Direct diastereoselective introduction of l-menthol residue into 1,2,4-triazin-5(4H)-one

Article abstract of DOI:10.1023/B:RUCB.0000042288.91508.68

The reaction of 3-phenyl-1,2,4-triazin-5(4H)-one (1) with l-menthol in the presence of aliphatic acid anhydrides results in (6S)- and (6R)-1-acyl-6-(l- menth-3-yl)-1,6-dyhydro-3-phenyl-1,2,4-triazin-5(4H)-ones. The reaction is diastereoselective with predominant formation of (6S)-isomers. The reaction diastereoselectivity increases with enhancement of the steric hindrance in the vicinity of the reaction center of the azine.

Full text of DOI:10.1023/B:RUCB.0000042288.91508.68

1290
Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1290—1294, June, 2004
Direct diastereoselective introduction of lꢀmenthol residue
into 1,2,4ꢀtriazinꢀ5(4H )ꢀone
G. V. Zyryanov,a V. L. Rusinov,a O. N. Chupakhin,a,b V. P. Krasnov,b
ꢀ
G. L. Levit,b M. I. Kodess,b and T. S. Shtukinaa
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: (343 3)74 0458. Eꢀmail: rusinov@htf.ustu.ru
bI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: (343 3)74 1189. Eꢀmail: ca@ios.uran.ru
The reaction of 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone (1) with lꢀmenthol in the presence of
aliphatic acid anhydrides results in (6S)ꢀ and (6R)ꢀ1ꢀacylꢀ6ꢀ(lꢀmenhtꢀ3ꢀyl)ꢀ1,6ꢀdyhydroꢀ3ꢀ
phenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀones. The reaction is diastereoselective with predominant formaꢀ
tion of (6S)ꢀisomers. The reaction diastereoselectivity increases with enhancement of the steric
hindrance in the vicinity of the reaction center of the azine.
Key words: 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone, lꢀmenthol, diastereoselectivity, acetic anꢀ
hydride, isobutyric anhydride, 1ꢀacylꢀ6ꢀ(lꢀmenthꢀ3ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdyhydroꢀ1,2,4ꢀ
triazinꢀ5(4H )ꢀones, nucleophilic addition.
In the series of πꢀdeficient (hetero)aromatic comꢀ
An example of transformation in which the product
stereochemistry is determined by participation of an optiꢀ
cally active acylating agent is provided by Sꢀprolineꢀcataꢀ
lyzed asymmetric addition of aliphatic ketones to 9ꢀtosylꢀ
3,4ꢀdihydrocarboline, resulting in the corresponding
Cꢀadducts with high degrees of optical purity.12
The stereoselective formation of a new asymmetric
center in the achiral azine substrate upon the attack by an
optically active nucleophile is represented by only few
examples. For example, in the presence of silver triflate or
chlorate, chiral allylsilanes add enantioselectively to actiꢀ
vated Nꢀacylquinolinium ions obtained from the correꢀ
sponding achiral quinolines and isoquinolines.13,14 The
stereoselective introduction of the lꢀmenthol residue into
substituted azoles has been reported.15 We have briefly
described the reaction of lꢀmenthol with 1,2,4ꢀtriazinꢀ
5(4H )ꢀone.16
pounds, nucleophilic substitution reactions of hydrogen
(SNH) cover an extensive group of twoꢀstep processes
whose common feature is the formation of nucleophilic
addition products (σHꢀadducts) in the first step.1
After the formation of these adducts, the prochiral
carbon atom in the azine ring acquires sp3ꢀhybridization
and becomes asymmetrical. Thus, in most cases, σHꢀadꢀ
ducts exist as mixtures of Rꢀ and Sꢀenantiomers which are
usually difficult to identify by conventional physicochemiꢀ
cal methods.2 In the presence of two or more asymmetric
carbon atoms in the substrate and/or nucleophile,
σHꢀadducts are produced as diastereomers. Moreover, the
asymmetric carbon atom introduced in the substrate molꢀ
ecule either directly or indirectly (for example, by in situ
acylation) is expected to determine the stereochemistry of
the addition product, i.e., to induce the stereoselective
formation of a new asymmetric center upon the attack of
an achiral nucleophile. In the ideal case, this may result
in the predominance of only one stereoisomer in the
nucleophilic addition product. Thus Lewis acidꢀ or
copper(I)ꢀcatalyzed addition of Grignard reagents or
allylsilanes to homochiral Nꢀacylium salts of pyridinꢀ4ꢀ
ones, prepared in situ on treatment with optically active
chloroformates, has been reported.3—8 In these transforꢀ
mations, the introduction of optically active fragments
into acyl groups allows one to attain a high degree of
asymmetric induction (de 88—98%), and the correspondꢀ
ing substituted pyridones are formed in high yields.9—11
This communication describes a detailed study of the
influence of the nature of acylating agents, namely, carꢀ
boxylic acid anhydrides, on the stereochemistry of the
products of lꢀmenthol addition to 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ
5(4H )ꢀone.
Results and Discussion
It was found that the reaction of 1,2,4ꢀtriazinone 1
with lꢀmenthol carried out in acetic anhydride for 6—12 h
at room temperature proceeds diastereoselectively, reꢀ
sulting in the predominant formation of (6S)ꢀ1ꢀacetylꢀ6ꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1238—1242, June, 2004.
1066ꢀ5285/04/5306ꢀ1290 © 2004 Plenum Publishing Corporation

Diastereoselective introduction of lꢀmenthol residue Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1291
Scheme 1
R = Me (2a,b), Pri (3a,b)
([1´R,3´R,4´S]ꢀmenthꢀ3ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ
1,2,4ꢀtriazinꢀ5(4H )ꢀone (2a) (molar ratio 2a : 2b =
60 : 40) (Scheme 1).
Diastereomers 2a,b were identified in the mixture
based on 1H NMR data (Table 1). In particular, the C(6)H
protons in products 2a and 2b are responsible for singlets
at δ 5.99 and 5.90, respectively. The C(3´)H protons of
the menthol fragment are manifested at δ 3.28—3.38 and
3.42—3.52 as resolved multiplets with an overall intensity
corresponding to one proton.
The chromatographic behaviors of diastereomers 2a
and 2b are different, which is favorable for their separaꢀ
tion. The stereoisomer 2a formed predominantly was sepaꢀ
rated by flash chromatography (de 94% based on HPLC
data). The absolute configuration of diastereomer 2a, in
particular, the mutual arrangement of the hydrogen atom
Table 1. Spectral characteristics of products 2a,b and 3a,b (400 МHz, CDCl3)
Prodꢀ
uct
1H NMR, δ (J/Hz)
1,2,4ꢀTriazinone
COR
R
lꢀMenthol
NH
C(6)H
C(2´)HAHB
0.95, 2.37
C(3´)H
C(4´)H
C(7´)H3 C(8´)H
C(9´)H3 C(10´)H3
2a 9.56
(s, 1 H)
6.34
(s, 1 H)
2.46 (s,
3 H, Me)
3.51
1.15
0.94
1.88
0.75
0.65
(both m, 1 H (td, 1 H,
(m, 1 H) (d, 3 H,
(sept.d,
J = 7.0,
J = 2.5)
2.11
(d, 3 H,
J = 7.1)
(d, 3 H,
J = 6.9)
each, СHA,
СHВ)
0.89, 2.10
J = 10.6,
J = 4.3)
3.51
J = 6.6)
2b 9.48
(s, 1 H)
6.24
(d, 1 H,
J = 0.8)
2.47 (s,
3 H, Me)
1.19
0.90
0.84
0.80
(both m, 1 H (td, 1 H,
(m, 1 H) (d, 3 H,
(m, 1 H) (d, 3 H,
(d, 3 H,
J = 6.9)
each, СHA,
СHВ)
1.18, 1.28 (both 0.92, 2.41
J = 10.6,
J = 4.3)
3.54
J = 6.5)
J = 7.1)
3a 9.51
(s, 1 H)
6.32
(d, 1 H,
J = 0.8)
1.12
0.96
1.88
(sept.d,
1 H,
J = 7.0,
J = 2.5)
2.15
0.75
0.63
d, 3 H each, Me, (both m, 1 H (td, 1 H,
(m, 1 H) (d, 3 H,
(d, 3 H,
J = 7.1)
(d, 3 H,
J = 6.9)
J = 6.9); 3.63
(m, 1 H, CH)
each, СHA,
СHВ)
J = 10.5,
J = 4.2)
J = 6.6)
3b 9.45
(s, 1 H)
6.26
(d, 1 H,
J = 0.8)
1.20, 1.29 (both 0.84, 2.02
≈3.62 a
1.15
0.87
0.85
0.84
d, 3 H each, Me, (both m, 1 H
(m, 1 H) (d, 3 H,
(m, 1 H) (d, 3 H,
(d, 3 H,
J = 6.9)
J = 6.9); 3.63
(m, 1 H, CH)
each, СHA,
СHВ)
J = 6.6)
J = 7.1)
a The signals are superimposed by the signals of the predominant isomer.

1292
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Zyryanov et al.
Table 2. Energy characteristics of (6S)ꢀ1ꢀacetylꢀ6ꢀ
([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀ
Table 4. Transformation of diastereomers 2a,b in a CDCl3 soluꢀ
tion in the presence of TFA (according to H NMR data)
1
triazinꢀ5(4H )ꢀones
(2a)
and
(6R)ꢀ1ꢀacetylꢀ6ꢀ
([1´R,3´R,4´S]menthꢀ3ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀ
triazinꢀ5(4H )ꢀones (2b)
τ/min
Contents of stereoꢀ
isomers (mol %)
Molar ratio
2a : 2b
2a
2b
Prodꢀ Etors
Etotal
∆Hf
EHOMO ELUMO
∆E*
uct
kcal mol–1
eV
0
50
47
42
44
39
37
35
33
34
26
29
23
22
15
19
14
13
07
03
2.5
50
53
51
54
55
53
53
52
53
47
48
45
44
39
41
35
33
27
21
18
1.00
0.88
0.82
0.81
0.71
0.69
0.66
0.63
0.64
0.55
0.60
0.51
0.50
0.38
0.46
0.40
0.39
0.25
0.14
0.13
12
18
20
22
24
26
28
30
32
34
36
38
40
50
60
70
80
105
165
2a
7.173 –99242.3 –85.244 –9.063 –0.739 8.324
2b 49.212 –99237.5 –72.893 –9.118 –0.296 8.822
* ∆E = ELUMO – EHOMO
.
Table 3. Transformation of diastereomers 2a,b in a DMSOꢀd6
solution at 140 °C (according to H NMR data)
1
τ/min
Contents of stereoꢀ
isomers (mol %)
Molar ratio
2a : 2b
2a
2b
0
50
40
35
30
27
25
50
30
25
20
18
17
1.00
0.75
0.71
0.66
0.66
0.68
12
15
20
25
35
and the menthol fragment at the sp3ꢀhybridized C(6) atom
and the position of the acetyl group were determined by
Xꢀray diffraction taking into account the known absolute
configuration of lꢀmenthol.16
The asymmetric course of this synthesis is directly
related to the fact that diastereomers 2a,b possess differꢀ
ent energies and, therefore, they are produced at different
rates. The energy, the charge, and orbital characteristics
of products 2a,b were calculated using the semiempirical
quantumꢀchemical PM3 method (Table 2). The calculaꢀ
tions confirm that the predominant formation of diastereoꢀ
mer 2a is due to its higher thermodynamic stability. As a
consequence, this isomer has a lower torsion energy (Etors),
total energy (Etotal), and heat of formation (∆Hf).
stereomers 2a and 2b in DMSOꢀd6 carried out in a
NMR tube (Table 3). The thermal dissociation of isomer
2a is less intensive, which may be due to the partial forꢀ
mation of this compound from thermodynamically less
stable 2b.
The calculated LUMO and HOMO energies for the
obtained diastereomers indicate that the electron transiꢀ
tions should be substantially easier in the molecule of 2a,
suggesting a higher reactivity for this isomer. The 1H NMR
monitoring of the hydrolysis of an equimolar mixture of
stereoisomers 2a,b (1% concentration) in CDCl3 in the
presence of a catalytic amount of TFA at room temperaꢀ
ture (Scheme 2) shows that dissociation of (3´R,6S)ꢀsteꢀ
reoisomer 2a into the starting compounds proceeds faster
than that of 2b (Table 4). The difference between the
dissociation rates of compounds 2a,b should be deterꢀ
This is supported by the data obtained by NMR moniꢀ
toring of thermolysis of an equimolar mixture of diaꢀ
Scheme 2

Diastereoselective introduction of lꢀmenthol residue Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1293
mined by the stability of the protonated species 2a* and
2b* they form.
Due to the higher steric accessibility of the oxygen
atom, protonated form 2a* is formed more easily, but its
subsequent heterolytic dissociation into the starting comꢀ
pounds also proceeds faster. In turn, the formation of the
less reactive protonated form 2b*, which is a secondary
process, accounts for the lower rate of decomposition of
2b in acid media.
In view of the spatial structure of products 2a,b, we
suggested that the enhancement of steric crowding near
the reaction center should have a pronounced effect on
the process stereoselectivity.
Indeed, the reaction of 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀ
one (1) with lꢀmenthol in the presence of isobutyric anꢀ
hydride at room temperature results in the predominant
formation of (6S)ꢀ1ꢀisobutyrylꢀ6ꢀ([1´R,3´R,4´S]ꢀmenthꢀ
3ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone
(3a) (Table 5), which was also isolated in the enantiopure
state (de 94% based on HPLC data).
The diagnostic parameters that would allow one to
identify products 3a,b as either (3´R,6S)ꢀ or (3´R,6R)ꢀdiaꢀ
Fig. 1. Newman projections for the transition state of lꢀmenthol
addition to Nꢀacylium salts of 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀ
one (1): I is synclinal structure (preferred), II is antiperiplanar
structure (less favorable).
stereomers, by analogy with compounds 2a,b, are proꢀ
1
vided by H NMR spectroscopy (see Table 1). Indeed,
1
the H NMR signals for the C(6)H protons of diastereoꢀ
mers 3a and 3b occur at δ 5.92 and 5.87, respectively.
Similarly, the C(3´)H protons of the menthol fragment
are responsible for signals at δ 3.25—3.38 and 3.42—3.55.
Thus, the steric pathways of the reactions proved to be
qualitatively similar; in both cases, (3´R,6S)ꢀdiastereomers
predominated and the reaction diastereoselectivity inꢀ
creased when sterically more crowded acylating reagent
was used.
Analysis of the results obtained leads to the concluꢀ
sion that the stereochemistry of the reaction between
3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone and lꢀmenthol is deꢀ
termined in the step of formation of the Nꢀacylium salt 1*,
which is postulated for these reactions. Subsequently, this
salt is attacked by the chiral nucleophile. Probably, the
axial nucleophilic attack of the azine ring, which is preꢀ
ferred from the stereoelectronic standpoint, results in a
synclinal transition state I, which precedes the formation
of thermodynamically more stable adducts 2a and 3a with
the Sꢀconfiguration of the C(6) atom in the azine ring.
Meanwhile, the structure of the antiperiplanar type tranꢀ
sition state II, resulting from the equatiorial nucleophilic
attack, corresponds to less stable (3´R,6R)ꢀadducts 2b
and 3b (Fig. 1).
Thus, in the 1,2,4ꢀtriazine series, we first demonstrated
the possibility of diastereoselective introduction of a chiral
Oꢀnucleophile, lꢀmenthol, into an achiral azine substrate.
It was shown that process diastereoselectivity can be inꢀ
creased by enhancing steric hindrance in the vicinity of
the azine reaction center.
Experimental
Table 5. Ratio of (6S)ꢀ1ꢀacylꢀ6ꢀ([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀ
yloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀones 2a, 3a
and (6R)ꢀ1ꢀacylꢀ6ꢀ([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ
1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀones 2b, 3b in the reaction
1
H NMR spectra were recorded on Bruker DRXꢀ400
(400 MHz) and Bruker WMꢀ250 (250 MHz) spectrometers in
DMSOꢀd6 or CDCl3 with Me4Si as the internal standard. Mass
spectra were run on a Varian MATꢀ311A instrument.
1
mixture (according to H NMR data)
HPLC was carried out on a Milikhrom 4ꢀUV chromatoꢀ
graph using a 64×2 mm column, Silasorbꢀ60 as the sorbent,
detection at 230 nm, an eluent velocity of 200 µL min–1, and a
80 : 1 hexane—PriOH solvent mixture as the mobile phase.
Column chromatography was performed in the flash chromaꢀ
tography mode on a dry column with the Silpearl silica gel
(Kavalier). TLC was carried out on Silufol UV plates (Kavalier)
in a benzene—AcOEt solvent system (8 : 2). The melting points
were measured on a Boetius hot stage and were not corrected.
Comꢀ
pound
Acyl
Ratio of stereoꢀ
isomers (mol %)
de (%)*
(3´R,6S)
(3´R,6R)
2
3
Ac
PriCO
60
40
20
70
85
15
* Diastereomeric yield of (3´R,6S)ꢀisomer 2a or 3a.

1294
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Zyryanov et al.
(6R,S)ꢀ1ꢀAcylꢀ6ꢀ([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ3ꢀpheꢀ
nylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀones (2a,b, 3a,b). 3ꢀPheꢀ
nylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone (1) (1 mmol) and lꢀmenthol
(1.2 mmol) in 3 mL of the corresponding anhydride was kept
for 6—24 h. The mixture was concentrated in vacuo to dryness.
The residue was triturated in ether or benzene, filtered off, and
crystallized from methanol.
(6S)ꢀ1ꢀAcylꢀ6ꢀ([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ
1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀones (2a, 3a). A mixture of
3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone (1) (1 mmol) and lꢀmenthol
(1.2 mmol) in 3 mL of the corresponding anhydride was kept for
6—24 h and concentrated in vacuo to dryness. The residue was
dissolved in chloroform and subjected to flash chromatography
(AcOEt—benzene, 99 : 1 to 85 : 15), the fraction with Rf = 0.62
being collected. The solvent was evaporated in vacuo and the
precipitate was recrystallized from methanol.
The authors are grateful to V. A. Potemkin
(Chelyabinsk State University) for performing quantumꢀ
chemical calculations.
This work was financially supported by the Russian
Foudation for Basic Research (Project No. 02ꢀ03ꢀ32627),
the American Civil Research and Development Foundaꢀ
tion (CRDF, grant EКꢀ005ꢀХ1), and President of the
Russian Federation (the State Program for the Support of
Leading Scientific Schools, grant NSh 1766.2003.3).
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Hydrolysis of an equimolar mixture of (6R)ꢀ1ꢀacetylꢀ6ꢀ
([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀ
triazinꢀ5(4H )ꢀone (2a) and (6S)ꢀ1ꢀacetylꢀ6ꢀ([1´R,3´R,4´S]ꢀ
menthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone
(2b). An equimolar mixture of (6R)ꢀ1ꢀacetylꢀ6ꢀ([1´R,3´R,4´S]ꢀ
menthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀ
one (2a) and (6S)ꢀ1ꢀacetylꢀ6ꢀ([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ
3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀone (2b) (0.01 g,
0.027 mmol) were placed in an NMR tube containing 1 mL of
CDCl3, and 0.002 mL of TFA was added. The measurements
were started 12 min after the addition of TFA and finished after
165 min. The molar content and the molar ratio of the isomers
were determined by comparing the integral intensities of the
signal of the menthol C(3´)H atom and the residual signal of
chloroformꢀd1.
Thermolysis of an equimolar mixture of diastereomers 2a
and 2b. An equimolar mixture of (6R)ꢀ1ꢀacetylꢀ6ꢀ
([1´R,3´R,4´S]ꢀmenthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀ
triazinꢀ5(4H )ꢀone (2a) and (6S)ꢀ1ꢀacetylꢀ6ꢀ([1´R,3´R,4´S]ꢀ
menthꢀ3´ꢀyloxy)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H )ꢀ
one (2b) (0.01 g, 0.027 mmol) were placed in an NMR tube
containing 1 mL of DMSOꢀd6 and the mixture was heated to
140 °C. The measurements were started 12 min after the temꢀ
perature was 140 °C and finished 35 min later. The molar conꢀ
tent and the molar ratio of the isomers were determined by
comparing the integral intensities of the signal of the menthol
C(3´)H protons and the residual signal of DMSOꢀd6.
Received December 29, 2003