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Copper-catalysed enantioselective intramolecular C–H insertion reactions of α-diazo-β-keto esters and α-diazo-β-keto phosphonates
Tetrahedron Letters 54 (2013) 2799–2801
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Copper-catalysed enantioselective intramolecular C–H insertion reactions of a-diazo-b-keto esters and a-diazo-b-keto phosphonates Catherine N. Slattery a, Anita R. Maguire b,⇑ a b
Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland Department of Chemistry, School of Pharmacy and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
a r t i c l e
i n f o
Article history: Received 21 January 2013 Revised 7 March 2013 Accepted 13 March 2013 Available online 22 March 2013 Keywords: Diazocarbonyl C–H insertion Copper catalysis Bis(oxazoline) NaBARF
a b s t r a c t Copper-catalysed intramolecular C–H insertion reactions of a-diazo-b-keto esters and a-diazo-b-keto phosphonates are described, with moderate-to-good levels of enantioselectivity achieved for reactions employing the borate additive sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF). Notably, the first example of asymmetric induction reported to date for intramolecular C–H insertion of an a-diazo-b-keto phosphonate is also described. Ó 2013 Elsevier Ltd. All rights reserved.
Carbenoid insertion into C–H bonds remains a key synthetic strategy in organic chemistry for the formation of C–C bonds. The use of copper catalysts dominated early investigations of C–H insertions, however, low levels of selectivity were a common feature of these studies.1 Since the first successful example of carbenoid insertion into a C–H bond in the presence of a rhodium catalyst in 1981,2 rhodium complexes have remained the catalysts of choice for the vast majority of C–H insertion processes. Great success has since been achieved for C–H insertion reactions employing a variety of rhodium(II) carboxylate and carboxamidate catalysts, providing access to a diverse range of insertion products with high chemo-, regio- and enantioselectivities commonly observed.3,4 We have demonstrated that copper-bis(oxazoline) complexes are highly effective catalysts for C–H insertion reactions of a-diazosulfones.5–8 In this previous work, thiopyran and cyclopentanone products were prepared in up to 98% and 91% ee, respectively, representing the highest levels of enantioselectivity reported to date for copper-catalysed C–H insertion, and thereby contributing to the re-emergence of copper compounds as a viable catalytic option for asymmetric C–H insertion reactions. In our previous work, the presence of NaBARF {BARF = tetrakis [3,5-bis(trifluoromethyl)phenyl]borate} in the reaction mixture was shown to be crucial for achieving insertions with high levels of enantioselectivity.6–8 The key role of this weakly-coordinating ⇑ Corresponding author. Tel.: +353 21 4901693; fax: +353 21 4901770. E-mail address: [email protected] (A.R. Maguire). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.03.078
borate species appears to be the generation of a naked sodium cation in the reaction medium. This alkali metal cation is believed to effect complete or partial chloride abstraction from the catalytic copper complex resulting in alteration of catalyst geometry leading to higher levels of enantiocontrol. In order to extend the scope of copper-bis(oxazoline) catalysed C–H insertions in the presence of NaBARF beyond the use of a-diazosulfones, we report herein the enantioselective copper-catalysed C–H insertions of a-diazo-b-keto ester 1 and adiazo-b-keto phosphonate 2 providing a-carboalkoxy cyclopentanone 3 and a-phosphoryl cyclopentanone 4, respectively, (Table 1). Asymmetric C–H insertion reactions employing a-diazo-b-keto esters have previously been conducted by both Hashimoto9–11 and Müller.and Boléa.12 Hashimoto and co-workers examined a range of a-diazo-b-keto ester substrates in the early 1990s, investigating a large variety of ester alkoxy groups and substituents adjacent to the C–H insertion site.9–11 Large variations in enantioselectivity were reported for these rhodium-catalysed cyclisations, ranging from 24% to 80% ee. Notably, high levels of asymmetric induction were achieved only for substrates possessing bulky substituents at the C–H insertion site and the alkoxy ester position. Copper-catalysed C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) were reported by Müller and Boléa in 2001.12 Reactions in this previous study were carried out in the presence of various chiral bis(oxazoline) ligands, with moderate enantioselectivity (51–60% ee) obtained only for insertions employing sterically bulky binaphthyl-derived ligand structures.
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C. N. Slattery, A. R. Maguire / Tetrahedron Letters 54 (2013) 2799–2801
Table 1 Copper-catalysed C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) and dimethyl (1-diazo-2-oxo-5-phenylpentyl)phosphonate (2)
O Ph
EWG
O
CuCl2 , L*, NaBARF
EWG
reflux
N2
Ph
1/2
3/4
Entry
Diazocarbonyl
EWG
Solvent
L⁄
Time (h)
Cyclopentanone
Yielda (%)
eeb,c (%)
1 2 3 4 5 6e 7e 8 9 10 11 12 13 14e
1 1 1 1 1 1 1 2 2 2 2 2 2 2
CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 C2H4Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 C2H4Cl2 C2H4Cl2
5 6 7 8 9 8 8 5 6 7 8 9 6 6
48 2 2 2 48 72 24 48 72 48 45 110 2 4
3 3 3 3 3 3 3 4 4 4 4 4 4 4
89d 93d 48d 53d 82d ––f ––g 77 71 42 64 64 84 62
65 51 37 61 46 –– –– 32 52 30 45 0 46 28
( ) (+) (+) (+) ( )
( ) (+) (+) (+) (+) (+)
a
Isolated yield after flash chromatography. Enantioselectivity values were determined by chiral HPLC (see Supplementary data for details). Stereochemical assignments for 3 are in agreement with previously reported data [(+) = (1S,5R), ( ) = (1R,5S)];19 stereochemical assignments for 4 were assigned by analogy to 3 and 2-phenylsulfonyl-3-phenylcyclopentanone,6 [(+) = (2S,3S), ( ) = (2R,3R)]. d Isolated product contained a mixture of keto (major) and enol (minor) tautomers; only the keto form was observed following prolonged product storage. No evidence for the presence of the product arising from insertion into the alkyl ester moiety of 1 was observed by 1H NMR analysis. e No NaBARF present in the reaction mixture. f Only starting material (1) was observed in the 1H NMR spectrum of the reaction mixture after reflux for 72 h. g A complex mixture of unknown decomposition products was observed in the 1H NMR spectrum of the reaction mixture after reflux for 24 h. b
c
Limited examples exist of asymmetric a-phosphoryl cyclopentanone synthesis via C–H insertion. Afonso and co-workers examined the intramolecular cyclisation of a-diazo-(dialkoxyphosphoryl)acetamides in the presence of various chiral rhodium(II) catalysts, however poor levels of enantioselectivity were achieved (640% ee).13 In 2006, Davies and co-workers reported the intermolecular rhodium-catalysed C–H insertions of dimethyl [diazo(phenyl)methyl]phosphonate and cyclohexa-1,4-diene.14 Good asymmetric induction (92% ee) was possible for this intermolecular reaction in the presence of Rh2(S-PTAD)4, however, insertions with other chiral rhodium catalysts were found to result in decreased levels of enantiocontrol. The intramolecular C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) and dimethyl (1-diazo-2-oxo-5-phenylpentyl)phosphonate (2) were carried out in refluxing dichloromethane in the presence of a copper catalyst generated in situ from CuCl2 (5 mol %), a bis(oxazoline) ligand (6 mol %) and NaBARF (6 mol %). Five different chiral bis(oxazoline) ligands 5–9 (Figure 1) were employed in this study. trans-Cyclopentanones 3 and 4 were the major products of the insertion reactions of 1 and 2, respectively, with minor amounts of by-product formation also observed in certain cases. Investigation of the a-diazo-b-keto ester C–H insertion was first conducted employing, for comparison purposes, the ester substrate 1, used in both Hashimoto’s and Müller’s previous studies.10–12 The time taken for complete insertion of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) was seen to vary (Table 1, entries 1–5). Cyclisations in the presence of bis(oxazolines) 6–8 were complete after 2 h of reflux, however, reactions employing ligands 5 and 9 required a reaction time of 48 h. This increased reaction time did not appear to affect the recorded yields or enantioselectivity. An attempted insertion reaction of a-diazo-b-keto ester 1 at room temperature employing ligand 8 provided no product after seven days. Hashimoto’s rhodium-catalysed insertion of a-diazo-b-keto ester 1 in the presence of Rh2(S-PTPA)4 was repeated at the
O
O N
O
O
N
N
N R
R 5
6: R = (R )-Bn 7: R= (R)-Ph O
O
Ph
N
Ph
N Ph
Ph
O
O N
N
t -Bu
t -Bu
(R, S)- 8
(S)-9
Figure 1. Bis(oxazoline) ligands.
beginning of this study to confirm the validity of our analytical method. The enantioselectivity for this reaction (72% ee) was found to be in the same range as that recorded by Hashimoto et al. (76% ee).10 Variations in enantioselectivities were recorded for our copper bis(oxazoline) catalysed cyclisations of 1 (37–65% ee). As was observed for our previous a-diazo-b-keto sulfone reactions,7 the indane-derived bis(oxazoline) 5 was found to provide the highest level of enantiocontrol (65% ee) (Table 1, entry 1), with the bis(oxazoline) 8 also providing good asymmetric induction (61% ee) (Table 1, entry 4). Although only moderate ee was recorded for the remaining ligands 6, 7 and 9 (Table 1, entries 2, 3 and 5), these results represent an improvement upon those previously recorded by Müller for Cu(OTf)2-catalysed C–H insertion of 1, in which poor levels of enantioselectivity (15–31% ee) were observed for reactions in the presence of similar bis(oxazoline) catalysts.12 In particular, a dramatic increase to 65% ee was observed for the cyclisation of a-diazo-b-keto ester 1 with ligand 5 (Table 1, entry 1) under our copper catalysis conditions (CuCl2, NaBARF) versus
C. N. Slattery, A. R. Maguire / Tetrahedron Letters 54 (2013) 2799–2801
Müller’s Cu(OTf)2-catalysed reaction employing the same ligand (31% ee). The enantioselectivities presented in this study for the C–H insertions of 1 are also comparable to those previously reported by Hashimoto and co-workers for the rhodium-catalysed reactions of the same substrate,10 in which ees in the range of 53–76% were recorded for cyclisations in the presence of a variety of chiral rhodium(II) carboxylate catalysts. Reaction of a-diazo-b-keto ester 1 with CuCl2 and bis(oxazoline) 8 in the absence of NaBARF (Table 1, entry 6) failed to produce any cyclopentanone product 3 after reflux for 72 h in dichloromethane. Attempted C–H insertion of 1 in refluxing dichloroethane with no NaBARF present (Table 1, entry 7) also resulted in no product formation after 24 h, with a complex mixture of unknown decomposition products instead observed. C–H insertion reactions of a-diazo-b-keto phosphonate 2 were next conducted. As was observed for the reactions of a-diazob-keto ester 1, large variations in reaction times were recorded for insertion in refluxing dichloromethane, ranging from 45– 110 h (Table 1, entries 8–12). Thus, reactions were slower than those with the comparable a-diazo-b-keto sulfones,6,7 which were typically complete after 2 h of reflux. The longer reaction times observed for the phosphonates may be rationalised by the inferior electron-withdrawing abilities of the dimethyl phosphonate group (rp = 0.50)15 compared to the phenylsulfonyl moiety (rp = 0.68),15 which results in a less electrophilic carbene in the phosphonate series.16,17 Reduction of the reaction time was possible by changing to a higher boiling point solvent (1,2-dichloroethane) (Table 1, entry 13), however, interestingly, increasing the reaction temperature was found to lead to only a modest decrease in enantiocontrol (Table 1, entry 13 vs entry 9). The level of enantioselectivity obtained for the cyclisations of 2 was found to be poor to moderate (0–52% ee). The highest enantiocontrol (52% ee) was observed for insertion in the presence of bis(oxazoline) 6 (Table 1, entry 9). Notably, this result represents, to the best of our knowledge, the highest level of enantioselectivity reported to date for intramolecular C–H insertion of a-diazo phosphonates, and the only example of asymmetric catalysis with a-diazo-b-keto phosphonates in the literature. Low levels of enantioselectivity (30–45% ee) were recorded for reactions with ligands 5, 7 and 8 (Table 1, entries 8, 10 and 11), while no asymmetric induction was observed for insertion employing the tert-butyl-derived ligand 9 (Table 1, entry 12) indicating that this is an unfavourable catalyst-substrate pairing. Once again, the absence of NaBARF from the catalytic mixture was found to result in reduced asymmetric induction (Table 1, entry 14 vs entry 13). Yields recorded for the C–H insertion reactions of a-diazob-keto phosphonate 2 were moderate to good, ranging from 42% to 77%. For all reactions conducted, a minor amount of by-product formation was observed in the 1H NMR spectra of the crude reaction mixtures. These by-products likely arise in part via Wolff rearrangement of the starting material which is a well documented competing reaction for insertions with a-diazo phosphonates.16,18
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Removal of these unwanted products was possible by column chromatography on silica gel, providing analytically pure 2-dimethoxyphosphoryl cyclopentanone 4 for chiral HPLC analysis. In conclusion, we have demonstrated that copper bis(oxazoline) catalysts, in the presence of the borate additive NaBARF, may be successfully employed in the intramolecular C–H insertion reactions of a-diazo-b-keto ester 1 and a-diazo-b-keto phosphonate 2. Although moderate enantioselectivities were obtained, these values represent an improvement upon Müller’s previous results in the ester series for Cu(OTf)2-catalysed insertion of 1 using similar ligand structures.11 In addition, the first example of enantioselectivity (up to 52% ee) reported to date for intramolecular C–H insertion of a-diazo-b-keto phosphonates has been achieved. The importance of NaBARF in the catalytic complex was once again6–8 observed, with reactions in the absence of this additive resulting in no product formation for the reaction of 1 and reduced asymmetric induction for the insertion of 2. Acknowledgments Financial support from the Irish Research Council for Science, Engineering and Technology, and Eli Lilly is gratefully acknowledged. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013 .03.078. References and notes 1. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York, 1998. 2. Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssié, P. J. Chem. Soc., Chem. Commun. 1981, 688. 3. Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681. 4. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. 5. Flynn, C. J.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R. J. Am. Chem. Soc. 2010, 132, 1184. 6. Slattery, C. N.; Maguire, A. R. Org. Biomol. Chem. 2011, 9, 667. 7. Slattery, C. N.; Clarke, L.-A.; O’Neill, S.; Ring, A.; Ford, A.; Maguire, A. R. Synlett 2012, 765–767. 8. Slattery, C. N.; Clarke, L.-A.; Ford, A.; Maguire, A. Tetrahedron 2013, 69, 1297– 1301. 9. Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990, 31, 5173. 10. Hashimoto, S.-i.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S. Tetrahedron Lett. 1993, 34, 5109. 11. Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Synlett 1994, 353. 12. Müller, P.; Bolea, C. Molecules 2001, 6, 258. 13. Gois, P. M. P.; Candeias, N. R.; Afonso, C. A. M. J. Mol. Catal. A: Chem. 2005, 227, 17. 14. Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437. 15. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165. 16. Corbel, B.; Hernot, D.; Haelters, J.-P.; Sturtz, G. Tetrahedron Lett. 1987, 28, 6605. 17. Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798. 18. Dayoub, W.; Diab, Y.; Doutheau, A. Tetrahedron Lett. 2001, 42, 845. 19. Müller, P.; Fernandez, D. Helv. Chim. Acta 1995, 78, 947.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Copper-catalysed enantioselective intramolecular C–H insertion reactions of a-diazo-b-keto esters and a-diazo-b-keto phosphonates Catherine N. Slattery a, Anita R. Maguire b,⇑ a b
Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland Department of Chemistry, School of Pharmacy and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
a r t i c l e
i n f o
Article history: Received 21 January 2013 Revised 7 March 2013 Accepted 13 March 2013 Available online 22 March 2013 Keywords: Diazocarbonyl C–H insertion Copper catalysis Bis(oxazoline) NaBARF
a b s t r a c t Copper-catalysed intramolecular C–H insertion reactions of a-diazo-b-keto esters and a-diazo-b-keto phosphonates are described, with moderate-to-good levels of enantioselectivity achieved for reactions employing the borate additive sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF). Notably, the first example of asymmetric induction reported to date for intramolecular C–H insertion of an a-diazo-b-keto phosphonate is also described. Ó 2013 Elsevier Ltd. All rights reserved.
Carbenoid insertion into C–H bonds remains a key synthetic strategy in organic chemistry for the formation of C–C bonds. The use of copper catalysts dominated early investigations of C–H insertions, however, low levels of selectivity were a common feature of these studies.1 Since the first successful example of carbenoid insertion into a C–H bond in the presence of a rhodium catalyst in 1981,2 rhodium complexes have remained the catalysts of choice for the vast majority of C–H insertion processes. Great success has since been achieved for C–H insertion reactions employing a variety of rhodium(II) carboxylate and carboxamidate catalysts, providing access to a diverse range of insertion products with high chemo-, regio- and enantioselectivities commonly observed.3,4 We have demonstrated that copper-bis(oxazoline) complexes are highly effective catalysts for C–H insertion reactions of a-diazosulfones.5–8 In this previous work, thiopyran and cyclopentanone products were prepared in up to 98% and 91% ee, respectively, representing the highest levels of enantioselectivity reported to date for copper-catalysed C–H insertion, and thereby contributing to the re-emergence of copper compounds as a viable catalytic option for asymmetric C–H insertion reactions. In our previous work, the presence of NaBARF {BARF = tetrakis [3,5-bis(trifluoromethyl)phenyl]borate} in the reaction mixture was shown to be crucial for achieving insertions with high levels of enantioselectivity.6–8 The key role of this weakly-coordinating ⇑ Corresponding author. Tel.: +353 21 4901693; fax: +353 21 4901770. E-mail address: [email protected] (A.R. Maguire). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.03.078
borate species appears to be the generation of a naked sodium cation in the reaction medium. This alkali metal cation is believed to effect complete or partial chloride abstraction from the catalytic copper complex resulting in alteration of catalyst geometry leading to higher levels of enantiocontrol. In order to extend the scope of copper-bis(oxazoline) catalysed C–H insertions in the presence of NaBARF beyond the use of a-diazosulfones, we report herein the enantioselective copper-catalysed C–H insertions of a-diazo-b-keto ester 1 and adiazo-b-keto phosphonate 2 providing a-carboalkoxy cyclopentanone 3 and a-phosphoryl cyclopentanone 4, respectively, (Table 1). Asymmetric C–H insertion reactions employing a-diazo-b-keto esters have previously been conducted by both Hashimoto9–11 and Müller.and Boléa.12 Hashimoto and co-workers examined a range of a-diazo-b-keto ester substrates in the early 1990s, investigating a large variety of ester alkoxy groups and substituents adjacent to the C–H insertion site.9–11 Large variations in enantioselectivity were reported for these rhodium-catalysed cyclisations, ranging from 24% to 80% ee. Notably, high levels of asymmetric induction were achieved only for substrates possessing bulky substituents at the C–H insertion site and the alkoxy ester position. Copper-catalysed C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) were reported by Müller and Boléa in 2001.12 Reactions in this previous study were carried out in the presence of various chiral bis(oxazoline) ligands, with moderate enantioselectivity (51–60% ee) obtained only for insertions employing sterically bulky binaphthyl-derived ligand structures.
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C. N. Slattery, A. R. Maguire / Tetrahedron Letters 54 (2013) 2799–2801
Table 1 Copper-catalysed C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) and dimethyl (1-diazo-2-oxo-5-phenylpentyl)phosphonate (2)
O Ph
EWG
O
CuCl2 , L*, NaBARF
EWG
reflux
N2
Ph
1/2
3/4
Entry
Diazocarbonyl
EWG
Solvent
L⁄
Time (h)
Cyclopentanone
Yielda (%)
eeb,c (%)
1 2 3 4 5 6e 7e 8 9 10 11 12 13 14e
1 1 1 1 1 1 1 2 2 2 2 2 2 2
CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 CO2CH(i-Pr)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2 PO(OMe)2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 C2H4Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 C2H4Cl2 C2H4Cl2
5 6 7 8 9 8 8 5 6 7 8 9 6 6
48 2 2 2 48 72 24 48 72 48 45 110 2 4
3 3 3 3 3 3 3 4 4 4 4 4 4 4
89d 93d 48d 53d 82d ––f ––g 77 71 42 64 64 84 62
65 51 37 61 46 –– –– 32 52 30 45 0 46 28
( ) (+) (+) (+) ( )
( ) (+) (+) (+) (+) (+)
a
Isolated yield after flash chromatography. Enantioselectivity values were determined by chiral HPLC (see Supplementary data for details). Stereochemical assignments for 3 are in agreement with previously reported data [(+) = (1S,5R), ( ) = (1R,5S)];19 stereochemical assignments for 4 were assigned by analogy to 3 and 2-phenylsulfonyl-3-phenylcyclopentanone,6 [(+) = (2S,3S), ( ) = (2R,3R)]. d Isolated product contained a mixture of keto (major) and enol (minor) tautomers; only the keto form was observed following prolonged product storage. No evidence for the presence of the product arising from insertion into the alkyl ester moiety of 1 was observed by 1H NMR analysis. e No NaBARF present in the reaction mixture. f Only starting material (1) was observed in the 1H NMR spectrum of the reaction mixture after reflux for 72 h. g A complex mixture of unknown decomposition products was observed in the 1H NMR spectrum of the reaction mixture after reflux for 24 h. b
c
Limited examples exist of asymmetric a-phosphoryl cyclopentanone synthesis via C–H insertion. Afonso and co-workers examined the intramolecular cyclisation of a-diazo-(dialkoxyphosphoryl)acetamides in the presence of various chiral rhodium(II) catalysts, however poor levels of enantioselectivity were achieved (640% ee).13 In 2006, Davies and co-workers reported the intermolecular rhodium-catalysed C–H insertions of dimethyl [diazo(phenyl)methyl]phosphonate and cyclohexa-1,4-diene.14 Good asymmetric induction (92% ee) was possible for this intermolecular reaction in the presence of Rh2(S-PTAD)4, however, insertions with other chiral rhodium catalysts were found to result in decreased levels of enantiocontrol. The intramolecular C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) and dimethyl (1-diazo-2-oxo-5-phenylpentyl)phosphonate (2) were carried out in refluxing dichloromethane in the presence of a copper catalyst generated in situ from CuCl2 (5 mol %), a bis(oxazoline) ligand (6 mol %) and NaBARF (6 mol %). Five different chiral bis(oxazoline) ligands 5–9 (Figure 1) were employed in this study. trans-Cyclopentanones 3 and 4 were the major products of the insertion reactions of 1 and 2, respectively, with minor amounts of by-product formation also observed in certain cases. Investigation of the a-diazo-b-keto ester C–H insertion was first conducted employing, for comparison purposes, the ester substrate 1, used in both Hashimoto’s and Müller’s previous studies.10–12 The time taken for complete insertion of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) was seen to vary (Table 1, entries 1–5). Cyclisations in the presence of bis(oxazolines) 6–8 were complete after 2 h of reflux, however, reactions employing ligands 5 and 9 required a reaction time of 48 h. This increased reaction time did not appear to affect the recorded yields or enantioselectivity. An attempted insertion reaction of a-diazo-b-keto ester 1 at room temperature employing ligand 8 provided no product after seven days. Hashimoto’s rhodium-catalysed insertion of a-diazo-b-keto ester 1 in the presence of Rh2(S-PTPA)4 was repeated at the
O
O N
O
O
N
N
N R
R 5
6: R = (R )-Bn 7: R= (R)-Ph O
O
Ph
N
Ph
N Ph
Ph
O
O N
N
t -Bu
t -Bu
(R, S)- 8
(S)-9
Figure 1. Bis(oxazoline) ligands.
beginning of this study to confirm the validity of our analytical method. The enantioselectivity for this reaction (72% ee) was found to be in the same range as that recorded by Hashimoto et al. (76% ee).10 Variations in enantioselectivities were recorded for our copper bis(oxazoline) catalysed cyclisations of 1 (37–65% ee). As was observed for our previous a-diazo-b-keto sulfone reactions,7 the indane-derived bis(oxazoline) 5 was found to provide the highest level of enantiocontrol (65% ee) (Table 1, entry 1), with the bis(oxazoline) 8 also providing good asymmetric induction (61% ee) (Table 1, entry 4). Although only moderate ee was recorded for the remaining ligands 6, 7 and 9 (Table 1, entries 2, 3 and 5), these results represent an improvement upon those previously recorded by Müller for Cu(OTf)2-catalysed C–H insertion of 1, in which poor levels of enantioselectivity (15–31% ee) were observed for reactions in the presence of similar bis(oxazoline) catalysts.12 In particular, a dramatic increase to 65% ee was observed for the cyclisation of a-diazo-b-keto ester 1 with ligand 5 (Table 1, entry 1) under our copper catalysis conditions (CuCl2, NaBARF) versus
C. N. Slattery, A. R. Maguire / Tetrahedron Letters 54 (2013) 2799–2801
Müller’s Cu(OTf)2-catalysed reaction employing the same ligand (31% ee). The enantioselectivities presented in this study for the C–H insertions of 1 are also comparable to those previously reported by Hashimoto and co-workers for the rhodium-catalysed reactions of the same substrate,10 in which ees in the range of 53–76% were recorded for cyclisations in the presence of a variety of chiral rhodium(II) carboxylate catalysts. Reaction of a-diazo-b-keto ester 1 with CuCl2 and bis(oxazoline) 8 in the absence of NaBARF (Table 1, entry 6) failed to produce any cyclopentanone product 3 after reflux for 72 h in dichloromethane. Attempted C–H insertion of 1 in refluxing dichloroethane with no NaBARF present (Table 1, entry 7) also resulted in no product formation after 24 h, with a complex mixture of unknown decomposition products instead observed. C–H insertion reactions of a-diazo-b-keto phosphonate 2 were next conducted. As was observed for the reactions of a-diazob-keto ester 1, large variations in reaction times were recorded for insertion in refluxing dichloromethane, ranging from 45– 110 h (Table 1, entries 8–12). Thus, reactions were slower than those with the comparable a-diazo-b-keto sulfones,6,7 which were typically complete after 2 h of reflux. The longer reaction times observed for the phosphonates may be rationalised by the inferior electron-withdrawing abilities of the dimethyl phosphonate group (rp = 0.50)15 compared to the phenylsulfonyl moiety (rp = 0.68),15 which results in a less electrophilic carbene in the phosphonate series.16,17 Reduction of the reaction time was possible by changing to a higher boiling point solvent (1,2-dichloroethane) (Table 1, entry 13), however, interestingly, increasing the reaction temperature was found to lead to only a modest decrease in enantiocontrol (Table 1, entry 13 vs entry 9). The level of enantioselectivity obtained for the cyclisations of 2 was found to be poor to moderate (0–52% ee). The highest enantiocontrol (52% ee) was observed for insertion in the presence of bis(oxazoline) 6 (Table 1, entry 9). Notably, this result represents, to the best of our knowledge, the highest level of enantioselectivity reported to date for intramolecular C–H insertion of a-diazo phosphonates, and the only example of asymmetric catalysis with a-diazo-b-keto phosphonates in the literature. Low levels of enantioselectivity (30–45% ee) were recorded for reactions with ligands 5, 7 and 8 (Table 1, entries 8, 10 and 11), while no asymmetric induction was observed for insertion employing the tert-butyl-derived ligand 9 (Table 1, entry 12) indicating that this is an unfavourable catalyst-substrate pairing. Once again, the absence of NaBARF from the catalytic mixture was found to result in reduced asymmetric induction (Table 1, entry 14 vs entry 13). Yields recorded for the C–H insertion reactions of a-diazob-keto phosphonate 2 were moderate to good, ranging from 42% to 77%. For all reactions conducted, a minor amount of by-product formation was observed in the 1H NMR spectra of the crude reaction mixtures. These by-products likely arise in part via Wolff rearrangement of the starting material which is a well documented competing reaction for insertions with a-diazo phosphonates.16,18
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Removal of these unwanted products was possible by column chromatography on silica gel, providing analytically pure 2-dimethoxyphosphoryl cyclopentanone 4 for chiral HPLC analysis. In conclusion, we have demonstrated that copper bis(oxazoline) catalysts, in the presence of the borate additive NaBARF, may be successfully employed in the intramolecular C–H insertion reactions of a-diazo-b-keto ester 1 and a-diazo-b-keto phosphonate 2. Although moderate enantioselectivities were obtained, these values represent an improvement upon Müller’s previous results in the ester series for Cu(OTf)2-catalysed insertion of 1 using similar ligand structures.11 In addition, the first example of enantioselectivity (up to 52% ee) reported to date for intramolecular C–H insertion of a-diazo-b-keto phosphonates has been achieved. The importance of NaBARF in the catalytic complex was once again6–8 observed, with reactions in the absence of this additive resulting in no product formation for the reaction of 1 and reduced asymmetric induction for the insertion of 2. Acknowledgments Financial support from the Irish Research Council for Science, Engineering and Technology, and Eli Lilly is gratefully acknowledged. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013 .03.078. References and notes 1. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York, 1998. 2. Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssié, P. J. Chem. Soc., Chem. Commun. 1981, 688. 3. Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681. 4. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. 5. Flynn, C. J.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R. J. Am. Chem. Soc. 2010, 132, 1184. 6. Slattery, C. N.; Maguire, A. R. Org. Biomol. Chem. 2011, 9, 667. 7. Slattery, C. N.; Clarke, L.-A.; O’Neill, S.; Ring, A.; Ford, A.; Maguire, A. R. Synlett 2012, 765–767. 8. Slattery, C. N.; Clarke, L.-A.; Ford, A.; Maguire, A. Tetrahedron 2013, 69, 1297– 1301. 9. Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990, 31, 5173. 10. Hashimoto, S.-i.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S. Tetrahedron Lett. 1993, 34, 5109. 11. Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Synlett 1994, 353. 12. Müller, P.; Bolea, C. Molecules 2001, 6, 258. 13. Gois, P. M. P.; Candeias, N. R.; Afonso, C. A. M. J. Mol. Catal. A: Chem. 2005, 227, 17. 14. Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437. 15. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165. 16. Corbel, B.; Hernot, D.; Haelters, J.-P.; Sturtz, G. Tetrahedron Lett. 1987, 28, 6605. 17. Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798. 18. Dayoub, W.; Diab, Y.; Doutheau, A. Tetrahedron Lett. 2001, 42, 845. 19. Müller, P.; Fernandez, D. Helv. Chim. Acta 1995, 78, 947.