University of Groningen Carbon-nitrogen bond formation via ......Chapter 2 24 Catalytic N-alkylation with alcohols Preliminary experiments using 4-methoxyaniline (1a) and a simple

University of Groningen

Carbon-nitrogen bond formation via catalytic alcohol activationYan, Tao

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21

Chapter 2

Iron catalyzed direct alkylation of amines with alcohols

The selective conversion of carbon-oxygen bonds into carbon-nitrogen bonds to

form amines is one of the most important chemical transformations for the

production of bulk and fine chemicals and pharma intermediates. An attractive

atom economic way of carrying out such C-N bond formations is the direct N-

alkylation of simple amines with alcohols through the so-called borrowing

hydrogen strategy. Recently, transition metal complexes based on precious noble

metals have emerged as suitable catalysts for this transformation; however, the

crucial change towards highly selective methodologies, which use abundant,

inexpensive and environmentally friendly metals, in particular iron, has not yet

been accomplished. In this chapter, the homogeneous, iron-catalyzed, direct

alkylation of amines with alcohols is described. The scope of this new methodology

includes the selective monoalkylation of anilines and benzyl amines with a wide

range of alcohols as well as the use of diols in the formation of five-, six- and

seven- membered nitrogen heterocycles, which are privileged structures in

numerous pharmaceuticals.

Part of this chapter was published:

T. Yan, B. L. Feringa, K. Barta, Nat. Commun., 2014, 5, 5602.

Chapter 2

22

Introduction

Amines are among the most valuable classes of compounds in chemistry,

omnipresent in natural products, in particular alkaloids[2a], and widely used as

pharmaceuticals, agrochemicals, lubricants and surfactants[1,2,3]. Therefore the

development of efficient catalytic methodologies for C-N bond formation is a

paramount goal in organic chemistry.

The choice of an alcohol[4,5] as substrate for direct C-N bond formation is highly

desirable in order to produce secondary and tertiary amines and N-heterocyclic

compounds (Figure 1).

Figure 1: Catalytic, direct N-alkylation of amines with alcohols. a Conventional conversion

of alcohol into amine via installing a leaving group before nucleophilic substitution with an

amine donor or oxidizing alcohols to carbonyl compounds followed by reductive amination.

b The direct C–N bond formation via coupling of primary alcohols and amines forms

secondary amine products R1–NH–R2. R1–OH is a short- or long-chain aliphatic alcohol and

may contain aromatic functionality. R2–NH2 is an aromatic or aliphatic amine. c Using diols

of various chain lengths the products are 5- (n=1), 6- (n=2) or 7- (n=3) membered N-

heterocycles.

Alcohols are readily available through a variety of industrial processes and are

highly relevant starting materials in view of recent developments in the field of

renewables as they can be obtained via fermentation or catalytic conversion of

lignocellulosic biomass.[6,7] Conventional non-catalytic transformations of an amine

with an alcohol take place via installing a suitable leaving group instead of the

alcohol functionality followed by nucleophilic substitution, or oxidizing alcohols to

carbonyl compounds followed by reductive amination; these multistep pathways

suffer from low atom economy[8] or limited selectivity and the production of

stoichiometric amounts of waste (Figure 1a).[9]

A privileged catalytic methodology for the direct coupling of alcohols with amines

is based on the so-called borrowing hydrogen strategy (Figure 1b, 1c and Figure

2). During the catalytic cycle an alcohol is dehydrogenated to the corresponding

carbonyl compound, which reacts with the amine to form an imine. The imine is in

Alkylation of amines with alcohols

23

situ reduced to the alkylated amine and the metal complex facilitates the required

hydrogen shuttling. In fact the hydrogen delivered by the alcohol is temporarily

stored in the metal complex. Key features are that the process is hydrogen neutral,

no other reagents are needed and the only stoichiometric by-product is water.

A number of transition metal complexes have proven effective in this catalytic C-

N bond formation, in particular those based on ruthenium[10-12] and iridium[13].

These and related methodologies have been extensively reviewed[1,3,4,14-16].

Despite recent progress, the key challenge is the development of catalysts that

rely on the use of widely abundant, inexpensive metals[3,17]. Iron is considered to

be the ultimate, sustainable alternative for ruthenium[18], however, no unequivocal

reductive amination via a borrowing hydrogen mechanism has been reported[19].

Direct N-alkylation of amines with alcohols is limited to iron-halogenides under

rather harsh reaction conditions (160-200 °C), not proceeding via a hydrogen

autotransfer pathway[20].

This work shows that a well-defined homogenous Fe-based catalyst can be

successfully used in this atom-economic process, with a broad substrate scope.

These direct, Fe-catalyzed transformations are highly modular, and provide water,

as the only stoichiometric byproduct. The products are valuable secondary and

tertiary amines or heterocycles, which contain diverse moieties R1 (from the

alcohol substrate) and R2 (from the amine substrate) (Figure 1).

The presented direct waste-free alcohol to amine functional group interconversions

are important toward the development of sustainable iron based catalysis and will

enable the valorization of biomass-derived alcohols in environment-benign

reaction media.

Results and discussion

We reasoned that direct C-N bond formation with an iron catalyst is possible

provided by the catalytic complex which shows high activity both in alcohol

dehydrogenation (Figure 2a, Step 1) and imine hydrogenation (Figure 2a, Step 3).

The realization of this concept for direct alkylation of amines with alcohols using

cyclopentadieneone iron tricarbonyl complex Cat 3, the precurse to form Knölker’s

complex[21] Cat 3-H, is presented here (Figure 2). Iron cyclopentadienone complex

Cat 3 (Figure 2b), has been recently employed in catalysis including hydrogenation

of ketones[22], reductive amination[23], transfer hydrogenation of carbonyl

compounds and imines[24a], Oppenauer-type oxidation of alcohols[24b] as well as

cooperative dual catalysis[25]. Given its unique reactivity, we considered Cat 3 a

promising candidate for the development of the desired iron-catalyzed hydrogen

borrowing methodology. To achieve the direct amination of alcohols, the key

challenge is to match alcohol dehydrogenation and imine hydrogenation steps by

establishing conditions under which the formed Fe-H species (Cat 3-H) from the

initial alcohol dehydrogenation step is able to reduce the imine at a sufficient rate,

not requiring the use of dihydrogen.

Chapter 2

24

Catalytic N-alkylation with alcohols Preliminary experiments using 4-

methoxyaniline (1a) and a simple aliphatic alcohol, 1-pentanol (2a), with 5 mol%

pre-catalyst Cat 3 and 10 mol% Me3NO oxidant (to form active Cat 3-O) at 110 °C

in toluene showed the formation of 4-methoxy-n-pentylaniline (3aa), albeit with

only 30% selectivity at 48% substrate conversion (Table 1, entry 1). Although

promising, the initial results using common organic solvents indicated low

conversion of 1a or low selectivity towards 3aa and analysis of the reaction

mixtures identified insufficient imine reduction as the key problem. We reasoned

that most probably a weakly coordinating ethereal solvent is needed to stabilize

the key iron intermediates Cat 3-O[27]. In addition, imine formation might be

facilitated in solvents, which have limited miscibility with water. The major

breakthrough came when the green solvent cyclopentyl methyl ether (CPME), one

that uniquely combines such properties, was selected as reaction medium. CPME

recently emerged as a low-toxicity, sustainable solvent alternative for

tetrahydrofuran[28].

Figure 2 Individual reaction steps in the iron-catalyzed N-alkylation of amines using iron

cyclopentadienone complexes. a The overall transformation is the direct coupling of an

alcohol (R1–OH) with an amine (R2–NH2) to form the product amine (R1–NH–R2). The

sequence of reaction steps starts with the dehydrogenation of R1–OH to the corresponding

aldehyde with iron complex Cat 3-O (Step 1). Thereby one ‘hydrogen equivalent’ is

temporarily stored at the bifunctional iron complex Cat 3-O, which is converted to its

reduced, hydride form Cat 3-H. In Step 2, the carbonyl intermediate reacts with amine

R2–NH2 to form an imine intermediate and water. In Step 3, the hydrogen equivalent

“borrowed” from alcohol R1–OH are used in the reduction of the imine intermediate to

obtain the desired product R1–NH–R2. The reduction is accompanied by conversion of iron

hydride Cat 3-H to Cat 3-O, thereby a vacant coordination site is regenerated and the

catalytic cycle closed. b Reactivity of Fe cyclopentadienone complexes: Cat 3 is an air- and

moisture-stable iron tricarbonyl precatalyst. The active Cat 3-O complex is in situ

generated from Cat 3 by the addition of Me3NO to remove one CO. Cat 3-O is readily

converted to Cat 3-H by reaction with an alcohol.


25

Table 1: Optimization of reaction conditions for N-alkylation of p-methoxyaniline

(1a) with 1-pentanol (2a).

Entry 2a

[eq.]

Sol. T

[°C]

Conv. 1a

[%]a

Sel. 3aa

[%]a

Sel. 4aa

[%]a

1 1 Toluene 110 48 30 10

2 2 Toluene 110 71 50 20

3 2 DCE 110 75 15 41

4 2 CH3CN 110 10

Chapter 2

26

Table 2: Product formation profiles for products 3aa, 4aa and substrate 1a.

Entry Time [h] Remain 1a

[%]a

Sel. 3aa

[%]b

Sel. 4aa

[%]b

1 1 92 11 6

2 2 59 31 8

3 3 48 40 8

4 5 21 70 4

5 7 1 92 1

General reaction conditions: General Procedure A, 1a (0.5 mmol), 2a (1 mmol), 130 °C,

CPME (2 ml). Reactions were set up in parallel and runs were stopped at given time. aConversion determined based on GC-FID using octadecane as internal standard. bSelectivity determined based on GC-FID and corresponding conversion.

Next, an in situ NMR study (Figure 3) was conducted, using d-8 toluene at 100 °C

that allowed the detection of all key reaction intermediates (as depicted in Figure

2a), that is, 1-pentanol (2a), 1-pentanal, amine 3aa and the corresponding imine,

in support of the borrowing hydrogen mechanism.

Selective monoalkylation of anilines The general applicability of this method

for the selective monoalkylation of substituted anilines was examined using 1-

pentanol 2a and 17 anilines 1a–1q with diverse electron density and steric

hindrance on the amino group. The isolated yields under optimized conditions are

shown in Table 3.


27

Figure 3: In situ 1H NMR study of the N-alkylation of p-methoxyaniline (1a) with 1-

pentanol (2a) in toluene-d8 at 100 °C. Full ppm range, showing 2 small absorptions at

9.41 and 7.65 ppm, which can be attributed to HA (pentane-1-al)[26a] and HI (imine 4aa)[26b].

Table 3: Selective monoalkylation of anilines with alcohols.

General reaction conditions: General Procedure A, 0.5 mmol 1, 1 mmol 2, 2 ml CPME,

130 °C, 18 h, isolated yields, unless otherwise specified. For details see Table 4 and Table

5. a120 °C; bselectivity determined by GC-FID; c2 mmol 2 was used.

Chapter 2

28

Monoalkylation of various anilines with 1-pentanol The reactivity of

substrates 1a–1q was also compared under standard reaction conditions (reaction

time 18 h) to assess substituent effects (Table 4). Selective monoalkylation was

observed in each case; however, the differences in reactivity were significant.

Para-substituted anilines were more reactive than ortho- or metasubstituted

analogues (Table 4, entry 1-2), wheras the reactivity of toluidines increased in the

order ortho (1c) < meta (1d) < para (1e) probably owing to a combination of

basicity and steric effects (Table 4, entry 4, 6 and 8). It was further more

established that anilines comprising electron-withdrawing substituents were less

reactive and that the reactivity of para-halogenated anilines decreased in the order:

fluoro (1h), chloro (1i) > iodo (1k) (Table 4, entry 13, 15 and 19). Whereas para-

substituted anilines bearing strong withdrawing groups including –COOCH3, -NO2,

-CN do not give desired products (Table 4, entry 20-22).

Table 4: Assessment of reactivity of functionalized anilines (1a-1q) in N-

alkylation with 1-pentanol (2a).

Entry 1 / R T

[h]

Temp.

[°C]

Conv.

1 [%]a

Sel. 3 [%]b

1 1a p-OCH3 18 130 97 3aa 94 (91)

2 1b o-OCH3 18 130 28 3ba 27

3 1b o-OCH3 38 120 63 3ba 51 (42)

4 1c o-CH3 18 130 23 3ca 12

5 1c o-CH3 39 120 83 3ca 71(49)

6 1d m-CH3 18 130 50 3da 40

7 1d m-CH3 62 130 >99 3da >95 (84)

8 1e p-CH3 18 130 88 3ea 75 (63)

9 1e p-CH3 22 130 >99 3ea 90 (91)

10 1f p-OH 18 130 >99 3fa 84 (69)

11 1f p-OH 4 130 96 3fa 92 (94)

12 1g o-F 18 130 25 3ga 13

13 1h p-F 18 130 84 3ha 60

14 1h p-F 42 120 >95 3ha 84(77)

15 1i p-Cl 18 130 73 3ia 54

16 1i p-Cl 63 120 87 3ia 77(76)

17 1j p-Br, m-CH3 18 130 33 3ja 18

18 1j p-Br, m-CH3 39 120 80 3ja 62(58)

19 1k p-I 18 130 16 3ka 8

20 1l p-COOCH3 18 130


29

Accordingly, the best result was obtained with p-hydroxyaniline, which was

converted to 3fa in excellent 94% isolated yield already after 4 h (Table 4, entry

11). This increased reactivity might be attributed to the enhanced nucleophilicity

of 1f or the presence of the relatively acidic phenol moiety, which likely catalyzes

the imine formation step. p-Methoxyaniline was converted to 3aa within 7 h (Table

2), and para-methylaniline (1e), being less reactive, gave 3ea in 91% isolated

yield after 22h (Table 4, entry 9). Unsubstituted aniline (1o) gave 3oa 90%

isolated yield after 25 h (Table 4, entry 24).

Other substrates required further optimization, which was initially conducted using

one of the least reactive substrates 1b. It was shown that prolonged reaction times

and the addition of molecular sieves (to accelerate the imine formation step) lead

to satisfactory results and products 3ba (Table 4, entry 3), as well as 3ca, 3da,

3ia and 3ja were isolated in moderate-to-high yields (42–84%) (Table 4, entry 5,

7, 16 and 18). Taking advantage of the distinct difference in reactivity between

substituted anilines, the selective monoalkylation of 1-methyl-2,4-diamino-

benzene (1q) resulted in preferential formation of 3qa in 58% isolated yield (Table

4, entry 26).

Table 5: N-alkylation of p-methoxyaniline (1a) with various alcohols (2b-2l).

Entry 2 Time [h] Conv.

1a [%]a

Sel. 3 [%]b Sel. 4 [%]b

1 2b n-Octanol 18 85 3ab 79 (69) 4ab 6

2 2c Ethanol 18 94 3ac 90 (85) 4ac 2

3 2d Methanol 18 8 3ad 0 4ad 0

4c 2e Propane-2-ol 24 42 3ae 12 4ae 24

5c 2f Cyclohexanol 24 50 3af 14 4af 32

6 2g Benzyl-alcohol 18 79 3ag 12 4ag 66

7 2h Phenylethanol 18 93 3ah 87 (75) 4ah 5

8 2i Ethane-1,2-diol 22 82 3ai 70 (74) 4ai 0

9 2k Hexane-1,6-diol 22 83 3ak 65 (43) 4ak 0

10d 2i Ethane-1,2-diol 24 80 3pi 40 4pi 0

11d 2i Ethane-1,2-diol 42 90 3pi 60 (45) 4pi 0

General reaction conditions: General Procedure A, 0.5 mmol 1a, 1 mmol 2a, 130 oC, 2 ml

CPME, isolated yield in parenthesis. aConversion determined by GC-FID; bSelectivity

determined by GC-FID; c2 mmol alcohol 2 was used; d3 mmol 2i was used and 2-

aminoaniline (1p) was used instead of 1a. Main products also see Table 3.

Monoalkylation of p-methoxyaniline with various alcohols Having

established the reactivity pattern of anilines, we found that the selective

monoalkylation of p-methoxyaniline (1a) proceeds with a variety of alcohols (2b-

2l) with excellent results (Table 5). For instance, octanol (2b), ethanol (2c) as

well as 2-phenyl-ethane-1-ol (2h) were readily converted to the corresponding

amines 3ab, 3ac and 3ah in 69–85% isolated yields (Table 5, entry 1, 2 and 7).

Chapter 2

30

Alkylations using methanol were not successful (Table 5, entry 3), probably

because the dehydrogenation of MeOH with employed catalytic system is

unfavored. Interestingly, selective mono-alkylation with ethane-1,2-diol (2i) and

hexane-1,6-diol (2k) delivered valuable amino-alcohols 3ai (74%) and 3ak (43%)

(Table 5, entry 8-9). Notably, 2,3-dihydro-quinoxaline (3pi) containing a

heterocyclic structure could also be constructed directly from inexpensive ethylene

glycol (Table 3; Table 5, entry 10-11).

N-alkylation of aliphatic amines with aliphatic alcohols It is important that

aliphatic amines could also be successfully used as reaction partners with various

alcohols (Figure 4). For instance, pentane-1-amine (5a) was alkylated with

benzylalcohol (2g), providing 6ag in 67% yield. The same monoalkylated amine

was obtained in 62% yield by a reverse route from benzylamine (7a) and 1-

pentanol (2a), showing the flexibility and versatility of the new catalytic

transformation. The reaction of piperidine (5b) with 2-phenylethylamine (2h)

afforded tertiary amine 6bh in 53% isolated yield. Interestingly, furfuryl-amine

(5c), which can be derived from lignocellulosic biomass through furfural, displayed

an interesting reactivity towards bis-N-alkylation. In the reaction of 5c with 3 equiv

of 2a, preferentially the corresponding tertiary amine (6caa) was formed.

Figure 4: N-Alkylation of various aliphatic amines with alcohols. a Modular synthesis with

aliphatic amines and alcohols. Pentyl-1-amine (5a) can be coupled with benzyl-alcohol (2g)

or benzyl amine (7a) is coupled with 1-pentanol (2a) to afford the same amine product. b

The methodology can be extended to secondary amines, piperidine (5b) is alkylated with

2-phenyl-1-ethanol (2h). c The reaction of furfuryl-amine (5c) with 1-pentanol (2a)

results in bis-N-alkylation product 6caa. aMolecular sieves were added.


31

N-alkylation of benzylamines N-alkylated benzyl amines are particularly

important targets, as these moieties are present in a variety of drug molecules[29].

Figure 5: Reactivity of various benzylamines (7) with 1-pentanol (2a) based on

conversion in 6 h. General reaction conditions: General Procedure A, 0.5 mmol 7, 1 mmol

2a, 130 oC, 2 ml CPME, conversion was determined by GC-FID using octadecane as internal

standard.

Again a distinct substituent effect was observed in the benzylamine reaction

partner (Table 6). Para-methyl substituted 7g and unsubstituted 7a showed lower

reactivity than meta-halogen substituted benzylamines (7b–7f), which reacted

much faster with 1-pentanol (2a). This is probably due to the increased rate of

reduction of the corresponding imines.[30] Substituted N-alkylated benzylamines

8ba, 8ca, 8da and 8ea were obtained in excellent, 80–95% isolated yield.

Following the alkylation over 6 h confirmed that the reactivity of benzyl amines

7a–7e, increases in the order 7a

Chapter 2

32

Table 6: N-Alkylation of benzylamines with 1-pentanol and diols.

General reaction conditions: General procedure A, 0.5 mmol 7, 1 mmol 2, 130 oC, 18-50

h, isolated yields after purification. aSelectivity determined by GC-FID.

Heterocycle formation with various benzylamines and diols Building on the

excellent reactivity of benzyl amines 7c–7e, we attempted the formation of

nitrogen-containing heterocycles of various sizes using diols of different chain

lengths (butane-1,4-diol 2m, pentane-1,5-diol 2l or hexane- 1,6-diol 2k) (Table

6). An additional advantage of the use of benzylamines is that the free N-

heterocycles can be readily obtained by common debenzylation procedures.

Despite the fact that a sequential catalytic N,N-dialkylation at the same nitrogen

has to occur involving each of the hydroxyl groups of the diol, we reasoned that

the first intermolecular alkylation is followed by an iminium ion-based alkylation,

likely facilitated by the intramolecular nature of the second alkylation step. To our

delight, pyrrolidine 9cm, containing a key five-membered heterocycle, was

obtained in 60% yield from 7c and butane-1,4-ol (2m). Six-membered piperidine

derivative 9cl was constructed using pentane-1,5 diol (2l) and 7c. As seven-

membered ring formation is generally challenging in organic synthesis, it is a

notable feature of our new Fe-based catalytic procedure that various azepane type

N-heterocyclic compounds were readily obtained using benzyl amines 7b–7e and

hexane-1,6-diol (2k). It is remarkable that in all these reactions, full conversion

and perfect product selectivity was observed. Among all derivatives, the chloro-

substituted 9bk was obtained with the highest isolated yield (85%). In contrast,


33

the reaction of unsubstituted benzylamine 7a with 2k afforded the monoalkylation

product, showing that the second cyclization step was much slower in this case.

These results highlight the value of this methodology in accessing biological

important nitrogen heterocycles, which contain -F and -CF3 substituents. These are

frequently encountered motives in pharmaceutically active compounds (Figure 6).

Synthesis of pharmaceutically relevant molecules To demonstrate the power

of the new C–N bond formation, we applied the Fe-catalyzed direct amine

alkylation as a key connection step in the synthesis of the N-arylpiperazine drug

Piribedil (12) (Figure 6), a dopamine antagonist used in the treatment of

Parkinson’s disease[11,31]. The application of iron-based homogeneous catalyst in

the preparation of pharmaceutically active molecules is highly desired, given the

limited allowed ppm levels of noble metal catalysts in the final products[29].

Commercially available 1-(2-pyrimidyl)-piperazine (10) and 4 equiv of piperonyl

alcohol (11) were used as the substrates, providing Piribedil in 54% isolated yield.

This direct, base free catalytic coupling illustrates several advantages for drug

syntheses: no auxiliary reagents are required, an iron catalyst and the green

solvent CPME are used, and water is the only waste product.

Figure 6: Direct synthesis of Piribedil 12.

Conclusion

We have developed a versatile Fe-based catalytic approach for the direct coupling

of amines and alcohols. Key elements are a single bifunctional Fe-catalyst for

alcohol dehydrogenation and imine hydrogenation, and the use of the green

solvent CPME. The variety of primary amines and alcohols, including those derived

from biomass, which can be coupled, provides an excellent basis for highly flexible

methodology to synthesize a broad array of secondary amines and nitrogen

heterocycles and holds promise for future application in diversity-oriented

synthesis strategies. The first upscaling experiments showed that this direct N-

alkylation can provide up to gram amounts of secondary amines. Mechanistic

investigations are needed to elucidate the role of steric and electronic parameters

in the rate-determining step, which can be both the imine formation as well as the

imine reduction. For example, p-hydroxy aniline was rapidly converted within 4 h,

whereas o-methoxy aniline was much less reactive. Similarly, benzyl-amines

display marked reactivity difference, depending on the nature and position of the

substituents at the aromatic ring. We foresee that control of the reactivity of well-

defined iron catalysts, as shown here successfully for the borrowing hydrogen

strategy in the direct alkylation of amines with alcohols, will enable the discovery

of a range of other new catalyst structures and sustainable transformations, using

abundant iron.

Chapter 2

34

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 oC 5 min (10 °C/min). 1H- and 13C NMR spectra

were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using

CDCl3 or CD2Cl2 as solvent. In situ 1H NMR spectra were recorded on a Varian Unity

Plus Varian-500 (500 MHz) using toluene-d8 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; CD2Cl2: 5.32 for 1H, 53.84 for 13C; toluene-d8: 7.09 for 1H).

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

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. Aniline, 4-

methylbenzylamine, benzylamine, 3-trifluoromethylbenzylamine were purified by

distillation. 4-Methylaniline was purified by recrystallization. 2-Methoxyaniline was

purified by column chromatography. All other reagents were purchased from

Sigma or Acros in reagent or higher grade and were used without further

purification. Complex Cat 3, Cat 3b was synthetized according to literature

procedures[32].

Preparation of Cat 3 and Cat 3b

1,8-Bis(trimethylsilyl)-1,7-octadiyne To a solution of 1,7-octadiyne (2 mL,

1.56 g, 15 mmol) in THF (20 mL), a solution of n-BuLi (20.6 mL of a 1.6M in

hexane solution, 33 mmol, 2.2 equiv) was added dropwise over 20 min at -78 °C

under N2, in a 100ml Schlenk tube. After stiring for 10 min at -78 °C, and 1 h

under room temperature, trimethylsilyl chloride (8.4 ml, 66 mmol, 4.4 equiv) was

added slowly and the mixture was stirred at room temperature for 16 hours. The

cloudy, white mixture was quenched with saturated aqueous NH4Cl (5 mL) followed

by water until all of the white precipitate dissolved. The organic layer was removed


35

and the aqueous layer was extracted with pentane. The combined organic layers

were dried over anhydrous Na2SO4 and the solvent was evaporated under reduced

pressure to give a yellow oil. Purification of the crude product by Kugelrohr

distillation afforded 3.56 g (95% yield) of a light yellow oil/solid mixture (product

is a low-melting solid). 1H NMR (400 MHz, CDCl3, ppm): δ 2.23–2.28 (m, 4H),

1.60–1.64 (m, 4H), 0.15 (s, 18H). The physical data were identical in all respects

to those previously reported.[32]

Tricarbonyl(1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-inden-2-

one)iron (Cat 3) A solution of 1,8-bis(trimethylsilyl)-1,7-octadiyne (1.2 g, 4.8

mmol) and diiron nonacarbonyl (1.74 g, 4.8 mmol, 1 equiv) in toluene (60 mL) in

a 250 ml oven-dried Schlenk tube was heated to 120 °C and stirred for 24 hours

under argon. After cooling, the mixture was filtered over celite. Then the solution

was concentrated and filtered over silica to remove all the iron black. The solution

was evaporated under reduced pressure. The remaining solid residue was washed

with cold pentane and crystalized in heptane affording yellow a crystalline solid,

which is air and moisture stable (1.36g, 68% yield). 1H NMR (400 MHz, CDCl3): δ

2.50–2.62 (m, 4H), 1.77–1.87 (m, 4H), 0.26 (s, 18 H). 13C NMR (100 MHz, CDCl3):

δ 209.04, 181.22, 110.99, 71.74, 24.77, 22.41, –0.28. The physical data were

identical in all respects to those previously reported.[32]

Acetonitrile dicarbonyl(1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-

inden-2-one)iron (Cat 3b) An oven-dried 250 ml Schlenk tube was charged with

100 ml dry acetone and 2 ml dry CH3CN and degassed with N2 for 20 min. Then 1

g Cat 3 (2.38 mmol) was added under N2, stirring for 1 min until it fully solubilized.

216 mg Me3NO (1.2eq) was added under N2. A direct color change from yellow to

orange was observed in 5 s. The conversion of Cat 3 can be monitored by TLC

(pentane/ethyl acetate = 1/1, on silica gel, RfCat1a = 0.95, RfCat1b = 0.35). After 1

h, the solvent was removed under a vacuum; Cat 3b was purified through flash

chromatography, and obtained as brown solid (0.91g, 88% yield). 1H NMR (400

MHz, CDCl3): δ 2.05 – 2.48 (m, 4H), 2.21 (s, 3H), 1.38 – 1.73 (m, 4H), 0.22 (s,

18 H). 13C NMR (100 MHz, CDCl3): δ 212.80, 180.12, 126.00, 106.58, 69.91, 24.83,

22.31, 4.43, -0.12. The physical data were identical in all respects to those

previously reported.[32]

Cat 3 and Cat 3b are slightly light sensitive but air stable.

Representative procedures

General procedure A: An oven-dried 20 ml Schlenk tube, equipped with a stirring

bar, was charged with amine (0.500 mmol, 1 equiv), alcohol (given amount), iron

complex Cat 3 (0.025 mmol, 10.5 mg), Me3NO (0.050 mmol, 3.75 mg) and

cyclopentyl methyl ether (solvent, 2 ml). Solid materials were weighed into the

Schlenk tube under air, the Schlenk tube was subsequently connected to an argon

line and vacuum-argon exchange was performed three times. Liquid starting

materials and solvent were charged under an argon stream. The Schlenk tube was

capped and the mixture was rapidly stirred at room temperature for 1 min, then it

was placed in a pre-heated oil bath at the appropriate temperature and stirred for

Chapter 2

36

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.

General procedure B (With molecular sieves): An oven-dried 20 ml Schlenk tube,

equipped with stirring bar, was charged with amine (0.5 mmol, 1 equiv), alcohol

(given amount), iron complex Cat 3 (0.025 mmol, 10.5 mg), Me3NO (0.05 mmol,

3.75 mg) and cyclopentyl methyl ether (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 35.0–45.0 mg activated molecular sieves 4A. The Schlenk

tube was capped and the mixture was rapidly stirred at room temperature for 1

minute, then 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.

Upscaling procedure for N-alkylation of p-methoxyaniline An oven-dried

100 ml Schlenk tube, equipped with a stirring bar, was charged with p-

methoxyaniline (7.40 mmol, 0.910 g, 1 equiv), iron complex Cat 3 (0.37 mmol,

155 mg, 0.05 equiv) and Me3NO (0.74 mmol, 55.5 mg, 0.10 equiv) under air and

the Schlenk tube was subsequently connected to an argon line and vacuum-argon

exchange was performed three times. Then 1-pentanol (14.8 mmol, 1.62 ml, 2

equiv), cyclopentylmethylether (solvent, 30 ml), 3Å molecular sieves (800 mg)

were charged under an argon stream. The Schlenk tube was capped and the

mixture was rapidly stirred at room temperature for 3 min, then was placed into a

pre-heated oil bath at 130 °C and stirred for 18 h. After cooling down to room

temperature, the crude mixture was concentrated in vacuo. The residue was

purified by flash column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5)

to provide 1.085 gram of p-methoxy-N-pentylaniline in 76% isolated yield.

General procedure for in situ 1H NMR study of the N-alkylation of p-

methoxyaniline (1a) with 1-pentanol (2a) in toluene-d8 at 100 °C. 0.12 mmol p-

anisidine (1a), 0.24 mmol 1-pentanol (2a), 0.012 mmol Cat 3, 0.024 mmol Me3NO

and 0.6 ml toluene-d8 were added in a J-Young NMR tube under argon. The tube

was sealed in an argon flow and placed in the pre-heated (100 °C) NMR machine,

shimming was performed at reaction temperature. In the following 8 h, 16 spectra

were recorded.


37

Spectral data of isolated compounds

4-methoxy-N-pentylaniline (3aa): Synthesized according to

General procedure A. p-Anisidine (0.062 g, 0.500 mmol) affords

3aa (0.088 g, 91% yield). Yellow oil obtained after column

chromatography (SiO2, N-pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.8 Hz,

2H), 3.75 (s, 3H), 3.06 (t, J = 7.2 Hz, 2H), 1.55 - 1.69 (m, 2H),

1.30 - 1.50 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 151.93, 142.79, 114.85, 114.00, 55.78, 44.99, 29.34, 22.50, 14.01. The

physical data were identical in all respects to those previously reported.[33]

2-methoxyl-N-pentylaniline (3ba): Synthesized according to

General procedure B. o-Anisidine (0.056 ml, 0.5 mmol) affords

3ba (0.041 g, 42% yield). Yellow oil obtained after column

chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 6.90 (td, J = 7.6, 1.1 Hz, 1H), 6.79 (d, J =

7.9 Hz, 1H), 6.58 – 6.74 (m ,2H), 4.05 – 4.35 (br.s, 1H), 3.87

(s, 3H), 3.14 (t, J = 7.1 Hz, 2H), 1.61 – 1.75 (m, 2H), 1.32 –

1.50 (m, 4H), 0.95 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 146.68, 138.47,

121.26, 116.02, 109.69, 109.29, 55.33, 43.67, 29.40, 29.23, 22.52, 14.02. HRMS

(APCI+, m/z): calculated for C12H20NO [M+H]+:194.15394; found: 194.15387.[34]

2-methyl-N-pentylaniline (3ca): Synthesized according to

General procedure B. o-Toluidine (0.053 ml, 0.5 mmol) affords 3ca

(0.043 g, 49% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.15 (m, J = 7.7 Hz, 1H), 7.07 (d, J = 7.2, 1H),

6.60 – 6.70 (m, 2H), 3.35 – 3.60 (br.s, 1H), 3.17 (t, J = 7.1 Hz,

2H), 2.16 (s, 3H), 1.64 – 1.74 (m, 2H), 1.35 – 1.50 (m, 4H), 0.96

(t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 146.36, 129.96,

127.10, 121.63, 116.58, 109.58, 43.93, 29.41, 29.30, 22.52, 17.42, 14.04. HRMS

(APCI+, m/z): calculated for C12H20N [M+H]+: 178.15903; found: 178.15896.[34]

3-methyl-N-pentylaniline (3da): Synthesized according to

General procedure A. m-Toluidine (0.054 ml, 0.5 mmol) affords

3da (0.074 g, 84% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.05 – 7.15 (m, 1H), 6.51 – 6.62 (m, 1H),

6.38 – 6.51 (m, 2H), 3.32 – 3.85 (br.s, 1H), 3.13 (t, J = 7.2 Hz,

2H), 2.32 (s, 3H), 1.57 – 1.72 (m, 2H), 1.32 – 1.52 (m, 4H), 0.96

(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148.52, 138.89, 129.03, 117.97,

113.42, 109.82, 43.95, 29.32, 29.26, 22.48, 21.59, 14.02. HRMS (APCI+, m/z):

calculated for C12H19N [M+H]+: 178.15903; found: 178.15874.[35]

Chapter 2

38

4-methyl-N-pentylaniline (3ea): Synthesized according to

General procedure A. p-Toluidine (0.054 g, 0.5 mmol) affords 3ea




2H), 3.08 (t, J = 7.1 Hz, 2H), 2.24, (s, 3H), 1.56 – 1.67 (m, 2H),

1.27 – 1.50 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 146.26, 129.65, 126.23, 112.87, 44.34, 29.34, 29.30, 22.50, 20.33,

14.02.[33]

4-(pentylamino)phenol (3fa): Synthesized according to General

procedure A. 4-Aminophenol (0.055 g, 0.5 mmol) affords 3fa (0.084

g, 94% yield).Yellow oil obtained after column chromatography

(SiO2, n-pentane/EtOAc 90:10 to 60:40). 1H NMR (400 MHz, CDCl3)

δ 6.68 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 8.2 Hz, 2H), 3.90 – 1.69

(br.s, 2H), 3.05 (t, J = 6.8 Hz, 2H), 1.52 – 1.69 (m, 2H), 1.28 –

1.45 (m, 4H), 0,91 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ

148.12, 142.23, 116.23, 114.83, 45.42, 29.30, 22.47, 13.99. HRMS

(APCI+, m/z): calculated for C11H25N [M+H]+: 180.13829; found: 180.13823.

4-fluoro-N-pentylaniline (3ha): Synthesized according to

General procedure A. 4-fluoroaniline (0.047 ml, 0.5 mmol) affords

3ha (0.070 g, 77% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 6.80 – 6.95 (m, 2H), 6.47 – 6.58 (m, 2H), 3.27

– 3.59 (br.s, 1H), 3.06 (t, J = 7.1 Hz, 2H), 1.55 - 1.67 (m, 2H),

1.31 - 1.44 (m, 4H), 0.88 – 0.99 (m, 3H). 13C NMR (100 MHz,

CDCl3) δ 155.61 (d, J = 234.4 Hz), 144.86, 115.53 (d, J = 22.3 Hz), 113.49 (d, J

= 7.4 Hz), 44.63, 29.30, 29.20, 22.48, 14.00.[36]

4-Chloro-N-pentylaniline (3ia): Synthesized according to

General procedure A. 4-Chloroaniline (0.063 g, 0.5 mmol)

affords 3ia (0.075 g, 76% yield). Yellow oil obtained after column



2H), 3.75 (s, 3H), 3.07 (t, J = 7.2 Hz, 2H), 1.55 - 1.67 (m, 2H),

1.27 - 1.44 (m, 4H), 0.92 (t, J = 6.7 Hz, 3H). 13C NMR (100

MHz, CDCl3) δ 147.02, 128.93, 121.45, 113.63, 44.03, 29.25,

29.08, 22.45, 13.98.[33]

4-bromo-3-methyl-N-pentylaniline (3ja): Synthesized

according to General procedure B. 4-Bromo-3-methylaniline

(0.092 g, 0.5 mmol) affords 3ja (0.074 g, 58% yield). Yellow

oil obtained after column chromatography (SiO2, n-

pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ

7.26 (d, J = 8.6 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.31 (dd, J

= 8.6, 2.8 Hz, 1H), 3.35 – 3.80 (br.s, 1H), 3.06 (t, J = 7.1 Hz,

2H), 2.31 (s, 3H), 1.50 – 1.65 (m, 2H), 1.30 – 1.42 (m, 4H), 0.92 (t, J = 6.8 Hz,


39

3H). 13C NMR (100 MHz, CDCl3) δ 147.74, 138.14, 132.56, 114.93, 111.83, 111.32,

43.99, 29.27, 29.12, 23.05, 22.47, 14.01. HRMS (APCI+, m/z): calculated for

C12H19NBr [M+H]+: 258.06954; found: 258.06738.

N-Pentylaniline (3oa): Synthesized according to General

procedure A. Aniline (0.046 ml, 0.5 mmol) affords 3oa (0.073 g,

90% yield). Yellow oil obtained after column chromatography (SiO2,

n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.15

– 7.25 (m, 2H), 6.68 – 6.67 (m, 1H), 6.59 – 6.67 (m, 2H), 3.45 –

3.80 (br.s, 1H), 3.13 (t, J = 7.2 Hz, 2H), 1.57 – 1.71 (m, 2H), 1.32

– 1.48 (m, 4H), 0.95 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148.45,

129.16, 117.03, 112.65, 43.94, 29.31, 29.22, 22.49, 14.02. The physical data

were identical in all respects to those previously reported.[33]

4-Methyl-N1-pentylbenzene-1,3-diamine (3qa): Synthesized

according to General procedure A. 2,4-Diaminotoluene (0.061 g, 0.5

mmol) affords 3qa (0.056 g, 58% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H

NMR (400 MHz, CDCl3) δ 6.85 (d, J = 8.0, 1H), 6.05 (dd, J = 8.0, 2.2

Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 3.25 – 3.65 (br.s, 3H), 3.07 (t, J =

7.2 Hz, 2H), 2.08 (s, 3H), 1.55 – 1.66 (m, 2H), 1.33 – 1.43 (m, 4H),

0.94 (t, J = 7.0, 3H). 13C NMR (100 MHz, CDCl3) δ 147.93, 145.17,

130.91, 111.44, 103.87, 99.64, 44.21, 29.29, 29.27, 22.46, 16.33, 14.00. NOESY-

NMR spectrum see figure 7. HRMS (APCI+, m/z): calculated for C12H21N2 [M+H]+:

193.16993; found: 193.16962.

1,2,3,4-Tetrahydroquinoxaline (3pi): Synthesized according to

General procedure A. o-Phenylenediamine (0.054 g, 0.5 mmol) affords

3pi (0.030 g, 45% yield). Orange solid obtained after column

chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H NMR (400

MHz, CDCl3) δ 6.55 – 6.63 (m, 2H), 6.46 – 6.54 (m, 2H), 3.42 (s, 4H), 3.25 –

3.54 (br.s, 2H). 13C NMR (100 MHz, CDCl3) δ 133.57, 118.77, 114.72, 41.34. The

physical data were identical in all respects to those previously reported.[37]

4-Methoxy-N-octylaniline (3ab): Synthesized according

to General procedure A. p-Anisidine (0.062 g, 0.5 mmol)

affords 3ab (0.081 g, 69% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 100:0 to

95:5). 1H NMR (400 MHz, CDCl3) δ 6.68 (d, J = 8.7 Hz, 2H),

6.60 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 3.06 (t, J = 7.2 Hz,

2H), 1.55 – 1.65 (m, 2H), 1.34 – 1.44 (m, 2H), 1.16 – 1.44

(m, 8H). 13C NMR (100 MHz, CDCl3) δ 151.96, 142.81, 114.88, 114.03, 55.81,

45.05, 31.81, 29.67, 29.42, 29.25, 27.19, 22.64, 14.08. The physical data were

identical in all respects to those previously reported.[38]

Chapter 2

40

4-Methoxy-N-ethylaniline (3ac): Synthesized according to General

procedure A. p-Anisidine (0.062 g, 0.5 mmol) affords 3ac (0.064 g, 85%

yield). Yellow oil obtained after column chromatography (SiO2, n-

pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J =

7.1 Hz, 2H), 6.60 (d, J = 7.3 Hz, 2H), 3.75 (s, 3H), 3.02 – 3.23 (m, 2H),

1.24 (t, J = 6.8, 3H). 13C NMR (100 MHz, CDCl3) δ 152.04, 142.70, 114.86,

114.10, 55.79, 39.44, 14.97. The physical data were identical in all respects to

those previously reported.[39]

4-Methoxy-N-phenethylaniline (3ah): Synthesized according to

General procedure A. p-Anisidine (0.062 g, 0.5 mmol) affords 3ah


chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5).1H NMR

(400 MHz, CDCl3) δ 7.28 - 7.46 (m, 2H), δ 7.12 – 7.28 (m, 3H),

6.79 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 3.75 (s, 3H),

3.37 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H). 13C NMR (100

MHz, CDCl3) δ 152.15, 142.16, 139.35, 128.73, 128.52, 126.32,

114.88, 114.36, 55.74, 46.01, 35.54. The physical data were identical in all

respects to those previously reported.[40]

2-((4-Methoxyphenyl)amino)ethanol (3ai): Synthesized

according to General procedure A. p-Anisidine (0.062 g, 0.5 mmol)

affords 3ai (0.062 g, 74% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 6.74 – 6.84 (m, 2H), 6.58 – 6.66 (m, 2H), 3.79

(t, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.23 (t, J = 5.2 Hz, 2H), 2.86 – 3.08

(br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 152.49, 142.14, 114.86,



6-((4-Methoxyphenyl)amino)hexan-1-ol (3ak):

Synthesized according to General procedure A. p-Anisidine

(0.062 g, 0.5 mmol) affords 3ak (0.048 g, 43% yield). Yellow

oil obtained after column chromatography (SiO2, n-


6.72 – 6.82 (m, 2H), 6.52 – 6.62 (m, 2H), 3.74 (s, 3H), 3.63

(t, J = 6.6 Hz, 2H), 3.06 (t, J = 7.1 Hz, 2H), 2.31 – 2.51 (br.s,

2H), 1.51 – 1.68 (m, 4H), 1.31 – 1.43 (m, 4H). 13C NMR (100

MHz, CDCl3) δ 151.99, 142.64, 114.85, 114.10, 62.75, 55.79, 44.94, 32.61, 29.56,

26.92, 25.55. HRMS (APCI+, m/z): calculated for C13H21NO2 [M+H]+: 224.16451;

found: 224.16428.

N,N-Dipentylfurfurylamine (6caa): Synthesized

according to General procedure B. Furfurylamine (0.044 ml,

0.5 mmol) affords 6caa (0.075 g, 63% yield). Yellow oil

obtained after column chromatography (SiO2, n-


7.35 (d, J = 2.0, 1H), 6.30 (dd, J = 2.8, 2.0 Hz, 1H), 6.15 (d, J = 3.0, 1H), 3.64


41

(s, 2H), 2.40 (m, J = 7.6, 2H), 1.40 – 1.62 (m, 4H), 1.15 – 1.40 (m, 8H), 0.88

(t, J = 7.0, 6H). 13C NMR (100 MHz, CDCl3) δ 152.88, 141.66, 109.88, 108.11,

53.84, 49.97, 29.71, 26.74, 22.60, 14.06. HRMS (APCI+, m/z): calculated for

C15H25NO [M+H]+: 238.21666; found: 238.21654.

1-Phenethylpiperidine (6bh): Synthesized according to General

procedure B. Piperidine (0.049 ml, 0.5 mmol) affords 6bh (0.050 g, 52%

yield). Yellow oil obtained after column chromatography (Al3O2, n-

pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CD2Cl2) δ 7.23 –

7.34 (m, 2H), 7.10 – 7.34 (m, 3H), 2.72 – 2.80 (m, 2H), 2.48 – 2.56

(m, 2H), 2.35 – 2.48 (m, 4H), 1.52 – 1.62 (m, 4H), 1.33 – 1.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 140.60, 128.66, 128.29, 125.88, 61.43,



N-Pentyl-phenethylamine (6ah or 6da): Synthesized

according to General procedure A. Phenethylamine (0.063 ml,

0.5 mmol) affords 6da (0.031 g, 32% yield). Amylamine (0.058

ml, 0.5 mmol) affords 6ah (0.014 g, 15% yield). Yellow oil

obtained after column chromatography (SiO2, MeOH/EtOAc

0:100 to 5:95). 1H NMR (400 MHz, CD2Cl2) δ 7.24 – 7.33 (m,

2H), 7.12 – 7.24 (m, 3H), 2.79 – 2.91 (m, 2H), 2.68 – 2.79 (m, 2H), 2.58 (t, J =

7.2 Hz), 1.38 – 1.48 (m, 2H), 1.22 – 1.32 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H). 13C

NMR (100 MHz, CD2Cl2) δ 141.03, 129.09, 128.68, 126.29, 51.65, 50.19, 36.83,



N-Pentylbenzylamine (6ag or 8aa): Synthesized according

to General procedure A. Benzylamine (0.055 ml, 0.5 mmol)

affords 8aa (0.055 g, 62% yield). Amylamine (0.058 ml, 0.5

mmol) affords 6ag (0.059 g, 67% 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.[43]

3-Chloro-N-pentylbenzylamine (8ba): Synthesized

according to General procedure A. 3-Chlorobenzylamine (0.061

ml, 0.5 mmol) affords 8ba (0.084 g, 80% yield). Yellow oil

obtained after column chromatography (SiO2, n-pentane/EtOAc

50:50 to 0:100). 1H NMR (400 MHz, CDCl3) 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,

CDCl3) δ 142.50, 134.17, 129.56, 128.14, 126.98, 126.16, 53.40, 49.37, 29.67,

Chapter 2

42

29.46, 22.56, 14.01. HRMS (APCI+, m/z): calculated for C12H19ClN [M+H]+:

212.12005; found: 212.11983.[44]

3-Fluoro-N-pentylbenzylamine (8ca): Synthesized

according to General procedure A. 3-Fluorobenzylamine (0.057

ml, 0.5 mmol) affords 8ca (0.085 g, 87% yield). Yellow oil

obtained after column chromatography (SiO2, n-pentane/EtOAc

50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.34 (m,

1H), 6.98 – 7.18 (M, 2H), 6.93 (td, J = 8.4, 2.1 Hz, 1H), 3.79

(s, 2H), 2.61 (t, J = 7.3 Hz, 2H), 1.76 – 2.04 (br.s, 1H), 1.45 – 1.61 (m, 2H), 1.22

– 1.37 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.93 (d,

J = 245.5 Hz), 142.96 (d, J = 7.3 Hz), 129.73 (d, J = 8.2 Hz), 129.63 (d, J = 2.8

Hz), 114.86 (d, J = 21.2 Hz), 113.70 (d, J = 21.2 Hz), 53.35, 49.31, 29.62, 29.47,

22.56, 14.00. HRMS (APCI+, m/z): calculated for C12H19FN [M+H]+: 196.14960;

found: 196.14938.[44]

3-Trifluoromethyl-N-pentylbenzylamine (8da):

Synthesized according to General procedure A. 3-

Trifluorobenzylamine (0.072 ml, 0.5 mmol) affords 8da (0.115

g, 94% 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. HRMS (APCI+, m/z): calculated for C12H29F3N [M+H]+: 246.14641; found:

246.14594.[44]

3-Fluoro-5-trifluoromethyl-N-pentylbenzylamine

(8ea): Synthesized according to General procedure A. 3-

Fluoro-5-trifluoromethylbenzylamine (0.073 ml, 0.5

mmol) affords 8ea (0.125 g, 95% yield). Yellow oil

obtained after column chromatography (SiO2, n-

pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.28

(d, J = 9.1 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 3.88 – 4.04 (br.s, 1H), 3.48 (s, 2H),

2.61 (t, J = 7.1 Hz, 2H), 1.43 – 1.59 (m, 2H), 1.25 – 1.37 (m, 4H), 0.88 (t, J =

6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.56 (d, J = 248.5 Hz), 143.59 –

143.81 (m), 132.39 (dd, J = 33.1, 7.8 Hz), 123.30 (dd, J = 272.4, 2.7 Hz), 120.52

– 120.74 (m), 118.50 (d, J = 21.6 Hz), 111.39 (dq, J = 24.5, 3.8 Hz), 52.62,

49.08, 29.35, 29.23, 22.48, 13.92. HRMS (APCI+, m/z): calculated for C13H18F4N

[M+H]+: 264.13699; found: 264.13668.

3-Chloro-4-fluoro-N-pentylbenzylamine (8fa): Synthesized according to

General procedure A. 3-Chloro-4-fluorobenzylamine (0.069 ml, 0.5 mmol) affords

8fa (0.050 g, 43% yield). Yellow oil obtained after column chromatography (SiO2,

n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.43 (m,


43

1H), 7.14 – 7.22 (m, 1H), 7.02 – 7.11 (m, 1H), 3.73 (s,

2H), 2.59 (t, J = 7.5 Hz, 2H), 1.93 – 2.08 (br.s, 1H), 1.43

– 1.58 (m, 2H), 1.25 – 1.37 (m, 4H), 0.83 – 0.93 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 157.07 (d, J = 247.5 Hz),

137.34, 130.15, 127.69 (d, J = 7.0 Hz), 120.69 (d, J = 17.8

Hz), 116.29 (d, J = 20.9 Hz), 52.71, 49.26, 29.56, 29.45,

22.54, 13.99.

1-(3-fluorobenzyl)pyrrolidine (9cm): Synthesized according to

General procedure A. 3-Fluorobenzylamine (0.057 ml, 0.5 mmol)

affords 9cm (0.054 g, 60% yield). Yellow oil obtained after column

chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CD2Cl2) δ 7.21 – 7.32 (m, 1H), 7.02 – 7.15 (m, 2H), 6.93

(td, J = 8.6, 2.2 Hz, 1H), 3.59 (s, 2H), 2.32 – 2.60 (m, 4H), 1.67 –

1.82 (m, 4H). 13C NMR (100 MHz, CD2Cl2) δ 162.87 (d, J = 245.1 Hz), 142.06 (d,

J = 6.2 Hz), 129.56 (d, J = 8.4 Hz), 124.27 (d, J = 2.8 Hz), 115.57 (d, J = 21.4

Hz), 113.70 (d, J = 21.4 Hz), 60.14, 54.14, 23.45. The physical data were identical

in all respects to those previously reported.[45]

1-(3-fluorobenzyl)piperidine (9cl): Synthesized according to


affords 9cl (0.060 g, 62% yield). Yellow oil obtained after column

chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400

MHz, CD2Cl2) δ 7.25 – 7.37 (m, 1H), 7.07 – 7.25 (m, 2H), 6.90 – 7.07

(m, 1H), 3.60 (s, 2H), 2.30 – 2.72 (m, 4H), 1.56 – 1.77 (m, 4H), 1.39

– 1.55 (m, 2H). 13C NMR (100 MHz, CD2Cl2) δ 163.34 (d, J = 244.1 Hz),

142.76 (d, J = 7.0 Hz), 129.87 (d, J = 8.3 Hz), 124.86 (d, J = 2.7 Hz), 115.81 (d,

J = 21.2 Hz), 113.80 (d, J = 21.2 Hz), 63.48 (d, J = 1.9 Hz), 54.93, 53.84, 26.51,

24.82. The physical data were identical in all respects to those previously

reported.[46]

1-(3-fluorobenzyl)azepane (9ck): Synthesized according to


affords 9ck (0.069 g, 67% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.18 – 7.30 (m, 1H), 7.00 – 7.18 (m, 2H), 6.84

– 6.98 (m, 1H), 3.63 (s, 2H), 2.45 – 2.72 (m, 4H), 1.43 – 1.84 (m,

8H). 13C NMR (100 MHz, CDCl3) δ 162.94 (d, J = 244.9 Hz), 143.01 (d, J = 6.0

Hz), 129.40 (d, J = 8.1 Hz), 124.06 (d, J = 2.7 Hz), 115.31 (d, J = 21.2 Hz),

113.49 (d, J = 21.3 Hz), 62.24 (d, J = 1.9 Hz), 55.61, 28.26, 26.97. HRMS (APCI+,

m/z): calculated for C12H19FN [M+H]+: 208.14960; found: 208.14928.

1-(3-chlorobenzyl)azepane (9bk) : Synthesized according to

General procedure A. 3-Chlorobenzylamine (0.061 ml, 0.5 mmol)

affords 9bk (0.095 g, 85% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.36 (s, 1H), 7.14 – 7.25 (m, 3H), 3.61 (s, 2H),

2.55 – 2.66 (m, 4H), 1.58 – 1.70 (m, 8H). 13C NMR (100 MHz, CDCl3)

Chapter 2

44

δ 142.36, 134.01, 129.32, 128.66, 126.82, 126.72, 62.15, 55.58, 28.20, 26.98.

HRMS (APCI+, m/z): calculated for C13H19ClN [M+H]+: 224.12005; found:

224.11979.

1-(3-(trifluoromethyl)benzyl)azepane (9dk): Synthesized

according to General procedure A. 3-Trifluoromethylbenzylamine

(0.072 ml, 0.5 mmol) affords 9dk (0.087 g, 68% yield). Yellow oil

obtained after column chromatography (Al2O3, n-pentane/EtOAc

100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.55 (d, J

= 7.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.41 (m, 1H), 3.69 (s, 2H),

2.51 – 2.70 (m, 4H), 1.53 – 1.72 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 143.31,

131.91, 130.43 (q, J = 21.7 Hz), 128.48, 125.25 (q, J = 3.8 Hz), 124.33 (d, J =

272.4 Hz), 123.53 (q, J = 3.8 Hz), 62.22, 55.60, 28.27, 26.98. HRMS (APCI+,

m/z): calculated for C14H19F3N [M+H]+: 258.14641; found: 258.14615.

1-(3-fluoro-5-(trifluoromethyl)benzyl)azepane (9ek): Synthesized

according to General procedure A. 3-Fluoro-5-

trifluoromethylbenzylamine (0.073 ml, 0.5 mmol) affords 9ek



(400 MHz, CDCl3) δ 7.40 (s, 1H), 7.32 (d, J = 9.7 Hz, 1H), 7.18 (d,

J = 8.2 Hz, 1H), 3.67 (s, 2H), 2.53 – 2.69 (m, 4H), 1.52 – 1.73

(m, 8H). 13C NMR (100 MHz, CDCl3) δ 162.58 (d, J = 247.7), 144.78 (d, J = 7.1

Hz), 132.08 (dd, J = 33.0, 8.3 Hz), 123.46 (dd, J = 272.5, 3.1 Hz), 120.67 –

120.86 (m), 118.65 (d, J = 21.2 Hz), 111.04 (dq, J = 24.9, 3.8 Hz), 61.90 (d, J =

1.6 Hz), 55.68, 28.36, 26.95. HRMS (APCI+, m/z): calculated for C14H18F4N

[M+H]+: 267.13699; found: 276.13666.

Piribedil (12): Synthesized according to General

procedure B. 1-(2-Pyrimidyl)piperazine (10) (0.082 g,

0.5 mmol) and 4 eq. piperonyl alcohol (11) affords 12


chromatography (Al2O3, n-pentane/EtOAc 90:10 to

50:50). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.7Hz, 2H), 6.88 (s, 1H), 6.75 (s,

2H), 6.45 (t, J = 4.7Hz, 1H), 5.93 (s, 2H), 3.81 (t, J = 4.9 Hz, 4H), 3.44 (s, 2H),

2.47 (t, J = 5.0Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 161.60, 157.62, 147.62,

146.62, 131.74, 122.19, 109.66, 109.45, 107.83, 100.85, 62.80, 52.77, 43.62.

The physical data were identical in all respects to those previously reported.[47,48]


45

Figure 7 NOESY-NMR spectrum of isolated compound 3qa.

Chapter 2

46

References

[1] G. Guillena, D. J. Ramon, M. Yus, Chem. Rev., 2010, 110, 1611–1641.

[2] a) A. Hager, N. Vrielink, D. Hager, J. Lefranc, D. Trauner, Nat. Prod. Rep., 2016, 33,

491–522; b) J. L. McGuire, Pharmaceuticals: Classes, Therapeutic agents, areas of

Application, Vol. 1–4, Wiley-VCH, 2000.

[3] S. Bähn, S. Imm, L.Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem, 2011,

3, 1853–1864.

[4] A. J. A. Watson, J. M. J. Williams, Science, 2010, 329, 635–636.

[5] C. Gunanathan, Y. Ben-David, D. Milstein, Science, 2007, 317, 790-792.

[6] P. J. Deuss, K. Barta, J. G. de Vries, Catal. Sci. Technol., 2014, 4, 1174-1196.

[7] K. Barta, P. C. Ford, Acc. Chem. Res., 2014, 47, 1503–1512.

[8] B. M. Trost, Science, 1991, 254, 1471–1477.

[9] P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice, Oxford University

Press, 1998.

[10] R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, N. J. Tongpenyai, J. Chem. Soc. Chem.

Commun., 1981, 611.

[11] M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A.

Watson, J. M. J. Williams, J. Am. Chem. Soc., 2009, 131, 1766–1774.

[12] S-I. Murahashi, K. Kondo, T. Hakata, Tetrahedron Lett., 1982, 23, 229–232.

[13] K.-I. Fujita, T. Fujii, R. Yamaguchi, Org. Lett., 2004, 6, 3525–3528.

[14] M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth. Catal., 2007, 349,

1555–1575.

[15] C. Gunanathan, D. Milstein, Science, 2013, 341, 1229712.

[16] G. E. Dobereiner, R. H. Crabtree, Chem. Rev., 2010, 110, 681–703.

[17] R. Martinez, D. J. Ramon, M. Yus, Org. Biomol. Chem., 2009, 7, 2176–2181.

[18] S. Enthaler, K. Junge, M. Beller, Angew. Chem. Int. Ed., 2008, 47, 3317–3321.

[19] M. Bala, P. K. Verma, U. Sharma, N. Kumar, B. Singh, Green Chem., 2013, 15,

1687–1693.

[20] Y. Zhao, S. W. Food, S. Saito, Angew. Chem. Int. Ed., 2011, 50, 3006–3009.

[21] H.-J. Knölker, E. Baum, H. Goesmann, R. Klauss, Angew. Chem. Int. Ed., 1999, 38,

2064-2066.

[22] C. P. Casey, H. Guan, J. Am. Chem. Soc., 2007, 129, 5816-5817.

[23] A. Pagnoux-Ozherelyeva, N. Pannetier, M. D. Mbaye, S. Gaillard, J.-L. Renaud, Angew.

Chem. Int. Ed., 2012, 51, 4976-4980.

[24] a) T. N. Plank, J. L. Drake, D. K. Kim, T. W. Funk, Adv. Synth. Catal., 2012, 354,

597-601; b) M. G. Coleman, A. N. Brown, B. A. Bolton, H. Guan, Adv. Synth. Catal.,

2010, 352, 967–970.

[25] a) S. Zhou, S. Fleischer, K. Junge, M. Beller, Angew. Chem. Int. Ed., 2011, 50, 5120–

5124; b) A. Quintard, T. Constantieux, J. Rodriguez, Angew. Chem. Int. Ed., 2013,

52, 12883–12887.

[26] a) 1H NMR spectrum of commercially available pentane-1-al in toluene-d8 at 100 °C.

The chemical shift of the indicative aldehyde proton (HA) is at 9.40 ppm; b) 1H NMR

spectrum of imine 4aa, in situ generated from 0.12 mmol p-methoxy-aniline (1a)

and 0.50 mmol pentane-1-al. The compounds were solubilized in 0.6 ml toluene-d8

at room temperature, after 0.5 hour the 1H NMR spectrum was recorded at 100 °C.

The indicative aldehyde proton HA is found at 9.40 ppm. The indicative imine proton

HI is found at 7.67 ppm, in agreement with the literature: J. C. Anderson, G. P. Howell,

R. M. Lawrence, C. S. Wilson, J. Org. Chem., 2005, 70, 5665–5670 (7.63 ppm for

4-methoxy-N-hexylaniline in C6D6 at r.t.).

[27] C. P. Casey, H. Guan, J. Am. Chem. Soc., 2009, 131, 2499–2507.

[28] K. Watanabe, N. Yamagiwa, Y. Torisawa, Org. Process Res. Dev., 2007, 11, 251–

258.

[29] M. A. Berliner, S. P. A. Dubant, T. Makowski, K. Ng, B. Sitter, C. Wager, Y. Zhang,

Org. Process Res. Dev., 2011, 15, 1052–1062.

[30] Although the benzene ring is not conjugated to the imine, the effect from the

substitutions to the reduction rate of imine might be non-linear.


47

[31] M. Jaber, S. W. Robinson, C. Missale, M. G. Caron, Neuropharmacology, 1996, 35,

1503–1519.

[32] T. N. Plank, J. L. Drake, D. K. Kim, T. W. Funk, Adv. Synth. Catal., 2012, 354, 597-

601.

[33] D. Jiang, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem., 2007, 72, 672-674.

[34] E. J. Debeer, J. S. Buck, W. S. Ide, A. M. Hjort, J. Pharm. Exp. Ther., 1936, 57, 19-

33.

[35] J. Barluenga, A. M. Bayón, G. Asensio, J. Chem. Soc. Chem. Commun., 1983, 1109-

1110.

[36] J. Lau, J. T. Kodra, M. Guzel, K. C. Santosh, A. M. M. Mjalli, R. C. Andrews, D. R.

Polisetti, PCT Int. Appl. WO 2003055482 A1, 2003.

[37] J. Wu, C. Wang, W. Tang, A. Pettman, J. Xiao, Chem. Eur. J., 2012, 18, 9525-9529.

[38] Q. Shen, S. Shekhar, J. P. Stambuli, J. F. Hartwig, Angew. Chem. Int. Ed., 2005, 44,

1371-1375.

[39] O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden, J. M. J. Williams, Angew. Chem.

Int. Ed., 2009, 48, 7375-7378.

[40] J. C.-H. Yim, J. A. Bexrud, R. O. Ayinla, D. C. Leitch, L. L. Schafer, J. Org. Chem.,

2014, 79, 2015-2028.

[41] M. Yang, F. Liu, J. Org. Chem., 2007, 72, 8969-8971.

[42] M. Utsunomiya, J. F. Hartwig, J. Am. Chem. Soc., 2004, 126, 2702-2703.

[43] S. Lu, J. Wang, X. Cao, X. Li, H. Gu, Chem. Comm., 2014, 50, 3512-3515.

[44] W. R. Meindl, E. V. Angerer, H. Schoenenberger, G. Ruckdeschel, J. Med. Chem.,

1984, 27, 1111-1118.

[45] S. D. Banister, L. M. Rendina, M. Kassiou, Bioorg. Med. Chem. Lett., 2012, 22, 4059-

4063.

[46] L. G. Erwan, D. Alexandre, M. Thierry, T. Michel, Synthesis, 2010, 249-254.

[47] M. Haniti, S. A. Hamid, J. M. J. Williams, Tetrahedron Lett., 2007, 48, 8263–8265.

[48] X. Cui, X. Dai, Y. Deng, F. Shi, Chem. Eur. J., 2013, 19, 3665-3675.

Chapter 2

48

Chapter 2

Documents

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