Vinylogous acyl triflates as an entry point to α,β-disubstituted cyclic enones via Suzuki–Miyaura cross-coupling

Daria E. Kim , Yingchuan Zhu and Timothy R. Newhouse *
Department of Chemistry, Yale University, 225 Prospect St, New Haven, CT 06520-8107, USA. E-mail:

Received 16th October 2018 , Accepted 14th November 2018

First published on 30th November 2018

An alternative protocol for the B-alkyl Suzuki–Miyaura reaction to produce cyclic α,β-disubstituted enones is reported. The use of β-triflyl enones as coupling partners in lieu of their halogenated analogs provides enhanced substrate stability to light and chromatography without adversely affecting reactivity. This protocol allows efficient access to the synthetically challenging α,β-disubstituted enone motif under mild conditions.


α,β-Disubstituted cyclic enones are useful and versatile synthetic retrons which provide access to substrates of greater stereochemical and functional complexity through addition reactions.1 However, these motifs can be inefficient to access from commonly available precursor scaffolds like ketones or unfunctionalised enones. As a result, alternative means of accessing this functionality have been devised.

One of the most commonly employed tactics is the Stork–Danheiser transposition, which allows for vinylogous esters to be converted to the corresponding α,β-disubstituted enones through treatment with various organolithium or Grignard reagents, followed by the elimination of the resulting β-alcohol.2 An alternative approach relies on 1,2-addition into an α-substituted enone, followed by Cr(VI) mediated oxidative transposition of the resulting allylic tertiary alcohol to the tetrasubstituted enone.3 Furthermore, the direct oxidative β-functionalization of enones reported by our laboratory utilized an initial 1,4-conjugate addition with zincate nucleophiles followed by oxidation of the resulting enolate with allyl-Pd catalysis.4 While these various strategies have seen broad application, one limitation of these approaches is the requirement of an organometallic nucleophile, thereby limiting functional group compatibility.

Conversely to this principle challenge, the B-alkyl Suzuki–Miyaura reaction provides a mild means of accessing α,β-disubstituted enones.5 This process has previously been reported with β-halo enones,6 whereas the corresponding transformation with vinylogous acyl triflates would possess several strategic advantages. Specifically, vinylogous acyl triflates possess enhanced photochemical stability and are more reliably purified by column chromatography.7–11 Furthermore, vinylogous acyl triflates are prepared from 1,3-diketones using mild reaction conditions, and also via other strategic approaches.12 Similar advantages for vinyl triflates over vinyl halides have broadly resulted in the wider application of vinyl triflates in the B-alkyl Suzuki–Miyaura coupling, as well as a number of other Pd-catalysed cross-couplings of other types.13 Herein, we report a mild protocol for a B-alkyl Suzuki cross coupling between vinylogous acyl triflates and alkyl boranes to synthesize α,β-disubstituted cyclic enones.14,15

Results and discussion

Optimization of reaction conditions

We began our study by assessing the relative efficiencies of the cross coupling of the -iodo, -bromo and -triflyl derivatives of cyclopentenone 1a, using two commonly reported conditions for the B-alkyl Suzuki reaction (Table 1).14 When aqueous NaOH and THF was employed the iodide (99%) was more efficient than either the bromide (59%) or triflate (76%) substrates. We speculated that the triflate was undergoing decomposition under the strongly basic reaction conditions, and thus we employed Cs2CO3 as base in a mixture of DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O. Under these more mild reaction conditions, the triflate could be used as a coupling partner in high yield (99%). Interestingly, under the alternative reaction conditions, both the bromide and iodide performed with similar efficiencies as when NaOH was employed as base, 57% and 99% respectively.
Table 1 Comparison of substratesa

image file: c8ob02573h-u1.tif

Entry R–X Base Solvent Yieldd
a Conditions: 1 (0.05 mmol), 2a (0.06 mmol), PdCl2(dppf) (2.5 mol%), base (2.0 equiv.) in 500 μL of solvent. b THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O (10[thin space (1/6-em)]:[thin space (1/6-em)]1). c DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O (7[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1). d [thin space (1/6-em)]1H-NMR analysis after aqueous work-up using 1,3,5-trimethoxybenzene as an internal standard.
1 –I NaOH THF[thin space (1/6-em)]:[thin space (1/6-em)]H2Ob 99
2 –Br NaOH THF[thin space (1/6-em)]:[thin space (1/6-em)]H2Ob 59
3 –OTf NaOH THF[thin space (1/6-em)]:[thin space (1/6-em)]H2Ob 76
4 –I Cs2CO3 DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2Oc 99
5 –Br Cs2CO3 DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2Oc 57
6 OTf Cs2CO3 DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2Oc 99

After reaction conditions that were efficient for the triflate substrate were identified, we performed a screen investigating a selection of catalysts, ligands and bases commonly utilized in analogous transformations (Table 2). We found that the conditions from the substrate comparison study outlined in Table 1 were the most favourable, with Pd(OAc)2 in concert with the dppf ligand showing closely comparable results. Additionally, we observed a marked trend with respect to the base additive, with K3PO4 consistently providing slightly diminished yields relative to Cs2CO3. For this reason, we selected the carbonate base for further use, despite the marginal difference in observed outcome for the PdCl2(dppf) catalysed reactions.

Table 2 Optimization of cross-couplinga

image file: c8ob02573h-u2.tif

Entry Catalyst Ligand Base Yieldc
a Conditions: 1a (0.05 mmol), 2a (0.06 mmol), catalyst (2.5 mol%), ligand (2.5 mol%), base (2.0 equiv.) in 500 μL of DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O (7[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1). b Ligand (5.0 mol%). c 1H-NMR analysis after aqueous work-up using 1,3,5-trimethoxybenzene as an internal standard.
1 PdCl2(dppf) n/a Cs2CO3 99
2 PdCl2(dppf) n/a K3PO4 98
3 Pd(OAc)2 PPh3[thin space (1/6-em)]b Cs2CO3 78
4 Pd(OAc)2 PPh3[thin space (1/6-em)]b K3PO4 73
5 Pd(OAc)2 rac-BINAP Cs2CO3 56
6 Pd(OAc)2 rac-BINAP K3PO4 40
7 Pd(OAc)2 dppf Cs2CO3 93
8 Pd(OAc)2 dppf K3PO4 91
9 Pd(PPh3)4 n/a Cs2CO3 91
10 Pd(PPh3)4 n/a K3PO4 83

Examination of substrate scope

After establishing the optimized conditions for the coupling of cyclopentenone fragment 1a with benzyl alcohol 2a, we investigated the scope of this transformation with respect to the B-alkyl reagents, as well as the β-triflyl enones. We chose a modest selection of precursor alkenes containing a range of substitution patterns and potentially sensitive functional elements. These substrates underwent hydroboration through treatment with 9-BBN and were subsequently subjected to our optimized cross-coupling conditions with cyclopentenone 1a, as shown in Table 3, and a cyclohexenone 1b, as shown in Table 4.
Table 3 Cyclopentenone substrate scopea

image file: c8ob02573h-u3.tif

Substrate (2) Product (3) Yieldb
a Conditions: 1a (0.25 mmol), 2a–2e (0.26 mmol), PdCl2(dppf) (2.5 mol%), Cs2CO3 (2.0 equiv.) in 2.0 mL of DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O (7[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1). b Isolated yield.
image file: c8ob02573h-u4.tif image file: c8ob02573h-u5.tif 99
image file: c8ob02573h-u6.tif image file: c8ob02573h-u7.tif 79
image file: c8ob02573h-u8.tif image file: c8ob02573h-u9.tif 32
image file: c8ob02573h-u10.tif image file: c8ob02573h-u11.tif 69
image file: c8ob02573h-u12.tif image file: c8ob02573h-u13.tif 56

Table 4 Cyclohexenone substrate scopea

image file: c8ob02573h-u14.tif

Substrate (2) Product (4) Yieldb
a Conditions: 1b (0.25 mmol), 2a–2e (0.26 mmol), PdCl2(dppf) (2.5 mol%), Cs2CO3 (2.0 equiv.) in 2.0 mL of DMF[thin space (1/6-em)]:[thin space (1/6-em)]THF[thin space (1/6-em)]:[thin space (1/6-em)]H2O (7[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1). b Isolated yield.
image file: c8ob02573h-u15.tif image file: c8ob02573h-u16.tif 94
image file: c8ob02573h-u17.tif image file: c8ob02573h-u18.tif 74
image file: c8ob02573h-u19.tif image file: c8ob02573h-u20.tif 73
image file: c8ob02573h-u21.tif image file: c8ob02573h-u22.tif 76
image file: c8ob02573h-u23.tif image file: c8ob02573h-u24.tif 67

The cross-coupling used in the optimization study, 2a with 1a, proceeded very efficiently, providing an isolated yield of 99%. We observed a slightly diminished yield with the TBS-protected analogue 2b, with 79% yield. The corresponding acetate 2c was associated with a sharp drop-off in efficiency, giving only 32% of the desired product 3c. This could possibly be the result of the increased base sensitivity of the acetate functional group that may be hydrolysed in the presence of the generated hydroxide. In addition to these hexenol derivatives, we also considered the coupling of the styrene derivative 2d which resulted in the formation of coupling product 3d in 69% yield. Finally, phthalimide 2e, another base sensitive functionality, gave the desired adduct 3e in 56% yield.

Next, we examined the scope and efficiency of this transformation with respect to the formation of α,β-functionalised cyclohexanones. The results of these transformations largely mirrored those obtained for compounds 3a–3e. The coupling of 1b with benzyl ether 2a resulted in the formation of 4a in 94% yield. TBS-protected substrate 2b gave 74% of the desired product 4b. The formation of acetate 4c, in this case, did not exhibit a significant depreciation in yield with the formation of 4c proceeding efficiently in 73% yield. Likewise, the cross-coupling of the styrene derivative 2d and phthalimide 2e adhered closely to the trends established in our initial investigation of substrate scope, giving 76% and 67% yield of their respective products.


This report describes the use of β-triflyl enones as efficient coupling partners in the B-alkyl Suzuki reaction, under mild conditions suitable for sensitive functional groups. The triflate, which has been observed to be comparable to the iodide in reactivity, benefits from possessing increased stability to chromatography and light, making it an attractive alternative retron to the more commonly utilized vinyl halides. It is our expectation that both the vinylogous acyl triflate retron and this mild protocol for B-alkyl Suzuki–Miyaura cross-coupling will see application to complex molecule synthesis.

Conflicts of interest

There are no conflicts to declare.


Financial support for this work was provided by Yale University, the Sloan Foundation, and Amgen. We are grateful to Yizhou Zhao for a procedural check and Evan Perez for the acquisition of HRMS data for compound 4e.

Notes and references

  1. For a review on various strategies for synthesizing tetrasubstituted olefins, including enones, see: A. B. Flynn and W. W. Ogilvie, Chem. Rev., 2007, 107, 4698 CrossRef CAS .
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  6. For examples of β-halo enones as coupling partners, see: (a) N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh and A. Suzuki, J. Am. Chem. Soc., 1989, 111, 314 CrossRef CAS ; (b) Y. Lee, H. Jang and A. M. Hoveyda, J. Am. Chem. Soc., 2009, 131, 18234 CrossRef CAS ; (c) R. Beretta, M. G. Gallotti, U. Pennè, A. Porta, J. F. G. Romero, G. Zanoni and G. Vidari, J. Org. Chem., 2015, 80, 1601 CrossRef CAS ; (d) X. Yu, F. Su, C. Liu, H. Yuan, S. Zhao, Z. Zhou, T. Quan and T. Luo, J. Am. Chem. Soc., 2016, 138, 6261 CrossRef CAS .
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  8. For examples of vinylogous acyl triflates as cross-coupling partners in Suzuki–Miyaura cross-coupling, see: (a) T. Oh-e, N. Miyaura and A. Suzuki, J. Org. Chem., 1993, 58, 2201 CrossRef CAS ; (b) J. Takagi, A. Kamon, T. Ishiyama and N. Miyaura, Synlett, 2002, 1880 CAS ; (c) T. Ishiyama, J. Takagi, A. Kamon and N. Miyaura, J. Organomet. Chem., 2003, 687, 284 CrossRef CAS ; (d) D. Keck, T. Muller and S. Bräse, Synlett, 2006, 3457 CAS ; (e) L. Overman and E. J. Velthuisen, J. Org. Chem., 2006, 71, 1581 CrossRef CAS ; (f) M. Amat, A. Pinto, R. Griera and J. Bosch, Chem. Commun., 2013, 49, 11032 RSC ; (g) D. Hog, F. Huber, G. Jiménez-Osés, P. Mayer, K. N. Houk and D. Trauner, Chem. – Eur. J., 2015, 21, 13646 CrossRef CAS .
  9. For examples of other vinylogous acyl sulfonates in Suzuki–Miyaura cross coupling, see: (a) M. Lüthy and R. J. K. Taylor, Tetrahedron Lett., 2012, 53, 3444 CrossRef ; (b) N. P. Cheval, A. Dikova, A. Blanc, J.-M. Weibel and P. Pale, Chem. – Eur. J., 2013, 19, 8765 CrossRef CAS ; (c) A. Dikova, N. P. Cheval, A. Blanc, J.-M. Weibel and P. Pale, Adv. Synth. Catal., 2015, 357, 4093 CrossRef CAS .
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  15. Cross-coupling procedure: A flame-dried, 5 mL microwave vial equipped with a magnetic stir bar was charged with enone 1a (61.0 mg, 0.25 mmol, 1.0 equiv.), PdCl2(dppf) (5.1 mg, 2.5 mol%) and Cs2CO3 (163.0 mg, 0.5 mmol, 2.0 equiv.), capped with an aluminium–PTFE crimp cap, sealed, evacuated and backfilled with argon three times, and placed under an argon atmosphere. Anhydrous DMF (0.15 M, 1.70 ml), which had been rigorously degassed using freeze–pump–thaw technique over three degassing cycles, was added to the vial in a single portion. Following this, a solution of alkylborane 2a (0.34 M, 760 μl), prepared as described on page SI-3, was added to the reaction mixture in a single portion. The resulting reaction mixture was warmed by transferring the reaction apparatus to a 60 °C oil bath. After stirring for 16 hours at this temperature, the reaction mixture was cooled back down to 25 °C by transferring the reaction apparatus to a lukewarm water bath. After stirring at this temperature for 5 minutes, the reaction mixture was diluted with diethyl ether (10 ml) and filtered through a pad of Celite®. The resulting filtrate was washed with sat. aq. NaHCO3 (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to provide a crude yellow oil. Purification by flash column chromatography on silica gel (Et2O/hexanes/CH2Cl2 = 0/1/1 to 1/49/50) afforded 3a (70.3 mg, 99%) as a colourless oil.


Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ob02573h

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