl ketones dipolarophiles in continuum solvation using DFT calculations, and the detailed reaction mechanisms as well as the high cis‐diastereoselectivities of the reactions have been firstly clarified [21]. As illustrated in Scheme 1.18, their calculated results reveal that the whole catalytic process is presumably initiated with the nucleophilic attack of phosphine catalyst at the allenoate to produce the zwitterionic intermediate 81, which subsequently undergoes γ‐addition to the electron‐poor C═O of trifluoromethyl ketone to form another intermediate 82. The following [1,3]‐hydrogen shift of 82 is demonstrated to proceed via two consecutive proton transfer steps without the assistance of protic solvent: the anionic O6 of 82 first acts as a base catalyst to abstract a proton from C1 to produce the intermediate 83, and then the OH group can donate the acidic proton to C3 to complete the [1,3]‐hydrogen shift and generate the intermedi-ate 84. Finally, the intramolecular Michael‐type addition generated an interme-diate 85, which released the phosphine catalyst to furnish the final product 86. High cis‐ diastereoselectivities are also predicted for this reaction, which is in good agreement with the experimental observations. For the reaction of alle-noates with trifluoromethyl ketones, the first proton transfer is found to be the

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diastereoselectivity‐determining step. The cumulative effects of the steric repulsion, electrostatic interaction as well as other weak interactions appear to contribute to the relative energies of transition states leading to the diastere-omeric products. In a similar manner, they also investigated the mechanism for the phosphine‐catalyzed [4+2] cycloadditions between allenoates and imines. The mechanism for phosphine‐catalyzed [4+2] cycloaddition of allenoate and imine is quite similar to the mechanism depicted in Scheme 1.18; however, the Michael‐type addition is found to be the diastereoselectivity‐determining step.

In 2007, Kwon and co‐worker [22] demonstrated that the [4+2] mode can apply to highly electron‐deficient olefins to enable the synthesis of cyclohex-enes. The Lewis base P(NMe2)3 (87) could catalyze the [4+2] cycloaddition of α‐ methylallenoate (88) and activated alkene (benzylidenemalononitrile 89) to exclusively afford cyclohexene 90a [the ratio of 90a/90b being 100 : 0] (Scheme 1.19). Wang and co‐workers conducted DFT calculations to under-stand the [4+2] cycloaddition reaction between α‐methylallenoate (88) and benzylidenemalononitrile (89) catalyzed by P(NMe2)3 (87) [23]. The cyclohex-ene 90a was identified as the predominated product in the experiment. Based

CO2Et74PR3

PR3

CO2Et

75

NTs

R

R

Ar

N

PR3

CO2Et

RAr

Ts

NH

PR3

CO2Et

RAr

Ts

N

PR3

CO2Et

RAr

Ts

N

CO2Et

RAr

Ts

7677

78

79

80

Scheme 1.17 Proposed mechanism for [4+2] cycloaddition reaction of Ts‐imine and α‐substituted allenoate.

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on the DFT calculation results, they verified the proposed mechanism and accounted for the exclusive regioselectivity. Their studies show that the catalytic cycle of the reaction can be characterized similarly by three stages (Scheme 1.20): Stage 1 being the addition of catalyst 87 to allenoate 88, gener-ating the 1,3‐dipole intermediate 91; Stage 2 being the addition of alkene 89 to 91 to give intermediate 92, followed by hydrogen transfer to generate the allylic phosphonium intermediate 93 and ring closure in 93 to give the six‐ membered‐ring intermediate 94; and Stage 3 being the release of catalyst 87 from 94 to form product 90a. Their calculation results reveal that the pathway leading to

CO2Et

88

H+

CN

CN

PhP(NMe2)3

Benzene, reflux

Ph

HCO2Et

CN CN

+

HCO2Et

PhNC

NC

90a

100%

90b

0%

87

89

Scheme 1.19 The [4+2] cycloaddition reaction of α‐methylallenoate and benzylidenemalononitrile catalyzed by P(NMe2)3.

CO2EtPR3

PR3

CO2Et

Ph

Ph

O

CF3PhH

HPh

OOEtPh3P

Ph

CF3O

HPh

OOEtPh3P

Ph

CF3O

H

H

Ph

OOEtPh3P

Ph

CF3O

O

PR3

HPh

Ph

F3C

O

OEt

OHPh

Ph

F3C

O

OEt

81

82 83

84

85

86

1

23

4

5

6

Scheme 1.18 A plausible mechanism for phosphine‐catalyzed [4+2] cycloaddition of allenoate and trifluoromethyl ketone.

c01.indd 18 3/10/2018 2:37:56 PM


the product 90b is substantially less favorable due to the difficult 1,4‐H shift in this case, which accounts for the exclusive regioselectivity (90a/90b = 100 : 0) of the reaction. The [4+2] cycloadditions are different from the conventional [3+2] cycloadditions of allenoates and activated alkenes. In the phosphine‐cat-alyzed [3+2] cycloadditions of allenoates and activated alkenes, a trace amount of water was demonstrated to be critical [16], even though the reactions are carried out in so‐called “anhydrous” solvents, because water is the only availa-ble hydrogen transfer mediator. In other words, the traditional [3+2] cycload-ditions would not occur if the solvent was absolutely free of water. In contrast, this [4+2] cycloaddition can take place, even though water is completely absent, because the carbon (CCN of alkene 89) bearing the nitrile groups can serve as the hydrogen transfer mediator.

1.2.3 Cycloaddition Reaction Modes Influenced By Catalysts

Although the amines and phosphines have some similarity as Lewis base catalysts, they still demonstrate different catalytic properties in some cycloaddi-tion reactions. In the catalysis of phosphine, the [3+2] cycloaddition reactions of allenoates and activated alkenes took place easily; however, switching to amines

CO2Et88

PR3

CO2Et

91

H

H

+CN

CN

PhP(NMe2)3

Benzene, reflux

Ph

HCO2Et

CN CN

PR3 = P(NMe2)3

CN

CN

PhPR3

CO2Et

92

HPhCN CN

PR3

CO2Et

93

PhCN CN

H PR3

CO2Et

94

PhCN CN

H

PR3

CO2Et

CN

CN

Ph

1,4-H shiftis unfavorable

PR3

CO2Et

Ph

H

NC

NC

PR3

CO2Et

PhNC

NC

PR3

CO2Et

PhNC

NC

CO2Et

PhNC

NC

87

89

90a

90b

Scheme 1.20 A plausible mechanism for [4+2] cycloaddition reaction of α‐methylallenoate and benzylidenemalononitrile catalyzed by P(NMe2)3.

c01.indd 19 3/10/2018 2:37:57 PM


as catalysts, the [2+4] cycloaddition reactions or via an intermediate Rauhut−Currier reaction to access [2+4] cycloaddition product occurred. Yu’s group investigated the cycloaddition reaction modes affected by catalysts through DFT calculations [24]. The addition of the catalyst to the allenoate is the first step in both pathways followed by the reaction with the enone. Their calculation results reveal that formation of the [3+2] phosphorus ylide is exergonic, and hence, the [3+2] cycloaddition is kinetically favored over the [2+4] addition (Scheme 1.21). Amines do not stabilize [3+2] ammonium ylides; however, electron‐withdrawing groups on the enone enable [2+4] cycloadditions (Scheme 1.21). The strength of the electron‐withdrawing group further controls the α/γ regioselectivity of the [2+4] cycloaddition, and the analysis of the highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO−LUMO) interactions explains why only E‐dihydropyrans from the direct γ‐[2+4] cycloaddition have been observed in experiments. The quantum calculations further reveal a new path to the α‐[2+4] product starting with an intermediate Rauhut−Currier reaction. This new path is kinetically favored over the direct amine‐catalyzed α‐[2+4] cycload-dition. Their study explains the origin of different reactivity between phosphine and amine catalysts and the substituent effect of the enone in amine catalysis.

Subsequently, Yu’s group further investigated the cycloaddition reactions of allenoates with enones catalyzed by different LB such as phosphines, amines, and NHCs; and they revealed the different catalytic properties of these LB cata-lysts [25]. Based on their DFT calculations, the addition of LBs to methyl alle-noate can yield either Z‐ or E‐adducts, and the Z‐pathway is preferred due to the strong binding electrostatic interactions between the carbonyl oxygen atom and the LB (Scheme 1.22). Among their studied LBs, the formation of NHC·allenoates is the most exergonic. As the dielectric constant of the solvent increases, the stability of the E‐adducts increases more pronouncedly than that of the Z‐adducts. The calculated barriers for the SN2 reaction of the LB·allenoates with CH3Cl show that Cα in the LB·allenoate is more nucleophilic than Cγ. The adducts can also react with ethylene to form [3+2] ylides. The analysis of the LB‐ylides shows that amines form less stable ylides than phosphines, which again are less stable than those derived from NHCs. The ELF analysis reveals a direct correlation between the strength of the ylidic bond and the overall stabil-ity of the forming five‐membered rings. The LB catalyzed reaction of allenoates with enones can either yield [3+2]‐(cyclopentenes) or [2+4]‐cycloadducts (dihy-dropyrans). When phosphines are used as catalysts, the [3+2] cycloaddition dominates, because the ring‐closing step is more favorable due to the exergonic formation of P‐ylides. The [3+2]‐cyclopentene products are also more stable than the [2+4]‐dihydropyrans. In general, the [3+2] cycloaddition dominates both kinetically and thermodynamically when phosphines are used as catalysts. If amines are used as catalysts, kinetic control favors the formation of [2+4]‐dihydropyrans over the cyclopentenes due to the instability of the [3+2] N‐ylides. The LB‐catalyzed reaction of allenoates with ketones yields [2+2]‐(oxetanes), [3+2]‐(dihydrofurans) or [2+2+2]‐cycloadducts (1,3‐dioxanes). The formation of NHC·allenoates is extremely exergonic and these adducts are even more sta-ble than the expected [2+2]‐products. Hence, the thermodynamically controlled [2+2+2] annulation is favored with NHCs as catalysts. On the other hand, the

c01.indd 20 3/10/2018 2:37:57 PM

CO

2R

+

R1

Oα-

[3+

2] c

yclo

addi

tion/

γ-[3

+2]

cyc

load

ditio

n

R1 O

C

PR

3

CO

2R

R1 O

C

CO

2R

Pho

sphi

ne-c

atal

yzed

γ-[2

+4]

cyc

load

ditio

n

O

CO

2R

R1

RO

2CR

1

O

O

R1

CO

2R

Rau

hut-

Cur

rier

CO

2R

+ CO

R1

Exe

rgonic

stab

le

Am

ine-

cata

lyze

d

R1 O

C

NR

3

CO

2R

Endergonic

unstab

le

E

α-[2

+4]

cyc

load

ditio

n

O

R1

CO

2R

Ann

ulat

ion

Sche

me

1.21

The

orig

in o

f diff

eren

t rea

ctiv

ity b

etw

een

phos

phin

e an

d am

ine

cata

lyst

s.

c01.indd 21 3/10/2018 2:37:57 PM


formation of DABCO·allenoates is endergonic, which leads to the kinetically preferred [2+2] products. When PPh3 is used as the catalyst, the [3+2] cycload-dition is both thermodynamically and kinetically favored. Despite NHCs having high initial reactivity, NHCs are less efficient than phosphines and N‐based LBs because the NHC·allenoate intermediates are extremely stable.

References

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Comprehensive Heterocyclic Chemistry III. Oxford: Elsevier.2 (a) Zhang, C. and Lu, X. (1995). J. Org. Chem. 60: 2906–2908. (b) Xu, Z. and Lu, X. (1998). J. Org. Chem. 63: 5031–5041. (c) Du, Y. and Lu, X. (2003). J. Org. Chem. 68: 6463–6465.3 (a) Zhu, X.‐F., Lan, J., and Kwon, O. (2003). J. Am. Chem. Soc. 127: 4716–4717.

(b) Tran, Y.S. and Kwon, O. (2005). Org. Lett. 7: 4289–4291. (c) Zhu, X.‐F., Schaffner, A.‐P., Li, R.C., and Kwon, O. (2005). Org. Lett. 7:

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LB

OR

O

or

PhosphinesX

CO2R

CO2R

O

CO2R

R1

+ NR3

+ LB

LB

ORO

X

R2R1

[3+2]R1 R2

X

R1R2

CO2R

+

X = CH-EWG (electron-deficient alkene)NTs (imine)O (ketone)

Amines

[2+4]

[2+2]

R2 R1

O

R2

R1 = Ph or EWG

X

R1R2X = O or NTs

NHCs

X

CO2R

R2

R1

+ NR3

O O

CO2R

F3C Ph

F3C

Ph + NHCs

O

CF3Ph

[2+2+2]

+ PR3

LB = PR3, NR3 or NHCs

Z-adduct

E-adduct

Scheme 1.22 The cycloaddition reaction modes affected by different LB catalysts.

c01.indd 22 3/10/2018 2:37:58 PM

References 23

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