Post on 06-Jul-2020
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.
0
10
20
30
40
50
60
0 2 3 4 5 6 8 10 15 30
Cru
de
NM
R Y
ield
(%
)
Water loading (eq.)
15
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
0
10
20
30
40
50
60
1 1.5 2 2.5 3
Cru
de
NM
R Y
ield
(%
)
PhCO3tBu Loading (eq.)
16
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
0
10
20
30
40
50
60
0.5 0.8 1 1.2 1.5 2 2.5 3
Cru
de
NM
R Y
ield
(%
)
KCN Loading (eq.)
18
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
0
10
20
30
40
50
60
70
10 15 20 25 35 50 100
Cru
de
NM
R Y
ield
(%
)
18-crown-6 Loading (mol %)
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.
0
10
20
30
40
50
60
70
40 50 60 70 80 90
Cru
de
NM
R Y
ield
(%
)
Reaction Temperature (oC)
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
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30
Cru
de
NM
R Y
ield
(%
)
Reaction Time (h)
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.
0
10
20
30
40
50
60
70
80
90
no addition 4.5 8
Cru
de
NM
R Y
ield
(%
)
Reaction time before second addition of Ox. and KCN (h)
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
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
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 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
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
39
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 (9.0 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.
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 (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
duplicate trials. The reported error is the standard deviation of two duplicate trials.
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
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
eq.), FeCl3 (1.7 mg, 6.25 μmol, 5 mol %), picolinic acid (0.77 mg, 6.25 μmol, 5 mol %),
40
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.),
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 4. Calibrated NMR yields of KCN 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 (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
duplicate trials. The reported error is the standard deviation of two duplicate trials.
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
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
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 (9.0 μL, 9.0 mg,
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
mmol), for 24 h at 50°C. Workup and analysis were performed as described above.
Table 5. Calibrated NMR yields of 18-crown-6 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 (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
(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
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
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 (9.0 μL, 9.0 mg,
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.
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 (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 – 90 °C. The yield is the average of two
duplicate trials. The reported error is the standard deviation of two duplicate trials.
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
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
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 (9.0 μL, 9.0 mg,
500 μmol, 4 eq.), potassium cyanide (9.8 mg, 150 μmol, 1.2 eq.), and 18-crown-6 (33
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:
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 (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
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
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 (9.0 μL, 9.0 mg,
500 μmol, 4 eq.), potassium cyanide (9.8 mg, 150 μmol, 1.2 eq.), and 18-crown-6 (33
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
By analogy to the general procedure for the cyanation 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
(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
By analogy to the general procedure for the indole reaction presented above
(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
By analogy to the general procedure for the indole reaction presented above
(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-
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
By analogy to the general procedure for the indole reaction presented above
(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-
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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