Communication
Scheme 2. Attempted synthesis of 6-iodopterin (10).
7 (N-iodosuccinimide (NIS), 2 equiv) afforded methyl 3-amino-
6-iodopyrazine-2-carboxylate (8) in 92% yield.[15] In DMSO, the
product precipitated after addition of water to the reaction
mixture. In the HMBC spectrum of 8, 5-H correlated to C-3 and
C-6, but only weakly to C-2, supporting the desired regioselec-
tivity. Attempts to exploit the ester function of 8 by condensa-
tion with guanidine in the presence of NaOMe and subsequent
cyclization to the pterin[16] failed. There was also the chance to
react methyl 3-chloro-6-iodopyrazine-2-carboxylate (9) with
guanidinium bicarbonate, a reaction that had worked for the
non-iodinated analogue.[17] After replacement of the amino
group of 8 by a chloro substituent (45%), treatment of 9 with
guanidinium bicarbonate at 1408C afforded a complex mixture
of fluorescent products, among which we isolated only 5% of
10.
As an alternative, we attempted to obtain guanidino partial
structure of 6-iodopterin by guanylation of the amino group of
8. However, neither cyanamide nor carbamimidic chloride were
effective, even at 1708C under neat conditions. Reaction of an-
thranilic acid with cyanamide had provided the corresponding
aminoquinazolinone.[18,19] Also, carbamimidic chloride reacted
with ethyl anthranilate in good yield.[20]
Scheme 3. Addition of aminoarenes to ethoxycarbonylisothiocyanate, cycli-
zation reactions.
to 82% by employing 9 equivalents of SCNCO2Et. Lacking the
methoxycarbonyl group, 2-aminopyrazine (19) gave a yield of
60% (20) with 1 equivalent of SCNCO2Et. In a test reaction,
methyl 2-(3-(ethoxycarbonyl)thioureido)nicotinate (16) was
converted to the pyrido[2,3-d]pyrimidine derivative 21 in good
yield (71%), indicating the general feasibility of the pathway.
Unfortunately, the improved conditions could not be trans-
ferred to the case of the iodinated pyrazine derivative 8, and it
was not possible to iodinate the pyrazine-based thiourea 17 at
C-6, either. Instead, reaction of 17 with NIS in DMSO afforded
the thiadiazolo[2,3-a]pyrazine 22 (Scheme 3). Both NH signals,
which were present in the starting material at d=11.7 and
11.9 ppm, had disappeared, and the CH carbons had experi-
enced a downfield shift of 11–13 ppm. Mechanistically, iodina-
tion of the sulfur should occur first, followed by nucleophilic
attack of the pyrazine nitrogen N4 at the iodinated sulfur.[25]
The alkynyl moiety at C6 had to be introduced prior to the
formation of the thiourea. Methyl 3-amino-6-iodopyrazine-2-
carboxylate (8) was alkynylated under Sonogashira conditions
with a variety of terminal alkynes, such as but-3-yn-1-ol or 4-
ethynyl-2,2-dimethyl-1,3-dioxolane. Ethynyltrimethylsilane (23)
afforded alkynyl pyrazine derivative 24 (85%, Scheme 4), which
we considered a suitable intermediate towards dephospho
Form A (4). Treatment of 24 with excess SCNCO2Et in MeCN
provided the thioureido pyrazine carboxylate 25. Introduction
of the remaining nitrogen and ring closure to ethynyl pterin
26 was achieved on reaction of 25 with excess of hexamethyl-
disilazane in the presence of EDCI (76%). Desilylation of 26
with tetra-n-butylammonium fluoride trihydrate (TBAF·3H2O) in
MeCN afforded the terminal alkyne 27 (48%), which proved to
be the end point of the sequence since all attempts to
hydroxylalkylate 27 were unsuccessful.
We turned to the condensation of ethoxycarbonylisothiocya-
nate (SCNCO2Et) with amino-substituted heterocycles, since
Stanovnik et al. had reacted benzyl 3-aminopyrazine-2-carbox-
ylate with SCNCO2Et in boiling chloroform and obtained the
corresponding 3-thioureidopyrazine-2-carboxylate, which was
cyclized further to 2-thioxo-2,3-dihydropteridin-4(1H)-one.[21]
Chowdhury et al. had condensed methyl 3-aminopyrazine-2-
carboxylate with ethyl isothiocyanatoacetate.[22] Fabis et al. had
accessed N-3 unsubstituted quinazolones from anthranilic acid
esters and SCNCO2Et, followed by activation of the thiourea
with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)
and reaction with hexamethyldisilazane.[23] The reaction is as-
sumed to start with the conversion of the thiourea moiety to a
carbodiimide by treatment with EDCI.[24]
In the absence of ring nitrogen atoms, starting from methyl
anthranilate (11), we obtained the thiourea 12 in moderate
yield (52%, Scheme 3). Introduction of one nitrogen into the
ring system did not hamper the condensation with SCNCO2Et
when compared to methyl anthranilate, as shown by products
14 and 16 that were obtained in 69% and 60% yield from 13
and 15, respectively. The presence of two nitrogen atoms in
methyl 3-aminopyrazine-2-carboxylate (7) diminished the yield
(25% of pyrazine-based thiourea 17), which could be improved
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Chem. Eur. J. 2017, 23, 1 – 5
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!