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One-Pot Synthesis of α‑Amino Acids through Carboxylation of Ammonium Ylides with CO2 Followed by Alkyl Migration Tsuyoshi Mita,* Masumi Sugawara, and Yoshihiro Sato* Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan S Supporting Information *
ABSTRACT: A simple, yet powerful protocol for α-amino acid synthesis using carbon dioxide (CO2) was developed. αAmino silanes could undergo four successive reactions (formation of ammonium salt, carboxylation, esterification, and 2,3- or 1,2-Stevens rearrangement) in the presence of allylic or benzylic halides under a CO2 atmosphere (1 atm). It is noteworthy that carboxylation at the position adjacent to a nitrogen atom proceeded via an ammonium ylide intermediate under mild conditions. n α-amino carbanion is a synthetically useful intermediate for preparing α-substituted amino compounds such as amino acids, amino alcohols, and diamines. Since the αhydrogen of amine derivatives is not acidic enough, the generation of an α-amino carbanion necessitated highly basic conditions in classical organic chemistry: (1) deprotonation of α-hydrogen of amine derivatives with a powerful base such as n-, s-, or t-BuLi;1 (2) transmetalation of α-amino stannanes with organolithium (Sn−Li exchange);1 and (3) reductive generation from imine equivalents with alkali metals or SmI2.2 In the former two cases, a chelating carbonyl group for a lithium cation (Boc, oxazolidinone, etc.) was introduced on the nitrogen atom to assist the event. In contrast, α-amino carbanions can also be accessed by treatment of α-amino silanes with a fluoride ion.3 These desilylative methods require neither toxic stannane reagents nor strong reductants. Moreover, carbanion formation can proceed under almost neutral conditions. Therefore, the desilylative substitution would have great potential for the synthesis of a variety of amine compounds. We have already developed desilylative carboxylation of αamino silanes with CO2,4 an abundant, inexpensive, and relatively nontoxic C1 source,5 to synthesize α-amino acids. Taking advantage of the accessibility of N-Boc-α-amino silanes from N-Boc-imines by silylation, we also developed a novel one-pot procedure for the synthesis of α-amino acids from imine precursors, α-amino sulfones. However, this carboxylation with CO2 limitedly proceeded at the benzylic and allylic positions, so that only phenyl and alkenyl glycine derivatives were able to be prepared (Figure 1A). Thereby, we next turned our attention to how to prepare α-alkylated amino acids. In order to realize fast and quantitative generation of an αcarbanion without an α-substituent for delocalizing the resultant anion, we considered employing ammonium ylide derived from a silylmethyltrialkylammonium salt (Figure 1B). Desilylative formation of ammonium ylide and its applications have been widely studied by several research groups, and it was
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© XXXX American Chemical Society
Figure 1. Our new strategy for carboxylation.
shown that ammonium ylide can be generated even without the assistance of the carbonyl group and charge delocalization by πconjugation. In 1979, Vedejs and co-workers developed a method for the generation of ammonium ylides using tertiary amines with TMSCH2OTf followed by treatment of CsF.6a This method has advantages over the use of organolithium reagents7 including (1) regioselective generation of ylides from the corresponding ammonium salts and (2) high functional group tolerability under mild conditions. There were several reports with regard to intramolecular rearrangements6 and ring expansion reactions.8 However, reactions of ammonium ylides generated in this manner with carbonyl compounds have been limited, and only the reaction with aldehydes was reported.9 If this species can react with CO2 selectively with suppression of rearrangement/ring expansion, the framework of an α-amino acid would be created. Our synthetic plan for α-alkylated α-amino acids is shown in Scheme 1. α-Amino silane, which is prepared from an amine and TMSCH2Cl, is alkylated with an allylic halide to form an ammonium salt. A fluoride ion such as CsF would then promote the formation of ammonium ylide followed by carboxylation with CO2, affording ammonium carboxylate. It would undergo 2,3-allylic rearrangement (2,3-Stevens rearrangement10,11) in the presence of an appropriate base after Received: April 14, 2016
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DOI: 10.1021/acs.joc.6b00837 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Scheme 1. Plan for the Synthesis of α-Alkylated α-Amino Acids
consumed even without CsF, but intermediate A depicted in Scheme 3 was obtained quantitatively (entry 7). This result suggested that the iodide ion of TBAI was not involved in silane activation. The addition of a catalytic amount of TBAI or a stoichiometric amount of tetrabutylammonium bromide (TBAB) instead of TBAI was not effective (entries 8 and 9). According to these results, TBAI is thought to be a stoichiometric iodide source to form β-methallyl iodide in situ, rather than either a silane activator or a phase transfer catalyst. Furthermore, the combination with TBAI actually worked well for less reactive β-methallyl chloride and tosylate (entries 10 vs 11 and entries 12 vs 13). With the optimal conditions in hand, we then investigated the substrate scope for allylic halides (Figure 2). The use of βsubstituted and nonsubstituted allylic halides gave 4a−c in good yields. The reaction with allyl bromide was readily scalable, and the product 4c was obtained with 2.2 g (10 mmol). α-Amino acids 4d and 4e were obtained in high yields with 1:1 dr from γ-monosubstituted allylic chloride and bromide. γ-Disubstituted and fully substituted allylic bromides were also applicable, affording 4f−h in good yields. The different substitution pattern between the ester moieties and the α-alkyl groups in 4d−h indicated that α-alkylation should occur via 2,3-Stevens rearrangement. Moreover, benzylic halides were also active in this one-pot carboxylation. When benzyl bromide and benzyl chlorides with an electron-donating substituent at the para-position were employed, 1,2-Stevens rearrangement products 4i−k were selectively obtained in moderate yields. In contrast, when p-bromobenzyl bromide was used, the migration pattern was changed to 2,3-allylic rearrangement (Sommelet−Hauser rearrangement10,11), affording 4l as a major product.11a Furthermore, one-pot reactions with 1-naphthylmethyl chloride and 2-naphthylmethyl bromide also selectively promoted Sommelet−Hauser rearrangement to afford 4m and 4n in good yields. Sommelet−Hauser rearrangement is comprised of 2,3-allylic rearrangement and the following rearomatization. Depending on substrate structures, however, an isotoluene intermediate was sometimes obtained ahead of rearomatization as a stable product.6c,12 Sato and coworkers demonstrated that rearomatization of the isotoluene intermediate was facilitated by DBU.6e According to their report, after completion of the reactions of p-bromobenzyl bromide and 2-naphthylmethyl bromide, the resulting mixtures were treated with 5 equiv of DBU to afford the products 4l and 4n in 52% and 57% yield, respectively. To obtain information about the reaction course, we first conducted carboxylation in the absence of allylic halide (Scheme 2a). The substrate was completely recovered at room temperature. Even when the reaction was conducted at a high temperature (150 °C, in NMP), 5 was obtained only in 26% yield after esterification. This result clearly indicated that the formation of ammonium ylide was inevitable for carboxylation with CO2. Next, potential intermediates (A, B, and C) in this one-pot reaction were prepared and subjected to the reaction conditions (Schemes 2b−d). In all cases, α-amino acid 4a was obtained in yields comparable to that of the onepot reaction (83% yield). Furthermore, 2,3-Stevens rearrangement of B did not proceed in the absence of allylic halide, suggesting that esterification is indispensable for the following base-induced alkyl migration (Scheme 2e). Based on the above experimental data, we propose a reasonable reaction mechanism for the one-pot α-amino acid synthesis from α-amino silane and CO2 (Scheme 3). The
esterification with allylic halide. If the base-induced 2,3-allylic rearrangements of ammonium ester can be mediated by the fluoride as well, all steps would be carried out in a single flask as a one-pot operation. To determine the feasibility of the planned one-pot α-amino acid synthesis, α-amino silane 1 was treated with β-methallyl iodide (2.2 equiv) and CsF (5 equiv) in DMF at 0 °C for 24 h under CO2 (1 atm: balloon). The desired one-pot reaction actually proceeded to afford the corresponding α-amino ester 4a in 60% yield (Table 1, entry 1). The use of β-methallyl Table 1. Condition Screening
entry
temp (°C)
X
additive
yield (%)a
1 2 3 4 5 6b 7c 8d 9 10 11 12 13
0 0 0 0 0 0 0 0 0 rt rt rt rt
I (2aa) Br (2ab) Br Br Br Br Br Br Br Cl (2ac) Cl OTs (2ad) OTs
− − NaI KI TBAI TBAI TBAI TBAI TBAB − TBAI − TBAI
60 40 0 34 73 (66) (83) 0 46 32 0 43 32 70
a
Yields were determined by 1H NMR analysis using 1,3,5trimethoxybenzene as an internal standard. Isolated yields are given in parentheses. bConducted in 5 mmol scale. cWithout CsF. d20 mol % of TBAI was added.
bromide instead of the iodide decreased the yield to some extent (entry 2). We then attempted in situ generation of the reactive β-methallyl iodide by adding an iodide salt. Although the yields did not improve with alkali metal iodides (entries 3 and 4), tetrabutylammonium iodide (TBAI) greatly accelerated the reaction, affording the desired product in 73% yield (entry 5). A larger-scale synthesis (5 mmol) improved the yield to 83% (entry 6). To confirm the role of TBAI, several reaction conditions were investigated. The substrate 1 was completely B
DOI: 10.1021/acs.joc.6b00837 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
Figure 2. Substrate scope for α-amino acid synthesis (0.2 mmol scale). Isolated yields are shown unless otherwise noted. a Conducted in 5 mmol scale. b Without TBAI. c Conducted in 10 mmol scale for 4c. d Determined by 1H NMR. Isolated yield was 38%.
Scheme 2. Mechanistic Studies
Scheme 3. Proposed Reaction Pathway
reaction is initiated by the formation of ammonium salt A from α-amino silane 1 and allylic halide followed by fluoridemediated silane activation to generate ammonium ylide 3. Carboxylation then takes place to give zwitterionic ammonium carboxylate B, which is esterified by an excess amount of allylic halide to form ammonium ester C. Finally, base-promoted 2,3Stevens rearrangement of C occurs to afford the target α-amino
acid 4. In this reaction sequence, CsF functions as both a silane activator and a base to promote the formation of ammonium ylides (the former: unstable ylide 3 to react with CO2; the latter: stable ylide to undergo allylic rearrangement). TBAI C
DOI: 10.1021/acs.joc.6b00837 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
by silica gel column chromatography (hexane/AcOEt, 5/1 to 2/1) to afford α-amino silane 1 (2.0 g, 8.7 mmol, 87% yield) as a colorless oil. 8-((Trimethylsilyl)methyl)-1,4-dioxa-8-azaspiro[4.5]decane (1). IR (neat): 2953, 2881, 2796, 1363, 1303, 1248, 1140, 1092, 1041, 850 cm−1; 1H NMR (500 MHz, CDCl3) δ = 3.91 (s, 4H), 2.52−2.36 (m, 4H), 1.91 (s, 2H), 1.74−1.63 (m, 4H), 0.03 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3) δ = 106.9, 64.1, 55.2, 50.3, 35.0, −1.3 ppm; HRMS (EI) m/z calcd for C11H23O2NSi [M]+: 229.1498. Found: 229.1491. Supply of Allylic and Benzylic Halides. Allylic halides 2aa,14 2b,15 2g,16 and 2h17 were prepared according to the reported methods. Allylic tosylate 2ad was prepared from 3-chloro-2-methylpropene using the reported method.18 The NMR data for 2ad were identical to those for the reported product.19 Other allylic/benzylic halides are commercially available. General Procedure of One-Pot Synthesis of α-Amino Acids. A test tube was charged with CsF (151.9 mg, 1.0 mmol, 5 equiv), which was dried with a heat gun for 2 min under vacuum (
