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Asymmetric Palladium-catalyzed Intramolecular Alpha-arylation Of Aldehydes.

J. García-Fortanet, S. L. Buchwald
Published 2008 · Medicine, Chemistry

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The prevalence of chiral quaternary stereocenters in many natural products has attracted a growing interest in the development of methods for their construction with absolute stereocontrol.[1,2] In recent years, the α-arylation of carbonyl compounds has received a great deal of attention.[3] Despite substantial advances, the asymmetric metal-catalyzed α-arylation of carbonyl compounds remains a formidable challenge, and few examples have been described.[4-7] To the best our knowledge, no examples of asymmetric metal-catalyzed α-arylation of aldehydes have yet been reported.[8] Herein, we present the first asymmetric metal-catalyzed α-arylation of aldehydes forming all-carbon-substituted chiral centers in high yields and enantioselectivities. (Scheme 1). Scheme 1 General scheme for the asymmetric intramolecular α-arylation of aldehydes. The racemic α-arylation of aldehydes remains challenging due to competing aldol condensation under the reaction conditions.[9] In 2007 our group described a general method for the α-arylation of aldehydes with both ArBr and ArCl.[9d] It was found that the catalytic system based upon Pd(OAc)2/BINAP provided the best results when aryl bromides were used. Given that BINAP has been successfully used as a ligand in related α-arylation methodologies[4-7] we decided to examine the utility of this ligand for the asymmetric α-arylation of 1a (Table 1). After some initial systematic screening of palladium sources, bases and solvents,[10] we obtained the desired compound 2a in 54% yield and 49% ee using DME as a solvent and Cs2CO3 as a base (Table 1, entry 1). Table 1 Screening of reaction conditions.[a] Encouraged by the initial results, we next examined the use of different chiral ligands in this transformation. Our experiments with other axially-chiral ligands such as CyBINAP (L2), CyMOP (L3), KenPhos (L4) and DTMB-SEGPHOS (L5), however, did not provide results with improved enantioselectivity (Table 1, entries 2-5). The use of of Josiphos (L6) or DIOP (L7) gave rise to 2a in 9 and 44% GC yield respectively (Table 1, entries 6 and 7), with very low enantioselectivity. Notably, the use of phosphinooxazoline-base ligands such as iPr-PHOX (L8)[11] provided the desired α-aryl aldehyde 2a in 68% ee, albeit in only 25% yield. Further optimization showed that higher enantioselectivities could be achieved by carrying out the process in polar solvents (Table 1, entries 9-12), with tBuOH providing the best results. It is well known that the substituent of the oxazoline moiety plays an important role in the enantioselectivity.[12] Indeed, the use of a more sterically encumbered tBu-PHOX (L9a) increased the optical purity of the product to 81% ee (Table 1, entry 14). Particularly significant is the effect of the α-substituent to the aldehyde (see below), thus, 1b afforded the desired compound 2b in 85% yield and 86% ee (Table 1, entry 15). We next focused our attention on the influence of both steric and electronic effects of the phosphine moiety of the PHOX ligands (Table 2). Although we observed no clear trend in electronic effects of the phosphine in the enantioselectivity and the yield of the reaction (Table 2, entry 7 vs 8), the size of the substituents has a substantial impact. Along these lines, the use of bulkier phosphine substituents resulted in lower enantioselectivity (Table 2, entry 2 vs 6). As depicted in Table 2, the best results were obtained when the reagents were stirred at 80 °C for 24 h using Cs2CO3 as the base and ligand L9i in tBuOH (0.1 M) affording the desired indane derivative 2b in 94% ee and 93% yield, respectively (Table 1, entry 9). Table 2 Screening of different PHOX ligands[a] With the optimized reaction conditions in hand, we further investigated the influence of the α-substituent to the aldehyde on the reaction outcome (Table 3). Substrates containing both α-alkyl and α-aryl substituents yielded the product aldehydes in high enantioselectivity. Generally, substrates with α-aryl substituents gave rise to products with higher optical purity than these with α-alkyl analogues (Table 3, entries 1-5 vs entries 6-8). In regard to the nature of the alkyl substituent, enantioselectivity increased with the size of the α-substituent to the carbonyl group (Table 3, entries 1-5). Under our reaction conditions, o-tolyl derivative 1h prove to be a difficult case, in which even higher catalysts loadings produced the desired product 2h in only 36% isolated yield, but with 98% ee (Table 3, entry 8).[14] The efficiency of the method dropped significantly for substrates in which a six-member ring was being formed; tetrahydronapthalene derivatives were prepared in moderate to good yields with moderate enantioselectivities (Table 2, entries 9-10). The absolute configuration of two of the products was established by X-ray crystallography of 2g (Figure 1)[15] and by comparison with a reported compound derived from 2a.[16,17] Figure1 Molecular structure of 2g with ellipsoids set at 50% probability. Hydrogen atoms are omitted for clarity. Table 3 Scope of the asymmetric Pd-catalyzed intramolecular α-arylation.[a] The fact that products with both aryl as well as alkyl α-substituents were of the same absolute configuration suggests that the enantioselectivity-limiting step in the catalytic system is common for both classes of substrates. The influence of the substitution pattern in the aromatic ring on the outcome reaction is shown in Table 4. The enantiomeric purity of the reaction product is not affected by the electronic character density of the aryl moiety (Table 4, entry 1 vs 4). Table 4 Scope of the asymmetric Pd-catalyzed intramolecular α-arylation.[a] Some representative applications of this methodology are illustrated in Scheme 2. For example, compound 5 was obtained from 2b by means of Lindgren oxidation,[18,19] Curtius rearrangement[20] and reaction of the resulting isocyanate with NaOtBu in 70% overall yield with no loss of the optical activity. This result is particulary interesting given the wide variety of pharmacologically active compounds with a chiral tertiary amine scaffold.[21] Alternatively, a one-pot oxidation or reduction of the corresponding aldehyde afforded the alcohol 6 or the carboxylic acid 7 in excellent overall yield. Scheme 2 Synthesis of different derivatives from 1b. In summary, we have developed the first asymmetric metal-catalyzed α-arylation of aldehydes. The high yields and enantioselectivities achieved make this process particularly attractive for further synthetic applications. Further investigations into this reaction and the development of an intermolecular protocol are currently underway in our laboratories.
This paper references
10.1002/ANIE.200703408
Bulky chiral carbene ligands and their application in the palladium-catalyzed asymmetric intramolecular alpha-arylation of amides.
E. P. Kuendig (2007)
10.1002/ANIE.200201614
Construction of quaternary stereocenters: new perspectives through enantioselective Michael reactions.
J. Christoffers (2003)
10.1073/PNAS.0307113101
Catalytic asymmetric synthesis of all-carbon quaternary stereocenters.
C. Douglas (2004)
10.1021/AR0201106
Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles
D. Culkin (2003)
10.1002/ANIE.200501841
Stable cyclic (alkyl)(amino)carbenes as rigid or flexible, bulky, electron-rich ligands for transition-metal catalysts: a quaternary carbon atom makes the difference.
V. Lavallo (2005)
10.1021/JO005761Z
Improved catalysts for the palladium-catalyzed synthesis of oxindoles by amide alpha-arylation. Rate acceleration, use of aryl chloride substrates, and a new carbene ligand for asymmetric transformations.
S. Lee (2001)
10.1002/ANGE.200201614
Aufbau quartärer Stereozentren: neue Möglichkeiten durch enantioselektive Michael‐Reaktion
J. Christoffers (2003)
10.1002/ANIE.199305661
Chiral Phosphinoaryldihydrooxazoles as Ligands in Asymmetric Catalysis: Pd‐Catalyzed Allylic Substitution
P. Matt (1993)
10.1016/S0040-4039(01)02077-9
Palladium-catalyzed α-arylation of aldehydes with aryl bromides
Y. Terao (2002)
10.1016/J.TETLET.2005.12.098
Development of an N-heterocyclic carbene ligand based on concept of chiral mimetic
Takafumi Arao (2006)
10.1002/ANIE.200703009
A General Method for the Direct α‐Arylation of Aldehydes with Aryl Bromides and Chlorides
R. Martin (2007)
10.1002/(SICI)1521-3757(19980216)110:4<402::AID-ANGE402>3.0.CO;2-6
Der katalytische enantioselektive Aufbau von Molekülen mit quartären Kohlenstoff‐Stereozentren
E. Corey (1998)
10.1021/JA017545T
Nickel-BINAP Catalyzed Enantioselective a-Arylation of a-Substituted ?-Butyrolactones
Dirk Spielvogel (2002)
10.1248/CPB.54.1743
Asymmetric construction of quaternary carbon stereocenter by Pd-catalyzed intramolecular alpha-arylation.
Takafumi Arao (2006)
10.1002/(SICI)1521-3773(19980302)37:4<388::AID-ANIE388>3.0.CO;2-V
The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters.
E. Corey (1998)
10.1002/ANGE.19931050430
Chirale Phosphinoaryldihydrooxazole als Liganden in der asymmetrischen Katalyse: Pd‐katalysierte allylische Substitution
P. Matt (1993)
10.1021/cr078340r
Asymmetric synthesis of tertiary alcohols and alpha-tertiary amines via Cu-catalyzed C-C bond formation to ketones and ketimines.
M. Shibasaki (2008)
10.1002/anie.200705357
Palladium-catalyzed alpha-arylation of aldehydes with bromo- and chloroarenes catalyzed by [{Pd(allyl)Cl}2] and dppf or Q-phos.
G. Vo (2008)
10.1007/978-3-642-58571-5
Comprehensive Asymmetric Catalysis I–III
E. Jacobsen (1999)
10.1016/S0040-4039(98)01173-3
Chiral phosphinooxazolines with a bi- or tricyclic oxazoline moiety - applications in Pd-catalyzed allylic alkylations
B. Wiese (1998)
10.1016/S0040-4039(00)60774-8
Phosphinoaryl- and phosphinoalkyloxazolines as new chiral ligands for enantioselective catalysis: Very high enantioselectivity in palladium catalyzed allylic substitutions
Jürgen Sprinz (1993)
10.1002/ANIE.200701207
Asymmetric Organocatalytic α‐Arylation of Aldehydes
José Alemán (2007)
10.1073/PNAS.0402416101
Contiguous stereogenic quaternary carbons: a daunting challenge in natural products synthesis.
E. Peterson (2004)
10.1016/S0040-4039(00)93403-8
Asymmetric palladium catalysed allylic substitution using phosphorus containing oxazoline ligands
G. Dawson (1993)
10.1039/b208045a
Oxazolines as chiral building blocks for imidazolium salts and N-heterocyclic carbene ligands.
F. Glorius (2002)
10.1016/S0040-4020(01)97963-3
Oxidation of α,β-un saturated aldehydes
B. Bal (1981)
10.1021/JA066991J
Enantioselective arylation of 2-methylacetoacetates catalyzed by CuI/trans-4-hydroxy-L-proline at low reaction temperatures.
X. Xie (2006)
10.1021/JA993912D
Highly Active and Selective Catalysts for the Formation of α-Aryl Ketones
J. Fox (2000)
10.1002/anie.200800756
Total synthesis of (+/-)-platencin.
Joji Hayashida (2008)
10.1021/JA00772A052
Diphenylphosphoryl azide. A new convenient reagent for a modified Curtus reaction and for the peptide synthesis.
T. Shioiri (1972)
10.1016/J.TET.2004.09.112
Palladium-catalyzed intramolecular α-arylation of aliphatic ketone, formyl, and nitro groups
H. Muratake (2004)
10.1021/JA973794Z
Asymmetric Arylation of Ketone Enolates
J. Ahman (1998)
10.1016/0040-4039(93)88075-T
Phosphine-borane complexes; direct use in asymmetric catalysis
H. Brisset (1993)
10.1021/JA074453G
Enantioselective alpha-arylation of ketones with aryl triflates catalyzed by difluorphos complexes of palladium and nickel.
Xuebin Liao (2008)
10.1021/CR00022A005
Asymmetric creation of quaternary carbon centers
Kaoru. Fuji (1993)
10.1021/JA011122+
An improved catalyst for the asymmetric arylation of ketone enolates.
T. Hamada (2002)



This paper is referenced by
10.1021/jacs.6b11610
Palladium-Catalyzed Asymmetric α-Arylation of Alkylnitriles.
Zhiwei Jiao (2016)
10.1002/SLCT.201803376
Tunable P‐Stereogenic P,N‐Phosphine Ligands Design: Synthesis and Coordination Chemistry to Palladium
Sébastien Lemouzy (2018)
10.1002/chem.201201394
Palladium-catalyzed mono-α-arylation of acetone with aryl imidazolylsulfonates.
Lutz Ackermann (2012)
10.1021/ol5015976
Stereocontrolled Synthesis of Bicyclic Sulfamides via Pd-Catalyzed Alkene Carboamination Reactions. Control of 1,3-Asymmetric Induction by Manipulating Mechanistic Pathways
Nicholas R. Babij (2014)
10.1002/asia.201300724
α-Arylation, α-arylative esterification, or acylation: a stoichiometry-dependent trichotomy in the Pd-catalyzed cross-coupling between aldehydes and aryl bromides.
Pradeep Nareddy (2013)
10.1021/jo301924e
Intramolecular Pd(0)-catalyzed reactions of (2-iodoanilino)-aldehydes: a joint experimental-computational study.
Daniel Solé (2012)
10.1039/C4QO00027G
A general method for asymmetric arylation and vinylation of silyl ketene acetals
Junfeng Yang (2014)
10.1002/anie.201300481
Weak arene C-H···O hydrogen bonding in palladium-catalyzed arylation and vinylation of lactones.
Zhiyan Huang (2013)
10.1002/9780470682531.PAT0858
Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates
Katerina M. Korch (2017)
10.1021/ACSCATAL.6B01001
Chiral Monophosphorus Ligands for Asymmetric Catalytic Reactions
Wenzhen Fu (2016)
10.1021/acs.orglett.5b02370
Catalytic Asymmetric Formal Insertion of Aryldiazoalkanes into the C-H Bond of Aldehydes: Synthesis of Enantioenriched Acyclic α-Tertiary Aryl Ketones.
B. Kang (2015)
10.1002/anie.200903424
Metal-catalyzed alpha-arylation of carbonyl and related molecules: novel trends in C-C bond formation by C-H bond functionalization.
C. C. C. Johansson (2010)
10.1021/ol402336u
Regio- and enantiospecific rhodium-catalyzed allylic substitution with an acyl anion equivalent.
P. Evans (2013)
10.1002/9783527635207.CH6
6. PHOX Ligands
Cory C. Bausch (2011)
10.1021/ar400104j
Controlling the ambiphilic nature of σ-arylpalladium intermediates in intramolecular cyclization reactions.
D. Solé (2014)
10.1002/chem.201403213
Efficient Pd-catalyzed allene synthesis from alkynes and aryl bromides through an intramolecular base-assisted deprotonation (iBAD) mechanism.
Natalie Nella (2014)
10.1002/9780470066935.CH7
Nucleophilic Aromatic Substitution
M. Crampton (2007)
10.1039/c2cc36452b
Enantioselective construction of sterically hindered tertiary α-aryl ketones: a catalytic asymmetric synthesis of isoflavanones.
M. Carroll (2012)
10.1039/c2ob25298h
Design and synthesis of a novel class of CK2 inhibitors: application of copper- and gold-catalysed cascade reactions for fused nitrogen heterocycles.
Y. Suzuki (2012)
10.1002/ADSC.201500183
Asymmetric Bio- and Organocatalytic Cascade Reaction – Laccase and Secondary Amine-Catalyzed α-Arylation of Aldehydes
Sanel Suljić (2015)
10.1021/ACS.ORGANOMET.6B00484
Computational Study on the Mechanism of the Palladium-Catalyzed Arylation of α,β-Unsaturated Aldehydes
Ivan Franzoni (2016)
10.1002/chem.201303384
Pd-catalyzed carbonylative α-arylation of aryl bromides: scope and mechanistic studies.
Dennis U Nielsen (2013)
10.1021/ACSCATAL.6B03355
Highly Enantioselective Construction of Sterically Hindered α-Allyl-α-Aryl Lactones via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation
Jinju James (2017)
10.1002/9781118309872.CH1
Transition Metal Catalysis in the Pharmaceutical Industry
C. Busacca (2012)
10.1002/ANGE.200903424
Metallkatalysierte α‐Arylierungen von Carbonylen und verwandten Molekülen: aktuelle Trends bei der C‐C‐Kupplung über C‐H‐Funktionalisierung
C. C. C. Johansson (2010)
10.1039/c8cc01735b
An organocatalytic enantioselective direct α-heteroarylation of aldehydes with isoquinoline N-oxides.
Giulio Bertuzzi (2018)
10.1002/anie.200904754
Anodic oxidation and organocatalysis: direct regio- and stereoselective access to meta-substituted anilines by alpha-arylation of aldehydes.
K. L. Jensen (2010)
10.1021/ja2066829
An enantioselective, intermolecular α-arylation of ester enolates to form tertiary stereocenters.
Zhiyan Huang (2011)
10.1002/anie.201300621
Arene CH-O hydrogen bonding: a stereocontrolling tool in palladium-catalyzed arylation and vinylation of ketones.
Zhiyan Huang (2013)
10.1002/chem.201602250
Highly Enantioselective Formation of α-Allyl-α-Arylcyclopentanones via Pd-Catalysed Decarboxylative Asymmetric Allylic Alkylation.
Ramulu Akula (2016)
10.1021/ja206050b
Enantioselective α-arylation of carbonyls via Cu(I)-bisoxazoline catalysis.
J. S. Harvey (2011)
10.15227/ORGSYN.091.0175
Enantioselective Organocatalytic α‐Arylation of Aldehydes
Pernille H.B. Poulsen (2014)
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