Chemical Society Reviews
Application of Bartoli Indole Synthesis
Journal: Chemical Society Reviews
Manuscript ID: CS-REV-01-2014-000045.R1
Article Type: Review Article
Date Submitted by the Author: 11-Mar-2014
Complete List of Authors: Dalpozzo, Prof. Renato; Universita` della Calabria, Chimica e Tecnologie Chimiche Bartoli, Giuseppe; Università di Bologna, Chimica Industriale ‘Toso Montanari’ Nardi, Monica; Università della Calabria, Chimica e Tecnologie Chimiche
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Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE
Application of Bartoli Indole Synthesis
Giuseppe Bartoli, a Renato Dalpozzo* b and Monica Nardi b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
5 In 1989, the reaction of vinyl magnesium halides with ortho substituted nitroarenes to lead to indoles was discovered. This reaction is now frequently reported as the “Bartoli reaction” or the “Bartoli indole synthesis” (BIS). It has rapidly become the shortest and most flexible route to 7 substituted indoles, because the classical indole syntheses generally fail in their preparation. The flexibility of Bartoli reaction is great as it can be extended to heteroaromatic nitro derivatives and can be run on solid support. This
10 review will focus on the use of the Bartoli indole synthesis as key step in preparations of complex indoles, which appeared in the literature in the last years.
10, 11, 16 46 one has to choose two principal synthetic strategies: Table of Contents starting with an indole core and adding the missing structural part, or starting from acyclic precursors. The choice between the 1. Introduction two strategies is suggested by what has to be constructed. In fact, 2. From Mechanism to Scope and Limitation 50 indole is an electron rich aromatic system which undergoes 15 3. Syntheses from 7 Haloindoles electrophilic substitutions in the 3 position ( i.e. in the 4. Syntheses from 7 Alkylindoles heterocyclic ring). Deprotonation of N-substituted indoles takes 5. Syntheses from 7 Hydroxyindoles place readily at the 2 position and a plethora of removable N 6. Syntheses from Azaindoles blocking groups are available, which allows the preparation of N- 7. Miscellaneous 55 unsubstituted 2 substituted indoles. On the other hand, 20 8. Conclusions substitution on the benzene ring only occurs in special cases, thus 9. Abbreviations one prefers to start from suitable precursors through pyrrole or 10. Notes and References benzene ring assembly, when a substituent is needed on the carbocycle moiety. 11 Although all methods certainly provide 1. Introduction 60 rapid assembly of the indole nucleus, the reaction conditions are Heterocycles are among the most important structural classes of generally relatively harsh. This is less important when the starting 1, 2 25 chemical substances, which are particularly well represented materials are readily available, but, when the starting materials among agrochemicals, herbicides, natural products, biological arise from multi step sequences, the conditions may not be electrical sensors and pharmaceuticals. It is estimated that more amenable. than 50 % of the published chemical literature contains 65 However, the construction of 7 substituted derivatives was heterocyclic structures and 70 % of all pharmaceutical products very difficult until the introduction of the Bartoli Indole Synthesis 47 30 possess heterocyclic structural subunits, because of a favourable (BIS), notwithstanding in many naturally occurring or combination of drug like properties. Bicyclic aromatic pharmaceutically important indoles, 7 substitution is often heterocycles containing nitrogen atoms, such as quinolines, needed (Figure 1). isoquinolines, and indoles are present in all classes of organic 70 BIS represents a general and efficient method for producing compounds in the biological and medicinal arena. 3 11 In indoles substituted on both the carbocycle and the pyrrole ring. It 35 particular, over ten thousand biologically active indole starts from nitroarenes of easy disposability with many different derivatives have been identified to date. Of those, over 200 are substitutions onto all the five aromatic positions and vinyl currently marked as drugs or undergoing clinical trials. 12 Grignard reagents also easy available or synthesizable. Reaction Furthermore, the indole nucleus is not only important in 75 conditions are very mild and this feature allows the survival of biological systems and in pharmaceutical research, but also it is a many sensitive organic functions. Thus, BIS has had an intensive 13, 14, 15 40 common moiety in material science, so it is referred to as development to prepare indoles bearing a large variety of “privileged structure”. Therefore, the search for an efficient substituents on the two rings and, consequently, the merits, 48 50 synthesis of the indole ring system is a longstanding goal, and drawbacks, and applicability are well established. effective methodologies for the synthesis of functionalized 80 The wide applicability outside academic research laboratories indoles bearing a number of useful properties are of great interest. fuelled the increasing popularity of the BIS, particularly in the 1, 2, 45 In the midst of many indole syntheses and functionalization, pharmaceutical industry, providing new avenues for the key steps
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of the synthetic sequences of drugs and natural products, and this review aims to present the most recent application in this field.
HO
O NH F H N Et N O HO H O O HO N O O O Cl N NH H N S Cl N O AcO O Cl Cl N O H O H Cl S N H Cl Cl
NH
Diazonamide A DG-041 CJ-12662 tr ans-Trikentrin A
HO OSO3Na H N Br NH Et H2N N O NH O OH N HN O HO N NH N H OH O HN HO OH N H OH OH cis-Trikentrin B Demethylasterriquinone B1 Dictyodendrin B Dragmacidin E
N O HN O O OMe N N N OH H N Cl N N N CO2H N HN N Ph O N N H NH OMe O N Cl
AJ-9677 LY290154 BMS-488043
O O OMe N NH NH
N Ph Ph NH N N N N H O
BMS-378806 Marinoquinoline C Marinoquinoline E Fig. 1 Some natural occurring products or drugs containing 7 substituted indole (blue) or azaindole (red) moiety
the excess Grignard reagent suggest that the indole nucleus
5 1. From Mechanism to Scope and Limitation incorporated one molecule of Grignard reagent, another reduces the nitro group, and the last serves as in an acid base function, Although accurate and classical kinetic investigations have never 52 15 thus the mechanism depicted in Scheme 1 was proposed. been made, the mechanism of the BIS proposed by us is now This mechanism was rationalized into our proposed SET accepted and further reactions all confirmed our initial mechanism for the reaction of Grignard reagents and nitroarenes, hypothesis. 51 in which the first interaction is an in cage electron transfer from 10 The first observation was that the stoichiometry of the reaction Grignard reagent to nitroarene. 53 The shape of the alkyl radical (3:1 Grignard vs. nitroarene ratio) and the products arising from 20 influences the attack to the radical centres of the radical anion. In
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particular, bent sp 2 vinyl radicals 54 attack onto the oxygen atom oxygen terminus leads to indole. Although attack at the oxygen of the nitro group and this attack is favoured by bending ( π or 1 atom of the nitrosoarene radical anion appears most probably, 55 trimethylsilyl substituted linear radicals gave lower yields) and nevertheless, steric hindrance emanating from the ortho position by crowding at the nitro position because a collapse of radical 35 could aid reorientation of the attack of the vinylmagnesium 5 species is much more sensitive to steric hindrance that polar bromide from the nitrogen to the oxygen atom of the transient reactions. 55 nitroso substrate. 51 Noteworthy, yield declines when a small fluorine atom instead of a voluminous bromine atom occupies the O O position adjacent to the nitro group. 55 In the solid supported BIS, N O O R1 BrMg N R 40 an ortho substituent is not necessary, because, very likely, the X R X R1 + MgBr entire solid support causes enough steric hindrance to address the 58 2 vinyl radical on the oxygen atom. 1 1 O NH4Cl R R R OH2 R1 OMgBr OH Cl HCl 10% 9 4 3 Cl 3a H R1 O MgBr R1 O MgBr O N N N N 2 X H X X X R R 9 H
7 6 5 2 R1 R N X 8 X N H MgBr R1 R H 1 56 R O BrMgO Scheme 2 Bisindolylmethane formation in strong acidic media N MgBr NMgBr NH4Cl R1 X R X R N 45 The third key step is the 1 aza 1’ oxa [3,3] sigmatropic rearrangement of the N aryl O vinylhydroxylamino magnesium H X salt 6 (Scheme 1) in order to justify the substitution pattern in the 9 final indole nucleus. 51 After publication of our hypothetical 2, 3, 4 a: R=R1=H mechanism, other reactions of aryl Grignard reagents with 1 b: R=Ph, R =H 50 nitroarenes were justified surmising a mechanism superimposable 1 c: R=Me, R =H with our speculation. For instance, the treatment of 3,4 d: R=R1=Me 1 dinitrothiophene with an aryl Grignard reagent (but not e: R=H, R =Me Scheme 1 Proposed mechanism 52 aryllithium reagents) was found to result in the reduction of one nitro group to the nitroso intermediate accompanied by binding of In a fashion of such a mechanism the first step consists in the 55 the aryl to the oxygen atom of the N O double bond and by 10 nitro group reduction to nitroso derivative and this step is the Claisen like rearrangement to 2 (3 aminothiophen 2 yl)phenols only with clear experimental evidences. In fact, indolization was (Scheme 3). 59 51 observed starting from nitrosoarenes ( 5). Moreover, the More recently, Kurti and co workers succeeded in the elimination of an enolate molecule ( 3) has to lead ultimately to an synthesis of biaryls from ortho substituted nitrobenzenes and aryl 60 aldehyde or a ketone ( 4). Actually, in our experiments, aldehyde 60 Grignard reagents. They found that ortho halonitrobenzenes 15 was detected among the reaction products, but in very low undergo reduction to ortho halonitrosoarenes, followed by O amounts, when water soluble and volatile. However, one mole of arylation and sigmatropic rearrangement to 2 amino 2′ hydroxy 51 non volatile aldehydes was recovered per mole of nitroarene. 1,1′ biaryls and supported the mechanism with DFT calculations Recently, Ishikura and co workers recovered bisindolylmethane at the M06 2X/6 31G (d,p) level (Scheme 4). Thus, they stated 56 on quenching the reaction with 10 % HCl instead of NH 4Cl. 65 that the ortho halogen substituent changes the regioselectivity of 20 Authors explained the presence of bisindolylmethane by the rapid the aryl addition across the N O bond, leading to 1,1′ linked hydrolysis of vinyloxymagnesium bromide under strongly acidic biaryl products that were not observed by Knochel, who used conditions, and then the acetaldehyde can add in a Friedel Crafts ortho unsubstituted nitroarenes. 57 fashion (Scheme 2). Deprotonation of the intermediate 7 by means of a third The second step involves a very fast further attack of Grignard 70 vinylmagnesium halide allows re aromatization of the six 25 reagent at the nitroso group. In a single electron transfer triggered member ring. This step takes the alkene molecule ( 8) found reaction, the vinyl carbanion is turned into a vinyl radical and its among the reaction products into account. The reaction with 51 coupling to both termini of the N=O double bond is reported. In ω−styrylmagnesium bromide ( 2b ) with 2 chloronitrobenzene our speculation, the attack at the nitrogen terminus leads (X=Cl) demonstrates that one mole of styrene per mole of indole ultimately to aniline, which is actually recovered among the 75 is formed and deuterium labelling experiments on the same 30 reaction product, at the same manner of the reaction reported by reaction show that the alkene is formed during the reaction 57 Knochel with aryl Grignard reagents, whereas attack at the course, and not by aqueous quenching of the excess reagent. 51
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BrMg Helder and co workers developed the BIS for the synthesis of O N NO O2N NO O N N 2 2 p-TolMgBr 2 O substituted 4 aminoindoles, with yields comparable to those of p-TolMgBr 68 35 other substitution patterns. The Boc group is the most effective
S S S N protecting group (Scheme 5). Obviously, a further equivalent p-TolOMgBr of vinyl Grignard reagent is necessary, because of the presence of an acidic NH framework. Alternatively, a combination of two protecting groups can also be employed to produce protected 4 BrMg 40 aminoindoles in useful yields. In these cases, the Boc group is O2N NH2 O2N N OH + O H3O removed from the final product. Moving the amino group round the benzene ring and the use of substituted vinyl reagents often S S did not yield indole. The reason of these failures is to date unclear.
Scheme 3 [3,3] Sigmatropic rearrangement of nitroarenes of Boc H Boc H 59 N N dinitrothiophene 2a,e (4 equiv) THF/Et2O, -40 °C Ar OMgBr 1 N R NO 2 13-64 % N + X=H H3O Ar H H N X X Ph X=Br,Me ArMgBr 1 + ArMgBr 5 X1 O MgBr Boc R R H ArOMgBr N N N 2a (3 equiv) X THF/Et2O, -40 °C
NO 2 30-47 % N H OH 1 Br Br NH2 X O X1 + MgBr H3O N R=Et, 4-MeOC H X 45 6 4 X Scheme 5 Synthesis of substituted 4 aminoindoles. 68
69 Conversely from the reaction of alkyl Grignard reagents, BIS 70,71 5 Scheme 4 Reaction of nitroarenes with aryl Grignard reagents; top occurs at 78 °C also on dinitrobenzene derivatives. from ref 57, bottom from ref 60 Considering the high stabilization of dinitrobenzene radical 72 50 anions, the occurrence of the reaction is quite surprising. At the end of the reaction, acid quenching adds hydrogen atoms BIS can be carried out on solid support, thus avoiding the to all the metallated positions and allows the aromatization step tedious separation procedures. 58 More recently, Braese’s group of the five membered ring by dehydration. presented scope and limitation of this procedure, finding the best 10 In conclusion, the Bartoli indolization follows a very complex yields and purities at −40 °C. 73 However, they observed the mechanism, but its comprehension makes predictable drawbacks, 55 failure of the reaction with 2 hydroxynitrobenzenes and 2 limitations, and advantages to allow chemists to use the reaction methoxynitrobenzenes that led to very complex mixtures. appropriately during retrosynthetic analysis. 52 Also Menendez’ group did not observed BIS with 5 (or 6 ) The greatest advantage of the BIS undoubtedly is the ready 70 61 nitroindoles, but products from vinylation through an addition– 15 availability of the starting materials. Many nitroarenes are elimination mechanism from ipso attack to a substituted ring available from chemical product suppliers or nitro group can be 60 position were recovered (Scheme 6). They attributed this directly introduced onto an aromatic ring by simple electrophilic preference to the fact that direct conjugation with the indole substitution through several methods. 61 Moreover, the BIS is nitrogen renders the N O double bond of the nitro group complete in few minutes at low temperatures ( 40 °C and lower), insufficiently electrophilic to be attacked by the Grignard reagent. 20 thus saving many labile substituents or protecting groups. The They supported this assumption, studying the product distribution reaction can be easy scaled up and many examples are reported in 65 of other reaction of vinylmagnesium bromides with some the literature. 62 65 aromatic compounds containing electron releasing substituents It is worth noting that the reactivity of Grignard reagents conjugated with the nitro group. 70 Related 5,8 dimethoxy 1,4 towards nitro and nitrosoarenes is much higher than that of many dimethyl 6 nitroquinolin 2(1H) one undergo both vinylation and 25 carbonyl functions, such that the reagent is completely consumed Bartoli indolization depending from substitution of the Grignard in the indole formation before having a chance to attack any other 70, 74 70 reagent. Moreover, methoxy substituted 4 nitroanilides reactive moiety. 58, 66, 67 Thus, only few very highly reactive undergo vinylation, 70 whilst methyl substituted ones undergo only electrophilic functions on the starting nitroarene need protection, Bartoli indole synthesis.75 in particular aldehyde and hydroxyl moieties. Actually, Dobson The main consequence of the mechanism described above is 30 was interested in these protections and set up the optimum that ortho substitution in the nitroarene is crucial for the reaction protecting groups for both hydroxyl and formyl moieties. 62, 63 75 to proceed in good yields. In fact, the addition of vinyl Grignard The amino group is another function needing protection.
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reagents to meta or para substituted nitrobenzenes for the aromatic nitro compounds, which possess peri steric hindrance, preparation of 4(6) or 5 substituted indoles, respectively, always give benzindoles. The steric hindrance emanated by the H 8 furnished unsatisfactory results (yields not exceeding 15 %). addresses vinylmagnesium halides towards oxygen atoms of 1 However, Dobbs found that bromine can work as a transient nitronaphthalene, 5 nitroquinoline 47, 78 or 5 nitroisoquinoline, 79 76 5 group. Actually, the Bartoli indolization of meta or para 25 leading to benzo or pyridoindoles respectively. substituted 2 bromonitrobenzenes followed by removal of the Silva and co workers proposed the synthesis of bromine atom by reduction with tributyltin hydride led to 4(6) or cyclopenta[g]indole derivatives taking advantage from the steric 5 substituted indoles in satisfactory overall yield (Scheme 7, top). hindrance of the nitrodihydronaphthalene (Scheme 8).80 The key This modification can give a significant reduction of the steps steps in the sequence are the BIS to build the indole nucleus and a 10 required for the preparation of many complex 7 unsubstituted 30 thallium(III) mediated ring contraction reaction to transform the indoles, whose functions are tolerant to the reaction conditions, cyclohexenone moiety into a functionalized cyclopentyl unit. but not to classical indole syntheses. 1. NaBH4, MeOH 2. TsOH R2 MgBr R3 4 3. 2a, THF, -45 °C R O O OMe R N 2 NO2 53 H R3 R4 N R OMe R O 1 O N % R 2 1 N R 1. Boc2O, DMAP, MeCN N 72 % OMe Me 2. Tl(NO3)3, CH(OMe)3 OMe Me - 50 °C
3 MeO OMe R R N O2N 2 R4 1 R MeO Boc R R Scheme 8 Synthesis of cyclopenta[g]indole 80 N O 2N Me R1 OMe R1 N NO 2 2a, THF, R -78°C to-20°C OMe Me N N 1 22-35 % N O O R H NO2 N 1 R R= OMe, O(2-FC6H4), Cl, R = H, Br Br Br 2 NO2 9 2a, THF, 1 R -78 °C to -20 °C R N
OMe OMe N 11-50 % N H Scheme 6 Limits of BIS with aromatic compounds containing R1 R 15 electron releasing substituents conjugated with the nitro group: top from 1 ref 70 , bottom from ref 77 R=Me, OBn, OMe, Cl, R = H, Cl 81 35 Scheme 9 Synthesis of 4 and 6 azaindoles NO2 2, R R X Bu3SnH X Br -40 °C, Wang and co workers successfully undertook a systematic study THF AIBN, PhMe 1 R R1 of Bartoli indolization on nitropyridines with the aim to develop a (43-65 %) N (81-92%) N general and efficient method for preparing azaindoles (Scheme X H H 9). 81 Yields (11–50 %) are comparable with most other indoles Br Br 40 obtained by BIS, and mainly, comparable or higher than the previous multi step syntheses of these compounds. 4 And 6 N 2a, THF, N -78 °C to -20 °C azaindoles were prepared, but not 5 azaindole, although the authors reported the probable application by the use of an N NO 2 18 % H appropriate nitropyridine. The presence of a chlorine atom in a 45 conjugated position to the nitro group increases the yields. H2, 206-276 kPa 88% Therefore, chlorine is sometimes used as a promoter similar to 95 % EtOH bromine in the indole series (Scheme 7, bottom). Interestingly, 2a, THF, Cl N -78 °C to -20 °C Cl N the effect of the chlorine atom on nitropyridine is not observed in the strictly related quinoline system. 82 In fact, Mansell and co NO2 N 50 workers found that 5 chloro 1H-pyrrolo[2,3 f]quinolines can be 50 % H prepared in a more efficient manner using the Batcho Scheme 7 Bromine (top) and chlorine atom (bottom) as promoters Leimgruber 83 than the Bartoli reaction, but they observed the opposite in the synthesis of 1H pyrrolo[2,3 f]quinolines. A BIS is extendible to more complex systems than nitrobenzenes, reasonable explanation of the two different behaviours is not yet 20 with crowding near the nitro group. For instance, bicyclo
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reported. 1. LiHMDS, THF, The substitution on 2 and 3 positions of the indole nucleus is MeOCH2Cl, KOH, I2, I -78°C to-20°C O unfortunately limited both by the availability of the DMF, 2. RuCl3.3H2O, corresponding Grignard reagents and by the shape of the vinyl 0 °C NaIO4, 0 °C O 5 radical intermediate. In the latter case, nitrosoarenes could be a N N N solution for instance in the preparation of 2 phenyl and 2 H H Br Br OMe (trimethylsilyl)indoles. 52 Moreover, the use of nitrosoarenes saves Br 10 one mole of the Grignard reagent, but they are less available, less 11 (overall yield 68%) stable, and, often, their dimeric forms lead to byproducts 84 Scheme 10 Synthesis of MOM protected 7 bromoisatin 10 lowering indole yield, if particular reaction conditions are not adopted. Luckily, indole chemistry has developed many strategies O2N for functionalization of 2 and 3 positions after the creation of the indole core, thus these drawbacks can be easy overcome. 46 Br OMe Notwithstanding the low atom economy of the reaction, BIS 12 15 should be considered a “green reaction” because magnesium ion is practically non toxic, so low concentrations into the recovered indole do not represent a problem when indole itself is used as a 2a, THF, <5 °C 1. BBr 3, CH2Cl2, -78 °C to rt 2. BnBr, K2CO3, Me2CO drug. Conversely, palladium salts, 40, 43 used as the catalysts in some indole syntheses, must be completely removed, owing to OMe O2N 20 their human high toxicity. In conclusion, since its appearance in the literature, the Bartoli Br OBn N indole synthesis has provided a useful way to key intermediates H for the synthesis of complex indoles. The core of this review is Br dedicated to synthetic applications of BIS appeared in literature 1. CuCN, DMF, 160°C 2a, THF, <5 °C 25 since 2005, being the more ancient literature covered by our 2. NaSEt, DMF, 120 °C 48 previous review. Syntheses will be itemized based on starting 7 OH OBn substituted indole.
2. Syntheses from 7-Haloindoles N N H H 7 Haloindoles, and in particular 7 bromoindole ( 10 ), are useful CN Br 30 intermediates in the synthesis of many interesting indole 13 derivatives. For instance, 10 is the starting material for the (18% overall yield) synthesis of MOM protected isatin 11 (Scheme 10). Compound 1. RX, Na 2CO3. DMF PdCl2(dppf). CH2Cl2 2. H2O 2, K2CO3, DMSO dppf, Et3N, EtOH, 11 is then employed as useful building block for the ring F and E 35barCO, 130 °C of the complex cytotoxic peptide diazonamide A (Figure 1, blue 84, 85 OR OBn 35 coloured), isolated from the marine ascidian Diazona species. Grant and co workers proposed BIS for the preparation the medicinal interesting 3 substituted 4 alkoxyindole 7 86 N N carboxamides. After construction of the indole ring by reaction H H of 5 methoxy 2 bromonitrobenzene ( 12 ) with vinylmagnesium CONH2 CO2Et 40 bromide, cyanation was performed using copper(I) cyanide 14 15 followed by demethylation with sodium ethanethiolate to afford (22 % overall yield) the 4 hydroxyindole 13 and, finally, hydration of nitrile to amide 60 Scheme 11 Synthesis of 3 substituted 4 alkoxyindole 7 carboxylic 86 14 (Scheme 11). This synthesis was not very efficient (18 % acid derivatives overall yield for the three steps from 12 to 13 ). However, benzyl It is interesting to note that 7 bromo (17 ) and 4,7 dibromo 5,6 45 protection of starting nitrophenol 12 and replacing the cyanation dimethoxyindole ( 18 ) are also obtained by treatment of the with a carbonylation reaction resulted in improved yields (22 % corresponding nitroarenes with 4 equiv. of vinylmagnesium overall with four reaction steps). Moreover, the reaction was 88 65 bromide. The nitroarenes, in turn, can be easily prepared by more scalable, providing more than 10 g of ester 15 . bromination of the commercially available 5 nitroguaiacol ( 16 ) Sugden and co workers prepared a series of 7 substituted (Scheme 12). 50 melatonin and 1 methylmelatonin analogues and tested them 4,7 Dibromoindole ( 19 ) was the starting material for the against human and amphibian melatonin receptors. 7 Substituents preparation of a series of 4,7 diarylindole derivatives ( 20 ), which reduced the agonist potency of all the analogues with respect to 70 show significant changes in UV Vis and fluorescent intensity melatonin in the Xenopus laevis melanophore, but 7 with addition of iodides, thus behaving as selective iodide bromomelatonin was among the less reducing compounds. 7 chemosensors (Scheme 13). 89 Moreover, compound 19 was used 55 Bromomelatonin was prepared from 2 bromo 4 also in the synthesis of an indolyldipeptide, starting material for 87 methoxynitrobenzene (see also section 2). the synthesis 2,5 diketopiperazines ( 21 ) promising compounds 90 75 for the treatment of some human diseases.
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OMe 1) Br2, AcOH OMe OMe NO2 2) K CO NBS, TFA OH 2 3, OMe Br OMe Br F F Me SO H2SO4 2c, THF 2 4 - 50 °C 68% 88% Br 42% N N Br H NO2 NO2 NO2 F Br Ar R 16 O 66% 2a, THF, -40° 2a, THF, -40° 38% S O N O H Br
MeO MeO R= CF3, 2-thienyl, 4,5-Cl2thien-2-yl, 4-FC6H4, 3,5-F2C6H3, 3,4-F2C6H3, 2,4,5-F3C6H2, N-piperidyl Ar= 4-F-C6H4, 3-CNC6H4, 3-MeOC6H4, 2,4-Cl2C6H3, 3,4-F2C6H3, 2- MeO N N H MeO naphthyl H N O Br Br O N N 17 18 O Scheme 12 Synthesis of 7 bromo 5,6 dimethoxyindole ( 17 ) and 4,7 88 dibromo 5,6 dimethoxyindole ( 18 ) Scheme 14 Synthesis of some indole derivatives analogues to human 91 EP 3 receptor antagonists Br Br Br CHO 1. 2a, THF, -40° NO 2. HClaq/THF POCl3 DMF 2 CHO X POCl3 47% 79% 2a,THF DMF NO N N 2 H H Br Br Br N 80% N H H 19 X X ArB(OH)2 4 steps S 22 23 24 a,b PdCl2(PPh3)2 40-81% (33%) a: X=Br a: 42% Cs2CO3, DMF/H2O b: X=F 70% S O b:14% O N c: X=Cl H Ar CO H O 2 AcOH, NaOAc HN 1. NaOH Br N N SH aq S 2. HCl S N H 50-70% HN O N N Ar H H 20 21 X X 30 Scheme 15 Synthesis of 7 haloindolylmercaptoacrylic acid Ar= 3-pyridyl, 3-thienyl, 3-FC6H4, 3-(CONR2)C6H4 derivatives 93 (R=Et, pyrrolidine, piperidine, O
HN 1. O O O N R 89 R N 5 Scheme 13 Synthesis of iodide chemosensors ( 20 ), and 2,5 piperidine, 110 °C 90 diketopiperazines ( 21 ) 2. CoCl2, NaBH4, N O MeOH/THF (1:1), rt H 24c Singh and co workers prepare some indole derivatives analogues N 91 25–50% H to human EP 3 receptor antagonists with good activity. The EP 3 X receptor is one of eight G protein coupled receptors that belong 25 R= Me, Et, Bu, i-Pr 10 to the prostanoid receptor family. Prostanoids are ubiquitous O Me autocrine mediators involved in numerous physiological and N pathological processes including inflammation. For the synthesis HN of 1,7 disubstituted analogues derived from 5 fluoro 3 S methylindole core, BIS revealed the reaction of choice for N H 15 laboratory scale (Scheme 14). However, scale up of the reaction 27 for the preparation of DG-041 (Figure 1) revealed difficult. 92 23c Cl 7 Halo 3 indolecarbaldehyde ( 23 ) prepared by the BIS and CH2Oaq, Me 2NH, MeNCS, Et3N,CH2Cl2, rt Vilsmeier Haack sequence is also the starting material for many AcOH, rt 1. (EtO2C)2CHNHCHO, biological interesting products. For instance, it served as key NaOH, toluene, heat COOH 2. aq NaOH, THF, rt, NMe2 20 building block for the synthesis of a series of monohalide 3. AcOH, 4. HCl heat, NH2 mercaptoacrylic acid derivatives, which were employed in a 5. pH adjusted to 6.0 study of SAR on the efficacy of these molecules for inhibition of 2+ 93 N N Ca activation of calpain 1 (Scheme 15). Yields reported in H H this work confirmed the decline from voluminous bromine to Cl Cl 26 55 25 small fluorine atom. Scheme 16 Synthesis of 5 (1H indol 3 ylmethyl)hydantoins ( 25 ) and 5 (1H Indol 3 ylmethyl) 2 thiohydantoins ( 27 ) 94
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Moreover, compound 23c allowed the synthesis of 5 (7 chloro 25 biological activities, such as potent carcinogenicity or 1H indol 3 ylmethyl)hydantoin ( 25 ) (Scheme 16), while 5 (7 antibacterial activity, thus Ishikura and co workers prepared chloro 1H indol 3 ylmethyl) 2 thiohydantoin ( 27 ) was prepared various derivatives combining BIS and Friedel Crafts reaction in from the corresponding tryptophan 26 , but always starting from the presence of an additional aldehyde or isatin in a one pot 94 56 5 7 chloriondole ( 23c ). These hydantoins are also called manner. necrostatins, since they are found to be involved in necroptosis 30 7 Bromo substituted indole derivative (30 ) showed activity inhibition and can provide lead compounds for therapeutic against human cytomegalovirus and varicella zoster virus development. A SAR study revealed that 7 substituted derivatives comparable to that of classical acyclovir. It was obtained in four such as 25 and 27 resulted in increased activity with respect steps from naturally occurring dehydroabietic acid (29 ), a natural 67 10 unsubstituted ones. occurring diterpenic compound (Scheme 18). Barret and co workers enantioselectively prepared 7 chloro 1 35 However, the most important application of haloindoles methyltryptophan derivative 28 from 1 chloro 2 nitrobenzene by prepared by BIS is the synthesis of cis and trans-trikentrins BIS (Scheme 17), 95 and used 26 as the key intermediate in a four (Figure 1). Trikentrins are cytotoxic indole alkaloids isolated steps synthesis of CJ 12662, (Figure 1) a potent anthelmintic from marine sponges of the Trikentrion genus. They are 15 natural product from the fermentation broth of Aspergillus constituted by a cyclopentane ring annulated to the 6 7 carbon 96 fischeri var . thermomutatus . 40 carbon bond of the benzene ring portion of the indole.
MeO CuBr 1. 2c, THF, -40°C 2, N Br t-BuONO Br 2. Boc O, DMAP, MeCN 2 MeCN, 3. NBS, AIBN, CCl 80°C Br2, rt, 1 h 4, 60°C, 1 h 4. 2(R)-isopropyl-3-6-dimethoxy- N CH2Cl2/MeOH 2,5-dihydropyrazine, n-BuLi, -80 °C OMe 22c NO2 99% Br NO2 90% Br NO 2
32% N NH2 NH2 Br Cl Boc 31 32
1. xylenes, 160 °C; NaH, 2a, THF, 50% MeI, DMF, 0 °C -40°C, 20min 76% 2. HCl/THF, 0-20 °C; (Boc)2O, Br Br EtNiPr2, dioxane, 0-20 °C NaH, PgX CO2Me
Br N N NH2 Br H Pg Br Br 33 N R Cl Boc Y R 28 N Pg Scheme 17 Synthesis of 7 chloro 1 methyltryptophan 95 N n-BuLi -78° to rt Br Y Pg Y=O, CH R2Zn R Y R 1. CH2N2 2. Br2, 0 °C, Br R Montmorillonite K10 Heck or Stille COOH COOMe N N 29 Y Pg HNO 3, overall Y Pg H2SO4 53% 34 -18 °C R2NH Br Br Buchwald-Hartwig Ar H ArB(OH)2 N NO2 Suzuki-Miyaura NR2 1. 2a, THF, -78 °C 2. NH4Claq N Y Pg N 70% COOMe COOMe Y Pg
30 Scheme 19 Synthesis of 4,6,7 tribromoindole 97 20 Scheme 18 Synthesis of 7 Bromo substituted indole from dehydroabietic acid 67 Buszek and co workers prepared the very versatile 4,6,7 tribromoindole ( 33 ) by BIS. This synthesis is an example of the In section 2, the synthesis of bisindolylmethane derivatives was 45 easy availability of the starting materials for BIS, since the already mentioned as a support of the reaction mechanism starting nitroarene is prepared in two easy steps from the (Scheme 2). However, many bisindolylmethane alkaloids show commercial 2 nitroaniline ( 31 , Scheme 19). 97 Starting from 33,
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they prepared two libraries (93 members98 and 66 members, 99 also the synthesis of (±) cis trikentrin B (Figure 1), but respectively) of annulated indoles, combining indole aryne application of the Bartoli indole synthesis to 2,3,4 cycloadditions at the 6,7 positions and both the Suzuki Miyaura tribromonitrobenzene afforded the desired 5,6,7 tribromoindole and Buchwald Hartwig condensation at the 4 position. These only in 32 % yield. They then succeeded in the synthesis of 102 5 structural entities could have unique chemical property and 30 desired indole in 61 % yield by Leimgruber–Batcho route. should be reasonably amenable to both biochemical and cell An alternative route to trikentrins contemplates a Friedel based assays. In particular, members of the 66 library were tested Crafts acylation of 7 alkylindole and it was especially employed in vitro in L1210 leukemic cells with promising results. 99 in the preparation of the more challenging trans trikentrins, the Buszek’s group also studied the effects of pyrrole and benzene synthesis of which have serious problems associated with the 10 ring substitution patterns on the regioselectivity of 6,7 indole 35 formation of the trans 1,3 dimethylcyclopentyl unit. aryne cycloadditions with 2 tert butylfuran. The results of this Silva and Craveiro synthesized trans trikentrin A preparing the investigation revealed a remarkable regiocontrol by substitution indole nucleus by BIS, from 4 bromoethylbenzene ( 37 ), followed at the 3 position, whereas most of 4 or 5 substituents generally by Heck coupling to add the carbon atoms that will originate the markedly reduced selectivity except for 4 ethyl and 4 iodo nonaromatic cycle. Friedel Crafts acylation allowed the second 100 15 cases. Moreover, they prepared intermediate 36 , a key 40 ring closure to 39 . Finally, the thallium(III) mediated ring intermediate for the preparation of (±) cis trikentrin A. contraction reaction 80 allowed to obtain the trans 1,3 disubstituted five membered ring in a diastereoselective manner 33 Et (Scheme 21). 103 76 % NaH, TBSOTf They were also successful in the first total synthesis of (+) DMF, 0 °C 45 trans trikentrin A by using a kinetic resolution of ester 40
Br performed by using the enzyme Amano PSCII, which is a NH2 formulation of Pseudomonas cepacia lipase immobilized on a 35 ceramic substrate, which achieved acid ( S) 41 (Scheme 22). 104 (CH2Cl)2, H2O This step is one of the eight necessary to transform 38 in 39 Br N 50-80 °C then 50 (Scheme 21). Br TBS 96% 1. Ac2O 2. HNO Et Et 89 % n-BuLi, PhMe, 3 Et -78 °C to rt 3. NaOH HNO 100% 3 2a, THF, -40° 0°, 3h Et 47% Br 37% N NO 2 H Br Br Br
NO 37 N 2 38 NH TBS 2 49% 7 steps
Br2/CuBr 2 t-BuONO 82% Et Et CF COOH 70 % Et2Zn, Pd2(dba)3 (4 mol%) MeCN, 50 °C 3 P(t-Bu)3.HBF4 (16 mol%) (CF3CO)2O THF 65 °C Et O N 55% N Et Ph Ph HOOC Br NO 2 39 N Br 18% 9 steps TBS 2a, THF, 52% -40 °C n-BuLi, PhMe, rac-trans-trikentrin A 36 -78 °C to rt Scheme 21 Syntheses of (±) trans trikentrin A proposed by Silva 103 77% Et Et KHMDS, Et Et TBSOTf kinetic 4 steps THF, -78 °C resolution
N 73% Br N rac-cis-trikentrin A Br N N H Br TBS Br MeO 2C Ph HO 2C Ph Scheme 20 Syntheses of (±) cis trikentrin A proposed by Buszek: 97 101 left ( ) right ( ) 40 (S)-41 Scheme 22 Kinetic resolution for asymmetric preparation of trans 20 The same research group published a second synthesis of (±) cis 104 55 trikentrin A trikentrin A from 4 ethyl aniline ( 35 ) by a very similar reaction sequence (Scheme 20). 101 The two reactions have similar yields Finally, enantiomerically enriched cis trikentrins A and B were (21 % overall from 31 to 36 with respect to 23 % overall from 35 prepared by asymmetric hydrovinylation of vinylindoles at −78 to 36 ). °C under 1 atm of ethylene. Starting 7 vinylindoles ( 42 and 44 ) 25 Prompted by these achievements, Buszek’s group attempted are achieved from BIS of the corresponding bromonitrobenzenes,
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105 followed by vinylation with vinylstannane (Scheme 23). 25 Toluene or xylene is used as solvent to allow increased reaction Enantioenriched compounds 43 and 45 were converted into (+) temperature and improve the solubility. Examples of these cis trikentrins A and B in 8 and 11 steps, respectively. reactions were already described in schemes 19, 21, 23. Moreover, an interesting Stille reaction is reported to give the 1. 2a, THF, -50 °C CH2=CH2 fluorescent 2’ and 4’ pyridyl 7 substituted indoles in good yield 2. SnBu3 cat (2 mol%), 30 from coupling between the corresponding pyridyl tri n NaBAr Pd(PPh3)4, KF, 3 butylstannane and 7 bromoindole (Scheme 24). 106 It is worth of PhMe, heat CH2Cl2, - 78 °C 22a note that the position of the nitrogen atom on the pyridylstannane 42 % N 98 % y N H 99 % ee H strongly influences the reaction yields, but no explanation is given. The ortho and para derivatives are obtained in 83 % and 35 25 % yields, respectively. 42 43 Manabe and co workers found that dichlorinated benzo fused CH2=CH2 nitrogen heterocycles, such as 5,7 dichlorindole, undergo site SnBu3 Et cat (2 mol%), Et NaBAr selective cross coupling with Grignard reagents in the presence of Pd(PPh3)4, KF, 3 PhMe, heat CH2Cl2, - 78 °C PdCl 2(PCy 3)2 at the ortho positions to the nitrogen. Authors 38 99 % y 40 envisaged that an interaction between Lewis acidic Mg and Cl of 68 % N N 107 H 96 % ee H the ortho position facilitates C–Cl bond cleavage (Scheme 25). This procedure allowed the preparation of 7 alkyl 5 chloroindole
44 45 starting from 2,4 dichloronitrobenzene, arranging BIS and site selective cross coupling. In addition, Suzuki coupling can attach 108 43 (+)-cis-trikentrin A 45 (+)-cis-trikentrin B 45 a 6 tetrahydroquinolinyl substituent to 7 bromoindoles.
NO2 1. 2a,THF, -40 °C Cl Cl 2. NH4Cl
N Ar= (yields not reported) H P Cl OO F3C CF3 Cl 4-MeOC6H4MgBr (3 equiv), Br2Ni PdCl2(PCy3)2 (4 mol %) 2 Cl THF, 18 h
Cl cat N H N 5 Scheme 23 Asymmetric synthesis of key intermediate for 60 % trikentrins 105 Pd MgBr Cl
N OMe N Sn(Bu)3 Sn(Bu)3 Scheme 25 Preparation of 7 alkyl 5 chloroindole 107
N Pd(PPh3)4, Pd(PPh3)4, N H PhMe, reflux PhMe, reflux H Finally, 7 bromoindole is the starting material of many 23a interesting key intermediates such as 7 formyl ,63 7 N 25% 109, 110 111 83% 50 carbomethoxy , and 7 amino indole, since these N procedures are more convenient than directed metallation of the Scheme 24 Synthesis of 2’ and 4’ pyridyl 7 substituted indoles by 7 unsubstituted indole. Stille reaction 106 3- Syntheses from 7-Alkylindoles 10 Differently from Buszek’s approach (see above), in this reaction the 6 substitution performed after indole nucleus formation This section will be devoted to reactions, which employ should be noted. 55 alkylnitrobenzenes for the preparation of 7 alkyl and 7 7 Alkyl and 7 arylindoles are another very important class of arylindoles. compounds widely used in the synthesis of naturally occurring Conversely from the 2’ and 4’ pyridyl derivatives (Scheme 15 indoles. Both compounds have been synthesized by means of a 24), the 7 (3’ pyridyl)indole synthesis is unsuccessful either by two step protocol involving Bartoli indolization that precedes or Stille (with 3’ pyridyl tri n butylstannane) or Suzuki (with 3’ follows classical couplings of aryl bromides. In this section, we 60 pyridylboronic acid) couplings on 7 bromoindole. The synthesis report reactions in which Bartoli indolization precedes the can be, however, accomplished by preceding Stille coupling to coupling. Bartoli indolization (Scheme 26). 106 20 For instance, Suzuki couplings of indole bromides and Moreover, when the appropriate 7 bromoindole is not commercially available substituted phenyl boronic acids all occur available (see previous section), ortho (6 tetrahydroquinolinyl) in high to excellent yields. Another typical reaction of aryl 65 nitrobenzenes can be cyclised by BIS with comparable yields, halides is the Stille coupling with arylstannanes, which is (Scheme 27). 108 By this way a series of nonsteroidal performed under anhydrous conditions in aprotic solvents. glucocorticoid receptor ligands based on a 6 indole 1,2,3,4
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tetrahydroquinoline scaffold was prepared. of insulin (Scheme 29). This synthesis is extended to a series of 30 methyl derivatives of DAQ B1 starting from the appropriate N bromonitrotoluenes, some commercially available, other easily Sn(Bu)3 prepared from the corresponding aniline by m CPBA 116 Pd(PPh3)4, 1. 2a,THF, -40 °C N oxidation. NO2 2. NH Cl PhMe, reflux 4 H 7 Piperazinylindoles ( 47 ) are also obtained starting from 2 22a 83% 58% 35 fluoronitrobenzene or fluoronitropyridines treated with N Boc N N piperazine and cyclised with vinylmagnesium bromide (Scheme Scheme 26 Synthesis of 3’ pyridyl 7 substituted indoles 106 30). Then, an aryl sulfonyl group is introduced onto the 3 position of the indole nucleus by reaction with the appropriate R R disulphide. Oxidation with m CPBA and acid deprotection, 40 complete the steps for the preparation of a series of indole O O N 117 N sulfones ( 48 ) with high 5 HT 6 receptor affinity. B H H Br Cl Cl 1. PhLi, -78 °C PdCl2dppf, Et3N, 2.Br /TMEDA dioxane, Na2CO3, 100 °C
HN HN 3. 2a (6 equiv), DME, -40°C (yields 4. NH4Claq not 22a report N R ed) 50 % H R
Br Br NO NO2 O 2 1. I2 55% 2. Boc O, DMAP PdCl2dppf, Et3N, Cl Cl 2 3. t-BuLi, Bu3SnCl dioxane, Na2CO3, Cl 100 °C 2a, THF, -40 °C O SnBu 3 (yields not reported) HN NH NH O N 5 Scheme 27 Synthesis of 6 indole 1,2,3,4 tetrahydroquinoline Pd 2(dba)3, P(OTol)3 derivatives 108 Cl Boc Cl 76%
TMS O Pd(PPh3)2Cl2, PPh3, 1. 2a, DME, -40 °C N NO 2 NaOH, MeOH CuI, NEt3, THF 2. NH4Claq H demethylasterriquinone B1 22a NH 100 % 87% 43% Scheme 29 Synthesis of demethylasterriquinone B1 116 TMS TMS Scheme 28 Synthesis of 7 alkynylindoles 112 R The reaction of choice for the synthesis of 7 alkynylindole is the 113 Y Y SO2 10 alkylation of nitrobenzenes by Sonogashira coupling, followed Y 112 by Bartoli reaction (Scheme 28). 7 Alkynylindole has been X X then used for Diels Alder reactions with cyclopentadienones, to NO2 N 1. NaH, DMF X H 2. [(R)C6H4S]2 N H afford substituted biaryls of biological interest. N 2a, THF, N 3. m-CPBA, CH2Cl2 -40 °C 4. HCl, dioxane N Furthermore, allyl bromides are found to react easily with 2 11-51% 15 lithionitrobenzene, carefully prepared from 2 bromonitrobenzene, N N 8-56% N to avoid biphenyls or by products arising from reduction of the Boc Boc H 114 nitro group. These compounds undergo BIS, if some 46 47 48 X=Y=CH, R=Cl modifications to the original procedure are made. In particular, X=N, Y=CH, R=H DME is used as the solvent to increase the solubility; otherwise, X=CH, Y=N, R=H 117 20 heterogeneous mixtures occur in other ethereal solvents. 45 Scheme 30 Synthesis of 7 piperazinylindoles Moreover, higher yield is obtained, if the Grignard reagent is Indolocarbazoles, namely indolo[6,7 a]pyrrolo[3,4 c]carbazoles, always in excess throughout the reaction. Therefore, the are potent inhibitors of cyclin D1/CDK4. Cyclin D1/CDK4 and nitroarene is added to a six fold excess of Grignard solution. 115 related molecules play an essential role in the transition of cells 7 Prenylindole, prepared by this method, was transformed into from G1 to S phase. Several tumours are found to have major 25 the Boc protected 3 tributylstannane derivative, followed by 50 alterations in this pathway. Numerous efforts are undertaken to Stille coupling with the appropriate indolylquinone and modify the polycyclic structure to obtain analogues with hydrolysis with methanolic NaOH targeting improved pharmacological profiles. Many syntheses start from 7 demethylasterriquinone B1 (DAQ B1), a small molecule mimetic substituted indoles and often represent an elegant application of
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BIS and its modifications. strategy is to perform a photo oxidation reaction. In particular in the range of years covered by this review, the During the preparation of a library of 5 vinyl 3 synthesis of indolo[6,7 a]pyrrolo[3,4 c]carbazoles has been 20 pyridinecarbonitriles to be evaluated as PKC θ inhibitors, published in two phases. 118, 119 Silyl protection of 2 (2 derivative 52 was prepared from 2,5 dimethyl 4 nitroaniline 75 5 nitrophenyl)ethanol followed by BIS produces the protected 7 (2 using vinyl Grignard reagent. Removal of the acetyl protecting hydroxyethyl)indole (Scheme 31). Glyoxylation with oxalyl group produced the desired 5 amino 4,7 dimethylindole, which chloride, followed by in situ quenching with MeOH/NaOMe, was then converted into 52 in two reaction steps (Scheme 32). It affords, after spontaneous desilylation, compound 49 . 25 was found to be the most potent and selective compound with an
IC 50 value of 34 nM for the inhibition of PKC θ and 41 fold NO 2 selectivity over PKC δ. Unfortunately, the yield of this synthesis OH is not reported. N H CHO NO2 1. TBDMSCl, 1. NaH, MeI H2N 54% imidazole, CH2Cl2 92% 2. EtOCOCl, NaCN, 1. 2a, THF 2. 2a, THF, -60 °C n-Bu4NCl, THF 2. KOH,EtOH N H NHAc Cl N N I CN H
EtO2CO CN N Ph OTBDMS EtOH Ph 1. (COCl) Et O, rt B(OH)2 I 57% 2, 2 Pd(PPh ) 1. H2 (344 kPa) Pd/C H 3 4 H 2. NaOMe, MeOH N OMe 84% 2. KOH, t-BuOH reflux N NaHCO 3 aq, DME O N N CN N CN N O H H N 52 N H 30 Scheme 32 Synthesis of 5 vinyl 4 indolyl 3 H2NOC 75 OH 50 pyridinecarbonitriles as PKC θ inhibitors
49 PhB(OH)2 (2.4 equiv) [Rh(C2H4)2Cl]2 (2.5 mol %)
NO 2 NO 2 72% t-BuOK, THF O
H N NBn2 O O (6 mol%) N KOH (2.5 equiv) Ph 5:1 dioxane:H2O Bu 80 °C, microwave Bu N 30 min H 79 % y 87 % ee HO 51 2a (3.3 equiv) CBr PPh 67% hν,DDQ,EtOAc 95% 87% 4, 3, THF, -40 °C CH2Cl2/THF Ph Bu
H H O N O O N O
N N N H
Scheme 33 Enantioselective synthesis of indole 120 N N H H Finally, a highly enantioselective rhodium catalysed additions of OH Br 35 arylboronic acids to alkenyl p nitroarenes appeared recently in 10 Scheme 31 Synthesis of the key intermediates for indolo[6,7 120 a]pyrrolo[3,4 c]carbazole derivatives. the literature. Authors reported the conversion of one product into indole by BIS, as an example of the synthetic utility of the 7 Formylindole, readily available from BIS,63 reacts with ethyl arylation products (Scheme 33). chloroformate to lead to cyanocarbonate. Hydrogenation and hydrolysis using KOH/ t BuOH at reflux afford an efficient 4. Syntheses from 7-Hydroxyindoles 15 practical synthesis of N methylindole 7 acetamide ( 50 ). The two indolic building blocks are coupled with t BuOK to form the bis 40 As reported above, the hydroxyl function cannot survive under indolylmaleimide 51 . For the carbazole formation, the preferred BIS reaction conditions; therefore, Dobson studied 2 nitrophenol
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protections in order to reach the optimum cyclisation yields. 62 The synthesis of (R) 3 (2 aminopropyl) 7 benzyloxyindole has Benzhydryl protecting group is demonstrated to be more efficient been accomplished starting from 7 benzyloxindole prepared by than both the originally suggested TMS group, 47 and many BIS. 124 After formylation at C 3, nitroaldol reaction provided the 62 others. Its efficiency is related both to the yields and to the ease 35 nitro olefin, which undergoes two reduction steps firstly with
5 of removal. NaBH 4 and then with Ni raney (Scheme 36). The racemic 7 Benzhydryloxindole obtained by this methodology was product is resolved with a tartrate salt. The (R) isomer (94 % ee) employed for the preparation of many biologically interesting is recovered as a solid, while the (S)-isomer remained in solution. indole derivatives. For instance, 3 bromo 7 benzhydryloxyindole The (S)-isomer can be then racemized and further resolved. is an intermediate used for the construction of the core structure 40 Compound 54 is the key chiral intermediate for the synthesis of 121 10 of the telomerase inhibitor dictyodendrin (Scheme 34). Starting AJ 9677 (Figure 1) a potent and selective adrenaline β3 agonist from indole 53 , strategies for different and orthogonal protections used in the treatment of obesity in diabetics. of both the 7 hydroxy and the NH moieties are also described. 2 Phenylpyrazolo[3,4 c]quinolin 4 ones, which are adenosine NO2 receptor antagonists, were prepared in fair yields from 7 CHO EtNO2, POCl3, AcONH4 15 substituted indoles derived by BIS from the appropriate DMF PhMe nitroarene. It should be noted that 53 , under these reaction N 99% N 95% N conditions, yielded a mixture (about 1:1) of the corresponding 6 H H H benzhydryloxy pyrazoloquinoline and of the 6 hydroxy OBn OBn OBn derivative (Scheme 35). 122 1. NaBH4, THF/MeOH Br 62% 2. H2 (0.1 MPa), NO2 2a, THF, NBS, THF Ni raney Ph2HCO -40 °C -78 °C to rt PhMe, 50 °C N 63% H 76% N NH2 H OCHPh2 OCHPh2 53
1. (Boc)2O, NaH, DMF 2. bis(pinacolato)diboron 78% KOAc, PdCl (dppf), N 2 H DMSO, 80 °C OBn O CO2H O p-Tol O B p-Tol
CO2H O dictyodendrin B (Figure 1) N + NH3 Boc OCHPh2 20 O COO- Scheme 34 Synthesis of the key intermediate for the preparation of 121 p-Tol dictyodendrin p-Tol N COO- O R R H H H PhNHNH2.HCl OBn ClCOCO2Et N AcOH/EtOH N O Et2O, reflux 2 N reflux 54 H 55-77 % 30-40 % N Scheme 36 Synthesis of (R) 3 (2 Aminopropyl) 7 R 124 45 benzyloxyindole CO2Et N R=OBn, Br, NHCO2Bn O Ph 1. H2, Pd/C 1. ClCOCO Et, 2 Ph2CHO OH 2. ClCH2CN Et2O, reflux H H 53 N 2. PhNHNH2.HCl, N O N O H AcOH/EtOH,reflux 65 % NC O 53 + 27 % 125 N N Scheme 37 Synthesis of 7 cyanomethoxyindole N N Merschaert group reported the synthesis in racemic and Ph Ph Scheme 35 Synthesis of 2 phenylpyrazolo[3,4 c]quinolin 4 ones 122 enantioenriched form of compound LY290154 (Figure 1) in a 50 gram scale starting from 7 cyanomethoxyindole prepared from 125 25 The bisindole alkaloid dragmacidin E (Figure 1) was isolated 53 (Scheme 37). LY290154 is a drug candidate to be an from a Spongosortes sp. collected in Australian waters. It is antagonist of leukotriene D4, the major slow reacting substance described as exhibiting potent serine threonine protein in human lung. Actually, asthma attacks are caused by production phosphatase inhibitory activity. The synthesis plan proposed by of slow reacting substances, triggered by pollen or other Feldman and Ngernmeesri commenced from 53, available via 55 allergens. 30 BIS. The synthesis led to the racemic form of dragmacidin E in over 25 steps. 123 5. Syntheses from Azaindoles
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Azaindoles, originated replacing one of the carbon atoms at In section 4, we mentioned indolocarbazoles as possible positions 4–7 in the indole template with a nitrogen atom, have 45 anticancer drugs (see for instance scheme 31), thus 3 medicinal relevance and they are frequently exploited as indole (azaindolyl) 4 arylmaleimides were prepared with the aim of bioisosteres in the design of biologically interesting molecules. In testing them for treatment of certain tumours. In particular 6 5 addition, azaindoles have also found applications in material azaindole derivatives were proepared from BIS like reaction synthesis and coordination chemistry. 126 128 through a reaction pathway surmising the synthesis of 6 137 Some applications of azaindoles prepared by Wang’s BIS 50 azaindole reported in Scheme 40. The only significant modification 81 are reported recently in the literature and are difference is the removal of chlorine atom with palladium on collected in this section. For instance, nitropyridines obtained charcoal in a basic medium. 10 from reaction of the appropriate fluoro compound with N Boc piperazine were successfully treated with vinylmagnesium I I bromide, as described above (Scheme 30), 117 to afford the desired 2 steps 2c, THF, 0 °C azaindoles. This experimental procedure was applied recently in N N N N patents relating to the design of 4 and 6 NO2 81% NO2 35 % H 129 131 Cl 15 azaindolyloxoacetylpiperazines as anti HIV drugs. OH Cl Moreover, in an effort to identify HIV 1 attachment inhibitors 56 with the potential to improve the clinical profiles of BMS 488043 4 steps and BMS 378806 (Figure 1), the same research group prepared a series of 6 azaindole, 132 and of 4 azaindole oxoacetic acid 133 20 piperazine benzamides by their modified BIS. X O Regueiro Ren and co workers prepared and tested another R= 3-ClC6H4, 3-BrC6H4, 3-MeOC6H4, 3-i-PrC6H4, 3CF3C6H4, 4-(THP), 2-MeOC6H4, series of HIV 1 attachment inhibitors with 4 fluoro 6 azaindole 2-ClC6H4, core, with the aim to target the viral envelope protein gp120. X= N-morpholino, NHCH2(4-THP), NH(4-THP), NHCH2(4-FC6H4), NH-cyclobutyl, N-pyrrolidinyl, N Substitution of the bromine atom in the 7 position of 55 with N-piperidinyl, N-azepinyl N H 25 amides, C , and N linked heterocycles provided compounds with HN good pharmacokinetic profiles in vivo . The synthesis of these R Scheme 39 Synthesis of azaindole derivatives for SAR of compounds used BIS modification as the key step for the 135 55 cannabinoid receptor agonist formation of indole nucleus (Scheme 38). 134
PdCl2(dppf), F NH2 F 2a,THF TMEDA, NaBH4, 5 steps 2a,THF -78 °C THF, rt, 24 h -20 to 0 °C N N N NO 2 38 % N N 71% H N N N H 29% NO2 23-33% N Cl Cl H OMe Br Br 55 14%
5 steps O Cl AlCl3, CH2Cl2, O RX, O O NaH, O X=CONH2, CONHMe, 5-oxazolyl, F N DMF N 2-(1,3-oxazolyl), 5-pirimidyl, 5-pyrazinyl, N 3-(1H-pyrazolyl), 1-(1H-pyrazolyl), 1-(1H-triazolyl), 2-(2H-triazolyl) 16-84 % N N RN HN N Ph H X O R=n-C5H11,MeO(CH2)2 30 Scheme 38 Synthesis of the 4 fluoro 6 azaindole core, key Scheme 40 Synthesis of azaindole derivatives for SAR of intermediate for preparation of HIV 1 attachment inhibitors 134 cannabinoid receptor agonist 136
135 136 Giblin’s and Blaazer’s groups independently proposed 6 R1 R1 1 3 steps azaindole derivatives as interesting candidates for structure R NO2 2a, THF R R activity relationships of cannabinoid receptor agonists. Both -78 °C N N 35 groups prepared the azaindole nucleus by BIS type cyclization R N X N N 43-47 % H 17-56 % H 2 from the appropriate chloronitropyridine with excess X CONHR R=H,Me, vinylmagnesium bromide. 1 R2=2-pyridyl, 2-(6-Me-pyridyl) 135 134 R =H,Me Giblin then used chlorine as well as Regueiro Ren used X=Cl,Br 2-(4-Me-thiazolyl), bromine, that is as a way for functionalization of the 7 position 3-(1-Me-1,2-diazolyl), 2-(4-Me-1,3-diazolyl) 40 (cfr compounds 55 and 56 , Schemes 38 and 39, respectively). On 138 the other hand, Blaazer’s group 136 used chlorine as promoter of 60 Scheme 41 Synthesis of 6 azaindole 7 carboxamides 81 the cyclization partially modifying the procedure of Wang (cfr 6 Azaindole 7 carboxamides constitute allosteric metabotropic Schemes 7 and 40). glutamate receptor (mGluR5) antagonists. 138 The different 7
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substitutents modify the physico chemical parameters for 42).139, 140 In particular, Panchal and co workers transformed 2,6 optimization of the aqueous solubility, without affecting high in 15 dichloro into 2,6 dibromo 3 nitropyridine, then built the indole vitro potency. The complete series of 2,3 unsubstituted like nucleus by BIS and finally substituted the halogens with azaindoles were obtained by BIS type reaction (Scheme 41), formation of 7 amino derivatives.139 On the other hand, Kim and 5 whereas 2 substituted azaindoles were obtained by copper co workers introduced the alkoxy substituent before cyclization catalysed cyclization of alkynylaminopyridines. and uses dichloropyridine without any halogen exchange and 140 20 finally synthesized 7 alkoxy 6 azaindoles. NO 2 Both reactions employed 1 methyl 1 propenylmagnesium Cl bromide ( 2d ) as the Grignard reagents and, remarkably, they N represent two of the few examples of preparation of 2,3 disubstituted indole like nuclei. The selective removal of the X 25 halogen atoms in the 2 and 6 positions in both reactions is also worth of note (Scheme 42).
X=Cl Very recently, 7 anilino and 7 aryl 6 azaindole 1 benzene ArCH2OH, 88 % Br2, AcOH TDA, KOH, 84-95 % sulfonamides were found to exhibit potent anticancer activity 50 °C K2CO3, PhMe against some cancer cell lines. The synthetic route to these 30 compounds starts from 2 bromo 3 nitropyridine under BIS NO2 NO2 conditions (Scheme 43). 141 Br O Br N N Ar 2a, THF, NO2 N -40 °C Br X N 60% N 22 % 2d, THF 2d,THF 12-39 % H 0 °C -78 °C Br Br X 1. 4-RC6H4NH2 1. 4-MeOC6H4SO2Cl 1. 4-MeOC6H4SO2Cl N pyridine 120-130 °C Bu4NHSO 4, KOH Bu4NHSO4, KOH N N H N (35-52 %) CH2Cl2, rt CH2Cl2, rt Br H 2. 4-MeOC6H4SO2Cl 2. 4-OHC6H4NH2 2. ArB(OH)2, Pd(PPh3)4 Ar O Bu NHSO KOH pyridine 120-130 °C K CO PhMe/EtOH amine, 4 4, 2 3, CH2Cl2, rt (overall 15 %) reflux 80 % K2CO3 190 °C (18-79 %) (20-63 %) X=Cl, X=H R HO Ar=4-FC6H4 15 % RBr, KOt-Bu, 41-76 % Br N CuCN, DMF, 18-crown-6, THF 160 °C Ar N N NC N N H HN N HN O S NH N N 2 N N H R N N O Ar O O2S O2S
10 examples MeO
Ar= Ph, 4-OHC6H4, 4-MeOC6H4, MeO MeO F 4-FC6H4, 4-NMe 2C6H4, 4-ClC6H4, 21-50 % R=H, OMe, F 4-CF3C6H4, 4-NO 2Ph, 4-pyridyl, Het O 2-furanyl, 2-thienyl 141 N Scheme 43 Synthesis of azaindoles with anticancer properties N R2N R N NH N Then reaction with various anilines in the presence of pyridine H 35 gave 7 anilino 6 azaindoles, whereas treatment with various O phenylboronic acids under conditions of the Suzuki reaction yielded 7 aryl 6 azaindoles. Finally, Sperry and Lindsay prepared marinoquinolines C and 11 examples E (figure 1), from 2 chloro 3 nitroquinoline by Bartoli
F 40 indolization and Suzuki coupling between 2 chloropyrroloquinoline and two different boronates.142 Authors 9 examples Scheme 42 Synthesis of 6 azaindoles as APAs Panchal’s procedure claimed their reaction as the first example of BIS on on the left; 139 Kim’s on the right 140 nitroquinoline, but other examples were reported as mentioned in section 2. 47, 78 10 7 Amino and 7 alkoxy 6 azaindole are candidates for clinical use as acid pump antagonists (APAs) also known as potassium 45 6. Miscellaneous competitive acid blockers (pCABs). Recently, two different SAR evaluation of these compounds appeared in the literature (Scheme At the end of section 3, we affirmed that 7 bromoindole is the
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starting material of 7 formyl ,63 and 7 amino indole. 111 All these acetal formation with n butanol and BIS with 1 methyl 1 indole derivatives are in turn starting materials for interesting and 45 propenylmagnesium bromide (another example of 2,3 more complex molecules. Moreover, in section 2, we already disubstituted indole). Methylation of the indole followed by reported that 7 formyl indole can also be obtained from protected reduction of the aldehyde provided 1,2,3 trimethylindole, which 63 5 2 nitrobenzaldehyde. in turn was coupled to the benzimidazolone core (Scheme 46). Recently, Fache and co workers utilized 2 nitrobenzaldehyde Other indoles (8 examples) were prepared similarly, starting from in an alternative manner. In fact, they prepared new indole 50 the appropriate nitrobenzaldehyde, but yields are not reported. derivatives, combining Prins cyclization and Bartoli indolization in one step procedure (Scheme 44). 143 Actually, Prins cyclization, 1. NH2(CH2) 2OH, AcOH, NaBH(OAc)3 10 modifying the aldehyde moiety, allows BIS reaction. The THP 2. Boc2O, MeCN, 0° N N indoles, thus obtained, are free from heavy metal and therefore H H CHO 80% suitable for drug preparation. NBoc 57 OH HO X X 2a THF X 58 TMSCl, neat - 40 °C O 75 % 2 steps CHO 22–35% N overall H H N OMe NO2 NO2 O O O O X=H, 6-Cl, 4,5-OCH O 2 steps 2 Cl O Cl N Cl OH cis/ trans 4:1-1:3 N CHO 1. N N TMSCl, neat O about 40% 2. 2a,e, THF, -40 °C N N Boc 24,30 % NO 2 R1 O R N 2 steps H GSK3-inhibitors 25 % R=O-iPr, NMe2, piperidinyl, morpholinyl, cis/ trans 4:1,7:3 143 H Scheme 44 Prins cyclization BIS sequence O N O
15 Aza 1,7 annulated indoles are the key structure of a class of orally available and efficacious glycogen synthase kinase 3 (GSK3) inhibitors. 144 They would be expected to have some of N N the same effects as insulin, such as ability to activate glycogen H synthase and to stimulate the conversion of glucose to glycogen, N 20 thereby lowering plasma glucose. In other words, they are very H attractive targets for the potential treatment of non insulin Scheme 45 synthesis of GSK3 inhibitors 144 and indolocarbazoles 145 dependent diabetes mellitus. The synthesis of GSK3 inhibitors CHO starts from 7 formylindole prepared by BIS. 144 The treatment of 1. n-BuOH, p-TsOH, Cl NO2 PhMe, reflux 7 formyl indoles with ethanolamine under reductive amination 2. 2d, THF, -40 °C 25 conditions followed by protection of the resulting secondary N amine with Boc gives alcohol 58 (Scheme 45). Further steps for Cl 5 % H CHO the synthesis of the maleidoimide derivative are very close to EtO2C those reported in Scheme 31. GSK3 inhibitors are then prepared 1. NaH, MeI, by incorporation of a variety of acyl groups on the diazepino N DMF, 0 °C 57 % 144 HO2C O 2. NaBH 30 nitrogen atom. The synthesis of 5 fluoro 7 formylindole from 1. 4, N MeOH, 0 °C the corresponding protected nitrobenzaldehyde has also been N H reported in 52% yield in this paper. DIAD, PPh3, O THF, rt The same synthetic route is also applied to the synthesis of 1,7 N 2. LiOH, Cl annulated indolocarbazoles by reaction of 3 indolylacetamide Cl 1,4-dioxane/H2O, rt 35 followed by cyclization with palladium acetate (Scheme 45). 54 % N Always starting from 7 formylindole, other indolocarbazoles with N 145 different 1,7 ring size were prepared. OH Lo’s group recently reported a new class of chymase (a chymotrypsin like serine protease) inhibitors featuring a Scheme 46 Synthesis of chymase inhibitors with indole as the 146 55 hydrophobic moiety 40 benzimidazolone core with an acid side chain and a hydrophobic moiety. In particular, the hydrophobic moiety could be 7 Formylindole is also the staring material for the synthesis of 146 represented by an indole framework. The general synthesis of indolide imine chelate ligands for living ethylene polymerization this indole starts from 3 chloro 5 nitrobenzaldehyde, followed by (Scheme 47). Both nickel 147 and titanium 148, 149 are used as the
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chelate metal. was carried out from 1,2 dinitrobenzene (Scheme 48). The 15 occurrence of BIS on dinitroarenes has to be underlined (see also section 2). The same research group also provided anion 1. BuLi 2. TiCl4 N receptors based on 7,7′ diamido 2,2′ diindolylmethane by using the same reaction to prepare 7 amino 3 methylindole. 150, 151
N TiCl 2 This procedure represents a valuable alternative synthesis of 7 2 111 R 20 amino indole with respect to that proposed by Owa, which starts from already prepared 7 bromoindole, via metallation, R=Ph, 2,6-F2-C6H3, + 2,4,6-F -C H C F RNH2, H 3 6 2, 6 5 azide substitution and finally reduction. In fact, from 57 nitrobenzene to 7 aminoindole, Jurczak’s method is a two steps 70-98 % 148 111 N procedure, while Owa’s reaction is a four steps one. H 25 Unfortunately, we cannot compare the efficiency of the two N methods, because Owa did not report the yield of his procedure. 1. KH N R Ph We can only surmise a higher efficiency of the shortest method. 2. t-(PPh3)2Ni(Ph)Cl Ni Owa used its procedure for the synthesis of a series of antitumor Ph3P N sulphonamides by coupling 7 aminoindoles with a variety of 152 30 substituted benzenesulfonyl chlorides (Scheme 49). Scheme 47 Synthesis of indolide imine nickel 147 and titanium 148, 149 chelate ligands 1. BuLi, THF, -70 °C X 2a, THF X 2. TsN3, - 70 °C X -40 °C 3. Red-Al, -40 °C O Ar O O Ar O NH HN N NO N NH HN NH HN 2 H H Br Br NH2 1 X SO Cl NH HN 2 unfavourable favourable O Ar O pyridine, THF, rt Ar=2,5-pyrrole, 1,3-azulene, 50-87 % 2,6-pyridine X Cl Cl 2a, THF X1 H Pd/C -60 °C 2, X=H, 4-Cl, 5-Cl, 4-F, 4-Br, 4-Me, 4-MeO, 4-Ph N 1 H X =4-MeO, 4-Cl, 4-NO 4-Me, 4-CN, 2-CN, 46 % 2, NH NO2 N 80 % N ref 71 3-CN, 4-CONH2, 4-SO2NH2 S H H O NO 2 2 NO2 NH2 Scheme 49 Synthesis of antitumor sulfonamides 152 37 % 2c, THF ref 148 -60 °C Et 7. Conclusions EtCHO HCl In conclusion, the difficulty of classical indolization in preparing NH HN 35 7 substituted indoles and the easy scaling up make BIS the N 70 % H O N reaction of choice for the synthesis of 7 substituted indoles. NO 2 NO2 2 Moreover, the conciseness of this reaction, the high 1. H Pd/C 79-92% 2, chemoselectivity of the Grignard reagents towards the nitroarene 2. RCOCl Et moiety, the tolerance to most electrophilic functions on the 40 benzene ring, the generality towards different nitro aromatic compounds, the synthesis of indoles on solid support outweigh NH HN the moderate yields, the substrate dependency and the often no clear reactivity trend. R HN HN R The reaction usefulness is also demonstrated by the interest 129 131, 153 O O 45 showed by the pharmaceutical industry. Generally, simple vinylmagnesium bromide is used, but R=Pr, Ph, 2-pyrrole 5 substituted alkenyl Grignard reagents can also be applied, and 71,150 Scheme 48 7 Aminoindole derivatives as anion receptors afford the corresponding indoles with substituents at the C 2 and C 3 positions. The combination of these results with the Differently from Schiff base indole derivatives described in 50 possibility of using the bromine or chlorine atoms as labile scheme 47 that are cation receptors, 7 aminoindole derivatives protecting groups makes the BIS a very easy strategy for the are interesting alternative to aniline for the construction of anion 71 construction of the indole backbone featuring substituents in all 10 receptors. Introduction of indole NH as an additional binding positions. site can improve anion binding in the presence of favourable Other efficient preparation of 7 substituted indoles such as ligand preorganization and in the absence of strong 154 83 55 Larock and Leimgruber–Batcho indole syntheses suffer from intramolecular hydrogen bonds. The synthesis of 7 aminoindole the use of transition metal catalyst. The purification of indoles for
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Renato Dalpozzo was born in 1957. He graduated from the University of Bologna in 1981, with a Laurea in Industrial Chemistry under the supervision of professor Bartoli. He was Researcher of Organic Chemistry at University of Bologna since 1983. In 1992, he moved to the University of Calabria as Associate Professor and then as Full Professor of Environmental and Cultural Heritage Chemistry and now of Organic Chemistry. His research interests include studies on the reactivity of organometallic compounds with aromatic systems, the use of dianions derived from enamino carbonyl compounds, the stereoselective reduction of various classes of ketones, the development of new Lewis acid systems, the chemistry of mimicry of social insects, and the enantioselective organocatalysis. Giuseppe Bartoli graduated from the University of Bologna in 1967 with a Laurea in Industrial Chemistry. Since 1968, he has been an Assistant Professor at the University of Bari (Italy), then Associate Professor at the University of Bologna (Italy) and, in 1986, Full Professor of Organic Chemistry at the University of Camerino. In 1993 he returned in Bologna. Head of the Department of Organic Chemistry ‘‘A. Mangini’’ and Chairman of the Industrial Chemistry degree course He retired at the end of 2011. His research interests include studies on the reactivity of organometallic compounds with aromatic systems, the use of enaminone dianions, the stereoselective reduction of ketones, the development of new Lewis acid systems, and the enantioselective organocatalysis. Monica Nardi was born in 1975. He graduated in 2001 with a Laurea in Chemistry under the supervision of Professor A. Procopio. After his degree he started a fellowship with Prof. Sindona’s research group and in 2002 he started his doctoral studies in Chemistry under the supervision of Prof. G. Sindona working on the development of new Lewis acid system and new synthetics methods in green chemistry. In 2005 he obtained his PhD degree and he joined Prof. G. Sindona’s group as a postdoctoral associate, studying new organocatalytic asymmetric reactions, and the application of green chemistry to substrates of natural origin. Page 25 of 25 Chemical Society Reviews
Application of Bartoli Indole Synthesis
Giuseppe Bartoli, a Renato Dalpozzo* b and Monica Nardi b Bartoli Indole Synthesis is the reaction of choice for the synthesis of many biologically interesting 7- substituted indoles.
NO N 2 H X X
partially reproduced with permission from Molecules 2013, 18(9), 10870-10900