Direct Reductive Alkylation of Amino Acids
Synthesis of Bifunctional Chelates for Nuclear ImagingMurali K. Levadala, Sangeeta Ray Banerjee, Kevin P. Maresca, John W. Babich, Jon ZubietaSynthesis 1759-1766 (2004)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/stab.amino.acid.reductive.alkylation.pdf)
AbstractA family of effective bifunctional chelators for technetium- and rhenium-based radiopharmaceuticals was conveniently synthesized in high yields through direct reductive N-alkylations of amino acids and their analogues with aldehydes, using NaBH(OAc)
3 as an efficient reagent. The mono-, di-, tetra- and even mixed alkylated amino acid derivatives were all prepared in one-pot synthesis.
In the case of amino acids, the reductive alkylation with aldehydes is generally performed after protection of the acid functionality as the ester, [17] rendering this a cumbersome three-step procedure. The reports that detail the reductive alkylation of amino acids with an open acid functionality (direct) are surprisingly few. The preferred reagent for this purpose is NaCNBH3 [18] , while NaBH4 [19] , H2/C-Pd(OH)2, [20] and NaHTe [21] have occasionally been used. Although NaCNBH3 is an excellent reagent, it is relatively toxic and the isolated products are often contaminated with cyanide residue. One limitation is that the reactions are restricted to polar medium, which is sometimes sluggish and often mitigated by poor yields. Furthermore, the scope of the substrate is limited in heterogeneous hydrogenations as many functional groups, such as nitro, alkene, alkyne, OBn etc., are susceptible under the reaction condition. The use of NaBH4 necessitates the preformed imine to avoid the reduction of aldehyde, and also alkaline medium, thereby limiting its practicality. Abdel-Magid et al. [22] have recently demonstrated that NaBH(OAc)3 can effectively be used as a mild reagent in the reductive amination of aldehydes and ketones with shorter reaction time and excellent yields. It is surprising, that with the exception of a single example, there are no major reports of use of NaBH(OAc)3 with free amino acids, [23e] even though there are several reports in the literature for the corresponding amino acid esters. [23] We sought to exploit the above method to provide direct access to ligands useful for applications to nuclear medicine.
We noted literature reports of reductive alkylation of phenylalanine with pyridine-2-carboxaldehyde for which a 21% yield with NaCNBH3 had been obtained for the monoalkyl derivative. [18b] We have now investigated the dialkylation of the same system with NaBH(OAc)3 in 1,2-dicholorethane (DCE) (Scheme [1] ). The reaction was complete within two hours, and the product 6 was isolated in 78% yield. Since DCE has been used in similar reactions, we employed the same medium, despite the insolubility of amino acids in DCE. It is noteworthy that the reaction was homogeneous in DCE despite the insolubility of amino acids while a suspension-like mixture was evident in the polar solvent MeCN. The rate of the reaction was significantly faster in chlorinated solvents, DCE and CH2Cl2 compared to THF and MeCN.
By appropriate stoichiometric manipulation of the amino acids and aldehydes, the mono-, di-, and even tetraalkylated amino acid derivatives could be obtained in good yields. In the case of tetraalkylation, the lysine dihydrochloride salt was treated with 4.5 equivalents of pyridine-2-carboxaldehyde and NaBH(OAc)3 (5 equivalents) to afford the tetrapyridyl derivative 10 in 79% yield, along with a small amount of the reduced alcohol of the aldehyde. It is noteworthy that four alkylation steps are performed in one-pot in the case of such tetraalkyl amino acids, an observation consistent with the direct use of the amino acid hydrochloride salt as starting materials without any need for prior neutralization or base addition to the reaction, at the expense of a slight excess of aldehyde (0.5 equiv).
The simplified workup procedure involves the addition of water to quench the reaction followed by extraction into the organic phase. The methodology was also amenable to large scale synthesis, as we have successfully scaled up the reductive alkylation of amino acids (compound 1) to a 10 g scale.
Encouraged by the above results, we then investigated the monoalkylation of similar systems with stoichiometric amounts of aldehyde and amine (compounds 12, 13). Unfortunately, the reaction resulted in the predominant formation of dialkylated product. However, it was subsequently found that the dialkylation could be significantly suppressed by forming the imine [25] in situ, i.e., refluxing the mixture of amino acid and aldehyde in DCE for 10 minutes under inert atmosphere (Scheme [2] ), followed by treatment with NaBH(OAc)3 at ambient temperature. This enabled us to isolate the monoalkylated products 12 and 13 in good yields with the formation of dialkylated products reduced to 10-15%. This small amount of dialkylation may be explained in light of the observation for amino esters by Abdel-Magid et al. [23c] that the monoalkylated product itself would add to the imine to form a dialkyliminium ion, which could then be reduced by NaBH(OAc)3 to afford the dialkylated product. We found that other aprotic solvents CH2Cl2, THF and MeCN along with protic solvents such as methanol were equally effective for the formation of imine.
Abstract
Dialkylation Reactions; Typical Procedure
To a mixture of Fmoc-l-lysine (10.0 g, 27.1 mmol) and NaBH(OAc)3 (14.4 g, 67.95 mmol) in DCE (150 mL), was added 2-pyridinecarboxaldehyde (6.4 g, 57.0 mmol) in DCE (15 mL) at 0 °C under argon. The suspension was stirred at r.t. for 1 h. The reaction mixture was decomposed with H2O (100 mL) and diluted with CHCl3 (100.0 mL). The separated organic layer was washed with H2O and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified through a pad of silica gel using MeOH-CHCl3 (1:6) as eluent to provide the dipyridylmethyl derivative of Fmoc-l-lysine (12.85 g, 86%).
Dialkylation Reactions; Typical Procedure
To a mixture of Fmoc-l-lysine (10.0 g, 27.1 mmol) and NaBH(OAc)3 (14.4 g, 67.95 mmol) in DCE (150 mL), was added 2-pyridinecarboxaldehyde (6.4 g, 57.0 mmol) in DCE (15 mL) at 0 °C under argon. The suspension was stirred at r.t. for 1 h. The reaction mixture was decomposed with H2O (100 mL) and diluted with CHCl3 (100.0 mL). The separated organic layer was washed with H2O and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified through a pad of silica gel using MeOH-CHCl3 (1:6) as eluent to provide the dipyridylmethyl derivative of Fmoc-l-lysine (12.85 g, 86%).
Mixed-Alkylation Reactions; Typical Reaction
A solution of Boc-d-lysine (2.0 g, 8.12 mmol) and 2-pyridinecarboxaldehyde (0.87 g, 8.12 mmol) in DCE (10 mL) was refluxed for 10 min under argon. The reaction mixture was cooled to 0 °C, and treated sequentially with NaBH(OAc)3 (4.30 g, 20.3 mmol) and 2-thiazolecarboxyaldehyde(0.91 g, 8.12 mmol). The reaction mixture was stirred at r.t. until the completion of reaction and purified as mentioned above to obtain the mixed derivative of Boc-d-lysine (3.39 g, 75%) along with 12% of the bis-alkyl derivative as a side product.
This procedure might be useful for the N-methylation of phenylalanine (for later reduction to methamphetamine) as discussed in
Post 512010
(java: "Question: methylating the amine in Phenylalanine", Stimulants) or possibly even for the N-methylation of plain amphetamine to form methamphetamine, as mentioned in
Post 450039 (missing)
(Kinetic: "Methylation", Stimulants).
This procedure is also very likely to be just as good for the N,N-dimethylation of tryptamine to DMT as the currently leading method:
Post 435056
(Rhodium: "DMT from Tryptamine/NaBH3CN/37% HCHO", Tryptamine Chemistry)Another use for this procedure could be the N,N-dialkylation of tryptophan to the correspoding N,N-Dialkyl-tryptophan, which is a simple decarboxylation away from a range of N,N-Dialkyltryptamines - a route discussed in
Post 445300 (missing)
(Vitus_Verdegast: "Can J Chem 80: 779-788 (2002)", Tryptamine Chemistry)Also, from reference
[19] in the article: NaBH
4 reductive alkylation of aminoacids:
Synthesis of novel 1,10-phenanthroline-2,9-bis-?-amino acid conjugatesWang Z-M.; Lin H-K.; Zhou Z-F.; Zhu S-R.; Liu T-F.; Chen Y-T.,
J. Chem. Res. (S), No. 4, pp. 170-171 (2000)AbstractStarting from 2,9-dimethyl-1,10-phenanthroline, the syntheses of eight novel 1,10-phenanthroline-2,9-bis-?-aminoacid conjugates (?-amino acids: DL-Ala, L-Val, L-Phe, L-His, L-Ile, L-Met, L-Glu, L-Asp) are described in detail.
The other reference,
Andruszkiewicz, R.;
Pol. J. Chem. 62, 257 (1988), may be written in polish, but I'm not sure.