Carbon-nitrogen bond formation via catalytic alcohol activation
Yan, Tao
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Chapter 3
Benzylamines via iron catalyzed direct amination of benzyl alcohols
Benzylamines play a prominent role in numerous pharmaceutically active compounds. Thus, the development of novel, sustainable catalytic methodologies to provide access to these privileged structural motifs is of central importance. Herein we describe the use of a well-defined homogeneous iron-complex for the construction of a large variety of benzylamines. The methodology consists of the direct coupling of readily available benzyl alcohols with simple amines through the borrowing hydrogen methodology. A variety of substituted secondary and tertiary benzylamines are obtained in moderate to excellent yields. Furthermore, we explore the versatility of this methodology in the one-pot synthesis of asymmetric tertiary amines, sequential functionalization of diols and the synthesis of N-benzyl piperidines, for the first time with an iron catalyst. In addition, direct conversion of renewable building block 2,5-furan-dimethanol to pharmaceutically relevant compounds is achieved.
Part of this chapter was published:
Introduction
Benzylamines are frequently encountered motifs in biological systems, and are highly valuable targets due to their versatility[1] (Scheme 1). Many pharmaceuticals contain a benzylamine moiety. Prominent examples include Rivastigmine[1b], a cholinergic agent for treating dementia due to Parkinson’s disease; Ezetimibe[1c], a drug that helps reducing plasma cholesterol levels; and Emend[1d], an aprepitant that blocks the neurokinin 1 (NK1) receptor. Developing efficient pathways that allow for selective synthesis of benzylamines, especially starting from readily available substrates using sustainable catalysts based on non-toxic and inexpensive metals is an important goal[2-4].
Scheme 1: Benzylamine based bio-active compounds.
Methods for the synthesis of benzylamine derivatives are shown in Scheme 2, A and B. Catalytic hydroamination of alkenes or alkynes is an efficient way to access 1-methyl-benzylamines.[2] Furthermore, benzylation of amines with benzyl-halides
via nucleophilic substitution[3] leads to the formation of stoichiometric amounts of waste. Reductive amination[4] is a catalytic and atom-economic alternative, however here the aldehyde reaction partner is usually unstable and frequently generates side-products.
Among these methods, direct amination of benzyl alcohols is a preferred method because these substrates are readily available and can even be obtained from renewable resources[5,6], making this route a highly sustainable alternative. However, direct nucleophilic substitution of the hydroxyl group of benzyl alcohols with amines is an energy and cost intensive process[7,8], while, installing a good leaving group instead of the hydroxyl functionality will suffer from low atom-efficiency. The desired, catalytic way to perform the direct coupling of benzyl alcohols with amines involves the borrowing hydrogen[9] strategy (Scheme 2, C). In this case, a specific sequence of reaction steps will occur: dehydrogenation of the alcohol to aldehyde (step a), imine formation (step b) reduction of imine (step c), which maintains high atom-efficiency[10] while requiring much lower activation
energy[9c]. Additionally, this method provides innocuous water as the only side product.
Scheme 2: Comparison of synthetic pathway to access benzylamine derivatives.
A Hydroamination of styrene with amine. B Comparison of amination of benzyl alcohols, benzyl halides and benzyl aldehydes. C Catalytic amination of alcohols through borrowing hydrogen.
Since the first examples of catalytic amination of alcohols through borrowing hydrogen reported by Grigg[11] and Watanabe[12] in 1981, considerable progress has been made in this area[13]. However, mostly precious metal catalysts containing ruthenium[14] or iridium[15] were used. Cheap, low-toxic and abundant transition metals like iron, have been only scarcely used for this transformation[16,18,19]. In Chapter 2, the first example of direct amination of alcohols catalyzed by a well-defined iron[17] complex through the borrowing hydrogen strategy is described.[18] This work focused on the use of diverse aromatic amines and aliphatic alcohols and diols. Two examples were also included using benzyl alcohol as substrate, however, these reactions suffered from rather low yields. Very recently, Wills and coworkers also reported on the iron catalyzed amination of alcohols[19a]. They observed no product formation when benzylamine was employed as the reaction partner. Later, Zhao and coworkers reported iron catalyzed amination of secondary alcohols with assistance of 0.4 equiv AgF[19b]. However, only a limited number of examples have been reported on the use of benzyl alcohols.
Here, a highly versatile method for the synthesis of a large variety of benzylamines through direct iron catalyzed amination of benzyl alcohols is presented. In addition to the impressive scope, important novel aspects are the one-pot synthesis of asymmetric tertiary amines as well as uncovering the reactivity trends in the sequential functionalization of benzyl alcohols. Moreover, a fully sustainable, two
step pathways from a cellulosic platform chemical to a pharmaceutically active compound is described.
Results and discussion
Optimization of reaction conditions 4-Methylbenzyl alcohol (1a) and morpholine (2a) were selected as the starting materials for optimization of the reaction conditions for direct coupling of benzyl alcohols with secondary amines (Table 1). Using the previously reported conditions[18] with additional assistance of molecular sieves, only 39% conversion was obtained (Table 1, entry 1). A solvent screening showed, that etherate solvents like tetrahydrofuran (THF) and dioxane gave low conversions (33% and 30%, respectively, Table 1, entry 2-3). Dichloroethane (DCE) gave full conversion but the desired product (3a) was not detected presumably due to nucleophilic substitution of the solvent (DCE) with morpholine (2a) (Table 1, entry 4). More polar solvents like acetonitrile and dimethylformamide (DMF) gave very poor conversion (Table 1, entry 5-6). In toluene, 64% conversion was obtained (Table 1, entry 7). When other iron sources such as FeCl3, Fe2(CO)9, and iron(II) phtalocyanine were applied instead of Cat 3, the conversions were unsatisfactory (Table 1, entries 8−10). Using Cat 3, the conversion improved to 87% when the temperature was increased to 135 °C in toluene, probably due to the acceleration of imine reduction (Table 1, entry 11). Similar results were obtained in CPME at 135 °C (82%, Table 1, entry 12). Increasing the loading of 1a to 2 mmol in toluene gave full conversion and an 87% isolated yield of 3a (Table 1, entry 13).
Table 1: Optimization of reaction conditions for amination of 4-methylbenzyl alcohol (1a) with morpholine (2a).
Entry 1a [mmol] Solvent T [°C] Conversion [%]
1 1 CPME 130 39 2 1 THF 130 33 3 1 Dioxane 130 30 4 1 DCE 130 >95a 5 1 CH3CN 130 <5 6 1 DMF 130 <5 7 1 Toluene 130 64 8b 1 Toluene 130 <5 9c 1 Toluene 130 <5 10d 1 Toluene 130 <5 11 1 Toluene 135 87 12 1 CPME 135 82 13 2 Toluene 135 >95 (87)
General reaction conditions: General procedure, 0.5 mmol 2a, 1 or 2 mmol 1a, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 2 ml solvent, 18 h, 130 or 135 °C, 95-105 mg molecular sieves, unless otherwise specified, isolated yield shown in parenthesis, conversion was determined by GC-FID using decane as the internal standard; aNo 3a has been observed based on
GC-mol% FeCl3 instead of Cat 3 and Me3NO; c2 mol% Fe2(CO)9 instead of Cat 3 and Me3NO;
d4 mol% Iron(II) phthalocyanine instead of Cat 3 and Me3NO.
Reactions of benzyl alcohols with secondary amines Next, under optimized reaction conditions, a variety of secondary amines and benzyl alcohols were tested (Table 2). Benzyl alcohol 1b with an electron-donating –OCH3 substituent reacted smoothly with 2a providing full conversion and 88% isolated yield of 3b (Table 2, entry 1). When less electron-rich substrates 1c and 1d were employed, lower reactivity was observed; 60% of 3c and 40% of 3d were isolated after 18 and 24 h reaction time, respectively (Table 2, entry 3). Interestingly, also for 2-thiophenemethanol (1e), a high isolated yield (74%) of 3e was obtained (Table 2, entry 4). For other secondary amines, such as 1-methyl-piperazine (2b), piperazine (2c) and di-n-butyl-amine (2d), the corresponding products were also obtained in good to excellent yields (Table 2, entry 5-9). Interestingly, when piperazine (2c), which has two reactive -NH sides, was tested with 2 mmol (4 equiv) of 1c under the general conditions (Table 2), 35% of mono N-benzylation and 55% of di-N-benzylation product was obtained. By increasing the amount of 1c to 3 mmol (6 equiv), the di-N-benzylation product (3h) was obtained in 90% isolated yield (Table 2, entry 7).
Table 2: Amination of benzyl alcohols with secondary amines.
Entry Substrate 1 Product 3 Yield [%]
1 1b 3b 88 2 1c 3c 60 3a 1d 3d 40 4a 1e 3e 74 5b 1a 3f 78 6 1f 3g 69 7cde 1c 3h 90 8cde 1e 3i 80 9a 1a 3j 65 10 1a 3k 91
11a 1d 3l 63
12a 1g 3m 69
13 1a 3n 89
14a 1e 3o 79
15a 1h 3p 59
General reaction conditions: General procedure, 0.5 mmol 2, 2 mmol 1a, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 135 °C, 95-105 mg molecular sieves, isolated yields are shown; a24 h; b0.03 mmol Cat 3 and 0.06 mmol Me3NO were employed; c3
mmol 1 was employed.
Next, secondary benzylic amines, which are less basic compared to secondary aliphatic amines[20], were used as the substrate (Table 2). N-methyl benzylamine (2e) reacted smoothly with 1a, 1d, 1g and the corresponding products were obtained in good to excellent yields (Table 2, entry 10–12). Similarly the reaction of 1,2,3,4-tetrahydroisoquinoline (2f) with alcohols 1a, 1e, 1h provided the corresponding products in high yields (Table 2, entry 13–15). Remarkably, alcohols, which possess hetero-aromatic moieties such as 1e and 1h, which have the possibility to act as chelating ligands[21], could also be used as shown in various entries in Table 2, and products 3e, 3i, 3o and 3p were obtained in good to excellent yield.
Reactions of benzyl alcohols with primary amines The synthesis of mono-N-alkylated benzylamines from the corresponding primary benzylamines and aliphatic alcohols was described in our previous work[18], which is also shown in chapter 2. Here we demonstrate a new alternative route to the same products, starting from benzyl alcohols and aliphatic amines (Table 3), which to the best of our knowledge has not been previously reported with any iron catalyst and allows great synthetic flexibility for the selection of the substrates and more insight into the reaction mechanism.
First, n-pentylamine (4a) was selected for the synthesis of a variety of functionalized benzyl alcohols (Table 3, entry 1–6). Selectivity towards the mono-alkylation products was sensitive to the amount of alcohol substrate added. For example, 2 equiv loading of 4-methoxybenzyl alcohol (1b) lead to preferential formation and 54% isolated yield of 5a (Table 3, entry 1), however further increasing 1b loading lead to more dialkylation product. On the other hand, only using 1.5 eq. of 1b, the corresponding imine was detected as the major product. The same behavior was observed with 4-methylbenzyl alcohol (1a). In addition, increasing Cat 3 loading to 6 mol% provided 61% isolated yield of 5b (Table 3, entry 2).
Table 3: Amination of benzyl alcohols with primary amines.
Entry Substrat 1 Product 5 Yield [%]b
1a 1b 5a 54 2a 1a 5b 61 3 1c 5c 59 4 1g 5d 53 5bc 1i 5e 42d 6bc 1j 5f 22e 7 1c 5g 60 8 1c 5h 61 9bc 1f 5i 60 10b 1a 5j 70 11bc 1a 5k 66 12bc 1c 5l 56
General reaction conditions: General procedure, 0.5 mmol 2, 2 mmol 1a, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 135 °C, 95-105 mg molecular sieves, isolated yields are shown. a1 mmol 1 was employed; b0.03 mmol Cat 3 and 0.06 mmol Me3NO
were employed; c24 h; d41% of corresponding was observed based on GC-FID integration; e58% of corresponding was observed based on GC-FID integration.
Interestingly, when less electron-rich substrates such as benzyl alcohol (1c) and 4-fluorobenzyl alcohol (1g) were examined, less di-N-benzylation product was observed and 59% and 53% of mono-N-benzylation products were isolated, respectively (Table 3, entry 3-4).
The reaction of 3-chlorobenzyl alcohol (1i) and 3-trifluoromethylbenzyl alcohol (1j) with n-pentylamine (4a) (Table 3, entry 5-6) was examined as comparison with our previous approach[18] that used 3-chloro and 3-trifluoromethyl substituted benzylamines. In the present case, both reactions provided preferentially imine. Increasing the catalyst loading to 6 mol% and reaction time to 24 h, provided more amine product 5e, but still low amount of desired amine 5f (Table 3, entry 5-6). Increasing the reaction temperature to 140 °C in order to facilitate imine reduction resulted in catalyst decomposition.
Scheme 3: Reactivity difference through different substrates.
In our previous study[18], electron-deficient benzylamines were more reactive towards mono-alkylation than their electron rich analogues. The results shown here, however, conclude that N-alkylated benzylamines are more readily obtained starting from electron-rich benzyl alcohols than from electron poor benzyl alcohols (Scheme 3). The reason for this reactivity difference can likely be attributed to differences in the rate of the imine reduction step.[22] It has to be noted that the imine intermediates formed from benzyl alcohols will possess a double bond in conjugation with the aromatic system (Scheme 3, Pathway A) and those formed from benzyl amines will not (Scheme 3, Pathway B). These reactivity differences under similar conditions, also show that isomerization of the imine double bond is not likely. The detailed understanding of these mechanistic details and rate limiting steps will be subject of future in depth studies.
Next, a series of other primary amines were tested as substrates (Table 3, Entry 7-12). Long chain amines like n-nonylamine (4b) and 2-phenylethamine (4c) were benzylated with benzyl alcohol (1c) providing 5g and 5h in good isolated yields (Table 3, entry 7-8). Furthermore, primary benzylamines and anilines could be applied to readily provide 5k and 5l (Table 3, entry 9–12).
Three component synthesis of asymmetric benzylic tertiary amines Taking advantage of the differences in reactivity between aliphatic and benzyl alcohols, we have developed a straightforward approach for the direct three component synthesis of asymmetric benzylic tertiary amines (Table 4). To this end, a method using benzyl alcohol (1c), n-pentylamine (4a) and n-butanol (8a) was implemented with 6 mol% Cat 3 loading, at 135 °C (Table 4, entry 1-3). Gratifyingly, the desired non-symmetric N-n-butyl-N-n-pentylbenzylamine (9a) was predominant in the reaction mixture that also contained smaller amounts of the expected di-N-benzyl-n-pentylamine (10a), and di-N-n-butyl-n-pentylamine (11a). The desired tertiary amine with three distinctly different alkyl moieties 9a was isolated in 51% yield (Table 4, entry 1). The one-pot procedure was extended
to the synthesis of other non-symmetric tertiary amines 9b and 9c (Table 4, entry 4–6).
Table 4: Three component synthesis of asymmetric benzylic tertiary amines.
Entry 1 / mmol 8a /
mmol Sel. 9 [%] Sel. 10 [%] Sel. 11 [%]
1 1c / 2 R = H 1.5 9a 64 (51) 7 21 2 1c / 1.5 R = H 2 9a 56 13 31 3 1c / 2 R = H 1 9a 47 21 12 4 1g / 2 R = 4-F 1.5 9b 49 (40) 4 28 5 1g / 0.75 R = 4-F 2 9b 23 1 51 6a 1b / 1 R = 4-OMe 1 9c 61 (43) 15 20
General reaction conditions: General procedure, 0.5 mmol 4a, 0.75-2 mmol 1, 1 or 1.5 mmol 8a, 0.03 mmol Cat 3, 0.06 mmol Me3NO, 2 ml toluene, 24 h, 135 °C, 195-205 mg molecular sieves, conversion and selectivity are based on GC-FID integration, isolated yields in parenthesis, unless specified; an-hexanol was used instead of n-butanol, hexyl-
group was formed instead of butyl- group.
Sequential functionalization of diols to obtain diverse diamines Sequential functionalization of diols is undoubtedly a valuable synthetic tool to obtain com-pounds with great diversity. Here we present, for the first time, a selective iron catalyzed method that allows for the preparation a non-symmetric functionalized diamines. This reaction sequence was demonstrated on the preparation of compound 14 whereby diol 12a was selectively mono-alkylated with 2a forming 13a. This was followed by amination of 13a with 2e to provide 14. (Scheme 4) Scheme 4: Sequential functionalization of diols.a
Condition a: General procedure, 0.5 mmol 2a, 1.5 mmol 12a, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 135 °C, 2 ml toluene, 18 h, 95-105 mg molecular sieves. 63% of 13a was isolated. Condition b: General procedure, 0.5 mmol 2e, 1 mmol 13a, 0.03 mmol Cat 3, 0.06 mmol Me3NO, 135 °C, 2 ml toluene, 18 h, 95-105 mg molecular sieves. 30% of 14
Diverse approaches to N-benzyl piperidines N-hetercycles are compounds of major interest due to their prominent role in bio-active compounds e.g. pharmaceuticals and agrochemicals.[23] In chapter 2, the direct synthesis of benzyl-protected five, six, and seven membered-heterocycles from benzylamines and diols has been shown.[18]
Scheme 5: A Retro-synthetic analysis of N-benzyl piperidines; B diverse approaches for synthesizing N-benzyl piperidines.a
aGeneral reaction conditions: General Procedure, 0.5 mmol 15a or 15b, 2 mmol 1, 0.02
mmol Cat 3, 0.04 mmol Me3NO, 135 °C, 2 ml toluene, 18 h, 95-105 mg molecular sieves, isolated yield are shown, unless otherwise specified; a24 h; byields were calculated based
on GC-FID using decane as the internal standard; c0.5 mmol 1c’, 1 mmol 15c’ were
Here, we have investigated versatile synthesis routes for the preparation of N-benzyl piperidines as representative example for N-benzyl protected N-heterocycles, illustrated in Scheme 5. The same N-benzyl piperidine 16 can be obtained via three distinct routes, starting from different substrates. For example, 16 can be synthesized from three sets of substrates through four pathways (Scheme 5, A). N-benzyl piperidine 16 can be obtained from benzyl alcohol (1) and piperidine (15a) through the formation of bond a (Scheme 5, A, Pathway 1). Alternatively, compound 16 can be obtained from alcohol 1 and 5-amino-1-pentanol (15b) through the sequential formation of bonds a and b (Scheme 5, A, Pathway 2a), or b and a (Scheme 5, A, Pathway 2b). Also, N-benzyl piperidine 16 can be synthesized starting from 1,5-pentanediol (15c’) and benzyl amine 1c’ during which bonds b and c are formed (Scheme 5, A, Pathway 3). These substrate variations allow for choosing the most suitable pathway[24] taking into account optimal balance of reactivity, selectivity and substrate abundance. In order to show the power of this method, N-benzyl piperidines 16a, 16b, 16c and 16d were synthesized through different pathways, with good to excellent yields (Scheme 5, B).
Scheme 6: Synthesis of key intermediate to muscarinic agonist, N-[5-([l'-substituted-acetoxy)methyl]-2-furfurylldialkylamines.
General reaction condition: General Procedure, 0.5 mmol 2e, 2 mmol 12b, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 135 °C, 2 ml toluene, 24 h, 95-105 mg molecular sieves. 60% of 13b was isolated.
From cellulose derived platform chemicals to pharmaceutically active molecules It was reported that furanic compounds of the general structure 18 shown on Scheme 6 are a class of pharmaceutically active compounds possessing potential antimuscarinic activity. Pharmaceutical studies have especially focused on systematic modifications on variations in the ester- and amine side chains.[25] Here we show an efficient and fully sustainable synthetic strategy towards obtaining key intermediate 13b. This compound can be prepared directly from benzyl amine derivative 2e and diol 12b using our iron catalyzed methodology. Diol 12b used in this reaction can be obtained in high yield from 5-(hydroxymethyl)furfural (HMF, 17), via a sustainable pathway we have recently reported[26]. In this procedure, HMF, which is one of the most important cellulose derived platform chemicals undergoes catalytic hydrogenation using robust, CuZn
easy, waste free synthesis of key bioactive intermediate 13b in 60% yield from renewable resources, using sustainable catalysis.
Conclusion
In conclusion, we have established, for the first time, general methodology for the catalytic formation of value-added benzylamines through amination of benzyl alcohols using a well-defined iron catalyst that operates through a hydrogen borrowing mechanism. Many synthetically challenging routes were systematically explored, starting from readily accessible substrates that do not require prior alcohol activation by stoichiometric methods. This included the one-pot synthesis of asymmetric tertiary amines, the sequential functionalization of diols, and the synthesis of important synthons, for example, N-benzylpiperidines, through diverse synthetic pathways. In addition, direct conversion of the renewable building block 2,5-furan-dimethanol to pharmaceutically relevant compounds was achieved with unprecedented simplicity.
Experimental section
General methods
Chromatography: Merck silica gel type 9385 230-400 mesh or Merck Al2O3 90 active neutral, TLC: Merck silica gel 60, 0.25 mm or Al2O3 60 F254 neutral. Components were visualized by UV, Ninhydrin or I2 staining. Progress of the reactions was determined by GC-MS (GC: HP 6890, MS: HP 5973) with an HP012 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). Conversions were determined by GC-FID (GC: HP 6890) with an HP-5 column (Agilent Technologies, Palo Alto, CA). GC-MS and GC-FID analysis method: 60 °C 5 min, 180 °C 5 min (10 °C/min), 260 °C 5 min (10 °C/min). 1H- and 13C NMR spectra were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration. All reactions were carried out under an Argon atmosphere using oven (110 °C) dried glassware and using standard Schlenk techniques. THF and toluene were collected from a MBRAUN solvent purification system (MB SPS-800). Dioxane (99.5%, extra dry), dichloroethane (DCE, 99.8%, extra dry), N,N-dimethylformamide (DMF, 99.8%, extra dry) and acetonitrile (CH3CN, 99.9%, extra dry) were purchased from Acros without further purification. Molecular sieves 4A were purchased from Acros, and heated in a Schlenck flask under 180 °C in vacuo overnight for activation before using. All other reagents were purchased from Sigma or Acros in reagent or higher grade and were used without further purification. Complex Cat 3 was synthesized according to literature procedures[27] with slight modifications. The synthesis of Cat 3 was carried out as described in Chapter 2.
Representative procedures
General procedure An oven-dried 20 ml Schlenk tube, equipped with a stirring bar, was charged with amine (0.5 mmol, 1 equiv), alcohol (given amount), iron complex Cat 3 (4–6 mol%), Me3NO (8–12 mol%) and toluene (solvent, 2 ml). The solid starting materials were added into the Schlenk tube under air, the Schlenk tube was subsequently connected to an argon line and a vacuum-argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream followed by addition of 95–105 mg activated molecular sieves 4A. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then it was placed into a pre-heated oil bath at the appropriate temperature and stirred for a given time. The reaction mixture was cooled down to room temperature and the crude mixture was filtered through celite, eluted with ethyl acetate, and concentrated in vacuo. The residue was purified by flash column chromatography to provide the pure amine product.
Reagents and characterization methods Reagents were of commercial grade and used as received, unless stated otherwise. Chromatography: Merck silica gel type 9385 230-400 mesh or Merck Al2O3 90 active neutral, TLC: Merck silica gel 60, 0.25 mm or Al2O3 60 F254 neutral. Components were visualized by UV, Ninhydrin or I2 staining. 1H- and 13C NMR spectra were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration.
Procedure of amination of 4-methoxybenzyl alcohol (1b) with morpholine (2a) provides 3b: An oven-dried 20 ml Schlenk tube, equipped with a stirring bar, was charged with 4-methoxybenzyl alcohol (2 mmol, 0.276 g), iron complex Cat 3 (4 mol%, 8 mg) and Me3NO (8 mol%, 3 mg) under air. The Schlenk tube was subsequently connected to an argon line and a vacuum-argon exchange was performed three times. Morpholine (0.5 mmol, 0.044 g), and toluene (solvent, 2 ml) were charged under an argon stream followed by addition of 95–105 mg activated molecular sieves 4A. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 135 °C and stirred for 18 h. The reaction mixture was cooled down to room temperature and the crude mixture was filtered through celite, eluted with ethyl acetate, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50) to provide the pure amine product 3b (0.091 g, 88% isolated yield).
Spectral data of isolated compounds
4-(4-Methylbenzyl)morpholine (3a): Synthesized according to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3a (0.083 g, 87% yield). Light yellow solid obtained after column chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 3.70 (t. J = 7.9 Hz, 4H),
3.47 (s, 2H), 2.36 – 2.51 (m, 4H), 2.34 (s, 3H). 13C NMR (100 MHz, CD3OD) δ 138.22, 134.90, 130.71, 129.93, 67.64, 64.08, 54.55, 21.15. The physical data were identical in all respects to those previously reported.[28]
4-(4-Methoxybenzyl)morpholine (3b): Synthesized according to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3b (0.091 g, 88% yield). Yellow oil obtained after column chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.26 (m, 2H), 6.18 – 6.90 (m, 2H), 3.79 (s, 3H), 3.70 (t, J = 4.7 Hz, 4H), 3.44 (s, 2H), 2.42 (t, J = 4.5 Hz, 4H. 13C NMR (100 MHz, CDCl
3) δ
158.73, 130.35, 129.52, 113.55, 66.91, 62.76, 55.18, 53.44. The physical data were identical in all respects to those previously reported.[28]
4-Benzylmorpholine (3c): Synthesized according to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3c (0.053 g, 60% yield). Yellow oil obtained after column chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CD2Cl2) δ 7.10 – 7.45 (m, 5H), 3.65 (t, J = 4.7 Hz, 4H), 3.48 (s, 2H), 2.35 – 2.46 (m, 4H).
13C NMR (100 MHz, CD2Cl2) δ 138.57 129.50, 128.53, 127.37, 67.33, 63.68, 54.06. The physical data were identical in all respects to those previously reported.[29]
4-(4-Chlorobenzyl)morpholine (3d): Synthesized according to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3d (0.042 g, 40% yield). Yellow oil obtained after column chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CD2Cl2) δ 7.21 – 7.37 (m, 4H), 3.57 – 3.74 (m, 4H), 3.45 (s, 2H), 2.26 – 2.51 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 136.17, 132.89, 130.42, 128.40, 66.89, 62.58,
53.50. The physical data were identical in all respects to those previously reported.[29]
4-(Thiophen-2-ylmethyl)morpholine (3e): Synthesized according to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3e (0.068 g, 74% yield). Yellow oil obtained after column chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.19
– 7.25 (m, 1H), 6.86 – 7.00 (m, 2H), 3.69 – 3.74 (m, 6H), 2.44 – 2.53 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 141.15, 128.05, 127.53, 126.47, 67.72, 58.07, 54.25. The physical data were identical in all respects to those previously reported.[29]
1-Methyl-4-(4-methylbenzyl)piperazine (3f): Synthesized according to General procedure. 1-Methylpiperazine (0.050 g, 0.50 mmol) affords 3f (0.081 g, 79% yield).Yellow oil obtained after column chromatography (SiO2, EtOAc/MeOH 100:0 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 3.46
(s, 2H), 2.20 – 2.70 (br.s, 8H), 2.33 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.52, 134.97, 129.11, 128.80, 62.71, 55.05, 52.97, 45.96, 21.05. The physical data were identical in all respects to those previously reported.[30] HRMS (APCI+, m/z): calculated for C13H21N2 [M+H]+: 205.16993; found: 205.16999.
1-Methyl-4-piperonyl piperazine (3g): Synthesized according to General procedure. 1-Methylpiperazine (0.050 g, 0.50 mmol) affords 3g (0.081 g, 69% yield). Yellow oil obtained after column chromatography (SiO2, EtOAc/MeOH 100:0 to 90:10). 1H NMR (400 MHz, CDCl3) δ 6.83 (s, 1H), 6.58 – 6.79 (m, 2H), 5.91 (s, 2H), 3.39 (s, 2H), 2.15 – 2.70 (br.s, 8H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl
3)
δ 147.51, 146.47, 132.00, 122.14, 107.74, 100.77, 62.64, 55.02, 52.80, 45.91. The physical data were identical in all respects to those previously reported.[31]
1,4-Dibenzylpiperazine (3h): Synthesized according to General procedure. Piperazine (0.043 g, 0.50 mmol) affords 3h (0.120 g, 90% yield). Yellow solid obtained after column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CD2Cl2) δ 7.27 – 7.55 (m, 8H), 7.07 – 7.27 (m,
2H), 3.49 (s, 4H), 2.26 – 2.63 (br.s, 8H). 13C NMR (100 MHz, CDCl3) δ 138.02, 129.19, 128.13, 126.95, 63.02, 53.00. The physical data were identical in all respects to those previously reported.[32]
1,4-Bis(thiophen-2-ylmethyl)piperazine (3i): Synthesized according to General procedure. Piperazine (0.043 g, 0.50 mmol) affords 3i (0.095 g, 68% yield). Brown solid obtained after column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.18 - 7.26 (m, 2H), 6.93 – 9.97 (m,
2H), 6.88 – 6.93 (m, 2H), 3.73 (s, 4H), 2.27 – 2.83 (br.s, 8H). 13C NMR (100 MHz, CDCl3) δ 141.23, 126.38, 126.13, 124.99, 56.94, 52.60. HRMS (APCI+, m/z): calculated for C14H19N2S2 [M+H]+: 279.09842; found: 279.09850.
Di-N-n-butyl-4-methylbenzylamine (3j): Synthesized according to General procedure. Di-n-butylamine (0.065 g, 0.50 mmol) affords 3j (0.076 g, 65% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 3.53 (s, 2H), 2.41 (t, J = 7.3 Hz, 4H), 2.35 (s, 3H), 1.40 – 1.55 (m, 4H), 1.25 – 1.37 (m, 4H), 0.90 (t, J = 7.3 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ 136.93, 136.03, 128.74, 128.70, 58.16, 53.39, 29.15, 21.07, 20.07, 20.61, 14.09. HRMS (APCI+, m/z): calculated for C16H28N [M+H]+: 234.22163; found: 234.22173.
N-benzyl-N-methyl-4-methylbenzylamine (3k): Synthesized according to General procedure.
N-Methylbenzylamine (0.061 g, 0.50 mmol) affords 3k (0.102 g, 91% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.44 (m, 4H), 7.23 – 7.28 (m, 3H), 7.08 – 7.17 (m, 2H), 3.52 (s, 2H), 3.51 (s, 2H), 2.34 (s, 3H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 139.17, 136.50, 135.99, 128.95, 128.91, 128.90, 128.19, 126.91, 61.69, 61.55, 42.11, 21.10. The physical data were identical in all respects to those previously reported.[33]
N-benzyl-N-methyl-4-chlorobenzylamine (3l):
Synthesized according to General procedure.
N-Methylbenzylamine (0.061 g, 0.50 mmol) affords 3l (0.077 g, 63% yield). Orange solid obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.50 (m, 2H), 3.54 (s, 2H), 3.50 (s, 2H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl
3) δ 138.90, 137.73, 132.55, 130.15, 128.86, 128.24, 128.23, 127.02, 61.77, 60.95, 42.12. HRMS (APCI+, m/z): calculated for C15H17ClN [M+H]+: 246.10440; found: 246.10451.
N-benzyl-N-methyl-4fluorobenzylamine (3m):
Synthesized according to General procedure. N-Methylbenzylamine (0.061 g, 0.50 mmol) affords 3m (0.079
g, 69% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.52 (m, 6H), 7.23 – 7.31 (m, 1H), 6.95 – 7.10 (m, 2H), 3.54 (s, 2H), 3.50 (s, 2H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.88 (d, J = 244.6 Hz), 139.12, 134.96 (d, J = 3.1 Hz), 130.29 (d, J = 7.7 Hz), 128.85, 128.21, 126.96, 114.95 (d, J = 21.1 Hz), 61.77, 60.95, 42.10. The physical data were identical in all respects to those previously reported.[33]
2-(4-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (3n): Synthesized according to General procedure. 1,2,3,4-Tetrahydroisoquinoline (0.067 g, 0.50 mmol) affords 3n (0.106
g, 89% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.27 – 7.35 (m, 2H), 7.15 – 7.21 (m, 2H), 7.03 – 7.15 (m, 3H), 6.97 – 7.03 (m, 1H), 3.67 (s, 2H), 3.65 (s, 2H), 2.91 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.68, 135.15, 134.85, 134.35, 129.05, 128.95, 128.65, 126.58, 126.03, 125.51. 62.46, 56.04, 50.51, 29.09, 21.12. The physical data were identical in all respects to those previously reported.[34]
2-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (3o): Synthesized according to General procedure.
1,2,3,4-Tetrahydroisoquinoline (0.067 g, 0.50 mmol) affords 3o (0.090 g, 79% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5).1H NMR (400 MHz, CDCl3) δ 7.24 - 7.32 (m, 1H), δ 7.05 – 7.23 (m, 3H), 6.90 – 7.04 (m, 3H), 3.93 (s, 2H), 3.72 (s, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.81 (t,
126.57, 126.41, 126.08, 125.94, 125.56, 125.03, 56.76, 55.68, 50.22, 29.04. The physical data were identical in all respects to those previously reported.[35]
2-((5-methylfuran-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (3p): Synthesized according to General procedure. 1,2,3,4-Tetrahydroisoquinoline (0.067 g, 0.50
mmol) affords 3p (0.067 g, 59% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.05 – 7.20 (m, 3H), 6.96 – 7.04 (m, 1H), 6.15 (d, J = 3.0 Hz, 1H), 5.80 – 6.03 (m, 1H), 3.67 (s, 4H), 2.93 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 151.94, 149.72, 134.57, 134.13, 128.55, 126.53, 126.01, 125.48, 109.64, 105.88, 77.32, 76.68, 55.47, 54.62, 50.26, 28.89, 13.68. HRMS (APCI+, m/z): calculated for C15H18NO [M+H]+: 228.13829; found: 228.13844.
N-n-Pentyl-4-methoxybenzylamine (5a): Synthesized
according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5a (0.056 g, 54% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl
3) δ 7.24 (d, J = 8.5 Hz, 2H), 6.86 (d, J =
8.6 Hz, 2H), 3.79 (s, 3H), 3.73 (s, 2H), 2.61 (t, J = 7.3 Hz, 2H), 1.87 – 2.03 (br.s, 1H), 1.44 – 1.61 (m, 2H), 1.17 – 1.39 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 158.57, 132.27, 129.30, 113.71, 55.18, 53.31, 49.23, 29.57, 29.50, 22.55, 13.99. The physical data were identical in all respects to those previously reported.[36]
N-n-Pentyl-4-methylbenzylamine (5b): Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5b (0.058 g, 61% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.8 Hz,
2H), 3.76 (s, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.34 (s, 3H), 2.10 – 2.20 (br.s, 1H), 1.46 – 1.60 (m, 2H), 1.24 – 1.38 (m, 4H), 0.90 (t, J = 6.80 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 136.92, 136.45, 129.00, 128.10, 53.57, 49.21, 29.52, 29.48, 22.54, 21.02, 13.99. The physical data were identical in all respects to those previously reported.[36]
N-n-Pentyl-benzylamine (5c): Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5c (0.052 g, 59% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz,
CD2Cl2) δ 7.26 – 7.37 (m, 4H), 7.16 – 7.26 (m, 1H), 3.77 (s, 2H), 2.61 (t, J = 7.2 Hz, 2H), 1.57 – 1.80 (br.s, 1H), 1.45 – 1.55 (m, 2H), 1.27 – 1.36 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CD2Cl2) δ 141.46, 128.62, 128.45, 127.07, 54.33, 49.89, 30.24, 30.01, 23.07, 14.27. The physical data were identical in all respects to those previously reported.[36]
N-n-Pentyl-4-fluorobenzylamine (5d): Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5d (0.052 g, 52% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.42 (m, 2H), 6.80 – 7.15 (m, 2H), 3.75 (s, 2H) 2.60 (t, J = 7.3 Hz, 2H), 1.53 – 1.65 (br.s, 1H), 1.42 – 1.57 (m, 4H), 1.20 – 1.40 (m, 4H), 0.89 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8 (d, J = 244.5 Hz) 136.1 (d, J = 3.4 Hz), 129.6 (d, J = 7.9 Hz), 115.1 (d, J = 21.1 Hz), 77.00, 53.26, 49.38, 29.69, 29.51, 22.58, 14.03. HRMS (APCI+, m/z): calculated for C12H19FN [M+H]+: 196.14960; found: 196.14961.
N-n-Pentyl-3-chloro-benzylamine (5e): Synthesized
according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5e (0.044 g, 42% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl 3) δ 7.32 (s, 1H), 7.06 – 7.25 (m, 3H), 3.76 (s, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.59 – 1.70 (br.s, 1H), 1.45 – 1.55 (m, 2H), 1.27 – 1.35 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl 3) δ 142.50, 134.17, 129.56, 128.14, 126.98, 126.16, 53.40, 49.37, 29.67, 29.46, 22.56, 14.01. The physical data were identical in all respects to those previously reported.[18]
N-n-Pentyl-3-trifluoromethylbenzylamine (5f): Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5f (0.27 g, 22% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100).
1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.46 – 7.56 (m, 2H), 7.37 – 7.46 (m, 1H), 3.84 (s, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.06 – 2.21 (br.s, 1H), 1.45 – 1.57 (m, 2H), 1.26 – 1.35 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 141.31, 131.44, 130.66 (q, J = 32.3 Hz), 128.72, 124.79 (q, J = 3.7 Hz), 124.20 (d, J = 272.2 Hz), 123.73 (q, J = 3.8 Hz), 53.41, 49.39, 29.61, 29.46, 22.55, 13.98. The physical data were identical in all respects to those previously reported.[18]
N-Benzyl-n-nonylamine (5g): Synthesized according to General procedure. n-Nonylamine (0.072 g, 0.50 mmol) affords 5g (0.070 g, 60% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl
3) δ 7.29 –
7.43 (m, 4H), 7.22 – 7.28 (m, 1H), 3.81 (s, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.32 – 2.42 (br.s, 1H), 1.46 – 1.60 (m, 2H), 1.05 – 1.42 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 139.72, 128.35, 128.22, 126.97, 53.73, 49.18, 31.83, 29.72, 29.51, 29.49, 29.23, 27.28, 22.62, 14.06. The physical data were identical in all respects to those previously reported.[37]
N-Benzyl-2-phenylethamine (5h): Synthesized according to General procedure. 2-Phenylethamine (0.061 ml, 0.50 mmol) affords 5h (0.064 g, 61% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR
– 2.89 (m, 2H), 2.64 – 2.73 (br.s, 1H). 13C NMR (100 MHz, CDCl
3) δ 139.78, 139.62, 128.69, 128.44, 128.38, 128.17, 127.01, 126.15, 77.32, 77.00, 76.68, 53.59, 50.28, 36.05. The physical data were identical in all respects to those previously reported.[38]
N-Piperonyl-3-trifluoromethylbenzylamine (5i):
Synthesized according to General procedure. 3-Trifluoromethylbenzylamine (0.088 ml, 0.50 mmol) affords 5i (0.093 g, 60% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H
NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.48 – 7.58 (m, 2H), 7.40 – 7.47 (m, 1H), 6.87 (s, 1H), 6.72 – 6.80 (m, 2H), 5.95 (s, 2H), 3.84 (s, 2H), 3.72 (s, 2H), 1.75 – 1.87 (br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 1.47.77, 146.64, 141.14, 133.76, 131.47 (q, J = 1.3 Hz), 130.69 (q, J = 32.0 Hz), 128.77, 124.83 (q, J = 3.8 Hz), 124.19 (d, J = 272.2 Hz), 123.82 (q, J = 3.9 Hz), 121.28, 108.65, 108.10, 100.92, 52.95, 52.36. HRMS (APCI+, m/z): calculated for C16H15F3NO2 [M+H]+: 310.10494; found: 310.10516.
N-(4-Methylbenzyl)-4-fluorobenzylamine (5j): Synthesized according to General procedure. 4-Fluorobenzylamine (0.063 g, 0.50 mmol) affords 5j (0.080 g, 70% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.38 (m, 2H), 7.20 – 7.26 (m, 2H), 7.12 – 7.20 (m, 2H), 6.95 – 7.09 (m, 2H), 3.78 (s, 4H), 2.36 (s, 3H), 1.75 – 1.81 (br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 161.87 (d, J = 244.6 Hz), 137.00, 136.55, 135.95 (d, J = 3.1 Hz), 129.63 (d, J = 8.0 Hz), 129.06, 128.06, 115.08 (d, J = 21.1 Hz), 52.75, 52.23, 21.05. HRMS (APCI+, m/z): calculated for C14H19N2S2 [M+H]+: 230.13395; found: 230.13404.
N-(4-Methylbenzyl)-4-methoxyaniline (5k): Synthesized
according to General procedure. 4-Methoxyaniline (0.062 g, 0.50 mmol) affords 5k (0.076 g, 67% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.28 (d, J = 7.8 Hz, 2H), 7.17 (d, J =
7.8 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz, 2H), 4.25 (s, 2H), 3.76 (s, 3H), 2.36(s, 3H). 13C NMR (100 MHz, CDCl
3) δ 152.16, 142.38, 136.75, 136.50, 129.22, 127.52, 114.86, 114.13, 55.76, 49.00, 21.06. The physical data were identical in all respects to those previously reported.[39]
N-Benzyl-4-methoxyaniline (5l): Synthesized according to General procedure. 4-Methoxyaniline (0.062 g, 0.50 mmol) affords 5l (0.060 g, 56% yield). Yellow oil obtained after column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.20 –
7.45 (m, 5H), 6.81 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.30 (s, 2H), 3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 152.17, 142.32, 139.59, 128.53, 127.51, 127.12, 114.86, 114.11, 55.75, 49.22. The physical data were identical in all respects to those previously reported.[39]
N-n-Butyl-N-n-pentylbenzylamine (9a): Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 9a (0.059 g, 51% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to
95:5). 1H NMR (400 MHz, CD2Cl2) δ 7.26 – 7.45 (m, 4H), 7.15 – 7.26 (m,1H), 3.56 (s, 2H), 2.32 – 2.50 (m, 4H), 1.40 – 1.55 (m, 4H), 1.20 – 1.38 (m, 6H), 0.80 – 1.00 (m, 6H). 13C NMR (100 MHz, CD2Cl2) δ 140.42, 128.76, 127.92, 126.48, 58.55, 29.60, 29.17, 26.62, 22.59, 20.53, 13.84, 13.79. HRMS (APCI+, m/z): calculated for C16H28N [M+H]+: 234.22163; found: 234.22160. N-n-Butyl-N-n-pentyl-4-fluorobenzylamine (9b):
Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 9b (0.050 g, 40% yield). Yellow oil obtained after column chromatography (Al2O3,
n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.42 (m, 2H), 6.85 – 7.10 (m, 2H), 3.51 (s, 2H), 2.29 – 2.51 (m, 4H), 1.37 – 1.57 (m, 4H), 1.15 – 1.37 (m, 6H), 0.77 – 1.01 (m, 6H). 13C NMR (100 MHz, CDCl
3) δ 161.25 (d, J = 243.1 Hz), 135.96, 129.75 (d, J = 7.8 Hz), 114.12 (d, J = 21.0 Hz), 57.37, 29.18, 28.79, 26.24, 22.17, 20.11, 13.44, 13.38. HRMS (APCI+, m/z): calculated for C16H27FN [M+H]+: 252.21220; found: 252.21233.
N-n-Hexyl-N-n-pentyl-4-methoxylbenzylamine
(9c): Synthesized according to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 9c (0.063 g, 43% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5).
1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 3.80 (s, 2H), 3.51 (s, 3H), 2.30 – 2.48 (m, 4H), 1.39 – 1.55 (m, 4H), 1.15 – 1.38 (m, 10H), 0.80 – 1.00 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 158.46, 130.01, 113.45, 57.76, 55.20, 53.52, 31.77, 29.66, 27.12, 26.74, 26.46, 22.65, 22.60, 14.08, 14.05. HRMS (APCI+, m/z): calculated for C19H34NO [M+H]+: 292.26349; found: 292.26360.
(3-(morpholinomethyl)phenyl)methanol (13a): Synthesized according to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 13a (0.065 g, 63% yield). Yellow solid obtained after column chromatography (SiO2, EtOAc/MeOH 100:0 to 90:10). 1H
NMR (400 MHz, CD2Cl2) δ 7.15 – 7.45 (m, 4H), 4.65 (s, 2H), 3.65 (t, J = 4.7 Hz, 4H), 3.49 (s, 2H), 2.42 (t, J = 4.7 Hz, 4H), 2.28 – 2.47 (br.s, 1H) 13C NMR (100 MHz, CD2Cl2) δ 141.80, 138.59, 128.68, 128.65, 128.08, 126.04, 67.25, 65.23, 63.65, 54.04. HRMS (APCI+, m/z): calculated for C12H18NO2 [M+H]+: 208.13321; found: 208.13327.
N-Benzyl-N-methyl-5-hydroxymethyl-furfurylamine (13b): Synthesized according to General procedure. N-Methylbenzylamine (0.061 g, 0.50 mmol) affords 13b (0.069 g, 60% yield). Yellow solid obtained after column chromatography (SiO2, EtOAc/MeOH 100:0 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.47 (m, 4H), 7.20 – 7.28 (m, 1H), 6.00 – 6.33 (m, 2H), 4.55 (s, 2H), 3.45 – 3.64 (m,
4H), 2.90 – 3.08 (br.s, 1H), 2.22 (s, 3H) 13C NMR (100 MHz, CDCl3) δ 153.81, 151.99, 138.07, 129.16, 128.19, 127.06, 109.44, 108.08, 61.12, 57.31, 53.27, 41.88. HRMS (APCI+, m/z): calculated for C14H18NO2 [M+H]+: 232.13321; found: 232.13323.
N-Benzyl-N-methyl-3-morpholinomethyl-benzylamine
(14): Synthesized according to General procedure. N-Methylbenzylamine (0.061 g, 0.50 mmol) affords 14 (0.047 g, 30% yield). Yellow solid obtained after column chromatography (Al2O3, n-pentane/EtOAc 90:10 to 80:20). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.42 (m, 5H), 7.24 – 7.29 (m, 3H), 7.18 – 7.24
(m, 1H), 3.71 (t, J = 4.7 Hz, 4H), 3.53 (s, 2H), 3.48 – 3.53 (m, 4H), 2.45 (t, J = 4.7 Hz, 4H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 139.18, 139.16, 137.60, 129.74, 128.91, 128.19, 128.12, 127.88, 127.80, 126.94, 66.99, 63.42, 61.78, 61.69, 53.60, 42.25. HRMS (APCI+, m/z): calculated for C20H27N2O [M+H]+: 311.21195; found: 311.21179.
1-Benzylpiperidine (16a): Synthesized according to General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17a (0.057 g, 65% yield). Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.05 – 7.55 (m, 5H), 3.46 (s, 2H), 2.27 – 2.49 (m, 4H), 1.52 – 1.66 (m, 4H), 1.40
– 1.51 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 139.58, 129.45, 128.43, 127.11, 64.10, 54.93, 26.51, 24.89. The physical data were identical in all respects to those previously reported.[31]
1-(4-Methylbenzyl)piperidine (16b): Synthesized according to General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17b (0.068 g, 72% yield). Yellow solid obtained after column chromatography (Al2O3,
n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.21 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 3.46 (s, 2H), 2.32 – 2.46 (m,
4H), 2.34 (s, 3H), 1.53 – 1.63 (m, 4H), 1.39 – 1.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 136.37, 135.26, 129.22, 128.74, 63.53, 54.36, 25.91, 24.35, 21.06. The physical data were identical in all respects to those previously reported.[31]
1-(4-Methoxybenzyl)piperidine (16c): Synthesized according to General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17c (0.080 g, 78% yield). Yellow solid obtained after column chromatography (Al2O3,
n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.42 (s, 2H), 2.20 – 2.50 (m, 4H), 1.50 – 1.65 (m, 4H), 1.35 – 1.50 (m, 2H) 13C NMR (100
MHz, CDCl3) δ 158.52, 130.49, 130.34, 113.40, 63.18, 55.16, 54.30, 25.93, 24.38. The physical data were identical in all respects to those previously reported.[28]
1-(thiophen-2-ylmethyl)piperidine (16d): Synthesized according to General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17d (0.053 g, 58% yield). Yellow solid obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ
7.18 – 7.25 (m, 1H), 6.92 – 6.98 (m, 1H), 6.86 – 6.92 (m, 1H), 3.70 (s, 2H), 2.34 – 2.51 (m, 4H), 1.54 – 1.63 (m, 4H), 1.36 – 1.47 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 141.79, 126.31, 125.92, 124.71, 57.74, 54.06, 25.89, 24.24. The physical data were identical in all respects to those previously reported.[40]
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