Download PDF
Synlett 2024; 35(09): 957-962
DOI: 10.1055/a-2179-6032
cluster
Chemical Synthesis and Catalysis in Germany

Catalytic C–H Functionalization of Trimethylamine

Dennis Geik
,
Alina Büker
,
Felix Fornfeist
,
Marc Schmidtmann
,
Sven Doye∗

We thank the Research Training Group ‘Chemical Bond Activation’ (GRK 2226) funded by the Deutsche Forschungsgemeinschaft for financial support of this project.
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Carbon–carbon bond-forming hydroaminoalkylation reactions between trimethylamine and alkynes, alkenes, allenes, or a methylenecyclopropane (MCP) are achieved in the presence of titanium catalysts. The reactions take place by C–H bond activation at the methyl group of trimethylamine and therefore offer flexible and direct methods for the C–H functionalization of trimethylamine. The importance of the developed procedures for the synthesis of pharmaceutically relevant dimethylaminomethyl-substituted products is underlined by a straightforward synthesis of the antidepressant butriptyline.


#

Key words

amines - C–H activation - hydroaminoalkylation - titanium - trimethylamine
Zoom Image
Scheme 1 Industrial synthesis and commercial applications of methylamines
Zoom Image
Figure 1 Examples of important pharmaceuticals with dimethylaminomethyl substructures (highlighted in red)[4]

Methylamines are very important intermediates in the chemical industry.[1] They are commercially produced on a million-ton scale[1b] [1c] [2] by the stepwise methylation of ammonia with methanol in the presence of a dehydration catalyst. Unfortunately, the selectivity of the methylation reaction can only be controlled to a certain degree (Scheme [1]). As a result, all three methylamines (methylamine, dimethylamine, and trimethylamine) are always formed together and typically at least 20 wt% of trimethylamine is obtained.[1–3] Problematic is the fact that, in terms of demand, significant differences exist between methylamine, dimethylamine, and trimethylamine. While dimethylamine and methylamine are widely used for the production of solvents, pharmaceuticals, agrochemicals, and detergents (e.g., DMF, DMAc, N-methylpyrrolidone, dimethyl urea, etc.), a lack of need exists in the case of trimethylamine.[1a] Although, for example, the industrial production of choline chloride relies on its use as a starting material,[1] trimethylamine is typically regarded as an undesired by-product of methyl- and dimethylamine production.[1a] This is particularly true because the formation of trimethylamine is thermodynamically favored and its separation from the other methylamines is difficult to achieve. Due to the formation of azeotropic mixtures, it requires energy-consuming, large-scale distillation, which increases the overall cost of the process.[2] Regarding the mentioned problems, it would be highly desirable to develop new and efficient chemical reactions that use trimethylamine as a starting material for the synthesis of valuable products. In this context, transformations that include a C–H functionalization of trimethylamine must be regarded as particularly promising because corresponding transformations would offer flexible synthetic pathways towards dimethylaminomethyl-substituted products. The corresponding substructure is a common structural motif of pharmaceuticals (Figure [1], highlighted in red), which, for example, can be found in many tricyclic antidepressants, such as amitriptyline and butriptyline.[4]

Unfortunately, reports of C–H functionalization reactions[5] of trimethylamine are extremely rare.[6] Rousselet et al. reported a copper-mediated oxidation of trimethylamine to trimethylamine-N-oxide that results in C–C coupling with an electron-deficient phenol.[6a] A corresponding cross-dehydrogenative coupling reaction between trimethylamine and phenols, performed in the presence of BrCCl3 and catalytic amounts of HAuCl4, has also been reported by Sun et al.[6b] Inspired by pioneering studies on hydroaminoalkylation reactions[7] [8] of alkenes with tertiary amines,[9] very recently, our group developed the first titanium-catalyzed hydroaminoalkylation reactions of alkynes with tertiary amines and, during this study, we also achieved three successful reactions in which the α-C–H bond of trimethylamine underwent an addition reaction across the C–C triple bond of diphenylacetylene, 2-cyclohexyl-1-phenylacetylene, or 2-benzyl-1-phenylacetylene.[6c] Herein, we now report the use of trimethylamine for several additional C–C bond-forming hydroaminoalkylation reactions that use alkynes, alkenes, allenes, or a methylenecyclopropane as unsaturated substrates. The reactions take place by C–H bond activation at the methyl group of trimethylamine and therefore offer flexible and direct methods for the C–H functionalization of trimethylamine, including a one-step synthesis of the antidepressant butriptyline.

Based on our previous report on hydroaminoalkylation of alkynes with tertiary amines,[6c] we initially explored the scope of corresponding reactions of trimethylamine with alkynes in more detail. To this end, trimethylamine was reacted with a range of symmetrical and unsymmetrical internal alkynes at 80 °C for 72 h in the presence of 10 mol% TiBn4, 10 mol% of the ligand precursor LH1, and 8 mol% of the Lewis acid [Ph3C][B(C6F5)4].[10] As can be seen in Scheme [2], diphenyl- as well as alkyl(phenyl)-substituted alkynes underwent successful addition reactions with trimethylamine to give E-allylamine products [(E)-1–(E)-7a] stereoselectively and, in most cases, these could be isolated in good to excellent yields. In this context, it should be emphasized that the stereoselective formation of the trisubstituted E-double bond of the products is in good agreement with the generally accepted mechanism of Ti-catalyzed hydroaminoalkylation reactions.[6c] [8f] Regarding regioselectivity, C–C bond formation took place preferentially at the alkyl-substituted carbon atom of the unsymmetrically substituted alkyl(phenyl)alkynes, but it was found that the steric bulk of the alkyl substituent of the alkyne influences the regioselectivity of the reaction significantly. While, for example, 1-phenylpropyne or 2-benzyl-1-phenylacetylene were selectively converted into a single regioisomer [(E)-3 or (E)-5], 2-cyclohexyl-1-phenylacetylene delivered both regioisomeric hydroaminoalkylation products in a ratio of only 80:20, with (E)-7a being the major product. The structure of (E)-7a could be confirmed unambiguously by single-crystal X-ray diffraction analysis of the corresponding hydrochloride (E)-7a·HCl (Figure [2]).[11] In this context, it should also be mentioned that additional experiments performed with a large variety of unsymmetrically substituted diarylacetylenes always gave mixtures of both regioisomeric hydroaminoalkylation products in ratios of approximately 1:1. Although terminal alkynes such as phenylacetylene were found to react unselectively under the reaction conditions (Scheme [3]), the formal linear hydroaminoalkylation product of phenylacetylene with trimethylamine, (E)-8, could be obtained by a two-step reaction sequence consisting of an initial regio- and stereoselective hydroaminoalkylation of (trimethylsilylethinyl)benzene and a subsequent HI-catalyzed protodesilylation.[12]

Zoom Image
Scheme 2 Ti-catalyzed hydroaminoalkylation reactions of alkynes with trimethylamine. Reaction conditions: trimethylamine (1.0 mmol), alkyne (1.5 mmol), TiBn4 (0.10 mmol, 10 mol%), LH1 (0.10 mmol, 10 mol%), [Ph3C][B(C6F5)4] (0.08 mmol, 8 mol%), toluene (4.5 mL), 80 °C, 72 h, sealed ampoule (V = 5 mL). Unless otherwise noted, yields refer to isolated pure compounds. If applicable, only the major regioisomer is shown. a The regioselectivity was determined by GC analysis prior to flash chromatography. b After chromatographic purification, a mixture of two regioisomers was obtained.

We next turned our attention towards corresponding reactions of alkenes and, after a brief ligand screening and an optimization of the reaction between 1-dodecene and trimethylamine,[10] we were able to isolate the corresponding hydroaminoalkylation product 10 in 80% yield (Scheme [4]). Best results were obtained with ligand precursor LH2 at 70 °C, and the reaction delivered the branched regioisomer 10 exclusively. Subsequently, under identical reaction conditions, a variety of additional monosubstituted alkenes were also reacted with trimethylamine to give the corresponding hydroaminoalkylation products 11–18. Although the products were obtained in modest to good yields (38–80%) in most cases (10–16), poor yields (14–34%) were observed in a few examples (17, 18), mainly due to poor conversion of the alkene starting materials. However, the good yield of 68% observed in the case of triisopropylsilylether 12 proves that the reaction also tolerates the presence of protected oxygen functionalities. In contrast, corresponding reactions of internal alkenes (cyclohexene, cyclooctene) or activated alkenes (styrene, methyl vinyl ketone) were not successful.

Zoom Image
Figure 2 Molecular structure of (E)-7a·HCl. Hydrogen atoms (except H1, H3, and H10) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and angles (°): N1–C1 1.499(1), C1–C2 1.528(1), C2–C3 1.344(1), Σ(angles)(C2) 360.0, Σ(angles)(C3) 359.9.[11]
Zoom Image
Scheme 3 Ti-catalyzed hydroaminoalkylation reactions of phenylacetylene and (trimethylsilylethinyl)benzene with trimethylamine. a The regioselectivity was determined by GC analysis prior to flash chromatography.
Zoom Image
Scheme 4 Ti-catalyzed hydroaminoalkylation reactions of alkenes with trimethylamine. Reaction conditions: trimethylamine (1.0 mmol), alkene (1.3 mmol or 1.5 mmol), TiBn4 (0.10 mmol, 10 mol%), LH2 (0.10 mmol, 10 mol%), [Ph3C][B(C6F5)4] (0.08 mmol, 8 mol%), toluene (4.5 mL), 70 °C, 24 h, sealed ampoule (V = 5 mL). Unless otherwise noted, yields refer to isolated pure compounds. a Reaction time 16 h. b The product was isolated as a mixture of two diastereoisomers. c The diastereoselectivity was determined by GC analysis prior to flash chromatography. d Reaction time 72 h.
Zoom Image
Scheme 5 Synthesis of butriptyline (21) and molecular structure of 21·HCl. Hydrogen atoms (except H1, H1A, H17, H8A, H8B, H9A, and H9B) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å): N1–C18 1.5040(8), C17–C18 1.5294(9).[11]

The fact that all the hydroaminoalkylation reactions shown in Scheme [4] took place with perfect regioselectivity to exclusively give branched regioisomers, inspired us to synthesize alkene 20 (Scheme [5]) as an additional substrate, which, upon hydroaminoalkylation with trimethylamine, would directly deliver the antidepressant butriptyline (21). To this end, according to a reported procedure,[13] commercially available dibenzosuberone was initially reduced to the corresponding alcohol 19 in 99% yield using NaBH4 as the reducing agent. Alcohol 19 was then reacted with allyltrimethylsilane in the presence of catalytic amounts of FeCl3 to give the desired alkene substrate 20 in 99% yield. With 20 in hand, we then performed a hydroaminoalkylation reaction with trimethylamine under the already established conditions and we were delighted to see that butriptyline (21) was formed in 78% yield.[14] The structure of 21 was confirmed unambiguously by single-crystal X-ray diffraction of the corresponding hydrochloride 21·HCl (Scheme [5]).[11]

Zoom Image
Figure 3 Molecular structure of 23·HCl. Hydrogen atoms (except H1, H2, H5, and H6) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and angles (°): N1–C10 1.507(2), C1–C10 1.505(2), C1–C2 1.339(2), C5–C6 1.330(2), Σ(angles)(C1) 359.8, C1-C2-C3 127.9(2), C4-C5-C6 127.0(2), C5-C6-C7 126.4(2).[11]

Table 1 Ti-Catalyzed Hydroaminoalkylation Reactions of Allenes with Trimethylaminea

Entry

Allene

Product(s)

Yield (%)b

1

(E)-22

79

2

23

86

3

(E/Z)-24

55c

4

(E/Z)-25

46d

5

(E/Z)-26

71e

6

(E)-27

22f

(Z)-27

 7f

7

28

62

a Reaction conditions: trimethylamine (1.0 mmol), allene (1.5 mmol), TiBn4 (0.10 mmol, 10 mol%), LH1 (0.10 mmol, 10 mol%), [Ph3C][B(C6F5)4] (0.08 mmol, 8 mol%), toluene (4.5 mL), 80 °C, 16 h, sealed ampoule (V = 5 mL).

b Unless otherwise noted, yields refer to isolated pure compounds.

c Mixture of two stereoisomers. Prior to flash chromatography, the ratio of the stereoisomers was determined by GC analysis to be 77:23.

d Mixture of two stereoisomers. Prior to flash chromatography, the ratio of the stereoisomers was determined by GC analysis to be 79:21.

e Mixture of two stereoisomers. Prior to flash chromatography, the ratio of the stereoisomers was determined by GC analysis to be 90:10.

f Prior to flash chromatography, the stereoselectivity was determined by GC analysis to be (E)-27/(Z)-27 = 76:24.

Additional reactions of trimethylamine with allenes[15] (Table [1]) also turned out to be successful, and, after a brief ligand screening using cyclonona-1,2-diene as the starting material, it became clear that, as in the case of alkynes, best results were obtained with ligand precursor LH1.[10] A corresponding reaction performed at 80 °C in the presence of 10 mol% TiBn4, 10 mol% LH1, and 8 mol% [Ph3C][B(C6F5)4] delivered the branched hydroaminoalkylation product (E)-22 selectively in 79% yield (Table [1], entry 1). It should be emphasized that, in this case, neither the corresponding Z-stereoisomer nor a linear regioisomer could be detected. Regarding chemoselectivity, an interesting result was then obtained with (Z)-cyclonona-1,2,6-triene (entry 2). Under the employed reaction conditions, the alkene moiety did not show any reactivity and, as a result, a highly selective allene hydroaminoalkylation occurred to give product 23 in 86% yield. The structure of 23 was confirmed unambiguously by single-crystal X-ray diffraction analysis of the corresponding hydrochloride 23·HCl (Figure [3]).[11] The assumption that ring strain is responsible for the stereoselective formation of E-allylamine products from the nine-membered cyclic allenes is strongly supported by the results obtained with cyclotrideca-1,2-diene and the acyclic 1,3-disubstituted allene pentadeca-7,8-diene (entries 3 and 4). In both cases, the allenes delivered the desired branched hydroaminoalkylation products as mixtures of the corresponding E- and Z-stereoisomer in ratios of approximately 4:1 [(E/Z)-24 or (E/Z)-25]. Comparable or even better stereoselectivities (up to 9:1) were observed with monosubstituted allenes (entries 5 and 6) and, in the case of (E)-27 and (Z)-27, the isomers could even be separated by column chromatography and characterized individually. While all the allene hydroaminoalkylation reactions performed so far gave branched products, we were only able to isolate the linear product 28 in 62% yield in the case of the 1,1-disubstituted allene vinylidenecyclohexane (entry 7). However, at the moment, we do not have a reasonable explanation for this result.

Finally, we also performed an initial hydroaminoalkylation of a methylenecyclopropane[15c] with trimethylamine (Scheme [6]), which gave access to the corresponding branched product 29 in 48% yield. In this case, best results were obtained with a reduced catalyst loading of only 5 mol% TiBn4 and LH1 at 60 °C.[10] The relative configuration of 29 was elucidated by single-crystal X-ray diffraction analysis of the corresponding hydrochloride 29·HCl (Figure [4]),[11] and it was found that 29 has the expected cis-orientation of the dimethylaminomethyl substituent and the cyclopropane hydrogen atoms. This finding is in good agreement with closely related DFT-calculations,[16] which have already shown that hydroaminoalkylation of a corresponding methylenecyclopropane with secondary amines can only occur from its convex side.

Zoom Image
Scheme 6 Ti-catalyzed hydroaminoalkylation of a methylenecyclopropane with trimethylamine
Zoom Image
Figure 4 Molecular structure of 29·HCl. Hydrogen atoms (except H1, H1A, and H2) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and angles (°): N1–C11 1.504(2), C9–C10 1.516(2), C9–C11 1.511(2), C11-C9-C1 112.9(1), C11-C9-C2 115.8(1), C1-C9-C2 59.74(9), C9-C1-C2 60.00(9), C9-C2-C1 60.26(9).[11]

In summary, we have shown that α-C–H bond activation of trimethylamine can be achieved efficiently in the presence of titanium catalysts. Taking advantage of this process, trimethylamine can be used as a substrate for C–C bond-forming hydroaminoalkylation reactions with alkenes, alkynes, allenes, and a methylenecyclopropane, which give various dimethylaminomethyl-substituted products directly. Although further optimization is needed to improve regio- and stereoselectivities in certain cases, the highly efficient synthesis of the antidepressant butriptyline strongly underlines the potential of the new reactions.


#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Jessica Reimer for experimental assistance and Kirstin Glaser, Karin Grittner, and Frank Fleischer for supplying the ampoules.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2179-6032.
  • Supporting Information

Corresponding Author

Sven Doye
Institut für Chemie, Universität Oldenburg
Carl-von-Ossietzky-Straße 9–11, 26129 Oldenburg
Germany   

Publication History

Received: 07 July 2023

Accepted after revision: 21 September 2023

Accepted Manuscript online:
21 September 2023

Article published online:
30 October 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Industrial synthesis and commercial applications of methylamines
Zoom Image
Figure 1 Examples of important pharmaceuticals with dimethylaminomethyl substructures (highlighted in red)[4]
Zoom Image
Scheme 2 Ti-catalyzed hydroaminoalkylation reactions of alkynes with trimethylamine. Reaction conditions: trimethylamine (1.0 mmol), alkyne (1.5 mmol), TiBn4 (0.10 mmol, 10 mol%), LH1 (0.10 mmol, 10 mol%), [Ph3C][B(C6F5)4] (0.08 mmol, 8 mol%), toluene (4.5 mL), 80 °C, 72 h, sealed ampoule (V = 5 mL). Unless otherwise noted, yields refer to isolated pure compounds. If applicable, only the major regioisomer is shown. a The regioselectivity was determined by GC analysis prior to flash chromatography. b After chromatographic purification, a mixture of two regioisomers was obtained.
Zoom Image
Figure 2 Molecular structure of (E)-7a·HCl. Hydrogen atoms (except H1, H3, and H10) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and angles (°): N1–C1 1.499(1), C1–C2 1.528(1), C2–C3 1.344(1), Σ(angles)(C2) 360.0, Σ(angles)(C3) 359.9.[11]
Zoom Image
Scheme 3 Ti-catalyzed hydroaminoalkylation reactions of phenylacetylene and (trimethylsilylethinyl)benzene with trimethylamine. a The regioselectivity was determined by GC analysis prior to flash chromatography.
Zoom Image
Scheme 4 Ti-catalyzed hydroaminoalkylation reactions of alkenes with trimethylamine. Reaction conditions: trimethylamine (1.0 mmol), alkene (1.3 mmol or 1.5 mmol), TiBn4 (0.10 mmol, 10 mol%), LH2 (0.10 mmol, 10 mol%), [Ph3C][B(C6F5)4] (0.08 mmol, 8 mol%), toluene (4.5 mL), 70 °C, 24 h, sealed ampoule (V = 5 mL). Unless otherwise noted, yields refer to isolated pure compounds. a Reaction time 16 h. b The product was isolated as a mixture of two diastereoisomers. c The diastereoselectivity was determined by GC analysis prior to flash chromatography. d Reaction time 72 h.
Zoom Image
Scheme 5 Synthesis of butriptyline (21) and molecular structure of 21·HCl. Hydrogen atoms (except H1, H1A, H17, H8A, H8B, H9A, and H9B) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å): N1–C18 1.5040(8), C17–C18 1.5294(9).[11]
Zoom Image
Figure 3 Molecular structure of 23·HCl. Hydrogen atoms (except H1, H2, H5, and H6) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and angles (°): N1–C10 1.507(2), C1–C10 1.505(2), C1–C2 1.339(2), C5–C6 1.330(2), Σ(angles)(C1) 359.8, C1-C2-C3 127.9(2), C4-C5-C6 127.0(2), C5-C6-C7 126.4(2).[11]
Zoom Image
Scheme 6 Ti-catalyzed hydroaminoalkylation of a methylenecyclopropane with trimethylamine
Zoom Image
Figure 4 Molecular structure of 29·HCl. Hydrogen atoms (except H1, H1A, and H2) are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) and angles (°): N1–C11 1.504(2), C9–C10 1.516(2), C9–C11 1.511(2), C11-C9-C1 112.9(1), C11-C9-C2 115.8(1), C1-C9-C2 59.74(9), C9-C1-C2 60.00(9), C9-C2-C1 60.26(9).[11]