Reactions of π-electron rich 1,2,4-triazines with organolithium nucleophiles

Article abstract of DOI:10.1039/b205058g

3,5-Bis(trimethylsilyloxy)-1,2,4-triazine 1 and 3-methylthio-5-methoxy-1,2,4-triazine 6 were subjected to reactions with organolithium reagents at low temperatures. An unexpected regioselectivity in the addition of butyllithiums to 1, which was strongly d

Full text of DOI:10.1039/b205058g

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Reactions of ꢀ-electron rich 1,2,4-triazines with organolithium
nucleophiles
Joanna Szczepkowska-Sztolcman, Andrzej Katrusiak, Hanna Wójtowicz-Rajchel and
Krzysztof Golankiewicz*
1
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland.
E-mail: golan@main.amu.edu.pl; Fax: ϩ48-061-8658-008; Tel: ϩ48-061-8291-384
Received (in Cambridge, UK) 24th May 2002, Accepted 18th September 2002
First published as an Advance Article on the web 24th October 2002
3,5-Bis(trimethylsilyloxy)-1,2,4-triazine 1 and 3-methylthio-5-methoxy-1,2,4-triazine 6 were subjected to reactions
with organolithium reagents at low temperatures. An unexpected regioselectivity in the addition of butyllithiums to 1,
which was strongly dependent on the temperature and substituents, was observed. For phenyllithium there was
competition between N(1)–C(6) addition and C(5) substitution. No addition of butyllithiums to 6 was detected,
only isolated reaction products showing zwitterionic structures.
positions. The preference for the bridging conformation is a
Introduction
result of stronger polarisation of the ring nitrogens and a more
Recently we have reported that π-electron deficient 6-azauracil
efficient contribution of the lithium p orbitals.8 Such an inter-
derivatives (1,2,4-triazine-3,5-diones) while reacting with tert-
butyllithium or LDA underwent either Lewis acid promoted
mediate could easily undergo nucleophilic attack at C(6) giving
normal isomers 2a,b, or at the N(1) position giving unexpected
isomers 3a,b. Following the lithiation at the two different nitro-
gens via the three centred complex we propose a polar addition
ring contraction or the addition of an organolithium reagent to
the double carbon–nitrogen bond.1 We have also attempted the
lithiation of 6-azauracils via both deprotonation and lithium–
mechanism to account for the products 2 and 3 respectively
bromine exchange, but under the conditions used, the desired
(Scheme 2).
overall electrophilic substitution reaction did not occur. The
We believe that the result can be explained in terms of the
high reactivity of 1,2,4-triazines towards nucleophilic addi-
HSAB9 principle if the N(2) nucleophilic centre in the bridged
tion2,3 makes the lithiation of these compounds more difficult
complex is assumed to be harder than the N(1) position.
than for diazines.4–6 The first ortho-directed metalation of 1,2,4-
Irrespective of the steric hindrance at C(3), attack by the hard
triazine derivatives has been performed quite recently.7 We have
Liϩ at the harder site becomes competitive and creates an
found, however, that nucleophilic addition of tert-butyllithium
to the nitrogen–carbon bond of 1,2,4-triazine followed by
hydration can proceed through two different paths to give two
electrophilic, soft (or eventually borderline) site at N(1). Attack
by the butyl anions, considered as soft bases, occurs exclusively
at this site.
isomeric compounds.1 Therefore, we have expanded our study
The alternative SET mechanism would involve electron
to the reactions of π-electron rich 6-azauracil derivatives with
different organolithium reagents.
transfer from butyllithium to compound 1 and the formation
of a radical pair in the solvent cage. The normal addition
products 2a,b should arise from the caged species by radical
combination, whereas compounds 3a,b should arise from the
reaction of butyl radicals that have “escaped” from the solvent
Results and discussion
We report in this paper the differences in the behavior of 1,2,4-
triazines 1 and 6 toward organolithium agents on varying the
temperature and the character of the organolithium nucleo-
philes.
The reaction of 3,5-bis(trimethylsilyloxy)-1,2,4-triazine
(compound 1) with different organolithium agents, such as n-
butyllithium, tert-butyllithium and phenyllithium, gave no
products arising from lithiation by abstraction of a weak acidic
proton. The only reaction undergone by both n-butyllithium
and tert-butyllithium is the addition reaction to a carbon–
nitrogen bond. Organolithium reagents had evidently acted
in general as nucleophiles rather than as lithiating agents
(Scheme 1).
The formation of two isomeric adducts 2 and 3 with the
predominance of compounds 3a and 3b was surprising. A polar
addition mechanism is suggested, but a single electron transfer
(SET) mechanism should also be considered. Compound 1 has
two unsubstituted nitrogen atoms N(1) and N(2) able to bind
Liϩ. Moreover, the neighbouring nitrogens in the 1,2,4-triazines
enable the formation of a bridged complex that exhibits
enhanced stability, where the Liϩ bridges the N(1) and N(2)
cage. The addition of a free butyl radical to a neutral moiety of
1 followed by electron transfer, then association with Liϩ and
subsequent protonation affords the unexpected isomers 3a,b.
The reactions with tert-butyllithium and n-butyllithium
proceeded either alone or in combination with a Lewis acid,
giving two isomeric adducts 2 and 3. For the reaction of 1 with
tert-butyllithium carried out at Ϫ100 ЊC the predominance
of the unexpected compound 3a is overwhelming; the ratio of
1
3a : 2a, based on the H-NMR spectra of the isolated crude
fraction, is 3.3 : 1. However, when the reaction was carried out
at Ϫ20 ЊC the compounds were isolated in a ratio 3a : 2a of
1 : 2.3. For compounds 2b and 3b, isolated from the reaction
of 1 with n-butyllithium at Ϫ100 ЊC, such a distinct difference
in the quantities of the two adducts was not visible, but still the
ratio of 3b : 2b is 1.3 : 1 and changes to 1 : 2.1 when the reaction
was carried out at Ϫ20 ЊC. This suggests that temperature is the
major factor in controlling the initial selectivity of the lithiation
of the nitrogens. At low temperatures compound 3a seems to be
thermodynamically favored whereas 3b is both kinetically and
thermodynamically favored.
Quite a large amount of compound 4 was separated as a
DOI: 10.1039/b205058g
J. Chem. Soc., Perkin Trans. 1, 2002, 2549–2553
This journal is © The Royal Society of Chemistry 2002
2549

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Scheme 1 Reagents and conditions: i. BuLi, THF, Ϫ100 ЊC and Ϫ20 ЊC respectively; ii. H2O; iii. PhLi, B(OEt)3, THF, Ϫ100 ЊC and Ϫ20 ЊC
respectively; iv. H2O.
Scheme 2 Mechanistic pathways for the formation of compounds 2 and 3.
product of the addition of n-butyllithium to 1 and subsequent
loss of LiH. No traces of a similar product were observed in the
reaction of tert-butyllithium with 1 carried out under the same
conditions.
The competitive reactions of nucleophilic addition to a
carbon–nitrogen bond of 1 are not general. When the reaction
of compound 1 was carried out at Ϫ100 ЊC with phenyllithium
in the absence of a Lewis acid, no addition reaction occurred
under the conditions used. However, the reaction proceeded in
the presence of triethyl borate as a mild Lewis acid giving two
products 2c and 5. Triethyl borate is not a typical, commonly
used Lewis acid, as, for example, boron trifluoride is preferred
Fig. 1 Molecule 5 as present in the crystalline phase at 90 K. The
thermal ellipsoids have been drawn at the 50% probability level.
for phenyllithium activation in arylation reactions and in addi-
tion to double bonds.10,11 However, we have used it successfully
in some of our syntheses, for instance as a good coordinating
agent in ring contraction reactions.1 The reaction, activated by
triethyl borate, is strongly dependent on temperature. When the
reaction of compound 1 with phenyllithium was carried out at
Ϫ100 ЊC in the presence of triethyl borate, we obtained mainly
Scheme 3 The mechanistic pathway for the formation of compound 5.
product 2c, whereas product 5 was formed in a negligible
amount. When compound 1 was subjected to the reaction
with phenyllithium at Ϫ20 ЊC compound 5 was obtained as
the major product with a minor amount of product 2c.
Attempts at arylation of compound 1 by the activation with
boron trifluoride gave a comparable result.
The attempts to obtain products by electrophilic substitution
of compound 1 and its 6-bromo derivative were unsuccessful.
Nevertheless, we tried to investigate the relationship between
substitution and addition to π-electron rich derivatives of
6-azauracil. For this purpose we obtained 3-methylthio-5-
methoxy-1,2,4-triazine (compound 6). This compound was
prepared in a moderate yield via sulfur compounds.12
Compound 6 was subjected to reactions with n-butyllithium,
tert-butyllithium and phenyllithium in the presence of triethyl
borate acting as an activating agent and, at the same time, as an
electrophile, at Ϫ100 ЊC and under similar conditions to those
of the reactions of compound 1 described above. We could
expect both competition between the formation of two adducts
and competition between electrophilic substitution promoted
by ortho directing methoxy groups and nucleophilic addition.
In fact, reactions with butyllithiums proceeded without any
At Ϫ100 ЊC the N(1)–C(6) addition reaction affords a single
regioisomer, no traces of the second isomeric product of
addition to the nitrogen–carbon bond were detected which may
be explained by the weaker nucleophilicity of phenyllithium.
At Ϫ20 ЊC N(4) lithiation took place in spite of the strong
hindering effect of two bulky trimethylsilyl groups. This inter-
mediate facilitates nucleophilic attack at C(5) giving compound
5. The structure of compound 5 was established by NMR and
mass spectrometry and by X-ray analysis. Fig. 1 shows the
structure of molecule 5, and its crystal data are listed in Table 1.
A simple mechanistic pathway for the formation of compound
5 is given in Scheme 3.
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Table 1 Crystal data and structure refinement for 5 and 7a
5
7a
Empirical formula
Formula weight
Temperature/K
Wavelength/Å
Crystal system, space group
Unit cell dimensions
a/Å
C9H7N3O
173.18
90(1)
0.71073
Monoclinic, C2/c
C8H13N3OS
199.27
293(2)
0.71073
Monoclinic, P21/c
20.708(3)
8.877(2)
b/Å
c/Å
6.9640(10)
12.305(2)
5.8520(10)
19.624(4)
β/deg
117.01(3)
1581.0(4)
8, 1.455
1579 / 0 / 141
1.470
101.84(3)
997.7(3)
4, 1.327
2666 / 0 / 146
1.267
Volume/Å3
Z, Calculated density/g cmϪ3
Data / restraints / parameters
Goodness-of-fit on F 2
Final R indices [I > 2σ(I)]
R1 = 0.0472, wR2 = 0.0632
R1 = 0.0513, wR2 = 0.0964
markedly detectable competition and gave the only isolable
products 7a and 7b in fair yields. The reaction of compound 6
with phenyllithium furnished exclusively product 8 as the
product of the expected normal addition to the nitrogen–
carbon bond followed by the subsequent elimination process
(Scheme 4).
Fig. 2 The molecule of 7a as present in the crystalline phase.
accomplished with phenyllithium, the reaction leads to the C(6)
nucleophilic substitution (as an addition–elimination process)
of a considerably weaker nucleophile giving compound 8.
Conclusion
Usually the addition reactions of highly reactive organolithium
reagents to carbon–nitrogen double bonds afford single
regioisomers. We showed that the seemingly simple reactions
of butyllithiums and phenyllithium with π-electron rich 6-
azauracil derivatives followed by hydration gave unexpected
products. Reactions of 3,5-bis(trimethylsilyloxy)-1,2,4-tri-
azine with n-butyl and tert-butyllithium exhibit temperature
dependent competition between attack at the C(6) and N(1)
atoms giving two regioisomeric products of normal and
unusual addition. Analogous reactions of 3-methylthio-5-
methoxy-1,2,4-triazine with these reagents show the total
regioselectivity of nucleophilic attack at the N(1) position and
give exclusively the zwitterionic alkylation products. Reactions
of both triazines with phenyllithium in general show the
regioselectivity of the nucleophilic attack to be at the C(6)
position.
Scheme 4 Reagents and conditions: i. BuLi, THF, B(OEt)3, Ϫ100 ЊC; ii.
PhLi, B(OEt)3, THF, Ϫ100 ЊC.
However, confirmation of the structure of crystalline com-
pound 7a and oily compound 7b by spectroscopic methods
was ambiguous. In the UV spectra of 7a we determined absorp-
tion bands at long wavelengths in several solvents (water,
methanol, acetonitrile and chloroform) and we noticed that
with decreasing solvent polarity the absorption bands shift to
lower energies (λmax(H2O) = 311 nm, λmax(CH3OH) = 319 nm,
λmax(CH3CN) = 320 nm and λmax(CHCl3) = 328 nm). Such a
solvent effect is characteristic of the band associated with an
electronic transition from the ground state with a high dipole
moment to an excited state with a lower dipole moment.13,14 UV
spectra of 7a recorded in a wide pH range showed the proto-
nation of the compound at lower pH. Significant solvato-
chromism and the pH dependent spectra of compound 7a
showed its strongly polar structure, which was confirmed by
X ray analysis. Molecule 7a in the crystal state is shown in
Fig. 2, and its crystal data are listed in Table 1.
Experimental
General
The observed structure indicates that the molecule is a
zwitterion with the positive charge at N(1) and the negative pole
at O(5). Zwitterionic derivatives of 1,2,4-triazines are known in
the literature and were derived from triazinium iodides by
thermolysis.15,16
The obtained compounds 7a and 7b distinctly show that at a
low temperature triazine 6, in the presence of butyllithiums,
prefers lithiation at the N(2) position and, as a consequence,
N(1) alkylation. In the case of arylation of compound 6
Melting points were determined on a Boetius apparatus and are
reported uncorrected. All 1H-NMR and 13C-NMR spectra
were recorded on a Varian Gemini 300 MHz spectrometer in
CDCl3 and DMSO-d6. Chemical shifts δ are reported in ppm
downfield from an internal SiMe4 standard. The UV spectra
were recorded on a UV-2101PC Shimadzu spectrophotometer.
The mass spectra were recorded on a AMD 402 spectrometer,
ionisation was achieved through electron impact (EI) and
fast atom bombardment (FAB). High resolution data were
J. Chem. Soc., Perkin Trans. 1, 2002, 2549–2553
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obtained on the same instrument using a peak matching
technique. The elemental compositions of the discussed ions
were determined with an error of less than 10 ppm in relation
to perfluorokerosene at a resolving power of 10000. The
elemental analyses were made on a Perkin-Elmer apparatus.
Tetrahydrofuran was distilled from sodium hydrate immedi-
ately before use. All reactions were carried out under an argon
atmosphere using standard conditions for exclusion of
moisture. The reaction temperature Ϫ100 ЊC was achieved
by cooling with a N2/hexane bath. 3,5-Bis(trimethylsilyloxy)-
1,2,4-triazine 117 and 3-methylthio-5-methoxy-1,2,4-triazine
612 were obtained according to literature methods. 1.5 M tert-
Butyllithium in pentane, 1.6 M n-butyllithium in hexanes
and 1.8 M phenyllithium in cyclohexane : ether 70 : 30 were
purchased from Aldrich.
m/z 171 (7) [M]ϩ, 115 (100) and 57 (56); HRMS: calculated for
C7H13N3O2 171.1008, found 171.1004; νmax (KBr) 3205, 3083,
1735 and 1694 cmϪ1; δH (DMSO-d6) 10.14 and 8.67 (2H, s, NH),
5.55 (1H, d, J = 6.0 Hz, N(1)H), 2.88 (1H, d, J = 6.0 Hz, C(6)H)
and 1.00 (9H, s, C–CH3); δC (DMSO-d6) 171.7, 154.0, 64.3, 33.5
and 27.5.
3a: Mp 210–212 ЊC (Found C, 49.14; H, 7.80; N, 24.69.
C7H13N3O2 requires C, 49.11; H, 7.65; N, 24.55%); MS (EI)
m/z 171 (12) [M]ϩ, 115 (23) and 57 (100); MS (FAB) m/z 172
[M ϩ 1]ϩ; HRMS: calculated for C7H13N3O2 171.1008, found
171.1012; νmax (KBr) 3257, 3183, 3052, 1725 and 1695 cmϪ1
;
δH (DMSO-d6) 10.35 and 9.06 (2H, s, NH), 3.60 (2H, s, C(6)H2)
and 1.03 (9H, s, C–CH3); δC (DMSO-d6) 171.0, 153.1, 59.1, 48.4
and 26.0.
Reaction of 1 with n-butyllithium. The crude yellow oil was
separated by column chromatography on silica gel using
CH2Cl2 as eluent and then CH2Cl2 : CH3OH 25 : 1 v/v to yield
compound 2b (244 mg, 16%), compound 4b (120 mg, 8%) and
compound 3b (23% based on the ratios from 1H-NMR spectra).
Unfortunately compound 3b undergoes slow decomposition on
silica gel. We were not able to obtain absolutely pure compound
3b for the melting point and HRMS determinations even after
fine work-up and separation using preparative TLC plates.
2b: Mp 212–215 ЊC (Found C, 49.04; H, 7.93; N, 24.78.
C7H13N3O2 requires C, 49.11; H, 7.65; N, 24.55%); MS (EI)
m/z: 171 (42) [M]ϩ, 114 (77), 86 (100) and 71 (32); HRMS: cal-
culated for C7H13N3O2 171.1008, found 171.1000; δH (DMSO-
d6) 10.14 and 8.72 (2H, s, NH), 5.44 (1H, d, J = 8.24 Hz,
N(1)H), 3.18 (1H, m, C(6)H), 1.39 (2H, m, C(6)–CH2–), 1.30
(4H, m, C(6)–C–CH2CH2–) and 0.86 (3H, t, J = 7.1 Hz, C(6)–
C–C–C–CH3); δC (DMSO-d6) 13.9, 21.9, 26.9, 27.7, 57.0, 154.0
and 173.0.
3b: δH (DMSO-d6) 10.41 and 9.27 (2H, s, NH), 3.56 (2H, s,
C(6)H2), 2.63 (2H, t, J = 7.1 Hz, N(1)–CH2–), 1.2–1.4 (4H, m,
N(1)–C–CH2CH2–) and 0.88 (3H, m, N(1)–C–C–C–CH3).
4b: MS (EI) m/z: 169(26) [M]ϩ, 149 (51), 127 (100), 112 (9), 83
(21) and 56 (24); HRMS: calculated for C7H11N3O2 169.0851,
found 169.0861; δH (DMSO-d6) 12.03 and 11.85 (2H, s, NH),
2.43 (2H, t, J = 7.7 Hz, C(6)–CH2–), 1.30 and 1.49 (4H, m,
C(6)–C–CH2–CH2–) and 0.88 (3H, t, J = 7.4 Hz, C(6)–C–C–C–
CH3); δC (DMSO-d6) 13.8, 21.8, 28.0, 28.8, 145.2, 149.4 and
157.1.
X-Ray crystallography
Experimental and crystal data are listed in Table 1. Data for 5
and 7a were measured on a KUMA KM4-CCD diffractometer.
The crystal of 5 was investigated at 90 K, mainly to optimize
the measurement conditions for the small sample. The structure
was solved by direct methods, and all the hydrogen atoms were
located from difference Fourier maps and refined by isotropic
temperature factors. The angle between the molecular rings is
19.6(3)Њ. The molecules are linked by a pair of NH–O hydrogen
bonds into dimers. The hydrogen-bond dimensions are: H(2)–
O(3i) 1.78(2) Å, N(2) ؒ ؒ ؒ O(3i) 2.787(2) Å, N(2)–H(2)–O(3i)
176(1)Њ, symmetry code (i) Ϫx, y, 0.5 Ϫ z. In 7a the structure
was solved by direct methods, the hydrogen at C(6) was located
from a difference Forurier map and refined by an isotropic
thermal parameter; the methyl hydrogens were calculated from
the molecular geometry and allowed to rotate as rigid groups
about the C–C or C–S pivoting bonds. Full data have been
deposited at the Cambridge Crystallographic Data Centre.†
General procedure for reactions of 3,5-bis(trimethylsilyloxy)-
1,2,4-triazine 1 with butyllithiums
3,5-Bis(trimethylsilyloxy)-1,2,4-triazine (2.3 g, 8.9 mmol) was
dissolved in dry, THF (80 ml) and cooled to Ϫ100 ЊC under an
argon atmosphere, using a N2/hexane bath. A solution of butyl-
lithium (2.1 mol equivalent) was injected through a septum at
such a rate that the internal temperature did not exceed Ϫ90 ЊC.
The temperature was decreased to Ϫ100 ЊC, the reaction
mixture kept at this temperature for 30 minutes and then it was
allowed to warm to room temperature over a period of 3 h.
The solution was evaporated to dryness under reduced pressure
and then water was added (40 ml). The aqueous solution was
acidified with 1 M HCl to pH 2–3. The solution was exhaust-
ively extracted with a mixture of CHCl3 : MeOH 4 : 1 v/v and
the combined extracts were dried over MgSO4. The solvents
were removed and the mixture of crude products was separated
by column chromatography.
Reaction of 3,5-bis(trimethylsilyloxy)-1,2,4-triazine 1 with
phenyllithium at ؊100 ؇C. 3,5-Bis(trimethylsilyloxy)-1,2,4-tri-
azine (950 mg, 3.7 mmol) was dissolved in dry, freshly distilled
THF (40 ml) and cooled to Ϫ100 ЊC under an argon atmos-
phere, using a N2/hexane bath. A solution of phenyllithium
(1.8 M solution, 6.2 ml, 11.1 mmol) was injected through a
septum at such a rate that the internal temperature did not
exceed Ϫ80 ЊC. The temperature was decreased to Ϫ100 ЊC and
triethyl borate (1.9 ml, 11.1 mmol) was added to the brownish
solution. The reaction mixture was kept at this temperature for
30 minutes and then was allowed to warm to room temperature
over a period of 3 h. The solution was evaporated to dryness
under reduced pressure and then water was added (40 ml). The
aqueous solution was acidified with 1 M HCl. The solution was
extracted with hexane to remove non-polar impurities and then
extracted with CHCl3 (3 × 30 ml). Combined CHCl3 fractions
were dried over MgSO4, the solvent was evaporated and the
crude product obtained was crystallized from EtOH giving
compound 5 (6.4 mg, 1%). After 24 hours a white precipitate
appeared which was filtered off and dried. The obtained crude
adduct containing traces of 6-azauracil was crystallized from a
mixture of AcOEt with small amount of EtOH giving pure
compound 2c (127mg, 18%)
Reactions at Ϫ20 ЊC were carried out using the same pro-
cedure described above except for the temperature conditions.
Regioselectivity ratios for both the low and high temperature
reactions were obtained on the basis of 1H NMR spectra of the
crude products.
Reaction of 1 with tert-butyllithium1. The crude solid mixture
was separated by column chromatography on silica gel with
CH2Cl2 and then with CH2Cl2 : CH3OH 25 : 1 v/v to yield
compound 3a (556 mg, 36%) and compound 2a (124 mg, 8%) as
white crystals.
2a: Mp 222–225 ЊC (Found C, 49.33; H, 7.79; N, 24.81.
C7H13N3O2 requires C, 49.11; H, 7.65; N, 24.55%); MS (EI)
† CCDC reference numbers 181717 (5) and 181716 (7a). See http://
www.rsc.org/suppdata/p1/b2/b205058g/ for crystallographic files in .cif
or other electronic format.
We did not recover residues of 6-azauracil remaining in the
aqueous solution.
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Reaction of 3,5-bis(trimethylsilyloxy)-1,2,4-triazine 1 with
phenyllithium at ؊20 ؇C. Reactions at Ϫ20 ЊC were carried out
using the same procedure described above except for tempera-
ture and the extractive work-up. The aqueous acidic solution
was extracted with hexane to remove non-polar impurities and
then exhaustively extracted with a mixture of CHCl3 : MeOH
4 : 1 v/v. Combined extracts were dried over MgSO4. The
solvent were removed and the mixture of crude products was
separated by column chromatography with CH2Cl2 and then
with CH2Cl2 : CH3OH 25 : 1 v/v to yield compound 5 (198 mg,
31%) and compound 2c (56 mg, 8%). Compound 5 for X-ray
studies was crystallized from H2O.
2c: Mp 240–242 ЊC (Found C, 56.46; H, 4.74; N, 21.74.
C9H9N3O2 requires C, 56.54; H, 4.74; N, 21.98%); MS (EI)
m/z: 191 (3) [M]ϩ, 162 (1), 120 (2), 113 (55), 104 (10), 70 (22) and
42 (100); HRMS: calculated for C9H9O2N3 191.0695, found
191.0703; δH (DMSO-d6) 10.46 and 8.89 (2H, s, NH), 7.39
(5H, m, Ph), 6.13 (1H, d, J = 5.8 Hz, N(1)H) and 4.54 (1H, d,
J = 5.5 Hz, C(6)H), (DMSO-d6 ϩ D2O) 7.39 (5H, m, Ph) and
4.55 (1H, s, C(6)H); δC (DMSO-d6) 60.1, 128.17, 128.24, 128. 57,
129. 60, 153. 9 and 171.5.
5: Mp 133–135 ЊC (Found C, 62.17; H, 4.04; N, 24.00.
C9H7N3O requires C, 62.42; H, 4.07; N, 24.26%); MS (EI)
m/z: 173 (100) [M]ϩ, 145 (1.6), 131 (2.5), 102 (84), 89 (20) and
77 (10); HRMS: calculated for C9H7N3O2 189.0538, found
189.0531; δH (DMSO-d6) 13.36 (1H, s, NH), 8.74 (1H, s,
C(6)H), 8.22 (2H, m, Ph) and 7.65 (3H, m, Ph), (DMSO-d6 ϩ
D2O) 8.72 (1H, s, C(6)H), 8.21 (2H, m, Ph) and 7.69 (3H, m,
Ph); δC (DMSO-d6) 128.4, 129.3, 131.2, 133.274, 133.293, 154.1
and 164.5.
m/z: 199 (22) [M]ϩ, 143 (54), 115 (11), 57 (100) and 41 (62);
δH (DMSO-d6) 8.11 (1H, s, C(6)H), 2.42 (3H, s, S–CH3) and
1.58 (9H, s, N(1)–tert-Bu); δC (DMSO-d6) 174.3, 163.9, 133.6,
71.2, 27.5 and 12.7.
Reaction of 6 with n-butyllithium
The product was isolated by column chromatography on silica
gel with CHCl3 : CH3OH 1 : 0–25 : 1 v/v to yield compound 7b
(83 mg, 16%) as a colorless oil.
7b: MS (EI) m/z: 199 (3) [M]ϩ, 167 (43), 148 (100), 115 (3) and
57 (39); HRMS calculated for C8H13N3OS: 199.07793, found
199.07631; δH (DMSO-d6) 7.60 (1H, s, C(6)H), 4.13 (2H, t,
Ϫ
J = 7.2 Hz, N(1)–CH2 ), 2.51 (3H, s, S–CH3), 1.98 and 1.38
Ϫ
(4H, m, N(1)–C–CH2CH2 ) and 0.99 (3H, t, J = 7.3 Hz, N(1)–
C–C–C–CH3); δC (CDCl3) 13.5, 13.8, 14.2, 27.7, 69.8, 133.0,
153.5 and 163.9.
Reaction of 6 with phenyllithium
The residue was purified by column chromatography on silica
gel with hexane : CHCl3 1 : 0–0 : 1 and then CHCl3 : CH3OH
25 : 1 v/v to yield an oily compound 8 (85 mg, 14%) which
solidified after a longer period of time.
8: (Found C, 56.47; H, 5.02; N, 17.72. C11H11N3OS requires
C, 56.63; H, 4.75; N, 18.01%); MS (EI) m/z: 233 (100) [M]ϩ,
218 (10), 190 (2), 148 (5), 132 (76), 117 (36) and 89 (64);
(FAB) m/z: 234 [Mϩ ϩ 1]; HRMS: calculated for C11H11ON3S
233.0623, found 233.0620; δH (DMSO-d6) 8.01(2H, m, Ph),
7.48(3H, m, Ph), 4.10 (3H, s, O–CH3) and 2.71 (3H, s, S–CH3);
δC (CDCl3) 14.1, 54.6, 128.3, 128.8, 130.0, 132.2, 146.2, 159.5
and 170.0.
General procedure for reactions of 3-methylthio-5-methoxy-
1,2,4-triazine 6 with butyllithiums and phenyllithium
References
Compound 6 (400mg, 2.6 mmol) was dissolved in dry, freshly
distilled THF (30 ml) and cooled to Ϫ100 ЊC under an argon
atmosphere. A solution of alkyllithium (7.8 mmol) was injected
through a septum at such a rate that the internal temperature
did not exceed Ϫ90 ЊC. The temperature was decreased to
Ϫ100 ЊC and triethyl borate (1.33 ml, 7.8 mmol) was injected.
The reaction mixture was kept at this temperature for an
additional 30 minutes and then was slowly allowed to warm to
room temperature. The solution was evaporated to dryness
under reduced pressure and water was added (30 ml) and the
aqueous solution was acidified with 1 M HCl. The solution was
extracted with CHCl3 (3 × 20 ml), the combined organic layer
was dried over Na2SO4 and solvent was evaporated to dryness
giving an oily residue. The crude products were purified by
column chromatography.
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Reaction of 6 with tert-butyllithium
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The crude mixture was separated by column chromatography
on silica gel with hexane : CHCl3 1 : 0–0 : 1 v/v. Crystallization
from AcOEt yielded compound 7a (124 mg, 24%) as pale yellow
crystals.
7a: Mp 232–233 ЊC (Found C, 48.41; H, 6.52; N, 21.06.
C8H13N3OS requires C, 48.22; H, 6.57; N, 21.09%); MS (EI)
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J. Chem. Soc., Perkin Trans. 1, 2002, 2549–2553
2553