Molecular Iodine: Recent Application in Heterocyclic ...

Current Organic Chemistry, 2011, 15, 0000-0000

1

Molecular Iodine: Recent Application in Heterocyclic Synthesis Hojat Veisi* Department of Chemistry, Payame Noor University (PNU), Iran Abstract: In this review, the use of molecular iodine as a catalyst in the synthesis of heterocyclic compounds is presented and reviewed. In recent years, the use of molecular iodine in organic chemistry has received considerable attention because the chemical (a) is inexpensive and readily available, (b) is less toxic than alternatives, (c) has an easy workup method, and (d) is a moisture-stable, mild Lewis acid. Many of the reactions using iodine are associated with mild conditions, greater stero- and regioselectivities, short reaction times, and simplicity in their operation.

Key Words: ??????????????????????????????????????????????. 1. INTRODUCTION AND BACKGROUND OF THE MOLECULAR IODINE Of the more than 20 million chemical compounds currently registered, about one half contain heterocyclic systems. Heterocycles are important, not only because of their abundance, but above all because of their chemical, biological and technical significance. Heterocycles count among their number many natural products, such as vitamins, hormones, antibiotics, alkaloids, as well as Pharmaceuticals, herbicides, dyes, and other products of technical importance (corrosion inhibitors, antiaging drugs, sensitizers, stabilizing agents, etc. Iodine has so much significance in chemistry, medicine, and biology, etc.; therefore, it is of utmost interest to all of us to know and understand its chemical and physical behavior, mode of reaction, and the types of reaction that it can effect/catalyze/induce/promote so that it can be effectively exploited. The Lewis acidity of iodine is the prime factor in its behavior as a catalyst and many beautiful applications in organic reactions. Physical properties, i.e., mp, bp, density (d) and electron affinity, of molecular iodine (I2, iodine) are 113.5 °C, 184.4 °C, 4.93 (25 °C), and 3.06 eV, respectively, and its operational treatment is rather simple. Iodine is a nearly bluish black, poisonous [the legal airborne permissible limit (PEL) is 0.1 ppm, lustrous, corrosive molecular solid at room temperature with an irritating pungent odor, and it readily sublimes to a deep-violetcolored vapor. Its name originates from the Greek word iodes, which means violet. B. Courtois discovered iodine in 1811. Its chemical relationship to chlorine, another member of the halogen family, was established in 1812 by Guy Lussac. However, at nearly the same time, Davy confirmed many of its chemical properties. Iodine resembles chlorine and bromine in many of its properties, but chemically, among the halogens, it is the least reactive and the most electropositive metallic halogen. It occurs sparingly in the form of iodides in seawater from which it is assimilated by seaweeds, Chilesn saltpeter, nitrate-bearing earth (known as caliche), and brines from old sea deposits, and in brackish waters from oil and salt wells. In a wonderful experiment performed by Courtois, the liquor obtained from the extraction of kelp (i.e., seaweed), which contain iodide salts,

*Address correspondence to this author at the Department of Chemistry, Payame Noor University (PNU), Iran; Tel: -------------------------------; Fax: -----------------------------; E-mail: [email protected] 1385-2728/11 $58.00+.00

was treated with sulfuric acid to produce a vapor with a violet color (i.e., I2) (Scheme 1). 2 NaI

+

I2

H2SO4

+

Na2SO4

+ H2

Scheme 1.

Iodine is produced from brine in Japan. Chiba Prefecture is the world’s largest production site of iodine from brine, which contains iodine species such as NaI mainly in the range of 100–150 ppm concentration. This brine is isolated from the underground, which is a closed system and is not connected to the ocean, together with natural methane gas. Now Japan produces ca. 8000 tons/year of iodine mainly, sodium iodide and potassium iodide, of the ca. 21000 tons/year of iodine production in the world, and most of these iodine species in Japan is produced from the Chiba Prefecture area. World demand for iodine and organic iodine compounds is as follows; X-ray contrast media (21%), disinfectants and biocides (20%), medium of organic reactions (19%), medicinal and pharmaceuticals (16%), animal feeds (9%), herbicides (4%), photographics (3%), etc. Chemical functional ability of iodine as disinfectants or biocides comes from the oxidizing ability of iodine itself, especially for SH groups to disulfides, iodination of aromatic rings in tyrosine and histidine in proteins. In organic chemistry, it has been used for the detection of an acetyl group with aqueous NaOH solution, and it is known as the Lieben iodoform reaction, to form CHI3 (iodoform) and carboxylic acid [1]. Iodine reacts with other halogens to form interhalogen compounds. With starch, it forms a blue-colored complex, which marks the basis of using a starch solution as an indicator for free elemental iodine in solution during titrations. Although, it has very low solubility in water, iodine is, however, soluble in potassium iodide solution because of the resulting formation of water-soluble potassium triiodide (Scheme 2). KI

+

I2

KI3

Scheme 2.

In the laboratory, iodine can be prepared by heating potassium or sodium iodide with dilute sulfuric acid and manganese dioxide (Scheme 3). 2 KI + MnO2 + 3 H2SO4

Scheme 3. © 2011 Bentham Science Publishers Ltd.

I2 + 2 KHSO4 + MnSO4 + 2 H2O

2 Current Organic Chemistry, 2011, Vol. 15, No. 16

Hojat Veisi

Iodides in soil and seawater are oxidized by sunlight to iodine, which is vaporized into the air. A portion of the iodides are returned to the soil by rain, but the lion’s share of iodine is lost to the stratosphere. This could be one reason for the phenomena of the continued depletion of iodine in soil and the lack of its capture by plants, and is the cause for iodine deficiency in humans, particularly at higher altitudes in countries where salt is not fortified with iodide. In recent years, the use of molecular iodine in organic chemistry has received considerable attention because the chemical (a) is inexpensive and readily available, (b) is less toxic than alternatives, (c) has an easy workup method, and (d) is a moisture-stable, mild Lewis acid. Many of the reactions using iodine are associated with mild conditions, greater stero- and regioselectivities, short reaction times, and simplicity in their operation. The simple addition of electrophilic reagents to double bonds is one of the conceptually important and synthetically useful processes in organic chemistry resulting in the development of many novel reaction protocols. These reactions have emerged as very general methods for the preparation of heterocyclic compounds. There are very few reviews on application of molecular iodine in organic reaction that covered many transformations in synthetic chemistry [2-5]. Also, recently there are many references in the synthesis of heterocyclic compounds using molecular iodine as catalyst, but there is no any significant review about the role of molecular iodine in this area, so i interested to report a review to cover iodine’s synthetic role in the synthesis of various important heterocyclic compounds.

nes are useful synthetic intermediates, which can be used in the preparation of nitrogen-containing functional compounds via ring opening and ring expansion reactions [5]. They are also found in some natural products as well as biologically active compounds such as mitomycins and azinomycines [6,7]. Iodine was found to be an efficient catalyst for the aziridination 1 of alkenes utilizing Chloramine-T (N-chloro-N-sodio-p-toluenesulfonamide) as a nitrogen source (Scheme 4) [8]. The reaction could be applied to other acyclic and cyclic alkenes such as 1-octene and cyclohexene. Ts Chloramine-T (1 mmol), I2 (10 mol%) MeCN, rt, 24h

Ph

76% Scheme 4.

The aziridination of p-substituted styrene derivatives 2-5 with Chloramine-T showed that electron rich alkenes reacted faster than electron-poor ones (Scheme 5). Several Chloramine-T analogs were also examined and were found to give the corresponding aziridines 6-9 in only moderate yields (Scheme 6). Suggested mechanism was shown below (Scheme 7). Chloramine-T immediately reacts with iodine to form iodine-ChloramineT complex 10. This complex then reacts with the alkene to give an iodonium cation intermediate 11. The iodoaminated intermediate 12 is formed by an attack of the nitrogen of Chloramine-T on the intermediate 11. Cyclization of compound 12 leads to the aziridine and the regeneration of 10. If this mechanism is correct, the aziridination proceeds with ICl instead of iodine. To examine this further, they carried out aziridination of styrene by employing a catalytic amount of ICl, and aziridine 1 was obtained in 64% yield.

The properties of three- and four-membered heterocycles are mostly a result of the great bond angle strain (BAEYER strain). The resultant ring strain imparts on the compounds high chemical reactivity. Ring opening leading to acyclic products is typical. Aziridi-

Ts

1: X = H 2: X = NO2 3: X = Cl 4: X = Me 5: X = OMe

N Chloramine-T (1 mmol), I2 (10 mol%) MeCN, neutral buffer (1:1), rt 2 mmol

O

Cl

X

Scheme 5.

R

S O

SO2R +

N Na

N

MeCN / neutral buffe (1/1) rt, 10 h

2 mmol

1 mmol

Scheme 6.

I2 (10 mol%) Ph

Ph 1

2 mmol

2. THREE-AND FOUR-MEMBERED HETEROCYCLES

X

N

Yield%

run

N source

1

R = p-MeC6H4

6

91

2

R = Ph

7

73

3

R = p-NO2C6H4

8

35

4

R = Me

9

29

Product

Ph 6: R = p-MeC6H4 7: R = Ph 8: R = p-NO2C6H4 9: R = Me

Molecular Iodine: Recent Application in Heterocyclic Synthesis

Current Organic Chemistry, 2011, Vol. 15, No. 16 3

TsNNaCl + I2

TsNICl + NaX

Ts

10

N

X = I or Cl

I

TsNNaCl

H2O

11

Ts

+ TsNCl

I

N Cl

12

I

HO

Scheme 7.

R2

O N R3

R1 N

R2 +

R1

R3 R3

13

15

CO2Et Br

R3

Zn, I2 (cat)

and/ or

dioxane, HIU, 5 min.

14

HN

R2

O OEt

R1 R1

R3

R3

= alkyl, aryl R2 = H, alkyl

16

R3 = H, alkyl, aryl Scheme 8.

N

Ar2

Ar2 +

BrH2C

CO2Et

Ar1 17

14

Zn "activated", I2 (cat) dioxane, HIU, 4-10 min. 70-95%

O N

Ar1 18

Ar1 = Ph, 4-Cl-Ph, 4-Me-Ph Ar2 = Ph or 4-MeO-Ph Scheme 9.

Bartsch and co-workers [9] have reported the synthesis of !lactams 15 via the US-promoted Reformatsky reaction using ‘not activated’ zinc dust and a catalytic amount of iodine. The reactions were subjected to high-intensity ultrasound (HIU) from a direct immersion horn. The Reformatsky reaction utilizing imines 13 as electrophiles can provide !-lactams 15, as well as the corresponding !-amino esters 16 (Scheme 8). When ethyl bromoacetate 14 was used, the reaction was not very selective. However, when ethyl "bromoisobutyrate was employed, the reaction was more selective. Electron-withdrawing substituents attached to the nitrogen atom

favored the formation of !-amino esters. A previous work [10] also demonstrated the formation of !-lactams 18, but under low intensity ultrasound (LIU) (Scheme 9). However, in this case the zinc dust was activated by washing with nitric acid in order to achieve high yields. The reactions were performed in a cleaning bath in the presence of catalytic I2 in dioxane, and products 18 were obtained in 70–95% yields. Under these conditions the formation of !-amino esters was not observed. The ring opening of epoxides 19 with elemental iodine in the presence of 2,6-bis[2-(o-aminophenoxy)methyl]-4-bromo-1methoxybenzene 20 as a new catalyst affords vicinal iodo alcohols


Hojat Veisi

O

I2

+

R

HO

BABMB (cat.) rt, CH2Cl2

R

19

I 21

NH2 O

H2N

R = Ph PhOCH n-Hex i-PrOCH2 ClCH2

OMe O

97% 94% 93% 99% 82%

Br BABMB 20 Scheme 10.

H

COC6H4C6H5

COC6H4C6H5

H benzene

C6H5

C6H5

H

H

N

23

R

+

24

RNH2-I2

R = C6H11 (94%) R = CH3 (74%)

22 Scheme 11.

R NH I2 R N H

25

O

+ O

HN

NH

O

26

R

R 27

Scheme 12.

21 in high yields [11]. This new procedure occurs regioselectively under neutral and mild conditions in various aprotic solvents even when sensitive functional groups are present (Scheme 10). Several new examples of the N-iodo amine 22 reaction with ",!-unsaturated ketones 23 to produce only trans-ethylenimine ketones 24 have been performed (Scheme 11) [12]. 3. FIVE-MEMBERED HETEROCYCLES Basic and higher life functions depend on indole, which provides the heterocyclic frame for the amino acid tryptophan, numerous alkaloids, plant growth factors, hormones, and neurotransmitters. Because of the broad importance of indole, evidence for bacterially transformed indole was investigated in depth. In recent years, the triarylalkanes, especially the symmetrical ones, have become increasingly important as dyes, for physicochemical studies, the preparation of cage compounds, and photochemical transformations [13-17].

Shun-jun et al. [18] reported a simple and efficient method for the synthesis of triindolylmethanes (TIM) 27 using molecular iodine as the catalyst. The reaction of various indoles 25 with triethyl orthoformate 26 catalyzed by I2 (5 mol%) at room temperature in 215 min under a solvent-free condition afforded the respective symmetrical triindolylmethanes 27 in good to excellent yields without any side products (Scheme 12). The possible mechanism is as follows (Scheme 13): In this process, iodine as Lewis acid activates the substrates and accelerates the reaction. Aldehydes and ketones react with electron-rich aromatics and olefins such as indole, silyl enol ethers, in the presence of a catalytic amount of iodine [19-22]. Thus, iodine promotes the reaction of indole with aldehydes 28 to form 1,1-bis(indolyl)alkanes 29 (Scheme 14). Also Mallik et al. found that indole in the reaction with ",!unsaturated ketones yields bis(indolyl)methanes (BIMs) 29 in 52-



OEt EtO

I2

I2

OEt

N H

OEt

EtO

OEt -EtOH

OEt

HN

-EtOH

EtO

EtO

N I2

N H

N I2

-EtOH

-I2

NH

HN

NH

N H Scheme 13.

H N indole I2 (0.2 equiv)

RCHO

R CH

MeCN, r.t.

R = Me(CH2)2 = Ph = p-MeOC6H4 = p-NO2C6H4

28 N H

87% 98% 99% 98%

29 Scheme 14.

O +

N H

Ar

Ar

O

dry EtOH N H

Ar

N H

H

I2

O

H-OEt Ar

Ar

N H

N H

N H 30

N H

29

Scheme 15.

63% yield (Scheme 15) [23]. The proposed mechanism via azafulven 30 is presented in Scheme 15. For the iodine-catalyzed Michael addition of indole 32 and pyrrole to ",!-unsaturated ketones 31 and nitro compounds at room

temperature see Scheme 16 [24-27]. Treatment of 2-(4chlorophenyl)-3-nitro-2H-chromene 34 with indole in the presence of iodine gave the corresponding 2H-benzopyrans 35 and 36, flavonol analogues, through the Michael addition (Scheme 17).


Hojat Veisi

R

O

O R

I2 (0.05 equiv)

+ N H 31

solvent-free, r.t.

N H

32

33 R=H 85% = NC 78% = PhO 72%

Scheme 16.

HN

HN

indole I2 (0.5 equiv)

NO2

NO2

NO2 +

Et2O, r.t.

O

O

Cl

O Cl

Cl

35

34

36

73%

26%

Scheme 17.

O

I2 (0.1 equiv) + O

RNH2

N

THF, r.t.

R

37 R = Ph 96% = PhCH2 95% = 1-Py 70%

38

Scheme 18.

Iodine promotes the reaction of 1,4-diketone 37 and primary amines (Paal–Knorr reaction) to provide N-substituted pyrroles 38 in high yields (Scheme 18) [28]. Treatment of 3(amino)methyleneindoline-2-thione (39) with iodine in pyridine generates brassilexin 40 (Scheme 19) [29]. Pyridine reacts with 2NH2

alkyl-1,4-naphthoquinones 41 in the presence of iodine to afford naphtho[2,3-b]indolizine-6,11-diones derivatives 42 (Scheme 20) [30]. 2-Imidazolines 43 are easily prepared in quite good yields from the reaction of aldehydes 5 with ethylenediamine in the presence of iodine (Scheme 21) [31]. Aldehydes also react with (R,R)(+)-1,2-diphenylethylenediamine to form 2-substituted (R,R)-3,4diphenylimidazoline in high yield. A single-step catalytic ring-expansion approach from 4oxoazetidine-2-carbaldehydes 44 to protected enantiopure 5-cyano3,4-dihydroxypyrrolidin-2-ones 45 has been achieved by the use of the commercially available and inexpensive reagent, molecular iodine, in the presence of tert-butyldimethyl cyanide (Scheme 22) [32]. A range of 2,4,5-triaryl substituted imidazoles 48 have been synthesized in very good yields under solvent-free conditions by

I2 (1.0 equiv)

S

N H

N H

40

39 I2

71% (-HI) (-HI) NH2 S N

39a Scheme 19.

S

Py, r.t.

I



O

O

CH2R R1

+

R

I2 (2.0 equiv) R1

Py, heating

N

N

O

O

41

42 R = R1 = H R = H, R1 = 2-CO2Et R = Ph, R1 = H R = CO2Et, R1 = H

O CH2R

H

O

71% 51% 61% 68%

I2 (-HI) O

R H H R1

N

N

R1 O 41d

41a I2 (-HI) O

O

CH2R

CHR

N

R1

O

N

(-H+)

O

41b

R1

41c

Scheme 20.

NH2

H2N

RCHO

H N

(1.1 equiv)

R

I2 (1.25 equiv) K2CO3 (1.25 equiv) t-BuOH, 70 ˚C

28

N 43

(-HI) I

H N

I2

R

N

=

N H

=

R

(-HI)

N H

R = Ph = p-MeOC6H4 = p-NO2C6H4

28a'

100% 100% 99% 94%

S 53%

Ph

28b'

Scheme 21.

MeO

MeO

O +

N O

TBSCN

PMP 44

OTBS

I2 (10 mol%) MeCN, rt

O

N

CN

PMP 45

Scheme 22.

grinding 1,2-diketones 46, aromatic aldehydes 47 and ammonium acetate in the presence of molecular iodine as catalyst (Scheme 23)

[33]. The short reaction time, cleaner reaction, and easy workup make this protocol practical and economically attractive.


Hojat Veisi

CHO R

O

I2 (10 mol%)

+ R

O

NH4OAc

R'

46

R

H N

R

N

47

R'

R = Ph, Tolyl, Furiyl 48

Scheme 23.

NH4OAc RCHO

NH3 NH3

+

+

RCH

I2 O +

Ph

NH

49

I2 Ph

HOAc

-H2O

NH3

-2HI

O I2

I2

Ph

O

Ph

O

Ph

NH

Ph

NH

+

RCH

R5

R1

NH

50 I2 H N

Ph

R N

Ph

Ph

O

Ph

N

-H2O -2HI

NH2 R

51

48 Scheme 24.

R5

O

R4

R1 +

R3

NH2NH2

OR2 R1 = H, CH3

DMSO-I2 30 min. Stirr at r.t.

R4 N N H

R3 53

52 Scheme 25.

The possible mechanism of this reaction is as follows: The Lewis acidic nature of molecular iodine makes it capable of binding with the carbonyl oxygen of aromatic aldehyde increasing the reactivity of the parent carbonyl compound and facilitates the formation of imines intermediate 49. Further catalyst iodine condenses with the carbonyl oxygens of the 1,2-diketone, which on dehydration afford the intermediate 50. Intermediates 49 and 50 combine for the formation of intermediate 51, which on dehydration and further cyclisation gives 2,4,5 triaryl substituted imidazoles 48 (Scheme 24). An efficient approach for the synthesis of indazoles 53 from ortho alkoxy acetophenone 52, hydrazine hydrate by using DMSO and molecular iodine has been described (Scheme 25) [34]. This reaction was performed in different solvents such as Methanol, Ethanol, Acetonitrile, Toluene, THF, DMF and DMSO. But DMSO gives good yield in comparison to the other solvents by using catalytic amount of molecular iodine. A practical method has been developed for conversion of unprotected and unmodified aldoses to aldobenzimidazoles and aldo-

naphthimidazoles 56. Using iodine as an oxidant or promoter in acetic acid solution, a series of mono-, di-, and trialdoses 54, including those containing carboxyl and acetamido groups, undergo an oxidative condensation reaction with o-phenylenediamine or 2,3naphthalenediamine 55 at room temperature to give the aldobenzimidazole and aldo-naphthimidazole products in high yields (Scheme 26) [35]. No cleavage of the glycosidic bond occurs under such mild reaction conditions. The composition analysis of saccharides is realized by the HPLC analysis of the fluorescent naphthimidazole derivatives. On the basis of the experimental results, they speculated that the reaction was initiated by formation of a Schiff base (e.g., the intermediate 59 in Scheme 27) by condensation of the aldose with one of the amino groups in o-phenylenediamine (58a-f) or naphthalenediamine 58g. The condensation of an aldehyde with an amine to form the Schiff base is a reversible process, in which formation of the Schiff base is favored under mild acidic conditions (e.g., at pH 4-6). This rationale showed that acetic acid is an appropriate solvent for the transformation of glucose to aldo-imidazoles. The subse-


OH


OH

O

O HO

OH

OH

OH

H2N

OH +

O

O HO

OH

OH

OH

O HO

rt, 6h; 98%

H2N OH

HO

I2, HOAc

N OH

OH 55

D-Lactose

HN

Naphthimidazole (fluorescent)

54

56

Scheme 26.

OH

OH O

HO HO

OH

HO HO

OH

OH

OH

H2N O

H2N

H

57a, D-Glucose

58, Diamine

OH

O2

OH

HO HO

HOAc -H2O

+

N OH

I2

OH HI +

OH

H2N

59, Schiff base

I

OH

HO HO

H

N

HN

61, Iodoimidazoline -HI OAc

OH OH

HO HO

OH

H H N

AcO AcO

I2 or O2

OAc N OAc

HN

HN

D-Glucobenzimidazole

60, Imidazoline

62a, R = H 62a-Ac, R =Ac

Ac2O, Pyr

Scheme 27. Ph

OH +

Ph

PhNH2

+

2 NH4OAc

+

O

ArCHO

I2 (10 mol%)

Ph

N

Ph

N

Ar Ph

63 64

Scheme 28.

quent nucleophilic addition of the other amino group to Schiff base 59 gave an imidazoline intermediate 60, which could be oxidized in air or by iodine to afford the observed product of aldobenzimidazole. The aldo-imidazole products might also form via a different pathway [36]. A prior N-iodination of the imine moiety in Schiff base 59 would facilitate the formation of iodoimidazoline intermediate 61, and the desired product of aldo-benzimidazole would be obtained by the subsequent elimination of an HI molecule. It was noted that another HI molecule was also generated during N-iodination of the Schiff base. In the HOAc media, the released I- ions might be oxidized in air to regenerate I2.

Kidwai et al. have introduced the molecular iodine as an efficient catalyst for the synthesis of 1,2,4,5-tetraarylimidazoles 64 using benzoin 63, an aromatic aldehyde and an amine in the presence of ammonium acetate (Scheme 28) [37]. Molecular iodine has been used an efficient catalyst for an improved and rapid one-pot synthesis 2,4,5-trisubstituted 48 and 1,2,4,5-tetrasubstituted imidazoles 65 in excellent yields (Schemes 29, 30) [38]. It can be observed that the process tolerates both electron withdrawing and electron donating substituents on the aldehydes. The aryl group substituted with different position of the


Ph

Hojat Veisi

O NH4OAc

+ Ph

+

I2 (5 mol%)

ArCHO

Ph

N

Ph

N H

Ar

O

48 Ar = Ph 4-OHC6H4 4-MeOC6H4 4-ClC6H4 2-Thiophenyl Piperanol

99% 99% 99% 99% 99% 98%

Scheme 29.

Ph

O +

Ph

NH4OAc

+

ArCHO

I2 (5 mol%)

PhNH2

+

Ph

N

Ph

N

Ar

O

Ph 65 Ar = Ph 4-OHC6H4 4-MeOC6H4 4-ClC6H4 2-Thiophenyl Piperanol

99% 97% 99% 99% 99% 99%

Scheme 30.

H

I2

O H

O

HO H

I2

H

NH2

NH2

NH3

NH3

R1

R1

NH2

I2

R1 I2

66 R1

H2O

I2 Ph

O

Ph

O I2

Ph

N

Ph

N H

[1,5]shift R1

Ph

N

Ph

N

HO Ph

H R1 67

Ph 2I2 2H2O

I2 NH

H

NH HO

R1 I2

Scheme 31.

aromatic ring has not shown much effect on the formation of the final product. Molecular iodine is capable of bonding with the carbonyl oxygen increasing the reactivities of the parent carbonyl compounds. As shown in Scheme 31, they gave the likely mechanism. Iodine facilitate the formation of a diamine intermediate 66, which under mild acid catalysis of iodine condenses further with the carbonyl carbon of 1,2 diketone followed by dehydration to afford the isoimidazole 67, which rearranges via [1,5] sigmatropic shift to the required imidazoles.

Synthetic study of 2-imidazoline units and imidazole units is very important due to their potent biological activity [39] and synthetic utility. [40,41] Aldehydes were converted to the corresponding 2-imidazolines 43 and 2-oxazolines 68 in good yields by the reaction with ethylenediamine and aminoethanol, respectively, using molecular iodine and potassium carbonate (Scheme 32) [42]. Aromatic aldehydes bearing electron-donating substituents and electron-withdrawing substituents can be successfully converted to the corresponding 2-arylimidazolines and 2-aryloxazolines in good yields.


H2N R CHO


NH2 (1.1 equiv.) I2 (1.25 equiv.)

R = Ph 100% 4-BrC6H4 97% 4-MeOC6H4 100% 2-ClC6H4 99% 2-Thiophenyl 94% 2-pyridinyl 97%

H N R

and K2CO3 (3.0 equiv.) t-BuOH 70 ˚C, 3h

N 43

H2N R CHO

OH (1.1 equiv.) I2 (2.0 equiv.)

O R


N

R = Ph 4-BrC6H4 4-MeOC6H4 4-CNC6H4 2-Thiophenyl

75% 75% 83% 55% 17%

R = Ph 4-BrC6H4 4-MeOC6H4 4-CH3C6H4 2-Thiophenyl 1-Adamantyl

99% 92% 99% 99% 99% 99%

R = Ph 4-BrC6H4 4-MeOC6H4 4-CH3C6H4 2-Thiophenyl 1-Adamantyl

81% 72% 83% 85% 33% 82%

68 Scheme 32.

H2N R CH2OH

NH2 (1.5 equiv.) I2 (2.25 equiv.)

H N R


H2N R CH2OH

N

OH (1.5 equiv.) I2 (2.0 equiv.)

O R


N

Scheme 33.

R CH2OH I2

1) I2 , K2CO3 2) H2NCH2CH2XH

X R

t-BuOH X = NH or O

N

(-HI)

(-HI) R H

H R C

I

X N I

O

I2 (-HI)

H

X R

(-HI) R C H

O

H2NCH2CH2XH (-H2O)

N H

N R H

XH

Scheme 34.

Moreover, primary alcohols were directly converted to the corresponding 2-imidazolines and 2-oxazolines via aldehydes in onepot manner with ethylenediamine and aminoethanol, respectively, using molecular iodine and potassium carbonate (Scheme 33) [42,43]. A plausible reaction pathway is shown in Scheme 34. The ratedetermining step is exactly the oxidation of alcohol to the aldehyde. Thus, it is required that ethylenediamine and aminoethanol should be added after the formation of aldehydes, to form the corresponding 2-substituted imidazoline and oxazoline effectively, since ethylenediamine and aminoethanol are smoothly oxidized by molecular iodine under the present reaction conditions.

Molecular iodine is found to catalyze efficiently the coupling of 4-hydroxyproline 70 with isatins 69 under mild conditions to produce 3-(1H-pyrrol-1-yl)indolin-2-one 71 and 11-(1H-pyrrol-1-yl)11H-indeno[1,2-b]quinoxalin-11-one 73 derivatives in excellent yields in a short reaction time with high selectivity (Scheme 35) [44]. Among various solvents such as methanol, ethanol and isopropanol tested, t-BuOH was found to give the best results. Other reagents such as LiI, KI and NaI failed to produce the desired product. The formation of the products may be explained by the formation of azomethine lade via decarboxylation and a subsequent 1,5-


Hojat Veisi

O

N

HO I2

O +

CO2H

N H

N H 69

O

t-BuOH 70 ˚C

N H

70 O

71 N

HO

N

N

I2

+

CO2H

N H

N

t-BuOH 70 ˚C

N

70

72

73

Scheme 35.

I2

O

H

t-BuOH

+

HI

HO

HO

HO

O N

O +

CO2H

N H

N H

t-BuOI

+

O

HI

N

-CO2 O

O

N H

N H

H N -H2O

H O

N

+ H+

N O

N H

- H+

O

N H

N H

Scheme 36.

I2 (8 equiv) K2CO3 (8 equiv) OH

THF

O 94%

74

75

Scheme 37.

proton shift to generate the more stable zwitterion as shown in Scheme 36. In 2006, Wang et al. have reported a new method for synthesis of benzofurans 75 and naphthofurans from 2-hydroxystilbene derivatives 74 via an intermolecular cyclization catalyzed by molecular iodine (Scheme 37) [45]. They proposed a plausible mechanism for the reaction as follows (Scheme 38). Firstly, 2-hydroxystilbene is activated by converting to its potassium salt 76, which is oxidized to yield a cationic intermediate 77. Then, compound 77 cyclizes to 78. The resulting 78 and 79 give rise to the product after losing a proton.

Lycogalic acid A (80) (Fig. 1) has been isolated from the slime mould Lycogala epidendrum [46,47] and from cultures of Chromobacterium violaceum (chromopyrrolic acid). Recently, two phenyl analogues of lycogalic acid A, designated as HPPD-1 (82) and HPPD-2 (81) (Figure 1), have been found in cultures of a marine Halomonas bacterium [48,49]. Both metabolites show effective antitumor activities. Several derivatives of 3,4-diaryl- 84 and 3,4-diindolylpyrrole2,5-dicarboxylic acids 83 including lycogalic acid A and two Halomonas metabolites were synthesized by oxidative dimerization of arylpyruvic acids or arylpyruvates in the presence of ammonia (Schemes 39, 40) [50].



K2CO3 OH

76

OK

I2 oxidation

2 cyclization

1

A

O

O

78

H

77

-H+ O

O 79 Scheme 38.

H N

HO2C

HO2C

CO2H

N H

R2

R1

H N

80

CO2H

N H

81, R1 = R2 = OH 82, R1 = OH, R2 = H

Fig. (1).

H N

H N

H N

I2 MeOH, NH3

2

(42%) MeO2C

HO

N H

CO2Me

CO2Me

83 Scheme 39.

R

I2 (0.5 equiv), 0 ˚C

R

R

(1) MeOH, NaOMe then NH4OH (2) CH2N2 MeO2C

O

MeO2C

N H

CO2Me

84a, R = OMe 84b, R = H Scheme 40.

4. SIX-MEMBERED HETEROCYCLES Iodine promotes the condensation of salicylic aldehydes 85 and 2,2-dimethoxypropane 86 to form 3,4-dihydro-2,4-dimethoxy-2methyl-2H-1-benzopyrans 87 (Scheme 41) [51,52]. Treatment of aldehydes 88, ethyl acetoacetate 89, and urea 90 in the presence of

iodine provides the corresponding 3,4-dihydropyrimidin-2(1H)ones 91 (Scheme 42) [53-55]. Thiourea can be also used instead of urea, to form 3,4-dihydropyrimidin-2(1H)- thiones. The same onepot, three-component reaction of aldehyde, ethyl acetoacetate 89, and cyclohexane-1,3-dione 92 in the presence of iodine can be also


Hojat Veisi

OH MeO

+ R

Me

CH2Cl2, r.t.

CHO 85

OMe

O

I2

OMe

R OMe

86

87 R=H = Me = Br = NO2

90% 88% 84% 75%

Scheme 41.

CHO

O

R

O

O

+

OEt

88

+

H2N

89

NH2 90

R

CO2Et

I2 (5% solution) HN

toluene,

NH

R=H = OMe = NO2

95% 91% 75%

O 91 Scheme 42.

O

carried out to form the corresponding 1,4-dihydropyridines 93 (Scheme 43) [56]. O

CHO

O

OEt

+ O

89

I2 (20 mol%) EtOH, r.t., 30 min (92 to >98%

RO2C

O

+

R2

NH2

Me

92

RO2C Me

R2

N

95

94 Scheme 44.

O O CO2Et

I2 (0.3 equiv) MeCO2NH4 EtOH, r.t.

N H

Me

93

99%

H O I

R2

I2, EtOH

RO2C

RO2C

NH2

Me

R2

NH2

Me

96

94

Scheme 43.

In all these reactions, the presence of a small amount of iodine is essential, and a small amount of hydrogen iodide formed through the reaction of iodine with the substrate or solvent is a key species for the reaction. The cyclodehydration of Bohlmann–Rahtz aminodienones 94 is catalysed by iodine in ethanol at room temperature to give 2,3,6trisubstituted pyridines 95 in excellent yield, with total regioncontrol and without the need for chromatographic purification (Scheme 44) [57]. The course of the reaction was rationalized by considering initial regioselective addition to give s-cis iodide 96, in equilibrium with the s-trans conformer (Scheme 45). Facile deprotonation,

O I RO2C Me

-H2O N

R2 Me

95

R2

E RO2C NH2 97

Scheme 45.

rather than intramolecular nucleophilic substitution, prevents the formation of pyrrole and gives instead the (4E)-hexadienone inter-



R2

mediate 97, thus avoiding the need for double bond isomerization. This will undergo spontaneous cyclodehydration under mild reaction conditions to give pyridine 95. This method provides 5substituted pyridines possessing latent functionality suitable for subsequent elaboration, a substitution pattern hitherto unavailable by traditional Bohlmann–Rahtz methodology. 4-Chloroisocoumarins 98 are effective irreversible inhibitors of serine proteases [58] and potent inhibitors of amyloid peptide production [59]. Since there is a remarkable similarity in bioactivities between the carbon species and their phosphorus counterparts [60], one would anticipate that phosphorus 4-chloroisocoumarin analogs 99–94 might have potential bioactivities similar to those of the 4chloroisocoumarins reported herein (Fig. 2). Cl

R1

P O

O 98

O

DMF rt

OEt

R1

99

O OEt

R2

Z = Et, H

O

R1

P OZ

EtO

I2 R2 2

Z

O

P

2

1

OEt

Z

O

P

O

R1

OEt

Z

103

105

104 I

I

R2

R2 R1

P O

O OEt

X = Br (100), Cl (101) Scheme 47.

O R1

R2 2

1

O

R1

I

R2

I

O

R1

OEt

They showed a plausible mechanism for this reaction in Scheme 47. Electrophilic addition of I2 to the C–C triple bond might form the corresponding intermediates 103, 104 or 105; their stabilities and the nucleophilicity of the phosphonyl oxygen play crucial roles in determining whether the alkynylphosphonates will cyclize or not. Intramolecular nucleophilic attack by the phosphonyl oxygen onto the position 2 of 103 or 105 would give the desired products 100 or 101. Alternatively, the phosphonyl oxygen might also attack onto the position 1 of 103 or 104 to give the fivemembered-ring products. However, all the examined substrates showed high regioselectivity for sixmembered-ring products, indicating that the 5-exo-dig process was very disadvantageous for 2(1-alkynyl)phenylphosphonates. The above regioselectivity might be caused by the following factors: (1) the longer bond lengths of C–P and P–O would make the phosphonyl oxygen much closer to the farther position of the triple bonds; (2) the tetrahedral phosphonates might further increase the ring strain and lower the stabililty of the corresponding five-memberedring products. In 2007, J. S. Yadav et al. [62] described an efficient and metal catalyst free Prins-cyclization for the rapid synthesis of spirocyclictetrahydropyrans from homoallylic alcohols and ketones using molecular iodine under neutral conditions. Accordingly, treatment of 3-buten-1-ol 107 with cyclohexanone 106 in the presence of mo-

A series of 4-iodophosphaisocoumarins 99 were prepared with high regioselectivity in good to excellent yields under mild conditions by the reaction of 2-(1-alkynyl)phenylphosphonic acid monoesters 102 with iodine in DMF (Scheme 46) [61]. Halocyclization reactions have been much affected by the substituents of the substrates, reaction solvents and electrophiles, which could be rationalized by the proposed mechanisms in Scheme 46.

1

O

Scheme 46.

Fig. (2).

I

P O

102

99: Z = I 100: Z = Br 101: Z = Cl

X = NO2, NH2, NHR, etc. Y = OR, Cl, etc.

OH

P

R1

R2

O

X

R2

I2

Z Y

I

P O OEt

O

P

OEt


Hojat Veisi

I

O +

I2

OH

CH2Cl2, r.t.

O

107 106

108

Scheme 48.

TMS

I O

+ Me

OH

TMS

I2

H

CH2Cl2, r.t.

Me

110

109

O 111

Scheme 49. CHO +

CO2Me

Ph3P

OH

113

1. I2, CHCl3 -20 ˚C, 40 min

I

2. DPE, 200 ˚C 14%

O

112

O

114

Scheme 50.

Ph O

O + NH2 115

Ph

O

CO2Et

I2 (1 mol%) H3C

OEt 89

EtOH, r.t., air 96% Yield

N

CH3

116

Scheme 51.

lecular iodine at ambient temperature for 30 min gave the corresponding 4-iodotetrahydropyran 108 in 96% yield (Scheme 48). Recently, the same research group reported the first direct and metal catalyst-free silylalkyne-Prins cyclization for the rapid synthesis of highly substituted dihydropyrans 111 from silylated secondary homopropargylic alcohols 109 and aldehydes 110 using molecular iodine under neutral conditions. Also, this method is highly stereoselective, affording cis-dihydropyrans exclusively (Scheme 49) [63]. 3-Iodocoumarin derivatives 114, by mixing orthohydroxybenzaldehyde 112 and methyl (triphenylphosphoranylidene)acetate 113 in the presence of molecular iodine was formed, but in a low yield (14%, Scheme 50) [64]. Quinolines are an important group of heterocyclic compounds. Several derivatives have been found to possess useful biological activities such as antimalarial, antibacterial, anti-asthmatic, antihypertensive, and anti-inflammatory [65-69]. In addition, quinolines are valuable synthons for the preparation of nano-and meso structures with enhanced electronic and photonic functions [70-73]. Thus, the synthesis of quinolines is an important and useful task in organic chemistry. The Friedländer annulation is a straightforward method for the synthesis of these compounds [74] which involves a condensation followed by a cyclodehydration between 2aminoarylketones and a-methylene ketones, and is catalyzed by both acids and bases. Wu et al. found that molecular iodine could be used as an excellent and efficient catalyst for the synthesis of quinolines 116 polycyclic quinolines via Friedländer annulation, in

excellent yields from 2-aminoaryl ketones 115 and carbonyl compounds 89 under mild conditions (Scheme 51) [75]. In 2009, Wu et al. [76] have described a convenient route to 2aryl-2,3-dihydroquinolin-4(1H)-ones 118 from 2'-aminochalcones 117 under solvent-free conditions in the presence of I2 (10 mol%) at 100 oC (Scheme 52). The simple experimental procedure, solventfree reaction conditions, utilization of an inexpensive and readily available catalyst, short period of conversion and excellent yields are the advantages of the present method. They showed a plausible mechanism for these reactions in Scheme 53. O

O Ar

NH2 117

I2 neat, 100 oC

N H

Ar

118 Ar = Ph = p-MeOC6H4 = p-ClC6H4 = p-NO2C6H4

92% 92% 85% 89%

Scheme 52.

Hantzsch 1,4-dihydropyridines (1,4-DHPs) and their derivatives have gained great importance in the field of organic and medicinal chemistry since they display a fascinating array of pharmacological



O

I2

O Ar

OH

I2

O

-I2

NH2

Ar

N H

N H

H

Ar

Ar

N H

Scheme 53.

O R

O H

+

R1

R

O

O R2

+

I2

NH4OAc

O R2

R2

r.t.

R1

N H

R1

119 O R

O H

+

O

CH3

CH3

R1

O

CH3

+

R'NH2

I2 r.t.

H3C

R

O

O

CH3 O

O R1

N

CH3

R1

R' 120 Scheme 54.

H

H

R

O

O

HO Iodine, TMOF

H

R

+

123

+

CH2Cl2, r.t.

OH 121

O

H

O

122 H

R O Scheme 55.

properties [77]. 1,4-DHPs have been explored for their calcium channel modulation [78] and the heterocyclic rings are found in a variety of bioactive compounds such as vasodilator, bronchodilator, antiatherosclerotic, antitumor, antidiabetic, eroprotective and heptaprotective agents [79]. They even possess neuroprotective platet antiaggregation activity [80]. The tremendous drug activity of these compounds has attracted many chemists to synthesize these molecules. Joshi et al. [81] introduced an efficient and simple one-pot synthesis of some new symmetrical, unsymmetrical and N-substituted Hantzsch 1,4-dihydropyridines 119, 120 using molecular iodine as catalyst from an aldehyde, a 1,3-dicarbonyl compound and ammonium acetate / aromatic amine in ethanol (Scheme 54). This new method has the advantage of good to excellent yields (80-95%) and short reaction times (2.5-5 h) at ambient temperature. Elemental iodine has been utilized as an efficient catalyst for the intramolecular [4+2] cycloaddition of o-quinomethanes 123 generated in situ from o-hydroxybenzaldehydes 121 and unsatu-

rated alcohols 122. The reaction takes place in the presence of trimethyl orthoformate to afford the corresponding trans-annelated pyrano[3,2-c]benzopyrans in high yields and with high diastereoselectivity (Scheme 55) [82]. In 2008, the same method was used for the diastereoselective synthesis of cis-fused pyranobenzopyrans and furanobenzopyrans 126 via 2 mol % of molecular iodine-catalyzed reaction of ohydroxybenzaldimines 124 with 3,4-dihydro-2H-pyran and 2,3dihydrofuran 125 at ambient temperature. 2-Butoxy-4-N-arylaminobenzopyrans were also synthesized from o-hydroxybenzaldimine and n-butyl vinyl ether using this procedure (Scheme 56) [83]. Banik et al. reported a facile and convenient iodine-catalyzed thioketalization for various carbonyl compounds in high yield (Scheme 57) [84]. The reactions can also be performed without solvent, using a catalytic amount of iodine supported on a neutral alumina surface [85]. Molecular iodine was found to be an efficient catalyst for the synthesis of 2-(alkyl/aralkyl-1H-benzimidazole-2-yl)-quinoxaline


Hojat Veisi

R2

N

HN

R1

I2 (2 mol%)

+

n

O

OH

HN

H

R1

THF, r.t.

O

n = 1, 2

124

R2

O

H

R1

+

n

R2

O

H

O

n

H

126

125 Scheme 56.

R1

X

HS

I2, (cat)

+ X

R2

CHCl3, r.t.

n

HS

R1

S

R2

S

n

X = -OMe, OEt, OAc XX = O, -O(CH2)3O-, -O(CH2)3 -(OCH2)2C(CH2O)3O-, n = 0, 1 Scheme 57.

R

R H2N

N

O

N

CH3

+ R1

H2N

127

N

N

I2, EtOH reflux, 2h

N

N

128

R1

129

Scheme 58.

R

R

N

O

N

CH2

130

H2N

-HI

+ H2N

I

N

R1

R

N

O

R1

H2N

R

N

N

H N

N

NH

N

N

-H2 R1

-H2O

N HO N H 131

R1

Scheme 59.

derivatives 129 in one-pot by refluxing 2-(alkyl/aralkyl-1Hbenzimidazole-2-yl)-ethanone 127 with substituted ophenylenrdiamine 128 in ethanol (Scheme 58) [86]. A plausible mechanism for this conversion via the intermediate 130 and 131 are provided in Scheme 59. Since the first isolation of an indolocarbazole (ICZ) alkaloid in 1977, the importance of this family of natural products has been recognized by chemists, biologists, physicians, and pharmaceutical companies [87]. compounds with this ring system possess significant biological activity. Therefore, considerable efforts have been made to prepare and synthetically alter these molecules to find useful compounds [88]. Indolo[2,3-b]carbazoles 132, 133 (Fig. 3) are one of the five possible isomeric indolocarbazole that possesses anti-tumor, anticancer activity.

In this area Pulak and co-workers have prepared the 6,12disubstituted 5,7-dihydroindolo[2,3-b]carbazoles 134 from the reaction of 1H-indole and aldehydes catalyzed by molecular iodine (Scheme 60) [89]. A reasonable mechanism for the formation of compounds 134 is outlined in Scheme 61. The reaction occurs via initial formation of bis(indol-3-yl)methane 135, which reacts with the second aldehyde molecule in the presence of iodine and eliminates a molecule of water to give the intermediate 136, which is not isolable and is subsequently oxidized to the fully aromatized 6,12-disubstituted 5,7-dihydroindolo[2,3-b]carbazole 134. The molecule of indole first catalyzed the reaction for the formation of bis(indol-3-yl)methane 135 and then enhances the electrophilic character of the second



EO2C

CO2Et

H N ICZ

N H

N H R

N H

R = H, CHO

OMe

133

132 Fig. (3).

R1 +

I2

R1CHO

N H

CH3CN, heat

N H

N H R1 134

R = Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 Me

75% 80% 79% 50% 25%

Scheme 60.

R1

R1 + R1CHO I2

N H

N H

N H

N H

I2 R1

N

H

R1

135

N H

O

R1

N H

-H2O

R1

N H

R1

N H

OH

R1

R1 [O] -H2 N H

N H R1 136

N H

N H R1 134

Scheme 61.

aldehyde molecule by a loose coordination with oxygen, to react and give the product. Recently a facile synthesis of 6,12-diaryl-5,11dihydroindolo[3,2-b]carbazoles 138 from aldehydes and indole catalyzed by HI followed by oxidation of the intermediate 137 with I2 has been developed (Scheme 62) [90].

The same group also synthesized indolo[3,2-b]carbazole 137 using 3,3'-bis(indol-3-yl)methanes 135 of aromatic aldehydes in the presence of molecular iodine as a catalyst in refluxing acetonitrile in good yields (Scheme 63) [91]. A plausible mechanism for the reaction is outlined in Scheme 64. The 3,3'-bis(indol-3-yl)methane 135 which can be considered as


ArCHO

+

Hojat Veisi

Ar

HI (57%) (0.2 equiv)

indole

H N

CH3CN 80 ˚C, 14h

N H Ar 137

Ar H N

I2 CH3CN

N H

80 ˚C, 14h

Ar 138 Scheme 62.

R

R

H N

I2

+ N H

CH3CN

N H

N H

N H R

135 137 Scheme 63.

R

N H

R

N H

135

N

N H

139 R

R + N

N H

N

N

140

H 139

I2

R

N

H

H

N

R

N

R

N

R

R

R H N

H N

[O]

N H

N H R

R 137

Scheme 64.

3-alkylated indoles, undergo 1,3-tautomerization and thus can exist in the indolenine form as 139 (Scheme 64). In the presence of iodine under thermal conditions this gives the intermediate 140 and indole. Under the reaction conditions, two molecules of the intermediate 140 then react and finally are oxidized to give the in-

dolo[3,2-b]carbazole 137. The isolation of the indole molecule eliminated during the reaction have been supported this mechanism. Among the various classes of nitrogen containing heterocyclic compounds, quinoxaline derivatives 143 are important components of several pharmacologically active compounds [92]. Although



R1

R1

+ O

25 ˚C 3-30 min.

NH2

R2

N

I2 (10 mol%) CH3CN

NH2

O

N

R2

142

R1

R1

143

141 O

I2 (10 mol%) CH3CN

NH2

H2N +

NH2

H2N

O

25 ˚C 40 min., 85%

N

N

Ph

Ph N

N

Ph

Ph 145

144 Scheme 65.

O CN N

N

NH2 N

NH2 H+ / H2O

O2N

O

N

O2N

NO2

NH N

NH2 ArCHO I2 / CH3CN

NO2

146

N

N X

O2N

NO2

147

148

Scheme 66.

O +

Paraformaldehyde

O

I2 CH2Cl2, rt

149

150

Scheme 67.

rarely described in nature, synthetic quinoxaline ring is a part of a number of antibiotics such as echinomycin, leromycin, and actinomycin, which are known to inhibit the growth of Gram-positive bacteria and are also active against various transplantable tumors [93-95]. Various biologically important quinoxaline derivatives were efficiently synthesized in excellent yields using inexpensive, nontoxic, and readily available bench top chemical, iodine in catalytic amount (10 mol %). Besides this, a systematic study was carried out to evaluate parameters such as solvent and catalyst loading. Several aromatic as well as aliphatic 1,2-diketones 141 and aromatic 1,2-diamines, such as substituted phenylene diamines 142, tetra amines 144 were further subjected to condensation using catalytic amounts of iodine to afford the products 143, 145 in excellent yield (Scheme 65) [96]. Also, the same results with the same conditions were reported by Pawar and his group [97]. Fused pyrimidinone derivatives have attracted the attention of numerous researchers over many years due to their important biological activities. The structural similarity of pyrazolo[3,4d]pyrimidines with purines [98] have made them a prime target for scientific research and in this context several reports dealing with

the synthesis of these fused heterocyclic compounds have appeared in the literature [98-101]. An array of biological activities such as antibacterial, antifungal [99,100], and herbicidal [101] has been reported to be shown by various pyrazolopyrimidines. Bakavoli and co-workers found that molecular iodine could be used as an excellent promotor in the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives 148 as potential antibacterial agents (Scheme 66) [102]. Iodocyclization of 5-amino-1-(2,4-dinitrophenyl)-1H-4-pyrazolcarboxamides 147 with aromatic aldehydes gave a new series of pyrazolo[3,4-d]pyrimidine derivatives 148 in a single step and their antibacterial activity comparable to Streptomycin as reference drug was evaluated. Iodine is found to be an effective reagent for the cross-coupling of olefins 149 with aldehydes under mild conditions to produce 4substituted 1,3-dioxane derivatives 150 in excellent yields and in short reaction times with high selectivity (Scheme 67) [103]. This method works not only with formaldehyde but also with acetaldehyde, propionaldehyde and cyclohexanecarboxaldehyde. A plausible reaction mechanism is depicted in Scheme 68.


Hojat Veisi

I2

Paraformaldehyde

HCHO H

H O

O

O +

H

O

O

H

Scheme 68.

I

I

GaI3 / I2

CHO +

N

CH2Cl2, rt

TsHN 151

N

+

Ts major

Ts minor

152

Scheme 69.

O O

O OMe

+

RCHO

+

NH2

HO

O

MeO

I2

OMe N

Neat 40 ˚C

153

89

R

CH2 H2C

OH

154 Scheme 70.

HO CH2 CH2 N

CHO 89

+

153

MeOOC

COOMe

MeOOC

COOMe

I2

+

Neat 40 ˚C CHO 155

N CH2 HO

CH2 156

Scheme 71.

Yadav and his group explored the synthesis of 4Iodopiperidines 152 in good yields and with high selectivity by means of aza-Prins-cyclization 151 using a catalytic amount of gallium(III) iodide and a stoichiometric amount of iodine under mild reaction conditions (Scheme 69) [104]. This is the first report on the preparation of 4-iodopiperidines via aza-Prins-cyclization. Zolfigol et al. [105] have reported the synthesis of novel Hantzsch N-hydroxyethyl 1,4-dihydropyridines under mild conditions catalyzed by molecular iodine. A mixture of ethanolamine 153 and acetic acid as ethanolammonium acetate and various aldehydes

in the presence of methyl acetoacetate were converted to Nhydroxyethyl 1,4-dihydropyridines under mild and solvent-free conditions in good to excellent yields. They synthesized the first example of different kinds of methyl 1-hydroxyethyl-1,4-dihydro2,6-dimethylpyridine-3,5-dicarboxylates 154 and bis(methyl 1hydroxyethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates) 156 under mild and solvent-free conditions (Schemes 70 and 71). In 2006, Wang and his research group have been described a mild, efficient, and general method for the synthesis of substituted quinolines 159 via a molecular iodine-catalyzed one-pot domino



R1 N

R2

157

R3

I2 (1 mol%) benzene

+

R1 N

reflux, 0.5 h

O R3

H

R2

159

158 Scheme 72.

O

O

O

I2 (10 mol%)

OO

O

ArCHO

+

H2O, 100 ˚C, 1atm

OH

OH

Ar

OH

160 Scheme 73.

O +

ArCHO

OO

I2 (10 mol%) H2O, 100 ˚C, 1atm

OH

OH

Ar

OH

161 Scheme 74.

reaction of imines 157 with enolizable aldehydes 158 (Scheme 72) [106]. Coumarins are an important group of organic compounds that are used as additives to food, cosmetic [107] and optical brightening agent [108]. Along with these, coumarin derivatives have recently revealed new biological activities with interesting potential in therapeutic application besides their traditional employment as anticoagulant (antivitamin K activity) [109] and sustaining agents (photosensitizing action of furocoumarin) [110], they have yielded important results as an antibiotics (novobiocin and analogs) [111] and antitumor drug (geiparvarin) [112]. Molecular iodine has been used an efficient catalyst for an improved and rapid one-pot synthesis of 3,3'-arylmethylenebis-(4-hydroxycoumarin) 160 (Scheme 73) and 2,2'-arylmethylenebis(3-hydroxyl-5,5-dimethyl-2-cyclohexen1-one) 161 (Scheme 74) in excellent yields using water as a reaction medium [113]. Molecular iodine is capable of binding with the carbonyl oxygen increasing the reactivities of parent carbonyl as it behaves as a mild Lewis acid. As shown in Scheme 75, first molecular iodine activates carbonyl group of aromatic aldehyde to give iodinealdehyde complex 162 and thus increases the electrophilicity carbonyl carbon of aldehyde. Nuleophilic addition of 4hydroxycoumarin to 162 to give 163 and followed by loss of H2O from 163 to afford 164, which is further activated by iodine. Another molecule of 4-hydroxycoumarin is added to 164 to give 165

and molecular iodine, which can catalyze reaction in a catalytic manner. Xanthenes and benzoxanthenes are important biologically active oxygen heterocycles possessing antibacterial and antiinflammatory [114]. These compounds are also utilized as antagonists for paralysing action of zoxazolamine [115] and fluorescent materials for visualization of biomolecules and in laser technologies [116]. Several polycyclic compounds possessing xanthene skeleton have also been reported from natural source [117,118]. Dos and co-workers [119] have developed a convenient and efficient method for the synthesis of 14-aryl or alkyl-14Hdibenzo[a,j]xanthenes 167 by single-pot condensation of 2naphthol 166 with aromatic or aliphatic aldehydes in the presence of molecular iodine (Scheme 76). The simple experimental procedure, solvent-free reaction conditions, utilization of an inexpensive and readily available catalyst, short period of conversion and excellent yields are the advantages of the present method. The same results were also reported by Pasha in 2007 [120]. A mild, highly efficient and metal-free synthetic method for aromatization of 1,4-dihydropyridines 168 employing urea– hydrogen peroxide (UHP) adduct as oxidant catalyzed by 20 mol % of molecular iodine was developed (Scheme 77) [121]. The reaction was carried out in ethyl acetate at room temperature and the products were isolated in high to excellent yields. A plausible freeradical mechanism is proposed based on results obtained with de-


Hojat Veisi

OH I2

H

H

O

I2

O

O

O

O

I2

O

162

O

O

163

OH

I2

OH

H2O

O

O

O

O 164 I2 OH

O

Ar

H O

OO

O

OH

I2

Ar

O

OH

OO

O

165 Scheme 75.

RCHO

+

R

I2 neat conditions

OH

R = aryl, alkyl

O

2-5 h

82-95%

166

167 Scheme 76.

R4

R4 R2O2C R3

CO2R2

20 mol% I2, AcOEt, rt )

R3

N

R2O2C

CO(NH2)2.H2O2

R3

CO2R2 N

H

H

168

169

R3

Scheme 77.

(Me)3Si

R N

Cl

O 170

I2 OEt

+

2 eq.

Si

R

CH2Cl2, rt

N CO2C2H5

171 172

Scheme 78.

rivatives having alkyl and aryl substituents in the 1,4dihydropyridine ring. N-acylated isoquinolines 170 reacted smoothly with 2 equiv allyltrimethylsilane 171 in the presence of a catalytic amount of io-

dine to produce the corresponding benzoisoquinuclidine s as a 1:1 mixtures of invertomers 172 (Scheme 78) [122]. Arylimines 174 generated in situ from aromatic aldehydes and anilines undergo smooth coupling with homophthalic anhydride



O

O O

PhCHO

+

+

PhNH2

O

I2

N H

CH2Cl2, rt H

173

CO2H 174

Scheme 79.

NH2

O +

2

NH2

R

175

solvent-fre, r.t.

Me

R

N

I2 (0.1 equiv)

H

N H

R

176 177

R N

H N

Me Me

R

R = Me = Et = Ph

95% 90% 94%

CH2 Me

N

N

R

R

175a

175b

Scheme 80.

O O

O +

NH

N N H

NH2

+

ArCHO

OH 178

O Ar

I2 (10 mol%) CH3CN, Under reflux 1 atm

N

H2N

N NH2

179 180

Scheme 81.

173 in the presence of 10 mol% of molecular iodine under mild and neutral conditions to afford the corresponding cis-1-oxo-1,2,3,4tetrahydroisoquinoline-4-carboxylic acids 174 in excellent yields with high cis selectivity(Scheme 79) [123]. This method provides an easy access to highly substituted 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids with diverse chemical structures. 5. SEVEN-MEMBERED HETEROCYCLES 2,3-Dihydro-1H-1,5-benzodiazepines 177 are directly prepared from the reaction of o-phenylenediamine 175 and ketones 176 in the presence of iodine (Scheme 80) [124]. When cyclic ketones are used, the corresponding tetracyclic 2,3-dihydro-1H-1,5-benzodiazepines bearing one spiro carbon are obtained in good yields. A simple and facile synthesis of 7-arylbenzopyrano[1,3]diazepines 180 has been accomplished by treatment of 4hydroxycoumarin 178, cyanoguanidine 179 with aromatic or heteroaromatic aldehydes using molecular iodine in non-protic solvent under reflux (Scheme 81) [125]. The surprising results were obtained when the same reaction was tried with different solvents. In protic polar solvents like

methanol, ethanol the condensation of 4-hydroxycoumarin with benzaldehyde facilitates bis adduct 3,3'-phenylmethanebis-(4hydroxycoumarin) 181 (Scheme 82). However, same reactions in non-protic solvents like dichloromethane and tetrahydrofuran leads to the formation of benzopyrano[1,3]diazepines with excellent yields (Table 1). Thus, it is concluded that formation of benzopyrano[1,3]diazepines are favoured only in the non-protic solvents. However, extent of polarity of solvents has not shown much effect on the formation of the desired product. In 2009, Li and co-workers [126] reported a selective method for the synthesis of 3-iodo-1,5-benzothiazepin-4-ones via the intramolecular iodocyclization of N-[2-(methylthio)phenyl]propiolamides. In the presence of I2, iodocyclizations of N-[2(methylthio)phenyl]propiolamides 182 were conducted smoothly to afford the corresponding 3-iodo-1,5-benzothiazepin-4-ones 183 in moderate to good yields (Scheme 83). 6. DIELS-ALDER REACTION Quinoline ring systems exist widely in nature and tetrahydroquinoline derivatives exhibit remarkable biological and pharmacol-


Hojat Veisi

O

O

O

NH

N

+

N H

NH2

+

CH3OH, Under reflux

Ar

O

OH 181

+

1 atm

OH 178

OH

I2 (10 mol%)

ArCHO

O

O

NH

N

179

N H

NH2

179 Scheme 82. Table 1. Effect of Solvent on the Synthesis of 7-arylbenzopyrano[1,3]diazepinesa

a b

Entry

Solvent

Product

Time (h)

Yield (%)

1

Methanol

181

3.5

48

2

Ethanol

181

3

51

3

Dichloromethane

180

2.9

92

4

Tetrahydrofuran

180

4.6

85

5

Acetonitrile

180

3.2

89

Reaction conditions: benzaldehyde (1 mmol); 4-hydroxycoumarin (1 mmol); cyanoguanidine (1 mmol); I2 (10 mol%); under reflux; 1 atm. Isolated and unoptimized yields.

Me

R1

S

I2

I

CH2Cl2, 40 ˚C R

R1

S

N

R

O

N

O

R2

R2

183

182 Scheme 83.

R1 I2 N

O

+

N

R2

185

184

solvent-free r.t.

O

O H

H R1

+

H

H N H

N H R2 cis-186

R1

R2 trans-186

Scheme 84.

ogical properties [127-129]. Among those, aza-Diels-Alder reactions are the most important approach via cyclo-addition of electron-poor azadiene such as N-arylimines 184 with electron-rich dienophiles 185. In 2008, Ji et al. have developed a new method to synthesize tetrahydroquinoline derivatives 186 via aza- Diels-Alder

reaction catalyzed by molecular iodine, which is very simple, efficient and environmentfriendly (Scheme 84) [130]. But under the same condition, indole-3-carbaldehyde derivatives could finely undergo the three-component aza-Diels-Alder reactions of N-vinyl-2-pyrrolidinone 184, aniline and indole-3-



O H

OHC N

O

R

+

NH2

I2

+

R1

solvent-free r.t.

N

H N H

R3 184

187

189

N R3

Scheme 85.

O

N

+

N

I

I N

I cis-Product

+

I

trans-Product

Scheme 86.

R O

NH2 I2 +

R

MeCN, rt

O

OH +

190 exo

190 endo

O Entry

Aromatic amines

a

R N

N 2

Yield (%)

endo /exo

NH2

85

34:66

F

NH2

75

64:36

c

Cl

NH2

70

30:70

d

Me

NH2

85

34:66

OMe

NH2

83

33:67

b

e

OH

Scheme 87.

carbaldehyde derivative 188, gave the corresponding products 189 (Scheme 85). In this reaction, aniline 187, indole-3-carbaldehyde 188 and iodine were first put into the reaction, which could go faster than without iodine, then the third component was added, when only cis-product was obtained in a good yield. A possible mechanism is proposed in Scheme 86, which has not been established yet, where the nitrogen of the 2-azadiene group is coordinated to molecular iodine to accelerate this cyclization.

A highly efficient method for the synthesis of 1,2,3,4tetrahydroquinoline derivatives 190 via a molecular iodine catalyzed domino reaction of anilines with cyclic enol ethers, such as 2,3-dihydrofuran and 3,4-dihydro-2H-pyran, is described (Scheme 87) [131]. The reaction may proceed through an aza-Diels–Alder process between an in situ generated 2-azadiene and another equivalent of cyclic enol.


Hojat Veisi

O I2

+ NH2

CH2Cl2

O

H

O

I2

OH

N

H

CH2Cl2

OH

N H

Scheme 88.

CHO R1

+

NH2 R2

I2 (10 mol%) +

O

R2

H H

rt, 3h

O

O +

NH

R2

H H

H

NH

H

R1

R1

191

192

Scheme 89.

O R1

H3C R3

I2 (5 mol%)

+

CH2Cl2, rt

R2 O

193

OH R1 R2

194

R3

O 195

Scheme 90.

O H3C O

R1

CH3

+

CH2Cl2, rt

R2 193

I2 (5 mol%)

196

R1 CH3 R2 197

R1 = H, R2 = OCH3 R1 = R2 = OCH3 R1 = R2 = (OCH2O) Scheme 91.

Molecular iodine catalyzes the reaction as a mild Lewis acid. The tentative mechanism to rationalize the product formation is shown in Scheme 88. The reaction may proceed via an aza-Diels– Alder process of 2-azadiene, which is generated in situ from cyclic enol ether and aniline, with another equivalent of cyclic enol resulting in the formation of tetrahydroquinolines. The successful use of molecular iodine as a catalyst in the intermolecular imino-Diels–Alder reaction is described. A one-pot synthesis of pyrano[3,2-c]quinolines 191, 192 was achieved by threecomponent coupling of aldehydes and anilines with 2,3dihydropyran catalyzed by iodine (Scheme 89) [132]. The reactions could be carried out smoothly at room temperature within three to six hours to offer the target products in good yields. It was found that each reaction could be carried out smoothly by iodine catalysis at room temperature, the products were obtained as cis/trans isomers without any other isomer detected.

1,4-Benzoquinones undergo smoothly [3 + 2] cycloaddition reactions with electron rich alkenes in the presence of 5 mol% iodine under mild conditions to afford the corresponding 2,3dihydrobenzofurans in excellent yields with trans-selectivity. Accordingly, the treatment of 1,4-benzoquinone 193 with transanethole (4-propenylanisole) 194 in the presence of 5 mol% I2 in dichloromethane resulted in the formation of trans-2-(4methoxyphenyl)-3-methyl-(2R,3R)-2,3-dihydrobenzo[b]furan-5-ol 195 in 85% yield (Scheme 90) [133]. The reaction of trans-anethole with methyl vinyl ketone 196 under similar conditions afforded the corresponding [2+2] crosscoupling products (trans-cyclobutane derivatives) 197 in high yields (Scheme 91). 7. CONCLUSIONS It should be noted that a correct and update citation and literature survey is very important for researchers to find relevant infor-



mation, pioneer ideas, and progress of any subject. On the other hand, published data using molecular iodine indicate a wide synthetic potential of the described reagent/catalyst and a great interest of researchers in these area. A wide range of original procedures for synthesizing various classes of heterocyclic compounds, have been developed on the basis of molecular iodine. In recent years, the use of molecular iodine in organic chemistry has received considerable attention because the chemical (a) is inexpensive and readily available, (b) is less toxic than alternatives, (c) has an easy workup method, and (d) is a moisture-stable, mild Lewis acid. Many of the reactions using iodine are associated with mild conditions, greater stero- and regioselectivities, short reaction times, and simplicity in their operation. Also, recently there are many references in the synthesis of heterocyclic compounds using molecular iodine as catalyst, but there is no any significant review about the role of molecular iodine in this area, so I interested to report a review to cover iodine’s synthetic role in the synthesis of various important heterocyclic compounds. We think that the present review article may be bringing a basic to advance information to this very important subject and to encourage active researchers in this field for the applications of molecular iodine in organic and heterocyclic synthesis.

[18]

ACKNOWLEDGEMENTS

[28]

We are thankful to Payame Noor University (PNU) for financial support. The authors thank their coworkers, named in the references, for their experimental and intellectual contributions.

[29]

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