Abstract
Primary aminothiourea derivatives are shown to catalyze enantioselective alkylation of α-arylpriopionaldehdyes with diarylbromomethane. Evidence for a stepwise, SN1 mechanism in the substitution reaction induced by anion binding to the catalyst is provided by catalyst structure-activity studies, kinetic isotope effects, linear free-energy relationship studies, and competition experiments.
The anion-binding properties of urea and thiourea derivatives have been exploited recently in enantioselective catalytic reactions involving heteroatom-stabilized carbocations, such as N-acyliminium and oxocarbenium ions.1,2 Experimental and computational data point to a consistent mechanistic framework wherein the H-bond donor catalysts promote these reactions by anion-abstraction from a neutral organic precursor to generate the more reactive cationic electrophile (Scheme 1).1b We reasoned that, with the appropriate catalyst and nucleophilic partner, this mode of electrophile activation might also be applicable to catalysis of SN1 pathways via formation and reactions of carbocations that are not heteroatom-stabilized.3 Herein we report the successful application of this activation mode to formation of benzhydryl cations in the context of an asymmetric α-alkylation of α-branched aldehydes.
Scheme 1.
Hydrogen-Bond Catalysis by Anion Binding
The α-alkylation of 2-phenylpropionaldehyde (6a) with bromodiphenylmethane (benzhydryl bromide, 7a) was chosen as a model reaction (Table 1). Classical studies with benzhydryl derivatives have helped to establish much of the conceptual foundations of carbocation reactivity,4 and these compounds have been especially useful for characterizing the nature and stereochemical properties of ion pairs.5 The α-alkylation of aldehydes was deemed particularly worthy of investigation because of the high value of chiral aldehydes bearing α-quaternary stereocenters as synthetic intermediates,6 and the inherent challenges associated with asymmetric catalysis of this type of transformation.7 A broad screen of potential catalysts in the alkylation of 2-phenylpropionaldehyde with bromodiphenylmethane led to the discovery that primary aminothiourea derivatives were unique in inducing good reactivity and enantioselectivity (Table 1).8 This class of catalysts has been applied previously in additions of aldehydes and ketones to nitroalkenes,9 through the proposed intermediacy of covalent catalyst-enamine derivatives. The presence of a primary amino group was shown to be necessary for catalysis in the present case, as well (Table 1, entries 1 and 4). The thiourea also plays an essential role in promoting reactivity and enantioinduction (entries 1-5 vs. entries 6-7), suggesting that the dual H-bond donor component may be involved directly in electrophile activation (vide infra).10 It is noteworthy that the relatively simple thiourea 111 proved to be optimal, as more elaborate primary aminothiourea catalysts bearing additional stereochemical elements afforded no advantage (e.g. 4, entry 5).8
Table 1.
Catalyst Structure Activity Relationship Study
 | ||||
|---|---|---|---|---|
| entry | catalyst | concentration (M) | yield (%)a | ee (%)b |
| 1 | 1 | 0.05 | 71 | 91 |
| 2 | 1 | 0.1 | 54 | 90 |
| 3 | 2 | 0.05 | 44 | 89 |
| 4 | 3 | 0.05 | 0 | -- |
| 5 | 4 | 0.05 | 26 | 89 |
| 6 | 5 | 0.05 | trace | n.d. |
| 7 | 5 | 0.1 | 2 | 20 |
Determined by 1H NMR analysis using 1, 3, 5-trimethoxybenzene as an internal standard.
Determined by HPLC analysis of alcohol following reduction with NaBH4.
Alkylation of a variety of 2-arylpropionaldehydes proceeded in moderate-to-good yield and high enantioselectivity in the presence of catalyst 1 (Table 2).12 The scope of the reaction also included halo-substituted benzhydryl electrophiles, which underwent alkylation to afford products 8g-8i in high ee. 13,14
Table 2.
Reaction Scope
 | ||||||
|---|---|---|---|---|---|---|
| entry | R | R1 | product | time (d) |
yield (%)a |
ee (%)b |
| 1 | C6H5 | H | 8a | 3 | 70 | 91 |
| 2 | 2-naphthyl | H | 8b | 2 | 68 | 92 |
| 3 | p-Br C6H4 | H | 8c | 4 | 56 | 94 |
| 4 | p-F C6H4 | H | 8d | 4 | 57 | 92 |
| 5 | p-(Me)C6H4 | H | 8e | 2 | 59 | 85 |
| 6 | p-(OMe)C6H4 | H | 8f | 3 | 52 | 85 |
| 7 | C6H5 | F | 8g | 3 | 60 | 90 |
| 8 | C6H5 | Cl | 8h | 3 | 61 | 91 |
| 9 | C6H5 | Br | 8i | 3 | 61 | 91 |
Yield of isolated alcohol after reduction with NaBH4 (entries 1-6, 8); Yield of isolated aldehyde (entries 7 and 9).
Determined by HPLC analysis of alcohol following reduction with NaBH4.
The essential role of the catalyst (thio)urea moiety in promoting these enantioselective alkylation reactions may be ascribed to electrophile activation by H-bonding to the leaving group in either of two limiting mechanisms: 1) general acid catalysis to induce a concerted, SN2-like substitution, or 2) formation of an ion-pair intermediate and promotion of an SN1-like pathway (Scheme 2). In an effort to distinguish between these possibilities, we analyzed the effects of isotopic and electronic substitution of the electrophile on reaction rate. A normal secondary kinetic isotope effect (kH/kD) of 1.12 was observed upon deuterium-substitution of the benzhydryl proton, indicating a change in hybridization of the electrophilic carbon from sp3 to sp2 in the transition state.15,16 A Hammett study revealed a strong dependence on the electronic properties of the electrophile, with benzhydryl derivatives bearing electron-donating substituents reactings more rapidly (ρ = −1.95).17,18 The results of both experiments provide strong evidence that this transformation proceeds through a discrete, catalyst-associated carbocation in an SN1-like substitution mechanism.
Scheme 2.
Possible Electrophile Activation Modes
Additional evidence for a catalyst-induced SN1 pathway was provided through the evaluation of benzyl bromide as a potential electrophile in the alkylation reaction. In competition experiments, alkylation of 1-cyclohexenylpyrrolidine was found to proceed exclusively with benzyl bromide in the presence of equimolar amounts bromodiphenylmethane, a degree of selectivity attributable to the relative reactivity of these electrophiles in SN2 pathways. In contrast, under the catalytic conditions using either 1 or 2, no alkylation of 2-phenylpropionaldehyde was obtained with benzyl bromide (Table 3, entries 1-2). This absence of reactivity was not ascribable to catalyst deactivation, as experiments with mixtures of benzyl bromide and bromodiphenylmethane (7a) demonstrated that the catalyst maintained activity (Table 3, entries 3-4).
Table 3.
Electrophile Competition Experiments
 | ||||||
|---|---|---|---|---|---|---|
| entry | catalyst |
7a (equiv) |
9 (equiv) |
yield
8a (%) |
ee
8a (%) |
yield
8j (%) |
| 1 | 1 | 0 | 2 | - | n.a. | 0 |
| 2 | 2 | 0 | 2 | - | n.a. | 0 |
| 3 | 1 | 2 | 2 | 49 | 90 | 0 |
| 4 | 2 | 2 | 2 | 42 | 85 | 0 |
Alkylations using enantioenriched p-chlorobenzhydryl chloride were found to proceed with nearly complete (95%) stereospecificity,19 which requires that addition of the catalyst-associated enamine to the ion-pair intermediate is rapid relative to ion-pair reorganization. This observation is in line with the known reactivity of benzhydryl cations and enamines as analyzed by Mayr,20 which would predict that these partners should undergo intermolecular reaction at a rate near the diffusion limit.21 This stands in sharp contrast to solvolyses of benzhydryl electrophiles, wherein substitution has been shown to be slow relative to racemization.5
This work demonstrates that urea and thiourea derivatives effectively induce alkylation pathways through simple carbocations via anion abstraction, and can control the reactivity of such cationic intermediates in enantioselective asymmetric bond-forming reactions. The possibility of extending this activation mode to enantioselective additions to prochiral carbocations is under investigation.
Supplementary Material
Acknowledgments
This work was supported by the NIH (GM-43214). We thank Abigail Doyle for helpful discussions and for experimental contributions in the secondary kinetic isotope effect studies.
Footnotes
Supporting Information Available: Complete experimental procedures and characterization data for products and all isolated intermediates. This material is available free of charge via the Internet at http://pubs.acs.org.
References
- 1.(a) Taylor MS, Jacobsen EN. J Am Chem Soc. 2004;126:10558. doi: 10.1021/ja046259p. [DOI] [PubMed] [Google Scholar]; (b) Raheem IT, Thiara PS, Peterson EA, Jacobsen EN. J Am Chem Soc. 2007;129:13404. doi: 10.1021/ja076179w. [DOI] [PubMed] [Google Scholar]; (c) Reisman SE, Doyle AG, Jacobsen EN. J Am Chem Soc. 2008;130:7198. doi: 10.1021/ja801514m. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.For other key examples of thiourea catalysis of anion-binding pathways, see: Kotke M, Schreiner PR. Tetrahedron. 2006;62:434.Kotke M, Schreiner PR. Synthesis. 2007:779.De CK, Klauber EG, Seidel D. J Am Chem Soc. 2009;131:17060. doi: 10.1021/ja9079435. For a review of this emerging topic, see: Zhang Z, Schreiner PR. Chem Soc Rev. 2009;38:1187. doi: 10.1039/b801793j.
- 3.For alternative approaches to asymmetric catalysis with carbocation intermediates, see: Braun M, Kotter W. Angew Chem, Int Ed. 2004;43:514. doi: 10.1002/anie.200352128.Feducia JA, Campbell AN, Doherty MQ, Gagné MR. J Am Chem Soc. 2006;128:13290. doi: 10.1021/ja064335d.Luzung MR, Mauleón P, Toste FD. J Am Chem Soc. 2007;129:12402. doi: 10.1021/ja075412n.Cozzi PG, Benfatti F, Zoli C. Angew Chem, Int Ed. 2009;48:1313. doi: 10.1002/anie.200805423.
- 4.Deno NC, Jaruzelski JJ, Schriesheim A. J Am Chem Soc. 1955;77:3044. [Google Scholar]; (b) Deno NC, Schriesheim A. J Am Chem Soc. 1955;77:3051. [Google Scholar]; (c) Mayr H, Bug T, Gotta MF, Hering N, Irrgang B, Janker B, Kempf B, Loos R, Ofial AR, Remennikov G, Schimmel H. J Am Chem Soc. 2001;123:9500. doi: 10.1021/ja010890y. [DOI] [PubMed] [Google Scholar]
- 5.Winstein S, Gall JS, Hojo M, Smith S. J Am Chem Soc. 1960;82:1010. [Google Scholar]; (b) Winstein S, Gall JS. Tetrahedron Lett. 1960;1:31. [Google Scholar]; (c) Winstein S, Ledwith A, Hojo M. Tetrahedron Lett. 1961;2:341. [Google Scholar]; (d) Goering HL, Briody RG, Levy JF. J Am Chem Soc. 1963;85:3059. [Google Scholar]
- 6.(a) Evans DA. In: Asymmetric Synthesis. Morrison JD, editor. Vol. 3. Academic Press; New York: 1984. pp. 1–110. [Google Scholar]; (b) Seebach D, Imwinkelried R, Weber T. In: Modern Synthetic Synthesis. Scheffold R, editor. Vol. 4. Springer; Berlin-Heidelberg: 1986. pp. 125–259. [Google Scholar]; (c) Crosby J. Tetrahedron. 1991;47:4789. [Google Scholar]
- 7.For alternative approaches to catalytic asymmetric aldehyde alkylation, see: Vignola N, List B. J Am Chem Soc. 2004;126:450. doi: 10.1021/ja0392566.Fu A, List B, Thiel W. J Org Chem. 2006;71:320. doi: 10.1021/jo052088a.Xie H, Zu L, Li H, Wang J, Wang W. J Am Chem Soc. 2007;129:10886. doi: 10.1021/ja073262a.Rios R, Sunden H, Vesely J, Zhao GL, Eriksson L, Cordova A. Adv Synth Cat. 2007;349:1028.Rios R, Vesely J, Sunden H, Ibrahem I, Zhao GL, Cordova A. Tetrahedron Lett. 2007;48:5835.Ibrahem I, Cordova A. Angew Chem, Int Ed. 2006;45:1952. doi: 10.1002/anie.200504021.Beeson TD, Mastracchio A, Hong JB, Ashton K, MacMillan DWC. Science. 2007;316:582.Mukherjee S, List B. J Am Chem Soc. 2007;129:11336. doi: 10.1021/ja074678r.Nicewicz DA, MacMillan DWC. Science. 2008;322:77. doi: 10.1126/science.1161976.Enders D, Wang C, Bats JW. Angew Chem, Int Ed. 2008;47:7539. doi: 10.1002/anie.200802532.Shaikh RR, Mazzanti A, Petrini M, Bartoli G, Melchiorre P. Angew Chem, Int Ed. 2008;47:8707. doi: 10.1002/anie.200803947. For recent highlights, see: Melchiorre P. Angew Chem, Int Ed. 2009;48:1360. doi: 10.1002/anie.200804995.Alba AN, Viciano M, Rios R. ChemCatChem. 2009;1:437.
- 8.Details of catalyst and reaction optimization studies are provided in the Supporting Information. Solvent, concentration, and the presence of additives are also important factors that influence both enantioselectivity and reactivity. The presence of water and acetic acid accelerate the reaction, presumably by influencing the imine and enamine formation and imine hydrolysis steps, while NEt3 serves to trap the HBr byproduct. Water and weak acid have been shown to be beneficial in other primary amine thiourea catalyzed reactions (See ref. 9b-c).
- 9.(a) Tsogoeva SB, Wei S. Chem Commun. 2006:1451. doi: 10.1039/b517937h. [DOI] [PubMed] [Google Scholar]; (b) Huang H, Jacobsen EN. J Am Chem Soc. 2006;128:7170. doi: 10.1021/ja0620890. [DOI] [PubMed] [Google Scholar]; (c) Lalonde MP, Chen Y, Jacobsen EN. Angew Chem, Int Ed. 2006;45:6366. doi: 10.1002/anie.200602221. [DOI] [PubMed] [Google Scholar]
- 10.The fact that both urea 2 and thiourea 1 display catalytic activity and similar enantioselectivity in this transformation (Table 1, entries 1 and 3) would appear to rule out any direct role of the thiocarbonyl moiety in the alkylation mechanism.
- 11.(a) Mei K, Jin M, Zhang S, Li P, Liu W, Chen X, Xue F, Duan W, Wang W. Org Lett. 2009;11:2864. doi: 10.1021/ol9010322. [DOI] [PubMed] [Google Scholar]; (b) Zhang XJ, Liu SP, Li XM, Li M, Chan ASC. Tetrahedron: Asymmetry. 2009;20:1451. [Google Scholar]; (c) Uehara H, Barbas CF., III Angew Chem, Int Ed. 2009;48:9848. doi: 10.1002/anie.200905313. [DOI] [PubMed] [Google Scholar]
- 12.Moderate yields are a result of starting material aldehyde decomposition via α-oxidation and incomplete conversion.
- 13.Benzhydryl electrophiles bearing strongly electron-withdrawing groups were unreactive under the catalytic conditions. In contrast, analogs bearing electron-donating groups such as (p-MeOC6H4)2CH(Br) effected alkylation to give racemic products without (thio)urea activation (i.e., similar results were obtained with 1, 2, and with catalytic cyclohexylamine).
- 14.No reactions with α,α-dialkyl aldehydes or α-alkoxy aldehydes were observed under the optimal catalytic conditions.
- 15.A KIE of 1.11 was observed for the reaction mediated by urea catalyst 2.
- 16.This KIE is consistent with what is observed in solvolysis reactions of benzhydryl chlorides: Klein HS, Streiwieser A. J Am Chem Soc. 1964;86:5170.
- 17.Plots of log krel vs. Hammett's substituent constants (σ+) are provided in the Supporting Information.
- 18.The rates of SN1 reactions of benhydryl bromides (solvolysis in DMSO) depend strongly on the electronic properties of the electrophile (ρ = −2.9), while the rates of SN2 reactions of benzhydryl bromides are only marginally affected and display poor Hammett correlations: Phan TB, Nolte C, Kobayashi S, Ofial AR, Mayr H. J Am Chem Soc. 2009;131:11392. doi: 10.1021/ja903207b.
- 19.See Supporting Information for experimental details and analysis.
- 20.For quantitative data describing the reactivity of these reacting partners, see ref. 4c and: Kempf B, Hampel N, Ofial AR, Mayr H. Chem Eur J. 2003;9:2209. doi: 10.1002/chem.200204666.
- 21.Reaction of 1-N-morpholino-1-phenylethene with benzhydryl cation, s=0.79, N=9.96 (ref. 20), and E=5.9 (ref. 4c), so log k (20 °C) = s(N + E) = 12.5.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.