Sequential one-pot combination of multireactions through multicatalysis: A general approach to rapid assembly of functionalized push-pull olefins, phenols, and 2-methyl-2 H-chromenes

J. Comb. Chem. 2010, 12, 855–876

855

Sequential One-Pot Combination of Multireactions through

Multicatalysis: A General Approach to Rapid Assembly of

Functionalized Push-Pull Oleﬁns, Phenols, and

2-Methyl-2H-chromenes

Dhevalapally B. Ramachary,* Kinthada Ramakumar, Adluri Bharanishashank, and

Vidadala V. Narayana

School of Chemistry, UniVersity of Hyderabad, Central UniVersity (PO), Hyderabad 500 046, India

ReceiVed June 16, 2010

A general, sustainable and practical process for the sequential cascade one-pot synthesis of library of highly

substituted push-pull oleﬁns, phenols and 2-methyl-2H-chromenes was reported through multicatalysis

cascade (MCC) reactions. Direct sequential one-pot combination of amine- or amino acid-catalyzed cascade

Knoevenagel/Michael/aldol condensation/decarboxylation with other reactions like amine- or amino acid-

catalyzed cascade Claisen-Schmidt/iso-aromatization, Claisen-Schmidt/isomerization, Claisen-Schmidt/

iso-aromatization/isomerization, Michael addition, Claisen-Schmidt/Michael, ruthenium-base-silica-catalyzed

ring closing metathesis/base-induced ring-opening/benzylic oxidation/[1,7]-sigmatropic hydrogen shift, or

ruthenium-base-heat-catalyzed ring closing metathesis/base-induced ring-opening/[1,7]-sigmatropic hydrogen

shift reactions of alkyl acetoacetates, a variety of aldehydes and alkyl halides furnished the highly

functionalized push-pull oleﬁns, phenols and 2-methyl-2H-chromenes with high yields. The yields and

regioselectivities were good to excellent. Evidence for a new reaction pathway involving in situ formation

of novel push-pull dienamines under amine- or amino acid-catalysis is presented along with examples

demonstrating the amenability of the process to MCC chemistry.

Introduction

Claisen-Schmidt/iso-aromatization/isomerization (CS/IA/I),

Claisen-Schmidt/Michael (CS/M), Michael addition, ring

closing metathesis (RCM), base-induced ring-opening (BIRO),

benzylic oxidation (BO), and [1,7]-sigmatropic hydrogen

shift ([1,7]-SHS) reactions that produce highly substituted

2-arylidene or 2-alkylidene cyclohexanones (push-pull ole-

ﬁns) 4, highly substituted push-pull phenols 5, functional-

ized aldehydes 6, highly functionalized (E)-1,3-dienes 7,

functionalized bis-enones 8, fully functionalized benzenes

9, functionalized benzo[b]oxepines 10, functionalized (Z)-

2-(buta-1,3-dienyl)phenols 11/12, and highly substituted

2-methyl-2H-chromenes 13/14 from commercially available

Hagemann’s esters 1, aldehydes 2, allyl bromide {1} or

propargyl bromide {2} and amines or amino acids 3 as shown

in Scheme 1. Push-pull oleﬁns and phenols 4/5 are attractive

intermediates in the synthesis of natural products and in

medicinal chemistry,⁴while functionalized 2-methyl-2H-

chromenes 13/14 and analogues thereof have broad utility

in pharmaceutical chemistry⁵and in organic synthesis (see

Chart 1). Hence, their economical and environmental friendly

preparation has continued to attract considerable synthetic

interest in developing new methods for their syntheses.⁶

Critical objectives in modern synthetic organic chemistry

include the catalytic asymmetric assembly of simple and

readily available precursor molecules into stereochemically

and electronically complex compounds under sustainable

reaction conditions as mimicking cellular reactions. In this

regard, the development of one-pot sequential combination

of multicatalysis and multicomponent reaction methodologies

can provide expedient access to complex products from

simple starting materials.¹Recently, amine- or amino acid-

catalysis (organocatalysis) has emerged as a promising

sustainable synthetic tool for the constructing combination

of C-C, C-N, C-O, C-S, C-P, C-F, and/or C-H bonds

in a single operation with high diastereo- and enantioselec-

tivity in a cascade or multicomponent process.²Generally

in organocatalysis, structurally simple and stable chiral

organoamines and amino acids facilitate iminium- and

enamine-based transformations with carbonyl compounds and

are used as catalysts in operationally simple and environ-

mentally friendly cascade reactions.

As part of our research program to engineer direct

combination of organocatalytic multicomponent and multi-

catalysis reactions,³herein we report the organocatalytic

regioselective direct cascade Claisen-Schmidt/iso-aromati-

zation (CS/IA), Claisen-Schmidt/isomerization (CS/I),

We envisioned that an amine- or amino acid would cata-

lyze the cascade Claisen-Schmidt condensation of a variety

of aldehydes 2 (Figure 1) with in situ generated push-pull

dienamine (1-amino-1,3-butadiene)⁷intermediate from Hage-

mann’s esters 1 (Figure 2) and amine/amino acid 3 to form

substituted push-pull oleﬁns (3-arylidene Hagemann’s ester)

* To whom correspondence should be addressed. E-mail: ramsc@

uohyd.ernet.in.

10.1021/cc100104k  2010 American Chemical Society

Published on Web 09/21/2010

856 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Scheme 1. Direct Organocatalytic Sequential One-pot Cascade Reactions Based on the Push-Pull Dienamine Platform

Chart 1. Some Natural/Non-Natural Products and Pharmaceuticals Containing Cascade Compounds Obtained from Push-Pull

Dienamine Chemistry

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 857

Figure 1. Diversity reagents 2{1-30}.

Figure 2. Diversity reagents 1{1-19}.

4 in a highly regioselective manner, which then undergoes

iso-aromatization to produce substituted push-pull phenols

5, isomerization to produce substituted (E)-1,3-dienes 7 or

Michael addition with 1 to produce substituted bis-enones 8

under base-catalysis based on the electronic nature of

aldehydes 2 and amines 3. Substituted push-pull phenols 5

were transformed into the push-pull benzo[b]oxepines 10,

push-pull (Z)-2-(buta-1,3-dienyl)phenols 11/12, and push-

pull 2-methyl-2H-chromenes 13/14 through RCM, BIRO, BO

and [1,7]-SHS reaction sequences respectively.

3c-catalysis in DMSO at 25 °C for 24 h furnished the CS

product 4{1,1} as a 1.25:1 mixture of E/Z isomers in 73%

yield and without cascade product 5{1,1} (Table 1, entry

4). Interestingly, the same reaction took longer reaction time

with lesser yield in dimethylformamide (DMF) as solvent,

and also CS product furnished with very poor yields in

MeOH as solvent (Table 1, entries 5-6). Interestingly, the

cascade reaction catalyzed by bifunctional catalyst, pyrro-

lidine 3d/AcOH in DMF at 25 °C for 12 h furnished the

Claisen-Schmidt/iso-aromatization (CS/IA) product 5{1,1}

in 30% yield and without isolation of CS product 4{1,1} as

shown in Table 1, entry 7.

Results and Discussions

Direct Amino Acid- or Amine-Catalyzed Cascade

Claisen-Schmidt and Claisen-Schmidt/Iso-Aromatization.

Reaction Optimization. We were surprised to ﬁnd that the

reaction of Hagemann’s ester 1{1} and 4-nitrobenzaldehyde

2{1} with a catalytic amount of L-proline 3a in dimethyl-

sulfoxide (DMSO) at 25 or 75 °C for 48 or 24 h respectively,

did not furnished the expected products 4{1,1} or 5{1,1} as

shown in Table 1, entries 1 and 2. Interestingly, the same

reaction catalyzed by phenylalanine 3b at 25 °C for 96 h

furnished the Claisen-Schmidt (CS) product 4{1,1} as a

1.25:1 mixture of E/Z isomers in 40% yield and without

formation of cascade product 5{1,1} (Table 1, entry 3). In a

similar manner, reaction of 1{1} with 2{1} under glycine

On the basis of the result of entry 7, we screened several

pyrrolidine-based catalysts 3d-m by monitoring the reaction

yield and regioselectivity of the cascade reaction of 1{1}

and 2{1} in DMF/DMSO. In the cascade CS/IA reaction of

1{1} and 2{1} catalyzed directly by pyrrolidine 3d, we found

that the solvent had a signiﬁcant effect on the rates and yields

(Table 1, entries 8-14). The cascade CS/IA reaction

produced the 5{1,1} with good yields in aprotic dipolar

solvents like DMF and DMSO, but did not furnish products

4{1,1} or 5{1,1} in protic polar solvents (H₂O, MeOH,

EtOH, CHCl₃, CH₃CN), the aprotic polar solvent (THF), and

in the ionic liquid [bmim]BF₄under the pyrrolidine 3d-

catalysis (results not presented in Table 1). The amine-

858 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Table 1. Optimization of the Direct Amine-Catalyzed Cascade

Claisen-Schmidt and Iso-aromatization Reaction of 1{1} and

2{1}^a

mixture of E/Z isomers and 5{1,1} in 5% yield (Table 1,

entry 12). At 60 °C, the same reaction with pyrrolidine 3d

furnished the cascade CS/IA product 5{1,1} in 61% yield

in reduced time (Table 1, entry 13). Piperidine 3e also

catalyzed the cascade CS/IA reaction in 61% yield, but there

is no reaction under morpholine 3f-catalysis (Table 1, entries

15 and 16). Primary amines like benzylamine 3g catalyzed

the CS reaction of 1{1} and 2{1} to furnish 4{1,1} in 30%

yield, but there is no reaction under aniline 3h-catalysis

(Table 1, entries 17 and 18). The tert-amines like DMAP

3i, triethylamine 3j, and DBU 3k did not catalyze the cascade

CS or CS/IA reaction, which is giving strong evidence for

the in situ enamine formation during these reactions.

After successful demonstration of glycine- and pyrrolidine-

catalyzed cascade CS and CS/IA reactions, we further

screened diamine-based catalysts to increase the reaction

yield and regioselectivity of the cascade reaction of 1{1}

and 2{1}. The (S)-1-(2-pyrrolidinylmethyl)pyrrolidine 3l

catalyzed the cascade CS/IA reaction of 1{1} and 2{1} at

25 °C for 7 h in DMF to produce 5{1,1} in 75% yield (Table

1, entry 22). Interestingly, the same reaction in DMSO at

25 °C for 7 h furnished the cascade CS/IA product 5{1,1}

in 80% yield, which is better-optimized condition compared

to glycine- and pyrrolidine-catalysis (Table 1, entry 23).

Surprisingly, cascade CS/IA reaction of 1{1} and 2{1} under

(S)-1-(pyrrolidin-2-ylmethyl)piperidine 3m-catalysis in DMF

or DMSO at 25 °C for 8 h furnished the product 5{1,1} in

62-66% yield, which is not superior compared to 3l-catalysis

(Table 1, entries 25 and 26). The optimal reaction conditions

for push-pull oleﬁn synthesis involved glycine 3c-catalysis

at 25 °C in DMSO with equimolar quantities of 1{1} and

2{1}, which furnished the CS product 4{1,1} in 73% yield

(Table 1, entry 4). The optimal reaction conditions for

push-pull phenol synthesis involved pyrrolidine 3d- or

diamine 3l-catalysis at 25 °C in DMF or DMSO with

equimolar quantities of 1{1} and 2{1}, which furnished the

cascade CS/IA product 5{1,1} in 75 or 80% yield respec-

tively (Table 1, entries 10 and 23). The regiochemistry of

products 4{1,1} and 5{1,1} was established by NMR

analysis.

^aReactions were carried out in solvent (0.5 M) with the same

proportions of Hagemann’s ester 1{1} and aldehyde 2{1} in the

presence of 20 mol % catalyst. ^bYield refers to the column-puriﬁed

product. ^c70 to 85% of unreacted Hagemann’s ester 1{1} was isolated.

^d1.25:1 Mixture of E/Z isomers were isolated. ^e1.25 equivalents of

ester 1{1} was used. ^f1:1 mixture of E/Z isomers were isolated.

Diversity-Oriented Synthesis of Push-Pull Oleﬁns

4{1,2}-4{1,21} and Functionalized Aldehydes 6{1,19}/

6{1,20} via Amine-Catalysis. With an efﬁcient amino acid-

or amine-catalyzed CS and CS/IA protocol in hand, the scope

of the glycine-catalyzed CS and pyrrolidine- or diamine-

catalyzed CS/IA reactions was investigated with various

aldehydes 2{2}-2{21} by monitoring the electronic nature

of aldehydes 2 or/and basic nature of catalyst 3 in cascade

CS and CS/IA reactions. A series of neutral, electron-

donating, electron-withdrawing and R,ꢀ-unsaturated alde-

hydes 2{2}-2{21} were reacted with 1.0 equiv of Hage-

mann’s ester 1{1} catalyzed by 20 mol % of glycine 3c,

pyrrolidine 3d, or diamine 3l at 25 °C for 7-48 h in DMSO

or DMF (Table 2). Interestingly, iso-aromatization did not

taken place in all these reactions and only the CS products,

3-arylidene Hagemann’s esters 4{1,2}-4{1,21} were isolated

in moderate to good yields with stereoselectivities favoring

the E-isomers except in the case of R,ꢀ-unsaturated aldehydes

2{19}-2{21}.

induced CS condensation looks like a strongly solvent-

dependent reaction. The ﬁrst step of the formation of the

1-amino-1,3-butadiene from the 1{1} and amine 3d, and its

addition to the carbonyl (or imine) group, is facilitated in

solvents of high polarity and the second step, 1,2-elimination,

may be inhibited by protic solvents. Thus, dipolar aprotic

solvents such as DMF and DMSO are especially useful for

amine-catalyzed CS condensations.⁷

The structurally simple pyrrolidine 3d catalyzed the

cascade CS/IA reaction of 1{1} and 2{1} to produce 5{1,1}

in 65% yield at 25 °C for 6 h and extension of the reaction

time to 12 h furnished the 5{1,1} in 75% yield (Table 1,

entries 8 and 10). Interestingly, the same reaction performed

at 25 °C for 2 h furnished the 4{1,1} in 60% yield with 1:1

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 859

Table 2. Synthesis of Chemically Diverse Libraries of 3-Arylidene-Hagemann’s Esters 4 via Amine-Catalysis^a

^aMethod-A: Reactions were carried out in DMSO (0.5 M) with the same proportions of Hagemann’s ester 1{1} and aldehyde 2 in the presence of

20 mol % glycine 3c.; Method-B: Reactions were carried out in DMF (0.5 M) with the same proportions of Hagemann’s ester 1{1} and aldehyde 2 in

the presence of 20 mol % pyrrolidine 3d.; Method-C: Reactions were carried out in DMF (0.5 M) with the same proportions of Hagemann’s ester 1{1}

and aldehyde 2 in the presence of 20 mol % diamine 3l. Yield refers to the column-puriﬁed product and E/Z ratio determined by NMR analysis.

^bHagemann’s ester 1{1} (1.0 mmol) reacted with aldehyde 2{8} (0.5 mmol) in the presence of 20 mol % glycine 3c at 65 °C for 12 h. ^cHagemann’s

ester 1{1} (1.0 mmol) reacted with aldehyde 2{21} (0.5 mmol) in the presence of 20 mol % diamine 3l at 0 °C in DMF for 0.5 h.

The ethyl (E)-3-benzylidene-2-methyl-4-oxo-cyclohex-1-

enecarboxylate 4{1,2} were obtained as major isomer with

excellent to good yields via 3c-, 3d-, or 3l-catalyzed CS

reaction of 1{1} with 2{2} at 25 °C in DMSO or DMF,

respectively (Table 2, entry 1). Unfortunately, the same CS

reaction of 1{1} with 2{2} under 3c-, 3d-, or 3l-catalysis at

70-75 °C in DMSO or DMF furnished the CS product

4{1,2} in only 25-30% yields, and this may be due to the

decomposition of 2{2} at higher temperatures (results not

shown in Table 2). The CS reaction of 1{1} with benzal-

dehydes containing an electron-withdrawing group 2{6}-

2{9} also under glycine 3c-catalysis furnished the CS

products (E)-4{1,6}-4{1,9} as major isomers with 10:1 to

1.5:1 E/Z ratio with good yields (Table 2, entries 5-8).

Interestingly, halogenated benzaldehydes 2{13}-2{15} and

heterocyclic aldehydes 2{16}-2{17} also furnished the

expected CS products 4{1,13}-4{1,17} with 1{1} under 3c-

catalysis in good yields with E-isomer as major (Table 2,

entries 11-15). Reaction of 1{1} with trans-cinnamaldehyde

2{19} under glycine 3c catalysis furnished the CS product

4{1,19} in 50% yield with a 1:8 E/Z ratio (Table 2, entry

17).

Compared to glycine-catalysis, pyrrolidine-catalysis gener-

ated the CS products 4{1,2}-4{1,17} with less yields and

860 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Figure 3. Crystal structure of ethyl 3-(4-ﬂuorobenzylidene)-2-methyl-4-oxo-cyclohex-1-enecarboxylate (4{1,13}).

high E-selectivity from 1{1} and benzaldehydes 2{2}-2{17}

at 25 °C for 12-24 h in DMF as shown in Table 2.

Observation of high E-selectivity in pyrrolidine-catalysis may

be due to the steric hindrance induced by 3d in the transition

state of CS reactions (for clear discussion, see in the

mechanistic insights). Reaction of 1{1} with trans-cinna-

maldehyde 2{19} under pyrrolidine 3d catalysis furnished

the Michael product 6{1,19} in 65% yield in a 1:1 diaster-

eomeric ratio, which is different from the glycine-catalysis

maybe because of the nature of 2{19} as Michael acceptor

under pyrrolidine-catalysis (Table 2, entry 18). Formation

of Michael adducts 6 from 1{1} and R,ꢀ-unsaturated

aldehyde under pyrrolidine-catalysis is conﬁrmed by one

more example as shown in Table 2, entry 19.

A series of neutral, electron-donating and R,ꢀ-unsaturated

aldehydes 2 were reacted with 1.0 equiv of Hagemann’s ester

1{1} catalyzed by 20 mol % of diamine 3l at 25 °C for 7-18

h in DMF or DMSO solvents (Table 2). Interestingly, in these

reactions also CS/IA products 5 are not furnished, and only

the CS products, 3-arylidene Hagemann’s esters 4 were

isolated in moderate to good yields with stereoselectivities

favoring the E-isomers for simple benzaldehydes and favor-

ing the Z-isomers for R,ꢀ-unsaturated aldehydes without

formation of Michael adducts 6 (Table 2).

of aldehydes 2 with good yields and selectivity. 2-Arylidenecy-

clohexanones, 2,6-bis(arylidene)cyclohexanones and related

compounds were evaluated for antitumor, anti-inﬂammatory,

antineoplastic, cytotoxic activity, and also for the inhibition

of mitochondrial function in yeast emphasizing the value of

this amino-acid catalyzed CS approach.^4a-eIn addition,

generation of molecular diversity around the 2-arylidenecy-

clohexanone scaffolds may allow for the identiﬁcation of

more potent species.

Diversity-Oriented Synthesis of Push-Pull Phenols 5

via Diamine-Catalysis. After thorough investigation of the

glycine 3c-, pyrrolidine 3d- and diamine 3l-catalyzed CS

reactions of Hagemann’s ester 1{1} with various aldehydes

2{1}-2{21} [Tables 1 and 2], we further screened only

benzaldehydes 2 containing an electron-withdrawing group

with variety of Hagemann’s esters 1{1}-1{19} under diamine

3l-catalysis to look at the high-yielding formation of CS/IA

products 5 (Table 3). A series of benzaldehydes 2 containing

an electron-withdrawing group and R,ꢀ-unsaturation were

reacted with 1.0 equiv of Hagemann’s esters 1{1}-1{19}

catalyzed by 20 mol % of (S)-diamine 3l at 25 °C for 7-72

h in DMSO. Interestingly, in all these reactions expected

CS/IA products or push-pull phenols 5 were furnished with

moderate to very good yields as shown in Table 3.

Interestingly, 4-(dimethylamino)benzaldehyde 2{12} and

benzene-1,4-dicarbaldehyde 2{18} furnished the only CS

products 4{1,12} and 4{1,18} with 1{1} under 3l-catalysis

in good yields with high E-selectivity as shown in Table 2.

Interestingly, reaction of 1{1} with trans-cinnamaldehyde

2{19} under diamine 3c-catalysis furnished the CS product

(E, Z, E)-triene 4{1,19} in 75% yield with 1:6 E/Z ratio,

which is different from the pyrrolidine-catalysis but similar

to the glycine-catalysis. Formation of CS product, (E, Z, E)-

triene from 1{1} and R,ꢀ-unsaturated aldehyde under di-

amine-catalysis is conﬁrmed by one more example as shown

in Table 2. Reaction of 2.0 equiv of 1{1} with 3,3-

dimethylacrolein 2{21} in DMF at 0 °C for 0.5 h under 3l-

catalysis furnished the selective conjugated (E, Z, E)-triene

4{1,21} in 60% yield with 1:5 E/Z ratio (Table 2, entry 20).

Structure and regiochemistry of CS products 4 were con-

ﬁrmed by NMR and mass analysis and also ﬁnally conﬁrmed

by X-ray structure analysis on 4{1,13} as shown in Figure

3.⁸

Functionalized push-pull phenols 5 are an important class

of compounds, which are widely used as intermediates in

the pharmaceuticals.^4f-lCompounds containing 2-alkyl-

push-pull phenols 5 have found pharmaceutical applications

as remedies for diabetes G, insulin resistance H, antiasth-

matic LTD4 antagonist ICI-204/219 I, lasiodiplodin ana-

logues J, and also starting materials for the synthesis of

natural products as shown in Chart 1.^4f-lAs such, the

development of new and more general catalytic methods for

their preparation is of signiﬁcant interest.⁶L-Diamine-

catalyzed cascade CS/IA reaction of 1{1} with 4-cyanoben-

zaldehyde 2{7} in DMSO at 25 °C for 7 h furnished the

expected product 5{1,7} in 75% yield (Table 3, entry 2).

The CS/IA reaction of 2-nitro- and 3-nitrobenzaldehydes

2{10}/2{9} with 1{1} catalyzed by ^L-3l in DMSO at 25 °C

for 7 h furnished the expected 5{1,10}/5{1,9} with 75-60%

yields respectively as shown in Table 3. After these interest-

ing results, we decided to investigate the scope and limita-

tions of the CS/IA reaction with other two aldehydes

containing an electron withdrawing group 2{6}/2{8} with

1{1} under L-diamine-catalysis at the ambient conditions

The results in Table 2 demonstrate the broad scope of this

novel CS methodology covering a structurally diverse group

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 861

Table 3. Synthesis of Chemically Diverse Libraries of Highly Substituted Phenols 5 via Diamine-Catalysis^a

^aAll reactions were carried out in DMSO (0.5 M) with the same proportions of Hagemann’s ester 1 and aldehyde 2 in the presence of 20 mol %

diamine 3 L. ^bYield refers to the column-puriﬁed product. ^cHagemann’s ester 1 (1.0 mmol) reacted with aldehyde 2{1} (0.5 mmol) in the presence of

20 mol % diamine 3l at 25 °C for 12-24 h. ^dHagemann’s ester 1{18} (1.0 mmol) reacted with aldehyde 2{1} (0.5 mmol) in the presence of 20 mol %

diamine 3l at 70 °C for 12 h.

(Table 3, entries 5-6). Interestingly, CS/IA reaction of

3-cyanobenzaldehyde 2{8} and 4-triﬂuoromethyl-benzalde-

hyde 2{6} with 1{1} under ^L-diamine-catalysis at 25 °C for

72-16 h furnished the expected push-pull phenols 5{1,8}

and 5{1,6} in 60/70% yields respectively as shown in Table

3, entries 5-6. Yield of cascade CS/IA product 5{1,8} was

increased to 85% when reaction was performed at 70 °C for

6 h as shown in Table 3, entry 5.

After these interesting results, we further decided to

investigate the scope and limitations of the CS/IA reaction

with a range of Hagemann’s esters 1{1}-1{19} including

chiral Hagemann’s esters 1{4}-1{5}, simple ester 1{6}, and

6-substituted Hagemann’s esters 1{7}-1{19} with 4-ni-

trobenzaldehyde 2{1}, 4-cyanobenzaldehyde 2{7}, 3-(2-

nitrophenyl)propenal 2{20}, and ethyl glyoxylate 2{22}

under ^L-diamine-catalysis in DMSO at the ambient conditions

862 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Figure 4. Crystal structure of ethyl 4-hydroxy-2-methyl-3-[3-(2-nitrophenyl)propenyl]-benzoate (5{1,20}).

Table 4. Synthesis of Chemically Diverse Libraries of

1,3-Dienes 7 via Diamine-Catalysis^a

to test the diversity nature of the CS/IA reaction (Table 3).

As shown in Table 3, CS/IA reaction of t-butyl ester 1{3}

with 2{1} under 3l-catalysis for 24 h furnished the phenol

5{3,1} with 75% yield (Table 3, entry 7). Interestingly, CS/

IA reaction of 4-nitrobenzaldehyde 2{1} with 2.0 equiv of

chiral Hagemann’s esters 1{4}-1{5} under 3l-catalysis in

DMSO at 25 °C for 24-12 h furnished the chiral push-pull

phenols (+)-5{4,1} in 80% yield and (-)-5{5,1} in 90%

yield as shown in Table 3, entries 8/9. Diamine-catalyzed

CS/IA reaction of 4-nitrobenzaldehyde 2{1} with simple

Hagemann’s esters 1{6}-1{9} in DMSO at 25 °C for 10-24

h furnished the expected push-pull phenols 5{6,1}-5{9,1}

in 60-85% yields respectively as shown in Table 3, entries

10-13. Interestingly, CS/IA reaction of 4-nitrobenzaldehyde

2{1} with 6-methyl-Hagemann’s ester 1{10} under 3l-

catalysis in DMSO at 25 °C for 12 h furnished the highly

functionalized push-pull phenol 5{10,1} in 65% yield as

shown in Table 3, entry 14. Generality of the diamine-

catalyzed CS/IA reaction of 6-substituted Hagemann’s esters

1 with 4-nitrobenzaldehyde 2{1} or 4-cyanobenzaldehyde

2{7} were conﬁrmed by 10 more examples with esters

1{10}-1{19} containing different functional groups under

3l-catalysis and furnished the expected highly substituted

push-pull phenols 5{10,1}-5{19,1} with 50-80% yields

respectively as shown in Table 3.

Interestingly, cascade reaction of 3-(2-nitrophenyl)propenal

2{20} and ethyl glyoxylate 2{22} with 1{1} under ^L-

diamine-catalysis furnished the novel products 5{1,20} in

65% yield via CS/IA/I and 5{1,22} in 20% yield via CS/IA

reactions as shown in Table 3, entries 25-27. Generality of

the 3l-catalyzed cascade CS/IA/I reaction was conﬁrmed by

one more example with 1{2} and 2{20} as shown in Table

3. Structure and regiochemistry of CS/IA/I products 5{1,20}/

5{2,20} were conﬁrmed by NMR and mass analysis and also

ﬁnally conﬁrmed by X-ray structure analysis on 5{1,20} as

shown in Figure 4.⁸Presently developed amine-catalyzed

CS/IA/I reaction looks as novel technology for the ortho-

vinylation of in situ generated functionalized phenols com-

pared to metal mediated ortho-vinylation of preformed

phenols.⁹Functionalized push-pull phenols 5 are useful

intermediates for the synthesis of analogues of remedies for

diabetes G, insulin resistance H, antiasthmatic LTD4 an-

tagonist ICI-204/219 I, lasiodiplodin analogues J, and also

for the synthesis of natural products as shown in Chart 1.^4f-l

This CS/IA technology may be suitable to develop a large

number of diverse-compounds of 5 to screen and identify

the suitable bioactive products.

^aHagemann’s ester 1{1} (1.0 mmol) reacted with aldehyde

2{23}-2{29} (0.5 mmol) in the presence of 20 mol % diamine 3l at 25

°C in DMSO for 0.5 to 24 h. ^bYield refers to the column-puriﬁed

product. ^cE/Z and dr ratio determined by NMR analysis. ^dReaction

stirred at 0 °C in DMF for 0.5 h.

Diversity-Oriented Synthesis of Highly Functional-

ized (E)-1,3-Dienes 7 via Diamine-Catalysis. After thor-

ough investigation of the diamine 3l-catalyzed CS, CS/IA,

and CS/IA/I reactions of Hagemann’s esters 1 with various

aldehydes 2, we further showed interest to screen aliphatic

aldehydes 2{23}-2{29} containing an R-hydrogen with

Hagemann’s ester 1{1} under diamine 3l-catalysis to look

at the effect of electronic factors of substrates on product

formation (Table 4). A series of aliphatic aldehydes 2{23}-

2{29} containing an R-hydrogen were reacted with 2.0 equiv

of Hagemann’s ester 1{1} catalyzed by 20 mol % of (S)-

diamine 3l at 25 °C for 0.5-24 h in DMSO (0.5 M).

Surprisingly, in all these reactions unexpected CS/I products

7 were furnished in moderate to very good yields with high

selectivity instead of CS products 4 as shown in Table 4.

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 863

Table 5. Optimization of the Direct Amine-Catalyzed Cascade

Claisen-Schmidt and Michael reaction of 1{1} and 2{30}^a

Interestingly, cascade reaction of optically pure (R)-(+)-

citronellal 2{23} with 2.0 equiv of Hagemann’s ester 1{1}

under 3l-catalysis in DMSO at 25 °C for 24 h furnished the

chiral functionalized (E)-1,3-diene (-)-7{1,23} in 65% yield

with >99:1 ratio of E:Z isomers and 1:1 ratio of diastereomers

as shown in Table 4, entry 1. Unexpected formation of

product (-)-7{1,23} from 1{1} and 2{23} via 3l-catalysis

can be explained through cascade Claisen-Schmidt/isomer-

ization (CS/I) reactions, and further reaction mechanism is

discussed in the mechanistic insights. Diamine-catalyzed CS/I

reaction of optically pure opposite enantiomer (S)-(-)-

citronellal 2{24} with simple Hagemann’s ester 1{1} in

DMSO at 25 °C for 24 h furnished the chiral functionalized

(E)-1,3-diene (+)-7{1,24} in 65% yield with >99:1 ratio of

E:Z isomers and 1:1 ratio of diastereomers as shown in Table

4, entry 2. The generality of the diamine-catalyzed CS/I

reaction of Hagemann’s ester 1{1} with chiral aliphatic

aldehyde was conﬁrmed by one more example with dimethyl

2-(3-oxo-1-phenylpropyl)malonate [93% ee, (-)-2{25}]

containing an R-hydrogen under 3l-catalysis, which furnished

the expected highly substituted chiral (E)-1,3-diene (+)-

7{1,25} in 50% yield with >99:1 ratio of E:Z isomers and

1:1 ratio of diastereomers as shown in Table 4, entry 3.

^aReactions were carried out in solvent (0.16 M) with the 2.0 equiv

of Hagemann’s ester 1{1} to 37% aqueous formaldehyde 2{30} in the

presence of 20 mol % catalyst. ^bYield refers to the column-puriﬁed

product. ^c1:1 ratio of ester 1{1} and 37% aqueous formaldehyde 2{30}

was used.

After successful demonstration of diamine-catalyzed cas-

cade CS/I reaction of 1{1} with chiral aldehydes 2{23}-

2{25}, we further investigated the scope and limitations of

the cascade CS/I reaction with a range of achiral aliphatic

aldehydes 2{26}-2{29} containing an R-hydrogen under

L-diamine-catalysis in DMSO at the ambient conditions to

test the diversity nature of the CS/I reaction (Table 4).

Cascade CS/I reaction of ester 1{1} with 3-phenylpropi-

onaldehyde 2{26} under 3l-catalysis for 17 h furnished the

achiral (E)-1,3-diene 7{1,26} in 80% yield with >99:1 ratio

of E:Z isomers as shown in Table 4, entry 4. In a similar

manner, cascade CS/I reaction of butyraldehyde 2{27} and

propionaldehyde 2{28} with 2.0 equiv of Hagemann’s ester

1{1} under 3l-catalysis in DMSO at 25 °C for 24/12 h

furnished the achiral (E)-1,3-dienes 7{1,27} in 50% yield

with >99:1 ratio of E:Z isomers and 7{1,28} in 70% yield

with >99:1 ratio of E:Z isomers, respectively as shown in

Table 4, entries 5/6. Interestingly, cascade CS/I reaction of

Hagemann’s ester 1{1} with acetaldehyde 2{29} under 3l-

catalysis in DMSO is not a clean reaction, but the same

reaction in DMF at 0 °C for 0.5 h furnished the only CS

product 4{1,29} in 40% yield with 1:>99 ratio of E:Z isomers

instead of expected 1,3-diene 7{1,29} as shown in Table 4,

entry 7.

Table 6. Synthesis of Dienones 8 via Direct Amine-Catalyzed

Cascade Claisen-Schmidt/Michael Reactions^{a b}

,

^aSee Experimental Section. ^bYield refers to the column puriﬁed

product.

Amine-induced cascade CS/I reaction is ﬁrst time to

observe, and certainly this CS/I technology is suitable to

develop a large number of diverse-compounds of 7 to screen

and identify the suitable intermediates for the bioactive and

natural product synthesis.

and 6). Interestingly, reaction of 37% aqueous formaldehyde

2{30} with 2.0 equiv of Hagemann’s ester 1{1} under proline

3a-catalysis in DMSO at 25 °C for 24 h furnished the

functionalized bis-enone 8{1,30} in 55% yield with >99%

de as shown in Table 5, entry 1. Unexpected formation of

product 8{1,30} from 1{1} and 2{30} via 3a-catalysis can

be explained through cascade Claisen-Schmidt/Michael (CS/

M) reactions and further information on the reaction mech-

anism is discussed in the mechanistic insights. Diversity-

oriented high-yielding one-pot synthesis of 8 through amine-

catalysis is very much needed because functionalized bis-

Diversity-Oriented Synthesis of Highly Functional-

ized bis-Enones 8 via Piperidine-Catalysis. After the

investigation of the amino acid- or amine 3-catalyzed CS,

CS/IA, CS/IA/I, and CS/I reactions of Hagemann’s esters

1{1}-1{19} with various aldehydes 2{1}-2{29}, we were

further interested to screen simple formaldehyde 2{30} with

Hagemann’s ester 1{1} under amine 3-catalysis (Tables 5

864 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Table 7. Sequential Combination of Cascade Knoevenagel/

enones 8 would be suitable intermediates for the synthesis

of terpenoid natural products.¹⁰

Michael/Aldol Condenasation/Decarboxylation and Cascade

Claisen-Schmidt/Iso-Aromatization Reactions in One-Pot^{a b}

,

For the high-yielding one-pot synthesis of bis-enone

8{1,30} from simple substrates 1{1} and 2{30}, we further

screened catalyst and solvent effect on the cascade CS/M

reaction as shown in Table 5. The cascade CS/M reaction

of 1{1} and 2{30} under glycine 3c-catalysis is similar to

3a-catalysis, but the same reaction under pyrrolidine 3d-

catalysis furnished the product 8{1,30} with improved yield

(76%) as shown in Table 5, entries 2-4. DMSO looks like

a better solvent for cascade CS/M reaction of 1{1} and 2{30}

compared to DMF under 3d-catalysis (Table 5, entry 5). The

CS/M reaction yield is increased to 80% under the piperidine

3e-catalysis in DMSO for 1 h at 25 °C as shown in Table 5,

entry 6. Diamine-catalyzed CS/M reaction of 2{30} with

1{1} in DMSO at 25 °C for 1 h furnished the functionalized

bis-enone 8{1,30} in 72% yield with >99% de, which is not

superior compared to piperidine-catalysis as shown in Table

5, entry 7. The optimized reaction conditions for bis-enone

synthesis involved piperidine 3e-catalysis at 25 °C in DMSO

with 2 equiv of 1{1} and 2{30}, which furnished the cascade

product 8{1,30} in 80% yield with >99% de (Table 5, entry

6).

^aSee Experimental Section. ^bYield refers to the column puriﬁed

product. ^cSecond reaction performed at 70 °C for 14 h.

Generality of the piperidine-catalyzed CS/M reaction of

formaldehyde 2{30} with Hagemann’s esters 1 was con-

ﬁrmed by two more examples with t-butyl ester 1{3} and

methyl ester 1{2} under 3e-catalysis, which furnished the

expected highly substituted bis-enones 8{3,30} in 20% yield

with >99% de and 8{2,30} in 60% yield with >99% de as

shown in Table 6.

combination of two cascade K/M/A/DC and CS/IA reactions

under piperidine-/diamine-catalysis was demonstrated by

three more examples with good yields as shown in Table 7,

and this one-pot synthetic strategy will show much impact

on the synthesis of functionalized phenols 5 from simple

substrates.

Applications of the Push-Pull Dienamine Chemistry.

A. Development of Sequential One-Pot Combination of

Cascade Reactions Based on the CS/IA Platform. Func-

tionalized phenols 5 are an important class of compounds,

which are widely used as intermediates in the pharmaceu-

ticals and natural product synthesis as shown in Chart 1.⁴

As such, the development of new and more general one-pot

catalytic methods for their high-yielding preparation is of

signiﬁcant interest.⁶Hagemann’s esters 1{1}-1{19} were

synthesized in good yields with minor modiﬁcations of

known methods of direct piperidine- or KO^tBu-catalyzed

cascade Knoevenagel/Michael/aldol condensation/decarboxy-

lation (K/M/A/DC) reactions of alkyl acetoacetates and

aldehydes (Table 7).^7bHerein, we utilized the direct sequen-

tial combination of piperidine-catalyzed cascade K/M/A/DC

and diamine-catalyzed cascade CS/IA of ethyl acetoacetate,

aldehydes and 4-nitrobenzaldehyde to furnish the function-

alized phenols 5 with high yields in one-pot (Table 7).

Cascade K/M/A/DC reaction of 2 equiv of ethyl acetoac-

etate and benzaldehyde 2{2} under piperidine-catalysis in

EtOH at 80 °C for 5-6 h furnished the expected Hagemann’s

ester 1{14} with >99% conversion, which on in situ treatment

with 4-nitrobenzaldehyde 2{1} at 25 °C in the same solvent

did not furnished the expected product 5{14,1} in good yield;

but removing the solvent EtOH by vacuum pump and adding

solvent DMSO, 20 mol % of diamine 3l and 4-nitrobenzal-

dehyde 2{1} to the reaction mixture of cascade K/M/A/DC

furnished the expected product 5{14,1} in 80% yield as

shown in Table 7, entry 1. Successful sequential one-pot

B. Base-Catalyzed Iso-Aromatization of CS Products.

After successful synthesis of functionalized push-pull phe-

nols 5 from Hagemann’s esters 1 and benzaldehydes 2

containing an electron-withdrawing group under diamine-

catalysis, we thought of testing how much the basic nature

of amine 3 and electronic nature of substrates 1/2 will control

the iso-aromatization of CS products 4 as shown in Scheme

2. Interestingly, treatment of pure CS product 4{1,1} with

20 mol % of diamine 3l in DMSO at 25 °C for 0.5 h

furnished the phenol 5{1,1} in 96% yield via iso-aromati-

zation as shown in Scheme 2. In a similar manner, treatment

of pure CS product 4{1,2} with 20 mol % of piperidine 3e

in DMSO at 70 °C for 12 h furnished the phenol 5{1,2} in

86% yield via iso-aromatization as shown in Scheme 2.

Unfortunately, reaction of 1{1} with 2{2} under pyrrolidine

3d-catalysis at 70 °C in DMSO or DMF furnished the only

CS product 4{1,2} in 30% yields without CS/IA (Scheme

2). These results suggest that the basic nature of amine 3,

the electronic nature of substrates 1/2, and also the reaction

temperature are important for the iso-aromatization of CS

products 4.

With an efﬁcient piperidine-catalyzed iso-aromatization

protocol in hand, we continued our investigation for the

synthesis of functionalized phenols 5 from Hagemann’s esters

1{1}/1{14} and benzaldehyde 2{2} under piperidine-

catalysis in DMSO at 70 °C for 18 h through cascade CS/

IA reactions as shown in Scheme 2. Cascade products 5{1,2}

and 5{14,2} were furnished in moderate yields without

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 865

Scheme 2. Controlled Experiments on Base-Induced

Iso-Aromatization of 3-Arylidene-Hagemann’s Ester 4 via

Amine-Catalysis

very good yields with high selectivity, and this method will

be showing much impact on the synthesis of functionalized

small molecules with quaternary carbon as shown in Schemes

3 and 4. Highly substituted 2-methyl-2H-chromenes 13 and

14 type compounds have gained importance in recent years

as they would be good starting materials and intermediates

for the synthesis of biologically active compounds, for

example, precocene insect growth regulators B, melatonin

receptor agonists C, anticancer agents D, and NMDA

antagonists E.⁵

Sequential cascade K/M/A/DC/CS/IA reaction of 2.0 equiv

of ethyl acetoacetate with 1.5 equiv of 4-nitrobenzaldehyde

2{1} under 35 mol % of piperidine-catalysis followed by

20 mol % of diamine-catalysis furnished the compound

5{18,1} with >99% conversion, which on in situ treatment

with allyl bromide {1} at 25 °C for 24-28 h furnished the

chemoselectively K/M/A/DC/CS/IA/A product 15{18,1,1}

with 60% yield as shown in Scheme 3. Claisen rearrangement

of 15{18,1,1} in DCB at 160-180 °C for 24 h furnished

the expected allylated-phenol 15′{18,1,1} in good yield,

which on O-allylation with allyl bromide {1} and O-

propargylation with propargyl bromide {2} under K₂CO₃in

DMSO at 25 °C for 24-28 h furnished the functionalized

diene 9{18,1,1,1} in 55% yield and enyne 9{18,1,1,2} in

55% yield, respectively. Interestingly, RCM reaction of diene

9{18,1,1,1} using 2 mol % of Grubbs’ ﬁrst generation

catalyst [Cl₂RudCHPh(PCy₃)₂] in CH₂Cl₂at 25 °C for 2-3

h furnished the benzo[b]oxepine 10{18,1,1,1} in >99%

conversion, which on in situ treatment with 2.0 equiv of

tBuOK in DMSO at 25 °C for 3 h furnished the function-

alized (Z)-2-(buta-1,3-dienyl)phenol 11{18,1,1,1} in only

56% yield through cascade base-induced ring-opening (BIRO)

and benzylic oxidation (BO)¹¹reactions in one-pot with

>99% Z-selectivity (result not shown in Scheme 3). But the

same sequential cascade RCM/BIRO/BO reactions of

9{18,1,1,1} under the 2 mol % of Grubbs’ second generation

catalyst followed by treatment with 2.0 equiv of tBuOK

furnished the functionalized (Z)-2-(buta-1,3-dienyl)phenol

11{18,1,1,1} in improved yield (75%) with >99% Z-

selectivity as shown in Scheme 3. Herein, we also tested

the in situ BIRO reaction induced by 2.0 equiv of NaH, but

reaction yield (66%) is not superior as compared to tBuOK

as base (result not shown in Scheme 3). Further reaction of

11{18,1,1,1} in DMF at 130-140 °C for 12 h furnished the

substituted 2-methyl-2H-chromene 13{18,1,1,1} in 65% yield

via [1,7]-SHS reaction as shown in Scheme 3. We envisioned

the optimized condition to be addition of 2 equiv of tBuOK

to the mixture of in situ generated 10{18,1,1,1} in DMSO

at 25 °C to furnish substituted (Z)-2-(buta-1,3-dienyl)phenol

11{18,1,1,1} in 75% yield with >99% Z-selectivity, which

on further heating in DMF at 130-140 °C for 12 h furnished

the substituted 2-methyl-2H-chromene 13{18,1,1,1} in 65%

yield (Scheme 3).

showing much of electronic factors in CS/IA reaction as

shown in Scheme 2. Functionalized phenols are of consider-

able importance in a variety of industries. These compounds

5 are widespread elements in natural products and have

attracted much attention from a wide area of science,

including physical chemistry, medicinal chemistry, natural

product chemistry, synthetic organic chemistry, and polymer

science.⁴As such, the development of new and more general

catalytic methods for their preparation is of signiﬁcant

interest, and our presently developed cascade chemistry will

be useful to develop a library of substituted phenols in very

good yields with high selectivity.

C. Sequential Cascade Synthesis of Substituted 2-Meth-

yl-2H-Chromenes through MCC Reactions Based on

CS/IA Platform. Stereoselective and economical synthesis

of highly functionalized 2-methyl-2H-chromenes is an

evergreen task in synthetic organic chemistry.⁵As part of

our research program to engineer direct multicatalysis

cascade (MCC) reactions in a sequential manner to deliver

the highly functionalized molecules and also based on the

demand of pharmaceutical applications, we extended the two-

component cascade K/M/A/DC/CS/IA and CS/IA reactions

into novel piperidine-/diamine-/K₂CO₃- or glycine-/piperi-

dine-/K₂CO₃-catalyzed three-component K/M/A/DC/CS/

IA/A and CS/IA/A reaction of ethyl acetoacetate, 4-nitroben-

zaldehyde 2{1}, and allyl bromide {1} or Hagemann’s esters

1{1}/1{14}, benzaldehydes 2{1}/2{2}, and allyl bromide

{1}, respectively, in one-pot, and the resulting products 15

were converted into 2-methyl-2H-chromenes 13 and 14 with

very good yields via four novel synthetic steps [Claisen

rearrangement, O-allylation or O-propargylation, RCM/

BIRO/BO or RCM/BIRO and [1,7]-SHS] as shown in

Schemes 3/4. MCC products 13 and 14 were constructed in

With the optimized reaction conditions in hand, the

scope of the ruthenium- and base-induced RCM/BIRO/

BO sequential one-pot reactions was investigated with

variety of functionalized enyne 9 and dienes 9 as shown

in Schemes 3 and 4. Interestingly, enyne metathesis

followed by base-induced ring-opening and benzylic

866 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Scheme 3. Rapid Five-step Synthesis of Highly Functionalized 2-Methyl-2H-chromenes via Sequential Combination of

Multi-catalysis Cascade Reactions

Scheme 4. Rapid Six-step Synthesis of Highly Functionalized 2-Methyl-2H-chromenes via Sequential Combination of

Multi-catalysis Cascade Reactions

oxidation of enyne 9{18,1,1,2} furnished the expected

product (Z)-2-(buta-1,3-dienyl)phenol 11{18,1,1,2} in

good yield, which on further treatment with silica gel in

CHCl₃at 25 °C for 5 h furnished the 2-methyl-2H-

chromene 13{18,1,1,2} in 50% yield with quaternary

carbon (Scheme 3).

To demonstrate the further scope of the ruthenium- and

base-induced RCM/BIRO/BO sequential one-pot reactions

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 867

and also to test the role of electronic factors in BO reactions,

we synthesized simple dienes 9{1,1,1,1}, 9{14,1,1,1},

9{1,2,1,1}, and 9{14,2,1,1} from corresponding Hagemann’s

esters 1{1}/1{14}, benzaldehydes 2{1}/2{2}, and allyl

bromide {1} through CS/IA/A, Claisen rearrangement/O-

allylation sequence with good yields as shown in Scheme 4.

Sequential one-pot treatment of dienes 9{1,1,1,1}/9{14,1,1,1}

containing single p-nitro group on phenyl rings with 2 mol

% of Grubbs’ ﬁrst generation catalyst followed by treatment

with 2.0 equiv of tBuOK furnished the functionalized (Z)-

2-(buta-1,3-dienyl)phenols 11{1,1,1,1}/11{14,1,1,1} in 60/

65% yield, respectively, with >99% Z-selectivity via RCM/

BIRO/BO reactions, which are transformed into substituted

2-methyl-2H-chromenes 13{1,1,1,1}/13{14,1,1,1} in 60/80%

yields respectively via [1,7]-SHS reaction induced by heat

as shown in Scheme 4. Interestingly, RCM reaction of diene

9{1,2,1,1} using 2 mol % of Grubbs’ ﬁrst generation catalyst

in CH₂Cl₂at 25 °C for 5 h furnished the benzo[b]oxepine

10{1,2,1,1} in >99% conversion, which on in situ treatment

with 2.0 equiv of tBuOK in DMSO at 25 °C for 3 h furnished

the functionalized (Z)-2-(buta-1,3-dienyl)phenol 12{1,2,1,1}

in 92% yield through BIRO reaction in one-pot with >99%

Z-selectivity without oxidation of benzylic methylene (Scheme

4). In a similar manner, we synthesized one more function-

alized (Z)-2-(buta-1,3-dienyl)phenol 12{14,2,1,1} in 90%

yield through sequential RCM/BIRO reactions in one-pot

with >99% Z-selectivity without oxidation of benzylic

methylene (Scheme 4). Two of the RCM/BIRO products,

(Z)-2-(buta-1,3-dienyl)phenols 12{1,2,1,1}/12{14,2,1,1} were

convertedintothesubstituted2-methyl-2H-chromenes14{1,2,1,1}/

14{14,2,1,1} in 75/80% yields, respectively, via [1,7]-SHS

reaction induced by heat as shown in Scheme 4. As revealed

in Schemes 3 and 4, oxidation of benzylic methylenes is

completely controlled by electronic factors of substrates

under the base-catalysis with air. For the pharmaceutical

applications, the diversity-oriented library of small molecules

13/14 could be generated by using our presently discovered

MCC technology.

reactive push-pull dienamines 17{1,a} and 17{1,d} were

established through NMR experiments as shown in Scheme

6 and Supporting Information, Figure S1. We favor mech-

anism 1 based on in situ NMR experiments.

As shown in Scheme 6, in situ generation of novel

push-pull dienamine 17{1,a} from 1{1} and 3a is a slow

process as compared to 17{1,d} from 1{1} and 3d, and a

similar kind of reactivity pattern is represented in their

reactions also as shown in Tables 1-7. Highly selective in

situ formation of push-pull dienamines 17{1,a} and 17{1,d}

over the Barbas dienamines (2-amino-1,3-butadienes)¹²

27{1,a} and 27{1,d} were established based on NMR and

mass analysis as shown in Scheme 6. Presently discovered

relatively stable push-pull dienamine 17{1,a} formation

from Hagemann’s ester 1{1} and amino acid, L-proline 3a

is very good supportive to the recently proposed enamine

mechanism in proline-catalyzed asymmetric reactions¹³as

revealed in Scheme 6 and Supporting Information, Figure

S1.

Next, the possible mechanism for regioselective synthesis

of cascade CS/IA/I and CS/I products, ortho-vinylated

phenols 5 and (E)-1,3-dienes 7 through reaction of Hage-

mann’s ester 1{1}, aldehydes 2, and diamine 3l is illustrated

in mechanism 3 and 4 of Scheme 5. Treatment of in situ

generated CS product, push-pull trienone (arylidene-Hage-

mann’s ester) 4 under the amine-catalysis furnished the ortho-

vinylated phenol 5 via IA/I reaction. In a similar manner,

reaction of in situ generated CS product, push-pull dienone

(alkylidene-Hagemann’s ester) 4 under the base-catalysis

furnished the unexpected (E)-1,3-dienes 7 via I reaction as

shown in Scheme 5. These two kinds of isomerizations (I)

on 4 through diamine-catalysis were completely controlled

by electronic factors and acidic nature of hydrogens as shown

in Scheme 5.

The possible reaction mechanism for BIRO/BO/[1,7]-SHS

reaction sequence is illustrated in mechanism 5 of Scheme

5. First, reaction of 10 with KO^tBu generates the carbanion

because of the acidic nature of allylic/benzylic hydrogen,

which will further rearrange into the ring opened product

cis-11 (X ) O) and cis-12 (X ) H) through concerted

pathway. In a similar time, dibenzylic methylene oxidized

to ketone with air under base-catalysis in compounds 10 via

electron transfer reactions may be due to the highly electron

withdrawing nature of both aryls connected to methylene.

A [1,7]-sigmatropic shift of the phenolic hydrogen in cis-11

(X ) O) and cis-12 (X ) H) gave to the ortho-quinone

methides 25 (X ) O) and 26 (X ) H), which rapidly cyclizes

to 13 (X ) O) and 14 (X ) H) under the standard reaction

conditions to regain the thermodynamic stability through oxa-

6π electrocyclization or [3,3]-rearrangement.

Mechanistic Insights. The possible reaction mechanisms

for the synthesis of push-pull oleﬁns 4, push-pull phenols

5, (E)-1,3-dienes 7, and 2-methyl-2H-chromenes 13/14 via

dienamine-catalysis are illustrated in Schemes 5 and 6 and

Supporting Information, Figure S1. First, reaction of amino

acids 3a-c, or amines (pyrrolidine 3d, piperidine 3e, or (S)-

diamine 3l) with the aldehyde 2 generates the imine cation

18, an excellent electrophile that undergoes Mannich type

reactions with the in situ generated push-pull dienamine

17 or dienolate 22{1} of Hagemann’s ester 1{1} to generate

Mannich products 19 and 23, respectively, as shown in

mechanism 1 and 2 of Scheme 5 (for the purpose of clarity,

we represented 3d as catalyst). Elimination reaction of

pyrrolidinium ions 20 and 24 would furnish selectively E/Z

mixtures of push-pull oleﬁn 4. Base-induced, electronically-

and temperature-controlled iso-aromatization (IA) of the CS

product 4 would then give push-pull phenol 5 as shown in

mechanism 1 and 2 of Scheme 5. The formation of imine

ion 18 and CS product 4 via Mannich and amine-elimination

reactions supports our hypothesis that aldol products did not

form in these reactions and also formation of the highly

Conclusions

In summary, we have developed the sequential one-pot

combination of amino acid-, amine-, K₂CO₃-, [Ru]-, KO^tBu-,

or SiO₂-catalyzed direct cascade CS, CS/IA, CS/IA/I, CS/I,

M, CS/M, K/M/A/DC/CS/IA, K/M/A/DC/CS/IA/A, RCM/

BIRO/BO, RCM/BIRO, and [1,7]-SHS reactions from simple

substrates. This experimentally simple cascade approach can

be used to construct a diversity-oriented library of highly

868 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Scheme 5. Proposed Reaction Mechanisms for Push-Pull Dienamine Chemistry

substituted push-pull oleﬁns, phenols, and 2-methyl-2H-

chromenes with good yields in a selective fashion. We have

demonstrated the in situ generation and application of novel

push-pull dienamines in sequential cascade chemistry.

Further work is in progress to utilize an asymmetric version

of this cascade processes and also for the application in total

synthesis of natural products.

in Table 2. The crude reaction mixture was worked up with

aqueous NH₄Cl solution, and the aqueous layer was extracted

with dichloromethane (2 × 20 mL). The combined organic

layers were dried (Na₂SO₄), ﬁltered, and concentrated. The

pure products 4{1,2}-{1,19} were obtained by column

chromatography (silica gel, mixture of hexane/ethyl acetate).

Data for Ethyl 2-Methyl-4-oxo-3-(4-triﬂuoromethyl-

benzylidene)-cyclohex-1-enecarboxylate (4{1,6}). Light

yellow solid, yield 81%. Mp 54 °C; IR (neat): ν_max2984,

1703 (CdO and O-CdO), 1456, 1324, 1241, 1168, 1126,

1064, 1017, and 838 cm^-1; ¹H NMR (400 MHz, CDCl₃, 2:1

ratio of E/Z isomers): δ 7.59 (4H, d, J ) 8.4 Hz), 7.53 (2H,

d, J ) 8.0 Hz), 7.44-7.40 (3H, m), 6.95 (1H, s, oleﬁnic-H),

4.26 (4H, q, J ) 7.2 Hz, 2 × OCH₂CH₃), 2.83-2.78 (4H,

m), 2.68 (2H, t, J ) 6.4 Hz), 2.47 (2H, t, J ) 6.4 Hz), 2.24

(3H, s, oleﬁnic-CH₃), 1.94 (3H, s, oleﬁnic-CH₃), 1.33 (3H,

t, J ) 7.2 Hz, OCH₂CH₃), 1.32 (3H, t, J ) 7.2 Hz,

Experimental Section

General Experimental Procedures for the MCC

Reactions. Glycine-Catalyzed Claisen-Schmidt Reac-

tions. In an ordinary glass vial equipped with a magnetic

stirring bar, to 0.5 mmol of the Hagemann’s ester 1{1} was

added 1.0 mL of DMSO solvent, then the catalyst glycine

3c (0.1 mmol, 7.5 mg) was added, and then 0.5 mmol of

aldehyde 2{2}-2{19} was added in one-portion, and the

reaction mixture was stirred at 25 °C for the time indicated

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 869

Scheme 6. NMR Experiment for the Detection of In Situ Generated Push-Pull Dienamines 17

OCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃, DEPT-135, 2:1

ratio of E/Z isomers): δ 201.4 (C, CdO), 200.5 (C, CdO),

168.4 (C, O-CdO), 167.1 (C, O-CdO), 142.6 (C), 139.9

(C), 139.5 (C), 139.3 (C), 138.9 (C), 138.1 (C), 134.8 (CH),

134.4 (CH), 131.2 (C), 130.8 (CF₃, q, J ) 33.0 Hz), 129.9

(2 × CH), 129.6 (C), 129.4 (2 × CH), 125.2 (2 × CH, q, J

) 3.0 Hz), 124.9 (2 × CH, q, J ) 3.0 Hz), 122.6 (C), 122.4

(C), 60.9 (CH₂, OCH₂CH₃), 60.8 (CH₂, OCH₂CH₃), 39.3

(CH₂), 34.7 (CH₂), 27.2 (CH₂), 23.1 (CH₂), 20.4 (CH₃,

oleﬁnic-CH₃), 16.5 (CH₃, oleﬁnic-CH₃), 14.2 (2 × CH₃,

OCH₂CH₃); LRMS m/z 338.30 (M⁺), calcd C₁₈H₁₇F₃O₃

338.1130; Anal. Calcd for C₁₈H₁₇F₃O₃(338.11): C, 63.90;

H, 5.06. Found: C, 63.85; H, 5.12%.

Hz), 7.28 (2H, br d, J ) 8.4 Hz), 7.20 (2H, br d, J ) 8.0

Hz), 6.88 (1H, s, oleﬁnic-H), 4.28 (2H, q, J ) 7.2 Hz,

OCH₂CH₃), 4.27 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 2.86-2.78

(4H, m), 2.70 (2H, t, J ) 6.4 Hz), 2.48 (2H, t, J ) 6.4 Hz),

2.25 (3H, t, J ) 2.0 Hz, oleﬁnic-CH₃), 2.00 (3H, t, J ) 1.2

Hz, oleﬁnic-CH₃), 1.36 (3H, t, J ) 7.2 Hz, OCH₂CH₃), 1.34

(3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃,

DEPT-135, 3.5:1 ratio of E/Z isomers): δ 201.4 (C, CdO),

200.8 (C, CdO), 168.4 (C, O-CdO), 167.1 (C, O-CdO),

143.1 (C), 140.5 (C), 138.1 (C), 137.1 (C), 135.5 (CH), 135.0

(CH), 134.4 (C), 134.0 (C), 131.6 (2 × CH), 131.3 (2 ×

CH), 131.2 (2 × CH), 131.1 (2 × CH), 130.6 (C), 128.8

(C), 123.6 (C), 122.8 (C), 60.8 (CH₂, OCH₂CH₃), 60.7 (CH₂,

OCH₂CH₃), 39.3 (CH₂), 34.8 (CH₂), 27.2 (CH₂), 23.1 (CH₂),

20.3 (CH₃, oleﬁnic-CH₃), 16.6 (CH₃, oleﬁnic-CH₃), 14.24

(CH₃, OCH₂CH₃), 14.19 (CH₃, OCH₂CH₃); LRMS m/z

349.00 (M + H⁺), calcd C₁₇H₁₇BrO₃348.0361; Anal. Calcd

for C₁₇H₁₇BrO₃(348.03): C, 58.47; H, 4.91. Found: C, 58.41;

H, 4.95%.

Pyrrolidine-Catalyzed Claisen-Schmidt and Michael

Reactions. In an ordinary glass vial equipped with a

magnetic stirring bar, to 0.5 mmol of the Hagemann’s ester

1{1} was added 1.0 mL of DMF solvent, then the catalyst

pyrrolidine 3d (0.1 mmol, 8.33 µL) was added, and then

0.5 mmol of aldehyde 2{2}-2{20} was added in one-portion,

and the reaction mixture was stirred at 25 °C for the time

indicated in Table 2. The crude reaction mixture was worked

up with aqueous NH₄Cl solution, and the aqueous layer was

extracted with dichloromethane (2 × 20 mL). The combined

organic layers were dried (Na₂SO₄), ﬁltered, and concen-

trated. The pure products 4 and 6 were obtained by column

chromatography (silica gel, mixture of hexane/ethyl acetate).

Data for Ethyl 3-(4-Bromobenzylidene)-2-methyl-4-

oxo-cyclohex-1-enecarboxylate (4{1,15}). Yellow liquid,

yield 35%. IR (neat): ν_max1692 (CdO and O-CdO), 1594,

(S)-1-(2-Pyrrolidinylmethyl)pyrrolidine-Catalyzed Clai-

sen-Schmidt Reactions. In an ordinary glass vial equipped

with a magnetic stirring bar, to 0.5 mmol of the Hagemann’s

ester 1{1} was added 1.0 mL of DMF solvent, then the

catalyst (S)-1-(2-pyrrolidinylmethyl)pyrrolidine 3l (0.1 mmol,

16.3 µL) was added, and then 0.5 mmol of aldehyde 2{2}-

2{21} was added in one-portion, and the reaction mixture

was stirred at 25 °C for the time indicated in Table 2. The

crude reaction mixture was worked up with aqueous NH₄Cl

solution, and the aqueous layer was extracted with dichlo-

romethane (2 × 20 mL). The combined organic layers were

dried (Na₂SO₄), ﬁltered, and concentrated. The pure products

1

1270, 1242, 1196, 1055, 652 cm^-1; H NMR (400 MHz,

CDCl₃, 3.5:1 ratio of E/Z isomers): δ 7.56 (1H, s, oleﬁnic-

H), 7.50 (2H, br d, J ) 8.4 Hz), 7.44 (2H, br d, J ) 8.4

870 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

4 were obtained by column chromatography (silica gel,

mixture of hexane/ethyl acetate).

for the time indicated in Table 4. The crude reaction mixture

was worked up with aqueous NH₄Cl solution, and the

aqueous layer was extracted with dichloromethane (2 × 20

mL). The combined organic layers were dried (Na₂SO₄),

ﬁltered, and concentrated. The pure cascade products 7 were

obtained by column chromatography (silica gel, mixture of

hexane/ethyl acetate).

Data for Ethyl 2-Methyl-3-(3-methylbut-2-enylidene)-

4-oxo-cyclohex-1-enecarboxylate (4{1,21}). Red liquid,

yield 60%. IR (neat): ν_max2978, 2930, 1713 (CdO), 1684

1

(O-CdO), 1597, 1447, 1372, 1246 cm^-1; H NMR (400

MHz, CDCl₃, 1:5 ratio of E/Z isomers, major isomer): δ 7.53

(1H, d, J ) 12.8 Hz), 6.29 (1H, d, J ) 12.8 Hz), 4.26 (2H,

q, J ) 7.2 Hz, OCH₂CH₃), 2.66 (2H, br t, J ) 6.4 Hz), 2.43

(2H, t, J ) 6.4 Hz), 2.38 (3H, s, oleﬁnic-CH₃), 1.98 (3H, s),

1.96 (3H, s), 1.34 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR

(100 MHz, CDCl₃, DEPT-135, 1:5 ratio of E/Z isomers,

major isomer): δ 201.5 (C, CdO), 167.7 (C, O-CdO),

150.9 (C), 143.9 (C), 133.5 (C), 133.2 (CH), 128.1 (C), 122.3

(CH), 60.5 (CH₂, OCH₂CH₃), 35.9 (CH₂), 27.6 (CH₃), 23.1

(CH₂), 21.6 (CH₃), 18.9 (CH₃, oleﬁnic CH₃), 14.3 (CH₃,

OCH₂CH₃); LRMS m/z 249.15 (M + H⁺), calcd C₁₅H₂₀O₃

248.1412; Anal. Calcd for C₁₅H₂₀O₃(248.14): C, 72.55; H,

8.12. Found: C, 72.61; H, 8.08%.

(S)-1-(2-Pyrrolidinylmethyl)pyrrolidine-Catalyzed Cas-

cade Claisen-Schmidt and Iso-Aromatization Reac-

tions. In an ordinary glass vial equipped with a magnetic

stirring bar, to 0.5 mmol of the Hagemann’s esters 1{1}-

{19} was added 1.0 mL of DMSO solvent, then the catalyst

(S)-1-(2-pyrrolidinylmethyl)pyrrolidine 3l (0.1 mmol, 16.3

µL) was added, and then 0.5 mmol of aldehydes 2{1}-{22}

was added in one-portion, and the reaction mixture was

stirred at 25 °C for the time indicated in Table 3. The crude

reaction mixture was worked up with aqueous NH₄Cl

solution, and the aqueous layer was extracted with dichlo-

romethane (2 × 20 mL). The combined organic layers were

dried (Na₂SO₄), ﬁltered, and concentrated. The pure cascade

products 5 were obtained by column chromatography (silica

gel, mixture of hexane/ethyl acetate).

Data for Ethyl (3R)-3-(3,7-dimethylocta-1,6-dienyl)-2-

methyl-4-oxo-cyclohex-2-enecarboxylate (7{1,23}). Color-

less oily liquid, yield 65%. [R]²⁵_D) -43.6 (c 0.54, CHCl₃);

IR (neat): ν 2960, 2912, 1730 (CdO), 1673 (O-CdO),

^m1^ax

1157 cm^-1; H NMR (400 MHz, CDCl₃, 1:1 mixture of

diastereomers, at 25 °C): δ 6.02 (2H, d, J ) 16.0 Hz), 5.76

(2H, dd, J ) 16.0, 8.0 Hz), 5.08 (2H, t, J ) 7.2 Hz), 4.19

(4H, q, J ) 7.2 Hz, 2 × OCH₂CH₃), 3.33 (2H, t, J ) 4.8

Hz), 2.64-2.55 (2H, m), 2.38 (2H, td, J ) 16.8, 5.6 Hz),

2.27-2.18 (4H, m), 2.05 (6H, s, 2 × oleﬁnic-CH₃), 1.98

(4H, m), 1.66 (6H, s, 2 × CH₃), 1.58 (6H, s, 2 × CH₃), 1.35

(4H, m), 1.27 (6H, t, J ) 7.2 Hz, 2 × OCH₂CH₃), 1.02 (6H,

d, J ) 6.8 Hz, 2 × CHCH₃); ¹³C NMR (100 MHz, CDCl₃,

DEPT-135, 1:1 mixture of diastereomers, at 25 °C): δ 197.3

(2 × C, CdO), 172.2 (2 × C, O-CdO), 149.6 (2 × C),

143.6 (CH), 143.5 (CH), 134.9 (2 × C), 131.2 (2 × C), 124.5

(2 × CH), 120.5 (2 × CH), 61.2 (2 × CH₂, OCH₂CH₃),

48.1 (CH), 48.0 (CH), 37.5 (2 × CH), 36.9 (2 × CH₂), 35.22

(CH₂), 35.16 (CH₂), 25.8 (2 × CH₂), 25.7 (2 × CH₃, oleﬁnic-

CH₃), 25.2 (2 × CH₂), 21.5 (2 × CH₃, oleﬁnic-CH₃), 20.4

(2 × CH₃, oleﬁnic-CH₃), 17.6 (2 × CH₃), 14.1 (2 × CH₃,

1

OCH₂CH₃); H NMR (400 MHz, CDCl₃, 1:1 mixture of

diastereomers, at -40 °C): δ 6.07 (1H, d, J ) 16.4 Hz),

6.06 (1H, d, J ) 16.4 Hz), 5.70 (1H, dd, J ) 8.0, 4.0 Hz),

5.66 (1H, dd, J ) 8.4, 4.0 Hz), 5.11 (2H, t, J ) 6.4 Hz),

4.22 (4H, q, J ) 7.2 Hz, 2 × OCH₂CH₃), 3.41 (2H, br s),

2.66-2.58 (2H, m), 2.45 (2H, td, J ) 17.2, 4.8 Hz),

2.27-2.24 (4H, m), 2.10 (6H, s, 2 × oleﬁnic-CH₃),

2.03-1.95 (4H, m), 1.70 (6H, s, 2 × CH₃), 1.61 (6H, s, 2 ×

CH₃), 1.38-1.30 (10H, m), 1.05 (6H, d, J ) 6.4 Hz, 2 ×

CHCH₃); ¹³C NMR (100 MHz, CDCl₃, DEPT-135, 1:1

mixture of diastereomers, at -40 °C): δ 198.16 (C, CdO),

198.13 (C, CdO), 172.4 (C, O-CdO), 172.3 (C, O-CdO),

150.5 (2 × C), 143.7 (CH), 143.6 (CH), 134.8 (2 × C), 131.6

(2 × C), 124.2 (2 × CH), 120.4 (CH), 120.3 (CH), 61.4 (2

× CH₂, OCH₂CH₃), 47.8 (CH), 47.6 (CH), 37.6 (CH), 37.5

(CH), 36.7 (2 × CH₂), 35.1 (CH₂), 34.9 (CH₂), 25.84 (2 ×

CH₂), 25.80 (2 × CH₃, oleﬁnic-CH₃), 25.0 (CH₂), 24.9 (CH₂),

22.01 (CH₃, oleﬁnic-CH₃), 21.98 (CH₃, oleﬁnic-CH₃), 20.60

(CH₃, oleﬁnic-CH₃), 20.55 (CH₃, oleﬁnic-CH₃), 17.7 (2 ×

CH₃), 14.1 (2 × CH₃, OCH₂CH₃); LRMS m/z 319.30 (M +

H⁺), calcd C₂₀H₃₀O₃318.2195; Anal. Calcd for C₂₀H₃₀O₃

(318.21): C, 75.43; H, 9.50. Found: C, 75.52; H, 9.48%.

Data for Ethyl 4-Hydroxy-2-methyl-3-(4-triﬂuoro-

methylbenzyl)-benzoate (5{1,6}). White solid, yield 70%.

Mp 120 °C; IR (neat): ν_max3347 (O-H), 1681 (O-CdO),

1

1580, 1326, 1262, 1156, 1112, 1068, 646 cm^-1; H NMR

(400 MHz, CDCl₃, at 25 °C): δ 7.72 (1H, d, J ) 8.4 Hz),

7.48 (2H, d, J ) 8.0 Hz), 7.22 (2H, d, J ) 8.0 Hz), 6.75

(1H, d, J ) 8.8 Hz); 6.74(1H, s, O-H), 4.34 (2H, q, J ) 7.2

Hz, OCH₂CH₃), 4.17 (2H, s, CH₂Ar), 2.47 (3H, s, Ar-CH₃),

1.38 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR (100 MHz,

CDCl₃, DEPT-135, at 40 °C): δ 168.8 (C, O-CdO), 157.3

(C), 144.2 (C), 141.1 (C), 130.7 (CH), 128.4 (2 × CH), 128.3

(CF₃, q, J ) 32.0 Hz), 126.0 (C), 125.2 (2 × CH, q, J ) 4.0

Hz), 123.8 (C), 123.0 (C), 112.6 (CH), 60.9 (CH₂,

OCH₂CH₃), 31.6 (CH₂, CH₂Ar), 17.0 (CH₃, Ar-CH₃), 14.2

(CH₃, OCH₂CH₃); LRMS m/z 339.00 (M + H⁺), calcd

C₁₈H₁₇F₃O₃338.1130; Anal. Calcd for C₁₈H₁₇F₃O₃(338.11):

C, 63.90; H, 5.06. Found: C, 63.85; H, 5.11%.

(S)-1-(2-Pyrrolidinylmethyl)pyrrolidine-Catalyzed Cas-

cade Claisen-Schmidt and Isomerization Reactions. In

an ordinary glass vial equipped with a magnetic stirring bar,

to 1.0 mmol of the Hagemann’s ester 1{1} was added 1.0

mL of DMSO solvent, then the catalyst (S)-1-(2-pyrrolidi-

nylmethyl)pyrrolidine 3l (0.1 mmol, 16.3 µL) was added,

and then 0.5 mmol of aldehyde 2{23}-2{29} was added in

one-portion, and the reaction mixture was stirred at 25 °C

Piperidine-Catalyzed Cascade Claisen-Schmidt and

Michael Reactions. In an ordinary glass vial equipped with

a magnetic stirring bar, to 0.5 mmol of the Hagemann’s ester

1 was added 1.5 mL of DMSO solvent, then the catalyst

piperidine 3e (0.05 mmol, 4.93 µL) was added, and then

0.25 mmol of formaldehyde 2{30} (37 wt % solution in

water) was added in one-portion, and the reaction mixture

was stirred at 25 °C for the time indicated in Table 6. The

crude reaction mixture was worked up with aqueous NH₄Cl

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 871

solution, and the aqueous layer was extracted with dichlo-

romethane (2 × 20 mL). The combined organic layers were

dried (Na₂SO₄), ﬁltered, and concentrated. The pure cascade

products 8 were obtained by column chromatography (silica

gel, mixture of hexane/ethyl acetate).

C₂₃H₂₁NO₅391.1420; Anal. Calcd for C₂₃H₂₁NO₅(391.14):

C, 70.58; H, 5.41; N, 3.58. Found: C, 70.45; H, 5.45; N,

3.65%.

Base-Induced Iso-Aromatization of 3-Arylidene Hage-

mann’s Esters: Synthesis of 5{1,1}. In an ordinary glass

vial equipped with a magnetic stirring bar, to 0.3 mmol of

the 2-methyl-3-(4-nitrobenzylidene)-4-oxo-cyclohex-1-en-

ecarboxylic acid ethyl ester 4{1,1} was added 0.6 mL of

DMSO solvent, then the catalyst (S)-1-(2-pyrrolidinylmeth-

yl)pyrrolidine 3l (0.06 mmol, 9.7 µL) was added, and the

reaction mixture was stirred at 25 °C for 0.5 h as indicated

in Scheme 2. The crude reaction mixture was worked up

with aqueous NH₄Cl solution, and the aqueous layer was

extracted with dichloromethane (2 × 20 mL). The combined

organic layers were dried (Na₂SO₄), ﬁltered, and concen-

trated. Pure cascade product 5{1,1} was obtained by column

chromatography (silica gel, mixture of hexane/ethyl acetate).

Data for Diethyl 3,3′-Methylenebis(2-methyl-4-oxocy-

clohex-2-enecarboxylate) (8{1,30}). Colorless oily liquid,

yield 80%. IR (neat): ν_max2928, 2859, 1728 (CdO), 1667

1

(O-CdO), 1622, 1512, 1451, 1372, 1157, 1042 cm^-1; H

NMR (400 MHz, CDCl₃, >99:1 ratio of diastereomers): δ

4.18 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 4.17 (2H, q, J ) 7.2

Hz, OCH₂CH₃), 3.44 (2H, d, J ) 12.8 Hz), 3.28 (1H, t, J )

4.8 Hz), 3.27 (1H, t, J ) 4.8 Hz), 2.59-2.50 (2H, m),

2.40-2.32 (2H, m), 2.26-2.13 (4H, m), 2.00 (3H, s, oleﬁnic-

CH₃), 1.95 (3H, s, oleﬁnic-CH₃), 1.28 (3H, t, J ) 7.2 Hz,

OCH₂CH₃), 1.27 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR

(100 MHz, CDCl₃, DEPT-135, >99:1 ratio of diastereomers):

δ 197.0 (C, CdO), 196.9 (C, CdO), 172.2 (C, O-CdO),

172.1 (C, O-CdO), 150.8 (C), 150.7 (C), 135.8 (C), 135.7

(C), 61.1 (2 × CH₂, OCH₂CH₃), 48.2 (CH), 48.1 (CH), 34.6

(CH₂), 25.5 (CH₂), 25.3 (CH₂), 22.3 (CH₂), 21.8 (CH₂), 21.0

(2 × CH₃, oleﬁnic-CH₃), 14.1 (2 × CH₃, OCH₂CH₃); LRMS

m/z 377.25 (M + H⁺), calcd C₂₁H₂₈O₆376.1886; Anal. Calcd

for C₂₁H₂₈O₆(376.18): C, 67.00; H, 7.50. Found: C, 67.49;

H, 7.54%.

Synthesis of 5{1,2}. In an ordinary glass vial equipped

with a magnetic stirring bar, to 0.18 mmol of the 3-ben-

zylidene-2-methyl-4-oxo-cyclohex-1-enecarboxylic acid ethyl

ester 4{1,2} was added 0.36 mL of DMSO solvent, then the

catalyst piperidine 3e (0.036 mmol, 3.55 µL) was added, and

the reaction mixture was stirred at 70 °C for 12 h as indicated

in Scheme 2. The crude reaction mixture was worked up

with aqueous NH₄Cl solution, and the aqueous layer was

extracted with dichloromethane (2 × 20 mL). The combined

organic layers were dried (Na₂SO₄), ﬁltered, and concen-

trated. The pure cascade product 5{1,2} was obtained by

column chromatography (silica gel, mixture of hexane/ethyl

acetate).

Sequential Combination of Piperidine-Catalyzed Cas-

cade Knoevenagel/Michael/Aldol Condensation/Decar-

boxylation and (S)-1-(2-Pyrrolidinylmethyl)pyrrolidine-

Catalyzed Claisen-Schmidt/Iso-Aromatization Reactions

in One-Pot. To a stirred solution of ethyl acetoacetate (2.0

mmol) and aldehyde (1.0 mmol) in EtOH (2 mL) was added

a catalytic amount of piperidine 3e (0.35 mmol, 35 mol %)

and the reaction mixture was stirred at 80 °C for 5-6 h.

Solvent ethanol and piperidine was evaporated by vacuum

pump, then solvent DMSO (1 mL) was added, and catalyst

(S)-1-(2-pyrrolidinylmethyl)pyrrolidine 3l (0.1 mmol, 16.3

µL), aldehyde 2 (0.5 mmol) were added, and the reaction

mixture was stirred at 25 °C for 13-24 h. The crude reaction

mixture was worked up with aqueous NH₄Cl solution, and

the aqueous layer was extracted with dichloromethane (2 ×

20 mL). The combined organic layers were dried (Na₂SO₄),

ﬁltered, and concentrated. Pure one-pot products 5 were

obtained by column chromatography (silica gel, mixture of

hexane/ethyl acetate).

One-Pot Synthesis of 5{1,2} and 5{14,2}. In an ordinary

glass vial equipped with a magnetic stirring bar, to 1.0 mmol

of the Hagemann’s ester 1{1} or 1{14} was added 1.0 mL

of DMSO solvent, then the catalyst piperidine 3e (0.1 mmol,

9.87 µL) was added, and then 0.5 mmol of benzaldehyde

2{2} was added in one-portion, and the reaction mixture was

stirred at 70 °C for 18 h as indicated in Scheme 2. The crude

reaction mixture was worked up with aqueous NH₄Cl

solution, and the aqueous layer was extracted with dichlo-

romethane (2 × 20 mL). The combined organic layers were

dried (Na₂SO₄), ﬁltered, and concentrated. The pure cascade

products 5{1,2} and 5{14,2} were obtained by column

chromatography (silica gel, mixture of hexane/ethyl acetate).

Data for Ethyl 4-Benzyl-5-hydroxy-3-methyl-biphenyl-

Data for Ethyl 5-Hydroxy-3-methyl-4-(4-nitrobenzyl)-

biphenyl-2-carboxylate (5{14,1}). Liquid, yield 80%. IR

(neat): ν_max3403 (O-H), 2978, 2930, 1688 (O-CdO), 1597,

2-carboxylate (5{14,2}). Yellow liquid, yield 40%. IR (neat):

ν_max3403 (O-H), 2986, 2926, 1694 (O-CdO), 1589, 1452,

1263, 1173, 1053 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.35

(5H, br s), 7.30-7.27 (3H, m), 7.21-7.19 (3H, m); 6.68

(1H, br s, O-H), 4.11 (2H, s, CH₂Ar), 4.01 (2H, q, J ) 7.2

Hz, OCH₂CH₃), 2.30 (3H, s, Ar-CH₃), 0.92 (3H, t, J ) 7.2

Hz, OCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃, DEPT-135)

δ 170.4 (C, O-CdO), 154.5 (C), 140.7 (C), 139.9 (C), 139.2

(C), 136.4 (C), 128.5 (2 × CH), 128.2 (6 × CH), 127.3 (CH),

127.1 (C), 126.1 (CH), 124.8 (C), 114.4 (CH), 61.0 (CH₂,

OCH₂CH₃), 31.7 (CH₂, CH₂Ar), 16.8 (CH₃, Ar-CH₃), 13.6

(CH₃, OCH₂CH₃); LRMS m/z 347.00 (M + H⁺), calcd

C₂₃H₂₂O₃346.1569; Anal. Calcd for C₂₃H₂₂O₃(346.15): C,

79.74; H, 6.40. Found: C, 79.65; H, 6.47%.

1

1518, 1344, 1263, 1171, 1053 cm^-1; H NMR (400 MHz,

CDCl₃): δ 8.02 (2H, d, J ) 8.4 Hz), 7.28-7.24 (7H, m);

6.69 (1H, br s, O-H), 6.59 (1H, s, Ar-H), 4.12 (2H, s, CH₂Ar),

4.00 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 2.21 (3H, s, Ar-CH₃),

0.90 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR (100 MHz,

CDCl₃, DEPT-135) δ 170.9 (C, O-CdO), 154.8 (C), 148.0

(C), 146.1 (C), 140.4 (C), 140.3 (C), 136.2 (C), 128.9 (2 ×

CH), 128.1 (2 × CH), 128.0 (2 × CH), 127.4 (CH), 126.6

(C), 123.6 (C), 123.5 (2 × CH), 114.2 (CH), 61.3 (CH₂,

OCH₂CH₃), 31.6 (CH₂, CH₂Ar), 16.7 (CH₃, Ar-CH₃), 13.4

(CH₃, OCH₂CH₃); LRMS m/z 390.15 (M - H⁺), calcd

872 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Experimental Procedures for the Synthesis of Highly

Functionalized 2-Methyl-2H-Chromenes. The synthesis of

highly functionalized 2-methyl-2H-chromenes 13 and 14

from corresponding Hagemann’s esters 1 involves the

following ﬁve or six-step sequence.

was allylated by treatment with allyl bromide (121.0 mg,

1.0 mmol) and K₂CO₃(207.3 mg, 1.5 mmol) in DMSO (2

mL, 0.1 M) at room temperature for 14-18 h. The crude

reaction mixture was worked up with aqueous NH₄Cl

solution, and the aqueous layer was extracted with dichlo-

romethane (2 × 20 mL). The combined organic layers were

dried (Na₂SO₄), ﬁltered, and concentrated. Pure products 15

were obtained by column chromatography (silica gel, mixture

of hexane/ethyl acetate).

Sequential Combination of Piperidine-Catalyzed Cas-

cade Knoevenagel/Michael/Aldol Condensation/Decar-

boxylation, (S)-1-(2-Pyrrolidinylmethyl)pyrrolidine-Cata-

lyzed Cascade Claisen-Schmidt/Iso-Aromatization, and

K₂CO₃-Catalyzed Alkylation Reactions in One-Pot. To a

stirred solution of ethyl acetoacetate (2.0 mmol) and 4-ni-

trobenzaldehyde 2{1} (1.0 mmol) in EtOH (2 mL) was added

a catalytic amount of piperidine 3e (0.35 mmol, 35 mol %),

and the reaction mixture was stirred at 80 °C for 5-6 h.

Solvent ethanol and piperidine were evaporated by vacuum

pump, then solvent DMSO (1.0 mL) was added, and catalyst

(S)-1-(2-pyrrolidinylmethyl)pyrrolidine 3l (0.1 mmol, 16.3

µL), 4-nitrobenzaldehyde 2{1} (0.5 mmol) were added, and

the reaction mixture was stirred at 25 °C for 14 h. To the

crude reaction mixture were added 5 equiv of K₂CO₃and 2

equiv of allyl bromide {1}, and stirred at 25 °C for 24-28

h. The crude reaction mixture was worked up with aqueous

NH₄Cl solution, and the aqueous layer was extracted with

dichloromethane (2 × 20 mL). The combined organic layers

were dried (Na₂SO₄), ﬁltered, and concentrated. Pure product

15{18,1,1} is obtained by column chromatography (silica

gel, mixture of hexane/ethyl acetate).

Data for Ethyl 4-Allyloxy-3-benzyl-2-methyl-benzoate

(15{1,2,1}). Light yellow liquid, yield 55%. IR (neat): ν_max

2980, 1714 (O-CdO), 1649, 1591, 1454, 1051, 775 cm^-1;

¹H NMR (400 MHz, CDCl₃): δ 7.83 (1H, d, J ) 8.4 Hz),

7.26 (2H, t, J ) 5.2 Hz), 7.16 (1H, t, J ) 6.8 Hz), 7.14 (2H,

d, J ) 7.2 Hz), 6.81 (1H, d, J ) 8.4 Hz), 6.02-5.94 (1H,

m, oleﬁnic-H), 5.35 (1H, dd, J ) 17.2, 1.6 Hz, oleﬁnic-H),

5.25 (1H, dd, J ) 10.4, 1.6 Hz, oleﬁnic-H), 4.59 (2H, d, J

) 4.8 Hz, OCH₂CHdCH₂), 4.35 (2H, q, J ) 7.2 Hz,

OCH₂CH₃), 4.20 (2H, s, ArCH₂Ar), 2.53 (3H, s, Ar-CH₃),

1.40 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR (100 MHz,

CDCl₃, DEPT-135): δ 168.1 (C, O-CdO), 159.0 (C), 140.4

(C), 140.2 (C), 132.8 (CH), 130.2 (CH), 128.8 (C), 128.1 (2

× CH), 128.0 (2 × CH), 125.6 (CH), 123.9 (C), 117.2 (CH₂,

CH)CH₂), 108.6 (CH), 68.8 (CH₂, OCH₂CHdCH₂), 60.4

(CH₂, OCH₂CH₃), 31.6 (CH₂), 16.9 (CH₃, Ar-CH₃), 14.3

(CH₃, OCH₂CH₃); LRMS m/z 311.00 (M + H⁺), calcd

C₂₀H₂₂O₃310.1569; Anal. Calcd for C₂₀H₂₂O₃(310.15): C,

77.39; H, 7.14. Found: C, 77.56; H, 7.08%.

Data for Ethyl 5-Allyloxy-3-methyl-4′-nitro-4-(4-ni-

trobenzyl)-biphenyl-2-carboxylate (15{18,1,1}). Yellow

liquid, yield 60%. IR (neat): ν_max2980, 1722 (O-CdO),

C-Allylation through Claisen Rearrangement. O-Ally-

lated compounds (1.0 mmol) and solvent DCB (2.0 mL, 0.5

M) were taken in a sealed glass tube, and the mixture was

heated at 160-180 °C under N₂for 24 to 28 h. Upon cooling

the reaction mixture to room temperature, the mixture was

diluted with dichloromethane (10 mL), washed with aqueous

NH₄Cl solution (2 mL) and brine (2 mL). The separated

organic layers were dried (Na₂SO₄), ﬁltered, and concentrated

under reduced pressure. Pure C-allylated phenols were

obtained by column chromatography (silica gel, mixture of

hexane/ethyl acetate).

1

1597, 1520, 1456, 1014, 736 cm^-1; H NMR (400 MHz,

CDCl₃): δ 8.22 (2H, d, J ) 8.4 Hz), 8.08 (2H, d, J ) 8.4

Hz), 7.54 (2H, d, J ) 8.8 Hz), 7.31 (2H, d, J ) 8.4 Hz),

6.79 (1H, s, Ar-H), 6.01-5.89 (1H, m, oleﬁnic-H), 5.30 (1H,

d, J ) 17.2 Hz, oleﬁnic-H), 5.23 (1H, d, J ) 10.8 Hz,

oleﬁnic-H), 4.61 (2H, d, J ) 4.8 Hz, OCH₂CHdCH₂), 4.25

(2H, s, ArCH₂Ar), 4.04 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 2.30

(3H, s, Ar-CH₃), 0.98 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C

NMR (100 MHz, CDCl₃, DEPT-135): δ 169.2 (C, O-CdO),

156.8 (C), 147.7 (C), 147.6 (C), 147.0 (C), 146.1 (C), 137.8

(C), 136.3 (C), 132.3 (CH), 129.1 (2 × CH), 128.8 (2 ×

CH), 126.9 (CH), 123.4 (2 × CH), 123.3 (2 × CH), 117.6

(CH₂, CH)CH₂), 110.5 (CH), 69.0 (CH₂, OCH₂CHdCH₂),

61.1 (CH₂, OCH₂CH₃), 31.7 (CH₂), 16.7 (CH₃, Ar-CH₃), 13.5

(CH₃, OCH₂CH₃); LRMS m/z 475.00 (M - H⁺), calcd

C₂₆H₂₄N₂O₇476.1584; Anal. Calcd for C₂₆H₂₄N₂O₇(476.15):

C, 65.54; H, 5.08; N, 5.88. Found: C, 65.48; H, 5.12; N,

5.96%.

Data for Ethyl 6-Allyl-5-hydroxy-3-methyl-4′-nitro-4-

(4-nitrobenzyl)-biphenyl-2-carboxylate (15′{18,1,1}). Light

yellow liquid, yield 60%. IR (neat): ν_max3512 (O-H), 2935,

1720 (O-CdO), 1637, 1599, 1520, 1444, 1014, 856 cm^-1;

¹H NMR (400 MHz, CDCl₃): δ 8.24 (2H, d, J ) 8.8 Hz),

8.13 (2H, d, J ) 8.4 Hz), 7.43 (2H, d, J ) 8.4 Hz), 7.34

(2H, d, J ) 8.4 Hz), 5.96-5.80 (1H, m, oleﬁnic-H), 5.54

(1H, s, O-H), 5.23 (1H, d, J ) 10.4 Hz, oleﬁnic-H), 5.10

(1H, d, J ) 17.6 Hz, oleﬁnic-H), 4.23 (2H, s, ArCH₂Ar),

3.92 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 3.15 (2H, d, J ) 4.8

Hz, CH₂CHdCH₂), 2.24 (3H, s, Ar-CH₃), 0.93 (3H, t, J )

7.2 Hz, OCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃, DEPT-

135) δ 169.2 (C, O-CdO), 153.8 (C), 147.6 (C), 147.3 (C),

146.3 (C), 145.8 (C), 137.0 (C), 134.8 (CH), 134.0 (C), 130.3

(2 × CH), 128.9 (2 × CH), 128.2 (C), 125.5 (C), 123.6 (2

× CH), 123.1 (2 × CH), 120.0 (C), 117.6 (CH₂, CH)CH₂),

61.0 (CH₂, OCH₂CH₃), 32.2 (CH₂), 32.1 (CH₂,

CH₂CHdCH₂), 16.8 (CH₃, Ar-CH₃), 13.7 (CH₃, OCH₂CH₃);

LRMS m/z 477.00 (M + H⁺), calcd C₂₆H₂₄N₂O₇476.1584;

Sequential Cascade Claisen-Schmidt/Iso-Aromatiza-

tion/Alkylation Reactions in One-Pot. In an ordinary glass

vial equipped with a magnetic stirring bar, to 0.5 mmol of

the Hagemann’s ester 1{1} or 1{14} was added 1.0 mL of

DMSO solvent, then the catalyst glycine 3c (0.1 mmol, 7.5

mg) was added, and then 0.5 mmol of benzaldehydes 2{1}

or 2{2} was added in one-portion, and the reaction mixture

was stirred at 25 °C for the 48 h. To the reaction mixture,

catalyst piperidine 3e (0.1 mmol) was added, and the reaction

mixture was stirred at 70 °C for 12-24 h as indicated in

Scheme 4. The in situ generated corresponding phenols 5

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 873

Anal. Calcd for C₂₆H₂₄N₂O₇(476.15): C, 65.54; H, 5.08; N,

5.88. Found: C, 65.41; H, 5.12; N, 5.81%.

(100 MHz, CDCl₃, DEPT-135): δ 168.7 (C, O-CdO), 156.1

(C), 147.3 (C), 146.4 (C), 145.1 (C), 137.8 (C), 136.0 (CH),

133.8 (C), 132.5 (C), 132.0 (C), 130.7 (2 × CH), 129.3 (C),

128.8 (2 × CH), 123.7 (2 × CH), 122.8 (2 × CH), 115.9

(CH₂, CH)CH₂), 78.1 (C, C’CH), 76.2 (CH, CtCH), 61.9

(CH₂, OCH₂CtCH), 61.1 (CH₂, OCH₂CH₃), 33.0 (CH₂),

31.8 (CH₂, CH₂CHdCH₂), 16.9 (CH₃, Ar-CH₃), 13.7 (CH₃,

OCH₂CH₃); LRMS m/z 515.00 (M + H⁺), calcd C₂₉H₂₆N₂O₇

514.1740; Anal. Calcd for C₂₉H₂₆N₂O₇(514.17): C, 67.70;

H, 5.09; N, 5.44. Found: C, 67.85; H, 5.15; N, 5.61%.

RCM Reactions: Method A. A 10 mL oven-dried round-

bottom ﬂask equipped with a stirring bar was charged with

diene 9 (0.2 mmol) and Grubbs’ ﬁrst generation catalyst (3.3

mg, 0.004 mmol, 2 mol %) in dry CH₂Cl₂(4 mL, 0.05 M),

and the reaction mixture was stirred under N₂at room

temperature for 3 to 5 h. Solvent CH₂Cl₂was distilled off at

ambient pressure, the crude reaction mixture was directly

loaded on silica gel column, and pure RCM products 10 were

obtained by column chromatography (silica gel, mixture of

hexane/ethyl acetate).

Method A: O-Allylation. The corresponding C-allylated

phenols 15′ (1.0 mmol) were allylated by treatment with allyl

bromide {1} (242.0 mg, 2.0 mmol) and K₂CO₃(414.6 mg,

3.0 mmol) in DMSO (10 mL, 0.1 M) at room temperature

for 24 h. The crude reaction mixture was worked up with

aqueous NH₄Cl solution, and the aqueous layer was extracted

with dichloromethane (2 × 20 mL). The combined organic

layers were dried (Na₂SO₄), ﬁltered, and concentrated. Pure

products 9 were obtained by column chromatography (silica

gel, mixture of hexane/ethyl acetate).

Data for Ethyl 6-Allyl-5-allyloxy-3-methyl-4′-nitro-4-

(4-nitrobenzyl)-biphenyl-2-carboxylate (9{18,1,1,1}). Light

yellow liquid, yield 92%. IR (neat): ν_max2924, 1726

1

(O-CdO), 1597, 1520, 1186, 852 cm^-1; H NMR (400

MHz, CDCl₃): δ 8.24 (2H, d, J ) 8.4 Hz), 8.15 (2H, d, J )

8.4 Hz), 7.45 (2H, d, J ) 8.4 Hz), 7.31 (2H, d, J ) 8.4 Hz),

6.02-5.91 (1H, m, oleﬁnic-H), 5.78-5.65 (1H, m, oleﬁnic-

H), 5.33 (1H, d, J ) 17.2 Hz, oleﬁnic-H), 5.22 (1H, d, J )

10.4 Hz, oleﬁnic-H), 4.91 (1H, d, J ) 10.0 Hz, oleﬁnic-H),

4.66 (1H, d, J ) 16.8 Hz, oleﬁnic-H), 4.23 (4H, s,

OCH₂CHdCH_2,ArCH₂Ar), 3.92 (2H, q, J ) 7.2 Hz,

OCH₂CH₃), 3.22 (2H, d, J ) 5.2 Hz, CH₂CHdCH₂), 2.15

(3H, s, Ar-CH₃), 0.94 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C

NMR (100 MHz, CDCl₃, DEPT-135): δ 168.9 (C, O-CdO),

156.9 (C), 147.5 (C), 147.2 (C), 146.4 (C), 145.3 (C), 137.8

(C), 136.2 (CH), 133.7 (C), 132.9 (CH), 132.0 (C), 131.7

(C), 130.7 (2 × CH), 129.2 (C), 128.8 (2 × CH), 123.8 (2

× CH), 122.8 (2 × CH), 117.3 (CH₂, CH)CH₂), 115.8 (CH₂,

CH)CH₂), 75.0 (CH₂, OCH₂CHdCH₂), 61.1 (CH₂,

OCH₂CH₃), 32.7 (CH₂), 31.7 (CH₂, CH₂CHdCH₂), 16.9

(CH₃, Ar-CH₃), 13.7 (CH₃, OCH₂CH₃); LRMS m/z 516.00

(M⁺), calcd C₂₉H₂₈N₂O₇516.1897; Anal. Calcd for

C₂₉H₂₈N₂O₇(516.18): C, 67.43; H, 5.46; N, 5.42. Found: C,

67.35; H, 5.36; N, 5.58%.

Method B: O-Propargylation. The enyne 9{18,1,1,2}

was prepared by treating the corresponding C-allylated

phenol 15′{18,1,1} (1.0 mmol) with propargyl bromide {2}

(238.0 mg, 2.0 mmol) and K₂CO₃(414.6 mg, 3.0 mmol) in

DMSO (10 mL, 0.1 M) at room temperature for 24 h. The

crude reaction mixture was worked up with aqueous NH₄Cl

solution, and the aqueous layer was extracted with dichlo-

romethane (2 × 20 mL). The combined organic layers were

dried (Na₂SO₄), ﬁltered, and concentrated. Pure product

9{18,1,1,2} was obtained by column chromatography (silica

gel, mixture of hexane/ethyl acetate).

Data for Ethyl 8-Methyl-9-(4-nitrobenzyl)-6-(4-nitrophe-

nyl)-2,5-dihydro-benzo[b]oxepine-7-carboxylate (10{18,

1,1,1}). Light yellow liquid, yield 95%. IR (neat): ν_max2918,

1718 (O-CdO), 1643, 1597, 1562, 1520, 1444, 1014, 858

1

cm^-1; H NMR (400 MHz, CDCl₃): δ 8.26 (2H, d, J ) 8.4

Hz), 8.14 (2H, d, J ) 8.4 Hz), 7.43 (2H, d, J ) 8.8 Hz),

7.34 (2H, d, J ) 8.4 Hz), 5.68-5.66 (1H, m, oleﬁnic-H),

5.40 (1H, d, J ) 11.2 Hz, oleﬁnic-H), 4.44 (2H, s,

OCH₂CHdCH), 4.25 (2H, s, ArCH₂Ar), 3.94 (2H, q, J )

7.2 Hz, OCH₂CH₃), 3.19 (2H, br s, CH₂CHdCH), 2.21 (3H,

s, Ar-CH₃), 0.95 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR

(100 MHz, CDCl₃, DEPT-135): δ 169.1 (C, O-CdO), 157.5

(C), 147.8 (C), 147.3 (C), 146.5 (C), 145.5 (C), 134.9 (C),

133.4 (C), 133.2 (C), 131.2 (C), 131.1 (C), 130.6 (2 × CH),

129.0 (2 × CH), 127.5 (CH), 125.0 (CH), 123.8 (2 × CH),

123.2 (2 × CH), 70.9 (CH₂, OCH₂CHdCH), 61.2 (CH₂,

OCH₂CH₃), 32.3 (CH₂), 27.0 (CH₂, CH₂CHdCH), 16.8

(CH₃, Ar-CH₃), 13.7 (CH₃, OCH₂CH₃); LRMS m/z 489.00

(M + H⁺), calcd C₂₇H₂₄N₂O₇488.1584; Anal. Calcd for

C₂₇H₂₄N₂O₇(488.15): C, 66.39; H, 4.95; N, 5.73. Found: C,

66.25; H, 4.88; N, 5.81%.

Method B. A 10 mL oven-dried round-bottom ﬂask

equipped with a stirring bar was charged with enyne

9{18,1,1,2} (0.2 mmol) and Grubbs’ ﬁrst generation catalyst

(8.3 mg, 0.01 mmol, 5 mol %) in dry CH₂Cl₂(4 mL, 0.05

M), and the reaction mixture was stirred under N₂at room

temperature for 24 h. Solvent CH₂Cl₂was distilled off at

ambient pressure, the crude reaction mixture was directly

loaded on silica gel column, and pure RCM product

10{18,1,1,2} was obtained by column chromatography (silica

gel, mixture of hexane/ethyl acetate).

Data for Ethyl 6-Allyl-3-methyl-4′-nitro-4-(4-nitrobenzyl)-

5-prop-2-ynyloxy-biphenyl-2-carboxylate (9{18,1,1,2}). Light

yellow liquid, yield 92%. IR (neat): ν_max3292 (CtC-H),

2982, 1724 (O-CdO), 1599, 1521, 1444, 1014, 734 cm^-1;

¹H NMR (400 MHz, CDCl₃): δ 8.23 (2H, d, J ) 8.4 Hz),

8.14 (2H, d, J ) 8.0 Hz), 7.44 (2H, d, J ) 8.4 Hz), 7.32

(2H, d, J ) 8.0 Hz), 5.73-5.69 (1H, m, oleﬁnic-H), 4.93

(1H, d, J ) 10.0 Hz, oleﬁnic-H), 4.69 (1H, d, J ) 16.8 Hz,

oleﬁnic-H), 4.45 (2H, s, OCH₂CtCH), 4.33 (2H, s,

ArCH₂Ar), 3.92 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 3.26 (2H,

s, CH₂CHdCH₂), 2.53 (1H, s, CtCH), 2.21 (3H, s,

Ar-CH₃), 0.94 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR

Data for Ethyl 8-Methyl-9-(4-nitrobenzyl)-6-(4-nitrophe-

nyl)-3-vinyl-2,5-dihydro-benzo[b]oxepine-7-carboxylate

(10{18,1,1,2}). Light yellow liquid, yield 55%. IR (neat):

ν_max2930, 1724 (O-CdO), 1599, 1520, 1452, 1059, 734,

702 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 8.28 (2H, d, J )

8.4 Hz), 8.17 (2H, d, J ) 8.0 Hz), 7.43 (2H, d, J ) 8.4 Hz),

7.36 (2H, d, J ) 8.4 Hz), 6.17 (1H, dd, J ) 18.0, 11.2 Hz,

oleﬁnic-H), 5.76 (1H, br s, oleﬁnic-H), 4.90 (1H, d, J ) 11.2

874 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6

Ramachary et al.

Hz, oleﬁnic-H), 4.77 (1H, d, J ) 18.0 Hz, oleﬁnic-H), 4.66

(2H, s, OCH₂), 4.23 (2H, s, ArCH₂Ar), 3.94 (2H, q, J ) 6.8

Hz, OCH₂CH₃), 3.27 (2H, d, J ) 4.8 Hz, CH₂CHdCH), 2.21

(3H, s, Ar-CH₃), 0.95 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C

NMR (100 MHz, CDCl₃, DEPT-135): δ 168.9 (C, O-CdO),

157.2 (C), 147.5 (C), 147.3 (C), 146.5 (C), 145.2 (C), 136.9

(CH), 135.9 (C), 134.7 (C), 133.4 (C), 132.6 (C), 131.4 (C),

130.8 (C), 130.5 (2 × CH), 129.0 (2 × CH), 127.1 (CH),

123.8 (2 × CH), 123.2 (2 × CH), 111.3 (CH₂, CHdCH₂),

70.6 (CH₂, OCH₂CHdCH), 61.2 (CH₂, OCH₂CH₃), 32.2

(CH₂), 26.7 (CH₂, CH₂CHdCH), 16.8 (CH₃, Ar-CH₃), 13.7

(CH₃, OCH₂CH₃); LRMS m/z 513.00 (M - H⁺), calcd

C₂₉H₂₆N₂O₇514.1740; Anal. Calcd for C₂₉H₂₆N₂O₇(514.17):

C, 67.70; H, 5.09; N, 5.44. Found: C, 67.85; H, 5.15; N,

5.56%.

Data for Ethyl 2,7-Dimethyl-8-(4-nitrobenzoyl)-5-(4-

nitrophenyl)-2H-chromene-6-carboxylate (13{18,1,1,1}).

Light yellow liquid, yield 65%. IR (neat): ν_max2928, 1724

1

(O-CdO), 1682, 1599, 1523, 1446, 1008, 706 cm^-1; H

NMR (400 MHz, CDCl₃): δ 8.34 (2H, d, J ) 8.0 Hz), 8.30

(2H, d, J ) 8.0 Hz), 8.08 (2H, d, J ) 7.6 Hz), 7.48 (2H, d,

J ) 8.0 Hz), 5.96 (1H, d, J ) 10.0 Hz, oleﬁnic-H), 5.63

(1H, dd, J ) 10.0, 2.4 Hz, oleﬁnic-H), 4.83 (1H, br s, OCH),

3.97 (2H, q, J ) 6.8 Hz, OCH₂CH₃), 2.17 (3H, s, Ar-CH₃),

1.18 (3H, d, J ) 6.4 Hz, OCHCH₃), 0.96 (3H, t, J ) 6.8

Hz, OCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃, DEPT-135):

δ 194.8 (C, CdO), 168.0 (C, O-CdO), 151.3 (C), 150.6

(C), 147.5 (C), 144.0 (C), 141.5 (C), 136.1 (C), 134.1 (C),

130.6 (2 × CH), 130.2 (2 × CH), 128.0 (CH), 128.0 (C),

127.1 (C), 123.9 (2 × CH), 123.3 (2 × CH), 119.9 (CH),

118.0 (C), 71.8 (CH, O-CH), 61.3 (CH₂, OCH₂CH₃), 20.9

(CH₃), 16.9 (CH₃, Ar-CH₃), 13.7 (CH₃, OCH₂CH₃); LRMS

m/z 502.35 (M⁺), calcd C₂₇H₂₂N₂O₈502.1376; Anal. Calcd

for C₂₇H₂₂N₂O₈(502.13): C, 64.54; H, 4.41; N, 5.58. Found:

C, 64.67; H, 4.38; N, 5.65%.

Base-Induced Ring-Opening (BIRO) Reactions. A 10

mL oven-dried round-bottom ﬂask equipped with a stir bar

was charged with 10 (0.2 mmol), dry DMSO (4 mL, 0.05

M), to that KOtBu (44.8 mg, 0.4 mmol, 2.0 equiv) was added

at 0 °C. The reaction mixture was stirred at 25 °C for 3-4

h. The crude reaction mixture was worked up with water,

and the aqueous layer was extracted with ether (2 × 20 mL).

The combined organic layers were dried (Na₂SO₄), ﬁltered,

and concentrated. Pure products 11 or 12 [11{18,1,1,2} is

an unstable product at 25 °C and which was rapidly

converted into 13{18,1,1,2}] were obtained by column

chromatography (silica gel, mixture of hexane/ethyl acetate).

Method B. To the crude compound 11{18,1,1,2}, 5 g of

silica (particle size 0.063-0.200 mm), 5 mL of CHCl₃was

added, and the reaction mixture stirred at 25 °C for 5.0 h.

Pure product 13{18,1,1,2} was obtained by column chro-

matography (silica gel, mixture of hexane/ethyl acetate).

Data for Ethyl 2,7-Dimethyl-8-(4-nitrobenzoyl)-5-(4-ni-

trophenyl)-2-vinyl-2H-chromene-6-carboxylate (13{18,1,1,2}).

Light yellow liquid, yield 50%. IR (neat): ν_max3106, 3079,

2982, 1707 (O-CdO), 1684, 1526, 1346, 1233, 1181, 845

Data for Ethyl 6-Buta-1,3-dienyl-5-hydroxy-3-meth

yl-4′-nitro-4-(4-nitrobenzoyl)-biphenyl-2-carboxylate (11-

{18,1,1,1}). Light yellow liquid, yield 75%. IR (neat): ν_max

3429 (O-H), 2980, 1722 (O-CdO), 1682, 1601, 1525, 1446,

1

cm^-1; H NMR (400 MHz, CDCl₃): δ 8.34 (2H, d, J ) 8.8

Hz), 8.31 (2H, d, J ) 8.8 Hz), 8.06 (2H, d, J ) 8.8 Hz),

7.49 (2H, d, J ) 8.8 Hz), 6.02 (1H, d, J ) 10.0 Hz, oleﬁnic-

H), 5.58 (1H, d, J ) 10.4 Hz, oleﬁnic-H), 5.54 (1H, d, J )

10.4 Hz, oleﬁnic-H), 5.09-5.05 (2H, m, oleﬁnic-H), 3.98

(2H, q, J ) 7.2 Hz, OCH₂CH₃), 2.17 (3H, s, Ar-CH₃), 1.29

(3H, s, CH₃), 0.96 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR

(100 MHz, CDCl₃, DEPT-135): δ 194.9 (C, CdO), 168.1

(C, O-CdO), 150.8 (C), 150.7 (C), 147.6 (C), 144.0 (C),

141.6 (C), 139.1 (CH), 136.1 (C), 134.1 (C), 130.9 (CH),

130.4 (CH), 130.3 (2 × CH), 129.1 (CH), 128.0 (C), 127.3

(C), 123.9 (2 × CH), 123.4 (2 × CH), 119.9 (CH), 117.7

(C), 115.5 (CH₂, CH)CH₂), 78.7 (C), 61.3 (CH₂, OCH₂CH₃),

26.8 (CH₃), 16.9 (CH₃, Ar-CH₃), 13.8 (CH₃, OCH₂CH₃);

LRMS m/z 529.00 (M + H⁺), calcd C₂₉H₂₄N₂O₈528.1153;

Anal. Calcd for C₂₉H₂₄N₂O₈(528.11): C, 65.90; H, 4.58; N,

5.30. Found: C, 65.78; H, 4.51; N, 5.45%.

1

1055, 736 cm^-1; H NMR (400 MHz, CDCl₃): δ 8.34 (2H,

d, J ) 8.4 Hz), 8.24 (2H, d, J ) 8.0 Hz), 8.07 (2H, d, J )

8.4 Hz), 7.41 (2H, d, J ) 8.4 Hz), 6.38 (1H, t, J ) 10.8 Hz,

oleﬁnic-H), 6.31-6.21 (1H, m, oleﬁnic-H), 5.90 (1H, s,

O-H), 5.79 (1H, d, J ) 10.8 Hz, oleﬁnic-H), 5.43 (1H, d, J

) 16.4 Hz, oleﬁnic-H), 5.36 (1H, d, J ) 10.0 Hz, oleﬁnic-

H), 3.97 (2H, q, J ) 7.2 Hz, OCH₂CH₃), 2.20 (3H, s,

Ar-CH₃), 0.95 (3H, t, J ) 7.2 Hz, OCH₂CH₃); ¹³C NMR

(100 MHz, CDCl₃, DEPT-135): δ 195.0 (C, CdO), 167.9

(C, O-CdO), 150.7 (C), 150.5 (C), 147.4 (C), 145.0 (C),

141.6 (C), 139.7 (C), 136.5 (CH), 134.6 (C), 131.4 (CH),

130.3 (4 × CH), 128.1 (C), 125.8 (C), 124.1 (2 × CH), 123.8

(CH₂, CH)CH₂), 123.2 (2 × CH), 121.8 (CH), 120.5 (C),

61.4 (CH₂, OCH₂CH₃), 17.2 (CH₃, Ar-CH₃), 13.7 (CH₃,

OCH₂CH₃); LRMS m/z 503.00 (M + H⁺), calcd C₂₇H₂₂N₂O₈

502.1376; Anal. Calcd for C₂₇H₂₂N₂O₈(502.13): C, 64.54;

H, 4.41; N, 5.58. Found: C, 64.71; H, 4.47; N, 5.48%.

Acknowledgment. This work was made possible by a

grant from the Department of Science and Technology

(DST), New Delhi [Grant DST/SR/S1/OC-65/2008]. K.R.,

A.B., and V.V.N. thank Council of Scientiﬁc and Industrial

Research (CSIR), New Delhi for their research fellowship.

We thank Dr. P. Raghavaiah for his help in X-ray structural

analysis.

[1,7]-Sigmatropic Hydrogen Shift Reactions: Method

A. Compounds 11 or 12 (0.1 mmol), DMF (1.0 mL, 0.1 M)

were taken in a glass sealed tube, and the mixture was heated

at 140 °C under N₂for 12 to 15 h. Upon cooling to room

temperature, the mixture was diluted with dichloromethane

(10 mL), washed with NH₄Cl solution (5 mL), and brine (5

mL). The separated organic layer was dried over anhydrous

Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

Pure products 13 or 14 were obtained by column chroma-

tography (silica gel, mixture of hexane/ethyl acetate).

Supporting Information Available. Complete experi-

mental procedures, compound characterization, X-ray crystal

structures and analytical data (¹H NMR, ¹³C NMR, HRMS

and elemental analysis) for all new compounds. Copies of

¹³C NMR spectrum of all new compounds. Crystallographic

Push-Pull Dienamine Chemistry

Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 875

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CC100104K

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Sequential one-pot combination of multireactions through multicatalysis: A general approach to rapid assembly of functionalized push-pull olefins, phenols, and 2-methyl-2 H-chromenes

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