Alkylation of 3-Formylbenzofurans

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Ru (II)-Catalyzed C–H Activation/Alkylation of 3Formylbenzofurans with Conjugated Olefins: Product Divergence Kolluru Srinivas, Shaziyaparveen K Siddiqui, Jyothi K Mudaliar, and Chepuri V. Ramana J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03267 • Publication Date (Web): 20 Mar 2019 Downloaded from http://pubs.acs.org on March 20, 2019

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The Journal of Organic Chemistry

Ru(II)-Catalyzed C–H Activation/Alkylation of 3Formylbenzofurans with Conjugated Olefins: Product Divergence Kolluru Srinivas, Shaziyaparveen K. Siddiqui, Jyothi K. Mudaliar and Chepuri V. Ramana* Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008 (India) ABSTRACT: A Ru-catalyzed alkylation of 3-formylbenzofuran with acrylates and acrylamides has

been

described.

Branched-selectivity

with

unsubstituted

or

-substituted

acrylates/acrylamides and linear-selectivity with -substituted acrylates has been observed. However, in all the cases, the intermediate alkylation products seem to undergo further reactions, either

cycloannulation

or

deformylation,

depending

upon

the

substrate

employed.

For example, with methyl acrylate, the intermediate branched alkylation product underwent cycloannulation with another molecule of methyl acrylate resulting in a densely functionalized cyclohexene ring formation. On the other hand, in case of N-monosubstituted acrylamides, the branched alkylation proceeded with intramolecular aldehyde-amide condensation, leading to pyridin-2-one ring annulation. However, with both methacrylate and crotonate, the deformylation of the initially formed alkylation products was observed.

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i

CO2Me

N or

CHO Z + O

R

[Ru]

R = H or Me Z = CO2Me or CONHiPr

O

O O

CO2Me

or

Me

Me

CO2Me

or O

Pr

CO2Me

O

INTRODUCTION During the last two decades, the directed functionalization of ortho sp2 C–H bonds has attracted a great deal of attention.1 A wide range of metal complexes and various directing groups have successfully been explored in this pursuit. Interestingly, the reports on formyl group directed C–H activation are limited.2 The weak donating ability and the ready deformylation are a couple of limiting factors.3 However, given the wide range of reactions that the aldehyde group can participate in the aldehyde directed C–H functionalization provides the possibility of developing interesting domino processes by integrating these two aspects (Scheme 1).4 In this manuscript, we document Ru-catalyzed directed functionalization of 3-formylbenzofuran with acrylates/acrylamides that results initially in alkylation (branched or linear depending upon the olefin-substitution) and subsequent cycloannulation or deformylation of resulting products by cashing in on the aldehyde functionalization. Scheme 1. Aldehyde directed C–H activation and functionalization with conjugated olefins


2

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Previous work: Jeganmohan (2012)2a

[RuCl2(p-Cymene]2 CO2Me AgSbF6, Cu(OAc)2

CHO +

1,2-dichloroethane 100 °C, 16 h open atmosphere

H Prabhu (2013)2b H CHO

N R Jia (2017)2i

+

CHO CO2Me

[RuCl2(p-Cymene]2 CO2Me CO2Me AgSbF6, Cu(OAc)2 CHO

1,2-dichloroethane 120 °C, 8-24 h, air (R = Bn, 70%) [RhCp*Cl2]2 AgSbF6, Cu(OAc)2 1,2-dichloroethane 110 °C, 4 h

N R

(R = H, 51%)

This work: a) CO2Me

CHO

O

O

CO2Me branched alkylation & cycloannualtion with another acrylate molecule CO2Me H Me

a)

Me

CO2Me

O

CO2Me

H Me

a)

CO2Me Me

linear alkylation & deformylation

O

CO2Me

i

N

b) H N O

branched alkylation & deformylation

Pr O

i

Pr

O

branched alkylation & cyclodehydration

Me

RuCl2(PPh3)3, AgOAc, K2CO3, toluene a) 160 °C, 36 h; b) 140 °C, 16 h

RESULTS AND DISCUSSION Easily accessible 3-formylbenzofuran (1a) has been selected for the alkylation reaction.5 Considering the weaker coordinating ability of the formyl group, from our earlier work on alkylation of 3-aroylbenzofurans, the alkylation of 3-formylbenzofuran with unsubstituted conjugated olefins is expected to result in branched alkylation.6 Initially, the alkylation of 1a with

methyl

acrylate

(2a,

5

equiv)

has

been

examined

with

dichlorotris(triphenylphosphine)ruthenium (II) (10 mol%), AgOAc (30 mol%), K2CO3 (5 equiv) in toluene at 120 °C, 140 °C and 160 °C for 24 h (Table 1). Only in case of the reaction at 160 °C was the formation of a new product in moderate yields noticed. Subsequently, prolonging the


3


Page 4 of 38

reaction time to 36 h improved the yield up to 62%. Initial LC-MS of this new compound revealed that two molecules of methyl acrylate are inserted and the analysis of its 1H, 13C NMR revealed the annulation of a tri-substituted cyclohexene ring to the benzofuran ring. The structure of the product 3aa was established with the help of spectral data analysis, which has been further confirmed by single crystal X-ray structural analysis. Table 1. Optimization of reaction condition H O O 1a

CO2Me (2a)

CO2Me

Catalyst (10 mol%) Additive (30 mol%) K2CO3 (5 equiv) Solvent, 160 °C, 36 h

O 3aa

CO2Me

A = RuCl2(PPh3)3 B = [RuCl2(P-cymene)]2 C = Ru3CO12 D = RuH2CO(PPh3)3 E = RuCl3

entry 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11 12. a

catalyst [A] [B] [C] [D] [E] [A] [A] [A] [A] [A] [A] [A]

solvent Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene 1,2-DCEb 1,4-Dioxaneb Toluenec Toluened

additive AgOAc AgOAc AgOAc AgOAc AgOAc Cu(OAc)2 tBu-CO H 2 AdCO2H AgOAc AgOAc AgOAc AgOAc

yield (3aa)% 62a Complex mixture 8 34 No reaction 21 43 37 5 42 51 Complex mixture

55% on 1 g Scale; bReaction performed at 140 °C. cReaction was performed with 3 equiv of

K2CO3. dReaction was performed with base Cs2CO3. Next, various other ruthenium catalysts have been screened for their compatibility for the current transformation. As shown in the Table 1, under the standard conditions, the reaction employing [RuCl2(p-Cymene)]2 resulted in the formation of a complex mixture (Table 1, entry


4

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2). On the other hand, the reaction with Ru3(CO)12 was sluggish, resulting in the product 3aa in 8% yield along with high amounts of intractable compounds in the mixture (Table 1, entry 3). When the RuH2CO(PPh3)3 catalyst was employed, the product 3aa was obtained in 34% yield (Table 1, entry 4). However, the reaction with RuCl3 was not fruitful, resulting in the recovery of the starting benzofuran 1a (Table 1, entry 5). Thus, among various ruthenium catalysts screened, RuCl2(PPh3)3 was found to be the best for the current transformation. Next, we examined the various additives such as Cu(OAC)2, PivCO2H, AdCO2H under standard condition employing the RuCl2 (PPh3)3 catalyst. As shown in Table 1, in all the cases, the requisite product 3aa was isolated in poor to moderate yields (Table 1, entries 6–8). Coming to the various polar solvents such as DMSO, DMF, NMP and H2O, in all the cases, the formation of an intractable complex mixture was observed. A similar observation was made when 1,2-dichloroethane was used as the solvent and 3aa could be isolated in 5% yield (Table 1, entry 9) from the complex mixture obtained. Interestingly, when 1,4-dioxane was used as the solvent, the product 3aa was obtained in 42% yield (Table 1, entry 10). The reaction performed by employing 3 equiv of K2CO3 or with other bases like Cs2CO3 was not fruitful. After having optimized conditions in hand, the compatibility of methyl methacrylate (2b) and methyl crotonate (2c) in the current transformation was examined (Scheme 2). With methyl methacrylate, a linear alkylation followed by deformylation and, with methyl crotonate, branched alkylation followed by deformylation resulted in the formation of 4ab and 5ac respectively. The formation of the complementary linear product 4ab with methyl methacrylate and of the branched product 5ac with methyl crotonate indicates that the steric hindrance associated with the substrate played a prominent role in deciding the approach of the acrylate to the Ru–C bond of the intermediate ruthenacycle, which, in turn, decides the mode of alkylation.6 In case of


5


Page 6 of 38

methyl methacrylate, the presence of C2-methyl seems to be hindering the coordination of this carbon with the ruthenium center, whereas, with methyl crotonate, since the methyl group is at C3, the selectivity is similar to that observed with methyl acrylate. Importantly, the ready deformylation when methyl methacrylate or methyl crotonate are employed reveals that alkylation is the first event in the cascade process that has been observed with the simple methyl acrylate. However, with either methyl methacrylate or with methyl crotonate, the subsequent cycloannulation seems to not be facile. Attempts to isolate the intermediate aldehyde by varying the temperature and the time of the reaction met with failure Scheme 2. Alkylation with methyl methacrylate (2b)/methyl crotonate (2c)a

Me H

Me CO2Me

(2b) CO2Me O

O 4ab, 63%

O 1a

Me Me (2c)

a)RuCl (PPh ) 2 3 3

CO2Me

O

CO2Me

5ac, 52%

(10 mol%), AgOAc (30 mol%) K2CO3 (5 equiv), toluene, 160 °C, 36 h

Next, we proceeded to examine the scope of these reactions employing differently substituted 3-formylbenzofurans 1b–h. As shown in Scheme 3, the cyloannulation of 3formylbenzofurans 1b–h with methyl acrylate (2a) proceeded smoothly and provided the corresponding tricyclic products 3ba–ha in good to moderate yields. The benzofurans containing electron donating groups gave better yields when compared to those substituted with electron withdrawing groups. Similarly the reaction of substrates 1b–g with methyl methacrylate (2b) under optimized reaction conditions resulted in deformylated linear alkylation products 4bb–gb and with methyl crotonate (2c) resulted in the formation of deformylated branched alkylation


6

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products 5bc–ec, 5gc in moderate yields. The reaction with benzofuran 1f was not fruitful, resulting in a complex mixture. In all the three instances, the reactions of 5-bromo-3formylbenzofuran (1h) led to a complex mixture. Only in case of the reaction with methyl acrylate (1a) could reasonable amounts of the cycloannulated product 3ha be isolated. However, in case of the reaction of 1h with methyl methacrylate (1b) and methyl crotonate (1c), though the expected alkylation/deformylation reaction was noticed, the isolated products were not sufficiently pure for further characterization. Scheme 3. Scope of 3-formylbenzofurans with acrylates 2a–c

H

O 2a/2b/2c

R

RuCl2(PPh3)3 (10 mol%) AgOAc (30 mol%)

Products

K2CO3 (5 equiv), toluene 160 °C, 36 h

O 1b1e CO2Me Cl

MeO

CO2Me

OMe

CO2Me

CO2Me

CO2Me

Me O

O

Me CO2Me

3ba, 66%

3ca, 41% CO2Me Br

CO2Me

O

Me CO2Me

3ga, 62%

3ha, 25% OMe

Me

O

Me CO2Me MeO

O

4eb, 68%

4fb, 23%

O 5dc, 54%

CO2Me

O 5ec, 58%

CO2Me O

4cb, 57% (X = Cl) X = Br - complex mixture

Alkylation of 3-Formylbenzofurans

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