Decarboxylative functionalization of cinnamic acids.

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Decarboxylative Functionalization of Cinnamic Acids Arun Jyoti Borah and Guobing Yan* Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x www.rsc.org/

Abstract: Decarboxylative functionalization of α,β-unsaturated carboxylic acids is an emerging area that has been developed significantly in recent years. This critical review focuses the different decarboxylative functionalization of cinnamic acids leading to the formation of various C-C and C-heteroatom bonds. Apart from metal carboxylates, decarboxylation in cinnamic acids has been achieved efficiently under metal-free conditions, particularly via the use of hypervalent iodine reagents. We believe this review encourage organic chemist to develop the vinylic decarboxylation in a more appealing way with understanding of new mechanistic insight.

1. Introduction Recently, the decarboxylative cross-coupling reaction has attracted much attention, since it opens a new avenue for the formation of carbon-carbon and carbon-heteroatom bonds. This method has advantages over the conventional transition metal catalyzed crosscoupling reactions concerning the regioselectivity as well as atom and step economy and environmental issues.1 Easy availability of the carboxylic acids compared to aryl halides or organometallic reagents as substrates also makes the process more attractive. Arene carboxylic acids are widely subjected to decarboxylation, and resulted in the formation of various C-C, C-N, C-P and C-S bonds.1 The general mechanistic path of metal catalyzed decarboxylation of carboxylic acids and subsequent functionalization is shown in Fig 1. The organometallic species are formed via extrusion of CO2 from metal-carboxylates, and undergo coupling reactions with other organic compounds via redox-neutral coupling and oxidative coupling. The difficulty associated with this process is that metal

Department of Chemistry, Lishui University, No. 1, Xueyuan Road, Lishui City 323000, Zhejiang Province, P. R. China. E-mail: [email protected]; Fax: (+86)-578-2271-250; Tel: (+86)-578-2271-250 Guobing Yan was born in Jiangxi, China, in 1975. He obtained B.Sc. degree from Jinggangshan Normal University, his M.Sc. degree from Suzhou University, and his Ph.D. degree from Tongji University in 2010. He spent two years in 2008 and 2009 as visiting student in profressor Jianbo Wang’S laboratory at Peking University. He has been at Lishui University since 2010 as an associate professor. In 2013, He joined Dr. Dong’s group at the University of Texas at Austin as a visiting professor and then returned to Lishui University in 2014. His current research interest focus on transition-metal-catalyzed the activation of inert chemical bonds and green synthetic chemistry. Arun Jyoti Borah was born in Dergaon, India in 1983. He received B. Sc. Degree from Dibrugarh University and M. Sc. degree from Gauhati University with specialization in Organic Chemistry. He received Ph. D. from Gauhati University in 2013 working under supervision of Prof. Prodeep Phukan. Recently he has joined as a visiting scholar in Lishui Uinversity with Dr. Guobing Yan research group. His research interest is on development of synthetic methodologies and specifically transition metal-catalyzed functionlaization of inert C-H bond.

salts of simple carboxylates generally require rather forcing conditions to extrude CO2. Under harsh reaction condition and the addition of a transition metal mediator, generally a copper or silver salt, the organometallic species (2, Fig 1) undergo fast protonation by the surrounding medium, giving the corresponding protonated products before a C–C or C–heteroatom bond can be formed.2 Hence, improving the decarboxylation activity of the catalyst system is often decisive when aiming at lower reaction temperatures. Such improved system can allow conversion of a broader scope of carboxylic acids, including sensitive, functionalized derivatives. It has been observed that radical addition-elimination process (Fig 2) allowed relatively mild reaction condition, increasing the scope of substrates. Although the decarboxylation of vinylic acids, the Hunsdiecker halodecarboxylation reaction has been remaining as a routine transformation in organic synthesis, the scope of decarboxylation is very limited and significant method development has been achieved during last few years, particularly with cinnamic acids. Cinnamic acids are relatively stable, inexpensive, structurally diverse, simple to handle and readily can be prepared by the Perkin reaction from aromatic aldehydes.The configuration of cinnamic acids may ensure high regio- and stereoselectivity. Thus, development of efficient and versatile methods to access various compounds using cinnamic acids as coupling substrates is highly desirable in synthetic chemistry. Apart from transition metal catalyst, cinnamic acids are found to undergo decarboxylation under metalfree conditions; particularly the use of hypervalent iodine reagents is very attractive. This comprehensive review highlights the decarboxylative coupling of cinnamic acids (trans) leading to the formation of various C-C and C-Heteroatom bonds. We have discussed the merits and limitations of different strategies and outlined the mechanisms. Hope this review will help the readers to develop the area of vinylic decarboxylation and motivate to find out new more mechanistic path for the decarboxylation process. O R

CO2

O OH

Cat .

R

O (1)

Cat .

Redox Neutral Coupling R-Cat . [O] (2)

Oxidative coupling

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Fig 1. Catalytic pathway for decarboxylative reaction of carboxylic acids

R

CO2

COOH

R'

R'

A, [O]

COOA

R'

R

R R = Alkyl, Nitro, Sulfonyl etc. A = Metal Catalyst or Stoichiometric Hypervalent Iodine Reagent (HIR)


Fig 2. Decarboxylation via radical addition-elimination mechanism.

chloride and CyJohnPhos ligand in the presence of Ag2CO3 as an additive (Scheme 3).5 This carbon-carbon bond formation proceeded with high selectivity and with very good functional-group tolerance. Both electron- rich and electron-poor cinnamic acids are effective under the reaction condition and could provide the desired product in moderate to high yield. Cinnamic acids bearing strong electronwithdrawing groups could provide satisfactory yields, such as NO2 and CN. Although the method was found to be very effective with various aryl iodides, aryl bromides cannot take part in the decarboxylation process. The mechanistic path may involves transmetalation of silver-alkenyl species.6

2. Decarboxylative carbon-carbon coupling of cinnamic acids

COOH R

Ar-I

2.1 Arylation Although decarboxylative arylation of aryl carboxylic acids has been described recently,3 the decarboxylation of vinyl carboxylic acids remains very limited, specially cinnamic acids. In 2007, Goossen reported Pd-catalyzed cross-coupling of cinnamic acids with aryl halides via decarboxylation process.4 The Pd/Cu bimetallic catalyst system was employed for this transformation. But the reaction was performed under tedious condition using 170 °C (Scheme 1). The mechanistic path of the reaction (Scheme 2) reveals that Cuphenanthroline complex mediates the extrusion of CO2 (4). Subsequent transmetalation with the Pd species 3 formed via oxidative addition of 4-bromotoluene and Pd(0) results formation of the species 5, which undergoes reductive elimination to provide the arylated product and regenerate the Pd(0). This reaction condition explored successful coupling of the cinnamic acids with aryl electrophiles without undergoing protodecarboxylation. PdBr2 (3 mol%) CuBr (10 mol%)

COOH

1,10-phenanthroline (10 mol%) K2CO3, NMP/quinoline, 170 oC

Br

CO2

79%

Scheme 1. Pd/Cu-catalyzed decarboxylative arylation of cinnamic acids. [Cu]

CO2

Br

4

O

decarboxylation

O-

L2Pd Br 3 L2Pd(0)

[Cu]+

transmetalation

L= 1,10-phenanthroline

O-

O2N

OMe

F

77%

86%

60%

OMe

OMe CF3 O

65%

55%

50%

Scheme 3. Pd/Ag-mediated decarboxylative arylation of cinnamic acids. Pd/Cu-bimetallic system has been successfully utilized further to achieve more arylation processes.7 Miura et al. synthesized hydroxylated stilbenes through palladium-catalyzed the vinylogous decarboxylative Suzuki reaction of hydroxyl-substituted cinnamic acids with arylboronic acids in presence of copper(II) salt as the oxidant (Scheme 4).7a Using Cu(OAc)2·H2O as oxidant and LiOAc as an additive, electron-rich cinnamic acids were decarboxylated at a much lower temperature (60°C), compared with the other methods. Limited scope of cinnamic acids is the major drawback of this protocol. The reaction proceeds via an initial transmetalation of Pd(II) with arylboronic acids, followed by ligand exchange with cinnamic acids (Scheme 4). Arylpalladium carboxylate intermediates subsequently underwent decarboxylation and reductive elimination to afford the stilbenes. The resulting Pd(0) species is reoxidized with the Cu(II) salt.

reductive elimination

CuBr

PCy2 CysJohnPhos

OMe

OMe

Pd(acac)2 (5 mol%) Cu(OAc)2 H2O ( 1.5 equiv)

COOH ArB(OH)2

L2 Pd

O

Ar

Selected examples:

R

anion exchange

PdCl2 (10 mol%) CysJohnPhos (20 mol%) R Ag2CO3 (3 equiv) DMA, 150 oC 50-86%

Ar R

LiOAc (4 equiv) DMF, 60 oC, 8h

36-82%

Mechanism:

5

PdX2

ArB(OH)2

Ar'

O

COOH ArPdO

ArPdX

Ar'

-CO2

Scheme 2. Possible mechanism.

2CuX2

This initiative cross-coupling of cinnamic acids opens the window for chemist to develop more efficient decarboxylative method for vinyl carboxylic acids systems. In 2009, Wu et al. reported a highly effective decarboxylative cross-coupling reaction of trans-cinnamic acids with aryl iodides catalyzed by a combination of palladium

-2CuX

Pd(0)

ArPd Ar'

Ar'

Ar

Scheme 4. Pd/Cu-mediated decarboxylative arylation of cinnamic acids with arylboronic acids.

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Zhang et al. described the annulations of indolizine with cinnamic acids via both C-H activation and decarboxylation strategy under Pdcatalysis.8 The oxidants play a very important role in determining the product. Using BQ as the oxidant in presence of KOAc base under O2 atmosphere, cinnamic acids underwent annulations (Scheme 5). Very few cinnamic acids were tested for the annulations process and products were isolated in moderate yields. In absence of the base, gem-selective alkenylation products were isolated. The mechanistic path revealed that β-hydride elimination of the intermediate 6 (Scheme 5) could provide the intermediate 7, which is scavenged by BQ/KOAc to form intermediate 8. Subsequent palladation gives the intermediate 9, which undergoes decarboxylation and reductive elimination to form the annulated products. The resulting Pd(0) species is oxidized by BQ to regenerate Pd(II). In the absence of base, the decarboxylation and reductive elimination of intermediate 9 afford the gem-selective alkenylation products.

COOH R1

Pd(OAc)2 (10 mol%) BQ (1 equiv), N2

N

DMF, 100 oC, 1 h

Pd(OAc)2 (10 mol%) BQ (1 equiv), O2

CN COOH N

KOAc (2 equiv) DMF, 120 oC, 12 h

R

R

R

4

o

110 C, 24h, Ar

R2

R3

R1

R4

31-78%, E/Z= 25:1 to 90:1

MeO

MeO

OMe 77% (>50:1)

76% (>40:1)

54% (>30:1)

MeO

MeO

Cl

Cl

54% (>25:1)

78% (>90:1)

65% (>90:1)

Scheme 6. Cu(II)-catalyzed decarboxylative coupling of cinnamic acids with different arenes. 68%

75%

9%

33%

CN

67% N

25%

23%

R

R= Ph (52%), p-Cl (46%), p-OMe (59%), 1-Napthyl (45%)

Mechanism:

CuO (10 mol%) DTBP (2 equiv)

R3

Selected examples:

53% CN

H R2

Fig 3. Regioselectivity at different position of the alkylating partner.

CN COOH R

N

PdX

6

CN

COOH R

N CN

CN N

COOPdH

PdX

7 N R PdX2

BQ / KOAc CN

[O] N

COOPdOAc

CO2 CN

Pd(0) CN N

N

8

Pd

-O

R O

9

Scheme 5. Pd(II)-catalyzed annulations of indolizine via C-H activation and decarboxylation. 2.2 Alkylation

mesitylenes, mono-coupling products could be isolated with good yield. Anisoles also provided the methylated product, albeit in lower yield (36%). Toluenes bearing substitution like Cl- ,Br-, I- are tolerable under the reaction condition. The alkylating partner have a pronounced effect on the selectivity of the process (E/Z varies from 25:1 to 90:1). The benzylic position is more favorable for the C-C bond formation process. The regioselectivity clearly evident from the reactions of n-propylbenzene, n-butylbenzene and ethyl benzene (Fig 3). With methylcyclohexane, primary position is highly activated. Low reactivity of the tertiary position might be due to steric reason. A mechanism has been proposed via radical reassembly (Scheme 7). The benzylic cation formed via SET process adds to the α-position of the double bond in cupric cinnamate 10 and generates an intermediate 11. The decarboxylation of intermediate 11 provides the product along with Cu(I). Oxidation of Cu(I) by the tBuO radical in the presence of cinnamic acids would regenerate the cupric cinnamate to complete the catalytic cycle. COOH

Ar

Compared to decarboxylative arylation of cinnamic acids, the scope of alkylation process{C(sp2)–C(sp3) coupling} has been developed to a reasonable extent. Mao et al. have successfully carried out copper-catalyzed decarboxylative alkylation of cinnamic acids.9 Toluene, xylene and mesitylene etc. were used as alkylating partners in presence of CuO catalyst and DTBP as the suitable oxidant (Scheme 6). Cinnamic acids with electron-donating group, OMe at para-position is favorable for the coupling process, compared to the electron-withdrawing halo substitiuents. With OMe as the substituent, it was observed that ortho- and meta- substituted cinnamic acids provided slightly lower yield compared to para one. With xylene and

Cu(II) H2O t-BuOH Ar

COOCu (II) 10

Ar

COOH

Ar'

CH3

t-BuO

t-BuOH Ar'

CH2

Ar'

CH3

1/2 t-BuOOtBu

Ar' CO2

Cu(I)

Ar

Ar COOCu(II) 11

Ar'

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Scheme 7. Possible mechanism. Cinnamic acids have been suitably subjected to decarboxylation process via radical addition-elimination process. Liu reported olefination of various sp3 C-H bonds via radical addition-elimination process using alcohols, ethers, and hydrocarbons providing the synthesis of allylic alcohols, allylic ethers, and substituted styrenes (Scheme 8).10 Successful transformation was achieved using copper catalyst with TBHP as the better oxidant. Both primary and secondary linear alcohols including cyclic ones were suitably transformed under the reaction conditions. Cinnamic acids bearing Cl and Br substituent were comparatively more effective in comparison to methoxy substituted cinnamic acids. Using this strategy, heteroaryl cinnamic acids could be transformed in moderate to high yields. Apart from alcohols, ethers, alkanes, toluene and its derivatives could also be olefinated successfully using the same reaction condition. In all cases only E products were isolated. The reactivity of the process is controlled by the stability of the carboncentered radical formed. The Fig. 4 reveals regioslectivity of the process at different carbon of alkanes and ethers. Methylene and methenyl groups are more favorable for the process COOH

Ar

Cu ( 2 mol%) TBHP (1.2 equiv)

OH 2 R H R1

alcohols, ethers, alkanes

OH 2 R R1

Ar

o

110 C, 12h

up to 99%, E-only

cinnamate. Similar mechanistic path was followed in alkylation with N,N-dimethylacetamides using DTBP as an efficient oxidant in presence of Cu(II) catalyst (CuO, 20 mol%).11 This method could provide moderate yield favoring electron-rich cinnamic acids. Decarboxylative alkylation via radical addition-elimination process using iron catalyst has been reported.12 Mao et al. used ferrocene or recyclable Fe3O4 nanoparticles as catalyst for alkylation with toluene compounds (Scheme 10).12a Both catalyst was used in presence of oxidant DTBP at 120°C. With ferrocene, cinnamic acids bearing electron-donating and weak electron-withdrawing group could provide the desired alkylated product in high yield. However, the strong electron-withdrawing group decreased the yield. Heterocyclic cinnamic acids also underwent the decarboxylation process effectively providing higher yield of the alkylated product. The scope of the benzylic hydrocarbons is broad and selectively monocoupling products could be achieved using mesitylene and xylenes. Halo substituted toluenes are well tolerated under the reaction condition. With electron-deficient anisole and thioanisole, moderate yields of the desired product were reported. Catalytic Fe3O4 nanoparticles can be employed for the same transformation. But few cinnamic acids were exemplified for the decarboxylation process. The advantage of this catalyst is that the nanoparticles can be recyclable up to 7 times. The mechanism of the reaction is outlined in scheme 11. The reaction proceeds via formation of ferricinium cinnamate, 13 in the presence of DTBP (Scheme 11)13

Selected examples: OH OH

OOH

OH

72%

73%

OH

O

64%

OH

OH

MeO

O

O

2 Ar

COOH

OH OH

OH

tBuOOH

Cu

COO Cu(II) 2

Ar

Cl 79%

57%

74%

OH

OH

COOCu(II)

Ar

O

Ar COOCu(II) 12

O

OH

52%

62%

44%

OH

Ar

CO2

Ar

Cu (I)

COOCu(II) 12

Scheme 8. Cu-catalyzed decarboxylative alkenylation of alcohols, ethers and hydrocarbons with cinnamic acids.

O

O

13%

30%

O

OH

Cu (I)

Ar

COOCu(II)

H2O

67% 33%

70%

COOH


54%

0% 100%

Ar

O

COOH

H R2

R3

R2

Ferrocene (15 mol%) 1

R

DTBP (2 equiv) 120 oC, 24h, Ar

90%

74%

0%

33%

Ar

R3

Ar

R1

21-86%, E/Z: >99:1

Selected examples:

N

N 26%

O

10% MeO

F

80%

85%

86%

Fig 4. Regioselectivity at different positions. The proposed mechanism is outlined in scheme 9. In this case carbon-centered radical generated by the hydrogen abstraction undergoes radical addition to the cupric cinnamate and generates the radical 12. Subsequent elimination of carbon dioxide and Cu(I) provides the desired product. Oxidation of Cu(I) by the hydroxyl radical in the presence of cinnamic acids would regenerate the cupric

O

NC NO2

21%

44%

68%

MeO

MeO

MeO

MeO

MeO

MeO

85%

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81%

I

63%




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ARTICLE FeCl3 (20 mol%) DTBP (2 equiv) DMSO,130 oC, Ar

COOH R

CH3 R 20-53%, E-only

2

OO

O

Selected examples: CH3

Ar' CH3

O

Ar'

OH

O2N COOH

Ar

FeCp2

OO

COOFe(III)Cp2

Ar


Ar

Ar

'

CH2

MeO

COOFe(III)Cp2 Ar'

Ar

Ar'

FeCp2

CO2

CH3

CH3 MeO

42%

Ar'

Ar

34%

53% CH3

COOFe(III)Cp2

Ar

13

MeOOC

NC 46%

13 COOFe(III)Cp2

CH3

CH3

CH2

OH

OMe 35%

34%

Scheme 13. Fe(III)-catalyzed decarboxylative coupling of cinnamic acids with DTBP.


COOH

Ar

Fe(III)

Using similar radical addition-elimination mechanism, Pan et al achieved alkylation with cycloalkanes in presence of Fe(acac)3 catalyst and DTBP (Scheme 12). 12b This reaction could also tolerate a wide range of substrates, and products were obtained in good to excellent yields. Cinnamic acids can also be subjected to alkylation with cycloalkane under metal-free condition using only the radical initiator. While alkene products were isolated reacting with DTBP, ketone products could be achieved by using additional TBHP (Scheme 12).14

COOFe(III)

Ar

tBuOH

O O Ar

COOH

2

O

CH3 14

O Fe(II)

Ar

CH3 COOFe(III)

n

Ar 71-95%

Fe(acac)3(20 mol%) DTBP (2 equiv) Ar 120 oC, 24h

COOH n

n ) Ar equiv P (2 DTB 4h up to 81% 2 , N o C, 2 120 DTBP O (1 equ TBHP iv n (4 equ ) Ar 120 o iv) C, N 2 , 24h up to 90%

Ar

CH3

CO2

Scheme 14. Possible mechanism. Scheme 12. Decarboxylative alkylation with cycloalkanes. Ni(II)-catlyst has also been reported in decarboxylative C(sp3)-H functionalization of cyclic ethers and amides with cinnamic acids in presence of TBHP oxidant.15 In an another report, the oxidant DTBP itself was used as the methylating agent in presence of FeCl3 catalyst (Scheme 13).16 Cu-based catalyst provides lower yield for this transformation under the same reaction condition. Although the method is not high yielding, electron-poor cinnamic acids were found to be favorable in comparison to methoxy-substituted cinnamic acids. Despite of exhibiting some merits, the method is limited by low yields. Mechanistic path involves addition of methyl radical, 14 to the ferric cinnamate and subsequent elimination of CO2 delivers the products (Scheme 14).

It is seen that alkyl radical addition to vinyl carboxylic acids 10-12,15-16 require transition-metal coordination to the carboxylate, followed by strong heating or strong oxidants to facilitate the CO2 extrusion. Such reaction conditions can limit their functional-group compatibility. Recently, hypervalent iodine reagents (HIR) have been used to achieve radical alkylation under mild reaction condition.17 Chen et al. successfully carried out chemoselective radical deboronative addition and decarboxylation of cinnamic acids with alkyltrifluoroborate/ boronic acids using photoredox catalysis in presence of acetoxybenziodoxole (BI-OAc) as oxidant at room temperature (Scheme 15). Trans-alkene products were exclusively obtained from cinnamic acids having either electron-rich or electrondeficient groups at the ortho-, meta-, and para-positions. Oxidation sensitive functional groups were well compatible and provided the alkene products which are generally difficult to access using other alkyl Heck type reactions. The mechanism is outlined in the scheme 16. BI-OAc not only served as an oxidant for alkyl R radical formation, but also contributing in formation of an reaction intermediate 15. Hypervalent iodine reagents are already reported to form iodoniumcarboxylate species with cinnmaic acids.18 The species 15 oxidized the photoexcited [Ru-(bpy)3]2+* to [Ru(bpy)3]3+ which deboronated alkyl trifluoroborate (or boronic acid) to an alkyl R radical. Then the alkyl R radical adds to the intermediate 15 and

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Scheme 10. Fe(II)-catalyzed decarboxylative coupling of cinnamic acids with toluenes.



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subsequently undergoes benziodoxole-facilitated decarboxylation to release the alkylated product and benziodoxole radical. The species 15 itself as a substrate can provide the desired alkylated product under the reaction condition.

COOH

Ar

(CH2O)n

Ar

COOH

R1

H2 O

R2

100 oC, 12h

Ar

N R2

R1

25-86% Selected examples: N

N O

MeO

BF3K

HN

[Ru(bpy)3](PF6)2 (2 mol%)

86%

blue LED, BI-OAC (1.5 equiv) Ar DCE/H2O, rt

N O

EtO

81%

25%

58-73%, E/Z> 20:1 N

N

Selected examples:

O

O

MeO

O

N

O

O

O MeO


HO

36%

88% (Z/E= 6.7/1)

73%

64%

Scheme 17. Decarboxylative alkylation of cinnamic acids under metal-free conditions.

72%

R1

H2N

Ar

72%

BI-OAc

Ar

R2

O

Ar

H

CO2

R1

O Ar

O-

N

H

R1 N

R2

R2 CO2-

H Ar

H

R1 N

C-C Rotation

H

H COO-

-

O Ar

RuII* OBI BI

R

E

H

Ar

RuIII

Ar

R2 H CO2-

H Ar

H

E Ar

R

CO2

R1

RuII

OBI

15

R

N R2

H

H2O

RBF3K or RB(OH)2

O OH

OH

63%

Scheme 15. Chemoselective deboronative/ decarboxylative alkenylation of cinnamic acids using photoredox catalysis. O

N H

O

S

F

63%

Ar

37% (Z/E=14.3/1)

MeO

Me

H

OOC


I O

Initiation BI-OCOR" (15)

O-

Scheme 16. Possible mechanism. Lee et al. developed a metal-free method for the stereospecific decarboxylative coupling of imine (formaldehyde and amine system) with cinnamic acids to synthesize allylamines (Scheme 17).19 This reaction is environmental friendly as it is conducted in H2O medium without using any additives. The reaction showed a broad substrate scope including cyclic and acyclic amines and excellent functional group tolerance. Cinnamic acids bearing electron donating groups are only favorable for this transformation. The stereochemistry of cinnamic acids was retained in the reactions. (E)-Cinnamic acids afforded the corresponding only (E)-allyl amines, whereas (Z)cinnamic acid derivatives provided a mixture with high Z-isomer. The mechanistic path (Scheme 18) revealed the formation of a benzyl carbocation, which drives the decarboxylation step to provide the desired stereospecific allylamine products.

Ag(II) can provide decarboxylation of carboxylic acids under oxidative conditions leading to the formation of either radical species or cationic species.20 Mai et al. developed a novel alkylation of cinnamic acids with aliphatic carboxylic acids via double decarboxylative strategy using Cu/Ag catalytic system.21 The oxidant K2S2O8 oxidizes Ag(I) to Ag(II), which decarboxylates aliphatic carboxylic acid and generates the key alkyl radical (Scheme 19). This alkyl radical attack the cinnamic acids via radical additionelimination process to provide the desired product in low to high yields. While a number of primary, secondary and tertiary aliphatic carboxylic acids are favorable under the reaction condition, only unsubstituted and cinnamic acids bearing weak electron-withdrawing groups are effective. Interestingly cinnamic acids bearing 4-OMe substitution could not furnish the required product. Although this method exhibits some novelties, the limited scope of cinnamic acids can be considered as major drawback. Cu (5 mol%) AgNO3 (20 mol %)

COOH R'-COOH

R

K2S2O8 (1 equiv) CH3CN/H2O, 90 oC

R' R up to 92%, E-only

R= H, Cl, Br, F, OMe, Me R' = Primary, secondary and tertiary Mechanism: Ag(II) S2O8Ar

Ag(I) R'-COOH

R'

COOH Cu(I)

-CO2 -Cu(I)

6 | J. Name., 2012, 00, 1-3

COO Cu(II)

Ar

S2O8Ar

R'

2

R'




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Scheme 19. Cu/Ag-catalyzed double decarboxylative alkylation of cinnamic acids


2.3 Alkenylation Decarboxylative vinyl-vinyl coupling of cinnamic acids is very rare and only few methods have been developed. Hence better understanding of reaction condition and mechanistic insight is required to develop this area. This area was pioneered by Miura et al.22 In 2010, they successfully coupled cinnamic acid derivatives with β-bromostyrenes or 1-bromo-4-phenylbutadiene under palladium catalysis to produce corresponding α,ω-diarylbutadienes and hexatrienes, respectively (Scheme 20).22a The reaction was carried out in presence of LiOAc as a base and LiCl as an additive. LiCl provides chloride anions as ligand to prevent the deactivation of Pd(0). A wide range of vinylbromides are efficient under the reaction condition. However, less reactive sterically hindered vinyl bromides were found to be more reactive in presence of PPh3. The scopes of the cinnamic acids are not satisfactory and only electron-rich cinnamic acids are favorable. The cinnamic acids bearing OMe and NMe2 substitiuents at para-position can provide decarboxylative product in presence of AgOAc, whereas OH group at the same position can undergo decarboxylation in its absence. Under a similar reaction condition, a mixture of hydroxylated cinnamic acids, aryl iodides and internal alkynes could also provide synthesis of 1,3dienes, albeit in moderate yield.22b

are more effective, whereas electron-withdrawing group diminishes the reactivity. Quinolinones also worked under the standard reaction condition, albeit lower yield. Requirement of longer reaction time is a noticeable limitation of this method. Mechanistic path revealed that more nucleophilic C3 of coumarin undergoes electrophilic palladation with a Pd-ligand species to provide the intermediate 16 (Scheme 22). Parallely formed alkenyl-silver species undergoes transmetallation to give the intermediate 17. Finally, the desired product would be released, regenerating the initial palladation species and resuming the catalytic cycle. The product 3styrylcoumarins show excellent fluorescence quantum yields. COOH

Pd(OAc)2 (20 mol%) Ag2CO3 (2 equiv)

R'

R

R R'

O 1,10-phenanthroline (20 mol%) DMSO, 130 oC, 72 h

X

X

O

40-78%, E-only

X=O, NMe Selected examples:

O

Cl

O

O

69%

O

O

72%

O 59% Cl

O

O

F

O

O

N

O

78%

53%

O

40%

Scheme 21. Pd(II)-catalyzed C3-olefination of the coumarins with cinnamic acids.

Br Br Pd(OAc)2 R 55-64%, E-only

LiOAc, LiCl PPh3 DMF, 120 oC

COOH R

Ar Pd(OAc)2

Ar

Ag(0)

R

LiOAc, LiCl DMF, 120 oC

N

Pd

N OAc

AcO

43-81%, E-only Ag(I)

O

O

Selected examples: NMe2

HO

HO OMe

Cl

OMe 68%

N N Pd H AcO O O

Ar

HO OMe

72%

L2Pd(0)

O

O

16

75%

Transmetalation MeO

MeO

MeO

HO

HO

OMe

Ar

HO

N

OMe Ar

79%

64%

64%

Pd O

N

Ag -CO2

Ar

COOH

O 17

Scheme 20. Pd(II)-catalyzed decarboxylative coupling of cinnamic acids with β-bromostyrenes and 1-bromo-4-phenylbutadiene. Coumarins were used as suitable olefinic partners for regioselective synthesis 3-styrylcoumarins from cinnamic acds. This oxidative Pd(II)-based decarboxylative alkenylation was achieved in presence of a suitable ligand, 1,10-phenanthroline (Scheme 21).23 Best results were achieved in DMSO solvent. The method is highly regioselective and C3 position of coumarin undergoes alkenylation. The scope of cinnamic acids in this method is also limited. The products were isolated in moderate yield with most of the cinnamic acids. It has been found that electron-rich cinnamic acids are more favorable compared to electron-deficient one. Courmarins, substituted with electron-donating groups at the C6 or C7 position

Scheme 22. Possible mechanism. 2.4 Trifluoromethylation Transition-metal-catalyzed trifluoromethylation for the direct construction of Cvinyl-CF3 bonds has not been well developed.24 Vinyl boronic acids, vinyl triflates, vinyl trifluoro borates etc. are suitably utilized in electrophilic and nucleophilic trifluoromethylation processes. Recently, cinnamic acids have been reported as suitable vinylic partners for trifluoromethylation process. Hu et al. reported decarboxylative fluoro alkylation of cinnamic acids using Cu(II)-catalyst with electrophilic Togni reagent.25 Using catalytic CuF2·H2O with TMEDA (N,N,N’,N’-

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Journal Name

tetramethylethylendiamine) as additive and H2O/DCE as solvent, IIIICF2SO2Ph reagent was successfully utilized to carry out difluoromethylation of cinnamic acids (Scheme 23). Both solvent and temperature were crucial for the reaction. The addition of water as a cosolvent and TMEDA as an additive can significantly increase the yields of the products. Electron-rich cinnamic acids were transformed to corresponding difluroalkylated product in high yields. This process is highly stereoselective providing only E-products. Under a different reaction condition without using TMEDA, electrophilic Togni reagent was successfully utilized to achieve trifluoromethylation products. This time also only electron-rich cinnamic acids proceeded smoothly to afford the corresponding CF3containing products. This method is also highly E-selective and in some cases, the formation of very low amount of Z-isomer was detected. The mechanistic path for this process is shown in scheme 24. The hypervalent iodine reagent generates a highly electrophilic iodonium salt 18, which coordinates to the carboxylic acid functionality to generate the intermediate 19. Successive intramolecular reaction between the alkene functionality and the iodonium ion results in the formation of intermediate 20, which undergoes decarboxylation and provides thermodynamically stable E-alkene intermediate 21. Then the desired product is formed via reductive elimination along with a species 22 which reacts with HF to regenerate the catalyst. F3C

PhO2SF2C I O

I O O

Ar

CuF2 2H2O (20 mol%)

CF3

H2O/dioxane, 80 oC, 12h

COOH

Ar

CuF2 2H2O (20 mol%) TMEDA (25 mol%) H2O/DCE, 80 oC, 12h

52-70% E/Z: 92: 8 to 100:0

CF2SO2Ph

Ar

65-90%, E-only

Selected examples: MeO

CF2SO2Ph

CF2SO2Ph

CF2SO2Ph

S

MeO OMe Ph

90% MeO

84%

70% CF3

CF3

CF3 S

(H3C)2N

MeO OMe

66% (E-only)

60% (E/Z=92:8)

52%, E-only

Scheme 23. Cu(II)-catalyzed (phenylsulfonyl)difluoromethylation and trifluromethylation of cinnamic acids.

CuF2

TMEDA

OH

PhO2SF2CI O F F

I

N

Cu

N

HF

I

CF2SO2Ph

O

Cu

F

N PhO2SF2C

N

22

I

O

Cu

F

N N

18

Ar

Ar

COOH

HF PhO2SF2C 21

I

O F Ar

Cu

N N PhO2SF2C

FCO2

I

O

Cu

O

Ar

N N

O 19

PhO2SF2C

O

I

Cu

O

Ar

N N

O 20

Scheme 24. Possible mechanism. Langlois reagent, NaSO2CF3 has found importance as reliable source of CF3 radical in radical trifluoromethylation reactions.26 Liu et al. developed radical di- and trifluoromethylation of cinnamic acids using Fe(II)- and Cu(II)-catalyst under mild reaction conditions, respectively (Scheme 25).27 Highly E-selective trifluoromethylation was achieved with NaSO2CF3 reagent in presence of TBHP as an oxidant. Cinnamic acids bearing electron-donating groups could provide reasonable yields of the trifluoromethylated product, irrespective of their position. But heteroaryl cinnamic acids provided decreasing yields. Interestingly, cinnamic acids bearing electronwithdrawing groups provided trifluoroketones products (Cl and NO2). Using Baran reagent, (CF2HSO2)2Zn and catalytic FeSO4·7H2O under the same reaction condition, they achieved difluoromethylation of cinnamic acids (Scheme 25). However, this difluoroalkylation process is inferior to Hu’s method.25 Only moderate yields were reported with electron-rich cinnamic acids. A successful breakthrough for trifluoromethylation of electron-poor cinnamic acids bearing NO2 group was made by Maiti et al. via a mild radical decarboxylation process mediated by stoichiometric FeCl3 and K2S2O8 radical initiator. (Scheme 26).28 In this report, apart from successful trifluoromethylation of electron-rich cinnamic acids, they achieved good yields with a nitro-substitution, which is noticeable advantage compared to the previous methods.

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ARTICLE


Page 9 of 21

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DOI: 10.1039/C5OB00727E

ARTICLE (CF2HSO2)2Zn

CF2H

Ar

35-68% E/Z up to 99/1

COOH

Ar

TBHP (5 equiv)

CF3SO2Na

CF3

Ar

TBHP (5 equiv)

FeSO4 7H2O (10 mol%) CH2Cl2/H2O, 50 oC

CuSO4 5H2O (10 mol%) CH2Cl2/H2O , 50 oC

41-85% E/Z up to 99/1

Selected examples: MeO

CF3

CF3

CF3

H2N

MeO

85%, E/Z=99/1

59%, E/Z=95/5


46%

CF3 MeO

CF2H

O

68%, E/Z=99/1

MeO

42%, E/Z=99/1

OMe

35%, E/Z=99/1

FeCl3 (1 equiv) K2S2O8 (4 equiv) MeCN/H2O, 50 oC, 12h

NaSO2CF3

Cl

Br 58%, E/Z>99:1

65%, E/Z>99:1

Scheme 25. Cu(II)-catalyzed trifluoromethylation and Fe(II)catalyzed difluoromethylation of cinnamic acids.

COOH

CF3

CF2 H

MeO

O

MeO

CF3

42%, E/Z= 94/6

50% CF2H

CF3 Ar TBHP (5 equiv) o DCE, 70 C, 24h 48-72%, E/Z up to >99:1

CF3

O2N

Cl

CuCl (20 mol%) Ag2CO3 (0.6 equiv)

Selected examples:

CF3 S

Ar

NaSO2CF3

60%, E/Z=98/2

O CF3

COOH

Ar

EtO

O

NaSO2CF324d, 29b,31 would attack the cupric cinnamate to provide the complex 25. Finally, the desired product would be formed along with Cu(I) species.

48%, E/Z>99:1

Scheme 28. Cu(I)-catalyzed decarboxylative trifluoromethylation of cinnamic acids. CF3SO2 + t-BuO

+ -OH

CF3SO2- + t-BuOOH

SO2 CF3

CF3

Ag(I)

Cu(II)

Ar

Ar 54-82%, E/Z up to 99:1

2

Ar

Selected examples: CF3

CF3

O2N

Ar

CF3

25

S

MeO

COOH

CO2

Cu (II)

2 CF3

TBHP

75%, E/Z=97:3

70%, E/Z=90:10

61%, E/Z>99:1

Ar

CF3

Cu(II)

Ag

Ar 24

Scheme 26. Fe(III)-mediated decarboxylative trifluoromethylation On the basis of literature, Liu et al. developed a mechanistic path (Scheme 27).27 The trifluoromethyl radical is generated by the reaction of tert-butyl peroxide with NaSO2CF3 and Cu(II).26,29 Addition of the trifluoromethyl radical to the cupric cinnamate would give radical 23, which then proceeds via an elimination of carbon dioxide and Cu(I) to generate the product. Cu(I) is oxidized by the hydroxyl radical and in the presence of cinnamic acid would regenerate the cupric cinnamate. CF3SO2Na

Cat. Cu(II) TBHP

Ar

Cat . Cu(II)

COOH

Ar

TBHP TBHP

Cu(I)

CF3 CO2

Cu(I)+TBHP

Ar CF3

COO

Cu(II)

2 addition

(COO)2Cu(II) Ar

CF3 23

elimination

Scheme 27. Possible mechanism. Duan et al. reported trifluoromethylation using Cu(I) catalyst with NaSO2CF3 in presence of TBHP oxidant and Ag2CO3 as an additive (Scheme 28).30 Cinnamic acids bearing electron-donating groups are more favorable under this transformation. This method exhibits advantage over the other methods, as halogenated substrates could provide moderate yields of the trifluoromethylated products. The decarboxylation step is mediated by Ag2CO3 ( alkenyl–silver species 24, scheme 29). Then the species 24 undergoes transmetalation with Cu(II) and provides a organocopper intermediate. Parallely formed CF3 radical by the reaction of tert-butyl hydroperoxide with

Scheme 29. Possible mechanism. Recently Liu et al. developed a metal-free radical protocol for trifluoromethylation using the Langlois’ reagent with I2O5 relatively at low temperature condition (Scheme 30).32 Although the high yields were obtained, the method could not achieve the advantage on substrate scope. Only electron-rich cinnamic acids can provide desired products, irrespective of the position of the substitiuents on the aromatic ring. The method is also inferior in terms of selectivity compared to the other methods. Obviously, the method is attractive, due to the features of low-cost, easy operation and metal-free conditions. They suggested a radical addition-elimination mechanism via spin trapping experiment (Scheme 31). Singleelectron oxidation of Langlois reagent by I2O5 would generate the trifluoromethyl radical, which adds to cinnamic acids. Subsequent SET, elimination of CO2 and deprotonation would provide the desired products. Recently, application of a photo-redox catalyst [fac-Ir(ppy)3] has been found to be an efficient alternatives for the decarboxylative trifluoromethylation process as it allows the process to occur at mild condition with excellent functional group tolerance.33

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ARTICLE

Journal Name I2O5 (3 equiv)

NaSO2CF3

CH2Cl2 / H2O, 60 oC, 22h

Ar

O

CF3

R

0-72%, E/Z up to >99:1

MeO

CF3

O2N

CF3

Br

EtO

MeO

80%, E/Z=32:1

MeO


I2O5

MeO 58% Br

Cl

Cl Cl

86%

41%

37%

I2

Scheme 32. LiOAc-catalyzed halodecarboxylation.

COOH

Ar CF3SO2Na

X 37-91%, E > 97%

I

65% Br

Scheme 30. I2O5-mediated decarboxylative trifluoromethylation of cinnamic acids with NaSO2CF3.

R

Cl

91%

0%

75%, E/Z=32:1

MeCN/ H2O, rt

O (X=Br, Cl, I) Selected examples:

Selected examples: CF3

LiOAc

N X

COOH

CF3

Ar

Addition

COOH CF3

Elimination Ar -e, -CO2 ,-H+

CF3

O Ar

COOH

N X

TBATFA DCE, rt

O


O Ar

3. Decarboxylative carbon-heteroatom coupling of cinnamic acids

X Ar up to 97%, E > 97%

O OH

Ar

O O-Bu4N+

NBS

O-Bu4n+

Ar Br

Bu4NOC(O)CF3

-CO2

Ar

Br

CF3COOH

3.1 C-Halogen bond formation

Scheme 33. Mechanism of decarboxylative bromination catalyzed by TBATFA.

The early development of the Hunsdiecker bromo-decarboxylation of cinnamic acids was not satisfactory and less than 15% βbromostyrene product formation was reported. Requirement of high temperature and the toxicity/hazard related to molecular bromine and salts of Hg, Tl, Pb, Ag greatly limited the synthetic utility of such methods.34 Development of electrophilic halogenium ion pathway able to overcome such limitations. In 1994, Stanczak reported an improved oxidative decarboxylation protocol of cinnamic acids using stoichiometric PhIO-NBS combination.18a Although this stoichiometric method provided moderate yield of β-bromostyrene (51-73%, high E selective), the development of catalytic protocols limited its utility. Roy et al. developed Mn(II)acetate-catalyzed bromo-decarboxylation of cinnamic acid in presence of Nbrmosuccinimide.35 They reported high yields of products with electron-rich cinnamic acids. Subsequently, they reported the use of LiOAc catalyst with NBS/NCS/NIS.36 However; the lower yields were obtained with cinnamic acids bearing halo functionality (Cl). NBS is more effective compared to NIS and NCS in this method. (Scheme 32). But these methods suffer from the drawbacks of limited substrates scope. In continuation, they developed metal-free protocols using tetrabutylammonium trifluroacetate (TBATFA) catalyst with N-halosuccinimide increasing the scope of cinnamic acids to heteroaryl.37 While electron-rich and unsubstituted cinnamic acids provided better yields with NBS and NCS compared to NIS, 2thiophenyl cinnamic acids could provide better yield only with NIS. From semi-empirical calculation, they proposed a mechanistic path (Scheme 33). They suggested an ionic pathway involving the attack of the halogenium ion across the carbon–carbon double bond, triggering the elimination of carbon dioxide. A notable advantage was achieved in reaction time using triethylamine catalyst.38 Electron-rich cinnamic acids underwent decarboxylation in high yield (60-98%) within 5 minutes at room temperature.

The observation on the relative efficacy of lithium acetate, TBATFA and triethylamine catalysts for the conversion of 4-methoxycinnamic acid to the 4-methoxy-β-bromostyrene revealed that in CH3CN-H2O solvent system, the efficacy order is lithium acetate > triethylamine > tetrabutylammonium trifluoroacetate. Under microwave condition Et3N catalyst can provide similar yield of the desired haloalkene product as in room temperature condition.38 But, the advantage of microwave assistance lies for reactions of cinnamic acids bearing electron-withdrawing groups (Cl, 54%). Solvent plays a vital role on this Et3N-mediated protocol. The reaction time of the LiOAccatalyzed halodecarboxylation process was also successfully reduced with the help of microwave irradiation (1-2 min).39 Microwave irradiation not only reduced the reaction time, but also provided successful transformation of cinnamic acids carrying electronwithdrawing groups. However, under such condition, decarboxylation of substituted cinnamic acids having a hydroxyl group at the para-position gave predominantly the corresponding styrene derivatives in the presence of a base.40 Additive-free decarboxylation has been reported with moderate yields using biscollidinehalogenium ion as a Br+ or I+ source.41 Comparatively, a greener protocol was achieved using KBr and H2O2 in presence of catalytic Na2MoO4·2H2O in aqueous medium.42 The decarboxylation is more favorable for para-substituted cinnamic acids while orthosubstituted cinnamic acids provided lower yield, due to steric crowding of the intermediate bromonium species (Scheme 34). The authors suggested a possible electrophilic mechanism. Peroxomolybdates generated from the reaction of H2O2 and MoO42react with Br2 to produce the equivalent of the Br+ species, which reacts with cinnamic acids to give cyclic bromonium ion which on successive decarboxylation provides the product.

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Ar


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Journal Name

ARTICLE Br

thermal decomposition of β-lactone is a well-established method for the stereoselective synthesis of substituted alkenes.

R

KBr / H2O2

5-85%

R= H,4-OMe, 4-Cl, 2-Me, 2-Cl

-

Mechanism: Na2MoO4 H2O2

[MoO(O2)3]2H

Ar

+

Br

O

[Mo(O2)4]2Ar

-

Br 28

O


-CO2

O

-

Ar

Br

Scheme 34. Mechanism of bromodecarboxylation catalyzed by Na2MoO4·2H2O. KBr was also used with heterogeneous molybdate-exchanged Mg– Al–LDH catalyst (LDH-MoO4) for the bromo-decarboxylation process (Scheme 35).43 Under this protocol, cinnamic acids bearing strong electron-withdrawing group, NO2 could provide the bromoalkene in 30% yield at a longer reaction time. The catalyst can be recycled up to 5th time without losing its activity. As recyclable heterogeneous catalysis, the method can exhibit advantages in organic transformations. The mechanistic path (Scheme 36) revealed oxidation of Br- to Br+. The LDH–MoO4 forms LDH– peroxomolybdate (26) on interaction with H2O2..The peroxomolybdate on interaction with bromide ion (27) reacts with cinnamic acid to give bromoalkene along with the evolution of CO2. LDH-MoO4

COOH

Br

Ar

KBr, 30% H2O2

30-90%

Selected examples: Br

Br

Br MeO 80%

OH 90%

44%

Br

Br

Br

O

O2N

Cl 80%

67%

30%

Scheme 35. Bromodecarboxylation catalyzed by LDH–MoO4. OBr-

nH2O

Br

H Br

Ar

Ar

Br

Br

DMP (1.1 equiv) TEAB (1.1 equiv) Anhyd CH2Cl2, rt

COOH

Ar

Anhyd CS2, rt

Br

Ar

O 2N DPTI, 80%, 12h DMP, 68%, 12h

Br

OH

Br

Kuang et al.39 showed that the CO2 can eliminate via the formation of a α-halo-β-lactone (Scheme 37) The bromonium ion 28, can convert to trans-α-bromo-β-lactone 29 or zwitterion 30, which would eliminate carbon dioxide to give (E)-β-arylvinyl bromide. The

DPTI, 85%, 12h DMP, 65%, 14h Br O

MeO DPTI, 90%, 6h DMP, 92%, 0.25 h


Br

Br

Br

DPTI, 90%, 9h DMP, 94%, 0.25 h

27

Ar

80-93%, E-selective

F

LDH-MoO4

DPTI (1.1 equiv) TEAB (1.1 equiv)

Selected examples:

Br

O

Br 29

Considerable success in bromodecarboxylation of electron-poor cinnamic acids was achieved by Telvekar (Scheme 38).44 Under mild reaction conditions using Dess–Martin Periodinane (DMP) in combination with tetraethylammonium bromide (TEAB) at room temperature, they isolated high yields of the products. While the electron-rich cinnamic acids could provide higher yield at a lower reaction time, electron-poor cinnamic acids also could provide good yields, albeit in a slower rate. They also used another iodine reagent, diphosphorus tetraiodide (DPTI) with TEAB under mild condition for the same transformation.45 Although this method can tolerate various functional groups, this iodine reagent is inferior to DMP in terms of rate of the transformation of electron-rich cinnamic acids (Scheme 38). Electron-poor cinnamic acids were better transformed with DPTI. The trans-configuration of the double bond in cinnamic acids retains during the bromodecarboxylation process. However, cis-cinnamic acids provided trans- bromoalkene with DPTI, but retained in the Des-Martin periodinate process. Heterocyclic cinnamic acids were also successfully transformed using these hypervalent iodine reagents.44,45 They also explored decarboxylative azidation process in presence of a another hypervalent iodine reagent namely [bis(trifluoroacetoxy)iodo]benzene with NaN3 in presence of TEAB. This reaction should proceed via bromodecarboxylation as in absence of TEAB, the decarboxylation could not be achieved.46

CO2

nH2O2

Ar

Scheme 37. Mechanism of bromodecarboxylation catalyzed by LiOAc with NBS.

HOBr

Br-

O

O

65-94%, E-selective O-

Ar

O

H

30

Ar

O

LDH-MoO4n(O)n226

O

OLi

[Br+ ] COOH

Ar

O

NBS

Ar

OH

O

Ar

O

LiOAc

DPTI, 93%, 7h DMP, 90%, 0.25 h

DPTI, 88%, 8h DMP, 92%, 0.25 h

Scheme 38. Comparison of bromodecarboxylation using DMP and DPTI with TEAB.

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Na2MoO4 2 H2O

COOH R



DOI: 10.1039/C5OB00727E

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Journal Name NaNO2, 48% aq. HBr O2, CH3CN, rt


Br

Ar

87-92%

Mechanism: NaNO2 + 4 HBr 2NOBr Ar-CH=CH-COOH NO + 1/2 O2 NO2 + 2HBr

2NOBr + 2NaBr +2 H2O Br2 + 2NO Ar-CH=CH-Br + HBr + CO2 NO2 Br2 + NO+ H2O


Scheme 39. Mechanism NaNO2/HBr/O2 sytem.

of

bromodecarboxylation

with

Later on, the same group carried out decarboxylation of all kinds of cinnamic acids at a faster reaction rate in excellent yield using NaNO2 catalyst with 48% aqueous HBr.47 Presence of O2 triggers the process to occur within short reaction time. The proposed mechanism is shown in scheme 39. The scope of halodecarboxylation of cinnamic acids has also been widened by the use of stoichiometric CAN/LiBr48 or LiCl, Oxone®/Sodium halide,49 Selectfluor/KBr50 and PhI(OAc)2/TEAB51 systems.

Under aerobic condition, Maiti et al. used t-butylnitrite (t-BuONO) as the source of NO2 radical for the nitrodecarboxylation process (Scheme 42).53 In presence of TEMPO, the nitroolefins were isolated exclusively in E-form. The TEMPO plays an important role on the stereoselectivity (Scheme 43).This method relatively exhibits a broad substrate scope including heterocyclic cinnamic acids. However, cinnamic acids bearing electron-withdrawing substitiuents provided lower yield. Steric factors were not pronounced during the reaction. The nitro radical is generated from t-BuONO via homolytic cleavage of O–NO bonds and subsequently underwent oxidation providing NO2 radical. The NO2 radical attack olefins to form a benzylic radical 31, which combined with TEMPO. Out of two possible pathways involving 31, addition of TEMPO would lead to preferential formation of energetically more favorable intermediate 32 over 33 giving exclusive E-product. In absence of TEMPO, a mixture of E and Z isomers were generated. t

Ar

3.2 C-N bond formation: Considerable success in decarboxylative C-N bond formation of cinnamic acids has been achieved with nitro functionalization. The literature reveled that cinnamic acids can be efficiently subjected to radical nitrodecarboxylation process rather than via an ionic pathway. This area pioneered by Roy et al. is very limited. Roy et al. used nitric acid and catalytic AIBN to achieve the nitrodecarboxylation product (Scheme 40, Nitro-Hunsdiecker Reaction).52 The scope of the substrates are limited and only cinnamic acids bearing electron-donating groups could provide higher yields. Unsubstituted cinnamic acids provided lower yield. Highly activated cinnamic acids underwent nitrodecarboxylation even at a lower temperature. The configuration of the double bond in cinnamic acids retains during the process. Hypothetically they established the radical mechanism for the reaction (Scheme 41). They had shown generation of an acyloxy radical either by the decomposition of acylnitrate (step 2) or by the reaction of an NO3 radical with the acid (step 4). Thereafter, the NO2 radical can combine in a bimolecular fashion with the acyloxy radical and underwent nitrodecarboxylation process (step 5). COOH HNO3 / AIBN ( 2mol%) MeCN, 50 oC

Ar

75%

NO2

OMe

70%

75%

95%

NO2

NO2

NO2 S NC

NO2

54%

34%

36%

Scheme 42. tBuONO/TEMPO-mediated nitrodecarboxylation of cinnamic acids. O NO

O

COO

Ar O

Ar

H Ar H 31

TEMPO

O

H Ar

31 O2N

without TEMPO

O

32

O

OTEMP H O

NO2

Ar Ar

(E) TEMPO + CO2

H Ar

NO2

33

(Z)

NO2 NO2

Ar

(E, Z)

40%

62%

O2N

OTEMP

gauche interaction NO2

NO2

OH

H

H

NO2

OOC

O2N H O2N

air

NO

COOH

Ar

NO2

O

MeO

34-95%, E-only

NO2

MeO

Selected examples: O

NO2

Ar

CH3CN, air, 50 oC

NO2

30-80% NO2

BuONO (2-4 equiv) TEMPO(0.8 equiv)

Selected examples:

OOC

Ar

COOH

Scheme 43. Possible mechanism. Scheme 40. HNO3/AIBN-mediated cinnamic acids. ArCH=CHCOOH + HNO3 ArCH=CHCOONO2 3HNO3 NO3 + ArCH=CHCOOH NO2 + ArCH=CHCOO

nitrodecarboxylation

ArCH=CHCOONO2 + H2O ArCH=CHCOO + NO2 NO2 + NO3 + (H2O.HONO2) ArCH=CHCOO + HNO3 ArCH=CHNO2 + CO2

of

(1) (2) (3) (4) (5)

NO2 radical generated from t-BuONO can be subjected to radical addition-elimination process in presence of Cu-catalyst. Prabhu et al. successfully synthesized the nitroolefins using catalytic CuCl with tBuONO under aerobic condition (Scheme 44)54 This catalytic protocol also failed to achieve high yields with electron-poor cinnamic acids. In presence of TEMPO, this Cu-catalyzed reaction provided reduce yield showing the radical transformation. The

12 | J. Name., 2012, 00, 1-3




COOH

Ar


Page 13 of 21

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DOI: 10.1039/C5OB00727E

Journal Name

ARTICLE


CuCl (10 mol%)

COOH

Ar

t

BuONO

t

COOH

Ar

CH3CN, air, 80 oC

BuONO

Ar

COO Cu(II)

O2N

80% (conventional, KNO3) 85% (sonication, KNO3) 82% (microwave, KNO3)

68% (conventional, KNO3) 72% (conventional, KNO3) 75% (sonication, KNO3) 72% (sonication, KNO3) 70% (microwave, KNO3) 75% ( microwave, KNO3)

O

COO Cu(II)

Ar

N

O

Cl

Cl

O

O

O Cl

O

H

2

NO2

2

Cl

Scheme 46. Nitrodecarboxylation under different conditions using (COCl)2/DMF.

-CO2 -Cu(I)

air NO2

NO2

MeO

NO2

Ar

NO + tBuO

Cu(II)

68-85%

NO2

NO2

36-92%

Cu(I)

air

R

1) Cnventional method, rt 2) Sonication 3) Microwave Irradiation

Selected examples:

NO2

Ar

NO2

(COCl)2/DMF/ KNO3 or NaNO2

R

O

N

N

Cl-

34

Scheme 44. Cu(I)-catalyzed nitrodecarboxylation of cinnamic acids with tBuONO.

COOH

Ar

KNO3

N

Cl

O

H ClCl

Cl

O

Ar

-HCl

-CO2, -CO

H ClCl 35

COOK

N

35

Fiorentino and co-workers reported nitrodecarboxylation of cinnamic acids using cerium(IV) ammonium nitrate (CAN) supported on silica (CAN/SiO2) as a nitrating reagent in solid phase.55 However, nitration of the aromatic ring was also observed, which dramatically limits the application of this reaction. After that, Rao and co-workers developed a mild method using CAN in acetonitrile at room temperature. It is worth noting that the solvent used in the reaction, acetonitrile, is crucial for the exclusive formation of the ipso-products, without the ring-substituted products.56 Metal nitrates can be used under solvent free condition to carry out the nitrodecarboxylation process. Variety of metal nitrates, MNO3 (M= Mg, Sr, Al, Ca, Ni, Cd, Zn etc) or ammonium nitrate etc. can be used with cinnamic acids under HNO357 or mineral acid free condition58 to obtain the nitro-olefins (Scheme 45). All these methods exhibit advantages in favor of electron-rich cinnamic acids. Cinnamic acids were also transformed to the nitro product using KNO3 or NaNO2 in oxalylchloride/DMF system (imminum salt).59 Under both conventional and nonconventional (ultrasonic and microwave) conditions, β-nitrostyrenes were isolated with high yield. Comparable results were drawn under both conventional and non conventional conditions (Scheme 46). However, cinnamic acids bearing electron withdrawing substitiuents could provide better yield compared to earlier metal nitrate mediated methods.57,58 The mechanistic path involves in situ generation of nitro methyliminium ion (36) via reaction of KNO3/NaNO2 with chloro methyliminium ion (35) intermediate (Scheme 47) which is generated from oxalylchloride/DMF system. Nitro methyliminium ion thus produced interacts with substrates and affords the β-nitro styrenes.

N

H ClONO2 36

HCl Me2NCH2OCl+ CO2 + KCl

NO2

Ar

Scheme 47. Possible mechanism. Zhang et al. carried out the annulation of 2-alkylazaarenes with cinnamic acids via benzylic C-H olefination and decarboxylative amination processes providing synthesis of C-2 arylated indolizines, which is generally very difficult to get via direct C-2 arylation process.60 Authors used catalytic Cu(II)-ligand system in presence of Ni-powder and LiOAc as additive for this annulations process (Scheme 48). The products could be obtained under high temperature condition and isolated in moderate yields. In this process, the electron-poor cinnamic acids are more favorable than an electron-rich one. Ortho-substituted cinnamic acid delivered relatively lower yield compared with its meta- or para-analogues, probably due to the steric hindrance. Heteroaryl cinnamic acids were also successfully transformed to the indolizine derivatives.

R'

R

N

COOH

Ar

Cu(OAc)2 (20 mol%) R C-H olefination 1,10-Phenantroline ((20 mol%) Ni Powder (0.5 equiv) Ar N LiOAc (2 equiv ) DMF, 140 oC decarboxylative amination 42-68%

Selected examples: Cl F

N 67%

CF3

N

N 64%

59%

S NO2

N

NO2 R

MNO3 / PEG Grinding/rt or MW

68-90%

COOH R

MNO3 / HNO3 Grinding/rt

R=electron-withdrawing and electron-donating groups MNO3 = Mg(NO3)2, Sr(NO3)2, Al(NO3)2, Ni(NO3)2, ZrO(NO3)2 etc.

OMe

N

N

NO2 R

60%

42%

49%

30-64%

Scheme 45. Metal nitrate-mediated nitrodecarboxylation.

Scheme 48. Synthesis of indolizine derivatives via C-H olefination and decarboxylative amination of 2-alkylazaarenes with cinnamic acids.

J. Name., 2013, 00, 1-3 | 13




COOH

suggested mechanism for this reaction is shown in scheme 44. The cinnamic acid derivatives react with CuCl to form the cupric cinnmate, which prevents the formation of carboxyl radical attacking with TBN. The cupric cinnmate then reacts with nitro radical to form radical 34. Subsequently elimination of CO2 and Cu(I) would provide the desired nitro products.



DOI: 10.1039/C5OB00727E

Journal Name

Very recently, Rovis et al. synthesized highly regioselective substituted pyridines through decarboxylative coupling of α,βunsaturated O-pivaloyl oximes with cinnamic acids under Rh(III)catalysis.61 Using [RhCp*Cl2]2 catalyst in combination with AgOTs additive and K2S2O8 oxidant, cinnamic acids were successfully decarboxylated to provide regioselective 5-substituted pyridines (Scheme 49). Mechanistic study revealed that decarboxylation does not occurred via the formation of picolinic acid intermediate (which may form in presence of Rh(III) and oxidant and has a probability to undergo decarboxylation in presence of the AgOTs). Rather decarboxylation occurs at a later stage from a rhodium complex 40 formed via C-N bond formation and N-O bond cleavage. AgOTS acts as a halogen scavenger to provide the active catalyst 37. Reversible C−H activation at the β-position of the oxime and ligand exchange provide cationic complex 38. The rhodacycle 39 formed via migratory insertion and deprotonation undergoes C−N bond formation and N−O bond cleavage to afford the intermediate 40. Subsequent protonation and deprotonation results a rhodacycle 41, which can undergo a retro [2+2+1] cycloaddition to extrude CO2 and provide the desired pyridine and a Rh(I) species. R1 R2

N

OPiv

COOH

Ar

3 [RhCp* Cl 2]2 (2.5 mol%) AgOTs (0.9 equiv)

S2O82-

1

R

2S2O42-

RhCp*Ln

O

Ar 1

R R2

R

R

retro [2+2+1]

Cp * Rh O O

CO2

Ar

HOOC

O

41

O

O S O

R1

R

Cp *

N Rh OPiv H O

Ar H 40

O

O S O

O

79%(80 oC)

R1 R2

C-N formation / N-O cleavage

O

O

O S O

CF3

Cl O S O

O

57%(100 oC)

O S O

44%(80 oC)

F

O S O

O Cl

67%(100 oC)

20%(100 oC)

Scheme 50. Decarboxylative C-S bond formation leading to synthesis of various 2-Sulfonylbenzo[b]furans. COOH

[Ag]

[RhCp* Cl2]2 + Ag+ + RCOOH

Base

OH

O

OH 42

O R S O-

Ar Cp * Rh R1 N PivO R2 38

OPiv N Cp * Rh O H

O S R' O

20-79%

F

56%(80 oC)

OMe

Ag(0)

Ag(I)

or Cat Cu(II) O

O S

42

Ag(I) O R S O

O R S O

BH+

O

Migratory Insertion

OH

OH O

O S

Ar O

O

3.3 C-S bond formation Vinyl sulfones are versatile building blocks and constitute a significant component in naturally occurring products and in drug discovery.62 Various synthetic approaches to prepare vinyl sulfones includes sulfonylation of alkynes, olefins, epoxides, vinyl halides, or boronic acids.63 Compared to decarboxylative C-C bond formation, C-S bond formation is very limited.64 Development of decarboxylative C-S bond formation of cinnamic acids add remarkable contribution to the Cvinyl-S bond formation. Liu et al. reported copper/silver-mediated synthesis of 2sulfonylbenzo[b]furans from trans-2-hydroxycinnamic acids and sodium sulfinates via protodecarboxylation/sulfonylation/cyclization cascade (Scheme 50).65 The reaction proceeds via formation of

R

Ag(0)

[CuIII]X

O R S O 43

II B+ [Cu ]X2 BHX

44

[Cu(1)]X

Reoxidized

R

39

Scheme 49. Rh(III)-catalyzed decarboxylative coupling of cinnmaic acids with unsaturated oxime ethers.

O S

R

H 2

O

DMF, 80-100 oC

37

Cp * N Rh O

R

Cs2CO3 (2.0 equiv)

Selected examples:

N

37-78% >20:1 regioselectivity

AgTFA (2.5 equiv) R'-SO2Na

OH

R1 R2

Ar

N

CuCl2 2H2O (50 mol%) COOH R

K2S2O8 (1.05 equiv) HFIP, 58oC

Mechanism:

R2

styrene intermediate via protodecarboxylation of cinnamic acid mediated by Ag(I).6 The base plays a very important role in the reaction system. The sulfonyl cation 43 reacts with the styrene to form α,β-unsaturated sulfone, 44 via elimination of H+ in presence of the base (Scheme 51). Successive Cu(II)-mediated C-H activation results formation of the 2-sulfonylbenzo[b]furans. Various aryl sodium sulfinates are effective under the reaction condition. Various substitiuents such as methoxy, methyl, fluoro, chloro and bromo on the aromatic ring of 2-hydroxy cinnamic acid were found to be welltolerated. However, cinnamic acids with substituent ortho to the -OH group inhibit this cascade process.

O

O

O S

R

O [CuII]X

O S R O

Scheme 51. Possible mechanism Using a different reaction condition using catalytic CuO and sulfinate under aerobic condition (Scheme 52), Guo et al.66 successfully added the sulfonyl cation to cupric cinnamate and provided a benzyl cation 45 (Scheme 53). The benzyl cation can be trapped by I- (46) and subsequently eliminated via decarboxylation process. Cinnamic acids bearing electron-withdrawing groups are relatively high yielding compared to electron-donating groups. The products can be isolated in similar yields, irrespective of the position of the substituent on the aromatic ring. While aryl sulfinates are effective under the reaction condition, methanesulfinate provided lower yields of sulfone. In this system, the sulfonyl radical may be formed via oxidation of benzenesulfinyl anion by Cu(II), air, or DMSO through a single-electron transfer process.67 Further singleelectron oxidation of this radical generates the sulfonyl cation.

14 | J. Name., 2012, 00, 1-3





ARTICLE


Page 15 of 21

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DOI: 10.1039/C5OB00727E

Ar

ARTICLE

COOH

CuO (20 mol%) KI (1.5 equiv) DMSO, air, 100 oC

R SO2Na R=Alkyl, aryl

O S R Ar O 33-85%, E-only

condition, cinnamic acids could be transformed to vinyl sulfones using Pd(OAc)2 as catalyst in presence of a suitable ligand and oxidant. Comparable results could be obtained irrespective of the electronic nature of substituent in the cinnamic acids. The mechanistic path has been proposed in two possible pathways (path a and path b, Scheme 55). These two ways differ in decarboxylation step. In Path b, initial decarboxylation of Pd-carboxylate leads to the formation of Pd-alkenyl species 47, which reacts with sulfinate to form 48. Subsequent reductive elimination results the formation of the product. Silver salt can reoxidize Pd(0) species. While in path a, decarboxylation occurs from an intermediate 49, which is formed via reaction of Pd-carboxylate and sulfinate.

Selected examples: O S

O S

O

HO

42% O S

O

O2N

MeO 34%


O S

O

66% O S

N

O

O S O

O

Br 85%

62%

33%

SO2Na

COOH

Scheme 52. Cu(II)-catalyzed decarboxylative C-S bond formation. PhSO2-

O Ph S O

Cu(II), O2 or DMSO

R'

R

O Ph S O

[O]

Ag2CO3

Ar

R'

50-88%

O

Pd(OAc)2

SO2Ph

Ar

O S O

R

Ag2CO3 (2 equiv) DMF, 75 oC

R= OMe, Me, Cl, Br, NO2 etc R'= H, Me, Br etc

O Ph S O

Pd(OAc)2 (10 mol%) dppb (10 mol%)

Ag2CO3

Pd(OAc)2

OH

SO2Ph

Ar

Pd(0)

Pd(0)

Ar

COOH

Cu(II)

COOCu(II)

Ar

O Ar

Cu(II)

Cu(I) O Ph S O

I Ar

O Ph S O COOCu(II)

KI

SO2Na

SO2Na

O

45

Ar

O Pd

SO2Ph

Ar

Scheme 55. Pd(II)- catalyzed decarboxylative C-S bond formation.

Scheme 53. Possible mechanism. Prabhu et al. Reported the C-S bond formation via radical additionelimination mechanism using sulfonyl radical generated via Cu(II) and TBHP system (Scheme 54).68 In presence of 1,10phenanthroline ligand, considerable enhancement in yield of the reaction was achieved. The method is effective only with electronrich cinnamic acids (except with OH and NH2 substitution) and could provide moderate yields in most of the cinnamic acids and sulfinate combination. Heteroaryl cinnamic acids were found to be disappointing. The proposed mechanism is shown in scheme 54. Products were isolated exclusively in E-form even from cis-cinnamic acids. The ligand may help in stabilizing the reaction intermediates. Cu(ClO4)2 6H2O ( 20 mol%) TBHP in decane ( 3 equiv) Ar' SO2Na

1,10-phenanthroline (20 mol%)

Selected examples: O O S

O O S HO

83%

Ar O O S

MeO

0%

34% O O S

Cl 44%

OO S Ar'

MeO

O O S MeO

Ar

MeO

A metal-free radical mechanism was reported by Jiang et al.70 They synthesized vinyl sulfones from sodium sulfinate using DMSO as the oxidant in presence of a base (Scheme 56). Mild and metal-free reaction conditions make this protocol more attractive. Under DMSO condition the sulfonyl radical can be generated from the sulfinate. The sulfonyl radical binds with carboxylate in presence of K2CO3 and subsequently undergoes decarboxylation to provide the desired product in high yields. Various alkyl and aromatic sodium sulfinates are effective under this transformation. Cinnamic acids bearing electron-withdrawing groups are high yielding compared to electron-donating ones. Ortho-substituted cinnamic acids could provide reasonable yields. The proposed mechanism of this reaction is shown in Scheme 57.

31-83%, E-only

CH3CN, 110 oC, 20 h

MeO

Pd(OAc) 47

49

COOH

Pd SO2Ph 48

O Ph S O COOCu(II)

Ar

46

CO2

Ar

Ar

Path b

O Pd(OAc)

48

O2

Ar

Path a

Pd SO2Ph

Ar

Br

Ar SO2Na

OO K2CO3 (50 mol%) S Ar DMSO, 100 oC, 10h Ar 66-94%, E-only

Selected examples: O O S

O O S

Me O O S

44%

COOH

MeO 87%

F3C 77%

O O S

S 31%

Scheme 54. Cu(II)/TBHP-mediated C-S bond formation.

79% O O S

NO2 94%

O O S

Cl 78%

O O S S 73%

Scheme 56. Metal-free C-S bond formation with sodium sulfinate.

Pd(II) has also been employed as a suitable catalyst for decarboxylative C-S bond formation with sodium sulfinate comparatively at lower temperature.69 Under mild reaction

J. Name., 2013, 00, 1-3 | 15




Journal Name



DOI: 10.1039/C5OB00727E

Journal Name Ar-SO2Na

Ar

DMSO

COOH

Ar

Cu2O (10 mol% )

O S O

COOH

Ar

Base

COO-

Ar

50

SO2Ar

Ar -O

-CO2 Ar

SO2Ar

NMP, 120 oC

20-94%

O P(Ph)2

O P(Ph)2

Selected examples:

O P(Ph)2

DMSO

Ar

SO2Ar

MeO 94%

O

60%

70%

O P(Ph)2

Scheme 57. Possible mechanism. NC


O P(Ph)2

Ar

2

50 O Ar S O

O 1,10-Phenanthroline (10 mol%) PH(Ph)2 Ag O (3 equiv )

Hypervalent iodine reagents have been reported in generation of sulfonyl radical.71 Very recently, Kuhakarn et al. developed PhI(OAc)2-mediated synthesis of vinyl sulfones.72 PhI(OAc)2 exhibits dual role in this reaction, helps in the the formation of sulfonyl radical as well as the aryliodonium carboxylate.18 The desired E-vinyl sulfones were synthesized through the radical addition-elimination process with good functional group tolerance.

O P(Ph)2 Cl

63%

O P(Ph)2 O

Cl 20%

60%

Scheme 58. Cu(I)-catalyzed decarboxylative C-P bond formation.

HP(O)Ph2 N

O P(Ph)2

Ar

Base

N Cu2O

3.4 C-P bond formation Alkenylphosphorus compounds are an important class of compounds, which are extensively used as biologically active molecules in medicinal chemistry and exhibits powerful applications in organic transformations.73 The strategies to achieve alkenylphosphorus compounds mainly include Heck-type coupling of vinylphosphonates with various aryl partners, olefin crossmetathesis and cross-coupling of P(O)H compounds with vinyl halides. However, these methods suffer from lack of stereoselectivity, limited substrate scope and the use of relatively drastic conditions that were not compatible with sensitive functional groups etc.74 Hence, decarboxylative C-P bond formation can address an efficient alternative protocol to overcome these drawbacks. Cinnamic acids and alkyne acids were subjected to decarboxylative C-P bond formation for the first time. Yang et al. reported the first examples of the catalytic decarboxylative C-P cross-coupling of cinnamic acids with di-substituted phosphine oxides using Cu2O and 1,10-phenanthroline ligand system (Scheme 58).75 The decarboxylation step is mediated by a silver additive. The cinnamic acids could provide high yields irrespective of the electronic nature of the substitiuents on the aromatic ring. Although electronic effect was not evident in the process, steric hindrance leads to lower yields. The method is highly regio and chemoselective and various functional groups are well tolerated under the reaction condition. In this method the scope of P(O)H compounds were limited. Authors suggested a mechanistic path for the crosscoupling process (Scheme 59). In the presence of Ag2O, the reaction of Ph2P(O)H with the copper/phen catalyst should provide the Cu(II)-phosphine complex 51. Alkenyl silver transfers the alkenyl group to copper via transmetalation to give the organocopper intermediate 52, which undergoes reductive elimination to give the desired product, along with the initial copper species.

N Cu Ar

N O P (Ph)2

N 52

X

Cu

N O P (Ph)2

51 Ar Ag2O Ar

Ag

Transmetalation

-CO2 COOH

Scheme 59. Possible mechanism. After that, Zhao et al. explored a Ni-catalyzed protocol enhancing the scope of P(O)H compounds (Scheme 60).76 They have synthesized different (E)-1-alkenylphosphonates, (E)-1alkenylphosphinate oxides, and (E)-1-alkenylphosphine oxides with high stereoselectivity. The method exhibits broad substrate applicability. However cinnamic acids bearing strong electronwithdrawing groups provided lower yield. (Z)- cinnamic acid provided high E-product probably due to Z-E tautomerism under the high-temperature conditions. In presence of the Ni catalyst the styrylsilver produces an intermediate 53 via ligand exchange process (Scheme 61). The active phosphorus species is a Ag-P species 54. The ligand exchange between 53 and 54 provides a tetracoordinated Ni(II) complex 55. Subsequently, an η2 Ni (0) complex 56 is formed through reductive elimination. The product is formed along with the regeneration of the catalyst Ni(dppf)Cl2 by Ag(I)-mediated oxidation. The mechanistic path revealed the possibility of deacrboxylative C-C and C-hetero bond formation of vinylic carboxylic acids in presence of Ni-based catalyst.

16 | J. Name., 2012, 00, 1-3




ARTICLE


Page 17 of 21

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DOI: 10.1039/C5OB00727E

Journal Name

ARTICLE O 1 R P 2 R

Ni(dppf)Cl2 ( 5 mol%)

Ar

Ag2O ( 2equiv) DMSO, 120 oC, N2

PhI(OAc)2 (0.5 equiv)

O P(OiPr)2

O P(OiPr)2

20-68%, E-only

MecN, 60 oC Mechanism: PhI(OAc)2

COOH

Ar'

Ar'

85%


O P Ph Ph

F3C

O2N

57

83%

O P Ph OEt

O P(OiPr)2

ArSeSeAr Ar'

COO-

2

ArSe+

58 COO-

Ar'

COO-

Ar'

or

F3C

Ar'

SeAr

or

Se Ar

SeAr

81%

57%

COO PhI 57

F 90%

SeAr

Ar'

ArSeSeAr (0.5 equiv)

up to 92%, E > 99%

Selected examples:

O P(OiPr)2

COOH

Ar'

O O

84% 59

Scheme 60. Ni(II)-catalyzed decarboxylative C-P bond formation with with P(O)H compounds.

-CO2

Ar'

COOH

Ar

61

60

SeAr

i

P(O)(O Pr)2

Ni(dppf)Cl2 Ar

-CO2

Ag2O

Scheme 62. Electrophilic selenization of cinnamic acids with

Ag

Ar

ArSeSeAr/PhI(OAc)2 system.

AgCl

AgCl

P

P

P Ni

P(O)(OiPr)2

4. Miscellaneous reaction

P Ni

Cl

Ar

53

56

P

P

=dppf

AgP(O)(OiPr)2 P

P

AgCl

Ni

(PrOi)2(O)P

4.1. Synthesis of Thioamides

Ar

AgOH

54

HP(O)(OiPr)2 Ar 55

Scheme 61. Possible mechanism. 3.5. C-Se bond formation Selenodecarboxylation of cinnamic acid derivatives with diorgano diselenide was achieved via the use of hypervalent iodine reagent, PhI(OAc)2 in acetonitrile under mild reaction conditions.18b Vinyl selenides could be isolated in moderate to excellent yields via electrophilic mechanism (Scheme 62). The decarboxylation is favorable only with activated cinnamic acids. During the course of reaction, a hypervalent iodine carboxylate species 57 is formed, prior to decarboxylation. PhSe+ formed via oxidation of iodine(III) in the dicinnamate salt 57 attacks with 58 to generate either of the three intermediates, an open benzylic carbocation 59, an episelenonium ion 60, or α-selenophenyl-β-lactone 61. Elimination of carbon dioxide could happen from either of these intermediates to afford vinyl selenide. This process is also effective under solid phase condition. Further improvement of reagent and conditions are required to increase the scope of substrates.

Thioamides are vital building blocks for the construction of biologically important sulfur-containing heterocycles77 and exhibits important synthetic utility.78 Conventionally thionation of amides and Willgerodt−Kindler reaction involving aryl alkyl ketones, elemental sulfur, and amine are used to carry out thioamidation.79 Other three component reactions that exploited the use of benzylamine, alkyne, and aldehydes in combination with elemental sulfur and amine has also been developed for the synthesis of thioamides.80 However, decarboxylative thioamidation strategy is relatively more attractive compared to these existing methods. Singh et al. carried out decarboxylation of cinnamic acids via a solvent-free three-component reaction involving amines and elemental sulfur powder, S8 (Scheme 63).81 The reaction has many advantages as it avoids use of transition metal and external oxidants. Although various substitution patterns were well tolerated under the reaction conditions, nitro group was reduced to NH2. Different amines excluding aromatic amines can afford the corresponding 2arylethanethioamidated products. Authors suggested a mechanistic path on the basis of literature data (Scheme 64). The addition of polysulfide across the double bond of cinnamic acid to give a βthioketo acid, which is condensed with amine to form the enamine. The enamine then successively undergoes reaction with sulfur and decarboxylation to provide a aziridinium-thiolate betaine intermediate, which finally affords the product.

J. Name., 2013, 00, 1-3 | 17




O H P R1 R2

COOH

Ar



DOI: 10.1039/C5OB00727E

ARTICLE

Journal Name HN

R1

R1

S8

R

Ar

80 oC

R2

O

COOH R

2

COOH

R'

S

61-87% O

H N

Ph S

MeO

87%


R

54-92 %

N H2N

S

OMe

86%

O

Me

O

O2N

F

Cl

66%

S

MeO

68%

O

N

S

Cl

75%

74%

N

O

OMe

S

Br

77%

S

O

N

N

S

MeO

O

Selected examples:

Selected examples:

MeO

AgNO3 (10 mol%) Na2S2O8 (2 equiv) R' K2CO3 (1 equiv) H2O, 100 oC

trace

78%

OMe

71%

Scheme 65. Ag(I)/Na2S2O8-mediated double-decarboxylative coupling of cinnamic acids with keto acids.

73%

61%

Scheme 63. Metal-free decarboxylative thioamidation with cinnamic acids.

O O-

Ar

HN

O Ar

R1 R2

OH

O O-

Ar 1

H2 N

R R2

R1 HN 2 R

R1 HN 2 R

S8

S

S8

CO2

HN

O

R1 R2

O-

Ar

H2 N R1 N

Ar

R1 Ar

N

Ag(II)

Na2S2O8

R2 O

CO2 + Ag(I)

O-

R1H2S R2

O Ag(I)

R2

Ar

O

S

Ar'

Ar

Ag(II)

O-

Ar'

4.2. Synthesis of Chalcones

O

Chalcones are biologically active molecules and widely used as the important building blocks in the organic transformations.82 Literature indicated that the development of new synthetic methods for the construction of chalcone skeletons are rare.83 The traditional methods are mainly based on the Claisen−Schmidt reactions. Hence development of methods to prepare chalcones is very important. Wang et al developed a silver-catalyzed double-decarboxylative strategy for the construction of chalcone derivatives via cascade coupling of substituted α-keto acids with cinnamic acids under a mild aqueous conditions (Scheme 65).84 The acyl radical can be generated from keto acids via Ag(I) system in the presence of S2O82oxidant under basic conditions (Scheme 66). In contrast to alkylation process,21 the electron-rich cinnamic acids can efficiently undergo the radical addition-elimination process. The catalytic efficiency was not affected by steric hindrance in α-keto acids. Unfortunately, the αketo acids bearing electron-withdrawing groups and aliphatic ones were the poor coupling partners in this transformation. A similar mechanistic path was followed by Guo etal. using Fe(II)/K2S2O8 system widening the scope of α-keto acids (including hetero analogues) and cinnamic acids (Scheme 67).85 Keto acids bearing electron-withdrawing groups and aliphatic ones were efficiently coupled with cinnamic acids, which was a limitation in the earlier protocol.84 In addition, heteroaryl cinnamic acids could be transformed in moderate to high yields.

COO-

Ar'

O


Ar

Scheme 66. Possible mechanism. O R

COOH

Ar

COOH

FeCl2 (10 mol%) HCOONa 2H2O (2 equiv)

K2S2O8 (2.5 equiv) H O/DMSO, N2, 120 oC R=Aryl, Heteroaryl, Alkyl, Amino etc. 2 Ar= Aryl, Heteroaryl Mechanism:

O R

Ar

up to 92 %

S2O82-

Fe(III)

O R

Fe(II)

COOH

O R

base

CO2 Ar

S2O82-

Fe(II)

O R

Fe(III)

O R

Ar

COOH

Ar COOH

CO2

Scheme 67. Fe(II)/K2S2O8-mediated double-decarboxylative coupling of cinnamic acids with keto acids. 4.3 Synthesis of Furan derivatives The great importance of furans in natural and synthetic substances,86 the development of more selective and novel approach to construct polysubstituted furans from simple and cheap chemical reagents is in great demand. Intermolecular protocols for furan synthesis provide more direct and regio-defined route to furan synthesis in comparison to intramolecular routes.87 Decarboxylative protocol can be considered as the significant novel alternatives for the synthesis of

18 | J. Name., 2012, 00, 1-3




COOH

Ar


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DOI: 10.1039/C5OB00727E

ARTICLE

furans. Zhang et al. synthesized highly regioselective 2,3,5trisubstituted furan derivatives using alkyl ketones with cinnamic acids via decarboxylation process.88 This annulation process was performed in presence of equimolar CuCl and Cu(OAc)2·2H2O combination under aerobic condition (Scheme 68). A variety of substitiuents on the aryl moiety of cinnamic acids and ketones has shown good compatibility to provide the corresponding furans. Cinnamic acids bearing electron-withdrawing groups are better yielding than electron-rich ones. Disubstituted furan products were synthesized under a modified reaction conditions using KOAc in place of Cu(OAc)2·2H2O, albeit in lower yields. Although this method provides successful route to furan synthesis, the requirement of high temperature is a noticeable drawback. Mechanistically, the alkyl radical formed under oxidative condition adds to the cupric cinnamate to form 62. Subsequently, a cationic intermediate 63 is formed via another SET process, which undergoes cyclization to provide the intermediate 64. Finally, deprotonation and elimination takes place to generate the furan products (Scheme 69). CuCl (1 equiv) COOH Cu(OAc)2 2H2O (1 equiv)

O R

R2

1

Ar

R1

1

Ph

O

Ph

O

53%

O

58%

Ph

O

67%

Ph

O

O

CF3

OMe 46%

Ph

Cl

66%

S

O

68%

Ph

O

MeO

55%

O

F

81%

Ph

58%

Scheme 68. Cu-mediated annulation of alkyl ketones with cinnamic acids. COOH

R3

Cu(II) R3

O R1

R2

COOCu(II)

O

O

SET [O]

R2

R1

COOCu(II) R3

R1 R2

62

SET [O] R2 R1

R2 O

R3

We thank the Natural Science Foundation of Zhejiang Province (No. LY12B02006) for financial support.

References

Ar O 37-81%

Selected examples:

Ph

Acknowledgements

R2

DMF, air, 140 oC

Ph

various C-C and C-hetero bond. The cinnamic acids can undergo decarboxylation under mild reaction condition with increasing scope of vinylic functionalization. It has been observed that radical addition-elimination process remains as the efficient mechanistic path in most of the functionalization. Hypervalent iodine reagents can play important role in achieving mild decarboxylation activity. The radical decarboxylative alkylation, trifluoromethylation and sulfonylation process in cinnamic acids opens new window to develop other vinylic radical functionalization processes like arylation and phosphorylation. The C-N bond formation area in cinnamic acids is strictly confined to nitration process and hence efforts require to achieve more decarboxylative amination processes. We hope this review encourage organic chemist to develop this emerging area in a more appealing way.

deprotonation elimination

R1

COOCu(II) O

R

3

64

O

COOCu(II) R3

R1 R2

63


5. Conclusion and perspectives In summary we have highlighted the decarboxylative functionalization of cinnamic acids providing the formation of

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J. Name., 2013, 00, 1-3 | 21





Journal Name

A Direct Metal-Free Decarboxylative Sulfono Functionalization (DSF) of Cinnamic Acids to α,β-Unsaturated Phenyl Sulfones.

Copper-catalyzed decarboxylative cross-coupling of cinnamic acids and ACCN via single electron transfer.

Peroxide promoted tunable decarboxylative alkylation of cinnamic acids to form alkenes or ketones under metal-free conditions.

Silver-catalyzed double-decarboxylative cross-coupling of α-keto acids with cinnamic acids in water: a strategy for the preparation of chalcones.

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids.

Production of Cinnamic and p-Hydroxycinnamic Acids in Engineered Microbes.

Decarboxylative Annulation of α-Amino Acids with γ-Nitroaldehydes.

Copper-catalyzed decarboxylative sulfonylation of α,β-unsaturated carboxylic acids.

Decarboxylative Fluorination of Aliphatic Carboxylic Acids via Photoredox Catalysis.

Palladium-catalyzed decarboxylative trifluoroethylation of aryl alkynyl carboxylic acids.

Nickel-catalyzed decarboxylative acylation of heteroarenes by sp2 C-H functionalization.

Green process for chemical functionalization of nanocellulose with carboxylic acids.

Isothiourea-mediated asymmetric functionalization of 3-alkenoic acids.

Effects of benzoic and cinnamic acids on membrane permeability of soybean roots.

Effects of benzoic and cinnamic acids on growth, mineral composition, and chlorophyll content of soybean.

Copper-catalyzed oxidative decarboxylative arylation of benzothiazoles with phenylacetic acids and α-hydroxyphenylacetic acids with O2 as the sole oxidant.

Decarboxylation of substituted cinnamic acids by enterobacteria: the influence on beer flavour.

Decarboxylative alkynylation and carbonylative alkynylation of carboxylic acids enabled by visible-light photoredox catalysis.

Palladium-catalyzed decarboxylative annulation of 2-arylbenzoic acids with [60]fullerene via C-H bond activation.

Elemental sulfur mediated decarboxylative redox cyclization reaction of o-chloronitroarenes and arylacetic acids.

Copper-catalyzed oxidative decarboxylative couplings of sulfoximines and aryl propiolic acids.

Enantioselective Decarboxylative Arylation of α-Amino Acids via the Merger of Photoredox and Nickel Catalysis.

Effect of cinnamic and acrylic acids' derivatives on luminol-enhanced chemiluminescence of neutrophils.

A Free-Radical-Promoted Stereospecific Decarboxylative Silylation of α,β-Unsaturated Acids with Silanes.