α-(3,7-Dioxa-r-1-azabicyclo[3.3.0]oct-c-5-ylmethoxy)-diazines. Part 1: Synthesis and stereochemistry. Extension to s-triazine series

Article abstract of DOI:10.1016/j.tet.2006.05.031

The general and efficient synthesis of the title compounds, consisting of the (selective) replacement of chlorine in commercial α-chlorodiazines and cyanuryl chloride by the 3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-ylmethoxy group (Williamson method) is described. The stereochemistry of this new series of derivatives is analysed in terms of different conformational chirality exhibited in solution (¹H NMR) versus solid state (X-ray diffractometry), meso against chiral forms, respectively. In solid state, the inclusion capacity of some chiral networks as well as their supramolecular aggregation is pointed out. A good correlation between rotameric behaviour of the c-5-di(s-tri)diazinyloxymethyl group in the two states is found.

Full text of DOI:10.1016/j.tet.2006.05.031

Tetrahedron 62 (2006) 7319–7338
a-(3,7-Dioxa-r-1-azabicyclo[3.3.0]oct-c-5-ylmethoxy)-diazines.
Part 1: Synthesis and stereochemistry. Extension
to s-triazine series
b
c
b
b
Camelia Berghian,a,b Pedro Lameiras, Loıc Toupet, Eric Condamine, Nelly Ple,
´
¨
Alain Turck,b Carmen Maiereanua,b and Mircea Darabantua,b,
*
aDepartment of Organic Chemistry, ‘Babes-Bolyai’ University, 11 Aranyi Jaꢀnos Str., RO-400028 Cluj-Napoca, Romania
b
´
Institut de Recherche en Chimie Organique Fine (I.R.C.O.F.), Universite de Rouen, BP 08, F-76131 Mont Saint-Aignan, France
c
´
Groupe Matieꢀre Condensee et Materiaux, Universite de Rennes I, F-35042 Rennes, France
´
´
Received 13 March 2006; revised 1 May 2006; accepted 11 May 2006
Available online 9 June 2006
Abstract—The general and efficient synthesis of the title compounds, consisting of the (selective) replacement of chlorine in commercial
a-chlorodiazines and cyanuryl chloride by the 3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-ylmethoxy group (Williamson method) is described.
The stereochemistry of this new series of derivatives is analysed in terms of different conformational chirality exhibited in solution (1H
NMR) versus solid state (X-ray diffractometry), meso against chiral forms, respectively. In solid state, the inclusion capacity of some chiral
networks as well as their supramolecular aggregation is pointed out. A good correlation between rotameric behaviour of the c-5-di(s-tri)-
diazinyloxymethyl group in the two states is found.
Ó 2006 Elsevier Ltd. All rights reserved.
H
H
1. Introduction
4
2
4
2
6
8
86 O7
3
5
5
3
7
O
N1
N1
The 3,7-dioxa-1-azabicyclo[3.3.0]octane heterocyclic satu-
ratedsystem Aisreadily availablebydouble cyclocondensation
between TRISÒ (2-amino-2-hydroxymethyl-1,3-propandiol)
and carbonyl compounds, yielding 5-hydroxymethyl-3,7-
dioxa analogous B of the core alkaloid, namely pyrrolizidine
C (Scheme 1).1–4
A
C
DOABO
CH2OH
CH2OH
2 eq.
R-CH= O
1
3
O
4
2
3
68 O7
2
5
HO
OH
N1
H+
NH2
TRIS®
∆
R
R
A series of various C-substituted compounds, having A as
their basic skeleton, have been shown to have high biological
interest: fertilisers, biocides, pesticides and anticancer
agents.5–14
B
DOABO-CH2OH
R = H, (functionalised)alkyl,
(het)aryl
N,X
N
X = C, N
Although focused mainly on applied research, only few of
the results reported previously validated this class as appro-
priate for further functionalisation.
O
6
D
4
5
3O
O7
N1
2
8
A method for direct substitution at the carbon ring is still un-
known. Functionality was ensured classically by the a priori
selection of the substituted starting carbonyl compound,
usually an aldehyde (Scheme 1). Thus, only compounds A
bearing a hydroxymethyl group at C-5 were mentioned
substitution as chiral or meso form:
H, Ph, 2-Py and spiranic moiety
Scheme 1.
to be suitable for functionalisation at this site by acyla-
tion,3–5,7,8,12,15 thionation16 and, recently, by Dess–Martin
oxidation.13 Depending on the new group linked at C-5,
the reported structures are of pharmaceutical7,8,12,13 and
Keywords: Diazines; s-Triazines; Oxazolidines; NMR; Chirality; X-ray
diffractometry.
* Corresponding author. Tel.: +40 264 59 38 33; fax: +40 264 59 08 18;
e-mail addresses: darab@chem.ubbcluj.ro; darabantu@cluj.astral.ro
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.031

7320
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
lately, of supramolecular interest as O-, N-, O-protected
forms of TRISÒ.17
Chiral 1b-trans, 1c, 1d-trans and 1d-cis were used as race-
mates.
Following on from our developments in the synthesis and
stereochemistry of substituted 3,7-DiOxa-r-1-AzaBi-
cyclo[3.3.0]-c-5-Octanes (hereafter throughout abbreviated
as DOABO, Scheme 1),y,18–20 we recently established
that some compounds of type B (Scheme 1, R¼H, Ph) can
be easily converted into 5-alkoxymethyl derivatives, via
potassium alkoxides, in much milder conditions than those
used earlier by Broadbent in 1976 (Williamson method).7,20
Not only they were efficient nucleophiles against aliphatic
halo compounds, but in a single testing example, against
an a-chloro-p-deficient system such as 2,6-dichloropyra-
zine.20
The study of the reaction between potassium alkoxides 2a–e
and a-chlorodiazines was performed using the following
protocol:
(i) For exhaustive substitution of chlorine, 1.05ꢀn equiva-
lents of 2a–e/equivalent of diazine possessing ‘n’ chlo-
rine atoms were used.
(ii) For selective substitution of chlorine, 1 equiv of 2a–e/
equivalent of chlorine to be replaced was used.
All syntheses were systematically TLC monitored.
Series of new compounds 4a–k were prepared starting from
the a-chloropyrazines 3a–c (Scheme 3, Table 1).
An extension of this result required a larger series of compe-
tent substrates. Referring to our previous data about the
selective (or exhaustive) nucleophilic replacement of chlo-
rine in certain p-deficient systems,20,26,27 we considered
a-chlorodiazines and cyanuryl chloride as a challenging
choice for investigating more elaborated building blocks
with potential biological and/or supramolecular interest.
Hence, we wish to report here the synthesis and stereochem-
istry of a new class as 3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-ylmethoxydi(s-tri)azines D (Scheme 1).
R1
R1
i
N
N
N
N
Cl
3a-c
O
4a-k
O
O
3a: R1 = H
3b: 1 = Cl
2
8
N
R5
R
R2
R3
3c: 1 = MeO
R4
R
i: 2a-e / THF, T(°C), t (hrs.)
2. Results and discussion
Scheme 3.
2.1. Synthesis of a-(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-ylmethoxy)-di(s-tri)azines
Only 2a exhibited a ‘methoxide-like reactivity’ regarding
yields and selectivity (entries 1, 7, 9 and 10). Indeed, in
a competitive experiment, equimolar amounts of 2-chloro-
pyrazine 3a/2a/potassium methoxide gave, in identical
conditions (entry 1), the equimolar ratio between 2-methoxy-
pyrazine and 4a. When 2b-cis, 2b-trans, 2c and 2e having
C-2, (-8) (di)substituted DOABO units with (het)aryl groups
were used as nucleophiles, the yields decreased slightly, 4a
(85%) versus 4b-cis (79%) versus 4b-trans (69%), or
strongly, 4a versus 4c (48%) and 4e (44%). The unfavoura-
ble influence of substitution at C-2, -8 was best illustrated
when the results of the one-pot replacement of the two chlo-
rine atoms in 2,6-dichloropyrazine, 2b-cis versus 2a (entries
8 and 10) were compared. Treatment of 3b with 2.1 equiv of
2b-cis yielded a complex mixture of monochloro derivative
4g, the (2Ph)DOABO–CH2O substituting pyrazinone 4h
(issued most probably from the partial hydrolysis of 4g
during the aqueous work-up) and, in traces only, the desired
product 4i. Using 2a as nucleophile, compound 4k was
obtained in a clean procedure as described in a previous
publication of our laboratory.20
The known DOABO derivatives 1a–e19,20 were reacted with
potassium hydride in conditions depicted in Scheme 2.
CH2O-K+
CH2OH
i
O
O
R4
O
O
8
2
8
2
N
N
R4
R1
R1
R2
R2
1a-e
R3
R3
2a-e
i: 1.05 eq. KH / THF / 40 °C / 1.0 - 1.5 hrs.
a: R1- R4 = H
b-cis: R1 = R3 = Ph, R2 = R4 = H
b-trans: R1 = R4 = Ph, R2 = R3 = H
c: R1 = Ph, R2 - R4 = H
d-trans + d-cis:
R1,R2 = CH2CH2[CH(t-Bu)]CH2CH2,
R3 = R4 = H
e: R1 = R3 = 2-Py, R2 = R4 = H
CH2O
Abbreviations:
R = H: (2H)DOABO-CH2O
R = Ph: (2Ph)DOABO-CH2O
O
O
N
The non-separable mixture of DOABO-spiranic derivatives
1d-trans/1d-cis (96:4) (Scheme 2) afforded the correspond-
ing 4d-trans/4d-cis as 96:4 ratio, respectively, in the crude
product and 75:25 after crystallisation from ligroin.
R
R
Scheme 2.
Next, the a-chloropyrimidines 5a–d produced the series
6a–m (Scheme 4, Table 2).
y
Stereochemical descriptor r (reference) is used in order to simplify discus-
sion arising from the basic stereochemistry of this molecule as cis fused
double oxazolidine system, the lone pair at N-1 being the fiducial substit-
uent.21 This spatial arrangement, together with the absence of pyramidal
inversion at N-1 are already well documented.7,11,18–20,22–25
With 2a as nucleophile, both one-pot exhaustive (entries 2, 4
and 6) and selective substitutions (entries 3, 5 and 7) were

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7321
Table 1. Results in the synthesis of a-(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-ylmethoxy)-pyrazines (preparation of compounds 4a–k)
Entry
Nucleophile/Compd
R1
R2
R3
R4
R5
T (ꢁC)
t (h)
Yield (%)
1
2
3
4
5
2a/4a
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
Ph
H
H
40
60
50
65
65
rt
16
20
14
11
2
85
79
69
2b-cis/4b-cis
2b-trans/4b-trans
2c/4c
2d-trans/4d-trans
2d-cis/4d-cis
2e/4e
Ph
Ph
Ph
48
CH2CH2[CH(t-Bu)]CH2CH2
46a
16a
44
12
5
6
H
2-Py
H
2-Py
H
rt
35
rt
65
18
6
52
7
8
2a/4f
2b-cis/4g
/4h
/4i
2a/4j
2a/4k
Cl
Cl
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
83b
34c
17c
6c
Ph
Ph
Ph
H
Ph
Ph
Ph
H
(2Ph)DOABO–CH2O
MeO
(2H)DOABO–CH2O
9
10
65
65
rt
24
3
14
33
H
H
76d
Isolated as a non-separable mixture of diastereomers 4d-trans/4d-cis 75:25 (bridged N-1 and t-Bu groups as references) as deduced from the 1H NMR
spectrum of the crystallised material.
a
Selectivity as 89:11 4f/4k in the 1H NMR spectrum of the crude reaction mixture.
As partial conversions of 3b into 4g–i.
Starting directly from 3b without isolation of the intermediate 4f.
b
c
d
R5
N
R2
N
DOABO–CH2O groups. Their individual assignment, as
well as for the 6b analogous (entry 2), was performed by
1
1
high-resolution H NMR experiments, 2D H–1H (COSY
and TOWNY),28,29 1H–13C (HSQC30,31 and HMBC32,33),
ROESY34,35 and NOESY.36,37
i
N
N
R6
R4
R3
R1
5a-d
6a-m
5a: R1 = Cl, R2 = R3 = H
5b: R1 = R2 = Cl, R3 = H
5c: R1 = H, R2 = R3 = Cl
5d: R1 - R3 = Cl
As in the a-chloropyrazine series, the use of 2b-cis gave
different results (entries 8 and 9): complete replacement
of chlorine in dichloropyrimidines was possible only in
the 2,4-regioisomer (5b/6k) with medium yield. In identi-
cal conditions, starting from 4,6-dichloropyrimidine 5c,
the separable mixture of 6l and 6m was obtained, suggest-
ing that the second substitution of chlorine in 6m was
difficult.
i: 2a, 2b-cis / THF, T(°C), t (hrs.)
Scheme 4.
performed with good yields. The depicted (regio)selectiv-
ities could be ensured in very mild conditions only. Surpris-
ingly (entry 7), the regioisomer 6h was largely dominant
against the expected 6i as confirmed by the NMR spectra
of the pure isolated 6h, which clearly displayed equal
intensity of signals for two magnetically non-equivalent
In the a-chloropyridazine series (Scheme 5, Table 3), we
limited our investigation to the reactivity of 2a exclusively.
Compounds 8a–c were prepared, supporting the validity of
our synthetic findings.
Table 2. Results in the synthesis of a-(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-ylmethoxy)-pyrimidines (preparation of compounds 6a–m)
Entry
Reaction
R4
R5
R6
T (ꢁC)
t (h)
Yield (%)
1
2
3
5a/6a
5b/6b
5b/6c
/6d
5c/6e
5c/6f
5d/6g
5d/6h
/6i
(2H)DOABO–CH2O
(2H)DOABO–CH2O
Cl
(2H)DOABO–CH2O
H
H
H
H
65
40
ꢂ78/rt
4
6
24
60
80
(2H)DOABO–CH2O
(2H)DOABO–CH2O
Cl
63 (71a)
(23a)
81
H
(2H)DOABO–CH2O
Cl
(2H)DOABO–CH2O
Cl
(2H)DOABO–CH2O
Cl
H
4
5
6
7
H
(2H)DOABO–CH2O
(2H)DOABO–CH2O
(2H)DOABO–CH2O
(2H)DOABO–CH2O
(2H)DOABO–CH2O
(2H)DOABO–CH2O
(2Ph)DOABO–CH2O
(2Ph)DOABO–CH2O
(2Ph)DOABO–CH2O
45
ꢂ78/rt
24
19
21
22
H
(2H)DOABO–CH2O
(2H)DOABO–CH2O
Cl
Cl
(2Ph)DOABO–CH2O
H
H
63 (82b)
58
65
ꢂ78/rt
76 (86c)
(8c)
/6j
(6c)
58
8
9
5b/6k
5c/6l
/6m
65
65
21
21
(2Ph)DOABO–CH2O
Cl
31d
23d
Regioselectivity according to the 1H NMR spectrum of the crude reaction mixture: 6% unreacted 5b.
18% 6e according to the 1H NMR spectrum of the crude reaction mixture.
Regioselectivity according to the 1H NMR spectrum of the crude reaction mixture.
Partial conversions of 5c.
a
b
c
d

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C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
Table 4. Results in the synthesis of 3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-
ylmethoxy-s-triazines (preparation of compounds 9a, b, 10a, b)
OCH2-(2H)DOABO
Cl
R
i
N
N
N
N
Entry Starting Nucleophile T (ꢁC)
material
t (h)
Results
Compounds Yield
(%)
R
8a-c
7a, b
1
2
3
1a
2a
2f
2b-cis
65
36
9a
10a
34
82
37
ꢂ78/rt 20
8a: R = Cl
7a: R = Cl
1b-cis
0
65
1
40
10b (51);
9b (10);
1b-cis (39)a
10b (46);
9b (8);
8b: R = MeO
7b: R = MeO
8c: R = (2H)DOABO-CH2O
i: 2a / THF, T(°C), t (hrs.)
4
2g-cis
ꢂ60/rt 20
29
rt
65
48
4
1b-cis (46)a
Scheme 5.
Contents according to the 1H NMR spectra of the crude reaction mixtures.
a
Table 3. Results in the synthesis of a-(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-ylmethoxy)-pyridazines (preparation of compounds 8a–c)
Compd
R
T (ꢁC)
t (h)
Yield (%)
Starting from 1b-cis, its potassium alkoxide 2b-cis rather
than 2g-cis gave this time a slightly higher content of the
trisubstituted product 10b in the crude reaction mixture
(entries 3 and 4). The bias between 9b and 10b was solved
by MS-(FAB+) spectrometry. With the isolated 9a, 10a, 9b
and 10b in our hands, the content of the crude reaction
8a
8b
8c
Cl
MeO
(2H)DOABO–CH2O
40
65
40
4
18
3
86 (96a)
51
78 (90b)
Selectivity according to the 1H NMR spectrum of the crude reaction
mixture: 4% 8c.
Starting directly from 7a without isolation of the intermediate 8a; content
a
b
1
mixtures (Table 4) based on their H NMR spectra was
determined.
according to the 1H NMR spectrum of the crude reaction mixture: 10% 8a.
2.2. Stereochemistry of a-(3,7-dioxa-r-1-azabicyclo-
[3.3.0]oct-c-5-ylmethoxy)-di(s-tri)azines
Finally, the nucleophilicity of the alkoxides based on 1a and
1b-cis was comparatively explored against a more p-defi-
cient system, cyanuryl chloride. Based on the literature
data reporting the reaction between alcohols and cyanuryl
chloride in neutral or basic conditions,38–41 the chemistry
followed is depicted in Scheme 6. The results are summar-
ised in Table 4.
2.2.1. Conformational considerations. As pyrrolizidine C
(Scheme 1), the skeleton of its 3,7-dioxa analogous A is het-
erofacial. All its (hetero)atoms are prostereogenic centres.20
Except H-5, the substitution of any of the hydrogen atoms
generates configurational chirality. We earlier described in
detail this stereochemistry.19,20
The target compounds were the trisubstituted s-triazines 10a
and 10b in a one-pot synthesis.
The basic molecule itself A, a cis fused double oxazolidine
system, as well as its c-C-5-achiral monosubstituted der-
ivatives (e.g., B, R¼H), can exist in a number of flexible
conformations upon pseudorotation occurring at each
oxazolidine ring. Few experimental studies confirmed this
flipping,19,20,23 presumably because determining the frozen
conformation in solution is a quite difficult task, for exam-
ple, in the case of compounds 1a and 1b-cis (Scheme 2).
A much greater dependence with respect to the starting 1a or
1b-cis and their deprotonated forms was observed. Thus, 2a
was efficient only in disubstitution of chlorinewith poor yield
(9a, entry 1). No intermediate of type monoalkoxy was de-
tected. In contrast, the use of its lithium alkoxide 2f (entry
2) permitted rapidly the optimisation of the synthesis towards
the desired 10a in gentle and clean reproducible conditions.
The mass spectra of 9a and 10a (ESI and FAB+, respectively)
fully confirmed the envisaged structures.
Our previous results of the ab initio RHF/6-31G* calcula-
tions20 in gas phase and solvation models predicted that
Cl
1/3 eq.
Cl
R2
N
N
N
CH2OH
CH2OM
Base / THF
N
Cl
N
N
O
O
N
O
O
N
(Base: KH, n-BuLi)
THF / T(°C) / t (hrs.)
R3
R3
R1
R1
R1
R1
2a, f, b-cis, g-cis
9a, b; 10a, b
1a, b-cis
1a: R1 = H
2a: R1 = H, M = K
9a: R2 = Cl, R3 = (2H)DOABO-CH2O
9b: R2 = Cl, R3 = (2Ph)DOABO-CH2O
10a: R2 = R3 = (2H)DOABO-CH2O
10b: R2 = R3 = (2Ph)DOABO-CH2O
2f : R1 = H, M = Li
(2H)DOABO-CH2OH
1b-cis: R1 = Ph
2b-cis: R1 = Ph, M = K
2g-cis: R1 = Ph, M = Li
(2Ph)DOABO-CH2OH
Scheme 6.

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7323
Aliphatic region
6
4
C-4-C-5-C-6
Face cis
5
1
N
3
7
O
O
Aminalic region
Face trans
2
8
O-3-C-2-N-1-C-8-O-7
R2
R2
R2
R2
3O
R1
5
R1
R1
R1
R1
5
5
5
3O
R1
O7
R1
O7
R1
2
∆E
∆E
∆E
1
2
N
N
N
N
1
2
8
1
1
2
1
8
2
2
8
8
O7
3O
3O
O7
O-3-syn-O-7-syn
(s,s)
O-3-syn-O-7-anti
(s,a)
O-3-anti-O-7-anti
(a,a)
O-3-anti-O-7-syn
(a,s)
R2
R2
R2
R2
5
5
5
3O
R1
O7
R1
3O
R1
O7
R1
O7
R1
3O
R1
O7
R1
5
3O 2
R1
N1
N1 8
N1
N1
2
2
8
8
2
8
M,P
M,M
P,M
P,P
meso form
chiral form
meso form
chiral form
∆E1 (kJ/mol)a
∆E2 (kJ/mol)a
Type of structure
Configuration
Achiral
Non-chiral
(meso form)
1r,2R,5s,8S
R1 = H; R2 = CH2OH (1a), MOM
-18.87
-14.86
-5.48
-8.54
R1 = Ph; R2 = CH2OH (1b-cis), MOM
aTypical ∆E values in vacuum and gas phase.19,20
Scheme 7.
the DOABO skeleton could be involved in three different
conformational equilibriums depicted in Scheme 7.
For the present work, we enlarged the analysis to compounds
comprising two, even three identical DOABO units tied
together by an achiral linker L (Schemes 8 and 9).z
Obviously, the linker should be highly symmetric, i.e.,
Cnh, Cnv groups, such as di(tri)methoxy-di(s-tri)azine
fragments. They are statistically achiral, considering the
angular geometry of the –O–CH2– sequence. The last one
can promote a preferred rotamerism, as we will mention
later.
Calculation suggested an oriented flexibility of the bicycle,
ascertained as a single oxazolidine ring inversion/equilib-
rium. It occurs regardless of the configurational nature, achi-
ral or non-chiral, of the structure. The four stereoisomers
were discriminated based on the sense of puckering in the
two oxazolidine rings, syn/anti O-3/O-7, revealed as fused
O-envelope conformers. The lone pair at N-1 was the fidu-
cial substituent for the descriptors syn/anti. The substitution
test shows that the steric relationships between homofacial
protons, aminalic H-2, -8 or aliphatic H-4, -6, are different
in the two types of conformers, enantiotopic in diastereo-
meric meso forms (s,s) or (a,a) but diastereotopic in chiral
forms (a,s) or (s,a).
3
O
7'
O
O
O
O
O
4
6
6'
4'
2
8
8'
2'
M
P
N
N
1N
L
N
N
N 1'
L
5
5'
M
P
O
O
I
II
7
3'
P,M-P,M
meso form
P,P-M,M
meso form
Next, in order to designate enantiomeric and meso form con-
formations, the two torsion angles in the aminalic part of the
skeleton, C-5–N-1–C-2–O-3 and C-5–N-1–C-8–O-7, were
selected and defined by using the helicity rules descriptors
M and P.
O
O
O
O
O
O
L
N
N
L
O
O
O
III
P,M-M,M
IV
P,P-P,M
chiral form
chiral form
As shown in Scheme 7, the occurrence of the meso (M,P)
conformer can be reasonably ruled out since it was found
much less stable than the alternativemeso (P,M)diastereomer
and the chiral conformers (M,M)h(P,P). Only the equilibri-
ums (M,M)$(P,M)$(P,P), consistingof two diastereomeric
inversions and, overall, an enantiomeric interconversion,
are to be considered. However, the magnitude of the cor-
responding DE2 values precluded an a priori assignment of
the frozen conformation in gas phase as well as in solution.20
O
O
O
O
O
O
N
N
N
N
L
L
V
VI
O
M,M-M,M
chiral form
P,P-P,P
chiral form
Scheme 8.
These results, issued from an apparently restrictive rotation
about the C–O–C bonds only, were proved by our inspection
of some earlier X-ray crystallographically determined struc-
tures in this class.20,24,25
z
In Schemes 8 and 9, the DOABO homomorphic substitution at C-2, -8 was
omitted for the reason of simplicity.

7324
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
8
2
1
N
N
N
P
M
O3
O
O
O
O
7
O
5
4
6
3"
6'
4"
O7'
8'
O
O
O
P
O
O
L
L
L
M
2"
5"
5'
1" N
N
N
N1'
N
N
6"
4'
M
P
3'O
P,M-P,M-P,M
O
O
7"O
2'
O
M,M-P,M-P,M
O
P,P-P,M-P,M
8"
VIII
IX
VII
chiral form
chiral form
meso form
N
O
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
L
O
O
L
L
L
N
N
N
N
N
N
N
N
O
O
M,M-P,M-P,M
O
P,P-P,M-P,P
O
O
M,M-P,P-P,M
O
P,P-M,M-P,M
O
O
X
XII
XIII
XI
meso form
meso form
chiral form
chiral form
120 °
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
L
L
L
L
N
N
N
N
N
N
N
N
O
O
P,P-P,P-P,P
O
O
O
XVII
O
O
O
P,P-M,M-P,P
XIV
XV
XVI
M,M-M,M-M,M
chiral form
M,M-M,M-P,P
chiral form
chiral form
chiral form
Scheme 9.
The stereoisomerism depicted in Schemes 8 and 9 is exacer-
bated although, by neglecting all the DOABO meso-(M,P)
type forms (Scheme 7), the conformational analysis is
simplified.
inversion. These two parameters were available by applying
the Eyring equations (Eqs. 1 and 2).21,42
À
Á
0:5
kc ¼ 2:22 Dn2 þ 6J2
½sꢂ1
ꢃ
ð1Þ
ð2Þ
In this purpose, we applied our previous proposal, namely
local stereochemistry, referring to compounds possessing
only one DOABO unit (Scheme 7) and global stereochemis-
try defining molecules built on two or three DOABO units
(Schemes 8 and 9).20 In this approach, ‘dimeric’ DOABO
derivatives can exist as two global meso forms, I and II,
and four global chiral forms, two racemates III–IV and
V–VI. ‘Trimeric’ DOABO derivatives, the s-triazines 10a,
10b, provide three global meso forms, VII, XII and XIII,
and eight global chiral forms, four racemates, VIII–IX,
X–XI, XIV–XVand XVI–XVII. The common feature is that
each conformer I/VI and VII/XVII can be generated,
step by step, in a single oxazolidine ring inversion/equilib-
rium, following the pathways depicted in Schemes 8 and 9.
DGs ¼ 19:14 Tcð10:32 þ log Tcoales:=kcÞ ½J=molꢃ
The results are listed in Table 6. They refer throughout to
a single oxazolidine ring inversion/equilibrium placed in
different environments, created by the number of DOABO
units (1–3)/compound.
The 1H DNMR behaviour of the simplest compound, 4a, is
shown in Figure 1.
We assigned the spectral shape above the coalescence
point as to refer to the fast conformational interconversion
involving the exchanging sites illustrated in Scheme 7
(Eq. 3):
2.2.2. Determining the stereochemistry in solution by 1H
DNMR. A stereochemical analysis, focused on compounds
4a, 4k, 6e, 6l, 10a and 10b, was carried out by 1H DNMR at
low temperature (293–173 K) in THF-d8 on 400 MHz time-
scale. The results obtained prompted us to discuss the behav-
iour of the two building heterocyclic systems separately.
4a ðM;MÞ$4a ðP;MÞ$4a ðP;PÞ
ð3Þ
Both equilibriums were seen as first-order reactions and
equally populated. Consequently, the kc value was approxi-
mated to be the same for the forward and the reverse pro-
cesses. The supporting reason is that the calculated DE2
values, chiral versus meso form (Scheme 7), were small
enough. Since the temperature of coalescence was revealed
to be the same for both the aminalic and aliphatic methylenes
(Fig. 1), we concluded that these two ‘internal clocks’ were
2.2.2.1. Conformational analysis of the DOABO coun-
terparts. In Table 5, the main chemical shifts at room tem-
perature (Ti), at coalescence (Tcoales.) and at the lowest
temperature (Tcalcd) are collected. The last one was used
for calculation of the rate constant at coalescence (kc) and
the free enthalpy of activation (DGs) of DOABO ring

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7325
Table 5. Relevant 1H DNMR data [d (ppm) in THF-d8] of compounds 4a, 4k, 6e, 6l, 10a and 10b
O
H-t
H-t
H-c
H-c
R
N
R
N
6(')(")
4(')(")
5(')(")
N
N
N
O
O
5
5
N
2
N
N
3
8(')(")
2(')(")
R1
R2
R
R
R
R
R
H-t H-t
4a: R1 = H, R2 = (2H)DOABO-CH2O 6e: R = (2H)DOABO-CH2O 10a: R = (2H)DOABO-CH2O
6l: R = (2Ph)DOABO-CH2O 10b: R = (2Ph)DOABO-CH2O
R = H-c, (2H)DOABO-CH2O
R = Ph, (2Ph)DOABO-CH2O
4k: R1 = R2 = (2H)DOABO-CH2O
Compd
Ti (K)
d
d
dd
Tcoales. (K)
Tcalcd (K)a
Aminalic methylenesb
Aliphatic methylenesc
Heteroaromatic
( )(
00
)
( )(
00
)
( )(
)
( )( )
00
H-2(8) 0 -c
H-2(8) 0 -t
H-4(6) 0 -c
H-4(6) 0 -t
00
4a
293
268
253
4.42
4.40
3.84
3.81
H-3: 8.20
H-3: 8.21
H-3: 8.23
4.41
4.41
4.39
4.39
3.83
3.82
4.42
4.42
4.40
4.40
3.84
3.84
3.82
3.81
4k
6e
293
263
183
H-3, -5: 7.78
H-3, -5: 7.79
H-3, -5: 7.85
4.45
4.39
4.38
4.38
3.88
3.78
3.81
3.76
293
273
173
H-5: 6.12
H-5: 6.15
H-5: 6.35
3.77
3.78
4.45
4.40
4.35
4.38
3.85
3.76
10a
293
273
213
—
—
—
3.80
3.84
3.78
3.76
4.43
4.37
6l
293
173
—
—
5.59
5.58
4.00
3.96
3.91
3.96
H-5: 5.75
H-5: 6.12
10b
293
233
193
—
—
—
5.58
5.58
5.58
3.98
3.92
—
—
—
3.96
3.99
3.94
Temperature at which the parameters Dn and 2J were extracted from the spectrum and used for calculation of parameters kc and DGs (see Table 6).
a
Doublets with 2J¼5.2–5.6 Hz and singlets in 6l, 10b above Ti and below Tcoales.
.
b
c
d
Doublets with 2J¼8.4–9.0 Hz.
Protons having ortho relationships with DOABO–CH2O groups.
synchronised. They provided similar DGs values (Table 6,
However, upon cooling, only in diazines 4k, 6e and s-tri-
azine 10b did the (2H)DOABO signals expose a single clear
point of coalescence followed by a new relevant splitting as
(AB)/(A2)/(AB) systems. For 4k and 6e only, it was
again possible to double-check the calculation of kc and
DGs, the values arising from the identical evolution of the
aminalic and aliphatic methylenes (Table 6, entries 2 and
3). The calculated energetic barriers of compounds 4a, 4k
and 6e agree with the literature data.43
entry 1).21
Below coalescence, we ascertained the spectral appearance
to depict the (2H)DOABO unit in 4a as frozen meso-(P,M)
conformer (Cs symmetry, Scheme 7) because the homofacial
aminalic (or aliphatic) protons were isochronous, hence
enantiotopic (e.g., H-2-c vs H-8-c, etc.).
In the same way, at room temperature, the DOABO units
in polysubstituted analogues 4k, 6e, 6l, 10a and 10b were
magnetically equivalent and flipping structures (Table 5).
The 1H DNMR spectra of the s-triazine 10a displayed
two points of coalescence, 293 K (aliphatic methylenes)
Table 6. 1H DNMR data, kc (sꢂ1) and DGs (kJ/mol) values of DOABO oxazolidine ring inversion in compounds 4a, 4k, 6e, 6l, 10a and 10b
Entry
Compd
Oxazolidine ring inversion data
Aminalic zone: H-2(8) 0 -c versus -t Aliphatic zone: H-4(6) 0 -c versus -t
( )(
)
( )(
00
)
00
a
b
a
b
Tcoales.
(K)
Tcalcd
(K)
Dn
(Hz)
2J
(Hz)
kc
(sꢂ1
DGs
(kJ/mol)
Tcoales.
(K)
Tcalcd
(K)
Dn
(Hz)
2J
(Hz)
kc
(sꢂ1
DGs
(kJ/mol)
)
)
1
2
3
4
5
6
4a
4k
6e
10a
6l
10b
268
263
273
273
—
253
183
173
213
—
6.8
28.8
38.1
23.0
—
5.6
5.2
5.4
5.4
—
68.0
139.8
179.1
117.3
—
56.0
53.3
54.9
55.8
—
268
263
273
293
173
233
253
183
173
213
—
9.0
29.0
37.9
29.4
—
9.0
8.6
8.7
8.9
—
105.7
159.1
192.9
162.5
—
55.0
53.1
54.7
59.3
—
—
—
—
—
—
—
193
19.9
9.1
132.8
47.1
Temperature at which the parameters Dn and 2J were extracted from the spectrum and used for calculations.
a
The kc values issued by applying Eq. 1 were multiplied by 2 since the DOABO system is a double oxazolidine structure.21,42
b

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C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
Pyrazine
H-5
(2H)DOABO-CH O
2
H-2(8) 5-OCH
-c, -t
H-4(6)
-c, -t
H-6
H-3
2
AB
AB
J
=1.32
2
2
J=1.54
A
A
2
2
A
A
2
2
AB
J=1.21
AB
J=1.00
2
2
Figure 1. 1H DNMR spectra of compound 4a (400 MHz, THF-d8).
and 273 K (aminalic methylenes) providing two notably dif-
ferent DGs values (Table 6, entry 4). The DGs value issued
from the analysis of the aliphatic methylenes was more
credible because the difference DT¼Tcoales.ꢂTcalcd was
00 00
greater (80 K) at C-4(6)(0)( ) than at C-2(8)(0)( ) (60 K).42
The higher DGs value of the oxazolidine ring inversion in

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7327
10a should be plausible since, as a trisubstituted structure, it
was the most crowded term in the series of (2H)DOABO–
CH2O group containing 4a, 4k and 6e.
This rotamerism could explain the observed splitting at
C-4(6) as two partially overlapping AB systems. In addition,
the resonance of the pyrazine proton H-3 was significantly
shifted downfield from 8.20 (294 K) to 8.29 ppm (183 K)
presumably because of its statistical coplanarity with one
of the lone pairs of the exocyclic oxygen (rotamer 4a
XIX). We entitled this spatial arrangement s-trans out bisec-
tional rotamer with reference to the orientation of the pyra-
zin-2-yloxymethyl fragment against the bicycle DOABO.
Nevertheless, in the case of a more crowded compound than
10a, (2Ph)DOABO–CH2O groups trisubstituting the s-tri-
azine 10b, the results of the DNMR experiments had to be
compared with those of 6l possessing two meta related
(2Ph)DOABO–CH2O groups. Thus, 6l presented but coales-
cence of the methylenes C-4(6)(0) at the limit of the temper-
ature domain, 173 K (Tables 5 and 6, entry 5) preventing us
to assign its rigid conformation. That is, pyrimidine 6l be-
haved like simpler (2Ph)DOABO–CH2OR (R¼H, Et, Me)
derivatives.19,20 In contrast, the s-triazine 10b reached
coalescence at 233 K (Table 6, entry 6).x The corresponding
DGs value was, however, the smallest in the entire series
under investigation, in agreement with our earlier results
referring to the faster flipping aptitude of the structures
(2Ph)DOABO against (2H)DOABO, for example, 1b-cis
against 1a.20
By decreasing the temperature (Table 5), deshielding of the
diazine protons ortho to the CH2O linkage in 4k, 6e and even
in the still flipping 6l was observed as well. If so, the same
nearly coplanar s-trans out bisectional conformation could
expose these protons to the deshielding proximity of one
of the lone pairs of the oxygen atoms in the CH2O connec-
tivity as rotamers of types XX and XXI. Accordingly, at
low temperature, as for 4a, our conclusion designates
diazines 4k, 6e and 6l to be statistically also s-trans out
bisectional rotamers.
Just below coalescence, the compounds 4k, 6e, 10a and 10b
were established as frozen double or triple local meso (P,M)
form DOABO conformers building global meso forms of
type I (Scheme 8, 4k and 6e) and of type VII (Scheme 9,
10a, 10b). The isochronous aminalic or aliphatic homofacial
protons, which were found enantiotopic (Table 5), motivate
this conclusion.
2.2.3. Determining the stereochemistry in solid state by
X-ray diffractometry. Compounds 4b-cis, 4c, 4k, 6l and
10b supplied crystals suitable for study by X-ray diffracto-
metry. Their crystallographically determined structures are
depicted in Figures 2–6. The relevant bond angles and
bond lengths are collected in Tables 7 and 8, respectively.
2.2.3.1. Local stereochemistry as frozen conformation
and blocked rotamerism (Scheme 11, Table 7). Inspec-
tion of all ORTEP diagrams showed exclusively the chiral
O-syn-O-anti opposite orientation of the two cis fused oxa-
zolidine rings as O-envelope conformers. Indeed, the corre-
sponding torsion angles are small enough, ranging between
0.19 and 7.2ꢁ. The torsion angles in the aminalic zone, used
to assign the conformational chirality of the DOABO skele-
ton (Schemes 7 and 11), are noteworthy, 16.8–28.9ꢁ in
2.2.2.2. Rotameric behaviour of the c-5(0)-di(s-tri)-
azinyloxymethyl sequence. In the case of compound 4a
only (Table 6, entry 1), for the calculation we had to use
spectral values Dn and 2J not well below the coalescence21,42
because a subsequent process occurred (Fig. 1). Besides the
broadening of all signals, an unexpected multiplicity of
those of methylenes C-4(6) appeared. The slow rotation of
pyrazine ring about the C-2(pyrazine)–O bond might be re-
sponsible for generating two distinct populations of rotamers
4a XVIII and 4a XIX (Scheme 10).
( )( )
( )( )
00
O-3 0 00 -syn rings and 21.3–28.0ꢁ in O-7 0 -anti rings.
The torsion angles describing the rotamerism of the c-5(0)( )
-
00
di(s-tri)azinyloxymethyl motif point to its almost coplanar,
bisectional, s-trans and out arrangement with respect to
the medium plane of the bicycle. The most significant devi-
ations from coplanarity, 13–17ꢁ, are observed regarding the
s-trans conformation of the bulky substituents about the
N
N
3
N
N
H
O
O
( )( )
00
( )( )
00
bonds C-9 0 –O-10 0 . The rest of deviations are con-
H4
H
5
H
H
5
siderably smaller, 0.2–6.0ꢁ.
4
6
6
N
N
H
H
H
H
O
O
O
O
None of the above assignments was mandatory to the
presence of phenyl groups linked in positions pseudo-
4a
4a
XVIII
XIX
equatorial-bisectional at C-2(0)( ) and pseudo-axial-orthogo-
00
H
O
N
N
H
O
nal at C-8(0)( )
.
00
3
5
N
N
5
O
O
2.2.3.2. Stereoelectronic effects creating local chirality
(Scheme 11, Table 8). In the O-7(0 00)-anti oxazolidine
H
6e, 6l
)(
4k
( )( )
rings, the contraction of the bonds N-1 0 00 –C-8(0)( ) versus
00
XX
XXI
N-1(0)(00)–C-5(0)( ) (selected as reference), found significant
00
Scheme 10.
˚
in all compounds, around 0.030 A, has been recently
explained by Pavia25 and then by us20 in terms of the hyper-
conjugative interaction (endo-anomeric effect)25 involving
x
The s-triazines 10a and 10b were the two cases in which, at the limit of the
temperature domain, 173 K, the non-equivalence between DOABO units
was displayed but the spectral appearances were not appropriate for
pertinent assignments.
( )( )
00
( )( )
00
( )( )
00
the orbitals lpN-1 0 ax. (donor)/s*C-8 0 –O-7 0
(acceptor). This stereoelectronic effect is due to their near
antiperiplanar position created by the frozen oxazolidine

7328
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
M,M
M,M
O-7-anti
O-7-anti
C-11
O-10
N-12
H-6-t
H-6-t
N-4
N-4
H-p
N-1
C-4
C-9
B
O-3-syn
A
A
C-5
C-6
N-1
C-2
H-p
N-4
N-4
C-8
O-7-anti
N-1
H-6-t
O-7-anti
H-6-t
O-7-anti
P,P
P,P
P,P
bisectional
orthogonal
(a)
(b)
Figure 2. (a) The X-ray crystallographically determined structure of compound 4b-cis; (b) the non-bonding interactions in the elementary cell.
NNX
(12)(')(")
12(')(")
11(')(")
10(')(")
N-12
( )(
)
O
ax.9 ' "
3(')(")
eq.
4(')(")
5(')(")
O
O-3-syn
C-4
6(')(")
C-12
N
O-10
1(')(")
2(')(")
C-11
8(')(")
7(')(")
O
C-2
O-3-syn-O-7-anti
bisectional
C-9
bonding
C-5
N-1
M,M
C-8
5(')(")
5(')(")
3(')(")
3(')(")
7(')(")
O-7(')(")
C-6
O
O+
O
+N
-N
O-7-anti
8(')(")
1(')(")
2(')(")
1(')(") 8(')(")
2(')(")
major
minor
non-bonding
XXIII
Figure 3. The X-ray crystallographically determined structure of com-
pound 4c.
non-bonding
XXII
Scheme 11.
O-3(0)(00)–C-2(0)(00). They were shorter than O-7(0)(00)–C-8(0)( )
00
˚
with about 0.17 A, covering however a larger domain of fluc-
˚
tuation, 0.05–0.050 A. As above, this contraction originates
C-11’
C-11
in the O-syn-envelope geometry of the ring favouring the
close to antiperiplanar arrangement of the orbitals lpO-
O-10’
O-10
C-4’
( )( )
( )( )
( )( )
00
3 0 00 eq./s*C-2 0 00 –N-1 0 , hence the second as weaker
N-12(’)
C-9’
C-6
delocalising interaction (e.g., Edel¼30.93 kJ/mol in 4k20).
C-9
C-6’
C-5
C-5’
N-1’
O-3’-syn
The matching minor non-bonding structures XXIII reveal
O-7’-anti
C-8’
C-4
O-7-anti
( )( )
a decreased basicity of the O-3 0 -syn atom.
00
C-8
O-3-syn
C-2’
N-1
We concluded that the chirality of the DOABO skeleton was,
in fact, the major consequence of the cross endo-anomeric
effect, consisting in two and identically oriented delocalisa-
tion in the syn–anti aminalic part of the bicycle. The differ-
ent basicity of the intracyclic oxygen atoms could be of
practical interest, as already outlined in the literature in the
case of the starting material 1b-cis.44,45
M,M
C-2
M,M
Figure 4. The X-ray crystallographically determined structure of compound
chiral 4k.
O-anti-envelope conformation. For example, in the case of
compound 4k, we lately estimated the energy of this deloc-
alisation, Edel.¼38.42 kJ/mol (NBO method).20 The corre-
2.2.3.3. Global stereochemistry and supramolecular
interactions. In solid state, the essential characteristic of
polysubstituted compounds 4k, 6l and 10b was their crystal-
lisation as global chiral forms. The same sense of chirality is
exposed by the DOABO groups in duplicate (4k, 6l), even in
triplicate (10b) (Figs. 4–6).
sponding major non-bonding structure XXII suggests the
( )( )
00
increased basicity of the O-7 0 -anti atom.
In the O-3(0)(00)-syn oxazolidine rings, a second noticeable
contraction was detected this time regarding the bonds

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7329
O-7-anti
bisectional
M,M
O-3-syn
H-4-c
C-2
N-1
C-4
C-5
O-7’-anti
H-4’-c
orthogonal
C-6
P,P
O-10
C-11
C-8
D
O-7-
anti
C-9
O-10’
C-6’
C-5’
C-9’
H-4’-c
N-12
O-7’-anti
M,M
C-11’
O-7’-anti
orthogonal
N-12’
C-8’
O-7-anti
P,P
H-4-c
N-1’
C-2’
C-4’
C
P,P
P,P
M,M
O-3’-syn
H-4-c
O-7-anti
H-4’-c
bisectional
(a)
O-7’-anti
M,M
(b)
Figure 5. (a) The X-ray crystallographically determined structure of compound 6l; (b) the non-bonding interactions in the network.
The network of 4k consisted in global chiral form units of
type V (Scheme 8) in a high occupation factor, 0.87 and
global meso form units (not depicted, type II, Scheme 8)
in a low occupation factor, 0.13. As shown in Figure 4, 4k
was a non-stoichiometric solvate of dichloromethane. The
solvent, located in the channels of the network, had an occu-
pation factor of 0.96. The dominant incidence of global
chiral against meso form units appeared to us mandatory
to the inclusion aptitude of chiral 4k. Indeed, the alternative
meso 4k structure exhibited strong geometric distortions,
discussed previously by us,20 hence, lower inclusion ability.
Moreover, the entire network was stable only in the presence
of the solvent.
Stronger dichloromethane incorporating capacity mani-
fested the network of the s-triazine 10b (Fig. 6), found as
triple chiral form of type XV (Scheme 9). It was ascertained
to be a stable equimolar adduct with dichloromethane (omit-
ted in Fig. 6 for the reason of simplicity).
Important non-bonding interactions were identified in the
networks of compounds 4b-cis and 6l.
O-7-anti
O-3-syn
C-2
C-4
orthogonal
C-8
bisectional
C-5
bisectional
N-12
O-10
C-6
N-1
C-6’’
O-10”
O-7’’-anti
C-9
P,P
C-11
C-5’’
C-11”
C-8’’
N-12’
N-12” C-9”
C-11’
N-1’’
C-2’’
C-4’’
orthogonal
O-3’-syn
P,P
C-4’
O-10’
O-3’’-syn
C-9’
C-2’
C-5’
P,P
C-6’
N-1’
bisectional
C-8’
O-7’-anti
orthogonal
bisectional
Figure 6. The X-ray crystallographically determined structure of compound 10b.

7330
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
Table 7. Relevant torsion angles (ꢁ) of compounds 4b-cis, 4c, 4k, 6l and 10b
Torsion angles
Compound
chiral 4ka
4b-cis
4c
6l
10b
Oxazolidines O-envelope conformation
0
00
O-3( )( )-syn rings
C-4–C-5–N-1–C-2
C-40–C-50–N-10–C-20
C-400–C-500–N-100–C-200
+1.3(2)
—
—
ꢂ1.46(16)
ꢂ6.8(3)
ꢂ7.2(3)
—
ꢂ0.26(13)
ꢂ0.19(13)
—
ꢂ4.1(3)
+3.8(3)
+4.1(3)
—
—
0
00
O-7( )( )-anti rings
C-6–C-5–N-1–C-8
C-60–C-50–N-10–C-80
C-600–C-500–N-100–C-800
ꢂ1.6(2)
—
—
+1.17(18)
—
—
ꢂ2.8(3)
ꢂ3.8(3)
—
ꢂ4.07(13)
ꢂ2.54(14)
—
ꢂ4.5(3)
ꢂ1.6(3)
ꢂ0.9(3)
DOABO units conformational chirality
0
00
O-3( )( )-syn rings
C-5–N-1–C-2–O-3
C-50–N-10–C-20–O-30
C-500–N-100–C-200–O-300
+23.3(2) P
—
—
ꢂ24.37(16) M
ꢂ18.6(3) M
ꢂ16.8(4) M
—
+23.80(14) P
+24.09(14) P
—
+28.9(3) P
+20.9(3) P
+22.3(3) P
—
—
0
00
O-7( )( )-anti rings
C-5–N-1–C-8–O-7
C-50–N-10–C-80–O-70
C-500–N-100–C-800–O-700
+24.0(2) P
—
—
ꢂ26.31(18) M
ꢂ21.6(4) M
ꢂ21.3(4) M
—
+27.60(13) P
+26.24(13) P
—
+28.0(3) P
+25.7(3) P
+24.8(3) P
—
—
( )(
00
)
Coplanarity of the c-5 0 -di(s-tri)azinyloxymethyl sequences
N-1–C-5–C-9–O-10
N-10–C-50–C-90–O-100
N-100–C-500–C-900–O-1000
ꢂ176.93(17)
+177.68(14)
—
—
+173.96(19)
174.78(19)
—
ꢂ177.10(10)
ꢂ175.54(11)
—
ꢂ176.0(2)
ꢂ176.9(2)
ꢂ174.2(2)
—
—
C-5–C-9–O-10–C-11
C-50–C-90–O-100–C-110
C-500–C-900–O-1000–C-1100
ꢂ172.91(19)
+167.01(15)
—
—
+178.57(19)
+178.2(2)
—
ꢂ168.55(11)
ꢂ163.21(11)
—
ꢂ163.9(3)
ꢂ173.4(3)
ꢂ179.3(3)
—
—
C-90–O-10–C-11–N-12
C-9 –O-100–C-110–N-120
C-900–O-1000–C-1100–N-1200
ꢂ3.3(3)
—
—
ꢂ2.5(2)
—
—
ꢂ6.1(3)
+3.2(3)
—
ꢂ4.77(19)
ꢂ2.82(19)
—
ꢂ178.0(3)
ꢂ176.7(3)
ꢂ0.2(4)
a
For the meso form 4k see text and Ref. 20.
˚
The elementary cell of 4b-cis was a tetramer (Fig. 2b), based
on two different types of intermolecular interactions (a)
and (b). The interatomic distances that we associated to
these interactions are: (a) H-6-t(DOABO)/N-4(pyrazine)
2.550(3) A and N-1(pyrazine)/H-para(C-2-pseudo-equa-
˚
torial-bisectional phenyl ring) 2.636(2) A. They are smaller
than the corresponding sum of the van der Waals radii
˚
46
(SvdW N/H) 2.74 A. The interactions (a) close two
˚
Table 8. Relevant bond lengths (A) of compounds 4b-cis, 4c, 4k, 6l and 10b
Compd
N-1–C-5
N-1–C-8
N-10–C-80
N-100–C-800
O-7–C-8
O-3–C-2
O-30–C-20
O-300–C-200
N-10–C-50
N-100–C-500
O-70–C-80
O-700–C-800
Length
Contractiona
Length
Contractionb
( )(
)
( )( )
00
00
O-7 0 -anti ring
O-3 0 -syn ring
4b-cis
1.486(3)
1.491(2)
1.460(3)
1.455(2)
ꢂ0.026
ꢂ0.036
1.425(3)
1.427(2)
1.416(3)
1.416(2)
ꢂ0.009
ꢂ0.011
4c
chiral
1.493(3)
1.480(3)
1.448(4)
1.454(4)
ꢂ0.045
1.403(4)
1.405(4)
1.398(4)
1.355(5)
ꢂ0.005
4kc
ꢂ0.026
ꢂ0.050
6l
1.4890(17)
1.4908(17)
1.4579(18)
1.4648(18)
ꢂ0.0311
ꢂ0.026
1.4411(18)
1.4391(17)
1.4227(17)
1.4172(17)
ꢂ0.0187
ꢂ0.0219
10b
1.483(4)
1.491(4)
1.486(4)
1.462(4)
1.465(4)
1.464(4)
ꢂ0.021
ꢂ0.026
ꢂ0.022
1.438(4)
1.437(5)
1.434(4)
1.421(4)
1.420(4)
1.427(4)
ꢂ0.017
ꢂ0.017
ꢂ0.007
( )(
)
( )( )
00
a
With respect to N-1 0 –C-5 0
.
.
00
( )(
00
)
( )(
00
)
b
c
With respect to O-7 0 –C-8 0
For the meso 4k see text and Ref. 20.

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7331
identical cavities A, meanwhile the interactions (b) lock the
central cavity B. Two 4b-cis partners, having an opposite
sense of chirality of the DOABO groups, are the building
blocks of each cavity.
were recorded on an ATI-Unicam AutomassÒ apparatus, fit-
ted (or not) with a GC-mass coupling. Microanalyses were
performed on a Carlo ErbaÒ CHNOS 1160 apparatus. All
syntheses were performed under dry nitrogen atmosphere.
THF was freshly distilled from Na/benzophenone prior to
use. All other solvents and starting materials were of com-
mercial quality.
The network of compound 6l was a polymeric structure
(Fig. 5b) in which the non-bonding interactions between
the 6l units are of the same type H-40-c/O-7-anti
2.464(1) A and H-4-c/O-70-anti 2.449(1) A (SvdW
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary pub-
lication numbers CCDC: compound 4b-cis CCDC 283623.
Unit cell parameters: a 13.0640(11), b 8.8414(7), c
17.2561(14); space group P1 21/c 1(14). Compound 4c
CCDC 283622. Unit cell parameters: a 5.9105(11),
b 18.196(3), c 14.199(3); space group P2(1)/n. Compound
4k CCDC 199978. Unit cell parameters: a 12.251,
b 11.072, c 15.243; space group P2(1)/n. Compound 6l
CCDC 238894. Unit cell parameters: a 27.3536(3),
b 11.8334, c 23.7369(3); space group C2/c. Compound
10b CCDC 272371. Unit cell parameters: a 8.9574(2),
b 12.2323(2), c 24.6520(4); space group P-1. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
˚
˚
O/H 2.60 A).46 Their magnitude is slightly different since
˚
the two DOABO groups in monomeric 6l are geometrically
not quite identical (Tables 7 and 8). Consequently, two
cavities labelled C and D are observed, comprising each
two 6l units with a reverse sense of the global chirality
one against the other.
3. Conclusions
Twenty-two examples demonstrate the Williamson proce-
dure to be as general as simple methodology starting from
c-5-hydroxymethyl-3,7-dioxa-r-1-azabicyclo[3.3.0]octanes
in reaction with a-chlorodiazines and cyanuryl chloride. The
nucleophilicity of the DOABO–CH2OH reagents in alkox-
ide form depends on the type of substituents at positions
C-2, -8 of the bicycle and the cation against the p-deficiency
of the substrates. A large variety of a-(3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-ylmethoxy)-di(s-tri)azines is available
in good yields and selectivity. The conformation analysis
The synthesis of compounds 1a–e and 4k we discussed else-
where.19,20
1
of some structures by X-ray diffractometry and H DNMR
4.1. General procedure for the preparation of
compounds 4a–j, 6a–m and 8a–c
indicates exclusively a chiral against meso form frozen
conformation of the DOABO skeleton in solid state versus
solution, respectively. The cross endo-anomeric effect in
the aminalic O–C–N–C–O DOABO sequence is responsible
for the chiral conformation in solid state. The rotamerism
of the c-5-di(s-tri)azinyloxymethyl group against bicycle is
bisectional and s-trans out oriented both in solution and solid
state. In solid state, an inclusion aptitude of the solvent by
the chiral networks is found as well as non-bonding inter-
action creating specific self-assembly.
In a 100 mL three-necked round bottom flask, potassium
hydride (1.000 g as 30% oily suspension, 0.300 g 100%,
7.48 mmol) was rapidly introduced and washed with stirring
three times with dry ligroin (optionally pentane, hexane)
(30 mL). THF (50 mL) was then introduced with stirring
to yield a fine grey suspension. Fine powdered c-5-hydroxy-
methyl-3,7-dioxa-1-azabicyclo[3.3.0]-c-5-octanes 1a–e
(7.12 mmol, Scheme 2) was added and the mixture was
heated at 40 ꢁC for 1.0–1.5 h (room temperature in the
case of 1e) until no more hydrogen was formed and a fine
suspension was obtained. For the synthesis attempting at
complete substitution of chlorine [compounds 4a, 4b-cis,
4b-trans, 4c, 4d-trans, 4d-cis, 4e, 4j (Table 1), 6a, 6b, 6e,
6g, 6k, 6l (Table 2), 8b, 8c (Table 3)] the corresponding
a-chlorodiazine (6.78/n mmol, n¼number of chlorine atoms
to be replaced) was rapidly injected as THF (10 mL) solu-
tion, at room temperature (see Tables 1–3 for temperatures
and time reaction). For selective substitution of chlorine,
in the case of compounds 6c, 6f and 6h the reaction mixture
was cooled to ꢂ78 ꢁC prior to the addition by injection of the
corresponding stoichiometric amount of a-chloropyrimidine
as THF (10 mL) solution. Then, it was allowed to slowly
reach room temperature. For selective substitution of chlo-
rine in the case of compounds 4f and 8a, stoichiometric
amounts of a-chlorodiazine were used (conditions as tem-
perature and time reaction are given in Tables 1 and 3).
TLC monitoring was performed until the starting materials
were absent or in small traces only. Double visualisation
was required if 2a was the nucleophile (Scheme 2): first
UV 254 nm then I2 bath, for the detection of 1a. During
condensation, the reaction mixture turned coloured and
The attempt at exploiting these findings in synthesis will be
discussed in part II of our report.
4. Experimental
Melting points are uncorrected; they were carried out on
a ELECTROTHERMALÒ 9100 apparatus.
Current NMR spectra were recorded on a BruckerÒ AM300
(300 MHz 1H, 75 MHz 13C) instrument. The NMR analysis
of the compounds 6b and 6h was also carried out on
1
a BruckerÒ DMX500 (500 MHz H, 125 MHz 13C) instru-
1
ment. H DNMR analysis of compounds 4a, 4k, 6e, 6l,
10a and 10b was carried out on a BruckerÒ AM400
1
(400 MHz H, 100 MHz 13C) instrument. TLC was per-
formed by using aluminium sheets with silica gel 60 F254
(MerckÒ); flash column chromatography was conducted
on silica gel Si 60 (40–63 mm, MerckÒ). IR spectra were per-
formed on a Perkin–ElmerÒ Paragom FTIR spectrometer.
Only relevant absorptions are listed [throughout in cmꢂ1
:
weak (w), medium (m) or strong (s)]. Mass spectra (MS)

7332
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
potassium chloride was formed. The reaction was quenched
at room temperature with water (100 mL) and dichloro-
methane (100 mL) with vigorous stirring. After separation,
the organic layer was washed with water (about 3ꢀ50 mL)
to pH¼7.5–8.0 then dried over MgSO4. After filtering, the
organic solution was evaporated under vacuum to dryness
to yield the crude product, which was directly crystallised
from an appropriate solvent or purified by flash column chro-
matography to yield the title compounds.
d, J¼11.1 Hz, 5-OCH2), 4.76 (1H, d, J¼11.1 Hz,
5-OCH2), 4.52 (1H, d, J¼9.0 Hz, H-4-c), 4.48 (1H, d,
J¼9.0 Hz, H-6-c), 4.15 (2H, d, J¼9.0 Hz, H-4, -6-t); dC
(75 MHz CDCl3) (hetero)aromatic: 160.1 (1C, C-2), 141.0
(1C, C-6), 140.2 (1C, Cq., Ph), 137.5 (1C, C-3), 136.2
(1C, C-5), 134.5 (1C, Cq., Ph), 128.9 (1C, CH, Ph), 128.5
(1C, CH, Ph), 128.4 (2C, CH, Ph), 128.1 (2C, CH, Ph),
127.6 (2C, CH, Ph), 127.5 (2C, CH, Ph); DOABO–CH2O:
94.7, 93.6 (2C, C-2, -8), 75.3, 73.6 (2C, C-4, -6), 72.9 (1C,
C-5), 69.9 (1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %):
(M+) 375 (<1), 266 (100), 239 (40), 192 (5), 177 (10), 160
(30), 105 (50), 77 (45), 51 (20).
4.1.1. 2-[(3,7-Dioxa-r-1-azabicyclo[3.3.0]oct-c-5-yl)-
methoxy]-pyrazine (4a). Yield 85%. Yellowish crystalline
powder, mp 128–129 ꢁC (pentane) [Found: C, 53.50; H,
6.09; N, 18.55. C10H13N3O3 requires: C, 53.81; H, 5.87;
N, 18.82%]. Rf (75% ligroin/acetone) 0.40. nmax (film
NaCl) 2868 (m), 1524 (s), 1465 (m), 1413 (s), 1361 (m),
1289 (s), 1134 (m), 1032 (s), 1002 (s), 915 (s), 832 (m),
692 (m) cmꢂ1. dH (300 MHz CDCl3) heteroaromatic: 8.19
(1H, d, J¼1.5 Hz, H-3), 8.09 (1H, d, J¼3.0 Hz, H-5), 8.01
(1H, dd, J¼3.0, 1.5 Hz, H-6); DOABO–CH2O: 4.47 (2H,
d, J¼5.7 Hz, H-2, -8-c), 4.41 (2H, d, J¼5.7 Hz, H-2, -8-t),
4.33 (2H, s, 5-OCH2), 3.83 (4H, s, H-4, -6, -c, -t); dC
(75 MHz CDCl3) heteroaromatic: 160.1 (1C, C-2), 140.9
(1C, C-6), 137.5 (1C, C-3), 136.1 (1C, C-5); DOABO–
CH2O: 88.6 (2C, C-2, -8), 74.4 (2C, C-4, -6), 71.9 (1C,
C-5), 69.0 (1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %):
223 (6), 178 (14), 163 (13), 114 (100), 98 (17), 86 (9), 68
(26), 58 (11), 42 (18), 41 (59).
4.1.4. 2-[(c-2-Phenyl-3,7-dioxa-r-1-azabicyclo[3.3.0]oct-
c-5-yl)methoxy]-pyrazine (4c). Yield 48%. White crystal-
line powder, mp 79–81 ꢁC (flash column chromatography,
eluent ligroin/AcOEt 2:1 v/v) [Found: C, 63.91; H, 6.02;
N, 13.74. C16H17N3O3 requires C, 64.20; H, 5.72; N,
14.04%]. Rf (67% ligroin/AcOEt) 0.58. nmax (film KBr)
3065 (m), 2860 (m), 1834 (w), 1580 (m), 1531 (s), 1471
(m), 1413 (s), 1305 (m), 1174 (m), 1106 (s), 1034 (m),
909 (s), 856 (w) cmꢂ1. dH (300 MHz CDCl3) (hetero)-
aromatic: 8.22 (1H, d, J¼1.3 Hz, H-3), 8.14 (1H, d,
J¼2.6 Hz, H-5), 8.07 (1H, dd, J¼2.6, 1.3 Hz, H-6), 7.52–
7.49 (2H, m, Ph), 7.39–7.34 (3H, m, Ph); DOABO–CH2O:
5.24 (1H, s, H-2-t), 4.57 (1H, d, J¼7.0 Hz, H-8-c), 4.50
(1H, d, J¼10.0 Hz, 5-OCH2), 4.40 (1H, d, J¼8.9 Hz, H-4-
c), 4.37 (1H, d, J¼10.0 Hz, 5-OCH2), 4.30 (1H, d, J¼
7.0 Hz, H-8-t), 4.06 (1H, d, J¼9.0 Hz, H-6-c), 3.83 (1H, d,
J¼8.9 Hz, H-4-t), 3.70 (1H, d, J¼9.0, H-6-t); dC (75 MHz
CDCl3) (hetero)aromatic: 160.2 (1C, C-2), 140.9 (1C, C-
6), 139.5 (1C, Cq., Ph), 137.5 (1C, C-3), 136.2 (1C, C-5),
129.5 (1C, CH, Ph), 128.8 (2C, CH, Ph), 127.8 (2C, CH,
Ph); DOABO–CH2O: 99.2 (1C, C-2), 88.2 (1C, C-8), 75.4
(1C, C-4), 73.6 (1C, C-6), 72.5 (1C, C-5), 69.7 (1C,
5-OCH2). MS (ES+); m/z (rel int. %): (M++1) 300 (39),
223 (2), 204 (100), 194 (36).
4.1.2. 2-[(c-2,c-8-Diphenyl-3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-yl)methoxy]-pyrazine (4b-cis). Yield
79%. Yellowish crystalline powder, mp 134–136 ꢁC (flash
column chromatography, eluent ligroin/AcOEt 3:1 v/v)
[Found: C, 70.17; H, 5.94; N, 10.95. C22H21N3O3 requires
C, 70.38; H, 5.64; N, 11.19%]. Rf (75% ligroin/AcOEt)
0.56. nmax (film KBr) 2877 (s), 1586 (m), 1540 (s), 1418
(s), 1388 (m), 1312 (s), 1135 (s), 1065 (s), 932 (s), 834 (s),
800 (m), 763 (s), 738 (s), 696 (s), 617 (m), 537 (m), 499
(w), 465 (m) cmꢂ1. dH (300 MHz CDCl3) (hetero)aromatic:
8.09 (1H, d, J¼2.6 Hz, H-5), 8.04 (1H, s, H-3), 8.01 (1H, dd,
J¼2.6, 1.3 Hz, H-6), 7.52 (4H, d, J¼6.0 Hz, Ph), 7.36–7.30
(6H, m, Ph); DOABO–CH2O: 5.61 (2H, s, H-2, -8-t), 4.27
(2H, s, 5-OCH2), 4.10 (2H, d, J¼9.0 Hz, H-4, -6-c), 4.00
(2H, d, J¼9.0 Hz, H-4, -6-t); dC (75 MHz CDCl3) (hetero)-
aromatic: 160.1 (1C, C-2), 140.8 (1C, C-6), 139.7 (2C,
Cq., Ph), 137.4 (1C, C-3), 136.1 (1C, C-5), 129.0 (2C, CH,
Ph), 128.7 (4C, CH, Ph), 127.6 (4C, CH, Ph); DOABO–
CH2O: 97.8 (2C, C-2, -8), 73.6 (2C, C-4, -6), 73.3 (1C,
C-5), 70.2 (1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %):
(M+) 375 (<1), 269 (30), 173 (100), 155 (33), 128 (21).
4.1.5. 2-{[2-(t-4-tert-Butylspirocyclohexyl)-3,7-dioxa-r-1-
azabicyclo[3.3.0]oct-c-5-yl]methoxy}-pyrazine (4d-trans)
(46%) and 2-{[2-(c-4-tert-butylspirocyclohexyl)-3,7-
dioxa-r-1-azabicyclo[3.3.0]oct-c-5-yl]methoxy}-pyrazine
(4d-cis). Yield 16%. Non-separable two-component mixture
(4d-trans/4d-cis 75:25) as yellow crystalline powder, mp
103–105 ꢁC (ligroin) [Found: C, 65.79; H, 8.19; N, 11.85.
C19H29N3O3 requires: C, 65.68; H, 8.41; N, 12.09%]. Rf
(75% ligroin/acetone) 0.60. nmax (film NaCl) 2940 (s),
2857 (m), 1529 (s), 1465 (m), 1408 (s), 1284 (s), 1080
(w), 1005 (m), 909 (w) cmꢂ1. Diastereomer 4d-trans: dH
(300 MHz CDCl3) heteroaromatic: 8.21 (1H, s, H-3), 8.11
(1H, d, J¼3.0 Hz, H-5), 8.03 (1H, d, J¼2.6 Hz, H-6);
DOABO–CH2O: 4.79 (1H, d, J¼7.5 Hz, H-8-c), 4.42
(1H, d, J¼10.6 Hz, 5-OCH2), 4.29 (1H, d, J¼10.6 Hz,
5-OCH2), 4.15 (1H, d, J¼7.5 Hz, H-8-t), 4.04 (1H, d,
J¼9.2 Hz, H-4-c), 3.86 (1H, d, J¼9.2 Hz, H-4-t), 3.77
(1H, d, J¼8.7 Hz, H-6-c), 3.65 (1H, d, J¼8.7 Hz, H-6-t);
1.97–1.79 (2H, m, spirocyclohexyl), 1.77–1.67 (1H, m,
spirocyclohexyl), 1.60–1.45 (2H, m, spirocyclohexyl),
1.44–1.15 (3H, m, spirocyclohexyl), 1.03–0.89 (1H, m,
spirocyclohexyl), 0.81 [9H, s, C(CH3)3]; dC (75 MHz
CDCl3) heteroaromatic: 160.3 (1C, C-2), 140.8 (1C, C-6),
137.4 (1C, C-3), 136.2 (1C, C-5); DOABO–CH2O: 98.1
(1C, C-2), 82.0 (1C, C-8), 73.8 (1C, C-6), 72.0 (1C, C-5),
4.1.3. 2-[(c-2,t-8-Diphenyl-3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-yl)methoxy]-pyrazine (4b-trans).
Yield 69%. Yellowish crystalline powder, mp 144–145 ꢁC
(pentane) [Found: C, 70.17; H, 5.94; N, 10.95.
C22H21N3O3 requires C, 70.38; H, 5.64; N, 11.19%]. Rf
(75% ligroin/AcOEt) 0.75. nmax (film KBr) 2859 (m), 1579
(m), 1528 (s), 1412 (s), 1309 (s), 1291 (s), 1265 (m), 1090
(s), 1060 (s), 1038 (m), 1028 (w), 839 (m), 760 (s), 731
(s) cmꢂ1. dH (300 MHz CDCl3) (hetero)aromatic: 8.48,
8.40, 8.34 (3H, s, H-3, -5, -6), 7.59–7.52 (2H, m, Ph),
7.48–7.33 (6H, m, Ph), 7.27–7.24 (2H, m, Ph); DOABO–
CH2O: 5.86 (1H, s, H-8-c), 5.49 (1H, s, H-2-t), 4.80 (1H,

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7333
71.6 (1C, C-4), 69.7 (1C, 5-OCH2), 47.5 (1C, CH, spiro-
cyclohexyl), 38.5, 32.7, 32.2, 24.7 (4C, CH2, spirocyclo-
hexyl), 28.0 [3C, C(CH3)3], 24.5 [1C, C(CH3)3].
Diastereomer 4d-cis: dH (300 MHz CDCl3 only distinct
peaks are listed) heteroaromatic: 8.09 (1H, s, H-5), 8.01
(1H, s, H-6); dC (75 MHz CDCl3) heteroaromatic: 136.3
(1C, C-5); DOABO–CH2O: 96.2 (1C, C-2), 68.4 (1C,
5-OCH2), 47.3 (1C, CH, spirocyclohexyl), 37.8 (1C, CH2,
spirocyclohexyl). MS (EI, 70 eV); m/z (rel int. %): (M+)
348 (50), 334 (11), 318 (27), 292 (13), 252 (100), 234
(15), 222 (35), 194 (50), 165 (7), 152 (9), 98 (70).
3060 (m), 2990 (m), 2878 (s), 1568 (s), 1528 (s), 1435 (s),
1409 (s), 1309 (s), 1209 (s), 1179 (s), 1131 (s), 1091 (s),
1064 (s), 1006 (s), 949 (m), 923 (s), 961 (s), 762 (s), 736
(s), 697 (s), 637 (m) cmꢂ1. dH (300 MHz CDCl3) (hetero)-
aromatic: 8.14 (1H, s, H-5), 7.89 (1H, s, H-3), 7.54–7.52
(4H, m, Ph), 7.40–7.31 (6H, m, Ph); DOABO–CH2O: 5.63
(2H, s, H-2, -8-t), 4.30 (2H, s, 5-OCH2), 4.10 (2H, d,
J¼9.0 Hz, H-4, -6-c), 4.00 (2H, d, J¼9.0 Hz, H-4, -6-t); dC
(75 MHz CDCl3) (hetero)aromatic: 159.0 (1C, C-6), 145.7
(1C, C-2), 139.5 (2C, Cq., Ph), 136.1 (1C, C-3), 133.3
(1C, C-5), 129.0 (2C, CH, Ph), 128.8 (4C, CH, Ph), 127.5
(4C, CH, Ph); DOABO–CH2O: 97.9 (2C, C-2, -8), 73.4
(2C, C-4, -6), 73.2 (1C, C-5), 70.6 (1C, 5-OCH2). MS (EI,
70 eV); m/z (rel int. %): (M+ꢂ1) 408 (<1), 267 (22), 266
(100), 160 (10), 105 (28).
4.1.6. 2-{[c-2,c-8-Bis(pyridin-2-yl)-3,7-dioxa-r-1-aza-
bicyclo[3.3.0]oct-c-5-yl]methoxy}-pyrazine (4e). Yield
44%. Yellow crystalline powder, mp 89–90 ꢁC (pentane)
[Found: C, 63.44; H, 5.17; N, 18.26. C20H19N5O3 requires
C, 63.65; H, 5.07; N, 18.56%]. Rf (100% acetone) 0.65.
nmax (film KBr) 3058 (m), 2863 (m), 15890 (s), 1534 (s),
1441 (m), 1414 (s), 1298 (s), 1129 (s), 1081 (s), 992 (s),
924 (m), 841 (m), 781 (s), 709 (m), 659 (m), 622 (m), 608
(w) cmꢂ1. dH (300 MHz CDCl3) heteroaromatic: 8.56 (2H,
d, J¼4.2 Hz, H-6, Py), 8.09 (1H, d, J¼1.9 Hz, H-5, pyra-
zine), 8.05 (1H, s, H-3, pyrazine), 8.00 (1H, s, H-6, pyra-
zine), 7.65 (2H, dd as t, J¼7.5, 7.5 Hz, H-4, Py), 7.54 (2H,
d, J¼7.9 Hz, H-3, Py), 7.20 (2H, dd as t, J¼5.7, 6.0 Hz,
H-5, Py); DOABO–CH2O: 5.79 (2H, s, H-2, -8-t), 4.31
(2H, s, 5-OCH2), 4.25 (2H, d, J¼9.0 Hz, H-4, -6-c), 4.07
(2H, d, J¼9.0 Hz, H-4, -6-t); dC (75 MHz CDCl3) hetero-
aromatic: 160.1 (1C, C-2, pyrazine), 159.2 (2C, C-2, Py),
149.6 (2C, C-6, Py), 140.8 (1C, C-6, pyrazine), 137.4 (1C,
C-3, pyrazine), 137.0 (2C, C-4 Py), 136.1 (1C, C-5, pyra-
zine), 123.6 (2C, C-5, Py), 121.7 (2C, C-3, Py); DOABO–
CH2O: 98.4 (2C, C-2, -8), 73.5 (1C, C-5), 73.4 (2C, C-4,
-6), 69.8 (1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %):
(M++1) 378 (62), 282 (83), 272 (19), 252 (18), 214 (13),
175 (100), 165 (23), 159 (42), 145 (37).
4.1.9. 6-[(c-2,c-8-Diphenyl-3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-yl)methoxy]-1H-pyrazin-2-one (4h).
White crystalline powder (as 17% conversion of 3b, Table
1, entry 8), mp 199–201 ꢁC (flash column chromatography,
eluent ligroin/AcOEt 1:1 v/v [Found: C, 67.42; H, 5.63;
N, 10.46. C22H21N3O4 requires: C, 67.51; H, 5.41; N,
10.74%]. Rf (50% ligroin/AcOEt) 0.60. nmax (film KBr)
3062 (m), 2978 (m), 2877 (s), 2442 (s), 1822 (s), 1612 (s),
1537 (s), 1449 (s), 1376 (s), 1315 (s), 1269 (s), 1188 (s),
1135 (s), 1091 (s), 921 (s), 836 (s), 757 (s), 732 (s), 695
(s) cmꢂ1. dH (300 MHz CDCl3) (hetero)aromatic: 7.77
(1H, s, H-5), 7.62 (1H, s, H-3), 7.52–7.50 (4H, m, Ph),
7.36–7.27 (6H, m, Ph), 7.03 (1H, br s, NH); DOABO–
CH2O: 5.60 (2H, s, H-2, -8-t), 4.17 (2H, s, 5-OCH2), 4.08
(2H, d, J¼9.0 Hz, H-4, -6-c), 3.98 (2H, d, J¼9.0 Hz, H-4,
-6-t); dC (75 MHz CDCl3) (hetero)aromatic: 158.1 (1C,
C-2), 157.0 (1C, C-6), 139.6 (2C, Cq., Ph), 129.1 (2C,
CH., Ph), 128.8 (4C, CH., Ph), 127.6 (4C, CH., Ph), 125.3
(1C, C-3), 124.2 (1C, C-5); DOABO–CH2: 97.7 (2C, C-2,
-8), 73.6 (2C, C-4, -6), 73.2 (1C, C-5), 70.5 (1C, 5-OCH2);
MS (EI, 70 eV); m/z (rel int. %): (M+) 391 (<5), 285 (50),
179 (15), 174 (100), 155 (13), 128 (17).
4.1.7. 2-Chloro-6-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-yl)methoxy]-pyrazine (4f). Yield 83%. Pale yellowish
crystalline powder, mp 88–89 ꢁC (flash column chromato-
graphy; eluent ligroin/acetone 3.5:1 v/v) [Found: C, 46.88;
H, 4.51; N, 16.50. C10H12N3O3Cl requires: C, 46.61; H,
4.69; N, 16.31%]. Rf (78% ligroin/acetone) 0.45. nmax (film
NaCl) 2857 (w), 2366 (w), 1563 (m), 1525 (s), 1409 (s),
1364 (m), 1309 (s), 1177 (s), 1093 (w), 1000 (m), 928
(w) cmꢂ1. dH (300 MHz CDCl3) heteroaromatic: 8.13 (1H,
s, H-5), 8.11 (1H, s, H-3); DOABO–CH2O: 4.48 (2H, d,
J¼5.7 Hz, H-2, -8-c), 4.42 (2H, d, J¼5.7 Hz, H-2, -8-t),
4.35 (2H, s, 5-OCH2), 3.83 (4H, s, H-4, -6-c, -t); dC
(75 MHz CDCl3) heteroaromatic: 159.1 (1C, C-6), 145.7
(1C, C-2), 136.3 (1C, C-3), 133.3 (1C, C-5); DOABO–
CH2O: 88.6 (2C, C-2, -8), 74.3 (2C, C-4, -6), 71.8 (1C,
C-5), 69.8 (1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %):
(M+) 257 (<1), 212 (6), 197 (10), 192 (4), 169 (4), 128
(6), 114 (100), 98 (20), 86 (10), 68 (24), 58 (9), 41 (52).
4.1.10. 2,6-Bis[(c-2,c-8-diphenyl-3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-yl)methoxy]-pyrazine (4i). White crys-
talline powder (as 8% conversion of 3b); this compound was
isolated only as a non-separable mixture (38%) with 4h
(62%) during the work-up by flash column chromatography
of the reaction between 3b and 2b-cis (Table 1, entry 8). dH
(300 MHz CDCl3) only distinct peaks are listed as DOABO–
CH2O: 5.63 (4H, s, H-2, -8-t), 4.15 (4H, s, 5-, 50-OCH2), 4.07
(4H, d, J¼9.1 Hz, H-4, -40, -6, -60-c); dC (75 MHz CDCl3)
(hetero)aromatic: 139.7 (4C, Cq., Ph), 125.0 (2C, C-3, -5);
DOABO–CH2O: 73.2 (4C, C-4, -40 -6, -60). MS (EI,
70 eV); m/z (rel int. %): (M+) 670 (<1).
4.1.11. 6-Methoxy-2-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-
c-5-yl)methoxy]-pyrazine (4j). Yield 33%. White crystal-
line powder, mp 99–100 ꢁC (flash column chromatography,
eluent ligroin/acetone 3.5:1 v/v) [Found: C, 52.30; H,
6.09; N, 16.76. C11H15N3O4 requires: C, 52.17; H, 5.97;
N, 16.59%]. Rf (78% ligroin/acetone) 0.76. nmax (film
KBr) 3076 (w), 2859 (m), 1590 (m), 1540 (s), 1414 (s),
13223 (s), 1270 (s), 1182 (s), 1034 (s), 941 (s), 843 (s),
720 (w), 679 (s), 623 (w), 489 (m), 458 (w) cmꢂ1. dH
(300 MHz CDCl3) heteroaromatic: 7.78, 7.75 (2H, s, H-3,
-5); DOABO–CH2O: 4.50 (2H, d, J¼5.5 Hz, H-2, -8-c),
4.1.8. 2-Chloro-6-[(c-2,c-8-diphenyl-3,7-dioxa-r-1-aza-
bicyclo[3.3.0]oct-c-5-yl)methoxy]-pyrazine (4g). White
crystalline powder (as 34% conversion of 3b, Table 1, entry
8), mp 128–129 ꢁC (flash column chromatography, eluent
ligroin/AcOEt 2:1 v/v) [Found: C, 64.59; H, 4.60; N,
10.51. C22H20N3O3Cl requires: C, 64.47; H, 4.92; N,
10.25%]. Rf (67% ligroin/AcOEt) 0.35. nmax (film KBr)

7334
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
4.44 (2H, d, J¼5.5 Hz, H-2, -8-t), 4.33 (2H, s, 5-OCH2),
3.90 (3H, s, –OCH3), 3.87 (4H, s, H-4, -6-c, -t); dC
(75 MHz CDCl3) heteroaromatic: 159.2, 158.4 (2C, C-2,
-6), 125.8, 124.9 (2C, C-3, -5); DOABO–CH2O: 88.5 (2C,
C-2, -8), 74.6 (2C, C-4, -6), 71.9 (1C, C-5), 69.2 (1C,
5-OCH2), 54.0 (1C, –OCH3). MS (EI, 70 eV); m/z (rel
int. %): (M+) 253 (<1), 127 (100), 97 (18).
170.4 (1C, C-4), 160.6 (1C, C-2), 159.5 (1C, C-6), 107.4
(1C, C-5); DOABO–CH2O: 88.6 (2C, C-2, -8), 74.2 (2C,
C-4, -6), 71.7 (1C, C-5), 69.9 (1C, 5-OCH2). MS (EI,
70 eV); m/z (rel int. %): 257 (<1), 212 (9), 197 (12), 169
(11), 114 (100), 86 (10), 68 (14), 58 (11), 42 (16), 41 (50).
4.1.15. 4-Chloro-2-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-yl)methoxy]-pyrimidine (6d). Yield 23%. This com-
pound was identified as side product in the synthesis of the
compound 6c (Table 2). Its identity was established accord-
ing to NMR spectra performed on the crude reaction mixture
together with the residue of the column chromatography
(6c+6d) after isolation of the pure 6c. dH (300 MHz
CDCl3) heteroaromatic: 8.36 (1H, d, J¼5.3 Hz, H-6), 7.00
(1H, d, J¼5.3 Hz, H-5); DOABO–CH2O: 4.49 (2H, d,
J¼5.7 Hz, H-2, -8-c), 4.44 (2H, d, J¼5.7 Hz, H-2, -8-t),
4.40 (2H, s, 5-OCH2), 3.88 (4H, s, H-4, -6, -c, -t); dC
(75 MHz CDCl3) heteroaromatic: 165.0 (1C, C-2), 163.0
(1C, C-4), 160.4 (1C, C-6), 115.9 (1C, C-5); DOABO–
CH2O: 88.6 (2C, C-2, -8), 74.6 (2C, C-4, -6), 71.6 (1C,
C-5), 71.2 (1C, 5-OCH2).
4.1.12. 2-[(3,7-Dioxa-r-1-azabicyclo[3.3.0]oct-c-5-yl)-
methoxy]-pyrimidine (6a). Yield 60%. White crystalline
powder, mp 107–109 ꢁC (pentane) [Found: C, 53.59; H,
5.61; N, 19.13. C10H13N3O3 requires: C, 53.80; H, 5.87; N,
18.82%]. Rf (75% ligroin/acetone) 0.40. nmax (film NaCl)
2858 (w), 1569 (s), 1431 (s), 1332 (s), 1300 (m), 1137 (w),
1021 (s), 925 (m), 814 (w), 682 (w) cmꢂ1. dH (300 MHz
CDCl3) heteroaromatic: 8.44 (2H, d, J¼4.9 Hz, H-4, -6),
6.90 (1H, dd as t, J¼4.9, 4.9 Hz, H-5); DOABO–CH2O:
4.45 (2H, d, J¼5.5 Hz, H-2, -8-c), 4.38 (2H, d, J¼5.5 Hz,
H-2, -8-t), 4.35 (2H, s, 5-OCH2), 3.87 (2H, d, J¼9.4 Hz,
H-4, -6-c), 3.84 (2H, d, J¼9.4 Hz, H-4, -6-t); dC (75 MHz
CDCl3) heteroaromatic: 165.2 (1C, C-2), 159.7 (2C, C-4,
-6), 115.8 (1C, C-5); DOABO–CH2O: 88.5 (2C, C-2, -8),
74.7 (2C, C-4, -6), 71.7 (1C, C-5), 70.6 (1C, 5-OCH2). MS
(EI, 70 eV); m/z (rel int. %): (M+ꢂ1) 222 (10), 206 (12),
176 (14), 148 (8), 128 (100), 109 (16), 98 (11).
4.1.16. 4,6-Bis[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-
yl)methoxy]-pyrimidine (6e). Yield 81%. White crystalline
powder, mp 146–148 ꢁC (pentane) [Found: C, 52.70; H,
5.88; N, 14.98. C16H22N4O6 requires: C, 52.45; H, 6.05;
N, 15.29%]. Rf (75% ligroin/acetone) 0.35. nmax (film
NaCl) 2950 (w), 2858 (m), 1593 (s), 1563 (s), 1457 (m),
1421 (m), 1341 (m), 1195 (m), 1137 (m), 1095 (m), 1039
(s), 933 (m), 674 (m) cmꢂ1. dH (300 MHz CDCl3) heteroaro-
matic: 8.38 (1H, s, H-2), 6.08 (1H, s, H-5); DOABO–CH2O:
4.49 (4H, d, J¼5.7 Hz, H-2, -20, -8, -80-c), 4.44 (4H, d,
J¼5.7 Hz, H-2, -20, -8, -80-t), 4.38 (4H, s, 5-, 50-OCH2),
3.84 (8H, s, H-4, -40, -6, -60, -c, -t); dC (75 MHz CDCl3) het-
eroaromatic: 171.0 (2C, C-4, -6), 157.8 (1C, C-2), 91.4 (1C,
C-5); DOABO–CH2O: 88.6 (4C, C-2, -20, -8, -80), 74.4 (4C,
C-4, -40, -6, -60), 71.9 (2C, C-5, -50), 69.4 (2C, 5-, 50-OCH2).
MS (EI, 70 eV); m/z (rel int. %): (M++1) 367 (<1), 274 (3),
252 (2), 168 (8), 128 (100), 98 (4).
4.1.13. 2,4-Bis[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-
yl)methoxy]-pyrimidine (6b). Yield 80%. White crystalline
powder, mp 136–137 ꢁC (pentane) [Found: C, 52.61; H,
6.01; N, 15.58. C16H22N4O6 requires: C, 52.45; H, 6.05;
N, 15.29%]. Rf (75% ligroin/acetone) 0.20. nmax (film
NaCl) 2590 (w), 2863 (w), 1585 (s), 1449 (m), 1416 (s),
1336 (m), 1274 (m), 1181 (w), 1098 (s), 1021 (m), 928
(m), 749 (w) cmꢂ1. dH (500 MHz benzene-d6) hetero-
aromatic: 8.05 (1H, d, J¼6.0 Hz, H-6), 6.15 (1H, d,
J¼6.0 Hz, H-5); DOABO–CH2O linked at C-2: 4.40 (2H,
s, 5-OCH2), 4.30 (2H, d, J¼5.3 Hz, H-2, -8-c), 4.05 (2H,
d, J¼5.3 Hz, H-2, -8-t), 3.77 (2H, d, J¼8.7 Hz, H-4, -6-c),
3.64 (2H, d, J¼8.7 Hz, H-4, -6-t); DOABO–CH2O linked
at C-4: 4.23 (2H, d, J¼5.3 Hz, H-2, -8-c), 4.21 (2H, s,
5-OCH2), 4.04 (2H, d, J¼5.3 Hz, H-2, -8-t), 3.56 (2H, d,
J¼8.9 Hz, H-4, -6-c), 3.51 (2H, d, J¼8.9 Hz, H-4, -6-t); dC
(125 MHz benzene-d6) heteroaromatic: 171.1 (1C, C-4),
165.5 (1C, C-2), 158.9 (1C, C-6), 102.3 (1C, C-5);
DOABO–CH2O linked at C-2: 88.1 (2C, C-2, -8), 74.3
(2C, C-4, -6), 72.7 (1C, C-5), 70.7 (1C, 5-OCH2);
DOABO–CH2O linked at C-4: 88.2 (2C, C-2, -8), 73.9
(2C, C-4, -6), 71.5 (1C, C-5), 69.2. (1C, 5-OCH2). MS (EI,
70 eV); m/z (rel int. %): 366 (<1), 238 (6), 208 (6), 128
(68), 114 (100), 98 (14), 68 (27), 42 (32), 41 (60).
4.1.17. 4-Chloro-6-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-yl)methoxy]-pyrimidine (6f). Yield 63%. White crystal-
line powder, mp 118–119 ꢁC (flash column chromatography,
eluent ligroin/acetone 3:1 v/v) [Found: C, 46.33; H, 5.02; N,
16.59. C10H12N3O3Cl requires: C, 46.61; H, 4.69; N,
16.31%]. Rf (75% ligroin/acetone) 0.60. nmax (film NaCl)
2956 (w), 2884 (s), 1574 (s), 1546 (s), 1454 (s), 1387 (w),
1343 (s), 1314 (m), 1264 (w), 1213 (w), 1140 (m), 1094
(s), 1040 (s), 1007 (s), 981 (m), 868 (w), 749 (s), 678 (w).
dH (300 MHz CDCl3) heteroaromatic: 8.50 (1H, s, H-2),
6.74 (1H, d, J¼0.8 Hz, H-5); DOABO–CH2O: 4.44 (2H, d,
J¼5.7 Hz, H-2, -8-c), 4.38 (2H, d, J¼5.7 Hz, H-2, -8-t),
4.38 (2H, s, 5-OCH2), 3.78 (4H, s, H-4, -6, -c, -t); dC
(75 MHz CDCl3) heteroaromatic: 170.2 (1C, C-6), 161.3
(1C, C-4), 158.5 (1C, C-2), 108.2 (1C, C-5); DOABO–
CH2O: 88.5 (2C, C-2, -8), 74.2 (2C, C-4, -6), 71.7 (1C,
C-5), 69.8 (1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %):
(M+ꢂ1) 256 (2), 240 (8), 210 (7), 128 (100), 98 (7).
4.1.14. 2-Chloro-4-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-yl)methoxy]-pyrimidine (6c). Yield 63%. White crystal-
line powder, mp 139–140 ꢁC (dichloromethane/pentane 1:2
v/v) [Found: C, 46.80; H, 4.81; N, 16.65. C10H12N3O3Cl
requires: C, 46.61; H, 4.69; N, 16.31%]. Rf (75% ligroin/
acetone) 0.50. nmax (film NaCl) 2857 (w), 1636 (s), 1582
(s), 1545 (m), 1446 (m), 1327 (s), 1230 (m), 1102 (w),
1017 (m) cmꢂ1. dH (300 MHz CDCl3) heteroaromatic:
8.30 (1H, d, J¼5.7 Hz, H-6), 6.67 (1H, d, J¼5.7 Hz, H-5);
DOABO–CH2O: 4.47 (2H, d, J¼5.3 Hz, H-2, -8-c), 4.42
(2H, d, J¼5.3 Hz, H-2, -8-t), 4.40 (2H, s, 5-OCH2), 3.81
(4H, s, H-4, -6, -c, -t); dC (75 MHz CDCl3) heteroaromatic:
4.1.18. 2,4,6-Tris[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-
yl)methoxy]-pyrimidine (6g). Yield 58%. Yellowish crys-
talline powder, mp 188–189 ꢁC (pentane/dichloromethane,
2:1 v/v) [Found: C, 51.53; H, 6.45; N, 14.11. C22H31N5O9

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7335
requires: C, 51.86; H, 6.13; N, 13.75%]. Rf (50% ligroin/ace-
tone) 0.50. nmax (film NaCl) 2857 (s), 1600 (s), 1405 (m),
1382 (s), 1325 (m), 1192 (w), 1095 (w), 923 (m) cmꢂ1. dH
(300 MHz CDCl3) heteroaromatic: 5.74 (1H, s, H-5);
DOABO–CH2O linked at C-2: 4.50 (2H, d, J¼5.5 Hz, H-2,
-8-c), 4.42 (2H, d, J¼5.5 Hz, H-2, -8-t), 4.325 (2H, s, 5-
OCH2), 3.88 (4H, s, H-4, -6, -c, -t); DOABO–CH2O linked
at C-4, -6: 4.48 (4H, d, J¼5.5 Hz, H-2, -20, -8, -80-c), 4.42
(4H, d, J¼5.3 Hz, H-2, -20, -8, -80-t), 4.331 (4H, s, 5-,
50-OCH2), 3.82 (8H, s, H-4, -40, -6, -60, -c, -t); dC (75 MHz
CDCl3) heteroaromatic: 172.4 (2C, C-4, -6), 164.3 (1C,
C-2), 84.9 (1C, C-5); DOABO–CH2O linked at C-2: 88.3
(2C, C-2, -8), 74.7 (2C, C-4, -6), 71.6 (1C, 5-OCH2), 70.8
(1C, C-5); DOABO–CH2O linked at C-4, -6: 88.6 (4C,
C-2, -20, -8, -80), 74.4 (4C, C-4, -40, -6, -60), 71.8 (2C,
5-, 50-OCH2), 69.4 (2C, C-5, -50). MS (EI, 70 eV); m/z (rel
int. %): 510 (8), 297 (<1), 256 (<1), 197 (4), 158 (4), 128
(100), 98 (4).
dH (300 MHz CDCl3) heteroaromatic: 6.72 (1H, s, H-5);
DOABO–CH2O: 4.48 (2H, d, J¼5.5 Hz, H-2, -8-c), 4.43
(2H, d, J¼5.5 Hz, H-2, -8-t), 4.43 (2H, s, 5-OCH2), 3.82
(4H, s, H-4, -6, -c, -t); dC (75 MHz CDCl3) heteroaromatic:
171.1 (1C, C-6), 162.1 (1C, C-2), 160.0 (1C, C-4), 106.7
(1C, C-5); DOABO–CH2O: 88.6 (2C, C-2, -8), 74.2 (2C,
C-4, -6), 71.7 (1C, C-5), 70.6 (1C, 5-OCH2). MS (EI,
70 eV); m/z (rel int. %): 292 (3), 128 (100), 98 (10).
4.1.22. 2,4-Bis[(c-2,c-8-diphenyl-3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-yl)methoxy]-pyrimidine (6k). Yield
58%. White crystalline powder, mp 168–170 ꢁC (pentane)
[Found: C, 71.52; H, 5.94; N, 8.07. C40H38N4O6 requires
C, 71.63; H, 5.71; N, 8.35%]. Rf (75% ligroin/AcOEt)
0.30. nmax (film KBr) 2874 (m), 1954 (w), 1591 (s), 1571
(s), 1450 (m), 1414 (m), 1331 (m), 1210 (m), 1098 (s),
1011 (m), 927 (m), 818 (s), 698 (s), 643 (w), 522
(w) cmꢂ1. dH (300 MHz CDCl3) (hetero)aromatic: 8.08
(1H, d, J¼5.8 Hz, H-6), 7.55–7.50 (8H, m, Ph), 7.36–7.28
(12H, m, Ph), 6.15 (1H, d, J¼5.8 Hz, H-5); DOABO–
CH2O linked at C-2: 5.61 (2H, s, H-2, -8-t), 4.26 (2H, s,
5-OCH2), 4.14 (2H, d, J¼9.2 Hz, H-4, -6-c), 4.02 (2H, d,
J¼9.2 Hz, H-4, -6-t); DOABO–CH2O linked at C-4: 5.60
(2H, s, H-2, -8-t), 4.23 (2H, s, 5-OCH2), 4.04 (2H, d,
J¼9.0 Hz, H-4, -6-c), 3.95 (2H, d, J¼9.0 Hz, H-4, -6-t); dC
(75 MHz CDCl3) (hetero)aromatic: 171.0 (1C, C-4), 164.9
(1C, C-2), 158.9 (1C, C-6), 139.7, 139.6 (4C, Cq., Ph),
129.0, 128.9 (4C, CH, Ph), 128.8, 128.7 (8C, CH, Ph),
127.6, 127.5 (8C, CH, Ph), 102.6 (1C, C-5); DOABO–
CH2O: 97.9, 97.6 (4C, C-2, -8), 73.9, 73.5 (4C, C-4, -6),
73.10, 73.07 (2C, C-5), 71.8, 70.2 (2C, 5-OCH2). MS (EI,
70 eV); m/z (rel int. %): 708 (20), 692 (100), 670 (10), 564
(5), 451 (6), 435 (22), 413 (10), 348 (5).
4.1.19. 4-Chloro-2,6-bis[(3,7-dioxa-r-1-azabicyclo[3.3.0]-
oct-c-5-yl)methoxy]-pyrimidine (6h). Yield 76%. White
crystalline powder, mp 142–144 ꢁC (flash column chromato-
graphy, eluent ligroin/acetone 2:1 v/v) [Found: C, 48.31; H,
4.99; N, 14.19. C16H21N4O6Cl requires: C, 47.95; H, 5.28;
N, 13.98%]. Rf (66% ligroin/acetone) 0.45. nmax (film
NaCl) 2852 (s), 1635 (w), 1577 (s), 1416 (m), 1325 (m),
1137 (m), 1093 (m), 1023 (m), 917 (w) cmꢂ1. dH
(300 MHz CDCl3) heteroaromatic: 6.43 (1H, s, H-5);
DOABO–CH2O linked at C-2: 4.49 (2H, d, J¼5.5 Hz, H-2,
-8-c), 4.42 (2H, d, J¼5.5 Hz, H-2, -8-t), 4.38 (2H, s,
5-OCH2), 3.87 (4H, s, H-4, -6, -c, -t); DOABO–CH2O linked
at C-6: 4.48 (2H, d, J¼5.5 Hz, H-2, -8-c), 4.41 (2H, d,
J¼5.5 Hz, H-2, -8-t), 4.35 (2H, s, 5-OCH2), 3.81 (4H, s,
H-4, -6, -c, -t); dC (75 MHz CDCl3) heteroaromatic: 171.9
(1C, C-6), 164.4 (1C, C-2), 162.4 (1C, C-4), 101.6 (1C,
C-5); DOABO–CH2O: 88.5 and 88.4 (4C, C-2, -8), 74.5,
74.2 (4C, C-4, -6), 71.7, 71.6 (2C, C-5), 71.2, 70.1 (2C,
5-OCH2). MS (EI, 70 eV); m/z (rel int. %): (M+ꢂ1) 400
(5), 365 (5), 128 (100), 98 (7).
4.1.23. 4,6-Bis[(c-2,c-8-diphenyl-3,7-dioxa-r-1-azabi-
cyclo[3.3.0]oct-c-5-yl)methoxy]-pyrimidine (6l). Yield
31%. White crystalline powder, mp 176–178 ꢁC (flash col-
umn chromatography, eluent ligroin/AcOEt 3:1 v/v) [Found:
C, 71.53; H, 5.93; N, 8.07. C40H38N4O6 requires C, 71.63; H,
5.71; N, 8.35%]. Rf (75% ligroin/AcOEt) 0.59. nmax (film
KBr) 2876 (m), 1595 (s), 1455 (s), 1430 (m), 1314 (w),
1256 (s), 1166 (m), 1089 (m), 989 (w), 921 (m), 838 (s),
752 (m), 694 (m), 470 (m) cmꢂ1. dH (300 MHz CDCl3)
(hetero)aromatic: 8.30 (1H, s, H-2), 7.52–7.49 (8H, m,
Ph), 7.38–7.29 (12H, m, Ph), 5.71 (1H, s, H-5); DOABO–
CH2O: 5.59 (4H, s, H-2, -20, -8, -80-t), 4.23 (4H, s, 5-,
50-OCH2), 4.05 (4H, d, J¼9.0 Hz, H-4, -40, -6, -60-c), 3.95
(4H, d, J¼9.0 Hz, H-4, -40, -6, -60-t); dC (75 MHz CDCl3)
(hetero)aromatic: 170.8 (2C, C-4, -40 -6, -60), 157.8 (1C,
C-2), 139.6 (4C, Cq., Ph), 129.0 (4C, CH, Ph), 128.8
(8C, CH, Ph), 127.6 (8C, CH, Ph); DOABO–CH2O: 97.8
(4C, C-2, -20, -8, -80), 73.6 (4C, C-4, -40, -6, -60), 73.2 (2C,
C-5, -50), 70.7 (2C, 5-, 50-OCH2). MS (EI, 70 eV); m/z (rel
int. %): (M+) 670 (31), 692 (14), 564 (9), 280 (100).
4.1.20. 2-Chloro-4,6-bis[(3,7-dioxa-r-1-azabicyclo[3.3.0]-
oct-c-5-yl)methoxy]-pyrimidine (6i). Yield 8%. This com-
pound was identified as side product in the synthesis of the
compound 6h (Table 2). Its identity was established accord-
ing to NMR spectra performed on the crude reaction mixture
together with the residue of the column chromatography
(6i+6h) after isolation of the pure 6h. dH (300 MHz CDCl3
only distinct peaks are listed) heteroaromatic: 5.96 (1H, s,
H-5); DOABO–CH2O: 4.43 (2H, d, J¼5.3 Hz, H-2, -20, -8,
-80, -c, -t), 4.33 (4H, s, 5-, 50-OCH2), 3.77 (4H, s, H-4, -40,
-6, -60, -c, -t); dC (75 MHz CDCl3) heteroaromatic: 171.8.0
(2C, C-4, -6); DOABO–CH2: 88.6 (4C, C-2, -20, -8, -80),
71.6 (2C, C-5, -50).
4.1.21. 2,4-Dichloro-6-[(3,7-dioxa-r-1-azabicyclo[3.3.0]-
oct-c-5-yl)methoxy]-pyrimidine (6j). White crystalline
powder (6% side product in the synthesis of 6h), mp 117–
119 ꢁC (flash column chromatography, eluent ligroin/
acetone 2:1 v/v) [Found: C, 40.89; H, 4.15; N, 14.58.
C10H11N3O3Cl2 requires: C, 41.12; H, 3.80; N, 14.39%].
Rf (66% ligroin/acetone) 0.70. nmax (film NaCl) 2857 (w),
1579 (s), 1528 (s), 1423 (w), 1367 (m), 1272 (m), 1119
4.1.24. 4-Chloro-6-[(c-2,c-8-diphenyl-3,7-dioxa-r-1-aza-
bicyclo[3.3.0]oct-c-5-yl)methoxy]-pyrimidine (6m). Yield
23%. Yellowish crystalline powder, mp 145–147 ꢁC (flash
column chromatography, eluent ligroin/AcOEt 3:1 v/v)
[Found: C, 64.32; H, 5.14; N, 10.19. C22H20N3O3Cl requires
C, 64.47; H, 4.92; N, 10.25%]. Rf (75% ligroin/AcOEt) 0.80.
nmax (film KBr) 3091 (m), 2874 (m), 1573 (s), 1454 (s), 1334
(m), 1258 (m), 1213 (m), 1088 (s), 1009 (s), 931 (w), 871
(m), 1020 (s), 909 (w), 824 (m), 754 (w), 672 (m) cmꢂ1
.

7336
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
(w), 804 (m), 753 (s), 696 (s), 535 (w) cmꢂ1. dH (300 MHz
CDCl3) (hetero)aromatic: 8.50 (1H, s, H-2), 7.51–7.48
(4H, m, Ph), 7.37–7.28 (6H, m, Ph), 6.53 (1H, s, H-5);
DOABO–CH2O: 5.60 (2H, s, H-2, -8-t), 4.33 (2H, s,
5-OCH2), 4.06 (2H, d, J¼9.0 Hz, H-4, -6-c), 3.96 (2H, d,
J¼9.0 Hz, H-4, -6-t); dC (75 MHz CDCl3) (hetero)aromatic:
170.0 (1C, C-6), 161.3 (1C, C-4), 158.5 (1C, C-2), 139.5
(2C, Cq., Ph), 129.1 (2C, CH, Ph), 128.8 (4C, CH, Ph),
127.5 (4C, CH, Ph), 108.2 (1C, C-5); DOABO–CH2O:
97.8 (2C, C-2, -8), 73.4 (2C, C-4, -6), 73.1 (1C, C-5), 70.8
(1C, 5-OCH2). MS (EI, 70 eV); m/z (rel int. %): (M++1)
410 (4), 386 (<1), 304 (100), 280 (42), 174 (98), 156 (23),
129 (11), 91 (18).
C-4, -5); DOABO-CH2O: 88.7 (4C, C-2, -20, -8, -80), 74.5
(4C, C-4, -40, -6, -60), 71.9 (2C, 5-, 50-OCH2), 69.8 (2C,
C-5, 50). MS (EI, 70 eV); m/z (rel int. %): (M++Na) 389
(14), (M+ꢂ1) 365 (4), 168 (4), 128 (100), 98 (5).
4.2. Preparation of compound 9a
To a suspension in THF (50 mL) of 2a (prepared from 1a,
1.450 g, 10.0 mmol and potassium hydride 1.337 g as 30%
KH in mineral oil suspension, 0.401 g 100%, 10.0 mmol,
Scheme 2), cyanuryl chloride (0.571 g, 3.1 mmol) was
added as THF (20 mL) solution. The reaction mixture was
heated at 65 ꢁC for 36 h. with vigorous stirring, until the
starting 1a was absent (TLC monitoring, eluent ligroin/
acetone 2:1 v/v). The reaction was quenched with isopropa-
nol (1 mL) with stirring for additional 30 min. The mineral
compounds were filtered off and washed with excess of
THF. The combined THF solution was evaporated under
vacuum to dryness to provide the crude product as yellow
oil. Purification by flash column chromatography (eluent
ligroin/acetone 2:1 v/v visualisation in I2-bath) afforded
the desired 9a as a yellowish crystalline powder: 0.420 g
(34% yield).
4.1.25. 3-Chloro-6-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-
5-yl)methoxy]-pyridazine (8a). Yield 86%. White crystal-
line powder, mp 130–132 ꢁC (pentane) [Found: C, 46.33;
H, 5.03; N, 16.13. C10H12N3O3Cl requires: C, 46.61; H,
4.66; N, 16.31%]. Rf (75% ligroin/acetone) 0.50. nmax (film
NaCl) 2852 (w), 2082 (w), 1643 (s), 1441 (m), 1310 (w),
1101 (m), 1044 (m) cmꢂ1. dH (300 MHz CDCl3) heteroaro-
matic: 7.37 (1H, d, J¼9.0 Hz, H-4), 6.97 (1H, d, J¼9.0 Hz,
H-5); DOABO–CH2O: 4.54 (2H, s, 5-OCH2), 4.50 (2H, d,
J¼5.7 Hz, H-2, -8-c), 4.45 (2H, d, J¼5.7 Hz, H-2, -8-t),
3.86 (4H, s, H-4, -6, -c, -t). dC (75 MHz CDCl3) heteroaro-
matic: 164.4 (1C, C-6), 152.0 (1C, C-3), 131.4 (1C, C-4),
120.4 (1C, C-5); DOABO–CH2O: 88.7 (2C, C-2, -8), 74.3
(2C, C-4, -6), 71.9 (1C, C-5), 70.4 (1C, 5-OCH2). MS (EI,
70 eV); m/z (rel int. %): 257 (<1), 212 (13), 199 (8), 169
(15), 127 (15), 114 (100), 97 (19), 68 (26), 58 (13), 42
(30), 41 (76).
4.2.1. 2-Chloro-4,6-bis[(3,7-dioxa-r-1-azabicyclo[3.3.0]-
oct-c-5-yl)methoxy]-s-triazine (9a). Yield 34%. Yellowish
crystalline powder, mp 91.8–93.4 ꢁC (flash column chroma-
tography, eluent ligroin/acetone 2:1 v/v) [Found: C, 44.91;
H, 5.19; N, 17.63. C15H20N5O6Cl requires: C, 44.84; H,
5.02; N, 17.43%]. Rf 0.75 (66% ligroin/acetone). nmax
(KBr) 2971 (m), 2868 (s), 1731 (s), 1390 (m), 1252 (s),
1138 (m), 1038 (s), 926 (s), 885 (w), 792 (m), 673 (s), 610
(s), 505 (w) cmꢂ1. dH (300 MHz CDCl3) 4.39 (4H, s, H-2,
-20, -8, -80-c), 4.37 (4H, s, H-2, -20, -8, -80-t), 4.06 (4H, s,
5-, 50-OCH2), 3.73 (4H, d, J¼9.0 Hz, H-4, -40, -6, -60-c),
3.68 (4H, d, J¼9.0 Hz, H-4, -40, -6, -60-t); dC (75 MHz
CDCl3) 171.0 (3C, C-2, -4, -6 s-triazine), 88.6 (4C, C-2,
-20, -8, -80), 74.2 (4C, C-4, -40, -6, -60), 71.5 (2C, C-5, -50),
66.9 (2C, 5-, 50-OCH2). MS (EI), m/z (rel int. %) (M++1)
402 (<1), 324 (38), 256 (57), 145 (58), 127 (100).
4.1.26. 6-Methoxy-3-[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-
c-5-yl)methoxy]-pyridazine (8b). Yield 51%. White crys-
talline powder, mp 117–119 ꢁC (dichloromethane/pentane
1:2 v/v) [Found: C, 51.89; H, 6.25; N, 16.91. C11H15N3O4
requires: C, 52.17; H, 5.97; N, 16.59%]. Rf (75% ligroin/ace-
tone) 0.30. nmax (film NaCl) 2360 (w), 1630 (s), 1476 (m),
1384 (s), 1268 (m), 1036 (w) cmꢂ1. dH (300 MHz CDCl3)
heteroaromatic: 6.92 (2H, s, H-4, -5); DOABO–CH2O:
4.51 (2H, d, J¼5.7 Hz, H-2, -8-c), 4.48 (2H, s, 5-OCH2),
4.46 (2H, d, J¼5.7 Hz, H-2, -8-t); 4.01 (3H, s, OCH3),
3.86 (4H, s, H-4, -6, -c, -t); dC (75 MHz CDCl3) heteroaro-
matic: 162.6, 161.9 (2C, C-3, -6), 122.0, 121.6 (2C, C-4, -5);
DOABO–CH2O: 88.8 (2C, C-2, -8), 74.5 (2C, C-4, -6), 72.0
(1C, C-5), 69.7 (1C, 5-OCH2), 55.0 (1C, OCH3). MS (EI,
70 eV); m/z (rel int. %): 253 (<1), 223 (9), 208 (20), 195
(18), 165 (25), 140 (13), 139 (16), 128 (20), 127 (26), 114
(100), 98 (26), 97 (20), 80 (13), 68 (46), 54 (24), 42 (40),
41 (95).
4.3. Preparation of compound 10a
A solution of c-5-hydroxymethyl-3,7-dioxa-r-1-azabicyclo-
[3.3.0]octane 1a (0.740 g, 5.10 mmol) in THF (25 mL) was
cooled at ꢂ78 ꢁC with stirring, then n-BuLi (1.6 M in
hexane, 3.35 mL, 5.35 mmol) was injected to provide a clear
white fine suspension. After 20 min, cyanuryl chloride
(0.320 g, 1.70 mmol) was injected as THF (15 mL) solution.
The reaction mixture was allowed to slowly reach room tem-
perature (20 h) with vigorous stirring then quenched with
water (5 mL). The reaction mixture was evaporated to dry-
ness, then water (50 mL) and dichloromethane (50 mL)
were added with stirring. After separation, the dichloro-
methane solution was washed with water to neutrality and
then dried over MgSO4. After filtering, the organic solution
was concentrated in vacuum to provide the crude product,
which was taken with Et2O to yield the compound 10a as
white crystalline powder: 0.720 g (82% yield).
4.1.27. 3,6-Bis[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-
yl)methoxy]-pyridazine (8c). Yield 78%. White crystalline
powder, mp 195–197 ꢁC (dichloromethane/pentane 1:2 v/v)
[Found: C, 52.75; H, 5.85; N, 15.55. C16H22N4O6 requires:
C, 52.45; H, 6.05; N, 15.29%]. Rf (75% ligroin/acetone)
0.30. nmax (film NaCl) 2868 (w), 2361 (w), 1467 (m), 1446
(s), 1267 (s), 1137 (w), 1039 (s), 920 (m) cmꢂ1. dH
(300 MHz CDCl3) heteroaromatic: 7.24 (2H, s, H-4, -5);
DOABO–CH2O: 4.80 (4H, d, J¼5.7 Hz, H-2, -20, -8, -80-c),
4.76 (4H, s, 5-, 50-OCH2), 4.75 (4H, d, J¼5.7 Hz, H-2, -20,
-8, -80-t), 4.16 (8H, s, H-4, -40, -6, -60, -c, -t); dC (75 MHz
CDCl3) heteroaromatic: 162.1 (2C, C-3, -6), 121.9 (2C,
4.3.1. 2,4,6-Tris[(3,7-dioxa-r-1-azabicyclo[3.3.0]oct-c-5-
yl)methoxy]-s-triazine (10a). Yield 82%. White crystalline
powder, mp 238.9–239.5 ꢁC (Et2O) [Found: C, 49.44; H,

C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
7337
5.98; N, 16.44. C21H30N6O9 requires: C, 49.41; H, 5.92; N,
16.46%]. Rf (50% ligroin/acetone) 0.30. nmax (KBr) 3444
(m), 2969 (w), 2858 (s), 1589 (s), 1414 (s), 1334 (s), 1189
(m), 1141 (m), 1096 (s), 1044 (s), 1028 (s), 943 (m), 807
(s), 750 (m), 718 (w), 676 (m), 572 (m) cmꢂ1. dH
(300 MHz CDCl3) 4.49 (6H, d, J¼5.6 Hz, H-2, -20, -200, -8,
-80, -800-c), 4.42 (6H, d, J¼5.6 Hz, H-2, -20, -200, -8, -80,
-800-t), 4.41 (6H, s, 5-, 50-, 500-OCH2), 3.85 (12H, s, H-4,
-40, -400, -6, -60, -600-c, -t); dC (75 MHz CDCl3) 173.3 (3C,
C-2, -4, -6 s-triazine), 88.5 (6C,0 C-2, -20, -200, -8, -80, -800),
74.3 (6C, C-4, -40, -400, -6, -6 , -600), 71.5 (3C, 5-, 50-,
500-OCH2), 71.3 (3C, C-5, -50, -500); MS (ESI), m/z (rel int.
%) (M+ꢂ1+Na+) 532 (100), (M+) 511 (40), 384 (10).
139.5 (6C, Cq., Ph), 129.1 (6C, CH, Ph), 128.8 (12C, CH,
Ph), 127.5 (12C, CH, Ph), 97.6 (6C, C-2, -20, -200, -8, -80,
-800), 73.6 (6C, C-4, -40, -400, -6, -60, -600), 72.8 (3C, 5-, 50-,
500-OCH2), 72.2 (3C, C-5, -50, -500); MS (FAB+), m/z (rel
int. %) (M++1) 967.9 (100).
Acknowledgements
The financial support from C.N.C.S.I.S. (Romania, Project
353/20, 2005) and A.U.F. (Project 6313PS571 2004, Brux-
elles) is gratefully acknowledged.
References and notes
4.4. Preparation of compounds 9b and 10b
1. Senkus, M. J. Am. Chem. Soc. 1945, 67, 1515–1519.
2. Senkus, M. U.S. Patent 2,401,196; Chem. Abstr. 1946, 40,
P5446. See Ref. 4 and related patents.
3. Pierce, S.; Lunsford, D. C.; Raiford, R. W., Jr.; Rush, J. L.;
Riley, D. W. J. Am. Chem. Soc. 1951, 73, 2595–2596.
4. Pierce, S.; Lunsford, D. C. J. Am. Chem. Soc. 1951, 73, 2596–
2598.
To a suspension in THF (50 mL) of 2b-cis (prepared from
1b-cis, 1.480 g, 5.0 mmol and potassium hydride 0.668 g
as 30% KH in mineral oil suspension, 0.200 g 100%,
5.0 mmol, Scheme 2), cyanuryl chloride (0.302 g,
1.64 mmol) was rapidly added as THF (30 mL) solution.
The reaction mixture was slowly heated at 65 ꢁC for 40 h
with vigorous stirring, until the starting 1b-cis was present
in traces only (TLC monitoring, eluent ligroin/acetone
3.5:1 v/v, visualisation in UV-254 nm). The reaction was
quenched with water (50 mL) and dichloromethane
(125 mL) with stirring for additional 30 min. After separa-
tion, the aqueous layer was extracted with dichloromethane
(3ꢀ25 mL) and the combined dichloromethane solution was
washed with water to neutrality. After drying on MgSO4, the
organic solution was evaporated under vacuum to yield
1.10 g of the crude reaction mixture. Purification by flash
column chromatography (eluent ligroin/acetone 3.5:1 v/v
visualisation in UV-254 nm) afforded the following frac-
tions: 0.137 g recovered 1b-cis; 0.370 g desired 10b as
a white crystalline powder. The column was then completely
eluted with pure acetone to afford 0.310 g mixture 10b
(66%)+9b (34%), according to the 1H NMR spectrum.
5. Tilford, C. H.; Van Campen, M. G., Jr.; Shelton, R. S. J. Am.
Chem. Soc. 1947, 69, 2902–2906.
´
6. Darabantu, M.; Mager, S.; Ple, G.; Puscas, C. Heterocycles
1995, 41, 2327–2356 and the references cited therein.
7. Broadbent, H. S.; Burnham, W. S.; Sheely, R. M.; Olsen, R. K.
J. Heterocycl. Chem. 1976, 13, 337–348.
8. Barbulescu, N.; Moga, S. G.; Sintamarian, A.; Cuza, O.;
Vasilescu, V. Rom. Patent 83,939; Chem. Abstr. 1985, 102,
P149252r and related patents.
9. Nouguier, R.; Crozet, M.; Vanelle, P.; Maldonado, J. Tetra-
hedron Lett. 1985, 26, 5523–5524.
10. Zayed, S. E. Pak. J. Sci. Ind. Res. 1987, 30, 432–438; Chem.
Abstr. 1988, 108, 94446y.
11. Vanelle, P.; De Meo, M. P.; Maldonado, J.; Nouguier, R.;
Crozet, M. P.; Laget, M.; Dumenil, G. Eur. J. Med. Chem.
1990, 25, 241–250.
12. Mattson, A.; Norin, T. Synth. Commun. 1994, 24, 1489–1491.
13. Bonnet, D.; Pascal, J.; Grass-Masse, H.; Melnyk, O. Tetra-
hedron Lett. 2001, 42, 1875–1877.
14. Japan, Jpn. Tokkyo Koho JP 08,325,147, 1996; conf. C. A.
1997, 126, 139880
15. Laurent, P. A.; Riehl, M.; Frazao, C. S. Bull. Soc. Chim. Fr.
1967, 10, 3868–3872.
16. Cobb, R. L. U.S. Patent 3,843,726; Chem. Abstr. 1975, 82,
P861193t.
4.4.1. 2-Chloro-4,6-bis[(c-2,c-8-diphenyl-3,7-dioxa-r-1-
azabicyclo[3.3.0]oct-c-5-yl)methoxy]-triazine (9b). Yield
8%. dH (300 MHz CDCl3) as detected from the mixture
with 10b: 5.59 (4H, s, H-2, -8-t), 4.31 (4H, s, 5-, 50-
OCH2), 4.06 (4H, d, J¼9.2 Hz, H-4, -40, -6, -60-c), 3.98
(4H, d, J¼9.2 Hz, H-4, -40, -6, -60-t); dC (75 MHz CDCl3),
171.8 (3C, C-2, -4, -6 s-triazine), 139.3 (4C, Cq., Ph),
127.5 (8C, CH, Ph). MS (FAB+), m/z (rel int. %) (M+ꢂ1)
704 (20).
17. Cardona, C.; Gawley, R. E. J. Org. Chem. 2002, 67, 1411–
1413.
´
4.4.2. 2,4,6-Tris[(c-2,c-8-diphenyl-3,7-dioxa-r-1-aza-
bicyclo[3.3.0]oct-c-5-yl)methoxy]-s-triazine (10b). Yield
37%. White crystalline powder, mp 162.5–164.2 ꢁC (flash
column chromatography, eluent ligroin/acetone 3.5:1 v/v)
[Found: C, 70.61; H, 5.70; N, 8.44. C57H54N6O9 requires:
C, 70.80; H, 5.63; N, 8.69%] Rf (78% ligroin/acetone)
0.40. nmax (KBr) 3063 (w), 2871 (m), 1571 (s), 1417 (s),
1334 (s), 1210 (m), 1131 (s), 1088 (m), 1068 (m), 922
(m), 820 (w), 762 (m), 735 (s), 698 (s) cmꢂ1. dH
(300 MHz CDCl3) 7.51 (12H, m, Ph), 7.32–7.26 (18H, m,
Ph), 5.59 (6H, s, H-2, -20, -200, -8, -80, -800-t), 4.24 (6H, s,
5-, 50-, 500-OCH2), 4.06 (6H, d, J¼9.2 Hz, H-4, -40, -400, -6,
-60 -600-c), 3.98 (6H, d, J¼9.2 Hz, H-4, -40, -400, -6, -60,
-600-t); dC (75 MHz CDCl3) 172.9 (3C, C-2, -4, -6 s-triazine),
18. Darabantu, M.; Ple, G.; Mager, S.; Gaina, L.; Cotora, E.; Mates,
A.; Costas, L. Tetrahedron 1997, 53, 1891–1908.
´
19. Darabantu, M.; Ple, G.; Maiereanu, C.; Silaghi-Dumitrescu, I.;
Ramondenc, Y.; Mager, S. Tetrahedron 2000, 56, 3799–3816.
20. Darabantu, M.; Maiereanu, C.; Silaghi-Dumitrescu, I.; Toupet,
´
L.; Condamine, E.; Ramondenc, Y.; Berghian, C.; Ple, G.;
´
Ple, N. Eur. J. Org. Chem. 2004, 12, 2644–2661.
21. Eliel, E. L.; Wilen, H. S. Stereochemistry of the Organic
Compounds; Wiley: New York, NY, 1994; pp 221–239, 488–
507, 1017, 1199.
22. Cookson, R. C.; Crabb, T. A. Tetrahedron 1968, 24, 2385–
2397.
23. Crabb, T. A.; Hall, M. J.; Williams, R. O. Tetrahedron 1973, 29,
3389–3398.

7338
C. Berghian et al. / Tetrahedron 62 (2006) 7319–7338
24. Brush, J. R.; Magee, R. J.; O’Connor, M. J.; Teo, S. B.; Geue,
R. J.; Snow, M. R. J. Am. Chem. Soc. 1973, 2034–2035.
37. Parella, T.; Sanchez-Ferrando, F.; Virgili, A. J. Magn. Reson.
1997, 125, 145–148.
´
´
25. Monge, S.; Selambaron, J.; Carre, F.; Verducci, J.; Roque, J. P.;
Pavia, A. A. Carbohydr. Res. 2000, 328, 127–133.
38. Dudley, J.R.;Thuyrston, J. T.;Schaefer, F. C.;Holm-Hansen,D.;
Hull, C. J.; Adams, P. J. Am. Chem. Soc. 1951, 73, 2986–2990.
39. Weber, A. J. M.; Huysmans, W. G. B.; Mijs, W. J.; Bovee,
W. M. M. J.; Smidt, J.; Vriend, J. Recl. Trav. Chim. Pays-Bas
1978, 97, 107–109.
´
26. Darabantu, M.; Lequeux, T.; Pommelet, J. C.; Ple, N.; Turck,
A.; Toupet, L. Tetrahedron Lett. 2000, 41, 6763–6767.
´
27. Darabantu, M.; Lequeux, T.; Pommelet, J. C.; Ple, N.; Turck,
A. Tetrahedron 2001, 57, 739–750.
28. Aue, W. P.; Bartholdi, E.; Ernst, R. R. J. Chem. Phys. 1976, 64,
2229–2246.
29. Hurd, R. E. J. Magn. Reson. 1990, 87, 422–425.
30. Bax, A.; Griffey, R. H.; Hawkins, B. L. J. Magn. Reson. 1983,
55, 301–315.
31. Bax, A.; Subramanian, S. J. Magn. Reson. 1986, 67, 565–569.
32. Bax, A.; Summers, M. F. J. Am. Chem. Soc. 1986, 108, 2093–
2094.
33. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn.
Reson. Chem. 1993, 31, 287–292.
34. Bothner-By, A. A.; Stephens, R. L.; Lee, J. M.; Warren, C. D.;
Jeanloz, R. W. J. Am. Chem. Soc. 1984, 106, 811–813.
35. Bax, A. A.; Davis, D. G. J. Magn. Reson. 1985, 63, 207–213.
36. Jeener, J.; Meier, B. H.; Bachman, P.; Ernst, R. R. J. Chem.
Phys. 1979, 71, 4546–4553.
40. Menicagli, R.; Malanga, C.; Peluso, P. Synth. Commun. 1994,
24, 2153–2158.
41. Cronin, J. S.; Ginah, F. O.; Murray, R. A.; Copp, D. J. Synth.
Commun. 1996, 26, 3491–3494.
42. Friebolin, H. Basic One- and Two Dimensional NMR
Spectroscopy; VCH Verlagsgesellschaft/VCH: Weinheim/
New York, NY, 1991; p 271.
43. Riedell, F. G. Cyclic Organonitrogen Stereodynamics;
Lambert, J. B., Takeuchi, Y., Eds.; VCH: New York, NY,
1992; p 159.
´
´
44. Selambarom, J.; Monge, S.; Carre, F.; Roque, P. J.; Pavia, A. A.
Tetrahedron 2002, 58, 9559–9566.
´
´
45. Selambarom, J.; Carre, F.; Fruchier, A.; Roque, P. J.; Pavia,
A. A. Tetrahedron 2002, 58, 4439–4444.
46. Emsley, J. Die Elemente; Walter de Gruyter: Berlin, New York,
NY, 1994; pp 166, 178, 206.