Ring-chain tautomerism and other versatile behaviour of 1,4-diimino- and 1,2-phenylene derivatives of some C-substituted serinols

Article abstract of DOI:10.1016/S0040-4020(02)00111-4

The behaviour of the title compounds, obtained from terephthaldicarboxaldehyde or 1,2-phthaldicarboxaldehyde and certain (non)chiral C-substituted serinols is discussed in terms of ring (chain)-chain (ring) tautomerism (1,4-phenylene derivatives) or formal intramolecular redox isomerisation (1,2-derivatives).

Full text of DOI:10.1016/S0040-4020(02)00111-4

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 2681±2693
Ring-chain tautomerism and other versatile behaviour
of 1,4-diimino- and 1,2-phenylene derivatives
of some C-substituted serinols
a
a,p
b
a
Carmen Maiereanu, Mircea Darabantu, Gerard Ple, Camelia Berghian, Eric Condamine,
b
Â
Â
Yvan Ramondenc,b Ion Silaghi-Dumitrescua and Sorin Magera
a
Á
Department of Organic Chemistry and CSOFSTM, Babes-Bolyai University, 11 Aranyi Janos Str., 3400 Cluj-Napoca, Romania
b
Â
Institute de Recherche en Chimie Organique Fine -I.R.C.O.F), Universite de Rouen, 76821 Mont-Saint Aignan Cedex, France
Received 14 September 2001; revised 2 January 2002; accepted 24 January 2002
AbstractÐThe behaviour of the title compounds, obtained from terephthaldicarboxaldehyde or 1,2-phthaldicarboxaldehyde and certain
,non)chiral C-substituted serinols is discussed in terms of ring ,chain)±chain ,ring) tautomerism ,1,4-phenylene derivatives) or formal
intramolecular redox isomerisation ,1,2-derivatives). q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
O-1±N-3-heterocyclic system ,type 1,3-oxazolidines nˆ0
and type 1,3-perhydro oxazines nˆ1, Scheme 1) are the
result of clear nucleophilic 5 ,and 6) endo±trig cyclisations,
respectively, but only the latter is favoured according to
Baldwin's rules.13
The ring-chain tautomerism of the Schiff bases derived from
aryl carbonyl compounds and aminoalcohols, as a reversible
addition of an hydroxyl group to an imine double bond, is
already a very well investigated feature ,Scheme 1).1
Following our initial ®ndings regarding the ring-chain
tautomerism exhibited by some simple Schiff bases of
l-p-nitrophenylserinol14 and highlighting recently reported
data on the double Schiff bases of the epimeric 1,2,3,4-
diaminobutanediols,15±17 we have now dedicated our
attention to double Schiff bases derived from an aromatic
dicarbonyl compound, such as terephthaldicarboxaldehyde
and a variety of C-substituted serinols. To the best of our
knowledge, both the problem to be solved and the
compounds are new ones. Preliminary results are hereafter
discussed in the context of 1,2-phthaldicarboxaldehyde
reactivity as an attempt to provide a more complete
approach.
Scheme 1.
According to the literature,2±7 the general approach in the
®eld indicates a preference for high resolution NMR
spectroscopic methods ,both in solution and solid state).
Starting from the pioneering review of Bergmann8 and
later developments over the years,9±12 the research has
focused on simple Schiff bases originating from aryl carbo-
nyls and monoamino monoalcohols. It was demonstrated
that the above equilibria ,Scheme 1) can be accurately
described by a Linear Free Energy Relationship ,LFER)
as Hammett±Brown plots ,log Kˆrs11log K0 where Kˆ
[ring]/[chain] and s1 being the constant for the substituent
linked to aryl moiety).9 Both types of possible saturated
2. Results and discussion
2.1. Reaction with terephthaldicarboxaldehyde
2.1.1. Synthesis. The compounds under investigation 2±6
,Scheme 2) were prepared from the corresponding serinols
1a±e ,1:2 molar ratio dialdehyde/serinol) by classical
methods with good yields.18
The E con®guration of the imine double bond in structures
of this type was previously discussed and assigned by us
based on NOE-diff. experiments.14 Indeed, all new
compounds 2±6 were unambiguously detected as unique
Keywords: chirality; oxazolidines; Schiff bases; NMR; tautomerism.
Corresponding author. Fax: 140-64-190-819;
e-mail: darab@chem.ubbcluj.ro
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00111-4

2682
C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
Scheme 2.
Scheme 3.

C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
2683
Scheme 4.
²
diastereomers [e.g. just one signal for imine positions
`classical' approach ,Schemes 3 and 4), all the double Schiff
bases 2±6 give rise to the same stereochemical problem: the
ring-chain tautomerism would result in two successive
multicomponent equilibria: the ®rst ring closure would
yield mono oxazolidine Schiff bases of type 2a±6a, then
double oxazolidines of type 2b±6b. In order to simplify
discussion, the expected ring stereoisomers are depicted
separately in Scheme 3 [,2±4)!,2a±4a)!,2b±4b) and
Scheme 4 [,5, 6)!,5a, 6a)!,5b, 6b)].
1
,around 8.35 and 161 ppm in H and 13C spectra, respec-
tively) as well as for 1,4-phenylene fragment ,around 7.45
and 128 ppm) in a 1:2 ratio]. Despite this incipient dia-
stereoselectivity, revealed by NMR, it is important to
point out some features.
Our selection of terephthaldicarboxaldehyde was motivated
by the expected interaction ,seen as `activation') between
the two imine groups in a 2±6 p conjugated system. On
the other hand, the corresponding mono Schiff bases of
1,4-terephthaldicarboxaldehyde appear to be unknown
structures.
As shown in Scheme 3, in the case of 2 and 3 eight distinct
ring epimers are expected ,216, if chiral, just one enan-
tiomer is depicted) including two meso forms 2b and 3b
cis-u-cis and trans-u-trans ,descriptors unlike u and like l
refer to the C-2 chiral centers in the oxazolidine moiety;
descriptors cis and trans refer to the disposal of C-4
hydroxymethyl and C-2 phenylene groups with respect to
each oxazolidine ring).20,21 Obviously, for 4 just one dia-
stereomer 4a and two 4b ,u and l) are to be considered.
The chosen C-2-substituted serinols 1a±c provide different
steric and electronic environments for the involved nucleo-
philes: the hydroxymethyl groups are enantiotopic in 1a, b
but homotopic in 1c ,the very well known TRISw, tris-
,hydroxymethyl)aminomethane).19 In contrast, the enantio-
meric pure 1-aryl serinols 1d, e possess the 1S,2S-con-
®guration.
Enantiomerically pure double Schiff bases 5 and 6 ,Scheme
4) would give ®ve stereoisomers: two epimers of type 5a
and 6a but only three of type 5b and 6b since the con-
®gurations in the oxazolidine ring as 4S,5S are preserved
from the starting materials. In turn, compounds 5 and 6
could rise the supplementary problem of regioselectivity
in the ring closure since the nucleophile involved could be
2.1.2. Stereochemical aspects of ring tautomers. In a
²
Although this can be assigned as well by simple inspection of Dreiding
models, the partial isomerisation of 2±6 towards their corresponding
,Z,Z) and ,Z,E) diastereomers was also considered. See later discussion.

2684
C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
Table 1. Equilibrium data between Schiff bases 2±6 ,chain form) and their tautomers ,ring forms, epimeric oxazolidines) 2a±6a and 2b±6b
Number
Composition ,%)
Time ,h)
KI
KII
Time zero
Equilibrium state
Chain form 2±6 Ring form 2a±6a Ring form 2b±6b Chain form 2±6 Ring form 2a±6a Ring form 2b±6b
2
3
4
5
6
82 %2)
13 %3)
0.25 %4)
100 %5)
95b %6)
18 %2a)
30 %3a)
14 %4a)
0 %5a)
0 %2b)
36 %2)
13 %3)
0.25 %4)
70a %5)
78b %6)
47 %2a)
30 %3a)
14 %4a)
0 %5a)
17 %2b)
57 %3b)
85.75 %4b)
30 %5b)
22 %6b)
5
±
±
24
24
1.31 0.36
2.3.1910
56.00 6.13
57 %3b)
85.75 %4b)
0 %5b)
±
±
±
±
0 %6a)
5 %6b)
0 %6a)
a
Assigned as a mixture of diastereomers: 88% ,E,E), 6% ,Z,Z) and 6% ,E,Z) of 5.
Assigned as a mixture of diastereomers: ,E,E), ,Z,Z) and ,E,Z) of 6 where minor diastereomers ,Z,Z1E,Z were found less than 5%).
b
Figure 1. 1H NMR spectrum at the equilibrium between species 4±4a±4b ,detail in the aromatic zone; 600 MHz, DMSO-d6, d in ppm, J in Hz; see Scheme 3),
from down®eld to up®eld: 8.39 ,2H, s, Him in 4), 8.36 ,1H, s, Him in 4a), 7.73 ,4H, s, 1,4-phenylene in 4), 7.67 ,2H, d, Jˆ8.2, 1,4-phenylene in 4a), 7.40 ,2H, d,
Jˆ8.1, 1,4-phenylene in 4a), 7.34 ,4H, s, 1,4-phenylene in 4b).
the primary or secondary hydroxyl group. Fortunately, as 1H
NMR spectra con®rmed, the resulting mono oxazolidines 5a
and 6a clearly exhibited the presence of a free C-4, -40
hydroxymethyl group, in complete agreement with our
previously reported results concerning the ring-chain tauto-
merism of mono Schiff bases of ,1S,2S)-p-nitrophenyl-
serinol, 1e.14 That is, the most acidic hydroxyl group
,although the most sterically hindered) is also the most
nucleophilic.11,14
by the IR spectra throughout performed in the solid state
,nujol). The results are summarised in Table 1.
The compositions listed in Table 1were calculated from
1H NMR ,and quantitative 13C NMR whenever possible)
spectra by choosing the best separated signals belonging
to all observed species. The relevant considered region
was the aromatic zone ,compounds 2±4) and heterocyclic
zone ,compounds 5, 6). For accurate calculation, correlation
between zones was carefully checked.
2.1.3. Results. The evaluation of the equilibria was made by
high resolution NMR in solution. An intrinsic drawback of
this was that all compounds only exhibited satisfactory solu-
bility in DMSO-d6; their free evolution was monitored
immediately after dissolution, at room temperature. The
We will start our analysis with the apparently most simple
case, the expected compound 4. The H NMR spectrum in
the aromatic region is depicted in Fig. 1.
1
1
®rst display of the H NMR spectrum was considered as
the time zero of our investigation. This was complemented
One may conclude that the reaction between TRIS 1c and
terephthaldicarboxaldehyde ,Scheme 2) did not yield, in

C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
2685
H-2 and the amine proton, revealed throughout in 4a and 4b
3
as JH-2±NHˆ11.3 Hz; hence, t1 ,lifetime of the involved
nuclei in a particular magnetic environment, e.g. a trans
con®guration14,23) should be greater than 1/Jˆ0.088 s in
both environments 4b u and l ,Scheme 3). Keeping in
mind this ascertained stereochemistry, the trans disposal
H-2±NH can also be the result of a strong anomeric effect
involving a well positioned donor ,lpN) overlapping with an
excellent acceptor spC-2±O-1as Fuchs
have recently reported for related ®ve and six membered
and Pavia24
15±17
1,3-oxazanes ,Scheme 5).
Thus, the iminium intermediate II ,Scheme 5) should be
responsible for the isomerisation 4b u±4b l ,I vs IV)
since it contains the key activating withdrawing group
Scheme 5.
Scheme 6.
fact, the Schiff base 4 but instead gave directly the double
oxazolidine 4b. That is, no unique structure at time zero
could be assigned but already a spontaneous equilibrium
state originating from two successive ring openings and
not ring closures ,e.g. `ring!chain' 4!4a!4b). The IR
spectrum con®rmed this assumption: just a single very
weak ,almost ¯at) band was found in the relevant zone at
1643 cm21 to be assigned as nCvNsk, hence a Ci symmetry of
against the other end of the molecule. Unfortunately, since
4b was only soluble in DMSO-d6, no NMR experiment
could be carried out at low temperature. Accordingly, in
solution, our diagnostic is the complete overlapping of
signals belonging to both diastereomers 4b u and l and an
isomerisation controlled by:
,i) the existence of three statistically equivalent hydroxy-
methyl groups vs one imine group ,SN1like mechanism
via open chain structure II, Scheme 5).
,ii) a strong anomeric effect ,also favoured by intra-
molecular hydrogen bonds as III) in both types of oxazo-
lidines 4a and 4b.
³
the dominant species as meso form 4b u. Although the
oxazolidine O-1±C-2±N-3 system, characterised by a
`classic triplet' of bands in the regions 1149±1185, 1116±
1139 and 1080±1114 cm21 was also found ,as described by
Bergmann since 1953),8 the multiplicity of signals made our
conclusion ambiguous and the stereochemistry of double
oxazolidine 4b ,u or l?) in solution was a remaining
We were particularly interested in evaluating this behaviour
because the literature exclusively reports substituted
1,3-oxazolidines from the reaction of TRIS with carbonyl
compounds.22 However, in 1990 the remarkable stability of
the imine derivatives of salicylaldehyde and certain amino
alcohols ,due to an intramolecular hydrogen bond between
o-phenolic group and imine nitrogen generating a six
membered chelate) was reported by Potapov et al.25 Exten-
sion to ring-chain tautomerism of this concept by us14 and
later by Fuchs17 demonstrated the absence ,or minor occur-
rence) of ring forms in such type of Schiff bases. This
prompted us to prepare the TRIS derivatives 7 and 8
,Scheme 6).
1
question. Both H and 13C NMR spectra displayed just
one complete set of signals even at the highest power of
detection used ,600 MHz). In contrast to the solid state, a
con®guration equilibrium between 4b u and 4b l ,ring±ring
tautomerism, as we previously described for other double
oxazolidines derived from TRIS22) was considered the most
plausible explanation. This would be consistent with the
unexpected great vicinal coupling pattern ,doublet) between
³
Valid for a frozen conformation as anti with respect to benzyl ,C-2, -20)
protons; in Scheme 3 they are depicted as syn C1V conformation for
reason of simplicity.

2686
C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
Figure 2. 1H NMR spectrum at the equilibrium state ,5 h) starting from the compound 2 ,detail in the aromatic zone; 300 MHz, DMSO-d6, d in ppm, J in Hz;
see Scheme 3), from down®eld to up®eld: 8.37 ,2H, s, Him in 2), 8.35 ,2H, s, Him in both cis trans 2a), 7.81,4H, s, 1,4-phenylene in 2), 7.76, 7.75, 7.50 and 7.48
,8H, d, Jˆ7.9±8.3, 1,4-phenylene in both cis trans 2a), 7.43 ,4H, s, 1,4-phenylene in 2b).
The NMR spectra of 7 were identical over time and hence
evidenced one authentic E imine structure ,e.g. Him at
8.57 ppm and the corresponding Cim at 164.4 ppm). In
turn, even at time zero, in the case of compound 8, a
clean 1:1 mixture of imine 8 ,Him at 8.28 and Cim at
159.7 ppm) and oxazolidine 8a ,H-2 at 5.44 ppm and C-2
at 101.3 ppm) was detected. No evolution of the compo-
sition ,8 vs. 8a) was observed. Thus, compared with a
stabilising intramolecular hydrogen bond ,compound 7,
Scheme 6), even one of the strongest donating groups
,p-Me2N, s1ˆ21.70)26 was unable to ®x the chain form
8 if more than two free hydroxyl groups are present b to
the imine double bond. In IR spectra, the nCvNsk absorption
were easily recognised as typical strong bands ,1636 cm21in
7 and 1607 cm21 in 8a).
four aromatic quaternary carbons ,142.6, 136.7 and 142.4,
136.8 ppm, respectively) as well as the epimers 2b ,almost
all detected, as the C-2 carbons located around 90 ppm,
seven distinct signals in lieu of ten).
On the other hand 2 was the single case which allowed
a kinetic estimation of the isomerisation 2!2a as a clear
1st order equilibrium ,see Section 4). The equilibrium state
was established after 5 h ,kaˆ2.22£1023 min21, k2aˆ
1.69£1023 min21, t1/2ˆ177 min, rˆ0.986, Table 1). Finally,
the IR spectrum enabled us to ascertain the compound 2,
as an authentic starting di-imine structure, by its strong
relevant absorption at 1631 cm21
.
Surprisingly, as for 4, it was impossible to detect for the
compound 3 ,Table 1) any progressive evolution but
directly an equilibrium state, presumably because of the
increased nucleophilicity of the hydroxyl groups ,though
the ®nal appearance of 1H and 13C NMR spectra was almost
identical with the above discussed 2).§ In the IR spectrum,
Isomerisations involving the di-imines 2 and 3 were found
to be not only more complicate ,Table 1) but also very
different. The H NMR spectrum of 2 is given below as
1
an illustrative example ,Fig. 2).
sk
a single relevant band nCvN was displayed ,again very
Calculations supported by 1H NMR spectra led us to estab-
lish that the process really starts from 2 which is partially
converted to an approximately 1:1 mixture of the inter-
mediate epimers ,E-cis and E-trans) of 2a. No diastereo-
selectivity was reasonably detected at this ®rst stage.
Consequently, in the second step, the singlet located at
7.43 ppm was assigned for all phenylene protons in all 2b
weak) at 1641 cm21 indicating a reverse process as
`ring!chain tautomerism' originating from the dominant
meso forms 3b cis-u-cis and/or 3b trans-u-trans ,Ci sym-
metry) ,Scheme 3).
The behaviour of chiral di-imines 5 and 6 evidence, besides
other unexpected aspects, the occurrence of a certain stereo-
selectivity. NMR spectra performed on the mixtures at
equilibrium indicated very similar shapes for 5 and 6.
1
species suggesting the limits of H NMR detection rather
than a certain diastereoselectivity. Indeed, for a more
complete picture of both stages ,2!2a!2b), we checked
the 13C NMR spectra ,quantitative experiment). They
con®rmed the above deductions: no con®gurational prefer-
ence was found for the entire isomerisation. Thus, despite
overlapping, the compounds 2a exhibited distinctly their
§
Evidence of the same anomeric effect in oxazolidines 2a, 2b, 3a and 3b as
compared with 4a and 4b remained obscure since the NH group displayed
its usual shape as a broad singlet although some splitting as a doublet of
H-2 ,7±11 Hz) was occasionally observed.

C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
2687
Figure 3. 1H NMR spectrum at the equilibrium state ,24 h) starting from the compound 6 ,detail in the heterocyclic zone; 300 MHz, DMSO-d6, d in ppm, J in
Hz; see Scheme 4), from down®eld to up®eld: 5.98 ,1H, d, 4.9, H-2 in 6a cis); 5.86 ,1H, d, Jˆ6.4, H-20 in 6b); 5.76 ,1H, d, Jˆ4.2, H-2 in 6a trans); 5.64 ,2H,
d, Jˆ5.3, OH in 6); 5.63 ,1H, d, Jˆ4.2, H-2 in 6b); 5.08 ,1H, dd, Jˆ4.9, 10.9, CH2OH in 6b), 5.07 ,1H, dd, Jˆ5.6, 10.9, CH2OH in 6b), 4.95 ,2H, dd as t,
Jˆ4.9, benzyl CH in 6), 4.92 ,1H, d, Jˆ5.3, H-50 in 6b), 4.90 ,1H, d, Jˆ6.8, H-5 in 6b), 4.63 ,2H, dd as t, Jˆ5.1, CH2OH in 6).
They were also very consistent with the same spectra of
simplest Schiff base of 1e and benzaldehyde.14 Moreover,
for 6, even the composition at equilibrium ,as 78% chain
form 6 vs. 22% ring form 6b, see Table 1) was identical with
that of its above mentioned mono Schiff base as E-2-benzyl-
ideneamino derivative of 1e.14
The following observations were also of interest:
Although very similar, only the isomerisation of 5 provides
the possibility of epimerisation at the benzyl carbon during
ring closure ,that is, the benzyl chiral center ,Scheme 4) is
epimerisable in all 5, 5a and 5b species).12 Based on our 1H
NMR data, we found no evidence that the initial 1S,2S
con®guration of the starting 5 would change since, in ring
form 5b, despite partially overlapping, protons H-5, -50 are
split as a doublet with a trans stereospeci®c coupling as
4.9±5.0 Hz ,hence indicating an S con®guration of the
C-5, -50 position).
We will consider the mixture at equilibrium as resulted from
the isomerisation of 6; its 1H NMR spectrum is depicted in
Fig. 3.
The equal intensity of signals belonging to epimers 6b
suggested two distinct oxazolidine environments as con-
®rmed by 13C NMR spectrum ,quantitative experiment)
which also showed an equal intensity of relevant peaks:
The absence of the intermediates 5a and 6a is plausible by
the increased acidity ,as autocatalysis) of the secondary
hydroxyl group in 5 and 6 as compared with 2 and 3. In
terms of chemical shifts, this group was located at 5.24 ppm
in 5 and 5.64 ppm in 6 whereas in 2 and 3 hydroxyl groups
were suf®ciently up®eld ,4.59 ppm in 2 and 4.78 ppm in 3).
Accordingly, as anticipated, the secondary hydroxyl is the
only nucleophile involved in ring closure.
0
C-2, -20 ,92.9 and 92.1ppm), C-5, -5 ,79.9 and
78.9 ppm) and C-4, -40 ,69.5 and 67.8 ppm). Next, in the
aromatic region, two different environments were evidenced
again for the two p-nitrophenyl fragments as four distinct
tertiary carbons ,126.8, 126.5, 123.6 and 123.4 ppm).
Finally, two types of tertiary carbon were found for the
1,4-phenylene moiety. No new imine carbon was detected
other than the signal belonging to starting 6. These data
demonstrate, in our opinion, the evolution of the equilibrium
towards the dominant diastereomer 6b cis-u-trans ,Scheme
4) issued from a statistically favoured succession of ring
closures as cis,trans) followed by trans,cis) of the discrete
intermediates 6a trans,cis). The latter were under the limit
of detection, at equilibrium, at least in 13C NMR spectra.
That is, in 1H NMR spectrum discussed above ,Fig. 3), one
could assign the two doublets located at about 5.98 and
5.76 ppm as belonging to H-2 in 6a cis and trans species
but we avoided a more conclusive interpretation.
Compared with the simple E-2-benzylideneamino deriva-
tive of 1e,14 the equilibrium state is reached about four
times more quickly ,24 h vs. 105 h) for 5 and 6, to demon-
strate the expected activation of an imine double against the
other one. However, although in a large series of ,hetero)-
arylideneamino derivatives of 1e we previously reported the
equilibration time of only E diastereomers,14 the same was
not valid for 5 and 6. Thus ,see Table 1) careful inspection
1
of the H NMR spectrum in the aromatic region of 5 at
equilibrium indicated the presence of the minor dia-
stereomers of 5 ,Him at 8.217 and 8.213 ppm and the

2688
C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
Scheme 7.
corresponding 1,4-phenylene signals at 7.82 and 7.79 ppm
in a clean 1:2 ratio, respectively; in turn, in the 13C NMR
spectrum, only the imine and benzyl carbons were distinct
,160.3 and 78.6 ppm, respectively). Similar behaviour was
exhibited by 6 when its minor diastereomers were detected
even at time zero to coexist with the epimer 6b. Obviously
this last detail indicates a more delicate approach. Without
extrapolating, this enables us to assume that the minor
diastereomers of 5 and 6 ,not detected in the series 2±4)
originate from a not total but almost complete diastereo-
selective ring opening of the discrete intermediates 5a
and 6a.
two oxazolidine rings linked in a 1,2-phenylene moiety
starting from the serinols 1a±e, the results revealed different
behaviour. The chemistry is depicted in Scheme 7.
Treatment of 1,2-phthaldicarboxaldehyde with 1c ,equi-
molar ratio or even excess of the later) in methanol, at
room temperature ,or re¯ux) afforded in good yield the
tetraheterocycle 9 ,in context, a masked N-substituted iso-
indoline). In the same conditions, 1-aryl serinols 1d and 1e
yielded N-substituted isoindoline-1-ones 10a and 10b. Due
to their similarity, we postulated that compounds 9 and
10 could have a common intermediate, assigned as the
1,3-dihydroxyindoline of type 11. Indeed, formation of 11
is plausible ,as a variant of classical Knorr±Paal synthesis
of N-substituted chiral pyrroles).27 It can be seen in a double
role as follows:
It is recognised that electronic factors dominate steric
requirements regarding the stereochemistry of double
oxazolidine 5b and 6b. Indeed, there is no preference for
a local disposal ,cis or trans) of the two ,C-2, -20 vs -5, -50)
aromatic fragments with respect to each oxazolidine ring in
5b and 6b in total agreement with the same stereochemistry
of simple epimeric mono oxazolidines derived from 1e and
a large series of ,hetero)aryl aledehydes.14
,a) As a source of stable benzylic carbocations to promote
the ring closure as two successive etheri®cations ,SN1
like mechanism) in reaction with the three hydroxy-
methyl groups of 1c, to give 9. The latter, together with
its C-11 methyl and ethyl analogues ,starting from 1a
and 1b), are known compounds, previously reported by
Shipchandler.28 However, their intimate formation
remained obscure as did their stereochemistry. In our
investigation, only compound 9 was prepared and
explored by means of combined NMR experiments
,ROESY). They con®rmed the trans disposal of the
aromatic ring vs. C-11 hydroxymethyl group and the
lone pair at N-14, in order to preserve the tent shape of
the basic heterobicycle skeleton. Its 7Sp,8Rp,11r,14s
con®guration ,meso form), assigned by us, is totally
different than that of other disubstituted 1-aza-3,7-dioxa-
bicyclo[3.3.0]octanes bearing ,hetero)aromatic rings
linked at C-2, -8 ,all cis).30,31
In the solid state, the compounds 5 and 6 were typical Schiff
bases as proved by the strong IR absorption of nCvNsk ,1643
and 1647 cm21, respectively).
2.2. Reactions with 1,2-phthaldicarboxaldehyde
The idea to perform reactions with 1,2-phthaldicarboxalde-
hyde was inspired by Broadbent's27 and Shipchandler's28
earlier works as well as our data regarding the unusual
isoindoline derivatives obtained by treatment of the above
dicarbonyl compound with 5-aminoketals of l-p-nitropenyl-
serinol.29 Although preliminary inspection of Drieding
models suggested that it had been possible to construct

C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
2689
,b) The evolution towards N-substituted isoindoline-1-
ones 10a and 10b of the same intermediate 11 could be
explained by the weaker reactivity ,e.g. due to steric
hindrance) of the secondary hydroxyl group in 1-aryl
serinols 1d, e as compared with 1a±c. Hence, the key
step of the reaction should consist, this time, in a 1±4
dehydration to generate the 2-hydroxy pyrrole derivatives
12a and 12b as tautomers of the more stable and isolated
10a and 10b. Thus, Shipchandler's previous assump-
tions28 regarding a related processes ,as a 1,4 shift
hydride and a prototropic transfer) to yield alkyl
1,3-oxazolines starting from simple b-aminoalcohols
was ruled out. In fact, if the global synthesis of
compounds 10a and 10b is deliberately considered only
from a redox point of view, one might better suppose
a preliminary Canizzaro type reaction involving the
1,2-phthaldicarboxaldehyde ,as a masked 1,4-dialde-
hyde) to provide the corresponding 2-hydroxymethyl
benzoic acid ,or its g-lactone). However, the speci®c
conditions required ,temperature and rhodium phosphine
complex, as reported by Bergens in 199032) are essen-
tially different to ours.
min. 150 mg/sample and D1ˆ10 s. All spectra were
measured in anhydrous commercially available DMSO-d6
at room temperature. For the resulting epimers, after equili-
bration, only distinct and/or characteristic peaks are listed.
All chemical shifts as d values are given throughout in ppm;
all coupling patterns as J values are given throughout in Hz.
TLC was performed by using aluminium sheets with silica
gel 60 F254 ,Merckw); ¯ash column chromatography was
conducted on Silica gel Si 60 ,40±63 mm, Merck). IR
spectra were performed on a FT/IR-615 Jascow instrument.
Only relevant absorption are listed ,throughout in cm21 as
very weak ,vw), weak ,w), medium ,m) or ,s) strong).
Speci®c rotations were performed on Jascow DIP-1000
Instrument. The compound 9 was prepared according to
literature.27,28
4.2. General procedure for the preparation of the
compounds 2 and 3b
2-Alkyl serinols 1a, b as a 0.60 M suspension in bezene
,p-TsOH as catalyst) and terephthaldicarboxaldehyde ,2:1
molar ratio, respectively) were re¯uxed in a Dean±Stark
trap for 8±10 h ,until no further water separated, TLC
monitoring, eluent benzene/acetone 3:1v/v, double visuali-
sation: UV 254 nm and I2 bath). The solvent was completely
removed under vacuum and the residue was crystallised from
an appropriate solvent to yield the title compounds 2 and 3b.
Scale-up of the synthesis: starting from 1.00±5.00 g 1a, b.
The identity of the new chiral compounds 10a and 10b was
fully con®rmed by means of combined NMR methods: the
sN±CvO moiety was assigned as amide based on typical
chemical shift of the carbonyl in 13C NMR spectrum
,around 168 ppm); the heterocyclic methylene exhibited
its unusual great vicinal coupling as about 18 Hz. Finally,
the double deuteriation of 10a enabled us to unambiguously
assign the two types of free hydroxyl group ,completely
4.3. Kinetic monitoring of the chain!ring tautomerism
for the compounds %2)!%2a)!%2b)
1
absent in the H NMR spectrum of 13, Scheme 7).
The following values were used: ,time in min)/,% 2; % 2a;
% 2b): ,12)/,82; 18; 0); 38/,73; 24; 3); ,63)/,63; 31; 6);
,102)/,55; 37; 8); 151/,48; 41; 11); ,177)/,45; 44; 11);
,307)/,38; 46; 16).
3. Conclusion
The isomerisations of the reaction products resulting from
1,4-dicarboxaldehyde and certain C-substituted serinols can
be seen either as `chain!ring' or `ring!chain' equili-
brations involving ,E,E)-double Schiff bases, double 1,3-
oxazolidines ,with dominant u con®guration at C-2) via
cis±trans mono oxazolidine Schiff bases. Diastereoselec-
tivity is rather poor in the double oxazolidine series. Equili-
brations are fast ,or spontaneous) as a result of activation
between the two imine groups and the number of free
hydroxymethyl groups. The products from the reaction
between C-substituted serinols and 1,2-phthaldicarboxalde-
hyde are of type isoindoline in nature, depending on the
nucleophilicity of the hydroxymethyl groups.
4.3.1. %E,E)-1,4-Bis-N-%1,3-dihydroxy-2-methylpropane-
2-yl)-phenylene diimine %2). ,92%) white crystalline
powder, mp 113±1148C ,Et2O) [Found: C, 62.0; H, 8.2;
N, 8.7. C16H24N2O4 requires C, 62.30; H, 7.84; N, 9.12%;
N ,after Kjeldahl) 9.0%]; Rf ,75% benzene/acetone) 0.75;
n
max ,Nujol) 1631 ,s, nCvNsk), 1461 ,s) cm21. dH ,300 MHz
DMSO-d6) 8.37 ,2H, s, CHvN), 7.81,4H, s, C Hv
1,4-phenylene), 4.59 ,4H, dd as t, Jˆ5.5, 5.5 Hz, OH),
3.51,4H, dd, Jˆ5.2, 10.6 Hz, CHaHbOH), 3.41,4H, dd,
Jˆ5.8, 10.8 Hz, CHaHbOH), 1.17 ,6H, s, Me); dC
,75 MHz DMSO-d6): 157.6 ,2C, CHvN), 138.3 ,2C, C-q
arom.), 127.9 ,4C, CHv arom.), 65.7 ,4C, CH2OH), 65.0
,2C, C-q), 18.4 ,2C, Me).
4. Experimental
4.1. General
4.3.2. 2-%E)-[4-%4-Hydroxymethyl-4-methyl-1,3-oxazo-
lidine-2-yl)-benzylideneamino]-2-methylpropane-1,3-diol
%2a). ,Both epimers 2a cis and 2a trans as detected by NMR
in solution after equilibration as 47%, Scheme 3, Fig. 2,
Table 1). dH ,300 MHz DMSO-d6) 8.35 ,2H, s, CHvN),
7.76 ,2H, d, Jˆ7.9 Hz, CHv arom.), 7.75 ,2H, d, Jˆ7.9 Hz,
CHv arom.), 7.50 ,2H, d, Jˆ8.3 Hz, CHv arom.), 7.48
,2H, d, Jˆ7.9 Hz, CHv arom.), 5.41,1H, s, H-2), 5.39
,1H, s, H-2), 5.00 ,2H, bs, OH), 4.57 ,4H, bs, OH), 3.78
,2H, d, Jˆ7.7 Hz, H-5), 3.77 ,2H, d, Jˆ7.7 Hz, H-5), 3.60±
3.25 ,12H, m, CHaHbOH), 2.80 ,2H, bs, NH), 1.116 ,3H, s,
Melting points are uncorrected. NMR spectra were recorded
on VARIANw GEMINI 300 instrument operating at 300 and
75 MHz for 1H and 13C nuclei and/or Bruckerw AM300 and
600 instrument operating at 300 ,600) and 75 ,150) MHz for
1H and 13C nuclei, respectively. No SiMe4 was added;
chemical shifts were measured against the solvent peak.
13C NMR spectra ,quantitative experiments) were per-
formed on VARIAN GEMINI 300 instrument by using

2690
C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
Me), 1.163 ,3H, s, Me), 1.154 ,3H, s, Me), 1.151 ,3H, s, Me);
dC ,75 MHz DMSO-d6) 142.6 ,1C, C-q arom.), 142.4 ,1C,
C-q arom.), 136.8 ,1C, C-q arom.), 136.7 ,1C, C-q arom.),
128.2 ,2C, CHv arom.), 128.0 ,2C, CHv arom.), 127.7
,2C, CHv arom.), 127.5 ,2C, CHv arom.), 91.7 ,1C,
C-2), 91.6 ,1C, C-2), 72.5 ,1C, C-5), 72.2 ,1C, C-5), 65.7
,4C, CH2OH), 64.96 ,2C, CH2OH), 64.7 ,2C, C-q), 63.3
,2C, C-4), 22.3 ,1C, Me), 22.2 ,1C, Me), 18.1 ,2C, Me).
140.25 ,C-q in 1,4-phenylene fragment), 126.2 ,4C, CHv
arom.), 91.3 ,2C, C-2), 71.9 and 71.6 ,2C, C-5), 63.0 ,2C,
C-4), 27.4 and 27.3 ,2C, CH2CH3), 8.41and 8.34 ,2C, Me).
4.4. General procedure for the preparation of the
compounds 4b, 5 and 6
1-Aryl serinols 1d, e as a 0.45 M suspension in ethanol ,for
1c as 0.70 M suspension in isopropanol) and terephthal-
dicarboxaldehyde ,2:1molar ratio, respectively) were
re¯uxed for 8±10 h ,TLC monitoring, eluent benzene/
4.3.3. 1,4-Bis%4-hydroxymethyl-4-methyl-1,3-oxazolidine-
2-yl)-benzene %2b). ,All six epimers as detected by NMR
in solution after equilibration as 17%, Scheme 3, Fig. 2,
Table 1). dH ,300 MHz DMSO-d6), 7.43 ,4H, s, CHv
1,4-phenylene), 5.43 ,2H, s, H-2), 4.83 ,2H, bs, OH),
1.138 ,3H, s, Me), 1.134 ,3H, s, Me), 1.127 ,3H, s, Me),
1.124 ,3H, s, Me); dC ,75 MHz DMSO-d6) 140.5, 140.3
and 140.2 ,C-q in 1,4-phenylene fragment), 126.6, 126.5,
126.3, 126.0 and 125.7 ,CHv in 1,4-phenylene fragment),
91.4, 91.3, 91.0, 90.75 and 90.67 ,C-2), 22.5 and 22.0
,Me).
acetone 3:1v/v, double visualisation: UV 254 nm and I
2
bath). The solvent was removed under vacuum and the resi-
due was crystallised from an appropriate solvent to yield the
title compounds 4b, 5 and 6. Scale-up of the synthesis:
starting from 1±5.00 g 1c±e.
4.4.1. %E,E)-1,4-Bis-N-%1,3-dihydroxy-2-hydroxymethyl-
propane-2-yl)-phenylene diimine %4). This compound
was detected by means of NMR in small traces only as
0.25% ,Scheme 3, Fig. 1, Table 1).
4.3.4. %E,E)-1,4-Bis-N-%2-ethyl-1,3-dihydroxypropane-2-
yl)-phenylene diimine %3). ,As detected by NMR in solu-
tion after equilibration 13%, Scheme 3, Table 1). dH
,300 MHz DMSO-d6) 8.40 ,2H, s, CHvN), 7.81,4H, s,
CHv 1,4-phenylene), 4.78 ,4H, dd as t, Jˆ5.5 Hz,
OH), 3.60±3.30 ,8H, m, CHaHbOH), 1.70±1.45 ,4H, m,
CH2CH3), 0.95±0.75 ,6H, m, Me); dC ,75 MHz DMSO-
d6) 157.8 ,2C, CHvN), 138.5 ,2C, C-q arom.), 127.8 ,4C,
CHv 1,4-phenylene), 66.0 ,4C, CH2OH), 65.9 ,2C, C-q),
24.7 ,2C, CH2CH3), 7.4 ,2C, Me).
4.4.2. 2-%E)-[4-%4,4-Bis-hydroxymethyl-1,3-oxazolidine-
2-yl)-benzylideneamino]-2-hydroxymethylpropane-1,3-
diol %4a). ,As detected by NMR in solution after equili-
bration as 14%, Scheme 3, Fig. 1, Table 1). dH ,600 MHz
DMSO-d6) 8.36 ,1H, s, CHvN), 7.67 ,2H, d, Jˆ8.2 Hz,
CHv arom.), 7.40 ,2H, d, Jˆ8.1Hz, C Hv arom.), 5.31
,1H, d, Jˆ11.1 Hz, H-2), 3.63 ,1H, d, Jˆ6.5 Hz, H-5),
3.59 ,1H, d, Jˆ7.6 Hz, H-5), 3.39 ,5H, dd, Jˆ5.2,
11.1 Hz, CHaHbOH), 3.33 ,5H, dd, Jˆ4.9, 11.7 Hz,
±CHaHbOH), 2.67 ,1H, d, Jˆ11.3 Hz, NH);
4.3.5. 2-%E)-[4-%4-Ethyl-4-hydroxymethyl-1,3-oxazolidine-
2-yl)-benzylideneamino]-2-ethylpropane-1,3-diol %3a).
,Both epimers 3a cis and 3a trans, as detected by NMR in
solution after equilibration as 30%, Scheme 3, Table 1). dH
,300 MHz DMSO-d6) 8.36 ,2H, s, CHvN), 7.75 ,2H, d,
Jˆ8.2 Hz, CHv arom.), 7.74 ,2H, d, Jˆ8.2 Hz, CHv
arom), 7.50 ,2H, d, Jˆ8.1Hz, C Hv arom.), 7.49 ,2H, d,
Jˆ8.1Hz, C Hv arom.), 5.42 ,1H, s, H-2), 5.37 ,1H, s,
H-2), 4.93 ,4H, dd as t, Jˆ5.2, 5.2 Hz, OH), 4.57 ,2H, dd
as t, Jˆ5.2, 5.2 Hz, OH), 3.77 ,1H, d, Jˆ7.6 Hz, H-5), 3.76
,1H, d, Jˆ7.7 Hz, H-5), 3.70 ,1H, d, Jˆ7.9 Hz, H-5), 3.69
,1H, d, Jˆ7.9 Hz, H-5), 3.60±3.30 ,12H, m, CHaHbOH),
2.80 ,2H, bs, NH), 1.70±1.45 ,8H, m, CH2CH3), 0.95±
0.75 ,12H, m, Me). dC ,75 MHz DMSO-d6) 142.6 ,1C,
C-q arom.), 142.4 ,1C, C-q arom.), 138.8 ,1C, C-q arom.),
136.7 ,1C, C-q arom.), 127.6 ,2C, CHv arom.), 127.5 ,2C,
CHv arom.), 126.4 ,2C, CHv arom.), 126.3 ,2C, CHv
arom.), 66.0 ,4C, CH2OH), 65.9 ,2C, CH2OH), 63.2 ,2C,
C-4), 62.8 ,2C, C-q).
4.4.3. 1,4-Bis%4,4-bis-hydroxymethyl-1,3-oxazolidine-2-
yl)-benzene %4b). ,87%) white crystalline powder, mp
138±1398C ,MeOH); [Found: C, 56.1; H, 6.9; N, 7.9.
C16H24N2O6 requires C, 56.44; H, 7.11; N, 8.26%; N ,after
Kjeldahl): 8.1%]; Rf ,75% benzene/acetone) 0.50; nmax
,Nujol) 1643 ,vw, nCvNsk), 1498 ,m, nCvCsk), 1165 ,w),
1128 ,w), 1083 ,s, nN±C±O) cm21; dH ,600 MHz DMSO-
d6) 7.34 ,4H, s, CHv 1,4-phenylene), 5.27 ,2H, d, Jˆ
11.2 Hz, H-2), 4.72 ,2H, dd as t, Jˆ5.5, 5.5 Hz, OH), 4.59
,2H, dd as t, Jˆ5.5, 5.5 Hz, OH), 3.62 ,2H, d, Jˆ7.8 Hz,
H-5), 3.58 ,2H, Jˆ7.9 Hz, H-5); 3.35 ,4H, d, Jˆ4.4 Hz,
CHaHbOH), 3.34 ,4H, d, Jˆ4.2 Hz, CHaHbOH), 2.63 ,2H,
d, Jˆ11.3 Hz, NH); dC ,150 MHz DMSO-d6) 141.2 ,2C,
C-q arom.), 126.9 ,4C, CHv arom.), 92.2 ,2C, C-2), 69.8
,2C, C-5), 68.1,2C, C-4), 64.0 ,2C, CH2OH), 63.2 ,2C,
CH2OH).
4.4.4.
%E,E)-1,4-Bis-N-[%1S,2S)-1-phenyl-1,3-propane-
diol-2-yl]-phenylene diimine %5). ,85%) white crystalline
powder, mp 122±1238C ,MeOH); [Found: C, 71.9; H, 6.9;
N, 6.1. C26H28N2O4 requires: C 72.18, H, 6.52, N 6.50%; N
,after Kjeldahl): 6.5%]; Rf ,75% benzene/acetone) 0.65;
4.3.6. 1,4-Bis%4-ethyl-4-hydroxymethyl-1,3-oxazolidine-
2-yl)-benzene %3b). ,59%) white crystalline powder, mp
114±1158C ,i-PrOH). [Found: C, 64.5; H 8.6; N, 8.0.
C18H28N2O4 requires C, 64.24; H 8.39; N, 8.36%. N ,after
Kjeldahl): 8.2%]; Rf ,75% benzene/acetone) 0.75; nmax
,Nujol) 1641 ,vw, nCvNsk), 1152 ,w), 1112 ,w) 1080 ,s,
20
[a]D ˆ19.6 ,c 1.0, MeOH); nmax ,Nujol) 1643 ,m,
nCvNsk), 1599 ,w), 1567 ,w), 1508 ,s), 1462 ,s,
nCvCsk) cm21; dH ,300 MHz DMSO-d6) 8.24 ,2H, s,
CHvN), 7.85 ,4H, s, CHv 1,4-phenylene), 7.40±7.25
,10H, m, CHv arom.), 5.24 ,2H, d, Jˆ6.0 Hz, OH), 4.73
,2H, s, benzyl CH), 4.51,2H, d, Jˆ3.0 Hz, CH2OH), 3.42
,6H, s, sCH±, CHaHbOH); dC ,75 MHz DMSO-d6) 161.0
,2C, CHvN), 143.6 ,2C, C-q arom.), 137.9 ,2C, C-q
n
N±C±O) cm21; dH ,300 MHz DMSO-d6) 7.48 ,4H, s,
CHv 1,4-phenylene), 5.35 ,2H, d, Jˆ11.7 Hz, H-2), 4.54
,2H, dd as t, Jˆ5.4, 5.4 Hz, OH), 3.60±3.30 ,8H, m, H-5,
CHaHbOH), 1.70±1.45 ,4H, m, CH2CH3), 0.95±0.75 ,6H,
m, Me); dC ,75 MHz DMSO-d6) 140.5, 140.4, 140.30,

C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
2691
arom.), 128.2 ,4C, CHv arom.), 127.8 ,4C, CHv arom.),
126.9 ,4C, CHv arom.), 126.3 ,2C, CHv arom.), 78.7 ,2C,
benzyl CH), 73.2 ,2C, sCH±), 61.8 ,2C, CH2OH).
ene ,50 mL) were re¯uxed in a Dean±Stark trap for 12 h
to complete removal of water ,TLC monitoring, eluent
benzene/methanol 3:1v/v, double visualisation: UV
254 nm and I2 bath). The reaction mixture, as a ®ne yellow
suspension, was cooled at room temperature, ®ltered off and
the crude product was washed with ether ,about 50 mL, to
complete removal of unreacted salicylaldehyde), then
recrystallised from hot toluene to yield the title compound
7 ,3.00 g, 88%) as a yellow crystalline powder, mp 164±
1668C ,toluene); [Found: C, 59.0; H, 6.7; N, 6.4. C11H15NO4
requires C, 58.64; H, 6.71; N, 6.24%]; Rf ,75% benzene/
methanol) 0.70; nmax ,Nujol) 1636 ,s, nCvNsk), 1607 ,m),
1556 ,w), 1536 ,s) cm21. dH ,300 MHz DMSO-d6) 9.50
,1H, bs, OH phenol); 8.57 ,1H, s, CHvN±), 7.41,1H, d,
Jˆ7.0 Hz, CHv arom.), 7.29 ,1H, dd as t, Jˆ7.2, 7.2 Hz,
CHv arom.), 6.79 ,2H, dd as t, Jˆ4.2, 4.2 Hz, CHv
arom.), 4.82 ,3H, bs, OH), 3.51,6H, s, C H2OH); dC
,75 MHz DMSO-d6) 164.4 ,1C, CHvN), 163.5 ,1C, C-q
arom.), 132.4 ,1C, CHv arom.), 132.2 ,1C, CHv arom.),
118.4 ,1C, C-q arom.), 117.5 ,1C, CHv arom.), 117.0 ,1C,
CHv arom.), 67.0 ,1C, C-q), 61.3 ,3C, CH2OH).
4.4.5.
%2R,20S,4S,40S,5S,50S)-1-%4-Hydroxymethyl-5-
phenyl-1,3-oxazolidine-2-yl)-4-%40-hydroxymethyl-50-
phenyl-10,30-oxazolidine-20-yl)-benzene %5b). ,As detected
by NMR in solution after equilibration as 30%, Scheme 4,
Table 1). dH ,300 MHz DMSO-d6) 7.64 ,2H, d, Jˆ8.3 Hz,
CHv 1,4-phenylene), 7.60 ,2H, d, Jˆ8.7 Hz, CHv
1,4-phenylene), 7.45±7.19 ,10H, m, CHv arom.), 5.81
,1H, s, H-20), 5.61 ,1H, s, H-2), 5.02 ,1H, dd as t, Jˆ5.5,
5.5 Hz, CH2OH), 4.94 ,1H, dd as t, Jˆ5.5, 5.5 Hz, CH2OH),
4.74 ,1H, d, Jˆ4.9 Hz, H-40), 4.72 ,1H, d, Jˆ4.9 Hz, H-4),
3.62 ,4H, m, ±CHaHbOH), 3.18 ,2H, bs, NH); dC ,75 MHz
DMSO-d6) 142.4 ,1C, C-q arom.), 142.1 ,1C, C-q arom.),
136.4 ,1C, C-q arom.), 136.2 ,1C, C-q arom.), 92.6 and 91.6
,2C, C-2, -20), 80.7 and 79.6 ,2C, C-4, -40), 69.5 and 67.7
,2C, CH2OH), 61.2 and 58.8 ,2C, C-5, -50).
4.4.6. %E,E)-1,4-Bis-N-[%1S,2S)-1-%4-nitrophenyl)-1,3-pro-
panediol-2-yl)-phenylene diimine %6). ,74%) yellowish
crystalline powder, mp 162±1638C ,MeOH); [Found: C,
59.6; H, 4.8; N, 11.0. C26H26N4O8 requires C, 59.74; H,
5.01; N, 10.76%]; Rf ,75% benzene/acetone) 0.70;
4.4.9.
2-%E)-%4-Dimethylaminobenzylideneamino)-2-
hydroxymethylpropane-1,3-diol %8). TRISw ,1.00 g, 8.25
mmol) and p-dimethylaminobenzaldehyde ,1.23 g, 8.25
mmol) in toluene ,25 mL) were re¯uxed in a Dean±Stark
trap for 12 h to complete removal of water ,TLC moni-
toring, eluent methanol/dichloromethane 2:1v/v, double
visualisation UV 254 nm and I2 bath). The reaction mixture,
as a ®ne suspension, was ®ltered hot and the insoluble
deposited TRIS was washed with hot toluene. The combined
toluene solution was cooled at room temperature and ®ltered
to give 1.00 g crude product. The latter was dissolved in
boiling toluene and ®ltered hot, to remove the traces of
unreacted TRIS, then cooled at 08C. The deposited solid
was ®ltered off and washed with cooled ether to yield the
title compound 8 ,0.30 g, 15%) as a yellow crystalline
powder, mp 146±1488C ,toluene); [Found: C, 62.2; H,
8.3; N, 10.8. C13H20N2O3 requires C 61, 86; H, 7.99; N,
11.15%]; Rf ,50% dichloromethane/methanol) 0.70; nmax
,Nujol) 1607 ,s, nCvNsk), 1528 ,s, nCvCsk) cm21; dH
,300 MHz DMSO-d6) 8.28 ,1H, s, CHvN), 7.60 ,2H, d,
Jˆ7.5 Hz, CHv arom.), 6.76 ,2H, d, Jˆ7.5 Hz, CHv
arom.), 4.55 ,3H, bs, OH), 3.48 ,6H, s, CH2OH), 3.28
,6H, s, Me); dC ,75 MHz DMSO-d6) 159.7 ,1C, CHvN),
129.2 ,2C, CHv arom.), 126.1 ,1C, C-q arom.), 124.2 ,1C,
C-q arom.), 111.4 ,2C, CHv arom.), 63.3 ,3C, CH2OH),
61.1 ,1C, C-q), 40.1 ,2C, Me).
20
[a]D ˆ115.7 ,c 1.0, MeOH); nmax ,Nujol) 1647 ,s,
nCvNsk) cm21. dH ,300 MHz DMSO-d6) 8.20 ,2H, s,
CHvN), 8.18 ,4H, d, Jˆ8.7 Hz, CHv arom.), 7.80 ,4H,
s, CHv 1,4-phenylene), 7.64 ,4H, d, Jˆ8.3 Hz, CHv
arom.), 5.64 ,2H, d, Jˆ5.3 Hz, OH), 4.95 ,2H, dd as t,
Jˆ4.9, 4.9 Hz, benzyl CH), 4.63 ,2H, dd as t, Jˆ5.1,
5.1Hz, CH 2OH), 3.64 ,2H, dd, Jˆ5.8, 11.1 Hz, CHaHbOH),
3.56 ,2H, dd, Jˆ4.5, 10.4 Hz, ±CHaHbOH), 3.45 ,2H, m,
H-4, -40); dC ,75 MHz DMSO-d6) 161.5 ,2C, CHvN),
151.6 ,2C, C-q arom.), 146.4 ,2C, C-q arom.), 137.9 ,2C,
C-q arom.), 128.2 ,4C, CHv arom.), 128.0 ,4C, CHv
arom.), 122.9 ,4C, CHv arom.), 77.7 ,2C, benzyl CH),
72.4 ,2C, sCH±), 61.6 ,2C, CH2OH).
4.4.7. %2R,20S,4S,40S,5S,50S)-1-[4-Hydroxymethyl-5-%4-
nitrophenyl)-1,3-oxazolidine-2-yl]-4-%40-hydroxymethyl-
50-%40-nitrophenyl)-10,30-oxazolidine-20-yl)-benzene %6b).
,As detected by NMR in solution after equilibration as 22%,
Scheme 4, Fig. 3, Table 1). dH ,300 MHz DMSO-d6) 8.26
,4H, m, CHv arom.), 7.75±7.57 ,8H, m, CHv arom.), 5.86
,1H, d, Jˆ6.4 Hz, H-20), 5.63 ,1H, d, Jˆ4.2 Hz, H-2), 5.08
,1H, dd, Jˆ4.9, 10.9 Hz, CH2OH), 5.07 ,1H, dd, Jˆ5.6,
10.9 Hz, CH2OH), 4.92 ,1H, d, Jˆ5.3 Hz, H-50), 4.90
,1H, d, Jˆ6.8 Hz, H-5), 3.68±3.52 ,4H, m, CHaHbOH),
3.50±3.42 ,2H, m, H-4, -40), 3.20 ,2H, bs, NH); dC
,75 MHz DMSO-d6 as quantitative carbon, QC NMR
experiment) 150.4 ,1C, C-q arom.), 150.3 ,1C, C-q
arom.), 142.0 ,1C, C-q arom.), 141.5 ,1C, C-q arom.),
136.3 ,1C, C-q arom.), 136.2 ,1C, C-q arom.),127.2 ,2C,
CHv arom.), 127.1 ,2C, CHv arom.), 126.8 ,2C, CHv
arom.), 126.5 ,2C, CHv arom.), 123.6 ,2C, CHv arom.),
4.4.10.
4,4-Bis%hydroxymethyl)-2-%4-dimethylamino-
phenyl)-1,3-oxazolidine %8a). ,As detected by NMR in
solution after equilibration as 50%, Scheme 6). nmax
,Nujol) 1185 ,m), 1127 ,m) and 1087 ,m, nN±C±O) cm21
;
dH ,300 MHz DMSO-d6) 7.28 ,2H, d, Jˆ8.7 Hz, CHv
arom.), 6.73 ,2H, d, Jˆ9.0 Hz, CHv arom.), 5.44 ,1H, s,
H-2), 4.92 ,1H, bs, OH), 4.50 ,1H, bs, OH), 4.20 ,2H, d,
Jˆ8.5 Hz, H-5), 3.78 ,2H, d, Jˆ8.5 Hz, H-5), 3.28 ,6H, s,
Me), 3.01,2H, d, Jˆ10.1 Hz, CHaHbOH), 2.92 ,2H, d, Jˆ
9.1Hz, CH aHbOH), 2.60 ,1H, bs, NH); dC ,75 MHz DMSO-
d6) 127.0 ,2C, CHv arom.), 126.1 ,1C, C-q arom.), 124.2
,1C, C-q arom.), 111.3 ,2C, CHv arom.), 101.3 ,1C, C-2),
82.6 ,1C, C-4), 71.0 ,1C, C-5), 63.3 ,2C, CH2OH), 40.0 ,2C,
Me).
0
123.4 ,2C, CHv arom.), 92.9 and 92.1,2C, C-2, -2 ), 79.9
and 78.9 ,2C, C-5, -50), 69.5 and 67.8 ,2C, C-4, -40), 61.6
and 59.0 ,2C, CH2OH).
4.4.8. 2-%E)-%2-Hydroxybenzylideneamino)-2-hydroxy-
methylpropane-1,3-diol %7). TRISw ,2.00 g, 16.5 mmol)
and salicylaldehyde ,1.90 mL, 2.22 g, 18.2 mmol) in tolu-

2692
C. Maiereanu et al. / Tetrahedron 58 -2002) 2681±2693
4.4.11. %7Sp,8Rp,11r,14s)-14-Aza-11-hydroxymethyl-9,13-
dioxatetracyclo[6.5.1.02,7.011,14]-tetradeca-2,4,6-triene %9).
,80%) white crystalline powder, mp 123±1258C ,methanol)
,lit. 123±1258C27,28); nmax ,Nujol) 1367 ,s, nsN±), 1153 ,m),
1136 ,m) 1108 ,m, nN±C±O) cm21; dH ,300 MHz DMSO-d6)
7.44 ,2H, ddd, Jˆ2.5, 3.5, 8.0 Hz, CHv arom.), 7.43 ,2H,
ddd, Jˆ3.4, 8.0, 10.0 Hz, CHv arom.), 5.73 ,2H, s, H-7,
-8), 4.99 ,1H, t, Jˆ5.3 Hz, OH), 3.98 ,2H, d, Jˆ8.6 Hz,
H-10, -12), 3.67 ,2H, d, Jˆ8.6 Hz, H-10, -12), 3.53 ,2H,
d, Jˆ4.6 Hz, CH2OH); dC ,75 MHz DMSO-d6 as quanti-
tative carbon, QC NMR experiment) 139.0 ,2C, C-q
arom.), 129.8 ,2C, CHv arom.), 124.0 ,2C, CHv arom.),
98.2 ,2C, C-7, -8), 73.3 ,1C, C-11), 72.6 ,2C, C-10, -12),
63.6 ,1C, CH2OH).
d6) 8.14 ,2H, d, Jˆ7.9 Hz, CHv arom.), 7.64 ,2H, d,
Jˆ8.3 Hz, CHv arom.), 7.65±7.56 ,4H, m, CHv arom.),
6.06 ,1H, d, Jˆ4.5 Hz, OH), 5.19 ,1H, dd as t, Jˆ4.3,
4.3 Hz, CH2OH), 4.97 ,1H, dd as t, Jˆ5.3, 5.3 Hz, benzyl
CH), 4.72 ,1H, d, Jˆ17.9 Hz, heterocyclic CHaHb), 4.57
,1H, d, Jˆ18.0 Hz, heterocyclic CHaHb), 4.56 ,1H, s,
sCH±), 3.79 ,1H, dd, Jˆ5.7, 10.6 Hz, CHaHbOH), 3.77
,1H, dd, Jˆ5.7, 11.4 Hz, CHaHbOH); dC ,75 MHz
DMSO-d6) 168.3 [1C, sN±C,vO)±], 151.9 ,1C, C-q
arom), 146.8 ,1C, C-q arom.), 142.8 ,1C, C-q arom.),
132.3 ,1C, C-q arom.), 131.4 ,1C, CHv arom.), 127.9
,1C, CHv arom.), 127.7 ,2C, CHv arom.), 123.5 ,1C,
CHv arom.), 123.4 ,2C, CHv arom.), 123.0 ,1C, CHv
arom.), 71.2 ,1C, benzyl CH), 60.0 ,1C, heterocyclic
CH2), 58.7 ,1C, sCH±), 48.7 ,1C, CH2OH). CARE! The
compound partially decomposes on column chroma-
tography; it is also sensitive to moisture ,see yield).
4.5. General procedure for the preparation of the
compounds 10a and 10b
4.5.3. N-[%1S,2S)-1,3-Bis-deuterioxy-1-phenylpropane-2-
yl)-isoindoline-1-one %13). This compound was obtained
directly in the NMR standard tube by adding one drop of
D2O in the DMSO-d6 solution of 10a. dH ,300 MHz DMSO-
d6) ,only modi®ed coupling patterns with respect to 10a are
listed): 4.93 ,1H, d, Jˆ6.0 Hz, benzyl CH), 4.61,1H, d,
Jˆ18.1 Hz, heterocyclic CHaHb), 4.52 ,1H, d, Jˆ18.1 Hz,
heterocyclic CHaHb), 4.42 ,1H, ddd as q, Jˆ6.0, 6.0, 6.0 Hz,
sCH±), 3.59 ,2H, d, Jˆ6.0 Hz, ±CHaHbOH).
1-Aryl serinols 1d, e ,as a 0.15 M suspension in methanol)
and the corresponding equimolar amount of 1,2-phthaldi-
carboxaldehyde were stirred at re¯ux for 4 h ,TLC monitor-
ing benzene/acetone 3:1v/v, double visualisation: UV
254 nm and I2 bath). The reaction mixture, as a clear solu-
tion, was evaporated in vacuo to give, in each case, an oily
residue. Starting from 1d, the oily residue was crystallised
from dichloromethane/ligroine 1:1 v/v to yield the title
compound 10a. Starting from 1e, the oily residue was
puri®ed by column chromatography ,eluent ligroine/THF
1:1 v/v) to yield the title compound 10b. Scale up of the
synthesis: starting from 0.50±1.00 g 1d, e.
References
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New York, 1985.
4.5.1.
N-[%1S,2S)-1-Phenylpropane-1,3-diol-2-yl)-iso-
indoline-1-one %10a). ,60%) white crystalline powder, mp
154±1568C ,dichloromethane/ligroine 1:1 v/v); [Found: C,
72.3; H, 6.1; N, 4.6. C17H17NO3 requires C, 72.05; H, 6.05;
N, 4.96%]; Rf ,75% benzene/acetone) 0.55; nmax ,Nujol)
Â
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È
1987, 52, 3821±3825.
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È
4. Pihlaja, K.; Parkkinen, A.; Lonnberg, H. J. Chem. Soc., Perkin
1651 ,s, nN±CvO), 1458 ,s) cm21; [a]D ˆ111.0 ,c 1.0,
20
Â
Â
MeOH); dH ,300 MHz DMSO-d6) 7.78 ,1H, d, Jˆ7.5 Hz,
CHv arom.), 7.76 ,1H, m, CHv arom.), 7.72 ,1H, d,
Jˆ7.5 Hz, CHv arom.), 7.62 ,1H, dd as t, Jˆ6.8, 6.8 Hz,
CHv arom.), 7.50 ,2H, dd as t, Jˆ7.0, 7.0 Hz, CHv
arom.), 7.45 ,2H, dd as t, Jˆ7.3, 7.3 Hz, CHv arom.),
7.38 ,1H, m, CHv arom.), 5.80 ,1H, d, Jˆ4.5 Hz, OH),
5.13 ,1H, dd as t, Jˆ5.1, 5.1 Hz, CH2OH), 4.97 ,1H, dd
as t, Jˆ5.5, 5.5 Hz, benzyl CH), 4.79 ,1H, d, Jˆ18.1 Hz,
heterocyclic CHaHb), 4.70 ,1H, d, Jˆ18.1 Hz, heterocyclic
CHaHb), 4.59 ,1H, ddd as q, Jˆ6.0, 6.0, 6.0 Hz, sCH±),
3.79 ,1H, d, Jˆ5.7 Hz, CHaHbOH), 3.77 ,1H, d, Jˆ
5.3 Hz, CHaHbOH); dC ,75 MHz DMSO-d6) 168.4 [1C,
sN±C,vO)±], 143.7 ,1C, C-q arom.), 142.8 ,1C, C-q
arom.), 132.8 ,1C, C-q arom.), 131.3 ,1C, CHv arom.),
128.3 ,2C, CHv arom.), 127.9 ,1C, CHv arom.), 127.4
,1C, CHv arom.), 126.6 ,2C, CHv arom.), 123.5 ,1C,
CHv arom.), 122.9 ,1C, CHv arom.), 71.3 ,1C, benzyl
CH), 59.9 ,1C, heterocyclic CH2), 59.3 ,1C, sCH±), 48.5
,1C, ±CH2OH).
Trans. 2 1983, 1223±1225.
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Â
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Â
14. Darabantu, M.; Ple, G.; Mager, S.; Cotora, E.; Gaina, L.;
4.5.2. N-[%1S,2S)-1-%4-Nitrophenyl)-propane-1,3-diol-2-
yl]-isoindoline-1-one %10b). ,33%) yellowish powder; mp
168±1708C; [Found: C, 62.0; H, 4.8; N, 8.2. C17H16N2O5
requires C, 62.17; H, 4.91; N, 8.57%]; Rf ,50% ligroine/
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20
THF) 0.65; [a]D ˆ19.1, c 1.0 MeOH); nmax ,Nujol)
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2000, 39, 2685±2689.
1653 ,s, nN±CvO), 1459 ,s) cm21; dH ,300 MHz DMSO-

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Â
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