1. 1
BSc Chemistry Project
2010/2011
Aziridine-Based Synthesis of Substrates for C-H Activation
Prathap Latchmanan
Oct 10 - Dec 10
00561753
Thorpe Laboratory, Department of Chemistry, Imperial College London, South
Kensington Campus, London SW7 2AZ, United Kingdom
A Third Year Organic Research Report submitted under the requirements for the degree of
Bachelor’s of Science, BSc (Chemistry), Imperial College London under the supervision of
Professor Donald Craig.

2. 2
Table Of Contents
Abstract & Report Layout 3
Acknowledgements 3
Abbreviations 4
Nomenclature and Stereochemical Notation 7
1.0 Introduction
1.1 Research carried out by the group 8
1.2 C-H bond activation in tetrahydropyridines 10
1.3 Reactivity of tetrahydropyridines 10
1.3.1 Palladium-Catalysed Reactions 11
1.3.1.a Heck Cross-Coupling Reaction 11
1.3.1.b Suzuki Cross-Coupling Reaction 13
2.0 Aim Of Work
2.1 Reaction summary 15
3.0 Results and Discussion
3.1 General strategy towards tetrahydropyridine 16
3.1.1 Synthesis of N-tosylaziridine 25 16
3.1.2 Synthesis of Dioxolane-substituted Alkylmagnesium Bromide 30 21
3.1.3 Ring-Opening of N-tosylaziridine 22
3.1.4 Synthesis of 1-(arylsulfonyl)-1,2,3,4-tetrahydropyridines 19 24
3.2 Synthesis of Iodo-N-tosyl tetrahydropyridine 27
4.0 Conclusions and Future Work 31
5.0 Experimental 33
6.0 References 41

3. 3
Abstract
This report details the synthesis and investigation into the possibility of selective functionalisation for an
aziridine-based substrate via C-H bond activations.
The first segment introduces and summarises previous synthetic reactions carried out by the Craig group
and others, discussing two key methods of selective functionalisation that will be considered for C-C bond
formation at the β-position of an alkene function group. The second segment explores attempts at substrate
synthesis and its subsequent reactivity. The content of the discussions will include the specific optimisation
modifications made to experimental methods adopted by the Craig group for tetrahydropyridine-related
synthesis and reactions.
Finally, an evaluative discussion will be carried out to discuss and recommend potential future work in
this area of research.
Acknowledgements
I would like to take this opportunity to express my heartfelt appreciation and gratitude towards my
supervisor, Professor Donald Craig for providing me with the constant guidance throughout the course of my
research project. I would also like to express my sense of obligation towards him for giving me such an
interesting project that only increased my passion towards chemistry. Although it was only 10 weeks, I believe
I experienced a steep learning curve and I am forever indebted for having been given this rare opportunity.
These 10 weeks have given me a chance to not only hone my lab skills but to also critically evaluate the results
and modify practices when necessary. This is indeed essential to this field for such skills can never be
holistically perfected within a lecture theatre. I would also like to express my sincere appreciation towards the
members of Thorpe Laboratory for providing me with such a friendly environment to work in. My special
mention goes towards Richard whom was there to guide and advice me since day one; at the same time, not
forgetting Jasprit, Shu Hui and Joseph who provided me with the additional assistance and encouragement
when I was unsure about certain experimental set-ups and reactions.
The last group I would like to thank would be the Imperial College NMR and Mass Spectrometry for
their constant help me in analyzing my many samples and returning to me the results as fast as they possibly
could. Without their persistent efficiency, my efficiency would not have been possible.

4. 4
List of Abbreviations
_________________________________________________________________________________________
[α]D specific optical rotation
Å Ångström(s)
Ac acetyl
atm atmosphere(s)
Bn benzyl
bp boiling point
n
Bu normal-butyl
t
Bu tertiary- or tert-butyl
o
C degrees centigrade
c concentration
cat. catalytic
conc. concentrated
calcd calculated
cm centimetre
CH2Cl2 dichloromethane
DMAP 4-dimethylaminopyridine
DMF dimethylformamide
DMSO dimethyl sulfoxide
dr diastereomeric ratio
eq equivalent(s)
Et ethyl
Et2O diethyl ether
EtOAc Ethyl acetate
g gram(s)
h hour(s)
IR infrared

5. 5
K kelvin
LiAlH4 lithium aluminium hydride
LiHMDS lithium bis(trimethylsilyl)amide
M mol dm−3
Me methyl
mg milligram
min minor or minute(s)
mL millilitre
mmol millimole
mol mole
m.p. melting point
MS mass spectrometry
n normal
NMR nuclear magnetic resonance
O/N overnight
Ph phenyl
i
Pr iso-propyl
R alkyl group
Rf retention factor
rt room temperature
Temp temperature
THF tetrahydrofuran
TLC thin layer chromatography
Ts p-toluene-sulfonyl (tosyl)
Δ reflux

6. 6
NMR
1D 1 dimensional
COSY correlation spectroscopy
δ chemical shift
DEPT distortionless enhancement by polarisation transfer
Hz hertz
J coupling constant
MHz megahertz
NOE nuclear Overhauser effect
ppm parts per million
s singlet
d doublet
dd double of doublets
t triplet
q quartet
m multiplet
br broad
IR
cm−1
wavenumbers
υmax maximum absorption
MS
CI chemical ionisation
EI electron impact
ESI electrospray ionisation
m/z mass / charge
[M]+
molecular ion

7. 7
Nomenclature And Stereochemical Notation
_________________________________________________________________________________________
The starting material being used is one that has a stereocentre (*) and is therefore an enantiomer,
making it important to define the stereochemical notations that will be used for the compound and subsequent
derivatives. The Maehr convention has been adopted to indicate the differences between the relative and
absolute stereochemistry of intermediates and products synthesised during the research.
⊥
Fig. 1 in Diagram 1 shows a structure of a compound that has relative stereochemistry. The
3-dimensional structure is not known but it is known that one structure will be the mirror image of the other and
so will be represented by solid lines. Fig. 2 in Diagram 1 shows the structure of a compound that has absolute
stereochemistry. It has a known 3-dimensional placement of ligands around the central atom. Bonds are
represented by wedges.
Diagram 1- Stereochemical representations
Diagram 2 shows the numbering sequence that will be implemented in discussions with regards to 6-
membered nitrogen heterocycles.
Diagram 2 – Carbon numbering in Heterocycles
⊥
Maehr, J. Chem. Educ.; 1985, 62, 114
Racemate
Relative Stereochemistry
(Figure 1)
Single Enantiomer
Absolute Stereochemistry
(Figure 2)
N
Ts
1 2
3
4
5
6
R1
R1= Me

8. 8
Introduction
1.0 Introduction to tetrahydropyridines
A significant number of compounds and drugs in the chemical and pharmaceutical industry contain
tetrahydropyridine-type heterocycles as key intermediates towards the formation of their piperidine analogues
(Diagram 3).7,8,9
They have been of major interest to organic chemists since the piperidine analogue is one of
the most common frameworks seen in biological compounds and has been used in drug synthesis. 9,10
Diagram 3 -Tetrahydropyridine as a key intermediate & a novel piperidine drug candidate
The tetrahydropyridine framework has the potential for poly-substitution via the selective
functionalisation and modification of the unsaturated C=C bond allowing the formation of more complex
molecules (Diagram 3).8,9,25
1.1 Research Carried out by the Group
Research carried out in the Craig group over the past ten years has focused on the novel reactivity of
functionalized piperidines.7-10
The compounds are synthesised via a sulfone-based 3-carbon homologating agent
and an enolate equivalent to form enantiomerically pure amino acid-derived N-tosylazridines. The aziridines are
treated with allylmagnesium based acetals to form the tetrahydropyridines via nucleophilic ring opening of the
aziridine followed by cyclocondensation of the isolable intermediate. Aziridine-based substrates such as
1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines 4 have been the subject of intense research by the Craig group.
O
N
Me
Ph
OH
HH
(-)-Sedacrine
2,6-disubstituted-1,2,5,6-tetrahydropyridine
O
N
Me
Ph
OH
HH
(-)-Sedinone
2,6-disubstituted piperidine analogue
1 2
N
H
C11H23Me
(-)-Solenopsin A
Novel Drug Candidate against Alzheimer's Disease
3

9. 9
Research efforts by the group have led to the synthesis of enantiomerically pure forms of the substrates
(Scheme 1).1-5
(a) 3a-e : R1
=CH2Ph, i-Pr, i-Bu, CH2OTBDPS, CH2(4-C6H4OMe); R2
=H, R3
=H, 50-91% 2,3
(b) 3f-h : R1
=CH2Ph, i-Pr, Me; R2
=Me, R3
=H, 72-100% 2,3
(c) 3i : R1
=CH2Ph ; R2
=H, R3
=Me, 100% 3
(d) 3j : R1
=Me; R2
=C11H23; R3
=H, 82% 2
(e) 3k : R1
=C12H25; R2
=H, R3
=H, 62% 4
(f) 3i : R1
=H; R2
=H, R3
=H, 90% 5
Scheme 1 : Tetrahydropyridines synthesised by the Craig group
(Diagram 2) summarises the different types of reactions carried out on
1,4-bis(arylsulfonyl)-1,2,3,4 tetrahydropyridines 4 by the group.6
The electron withdrawing nature of the tosyl
group at the C4 position facilitates activation of the C-H bond at the C3 position; incoming halide displaces the
C-H bond. Recent research by the group has shown that alkylation at the C4 position prior to the addition of the
halide has been unsuccessful due to the steric hindrance imposed by the alkyl group at C4.6, 24
Diagram 4- Summary of Key reactions carried out with 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines24
N
R3
R2 R1 NH
Ts
R1
Ts
R3
R2
Ts
R3
R2
OMe
OMe
N
Ts
R1
Ts
Ts
4 5 6 7
OMe
OMe
N
Ts
Ts
R
(i) OsO4
N
Ts
Ts
R
HO
HO
(ii) Base,
E-X
N
Ts
Ts
R
E
N
Ts
RNu
(iii) SN1'
Nu-
(iv) Halogenation
N
Ts
Ts
R
X
N
Ts
Ts
R
E
X (V)
(Vi) Stille/Suzuki
Coupling
N
Ts
Ts
R
N
Ts
R
MeO2C CO2Me
(Vii) SN18
15
14 13
12
11
10
9

10. 10
1.2 C-H bond activation in tetrahydropyridines
C-H bond activation activates the thermodynamically stable C-H bond to a more reactive state.26
This in
effect allows it to dissociate or be substituted in further reactions. The thermodynamic stability of the C-H bond
is due to the strong sigma-sigma orbital overlap; activation will generally occur via the formation of a transition
metal complex which coordinates the hydrocarbon to the inner metal sphere.27
The overlap between the metal’s
d-orbitals and the atoms reduces the electron density in the C-H bond making it more reactive towards
nucleophilic reagents, and creating the possibility of substitution of the H atom.27
This C-H bond activation
which occurs at the C3 position can be employed to form new C-C bonds which allows the formation of a more
complex heterocyclic molecule from the simple substrate framework. The incoming group is influenced by
sterics and stereoelectronics of the molecule which has been highlighted in previous research carried out by the
group.1,2,15
C-H activation of 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines 4 towards displacement proved
unsuccessful, possibly due to the presence of the tosyl group and R group at the C4 position that sterically
hinders the incoming electrophile.
1.3 Reactivity of tetrahydropyridines
1-arylsulfonyl-1,2,3,4-tetrahydropyridines 16 do not have any steric hindrance inhibiting the C3 for C-H
bond activation. However, absence of the tosyl group at the C4 position makes the C-H bond of the C3 position
less acidic and less readily displaced. The influence of the electron donating methyl group is also pertinent, as it
increases the electron density towards the heteroatom.
1-arylsulfonyl-1,2,3,4-tetrahydropyridines 16 are used in the preparation of complex heterocycles by
selective functionalisation. The double bond is nucleophilic enough to give rise to C-H activation at C5
(Mechanism A).
Mechanism A – Direct addition-elimination substitution reaction for C-C bond formation
N
Ts1
2
3
45
6 R1
HE
N
Ts1
2
3
4
5
6
R1
R1= Me
H
E
N
Ts
1
2
3
4
5
6
R1
E
16 17 18

11. 11
1.3.1 Palladium-Catalysed Reactions
Palladium catalysis is used in cross-coupling reactions such as the Suzuki and Heck
reactions.11,13
The palladium metal is suitable for this as it readily interconverts between the activated Pd(0)
species and inactive Pd(II) species. Cross-coupling generally involves two chemically distinct partners where
one is a R-X type halide and the other with greater variation (eg. Alkenes [Heck reaction], Alkyne
[Sono-Gashira] ). Table 1 summarises the key conditions for the two different C−C coupling reactions
considered.
Table 1 - Summary of key palladium-catalysed reactions
1.3.1.a Heck Reaction11,12
The Mizoroki−Heck reaction involves an unsaturated halide (RX) cross-coupled with an alkene. The
reaction is carried out with a base and palladium catalyst to form the substituted alkene. This results in the
displacement of the alkene C-H bond to form the C-C bond via the R-group. The olefin contains at least one
proton (H) and is electron deficient as it is commonly found adjacent to an electron-withdrawing group (X).
Scheme A - General Overview of the Heck Reaction
In Heck reactions, the first step involves the generation of the activated palladium species Pd(0), which
is formed in situ via organic pre-catalysts such as Pd(OAc)2 and Pd(PPh3)4. The rate of the reaction is inversely
proportional to the sterics imposed by the olefin where, larger substituents on the olefins result in a slower rate
of reaction. Also, type of halide (X) used influences the rate of reaction where I > Br >> Cl due to their
decreasing electronegativity.11
Cross Coupling Reaction Reactant A Reactant B Base Required ?
Heck Reaction11,12
R-X Alkene Yes
Suzuki Reaction13,14
R-X RB (OR)2 Yes
R1 X
R2
Pd(0) / Pd(II) catalyst
Base
H
R1 R2
Minor Product when
R groups are small
R1
R2
Major Product
H X
R1 : Aryl , Benzyl , Alkenyl , Alkynyl
R2 : Esters(COOR), OR, Alkyl, Aryl, SiR3
X : Halogen

12. 12
Diagram 4 - General Mechanism of the Heck Reaction
The Pd(II) salts such as Pd(OAc)2 are reduced to Pd(0) to generate the catalytically active species. The
primary reduction of the metal centre is achieved by the use of phosphine ligands to displace the acetate anions.
The first step (Diagram 4, A) details the activation of the metal catalyst by forming the 14-electron complex,
which provides the two coordination sites for the succeeding reaction. The second step (Diagram 4, B) is the
oxidative addition of the R1
X across the metal centre. As the two bonds formed are concerted they must be on
the same ‘face’ of the complex (ie. syn to each other). (Diagram 4, C and D) details the migratory insertion of
the η2
co-ordinated alkene into the Pd-R1
bond. Migratory insertion takes place as a concerted process and not
the SN2 type explaining the syn-addition. The product alkene is liberated via β-hydride elimination (Diagram 4,
E) and occurs via internal rotation about the Pd-C bond to allow syn-coplanar coordination of the alkene
hydride to the metal centre. The concerted strong agostic interaction results in the four-centered transition state
and leads to the syn-elimination of the alkene (Diagram 4, F), resulting in the adoption of the energetically and
sterically favoured E-stereochemistry.
There are some considerations to be made when using the Heck cross-coupling. The principal
drawbacks are the potential for the premature elimination of any substrate that contains β-hydrogens, to give
olefins as a side product. For the R-X compound, chlorides cannot be used as they react very slowly (if at all).4,6
Pd(PPh3)4
(A)
Pd0(PPh3)2
-2 PPh3
R1 X
Pd(II)
PPh3
PPh3
R1
(B)
R2
(C)
Pd(II)
PPh3
R1
X
R2
(D)
Pd(II)
PPh3X
R2
H
Ph3P
R1
H
H(E)
Pd(II)
PPh3X
R2
H
Ph3P
R1
H
H
(F)
Pd(II)
PPh3
X
Ph3P
H
R1
R2
(G)Base
H
X

13. 13
1.3.1.b Suzuki Reaction13,14
The Suzuki cross-coupling reaction is catalysed by a Pd(0) complex to form poly-olefins, substituted
biphenyls and styrenes via a reaction between an aryl/vinyl halide and aryl/vinyl boronic acid.
Scheme B - General Overview of the Suzuki Reaction
The cross-coupling reaction mechanism of the Suzuki reaction involves the three following steps: (i)
Oxidative addition, (ii) transmetallation and (iii) reductive elimination. The primary reduction of the metal
centre is achieved by the use of phosphine ligands to displace the acetate anions. The Suzuki reaction is
mechanistically different as it involves transmetallation as opposed to the key β-hydride elimination step of the
Heck reaction. Compounds that have β-hydrogens are consequently cross-coupled via the Suzuki reaction.
Diagram 5 - General Mechanism of the Suzuki Reaction
Pd(0)(PPh3)2
Pd(PPh3)4
(A)
(B) R1 X
Pd(II)
PPh3
Ph3P R1
X
Pd(II)
PPh3
Ph3P R1
BuOt
NaOtBu
NaX
(C)
Pd(II)
PPh3
Ph3P
R1
R2
(D)
B
X
X'
OtBuR2
(ii)
(i)
B
R2
X
X
NaOtBu
B
X
BuOt
OtBu
R2
Na
(E)
R1 R2
R1 X
Pd(0) / Pd(II) catalyst
Base
B
OR
R2 OR R1 R2
R1 : Alkyl, Aryl or Vinyl
R2 : Aryl or Vinyl
X : Halogen

14. 14
The palladium complex is activated by the displacement of two ligands to give PdL2 complex (Diagram
5, A). The phosphine ligand is favoured as it is readily formed and stable in air. The zero valences allows
oxidative addition of the R-X bond (Diagram 5, B) to give the trans-Pd(II) complex, which is more stable than
the cis-stereoisomer.13
The alkenyl type halides show complete retention of stereochemistry but the allylic and
benzylic types give rise to inversion of the stereochemistry at the palladium centre. This addition is often the
rate-determining step.
Nucleophilic attack at the electron-deficient boron centre forms the active ‘boronate’ species (Diagram
5, C and D), which is sufficiently nucleophilic to allow for transmetallation, transferring the R2
alkyl group to
the palladium centre with retention of stereochemistry (Diagram 5, D). The two R-groups of the palladium(II)
complex undergo reductive elimination via isomerization to the cis form. The elimination forms the product and
regenerates the palladium catalyst (Diagram 5, E).
2.0 Aim
The aim of this project is to expand on previous work carried out on tetrahydropyridines of similar
motifs such as the 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridine 4 and 1-N-Boc-2-piperidone. New modes of
reactivity such as C-H bond activation will be considered via palladium catalysed C-C bond formations and
more direct C-H activation processes. It is hoped that the substrate 20 formed via C5 halogenation of 19 will be
displaced to form a more complex substituent 21 via C-C bond formation at the C5 position (Scheme C).
Scheme C - Expected synthetic Route to C-H activated aziridine substrates
The effect of the tosyl group on substrate reactivity and the viability of the synthesis of 19 will be
examined.
N
Ts
Me
(i)
N
Ts
Me
I
N
Ts
Me
R
(ii)
19 20 21

15. 15
2.1 Summary of reactions
Diagram 6 - Summary of reactions developed towards synthesis and further reactions of tetrahydropyridines
Me
O
OH
NH2
Me
O
OH
NHTs
Me
OH
NHTs
N
Ts
Me
O
O
O
O
Br
O
O
HTsN
Me
O
O
N
Ts
Me
N
Ts
Me N
Ts
Me
( Major Pdt ) (Minor Pdt)
I
I
N
Ts
Me
I
O
Me
N
Ts
Me
I
N
Ts
Me
R
Reaction step successfully carried out
Reaction step tried but failed to achieve
expected product
Reaction step not attempted
Br
O
O
BrMg
O
O
BrMg
22 23 24 25
26 2827
29 30
3320
21
3220
19
31

16. 16
3. General Strategy towards tetrahydropyridine
Previous research carried out in the Craig group1,2,3,15
has provided a route to robust pyridine
(1,2,3,4-tetrahydro-2-methyl-1-[(4-methylphenyl)sulfonyl]) via a reaction of cyclic 30 or acyclic 28
dioxolanemagnesium bromide and N-tosyl aziridine 25. The nucleophilic ring-opening of the aziridine forms
the isolable intermediate 31, from which cyclocondensation forms the desired substrate 19.
3.1 Synthesis of N-tosylaziridine 6
Scheme 1-A Reagents & conditions: (i) TsCl (1.3 equiv), EtOAc, H2O, NaOH (2.7 equiv), rt,4h, 76%
Mechanism 1-A Synthesis of tosyl-protected L-Alanine 23
L-alanine 22 was tosylated under standard conditions, via the addition of TsCl in EtOAc to yield the
N-tosyl-protected L-alanine 23 (63 %). Improvements to the experimental procedures were carried out to
maximise the yield of 23. This was achieved by conducting a series of experiments in which the concentration
of TsCl, duration of stirring and concentration of base were varied. The optimal synthesis conditions (Scheme
1-A) resulted in a higher yield of 23 (76 %).1,2
N-tosylated L-alanine 23 was reduced to N-tosylated-L-alaninol 24 using LiAlH4.1
The synthesis
involved the complete reduction of COOH functional group to the primary hydroxyl group CH2OH.
Scheme 1-B Reagents & conditions: (i) N-tosyl-L-alanine 23 (1.0 equiv), LiAlH4 (3.0 equiv), Et2O-THF, 60°C, 1h; (ii) aq.
NaOH (1M; 50 mL), HCl (2M; 10 mL), rt, 87 %
Me
OH
O
H2N
22
Me
OH
O
NHS
O
O
Me
23
Me
N
H H
O
OH
S OO
Cl Me
O
OH
N
H
SO O
H
OH
Cl
Me
O
OH
N
H
SO O
2322
NaOH
Na Cl
EtOAc
H2O
H2O
Me
OH
O
NHS
O
O
Me
23
Me
OH
N
H
S
O
O
Me
24
(i)
(ii)

17. 17
Mechanism 1-B synthesis of N-tosylated-L-alaninol 24
Initial experiments (Table 2, A) proved unsuccessful due to the use of poor-quality LiAlH4. This led to a
failed/partial reduction of the carboxylic group, resulting in starting material 23 and partially reduced product
(aldehyde) to be recovered. The mass spectroscopic analysis gave the 100 % peak at 261, indicative of MNH4
+
ion where M= 23. The 1
H NMR and IR spectra confirmed the absence of the hydroxyl functional group. For the
complete reduction to a primary alcohol, the expected onset of the CH2 group was not observed in both spectra.
Thus it was concluded that the full reduction of 23 to 24 was initially not successful (Diagram 7).
Me
O
O
N
H
SO O
23
H
Li
AlH3
H
H2 (g)
Me
O
O
N
H
SO O
Li
AlH3
Me
O
O
N
H
SO O
Li
AlH2
H
Me
O
O
N
H
SO O
Li
AlH2
H
Me
O
O
N
H
SO O
Li AlH2
H
(Aldehyde Intermediate)
Me
O
N
H
SO O
H LiAlH4
Li
AlH3
H
Me
O
N
H
SO O
H H
Me
OH
N
H
SO O
H
24

18. 18
PL10-03-X LiAlH4 (Batch / equiv.) Reflux Duration (mins) Product Yield (%)
A Old / 3.0 30 0*
B New / 3.0 30 80
C New / 3.0 60 87
* Starting material and partially reduced aldehyde of the N-tosylated-L-alanine was attained instead
Table 2 - Table comparing yields of N-tosylated-L-alaninol 24 via varying experimental conditions
A new supply of the reducing agent (LiAlH4) was introduced since all other potential sources of errors
such as experimental procedure and the quality of other reagents were ruled out. Initial experimental conditions
(Table 2, B) were low-yielding, and so a series of experiments were carried out in efforts to maximize yield the
of 24, by varying the duration of reflux and ensuring the quality of reducing agent (Table 2). TLC monitoring
of the reaction showed significant amounts of starting material still remaining after 30 mins of reflux, and
therefore reflux duration was increased to 60 mins. The significant number of transfers and filtration resulted in
some loss of mass to give 87% of 24 as compared to 80% via the 30 min reflux.
Diagram 7 - Comparing the failed reduction (left) with a successful full reduction (right)
The final step in the aziridine synthesis involved the conversion of the alcohol 24 to aziridine 25 by
exposing 24 to a base that facilitated the 3-membered ring formation. Three different experimental methods
were evaluated to determine the method that gave the highest percentage yield of 25.

19. 19
Scheme 1-C-8A1,17
Reagents & conditions: (i) (S)-2-[[4-Methylphenyl) sulfonyl]amino]propan-1-ol 24 (1.0 equiv),
DCM, TsCl (1.3 equiv), DMAP (0.2 equiv), pyridine (3.0 equiv), rt 16h, (ii) Amberjet IRA-4400(OH) ion exchange resin
(5.0 equiv), rt 6h, 0%
Scheme 1-C-8B16
Reagents & conditions: (i) (S)-2-[[4-Methylphenyl)sulfonyl]amino]propan-1-ol 24 (1.0 equiv), THF,
Et2O, TsCl (1.1 equiv), KOH (4.2 equiv), reflux 2h, rt, 48%.
Scheme 1-C-8C18
Reagents & conditions: (i) N-tosylsulfonamide (1.0 equiv), THF, Sodium hydride (1.5 equiv), rt 2h,
33%.
No. Crude Yield (%) Purified Yield (%) By Product (%)
8-A 20 0 15
8-B 62 48 11
8-C 55 33 10
Table 3 - Table comparing yields of N-tosylated Aziridine via various experimental methods
Three different aziridination methods (Scheme 1-C) were evaluated (Table 3). 8-C used the hydride ion
to displace the OTs functional group in the sulfonamide 34. The reaction was successful and provided 33%
yield of the aziridine 25. A small amount of isolated by-product was attained. This condition was again present
via 8-B which used the hydroxyl anion to form 25 (48 %). 8-A was expected to be most favourable as it had the
highest theoretical yield.1,2
8-A involved the use of an ion-resin to ‘repel’ the free hydroxyl anions, which
Me
OH
N
H
S
O
O
Me
(i)
Me
N
S
O
O
Me
24 25
Me
OH
N
H
S
O
O
Me
(i)
Me
N
S
O
O
Me
24 25
O
S
O
O
Me
N
H
S
O
O
N
S
O
O
Me
(i)
34 25

20. 20
significantly minimised degradation via ring-opening of aziridine 25. However, as the type of resin used in
literature was different (resin size and packing) from that available in the laboratory, literature conditions were
not replicated, resulting in two failed attempts (both led to a black solid which was mainly deteriorated starting
material).1
Thus, 8-B which used KOH was chosen as the best method for the preparation of 25.16
Mechanism 8B-1 - Ring closing via OH-
ions
Mechanism 8B-2 - By-products of 34 and 35 via hydroxyl / chloride anion interactions
An excess of KOH facilitates de-protonation (Mechanism 8B-1). The use of KOH and TsCl in excess
allowed the OH−
and Cl−
ions to function as nucleophiles by attacking the less hindered carbon site of aziridine
25. This led to the cleaving of the C-N bond and resulted in the formation of a ring-opened by-product
(Mechanism 8B-2 / Diagram 8). This may explain why the reaction was yielding (48%) of aziridine 25, as ion
resins used were unsuccessful in preventing degradation of 25.16
The 1
H NMR spectra (Diagram 8) for the
isolated by-product 35, confirmed the presence of an N-H peak. Thus Mechanism 8B-2 via hydroxyl anions is
highly probable; explaining the low yields of 25.
Initial low yields of 25 via 8-B led to a series of experiments being carried out in which the equivalents
of TsCl, KOH and reflux duration were varied in efforts to maximise yield of 25 (Table 4).
Reaction No. Cl−
(Equiv.) KOH (Equiv.) Reflux (Hrs) Product (25) Yield (%)
8B-1 1.3 4.2 2 40.4
8B-2 1.1 4.2 2 44.2
8B-3 1.1 2.1 2 48.1
8B-4 1.1 2.1 4 42.6
Table 4 - Table comparing yields of N-tosylated aziridine via varying experimental conditions
Me
NHTs
O
H
KOH
Me
N
Ts
OTs
K
H2O
Cl
H
OH
K OTs N
Me
Ts
24 25
TsCl
H2O
N
Me
Ts
OH
N
H
Me
Ts OH
Ring Opened By-Product
N
Me
Ts
Cl
N
H
Me
Ts Cl
Ring Opened By-Product
25 35 25 36

21. 21
From table 4, it can be seen that an increased TsCl concentration led to a decrease in yields of aziridine
25. Thus TsCl was reduced to the minimal amount needed (1.1) equiv. Reduction of KOH concentration
increased the yield of the aziridine 25 formed (Table 4, 8B-3). This is probably due to a decrease in the number
of free anions available for degradation of 25. Equivalence of KOH was kept to a minimum of two since a 1:2
ratio was needed for the ring closing (Mechanism 8B-1). Increased duration of reflux resulted in lower yield of
25. The C-N bond is 276 kJ mol-1
(C-H 414 kJ mol-1
); weak bond that is broken via extended heating periods
and availability of free ions.4
Thus the most ideal conditions are those used in 8B-3. Also, as 25 is susceptible
to polymerization; steps were taken to reduce this possibility by having shorter reaction times (30 mins), drying
over Na2SO4 instead of MgSO4 and taking care not to overheat the product during solvent evaporation (keeping
temperatures below 40 °C).
Diagram 8- Comparing the aziridine 25 1
H NMR spectra (left) with the by-product 34 1
H NMR spectra (right)
3.1.2 Synthesis of Dioxolane-substituted AlkylMagnesium Bromide 20
In order to obtain the six-membered tetrahydropyridine heterocycle, the dioxolane-substituted
alkylmagnesium bromide 30 was synthesised to act as the nucleophile in the ring-opening of the aziridine 25.
Scheme 7- Reagents & conditions: (i) Dioxolane 29 (1.0 equiv), dry THF, Mg (1.3 equiv), rt, 82%
O O
Br
(i) O O
MgBr
29 30

22. 22
Initial experiments carried out to prepare 30 failed due to unreactive magnesium flakes which failed to
form the Grignard. A series of experiments were carried out via varying the stirring time to determine the
duration needed for the activation of the magnesium flakes to effectively form 30 (Table 5). As the reaction was
carried out under inert atmosphere, mechanical grinding of the flakes to remove the oxides was not ideal.
Instead a stirrer bar was used to ‘grind’ the flakes against the glass surface of the flask to remove the oxide
layer. Testing against 1,10-phenanthroline allowed the volume needed for the colour change to observed;
concentration of 30 to be determined for successive reactions that followed.
• The pink-red solution formed is indicative that the Grignard 30 has been formed
Table 5 - Table comparing methods for activation of magnesium to form 30
3.1.3 Ring-Opening of N-tosylaziridine 20
The nucleophilic ring-opening of the aziridine 25 by dioxolane-substituted alkylmagnesium
bromide 30 readily occurred since the three-membered ring was subjected to high ring strain and readily lost
the strain to form the isolable intermediate 31. Cu(I)Br served as a catalyst for the nucleophilic attack of the
dioxolane 30 on the aziridine 25. The dioxolane nucleophile 30 favourably attacked at the non-methyl carbon
site, as it was subjected to lesser steric hindrance making it kinetically more favoured.
Scheme 8- Reagents & conditions: (i) CuBr.DMS (0.4 equiv), DMS (3 mL), Grignard 30 (2.0 equiv), -78 °C 2 hr. (ii)
Aziridine 25 (1.0 equiv), THF, -78 °C à r.t 10min à 24h, 75 %.
Mechanism 8 - Ring-opening of N-tosylated aziridine 25
PL10-07-X Mg (g) Stirring Time (hrs) Effect of Titration
A 484 1 Nil
B 484 20 Nil
C 484 48 Cloudy White ppt
D 484 96 Pink-red Solution (Positive)*
E 968 96 Pink-red Solution (Positive)*
O O
MgBr
30
O O
MgBr
R
MgBr R
NTs
Me
25
H
30
Cu(I)Br
Catalysed
R
NHTs
Me
31
H
O
O
MgBr
30
N MeTs
25
(i)
(ii)
31
Me
TsHN
O
O

23. 23
Initial experimental synthesis gave rise to a product yield of 68 % (Table 6, A). In an attempt to
maximise the yield of 31, a series of experiments were carried out in which the equivalents of the reagents and
stirring time were varied (Table 6). Continuous monitoring by TLC showed that after overnight (16h) stirring
there was still starting material present in the reaction mixture.
PL10-09-X CuBr.DMS
(Equiv)
Grignard (Equiv) Initial Stirring (hr) Final
stirring
Product Yield
(%)
A 0.4 2.0 1 Overnight 68
B 0.4 4.0 1 Overnight 66
C 0.8 2.0 1 Overnight 64
D 0.4 2.0 2 24h 75
Table 6 - Table comparing methods for optimization of yield by varying reaction steps
Comparing A and B, increments made towards Grignard equivalence had minimal/no influence towards
maximizing yield of 31. Similarly, increased equivalence of the catalyst Cu(I)Br did not have any significant
influence on the yield. However, increased time allocated (Table 6, C and D) for stirring resulted in an increase
of the yield. This was complemented by the more faint spot observed via TLC monitoring (Diagram 9).
Five distinct spots, of which those labeled as ‘side products’ did not contain the expected 1
H NMR
spectra peaks of the product and were unassigned as enough was not obtained to allow for full 1
H NMR spectra
analysis. However, ring-opened intermediate 31 was UV- active and identified by 1
H and 13
C NMR spectrum
analysis (Diagram 9).
Diagram 9 - TLC plate representation of reaction mixture (left) and 1
H NMR of ring opened product 7 (right)
Ring Opened
Intermediate
Side Product
Starting Aziridine
Side Product
Side Product
30% EtOAc / Hexane

24. 24
3.1.4 Synthesis of 1-(arylsulfonyl)-1,2,3,4-tetrahydropyridines 20
Two different methods of synthesis (Scheme 9) were evaluated based on the yield of 19 and how easily
19 was isolated. Method 9-A involved the use of a strong acid to initiate the cyclocondensation (Scheme 9-A).
Method 9-B whereas involved the use of BF3 as a lewis acid to induce the cyclocondensation (Scheme 9-B).
Scheme 9-A Reagents & conditions: (i) Intermediate 31 (1.0 equiv), 1M HCl (5.0 equiv), Acetone (20 mL), rt, 16h, 80 %.
Scheme 9-B Reagents & conditions: (i) Intermediate 31 (1.0 equiv), DCM (10 mL), BF3.OEt2 (5 equiv),
-30°C (ii) -30°Cà0°C, 1hr (iii) 0°Cà rt 3h, 33%
Mechanism 9-A Cyclocondensation of the ring-opened intermediate 31 to form 19 via scheme 9-A
31
(i) (ii)
(iii)
N
Ts
Me
19
Me
TsHN
O
O
31
(i)
N
Ts
Me
19
Me
TsHN
O
O
Me
TsHN
O
O
31
Me
TsHN
O
O
H
Me
HTs
N
O
HO NTsMe O
OH
H
H
N
Ts
Me O
H
OH
H
N
Ts
Me
H
Cl Cl
H
Cl
19
OHHO
-HCl

25. 25
Mechanism 9-B Cyclocondensation of the ring-opened intermediate 31 to form 19 via scheme 9-B
Diagram 10 - Comparing TLC plate representations via Scheme 9-A (left) against Scheme 9-B (right)
Mechanistic analysis of scheme 9-A concluded that 19 is formed as it had minimal ring strain. The
intermediate steps remained reversible but the driving force was the displacement of the diol to form 19
(Mechanism 9-A). Minimal side products formed since spots observed were faint. Distinct Rf values meant the
product 19 was readily isolable (Diagram 10-left).
However via scheme 9-B, electron deficient BF3 had available empty Pz orbital to function as an lewis
acid. This allowed the lone pair on the nitrogen to attack the carbon inducing cyclocondensation to form
product 19 (Mechanism 9-B). The reaction resulted in a greater amount of by-products which were of more
similar Rf values to 19 (Diagram 10-right). Scheme 9-B required more careful isolation but gave a smaller yield
of 19 since more side-reactions were observed.
Scheme 9-A resulted in a ‘cleaner’ crude 1
H NMR spectrum of the product; a flash column could be
more easily carried out to isolate the desired product unlike via scheme 9-B, which had greater amount of
impurities present. 9-A method involved a simple experimental set-up and was of a higher initial yield of 19
(75%). However, in efforts to maximise the yield of 19, a set of experiments were carried out in which the
equivalence of HCl, duration for stirring and heat were varied (Table 7, C, 81 %).
Ring Opened
Intermediate
PL10-09
Product
Side Product A
Ring Opened
Intermediate
PL10-09
Product
Side Product A
Side Product B
Diastereoisomer
Me
TsHN
O
O
31
BF3
Me
TsHN
O
O
BF3
Me
HTs
N O
O
BF3
N
HTs
Me O
O
BF3
BF3
H
N
HTs
Me O
O
BF3
BF3
H
N
HTs
Me
O O
BF3
F3B
Proton
TransferN
Ts
Me
19

26. 26
PL10-10-X HCl (equiv) Stirring Heat Product Yield (%)
A 5.0 16h No 75
B 3.0 16h No 60
C 5.0 24h No 81
D 5.0 24h 10 min reflux 72
Table 7 - Optimization of cyclocondensation
A decreased concentration of HCl (Table 7) was found to reduce the yield of 19. TLC plate analysis
indicated that significant starting material remained after 16 hrs into the reaction (Diagram 10-left). Increasing
reaction duration to 24 hours resulted in an increase in product yield (Table 7,C). Introducing heat to the
reaction resulted in (Table 7,D) a smaller percentage yield of product 19.
The peaks of the 1
H NMR spectrum via scheme 9A (Diagram 11) corresponds to the expected peaks of
product 19. This was indicative that a relatively pure sample of 19 had been synthesized in high yields (81 %).
Diagram 11 -Annotated 1
H NMR of N-tosylated tetrahydropyridine 19
3.2 Synthesis of Iodo-N-tosyl tetrahyropyridine via C-H bond activation 22,23
Upon successful synthesis of 19, C-H bond activation at the β-position is attempted by displacing the C-H bond
in 19 with a C-I bond 20. This will then allow successive cross-coupling to achieve C-C bond formation at the
β-position.

27. 27
Scheme R-1 Reagents & conditions: (i) tetrahydropyridine 19 (1.0 equiv), NIS (1.1 equiv), CH2Cl2 (2.8 mL), HTIB (0.1
equiv), 50 °C 20h, (ii) Et3N 11%.
Two different methods of were considered for the synthesis of 20. Direct iodination (Table 8, A and B) was
compared to the use of NIS (Table 8, C and D). Direct iodination via 19 was found to be unsuccessful,
returning only starting material 19 in the 1
H NMR. This was possibly due to the C-H bond not being
sufficiently activated to form the C-I bond via reaction with I2.
However, the reaction via NIS (Table 8, C and D) resulted in the successful mono-iodination of 19, in an 11%
yield (Scheme R-1). The by-product was identified as decomposed starting material 19 while the other spot that
was in a ‘streak’ contained 20 (Diagram 12, left). In an attempt to maximise the yield of 20, a set of
experiments were carried with the effect of temperature and duration of stirring (Table 8, C and D) investigated.
PL10-R1-X Method adopted Reagent (equiv) Conditions implemented Product Yield
A
Direct Iodination
I2 (1.1) Dry CH2Cl2, rt, 24h 0*%
B
I2 (4.0)
Dry CH2Cl2,
40 °C 1 hr, rt 16h 0*%
C β-position Iodination HTIB (0.1), NIS (1.1) Dry CH2Cl2, 45 °C, 20h 67 %
D HTIB (0.1), NIS (1.1) Dry CH2Cl2, 50 °C, 48h 60 %
* Starting material 19 and its decomposed form was obtained
Table 8 – Optimisation for Iodination of 19
Diagram 12- TLC Plate monitoring reaction end state via Scheme R-1 (left) and Scheme R-2 (right)
By product
4.4cm
Expected Product
Starting Material
0.9cm
1.7cm
3.3cm
Starting
Material
Non-isolable
By-product
Intermediate
product
30% EtOAc / Petrol
N
Ts
Me
19
(i) NIS (1.1), HTIB (0.1)
(ii) Et3N (1.1) N
Ts
Me
20
I

28. 28
Analysis of the 1
H NMR spectrum showed a doublet at 7.8 ppm instead of the expected singlet. The doublet of
the ortho-tosyl expected at 7.7 ppm resulted in a multiplet instead. Similarly, doublet of the meta-tosyl protons
expected at 7.3 ppm resulted in a doublet of doublets. Two methyl peaks observed at 2.4 and 2.4 ppm
respectively, indicating more than one structurally similar product 20 was present in the product (Diagram 13,
left). The two products gave rise to similar peaks in the 1
H NMR spectra, and had similar Rf values (Diagram
12, left).
Analysis of the 13
C NMR spectrum showed peaks at 129.7 ppm and 126.7 which are highly likely to be that of
two distinct ortho-tosyl carbon environments; each contributing two meta/ortho-tosyl carbons (Diagram 13,
right). The difference in the peaks being only 3.0 ppm is indicative that they would be in relatively similar
chemical environments. Thus, it was concluded there was both the α-substituted 32 and β-substituted 20 iodo
tetrahydropyridines in the sample. This conclusion was supported by the similar Rf values, as they are
geometric isomers, making isolation via flash column chromatography difficult and time-consuming.
Diagram 13- Annotated 1
H(left) and 13
C(right) NMR of expected product mixtures 20 and 32
Comparing the ratio of the intensity of peaks (4:1) in the 1
H NMR spectra (Diagram 13, left), the β
mono-substituted product 20 was the major product while the α mono-substituted product 32 was the minority.
The product 20 being iodo-substituted was expected to be relatively unstable and carrying out the column
chromatography on silicon, which is acidic, could have led to the early deterioration of the compound. Thus,
successful separation of the two compounds was not achieved due to rapid deterioration of the sample and due
to the lack of research time.
For future work with regards to this reaction, 20 would have resonance stabilization; C-I bond is more stable at
the β-position as compared to the α-position, which does not have the same extent of the resonance stabilization

29. 29
(Diagram 14). The use of a large hindered base would be hypothesized to displace the iodine from the
α-position, allowing the reformation of the starting material 19 resulting in the Rf values of 19 and 20 to be
more distinct. This will allow the desired product 20 to be readily isolated via column chromatography
(Diagram 15).
Diagram 14- Resonance stabilisation of the β-substituted position mono-iodinated product 20
Diagram 15 - Potential Mechanism for isolation of the major product 20
As R-1 resulted in failure to isolate 20, another approach was undertaken (Scheme R-2) to form the iodo-
tetrahydropyridine 20 via the formation of an intermediate 33, which had both the iodo and methoxy
substituents at the β and α positions respectively.
Scheme R-2-A : Reagents & conditions: (i) tetrahydropyridine 19 (1.0 equiv), NIS/ICl (1.2 equiv), MeOH (1.2), CH2Cl2,
-78 °C 2h, (ii) NaHCO3, 70%
Scheme R-2-B : Reagents & conditions: (i) Intermediate 33 (1.0 equiv), TFA (0.01 equiv), toluene,
N
Ts
Me
20
I
N
Ts
Me
20-a
I
N
Ts
Me
20-b
I
N
Ts
Me N
Ts
Me
I
I
Minor Product Major Product
32 20
Large Hindered Base
(LDA)
N
Ts
Me
I
Major Product
20
N
Ts
Me
19
N
Ts
19
(i) MeOH (1.2) NIS (1.2)
(ii) NaHCO3
N
Ts
Me
33
OMe
I
Me
N
Ts
Me
33
OMe
I
N
Ts
Me
20
I
(i) TFA (1.1)
Heat

30. 30
90 °C 1h, (ii) Et3N (0.003 equiv.)
Table 9 - Comparing methods for optimising yield of 10 by varying reaction conditions for R-2-A
The use of NIS as the iodine source was found to be almost twice as effective in yielding 33 (Table 9). This
indicated that NIS was a much preferred reagent for scheme R-2-A (Table 9, A and B). To maximise the yield of
33 via NIS, a series of experiments were carried out in which the stirring duration was varied (Table 9). The
stirring duration was found to be initially proportional to the reaction time.
On increasing the reaction time, the spot for the starting material got ‘fainter’ indicative of a smaller amount
starting material 19 (Diagram 12, right). When stirring duration was carried out for 180 mins (Table 9, D), no
significant increase in the amount of product 33 was observed. It could be speculated that the other reagents
could have been utilised in possible side reactions that led to an insufficient amount to fully consume all the
starting material via the main reaction pathway. The 1
H NMR spectrum (Diagram 16) reaffirmed the formation
of the intermediate with minimal, isolable by-products being formed as the expected proton peaks were present
with minimal unaccounted peaks.
Diagram 16- Annotated 1
H NMR spectrum of the expected product
PL10-R2-X MeOH (equiv) Iodide Source (equiv) Temp Stirring time Yield Attained
A20
1.2 ICl (1.1) -78 °C à rt 30 mins 32 %
B21,22
1.2 NIS (1.2) -78 °C à rt 30 mins 60 %
C21,22
1.2 NIS (1.1) -78 °C à rt 60 mins 72 %
D21,22
1.2 NIS (1.1) -78 °C à rt 180 mins 70 %

31. 31
The removal of the methoxy group to form and isolate β-substituted substrate 20 was attempted via the use of
the TFA and heat (Scheme R-2-B). However, due to the lack of time, the 1
H NMR spectrum of only the crude
product 20 was prepared. A TLC analysis of the reaction carried out showed a new spot appearing slightly
higher than the intermediate product 33, which was assigned to the mono-iodinated product 20. The crude 1
H
NMR spectra showed the absence of the singlet OCH3 peak, and the presence of the key Tosyl group peaks,
tetrahydropyridine framework protons and the proton due to the C-I bond (Diagram 17). These were indicative
that the methoxy group had been removed while keeping the 6-membered ring intact. However, due to the lack
of research time, full characterisation could not be achieved. Nonetheless, sufficient data was present to
conclude that the mono-substituted product 20 had been formed.
Diagram 14- Annotated crude 1
H NMR spectrum of the crude product 20
4. Conclusions and Future Work
Diagram 15 - Retrosynthetic synthesis for 19
N
Ts
Me
19 31
Me
N
S
O
O
Me
BrO
O
2529
Me
OH
N
H
S
O
O
Me
Me
OH
O
NHS
O
O
Me
23
Me
OH
O
H2N
22 24
Me
TsHN
O
O

32. 32
The synthesis of 19 was achieved in 75% yield (Diagram 15) where optimisation of individual intermediate
steps were successful in increasing the overall yield of 19, 81% (Table 10). Also, reagents used were optimised
towards minimising the amount of side products formed (e.g. synthesis of 25).
Substrate 23 24 25 29 31 19
Initial Yield (%) 63 80 48 - 70 75
Optimised Yield (%) 76 87 48 - 75 81
*Values above are independent of each successive step; 29 was commercially purchased
Table 10 –Initial and optimized yields towards synthesis of 19
Diagram 16 - Retrosynthetic synthesis for 20
The synthesis of 20 was carried out over 2 possible synthetic operations (Diagram 16). Successful optimisation
intermediate steps were carried out (Table 11). However the extent of optimization was only carried out for the
synthesis 33 from 60% to 72%. The yield of 20 via both routes was not determined due to insufficient research
time and the rapid degradation of the potential product. But sufficient characterization was carried out on both
expected mono-iodinated compounds to conclude that synthesis of 20 was successful.
Diagram 17 – Future cross-coupling reactions for 20
Future work could consider continuing with palladium-catalysed cross-coupling reactions for C-C bond
formation at the β position. This is expected to give small yields (if any) since the PdII
catalysed homocoupling
of organometallic reagents via Suzuki cross-coupling is kinetically faster that C-H activation.28
Also, the
Palladium-substituted heterocycle formed from the C-H activation step can catalyse homocoupling where
reductive elimination and transmetallation must be faster (Scheme B; Diagram 5).28,29
N
Ts
Me
I
20
Suzuki
cross-coupling
N
Ts
Me
R
21
N
Ts
Me
R
21
Heck
cross coupling
N
Ts
Me
I
20
N
Ts
Me
I
MeO
33
N
Ts
Me
19
N
Ts
Me
19

33. 33
Synthesis of 21 has only been considered for a substrate possessing the methyl group at the C5 position.
Variation of the methyl substituent could be considered to determine the influence of different alkyl groups on
the efficiency of synthesis of 19 and subsequent synthesis of 21.2,3
The N-group used is Tosyl 19 and in a
previous experiment, the Boc group had been utilised.23
Other groups could also be looked into such as SES to
determine their effectiveness and influence towards C−H bond activations.
5. Experimental
5.1 General Procedures
The experimental procedures carried out during the course of the research adheres to the standard
laboratory techniques learnt in undergraduate laboratories with specific modifications practiced by the Craig
group. All reactions were carried out under a nitrogen atmosphere, as many of the key processes were
water-sensitive. All apparatus used in the experiments was oven dried.
NMR Spectroscopy: 1
H NMR spectra were recorded at a frequency of 400 MHz using the Bruker Ultra-Shield
AV400 spectrometer. The 13
C NMR spectra were recorded at 101 MHz frequency via the Bruker Ultra-Shield
AV400 spectrometer. The spectra were recorded in CDCl3 unless otherwise stated. The chemical shifts are
recorded in parts per million (ppm) and references relative to the residual proton-containing solvent (1
H NMR:
7.3 ppm for CDCl3, 2.6 ppm for DMSO; 13
C NMR: 77.0 ppm for CDCl3, 40.8 ppm for DMSO). For accuracy
of results, coupling constants are given with accuracy to the 0.1 Hz.
Melting points: A small sample was taken and determined via the Stuart Scientific SMP1 melting point
apparatus.
FTIR: The spectra were taken on the Matterson 5000 FT−IR machine and Perkin−Elmer spectrum RX FT−IR
system spectrometers as thin films where possible. The solvent used to dissolve the solids (where appropriate)
was CH2Cl2. In specific instances when dichloromethane was not able to dissolve the solid, it was done ‘neat’
to still result in credible results.
Mass Spectra: (CI and ES) were recorded using the Micromass AutoSpec−Q or the Micromass platform II
instruments.
Solvents and Reagents: Standard solvents were distilled under nitrogen prior to use. THF from
sodium−benzophenone ketyl, CH2Cl2 and acetonitrile from CaH2 and toluene from sodium. All other solvents
and regents used were attained from the supplier. Petrol refers to petroleum ether b.p. 40–60 °C.

34. 34
Chromatography: Analytical thin layer chromatography (TLC) was performed on pre−coated
Aluminum−backed Merck Silica gel 60 F254 plates. Visualisation was effected with ultraviolet light, vanillin or
potassium permanganate as required. Flash column chromatography was performed using BDM (40−63 µm)
silica gel.
(S)-2-[[(4-Methylphenyl)sulfonyl]amino]propionic acid 2,3,6
To a rapidly stirred solution of (S)-(+)-alanine 22 (15.1 g, 172 mmol, 1.0 equiv.) and finely divided
4-toluenesulfonyl chloride (42.1 g, 220 mmol, 1.3 equiv.) in EtOAc (400 mL) and H2O (120 mL) was added
NaOH (230 mL of 2M aqueous solution, 460 mmol, 2.7 equiv.) drop-wise over 2.5 hrs. Upon formation of a
homogenous pale yellow reaction mixture, the reaction mixture was further stirred at r.t. for 5 hrs. The aqueous
layer was separated, washed with Et2O (3 x 250 mL) and acidified (pH 1) with concentrated HCl (25 mL). The
aqueous layer was then extracted with EtOAc (3 x 250 mL) and the combined organic extracts were washed
with brine (2 x100 mL), dried over MgSO4 and concentrated under reduced pressure to yield
(S)-2-[[(4-Methylphenyl)sulfonyl]amino]propionic acid 23 (31.4g, 76.4%) as a white crystalline solid. An
analytical sample was prepared by recrystallisation from 1:1 EtOAc−petrol; Rf = 0.32 (15% EtOAc−Hexane);
m.p. 130−132°C, [132−133°C Lit6
]; [α]D
6
−29.8 (c 1.010; CH2Cl2), −10.7 [c. 1.023; CH2Cl2 Lit6
]; FTIR (Thin
film) cm−1
: 3271.8 (m, broad, -OH), 1708 (s, sharp, -S=O), 1654 (w, sharp, C=O), 1599.3, 1340 (m, sharp,
C-N), 1229, 1147.4, 1090, 1055, 969, 842, 810.1, 677; 1
H NMR (400 MHz, DMSO): δ 12.67 (1H, s, COOH),
8.09 (1H, d, J 7.6 Hz, NHTs), 7.70 (2H, d, J 8.3 Hz, Ortho-Ts), 7.40 (2H, d, J 8.3 Hz, Meta-Ts), 3.81-3.70 (1H,
m, CHNHTs), 2.41 (3H, s, CH3SO2C6H5), 1.16 (3H, d, J 7.1 Hz, NHTsCHCH3); 13
C NMR (100.6 MHz,
DMSO): δ 173.7 (COOH), 142.9 (Ipso-Ts), 138.90 (Para-Ts), 129.93 (Ortho-Ts), 126.94 (Meta-Ts), 51.56
(HCNH), 21.42 (CH3SO2C6H5), 18.90 (CH3COOH); m/z (CI) 261 [M+NH4]+
100%, 244 [MH]+
3%, 215, 198
[M-COOH]+
4.5%, 189, 174 32%, 156 [TsH]+
6%, 139 7%, 107 8%, 52 11%, 44 35% [Calculated Mass of 23
243 g mol-1
]6
Me
OH
O
H2N
22
Me
OH
O
NHS
O
O
Me
23

35. 35
(S)-2-[[(4-Methylphenyl)sulfonyl]amino]propan-1-ol 2,3
To a stirred suspension of LiAlH4 (4.7 g, 123 mmol, 3.0 equiv.) in Et2O (250 mL) under argon at r.t. a solution
of (S)-2-[[(4-Methylphenyl)sulfonyl]amino]propionic acid 23 (10.0 g, 41 mmol) in Et2O-THF (1:1; 250 mL)
was added dropwise. Upon completion of addition (approx 1.5 hrs) the mixture was heated under reflux for 1 hr.
The reaction mixture was cooled to –10 °C and aq. NaOH (1M; 50mL) was added cautiously. The resulting
white suspension was filtered through Celite® and residue was washed with EtOAc (100 mL). The combined
filtrate and washings were acidified (pH 5) by the addition of approx. 10 mL aq. HCl (2M) and the resulting
mixture saturated with NaCl and extracted with EtOAc (4 x 50 mL). Combined extracts were washed with brine
(3 x 50 mL), dried over (MgSO4), decolourised (charcoal) and filtered through Celite® The filtrate was
concentrated under reduced pressure to give a colourless oil, which dried over under high vacuum to remove
the solvents to yield a colourless oil. The oil was triturated with 1:1 Et2O–Petrol to give the off-white product of
(S)-2-[[(4-Methylphenyl)sulfonyl]amino]propan-1-ol 24 (5.7 g, 61%). An analytical sample was prepared by
recrystallisation from 1:1 Et2O-petrol; Rf value of 0.26 (20% EtOAc–Hexane) m.p. 56−59°C, 57−58°C (Lit2,3
);
[α]D
2
−9.5 (c 1.000; CH2Cl2), −2.8 [c. 1.021; CH2Cl2 Lit2,3
]; FTIR (Thin film) cm−1
: 3497.2 (m, broad, -NH
stretch), 3271.3 (m, broad, -OH), 2979 (w, sharp, -CH3), 2938, 1636 (m, -NH bending), 1289, 1317 & 1156 (s,
sharp, S=O), 1089 (s, sharp, C-N), 1047, 972, 814 (w, meta- C-H bend), 663, 611 (w, Ortho C-H bend); 1
H
NMR (400 MHz, CDCl3): δ 7.80 (2H, d, J 8.4 Hz, Ortho-Ts), 7.33 (2H, d, J 8.4 Hz, Meta-Ts), 4.95 (1H, broad,
NHTs), 3.59–3.42 (3H, m, CHCH2(OH), 2.45 (3H, s, CH3SO2C6H5), 1.97 (1H, s, OH), 1.05 (3H, d,
CH3CHNTs); 13
C NMR (100.6 MHz, CDCl3): δ 143.5 (Ipso-Ts), 137.5 (Para-Ts), 129.8 (Ortho-Ts), 127.1
(Meta-Ts), 66.2 (CH2OH), 51.5 (HCNH), 21.6 (CH3SO2C6H5), 17.6 (CH3CHNTs); m/z (CI) 247 [MNH4]+
100%, 230 [MH]+
60%, 215, 198 [M-CH2OH]+
10%, 189, 174 2%, 155 [Ts]+
1%, [Calculated Mass of 24 229 g
mol-1
]2
(S)-N-Tosyl-2-methylaziridine 2
Me
OH
O
NHS
O
O
Me
23
Me
OH
N
H
S
O
O
Me
24
Me
OH
N
H
S
O
O
Me
Me
N
S
O
O
Me
24 25

36. 36
Freshly grounded KOH flakes (0.95g, 32.1 mmol, 2.2 equiv., 85% assay) was added in one portion to crude
(S)-2-[[(4-Methylphenyl)sulfonyl]amino]propan-1-ol 24 (1.75 g, 7.64 mmol, 1.0 equiv.) and 4-toluenesulfonyl
chloride (1.6 g, 8.4 mmol, 1.1 equiv.) in Et2O (25 mL) and THF (25 mL). The pale white mixture was heated
for 2 h, cooled to r.t and 15 mL H2O was added to dissolve the white precipitate. The aqueous layer was
separated and was extracted with Et2O (4 x 25 mL). The combined organic layers were washed with brine (4 x
25 mL), dried over MgSO4, and concentrated under reduced pressure. Flash column purification from
(2.5-15%) EtOAc−Hexane yielded 25 (0.98 g, 56%) as a white solid. An analytical sample was prepared by
recrystallisation from 1:1 Et2O–petrol to provide the following data. Rf of 0.32 (25% EtOAc–Hexane); m.p.
58°C, 58−59°C (Lit2
); [α]D +35.4 (c 1.000; CH2Cl2), +32.1 [c. 1.023; CH2Cl2 Lit2
]; FTIR (Thin film) cm−1
:
2976 (CH stretch), 2932 (w, sharp, -CH3 Stretch), 1926, 1597 (m, -NC bending), 1494.9 (m, -CH bend), 1452.2,
1399.0, 1305, 1318.6, 1236.0, 1155 (s, sharp, S=O), 1034 (s, sharp, C-N), 981, 815, 711; 1
H NMR (400 MHz,
CDCl3): δ 7.82 (2H, d, J 8.2 Hz, Ortho-Ts), 7.34 (2H, d, J 8.2 Hz, Meta-Ts), 2.82–2.87 (1H, dq, chiral centre),
2.68 (1H, d, J 7.2 Hz, CH(H)NTs), 2.42 (3H, s, CH3SO2C6H5), 2.09 (1H, d, J 4.6 Hz, CH(H)NTs), 1.29 (3H, d,
J 5.4 Hz, CH3CHNTs); 13
C NMR (100.6 MHz, CDCl3): δ 143.4 (Ipso-Ts), 139.3 (Para-Ts), 126.2 (Ortho-Ts),
129.4 (Meta-Ts), 33.8, 32.7, 20.7 (CH3SO2C6H5), 15.8 (CH3CHNTs); m/z (CI) 440 [M2+NH4]+
18%, 423
[M2H]+
20%, 229 [M+NH4]+
75%, 212 [MH]+
100%, 56 [NCH2CHCH3]+
50%, [Calculated Mass of 25 211 g
mol-1
]2,3
(S)-N-Tosyl-2-methylaziridine 2
Crude (S)-2-[[(4-tosylsulfonyl]amino]propan-1-ol 24 (1.75 g, 7.64 mmol, 1.0 equiv.) in THF (25 mL) was
added drop wise to a condenser fitted suspension of hexane–washed sodium hydride (9.45 mmol) in THF (5
mL). The resulting pale white mixture was stirred for 4 hrs; the reaction was followed by TLC in 1 hr intervals.
A significant amount of effervescence was observed during the initial stages of the reaction. After 1.5 hrs 15
mL H2O was added and the aqueous phase was extracted with Et2O (4 x 25 mL). The combined organic layers
were washed with 2M NaOH (3 x 20 mL), dried over MgSO4, and concentrated under reduced pressure. Flash
column purification (5-20%) EtOAc−Hexane yielded 25 (0.46g, 47%) as a white solid. An analytical sample
was prepared by recrystallisation from 1:1 Et2O–petrol to provide the following data. Rf of 0.33 (25%
EtOAc−Hexane); m.p. 57−59°C, 58−59°C (Lit2
); [α]D +40.4 (c 1.010; CH2Cl2), +32.1 [c. 1.023; CH2Cl2 Lit2
];
1
H NMR (400 MHz, CDCl3): δ 7.85 (2H, d, J 8.3 Hz, Ortho-Ts), 7.34 (2H, d, J 8.3 Hz, Meta-Ts), 2.82−2.89
(1H, dq, chiral centre), 2.64 (1H, d, J 7.2 Hz, CH(H)NTs), 2.47 (3H, s, CH3SO2C6H5), 2.05 (1H, d, J 4.8 Hz,
CH(H)NTs), 1.28 (3H, d, J 5.8 Hz, CH3CHNTs); 13
C NMR (100.6 MHz, CDCl3): δ 144.4 (Ipso- Ts), 135.3
Me
OH
N
H
S
O
O
Me
Me
N
S
O
O
Me
24 25

37. 37
(Para-Ts), 129.7 (Ortho-Ts), 127.8 (Meta-Ts), 35.8, 34.7, 21.7 (CH3SO2C6H5), 16.8 (CH3CHNTs); m/z (CI)
440 [M2+NH4]+
18%, 423 [M2H]+
20%, 229 [M+NH4]+
75%, 212 [MH]+
100%, 56 [NCH2CHCH3]+
60%,
[Calculated Mass of 25 211 g mol-1
]2,3
(S)-N-(4-[1,3]dioxolan-2-yl-1-methyl-butyl)-4-methyl-benzene sulfonamide
The synthesis of the benzene sulfonamide is made up of two segments (i) preparation of the Buchi Grignard
Reagent (ii) Synthesis of benzenesulfonamide.
Preparation of the Buchi Grignard Reagent 19
To a 50 mL two-necked flask fitted with a reflux condenser was added pre-activated magnesium
turnings (484 mg, 17.25 mmol, 1.7 equiv.), THF (10 mL), and 2-(2-bromo-ethyl)-[1,3] dioxolane 29 (1.2 mL,
10.2 mmol, 1 equiv.) dropwise. Upon addition, significant effervescence was observed and temperature
increased to 55 °C. The solution was kept stirring and allowed to cool to room temperature. Concentration of
the Grignard solution was assessed by titration.
Titration was carried out with 31 mg (L)-menthol, 5 mg 1,10-phenanthroline and 1.5 mL THF to create a
2 mmol solution. The Grignard solution prepared upon cooling was titrated against the menthol solution until a
red-purple colour persisted. 0.60 mL of the Grignard solution was added making the molarity of the Grignard
solution (0.60 mL / 0.2) = 0.33M.
Preparation of the Benzene Sulfonamide 19
A solution of CuBr.DMS (135 mg, 0.66 mmol, 0.4 equiv.) in DMS (3 mL) was added to the Buchi
Grignard solution 30 (9.9 mL, 0.33M, 3.29 mmol, 2 equiv.) at –78°C and stirred for 1 hour. A solution of
aziridine 25 (347 mg, 1.65 mmol, 1 equiv.) in THF (3 mL) was added at –78°C and stirred for 10 mins. The
solution was left stirring and allowed to warm to room temperature overnight. The reaction upon total
consumption of starting material, as monitored by TLC, H2O (50 mL) was added and the aqueous layer
extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with brine (4 x 50 mL),
dried over MgSO4 and concentrated under reduced pressure. Flash column chromatography (5-20%
EtOAc−Hexane) to give the product as a white-powdered solid 31, 386 mg (75.1%). m.p. 88−91°C, 89−93°C
Me
N
S
O
O
Me
BrO
O
25 29 31
Me
TsHN
O
O

38. 38
(Lit20
); [α]D −33 (c 1.035 g/mL, CH2Cl2), −27 [c. 1.000; CH2Cl2 Lit20
]; FTIR (Thin film) cm−1
: 3285 (m, broad,
-NH), 3272 (m, broad, -NH), 2943 (m, sharp, -CH stretch), 2876 (m, sharp, -CH stretch), 1598 (w, sharp, C=C
aromatic), 1325 (m, sharp), 1160 (s, sharp, -S=O), 1092 (m, sharp, C-O-C stretch), 815 (w, sharp, tri-substituted
C-H bend); 1
H NMR (400 MHz, CDCl3): δ 7.78 (2H, d, J 8.2 Hz, Ortho-Ts), 7.32 (2H, d, J 8.2 Hz, Meta-Ts),
4.78 (1H, t, J 4.7 Hz, HCOOC), 4.21 (1H, d, J 8.1 Hz, (H)NTs), 3.83–3.91 (4H, m, OCH2-CH2O), 3.30−3.35
(1H, m, C(H)(H)NTs), 2.45 (3H, s, CH3SO2C6H5), , 1.29–1.49 (6H, m, CH2CH2CH2), 1.06 (3H, d, J 6.5 Hz,
CH3NHTs; 13
C NMR (100.6 MHz, CDCl3): δ 144.4 (Ipso-Ts), 138.3 (Para-Ts), 129.7 (Ortho-Ts), 127.1 (Meta-
Ts), 104.2, 64.8, 49.9, 37.2, 33.3, 21.7, (CH3SO2C6H5); m/z (CI) 377.15 60%, 336.1 [MNa+
] 70%, 331.7
[MNH4
+
] 20%, 252.1 100% ; [Calculated Mass of 31 313 g mol-1
]2,3
(S)-2-methyl-1-Tosyl-1,2,3,4-tetra hydropyridine 20
HCl (1M, 7.13 mL, 7.13 mmol, 7.7 equiv.) was added to a solution of 31 (288 mg, 0.93 mmol, 1 equiv.)
in acetone (18.5 mL). The reaction mixture was allowed to stir overnight at room temperature. Upon
consumption of starting material 31 a saturated solution of K2CO3 (25 mL) was added, and the aqueous layer
was extracted with EtOAc (4 x 25 mL). The combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. Flash column chromatography (5-15% EtOAc−Hexane) to give 19 as
yellow oil, 80.4 %. [α]D +499 (c 1.010 g/mL, CH2Cl2); +511 [c. 0.009 g/mL; CH2Cl2 Lit20
]; FTIR (Thin film)
cm−1
: 3426 (m, broad), 3064.35 (w, sharp, =C-H stretch), 2978, 2929, & 2848(m, sharp, C-H stretch), 1645 (s,
sharp, C=C asymmetric stretch), 1597 & 1495 (m, sharp, C=C in ring), 1446 (m, sharp, CH bends), 1402, 1360
& 1340 (s, sharp, -S=O stretch), 1261 (m, sharp, C-N stretch), 1169 & 1136 (s, sharp, -S=O bend), 1103, 1020,
995 & 883 (s, sharp, =C-H bends), 816, 685 (s, sharp, C-H bend) 549; 1
H NMR (400 MHz, CDCl3): δ 7.67 (2H,
d, J 8.2 Hz, Ortho-Ts), 7.30 (2H, d, J 8.2 Hz, Meta-Ts), 6.62 (1H, d, J 8.2 Hz, HCCHNTs), 4.98–5.05 (1H, m, J
6.8 Hz, HCCHNTs), 4.09–4.18 (1H, m, HCCH3NTs), 2.42 (3H, s, CH3SO2C6H5), 1.79–2.02 (1H, m, Ipso-CH2),
1.26–1.43 (1H, m, Ortho-CH2), 1.16 (3H, d, J 6.7 Hz, H3CCHNTs), 1.03–1.09 (1H, m, Ortho-CH2); 13
C NMR
(100.6 MHz, CDCl3): δ 143.3 (1C, Ipso- Ts), 136.4 (1C,Para-Ts), 129.6 (2C, Ortho-Ts), 126.8, 123.2 (2C,
Meta-Ts), 107.7, 48.5 (1C, C(CH3)NTs), 25.2, 21.5(1C C(CH3)NTs), 18.2, 16.7, and 14.2 ; M/z (CI) 252 [MH+
]
100%, 269 [MNH4
+
] 20%. [Calculated Mass of 19 251 g mol-1
]2
N
Ts
Me
1931
Me
TsHN
O
O

39. 39
(S)-2-methyl-1-Tosyl-1,2,3,4-tetrahydropyridine 2,3
To a solution of BF3
.
OEt2 (0.204 mL, 1.61 mmol, 5 equiv.) at –30 °C was added to reactant 31 (100 mg,
0.32 mmol, 1 equiv.) in CH2Cl2 (10 mL). Upon addition, the reaction mixture was warmed up over three hours
to room temperature. The reaction was monitored by TLC, upon consumption of starting material 31, the
saturated aqueous NaHCO3 (90 mL) was added and the aqueous phase was extracted with CH2Cl2 (2 x 75 mL).
The combined organics were washed with brine (4 x 50 mL), dried over MgSO4 and concentrated under
reduced pressure. Flash column chromatography (5-25% EtOAc−Hexane) yielded 19 (33% yield) as a pale
yellow-oil. *
1
H NMR (400 MHz, CDCl3): δ 7.76 (2H, m, Ortho-Ts), 7.30 (2H, dd, J 8.1 Hz, Meta-Ts), 6.70 (1H, d, J 8.9 Hz,
HCCHNTs ), 4.98–5.05 (1H, s, HCCHNTs), 4.70 (1H, m, HCCH3NTs), 2.42 (3H, s, CH3SO2C6H5), 1.90 (1H,
m, Ipso-CH2) , 1.40–1.55 (1H, m, Ortho-CH2), 1.06 (3H, d, J 6.7 Hz, H3CCHNTs), 1.02 (1H , m , Ortho-CH2)
* Insufficient time/yield for the complete analysis of the product due to degradation.
(S)-5-iodo-2-methyl-1-Tosyl-1,2,3,4-tetra hydropyridine 24
To a stirred solution tetrahydropyridien 19 (0.132g, 0.3430 mmol, 1.0 equiv.) in CH2Cl2 (2.6 mL) was
added to NIS (0.062 g, 0.280 mmol, 1.1 equiv.) and hydroxyl-(tosyloxy)-iodo-benzene (HTIB) (0.010 g, 0.026
mmol, 0.1 equiv.). The resulting pink solution was heated at reflux for 20 hrs, after which Et3N (0.100 mL,
0.280 mmol, 1.1 equiv.) was added and the reaction mixture was diluted with CH2Cl2 (10 mL) and washed with
Na2S2O3 (2 x 10 mL) and the aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic
layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a
yellow-orange oil. Flash column chromatography (5-50% EtOAc−Hexane) resulted in two products 20 and 32
(67% combined yield) of very similar Rf values and so a further re-column was carried out (5-30%
EtOAc−Hexane). FTIR (Thin film) cm−1
: 2930 (m, sharp), 1650 (w, sharp, C=C stretch), 1597, 1493, 1454,
1342 (s, sharp, -S=O stretch), 1250 (w, sharp, C-N stretch), 1159 (s, sharp, -S=O bend), 1091, 1019, 996 & 823
N
Ts
Me N
Ts
Me N
Ts
Me
I
I
(Major Product) (Minor Product)
3219 20
+
N
Ts
Me
1931
Me
TsHN
O
O

40. 40
(s, sharp, =C-H bends), 815, 685 (s, sharp, C-H bend), 666.9 (C-I stretch), 551.9; 1
H NMR (400 MHz, CDCl3):
δ 7.78 (1H, d, J 8.4 Hz, NCHCI), 7.65 (2H, m, Ortho-Ts), 7.31 (2H, dd, J 8.2 Hz, Meta-Ts), 6.62 (1H, d, J 8.2
Hz, HCCHNTs), 4.98–5.09 (1H, m, J 6.8 Hz, HCCHNTs), 4.09–4.15 (1H, m, HCCH3NTs), 2.49 (3H, s,
CH3SO2C6H5), 1.72–2.07 (1H, m, Ipso-CH2), 1.21–1.49 (1H, m, Ortho-CH2), 1.08 (3H, d, J 6.7 Hz,
H3CCHNTs); 13
C NMR (100.6 MHz, CDCl3): δ 143.4 (Ipso-Ts), 138.4 (Para-Ts), 136.0 (CHCHNTs) 129.7
(Ortho-Ts), 129.6 (Ortho-Ts), 126.9 (Meta-Ts), 126.7 (Meta-Ts), 120.2 119.3, 48.5 (C(CH3) NTs), 37.4 (NCH2)
25.2, 21.5 (C(CH3)NTs), 18.2.
(S)-6-methoxy-5-iodo-2-methyl-1-Tosyl-1,2,3,4-tetrahydro pyridine 20,21
To a stirred solution of NIS (1.91g, 85.68 mmol, 1.20 equiv.) and MeOH (200 µL, 85.68 mmol, 1.20
equiv.) in CH2Cl2 at –78°C, N-tosyl-1,2,3,4-tetrahydropyridine 19 (255 mg, 1.39 mmol, 1.0 equiv.). After two
hrs, the yellow reaction mixture was poured onto cold saturated aqueous solution of NaHCO3 (30 mL). The
aqueous layer was extracted with CH2Cl2 (3 x 15 mL) to give the reddish-purple combined organic layer. The
organic extracts were washed with brine (4 x 20 mL), dried over Na2SO4 and concentrated under reduced
pressure to yield (72.2%) reddish-purple solid 33. [α]D +255 (c 1.010 g/mL, CH2Cl2); FTIR (Thin film) cm−1
:
2927 & 2850 (w, CH stretch), 1712 (s, C-O stretch), 1598 (w, C-C aromatic stretch), 1445 & 1397 (m, CH
bending), 1332 (s, C-N stretch), 1167 & 1062 (s, S=O bend), 677 (s, C-I stretch) cm−1
; 1
H NMR (400 MHz,
CDCl3): δ 7.94 (2H, d, J 8.2 Hz, Ortho-Ts), 7.32 (2H, d, J 8.2 Hz, Meta-Ts), 5.42 (1H, d, J 8.2 Hz,
CH(OMe)NTs), 4.56 (1H, broad, s, HC(Me)NTs), 3.82 (1H, m, HCI), 3.48 (3H, s, OMe), 2.45 (3H, s,
Ts-methyl), 1.96–1.78 (2H, m, Ipso-CH2), 1.74–1.64 (2H, m, Ortho-CH2), 1.39 (3H, d, J 6.9 Hz,
CH3C(H)NTs); 13
C NMR (100.6 MHz, CDCl3): δ 143.5 (Ipso-Ts), 136.7 (Para-Ts), 129.3 (Ortho-Ts), 128.4
(Meta-Ts), 88.6 (CH3O), 55.7 (C(OMe)H) 48.5 (C(CH3)NTs), 29.6, 29.4, 28.9 (CH2), 26.2 (CH2), 23.2, 21.6
(1C, Ts-CH3), 20.6 (CH3CNTs)
(S)-5-iodo-2-methyl-1-Tosyl-1,2,3,4-tetra hydropyridine 21,22
N
Ts
Me
I
MeO N
Ts
Me
I
2033
N
Ts
Me N
Ts
Me
I
MeO
19 33

41. 41
To a stirred solution of iodomethoxyamine 33 (173 mg, 0.477 mmol, 1.0 equiv.) in toluene (15 mL) at
room temperature, distilled TFA (3.75 µL, 0.010 equiv.) was added. The reaction mixture was heated to 90 °C
with vigourous stirring; a change in colour of the solution to pink-purple was observed. The reaction mixture
was cooled to r.t after 15 mins of vigorous stirring. After 1 hour, Et3N (15 µL, 0.003 equiv.) was added which
resulted in a pale yellow solution. The solvent was removed under reduced pressure to give a yellowish solid.
Base washed silica (5% Et3N–Hexane) was used via silica column chromatography to purify the product
(5-20% EtOAc−hexane) to give a yellow oil (12%) 20.
5. References
1.
Craig, D.; McCague, R.; Potter, G.A.; Williams, M.R. V. Synlett 1998, 55–57.
2.
Berry, M. B.; Craig, D. Synlett 1992, 41–44.
3.
Thibault, O. Synthesis of Polysubstituted Pyridines, Erasmus ProJect, Imperial College London- Ecole
Polytechnique, 1996.
4.
Adelbrecht, J-C. Bis(arylsulfonyl)tetrahyrdopyridines: Application to the synthesis of Piperidines, PhD
Thesis, University of London, 2003.
5.
Fleming, A. J. Novel Chemistry of Tetrahydropyridines, PhD Thesis, University of London, 2006.
6
McChensey, E. W.; Swann, W, K.J, Am, Chem, Soc,. 1937 , 59, 1116.
7
Watson, P. S.; Jiang, B,; Scott, B. Organic Letters. 2000, 23, 3679–3680.
8
Wang, C. J.; Wuonola, M. A. Orgainc Prep. Proced. Int. 1992, 24, 583–618.
9
Lotter, H. L.; Abraham, D. J.; Tuner, C. E.; Knapp, J. E.; Schiff, P. L.; Slatkin, D. J. Tetrahedron Lett.
1975, 7, 2815–2817.
10
Karrer, Von P.; Eugster, C. Helv. Chim. Acta 1948, 31, 1062–1065.
11
Cortese, N.A.; Ziegler, C.B.; HrnJez, B.J.; Heck, R.F. J. Org. Chem., 1978, 43, 2952.
12
Heck, R.F. Organic React., 1982, 27, 345.
13
Suzuki–Miyaura Cross-Coupling Reactions of Potassium Alkenyltrifluoroborates G. A. Molander, C. R.
Bernardi, J. Org. Chem., 2002, 67, 8424–8429.
14
General Reaction Conditions for the Palladium–Catalyzed Vinylation of Aryl Chlorides with Potassium
Alkenyltrifluoroborates E. Alacid, C. NáJera, J. Org. Chem., 2009, 74, 8191–8195.
15
Adelbreht, J-C.; Craig, D.; Fleming, A. J.; Martin, F. M. Synlett 2005, 17, 2643–2647.
16
Lothar W. B.; Maria C. F. Molecules 2002, 7, 902–906.
17
Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron, 1988, 44, 3919.
18
Magnus, C.; Adolfsson, H.; Moberg, C.; Tetrahedron : Asymmetry 1997, 8, 2655–2662
19
Lin, H., Paquette, L. A., Synth. Commun, 1994, 24, 17, 2503
20
Stephen A. S.; Joseph P. A. Harrity. Organic Letters 2006, 8, 3089–3091
21
Kiewel, K.: Luo, Z.;Sulikowski, G. A. Organic letters 2005, 7, 5163

42. 42
22
Spivey, A. C.; Fekner, T.; Spey, S. E. The Journal of Organic Chemistry 2000, 65, 3154.
23
Gao, Jiahui, Studies towards Selective Functionalisation of Cyclic Ene–carbamates, Bsc report, Imperial
College London, 2010
24
Doyle, C., Cascade Based Approach to Synthesis of Nitrogen Heterocycles, Imperial College London, 2008
25
Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 33, 599–617
26
Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154
27
Halpern, J. Inorg. Chim. Acta 1985, 100, 41–48
28
Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 13662
29
Chen, X.; Li, J-J.; Hao, X-S,; Goodhue, C. E.; Yu, Jin-Quan J. Am. Chem. Soc. 2006, 128, 78-79