Tandem Copper-Catalyzed Conjugate Addition-Diastereoselective

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Cite This: Org. Lett. 2018, 20, 6099−6103

Tandem Copper-Catalyzed Conjugate Addition-Diastereoselective Protonation of (E)‑α-Trialkylsilyl-β-Alkyl(Aryl)-α,β-Unsaturated Esters David A. Johnson and Michael P. Jennings* Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States

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S Supporting Information *

ABSTRACT: A tandem Cu(I)-catalyzed conjugate addition of Kharasch reagents/diastereoselective protonation of (E)-α-trialkylsilyl-β-alkyl(aryl)-α,β-unsaturated esters afforded the saturated products with d.r. values of >20:1 favoring the anti-diastereomer in modest to excellent isolated yields.

T

reagents as noted above. Our preliminary results on the highly stereoselective conjugate addition, coupled with a stereochemical induction model, are reported herein. With this idea in mind, optimization studies commenced by examining the Cu-catalyzed conjugate addition of EtMgBr to the β-ethyl ester 1a in the presence of the Lewis-acid additives, TMSOTf and TMSCl, as described in Table 1.8a Much to our

he conjugate addition of nucleophiles, via cuprate reagents, with α,β-unsaturated carbonyls is one of the most employed methods for C−C bond formation in organic synthesis.1 First disclosed by Kharasch and Tawney in 1941, the Cu(I)-catalyzed addition of a Grignard reagent to an α,βunsaturated ketone chemoselectively provided the conjugate addition product in lieu of the 1,2 adduct.2 Other nucleophilic organocopper(I) reagents (i.e., Gilman) have been extensively developed; however, they are utilized stoichiometrically in practice.3 Thus, Kharasch reagents are significantly more attractive due to the catalytic turnover by relying only on a substoichiometric amount of the Cu(I) metal. Surprisingly, there are only a few disclosures of α-trialkylsilylα,β-unsaturated esters functioning as Michael acceptors. Unfortunately, the reported examples are very limited in scope and mainly involve methyl α-trimethylsilyl acrylate. Tsuge and Tanaka developed a tandem conjugate addition-Peterson olefination process with a variety of nucleophiles and methyl α-trimethylsilyl acrylate to afford β-substituted products in modest to good yields.4,5 Yamazaki and co-workers have reported the lone example of an α-trialkylsilyl-α,β-unsaturated ester bearing a β-substituent operating as a Michael acceptor.6 They observed that two Grignard reagents [without the addition of Cu(I)] underwent conjugate additions in moderate yields and diastereoselectivities of the saturated ester products. The assembly of elaborate stereochemically pure organosilane reagents for further streamlining organic synthesis would be highly desirable as natural product targets become more complex. Along this line, we recently reported a reduction/ olefination protocol of saturated α-trialkylsilyl esters to afford functionalized allyl silanes and investigated further reactions with a variety of electrophiles.7 In addition, we have reported on the stereoselective syntheses of a variety of stereodefined αtrialkylsilyl-β-substituted-α,β-unsaturated esters via a tandem catalytic carbocupration/trialkylsilyl tautomerization of propiolate esters.8 Given the limited reports on utilizing these types of electrophiles as Michael acceptors, we were interested in investigating the conjugate addition of Grignard reagents under Cu(I) catalysis to a diverse set of α-trialkylsilyl-βalkyl(aryl)-α,β-unsaturated esters with the anticipation of further transforming the products into functionalized allyl silane © 2018 American Chemical Society

Table 1. TMSX Promoted Copper-Catalyzed Conjugation Addition of EtMgBr to α-Trimethylsilyl-β-ethyl-α,βunsaturated Ester 1a

entry

catalyst mol %

TMSX

T, °Ca

Yield/%b

1 2 3c 4 5d 6 7 8 9

15 5 5 2 2 5 5 5 5

TMSOTf TMSOTf TMSOTf TMSOTf TMSOTf TMSCl TMSCl TMSCl TMSCl

−78 → rt −78 → rt −78 → rt −78 → rt −78 → rt −78 → rt −40 → rt −20 → rt −10 → rt

83 81 80 73 71 84 86 83 78

Reactions ran at −78 °C for 2 h, then slowly warmed to rt and held for 2 additional h. bPurified, isolated yield of 2a. c5 mol % of PPh3 present during the reaction. dReaction allowed to remain at rt for 4 h. a

delight, conjugate addition of EtMgBr (1.2 equiv) at −78 °C → rt in the presence of 15 mol % of CuI·2LiCl and 1.2 equiv of TMSOTf to Michael acceptor 1a readily proceeded and afforded the saturated ester 2a post protonation in 83% yield.9 Lowering the catalyst loading from 15 to 5% had little effect on the yield of ester 2a (entry 2) and the addition of 5 mol % of Received: August 7, 2018 Published: September 14, 2018 6099

DOI: 10.1021/acs.orglett.8b02527 Org. Lett. 2018, 20, 6099−6103

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Organic Letters

Table 3. Vicinal Functionalization via a Catalytic Cu(I) Mediated Conjugate Addition-Protonation Sequence with 1a and 1ca

PPh3 in a separate reaction (entry 3) provided 2a in a virtually identical yield to that of entries 1 and 2. Further decreasing the catalyst loading from 5 to 2 mol % did furnish slightly reduced yields (73 and 71%) of 2a, even with a prolonged reaction time. Unfortunately, Grignard reagents were not compatible with TMSOTf at temperatures > −40 °C and thus reaction yields for 2a dramatically decreased upon warming the medium. Due to this drawback, we chose to examine TMSCl in lieu of TMSOTf. As noted in entries 6−9 in Table 1, the carbocupration of 1a under the aforementioned conditions (5 mol % catalyst, 1.2 equiv of EtMgBr), but with TMSCl, readily proceeded at a range of temperatures (−78 to −10 °C) and afforded ester 2a with virtually identical yields ranging from 78 to 86%.10 With the proof of concept results as shown in Table 1 in hand, our attention was turned to the diastereoselective vicinal functionalization of α-trimethylsilyl-β-benzyl-α,β-unsaturated ester 1b, while varying the proton source. The preliminary assessments of different acidic species for the diastereoselective quench were performed at −78 °C followed by warming to rt for 0.5 h as delineated in Table 2. The initial reactions investigated Table 2. Examination of Various H+ Sources for Vicinal Functionalization of 1b via Conjugate Addition/Protonation

entrya

proton source

T, °C

yield/%b

d.r.c

1 2 3 4 5 6 7 8 9 10 11 12 13

sat. NH4Cl pivalic acid PTSA (1S)-(+)-10-CSA t-butanol (−)-menthol BHT TFA TFA sat. NH4Cl sat. NH4Cl sat. NH4Cl sat. NH4Cl

−78 → rt −78 → rt −78 → rt −78 → rt −78 → rt −78 → rt −78 → rt −78 → rt −78 −40 −20 −10 0

82 94 82 83 81 82 85 81 80 86 83 83 83

4/1 2.5/1 3.5/1 3.5/1 2.2/1 3.8/1 2.0/1 3.7/1 3.7/1 4/1 4/1 4/1 4/1

a All cuprate additions were performed at −78 °C and the proton source added at the noted temperatures. bPurified, isolated yield of vinyl silane. cd.r. determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture via integration of the α-Hs of 2b (see the Supporting Information for specific example). a

See the Supporting Information for specific reaction details. Purified, isolated yield of the noted product. cd.r. determined by 1 H NMR (360 or 500 MHz) from the crude reaction mixture via integration of the α-Hs (see the Supporting Information for specific example). b

organic acids, alcohols, and NH4Cl as the proton source. As described in entries 1−8, a modest range was observed in the final product dr (2.5−4/1) of ester 2b while yields remained consistently above 80%. Both TFA and NH4Cl provided the highest level of diastereoselectivity ranging from 3.7 to 4/1. Furthermore, additional experiments varying the temperature (−78 → 0 °C) at which the proton sources (both TFA and NH4Cl) were added exhibited little to no effect on the d.r. of ester 2b (entries 1 and 8−13). With the generalized reaction conditions in hand from Tables 1 and 2, we set out to examine the scope and limitations of Kharasch based cuprate additions to α-trialkylsilyl-β-substituted-α,β-unsaturated esters 1a and 1c. As shown in Table 3, the addition of 1.2 equiv of PhMgBr to ester 1a in the presence of

CuI·2LiCl (5 mol %) and TMSCl (1.2 equiv) at −10 °C afforded saturated ester 2c upon protonation of the presumed silyl ketene acetal intermediate with aqueous NH4Cl in 60% yield with a d.r. of 5/1 favoring the anti stereochemistry. It is worth noting that the initial stereochemistry (syn versus anti) of the saturated ester products 2c−2l were assigned tentatively as the anti-stereoisomers, vide inf ra. Likewise, the conjugate addition of iPrMgCl (2.5 equiv) to β-ethyl unsaturated ester 1a readily proceeded under virtually identical reaction 6100

DOI: 10.1021/acs.orglett.8b02527 Org. Lett. 2018, 20, 6099−6103

Letter

Organic Letters conditions as noted above to furnish ester 2d with a significantly improved d.r. of 15/1 (for the anti isomer) coupled with a greater isolated yield of 85%. Similarly, substituting ChxMgCl for iPrMgCl as the Kharasch reagent precursor provided very similar results with respect to yield (85%) and a high level d.r. (>20/1) for product ester 2e from starting material 1a. Analogous to ester 1a, addition of 1.2 equiv of PhMgBr to ester 1c coupled with CuI·2LiCl (5 mol %) and TMSCl (1.2 equiv) at −20 °C furnished saturated ester 2f in 84% yield with a d.r. of 7/1 favoring the anti stereochemistry. The conjugate addition of iPrMgCl (1.2 equiv) to unsaturated ester 1c smoothly progressed to afford ester 2g with a d.r. of 18/ 1 combined with an isolated yield of 80%. As noted above, replacing ChxMgCl for iPrMgCl furnished very similar results with respect to yield (71%) and a high level d.r. (>20/1) for product ester 2h from starting material 1c. In comparison to ester 1a, only 1.2 equiv of iPrMgCl and ChxMgCl were required for the complete consumption of 1c, coupled with a slightly lower reaction temperature (−20 versus −10 °C). Lastly, the conjugation addition of EtMgBr to 1c, under slightly modified reaction conditions (−40 °C), readily proceeded and provided ester 2i in 75% yield, however the d.r. was significantly diminished to 1.4/1. A few noteworthy observations were made when evaluating esters 1a and 1c. The isolated yields were generally similar for both substrates 1a and 1c. Second, the d.r. of the products were generally analogous to or higher in a couple of examples when 1c was utilized as contrasted to 1a. Finally, no conjugate addition products were detected in the absence of the CuI·2LiCl catalyst as only decomposed starting materials were observed in both cases for 1a and 1c. Having initially defined the reaction scope with esters 1a and 1c, our attention was shifted to investigating a series of Michael acceptors with differing steric environments. As highlighted in Table 4, addition of 1.2 equiv of EtMgBr to ester 1d in the presence of CuI·2LiCl (5 mol %) and TMSCl (1.2 equiv) at −40 °C furnished bis-TMS ester 2j upon protonation with aqueous NH4Cl in 91% yield with a d.r. of 4/1 favoring the anti stereochemistry. Likewise, the treatment of unsaturated ester 1d with iPrMgCl readily proceeded under similar reaction conditions (−10 °C versus −40 °C, 2.5 equiv of RMgCl and TMSCl) as noted above to furnish ester 2k with an enhanced d.r. of 11/1 (for the anti isomer) together with a slightly lower isolated yield of 75%. In addition, two esters 1e and 1f were examined as Michael acceptors entries 4 and 5, Table 4) with EtMgBr as the nucleophilic coupling partner in the presence of CuI·2LiCl and TMSCl. It is worth noting that the polarity of the reactants have been reversed from entries 1 and 2 in Table 3. Thus, the reaction of both 1e and 1f smoothly proceeded and afforded the previously noted product saturated esters 2d and 2c in good yields ranging from 81 to 90% and d.r. of 15/1 for 2d to 4/1 for 2c. In the last example of Table 4, the TES ester 1g was investigated as a Michael acceptor under the analogous reaction conditions to that of 1a with iPrMgCl. Much to our delight, the conjugate addition/silyl ketene protonation of 1g furnished the corresponding saturated ester product 2l in 84% isolated yield with a d.r. of 13/1 favoring the anti diastereomer. Interestingly ester 2l had a slightly decreased d.r. compared to the TMS variant 2d. As noted above, the initial relative stereochemistry for all of the saturated ester products 2b−2l were tentatively assigned as the anti diastereomer based on the previous account by Liu and Yu.11 With the supposition of a locked conformation, the relative stereochemistry of a compound similar to 2c was deduced by

Table 4. Cu(I) Catalyzed Vicinal Functionalization with a Variety of Michael Acceptors and Grignard Reagents of Varying Steric Environmentsa

a

See the Supporting Information for specific reaction details. Purified, isolated yield of the noted product. cd.r. determined by 1 H NMR (360 or 500 MHz) from the crude reaction mixture via integration of the α-Hs (see the Supporting Information for specific example). b

observing specific cross-peaks in the 2D-ROESY spectra. As described in Figure 1, the coupling constant (J = 11.9 Hz) between the Hα−Hβ in ester 2c was indicative of anti-geometry via an analogous conformation. Thus, the relative antistereochemistry for the major diastereomer of 2c was persuasively established by 1D NOE by observing a key crosspeak enhancement between the noted phenyl and TMS protons. By analogy, the relative stereochemistry of the remaining products 2b and 2d−2l were assigned as the anti stereochemistry and further allowed us to construct a conformationally based stereochemical induction model based on a similar proposal by Yamamoto.12 Centered on the observed stereochemistry, it appeared that the protonation of the intermediate silyl ketene acetal post conjugate addition occurred through an eclipsed, as opposed to a bisected, conformation while 6101

DOI: 10.1021/acs.orglett.8b02527 Org. Lett. 2018, 20, 6099−6103

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minimizing A1,3 strain. Grounded on steric considerations, the incoming H+ would be positioned in a syn-periplanar relationship with the small substituent (RS) leading to the observed antidiastereomeric product. Thus, the level of diastereoselectivities (ranging from 1.4 → 20/1) can be explained by the variations in steric environments of the RS and RL groups (i.e., Me versus iPr in ester 2g) resident on the β-carbon of the intermediate silyl ketene intermediates via the eclipsed conformation during the external protonation. In conclusion, we have reported that a tandem Cu(I)catalyzed conjugate addition of Grignard reagents/diastereoselective protonation using (E)-α-trialkylsilyl-β-alkyl(aryl)-α,βunsaturated esters provided products with d.r. values of >20:1 favoring the anti-diastereomer. In addition, a stereochemical induction model was proposed and has been utilized to rationalize the observed products. Future directions will include exploration into an asymmetric, catalytic version of this reaction as a novel means to synthesize enantiomerically pure organosilane intermediates.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02527. Experimental procedures and spectroscopic data for all new compounds (PDF)

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REFERENCES

(1) For some leading references, see (a) Yoshikai, N.; Nakamura, E. Mechanisms of Nucleophilic Organocopper(I) Reactions. Chem. Rev. 2012, 112, 2339−2372. (b) Woodward, S. Decoding the ‘Black Box’ Reactivity That is Organocuprate Conjugate Addition Chemistry. Chem. Soc. Rev. 2000, 29, 393−401. (c) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Recent Advances in Enantioselective Copper-Catalyzed 1,4-Addition. Chem. Soc. Rev. 2009, 38, 1039−1075. (d) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Catalytic Asymmetric Conjugate Addition and Allylic Alkylation with Grignard Reagents. Chem. Rev. 2008, 108, 2824−2852. (e) Lopez, F.; Minnaard, A. J.; Feringa, B. L. Catalytic Enantioselective Conjugate Addition with Grignard Reagents. Acc. Chem. Res. 2007, 40, 179−188. (f) Harutyunyan, S. R.; Lopez, F.; Browne, W. R.; Correa, A.; Peña, D.; Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. On the Mechanism of the Copper-Catalyzed Enantioselective 1,4-Addition of Grignard Reagents to α,β-Unsaturated Carbonyl Compounds. J. Am. Chem. Soc. 2006, 128, 9103−9118. (2) Kharasch, M. S.; Tawney, P. O. Factors Determining the Course and Mechanisms of Grignard Reactions. II. The Effect of Metallic Compounds on the Reaction Between Isophorone and Methylmagnesium Bromide. J. Am. Chem. Soc. 1941, 63, 2308−2315. (3) (a) Gilman, H.; Jones, R. G.; Woods, L. A. Relative Reactivities of Organometallic Compounds. LXXI. The Preparation of Methylcopper and Some Observations on the Decomposition of Organocopper Compounds. J. Org. Chem. 1952, 17, 1630−1634. (b) House, H. O.; Respess, W. L.; Whitesides, G. M. The Chemistry of Carbanions. XII. The Role of Copper in the Conjugate Addition of Organometallic Reagents. J. Org. Chem. 1966, 31, 3128−3141. (4) Tsuge, O.; Kanemasa, S.; Ninomiya, Y. Michael Addition-Peterson Olefination Sequence of Methyl 2-(trimethylsilyl)Acrylate as a Convenient Method for Consecutive Formation of Carbon-Carbon Single and Double Bonds. Chem. Lett. 1984, 13, 1993−1996. (5) Tanaka, J.; Kanemasa, S.; Ninomiya, Y.; Tsuge, O. Michael Addition of Methyl 2-(trimethylsilyl)Propenoate with Organomagnesiums or Organolithiums Leading to 1:1 and/or 2:1 Adducts and Subsequent Peterson Olefination by Condensation with Carbonyl Compounds. Bull. Chem. Soc. Jpn. 1990, 63, 466−475. (6) Yamazaki, T.; Takita, K.; Ishikawa, N. Building Blocks for Trifluoromethylated Organic Molecules. III. Synthesis and Reactions of Allylsilane and Vinylsilane Compounds Containing a Trifluoromethyl Group. Nippon Kagaku Kaishi 1985, 2131−2139. (7) Albury, A. M. M.; Jennings, M. P. TiCl4 Mediated Preparation of (E)-Non-Conjugated Homoallylic Alcohols with α-Substituted Allylsilanes. Tetrahedron Lett. 2013, 54, 4487−4490. (8) (a) Johnson, D. A.; Mueller Hendrix, A. J.; Jennings, M. P. Diastereoselective Syntheses of (E)-α-Trialkylsilyl-α,β-Unsaturated Esters, α-Silane Substituted Conjugated Silyl Ketene Acetals, and α,γSubstituted Allyl Silanes. J. Org. Chem. 2018, 83, 9914−9928. (b) Mueller Hendrix, A. J.; Jennings, M. P. Vicinal Functionalization of Propiolate Esters via Catalytic Carbocupration: Stereoselective Formation of Substituted Vinyl Silanes. Org. Lett. 2010, 12, 2750− 2753. (9) Reetz, M. T.; Kindler, A. The Kharasch Reaction Revisited: CuX3Li2-Catalyzed Conjugate Addition Reactions of Grignard Reagents. J. Organomet. Chem. 1995, 502, C5−C7. (10) (a) Nakamura, E.; Kuwajima, I. Copper-Catalyzed Acylation and Conjugate Addition of Zinc Homoenolate. Synthesis of 4- and 5-Oxo Esters. J. Am. Chem. Soc. 1984, 106, 3368−3370. (b) Corey, E. J.; Boaz, N. W. The Reactions of Combined Organocuprate-Chlorotrimethylsilane Reagents with Conjugated Carbonyl Compounds. Tetrahedron Lett. 1985, 26, 6019−6022. (c) Alexakis, A.; Berlan, J.; Besace, Y. Organocopper Conjugate Addition Reaction in the Presence of Trimethylchlorosilane. Tetrahedron Lett. 1986, 27, 1047−1050. (d) Frantz, D. E.; Singleton, D. A. Isotope Effects and the Mechanism of Chlorotrimethylsilane-Mediated Addition of Cuprates to Enones. J. Am. Chem. Soc. 2000, 122, 3288−3295. (11) Liu, D.; Yu, X. Ireland-Claisen Rearrangement of Secondary Allyl Acetate Revisited: Inevitable C-Silylation Circumvented by One-Pot

Figure 1.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Michael P. Jennings: 0000-0002-1069-6246 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Support for this project was provided by the University of Alabama. 6102

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Organic Letters Application of Excessive LDA/TMSCl and TBAF. Tetrahedron Lett. 2012, 53, 2177−2180. (12) Yamamoto, Y.; Yamada, J.-i.; Uyehara, T. Do the Organocopper Additions to α,β-Unsaturated Esters Proceed in a 1,4- or 1,2-Fashion. J. Am. Chem. Soc. 1987, 109, 5820−5822.

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DOI: 10.1021/acs.orglett.8b02527 Org. Lett. 2018, 20, 6099−6103