Download PDF
Synlett 2019; 30(11): 1308-1312
DOI: 10.1055/s-0037-1611551
letter
© Georg Thieme Verlag Stuttgart · New York

A Simple Method for the Preparation of Stainless and Highly Pure Trichloroacetimidates

Kazutada Ikeuchi  *
a   School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan   Email: hidetosh@kwansei.ac.jp
b   Department of Chemistry, Faculty of Science, Hokkaido University, West 8, North 10, Kita-ku, Sapporo 060-0810, Japan   Email: ikeuchi@sci.hokudai.ac.jp
,
Kentaro Murasawa
a   School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan   Email: hidetosh@kwansei.ac.jp
,
Hidetoshi Yamada  *
a   School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan   Email: hidetosh@kwansei.ac.jp
› Author Affiliations

The Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan supported the program for the Strategic Research Foundation at Private Universities (Grant No. S1311046), and the Japan Society for the Promotion of Science (JSPS) (KAKENHI) (Grant No. JP16H01163 in Middle Molecular Strategy, and Grant No. JP16KT0061) partly supported this work.
Further Information

Publication History

Received: 10 April 2019

Accepted after revision: 29 April 2019

Publication Date:
15 May 2019 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

We describe a method for obtaining various allylic, benzylic, and glucosyl 2,2,2-trichloroacetimidates (TCAIs) as stainless liquids or solids at the crude stage. The general synthetic method for the preparation of TCAIs often leads to stained products, and further purification of crude TCAIs causes decomposition due to their instability. In the described method, we use a solvent that barely dissolves the reactant, providing stainless and sufficiently pure TCAIs without requiring a purification step. Furthermore, the reaction mixture is turbid at the beginning and clear at the end, allowing us to monitor the progress of the reaction visually.


#

Key words

preparation - 2,2,2-trichloroacetimidates - stainless - solvent optimization - visual detection

2,2,2-Trichloroacetimidates (TCAIs), adducts of alcohols and Cl3CCN, are widely used in organic synthesis. For instance, benzyl (Bn)- and p-methoxybenzyl (PMB)-TCAIs (1 and 2) are utilized when installing the corresponding protecting groups (Scheme [1a]).[1] [2] Because the installation is implemented under acidic reaction conditions, the method is an alternative to the Williamson ether synthesis that requires basic reaction conditions.[3] In addition, TCAIs derived from allyl alcohols act as reactants in the Overman rearrangement (Scheme [1b]),[4] which incorporates a nitrogen atom into a hydrocarbon skeleton in natural product synthesis.[5] Furthermore, glycosyl TCAIs are standard glycosyl donors in oligosaccharide syntheses, such as the Schmidt glycosylation (Scheme [1c]).[6]

Zoom Image
Scheme 1 Typical transformations using TCAIs; PG = protecting group
Zoom Image
Scheme 2 Stained crude products prepared using the standard procedure

A major driving force in the aforementioned reactions is the instability of the TCAIs, which transform into more stable trichloroacetamides. This instability frequently causes degradation even in their preparation, and especially during chromatographic purification on silica gel; therefore, this purification should ideally be avoided. However, crude TCAIs are often stained when they are prepared by standard procedures (Scheme [2]). Although, in general, staining is not considered to affect the purity of the TCAIs, the pigment is actually a by-product (or by-products) of their synthesis, resulting in some level of contamination. Thus, staining should be avoided. Herein, we report an improved method to prepare stain-free TCAIs of sufficient purity in their crude form.

In general, TCAIs are prepared by treating an alcohol with Cl3CCN in the presence of a catalytic amount of a base in a solvent. Two standard base/solvent combinations are NaH/Et2O[7] [8] [9] [10] and DBU/CH2Cl2.[11] [12] [13] [14] Using NaH/Et2O involves a potential risk of contamination by the mineral oil that is supplied with NaH. In addition, the method stains the products (Scheme [2]). By contrast, using DBU/CH2Cl2 is preferable because DBU can be removed by liquid–liquid extraction (LLE) with an aqueous acid. However, this method also stains the products (Scheme [3], the fifth vial from the right).

Zoom Image
Scheme 3 Color of crude 2 when varying the reaction solvent. The reaction solvent is written on the corresponding vial. DMF = N,N-dimethylformamide, THF = tetrahydrofuran.

A clue to removing the stain was obtained through the screening of reaction solvents for the preparation of PMB-TCAI (2), the instability of which is known (Scheme [3]).[15] In each trial, a mixture of PMBOH and Cl3CCN (1.1 equiv) with DBU (10 mol%) in a solvent was stirred at 0 °C for 30 minutes, followed by LLE and concentration under reduced pressure to obtain the crude product 2. Acetone, pyridine, THF, DMF, MeCN, toluene, CH2Cl2, EtOAc, CHCl3, Et2O or hexane was used as the reaction solvent. Among them, the use of CH2Cl2 with DBU is well known,[12] which provided a pale-yellow crude product; therefore, purification using a short silica gel or Al2O3 column is required to obtain colorless 2 as reported.[12] Et2O, a preferred reaction solvent for the synthesis of 2 when catalytic NaH was used as the base, produced a stainless crude product. However, starting material remained due to the slow reaction rate (see page S7 of the Supporting Information). Using acetone, pyridine, THF, DMF, MeCN or toluene instead of CH2Cl2 intensified the staining of the crude product. The reaction in EtOAc also produced a slightly yellow crude product. Although a colorless crude product was obtained when CHCl3 was used as the solvent, a by-product was detected (see page S15 of the Supporting Information). This by-product seemed to be ethyl TCAI derived from ethanol, which had been added to CHCl3 as a stabilizer. Surprisingly, although hexane hardly dissolved PMBOH, the reaction proceeded smoothly to produce 2 in 96% yield without staining the product.[16]

The use of hexane presented another advantage; namely, the progress of the reaction could be detected visually. Because of the low solubility of PMBOH in hexane, the reaction mixture was a suspension at the beginning. In contrast, the mixture became a solution at the end of the reaction, as product 2 easily dissolves into hexane. This visual detection was useful since 2 decomposed on silica gel to produce PMBOH. Even after completion of the reaction, TLC indicated a spot due to PMBOH. In this case, typical TLC monitoring was unsuitable; hence, this visual change could be a useful index for estimating the endpoint of the reaction. Such a visual change may be applied to automatous monitoring of the reaction using light transmission.

The reaction conditions using hexane as the solvent were applicable when the scale was increased and when heptane was used to give unstained and substantially pure 1 and 2 (Scheme [4]). Thus, on scales of 500 mg and 1.0 g, treatment of Cl3CCN with BnOH and PMBOH, respectively, in the presence of catalytic DBU in hexane or heptane at 0 °C produced 1 and 2, both in quantitative yields as colorless liquids. Hexane has neurotoxicity[17] and an electrostatic ignition hazard.[18] Therefore, substitution with heptane is recommended for large-scale synthesis.[19] 1H NMR and 13C NMR spectra showed that the products were substantially pure after LLE without further purifications (see pages S20–27 of the Supporting Information).

Zoom Image
Scheme 4 Syntheses of Bn-TCAI (1) and PMB-TCAI (2): (a) on 500 mg scale in hexane, (b) on 1.0 g scale in heptane.

The typical procedure was as follows (Figure [1]). The reaction could be carried out in the open air. Strict anhydrous settings were not necessary. DBU (10 mol%) was added to a stirred mixture of a reactant (BnOH or PMBOH) and Cl3CCN (1.1 equiv) in hexane or heptane (ca. 0.4 M) at 0 °C. The purity of the used hexane or heptane was ≥95.0% and ≥98.5%, respectively. At the beginning of the reaction, the mixture was a suspension (Figure [1], photograph i). The reaction was finished in about 30 minutes. At the end of the reaction, the mixture changed to a solution (Figure [1], photograph ii). A yellow and undissolved substance frequently appeared, sticking to the glassware wall when the scale of the reaction was 1.0 g. The mixture was diluted at 0 °C with hexane or heptane (the same solvent used for the reaction), the volume of which was approximately equal to that of the reaction solvent. Subsequently, saturated aqueous NH4Cl (a volume nearly equal to the sum of the reaction and diluting solvent) was added at the same temperature. The mixture was transferred to a separating funnel and LLE was conducted. After removal of the aqueous layer, the organic layer was again washed with saturated aqueous NH4Cl. The LLE process removed DBU and the yellow by-product into the aqueous layer. The separated organic layer was dried over Na2SO4 and filtered. The concentration of the filtrate using a rotary evaporator gave 1 or 2 as a colorless liquid in a higher than 98% yield.[20] Note that the crude product was occasionally stained when the reaction was performed at room temperature. Additionally, the quenching of the reaction should be conducted immediately after the reaction is completed because keeping the reaction at 0 °C for a long time also stains the crude product.

Zoom Image
Figure 1 Reaction procedure when heptane was used for the synthesis of 2. The appearance is similar when 1 is synthesized and when hexane is used. (i) At the beginning of the reaction, the mixture is a suspension. (ii) At the end of the reaction, the mixture is a solution. The yellow pigment, which moves into the aqueous layer in the LLE process, is not product 2.

The advantages of the method were the following. (1) The products were colorless and pure after LLE without further purification. (2) The yields were more than 98%. (3) The obtained TCAIs 2 could be preserved at –10 °C for more than a year without degradation (see page S28 of the supporting information). (4) The operation was easy, allowing open air execution without concern for strict anhydrous conditions and the grade of the solvents.

The method using hexane as the solvent could be applied to the syntheses of various benzylic and allylic TCAIs (Scheme [5]).[21] Treatment of 3,4-dimethoxybenzyl alcohol (3a) and 2,4,6-trimethylbenzyl alcohol (3b) with Cl3CCN in the presence of a catalytic amount of DBU uneventfully afforded 4a and 4b, both of which are considered more unstable than PMB-TCAI (2). 4-Bromobenzyl TCAI (4c) was also prepared without reducing the yield. Application of this method to cinnamyl alcohol (3d) and geraniol (3e), both primary allylic alcohols, provided the corresponding TCAIs 4d and 4e in excellent yields. The use of secondary allylic alcohol 3f gave 4f in 87% yield. The reaction using cyclohex-2-ene-1-ol (3g) proceeded smoothly, but the crude 4g was stained orange. However, this result was at least better than that obtained when using CH2Cl2, which gave 4g as a brown crude product (see page S35 of the Supporting Information). The reaction of linalool (3h) did not occur due to steric hindrance.

Zoom Image
Scheme 5 Scope and limitations of benzylic and allylic alcohols

Solvent selection is a key factor toward application to glycosyl TCAIs (Scheme [6]). In the case of 2,3,4,6-tetra-O-acetyl-β-d-glucopyranose (5), the aforementioned reaction conditions provided 6 in only a 5% yield (Scheme [6a]). The poor yield was the result of the extremely low solubility of 5 in hexane (0.6 mg/mL). Changing the solvent from hexane to t-BuOMe improved the yield. The solubility of 5 in t-BuOMe was still low (20 mg/mL); however, the reaction proceeded easily without staining to give the desired TCAI 6 in a 98% yield as a mixture of anomers (α/β = 11:1).[21] This result suggests that the use of a reaction solvent where a reactant can be barely dissolved is the key point in synthesizing stainless TCAI. Additional examinations using Bn-protected glucose 7 and a mannofuranose derivative 8 supported this suggestion (Scheme [6b]).[21] Because the solubility of 7 and 8 in hexane and toluene was 0.2 and 5.5 mg/mL, and 0.2 and 23 mg/mL, respectively, we prepared their TCAIs in toluene. No reaction proceeded at 0 °C, but 7 gave stainless 9 in 98% yield at room temperature. On the other hand, 8 easily reacted at 0 °C to give only α-10 in 96% yield. Unfortunately, our method was not suited to a glucosamine derivative 11 (Scheme [6c]). Because 11 barely dissolved in EtOAc (12 mg/mL), EtOAc was used as the solvent. Despite observing that the reaction mixture changed from a suspension to a clear solution, the reaction did not go to completion, instead giving a 3:2 mixture of β-12 and 11. The reason might be attributed to the low reactivity of 11 due to the decrease of the nucleophilicity of the hydroxy group induced by the presence of electron-withdrawing protecting groups and a hydrogen bond in the phthaloyl group.

Zoom Image
Scheme 6 Application to four glycosyl TCAIs: (a) 2,3,4,6-tetra-O-acetyl-β-d-glucopyranose (5), (b) 2,3,4,6-tetra-O-benzyl-d-glucopyranose (7) and 2,3:5,6-bis-O-isopropylidene-d-mannofuranose (8), (c) 3,4,6-tri-O-benzoyl-2-deoxy-2-phthalimido-d-glucopyranose (11)

In summary, we have developed a method for obtaining stainless TCAI compounds without purification by chromatography or distillation. The crucial aspect was the selection of a solvent that barely dissolved the reactant alcohol. The method effectively provided Bn- and PMB-TCAIs (1 and 2), commonly used for protecting alcohols. We also confirmed that the method was applicable not only for the gram-scale synthesis of 1 and 2, but also for the preparation of various allylic and glycosyl TCAIs (4a–f, 6, 9 and 10). This method is proposed here as a new standard procedure for the preparation of TCAIs.


#

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1611551.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Typical transformations using TCAIs; PG = protecting group
Zoom Image
Scheme 2 Stained crude products prepared using the standard procedure
Zoom Image
Scheme 3 Color of crude 2 when varying the reaction solvent. The reaction solvent is written on the corresponding vial. DMF = N,N-dimethylformamide, THF = tetrahydrofuran.
Zoom Image
Scheme 4 Syntheses of Bn-TCAI (1) and PMB-TCAI (2): (a) on 500 mg scale in hexane, (b) on 1.0 g scale in heptane.
Zoom Image
Figure 1 Reaction procedure when heptane was used for the synthesis of 2. The appearance is similar when 1 is synthesized and when hexane is used. (i) At the beginning of the reaction, the mixture is a suspension. (ii) At the end of the reaction, the mixture is a solution. The yellow pigment, which moves into the aqueous layer in the LLE process, is not product 2.
Zoom Image
Scheme 5 Scope and limitations of benzylic and allylic alcohols
Zoom Image
Scheme 6 Application to four glycosyl TCAIs: (a) 2,3,4,6-tetra-O-acetyl-β-d-glucopyranose (5), (b) 2,3,4,6-tetra-O-benzyl-d-glucopyranose (7) and 2,3:5,6-bis-O-isopropylidene-d-mannofuranose (8), (c) 3,4,6-tri-O-benzoyl-2-deoxy-2-phthalimido-d-glucopyranose (11)