Honors Cup Synthetic Proposal
Section: 211
Group Members: Andrew Brod, Jamie (Brian) Magnuson, Nizar Taki
Title: Synthesis of 5-Amino-1,3-dimethylurcil (Precursor to Caffeine)
Introduction: (what makes your target interesting?)
Although caffeine occurs naturally in at least sixty-three different plant species, it has been
manufactured and used because of its unique effects on our bodies. It is found mainly in
beverages, but is also used in several types of prescription medications, diuretics, and pain
relievers. Caffeine is sought by many for its abilities to increase alertness and energy. As energy
drinks such as Red Bull ™ and Amp ™ become more and more popular, caffeine continues to
stretch its influence. 5-Amino-1,3-dimethylurcil is a precursor to caffeine and has many of the
same functional groups. Here we produce it in a three-step synthesis.
Overall synthetic reaction scheme: (a Chemdraw or similar drawing of all three steps)
O
O
H3C
HN
O
N
NaH
DMSO,
CH3I
N
H
O
N
CH3
1,3-dimethyluracil
Uracil
HNO3
H2SO4
O
O
H3 C
O
H3C
NO2
N
Fe/HCl
N
CH3
1,3-dimethyl-5-nitrouracil
NH2
N
O
N
CH3
5-amino-1,3-dimethyluracil
1
Step 1
Synthetic transformation 1: (Chemdraw picture of first transformation)
O
O
H3C
HN
O
N
NaH
N
H
DMSO,
CH3I
O
N
CH3
Uracil
1,3-dimethyluracil
Experimental 1 (notes if this transformation is not exactly the one reported in literature (e.g. on
a different scale) and how it was modified):







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6.0 g (.053 mol) of uracil were stirred for a week (changed from “overnight”) in 300 mL
of DMSO at room temperature.
5.1 g (.265 mol) of sodium hydride were added carefully to the solution of uracil.
37.6 g (.265 mol) of methyl iodide were added slowly over a period of ten minutes.
The mixture was stirred for forty minutes and then diluted with 100 mL of water to
remove excess of hydride.
Concentrated HCl was added to the solution until it reached a pH of 1-2.
The product was then extracted with methylene chloride and washed with saturated
bicarbonate solution until neutral.
After removing the dichloromethane, 1,3-dimethyl-uracil should be left behind.
HNMR peaks: 3.29 (s, 3H), 3.37 (s, 3H), 5.65 (d, J = 15 Hz, 1H, HC=), 7.1 (d, J = 15 Hz,
1H, HC=)
Notes:
 The reaction mixture was stirred for a week instead of overnight because we cannot come
to lab every day (it’s a darn shame…).
Expected yield: 61% , 8.6 g
Safety, disposal and green issues 1:
Uracil

Minimize contact
Sodium Hydride (NaH)



Reacts violently with water
Incompatible with water, acids, alcohols, and strong oxidizing agents
Dispose of correctly
2
Methyl Sulfoxide (DMSO)

Harmful in inhaled
Methyl Iodide (CH3I)



Fatal if inhaled or absorbed through skin
Highly toxic
May cause cancer
Step 2
Synthetic transformation 2: (Chemdraw picture of second transformation)
O
O
H3 C
H3C
NO2
N
N
HNO3
O
N
CH3
1,3-dimethyluracil
H2SO4
O
N
CH3
1,3-dimethyl-5-nitrouracil
Experimental 2 (notes if this transformation is not exactly the one reported in literature (e.g. on
a different scale) and how it was modified):
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1.6 g (.0114 mol) of 1,3-Dimethyl-5-nitrouracil were added carefully to a mixture of 1.2
mL of fuming nitric acid and 1.2 mL of concenetrated sulfuric acid and stirred carefully
for thirty minutes at room temperature.
The solution was refluxed for an hour.
The solution was then added carefully to 6 mL of ice cold water.
The light yellow colored crystals were filtered and washed with ice water
M.p.: 121-122 C, IR (mull): 1720, 1675.
Notes:
 Reaction ingredients were scaled up by a factor of two to obtain the target .5 grams of
product
Expected yield: 54 %, 1.1475 g
Safety, disposal and green issues 2:
1,3-Dimethyluracil
3
 Minimize contact
Nitric Acid (HNO3)



Corrosive, may cause fire
May be fatal if inhaled
Use adequate ventilation
Sulfuric Acid (H2SO4)



Reacts violently with water and metals
Avoid inhalation or other contact
Causes severe burns, may be carcinogenic
Step 3
Synthetic transformation 3: (Chemdraw picture of third transformation)
O
O
H3 C
O
H3C
NO2
N
N
CH3
1,3-dimethyl-5-nitrouracil
NH2
N
Fe/HCl
O
N
CH3
5-amino-1,3-dimethyluracil
Experimental 3 (notes if this transformation is not exactly the one reported in literature (e.g. on
a different scale) and how it was modified):
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One gram (.0054 mol) of 1,3-Dimethyl-5-nitrouracil was dissolved in 2.7 mL THF
(forming a 2M solution). Another 2.7 mL of 1 M HCl was added followed by 3.04 g of
active iron powder.
The solution was refluxed for thirty minutes and then neutralized with saturated
bicarbonate solution.
The reduced product was extracted into methylene chloride and purified using flash
chromatography on silica gel using ethyl acetate.
The product was then characterized by IR and NMR.
IR (mull): 3400 (W), 1725, 1665. HNMR: 3.45 (s, 3H), 3.75 (s, 3H), 5.6 (s, 1H), 9 (s,
1H)
Notes
 Reaction ingredients were scaled up by a factor of two to obtain the target .5 grams of
product
Expected yield: 60 %, .514 g
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Safety, disposal and green issues 3:
1,3-dimethyl-5-nitro-uracil

Minimize contact
Iron (Fe)

Dust harmful if inhaled
Hydrochloric acid (HCl)


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Very corrosive
Inhalation of vapor dangerous
Causes severe damage to skin
Dangerous for environment
Methylene Chloride (CH2Cl2)



Harmful if swallowed or inhaled
Avoid skin contact
Possible carcinogen and mutagen
Overall budget:
Chemical
Uracil
NaH
DMSO
CH3I
HNO3
H2SO4
Fe
Supplier
Pfaltz & Bauer
Pfaltz & Bauer
EMD
Biosciences
Pfaltz & Bauer
Pfaltz & Bauer
Pfaltz & Bauer
Pfaltz & Bauer
Cost
$60.90/25 g
$61.95/100 g
$23.00/100 mL
Amt. Needed
6.0 g
5.1 g
300 mL
Total
$14.62
$3.16
$69.00
$128.10/100 g
$54.85/PT
$50.40/500 mL
$86.10/500 g
37.6 g
1.2 mL
>1.2 mL
3.04 g
$48.17
$0.14
>$0.12
$0.52
Total costs per synthesis: ___$135.622___
References (include at least two different sources for your experimentals):
Hartley, Jack. “Caffeine and Sports Performance.” Vanderbilt University, 6 February 2004
<http://www.vanderbilt.edu/AnS/psychology/health_psychology/caffeine_sports.htm>.
Kowal, M. G.; Narayan, S.; Zajac, M. A.; Zakrzewski, A. G. Synth. Comm. 2003, 33, 3291-3297.
Song, Q. H.; Hei, X.; Xu, Z.; Zhang, X.; Guo, Q. Bioorg. Chem. 2003, 31, 357-366.
5
Itahara, T.; Ebihara, R.; Kawasaki, K. Bulletin Chem. Soc. Japan 1893, 56, 2171-2172.
Pecorari, P.; Vampa, G.; Albasini, A.; Rinaldi, M.; Melegari, M.; Costi, M. P. Farmaco.
Edizione Scientifica 1988, 43, 311-318.
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