Lactic acid as an invaluable bio-based solvent for organic reactions

naturally by fermentation of carbohydrates such as

glucose, sucrose, or lactose.¹⁹In solution, lactic acid can lose

Results and discussion

a

proton from the acidic group, producing the lactate Our initial studies started with a three-component reaction of

ion CH₃CH(OH)COO⁻. Compared to acetic acid, its pK_ais sesamol (1a), formaldehyde and 4-methylstyrene (2a), with

1 unit smaller, meaning lactic acid loses its proton ten which a densely substituted chroman 3a could be formed

times as easily as acetic acid does. Although ethyl lactate was through a cascade Knoevenagel/oxo Diels–Alder reaction. Pre-

recognized as a good bio-based solvent, surprisingly, lactic viously, acetic acid has been used in an analogous three-com-

acid that is one of the starting materials for the synthesis ponent reaction of α-methylstyrene, HCHO and 2-naphthol.²³

of ethyl lactate has never been considered when we need a However, in the model reaction, acetic acid was found to be

solvent.²⁰

On the other hand, acetic acid has been widely used of reaction at 100 °C (Table 1, entry 1). No desired product was

solvent in many organic reactions, in which the obtained under solvent-free conditions (entry 2). Many other

less eﬀective and only 25% of yield was obtained after 3 hours

as

a

promoting eﬀect of acetic acid is often indispensable for solvents including water, glycerol, gluconic acid aqueous

the reactions. However, due to the high boiling point of acetic solution (GAAS), DMSO, toluene and an ionic liquid, [BMIm]-

acid, recycling the used acetic acid by distillation is not always BF₄, were then examined in the model reaction. However, as

economically profitable.²¹And as a result, a large amount shown in Table 1, most of the starting materials remain

of acetic acid solvent was neutralized by an inorganic base at unchanged in these cases, and as a result, only a tiny amount

the end of the reaction. This not only increased the synthetic of product was obtained (entries

3 to 8). Addition of

cost, but also generated a lot of waste that has to be carefully some readily available acids, such as Sc(OTf)₃, Bi(OTf)₃, InCl₃,

disposed of. We viewed that lactic acid might be a good toluenesulfonic acid (p-TsOH), H₃BO₃and Amberlyst-15, to

alternative solvent to acetic acid. The reasons are multifold: the reaction system can slightly improve the performance

(i) pure form of lactic acid is a liquid at 25 °C that has a com- of the reaction, however, the yields obtained are still far from

parable acidity with acetic acid; this point is very important satisfactory (entries 9 to 14).

because most of the reactions in acetic acid are actually bene-

In view of the fact that acetic acid gave better results

fited from the high concentration of the COOH group of the than the other solvent systems, we then tried to replace acetic

medium; in this context, pure lactic acid has an advantage acid with some other carboxylic acids, such as lactic acid, tri-

over others because it has a similar molecular size to acetic fluoroacetic acid (TFA), and citric acid aqueous solution

acid while the acid strength is slightly higher than that of

acetic acid; (ii) technical lactic acid is an inexpensive bio-

Table 1 Optimization of three-component reaction of 1a, 2a and HCHO^a

based chemical that is composed of free lactic acid

(60–80%), dimers, and higher polymers of lactic acid (10–25%)

and water (5–20%),²²which can be prepared in an industrial

scale through an environmentally benign method. This

ensures the use of lactic acid in both academic laboratory

and industrial plant to be not prohibitive if it really works

in their reactions; (iii) lactic acid is immiscible with non-

polar organic solvents, such as ether and n-heptane; this prop-

erty might allow an easy extraction of organic products from

the solvent, and consequently facilitates recovery of lactic

acid. Out of these considerations, we started, some time

ago, a research program on using lactic acid as a reaction

medium for organic reactions. Herein, we disclose the success-

ful outcome of this endeavor, in which lactic acid was used,

for the first time, as an alternative medium to acetic acid

in the following four reactions: (i) three-component reactions

of styrenes, formaldehyde and an active phenolic com-

pound or N,N-dialkylacetoacetamides; (ii) three-component

reactions of diethyl acetylenedicarboxylate, benzaldehydes and

anilines; (iii) aniline-catalyzed condensations between salicyl-

aldehydes and diethyl acetylenedicarboxylate, and (iv) the syn-

thesis of substituted quinolines through condensations

between 2′-aminoacetophenone and 1,3-dicarbonyl com-

Entry

Catalyst

Solvent

Yield (%)

1

—

Acetic acid

—

H₂O

Glycerol

GAAS

DMSO

25

2

0

3

<5

4

Trace

<5

5

6

Trace

<5

7

Toluene

[BMIM]BF₄

CH₃CN

Lactic acid

CF₃CO₂H

CAAS

8

Trace

0

9

—

10^b

11^b

12^b

13^c

14^d

15

16

17^e

18^f

19^g

Bi(OTf)₃

49

Sc(OTf)₃

53

p-TsOH

48

H₃BO₃

<5

Amberlyst 15

55

—

73

Trace

15

Lactic acid

74

71

pounds. In these reactions, the use of lactic acid as a ^aSolvent 1.0 ml, 2a: 0.65 mmol, 1a : 2a : HCHO = 1.5 : 1.0 : 2.0, the

yield was calculated with respect to 2a. ^b10 mol%. ^c50 mol%.

solvent not only improves the reaction yield, but also facilitates

the isolation of the reaction product or recycling of the

solvent.

^d23 mg. ^eCAAS: citric acid aqueous solution (50 wt%). ^fLactic acid

was reused for the third time. ^gThe reaction was carried out in

10.0 mmol scale.

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Paper

(CAAS). To our great delight, a significant improvement was liquid–liquid extraction. This method avoids neutralization of

observed when lactic acid was used as the reaction medium, an acidic solvent with an inorganic base, thus minimizing

and the yield of 3a could be increased to 73% (entries 15 to the generation of waste. The recovered lactic acid solvent was

17). Importantly, because lactic acid is immiscible with non- then subjected to the next run after removing volatile light

polar organic solvents, such as diethyl ether and n-heptane, components. With this procedure, the lactic acid solvent can

the unreacted starting materials and the generated product 3a be reused three times in the model reaction without signifi-

can be easily isolated from lactic acid phase by means of cant loss of its activity (entry 18). Furthermore, under the

optimal conditions, a reaction scaled up to 10 mmol provided

a uniform result, indicating the usefulness of the present

three-component reaction for practical synthesis (entry 19). In

view of all these properties, and also taking into consideration

the bio-based origin of lactic acid, conferring a green creden-

tial to our system is quite reasonable.

With the optimized conditions in hand, we probed the

scope of the reaction with respect to both the styrene and the

phenol components. As evidenced by the results in Scheme 1,

both electron-rich and moderately electron-poor styrenes

readily participated in the three-component reactions of

sesamol and HCHO in lactic acid, producing the correspond-

ing substituted chromans in generally moderate to good

yields. Styrenes with methyl groups in the α-position aﬀorded

better yields than those without substituents. An acid-labile

styrene, 4-methoxystyrene, can be used as well, however, in

order to get a better yield, the reaction has to be performed

in an aqueous solution of lactic acid. Scheme 2 shows the

results of extending the substrate scope of phenolic com-

ponents. Various C–H acids, such as tetronic acid, 4-hydroxy-

6-methyl-2-pyrone, 2-naphthol, 6-bromo-2-naphthol, 4-hydroxy-

coumarin and 2-hydroxy-1,4-naphthoquinone, smoothly reacted

Scheme 1 Three-component reactions of styrenes, 1a and HCHO in lactic acid.

with α-methylstyrene or 4-methylstyrene, producing the

Scheme 2 Three-component reactions of styrenes, HCHO and some C–H acids in lactic acid.

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Green Chemistry

corresponding products in good to excellent yields. In our pre- class of compounds. As part of our ongoing studies on the syn-

vious report, the reaction of 2-hydroxy-1,4-naphthoquinone 1g thesis of substituted dihydropyrans,³⁰we envisioned that a

tended to produce two products in acetic acid without regio- sequential Knoevenagel/oxo Diels–Alder reaction of N,N-dialkyl-

selectivity.²²Interestingly, only one product, 4f, was obtained acetoacetamides, styrenes and formaldehyde should oﬀer a

when lactic acid was used as a solvent. Although we cannot yet fascinating opportunity to build up 5,6-dihydro-(4H)-pyran-

oﬀer an explanation for this behavior, the exclusive selectivity 3-carboxamides. Out of this consideration, we then performed

might be benefited from a superposition of several factors, a three-component reaction of N,N-diethylacetoacetamide,

such as relatively higher acid strength and intervention of a α-methylstyrene and HCHO at 80 °C, and the results are listed

hydroxyl group in the reaction. This point deserves further in Scheme 3. Among diﬀerent solvents tested in the reaction,

investigation. It is noteworthy that these products were all iso- lactic acid clearly stood out, producing the desired product 6a

lated from lactic acid with extraction. Although some of these with the highest yield (55%), with acetic acid and GAAS in a

products can be obtained in acetic acid, however, the need to distant second place (yields = 40–45%). In water, glycerol,

neutralize the acid with a base negated much of the potential DMSO and toluene, no 6a was detected. More interestingly,

advantage of acetic acid solvent. In this context, the lactic acid lactic acid solvent was amenable to the reactions of a wide

system oﬀers an alternative and environmentally benign range of N,N-dialkylacetoacetamides and styrenes. Random

method to access these densely substituted chroman combination of the three starting materials could give the final

derivatives.

products with up to 75% yield. It should be noted that all the

The above-mentioned results manifested clearly that lactic products in these reactions were obtained without neutraliz-

acid can indeed be used as an eﬀective medium for organic ation of lactic acid, thus, minimizing the generation of waste.

synthesis. After demonstrating the feasibility, we then focused

An important point should be clarified when using lactic

our attention on exploring the applications of this green acid as a solvent. It is well known that pure lactic acid tended

solvent in organic synthesis, from which the necessity of using to form its oligomers at high temperature. The above-

lactic acid as a solvent might be documented as well. 5,6- mentioned reactions were performed at temperatures ranging

Dihydro-(4H)-pyran-3-carboxamides are important herbicides from 80 °C to 100 °C, over which the oligomerization of lactic

and fungicides.²⁴Particularly, because of the pharmacological acid might also take place. Fortunately, by analysis with GC

activities of 5,6-dihydro-(4H)-pyran-3-carboxamides, some of and HPLC, we found that the amount of lactic acid oligomers

these derivatives have been used in inhibiting Botrytis,²⁵treat- is negligible in the acid phase. This may be benefited from the

ing hyperproliferative skin disease,²⁶and acting as antagonists use of an aqueous solution of formaldehyde as a HCHO

of CB1 cannabinoid receptors.²⁷For the synthesis of these source, which injected simultaneously a remarkable amount

compounds, some methods are available in the literature, of water into the reaction system that inhibited naturally the

which however lack simplicity in their experimental pro- oligomerization of lactic acid.

cedures.²⁸Some reactions are multi-step syntheses with iso-

The next reaction we examined in lactic acid is three-com-

lation and purification of intermediates at each step.²⁹In view ponent condensation of benzaldehydes, anilines and diethyl

of these facts, there is a definite need to develop an eﬃcient acetylenedicarboxylate, which has just been reported to be

and environmentally benign method for the synthesis of this able to form a series of polysubstituted pyrrolidinones.³¹

Scheme 3 Three-component reactions of N,N-dialkylacetoacetamides, styrenes and HCHO.

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Previously, the reaction was performed in ethanol in the pres- component reaction, conferring thus to this system an excel-

ence of p-TsOH or SnCl₂. However, the reaction has to be lent substrate compatibility. Although, in a few cases, the

carried out in a stepwise procedure with a long reaction time yields obtained in acetic acid solvent are comparable with

(24 hours), which lacks simplicity of operation and time those in lactic acid, most of the results followed our previous

eﬃciency. Intriguingly, we found that this three-component estimation, in which lactic acid has a better activity than acetic

reaction proceeded very well in lactic acid, producing the corres- acid for this type of three-component reaction. It should be

ponding polysubstituted pyrrolidinones 8a–8j in good yields noted that no 2-hydroxy-N-phenyl propanamides were observed

within a few hours. In addition, because the reactions were in these reactions although the amidation of carboxylic acids

performed in lactic acid with a single step, the operation was with anilines was known to be not so diﬃcult.³²In spite of

simplified as well. Although acetic acid can also be used as the this observation, we speculated that high temperature should

solvent of the reaction, lactic acid solvent displayed its indis- be avoided when anilines or amines were used as substrates in

pensability in the separation of the reaction product. In the lactic acid, which otherwise favor the possible amidation

case of lactic acid, although all the starting materials are reaction.

readily soluble in the solvent, as the reaction advanced, phase

Interestingly, when 3-methoxysalicylaldehyde was used in

separation was quickly seen to occur, facilitating the isolation the above-mentioned three-component reaction, an un-

of the products (Fig. 1(b)). However, when acetic acid was used expected product, 9a, was obtained exclusively in the presence

as a solvent, only a small amount of the product was obtained of stoichiometric amounts of aniline (Table 2, entry 1).

with the same operational procedure due to the fact that acetic Because of the fact that the skeleton of 9a does not contain the

acid can partially dissolve the product (Fig. 1(a)). As indicated fragment of aniline, it is conceivable that aniline might act as

in Scheme 4, various types of aromatic aldehydes and anilines a catalyst. As we expected, a catalytic amount of aniline was

were successfully used in this lactic acid-mediated three- found to be suﬃcient enough to achieve a high reaction yield

(entry 2). No 9a was obtained when aniline is absent (entry 3).

Replacing aniline with 4-methylaniline resulted in a slight

decrease of the yield (entry 4). However, when the reaction was

catalyzed by benzamide or 4-nitroaniline, no 9a was obtained

(entries 5 and 6). Similarly, no 9a was found using aliphatic

amines as catalysts, such as n-butylamine, dibutylamine and

homoveratrylamine (entries 7 to 9). This result gave us the

impetus to carry out the synthesis of 9a using many other

solvent systems, such as solvent-free conditions, acetic acid,

TFA, glycerol, GAAS and CAAS, however, no good result was

Fig. 1 Comparison of lactic acid and acetic acid solvents in the three-com-

ponent reaction of 4-chlorobenzaldehyde, aniline and 7a. The pictures were

obtained in all these cases (entries 10 to 15). Previously, syn-

thesis of 9a-type compounds was also started from a reaction

taken after 30 minutes of the reaction. (a) Reaction in acetic acid; (b) reaction in

lactic acid.

Scheme 4 Three-component reactions of aromatic aldehydes, anilines and 7a in lactic acid.

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Green Chemistry

Table 2 Reaction of salicylaldehyde derivatives and 7a in diﬀerent solvents in

the presence of aniline^a

Scheme 5 The reaction of 3-methoxysalicylaldehyde and 7c in lactic acid.

Entry

R

Solvent

Product

Yield (%)

1^b

2

3-OMe

H

Lactic acid

—

9a

9b

9c

9d

9e

95^m

91^m

0

3^c

4^d

5^e

88^m

0

6^f

0

7^g

8^h

9ⁱ

0

10

11

12

13

14

15

16

17

18

19^l

0

Acetic acid

CF₃CO₂H

Glycerol

32

<5

0

GAAS^j

6

CAAS^k

15

83

92^m

90

51

Lactic acid

Fig. 2 Possible reaction pathway for the synthesis of 9.

3-OEt

5-Br

4-NEt₂

^aSalicylaldehyde: 1.0 mmol, 7a 1.0 mmol, solvent: 1.0 ml, 30 °C,

24 h. ^bAniline: 100 mol%. ^cIn the absence of aniline. ^dCatalyst:

4-methylaniline. ^eCatalyst: benzamide. ^fCatalyst: 4-nitroaniline.

^gCatalyst: n-butylamine. ^hCatalyst: dibutylamine. ⁱCatalyst:

homoveratrylamine. ^jGAAS: gluconic acid aqueous solution

(50 wt%). ^kCAAS: citric acid aqueous solution (50 wt%). ^lAniline:

30 mol%, reaction time: 2 days. ^mThe product was isolated by

filtration.

of salicylaldehyde and 7a, but it was generally performed by a

sequence of separate reaction steps including (i) base-catalyzed

condensation and (ii) acid-catalyzed isomerization.³³Because

the reaction conditions of these two steps are not compatible,

therefore, each step requires own solvent and catalyst. In order

to simplify the synthetic procedure, the condensation has

recently been conducted under solvent-free conditions in the

Scheme 6 Three-component reaction of salicylaldehyde, 7a and 4-nitroaniline

in lactic acid.

presence of silica gel. Unfortunately, in this case, the yield of in Fig. 2. Initially, salicylaldehyde condenses with aniline, pro-

9a is rather low due to the extensive generation of another ducing imine A. At the same time, 7a undergoes hydrolysis in

product.³⁴Now, we would be able to overcome such diﬃculty lactic acid, providing an intermediate 7b. Nucleophilic attack

by conducting the synthesis in lactic acid. Our method not of 7b on imine A allows formation of an intermediate B. Then,

only opens a facile way for the synthesis of 9a-type compounds, the intermediate B could be transformed into another inter-

but also facilitates isolation of the product because 9a is inso- mediate, C. And then, an intramolecular condensation

luble at the reaction temperature in lactic acid and could between the phenolic hydroxyl and ketone carbonyl group

be directly obtained by simple filtration. With the present gives rise to the formation of an intermediate D. Finally, under

method, some other 9a-type compounds were also obtained in acidic conditions, one molecule of aniline was eliminated

good yields (entries 16 to 19).

from D to form the desired product 9. As we have mentioned

In order to shed light on the mechanism, we conducted before, when 4-nitroaniline was used as a catalyst, no 9a was

an aniline-catalyzed reaction of 3-methoxysalicylaldehyde and obtained. But if the reaction of salicylaldehyde and 7a was per-

diethyl oxalacetate sodium salt, 7c, in lactic acid. As shown in formed in the presence of stoichiometric amount of 4-nitro-

Scheme 5, the desired product 9a was isolated in 64% yield. aniline, a new compound, 10a, could be obtained in 89% yield

This result implies that the dipolar intermediate 7b might be (Scheme 6, eqn (a)). It should be noted that, in this reaction,

involved in the mechanism. A plausible pathway for the no 9b was detected, indicating the fact that cleavage of the

aniline-catalyzed reaction of salicylaldehyde and 7a is shown C–N bond could not occur under the present conditions.

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Scheme 7 Friedländer annulation between 11a and 1,3-dicarbonyl compounds in lactic acid.

Interestingly, if the reaction temperature was increased to

100 °C at the end of the reaction, 9b could be obtained in 75%

yield after 6 hours of stirring (Scheme 6, eqn (b)). All these

results imply that formation of the intermediate D might

indeed be involved in the reaction mechanism.

Finally, lactic acid was used as a solvent for the synthesis of

quinolines through Friedländer annulation between 2′-amino-

acetophenone and 1,3-dicarbonyl compounds. Generally, the

Friedländer reaction is carried out by refluxing an aqueous or

an alcoholic solution of reactants in the presence of a base at

Fig. 3 Visible diﬀerence in the reaction between 11a and tetronic acid using

high temperature.³⁵However, many of these procedures have

drawbacks such as poor functional group tolerance, limited

substrate scope and diﬃculties in the work-up procedure. For

instance, under basic conditions, o-aminobenzophenone does

not react with β-ketoesters. In an attempt to improve these

reactions, various Lewis and Brønsted acids have been used

for the quinoline synthesis through Friedländer annulation,

such as Bi(OTf)₃, Zr(NO₃)₄, Y(OTf)₃, ZnCl₂, AuCl₃, phosphoric

acid, dodecylphosphonic acid, o-benzenedisulfonimide, SO₃H-

functionalized ionic liquids, propylphosphonic anhydride,

and CAN (cerium(^IV) ammonium nitrate).³⁶Some solid acids

have also been employed in Friedländer annulation, such as

HClO₄–SiO₂, sulfamic acid, Amberlyst-15, silver phosphotung-

state and CuBTC metal–organic-framework.³⁷Although some

of these methods have convenient protocols with good to high

yields, most of them suﬀer from drawbacks such as the use of

hazardous and toxic solvents, low time eﬃciency and involve-

ment of expensive, toxic or non-commercially available cata-

lysts. Furthermore, because quinoline derivatives were widely

used in the synthesis of drugs and pharmaceuticals, removal

of residual metal species is also a hard task when a metal-

containing catalyst was used. In view of these facts, there is a

definite need to develop a cost-eﬀective and environmentally

benign method for Friedländer annulation.

(a) lactic acid and (b) acetic acid as solvents.

Scheme 7 shows the results of Friedländer annulation

between 11a and 1,3-dicarbonyl compounds in lactic acid. As

we expected, lactic acid was found again to be an eﬀective pro-

moting medium for the reaction of 11a and acetylacetone, and

the corresponding quinoline 13a was obtained in 95% yield.

Although acetic acid can also promote the same reaction, but

the yield obtained is slightly inferior as compared with that of

lactic acid. Various 1,3-dicarbonyl compounds, including both

acyclic and cyclic, can readily be condensed with 11a in lactic

acid, producing the desired densely substituted quinolines in

generally high yields. Although the reactions were performed

at 80 °C, because of the poor amidating reactivity of 11a, no

amidation product of lactic acid was observed. Interestingly,

when tetronic acid and 1,3-dioxoindane were used, the formed

quinolines, 13i and 13j, could be obtained by filtration, obviat-

ing thus the use of silica column chromatography (Fig. 3). It

should be noted that, in other cases, no solid was observed at

the end of the reaction. In order to get a high reaction yield,

lactic acid has to be neutralized by an aqueous solution of

sodium hydroxide. This procedure generated an aqueous solu-

tion of sodium lactate that needed to be treated after the

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Green Chemistry

reaction. Fortunately, sodium lactate is a non-toxic and eco- (VERTEX 70) spectrophotometer and the values are expressed

compatible species and has been widely used as a food addi- as ν_maxcm⁻¹

tive.³⁸As it is an eﬀective moisturizer, sodium lactate has also

.

Materials

been used in shampoo products and other similar items such

as liquid soaps.³⁹All these properties ensure that treating the We synthesized three kinds of N,N-dialkylacetoacetamides.⁴⁰

generated aqueous solution of sodium lactate is not a hard All other chemicals were commercial and were purchased from

task, and can be accomplished in common equipment used in Alfa Aesar or Sinopharm and were used as received.

the waste water industry.

General procedure for the three-component reaction of

formaldehyde, sesamol and styrenes

All reactions were conducted in a 10 ml V-type flask equipped

Conclusion

with a triangle magnetic stirring bar. In a typical reaction,

In conclusion, lactic acid was demonstrated, for the first lactic acid (1.0 ml) was mixed with formaldehyde (105 mg,

time, to be an eﬀective promoting medium for some organic 1.3 mmol), sesamol (135 mg, 0.98 mmol) and 4-methylstyrene

reactions including (i) three-component reactions of styrenes, (76 mg, 0.65 mmol) for 3 h at 100 °C. After completion of the

formaldehyde and an active phenolic compound or N,N- reaction, the mixture was cooled to room temperature and

dialkylacetoacetamides; (ii) three-component reactions of 7a, extracted with the mixture of petroleum ether and ethyl acetate

aromatic aldehydes and anilines; (iii) aniline-catalyzed con- (PE : EA = 2 : 1, 5 × 2 ml). The obtained organic layer was dried

densations between salicylaldehydes and diethyl acetylene- over Na₂SO₄and the solvent was removed under reduced

dicarboxylate; and (iv) the synthesis of substituted quinolines pressure. The residue was purified by preparative TLC using

through Friedländer annulation between 2′-aminoacetophe- the mixture of petroleum ether and ethyl acetate (8/1, v/v) as

none and 1,3-dicarbonyl compounds. All the selected reactions the eluting solvent to give the desired product, 3a, 127 mg,

were performed in lactic acid without the use of any catalyst. yield = 73%. Tests for substrate scope were all performed with

Although acetic acid is a strong competitor, performing these an analogous procedure.

reactions in lactic acid significantly boosted the yield of the

desired product, enhanced reaction rates, and in some cases,

Spectroscopic data of new compounds

facilitated isolation of the product. When the product is less-

6-(^P-TOLYL)-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE (3A).

polar, it could be easily removed from lactic acid phase, and Brown solid, mp: 98–100 °C; ¹H NMR (CDCl₃): 1.97–2.08

thus the lactic acid solvent could be recycled. The concept of (m, 1H), 2.08–2.16 (m, 1H), 2.34 (s, 3H), 2.61–2.69 (m, 1H),

using lactic acid as a solvent not only extended the diversity of 2.82–2.92 (m, 1H), 4.92 (dd, J_a= 2.4 Hz, J_b= 10.0 Hz, 1H), 5.84

bio-based green solvents, but also enriched their versatility, (dd, J_a= 1.6 Hz, J_b= 2.8 Hz, 2H), 6.44 (s, 1H), 6.51 (s, 1H), 7.17

broadening thus the potential applications of bio-based green (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃):

solvents in many other reactions. We believe that, in the 21.3, 25.3, 29.9, 77.7, 98.9, 100.8, 108.2, 113.3, 126.1, 129.3,

future, lactic acid solvent will play a more potent role than 137.6, 138.8, 141.4, 146.5, 149.8; IR (cm⁻¹): 3071, 2922, 2774,

we have shown in this paper. Although lactic acid solvent has, 1904, 1728, 1689, 1663, 1624, 1503, 1479, 1440, 1382, 1358,

at this stage, some problems, such as thermal and chemical 1341, 1343, 1286, 1249, 1210, 1192, 1146, 1069, 1033, 976, 933,

stability, and removal of water and some other organic 915, 901, 857, 834, 808; HRMS m/z (ESI) calcd for C₁₇H₁₆NaO₃

residuals from the recycled lactic acid, if researchers could [M + Na]⁺291.0997 found 291.0991.

find well-suited solvent substitution for a given application

6-P^HENYL-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE (3B). Pale

with lactic acid, its necessity to be used as a green solvent will brown solid, mp: 74–76 °C; ¹H NMR (CDCl₃): 1.98–2.09 (m,

be naturally elucidated. Now we are working on designing 1H), 2.11–2.19 (m, 1H), 2.62–2.70 (m, 1H), 2.83–2.94 (m, 1H),

some environmentally benign systems that can show invalu- 4.97 (dd, J_a= 2.4 Hz, J_b= 10.0 Hz, 1H), 5.85 (dd, J_a= 1.2 Hz, J_b

able contribution of lactic acid for the construction of green = 2.8 Hz, 2H), 6.46 (s, 1H), 6.52 (s, 1H), 7.27–7.33 (m, 1H),

systems.

7.34–7.42 (m, 4H); ¹³C NMR (CDCl₃): 25.2, 30.0, 77.8, 98.9,

100.9, 108.2, 113.3, 126.1, 127.9, 128.6, 141.5, 141.8, 146.5,

149.7; IR (cm⁻¹): 3067, 2954, 2921, 1726, 1626, 1450, 1478,

1436, 1370, 1341, 1310, 1281, 1246, 1234, 1217, 1195, 1152,

1069, 1037, 974, 941, 917, 897, 867, 753, 696; HRMS m/z (ESI)

calcd for C₁₆H₁₄NaO₃[M + Na]⁺277.0841 found 277.0835.

6-M^ETHYL-6-PHENYL-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE

Experimental section

General

Preparative thin layer chromatography (GF254) was used to

purify the product. The ¹H NMR and ¹³C NMR spectra were (3C). Brown liquid; ¹H NMR (CDCl₃): 1.60 (s, 3H), 1.97–2.07

recorded on a Bruker AV-400 respectively, using TMS as an (m, 1H), 2.28–2.39 (m, 2H), 2.47–2.58 (m, 1H), 5.83 (dd, J_a=

internal standard. The chemical shift values are recorded on 1.2 Hz, J_b= 4.8 Hz, 2H), 6.38 (s, 1H), 6.53 (s, 1H), 7.20 (tt, J_a=

δ scale and the coupling constants (J) are in Hz. Melting points 1.2 Hz, J_b= 7.2 Hz, 1H), 7.28 (td, J_a= 1.6 Hz, J_b= 6.4 Hz, 2H),

were determined on a melting point apparatus and are un- 7.34 (dt, J_a= 1.6 Hz, J_b= 8.8 Hz, 2H); ¹³C NMR (CDCl₃): 22.8,

corrected. IR (KBr) spectra were recorded on an FT-IR Bruker 30.3, 32.9, 78.3, 98.8, 100.8, 108.2, 113.1, 125.0, 126.8, 128.4,

This journal is © The Royal Society of Chemistry 2012

Green Chem., 2012, 14, 3304–3317 | 3311

Paper

141.2, 145.6, 146.6, 148.6; IR (cm⁻¹): 3084, 2928, 1726, 1630, 1039, 1013, 940, 828; HRMS m/z (ESI) calcd for C₁₇H₁₅ClNaO₃

1602, 1582, 1499, 1480, 1439, 1376, 1329, 1273, 1255, 1233, [M + Na]⁺325.0607 found 325.0600.

1213, 1168, 1154, 1097, 1075, 1038, 940, 875, 855; HRMS m/z

6-(4-M^ETHOXYPHENYL)-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE

(ESI) calcd for

291.0991.

C

₁₇H₁₆NaO₃[M

+

Na]⁺291.0997 found (3I). White solid, mp: 94–96 °C; ¹H NMR (CDCl₃): 1.98–2.08

(m, 1H), 2.08–2.16 (m, 1H), 2.63–2.71 (m, 1H), 2.83–2.94 (m,

6-(4-(^TERT-BUTYL)PHENYL)-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE 1H), 3.80 (s, 3H), 4.91 (dd, J_a= 2.8 Hz, J_b= 10.0 Hz, 1H), 5.85

(3D). White solid, mp: 118–120 °C; ¹H NMR (CDCl₃): 1.32 (s, (dd, J_a= 1.6 Hz, J_b= 2.8 Hz, 2H), 6.44 (s, 1H), 6.52 (s, 1H), 6.91

9H), 1.99–2.09 (m, 1H), 2.09–2.18 (m, 1H), 2.62–2.72 (m, 1H), (dt, J_a= 2.4 Hz, J_b= 8.8 Hz, 2H), 7.33 (dt, J_a= 2.4 Hz, J_b

=

2.82–2.94 (m, 1H), 4.93 (dd, J_a= 2.4 Hz, J_b= 10.4 Hz, 1H), 5.84 8.4 Hz, 2H); ¹³C NMR (CDCl₃): 25.4, 29.9, 55.4, 77.5, 98.9,

(dd, J_a= 1.2 Hz, J_b= 2.8 Hz, 2H), 6.45 (s, 1H), 6.51 (s, 1H), 7.33 100.9, 108.2, 113.3, 114.0, 127.5, 133.9, 141.5, 146.5, 149.9,

(dt, J_a= 2.0 Hz, J_b= 8.4 Hz, 2H), 7.40 (dt, J_a= 2.0 Hz, J_b

=

159.4; IR (cm⁻¹): 3067, 2953, 2776, 1726, 1678, 1613, 1585,

8.4 Hz, 2H); ¹³C NMR (CDCl₃): 25.3, 29.8, 31.5, 34.7, 77.7, 98.9, 1507, 1482, 1443, 1420, 1382, 1363, 1344, 1310, 1296, 1249,

100.8, 108.2, 113.3, 125.5, 125.9, 138.7, 141.4, 146.5, 149.9, 1211, 1191, 1179, 1151, 1075, 1040, 939, 920; HRMS m/z (ESI)

150.9; IR (cm⁻¹): 2954, 2861, 1729, 1630, 1505, 1480, 1444, calcd for C₁₇H₁₆NaO₄[M + Na]⁺307.0946 found 309.0940.

1406, 1383, 1360, 1340, 1197, 1150, 1080, 1036, 978, 937, 919,

2-(^P-TOLYL)-3,4-DIHYDRO-2H-FURO[3,4-B]PYRAN-5(7H)-ONE (4A).

1

900, 836; HRMS m/z (ESI) calcd for C₂₀H₂₂NaO₃[M + Na]⁺White solid, mp: 144–146 °C; H NMR (CDCl₃): 1.96–2.08 (m,

333.1467 found 333.1476.

1H), 2.15–2.25 (m, 1H), 2.37 (s, 3H), 2.28–2.47 (m, 2H), 4.64 (d,

6-(4-C^HLOROPHENYL)-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE J = 15.6 Hz, 1H), 4.69 (d, J = 16.0 Hz, 1H), 5.13 (dd, J_a= 1.6 Hz,

(3E). Pale brown solid, mp: 82–84 °C; ¹H NMR (CDCl₃): J_b= 10.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.8 Hz,

1.93–2.03 (m, 1H), 2.10–2.18 (m, 1H), 2.62–2.70 (m, 1H), 2H); ¹³C NMR (CDCl₃): 16.8, 21.2, 28.5, 66.5, 81.9, 100.2, 126.1,

2.82–2.93 (m, 1H), 4.94 (dd, J_a= 2.4 Hz, J_b= 10.0 Hz, 1H), 5.87 129.5, 135.8, 138.7, 173.0, 174.5; IR (cm⁻¹): 2922, 1757, 1668,

(dd, J_a= 1.2 Hz, J_b= 2.4 Hz, 2H), 6.44 (s, 1H), 6.51 (s, 1H), 7.33 1517, 1450, 1427, 1355, 1303, 1287, 1241, 1204, 1186, 1132,

(s, 4H); ¹³C NMR (CDCl₃): 25.0, 30.0, 77.0, 98.8, 100.9, 108.2, 1065, 1023, 996, 942, 820, 751; HRMS m/z (ESI) calcd for

113.2, 127.5, 128.8, 133.6, 140.3, 141.7, 146.6, 149.4; IR (cm⁻¹): C₁₄H₁₄NaO₃[M + Na]⁺253.0841 found 253.0834.

2916, 1728, 1667, 1630, 1503, 1480, 1441, 1407, 1385, 1340,

7-M^ETHYL-2-(P-TOLYL)-3,4-DIHYDROPYRANO[4,3-B]PYRAN-5(2H)-ONE

1

1319, 1289, 1250, 1223, 1199, 1151, 1085, 1071, 1036, 1012, (4B). White solid, mp: 135–137 °C; H NMR (CDCl₃): 1.94–2.05

940, 922, 837; HRMS m/z (ESI) calcd for C₁₆H₁₃ClNaO₃(m, 1H), 2.20 (s, 3H), 2.20–2.26 (m, 1H), 2.37 (s, 3H), 2.46–2.62

[M + Na]⁺311.0451 found 311.0445.

(m, 2H), 5.02 (dd, J_a= 2.4 Hz, J_b= 10.4 Hz, 1H), 5.81 (s, 1H),

6-(4-B^ROMO-PHENYL)-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]CHROMENE 7.20 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H); ¹³C NMR

(3F). Brown solid, mp: 120–122 °C; ¹H NMR (CDCl₃): 1.92–2.05 (CDCl₃): 19.0, 19.8, 21.2, 28.7, 79.1, 98.3, 100.4, 126.0, 129.4,

(m, 1H), 2.09–2.18 (m, 1H), 2.60–2.71 (m, 1H), 2.82–2.94 (m, 136.7, 138.4, 160.0, 165.0, 165.2; IR (cm⁻¹): 3089, 2932, 2853,

1H), 4.93 (dd, J_a= 2.0 Hz, J_b= 10.0 Hz, 1H), 5.87 (dd, J_a

=

1696, 1650, 1614, 1582, 1515, 1448, 1410, 1359, 1319, 1300,

1.2 Hz, J_b= 2.4 Hz, 2H), 6.44 (s, 1H), 6.52 (s, 1H), 7.27 (dt, J_a= 1230, 1205, 1142, 1111, 1073, 1045, 1029, 996, 957, 815, 750;

2.0 Hz, J_b= 7.6 Hz, 2H), 7.49 (dt, J_a= 2.0 Hz, J_b= 8.4 Hz, 2H); HRMS m/z (ESI) calcd for C₁₆H₁₆NaO₃[M + Na]⁺279.0997

¹³C NMR (CDCl₃): 25.0, 29.9, 77.0, 98.8. 100.9, 108.2, 113.1, found 279.0989.

121.6, 127.7, 131.6, 140.7, 141.6, 146.5, 149.3; HRMS m/z (ESI)

2-(^P-TOLYL)-3,4-DIHYDROPYRANO[3,2-C]CHROMEN-5(2H)-ONE (4E).

White solid, mp: 138–140 °C; H NMR (CDCl₃): 2.03–2.15 (m,

1

calcd for C₁₆H₁₃BrNaO₃[M + Na]⁺354.9946 found 354.9940.

6-(4-F^LUOROPHENYL)-6-METHYL-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]- 1H), 2.28–2.37 (m, 1H), 2.40 (s, 3H), 2.60–2.77 (m, 2H), 5.20

CHROMENE (3G). Pale brown liquid; ¹H NMR (CDCl₃): 1.57 (s, (dd, J_a= 2.0 Hz, J_b= 10.0 Hz, 1H), 7.20–7.28 (m, 3H), 7.28–7.36

3H), 1.95–2.05 (m, 1H), 2.24–2.38 (m, 2H), 2.48–2.58 (m, 1H), (m, 3H), 7.49 (td, J_a= 1.6 Hz, J_b= 6.8 Hz, 1H), 7.78 (dd, J_a=

5.83 (dd, J_a= 1.2 Hz, J_b= 4.8 Hz, 2H), 6.38 (s, 1H), 6.51 (s, 1H), 1.6 Hz, J_b= 7.6 Hz, 1H); ¹³C NMR (CDCl₃): 19.6, 21.2, 28.6,

6.96 (tt, J_a= 2.0 Hz, J_b= 8.8 Hz, 2H), 7.27–7.33 (m, 2H); ¹³C 79.2, 101.1, 115.6, 116.4, 122.4, 123.7, 125.8, 129.4, 131.4,

NMR (CDCl₃): 22.7, 30.3, 32.9, 77.9, 98.8, 100.8, 108.2, 112.9, 136.6, 138.3, 152.3, 160.1, 162.9; IR (cm⁻¹): 3049, 2923, 1964,

115.1, 115.3, 126.7, 126.8, 141.3, 141.3, 141.4, 146.7, 148.4, 1820, 1702, 1629, 1610, 1575, 1514, 1492, 1453, 1429, 1400,

160.5, 162.9; IR (cm⁻¹): 3071, 2929, 2770, 1725, 1630, 1604, 1362, 1319, 1302, 1288, 1222, 1200, 1176, 1161, 1109, 1078,

1507, 1439, 1405, 1377, 1328, 1271, 1230, 1169, 1154, 1088, 1050, 1034, 990, 970, 914, 818, 754; HRMS m/z (ESI) calcd for

1039, 1017, 940, 878, 836; HRMS m/z (ESI) calcd for C₁₉H₁₆NaO₃[M + Na]⁺315.0997 found 315.0995.

C₁₇H₁₅FNaO₃[M + Na]⁺309.0903 found 309.0900.

1-(4-M^ETHYL-PIPERIDIN-1-YL)-BUTANE-1,3-DIONE (5C). Yellow liquid;

6-(4-C^HLOROPHENYL)-6-METHYL-7,8-DIHYDRO-6H-[1,3]DIOXOLO[4,5-G]- ¹H NMR (CDCl₃): 0.91 (d, J = 6.4 Hz, 3H), 1.00–1.13 (m, 2H),

CHROMENE (3H). Pale green liquid; ¹H NMR (CDCl₃): 1.57 (s, 1.50–1.60 (m, 1H), 1.60–1.69 (m, 2H), 1.90 (s, 0.36H), 2.22 (s,

3H), 1.96–2.05 (m, 1H), 2.25–2.37 (m, 2H), 2.48–2.57 (m, 1H), 2.76H), 2.55 (td, J_a= 2.8 Hz, J_b= 12.8 Hz, 1H), 2.97 (td, J_a=

5.84 (dd, J_a= 1.2 Hz, J_b= 5.2 Hz, 2H), 6.37 (s, 1H), 6.51 (s, 1H), 2.8 Hz, J_b= 12.8 Hz, 1H), 3.51 (s, 1.72H), 3.59–3.68 (m, 1H),

7.22–7.29 (m, 4H); ¹³C NMR (CDCl₃): 22.7, 30.2, 32.7, 77.9, 4.46–4.55 (m, 1H), 5.12 (s, 0.10H), 14.87 (s, 0.10H); ¹³C NMR

98.8, 100.9, 108.2, 112.9, 126.6, 128.6, 132.6, 141.4, 144.2, (CDCl₃): 21.6, 21.6, 22.0, 30.1, 30.9, 31.0, 33.6, 34.1, 34.4, 42.2,

146.7, 148.3; IR (cm⁻¹): 2976, 2929, 1726, 1630, 1597, 1481, 46.8, 50.2, 86.4, 164.7, 170.4, 174.8, 202.5; HRMS m/z (ESI)

1438, 1396, 1378, 1327, 1272, 1232, 1213, 1167, 1154, 1092, calcd for C₁₀H₁₇NNaO₂[M + Na]⁺206.1157 found 206.1151.

3312 | Green Chem., 2012, 14, 3304–3317

This journal is © The Royal Society of Chemistry 2012

Green Chemistry

2,6-DIMETHYL-6-PHENYL-5,6-DIHYDRO-4H-PYRAN-3-CARBOXYLIC

ACID

(2,6-D^IMETHYL-6-PHENYL-5,6-DIHYDRO-4H-PYRAN-3-YL)-(4-METHYL-

^DIETHYLAMIDE(6A). Pale yellow liquid; ¹H NMR (CDCl₃): 0.76 (bs, PIPERIDIN-1-YL)-METHANONE (6F). Pale yellow solid, mp: 62–64 °C;

3H), 1.06 (bs, 3H), 1.51 (s, 3H), 1.65–1.78 (m, 1H), 1.85 (t, J = ¹H NMR (CDCl₃): 0.77–1.22 (m, 5H), 1.18–1.36 (m, 1H),

1.6 Hz, 3H), 1.89–2.01 (m, 1H), 2.10–2.19 (m, 1H), 2.28–2.36 1.40–1.50 (m, 1H), 1.53 (s, 3H), 1.57–1.78 (m, 2H), 1.87 (d, J =

(m, 1H), 2.70–3.00 (m, 2H), 3.14–3.48 (m, 2H), 7.23 (sext, J = 14.8 Hz, 3H), 1.91–2.01 (m, 1H), 2.05–2.25 (m, 1H), 2.26–2.38

4.4 Hz, 1H), 7.32 (d, J = 4.4 Hz, 4H); ¹³C NMR (CDCl₃): 12.7, (m, 1H), 2.42–2.72 (m, 2H), 3.18 (bs, 1H), 4.46 (s, 1H), 7.24

14.3, 18.0, 21.2, 30.4, 31.9, 38.5, 42.2, 78.1, 105.8, 126.8, 128.3, (six, J = 4.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 4H); ¹³C NMR (CDCl₃):

145.6, 147.1, 171.2; IR (cm⁻¹): 2922, 1757, 1668, 1517, 1450, 18.1, 21.1, 21.7, 30.3, 31.1, 32.0, 33.9, 35.0, 41.7, 46.5, 78.2,

1427, 1355, 1303, 1287, 1241, 1204, 1186, 1132, 1065, 1023, 105.4, 124.6, 126.9, 128.3, 145.6, 147.6, 170.3; IR (cm⁻¹): 3027,

996, 942, 820, 751; HRMS m/z (ESI) calcd for C₁₈H₂₅NNaO₂2949, 2924, 2850, 1678, 1624, 1494, 1441, 1379, 1343, 1307,

[M + Na]⁺310.1783 found 310.1778.

1276, 1259, 1238, 1204, 1166, 1125, 1106, 1008, 990, 967, 921,

6-(4-F^LUORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-CARBOXYLIC 872, 836, 766, 702; HRMS m/z (ESI) calcd for C₂₀H₂₇NNaO₂

1

^{ACID DIETHYLAMIDE}(6B). Pale yellow liquid; H NMR (CDCl₃): 0.79 [M + Na]⁺336.1939 found 336.1933.

(bs, 3H), 1.05 (bs, 3H), 1.48 (s, 3H), 1.64–1.77 (m, 1H), 1.82 (t, J

[6-(4-C^HLORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-YL]-

= 1.6 Hz, 3H), 1.87–1.97 (m, 1H), 2.08–2.18 (m, 1H), 2.22–2.28 (4-^METHYL-PIPERIDIN-1-YL)-METHANONE (6G). White solid, mp:

(m, 1H), 2.75–3.02 (m, 2H), 3.18–3.28 (m, 1H), 3.34–3.44 (m, 138–140 °C; ¹H NMR (CDCl₃): 0.78–1.02 (m, 5H), 1.20–1.32 (m,

1H), 6.95–7.03 (m, 2H), 7.24–7.31 (m, 2H); ¹³C NMR (CDCl₃): 1H), 1.49 (s, 4H), 1.55–1.76 (m, 2H), 1.85 (s, 3H), 1.89–1.99 (m,

12.6, 14.3, 17.921.130.3, 31.9, 38.6, 42.3, 77.7, 105.7, 115.0, 1H), 2.04–2.29 (m, 2H), 2.46–2.78 (m, 2H), 2.96–3.36 (m, 1H),

115.2, 126.2, 126.3, 141.4, 141.4, 146.9, 160.4, 162.9, 171.1; 4.34–4.64 (m, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.29 (dd, J_a= 2.0 Hz,

HRMS m/z (ESI) calcd for C₁₈H₂₄FNNaO₂[M + Na]⁺328.1689 J_b= 8.8 Hz, 2H); ¹³C NMR (CDCl₃): 18.0, 21.0, 21.7, 30.0, 31.1,

found 328.1682.

31.9, 33.9, 35.0, 41.8, 46.5, 77.8, 105.4, 126.2, 128.5, 132.7,

6-(4-C^HLORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-CARBOXYLIC 144.3, 147.5, 170.1; IR (cm⁻¹): 2951, 2925, 2851, 1715, 1678,

^{ACID DIETHYLAMIDE}(6C). Pale yellow liquid; ¹H NMR (CDCl₃): 0.82 1619, 1491, 1445, 1380, 1344, 1307, 1276, 1238, 1206, 1165,

(bs, 3H), 1.08 (bs, 3H), 1.50 (s, 3H), 1.65–1.79 (m, 1H), 1.84 (s, 1103, 1011, 967, 832, 731; HRMS m/z (ESI) calcd for

3H), 1.90–2.00 (m, 1H), 2.12–2.21 (m, 1H), 2.23–2.32 (m, 1H), C₂₀H₂₆ClNNaO₂[M + Na]⁺370.1550 found 370.1545.

2.76–3.05 (m, 2H), 3.19–3.48 (m, 2H), 7.25–7.33 (m, 4H); ¹³C

[6-(4-F^LUORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-YL]-

NMR (CDCl₃): 12.7, 14.3, 18.0, 21.1, 30.2, 31.8, 38.6, 42.4, 77.8, PIPERIDIN-1-YL-METHANONE (6H). Pale yellow liquid; ¹H NMR

105.8, 126.1, 128.5, 132.6, 144.3, 147.0, 171.1; IR (cm⁻¹): 2974, (CDCl₃): 1.14–1.34 (m, 2H), 1.38–1.58 (m, 7H), 1.62–1.74 (m,

2931, 1716, 1677, 1620, 1489; HRMS m/z (ESI) calcd for 1H), 1.83 (s, 3H), 1.87–1.97 (m, 1H), 2.07–2.17 (m, 1H),

C₁₈H₂₄ClNNaO₂[M + Na]⁺344.1393 found 344.1387.

2.19–2.28 (m, 1H), 2.89 (bs, 2H), 3.47 (bs, 2H), 6.99 (t, J =

6-(4-C^HLORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-CARBOXYLIC 8.4 Hz, 2H), 7.23–7.31 (m, 2H); ¹³C NMR (CDCl₃): 18.0, 21.0,

ACID ^DIBUTYLAMIDE(6D). White solid, mp: 63–65 °C; ¹H NMR 24.5, 25.6, 26.7, 30.1, 32.0, 42.4, 47.3, 77.7, 105.3, 115.0, 115.2,

(CDCl₃): 0.72–0.80 (m, 3H), 0.84–1.00 (m, 5H), 1.08–1.34 (m, 126.3, 126.4, 141.4, 141.4, 147.4, 160.4, 162.9, 170.2; IR (cm⁻¹):

4H), 1.41–1.51 (m, 5H), 1.64–1.79 (m, 1H), 1.83 (s, 3H), 2934, 2856, 1717, 1677, 1617, 1509, 1439, 1381, 1349, 1282,

1.87–1.97 (m, 1H), 2.09–2.21 (m, 1H), 2.22–2.32 (m, 1H), 1230, 1163, 1125, 1103, 1014, 990, 840, 731; HRMS m/z (ESI)

2.73–3.01 (m, 2H), 3.02–3.12 (m, 1H), 3.37–3.52 (m, 1H), calcd for C₁₉H₂₄FNNaO₂[M + Na]⁺340.1689 found 340.1682.

7.24–7.31 (m, 4H); ¹³C NMR (CDCl₃): 13.8, 13.8, 18.0, 19.9,

(2,6-D^IMETHYL-6-PHENYL-5,6-DIHYDRO-4H-PYRAN-3-YL)-PIPERIDIN-1-YL-

1

20.3, 21.1, 29.4, 30.5, 30.9, 31.7, 43.7, 48.0, 77.7, 105.6, 126.1, METHANONE (6I). Pale yellow liquid; H NMR (CDCl₃): 1.14–1.32

128.6, 132.7, 144.3, 147.1, 171.4; IR (cm⁻¹): 2958, 2931, 2872, (m, 2H), 1.42–1.54 (m, 7H), 1.62–1.79 (m, 1H), 1.86 (s, 3H),

1721, 1677, 1621, 1549, 1491, 1455, 1423, 1381, 1297, 1272, 1.90–1.99 (m, 1H), 2.08–2.18 (m, 1H), 2.26–2.38 (m, 1H), 2.86

1230, 1195, 1171, 1126, 1098, 1012, 989, 949, 830, 750; HRMS (bs, 2H), 3.35–3.56 (m, 2H), 7.22 (sext, J = 4.0 Hz, 1H), 7.31 (d, J

m/z (ESI) calcd for C₂₂H₃₂ClNNaO₂[M + Na]⁺400.2019 found = 4.0 Hz, 4H); ¹³C NMR (CDCl₃): 18.1, 21.1, 24.5, 25.6, 26.8,

400.2013.

30.2, 31.9, 42.4, 47.2, 78.2, 105.4, 124.6, 126.8, 128.3, 145.6,

[6-(4-F^LUORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-YL]- 147.6, 170.4; IR (cm⁻¹): 3027, 2933, 2854, 1714, 1678, 1620,

(4-^METHYL-PIPERIDIN-1-YL)-METHANONE

(6E). White solid, mp: 1494, 1439, 1380, 1347, 1281, 1235, 1196, 1166, 1125, 1104,

80–82 °C; ¹H NMR (CDCl₃): 0.76–1.12 (m, 5H), 1.18–1.30 1069, 1027, 990, 956, 917, 877, 766; HRMS m/z (ESI) calcd for

(m, 1H), 1.48 (s, 4H), 1.55–1.75 (m, 2H), 1.84 (s, 3H), C₁₉H₂₅NNaO₂[M + Na]⁺322.1783 found 322.1777.

1.88–1.98 (m, 1H), 2.04–2.32 (m, 2H), 2.42–2.78 (m, 2H), 3.18

[6-(4-C^HLORO-PHENYL)-2,6-DIMETHYL-5,6-DIHYDRO-4H-PYRAN-3-YL]-

(bs, 1H), 4.47 (s, 1H), 6.99 (t, J = 8.4 Hz, 2H), 7.24–7.32 (m, PIPERIDIN-1-YL-METHANONE (6J). Pale yellow liquid; ¹H NMR

2H); ¹³C NMR (CDCl₃): 18.0, 21.0, 21.7, 30.2, 31.1, 32.0, 33.8, (CDCl₃): 1.13–1.35 (m, 2H), 1.39–1.57 (m, 7H), 1.62–1.74 (m,

35.0, 41.7, 46.5, 77.7, 105.3, 115.0, 115.2, 126.3, 126.4, 141.4, 1H), 1.83 (s, 3H), 1.88–1.97 (m, 1H), 2.08–2.17 (m, 1H),

147.4, 160.5, 162.9, 170.2; IR (cm⁻¹): 2951, 2850, 1715, 1678, 2.19–2.32 (m, 1H), 2.89 (bs, 2H), 3.47 (bs, 2H), 6.99 (t, J =

1621, 1509, 1445, 1382, 1345, 1307, 1277, 1259, 1235, 1162, 8.4 Hz, 2H), 7.23–7.30 (m, 2H); ¹³C NMR (CDCl₃): 18.0, 21.0,

1125, 1107, 1084, 1067, 1012, 988, 968, 839, 731; HRMS m/z 24.5, 25.6, 26.7, 30.0, 31.9, 42.4, 47.2, 77.7, 105.3, 126.2, 128.4,

(ESI) calcd for C₂₀H₂₆FNNaO₂[M + Na]⁺354.1845 found 132.6, 144.2, 147.4, 170.0; IR (cm⁻¹): 2977, 2937, 2857, 1719,

354.1838.

1681, 1618, 1493, 1469, 1443, 1400, 1386, 1375, 1353, 1286,

Green Chem., 2012, 14, 3304–3317 | 3313

Paper

1237, 1203, 1168, 1128, 1106, 1096, 1068, 1028, 1014, 991, 956, 1.2 Hz, J_b= 8.8 Hz, 2H), 9.08 (bs, 1H); ¹³C NMR (d₆-DMSO):

924, 876, 853, 832, 733; HRMS m/z (ESI) calcd for 14.4, 21.1, 60.2, 60.9, 112.8, 122.9, 125.7, 128.0, 129.1, 129.3,

C₁₉H₂₄ClNNaO₂[M + Na]⁺356.1393 found 356.1387.

133.8, 136.8, 137.6, 152.9, 162.5, 164.4; IR (cm⁻¹): 3299, 2985,

4-H^YDROXY-2-(2-METHOXY-PHENYL)-5-OXO-1-PHENYL-2,5-DIHYDRO-1H- 1715, 1685, 1656, 1599, 1501, 1443, 1371, 1314, 1256, 1136,

PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8A). White solid, mp: 1033; HRMS m/z (ESI) calcd for C₂₀H₁₉NNaO₄[M + Na]⁺

1

193–195 °C; H NMR (CDCl₃): 1.14 (t, J = 7.2 Hz, 3H), 3.89 (s, 360.1212 found 360.1209.

3H), 4.16 (q, J = 7.2 Hz, 2H), 6.31 (s, 1H), 6.83 (t, J = 7.6 Hz,

4-H^YDROXY-5-OXO-1-P-TOLYL-2-(4-TRIFLUOROMETHYL-PHENYL)-2,5-DIHYDRO-

2H), 6.99 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 7.19 (td, J_a1H-^PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8F). White solid, mp:

1

= 1.6 Hz, J_b= 8.0 Hz, 1), 7.26 (t, J = 8.4 Hz, 2H), 7.56 (d, J = 176–178 °C; H NMR (CDCl₃): 1.20 (t, J = 7.2 Hz, 3H), 2.27 (s,

7.6 Hz, 2H), 9.10 (s, 1H); ¹³C NMR (d₆-DMSO): 14.3, 56.3, 60.0, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.79 (s, 1H), 7.10 (d, J = 8.4 Hz,

112.2, 120.9, 122.2, 124.3, 125.6, 129.0, 129.7, 137.0, 153.7, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.53 (d, J =

158.2, 162.5, 164.7; IR (cm⁻¹): 3329, 2988, 1707, 1681, 1656, 8.0 Hz, 2H), 9.11 (bs, 1H); ¹³C NMR (CDCl₃): 13.9, 20.9, 61.1,

1596, 1499, 1465, 1441, 1372, 1312, 1292, 1261, 1213, 1190, 61.4, 112.5, 122.3, 122.4, 125.1, 125.6, 125.6, 125.6, 128.0,

1140, 1030; HRMS m/z (ESI) calcd for C₂₀H₁₉NNaO₅[M + Na]⁺129.7, 130.2, 130.6, 130.9, 133.3, 136.1, 139.6, 156.7, 162.7,

376.1161 found 376.1155.

164.7; IR (cm⁻¹): 3305, 2986, 1729, 1690, 1659, 1517, 1446,

4-H^YDROXY-5-OXO-1-PHENYL-2-(4-TRIFLUOROMETHYL-PHENYL)-2,5-DIHYDRO- 1420, 1372, 1327, 1255, 1213, 1168, 1143, 1112, 1066, 1022;

1H-^PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8B). White solid, mp: HRMS m/z (ESI) calcd for C₂₁H₁₈F₃NNaO₄[M + Na]⁺428.1086

172–174 °C; ¹H NMR (CDCl₃): 1.21 (t, J = 7.2 Hz, 3H), 4.22 found 428.1081.

(q, J = 7.2 Hz, 2H), 5.83 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.30 (t,

4-H^YDROXY-1-(4-NITRO-PHENYL)-5-OXO-2-P-TOLYL-2,5-DIHYDRO-1H-

J = 7.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8G). White solid, mp:

1

2H), 7.55 (d, J = 8.0, 2H), 9.10 (bs, 1H); ¹³C NMR (d₆-DMSO): 182–184 °C; H NMR (CDCl₃): 1.24 (t, J = 7.2 Hz, 3H), 2.29 (s,

14.3, 60.3, 60.5, 112.1, 122.9, 123.1, 125.5, 125.6, 125.8, 126.0, 3H), 4.24 (qd, J_a= 0.8 Hz, J_b= 7.2 Hz, 2H), 5.79 (s, 1H), 7.12 (q,

128.5, 128.8, 129.1, 129.2, 129.2, 136.5, 142.1, 152.6, 162.4, J = 8.0 Hz, 4H), 7.81 (dt, J_a= 2.0 Hz, J_b= 9.6 Hz, 2H), 8.14 (dt,

164.4; IR (cm⁻¹): 3303, 2986, 1724, 1689, 1595, 1501, 1446, J_a= 2.0 Hz, J_b= 9.2 Hz, 2H); ¹³C NMR (d₆-DMSO): 14.4, 21.0,

1425, 1375, 1328, 1259, 1166, 1118, 1020; HRMS m/z 60.4, 60.6, 113.8, 122.0, 124.8, 128.0, 129.5, 133.3, 137.9, 142.5,

(ESI) calcd for C₂₀H₁₆F₃NNaO₄[M + Na]⁺414.0929 found 143.9, 152.2, 162.3, 165.2; IR (cm⁻¹): 3305, 2987, 1736, 1690,

414.0922.

1660, 1595, 1508, 1447, 1366, 1332, 1266, 1220, 1188, 1139,

4-H^YDROXY-2-(2-NITRO-PHENYL)-5-OXO-1-PHENYL-2,5-DIHYDRO-1H-PYRROLE- 1114, 1022; HRMS m/z (ESI) calcd for C₂₀H₁₈N₂NaO₆[M + Na]⁺

3-^{CARBOXYLIC ACID ETHYL ESTER}(8C). White solid, mp: 178–180 °C; 405.1063 found 405.1055.

¹H NMR (CDCl₃): 1.16 (t, J = 7.2 Hz, 3H), 4.12–4.25 (m, 2H),

4-H^YDROXY-1-(4-NITRO-PHENYL)-5-OXO-2-(4-TRIFLUOROMETHYL-PHENYL)-

7.10–7.20 (m, 3H), 7.33 (tt, J_a= 2.0 Hz, J_b= 8.0 Hz, 2H), 7.40 2,5-^DIHYDRO-1H-PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8H). White

(td, J_a= 1.6 Hz, J_b= 8.0 Hz, 1H), 7.49 (td, J_a= 1.2 Hz, J_b

solid, mp: 175–177 °C; ¹H NMR (CDCl₃): 1.24 (t, J = 7.2 Hz,

=

7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.95 (dd, J_a= 0.8 Hz, J_b= 3H), 4.25 (q, J = 7.2 Hz, 2H), 5.90 (s, 1H), 7.42 (d, J = 8.0 Hz,

8.0 Hz, 1H), 9.11 (bs, 1H); ¹³C NMR (d₆-DMSO): 14.4, 55.0, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 9.2 Hz, 2H), 8.17 (d, J =

60.4, 112.2, 122.7, 125.2, 126.2, 127.8, 129.4, 129.8, 131.6, 9.2 Hz, 2H); ¹³C NMR (CDCl₃): 13.9, 60.5, 61.9, 113.5, 120.6,

134.3, 136.6, 150.5, 153.9, 162.3, 164.8; IR (cm⁻¹): 3298, 2984, 122.2, 125.9, 126.0, 126.1, 127.8, 130.9, 131.2, 131.5, 138.7,

1724, 1682, 1595, 1530, 1500, 1444, 1372, 1344, 1312, 1260, 141.6, 144.5, 155.8, 163.1, 164.5; IR (cm⁻¹): 3321, 2994, 1738,

1213, 1185, 1139, 1022; HRMS m/z (ESI) calcd for 1692, 1596, 1514, 1449, 1424, 1367, 1330, 1265, 1218, 1191,

C₁₉H₁₆N₂NaO₆[M + Na]⁺391.0906 found 391.0900.

2-(4-C^HLORO-PHENYL)-4-HYDROXY-5-OXO-1-PHENYL-2,5-DIHYDRO-1H- C₂₀H₁₅F₃N₂NaO₆[M + Na]⁺459.0780 found 459.0778.

1166, 1122, 1069, 1021; HRMS m/z (ESI) calcd for

PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8D). White solid, mp:

4-H^YDROXY-2-(2-NITRO-PHENYL)-5-OXO-1-P-TOLYL-2,5-DIHYDRO-1H-

176–178 °C; ¹H NMR (CDCl₃): 1.22 (t, J = 7.2 Hz, 3H), 4.22 (q, J PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8I). White solid, mp:

1

= 7.2 Hz, 2H), 5.74 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.18 (dd, J_a= 173–175 °C; H NMR (CDCl₃): 1.15 (t, J = 7.2 Hz, 3H), 2.26 (s,

2.0 Hz, J_b= 6.8 Hz, 2H), 7.24 (dd, J_a= 2.0 Hz, J_b= 6.8 Hz, 2H), 3H), 4.12–4.24 (m, 2H), 7.10 (d, J = 4.2 Hz, 2H), 7.12 (s, 1H),

7.29 (td, J_a= 2.0 Hz, J_b= 6.8 Hz, 2H), 7.46 (dd, J_a= 1.2 Hz, J_b= 7.17 (d, J = 7.6 Hz, 1H), 7.39 (td, J_a= 1.2 Hz, J_b= 8.0 Hz, 1H),

8.4 Hz, 2H), 9.12 (bs, 1H); ¹³C NMR (d₆-DMSO): 14.4, 60.2, 7.48 (td, J_a= 1.2 Hz, J_b= 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H),

60.4, 112.3, 123.0, 125.9, 128.7, 129.2, 130.1, 132.9, 136.2, 7.93 (d, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃): 13.9, 20.9, 54.4,

136.5, 153.3, 162.4, 164.4; IR (cm⁻¹): 3306, 2927, 1719, 1659, 61.7, 112.9, 121.7, 125.1, 127.2, 129.3, 129.8, 130.8, 133.4,

1593, 1496, 1444, 1396, 1311, 1255, 1213, 1187, 1138, 1030, 133.8, 135.9, 150.1, 157.1, 162.8, 164.6; IR (cm⁻¹): 3307, 2987,

1022; HRMS m/z (ESI) calcd for C₁₉H₁₆ClNNaO₄[M + Na]⁺1728, 1689, 1656, 1612, 1524, 1446, 1414, 1375, 1348, 1309,

380.0666 found 380.0660.

1260, 1211, 1187, 1142, 1113, 1023; HRMS m/z (ESI) calcd for

4-H^YDROXY-5-OXO-1-PHENYL-2-P-TOLYL-2,5-DIHYDRO-1H-PYRROLE- C₂₀H₁₈N₂NaO₆[M + Na]⁺405.1063 found 405.1058.

3-^{CARBOXYLIC ACID ETHYL ESTER}(8E). White solid, mp: 179–181 °C;

4-H^YDROXY-1-(4-METHOXY-PHENYL)-5-OXO-2-(4-TRIFLUOROMETHYL-PHENYL)-

¹H NMR (CDCl₃): 1.22 (t, J = 7.2 Hz, 3H), 2.27 (s, 3H), 4.21 (q, J 2,5-^DIHYDRO-1H-PYRROLE-3-CARBOXYLIC ACID ETHYL ESTER (8J). White

= 7.2 Hz, 2H), 5.72 (s, 1H), 7.06 (d, J = 8.0 Hz, 2H), 7.12 (d, J = solid, mp: 162–164 °C; ¹H NMR (CDCl₃): 1.16 (t, J = 7.2 Hz,

8.0 Hz, 2H), 7.28 (td, J_a= 2.0 Hz, J_b= 6.8 Hz, 2H), 7.50 (dd, J_a= 3H), 3.71 (s, 3H), 4.17 (q, J = 7.2 Hz, 2H), 5.74 (s, 1H), 9.79

3314 | Green Chem., 2012, 14, 3304–3317

Green Chemistry

(d, J = 9.2 Hz, 2H), 7.30 (t, J = 9.2 Hz, 2H), 7.35 (t, J = 8.0 Hz, (ESI) calcd for C₂₁H₂₂N₂NaO₈[M + Na]⁺453.1274 found

2H), 7.51 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃): 13.9, 55.3, 61.3, 453.1268.

61.7, 112.5, 114.4, 122.5, 124.3, 125.2, 125.5, 125.5, 125.6,

3,9-D^IMETHYL-3,4-DIHYDRO-2H-ACRIDIN-1-ONE (13G). White solid,

125.6, 128.1, 128.7, 130.2, 130.5, 130.9, 131.1, 139.6, 156.3, mp: 78–80 °C; ¹H NMR (CDCl₃): 1.09 (d, J = 6.4 Hz, 3H),

157.8, 163.1, 164.4; HRMS m/z (ESI) calcd for C₂₁H₁₈F₃NNaO₅2.23–2.40 (m, 2H), 2.71–2.85 (m, 2H), 2.90 (s, 3H), 3.16–3.27

[M + Na]⁺444.1035 found 444.1030.

(m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.64 (td, J_a= 0.8 Hz, J_b=

2-H^YDROXY-8-METHOXY-2H-CHROMENE-2,3-DICARBOXYLIC ACID DIETHYL 8.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H);

^ESTER(9A). Pale yellow solid, mp: 114–116 °C; ¹H NMR (CDCl₃): ¹³C NMR (CDCl₃): 15.8, 21.1, 28.4, 42.8, 49.1, 124.5, 125.3,

1.26 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 3.82 (s, 3H), 126.2, 127.5, 129.1, 131.3, 147.9, 129.6, 161.4, 200.3; HRMS

4.20–4.32 (m, 3H), 4.33–4.43 (m, 1H), 5.33 (s, 1H), 6.89–6.97 m/z (ESI) calcd for C₁₅H₁₅NNaO [M + Na]⁺248.1051 found

(m, 3H), 7.79 (s, 1H); ¹³C NMR (CDCl₃): 13.8, 14.1, 56.2, 61.1, 248.1046.

63.4, 93.1, 115.2, 118.8, 120.9, 121.7, 122.2, 135.1, 140.7, 148.1,

163.9, 169.0; IR (cm⁻¹): 3446, 2982, 1756, 1699, 1642, 1580,

1480, 1442, 1404, 1370, 1298, 1262, 1215, 1189, 1148, 1113;

HRMS m/z (ESI) calcd for C₁₆H₁₈NaO₇[M + Na]⁺345.0950

Acknowledgements

found 345.0945.

2-H^YDROXY-2H-CHROMENE-2,3-DICARBOXYLIC ACID

The authors thank Dr John Fossey (the University of

Birmingham) for helpful discussions. The authors thank

National Natural Science Foundation of China for the financial

support (21173089). The authors are also grateful to all the

staﬀ members in the Analytical and Testing Center of HUST,

for their contributions to our work. The Program for new

Century Excellent Talents in the University of China (NCET-10-

0383) and Chutian Scholar Program of the Hubei provincial

government are also acknowledged. The authors also thank

the Specialized Research Fund for the Doctoral Program of

Higher Education (20090142120081).

DIETHYL

ESTER

1

(9B). White solid, mp: 86–88 °C; H NMR (CDCl₃): 1.28 (t, J =

7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 4.21–4.40 (m, 4H), 5.33 (s,

1H), 6.94–7.04 (m, 2H), 7.26–7.36 (m, 2H), 7.80 (s, 1H); ¹³C

NMR (CDCl₃): 13.8, 14.1, 61.1, 63.3, 93.2, 116.8, 118.1, 121.6,

122.4, 129.1, 132.5, 135.0, 151.3, 164.0, 169.2; IR (cm⁻¹): 3442,

2983, 1740, 1704, 1642, 1607, 1573, 1459, 1418, 1370, 1298,

1223, 1146, 1118, 1102, 1050, 1015; HRMS m/z (ESI) calcd for

C₁₅H₁₆NaO₆[M + Na]⁺315.0845 found 315.0838.

8-E^THOXY-2-HYDROXY-2H-CHROMENE-2,3-DICARBOXYLIC ACID DIETHYL

^ESTER(9C). White solid, mp: 152–154 °C; ¹H NMR (CDCl₃): 1.25

(t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz,

3H), 3.98–4.08 (m, 2H), 4.19–4.31 (m, 3H), 4.31–4.41 (m, 1H),

5.31 (s, 1H), 6.88–6.96 (m, 3H), 7.77 (s, 1H); ¹³C NMR (CDCl₃):

13.8, 14.1, 14.7, 61.1, 63.3, 65.2, 93.1, 117.5, 119.0, 121.1,

121.7, 122.1, 135.2, 141.2, 147.5, 164.0, 169.1; IR (cm⁻¹): 3452,

2989, 1749, 1713, 1642, 1576, 1472, 1370, 1298, 1271, 1234,

1145, 1102; HRMS m/z (ESI) calcd for C₁₇H₂₀NaO₇[M + Na]⁺

359.1107 found 359.1101.

Notes and references

1 (a) P. G. Jessop, Green Chem., 2011, 13, 1391; (b) J. H. Clark

and S. J. Tavener, Org. Process Res. Dev., 2007, 11, 149;

(c) D. Reinhardt, F. Ilgen, D. Kralisch, B. König and

G. Kreisel, Green Chem., 2008, 10, 1170; (d) K. Alfonsi,

J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A. Johnson,

H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and

M. Stefaniak, Green Chem., 2008, 10, 31; (e) C. A. Eckert,

D. Bush, J. S. Brown and C. L. Liotta, Ind. Eng. Chem. Res.,

2000, 39, 4615.

2 (a) F. M. Kerton, in Alternative Solvents for Green Chemistry,

RSC Green Chemistry Series, Series ed. J. Clark, 2009;

(b) W. Leitner, Green Chem., 2007, 9, 923; (c) W. Leitner,

Green Chem., 2009, 11, 603.

3 (a) M. Avalos, R. Babiano, P. Cintas, J. L. Jiménez and

J. C. Palacios, Angew. Chem., Int. Ed., 2006, 45, 3904;

(b) D. J. C. Constable, P. J. Dunn, J. D. Hayler,

G. R. Humphrey, J. L. Leazer, R. J. Linderman, K. Lorenz,

J. Manley, B. A. Pearlman, A. Wells, A. Zaks and

T. Y. Zhang, Green Chem., 2007, 9, 411.

7-D^IETHYLAMINO-2-HYDROXY-2H-CHROMENE-2,3-DICARBOXYLIC

ACID

1

^{DIETHYL ESTER}(9E). Orange liquid; H NMR (CDCl₃): 1.16 (t, J =

7.2 Hz, 6H), 1.30 (t, J = 7.2 Hz, 6H), 3.35 (q, J = 7.2 Hz, 4H),

4.18–4.26 (m, 2H), 4.28–4.41 (m, 2H), 6.22 (d, J = 2.4 Hz, 1H),

6.34 (dd, J_a= 2.4 Hz, J_b= 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H),

7.74 (s, 1H); ¹³C NMR (CDCl₃): 12.6, 13.9, 14.2, 44.6, 60.5, 63.2,

93.7, 98.2, 106.3, 106.7, 114.9, 130.4, 135.8, 151.7, 153.5, 164.7,

169.9; IR (cm⁻¹): 3473, 2977, 1747, 1700, 1609, 1527, 1447,

1411, 1373, 1357; HRMS m/z (ESI) calcd for C₁₉H₂₅NNaO₆

[M + Na]⁺386.1580 found 386.1575.

2-H^YDROXY-4-(4-NITRO-PHENYLAMINO)-CHROMAN-2,3-DICARBOXYLIC ACID

DIETHYL ^ESTER(10A). Yellow solid, mp: 101–103 °C; ¹H NMR

(CDCl₃): 1.07 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 3.85 (d,

J = 6.0 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.38–4.49 (m, 2H), 5.09

(s, 1H), 5.49 (dd, J_a= 10.8 Hz, J_b= 6.0 Hz, 1H), 5.90 (d, J =

10.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H),

6.99 (td, J_a= 1.2 Hz, J_b= 8.0 Hz, 1H), 7.23–7.31 (m, 2H), 8.13

(d, J = 9.2 Hz, 2H); ¹³C NMR (CDCl₃): 13.9, 13.9, 47.4, 47.8,

61.6, 63.6, 93.6, 111.6, 118.0, 122.3, 122.7, 126.5, 128.7, 130.1,

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