Substituent effects in ring-chain tautomerism of the condensation products of non-racemic 1,2-aminoalcohols with aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2011.11.011

The condensation of (S)-2-amino-2-phenylethanol or (S)-2-amino-3- phenylpropanol with substituted benzaldehydes in methanol or water led to crystalline products, which proved to exist in CDCl₃ at 300 K as three-component (ring^cis-ope

Full text of DOI:10.1016/j.tetasy.2011.11.011

Tetrahedron: Asymmetry 22 (2011) 2012–2017
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Substituent effects in ring-chain tautomerism of the condensation products
of non-racemic 1,2-aminoalcohols with aromatic aldehydes
Márta Juhász a, László Lázár a, , Ferenc Fülöp a,b,
⇑
⇑
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary
b Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The condensation of (S)-2-amino-2-phenylethanol or (S)-2-amino-3-phenylpropanol with substituted
benzaldehydes in methanol or water led to crystalline products, which proved to exist in CDCl3 at
300 K as three-component (ringcis-open-ringtrans) tautomeric mixtures. The electronic effects of the 2-aryl
substituents on the tautomeric equilibria were described by the Hammett equation. Good correlations
were found between the equilibrium constants and the Hammett–Brown parameter (
ent X on the 2-phenyl group.
Received 17 October 2011
Accepted 21 November 2011
Available online 4 January 2012
r
+) of the substitu-
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
sky9 and Ugi reactions10 with the participation of the open tauto-
meric forms, or N-acetylation of the cyclic forms via iminium
intermediates.11
The diastereoselective formation of bicyclic lactams in the
domino ring-closure reactions of chiral phenylglycinols with
The synthesis and derivatization of 1,2- and 1,3-aminoalcohols
are of both pharmaceutical and chemical interest. These di-
functional moieties are frequently occurring structural motifs in
biologically active compounds. Non-racemic 1,2- and 1,3-aminoal-
cohols are often utilized as resolving agents in the preparation of
enantiopure substances or as chiral auxiliaries in various asym-
metric transformations.1
Oxazolidine derivatives, obtained by the condensation of
1,2-aminoalcohols with oxo compounds, are also widely applied
as intermediates or catalysts in asymmetric syntheses.2 Excellent
enantioselectivities have been achieved in the alkynylation of alde-
hydes,3 in the Diels–Alder reactions of 1,2-dihydropyridines4 and
in a domino Michael–aldol reaction5 through the use of chiral oxa-
zolidine organocatalysts. Also, high yields and enantiomeric ex-
cesses have been attained in the bisoxazolidine-catalyzed
nitroaldol reactions of different aliphatic and aromatic aldehydes.6
The structures of N-unsubstituted oxazolidines can be charac-
terized by tautomeric equilibria of the cyclic and the corresponding
Schiff base open-chain forms. Although Baldwin’s rules suggest
that ring closure of the open form is an unfavored 5-endo-trig pro-
cess, a rapid equilibrium reaction has been observed to occur in
solution.7,8
c-, d- or e-keto acids was earlier rationalized in terms of the differ-
ences in the rates of the acylation steps for the ring-chain tauto-
meric oxazolidine intermediates. These lactams are valuable
building blocks in the enantioselective synthesis of structurally
diverse piperidine-containing natural products and bioactive mol-
ecules.12 Thanks to their ring-chain tautomeric character, oxazoli-
dines have been applied as aldehyde sources in carbon-transfer
reactions toward fused pyran and pyridine derivatives13 and in
the modified Pictet–Spengler synthesis of tetrahydro-b-carbo-
lines.14 Reductive aminations of oxo compounds with 1,2-aminoal-
cohols occur via oxazolidine intermediates,15 and the ring-chain
tautomeric character of oxazolidines also contributes to the devel-
opment of prodrugs16 or the creation of dynamic combinatorial
libraries.17
As concerns the analogous N-unsubstituted 1,3-X,N-heterocy-
cles (X = O, S, NR), the substituent dependence of the ring-chain
tautomeric equilibria of oxazolidines was thoroughly studied ear-
lier.7,8,18,19 Investigations of a considerable number of 2-aryl-
substituted derivatives led to the conclusion that the tautomeric
ratios were substantially influenced by the electronic properties
of the aryl substituents. For the tautomeric equilibria of 2-(X-phe-
nyl)-substituted oxazolidines, a linear Hammett-type correlation
was found between the logK (K = [ring]/[chain]) values of the
The ring-chain tautomeric character of oxazolidine derivatives
provides these compounds with dual reactivity (substitution at
the NH and/or addition at the C@N group), which is widely utilized
in various synthetic transformations, for example the Reformat-
equilibria and the Hammett–Brown electronic parameter (
r
+) of
substituent X on the 2-phenyl group (Eq. 1):7,8,18,19
⇑
Corresponding authors. Tel.: +36 62 545562; fax: +36 62 545705.
E-mail addresses: lazar@pharm.u-szeged.hu (L. Lázár), fulop@pharm.u-szeged.
log K ¼
q
rþ þ log KX¼H
ð1Þ
hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.011

M. Juhász et al. / Tetrahedron: Asymmetry 22 (2011) 2012–2017
2013
In contrast with these earlier reports on ring-chain tautomer-
ism, unusual results were presented in a recent paper.20 Benzylide-
neamino derivatives were synthesized through the condensations
of (S)-2-amino-2-phenylethanol or (S)-2-amino-3-phenylpropanol
with substituted benzaldehydes, these reactions reportedly fur-
nishing two-component ring-chain tautomeric mixtures.
pound 3a–i, 4a–i was obtained as a stable crystalline product
(Scheme 1). When the condensations of aminoalcohol 1 or 2 with
the equivalent amounts of aldehydes were performed in distilled
water, the mixtures were stirred vigorously at room temperature
for 1 h and the precipitated products 3a–i, 4a–i were collected by
filtration. The yields for the aqueous reactions proved to be some-
what higher than those for the condensations in MeOH.
Since the compounds synthesized in MeOH and in H2O are nec-
essarily identical, we studied the tautomerism only on the com-
pounds synthesized in MeOH. We found that in CDCl3 solution at
300 K compounds 3 and 4 participated in three-component ring-
chain tautomeric equilibria involving C-2 epimeric cyclic forms
(B and C) besides the open tautomer (A) (Scheme 1). Since the
NMR spectroscopic characterizations were very similar for 3a–i
and 4a–i, only the data on 3a and 4a were chosen to illustrate
the 1H NMR spectra of the tautomeric compounds prepared and
the relative configurations of the major and minor ring-closed tau-
tomers (see Section 4). The NOE interaction observed between H-2
and H-4 in the NOESY spectra indicated that the major ring form
had the cis configuration B. 2,4-Diaryl substituents did not change
the sequence of the chemical shifts of the characteristic O–CHAr–N
and N@CHAr protons.
Rather surprisingly, the amount of the Schiff base form in the
tautomeric mixtures of the products formed in the reactions of
(S)-2-amino-2-phenylethanol with substituted benzaldehydes var-
ied from 92% to 99%. Interestingly, significant differences were not
observed in the amounts of the open-chain form in the tautomeric
mixtures of products formed in the reactions of (S)-2-amino-3-
phenylpropanol with substituted benzaldehydes. For example,
the amounts of (S)-2-(4-nitrobenzylideneamino)-3-phenylpropa-
nol and (S)-2-(4-dimethylamino-benzylideneamino)-3-phenylpro-
panol in the tautomeric mixtures were 90% and 87%, respectively.
Furthermore, for the ring-closed tautomer formed in the tauto-
meric mixture, a distinction of two epimers was not reported.20
In order to clarify this situation, we have re-examined the data
presented in the paper of Wu et al.20 We prepared the same (S)-2-
benzylideneamino-2-phenylethanols and (S)-2-benzylideneami-
no-3-phenylpropanols and also additional model compounds.
In contrast with the three-component tautomeric equilibria de-
tected in our work, Wu et al. reported only two components A and
B in the tautomeric mixtures of the oxazolidines prepared. They
did not describe the minor trans C-2 epimeric form C.20
2. Results and discussion
Harsh reaction conditions (e.g. long reflux times in high-boil-
ing-point solvents, with the application of water traps or dehydrat-
ing agents) have at times been applied for the condensation of
amino alcohols with aldehydes.21 Wu et al. reacted (S)-2-amino-
2-phenylethanol 1 or (S)-2-amino-3-phenylpropanol 2 with equiv-
alent amounts of different benzaldehydes in anhydrous THF in the
presence of MgSO4 for 1 h.20
We earlier reported that 1,2- and 1,3-aminoalcohols react con-
veniently with aromatic aldehydes without any additive to yield
the condensation products quantitatively within a few hours in
MeOH or EtOH even at room temperature.18,19 In the present study
we followed this synthetic procedure. Moreover, in view of the
emerging importance of water as a versatile solvent in organic syn-
thesis,22 including various condensations (e.g. the Ugi four-center
three-component reaction,23 or cyclocondensations of b-amino-
carboxamides and various ketones24), the reactions of aminoalco-
hols 1 and 2 with aromatic aldehydes were also attempted in
aqueous medium.
Figures 1 and 2 show the 500 MHz 1H NMR spectra of the prod-
ucts 3a, and 4a of the reactions of (S)-2-amino-2-phenylethanol or
(S)-2-amino-3-phenylpropanol with p-nitrobenzaldehyde. In Fig-
ure 1, the singlets at 5.70 and 5.83 ppm are those of H-2 in the
two ring-closed tautomers, while the azomethine singlet is at
8.48 ppm. In Figure 2, the corresponding singlets are shifted to
lower values, with the H-2 singlets of the ring-closed tautomers
at 5.55 and 5.70 ppm and the azomethine singlet at 8.02 ppm. Both
spectra also contain the corresponding triplets or multiplets of H-4
of the epimeric ring forms of 3a and 4a.
In Figure 1, the well-separated triplets at 4.37 and 4.43 ppm
correspond to H-4 in the major and minor ring forms of 3a. In
4a, multiplets appear at 3.73–3.81 ppm for H-4 of the major epi-
meric ring form, and overlapping multiplets are observed at
3.81–3.90 ppm for H-4 in the minor epimer (Fig. 2). The amounts
of the tautomeric forms are also indicated in the spectra. Of the
C-2 epimers, the major ring form in the tautomeric equilibria of
3a and 4a contains H-2 and H-4 in the cis position B (Tables 1
and 2).
When 1 or 2 was reacted with an equivalent amount of the cor-
responding aldehyde in absolute MeOH, and the mixture was left
to stand at room temperature for 1 h, condensations took place
nearly quantitatively. After evaporation of the solution, each com-
The reported contents of the tautomeric forms in the tautomeric
equilibria in the two studies differ drastically.19 For instance, Wu
OH
(
)
S
R
NH2
1 2
,
O
O
(
)
S
(R)
X
X
(
)
S
(
)
S
i
N
H
N
H
R
R
3B-4Ba-i
3C-4Ca-i
OH
N
(
)
S
R
X
3A-4Aa-i
R = Ph: 1, 3; R= CH2 Ph: 2, 4; X = a, NO2; b, CN; c, Br; d, Cl; e, H; f, F; g, He; h, OMe; i, HMe2
.
Scheme 1. Reagents, conditions and yields: (i) XC6H4CHO, MeOH or H2O, rt, 1 h, 61–99%.

2014
M. Juhász et al. / Tetrahedron: Asymmetry 22 (2011) 2012–2017
Figure 1. Part of the 1H NMR spectrum of 3a. Chemical shifts of the characteristic N@CH and N–CH–O protons in the three tautomeric forms are indicated, together with the
amounts determined for the three tautomers. The spectrum was recorded after the solution in CDCl3 had been allowed to stand at 300 K for 1 day.
Figure 2. Part of the 1H NMR spectrum of 4a. Chemical shifts of the characteristic N@CH and N–CH–O protons in the three tautomeric forms are indicated, together with the
amounts determined for the three tautomers. The spectrum was recorded after the solution in CDCl3 had been allowed to stand at 300 K for 1 day.
et al. gave the measured amount of the open-chain form for p-NO2-
substituted compound 3a as 92%, whereas in the present work it
was only 65.3%. Wu et al. detected the Schiff base form in almost
identical amounts in the ring-chain tautomeric mixtures of the
various condensation products. As an example, for compound 4a
with a p-NO2 group and compound 4h with a p-OMe substituent,
the amounts of open-chain form detected were 90% and 87%,
respectively. The measured values did not indicate any correlation
between the open-chain form (or cyclic form) and the different
electronic characters of groups X.
r+ of substituent X on the 2-phenyl group, for both the B ꢀ A
and the C ꢀ A equilibria (Fig. 3 and Table 3).
3. Conclusion
Our results demonstrate that, in contrast with the recently re-
ported data,20 the condensation products of (S)-2-amino-2-phenyl-
ethanol or (S)-2-amino-3-phenylpropanol with substituted
benzaldehydes exist in CDCl3 at 300 K as three-component tauto-
meric mixtures containing not only the open tautomeric form,
but also C-2 epimeric oxazolidines as minor components. Careful
analysis of the influence of the electronic character of the aryl sub-
stituents at position 2 on the ring-chain tautomeric equilibria re-
vealed that it could be described by the Hammett equation.
To study the 2-aryl substituent dependence of logKB and logKC
(KB = [B]/[C], KC = [C]/[A]), we applied Eq. 1 to the data on com-
pounds 3 and 4. Good linear correlations were obtained between
the logKB and logKC values and the Hammett–Brown parameter

M. Juhász et al. / Tetrahedron: Asymmetry 22 (2011) 2012–2017
2015
Kieselgel 60 F254 plates were used for TLC. 1H NMR spectra were re-
corded in CDCl3 solutions at 300 K on a Bruker AVANCE DRX 500
Table 1
Amounts (%) of tautomeric forms A, B, and C in tautomeric equilibria for compounds 3
(CDCl3, 300 K) determined in the present study, and amounts (%) of Schiff base form A
in the tautomeric mixture for compounds 3a, 3d, 3e, 3g and 3h (CDCl3) reported in a
previous study20
spectrometer at 500.13 MHz. Chemical shifts are given in
d
(ppm) relative to TMS as an internal standard; multiplicities were
recorded as s (singlet), br s (broad singlet), d (doublet), dd (double
doublet), t (triplet), q (quartet) or m (multiplet). For the equilibria
in the tautomeric compounds to be established, the samples were
dissolved in CDCl3 and the solutions were allowed to stand at
ambient temperature for 24 h before the 1H NMR spectra were run.
(S)-2-Amino-2-phenylethanol 1 and (S)-2-amino-3-phenylpro-
panol 2 were purchased from Aldrich.
Compound
X
r+
A (%)
B (%)
C (%)
Aa (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-NO2
p-CN
p-Br
p-Cl
H
0.79
0.659
0.15
0.114
0
ꢀ0.07
ꢀ0.311
ꢀ0.778
ꢀ1.7
65.3
67.6
79.7
81.1
83.5
85.1
87.6
91.7
97.0
17.8
16.8
11.0
10.5
9.2
8.4
7.2
4.5
1.6
16.9
15.6
9.3
8.4
7.3
6.5
5.2
3.8
1.4
92
—
—
98
99
—
94
95
—
p-F
p-Me
p-OMe
p-NMe2
4.1. Reactions of (S)-2-amino-2-phenylethanol 1 or (S)-2-amino-
3-phenylpropanol 2 with aromatic aldehydes
a
Data from Ref. 20.
Method A: Aminoalcohol 1 or 2 (3 mmol) was dissolved in
MeOH (20 mL) and an appropriate aromatic aldehyde (3 mmol)
was added. After the mixture had stood for 1 h at room tempera-
ture, the solvent was evaporated off and the oily products were
crystallized on treatment with diisopropyl ether or n-hexane.
Yields: 61–99%.
Method B: A mixture of aminoalcohol 1 or 2 (3 mmol), distilled
water (20 mL) and an equivalent amount of aromatic aldehyde
(3 mmol) was stirred vigorously at room temperature for 1 h. The
precipitated crystalline product was filtered off. Yields: 71–99%.
All compounds (3a–3i and 4a–4i) gave satisfactory data on ele-
mental analysis (C, H, N 0.3%).
Table 2
Amounts (%) of tautomeric forms A, B and C in tautomeric equilibria for compounds 4
(CDCl3, 300 K) determined in the present study, and amounts (%) of Schiff base form A
in the tautomeric mixture for compounds 4a, 4d, 4e, 4g, and 4h (CDCl3) reported in a
previous study20
Compound
X
r+
A (%)
B (%)
C (%)
Aa (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
p-NO2
p-CN
p-Br
p-Cl
H
0.79
0.659
0.15
0.114
0
ꢀ0.07
ꢀ0.311
ꢀ0.778
ꢀ1.7
62.8
65.6
79.5
80.0
82.5
84.3
86.8
93.2
97.6
18.8
17.9
11.6
11.3
9.9
9.0
7.9
4.2
1.4
18.4
16.5
8.9
8.7
7.6
6.7
5.3
2.6
1.0
90
—
—
96
98
—
94
87
—
p-F
p-Me
p-OMe
p-NMe2
With regard to the similarities in the 1H and 13C NMR spectro-
scopic data for compounds 3a–3i and compounds 4a–4i, the full
spectra of the major tautomers are described for only two repre-
sentatives 3a and 4a of these sets of compounds. For the other
cases, only the characteristic O–CHAr–N and N@CHAr protons are
listed.
a
Data from Ref. 20.
Compound 3a: Yellow crystals. Yield: 0.66 g (82%, Method A),
0.81 g (99%, Method B), mp 74.5–76.5 °C (iPr2O). Anal. Calcd. for
a
b
log KB
log KC
C
15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.46; H, 5.21;
N, 10.39.
Compound 3aA: 1H NMR: d 8.48 (s, 1H, N@CHAr), 8.28 (d,
0
0
-1
-2
J = 8.7 Hz, 2H, C6H4NO2), 7.98 (d, J = 8.7 Hz, 2H, C6H4NO2), 7.75
(dd, J = 8.9, 2.9 Hz, 2H, C6H5), 7.44 (d, J = 7.5 Hz, 2H, C6H5), 7.39
(d, J = 7.0 Hz, 2H, C6H5), 4.56 (q, J = 4.7 Hz, 1H, NCH,), 4.05–3.90
(m, 2H, OCH2), 1.81 (br s, 1H, OH) ppm. 13C NMR: d 160.8 (C-2),
149.7, 141.9, (C6H4NO2), 129.8 (C6H4NO2), 129.5, 128.6, 128.1
(C6H5), 124.6 (C6H4NO2), 77.2 (C-4), 68.3 (C-5) ppm. Compound
3aB: 1H NMR: d 5.70 (s, 1H, NCHO) ppm. Compound 3aC: 1H
NMR: d 5.83 (s, 1H, NCHO) ppm.
-1
-2
-3
-2
σ+
-3
-2
σ+
-1
0
1
-1
0
1
Figure 3. (a) Plots of log KB (CDCl3, 300 K) for 3B (Ç) and 4B (e) versus Hammett–
Compound 3b: Yellow crystals. Yield: 0.60 g (79%, Method A),
0.61 g (81%, Method B), mp 70–72.5 °C. Anal. Calcd for
Brown parameter
r
+. (b) Plots of logKC (CDCl3, 300 K) for 3C (ꢁ) and 4C (h) versus
Hammett–Brown parameter r+
.
C
16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.40; H, 5.63;
N, 11.23. Compound 3bA: 1H NMR: d 8.43 (s, 1H, N@CHAr). Com-
pound 3bB: 1H NMR: d 5.65 (s, 1H, NCHO) ppm. Compound 3bC:
1H NMR: d 5.78 (s, 1H, NCHO) ppm.
Table 3
Linear regression analysis data on the tautomeric equilibria of compounds 3 and 4
Slopea
(q
)
Intercepta
(logKX=H
Correlation
coefficient
Compound 3c: White crystals. Yield: 0.57 g (63%, Method A),
0.79 g (87%, Method B), mp 71–73 °C (iPr2O). Anal. Calcd for
Equilibrium
No. of points
)
C
15H14BrNO: C, 59.23; H, 4.64; N, 4.60. Found: C, 58.96; H, 4.66;
3A ꢀ 3B
3A ꢀ 3C
4A ꢀ 4B
4A ꢀ 4C
9
9
9
9
0.49 ( 0.01)
0.50 ( 0.02)
0.54 ( 0.01)
0.60 ( 0.02)
ꢀ0.94 ( 0.01)
ꢀ1.02 ( 0.02)
ꢀ0.92 ( 0.01)
ꢀ1.03 ( 0.01)
0.999
0.994
0.999
0.997
N, 4.63.
Compound 3cA: 1H NMR: d 8.35 (s, 1H, N@CHAr). Compound
3cB: 1H NMR: d 5.56 (s, 1H, NCHO) ppm. Compound 3cC: 1H
NMR: d 5.66 (s, 1H, NCHO) ppm.
a
Standard error in parentheses.
Compound 3d: White crystals. Yield: 0.55 g (70%, Method A),
0.55 g (71%, Method B), mp 60–63 °C (iPr2O). Anal. Calcd for
4. Experimental
C15H14ClNO: C, 69.36; H, 5.43; N, 5.39. Found: C, 69.19; H, 5.45;
N, 5.37.
Melting points were recorded on a Kofler hot-plate microscope
apparatus and are uncorrected. Elemental analyses were per-
formed with a Perkin-Elmer 2400 CHNS elemental analyzer. Merck
Compound 3dA: 1H NMR: d 8.36 (s, 1H, N@CHAr). Compound
3dB: 1H NMR: d 5.58 (s, 1H, NCHO) ppm. Compound 3dC: 1H
NMR: d 5.67 (s, 1H, NCHO) ppm.

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M. Juhász et al. / Tetrahedron: Asymmetry 22 (2011) 2012–2017
Compound 3e: White crystals. Yield: 0.56 g (83%, Method A),
C
16H16ClNO: C, 70.20; H, 5.89; N, 5.12. Found: C, 70.35; H, 5.86;
0.67 g (99%, Method B), mp 69–70 °C (lit.25 mp 70–71 °C). Anal.
Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 80.29;
H, 6.68; N, 6.24.
N, 5.10.
Compound 4dA: 1H NMR: d 7.93 (s, 1H, N@CHAr). Compound
4dB: 1H NMR: d 5.42 (s, 1H, NCHO) ppm. Compound 4dC: 1H
NMR: d 5.56 (s, 1H, NCHO) ppm.
Compound 3eA: 1H NMR: d 8.40 (s, 1H, N@CHAr). Compound
3eB: 1H NMR: d 5.61 (s, 1H, NCHO) ppm. Compound 3eC: 1H
NMR: d 5.67 (s, 1H, NCHO) ppm.
Compound 3f: Yellow crystals. Yield: 0.64 g (88%, Method A),
0.61 g (84%, Method B), mp 63–65 °C (n-hexane). Anal. Calcd for
Compound 4e: White crystals. Yield: 0.66 g (91%, Method A),
0.68 g (95%, Method B), mp 78.5–79.5 °C (lit.26 mp 78–80 °C). Anal.
Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 79.92; H,
7.13; N, 5.87.
C
15H14FNO: C, 74.06; H, 5.80; N, 5.76. Found: C, 74.17; H, 5.83;
Compound 4eA: 1H NMR: d 8.02 (s, 1H, N@CHAr). Compound
4eB: 1H NMR: d 5.46 (s, 1H, NCHO) ppm. Compound 4eC: 1H
NMR: d 5.58 (s, 1H, NCHO) ppm.
N, 5.73.
Compound 3fA: 1H NMR: d 8.37 (s, 1H, N@CHAr). Compound
3fB: 1H NMR: d 5.58 (s, 1H, NCHO) ppm. Compound 3fC: 1H
NMR: d 5.66 (s, 1H, NCHO) ppm.
Compound 4f: White crystals. Yield: 0.53 g (61%, Method A),
0.55 g (72%, Method B), mp 81.5–83 °C (iPr2O). Anal. Calcd for
Compound 3g: White crystals. Yield: 0.65 g (90%, Method A),
0.68 g (94%, Method B), mp 75.5–76.5 °C (iPr2O). Anal. Calcd for
C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.20; H, 7.19; N,
5.88.
C
16H16FNO: C, 74.69; H, 6.27; N, 5.44. Found: C, 74.41; H, 6.29;
N, 5.41.
Compound 4fA: 1H NMR: d 7.94 (s, 1H, N@CHAr). Compound
4fB: 1H NMR: d 5.43 (s, 1H, NCHO) ppm. Compound 4fC: 1H
NMR: d 5.56 (s, 1H, NCHO) ppm.
Compound 4g: White crystals. Yield: 0.67 g (88%, Method A),
0.69 g (91%, Method B), mp 88.5–89.5 °C. Anal. Calcd for
Compound 3gA: 1H NMR: d 8.37 (s, 1H, N@CHAr). Compound
3gB: 1H NMR: d 5.57 (s, 1H, NCHO) ppm. Compound 3gC: 1H
NMR: d 5.63 (s, 1H, NCHO) ppm.
Compound 3h: White crystals. Yield: 0.74 g (92%, Method A),
0.75 g (96%, Method B), mp 88.5–89.5 °C. Anal. Calcd for
C
16H16N2O3: C, 80.60; H, 7.56; N, 5.53. Found: C, 80.45; H, 7.53;
N, 5.50.
C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.41; H, 6.69;
Compound 4gA: 1H NMR: d 7.98 (s, 1H, N@CHAr). Compound
N, 5.47.
4gB: 1H NMR: d 5.42 (s, 1H, NCHO) ppm. Compound 4gC: 1H
NMR: d 5.54 (s, 1H, NCHO) ppm.
Compound 3hA: 1H NMR: d 8.34 (s, 1H, N@CHAr). Compound
3hB: 1H NMR: d 5.56 (s, 1H, NCHO) ppm. Compound 3hC: 1H
NMR: d 5.61 (s, 1H, NCHO) ppm.
Compound 4h: White crystals. Yield: 0.53 g (66%, Method A),
0.77 g (95%, Method B), mp 78–79 °C (iPr2O). Anal. Calcd for
Compound 3i: White crystals. Yield: 0.64 g (80%, Method A),
C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.98; H, 7.14;
0.73 g (91%, Method B), mp 65–65.5 °C (iPr2O). Anal. Calcd for
N, 5.22.
C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C, 75.93; H, 7.48;
Compound 4hA: 1H NMR: d 7.93 (s, 1H, N@CHAr). Compound
N, 10.40.
4hB: 1H NMR: d 5.41 (s, 1H, NCHO) ppm. Compound 4hC: 1H
NMR: d 5.52 (s, 1H, NCHO) ppm.
Compound 4i: White crystals. Yield: 0.65 g (77%, Method A),
0.75 g (89%, Method B), mp 119.5–120.5 °C. Anal. Calcd for
Compound 3iA: 1H NMR: d 8.24 (s, 1H, N@CHAr). Compound
3iB: 1H NMR: d 5.53 (s, 1H, NCHO) ppm. Compound 3iC: 1H
NMR: d 5.57 (s, 1H, NCHO) ppm.
Compound 4a: Yellow crystals. Yield: 0.75 g (88%, Method A),
0.78 g (92%, Method B), mp 96–97.5 °C. Anal. Calcd for
C
18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C, 76.80; H, 7.89;
N, 9.88.
C
16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.81; H, 5.64;
N, 9.82.
Compound 4aA: 1H NMR: d 8.25 (d, J = 8.7 Hz, 2H, C6H4NO2),
Compound 4iA: 1H NMR: d 7.87 (s, 1H, N@CHAr). Compound
4iB: 1H NMR: d 5.38 (s, 1H, NCHO) ppm. Compound 4iC: 1H
NMR: d 5.49 (s, 1H, NCHO) ppm.
8.02 (s, 1H, N@CHAr), 7.82 (d, J = 8.8 Hz, 2H, C6H4NO2), 7.67 (dd,
J = 8.8, 1.0 Hz, 1H, CH2C6H5), 7.23 (d, J = 7.7 Hz, 2H, CH2C6H5),
7.12 (d, J = 7.5 Hz, 2H, CH2C6H5), 3.86 (t, J = 3.2 Hz, 2H, OCH2), 3
67–3.52 (m, 1H, NCH), 3.02 (dd, J = 10.0, 5.3 Hz, 1H, CH2C6H5),
2.88 (dd, J = 13.4, 8.5 Hz, 1H, CH2C6H5), 1.78 (br s, 1H, OH) ppm.
13C NMR: d 160.5 (C-2), 149.6, 141.9 (C6H4NO2), 138.8, 130.3
(CH2C6H5), 129.5 (C6H4NO2), 129.1, 127.1, (CH2C6H5), 124.5
(C6H4NO2), 74.9 (C-4), 66.5 (C-5), 39.5 (CH2C6H5) ppm. Compound
4aB: 1H NMR: d 5.55 (s, 1H, NCHO) ppm. Compound 4aC: 1H NMR:
d 5.70 (s, 1H, NCHO) ppm.
Acknowledgements
The authors thank TÁMOP-4.2.1/B-09/1/KONV-2010-0005 and
OTKA K 75433 for the financial support.
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