Tautomerism of β-dicarbonyl and β,β'-tricarbonyl compounds in protogenic media: The prototropy of hydroxonium derivatives of keto-enols

Full text of DOI:10.1134/S0012500807070014

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ISSN 0012-5008, Doklady Chemistry, 2007, Vol. 415, Part 1, pp. 155–160. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © O.V. Gulyakevich, A.L. Mikhal’chuk, 2007, published in Doklady Akademii Nauk, 2007, Vol. 415, No. 1, pp. 55–60.
CHEMISTRY
Tautomerism of b-Dicarbonyl and b,b'-Tricarbonyl Compounds
in Protogenic Media: The Prototropy
of Hydroxonium Derivatives of Keto–Enols
O. V. Gulyakevich and A. L. Mikhal’chuk
Presented by Academician Yu.D. Tret’yakov March 9, 2007
Received March 9, 2007
DOI: 10.1134/S0012500807070014
The tautomerism of β-dicarbonyl and β,β'-tricarbonyl and β,β'-tricarbonyl fragments in the presence of strong
compounds (β-diCCs and β,β'-triCCs, respectively) has organic (CF3COOD) and mineral (D2SO4, HCl) acids [8].
been known for over a century [1, 2]. Nonetheless, many
aspects of this phenomenon remain to be studied and dis-
cussed at present. The discovery of keto–enol tautomerism
of β-diCC and β,β'-triCC anions [3] made it possible to
gain insight into the properties of this important and large
class of organic compounds widespread in nature and often
used in the laboratory and industry [4, 5], but did not solve
problems arising during studies in this area. These prob-
lems are exemplified by the annelation of 3,4-dihydroiso-
quinolines with 2-chloroacetylcyclohexane-1,3-diones or
3-acetyltetronic, -tetramic, and 3-acylthiotetronic acids,
which takes place only under strong acid catalysis condi-
It should be noted that the tautomerism of β-diCCs and
β,β'-triCCs in protogenic media, in contrast to their tau-
tomerism in amphiprotic and polar aprotic media, was not
considered previously because it was believed to be identi-
cal to the acid-catalyzed tautomerism of carbonyl com-
pounds and, therefore, was explained on the same basis.
This is due to the erroneous notion that acid-catalyzed pro-
totropic reactions of carbonyl compounds, β-diCCs, and
β,β'-triCCs in a protogenic medium are also identical.
The existing concept on the tautomerism of β-diCCs
and β,β'-triCCs in amphiprotic (HS:) and polar aprotic
tions [6, 7], or the H/D exchange of the protons of methyl, (S:) media, considered in [3], is shown in the most gen-
methylene, and methyne groups adjacent to β-dicarbonyl eral form in Scheme 1.
+
+HO HO
+HO
Z
O
HO
O
X
OH OH+
R
R
R
R
H
X
Z
Z
Z
–SH
+X
+X
keexo
kk+
keendo
TS
[HSH + HS:
HS– + HS:H+]
O
O
OH
O
O
OH
X
O
O
X
α
R
α
R
α
R
R
HS:
HS:
HS:
Z
Z
Z
Z
HS:H+
X
X
a7
kk
keendo
keexo
S:H+ S:
O
O
O
OH
HO
O
X
–
–
–
γ
R
R
R
β
α'
S:H+/∆
S:H+
α
Z
Z
Z
β'
a3
X
X
eaexo
γ'
eaendo
Scheme 1.
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Zhodinskaya 5/2, Minsk, 220045 Belarus
155

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156
GULYAKEVICH, MIKHAL’CHUK
Equilibria {[kk
keendo
keexo]
a7} gen-
acids [6, 7, 9–12]. Hence, experimental data [8–12]
indicate the existence of prototropic processes of spe-
cific β-diCCs and β,β'-triCCs in protogenic media. To
elucidate this issue, we have studied the prototropy and
condensations of β-diCCs and β,β'-triCCs under acid
catalysis conditions and in protogenic media.
eralize the ionization and prototropy processes of the
α-methyne or α-enol proton of β-diCCs (X = H2) and
β,β'-triCCs (X = O) existing in amphiprotic media.
β-DiCCs and β,β'-triCCs are acids and, therefore, their
prototropy (keto–enol tautomerism) is an autocatalytic
process. The use of acid catalysis (HSH is a mineral or
organic H-acid) in an amphiprotic medium (HS:) leads
to the production of conjugate acids (HS:H+) and bases
The study of H/D exchange in 2-acetyldimedone in
a
deuterotropic medium using acid catalysis
(CDCl3/D2O : D2SO4 catalyst, 20–50°C) has shown
(HS–): {HS: + HSH
HS– + HS:H+}, accelerating
(1H NMR) that, under these conditions, as in the
absence of acid catalysis, only the enol proton under-
goes H/D exchange (acetyldimedone is completely
general proton exchange in the reaction medium, and
favors the protonation of β-diCCs and β,β'-triCCs to
form hydroxonium intermediates kk+, kee+ndo , kee+xo
1
enolized, H NMR: δenol 19.1 ppm) and the integrated
and the solvolysis of the leaving protons, thus acceler-
ating the proton exchange and the establishment of
equilibrium between ketone kk and enol keendo and
keexo tautomers of β-diCCs and β,β'-triCCs, for exam-
intensities of the other resonance signals, e.g., of
methyl groups of the acetyl and dimedone fragments,
remain unchanged.
ple, through transition state TS. The production of a7
anions in this case is obviously suppressed and, hence,
the tautomeric transformations proceed without the dis-
sociation stage. It should be noted that the triad, e.g., a3,
rather than heptad a7 structure is thermodynamically
preferable for anions (Scheme 1) [3], which does not
rule out some, although very little, population of heptad
anions a7.
At the same time, the H/D exchange of 2-
acetyldimedone in
a
deuterogenic medium
(CDCl3/D2O : D2SO4 = 2 : 1, 20°C) showed that both
the enol proton and the protons of the methyl group of
the acetyl fragment underwent isotope exchange (1H
NMR: δenolH 19.1 ppm; δMe 2.62 ppm) to form [2,2',2',2'-
(n)2H]-labeled derivatives of 2-acetyldimedone.
[2',2',2'-(n)2H]-Labeled derivative AD(D/H)3 ([M+]
185–183) [3] was isolated in individual state from the
reaction mixture. At an H/D ratio of 8.25 : 1 in the reac-
tion medium and an H/D exchange coefficient of ~0.75,
the H/D exchange leads to the [2',2',2'-(3)2H] isoto-
pomer ADd3 (89%, C10H11D3O3, M 175.24, [M+] 185,
isotopic purity 70% from GC/MS). H/D exchange at
elevated temperatures (60–80°C, ampoule) also brings
about proton exchange at the C4- and C6-methylene
groups of the dimedone ring to give [4,4,6,6,2',2',2'-
(n)2H]-labeled derivatives AD(D/H)7 ([M+] 189–183).
A partial decomposition of acetyldimedone is observed
under these conditions (among other products, [4,4,6,6-
(n)2H]dimedone is formed, [M+] 160–157), which indi-
cates the lability of the latter compound under acidic
conditions at elevated temperatures. Nonetheless, we
Equilibria [a3
aeexo
aeendo] generalize the
prototropy of β-diCCs and β,β'-triCC anions or the pro-
totropy of hydrogen atoms of methyl (R = H), methyl-
ene (R = Me, Et, etc.), and methyne groups adjacent to
β-dicarbonyl (X = H2) and β,β'-tricarbonyl (X = O)
fragments (α', γ, and γ' protons). It is impossible to
induce the keto–enol tautomerism of β-diCC and
β,β'-triCC anions [a3
aeexo
aeendo] with the use
of acid catalysis since the presence of an acid prevents
the formation of a3–7 anions.
It is obvious that, within the framework of this con-
cept, it is impossible to explain the H/D exchange in the
positions adjacent to β-dicarbonyl and β,β'-tricarbonyl
fragments (α', γ, and γ') in protogenic media [8], as it is
impossible to explain the [2 + 4] cyclocondensations of
3,4-dihydroquinolines with 2-chloroacetylcyclohexane-
1,3-diones or 3-acetyltetronic, -tetramic, and -thiotetronic obtained the [4,4,6,6,2',2',2'-(7)2H] isotopomer of
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TAUTOMERISM OF β-DICARBONYL AND β,β'-TRICARBONYL COMPOUNDS
157
acetyldimedone ADd7 (70%, C10H7D7O3, M 189.27, purity 66% from GC/MS). The preparation of highly
2
[M+] 189, isotopic purity 65% from GC/MS) using this
method. The D/H exchange of the ADd7 derivative
(CDCl3/H2O : CF3COOH = 1 : 1, 20°C) leads to the
[4,4,6,6-(4)2H] isotopomer of acetyldimedone ADd4
(95%, C10H10D4O3, M 186.24, [M+] 186, isotopic
enriched H-isotopomers of acetyldimedone ADd3,
ADd4, and ADd7 (with an isotopic purity up to 90–
95%) was achieved by multiple repetition of H/D
exchange with fresh portions of D2O · DSD (DSD is a
mineral or organic deuterated acid).
OH
O
O
O
O
OH
O
O
O
O
C(D/H)3
O
(D/H)2
CD3 Ph
C(D/H)3
C(D/H)3
(D/H)3C
C(D/H)3
AD(D/H)3
(D/H)2 AD(D/H)7
BA(D/H)3
TAM(D/H)9
OH
O
O
OH
O
OH
O
O
O
D
D
D
D
CD3
CD3
(D/H)3C
C(D/H)3
O
O
D D
ADd4
D D
ADd7
ADd3
AA(D/H)6
Scheme 2.
Similar results were also obtained for β-diCCs. In
particular, the H/D exchange of acetyl- and benzoylac-
etone (2,4-pentanedione and 1-phenyl-1,3-butanedi-
The H/D exchange of triacetylmethane in a deutero-
genic medium (CDCl3/D2O : CF3COOD = 1 : 1, 20°C)
leads to [1,1,1,5,5,5,2',2',2'-(n)2H]triacetylmethane
TAM(D/H)9 in moderate yield (55%, M 151.21,
one, respectively) in
a
deuterogenic medium
[M+] 148–143). [1,1,1,5,5,5-(n)2H]Acetylacetone
(CDCl3/D2O : CF3COOD = 1 : 1, 20–60°C) showed
that, in this case, the protons of the methyl groups
undergo H/D exchange along with α-methylene pro-
tons (1H NMR). We isolated [4,4,4-(n)2H]benzoylace-
tone BA(D/H)3 (95%, [M+] 165–163) and [1,1,1,5,5,5-
AA(D/H)6 was also isolated from the reaction mix-
ture (15%, M 106.15, [M+] 106–101), which con-
firms the lability of β,β'-triCCs in protogenic
media.
The annelation of 3,4-dihydroisoquinolines I with
2-chloroacetylcyclohexane-1,3-diones II under the
conditions of the general method of [2 + 4] cyclocon-
densations [6, 7, 13] results in the formation of
benzo[b]furanones IV and 3,4-dihydroisoquinoline
hydrochloride V. Indeed, the [2 + 4] cyclocondensa-
tions of azomethines with β-diCCs and β,β'-triCCs pro-
ceed through the intermediate formation of salts III
(n)2H]acetylacetone AA(D/H)6 (92%, [M+] 106–101).
The absence of a 2H label in the α positions of the iso-
lated products is caused by the keto–enol tautomerism
and acidity of β-diCCs, resulting in the spontaneous
D/H exchange of α-deuterons with protons of the envi-
ronment during isolation and purification manipula-
tions [3].
DOKLADY CHEMISTRY Vol. 415 Part 1 2007

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158
GULYAKEVICH, MIKHAL’CHUK
[13]. In the case of 2-chloroacetylcyclohexane-1,3- SN2 reaction to give benzo[b]furan-3,4-diones IV and
diones, the resultant anions A undergo intramolecular escape the reaction area [14].
H
O
O
O
O
O
O
O
O
+
NH
Cl
R
R
R
R
Cl
N
EtOH
+ V
EtOH
+
·
Z
Z
Z
Z
O
I
II
IV
Ä
III
MeOH · HCl
O
O
OH
O
Cl–
Cl–
+
NH
R
R
+
N
R
R
R
Z
MeOH · HCl
N
+ II
∆
–HCl
R
V
VI
VII
H
O
O
N
O
O
H
O
O
O
11
17
(H/D)2
(H/D)
(H/D)2
O
O
2'
Cl
(H/D)2
11
2'
S
15
(H/D)3C
S
(H/D)2
N
15
5
(H/D)2
O
(H/D)2
VIII
IX
X
XI
R = H, OMe; Z = CH2, CMe2
Scheme 3.
At the same time, the reaction of 3,4-dihydroiso- dione) VIII. This result is caused by the formation of
[4,4,6,6,2',2'-(n)2H]-2-chloroacetyldimedone IX under
the reaction conditions, which is the synthetic precursor
of 8-aza-D-homogonane condensation product VIII
labeled at the 11-position. This conclusion is confirmed
by the fact that H/D exchange of compound VI (R = H,
Z = CMe2) under adequate conditions leads to H/D
exchange at the C15 and C17 methylene groups but does
not affect the hydrogen atom at C11. This result indi-
cates unambiguously the existence of prototropy in a
protogenic medium for 2-chloroacetyldimedone as a
representative of β,β'-triCCs that proceeds via the
hydroxonium derivatives of the keto–enols of β-diCCs
and β,β'-triCCs.
quinolines I with 2-chloroacetylcyclohexane-1,3-
diones II in the presence of 1–3 equiv of HCl prevents
the formation of benzo[b]furanones IV and leads to
mixtures of 3,4-dihydroisoquinoline hydrochloride V
with 2-chloroacetylcyclohexane-1,3-diones II. The
reaction in the presence of 5–10 equiv of HCl gives rise
to isoquino[2,1-a]quinoline hydrochlorides VI, which
after treatment with bases give target isoquino[2,1-
a]quinolines VII [9]. It is obvious that, under protoge-
nic conditions, 2-chloroacetylcyclohexane-1,3-diones
show 1,4-dipolarophilic properties, which are lacking
when acid catalysis is used. Consequently, the nature of
their dipolarophilic properties and the mechanism of
the annelation of 3,4-dihydroisoquinoline under proto-
genic conditions differ from the mechanism discussed
for amphiprotic media [6, 7, 13]. The condensation of
3,4-dihydroisoquinoline with chloroacetyldimedone in
a deuterogenic medium (CD3OD · D2O · DCl = 2 : 2 : 1,
The [2 + 4] cyclocondensation of 3,4-dihydroiso-
quinoline I (R = H) with 3-acetylthiotetronic acid in a
deuterogenic medium (CD3OD · D2O · CF3COOD 2 : 1 :
1, ∆, 17 h) leads to [11,11-(n)2H]-5,6,10b,11-tetrahy-
∆, 24 h) leads to [2,2,4,4,12-(n)2H]isoquino[2,1-a]quin- dro-1H-thieno[3,4:5,6]pyrido[2,1-a]isoquinoline-
oline
([11,15,15,17,17-(n)2H]-15,15-dimethyl-8- 1,12(3H)-dione
([11,11-(n)2H]-8-aza-16-thiagona-
aza-D-homogona-1,3,5(10),9(11),13-pentaene-12,17a-
1,3,5(10),13-tetraene-12,17-dione) X, which is caused
DOKLADY CHEMISTRY Vol. 415 Part 1 2007