hetero cyclic

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Aminonaphthoquinones in heterocyclization

Journal: Journal of Heterocyclic Chemistry

Manuscript ID: JHET-10-0270.R1

Wiley - Manuscript type: Reviews

Date Submitted by the Author:

16-Jul-2010

Complete List of Authors: Aly, Ashraf; El-Minia University, Chemistry

Keywords: Aminonaphthoquinones, biological activities, synthesis, heterocyclization

John Wiley & Sons

Journal of Heterocyclic Chemistry

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Aminonaphthoquinones in heterocyclization

Ashraf A. Aly,ab* Esam A. Ishakc, Musaed A. Alsharari,b

Nayef S. Al-Muaikel,d and Tarek M. I. Bedaira

a Chemistry Department, Faculty of Science, El-Minia University, 61519-El-Minia, Egypt b Chemistry Department, College of Science, Al-Jouf University, Al-Jouf, Sakaka, Saudi Arabia

c Chemistry Department, Faculty of Science, El-Azhar University, Assiut, Egypt d Chemistry Department, College of Pharmacy, Al-Jouf University, Al-Jouf, Sakaka, Saudi Arabia

Corresponding Author: Prof. Ashraf A. Aly; E-mail: [email protected].

O

O

NH2

O

O

NH2

NH2

Heterocyclization process

Abstract: Due to the interesting biological activities of aminonaphthoquinones, in this review we survey two classes of amino-1,4-naphthoquinones: 2,3-diamino-1,4-naphthoquinone and 2-amino-1,4-naphthoquinone. The review includes synthetic methodologies for these classes in addition to their heterocyclization processes.

Keywords: Aminonaphthoquinones, biological activities, synthesis, heterocyclization.

Table of Contents Introduction Discussion 1. 2,3-Diamino-1,4-naphthoquinone and its derivatives 1.1. Synthesis 1.2. Reactions 1.2.1. Substitution reaction 1.2.2. Synthesis of imidazoles 1.2.3. Synthesis of thia- or selena-diazole derivatives

1.2.4. Synthesis of fused pyridine derivatives 1.2.5. Synthesis of quinoxalinediones 1.2.6. Synthesis of diazepine derivatives

2. Chemistry of 2-amino-1,4-naphthoquinone 2.1. Synthesis 2.2. Reactions 2.2.1. Substitution reactions 2.2.2. Synthesis of pyrroles 2.2.3. Synthesis of azepines 2.2.4. Synthesis of indoles 2.2.5. Synthesis of quinoline derivatives 2.2.6. Synthesis of 1,4-dihydropyridines

2.2.7. Synthesis of oxazine, terahydrobenzo[g]chinazoline and pyridoacridines derivatives References

1. Introduction

Naphthoquinones are widely distributed in plants, fungi, and some animals. Their biological activities have been studied including their effects on prokaryotic and eukaryotic cells. [1,2] Plumbagone, juglone and lawsone are naturally occurring naphthoquinones of plant origin that have antibacterial effects on several species of both aerobic and anaerobic organisms, [3] and toxins derived from naphthazarin (5,8-dihydroxy-1,4- naphthoquinone) are produced by Fusarium solani and attack plants, other fungi and bacteria. [4] The natural naphthoquinone products alkannin and shikonin and their derivatives, in general, are active against Gram-positive bacteria such as Staphylococcus

aureus, Enterococcus faecium, and Bacillus subtilis, but are inactive against Gram-negative bacteria. [5] 2,3-Diamino-1,4-naphthoquinone itself was found to act as an antibacterial agent against S. aureus, with IC50 values ranging from 30 to 125 µg/mL. 2,3-Diamino-1,4-naphthoquinone presented a minimal bactericidal concentration higher than 500 µg/mL, indicating that its effect was bacteriostatic. [6]

Carnivorous plants have evolved special mechanisms for trapping insects and consuming their components when grown under harsh conditions. [7] Carnivory is also characterized by the synthesis of secondary metabolites in the insect-trap tissues, which contain the aminonaphthoquinone moiety. [8] The synthesis of protecting secondary metabolites is very common in

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Ashraf A. Aly, Musaed A. Alsharar, Esam A. Ishak,

Nayef S. Al-Muaikel, and Tarek M. I. Bedair

many plants and occurs in response to chemical, biotic or

physical stress. [8-10] Aminonaphthoquinones, considered to be potential antifungal drugs, are also produced by many plants that belong to the Caryophyllales families, [8] including Nepenthaceae. [11] Droseraceae, [12] Plumbaginaceae, [13] Drosophyllaceae, [14]

and Ebenaceae. [15] In vitro assays showed that several 2,3-di-substituted 1,4-naphthoquinones are as effective as the clinically used antifungal drugs Fluconazole and Amphotericin-B. [16] In addition, the 4-aminoquinolines (chloroquine [CQ] for adults/amodiaquine for children) have been used as the first-line anti-malarial drugs for many years. However, the therapeutic efficacy of the 4-aminoquinolines, particularly of chloroquine, has declined over the years [17] since the mid-70's. [18]

Malaria is a major tropical disease, which kills two million people annually. Since antimalarials are the major arsenal for treatment of the disease, there is an urgent need for newer drugs with novel mechanisms of action, which will be effective against all strains of the parasite. Several synthetic and natural naphthoquinones as potential antimalarial agents have identified aminonaphthoquinones, as a class of antimalarial compounds with antimalarial activity against Plasmodium falciparum. Among these compounds, 2-amino-3-chloro-1,4-naphthoquinone is the most potent. It had an IC50 of 0.18 micro M (37.3 ng ml (-1)) against the W2 clone, and is more potent than chloroquine, which had an IC50 of 0.23 micro M (72 ng ml (-1). It was also active against the D6 clone. In general, 2-amino-1,4-naphthoquinone analogs and the 4-amino-1,2-napthoquinone analog showed promising antimalarial activity in the bioassay. In contrast, a number of 2-hydroxy-1,4-naphthoquinones and dimeric quinones were less active. [19]

The synthesis and investigation of tumor-inhibitory activity of a series of aminonaphthoquinone derivatives of diospyrin (a bisnaphthoquinone), which was isolated from Diospyros

montana Roxb., have been reported. [20] An aminoacetate derivative showed the maximum ( 93%) increase in life span in vivo against murine Ehrlich ascites carcinoma (EAC) at a dose of 1 mg kg−1 day−1 (ip; five doses), and the lowest IC50 (0.06 µM) in vitro. Further, the same analogue also exhibited considerable enhancement in antiproliferative activity when evaluated against human cell lines, viz. malignant skin melanoma and epidermoid laryngeal carcinoma (IC50 = 0.06 and 0.92 µM, respectively) in comparison to the natural precursor, diospyrin (IC50 = 0.82 and 3.58 µM, respectively). Moreover, diospyrin and all its derivatives were found to show significantly greater ( 17- to 1441-fold) cytotoxicity against the tumor cells as compared to normal human lymphocytes. All these quinonoids generated substantial amounts of reactive oxygen species in EAC cells, more or less commensurate to their respective IC50 values. [20]

Previously, Aly et al [21] investigated the reaction of 1,8-

diaminonaphthalene (1) (as a structural resembled analogous to 2,3-diamino-1,4-naphthoquinone) with π-acceptors. Various heterocyclic compounds were obtained during the addition of compound 1 to 1,1,2,2-tetracyanoethylene (TCNE, 2), 7,7',8,8'-tetracyanoquinodimethane (TCNQ, 3), 2-dicyano-methyleneindane-1,3-dione (CNIND, 4), 2-(2,4,7-trinitro-9H-

fluoren-9-ylidene)propane-dicarbonitrile (DTF, 5), 2,3,5,6-tetrachloro-1,4-benzoquinone (CHL-p, 6a) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 6b) (Figure 1). [21] Although most of the examples herein involve cyclization reactions of aminonaphthoquinones, a few of these expected novel syntheses of heterocycles have been reported. So, it is of interest to report on the vital target class of compounds. [21]

NH2NH2

CN

CNNC

NC CN

CN

NC

NC

O

O

CN

CN

NCCN

NO2

O2N

NO2

O

O

X

X

Cl

Cl

1

23 4

56a,ba, X = Clb, X = CN

Figure 1

2. Discussion

In the light of the aforementioned interesting biological activities of aminonaphthoquinones, our attention is turned to the synthesis of 2,3-diamino-1,4-naphthoquinone and 2-amino-1,4-naphthoquinone. Additionally, we report on the utility of these two substances in heterocyclization.

1. 2,3-Diamino-1,4-naphthoquinone

1.1. Synthesis

1.1.1. Reaction of 2,3-dichloro-1,4-naphthoquinone (7) with two equiv of sodium azide produced in good yield the diazido derivative 8, [22] which was reduced with Na2S2O4 to give the compound 9 (Scheme 1). [23,24]

O

O

Cl

Cl

O

O

N3

N3

O

O

NH2

NH2Na2S2O4NaN3

7 8 9

Scheme 1

1.1.2. Díaz et al used the published procedure [25] of the synthesis of intermediated compounds 10-12 (Scheme 2). [25]

Thereafter addition of hydrochloric acid gas in methanol to 12 produced the corresponding salt of compound 9 as shown in Scheme 2. [25]

O

O

710

11

Cl

Cl

NHCOCH3

O

O

NH2

CH3COClNH3(gas)NH3(gas)

Ethanol

Methanol

HCl(gas)

1,4-Dioxan

12

NHCOCH3

O

O

Cl

NH2

O

O

NH2

9

O

O

NH2

Cl

.HCl

Scheme 2

1.1.3. Winkelmann [26] reported that reaction of compound 7 with two equiv of potassium phthalimide proceeded to afford

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diphthalimido naphthoquinone 13, which was allowed to react with hydrazine hydrate to give compound 9 (Scheme 3). [26]

O

O

Cl

Cl

O

O

X

X

H 2N -N H 2X -K

N

O

O7 13

9

X =

Scheme 3

1.2. Reactions

1.2.1. Substitution reaction

1.2.1.1. Treatment of 2,3-diaminonaphthalene-1,4-dione (9) with benzoyl chloride in chloroform afforded N-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzamide (14; Scheme 4). [27]

O

O

NH2

NH2

Cl

O

+CHCl3

O

O

NHCOPh

NH2

20 oC, 30 min

9 14

Scheme 4

1.2.1.2. Similarly, reaction of compound 9 with ethyl chloroformate afforded ethyl 3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-ylcarbamate (15, Scheme 5). [28]

O

O

NH2

NH2

ClCO2EtCHCl3

O

O

NHCO2Et

NH2

+ref lux, 2 h

9 15

Scheme 5

1.2.1.3. Reaction of compound 9 with diethyl 2-

(ethoxymethylene)-malonate gave in good yield tetraethyl 2,2'-(1,4-dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(azanediyl)bis-(methan-1-yl-1-ylidene)-dimalonate (16) as shown in Scheme 6. [29]

O

O

NH2

NH2

CHC

EtOOC

EtOOC

OC2H5

O

O

HN

NH

CH

CH

C(COOEt)2

C(COOEt)2

+

916

Scheme 6

1.2.1.4. Heating of compound 9 in acetic anhydride for 2 h produced 1,4-dioxo-1,4-dihydro-naphthalene-2,3-diyl)-diacetamide (17) as shown in Scheme 7. [28]

Ac2O

O

O

NHCOCH3

NHCOCH3160 oC, 2 h

17

9

Scheme 7

1.2.1.5. Benzoylation of compound 9 was achieved by refluxing 9 with two equivs of benzoyl chloride in p-xylene for 2 h. The dibenzoyl product of 9, identified as N,N'-(1,4-dioxo-1,4-dihydronaphthalene-2,3-diyl)dibenzamide (18), was obtained in good yield (Scheme 8). [30]

xylene, ref lux

O

O

NHCOPh

NHCOPh

+2 h

9

18

2 PhCOCl

Scheme 8

1.2.2. Synthesis of imidazoles

1.2.2.1. Compound 9 reacted with potassium xanthogenate to give 2-thioxo-2,3-dihydro-1H-naphtho[2,3-d]imidazole-4,9-dione (19). Various 2-(2-oxoalkylthio)-1H-naphtho[2,3-d]-imidazole-4,9-diones 20 were obtained by the reaction of 19 with α–halo carbonyl compounds as shown in Scheme 9. Eleven examples were described. [30]

EtOH

O

O

NH

HN

SR1-CH(Cl)C(=O)R2

O

O

NH

N

SCHCR2

O

R1

CS2, KOH9

1920

Scheme 9

1.2.2.2. Reaction of compound 9 with diethyl 2-benzylidenemalonate (21) afforded 2-phenyl-1H-naphtho[2,3-d]imidazole-4,9-dione (22a) as shown in Scheme 10. [29]

CH

EtO2C

EtO2C

Ph

O

O

NH

N

Ph+

22a21

9

Scheme 10

1.2.2.3. Imidazole 22a was also obtained via the reaction of 2-amino-3-benzoylamino-1,4-naphthoquinone (14) with alcoholic KOH for 3 h (Scheme 11). [30]

O

O

NHCOPh

NH2

O

O

NH

N

PhKOH

14 22a

Scheme 11

1.2.2.4. On refluxing a mixture of compound 9 in formic acid for 2 h, the reaction afforded in poor yield 1H-naphtho[2,3-d]imidazole-4,9-dione (23) as shown in Scheme 12. [30]

O

O

NH

NHCOOH9

23

+reflux

2 h

Scheme 12

1.2.2.5. Aly et al. [31] have recently reported that imidazoles

derived from compound 9 were easily directly prepared by addition of stoichiometric quantities of the appropriate aldehydes in dimethyl sulfoxide as a solvent as shown in Scheme 13. [31] The reaction proceeds, in few hours. to give mono- and bis- imidazoles 22a-g, 25 and 26. That procedure can be generalized to different classes of aldehydes. 2-Methyl-1H-

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naphtho[2,3-d]imidazole-4,9-dione (24) was also obtained, by refluxing in acetic acid. [31]

OH C-R

O

O

NH

N

RDM SO

O

O

NH

N

C H 3

C H 3C O OH

O HC CH O

O

O

NH

N

D M S O

O

O

NH

N

NH

N

O

O

O HC

CH O

H N

N

O

O

9 +

22a-g24

2625

a : R = C 6H 5- (85% ) ; b : R = 4-H 3C -OC 6H 4- (90% ) , c : R = 4-C l- C6H 4- (80% ); d : R = 3 ,4 - O-C H 2 -O C 6H 3 - (94% ) ; e : R = 2-F ury l (76% )and f : R = 4-[ 2 .2 ]Pa racyclophany l (74% )

Scheme 13

1.2.3. Synthesis of thia- or selena-diazole derivatives

1.2.3.1. Compound 9 reacted with thionyl chloride or selenium oxychloride to afford the corresponding thia- or selenadiazole derivatives 27a,b as shown in Scheme 14. [32] Either compound 27a and/or 27b can then be condensed with substituted hydrazines and/or hydroxylamine hydrochloride to give compound 28a,b and/or 29 (Scheme 14). [32]

XOCl2

O

O

NX

N

N

N

NX

N

OH

OH

RNHNH2 (R = H, Ts)

O

N

NX

N

NH

R

9

27a: X = S27b: X = Se

28a,b

29

H2NOH.HCl

Scheme 14

1.2.4. Synthesis of fused pyridine derivatives

1.2.4.1. Synthesis of Discorhabdin C A model study designed for the total synthesis of Discorhabdin C (30) is presented (Figure 2). The key reaction is the para alkylation of the phenolate derived from the dibromomesyloxy phenol 31. The desired product 32 (Figure 2) contains the tetrayclic aza-spirobicyclic system present in this class of marine alkaloids. [33]

O

O

HN

H 3CO

B r

B r

HO

O

O

NH

O

BrBr

N

O

NH

O

BrBr

NH

30

31

32

Figure 2

1.2.4.2. Synthesis of 1-aza-anthraquinones A series of 1-aza-anthraquinones 34 were characterized, besides the expected N-alkylamino derivatives 35, from the

substitution reactions of 2-methoxylapachol (33) with primary amines. An investigation of the reaction conditions allowed reasonable selectivity in the products distribution (Scheme 15). [34]

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5

O

O

NH R 1

O

O

O C H 3

p r im a ry am in es

O

O

R 1N

+

3435

3 3

Scheme 15

1.2.5. Synthesis of quinoxalinediones

1.2.5.1. Interestingly, reaction of 9 with oxalyl chloride afforded the tetralone, which directly reacted with thionyl chloride to give the dichloride followed by Gabriel reaction to obtain compound 36, which was directly reacted with thionyl chloride, to yield compound 37a. The reaction of 36 with selenium oxychloride produced compound 37b as shown in Scheme 16. [35]

O

O

NH2

NH2

(COCl)2

O

O

HN

NH

O

O

O

O

N

N

Cl

Cl

SOCl2

NK

O

O

O

O

N

N

NH2

NH2

O

O

N

N N

X

N1)

2) H2N-NH2.H2O

SOCl2 orSeOCl2

36 37a,b

9

37a: X = S37b: X = Se

Scheme 16 1.2.5.2. Condensation of compound 9 with 1,4-dibromobutane-2,3-dione led to 2,3-bis(bromo-methyl)-benzo[g]quinoxaline-5,10-dione, [36] which was converted to compound 38 by classical chlorination using lithium chloride as illustrated in Scheme 17. [36]

O

O

NH2

NH2

O

O

Br

Br

O

O

N

N

Br

Br

LiClO

O

N

N

Cl

Cl

+1,4-Dioxan

9

38

Scheme 17

1.2.5.3. Reaction of compound 9 with α-dicarbonyl compounds afford 2,3-disubstituted benzoquinoxaline-5,10-diones 39 as shown in Scheme 18. [36]

O

O

R 2

R 1

O

O

N

N R 1

R 2

+

R1 = R 2 = HR1 = R 2 = - C6H 5R1 = R 2 = - CH 3R1 = R 2 = - O H3 9

9

Scheme 18

1.2.5.4. It was reported that refluxing of compound 9 with 1,2-di(1H-pyrrol-2-yl)ethane-1,2-dione (40) in glacial acetic acid for 12 h afforded 2,3-di(1H-pyrrol-2-yl)benzo[g]-quinoxaline-5,10-dione (41) as illustrated in Scheme 19. [37] Refluxing of 9 with naphthalene-1,2-dione (42) in 10% acetic acid for 2-3 h gave dibenzo[a,i]phenazine-8,13-dione (43, Scheme 19). [37] Similarly reaction of 9 with phenanthrene-9,10-dione (44) produced tribenzo[a,c,i]phenazine-10,15-dione (45, Scheme 19). [37] Benzo[i]dipyrido[3,2-a:2',3'-c]phenazine-10,15-dione (47) can be obtained from the reaction of 9.HCl with 1,10-phenanthroline-5,6-dione (46) in refluxing ethanol for 1.5 h (Scheme 19). [37-39]

O

O

N H 2

N H 2 O

O

H N

HN

O

O

N

N

H N

HN

A cO H+

12 h

9

4140

O

O O

O

N

N

O

ON

N

O

O

910% A cO H

4543

10% AcO H

42 44

N

N

O

O

O

O

N

N

N

N

R ef lux 1 .5 h

47

46

Scheme 19

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1.2.5.5. It was indicated that different aromatic aldehydes can react with 2,3-diamino-naphthalene-1,4-diol to yield 2,3-disubstituted 1,2,3,4-tetrahydrobenzo[g]-quinoxaline-5,10-diones 48 as shown in Scheme 20. [40]

O H

O H

NH 2

NH 2

+ C

O

H R (R ')

O H

O H

N

N

CH R

C H R'+

O H

O H

N

N

CH R

C H R'

O H

O H

N

N HR

R '

HNH

HN

O

O

HR

HR '

2H 2O

48

Scheme 20

1.2.5.6. Katritzky [41] and his group reported that the reaction of compound 9 with 2,3-dichloro-naphthalene-1,4-dione (7) in

absolute ethanol afforded dibenzo[b,i]phenazine-5,7,12,14(6H,13H)-tetraone (49) as shown in Scheme 21. [41]

O

O

Cl

Cl

O

O

HN

NH

O

O

+

7

9

4 9

eth an o lr ef lu x1 0 h

Scheme 21

1.2.6. Synthesis of diazepine derivatives

1.2.6.1. Compound 9 reacted with various derivatives of diethyl malonate to afford condensed products, which in the presence of potassium hydroxide gave 3-substituted 1H-naphtho[2,3-b][1,4]diazepine-2,4,6,11(3H,5H)-tetraones 50 as illustrated in Scheme 22. [27]

E tO 2CC H R

E tO 2C+

O

ON H 2

HN

O

C HR

E tO 2CNH

H C

HN

R

O

O

O

O

K O H9

eth a n ol

5 0R = C 6H 5 , p -to ly l, p -a nisy l , p - C l- C 6H 4

Scheme 22

1.2.6.2. A rapid route to a series of naphthoquinone-fused indole derivatives 51 (Figure 3) via irradiation in a modified commercial domestic microwave was reported. [42] The desired products were produced in high yields and short reaction times. The naphthoquinone-fused indole derivatives 51 were evaluated for their pro-inflammatory cytokines responses using lipopolysaccharide (LPS)-stimulated RAW264.7 marine macrophages. The results showed that most of the tested compounds inhibit the production of nitric oxide (NO), prostaglandin (PG)E2, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in RAW264.7 cells treated with LPS. [42]

R1

O

O

N

R3

HN

R2R1 = R2 = H, OCH3R3 = H, CH3, C3H7, Allyl, Bn

51

Figure 3

1.2.6.3. Reaction of 2,3-bis(arylamino)naphthalene-1,4-diones 52 (1 equiv), aldehydes (1.1 equiv) and BF3.Et2O (2 equiv) in acetonitrile afforded the diazepine derivatives 53 and 54 (Scheme 23). [43] The reaction involves the formation of iminium ion intermediates, followed by cyclization to produce seven-membered rings (Scheme 23). Thirteen examples were described. [43]

O

O

N H

N H

R 1

R 2

R 3C HO

O

O

N H

N R 3

R 1

R 2

O

O

N

N H

R 3

R 2

R 1

O

O

HN

NR 3

O

O

N

NH

R 3

R 1

+

R 2

R 1

R 2

BF 3.E t2OCH 3 CN , r.t.

53

5452

Scheme 23

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2. Chemistry of 2-amino-1,4-naphthoquinone

It was previously reported that the nucleophilicity of the amino group in 55 is greater than expected for its vinylogous amide structure. Thus, 2-amino-1,4-naphthoquinone (55) reacts as an N-nucleophile with some bis-electrophiles. [44] On the other hand, Michael addition between 55 and activated unsaturated bonds is differed from those generally found in β-imino-α,β-unsaturated carbonyl compounds. [45] These results indicate that the mesomeric interaction between the nitrogen lone pair and the C=O group in 55 is not very important and,

consequently, C-alkylations proceeding on the enol tautomer 55'

(Figure 4) through the electronic interaction of the lone pair on the nitrogen atom with the quinoid structure, are less favored than in related systems. The mesomeric effect explains the shift of the E1/2 value of 55 (at pH 7.0) of ca. 225 mV to more negative potential, as compared with unsubstituted naphthoquinone. [46] However, this value might be also explained by a hydrogen bond interaction between the C1=O and NH2 groups, stabilizing the quinoid form (55'', Figure 4). [47]

O

O

N H 2

O

O

NH 2

O H

O

NH

H

O

O

N H

55

5 5 '

5 5 ''

Figure 4

For instance, the intramolecular N-acylation of some aminoquinones has required their prior reduction to the more basic aminonaphthohydroquinone derivatives. [48,49] Lately, 2-amino-1,4-naphthoquinone (55) has been shown to have some reactivity with some electrophiles such as β-dielectrophiles, [50]

and methyleniminium salts (Figure 5). [50] In these reactions, the principal product was found to be that of N-alkylation. The reaction of 55 with electrophiles follows the general sequence

outlined in Figure 5. The reaction follows path "a" leading to N-

alkylated product 57 or path "b" leading to C-alkylated product 58. In these reactions, the principal product was found to be that of N-alkylation. The reaction of 55 with electrophiles follows the general sequence outlined in Figure 5. [51]

O

O

NH2

O

O

NH2

E

O

O

NH

E

O

O

NH2

O

O

NH2

EH

O

O

NH2

E

55

E

path a- H

E

path b

- H

57

5856

Figure 5

2.1. Synthesis

2-Amino-1,4-naphthoquinone (55) can be prepared by the reaction of naphthoquinone (59) with hydrazoic acid at 0 oC for about 5-15 min. Compound 59 is first reduced by hydrazoic acid to the corresponding hydroquinone 60 (Scheme 24). The obtainable 2-azidohydroquinone 61, which is in equilibrium

with its keto form (61a 61b), is unstable and is converted to 2-aminonaphthoquinone (55) or 2-azidonaphthoquinone (62), depending on the reaction conditions as shown in Scheme 24. [52] The mechanism of the formation of 2-amino-naphthoquinone is illustrated in Scheme 25. [52]

O

O

HN3

H

OH

OH

N3

H

O

OH

N3

OH

OH

N3

O

O

N3

O2

O

O

NH2

O

O

N3

fast

slow

Ar, H

fast

slow59 60

61b

55

62

61a

Scheme 24

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O

O

N N N

O

O

N N N

H

O

O

NH

N N

- N2

O

O

NH

O

O

NH2

- H

Scheme 25

2.2. Reactions

2.2.1. Substitution reactions

2.2.1.1. Reaction of formaldehyde with 2-amino-1,4-naphthoquinone (55) in chloroform at rt gives exclusively N-(hydroxymethyl)aminoquinone (63) in 64% yield (Scheme 26). [51] There is no observed product corresponding to nucleophilic substitution at C-3 (compound 64). This means that 55 did not act as an enamine compound and the reaction follows path "a" in Scheme 26. [51]

O

O

NH2

O

CH H O

O

NH

OH

O

O

NH2

OH

55

63

64

Scheme 26

2.2.1.2. Reaction of 55 with simple aldehydes and ketones under neutral conditions gave N-(alkenyl)-aminoquinones 65a-d in 45-56% yield (Scheme 27). Four examples were described. [51]

O

O

NH2

OCH HR1R2

O

O

NH

R1

R255

+

65a-d

Scheme 27

2.2.1.3. Reaction of 2-dimethylamino-1,4-naphthoquinone (66a) with two equivs of cyano-methylenetriphenylphosphorane afforded the adduct 67, which was obtained through an internal elimination of triphenylphosphine from the intermediate (B) (Scheme 28). [53]

O

O

NCH3

CH3

CHCNPh3P

O

O

NCH3

CH3

CHCNH

PPh3

CHCNPh3P+

OH

O

NCH3

CH2

HC

H

HC

CN

PPh3

CN

OH

OH

N CH3

CH3

C CH

CN CN

(B)

+

- TPP - TPP

67

66a

Scheme 28

2.2.1.4. Previously Bestmann et al reported that the reaction of 2-anilinophenyl-1,4-naphthoquinone (66b) with benzylidenetriphenylphosphorane (68a) yielded the respective quinonemethide 69 and triphenylphosphine oxide (Scheme 29). [54]

O

O

HN C6H5

HC

O

HN C6H5

C6H5

Ph3POC PPh3Ph

H+ +

68a 6966b

Scheme 29

2.2.2. Synthesis of pyrroles

2.2.2.1. Reaction of one equiv of 2-substituted amino-1,4-naphthoquinones 66b,c,d with two equivs of the phosphonium ylide 68b,c afforded the phosphorane adduct 70a-f in good yield along with triphenylphosphine oxide (Scheme 30). [53]

O

O

NHR1

C PPh3R

H

O

CHR

NO

PPh3

R1

66b: R1 = C6H5

66c: R1= CH366d: R1 = C2H5

+

68 b, R = R2CO, R2 = CO2CH3c, R = R2CO, R2 = CO2C2H5

70a, R = CO2CH3; R1 = C6H5b, R = CO2C2H5; R1 = CH3c, R = CO2CH3; R1 = C2H5

d, R = CO2C2H5; R1 = C6H5e, R = CO2CH3; R1 = CH3

f , R = CO2C2H5; R1 = C2H5

Scheme 30

Mechanistically, quinone 66b-d reacted with 1 mol of ylide 68 to give triphenylphosphine oxide (TPPO) and the reactive olefinic intermediate (A) via a 1,2-addition, which reacted with another molecule of ylide 68 to afford the cyclic phosphorane adduct B, through loss of a suitable moiety (i.e. R ). That was followed by autoxidation to attain the aromaticity and therefore compounds 70a-f were formed (Scheme 31). [53]

O

O

NHR1

(C6H5)3P CHR

O

CHR

NHR1

O

CHR

NHR1

C

PPh3

O

R2H

Ph3PO +(C6H5)3P CHCOR2

O

CHR

N

R1

R2

OPPh3

H

66

70a-fAutoxidation

A B

H - R2H

68

Scheme 31

2.2.2.2. Reaction of 2-aminonaphthoquinones 66a-d with active methylene compounds (2 equivs) in the presence of manganese(III) acetate in acetic acid for 2 h afforded compounds 71 in not bad yields (Scheme 32). [54]

O

O

NR1

H

R2

EE

Mn(OAc)3

O

O

N

R1

O

ER2

+

66a-d 71E = CO2Et

Scheme 32

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The proposed mechanism for the formation of 71 is outlined in Scheme 33. The addition of malonyl radical 72 to quinone ring followed by oxidation gives 73, which undergoes lactamization to produce 71 (Scheme 33). [55]

Mn(OAc)3

Me

E E

O

O

N

E E

Me

H

Tol

Mn(III)

O

O

N

E E

Me

H

Tol

66

72

66

73

71

R2

EE

Scheme 33

2.2.2.3. Chuang et al indicated that upon treatment of 2-(ethylamino)-1,4-naphthoquinone (66d) with 2,4-pentanedione and manganese (III)acetate under similar conditions, compound 76a was obtained in 65% yield and other by-cyclized products 77 and 78 (Scheme 34). [56] Oxidation of the β-keto ester by manganese(III) acetate gives radical 79. Addition of the radical intermediate to the quinone ring, followed by oxidation, gives 80 (Scheme 35). [56] Compound 80 underwent condensation to produce 76 (path a). With larger R5, 80 undergoes either condensation to generate 76 (path a) or oxidation to produce

radical 81. Radical 81 undergoes either cyclization with (R = H, Me, i-Pr) to give 82, followed by alkyl group migration and oxidation to produce 77 (path b) or oxidation (with R = p-tolyl) by manganese(III) acetate to produce imine 84. Imine 84

underwent further intramolecular nucleophilic addition followed by retro-Claisen condensation and oxidation to produce 78 (Scheme 35). [56] The free radical mechanism might here explained the rather difficulty arises in Scheme 35, where an ethyl group on the nitrogen in 81 somehow becomes a propylidene group (in 84), thereafter becoming entangled with the incoming diacylmethyl group, the ethyl group eventually winding up on C(2) (85 →78) (Scheme 35). [56] The proposed free radical mechanism can describe unexpected products formation such as those 77 and 78 (Scheme 34).

O

O

NC H 2C H 3

R5

C O R 6

O

O

N H CH 2CH 3

O

R 5 R6

O

M n(O A c )3

O

O

HN

CH 2C H 3

C O R 6

O

O

NC H 2CH 3

O

C O R 6R 5

66 d 7 6

+

+

7 7 78

Scheme 34

O

R 5 R 6

O

O

O

N H C 2H 5

O

O

N H C2H 5

C O R 6

C O R 5

O

O

NC 2H 5

R 5

C O R 6

O

O

N

CO R 6

C2H 5

R 5

O H

O

O

C O R6

R 5 O H

NC 2H 5

M n(III )

O

O

NC 2H 5

R 5

O HCO R 6

O

O

NC2H 5

O H

CO R 6R 5

M n(I II) NC 2H 5

O

C O R 6R5

O

O

O

O

HN

C 2H 5

C O R 6C O R 5

O

O

HN

C2H 5

C O R 6

O

R 5 R 6

OM n(III )

77

84

66d

path a

76

81

path cpath b

82

83

85

78

80

79

Scheme 35

2.2.2.4. Upon reaction of 2-(substituted-amino)-1,4-naphthoquinone 66a-d with substituted acetones and manganese (III)acetate in acetic acid at 45 oC, compounds 86 was obtained in good yields (Scheme 36). [57]

O

O

NHR

O

R2R1

O

O

NR2

R1

R

Mn(OAc)3, AcOH

86

66a-d Scheme 36

Similarly and as mentioned before, initiation occurs with the manganese (III) acetate oxidation of acetone to produce its radical. This radical intermediate underwent intermolecular addition to the quinone ring followed by oxidation process. Most indicative is the high chemoselectivity of that reaction, which was observed in different solvents. [57a,b]

2.2.2.5. Treatment of N-substituted 2-amino-1,4-

naphthoquinones 66a-d with 1,3-dione derivatives and

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manganese(III) acetate at rt gave only one compound 87, the structure of which is shown in Scheme 37. [58,59]

O

O

NHRO O

R2

R1 R1+

O

O

N

R2

R

R1

66a-d

Mn(OAc)3, AcOH

87

Scheme 37

2.2.3. Synthesis of azepine derivatives 2.2.3.1. Vargas's group reacted 2-(2,2-dimethoxyethylamino)-

3-(3-methylbut-2-enyl)-naphthalene-1,4-dione (88) with a mixture of tetrahydrofuran and 10% H2SO4 in methanol for 1 h. An intramolecular Prins pathway proceeded, to afford compounds 89a,b and 90a,b (Scheme 38). [60]

O

O

HN

O

O CH3

CH3

CH3

CH3O

O

N

H

OH

OR

+

O

O

N

H

OH

OR

CH3OH, THF10% H2SO4

ref lux

88

89 a R = H89 a R = CH3

90 b R = H90 b R = CH3

Scheme 38

2.2.3.2. The same group also reported that compound 88 reacted with formic acid at room temperature for 2 h, to afford regioselectively compound 91 (Scheme 39). [60]

O

O

HN

O

O CH3

CH3

CH3

CH3

O

O

N

H

OR

OR'

88

formic acid

2h, stirring

91 R = H, R' = CHO

Scheme 39

2.2.4. Synthesis of indole derivatives Reaction of 2-(methylamino)-1,4-naphthoquinone (66a) with

1,3-cyclohexanedione and cerium(IV) sulfate in methanol at room temperature gave 92 in 18% yield and no trace of the desired product 93 could be found. A better yield of compound

93 (42%) was obtained when CAN was used (Scheme 40). [61] O

OO

NHCH3

O

O

O

N

OMe

CH3

CO2Me

N

OO

O CH3

66a

Ce(IV), CH3OH

+

93 (traces)92 (18%)

+

CAN/ AcOH

92 (42%) 93 (5%)

Scheme 40

2.2.5. Synthesis of quinoline derivatives 2.2.5.1. Reaction of 2-(p-toluidino)-1,4-naphthoquinone (66f)

with 2,4-pentanedione in presence of manganese(III) acetate in acetic acid at room temperature afforded compounds 94 and 76

in 77% and 18% yields, respectively (Scheme 41). [56] O

O

NH

Tol

O

H3C CH3

OMn(OAc)3

O

O

N

CH3

COCH3

O

O

NCH3

COCH3

Tol

+

94 (77%)

+

Tol: p -Tolyl

76 (18%)66

Scheme 41

2.2.6. Synthesis of 1,4-dihydropyridines

2.2.6.1. Upon thermal cyclization of 55 with ethyl 2,2-diethoxyacetate (95), 6H-dibenzo[b,i]carbazole-5,13:7,12-diquinone (96) was obtained. This transformation constitutes a new example of Huntzsch synthesis of 1,4-dihydropyridines [62] and has to involve a nucleophilic substitution of 48 at C-3. [57b] This means that 48 is acting here as an enamine compound (Scheme 42). [57b]

(E tO )2C H C O 2Et

O

O

NH

O

O

R

55R = CO 2Et

96

95

Scheme 42

A plausible reaction mechanism involves C-3-alkylation, ethanol elimination, Michael addition of a second molecule of 55 and cyclization with elimination of ammonia to give 96 as illustrated in Scheme 43. [62]

O

O

N H 2

C O 2E t

O E tE tO

- E tO H

O

N H

O E t

C O 2E tH

- E tO H

O

O

N H

C H C O 2E t

O

O C O 2E tO

O

H NN H 2

- N H 3+ 5 59 6

5 5

95

O

Scheme 43

2.2.7. Synthesis of oxazine, terahydrobenzo[g]chinazoline and pyridoacridines derivatives

2.2.7.1. Reaction of 55 with 95 catalyzed by H2SO4 afford (±)-cis-diethyl-5,8-dioxo-1H-2,4-dihydronaphtho[2,3-d]1,3-oxazine-2,4-dicarboxylate (97) after 6 d (Scheme 44). [62]

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+

O

ONH

CH

O E tC O 2E t

HCO E t

CO 2E t

H X

- E tO H

O

ONH

CH

OCO 2E t

CH

CO 2E t

E tX - X E t

O

ONH

O

C O 2E t

C O 2E t55

H 2S O 4 , rtX = H S O 4

97 (2 0% )

9 5

Scheme 44

2.2.7.2. Reactions of compound 55 with aldehydes in the presence of a catalytic amount of trifluoroacetic acid at rt produce substituted 1H-2-dihydronaphtho-[2,3-d]1,3-oxazine-5,10-diones (98 and 99) in 54-70% yield as illustrated in Scheme 45. [51]

O

CH RCF3COOH

O

O

NH

O

H

H

R

R

O

O

NH

O

H

R

R

H55 + +

98 99R = Me, Et, Pr

Scheme 45

A plausible reaction mechanism for the formation of the products 98 and 99 involves C-3 alkylation, followed by water elimination to produce the azadiene intermediate (101; Scheme 46). This intermediate is reactive enough to produce the cyclized product by trapping another aldehyde molecule, most likely by Diels-Alder reaction. [51]

O

O

NH2

OCH R

H O

ONH

H

R

OHH

O

ONH

R

H

O

CH R

- H2O

55 100

101

..

98 and/or 99

Scheme 46

2.2.7.3. 2-Amino-1,4-naphthoquinone (55) behaves as a

bidentate nucleophile with primary amines and formaldehyde to give 3-substituted 1,2,3,4-terahydrobenzo[g]chinazoline-5,10-diones 102 in poor to moderate yields (Scheme 47). [50]

O

O

NH

NR

55RNH2, 2CH2O

102

Scheme 47

2.2.7.4. Several pyridoacridines 104 were synthesized in a two step reaction of β,β’-diaminoketones (103a,b) with 1,4-naphthoquinone (59) (Scheme 48). The prepared pyridoacridines showed moderate effect in-vitro cytotoxicity against P-388 mouse lymphoma cells. [63]

O

O

+

R

C eCl3 .7 H 2O

air , E tO H , re f lux

O

O

N

R

O

H 2N

H 2N

R

O

H 2N2 5% N H 4O H

M eO H , r .t.

a , R = Hb , R = O C H 3

N

O

N

R

R

103a ,b5 9

10 4a ,b

Scheme 48

3. References

[1] Perry, N. B.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod.

1991, 54, 978. [2] Thomson, R. H. Naturally Occurring Quinones, 2nd ed.; Academic: London, 1971. [3] Didry, N.; Pinkas, M.; Dubreuil, L. Ann. Pharm. Fr. 1986, 44, 73. [4] Phelps, D. C.; Nemec, S.; Baker, R.; Mansell, R. Phytopathology 1990, 80, 298. [5] Papageorgiou, V. P.; Assimopoulou, A. N.; Couladouros, E.

A.; Hepworth, D.; Nicolaou, K. C. Angew. Chem. Int. Ed. 1999, 38, 270.

[6] Riffel, A.; Medina, L. F.; Stefani, V.; Santos, R. C.; Bizani, D.; Brandelli, A. Braz. J. Med. Biol. Res. 2002, 35, 811.

[7] Ellison, A. M.; Gotelli, N. J. J. Exp. Bot. 2009, 60,19.

[8] Rischer, H.; Hamm, A.; Bringmann, G. Phytochemistry 2002, 59, 603. [9] Bringmann, G.; Feineis, D. J. Exp. Bot. 2001, 52, 2015. [10] Babula, P; Adam, V; Havel, L; Kizek, R. Curr. Pharm.

Anal. 2009, 5, 47. [11] Akins, R. A. Med. Mycol. 2005, 43, 285. [12] Bringmann, G.; Rischer, H.; Wohlfarth, M.; Schlauer, J.; Assi, L. A. Phytochemistry 2000, 53, 339. [13] Didry, N. I.; Dubreuil, L.; Trotin, F.; Pinkas, M. J. Ethnopharmacol. 1998, 60, 91. [14] de Paiva, S. R.; Figueiredo, M. R.; Aragao, T. V.; Kaplan,

M. A. C. Mem. Inst.Oswaldo Cruz 2003, 98, 959. [15] Bringmann, G.; Wohlfarth, M.; Rischer, H.; Rückert, M.;

Schlauer J. Tetrahedron Lett.1998, 39, 8445. [16] Dzoyem, J. P.; Tangmouo, J. G.; Lontsi, D.; Etoa, F. X.;

Lohoue, P. J. Phytotherapy Res. 2007, 21, 671.

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[17] Tandon, V. K.; Maurya, H. K.; Tripathi, A.; Shivakeshava, G. B.; Shukla, P. K.; Srivastava, P.; Panda, D. Eur. J. Med.

Chem. 2009, 44, 1086. [18] Dulay, I. S.; Gibson, F. D.; Eyeson-Annan, M. B.; Narara,

A. Papua New Guinea Med. J. 1987, 30, 281. [19] Das Sarma, M.; Ghosh, R.; Patra, A.; Hazra, B. Eur. J.

Med. Chem. 2008, 43, 1878. [20] Kapadia G. J.; Azuine, M. A.; Balasubramanian, V.;

Sridhar, R. Pharmcol. Res. 2001, 43, 363. [21] Aly, A. A.; El-Shaieb, K. M. Tetrahedron 2004, 60, 3797. [22] (a) Schellhammer, C. W.; Petersen, S.; Domagk, G. (to

Fabrenfabriken Bayer A.-G.) U.S. Pat. 3,084,165, 1963; Chem. Abstr. 1963, 59, 13956e. (b) Fries, K.; Ochwat, P. Ber. Dtsch. Chem. Ges. 1923, 56B, 1291.

[23] Remusat, V.; Terme, T.; Gellis, A.; Rathelot, P.; Vanelle, P. J. Heterocycl. Chem. 2004, 41, 221.

[24] (a) Hoover, J. R. E.; Day, A. R. J. Am. Chem. Soc. 1954, 76, 4148. (b) Lien, J.-C.; Huang, L.-J.; Wang, J.-P.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C. Chem. Pharm. Bull. 1996, 44, 1181. (c) Anacona, J. R.; Bastardo, E.; Camus, J. Transition Met. Chem. 1999, 24, 478.

[25] Díaz, R.; Reyes, O.; Francois, A.; Leiva, A. M.; Loeb, B. Tetrahedron Letts. 2001, 42, 6463. [26] Winkelmann, E. Tetrahedron 1969, 25, 2427. [27] Loskutov, V. A.; Lukonina, S. M.; Korobeinicheva, I. K.;

Fokin, E. P. Zh. Org. Khim. 1978, 14, 172. [28] Krieg, B.; Urban, R. Liebigs Ann. Chem. 1988, 799. [29] Kuznetsov, V. S.; Éfros, L. S. J. Org. Chem. USSR 1965, 1, 1479. [30] Nakamori, T.; Osaki, I.; Kasai, T. Nippon Kagaku Kaishi 1982, 450. [31] Aly, A. A.; Brown, A. B.; Hasaan, A. A.; El-Shaieb, K. M.; Bedair, T. M. I. J. Heterocylc. Chem. 2010 (under publication). [32] Neidlein, R.; Tran-Viet, D.; Gieren, A.; Kokkinidis, M.; Wilckens, R.; Geserich, H.-P.; Ruppel, W. Chem. Ber. 1982, 115, 2898. [33] Kublak, G. G.; Confalone, P. N. Tetrahedron Letts. 1990, 31, 3845.

[34] Camara, C. A.; Pinto, A. C.; Rosa, M. A. Vargas, M. D. Tetrahedron 2001, 57, 9569. [35] Yamashita, Y.; Tsubata, Y.; Suzuki, T.; Miyashi, T.; Mukai, T.; Tanaka, S. Chem. Lett. 1990, 445. [36] Giorgi-Renault, S.; Renault, J.; Baron, M.; Servolles, P.; Paoletti, C.; Cros, S. Eur. J. Med. Chem. 1985, 20, 144. [37] Anzenbacher, P.; Jr., P. M. A.; Jursiková, K.; Marquez, M. Org. Lett. 2005, 7, 5027. [38] Chung, W.-S.; Liu, J.-H. Chem. Commun. (Cambridge) 1997, 205. [39] Efimova, G. A.; Efros, L. S. Zh. Org. Khim. 1966, 2, 531. [40] Haug, J.; Scheffler, K.; Stegmann, H. B.; Vonwirth, S.; Weiß, J. E.; Conzelmann, W.; Hiller, W. Chem. Ber. 1987, 120, 1125.

[41] Katritzky, A. R.; Fan, W.-Q.; Li, Q.-L.; Bayyuk, S. J. Heterocycl. Chem. 1989, 26, 885. [42] Phutdhawong, P. S.; Ruensamran, W.; Phutdhawong, W.; Taechowisan, T. Biorg. & Med. Chem. Letts. 2009, 19, 5753. [43] Wang, X. L.; Zheng, X. F.; Liu, R. H.; Reiner, J.; Chang, J. B. Tetrahedron 2007, 63, 3389. [44] (a) Marcos, A.; Pedregal, C.; Avendano, C. Tetrahedron 1994, 50, 12941. (b) Tetrahedron 1995, 51, 1763. [45] Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33, 1089. [46] Dähne, S.; Ranft, J.; Paul, H. Tetrahedron Lett. 1964, 5, 3355. [47] Driebergen, R. J.; den Hartigh, J.; Holthuis, J. J. M.; Hulshoff, A.; Van Oort, W. J.; Kelder, S. J. P.; Verboom, W.; Reinhoudt, D. N.; Bos, M.; Van Der Linden, W. E. Anal. Chim. Acta 1990, 233, 351. [48] Hamdan, A. J.; Moore, H. W. J. Org. Chem. 1985, 50, 3427. [49] Corey, E. J.; Clark, D. A. Tetrahedron Lett. 1980, 21, 2045. [50] Möhrle, H.; Herbrüggen, G. S. Arch. Pharm. 1991, 324, 165. [51] Hamdan, A. J.; Al-Jaroudi, S. Arabian J. Sci. Eng., Sect. A 2003, 28, 51. [52] Couladouros, E. A.; Plyta, Z. F.; Haroutounian, S. A.; Papageorgiou, V. P. J. Org. Chem. 1997, 62, 6. [53] Boulos, L. S.; Arsanious, M. H. N. Tetrahedron 1997, 53, 3649. [54] Bestmann, H. J.; Lang, H. J. Tetrahedron Letts. 1969, 10, 2101. [55] Chuang, C.-P.; Wang, S.-F. Tetrahedron 1998, 54, 10043. [56] Jiang, M.-C.; Chuang, C.-P. J. Org. Chem. 2000, 65, 5409. [57] (a) Wu, Y.-L.; Chuang, C.-P.; Lin, P.-Y. Tetrahedron 2001, 57, 5543. (b) Marcos, A.; Pedregal, C.; Avendano, C. Tetrahedron 1995, 51, 6565. [58] Chuang, C.-P.; Wang, S.-F.; Lee, J.-H. Heterocycles 1999, 50, 489. [59] Tseng. C.-C.; Wu, Y.-L.; Chuang, C.-P. Tetrahedron 2002, 58, 7625. [60] Camara, C. A.; Pinto, A. C.; Vargas, M. D.; Zukerman- Schpector, J. Tetrahedron 2002, 58, 6135. [61] Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem. Int. Ed. 1981, 20, 762. [62] Martins, F. J. C.; Viljoen, A. M.; Strydom, S. J.; Fourie, L.; Wessels, P. L. Tetrahedron 1988, 44, 591. [63] Koller, A.; Rudi, A.; Gravalos, M. G.; Kashman, Y. Molecules 2001, 6, 300.

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