Substituent effects in the ring-chain tautomerism of 4-alkyl-2-aryl substituted oxazolidines and tetrahydro-1,3-oxazines

Article abstract of DOI:10.1002/jhet.5570440635

(Chemical Equation Presented) The condensation products of 2-aminoethanol or 3-aminopropanol (bearing an alkyl substituent on the carbon adjacent to the nitrogen) with substituted benzaldehydes proved to exist in CDCl₃ at 300 K as three-component tautomeric mixtures of the diastereomeric five- or six-membered 1,3-O,N-heterocyclic ring forms and the corresponding imines. For each equilibrium, the electronic effects of the 2-aryl substituents were characterized by the Hammett equation. The steric effects of the alkyl groups could be described by Hansch-type equations for the equilibria involving oxazolidine ring forms. While the alkyl substituents did not cause any significant effect on the ring cis-chain and the ring trans-chain equilibria for tetrahydro-1,3-oxazines, increasing bulk of the 4-alkyl group increased the stability of the cyclic tautomers for the analogous oxazolidines.

Full text of DOI:10.1002/jhet.5570440635

Nov-Dec 2007
1465
Substituent Effects in the Ring-Chain Tautomerism of 4-Alkyl-2-
aryl substituted Oxazolidines and Tetrahydro-1,3-oxazines
Márta Juhász, László Lázár and Ferenc Fülöp*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 427, Hungary
*Corresponding author. Tel.: +36-62-545564; Fax: +36-62-545705; e-mail: fulop@pharm.u-szeged.hu
Received March 28, 2007
OH
( )n
R
NH2
CHO
X
O
O
( )n
( )n
N
H
X
N
H
X
R
R
OH
( )n
R
N
X
R = Me, Et, iPr; tBu; n = 1, 2
X = p-NO2, m-Br; p-Cl, H, p-Me, p-OMe, p-NMe2
The condensation products of 2-aminoethanol or 3-aminopropanol (bearing an alkyl substituent on the
carbon adjacent to the nitrogen) with substituted benzaldehydes proved to exist in CDCl3 at 300 K as three-
component tautomeric mixtures of the diastereomeric five- or six-membered 1,3-O,N-heterocyclic ring
forms and the corresponding imines. For each equilibrium, the electronic effects of the 2-aryl substituents
were characterized by the Hammett equation. The steric effects of the alkyl groups could be described by
Hansch-type equations for the equilibria involving oxazolidine ring forms. While the alkyl substituents did
not cause any significant effect on the ring cis-chain and the ring trans-chain equilibria for tetrahydro-1,3-
oxazines, increasing bulk of the 4-alkyl group increased the stability of the cyclic tautomers for the
analogous oxazolidines.
J. Heterocyclic Chem., 44, 1465 (2007).
Because of the practical importance of this phenomenon,
the substituent effects influencing the ring-chain tautomeric
processes of 1,3-O,N-heterocycles have been studied
thoroughly in the past 20 years. Such studies have been
extended from simple, two-component equilibria to
multicomponent, complicated mixtures and from the liquid
to the gas and the solid phases [1,8]. It was recently
demonstrated that 2-aryldihydro-3,1-benzoxazines exhibit
ring-chain tautomerism under unusual conditions, inside a
self-assembled capsule [9].
For the tautomeric equilibria of oxazolidines and
tetrahydro-1,3-oxazines bearing a substituted phenyl
group at position 2, in both the liquid and the gas phase, a
linear Hammett-type correlation was found between the
log K (K = [ring]/[chain]) values of the equilibria and the
electronic character (ꢀ+) of the substituents X on the 2-
phenyl group (Eq. 1) [1]:
INTRODUCTION
The reversible intramolecular addition of a hydroxy
group to a C=N double bond to form a cyclic structure is a
well-known phenomenon among N-unsubstituted 1,3-
O,N-heterocycles. This ring-chain tautomeric process
influences the reactivity and therefore the synthetic
applicability of these compounds [1]. The reduction of
ring-chain tautomeric 1,3-O,N-heterocycles is a method
that has often been applied for the preparation of N-
substituted 1,2- and 1,3-amino alcohols [2]. Reformatsky
and Mannich reactions with the participation of the C=N
bond of the open tautomeric form of chiral, non-racemic
oxazolidines provided a stereoselective procedure for the
synthesis of ꢀ-amino esters [3]. Because of their ring-
chain tautomeric character, oxazolidines and tetrahydro-
1,3-oxazines have been applied as aldehyde sources or
aldehyde protecting groups in various inter- or intra-
molecular carbon-transfer reactions [4,5]. The differences
in the reactivities of the ring-chain tautomeric forms of
1,3-O,N-heterocycles have been utilized in the
diastereoselective transformations of chiral, non-racemic
amino alcohols towards bicyclic lactams or 1,2,4-
trisubstituted oxazolidines [6,7].
log K = ꢁꢀ+ + log KX=H
(Eq. 1)
In contrast with the great number of studies on the
aromatic substituent dependence of the tautomeric equilibria
caused by a substituted phenyl group at position 2 of 1,3-
O,N-heterocycles, only a few examples are known of the

1466
M. Juhász, L. Lázár, F. Fülöp
Vol 44
steric and/or electronic effects of other substituents in 2-
aryl-1,3-O,N-heterocyclic systems [10-12]. Anomeric
effects of the aryl and alkyl substituents proved to exert a
significant influence on the tautomeric ratios of 1,3-diaryl-
naphth[1,2-e]oxazines, 2,4-diarylnaphth[2,1-e]oxazines and
1-alkyl-3-arylnaphth[1,2-e]oxazines, the equilibria of which
could be characterized by Hansch-type equations [11,12].
As a continuation of our previous quantitative studies
on the double substituent effects in the ring-chain tauto-
merism of five- and six-membered 1,3-O,N-heterocycles
[10-12], our present aim was to investigate the tautomeric
character of 4-alkyl-2-aryl-substituted oxazolidines and
the corresponding 3,4,5,6-tetrahydro-2H-1,3-oxazines.
We set out to study the scope and limitations of the
application of Hansch-type equations for the tautomeric
equilibria of 1,3-O,N-heterocycles.
Scheme I
OH
R
NH2
1-4
O
O
X
X
N
H
N
H
i
R
R
5B-8Ba-g
5C-8Ca-g
OH
R
N
X
5A-8Aa-g
1, 5: R = Me; 2, 6: R = Et; 3, 7: R = iPr; 4, 8: R = tBu
a: X = p-NO2; b: m-Br; c: p-Cl; d: H; e: p-Me; f: p-OMe; g, p-NMe2
Reagents and conditions: (i) XC6H4CHO, MeOH, r.t., 1 h, 65-100%
substituted derivatives (5a–8a; 17a–20a), the NOESY
spectra of which unequivocally showed that the major
ring forms in the tautomeric equilibria of 5–8 and 17–20
contain H-2 and H-4 in the cis position (B). 4-Alkyl and
2-aryl substituents did not change the sequence of the
chemical shifts of the characteristic O–CHAr–N and
N=CHAr protons (see Experimental).
RESULTS AND DISCUSSION
The condensations of 2-aminoethanols bearing
homologous alkyl substituents with increasing bulk (Me,
Et, iPr or tBu) at position 2 (1–4) with equivalent amounts
of aromatic aldehydes resulted in model oxazolidine
compounds 5–8 (Scheme I). The similar reactions of 3-
aminopropanols analogously substituted at position 3 (13–
16), obtained by LiAlH4 reduction of the corresponding ꢀ-
substituted ꢀ-amino acids 9–12 [13], led to the tetrahydro-
Scheme II
COOH
1
OH
NH2
i
1,3-oxazines 17–20 (Scheme II). The H nmr spectra of
5–8 and 17–20 revealed that, in CDCl3 solution at 300 K,
each compound participated in three-component ring-
chain tautomeric equilibria involving C-2 epimeric cyclic
forms (B and C) besides the open tautomer (A).
R
NH2
R
9-12
13-16
O
O
ii
R
N
R
N
The proportions of the chain (A) and diastereomeric
ring forms (B and C) of the tautomeric equilibria of 5–8
and 17–20 were determined by integration of the well-
separated O–CHAr–N (ring) and N=CHAr (chain) proton
singlets in the 1H nmr spectra (Tables 1 and 2). In
consequence of the very similar nmr spectroscopic
characteristics of the 2,4-disubstituted oxazolidines 5–8
and tetrahydro-1,3-oxazines 17–20, determination of the
relative configurations of the major and minor ring-closed
tautomers was performed only for the 2-(p-nitrophenyl)-
H
X
H
X
17B-20Ba-g
OH
17C-20Ca-g
R
N
X
17A-20Aa-g
9, 13, 17: R = Me; 10, 14, 18: R = Et; 11, 15, 19: R = iPr; 12, 16, 20: R = tBu
a: X = p-NO2; b: m-Br; c: p-Cl; d: H; e: p-Me; f: p-OMe; g, p-NMe2
Reagents and conditions: (i) LiAlH4, THF, reflux, 8 h, 68-81%;
(ii) XC6H4CHO, MeOH, r.t., 1 h, 61-100%
Table 1
Proportions (%) of the ring-closed tautomeric forms (B and C) in tautomeric equilibria for compounds 5–8 (CDCl3, 300 K).
Compd.
5
6
7
8
R(Va)
ꢀ+
Me (2.84)
Et (4.31)
iPr (5.74)
tBu (7.16)
X
B
C
B
C
B
C
B
C
a
b
c
d
e
f
p-NO2
m-Br
p-Cl
0.79
0.405
0.114
0
19.9
15.1
11.7
10.3
8.2
18.5
11.1
7.9
21.7
16.9
13.4
12.1
9.2
20.4
12.5
9.3
8.1
5.4
32.9
31.0
26.8
25.6
10.4
14.1
7.5
26.8
19.7
15.2
14.8
20.6
7.4
39.5
39.1
36.1
33.5
29.1
22.6
10.0
35.7
26.4
23.0
22.6
17.6
13.5
5.1
H
6.1
p-Me
p-OMe
p-NMe2
-0.311
-0.778
-1.7
4.7
4.7
2.8
5.3
3.2
1.3
g
2.3
0.8
2.3
2.1

Nov-Dec 2007
Substituent Effects in the Ring-Chain Tautomerism
1467
When Eq. 1 was applied to the log KB and log KC values
(KB = [B]/[A], KC = [C]/[A]) of 5–8 and 17–20, good linear
correlations were obtained vs the Hammett-Brown
parameter ꢀ+ of the substituent X on the 2-phenyl group,
aryloxazolidine [15] (21: log K0 = –1.10) or 2-arylte-
trahydro-1,3-oxazine [16] (22: log K0 = –0.15): cs = log KX=H
– log K0. A positive value of cs means a more stable ring
form relative to the corresponding parent 2-arylperhydro-
1,3-O,N heterocycle. The different trends observed in the
influences of the 4-alkyl substituents in the ring-chain
for both the B
A and the C
A equilibria (Figure 1
and Table 3). As usual for 2-aryl-1,3-O,N-heterocycles, the
Table 2
Proportions (%) of the ring-closed tautomeric forms (B and C) in tautomeric equilibria for compounds 17–20 (CDCl3, 300 K)
17
18
19
20
Compd.
R(Va)
ꢀ+
Me (2.84)
Et (4.31)
iPr (5.74)
tBu (7.16)
B
C
B
C
B
C
B
C
X
a
b
c
d
e
f
p-NO2
m-Br
p-Cl
0.79
0.405
0.114
0
91.5
86.7
85.4
75.0
67.9
57.1
14.0
3.2
2.9
2.1
3.4
1.3
1.7
0.7
89.9
81.0
76.9
71.1
61.4
47.1
19.4
3.6
2.9
2.9
2.3
1.8
1.4
1.1
88.4
83.0
79.9
74.6
63.3
53.5
22.6
3.6
2.9
2.9
1.8
1.5
1.0
0.8
88.4
88.4
82.1
79.4
71.7
60.7
22.9
3.5
2.1
2.6
1.8
1.3
1.2
0.4
H
p-Me
p-OMe
p-NMe2
-0.311
-0.778
-1.7
g
value of ꢁ was positive in each case, i.e. the electron-
withdrawing property of substituent X on the 2-phenyl ring
favours the ring-closed tautomer. This behavior stems from
the dipolar trend in the electron density induced at the C=N
moiety by the electronic character of substituent X [14].
In contrast with the corresponding 1,3-oxazines 17–20,
increasing bulk of the 4-alkyl group proved to enhance the
stability of the cyclic tautomers for oxazolidines 5–8, which
can be followed by the substitution effect parameter (cs)
introduced earlier to characterize the effects of the substi-
tuents at positions 4–6 on the stability of the ring form.
Parameter cs is calculated as the difference in the intercepts
for the given compound (5–8 or 17–20) and the parent 2-
equilibria of the homologous 1,3-O,N-heterocycles can be
explained by the different conformations of the oxazolidine
and oxazine rings, which allows different energetic plots of
these cyclic tautomeric forms and influences the stereo-
electronic effects of alkyl and aryl substituents on the
equilibria of oxazolidines 5–8 [12]. Further examinations of
the effect of this alkyl substituent are in progress.
The stability differences between the cis (B) and trans
(C) isomers of the 2,4-disubstituted cyclic forms can be
characterized by the differences in their substitution effect
parameters (cs), which are considerably smaller (ꢀcs:
0.15–0.24) for the epimeric oxazolidines (B, C) than for
the homologous epimeric oxazines (ꢀcs: 1.45–1.60).
log K
2
log K
1
1
0
0
-1
-2
-1
-2
-3
-3
ꢀ +
ꢀ +
-2
-1
0
1
-2
-1
0
1
a)
b)
Figure 1. (a) Plots of log KB or log KC (CDCl3, 300 K) for 5B ( ), 5C (+), 6B (ꢀ), 6C (ꢁ), 7B (ꢂ), 7C (ꢀ), 8B (ꢃ), 8C (ꢁ) vs Hammett-Brown
parameter ꢀ+. (b) Plots of log KB or log KC (CDCl3, 300 K) for 17B ( ), 17C (+), 18B (ꢀ), 18C (ꢁ), 19B (ꢂ), 19C (ꢀ), 20B (ꢃ), 20C (ꢁ) vs
Hammett-Brown parameter ꢀ+.

1468
M. Juhász, L. Lázár, F. Fülöp
Vol 44
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88BB
88CC
77
77
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77
77
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77
77
77
77
77
77
77
77
77
77
00..4466((±±00..0022))
00..6622((±±00..0022))
00..4499((±±00..0011))
00..5566((±±00..0033))
00..4411((±±00..0011))
00..5588((±±00..0022))
00..4466((±±00..0011))
00..5544((±±00..0011))
00..6600((±±00..0044))
00..8800((±±00..0044))
00..7733((±±00..0055))
00..6688((±±00..0044))
00..6633((±±00..0077))
00..6633((±±00..0022))
00..6688((±±00..0088))
00..6655((±±00..0044))
00..8800((±±00..0044))
00..7744((±±00..0066))
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00..999933
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00..999966
00..999966
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00..998899
00..999944
00..999900
00..999933
00..996688
00..999966
00..997711
00..999922
00..999944
00..998844
00..2222
00..0033
00..2288
00..1133
00..7711
00..4477
00..9977
00..8800
00
66AA
66AA
77AA
77AA
88AA
88AA
cc
2211AA
1177AA
1177AA
1188AA
1188AA
1199AA
1199AA
2200AA
2200AA
2222AA
2211BB
1177BB
1177CC
1188BB
1188CC
1199BB
1199CC
2200BB
2200CC
00..7777
––00..7711
00..6644
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00..6688
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00
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2222BB
OOHH
OO
(())
(())
nn
nn
NN
HH
XX
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XX
AA
BB
nn==11::2211,, nn==22::2222
a
b
c
d
a
b
c
d
Standard error in parentheses. For the meaning of substitution effect parameter (cs), see the text. Data from ref. [15]. Data from ref. [16].
Standard error in parentheses. For the meaning of substitution effect parameter (cs), see the text. Data from ref. [15]. Data from ref. [16].
To study the double substituent dependence of log KB
and log KC, multiple regression analysis was performed
for equilibria 5–8 and 17–20 according to the Hansch-
type equation (Eq. 2), introduced earlier to characterize
the ring-chain equilibria of 1-alkyl-3-arylnaphth[1,2-e]-
oxazines [12], where PR is an alkyl substituent parameter
and ꢀ+X is the Hammett-Brown parameter of substituent X
on the 2-phenyl ring. In order to find the accurate
dependence of log KB and log KC, four different alkyl
substituent parameters were investigated: ES (calculated
from the hydrolysis and aminolysis of esters) [17],
ꢁ (derived from the van der Waals radii [18], Va (the
volume of the portion of the substituent that is within 0.3
nm of the reaction centre) [17] and G (which characterizes
the shape by the ratio of the surface area of the substituent
to its volume) [17]. The last three steric parameters are
independent of any kinetic data.
log K = k + ꢂRPR + ꢂXꢀ+X
(Eq. 2)
Multiple linear regression analysis was performed
with the SPSS statistical software, and a value of 0.05
was chosen as the level of significance [19]. For the
equilibria of oxazolidines (5–8), the best correlations
were observed for the Meyer parameter (Va), while for
the equilibria of 1,3-oxazines (17–20), none of the four
alkyl substituent parameters resulted in a significant
value of ꢂR (Table 4). It is interesting to note that, in
contrast with the corresponding tautomeric equilibria of
1-alkyl-3-arylnaphth[1,2-e][1,3]oxazines
[12],
the
slopes of the alkyl substituent parameters (ꢂR) for the

Nov-Dec 2007
Substituent Effects in the Ring-Chain Tautomerism
1469
equilibria 5–8B
5-8A and 5–8C
5–8A are
To refine further the effects of the substituents on the
equilibria involving oxazolidines (5–8B 5–8A, 5–8C
5–8A) and tetrahydro-1,3-oxazines (17–20B 17–
20A, 17–20C 17–20A), another Hansch-type equation
practically the same positive values, which means that
the increasing proportion of the cyclic forms B and C
correlates with the increasing bulk of the alkyl
substituents to nearly the same extent (ꢀꢀR: <0.02) for
X
(Eq. 3) was applied, including the inductive (ꢁF ) and
a)
b)
Figure 2. (a) Plots of log KB for 5–8B vs Meyer (Va) and Hammett-Brown parameters (ꢁ+). (b) Plots of log KC for 5–8C vs Meyer (Va) and Hammett-
Brown parameters (ꢁ+).
Table 4
Multiple linear regression analysis of log KB and log KC values for 5–8 and 17–20 according to Eq. 2.
k
ꢀR
ꢀX
r
PR = Va
PR = ꢂ
PR = Es
PR = G
PR = Va
PR = ꢂ
PR = Es
PR = G
–1.500
–1.681
–1.352
–1.548
–1.393
–1.592
3.145
0.189
0.188
1.035
1.048
–0.476
–0.484
–0.252
0.453
0.573
0.453
0.573
0.453
0.573
0.453
0.573
0.689
0.712
0.689
0.712
0.689
0.712
0.689
0.712
0.982
0.989
0.972
0.987
0.968
0.985
0.951
0.966
0.984
0.978
0.986
0.977
0.986
0.977
0.983
0.979
5–8B
5–8C
5–8A
5–8A
5–8B
5–8A
5–8C
5–8A
5–8B
5–8A
5–8C
5–8A
5–8B
5–8A
2.942
–0.251
5–8C
5–8A
a
0.510
17–20B
17–20C
17–20B
17–20C
17–20B
17–20C
17–20B
17–20C
17–20A
17–20A
17–20A
17–20A
17–20A
17–20A
17–20A
17–20A
a
a
a
a
a
a
a
–0.801
0.469
–0.851
0.460
–0.847
0.655
–1.587
a Insignificant (level of significance 0.05)
X
resonance effects (ꢁR ) of the aromatic substituents
besides the Meyer parameter (Va):
both equilibria. The similar behaviour of the tautomeric
equilibria 5–8 can probably be rationalized in terms of
the similar hyperconjugative (anomeric) effects
occurring in the C-2 epimeric cyclic forms [12b,20].
log K = k + ꢀRVa + ꢀF ꢁFX + ꢀRXꢁR
(Eq. 3)
X
X

1470
M. Juhász, L. Lázár, F. Fülöp
Vol 44
The data resulting from the multiple linear regression
analyzer. Merck Kieselgel 60F254 plates were used for TLC. The
1H nmr spectra were recorded in CDCl3 solutions at 300 K on a
Bruker AVANCE DRX 400 spectrometer at 400.13 MHz.
analysis according to Eq. 3 (Table 5) show that the
equilibria of tetrahydro-1,3-oxazines are influenced by
both the inductive and resonance effects of the aromatic
Chemical shifts are given in ꢀ (ppm) relative to TMS as internal
Table 5
Multiple linear regression analysisa of log KB and log KC values for 5–8 and 17–20 according to Eq. 3.
X
X
k
ꢀR
ꢀF
ꢀR
r
5–8B
5–8C
5–8A
–1.532
–1.748
0.422
0.189
0.386
0.567
0.735
0.930
1.114
1.384
1.607
1.590
0.974
0.983
0.966
0.976
5–8A
0.190
a
17–20B
17–20C
17–20A
17–20A
a
–0.938
a Insignificant (level of significance 0.05). b 2-(m-Bromophenyl) derivatives (b) were omitted from the calculations
standard; multiplicites were recorded as s (singlet), bs (broad
singlet), d (doublet), dd (double doublet), ddd (double double
doublet), dt (double triplet), t (triplet), q (quartet) and m
(multiplet). In the cases of 5–8 and 17–20, the solutions were
left to stand at ambient temperature for 1 day for the equilibria
to be established before the 1H nmr spectra were run.
The (±)-2-amino-1-propanol (1), (±)-2-amino-1-butanol (2),
(±)-2-amino-3-methyl-1-butanol (3), (2S)-2-amino-3,3-dimethyl-1-
butanol (4) and (±)-3-aminobutanoic acid (9) were purchased
from Aldrich. (±)-3-Aminopentanoic acid (10), (±)-3-amino-4-
methylpentanoic acid (11) and (±)-3-amino-4,4-dimethyl-
pentanoic acid (12) were prepared according to known
procedures [13].
substituents to a higher extent than for the analogous
equilibria of oxazolidines. While the equilibria involving
diastereomeric oxazolidine ring forms exhibited
X
considerable differences in the values of both ꢀFX and ꢀR ,
X
the values of ꢀR were found to be less sensitive to the
relative configuration of the cyclic tautomer for the
equilibria involving tetrahydro-1,3-oxazines.
CONCLUSIONS
Through the condensations of 2-alkyl-2-aminoethanols or
3-alkyl-3-aminopropanols with substituted benzaldehydes,
4-alkyl-2-aryl-substituted oxazolidines and tetrahydro-1,3-
oxazines were prepared, which proved to exist in CDCl3 at
300 K as three-component tautomeric mixtures of the
diastereomeric five- or six-membered 1,3-O,N-heterocyclic
ring forms and the corresponding imines. Electron-
withdrawing substituents on the 2-phenyl ring preferred the
ring-closed tautomers. Each equilibrium could be
characterized by the Hammett equation, the parameters of
which indicated that the stability differences between the cis
and the trans cyclic forms are higher for the C-2 epimeric
tetrahydro-1,3-oxazines than for the C-2 epimeric
oxazolidines. Multiple linear regression analysis of the log K
values led to the conclusion that not only the electronic
effect of the 2-aryl substituent, but also the steric effect of
the 4-alkyl substituent, influenced the tautomeric equilibria
of the oxazolidines, which could be described by Hansch-
type equations. Increasing bulk of the 4-alkyl group proved
to enhance the proportion of the cyclic tautomers in the
equilibria involving oxazolidines. The inductive and
resonance effects of the aryl group influenced the equilibria
involving tetrahydro-1,3-oxazines more markedly than those
for the oxazolidines.
General Procedure for the Preparation of 3-Substituted 3-
amino-1-propanols (13–16). To a stirred and cooled suspension
of LiAlH4 (4.74 g, 125 mmol) in dry THF (100 mL), the
corresponding ꢁ-substituted amino acid (9–12, 50 mmol) was
added in small portions. The mixture was stirred and refluxed
for 8 h and then cooled, and the excess of LiAlH4 was
decomposed by the addition of a mixture of water (9.5 mL) and
THF (50 mL). The inorganic salts were filtered off and washed
with EtOAc (3 ꢂ 100 mL). The combined organic filtrate and
washings were dried (Na2SO4) and evaporated under reduced
pressure to give an oily product, which was distilled in vacuo to
yield 13–16 as colourless oils.
13: yield: 3.04 g (68%); bp 95-97 ºC (21 torr). The 1H nmr data
on the product correspond to the literature [21] data.
14: yield: 3.60 g (70%); bp 75-76 ºC (4 torr). 1H nmr: ꢀ 0.92 (t,
3H, CH3 J = 7.4 Hz), 1.28-1.55 (m, 3H, CHCH2), 1.62-1.70 (m, 1H,
CHCH2), 2.66 (bs, 3H, NH2, OH), 2.77-2.86 (m, 1H, NCH), 3.75-
3.86 ppm (m, 2H, OCH2). Anal. Calcd. for C5H13NO (103.16): C,
58.21; H, 12.70; N, 13.58. Found: C, 57.95; H, 12.44; N, 13.38.
15: yield: 4.77 g (81%); bp 80-81 ºC (3 torr). 1H nmr: ꢀ 0.88 (d,
3H, CH3, J = 6.0 Hz), 0.89 (d, 3H, CH3, J = 6.0 Hz), 1.42-1.68 (m,
3H, CCH2, CCH), 2.50-2.90 (m, 4H, NCH, NH2, OH), 3.75-3.87
ppm (m, 2H, OCH2). Anal. Calcd. for C6H15NO (117.19): C,
61.49; H, 12.90; N, 11.95. Found: C, 61.20; H, 12.68; N, 12.03.
1
16: yield: 4.71 g (72%); bp 81-83 ºC (4 torr). H nmr: ꢀ 0.87
EXPERIMENTAL
(s, 9H C(CH3)3), 1.32-1.44 (m, 1H, CCH2), 1.65-1.73 (m, 1H,
CCH2), 2.52 (dd, 1H, NCH, J = 2.1, 11.2 Hz), 2.81 (bs, 3H, NH2,
OH), 3.75-3.87 ppm (m, 2H, OCH2). Anal. Calcd. for C7H17NO
(131.22): C, 64.07; H, 13.06; N, 10.67. Found: C, 64.39; H,
12.76; N, 10.47.
Melting points were recorded on
a Kofler hot-plate
microscope apparatus and are uncorrected. Elemental analyses
were performed with a Perkin–Elmer 2400 CHNS elemental

Nov-Dec 2007
Substituent Effects in the Ring-Chain Tautomerism
1471
Table 6
Physical and nmr spectroscopic data on 4-alkyl-2-aryloxazolidines (5–8).
Compd.
Mp (°C)
Yield
(%)
Formula
M.W.
ꢀ (ppm)
N=CH (s) (A)
N–CH–O (s) (B)
N–CH–O (s)
(C)
5a
5b
5c
5d
5e
5f
89-91a
oil
65
~100
72
C10H12N2O3
C10H12BrNO
C10H12ClNO
C10H13NO
208.22
242.12
197.67
163.22
177.25
193.25
206.29
222.25
256.14
211.69
177.25
191.28
207.27
220.32
236.27
270.17
225.72
191.28
205.30
221.30
234.34
250.30
284.20
239.75
205.30
219.33
235.33
248.37
8.44
8.29
8.31
8.35
8.32
8.29
8.16
8.40
8.25
8.26
8.30
8.27
8.22
8.19
8.36
8.22
8.23
8.29
8.23
8.21
8.14
8.34
8.20
8.23
8.28
8.24
8.21
8.13
5.54
5.42
5.42
5.46
5.43
5.41
5.19
5.53
5.41
5.41
5.44
5.41
5.39
5.37
5.53
5.41
5.41
5.45
5.41
5.39
5.38
5.49
5.37
5.37
5.40
5.37
5.36
5.33
5.72
5.58
5.57
5.58
5.54
5.52
5.39
5.67
5.52
5.50
5.50
5.46
5.44
5.40
5.65
5.49
5.48
5.48
5.43
5.41
5.37
5.59
5.40
5.40
5.38
5.34
5.32
5.27
81-84b
62-63a
85-86a
73.5-74a
106-108a
82-83a
oil
80
78
C11H15NO
73
C11H15NO2
C12H18N2O
C11H14N2O3
C11H14BrNO
C11H14ClNO
C11H15NO
5g
6a
6b
6c
6d
6e
6f
77
70
~100
~100
~100
~100
~100
71
oil
oil
oil
C12H17NO
oil
65-67a
C12H17NO2
C13H20N2O
C12H16N2O3
C12H16BrNO
C12H16ClNO
C12H17NO
6g
7a
7b
7c
7d
7e
7f
oil
98
oil
83
oil
99
oil
75
oil
91
C13H19NO
oil
71-73b
76
C13H19NO2
C14H22N2O
C13H18N2O3
C13H18BrNO
C13H18ClNO
C13H19NO
7g
8a
8b
8c
8d
8e
8f
65
oil
~100
~100
88
oil
68-71a
oil
75-77b
oil
82
61
C14H21NO
~100
79
C14H21NO2
C15H24N2O
8g
54-56a
aRecrystallized from diisopropyl ether. bRecrystallized from n-hexane.
(B or C). In consequence of the small relative concentrations, only
the characteristic O–CHAr–N and N=CHAr protons are listed for
the detectable minor tautomeric forms (see Tables 6 and 7).
General Procedure for the Preparation of 4-Alkyl-2-aryl-
substituted oxazolidines (5–8) and tetrahydro-1,3-oxazines
(17–20). To a solution of the corresponding amino alcohol (1–4
or 13–16) (3 mmol) in absolute MeOH (20 mL), an equivalent
amount of aromatic aldehyde was added (for liquid aldehydes, a
freshly distilled sample was used), and the mixture was allowed
to stand at ambient temperature for 1 h. The solvent was then
evaporated off. The oily products were dried in a vacuum
desiccator for 24 h. The nmr spectra proved that the purities of
these compounds were greater than 95%. Crystalline products
were collected by filtration and recrystallized. All of the
recrystallized new compounds (5a–8g, 17a–20g) gave
satisfactory data on elemental analysis (C, H, N ±0.3%).
1
5aA: H nmr: ꢀ 1.26 (d, 3H, CH3, J = 6.6 Hz), 1.80 (bs, 1 H,
OH), 3.50-3.66 (m, 1H, NCH), 3.73 (d, 2H, OCH2, J = 2.5 Hz),
7.92 (d, 2H, C6H4, J = 8.6 Hz), 8.27 (d, 2H, C6H4, J = 8.6 Hz)
8.44 ppm (s, 1H, N=CHAr). 13C nmr: ꢀ 18.4 (CH3), 67.6 (C-5),
68.0 (C-4), 124.3, 129.3, 141.9, 149.5 (C6H4), 159.3 ppm (C-2).
1
6aA: H nmr: ꢀ 0.88 (t, 3H, CH3, J = 7.6 Hz), 1.46-1.75 (m,
2H, CH2CH3), 1.78 (bs, 1H, OH), 3.36-3.46 (m, 1H, NCH), 3.78
(d, 2H, OCH2, J = 5.5 Hz), 7.92 (d, 2H, C6H4, J = 8.8 Hz), 8.27
(d, 2H, C6H4, J = 8.8 Hz), 8.40 ppm (s, 1H, N=CHAr). 13C nmr:
ꢀ 11.0 (CH3), 25.3 (CH2CH3), 66.31 (C-5), 75.0 (C-4), 124.3,
129.3, 141.7, 149.4 (C6H4), 159.7 ppm (C-2).
The physical data and the chemical shifts of the characteristic
7aA: 1H nmr: ꢀ 0.93 (d, 3H, CH3, J = 4.5 Hz), 0.96 (d, J = 4.5
Hz, 3H, CH3), 1.92-2.04 (m, 1H, CH(CH3)2), 2.08 (bs, 1H, OH),
3.07 (q, 1H, NCH, J = 5.5 Hz), 3.84 (d, 2H, OCH2, J = 5.5 Hz),
7.92 (d, 2H, C6H4, J = 8.7 Hz), 8.24 (d, 2H, C6H4, J = 8.7 Hz),
8.36 ppm (s, 1H, N=CHAr). 13C nmr: ꢀ 19.5, (CH3), 20.8 (CH3),
30.4 (CH(CH3)2), 64.7 (C-5), 79.5 (C-4), 124.2, 129.3, 141.9,
149.4 (C6H4), 159.7 ppm (C-2).
N–CH–O and N=CHAr protons for compounds 5–8 and 17–20
are listed in Tables 6 and 7.
With regard to the similarities in the 1H nmr data for the
members a–g of each set of oxazolidines (5–8) and tetrahydro-1,3-
oxazines (17–20), the full spectra of the major tautomers are
described only for eight representatives of these sets of
compounds (5a, 6a, 7a, 8a, 17a, 18a, 19a, 20a). The protons of
the open form (A) are numbered according to the corresponding
protons of the cyclic oxazolidine or tetrahydro-1,3-oxazine forms
1
8aB: H nmr: ꢀ 0.97 (s, 9H, C(CH3)3), 1.58 (bs, 1 H, NH),
3.65 (t, J = 7.6 Hz, 1H, NCH), 3.90-3.97 (m, 2H, OCH2), 5.49 (s,

1472
M. Juhász, L. Lázár, F. Fülöp
Vol 44
Table 7
Physical and nmr spectroscopic data on and 4-alkyl-2-aryl-3,4,5,6-tetrahydro-2H-1,3-oxazines (17–20).
Compd.
Mp (°C)
Yield
(%)
Formula
M.W.
ꢀ (ppm)
N=CH (s)
(A)
N–CH–O (s)
(B)
N–CH–O (s)
(C)
17a
17b
17c
17d
17e
17f
oil
oil
~100
~100
~100
~100
~100
~100
~100
~100
~100
~100
~100
~100
~100
75
C11H14N2O3
C11H14BrNO
C11H14ClNO
C11H15NO
222.25
256.14
211.69
177.25
191.28
207.27
220.32
236.27
270.17
225.72
191.28
205.30
221.30
234.34
250.30
284.20
239.75
205.30
219.33
235.33
248.37
264.33
298.23
253.77
219.33
233.36
249.36
262.40
8.38
8.02
8.24
8.28
8.23
8.28
8.20
8.33
8.17
8.19
8.23
8.18
8.15
8.04
8.30
8.14
8.17
8.21
8.16
8.12
8.04
8.29
8.14
8.17
8.21
8.16
8.13
8.08
5.21
5.11
5.12
5.15
5.12
5.11
5.08
5.20
5.10
5.11
5.15
5.11
5.10
5.07
5.19
5.09
5.10
5.14
5.10
5.09
5.06
5.19
5.09
5.09
5.13
5.10
5.08
5.06
5.58
5.49
5.50
5.54
5.51
5.49
5.49
5.58
5.49
5.50
5.53
5.50
5.49
5.49
5.64
5.56
5.57
5.61
5.58
5.57
5.58
5.74
5.67
5.68
5.73
5.71
5.70
5.70
oil
oil
oil
C12H17NO
oil
C12H17NO2
C13H20N2O
C12H16N2O3
C12H16BrNO
C12H16ClNO
C12H17NO
17g
18a
18b
18c
18d
18e
18f
oil
oil
oil
oil
oil
oil
C13H19NO
oil
C13H19NO2
C14H22N2O
C13H18N2O3
C13H18BrNO
C13H18ClNO
C13H19NO
18g
19a
19b
19c
19d
19e
19f
78-79b
63-65a
oil
72
~100
~100
~100
~100
~100
61
oil
oil
oil
C14H21NO
oil
C14H21NO2
C15H24N2O
C14H20N2O3
C14H20BrNO
C14H20ClNO
C14H21NO
19g
20a
20b
20c
20d
20e
20f
60-61b
75-76.5a
oil
77
~100
~100
~100
~100
~100
73
oil
oil
oil
C15H23NO
oil
83-84.5b
C15H23NO2
C16H26N2O
20g
aRecrystallized from diisopropyl ether. bRecrystallized from n-hexane.
1H, NCHO), 7.69 (d, 2H, C6H4, J = 8.7 Hz), 8.23 ppm (d, 2H,
C6H4, J = 8.8 Hz). 13C nmr: ꢀ 26.8 (C(CH3)3), 34.0 (C(CH3)3),
67.7 (C-5), 69.1 (C-4), 92.1 (C-2), 123.8, 127.6, 148.1, 148.3
ppm (C6H4).
24.2 Hz), 1.59 (ddd, 1H, H-5eq, J = 2.3, 4.3, 13.6 Hz), 1.89-2.01
(m, 1H, CH(CH3)2, 2.73 (ddd, 1H, NCH, J = 3.0, 6.3, 10.8 Hz),
3.90 (dt, 1H, H-6ax, J = 2.3, 11.8 Hz), 4.34 (ddd, H-6eq, J = 1.5,
4.8, 11.3 Hz), 5.19 (s, 1H, NCHO), 7.71 (d, 2H, C6H4, J = 8.7 Hz),
8.19 ppm (d, 2H, C6H4, J = 8.9 Hz). 13C nmr: ꢀ 18.9 (CH3), 19.3
(CH3), 30.1 (C-5), 33.7 (CH(CH3)2), 60.9 (C-4), 68.1 (C-6), 88.0
(C-2), 123.7, 127.5, 141.3, 148.2 ppm (C6H4).
17aB: 1H nmr: ꢀ 1.17 (d, 3H, CH3, J = 6.6 Hz), 1.61 (ddd, J = 3.0,
4.45, 14.1 Hz, 1H, H-5eq), 1.44 (ddd, 1H, H-5ax, J = 4.5, 12.1, 23.7
Hz), 1.32 (bs, 1H, NH), 3.91 (dt, 1H, H-6ax, J = 2.5, 12.1 Hz), 3.07-
3.17 (m, 1H, NCH), 4.29 (ddd, 1H, H-6eq, J = 1.0, 4.5, 11.6 Hz),
5.21 (s, 1H, NCHO), 7.70 (d, 2H, C6H4, J = 8.7 Hz), 8.19 (d, 2H,
C6H4, J = 8.8 Hz), ppm. 13C nmr: ꢀ 22.6 (CH3), 35.4 (C-5), 51.2 (C-
4), 68.3 (C-6), 88.2 (C-2), 124.1, 128.1, 132.9, 148.3 ppm (C6H4).
Acknowledgements. The authors thank Dr. István Szatmári
for his help in the SPSS calculations, and the Hungarian
Scientific Research Foundation (Grant No. OTKA T 049407) for
financial support.
1
18aB: H nmr: ꢀ 0.99 (t, 3H, CH2CH3, J = 7.6 Hz), 1.28 (bs,
1H, NH), 1.35-1.47 (m, 2H, CH2CH3), 1.35-1.58 (m, 1H, H-5ax),
1.62 (ddd, 1H, H-5eq, J = 2.5, 4.0, 13.1 Hz), 2.86–2.95 (m, 1H,
NCH), 3.91 (dt, 1H, H-6ax, J = 2.0, 12.1 Hz), 4.31 (ddd, 1H, H-
6eq, J = 1.5, 4.5, 11.6 Hz), 5.20 (s, 1H, NCHO), 7.70 (d, 2H,
C6H4, J = 8.7 Hz), 8.18 ppm (d, 2H, C6H4, J = 8.9 Hz) ppm. 13C
nmr: ꢀ 10.4 (CH3), 30.1 (CH2CH3), 32.9 (C-5), 56.7 (C-4), 68.0
(C-6), 87.9 (C-2), 123.7, 127.5, 141.0, 148.1 ppm (C6H4).
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Nov-Dec 2007
Substituent Effects in the Ring-Chain Tautomerism
1473
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