iron-catalyzed c -h functionalization of tertiary, acyclic, aliphatic … › ... ›...

Worcester Polytechnic Institute

Department of Chemistry and Biochemistry

Iron-Catalyzed Cα-H Functionalization of

Tertiary, Acyclic, Aliphatic Amines

A Major Qualifying Project submitted for review to the faculty of

WORCESTER POLYTECHNIC INSTITUTE

In partial fulfillment of the requirements for the

Degree of Bachelor of Science

Submitted by:

Brian O’Day

Project advisor:

Dr. Marion H. Emmert, WPI Department of Chemistry and Biochemistry

2016

Table of Contents

Abstract ........................................................................................................................... 4

1 Introduction .................................................................................................................. 5

1.1 Motivation ............................................................................................................... 5

1.2 Classical approaches to synthesis of Nitriles ......................................................... 6

1.3 C-H activation / α-amino nitrile formation ............................................................... 7

1.4 Significance ............................................................................................................ 9

1.5 Knowledge at project start and approach ............................................................... 9

2 Results and Discussion .............................................................................................. 12

2.1 Initial Experiments ................................................................................................ 12

2.2 Water optimization. .............................................................................................. 13

2.3 Oxidant optimization ............................................................................................ 15

2.4 KCN optimization ................................................................................................. 16

2.5 18-crown-6 Optimization. ..................................................................................... 18

2.6 Temperature optimization .................................................................................... 19

2.7 Time Optimization ................................................................................................ 21

2.8 Additional loading of KCN and Oxidant ................................................................ 22

2.9 Substrate scope ................................................................................................... 24

2.9.1 Cyanation of triethylamine ............................................................................. 24

2.9.2 Cyanation of tributylamine ............................................................................. 25

2.9.3 Cyanation of Pyrrolidine and piperidine ......................................................... 26

2.10 Nucleophile scope .............................................................................................. 27

2.10.1 Literature precedent ..................................................................................... 28

2.10.2 Indole ........................................................................................................... 29

2.10.3 Trifluoromethyl ............................................................................................. 30

3 Summary, Conclusions, and Future Directions .......................................................... 32

4 Experimental Section ................................................................................................. 35

4.1 General procedures: techniques, solvents and chemicals ................................... 35

4.2 Analytical methods ............................................................................................... 35

4.2.1 NMR spectroscopy ........................................................................................ 35

4.2.2 GCMS ............................................................................................................ 35

4.2.3 Literature search ............................................................................................ 36

3

4.3 Catalytic cyanation studies ................................................................................... 36

4.3.1 Typical procedure for cyanation reactions ..................................................... 36

4.3.2 Water optimization ......................................................................................... 36

4.3.3 Oxidant optimization ...................................................................................... 38

4.3.4 Temperature optimization .............................................................................. 38

4.3.5 KCN optimization ........................................................................................... 39

4.3.6 18-Crown-6 Optimization ............................................................................... 40

4.3.7 Temperature Optimization ............................................................................. 41

4.3.8 Time Optimization .......................................................................................... 42

4.3.9 Additional loading of KCN and Oxidant .......................................................... 43

4.3.10 Substrate scope development ..................................................................... 44

4.4 Nucleophile and substrate studies ....................................................................... 47

4.4.1 Typical procedure for indole reactions ........................................................... 47

4.4.2 Substrate scope of amine indolation .............................................................. 47

4.4.3 Solvent scope of amine indolation ................................................................. 48

4.4.4 Acid catalyzed amine indolation ..................................................................... 49

4.4.5 Amine indolation without water ...................................................................... 49

4.4.5 Typical procedure for amine trifluoromethylation ........................................... 50

4.4.6 Substrate scope of amine trifluoromethylation ............................................... 50

4.4.7 Tetrabutylammonium fluoride as source of F- in amine trifluoromethylation .. 51

5.0 Additional Information .............................................................................................. 51

References .................................................................................................................... 53

4

Abstract

Amine groups are present in many pharmaceuticals and biologically active

molecules, many of which have functionalizations at the α-carbon. As an example, α-

aminonitriles are intermediates for synthesis of α-functionalized amines. Methodologies

for accessing α-aminonitriles largely use alkyl halides. Many of these molecules are

toxic and generate stoichiometric amounts of halogenated waste upon transformation.

Therefore the development of a one pot synthesis for α-aminonitriles from amines is an

important area of study. Our previous research on iron-catalyzed tertiary alkyl amine

oxidation is thought to proceed through an iminium intermediate, which is described in

current α-cyanation protocols of tertiary amines. Therefore, we employed cyanide as a

nucleophile for α-cyanations of tertiary aliphatic amines, resulting in the generation of

the corresponding α-aminonitriles. Indolation and trifluoromethylation reactions were

explored during the development of the α-cyanation protocol.

5

1 Introduction

1.1 Motivation

Pharmaceuticals tend to be complex molecules, containing a variety of functional

groups that are required to obtain proper biological activity. Amine functional groups are

ubiquitous in pharmaceuticals, many of which include α-functionalized amines. Having

an atom-economical methodology for synthesizing these compounds is both

environmentally-friendly as well as cost efficient.

Plavix and Diovan (Figure 1) grossed nearly 10 billion dollars in worldwide sales

in 20091. These compounds contain α-functionalized amines which can be synthesized

by transformations of α-amino nitriles, important intermediates in synthetic chemistry2,3

(e.g., one step in the existing synthesis of Plavix is shown in Scheme 1). Developing a

mild, synthetically useful, single step process for amine α-cyanation would thus be

beneficial for the synthesis of complex pharmaceuticals.

Figure 1. Pharmaceuticals containing tertiary amines with α-functionalizations1

6

Scheme 1. Synthesis of Plavix2. TEBA = triethylbenzylammonium chloride

1.2 Classical approaches to synthesis of Nitriles

Many traditional methods to synthesize compounds with cyano groups employ

alkyl or aryl halides4,5. The syntheses of these reagents and can be highly toxic and are

waste intensive, generating stoichiometric amounts of halogenated waste. For

examples, α-aminonitriles can be synthesized by reaction of secondary amines with 2-

chloroacetonitrile in acetonitrile (Scheme 2). This reaction requires potassium carbonate

in order to neutralize the generated byproduct hydrochloric acid4. Insertion of a cyano

group into a heteroarene can be achieved using similar conditions, utilizing halogenated

substrates and sodium cyanide as the nucleophile source5 (Scheme 3). Both of these

reactions are waste-intensive due to the use of halogenated reagents generating

hydrochloric acid upon transformation. This acid needs to be neutralized requiring an

addition of base such as KCO3, which lowers the atom economy of the reaction

(Scheme 2).

7

Scheme 2. Synthesis of a-amino nitrile using alkyl halide

Scheme 3. Synthesis of a-amino nitrile using aryl halide

1.3 C-H activation / α-amino nitrile formation

Transition metal-catalyzed C-H functionalization has enabled the synthesis of α-

aminonitriles without the use of halogenated stoichiometric reagents. Transition metal

catalysts such as vanadium, ruthenium, and iron have been employed in order to

functionalize Cα-H bonds in tertiary amines in α-cyanation6,7,8,9 (Schemes 4 and 5).

Scheme 4. Ruthenium/vanadium catalyzed cyanation of dimethylaniline.

8

Scheme 5. Iron catalyzed cyanation of dimethylaniline

Recent examples of tertiary amine oxidation protocols do not employ transition

metal catalysts, but also achieve α-cyanation10,11. Such reactivity can be observed with

the use of t-butyl peroxide as oxidant and tetrabutylammonium iodide as a catalyst10

(Scheme 6). This reaction has a limited substrate scope, which includes only substituted

tertiary anilines. The protocol in scheme 5 was developed for α-cyanation of tertiary

amines to give a non-catalyzed reaction using a safer source of cyanide11(Scheme 7).

This reaction is applicable to a wider variety of substrates, including tertiary aliphatic

amines.

Scheme 6. Oxidative cyanation of dimethylaniline

Scheme 7. Cyanation of tertiary amine using potassium thiocyanate

9

1.4 Significance

α-aminonitriles are intermediates in synthetic reactions due to the versatility of

reactions that can be performed to transform nitriles into a variety of functional groups2,

12. Functional groups that can be synthesized by transforming nitrile groups include

ketones, amines, amides, ethers, alcohols and aldehydes. Achieving α-cyanation using

a cheap source such as potassium cyanide would enable a cost effective approach to

functionalization of complex molecules. Furthermore, developing a system that can use

a variety of nucleophiles, such as cyanide, indole, trifluoromethyl and fluoride would be

a great accomplishment in synthetic chemistry.

1.5 Knowledge at project start and approach

The iron catalyzed amide synthesis developed in prior work in the Emmert

laboratory functionalizes tertiary amines; one possible mechanism is a reaction pathway

through an iminium intermediate 2 (Scheme 8)13. This pathway begins by a single

electron transfer to the iron catalyst, followed by a hydrogen atom transfer14. Water then

acts as a nucleophile, attacking the generated iminium ion, forming a hemiaminal

intermediate 3. The hemiaminal intermediate is transformed into the amide through an

additional oxidation step. The hemiaminal is also shown to undergo hydrolysis to

produce a secondary amine and aldehyde. The formation of amide versus hydrolysis

products is controlled by varying the water concentration.

10

Scheme 8. Mechanism proposed for tertiary amine oxidation

We hypothesized that the addition of cyanide ion would out compete water as a

nucleophile and produce α-aminonitriles in high yield. After testing our hypothesis using

dimethylaniline (Scheme 9) cyanation products were obtained suggesting the presence

of an iminium intermediate.

Scheme 9. Cyanation of diethylaniline using KCN and 18-crown-6

A variety of different protocols show α-cyanation of tertiary aniline structures6-11.

A substrate scope was to be conducted to explore the versatility of our iron catalyzed

methodology in order to include tertiary aliphatic amines. Optimization variables

11

included water, oxidant, cyanide and 18-crown-6 loadings as well as the reaction

temperature. Water is important in the formation of the iminium intermediate and needs

to be present in the reaction for optimal yield, however too much water might drive the

reaction to produce more amide byproduct or dealkylation byproducts. There is one

oxidation step in the synthesis of α-aminonitriles indicating one equivalent is necessary,

however the oxidant could be used up in side reactions, which may make the α-

cyanation require more than one equivalent. The concentration of cyanide ion in

solution is important to consider because it is the source of the cyano group. In order to

solubilize the potassium cyanide, 18-crown-6 was used as a phase transfer catalyst

helping bring potassium ions into the organic phase15. By systematically varying these

reactants, we hope to find conditions to access α-aminonitriles in high yield. In addition

to cyanation reactions, the scope of the Cα-H functionalizations was to be further

explored, including nucleophiles which would provide interesting functionalized

products.

12

2 Results and Discussion

2.1 Initial Experiments

Tripropylamine was used as a substrate to demonstrate that aliphatic amines can

undergo α-cyanation under our conditions. We hypothesized that aliphatic amines could

undergo α-cyanation because the iminium intermediate was accessed in the amine

oxidation reaction for aliphatic amines13. The reaction conditions used were the same as

the diethylaniline cyanation conditions. The cyanation product was identified by GCMS

and was determined to be 21% yield by NMR(Scheme 10).

Scheme 10. Cyanation of tripropylamine

The method for preparing samples for yield determination was optimized in order

to take clean NMR spectra. If iron is present in the sample then the spectra would show

broad signals that could not be integrated properly. The NMR spectra of a crude

reaction contains signals that overlap the desired signal from the product. In order to

take a clean spectra, the reaction needed to be put under vacuum to remove the

impurity that overlapped the desired signal. When the volatiles were removed, hexane

13

was added in order to solubilize the product without bringing the iron into the sample.

This method provided clean spectra without destroying the product.

All reactions were run at least in duplicate in order to calculate the standard

deviation of the yield in each reaction. When standard deviations are large then trends

become unclear. Precision is key to optimizing a chemical reaction. Small standard

deviations which do not overlap are necessary in order to have meaningful data that

indicates what conditions lead to higher yield.

Further optimization of the tripropylamine oxidation protocol was required to

achieve synthetically useful yields. Optimization was now possible with a proper work

up established.

2.2 Water optimization

Water was the first variable to be optimized because of its role in the mechanism

described above. In the cyanation reaction, water is no longer acting as a nucleophile

suggesting that amide conditions (11 eq. of water) contain too much water for optimal

cyanation conditions. We hypothesized that adding too much water could drive the

equilibrium towards the hemiaminial intermediate away from the iminium intermediate,

leading to amide formation or hydrolysis rather than cyanation product formation. For

this study all reagents were kept constant besides the water loading(Figure2).

14

Figure 2. Water Optimization

The water study shows that very high water loadings (6 to 30 eq. H2O) decreases

the amount of product formed. Furthermore, the data shows that the yield decreases

when lowering the water loading below four equivalents. This indicates that water plays

a key role in product formation. Notably, when using four equivalents of water, the yield

increases significantly to 48% from the yields seen at three and five equivalents of

water. Four equivalents of water is low enough to not promote hemiaminal formation,

while lower than four equivalents is not enough for optimal yield. Although water is not

the nucleophile in the cyanation reaction, it proves to be an important variable in the

reaction.

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2.3 Oxidant optimization

The next variable to be optimized was the oxidant loading due to its importance

in the mechanism. There is one oxidation step in the formation of the iminium

intermediate, which is required for the α-cyanation. Amide formation requires two

oxidation steps; the oxidation to the iminium intermediate and the oxidation from

hemiaminal to amide. Although there is only one oxidation step in the cyanation

reaction, it may be necessary to use more than one equivalent due to potential side

reactions that may take place. However, increasing the oxidant may promote amide

formation. An increase in the concentration of oxidant may also have favorable effects

on kinetics that would increase reaction yields. All reagents were kept constant besides

the oxidant loading(Figure 3). Water was kept at four equivalents due to the yield of

48% found in the water optimization.

Figure 3. Oxidant Optimization

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The data shows that at four equivalents of water two equivalents of oxidant are

needed to achieve maximum yield. Below 1.5 equivalents of oxidant the yield drops

significantly indicating the oxidant is being consumed in side reactions, thus requiring

more than one equivalent. When the oxidant loading exceeds 2.5 equivalents, amide

formation is promoted leading to a decrease in cyanation product yield. With water and

oxidant loading optimized, the next important variable was the cyanide source.

2.4 KCN optimization

The concentration of cyanide ion in solution is important when considering the

rate of α-cyanation compared to the rate of hemiaminal formation. For this reason we

hypothesized that increasing the cyanide concentration would increase the α-

aminonitrile generation rather than hydrolysis or amide side products. Crown ether is

used to help dissolve KCN into the organic phase by stabilizing the K+ ion and is kept at

30 mol % for this study, the amount used for diethylaniline cyanation15. Optimal water

and oxidant loadings were used and kept constant for this study along with the other

reagents.

17

Figure 4. KCN Optimization

Interestingly the highest yield is obtained when using around 1.0 equivalent of

potassium cyanide; the yield drops off significantly when decreasing and increasing the

loading from this ideal value. This does not support our hypothesis that increasing the

potassium cyanide would increase the rate of cyanation increasing yield. The decrease

in yield at loadings over 1.2 equivalents may indicate that the cyanide ion is degrading

the oxidant by nucleophilic substitution. It may also indicate that the catalyst is being

degraded by the cyanide ion possibly creating stable complexes such as potassium

ferricyanide K3[Fe(CN)6] and potassium ferrocyanide K4[Fe(CN)6]. The reactions with

1.0 and 1.2 equivalents of KCN had the highest yields of 52%, however at 1.2

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equivalents the standard deviation is smaller. Further optimization studies will use a

KCN loading of 1.2 equivalents.

2.5 18-crown-6 Optimization

Increasing the loading of crown ether is required in order to increase the

concentration of cyanide ion in solution without increasing the KCN loading. Therefore

we hypothesized that by increasing the 18-crown-6 loading we would increase the yield.

KCN, water and oxidant were kept at optimal loadings found above; 1.2, 4, and 2

equivalents respectively. All other conditions were kept constant from previous studies,

besides 18-crown-6 loading, which was varied from 10 mol % to 100 mol %.

Figure 5. 18-crown-6 Optimization

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19

The data shows that as the 18-crown-6 loading is increased from 10 mol % to

100 mol % the yield increases from 25% to 61%. The reaction containing 100 mol % of

18-crown-6 was the first to have a reported yield over 60%. 18-crown-6 is the most

expensive reagent in the cyanation reaction and this study shows that the loading needs

to be at least three times the previous loading to achieve optimal yield. Although the

increased crown ether loading increases the cost of the reaction, both GCMS and NMR

show that the 18-crown-6 is still present at the end of the reaction, potentially enabling it

to be reused in a batch process. 18-crown-6 loading was kept at 100 mol % for the

following optimization reactions.

2.6 Temperature optimization

After finding optimal water, oxidant, KCN and 18-crown-6 loadings, it was

necessary to optimize temperature of the reaction. The closer the reaction can run to

room temperature the better so that no additional energy has to be spent to construct

these chemicals, however by increasing the temperature you can change the kinetics of

the experiment which may allow for improved yields.

20

Figure 5. Temperature Optimization

This experiment shows that temperatures between 50 – 80 °C have little

influence on the overall yield of reaction; however, when the temperature drops to 40 °C

the yield drops significantly, suggesting at 40 °C there is not enough energy to achieve

Cα-H activation. Above 80 °C the yield also decreases, suggesting that at higher

temperatures the reaction contains more undesirable side products. The increased heat

may potentially promote the hydrolysis of the cyano group in the α-aminonitrile to give

the corresponding carboxylic acid. The temperature that will be used in the following

experiments will be 50 °C.

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21

2.7 Time Optimization

A time study was conducted in order to see when the majority of the reaction had

taken place. We hypothesized that most of the product formation would take place

before 24 hours; the reaction time for all previous studies. The best conditions found in

the previous optimization reactions were used in this study and kept constant for each

reaction. When the desired time had passed, the reactions were immediately prepared

to determine yield using NMR.

Figure 6. Time optimization

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22

The data shows that product formation is fastest in the first few hours, when the

majority of reactants are present. After about eight hours of reaction time the rate of

product formation decreases significantly, raising only an additional 10% in the

remaining 16 hours.

2.8 Additional loading of KCN and Oxidant

In the KCN optimization, decomposition of the catalyst was discussed as a

potential reasoning for decreased yield with increased KCN loading. In order to test if

the catalyst is being destroyed, an additional loading of KCN and oxidant were added

after the majority of the reaction had taken place. Amine starting material was identified

by GCMS in a 24 hour tributylamine cyanation reaction, indicating the yield could

increase if the reaction proceeded (Figure 7). We hypothesized that if the catalyst was

still present in an active form, then the yield of the reaction will increase when these

reagents are added. If the yield does not increase when adding an additional loading of

KCN and oxidant then we would conclude that the catalyst has been destroyed.

The best conditions found in previous optimization reactions were used. The time

study indicates that the majority of the cyanation reaction is complete at eight hours.

Three sets of reactions were prepared; one with no additional KCN and oxidant added,

one where the KCN and oxidant were added at 4.5 hours and one where KCN and

oxidant were added at eight hours.

23

Figure 7. Additional loading of oxidant and KCN

The data shows that by adding an additional loading of oxidant and KCN the

yield increases significantly from 61% in the optimized reaction with no loading to 77%

with addition at 4.5 hours and 82% with addition at 8 hours. This data indicates that the

catalyst is still present in the reaction allowing the reaction to continue. This also gives

evidence that the oxidant is the reagent that halts the product formation when KCN

loading is increased. A yield of 82% is the highest reported for the α-cyanation of

aliphatic amines.

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24

2.9 Substrate scope

All substrates were subjected to best cyanation reaction conditions of

tripropylamine. GCMS was used in order to determine if the cyanation product was

formed. Triethylamine and tributylamine were tested to show that this cyanation protocol

works well with acyclic, aliphatic tertiary amines. Piperidine and pyrrolidine were used to

test if the cyantion protocol works with cyclic, aliphatic secondary amines.

2.9.1 Cyanation of triethylamine

In analogous fashion to the cyanation of tripropylamine, triethylamine was

subjected to the best reaction conditions, with exception of 18-crown-6 loading which

was kept at 30 mol %(Scheme 11). The GCMS trace shows few major compounds in

this reaction. The three largest signals present are the cyanation product, 18-crown-6,

and methyl benzoate. Methyl benzoate is likely a side product that comes from the

oxidant tert-butylperoxybenzoate. Side products include diethylbenzamide, which we

hypothesize is formed from diethylamine reacting with tert-

butylperoxybenzoate(Scheme 12); diethylamine itself can likely be formed through

hydrolysis of the hemiaminal intermediate described in the mechanism. The cyanation

of trimethylamine produces a relatively clean reaction. This reaction was prepared for

NMR which yielded 43% cyanation product.

25

Scheme 11. Cyanation of triethylamine

Scheme 12. Nucleophilic addition of diethylamine to tert -butylperoxybenzoate

2.9.2 Cyanation of tributylamine

Tributylamine was subjected to cyanation conditions analogous to the cyanation

of triethylamine. GCMS analysis of the resulting reaction shows more side products

than have been observed in the cyanation of triethylamine. Two of these side products,

dibutylamine and N-butylbutan-1-imine, are due to dealkylation of the substrate

occurring through hydrolysis of the hemiaminal intermediate. The other side products

that are formed in the reaction mixture for tributylamine cyanation are double-oxidation

products such as dibutylbutanamide, caused by oxidation of the hemiaminal

intermediate13. Although there are many side products in the GCMS trace, the cyanation

product is present in the highest yield. This reaction was prepared for NMR which

yielded 54% cyanation product. Based on the cyanation of triethylamine, tripropylamine

26

and tributylamine, we can conclude that our cyanation protocol excels with tertiary

aliphatic amines.

Scheme 13. Cyanation of tributylamine

2.9.3 Cyanation of Pyrrolidine and piperidine

The cyanation of cyclic tertiary amines has previously been accomplished by

others using various transition metal catalysts, however most include the cyanation at

benzylic C-H bonds16-21. Piperidine and pyrrolidine were subjected to cyanation

conditions analogous to the cyanation of triethylamine(Scheme 14). We hypothesized

that the cyanation of these cyclic amines would be difficult because they have not

shown to undergo oxidation under the amide protocol. Both the cyanation of piperidine

and pyrrolidine show similar side products in the GCMS trace. Neither the piperidine or

pyrrolidine reaction had a significant amount of product formation, yielding crude NMR

yields of 5% and 12%. The major side product seen is a result of nucleophilic reaction

between the secondary amine substrates and the oxidant(Scheme 15). Although the

desired products were not preferentially formed, they are still present in the reactions

indicating the α-cyanation can be achieved for cyclic amines. This is the first time we

have been able to functionalize cyclic amines with our reaction conditions.

27

Scheme 14. Cyanation of piperidine and pyrrolidine

Scheme 15. Nucleophilic addition of piperidine to tert-butylperoxybenzoate

2.10 Nucleophile scope

After the optimization of tripropylamine and the substrate scope were concluded,

we investigated other potential nucleophiles for the functionalization of tertiary amines.

We hypothesized that these potential nucleophiles could access the same proposed

iminium intermediate discussed for the cyanation reaction. Nucleophiles we are most

interested in are indole and trifluoromethyl cation. Indole would show that electron rich

pi systems could add to iminium ion intermediates and could potentially make complex

biologically active compounds. The addition of trifluoromethyl cation could allow for the

creation of compounds that are both biologically active and can also be monitored due

28

to the fluorinated group. Development of reactions that afford new C-C bond formation

is crucial to the advancement of organic chemistry.

2.10.1 Literature precedent

Indole can be coupled with an enamide showing preferential addition to the alpha

position of tertiary amine (Scheme 16). This reaction supports the hypothesis that if the

iminium intermediate is formed during the reaction then indole could couple using its pi

electrons 22, 23.

Scheme 16. FeCl3 promoted alkylation of indole by reaction with an enamide

Iron chloride and di-tert-butyl peroxide were used for the addition of indole to a

tertiary amine24(Scheme 17). This reaction also uses a cyclic amine substrate that is

adjacent to a benzene ring, much like tribenzylamine. The substrate also contains

diethylaniline substructure which may be necessary for the reaction to take place. Both

of these factors lower the bond dissociation energy of the C-H bond making the reaction

more facile.

29

Scheme 17. Iron catalyzed oxidative coupling of alkylamines

2-phenyl-1,2,3,4-tetrahydroquinoline has been used as a substrate with CuBr

and di-benzyl peroxide (Scheme 18)25 to provide the α-functionalized amine.

Trifluoromethylation of tertiary amines has only been demonstrated with this substrate

which contains benzylic C-H bonds within a tertiary aniline structure.

Scheme 18. Trifluoromethylation of tertiary amines with

trimethyl(trifluoromethyl)silane

2.10.2 Indole

Tribenzylamine and diethylaniline were used with indole in our catalytic system to

see if bond formation was possible. Diethylaniline is often used for Cα-H

30

functionalization and tribenzylamine contains three sites where benzylic C-H bonds can

be oxidized, making these substrates good candidates for the coupling with indole.

Reactions with tripropylamine, diethylaniline and piperidine have shown no signal

on the GCMS that corresponds to the coupling of amine and indole. Tribenzylamine

reaction with indole shows a peak that has a mass spectrum that corresponds to the

coupling with indole, reaction conditions seen in Scheme 19. None of the products of

amine and indole coupling have been reported, which makes identification by mass

spectrometry difficult. However, it gives a good idea about what substructures are

present in each signal. The GCMS trace of tribenzylamine and indole reaction is shown

in figure 13.

Scheme 19. Indolation of tribenzylamine

2.10.3 Trifluoromethyl

With similar reasoning as above, having benzylic C-H bonds and an aniline

substructure, tribenzylamine and diethylaniline were used for the addition of

trifluoromethyl cation to iminium intermediates. Tripropylamine was also used to test

these conditions. The reactions were set up using trimethyl(trifluoromethyl)silane as the

31

source for the trifluoromethyl cation. KF was added to activate the trifluoromethyl

cation(Scheme 20). The reactions were run without water because water has shown to

shut the reaction down25. The addition of a trifluoromethyl group has so far been

unsuccessful.

Scheme 20. Activation of trifluoromethyl cation25

32

3 Summary, Conclusions, and Future Directions

We have successfully developed the cyanation reaction of tertiary alkyl amines

through carefully optimizing the tripropylamine cyanation. We have learned that the

cyanation of tripropylamine is water dependent requiring 4 equivalents of water for

optimal yield. We have also learned that the reaction requires 1.0 equivalent of 18-

crown-6 to achieve cyanation yields over 60%. We have shown that the yield drops

when adding more than 1.2 equivalents of KCN at the start of the reaction, likely

degrading the oxidant. We have also shown that by adding more than 2.5 equivalents of

tert-butylperoxybenzoate at the start of the reaction, the yield drops, likely due to double

oxidation side products. However, more cyanation product is formed when adding an

additional KCN and oxidant loading after eight hours. This increased yield suggests that

either the KCN or oxidant is depleted before the substrate is consumed. It also suggests

that the iron catalyst is not destroyed in the presence of cyanide ion, which was

suggested when discussing the drop in yield with high KCN loadings. Through

investigating the cyanation of tripropylamine we have learned that our iron catalyzed

system produces α-aminonitriles in high yield.

Continuation of the cyanation of tertiary amines would focus on the development

of the substrate scope. This will give information about the versatility of the cyanation

protocol, as well as give information about the types of substrate that are required for

this type of bond formation. Optimization of the cyanation of cyclic secondary amines

could provide a useful yielding reaction. The cyanation of more complex amines, such

as those with other functional groups, would demonstrate a selective functionalization

without altering the rest of the molecule.

33

Following cyanation optimization of a variety of substrates will be the

development of a nucleophile scope. Most additions of indole and trifluoromethyl to

tertiary amines require both benzylic C-H bonds and an aniline substructure23, 24. Since

our cyanation reaction works with tertiary aliphatic amines, it may lead to products that

have not since been synthesized and characterized. Optimizing the indolation and

trifluoromethylation of tertiary amines should be developed further in the Emmert Lab.

In general, the nucleophile scope has shown little potential for the

functionalization of tertiary aliphatic amines. However the indolation of tribenzylamine

looks possible from our preliminary results, suggesting the reaction requires a benzylic

C-H bond. If the product peak found on the GCMS corresponds to the desired product,

then that is the first time that compound has been synthesized. Achieving new C-C

bond formation through tertiary amine functionalization can allow for the creation of

complex molecules which were previously either unattainable or difficult to create.

When creating new C-C bonds in the α-position of tertiary amines, a chiral center

is formed. Many pharmaceuticals require specific chiral centers to have biological

activity, while the undesired chiral center may have no activity or harmful side effects.

Having specificity in alpha functionalized reactions would lead to more desirable

reactions. We believe that our cyanation reaction produces a racemic mixture of the

cyanation products. If we were to know what the catalyst looked like and how the amine

was oriented when the reaction takes place, we could potentially design ligands to

enable an enantioselective addition, providing one chiral center. So far we do not know

what the iron catalyst looks like in solution. We believe that the ligands around the iron

are picolinic acid, pyridine and water, however we have not obtained the crystal

34

structure. Future work should focus on gathering information on what the catalyst looks

like in solution, starting with the crystallization of the complex.

35

4 Experimental Section

4.1 General procedures: techniques, solvents and chemicals

All reactions were performed in air unless stated otherwise. Pyridine used in

experiments had 150uL of water added per 500mL, other reagents were used without

additional work up. Standard solutions of reagents were made with volumetric flasks in

order to increase the accuracy of reaction preparation. Stir bars used in reactions were

cleaned with aqua regia, followed by a thorough rinse with water, then dried in the oven

at 120 °C. Yields are reported as averages of at least two experimental procedures and

error is given as a standard deviation.

4.2 Analytical methods

4.2.1 NMR spectroscopy

1H NMR spectra were recorded on a Bruker BioSpin 500MHz Avance III Digital

NMR spectrometer (1H: 500 MHz). To determine yields for catalytic reactions, NMR

spectra were referenced to an internal standard of trichloroethane. The shift of the

standard signal in CDCl3 was calibrated to 7.26ppm. Details on quantitative

measurements of product are found in additional information.

4.2.2 GCMS

GCMS methods were used to confirm the presence of products and to identity

possible side products in all catalytic reactions. GCMS measurements were performed

on a GCMS System 5975 Series Quadrupole.

36

4.2.3 Literature search

Literature searches were frequently used to find synthetic procedures and

spectra. SciFinder and the WPI Library were utilized to gather information on similar

catalytic reactions to aid in reaction development. Reaxys was used for gathering

organic synthesis procedures.

4.3 Catalytic cyanation studies

4.3.1 Typical procedure for cyanation reactions

To a 4mL scintillation vial, equipped with a Teflon coated stir bar, potassium

cyanide (8.1 mg, 125 μmol, 1.0 eq.) and 18-crown-6 (9.9 mg, 30 mol %) were added. To

this vial a standard solution of picolinic acid (0.77 mg, 5.0 mol %), iron chloride

hexahydrate (1.7 mg, 5 mol %) and pyridine (0.45 mL, 5.6 mmol) was added. Water (9.0

μL, 4 eq.) followed by tert-butylperoxybenzoate (47 μL, 2 eq.) were added to this vial.

Finally substrate (125 μmol, 1 eq.) was added to the vial. The vial was sealed with a

Teflon lined cap and heated to 50° C on vial hot plate, stirring at 800 rpm for 24 hours.

NMR samples were prepared by removing pyridine by vacuum and adding

trichloroethane (125 μmol, 11.5 μL) and hexane ( 0.5 mL). The reaction vial was then

vigorously shaken and the organic layer was taken for NMR.

4.3.2 Water optimization

By analogy to the general procedure for the cyanation reaction presented above

(Error! Reference source not found.), tripropylamine (24 μL, 18 mg, 125 μmol, 1.0

37

eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol %), picolinic acid (0.77 mg, 6.25 μmol, 5 mol %),

tert-butyl peroxybenzoate (58.3 mg, 60 mg, 313 μmol, 2.5 eq.), water (0 – 67.5 μL, 0 –

67.5 mg, 0 – 3.75 mmol, 0 – 30 eq.), potassium cyanide (8.1 mg, 125 μmol, 1.0 eq.),

and 18-crown-6 (9.9 mg, 37.5 μmol, 30 mol %), were reacted in pyridine (0.45 mL, 5.6

mmol), for 24 h at 50°C. Workup and analysis were performed as described above.

Table 1. Calibrated NMR yields of water optimization study with FeCl3 catalyst system. Conditions:

Tripropylamine (24 μL, 18 mg, 125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol %), picolinic acid (0.77

mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (58.3 mg, 60 mg, 313 μmol, 2.5 eq.), water (0 – 67.5

μL, 0 – 67.5 mg, 0 – 3.75 mmol, 0 – 30 eq.), potassium cyanide (8.1 mg, 125 μmol, 1.0 eq.), 18-crown-6

(9.9 mg, 37.5 μmol, 30 mol %), pyridine (0.45 mL, 5.6 mmol), 50°C. The yield is the average of two

duplicate trials. The reported error is the standard deviation of two duplicate trials.

Entry Amount (μL) Equivalents Yield

2BJO57A/B 0 0 18.5% +/- 1.4

2BJO57C/D 4.5 2 26.9% +/- 0.4

2BJO63A/B 6.8 3 32.5% +/- 0.7

2BJO57E/F & 63C/D 9.0 4 48.0% +/- 2.0

2BJO63E/F 11.7 5 31.5% +/- 0.7

2BJO57G/H 13.5 6 24.4% +/- 1.3

2BJO57I/J 18.0 8 17.8 +/- 1.0

2BJO57K/L 22.5 10 14.8% +/- 0.0

2BJO57M/N 33.8 15 9.3% +/- 0.7

2BJO57O/P 67.5 30 4.2% +/- 0.1

38

4.3.3 Oxidant optimization




tert-butyl peroxybenzoate (23.3 – 69.9 μL, 24.2 – 72.7 mg, 125 – 375 μmol, 1.0 – 3.0

eq.), water (9 μL, 9 mg, 500 mmol, 4 eq.), potassium cyanide (8.1 mg, 125 μmol, 1.0

eq.), and 18-crown-6 (9.9 mg, 37.5 μmol, 30 mol %), were reacted in pyridine (0.45 mL,

5.6 mmol), for 24 h at 50°C. Workup and analysis were performed as described above.

Table 2. Calibrated NMR yields of oxidant optimization study with FeCl3 catalyst system.

Conditions: Tripropylamine (24 μL, 18 mg, 125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol %),

picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (23.3 – 69.9 μL, 24.2 – 72.7 mg,

125 – 375 μmol, 1.0 – 3.0 eq.), water (9.0 μL, 9.0 mg, 500 μmol, 4 eq.), potassium cyanide (8.1 mg, 125

μmol, 1.0 eq.), 18-crown-6 (9.9 mg, 37.5 μmol, 30 mol %), pyridine (0.45 mL, 5.6 mmol), 50°C. The yield

is the average of two duplicate trials. The reported error is the standard deviation of two duplicate trials.

Entry Amount (μL) Equivalents Yield

2BJO64A/B 23.3 1.0 26.0% +/- 1.4

2BJO64C/D 35.0 1.5 46.0% +/- 3.0

2BJO64E/F & 65A/B 46.7 2.0 52.0% +/- 2.0

2BJO64G/H & 65C/D 58.3 2.5 48.0% +/- 2.0

2BJO64I/J 69.9 3.0 39.0 +/- 0.0

4.3.4 Temperature optimization



39


tert-butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), water (9.0 μL, 9.0 mg,

500 μmol, 4 eq.), potassium cyanide (8.1 mg, 125 μmol, 1.0 eq.), and 18-crown-6 (9.9

mg, 37.5 μmol, 30 mol %), were reacted in pyridine (0.45 mL, 5.6 mmol), for 24 h at 40°

– 70° C. Workup and analysis were performed as described above.

Table 3. Calibrated NMR yields of temperature optimization study with FeCl3 catalyst system.


picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0

eq.), water (9.0 μL, 9.0 mg, 500 μmol, 4 eq.), potassium cyanide (8.1 mg, 125 μmol, 1.0 eq.), 18-crown-6

(9.9 mg, 37.5 μmol, 30 mol %), pyridine (0.45 mL, 5.6 mmol), 40° – 70° C. The yield is the average of two


Entry Temperature (oC) Equivalents Amount (μL) Yield

2BJO47E/F 70 1.5 35.0 56.0% +/- 3.0

2BJO47G/H 70 2.5 58.3 57.0% +/- 5.0

2BJO49E/F 60 1.5 35.0 46.0% +/- 3.0

2BJO49G/H 60 2.5 58.3 46.0% +/- 0.4

2BJO47A/B 50 1.5 35.0 50.0% +/- 2.0

2BJO47C/D 50 2.5 58.3 63.5% +/- 0.7

2BJO49I/J 40 1.5 35.0 25.0 +/- 2.0

2BJO49K/L 40 2.5 58.3 33.0% +/- 0.7

4.3.5 KCN optimization




40


500 μmol, 4 eq.), potassium cyanide (4.0 – 24.4 mg, 62.5 – 375 μmol, 0.5 – 3.0 eq.),

and 18-crown-6 (9.9 mg, 37.5 μmol, 30 mol %), were reacted in pyridine (0.45 mL, 5.6


Table 4. Calibrated NMR yields of KCN optimization study with FeCl3 catalyst system. Conditions:


mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), water (9.0 μL,

9.0 mg, 500 μmol, 4 eq.), potassium cyanide (4.0 – 24.4 mg, 62.5 – 375 μmol, 0.5 – 3.0 eq.), 18-crown-6

(9.9 mg, 37.5 μmol, 30 mol %), pyridine (0.45 mL, 5.6 mmol), 50°C. The yield is the average of two


Entry Amount (mg) Equivalents Yield

2BJO68A/B 4.1 0.5 24.5% +/- 0.7

2BJO68C/D 6.5 0.8 27.0% +/- 0.0

2BJO67A/B 8.1 1.0 52.0% +/- 2.0

2BJO68E/F 9.8 1.2 53.0% +/- 0.0

2BJO67C/D 12.2 1.5 30.0% +/- 0.0

2BJO67E/F 16.3 2.0 28.5% +/- 2.0

2BJO67G/H 20.4 2.5 27.0% +/- 1.4

2BJO67I/J 24.4 3.0 22.0% +/- 2.0

4.3.6 18-Crown-6 Optimization





41

500 μmol, 4 eq.), potassium cyanide (9.8 mg, 150 μmol, 1.2 eq.), and 18-crown-6 (3.3 –

33 mg, 12.5 – 125 μmol, 10 – 100 mol %), were reacted in pyridine (0.45 mL, 5.6


Table 5. Calibrated NMR yields of 18-crown-6 optimization study with FeCl3 catalyst system.




(3.3 mg – 33 mg, 12.5 – 125 μmol, 10 – 100 mol %), pyridine (0.45 mL, 5.6 mmol), 50°C. The yield is the

average of two duplicate trials. The reported error is the standard deviation of two duplicate trials.

Entry Amount (mg) Mol % Yield

2BJO72A/B 3.3 10 26.0% +/- 4.0

2BJO72C/D 5.0 15 25.5% +/- 2.0

2BJO72E/F 6.6 20 31.5% +/- 3.5

2BJO72G/H & 75A/B 8.3 25 35.0% +/- 5.0

2BJO72I/J & 75C/D 11.6 35 43% +/- 5.0

2BJO75E/F 16.5 50 50.0% +/- 2.3

2BJO72K/L 33 100 65.5% +/- 0.7

4.3.7 Temperature Optimization





500 μmol, 4 eq.), potassium cyanide (9.8 mg, 150 μmol, 1.2 eq.), and 18-crown-6 (33

42

mg,125 μmol, 100 mol %), were reacted in pyridine (0.45 mL, 5.6 mmol), for 24 h at 50

– 90 °C. Workup and analysis were performed as described above.

Table 6. Calibrated NMR yields of temperature optimization study with FeCl3 catalyst system.




(33 mg, 125 μmol, 100 mol %), pyridine (0.45 mL, 5.6 mmol), 50 – 90 °C. The yield is the average of two


Entry Temperature (°C) Yield

2BJO78G/H 40 48% +/- 1.4

2BJO78C/D 50 61.0% +/- 4.5

2BJO78E/F & 79A/B 60 61.5% +/- 2.0

2BJO78A/B 70 61.5% +/- 3.0

2BJO79C/D 80 58.0% +/- 0.0

2BJO79E/F 90 47.0% +/- 4.0

4.3.8 Time Optimization






mg,125 μmol, 100 mol %), were reacted in pyridine (0.45 mL, 5.6 mmol), for 1 – 24 h at

50 °C. Workup and analysis were performed as described above.

43

Table 7. Calibrated NMR yields of time optimization study with FeCl3 catalyst system. Conditions:


mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), water (9.0 μL,

9.0 mg, 500 μmol, 4 eq.), potassium cyanide (9.8 mg, 150 μmol, 1.2 eq.), 18-crown-6 (33 mg, 125 μmol,

100 mol %), pyridine (0.45 mL, 5.6 mmol), 50 °C. The yield is the average of two duplicate trials. The

reported error is the standard deviation of two duplicate trials.

Entry Time (h) Yield

2BJO76A/B 1 28.5% +/- 0.5

2BJO76C/D 2 35.0% +/- 2.5

2BJO76E/F 3 39.0% +/- 2.0

2BJO76G/H 4 42.5% +/- 2.0

2BJO80A/B 6.5 43.6% +/- 1.2

2BJO80C/D 8.5 50.6% +/- 2.0

2BJO78C/D 24 61.0% +/- 4.5

4.3.9 Additional loading of KCN and Oxidant






mg,125 μmol, 100 mol %), were reacted in pyridine (0.45 mL, 5.6 mmol), for 4.5 and 8 h

at 50 °C. Afterwards an additional loading of potassium cyanide (9.8 mg, 150 μmol, 1.2

eq.) and 18-crown-6 (33 mg,125 μmol, 100 mol %) were added. Workup and analysis

were performed as described above.

44

Table 8. Calibrated NMR yields of additional loading of oxidant and KCN study with FeCl3 catalyst

system. Conditions: Tripropylamine (24 μL, 18 mg, 125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol

%), picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), 2 x tert-butyl peroxybenzoate (46.7 μL, 48.6 mg, 250

μmol, 2.0 eq.), water (9.0 μL, 9.0 mg, 500 μmol, 4 eq.), 2 x potassium cyanide (9.8 mg, 150 μmol, 1.2

eq.), 18-crown-6 (33 mg, 125 μmol, 100 mol %), pyridine (0.45 mL, 5.6 mmol), 50 °C. The yield is the

average of two duplicate trials. The reported error is the standard deviation of two duplicate trials.

Entry Time before second addition (h)

Yield

2BJO78C/D No addition 61.0% +/- 4.5

2BJO80E/F 4.5 77.0% +/- 3.0

2BJO80G/H 8 81.5% +/- 2.0

4.3.10 Substrate scope development


(Error! Reference source not found.), amine (125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25

μmol, 5 mol %), picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate

(58.3 mg, 60 mg, 313 μmol, 2.5 eq.), water (9.0 μL, 9.0 mg, 500 μmol, 4 eq.), potassium

cyanide (9.8 mg, 150 μmol, 1.2 eq.), and 18-crown-6 (9.9 mg, 37.5 μmol, 30 mol %),

were reacted in pyridine (0.45 mL, 5.6 mmol), for 24 h at 50°C. Workup and analysis

were performed as described above. Amines used shown in figure 11. GCMS trace

shown in Figures 12-15.

45

Figure 11: Substrates Used with Cyanation Reaction

Figure 8. GCMS trace of triethylamine cyanation reaction

46

Figure 9. GCMS trace of tributylamine cyanation reaction

Figure 10. GCMS trace of pyrrolidine cyanation reaction

Figure 11. GCMS trace of pyrrolidine cyanation reaction

47

4.4 Nucleophile and substrate studies

4.4.1 Typical procedure for indole reactions

To a 4mL scintillation vial, equipped with a Teflon coated stir bar, indole (14.6

mg, 150 μmol, 1.2 eq.) was added. To this vial a standard solution of picolinic acid (0.77

mg, 6.25 μmol, 5.0 mol %), iron chloride hexahydrate (1.7 mg, 6.25 μmol, 5 mol %) and

pyridine (0.45 mL, 5.6 mmol) was added. Water (9.0 μL, 9 mg, 500 μmol, 4 eq.)

followed by tert-butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.) were added

to this vial. Finally substrate (125 μmol, 1 eq.) was added to the vial. The vial was

sealed with a Teflon lined cap and heated to 80° C on vial hot plate, stirring at 800 rpm

for 24 hours.

GCMS samples were prepared by adding four drops of crude reactions mixture

to GCMS vial and diluting with 1.0 mL of ethyl acetate.

4.4.2 Substrate scope of amine indolation

By analogy to the general procedure for the indole reaction presented above

(Error! Reference source not found.), amine (125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25

μmol, 5 mol %), picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate

(46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), water (9 μL, 9 mg, 500 mmol, 4 eq.), and indole

(14.6 mg, 150 μmol, 1.2 eq.), were reacted in pyridine (0.45 mL, 5.6 mmol), for 24 h at

80°C. Workup and analysis were performed as described above. Amines used shown in

figure 12.

48

Figure 12: Substrates Used with Indole Reaction

Figure 13. GCMS Trace of Tribenzylamine Indole Reaction

4.4.3 Solvent scope of amine indolation


(Error! Reference source not found.), tribenzylamine (35.9 mg, 125 μmol, 1.0 eq.),

FeCl3 (1.7 mg, 6.25 μmol, 5 mol %), picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-

49

butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), and indole (14.6 mg, 150

μmol, 1.2 eq.), were reacted in a solvent (0.45 mL), for 24 h at 80°C. Solvents used

were pyridine, toluene, dichloromethane and acetonitrile. Workup and analysis were

performed as described above.

4.4.4 Acid catalyzed amine indolation




butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), indole (14.6 mg, 150 μmol,

1.2 eq.), and acetic acid (1.0 μL, 12.5 μmol, 15 mol %), were reacted in either pyridine

(0.45 mL, 5.6 mmol) or toluene (0.45 mL, 4.2 mmol), for 24 h at 80°C. Workup and

analysis were performed as described above.

4.4.5 Amine indolation without water




butyl peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.), indole (14.6 mg, 150 μmol,

1.2 eq.), and acetic acid (1.0 μL, 12.5 μmol, 15 mol %), were reacted in dry toluene

(0.45 mL, 4.2 mmol), for 24 h at 80°C. Toluene was dried with molecular sieves.

50

Molecular sieves were added to the reaction to reduce water content. Workup and

analysis were performed as described above.

4.4.5 Typical procedure for amine trifluoromethylation

To a 4mL scintillation vial, equipped with a Teflon coated stir bar, tetra-butyl

ammonium fluoride (39.2 mg, 150 μmol, 1.2 eq.) was added. To this vial a standard

solution of picolinic acid (0.77 mg, 6.25 μmol, 5.0 mol %), iron chloride hexahydrate (1.7

mg, 6.25 μmol, 5 mol %) and pyridine (0.45 mL, 5.6 mmol) was added.

Trimethyl(trifluoromethyl)silane (22.2 μL, 21.3 mg, 150 μmol, 1.2 eq.) and tert-butyl

peroxybenzoate (46.7 μL, 48.6 mg, 250 μmol, 2.0 eq.) were added to this vial. Finally

substrate (125 μmol, 1 eq.) was added to the vial. The vial was sealed with a Teflon

lined cap and heated to 80° C on vial hot plate, stirring at 800 rpm for 24 hours.

GCMS samples were prepared by adding four drops of crude reactions mixture

to GCMS vial and diluting with 1.0 mL of ethyl acetate.

4.4.6 Substrate scope of amine trifluoromethylation

By analogy to the general procedure for the trifluoromethylation reaction

presented above (4.4.5), amine (125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol %),

picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (46.7 μL, 48.6

mg, 250 μmol, 2.0 eq.), potassium fluoride (8.7 mg, 150 μmol, 1.2 eq.), 18-crown-6 (9.9

mg, 37.5 μmol, 30 mol %), and trimethyl(trifluoromethyl)silane (21.2 mg, 22.0 μL, 150

51

μmol, 1.2 eq.), were reacted in pyridine (0.45 mL, 5.6 mmol), for 24 h at 80°C. Workup

and analysis were performed as described above. Amines used shown in figure 14.

Figure 14: Substrates Used with Trifluoromethylation Reaction

4.4.7 Tetrabutylammonium fluoride as source of F- in amine trifluoromethylation

By analogy to the general procedure for the trifluoromethylation reaction

presented above (4.4.5), amine (125 μmol, 1.0 eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol %),

picolinic acid (0.77 mg, 6.25 μmol, 5 mol %), tert-butyl peroxybenzoate (46.7 μL, 48.6

mg, 250 μmol, 2.0 eq.), tetrabutylammonium fluoride trihydrate (47 mg, 150 μmol, 1.2

eq.), and trimethyl(trifluoromethyl)silane (21.2 mg, 22.0 μL, 150 μmol, 1.2 eq.), were

reacted in dry pyridine (0.45 mL, 5.6 mmol), for 24 h at 80°C. Workup and analysis were

performed as described above. Amines used shown in figure 14.

5.0 Additional Information

The NMR signal on the right corresponds to the proton on the α-carbon that has

undergone cyanation in tripropylamine. This proton is more deshielded than the rest of

the protons in the product, which tend to be masked by other organics in the reaction,

52

allowing this integral to represent the population of product. The signal on the left is the

NMR standard trichloroethane.

Figure 13. 1,1,2-trichloroethane (left) and α-amoninitrile (right) NMR signals

The solvent peak was used to calibrate the axis (7.26 ppm). The product peak

was found at 3.50 ppm. The ratio of integrals between product and standard peaks were

used to determine yield. Standard integral of trichloroethane was calibrated to 1. If 1

equivalent of NMR standard is used then Eq. 1 can be used to determine yield.

𝑝𝑒𝑟𝑐𝑒𝑛𝑡 𝑦𝑖𝑒𝑙𝑑 = 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 𝑖𝑛𝑡𝑒𝑔𝑟𝑎𝑙 × 100

Eq. 1

53

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