Anilines and ethyl vinyl ether can be combined in a safe continuous-flow process to achieve efficient and mono-selective formal α-arylation of acetaldehyde. The mild non-basic reaction conditions of this method allow for high functional group tolerance. This process also provides means for a safe and scalable generation of aryldiazonium salts and enables preparation of an array of synthetically valuable monoarylated acetaldehydes.
N. Chernyak, S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 12466-12469.
The rational design of a phosphine ligand for the Pd-catalyzed mono-α-arylation of acetone enables the conversion of a broad range of aryl chlorides and provides excellent product yields with down to 0.1 mol % Pd. Preliminary investigations suggest that the rate-limiting step for the proposed system is the oxidative addition of aryl chlorides.
W. C. Fu, C. M. So, W. K. Chow, O. Y. Yuen, F. Y. Kwong, Org. Lett., 2015, 17, 4612-4615.
The use of appropriately designed P,N-ligands proved to be the key to controlling the reactivity and selectivity in Pd-catalyzed mono-α-arylation of acetone with aryl chlorides, bromides, iodides, and tosylates. The reaction affords good yields with substrates containing a range of functional groups at modest Pd loadings using Cs2CO3 as the base and employing acetone as both a reagent and the solvent.
K. D. Hesp, R. J. Lundgren, M. Stradiotto, J. Am. Chem. Soc., 2011, 133, 5194-5197.
The merger of aerobic oxidative Cu catalysis with decarboxylative enolate interception enables a decarboxylative carbonyl α-arylation of arylboron nucleophiles with malonic acid derivatives. This method converts substrates containing electrophilic functional groups that are incompatible with existing α-arylation methods.
P. J. Moon, S. Yin, R. J. Lundgren, J. Am. Chem. Soc., 2016, 138, 13826-13829.
A palladium-catalyzed coupling of aryl halides and ester enolates produced α-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl acetate and the efficient arylation of α,α-disubstituted esters were developed with LiNCy2 as base and P(t-Bu)3 as ligand.
M. Jørgensen, S. Lee, X. Liu, J. P. Wolkowski, J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 12557-12565.
Palladium-catalyzed α-arylations of chloroarenes with the sodium enolates of tert-butyl propionate and methyl isobutyrate occur in high yields using P(t-Bu)3 as ligand. The reactions of chloroarenes with the Reformatsky reagent of tert-butyl acetate were most challenging but occurred in high yields for chlorobenzene and electron-poor chloroarenes.
T. Hama, J. F. Hartwig, Org. Lett., 2008, 10, 1549-1552.
A catalyst system, consisting of [Pd(2-butenyl)Cl]2 and MorDalPhos, exhibited high catalytic reactivity toward a mono-α-arylation of aryl and heteroaryl ketones with aryl phosphates. A wide range of aryl phosphates were efficiently coupled with aryl and heteroaryl ketones with good selectivity and very good yields.
X. Chen, Z. Chen, C. M. So, J. Org. Chem., 2019, 84, 6337-6346.
An easily available NHC-Pd(II)-Im complex is an efficient catalyst for the α-arylation reaction between ketones and aryl chlorides. Under the optimal conditions, all reactions proceeded smoothly to give the desired products in very good yields within hours.
Z.-K. Xiao, L.-X. Shao, Synthesis, 2012, 44, 711-716.
Enhanced steric congestion of an indolyl-derived phosphine ligand enables a Pd-catalyzed mono-α-arylation of aryl- and heteroarylketones with aryl mesylates and tosylates. This protocol is suitable for modifications of biological phenolic compounds, rendering it amenable for functionalization of phenolic (pro)drugs.
W. C. Fu, C. M. So, O. Y. Yuen, I. T. C. Lee, F. Y. Kwong, Org. Lett., 2016, 18, 1872-1875.
An efficient monoarylation of acetate esters and aryl methyl ketones with aryl chlorides is easily accomplished under mild conditions, that tolerate a wide array of heterocyclic substrates, using recently reported palladium precatalysts.
M. R. Biscoe, S. L. Buchwald, Org. Lett., 2009, 11, 1773-1775.
The complex (IPr)Pd(acac)Cl has proven to be a highly active PdII precatalyst in Buchwald-Hartwig reactions and α-ketone arylations of a wide range of substrates including unactivated, sterically hindered, and heterocyclic aryl chlorides.
N. Marion, E. C. Ecarnot, O. Navarro, D. Amoroso, A. Bell, S. P. Nolan, J. Org. Chem., 2006, 71, 3816-3821.
β-Diketones can undergo a reaction with aryl halides in the presence of Cu(I) or Cu(II) salts in DMSO using K3PO4 • 3 H2O without ligands to form various α-aryl ketones. H2O assists the C-C activation. This simple, practical method complements classic methods for the rapid construction of C-C bonds to a carbonyl moiety.
C. He, S. Guo, L. Huang, A. Lei, J. Am. Chem. Soc., 2010, 132, 8273-8275.
The use of gem-bis(boronates) as precursors enables a construction of quaternary α-aryl aldehydes, in which both groups are installed simultaneously. This methodology provides a general strategy to produce quaternary α-aryl aldehydes with broad scopes and synthetic convenience. In addition, gem-bis(boronates) are readily available from ketones.
P. Zheng, Y. Zhai, X. Zhao, T. Xu, Org. Lett., 2019, 21, 393-396.
An improved protocol for the Pd-catalyzed α-arylation of aldehydes with aryl halides allows the coupling of an array of substrates including challenging electron-rich aryl bromides and less reactive aryl chlorides. The utility of this method has been demonstrated in a total synthesis of (±)-sporochnol.
R. Martín, S. L. Buchwald, Org. Lett., 2008, 10, 4561-4564.
A Rh(I)-catalyzed cross-coupling of diazoesters with arylsiloxanes enables the synthesis of α-aryl esters via Rh(I)-carbene migratory insertion. The reaction represents the first example of utilizing arylsiloxane as the coupling partner in a carbene-involved cross-coupling reaction.
Y. Xia, Z. Liu, S. Feng, F. Ye, Y. Zhang, J. Wang, Org. Lett., 2015, 17, 956-959.
A general, chemoselective, and efficient synthesis of diarylacetate was accomplished through rhodium catalyzed direct arylation of diazo compounds with arylboronic acids. The reaction tolerates various boronic acid derivatives and functional groups.
J. Ghorai, P. Anbarasan, J. Org. Chem., 2015, 80, 3455-3461.
An enantioselective α-arylation of aldehydes has been accomplished using diaryliodonium salts and a combination of copper and organic catalysts. These mild catalytic conditions allow the enantioselective construction and retention of enolizable α-formyl benzylic stereocenters, a valuable synthon for the production of medicinal agents.
A. E. Allen, D. W. C. MacMillan, J. Am. Chem. Soc., 2011, 133, 4260-4263.
A catalytic asymmetric cross-coupling of α-halo carbonyl compounds with aryl metal reagents generates synthetically useful α-aryl carboxylic acid derivatives in good enantiomeric excess. The method can also be applied to enantioselective alkenylation reactions.
X. Dai, N. A. Strotman, G. C. Fu, J. Am. Chem. Soc., 2008, 130, 3302-3303.
A palladium-catalyzed deprotonative cross-coupling process (DCCP) enables a γ-arylation of aryl acetic acids with wide range of aryl bromides and chlorides. A procedure for the palladium-catalyzed α-arylation of styryl acetic acids is also described.
S.-C. Sha, J. Zhang, P. J. Walsh, Org. Lett., 2015, 17, 410-413.
In a simple protocol for the synthesis of α-diarylacetic esters from benzoins, in situ generated acetals assist rapid 1,2-aryl migration in a stereospecific manner, paving the way to make enantioenriched α-diarylacetic esters from easily accessible enantiopure benzoins.
R. B. Kothapalli, R. Niddana, R. Balmurugan, Org. Lett., 2014, 16, 1278-1281.
An iron-catalyzed oxidative dehydrogenation enables an α-arylation of deoxybenzoins with non-prefunctionalized arenes with broad substrate scope and functional group tolerance. The reaction provides efficient access to synthetically useful 1,2,2-triarylethanones.
T. Chen, Y.-F. Li, Y. An, F.-M. Zhang, Org. Lett., 2016, 18, 4754-4757.
2-aryl-1,3-dicarbonyl compounds are produced in good yields by a CuI/L-proline-catalyzed arylation of activated methylene compounds with aryl iodides and aryl bromides in DMSO at 40-50°C in the presence of Cs2CO3.
X. Xie, G. Cai, D. Ma, Org. Lett., 2005, 7, 4693-4695.
In a Pd-catalyzed formation of arylnitromethanes from readily available aryl halides or triflates, 2-10 equiv of nitromethane in dioxane as solvent can be employed in comparison to prior work that used nitromethane as solvent (185 equiv). The present transformation reduces the hazards associated with MeNO2, provides high yields at relatively low temperatures, and tolerates an array of functionality.
R. R. Walvoord, M. C. Kozlowski, J. Org. Chem., 2013, 78, 8859-8864.
An efficient cross-coupling reaction of aryl halides and nitromethane gives arylnitromethane products, that are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl equivalent, providing a mild and convenient formylation method.
R. R. Walvoord, S. Berritt, M. C. Kozlowski, Org. Lett., 2012, 14, 4086-4089.
An efficient, mild, and metal-free arylation of nitroalkanes with diaryliodonium salts has gives convenient access to tertiary nitro compounds in high yields without the need for excess reagents. The C-arylation can be extended to α-arylation of nitroesters and tolerates other easily arylated functional groups, such as phenols and aliphatic alcohols.
C. Dey, E. Lindstedt, B. Olofsson, Org. Lett., 2015, 17, 4554-4557.
The use of tBuXPhos as ligand enabled palladium-catalyzed cross-coupling of aryl bromides with very acidic nitroacetates to afford 2-aryl-2-nitroacetates.
A. E. Metz, S. Berritt, S. D. Dreher, M. C. Kozlowski, Org. Lett., 2012, 14, 760-763.
A general method for the Suzuki-Miyaura and carbonyl enolate coupling of unactivated arenesulfonates was developed utilizing Pd(OAc)2 and XPhos as ligand. The catalyst system effects the coupling of various aryl, heteroaryl, and extremely hindered arylboronic acids and carbonyl enolates with different aryl tosylates, under mild conditions.
H. N. Nguyen, X. Huang, S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 11818-11819.
The reaction between aryl- or vinylboroxines with α-diazocarbonyl compounds offers an alternative approach for α-arylation and α-vinylation of carbonyl compounds. α-Arylated or α-vinylated carbonyl compounds are formed under mild conditions.
C. Peng, W. Zhang, G. Yan, J. Wang, Org. Lett., 2009, 11, 1667-1670.
Reaction of β-bromo alcohols with 0.6 equiv of Et2Zn forms a zinc complex in CH2Cl2 at room temperature, followed by 1,2-migration to give the corresponding carbonyl compounds. This mild and clean rearrangement is general for acyclic and cyclic bromohydrins, and a variety of ring-expansive and -contractive carbonyl compounds were obtained in very good yields.
L. Li, P. Cai, Q. Guo, S. Xue, J. Org. Chem., 2008, 73, 3452-3459.
An efficient Pd-catalyzed direct intermolecular α-arylation of acetamide derivatives with aryl chlorides offers chemoselectivities up to 10:1 in mono- and diarylation by careful selection of bases, solvents, and stoichiometry. Bis-arylated amides can be prepared in up to 95% yield.
B. Zheng, T. Jia, P. Walsh, Org. Lett., 2013, 15, 4150-4153.
The use of zinc enolates (isolated Reformatsky reagents or generated in situ from α-bromo amides or lithium enolates) instead of alkali metal enolates, greatly expands the scope of the palladium-catalyzed α-arylation of aryl bromides and vinyl bromides.
T. Hama, D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc., 2006, 128, 4976-4985.
Aryl radicals generated in situ from arene diazonium fluoroborates promoted by ascorbic acid enable a convenient and general oxidative arylation of vinyl arenes in air at room temperature in the absence of any additive and visible light irradiation. Various 2-aryl acetophenones have been obtained in good yields.
B. Majhi, D. Kundu, B. C. Ranu, J. Org. Chem., 2015, 80, 7739-7745.
The copper-catalyzed highly regioselective reaction of aryl alkyl alkynes and arylpropargylic alcohols with diaryliodonium salts gives α-arylketones in good yields under mild conditions. Depending on the internal alkyne substrate, two different arylation-oxygenation pathways under different reaction conditions have been elaborated based on deuterated experiments, controlling experiments, and spectroscopic analysis of reaction intermediates.
Z.-F. Xu, C.-X. Cai, J.-T. Liu, Org. Lett., 2013, 15, 2096-2099.
A protocol for Pd(II)-catalyzed asymmetric arylation of N-aryl imino esters affords a practical and direct access to chiral arylglycine derivatives in good yields and with high enantioselectivities.
J. Chen, X. Lu, W. Lou, Y. Ye, H. Jiang, W. Zeng, J. Org. Chem., 2012, 77, 8541-8548.
The coupling of aryl iodides and diethyl malonate in the presence of Cs2CO3 and catalytic amounts of CuI and 2-phenylphenol gave α-aryl malonates in good to excellent yields. This mild method tolerates various functional groups.
E. J. Hennessy, S. L. Buchwald, Org. Lett., 2002, 4, 269-272.
β-Ketoesters can directly be transformed to the corresponding α-hydroxymalonic esters, tartronic esters, with molecular oxygen catalyzed by calcium iodide under visible light irradiation from a fluorescent lamp. This convenient tandem oxidation/rearrangement reduces consumption of energy, time, and solvents.
N. Kanai, H. Nakayama, N. Tada, A. Itoh, Org. Lett., 2010, 12, 1948-1951.
A one-pot procedure for the synthesis of 2-alkyl-2-arylcyanoacetates based on a Pd(OAc)2/dppf-catalyzed enolate arylation followed by in situ alkylation tolerates a diverse range of aryl and heteroaryl bromides, and provides a rapid entry to a wide range of products in very good to yield.
X. Wang, A. Guram, E. Bunel, G.-Q. Cao, J. R. Allen, M. M. Faul, J. Org. Chem., 2008, 73, 1643-1645.
A direct α-arylation of secondary β-keto amides with arynes, generated by fluoride-induced elimination of ortho-silyl aryltriflates, proceeds via an interrupted insertion reaction of arynes and leads to densely functionalized aromatic compounds exhibiting a chiral ‘all carbon’ quaternary center under transition-metal-free conditions. An organocatalytic asymmetric version of the reaction also proved possible.
K. Mohanan, Y. Coquerel, J. Rodriguez, Org. Lett., 2012, 14, 4686-4689.
A catalyst system derived from commercially available Pd2(dba)3 and PtBu3 enables the coupling of α-keto ester enolates and aryl bromides to provide an array of β-stereogenic α-keto esters. The derived products are of broad interest given the prevalence of the α-keto acid substructure in biologically important molecules.
B. P. Zavesky, S. L. Bartlett, J. S. Johnson, Org. Lett., 2017, 19, 2126-2129.
A protected pyruvate equivalent allows arylation and arylation/alkylation reactions to be performed at the methyl group. For example, palladium catalyzed arylation reactions of the OBO derivative of the pyruvate ester can be followed by alkylation under basic conditions. Moreover, the OBO protecting group could be easily removed in one step to provide access to a wide range of substituted pyruvate derivatives.
C. H. A. Esteves, C. J. J. Hall, P. D. Smith, T. J. Donohoe, Org. Lett., 2017, 19, 5248-5251.
A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester proceeds through Suzuki coupling, base-induced fragmentation, and deformylation. Under optimized conditions (PdCl2dppf, KF, DMSO/H2O, 130 °C) a broad spectrum of aryl bromides could be converted into arylacetonitriles in good yields.
J. Velcicky, A. Soicke, R. Steiner, H.-G. Schmalz, J. Am. Chem. Soc., 2011, 133, 6948-6951.
A general method for the direct α-arylation of nitriles with aryl chlorides was developed. With a catalytic system generated from palladium and a commercially available ligand, it is now possible to effect direct α-arylation using a wide variety of starting materials.
J. You, J. G. Verkade, Angew. Chem., 2003, 115, 5205-5207.
TMPZnCl·LiCl as a kinetically highly active base enables a Pd-catalyzed α-arylation of nitriles and esters under mild conditions. Remarkably, even a regioselective γ-arylation or a γ-alkenylation of α,β- or β,γ-unsaturated nitriles can be observed.
S. Duez, S. Bernhardt, J. Heppekausen, F. F. Fleming, P. Knochel, Org. Lett., 2011, 13, 1690-1693.
A palladium-catalyzed α-arylation of nitriles was developed by exploring the structure and reactivity of arylpalladium cyanoalkyl complexes. The high yields and short reaction times observed for BINAP-ligated complexes suggested that BINAP-ligated palladium catalysts might be appropriate for the arylation of nitriles. Initial results on a palladium-catalyzed process for the direct coupling of aryl bromides and primary, benzylic, and secondary nitrile anions to form α-aryl nitriles in good yields are reported.
D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 9330-9331.
α-Cyanohydrin triflates undergo Pd-catalyzed cross-coupling with aryl and vinyl boronic acids under mild conditions. Coupling proceeds with complete inversion of configuration at the stereogenic carbon. The resultant nitrile can be easily converted into a variety of alternative functional groups of value in organic synthesis and thus a high level of molecular diversity can be achieved.
A. He, J. R. Falck, J. Am. Chem. Soc., 2010, 132, 2524-2525.
Palladium-N-heterocyclic carbene (NHC) complexes were found to be active catalysts for the arylation of various ketones with aryl chlorides, bromides, and triflates in short reaction times.
M. S. Viciu, R. F. Germaneau, S. P. Nolan., Org. Lett., 2002, 4, 4053-4056.
A convenient method has been developed for the palladium-catalyzed arylation of malononitrile in high yields with aryl bromides and chlorides, respectively. The influence of several reaction parameters such as base, ligand, solvent or temperature were investigated.
A. Schnyder, A. F. Indolese, T. Maetzke, J. Wenger, H.-U. Blaser, Synlett, 2006, 3167-3168.
Potassium tert-butoxide promotes a direct arylation of 2-substituted malononitriles using diaryliodonium salts without transition-metal catalysts. The desired 2-substituted α-arylmalononitriles derivatives were synthesized in very good yields.
J. Han, X. Qian, B. Xu, L. Wang, Synlett, 2017, 28, 2139-2142.
In a palladium catalyzed Negishi-type α-arylation of sulfones and sulfonamides with a broad range of aryl bromides, the substrates are selectively metalated in situ with tmp·ZnCl·LiCl base and cross-coupled in the presence of a catalyst system that is generated from Pd(dba)2 and XPhos.
T. Knauber, J. Tucker, J. Org. Chem., 2016, 81, 5636-5648.
Deprotonation of the weakly acidic α-protons of sulfoxides with LiOtBu and the use of a palladium phosphine complex as catalyst facilitates an α-arylation of various aryl methyl sulfoxides with aryl bromides. More challenging coupling partners, such as alkyl methyl sulfoxides (including dimethyl sulfoxide) and aryl chlorides proved to be suitable under optimized conditions.
T. Jia, A. Bellomo, K. El Baina, S. D. Dreher, P. J. Walsh, J. Am. Chem. Soc., 2013, 135, 3740-3743.
A Pd(OAc)2/Xantphos-based catalyst enabled a deprotonative cross-coupling process between benzyl diphenyl or dicyclohexyl phosphine oxide derivatives and aryl bromides to prepare diarylmethyl phosphine oxides in very good yields.
S. Montel, T. Jia, P. J. Walsh, Org. Lett., 2014, 16, 130-133.
A deprotonative cross-coupling process (DCCP) enables a new synthetic route to access diarylmethyl phosphonates via introduction of aromatic groups on benzylic phosphonates. A catalytic system based on Pd(OAc)2/CataCXium A allows a reaction between benzyl diisopropyl phosphonate derivatives and aryl bromides in very good isolated yields.
S. Montel, L. Raffier, Y. He, P. J. Walsh, Org. Lett., 2014, 16, 1446-1449.
A Rh(III)-catalyzed cascade arylation and chlorination of α-diazocarbonyl compounds with arylboronic acids and N-chlorosuccinimide exhibits excellent functional group tolerance on the organoboron and the diazo reagents. Functionalized α-aryl-α-chlorocarbonyl compounds were obtained in good yields.
F.-N. Ng, Y.-F. Lau, Z. Zhou, W.-Y. Yu, Org. Lett., 2015, 17, 1676-1679.
An efficient, mild, and general method for the C-arylation of β-enamino esters and ketones with arynes provides a facile and direct access to various substituted aromatic β-enamino compounds in good yield.
Y. K. Ramtohul, A. Chartrand, Org. Lett., 2007, 9, 1029-1032.
An efficient α-arylation of imino amides with arylboronic acids provides an alternative approach for the synthesis of α-functionalized glycine derivatives. Different substrates were examined for this arylation reaction.
L. Zhao, X. Liao, C.-J. Li, Synlett, 2009, 2953-2956.
Cu-catalyzed asymmetric conjugate reduction of β-substituted ketones leads to enantiomerically enriched diphenylsilyl enol ethers, which are utilized in a diastereoselective Pd-catalyzed α-arylation of various aryl bromides to yield disubstituted cycloalkanones with excellent levels of enantiomeric and diastereomeric purity. The procedure can be carried out in one-pot.
J. Chae, J. Yun, S. L. Buchwald, Org. Lett., 2004, 6, 4809-4812.
A very simple method for the α-arylation of N-protected 2-piperidinones in high yield is described. Key factors are the use of ZnCl2 and Pd(dba)2 and the nature of the base.
A. de Filippis, D. G. Pardo, J. Cossy, Tetrahedron, 2004, 60, 9757-9767.
Chiral N-heterocyclic carbene (NHC) ligands having a 2,2′-bisquinoline-based C2 symmetric skeleton exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.
L. Liu, N. Ishida, S. Ashida, M. Murakami, Org. Lett., 2011, 13, 1666-1669.
A catalyst generated from Pd(dba)2 and a bulky electron-rich phosphine ligand is effective for the α-arylation of oxindoles. Generation of the potassium-enolates of a range of oxindoles enables the coupling with aryl chlorides, bromides, and triflates.
M. J. Durbin, M. C. Willis, Org. Lett., 2008, 10, 1413-1415.
A small library of α,β-unsaturated oxindoles was prepared by an efficient microwave-assisted one-pot sequence comprising an aromatic substitution followed by an ionic Horner-Wadsworth-Emmons olefination.
A. Teichert, K. Jantos, K. Harms, A. Studer, Org. Lett., 2004, 6, 3477-3480.
The use of an oxazaborolidinium ion catalyst enables a highly stereoselective synthesis of (Z)-silyl enol ethers from alkyl aryl ketones and trimethylsilyldiazomethane (TMSD). The conversion of cyclic ketones gives ring-expanded silyl enol ethers.
B. Chul, Kang, S. Y. Shim, D. H. Ryu, Org. Lett., 2014, 16, 2077-2079.
A sequential hydroboration/Suzuki-Miyaura coupling of ynol ethers allows a highly regio- and stereoselective synthesis of stereodefined β,β-disubstituted alkenyl ethers. A number of functional groups are well-tolerated under the reaction conditions. Furthermore, the reaction enables a facile entry to labile diarylacetaldehydes by TFA-mediated hydrolysis of the β,β-disubstituted vinyl ethers.
W. Cui, M. Mao, Z. He, G. Zhu, J. Org. Chem., 2013, 78, 9815-9821.
Functionalized α-tertiary and -quaternary 2-arylcycloalkanones are rapidly accessed by scandium(III) triflate-catalyzed diazoalkane-carbonyl homologations. Pairing readily available bis- and tris(oxazoline) based ligands with scandium triflate allows access to arylated medium ring carbocycles with high enantioselectivities and excellent yield.
V. L. Rendina, H. Z. Kaplan, J. S. Kingsbury, Synthesis, 2012, 44, 686-693.