An improved microwave assisted protocol for Yonemitsu-type trimolecular condensation

Tetrahedron 70 (2014) 6781e6788

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Tetrahedron journal homepage: www.elsevier.com/locate/tet

An improved microwave assisted protocol for Yonemitsu-type trimolecular condensation Angelo Viola, Lucia Ferrazzano, Giulia Martelli, Sebastiano Ancona, Luca Gentilucci, Alessandra Tolomelli * Department of Chemistry “G. Ciamician”, University of Bologna, Via Selmi 2, 40126 Bologna, Italy

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 May 2014 Received in revised form 3 July 2014 Accepted 15 July 2014 Available online 22 July 2014

Due to the presence of the indole ring in a number of bioactive compounds, novel methods for the preparation of polyfunctionalized indole derivatives are of great interest. The combined use of Lewis acid catalysis and microwave irradiation furnished satisfactory results in the Yonemitsu-type trimolecular condensation of indoles with aldehydes and 1,3-dicarbonyl compounds, such as malonates and acetoacetates. The main advantage of this procedure is the use of a catalytic amount of the Lewis acid and reduction in reaction time. The one pot procedure avoids the isolation and purification of intermediates, thus making the process more environmentally sustainable. The protocol has also been successfully applied to the preparation of novel indole-coumarin derivatives of potential biological interest. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Multicomponent reactions Microwave irradiation Indole Dicarbonyl compounds Coumarins

1. Introduction The development of solutions for efficient and economical multiple bond-forming transformations is an important goal for sustainable chemistry development.1 In a recent perspective paper, members of the American Chemical Society’s Green Chemistry Roundtable emphasized the fundamental importance of considering the potential time, energy, and solvent savings afforded by ‘telescoping’ synthesis. Collapsing a multistep process into a smaller number of operations will soon become necessary to move toward more environmentally sustainable processes.2 In this field, fast and high yielding processes for the synthesis of 3substituted indoles have been deeply investigated since tryptophan, tryptamine, and other indole derivatives are present in a number of bioactive natural compounds,3 pharmaceutical products,4 agrochemicals,5 and functional materials.6 b-Alkyl-tryptophans in particular have been recently deeply studied for the conformational properties they induce in peptide fragments and for the effect that this secondary structures have on the bioactivity of small peptides.7 The trimolecular condensation of indole with Meldrum’s acid and an aldehyde, first reported by Yonemitsu and co-workers in the late seventies,8 facilitates the synthesis of 3-substituted indoles. Recently, Sapi and co-workers,9 efficiently applied this reaction to

* Corresponding author. Tel.: þ39 051 2099575; fax: þ39 051 2099456; e-mail address: [email protected] (A. Tolomelli). http://dx.doi.org/10.1016/j.tet.2014.07.062 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

the diastereoselective synthesis of chiral derivatives from sugarderived aldehydes in the presence of proline as catalyst. This MCR (multicomponent reaction) has been reinvestigated in order to overcome its limitations. Under the standard conditions, poor results were obtained when Meldrum’s acid was replaced with other active methylene compounds, probably due to the difference in pKa values. This MCR may be considered to be a one-pot two steps €evenagel condensation between process (Fig. 1), since the first Kno Meldrum’s acid and aldehyde (step 1) is followed by the Michael addition of indole to the alkylidene malonate intermediate (step 2).

Fig. 1. Steps of the Yonemitsu multicomponent reaction.

Additives and catalysts able to activate both steps have been introduced to promote the reaction. Recently Fontana and coworkers10 successfully performed a Yonemitsu-type reactions with 1,3-dicarbonyl compounds using Ti(IV) derivatives and triethylamine to promote trimolecular condensations. Their procedure allowed the isolation in excellent yields of the compounds derived

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from malonates, while the reaction involving acetoacetates afforded the desired compounds in 40e50% yields, together with products due to further condensation. The synthetic protocol always required the use of stoichiometric amounts of TiCl4 or TiCl2(Oi-Pr)2 and triethylamine. In a recent paper, Curini and coworkers11 reported their results in the condensation of indole with aldehyde and dimethyl malonate in the presence of catalytic Yb(OTf)3, by promoting the reaction with ultrasonication for 12 h. The main drawbacks of this procedure are the long reaction times as well as the unsatisfactory yields. The use of microwave heating to increase reaction rate, while reducing side products in multicomponent reactions, has been deeply investigated in the last 15 years.12 Recently, our research group has been interested in enhancing reaction efficiency by means of MAOS (microwave assisted organic synthesis). In partic€evenagel reaction ular, we have applied this technology to the Kno between 1,3-dicarbonyl compounds and aldehydes to afford building blocks for bioactive compounds preparation.13 2. Results and discussion On the basis of this expertise, we decided to explore the effect of microwaves on Yonemitsu-type multicomponent reactions, to verify the possibility of overcoming the need to use stoichiometric amount of catalyst or a very long reaction times. To optimize conditions, we chose as standard reaction the condensation of dimethyl malonate with isobutanal and indole (Scheme 1). As a first approach, we tried to perform a domino MCR by adding all the reagents simultaneously in the microwave reactor and irradiating the neat mixture at 250 W for 20 min. Under these conditions several products were observed in the crude 1H NMR spectra, which is likely because a number of condensations among the reagents can occur, therefore we decided to optimize the reaction by searching the best conditions for each step. The first step had been already optimized and reported in previous papers.11 By submitting equimolar amounts of dimethyl malonate or acetoacetate and isobutanal in the presence of 15% of piperidine to microwave irradiation at 250 W for 7 min, alkylidene malonate 1a or alkylidene acetoacetate 1b were isolated in 90% yield after flash chromatography. We then focused our attention on the second step that was initially performed on purified 1a. The conjugate addition of indole to alkylidene malonate has been deeply explored and many successful examples of Lewis acid catalyzed diastereoand enantioselective reactions have been reported in the literature14 but, to our knowledge, no microwave catalyzed procedure has been developed. The reaction was tested under different conditions, by changing catalyst, irradiation power, solvent, and times. Selected results are reported in Table 1.

Scheme 1. Steps of the condensation among isobutanal, dimethyl malonate, and indole.

Table 1 Optimization of the reaction of alkylidene malonate 1a and alkylidene acetoacetate 1b with indole Entrya

Reagent

Solvent

Lewis acid

Yieldb (%) 2

3

4

1 2 3 4 5 6 7 8 9 10 11

1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1b

Toluene DMF CH3CN DMF DMF DMF DMF DMF DMF DMF DMF

Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Cu(OTf)2 Zn(OTf)2 Sc(OTf)3 Yb(OTf)3 Cu(OTf)2 Zn(OTf)2 Sc(OTf)3 d

28 41 6 51 18 57 19 d d 41 d

36 21 29 21 d d 9 12 9 7 18

d 15 d 7 5 16 55 75 38 44 d

a

Microwave power 250 W for 20 min. Yields were calculated both by integration of 1H NMR signals and by integration of HPLC peaks. The remaining amount is unreacted alkylidene malonate. b

On the basis of previously reported methods,10 we choose to begin our screening by using Yb(OTf)3 as catalyst in different solvents (entries 1e3). When toluene or acetonitrile was used to dissolve the reagents, compound 3 was obtained as the major product. On the contrary, the reaction performed in DMF gave better results: the desired adduct 2a could be isolated in 41% yield. The formation of bis-indolic derivative 3 can be easily rationalized in the one pot reaction, where a double addition of indole to the aldehyde is assumed, but this is quite unexpected starting from purified alkylidene malonate. As already suggested by Gao and Wu,15 the adduct 2 is probably converted into a reactive indolenine derivative16 by the loss of the active methylene fragment, which reacts with another molecule of indole (Fig. 2).

Fig. 2. Proposed mechanism of formation of bis-indole derivative 3 starting from adduct 2.

We then selected the optimal catalyst, by changing the metal salt. In the presence of Cu(OTf)2, compound 2a could be isolated in 51% yield, but evolution into compound 3 (21%) and decarboxylation to 4a (5%) was always observed (entry 4). On the contrary, Zn(OTf)2 was not an efficient catalyst affording, under the same conditions, a very low yield of product (entry 5). The reaction performed in the presence of Sc(OTf)3 afforded a satisfactory amount of product (entry 6), while completely avoiding the formation of undesired bis-indolic derivative 3. Attempts to enhance the yield by changing microwave power or reaction times did not afford any advantage, since an increase in the side-products was always observed. Following the same approach, the reaction with acetoacetate 1b was studied step by step. Optimization of the first step was previously developed, as reported above.13 Concerning the conjugate addition, the reaction of indole with alkylidene acetoacetate has been less explored than the corresponding reaction on alkylidene malonate. This is probably due to the fact that, in this case, the newly formed adduct has two stereocenters and, unfortunately, maintenance of diastereocontrol is quite difficult due to the strong

A. Viola et al. / Tetrahedron 70 (2014) 6781e6788

acidity of the acetoacetic proton. Equilibration to a 60/40 diastereomeric mixture indeed often occurs by storing compounds at room temperature. The conjugate addition of indole to alkylidene acetoacetate 1b required milder conditions. Microwave irradiation at 250 W for 20 min in the presence of Yb, Cu or Zn triflates always afforded complete conversion of the starting material mainly to bisindole derivative 3 or decarboxylated adduct 4b (entries 7e9). Only Sc(OTf)3 allowed us to isolate 2b in 41% yield, together with an equal amount of 4b (entry 10). When the reaction was performed without Lewis acid, the presence of 80% of starting material was observed in the crude mixture together with 18% of bis-indole compound 3, but no traces of the adduct 2b could be detected (entry 11). These results showed that isolation of satisfactory amount of 2b is quite difficult, since evolution into 3 or 4b always occurs before complete transformation of the starting material. On these basis, we thought that microwave activation should be avoided in the second step for alkylidene acetoacetate 1b. By merging the information obtained from the two distinct step, we performed the one-pot/two steps reaction, by adding the reagents in a sequential way without isolating the unsaturated intermediate. The reactions were performed by adding the reagents for the second step directly into the vessel, without performing any work-up on the first step. The conditions for the dimethyl malonate reaction were initially studied. We first verified that simple introduction of pure indole, without adding solvent or catalyst, is not sufficient to induce product formation and only the bis-indole derivative was observed in small amount. Since the reagents unreacted in the first step could be still present in the vessel, we checked for products deriving from the condensation of aldehyde, indole, and piperidine,17 but no traces of these derivatives were ever observed. We then tested the reaction under the same conditions (250 W, 10 min, neat) in the presence of Yb(OTf)3, but this led to complete recovery of the alkylidene intermediate 1a, thus showing failure of the second step in the absence of solvent. After these preliminary experiments, the one-pot/two steps reaction was performed with all of the reagents. Some selected results reported in Table 2. The experiments performed under MW irradiation in DMF afforded yields ranging from 33% to 45% but, as expected, a large amount of compound 3 was also obtained both with scandium or ytterbium triflates (entries 1 and 2). On the basis of these results, we performed the second step at room temperature (entry 3). Acetonitrile was found to be the more suitable solvent to our purposes under these conditions, even if the yield was comparable to those obtained under microwave conditions. Following the same approach, we also studied the one-pot two step reaction starting from ethyl acetoacetate. When both steps were performed under microwave catalyzed conditions the reaction

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didn’t give satisfactory results (entry 4), since decarboxylation of 2b cannot be avoided, as previously observed when the second step was performed on isolated 1b. By performing the second step at room temperature in DMF we could observe the presence of the unsaturated intermediate 1b as major product, thus confirming that under these conditions DMF is not the best solvent (entries 5 and 6). The reaction in CH3CN finally afforded the desired product 2b in satisfactory yield. By changing the Lewis acid (entries 7e10), we could verify that Yb(OTf)3 or Sc(OTf)3 is the best catalyst, since bis-indole 3 and alkylidene intermediate 1b were isolated in considerable amounts from the reaction with copper or zinc. Lowering the reaction temperature in the second step, allowed an enhancement of the diastereomeric ratio from 51/49 at room temperature up to 75/25 at 20  C (entries 11e13). The (2S*,3S*) stereochemistry of the major stereoisomer was assigned by comparison with the literature.10 Anyway, the diastereomeric excess of the mixture is unstable due to the acidity of the a-proton, and fast equilibration to 60/40 mixture occurs under mild basic conditions. To extend our study, we applied the optimized conditions for the reaction of ethyl acetoacetate to the condensation with aliphatic, aromatic aldehydes, substituted aromatic aldehydes, and substituted indoles (Table 3). The reactions performed with benzaldehyde gave modest yields (entries 1e4); a maximum 39% yield was obtained only in the reaction with 5-Feindole (entry 2). Moreover, the presence of a large amount of bis-indolic derivative could never be avoided. Under these conditions, the electron withdrawing or donating nature of the substituent to the indole ring doesn’t seem to have a great influence on the reactivity. On the other hand, by reacting isobutanal with 5-substituted indoles, quite satisfactory yields could be observed, together with a reduced amount of side product (entries 5e7). In particular, the reaction with 5-Feindole gave an excellent result, since the product 2g was obtained in 55% yield and no traces of bis-indolic derivative could be detected in the crude by 1H NMR nor it could be isolated after flash chromatography. The reaction of 1-Meeindole with isobutanal afforded 2i in 61% yield (entry 7), a result similar to that obtained with unsubstituted indole, while a very unsatisfactory yield was observed when the same reaction was performed with benzaldehyde (entry 4). By changing the isobutanal with cyclohexanecarboxaldehyde (entry 8), the product was isolated in 45% yield, without traces of the bis-indolic derivative. We then turned our attention to substituted benzaldehydes, as 4NO2ebenzaldehyde and OH-substituted aldehydes. The reaction of indole with 4-NO2ebenzaldehyde afforded the product with satisfactory yield (55%, entry 1), showing that the nitro substitution favors the reaction. When the reaction was tested on 4hydroxybenzaldehyde or 3-hydroxybenzaldehyde, complex

Table 2 MCR via one-pot two steps method Entry

Reagent

Second stepa

Solvent

Lewis acid

Yield 2b (%)

Yield 3b,c (%)

Yield 1b (%)

1 2 3 4c 5 6 7 8 9 10 11 12 13

A A A B B B B B B B B B B

250 W-20 min 250 W-20 min rt-4 h 250 W-20 min rt-4 h rt-4 h rt-4 h rt-4 h rt-4 h rt-4 h 0  C-17 h 0  C-17 h 20  C-4 h

DMF DMF CH3CN DMF DMF DMF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

Sc(OTf)3 Yb(OTf)3 Yb(OTf)3 Sc(OTf)3 Yb(OTf)3 Sc(OTf)3 Yb(OTf)3 Sc(OTf)3 Cu(OTf)2 Zn(OTf)2 Sc(OTf)3 Yb(OTf)3 Yb(OTf)3

33 45 30 d d d 67 75 47 23 71 66 29

16 25 3 5 6 6 d 7 16 8 7 8 2

16 8 9 12 77 85 5 16 12 43 16 12 34

a b c

The first step was always performed under MW irradiation 250 W for 7 min. Yields were calculated both by integration of 1H NMR signals and by integration of HPLC peaks. Products of decarboxylation or decomposition were mainly observed.

(51/49) (63/37) (50/50) (51/49) (70/30) (60/40) (75/25)

Table 3 MCR via one-pot two steps method with substituted indoles on aliphatic and aromatic aldehydes

Entry

R1

R2

R3

Product

Yield 2a (%)

Yield bis-indolea (%)

1

Ph

H

H

2c

36

27

2

Ph

F

H

2d

39

30

3

Ph

Me

H

2e

32

29

4

Ph

H

Me

2f

23

33

5

i-Pr

F

H

2g

55

<5

6

i-Pr

Me

H

2h

50

18

7

i-Pr

H

Me

2i

61

18

8

Cyclohexyl

H

H

2j

45

<5

9

4-NO2ePh

H

H

2k

55

22

10

4-AcOePh

H

H

2l

40

26

11

3-AcOePh

H

H

2m

53

13

a Yields were calculated both by integration of 1H NMR signals and by integration of HPLC peaks. The remaining amount is unreacted alkylidene malonate. The products were always obtained as a 60/40 mixture of diastereoisomers.

A. Viola et al. / Tetrahedron 70 (2014) 6781e6788

mixtures of compounds were obtained but no traces of the desired products could be detected, probably due to the interfering role of the acidic proton of the phenol. By protecting the hydroxyl moiety as acetyl group, the corresponding OAcebenzaldehydes were prepared and exploited as starting materials for the Yonemitsu condensation. The reaction performed on 4-OAcebenzaldehyde afforded the product in 40% yield, together with a 26% amount of bis-indolic side product. A good result was also observed in the reaction of 3-OAcebenzaldehyde, that afforded the product in 53% yield, together with a limited amount of side product (13%). The reaction performed with 2-OHebenzaldehyde (salicylaldehyde) deserved particular attention. It is well known that the € evenagel reaction between this aldehyde and products of the Kno dicarbonyl compounds spontaneously cyclize to afford 3-carboxycoumarin derivatives that have been studied for their particular bioactivity.18 On the other hand, the presence of the indole moiety into a molecular backbone is known to invoke particular pharmacological properties.3e7 For this reason, merging the two structures into a single molecule could give access to novel compounds possessing interesting activity. Coumarin bis-indole hybrids have been recently reported to be excellent lipid lowering agents in hamster models.19 With this aim, very recently, Xiao and co-workers20 reported the successful catalyst-free Michael addition of indole to coumarin-3-carboxylic acids and their thio-analogues. The authors suggested a fundamental role of the carboxylic acid in the reaction mechanism, since no results could be obtained with the corresponding ethyl ester and methyl ketone. Inspired by these results, we performed the MCR of malonate and acetoacetate with salicyl aldehyde, whose second step corresponds to Xiao’s failed conjugate addition on ester and ketone coumarin derivatives (Scheme 2).

Scheme 2. MCR with salicyl aldehyde to afford novel coumarin derivatives.

Entry

Reagent

Cat (%)-indole (equiv)

Conditions

Time (min)

1 2 3 4 5 6 7 8

A A A A A B B B

10%-1 10%-1 10%-1 50%-1 10%-2 10%-1 10%-1 10%-1

rt MW-250 MW-250 MW-250 MW-250 rt MW-250 MW-250

240 50 90 50 50 240 20 90

a

equiv equiv equiv equiv equiv equiv equiv equiv

W W W W W W

Yield (%) 5

int

5 40 45 10 15 5 25 27

95 60 55 90 45a 95 75 73

The rest being decarboxylated product.

€ evenagel condensation completely occurs under the The Kno above reported conditions, while, in agreement to Xiao’s observation, the conjugate addition reaction is very slow at room temperature, both on malonate and acetoacetate derivatives, even in the presence of the catalyst (entries 1 and 6). By submitting the reaction mixture to microwave irradiation also during the second step, better results were observed. The reaction on malonate afforded the product 5a in 40% yield after 50 min at 250 W (entry 2). Elongation of the reaction time (entry 3), introduction of a larger amount of catalyst (entry 4) or the use of an excess of indole (entry

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5), didn’t afford great advantages. In a similar way, the reaction with acetoacetate afforded 5b in 27% maximum yield after 90 min at 250 W. 3. Conclusions The combined use of a Lewis acid and microwave irradiation allowed to achieve satisfactory results in the Yonemitsu-type trimolecular condensation of indoles with aldehydes and malonates or acetoacetates. The procedure was applied to aliphatic and aromatic aldehydes, as well as to substituted indoles. Optimization of the conditions for malonate and acetoacetate gave satisfactory results for both substrates. Even if the yields are not high, they are comparable with those already reported for this kind of trimolecular condensation. The main advantage of this procedure is represented by the use of a catalytic amount of the Lewis acid and by the great reduction of reaction times, due to microwave activation in the first step. Moreover, isolation and purification of the €evenagel intermediate was avoided, thus making this one-pot Kno process an environmentally sustainable route to polyfunctionalized indole derivatives. Finally, by applying our protocol to coumarin derivatives we could obtain novel indoleecoumarin compounds with potential bioactivity, whose synthesis could not be achieved with other methodologies. 4. Experimental section 4.1. General All chemicals were purchased from commercial suppliers and used without further purification. Microwave assisted reactions were performed in a Milestone Mycrosynth instrument, with dual magnetron system with pyramid-shaped diffuser, 1000 W maximum output power, temperature monitor, and control via optic fiber up to 250  C in the vessel. Flash chromatography was performed on silica gel (230e400 mesh). DOWEXÒ 50WX2-200(H) ion exchange resin was used for purification of free amino acids or free amines. NMR Spectra were recorded with Varian Gemini 200, Mercury Plus 400 or Unity Inova 600 MHz spectrometers. Chemical shifts were reported as d values (ppm) relative to the solvent peak of CDCl3 set at d¼7.27 (1H NMR) or d¼77.0 (13C NMR). Coupling constants are given in hertz. LCeMS analyses were performed on an HP1100 liquid chromatograph coupled with an electrospray ionization-mass spectrometer (LCeESI-MS), using H2O/CH3CN as solvent at 25  C (positive scan 100e500 m/z, fragmentor 70 V). Complete characterization of 1a,b has been already reported in previous papers.12 Spectra of 3, 4a, and 4b have been compared with already reported data in the literature.8,21 4.2. Representative procedure for one-pot two steps trimolecular condensation (second step with microwaves) Dimethyl malonate or ethyl acetoacetate (1 mmol), aldehyde (1 equiv, 1 mmol), and piperidine (0.15 equiv, 0.15 mmol, 15 mL) were mixed in the microwave reactor and submitted to irradiation at 250 W for 7 min. The mixture was allowed to reach room temperature and diluted with DMF (1 mL). Indole (1 equiv) and Lewis acid (0.1 equiv) were then added and the solution was submitted to microwave irradiation at 250 W for 20 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (310 mL). The extract was then dried over Na2SO4. Evaporation of solvent left the crude products, which were purified by column chromatography over silica (cyclohexane/ethyl acetate 90/10).

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A. Viola et al. / Tetrahedron 70 (2014) 6781e6788

4.3. Representative procedure for one-pot two steps trimolecular condensation (second step at rt) Dimethyl malonate or ethyl acetoacetate (1 mmol), aldehyde (1 equiv, 1 mmol), and piperidine (0.15 equiv, 0.15 mmol, 15 mL) were mixed in the microwave reactor and submitted to irradiation at 250 W for 7 min. The mixture was allowed to reach room temperature and diluted with the solvent of choice (1 mL). Indole (1 equiv) and Lewis acid (0.1 equiv) were then added and the solution was left stirring at room temperature for 4 h. The reaction was monitored by TLC and stopped at disappearance of the starting material. The reaction mixture was diluted with water and then extracted with EtOAc (310 mL). The extract was then dried over Na2SO4. Evaporation of solvent left the crude products, which were purified by column chromatography over silica (cyclohexane/ethyl acetate 90/10). Compound 2a: 1H NMR (400 MHz, Chloroform-d) d 8.08 (s, 1H), 7.68 (dd, J¼7.8, 1.5 Hz, 1H), 7.38e7.29 (m, 1H), 7.14e7.07 (m, 2H), 7.04 (d, J¼2.5 Hz, 1H), 4.00 (d, J¼11.0 Hz, 1H), 3.83 (dd, J¼11.0, 4.9 Hz, 1H), 3.75 (s, 3H), 3.36 (s, 3H), 2.17e1.97 (m, 1H), 0.88 (d, J¼6.7 Hz, 6H). 13C NMR (100 MHz, Chloroform-d) d 169.3, 168.7, 135.6, 128.4, 122.6, 121.8, 119.6, 119.3, 113.0, 110.8, 56.3, 52.6, 52.2, 42.1, 30.6, 21.9, 17.9. LCeESI-MS rt 10.41 min, m/z 304 (Mþ1), 326 (MþNa), 629 (2MþNa). IR (film) cm1 3405, 3057, 2957, 2874, 1732, 1619, 1542, 1457, 742. Rf¼0.44 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C17H21NO4 (303.1): C, 67.31; H, 6.98; N, 4.62. Found: C, 67.50; H, 6.99; N, 4.62. Compound 2b: 1H NMR (400 MHz, Chloroform-d) 6/4 mixture of isomers d 8.19 (s, 0.4H, minor), 8.14 (s, 0.6H, major), 7.75e7.56 (m, 1H), 7.33 (dd, J¼8.0, 3.8 Hz, 1H), 7.21e7.04 (m, 2H), 6.99 (d, J¼2.5 Hz, 0.6H), 6.89 (d, J¼2.0 Hz, 0.4H), 4.02 (d, J¼11.5 Hz, 0.6H), 3.95 (d, J¼12.1 Hz, 0.4H), 3.86 (dd, J¼11.5, 4.1 Hz, 0.6H), 3.86 (dd, J¼12.1, 4.1 Hz, 0.4H), 2.32 (s, 3H), 2.03e2.10 (m, 0.6H), 2.02e1.95 (m, 0.4H), 1.90 (s, 3H), 1.50 (s, 9H), 0.99e0.75 (m, 6H). 13C NMR (100 MHz, Chloroform-d) mixture of isomers d 203.9, 203.2, 168.5, 167.5, 135.5, 135.4, 128.9, 128.4, 123.3, 122.9, 121.9, 121.7, 119.9, 119.6, 119.3, 119.2, 113.3, 112.4, 111.0, 110.7, 82.0, 81.3, 66.3, 66.0, 41.9, 41.4, 30.6, 30.4, 29.0, 27.9, 27.4, 27.1, 22.2, 22.1, 17.5, 17.2. LCeESI-MS rt 10.54 min (major), 11.05 min (minor), m/z 352 (MþNa). IR (film) cm1 3336, 3186, 2926, 2853, 1728, 1697, 1461, 1376, 733. Rf¼0.56 (7/3 EtOAc/ cyclohexane as eluent). Anal. Calcd for C18H23NO3 (329.2): C, 72.92; H, 8.26; N, 4.25. Found: C, 72.43; H, 8.24; N, 4.24. Compound 3: 1H NMR (400 MHz, Chloroform-d) d 7.77 (s, 2H), 7.67 (d, J¼8.2 Hz, 2H), 7.25 (dd, J¼8.0, 1.0 Hz, 2H), 7.21e7.03 (m, 4H), 6.99 (d, J¼2.4 Hz, 2H), 4.27 (d, J¼8.4 Hz, 1H), 2.76e2.54 (m, 1H), 1.03 (d, J¼6.6 Hz, 6H). 13C NMR (100 MHz, Chloroform-d) d 137.0, 136.1, 123.6, 121.5, 119.2, 118.7, 110.9, 110.8, 58.9, 41.0, 21.8. LCeESI-MS rt 10.91 min, m/z 289 (Mþ1), 311(MþNa). IR (Nujol) cm1 3422, 3020, 1596, 1454, 1376, 744, 704. Rf¼0.62 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C20H20N2 (288.2): C, 83.30; H, 6.99; N, 9.71. Found: C, 83.23; H, 6.97; N, 9.73. Compound 4a: 1H NMR (400 MHz, Chloroform-d) d 8.00 (s, 1H), 7.65 (dd, J¼8.0, 1.3 Hz, 1H), 7.35 (dd, J¼8.2, 1.0 Hz, 1H), 7.14e7.20 (m, 2H), 6.99 (d, J¼2.4 Hz, 1H), 3.53 (s, 3H), 3.42e3.29 (m, 1H), 2.83 (dd, J¼15.0, 5.7 Hz, 1H), 2.71 (dd, J¼15.0, 9.6 Hz, 1H), 2.20e1.97 (m, 1H), 0.94 (d, J¼6.7 Hz, 3H), 0.92 (d, J¼6.7 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) 170.6, 136.1, 127.5, 121.7, 120.9, 119.2, 119.0, 117.9, 110.9, 49.6, 40.1, 32.6, 30.3, 20.5, 20.1. LCeESI-MS rt 9.36 min, m/z 246 (Mþ1), 268 (MþNa). IR (film) cm1 3314, 3078, 2944, 2861, 1698, 1462, 1358, 753. Rf¼0.62 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C15H19NO2 (245.1): C, 73.44; H, 7.81; N, 5.71. Found: C, 73.61; H, 7.82; N, 5.70. Compound 4b: 1H NMR (400 MHz, Chloroform-d) d 8.01 (s, 1H), 7.66 (dd, J¼8.1, 1.3 Hz, 1H), 7.44e7.29 (d, 2H, J¼7.2 Hz), 7.24e7.03 (m, 1H), 6.95 (d, J¼2.4 Hz, 1H), 3.35 (dt, J¼8.0, 6.6 Hz, 1H), 2.95 (dd, J¼15.0, 8.0 Hz, 1H), 2.77 (dd, J¼15.0, 6.6 Hz, 1H), 2.18e2.02 (m, 1H),

1.99 (s, 3H), 0.94 (d, J¼6.7 Hz, 3H), 0.89 (d, J¼6.7 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) 209.4, 136.3, 127.2, 121.9, 121.7, 119.3, 119.0, 117.3, 111.2, 47.0, 39.3, 32.7, 30.1, 20.5, 20.3. LCeESI-MS rt 8.71 min, m/z 230 (Mþ1), 252 (MþNa), 268 (MþK). IR (film) cm1 3283, 3055, 2959, 2870, 1694, 1456, 1360, 744. Rf¼0.66 (7/3 EtOAc/ cyclohexane as eluent). Anal. Calcd for C15H19NO (229.1): C, 78.56; H, 8.35; N, 6.11. Found: C, 78.36; H, 8.34; N, 6.13. Compound 2c: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 8.03 (br s, NH), 7.55 (d, 1H, J¼5.0 Hz), 7.35e7.02 (m, 9H), 5.06 (d, 1H, J¼8.0 Hz), 4.39 (d, 1H, J¼8.0 Hz), 3.96 (q, 2H, J¼7.2 Hz), 2.16 (s, 3H), 1.01 (t, 3H J¼7.2 Hz). 13C NMR (100 MHz, Chloroform-d) d: 203.1, 168.1, 141.3, 136.2, 128.3, 128.0, 126.7, 126.4, 122.4, 121.4, 119.4, 111.2, 66.6, 61.4, 43.0, 30.3, 13.7 LCeESI-MS rt 9.8 min; m/z¼358 (Mþ23); 693 (2Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 8.00 (br s, NH), 7.55 (d, 1H, J¼5.0 Hz), 7.35e7.02 (m, 9H), 5.09 (d, 1H, J¼8.0 Hz), 4.51 (d, 1H, J¼8.0 Hz), 3.98 (q, 2H, J¼7.2 Hz), 2.03 (s, 3H), 0.99 (t, 3H, J¼7.2 Hz). 13C NMR (100 MHz, Chloroform-d) d: 202.2, 168.0, 141.3, 136.1, 128.6, 128.1, 126.7, 126.6, 122.2, 120.7, 119.6, 117.2, 111.0, 65.8, 61.6, 42.6, 30.9, 13.6. LCeESI-MS rt 9.6 min; m/z¼358 (Mþ23); 693 (2Mþ23). IR (film) cm1 3397, 3060, 2931, 2872, 1737, 1715, 1456, 1367, 742. Rf¼0.37 (7/3 EtOAc/ cyclohexane as eluent). Anal. Calcd for C21H21NO3 (335.1): C, 75.20; H, 6.31; N, 4.18. Found: C, 75.15; H, 6.29; N, 4.20. Compound 2d: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 8.00 (br s, NH), 7.39e7.11 (m, 7H), 6.99 (d, 1H, J¼2.0 Hz), 6.85e6.95 (m, 1H), 6.68 (s, 1H), 4.96 (d, 1H, J¼12.0 Hz), 4.37 (d, 1H, J¼12.0 Hz), 3.95 (q, 2H, J¼7.2 Hz), 2.20 (s, 3H), 0.98 (t, 3H, J¼7.2 Hz). 13 C NMR (100 MHz, Chloroform-d) d: 202.1, 167.9, 157.8 (d, JCeF¼214 Hz), 140.9, 132.7, 128.4 (d, JCeF¼10 Hz), 128.0, 127.3, 126.9, 123.0, 119.3, 111.7, 110.4 (d, JCeF¼9 Hz), 104.6 (d, JCeF¼23 Hz), 66.3, 61.5, 29.6, 28.4, 13.9. LCeESI-MS rt 9.7 min; m/z¼376 (Mþ23); 729 (2Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 7.97 (br s, NH), 7.39e7.11 (m, 7H), 6.98 (d, 1H, J¼2.0 Hz), 6.68 (s, 1H), 6.85e6.95 (m, 1H), 5.00 (d, 1H, J¼11.6 Hz), 4.48 (d, 1H, J¼11.6 Hz), 3.97 (q, 2H, J¼7.2 Hz), 2.20 (s, 3H), 0.98 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroform-d) d: 202.9, 168.0, 157.5 (d, JCeF¼214 Hz), 143.3, 133.2, 128.5 (d, JCeF¼10 Hz), 127.9, 127.2, 126.4, 122.5, 119.3, 111.6, 110.1 (d, JCeF¼8 Hz), 104.8 (d, JCeF¼23 Hz), 65.6, 61.5, 30.4, 28.4, 13.7. LCeESI-MS rt 9.9 min; m/z¼376 (Mþ23); 729 (2Mþ23). IR (film) cm1 3389, 2963, 2929, 2866, 1739, 1711, 1459, 1282, 1202, 799. Rf¼0.34 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C21H20FNO3 (353.1): C, 71.37; H, 5.70; N, 3.96. Found: C, 71.22; H, 5.71; N, 3.97. Compound 2e: Major isomer: 1H NMR (400 MHz, Chloroform-d) d: 7.95 (br s, NH), 7.37e6.95 (m, 9H), 5.04 (d, 1H, J¼12.0 Hz), 4.36 (d, 1H, J¼12.0 Hz), 3.96e4.00 (m, 2H), 2.40 (s, 3H), 2.05 (s, 3H), 0.98 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroform-d) d: 202.3, 168.2, 141.4, 134.5, 128.7, 128.2, 127.9, 127.8, 126.6, 124.0, 121.4, 118.7, 115.7, 110.6, 66.0, 61.4, 30.3, 28.0, 21.6, 13.6. LCeESI-MS rt 10.4 min; m/ z¼372 (Mþ23); 721 (2Mþ23). Minor isomer 1H NMR (400 MHz, Chloroform-d) d: 8.00 (br s, NH), 7.37e6.95 (m, 9H), 5.07 (d, 1H, J¼11.8 Hz), 4.49 (d, 1H, J¼11.8 Hz), 3.96e4.00 (m, 2H), 2.40 (s, 3H), 2.05 (s, 3H), 1.01 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroformd) d: 203.1, 168.0, 141.4, 134.5, 128.9, 128.5, 127.9, 127.8, 126.8, 124.1, 121.5, 118.9, 116.7, 110.7, 66.8, 61.2, 30.4, 28.2, 21.4, 13.8. LCeESI-MS rt 10.2 min; m/z¼372 (Mþ23); 721 (2Mþ23). IR (film) cm1 3397, 3089, 2924, 2854, 1740, 1712, 1456, 1366, 701. Rf¼0.41 (7/3 EtOAc/ cyclohexane as eluent). Anal. Calcd for C22H23NO3 (349.4): C, 75.62; H, 6.63; N, 4.01. Found: C, 75.64; H, 6.60; N, 4.02. Compound 2f: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 7.69e7.11 (m, H), 7.00 (m, 1H), 6.94 (s, 1H), 5.07 (d, 1H, J¼11.0 Hz), 4.39 (d, 1H, J¼11.0 Hz), 3.98e4.05 (m, 2H), 3.70 (s, 3H), 2.06 (s, 3H), 0.98 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroform-d) d: 202.0, 167.9, 141.2, 136.9, 130.6, 128.0, 127.7, 126.6, 125.5, 121.7, 119.1, 118.9, 115.6, 109.0, 65.9, 61.3, 42.6, 30.1, 13.8. LCeESI-MS rt 11.2 min; m/ z¼372 (Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d:

A. Viola et al. / Tetrahedron 70 (2014) 6781e6788

7.69e7.11 (m, 8H), 7.00 (m, 1H), 6.94 (s, 1H), 5.10 (d, 1H, J¼11.2 Hz), 4.50 (d, 1H, J¼11.2 Hz), 3.98e4.05 (m, 2H), 3.70 (s, 3H), 2.18 (s, 3H), 1.00 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroform-d) d: 202.9, 168.0, 141.6, 136.9, 129.5, 128.2, 127.9, 126.8, 126.0, 121.9, 119.3, 118.9, 114.7, 109.1, 66.6, 61.3, 43.0, 30.8, 13.7. LCeESI-MS rt 10.7 min; m/z¼372 (Mþ23). IR (film) cm1 3058, 2980, 2927, 1714, 1698, 154, 1471, 741. Rf¼0.53 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C22H23NO3 (349.2): C, 75.62; H, 6.63; N, 4.01. Found: C, 75.49; H, 6.62; N, 4.03. Compound 2g: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 8.32 (br s, NH), 7.29 (dd, 1H, JHeH¼1 Hz, JHeF¼9.6 Hz), 7.21 (dd, 1H, JHeH¼9.2 Hz, JHeF¼4.4 Hz), 6.89 (d, 1H, J¼2.4 Hz), 6.87 (dd, 1H, JHeH¼9.2 Hz, JHeF¼2.4 Hz), 4.12e4.30 (m, 2H), 4.02 (d, 1H, J¼12.0 Hz), 3.77 (m, 1H), 2.03 (m, 1H), 1.94 (s, 3H), 1.31 (t, 3H, J¼7.2 Hz), 0.85 (d, 6H, J¼6.6 Hz). 13C NMR (100 MHz, Chloroformd) d: 203.3, 169.1, 157.9 (d, JCeF¼233 Hz), 132.1, 129.0 (d, JCeF¼10 Hz), 125.1, 113.4, 111.6, 110.6 (d, JCeF¼12 Hz), 104.5 (d, JCeF¼18 Hz), 64.7, 61.5, 42.0, 30.6, 27.2, 21.9, 17.7, 14.0. LCeESI-MS rt 10.1 min; m/z¼342 (Mþ23), 661 (2Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d 8.20 (1H, br s), 7.29 (dd, 1H, JHeH¼1 Hz, JHeF¼9.6 Hz), 7.21 (dd, 1H, JHeH¼9.2 Hz, JHeF¼4.4 Hz), 7.02 (d, 1H, J¼2.8 Hz), 6.87 (dd, 1H, JHeH¼9.2 Hz, JHeF¼2.4 Hz), 4.12e4.30 (m, 2H), 4.10 (d, 1H, J¼10.8 Hz), 3.77 (m, 1H); 2.31 (s, 3H), 1.98 (m, 1H), 0.83 (d, 6H, J¼6.6 Hz), 0.77 (t, 3H, J¼7.2 Hz). 13C NMR (100 MHz, Chloroform-d) d: 202.8, 168.5, 158.0 (d, JCeF¼233 Hz), 132.0, 128.7 (d, JCeF¼10 Hz), 124.6, 113.3, 112.4, 110.1 (d, JCeF¼12 Hz), 103.4 (d, JCeF¼18 Hz), 64.8, 61.0, 41.7, 30.9, 29.1, 22.0, 17.2, 13.4. LCeESI-MS rt 9.8 min; m/z¼342 (Mþ23), 661 (2Mþ23). IR (film) cm1 3376, 2987, 2929, 2857, 1736, 1704, 1454, 1274, 1211, 788. Rf¼0.48 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C18H22FNO3 (319.1): C, 67.69; H, 6.94; N, 4.39. Found: C, 67.71; H, 6.90; N, 4.38. Compound 2h: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 7.97 (br s, NH), 7.45 (s, 1H), 7.23e6.86 (m, 3H), 4.25 (q, 2H, J¼7.2 Hz), 4.10 (d, 1H, J¼11.0 Hz), 3.83 (dd, 1H, J¼2.8, 11.0 Hz), 2.47 (s, 3H), 2.31 (s, 3H), 1.90e2.14 (m, 1H), 1.31 (t, 3H, J¼7.2 Hz), 0.88 (d, 6H, J¼6.6 Hz); 13C NMR (100 MHz, Chloroform-d) d: 203.6, 169.4, 134.6, 128.8, 128.3, 123.6, 121.9, 119.2, 112.5, 110.6, 65.0, 61.0, 41.6, 31.0, 29.2, 21.9, 17.8, 17.3, 13.5. LCeESI-MS rt 10.5 min; m/z¼338 (Mþ23); Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 8.02 (br s, NH), 7.45 (s, 1H), 7.23e6.86 (m, 3H), 4.02 (d, 1H, J¼12.0 Hz), 3.86 (dd, 1H, J¼4.0, 12.0 Hz), 3.80 (q, 2H, J¼7.6 Hz), 2.43 (s, 3H), 1.90e2.14 (m, 1H), 1.92 (s, 3H), 1.02 (d, 3H, J¼6.6 Hz), 0.88 (d, 6H, J¼6.6 Hz), 0.81 (t, 3H, J¼7.6 Hz); 13C NMR (100 MHz, Chloroform-d) d: 203.3, 168.6, 134.0, 128.7, 128.1, 123.3, 121.8, 119.0, 111.5, 110.4, 64.9, 61.4, 41.8, 30.8, 29.0, 21.5, 17.6, 17.1, 14.1. LCeESI-MS rt 10.8 min; m/z¼338 (Mþ23). IR (film) cm1 3404, 2960, 2924, 2871, 1735, 1707, 1464, 1367, 795. Rf¼0.53 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C19H25NO3 (315.2): C, 72.35; H, 7.99; N, 4.44. Found: C, 72.42; H, 7.96; N, 4.45. Compound 2i: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 7.65 (d, 1H, J¼8.0 Hz), 7.25e7.08 (m, 3H), 6.74 (s, 1H), 4.23 (q, 2H, J¼7.2 Hz), 4.09 (d, 1H, J¼10.8 Hz), 3.81 (dd, 1H, J¼4.4, 10.8 Hz), 3.70 (s, 3H), 1.96e2.04 (m, 1H), 1.91 (s, 3H), 1.28 (t, 3H, J¼7.2 Hz), 0.84 (d, 3H, J¼6.6 Hz), 0.83 (d, 3H, J¼6.6 Hz), 13C NMR (100 MHz, Chloroform-d) d: 203.3, 169.5, 128.7, 127.5, 121.5, 119.7, 119.0, 110.4, 109.1, 64.8, 61.4, 41.7, 32.8, 30.6, 29.0, 22.1, 17.7, 14.1; LCeESI-MS rt 10.8 min; m/z¼338 (Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 7.65 (d, 1H, J¼8.0 Hz), 7.25e7.08 (m, 3H), 6.88 (s, 1H), 4.20 (q, 2H, J¼7.2 Hz), 4.01 (d, 1H, J¼12.0 Hz), 3.86 (dd, 1H, J¼4.0, 12.0 Hz), 3.71 (s, 3H), 2.28 (s, 3H), 1.96e2.04 (m, 1H), 0.84 (d, 3H, J¼6.6 Hz), 0.83 (d, 3H, J¼6.6 Hz), 0.73 (t, 3H, J¼7.2 Hz). 13C NMR (100 MHz, Chloroform-d) d: 203.2, 168.5, 136.4, 129.0, 121.2, 119.3, 118.8, 111.4, 108.8, 65.0, 60.8, 42.0, 32.7, 30.4, 27.6, 22.0, 17.2, 13.4. LCeESI-MS rt 10.5 min; m/z¼338 (Mþ23). IR (film) cm1 3055, 2961, 2933, 2876, 1710, 1614, 1467, 1356, 739. Rf¼0.62 (7/3 EtOAc/

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cyclohexane as eluent). Anal. Calcd for C19H25NO3 (315.2): C, 72.35; H, 7.99; N, 4.44. Found: C, 72.60; H, 7.98; N, 4.43. Compound 2j: 1H NMR (400 MHz, Chloroform-d) mixture of isomers d 8.14 (br s, 0.7H, major), 8.09 (br s, 0.3H, minor), 7.72 (d, J¼7.6 Hz, 0.3H, minor) 7.67 (d, J¼8.0 Hz, 0.7H, major), 7.34 (br d, J¼8.0 Hz, 1H), 7.21e7.09 (m, 2H), 7.03 (d, J¼2.5 Hz, 0.3H, minor), 6.90 (d, J¼2.4 Hz, 0.7H, major), 4.34e4.16 (m, 2H), 4.18 (d, J¼10.8 Hz, 0.3H, minor), 4.11 (d, J¼11.6 Hz, 0.7H, major), 3.86 (dd, J¼11.6, 3.5 Hz, 0.7H), 3.83 (dd, J¼10.8, 5.2 Hz, 0.3H), 2.30 (s, 0.9H, minor), 2.18 (s, 2.1H, major), 1.82e1.50 (m, 7H), 1.39 (t, J¼7.2 Hz, 0.9H, minor) 1.31 (t, J¼7.2 Hz, 2.1H, major), 1.05e1.30 (m, 2H). 13C NMR (100 MHz, Chloroform-d) mixture of isomers d 203.8, 203.3, 169.3, 168.6, 135.6, 135.5, 128.1, 128.0, 123.3, 122.9, 121.8, 121.6, 121.4, 121.3, 119.5, 119.4, 119.2, 119.1, 113.6, 112.7, 111.0, 110.8, 64.3, 64.0, 61.4, 41.1, 40.9, 32.4, 32.3, 26.5, 26.4, 26.2, 26.1, 26.0, 25.9, 14.1, 13.3. LCeESI-MS rt 11.32 min (minor), 11.63 min (major), m/z 364 (MþNa). IR (film) cm1 3439, 2972, 2921, 2851, 1731, 1705, 1487, 1367, 754. Rf¼0.61 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C21H27NO3 (341.5): C, 73.87; H, 7.97; N, 4.10. Found: C, 73.89; H, 7.94; N, 4.12. Compound 2k: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 8.47 (br s, NH), 8.00e8.10 (m, 2H), 7.45e7.00 (m, 8H), 5.20 (d, 1H, J¼12.0 Hz), 4.45 (d, 1H, J¼12.0 Hz), 3.95e4.08 (m, 2H), 2.18 (s, 3H), 1.07 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroform-d) d: 201.7, 167.6, 149.3, 146.5, 136.2, 126.2, 123.7, 122.7, 121.8, 119.9, 118.5, 114.6, 111.3, 65.3, 61.8, 42.2, 30.9, 13.8. LCeESI-MS rt 9.7 min; m/z¼398 (Mþ18), 403 (Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 8.42 (br s, NH), 8.00e8.10 (m, 2H), 7.45e7.00 (m, 8H), 5.23 (d, 1H, J¼12.0 Hz), 4.55 (d, 1H, J¼12.0 Hz), 3.95e4.08 (m, 2H), 2.16 (s, 3H), 0.99 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroformd) d: 201.0, 167.4, 149.5, 146.6, 136.3, 129.0, 125.9, 123.6, 122.5, 121.2, 119.7, 118.7, 115.4, 111.5, 65.4, 61.7, 41.8, 30.2, 13.6. LCeESI-MS rt 9.6 min; m/z¼398 (Mþ18), 403 (Mþ23). IR (film) cm1 3405, 3111, 2981, 2856, 1738, 1714, 1519, 1420, 744. Rf¼0.20 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C21H20N2O5 (380.1): C, 66.31; H, 5.30; N, 7.36. Found: C, 66.10; H, 5.29; N, 7.37. Compound 2l: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 7.98 (br s, NH), 7.52e6.93 (m, 9H), 5.09 (d, 1H, J¼12.0 Hz), 4.45 (d, 1H, J¼12.0 Hz), 3.95e4.05 (m, 2H), 2.22 (s, 3H), 2.05 (s, 3H), 1.04 (t, 3H, J¼7.2 Hz) 13C NMR (100 MHz, Chloroform-d) d: 203.0, 169.3, 168.0, 149.3, 138.9, 136.7, 136.1, 129.0, 127.0, 126.2, 122.5, 121.7, 119.9, 111.2, 65.8, 61.6, 41.8, 30.4, 28.2, 21.0, 13.8. LCeESI-MS rt 9.0 min; m/ z¼411 (Mþ18), 416 (Mþ23). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 8.04 (br s, NH), 7.52e6.93 (m, 9H), 5.05 (d, 1H, J¼12.0 Hz), 4.32 (d, 1H, J¼12.0 Hz), 3.95e4.05 (m, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 0.94 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroformd) d: 202.1, 169.3, 167.9, 154.0, 138.8, 136.7, 136.2, 129.7, 127.0, 126.4, 123.5, 121.5, 119.7, 111.0, 66.6, 61.5, 42.3, 30.5, 29.6, 21.1, 13.7. LCeESI-MS rt 9.2 min; m/z¼411 (Mþ18), 416 (Mþ23). IR (film) cm1 3407, 2980, 2927, 2871, 1740, 1738, 1710, 1506, 1368, 1201, 743. Rf¼0.24 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C23H23NO5 (393.4): C, 70.21; H, 5.89; N, 3.56. Found: C, 70.24; H, 5.91; N, 3.55. Compound 2m: Major isomer 1H NMR (400 MHz, Chloroform-d) d: 8.10 (br s, NH), 7.55e6.91 (m, 8H), 6.79 (br s, 1H), 5.11 (d, 1H, J¼12.2 Hz), 4.36 (d, 1H, J¼12.2 Hz), 4.01e3.97 (m, 2H), 2.26 (s, 3H), 2.06 (s, 3H), 1.03 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, Chloroformd) d: 203.0, 169.4, 167.9, 150.6, 143.1, 136.1, 129.4, 126.2, 125.4, 122.3, 121.6, 121.1, 119.8, 119.6, 118.8, 115.6, 111.1, 66.2, 61.6, 42.5, 30.6, 21.0, 13.6. LCeESI-MS rt 9.0 min; m/z¼411 (Mþ18). Minor isomer: 1H NMR (400 MHz, Chloroform-d) d: 8.06 (br s, NH), 7.55e6.91 (m, 8H), 6.67 (br s, 1H), 5.08 (d, 1H, J¼12.4 Hz), 4.49 (d, 1H, J¼12.4 Hz); 4.01e3.97 (m, 2H); 2.25 (s, 3H); 2.08 (s, 3H), 0.98 (t, 3H, J¼7.2 Hz); 13 C NMR (100 MHz, Chloroform-d) d: 202.3, 169.3, 167.8, 150.5, 143.1, 136.1, 129.1, 126.3, 125.7, 122.1, 121.6, 121.0, 119.8, 119.4, 119.1, 115.2, 111.2, 65.5, 61.5, 42.2, 28.4, 20.9, 14.0. LCeESI-MS rt 8.9 min;

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m/z¼411 (Mþ18). IR (film) cm1 3400, 2982, 2926, 2854, 1741, 1738, 1725, 1486, 1368, 1206, 744. Rf¼0.22 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C23H23NO5 (393.4): C, 70.21; H, 5.89; N, 3.56. Found: C, 70.23; H, 5.87; N, 3.53. Compound 5a: 1H NMR (400 MHz, Chloroform-d) d: 8.16 (br s, NH), 7.65e7.02 (m, 8H), 6.81 (d, 1H, J¼3.6 Hz), 5.01 (d, 1H, J¼7.2 Hz), 4.38 (q, 2H, J¼7.2 Hz), 4.18 (d, 1H, J¼7.2 Hz), 1.38 (t, 3H, J¼7.2 Hz); 13 C NMR (100 MHz, Chloroform-d) d: 166.9, 164.6, 150.6, 148.5, 136.6, 134.2, 129.4, 124.7, 124.6, 123.8, 123.4, 121.9, 117.6, 116.4, 116.3, 111.8, 61.6, 52.9, 36.4, 13.9. LCeESI-MS rt 9.7 min; m/z¼336 (Mþ1), 358 (Mþ23). IR (film) cm1 3357, 3060, 2982, 2931, 2851, 1768, 1715, 1486, 1375, 1244, 1201, 761. Rf¼0.35 (7/3 EtOAc/cyclohexane as eluent). Anal. Calcd for C20H17NO4 (335.1): C, 71.63; H, 5.11; N, 4.18. Found: C, 71.65; H, 5.14; N, 4.20. Compound 5b: 1H NMR (400 MHz, Chloroform-d) d: 8.18 (br s, NH), 7.44e7.04 (m, 8H), 6.82 (d, 1H, J¼3.6 Hz), 5.02 (d, 1H, J¼7.2 Hz), 4.26 (d, 1H, J¼7.2 Hz), 2.20 (s, 3H); 13C NMR (100 MHz, Chloroformd) d: 201.1, 169.5, 165.7, 150.5, 137.0, 136.7, 36.5, 128.8, 128.0, 125.1, 123.4, 122.5, 121.4, 119.9, 118.5, 116.7, 111.8, 59.1, 35.2, 29.7. LCeESIMS rt 8.8 min; m/z¼306 (Mþ1), 633 (2Mþ23). IR (film) cm1 3405, 3058, 2924, 2854, 1752, 1718, 1486, 1339, 745. Rf¼0.34 (7/3 EtOAc/ cyclohexane as eluent). Anal. Calcd for C19H15NO3 (305.3): C, 74.74; H, 4.95; N, 4.59. Found: C, 74.76; H, 4.97; N, 4.61.

Acknowledgements This study has been carried out with the fundamental contribution of ‘Fondazione del Monte di Bologna e Ravenna’ (FdM1706), MIUR (PRIN project 2010NRREPL_009: synthesis and biomedical applications of tumor-targeting peptidomimetics), and University of Bologna. We also thank MAE (Italian Minister for Foreign Affair, General Direction for the Cultural Promotion and Cooperation) (PGR00083) for financial support to bilateral projects between Italy and Mexico. Mr. Andrea Garelli is gratefully acknowledged for the LCeESI-MS analysis.

Supplementary data 1

H NMR spectra, 13C NMR spectra, and LCeMS analysis of all novel derivatives are available. Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2014.07.062.

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