Synthesis of 4-Quinolones: N,O-Bis(trimethylsilyl)acetamide-Mediated Cyclization with Cleavage of Aromatic C-O Bond

DOI: 10.1002/ejoc.201600178

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1,4-Dihydro-4-oxoquinolines

Synthesis of 4-Quinolones: N,O-Bis(trimethylsilyl)acetamide-

Mediated Cyclization with Cleavage of Aromatic C–O Bond

Ondřej Píša*^[a,b]and Stanislav Rádl^[a,b]

Abstract: The synthesis of 1,4-dihydro-4-oxoquinoline deriva- high yields of pure products following simple aqueous work-

tives (4-quinolones) based on a BSA [N,O-bis(trimethylsilyl)acet- up. The versatility of the approach is exemplified by a wide

amide]-mediated cyclization of substituted 1-(2-methoxy- range of 1-alkyl/aryl 3-carboxylates and 3-nitriles that have

phenyl)-3-(alkyl/arylamino)prop-2-en-1-ones is described. The been prepared. A crucial advantage of this approach is the fac-

reaction belongs to a rare set of cyclizations in which a methoxy ile availability of starting methoxy compounds enabling new

group serves as the leaving group. Reaction takes place by the synthetic possibilities as well as improved cost efficiency.

action of silylating agent under mild conditions and provides

Introduction

The 1,4-dihydro-4-oxoquinoline framework is present in many

therapeutically significant molecules; antibacterial,^[1]anti-

malarial,^[2]antimitotic^[3]or antitumor^[4]activities have all been

noted for members of the compound class. In the last two dec-

ades, the quinolone moiety has also been successfully incorpo-

rated into molecules of other potential drugs such as the HIV

integrase inhibitor elvitegravir (EVG, formerly GS-9137)^[5]

launched in 2012 and anticancer TOPO II inhibitor voreloxin

(vosaroxin) (Figure 1).^[6]

Scheme 1. Synthetic methods for the preparation of 4-quinolones.

The well-explored pathway a (Scheme 1) is known also as

the Gould–Jacobs reaction (a modification of the Conrad–Lim-

pach synthesis^[8]). This method is based on the reaction of a

suitable aromatic amine with the corresponding enol ether to

generate intermediate A, which is then cyclized under harsh

conditions to give the quinolone moiety.^[9]On the other hand,

reaction pathway b (Scheme 1) includes an Ar_Ncyclization of

intermediate B bearing F, Cl or NO₂leaving groups (see b in

the Scheme 1). This methodology was first reported in the syn-

thesis of ciprofloxacin and its analogues.^[10]This kind of trans-

formation is usually facilitated by potassium carbonate in DMF.

There are also reports detailing the use of the OMe group in-

stead of F, Cl or NO₂for pathway b (Scheme 1) although these

are quite scarce.^[11–14]Cleavages of aromatic C–O bonds are

generally more demanding than those of aromatic C–X (X = Cl,

Br, I) bonds due to their higher bond strengths.^[15]However,

such cleavage reactions have promise due, in large part, to the

ubiquity of phenol motifs in both natural products and com-

mercially available “man-made” materials.^[16]

Figure 1. Structures of elvitegravir and voreloxin.

Among the traditional methods for synthesis of 4-quinol-

ones, cyclocondensation of a preformed acyl A is, by far, the

most common strategy (Scheme 1).^[7]

[a] Zentiva k.s., Department of API Development,

U Kabelovny 130, 102 00 Prague, Czech Republic

E-mail: ondrej_pisa@centrum.cz

As part of our recent research efforts,^[12]K₂CO₃-mediated cy-

clization of substrate C (Scheme 2) bearing an OMe group in

the case of synthesis of elvitegravir (Figure 1) led to desired

product D accompanied by two undesired products F (from

elimination in the valinol moiety) and G (a transesterification

adduct) (Scheme 2). To suppress the formation of these side

products, TMS protection of the OH group on substrate C was

www.zentiva.cz

[b] UCT Prague, Department of Organic Chemistry,

Technická 5, 166 28 Prague 6 – Dejvice, Czech Republic

www.vscht.cz

Supporting information and ORCID(s) from the author(s) for this article are

available on the WWW under http://dx.doi.org/10.1002/ejoc.201600178.

Eur. J. Org. Chem. 2016, 2336–2350

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Scheme 2. Cyclization step in the synthesis of elvitegravir.

carried out. To our great delight, the use of BSA [N,O-bis(tri-

methylsilyl)acetamide],^[17]among other silylating agents, pro-

vided not only the desired TMS ether, but also very pure cy-

clized product E (Scheme 2) which could be employed directly

in the subsequent Negishi coupling step.^[12]To the best of our

knowledge, detailed study of this transformation has never

been described in the literature. In drawing a comparison be-

tween potassium carbonate and BSA as reagents for effecting

this transformation, signs of potentially different mechanisms

became apparent. Since BSA is a reagent associated with libera-

tion of neutral by-products,^[18]we decided to shed more light

on this undiscovered area of quinolone synthesis.

Table 1. Synthesis of precursors 4a–l from acetophenones.

Results and Discussion

In order to investigate the scope of this transformation and

electronic and substituent effects, a few series of suitable sub-

strates 4a–l (Table 1), 4m–u (Table 2) and 4v and 4w

(Scheme 3) were prepared; all bear an OMe group at the posi-

tion required for desired cyclization.

Starting from acetophenones 1a–c (Pathway A, Table 1), ꢀ-

keto esters 2a and 2b,c as a mixture of keto–enol tautomers

were prepared in good yields using sodium hydride as a base

(common bases like tBuOK, EtONa, MeONa failed to provide any

results) and dimethyl carbonate as an acylating reagent. Further

reaction of 2a–c with N,N-dimethylformamide dimethyl acetal

(DMFDMA) afforded expected acrylates 3a–c, respectively,

which were suitable for preparation of compounds 4a–l. In the

case of hydrazone 4h (X = N, Pathway B, Table 1), a different

approach was adopted. ꢀ-Keto ester 2a was treated with a di-

azonium salt generated in situ from aniline, thus providing de-

sired product 4h.

R³

R²

R¹

X

Conditions

MeOH, r.t.

Yield^[a][%]

4a

4b

4c

4d

4e

4f

4g

4h

4i

Et

OMe

H

C

96

93

79

80

94

66

76

77

95

67

96

70

Cpr^[b]

tBu

Ph

p-OBnC₆H₄

p-MeC₆H₄

p-CF₃C₆H₄

Ph

MeOH, r.t.

MeOH, 50 °C

toluene, 100 °C

MeOH/dioxane, 0 °C

MeOH, 50 °C

toluene, 100 °C

MeOH, r.t.

N

C

Cpr

Ph

Cpr

Ph

Me

H

4j

4k

4l

H

toluene, 100 °C

[a] All given yields are isolated. [b] Cpr = cyclopropyl.

For synthesis of ꢀ-keto esters 4m–u, an efficient protocol

employing acyl chlorides derived from 5a–c was developed. An

enolate generated in situ from EtOAc by the action of LiHDMS

was treated with corresponding acyl chlorides to provide the

ꢀ-keto–esters 6a–c (Table 2) with compounds 6b and 6c as a

above for the synthesis of 4a–l (Table 1), acrylates 4m–u were

obtained in moderate to high yields.

Acrylonitriles 4v and 4w were prepared from acetophenone

mixture of keto–enol tautomers. the procedure described 1a, which was transformed into isoxazole 8. Subsequent ring

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Table 2. Synthesis of precursors 4m–u from benzoic acids.

atures) and BSA's intolerance of protic solvents.^[11,13,14]DMF and

ACN were identified as the best solvent options.

Table 3. Comparison between BSA- and K₂CO₃-mediated cyclization of model

substrates 4a–d.

Entry

R

Cond.^[a][°C]

Yield^[a][%]

77 %

59 %

50 %

89 %

85 %

Cond.^[b][°C] Yield^[b][%]

1

Et

6 h, 95

6 h, 105

1 h, 80

24 h, r.t.

6 h, 115

6 h,115

24 h, r.t..

74

38

0

65

n.r.

2

3

4

5

Cpr^[c]

tBu

C₆H₅

[a] Cyclization reaction with BSA (2.3 equiv.) in DMF. [b] Cyclization reaction

with K₂CO₃(0.4 equiv.) in DMF; n.r.: no reaction. [c] Cpr = cyclopropyl.

All model compounds 4a–d (Table 3) cyclized smoothly

upon subjection to BSA under the tested conditions; 4d (R =

Ph) was found to be the most reactive being able to cyclize

even at room temperature. Aliphatic derivatives 4a–c (R = Et,

Cpr, tBu) gave cyclized products in yields that seem to correlate

with the bulkiness of the aliphatic part. Regarding the cycliza-

tion with K₂CO₃, 4a (R = Et) and 4d (R = Ph) also provided good

yields of cyclized products 14a and 14d. Conversely, reaction

of compound 4b (R = Cpr) gave only 38 % of cyclized product

14b and 4c (R = tBu) failed to react at all (see Table 3 for more

details). From the nature of the reagents, conditions and the

results (Table 3), it is evident that different mechanisms are at

play.

R¹

R²

Conditions

MeOH, r.t.

toluene, 100 °C

MeOH, r.t.

toluene, 100 °C

MeOH, r.t.

toluene, 95 °C

Yield^[a][%]

4m

4n

4o

4p

4q

4r

4s

4t

4u

6-OMe

5-OMe

5-Cl

Cpr^[b]

Ph

97

75

55

63

91

77

93

85

58

o-Cl-m-MeC₆H₃

Cpr^[b]

Ph

Mes^[c]

Cpr^[b]

5-Cl

Ph

o-Br-p-MeC₆H₃

[a] All given yields are isolated. [b] Cpr = cyclopropyl. [c] Mes = mesitylene.

BSA-mediated cyclization is a homogeneous reaction, and

for reasons explained by the plausible mechanism, requires

opening under basic conditions provided ꢀ-keto nitrile 9, which 2.3 equiv. of BSA (see Scheme 5 and the Supporting Informa-

gave acrylonitrile 10. This precursor afforded desired products tion for more details). Moreover, the BSA-mediation cyclization

4v and 4w upon treatment with amines using the protocol de- proceeds over a wide temperature range spanning from r.t. to

scribed above (Scheme 3).

105 °C and does not generate any crucial impurities. A valuable

benefit of this reaction is its amenability to aqueous work-up

which provides pure solid product in all cases with the excep-

tion of 4c (due to low conversion) (Table 6).

In an effort to understand the principal difference between

K₂CO₃- and BSA-mediated cyclizations (Table 3) leading to 4-

quinolones, compounds 4a–d were selected as model sub-

strates. Conditions were chosen with respect to previous data

Contrary to the BSA-mediated cyclization, cyclization in the

about K₂CO₃-mediated cyclization (which requires high temper- presence of K₂CO₃is heterogeneous. This particular cyclization

Scheme 3. Preparation of enamines 4v and 4w.

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was found to work catalytically with 0.4 of equiv. K₂CO₃in ac-

cordance with previously published work (see Scheme 5).^[14]

Moreover, in our hands, the reaction requires a high tempera-

ture of 115 °C in order to proceed with a reasonable rate.

For cyclization of 4d, the most reactive model compound, we

also used TMS-Cl and N,O-bis(trimethylsilyl)trifluoroacetamide

under various conditions. However, these conditions failed to

induce cyclization of 4d indicating that silylation itself is insuffi-

cient to promote substrate cyclization.

Table 4. Comparison of cyclization rates for 4h with different salts.^[a]

Entry

M

Solubility^[22][g/100g]

in DMSO at 25 °C

Relative reaction rate

1

2

3

Li

K

Na

41.1

20

30

2.4

1.2

1

An interesting observation was made during efforts to

broaden the model series with a decarboxylated analogue of

hydrazone 4h. We expected that the use of LiCl in DMSO/H₂O

at high temperature (Krapcho method^[19]) should have been

effective at inducing the desired transformation. However, these

conditions surprisingly afforded cyclized product 14h (Table 4)

in 40 % yield. Comparison with other salts revealed an en-

hanced performance of Li during the cyclization reaction

(Table 4). Taking into account the affinity of Li and Si for oxygen

atoms,^[20,21]we conclude that, generally speaking, the ability to

form enolates analogous to IB and IIB (Figure 2 and Scheme 5)

is beneficial to the cyclization process.

We also investigated the reaction mechanisms of BSA- and

K₂CO₃-mediated reactions using dynamic NMR experiments in-

volving substrate 4d. As the acrylate/acrylonitrile precursors

4a–w show E/Z isomerism, we could exploit this fact to confirm

our hypotheses. Spectrum B (Figure 2) depicts the E/Z ratio of

[a] Relative reaction rates as calculated from conversions measured by HPLC.

blets indicates the disappearance of E/Z isomerism and can be

explained by the dynamic equilibrium between corresponding

deprotonated structures IA and IIA (Figure 2, A). Spectrum C

(Figure 2) represents the reaction with BSA. Compared to the

reaction with K₂CO₃(Figure 2, A), we see a clear difference. Two

singlets represent two plausible silylated enolates IB and IIB

which then cyclize to desired product 14d over the course of

reaction.

More information about the mechanism has been revealed

by testing of substrates 4d–g bearing different substituents in

the respective para positions (Table 5).

The presence of electron-donating groups (EDG) in deriva-

starting compound 4d (two shifted doublets of NH protons por- tives 4d–f, respectively, is reflected in a higher reactivity in the

trays relevant E/Z isomerism). Spectrum A (Figure 2) implies the BSA-mediated reaction compared to 4g which bears the

situation after addition of K₂CO₃. In this case, the loss of dou- strongly electron accepting CF₃group (Table 5). EDG groups

Figure 2. NMR spectra of (A) Substrate 4d treated with K₂CO₃at 80 °C (B) Starting compound 4d at 60 °C. (C) Substrate 4d treated with BSA at 60 °C.

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Table 5. Conversion data for BSA- and K₂CO₃-mediated cyclization of 4d–

4g.^[a]

Table 6. Conversion data for BSA- and K₂CO₃-mediated cyclization of 4c and

15.^[a]

Entry

Substrate

Conversion [%]

(BSA, 12 h)

Conversion [%]

(K₂CO₃, 12 h)

Entry

Substrate

Conversion [%]

(BSA, 20 min)

Conversion [%]

(K₂CO₃, 60 min)

1

2

4c (R = OMe)

11 (R = F)

53

49

0

100

1

2

3

4

4e (R = OBn)

4d (R = H)

4f (R = CH₃)

4g (R = CF₃)

75

58

51

35

3

4

5

[a] Conversion was measured by HPLC (mobile phase: ACN/pH 3 phosphate

buffer).

[a] Conversions as determined on basis of HPLC analyses.

The moderate conversion of 4c achieved by the action of

BSA led us to hypothesize that this conversion is limited by the

collapse of the O–Si bond. It is well-known that this process

can be accelerated by the addition of F anion. Employing this

method, we were not able to improve the conversion, although

we surprisingly obtained cyclized ester 14c and a correspond-

ing amide 12 (Scheme 4), which is quite unusual. Striving to

exploit this fact, we optimized these conditions to produce a

mixture of 12 and 14c in the ratio of 9:1. Subsequent precipita-

tion by the action of water afforded pure amide 12 (Scheme 4).

Both 12 and the mixture of 12 and 14c can then be hydrolyzed

to the corresponding carboxylic acid, the most commonly

found pattern in the quinolone drugs.^[23]

Inspection of the ingredients in this reaction (Scheme 4) re-

veals that BSA is the only possible source of nitrogen in the

reaction mixture. Thus, formation of amide 12 suggests that

BSA acts both as a silylating agent (Scheme 5) and as a nucleo-

phile/base. This is in accordance with the work of Zhang and

Zhao who have proposed that desilylation of BSA by the action

of base occurs on the N–Si bond and that the cyclization of

diyne intermediates is promoted by the corresponding anion

of BSA.^[24]Work to extend this methodology to other substrates

is currently underway.

probably accelerate the reaction with BSA due to the increased

electron density on carbonyl oxygen atoms thus facilitating

enolate formation. The conversion trend observed in the case

of BSA-mediated cyclization of substrates 4d–g adheres to the

expected trend in results. Conversely, K₂CO₃-mediated cycliza-

tion proceeded very slowly in all cases (Table 1) with no signifi-

cant trend.

In an effort to test the limitations of the cyclization, we ob-

served that K₂CO₃was not able to promote cyclization of the

bulky substrate 4c (Table 3). NMR Experiments revealed that

K₂CO₃in [D₇]DMF at 115 °C completely failed to deprotonate

(Scheme 5) substrate 4c (Entry 1, Table 3). Under the same con-

ditions, even NaH failed to deprotonate 4c. Our initial hypothe-

sis concerning the steric hindrance of the tBu group was refuted

upon cyclization of compound 11 bearing an F atom instead of

the OMe group (Table 6). BSA-mediated cyclization in both

cases led to similar conversions and K₂CO₃-mediated cyclization

of 4c and 11 provided completely contradictory results

(Table 6). As we can see in this example, reaction with K₂CO₃is

probably controlled electronically, whereas the BSA-mediated

reaction is likely sterically controlled as two isomeric enolates

IB and IIB (Scheme 5) are involved. Moreover, for the K₂CO₃-

At the forefront of our mechanistic proposal for BSA-medi-

mediated cyclization of compound 11 to occur, a stoichiometric ated cyclization stands silylated intermediates IB and IIB (Fig-

amount of K₂CO₃was required. This observation indirectly sup- ure 2, C and Scheme 5). All efforts to isolate silylated intermedi-

ports the proposed mechanism (Scheme 5) since the ability to ates for compounds 4a–w failed. However, we obtained indirect

regenerate base is impaired in this case.

evidence of IB and IIB by using N,O-bis(tert-butyldimethyl-

Scheme 4. BSA-mediated cyclization leading to amide 12.

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Scheme 5. Plausible cyclization mechanisms of K₂CO₃- (addition–elimination mechanism) and BSA-mediated (electrocyclization) cyclization.

silyl)acetamide instead of BSA [N,O-bis(trimethylsilyl)acetamide] mechanisms of the K₂CO₃-mediated and BSA-mediated cycliza-

to induce cyclization. Notably, the use of N,O-bis(tert-butyldi- tion (Scheme 5) have been proposed.

methylsilyl)acetamide instead of BSA leads to increased O–Si

bond stability.^[25]Although the silylated intermediates were not

isolated, a significant drop in the reaction rate was observed in

accord with a slower rate of collapse of silylated intermediates

IB and IIB (Scheme 5).

Based on all observations, kinetics studies suggesting a 1^stpresence of K₂CO₃afforded two different methylated structures

order reaction, NMR analyses of the shift of the leaving OMe 13a and 13b and only traces of cyclized product 14d, the BSA-

group after cyclization (see Supporting Information for detailed mediated reaction (with even 5 equiv. of MeI present) provided

description) and references about reagents,^[14,18]plausible cyclic compound 14d as the sole product (Scheme 6).

The plausibility of these two mechanisms has been further

supported by a methylation experiment which is in accordance

with the anionic nature of the mechanism involving K₂CO₃and

the electrocyclic nature for the BSA system (compare Schemes 5

and 6). Whereas the reaction of 4d with 1 equiv. of MeI in the

Scheme 6. Methylation experiment with 4d supporting the plausibility of proposed mechanisms.

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Table 7. Summary of the scope of BSA- and K₂CO₃-mediated cyclization providing 4-quinolones 14a–w.

R1

R²

R³

R⁴

R⁵

R⁶

X

Yield^[a][%]

Yield^[b][%]

14a

14b

14c

14d

14e

14f

14g

14h

14i

H

Me

H

OMe

H

OMe

Cl

H

OMe

H

COOMe

COOEt

CN

Et

C

N

C

77

59

74

38

0

Cpr^[f]

tBu

Ph

p-OBnC₆H₄

p-MeC₆H₄

50^[e]

89

65

72

62

80

22

33

31

41

48

0

94

67

0

15

0

77

82

75

p-CF₃C₆H₄

Ph

79

Cpr^[f]

67^[c]

91

14j

14k

14l

Ph

Cpr^[f]

69

67

95

93

94

64

Ph

14m

14n

14o

14p

14q

14r

14s

14t

Cpr^[f]

Ph

o-Cl-m-MeC₆H₃

Cpr^[f]

Ph

70

Mes^[g]

89^[c]

78

H

Cpr^[f]

52

23

50

0

H

OMe

Ph

80

14u

14v

14w

o-Br-p-MeC₆H₃

97

Cpr^[f]

Ph

57^[d]

90

H

CN

72

[a] Cyclization reaction with BSA (2.3 equiv.) in DMF typically at 80–105 °C. [b] Cyclization reaction with K₂CO₃(0.4 equiv.) in DMF at 115 °C. [c] Aqueous work-

up did not work, therefore the reaction mixture was extracted. [d] Reaction was carried in ACN instead of DMF. [e] Complete conversion could not be

achieved. [f] Cpr = cyclopropyl. [g] Mes = mesitylene.

The scope of BSA- and K₂CO₃-mediated reactions is summa- more favorable substitution patterns in terms of electronic ef-

rized in Table 7. It indicates clearly that the BSA-mediated fects and symmetry. The scope of the reaction was evaluated

(2.3 equiv.) reaction provides higher yields of pure products using a few series of substrates bearing all kinds of amine moie-

14a–t at 80–105 °C following simple aqueous work-up. Al- ties. Important benefits of the BSA-mediated reaction versus

though the K₂CO₃-mediated reaction can be carried out catalyt- the reported traditional methods include aqueous work-up,

ically (0.4 equiv.) at 115 °C, it depends on the electronic effects better functional group tolerances, milder conditions, higher

of substrates, usually provides variable yields with impurities achievable yields and fewer impurities. The methodology de-

caused by the basic conditions at high temperatures and tedi- scribed here can be utilized to prepare various quinolone struc-

ous isolations are typically required after aqueous work-up. Tak- tures. Furthermore, we have found a new application of BSA as

ing into account its milder temperatures, good tolerance of a cyclization inducer capable of simultaneously enabling ester

functional groups, neutrality, easy work-ups and good availabil- to amide conversions (Scheme 4).

ity of BSA, the BSA-mediated cyclization of 1-(2-methoxy-

phenyl)-3-(alkyl/arylamino)prop-2-en-1-ones appears to be su-

perior to the K₂CO₃-mediated system.

Experimental Section

General: Dry solvents (DMF, DMSO) were purchased from commer-

cial sources. Cyclization reactions were performed in closed tubes

Conclusions

under nitrogen atmosphere using Carousel 12 Plus Reaction Station

We have developed an efficient protocol for BSA-mediated

(Radleys). Melting points were determined with a digital melting

cyclization of substituted 1-(2-methoxyphenyl)-3-(alkyl/aryl-

point apparatus Stuart SMP30 and are uncorrected. NMR spectra

amino)prop-2-en-1-ones to 4-quinolones. A common OMe leav-

ing group present in the uncommon aromatic substitution step

has the potential to enrich the scope of starting substrates used

were recorded with Bruker AVANCE 500 (probe Prodigy 5 mm) and

Bruker AVANCE 250 (probe QNP 250 MHz SB 5 mm) spectrometeres

in the indicated solvents. Chemical shifts (δ) are reported in ppm

to date with substrates: i) that are cheap, and ii) that may have downfield from tetramethylsilane. Deuterated chloroform and

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DMSO were used as solvents and spectra were calibrated against

the residual solvent peak (chloroform: 7.26 ppm for ¹H and

192.9 ppm. HRMS (APCI, m/z): calcd. for C₁₃H₁₇O₅[M + H] 253.1076,

found 253.1075. (mixture of keto–enol tautomers).

1

77.0 ppm for ¹³C; DMSO: 2.50 ppm for H and 39.70 ppm for ¹³C).

Methyl 3-(2-Methoxyphenyl)-3-oxopropanoate (2c): 60 % NaH in

mineral oil (6.47 g, 0.2 mol) was washed with petroleum ether

(75 mL) three times to remove oil and the flask was charged with

toluene (100 mL), and dimethyl carbonate (6.75 g, 0.075 mol). To

this mixture, a solution of 2′-methoxyacetophenone 1c (7.5 g,

0.05 mol) in toluene (50 mL) was added dropwise over the course

of 1 h. The gray solution turned yellow to orange. The reaction

mixture was stirred at the same temperature for 3 h. The orange

contents of the flask was then cooled to r.t. and poured onto ice

(500 g) under vigorous stirring. Adjustment to pH 7 with 10 % HCl

gave a suspension which was dissolved by addition of EtOAc. Aque-

ous phase was extracted with EtOAc (3 × 150 mL) and the com-

bined organic extracts were rinsed consecutively with saturated

NaHCO₃(150 mL) and brine (150 mL) and dried with MgSO₄. The

residue after evaporation (4.1 g) was distilled (0.24 kPa or 1.8 Torr,

Chemical shifts δ are given in ppm, coupling constants J are given

in Hz. High resolution/accurate mass (HRAM) MS experiments were

performed using a LTQ XL Orbitrap Mass Spectrometer (Thermo,

San Jose, USA) coupled to an HPLC HTS PAL system (CTC Analytics,

Switzerland). LC separation was performed with a Kinetex C18,

150 × 3.0 mm, 2.6 μm (Phenomenex, Torrance, USA) column using

0.6 mL/min flow rate. The gradient elution employed solutions A

and B as mobile phase components. The solvent A was 10 m

M

ammonium formate, pH 6.3, whereas solvent B was acetonitrile. The

gradient program was set as follows: time/% of solvent B: 0/30, 4/

30, 18/100, 23/100, 25/30 with an equilibration time of 5 min. For

an ionisation of the analytes an ESI ion source was operated in the

positive ion mode (capillary temperature 300 °C, tube lens voltage

60 V, spray voltage 4 kV). UV/Vis measurements were performed

using Perkin–Elmer Lambda 25 UV/Vis Spectrometer. Thin-layer

chromatography (TLC) was performed on aluminum sheets pre-

1

152–158 °C) to give 2.2 g (21 %) of clear liquid. H NMR (500 MHz,

CDCl₃): δ = 3.71 (s, 2.69 H), 3.79 (s, 0.25 H), 3.89 (s, 3.0 H), 3.98 (s,

1.81 H), 6.03 (s, 0.08 H), 6.93–6.99 (m, 1.00 H), 6.99–7.05 (m, 1.00 H),

7.37–7.41 (m, 0.08 H), 7.47–7.53 (m, 0.91 H), 7.84 (dd, J = 7.9, 1.8 Hz,

0.09 H), 7.87 (dd, J = 7.9, 1.8 Hz, 0.90 H), 12.59 (s, 0.08 H) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 50.5, 51.4, 52.2, 55.5, 55.7, 111.7, 121.0,

126.3, 131.2, 134.9, 159.3, 168.7, 193.0 ppm. HRMS (APCI, m/z): calcd.

for C₁₁H₁₃O₄[M + H] 209.0814, found 209.0808. (mixture of keto–

enol tautomers).

coated with TLC silicagel 60 F₂₅₄

.

Methyl 3-(2,4-Dimethoxyphenyl)-3-oxopropanoate (2a): 60 %

NaH in mineral oil (32 g, 0.8 mol) was washed with hexane (150 mL)

three times to remove oil and the flask was charged with toluene

(350 mL), THF (50 mL) and dimethyl carbonate (27 g, 0.3 mol). To

this mixture, a solution of 2′,4′-dimethoxyacetophenone 1 (36 g,

0.2 mol) in dry THF (250 mL) was added dropwise over the course

of 1 h at 70 °C resulting in a slurry which was mechanically stirred

at the same temperature for 2.5 h. The reaction mixture was cooled

to r.t. and poured onto ice (800 g) under vigorous stirring. Adjust-

ment to pH 7 with 10 % HCl gave suspension which was dissolved

in EtOAc (250 mL). Aqueous phase was extracted with EtOAc (1 ×

200 mL) and the combined organic extracts were rinsed consecu-

tively with saturated NaHCO₃(150 mL) and brine (150 mL) and dried

with MgSO₄. The residue after evaporation was crystallized from

MeOH giving 37.8 g (79 %) of white solid, m.p. 64.4–69.1 °C. ¹H

NMR (500 MHz, [D₆]DMSO): δ = 3.62 (s, 3.00 H), 3.85 (s, 6.00 H), 3.87

(s, 2.00 H), 6.60–6.67 (m, 2.00 H), 7.43–7.47 (m, 1.00 H) ppm. ¹³C

NMR (125 MHz, [D₆]DMSO): δ = 49.7, 51.6, 55.7, 55.7, 98.3, 106.5,

118.6, 132.1, 161.1, 165.0, 168.5, 190.4 ppm. HRMS (APCI, m/z): calcd.

for C₁₂H₁₅O₅[M + H] 239.0919, found 239.0913.

Methyl 2-(2,4-Dimethoxybenzoyl)-3-(dimethylamino)acrylate

(3a): A solution of 2 (20 g, 0.11 mol) in DMFDMA (40 mL) was

stirred at 70 °C overnight. Solvent was evaporated giving 22.9 g

(93 %) of orange oil. It was used for next reaction steps without

further purification.

Methyl 2-(2,4-Dimethoxy-3-methylbenzoyl)-3-(dimethylamino)-

acrylate (3b): A solution of 2b (790 mg, 3.12 mmol) in DMFDMA

(5 mL) was stirred at 50 °C for 12 h. Solvent was evaporated to give

910 mg (95 %) of a yellow, low freezing oil. It was used for next

reaction steps without further purification.

Methyl 3-(Dimethylamino)-2-(2-methoxybenzoyl)acrylate (3c):

To a solution of 2c (1.05 g, 5 mmol) in toluene (15 mL) was added

DMFDMA (0.73 mL, 5.5 mmol) and the reaction mixture was stirred

at 65 °C for 12 h. Solvent was evaporated to give 1.31 g (99 %)

of orange oil. It was used for next reaction steps without further

purification.

Methyl

3-(2,4-Dimethoxy-3-methylphenyl)-3-oxopropanoate

(2b): 60 % NaH in mineral oil (2.15 g, 0.07 mol) was washed with

petroleum ether (50 mL) three times to remove oil and the flask

was charged with toluene (50 mL), and dimethyl carbonate (2.25 g,

General Procedure for Synthesis of ꢀ-Keto Esters 6a–c: To a solu-

tion (or suspension) of carboxylic acid 5a (5 mmol) in dry CH₂Cl₂

0.025 mol). To this mixture, a solution of 2′,4′-dimethoxy-3′-methyl- (5 mL) was added oxalyl chloride (5.5 mmol) and the reaction was

acetophenone 1b (3.3 g, 0.017 mol) in toluene (30 mL) was added initiated by the addition of DMF (one droplet). The reaction mixture

dropwise over the course of 1 h and the reaction mixture was

stirred at the same temperature for 6 h. The contents of the flask

was then cooled to r.t. and poured onto ice (400 g) under vigorous

stirring. Adjustment to pH 7 with 10 % HCl gave a suspension which

was dissolved by addition of EtOAc. Aqueous phase was extracted

with EtOAc (3 × 100 mL) and the combined organic extracts were

rinsed consecutively with saturated NaHCO₃(100 mL) and brine

(100 mL) and dried with MgSO₄. The residue after evaporation was

purified by column chromatography (eluent: heptane/EtOAc, 5:1) to

was stirred typically for 3 h at r.t. until the end of the reaction

indicated by the cease of gas evolution. Solvent was evaporated

and the residue was dissolved in toluene (5 mL) to allow another

evaporation for removing the residual oxalyl chloride. As a next

step, a solution of commercially available 1

M LiHDMS in THF

(10 mmol) and EtOAc (5 mmol; dried with molecular sieves) in THF

(5 mL) was prepared and stirred for 30 min at –78 °C under N₂

atmosphere. To this mixture, a solution of acyl chloride (which was

prepared above from 1a) in THF (5 mL) was added dropwise over

give 1.48 g (35 %) of yellow solid, m.p. 46.9–50.8 °C. ¹H NMR the course of 10 min. The reaction mixture was then stirred for

(500 MHz, CDCl₃): δ = 2.15 (s, 3.00 H), 3.70 (s, 0.40 H), 3.74 (s, 2.57

H), 3.75 (s, 2.58 H), 3.78 (s, 0.43 H), 3.86 (s, 0.40 H), 3.88 (s, 2.70 H),

30 min and quenched by the addition of saturated solution of

NH₄Cl (2 mL). After warming to r.t., water (25 mL) was added and

4.01 (s, 1.75 H), 5.97 (s, 0.11 H), 6.66–6.71 (m, 1.00 H), 7.63 (d, J = the reaction mixture was extracted with EtOAc (3 × 25 mL). Com-

8.6 Hz, 0.13 H), 7.68 (d, J = 8.6 Hz, 0.82 H), 12.61 (s, 0.12 H) ppm.

bined organic phases were rinsed with saturated solution of NaH-

¹³C NMR (125 MHz, CDCl₃): δ = 48.9, 51.4, 52.3, 55.8, 56.0, 60.7, CO₃(25 mL), brine (25 mL) and dried with MgSO₄. Evaporation of

62.0, 89.8, 106.0, 106.3, 120.3, 124.2, 127.6, 129.7, 159.7, 163.0, 168.8, the solvent provided ꢀ-keto ester 6a.

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Ethyl 3-(2,6-Dimethoxyphenyl)-3-oxopropanoate (6a): Yellow

crystals, yield 65 % (820 mg), m.p. 63.2–69.7 °C. H NMR (500 MHz,

absolute EtOH (40 mL), was added in three portions into a suspen-

sion of isoxazole derivative 8 (2.05 g, 10 mmol). The reaction mix-

ture was then stirred at r.t. for 6 h. The residue after evaporation

was dissolved in EtOAc (100 mL) and the solution was washed with

diluted aqueous HCl (1:5, 60 mL). The aqueous phase was extracted

with EtOAc (3 × 100 mL) and the combined organic extracts were

rinsed with saturated solution of NaHCO₃(3 × 100 mL) and brine

(100 mL) and dried with anhydrous MgSO₄. Evaporation of solvent

1

[D₆]DMSO): δ = 1.14 (t, J = 7.0 Hz, 3.00 H), 3.74 (s, 2.30 H), 3.75 (s,

6.00 H), 3.98 (q, J = 7.0 Hz, 2.00 H), 6.71 (d, J = 8.4 Hz, 2.00 H), 7.36

(t, J = 8.4 Hz, 1.00 H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 13.9,

51.0, 55.9, 60.4, 104.3, 118.1, 131.6, 156.5, 166.4, 195.5 ppm. HRMS

(APCI, m/z): calcd. for C₁₃H₁₇O₅[M + H] 253.1076, found 253.1068.

Ethyl 3-(2,5-Dimethoxyphenyl)-3-oxopropanoate (6b): Yellow oil

(purified by column chromatography, eluent: hexane/EtOAc, 4:1),

yield 68 % (0.43 g). ¹H NMR (500 MHz, CDCl₃): δ = 1.19 (t, J = 7.2 Hz,

0.387 H), 1.10 (t, J = 7.2 Hz, 2.80 H), 3.59–3.65 (m, 3.04 H), 3.66–3.72

(m, 3.00 H), 3.82 (s, 1.72 H), 4.04 (q, J = 7.2 Hz, 1.78 H), 4.11 (q, J =

7.2 Hz, 0.22 H), 5.97 (s, 0.10 H), 6.58–6.81 (m, 1.18 H), 6.92 (dd, J =

9.2, 3.4 Hz, 0.86 H), 7.26 (d, J = 3.2 Hz, 0.83 H), 7.28 (d, J = 3.2 Hz,

0.12 H), 12.66 (s, 0.10 H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ =

14.0, 14.1, 50.4, 55.4, 55.5, 55.6, 55.6, 55.8, 60.1, 60.2, 60.7, 72.9, 92.2,

112.1, 112.7, 113.1, 113.3, 113.8, 117.3, 121.3, 122.4, 126.1, 153.2,

153.4, 153.6, 168.0, 168.1, 171.7, 173.6, 192.4 ppm. HRMS (APCI,

m/z): calcd. for C₁₃H₁₇O₅[M + H] 253.0919, found 253.1071. (mixture

of keto–enol tautomers).

1

provided 1.3 g (63 %) of yellowish crystals, m.p. 148.1–154.2 °C. H

NMR (500 MHz, CDCl₃): δ = 3.88 (s, 3.10 H), 3.95 (s, 3.00 H), 4.03 (s,

2.00 H), 6.47 (d, J = 2.5 Hz, 1.00 H), 6.58 (dd, J = 9.0, 2.5 Hz, 1.00 H),

7.93 (dd, J = 9.0 Hz, 1.00 H), 7.30 (d, J = 8.2 Hz, 1.00 H), 7.87 (s, 1.00

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 34.17, 55.9, 98.4, 106.3,

115.1, 117.8, 133.8, 161.4, 166.2, 186.1 ppm. HRMS (APCI, m/z): calcd.

for C₁₁H₁₂NO₃[M + H] 206.0817, found 206.0817.

2-(2,4-Dimethoxybenzoyl)-3-(dimethylamino)acrylonitrile (10):

To a suspension of ꢀ-ketonitrile 9 (0.82 g; 4 mmol) in toluene

(15 mL) was added DMFDMA (0.58 mL, 4.4 mmol) in one portion

and the reaction mixture was stirred at 100 °C for 3 h. After cooling,

solids were filtered off to obtain 0.71 g (68 %) of 10 as a white solid,

1

Ethyl 3-(5-Chloro-2-methoxyphenyl)-3-oxopropanoate (6c): Yel-

m.p. 129.8–134.2 °C. H NMR (500 MHz, CDCl₃): δ = 3.24 (s, 3.00 H),

low oil (purified by column chromatography, eluent: hexane/EtOAc,

4:1), yield 65 % (0.42 g). H NMR (500 MHz, CDCl₃): δ = 1.18 (t, J = 1.00 H), 6.50 (dd, J = 8.3, 2.3 Hz, 1.00 H), 7.30 (d, J = 8.3 Hz, 1.00 H),

3.42 (s, 3.00 H), 3.82 (s, 3.00 H), 3.86 (s, 3.00 H), 6.46 (d, J = 2.3 Hz,

1

7.3 Hz, 2.54 H), 1.28 (t, J = 7.0 Hz, 0.59 H), 3.8–3.85 (m, 2.95 H), 3.89

(s, 1.67 H), 4.12 (q, J = 7.0 Hz, 1.65 H), 4.20 (q, J = 7.3 Hz, 0.35 H),

6.00 (s, 0.17 H), 6.83 (d, J = 9.0 Hz, 0.17 H), 6.87 (d, J = 9.0 Hz, 0.82

H), 7.72–7.78 (m, 0.92 H); 12.66 (s, 0.16 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 14.1, 14.2, 50.4, 55.8, 55.9, 60.4, 60.9, 92.9, 112.8, 113.3,

126.1, 127.1, 28.9, 130.4, 131.3, 134.1, 157.6, 167.8, 191.7 ppm.

HRMS (APCI, m/z): calcd. for C₁₂H₁₄ClO₅[M + H] 257.0581, found

257.0576 (mixture of keto–enol tautomers).

7.87 (s, 1.00 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 39.0, 48.1,

55.5, 55.8, 82.8, 98.7, 104.8, 120.1, 122.3, 130.5, 158.0, 158.5, 162.9,

189.9 ppm. HRMS (APCI, m/z): calcd. for C₁₄H₁₇N₂O₃[M + H]

261.1239, found 261.1241.

General Procedure A for Synthesis of Enamines 4a–d, 4i, 4k,

4m–n, 4p–q, 4s–t, 4w: To a solution or suspension of 3a–c, 7a–c

or 10 (1 mmol) in MeOH (4 mL) was added corresponding alkyl-

or arylamine (or corresponding hydrochloride) (1.2 mmol) and the

mixture was stirred at temperatures from r.t. to 50 °C. The reaction

was checked by TLC and typical reaction time was 8 h. If spontane-

ous precipitation of product did not occur, then the residue after

evaporation was either crystallized or purified by column chroma-

tography giving 4a–d, 4i, 4k–n, 4p–q, 4s–t, 4w.

General Procedure for Synthesis of Enamines 7a–c: To a solution

of 6a (1.2 mmol) in toluene (6 mL) was added DMFDMA (2.4 mmol)

and the mixture was heated at 45 °C for 12 h. The solvent was

evaporated to give crude 7a in the form of oil which was used for

the next reaction steps without further purification.

Ethyl

(7a): Orange, low freezing oil, yield 92 % (0.34 g).

Ethyl 2-(2,5-Dimethoxybenzoyl)-3-(dimethylamino)acrylate

2-(2,6-Dimethoxybenzoyl)-3-(dimethylamino)acrylate

Methyl 2-(2,4-Dimethoxybenzoyl)-3-(ethylamino)acrylate (4a).

General Procedure A (at 50 °C): Yellow crystals, yield 96 % (1.21 g),

m.p. 91.6–99.7 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.28–1.33 (m, 3.00

H), 3.39–3.45 (m, 2.00 H), 3.51 (s, 2.40 H), 3.51 (s, 0.60 H), 3.74 (s,

3.00 H), 3.82 (s, 2.40 H), 3.83 (s, 0.60 H), 6.39–6.40 (m, 1.00 H), 6.48–

6.50 (m, 1.00 H), 7.28 (d, J = 8.5 Hz, 0.80 H), 7.39 (d, J = 8.5 Hz, 0.20

H), 7.91 (d, J = 14.5 Hz, 0.20 H), 7.94 (d, J = 14.9 Hz, 0.80 H), 8.97

(m, 0.20 H), 10.78 (m, 0.80 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

15.8, 15.9, 44.4, 44.6, 50.4, 50.8, 55.3, 55.4, 55.6, 98.0, 98.1, 102.0,

104.2, 125.7, 129.7, 130.4, 157.8, 158.8, 159.2, 161.9, 168.5,

192.9 ppm. HRMS (APCI, m/z): calcd. for C₁₅H₂₀NO₅[M + H]

294.1341, found 294.1335.

(7b): Orange, low freezing oil, yield 90 % (0.33 g).

Ethyl 2-(5-Chloro-2-methoxybenzoyl)-3-(dimethylamino)acryl-

ate (7c): Orange, low freezing oil, yield 91 % (0.34 g).

5-(2,4-Dimethoxyphenyl)isoxazole (8): A mixture of acetophen-

one 1a (5.4 g, 30 mmol), guanidine-acetic acid (351 mg, 3 mmol)

and DMFDMA (15 mL) was stirred at 100 °C under N₂atmosphere

for 18 h. After cooling to r.t., solvent was evaporated and the resi-

due was subject to purification by flash chromatography (eluent:

EtOAc/MeOH, 9:1) giving 4 g (57 %) of a low freezing orange oil. A

solution of product obtained in the previous reaction (4 g,

17 mmol), NH₂OH·HCl (2.28 g, 32.81 mmol) and a catalytic amount

of HCl in EtOH (75 mL) was then stirred at r.t. overnight. White

solids appearing in the reaction mixture were filtered off to obtain

2.81 g (80 %) of pure product, m.p. 87.4–91.6 °C. ¹H NMR (500 MHz,

CDCl₃): δ = 3.87 (s, 2.95 H), 3.93 (s, 3.00 H), 6.55 (d, J = 2.3 Hz, 0.95

H), 6.61 (dd, J = 8.7, 2.3 Hz, 0.97 H), 6.65 (s, J = 1.6 Hz, 0.91 H), 7.91

(d, J = 8.7 Hz, 0.93 H), 8.25 (d, J = 1.6 Hz, 0.93 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 55.7, 55.7, 98.9, 101.0, 105.3, 109.9, 129.1,

151.0, 157.8, 162.4, 165.7 ppm. HRMS (APCI, m/z): calcd. for

C₁₁H₁₂NO₃[M + H] 206.0817, found 206.0814.

Methyl 3-(Cyclopropylamino)-2-(2,4-dimethoxybenzoyl)acrylate

(4b). General Procedure A (at 50 °C): Yellow solid (purified by

column chromatography, hexane/EtOAc, 1:1), yield 93 % (1.14 g),

m.p. 84.0–90.1 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.50 (s, 0.60 H),

3.52 (s, 2.40 H), 3.73 (s, 3.00 H), 3.82 (s, 2.40 H), 3.83 (s, 0.60 H), 6.38

(d, J = 2.3 Hz, 1.00 H), 6.49 (s, J = 8.4, 2.3 Hz, 1 H), 7.27 (d, J = 8.1 Hz,

0.80 H), 7.41 (d, J = 8.4 Hz, 0.20 H), 7.96 (d, J = 14.2 Hz, 0.20 H),

8.03 (d, J = 13.5 Hz, 0.80 H), 8.99 (d, J = 14.2 Hz, 0.20 H), 10.73 (d,

J = 13.5 Hz, 0.80 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 6.5, 6.6,

29.7, 30.0, 50.5, 50.8, 55.3, 55.4, 55.6, 97.9, 98.1, 102.8, 103.1, 104.2,

125.1, 125.5, 129.8, 131.2, 157.9, 158.6, 159.3, 159.7, 162.1, 162.5,

168.3, 190.1, 192.8 ppm. HRMS (APCI, m/z): calcd. for C₁₆H₂₀NO₅[M

+ H] 306.1341, found 306.1345.

3-(2,4-Dimethoxyphenyl)-3-oxopropanenitrile (9): A solution of

EtONa/EtOH, freshly prepared from sodium (0.69 g; 30 mmol) and

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Methyl 3-(tert-Butylamino)-2-(2,4-dimethoxybenzoyl)acrylate

(4c). General Procedure A (at 50 °C): White crystals (crystallized

from MeOH), 79 % (1.01 g), m.p. 139.8–146.8 °C. ¹H NMR (500 MHz,

CDCl₃): δ = 1.35 (s, 1.60 H), 1.39 (s, 7.40 H), 3.51 (s, 2.40 H), 3.51 (s,

Ethyl 3-(cyclopropylamino)-2-(2,6-dimethoxybenzoyl)acrylate

(4n). General Procedure A (at room temp.): White solid (crystal-

lized from iPrOH), yield 97 % (0.20 g), m.p. 97.9–103.8 °C. ¹H NMR

(500 MHz, CDCl₃): δ = 0.70–1.01 (m, 7.13 H), 2.87–2.99 (m, 1.00 H),

0.60 H), 3.74 (s, 0.60 H), 3.75 (s, 2.40 H), 6.38–6.40 (m, 1.00 H), 6.49 3.75 (s, 6.13 H), 3.92 (q, J = 7.2 Hz, 1.00 H), 6.49–6.56 (m, 2.04 H),

(dd, J = 8.4, 2.3 Hz, 1.00 H), 7.27 (d, J = 8.4 Hz, 0.80 H), 7.37 (d, J = 7.16–7.23 (m, 1.00 H), 8.18 (d, J = 13.5 Hz, 0.85 H), 8.33 (d, J =

8.34 Hz, 0.20 H), 8.06 (d, J = 14.5 Hz, 0.20 H), 8.07 (d, J = 14.8 Hz,

0.80 H), 9.35 (d, J = 14.5 Hz, 0.20 H), 11.21 (d, J = 14.8 Hz, 0.80

13.5 Hz, 0.85 H), 11.20 (d, J = 11.5 Hz, 0.74 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 6.5, 6.5, 6.63, 13.9, 30.2, 30.4, 56.1, 59.3, 59.4,

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 29.9; 29.9; 50.4; 50.8; 53.6; 103.0, 104.0, 104.1, 122.5, 129.1, 129.2, 156.5, 156.7, 160.6, 160.8,

53.6; 55.3; 55.4; 55.4; 55.6; 98.0; 98.1; 101.7; 104.1; 104.1; 125.5;

167.2, 193.3 ppm. HRMS (APCI, m/z): calcd. for C₁₇H₂₂NO₅[M + H]

125.8; 129.7; 130.8; 155.0; 157.8; 158.3; 161.9; 162.2; 168.8; 170.1; 320.1498, found 320.1503.

190.2; 192.6 ppm. Mixture of E/Z isomers. HRMS (APCI, m/z): calcd.

for C₁₇H₂₄NO₅[M + H] 322.1654, found 322.1658.

Ethyl 2-(2,6-Dimethoxybenzoyl)-3-(phenylamino)acrylate (4m).

General Procedure A (at room temp.): White solid, yield 75 %

Methyl 2-(2,4-Dimethoxybenzoyl)-3-(phenylamino)acrylate

(0.17 g), m.p. 144.7–148.3 °C. ¹H NMR (500 MHz, [D₆]DMSO): δ =

(4d). General Procedure A (at room temp.): White crystals (crys- 0.82–0.92 (m, 3.00 H), 3.67 (s, 3.00 H), 3.68 (s, 3.00 H), 3.86 (q, J =

tallized from MeOH), yield 80 % (1.09 g), m.p. 110.7–114.1 °C. ¹H

NMR (500 MHz, CDCl₃): δ = 3.59 (s, 0.75 H), 3.59 (s, 2.25 H), 3.76 (s,

0.75 H), 3.77 (s, 2.25 H), 3.85 (s, 2.25 H), 3.86 (s, 0.75 H), 7.12–7.23

(m, 3.00 H), 7.34–7.43 (m, 2.80 H), 7.55 (d, J = 8.37 Hz, 0.18 H), 8.34

(d, J = 13.8 Hz, 0.25 H), 8.43 (d, J = 13.2 Hz, 0.75 H), 10.69 (d, J =

7.1 Hz, 1.61 H), 3.94 (q, J = 7.1 Hz, 0.41 H), 6.60–6.70 (m, 2.00 H),

7.16–7.31 (m, 2.01 H), 7.31–7.52 (m, 4.00 H), 8.38 (d, J = 13.6 Hz,

0.20 H), 8.49 (d, J = 13.6 Hz, 0.80 H), 10.88 (d, J = 13.6 Hz, 0.20 H),

12.58 (d, J = 13.6 Hz, 0.79 H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO):

δ = 13.4, 13.6, 55.6, 55.7, 59.0, 59.1, 104.1, 104.1, 104.5, 117.8, 118.2,

13.8 Hz, 0.25 H), 12.37 (d, J = 13.2 Hz, 0.75 H) ppm. ¹³C NMR 121.6, 125.1, 125.4, 129.2, 129.3, 129.8, 139.0, 139.3, 151.6, 156.0,

(125 MHz, CDCl₃): δ = 30.4, 50.3, 50.6, 54.8, 54.9, 54.9, 55.0, 76.2, 156.2, 165.9, 167.4, 188.5, 192.4 ppm. HRMS (APCI, m/z): calcd. for

76.5, 76.7, 97.4, 97.5, 103.9, 103.9, 104.8, 116.4, 116.9, 117.0, 124.2,

124.3, 124.6, 129.3, 129.8, 131.2, 138.7, 149.4, 149.8, 157.7, 162.1,

167.7, 192.7 ppm. HRMS (APCI, m/z): calcd. for C₁₉H₂₀NO₅[M + H]

342.1341, found 342.1331.

C₁₂H₂₂NO₅[M + H] 356.1498, found 356.1491.

Ethyl 3-(cyclopropylamino)-2-(2,5-dimethoxybenzoyl)acrylate

(4p). General Procedure A (at room temp.): Yellow amorphous

compound (purified by column chromatography; eluent: hexane/

Methyl

3-{[4-(Benzyloxy)phenyl]amino}-2-(2,4-dimethoxy- EtOAc, 6:4), yield 63 % (0.130 g). ¹H NMR (500 MHz, CDCl₃): δ =

benzoyl)acrylate (4e). General Procedure A (at 50 °C): White

solid, yield 56 % (0.5 g), m.p. 151.6–155.6 °C. ¹H NMR (500 MHz,

CDCl₃): δ = 3.58 (s, 3.00 H), 3.77 (s, 3.00 H), 3.84 (s, 2.40 H), 3.85 (s,

0.60 H), 5.06 (s, 0.40 H), 5.07 (s, 1.62 H), 6.41 (d, J = 2.2 Hz, 1.00 H),

0.79–0.89 (m, 4.20 H), 0.90–0.97 (t, J = 7.13 Hz, 2.30 H), 2.86–2.97

(m, 1.00 H), 3.72 (s, 2.98 H), 3.74–3.77 (m, 3.10 H), 3.88–3.99 (m, 2.01

H), 6.73–6.89 (m, 3.00 H), 8.06–8.17 (m, 0.95 H), 9.23 (d, J = 13.5 Hz,

0.15 H), 10.87 (d, J = 13.8 Hz, 0.68 H) ppm. ¹³C NMR (125 MHz,

6.51–6.56 (m, 1.00 H), 6.95–7.01 (m, 2.00 H), 7.06–7.09 (m, 0.38 H), CDCl₃): δ = 6.6, 6.7, 13.7, 14.0, 30.0, 30.3, 55.9, 56.0, 56.3, 56.5, 59.4,

7.12–7.17 (m, 1.63 H), 7.31–7.57 (m, 5.77 H),7.52 (d, J = 8.5 Hz, 0.23

H), 8.27 (d, J = 14.0 Hz, 0.19 H), 8.34 (d, J = 13.3 Hz, 0.81 H), 10.62

(d, J = 14.0 Hz, 0.18 H), 12.47 (d, J = 13.3 Hz, 0.75 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 51.2, 55.5, 70.6, 98.1, 104.5, 116.2, 118.7,

119.2, 127.6, 128.3, 128.8, 130.3, 133.1, 151.2, 156.7, 162.6,

193.2 ppm. HRMS (APCI, m/z): calcd. for C₂₆H₂₅NO₆[M + H]

448.1760, found 448.1768.

59.7, 102.8, 111.7, 112.1, 113.2, 113.7, 115.5, 115.8, 133.7, 150.4,

153.5, 160.1, 160.2, 167.7, 193.8 ppm. HRMS (APCI, m/z): calcd. for

C₁₇H₂₂NO₅[M + H] 320.1498, found 320.1494.

Ethyl 2-(2,5-Dimethoxybenzoyl)-3-(phenylamino)acrylate (4q).

General Procedure A (at room temp.): Yellow amorphous com-

pound (purified by column chromatography; eluent: hexane/EtOAc,

6:4), yield 91 % (0.21 g). ¹H NMR (500 MHz, CDCl₃): δ = 0.89–0.95 (t,

J = 7.4 Hz, 0.72 H), 0.97–1.02 (t, J = 7.4 Hz, 2.17 H), 3.72–3.76 (m,

2.93 H), 3.80 (s, 3.05 H), 4.02 (q, J = 7.4 Hz, 2.00 H), 6.67–6.82 (m,

Methyl 3-(Cyclopropylamino)-2-(2,4-dimethoxy-3-methylbenzo-

yl)acrylate (4i). General Procedure A (at 50 °C): Yellow solid, yield

95 % (0.1 g), m.p. 99.8–106.1 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.80 H), 6.89–6.94 (m, 1.00 H), 6.99–7.01 (d, J = 3.2 Hz, 0.21 H), 7.12–

0.69–0.91 (m, 4.00 H), 2.12 (s, 3.18 H), 3.48 (s, 2.22 H), 3.55 (s, 0.78 7.28 (m, 4.00 H), 7.35–7.43 (m, 1.97 H), 8.45–8.53 (m, 0.94 H), 10.89

H), 3.6 (s, 2.99 H), 3.81–3.87 (m, 3.11 H), 6.61 (d, J = 8.5 Hz, 1.00 H),

7.12 (d, J = 8.5 Hz, 0.71 H), 7.26 (d, 0.25 H), 7.93 (d, J = 13.8 Hz, 0.25

H), 8.09 (d, J = 13.5 Hz, 0.72 H), 9.16 (d, J = 13.8 Hz, 0.22 H), 10.78

(d, J = 13.6 Hz, 0.20 H), 12.52 (d, J = 13.2 Hz, 0.69 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 13.7, 14.0, 55.9, 56.0, 56.2, 56.4, 59.8, 60.0,

105.2, 111.7, 112.1, 113.4, 114.0, 115.3, 116.3, 116.7, 117.3, 117.8,

(d, J = 13.5 Hz, 0.63 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 6.7, 118.8, 125.1, 125.6, 129.4, 130.0, 130.0, 133.0, 139.2, 150.7, 151.1,

8.9, 30.0, 30.2, 50.1, 51.1, 54.2, 55.7, 61.7, 102.4, 105.4, 105.6, 119.1, 151.3, 153.6, 153.7, 167.6, 194.4 ppm. HRMS (APCI, m/z): calcd. for

126.1, 127.7, 129.4, 156.6, 159.8, 159.9, 168.5, 194.0 ppm. HRMS C₂₀H₂₂NO₅[M + H] 356.1498, found 356.1491.

(APCI, m/z): calcd. for C₁₇H₂₂NO₅[M + H] 320.1498, found 320.1492.

Ethyl

2-(5-Chloro-2-methoxybenzoyl)-3-(cyclopropylamino)-

Ethyl 3-(Cyclopropylamino)-2-(2-methoxybenzoyl)acrylate (4k).

General Procedure A (at room temp.): White solid (crystallized

from iPrOH), yield 95 % (0.23 g), m.p. 88.6–91.8 °C. ¹H NMR

(500 MHz, CDCl₃): δ = 0.71–0.90 (m, 4.00 H), 2.85–2.96 (m, 1.00 H),

3.49 (s, 3.00 H), 3.77 (s, 3.00 H), 6.85 (d, J = 8.6 Hz, 1.00 H), 6.96 (t,

J = 7.6 Hz, 1.00 H), 7.23 (d, J = 7.6 Hz, 0.81 H), 7.29–7.36 (m, 1.16

H), 8.05 (d, J = 13.6 Hz, 0.15 H), 8.10 (d, J = 14.3 Hz, 0.82 H), 9.19

(m, 0.12 H), 10.92 (d, J = 11.7 Hz, 0.65 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 6.6, 6.6, 6.7, 30.3, 50.9, 55.6, 102.6, 110.5, 120.6, 120.6,

acrylate (4s). General Procedure A (at room temp.): White solid

(crystallized from iPrOH), yield 93 % (0.20 g), m.p. 101.9–104.2 °C.

¹H NMR (500 MHz, CDCl₃): δ = 0.74–1.00 (m, 7.19 H), 2.88–3.00 (m,

0.99 H), 3.75 (s, 3.09 H), 3.87–4.01 (m, 2.04 H), 6.77 (d, J = 8.81 Hz,

1.00 H), 7.16 (d, J = 2.6 Hz, 0.74 H), 7.22–7.28 (m, 1.24 H), 8.14 (d,

J = 13.5 Hz, 0.77 H), 8.20 (d, J = 14.3 Hz, 0.19 H), 9.32 (d, J = 13.3 Hz,

0.14 H), 10.91 (d, J = 13.2 Hz, 0.65 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 6.6, 6.7, 13.7, 14.0, 30.4, 56.0, 56.0, 59.4, 59.7, 102.4,

111.8, 111.8, 125.5, 127.6, 129.5, 129.6, 134.5, 154.6, 160.4, 167.4,

127.9, 130.4, 130.8, 132.8, 156.1, 160.0, 168.0, 194.3 ppm. HRMS 167.4, 192.6 ppm. HRMS (APCI, m/z): calcd. for C₁₆H₁₉ClNO₄[M + H]

(APCI, m/z): calcd. for C₁₅H₂₈NO₄[M + H] 276.1236, found 276.1231. 324.1003, found 324.0095.

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Methyl 2-(5-Chloro-2-methoxybenzoyl)-3-(phenylamino)acryl-

ate (4t). General Procedure A (at room temp.): Yellowish oil (puri-

fied by column chromatography; eluent: hexane/EtOAc, 6:4), yield

85 % (0.20 g). ¹H NMR (500 MHz, CDCl₃): δ = 0.92 (t, J = 7.3 Hz, 0.75

H), 1.04 (t, J = 7.3 Hz, 0.75 H), 3.75 (s, 3.09 H), 3.87–4.01 (m, 2.04 H),

Methyl 2-(2,4-Dimethoxy-3-methylbenzoyl)-3-(phenyl-

amino)acrylate (4j). General Procedure B (at 100 °C): Yellow solid

(crystallization from iPrOH), yield 67 % (0.19 g), m.p. 121.6–124.3 °C.

¹H NMR (500 MHz, [D₆]DMSO): δ = 2.05 (s, 2.00 H),2.06 (s, 1.00 H),

3.45 (s, 2.00 H), 3.50 (s, 0.96 H), 3.54 (s, 3.00 H),3.83 (s, 3.05 H), 6.74–

6.77 (d, J = 8.8 Hz, 1.00 H), 3.81 (s, 3.12 H), 4.00–4.12 (m, 2.14 H), 6.84 (m, 1.00 H), 7.12–7.51 (m, 6.07 H), 8.21 (d, J = 13.1 Hz, 0.32 H),

6.71–6.86 (m, 2.02 H), 7.15–7.51 (m, 6.00 H), 8.52–8.60 (m, 0.95 H), 8.44 (d, J = 13.5 Hz, 0.68 H), 10.50 (d, J = 13.1 Hz, 0.31 H), 12.07 (d,

11.00 (d, J = 13.8 Hz, 0.20 H), 12.58 (d, J = 14.1 Hz, 0.72 H) ppm.

J = 13.5 Hz, 0.67 H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 8.6,

8.6, 50.6, 50.8, 55.7, 61.4, 61.5, 104.2, 105.7, 105.8, 117.5, 117.8,

¹³C NMR (125 MHz, CDCl₃): δ = 55.1, 51.8, 55.8, 55.9, 56.0, 59.8, 60.1,

104.7, 104.9, 111.8, 111.9, 115.4, 117.5, 118.0, 125.4, 125.6, 125.9, 117.9, 124.5, 125.1, 126.7, 128.0, 128.2, 129.7, 129.7, 139.2, 139.6,

127.9, 128.7, 129.4, 130.0, 130.0, 130.1, 130.3, 133.9, 139.0, 139.1, 149.8, 150.3, 156.5, 159.6, 167.6, 167.2, 192.6 ppm. HRMS (APCI,

151.5, 151.9, 154.9, 155.4, 167.2, 193.2 ppm. HRMS (APCI, m/z): calcd.

m/z): calcd. for C₂₀H₂₂NO₅[M + H] 356.1498, found 356.1492.

for C₁₉H₁₉ClNO₄[M + H] 360.1003, found 360.0995.

Methyl 2-(2-Methoxybenzoyl)-3-(phenylamino)acrylate (4l).

3-(Cyclopropylamino)-2-(2,4-dimethoxybenzoyl)acrylonitrile

General Procedure B (at 100 °C): Yellowish oil (purified by column

(4w). General Procedure A (at 50 °C): Yellow, low freezing (puri- chromatography; eluent: hexane/EtOAc, 6:4), yield 70 % (0.19 g). ¹H

fied by column chromatography; eluent: hexane/EtOAc, 6:4), yield

83 % (0.18 g). H NMR (500 MHz, CDCl₃): δ = 0.77–0.91 (m, 4.16 H),

NMR (500 MHz, CDCl₃): δ = 3.59 (s, 2.41 H), 3.60 (s, 0.55 H), 3.82 (s,

3.00 H), 6.76–7.52 (m, 9.00 H), 8.45 (d, J = 14.0 Hz, 0.20 H), 8.52 (d,

1

2.91 (m, 0.98 H), 3.82 (s, 3.00 H), 3.87 (s, 3.07 H), 6.47 (d, J = 2.2 Hz, J = 13.4 Hz, 0.80 H), 10.90 (d, J = 14.0 Hz, 0.17 H), 12.60 (d, J =

0.99 H), 6.50 (dd, J = 8.5, 2.2 Hz, 1.09 H), 7.32 (d, J = 8.5 Hz, 0.93 H),

7.36 (d, J = 8.5 Hz, 0.07 H), 7.21 (d, J = 13.5 Hz, 0.93 H), 8.15 (d, J =

14.8 Hz, 0.04 H), 10.80 (d, J = 13.5 Hz, 0.85 H) ppm. ¹³C NMR

13.4 Hz, 0.73 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 51.2, 55.6,

55.8, 104.9, 110.5, 110.7, 115.8, 117.3, 117.8, 117.9, 120.7, 125.2,

125.6, 128.3, 129.4, 129.5, 130.0, 131.1, 131.4, 132.2, 139.2, 151.3,

(125 MHz, CDCl₃): δ = 6.6, 6.6, 14.3, 21.2, 30.4, 55.6, 55.7, 55.7, 60.5, 151.6 156.4, 167.9, 194.8 ppm. HRMS (APCI, m/z): calcd. for

84.5, 98.8, 104.9, 120.7, 122.1, 130.5, 158.5, 160.3, 163.2, 192.4 ppm. C₁₈H₁₈NO₄[M + H] 312.1236, found 312.1232.

HRMS (APCI, m/z): calcd. for C₁₅H₁₇N₂O₃[M + H] 273.1239, found

273.1233.

Ethyl 3-[(3-Chloro-2-methylphenyl)amino]-2-(2,6-dimethoxy-

benzoyl)acrylate (4o). General Procedure B (at 100 °C): White

General Procedure B for Synthesis of Enamines 4f, 4g, 4j, 4l, 4o,

4r, 4u, 4v: To a solution or suspension of 3a–c, 7a–c or 10 (1 mmol)

in toluene (4 mL) was added corresponding arylamine (1.2 mmol)

and the mixture was stirred at temperatures from r.t. to 100 °C. The

reaction was checked by TLC and the typical reaction time was 12 h.

The residue after evaporation was either crystallized or purified by

column chromatography giving 4f, 4g, 4j, 4l, 4o, 4r, 4u, 4v.

solid (precipitated after cooling), yield 55 % (0.11 g), m.p. 162.7–

168.8 °C. H NMR (500 MHz, CDCl₃): δ = 0.90 (t, J = 7.1 Hz, 0.52 H),

1

0.94 (t, J = 7.3 Hz, 2.44 H), 2.43 (s, 0.50 H), 2.51 (s, 2.45 H), 3.74–3.79

(m, 6.00 H), 3.94–4.06 (m, 1.99 H), 6.53–6.60 (m, 2.13 H), 7.14–7.32

(m, 4.00 H), 8.56 (d, J = 13.6 Hz, 0.82 H), 8.65 (d, J = 13.2 Hz, 0.16

H), 11.36 (d, J = 13.2 Hz, 0.13 H), 13.09 (d, J = 13.6 Hz, 0.67 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 13.6, 13.9, 14.3, 14.6, 56.1, 56.2, 59.9,

104.0, 104.1, 106.0, 114.7, 114.7, 121.7, 126.1, 126.4, 126.6, 127.7,

127.8, 129.6, 129.8, 136.0, 139.5, 152.5, 153.3, 156.7, 156.9, 166.9,

194.5 ppm. HRMS (APCI, m/z): calcd. for C₂₁H₂₃ClNO₅[M + H]

404.1265, found 404.1260.

Methyl 2-(2,4-Dimethoxybenzoyl)-3-(p-tolylamino)acrylate (4f).

General Procedure B (at 100 °C): Brown, low freezing oil (purified

by column chromatography; eluent: hexane/EtOAc, 4:1 and crystalli-

1

zation from iPrOH), yield 66 % (0.44 g), m.p. 94.3–96.7 °C. H NMR

(500 MHz, CDCl₃): δ = 2.33 (s, 0.51 H), 2.34 (s, 2.53 H), 3.58 (s, 3.00

H), 3.75–3.78 (m, 3.00 H), 3.84 (s, 2.54 H), 3.86 (s, 0.61 H), 6.40 (d,

J = 2.0 Hz, 1.00 H), 6.53 (dd, J = 8.5, 2.0 Hz, 1 H), 7.03 (d, J = 8.5 Hz,

0.34 H), 7.10 (d, J = 8.41 Hz, 1.69 H), 7.16 (d, J = 8.5 Hz, 0.34 H),

7.18 (d, J = 8.6 Hz, 1.69 H), 7.39 (d, J = 8.5 Hz, 0.84 H), 7.53 (d, J =

8.6 Hz, 0.17 H), 8.32 (d, J = 13.6 Hz, 0.16 H), 8.40 (d, J = 13.5 Hz,

0.84 H), 10.68 (d, J = 13.6 Hz, 0.16 H), 12.40 (d, J = 13.5 Hz, 0.80

Ethyl 2-(2,5-Dimethoxybenzoyl)-3-(mesitylamino)acrylate (4r).

General Procedure B (at 100 °C): Yellowish oil (purified by column

chromatography; eluent: hexane/EtOAc, 4:1), yield 70 % (0.20 g). ¹H

NMR (500 MHz, CDCl₃): δ = 0.94–1.02 (m, 2.94 H), 2.22–2.35 (m, 9.00

H), 3.71–3.79 (m, 6.17 H), 3.93–4.01 (m, 2.00 H), 6.74–6.95 (m, 5.00

H), 7.91 (d, J = 14.2 Hz, 0.21 H), 8.05 (d, J = 13.7 Hz, 0.21 H), 10.41

(d, J = 14.1 Hz, 0.21 H), 12.03 (d, J = 13.7 Hz, 0.21 H) ppm. ¹³C NMR

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.8, 50.8, 51.1, 55.4, 55.4, (125 MHz, CDCl₃): δ = 13.8, 13.9, 14.1, 18.4, 18.5, 20.9, 43.3, 55.7,

55.4, 55.6, 97.9, 104.4, 117.0, 117.5, 125.0, 130.3, 130.3, 130.3, 135.1, 55.8, 56.2, 56.4, 59.6, 59.7, 60.4, 103.5, 111.9, 112.2, 113.2, 113.3,

136.8, 150.6, 162.6, 168.3, 193.1 ppm. HRMS (APCI, m/z): calcd. for 113.8, 115.9, 116.0, 129.6, 129.6, 132.4, 133.3, 135.2, 136.8, 136.9,

C₂₀H₂₂NO₅[M + H] 356.1498, found 356.1499.

150.5, 153.5, 158.8, 159.4, 167.6, 194.2 ppm. HRMS (APCI, m/z): calcd.

for C₂₃H₂₈NO₅[M + H] 398.1967, found 398.1973.

Methyl 2-(2,4-Dimethoxybenzoyl)-3-{[4-(trifluoromethyl)-

phenyl]amino}acrylate (4g). General Procedure B (at 100 °C):

White solid (crystallization from iPrOH), yield 76 % (0.31 g), m.p.

Ethyl 3-[(2-Bromo-4-methylphenyl)amino]-2-(5-chloro-2-meth-

oxybenzoyl)acrylate (4u). General Procedure B (at 100 °C): Yel-

low, low freezing oil (purified by column chromatography; eluent:

hexane/EtOAc, 6:4), yield 58 % (0.17 g). ¹H NMR (500 MHz, CDCl₃):

δ = 0.91 (t, J = 7.3 Hz, 0.87 H), 1.00 (t, J = 7.1 Hz, 2.26 H), 2.31–2.36

(m, 3.00 H), 3.76 (s, 3.06 H), 3.99–4.08 (m, 2.04 H), 6.75–6.82 (m, 1.00

H), 7.13–7.22 (m, 1.04 H), 7.27–7.50 (m, 3.86 H), 8.42–8.52 (m, 1.00

H), 11.21 (d, J = 13.8 Hz, 0.25 H), 12.74 (d, J = 13.1 Hz, 0.72 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 14.0, 20.6, 20.7, 55.9, 56.0,

60.0, 60.2, 105.7, 105.0, 111.7, 111.8, 113.7, 114.1, 116.2, 116.4, 125.7,

1

119.6–127.2 °C. H NMR (500 MHz, CDCl₃): δ = 3.60 (s, 3.00 H), 3.76

(s, 3.00 H), 3.85 (s, 3.00 H), 6.40 (d, J = 2.4 Hz, 1.00 H), 6.55 (dd, J =

8.6, 2.4 Hz, 1.00 H), 7.27 (d, J = 8.6 Hz, 2.00 H), 7.45 (d, J = 8.6 Hz,

0.87 H), 7.63 (d, J = 8.6 Hz, 2.00 H), 8.28 (d, J = 12.9 Hz, 0.06 H),

8.38 (d, J = 12.8 Hz, 0.91 H), 10.68 (d, J = 12.9 Hz, 0.06 H), 12.27 (d,

J = 12.8 Hz, 0.89 H) ppm. ¹³C NMR (500 MHz, CDCl₃): δ = 51.3, 55.3,

55.4, 97.9, 98.0, 104.6, 104.7, 106.98, 116.5, 117.0, 120.7 (q, J_C,F

272 Hz, CF₃), 122.9 (q, J_C,F= 272 Hz, CF₃), 124.3, 125.0 (q, J_C,F

=

272 Hz, CF₃), 126.54, 126.8, 127.1, 127.1, 127.2 (q, J_C,F= 272 Hz, CF₃), 125.7, 128.3, 128.8, 129.6, 129.7, 130.4, 130.5, 133.7, 133.8, 134.0,

127.2, 127.2, 130.8, 142.2, 148.8, 158.5, 163.2.168.0, 193.3 ppm. ¹⁹F 135.2, 135.2, 136.2, 136.7, 150.1, 150.4, 155.0, 155.6, 167.3, 168.5,

NMR (500 MHz, CDCl₃): δ = –62.15 ppm. HRMS (APCI, m/z): calcd.

190.5, 192.9 ppm. HRMS (APCI, m/z): calcd. for C₂₀H₂₀BrClNO₅[M +

for C₂₀H₁₉F₃NO₅[M + H] 410.1215, found 410.1217.

H] 452.0264, found 452.0262.

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2-(2,4-Dimethoxybenzoyl)-3-(phenylamino)acrylonitrile

General Procedure B (at 100 °C): White solid (precipitated after

cooling to –10 °C), yield 75 % (0.46 g), mp. 176.5–182.1 °C. H NMR

(4v).

solid, yield 77 %, m.p. 239.8–243.7 °C. General Procedure B: White

solid, yield 74 %, m.p. 239.6–243.9 °C. ¹H NMR (250 MHz, CDCl₃):

δ = 1.54 (t, J = 7.4 Hz, 3.10 H), 3.93 (m, 5.83 H), 4.19 (q, J = 7.4 Hz,

1

(500 MHz, CDCl₃): δ = 3.86 (s, 3.06 H), 3.91 (s, 2.99 H), 6.51 (d, J = 2.04 H), 6.81 (d, J = 2.3 Hz, 0.97 H), 7.02 (dd, J = 9.0, 2.3 Hz, 1.00 H),

2.3 Hz,1.01 H), 6.55 (dd, J = 8.5, 2.3 Hz, 1.02 H); 7.16–7.20 (m, 2.00

H), 7.22–7.26 (m, 0.98 H), 7.39–7.45 (m, 3.06 H), 7.93 (d, J = 12.8 Hz,

1.00 H), 8.57 (d, J = 14.9 Hz, 0.02 H), 12.55 (d, J = 14.0 Hz, 0.90

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 55.6, 55.8, 87.0, 98.8, 105.1,

117.7, 117.8, 120.3, 121.7, 126.3, 130.2, 130.9, 138.4, 152.4, 158.8,

163.7, 192.7 ppm. HRMS (APCI, m/z): calcd. for C₁₈H₁₇N₂O₃[M + H]

309.1239, found 309.1224.

8.47–8.51 (m, 1.87 H) ppm. ¹³C NMR (250 MHz, CDCl₃): δ = 14.4,

48.9, 52.2, 55.8, 99.4, 110.7, 112.5, 123.4, 130.2, 140.3, 148.9, 163.2,

166.9, 173.9 ppm. HRMS (APCI, m/z): calcd. for C₁₄H₁₆NO₄[M + H]

262.1079, found 262.1072.

Methyl 1-Cyclopropyl-7-methoxy-4-oxo-1,4-dihydroquinoline-

3-carboxylate (14b). General Procedure A (at 95 °C): White solid,

yield 59 %, m.p. 239.8–243.7 °C. General Procedure B: White solid,

yield 38 %, m.p. 239.7–243.5 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.15

(s, 2.02 H), 1.33 (m, 2.04 H), 3.43 (m, 1.01 H), 3.93 (s, 3.03 H), 3.96 (s,

3.13 H), 7.04 (dd, J = 8.9, 2.3 Hz, 1.02 H), 7.29 (d, J = 2.3 Hz, 1.02 H),

8.44 (d, J = 8.9 Hz, 1.00 H), 8.58 (s, 1.00 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 34.4, 52.1, 55.7, 99.9, 110.7, 112.9, 122.6, 129.7, 142.2,

148.9, 162.9, 166.7, 173.9 ppm. HMRS (APCI, m/z): calcd. for

Methyl 3-(2,4-Dimethoxyphenyl)-3-oxo-2-(2-phenylhydrazono)-

propanoate (4h): A solution of NaNO₂(332 mg, 4.8 mmol) in water

(3 mL) was added over the course of 30 min to a solution of aniline

(450 mg, 4.8 mmol) in diluted HCl (3 mL, 1:3) cooled to 0 °C. Reac-

tion mixture was stirred at 0 °C for 1 h and the solution of di-

azonium salt prepared in this manner was dropped into a solution

of compound 2a (952 mg, 4 mmol) and AcOK (1.2 g, 12 mmol) in

MeOH/dioxane (13 mL/5 mL) at 0 °C over the course of 15 min. The

resulting yellow suspension was stirred for 30 min at 0 °C and then

1 h at r.t. Filtration provided 94 % (1.28 g) of yellowish crystals of

desired product, m.p. 118.3–123.6 °C. ¹H NMR (500 MHz, CDCl₃): δ =

3.75 (s, 3.00 H), 3.78 (s, 3.00 H), 3.86 (s, 3.00 H), 6.38 (d, J = 2.2 Hz,

1 H), 6.58 (dd, J = 8.6, 2.2 Hz, 1.00 H), 7.12 (s, 1.00 H), 7.33–7.44 (m,

4.00 H), 7.60 (d, J = 8.6 Hz, 1.00 H), 13.89 (s, 1.00 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 51.9, 55.2, 55.6, 97.9, 105.5, 116.0, 122.4,

124.8, 129.3, 129.5, 132.0, 142.0, 159.3, 164.4, 165.9, 188.7 ppm.

HRMS (APCI, m/z): calcd. for C₁₈H₁₉N₂O₄[M + H] 343.1294, found

343.1298.

C₁₅H₁₆NO₄[M + H] 274.1079, found 274.1081.

Methyl 1-(tert-Butyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-

carboxylate (14c). General Procedure A (at 105 °C): White solid

(crystallized from iPrOH), yield 50 %, m.p. 178.3–182.2 °C. General

Procedure B: No reaction. ¹H NMR (500 MHz, CDCl₃): δ = 1.87 (s,

9.03 H), 3.92 (s, 6.00 H), 7.03 (dd, J = 9.0, 2.2 Hz, 0.98 H), 7.31 (d, J =

2.2 Hz, 0.99 H), 8.56 (d, J = 9.0 Hz, 0.96 H), 8.88 (s, 1.00 H) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 30.8, 52.2, 55.8, 63.0, 105.0, 109.6, 111.6,

124.9, 130.5, 140.4, 146.6, 161.7, 167.6, 173.6 ppm. HMRS (APCI,

m/z): calcd. for C₁₆H₁₉NO₄[M + H] 290.1392, found 290.1387.

Methyl

7-Methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-

carboxylate (14d). General Procedure A (at 80 °C): White solid,

yield 89 % (0.41 g), m.p. 180.2–187.7 °C. General Procedure B:

White solid, yield 65 % (0.30 g), m.p. 180.1–187.8 °C. ¹H NMR

(500 MHz, CDCl₃): δ = 3.72 (s, 3.00 H), 3.91 (s, 3.00 H), 6.33 (d, J =

2.3 Hz, 1.00 H), 6.99 (dd, J = 8.94, 2.3 Hz, 1.00 H), 7.39–7.46 (m,

2.00 H), 7.57–7.64 (m, 3.00 H), 8.45–8.49 (m, 2.00 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 51.6, 55.0, 100.4, 110.4, 112.7, 122.0, 126.8,

129.0, 129.5, 129.9, 140.1, 141.7, 148.4, 162.3, 165.9, 173.4 ppm.

HRMS (APCI, m/z): calcd. for C₁₈H₁₆NO₄[M + H] 310.1079, found

310.1081.

1-(tert-Butyl)-7-Methoxy-4-oxo-1,4-dihydroquinoline-3-carb-

oxamide (12): BSA (440 μL, 1.83 mmol) was added in one portion

to a solution of 4c (234 mg, 0.73 mmol) and KF (220 mg, 2.92 mmol)

in DMSO (4 mL). The reaction mixture was heated at 100 °C under

nitrogen atmosphere for 8 h. To the cooled down reaction mixture

was added ice water (10 mL). Solids precipitated in the stirring mix-

ture in the course of time were filtered off and rinsed with a few

portions of water to give 110 mg (55 %) of 12 in the form of beige

crystals, m.p. is N/A (decomposition over 218.5 °C, bubbles were

observed). ¹H NMR (500 MHz, CDCl₃): δ = 1.89 (s, 9.23 H), 3.94 (s,

3.14 H), 5.73 (s, 0.91 H), 7.08 (dd, J = 8.94, 2.3 Hz, 0.97 H), 7.38 (d,

J = 2.3 Hz, 0.96 H), 8.54 (d, J = 9.2 Hz, 1.00 H), 9.14 (s, 0.97 H), 9.80

(s, 0.87 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 30.7, 40.9, 55.7,

63.36, 104.7, 110.2, 112.0, 123.44, 129.7, 140.7, 145.3, 161.7, 167.4,

175.6 ppm. MS (APCI, m/z): calcd. for C₁₅H₁₉N₂O₃[M + H] 275.1396,

found 275.1399.

Methyl 1-[4-(benzyloxy)phenyl]-7-methoxy-4-oxo-1,4-dihydro-

quinoline-3-carboxylate (14e). General Procedure A (at 75 °C):

White solid, yield 77 % (80 mg), m.p. 142.1–148.3 °C. General Proce-

dure B: White solid, yield 72 % (75 mg), m.p. 142.0–148.6 °C. ¹H

NMR (250 MHz, CDCl₃): δ = 3.67 (s, 3.00 H), 3.85 (s, 3 H), 5.10 (s,

2.00 H), 6.28 (d, J = 1.8 Hz, 1.00 H), 6.93 (dd, J = 8.8, 1.8 Hz, 1.00 H),

7.09 (d, J = 6.9 Hz, 1.00 H), 7.17–7.46 (m, 8.00 H), 8.36–8.45 (m, 2.00

H) ppm. ¹³C NMR (63 MHz, CDCl₃): δ = 52.1, 55.6, 70.5, 101.0, 110.9,

113.3, 116.4, 122.5, 127.5, 128.4, 128.5, 128.8, 129.5, 133.6, 136.1,

142.7, 149.3, 159.6, 162.8, 166.5, 174.0 ppm. HRMS (APCI, m/z): calcd.

for C₂₅H₂₂NO₅[M + H] 415.1420, found 415.1425.

General Procedure A for Cyclization Using BSA (14a–w): To a

solution 4a (0.1 mmol) in 1 mL of dry DMF (ACN in the case of 14v)

under N₂atmosphere was added BSA (0.23 mmol) and the mixture

was stirred at 75–105 °C typically for 12–24 h. The reaction mixture

was cooled to r.t. and ice cold water (15 mL) was added to enable

precipitation of pure cyclized product 14a (14i and 14r had to be

extracted with EtOAc). Solid products could be generally crystal-

lized from iPrOH.

Methyl

7-Methoxy-4-oxo-1-(p-tolyl)-1,4-dihydroquinoline-3-

carboxylate (14f). General Procedure A (at 75 °C): White solid,

yield 82 % (40 mg), m.p. 219.7–229.9 °C. General Procedure B:

White solid, yield 62 % (30 mg), m.p. 219.3–230.2 °C. ¹H NMR

(250 MHz, CDCl₃): δ = 2.49 (s, 3.00 H), 3.72 (s, 3.10 H), 3.95 (s, 3.02

H), 6.35 (d, J = 2.1 Hz, 0.96 H), 6.99 (dd, J = 9.3, 2.1 Hz, 0.97 H), 7.28

(d, J = 8.1 Hz, 2.00 H), 7.40 (d, J = 8.1 Hz, 1.98 H), 8.43–8.52 (m, 1.92

H) ppm. ¹³C NMR (62.89 MHz, CDCl₃): δ = 21.3, 52.1, 55.5, 100.9,

110.9, 113.2, 127.0, 129.5, 130.0, 138.2, 140.3, 142.4, 149.1, 162.8,

166.6, 173.9 ppm. HRMS (APCI, m/z): calcd. for C₁₉H₁₈NO₄[M + H]

324.1236, found 324.1241.

General Procedure B for Cyclization Using K₂CO₃(14a,b, 14d–l,

14n,o, 14q, 14s–u, 14t): To a solution 4a (0.1 mmol) in 1 mL of

dry DMF under N₂atmosphere was added K₂CO₃(0.04 mmol) and

the mixture was stirred at 115 °C typically for 12–24 h. The reaction

mixture was cooled down to r.t. and ice cold water (15 mL) was

added to enable precipitation of cyclized product 14a. Solid prod-

ucts could be crystallized generally from iPrOH.

Methyl 1-Ethyl-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carb-

oxylate (14a) Following General Procedure A (at 95 °C): White

Methyl 7-Methoxy-4-oxo-1-[4-(trifluoromethyl)phenyl]-1,4-di-

hydroquinoline-3-carboxylate (14g). General Procedure A (at

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75 °C): White solid, yield 75 % (141 mg), m.p. is N/A (decomposition

over 215.0 °C). General Procedure B: White solid, yield 80 %

(150 mg), m.p. is N/A (decomposition over 215.0 °C). ¹H NMR

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 52.3, 111.1, 117.8, 125.5,

127.5, 127.7, 128.6, 130.2, 130.6, 132.5, 140.7, 140.8, 149.1, 166.5,

174.5 ppm. HRMS (APCI, m/z): calcd. for C₁₇H₁₄NO₃[M + H]

(500 MHz, CDCl₃): δ = 3.76 (s, 3.21 H), 3.91 (s, 2.98 H), 6.30 (d, J = 280.0974, found 280.0970.

2.2 Hz, 0.96 H), 7.03 (dd, J = 8.9, 2.2 Hz, 1 H), 7.61 (d, J = 8.4 Hz,

2.13 H), 8.45 (s, 0.94 H), 8.50 (d, J = 8.9 Hz, 0.99 H) ppm. ¹³C NMR

(500 MHz, CDCl₃): δ = 52.2, 55.7, 100.8, 111.7, 113.2, 122.5, 127.8,

128.1, 129.9, 132.2, 141.8, 143.7, 148.3, 163.1, 166.2, 173.7 (green

are the quaternary carbons identified by HMBC, see Supplementary

Data) ppm. ¹⁹F NMR (500 MHz, CDCl₃): δ = –62.20 ppm. HRMS (APCI,

m/z): calcd. for C₁₉H₁₅F₃NO₄[M + H] 378.0953, found 378.0957.

Ethyl 1-Cyclopropyl-5-methoxy-4-oxo-1,4-dihydroquinoline-3-

carboxylate (14m). General Procedure A (at 100 °C): White solid,

yield 78 % (45 mg), m.p. 183.9–187.8 °C. General Procedure B: No

reaction. ¹H NMR (500 MHz, CDCl₃): δ = 1.03–1.13 (m, 2.09 H), 1.24–

1.32 (m, 2.17 H), 1.38 (t, J = 7.2 Hz, 2.96 H), 3.34–3.42 (m, 1.00 H),

3.96 (s, 3.05 H), 4.37 (q, J = 7.2 Hz, 2.00 H), 6.85 (d, J = 8.4 Hz, 0.99

H), 7.47 (d, J = 8.4 Hz, 1.01 H), 7.52–7.60 (m, 1.00 H), 8.45 (s, 0.99

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 8.7, 14.6, 35.3, 56.5, 61.0,

107.1, 108.4, 132.8, 143.4, 147.4, 161.5, 166.5, 174.7 ppm. HRMS

(APCI, m/z): calcd. for C₁₆H₁₈NO₄[M + H] 288.1236, found 288.1233.

Methyl 7-Methoxy-4-oxo-1-phenyl-1,4-dihydrocinnoline-3-carb-

oxylate (14h). General Procedure A (at 80 °C): Brownish solid,

yield 79 % (240 mg), m.p. 181.4–185.4 °C. General Procedure B:

Brownish solid, yield 22 % (67 mg), m.p. 181.4–185.4 °C. ¹H NMR

(500 MHz, CDCl₃): δ = 3.74 (s, 3.00 H), 3.96 (s, 3.03 H), 6.48 (d, 0.99

H), 7.07 (dd, J = 9.1, 2.4 Hz, 1.00 H), 7.48–7.64 (m, 5.13 H), 8.36 (d,

J = 9.1 Hz, 1.0 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.4, 48.9,

52.2, 55.8, 99.4, 110.7, 112.5, 123.4, 130.2, 140.3, 148.9, 163.2, 166.9,

173.92 ppm. HRMS (APCI, m/z): calcd. for C₁₇H₁₅N₂O₄[M + H]

311.1032, found 311.1035.

Ethyl 5-Methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carb-

oxylate (14n). General Procedure A (at 100 °C): White solid, yield

93 % (30 mg), m.p. 197.3–203.6 °C. General Procedure B: Beige

solid, yield 94 % (31 mg), m.p. 197.0–203.9 °C. ¹H NMR (500 MHz,

[D₆]DMSO): δ = 1.24 (t, J = 7.2 Hz, 3.16 H), 3.85 (s, 3.05 H), 4.18 (q,

J = 7.2 Hz, 2.03 H), 3.38 (d, J = 8.3 Hz, 1.00 H), 6.96 (d, J = 8.3 Hz,

1.00 H), 7.45–7.52 (m, 1.00 H), 7.56–7.69 (m, 5.16 H), 8.22 (s, 1.02

H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 14.2, 56.1, 59.8, 107.0,

109.6, 112.5, 117.5, 127.7, 129.8, 130.4, 132.9, 141.1, 143.0, 146.4,

160.2, 164.4, 173.0 ppm. HRMS (APCI, m/z): calcd. for C₁₉H₁₈NO₄[M

+ H] 324.1236, found 324.1221.

Methyl 1-Cyclopropyl-7-methoxy-8-methyl-4-oxo-1,4-dihydro-

quinoline-3-carboxylate (14i). General Procedure A (at 100 °C):

Beige solid, yield 67 % (29 mg), m.p. is N/A (decomposition over

175.1 °C). General Procedure B: Brownish solid, yield 33 % (15 mg),

m.p. is N/A (decomposition over 175.1 °C). ¹H NMR (500 MHz,

CDCl₃): δ = 0.77–0.86 (m, 2.02 H), 1.04–1.10 (m, 2.00 H), 2.53 (s, 2.96

H), 3.82 (s, 3.05 H), 3.84–3.92 (m, 3.96 H), 6.92 (d, J = 9.1 Hz, 1.00

H), 8.25 (d, J = 9.1 Hz, 0.97 H), 8.59 (s, 1.00 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 11.2, 14.2, 40.1, 42.2, 46.3, 109.1, 110.3, 114.6,

124.0, 127.0, 142.5, 153.1, 161.8, 166.6, 173.4 ppm. HRMS (APCI,

m/z): calcd. for C₁₆H₁₇N₂O₄[M + H] 288.1236, found 288.1233.

Ethyl

1-(2-Chloro-3-methylphenyl)-5-methoxy-4-oxo-1,4-di-

hydroquinoline-3-carboxylate (14o). General Procedure A (at

100 °C): Brown solid, yield 94 % (35 mg), m.p. is N/A (decomposi-

tion over 175.2 °C). General Procedure B: Yellowish solid, yield

67 % (25 mg), m.p. is N/A (decomposition over 175.3 °C). ¹H NMR

(500 MHz, CDCl₃): δ = 1.31–1.44 (m, 3.19 H), 1.57 (s, 3.44 H), 2.08 (s,

3.00 H), 3.99 (s, 3.08 H), 4.30–4.43 (m, 1.98 H), 6.24 (d, J = 8.5 Hz,

0.97 H), 6.82 (d, J = 8.5 Hz, 0.98 H), 7.32–7.42 (m, 2.14 H), 7.60 (d,

J = 8.5 Hz, 1.07 H), 8.21 (s, 1.00 H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 14.6, 15.1, 56.6, 61.1, 107.1, 109.1, 114.0, 127.0, 128.5, 131.3,

133.1, 135.1, 136.7, 141.4, 146.8, 161.6 ppm. HRMS (APCI, m/z): calcd.

for C₂₀H₁₉ClNO₄[M + H] 372.1003, found 372.1002.

Methyl 7-Methoxy-8-methyl-4-oxo-1-phenyl-1,4-dihydroquin-

oline-3-carboxylate (14j). General Procedure A (at 100 °C):

White solid (crystallized from iPrOH), yield 91 % (50 mg), m.p. is N/

A (decomposition over 172.4 °C). General Procedure B: Brownish

solid, yield 31 % (10 mg), m.p. is N/A (decomposition over 172.4 °C).

¹H NMR (500 MHz, CDCl₃): δ = 1.50–1.52 (m, 4.16 H), 3.91 (s, 6.00

H), 7.09 (d, J = 9.4 Hz, 0.99 H), 7.34 (d, J = 7.3 Hz, 1.97 H), 7.42–7.55

(m, 3.04 H), 8.47 (d, J = 9.4 Hz, 1.03 H), 8.52 (s, 0.95 H) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 13.5, 31.1, 52.2, 56.2, 109.6, 110.7, 114.7,

124.2, 125.9, 127.1, 128.7, 130.2, 140.7, 145.6, 152.9, 161.8, 166.5,

174.6 ppm. HRMS (APCI, m/z): calcd. for C₁₉H₁₈NO₄[M + H]

324.1236, found 324.1234.

Ethyl 1-Cyclopropyl-6-methoxy-4-oxo-1,4-dihydroquinoline-3-

carboxylate (14p). General Procedure A (at 100 °C): Brownish

solid, yield 64 % (36 mg), m.p. is N/A (decomposition over 199.8 °C).

1

General Procedure B: No reaction. H NMR (500 MHz, [D₆]DMSO):

δ = 1.06–1.12 (m, 2.08 H), 1.21–1.27 (m, 1.94 H), 1.29 (t, J = 7.2 Hz,

3.13 H), 3.63–3.71 (m, 1.11 H), 3.88 (s, 3.10 H), 4.23 (q, J = 7.2 Hz,

2.02 H), 7.46 (dd, J = 9.2, 3.1 Hz, 0.99 H), 7.67 (d, J = 3.1 Hz, 0.98 H),

8.06 (d, J = 9.2 Hz, 1.01 H), 8.45 (s, 1.00 H) ppm. ¹³C NMR (125 MHz,

[D₆]DMSO): δ = 7.5, 14.3, 34.8, 55.5, 59.7, 106.5, 108.8, 119.4, 121.7,

129.1, 134.8, 147.1, 156.8, 164.6, 172.3 ppm. HRMS (APCI, m/z): calcd.

for C₁₆H₁₈NO₄[M + H] 288.1236, found 288.1228.

Methyl 1-Cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxyl-

ate (14k). General Procedure A (at 100 °C): White solid, yield

69 % (25 mg), m.p. is N/A (decomposition over 237.5 °C). General

Procedure B: White solid, yield 41 % (15 mg), m.p. is N/A (decom-

position over 237.5 °C). ¹H NMR (500 MHz, CDCl₃): δ = 1.11–1.17

(m, 1.95 H), 1.29–1.37 (m, 1.95 H), 3.38–3.56 (m, 1.00 H), 3.92 (s, 3.00

H), 7.42–7.48 (m, 0.99 H), 7.67–7.73 (m, 1.00 H), 7.92 (d, J = 8.4 Hz,

1.01 H), 8.50 (d, J = 8.4 Hz, 1.02 H), 8.63 (s, 1.01 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 8.3, 34.6, 52.2, 110.8, 116.5, 125.4, 127.8,

128.8, 132.6, 140.7, 1449.0, 166.7, 174.4 ppm. HRMS (APCI, m/z):

calcd. for C₁₄H₁₄NO₃[M + H] 244.0974, found 244.0964.

Ethyl 6-Methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carb-

oxylate (14q). General Procedure A (at 80 °C): Beige solid, yield

70 % (45 mg), m.p. 193.0–197.2 °C. General Procedure B: Dark

solid, yield 15 % (10 mg), m.p. not determined due to insufficient

purity. ¹H NMR (500 MHz, CDCl₃): δ = 1.41 (t, J = 7.4 Hz, 3.00 H),

3.93 (s, 2.94 H), 4.40 (q, J = 7.4 Hz, 1.99 H), 6.94 (d, J = 9.3 Hz, 0.98

H), 7.13 (dd, J = 9.3, 2.6 Hz, 0.97 H), 7.43 (d, J = 7.2 Hz, 1.99 H), 7.57–

7.66 (m, 2.97 H), 7.98 (d, J = 2.6 Hz, 0.97 H), 8.49 (s, 0.97 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 14.6, 56.0, 61.1, 107.0, 110.5, 119.5,

122.9, 127.5, 130.2, 130.5, 135.2, 141.0, 147.7, 157.6, 162.6, 166.2,

174.0 ppm. HRMS (APCI, m/z): calcd. for C₁₉H₁₈NO₄[M + H]

324.1236, found 324.1232.

Methyl

4-Oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylate

(14l). General Procedure A (at 100 °C): White solid, yield 67 %

(28 mg), m.p. is N/A (decomposition over 234.4 °C). General Proce-

dure B: White solid, yield 48 % (20 mg), m.p. is N/A (decomposition

1

over 234.4 °C). H NMR (500 MHz, CDCl₃): δ = 3.92 (s, 3.00 H), 6.99

(d, J = 8.5 Hz, 0.99 H), 7.39–7.68 (m, 7.09 H), 8.51–8.58 (m, 1.99

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Ethyl 1-Mesityl-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carb-

oxylate (14r). General Procedure A (at 95 °C): Brown oil, yield

70 % (50 mg). General Procedure B: No reaction. ¹H NMR

(500 MHz, CDCl₃): δ = 1.38 (t, J = 7.1 Hz, 3.05 H), 1.94 (s, 6.00 H),

2.37 (s, 3.02 H), 3.89 (s, 3.10 H), 4.36 (q, J = 7.1 Hz, 2.04 H), 6.67 (d,

J = 9.2 Hz, 0.99 H), 7.04 (s, 2.00 H), 7.08 (dd, J = 9.2, 3.1 Hz, 0.99 H),

7.96 (d, J = 3.1 Hz, 0.99 H), 8.29 (s, 0.96 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 14.5, 17.2, 21.2, 43.3, 55.9, 60.8, 10.1, 110.9, 118.4, 123.2,

130.0, 130.0, 134.2, 135.6, 136.1, 140.2, 147.6, 157.6, 165.9,

174.2 ppm. HRMS (APCI, m/z): calcd. for C₂₂H₂₄NO₄[M + H]

366.1705, found 366.1703.

3.69 (s, 3.04 H), 3.95 (s, 3.00 H), 6.26 (d, J = 2.2 Hz, 1.00 H), 7.19 (dd,

J = 9.0, 2.2 Hz, 1.04 H), 7.62–7.72 (m, 5.10 H), 8.20 (d, J = 9.0 Hz,

1.02 H), 8.84 (s, 1.00 H) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ =

55.6, 94.4, 101.2, 114.1, 116.1, 119.5, 127.6, 127.9, 130.1, 130.3, 139.8,

142.4, 150.7, 162.8, 173.3 ppm. HRMS (APCI, m/z): calcd. for

C₁₇H₁₃N₂O₂[M + H] 277.0977, found 277.0973.

Acknowledgments

Financial support of Zentiva k.s., Czech Republic is gratefully

acknowledged. The authors also thank Jiří Břicháč and Stanislav

Kalášek for LC-MS and HRMS data and Lukáš Vrzal, Jiří Mikšátko

and Markéta Zajícová for NMR spectroscopic data.

Ethyl

6-Chloro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-

carboxylate (14s). General Procedure A (at 105 °C): White solid

(crystallized from iPrOH), yield 78 % (45 mg), m.p. is N/A (decompo-

sition above 167.5 °C). General Procedure B: Yellow solid, yield

1

52 % (30 mg), m.p. is N/A (decomposition above 167.4 °C). H NMR

(500 MHz, CDCl₃): δ = 1.10–1.18 (m, 2.14 H), 1.34 (q, J = 7.0 Hz, 2.05

H), 1.41 (t, J = 7.0 Hz, 3.07 H), 3.42–3.50 (m, 1.01 H), 4.39 (q, J =

7.0 Hz, 2.00 H), 7.63 (dd, J = 9.0, 2.6 Hz, 0.98 H), 7.87 (d, J = 9.0 Hz,

1.00 H), 8.42 (d, J = 2.6 Hz, 0.94 H), 8.58 (s, 1.00 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 8.4, 14.6, 34.7, 61.2, 111.5, 118.2, 127.3, 129.9,

131.8, 132.8, 139.2, 148.8, 165.7, 173.3 ppm. HRMS (APCI, m/z): calcd.

for C₁₅H₁₅ClNO₃[M + H] 292.0740, found 292.0738.

Keywords: Nitrogen heterocycles · C–O bond cleavage ·

Cyclization · Aromatic substitution · Silanes

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Ethyl

6-Chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carb-

oxylate (14t). General Procedure A (at 80 °C): White solid (crystal-

lized from iPrOH), yield 80 % (51 mg), m.p. is N/A (decomposition

over 218.7 °C). General Procedure B: Yellow solid, yield 52 %

(30 mg), m.p. is N/A (decomposition over 218.5 °C). ¹H NMR

(500 MHz, CDCl₃): δ = 1.39 (t, J = 7.1 Hz, 2.99 H), 4.39 (q, J = 7.1 Hz,

2.00 H), 6.94 (d, J = 9.0 Hz, 0.99 H), 7.38–7.50 (m, 3.03 H), 7.58–7.69

(m, 3.04 H), 8.46–8.52 (m,1.98 H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 14.6, 61.2, 111.8, 119.5, 127.0, 127.4, 129.6, 130.4, 130.7, 131.8,

132.7, 139.2, 140.6, 148.8, 165.4, 173.3 ppm. HRMS (APCI, m/z): calcd.

for C₁₈H₁₅ClNO₃[M + H] 328.0740, found 328.0738.

Ethyl 1-(2-Bromo-4-methylphenyl)-7-chloro-4-oxo-1,4-dihydro-

quinoline-3-carboxylate (14u). General Procedure A (at 85 °C):

Brown solid, yield 97 % (55 mg), m.p.180.5–187.9 °C. General Proce-

dure B: Orange solid, yield 50 % (28 mg), m.p. 180.3–188.1 °C. ¹H

NMR (500 MHz, CDCl₃): δ = 1.39 (t, J = 7.2 Hz, 2.98 H), 2.49 (s, 3.00

H), 4.39 (q, J = 7.2 Hz, 2.00 H), 6.71 (d, J = 9.0 Hz, 1.00 H), 7.34–7.40

(m, 2.00 H), 7.44 (dd, J = 9.0, 2.3 Hz, 1.04 H), 7.66 (s, 0.98 H), 8.34

(s, 0.97 H), 8.48 (d, J = 2.3 Hz, 0.99 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 13.8, 14.5, 21.2, 23.1, 45.9, 61.2, 112.1, 112.2, 119.0,

122.3, 127.1, 129.4, 129.4, 130.3, 131.8, 132.9, 135.0 136.6, 138.7,

143.1, 148.9, 165.3, 173.5 ppm. HRMS (APCI, m/z): calcd. for

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K. Grohe, H.-J. Zeiler, K. G. Metzger, Bayer, US4544658, 1985.

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Sciences, WO2008/33836 A2, 2008.

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2003.

C₁₉H₁₆BrClNO₃[M + H] 420.0002, found 420.0007.

1-Cyclopropyl-7-Methoxy-4-oxo-1,4-dihydroquinoline-3-carbo-

nitrile (14v). General Procedure A (at 70 °C): Yellow solid, yield

57 % (15 mg), m.p. is N/A (decomposition started at 229.9 °C). Gen-

1

eral Procedure B: No reaction. H NMR (500 MHz, [D₆]DMSO): δ =

1.11–1.17 (m, 2.01 H), 1.18–1.27 (m, 1.99 H), 3.59–3.67 (m, 1.02 H),

3.95 (s, 3.00 H), 7.18 (dd, J = 8.9, 2.4 Hz, 1.00 H), 7.47 (d, J = 2.4 Hz,

0.99 H), 8.12 (d, J = 8.9 Hz, 1.00 H), 8.71 (s, 1.00 H) ppm. ¹³C NMR

(125 MHz, [D₆]DMSO): δ = 7.5, 35.0, 55.9, 93.6, 100.8, 114.3, 116.5,

119.5, 127.7, 142.6, 150.4, 163.0, 173.3 ppm. HRMS (APCI, m/z): calcd.

for C₁₄H₁₃N₂O₂[M + H] 241.0977, found 241.0972.

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7-Methoxy-4-Oxo-1-phenyl-1,4-dihydroquinoline-3-carbo-

nitrile (14w). General Procedure A (at 70 °C): Flesh coloured solid,

yield 90 % (50 mg), m.p. is N/A (decomposition over 246.4 °C). Gen-

eral Procedure B: Yellow solid, yield 72 % (25 mg), m.p. is N/A

1

(decomposition over 246.4 °C). H NMR (500 MHz, [D₆]DMSO): δ =

Eur. J. Org. Chem. 2016, 2336–2350

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Full Paper

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Received: February 17, 2016

Published Online: April 13, 2016

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Article Doi

Synthesis of 4-Quinolones: N,O-Bis(trimethylsilyl)acetamide-Mediated Cyclization with Cleavage of Aromatic C-O Bond

DOI: 10.1002/ejoc.201600178

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