A novel method of caffeine synthesis from uracil

Article abstract of DOI:10.1081/SCC-120023986

An inexpensive and novel method of caffeine synthesis starting from uracil in six simple steps is described. Uracil 1 is first converted to I, 3-dimethyluracil 2, followed by nitration, reduction, and cyclization to theophylline and finally methylation of theophylline forms caffeine.

Full text of DOI:10.1081/SCC-120023986

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A Novel Method of Caffeine Synthesis from Uracil
a
a
a
Matthew A. Zajac , Anthony G. Zakrzewski , Mark G. Kowal & Saraswathi Narayan Ph.D.
a
a
Science Department, Villa Julie College, Stevenson, Maryland, USA
Available online: 15 Aug 2006
To cite this article: Matthew A. Zajac, Anthony G. Zakrzewski, Mark G. Kowal & Saraswathi Narayan Ph.D. (2003): A Novel
Method of Caffeine Synthesis from Uracil, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:19, 3291-3297
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 19, pp. 3291–3297, 2003
A Novel Method of Caffeine Synthesis
from Uracil
Matthew A. Zajac, Anthony G. Zakrzewski,
Mark G. Kowal, and Saraswathi Narayan*
Science Department, Villa Julie College,
Stevenson, Maryland, USA
ABSTRACT
An inexpensive and novel method of caffeine synthesis starting from
uracil in six simple steps is described. Uracil 1 is first converted to I,
3
-dimethyluracil 2, followed by nitration, reduction, and cyclization
to theophylline and finally methylation of theophylline forms
caffeine.
Key Word: Caffeine synthesis.
*Correspondence: Saraswathi Narayan, Ph.D., Science Department, 1525,
Greenspring-valley Road, Villa Julie College, Stevenson, MD 21153, USA; Fax:
410-580-5386; E-mail: f-naraya@mail.vjc.edu.
3
291
DOI: 10.1081/SCC-120023986
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3
292
Zajac et al.
Caffeine 7 (3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione or 1,3,7-
trimethylxanthine) is a well-known compound that occurs in nature in
coffee, tea, cola nuts, mate’ leaves, guarana paste, and other related
natural products. It is also obtained as a byproduct in the manufacture
[1]
of caffeine-free caffeine. This is perhaps one of the reasons that there
2–7]
[
are only few methods of synthesis described in the literature.
methods date back to either late 19th or the beginning to mid-20th
These
[
2,3]
century. Some of the early methods (Fischer and Traube’s)
were not
aimed directly at the synthesis of caffeine, rather they were based on
purine and related derivatives starting from urea or uric acid in several
steps. In addition, Fischer’s method was used to prove the structure of
caffeine and other xanthine derivatives. The other references are some
[
1]
patents in the 50’s and 60’s. Other than these there are no recent reports
in the literature on the direct synthesis of caffeine. In this report, we
wish to describe asimple synthesis of c aff eine 7 from uracil 1 by N-
methylation, nitration, reduction, and cyclization reactions (Schs. 1 and
2). Alternative methods for some of the intermediates have also been
described. Yields are good to excellent (Table 1) throughout all the
steps. The purity of the samples was checked by mixed melting point
methods. Wherever possible the IR and NMR were used to prove the
structures of the intermediates and caffeine.
The reaction of uracil with excess of methyl iodide with potassium
hydroxide and ethanol (Method 1) or in an aqueous ethanol medium
(
Method 2) resulted in avery poor yield of 1,3-dimethylur ac il 2 (Sch. 1
and Table 1)
On the other hand, the presence of a strong base such as sodium
hydride in dimethylsulfoxide (DMSO), a nonaqueous solvent facilitates
the methylation tremendously (Method 3, Sch. 1). This results in an
increased yield of 60% of 1,3-dimethyluracil 2, compared to Method
1
(10%) or Method 2 (20%).
O
O
N
method 1
EtOH-KOH/ CH3I
CH3
O
NH
N
method 2
N
H
O
EtOH-H O/ CH I
2
3
CH3
1,3 dimethyluracil 2
method 3
Uracil 1
NaH/DMSO/CH3I
Scheme 1.

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Caffeine Synthesis from Uracil
Table 1. Synthesis of compounds 1–7.
3293
ꢀ
a
Compound
Method
M.p. ( C)
Yield (%)
2
2
2
3
1
119.0–121.5
121.0–122.0
294.0–295.5
10
20
60
64
2
3
Nitration
with
3 2 4
HNO /H SO
4
5
6
7
70
In situ
75
273.0–274.5
234.0–236.5
3
95
a
Purity of the samples was checked by mixed melting point
methods.
Nitration of 1,3-dimethyluracil 2, using dinitrogen tetroxide similar
[
8]
to the method reported for cyclooctene was very time consuming, and
resulted in extremely poor yield for compound 3 (<10%, the method is
not described). Conventional nitration using a nitrating mixture of
fuming nitric acid and sulfuric acid produces 64% yield of 3. The reaction
was rapid and isolation of the compound was very easy. The nitro group
in compound 3 was reduced using iron and hydrochloric acid in
tetrahydrofuran (THF) to produce 5-amino-1,3-dimethyluracil 4.
O
O
O
H
N
H
3
C
O
NO
2
3
H C
NH
2
H
3
C
1
.HCCOH/heat
2. HNO /H SO
4
N
N
HNO
3
N
Fe/HCl
H
2
O
N
NO
2
H
2
SO
4
N
O
N
3
2
O
CH
3
CH
3
CH
3
1
,3-Dimethyl-5-nitrouracil
5-Amino-1,3-dimethylurcil
Intermediate
5
Fe/AcOH
Heat
3
4
O
O
N
CH
3
H
3
H C
N
H
C
3
N
N
NaH/DMSO/CH
3
I
N
N
N
O
N
O
CH
3
CH
3
Theophylline
6
Caffeine
7
Scheme 2.

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294
Zajac et al.
Heating compound 4 with formic acid generated in situ, the form-
amide derivative of compound 4 (not shown). Nitration of the formamide
derivative introduces a nitro group in position 6 of uracil to produce
compound 5 as a light yellow colored solid (see Sch. 2).
Reduction and intramolecular heterocyclization of compound 5 was
simultaneously carried out with iron and acetic acid to produce theophyl-
line (75%) 6. Theophylline was purified by flash chromatography on
silicagel using ethyl acetate as the solvent. The final step of the synthesis
involves N-methylation at position 7 of theophylline using method 3 to
produce caffeine 7. Mixed melting point, IR, and NMR confirmed the
identities of the compounds 2–6, and caffeine 7.
In conclusion, caffeine 7 can be synthesized by a fast efficient, simple,
and novel method starting from the inexpensive uracil 1. Most of the
intermediates as well as caffeine were produced in good to high yields
under mild conditions. The IR and NMR of the intermediates and the
[
9,10]
final product matched with the literature spectra.
EXPERIMENTAL
1
H NMR spectra were recorded on a Varian 200 MHz FT-NMR
spectrometer. Tetramethylsilane (TMS) was used an internal standard.
CDCl and deuterated acetone were used as solvents for NMR. IR
3
spectra were recorded on Perkin–Elmer Paragon 500 FT-IR spectrometer
using nujol mull. Fisher–John melting point apparatus was used to
determine the melting points. Flash chromatography was performed on
silica gel column using ethyl acetate as the solvent. Thin layer chromatog-
raphy (TLC) was performed on silica gel plate using ethyl acetate as the
solvent. Completeness of all the reactions was determined by following
the reaction on TLC plate using ethyl acetate as the solvent. All reagents
and solvents were of high purity grade purchased from Aldrich Chemical
Company.
1,3-Dimethyluracil: 2
Method 1. Uracil[2,4-(1H,3H)-pyrimidinedione] (6.4 g, 0.057 mol)
was dissolved in an aqueous solution of potassium hydroxide (80 mL,
1.5 M). A solution of methyl iodide (CH I) (16.4 g, 0.146 mol) in ethanol
3
(80 mL) was added slowly. The solution was refluxed for 4 h. The product
was extracted with toluene (100 mL). Zero point eight one gram

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Caffeine Synthesis from Uracil
3295
(
sublimation. M.p.: 119.5–121.5 C (Lit. 119–122 C).
0.0051 mol) (10% yield) was recovered. The compound was purified by
ꢀ
[1]
ꢀ
Method 2. Similar to Method 1, however, in place of aqueous
potassium hydroxide, ethanolic potassium hydroxide was used. This
method yielded 20% (1.62 g, 0.0102 mol) of the product 2.
Method 3. A solution of uracil 1 (6.0 g, 0.053 mol) in DMSO
300 mL) was stirred overnight at room temperature. Four equivalents
(
of sodium hydride (5.1 g, 0.21 mol) were added carefully to the solution of
uracil. Five equivalents (37.6 g, 0.265 mol) methyl iodide was added
slowly over a period of 10 min. The mixture was stirred for another
40 min and diluted with 100 mL of water to remove excess of hydride.
The solution was then acidified with conc. HCl to pH 1–2. The product
was then extracted with methylene chloride and washed with saturated
bicarbonate solution until neutral. Eight point six grams of 1,3-dimethyl-
uracil 3 (61%) was isolated after removing the dichloromethane.
1
H NMR of the compound shows the following peaks. ꢀ (CDCl3):
3
.29 (s, 3H), 3.37 (s, 3H), 5.65 (d, J ¼ 15 Hz, 1H, HC¼), 7.1 (d, J ¼ 15 Hz,
1H, HC¼).
1,3-Dimethyl-5-nitrouracil: 3
Compound 2 (0.80 g, 0.0057 mol) was added carefully to an equal
volume of a mixture of fuming nitric and conc. sulfuric acid (1.2 mL)
and stirred for 30 min at room temperature. The solution was then
refluxed for an hour and added carefully to ice cold water (ca. 3 mL).
The light yellow colored crystals of compound 3 were filtered, washed
with ice cold water. The percent of the product was 64 (0.68 g,
ꢀ
[9]
ꢀ
ꢁ1
0
1
.00356 mol). M.p.: 121–122 C. (Lit. 121–122 C). IR (mull): ꢁ/cm
720, 1675.
5-Amino-1,3-dimethyluracil: 4
Zero point five gram (0.0027 mol) of 3 was dissolved in enough THF
to form a 2 M solution. Equal volume 1 M HCl was added followed by
1
3
0 equiv. of (1.52 g) of active iron powder. The solution was refluxed for
0 min. The reduced product was extracted into methylene chloride after
neutralizing with saturated bicarbonate solution. A 70% yield (0.30 g) of
the reduced product 4 was formed. After purification of the product by

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296
Zajac et al.
flash chromatography on silica gel using ethyl acetate, the product was
ꢁ
1
identified by IR and NMR. IR (mull): ꢁ/cm split peak at 3300 from
NH stretch, 1600 overlapped C¼O. NMR: ꢀ CDCl 1.61 (s, 2H), 3.4
2
3
ꢀ
[9]
s, 3H), 3.6 (s, 3H), 5.32 (s, 1H). M.p.: 294.0–295.5 C. (Lit. 295 C).
ꢀ
(
Formylation and Nitration of Compound 4
One hundred milligrams (0.00065 mol) of compound 4 was dissolved
in excess of formic acid and refluxed overnight to formylate the
amino group. After bicarbonate workup with saturated NaHCO3
solution 100 mg of the product was formed (not shown in the
scheme). The 100 mg of the crude product was nitrated with
(
1.2 mL) an equal volume of a mixture of fuming nitric and conc.
sulfuric acid (1.2 mL). The mixture was heated under reflux for an
hour. It was added to ice cold water (5 mL). A 100-mg of a light
yellow-colored compound 5 was formed in 54% yield.
Theophylline 6
3,7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione)
(
The intramolecular cyclization of compound 5 was carried out by
using iron and acetic acid. Two milliliters of glacial acetic acid and
10 equiv. of iron powder (0.30 g) were mixed with 100 mg of compound 5.
The mixture was refluxed for 30 min. The mixture was washed with water
and neutralized with saturated bicarbonate solution. The product was
extracted with a 1:1 mixture of ethyl acetate and dichloromethane.
After evaporating the solvent the crude product was purified using
flash chromatography on silica gel with ethyl acetate. Seventy-five
percent yield (69 mg) of theophylline 6 was recovered. M.p.: 273.0–
ꢀ
274.5 C. The purity was further confirmed by mixed melting point
using standard theophylline (Lit. 270–274 C). IR and NMR confirmed
[
1]
ꢀ
ꢁ
1
the identity of the product. IR (mull): ꢁ/cm 3400 (W), 1725, 1665.
NMR ꢀ CDCl : 3.45 (s, 3H), 3.75 (s, 3H), 5.6 (s, 1H), 9 (s, 1H).
3
Caffeine 7 (3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione)
The N-methylation of theophylline was carried out in a similar
manner to N-methylation of uracil method 3, described above for com-
pound 2. Five grams (0.029 mol) of theophylline 6 and (20.6 g, 0.145 mol)

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Caffeine Synthesis from Uracil
3297
methyl iodide was dissolved in 300 mL DMSO. The solution was stirred
at room temperature for 24 h. Four equivalents of NaH (2.7 g, 0.116 mol)
were added carefully to the DMSO solution. After the addition of NaH
the color of the solution turns from yellow to turbid white.
Approximately after 45 min the solution turns yellow again. The mixture
was diluted with equal volumes of water, and neutralized with dilute HCl.
The product was extracted into methylene chloride. Caffeine was further
purified by flash chromatography on silica gel using ethyl acetate. A
ꢀ
(
5.4 g) 95% of the product was recovered. M.p.: 234.0–236.5 C sublimes
ꢀ
[
1]
(
values.
Lit. 238 C). The IR and NMR peaks match well with the literature
[9,10]
ꢁ1
IR (mull): ꢁ/cm 1710 and 1660. NMR ꢀ (CD COCD ):
3 3
3.56 (s, 3H), 3.78 (s, 3H), 4.28 (s, 3H), 8.10 (s, 1H).
ACKNOWLEDGMENT
The authors wish to thank Villa Julie College for supporting this
project.
REFERENCES
1. The Merck Index, 12th Ed.; Merck & Co., Inc.: Whitehouse Station,
NJ, 1996; 268 pp.
. Fischer, A. Ber. 1895, 28, 2473, 3135.
. Traube, S. Ber. 1900, 33, 3035.
. Gepner, B.; Kreps, L. J. Gen. Chem. USSR 1946, 16, 179.
. Finar, I.L. Organic Chemistry, 2nd Ed.; John Wiley & Sons Inc.:
New York, 1959; 700–704.
2
3
4
5
6. Brederick, H.; Schuh, Hv.; Martini, A.S. Chem. Ber. 1950, 83,
201–211.
7
8
9
. Brederick, H.; Gotsmann, U. Ber. 1962, 95, 1902–1909.
. Seifert, W.K. Organic Synthesis 1988, 6, 837.
. The Aldrich Library of FT-IR Spectra, 1st Ed.; Charles J. Pouchert,
Ed.; Aldrich Chemical Co.: Milwaukee, 1985.
0. The Aldrich Library of FT-NMR Spectra, 1st Ed.; Charles J. Pouchert,
1
Jacquelyn, Behnke, Eds.; Aldrich Chemical Co.: Milwaukee, 1993.
Received in the USA March 12, 2003

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