Ring-chain tautomerism in 2-substituted 1,2,3,4-tetrahydroquinazolines A 1H, 13C and 15N NMR study

Article abstract of DOI:10.1016/S0040-4020(03)00148-0

In this work 32 1,2,3,4-tetrahydroquinazoline derivatives were synthesized by the reaction of 2-aminomethylaniline with aldehydes and ketones and their ring-chain tautomerism studied by ¹H, ¹³C and ¹⁵N NMR spectroscopy. Th

Full text of DOI:10.1016/S0040-4020(03)00148-0

Tetrahedron 59 (2003) 1939–1950
Ring-chain tautomerism in 2-substituted
1
1,2,3,4-tetrahydroquinazolines A H, 13C and 15N NMR study
b
b
b
Jari Sinkkonen,a Kirill N. Zelenin, Abdul-Kadir A. Potapov, Igor V. Lagoda,
,
*
Valeriy V. Alekseyevb and Kalevi Pihlajaa
aStructural Chemistry Group, Department of Chemistry, University of Turku, Vatselankatu 2, FIN-20014 Turku, Finland
bRussian Military Medical Academy, 194044 Saint-Petersburg, Russian Federation
Received 23 September 2002; revised 23 December 2002; accepted 23 January 2003
Abstract—In this work 32 1,2,3,4-tetrahydroquinazoline derivatives were synthesized by the reaction of 2-aminomethylaniline with
1
aldehydes and ketones and their ring-chain tautomerism studied by H, 13C and 15N NMR spectroscopy. The ketone, as well as the alkyl
aldehyde, derivatives were found to favor exclusively ring forms, whereas tautomeric equilibria were observed for aryl aldehyde derivatives.
For para-phenyl substituted compounds, good linear correlations were found between the Hammett–Brown s þ parameter and log K
(K¼[ring]/[chain]) and also between s þ and dNvC (NvC nitrogen chemical shift). An excellent correlation was also found between log K
and dNvC, which shows that the electronic character of the aryl substituent is carried by the conjugation effect to the environment of the
nitrogen atom. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
system as well as on the circumstances during measurement,
i.e. on the solvent and temperature. A good linear corre-
lation has been found also between the NvC nitrogen
chemical shifts and Hammett’s parameters in compounds
having structure X–C6H4–CvN–R17 (Eq. (2)).
The structural properties, especially ring-chain tautomer-
ism, of five- and six-membered 1,3-X,Y-heterocycles (X,
Y¼O, S, NR) have been under active study in recent years.1
Ring-chain tautomerism is known to occur in hetero-
cyclic systems closely related to quinazolines, such as
1,3-imidazolidines2 and piperimidines,3 as well as in their
oxygen-containing analogs, 1,3- and 3,1-benzoxazines,4–9
which have been subjected to numerous studies during last
decades. Tetrahydroquinazolines have been investigated in
several studies,10–14 but only very recently, the ring-chain
tautomerism of 3-substituted tetrahydro-15 and decahydro-
dNvC ¼ asþ þ b
ð2Þ
The chain form, Schiff base, has a structure like that above,
which allows us to expect that the dependence in Eq. (2) is
valid also in this case for tetrahydroquinazolines. Thus, we
should, by combining Eqs. (1) and (2), be able to find a new
linear correlation between log K and the NvC nitrogen
chemical shifts (Eq. (3)).
quinazolines16 has been found by Fu¨lop and co-workers.
¨
The ring-chain tautomeric equilibrium depends greatly
on the substituent at position 2. In 2-aryl substituted
compounds the ring-chain ratio has been found to depend
on the electronic character of the substituent on the aromatic
ring.1,3–8,15,16 In these cases a linear correlation has been
found between the logarithm of equilibrium constant KX
(K¼[ring]/[chain]) and the Hammett-Brown parameter s þ
that describes the electronic character of the substituent X
on the phenyl ring (Eq. (1)).
log KX ¼ AdNvC þ B
ð3Þ
In this case dependence between two real physical quantities
would exist without involving the Hammett’s parameter.
In this work, a set of 2-substituted 1,2,3,4-tetrahydroquinazo-
lines was synthesized from 2-aminomethylaniline and
corresponding carbonyl compounds (Table 1). Structure
determination and the analysis of tautomeric equilibria were
performed by NMR spectroscopy mainly in DMSO-d6. In
addition to 1H and 13C NMR results, 15N spectra were also
measured for selected compounds. The aims of the work
were to determine the structures by NMR, to study the effect
of the substituent(s) at position 2 on the tautomeric
equilibrium and to investigate the suitability of the linear
correlations (Eqs. (1)–(3)) for 2-aryl-substituted
compounds.
log KX ¼ rsþ þ log KH
The value r has been found to be dependent on the ring
ð1Þ
Keywords: 1,2,3,4-tetrahydroquinazolines; ring-chain tautomerism; NMR
spectroscopy; Hammett’s equation.
*
Corresponding author. Tel.: þ358-2-3336830; fax: þ358-2-3336700;
e-mail: jari.sinkkonen@utu.fi
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00148-0

1940
J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
Table 1. Structures of studied compounds with the percentage amounts of
the ring form in DMSO-d6 at 308C
chain ratios. NMR data for all compounds are provided in
Section 4.
In 1,3-unsubstituted tetrahydroquinazolines can occur
chain-ring-chain tautomeric equilibria containing one cyclic
form and two linear forms: aniline (A, Scheme 1) and
benzylamine (B, Scheme 1) type structures. The chain form
is easy to differentiate from the ring form based on the
proton and carbon signals (dH 8.3–8.7 and dC 160–
166 ppm, respectively) of sp2-hybridized CvN carbon
and proton attached to it. In addition, the cyclic form can
be easily identified from magnetically nonequivalent
methylene protons at position 4 (C, Scheme 1). In the
spectra only the aniline type chain form (A) was observed.
It can be identified from the long-range heteronuclear
correlations observed between the methylene carbon/
protons and H–CvN proton/carbon in HMBC spectrum,
which are possible only in the aniline type linear forms. The
preference of chain form (A) is explained by the difference
in chemical nature of N-1 and N-3. N-1, which is directly
attached to phenyl ring, is much more acidic (pKa(aniline)¼
4.6 and pKa(benzylamine)¼9.3) than N-3. Thus its ability to
form stabilizing intramolecular hydrogen bond with NvC
nitrogen in linear form is much stronger than the one of N-3.
Furthermore, the formation of the intramolecular hydrogen
bond is also sterically favored in aniline type chain form. A
similar behavior has been observed also for oxygen analogs.
The 1,3-benzoxazines have been found to favor chain form
more than the 3,1-benzoxazines.7
Compound
R1
R2
Ring (%)
1a
1b
1c
1d
1e
2a
2b
2c
2d
3
4a
4b
4c
4d
4e
4f
H
H
Me
Pr
i-Pr
Me
100
100
100
100
100
100
100
100
100
100
100
96.2
95.2
95.2
85.5
84.0
76.9
55.6
50.0
38.0
100
100
100
98.0
96.2
83.3
75.2
47.6
0
H
Me
–(CH2)5–
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
4-Me-C6H4
4-NO2-C6H4
4-OMe-C6H4
2-Naphthyl
4-NO2-C6H4
4-Cl-C6H4
C6H5
4-F-C6H4
4-OMe-C6H4
4-OEt-C6H4
4-OH-C6H4
4-NMe2-C6H4
4-NEt2-C6H4
2-OH-C6H4
4g
4h
4i
5a
5b
5c
6a
6b
6c
6d
6e
6f
3-NO2-C6H4
3-I-C6H4
2-OMe-5-NO2-C6H3
2,4-Cl2-C6H3
2-Cl-6-NO2-C6H3
3,4-(OMe)2-C6H3
2-OH-3,5-Cl2-C6H2
2-OH-5-OMe-C6H3
2-OH-1-Naphthyl
H
H
H
H
H
H
2.2. Compounds 1–3
7
These compounds include the products of the alkyl
aldehydes and ketones (1) as well as of the aromatic
ketones (2,3). The common factor for these compounds is
that they do not contain observable amounts of forms other
than ring forms. For alkyl substituted compounds 1, the
reason for this is most likely the lack of steric hindrance
around position 2 that makes molecules very stable in cyclic
form. The analogous 1,3-benzoxazines were also found to
exhibit only ring form.4 The aromatic ketone products 2,3,
unlike their aldehyde analogs (vide infra) are also
completely cyclic. Undoubtedly, the methyl substituent is
responsible for this fact. A similar effect has also been
observed in 2-aryl-2-methyl-1,3-oxazolidines.6 The effect
can be explained either by the increase of the ring stability,
or by the growth of n,p-repulsive interactions, which
destabilizes the linear form. Likely, both phenomena are, in
some degree, responsible for the preference of ring form in
acetophenone derivatives. However, the linear forms have
been recently observed in 2-methyl substituted amide
derivatives.18
2. Results and discussion
2.1. NMR analysis and structure determination
The NMR measurements were made mainly in DMSO-d6
and for compounds 4 also in CDCl3. Initially, the proton
spectra were measured as quickly as possible after
dissolving the compound (usually within 15 min). The
spectra were taken again after one day but no change was
found in tautomeric ratios, so the equilibrium is reached
quickly in solution. Chemical shift assignments were based,
in addition to information from normal proton and carbon
measurements, mainly on DEPT 1358, phase-sensitive
DQF-COSY and f1-decoupled CH-shift correlation spectra.
Long-range correlation spectra (long-range DQF-COSY
and HMBC or COLOC) were also measured when more
information was needed for assignments. Nitrogen spectra
1
were measured using H–15N-HMQC and -HMBC exper-
iments. The ring-chain ratios were determined from the
integrals of the 4-CH2 protons (Scheme 1). In some cases
other well-separated peaks were used to calculate the ring-
2.3. Compounds 4–7
These compounds include the aromatic aldehyde products.
Compounds 4 consist of a set of para-substituted,
compounds 5 of ortho- or meta-substituted and compounds
6 of di- or trisubstituted phenyl substituents. Compound 7 is
somewhat different from others being the only naphthyl
derivative. Most of these compounds were found to exhibit
ring-chain tautomeric equilibria between the cyclic and the
aniline type linear forms.
Scheme 1. Ring-chain equilibrium including numbering for compounds
studied. A and B refer to aniline and benzylamine type chain forms,
respectively.

J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
1941
Table 2. Ring proportions (in DMSO-d6 at 308C and CDCl3 at 258C) and 15N shifts (CvN, chain form, in DMSO-d6) for para-substituted 2-phenyl-1,2,3,4-
tetrahydroquinazolines (4) and Hammett–Brown parameters (s þ) for substituents X
Compound
X
s þ
Ring(%) in DMSO-d6
Ring (%) in CDCl3
dNvC (ppm) in DMSO-d6
4a
4b
4c
4d
4e
4f
4g
4h
4i
NO2
Cl
H
0.79
0.11
0
20.07
20.78
20.83
20.92
21.70
22.09
100
96.2
95.2
95.2
85.5
84.0
76.9
55.6
50.0
97.1
94.3
94.3
93.5
86.2
85.5
87.7
69.4
64.5
–
250.5
252.4
254.1
261.1
261.1
264.9
270.5
272.6
F
OMe
OEt
OH
NMe2
NEt2
The relative amount of the linear form in compounds 4 was
found to increase with the Hammett-Brown s þ parameter
of the para-substituent X (Table 2). To investigate the
solvent dependence of the tautomeric equilibria, measure-
ments were also made in CDCl3. The plots based on Eq. (1)
were made in both solvents and good linear correlations
were found (Fig. 1 and Table 3). It can be noted that the
solvent has a clear effect on the slope, however, the effect to
the intercept is rather small. The linear correlation in
DMSO-d6 is steeper than the one in CDCl3. These results
are opposite to those obtained for 2-aryl substituted
1,3-oxazolidines,1,6 in which the slope of the Hammett
plot was observed to be fairly independent of solvent,
especially in the case of DMSO-d6 (0.48) and CDCl3 (0.47).
Furthermore KH was found to be very dependent on solvent,
DMSO-d6 (0.11) and CDCl3 (1.59), i.e. increasing solvent
proton-accepting ability stabilized the open-chain tauto-
mer.1 In the case of our compounds we explained the
preference of the aniline type chain form by intramolecular
hydrogen bonding (see above). Thus, polar DMSO-d6, by
forming intermolecular hydrogen bonds, inhibits the
formation of intramolecular hydrogen bonding and makes
Figure 1. Plots of log K (K¼[ring]/[chain]) in DMSO-d6 (X) and in CDCl3 (W) versus Hammett–Brown parameter s þ
.
Table 3. Linear regression analysis data for compounds 4a–i (see Figs. 1–3 for plots)
Plot
Number of points
Slopea
Intercepta
Correlation coefficient
log KDMSO vs s þ
log KCDCl3 vs s þ
8
9
8
8
0.67 (4)
0.45 (2)
10.1 (7)
0.066 (3)
1.29 (5)
1.18 (2)
253.0 (8)
4.78 (13)
0.989
0.993
0.987
0.996
d
NvC vs s þ
log KDMSO vs dNvC
a
Standard deviations are given in parentheses.

1942
J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
Figure 2. Plot of chemical shift of double-bond nitrogen dNvC in chain form (ppm in DMSO-d6 at 308C) versus Hammett–Brown parameter s þ
.
the linear form less favored than expected based on data for
1,3-oxazolidines, in which the intramolecular hydrogen
bonds does not play an important role in the equilibrium.
hexahydropyrimidines:3 c¼0.932(20.15)¼1.08, where
the 20.15 is the intercept for the 2-aryl-1,3-oxazines.7
Thus the increase in the stability of the ring form is almost
equal when replacing the O by NH, whether there is a
benzene ring condensed to the structure or not. For
3-substituted N,N-analogs it has been observed that the
larger the substituent the less stable is the ring form.15
The differences in stabilities of the closed ring forms can be
discussed based on the value of c, which is the intercept for
the 2-aryl-1,3-O,N-heterocycle subtracted from the one for
the corresponding 2-aryl-1,3-N,N-heterocycle. Thus a
positive c value means a more stable ring form than that
for the oxygen analog. For compounds 4 (in CDCl3),
c¼0.452(20.66)¼1.11, where the 20.66 is the intercept
for the 2-aryl-3,4-dihydro-2H-1,3-benzoxazines.7,15 It is
interesting to calculate the value c also for 2-aryl-
Also 15N NMR spectra (in DMSO-d6) were measured for
compounds 4. For NH-nitrogens no significant difference
was noted depending on the tautomeric ratio. However, a
clear effect was observed on the chemical shifts of NvC-
nitrogen in chain form ranging from 272.6 (NEt2) to
Figure 3. Plot of log K (K¼[ring]/[chain]) versus chemical shift of double-bond nitrogen dNvC in chain form (ppm in DMSO-d6 at 308C).

J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
1943
250.5 ppm (Cl) (Table 2). A linear fit according to Eq. (2)
was made and a fairly good correlation was found (Fig. 2
and Table 3). This correlation can be explained by
the electron-donating/electron-withdrawing character of
the substituent X that affects the charge density of the
conjugated CvN unit.17 Thus, for example, electron-
donating substituent NEt2 increases the charge density on
CvN nitrogen, which also increases the shielding of the
nitrogen causing the upfield chemical shift.
Figure 4. The structures of compounds 8 and 9.
After the correlations above, it was natural to make the
linear fit also between the logarithm of the equilibrium
constant K and 15N chemical shift (Eq. (3). A very good
correlation was found for this fit (Fig. 3 and Table 3). As far
as we know, this is the first time that this correlation has
been found in ring-chain tautomeric systems. It gives a
direct link between the K and dNvC without involving the
Hammett’s constant.
identified as (pseudo)axial and NH-1 and H-4x as (pseudo)
equatorial. The large aryl substituent therefore adopts
equatorial orientation as was expected.
Hydroxynaphthyl derivative 7 was found to be completely
in the chain form. The strong preference of the linear form
can be explained not only by the steric factors but also by
the existence of rapidly exchanging equilibrium of the
enolimine and ketoenamine forms20 that stabilizes the linear
form. The results are in agreement with literature.20–22
It has been found for 1,3-O,N-heterocyclic systems, based
on the theoretical charge calculations, that electron-
donating substituents stabilize the chain tautomer by
increasing its resonance stabilization via polarization of
the CvN unit and by strengthening the intramolecular
hydrogen bond.19 This observation is in harmony with our
results, that provide the experimental proof for these
theoretical conclusions. It is very probable that a correlation
in Eq. (3) would also be found for other, e.g. 1,3-O,N-
heterocyclic ring-chain tautomeric systems.
2.4. Compounds 8–9
This set contains compounds that clearly differ from the
previous ones (Fig. 4). These compounds were obtained
when the non-equimolar solution of the reactants was boiled
for one week (8) or 48 h (9) instead of letting it be at room
temperature (Section 4). Compound 8 was easy to identify
from its NMR data, especially from the C-2 shift
(173.47 ppm). The bilinear compounds 9 were formed
when a 2:1 mole ratio of aldehyde and 2-aminomethylani-
line was used. For the identification of 9a the long-range
HMBC correlations (Fig. 4) proved a useful method.
The meta-substituted compounds 5b,c did not contain
observable amounts of the chain form in DMSO-d6 (Table
1) due to the large values of the Hammett’s constant for
m-NO2 (0.71) and m-I (0.35). Hence they were excluded
from correlation studies, although meta-substituted com-
pounds usually behave similarly to para-substituted ones.
Compound 5a (o-hydroxy-substituted) was found to be
predominantly in the chain form. The 15N shift for CvN
was also measured for this compound (286.2 ppm), but it
did not fit to the straight line in Figure 3. This demonstrates
that Eq. (3) is not valid for ortho-substituted compounds
where steric effects also strongly affect the ring-chain ratio.
In this sense, Eq. (3) does not provide anything new
compared with Hammett’s relations.
3. Conclusion
A set of 2-substituted 1,2,3,4-tetrahydroquinazolines was
prepared from 2-aminomethylaniline and corresponding
aldehyde or ketone and their properties, especially ring-
1
chain tautomerism, were studied by H, 13C and 15N NMR
spectroscopy. All 2-alkyl-substituted (1) as well as all
2,2-disubstituted (2,3) compounds were found to be
completely in the ring form. However, the 2-aryl-substituted
(4–7) compounds displayed ring-chain tautomeric equi-
libria containing one ring and one chain form. The chain
form was concluded to be the aniline type linear form based
on HMBC long-range correlations observed between the
methylene carbon/protons and H–CvN proton/carbon. The
preference for the aniline type linear form can be explained
by the intramolecular hydrogen bonding between the NH2
proton(s) and CvN nitrogen. In some cases (9), the
formation of the bilinear form was also observed when a
2:1 mole ratio between the aldehyde and 2-aminomethyl-
aniline was used.
The ring-chain tautomeric ratios in di- or tri-substituted
compounds 6 depend greatly on the substituents. The
structures containing the electron-withdrawing NO2 group
tend to prefer the ring form in spite of the position of
substitution, whereas the structures containing hydroxyl
group at the ortho position favor chain forms. Compound 6c
provides the chance to discuss the conformations of the
heteroring, since it was the only compound where the NH-3
signal was not broadened and the 1H–1H coupling constants
were extractable from the proton spectrum. This follows
most likely from the oxygen(s) of the o-NO2 substituent that
can form a tight hydrogen bond with NH-3 and prevent
rapid exchange. The following J-values (in Hz) are found
For para-substituted 2-aryl-1,2,3,4-tetrahydroquinazolines
(4) log K and dNvC gave good linear correlations with the
Hammett–Brown parameter s þ that describes the elec-
tronic character of the substituent on the phenyl ring
(Eqs. (1) and (2)). Furthermore, an excellent linear
correlation was found between log K and dNvC. This
(Section 4): JNH-3,H-4x¼3.2, JNH-3,H-4y¼10.2, JNH-3,H-2
¼
11.3 and JNH-1,H-2 small (not resolved). These values are in
agreement with the torsion angles for half-chair structure, in
which atoms 1 and 4 are in plane with condensed benzene
ring. Therefore, protons H-2, NH-3 and H-4y can be

1944
J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
shows that ring-chain equilibrium ratio depends on the
charge density, or nuclear shielding, of the CvN nitrogen
atom. Thus the substituent’s electronic character plays an
essential role at the stability of the linear form affecting
nitrogen’s charge density through the conjugated CvN
double bond.
(10 mL), the mixture was kept for 24 h at room temperature,
concentrated in vacuo, and the residue was recrystallized.
4.2.1. 2-Methyl-1,2,3,4-tetrahydroquinazoline (1a). Yield
79% (yellow crystals); mp 64–668C (pentane); Rf 0.55
(acetonitrile–pyridine, 1:1). dH (DMSO-d6): 1.19 (3H, d,
J¼6.0 Hz, CH3), 3.72 (1H, d, J¼16.5 Hz, H-4x), 3.88 (1H,
d, J¼16.5 Hz, H-4y), 4.08 (1H, q, J¼6.0 Hz, H-2), 5.67
(1H, s, NH-1), 6.44 (1H, d, J¼7.7 Hz, H-8), 6.45 (1H, t,
J¼7.2 Hz, H-6), 6.76 (1H, d, J¼7.2 Hz, H-5), 6.85 (1H, dd,
J¼7.2, 7.7 Hz, H-7), NH-3 proton was not detected. dC
(DMSO-d6): 21.98 (CH3), 45.78 (C-4), 62.12 (C-2), 113.75
(C-8), 115.62 (C-6), 120.47 (C-4a), 125.55 (C-5), 126.38
(C-7), 144.64 (C-8a). Anal calcd for C9H12N2: C, 72.94; H,
8.16; N, 18.90. Found C, 72.92; H, 8.15; N, 18.88%.
4. Experimental
4.1. General
NMR-spectra were acquired using a JEOL JNM-A-500
spectrometer operating at 500.16 MHz for 1H, 125.78 MHz
for 13C and 50.69 MHz for 15N or a JEOL JNM-L-400
spectrometer operating at 399.78 MHz for 1H and
100.54 MHz for 13C. Spectra were recorded at 308C in
DMSO-d6 and at 258C in CDCl3. Proton and carbon spectra
in DMSO-d6 were referenced internally to the solvent
4.2.2. 2-Propyl-1,2,3,4-tetrahydroquinazoline (1b). Yield
36% (yellow crystals); mp 64–668C (pentane); Rf 0.52
(ethyl acetate–benzene, 1:1). dH (DMSO-d6): 0.90 (3H, t,
J¼6.9 Hz, CH3), 1.45 (6H, m, 2CH2), 2.60 (1H, br. s,
NH-3), 3.73 (1H, d, J¼16.6 Hz, H-4x), 3.86 (1H, d, J¼
16.6 Hz, H-4y), 3.94 (1H, q, J¼4.9 Hz, H-2), 5.57 (1H, s,
NH-1), 6.44 (1H, t, J¼7.4 Hz, H-6), 6.47 (1H, d, J¼8.1 Hz,
H-8), 6.75 (1H, d, J¼7.4 Hz, H-5), 6.85 (1H, dd, J¼7.4,
8.1 Hz, H-7). dC (DMSO-d6): 14.05 (CH3), 17.72 (CH2-20),
37.98 (CH2-10), 45.69 (C-4), 65.83 (C-2), 113.90 (C-8),
115.52 (C-6), 120.83 (C-4a), 125.49 (C-5), 126.35 (C-7),
144.63 (C-8a). Anal calcd for C11H16N2: C, 74.96; H, 9.15;
N, 15.89. Found C, 74.85; H, 9.15; N, 15.26%.
1
signals using values 2.49 ppm for H and 39.50 ppm for
13C. Nitrogen spectra were referenced externally to the
standard sample of nitromethane (10% deuterated) using a
value of 0.00 ppm.
1H spectra were acquired with normal single-pulse exci-
tation, 458 flip-angle consisting of 32k data points. 1D
carbon spectra were acquired with normal single-pulse
excitation, broad-band proton decoupling, 458 flip-angle and
with spectral widths of 30 kHz consisting of 65k data points
and with 0.3–0.5 Hz exponential weighting applied prior
to Fourier transformation. DEPT spectra were acquired as
carbon spectra. 2D heteronuclear correlation experiments
were acquired using either carbon detected CH-shift
correlation with partial homonuclear decoupling in the f1
dimension or proton detected HMQC with gradient selec-
tion. Heteronuclear long-range correlation spectra were
made using either carbon detected COLOC or proton
detected HMBC sequence with gradient selection. One-
bond coupling constant was 145 Hz in proton–carbon
correlation spectra and 95 Hz in proton–nitrogen HMQC
spectrum. In 1H–13C and 1H–15N HMBC spectra 8 Hz was
used as a long-range coupling constant nJCH or nJNH (n¼2 or
3) between proton and hetero nuclei. 2D homonuclear
H,H-correlation experiments were acquired using phase-
sensitive double quantum filtered COSY. The spectral
widths of 2D spectra were in proton and carbon measure-
4.2.3. 2-i-Propyl-1,2,3,4-tetrahydroquinazoline (1c).
Yield 36%; yellow oil; Rf 0.44 (ethanol). dH (DMSO-d6):
0
0.94 (3H, d, J¼7.0 Hz, CH3), 0.96 (3H, d, J¼6.8 Hz, CH3 ),
1.73 (1H, m, CH-10), 3.74 (1H, d, J¼16.4 Hz, H-4x), 3.76
(1H, q, J¼5.6 Hz, H-2), 3.85 (1H, d, J¼16.4 Hz, H-4y),
5.49 (1H, s, NH-1), 6.44 (1H, t, J¼7.3 Hz, H-6), 6.53 (1H, d,
J¼7.9 Hz, H-8), 6.75 (1H, d, J¼7.3 Hz, H-5), 6.85 (1H, dd,
J¼7.3, 7.9 Hz, H-7), NH-3 proton was not detected. dC
0
(DMSO-d6): 17.15 (CH3), 18.10 (CH3 ), 32.07 (CH-10),
45.87 (C-4), 70.78 (C-2), 114.04 (C-8), 115.45 (C-6),
120.95 (C-4a), 125.38 (C-5), 126.31 (C-7), 144.91 (C-8a).
Anal calcd for C11H16N2: C, 74.96; H, 9.15; N, 15.89.
Found C, 74.89; H, 9.15; N, 15.18%.
4.2.4. 2,2-Dimethyl-1,2,3,4-tetrahydroquinazoline (1d).
Yield 68%; colorless oil; Rf 0.50 (ethanol). dH (DMSO-d6):
1.33 (6H, s, 2CH3), 3.95 (2H, s, H-4), 6.52 (1H, d, J¼
8.1 Hz, H-8), 6.55 (1H, t, J¼7.4 Hz, H-6), 6.92 (1H, d,
J¼7.4 Hz, H-5), 6.95 (1H, dd, J¼7.4, 8.1 Hz, H-7),
NH-protons were not detected. dC (DMSO-d6): 26.22
(2CH3), 40.44 (C-4), 62.50 (C-2), 114.47 (C-8), 116.05
(C-4a), 116.27 (C-6), 126.20 (C-5), 127.22 (C-7), 142.04
(C-8a). Anal calcd for C10H14N2: C, 74.03; H, 8.70; N,
17.27. Found C, 74.10; H, 8.68; N, 17.28%.
1
ments optimised from 1D spectra. In H–15N HMBC and
1H–15N HMQC spectra, 512 points were used in f1 axis
consisting of 500 ppm frequency range giving 1 ppm
resolution. Thus the deviation in nitrogen shifts is
^0.5 ppm. However, the comparison with the results by
refocused INEPT with 32k data points, showed very good
(^0.1 ppm) correspondence between the 1D and 2D
methods. All spectra were measured using standard pulse
sequences.23
4.2.5. 30,40-Dihydro-10H-spiro[cyclohexane-1,20-quinazo-
line] (1e). Yield 61% (white crystals); mp 63–658C
(hexane–benzene); Rf 0.47 (ethyl acetate). dH (DMSO-
d6): 1.26–1.62 (10H, m, 4H-10, 4H-20, 2H-30), 3.71 (2H, s,
2H-4), 5.60 (1H, s, NH-1), 6.40 (1H, t, J¼7.3 Hz, H-6), 6.47
(1H, d, J¼7.8 Hz, H-8), 6.76 (1H, d, J¼7.3 Hz, H-5), 6.83
(1H, dd, J¼7.3, 7.8 Hz, H-7), NH-3 proton was not detecte0d.
dC (DMSO-d6): 21.47 (C-30), 25.63 (2C-20), 36.37 (2C-1 ),
The purity of the synthesized compounds was checked by
tlc (Silufol UV-254 plates).
4.2. General procedure for synthesis of compounds 1–3
Carbonyl compound (3 mmol) was added to a solution of
2-aminomethylaniline (3 mmol) in water-free benzene

J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
1945
40.94 (C-4), 64.51 (C-2), 113.82 (C-8), 114.84 (C-6),
119.67 (C-4a), 125.34 (C-5), 126.34 (C-7), 143.60 (C-8a).
Anal calcd for C13H18N2: C, 77.18; H, 8.97; N, 13.85.
Found C, 77.15; H, 8.85; N, 13.86%.
119.83 (C-40a), 125.37 (C-5), 126.47 (C-7), 127.64 (2C-20),
139.14 (C-1 ), 143.69 (C-8a), 157.88 (C-40). Anal calcd for
C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found C, 75.46; H,
7.53; N, 11.27%.
4.2.6. 2-Methyl-2-phenyl-1,2,3,4-tetrahydroquinazoline
(2a). Yield 37% (white crystals); mp 95–978C (hexane–
benzene); Rf 0.46 (ethyl acetate–benzene, 1:1). dH (DMSO-
d6): 1.46 (3H, s, CH3), 2.96 (1H, br. s, NH-3), 3.33 (1H, d,
J¼16.8 Hz, H-4x), 3.61 (1H, d, J¼16.8 Hz, H-4y), 6.39
(1H, dd, J¼6.9, 7.3 Hz, H-6), 6.61 (1H, s, NH-1), 6.65 (1H,
d, J¼7.8 Hz, H-8), 6.66 (1H, d, J¼6.9 Hz, H-5), 6.89 (1H,
dd, J¼7.3, 7.8 Hz, H-70), 7.16 (1H, t, J¼7.2 Hz, H-40),0 7.27
(2H, t, J¼7.2 Hz, 2H-3 ), 7.54 (2H, d, J¼7.2 Hz, 2H-2 ). dC
(DMSO-d6): 32.25 (CH3), 42.17 (C-4), 68.64 (C-2), 113.41
(C-8), 115.14 (C-6), 119.75 (C-4a), 125.37 (C-5), 126.38
(C-7), 126.46 (C-20), 126.48 (C-40), 127.95 (C-30), 143.59
(C-8a), 147.33 (C-10). Anal calcd for C15H16N2: C, 80.32;
H, 7.19; N, 12.49. Found C, 80.35; H, 7.22; N, 12.45%.
4.2.10. 2-Methyl-2-naphthalen-2-yl-1,2,3,4-tetrahydro-
quinazoline (3). Yield 39% (yellow crystals); mp 113–
1158C (hexane–benzene); Rf 0.64 (ethyl acetate–benzene,
1:1). dH (DMSO-d6): 1.53 (3H, s, CH3), 2.89 (1H, br. s,
NH-3), 3.32 (1H, d, J¼16.7 Hz, H-4x), 3.64 (1H, d, J¼
16.7 Hz, H-4y), 6.39 (1H, dd, J¼6.8, 7.1 Hz, H-6), 6.64
(1H, d, J¼7.9 Hz, H-8), 6.71 (1H, d, J¼7.1 Hz, H-5), 6.74
(1H, s,0NH-1), 6.92 (1H, dd, J¼6.8, 7.9 H0z, H-7), 7.46 (2H,
m, H-6 and H-70), 7.74–7.76 (2H, m, H-3 and H-80), 7.83–
7.84 (2H, m, H-40 and H-50), 7.94 (1H, s, H-10). dC (DMSO-
d6): 32.02 (CH3), 42.30 (C-4), 68.86 (C-2), 113.49 (C-8),
115.17 (C-6), 119.80 (C-4a), 125.12 (C-10), 125.016 (C-300),
125.39 (C-5), 125.54 (C-600 or C-70), 125.80 (C-6 or C-70),
126.58 (C-7)0, 127.26 (C-5 ), 127.74 (C-80), 127.78 (C-4 ),
132.01 (C-4a ), 132.68 (C-8a0), 143.57 (C-8a) 144.94 (C-5).
Anal calcd for C19H18N2: C, 83.18; H, 6.61; N, 10.21.
Found C, 82.97; H, 6.95; N, 10.27%.
4.2.7. 2-Methyl-2-(4-methylphenyl)-1,2,3,4-tetrahydro-
quinazoline (2b). Yield 43% (white crystals); mp 87–
898C (hexane–benzene); Rf 0.65 (ethyl acetate–benzene,
1:1). dH (DMSO-d6): 1.43 (3H, s, 2-CH3), 2.23 (3H, s,
40-CH3), 2.63 (1H, br. s, NH-3), 3.32 (1H, d, J¼16.6 Hz,
H-4x), 3.58 (1H, d, J¼16.6 Hz, H-4y), 6.38 (1H, dd, J¼6.8,
7.3 Hz, H-6), 6.56 (1H, s, NH-1), 6.63 (1H, d, J¼7.9 Hz,
H-8), 6.64 (1H, d, J¼6.8 Hz, H-5), 6.88 (1H, dd, J¼7.3,
7.9 Hz, H-7), 7.07 (2H, d, J¼7.9 Hz, 2H-30), 7.40 (2H, d,
J¼7.9 Hz, 2H-20). dC (DMSO-d6): 20.45 (40-CH3), 32.24
(2-CH3), 42.12 (C-4), 68.44 (C-2), 113.37 (C-8), 115.05
(C-6), 119.75 (C-4a0), 125.30 (C-5), 126.38 (2C-20), 126.40
(C-7), 128.52 (2C-3 ), 135.30 (C-40), 143.65 (C-8a or C-10),
144.28 (C-8a or C-10). dN (DMSO-d6): 2297.8 (N-1),
2331.7 (N-3). Anal calcd for C16H18N2: C, 80.63; H, 7.61;
N, 11.75. Found C, 80.53; H, 7.66; N, 11.74%.
4.3. General procedure for synthesis of compounds 4–7
Carbonyl compound (3 mmol) was added to a solution of
2-aminomethylaniline (3 mmol) in methanol (10 mL), the
mixture was kept for 24 h at room temperature, concentrated
in vacuo, and the residue was recrystallized.
4.3.1. 2-(4-Nitrophenyl)-1,2,3,4-tetrahydroquinazoline
(4a). Yield 56% (orange crystals); mp 105–1078C (metha-
nol, 100–1028C11); Rf 0.60 (ethyl acetate–benzene, 1:1). dH
(DMSO-d6): 2.99 (1H, br. s, NH-3), 3.61 (1H, d, J¼16.6 Hz,
H-4x), 3.90 (1H, d, J¼16.6 Hz, H-4y), 5.27 (1H, s, H-2),
6.32 (1H, s, NH-1), 6.52 (1H, t, J¼7.3 Hz, H-6), 6.64 (1H, d,
J¼7.9 Hz, H-8), 6.82 (1H, d, J¼7.3 Hz, H-5), 6.94 (1H, dd,
J¼7.3, 7.9 Hz, H-7), 7.76 (2H, d, J¼8.7 Hz, 2H-20), 8.22
(2H, d, J¼8.7 Hz, 2H-30). dC (DMSO-d6): 43.98 (C-4),
66.89 (C-2), 0114.31 (C-8), 116.16 (C-6), 120.78 (C-4a),
123.20 (2C-3 ), 125.69 (C-5), 126.67 (C-7), 128.42 (2C-20),
143.75 (C-8a), 146.86 (C-40), 150.52 (C-10). Anal calcd for
C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found C, 65.58;
H, 5.17; N, 16.53%.
4.2.8. 2-Methyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydro-
quinazoline (2c). Yield 44% (orange crystals); mp 143–
1458C (benzene); Rf 0.52 (ethyl acetate–benzene, 1:1). dH
(DMSO-d6): 1.47 (3H, s, 2-CH3), 2.96 (1H, br. s, NH-3),
3.25 (1H, d, J¼16.7 Hz, H-4x), 3.64 (1H, d, J¼16.7 Hz,
H-4y), 6.41 (1H, dd, J¼6.6, 7.3 Hz, H-6), 6.65 (1H, d,
J¼7.8 Hz, H-8), 6.67 (1H, d, J¼6.6 Hz, H-5), 6.76 (1H, s,
NH-1), 6.90 (1H, dd, J¼7.3, 7.8 Hz, H-7), 7.78 (2H, d, J¼
8.7 Hz, 2H-20), 8.15 (2H, d, J¼8.7 Hz, 2H-30). dC (DMSO-
d6): 31.68 (CH3), 42.06 (C-4), 68.79 (C-2), 113.57 (C-8),
115.58 (C-6), 119.54 (C-4a0), 123.34 (2C-30), 125.49 (C-5),
126.66 (C-7), 128.00 (2C-2 ), 142.98 (C-8a), 146.39 (C-40),
155.66 (C-10). Anal calcd for C15H15N3O2: C, 66.90; H,
5.61; N, 15.60. Found C, 66.94; H, 5.66; N, 15.57%.
4.3.2. 2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinazoline
(4b). Yield 70% (white crystals); mp 88–908C (hexane–
benzene); Rf 0.64 (ethyl acetate–benzene, 1:1). dH (DMSO-
d6, ring): 2.84 (1H, br. s, NH-3), 3.66 (1H, d, J¼16.3 Hz,
H-4x), 3.92 (1H, d, J¼16.3 Hz, H-4y), 5.11 (1H, s, H-2),
6.15 (1H, s, NH-1), 6.51 (1H, t, J¼7.3 Hz, H-6), 6.60 (1H, d,
J¼7.9 Hz, H-8), 6.81 (1H, d, J¼7.3 Hz, H-5), 6.91 (1H, dd,
J¼7.3, 7.9 Hz, H-7), 70.41 (2H, d, J¼8.6 Hz, 2H-30), 7.51
(2H, d, J¼8.6 Hz, 2H-2 ). dC (DMSO-d6, ring): 44.52 (C-4),
67.18 (C-2), 114.20 (C-8), 115.97 (C-6), 120.69 (C-4a),
125.61 (C-5), 126.53 (C-7), 127.94 (2C-30), 128.92 (2C-20),
131.95 (C-40), 141.83 (C-10), 144.18 (C-8a). dN (DMSO-d6,
ring): 2302.8 (N-1), 2339.2 (N-3). dH (DMSO-d6, chain):
4.64 (2H, s, H-4), 5.03 (2H, s, NH2-1), 6.53 (1H, dd, J¼6.5,
7.5 Hz, H-6), 6.68 (1H, d, J¼7.9 Hz, H-8), 6.98 (1H, dd,
J¼6.5, 7.9 Hz, H-7), 7.01 (1H, d, J¼7.5 Hz, H-5), 7.51 (2H,
d, J¼8.5 Hz, H-30), 7.78 (2H, d, J¼8.5 Hz, H-20), 8.45 (1H,
s, H-2). dC (DMSO-d6, chain): 61.17 (C-4), 114.80 (C-8),
4.2.9. 2-(4-Methoxyphenyl)-2-methyl-1,2,3,4-tetrahydro-
quinazoline (2d). Yield 61% (yellow crystals); mp 86–
888C (hexane–benzene); Rf 0.54 (ethyl acetate–benzene,
1:1). dH (DMSO-d6): 1.44 (3H, s, 2-CH3), 3.33 (1H, d, J¼
16.7 Hz, H-4x), 3.59 (1H, d, J¼16.7 Hz, H-4y), 3.69 (3H, s,
40-OCH3), 6.39 (1H, t, J¼7.2 Hz, H-6), 6.55 (1H, s, NH-1),
6.64 (1H, m, H-5 or H-8), 6.65 (1H, m, H-5 or H-8), 6.82
(2H, d, J¼8.8 Hz, 2H-30), 6.89 (1H, t, J¼7.5 Hz, H-7), 7.43
(2H, d, J¼8.8 Hz, 2H-20), NH-3 proton was not detected. dC
(DMSO-d6): 32.34 (2-CH3), 42.15 (C-4), 54.88 (40-OCH3),
68.31 (C-2), 113.33 (2C-30), 113.44 (C-8), 115.12 (C-6),

1946
J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
116.15 (C-6)0, 122.84 (C-4a), 127.67 (C-70), 128.67 (C-5),
128.72 (2C-3 ), 129.50 (2C-20), 134.84 (C-4 ), 135.24 (C-10),
146.34 (C-8a), 160.11 (C-2). dN (DMSO-d6, chain): 250.5
(N-3), N-1 was not detected. Anal calcd for C14H13ClN2: C,
68.71; H, 5.35; N, 11.45. Found C, 68.89; H, 5.47; N,
11.27%.
1:1). dH (DMSO-d6, ring): 3.70 (1H, d, J¼16.4 Hz, H-4x),
3.74 (3H, s, OCH3), 3.95 (1H, d, J¼16.4 Hz, H-4y), 5.04
(1H, s, H-2), 6.02 (1H, s, NH-1), 6.49 (1H, t, J¼7.3 Hz,
H-6), 6.58 (1H, d, J¼7.9 Hz, H-8), 6.80 (1H, d, J¼7.3 Hz,
H-5), 6.90 (1H, dd, J¼7.3, 7.9 Hz, H-7), 60.91 (2H, d, J¼
8.4 Hz, 2H-30), 7.41 (2H, d, J¼8.4 Hz, 2H-2 ), NH-3 proton
was not detected. dC (DMSO-d6, ring): 45.08 (C-4), 55.03
(OCH3), 67.68 (C-2), 113.35 (2C-30), 114.14 (C-8), 115.79
(C-6), 120.63 (C-4a), 125.57 (C-5), 126.44 (C-7), 128.08
(2C-20), 134.88 (C-10), 144.60 (C-8a), 158.70 (C-40). dN
(DMSO-d6, ring): 2301.9 (N-1), 2337.3 (N-3).dH (DMSO-
d6, chain): 3.79 (3H, s, OCH3), 4.59 (2H, s, H-4), 5.04 (2H,
s, NH2-1), 6.53 (1H, t, J¼7.5 Hz, H-6), 6.67 (1H, d, J¼
7.7 Hz, H-8), 6.97 (1H, n.r., H-7), 6.99 (2H, n.r., H-30), 7.00
(1H, n.r., H-5), 7.70 (2H, d, J¼8.5 Hz, H-20), 8.36 (1H, s,
H-2). dC (DMSO-d6, chain): 55.23 (OCH3), 61.34 (C-4),
114.02 (2C-30), 114.74 (C-8), 116.12 (C-06), 123.38 (C-4a),
127.54 (C-7), 128.56 (C-5), 128.87 (C-1 ), 129.47 (2C-20),
146.36 (C-8a), 160.50 (C-2), 161.22 (C-40). dN (DMSO-d6,
chain): 261.1 (N-3), N-1 was not detected. Anal calcd for
C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found C, 75.02; H,
6.78; N, 11.68%.
4.3.3. 2-Phenyl-1,2,3,4,-tetrahydroquinazoline (4c). Yield
61% (white crystals); mp 102–1058C (methanol, 102–
1038C10); Rf 0.52 (ethyl acetate–benzene, 1:1). dH (DMSO-
d6, ring): 2.70 (1H, br. s, NH-3), 3.71 (1H, d, J¼16.5 Hz,
H-4x), 3.96 (1H, d, J¼16.5 Hz, H-4y), 5.10 (1H, s, H-2),
6.10 (1H, s, NH-1), 6.50 (1H, dd, J¼6.6, 7.2 Hz, H-6), 6.60
(1H, d, J¼8.0 Hz, H-8), 6.81 (1H, d, J¼7.2 Hz, H-5), 6.91
(1H, dd, J¼6.6, 8.0 Hz, H-7), 7.30 (H, t, J¼7.1 Hz, H-40),
7.36 (2H, t, J¼7.1 Hz, 2H-30), 7.50 (2H, d, J¼7.1 Hz,
2H-20). dC (DMSO-d6, ring): 44.96 (C-4), 68.08 (C-2),
114.17 (C-8), 115.84 (C-60), 120.68 (C-4a), 125.60 (C-5),
126.48 (C-7), 126.98 (2C-2 ), 127.47 (C-400), 128.00 (2C-30),
142.76 (C-8a or C-10), 144.52 (C-8a or C-1 ). dN (DMSO-d6,
ring): 2302.3 (N-1), 2337.5 (N-3). dH (DMSO-d6, chain):
4.65 (2H, s, H-4), 5.05 (2H, s, NH2-1), 6.54 (1H, dd, J¼6.4,
7.5 Hz, H-6), 6.69 (1H, d, J¼7.9 Hz, H-8), 6.98 (1H, t,
J¼6.4,07.9 Hz, H-7), 7.02 (1H, d, J¼7.5 Hz, H-5), 7.46 (3H,
m, H-3 and H-40), 7.77 (2H, d, J¼7.3 Hz, H-20), 8.46 (1H, s,
H-2). dC (DMSO-d6, chain): 61.28 (C-4), 114.78 (C-8),
116.15 (C-6), 123.06 (C-4a), 127.63 (C-7)0, 127.86 (2C-200),
128.62 (2C-30), 128.64 (C-5), 130.65 (C-4 ), 136.02 (C-1 ),
146.37 (C-8a), 161.28 (C-2). dN (DMSO-d6, chain): 2322.1
(N-1), 252.4 (N-3). Anal calcd for C14H14N2: C, 79.97; H,
6.71; N, 13.32. Found C, 79.71; H, 6.76; N, 13.52%.
4.3.6. 2-(4-Ethoxyphenyl)-1,2,3,4-tetrahydroquinazoline
(4f). Yield 42% (white crystals); mp 96–988C (methanol);
Rf 0.44 (ethyl acetate–benzene, 1:1). dH (DMSO-d6, ring):
1.31 (3H, t, J¼7.0 Hz, CH3), 2.62 (1H, br. s, NH-3), 3.69
(1H, d, J¼16.4 Hz, H-4x), 3.94 (1H, d, J¼16.4 Hz, H-4y),
4.01 (2H, q, J¼7.0 Hz, OCH2), 5.03 (1H, s, H-2), 6.01 (1H,
s, NH-1), 6.48 (1H, t, J¼7.3 Hz, H-6), 6.57 (1H, d, J¼
7.9 Hz, H0-8), 6.80 (1H, d, J¼7.3 Hz, H-5), 6.89 (3H, m, H-7
and 2H-3 ), 7.38 (2H, d, J¼8.8 Hz, 2H-20). dC (DMSO-d6,
ring): 14.61 (CH3), 45.07 (C-4), 62.92 (OCH2), 67.67 (C-2),
113.85 (2C-30), 114.11 (C-8), 115.76 (C-60), 120.62 (C-4a),
125.56 (C-5), 126.42 (C-7), 128.06 (2C-2 ), 134.76 (C-10),
144.61 (C-8a), 157.93 (C-40). dN (DMSO-d6, ring): 2301.8
(N-1), 2337.5 (N-3).dH (DMSO-d6, chain): 1.33 (3H, t, J¼
6.8 Hz, CH3), 4.06 (2H, q, J¼6.8 Hz, OCH2), 4.58 (2H, s,
H-4), 5.03 (2H, s, NH2-1), 6.52 (1H, t, J¼7.3 Hz, H-6), 6.66
(1H, d, J¼7.9 Hz, H-8), 6.96 (1H, n.r., H-7), 6.97 (2H, n.r.,
H-30), 6.99 (1H, n.r., H-5), 7.68 (2H, d, J¼8.7 Hz, H-20),
8.35 (1H, s, H-2). dC (DMSO-d6, chain): 14.50 (CH3), 61.28
(C-4), 63.19 (OCH2), 114.43 (2C-30), 114.73 (C-8), 116.10
(C-6), 123.39 (C-4a),0 127.52 (C-7), 128.53 (C-5), 128.71
(C-10), 129.46 (2C-2 ), 146.35 (C-8a), 160.50 (C-2 and
C-40). dN (DMSO-d6, chain): 2322.1 (N-1), 261.1 (N-3).
Anal calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01.
Found C, 75.50; H, 7.13; N, 11.08%.
4.3.4. 2-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinazoline
(4d). Yield 47% (white crystals); mp 95–978C (hexane–
benzene); Rf 0.62 (ethyl acetate–benzene, 1:1). dH (DMSO-
d6, ring): 2.75 (1H, br. s, NH-3), 3.69 (1H, d, J¼16.4 Hz,
H-4x), 3.95 (1H, d, J¼16.4 Hz, H-4y), 5.11 (1H, s, H-2),
6.12 (1H, s, NH-1), 6.52 (1H, t, J¼7.3 Hz, H-6), 6.61 (1H, d,
J¼8.1 Hz, H-8), 6.82 (1H, d, J¼7.3 Hz, H-5), 6.92 (1H, dd,
J¼7.3, 8.1 Hz, H-7), 7.17 (2H, t, J¼8.8 Hz (JH and JF),
2H-30), 7.54 (2H, dd, J¼5.6 (JF), 8.8 (JH) Hz, 2H-20). dC
(DMSO-d6, ring): 44.81 (C-4), 67.37 (C-2), 114.23 (C-8),
114.67 (2C-30, JF¼21.5 Hz), 115.98 (C-6), 120.70 (C-4a),
125.63 (C-5), 126.52 (C-7), 128.98 (2C-20, JF¼8.3 Hz),
139.04 (C-10, JF¼2.8 Hz), 144.37 (C-8a), 161.58 (C-40,
JF¼242.8 Hz). dN (DMSO-d6, ring): 2302.8 (N-1), 2337.5
(N-3). dH (DMSO-d6, chain): 4.64 (2H, s, H-4), 5.05 (2H, s,
NH2-1), 6.54 (1H, t, J¼7.3 Hz, H-6), 6.70 (1H, d, J¼7.9 Hz,
H-8), 6.99 (1H, dd, J¼7.3, 7.9 Hz, H-7), 7.02 (1H, d,
J¼7.3 Hz, H-5), 7.27 (2H, t, J¼8.8 Hz (JH and JF), H-30),
7.83 (2H, dd, J¼5.8 (JF), 8.8 (JH) Hz, H-20), 8.45 (1H, s,
H-2). dC (DMSO-d6, chain): 61.19 (C-4), 114.82 (C-8),
115.63 (2C-30, JF¼21.5 Hz), 116.18 (C-6), 123.03 (C-4a),
127.66 (C-7), 128.65 (C-5), 130.08 (2C-20, JF¼8.7 Hz),
132.66 (C-10, JF¼2.8 Hz), 146.36 (C-8a), 160.00 (C-2)
163.54 (C-40, JF¼248.3 Hz). dN (DMSO-d6, chain): 254.2
(N-3), N-1 was not detected. Anal calcd for C14H13FN2: C,
73.66; H, 5.74; N, 12.27. Found C, 73.62; H, 5.46; N,
11.99%.
4.3.7. 4-(1,2,3,4-Tetrahydroquinazoline-2-yl)phenol (4g).
Yield 71% (white crystals); mp 173–1758C (methanol); Rf
0.45 (ethyl acetate). dH (DMSO-d6, ring): 2.51 (1H, br. s,
NH-3), 3.71 (1H, d, J¼16.2 Hz, H-4x), 3.95 (1H, d, J¼
16.2 Hz, H-4y), 4.98 (1H, s, H-2), 5.95 (1H, s, NH-1), 6.48
(1H, t, J¼7.4 Hz, H-6), 6.57 (1H, d, J¼8.1 Hz, H-8), 6.74
(2H, d, J¼8.6 Hz, 2H-30), 6.80 (1H, d, J¼7.4 Hz, H-5), 6.89
(2H, dd, J¼7.4, 8.1 Hz, H-7), 7.28 (2H, d, J¼8.6 Hz, 2H-20),
9.38 (1H, br. s, OH). dC (DMSO-d6, ring): 45.29 (C-4),
67.94 (C-2), 114.13 (C-8), 114.71 (2C-30), 115.76 (C-6),
120.61 (C-40a), 125.59 (C-5), 126.44 (C-7), 128.04 (2C-20),
133.16 (C-1 ), 144.73 (C-8a), 156.82 (C-40). dN (DMSO-d6,
ring): 2300.9 (N-1), 2336.5 (N-3).dH (DMSO-d6, chain):
4.57 (2H, s, H-4), 5.03 (2H, s, NH2-1), 6.52 (1H, t,
4.3.5. 2-(4-Methoxyphenyl)-1,2,3,4,-tetrahydroquinazo-
line (4e). Yield 58% (white crystals); mp 105–1078C
(hexane, 108–1098C;10 Rf 0.56 (ethyl acetate–benzene,

J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
1947
J¼7.5 Hz, H-6), 6.66 (1H, d, J¼7.9 Hz, H-8), 6.82 (2H, d,
J¼8.5 Hz, H-30), 6.97 (1H, dd, J¼7.5, 7.9 Hz, H-7), 6.99
(1H, d, J¼7.5 Hz, H-5), 7.59 (2H, d, J¼8.5 Hz, H-20), 8.30
(1H, s, H-2), 9.38 (1H, br. s, OH). dC (DMSO-d6, chain):
61.35 (C-4), 114.75 (C-8), 0115.44 (2C-30), 116.15 (C-6),
123.57 (C-4a0), 127.37 (C-1 ), 127.53 (C-70), 128.56 (C-5),
129.64 (2C-2 ), 146.36 (C-8a), 159.87 (C-4 ), 160.67 (C-2).
dN (DMSO-d6, chain): 2322.1 (N-1), 264.9 (N-3). Anal
calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found C,
74.21; H, 6.24; N, 12.28%.
(DMSO-d6, chain): 272.6 (N-3), 2307.6 (N(Et)2), N-1 was
not detected. Anal calcd for C18H23N3: C, 76.83; H, 8.24; N,
14.93. Found C, 76.88; H, 8.24; N, 14.95%.
4.3.10. 2-(1,2,3,4-Tetrahydroquinazoline-2-yl)phenol
(5a). Yield 70% (yellow crystals); mp 102–1038C (hexane–
benzene, 109–1118C11); Rf 0.69 (ethyl acetate–benzene,
1:1). dH (DMSO-d6, ring): 3.65 (1H, d, J¼16.3 Hz, H-4x),
3.90 (1H, d, J¼16.3 Hz, H-4y), 5.35 (1H, d, J¼2.1 Hz,
H-2), 6.33 (1H, br. d, J¼2.1 Hz, NH-1), 6.51 (1H, t, J¼
7.5 Hz, H-6), 6.67 (1H, d, J¼7.9 Hz, H-8), 6.76 (1H, t,
J¼7.5 Hz, H-50), 6.77 (1H, d, J¼7.7 Hz, H-30), 6.80 (1H, d,
J¼7.5 Hz, H-5), 6.94 (1H,0 dd, J¼7.5, 7.9 Hz, H-7), 7.12
(1H, dd, J¼7.5, 7.7 Hz, H-4 ), 7.27 (1H, d, J¼7.5 Hz, H-60),
13.5 (1H, br.s, OH), NH-3 was not detected. dC (DMSO-d6,
ring): 42.84 (C-4), 64.24 (C-2), 114.33 (C-8), 115.66 (C-30),
116.13 (C-6), 118.45 (C-60), 119.35 (C-4a), 125.90 (C-5),
126.29 (C-10), 126.80 (C-7), 127.87 (C-60), 128.69 (C-40),
143.26 (C-8a), 156.15 (C-20). dN (DMSO-d6, ring): 2308.7
(N-1), 2343.3 (N-3). dH (DMSO-d6, chain): 4.67 (2H, s,
H-4), 5.05 (2H, s, NH2-1), 6.54 (1H, t, J¼7.3 Hz, H-6), 6.69
(1H, d, J¼7.7 Hz, H-8), 6.87 (1H, d, J¼7.5 Hz, H-30), 6.88
(1H, t, J¼7.5 Hz, H-50), 7.00 (1H, dd, J¼7.3, 7.7 Hz, H-7),
7.01 (1H, d, J¼7.3 Hz, H-5), 7.31 (1H, t, J¼7.5 Hz, H-40),
7.42 (1H, d, J¼7.5 Hz, H-60), 8.64 (1H, s, H-2), 13.5 (1H,
br.s, OH). dC (DMSO-d6, chain): 58.36 (C-4), 114.86 (C-8),
116.13 (C-6), 116.45 (C-30), 118.39 (C-50), 118.71 (C-100),
121.40 (C-40a), 128.07 (C-7), 128.89 (C-5), 131.54 (C-6 ),
132.21 (C-4 ), 146.25 (C-8a), 160.63 (C-20), 165.75 (C-2).
dN (DMSO-d6, chain): 2321.8 (N-1), 286.2 (N-3). Anal
calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found C,
74.28; H, 6.25; N, 12.40%.
4.3.8. N-(2-Aminobenzyl)-N-{(1E)-[4-(dimethylamino)-
phenyl]methylene}amine (4h). Yield 61% (yellow crys-
tals); mp 96–988C (hexane–benzene, 97–998C11); Rf 0.35
(ethyl acetate–benzene, 1:1). dH (DMSO-d6, ring): 2.87
(6H, s, 2CH3), 3.72 (1H, d, J¼16.2 Hz, H-4x), 3.95 (1H, d,
J¼16.2 Hz, H-4y), 4.98 (1H, s, H-2), 5.92 (1H, s, NH-1),
6.48 (1H, dd, J¼6.9, 7.3 Hz, H-6), 6.57 (1H, d, J¼7.7 Hz,
H-8), 6.70 (2H, d, J¼8.8 Hz, 2H-30), 6.79 (1H, d, J¼6.9 Hz,
H-5), 6.88 (1H, dd, J¼7.3, 7.7 Hz, H-7), 7.29 (2H, d, J¼
8.8 Hz, 2H-20), NH-3 proton was not detected. dC (DMSO-
d6, ring): 40.23 (2CH3), 45.30 (C-4), 67.93 (C-2), 111.98
(2C-30), 114.06 (C-8), 115.62 (C-6), 120.59 (C-4a), 125.53
(C-5), 126.37 (C-7), 127.50 (2C-20), 130.46 (C-10), 144.77
(C-8a), 150.07 (C-40). dN (DMSO-d6, ring): 2300.8 (N-1),
other nitrogens were not detected. dH (DMSO-d6, chain):
2.95 (6H, s, 2CH3), 4.55 (2H, s, H-4), 5.04 (2H, s, NH2-1),
6.52 (1H, t, J¼7.5 Hz, H-6), 6.66 (1H, d, J¼7.7 Hz, H-8),
6.72 (2H, d, J¼8.7 Hz, H-30), 6.96 (1H, dd, J¼7.5, 7.7 Hz,
H-7), 6.99 (1H, d, J¼7.5 Hz, H-5), 7.56 (2H, d, J¼8.7 Hz,
H-20), 8.25 (1H, s, H-2). dC (DMSO-d6, chain): 39.69
(2CH3), 61.50 (C-4), 111.43 (2C-30), 114.68 (C-8), 116.07
(C-6), 123.85 (C-4a or C-10), 123.87 (C-4a or C-10), 127.41
(C-7), 128.46 (C-5), 129.16 (2C-20), 146.37 (C-8a), 151.83
(C-40), 160.78 (C-2). dN (DMSO-d6, chain): 270.5 (N-3),
other nitrogens were not detected. Anal calcd for C16H19N3:
C, 75.85; H, 7.56; N, 16.59. Found C, 75.87; H, 7.58; N,
16.59%.
4.3.11. 2-(3-Nitrophenyl)-1,2,3,4-tetrahydroquinazoline
(5b). Yield 90% (orange crystals); mp 89–918C (methanol,
91–938C11); Rf 0.64 (ethyl acetate–benzene, 1:1). dH
(DMSO-d6): 3.02 (1H, br. s, NH-3), 3.63 (1H, d, J¼
16.4 Hz, H-4x), 3.92 (1H, d, J¼16.4 Hz, H-4y), 5.27 (1H, d,
J¼1.6 Hz, H-2), 6.34 (1H, d, J¼1.6 Hz, NH-1), 6.53 (1H, t,
J¼7.4 Hz, H-6), 6.64 (1H, d, J¼7.9 Hz, H-8), 6.82 (1H, d,
J¼7.4 Hz, H-5), 6.940 (1H, dd, J¼7.4, 7.9 Hz, H-7), 7.66
(1H, t, J¼7.9 Hz, H-50), 7.96 (1H, d, J¼7.9 Hz, H-60), 8.16
(1H, d, J¼7.9 Hz, H-4 ), 8.36 (1H, s, H-20). dC (DMSO-d6):
44.13 (C-4), 66.75 (C-2),0 114.36 (C-8)0, 116.23 (C-6),
120.82 (C-4a), 121.83 (C-2 ), 122.42 (C-4 ), 125.70 (C-5),
126.69 (C-7), 129.62 (C-50), 134.05 (C-60), 143.83 (C-8a),
145.35 (C-10), 147.73 (C-30). Anal calcd for C14H13N3O2: C,
65.87; H, 5.13; N, 16.46. Found C, 65.87; H, 5.74; N,
16.36%.
4.3.9. N-(2-Aminobenzyl)-N-{(1E)-[4-(diethylamino)phe-
nyl]methylene}amine (4i). Yield 57% (brown crystals); mp
122–1248C (methanol); Rf 0.66 (ethyl acetate–benzene,
1:1). dH (DMSO-d6, ring): 1.07 (6H, t, J¼7.0 Hz, 2CH3),
3.31 (4H, q, J¼7.0 Hz, 2CH2), 3.72 (1H, d, J¼16.2 Hz, H-
4x), 3.95 (1H, d, J¼16.2 Hz, H-4y), 4.95 (1H, s, H-2), 5.90
(1H, s, NH-1), 6.47 (1H, t, J¼7.3 Hz, H-6)0, 6.56 (1H, d,
J¼7.8 Hz, H-8), 6.63 (2H, d, J¼8.8 Hz, 2H-3 ), 6.80 (1H, d,
J¼7.3 Hz, H-5), 6.88 (1H, dd, J¼7.3, 7.7 Hz, H-7), 7.25
(2H, d, J¼8.8 Hz, 2H-20), NH-3 proton was not detected. dC
(DMSO-d6, ring): 12.34 (2CH3), 43.66 (2CH2), 45.45 (C-4),
68.06 (C-2), 111.14 (2C-30), 114.03 (C-8), 115.58 (C-6),
120.53 (C-40a), 125.53 (C-5), 126.35 (C-7), 127.79 (2C-20),
129.22 (C-1 ), 144.84 (C-8a), 146.93 (C-40). dN (DMSO-d6,
ring): 2300.4 (N-1), 2336.5 (N-3), 2298.9 (N(Et)2). dH
(DMSO-d6, chain): 1.09 (6H, t, J¼7.1 Hz, 2CH3), 3.35 (4H,
q, J¼7.1 Hz, 2CH2), 4.54 (2H, s, H-4), 5.04 (2H, s, NH2-1),
6.52 (1H, t, J¼7.2 Hz, H-6), 6.66 (3H, m, H-8 and 2H-30),
6.96 (1H, dd, J¼7.2, 7.6 Hz, H-7), 6.99 (1H, d, J¼7.2 Hz,
H-5), 7.53 (2H, d, J¼9.0 Hz, H-20), 8.22 (1H, s, H-2). dC
(DMSO-d6, chain): 12.34 (2CH3), 43.66 (2CH2), 61.51
(C-4), 110.75 (2C-30), 114.66 (C-8), 116.05 (C-6), 123.02
(C-10)0, 123.38 (C-4a), 127.36 (C-7), 128.38 (C-5), 129.49
(2C-2 ), 146.36 (C-8a), 149.15 (C-40), 160.72 (C-2). dN
4.3.12. 2-(3-Iodophenyl)-1,2,3,4-tetrahydroquinazoline
(5c). Yield 64% (white crystals); mp 79–818C (hexane–
benzene); Rf 0.65 (ethyl acetate–benzene, 1:1). dH (DMSO-
d6): 2.82 (1H, br. s, NH-3), 3.64 (1H, d, J¼16.0 Hz, H-4x),
3.91 (1H, d, J¼16.5 Hz, H-4y), 5.07 (1H, s, H-2), 6.17 (1H,
s, NH-1), 6.50 (1H, dd, J¼7.0, 7.5 Hz, H-6), 6.58 (1H, d,
J¼8.1 Hz, H-8), 6.80 (1H, d, J¼7.0 Hz, H-5), 6.91 (1H, dd,
J¼7.5, 8.1 Hz, H-7), 7.16 (1H, t, J¼7.9 Hz, H-50), 7.50 (1H,
d, J¼7.9 Hz, H-60), 7.65 (1H, d, J¼7.9 Hz, H-40), 7.86 (1H,
s, H-20). dC (DMSO-d6): 44.58 (C-4), 67.11 (C-2), 94.46
(C-30), 114.18 (C-8), 115.98 (C-6), 120.67 (C-4a), 125.61
(C-5), 126.54 (C-7), 126.60 (C-60), 130.27 (C-50),0 135.66
(C-20), 136.12 (C-40), 144.14 (C-8a), 145.46 (C-1 ). Anal

1948
J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
calcd. for C14H13IN2: C, 50.02; H, 3.90; N, 8.33. Found C,
50.22; H, 3.97; N, 8.39%.
J¼7.9 Hz, H-30), 7.88 (1H, d, J¼7.9 Hz, H-50). dC (DMSO-
d6, chain): 61.47 (C-4), 114.91 (C-8), 116.32 (C-6), 121.83
(C-4a), 122.89 (C-50), 127.66 (C-10), 127.86 (C-7), 128.66
(C-5), 131.71 (C-40), 133.60 (C-30), 134.13 (C-20), 146.27
(C-8a), 149.61 (C-60), 155.54 (C-2). Anal calcd for
C14H12ClN3O2: C, 58.04; H, 4.17; N, 14.50. Found C,
58.02; H, 4.17; N, 14.55%.
4.3.13. 2-(2-Methoxy-5-nitrophenyl)-1,2,3,4-tetrahydro-
quinazoline (6a). Yield 91% (orange crystals); mp 93–
958C (methanol); Rf 0.57 (ethyl acetate–benzene, 1:1).dH
(DMSO-d6): 2.96 (1H, br. s, NH-3), 3.72 (1H, d, J¼16.4 Hz,
H-4x), 3.95 (1H, d, J¼16.4 Hz, H-4y), 3.96 (3H, s, OCH3),
5.42 (1H, br. s, H-2), 5.98 (1H, br. s, NH-1), 6.54 (1H, t,
J¼7.3 Hz, H-6), 6.59 (1H, d, J¼7.7 Hz, H-8), 6.85 (1H, d,
J¼7.3 Hz, H-5), 6.930 (1H, dd, J¼7.3, 7.7 Hz, H-7), 7.25
(1H, d, J¼9.0 Hz, H-3 ), 8.204 (1H, dd, J¼2.8, 9.0 Hz, H-40),
8.35 (1H, d, J¼2.8 Hz, H-6 ). dC (DMSO-d6): 45.13 (C-4),
56.53 (OCH3), 62.03 (C-2), 111.53 (C-30), 114.27 (C-8),
116.24 (C-6), 120.72 (C-4a), 123.25 (C-60), 125.15 (C-400),
125.73 (C-5), 126.61 (C-7), 131.56 (C-10), 140.47 (C-5 ),
144.52 (C-8a), 161.81 (C-20). Anal calcd for C15H15N3O3:
C, 63.15; H, 5.30; N, 14.73. Found C, 63.36; H, 5.12; N,
14.53%.
4.3.16. 2-(3,4-Dimethoxyphenyl)-1,2,3,4-tetrahydro-
quinazoline (6d). Yield 91% (white crystals); mp 118–
1208C (methanol); Rf 0.35 (ethyl acetate–benzene, 1:1). dH
(DMSO-d6, ring): 3.73 (1H, d, J¼16.5 Hz, H-4x), 3.73 (3H,
s, 30-OCH3 or 40-OCH3), 3.75 (3H, s, 30-OCH3 or 40-OCH3),
3.97 (1H, d, J¼16.5 Hz, H-4y), 5.02 (1H, s, H-2), 6.00 (1H,
s, NH-1), 6.49 (1H, t, J¼7.3 Hz, H-6), 6.58 (1H, d, J¼
8.0 Hz, H-8), 6.81 (1H, d, J¼7.3 Hz, H-5), 6.90 (1H, dd,
J¼7.3, 8.0 Hz, H-70), 6.91 (1H, d, J¼8.3 Hz, H-50), 7.00 (1H,
d, J¼8.3 Hz, H-6 ), 7.11 (1H, s, H-20), NH-3 was not
detected. dC (DMSO-d6, ring): 45.28 (C-4), 55.45 (30-OCH3
or 40-OCH3), 55.58 (30-OCH3 or 40-OCH3), 68.03 (C-2),
110.79 (C-200), 111.35 (C-50), 114.20 (C-8), 115.88 (C-6),
119.08 (C-6 ), 120.67 (C-4a), 125.61 (C-5), 126.47 (C-7),
135.31 (C-10), 144.65 (C-8a), 148.32 0(C-40), 148.58 (C-30).
dH (DMSO-d6, chain): 3.85 (3H, s, 3 -OCH3 or 40-OCH3),
3.89 (3H, s, 30-OCH3 or 40-OCH3), 4.59 (2H, s, H-4), 5.02
(2H, s, NH2-1), 6.53 (1H, t, J¼7.5 Hz, H-6), 6.67 (1H, d,
J¼7.9 Hz, H-8), 6.97 (1H, n.r., H-7), 7.00 (2H, m, H-5 and
H-50), 7.24 (1H, d, J¼8.3 Hz, H-60), 7.38 (1H, s, 0H-20), 8.33
(1H, s, H-2). dC (DMSO-d6, chain): 55.36 (3 -OCH3 or
40-OCH3), 55.54 (30-OCH3 or 40-OCH3), 61.09 (C-4),
109.22 (C-200), 111.24 (C-50), 114.80 (C-8), 116.18 (C-6),
122.51 (C-6 ), 123.30 (C-4a), 127.61 (C-7), 128.75 (C-5),
129.05 (C-10), 146.39 (C-8a), 148.94 (C-40), 151.10 (C-30),
160.80 (C-2). Anal calcd for C16H18N2O2: C, 71.09; H,
6.71; N, 10.36. Found C, 71.39; H, 6.79; N, 10.46%.
4.3.14. 2-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydroquinazo-
line (6b). Yield 70% (white crystals); mp 90–928C
(methanol); Rf 0.72 (ethyl acetate). dH (DMSO-d6, ring):
2.85 (1H, br. s, NH-3), 3.67 (1H, d, J¼16.3 Hz, H-4x), 3.93
(1H, d, J¼16.3 Hz, H-4y), 5.42 (1H, s, H-2), 6.10 (1H, s,
NH-1), 6.53 (1H, t, J¼7.3 Hz, H-6), 6.58 (1H, d, J¼7.9 Hz,
H-8), 6.84 (1H, d, J¼7.3 Hz, H-5), 6.93 (1H, dd, J¼7.3,
7.9 Hz, H-7), 7.44 (1H, dd, J¼2.1, 8.5 Hz, H-50), 7.59 (1H,
d, J¼2.1 Hz, H-30), 7.61 (1H, d, J¼8.5 Hz, H-60). dC
(DMSO-d6, ring): 44.58 (C-4), 64.63 (C-2), 114.14 (C-8),
116.16 (C-6), 120.59 (C-4a), 125.69 (C-5), 126.65 (C-7),
127.07 (C-50), 128.64 (C-300), 130.00 (C-600), 132.77 (C-20 or
C-40), 133.05 (C-20 or C-4 ), 138.81 (C-1 ), 144.24 (C-8a).
dN (DMSO-d6, ring): 2304.8 (N-1), 2340.5 (N-3). dH
(DMSO-d6, chain): 4.72 (2H, s, H-4), 5.03 (2H, s, NH2-1),
6.53 (1H, n.r., H-6), 6.68 (1H, d, J¼7.7 Hz, H-8), 6.98 (1H,
n.r., H-7), 7.00 (1H, n.r., H-5), 7.48 (1H, n.r., H-500), 7.69
(1H, d, J¼1.9 Hz, H-30), 8.00 (1H, d, J¼8.6 Hz, H-6 ), 8.74
(1H, s, H-2). dC (DMSO-d6, chain): 61.21 (C-4), 114.84
(C-8), 116.16 (C-6), 122.41 (C-4a), 127.81 (C-7), 128.86
(C-5), 129.2–134.8 (5C, C-20, C-30, C-40, C-50 and C-60),
135.91 (C-10), 146.38 (C-8a), 156.44 (C-2). Anal calcd for
C14H12Cl2N2: C, 60.23; H, 4.33; N, 10.03. Found C, 60.19;
H, 4.27; N, 10.03%.
4.3.17. 2,4-Dichloro-6-(1,2,3,4-tetrahydroquinazolin-2-
yl)phenol (6e). Yield 74% (orange crystals); mp 200–
2028C (methanol); Rf 0.69 (ethyl acetate-benzene, 1:1). dH
(DMSO-d6, ring): 3.57 (1H, d, J¼16.4 Hz, H-4x), 3.87 (1H,
d, J¼16.4 Hz, H-4y), 5.46 (1H, s, H-2), 6.55 (1H, t, J¼
7.2 Hz, H-6), 6.7 (1H, br. s, NH-1), 6.73 (1H, d, J¼8.1 Hz,
H-8), 6.81 (1H, d, J¼7.2 Hz, H-5), 6.99 (1H, dd0, J¼7.2,
8.1 Hz, H-7), 7.21 (1H, s, H-60), 7.38 (1H, s, H-4 ), NH-3
and OH were not detected. dC (DMSO-d6, ring): 41.04
(C-4), 63.86 (C-2),0 114.50 (C-8), 116.71 (C-6), 118.40
(C-4a), 120.53 (C-3 ), 121.67 (C-50), 126.16 (C-5), 126.57
(C-60), 127.23 (C-7), 128.19 (C-40), 128.87 (C-10), 141.72
(C-8a), 152.00 (C-20). dH (DMSO-d6, chain): 4.73 (2H, s,
H-4), 5.22 (2H, s, NH2-1), 6.55 (1H, n.r., H-6), 6.70 (1H,
n.r., H-8), 7.02 (1H, n.r., H-7), 7.05 0(1H, d, J¼7.1 Hz, H-5),
7.41 (1H, s, H-60), 7.54 (1H, s, H-4 ), 8.59 (1H, s, H-2). dC
(DMSO-d6, chain): 54.21 (C-4), 115.14 (C-8), 116.21 (C-6),
117.18 (C-10), 117.46 (C-50), 119.39 (C-4a), 124.19 (C-300),
128.85 (C-7), 129.54 (C-5), 130.17 (C-60), 132.62 (C-4 ),
146.55 (C-8a), 162.56 (C-20), 164.85 (C-2). Anal calcd for
C14H12Cl2N2O: C, 56.97; H, 4.10; N, 9.49. Found C, 56.94;
H, 4.17; N, 9.32%.
4.3.15. 2-(2-Chloro-6-nitrophenyl)-1,2,3,4-tetrahydro-
quinazoline (6c). Yield 72% (yellow crystals); mp 104–
1068C (methanol); Rf 0.69 (ethyl acetate–benzene, 1:1). dH
(DMSO-d6, ring): 2.87 (1H, m, NH-3), 3.86 (1H, dd, J¼3.2,
16.4 Hz, H-4x), 4.01 (1H, dd, J¼10.2, 16.4 Hz, H-4y), 5.68
(1H, d, J¼11.3 Hz, H-2), 6.14 (1H, s, NH-1), 6.45 (1H, d,
J¼7.9 Hz, H-8), 6.59 (1H, t, J¼7.4 Hz, H-6), 6.86 (1H, d,
J¼7.4 Hz, H-5), 6.93 (1H,0 dd, J¼7.4, 7.9 Hz, H-7), 7.56
(1H, dd, J¼7.5, 7.9 Hz, H-4 ), 7.71 (1H, d, J¼7.5 Hz, H-50),
7.78 (1H, d, J¼7.9 Hz, H-30). dC (DMSO-d6, ring): 45.90
(C-4), 65.70 (C-2),0 115.20 (C-8), 117.24 (C-6), 121.80
(C-40a), 123.01 (C-5 ), 125.63 (C-5), 126.68 (C-7), 130.30
(C-4 ), 131.60 (C-100), 133.03 (C-30), 134.32 (C-20), 143.99
(C-8a) 151.74 (C-6 ). dN (DMSO-d6, ring): 2306.4 (N-1),
2341.1 (N-3), 23.3 (NO2). dH (DMSO-d6, chain): 4.68
(2H, s, H-4), 4.92 (2H, s, NH2-1), 6.55 (1H, t, J¼7.3 Hz,
H-6), 6.70 (1H, d, J¼7.7 Hz, H-8), 6.98 (1H,0n.r., H-7), 7.00
(1H, n.r., H-5), 7.66 (1H, t, J¼7.9 Hz, H-4 ), 7.84 (1H, d,
4.3.18. 2-{(E)-[(2-Aminobenzyl)imino]methyl}-4-meth-
oxyphenol (6f). Yield 58% (yellow crystals); mp 116–
1188C (methanol); Rf 0.53 (ethyl acetate–benzene, 1:1).
dH (DMSO-d6, ring): 3.63 (3H. s, OCH3), 3.65 (1H, d,

J. Sinkkonen et al. / Tetrahedron 59 (2003) 1939–1950
1949
J¼16.0 Hz, H-4x), 3.89 (1H, d, J¼16.0 Hz, H-4y), 5.30
(1H, s, H-2), 6.29 (1H, s, NH-1), 6.51 (1H, t, J¼7.4 Hz,
H-6), 6.65 (1H, n.r., H-8), 6.69 (1H, n.r., H-30), 6.71 (1H,
n.r., H-40), 6.79 (1H, d, J¼7.4 Hz, H-5), 6.88 (1H, s, H-60),
6.93 (1H, n.r., H-7), NH-3 and OH were not detected. dC
(DMSO-d6, ring): 43.03 (C-4), 55.34 (OCH3), 64.13 (C-2),
113.44 (C-40), 113.98 (C-60), 114.37 (C-8), 116.07 (C-30),
116.20 (C-6), 119.56 (C-4a), 125.91 (C-5), 126.83 (C-7),
127.22 (C-10), 143.38 (C-8a), 149.66 (C-20), 151.91 (C-50).
dH (DMSO-d6, chain): 3.71 (3H. s, OCH3), 4.66 (2H, s,
H-4), 5.04 (2H, s, NH2-1), 6.53 (1H, t, J¼7.4 Hz, H-6), 6.67
(1H, n.r., H-8), 6.81 (1H, d, J¼9.0 Hz, H-30), 6.93 (1H, n.r.,
H-40), 6.99 (2H, m, H-5 and H-7), 7.02 (1H, s, H-60), 8.58
(1H, s, H-2). dC (DMSO-d6, chain): 55.53 (OCH3), 58.64
(C-4), 114.78 (C-600), 114.89 (C-8), 116.16 (C-6), 117.17
(C-30), 118.60 (C-1 ), 119.24 (C-40), 121.52 (C-4a), 128.09
(C-7), 128.92 (C-5), 146.29 (C-8a), 151.55 (C-50), 154.37
(C-20), 165.43 (C-2). Anal calcd for C15H16N2O2: C, 70.29;
H, 6.29; N, 10.93. Found C, 70.21; H, 6.29; N, 11.12%.
J¼7.9 Hz, H-b-30), 6.86 (1H, t, J¼7.5 Hz, H-b-50), 6.98 (2H,
m, H-a-30 and H-a-50), 7.29 (1H, dd, J¼7.5, 7.9 Hz, H-b-400),
7.31 (1H, t, J¼7.4 Hz, H-7), 7.370 (2H, m, H-8 and H-b-6 ),
7.42 (03H, m, H-5, H-6 and H-a-4 ), 7.68 (1H, d, J¼7.9 Hz,
H-a-6 ), 8.65 (1H, s, b-CvH), 8.89 (1H, s, a-CvH), 12.9
(1H, br.s, a-OH or b-OH), 13.3 (1H, br.s, a-OH or b-OH). dC
(DMSO-d6, a and b refer to aniline and benzylamino type
linear moietie0s, respectively): 058.72 (C-4), 116.34 (C-b-30),
116.54 (C-a-6 ), 118.54 (C-b-5 ), 1108.56 (C-8), 118.63 (C-b-
10), 119.11 (C-a-50), 119.46 (C-a-1 ), 126.96 (C-7), 128.81
(C-6), 0129.07 (C-5), 131.59 (C-b-60), 132.07 (C-4a), 132.30
(C-b-4 ), 132.406 (C-a-60), 133.37 0(C-a-40), 147.03 (C-8a),
160.14 (C-a-2 ), 160.32 (C-b-2 ), 163.62 (C-a-CvN),
166.51 (C-b-CvN). dN (DMSO-d6, a and b refer to aniline
and benzylamino type linear moieties, respectively): 287.0
(a-N), 285.1 (b-N). Anal calcd for C21H18N2O2: C, 76.31;
H, 5.49; N, 8.48. Found C, 76.28; H, 5.45; N, 8.40%.
4.4.3. 2-{(E)-[(2-{[(1E)-(2-Hydroxy-5-nitrophenyl)-
methylene]amino}benzyl)imino]methyl}-4-nitrophenol
(9b). Synthesized as compound (Ia) from 2-hydroxy-5-
nitro-benzaldehyde and 2-aminomethylaniline. Yield 96%
(yellow crystals); mp 248–2508C (ethanol); Rf 0.54 (ethyl
acetate–benzene, 1:1). dH (DMSO-d6, a and b refer to
aniline and benzylamino type linear moieties, respectively):
5.05 (2H, s, H-4), 60.69 (1H, d, J¼9.5 Hz, H-a-20), 7.13 (1H,
d, J¼9.0 Hz, H-b-2 ), 7.38 (2H, m, H-6 and H-8), 7.50 (2H,
m, H-5 and H-7),08.05 (1H, d, J¼9.5 0Hz, H-a-30), 8.27 (H, 0d,
J¼9.0 Hz, H-b-3 ), 8.34 (H, s, H-a-5 ), 8.75 (1H, s, H-b-5 ),
8.84 (1H, s, b-CvH), 9.00 (1H, s, a-CvH), OH protons
were not detected. Anal calcd for C21H16N4O6: C, 60.00; H,
3.84; N, 13.33. Found C, 60.02; H, 3.78; N, 13.35%.
4.3.19. 1-(1,2,3,4-Tetrahydroquinazolin-2-yl)-naphthal-
en-2-ol (7). Yield 86% (yellow crystals); mp 176–1788C
(hexane); Rf 0.51 (ethyl acetate). dH (DMSO-d6): 4.74 (2H,
s, H-4), 5.28 (2H, s, NH2-1), 6.57 (1H, t, J¼7.6 Hz, H-6),
6.71 (2H, m, H-8 and H-30), 7.04 (1H, t, J¼7.6 Hz, H-7),
7.16 (1H, d, J¼7.6 Hz, H-5), 7.18 (1H, 0dd, J¼7.4, 7.9 Hz,
H-60), 7.42 0(1H, dd, J¼7.4, 8.3 Hz, H-7 ), 7.61 (1H, d, J¼
7.9 Hz, H-5 0), 7.71 (1H, d, J¼9.4 Hz, H-40), 8.04 (1H, d, J¼
8.3 Hz, H-8 ), 9.22 (1H, s, H-2), 14.1 (1H, br.s, OH). dC
(DMSO-d6): 51.14 (C-4), 105.71 (C-10), 115.13 (C-8),
116.22 (C-6), 118.28 (C-80), 120.19 (C-4a), 122.09 (C-60),
125.17 (C-4a0), 125.49 (C-30), 127.83 (C-70), 128.82 (C-7),
128.86 (C-50), 129.46 (C-5), 134.33 (C-8a0), 137.02 (C-40),
146.52 (C-8a), 158.57 (C-2), 177.22 (C-20). Anal calcd for
C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found C, 78.35; H,
5.52; N, 10.34%.
Acknowledgements
The authors wish to thank the Academy of Finland for
financial support.
4.4. Compounds 8–9
4.4.1. 2-Methyl-3,4-dihydroquinazoline (8). A solution of
acetone (0.17 g, 3 mmol) with 2-aminomethylaniline
(0.36 g, 3 mmol) in methanol (10 mL), was boiled for a
week, concentrated in vacuo, and the residue was recrys-
tallized. Yield 47% (white crystals); mp 204–2058C
(ethanol, 204–2058C24,25); Rf 0.52 (acetic acid–ethanol,
1:1). dH (DMSO-d6): 1.79 (3H, s, CH3), 3.73 (2H, s, H-4),
6.52 (1H, t, J¼7.4 Hz, H-6), 6.64 (1H, d, J¼8.1 Hz, H-8),
6.98 (1H, t, J¼7.4, 8.1 Hz, H-7), 7.05 (1H, d, J¼7.4 Hz,
H-5), NH-1 proton was not detected. dC (DMSO-d6): 22.89
(CH3), 40.93 (C-4), 114.91 (C-8), 115.87 (C-6), 122.37
(C-4a), 127.97 (C-5), 129.07 (C-7), 146.79 (C-8a), 173.47
(C-2). Anal calcd for C9H10N2: C, 73.93; H, 6.89; N, 19.16.
Found C, 73.97; H, 6.98; N, 19.11%.
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