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Synthesis of indoles
Indoles, dihydroisoquinolines, and dihydroquinolines were efficiently prepared by ruthenium-catalyzed heterocyclizations of aromatic homo- and bis-homopropargyl amines or amides in the presence of pyridine. These regioselective 5-endo and 6-endo cyclizations most probably occur by nucleophilic trapping of key ruthenium-vinylidene intermediates.
A. Varela-Fernández, J. A. Varela, C. Saá, Synthesis, 2012, 44, 3285-3295.
Nitrogen-containing heterocycles, including 1H-indoles and electron-deficient 1H-pyrroles, undergo a smoth and mild palladium/norbornene-cocatalyzed regioselective alkylation with primary alkyl bromides at the C-H bond adjacent to the NH group to give 2-alkyl-1H-indoles and 2-substituted or 2,3-disubstituted 5-alkyl-1H-pyrroles in good yields.
L. Jiao, T. Bach, Synthesis, 2014, 46, 35-41.
An operationally simple, atom-economic, palladium-catalyzed cyclization reaction of N-aryl imines, affords indoles via an oxidative linkage of two C-H bonds under mild conditions in the presence of oxygen. The process allows quick assembly of indole rings from inexpensive and readily available anilines and ketones and tolerates a broad range of functional groups.
Y. Wei, I. Deb, N. Yoshikai, J. Am. Chem. Soc., 2012, 134, 9098-9101.
The reaction of (2-aminobenzyl) triphenylphosphonium bromide with aromatic aldehydes or α,β-unsaturated aldehydes under microwave-assisted conditions allows the synthesis of 2-substituted indoles in high yields in a one-pot reaction.
G. A. Kraus, H. Guo, Org. Lett., 2008, 10, 3061-3063.
Functionalized indoles are synthezised under mild conditions in a tartaric acid-dimethylurea melt, that serves as the solvent and as the catalyst. Under these reaction conditions, sensitive functional groups such as N-Boc, N-Cbz, or azides are tolerated.
S. Gore, S. Baskaran, B. König, Org. Lett., 2012, 14, 4568-4571.
An efficient cascade methodology toward the synthesis of 2-substituted indoles proceeds via a palladium-catalyzed cross-coupling reaction of o-nitrobenzyl cyanides with boronic acids in the presence of Fe as co-catalyst.
J. Jadhav, V. Gaikwad, R. Kurane, R. Salunkhe, G. Rahsinkar, Synlett, 2012, 23, 2511-2515.
Indium-catalyzed cyclization of 2-ethynylanilines produced various polyfunctionalized indole derivatives in good yields for substrates having an alkyl or aryl group on the terminal alkyne. In contrast, substrates with a trimethylsilyl group or without substituent on the triple bond afforded polysubstituted quinoline derivatives in good yields via an intermolecular dimerization.
N. Sakai, K. Annaka, A. Fujita, A. Sato, T. Konakahara, J. Org. Chem., 2008, 73, 4160-4165.
Gold(III)-catalyzed annulation of 2-alkynylanilines in EtOH or EtOH-water mixtures at room temperature gives indoles derivatives in good yields. One-flask protocol for the gold-catalyzed conversion of 2-alkynylanilines to 3-bromo and 3-iodoindoles is also reported.
A. Arcadi, G. Bianchi, F. Marinelli, Synthesis, 2004, 610-618.
Cross-coupling of 1-alkynes with vinyl iodides catalyzed by CuI/N,N-dimethylglycine affords conjugated enynes in good to excellent yields. Heating a mixture of 2-bromotrifluoroacetanilide, 1-alkyne in the presence of CuI/L-proline leads to the formation of the corresponding indole.
F. Liu, D. Ma, J. Org. Chem., 2007, 72, 4844-4850.
A copper(II)-catalyzed cyclization of 2-ethynylaniline derivatives to indoles can be carried out in a mixture of H2O and MeOH in the presence of 1-ethylpiperidine at room temperature. A catalyst recycling reaction system was established.
K. Hiroya, S. Itoh, T. Sakamoto, Tetrahedron, 2005, 61, 10958-10964.
A Pd(0)-catalyzed C-N bond-forming reaction enables the synthesis of brominated indoles in the presence of PtBu3 as phosphine ligand. The bulky ligand serves to prevent inhibition of the catalyst by facilitating reversible oxidative addition into the product C-Br bond.
S. G. Newman, M. Lautens, J. Am. Chem. Soc., 2010, 132, 11416-11417.
A highly efficient and stereoselective arylation of in situ-generated azavinyl carbenes affords 2,2-diaryl enamines at ambient temperatures. These transition-metal carbenes are directly produced from readily available and stable 1-sulfonyl-1,2,3-triazoles in the presence of a rhodium carboxylate catalyst. In several cases, the enamines can be cyclized into substituted indoles employing copper catalysis.
N. Selander, B. T. Worrell, S. Chuprakov, S. Velaparthi, V. V. Fokin, J. Am. Chem. Soc., 2012, 134, 14670-14673.
A practical one-pot and regiospecific three-component process gives 2,3-disubstituted indoles from 2-bromoanilides via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.
B. Z. Lu, H.-X. Wei, Y. Zhang, W. Zhao, M. Dufour, G. Li, V. Farina, C. H. Senanayake, J. Org. Chem., 2013, 78, 4558-4562.
Central to an alternative source of substrates for Fischer indolizations was a palladium-catalyzed coupling to prepare N-aryl benzophenone hydrazones. Hydrolysis of the hydrazones in the presence of ketones produced enolizable hydrazones that underwent Fischer indolization.
S. Wagaw, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 6621-6622.
In a new version of the Fischer indole synthesis, primary and secondary alcohols have been catalytically oxidized in the presence of phenylhydrazines and Lewis acids to give the corresponding indoles in one step. The use of alcohols instead of aldehydes or ketones broadens the scope of available starting materials and offers easy handling and safety.
A. Porcheddu, M. G. Mura, L. De Luca, M. Pizzetti, M. Taddei, Org. Lett., 2012, 14, 6112-6115.
A Rh(III)-catalyzed cyclization of N-nitrosoanilines with alkynes enables a streamlined synthesis of indoles. The C-H activation-based intermolecular redox-neutral protocol uses an N-N bond as internal oxidant, which offers a valuable complement to the widely used N-O variants. The reaction tolerates various functional groups and can be conducted under acidic as well as basic conditions.
B. Liu, C. Song, C. Sun, S. Zhou, J. Zhu, J. Am. Chem. Soc., 2013, 135, 16625-16631.
The addition of N-tosyl hydrazones to arynes, generated through fluoride activation of 2-(trimethylsilyl)phenyl triflate precursors, leads to efficient N-arylation. Addition of a Lewis acid to the same reaction pot then affords N-tosylindole products via Fischer cyclization.
D. McAusland, S. Seo, D. G. Pintori, J. Finlayson, M. F. Greaney, Org. Lett., 2011, 13, 3667-3669.
A three-component synthesis of substituted indoles starts from ortho-dihaloarenes through the use of a multicatalytic system consisting of an N-heterocyclic carbene palladium complex and CuI. Indole derivatives are obtained as single regioisomers in high yields.
L. T. Kaspar, L. Ackermann, Tetrahedron, 2005, 61, 11311-11316.
A Pd-catalyzed cascade process consisting of isocyanide insertion and benzylic C(sp3)-H activation allows the construction of the indole skeleton. Slow addition of isocyanide is effective for reducing the amount of catalyst needed and Ad2PBu is a good ligand for C(sp3)-H activation. The construction of the tetracyclic carbazole skeleton was also achieved by a Pd-catalyzed domino reaction incorporating alkyne insertion.
T. Nanjo, C. Tsukano, Y. Takemoto, Org. Lett., 2012, 14, 4270-4273.
Treatment of o-bromonitrobenzenes with various vinyl Grignard reagents gives 7-bromoindoles in good yields, using the o-bromine atom to direct the cyclization. A subsequent reduction using a heteroaryl radical methodology gives 7-unsubstituted indoles in nearly quantitative yields.
A. Dobbs, J. Org. Chem., 2001, 66, 638-641.
A new, mild, and efficient method for the synthesis of polyfunctionalized indoles by direct reaction of substituted 2-chloroanilines with cyclic or acyclic ketones was developed. This procedure is simple to carry out and broadly applicable.
M. Nazare, C. Schneider, A. Lindenschmidt, D. W. Will, Angew. Chem. Int. Ed., 2004, 43, 4526-4528.
One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-iodoanilines and aldehydes is realized under mild ligandless conditions, whereas X-Phos is found to be the ligand of choice for coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes.
Y. Jia, J. Zhu, J. Org. Chem., 2006, 71, 7826-7834.
A new palladium-catalyzed route to N-functionalized indoles has been developed in which the N fragments are introduced in a single-step cascade sequence onto a acyclic carbon framework.
M. C. Willis, G. N. Brace, I. P. Holmes, Angew. Chem. Int. Ed., 2005, 44, 403-406.
The Pd-catalyzed tandem C-N/Suzuki-Miyaura coupling of readily prepared ortho-gem-dihalovinylanilines with boronic acids, esters, alkyl 9-BBN derivatives, and trialkylboranes gave 2-substituted indoles in good to excellent yields. Optimal conditions used low loadings of a Pd(OAc)2/S-Phos catalyst in the presence of K3PO4ˇH2O.
Y.-Q. Fang, M. Lautens, Org. Lett., 2005, 7, 3549-3552.
The solid-state reaction between anilines and phenacyl bromides in the presence of an equimolecular amount of sodium bicarbonate or a second equivalent of the aniline followod by microwave irradiation provides a mild, general, and environmentally friendly method for the synthesis of 2-arylindoles in good overall yields.
V. Sridharan, S. Perumal, C. Avendańo, J. C. Menéndez, Synlett, 2006, 91-95.
A practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles based on Cacchi's protocol was developed. This mild Pd-catalyzed domino indolization procedure allows rapid access to various indoles via consecutive Sonogashira coupling, amidopalladation, and reductive elimination.
B. Z. Lu, W. Zhao, H.-X. Wei, M. Dufour, V. Farina, C. H. Senanayake, Org. Lett., 2006, 8, 3271-3274.
A palladium-catalyzed synthesis of free N-H 2,3-disubstituted indoles from arenediazonium tetrafluoroborates and 2-alkynyltrifluoroacetanilides tolerates a variety of useful substituents in the substrates, including bromo and chloro substituents, nitro, cyano, keto, ester, and ether groups.
S. Cacchi, G. Fabrizi, A. Goggiamani, A. Perboni, A. Sferrazza, P. Stabile, Org. Lett., 2010, 12, 3279-3281.
An efficient, mild Pd-catalyzed oxidative coupling of aromatic primary amines and alkenes under molecular oxygen provides a rapid access to (Z)-enamines with exceptional functional group tolerance and excellent regio- and stereoselectivity. The resultant enamines could be conveniently transformed into a series of N-containing heterocycles, thus illustrating its potential applications in synthetic and medicinal chemistry.
X. Ji, H. Huang, W. Wu, X. Li, H. Jiang, J. Org. Chem., 2013, 78, 11155-11162.
Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords 3-ethoxycarbonylindoles. This mild and efficient synthesis of indoles displays both excellent functional group tolerance and perfect regiochemical control. Various indole building blocks were synthesized from 2-aminobenzaldehydes derived from readily available anthranilic acids.
P. Levesque, P.-A. Forunier, J. Org. Chem., 2010, 75, 7033-7036.
A practical iron-catalyzed intramolecular C-H amination reaction with commercially available iron(II) triflate as catalyst can be used for the synthesis of indole derivatives.
J. Bonnamour, C. Bolm, Org. Lett., 2011, 13, 2012-2014.
Gold(I)-catalyzed cycloisomerization of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols enables the preparation of 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols in the presence of N-iodosuccinimide (NIS). The reactions were shown to be operationally simplistic and proceed efficiently for a wide variety of substrates, affording the corresponding products in very good yields.
P. Kothandaraman, S. R. Mothe, S. S. M. Toh, P. W. H. Chan, J. Org. Chem., 2011, 76, 7633-7640.
The use 10 mol % of Cu(OTf)2 enables the coupling of α-diazoketones with β-enaminoketones and esters to yield 2,4,5-trisubstituted pyrrole derivatives. A wide range of 2,3-disubstituted indole derivatives were also prepared from α-diazoketones and 2-aminoaryl or alkyl ketones.
B. V. S. Reddy, M. R. Reddy, Y. G. Rao, J. S. Yadav, B. Srighar, Org. Lett., 2013, 15, 464-467.
An iridium-catalyzed hydrogen transfer in the presence of p-benzoquinone allows the synthesis of various substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.
B. Anxionnat, D. G. Pardo, G. Ricci, K. Rossen, J. Cossy, Org. Lett., 2013, 15, 3876-3879.
Palladium-catalyzed isocyanide insertion and oxypalladation of an alkyne enables the synthesis of 3-acyl-2-arylindole derivatives. In addition, domino cyclizations for the synthesis of several tetracyclic indole derivatives were also achieved.
T. Nanjo, S. Yamamoto, C. Tsukano, Y. Takemoto, Org. Lett., 2013, 15, 3754-3757.
Palladium-catalyzed intramolecular N-arylative and N-alkylative/N-arylative trappings of the Blaise reaction intermediates enable the construction of the indole moiety in a tandem one-pot manner from nitriles.
J. H. Kim, S.-g. Lee, Org. Lett., 2011, 13, 1350-1353.
Various 2-aryl-3-arylamino-2-alkenenitriles give N-arylindole-3-carbonitriles in a one-pot manner through NBS- or NCS-mediated halogenation followed by Zn(OAc)2-catalyzed intramolecular cyclization. The process involves the formation of arylnitrenium ion intermediates, which undergo an electrophilic aromatic substitution to give the cyclized N-arylindoles.
Q. Yan, J. Luo, D. Zhang-Negrerie, H. Li, X. Qi, K. Zhao, J. Org. Chem., 2011, 76, 8690-8697.
The reaction of easily accessible N-(2-formylphenyl)trifluoroacetamides and α-bromoacetophenones in the presence of K2CO3 enables a one-pot and environmentally benign approach to the synthesis of highly functionalized 3-unsubstituted 2-aroylindoles. PEG-400 is an efficient and reusable solvent in this process.
Y. Zhao, D. Li, L. Zhao, J. Zhang, Synthesis, 2011, 873-880.
Cu-catalyzed sp3 C-H bond activation α to the nitrogen atom of o-alkynylated N,N-dimethylamines followed by an intramolecular nucleophilic attack with the alkyne, using an aqueous solution of tert-butyl hydroperoxide (TBHP) as the oxidant, enables a tandem catalytic synthesis of 3-aroylindoles. In this synthesis, both C-C and C-O bonds are installed at the expense of two sp3 C-H bond cleavages.
A. Gogoi, S. Guin, S. K. Rout, B. K. Patel, Org. Lett., 2013, 15, 1802-1805.
A copper-catalyzed domino reaction of 2-haloanilines and 1,3-dicarbonyl compounds, 1,3-diketones, β-keto esters and β-keto amides under ligand-free conditions provides a simple, general and atom economical process for the synthesis of polysubstituted indoles at moderate temperature.
M. A. Ali, T. Punniyamurthy, Synlett, 2011, 623-626.
Lewis acids catalyze the cyclization of methyl phenyldiazoacetates with an ortho-imino group, prepared from o-aminophenylacetic acid, to give 2,3-substituted indoles in quantitative yields.
L. Zhou, M. P. Doyle, J. Org. Chem., 2009, 74, 9222-9224.
A general and concise synthesis of functionalized indoles via electrophilic activation of N-aryl amides and addition of ethyl diazoacetate to these highly activated amides offers a great potential for the synthesis of biologically active and naturally occurring indole derivatives.
S.-L. Cui, J. Wang, Y.-G. Wang, J. Am. Chem. Soc., 2008, 130, 13526-13527.
Rhodium(II) perfluorobutyrate-mediated decomposition of vinyl azides allows rapid access to a variety of complex, functionalized N-heterocycles in two steps from commercially available starting materials.
B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver, J. Am. Chem. Soc., 2007, 129, 7500-7501.
Various N-arylated and N-alkylated indoles and pyrrole-fused aromatic compounds were synthesized by a phenyliodine bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization.
Y. Du, R. Liu, G. Linn, K. Zhao, Org. Lett., 2006, 8, 5919-5922.
Various substituted enamine derivatives can be conveniently converted to the corresponding 2H-azirines mediated by phenyliodine (III) diacetate (PIDA). The formed 2-aryl-2H-azirines allow the synthesis of indole-3-carbonitriles or isoxazoles via thermal rearrangements.
X. Li, Y. Du, Z. Liang, X. Li, Y. Pan, K. Zhao, Org. Lett., 2009, 11, 2643-2646.
CuI/l-proline-catalyzed cross-coupling of 2-halotrifluoroacetanilides with β-keto esters and amides followed by acidic hydrolysis delivered 2,3-disubstituted indoles. 2-halotrifluoroacetanilides bearing a strong electron-withdrawing group in the 4-position can undergo in situ basic hydrolysis to provide the corresponding indoles.
Y. Chen, X. Xie, D. Ma, J. Org. Chem., 2007, 72, 9329-9334.
A novel one-step synthesis of valuable 2-vinylic indoles and their tricycle derivatives occurs via an efficient Pd-catalyzed tandem Buchwald-Hartwig/Heck reaction using a gem-dibromovinyl unit as a readily available starting material.
A. Fayol, Y.-Q. Fang, M. Lautens, Org. Lett., 2006, 8, 4203-4206.
A Brönsted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans via in situ formation of aminobenzylfuran followed by its recyclization into the indole core proved to be efficient for a wide range of substrates. The resulting indoles can easily be transformed into other scaffolds, including 2,3- and 1,2-fused indoles, and indoles possessing an α,β-unsaturated ketone moiety at the C-2 position.
A. Kutznetsov, A. Makarov, A. E. Rubtsov, A. V. Butin, V. Gevorgyan, J. Org. Chem., 2013, 78, 12144-12153.
2-Ethynylanilines were converted to various substituted 2-(aminomethyl)indoles in good to excellent yields in the presence of a secondary amine and an aldehyde by a copper-catalyzed domino three-component coupling-cyclization. Utilizing this domino reaction and C-H functionalization at the indole C-3 position, polycyclic indoles were readily synthesized.
Y. Ohta, H. Chiba, S. Oishi, N. Fujii, H. Ohno, J. Org. Chem., 2009, 74, 7052-7058.
2-Amidoindoles and tetrahydroindolo[1,2-a]quinazolines can be formed directly from gem-dibromovinylanilides and sulfonamides in a one-pot fashion through a Cu(I)-catalyzed in situ generation of ynamides followed by a base-promoted intramolecular hydroamidation.
S. E. Kiruthika, P. T. Perumal, Org. Lett., 2014, 16, 484-487.
The synthesis of a series of indole and carbazole derivatives from 2-fluorophenyl imines is reported. 2-Fluoroaniline-d4 is prepared and used to investigate the mechanism of this indolization.
L. V. Kudzma, Synthesis, 2003, 1661-1666.
An effective reductive alkylation of electron-deficient o-chloroarylamines was developed. The derived N-alkylated o-chloroarylamines were elaborated to N-alkylazaindoles and N-alkylindoles via a novel one-pot process comprising copper-free Sonogashira alkynylation and a base-mediated indolization reaction.
M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett., 2006, 8, 3307-3310.
The reaction of Boc-protected ortho-aminostyrenes with alkyllithiums, followed by the addition of specific electrophiles sets up a cascade reaction process between the reacted electrophile and the ortho-amino substituent, facilitating an in situ ring closure and dehydration to generate an indole ring system.
C. M. Coleman, D. F. O'Shea, J. Am. Chem. Soc., 2003, 125, 4054-4055.
[RuCl2(CO)3]2/dppp is a highly effective catalyst system for the intramolecular oxidative amination of various aminoalkenes in presence of K2CO3 and allyl acetate in N-methylpiperidine to give the corresponding cyclic imines and indoles in excellent yields.
T. Kondo, T. Okada, T.-A. Mitsudo, J. Am. Chem. Soc., 2002, 124, 186-187.
Zn(OTf)2 catalyzed the cyclization of propargyl alcohols with anilines and phenols in toluene at 100°C without additive and gave various indole and benzofuran products with different structures. The cyclization of propargyl alcohols and amides gave oxazoles. Mechanisms for the different substituation patterns are discussed.
M. P. Kumar, R.-S. Liu, J. Org. Chem., 2006, 71, 4951-4955.
Various 3-iodoindoles have been prepared in excellent yields by a Sonogashira coupling of terminal acetylenes with N,N-dialkyl-o-iodoanilines, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows: Me > n-Bu, Me > Ph, and cyclohexyl > Me.
D. Yue, T. Yao, R. C. Larock, J. Org. Chem., 2006, 71, 62-69.
A ring-closing olefin metathesis (RCM)/elimination sequence or an RCM/tautomerization sequence of functionalized pyrrole precursors enabled the selective synthesis of substituted indoles. The RCM/elimination sequence was also applied to double ring closure to yield a substituted carbazole.
K. Yoshida, K. Hayashi, A. Yanagisawa, Org. Lett., 2011, 13, 4762-4765.
A reverse aromatic Cope rearrangement of 2-allyl-3-alkylideneindolines obtained by Horner-Wadsworth-Emmons olefination of 2-allylindolin-3-ones with diethyl cyanomethylphosphonate provided α-allyl-3-indole acetonitriles. When 2-allylindolin-3-ones were treated with phosphonium ylides in refluxing toluene, domino Wittig reaction and reverse aromatic Cope rearrangement took place to give α-allyl-3-indole acetate derivatives in good yields.
T. Kawasaki, Y. Nonaka, K. Watanabe, A. Ogawa, K. Higuchi, R. Terashima, K. Masuda, M. Sakamoto, J. Org. Chem., 2001, 66, 1200-1204.
An efficient, practical, and highly regioselective direct palladium-catalyzed C-3 arylation of electron-rich free (NH)-indoles with various aryl bromides under ligandless conditions in refluxing toluene in the presence of K2CO3 as the base can be run outside a glovebox without purification of solvent and reagents.
F. Bellina, F. Benelli, R. Rossi, J. Org. Chem., 2008, 73, 5529-5535.
A mild, Pd(OAc)2-catalyzed regioselective cross-coupling between indoles and potassium aryltrifluoroarylborates gives 2-aryl indoles in moderate yields in the presence of Cu(OAc)2 in acetic acid at room temperature.
J. Zhao, Y. Zhang, K. Cheng, J. Org. Chem., 2008, 73, 7428-7431.
A range of biaryl compounds can be efficiently prepared in high yields by a palladium-catalyzed cross-coupling reaction between ortho-substituted triarylindium reagents and aryl halides. The triarylindium reagents are prepared by directed ortho-lithiation and transmetallation to indium from the corresponding benzene derivatives.
M. A. Pena, J. P. Sestelo, L. A. Sarandeses, J. Org. Chem., 2007, 72, 1271-1275.
N-Indolyltriethylborate is a useful reagent for dearomatizing C3-alkylation of 3-substituted indoles with both activated and nonactivated alkyl halides to give C3-quaternary indolenines, pyrroloindolines, furoindoline, and hexahydropyridoindoline under mild reaction conditions.
A. Lin, J. Yang, M. Hashim, Org. Lett., 2013, 15, 1950-1953.
Iodine-mediated intramolecular cyclization of enamines leads to a various 3H-indole derivatives bearing multifunctional groups in good to high yields under transition metal-free reaction conditions.
Z. He, H. Li, Z. Li, J. Org. Chem., 2010, 75, 4296-4299.
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