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Allylic amination

Laboratorio de Quımica Organica y Bioorgan

Inorganica, Universidad de Extremadura,

E-mail: cfernan@unex.es; aneo@unex.es

† Electronic supplementary information (See DOI: 10.1039/c4ra05719h

Cite this: RSC Adv., 2014, 4, 40044

Received 13th June 2014Accepted 18th August 2014

DOI: 10.1039/c4ra05719h

www.rsc.org/advances

40044 | RSC Adv., 2014, 4, 40044–400

of Passerini adducts. Applicationto the selective synthesis of chromone-substituteda-and g-amino acid peptidic and retropeptidicunits†

Ana G. Neo,* Lucıa Lopez-Garcıa and Carlos F. Marcos*

The first allylic amination of Passerini acetates is described, where both a and g-substitution products are

obtained regioselectively from chromone derived adducts. While a-substitution occurs in THF, CuCl in

methanol catalyses a tandem amination followed by a rearrangement leading to g-amino acid-derived

chromones.

Introduction

Non-proteinogenic amino acids are valuable building blocksfor the generation of novel biomimetic functional materials1

and innovative tools in protein engineering and molecularmedicine.2 Importantly, heterocyclic-substituted a-aminoacids combine the privileged ability of heterocycles to bind tobiological targets and the inherent capacity of amino acids toassemble into conformationally diverse peptides.3 Also,heterocyclic-substituted g-amino acids have considerableinterest as rigid GABA analogues4 and as key motifs to mimicsecondary and tertiary structural features of proteins in pep-tidomimetics.5 Noteworthy, heterocyclic a- and g-aminoamides are in the structure of many natural small peptides,6

such as microtubule disruptor dolastatins.7

Although numerous procedures for the synthesis of aminoacids are known, the development of novel efficient methods forthe preparation of heterocyclic amino amides is still challenging.

The amination of allyl esters is one of the most useful carbon–nitrogen bond forming reactions.8 Several transition metal cata-lysts, including Pd,9 Ir,10 Ru,11 Rh 12 and, in minor extent, Cu,13

catalyse these reactions, leading to high yields and selectivity.Moreover, the starting allyl compounds can be easily obtained bydifferent procedures, such as the Baylis–Hillman reaction.14 Forexample, it has been shown that the allylic amination of Baylis–Hillman acrylamide adducts successfully affords b-amino amidesin the presence of a Pd diaminophosphine oxide catalyst(Scheme 1).15 Surprisingly, this reaction has never been applied tothe synthesis of a- or g-amino acid derivatives. Prompted by ourinterest in the use of multicomponent reactions of isocyanides

ica (L.O.B.O.), Dept. Quımica Organica e

Fac. Veterinaria, 10071 Caceres, Spain.

ESI) available: Copies of NMR spectra.

53

for the synthesis of peptidomimetics,16 we envisaged that theallylic amination of Passerini acetates derived from a,b-unsatu-rated aldehydes would easily lead to a- and g-amino amides(Scheme 1).

To prove this idea, we decided to use allyl acetates (1), readilyavailable by the Passerini condensation of 3-formylchromones(2), isocyanides (3) and acetic acid (4), as substrates of allylicamination. Modication of biologically privileged17 chromonecore with peptidic or pseudopeptidic segments has a greatpotential to modulate its affinity for the different biologicaltargets and to improve its pharmacodynamic properties.18 Here,we report the application of this novel methodology to selectivelyobtain chromone a- or g-amino amides (5 and 6; Scheme 2).

Scheme 1 Allylic amination of Baylis–Hillman and Passerini acetates.

This journal is © The Royal Society of Chemistry 2014

Scheme 2 Proposed mechanism of the formation of 5 and 6 in theabsence of catalyst.

Table 2 Reaction of Passerini adduct 1a with benzylamine

Entry Solvent Conditionsa 5a : 6a ratio

1 PhCH3 0.2 M, rt, 2.5 h 82 : 182 PhCH3 0.2 M, 100 �C, 10 min mw 84 : 163 THF 0.2 M, rt, 2 h 100 : 04 THF 0.2 M, 90 �C, 10 min mw 100 : 05 CH3CN 0.2 M, rt, 3 h 100 : 06 CH3OH 0.2 M, rt, 3 h 55 : 457 CH3OH 0.2 M, 75 �C, 5 min mw 38 : 628 CH3OH 0.2 M, L-Boc-Pro, rt, 24 h 57 : 439 CH3OH 0.2 M, sulfonamide,b rt, 24 h 43 : 5710 CH3OH 0.02 M, rt, 4 h 18 : 8211 CH3OH 0.01 M, rt, 5.5 h 19 : 8112 CH3OH 0.02 M, 0 �C, 15 h 20 : 8013 CH3OH 0.02 M, reux, 4 h 20 : 8014 CH3OH 0.02 M, ZnCl2, rt, 24 h 18 : 8215 CH3OH 0.02 M, In(OTf)3, rt, 24 h 15 : 8516 CH3OH 0.02 M, Sc(OTf)3, rt, 24 h 18 : 8217 CH3OH 0.02 M, LiClO4, rt, 24 h 20 : 8018 CH3OH 0.02 M, CuI, rt, 8 h 0 : 10019 CH3OH 0.02 M, CuCl, rt, 8 h 0 : 10020 CH3OH 0.2 M, CuCl, rt, 5 h 0 : 10021 CH3OH 0.2 M, CuCl, 75 �C, 5 min mw 0 : 10022 THF 0.2 M, CuCl, rt, 5 h 100 : 0

a The yields are quantitative by NMR in all the experiments. b (S,S)-N,N0-Bis(a-methyl)benzylsulfonamide.

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Results and discussion

The Passerini condensation of 3-formylchromones (2), iso-cyanides (3) and acetic acid (4) in diethyl ether at 0 �C affords2-acetoxy-2-(4-oxo-4H-chromen-3-yl)acetamides (1) in good yield(Table 1). (tert-Butylcarbamoyl)(4-oxo-4H-chromen-3-yl)methylacetate 1a (Table 1, entry 1) was chosen as a model compoundto study the nucleophilic substitution with amines.

Accordingly, treatment of a 0.2 M solution of 1a in toluenewith 2 equivalents of benzylamine (7a) at rt results in thecomplete transformation of the starting material into an 8 : 2mixture of the expected a-substitution product (5a), and theisomeric 2-amido chromone 6a (Table 2, entry 1).

Control of the regiochemistry of allylic aminations is a chal-lenging problem as isomerization oen leads to mixture of kinetic

Table 1 Passerini reaction of 3-formylchromones

Entry R1 R2 Producta (% yield)

1 H t-Bu 1a (72)2 H c-C6H11 1b (67)3 H CH2Ph 1c (62)4 CH3 c-C6H11 1d (80)5 Cl c-C6H11 1e (47)

a A suspension of 3-formylchromone 2 (5 mmol), acetic acid (4, 5 mmol),and isocyanide (3, 5 mmol) in Et2O (5 mL) is stirred 30 min at 0 �C andthen 48 hours at rt.

This journal is © The Royal Society of Chemistry 2014

and thermodynamic products. In order to improve the selectivity,we examined different reaction conditions. Solvent showed tomarkedly inuence the product ratio. Thus, successfully, whenTHF (Table 2, entries 3 and 4) or CH3CN (entry 5) is used, 5a isobtained as the only product. The reaction is completed in 2–3hours at rt (entries 3 and 5), or in just 10minutes undermicrowaveactivation (entry 4). This result is in sharp contrast with theoutcome of the reaction of amines with acylated Baylis–Hillmanadducts of chromone and benzaldehydes, recently reported byZhong and co-workers,14 which does not give the expected a- org-allyl substitution products, but results exclusively in rearranged3-aminomethyleneavones. Thus, successfully, amination ofPasserini acetate 1a selectively affords chromone derived a-aminoamide 5a. Nucleophilic attack of the amine is probably facilitatedby the presence of the electron-withdrawing amide group on 1a.Moreover, in opposition to the synthesis of Baylis–Hillman chro-mone esters, which is sluggish, involves the use of harsh strongbases, as methoxide, and requires derivatisation of the allylicalcohol to incorporate an activated leaving group, chromonePasserini acetates are effectively obtained in a single step 3-component condensation.

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Importantly, the initially obtained minor product 6a can beconsidered a structurally constrained g-amino acid derivative.Consequently, we were challenged to enhance the formation ofthis regioisomer. Thus, when the reaction is performed at rt inmethanol, an almost equimolar mixture of 5a and 6a isobtained (Table 2, entry 6). Moreover, performing the reactionin diluted conditions unexpectedly shows to notably favour theformation of 6a. As a result, a 2 : 8 ratio of 5a to 6a is obtainedwhen the reaction is performed in a 0.02 M solution of 1a inmethanol (entry 10). Conversely, using lower or higher reactiontemperatures (entries 12 and 13), or further increasing thedilution (entry 11) does not change the product ratio. Also,addition of proton donor catalysts (entries 8 and 9) or Lewisacids (entries 14–17) does not signicantly affect the productdistribution, and reduces the reaction rate. However, the use ofcopper(I) salts, completely shis the reaction selectivity toafford exclusively 6a, with no detectable traces to 5a (entries18–21). It is noteworthy that, such catalytic effect is not observedin THF, where only carboxamide 5a is obtained, even in thepresence of CuCl (entry 22).

Once selective conditions have been found for the independentpreparation of isomeric a- and g-amino amides 5a (Table 2, entry3) and 6a (entry 21), we proceeded to explore the scope of thereaction. Therefore, amidochromones 1a–e were reacted withdifferent amines (7a–g). Accordingly, the optimized conditionsfound for the synthesis of 5a were successfully applied to obtaina-(chromon-3-yl)-glycinamides (5a–o) with good to excellent yieldsand complete selectivity (Table 3). The use of primary alkylamines,as benzylamine or piperonylamine, leads to good yields of theexpected 3-(aminomethyl)-4H-chromen-4-ones (5) aer reactiontimes of 2–5 hours (Table 3, entries 1–9). More hindered primaryamines, as L-valine esters (entries 10 and 11), require longerreaction times. The reaction also takes place successfully withcyclic secondary amines (entries 12–15). However, no reaction wasobserved either with highly hindered secondary amines, as dii-sopropylamine or N-benzylpropylamine, or aromatic amines.

Table 3 a-Allyl amination of Passerini adducts (1)

Entry R1 R2 Amine Producta,b (% yield)

1 H t-Bu PhCH2NH2 5a (95)2 H t-Bu 3,4-(OCH2O)PhCH2NH2 5b (86)3 H c-C6H11 PhCH2NH2 5c (81)4 H c-C6H11 3,4-(OCH2O)PhCH2NH2 5d (90)5 H CH2Ph PhCH2NH2 5e (95)6 CH3 c-C6H11 PhCH2NH2 5f (78)7 CH3 c-C6H11 3,4-(OCH2O)PhCH2NH2 5g (60)8 Cl c-C6H11 PhCH2NH2 5h (68)9 Cl c-C6H11 3,4-(OCH2O)PhCH2NH2 5i (84)10 H t-Bu L-Val-OMe 5j (98)c

11 H t-Bu L-Val-OEt 5k (60)c

12 H t-Bu Pyrrolidine 5l (55)13 H t-Bu Piperidine 5m (97)14 H t-Bu L-Pro-OMe 5n (70)c

15 Cl c-C6H11 L-Pro-OMe 5o (90)c

a A solution 0.2 M of the Passerini adduct (1) in dry THF and 2 equiv. ofthe amine (7) is stirred at room temperature for 2–5 hours. b Isolatedyields. c Reaction time: 72 h.

40046 | RSC Adv., 2014, 4, 40044–40053

Interestingly, the use of C-protected amino acids (entries 10, 11, 14and 15) allows to obtain chromone-derived retropeptidicsequences.

In order to obtain chromone derived g-amino amides (6), weperformed the reaction of Passerini adducts with amines in dilutemethanol solution, and in the presence of Cu(I) (Table 4).Conveniently, microwave irradiation of a solution of chromoneacetates (1), unhindered primary amines (7a–b) and catalyticCuCl selectively affords g-amino amides (6) in just 5minutes. Thenature of the substituent on the chromone seems to signicantlyaffect the course of the reaction. Thus, in absence of coppercatalyst, 6 : 5 ratio increases with the electron-withdrawing natureof the substituents, and 6-chloro chromone g-amino amides(6h–i, p) are obtained with high (Table 4, entry 13) or completeselectivity (entries 7 and 8). Less reactive methyl-substituted andunsubstituted chromones require CuCl for complete selectivity(entries 1–6). In contrast, cyclic secondary amines give only theproducts of a-substitution (5l–o) or do not react, even in thepresence of CuCl (entries 10–12). Interestingly, the reaction ofchromone 1e with glycine selectively affords retropeptidic deriv-ative 6p, containing a retro-a-g-amino acid sequence (entry 13).Hindered amino acid derivative valine methyl ester affords a 7 : 3mixture of the products of a and g substitution (5j and 6j; entry 9).

To probe the mechanism of the formation of 5 and 6,compound 5a was treated with 2 equiv. of benzylamine and CuClin methanol. Analogously, 6a was treated with 2 equiv. of benzyl-amine in THF. In both cases no transformation was observed.These results prove that chromones 5 and 6 are not inter-convertible in the reaction conditions, suggesting they arerespectively obtained through independent routes.

Previous studies have shown that nucleophilic attack onBaylis–Hillman acetates can take place either at the g-carbon viaa SN20 reaction or at the a-carbon through a SN20–SN20 process.19

Thus, we hypothesize that, in the absence of catalyst, theformation of both 5 and 6 begins with an initial allylic aminationof the Passerini adduct (1) by addition of the amine (7) to chro-mone position 2 to give common intermediate 8 (Scheme 2). Theaddition of a second molecule of the amine would lead to a-substitution product 5. This bimolecular reaction is the preferredprocess at relative high concentrations, in non-protic solvents,such as THF. On the other hand, an intramolecular processleading to open intermediate 9 is preferred in diluted conditions.This transformation requires the participation of the lone electronpair on the amine nitrogen atom in 8, and the protonation of theoxygen leaving group, which is only possible in protic solvents,such as methanol. Then, an intra-molecular oxo-Michael additionon intermediate 9 affords g-amino amide 6. An analogous rear-rangement on Baylis–Hillman adducts was observed by Liu and co-workers.14,20 Electron-withdrawing substituents on the aromaticring make the phenol a better leaving group, favouring this reac-tion path. The observed decrease on the reaction rate in thepresence of Lewis acids may be explained by their complexationwith the nitrogen electron pair, which would hamper the forma-tion of the imine and the concomitant opening of the pyran ring(Scheme 2).

In contrast, compound 6 is rapidly formed in the presence ofCuCl. In these conditions a copper(III) p-allyl complex (Fig. 1) is

This journal is © The Royal Society of Chemistry 2014

Table 4 g-Allyl amination of Passerini adducts (1)

Entry R1 R2 Amine

Method Aa Method Bb

Products (yield)c 5 : 6 ratio Products (yield)c 5 : 6 ratio

1 H t-Bu PhCH2NH2 5a + 6a (85) 20 : 80 6a (98) 0 : 1002 H t-Bu 3,4-(OCH2O)PhCH2NH2 5b + 6b (60) 20 : 80 6b (59) 0 : 1003 H c-C6H11 PhCH2NH2 5c + 6c (63) 14 : 86 6c (89) 0 : 1004 H c-C6H11 3,4-(OCH2O)PhCH2NH2 5d + 6d (85) 18 : 82 6d (90) 0 : 1005 CH3 c-C6H11 PhCH2NH2 5f + 6f (96) 37 : 63 6f (52) 0 : 1006 CH3 c-C6H11 3,4-(OCH2O)PhCH2 5g + 6g (72) 37 : 63 6g (60) 0 : 1007 Cl c-C6H11 PhCH2NH2 6h (70) 0 : 100 — —8 Cl c-C6H11 3,4-(OCH2O)PhCH2NH2 6i (84) 0 : 100 — —9 H t-Bu L-Val-OMe 5j (85) 100 : 0d 5j +6j (76) 67 : 3310 H t-Bu Pyrrolidine 5l (58) 100 : 0 dece —11 H t-Bu L-Pro-OMe 5n (46) 100 : 0 5n (64) 100 : 012 Cl c-C6H11 L-Pro-OMe 5o (59) 100 : 0 5o (67) 100 : 013 Cl c-C6H11 L-Gly-OMe 5p + 6p (70) 5 : 95f 6p (65) 0 : 100

a A solution 0.02M of the Passerini adduct (1) in MeOH and 2 equiv. of the amine (7) is stirred at room temperature for 2–5 hours. b A solution 0.2 Mof the Passerini adduct (1), 2.3 equiv. of the amine (7) and 10%mol CuCl in MeOH is irradiated with mw 5–7 min at 75 �C. c Isolated yields. d Tracesof 6 are obtained. e The starting material decomposes. f Determined by 1H NMR.

Fig. 1 Proposed copper(III)p-allyl complex leading to the formation of 6.

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probably involved in the reaction mechanism. Similar coppercomplexes were observed in the allyl aminations of alkenes.21 Avisible change of colour when the amine is added to the reactionmedium also suggests its coordination to copper favouring itsattack to chromone position 2. This is key for the selectivity of thereaction, which would essentially take place in an intramolecularfashion around the coordination sphere of the metal.

Conclusions

In conclusion, we have developed an efficient method for theallylic amination of chromone Passerini adducts. Carefulcontrol of the reaction conditions permits to obtain a- andg-amino amidochromones with high yield and completeregioselectivity when unhindered primary amines are used.These novel heterocyclic amino acid derivatives may haveinterest as building blocks with new properties in the synthesisof peptidomimetics.

Our results gain particular synthetic value as the nucleo-philic substitution of Passerini adducts derived from allylicaldehydes may constitute a powerful general method for theformation of C–C and C–heteroatom bonds. This strategy hasrevealed as an advantageous alternative to the allylic aminationof Baylis–Hillman acetates. Moreover, the mechanism of thereaction provides opportunities to develop new stereoselective

This journal is © The Royal Society of Chemistry 2014

aminations and extend its scope to other nucleophiles, sofurther research is ongoing in our lab.

ExperimentalGeneral

Melting points are uncorrected. IR spectra were recorded as KBrpellets. Proton and carbon-13 nuclear magnetic resonance(1H NMR or 13C NMR) spectra were obtained on a 400 or500 MHz spectrometer. The assignments of signals in 13CNMR were made using DEPT. Mass spectra (MS) and HighResolution Mass Spectra (HRMS) were recorded using Elec-tronic Impact (EI), Chemical Ionization (CI) with CH4, FAB orESI-TOF. Liquid reagents were measured using positive-displacement micropipettes with disposable tips andpistons. Experiments under microwave irradiation were per-formed in closed vials, using a focused single-mode micro-wave reactor.

Synthesis of the Passerini adducts

3-Formylchromone 2 (5 mmol) was suspended in 5 mL of Et2O.The solution was cooled at 0 �C and acetic acid (4, 5 mmol), andthe corresponding isocyanide (3, 5 mmol) were successivelyadded. Aer 48 hours stirring at room temperature, an abun-dant precipitate was formed, which was ltered and washedwith i-Pr2O and hexane, yielding a product (1) usually pureenough to be used in the following reaction.

(tert-Butylcarbamoyl)(4-oxo-4H-chromen-3-yl)methyl acetate(1a). (72%) obtained as a white solid; mp 170–172 �C; IR (cm�1)3319, 1743, 1679, 1643, 1561, 1463, 1365, 1345, 1312, 1234,1221; 1H NMR (400 MHz, CDCl3) d 8.23 (d, J ¼ 8.0 Hz, 1H), 8.21(s, 1H), 7.72 (t, J ¼ 7.5 Hz, 1H), 7.50 (d, J ¼ 8.4 Hz, 1H), 7.45 (d, J¼ 7.5 Hz, 1H), 6.72 (bs, 1H), 6.00 (s, 1H), 2.22 (s, 3H), 1.35(s, 9H); 13C NMR (100 MHz, CDCl3) d 176.40 (C), 169.48 (C),166.21 (C), 156.20 (C), 155.14 (CH), 134.17 (CH), 125.80 (CH),

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125.56 (CH), 123.74 (C), 119.68 (C), 118.25 (CH), 68.50 (CH),51.46 (C), 28.53 (CH3), 20.83 (CH3); MS (FAB) m/z (%) 318(M+ + 1, 100), 175 (30); HRMS (FAB) calcd for C17H20NO5:318.1341. Found: 318.1338.

(Cyclohexylcarbamoyl)(4-oxo-4H-chromen-3-yl)methyl acetate(1b). (67%) obtained as a white solid; mp 135–137 �C; IR (cm�1)3308, 3090, 2930, 2858, 1736, 1665, 1557, 1467, 1405, 1352,1245, 1227; 1H NMR (400 MHz, CDCl3) d 8.26–8.20 (m, 2H), 7.72(t, J ¼ 7.8 Hz, 1H), 7.50 (d, J ¼ 8.4 Hz, 1H), 7.45 (t, J ¼ 7.6 Hz,1H), 6.74 (d, J¼ 7.7 Hz, 1H), 6.06 (s, 1H), 3.83–3.66 (m, 1H), 2.22(s, 3H), 2.07–1.06 (m, 10H); 13C NMR (100 MHz, CDCl3) d 176.36(C), 169.53 (C), 166.26 (C), 156.18 (C), 155.35 (CH), 134.182 (CH),125.779 (CH), 125.581 (CH), 123.746 (C), 138.34 (C), 119.55 (C),118.26 (CH), 68.51 (CH), 48.37 (CH), 32.72 (CH2), 32.56 (CH2),25.44 (CH2), 24.60 (CH2), 20.86 (CH3); MS (FAB)m/z (%) 344 (M+

+ 1, 100), 284 (14), 256 (12), 175 (18); HRMS (FAB) calcd forC19H22NO5: 344.1498. Found: 344.1495.

2-(Benzylamino)-2-oxo-1-(4-oxo-4H-chromen-3-yl)ethyl acetate(1c). (62%) obtained as a white solid; mp 120–121 �C; IR (cm�1)3445, 3292, 1735, 1668, 1648, 1560, 1470, 1351, 1250, 1231; 1HNMR (400 MHz, CDCl3) d 8.24 (s, 1H), 8.20 (d, J ¼ 7.9 Hz, 1H),7.72 (t, J¼ 7.7 Hz, 1H), 7.50 (d, J¼ 8.4 Hz, 1H), 7.44 (t, J¼ 7.6 Hz,1H), 7.35–7.13 (m, 6H), 6.14 (s, 1H), 4.55 (dd, J ¼ 15.0, 6.0 Hz,1H), 4.42 (dd, J ¼ 15.0, 5.7 Hz, 1H), 2.21 (s, 3H); 13C NMR (100MHz, CDCl3) d 176.37 (C), 169.57 (C), 167.42 (C), 156.23 (C),155.55 (CH), 137.72 (C), 134.27 (CH), 128.59 (CH), 127.48 (CH),127.33 (CH), 125.78 (CH), 125.65 (CH), 123.73 (C), 119.34 (C),118.28 (CH), 68.57 (CH), 43.43 (CH2), 20.82 (CH3). MS (FAB) m/z(%) 352 (M+ + 1, 100); HRMS (FAB) calcd for C20H18NO5:352.1185. Found: 352.1190.

(Cyclohexylcarbamoyl)(6-methyl-4-oxo-4H-chromen-3-yl)methylacetate (1d). (80%) obtained as a white solid; mp 200–202 �C; IR(cm�1) 3290, 2928, 2852, 1734, 1666, 1647, 1561, 1488, 1379,1345, 1256, 1231. 1H NMR (400 MHz, CDCl3) d 8.20 (s, 1H), 8.00(d, J ¼ 1 Hz, 1H), 7.52 (dd, J ¼ 8.6, 2.0 Hz, 1H), 7.39 (d, J ¼ 8.5Hz, 1H), 6.76 (d, J ¼ 8.0 Hz, 1H), 6.06 (s, 1H), 3.81–3.68 (m, 1H),2.47 (s, 3H), 2.21 (s, 3H), 2.05–1.05 (m, 10H). 13C NMR (100MHz, CDCl3) d 176.43 (C), 169.51 (C), 166.35 (C), 155.10 (CH),154.50 (C), 135.66 (C), 135.45 (CH), 125.01 (CH), 123.38 (C),119.34 (C), 117.99 (CH), 68.48 (CH), 48.31 (CH), 32.71 (CH2),32.54 (CH2), 25.43 (CH2), 24.57 (CH2), 20.89 (CH3), 20.83 (CH3);MS (CI)m/z (%) 358 (M+ + 1, 40), 298 (100), 201 (45); HRMS (ESI-TOF) calcd for C20H24NO5: 358.1654. Found: 358.1649.

(Cyclohexylcarbamoyl)(6-chloro-4-oxo-4H-chromen-3-yl)methylacetate (1e). (47%) obtained as a white solid; mp 212 �C (dec.); IR(cm�1) 3283, 2931, 2855, 1733, 1665, 1650, 1565, 1469, 1379,1342, 1258, 1158, 1093; 1H NMR (400MHz, CDCl3) d 8.21 (s, 1H),8.17 (d, J ¼ 2.5 Hz, 1H), 7.63 (dd, J ¼ 2.5, 8.9 Hz, 1H), 7.44 (s,1H), 6.63 (d, J ¼ 7.8 Hz, 1H), 6.00 (s, 1H), 2.20 (s, 3H), 1.79–1.04(m, 10H); 13C NMR (100 MHz, CDCl3) d 169.50 (C), 168.97 (C),166.05 (C), 161.51 (C), 155.64 (C), 155.07 (C), 134.23 (C), 134.44(CH), 125.22 (CH), 120.04 (CH), 68.50 (CH), 48.45 (CH), 48.00(CH), 32.72 (CH2), 32.59 (CH2), 25.43 (CH2), 24.94 (CH2), 24.61(CH2), 20.85 (CH3); MS (CI) m/z (%) 380 (M+ + 3, 8), 378 (M+ + 1,22), 342 (11), 336 (28), 320 (64), 318 (100), 290 (80), 279 (37), 209(91); HRMS (CI) calcd for C19H21ClNO5: 378.1108. Found:378.1118.

40048 | RSC Adv., 2014, 4, 40044–40053

General procedure for the nucleophilic a-substitution ofPasserini adducts with amines in THF

To a solution of the corresponding Passerini adduct (1, 0.2mmol) in anhydrous THF (1 mL), the corresponding amine(7, 0.4 mmol) was added under inert atmosphere. Aer 2–5hours stirring at room temperature, the reaction mixture waspoured onto water (10 mL) and 10% HCl (1 mL) was added. Theresulting mixture was extracted CH2Cl2 (3� 15 mL), the organicphase was dried with Na2SO4, concentrated and the residue waspuried by ash column chromatography (SiO2; hexane–EtOAcgradient), giving the corresponding product 5a–o.

2-(Benzylamino)-N-(tert-butyl)-2-(4-oxo-4H-chromen-3-yl)acetamide (5a). (95%) obtained as a yellow gum; IR (cm�1):3420, 3327, 1656, 1631, 1557, 1467, 1385, 732; 1H NMR(500 MHz, CDCl3) d 8.23 (dd, J ¼ 8.5, 1.7 Hz, 1H), 7.99 (s, 1H),7.71 (dt, J ¼ 7.1, 1.7 Hz, 1H), 7.52 (bs, 1H), 7.49 (dd, J ¼ 8.5,0.4 Hz, 1H), 7.43 (dt, J ¼ 7.1, 1.7 Hz, 1H), 7.35–7.31 (m, 4H),7.28–7.24 (m, 1H), 4.07 (s, 1H), 3.86 (d, J ¼ 13.1 Hz, 1H), 3.75(d, J ¼ 13.2 Hz, 1H), 2.66 (bs, 1H), 1.38 (s, 9H); 13C NMR(126 MHz, CDCl3) d 177.91 (C), 170.14 (C), 156.42 (C), 154.67(CH), 139.37 (C), 133.87 (CH), 128.50 (CH), 128.18 (CH), 127.23(CH), 125.81 (CH), 125.22 (CH), 123.93 (C), 122.03 (C), 118.19(CH), 59.32 (CH), 52.28 (CH2), 50.98 (C), 28.70 (CH3); MS (CI) m/z(%) 365 (M+ + 1, 85), 264 (94), 17 (19), 149 (15), 43 (100); HRMS(CI) calcd for C22H25N2O3 365.1865. Found: 365.1862.

2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)-N-(tert-butyl)-2-(4-oxo-4H-chromen-3-yl)acetamide (5b). (86%) obtained as ayellow gum; IR (cm�1): 3418, 2965, 2921, 1642, 1466, 1384, 1352,1248, 1037, 761; 1H NMR (500 MHz, CDCl3) d 8.22 (dd, J ¼ 8.0,1.5 Hz, 1H), 7.98 (s, 1H), 7.70 (dt, J ¼ 7.1, 1.7 Hz, 1H), 7.50–7.46(m, 2H), 7.43 (dt, J ¼ 8.1, 1.0 Hz, 1H), 6.84 (s, 1H), 6.75 (s, 2H),5.93 (dd, J ¼ 7.6, 1.5 Hz, 2H), 4.05 (s, 1H), 3.75 (d, J ¼ 13.0 Hz,1H), 3.66 (d, J ¼ 13.0 Hz, 1H), 3.26 (bs, 1H), 1.37 (s, 9H); 13CNMR (101 MHz, CDCl3) d 177.88 (C), 170.15 (C), 156.39 (C),154.67 (CH), 147.80 (C), 146.75 (C), 133.89 (CH), 133.17 (C),125.80 (CH), 125.23 (CH), 123.89 (C), 121.92 (C), 121.40 (CH),118.19 (CH), 108.68 (CH), 108.12 (CH), 100.93 (CH2), 59.00 (CH),52.01 (CH2), 51.01 (C), 28.69 (CH3); MS (CI) m/z (%) 409 (M+ + 1,17), 308 (88), 259 (8), 202 (23), 174 (26), 150 (15), 135 (100);HRMS (CI) calcd for C23H25N2O5 409.1763. Found: 409.1766.

2-(Benzylamino)-N-cyclohexyl-2-(4-oxo-4H-chromen-3-yl)acetamide (5c). (81%) obtained as a yellow solid; mp 112–115 �C;IR (cm�1): 3368, 2927, 2853, 1670, 1637, 1510, 1464, 1400, 1355,1107, 866, 771, 699; 1H NMR (500 MHz, CDCl3) d 8.22 (dd, J¼ 8.0,1.6 Hz, 1H), 8.02 (s, 1H), 7.71 (dt, J¼ 7.1, 1.7 Hz, 1H), 7.53 (bs, 1H),7.50 (d, J¼ 8.2 Hz, 1H), 7.44 (d, J¼ 7.5 Hz, 1H), 7.36–7.31 (m, 4H),7.29–7.25 (m, 1H), 4.17 (s, 1H), 3.86 (d, J¼ 13.1 Hz, 1H), 3.83–3.75(m, 1H), 3.76 (d, J ¼ 13.1 Hz, 1H), 3.38 (bs, 1H), 2.02–1.11 (m,10H); 13C NMR (126 MHz, CDCl3) d 177.93 (C), 170.03 (C), 156.39(C), 154.75 (CH), 139.22 (C), 133.93 (CH), 128.53 (CH), 128.23(CH), 127.29 (CH), 125.79 (CH), 125.29 (CH), 123.87 (C), 121.90(C), 118.23 (CH), 58.67 (CH), 52.19 (CH2), 48.15 (CH), 33.02 (CH2),32.74 (CH2), 25.57 (CH2), 24.66 (CH2); MS (CI)m/z (%) 391 (M+ + 1,46), 389 (13), 284 (24), 264 (95), 245 (29), 91 (100); HRMS (CI) calcdfor C24H27N2O3 391.2022. Found: 391.2025.

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2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)-N-cyclohexyl-2-(4-oxo-4H-chromen-3-yl)acetamide (5d). (90%) obtained as ayellow gum; IR (cm�1): 3426, 2927, 1636, 1508, 1463, 1384, 1245,1103, 1037; 1H NMR (500MHz, CDCl3) d 8.22 (dd, J¼ 8.0, 1.5 Hz,1H), 8.02 (s, 1H), 7.71 (dt, J¼ 8.6, 1.7 Hz, 1H), 7.51–7.41 (m, 3H),6.85 (s, 1H), 6.76 (d, J ¼ 1.1 Hz, 2H), 5.95 (dd, J ¼ 5.5, 1.4 Hz,2H), 4.15 (s, 1H), 3.78–3.75 (m, 1H), 3.76 (d, J ¼ 13.0 Hz, 1H),3.68 (d, J ¼ 13.0 Hz, 1H), 1.98–1.08 (m, 10H); 13C NMR(101 MHz, CDCl3) d 177.92 (C), 170.00 (C), 156.38 (C), 154.70(CH), 147.82 (C), 146.78 (C), 133.94 (CH), 133.08 (C), 125.79(CH), 125.30 (CH), 123.85 (C), 121.86 (C), 121.45 (CH), 118.23(CH), 108.71 (CH), 108.15 (CH), 100.96 (CH2), 58.38 (CH), 51.95(CH2), 48.16 (CH), 33.02 (CH2), 32.75 (CH2), 25.55 (CH2), 24.67(CH2); MS (CI) m/z (%) 435 (M+ + 1, 81), 308 (18), 284 (29), 202(11), 163 (12), 150 (25), 135 (100); HRMS (CI) calcd forC25H27N2O5 435.1920. Found: 435.1905.

N-Benzyl-2-(benzylamino)-2-(4-oxo-4H-chromen-3-yl)acetamide(5e). (95%) obtained as a white solid; mp 110–112 �C; IR (cm�1):3380, 3339, 3292, 1640, 1466, 764, 698; 1H NMR (400 MHz,CDCl3) d 8.29 (dd, J¼ 8.0, 1.6 Hz, 1H), 8.10 (s, 1H), 8.06 (bs, 1H),7.79 (dt, J ¼ 7.1, 1.7 Hz, 1H), 7.58 (d, J ¼ 8.5 Hz, 1H), 7.54–7.48(m, 1H), 7.44–7.29 (m, 10H), 4.65–4.51 (m, 2H), 4.27 (s, 1H), 3.95(d, J ¼ 13.1 Hz, 1H), 3.83 (d, J ¼ 13.1 Hz, 1H), 2.88 (bs, 2H); 13CNMR (101 MHz, CDCl3) d 177.94 (C), 171.03 (C), 156.45 (C),154.86 (CH), 138.33 (C), 134.03 (CH), 128.63 (CH), 128.57 (CH),128.30 (CH), 127.54 (CH), 127.40 (CH), 127.30 (CH), 125.79(CH), 125.35 (CH), 123.89 (C), 121.90 (C), 118.24 (CH), 58.89(CH), 52.00 (CH2), 43.49 (CH2); MS (CI) m/z (%) 399 (M+ + 1, <5),264 (11), 219 (100), 169 (19), 131 (38); HRMS (CI) calcd forC25H23N2O3 399.1709. Found: 399.1702.

2-(Benzylamino)-N-cyclohexyl-2-(6-methyl-4-oxo-4H-chromen-3-yl)acetamide (5f). (78%) obtained as a yellow oil; IR (cm�1):3308, 2930, 2854, 1645, 1540, 1484, 1451, 1342, 1228, 818; 1HNMR (400 MHz, CDCl3) d 8.01 (s, 1H), 8.00 (bs, 1H), 7.56–7.48(m, 2H), 7.42–7.22 (m, 6H), 4.28 (bs, 1H), 4.19 (s, 1H), 3.88–3.72 (m, 3H), 2.47 (s, 3H), 2.03–1.12 (m, 10H); 13C NMR (101MHz, CDCl3) d 177.97 (C), 170.17 (C), 154.68 (CH), 154.65 (C),139.28 (C), 135.27 (C), 135.20 (CH), 128.50 (CH), 128.22 (CH),127.24 (CH), 125.00 (CH), 123.51 (C), 121.69 (C), 117.96 (CH),58.60 (CH), 52.20 (CH2), 48.15 (CH), 33.01 (CH2), 32.73 (CH2),25.56 (CH2), 24.68 (CH2), 24.66 (CH2), 20.96 (CH3); MS (CI) m/z (%) 405 (M+ + 1, 81), 358 (25), 316 (100), 298 (83), 268 (69),189 (84); HRMS (CI) calcd for C25H29N2O3 405.2178. Found:405.2178.

2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)-N-cyclohexyl-2-(6-methyl-4-oxo-4H-chromen-3-yl)acetamide (5g). (60%) obtainedas a yellow oil; IR (cm�1): 3419, 2929, 1643, 1485, 1444, 1384,1248, 1038; 1H NMR (500 MHz, CDCl3) d 8.00 (s, 2H), 7.53–7.49(m, 1H), 7.47 (d, J ¼ 8.0 Hz, 1H), 7.40 (t, J ¼ 9.8 Hz, 1H), 6.76(s, 2H), 5.94 (d, J ¼ 3.1 Hz, 2H), 4.16 (s, 1H), 3.81–3.63 (m, 3H),2.98 (bs, 2H), 2.48 (s, 3H), 2.10–0.98 (m, 10H); 13C NMR (126MHz, CDCl3) d 177.97 (C), 170.13 (C), 154.70 (C), 154.61 (CH),147.80 (C), 146.75 (C), 135.28 (C), 135.20 (CH), 133.24 (C), 125.02(CH), 123.53 (C), 121.76 (C), 121.41 (CH), 117.96 (CH), 108.72(CH), 108.13 (CH), 100.93 (CH2), 58.34 (CH), 52.00 (CH2), 48.15(CH), 33.02 (CH2), 32.74 (CH2), 25.57 (CH2), 24.66 (CH2), 20.95

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(CH3); MS (CI) m/z (%) 449 (M+ + 1, 10), 298 (17), 189 (30), 135(84), 59 (100); HRMS (CI) calcd for C26H29N2O5 449.2076. Found:449.2082.

2-(Benzylamino)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-N-cyclo-hexylacetamide (5h). (68%) obtained as a yellow oil; IR (cm�1):3348, 2931, 2851, 1675, 1646, 1517, 1467, 1446, 821; 1H NMR(500 MHz, CDCl3) d 8.18 (d, J ¼ 2.6 Hz, 1H), 8.00 (s, 1H), 7.65(dd, J ¼ 8.9, 2.6 Hz, 1H), 7.46 (d, J ¼ 8.9 Hz, 1H), 7.44 (bs, 1H),7.35–7.31 (m, 5H), 4.13 (s, 1H), 3.85 (d, J ¼ 13.1 Hz, 1H), 3.76(d, J ¼ 13.1 Hz, 1H), 3.77–3.74 (m, 1H), 2.18–0.73 (m, 10H); 13CNMR (101 MHz, CDCl3) d 176.84 (C), 169.80 (C), 154.90 (CH),154.74 (C), 139.19 (C), 134.22 (CH), 131.32 (C), 128.60 (CH),128.25 (CH), 127.38 (CH), 125.22 (CH), 124.79 (C), 122.16 (C),120.01 (CH), 58.62 (CH), 52.26 (CH2), 48.23 (CH), 33.06 (CH2),32.78 (CH2), 29.75 (CH2), 25.59 (CH2), 24.71 (CH2); MS (CI) m/z(%) 425 (M+ + 1, 31), 318 (11), 298 (83), 208 (9), 91 (100); HRMS(CI) calcd for C24H26ClN2O3 425.1632. Found: 425.1630.

2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-N-cyclohexylacetamide (5i). (84%) obtainedas a white solid; mp 126–128 �C; IR (cm�1): 3343, 2934, 2852,2362, 1646, 1630, 1553, 1502, 1489, 1444, 1405, 1252, 1039, 921,825; 1H NMR (500 MHz, CDCl3) d 8.18 (d, J ¼ 1.8 Hz, 1H), 8.00(s, 1H), 7.64 (dd, J ¼ 8.7, 2.0 Hz, 1H), 7.45 (d, J ¼ 8.9 Hz, 1H),7.38 (d, J ¼ 7.7 Hz, 1H), 6.84 (s, 1H), 6.78 (s, 1H), 6.75 (s, 2H),5.96 (s, 1H), 5.94 (d, J¼ 4.2 Hz, 2H), 4.13 (s, 1H), 3.75 (d, J¼ 12.9Hz, 1H), 3.80–3.53 (m, 1H), 3.67 (d, J ¼ 13.0 Hz, 1H), 2.02–1.08(m, 10H); 13C NMR (126 MHz, CDCl3) d 176.77 (C), 169.80 (C),154.83 (CH), 154.70 (C), 147.84 (C), 146.81 (C), 134.17 (CH),133.07 (C), 131.28 (C), 125.18 (CH), 124.75 (C), 122.13 (C), 121.41(CH), 119.96 (CH), 108.67 (CH), 108.15 (CH), 100.98 (CH2), 58.29(CH), 51.98 (CH2), 48.21 (CH), 33.01 (CH2), 32.73 (CH2), 25.54(CH2), 24.66 (CH2); MS (CI) m/z (%) 469 (M+ + 1, 38), 342 (57),335 (19), 318 (18), 208 (52), 150 (32), 135 (100); HRMS (CI) calcdfor C25H26ClN2O5 469.1530. Found: 469.1526.

(2S)-Methyl-2-((2-(tert-butylamino)-2-oxo-1-(4-oxo-4H-chromen-3-yl)ethyl)amino)-3-methylbutanoate (5j). (98%);obtained as a mixture of diastereoisomers in ratio 45 : 55; IR(cm�1): 3348, 2966, 2922, 1735, 1683, 1639, 1508, 1465, 1384,1200, 765; MS (CI) m/z (%) 389 (M+ + 1, 5), 288 (15), 202 (6), 57(100); HRMS (CI) calcd for C21H29N2O5 389.2076. Found:389.2082.

Diastereoisomer A. Diastereoisomer A obtained as a whitesolid; mp 88–90 �C; 1H NMR (500 MHz, CDCl3) d 8.21 (dd, J ¼8.1, 1.6 Hz, 1H), 7.88 (s, 1H), 7.70–7.63 (m, 2H), 7.45 (d, J ¼ 8.1Hz, 1H), 7.41 (t, J¼ 8.1 Hz, 1H), 3.79 (s, 1H), 3.42 (s, 3H), 2.99 (d,J ¼ 6.9 Hz, 1H), 1.99–1.88 (m, 1H), 1.40 (s, 9H), 1.04 (d, J ¼ 6.8Hz, 3H), 0.97 (d, J ¼ 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) d177.21 (C), 174.55 (C), 169.86 (C), 156.29 (C), 154.01 (CH), 133.78(CH), 125.85 (CH), 125.17 (CH), 124.00 (C), 122.16 (C), 118.06(CH), 68.18 (CH), 61.24 (CH), 51.39 (CH3), 50.86 (C), 31.71 (CH),28.66 (CH3), 19.39 (CH3), 18.85 (CH3).

Diastereoisomer B. Diastereoisomer B obtained as a whitesolid; mp 102–104 �C; 1H NMR (500 MHz, CDCl3) d 8.26 (s, 1H),8.24 (t, J ¼ 3.0 Hz, 1H), 7.72 (dt, J ¼ 7.2, 1.6 Hz, 1H), 7.52 (d, J ¼8.7 Hz, 1H), 7.46 (t, J ¼ 7.2 Hz, 1H), 7.37 (bs, 1H), 4.20 (s, 1H),3.71 (s, 3H), 3.02 (d, J ¼ 5.7 Hz, 1H), 2.09–2.00 (m, 1H), 1.34(s, 9H), 0.99 (dd, J¼ 6.8, 3.7 Hz, 6H); 13C NMR (126 MHz, CDCl3)

RSC Adv., 2014, 4, 40044–40053 | 40049

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d 178.57 (C), 174.74 (C), 169.73 (C), 156.38 (C), 155.56 (CH),133.96 (CH), 125.81 (CH), 125.34 (CH), 123.71 (C), 122.44 (C),118.29 (CH), 65.72 (CH), 57.00 (CH), 51.65 (CH3), 51.03 (C),31.40 (CH), 28.66 (CH3), 19.63 (CH3), 18.28 (CH3).

(2S)-Ethyl-2-((2-(tert-butylamino)-2-oxo-1-(4-oxo-4H-chromen-3-yl)ethyl)amino)-3-methylbutanoate (5k). (60%); obtained as amixture of diastereoisomers in ratio 65 : 35; IR (cm�1): 3434,2965, 1733, 1648, 1517, 1466, 1385, 1363, 1188, 1144, 1027, 763;MS (CI)m/z (%) 403 (M+ + 1, 80), 329 (38), 302 (100), 258 (15), 202(23), 174 (25), 102 (27); HRMS (CI) calcd for C22H31N2O5

403.2233. Found: 403.2229.Diastereoisomer A. Diastereoisomer A obtained as a white

solid; mp 67–69 �C; 1H NMR (500 MHz, CDCl3) d 8.21 (dd, J ¼8.0, 1.5 Hz, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.67 (dt, J¼ 7.2, 1.7 Hz,1H), 7.46–7.43 (m, 1H), 7.42–7.39 (m, 1H), 3.96–3.84 (m, 1H),3.80–3.72 (m, 2H), 2.96 (d, J ¼ 6.9 Hz, 1H), 1.40 (s, 9H), 1.05 (t, J¼ 5.0 Hz, 3H), 1.04 (d, J ¼ 6.8 Hz, 3H), 0.98 (d, J ¼ 6.8 Hz, 3H);13C NMR (126 MHz, CDCl3) d 177.21 (C), 174.11 (C), 169.90 (C),156.32 (C), 154.00 (CH), 133.75 (CH), 125.87 (CH), 125.12 (CH),124.06 (C), 122.29 (C), 118.04 (CH), 68.35 (CH), 61.46 (CH), 60.52(CH2), 50.83 (C), 31.79 (CH), 28.67 (CH3), 19.40 (CH3), 18.81(CH3), 13.88 (CH3).

Diastereoisomer mixture A : B (0.65 : 0.35). Diastereoisomermixture A : B (0.65 : 0.35) 1H NMR (500 MHz, CDCl3) d 8.26 (dd,J ¼ 3.8, 1.3 Hz, 0.35Hb), 8.25 (t, J ¼ 1.9 Hz, 0.35Hb), 8.23(s, 0.35Hb), 8.21 (dd, J ¼ 8.0, 1.5 Hz, 0.65Ha), 7.88 (s, 0.65Ha),7.76–7.65 (m, 2H), 7.54–7.38 (m, 3H), 4.26–4.18 (m, 0.35Hb),4.19 (s, 0.35Hb), 4.17–4.10 (m, 0.35Hb), 3.81–3.73 (m, 0.65Ha),3.77 (s, 0.65Ha), 3.81–3.73 (m, 0.65Ha), 2.99 (d, J ¼ 5.7 Hz,0.35Hb), 2.96 (d, J ¼ 6.9 Hz, 0.65Ha), 1.98–1.89 (m, 1H), 1.40(s, 5.85Ha), 1.34 (s, 3.15Hb), 1.05 (d, J ¼ 3.0 Hz, 1.95Ha), 1.03(d, J ¼ 2.6 Hz, 1.05Hb), 1.00 (d, J ¼ 2.1 Hz, 1.05Hb), 0.98 (d, J ¼6.8 Hz, 1.95Ha).

N-(tert-Butyl)-2-(4-oxo-4H-chromen-3-yl)-2-(pyrrolidin-1-yl)acetamide (5l). (55%) obtained as a yellow solid; mp 105–107 �C(dec.); IR (cm�1): 3344, 2961, 2800, 1679, 1631, 1566, 1537, 1466,1220, 768; 1H NMR (500 MHz, CDCl3) d 8.23 (dd, J ¼ 8.0, 1.5 Hz,1H), 8.13 (s, 1H), 7.68 (dt, J ¼ 7.1, 1.7 Hz, 1H), 7.47 (d, J ¼ 8.2,Hz, 1H), 7.42 (t, J ¼ 8.1 Hz, 1H), 7.09 (s, 1H), 4.13 (s, 1H), 2.67–2.54 (m, 4H), 1.81–1.77 (m, 4H), 1.38 (s, 9H); 13C NMR (101MHz,CDCl3) d 176.86 (C), 169.64 (C), 156.12 (C), 155.77 (CH), 133.70(CH), 126.06 (CH), 125.23 (CH), 124.01 (C), 120.35 (C), 118.15(CH), 65.37 (CH), 51.75 (CH2), 50.98 (C), 28.66 (CH3), 23.41(CH2); MS (CI) m/z (%) 329 (M+ + 1, 28), 269 (6), 228 (100), 202(36); HRMS (CI) calcd for C19H25N2O3 329.1865. Found:329.1864.

N-(tert-Butyl)-2-(4-oxo-4H-chromen-3-yl)-2-(piperidin-1-yl)acetamide (5m). (97%) obtained as a yellow solid; mp 135–137 �C;IR (cm�1): 3324. 2932, 1678, 1633, 1509, 1465, 1361, 1217,763; 1H NMR (400 MHz, CDCl3) d 8.22 (dd, J ¼ 8.0, 1.6 Hz, 1H),7.97 (s, 1H), 7.68 (dt, J ¼ 8.7, 7.1, 1.7 Hz, 1H), 7.57 (s, 1H), 7.49–7.45 (m, 1H), 7.44–7.38 (m, 1H), 4.39 (s, 1H), 2.50 (s, 4H), 1.68–1.51(m, 6H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) d 177.27 (C),169.46 (C), 156.22 (CH), 156.09 (C), 133.63 (CH), 126.10 (CH),125.19 (CH), 123.91 (C), 118.08 (CH), 117.79 (C), 65.83 (CH),51.74 (CH2), 50.83 (C), 28.66 (CH3), 26.40 (CH2), 23.96 (CH2);

40050 | RSC Adv., 2014, 4, 40044–40053

MS (CI)m/z (%) 343 (M+ + 1, 21), 242 (100), 197 (9), 159 (10); HRMS(CI) calcd for C20H27N2O3 343.2022. Found: 343.2020.

(2S)-Methyl-1-(2-(tert-butylamino)-2-oxo-1-(4-oxo-4H-chromen-3-yl)ethyl)pyrrolidine-2-carboxylate (5n). (70%); obtained as amixture of diastereoisomers in ratio 65 : 35; IR (cm�1): 3434,2968, 1738, 1643, 1524, 1467, 1384, 1219, 764; MS (CI) m/z (%)387 (M+ + 1, 72), 327 (30), 286 (100), 258 (24), 241 (11), 202 (31),187 (43); HRMS (CI) calcd for C21H27N2O5 387.1920. Found:387.1918.

Diastereoisomer A. Diastereoisomer A obtained as a yellowgum; 1H NMR (500 MHz, CDCl3) d 8.22 (dd, J ¼ 7.9, 1.6 Hz, 1H),8.12 (bs, 1H), 8.02 (s, 1H), 7.69 (dt, J ¼ 7.0, 1.7 Hz, 1H), 7.48 (d, J¼ 8.0 Hz, 1H), 7.42 (t, J ¼ 7.1 Hz, 1H), 4.83 (s, 1H), 3.99 (dd, J ¼9.7, 3.9 Hz, 1H), 3.76 (s, 3H), 2.89–2.83 (m, 1H), 2.54–2.45(m, 1H), 2.10–2.03 (m, 1H), 1.95–1.78 (m, 3H), 1.42 (s, 9H); 13CNMR (101 MHz, CDCl3) d 177.64 (C), 175.98 (C), 169.55 (C),156.74 (CH), 156.12 (C), 133.69 (CH), 126.01 (CH), 125.19 (CH),118.30 (C), 118.14 (CH), 63.48 (CH), 60.29 (CH), 51.97 (CH3),50.74 (CH2), 47.72 (C), 29.93 (CH2), 28.67 (CH3), 24.24 (CH2).

Diastereoisomer mixture A : B (0.65 : 0.35). Diastereoisomermixture A : B (0.65 : 0.35) 1H NMR (500 MHz, CDCl3) d 8.25–8.21(m, 1H), 8.13 (bs, 0.65Ha), 8.07 (bs, 0.35Hb), 8.02 (s, 0.65Ha),7.90 (s, 0.35Hb), 7.74–7.66 (m, 1H), 7.52–7.39 (m, 2H), 4.84(s, 0.65Ha), 4.57 (s, 0.35Hb), 3.99 (dd, J ¼ 9.7, 3.9 Hz, 0.65Ha),3.76 (s, 1.95Ha), 3.56 (s, 1.05Hb), 3.50 (dd, J ¼ 9.1, 3.8 Hz,0.35Hb), 3.29–3.22 (m, 0.35Hb), 3.02–2.96 (m, 0.35Hb), 2.89–2.83 (m, 0.65Ha), 2.54–2.45 (m, 0.65Ha), 2.14–1.69 (m, 4H), 1.44(s, 3.15Hb), 1.43 (s, 5.85Ha); 13C NMR (101 MHz, CDCl3) d

177.64 (C), 177.19 (C), 176.44 (C), 175.99 (C), 170.32 (C), 169.56(C), 156.74 (CH), 156.12 (C), 155.83 (CH), 134.24 (CH), 133.85(CH), 133.69 (CH), 126.09 (CH), 126.01 (CH), 125.88 (CH),125.64 (CH), 125.41 (CH), 125.19 (CH), 123.96 (C), 123.79 (C),120.75 (C), 118.34 (CH), 118.29 (C), 118.14 (CH), 118.09 (CH),63.48 (CH), 62.78 (CH), 60.99 (CH), 60.29 (CH), 54.12 (CH2),51.97 (CH3), 51.74 (CH3), 50.94 (C), 50.74 (C), 47.71 (CH2), 30.80(CH2), 29.93 (CH2), 28.67 (CH3), 28.61 (CH3), 24.24 (CH2), 24.13(CH2).

(2S)-Methyl-1-(1-(6-chloro-4-oxo-4H-chromen-3-yl)-2-(cyclohexylamino)-2-oxoethyl)pyrrolidine-2-carboxylate(5o). (90%); obtained as a mixture of diastereoisomers in ratio70 : 30 IR (cm�1): 3427, 2932, 2854, 1738, 1644, 1521, 1467,1384, 1337, 1206, 824; MS (CI)m/z (%) 447 (M+ + 1, 85), 387 (13),336 (12), 320 (100), 290 (38), 221 (63), 209 (43); HRMS (CI) calcdfor C23H28ClN2O5 447.1687. Found: 447.1691.

Diastereoisomer A. Diastereoisomer A obtained as a yellowgum; 1H NMR (500 MHz, CDCl3) d 8.22 (bs, 1H), 8.18 (d, J ¼ 2.6Hz, 1H), 8.03 (s, 1H), 7.62 (dd, J ¼ 8.9, 2.6 Hz, 1H), 7.44 (d, J ¼8.9 Hz, 1H), 4.91 (s, 1H), 4.01 (dd, J ¼ 9.7, 3.9 Hz, 1H), 3.88–3.72(m, 1H), 3.76 (s, 3H), 2.86–2.81 (m, 1H), 2.50–2.41 (m, 1H), 2.09–1.18 (m, 14H); 13C NMR (126 MHz, CDCl3) d 176.53 (C), 176.01(C), 169.15 (C), 156.96 (CH), 154.45 (C), 133.97 (CH), 131.19 (C),125.42 (CH), 124.85 (C), 119.93 (CH), 118.33 (C), 63.57 (CH),59.59 (CH), 52.05 (CH), 48.07 (CH3), 47.55 (CH2), 33.28 (CH2),32.63 (CH2), 29.95 (CH2), 25.59 (CH2), 24.75 (CH2), 24.69 (CH2),24.22 (CH2).

Diastereoisomer mixture A : B (0.55 : 0.45). Diastereoisomermixture A : B (0.55 : 0.45) 1H NMR (500 MHz, CDCl3) d 8.22

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(d, J ¼ 8.2 Hz, 0.55Ha), 8.19 (dd, J ¼ 6.4, 3.2 Hz, 1H), 8.09 (d, J ¼8.3 Hz, 0.45Hb), 8.03 (s, 0.55Ha), 7.89 (s, 0.45Hb), 7.68–7.60(m, 1H), 7.50–7.41 (m, 1H), 4.91 (s, 0.55Ha), 4.63 (s, 0.45Hb),4.01 (dd, J ¼ 9.7, 3.9 Hz, 0.55), 3.87–3.78 (m, 1H), 3.76(s, 1.65Ha), 3.57 (s, 1.35Hb), 3.48 (dd, J ¼ 9.0, 3.7 Hz, 0.45Hb),3.29–3.23 (m, 0.45Hb), 3.02–2.96 (m, 0.45Hb), 2.86–2.80(m, 0.55Ha), 2.50–2.41 (m, 0.55Ha), 2.12–1.14 (m, 14H); 13CNMR (126 MHz, CDCl3) d 176.53 (C), 176.33 (C), 176.01 (C),169.84 (C), 169.15 (C), 156.96 (CH), 156.06 (CH), 154.45 (C),134.13 (CH), 133.97 (CH), 131.43 (C), 131.19 (C), 125.48 (CH),125.42 (CH), 125.24 (C), 124.85 (C), 124.70 (C), 120.67 (C), 120.07(C), 119.92 (CH), 119.86 (CH), 118.33 (C), 68.53 (CH3), 63.57(CH), 62.31 (CH), 61.10 (CH), 59.59 (CH), 54.13 (CH), 52.04 (CH),51.82 (CH), 48.07 (CH3), 47.55 (CH2), 33.28 (CH2), 33.05 (CH2),32.93 (CH2), 32.62 (CH2), 29.95 (CH2), 25.59 (CH2), 25.54 (CH2),24.79 (CH2), 24.69 (CH2), 24.22 (CH2), 24.09 (CH2).

General procedures for the nucleophilic substitution ofPasserini adducts with amines in MeOH

Method A. To a solution of the Passerini adduct (1, 0.2mmol) in MeOH (10 mL), the amine (7, 0.4 mmol) was added.Aer 2–5 hours stirring at room temperature, the solvent waseliminated and the residue was dissolved in CH2Cl2 and pouredonto water (10 mL). The resulting mixture was extracted withCH2Cl2 (3 � 15 mL), the organic phase was dried (Na2SO4) andconcentrated, and the residue was puried by ash columnchromatography (SiO2; hexane–EtOAc gradient), giving thecorresponding product 6.

Method B. A solution 0.2 M of the Passerini adduct (1), 2.3equiv. of the amine (7) and 10% mol CuCl in MeOH was irra-diated with mw 5–7 min at 75 �C. The solvent was eliminatedand the crude was dissolved in CH2Cl2 and poured onto water(10 mL) and saturated NH4Cl (1 mL). The resulting mixture wasextracted with CH2Cl2 (3 � 15 mL), the organic phase was dried(Na2SO4) and concentrated, and the residue was puried byash column chromatography (SiO2; hexane–EtOAc gradient),giving the corresponding product 6.

(Z)-3-((Benzylamino)methylene)-N-(tert-butyl)-4-oxochroman-2-carboxamide (6a). (Method B: 98%) obtained as a yellow gum;IR (cm�1): 3425, 2966, 1647, 1608, 1560, 1466, 1384, 759; 1HNMR (500 MHz, CDCl3) d 10.72–10.60 (m, 1H), 7.92 (dd, J ¼ 7.7,1.7 Hz, 1H), 7.42 (dt, J ¼ 7.3, 1.7 Hz, 1H), 7.39–7.35 (m, 2H),7.33–7.29 (m, 3H), 7.24 (d, J ¼ 2.7 Hz, 1H), 7.10 (dt, J ¼ 7.7, 1.0Hz, 1H), 6.99 (dd, J¼ 7.3, 1.3 Hz, 1H), 6.34 (bs, 1H), 5.21 (s, 1H),4.55–4.46 (m, 2H), 1.33 (s, 9H); 13C NMR (101 MHz, CDCl3) d180.10 (C), 168.79 (C), 156.68 (C), 152.45 (CH), 137.26 (C), 133.76(CH), 128.88 (CH), 127.89 (CH), 127.38 (CH), 126.73 (CH),123.53 (C), 122.41 (CH), 116.51 (CH), 96.97 (C), 78.25 (CH), 53.08(CH2), 51.29 (C), 28.62 (CH3); MS (CI) m/z (%) 365 (M+ +1, 68),292 (13), 264 (100), 200 (8), 91 (58); HRMS (CI) calcd forC22H25N2O3 365.1865. Found: 365.1869.

(Z)-3-(((Benzo[d][1,3]dioxol-5-ylmethyl)amino)methylene)-N-(tert-butyl)-4-oxochroman-2-carboxamide (6b). (Method B:59%) obtained as a yellow solid; mp 45–47 �C; IR (cm�1): 3420,2966, 1646, 1606, 1589, 1466, 1444, 1384, 1037, 808; 1H NMR(500 MHz, CDCl3) d 10.62–10.55 (m, 1H), 7.91 (dd, J ¼ 7.7, 1.6

This journal is © The Royal Society of Chemistry 2014

Hz, 1H), 7.43 (dt, J ¼ 7.5, 1.7 Hz, 1H), 7.21 (d, J ¼ 12.7 Hz, 1H),7.09 (dt, J¼ 11.1, 2.1 Hz, 1H), 6.98 (dd, J¼ 8.1, 4.0 Hz, 1H), 6.82–6.73 (m, 3H), 6.34 (bs, 1H), 5.97 (s, 2H), 5.21 (s, 1H), 4.45–4.34(m, 2H), 1.33 (s, 9H); 13C NMR (101 MHz, CDCl3) d 180.07 (C),168.78 (C), 156.66 (C), 152.17 (CH), 148.12 (C), 147.35 (C), 133.77(CH), 131.01 (C), 126.72 (CH), 123.51 (C), 122.42 (CH), 120.95(CH), 116.51 (CH), 108.45 (CH), 108.02 (CH), 101.18 (CH2), 96.92(C), 78.21 (CH), 52.88 (C), 51.31 (CH2), 28.62 (CH3); MS (CI) m/z(%) 409 (M+ + 1, 29), 392 (7), 336 (15), 308 (100), 273 (23), 202(23), 163 (21), 150 (21), 135 (100); HRMS (CI) calcd forC23H25N2O5 409.1763. Found: 409.1768.

(Z)-3-((Benzylamino)methylene)-N-cyclohexyl-4-oxochroman-2-carboxamide (6c). (Method B: 89%) obtained as a yellow solid;mp 180–182 �C (dec.); IR (cm�1): 3423, 2931, 2860, 1649, 1602,1567, 1542, 1467, 1451, 1107, 749, 697; 1H NMR (500 MHz,CDCl3) d 10.71–10.59 (m, 1H), 7.91 (dd, J¼ 7.8, 1.7 Hz, 1H), 7.42(dt, J ¼ 8.0, 1.3 Hz, 1H), 7.38–7.34 (m, 2H), 7.33–7.27 (m, 4H),7.09 (dt, J ¼ 7.8, 1.0 Hz, 1H), 7.00 (dd, J ¼ 8.2, 0.7 Hz, 1H), 6.39(d, J ¼ 8.0 Hz, 1H), 5.31 (s, 1H), 4.51 (d, J ¼ 6.0 Hz, 2H), 3.83–3.73 (m, 1H), 1.99–0.99 (m, 10H); 13C NMR (126 MHz, CDCl3) d180.10 (C), 168.72 (C), 156.77 (C), 152.54 (CH), 137.28 (C), 133.81(CH), 128.89 (CH), 127.89 (CH), 127.35 (CH), 126.76 (CH),123.53 (C), 122.45 (CH), 116.53 (CH), 96.86 (C), 78.04 (CH), 53.09(CH2), 48.04 (CH), 32.78 (CH2), 32.72 (CH2), 25.42 (CH2), 24.56(CH2), 24.45 (CH2); MS (EI) m/z (%) 390 (M+, 15), 264 (100), 251(35), 159 (30); HRMS (EI) calcd for C24H26N2O3 390.1943. Found:390.1942.

(Z)-3-(((Benzo[d][1,3]dioxol-5-ylmethyl)amino)methylene)-N-cyclohexyl-4-oxochroman-2-carboxamide (6d). (Method B: 90%)obtained as a yellow solid; mp 134–136 �C; IR (cm�1): 3303,2930, 2853, 1647, 1608, 1592, 1549, 1289, 1038, 810; 1H NMR(500 MHz, CDCl3) d 10.62–10.55 (m, 1H), 7.91 (dd, J ¼ 7.8, 1.7Hz, 1H), 7.42 (dt, J ¼ 5.6, 1.7 Hz, 1H), 7.24 (d, J ¼ 12.7 Hz, 1H),7.09 (dt, J ¼ 6.9, 1.0 Hz, 1H), 7.00 (dd, J ¼ 5.7, 0.7 Hz, 1H), 6.81–6.74 (m, 3H), 6.38 (d, J ¼ 8.0 Hz, 1H), 5.97 (s, 2H), 5.30 (s, 1H),4.40 (d, J ¼ 5.9 Hz, 2H), 3.83–3.74 (m, 1H), 2.00–1.02 (m, 10H).;13C NMR (101 MHz, CDCl3) d 180.08 (C), 168.67 (C), 156.76 (C),152.21 (CH), 148.13 (C), 147.35 (C), 133.81 (CH), 131.06 (C),126.74 (CH), 123.52 (C), 122.44 (CH), 120.89 (CH), 116.53 (CH),108.45 (CH), 107.98 (CH), 101.18 (CH2), 96.84 (C), 78.02 (CH),52.89 (CH2), 48.03 (CH), 32.79 (CH2), 32.72 (CH2), 25.42 (CH2),24.57 (CH2), 24.46 (CH2); MS (CI) m/z (%) 435 (M+ + 1, 24), 308(88), 284 (11), 135 (100); HRMS (CI) calcd for C25H27N2O5

435.1920. Found: 435.1919.(Z)-3-((Benzylamino)methylene)-N-cyclohexyl-6-methyl-4-

oxochroman-2-carboxamide (6f). (Method B: 52%) obtainedas a yellow solid; mp 174–176 �C; IR (cm�1): 3424, 2922, 2851,1647, 1618, 1553, 1489, 1453, 1384, 1280, 699; 1H NMR (400MHz, CDCl3) d 10.64 (s, 1H), 7.70 (s, 1H), 7.41–7.17 (m, 7H), 6.89(d, J ¼ 8.3 Hz, 1H), 6.39 (d, J ¼ 7.6 Hz, 1H), 5.26 (s, 1H), 4.50 (d,J ¼ 5.9 Hz, 2H), 3.84–3.69 (m, 1H), 2.34 (s, 3H), 2.01–0.95 (m,10H); 13C NMR (126MHz, CDCl3) d 180.43 (C), 168.75 (C), 154.73(C), 152.37 (CH), 137.37 (C), 134.63 (CH), 131.87 (C), 128.89(CH), 127.86 (CH), 127.30 (CH), 126.66 (CH), 123.17 (C), 116.31(CH), 97.04 (C), 77.96 (CH), 53.05 (CH2), 48.02 (CH), 32.83 (CH2),32.76 (CH2), 25.44 (CH2), 24.61 (CH2), 24.50 (CH2), 20.62 (CH3);MS (CI) m/z (%) 405 (M+ + 1, 29), 298 (27), 278 (19), 149 (64), 57

RSC Adv., 2014, 4, 40044–40053 | 40051

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(100); HRMS (CI) calcd for C25H29N2O3 405.2178. Found:405.2173.

(Z)-3-(((Benzo[d][1,3]dioxol-5-ylmethyl)amino)methylene)-N-cyclohexyl-6-methyl-4-oxochroman-2-carboxamide (6g).(Method B: 60%) obtained as a yellow solid; mp 153–155 �C; IR(cm�1): 3424, 2924, 2852, 1646, 1488, 1384, 1249, 1037; 1H NMR(500 MHz, CDCl3) d 10.62–10.53 (m, 1H), 7.69 (d, J¼ 1.8 Hz, 1H),7.24–7.20 (m, 2H), 6.89 (d, J ¼ 8.3 Hz, 1H), 6.81–6.73 (m, 3H),6.38 (d, J ¼ 8.0 Hz, 1H), 5.97 (s, 2H), 5.26 (s, 1H), 4.39 (d, J ¼ 5.9Hz, 2H), 3.82–3.73 (m, 1H), 2.34 (s, 3H), 2.00–1.03 (m, 10H); 13CNMR (101 MHz, CDCl3) d 180.53 (C), 168.87 (C), 154.85 (C),152.19 (CH), 148.26 (C), 147.46 (C), 134.75 (CH), 131.99 (C),131.29 (C), 126.77 (CH), 123.29 (C), 120.96 (CH), 116.43 (CH),108.58 (CH), 108.08 (CH), 101.31 (CH2), 97.16 (C), 78.09 (CH),52.98 (CH2), 48.16 (CH), 32.96 (CH2), 32.89 (CH2), 25.57 (CH2),24.74 (CH2), 24.63 (CH2), 20.75 (CH3); MS (CI)m/z (%) 449 (M+ +1, 18), 322 (93), 296 (28), 135 (100); HRMS (CI) calcd forC26H29N2O5 449.2076. Found: 449.2076.

(Z)-3-((Benzylamino)methylene)-6-chloro-N-cyclohexyl-4-oxochroman-2-carboxamide (6h). (Method A: 70%) obtainedas a yellow solid; mp 182–184 �C; IR (cm�1): 3314, 2927, 1648,1604, 1550, 1466, 1383, 1286, 817; 1H NMR (500 MHz, CDCl3) d10.73–10.65 (m, 1H), 7.86 (d, J ¼ 2.5 Hz, 1H), 7.41–7.26 (m, 7H),6.95 (d, J¼ 8.7 Hz, 1H), 6.33 (d, J¼ 7.7 Hz, 1H), 5.30 (s, 1H), 4.52(d, J ¼ 6.0 Hz, 2H), 3.83–3.71 (m, 1H), 2.00–1.02 (m, 10H); 13CNMR (101 MHz, CDCl3) d 178.69 (C), 168.21 (C), 155.15 (C),152.92 (CH), 137.02 (C), 133.46 (CH), 128.95 (CH), 127.99 (CH),127.84 (C), 127.34 (CH), 126.36 (CH), 124.63 (C), 118.14 (CH),96.43 (C), 78.06 (CH), 53.17 (CH2), 48.15 (CH), 32.88 (CH2), 32.78(CH2), 25.40 (CH2), 24.64 (CH2), 24.55 (CH2); MS (CI)m/z (%) 427(M+ + 3, 5), 425 (M+ + 1, 16), 320 (18), 318 (39), 300 (16), 298 (45),221 (11), 209 (21), 106 (25), 91 (100); HRMS (CI) calcd forC24H26ClN2O3 425.1632. Found: 425.1640.

(Z)-3-(((Benzo[d][1,3]dioxol-5-ylmethyl)amino)methylene)-6-chloro-N-cyclohexyl-4-oxochroman-2-carboxamide (6i).(Method A: 84%) obtained as a yellow solid; mp 163–165 �C; IR(cm�1): 3310, 2931, 2855, 1647, 1604, 1549, 1465, 1446, 1250,1039; 1H NMR (500 MHz, CDCl3) d 10.56–10.49 (m, 1H), 7.76 (d,J¼ 2.6 Hz, 1H), 7.26 (dd, J¼ 8.7, 2.7 Hz, 1H), 7.17 (d, J¼ 12.9 Hz,1H), 6.85 (d, J ¼ 8.7 Hz, 1H), 6.74–6.64 (m, 3H), 6.23 (d, J ¼ 7.8Hz, 1H), 5.88 (s, 2H), 5.20 (s, 1H), 4.31 (d, J ¼ 5.9 Hz, 2H), 3.74–3.63 (m, 1H), 1.91–0.93 (m, 10H); 13C NMR (101 MHz, CDCl3) d178.68 (C), 168.26 (C), 155.19 (C), 152.65 (CH), 148.22 (C), 147.47(C), 133.49 (CH), 130.81 (C), 127.87 (C), 126.38 (CH), 124.65 (C),120.96 (CH), 118.18 (CH), 108.53 (CH), 107.99 (CH), 101.26(CH2), 96.46 (C), 78.11 (CH), 53.00 (CH2), 48.20 (CH), 32.92(CH2), 32.81 (CH2), 25.44 (CH2), 24.68 (CH2), 24.59 (CH2); MS(CI) m/z (%) 469 (M+ + 1, 3), 342 (6), 150 (18), 135 (100); HRMS(CI) calcd for C25H26ClN2O5 469.1530. Found: 469.1528.

Methyl(((Z)-2-(tert-butylcarbamoyl)-4-oxochroman-3-yli-dene)methyl)-L-valinate (6j). (Method B: 75%, 5j : 6j in ratio67 : 33), 6j was obtained as a yellow gum in a mixture of dia-stereoisomers in ratio 60 : 40; IR (cm�1): 3435, 2963, 1742, 1648,1608, 1466, 1384, 761; 1H NMR (500 MHz, CDCl3) d 10.71–10.57(m, 1H), 7.95 (dd, J ¼ 7.8, 1.7 Hz, 1H), 7.56–7.41 (m, 2H), 7.14–7.04 (m, 1H), 6.99 (d, J ¼ 8.2 Hz, 1H), 6.38 (s, 0.6Ha), 6.35(s, 0.4Hb), 5.22 (d, J¼ 0.7 Hz, 0.6Ha), 5.21 (d, J¼ 0.7 Hz, 0.4Hb),

40052 | RSC Adv., 2014, 4, 40044–40053

3.79 (s, 1.8Ha), 3.79 (s, 1.2Hb), 3.76–3.71 (m, 1H), 2.30–2.22(m, 1H), 1.36 (s, 5.4Ha), 1.34 (s, 3.6Hb), 1.04–0.97 (m, 6H); 13CNMR (101 MHz, CDCl3) d

13C NMR (101 MHz, CDCl3) d 180.75(C), 180.53 (C), 171.01 (C), 170.86 (C), 168.62 (C), 168.40 (C),156.83 (C), 156.78 (C), 151.32 (CH), 133.93 (CH), 126.87 (CH),126.83 (CH), 123.49 (C), 123.44 (C), 122.49 (CH), 118.31 (CH),116.67 (CH), 116.58 (CH), 97.53 (C), 97.44 (C), 78.09 (CH), 68.01(CH3), 52.48 (CH), 52.43 (CH), 51.33 (C), 51.29 (C), 32.14 (CH),32.03 (CH), 29.94 (CH), 28.64 (CH3), 19.20 (CH3), 19.16 (CH3),17.52 (CH3), 17.41 (CH3); MS (CI) m/z (%) 389 (M+ + 1, 32), 329(8), 288 (100), 258 (7); HRMS (CI) calcd for C21H29N2O5

389.2076. Found: 389.2079.(Z)-Methyl-2-(((6-chloro-2-(cyclohexylcarbamoyl)-4-oxochroman-

3-ylidene)methyl)amino)acetate (6p). (Method B: 65%) obtainedas a yellow solid; mp 177–179 �C; IR (cm�1): 3281, 2933, 2855,1742, 1642, 1555, 1468, 1434, 1343, 1208; 1H NMR (400 MHz,CDCl3) d 10.47–10.35 (m, 1H), 7.89 (d, J ¼ 2.7 Hz, 1H), 7.37 (dd,J ¼ 8.7, 2.7 Hz, 1H), 7.15 (d, J ¼ 12.6 Hz, 1H), 6.96 (d, J ¼ 8.7 Hz,1H), 6.36 (d, J¼ 8.2 Hz, 1H), 5.30 (s, 1H), 4.09 (d, J¼ 6.2 Hz, 2H),3.80 (s, 3H), 3.79–3.71 (m, 1H), 2.02–1.04 (m, 10H); 13C NMR(101 MHz, CDCl3) d 179.43 (C), 169.18 (C), 167.94 (C), 155.34 (C),152.44 (CH), 133.76 (CH), 127.91 (C), 126.51 (CH), 124.42 (C),118.28 (CH), 97.55 (C), 77.90 (CH), 52.67 (CH3), 49.87 (CH2),48.21 (CH), 32.87 (CH2), 32.79 (CH2), 25.39 (CH2), 24.65 (CH2),24.58 (CH2); MS (CI) m/z (%) 407 (M+ + 1, 12), 318 (8), 280 (100),245 (18); HRMS (CI) calcd for C20H24ClN2O5 407.1374. Found:407.1375.

Acknowledgements

We thank nancial support from Junta de Extremadura andFEDER.

Notes and references

1 (a) C. T. Walsh, R. V. O'Brien and C. Khosla, Angew. Chem.,Int. Ed., 2013, 52, 7098; (b) A. M. Kushner and Z. Guan,Angew. Chem., Int. Ed., 2011, 50, 9026.

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RSC Adv., 2014, 4, 40044–40053 | 40053