Dipole-stabilized carbanions in the series of cyclic aldonitrones 3. The influence of the configuration of the nitrone group on H-D exchange of the methine hydrogen atom and metallation of aldonitrones

Article abstract of DOI:10.1023/A:1015459811377

The spin-spin coupling constants ³J_C,H between the hydrogen atom of the aldonitrone group and the carbon atom bound to the nitrogen atom of the N-oxide fragment were determined for a wide range of cyclic and acyclic aldonitrones. Based on comparison of these constants (trans-³J_C,H (E isomer) > cis-³J_C,H (Z isomer)), the Z configuration was assigned to acyclic nitrones. Coordination of organolithium compounds to the oxygen atom of the N->O group was revealed by 13C NMR spectroscopy. This coordination is the necessary condition for the metallation of aldonitrones. The configuration of the nitrone group is responsible for the ability of the F form of acyclic aldonitrones to undergo CD3ONa-catalyzed isotope exchange of the methine proton in CD3OD and metallation with Bu^sLi.

Full text of DOI:10.1023/A:1015459811377

Russian Chemical Bulletin, International Edition, Vol. 51, No. 2, pp. 297—305, February, 2002
297
Dipoleꢀstabilized carbanions in the series of cyclic aldonitrones
3.* The influence of the configuration of the nitrone group
on H—D exchange of the methine hydrogen atom and metallation of aldonitrones

M. A. Voinov and I. A. Grigor´ev
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 4752. Eꢀmail: maxx@nioch.nsc.ru
3
The spinꢀspin coupling constants JC,H between the hydrogen atom of the aldonitrone
group and the carbon atom bound to the nitrogen atom of the Nꢀoxide fragment were deterꢀ
mined for a wide range of cyclic and acyclic aldonitrones. Based on comparison of these
constants (transꢀ3JC,H (E isomer) > cisꢀ3JC,H (Z isomer)), the Z configuration was assigned to
acyclic nitrones. Coordination of organolithium compounds to the oxygen atom of the N→O
group was revealed by 13C NMR spectroscopy. This coordination is the necessary condition for
the metallation of aldonitrones. The configuration of the nitrone group is responsible for the
ability of the E form of acyclic aldonitrones to undergo CD3ONaꢀcatalyzed isotope exchange
of the methine proton in CD3OD and metallation with BusLi.
Key words: cyclic and acyclic aldonitrones, configuration of the nitrone group, spinꢀspin
3
coupling constants JC,H, metallation, dipoleꢀstabilized carbanions.
As part of continuing studies of dipoleꢀstabilized carꢀ
banions, which are generated upon metallation of cyclic
aldonitrones, and their reactions with electrophilic reꢀ
agents,1,2 we examined acyclic aldonitrones. However, it
has previously been found2 that acyclic CꢀphenylꢀNꢀtertꢀ
butylnitrone (PBN, 1) differs dramatically from other cyꢀ
clic aldonitrones in acidity. The methine H atom in PBN,
unlike those in cyclic aldonitrones, is not subjected to
CD3ONaꢀcatalyzed H—D exchange in CD3OD and is
not replaced by the Li atom under the action of LDA and
BunLi. CꢀArylꢀNꢀalkylnitrones, contrastingly, undergo
CD3ONaꢀcatalyzed exchange of the methine hydrogen
atom for deuterium in CD3OD.3 In addition, the nitrone
group in PBN exists in the Z configuration unlike the E
configuration observed in cyclic aldonitrones.4 To acꢀ
count for the difference in the reactivity of cyclic aldoꢀ
nitrones and PBN, we suggested that abstraction of the
methine H atom is directly preceded by coordination of
CD3ONa or RLi to the oxygen atom of the nitrone group,
which is kinetically favorable for H—D exchange and
metallation of aldonitrones. Previously,5—8 an analogous
coordination was proposed as an explanation for preferꢀ
ential synꢀmetallation of amides. In the case of cyclic
aldonitrones 2—7 (Table 1) existing in the rigidly fixed E
configuration, the formation of complex A (Scheme 1)
between the organometallic compound and the oxygen
atom of the nitrone group facilitates proton abstraction
from the syn position with respect to the oxygen atom of
the N→O group.
Scheme 1
M is metal
In the case of PBN existing as the Z isomer,4 the
configuration of the aldonitrone group does not hinder
the formation of the complex but excludes the attack of
the electrons of the C—M bond on the H atom located on
the opposite side of the C=N bond (Scheme 2).
Hence, the configuration of the nitrone group could
be a factor responsible for the ability of aldonitrones to
undergo H—D exchange and metallation.
* For Part 2, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 283—290, February, 2002.
1066ꢀ5285/02/5102ꢀ297 $27.00 © 2002 Plenum Publishing Corporation

298
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
Voinov and Grigor´ev
3
Table 1. H—D exchange rates and the spinꢀspin coupling constants JC,H for cyclic and acyclic
aldonitrones
Nitrone
Exchange
time/h
[CD3ONa]
/mol L–1
δ
3JC,H/Hz
H
a
(1)
(2)
—
1.2
1.2
7.91
7.89
1.5
4.5
40
15
(3)
(4)
1.2
0.5
6.94
8.23
7.5
7.3
7
7
(5)
0.85
7.74
5.2
(6)
(7)
6
4
0.5
1.2
7.90
7.17
3.6
—
b
(8)
1.2
8.64
1.4
—
b
(9)
1.2
1.2
8.01
8.06
1.8
1.5
—
(10)
90
88
(11)
1.2
7.93
1.5
(to be continued)

Configuration and reactivity of the nitrone group
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
299
Table 1 (continued)
Nitrone
Exchange
time/h
[CD3ONa]
/mol L–1
δ
3JC,H/Hz
H
(12)
(13)
75
22
1.2
1.2
8.47
8.01
1.4
2.2
(14)
(15)
>200
>250
1.2
1.2
7.84
8.01
2.4
1.8
(16)
(17)
30
5
1.2
1.2
8.02
1.7
6.21
6.62
1.5 (cis)
6.5 (trans)
(18)
16
1.2
8.06
1.5
a
(19)
(20)
1.2
1.2
7.84
7.98
2.0
1.8
—
c
—
a The intensities of the signals for the methine protons remained unchanged over one month.
b The compound is unstable under the conditions of H—D exchange.
c After one month, 20% of methine protons were exchanged.
The aim of the present study was, first, to reveal the
relationship between the configuration of the nitrone
group in aldonitrones and their ability to undergo H—D
exchange and metallation and, second, to obtain supportꢀ
ing evidence for the formation of a complex between the
O atom of the nitrone group and an organometallic comꢀ
pound as a step necessary for the metallation of aldoꢀ
nitrones.

300
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
Voinov and Grigor´ev
Scheme 2
The data on the CD3ONaꢀcatalyzed isotope exchange
of the methine proton in aldonitrones in CD3OD are
given in Table 1. As can be seen from these data, there is
no direct relationship between the rate of exchange of the
methine proton and the electronic effect of the aromatic
substituent at the C atom of the nitrone group in the
structural analogs of PBN. Thus the influence of the subꢀ
stituents at the αꢀcarbon atom of the nitrone group on the
rate of H—D exchange increases in the following series:
Ph, pꢀCH3OC6H4 < pꢀCF3C6H4 < 2ꢀpyridyl < 2ꢀfuryl <
< 2ꢀthienyl < 4ꢀpyridyl < 4ꢀC5H4N→O < H.
At the same time, according to the σp– constants,11—13
which characterize the effect of the substituents on the
developing carbanionic center, the aboveꢀmentioned subꢀ
stituents are arranged in the following qualitative series:
2ꢀfuryl < 2ꢀthienyl < Ph < 2ꢀpyridyl < 4ꢀpyridyl <
< 4ꢀC5H4N→O.
To reveal the relationship between the configuration
of aldonitrones and their ability to undergo metallation,
we determined the configurations of acyclic aldonitrones
8—20 (see Table 1), which are structural analogs of PBN,
and examined CD3ONaꢀcatalyzed H—D exchange of the
H atom of the aldonitrone group in these compounds as
the criterion for their ability to undergo metallation (cf.
lit. data2).
Hence, the experimental dependence is inconsistent
with the published data on the influence of the substituꢀ
ents on the developing carbanionic center. For example,
the electronꢀdonating 2ꢀfuryl, 2ꢀfurylꢀ5ꢀmethyl, and
2ꢀthienyl substituents are similar in their influence on
H—D exchange to the electronꢀwithdrawing 4ꢀpyridyl
substituent (cf. the data on exchange in nitrones 10—12
and 16 given in Table 1). In nitrone 1 containing the
phenyl substituent, H—D exchange was not observed
at all, while this exchange proceeded most readily in
methylenenitrone 17 containing no electronꢀwithdrawꢀ
ing substituents at the αꢀcarbon atom of the nitrone group.
It is known14—19 that CꢀarylꢀNꢀalkylnitrones undergo
isomerization with respect to the C=N bond and exist in
solutions as an equilibrium mixture of the E and Z isoꢀ
mers. Apparently, the ease of exchange in acyclic aldoꢀ
nitrones under study could also be associated with their
ability to undergo transformation into the E isomer.
Actually, the ease of isomerization of nitrones 10—13
and, consequently, of exchange can result from the elecꢀ
tronic character of the aromatic substituents due to Couꢀ
lomb repulsions between the negatively charged oxygen
atom of the nitrone group and the aromatic ring.15
Besides, isomerization can proceed by an alternative
mechanism through free rotation about the C—N bond in
adduct D resulted from the reversible addition of MeOH
at the C=N bond of the nitrone group (Scheme 3).
It is quite possible that this pathways is realized in the
case of nitrones 15 and 16. This assumption is evidenced
1
According to data from H and 13C NMR spectrosꢀ
copy, acyclic nitrones under study exist in solutions as the
only isomer. The configuration of the nitrone group was
determined using the procedure, which has been employed
previously9,10 in the investigations of the geometry of
nitrones. This method is based on the difference in the
vicinal spinꢀspin coupling constants cisꢀ and transꢀ3JC,H
.
In the case of aldonitrones, we determined the spinꢀspin
3
coupling constant JC,H between the H atom of the
aldonitrone group and the C atom bound to the N atom
of the N→O fragment. Cyclic aldonitrones 2—6 possessꢀ
ing the known fixed E configuration and methylenenitrone
17, which contains the methine H atoms both in the cis
and trans positions with respect to the oxygen atom of
Nꢀoxide, were used as the reference compounds. The
spinꢀspin coupling constants for nitrones 2—6 and the
constant transꢀ3JC,H for nitrone 17 (see Table 1) are subꢀ
stantially larger than the corresponding constants for acyꢀ
clic nitrones and the constant cisꢀ3JC,H for compound 17,
which allowed the unambiguous assignment of the Z conꢀ
figuration to nitrones 8—20. The Z configuration of
CꢀphenylꢀNꢀtertꢀbutylnitrone (1) has been independently
established previously.4
Scheme 3

Configuration and reactivity of the nitrone group
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
301
by the following facts. In the UV spectrum of a solution of
nitrone 16 in a CD3ONa—CD3OD mixture, the extincꢀ
tion coefficient of the band corresponding to the absorpꢀ
tion maximum of the nitrone group decreased from 23360
to 2194 upon storage for 10 days. After prolonged storage
of nitrones 15 and 16 in a CD3ONa—CD3OD solution,
34.6 kcal mol–1).15 Hence, the rate of isotope exchange in
acyclic aldonitrones can actually be associated with the
ease of isomerization with respect to the C=N bond.
1
According to the data from H NMR spectroscopy,
treatment of aldonitrones 1 and 19 with BusLi at –70 °C
for 2 h followed by quenching of the reaction mixture
with D2O did not lead to exchange of the methine H atom
for the D atom. Treatment of nitrones 15—17 with BusLi
followed by the addition of PhCHO was accompanied by
destruction of the starting compounds. Under the aboveꢀ
mentioned conditions, nitrone 10 was metallated at posiꢀ
tion 5 of the furyl ring to form Nꢀtertꢀbutyl[5ꢀ(αꢀhydroxyꢀ
benzyl)ꢀ2ꢀfurfurylideneamine] Nꢀoxide (23) in 65% yield
(Scheme 4).
1
their H NMR spectra showed signals for the aromatic
protons of the starting nitrones (at δ 7.49, 7.95, 8.65, and
9.02 for 15 and at δ 8.25 and 8.64 for 16) along with sets of
signals, which are analogous in multiplicities to the aboveꢀ
mentioned signals but are shifted upfield (at δ 7.28, 7.49,
7.80, and 8.48 for 15 and at δ 7.49 and 8.45 for 16). The
ratio of the signals were 1 : 2.5 (>3 days for nitrone 15)
and 1 : 3.5 (after 30 h for nitrone 16) with the starting
compounds predominating. The minor signals can be asꢀ
signed to an addition product of MeOH to the nitrone
group, which was accumulated in the reaction mixture.
The signals for the aromatic protons in the Z isomers of
the starting nitrones are shifted downfield due to the
deshielding effect of the oxygen atom of the Nꢀoxide
group.20—23 In the 13C NMR spectrum of the reaction
mixture (for nitrone 16), the intensity of the signal for the
C atom of the nitrone group at δ 130.77 is decreased and
the minor signals appeared at δ 25.48, 123.05, 149.74, and
139.83. The latter signals are assigned respectively to the
tertꢀbutyl group and the C(3), C(2), and C(4) atoms of
the pyridine ring in the adduct with MeOH.
Scheme 4
In the case of nitrone 11, metallation cannot proceed
at position 5 of the furyl ring and the starting compound
was completely recovered.
In methylenenitrone 17, the H atoms located both in
the cis and trans positions with respect to the O atom of
the nitrone group are exchanged for the deuterium atoms
with equal facility, the H—D exchange in nitrone 17 proꢀ
ceeding most rapidly compared to all the other acyclic
aldonitrones under study. Consequently, if our assumpꢀ
tion is correct, nitrone 17 should be characterized by the
lowest barrier to isomerization with respect to the C=N
bond. The rate constant of the configuration exchange (k)
in nitrone 17 was determined (in 1,2ꢀdichlorobenzene,
k = 88.6 s–1 at 133 °C) and the activation energy for
isomerization was estimated (∆G≠ = 20.3 kcal mol–1) by
1H NMR spectroscopy at the temperature of coalescence
of the signals for the methylene protons.24 The ∆G≠ value
determined by us is somewhat lower than that reported
for Nꢀ(1ꢀethylcyclohexyl)methylideneamine Nꢀoxide (21)
Inertness of nitrone 11 with respect to BusLi, even
though it rather readily undergoes CD3ONaꢀcatalyzed isoꢀ
tope exchange, is probably associated with "freezing" of
the E—Z isomerization of the nitrone relative to the C=N
bond at the temperature of metallation (–70 °C). In this
case, the thermodynamically more stable Z isomer reꢀ
mains in solution and metallation does not take place.
Apparently, this conclusion can be extended not only to
the nitrones under study but also to all acyclic aldoꢀ
nitrones.
To some approximation, cyclic aldonitrone 2 can be
considered as the fixed E form of nitrone 1. In compound
2, the H atom of the aldonitrone group was rather readily
exchanged for the D atom (see Table 1), and nitrone 2
was metallated with BusLi at —70 °C to form a brightꢀ
violet solution whose reaction with PhCHO gave rise
to 1ꢀ(αꢀhydroxybenzyl)ꢀ3,3ꢀdimethylꢀ3,4ꢀdihydroisoꢀ
quinoline 2ꢀoxide (24) (Scheme 5).
(k = 53.5 s–1 at 180 °C, ∆G≠ = 23.2 kcal mol–1 25
)
and is substantially lower than that for Cꢀsubstituted
nitrone Nꢀ(2,3,4,5,6ꢀpentamethylbenzylidene)methylꢀ
amine Nꢀoxide (22) (k = 0.9•10–5 s–1 at 147 °C, ∆G≠ =
Probably, it is this difference in the configuration of
the nitrone groups that is responsible for such different
behavior of nitrones 1 and 2 in metallation. A change in
CHꢀacidity of the aldonitrone group upon its incorporaꢀ
tion into the dihydroisoquinoline ring owing to changes
in the bond angles seems to be unlikely because it is highly
improbable that the incorporation of the C atom into the
weakly strained sixꢀmembered ring can lead to a substanꢀ

302
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
Voinov and Grigor´ev
Scheme 5
Table 2. Chemical shifts (δ) of the methine C atom in the
13C NMR spectra of compounds 1, 2, 4, 7, and 11 in the presꢀ
ence of variable amounts of LiClO4
Nitrone
δ
δ
δ
∆δ
1
2
(THF)
(2 equiv.
(5 equiv.
(δ – δ)
2
of LiClO4)
of LiClO4)
1
2
127.25
129.31
129.02
128.06*
134.45
131.76*
125.90
140.54
120.17
130.77
135.42
3.52
6.11
4
7
11
123.79
132.45
119.18
127.95
140.70
123.11
4.16
8.25
3.93
* The chemical shifts in the presence of 2 equiv. of dicycloꢀ
hexanoꢀ18ꢀcrownꢀ6.
tial change in the s character of the orbital of the C atom
involved in the C—H bond. This statement is supported
by the similarity of the chemical shifts of the C atoms of
the nitrone group in these compounds (δ 127.17 and 129.64
for 1 and 2, respectively; the spectra were measured in
CCl4). We believe that this comparison for structurally
similar nitrones 1 and 2 is acceptable. In addition, we
determined the spinꢀspin coupling constants JC,H for the
aldonitrone group in compounds 1 and 2 (170 and 182 Hz,
respectively) from their 13C NMR spectra. Taking into
account the wellꢀknown correlation26 between the spinꢀ
spin coupling constants and the s character of the orbitals
of the C atom, we estimated the s character of the exoꢀ
cyclic orbital of the αꢀcarbon atom of the nitrone group
(0.34 and 0.36 in compounds 1 and 2, respectively). These
values indicate that the structural differences have a negꢀ
ligible effect on thermodynamical CHꢀacidity of nitrones
1 and 2. Consequently, the formation of the complex
between the organolithium compound and the oxygen
atom of the nitrone group could be kinetically favorable
for metallation of the E isomer of nitrone.
The complex of type A (see Scheme 1, M = Li) of the
RLi compound with the O atom of the N→O group was
detected by 13C NMR spectroscopy. We used LiClO4,
which is readily soluble in etherꢀtype solvents, as a comꢀ
pound simulating RLi because we could not use LDA and
BusLi in the case of cyclic aldonitrones. We found that
the addition of LiClO4 to solutions of aldonitrones 1, 2,
4, 7, and 11 in THF led to a noticeable downfield shift of
the signal for the C atom of the nitrone group in the
13C NMR spectra (Table 2).
Upon the addition of dicyclohexanoꢀ18ꢀcrownꢀ6 to
the sample under study, the signal for the C atom of the
nitrone group was shifted back to high field. This fact
indicates that the downfield shift of the signal for the C
atom of the nitrone group is not a consequence of
the increase in polarity of the solution upon addition
of LiClO4.
The difference between the chemical shifts of the startꢀ
ing nitrone and the coordinated form increases with inꢀ
creasing concentration of LiClO4 due to the shift of the
equilibrium to the coordinated form. As can be seen from
Table 2, the difference (∆δ) between the chemical shifts
of free (δ) and coordinated (δ2) forms are noticeably difꢀ
ferent for cyclic and acyclic nitrones. For example, the
values ∆δ for structurally similar nitrones 1 and 2 differ by
a factor of ∼2. Apparently, this is associated with the difꢀ
ference in efficiency of the conjugation between the
nitrone group and the aromatic substituent in the comꢀ
pounds under study. As a result, in the case of formation
of the complex of type A (see Scheme 1), nitrone 7 conꢀ
taining the isolated aldonitrone group cannot compensate
for deficiency of the electron density on the C atom of the
nitrone group at the expense of other fragments of the
molecule through the conjugation system. Because of this,
∆δ for compound 7 has the maximum value (see Table 2).
An analogous change in the chemical shift was obꢀ
served in the 13C NMR spectrum of nitrone 1 recorded in
an ethereal solution of LDA at –70 °C. In this case, the
signal for the C atom of the nitrone group is shifted
downfield (from 127 to 140 ppm). In addition, the
13C NMR spectrum recorded under the conditions of
monoresonance shows spinꢀspin coupling between the C
atom of the nitrone group and the methine hydrogen
atom (JC,H = 170 Hz), which confirms the absence of
exchange of the H atom for the Li atom.
These changes in the chemical shifts are analogous to
those observed27 upon protonation of the O atom of the
nitrone group and are indicative of the interaction beꢀ
tween the N→O group and the Li ion.
When equimolar amounts of dicyclohexanoꢀ18ꢀ
crownꢀ6 and BusLi were mixed before the addition of

Configuration and reactivity of the nitrone group
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
303
Experimental
aldonitrone 4, the reaction mixture did not develop a
brightꢀcrimson color characteristic of metallated aldoꢀ
nitrone. Treatment of the reaction mixture with PhCHO
followed by its quenching with water led only to recovery
of the starting compound. Apparently, efficient binding
of Li of the organolithium compound to crown ether preꢀ
vents coordination of the R—Li molecule to the oxygen
atom of the nitrone group (cf. lit. data28) and, hence,
inhibits metallation. Thus, coordination of the organoꢀ
metallic compound to the O atom of the nitrone group
(the formation of complex A, see Scheme 1) is a prerequiꢀ
site step preceding deprotonation.
The aboveꢀdescribed experiments on the influence of
coordination of the RLi molecule with the N→O group
on metallation suggest that the mechanism of metallation
with organolithium compounds in aprotic solvents, which
was postulated in the introduction to the present study, is
similar to the mechanism of CD3ONaꢀcatalyzed deꢀ
protonation in CD3OD. Actually, deprotonation in
MeOH proceeded, most likely, under the action of the
solventꢀseparated ion pair Na+...O(R)—H...–OR (it is
known29—32 that CH3ONa exists in this form in solution).
Due to coordination with the N→O group, the cation,
which is involved in the Coulomb interaction with the
anion, brings the latter to the hydrogen atom to be abꢀ
stracted (Scheme 6).
The IR spectra were recorded on SpecordꢀIR and Bruker
Vectorꢀ22 spectrometers in KBr pellets. The UV spectra were
measured on a Specord UVꢀVIS spectrometer in EtOH. The 1H
and 13C NMR spectra were recorded on Bruker ACꢀ200 (200.132
and 50.323 MHz for 1H and 13C, respectively) and Bruker
AMꢀ400 instruments (400.136 and 100.614 MHz for 1H and
13C, respectively) with the use of the signal of the solvent as the
internal standard. The melting points were determined on a
Kofler plate. Elemental analyses were carried out at the Laboraꢀ
tory of Microanalysis of the N. N. Vorozhtsov Novosibirsk Inꢀ
stitute of Organic Chemistry of the Siberian Branch of the Rusꢀ
sian Academy of Sciences. Nitrones 2,34 4,35 7,36 8,37 9,38 13,19
and 14 19 were synthesized according to procedures reported
previously. Nitrone 3 was kindly supplied by Prof. V. A.
Reznikov. Nitrones 5 and 6 were prepared by D. G. Mazhukin
and I. A. Kirilyuk and will be described elsewhere.
Synthesis of acyclic aldonitrones 10—12, 15, 16, and 18—20
(general procedure). A solution of Nꢀtertꢀbutylhydroxylamine
hydrochloride (1.35•10–2 mol) in MeOH (5 mL) was added to a
solution of the corresponding aldehyde (1.4•10–2 mol) in MeOH
(5 mL). The reaction mixture was cooled to 5—10 °C, made
alkaline with 1 M solution of MeONa in MeOH (pH ≈ 10), and
kept for two days. Then the reaction mixture was poured into
water (50 mL) and extracted with CH2Cl2 (5×10 mL). The
extract was dried with K2CO3, the solvent was distilled off under
reduced pressure, and the solution of the residue in CHCl3 was
passed through a column with SiO2. The spectroscopic characꢀ
teristics of nitrones 16,39 19,40 and 20 41 are identical with those
reported in the literature.
Scheme 6
NꢀtertꢀButyl(2ꢀfurfurylideneamine) Nꢀoxide (10). The yield
was 65%, m.p. 64—66 °C (from light petroleum). Found (%):
C, 64.51; H, 7.77; N, 8.43. C9H13NO2. Calculated (%): C, 64.67;
H, 7.78; N, 8.38. IR, ν/cm–1: 1550 (C=N). UV, λmax/nm (ε):
1
305 (23780). H NMR (acetoneꢀd6), δ: 1.53 (s, 9 H, 3 Me);
6.56, 7.62, and 7.69 (all m, 1 H each, furyl); 7.83 (s, 1 H,
H—C=N). 13C NMR (acetoneꢀd6), δ: 28.20 (C(CH3)3); 70.33
(C(CH3)3); 112.50 (C(3), furyl); 113.84 (C(4), furyl); 143.95
(C(5), furyl); 120.42 (C=N); 149.45 (C(2), furyl).
NꢀtertꢀButyl(5ꢀmethylꢀ2ꢀfurfurylideneamine) Nꢀoxide (11).
The yield was 68%, m.p. 82—84 °C (from hexane). Found (%):
C, 66.38; H, 8.31; N, 7.68. C10H15NO2. Calculated (%):
C, 66.30; H, 8.29; N, 7.73. UV, λmax/nm (ε): 314 (28280).
1H NMR (acetoneꢀd6), δ: 1.52 (s, 9 H, 3 Me); 2.29 (s, 3 H, Me);
6.16 and 7.58 (both d, 1 H each, furyl, 3JH,H = 3.5 Hz); 7.73 (s,
1 H, H—C=N). 13C NMR (acetoneꢀd6), δ: 13.59 (Me); 28.21
(C(CH3)3); 69.89 (C(CH3)3); 108.90 (C(4), furyl); 115.29 (C(3),
furyl); 120.25 (C=N); 148.11 (C(2), furyl); 153.75 (C(5), furyl).
NꢀtertꢀButyl(2ꢀthienylmethylideneamine) Nꢀoxide (12). The
yield was 85%, m.p. 162—164 °C (from AcOEt). Found (%): C,
59.22; H, 7.18; N, 7.40. C9H13NOS. Calculated (%): C, 59.02;
H, 7.10; N, 7.65. IR, ν/cm–1: 1577 (C=N). UV, λmax/nm (ε):
312 (18692). 1H NMR (CDCl3), δ: 1.56 (s, 9 H, 3 Me); 7.10 (dd,
To summarize, the aboveꢀconsidered experimental
data provide evidence in favor of the assumption that the
ability of aldonitrones to undergo metallation and H—D
exchange is determined by the configuration of the nitrone
group. This steric requirement is apparently associated
with the fact that deprotonation occurs in the complex
formed by an organometallic compound or alkoxide and
the oxygen atom of the nitrone group in the step directly
preceding proton abstraction. The formation of this comꢀ
plex is kinetically favorable for proton abstraction from
the Z position with respect to the Nꢀoxide group. Taking
into account that this complex is involved in deprotoꢀ
nation, metallation of aldonitrones can be assigned to
CIPEꢀcontrolled processes33 (CIPE is Complex Induced
Proximity Effect).
3
3
1 H, H(4) thienyl, JH,H = 4 Hz, JH,H = 5 Hz); 7.38 (dd, 1 H,
4
H(5) thienyl, 3JH,H = 5 Hz, JH,H = 1 Hz); 7.41 (dd, 1 H, H(3)
3
4
thienyl, JH,H = 4 Hz, JH,H = 1 Hz); 8.00 (s, 1 H, H—C=N).
13C NMR (CDCl3), δ: 27.97 (C(CH3)3); 68.76 (C(CH3)3);
125.30 (C=N); 126.16, 128.04, 128.96 (thienyl); 133.23 (C(2),
thienyl).

304
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 2, February, 2002
Voinov and Grigor´ev
NꢀtertꢀButyl(2ꢀpyridylmethylideneamine) Nꢀoxide (15). The
NꢀtertꢀButyl[5ꢀ(αꢀhydroxybenzyl)ꢀ2ꢀfurfurylideneamine]
Nꢀoxide (23) was isolated by chromatography on SiO2 (1 : 20
CH2Cl2—MeOH mixture as the eluent), m.p. 199—201 °C
(hexane—EtOAc, 1 : 20). Found (%): C, 70.33; H, 7.22; N, 5.26.
C16H19NO3. Calculated (%): C, 70.33; H, 6.96; N, 5.13.
IR (CHCl3), ν/cm–1: 1525 (C=N), 3605 (OH). IR (KBr),
ν/cm–1: 1518 (C=N), 3220 (OH). UV, λmax/nm (ε): 314 (17078).
1H NMR (CDCl3), δ: 1.52 (s, 9 H, Me); 2.91 (d, 1 H, OH,
yield was 70%, m.p. 63—65 °C (from light petroleum).
Found (%): C, 67.41; H, 7.89; N, 15.71. C10H14N2O. Calcuꢀ
lated (%): C, 67.42; H, 7.86; N, 15.73. IR, ν/cm–1: 1555 (C=N).
1
UV, λmax/nm (ε): 302 (16800). H NMR (acetoneꢀd6), δ: 1.59
(s, 9 H, 3 Me); 7.31, 7.82, 8.62, and 9.18 (all m, 1 H each, py);
7.85 (s, 1 H, H—C=N). 13C NMR (acetoneꢀd6), δ: 28.33
(C(CH3)3); 72.11 (C(CH3)3); 123.37 (C(5), py); 124.44 (C(3),
py); 137.17 (C(4), py); 150.30 (C(6), py); 151.92 (C(2), py);
131.20 (C=N).
3
3JH,H = 4.5 Hz); 5.79 (d, 1 H, CH, JH,H = 4.5 Hz); 6.28 and
3
7.63 (both d, 1 H each, furyl, JH,H = 3.9 Hz); 7.32—7.42 (m,
NꢀtertꢀButyl(4ꢀpyridylmethylideneamine) Nꢀoxide (16).
13C NMR (acetoneꢀd6), δ: 28.35 (C(CH3)3); 72.78 (C(CH3)3);
122.11 (C(3), py); 139.02 (C(4), py); 150.94 (C(2), py);
127.95 (C=N).
5 H, Ph); 7.65 (s, 1 H, H—C=N). 13C NMR (CDCl3), δ: 27.95
(Me); 69.60 (C(CH3)3); 70.10 (CH); 109.96, 115.50 (CH, furyl);
121.37 (C=N); 126.53 (oꢀC(Ph)); 129.12 (pꢀC(Ph));
129.44 (mꢀC(Ph)); 140.35 (ipsoꢀC(Ph)); 147.36, 158.93
(2 ipsoꢀC(furyl)).
NꢀtertꢀButyl(methylideneamine) Nꢀoxide (17). A solution of
Nꢀtertꢀbutylhydroxylamine hydrochloride (2 g, 1.6•10–2 mol)
in MeOH (5 mL) was made alkaline with 1 M solution of MeONa
in MeOH (pH ≈ 10), and cooled to 5 °C. Then 30% formaline
(3.5 mL) was added, whereupon the reaction mixture slightly
warmed up. After 15 min, the reaction mixture was concenꢀ
trated and water (3 mL) was added. The reaction mixture was
extracted with CH2Cl2 (5×10 mL), the extract was dried with
MgSO4, the solvent was distilled off under reduced pressure,
and the residue was sublimed. The yield was 1.13 g (70%). The
spectroscopic characteristics are identical with those reported in
the literature.42 13C NMR (CDCl3), δ: 27.92 (C(CH3)3); 69.87
(C(CH3)3); 119.44 (C=N).
1ꢀ(αꢀHydroxybenzyl)ꢀ3,3ꢀdimethylꢀ3,4ꢀdihydroisoquinoline
2ꢀoxide (24) was isolated by chromatography on Al2O3 (a 3 : 2
light petroleum—AcOEt mixture as the eluent). The yield
was 75%, m.p. 166—168 °C (hexane—AcOEt, 1 : 1). Found:
C, 76.92; H, 6.79; N, 4.91. C18H19NO2. Calculated: C, 76.87;
H, 6.76; N, 4.98. IR, ν/cm–1: 1529 (C=N), 3213 (OH). UV,
1
λ
max/nm (ε): 303 (14428). H NMR (CDCl3), δ: 1.35 and 1.47
(both s, 3 H each, 2 Me); 3.01 and 3.14 (AB system, 2 H, CH2,
3
JH,H = 16 Hz); 5.98 (d, 1 H, CH, JH,H = 11 Hz); 7.18—7.43
3
(m, 9 H, arom.); 7.49 (d, 1 H, OH, JH,H = 11 Hz). 13C NMR
(CDCl3), δ: 23.76, 24.46 (Me); 41.54 (CH2); 66.70 (C(3));
71.09 (HCOH); 125.80 (oꢀC(Ph)); 128.03 (pꢀC(Ph)); 128.52
(mꢀC(Ph)), 123.33 (Ar); 127.61 (Ar); 129.52 (Ar); 128.33, 130.66
(ipsoꢀC(Ar)); 140.63 (ipsoꢀC(Ph)); 144.14 (C=N).
Study of H—D exchange in acyclic aldonitrones. Nitrone
(3.8•10–5 mol) was placed in an NMR tube, a freshly prepared
solution (0.5 mL) of CD3ONa in CD3OD was added, and the
reaction mixture was stirred until the sample was completely
dissolved. The concentrations of the solutions of CD3ONa in
CD3OD are given in Table 1. The course of the isotope exꢀ
In an independent experiment with nitrone 1, the reaction
mixture was kept at –70 °C for 2 h and warmed to –20 °C. Then
D2O (2 mL) was added. The organic layer was separated and
dried with MgSO4 and the solvent was distilled off under reꢀ
1
1
change was monitored by H NMR spectroscopy by following
duced pressure. Analysis of the residue by H NMR spectrosꢀ
the changes in the integral intensity ratio of the signals for the
methine proton and the signals for the protons of the geminal
Me groups (for cyclic aldonitrones), the protons of the tertꢀbutyl
group (for CꢀRꢀNꢀtertꢀbutylnitrones), or the aromatic H atoms
(for nitrones 13 and 14). The course of the reaction was moniꢀ
tored until the conversion reached ∼85% (the ratio of the signals
for the methine proton and the protons of the tertꢀbutyl group
was 1 : 60 and the ratio of the signals for the methine proton and
the protons of the geminal Me groups was 1 : 40).
Study of the reactions of aldonitrones with BusLi. A solution
of BusLi in hexane (2.3 mL, 2.3•10–3 mol) was placed in a flask
(which was preliminarily filled with argon) equipped with a
magnetic stirred, a dropping funnel, and a thermometer and
cooled to –70 °C. Then a solution of aldonitrone 1, 2, 10, 11,
15—17, or 19 (1.9•10–3 mol) in THF (2 mL) was added dropwise
to a solution of BusLi over 15 min. The reaction mixture was
stirred at –70 °C for 10—15 min and a solution of PhCHO
(2.5•10–3 mol) in THF (3 mL) was added. The reaction mixture
was stirred at –70 °C for 10 min, warmed to –20 °C, and
quenched with water (2 mL). The organic layer was separated
and the aqueous layer was extracted with CHCl3 (2×5 mL). The
combined organic extracts were dried with MgSO4 and concenꢀ
trated. The recovery of nitrones 1, 11, and 19 was 95—98%.
The identity of the compounds isolated and the startꢀ
ing nitrones were determined by comparing their IR and
1H NMR spectra. Nitrones 23 and 24 were isolated by preparaꢀ
tive TLC.
copy (in CD3OD) revealed the presence of the signal for the
methine proton (δ 7.91) with the intensity ratio of 1 : 5 relative
to the signals for the aromatic protons.
Study of coordination of the N→O group of aldonitrones with
LiClO4 and LDA. A. Nitrone 1, 2, 4, 7, or 11 (1.3•10–4 mol)
was placed in an NMR tube and a solution (0.5 mL) of LiClO4
in dry THF was added (LiClO4 was preliminarily calcined at
120 °C for 24 h). The resulting mixture was stirred until the
compound under study was completely dissolved and then kept
for 0.5 h.
B. A solution of nitrone 1 (0.3 g, 1.9•10–3 mol) in ether
(5 mL) was added to an ethereal solution of LDA (25 mL,
9.5•10–3 mol), which was preliminarily cooled to –70 °C, under
argon. The resulting mixture was stirred at –70 °C for 10 min
and then transferred into an NMR tube filled with argon and
placed in solid carbon dioxide. The 13C NMR spectrum was
recorded at –70 °C.
We thank O. P. Shkurko for helpful discussion.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 97ꢀ03ꢀ
32864a).
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Received August 21, 2000;
in revised form July 24, 2001