Letter pubs.acs.org/OrgLett
Additions of Organomagnesium Halides to α‑Alkoxy Ketones: Revision of the Chelation-Control Model Jacquelyne A. Read, Yingying Yang, and K. A. Woerpel* Department of Chemistry, New York University, New York, New York 10003, United States S Supporting Information *
ABSTRACT: The chelation-control model explains the high diastereoselectivity obtained in additions of organometallic nucleophiles to α-alkoxy ketones but fails for reactions of allylmagnesium halides. Low diastereoselectivity in ethereal solvents results from no chelation-induced rate acceleration. Additions of allylmagnesium bromide to carbonyl compounds are diastereoselective using CH2Cl2 as the solvent even though rate acceleration is still absent. Stereoselectivity likely arises from the predominance of the chelated form in solution. Therefore, a revised chelation-control model is proposed. dditions of alkylmagnesium and alkyllithium reagents to αalkoxy carbonyl compounds are powerful reactions for organic synthesis,1 particularly because these reactions are often highly diastereoselective.2,3 The stereochemical courses of these reactions are generally explained using the chelation-control model,2 which proposes that the α-chelated intermediate (1, Figure 1) has sterically differentiated diastereotopic faces that
A
not more reactive than the nonchelated form. Instead, the chelated form is more populated in CH2Cl2, so, in accordance with the Winstein−Holness kinetic model,11 most of the product is formed by reaction of the chelated intermediate. These experiments justify a revision of the chelation-control model to include this scenario. The low selectivity exhibited in reactions of allylmagnesium halides with chiral, α-alkoxy ketones is evident when direct comparisons to other organomagnesium reagents are made.12 For example, we found that whereas addition of n-propylmagnesium chloride to ketone 2 was highly selective for the chelation-control product (eq 1), addition of allylmagnesium chloride proceeded with low stereoselectivity, favoring the opposite stereoisomer (eq 2).13
Figure 1. Chelated intermediate formed in reactions of RMgX with αalkoxy carbonyl compounds.
react with the nucleophile at different rates. Studies using Me2Mg established that reactions are diastereoselective because the chelated intermediate, which is a minor component of the reaction mixture in ethereal solvents, reacts more rapidly with the nucleophile than nonchelated intermediates do.4−7 While the chelation-control model can predict and rationalize the outcomes of many reactions, it exhibits notable failures.8 For example, additions of allylmagnesium halides to α-alkoxy carbonyl compounds generally do not occur with high diastereoselectivity, which is problematic considering how frequently these reactions are used in synthesis.9,10 In this paper, we report experiments that demonstrate why the chelation-control model cannot generally predict or explain reactions of allylmagnesium halides with α-alkoxy carbonyl compounds in ethereal solvents. The chelated intermediate is not the only species that reacts in this case. Products are also produced from nonchelated intermediates, which react with little diastereoselectivity. High diastereoselectivity for the allylation product expected from chelation control can be achieved using CH2Cl2 as the solvent. The chelation-control model also cannot explain this phenomenon, however, because the chelated form is © 2017 American Chemical Society
This dichotomy was general (Figure 2). Reactions of ketones with alkyl- and alkenylmagnesium halides in THF or Et2O gave the products predicted by the chelation-control model with high diastereoselectivity.14 By contrast, reactions with allylmagnesium halides exhibited low selectivity. The disparate selectivities observed between alkylmagnesium and allylmagnesium reagents are largely independent of the precise structure of the reagent. Selectivities of additions to Received: April 17, 2017 Published: June 15, 2017 3346
DOI: 10.1021/acs.orglett.7b01161 Org. Lett. 2017, 19, 3346−3349
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Table 2. Relative Rates of Additions to Chelating Ketone 13 Versus Propiophenone (14)
Figure 2. Diastereoselectivities of additions of RMgX to α-alkoxy ketones in THF at −78 °C.
1 2 3 4 5 6 7 8
RMgX b
MeMgBr MeMgBr MeMgCl (Me)2Mg H2CCHCH2MgBrb H2CCHCH2MgBr H2CCHCH2MgCl (H2CCHCH2)2Mg
solvent
dra
Et2O Et2O THF THF Et2O Et2O THF THF
>97:3 >97:3 >97:3 >97:3 79:21 76:24 59:41 58:42
product
15:16a
1 2 3 4 5 6
MeMgCl MeMgClb n-PrMgCl H2CCHMgBr H2CCHCH2MgCl H2CCHCH2MgBr
a a b c d d
104:1 17:1 338:1 27:1 49:51c 45:55c
that these outcomes parallel observations with Me2Mg,5 the results with organomagnesium halides provide additional evidence that the Schlenk equilibrium and aggregation are not the most important predictors of stereoselectivity. In accordance with the lack of diastereoselectivity observed for additions of allylmagnesium halides to chiral, α-alkoxy ketones (Figure 2), these reagents reacted with both ketones 13 and 14 at similar rates (Table 2, entries 5 and 6). The results shown in Table 2 reveal why reactions of highly reactive21,23 allylmagnesium halides deviate from the chelationcontrol model. These reagents do not preferentially react through chelated intermediates, which are likely to be minor species in solution.5 Because the majority of the carbonyl compound in solution is not in a chelated form, low selectivity could result because these electrophiles would have little steric differentiation between their diastereotopic faces. Competition experiments also suggest why additions of organomagnesium halides to α-alkoxy aldehydes generally proceed with low stereoselectivity.3,24 The addition of either MeMgCl or allylmagnesium chloride to a mixture of α-alkoxy aldehyde 17 and alkyl aldehyde 18 resulted in the formation of both addition products (eq 4).25 The low selectivity observed in
a
Ratios determined by GC or NMR spectroscopic analysis of the reaction mixture. bReactions run at 1.0 M and warmed to 0 °C.
ketone 12 were not significantly affected by concentration (entries 1 and 5 compared to entries 2 and 6), which would be expected to change the aggregation state of the reagent.15 The position of the Schlenk equilibrium16 (eq 3) also had little influence on selectivity. As shown in Table 1 (entries 2, 3, 6, and 7), contrasting selectivities between methyl- and allylmagnesium reagents were observed in Et2O, where the RMgX form predominates (Keq ≈ 400),17 and in THF, where dialkylmagnesium reagents are also present (Keq ≈ 4).18,19 Even in reactions with prepared R2Mg, where there is no halide ion to establish the Schlenk equilibrium, selectivity trends remained constant (entries 4 and 8). In all cases, allylmagnesium reagents exhibited low diastereoselectivity, whereas methylmagnesium reagents reacted with high stereoselectivity.20
the reaction of MeMgCl with aldehydes 17 and 18 contrasts significantly with the high selectivities observed in competition experiments with ketones 13 and 14 (Table 2, entries 1 and 2). Unlike with α-alkoxy ketones, the presence of an α-alkoxy group in an aldehyde does not accelerate the addition of allyl- or alkylmagnesium halides.26 As a result, a central premise of the chelation control model is not met, so stereoselectivity need not be observed. Additions of allylmagnesium bromide to α-alkoxy carbonyl compounds can be highly diastereoselective, however, in nonLewis basic solvents.27 When the ethereal solvent of the reagent was exchanged for CH2Cl2 by evacuating it to dryness (0.2 mbar) then suspending the resulting solids in CH2Cl2, reactions were highly diastereoselective (Figure 3). This significant increase in selectivity compared to selectivities in ethereal solvents was general for the substrates that had reacted with low selectivity in
K eq
R 2Mg + MgX 2 HooI 2RMgX
RMgX
a Ratios determined by GC analysis of the reaction mixture. bReaction run in 2:1 Et2O/THF. cProduct ratio was corrected for FID response factors.
Table 1. Testing the Effect of Solvent, Halide, and Reactive Magnesium Species on Diastereoselectivity
entry
entry
(3)
5,21
Competition experiments provided insight into why additions of alkyl- and alkenylmagnesium halides were diastereoselective but additions of allylmagnesium halides were not. Considering that the chelation-control model requires the chelated intermediate to be the most reactive species in solution, substrates that can chelate should be more reactive than substrates that cannot.4,5 This important condition is met for alkyl- and alkenylmagnesium halides, where additions occurred almost exclusively to an α-alkoxy ketone (13) instead of to a ketone without a chelating group (Table 2, entries 1−4).22 Considering 3347
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addition to one diastereotopic face of the chelated intermediate be faster than addition to the other face. 1 H and 13C NMR spectroscopic studies5,30 of ketone 12 in the presence of MgBr2 provided evidence that the chelated form of an α-alkoxy carbonyl compound is more favored in CH2Cl2 than it is in THF.31 The chemical shifts of ketone 12 in THF-d8 and CD2Cl2 responded differently to the presence of MgBr2. The downfield shifts (Δδ) for selected 1H and 13C resonances of ketone 12 upon binding to MgBr2 are given in Figure 4. In THF-
Figure 3. Diastereoselectivities for additions of RMgBr as suspensions in CH2Cl2 to α-alkoxy carbonyl compounds.
THF (eq 2 and Figure 2). The allylation of an α-alkoxy aldehyde to form secondary alcohol 21 was also diastereoselective in CH2Cl2, and selectivity with an alkylmagnesium reagent remained high in this solvent. Reactions of organomagnesium reagents with carbonyl compounds in CH2Cl2 were noticeably slower than reactions in ethereal solvents, however. The reagents in CH2Cl2 are heterogeneous, suggesting that their aggregation states are quite different than they are in THF and Et2O. Reactions in CH2Cl2 could be slower because the additional steps of diffusion and mass transfer between solid and liquid phases could be ratelimiting.28,29 To observe full conversion, more equivalents of the reagent (5 equiv compared to 1.2 equiv) and longer reaction times were necessary (≥3 h compared to ≤15 min). Even though the nature of the reagents in CH2Cl2 must be much different than in ethereal solvents, the results of intermolecular competition experiments were similar. Although addition of n-propylmagnesium chloride in CH2Cl2 occurred faster to the α-chelating ketone 13 than to ketone 14, allylmagnesium bromide showed no preference (eq 5). These data correlate with those obtained in THF (Table 2).
Figure 4. Downfield 1H and 13C NMR resonance shifts (ppm) observed upon mixing ketone 12 (0.1 M) with MgBr2 (2 equiv).
d8, the chemical shifts associated with the carbonyl group and the α-methine proton underwent only moderate changes,32 whereas they were more pronounced in CD2Cl2. Similarly, the downfield shift of the resonance for the α-methoxy group in CD2Cl2 is nearly four times its shift in THF-d8. The magnitude of the downfield shift observed in CD2Cl2 is consistent with earlier observations of two-point binding involving an α-methoxy group.5 Assuming that the interactions with MgBr2 are similar to an organomagnesium reagent, the spectroscopic data suggest that more of the chelated intermediate resembling 1 is present in CD2Cl2 than it is in THFd8 . These experiments lead to a deeper understanding of the chelation-control model in reactions with organomagnesium halides. Experiments originally conducted with Me2Mg in THF4,5 stipulated that, in accordance with the Curtin−Hammett principle,11 the chelated form of the carbonyl compound must be more reactive than the nonchelated form. The experiments reported here show that this situation also holds for reactions of ketones in THF and Et2O with the more commonly used RMgX form of the reagent instead of R2Mg. In the case of allylmagnesium halides, however, this requirement is not met, so chelationcontrolled selectivity was not observed. These studies also illustrate that the chelation-control model requires revision. The chelated form of the carbonyl compound need not react faster than the nonchelated form if the chelated intermediate predominates in solution; it is only necessary that the two diastereotopic faces of the carbonyl compound react at different rates. This revision broadens the model to incorporate not only a Curtin−Hammett kinetic scenario but also the Winstein−Holness kinetic scenario in which the major product is formed from the most abundant reactive intermediate.11 Consequently, caution should be used when interpreting results involving additions to α-alkoxy carbonyl compounds using the chelation-control model. Should a reaction be stereoselective, it should be established whether chelation is rate-accelerating or whether the chelated form predominates in solution, which is possible in CH2Cl2.
The competition experiments shown in eq 5 reveal that the chelation-control model is not consistent with the stereoselectivities in Figure 3. Because the chelated form was not more reactive than other species present, application of the chelation-control model would lead to a prediction that reactions should not be diastereoselective, as has been observed for βalkoxy carbonyl compounds.3−5 Instead, these reactions were highly diastereoselective (Figure 3). An alternative hypothesis can be proposed for why additions of allylmagnesium bromide in CH2Cl2 are diastereoselective. The requirement that the chelated form (1) of the carbonyl compound be more reactive than the nonchelated form5 is necessary only if the chelated form is a minor component of the reaction mixture, as it is in ethereal solvents. In THF or Et2O, the chelated reaction pathway must be significantly faster than competing nonchelated pathways for diastereoselectivity to be observed. If most of the carbonyl compound were in the chelated form resembling 1, however, it could react at the same rate as nonchelated forms would, as observed for allylmagnesium halides, and the reactions could be diastereoselective. All that is required for selectivity is that
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01161. 3348
DOI: 10.1021/acs.orglett.7b01161 Org. Lett. 2017, 19, 3346−3349
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Experimental procedures, characterization data, 1H and 13 C NMR spectroscopic data, GC traces, stereochemical correlations, and X-ray structures (PDF) X-ray data for compound S5 (CIF) X-ray data for compound S11′ (CIF)
K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048. (b) Cardona, F.; D'Orazio, G.; Silva, A. M. S.; Nicotra, F.; La Ferla, B. Eur. J. Org. Chem. 2014, 2549. (c) Zhang, J.; Zheng, S.; Peng, W.; Shen, Z. Tetrahedron Lett. 2014, 55, 1339. (11) Seeman, J. I. Chem. Rev. 1983, 83, 83. (12) For examples where allylmagnesium halides exhibit low selectivity but other reagents are selective, see: (a) Marco, J. A.; Carda, M.; González, F.; Rodríguez, S.; Castillo, E.; Murga, J. J. Org. Chem. 1998, 63, 698. (b) Qian, X.; Sujino, K.; Otter, A.; Palcic, M. M.; Hindsgaul, O. J. Am. Chem. Soc. 1999, 121, 12063. (c) Smaltz, D. J.; Švenda, J.; Myers, A. G. Org. Lett. 2012, 14, 1812. (13) Selectivities were determined by 1H and 13C NMR spectroscopy. The first number in each product ratio corresponds to the indicated stereoisomer. Details of stereochemical proofs are provided as Supporting Information. (14) The 1-propenyl Grignard reagent was used as an E/Z mixture. (15) Walker, F. W.; Ashby, E. C. J. Am. Chem. Soc. 1969, 91, 3845. (16) Schlenk, W.; Schlenk, W., Jr. Ber. Dtsch. Chem. Ges. 1929, 62, 920. (17) Ashby, E. C.; Laemmle, J.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272. (18) Parris, G. E.; Ashby, E. C. J. Am. Chem. Soc. 1971, 93, 1206. (19) Schnegelsberg, C.; Bachmann, S.; Kolter, M.; Auth, T.; John, M.; Stalke, D.; Koszinowski, K. Chem. - Eur. J. 2016, 22, 7752. (20) A variety of Lewis acid additives such as MgBr2·Et2O, SnCl4, and TiCl4 were screened, and no increase in diastereoselectivity was observed. Attempts at influencing the selectivity by modifying the ligands on magnesium also did not give satisfactory results. (21) Read, J. A.; Woerpel, K. A. J. Org. Chem. 2017, 82, 2300. (22) Rate acceleration due to the presence of α-alkoxy substituents has also been observed in Mukaiyama aldol and hetero-Diels−Alder reactions: Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (23) Benkeser, R. A. Synthesis 1971, 347. (24) For examples of α-alkoxy aldehydes reacting with low diastereoselectivity, see: (a) Yang, W.-Q.; Kitahara, T. Tetrahedron 2000, 56, 1451. (b) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126, 12432. (c) Suzuki, A.; Sasaki, M.; Nakagishi, T.; Ueda, T.; Hoshiya, N.; Uenishi, J. Org. Lett. 2016, 18, 2248. (25) Obtaining precise relative rates of addition in this case is complicated, presumably due to competitive enolization. HRMS confirmed the presence of multiple aldol addition and condensation products in the reaction mixture. (26) The absence of chelation-induced rate acceleration in these reactions with α-alkoxy aldehydes may be due to the markedly higher reactivity of aldehydes compared to ketones: Brown, H. C.; Wheeler, O. H.; Ichikawa, K. Tetrahedron 1957, 1, 214. (27) Charette, A. B.; Benslimane, A. F.; Mellon, C. Tetrahedron Lett. 1995, 36, 8557. (28) Wen, C. Y. Ind. Eng. Chem. 1968, 60, 34. (29) We cannot definitively assign the rate-determining step, however. Due to the heterogeneity of the reaction mixture, the reaction could occur in solution, within the suspended solid, or at the surface of that solid. (30) For other NMR studies of complexes between carbonyl compounds and Lewis acids, see: (a) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847. (b) Reetz, M. T.; Hüllmann, M.; Seitz, T. Angew. Chem., Int. Ed. Engl. 1987, 26, 477. (c) Stanton, G. R.; Johnson, C. N.; Walsh, P. J. J. Am. Chem. Soc. 2010, 132, 4399. (31) Binding constants could not be determined because the signal associated with the ketone decreased upon addition of MgBr2. After addition of 2 equiv, only 25% of ketone 12 was in solution, as determined by 1H NMR spectroscopy with an internal standard. (32) In the chelation experiments reported in ref 5, a phenyl ketone with an α-OTBS group (not generally capable of chelation) shows larger downfield shifts in CD2Cl2 than those observed here with ketone 12 in THF-d8.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
K. A. Woerpel: 0000-0002-8515-0301 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund for partial support of this research (57206-ND1). Additional support was provided by the National Institutes of Health, National Institute of General Medical Sciences (GM-61066). J.A.R. was supported by a Margaret Strauss Kramer Fellowship from the NYU Department of Chemistry. K.A.W. thanks the Global Research Initiatives, NYU and NYU Florence, for a fellowship. We thank Dr. Elizabeth M. Valentı ́n (NYU) for valuable discussions. We thank Dr. Chin Lin (NYU) for assistance with NMR spectroscopy and mass spectrometry and Dr. Chunhua Hu (NYU) for assistance with crystallographic studies.
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DEDICATION We dedicate this paper to the memory of the late Professor Robert A. Benkeser of Purdue University (1920−2017), who made important contributions to the study of allylic Grignard reagents and their reactions.
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REFERENCES
(1) For recent examples in natural product synthesis, see: (a) Crimmins, M. T.; Dechert, A.-M. R. Org. Lett. 2012, 14, 2366. (b) Matthies, S.; Stallforth, P.; Seeberger, P. H. J. Am. Chem. Soc. 2015, 137, 2848. (c) Trost, B. M.; Biannic, B.; Brindle, C. S.; O’Keefe, B. M.; Hunter, T. J.; Ngai, M.-Y. J. Am. Chem. Soc. 2015, 137, 11594. (2) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748. (3) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556. (4) Frye, S. V.; Eliel, E. L.; Cloux, R. J. Am. Chem. Soc. 1987, 109, 1862. (5) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1992, 114, 1778. (6) Mori, S.; Nakamura, M.; Nakamura, E.; Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1995, 117, 5055. (7) This rate acceleration resulting from chelation to magnesium is not present in reactions of β-alkoxy ketones, but a kinetic advantage is observed when β-alkoxy ketones chelate with titanium and chromium reagents: Kauffmann, T.; Mö ller, T.; Rennefeld, H.; Welke, S.; Wieschollek, R. Angew. Chem., Int. Ed. Engl. 1985, 24, 348. (8) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191. (9) For recent examples, see: (a) Crimmins, M. T.; Ellis, J. M.; Emmitte, K. A.; Haile, P. A.; McDougall, P. J.; Parrish, J. D.; Zuccarello, J. L. Chem. Eur. J. 2009, 15, 9223. (b) Yamashita, S.; Ishihara, Y.; Morita, H.; Uchiyama, J.; Takeuchi, K.; Inoue, M.; Hirama, M. J. Nat. Prod. 2011, 74, 357. (c) Moumé-Pymbock, M.; Furukawa, T.; Mondal, S.; Crich, D. J. Am. Chem. Soc. 2013, 135, 14249. (d) Kita, M.; Oka, H.; Usui, A.; Ishitsuka, T.; Mogi, Y.; Watanabe, H.; Tsunoda, M.; Kigoshi, H. Angew. Chem., Int. Ed. 2015, 54, 14174. (10) Some reactions of allylmagnesium halides can give the product expected by the chelation-control model. For examples, see: (a) Shimada, 3349
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