1.

Introduction
Humans have come a long way on the path of drug synthesis from using natural products
derived from plants and animals to modern synthetically produced drugs such as aspirin in the
late 1900s (Center for Drug Discovery, 2013).

Along this path, both the efficiency and

effectiveness of drugs have been improved and one method of doing this was accomplished
through changing the shape of the drug (conformation) which directly affects its function. Two
molecules of the same drug can have different shapes (enantiomers) and therefore different
effects just like how puzzle pieces with different shapes do not fit in the same spot. This
research explores using a novel reaction to promote one particular enantiomer of a drug over the
other. To understand why this increases the efficacy of the drug, we first have to understand
what enantiomers are and their importance to drug synthesis.
Enantiomers are two mirror images of the same compound. This is based on the fact that
there are certain carbon atoms in organic molecules with four groups attached in such a way that
their rearrangement causes a conformation to be obtained which cannot just be obtained by
rotating or transposing the original orientation. This principle is also true of your right and left
hands and is known as chirality. If you look at your hands, you can see that although your hands
are identical, there is no way to rotate or transpose your right hand so it sits perfectly on top of
your left. Molecules behave the same way and enantiomers of two molecules occur when every
chiral center has been flipped to give you the perfect mirror image.
Although they only involve a small conformational change, enantiomers can have very
different properties. This is very similar to enzymes in biology. A certain enzyme can only bind
to certain substrates because of its shape, similar to how a key can only fit in its corresponding

Introduction

lock. Enantiomers behave similarly which makes certain enantiomers of a drug more effective
than others.1 An extreme example of how enantiomers can be the difference between life and
death is the drug thalidomide. Used to treat morning sickness, it was later discovered that
thalidomide was caused serious birth deformities (teratogenic).

Recently though, research

elucidated that only the S-enantiomer of thalidomide was teratogenic in mice and rats while the
R-enantiomer was truly useful in treating diseases.2 Although this example is an extreme case
where enantioselectivity is a matter of life and death, most drugs (even common ones like
ibuprofen) have an ineffective and effective enantiomer.1 The majority of drugs are also sold as
racemic mixtures (equal amounts of each enantiomer), so taking 100 mg of ibuprofen would
have the same effect as taking 50 mg of the S-enantiomer (the effective enantiomer). Therefore,
being able to synthesize or isolate a specific enantiomer of a drug greatly improves efficiency.
The challenge with obtaining a specific enantiomer of a drug lies in the fact that
enantiomers are so similar to one another. Since only their spatial conformations are different,
enantiomers have the same physical properties such as boiling point and Rf (retardation factor),
making them impossible to separate through conventional methods such as distillation or column
chromatography. Thus it is easier to synthesize drugs enantioselectively rather than isolate
enantiomers from racemic mixtures. By changing on the location and method nucleophiles
attack molecules, researchers can obtain certain enantiomers over the other.

However,

increasing the enantioselectivity of reactions is very difficult since we do not fully understand the
reaction mechanisms of most reactions and cannot fully predict how nucleophiles will attack
molecules. Thus, enantioselective synthesis has been and will remain a major focus of 21st
century research.

Introduction

An unique new method developed

by Yamaguchi et al in 2008 to tackle this
problem proposed using cyclopropane

Figure 1 - Geometry of a
cyclopropane ring

groups to restrict the conformation of

drug molecules.3 Since a cyclopropane is
a relatively small group, the researchers
found that it did not significantly affect
the chemical properties of the drug and
3

could significantly restrict conformation

to obtain the correct enantiomer.

Figure 2 (from Yamaguchi et al. ) Effect of the

cyclopropane ring on the conformation of adjacent
carbons

This

reaction works in a very simple way. A

cyclopropane ring essentially forces the
two substituents attached to each carbon

Figure 3 - Reaction from previous literature used to

create cyclopropane analogs

in the ring into a cis position (either both

position A or B on Figure 1) or a trans
position (position A on one carbon and B
on the other).

However, if the two

substituents are in the cis position,

Figure 4 Proposed novel reaction to produce

cyclopropane analogs

potential energy is much greater than if they are in the trans position, so the trans position is
favored. Furthermore, the cyclopropane structure forces the carbons into an eclipsed state,
further increasing the force, termed cyclopropylic strain, between each substituent. This strain
affects conformation because any carbon center adjacent to the cyclopropane would prefer an
orientation in which the smallest substituent (least bulky) is closest to the R-group (Figure 2a.)

Introduction

and the largest substituent is furthest away.7 This is illustrated in Figure 2 as both compounds
tend to be restricted towards conformation B. Cyclopropylic strain creates a valuable tool in the
creation of conformationally restricted drugs and researchers demonstrated the efficacy of this
technique in the synthesis of various enantiomers of analogs of the drug haloperidol which
displayed increased biological activity.

Yamaguchi et al accomplished synthesis of

cyclopropane derivatives using the JohnsonCoreyChaykovsky reaction with a Weinreb amine

which simply adds an extra carbon to form the conformationally restricted cyclopropane analog
(Figure 3).3 In this research, another reaction mechanism was found using a reaction called
hydroamination where a portion of the drug structure was added directly to the cyclopropane
group

(Figure

4),

efficiently producing

the

conformationally-restricted cyclopropane derivative

of the drug shown in Figure 5, a product

synthesized in this research restricted so that the

B

imdazolidinone ring is as far away from the phenyl

Figure 5 3-D structure of synthesized compound
showing the cyclopropyllic strain and resulting
conformationally restricted product. If hydrogens A and
B were replaced with functional groups, the bulkier
group would replace hydrogen A because that position
is furthest away from any other substituents.

ring as possible.
1.1 Hydroamination

The hydroamination reaction is classified under an umbrella of reactions collectively

called hydrofunctionalization reactions, which involve the addition of functional groups and a
hydrogen across double and triple bonds.

In particular, this research focused on

hydroaminations, the addition of amines across C-C multiple bonds. This process is a more
atom-economical and efficient way to add the N-H bond of an amine across the C=C bonds of
various molecules.

Preliminary research into the mechanism of the reaction showed that

thermodynamically, the reaction had a high activation energy and a negative entropy, making it

Introduction

very unlikely to take place at high temperatures.4

This means that the reaction requires a

catalyst to proceed. Early progress has already been made on synthesizing catalysts for this
reaction which involve the use of alkali metal amides, lanthanide metallocene complexes, acidic
zeolites, or Ru(II)/Rh(III)/Pt(II) metal complexes.5, 6 The hydroamination reactions run in this
experiment used a novel gold catalyst synthesized by other members of the lab.
Although gold catalysts have been used before in hydroaminations to good effect, the
results in this report show that the novel catalyst incorporating a new N-heterocyclic carbene
ligand performs better than the standard gold catalyst system for this particular reaction. Typical
gold catalyst systems use a gold catalyst with an electron-rich ligand in conjunction with a silver
co-catalyst. The reaction mechanism will be discussed later in this report, but examples of these
catalyst systems from past literature include variants of PPh3AuCl as the gold catalyst and
AgSbF6, AgOTf, and AgBF4 as co catalysts.3,4,8,9,10 A common problem with hydroamination
and many other reactions is that there is not a single set of catalysts that will work for all
hydroamination reactions; there are a large number of different variables which can all affect the
effectiveness of a catalyst. Therefore, there are many different combinations of factors which
can all impact the reaction differently.
A catalyst system for gold-catalyzed hydroamination typically has two components: a
gold catalyst and a silver co-catalyst. The purpose of the silver co-catalyst is twofold. First,
since the gold catalyst is in the form of a chloride salt, the silver from the co-catalyst works to
precipitate the chloride ion so that it does not interfere with the rest of the reaction. Second, the
anion of the silver salt then forms a gold catalyst complex which binds to the substrate and
completes the reaction.4 The gold catalyst itself is made up of two more components, the gold
center and the ligand attached to the gold. After the hydroamination reaction mechanism was

Introduction

elucidated by Kovacs et al, researchers began to focus on developing electron rich ligands since
they were found to be the most effective in catalyzing the reaction.4 Later on, new classes of
more complicated ligands were developed: N-heterocyclic carbene ligands (NHC), like the
catalyst used in this research, and cyclic alkyl amino carbene ligands (CAAC).16 Since there are
so many factors that influence the reaction, a small change in the type of catalyst system used
can have a large effect on how that system catalyzes the reaction. The reactions in this research
were first run with standard gold catalysts and then changed for this reason.

2. Methods and Procedures

2-phenyl-1-methylene-cyclopropane was synthesized and used it as the starting material
for several intermolecular hydroamination reactions. The procedures used were adapted from
existing literature and procedures used by the lab. While I performed all of these procedures, my
PI and the grad student supervising me helped me run and interpret my NMR samples and
provided me with the materials, including their novel gold catalyst, used in the experiment.
2.1 Synthesis of 2-phenyl-1-methylenecyclopropane7 (Adapted from previous literature)

Figure 6 Reaction mechanism to form starting material adapted from previous literature.

First, 2.2 equivalence of sodium bis(trimethylsilyl)amide and 1.1 equivalence of anhydrous

styrene and 48 mL of toluene were mixed in a 50 mL two-neck round bottom flask with a three-

Introduction

way stopcock under a nitrogen atmosphere (5.3 g sodium

bis(trimethylsilyl)amide, 28.8 mmol and 1.5 g of styrene, 14.4
mmol)
Next, 1.0 equivalence of 1,1-dibromoethane (2.44 g of 1,1dibromoethane, 13 mmol) was added dropwise in an ice bath
at 0C and the mixture was stirred at 25C for 24 hours. After
the reaction was completed, the reaction mixture was quenched
using NH4Cl solution and washed with water. The organic
layer was extracted using a separatory funnel and diethyl ether

Figure 7 oil bath with microwave tube

running reaction

as the organic solvent. Then the organic layers were washed using brine to remove the entire
aqueous layer. The final organic layer was dried over anhydrous CaSO4 desiccant to remove any
remaining water. The mixture was then purified using flash column chromatography and pure
hexane as the eluent to obtain 1-bromo-1-methyl-2-phenylcyclopropane. Using this as starting
material

equivalence

of

1-bromo-1-methyl-2-

phenylcyclopropane was added dropwise to a solution

of potassium tert-butoxide and DMSO solvent under a
nitrogen atmosphere at 0C

(1.02 g of 1-bromo-1-

methyl-2-phenylcyclopropane, 4.84 mmol and 600 mg

potassium tert-butoxide, 5.35 mmol).

The reaction

mixture was stirred at 25C for 24 hours and extracted

using the same technique previously used to obtain the
final product 2-phenyl-1-methylenecyclopropane.

Figure 8 Column used to separate products

Methods and Procedures

2.2 Hydroamination Procedure (using silver salt)

A microwave tube was flame dried and placed in a
desiccator. After the tube cooled, 0.05 equivalence
of

(tBu2-o-biphenyl)PAuCl

catalyst

and

1.1

equivalence of 1-methyl-2-imdazolidinone were

added (In this experiment, 5.4 mg of AuCl (0.01

Figure 9 TLC plates used to separate fractions based

on products.

mmol) and 26 mg of imidazolidinone (0.21 mmol) were used). In a glove box, 0.05 equivalence
of AgSBF6 was measured out and added to the microwave tube with AuCl catalyst and
imidazolidinone (3.4 mg of AgSbF6, 0.01 mmol). Using a microsyringe, 1.0 equivalence of 2phenyl-1-methylene-cyclopropane was added (29.1 L, 0.21 mmol). The microwave tube was
sealed and 1 mL of dioxane was added. The reaction proceeded in an oil bath of experimental
temperature (Figure 7), monitored every hour using gas chromatography (GC). After reaction
was completed, flash column chromatography was run (Figure 8) using 300mL EtOAc/Hexanes
(4:1). Each fraction was spotted from the column onto TLC plates and run using pure EtOAc as
solvent (Figure 9). Spots were observed under UV light to make sure there are no impurities,
(since none of the products were UV active, any spots under UV light would be impurities). The
TLC plates were then stained using CAM stain and heated using
heat gun for 1 minute.

The spots that showed up after heating

were marked and fractions containing each different product

visible from the TLC were mixed so all fractions with the same
product (same Rf) were collected together. A Rotovap machine
(Figure 10) was used on the solutions to remove excess solvent
Figure 10 Rotovapor machine used
to remove solvent from sample

Methods and Procedures

and isolate the products. The product was weighed out and yields were calculated
2.3 Hydroamination Procedure (without silver salt)
A microwave tube was flame dried and placed in a desiccator. After the tube cooled, 0.05
equivalence of MeCnAuP(Cy2-o-biphenyl)AgSbF6 catalyst and 1.1 equivalence of 1-methyl-2imdazolidinone (7.4 mg of gold catalyst (0.009 mmol), 19.8 mg of imidazolidinone (0.180
mmol)) were added.

Using a microsyringe, 1.0 equivalence of 2-phenyl-1-methylene-

cyclopropane was added (25 L, 0.180 mmol).

The rest of the procedure was completed

according to the hydroamination procedure with a silver salt.

3. Results
3.1 Raw Data
To confirm the identity of the products, H-NMR spectra was run on the samples and
TLC/GC were used to monitor reactions. The raw data from these analytical techniques are
displayed below:

Figure 11 H-NMR of starting material confirms the identity of 2-phenyl-1-methylenecyclopropane

with minimal impurities. Some residual tBuOH remained which was then removed by evaporation
under the house vacuum.

Methods and Procedures

Figure 12 GC printout of 80 MeCnAuP(Cy2-o-biphenyl)AgSbF6-catalyzed reaction mixture at 2 hours. Reaction took 3 hours

to complete and there is a 1-phenyl-2-methylenecyclopropane peak at 4.241 and product peaks (2 major 1 minor) at 9.477,
9.862, and 10.055. Peaks at around 5-6 are probably impurities or the other starting materials

Product A

Product B

Product C

Figure 13 TLC plate from same reaction showing 3 products with 3

different Rfs. A stained plate is shown on the right from a different
reaction which shows product spots more clearly.

Data Analysis

10

Figure 14 H-NMR of product A, the minor product. Around 5-5.7 ppm, we can see the peaks that are the result of vinyl
hydrogens, hydrogens attached to sp carbons (double bonds). We can see two distinct signals, a singlet and a doublet of
doublets (singlet at 5.6 ppm and dd at 5 ppm) which suggests the structure shown above since there are 2 distinct hydrogen
signals on the double bond as opposed to what well see in product B. We can also see phenyl peaks >7 ppm and peaks from
the imidazolidinone at 3 ppm and <2 ppm.

Figure 15 H-NMR of product B, one of the major products. More vinyl peaks around 5 ppm which shows that there is still a
methylene group. In contrast with product A, product B shows only one unique signal, a doublet of doublets at 5 which
suggests that there is only one distinct hydrogen signal. This fact is supported by the structure shown above since there are
only 2

Data Analysis

11

Figure 16 H-NMR of product C which shows a space where vinyl peaks on previous products were. This means that there is
not double bond which then supports the structure above since the only way to lose the vinyl hydrogens is for the
nucleophile to add across the double bond and keep the cyclopropane ring. This reasoning is supported because we can also
see peaks from 1-2 ppm which suggests the cyclopropane ring is still intact.

3.2 Data Analysis

After synthesizing and verifying the structure of the starting material through H-NMR as
shown above, test reactions were run using the standard catalyst and procedure 1 from above.
Based on the mechanism for hydroamination that will be elucidated later in this paper, it was
expected that the amine group on the 1-methyl-2-imdazolidinone would add across the
cyclopropane and form compounds A and B as the major products, but flash column
chromatography and TLC results show three products. These products were run through a GC
and determined that of the three products A, B, and C (A had the highest R f and C had the
lowest), B and C were the major products and A was a minor product (Figure 17). NMR data

Data Analysis

12

showed unexpected results (Figure 16). Although it was initially thought that the two major
products were isomers or diastereomers of when the amine group added across different carbons
in the cyclopropane ring, what was found instead was that even though
one of the major products did open up the ring, the other major product
added across the double bond (Figures 14-16). This addition was very
intriguing since in previous literature, Zhang et al used gold catalysts for
a similar reaction reaction in a ring-opening synthesis of pyrrolidines.11
Using standard gold catalysts very similar to the one used in this
research (previous literature used Ph3PAuCl/AgOTf) as well as
palladium catalysts, previous research showed the opening of the
cyclopropane ring and addition across the ring as opposed to the alkylene
which was observed in this research.12
Figure 17 From top to
bottom: Products A, B,
and C

In the beginning, yields for this reaction were relatively low (Entry

5, Table 1) specifically the yields for product C, the desired product. The ratio between the two
major products was also undesirable at 2:1 in favor of product B, the one predicted by previous
literature where the ring was opened. However, by changing the catalyst, temperature, and
nucleophile (since catalyst systems have such a large effect on hydroamination reactions) the
reaction yields and ratios were improved. The first variable changed was the gold catalyst (Entry
1). Although the ratio remained biased towards product B, changing the catalyst from a standard
gold catalyst to a novel silver-free NHC-ligand catalyst synthesized by the lab more than doubled
the yields. The second variable tested was more successful in biasing the reaction towards the
desired product. The reaction was run at two lower temperatures and at each temeprature, the
ratios of products C:B improved (at 80C and 60C respectively, the ratios of products C:B were

Data Analysis

13

1:1.5 and 1.5:1). Although decreasing the temperature increased the reaction time, the increase
was small enough that the reaction is still useful at lower temperature. Reaction times for other
gold-catalyzed intermolecular hydroaminations found in previous literature were typically
around 24 hours, showing that reaction time is not a problem.5 After testing the 60 C reaction,
another reaction was run at room temperature (Entry 4) but unfortunately, the reaction did not
run to completion. Based on GC data, the products decayed back into the alkene and the reaction
was stopped after 72 hours because all the gold catalyst had been consumed. The third factor
tested was the effect of the nucleophile on the reaction; specifically whether or not this reaction
would continue to produce the desired product using a less reactive nuclephile. To test this, two
new nucelophiles were used: benzyl carbamate and anniline. The difference between these two
new nucleophiles and 1-methyl-2-imidazolidinone is that the new nucleophiles contain primary
amines which are less likely to undergo hydroamination.

The benzyl carbamate reaction

proceeded in a similar fashion as the previous reactions using 1-methyl-2-imidazolidinone and

produced slightly higher yields, but only a 1:3 ratio between product C and B and took
significantly longer (12 hours) to complete. While the primary amine in the benzyl carbamate
underwent the reaction, the primary amine in aniline was completely unreactive.

This is

important because the goal of this research is to find a reaction that can be used with a large
variety of nucleophiles.
Entry

Catalyst System

Reaction Condition

Yield B

Yield C

Time

MeCnAuP(Cy2-o-biphenyl)SbF6

100

57.5%

28.6%

30 minutes

MeCnAuP(Cy2-o-biphenyl)SbF6

80

28.7%

19.1%

3 hours

MeCnAuP(Cy2-o-biphenyl)SbF6

60

38.3%

57.2%

6 hours

MeCnAuP(Cy2-o-biphenyl)SbF6

rt

0.0%

0.0%

NA

(t-Bu2-o-biphenyl)PAuCl/AgSbF6

100

24.7%

14.3%

5 hours

MeCnAuP(Cy2-o-biphenyl)SbF6

100

35.7%

11.5%

12 hours

MeCnAuP(Cy2-o-biphenyl)SbF6

100

0.0%

0.0%

NA

Table 1 All reactions were done under nitrogen atmosphere using dioxane as solvent. 2-phenyl-1-methylenecyclopropane was
used as the alkene and a 5% catalyst loading was used. For entries 1-5, 1-methyl-2-imidazolidinone was used as the nucleophile,
benzyl carbamate was used in entry 6, and aniline was used in entry 7.

Data Analysis

14

4. Discussion
The goal of this research was to create cyclopropane derivatives to restrict the
conformation of molecules. Although only one product maintained the cyclopropane ring, this
research shows promise because product C only appeared in one enantiomer, showing that
cyclopropane derivatives can indeed restrict conformation and aid in enantioselective synthesis.
From the data, it can be seen that the optimal temperature using this particular catalyst system
and other reaction conditions was 60 C. Since other systems and even nucleophiles will have
different optimal conditions, these conditions will need to be optimized for each set of reaction
conditions.

Another important observation was that these reactions were very fast.

As

previously noted, a similar reaction using the same catalyst ((t-Bu2-o-biphenyl)PAuCl and
AgSbF6) and same nucleophile (1-methyl-2-imidazolidinone) took significantly longer to
complete.5 The high reaction rate of this reaction is advantageous, giving the reaction good
commercial value since it can yield more product in less time.
Although the yields are rather low, this reaction is very promising due to the unexpected
result. While it seems more intutitve for the amine bond to add across the cyclopropane group
because of the torsional strain and the energy that would be released with the breaking of the
ring, the unexpected addition can be explained by the reaction mechanism of hydroamination.
This reaction mechanism is a three part mechanism in which the
2

gold center of the catalyst first adds across a bond and breaks it,

3
1

forming a temporary catalyst substrate complex. This bonding

4

then causes a carbocation to be formed on an adjacent carbon

which the nucleophile attacks and bonds to. The final stage
Figure 18 Potential positions where
nucleophiles could attack the alkene

Discussion

15

transfers the hydrogen that the nucleophile loses to the substrate to the gold catalyst which then
kicks off the gold catalyst and allows the process to repeat.4 In the case of the hydroamination of
methylene cyclopropanes, the most likely location to attack would be the carbon at position 1
(Figure 18) since the most stable carbocation would be formed there. After the gold bonds to
carbon 1, either the ring or the double bond can be broken based on where the nucleophile
attacks. If the nucleophile attacks position 2 or 3, the ring will be opened and product A and
product B are formed respectively. On the other hand, if the nucleophile attacts position 4 and
adds across the double bond, the ring will be maintained and it will form product C instead. This
position of attack has not been observed before for this specific reaction and more research will
be needed to understand why product C forms and why lowering the temperature increases the
its yields.
Looking back at our original goal of finding a way to enantioselectively syntheisze drugs,
we can see that the hydroamination of methylene cyclopropanes provides an unexpected, yet
viable way to achieve this. However, this reaction could also have implications in fields other
than drug synthesis as many important chemical and biological molecules used to study various
fields are sensitive to the enantiomer used. For example,
pactamycin (Figure 19) is only useful to biochemists in the
form shown and by the addition to cyclopropane derivatives
found in this research, these conformations could be locked
and a cyclopropane derivative of pactamycin can be made.
Although current selectivities are not optimal, there are
Figure 19 Pactamycin, a natural product
that has been the goal of many synthesis
experiments. It is a useful biochemical
molecule and is isolated naturally to study
ribosomes and other cellular functions.

many other reaction conditions that could be changed which

may increase the yield of the desired product. For example,

Discussion

16

by experimenting with more catalysts, the reaction can be further biased towards product C and
yields can be increased. There is another limitation to this reaction which is evident in the failure
of the anniline reaction. Since 1-methyl-2-imidazolidinone contains a secondary amine, it is
more easily deprotonated (in the third stage of the hydroamination reaction mechanism, the
hydrogen on the nucleophile leaves the nucleophile and bonds to the gold) than a primary amine
such as those present in benzyl carbamate and aniline. The reason benzyl carbamate still reacts
is the high electronegativity of the carbamate group which contains two oxygen atoms that
deprotect the hydrogens. Aniline has no groups that cause a downshift in the hydrogen, so
deprotonation is considerably less likely (pKa values support these explanations: pKa of
imidazolidinone < 15, pKa(benzyl carbamate) = 23.0, pKa(anniline) = 30.6; pKa values from
values found by Bordwell et al. in DMSO)13 Therefore, a major goal for future reactions is to
expand them to encompass more functional groups. This goal goes hand in hand with increasing
yields as changing the catalyst system will also have an effect on which nucleophiles can be
used. On the other hand the fact that benzyl carbamate followed the same pattern as 1-methyl-2imdazolidinone shows that the reaction is not specific to the imdazolidinone and can be used
with a variety of nucleophiles.
5. Conclusion
In conclusion, this research discovered an atom-efficient way to add amines to
cyclopropane derivatives. The ultimate goal would be to be able to expand this reaction to more
functional groups and eventually find a way to add any functional group to a cyclopropane
without opening the ring. Thus the logical first step is to use the same catalyst system for
different functional groups similar to what was done with the benzyl carbamate reaction. The
next step would be optimizing the catalyst and conditions for each type of nucleophile since each

Discussion

17

functional group responds differently to the catalysts. More reactions can be run using different
catalyst systems and solvents which can further optimize yields and the ratio between the desired
and undesired product. Aniline, for example, has been successfully used as the nucleophile in
intermolecular hydroaminations in previous literature using the silver co-catalyst AgNTf2, so it is
possible to find a suitable catalyst system for this reaction.15 The final step is compiling all these
results so that future researchers can have a set of optimal reaction conditions for the addition of
any functional group to cyclopropane derivatives.
Although data from this research demonstrates the formation of an unexpected product
from this reaction, the procedures should be repeated to confirm that the cyclopropane ring is
indeed unopened in a major product and for data replication. This is especially important since
previous research has never shown this particular product being formed during the reaction.11
Perhaps the most important data that still needs to be collected is the effectiveness of this
technique in synthesizing known cyclopropane derivatives of
drugs, the enantioselectivity of that process, and the efficacy
Figure 20 1-(1-(3-Methoxyphenyl)-Nmethylethanamine))-2-phenylcyclopropane made by researchers as a
3
possible drug analog.

of the final products. The most useful future work in this

reaction would be the synthesis of usable drugs like Figure 20,

a conformationally restricted product found to be effective in treatment of diseases that are the
result of calcium imbalances, instead of compounds synthesized just to show the efficacy of this
reaction like the compounds made in this research.14
Although several issues must be addressed (low yields and compatibility with other
functional groups) and results must be replicated, this reaction can be useful as an efficient
method to add functional groups to cyclopropane derivatives to synthesize conformationally
restricted drug analogs as well as many other enantioselective products.

Conclusions

18

6. Works Cited
[1] McConathy, J., & Owens, M. J. (2003). Stereochemistry in Drug Action. Primary care
companion to the Journal of clinical psychiatry, 5(2), 7073. Retrieved from
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=353039&tool=pmcentrez&re
ndertype=abstract
[2] Eriksson, T., Bjurkman, S., Roth, B., Fyge, . and Huglund, P. (1995), Stereospecific
determination, chiral inversion in vitro and pharmacokinetics in humans of the
enantiomers of thalidomide. Chirality, 7: 4452. doi: 10.1002/chir.530070109
[3] Yamaguchi, K., Kazuta, Y., Hirano, K., Yamada, S., Matsuda, A., & Shuto, S. (2008).
Synthesis of 1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic
agents: cyclopropane-based conformationally restricted analogs of haloperidol.
Bioorganic & medicinal chemistry, 16(19), 887581. doi:10.1016/j.bmc.2008.08.061
[4] Kovcs, G., Ujaque, G., & Lleds, A. (2008). The reaction mechanism of the
hydroamination of alkenes catalyzed by gold(I)-phosphine: the role of the counterion and
the N-nucleophile substituents in the proton-transfer step. Journal of the American
Chemical Society, 130(3), 85364. doi:10.1021/ja073578i
[5] Zhang, Z., Lee, S. Du, & Widenhoefer, R. a. (2009). Intermolecular hydroamination of
ethylene and 1-alkenes with cyclic ureas catalyzed by achiral and chiral gold(I)
complexes. Journal of the American Chemical Society, 131(15), 53723.
doi:10.1021/ja9001162

Works Cited

19

[6] Roesky, P. W., & Mller, T. E. (2003). Enantioselective catalytic hydroamination of alkenes.
Angewandte Chemie (International ed. in English), 42(24), 270810.
doi:10.1002/anie.200301637
[7] Kippo, T., Hamaoka, K., & Ryu, I. (2012). Bromine Radical-Mediated Sequential Radical
Rearrangement and Addition Reaction of Alkylidenecyclopropanes. Journal of the
American Chemical
[8] LaLonde, R. L., Sherry, B. D., Kang, E. J., & Toste, F. D. (2007). Gold(I)-catalyzed
enantioselective intramolecular hydroamination of allenes. Journal of the American
Chemical Society, 129(9), 24523. doi:10.1021/ja068819l
[9] Butler, K. L., Tragni, M., & Widenhoefer, R. a. (2012). Gold(I)-catalyzed stereoconvergent,
intermolecular enantioselective hydroamination of allenes. Angewandte Chemie
(International ed. in English), 51(21), 51758. doi:10.1002/anie.201201584
[10] Li, H., Lee, S. Du, & Widenhoefer, R. a. (2011). Gold(I)-Catalyzed Enantioselective
Intramolecular Hydroamination of Allenes with Ureas. Journal of organometallic
chemistry, 696(1), 316320. doi:10.1016/j.jorganchem.2010.09.045
[11] Zhang, D.-H., Du, K., & Shi, M. (2012). Gold(I)-catalyzed intramolecular hydroamination
and ring-opening of sulfonamide-substituted 2-(arylmethylene)cyclopropylcarbinols.
Organic & biomolecular chemistry, 10(18), 37636. doi:10.1039/c2ob25512j
[12] Nakamura, I., & Itagaki, H. (1998). Ring Opening in the Hydroamination of
Methylenecyclopropanes Catalyzed by Palladium, 3263(10), 64586459.

Works Cited

20

[13] Bordwell, F. (1988). Equilibrium acidities in dimethyl sulfoxide solution. Accounts of

Chemical Research, 2(10), 33053312. Retrieved from
http://pubs.acs.org/doi/abs/10.1021/ar00156a004
[14] Cohen, Judith H., Donald W. Combs, and Phillip J. Rybczynski. "1,2-disubstituted
Cyclopropanes." (n.d.): n. pag. Web.
<http://www.google.com/patents/US6172091?cl=en>.
[15] Zhang, X., Yang, B., Li, G., Shu, X., Mungra, D., & Zhu, J. (2012). Highly Regioselective
AgNTf2-Catalyzed Intermolecular Hydroamination of Alkynes with Anilines. Synlett,
23(04), 622626. doi:10.1055/s-0031-1290341
[16] Hashmi, A. S. K., & Lothschtz, C. (2010). Triazolate Counter Ions in Au I Complexes:
Catalysts with Improved Thermal Stability. ChemCatChem, 2(2), 133134.
doi:10.1002/cctc.20090028
[17] "Center for Drug Discovery." History and Background of Drug Discovery. University of
Georgia, n.d. Web. 20 Sept. 2013.

Works Cited

21