Reaction of phosgene with the tricycle related to the minor base of phenylalanine transfer ribonucleic acids

Article abstract of DOI:10.1248/cpb.50.1584

1-Benzylwye (8) underwent electrophilic substitution at the 7-position in the presence of phosgene and pyridine in tetrahydrofuran (THF) to afford the 1,4-dihydropyridines (11, 10, and 14) together with the carboxylic acid 6 and its methyl ester 2 after s

Full text of DOI:10.1248/cpb.50.1584

1584
Chem. Pharm. Bull. 50(12) 1584—1588 (2002)
Vol. 50, No. 12
Reaction of Phosgene with the Tricycle Related to the Minor Base of
Phenylalanine Transfer Ribonucleic Acids
Taisuke ITAYA* and Tae KANAI
Faculty of Pharmaceutical Sciences, Kanazawa University; Takara-machi, Kanazawa 920–0934, Japan.
Received July 31, 2002; accepted September 27, 2002
1-Benzylwye (8) underwent electrophilic substitution at the 7-position in the presence of phosgene and pyri-
dine in tetrahydrofuran (THF) to afford the 1,4-dihydropyridines (11, 10, and 14) together with the carboxylic
acid 6 and its methyl ester 2 after short treatment of the reaction mixture with methanol and then with water.
When triethylamine was used instead of pyridine, phosgene reacted with triethylamine rather than 8, producing
(E)-3-(diethylamino)propenoyl chloride (17) and diethylcarbamoyl chloride (18).
Key words phosgene; aromatic electrophilic substitution; dihydropyridine; nucleic acid minor base; (chlorocarbonyl)triethylam-
monium elimination
In the course of our syntheses of the hypermodified nucle- phosgene, giving 2 in somewhat lower yield (50%). Triphos-
osides (1)1—5) of phenylalanine transfer ribonucleic acids, we gene could be used instead of phosgene: 2 was obtained in
required methyl 1-benzyl-4,6-dimethyl-9-oxo-4,9-dihydro- 52% yield together with 8 (38%) in the reaction conducted in
1H-imidazo[1,2-a]purine-7-carboxylate (2) in order to eluci- dichloromethane.
date the substituent effect on the stability of the condensed
The recovery of 8 deserved further investigation because
tricycle.6) We first attempted to obtain the corresponding car- methanol was added to the reaction mixture after 8 had been
boxylic acid 6 by oxidation of 1-benzyl-4,6-dimethyl-9-oxo- consumed. TLC analysis of the reaction mixture suggested
4,9-dihydro-1H-imidazo[1,2-a]purine-7-carbaldehyde.7) that the methyl ester 2 was rapidly formed after the addition
However, this aldehyde resisted oxidation with potassium of methanol, while 8 generated slowly. In a separate run, we
permanganate in aqueous acetone8) or hot water,9) pyridinium obtained a complex mixture of products after short treatment
dichromate in N,N-dimethylformamide,10) Jones reagent,11) of the reaction mixture with methanol followed by aqueous
or silver oxide in water12) or boiling ethanol.13) Treatment of treatment. The carboxylic acid 6 (10%), the dihydropyridine
the aldehyde with a mixture of 30% aqueous hydrogen per- derivative 11 (2.5%), and the 4-substituted pyridine 9 (0.7%)
oxide and formic acid14) gave a complex mixture of products. besides 2 (43%) were obtained. The structures of other com-
1
We next attempted chlorocarbonylation of 1-benzylwye pounds that formed were suggested by means of H-NMR
(8),7) which had been utilized as a versatile intermediate for spectroscopy to be the dihydropyridine derivatives [10, 12
the syntheses of condensed tricyclic minor bases of (YϭCl), and 14] and the acid anhydride 7. These compounds
tRNAsPhe 3,7,15,16)
Phosgene reacts with some aromatic rings were obtained in 7%, 4%, 5%, and 7% yields, respectively,
.
to afford the corresponding aroyl chlorides in the presence of together with the carboxylic acid 6 (35%) by treating the re-
aluminum chloride.17) However, we have already reported action mixture with water instead of methanol. The anhy-
that the Friedel–Crafts reactions of 8 in the presence of a dride 7 was alternatively prepared in 30% yield by treatment
Lewis acid give unsatisfactory results.7) On the other hand, of 6 with thionyl chloride in chloroform in the presence of
Michler reported that N,N-dimethylaniline reacted with an triethylamine. To present further evidence to support the an-
excess of phosgene to provide 4-(dimethylamino)benzoyl hydride structure for 7, we treated 7 with methanol in THF in
chloride in the absence of a Lewis acid.18) As our substrate 8 the presence of pyridine at 50 °C for 70 h. We found to our
is highly activated at the 7-position toward electrophilic sub- surprise that the product was suggested to be an almost 1 : 1
stitution,3,6,7) the desired acyl chloride 4 (YϭCl) might be mixture of the methyl ester 2 and 8 by 1H-NMR spec-
formed from the reaction with phosgene. Thus, we treated 8 troscopy. Only a small amount of the carboxylic acid 6 re-
with excesses of phosgene and pyridine in tetrahydrofuran mained in the mixture, indicating that 6 had undergone al-
(THF) at room temperature for 9 h and then with methanol most complete decarboxylation. The carboxylic acid 6 in-
overnight to obtain the objective methyl ester 2 in 65% yield, deed underwent facile decarboxylation in methanol at room
together with 32% recovery of 8. Replacement of the solvent temperature in the presence of pyridine hydrochloride, pro-
by dichloromethane much accelerated the reaction of 8 with viding 8 in quantitative yield probably by the mechanism il-
lustrated in Chart 2. Compound 6 was also quantitatively
transformed into 8 by heating at 180 °C. A likely mechanism
is illustrated in Chart 3.19)
Many examples of electrophilic aromatic substitutions lead-
ing to dihydropyridines have already been reported for N-
acylpyridinium and N-(alkoxycarbonyl)pyridinium ions.20—30)
Furthermore, it has been reported that phosgene reacts with
pyridine to form the carbamoyl chloride 5 through the pyri-
dinium chloride 3.31) However, the formation of 12 (YϭCl),
11, 10, 14, or 9 described above is the first example of aro-
* To whom correspondence should be addressed. e-mail: itaya@mail.p.kanazawa-u.ac.jp
© 2002 Pharmaceutical Society of Japan

December 2002
1585
Chart 1
Chart 2
Chart 3
Chart 4
matic substitution with 3 or 5. When the carbamoyl chloride and/or through the methyl ester 11 by such a mechanism as
12 (YϭCl) was treated with pyridine hydrochloride in illustrated in Chart 4. Compound 11 was indeed transformed
methanol at room temperature for 20 h, 8 was obtained in into 8 almost quantitatively upon similar treatment. On the
50% yield. Compound 8 might be formed directly from 12 other hand, 2 was stable under these conditions. These results

1586
Vol. 50, No. 12
Chart 5
carboxylic Acid Methyl Ester (2) i) By Reaction of Phosgene in THF: A
2 M solution of phosgene in toluene (12.5 ml, 25 mmol) was diluted with dry
THF (25 ml) and added to a stirred mixture of 87) (1.47 g, 5 mmol), pyridine
(8.1 ml, 0.1 mol), and THF (50 ml) at 0 °C over a period of 15 min. The re-
sulting mixture was stirred at room temperature for 9 h, during which time
almost all the starting material 8 was found to be consumed by TLC. Dry
methanol (25 ml) was then added to the mixture at 0 °C with stirring, and the
whole was stirred at room temperature overnight. The mixture was concen-
trated in vacuo, and the residue was dissolved in dichloromethane (100 ml).
The solution was washed successively with water (100 ml), 5% aqueous cit-
ric acid (2ϫ100 ml), and saturated aqueous sodium bicarbonate (100 ml),
dried over magnesium sulfate, and concentrated in vacuo. The residue was
purified by flash chromatography [ethyl acetate–ethanol (20 : 1, v/v)] to give
2 (1.14 g, 65%), mp 171.5—176 °C, and 8 (464 mg, 32%), mp 200—
206.5 °C. Recrystallization of crude 2 from methanol afforded an analytical
sample as faintly yellow prisms, mp 176—177 °C. MS m/z: 351 (Mϩ). UV
lmax (95% EtOH) nm (e): 250 (23700), 285 (sh) (7300), 306 (10500). IR
permit us to propose that the reaction of 8 with phosgene in
the presence of pyridine followed by treatment with methanol
and then with water follows the sequence as shown in Chart
1. Compound 9 was most likely formed from 12 through sub-
sequent hydrolysis, decarboxylation, and oxidation.
We next attempted to improve the yield of 2 by controlling
the formation of the dihydropyridine 12. Triethylamine might
be a good substitute for pyridine for this purpose. Somewhat
surprisingly, 8 was recovered unchanged in 90% yield on
treatment with phosgene in THF in the presence of a large
excess of triethylamine at room temperature for 5 h. Instead,
methyl (E)-3-(diethylamino)propenoate (19),32) dimethyl 2-
[(diethylamino)methylidene]propanedioate (20),33) and di-
ethylcarbamoyl chloride (18) were obtained in 8%, 6%, and
18% yields, respectively, after treatment of the reaction mix-
ture with methanol. We then treated phosgene with an excess
of triethylamine in THF at room temperature in the absence
of 8 for 6 h and quenched the reaction with methanol, obtain-
ing 18 (14%), 19 (21%), and 20 (6%). When the solvent was
replaced by dichloromethane, the products were shown to be
methyl diethylcarbamate (28%) and 18 (12%).
1
nmax (Nujol) cmϪ1: 1721, 1696 (CϭO). H-NMR (CDCl3) d: 2.49 [3H, s,
C(6)-Me], 3.94 (3H, s, NMe or CO2Me), 3.95 (3H, s, CO2Me or NMe), 5.62
(2H, s, PhCH2), 7.36 (5H, s, Ph), 7.66 [1H, s, C(2)-H]. Anal. Calcd for
C18H17N5O3: C, 61.53; H, 4.88; N, 19.93. Found: C, 61.36; H, 4.92; N,
19.91.
ii) By Reaction of Triphosgene in Dichloromethane: A solution of pyri-
dine (0.28 ml, 3.4 mmol) in dry dichloromethane (2 ml) was added to a solu-
tion of 87) (117 mg, 0.399 mmol) and triphosgene (198 mg, 0.667 mmol) in
dichloromethane (4 ml) at 0 °C over a period of 20 min, and the resulting
suspension was stirred at 0 °C for a further 45 min. Methanol (2 ml) was
added to the reaction mixture at 0 °C, and the resulting solution was stored
Although the formation of 18 has already been reported
for the reaction of phosgene and triethylamine,34,35) that of a
vinylamine derivative such as 16 from triethylamine has not at room temperature for 18 h. The mixture was concentrated in vacuo, and
the residue was dissolved in dichloromethane (20 ml). The solution was
washed successively with water (20 ml), 5% aqueous citric acid (2ϫ20 ml),
and saturated aqueous sodium bicarbonate (20 ml), dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by flash chro-
matography [ethyl acetate–ethanol (20 : 1, v/v)] to give 2 (73 mg, 52%), mp
172—175.5 °C, and 8 (45 mg, 38%), mp 200—207.5 °C.
been reported except for the reactions with perhalogenated
acyl chlorides35) including trichloroacetyl chloride,36,37)
trichloroacetic anhydride,38) or hexachloroacetone.39) The re-
action sequences similar to that delineated in Chart 5 have al-
ready been proposed36,38,39) for these reactions.
Reaction of 8 with Phosgene in the Presence of Pyridine Followed by
Short Treatment with Methanol Compound 87) (352 mg, 1.2 mmol) was
treated with phosgene in a manner similar to that described above, and dry
methanol (6 ml) was added to the resulting mixture at 0 °C with stirring. The
whole was stirred at room temperature for 5 min. The mixture was then par-
titioned between chloroform and saturated aqueous sodium bicarbonate
(50 ml each). The aqueous layer was brought to pH 3 with 10% aqueous
phosphoric acid and extracted with chloroform (4ϫ10 ml). The extracts
were dried over magnesium sulfate and concentrated in vacuo to leave 1-
benzyl-4,6-dimethyl-9-oxo-4,9-dihydro-1H-imidazo[1,2-a]purine-7-car-
boxylic acid (6) (41 mg, 10%), mp 170—180 °C (dec. and resolidified),
206—207 °C. Recrystallization of this product from ethanol afforded an ana-
lytical sample of 6 having unchanged mp as colorless needles. MS m/z: 337
(Mϩ), 293 (MϩϪCO2); UV lmax (95% EtOH) nm (e): 252 (sh) (28400), 256
(31100), 294 (sh) (6900), 312 (8500). IR nmax (Nujol) cmϪ1: 2561 (OH),
1705, 1648 (CϭO). 1H-NMR (CDCl3) d: 2.74 [3H, s, C(6)-Me], 4.03 (3H, s,
NMe), 5.61 (2H, s, PhCH2), 7.38 (5H, m, Ph), 7.87 [1H, s, C(2)-H], 14.48
(1H, br s, CO2H). Anal. Calcd for C17H15N5O3: C, 60.53; H, 4.48; N, 20.76.
Found: C, 60.75; H, 4.38; N, 20.74. On the other hand, the organic layer was
washed successively with 5% aqueous citric acid (2ϫ50 ml) and saturated
aqueous sodium bicarbonate (50 ml), dried over magnesium sulfate, and
concentrated in vacuo, leaving a brown foam (451 mg). The residue was pu-
rified by flash chromatography [ethyl acetate–ethanol (10 : 1, v/v) and then
chloroform–methanol (10 : 1, v/v)] to give a 48 : 7 : 5 (estimated by 1H-NMR
In conclusion, we have revealed that 1-benzylwye (8) un-
dergoes electrophilic substitution at the 7-position to produce
reactive compounds (4 and 12) on treatment with phosgene
in the presence of pyridine. We have also shown that phos-
gene activates tertiary amines such as pyridine and trieth-
ylamine to produce a variety of compounds, demonstrating
that the choice of the base to be employed may be of prime
importance for the reactions with phosgene or its analogues.
Experimental
General Notes All melting points were determined by using a Yamato
MP-1 or Büchi model 530 capillary melting point apparatus and values are
corrected. Spectra reported herein were recorded on a JEOL JMS-SX102A
mass spectrometer, a Hitachi model 320 UV spectrophotometer, a Shimadzu
FTIR-8100 IR spectrophotometer, a JEOL JNM-EX-270 or a JNM-GSX-
500 NMR spectrometer (measured at 25 °C with Me4Si as an internal stand-
ard). MS measurements and elemental analyses were performed by Dr. M.
Takani and her associates at Kanazawa University. Flash chromatography
was performed according to the reported procedure.40) The following abbre-
viations are used: brϭbroad, dϭdoublet, mϭmultiplet, qϭquartet, sϭsin-
glet, shϭshoulder, and tϭtriplet.
1-Benzyl-4,6-dimethyl-9-oxo-4,9-dihydro-1H-imidazo[1,2-a]purine-7-

December 2002
1587
spectroscopy) mixture (298 mg) of 2, 11, and 12 (YϭCl) as a yellow foam
from the earlier fraction. From the later fraction was obtained a 1 : 5 : 16 : 23
mixture (70 mg) of 7, 9, 10, and 14 as a brown glass. The mixture of the
three compounds was recrystallized from methanol, giving 2 (156 mg), mp
170—173 °C. The mother liquor of recrystallization was concentrated in
vacuo, and the residue was purified by flash chromatography [ethyl acetate–
ethanol (10 : 1, v/v)] followed by preparative TLC on silica gel [1,2-
dichloroethane–ethanol (20 : 1, v/v)] to provide a second crop of 2 (24 mg,
the total yield was 43%), mp 170—174 °C, and 4-(1-benzyl-4,6-dimethyl-9-
oxo-4,9-dihydro-1H-imidazo[1,2-a]purin-7-yl)-1(4H)-pyridinecarboxylic
acid methyl ester (11) (13 mg, 2.5%), mp 208—213 °C (dec.). Recrystalliza-
tion of this product from methanol afforded an analytical sample of 11 as
colorless needles, mp 211.5—213.5 °C (dec.). MS m/z: 430 (Mϩ). UV lmax
(95% EtOH) nm (e): 246 (52700), 318 (5800). IR nmax (Nujol) cmϪ1: 1715,
1690 (CϭO). 1H-NMR (CDCl3) d: 2.29 [3H, s, C(6)-Me], 3.84 (3H, s, NMe
or CO2Me), 3.89 (3H, s, CO2Me or NMe), 4.98, 5.05 [1H each, m, dihy-
dropyridine C(b)-H], 5.59 (2H, s, PhCH2), 5.84 [1H, m, dihydropyridine
C(g)-H], 6.79, 6.93 [1H each, m, dihydropyridine C(a)-H], 7.36 (5H, m,
Ph), 7.64 [1H, s, C(2)-H]. Anal. Calcd for C23H22N6O3: C, 64.17; H, 5.15; N,
19.52. Found: C, 64.13; H, 5.16; N, 19.64. Purification of the mixture of the
four compounds described above by repeated preparative TLC on silica gel
[1,2-dichloroethane–ethanol (10 : 1, v/v)] afforded 1-benzyl-4,6-dimethyl-7-
(4-pyridinyl)-1,4-dihydro-9H-imidazo[1,2-a]purin-9-one (9) (3 mg, 0.7%) as
a slightly yellow glass. Recrystallization from methanol afforded an analyti-
cal sample of 9 as yellow plates, mp 244—248 °C (dec.). MS m/z: 370 (Mϩ).
UV lmax (95% EtOH) nm (e): 234 (29600), 260 (13600), 316 (14400). IR
Bis[4-(1-benzyl-4,6-dimethyl-9-oxo-4,9-dihydro-1H-imidazo[1,2-a]purin-
7-yl)-1(4H)-pyridinecarboxylic] Anhydride (14): A yellow glass. FAB-MS
1
m/z: 815 (MHϩ). H-NMR (CDCl3) d: 2.30 [6H, s, C(6)-Me], 3.90 [6H, s,
N(4)-Me], 5.16, 5.29 [2H each, m, dihydropyridine C(b)-H], 5.59 (4H, s,
PhCH2), 5.90 [2H, m, dihydropyridine C(g)-H], 6.72, 6.96 [2H each, m, di-
hydropyridine C(a)-H], 7.34 (10H, m, Ph), 7.66 [2H, s, C(2)-H].
Bis(1-benzyl-4,6-dimethyl-9-oxo-4,9-dihydro-1H-imidazo[1,2-a]purine-
7-carboxylic) Anhydride (7) A solution of thionyl chloride (0.05 ml,
0.7 mmol) in dry chloroform (0.2 ml) was added to a stirred solution of 6
(100 mg, 0.296 mmol) and triethylamine (0.18 ml, 1.3 mmol) in chloroform
(1 ml) at 0 °C over a period of 2 min. The resulting mixture was stirred at
room temperature for 21 h, diluted with chloroform (5 ml), extracted with
saturated aqueous sodium bicarbonate (2ϫ6 ml), dried over magnesium sul-
fate, and concentrated in vacuo. The residue was purified by flash chro-
matography [ethyl acetate–ethanol (3 : 1, v/v)] followed by preparative TLC
on silica gel [1,2-dichloroethane–ethanol (10 : 1, v/v)] to provide 7 (29 mg,
30%), mp 216—227 °C (dec.). Recrystallization of this product from chloro-
form–ether (1 : 5, v/v) afforded an analytical sample of 7 as colorless plates,
mp 225—231 °C (dec.). MS m/z: 656 (Mϩ). UV lmax (95% EtOH) nm (e):
(unstable) 245 nm (ca. 32000), 316 (ca. 21000). IR nmax (Nujol) cmϪ1: 1767,
1707 (CϭO). 1H-NMR (CDCl3) d: 2.65 [6H, s, C(6)-Me], 3.96 [6H, s, N(4)-
Me], 5.50 (4H, s, PhCH2), 7.26 (10H, s, Ph), 7.65 [2H, s, C(2)-H]. 1H-NMR
[(CD3)2SO] d: 2.44 [6H, s, C(6)-Me], 3.82 [6H, s, N(4)-Me], 5.47 (4H, s,
PhCH2), 7.15—7.28 (10H, s, Ph), 8.47 [2H, s, C(2)-H]. Anal. Calcd for
C34H28N10O5: C, 62.19; H, 4.30; N, 21.33. Found: C, 61.92; H, 4.23; N,
21.12.
1
nmax (Nujol) cmϪ1: 1696 (CϭO). H-NMR (CDCl3) d: 2.32 [3H, s, C(6)-
Aqueous sodium bicarbonate extracts were brought to pH 3—4 by the ad-
dition of 10% aqueous phosphoric acid and extracted with chloroform (2ϫ
6 ml). The organic layer was dried over magnesium sulfate and concentrated
in vacuo, leaving 6 (25 mg, 25%), mp 175—185 °C (dec. and resolidified),
202—204 °C.
Me], 3.99 (3H, s, NMe), 5.57 (2H, s, PhCH2), 7.24—7.40 [7H, m, pyridine
C(b)-H, Ph], 7.65 [1H, s, C(2)-H], 8.64 [2H, m, pyridine C(a)-H]. Anal.
Calcd for C21H18N6O: C, 68.09; H, 4.90; N, 22.69. Found: C, 68.13; H, 4.87;
N, 22.63.
Reaction of 8 with Phosgene in the Presence of Pyridine Followed by
Aqueous Treatment Reaction of 87) (587 mg, 2 mmol) and phosgene was
conducted in a manner similar to that described above. Chloroform (100 ml)
was added to the resulting mixture, and the solution was extracted with satu-
rated aqueous sodium bicarbonate (3ϫ50 ml). The aqueous layer was
brought to pH 3—4 by the addition of 10% aqueous phosphoric acid and
then extracted with chloroform (3ϫ50 ml). The extracts were dried over
magnesium sulfate and concentrated in vacuo, leaving 6 (237 mg, 35%), mp
170—180 °C (dec. and resolidified), 206—207 °C. The organic layer was
washed successively with 5% aqueous citric acid (2ϫ100 ml) and saturated
aqueous sodium bicarbonate (50 ml), dried over magnesium sulfate, and
concentrated in vacuo, leaving a brown foam (650 mg). This was purified by
flash chromatography [ethyl acetate–ethanol (10 : 1, v/v) and then chloro-
form–methanol (10 : 1, v/v)]. A yellow glass (97 mg) obtained from the ear-
lier fraction was further purified by preparative TLC on silica gel [chloro-
form–methanol (30 : 1, v/v)] to give 4-(1-benzyl-4,6-dimethyl-9-oxo-4,9-di-
hydro-1H-imidazo[1,2-a]purin-7-yl)-1(4H)-pyridinecarbonyl chloride [12
(YϭCl)] (37 mg, 4%) as a yellow glass, MS 434, 436 (Mϩ), 371 (MϩϪ
COCl). 1H-NMR (CDCl3) d: 2.27 [3H, s, C(6)-Me], 3.91 (3H, s, NMe),
5.23, 5.33 [1H each, m, dihydropyridine C(b)-H], 5.59 (2H, s, PhCH2), 5.90
[1H, m, dihydropyridine C(g)-H], 7.01 [2H, m, dihydropyridine C(a)-H],
7.36 (5H, m, Ph), 7.67 [1H, s, C(2)-H]. 1-Benzyl-4,6-dimethyl-9-oxo-4,9-di-
hydro-1H-imidazo[1,2-a]purine-7-carboxylic acid ethyl ester (12 mg, 2%)
was also obtained as a slightly yellow glass, 1H-NMR (CDCl3) d: 1.39 (3H,
t, Jϭ7 Hz, MeCH2), 2.50 [3H, s, C(6)-Me], 3.94 (3H, s, NMe), 4.42 (4H, q,
Jϭ7 Hz, MeCH2), 5.61 (2H, s, PhCH2), 7.36 (5H, s, Ph), 7.67 [1H, s, C(2)-
H].
A brown foam (332 mg) obtained from the later fraction of the above flash
chromatography was further purified by flash chromatography [ethyl ac-
etate–ethanol (3 : 1, v/v)]. The crude product (56 mg) obtained from the ear-
lier fraction was purified by preparative TLC [1,2-dichloroethane–ethanol
(10 : 1, v/v)] on silica gel, providing 7 (46 mg, 7%) as a yellow solid, mp
165—177 °C (dec.). Repeated preparative TLC [1,2-dichloroethane–ethanol
(10 : 1, v/v)] on silica gel of the crude product (196 mg) obtained from the
later fraction afforded 2 (2 mg, 0.3%), 10 (53 mg, 7%), and 14 (40 mg, 5%).
1-Benzyl-4,6-dimethyl-9-oxo-4,9-dihydro-1H-imidazo[1,2-a]purine-7-
carboxylic 4-(1-Benzyl-4,6-dimethyl-9-oxo-4,9-dihydro-1H-imidazo[1,2-a]-
purin-7-yl)-1(4H)-pyridinecarboxylic Anhydride (10): A yellow glass. FAB-
MS m/z: 736 (MHϩ). 1H-NMR (CDCl3) d: 2.30 [3H, s, C(6Љ)-Me], 2.60 [3H,
s, C(6)-Me], 3.89 [3H, s, N(4Љ)-Me], 3.97 [3H, s, N(4)-Me], 5.06, 5.25 [1H
each, m, dihydropyridine C(b)-H], 5.59 (4H, s, PhCH2), 5.89 [1H, m, dihy-
dropyridine C(g)-H], 6.99 [2H, m, dihydropyridine C(a)-H], 7.34 (10H, m,
Ph), 7.65 [1H, s, C(2Љ)-H], 7.71 [1H, s, C(2)-H].
Acid-Catalyzed Fragmentation of 12 (Y؍Cl) Leading to 8 Pyridine
(0.7 ml, 8.7 mmol) and 10% hydrogen chloride in methanol (1.6 g, 4.4 mmol)
was dissolved in dry methanol to make the whole volume 10 ml. Compound
12 (YϭCl) (30 mg, 0.069 mmol) was dissolved in this solution (3 ml) and
stored at room temperature for 20 h. The resulting solution was concentrated
in vacuo, and the residue was dissolved in chloroform (5 ml). The solution
was washed successively with water (5 ml), 5% aqueous citric acid
(2ϫ5 ml), and saturated aqueous sodium bicarbonate (5 ml), dried over mag-
nesium sulfate, and concentrated in vacuo, leaving a slightly yellow glass.
This was purified by preparative TLC on silica gel [ethyl acetate–ethanol
(10 : 1, v/v)] to provide 8 (10 mg, 50%), mp 194—203 °C.
Acid-Catalyzed Fragmentation of 11 Leading to 8 Compound 11
(20 mg, 0.046 mmol) was suspended in the pyridine hydrochloride–pyri-
dine–methanol solution (5 ml) described above, and the mixture was stirred
at room temperature for 13 h. The resulting solution was concentrated in
vacuo, and the residue was dissolved in chloroform (5 ml). The solution was
washed successively with 5% aqueous citric acid (2ϫ5 ml) and saturated
aqueous sodium chloride (5 ml), dried over magnesium sulfate, and concen-
trated in vacuo, leaving 8 (13 mg, 93%), mp 200—201.5 °C.
Acid-Catalyzed Decarboxylation of 6 Leading to 8 A solution of 6
(20 mg, 0.059 mmol) in the pyridine hydrochloride–pyridine–methanol solu-
tion (5 ml) described above was stored at room temperature for 5 h and con-
centrated in vacuo. The solution of the solid residue in chloroform (5 ml)
was washed successively with 5% aqueous citric acid (2ϫ5 ml) and satu-
rated aqueous sodium chloride (5 ml), dried over magnesium sulfate, and
concentrated in vacuo, leaving 8 (17 mg, 100%), mp 205.5—207 °C.
Pyrolytic Decarboxylation of 6 Leading to 8 Compound 6 (20 mg,
0.059 mmol) began to melt with evolving at 180 °C. It was heated at 200 °C
for 5 min to resolidify, giving 8 (17 mg, 100%), mp 206—207 °C.
Reaction of Phosgene and Triethylamine i) In THF: A 2 M solution of
phosgene in toluene (4.0 ml, 8 mmol) was diluted with dry THF (8 ml) and
added to a solution of triethylamine (4.5 ml, 32 mmol) in THF (16 ml) at
0 °C over a period of 15 min. The resulting suspension was stirred at room
temperature for 6 h. Dry methanol (8 ml) was added to this suspension with
stirring at 0 °C, and the mixture was stirred at room temperature for 1 h.
After being stored at room temperature overnight, the mixture was concen-
trated in vacuo. The residual gum was partitioned between ether (50 ml) and
saturated aqueous sodium chloride (40 ml). The organic layer was dried over
magnesium sulfate and concentrated in vacuo, leaving a deep violet oil. This
was extracted with hexane (10 ml), and the extracts were purified by flash
chromatography [hexane–ethyl acetate (2 : 1, v/v)]. Diethylcarbamoyl chlo-
ride (18) (155 mg, 14%) was obtained from the fast eluting fraction as a col-
1
orless oil, H-NMR (CDCl3) d: 1.21, 1.24 (3H each, t, Jϭ7.3 Hz, MeCH2),

1588
Vol. 50, No. 12
3.42, 3.49 (2H each, q, Jϭ7.3 Hz, MeCH2). Methyl (E)-3-(diethylamino)-2-
propenoate (19)32) (130 mg, 21%) was obtained from the second fraction,
1H-NMR (CDCl3) d: 1.16 (6H, t, Jϭ7 Hz, MeCH2), 3.19 (4H, q, Jϭ7 Hz,
MeCH2), 3.66 (3H, s, CO2Me), 4.57 (1H, d, Jϭ13 Hz, Et2NCH), 7.44 (1H, d,
Jϭ13 Hz, CHCO2Me). Dimethyl 2-[(diethylamino)methylidene]propane-
14) Dodd R. H., Le Hyaric M., Synthesis, 1993, 295—297.
15) Itaya T., Mizutani A., Iida T., Chem. Pharm. Bull., 39, 1407—1414
(1991).
16) Itaya T., Watanabe N., Iida T., Kanai T., Mizutani A., Tetrahedron, 51,
6419—6430 (1995).
17) Beilstein’s “Handbuch der Organischen Chemie,” 3, 16 (1921).
18) Michler W., Ber. Dtsch. Chem. Ges., 9, 400—402 (1876).
19) A preliminary communication of this work has been published: Itaya
T., Kanai T., Heterocycles, 46, 101—104 (1997).
1
dioate (20)33) (35 mg, 6%) was obtained from the third fraction, H-NMR
(CDCl3) d: 1.19 (6H, t, Jϭ7 Hz, MeCH2), 3.28 (4H, q, Jϭ7 Hz, MeCH2),
3.74 (6H, br s, CO2Me), 7.50 (1H, s, CHϭC).
ii) In Dichloromethane: A 2 M solution of phosgene in toluene (1.0 ml,
2 mmol) was diluted with dry dichloromethane (2 ml) and added to a solu-
tion of triethylamine (1.12 ml, 8 mmol) in dichloromethane (4 ml) at 0 °C
over a period of 5 min. The resulting solution was stored at room tempera-
ture for 8 h. Dry methanol (3 ml) was added to this solution, and the mixture
was stored at room temperature overnight. The resulting solution was con-
centrated in vacuo. The residual solid was dissolved in dichloromethane
(10 ml). The solution was washed successively with water and saturated
aqueous sodium bicarbonate (10 ml each), dried over magnesium sulfate,
and concentrated in vacuo, leaving a 2.3 : 1 mixture of methyl diethylcarba-
mate [1H-NMR (CDCl3) d: 1.11 (6H, t, Jϭ7 Hz, MeCH2), 3.27 (4H, br,
MeCH2), 3.69 (3H, s, CO2Me)] (28%) and diethylcarbamoyl chloride (18)
(12%) as an orange oil (116 mg).
20) Weber S., Slates H. L., Wendler N. L., J. Org. Chem., 32, 1668—1669
(1967) and references cited therein.
21) Sheinkman A. K., Samoilenko G. V., Baranov S. N., Zh. Obshch.
Khim., 40, 2339—2340 (1970) [Chem. Abstr., 74, 53443f (1971)].
22) Steglich W., Höfle G., Chem. Ber., 104, 3644—3652 (1971).
23) Deubel H., Wolkenstein D., Jokisch H., Messerschmitt T., Brodka S.,
von Dobeneck H., Chem. Ber., 104, 705—716 (1971) and references
cited therein.
24) Bailey A. S., Buckley A. J., Warr W. A., Wedgwood J. J., J. Chem.
Soc., Perkin Trans. 1, 1972, 2411—2415.
25) Deikalo A. A., Sheinkman A. K., Baranov S. N., Khim. Geterotsikl.
Soedin., 1972, 1359—1365 [Chem. Abstr., 78, 43343s (1973)].
26) Bergman J., Bäckvall J.-E., Lindström J.-O., Tetrahedron, 29, 971—
976 (1973) and references cited therein.
References and Notes
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