Two isolated intermediates of the Tr?ger's base: synthesis and mechanism

Article abstract of DOI:10.1016/j.tet.2010.03.057

By controlling the amount of catalyst 1-methyl-3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium chloride, two new intermediates of Tr?ger's bases (11, 1,6-dimethyl-3-(4-methylphenyl)-1,4-dihydroquinazolin-3-ium tetrafluoroborate and 12, 8-methyl-2,5-bis-(4-methylp

Full text of DOI:10.1016/j.tet.2010.03.057

Tetrahedron 66 (2010) 3405–3409
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
¨
Two isolated intermediates of the Troger’s base: synthesis and mechanism
,
Yu Wan a b, Rui Yuan a, Wei-chao Zhang a, Yan-hui Shi a, Wei Lin a, Wei Yin a, Rong-cheng Bo a,
,b,
Jing-jing Shi a, Hui Wu a
*
a School of Chemistry and Chemical Engineering, Xuzhou Normal University, Jiangsu 221116, China
b Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu, 221116, China
a r t i c l e i n f o
a b s t r a c t
Article history:
By controlling the amount of catalyst 1-methyl-3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium chloride, two
new intermediates of Tro¨ger’s bases (11, 1,6-dimethyl-3-(4-methylphenyl)-1,4-dihydroquinazolin-3-ium
tetrafluoroborate and 12, 8-methyl-2,5-bis-(4-methylphenyl)-3,5,6,7-tetrahydropyrimido[5,6,1-ij]quina-
zoline-2-ium tetrafluoroborate) were simply obtained from the one-pot reaction of aromatic amine and
formaldehyde in ionic liquid at ambient temperature. These results support the mechanism for Tro¨ger’s
base formation supposed by Fernando Coelho and co-workers. However, the crystal structure of 12 and
correlative quantum chemistry calculation results are not reconciled with their report.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 January 2010
Received in revised form
10 March 2010
Accepted 16 March 2010
Available online 20 March 2010
Keywords:
Tro¨ger’s base
Intermediates
Synthesis
Mechanism
1. Introduction
Intermediate 5 has been, however, questioned by Farrar,12 who
proposed compound 6 as the right structure (Fig. 2). Farrar isolated
As a class of fascinating molecules,1 Tro¨ger’s bases (TB, 1, Fig. 1)
was first synthesized by Julius Tro¨ger in 1887.2 These relatively
simple bicyclic molecules have geometrically rich V-shape, their
dissymmetry was resulted from the impossibility of nitrogen in-
version. TB chemistry has grown in importance over the years due
to their applications in the fields of stereoselective catalysis,3 rec-
ognition phenomena,4 drug development,5 bioorganic chemistry6
and supra-molecular chemistry.7
a byproduct identified as diazajulolidine 7 and thus he proposed 8
as an additional intermediate, which led to 7.12 Cooper and
N
N
H3C
CH3
1
Figure 1. The structure of Tro¨ger’s base (1).
Generally, TB derivatives are synthesized by heating a mixture of
aromatic amine and formaldehyde in absolute ethanol or DMSO in
the presence of concentrated hydrochloric or trifluoroacetic acid
(TFA).4b,8–10
The mechanism of the formation of the TB was firstly studied by
Wagner.11 In these works he assumed that there were four in-
termediates [2þH]þ and 3–5 (Scheme 2) in the formation of TB.
* Corresponding author. Fax: 86 516 8536977; e-mail address: wuhui72@yahoo.
com.cn.
Figure 2. Intermediates ([2þH]þ, 3–5,11 6–8,12 9,13 [7ꢀH]þ-1014) proposed previously.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.057

3406
Y. Wan et al. / Tetrahedron 66 (2010) 3405–3409
Partridge13 demonstrated that Tro¨ger’s bases could also be
obtained via 9. Coelho14 and co-workers used direct infusion
electrospray ionization mass and tandem mass spectrometric ex-
periments (ESI-MS/MS) to monitor the formation of Tro¨ger’s base
from different methylene source (formaldehyde or urotropine) and
formaldehyde in neat TFA. When formaldehyde was used, three
intermediates [2þH]þ (m/z 120), [4ꢀH]þ (m/z 237), [5ꢀH]þ (m/z
267) were detected via analyzing the main fragment in ESI-MS/MS.
When urotropine was used as methylene source, some new in-
termediates, such as [4ꢀ3H]þ (m/z 237) and [7ꢀH]þ (m/z 368) were
found (Fig. 2).
Table 1
Synthesis of compound 11
Compound
R
Time (h)
Yield (%)
Mp (ꢁC)
11a
11b
11c
11d
11e
11f
4-CH3
4-Cl
4-Br
4-F
3-Cl-4-F
3-Cl-4-CH3
20
22
24
24
23
19
75
80
95
62
78
93
194.3–195.5
182.2–183.4
>300.0
>300.0
287.9–288.3
255.9–257.0
However, in all of these proposed intermediates, only 712 and 913
have been isolated. So, it is still significant to obtain new kind of
intermediates to study the mechanism during the formation of TB
derivatives.
2. Result and discussion
According to our previous experiments, the high active amine
could afford the corresponding Tro¨ger’s base derivatives via a cat-
alyst-free one-pot procedure.15 So, there is no way to isolate any
intermediates. p-Toluidine, an aromatic amine with lower activity
was tested subsequently. Unfortunately, there was no reaction
taking place in previous reaction conditions.
This problem was solved by using a suitable amount of catalyst
1-methyl-3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium chloride, which
was synthesized in our lab.16 Two new intermediates of TB (1,6-di-
methyl-3-(4-methylphenyl)-1,4-dihydroquinzoli-3-ium tetrafluoro-
borate, Fig. 3) (11) and (8-methyl-2,5-bis-(4-methylphenyl)-3,5,6,7-
tetrahydroprimido [5,6,1-ij]quinazoline-2-ium tetrafluoroborate,
Fig. 3) (12) were obtained in ionic liquid 1-butylpyridiniumtetra-
fluoroborate ([BPY][BF4]).
Figure 4. X-ray diffraction of 11b.
N
[BPY][BF4] (2 mL)
rt, cat. (0.8 mmol)
CH2O
cat. =
+
N
BF4
N
NH2
Cl
OSO3H
N
N
H3C
N
12
R
N
Scheme 2. The synthesis of 12.
N
BF4
R
N
BF4
N
12
11
Figure 3. Two new intermediates of Tro¨ger’s bases.
Initially, a series of 11 was obtained under the suitable condition
(Scheme 1 and Table 1), the X-ray diffraction of 11b was shown in
Figure 4. Subsequently, double amount of catalyst was added into
the mixture of p-toluidine and formaldehyde, another intermediate
12 was isolated after 48 h in the yield of 60% (Scheme 2 and Fig. 5).
R
R
N
[BPY][BF4] (2 mL)
rt, cat. (0.4 mmol)
R
CH2O
cat. =
+
BF4
N
NH2
CH3
Cl
OSO3H
N
N
H3C
11
Scheme 1. The synthesis of 11.
Figure 5. X-ray diffraction of 12.
The results in Table 1 indicated that halogen is favourable in the
reaction. That mentioned the formation of cation in this procedure.
The lone pair electron of halogen can stabilize these cation in-
termediates and promote their resonance. The explanation will be
put forward in the mechanism section.
Interestingly, as shown in Figure 5, it is clearly that the X-ray
diffraction of 12 is different from the structure of [7ꢀH]þ (m/z 368)
supposed by Fernando14 and co-workers (Scheme 2). Theoretically,
both of these two structures ([7ꢀH]þ and 11) are possible.

Y. Wan et al. / Tetrahedron 66 (2010) 3405–3409
3407
To further support our result, theoretic calculations about the
stability of the two compounds were performed. The geometry
structures of these two molecules on the potential energy surface
were fully optimized using density functional theory with the
Becke 3-parameter hybrid exchange17 and Lee-Yang-Parr18 corre-
lation density functional (B3LYP) in conjunction with the 6–31 G (d)
basis set. The optimized geometry structures of the two possible
structure at the B3LYP/6-31 G (d) level are shown in Figure 6. It is
clear that in the optimized geometrics of 12, N–C–Nþ can form
a stable conjugated system, whereas [7ꢀH]þ cannot.
Their total energies of [7ꢀH]þ and 12 are ꢀ1131.892157 and
ꢀ1131.910257 hartree, respectively, which showed that the energy
of 12 is 47.52 kJ/mol lower than that of [7ꢀH]þ. Therefore, 12 is the
more reasonable structure for the intermediate of TB.
On the basis of our experimental result, a reasonable mecha-
nism for the formation of 12 was outlined in Scheme 3 and Scheme
4. It was considered that 10, which was detected by Fernando14 and
co-workers by on-line ESI-MS/MS, was a key intermediate in the
formation of 11, 12 and TB. Both of 11 and 12 could give TB by
relative resonance or reversible process.
Scheme 3. A possible mechanism for the formation of 11.
Scheme 4. A possible mechanism for the formation of 12 and TB.
Actually, heating 11a or 12 at 150 ꢁC for 48 h with more form-
aldehyde (36–40%, aq 2.0 equiv) and catalyst (0.8 mmol) in ionic
liquid [BPY][BF4] (ca. 4 mL) yield the expected Tro¨ger’s base in 33%
and 25% yield, respectively.
To further confirm this supposed mechanism, compound 11
was dealt with NaOH in EtOHdthe reversible condition of its
formation at room temperature. As expected, a new kind of
compound 3-aryl-3,4-dihydroquinazolines was easily obtained
(Scheme 5, 6 and Table 2). This interesting reaction showed
the rationality of the mechanism outlined in Scheme 3 and
Scheme 4.
R
R
N
N
NaOH
EtOH, r.t.
R
BF4
R
N
N
11
13
Scheme 5. The synthesis of compound 13.
3,4-Dihydroquinazoline is an effective substrate to form and
stabilize an N-heterocyclic Carbene (NHC) tautomer in heterocycle/
olefin coupling. For example, Ellman and co-workers19 selected it to
form a Rh–NHC complex to study Rh(I)-mediated heterocycle C–H
activation reactions. However, the direct synthesis of 3-aryl-3,4-
dihydroquinazolines is underdeveloped. Only three papers have
ever reported the synthesis of some analogous framework.20–22 The
discovery may offer the most straightforward route to synthesize
3-aryl-3,4-dihydroquinazolines.
Figure 6. The optimized geometrics of [7ꢀH]þ and 12 at the B3LYP/6-31 G (d) level.

3408
Y. Wan et al. / Tetrahedron 66 (2010) 3405–3409
4.2.1. 1,6-Dimethyl-3-(4-methylphenyl)-1,4-dihydroquinazolin-3-
ium tetrafluoroborate (11a). dH (400 MHz, DMSO-d6) 8.84 (s, 1H,
]CH), 7.55 (d, J 8.4 Hz, 2H, Ar–H), 7.41 (d, J 8.4 Hz, 2H, Ar–H), 7.30–
7.32 (m, 2H, Ar–H), 7.14 (s, 1H, Ar–H), 5.26 (s, 2H, –CH2), 3.62 (s, 3H,
–CH3), 2.39 (s, 3H, –CH3), 2.34 (s, 3H, –CH3); dC (100 MHz, DMSO-
d6) 151.6, 148.1, 144.0, 138.5, 137.7, 130.2, 129.4, 127.4, 125.6, 121.6,
118.6, 116.9, 65.9, 48.9, 37.8; MS [ESI] m/z for [C17H19N2ꢀ2]þ found
249.1597, requires 249.1543.
4.2.2. 1-Methyl-6-chloro-3-(4-chlorophenyl)-1,4-dihydroquinazolin-
3-ium tetrafluoroborate (11b). dH (400 MHz, DMSO-d6) 8.94 (s, 1H,
]CH), 7.69–7.73 (m, 4H, Ar–H), 7.56 (s, 1H, Ar–H), 7.46 (d, J 8.8 Hz,
2H, Ar–H), 5.30 (s, 2H, –CH2), 3.64 (s, 3H, –CH3); dC (100 MHz,
DMSO-d6) 152.7, 139.1, 133.2, 132.2, 130.6, 129.8, 129.0, 126.7, 123.8,
121.5, 117.5, 47.8, 37.7; MS [ESI] m/z for [C15H13Cl2N2]þ found
291.0473, requires 291.0456.
Scheme 6. A possible mechanism for the formation of 13.
Table 2
Crystal data for 11b. Empirical formula C15H13BCl2F4N2, yellow,
crystal dimension 0.37ꢂ0.16ꢂ0.15 mm, monoclinic, space group
P2(1)/c, a¼14.5133 (19) Å, b¼16.628(3) Å, c¼13.5067(16) Å,
Synthesis of compound 13
Compound
R
Time (h)
Yield (%)
Mp (ꢁC)
a
¼90.00ꢁ,
b
¼90.171(2)ꢁ,
g
¼90.00ꢁ, V¼3259.4(8) Å3, Mr¼378.98,
13a
13b
13c
13d
13e
13f
4-CH3
4-Cl
4-Br
4-F
3-Cl-4-F
3-Cl-4-CH3
10
12
12
12
12
9
65
75
85
30
80
85
157.0–159.2
181.2–183.8
189.3–192.1
240.5–243.2
170.2–172.6
187.4–188.9
Z¼8, Dc¼1.545 Mg/m3,
l¼0.71073 Å,
m
(Mo Ka)¼0.439 mmꢀ1
,
F(000)¼1536.0, S¼1.000, R1¼0.0511, wR2¼0.0719. Crystallographic
data for the structures of 11b reported in this letter have been
deposited with the Cambridge Crystallographic Date Centre as
supplementary publication No. CCDC-070729a.
3. Conclusion
4.2.3. 1-Methyl-6-bromo-3-(4-bromophenyl)-1,4-dihydroquinazolin-
3-ium tetrafluoroborate (11c). dH (400 MHz, DMSO-d6) 8.99 (s, 1H,
]CH), 7.85 (d, J 8.4 Hz, 2H, Ar–H), 7.70 (d, J 8.8 Hz, 1H, Ar–H), 7.63
(d, J 8.8 Hz, 2H, Ar–H), 7.57 (s, 1H, Ar–H), 7.39 (d, J 8.8 Hz, 1H, Ar–H),
5.31 (s, 2H, –CH2), 3.63 (s, 3H, –CH3); dC (100 MHz, DMSO-d6) 150.0,
139.7, 132.6, 132.0, 129.7, 128.9, 124.3, 124.0, 121.5, 120.8, 119.5, 48.0,
37.9; MS [ESI] m/z for [C15H13Br2N2þH]þ found 381.9509, requires
381.9503.
In summary, by controlling the amount of catalysis 1-methyl-
3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium chloride, two new
intermediates of Tro¨ger’s bases (11, 1,6-dimethyl-3-(4-methyl-
phenyl)-1,4-dihydroquinazolin-3-ium tetrafluoroborate and 12,
8-methyl-2,5-bis-(4-methylphenyl)-3,5,6,7-tetrahydropyrimido-
[5,6,1-ij]quinazoline-2-ium
tetrafluoroborate)
were
simply
obtained from the one-pot reaction of aromatic amine and form-
aldehyde in ionic liquid at ambient temperature. These results
support the mechanism for Tro¨ger’s base formation supposed by
Coelho and co-workers. However, the crystal structure of 12 and
correlative quantum chemistry calculation results are not recon-
ciled with their report. Compound 11 can be easily transform into
3-aryl-3,4-dihydroquinazolines in mild condition. Moreover, these
two types of new compounds, which have multi modifiable site can
be used as active synthon to synthesize more interesting molecules.
4.2.4. 1-Methyl-6-fluoro-3-(4-fluorophenyl)-1,4-dihydroquinazolin-
3-ium tetrafluoroborate (11d). dH (400 MHz, DMSO-d6) 8.88 (s, 1H,
]CH), 7.71–7.74 (m, 2H, Ar–H), 7.47–7.51 (m, 3H, Ar–H), 7.34–7.38
(m, 1H, Ar–H), 7.24 (d, J 8.8 Hz, 1H, Ar–H), 5.30 (s, 2H, –CH2), 3.63 (s,
3H, –CH3); dC (100 MHz, DMSO-d6) 162.8, 162.2, 159.7, 152.4, 136.8,
128.2, 124.6, 121.9, 117.9, 116.8, 115.9, 114.2, 89.6, 48.4, 37.8; MS [ESI]
m/z for [C15H13F2N2ꢀ2H]þ found 257.0786, requires 257.0879.
4. Experimental
4.1. General
4.2.5. 1-Methyl-5-chloro-6-fluoro-3-(3-chloro-4-fluorophenyl)-1,4-
dihydroquinazolin-3-ium tetrafluoroborate (11e). dH (400 MHz,
DMSO-d6) 8.95 (s, 1H, ]CH), 8.10–8.16 (m, 1H, Ar–H), 7.61–7.80 (m,
3H, Ar–H), 7.47–7.50 (m, 1H, Ar–H), 5.34 (s, 2H, –CH2), 3.65 (s, 3H,
–CH3); dC (100 MHz, DMSO-d6) 153.1, 152.6, 137.2, 128.9, 125.5,
123.8, 123.2, 120.6, 118.4, 117.8, 116.1, 115.5, 89.1, 47.9, 37.6; MS [ESI]
m/z for [C15H11Cl2F2N2þH]þ found 328.0336, requires 328.0340.
All reagents were purchased from commercial sources and used
without further purification. NMR spectra were measured in
DMSO-d6 or CDCl3 with Me4Si as the internal standards on a Bruker
Advance DPX-400 at room temperature. IR spectra were recorded
on Bruker FTIR spectrometer, absorbance were reported in cmꢀ1
.
4.2.6. 1-Methyl-5-chloro-6-methyl-3-(3-chloro-4-methylphenyl)-
1,4-dihydroquinazolin-3-ium tetrafluoroborate (11f). dH (400 MHz,
CDCl3) 8.48 (s, 1H, ]CH), 7.52–7.54 (m, 2H, Ar–H), 7.46–7.48 (m, 1H,
Ar–H), 7.37 (d, J 8.4 Hz, 1H, Ar–H), 7.08 (d, J 8.0 Hz, 1H, Ar–H), 5.20
(s, 2H, –CH2), 3.78 (s, 3H, –CH3), 2.45 (s, 3H, –CH3), 2.43 (s, 3H,
–CH3); dC (100 MHz, CDCl3) 151.9, 139.3, 136.5, 135.9, 134.0, 132.1,
131.4, 122.8, 120.9, 117.9, 114.1, 47.5, 46.9, 38.2, 19.4; MS [ESI] m/z for
[C17H17Cl2N2]þ found 320.0874, requires 320.0847.
Mass spectra were recorded on Bruker TOFMS high resolution mass
spectrometer.
The preparation of 1-methyl-3-(2-(sulfooxy)ethyl)-1H-imida-
zol-3-ium chloride was according to the reported method.16
4.2. General procedure for the synthesis of 11
A
mixture of aromatic amine (2.0 mmol), formaldehyde
(2.5 mmol) and 1-methyl-3-(2-(sulfooxy)ethyl)-1H-imidazol-3-
ium chloride (0.4 mmol) was stirred in [BPY][BF4] (2 mL) at room
temperature. After 19–24 h reaction, water was added and the
precipitate was collected and then purified from 95% EtOH–DMF
(10:1) after washed with water three times. The analytical data for
represent compound are shown below.
4.3. The procedure for the synthesis of 12
A mixture of p-toluidine (2.0 mmol), formaldehyde (2.5 mmol)
and 1-methyl-3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium chloride
(0.8 mmol) was stirred in [BPY][BF4] (2 mL) at room temperature

Y. Wan et al. / Tetrahedron 66 (2010) 3405–3409
3409
for 48 h. The following procedure was same as the preparation of
11, 12 was obtained in 60% yield.
7.21–7.26 (m, 2H, Ar–H), 7.10–7.04 (m, 3H, Ar–H), 4.93 (s, 2H, –CH2);
MS [ESI] m/z for [C16H8Cl2F2N2]þ found 312.0021, requires 312.0033.
4.3.1. 8-Methylphenyl-3,5,6,7-tetrahydropyrimido[5,6,1-ij]quinazo-
line-2-ium tetrafluoroborate (12). dH (400 MHz, DMSO-d6) 8.95 (s,1H,
]CH), 7.52 (d, J 8.4 Hz, 2H, Ar–H), 7.42 (d, J 8.4 Hz, 2H, Ar–H), 7.16 (s,
1H, Ar–H), 7.09 (d, J 8.8 Hz, 2H, Ar–H), 7.05 (d, J 8.8 Hz, 2H, Ar–H),
6.95 (s, 1H, Ar–H), 5.56 (s, 2H, –CH2), 5.21 (s, 2H, –CH2), 4.76 (s, 2H,
–CH2), 2.38 (s, 3H, –CH3), 2.29 (s, 3H, –CH3), 2.19 (s, 3H, –CH3); MS
[ESI] m/z for [C25H26N3þH]þ found 369.2235, requires 369.2205.
Crystal data for 12. Empirical formula C56H68B2F8N8O3, colour-
less, crystal dimension 0.50ꢂ0.44ꢂ0.42 mm, monoclinic, space
group C2/c, a¼19.1132(19) Å, b¼10.1581(10) Å, c¼28.007(2) Å,
4.5.6. 7-Chloro-3-(3-chloro-4-methylphenyl)-3,4-dihydro-6-methyl-
quinazoline (13f). dH (400 MHz, DMSO-d6) 7.47 (s, 1H, ]CH), 7.27–
7.25 (m, 2H, Ar–H), 7.19 (s, 1H, Ar–H), 7.14 (s, 1H, Ar–H), 6.84 (s, 1H,
Ar–H), 4.92 (s, 2H, –CH2), 2.37 (s, 3H, –CH3), 2.33 (s, 3H, –CH3); MS
[ESI] m/z for [C16H14Cl2N2]þ found 304.0521, requires 304.0534.
Acknowledgements
We are grateful to the ‘National Natural Sciences Foundation of
China’ (No. 20772103), ‘Natural Sciences Foundation of Xuzhou
Normal University’ (No. 09XLA17), and the ‘Qin Lan Project in
Jiangsu Province’ (No. QL200607, 08QLT001) for financial support.
a
¼90.00ꢁ,
b
¼91.069(2)ꢁ,
g
¼90.00ꢁ, V¼5436.7(9) Å3, Mr¼1074.80,
Z¼4, Dc¼1.313 Mg/m3,
l¼0.71073 Å,
m
(Mo Ka)¼0.100 mmꢀ1
,
F(000)¼2264.0, S¼1.018, R1¼0.0626, wR2¼0.2198. Crystallographic
data for the structures of 12 reported in this letter have been de-
posited with the Cambridge Crystallographic Date Centre as sup-
plementary publication No. CCDC-080319f.
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C.; Collet, A.; Lhomme, J. J. Chem. Soc., Chem. Commun. 1999, 161–162.
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A. J. Org. Chem. 2001, 66, 1607–1611; (b) Manjula, A.; Nagarajan, M. Tetrahedron
1997, 53, 11859–11868; (c) Crossley, M. J.; Hambley, T. W.; Machay, L. G.; Try, A.
C.; Walton, R. J. Chem. Soc., Chem. Commun. 1995, 1077–1079.
4.5. The procedure for the synthesis of 13
Added NaOH (0.2 mmol) in the anhydrous ethanol (5 mL) so-
lution of 11 (2.0 mmol), then stirred the mixture at room temper-
ature. After 9–12 h reaction, collected and purified the precipitate
from anhydrous EtOH to afford 13.
4.5.1. 3,4-Dihydro-6-methyl-3-p-tolylquinazoline (13a). dH (400 MHz,
DMSO-d6) 7.49 (s, 1H, ]CH), 7.02 (d, J 8.8 Hz, 1H, Ar–H), 6.93 (d, J
8.8 Hz, 1H, Ar–H), 6.91 (s, 1H, Ar–H), 6.89 (d, J 8.4 Hz, 2H, Ar–H), 6.13
(d, J 8.4 Hz, 2H, Ar–H), 4.92 (s, 2H, –CH2), 2.35 (s, 3H, –CH3), 2.32 (s,
3H, –CH3); MS [ESI] m/z for [C16H16N2]þ found 236.1301, requires
236.1313.
8. (a) Jenson, J.; Warnmark, K. Synthesis 2001, 1873–1877; (b) Jenson, J.; Strozyk,
M.; Wa¨rnmark, K. Synthesis 2002, 1912–2002; (c) Li, Z.; Xu, X. Y.; Peng, Y. Q.;
Jiang, Z. X.; Ding, C. Y.; Qian, X. H. Synthesis 2005, 1228–1230.
¨
9. (a) Cerrada, L.; Cudero, J.; Elguero, J.; Pardo, C. J. Chem. Soc., Chem. Commun.
1993, 1713–1714; (b) Ta´las, E.; Margitfalvi, J.; Machytka, D.; Czugler, M. Tetra-
hedron: Asymmetry 1998, 9, 4151–4156; (c) Salez, H.; Wardani, A.; Demeunynck,
M.; Tatibouet, A.; Lhomme, J. Tetrahedron Lett. 1995, 36, 1271–1274; (d)
4.5.2. 6-Chloro-3-(4-chlorophenyl)-3,4-dihydroquinazoline
(13b). dH (400 MHz, DMSO-d6) 7.48 (s, 1H, ]CH), 7.12(s, 1H, Ar–H),
6.88 (s, 1H, Ar–H), 6.80 (d, 1H, Ar–H), 6.75 (d, J 8.8 Hz, 2H, Ar–H),
6.41 (d, J 8.8 Hz, 2H, Ar–H), 4.92 (s, 2H, –CH2); MS [ESI] m/z for
[C14H10Cl2N2]þ found 276.0201, requires 276.0221.
ꢀ
ꢁ
ˇ
Cekavicus, B.; Liepinsh, E.; Vıgante, B.; Sobolevs, A.; Ozols, J.; Duburs, G. Tet-
rahedron Lett. 2001, 42, 4239–4241.
10. (a) Abonia, R.; Albornoz, A.; Larrahondo, H.; Quiroga, J.; Insuasty, B.; Insuasty,
H.; Hormaza, A.; Sa´nchez, A.; Nogueras, M. J. Chem. Soc., Perkin Trans. 1 2002,
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´
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´
1588–1591; (b) Valı´k, M.; Dolensky, B.; Petrıckova, H.; Vasek, P.; Kral, V. Tet-
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Soc. 1991, 113, 678–680; (d) Cudero, J.; Pardo, C.; Ramos, M.; Gutierrez-Puebla,
E.; Monge, A.; Elguero, J. Tetrahedron 1997, 53, 2233–2240.
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E. C. J. Am. Chem. Soc. 1941, 63, 832–836.
4.5.3. 6-Bromo-3-(4-chlorophenyl)-3,4-dihydroquinazoline (13c). dH
(400 MHz, DMSO-d6) 7.86 (d, J 8.8 Hz, 2H, Ar–H), 7.53 (d, J 8.4 Hz,
2H, Ar–H), 7.51 (s, 1H, ]CH), 7.20 (s, 1H, Ar–H), 7.18 (d, J 8.4 Hz, 1H,
Ar–H), 7.05 (d, J 8.4 Hz, 1H, Ar–H), 4.95 (s, 2H, –CH2); MS [ESI] m/z
for [C14H10Br2N2]þ found 363.9201, requires 363.9211.
12. Farrar, W. V. J. Appl. Chem. 1964, 14, 389–399.
13. Cooper, F. C.; Partridge, M. W. J. Chem. Soc. 1955, Part 3, 991–994.
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Chem. 2007, 72, 4048–4054.
4.5.4. 6-Fluoro-3-(4-chlorophenyl)-3,4-dihydroquinazoline (13d). dH
(400 MHz, DMSO-d6) 7.49 (s, 1H, ]CH), 7.12 (d, J 8.4 Hz, 1H, Ar–H),
6.82 (s, 1H, Ar–H), 6.72 (d, J 8.8 Hz, 1H, Ar–H), 6.75 (d, J 8.4 Hz, 2H,
Ar–H), 6.41 (d, J 8.4 Hz, 2H, Ar–H), 4.91 (s, 2H, –CH2); MS [ESI] m/z
for [C14H10F2N2]þ found 244.0803, requires 244.0812.
15. Wu, H.; Zhang, P.; Shen, Y.; Zhang, F. R.; Wan, Y.; Shi, D. Q. Synlett 2007, 336–338.
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Ma, R.; Yue, C. H. J. Heterocycl. Chem. 2009, 46, 702–707.
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4.5.5. 7-Chloro-3-(3-chloro-4-fluorophenyl)-6-fluoro-3,4-dihydro-
quinazoline (13e). dH (400 MHz, DMSO-d6) 7.38 (s, 1H, ]CH),