Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction

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Tandem synthesis of 4-aminoxanthones is

controlled by a water-assisted tautomerization:

Cite this: DOI: 10.1039/c8ob02527d

a general straightforward reaction†

Ana Bornadiego, Jesús Díaz * and Carlos F. Marcos

*

Aminoxanthones constitute a group of therapeutically promising compounds that so far have been syn-

thetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized

aminoxanthones by an easy to perform, one-step multicomponent reaction of isocyanides, 3-carbonyl-

chromones and dienophiles. The mechanism of the reaction involves a sequence of a [4 + 1] cyclo-

addition, iminolactone-aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring opening and aro-

matization. Remarkably, DFT quantum chemical computations revealed that the iminolactone-aminofuran

tautomerization requires the assistance of a water molecule and, contrary to intuition, it is the rate-deter-

mining step. Conversely, both the [4 + 1] and the [4 + 2] cycloadditions have relatively low calculated

energy barriers, regardless the substituents on the starting materials. Thus, we have stablished a straight-

forward and a wide-ranging synthesis of diversely substituted xanthones. This highly convergent process

has also been applied to the synthesis of biologically important chromenophenantridines and secalonic

acid related xanthone dimers.

Received 11th October 2018,

Accepted 14th January 2019

DOI: 10.1039/c8ob02527d

rsc.li/obc

synthesis of biologically relevant dimeric xanthones are rela-

tively scarce, making them synthetically challenging targets.⁶

Introduction

Xanthones are secondary metabolites occurring in many In a recent work, we have reported the generation of 2-amino-

plants, fungi, lichens and bacteria.¹They exist as either par- furanes by a [4 + 1] cycloaddition of α,β-unsaturated carbonyl

tially hydrogenated or fully aromatized derivatives and often compounds and isocyanides. These 2-aminofuran intermedi-

exhibit distinct biological activities, which depend on the ates have been conveniently trapped in situ with dienophiles to

degree of oxidation of the rings and their substitution give anilines with good yields.⁷We have found that 4-aminodi-

pattern.²Many biologically active xanthones contain hydrogen hydroxanthones (7)⁸and 4-aminoxanthones (8)⁹could be pre-

bond donating or accepting substituents, such as hydroxyl or pared through a similar tandem [4 + 1]–[4 + 2] cycloaddition of

amino groups, which facilitate key interactions with their bio- 3-carbonylchromones (1), isocyanides (2) and dienophiles (3)

logical targets.³For instance, aminoxanthones have been pro- (Scheme 1).

posed as chemotherapeutic agents for the treatment of dis-

The mechanism of the reaction is explained by a [4 + 1]

eases, such as diabetes, HIV, and multidrug resistant cancers, cycloaddition of the 3-carbonylchromone (1) with the iso-

due to their interaction with negatively charged nucleic acids, cyanide (2) to give an iminolactone intermediate (4).

proteins and cell substructures.⁴

Tautomerization to aminofuran (5), which suﬀers a [4 + 2]

Although diﬀerent methods for the synthesis of xanthones cycloaddition with the dienophile (3), leads to 7-oxabicyclo

are available, they are mostly limited to fully aromatized [2.2.1]heptane (6). This is readily transformed to 1-hydroxydi-

derivatives. Moreover, the introduction of amino substituents hydroxanthone (7) by the opening of the oxygen bridge

almost invariably implies long, indirect procedures and harsh assisted by the nitrogen lone pair. Dehydration finally aﬀords

reaction conditions.⁵Additionally, literature reports on the the aromatic 4-aminoxanthone (8; Scheme 1).

So far, this reaction was limited to electron-poor chromones

such as those containing electron-withdrawing groups

Laboratory of Bioorganic Chemistry & Membrane Biophysics (L.O.B.O.),

attached to the carbonyl, which we thought would favour the

School of Veterinary Sciences, University of Extremadura, 10071 Cáceres, Spain.

first [4 + 1] cycloaddition leading to the purportedly highly

E-mail: cfernan@unex.es, jdal@unex.es

reactive 2-aminofuran intermediate.^8,9

†Electronic supplementary information (ESI) available: Experimental pro-

cedures, computational details, product characterization data, and ¹H and ¹³C

NMR spectra for new compounds (PDF and zip). See DOI: 10.1039/c8ob02527d

In this full paper, we demonstrate that it is possible to

extend this methodology^8,9to synthesize diversely substituted

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Results and discussion

Electron-poor 3-methoxalylchromone (1a, Table 1), in which a

CO₂CH₃substituent is on the carbonyl group, was initially

chosen as starting material in order to facilitate the formation

of the 2-aminofuran, which we hypothesized would rapidly

react with the dienophile.⁹To our delight, the reaction of

methoxalylchromones (1a–e), isocyanides (2a–g) and cyclic

maleic acid derivatives (3a–d) in THF at 25–35 °C readily

aﬀorded 4-aminoxanthone-1-carboxylates (8a–t) with yields up

to 99% (Table 1). Reaction times range from 24 to 144 h and

the products were isolated with high purity by simple filtration

from the reaction medium.

The process shows wide tolerance to diﬀerent substituents

on the chromone core, isocyanides and maleic acid derivatives.

As a result, xanthones with diverse substituents on both aro-

matic rings are obtained. However, a closer analysis of the

results displayed in Table 1 show that, unexpectedly, donor sub-

stituents on the chromone aromatic ring, such as 7-methoxy

(Table 1, entry 8) and 6-methyl (Table 1, entry 10) seem to

facilitate the overall process, considerably reducing the time of

the reaction. Conversely, the electron-withdrawing group-

containing 6-chlorochromone requires longer reaction times

and/or higher temperatures (Table 1, entries 9, 12 and 20).

These results are not consistent with the initial mechanistic

hypothesis of a slow [4 + 1] cycloaddition followed by a rapid

Scheme 1 Our synthesis of xanthones and dihydroxanthones.

xanthones and dihydroxanthones, starting from carbonylchro-

mones containing both electron-withdrawing and electron-

donating groups. A complete theoretical mechanistic study has

been performed in order to delimitate the scope and limit-

ations of this process.

Table 1 General synthesis of 4-aminoxanthones from methoxalylchromones (1a–e)^a

Entry

Chromone

R¹

R²

R³

Isocyanide

R⁴

Dienophile

X

T, °C

Time, h

Product (yield, %)

1

2

3

4

5

6

7

8

1a

1b

1c

1d

1e

1c

1a

1b

1a

1b

1a

1b

1d

1c

H

Benzo

H

Cl

Me

H

OMe

H

OMe

H

OMe

H

OMe

H

2a

2b

2c

2d

2e

2f

2g

2a

2b

2a

2d

2b

2c

c-C₆H₁₁

t-Bu

2,6-Me₂C₆H₃

PhCH₂

3a

3b

3c

3d

N-C₆H₅

N-CH₃

O

35

25

35

25

35

25

85

96

144

78

22

49

24

96

24

140

120

32

23

96

72

80

6

8a (99)

8b (93)

8c (67)

8d (93)

8e (97)

8f (99)

8g (82)

8h (99)

8i (81)

8j (75)

8k (30)

8l (85)

8m (94)

8n (81)

8o (83)

8p (87)

8q (86)

8r (30)

8s (70)

8t (53)

C₅H₁₁

4-MeOC₆H₄

CH₂CO₂t-Bu

c-C₆H₁₁

t-Bu

c-C₆H₁₁

PhCH₂

9

10

11

12

13

14

15

16

17

18

19

20

Cl

H

Me

Cl

O

NH

H

t-Bu

2,6-Me₂C₆H₃

NH

^aGeneral procedure: isocyanide 2 (1.1 equiv.) and dienophile 3 (1.1 equiv.) were added under nitrogen to a solution of chromenone 1 (1 equiv.)

in THF and stirred at the specified temperature.

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[4 + 2] trapping of the 2-aminofuran. Thus a detailed study of

As the synthesis of both xanthones (8) and dihydrox-

the mechanism became necessary in order to both find anthones (7) was successfully carried out from chromones con-

optimal reaction conditions and broaden the scope of the reac- taining electron-donating or electron-withdrawing groups on

tion. Nonetheless, good yields are generally obtained regard- the aromatic ring, we wondered if the extension of this reac-

less of the nature of these substituents.

tion to 3-carbonylcromones other than 3-methoxalylchro-

Interestingly, the use of non-symmetric dienophiles con- mones would be possible. This would allow the formation of

taining only one electron-withdrawing group (3e–f) makes the xanthones with diﬀerent substituents on carbon 1. Notably,

isolation of the [4 + 1]/[4 + 2] cycloadduct (7) prior to aromati- the substituent on this position seems to be determinant for

zation possible (Table 2). Notably, the Diels–Alder reaction was the biological activity of xanthones.¹²

shown to be regioselective, exclusively leading to the

Accordingly, 3-carbonylchromones containing both elec-

1-hydroxy-1H-xanthen-9(2H)-ones (7u–ae) with the electron- tron-withdrawing and electron-donating substituents on the

withdrawing group on position C3.⁸The lack of acidic hydro- carbonyl group were prepared in order to be used in the syn-

gens on C2 precludes the spontaneous dehydration to aro- thesis of xanthones. Thus, 3-acetylchromones (1f, Y = CH₃)

matic 4-aminoxanthones (8), which occurs when the reaction and 3-trifluoroacetylchromones (1g–h, Y = CF₃) were readily

is performed with symmetric dienophiles. This constitutes a obtained from (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-

remarkably straightforward and eﬃcient route to 1-hydroxy-9- 2-en-1-ones (9) and the corresponding anhydride (10), by a

oxo-2,9-dihydro-1H-xanthene-1-carboxylates (7), which are modification of Yokoe’s method (Scheme 2).¹³

structurally similar to biologically active globosuxanthones¹⁰

On the other hand, the reaction of 3-(dimethylamino)-1-(2-

and diversolonic acids.¹¹Here again, the reaction was hydroxyphenyl)propen-1-one (9) with ortho- or para-nitrobezoyl

shown to be tolerant of various isocyanides, dienophiles, and chlorides in Yokoe’s conditions always led to mixtures of the

substituents on the chromone (Table 2). Additionally, further desired benzoylchromones and unsubstituted chromones in

dehydration of dihydroxanthones (7) in the presence of a low yields. Consequently, we developed an alternative syn-

base such as DBU, cleanly leads to corresponding thesis through the Baylis–Hillman (B–H) condensation of chro-

aromatized xanthones (8). These can also be conveniently mone (11) and the corresponding nitro-substituted benzal-

obtained in a sequential two-step one-pot procedure, as shown dehydes (12), followed by oxidation of the resulting alcohols.

in Table 3.

The B–H reaction was successfully achieved in methanol,

The isolation of 1-hydroxydihydroxanthones (7u–ae) using sodium methoxide as a base.¹⁴The adducts were cleanly

strongly supports the initially proposed reaction mechanism oxidised with MnO₂,¹⁵aﬀording the expected chromones 1i–j

involving the sequence of [4 + 1] cycloaddition, iminolactone- in moderate yields (Scheme 2).

aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring

The reaction of these chromones (1f–j) with isocyanide (2a,

opening and aromatization (Scheme 1). However, again, e–f) and maleic acid derivatives (3a–d) in the conditions pre-

observing the influence of the chromone substituents on the viously used with methoxalylchromones was extremely slug-

reaction does not indicate the rate-determining step.

gish, and aﬀorded the resulting xanthones (8) in poor yields

Table 2 Synthesis of 4-amino-1-hydroxydihydroxanthones

Entry

Chromone

R²

R³

Isocyanide

R⁴

Dienophile

R⁵

Time, h

Product (yield, %)

1

2

3

4

5

6

7

8

1a

1b

1c

1d

1a

1b

1c

1d

H

Cl

Me

H

Cl

Me

H

OMe

H

OMe

H

2a

2f

2a

2f

c-C₆H₁₁

4-MeOC₆H₄

c-C₆H₁₁

4-MeOC₆H₄

C₅H₁₁

3e

3f

CN

2

4.5

2

9

0.5

1

2

7u (81)^a

7v (82)^a

7w (83)^a

7x (76)^a

7y (28)^a

7z (70)^b

7aa (74)^b

7ab (90)^b

7ac (78)^b

7ad (62)^b

7ae (83)^b

CN

COMe

9

10

11

H

2e

1

^aMethod A: A solution of 1 (1 equiv.), 2 (1.2 equiv.), and 3e (2 equiv.) in THF is heated 2–9 h at 70 °C. ^bMethod B: A solution of 1 (1 equiv.), 2 (1.2

equiv.), and 3f (1.2 equiv.) in THF is irradiated with MW 0.5–2 h in a close vial at 100 °C.

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Table 3 One-pot synthesis of xanthones (8) from asymmetric dienophiles (3e–f)

Entry

Chromone

R²

R³

Isocyanide

R⁴

Dienophile

R⁵

t₁/t₂, h

Product (yield, %)

1

2

3

4

5

6

7

8

1a

1b

1c

1d

1a

1b

1c

1d

1b

1c

1b

1c

H

Cl

Me

H

OMe

H

OMe

H

2a

2f

2e

2b

2f

c-C₆H₁₁

4-MeOC₆H₄

C₅H₁₁

t-Bu

4-MeOC₆H₄

C₅H₁₁

3e

3f

CN

2/0.5

0.5/0.2

9/1

8u (78)^a

8u (75)^b

8v (65)^a

2.5/0.5

5/1.5

0.5/1

1/1.5

1/0.3

6.5/1

3/0.5

1.5/1

3/0.5

1/0.2

3.5/0.5

3/0.5

8/0.5

0.5/0.5

8w (70)^a

8x (68)^a

CN

COMe

CN

8z (76)^b

H

8aa (75)^b

8ab (68)^b

8ac (70)^b

8ad (70)^b

8ae (44)^b

8af (69)^a

8af (69)^b

8ag (78)^a

8ah (40)^a

8ai (27)^a

8aj (48)^b

Cl

Me

H

Cl

H

9

10

11

12

13

14

15

16

17

H

3f

OMe

H

OMe

H

3e

3f

Cl

2f

2e

H

COMe

^aMethod A: A solution of 1 (1 equiv.), 2 (1.2 equiv.), and 3e (2 equiv.) was heated in THF at 70 °C for 2–9 h before the addition of 2 equiv. DBU

and further heating of the reaction mixture for 25–75 min at the same temperature. ^bMethod B: A solution of 1 (1 equiv.), 2 (1.2 equiv.), and 3f

(1.2 equiv.) in THF was irradiated with MW in a sealed vial at 100 °C for 0.5–6 h. Then DBU (2 equiv.) was added and the reaction mixture was

further irradiated of for 10–90 min.

Accordingly, the reaction with trifluoroacetylchromones (1g–h;

Table 4, entries 6, 8–11) and ortho-nitrobenzoylchromone (1i;

Table 4, entries 13–15) is typically completed in less than 30 h.

Intermediate reaction times were observed when para-nitro-

benzoylchromone (1j) was used (Table 4, entries 17–19, 21–22).

In an attempt to reduce the reaction times, the possible

catalytic eﬀect of Lewis acids was explored. However, the

addition of either yttrium triflate or lithium perchlorate to the

reaction mixture led to longer reaction times (Table 4, entries

3 and 4).

The previous results demonstrate that the reaction is

equally feasible with 3-carbonylchromones containing both

electron-withdrawing and electron-donating substituents on

the carbonyl group. Additionally, diﬀerent dienophiles and iso-

cyanides can also be used. Moreover, the data above indicate

that increasing the reaction temperature allows to readily

reach the activation energy, resulting in high yields and

Scheme 2 Synthesis of 3-carbonylchromones.

increased reaction rates. However, puzzlingly, there does not

seem to be a clear influence of the electronic nature of the

starting chromone on either the yields or the reaction times.

(Table 4, entries 1, 5, 7, 12, 16 and 20). However, increasing

As expected, the 3-component reaction of chromones 1g,h,j,

the reaction temperature to 80 °C aﬀords the corresponding isocyanide 2a and asymmetric dienophiles 3e,f, carried out at

4-aminoxanthones 8ak–ax in moderate to excellent yields in a 100 °C, aﬀords regioselectively the xanthones (8ay–ba) with no

reasonable reaction time (Table 4).

substituent in position 3 (Table 5).

Thus, the reaction with acetylchromone (1f) requires

Going a step forward, as the absence of an electron group

40 hours to complete. As expected, the reaction times with attached to the carbonyl group of 3-carbonylchromones does

more electron-poor chromones (1g–j) are significantly shorter. not seem to drastically aﬀect their reactivity, we considered

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Table 4 3-Component reactions of chromones 1f–j with isocyanides and maleic acid derivatives

Entry

Chromone

R²

R³

Y

Isocyanide

R⁴

Dienophile

X

T, °C

Time

Product (yield, %)

1

2

3

4

5

6

7

8

1f

1g

1h

1g

1h

1g

1i

1j

H

OMe

H

OMe

H

CH₃

CF₃

2a

2f

2a

2e

2f

c-C₆H₁₁

4-MeOC₆H₄

c-C₆H₁₁

C₅H₁₁

3a

3b

3bf

3a

3d

3c

3a

3b

3d

3c

3a

N-Ph

N-CH₃

N-Ph

N-H

35

80

35

80

35

80

35

80

35

80

35

80

14 d

40 h

>7.5 d

68 h

8 d

21 h

14 d

13 h

17 h

31 h

6 d

8ak (39)

8ak (95)

8ak (IR)^a,b

8ak (95)^c

8al (31)

8al (61)

8am (29)

8am (58)

8an (26)

8ao (59)

8ap (53)

8aq (67)

8aq (77)

8ar (37)

8as (88)

8at (IR)^b

8at (93)

8au (68)

8av (66)

8aw (IR)^b

8aw (59)

8ax (51)

9

CF₃

10

11

12

13

14

15

16

17

18

19

20

21

22

o-NO₂Ph

p-NO₂Ph

7 h

31 h

22 h

16 d

35 h

20 h

5 d

16 d

5 d

6 d

O

N-Ph

N-CH₃

N-H

O

1j

C₅H₁₁

4-MeOC₆H₄

H

N-Ph

^aThe experiment was made with 5% of yttrium triflate. ^bIR: incomplete reaction. ^cThe experiment was made with 7% of lithium perchlorate.

Table 5 Reactions of chromones 1g,h,j with asymmetric dienophiles

Entry

Chromone

R²

R³

Y

Isocyanide

R⁴

Dienophile

R⁵

T, °C

t₁, h

t₂, min

Product (% yield)^a

1

2

3

1g

1h

1j

H

OMe

H

CF₃

p-NO₂Ph

2a

c-C₆H₁₁

3e

3f

3e

CN

COMe

CN

100

2

5

20

30

15

8ay (28)

8az (41)

8ba (56)

^aGeneral procedure: a solution of 1 (1 equiv.), 2a (1.2 equiv.), and 3e (2 equiv.) or 3f (1.2 equiv.) in THF was irradiated with MW in a sealed vial at

100 °C for 2–5 h. Then DBU (2 equiv.) was added and the reaction mixture was further irradiated of for 15–30 min.

using 3-formylchromones as starting materials in the synthesis and 2). Thus, in order to find better reaction conditions, we

of xanthones.^16,17This provides two advantages: 3-formylchro- tried diﬀerent solvents and temperatures (Table 6). To our

mones are readily available and the resulting xanthones that delight, when the reaction was performed in refluxing toluene

are unsusbstituted on position 1 could be easily transformed for 41 hours, the expected xanthone 8bb was obtained in 89%

into other xanthones of biological interest.

yield (Table 6, entry 3). The structure was confirmed by the

1

The reaction of 3-formylchromone (1k) with cyclohexyl iso- usual spectroscopic data. Significantly, H-NMR of 8bb shows

cyanide (2a) and N-phenylmaleimide (3a) in THF proceeds a singlet at 8.11 ppm, corresponding to the characteristic aro-

quite slowly, even at refluxing temperature (Table 6, entries 1 matic hydrogen in position 4 of the xanthone.

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Table 6 Reactions of 3-formylchromones with isocyanides and dienophiles^a

Entry

Chromone

R²

R³

Isocyanide

R⁴

Dienophile

X

T, °C

Solvent

Time, h

Product (yield, %)

1

2

3

4

5

6

7

8

1k

1l

1m

1k

1m

1k

H

Cl

Me

H

Me

H

2a

2b

2f

c-C₆H₁₁

t-Bu

3a

3d

3b

3c

3a

3c

N-Ph

N-H

35

80

THF

168

107

41

11

26

68

44

25

60

48

59

62

124

29

41

95

360

8bb (IR)^b

8bb (71)

110

150

110

35

Toluene

Dioxane

Dibutylether

Toluene

DCM

8bb (89)

8bb (CM)^c,d

8bb (44)^e

8bb (90)

8bb (88)

8bc (92)

8bd (87)

8be (87)

8bf (70)

8bg (46)

8bh (58)

8bi (33)

9

10

11

12

13

14

15

16

17

18

N-CH₃

O

N-Ph

O

t-Bu

4-MeOC₆H₄

CH₂CO₂t-Bu

t-Bu

8bj (42)

2g

2b

8bk (85)

H

8bh (67, IR)^b,17

8bl (33, IR)^b,17

t-Bu

35

DCM

^aGeneral procedure: Isocyanide 2 (1.2 equiv.) and dienophile 3 (1.2 equiv.) were added under nitrogen to a solution of chromenone 1 (1 equiv.)

in the specified solvent and stirred at the specified temperature. ^bIR: the reaction did not reach completion and a mixture of starting materials

and product was obtained. ^cCM: complex mixture. ^dAlCl₃(5%mol). ^eY(OTf)₃(5%mol).

The use of catalytic Lewis acids such as AlCl₃and Y(OTf)₃

(Table 6, entries 4 and 5), does not improve the performance

of the reaction. Despite the increased reaction rate, several

side products are formed, the work up and isolation of the

product is complex and tedious, and the resulting yield is

lower.

The optimized reaction conditions were applied to other

combinations of commercially available formylchromones (1k–

m), maleimide derivatives (3a–d) and isocyanides (2a–g)

(Table 6, entries 8–18). The process gave moderate to excellent

yields and was shown to be tolerant to diﬀerent isocyanides,

dienophiles, and substituents on the chromone. As previously

t

noted with chrome 1a, less hindered cyclohexyl or CH₂CO₂Bu

isocyanide gave better results in the tandem reaction than tert-

butyl isocyanide, which took 5 days to complete in refluxing

toluene.

In a previous work, we have shown that 3-formylchromones

Scheme 3 Proposed mechanism for the reaction of formylchromones

and isocyanides.¹⁸

react with isocyanides to give chromenylmethylene furochro-

menones (14), purportedly through a 2-aminofuran intermedi-

ate (5; Scheme 3).¹⁸This reaction takes just 5 to 8 hours in

refluxing THF, in contrast with the unexpectedly slow reaction

of 3-formylchromones, isocyanides and dienophiles, which was

DFT calculations

supposed to occur through the same 2-aminofuran intermedi- In an attempt to explain the lack of consistency between the

ate (4). Obviously, this suggests that either the [4 + 1] cyclo- experimental results and our initial mechanistic hypothesis of

addition leading to 2-aminofuran (5) is not the rate determining a slow [4 + 1] cycloaddition leading to iminolactone (4), fol-

step of the synthesis of xanthones (8; Scheme 1), or the mecha- lowed by a rapid tautomerization and [4 + 2] trapping of the

nism for the synthesis of 14 outlined in Scheme 3 is not valid.

2-aminofuran (5), we decided to carry out a computational

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study of all the reactants, products, and transition states. With

this aim, density functional theory (DFT) calculations were per-

formed with Gaussian 16. The geometries of the reactants, pro-

ducts, intermediates, and transition states (TS) involved in this

mechanistic study were fully optimized in both THF and

toluene with the Polarizable Continuum Model (PCM) at the

B3LYP/6-31+G* level of theory. The reaction was initially mod-

elled with 3-formylchromone (I, 1k), methyl isocyanide (II) and

N-methylmaleimide (3b) in THF (Scheme 4). The reliability of

the method and basis set used was further confirmed with cal-

culations at the PCM-M06-2X/6-31+G** level in Gaussian 09

(see ESI Table S5†).

The computational data reveals that the driving force of the

reaction is undoubtedly the thermodynamic stability of the

final xanthone (VII), with an energy value 43 kcal mol⁻¹lower

than the initial multicomponent precursors. According to the

proposed mechanism, 3-carbonyl chromone (I) and isocyanide

Scheme 5 Calculated TS for the iminolactone-aminofuran tautomeri-

zation, without and with the participation of water molecules.

(II) react to produce the intermediate iminolactone (IVa), calculations leads to much lower transition states (TSVa (H₂O)

which is 8.5 kcal mol⁻¹less stable than the reactants and TSVa (2H₂O); Scheme 5) of 50.4 and 44.5 kcal mol⁻¹

,

(Scheme 4). In congruence with previous studies,¹⁹we found respectively. However, the activation barrier for the tautomeri-

that this step proceeds through a [4 + 1] stepwise cyclo- zation step is still 36 kcal mol⁻¹. This makes the tautomeriza-

addition, in which an activation energy of 30 kcal mol⁻¹must tion the rate limiting step of the overall process, and explains

be overcome to reach a first zwiterionic intermediate (III). This why heating is required for this reaction.

intermediate quickly reacts, crossing a small energy barrier of

We found an energy barrier of 23.1 kcal mol⁻¹for the [4 + 2]

cycloaddition of the aminofuran (V) and N-methylmaleimide

2.5 kcal mol⁻¹, to form the iminolactone ring (IVa).

To our surprise, tautomerization of the iminolactone (IVa) (3b), which is considerably lower than that found for the imino-

to the aminofuran (V) was shown to be a high-energy cost lactone-aminofuran tautomerization (Tables 7 and 8). Finally,

process, which should reach a TS (TSVa) of 83.2 kcal mol⁻¹all the attempts to find TSs for the opening of the oxygen

(see ESI†). In order for this process to be feasible, either sol- bridge and dehydration steps were unsuccessful. These two

vents or other molecules should necessarily participate in the transformations likely have low energy barriers and take place

transition state. Water released in the final dehydration step quite quickly due to the much higher stability of the final

may assist the hydrogen shift process aﬀording aminofuran xanthone (VII). Calculations using toluene instead of THF gave

(V). There is evidence that other similar tautomerism pro- similar energy values (Table 7).

cesses are assisted by either water or other solvent molecules.²⁰

An alternative pathway for the transformation of zwitter-

Indeed, the inclusion of one or two molecules of water in the ionic intermediate III into aminofuran V can also be envi-

Scheme 4 Reaction proﬁle for the multicomponent synthesis of xanthones (8), calculated at B3LYP/6-31+G* level of theory.

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Table 7 Energies of the principal transition states and intermediates calculated at B3LYP/6-31+G* level of theory^a

Chromone (I) & methyl

isocyanide (II)

TS_III

Zwiterion (III)

TS_IVa

Iminolactone (IVa)

TS_Va(2H₂O)

Aminofuran (V)

TS_VI

Xanthone (VII)

1k (THF)

1k (toluene)

1a

1i

1j

30.03

31.14

28.10

30.54

30.21

27.76

30.24

25.18

26.15

27.11

30.33

32.29

32.26

28.89

29.62

8.54

7.13

14.64

7.04

44.54

41.56

42.07

42.09

39.48

2.68

1.05

3.76

−0.26

−5.92

25.76

25.22

38.51

33.00

27.91

−42.96

−43.97

−35.65

−36.43

−36.38

4.24

^aCalculations were fully performed with Gaussian 16.

Table 8 Calculated energy barriers including the temperature thermodynamic eﬀect

Room temperature

Real temperature of reaction

Δ(TS_III-I&II) Δ(TS_IVa-III)

Δ(TS_III-I & (II)) Δ(TS_IVa-III)

Δ(TS_Va-IVa)

Δ(TS_VI-V)

Δ(TS_Va-IVa)

Δ(TS_VI-V)

Chromone

[4 + 1] step 1

[4 + 1] step 2 tautomerization Diels–Alder [4 + 1] step 1 [4 + 1] step 2 tautomerization Diels–Alder

1k (THF)

1k (toluene) 31.14

1a

1i

1j

30.03

2.56

2.05

7.08

2.75

2.51

36.01

34.42

27.43

35.06

35.24

23.08

24.17

34.74

33.26

33.84

31.51

34.25

28.10

32.01

31.71

2.73

2.53

7.08

2.97

2.82

38.92

40.50

27.43

37.97

38.18

24.84

28.01

34.74

35.25

35.80

28.10

30.54

30.21

sioned, considering the direct abstraction of the hydrogen in CO₂Me being out of the plane of the molecule. Also, the strong

chromone position 2 by the carbonylic oxygen (see ESI electron-withdrawing character of the substituent CO₂Me

Mechanism B, Scheme S1 and Table S2†). DFT calculations enhances the acidity of the hydrogen α to the imine group in

show that this alternative mechanism requires overcoming a IVa, facilitating the tautomerization. As a result, the activation

maximum energy barrier (TSIVb) of 48.3 kcal mol⁻¹, which is energy is only 27.4 kcal mol⁻¹, significantly lower than the

significantly higher than the 44.5 kcal mol⁻¹corresponding to barrier corresponding to the [4 + 2] cycloaddition. This is in

the higher energy transition state (TSVa (2H₂O)) in the first accordance with the experimental results, which demonstrate

proposed mechanism (see ESI†). Calculations also show that that the reaction with chromone 1a can take place at lower

this alternative TSIVb is not stabilized by water. Thus, the reac- temperature, between 25–35 °C. Furthermore, experimental

tion most probably occurs through the stepwise [4 + 1] cyclo- results with substituted methoxalylchromones (1a–e; Table 1)

addition leading to iminolactone IVa, followed by water-facili- show that electron-donating substituents on the aromatic ring

tated tautomerization to aminofuran V. Moreover, there are of the starting chromone seem to favor the reaction, which is

strong experimental evidences that support the mechanism via consistent with the rate-determining step being the [4 + 2]

the iminolactone-aminofuran tautomerization. These include cycloaddition in this case.

the isolation of related iminolactones reported in the litera-

ture²¹and the influence of added water in the reaction rate reach each of the successive transition states, including the

(see below). temperature thermodynamic eﬀect. The calculations show

Table 8 summarizes the activation energies required to

We also performed calculations with chromones substi- that, although aminofuran (V) is more stable in each case than

tuted with CO₂Me (1a), o-nitrophenyl (1i) and p-nitrophenyl its iminolactone counterpart (IVa), their interconversion

(1j) on the carbonyl group (Tables 7 and 8). The reaction coor- requires the assistance of water and it is still a rather slow

dinates are similar for each of the four examples. The acti- process. Tautomerization is thus the rate determining step in

vation energies for the [4 + 1] and [4 + 2] reactions are moder- all the cases, except for the reactions with methoxalylchro-

ate in each case, between 23–35 kcal mol⁻¹. The energy barrier mone (1a).

for the [4 + 1] cycloaddition is almost independent of the

On the other hand, a new rationale should be determined

nature of the substituent on the carbonyl group. On the con- for the synthesis of furochromones (14), as the mechanism

trary, the presence of electro-withdrawing groups in 1a,i–j showed in Scheme 3 is not compatible with the relatively short

results in significantly higher activation energies for the Diels– reaction times observed, considering the high energy barriers

Alder reaction (Tables 7 and 8).

for the aminolactone-aminofuran tautomerization.¹⁸The for-

The iminolactone-aminofuran tautomerization is the mation of furochromones (14) can thus be explained by a viny-

slowest step in most of the cases, with energy barriers around logous aldol addition²²of a second chromone molecule on the

35 kcal mol⁻¹. An exception is the reaction with chromone 1a, iminolactone (4), which implies that the aminofuran (5) does

in which intermediate IVa is destabilized by the substituent not even form (Scheme 6; cf. Scheme 3). The reaction may be

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2), and slightly lowered the yield from 71% to 69%. Similar

results were observed for the synthesis of xanthones 8bd

(Table 6, entry 9 and Table 9, entry 3) and 8bh (Table 6, entry

13 and Table 9, entry 4).

In order to evaluate the multicomponent synthesis of

xanthones toward the construction of more complex and natu-

rally occurring xanthone scaﬀolds, dimeric dihydroxanthone

18⁸and xanthone 19 were readily synthesized from commer-

cially available bisphenol (15). The common precursor bischro-

mone 17 was obtained by acetylation, acid catalyzed Fries

rearrangement,²³aldol condensation with dimethylformamide

dimethyl acetal and cyclization in the presence of 2-chloro-2-

oxoacetate (Scheme 7).

The reaction of bischromone 17, cyclohexyl isocyanide (2a),

and acrylonitrile (3e) under reflux in toluene successfully

aﬀorded dihydroxanthone 18 with a 55% yield over three

steps.⁸Similarly, when N-phenylmaleimide (3a) was substi-

Scheme 6 Mechanism for the synthesis of chromenylmethylene furo-

chromenones (14), based on computational studies.

catalyzed by external bases, such as water molecules or any tuted for acrylonitrile (3e), xanthone 19 was obtained with a

products or intermediates containing basic nitrogen atoms 79% yield (Scheme 7).

present in the reaction medium. Abstraction of the proton on

Interestingly, the new xanthones could be further trans-

C-3 of iminolactones and the subsequent addition of electro- formed into other polyheterocyclic molecules of biological

philes to C-5 in the presence of catalytic Lewis acid has been interest. For example, 1-aryl-substituted xanthones could be

reported by Chatani and co-workers.^21a

useful intermediates for the synthesis of chromenophenantri-

In congruence with theoretical calculations, the addition of dines, which are interesting materials for organic electronic

water to the reaction medium should facilitate the tautomeri- applications²⁴and have shown high eﬃcacy in tumor cell

zation reaction, speeding up the whole process. To probe this growth inhibition due to their telomeric DNA G-quadruplex

hypothesis, we performed some experiments in which 8 binding properties.²⁵

equivalents of water was added to the reaction of fomylchro-

Therefore, 1-(ortho-nitrophenyl)xanthones 8aq–as were

mones (1k,m), isocyanides (2a,b), and N-phenylmalimide (3a), readily reduced and cyclized with iron in acetic acid at 130 °C

either in THF or toluene. As expected, the reactions were sig- to give phenanthridine derivatives 20aq–as (Scheme 8).

nificantly quicker, but lower yields were usually obtained. This

These phenantridines were highly intense red fluorescent,

could be attributed to the formation of side products, as in contrast to precursor xanthones, which show yellow fluo-

observed on tlc, and a consequent more complicated work up rescence. They show distinctive IR bands at ca. 1700 and

and purification (Table 9; cf. Table 6). Thus, xanthone 8bb was 1750 cm⁻¹(20aq, 20ar) or 1740 and 1800 cm⁻¹(20as), charac-

obtained in only 6 h in refluxing toluene (Table 9, entry 1), teristic of maleimides and maleic anhydrides, respectively.

compared to the 41 h required in anhydrous conditions This supports that cyclization of the intermediate aniline takes

(Table 6, entry 3). However, the yield was reduced from 89% in place through the carbonyl of the chromone, and the maleic

anhydrous conditions to 63% in the presence of water. moiety remains unchanged. This was also confirmed by the

Analogously, in THF, the addition of water reduced the reac- loss in 20aq of the ¹³C-NMR signal at 180 ppm corresponding

tion time from 107 (Table 6, entry 2) to 6 hours (Table 9, entry to the chromone carbonyl in the starting material.

Table 9 Synthesis of xanthones 8 in the presence of added water

Entry

Chromone

R²

R³

Isocyanide

R⁴

T, °C

Solvent

Time, h

Product (yield, %)

1

2

3

4

1k

1m

1k

H

Me

H

2a

2b

c-C₆H₁₁

tBu

110

80

Toluene

THF

6

5

8bb (63)

8bb (69)

8bd (67)

8bh (50)

80

THF

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Scheme 7 Synthesis of dimeric xanthones 18 and 19.

pates in the transition state facilitating the hydrogen shift

process. Accordingly, water was experimentally shown to sig-

nificantly increase the rate of the reaction.

We have demonstrated the utility of this methodology for

the synthesis of biologically relevant chromenophenantridines

and dimeric xanthones and dihydroxanthones structurally

related to secalonic acid. These compounds, that otherwise

require long and complex syntheses, can be straightforwardly

obtained with high yields and selectivity.

Scheme 8 Synthesis of phenanthridines.

Experimental section

Computational details

Quantum chemical computations were carried out with the

Gaussian 16 series of programs.²⁶Full geometry optimizations

of stable species were performed in the appropriate solvent by

Conclusions

In conclusion, we have successfully designed a straightforward employing the hybrid density functional B3LYP²⁷with the 6-

multicomponent synthesis of xanthones and dihydrox- 31+G(d) basis set.²⁸The B3LYP functional combines the Becke’s

anthones. The highly convergent and atom economic process three-parameter nonlocal hybrid exchange potential with the

takes place in one-pot, in very mild conditions and with no nonlocal correlation functional of Lee, Yang, and Parr. The

need of catalysts. Theoretical calculations demonstrate that nature of the stationary points was verified by analytical compu-

the reaction occurs as an ordered sequence of a [4 + 1] step- tations of harmonic vibrational frequencies. The reliability of the

wise cycloaddition, iminolactone-aminofuran tautomerization, calculations were performed at M06-2X²⁹with the 6-31+G(d,p)

[4 + 2] cycloaddition, oxygen ring opening and aromatization. basis set. Solvent eﬀects were considered using the integral

Tautomerization is the rate-limiting step, and it has been equation formalism variant of the polarizable continuum model

shown to be possible only in the presence of water that partici- (IEF-PCM) with the Polarizable Continuum Model (PCM).³⁰

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Synthesis of chromones (1f–1j)

Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.53–7.50 (m, 2H), 7.45–7.39

(m, 5H), 6.77 (bs, 1H, NH), 4.27 (m, 1H), 3.19 (s, 3H), 2.13 (m,

2H), 1.84 (m, 2H), 1.67–1.25 (m, 6H) ppm; ¹³C NMR (101 MHz,

CDCl₃): 178.8 (C), 168.3 (C), 167.1 (C), 154.5 (C), 151.7 (C),

137.1 (C), 135.1 (CH), 131.8 (C), 131.6 (C), 129.1 (CH), 128.8

(CH), 128.3 (CH), 127.1 (CH), 126.8 (CH), 125.3 (CH), 125.0 (C),

123.0 (C), 122.6 (C), 117.3 (CH), 114.2 (C), 54.6 (CH),

34.9 (CH₂), 25.8 (CH₂), 24.9 (CH₂), 15.9 (CH₃) ppm; MS (CI)

m/z (%) 453 (M + 1, 39), 452 (M⁺, 13), 375 (22), 347 (93),

298 (100); HRMS (EI) Calcd for C₂₈H₂₄N₂O₄: 452.17361. Found:

452.1735.

3-Acetyl-4H-chromen-4-one (1f).³¹A solution of (E)-3-(di-

methylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 9a (214 mg,

1.16 mmol) in pyridine (1 mL) and two drops of piperidine

was cooled in an ice-bath and then acetic anhydride 10a

(1 mL, 9 mmol) was added dropwise. The reaction was let to

slowly reach the room temperature overnight and then it was

heated at 120 °C until the starting material was consumed

(2 hours). The residue was washed with saturated aqueous

brine (3 × 15 mL) and CuSO₄(3 × 15 mL) and extracted

with CH₂Cl₂(3 × 15 mL). The organic phase was dried over

Na₂SO₄and concentrated, and the crude was purified by

Dimethyl 4,4′-bis(cyclohexylamino)-1,1′,3,3′,10,10′-hexaoxo-

2,2′-diphenyl-1,1′,2,2′,3,3′,10,10′-octahydro-[8,8′-bichromeno

column

chromatography

(silica

gel,

hexane–EtOAc

[2,3-f]isoindole]-11,11′-dicarboxylate (19). Obtained as

a

gradient), giving the desired chromone 1f (129 mg,

59%), obtained as a white solid; mp: 128–132 °C (lit.³¹

125–128 °C).

yellow solid (79%); mp: 355 °C (dec); IR (cm⁻¹): 3455, 2929,

1

1762, 1701, 1664, 1614; H NMR (500 MHz, CDCl₃) δ 8.16 (s,

2H), 8.01 (d, J = 7.9 Hz, 2H), 7.59–7.42 (m, 11H), 6.78 (s, 2H),

4.34 (s, 2H), 4.18 (s, 6H), 4.12 (s, 1H), 2.15–1.30 (m, 20H) ppm;

¹³C NMR (126 MHz, CDCl₃): 175.1 (C), 167.7 (C), 166.8 (C),

164.7 (C), 154.2 (C), 148.8 (C), 138.7 (C), 136.2 (C), 134.4 (CH),

131.4 (C), 129.3 (CH), 128.4 (CH), 126.6 (CH), 124.2 (CH), 123.7

(C), 122.4 (C), 121.3 (C), 119.3 (CH), 118.2 (C), 112.6 (C), 54.4

(CH), 53.4 (CH₃), 34.4 (CH₂), 25.6 (CH₂), 24.5 (CH₂) ppm;

HRMS (ESI-ICP-Q-TOF) Calcd for C₅₈H₄₆N₄O₁₂H⁻: 989.3039.

Found: 989.3069.

3-(2-Nitrobenzoyl)-4H-chromen-4-one (1i).³²To a solution of

4H-chromen-4-one 11 (184 mg, 1.25 mmol) and o-nitrobenzal-

dehyde 12a (158 mg, 1 mmol) in dry methanol (0.5 mL),

sodium tert-butoxide (27 mg, 0.267 mmol) in methanol

(2.5 mL) was added dropwise under a nitrogen atmosphere.

Once the chromone 11 was consumed (72 hours), a solution of

HCl 1N (2 mL) was added to the reaction mixture. The solvents

were removed in the rotary evaporator, and the residue was re-

dissolved in ethyl acetate and washed with H₂O (3 × 15 mL).

The organic phase was dried over Na₂SO₄and concentrated,

and the resulting solid was washed with methanol and ethyl Synthesis of 8-(cyclohexylamino)-6-phenyl-5H-chromeno[4,3,2-

acetate, giving the Baylis–Hillman intermediate 3-(hydroxy(2- gh]pyrrolo[3,4-k]phenanthridine-5,7(6H)-dione (20aq)

nitrophenyl)methyl)-4H-chromen-4-one (196 mg, 66%), as a

white solid.

A solution of xanthone 8aq (25 mg, 0.044 mmol) and iron

(18 mg, 0.323 mmol) in acetic acid (1 mL) was heated at

A

solution

of

3-(hydroxy(2-nitrophenyl)methyl)-4H-

130 °C under nitrogen until the starting xanthone was con-

sumed (15 h). Then the organic phase was filtered over Celite,

and washed with NaOH 2 M (3 × 20 mL), dried over Na₂SO₄

and purified by chromatographic column (gradient

AcOEt : hexane) yielding the desired product 13aq

(12 mg, 54%), obtained as a red solid; mp: 190 °C; IR (cm⁻¹):

3423, 2924, 2849, 1745, 1693, 1586; ¹H NMR (500 MHz,

CDCl₃) δ 9.82 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 7.9 Hz, 1H), 7.85

(d, J = 8.0 Hz, 1H), 7.58–7.41 (m, 8H), 7.30 (t, J = 7.1 Hz, 1H),

7.15 (bs, NH, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.17 (m, 1H), 2.16

(m, 2H), 1.86 (m, 2H), 1.60–1.38 (m, 6H) ppm; ¹³C NMR

(101 MHz, CDCl₃): 168.9 (C), 166.8 (C), 152.3 (C), 145.9 (C),

144.9 (C), 144.7 (C), 134.6 (C), 132.4 (CH), 131.9 (C),

129.9 (CH), 129.4 (CH), 129.2 (CH), 128.9 (CH), 128.3 (CH),

127.1 (CH), 126.4 (CH), 125.6 (CH), 125.2 (CH), 124.3 (C), 122.3

(C), 121.0 (C), 119.0 (C), 118.4 (C), 117.8 (C), 116.6 (CH),

54.1 (CH), 35.1 (CH₂), 25.8 (CH₂), 24.9 (CH₂) ppm; MS (CI) m/z

(%) 513 (M + 2, 33), 512 (M + 1, 59), 511 (M⁺, 41), 478 (14),

350 (10); HRMS (EI) Calcd for C₃₃H₂₅N₃O₃: 511.1896. Found:

511.1892.

chromen-4-one (96 mg, 0.38 mmol) and MnO₂(667 mg,

7.7 mmol) in CH₂Cl₂(6 mL) was stirred at room temperature

under a nitrogen atmosphere until the starting material was

consumed (1.25 hours). Then the mixture was filtered over

Celite, washing with CH₂Cl₂(20 mL), and the organic residue

was evaporated, giving a white solid, which was washed with

cyclohexane aﬀording 1i (103 mg, 92%).

General procedure for the synthesis of xanthones (8a–bk)

Isocyanide 2a–g (1.2 mmol) and dienophile 3a–f (1.2 mmol)

are successively added to a solution of chromenone 1a–m

(1 mmol) in the appropriate solvent (2 mL). The resulting

mixture is stirred at the appropriate temperature under a nitro-

gen atmosphere until the chromone (1) is consumed. HCl 1 N

(2 mL) is then added to the reaction mixture, and after

30 minutes, the crude is washed with brine (15 mL), and

extracted with CH₂Cl₂(3 × 15 mL). The organic phase is dried

over Na₂SO₄and concentrated. The resulting residue is puri-

fied by column chromatography (silica gel, hexane–EtOAc

gradient), giving the desired product 8.

4-(Cyclohexylamino)-11-methyl-2-phenylchromeno[2,3-f]iso-

indole-1,3,10(2H)-trione (8ak). Obtained as a yellow solid

Conﬂicts of interest

(95% yield); mp: 214 °C; IR (cm⁻¹): 3430, 2922, 2853, 1754,

1

1694, 1656, 1611; H NMR (500 MHz, CDCl₃): δ 8.28 (d, J = 8.0 There are no conflicts to declare.

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16 A. Bornadiego Suárez, PhD thesis, University of

Extremadura, 2016.

Acknowledgements

We thank financial support from Junta de Extremadura and 17 M. B. Teimouri and S. Mohammadnia, Tetrahedron, 2018,

FEDER (IB16095). We are also grateful to CenitS and 74, 1767.

COMPUTAEX for allowing us the use of supercomputing 18 A. G. Neo, L. Garrido, J. Díaz, S. Marcaccini and

facilities.

C. F. Marcos, Synlett, 2012, 23, 2227.

19 Y. Wu, K. Xu and D. Xie, Tetrahedron, 2005, 61, 507.

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Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction

DOI: 10.1039/C8OB02527D

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