DOI: 10.1002/chem.201404159
Communication
& Synthetic Methods
Stereoselective Synthesis of Aryl Cyclopentene Scaffolds by Heck–Matsuda Desymmetrization of 3-Cyclopentenol Ricardo A. Angnes, Juliana M. Oliveira, Caio C. Oliveira, Nelson C. Martins, and Carlos Roque D. Correia*[a] Abstract: A new enantioselective Heck–Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee’s, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cisarrangement in the formation of the 4-aryl-cyclopentenols.
Desymmetrizations are powerful strategies in organic synthesis for the construction of enantioenriched molecules from prochiral starting materials.[1] Chiral transition metal catalysis has been instrumental in the development of the desymmetrization strategy.[2] Advances within this strategy have also brought enormous benefits to the field of enantioselective catalysis, mainly when associated with organic synthesis.[1, 2] The enantioselective Heck reaction has been a pivotal tool in organic synthesis, with new versions bringing significant advances to the field. This is certainly the case for the Heck–Matsuda reaction, which involves the arylation of olefins using arenediazonium salts.[3] In 2012, we reported the first example of an enantioselective Heck–Matsuda reaction: the desymmetrization of unactivated olefin 2 employing the chiral bisoxazoline ligand L1.[4] Later on, this enantioselective arylation was applied to both butene-diol isomers 4 on route to the synthesis of valuable aryl-lactones 6, as shown in Scheme 1.[5a] Aiming at expanding the usefulness and synthetic potential of this strategy, we envisioned its application with the symmetrical cyclopentenol 7 for the construction of important arylated five-membered carbocycles scaffolds in a straightforward and efficient manner. Substituted cyclopentenes are structural motifs of many natural products and bioactive compounds.[6]
We describe herein our results on the enantioselective synthesis of cis-aryl-cyclopentenols 8, with the aryl cyclopentanones 9 as a minor product (Scheme 1). Equally important is the practical way by which these reactions can be carried out and the mechanistic insights they provide. We began our studies by evaluating the enantioselective Heck arylation of the commercially available cyclopentenol 7 using bisoxazoline L1 as a ligand, applying a protocol previously reported by us.[4] The reaction was completed in 30 min at 60 8C, and, contrary to our initial expectations, we obtained two products which were readily isolated and purified by flash chromatography in a combined yield of 63 %. The products were identified as the novel cis-(1S,4R)-4-(4-methoxyphenyl)cyclopent-2-enol (8 a) and (S)-3-(4-methoxyphenyl)cyclopentanone (9 a) as the minor product. Aryl cyclopentenol 8 a was identified by spectroscopic and spectrometric analysis and by comparison to its known trans analogue.[7] Aryl-cyclopentanone 9 a is a well-known compound and its specific rotation provided the basis for the assignment of its absolute stereochemistry as S. This absolute stereochemistry was also confirmed by the straightforward transformation of 8 a into arylcyclopentanone 9 a by double bond hydrogenation followed by Jones oxidation (Scheme 2).
Scheme 1. Heck–Matsuda-based enantioselective desymmetrizations. [a] R. A. Angnes, Dr. J. M. Oliveira, C. C. Oliveira, Dr. N. C. Martins, Prof. Dr. C. R. D. Correia Institute of Chemistry State University of Campinas- Unicamp C.P. 6154, CEP. 13083-970, Campinas, S¼o Paulo (Brazil) E-mail: [email protected] Homepage: www.correia-group.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404159. Chem. Eur. J. 2014, 20, 13117 – 13121
The Heck products shown above are valuable and useful intermediates for organic synthesis. In particular, formation of aryl cyclopentenol 8 a is mechanistically intriguing, because desymmetrization led to the formation of a highly functionalized compound bearing two stereogenic centers in an unprecedented cis arrangement.[8] 13117
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Scheme 2. Enantioselective arylation of 7 using L1.
Scheme 3. Ligand screening for the enantioselective arylation of 7.
Scheme 4. Scope of the reaction regarding formation of aryl-cyclopentenols 8.
Several N,N-ligands were then screened to evaluate the influence of the ligand and also to optimize the Heck reaction. Some illustrative results are presented in Scheme 3. Following the trend observed for the bisoxazoline L1, ligand L2 provided a slight increase in the yield of the Heck products 8 a/9 a (71 %) with a decreased product ratio of about 2:1 and ee’s of 61 % for 8 a and 28 % for 9 a. Unexpectedly, the PyBOX ligand L3 exclusively produced aryl cyclopentenol 8 a with a 56 % yield, albeit in only 25 % ee. Higher yields and enantiomeric excesses were observed with PyOX ligands L4 and L5. With ligand L5, the Heck products were obtained in a combined yield of 88 % in a ratio of 2.5:1 producing the major product (1S,4R)-aryl cyclopentenol 8 a in a good 82 % ee, and, surprisingly, aryl-cyclopentanone 9 a of inverted configuration (ent9 a; 3R) in only 16 % ee. Similar results were obtained with PyOX ligand L4, which also provided the cyclopentenol 8 a (72 % ee) and the ent-9 a (21 % ee) in a combined yield of 72 %. In another surprising event, QUINOX ligand L6 produced almost exclusively the aryl-cyclopentanone ent-9 a with an excellent 84 % yield and an ee of 46 %. The inversion of configuration for the aryl-cyclopentanone 9 a when using ligands L4–L6 was a striking observation. Although not clear at this stage, we speculate that kinetic resolution might be operating in the case of L4 and L5 with electron-rich diazonium salts leading to the conversion of aryl cyclopentenol ent-8 a into aryl-cyclopentanone ent-9 a by means of some free chiral Pd hydride complex (for a possible rationale, see supporting information).
Further optimization, using palladium(II) trifluoroacetate, (Pd(TFA)2, 2.5 mol %), lower temperature (40 8C), and 1 equiv of DTBMP as base, gave 8 a in 64 % yield and 92 % ee (Scheme 4). Next, to access its synthetic potential, the reaction scope was evaluated with several diazonium salts containing electron donating (ED) or electron withdrawing (EW) groups in different substitution patterns. Gratifyingly, the enantioselective Heck–Matsuda reaction demonstrates good scope, as arylations can be carried out with arenediazonium salts bearing ED and EW substituents.[9] More importantly, the ee’s of the major product aryl-cyclopentenols 8 a-o were excellent in all cases, ranging from 85 % up to 99 %. Surprisingly, the o-phenol-cyclopentenol 8 f was obtained as the exclusive Heck product in 92 % ee. Aryl-cyclopentenol 8 f is a particularly interesting compound and its structure was further confirmed by its conversion to o-OMe arylcyclopentenol 8 b (Scheme 4). Notably, electron deficient arenediazonium salts produced aryl-cyclopentenols 8 h–o in uniformly higher ee’s (93–99 %). The electronically borderline benzenediazonium tetrafluoroborate gave the aryl-cyclopentenol 8 g in a low to moderate 44 % yield with an excellent 95 % ee. Regardless of electronic bias, the ortho-substituted arenediazonium salts provided lower yields of the arylated products, indicating some steric influence in the arylation process, although this does not constitute a general trend, as can be seen for compounds 8 b and 8 f. Assignment of the absolute stereochemistry for compounds in Scheme 4 was confirmed by the X-ray diffraction of 8 h (Figure 1).
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Figure 1. ORTEP diagram for the compound 8 h. Displacement ellipsoids are drawn at the 50 % probability level. Hydrogen atoms are shown as small spheres of arbitrary radius.
Although the mechanistic details of this enantioselective Heck–Matsuda arylation are still under investigation, a catalytic cycle for the formation of the aryl-cyclopentenols 8 is proposed using the PyOX ligand L5 (Scheme 5).10] Formation of
Scheme 5. Proposed catalytic cycle for the enantioselective arylation of 7.
cis-aryl-cyclopentenols 8 can be rationalized by a somewhat intriguing endo orientation of the hydroxyl group in the enantiodetermining step as indicated by transition state D. We hypothesize that a weak Lewis acid–base interaction of the endooriented hydroxyl group towards the cationic PdII (D) is the major driving force favoring this transition state and formation of the (1S,4R)-4-(phenyl)cyclopent-2-enol Heck product.[11] Formation of the majority of the aryl-cyclopentanones 9 observed in this study probably involves a transition state similar to the one proposed in Scheme 5, but in which the hydroxyl group of cyclopentenol 7 assumes an exo orientation in the carbopalladation step (transition state G, Scheme 6). As carbopalladation occurs on the opposite face of the hydroxyl group, an interesting palladium syn chain walking then leads to the carbinol–Pd complex L, which, by a terminal Wacker-type oxidation, probably with the participation of the solvent methanol, forms the aryl-cyclopentanones 9.[12] Chem. Eur. J. 2014, 20, 13117 – 13121
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In all cases examined, the aryl-cyclopentanones were obtained as a minor component of the reaction, and only cyclopentanones isolated in yields higher than 8 % are shown in Scheme 7. The aryl-cyclopentenol 8 to aryl-cyclopentanone 9 ratio varied from 2.2:1 up to > 20:1 depending on the aryldiazonium salt used. It should be highlighted that both compounds are readily separated by column chromatography. Somewhat unexpectedly, aryl-cyclopentanones 9 a, 9 c, and 9 e derived from ED-substituted aryldiazonium salts have an R configuration with ee’s varying from 17 to 22 %. The reasons for such stereochemical inversion are not clear at present, but, as mentioned before, we hypothesize that kinetic resolution might be involved in the formation of those compounds (see supporting information for a rationale). On the other hand, phenyl- and halogen-substituted aryldiazonium salts provided aryl-cyclopentanones 9 g, 9 h, and 9 i with the expected S configuration in low to moderate ee’s (18–58 %), whereas EW-substituted diazonium salts furnished, in general, aryl cyclopentanones 9 j and 9 l in good to high ee’s (88 and 93 %, respectively), with the surprising exception of 9 m. Interestingly, 3-aryl-cyclopentanones derived from meta-substituted diazonium salts displayed lower ee’s, regardless of their electronic nature (compounds 9 c, 9 k, and 9 n, Scheme 7). Despite effective alternatives available in the literature,[13] from the synthetic standpoint, aryl cyclopentanones 9 can also be obtained in good yields and high ee’s from aryl-cyclopentenols 8, as indicated in Scheme 2, thus further demonstrating the potential of the enantioselective Heck–Matsuda reaction to produce distinct and synthetically useful intermediates. In conclusion, the enantioselective Heck–Matsuda arylation of the symmetrical cyclopent-3-enol (7) using PyOX ligand L5 provides two Heck products with good to excellent selectivities (2.2 up to > 20:1). The major products, the cis-4-arylcyclopent-2-enols 8 can be obtained in moderate to good yields in ee’s varying from 85 to 99 % and constitute novel and highly functionalized five-membered scaffolds that open up new synthetic opportunities.[6, 8] Moreover, the minor and mechanistically relevant 3-aryl-cyclopentanones 9 were obtained in ee’s varying from 17 up to 93 %. A rationale is provided for the formation of those Heck products featuring an intriguing directing effect of the hydroxyl group of the symmetrical cycloalkenol in the catalytic cycle. Formation of the 3-aryl-cyclopentanones 9 features an interesting syn Pd walking ending up in a Wacker-type oxidation. As a synthetically oriented method, these Heck arylations are operationally simple to carry out. They are clean, fast, and do not require any special technique in the laboratory.
Experimental Section A 15 mL vessel containing a magnetic stir bar was charged with Pd(TFA)2 (2.5 mol %), ligand L5 (5.0 mol %) and methanol (5.3 mL, 0.075 m). The resulting light-orange solution was then stirred for 10 min at 40 8C. At this point, we added DTBMP (2,6-di-tert-butyl-4methylpyridine) (1 equiv), olefin 7 (2 equiv), followed by the addition of the appropriate arenediazonium salt 1 (1 equiv). The reaction was monitored by TLC until complete consumption of the di-
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Scheme 6. Proposed catalytic cycle for the enantioselective synthesis of cyclopentanones 9 involving a Pd syn chain walking and a Wacker-type oxidation.
remove the polar components. The resulting solution was concentrated under vacuum and the crude products purified by flash chromatography using EtOAc/hexanes 30 % as eluent to obtain the major Heck products aryl-cyclopentenols 8 a–o and the minor arylcyclopentanones 9 a–n.
Acknowledgements Financial support was provided by the S¼o Paulo Research Foundation - Fapesp (2011/23832-6; 2013/07600-3). We are also grateful to Dr. Cristiane Schwalm for her help with the X-ray diffraction. Keywords: aryldiazonium salts · chiral N,N desymmetrization · Heck reaction · palladium
Scheme 7. Scope of the reaction regarding formation of aryl-cyclopentanones 9.
azonium salt (b-napthol test). Next, the crude reaction mixture was concentrated in a vacuum, dissolved in a 50:50 EtOAc/hexanes solvent mixture, and filtered through a short pad of silica gel to Chem. Eur. J. 2014, 20, 13117 – 13121
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ligands
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[1] a) C. Sun, B. Potter, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 6534 – 6537; b) X. Chen, F. Xiong, W. Chen, Q. He, F. Chen, J. Org. Chem. 2014, 79, 2723 – 2728; c) D. W. Tay, G. Y. C. Leung, Y.-Y. Yeung, Angew. Chem. 2014, 126, 5261 – 5264; Angew. Chem. Int. Ed. 2014, 53, 5161 – 5164; d) Z.-Q. Rong, H.-J. Pan, H.-L. Yan, Y. Zhao, Org. Lett. 2014, 16, 208 – 211; e) C. Roux, M. Candy, J.-M. Pons, O. Chuzel, C. Bressy, Angew. Chem. 2014, 126, 785 – 789; Angew. Chem. Int. Ed. 2014, 53, 766 – 770; f) E. Garca-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2011, 111, 110 – 180. [2] a) W. Yang, J. Yan, Y. Long, S. Zhang, J. Liu, Y. Zeng, Q. Cai, Org. Lett. 2013, 15, 6022 – 6025; b) L. Chu, X.-C. Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 16344 – 16347; c) M. Shibasaki, T. Ohshima, in The Mizoroki-Heck Reaction (Ed.:M. Oestreich), John Wiley & Sons, Chichester, 2009, pp. 463 – 483.
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Communication [3] For reviews, see: a) A. Roglans, A. Pla-Quintana, M. Moreno-MaÇas, Chem. Rev. 2006, 106, 4622 – 4643; b) J. G. Taylor, A. V. Moro, C. R. D. Correia, Eur. J. Org. Chem. 2011, 2011, 1403 – 1428; c) F.-X. Felpin, L. NassarHardy, F. Le Callonnec, E. Fouquet, Tetrahedron 2011, 67, 2815 – 2831; d) M. Oestreich, Angew. Chem. 2014, 126, 2314 – 2317; Angew. Chem. Int. Ed. 2014, 53, 2282 – 2285. For other recent examples, see: e) P. Prediger, A. R. Da Silva, C. R. D. Correia, Tetrahedron 2014, 70, 3333 – 3341; f) N. Oger, F. Le Callonnec, D. Jacquemin, E. Fouquet, E. Le Grognec, F. X. Felpin, Adv. Synth. Catal. 2014, 356, 1065 – 1071; g) B. Schmidt, R. Berger, Adv. Synth. Catal. 2013, 355, 463 – 476; h) O. El Bakouri, M. Fernndez, S. Brun, A. Pla-Quintana, A. Roglans, Tetrahedron 2013, 69, 9761 – 9765; i) F. Kawagishi, T. Toma, T. Inui, S. Yokoshima, T. Fukuyama, J. Am. Chem. Soc. 2013, 135, 13684 – 13687; j) B. Schmidt, N. Elizarov, R. Berger, F. Hçlter, Org. Biomol. Chem. 2013, 11, 3674 – 3691. [4] C. R. D. Correia, C. C. Oliveira, A. G. Salles Jr., E. A. F. Santos, Tetrahedron Lett. 2012, 53, 3325 – 3328. [5] a) C. C. Oliveira, R. A. Angnes, C. R. D. Correia, J. Org. Chem. 2013, 78, 4373 – 4385. For other examples of enantioselective Heck – Matsuda reactions with nonsymmetrical alkenols, see: b) E. W. Werner, T.-S. Mei, A. J. Burckle, M. S. Sigman, Science 2012, 338, 1455 – 1458. [6] B. Heasley, Curr. Org. Chem. 2014, 18, 641 – 686. [7] Y. Kobayashi, K. Nakata, T. Ainai, Org. Lett. 2005, 7, 183 – 186. [8] For the synthesis of trans disubstituted cyclopentenes, see: S. Liu, J. Zhou, Chem. Commun. 2013, 49, 11758 – 11760. [9] Aryl-cyclopentanones 9 were obtained as a minor Heck product in all cases, in yields varying from trace up to 24 %. [10] For recent mechanistic investigations, see: a) L. Xu, M. J. Hilton, X. Zhang, P.-O. Norrby, Y.-D. Wu, M. S. Sigman, O. Wiest, J. Am. Chem. Soc.
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2014, 136, 1960 – 1967; b) Y. Dang, S. Qu, Z.-X. Wang, X. Wang, J. Am. Chem. Soc. 2014, 136, 986 – 998. [11] For other examples of substrate directable Heck – Matsuda reactions in cyclopentenes, see: C. C. Oliveira, E. A. F. dos Santos, J. H. B. Nunes, C. R. D. Correia, J. Org. Chem. 2012, 77, 8182 – 8190. [12] The Wacker-type nomenclature adopted herein to describe the formation of aryl-cyclopentanones 9 is based on the putative presence of the carbinol–palladium intermediate L (Scheme 6) proposed in Wacker oxidation. In the case of the Heck-Matsuda reaction, the aryldiazonium salts act as oxidant converting Pd0 to the corresponding cationic arylPdII, which restarts the redox system. For similar redox systems, see: a) L. Huang, J. Qi, X. Wu, K. Huang, H. Jiang, Org. Lett. 2013, 15, 2330 – 2333; b) W. Smadja, S. Czernecki, G. Ville, C. Georgoulis, Organometallics 1987, 6, 166 – 169. For further details on the Wacker oxidation, see: c) H. Eshthiagh Hosseini, S. Beyramabadi, A. Morsali, M. R. Housaindokht, J. Mol. Struct. 2010, 941, 138 – 143; d) J. A. Keith, J. Oxgaard, W. A. Goddard III, J. Am. Chem. Soc. 2006, 128, 3132 – 3133. However, as pointed out by a reviewer, we cannot completely rule out a redox-isomerization as a possible mechanism for the formation of aryl cyclopentanones 9. [13] For alternative methodologies to synthesize aryl-cyclopentanones, see: a) F. Berhal, Z. Wu, J.-P. Genet, T. Ayad, V. Ratovelomanana-Vidal, J. Org. Chem. 2011, 76, 6320 – 6326; b) J. Csizmadiov, M. Mecˇiarov, E. Rakovsky´, B. Horvth, R. Sˇebesta, Eur. J. Org. Chem. 2011, 6110 – 6116; c) T. Gendrineau, O. Chuzel, H. Eijsberg, J.-P. Genet, S. Darses, Angew. Chem. 2008, 120, 7783 – 7786; Angew. Chem. Int. Ed. 2008, 47, 7669 – 7672. Received: June 28, 2014 Published online on August 26, 2014
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Stereoselective Synthesis of Aryl Cyclopentene Scaffolds by Heck–Matsuda Desymmetrization of 3-Cyclopentenol Ricardo A. Angnes, Juliana M. Oliveira, Caio C. Oliveira, Nelson C. Martins, and Carlos Roque D. Correia*[a] Abstract: A new enantioselective Heck–Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee’s, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cisarrangement in the formation of the 4-aryl-cyclopentenols.
Desymmetrizations are powerful strategies in organic synthesis for the construction of enantioenriched molecules from prochiral starting materials.[1] Chiral transition metal catalysis has been instrumental in the development of the desymmetrization strategy.[2] Advances within this strategy have also brought enormous benefits to the field of enantioselective catalysis, mainly when associated with organic synthesis.[1, 2] The enantioselective Heck reaction has been a pivotal tool in organic synthesis, with new versions bringing significant advances to the field. This is certainly the case for the Heck–Matsuda reaction, which involves the arylation of olefins using arenediazonium salts.[3] In 2012, we reported the first example of an enantioselective Heck–Matsuda reaction: the desymmetrization of unactivated olefin 2 employing the chiral bisoxazoline ligand L1.[4] Later on, this enantioselective arylation was applied to both butene-diol isomers 4 on route to the synthesis of valuable aryl-lactones 6, as shown in Scheme 1.[5a] Aiming at expanding the usefulness and synthetic potential of this strategy, we envisioned its application with the symmetrical cyclopentenol 7 for the construction of important arylated five-membered carbocycles scaffolds in a straightforward and efficient manner. Substituted cyclopentenes are structural motifs of many natural products and bioactive compounds.[6]
We describe herein our results on the enantioselective synthesis of cis-aryl-cyclopentenols 8, with the aryl cyclopentanones 9 as a minor product (Scheme 1). Equally important is the practical way by which these reactions can be carried out and the mechanistic insights they provide. We began our studies by evaluating the enantioselective Heck arylation of the commercially available cyclopentenol 7 using bisoxazoline L1 as a ligand, applying a protocol previously reported by us.[4] The reaction was completed in 30 min at 60 8C, and, contrary to our initial expectations, we obtained two products which were readily isolated and purified by flash chromatography in a combined yield of 63 %. The products were identified as the novel cis-(1S,4R)-4-(4-methoxyphenyl)cyclopent-2-enol (8 a) and (S)-3-(4-methoxyphenyl)cyclopentanone (9 a) as the minor product. Aryl cyclopentenol 8 a was identified by spectroscopic and spectrometric analysis and by comparison to its known trans analogue.[7] Aryl-cyclopentanone 9 a is a well-known compound and its specific rotation provided the basis for the assignment of its absolute stereochemistry as S. This absolute stereochemistry was also confirmed by the straightforward transformation of 8 a into arylcyclopentanone 9 a by double bond hydrogenation followed by Jones oxidation (Scheme 2).
Scheme 1. Heck–Matsuda-based enantioselective desymmetrizations. [a] R. A. Angnes, Dr. J. M. Oliveira, C. C. Oliveira, Dr. N. C. Martins, Prof. Dr. C. R. D. Correia Institute of Chemistry State University of Campinas- Unicamp C.P. 6154, CEP. 13083-970, Campinas, S¼o Paulo (Brazil) E-mail: [email protected] Homepage: www.correia-group.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404159. Chem. Eur. J. 2014, 20, 13117 – 13121
The Heck products shown above are valuable and useful intermediates for organic synthesis. In particular, formation of aryl cyclopentenol 8 a is mechanistically intriguing, because desymmetrization led to the formation of a highly functionalized compound bearing two stereogenic centers in an unprecedented cis arrangement.[8] 13117
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Scheme 2. Enantioselective arylation of 7 using L1.
Scheme 3. Ligand screening for the enantioselective arylation of 7.
Scheme 4. Scope of the reaction regarding formation of aryl-cyclopentenols 8.
Several N,N-ligands were then screened to evaluate the influence of the ligand and also to optimize the Heck reaction. Some illustrative results are presented in Scheme 3. Following the trend observed for the bisoxazoline L1, ligand L2 provided a slight increase in the yield of the Heck products 8 a/9 a (71 %) with a decreased product ratio of about 2:1 and ee’s of 61 % for 8 a and 28 % for 9 a. Unexpectedly, the PyBOX ligand L3 exclusively produced aryl cyclopentenol 8 a with a 56 % yield, albeit in only 25 % ee. Higher yields and enantiomeric excesses were observed with PyOX ligands L4 and L5. With ligand L5, the Heck products were obtained in a combined yield of 88 % in a ratio of 2.5:1 producing the major product (1S,4R)-aryl cyclopentenol 8 a in a good 82 % ee, and, surprisingly, aryl-cyclopentanone 9 a of inverted configuration (ent9 a; 3R) in only 16 % ee. Similar results were obtained with PyOX ligand L4, which also provided the cyclopentenol 8 a (72 % ee) and the ent-9 a (21 % ee) in a combined yield of 72 %. In another surprising event, QUINOX ligand L6 produced almost exclusively the aryl-cyclopentanone ent-9 a with an excellent 84 % yield and an ee of 46 %. The inversion of configuration for the aryl-cyclopentanone 9 a when using ligands L4–L6 was a striking observation. Although not clear at this stage, we speculate that kinetic resolution might be operating in the case of L4 and L5 with electron-rich diazonium salts leading to the conversion of aryl cyclopentenol ent-8 a into aryl-cyclopentanone ent-9 a by means of some free chiral Pd hydride complex (for a possible rationale, see supporting information).
Further optimization, using palladium(II) trifluoroacetate, (Pd(TFA)2, 2.5 mol %), lower temperature (40 8C), and 1 equiv of DTBMP as base, gave 8 a in 64 % yield and 92 % ee (Scheme 4). Next, to access its synthetic potential, the reaction scope was evaluated with several diazonium salts containing electron donating (ED) or electron withdrawing (EW) groups in different substitution patterns. Gratifyingly, the enantioselective Heck–Matsuda reaction demonstrates good scope, as arylations can be carried out with arenediazonium salts bearing ED and EW substituents.[9] More importantly, the ee’s of the major product aryl-cyclopentenols 8 a-o were excellent in all cases, ranging from 85 % up to 99 %. Surprisingly, the o-phenol-cyclopentenol 8 f was obtained as the exclusive Heck product in 92 % ee. Aryl-cyclopentenol 8 f is a particularly interesting compound and its structure was further confirmed by its conversion to o-OMe arylcyclopentenol 8 b (Scheme 4). Notably, electron deficient arenediazonium salts produced aryl-cyclopentenols 8 h–o in uniformly higher ee’s (93–99 %). The electronically borderline benzenediazonium tetrafluoroborate gave the aryl-cyclopentenol 8 g in a low to moderate 44 % yield with an excellent 95 % ee. Regardless of electronic bias, the ortho-substituted arenediazonium salts provided lower yields of the arylated products, indicating some steric influence in the arylation process, although this does not constitute a general trend, as can be seen for compounds 8 b and 8 f. Assignment of the absolute stereochemistry for compounds in Scheme 4 was confirmed by the X-ray diffraction of 8 h (Figure 1).
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Figure 1. ORTEP diagram for the compound 8 h. Displacement ellipsoids are drawn at the 50 % probability level. Hydrogen atoms are shown as small spheres of arbitrary radius.
Although the mechanistic details of this enantioselective Heck–Matsuda arylation are still under investigation, a catalytic cycle for the formation of the aryl-cyclopentenols 8 is proposed using the PyOX ligand L5 (Scheme 5).10] Formation of
Scheme 5. Proposed catalytic cycle for the enantioselective arylation of 7.
cis-aryl-cyclopentenols 8 can be rationalized by a somewhat intriguing endo orientation of the hydroxyl group in the enantiodetermining step as indicated by transition state D. We hypothesize that a weak Lewis acid–base interaction of the endooriented hydroxyl group towards the cationic PdII (D) is the major driving force favoring this transition state and formation of the (1S,4R)-4-(phenyl)cyclopent-2-enol Heck product.[11] Formation of the majority of the aryl-cyclopentanones 9 observed in this study probably involves a transition state similar to the one proposed in Scheme 5, but in which the hydroxyl group of cyclopentenol 7 assumes an exo orientation in the carbopalladation step (transition state G, Scheme 6). As carbopalladation occurs on the opposite face of the hydroxyl group, an interesting palladium syn chain walking then leads to the carbinol–Pd complex L, which, by a terminal Wacker-type oxidation, probably with the participation of the solvent methanol, forms the aryl-cyclopentanones 9.[12] Chem. Eur. J. 2014, 20, 13117 – 13121
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In all cases examined, the aryl-cyclopentanones were obtained as a minor component of the reaction, and only cyclopentanones isolated in yields higher than 8 % are shown in Scheme 7. The aryl-cyclopentenol 8 to aryl-cyclopentanone 9 ratio varied from 2.2:1 up to > 20:1 depending on the aryldiazonium salt used. It should be highlighted that both compounds are readily separated by column chromatography. Somewhat unexpectedly, aryl-cyclopentanones 9 a, 9 c, and 9 e derived from ED-substituted aryldiazonium salts have an R configuration with ee’s varying from 17 to 22 %. The reasons for such stereochemical inversion are not clear at present, but, as mentioned before, we hypothesize that kinetic resolution might be involved in the formation of those compounds (see supporting information for a rationale). On the other hand, phenyl- and halogen-substituted aryldiazonium salts provided aryl-cyclopentanones 9 g, 9 h, and 9 i with the expected S configuration in low to moderate ee’s (18–58 %), whereas EW-substituted diazonium salts furnished, in general, aryl cyclopentanones 9 j and 9 l in good to high ee’s (88 and 93 %, respectively), with the surprising exception of 9 m. Interestingly, 3-aryl-cyclopentanones derived from meta-substituted diazonium salts displayed lower ee’s, regardless of their electronic nature (compounds 9 c, 9 k, and 9 n, Scheme 7). Despite effective alternatives available in the literature,[13] from the synthetic standpoint, aryl cyclopentanones 9 can also be obtained in good yields and high ee’s from aryl-cyclopentenols 8, as indicated in Scheme 2, thus further demonstrating the potential of the enantioselective Heck–Matsuda reaction to produce distinct and synthetically useful intermediates. In conclusion, the enantioselective Heck–Matsuda arylation of the symmetrical cyclopent-3-enol (7) using PyOX ligand L5 provides two Heck products with good to excellent selectivities (2.2 up to > 20:1). The major products, the cis-4-arylcyclopent-2-enols 8 can be obtained in moderate to good yields in ee’s varying from 85 to 99 % and constitute novel and highly functionalized five-membered scaffolds that open up new synthetic opportunities.[6, 8] Moreover, the minor and mechanistically relevant 3-aryl-cyclopentanones 9 were obtained in ee’s varying from 17 up to 93 %. A rationale is provided for the formation of those Heck products featuring an intriguing directing effect of the hydroxyl group of the symmetrical cycloalkenol in the catalytic cycle. Formation of the 3-aryl-cyclopentanones 9 features an interesting syn Pd walking ending up in a Wacker-type oxidation. As a synthetically oriented method, these Heck arylations are operationally simple to carry out. They are clean, fast, and do not require any special technique in the laboratory.
Experimental Section A 15 mL vessel containing a magnetic stir bar was charged with Pd(TFA)2 (2.5 mol %), ligand L5 (5.0 mol %) and methanol (5.3 mL, 0.075 m). The resulting light-orange solution was then stirred for 10 min at 40 8C. At this point, we added DTBMP (2,6-di-tert-butyl-4methylpyridine) (1 equiv), olefin 7 (2 equiv), followed by the addition of the appropriate arenediazonium salt 1 (1 equiv). The reaction was monitored by TLC until complete consumption of the di-
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Scheme 6. Proposed catalytic cycle for the enantioselective synthesis of cyclopentanones 9 involving a Pd syn chain walking and a Wacker-type oxidation.
remove the polar components. The resulting solution was concentrated under vacuum and the crude products purified by flash chromatography using EtOAc/hexanes 30 % as eluent to obtain the major Heck products aryl-cyclopentenols 8 a–o and the minor arylcyclopentanones 9 a–n.
Acknowledgements Financial support was provided by the S¼o Paulo Research Foundation - Fapesp (2011/23832-6; 2013/07600-3). We are also grateful to Dr. Cristiane Schwalm for her help with the X-ray diffraction. Keywords: aryldiazonium salts · chiral N,N desymmetrization · Heck reaction · palladium
Scheme 7. Scope of the reaction regarding formation of aryl-cyclopentanones 9.
azonium salt (b-napthol test). Next, the crude reaction mixture was concentrated in a vacuum, dissolved in a 50:50 EtOAc/hexanes solvent mixture, and filtered through a short pad of silica gel to Chem. Eur. J. 2014, 20, 13117 – 13121
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ligands
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[1] a) C. Sun, B. Potter, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 6534 – 6537; b) X. Chen, F. Xiong, W. Chen, Q. He, F. Chen, J. Org. Chem. 2014, 79, 2723 – 2728; c) D. W. Tay, G. Y. C. Leung, Y.-Y. Yeung, Angew. Chem. 2014, 126, 5261 – 5264; Angew. Chem. Int. Ed. 2014, 53, 5161 – 5164; d) Z.-Q. Rong, H.-J. Pan, H.-L. Yan, Y. Zhao, Org. Lett. 2014, 16, 208 – 211; e) C. Roux, M. Candy, J.-M. Pons, O. Chuzel, C. Bressy, Angew. Chem. 2014, 126, 785 – 789; Angew. Chem. Int. Ed. 2014, 53, 766 – 770; f) E. Garca-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2011, 111, 110 – 180. [2] a) W. Yang, J. Yan, Y. Long, S. Zhang, J. Liu, Y. Zeng, Q. Cai, Org. Lett. 2013, 15, 6022 – 6025; b) L. Chu, X.-C. Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 16344 – 16347; c) M. Shibasaki, T. Ohshima, in The Mizoroki-Heck Reaction (Ed.:M. Oestreich), John Wiley & Sons, Chichester, 2009, pp. 463 – 483.
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Communication [3] For reviews, see: a) A. Roglans, A. Pla-Quintana, M. Moreno-MaÇas, Chem. Rev. 2006, 106, 4622 – 4643; b) J. G. Taylor, A. V. Moro, C. R. D. Correia, Eur. J. Org. Chem. 2011, 2011, 1403 – 1428; c) F.-X. Felpin, L. NassarHardy, F. Le Callonnec, E. Fouquet, Tetrahedron 2011, 67, 2815 – 2831; d) M. Oestreich, Angew. Chem. 2014, 126, 2314 – 2317; Angew. Chem. Int. Ed. 2014, 53, 2282 – 2285. For other recent examples, see: e) P. Prediger, A. R. Da Silva, C. R. D. Correia, Tetrahedron 2014, 70, 3333 – 3341; f) N. Oger, F. Le Callonnec, D. Jacquemin, E. Fouquet, E. Le Grognec, F. X. Felpin, Adv. Synth. Catal. 2014, 356, 1065 – 1071; g) B. Schmidt, R. Berger, Adv. Synth. Catal. 2013, 355, 463 – 476; h) O. El Bakouri, M. Fernndez, S. Brun, A. Pla-Quintana, A. Roglans, Tetrahedron 2013, 69, 9761 – 9765; i) F. Kawagishi, T. Toma, T. Inui, S. Yokoshima, T. Fukuyama, J. Am. Chem. Soc. 2013, 135, 13684 – 13687; j) B. Schmidt, N. Elizarov, R. Berger, F. Hçlter, Org. Biomol. Chem. 2013, 11, 3674 – 3691. [4] C. R. D. Correia, C. C. Oliveira, A. G. Salles Jr., E. A. F. Santos, Tetrahedron Lett. 2012, 53, 3325 – 3328. [5] a) C. C. Oliveira, R. A. Angnes, C. R. D. Correia, J. Org. Chem. 2013, 78, 4373 – 4385. For other examples of enantioselective Heck – Matsuda reactions with nonsymmetrical alkenols, see: b) E. W. Werner, T.-S. Mei, A. J. Burckle, M. S. Sigman, Science 2012, 338, 1455 – 1458. [6] B. Heasley, Curr. Org. Chem. 2014, 18, 641 – 686. [7] Y. Kobayashi, K. Nakata, T. Ainai, Org. Lett. 2005, 7, 183 – 186. [8] For the synthesis of trans disubstituted cyclopentenes, see: S. Liu, J. Zhou, Chem. Commun. 2013, 49, 11758 – 11760. [9] Aryl-cyclopentanones 9 were obtained as a minor Heck product in all cases, in yields varying from trace up to 24 %. [10] For recent mechanistic investigations, see: a) L. Xu, M. J. Hilton, X. Zhang, P.-O. Norrby, Y.-D. Wu, M. S. Sigman, O. Wiest, J. Am. Chem. Soc.
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2014, 136, 1960 – 1967; b) Y. Dang, S. Qu, Z.-X. Wang, X. Wang, J. Am. Chem. Soc. 2014, 136, 986 – 998. [11] For other examples of substrate directable Heck – Matsuda reactions in cyclopentenes, see: C. C. Oliveira, E. A. F. dos Santos, J. H. B. Nunes, C. R. D. Correia, J. Org. Chem. 2012, 77, 8182 – 8190. [12] The Wacker-type nomenclature adopted herein to describe the formation of aryl-cyclopentanones 9 is based on the putative presence of the carbinol–palladium intermediate L (Scheme 6) proposed in Wacker oxidation. In the case of the Heck-Matsuda reaction, the aryldiazonium salts act as oxidant converting Pd0 to the corresponding cationic arylPdII, which restarts the redox system. For similar redox systems, see: a) L. Huang, J. Qi, X. Wu, K. Huang, H. Jiang, Org. Lett. 2013, 15, 2330 – 2333; b) W. Smadja, S. Czernecki, G. Ville, C. Georgoulis, Organometallics 1987, 6, 166 – 169. For further details on the Wacker oxidation, see: c) H. Eshthiagh Hosseini, S. Beyramabadi, A. Morsali, M. R. Housaindokht, J. Mol. Struct. 2010, 941, 138 – 143; d) J. A. Keith, J. Oxgaard, W. A. Goddard III, J. Am. Chem. Soc. 2006, 128, 3132 – 3133. However, as pointed out by a reviewer, we cannot completely rule out a redox-isomerization as a possible mechanism for the formation of aryl cyclopentanones 9. [13] For alternative methodologies to synthesize aryl-cyclopentanones, see: a) F. Berhal, Z. Wu, J.-P. Genet, T. Ayad, V. Ratovelomanana-Vidal, J. Org. Chem. 2011, 76, 6320 – 6326; b) J. Csizmadiov, M. Mecˇiarov, E. Rakovsky´, B. Horvth, R. Sˇebesta, Eur. J. Org. Chem. 2011, 6110 – 6116; c) T. Gendrineau, O. Chuzel, H. Eijsberg, J.-P. Genet, S. Darses, Angew. Chem. 2008, 120, 7783 – 7786; Angew. Chem. Int. Ed. 2008, 47, 7669 – 7672. Received: June 28, 2014 Published online on August 26, 2014
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