ASILA Victoire

Master Degree in Chemistry2016-2017(From 23rd March to 26th August 2017)
Internship Report 4C0I1

Development of Copper-Catalyzed Aminothiolation ofDienes with N-Fluorobenzenesulfonimide and Thiols
Academic advisor:
Dr. Anne-Lise DHIMANE
Tutor:
Pr. Yasushi NISHIHARA
Location:
OKAYAMA UNIVERSITY
Professor Yasushi NISHIHARA’s laboratory
Division of Earth, Life and Molecular Sciences, Graduate School of Natural Scienceand Technology
3-1-1 Tsushimanaka, Kita-ku,
Okayama 700-8530, Japan

1

AKNOWLEGMENTS
This internship was done in one of the laboratory of the faculty of science inOkayama University, Japan.

First of all, I would like to thank Prof. Nishihara for welcoming me in his laboratory,
helping me through the administrative procedures that allowed me to come to Japan,
supporting me financially and for integrating me into his team. I would also like tothank Dr. Iwasaki, Dr. Mori and all of the laboratory’s students who helped me andgave me great advice either in the Chemistry field, in the way to use the laboratory
equipments or on the Japanese way of life.
I would like to specifically thank Dr. Iwasaki for guiding me in my research topic, whoalways have been available when needed, and Ms. Miki who has been of great help
when I arrived and took her precious time to help me do all of the necessary official
documents I needed to stay in Okayama.
Therefore, I would like to thank the Japan Student Servie Organization (JASSO) for
their financial support during the month of March.
Also, I would like to thank all of the Okayama University staff for their availability andtheir understanding toward me, especially since I don’t speak Japanese. Moreover, I
would like to thank Japanese citizen for making this internship one of the mostincredible experience in my life.

Of course, I would like to thank UPMC, the Chemistry Master and Dr. Dhimane who
made it possible for me to come to Okayama and has always been helpful and ofgood guidance.

Last but not least, I would like to thank deeply my family and my friends who
supported me all along this journey.

2

SUMMARY

AKNOWLEDGMENTS

2

SUMMARY3

INTRODUCTION

4

I. Presentation of the Internship51) Presentation of the Laboratory

52) Introduction to the Research Topic

6

II. Working Process and Experimental Procedures

81) Preparation of Starting Materials

82) Aminothiolation Reactions

9

III. Results: Analysis and Interpretation

12

CONCLUSION

15ANNEXESIGLOSSARYI

BIBLIOGRAPHY

I

EXPERIMENTAL PROCEDUREIIANALYSIS TECHNIQUES

III

3

SPECTRUMV

INTRODUCTION
Okayama University is a top-class national university in Japan with over 140 years ofhistory. It has 11 faculties, 7 graduate schools and various programs (Figure 1).[1]Figure 1: History of Okayama University

13000 students are enrolled in this University including approximatively 600
international students. Indeed, 1600 teachers and staff are engaged for the “Creationof advanced knowledge and inheritance of precise knowledge.”[1]Prof. Nishihara’s laboratory is the functional organic chemistry laboratory of thefaculty of science of the university and intends to the development of syntheticorganic reactions catalyzed by organometallic complexes and their application tofunctional materials. More detailed by using transition-metal catalysts, they develop
organometallic reagents which show interesting reactivities and selectivities different
than the ones conventionally observed in chemistry. These reagents would be used
for the development of new carbon-carbon bond formation reactions which is a basis
for synthetic organic reactions. As it is explained on their website they are also
working on the development of: « environmentally friendly reactions for "Green
Chemistry" which is one of the most important task for chemists in the 21th
century. »[2][3]As for my research subject, the difunctionalization of dienes is historically an
attractive method to install molecular complexity into simple and abundant molecular
structures. Despite the prevalence of these transformations, the ability to introduce
nitrogen and sulfur functional groups is an enduring challenge due to their diverse4and conflicting reactivity. Such a transformation would find greater applications in the
medicinal and material sciences fields.[4]My main goal is to conduct copper-catalyzed aminothiolation reactions with Nfluorobenzenesulfonimide and thiols and then to demonstrate that the reactions
proceed through a radical pathway.
First, I will introduce my laboratory and more precisely my research subject. Then, I
will present my work by explaining the conducted experiments Following that, I will
present my results and analyze them. Finally, I will conclude this internship report byanswering the problematic posed by this subject.

I.

Presentation of the Internship

1) Presentation of the laboratory
The Nishihara’s laboratory is the functional organic chemistry laboratory of
Okayama’s University It has eighteen members (myself included) and the team iscurrently composed of Professor Nishihara, 2 Assistant Professors Iwasaki and Mori,
3 Ph.D’s students, 6 master’s students, 4 undergraduate students and me as atemporary special research student. In fact, the laboratory is subdivided in twolaboratories (Figure2):- laboratory 1 under Dr. Iwasaki supervision. It is specialized in catalytic synthesis
and 7 students are working there (including me).[2]- laboratory 2 under Dr. Mori supervision. It is specialized in organic polymers
synthesis and characterization. Actually, 7 students are working there.

5

Figure 2 : Organization Chart of the Nishihara’s Lab
In these laboratories, they are working on the development of new synthetic organic
reactions and methodologies by means of organometallic compounds toward new
types of organic molecules and polymers for functional materials, for example, solar
cells. They have a particular interest in catalytic coupling reactions with good regio-,
stereo-, and chemoselectivities to construct carbon-carbon bonds and are aiming at
the activation of various unreactive chemical bonds.[3]The whole team is very dynamic and is trying to be as much productive as possible.
Indeed, every two weeks each member of the laboratory has to submit a BWR which
is a report of the work carried out over the last two weeks. During a meeting they
discuss with the professors about their latest advances and their future plans.
Moreover, each student has to be aware of the latest finding concerning theirresearch subject. Then, once a month they have to choose interesting articles andpresent them to the team.
Finally, Nishihara’s team is committed to seek for reactions that can afford 100%
atom efficiency. Furthermore, they strictly regulate the use of compounds and theirrecycling process so as to respect the principles of Green Chemistry.[2]2) Introduction to the Research TopicMy research topic is about aminothiolation of dienes. Before getting interested in thisparticular reaction, the laboratory explored other types of difunctionalization
reactions, for example, the transition-metal-catalyzed regio- and stereoselective
halothiolation of alkynes or the transition-metal-catalyzed aminothiolation of alkenes.

6Indeed, in 2014, the laboratory published two papers about the halothiolation ofalkynes. They were able to reveal that transition-metal-catalysts could control theselectivity of the chlorothiolation of alkynes with high selectivities (Scheme 1 and 2).

Scheme 1 : Chlorothiolation of Alkynes[2]Scheme 2 : Iron-Induced Regio- and Stereoselective Addition of Sulfenyl Chlorides to
Alkynes via a Radical Pathway. [5][6]7More recently they worked on the aminothiolation of alkenes (Scheme 3). Mr. Zou
achieved the reaction of styrene (1a, R= Ph) to give product 2a in 89% yield. Thenthey were able to prove that the reaction proceed through a radical pathway. They
are currently working on expanding the substrate scope of the reaction and find ways
to further optimize it.

Scheme 3 : Aminothiolation of Alkenes
Actually, my research is really similar to the previous one. The main difference beingthat I work with dienes and not alkenes. Thereby, I started my work with all theprevious informations.

II.
1)

Working Process and Experimental Procedures

Preparation of Starting Materials

For my first experiments in the laboratory I was asked to prepare starting
compounds.
Thus, I carried out synthesis of two dienes which are 4-methyl-N,N-di(2methylallyl)benzenesulfonamide (2a) and N,N-diallyl-4-methylbenzenesulfonamide(2b) as shown in equation 1 and 2.
As a result, product 2a was obtained in 100% yield (439.5 mg) as a colorless oil after
a silica gel column chromatography. The purity of 2a was confirmed by TLC analysis
with hexane:ethyl acetate (5:1) as an eluant and by 1H NMR spectroscopic analysis.
In addition, product 2b was obtained in 97% yield (4426.7 mg) as a colorless oil after
two silica gel column chromatography. After the first purification, a yellow oil was
obtained, which is different from what was reported in the paper. Although TLC
analysis showed the single spot, a further purification was conducted with column
chromatopraphy. I was not sure of the purity of 2b because the reference shows that2b should be colorless.
The allylation of tosylamide (1) proceeded very efficiently. The only thing I had to becarefull about was to make sure to keep the reaction under an argon atmosphere.
The isolation process was also quite easy since there was almost no impurities in thereaction mixture. :8Scheme 4 : Preparation of Starting Materials 2a and 2b [7][8]2)Aminothiolation of Dienes

A)

Ring-Closing Aminothiolation of Dienes

After preparation of starting materials, I had to carry out a reproducible experiment. I
conducted aminothiolation of styrene (2) (Scheme 5).

Scheme 5 : Reproducible Experiment
Previously, Mr. Zou reported that the targeted product 3 was obtained in 89%
isolated yield. When I tried to reproduce the reaction a first time and the product 3
was only obtained in 45% NMR yield. The same reaction was conducted again, but
the yield was decreased to 34% NMR yield. Since the yields were really low
compared to the one reported by Mr. Zou, I tried to figure out why the results were
not as good as expected. First possible reason was the solvent volume. Indeed,
Mr.Zou conducted the reaction with 0.5 mL of CH2Cl2 but I used 1 mL of the solvent.
Second possible reason was the formation of byproduct, disulfide, due to oxidation.
We concluded that we had to avoid incoming air inside the reactor. Moreover, thecatalyst used in this reaction is really sensitive to oxidation.

9

After decreasing solvent volume to 0.5 ml and avoiding air from the reaction flask, thereaction was carried out. Finally, the desired product 3 was obtained in 100% NMR
yield.

After the reproducibility of the reaction of styrene 2 was confirmed. I used thesynthesized dienes 2a and 2b to carry out the aminothiolation with NFSI and ptoluenethiol (Scheme 6). We expected ring-closing aminothiolation of dienes
proceeds in the presence of a copper catalyst through a radical pathway to givecompounds 3a and 3b.

Scheme 6 : Aminothiolation of 2a and 2b
The reaction of diene 2a was conducted. After separation of the crude mixture bysilica gel column chromatography with CH2Cl2 : hexane (1:2) as the eluant, 1H NMR
measurements and mass spectroscopy revealed that the targeted product 3a was
not generated. Neither experiments with 0.5 mL or 1 mL of solvent did not give 3a.
Next, the diene 2b was employed. 1 mL of solvent seemed to give better results than
0.5 mL of solvent from 1H NMR analysis of the crude mixture. The reaction provided
the desired adduct 3b and disulfide in 6% and 37% NMR yield, respectively.
Nevertheless, the product still needs further purification because even after twocolumns there are still some remaining impurities. Fully characterization of 3b is
ongoing.

Later, the reaction of 1,6-octadiene (2c) and 1,6-heptadiene (2d) were investigated(Scheme 7). Under the identical reaction conditions aminothiolation of diene 2c did
not give the product 3c and disulfide 4 was only detected. On the other hand,reaction of 2d gave the product 3d in 13% NMR yield, along with disulfide 4 in 32%
yield. It seemed that the yield with 1 mL solvent was better than the one with 0.5 mL.
However, the product is still under purification.

10

Scheme 7 : Aminothiolation of 2c and 2d

B)

Aminothiolation of Conjugated Dienes 2e and 2f

Since ring-closing aminothiolation products seemed to be hard. We focused onaminothiolation of conjugated dienes.
First of all, I carried out the reaction of 2,3-dimethyl-1,3-butadiene (2e) as a starting
material. After two silica gel column chromatography, the first one with CH2Cl2 :hexane (1:2) and the second one with CH2Cl2 : hexane (1:3) as the eluent, it was not
pure yet. Disulfide 4 was isolated in 34% yield as a byproduct. Further purification
was performed by HPLC and 3e was finally isolated in 9% yield which is a 2.6:1
mixture of isomers.
This is the only example where the desired product was isolated out of all theaminothiolation reactions carried out from now. Since the yield is quite low, further
optimization of reactions conditions is necessary.

Scheme 8 : Aminothiolation of 2e
The same reaction was carried out with cyclohexadiene (2f) as a starting material(Scheme 9). As a result, the desired product 3f was obtained in 44% NMR yield.
Purification by silca gel column chromatography did not give the pure compound.
Further purification is needed to identify 3f. Simultaneously, disulfide 4 was obtainedin 29% yield11

Scheme 9 : Aminothiolation of 2f

III.

Results : Analysis and Interpretation

The results of ring-closing aminothiolation of dienes are summerized in table 1.

Table 1 : Aminothiolation of Dienes 2b and 2d
The reaction might proceed through a radical pathway as shown in figure 3. First ofall, through a single electron transfer, a nitrogen-centered radical specie is generated
from NFSI. Then the formed radical specie attacks the more reactive position of thediene to generate a carbon centered radical. Subsequently, 5-exo cyclization
provides an alkyl radical, which reacts with thiol to give the product.

Figure 3 : Possible Radical Pathway
1

H NMR analysis revealed that the targeted products were obtained, but it is hard toisolate them even after several purifications above mentioned. At present, therefore,
the product yields were not determined. In addition, the formation of a plenty amountof disulfide as a byproduct was confirmed. Effort to decrease the amount of disulfide
12

by preventing air from the reaction mixture, which would act as an oxidant, did notgive better results. In fact, the undesired side reaction occurs because NFSI does not
only acts as an amination reagent but also as an oxidant. Hence, it is difficult to avoid
the formation of disulfide in the present reaction system.
During investigation to improve the product yield, the solvent quantity was found tohave a significant impact on the product yield. Indeed, the reactions shown in table 1
gave better results with 1 mL of solvent than with 0.5 mL. The reason why it has suchan impact is not clear yet.
The obtained results lend us to focus on aminothiolation of conjugated dienes which
did not involve the cyclization process. The reaction pathway would be similar to theone above mentioned. Fortunately, the desired product 2e was isolated in 9% yield(Scheme 10). Moreover, 1H NMR analysis confirmed the presence of stereoisomers
in the proportions of 2.6:1. 2D NMR measurement is neccesary to know which
regioisomer is mejor product. We propose that the reaction proceeds through radical
pathway. Further experiments such as radical clock experiment is needed to confirm
the radical mechanism.

Scheme 10 : Aminothiolation of Diene 2e

In the same idea, the reaction of diene 2f was investigated (Scheme 11).
NMR analysis revealed that the desired product 3f seemed to be formed, but fullcharacterization of 3f has yet to be achieved due to the contamination of impurities.
Although the solvent was dried out from the reaction mixture for better visibility on the
NMR chart it did not change a lot. When the internal standard in the NMR sample
was changed from dibromomethane to dibenzyl ether to identify some characteristics
signals of 3f, NMR yields was drastically decreased, which did not correspond to theone obtained from dibromomethane.
Therefore, I decided to reproduce this experiment to see if the same results are
obtained again and if further purification is needed. If the second run does not givereasonable results I better consider investigation of other dienes.

13

Scheme 11 : Aminothiolation of Diene 2f

Achieving these reactions lies on several factors, but the catalyst employed is one of
the most important factors. CuBr•SMe2 was used in the present reaction, which is
widely used to generate organocopper reagents (for example, for the addition ofalkyl, alkenyl, and aryl Grignard reagents to fullerenes). The catalyst It is formed by
the reduction of copper(II) bromide with sulfite. It should not be kept under reducedpressure, as it will lose the sulfide ligand and the copper(I) is easily oxidized in air.

I tried to figure out how the copper catalyst could react and catalyze the present
reaction. Taking the mechanism of aminothiolation of alkenes as an example, we
propose reaction mechanism for the synthesis of 3e as shown in scheme 11:
First of all, a nitrogen-centerd radical species is generated through a single electrontransfer from copper(I) to NFSI. Simultaneously, the fluoride anion combines with theformed copper(II). Subsequently, the amyl radical reacts with diene to generate acarbon-centered radical species. The generated secondary allyl radical undergoes
isomerization to give less-hindered primary allyl radical intermediate, from which
recombination with copper(II) complex to give a copper(III). Finally, ligand exchange
between fruoride and thiol, followedby reductive elimination provides 3e andregenerates the initial copper(I) species.

Then the amino radical reacts with the diene to generate a radical specie which
through re-arrangments gives an alkene radical specie.
Next, by oxidative addition it bonds to the copper II complex to give a copper III
complex.
Then there is a ligand exchange between the Fluor anion and the aryl sulfide.
Finally, through reductive elimination 2e is created and our copper catalyst form the
beginning is regenerated.
Making as a hypothesis that the reaction proceed through a radical pathway this
could be a possible mechanism.

14

Scheme 12 : A Proposed Reaction Pathway

CONCLUSION
The goal of my internship is, for now, to carry out aminothiolation of dienes. So far, I
carried out the reaction of seven different dienes, including two dienes prepared bymyself.

15

Concerning reproducible experiments, I was able to achieve good yields and theaminothiolation of alkenes helped me to identify the limiting factors.
Furthermore, during investigation of new reactions, even though I tried a lot ofdifferent experiments, only few of them were successful.
I still do not have all the keys to understand why some of the reactions worked better
than the others but I learned that exploring unknown reactions is always a difficult
task. To this end, I need to conduct further research and experiments. Hopefully, I willfind some interesting transformations by the end of my internship.
Besides, I gained a lot of ability thanks to this internship. I learned how to use
different analytic techniques and I am more at ease in a laboratory thanks to thelaboratory members.
I developed my scientifical knowledge in a dynamic team and I adapted quite well tolaboratory life. Indeed, in Japan students are encouraged to develop their practicalskills in chemistry. They spend more time in the laboratory than in classes compared
to us in France.
I also learned how to cope with the failures and how to keep going on because this is
the daily life of a researcher.
Moreover, I developed my ability to read scientifical papers, present the results, anddiscuss about them.
Not only in the scientific field but in general this internship allowed me to have apersonal growth.
Living in a foreign country alone which culture is so different from mine required toadapt quickly to the new environment. In this country I was able to travel anddiscover a lot of different landscapes all following the Japanese tradition.
I was reassured by the fact that having an experience in a foreign country is clearlyan advantage for a student.
Last but not least, even though I am far from my objectives, I am currently doing mybest to develop my knowledge in Japanese language so that even after my return inFrance I can keep on learning and gain a new ability.

16

17