Mechanism of formation and stabilities of the new dioxadiazadecalin systems. Ring-chain tautomerism

Article abstract of DOI:10.1021/jo9815554

A linear free energy relationship study is presented for the reactions of threo- and erythro-1,4-diamino- and -2,3-diaminobutanediols (1, 2) with six p-substituted benzaldehydes, the end products of which are the novel cis- and trans-1,5-dioxa-3,7-diazadecalin (DODAD, 7ci, 7tr) and -1,5-diaza-3,7- dioxadecalin (DADOD, 8ci, 8tr) systems. The consecutive double 1,3-oxazane ring closures take place mostly via Schiff bases and are moderately polar ring-chain tautomeric reactions with low positive p-values (0.69) affected by steric strain, stereoelectronic effects, and intramolecular hydrogen bonds. These are relatively slow processes, which may occur in the solid as well, but are greatly enhanced by acid catalysis.

Full text of DOI:10.1021/jo9815554

1166
J . Org. Chem. 1999, 64, 1166-1172
Mech a n ism of F or m a tion a n d Sta bilities of th e New
Dioxa d ia za d eca lin System s. Rin g-Ch a in Ta u tom er ism 1
Alexander Star and Benzion Fuchs*,†
School of Chemistry (Raymond and Beverly Sackler Faculty of Exact Sciences), Tel-Aviv University,
Ramat-Aviv, 69978 Tel-Aviv, Israel
Received August 3, 1998
A linear free energy relationship study is presented for the reactions of threo- and erythro-1,4-
diamino- and -2,3-diaminobutanediols (1, 2) with six p-substituted benzaldehydes, the end products
of which are the novel cis- and trans-1,5-dioxa-3,7-diazadecalin (DODAD, 7ci, 7tr) and -1,5-diaza-
3,7-dioxadecalin (DADOD, 8ci, 8tr) systems. The consecutive double 1,3-oxazane ring closures take
place mostly via Schiff bases and are moderately polar ring-chain tautomeric reactions with low
positive F-values (0.69) affected by steric strain, stereoelectronic effects, and intramolecular hydrogen
bonds. These are relatively slow processes, which may occur in the solid as well, but are greatly
enhanced by acid catalysis.
In tr od u ction
(Scheme 2); these systems have been studied in detail in
the Fu¨lo¨p-Berna´th, Pihlaja, and Riddell groups.5-7 In
these processes, according to Baldwin’s rules,8 the endo-
trig type ring-closure reaction should be favored for 1,3-
oxazanes (tetrahydro-1,3-oxazines) (6-endo-trig), but dis-
favored for oxazolidines (5-endo-trig).
In the quest for novel supramolecular host compounds,
we have recently been exploring the 1,3,5,7-tetrahetero-
decalin system (THD) (Scheme 1) and have already
described significant results in the tetraoxadecalin (TOD,
X ) Y ) O)2 and tetraazadecalin (TAD, X ) Y ) NH)3
series. Recently we reported4 the new 1,5-dioxa-3,7-
diazadecalin (DODAD) and 1,5-diaza-3,7-dioxadecalin
(DADOD) systems (Scheme 1), which we have prepared
by acid- promoted condensation of formaldehyde with 1,4-
diamino-2,3-butanediol (1) or 2,3-diamino-1,4-butanediol
(2), respectively. The reactions are fully stereospecific,
i.e., threo-1 or 2 provides with aldehydes cis-DODAD or
-DADOD and erythro-1 or 2 leads to trans-DODAD or
-DADOD systems, respectively. Indeed, the meso char-
acter of, e.g., erythro-1m is preserved in the centrosym-
metric (Ci) trans-DODAD (7tr), while the (C2) axial
symmetry of the threo-1t is preserved in the cis-DODAD
(7ci) product; similar results are found for the DADOD
series. For the cis configuration, it should be mentioned
that of the two interconverting (by ring inversion or ring-
chain tautomerism) forms4 (Scheme 1), the X,Y-inside
diastereoisomer is the most stable one.
For 2-aryl-substituted saturated 1,3-O,N-heterocycles,
the ring-chain tautomeric process has been analyzed5,6a
using the Hammett equation: log K ) Fσ+ + log K0,
where K ) [ring]/[chain], σ+ is the Hammett-Brown
constant of the 2-aryl substituent, and the slope F is a
characteristic of the ring system. A F value of 0.76 ( 0.04
has been found5,6a for regular 1,3-oxazanes in CDCl3
solution at room temperature, which gets lower at higher
temperatures6c or for multicomponent tautomeric mix-
tures7a (both affecting the entropy term) (vide infra).
With the DODAD and DADOD systems being fused
1,3-oxazanes, we felt compelled to subject them to a ring-
chain LFER analysis, to assess the relative stability of
the intermediate and final products, and to understand
the steric and electronic factors in their synthesis and
behavior. These interrelationships are also of consider-
able interest in the context of the diastereomeric starting
1,2,3,4-diaminobutanediols and their derivatives and
complexes, which had received attention for their en-
hanced anticancer properties9a-c and, in particular the
dissymmetric (C2) ones, as HIV protease inhibitors.9d
The products of the reaction of amino alcohols with
aldehydes exist as ring-chain tautomeric mixtures of 1,3-
O,N-heterocycles and the corresponding Schiff bases
† Fax: (+972-3) 640 9293. E-mail: bfuchs@post.tau.ac.il.
(1) New Supramolecular Host Systems, part 10. (a) For part 9, see:
Reany, O.; Goldberg, I.; Abramson, S.; Star, A.; Golender, L.; Ganguly,
B.; Fuchs, B. The 1,3,5,7-Tetraazadecalins. Theory vs Experiment. J .
Org. Chem. 1998, 63, 8850.
(2) (a) Senderowitz, H.; Linden, A.; Golender, L.; Abramson, S.;
Fuchs, B. Tetrahedron 1994, 50, 9691. (b) Senderowitz, H.; Golender,
L.; Fuchs, B. Tetrahedron 1994, 50, 9707. (c) Abramson, S.; Ashkenazi,
E.; Goldberg, I.; Greenwald, M.; J atzke, H.; Vardi, M.; Weinman, S.;
Fuchs, B. J . Chem. Soc., Chem. Commun. 1994, 1611. (d) Frische, K.;
Abramson, S.; Ashkenazi, E.; Greenwald, Lemcoff, N. G.; Fuchs, B.
Tetrahedron Lett. 1995, 36, 9193. (e) J atzke, H.; Frische, K.; Green-
wald, Golender, L.; Fuchs, B. Tetrahedron 1997, 53, 4821. (f) M.
Grabarnik, I. Goldberg, B. Fuchs, J . Chem. Soc., Perkin Trans. 1 1997,
3123. (g) Linden, A.; Ru¨chardt, Chr.; Beckhaus, H.-D.; Verevkin, S.
P.; Ganguly, B.; Fuchs, B. J . Org. Chem. 1998, 63, 8205.
(3) (a) Reany, O.; Goldberg, I.; Grabarnik, M.; Abramson, S.; Star,
A.; Fuchs, B. Tetrahedron Lett. 1997, 38, 8073.
Resu lts a n d Discu ssion
Following our initial findings4 and avoiding acid condi-
tions, Schiff bases could be observed and we proceeded
(5) (a) Valters, R. E.; Fu¨lo¨p, F.; Korbonits, D. Adv. Heterocycl. Chem.
1996, 66, 1. (b) Fu¨lo¨p, F.; Berna´th, G.; Pihlaja, K. Adv. Heterocycl.
Chem. 1998, 69, 349, in particular pp 447-450 and references cited
therein.
(6) (a) Fu¨lo¨p, F.; Pihlaja, K.; Mattinen, J .; Berna´th, G. J . Org. Chem.
1987, 52, 3821. (b) Fu¨lo¨p, F.; Pihlaja, K.; Neuvonen, K.; Berna´th, G.;
Argay, G.; Ka´lman, A. J . Org. Chem. 1993, 58, 1967. (c) Parkkinen,
A.; Fu¨lo¨p, F.; Pihlaja, K. Acta Chem. Scand. 1990, 44, 364.
(7) (a) La´za´r, A.; Lakatos, A. G.; Fu¨lo¨p, F.; Berna´th, G.; Riddell, F.
G. Tetrahedron 1997, 53, 1081. (b) Szakony, Z.; Fu¨lo¨p, F.; Berna´th,
G.; Evanics, F.; Riddell, F. G. Tetrahedron 1998, 54, 1013. (c) Riddell,
F. G.; Rogerson, M.; Fu¨lo¨p F.; Berna´th, G. Magn. Reson. Chem. 1995,
33, 600.
(4) (a) Star, A.; Lemcoff, N. G.; Goldberg, I.; Fuchs, B. Tetrahedron
Lett. 1997, 38, 3573. (b) Star, A.; Lemcoff, N. G.; Goldberg, I.; Fuchs,
B., submitted.
(8) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
10.1021/jo9815554 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/02/1999

New Dioxadiazadecalin Systems
J . Org. Chem., Vol. 64, No. 4, 1999 1167
Sch em e 1. F or m a tion a n d Ster eoch em istr y of 1,3,5,7-Tetr a h eter od eca lin (THD), Esp ecia lly
1,5-Dioxa -3,7-d ia za d eca lin (DODAD) a n d 1,5-Dia za -3,7-d ioxa d eca lin (DADOD)
Sch em e 2. Rin g-Ch a in Ta u tom er ism in
Tetr a h yd r o-1,3-oxa za n es
to probe the effect of electron-withdrawing (EW) and
-donating (ED) groups: the reaction of threo-1,4-diamino-
2,3-butanediol (1t) with p-EW-substituted benzaldehydes
(Scheme 3) in water provided the metastable Schiff bases
(e.g., 3t), followed by (mainly) the DODAD products (e.g.,
7ci), whereas threo-2,3-diamino-1,4-butanediol (2t) gave
directly the cis-DADOD analogues (e.g., 8ci). Reaction in
water was successful only with electron deficient alde-
hydes (a -c); in the case of ED substituents (d -f),
hydrolysis was significant and the cyclic products were
all but absent. Ethanol, however, behaved consistently
along the entire series and was the solvent of choice.
The four meso and threo 1,4-diamino-2,3-butanediols
(1m, 1t) and 2,3-diamino-1,4- butanediols (2m, 2t)4 were
reacted with six different p-substituted benzaldehydes
in ethanol at room temperature. In these reactions, a
ring-chain tautomeric mixture containing 11 compo-
nents could be envisaged (Schemes 3 and 4). We found,
however, that ring closure to 1,3-oxazane (Scheme 3) was
largely preferred and five-membered ring products
(Scheme 4) were absent or minor (<10%) and were
disregarded. The condensations took place in good to
excellent yields; some of the products, especially in the
F igu r e 1. Linear regression analysis of the equilibrium data
in the tautomeric mixtures of DODAD and DADOD in CDCl3.
meso series, crystallized from the reaction solution, while
the others were isolated after evaporation and recrys-
tallization. Pure products or their natural tautomeric
mixtures were isolated this way and characterized in the
solid and/or in solution.
The allowed (6-endo-trig) first 1,3-oxazane ring closure
of 3t may form in principle two 5,6-cis isomers and that
of 3m, two 5,6-trans isomers (with axial/equatorial or
diequatorial 5,6 substituents, respectively) on the corre-
sponding 1,3-oxazane intermediates (5). As expected from
conformational analytical tenets, all these intermediates
(5) had equatorial 2-aryl and N-aral-6-aminomethylene
groups, while the 5-hydroxyl occurred in cis-axial or
trans-equatorial conformation, respectively. The second
ring closure gave invariably the corresponding 2,6-
diequatorially substituted cis- or trans-DODAD (7ci, 7tr).
As to the CdN double bond in 5, both Z and E isomers
coexist, with a preponderance of the latter.
(9) (a) Hanessian, S.; Gauthier, J .-Y.; Okamoto, K.; Beauchamp, A.
L.; Theophanides, T. Can. J . Chem. 1993, 71, 880. (b) Haines, A. H.;
Morley, C.; Murrer, B. A. J . Med. Chem. 1989, 32, 742. (c) Kim, D.-K.;
Kim, G.; Gam, J .; Cho, Y.-B.; Kim H.-T.; Tai, J .-H.; Kim, K. H.; Hong,
W.-S.; Park, J .-G. J . Med. Chem. 1994, 37, 1471. (d) Gurjar, M. K.;
Pal, S.; Rama Rao, A. V.; Pariza, R. J .; Chorghade, M. S. Tetrahedron
1997, 53, 4769 and other references cited therein.

1168 J . Org. Chem., Vol. 64, No. 4, 1999
Star and Fuchs
Sch em e 3. Con d en sa tion P r od u cts of 1,4- a n d 2,3-Dia m in obu ta n ed iols w ith Ar om a tic Ald eh yd es
Sch em e 4. P ossible Byp r od u cts in th e Rin g-Closu r e P r ocess of 3 a n d 4: Tw o Oxa zolid in e a n d Th r ee
Bi(5-oxa zolid in yl) Dia ster eoisom er s
Ta ble 1. Resu lts of Lin ea r Regr ession An a lysis of
Equ ilibr ia in th e DODAD a n d DADOD Ser ies: Cis Ser ies
in CDCl3 (F igu r e 1) a n d Tr a n s in DMSO-d 6 (F igu r e 2)
series
slope (F)
log K0
cb
rc
3t to 5ci
5ci to 7ci
3t to 7ci
4t to 6ci
6ci to 8ci
4t to 8ci
3m to 5tr
5tr to 7tr
4m to 6tr
6tr to 8tr
3m to 5trg
4m to 6trg
0.68 ( 0.03
0.69 ( 0.04
1.40 ( 0.06d
0.65 ( 0.00e
0.52 ( 0.06e
1.18 ( 0.07d,e
0.36 ( 0.03
0.35 ( 0.04
0.70 ( 0.05
0.80 ( 0.00
1.19 ( 0.07
2.00 ( 0.07
0.09f
0.51
0.50
0.995
0.992
0.996
0.999
0.993
0.998
0.95
1.34
-
0.24
-0.63
1.30
-1.17
-0.78f
1.15f
-1.32f
0.42 ( 0.02
0.47 ( 0.01
-0.14 ( 0.02
0.33 ( 0.01
0.994
0.999
Intercept. c has been defined (by Fu¨lo¨p et al.5,6a) as the sum
of the steric and electronic effects of the substituents at positions
4, 5, and 6 in 1,3-oxazanes and expressed as the difference of
intercepts for any substituted derivatives and the parent 2-phenyl-
1,3-oxazane (-0.15): a positive c-value means better stabilization
of the cyclic product with respect to the open chain precursor as
compared to the phenyl-substituted system (and the other way
a
b
F igu r e 2. Linear regression analysis of the equilibrium data
in the tautomeric mixtures of trans-DODAD and trans-
DADOD in DMSO-d6.
analysis of the tautomeric mixtures in terms of three
major components: the double Schiff base (3), the 1,3-
oxazane (5), and the final dioxadiazadecalin products (7).
(Scheme 3). The presence of minor, five-membered ring
byproducts (Scheme 4) should not affect the equilibrium
under scrutiny, and they were disregarded. We analyzed
the Hammett equations of the two processes 3 to 5 (Z +
E) and 5 (Z + E) to 7 and, implicitly, 3 to 7 (Figure 1).
To the best of our knowledge, the present paper describes
d
around). c Correlation coefficient. F1 + F2 ) 2F. e Measurements
reach scale limit. f Direct ratio measurements in CDCl3 for 7trc
and 8trc only (σ+ ) 0) (see text). gIn DMSO-d6.
The compounds in the cis-DODAD series (7) (Scheme
3) were soluble in chloroform and could be used for
equilibrium analysis. Linear correlations with good cor-
relation coefficients were indeed obtained, following the

New Dioxadiazadecalin Systems
J . Org. Chem., Vol. 64, No. 4, 1999 1169
Ta ble 2. Obser ved (X-r a y)a vs Ca lcu la ted (MM3)b
Selected Str u ctu r a l P a r a m eter s of
2,6-Di(p-n itr op h en yl)-DODAD (7cia )
L (bond lengths, Å)
X-rayc
MM3b
O1-C2
O5-C6
O1-C9
O5-C10
C2-N3
C6-N7
N3-C4
N7-C8
C4-C10
C8-C9
C9-C10
1.424
1.425
1.438
1.425
1.425
1.447
1.472
1.474
1.517
1.501
1.527
1.419
1.419
1.424
1.424
1.456
1.456
1.461
1.461
1.525
1.525
1.521
T (torsion angles, deg)
X-ray
MM3b
O1-C2-N3-C4
O5-C6-N7-C8
O1-C9-C10-O5
N3-C4-C10-O5
N7-C8-C9-O1
O1-C2-C11-C12
O5-C6-C20-C21
57.6
58.5
71.9
-74.7
-76.5
13.3
65.8
65.8
68.2
-70.4
-70.4
-151.0
-151.0
-177.8
a
b
Reference 4a and Cambridge Structural Database. The
MM3(92) force field10 was used, including our modification for the
gauche effect in O-C-C-O systems (MM3-GE).2b c esd’s 0.006-
0.008.
1). Furthermore, we attempted a study of trans-DODAD
1
and trans-DADOD compounds by H NMR in DMSO-d6
(Tables 12 and 13, see Supporting Information), but only
the 3 to 5 and 4 to 6 ratios could be calculated. Linear
correlations were observed (Figure 2), albeit with low
accuracy, because of complete prevalence of the open-
chain tautomers in DMSO solution and the measured
F-values (0.42-0.47) were considerably lower than those
in chloroform. The 1H NMR data of the half-closed,
monocyclic 1,3-oxazanes are displayed in two columns in
Tables 13 and 14 (see Supporting Information) to stress
the interesting fact that they are practically superim-
posed spectra of a Schiff base and 1,3-oxazane moiety.
While the first ring closure in DODAD and DADOD
systems behaves similarly in both the cis and trans
series, the second ring closure is relatively preferred in
the cis series of both systems. The following trend in the
ease of the second cyclization, as compared to the first
one, could be observed: cis-DADOD > cis-DODAD >
trans-DODAD > trans-DADOD. The cis-bicyclic tau-
tomers (7ci, 8ci) are more stable (c > 0, see footnote b in
Table 1) whereas the trans-fused bicyclic systems (7tr,
8tr) are destabilized (c < 0) with respect to the reference
2-phenyltetrahydro-1,3-oxazanes.5,6a
This is in contrast to cyclohexane-fused oxazanes, for
which trans-fused systems have better stability than the
cis-fused ones.5,7a In both trans series the second cycliza-
tion steps appear to be handicapped by strain in the
transition state, more than in the cis series. At the same
time, the cis bicyclic products are stabilized by intramo-
lecular hydrogen bonding, especially in cis-DADOD.4 This
peculiar NH- - -O bond is one of the reasons for the N-H
axial conformations in most of the structurally defined
DODAD and DADOD compounds at hand (the main
reason being the anomeric effect in the N-C-O moieties,
vide infra).
F igu r e 3. UV spectrophotometrically monitored reaction
kinetics of the acid (TFA, 10-5 M) catalyzed ring closure of
3ta to 7cia at 28 °C.
the first example of such two-step ring-chain equilibria.
In this cis-DODAD (3) series, the same F-value (0.69 (
0.04) was found for both the first and the second ring
closures (Table 1). This value is somewhat smaller than
the standard oxazane value (0.76 ( 0.04);5,6a however, it
is almost identical to the F-value which had been obtained
for certain multicomponent tautomeric mixtures.7a The
7 to 3 ratio showed a very good linear correlation
coefficient, and the slope was 1.40 ( 0.06, i.e., close to
the theoretical 2F-value.
In all these cases, the ring-chain tautomeric ratio
could be monitored by NMR, by integrating appropriate
protons, viz., azomethine protons (8 ppm) in 3 to 5 and
2-oxazane protons (5 ppm) in 5 to 7 (Tables 3, 5, 8, and
10ssee Experimental Section and Supporting Informa-
tion).
The cis-DADOD (8) series showed in CDCl3 an ex-
tremely high ring/chain ratio, and open chain intermedi-
ates were detected only in the case of electron-donating
groups (Scheme 3, d -f). This precluded a reliable linear
analysis (Table 1) but sufficed for estimating the inter-
cepts in this series (vide infra).
The trans-DODAD (7tr) and trans-DADOD (8tr) tau-
tomeric mixtures (except those of 7trc,d and 8trc,d ) were
also not amenable to reliable analysis in chloroform, since
the intermediates or end products exhibited poor solubil-
ity (precipitation of one of the components shifted the
equilibrium arbitrarily). For this reason, a less reliable
linear correlation was obtained, but 7trc and 8trc could
be used for evaluation of the interceptsc-values (Table

1170 J . Org. Chem., Vol. 64, No. 4, 1999
Star and Fuchs
Ta ble 3. 1H NMR Da ta of 2,6-Dia r yl-cis-DODAD (7ci, cf. Sch em e 3) in CDCl3/TMS (δ in p p m , Mu lt., J in h er tz)
H4
Ar
H2
δ
H9
δ
Ar
7ci
δ
2J
3J
δ
3J
p-nitrophenyl
a
5.38 s
3.44 dd
3.31 d
3.36 dd
3.24 d
3.39 d
3.26 d
3.36 d
3.24 d
3.36 d
3.23 d
14.4
14.4
14.3
14.3
14.5
14.5
14.5
14.5
14.5
14.5
0.9
3.75 bs
3.66 bs
3.68 bs
3.65 bs
3.65 bs
8.20 d
7.74 d
7.48 d
7.40 d
7.38 m
8.8
8.8
8.4
8.4
3J ) 10a
5.25 s
p-bromophenyl
phenyl
b
c
d
e
f
0.8
5.31 s
5.27 s
5.26 s
5.22 s
p-tolyl
7.41 d
7.17 d
7.45 d
6.90 d
8.0
8.0
8.5
8.5
p-anisyl
p-Me2N-phenyl
overlapping signals
a
When taken immediately after extraction from basic aqueous solution, vicinal coupling of (axial) N-H with H2 could be observed.
Ta ble 4. 13C NMR Da ta of 2,6-Dia r yl-cis-DODAD (7ci, cf.
Sch em e 3) in CDCl3/TMS (δ in p p m , Mu lt.)
Ta ble 5. 1H NMR Da ta of 2,6-Dia r yl-cis-DADOD (8ci, cf.
Sch em e 3) in CDCl3/TMS (δ in p p m , Mu lt., J in h er tz)
H4
2J 3J
4.26 d 11.8
Ar
C2
C4
(t)
C9
(d)
Ar
δ
H2
H9
δ
Ar
8ci
δ
δ
δ
3J
Ar
7ci δ (d)
p-nitrophenyl
p-bromophenyl
phenyl
a
b
c
d
e
f
87.0 49.7 69.7 127.0, 123.4
88.2 50.4 70.3 132.0, 128.4
88.3 49.9 69.7 128.7, 128.4, 125.9
88.9 50.5 70.3 126.4, 129.0
88.7 50.5 70.3 129.1, 114.8
p-nitrophenyl
a
5.32 s
3.12 bs 8.19 d 8.9
3J ) 11a 7.72 d 8.9
3.05 bs 7.49 d 8.6
7.40 d 8.6
3.08 bs 7.72 m
7.50 m
3.04 bs 7.40 d 8.0
7.16 d 8.0
3.03 bs 7.43 d 8.6
6.89 d 8.6
3J ) 13.2a 4.15 d 11.8
p-bromophenyl b 5.21 s
4.20 d 11.8
4.09 d 11.8
4.23 d 11.8
4.11 dd 11.8, 1.1
4.20 d 11.8
4.09 dd 11.8 1.5
4.20 d 11.9
4.09 dd 11.9, 1.6
4.25 d 11.8
p-tolyl
p-anisyl
p-Me2N-phenyl
phenyl
p-tolyl
c
d
e
5.27 s
5.23 s
5.22 s
5.19 s
While threo-2,3-diamino-1,4-butanediol (2t) reacted
with p-EW-substituted benzaldehydes to give right away
the corresponding cis-DADOD (8ci) products and we were
not able to see any of the Schiff base intermediates, the
time required by the metastable Schiff bases (e.g., 3ta )
made from threo-1,4-diamino-2,3- butanediol (1t) with
p-EW-substituted benzaldehydes (Scheme 3), to undergo
ring closure in chloroform solution, ranged from 1 to
several weeks. In fact, the slow kinetics of these tauto-
meric mixtures made possible the isolation of the various
components. The process could be, however, acid cata-
lyzed (by trifluoroacetic acid), as shown by the ring
closure of the double Schiff base (3ta ) (λmax 217 nm, ꢀ 18
400; 284.5 nm, ꢀ 30 800) or, rather, of its instantaneously
protonated form (λmax 259.5 nm) to cis-DODAD (7cia )
(λmax 264 nm, ꢀ 5500) in acetonitrile. This UV-monitored
process (Figure 3a) proceeded with practically first-order
kinetics (k ) 0.129 min-1, t1/2 5.3 min) (Figure 3b). This
and the occurrence of three virtual isosbestic points
(Figure 3a) imply that the monocyclic intermediate is
very short-lived in these conditions.
p-anisyl
p-Me2N-phenyl f
7.36 d 8.7
6.66 d 8.7
4.08 d 11.8
a
When taken immediately after extraction from basic aqueous
solution, vicinal coupling of (axial) N-H with H2 and H9 could be
observed.
Ta ble 6. 13C NMR Da ta of 2,6-Dia r yl-cis-DADOD (8ci, cf.
Sch em e 3) in CDCl3/TMS (δ in p p m )
C2
C4
C9
Ar
δ
Ar
8ci δ (d) δ (t) δ (d)
p-nitrophenyl
p-bromophenyl
phenyl
p-tolyl
p-anisyl
a
b
c
d
e
f
87.0 71.3 49.6 127.0, 123.5, 147.9, 146.4
88.2 71.9 50.2 132.1, 128.3
88.9 72.0 50.3 129.1, 126.4
88.8 71.9 50.1 126.2, 129.6
88.7 71.9 50.2 127.5, 114.3, 132.9, 130.6
89.0 71.9 50.2 130.6, 112.2
p-Me2N-phenyl
modification for the gauche effect in O-C-C-O-contain-
ing systems, MM3-GE.2b
While the MM3 calculated structures where inevitably
C2 symmetric (Table 2), the X-ray structure showed albeit
gross conformational C2 symmetry, but departure from
it in certain geometrical details. The most remarkable
discrepancy was that between C2-N3 and C6-N7. It can
be easily interpreted as a consequence of the above ring-
chain tautomerism, especially in the second stage of
DODAD closure. One should, however, remember that
we deal here with systems bearing, R-N-C-O-R′ units,
which are prone to the known anomeric effect.11,12 In fact,
two unequal anomeric effects may operate in the ap-
propriate conformation: a weak lpO-σ*C-N one, ac-
companying the strong, synergized lpN-σ*C-O anomeric
We could observe an interesting expression of this
behavior, namely, the spontaneous but slow (1 month)
ring-closing process of 3ta to 7cia in the solid phase. We
found, however, a closely related precedent, viz., 2-p-
nitro-1-oxa-3-aza-cis-decalin, formed by ring closure of
the corresponding Schiff base in the crystal, as found by
CP/MAS 13C NMR by Riddell et al.7c
Another interesting manifestation of this ring-chain
tautomerism in the crystal was found while some rel-
evant geometrical parameters were scrutinized (Table 2)
in the reported4a X-ray diffraction structure of 2,6-di(p-
nitrophenyl)-DODAD (7cia ), in particular, the bond
lengths and torsion angles (the results of the analogous
DADOD molecule, 8cia , were of relatively low precision4a
and, hence, the geometrical data not good enough for
discussion in this context). At the same time, we were
interested in probing the MM3 force field10 as a compu-
tational tool for these systems, especially for emulation
of structural and conformational details; we used our
(10) MM3. QCPE (latest public version) or the official distributors
are Technical Utilization Corporation, Inc., 235 Glen Village Court,
Powell, OH 43065, and Tripos Associates, 1699 S. Hanley Road, St.
Louis, MO 63144. (b) Allinger, N. L.; Yuh, Y. H.; Lii, J .-H. J . Am. Chem.
Soc. 1989, 111, 8551 and subsequent articles.
(11) (a) Senderowitz, H.; Aped P.; Fuchs B. Helv. Chim. Acta 1990,
73, 2113. (b) Senderowitz, H.; Aped P.; Fuchs B. J . Comput. Chem.
1993, 14, 944.
(12) Senderowitz, H.; Fuchs, B., J . Mol. Struct. THEOCHEM 1997,
395/ 396, 123.

New Dioxadiazadecalin Systems
J . Org. Chem., Vol. 64, No. 4, 1999 1171
Ta ble 7. P h ysica l a n d An a lytica l Da ta of Va r iou s Cis a n d Tr a n s DODAD a n d DADOD Equ ilibr iu m P r od u cts a n d
Mixtu r esa
elemental analysis or HR-DCI-MS (m/z: MH+)
compd
mp (°C)b
cis-DODAD series
a
b
c
d
e
f
176 (dec)b,c
192b,c
C18H18N4O6
C18H18N2O2Br2
C18H20N2O2
C20H24N2O2
C20H24N2O4
C22H30N4O2
C 55.94, H 4.70, N 14.51; found C 55.80, H 4.63, N 14.42
DCI-MS: 455.1
140b,d
297.1603 obsd 297.1601
325.1916 obsd 325.1919
357.1814 obsd 357.1813
383.2447obsd 383.2447
145b,d
115b,d
158b,d
cis-DADOD series
a
b
170b,d
150b,e
C18H18N4O6
C18H18N2O2Br2
C 55.96, H 4.70, N 14.50, found C 55.97, H 4.68, N 14.43
DCI-MS: 455.0
c
d
e
f
C
18H20N2O2
297.1603 obsd 297.1603
325.1916 obsd 325.1916
357.1814 obsd 357.1822
383.2447 obsd 383.2447
105b,f
122b,f
155b,d
C20H24N2O2
C20H24N2O4
C22H30N4O2
trans-DODAD series
a
b
c
d
e
f
215b,d
186b,d
144b,e
148b,e
161b,c
199b,c
C18H18N4O6
C18H18N2O2Br2
C18H20N2O2
C20H24N2O2
C20H24N2O4
C22H30N4O2
387.1305 obsd 387.1306
DCI-MS: 455.1
297.1603 obsd 297.1602
325.1916 obsd 325.1912
357.1814 obsd 357.1811
383.2447 obsd 383.2451
trans-DADODseries
a
b
c
d
e
f
178
184
116
C
C
C
C
18H18N4O6
18H18N2O2Br2
18H20N2O2
20H24N2O2
387.1305 obsd 387.1303
DCI-MS: 455.1
297.1603 obsd. 297.1600
325.1916 obsd 325.1907
357.1814 obsd 357.1814
383.2447 obsd 383.2447
153
183b,c
219b,c
C20H24N2O4
C22H30N4O2
a
The pure end products show the same properties, since on heating they attain rapidly the equilibrium composition. All physical data
b
and analyses should be understood accordingly. Recrystallized from c, EtOH; d, iPrOH; e, MePh; f, t-BuOMe.
interaction, due to the good lp donor (N) anti positioned
to an excellent acceptor (O) (see below). Notably, the
valence bond representation of this molecular orbital
mixing, is a double bond-no bond resonance, the ther-
modynamic counterpart of which is the above-discussed
ring-chain tautomerism.
to be of considerable significance in the design of new
ligands and complexes based on the DODAD and DADOD
and the double Schiff base systems as well as of new
potential anticancer and C2 HIV protease inhibitor
drugs.9
Exp er im en ta l Section
Gen er a l. Melting points were determined on a capillary
melting point apparatus and are not corrected. Elemental
analyses were performed at the Microanalytical Laboratory,
Hebrew University, J erusalem. Mass spectra were measured
in DCI-MS and HR-MS mode. H and 13C NMR spectra were
1
This conformation demands an axially positioned
hydrogen on N, as is indeed observed in the X-ray
structure of 7cia (Table 2). In fact, this was proven by
NOE and double irradiation experiments of 7cia in
(acidless) solution as well (Table 3).
recorded on 200 or 500 MHz spectrometers and referenced to
TMS. Conformational assignments were based on NOE experi-
ments. UV spectra were measured on a UV spectrophotometer
with kinetic attachments. Commercially available reagents
and solvents were purified and dried when necessary by
common methods.
Sta r tin g Ma ter ia ls. The starting diastereoisomeric diami-
nobutanediols (1 and 2) dihydrochlorides were prepared as
described4 and purified as follows.
Con clu sion s
In conclusion, an LFER study of the ring-chain
tautomeric reactions of threo- and erythro-1,4-diamino-
and -2,3-diaminobutanediols (1, 2) with six p-substituted
benzaldehydes enabled us to understand them and to
anticipate the outcome of such future processes. The end
products are the novel cis- and trans-1,5-dioxa-3,7-
diazadecalin (DODAD, 7ci, 7tr) and -1,5-diaza-3,7-dioxa-
decalin (DADOD, 8ci, 8tr) systems. The double 1,3-
oxazane ring closures take place mostly via Schiff bases
and are moderately polar ring-chain tautomeric reac-
tions with low positive F-values (0.69), affected by solvent,
steric strain, stereoelectronic effects, and intramolecular
hydrogen bonds. These are relatively slow processes,
which may occur in the solid as well but are greatly
enhanced by acid catalysis. The insight gained is expected
threo-1,4-Diamino-2,3-butanediol dihydrochloride (1t‚2HCl)
(600 mg) was dissolved in a methanol/water solution, passed
through a strongly basic anion exchange column (Amberlist
A-26, OH- form), and eluted with methanol/water. Evaporation
gave 346 mg of threo-1,4-diamino-2,3- butanediol (1t) (93%).
A similar procedure was used for threo-2,3-diamino-1,4-bu-
tanediol (1m). The meso diaminobutanediols (1m and 2m) were
isolated as in the original procedures.4
Gen er a l Rea ction a n d Equ ilibr iu m P r oced u r e. A total
of 50 mg of the free base (e.g., 1t) was dissolved in 10 mL of
ethanol, and an appropriate aromatic aldehyde (2.2 molar
equiv ) was added. After standing overnight at room temper-
ature, the crystalline product was collected from the ethanol
solution; alternatively, the solvent was evaporated and the
solid residue was washed of excess aldehyde and crystallized
from a suitable solvent, usually i-PrOH (yields: 70-90%).

1172 J . Org. Chem., Vol. 64, No. 4, 1999
Star and Fuchs
Each of these products was taken up in chloroform-d or DMSO-
d6 and left to reach constant composition at room temperature.
All plotted correlation data were recorded on these equilibrium
mixtures.
The resolved NMR spectral data of the DODAD and DADOD
products are given in Tables 3-6 for clearer scrutiny of the
like vs unlike, i.e., coupling constants vs chemical shifts,
respectively. Other relevant physical data of all isolated
compounds or equilibrium mixtures are assembled in Table
7. The NMR spectral data of the Schiff bases and intermediate
products are given in Tables 8-14, available as Supporting
Information.
Ack n ow led gm en t. This work was supported in part
by a grant from the Israel Science Foundation and by
an Intel scholarship (to A.S.). Mr. Shimon Hauptman
provided valuable mass spectrometric assistance, and
Ms. Galia Mayan contributed as an undergraduate
research student.
Su p p or tin g In for m a tion Ava ila ble: NMR spectral data
of Schiff bases and intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9815554