CH4220: Advanced Chemistry Laboratory

Expt.: Synthesis of Enantioenriched Propargylamines

Aim and Objectives: Catalytic Asymmetric One-Pot Direct Synthesis of Propargylamine using
Cu(I)-Complex of (S)-Ph-PYBOX

[(S)-Ph-PYBOX = (S)-Phenyl Pyridine Bis-Oxazoline]

Reaction Scheme:

Apparatus Requirement:

Round Bottom (RB) flask; Conical flask; Measuring cylinder; Beaker; Separating funnel.

Chemicals Requirement:

1. 3-Methyl Benzaldehyde
2. 4-Toluidine
3. Phenylacetylene
4. Cu(I)OTf
5. (S)-Ph-PYBOX

Molecular Wt. and Physical Details of Reagents:

Molecular formula of 3-methyl benzaldehyde= C8H8O

Molecular weight of 3-methyl benzaldehyde= 120.15 g/mole
Density of 3-methyl benzaldehyde= 1.019 g/cm3
Molecular formula of p-toluidine =C7H9N
Molecular weight of p-toluidine = 107.15 g/mole

Molecular formula of phenylacetylene =C8H6

Molecular weight of phenylacetylene = 102.13 g/mole
Density of meta phenylacetylene = 0.939 g/cm3

Molecular formula of copper(I) trifluoromethanesulfonate = Cu(I)OTf

Molecular weight of copper(I) trifluoromethanesulfonate = 212.62 g/mole

Molecular formula of S -phenyl PIBOX ligand = C24H20O2N2

Molecular weight of S -phenyl PIBOX ligand = 368.44 g/mole

Experimental Procedure:

In a 10 ml round-bottom (RB) flask 10 mol% Cu(I)OTf - (S)-Ph-PYBOX was prepared via the
following method:

Under an inert atmosphere (argon atmosphere), in a round-bottom (RB) flask, 10 mol% Cu(I)OTf
[copper(I) trifluoromethanesulfonate] (9 mg, 0.1 mmol, 0.10 equiv.) was taken in anhydrous toluene
at room temperature.

To this solution was added 12 mol% of (S)-Ph-PYBOX (20 mg, 0.12 mmol, 0.12 equiv.) in one
portion and the reaction mixture was stirred for 15 minutes under the inert atmosphere (under argon
atmosphere).

Next, 3-methyl benzaldehyde (54 µl, 0.46 mmol, 1.0 equiv.) was added to this reaction mixture
mixture at room temperature and again purged with a N2 balloon (to maintain inert atmosphere).

Further, to this RB was added p-toluidine (50 mg, 0.46 mmol, 1.0 equiv.) was added and stirred for
an additional 10 minutes.

Then, phenylacetylene (50 µl, 0.46 mmol, 1.0 equiv.) was added to the reaction mixture at room
temperature and stirring was continued for 48 h.

After complete consumption of starting materials (monitored by TLC), the reaction mixture was
washed with saturated aqueous sodium bicarbonate solution (2 mL X 2), extracted with ethyl
acetate (5 mL X 2).

All the organic layers were taken in a conical flask and dried with anhydrous sodium sulfate.

The volatiles were removed under reduced pressure and the crude mixture was purified via silica
gel column chromatography using n-hexane to get compound A as white solid.

Melting Point: 92 – 94°C

Rf (n-Hexane) = 0.3
Note: Copper(I) OTf is very much air and moisture sensitive so use it very carefully.

Results & Observation:

Yield: 224 mg % of Yield: 72% MP: 92 – 94 °C

TLC System: Rf = 0.3 (in n-hexane)

ee of propargylamine =

Conclusion:

In summary, we have done a direct catalytic asymmetric synthesis of propargylamine synthesis

from a reaction of m-tolualdehyde, p-toluidine, and phenylacetylene.

This is a direct coupling reaction to provide efficient synthesis of propargylamine (70% yield) in the
presence of 10 mol% Cu(I)OTf - (S)-Ph-PYBOX.

Further, the compound was characterised by IR spectra, NMR spectra and melting point was also
checked.
Plausible Pathway:
Compound Characterization:

1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.3 Hz, 2H), 7.47 – 7.43 (m, 2H), 7.36 – 7.29 (m, 4H),
7.18 (d, J = 7.5 Hz, 1H), 7.08 – 7.03 (m, 2H), 6.77 – 6.71 (m, 2H), 5.45 (s, 1H), 4.04 (s, 1H), 2.42
(s, 3H), 2.29 (s, 3H).

13C NMR (126 MHz, CDCl3) δ 144.4, 139.9, 138.5, 131.8, 129.7, 128.8, 128.7, 128.2, 128.0, 127.8,
124.4, 123.0, 114.4, 88.9, 84.9, 51.1, 21.5, 20.5.

IR (film)υmax 3371, 3046, 3019, 2944, 2918, 2860, 1608, 1513, 1488, 1441, 1402, 1275, 1238,
1073, 975 cm-1

HRMS (ESI) m/z 312.1775 [M + H]+; calculated for [C23H22N]+: 312.1752.

Spectroscopic Analysis

IR Data of A
1
H NMR (500 MHz, CDCl3) of A
13
C NMR (125 MHz, CDCl3) of A
HRMS data of A