Synthesis of 2-amino-3,4-dihydroquinazolines and imidazo[2,1-b]quinazoline- 2-ones

Article abstract of DOI:10.1055/s-0029-1217603

A straightforward method for the synthesis of 2-amino-3,4- dihydroquinazolines from Baylis-Hillman derivatives is disclosed. The protocol involves sequential SN2 reaction of a primary amine on the Baylis-Hillman acetate derived from 2-nitrobenzaldehyde, c

Full text of DOI:10.1055/s-0029-1217603

PAPER
3077
Synthesis of 2-Amino-3,4-dihydroquinazolines and
Imidazo[2,1-b]quinazoline-2-ones1
S
ynthesis of 2-A
m
m
ino-3,4-dihydroquin
i
azoline
t
s
a Mishra, Sanjay Batra*
Medicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
Fax +91(522)2623405; E-mail: batra_san@yahoo.co.uk
Received 5 May 2009
thesis of imidazo[2,1-b]quinazoline-2-ones which are
component units of hypotensive, ionotropic, antimetastat-
ic and hypoglycemic agents.5 Various 2-amino-3,4-dihy-
droquinazolines are reported to display pharmacological
Abstract: A straightforward method for the synthesis of 2-amino-
3,4-dihydroquinazolines from Baylis–Hillman derivatives is dis-
closed. The protocol involves sequential SN2 reaction of a primary
amine on the Baylis–Hillman acetate derived from 2-nitrobenzalde-
hyde, cyanogen bromide-mediated nitrile addition, and iron–acetic properties,6 and numerous strategies are available for their
preparation.7 Notably, these derivatives are either unsub-
acid promoted reductive cyclization. This approach is also applied
to the preparation of imidazo[2,1-b]quinazoline-2-ones and imida-
zo[2,1-b]quinazolines in one pot.
stituted at C-4, or possess an aromatic group or a carbonyl
moiety at this position. An approach using Baylis–
Hillman chemistry would provide a new method to obtain
2-aminoquinazolines bearing a vinyl chain at C-4 which
Key words: quinazoline, anagrelide, Baylis–Hillman, imidazo[2,1-
b]quinazoline, allyl amine
may serve as a handle for further synthetic modifications.
This investigation commenced with the synthesis of
As part of our program to develop heterocyclic systems of
Baylis–Hillman adducts 1–4 starting from 2-nitrobenzal-
biological relevance from Baylis–Hillman derivatives,2
dehydes following a standard procedure.2c Conversion of
we recently reported a general protocol for obtaining py-
1–4 into the corresponding acetates 5–8 was achieved us-
rimido[2,1-b]quinazolines from primary allyl amines pre-
ing acetyl chloride in the presence of pyridine. The SN2 re-
pared from Baylis–Hillman acetates.3 In continuation of
action of compound 5 with benzylamine in the presence of
this work, we have extended this methodology to the syn-
1,4-diazabicylo[2.2.2]octane under aqueous conditions
thesis of substituted imidazo[2,1-b]quinazoline-2-ones;
gave the required allyl amine 9a in 71% yield. Treatment
this particular framework is found in the drug,
of 9a with cyanogen bromide and sodium bicarbonate in
anagrelide.4 The retrosynthesis shown in Scheme 1 pro-
methanol at room temperature for 48 hours resulted in the
vides the basis for our work in this direction. Cleavage of
formation of the cyanamide derivative 13a in 81% yield
the imidazole ring leads to 2-aminoquinazoline I which in
(Scheme 2). Next, following optimization of the reaction
turn can be generated from the cyanamide II. Intermediate
conditions, reductive cyclization of cyanamide 13a was
II can be obtained from the allyl amine III, itself prepared
accomplished using a mixture of iron powder and acetic
via an SN2¢–SN2¢ displacement reaction (SN2 reaction) of
acid with heating at 95 °C for 20 minutes to afford the de-
a primary amine with the Baylis–Hillman acetate V.
sired 2-aminoquinazoline 17a. This protocol was general
in nature and 2-aminoquinazolines 17b–e and 18a,b were
obtained in moderate to good yields from amines 9b–e
A survey of the literature revealed that substituted 2-ami-
noquinazolines have been used as precursors for the syn-
EWG
EWG
EWG
N
N
CO2Me
NH2
N
CO2Me
O
CN
N
N
N
NO2
H
II
imidazo[2,1-b]quinazolin-2-one
(anagrelide framework)
I
EWG
EWG
EWG
N
CO2Me
N
H
CO2Me
OAc
NO2
H
NO2
NO2
IV
V
III
Scheme 1 Retrosynthesis of imidazo[2,1-b]quinazoline-2-ones
SYNTHESIS 2009, No. 18, pp 3077–3088
x
x.
x
x
.
2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217603; Art ID: P06809SS
© Georg Thieme Verlag Stuttgart · New York

3078
A. Mishra, S. Batra
PAPER
NO2 NHR1
NO2 OAc
NO2 OH
EWG
EWG
EWG
ii
i
R
R
R
9a–e
10a,b
11a–d
12a
1–4
5–8
R1
NH2
NO2
N
CN
R1
a R1 = Bn
N
N
EWG
iv
iii
b R1 = c-Hex
c R1 = c-Pr
d R1 = n-Pr
e R1 = s-Bu
EWG
R
R
13a–e
17a–e
18a,b
19a,d
20a
14a,b
15a–d
16a
Scheme 2 Reagents and conditions: (i) AcCl, py, CH2Cl2, 0 °C, 30 min; (ii) R1NH2, DABCO, THF–H2O (1:1), 2 h; (iii) CNBr, NaHCO3,
MeOH, r.t., 40–48 h (EWG = CN), 6–7 h (EWG = CO2Me); (iv) Fe–AcOH, 95 °C, 20 min.
and 10a,b (Table 1). Acetates 7 and 8, obtained from ad- Having established efficient conditions for the synthesis
ducts 3 and 4, were converted into allyl amines 11a–d and of 2-aminoquinazolines, we next turned our attention to-
12a in good yields. Interestingly, and unlike cyanamides wards the synthesis of imidazo[2,1-b]quinazoline-2-ones.
13a–e and 14a,b, cyanamides 15a–d and 16a were ob- Consequently, secondary allyl amines 9f–12f were pre-
tained in only six to seven hours. Reduction of the nitro pared by reaction between Baylis–Hillman acetates 5–8
group in 15b–d and 16a in the presence of iron–acetic and methyl glycinate (Scheme 3).8 Applying the opti-
acid followed by cyclization produced the corresponding mized conditions, these amines were initially converted
2-aminoquinazolines 19b–d and 20a. In contrast, cyan- into cyanamides 13f–16f by reaction with cyanogen bro-
amide 15a did not undergo neat transformation in the mide. Reduction of the aromatic nitro group with iron–
presence of iron–acetic acid. Fortunately, however, we acetic acid resulted in clean reactions leading to the de-
found that replacing acetic acid with hydrochloric acid sired products 21–24 in 55–60% yields. These products
gave 2-aminoquinazoline 19a in 60% yield.
were identified as imidazo[2,1-b]quinazoline-2-ones 21–
24 based on spectroscopic analyses These results indicate
CH2CO2Me
NO2 NHCH2CO2Me
EWG
NO2
N
CN
EWG
NO2 OAc
EWG
i
ii
R
R
R
9f–12f
5–8
13f–16f
EWG
N
iii
R
O
N
H
N
21–24
Scheme 3 Reagents and conditions: (i) methyl glycinate, DABCO, THF–H2O (1:1), 2 h; (ii) CNBr, NaHCO3, MeOH, r.t., 48 h (EWG = CN),
5 h (EWG = CO2Me); (iii) Fe–AcOH, 95 °C, 20 min.
CH2CH(OMe)2
NO2 NHCH2CH(OMe)2
NO2
N
CN
EWG
NO2 OAc
EWG
ii
EWG
i
R
R
R
9g,11g
13g,15g
5,7
NH2
N
EWG
N
CH2CH(OMe)2
EWG
iii
N
R
R
N
H
N
17g,19g
25,26
Scheme 4 Reagents and conditions: (i) 2,2-dimethoxyethanamine, DABCO, THF–H2O (1:1), 2 h; (ii) CNBr, NaHCO3, MeOH, r.t., 42 h
(EWG = CN), 6 h (EWG = CO2Me); (iii) a) Fe–AcOH, 95 °C, 20 min; b) AcOH–HCl, 100 °C, 30 min.
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,4-dihydroquinazolines
3079
Table 1 Structures and Yields of Intermediates and Products
(continued)
that reduction of the nitro group triggered a cascade reac-
tion to afford the final products.
Compound R
EWG
R1
Yield
(%)
Table 1 Structures and Yields of Intermediates and Products
15g
16a
16f
17a
17b
17c
17d
17e
17g
18a
18b
19a
19b
19c
19d
19g
20a
21
H
CO2Me
CO2Me
CO2Me
CN
CH2CH(OMe)2
CH2Ph
83
75
57
53
66
67
60
61
65
55
66
60a
58
60
60
60
56
55
60
55
53
72
65
Compound R
EWG
R1
Yield
(%)
4,5-(MeO)2
9a
H
CN
CH2Ph
71
70
80
87
63
60
81
71
64
64
65
70
75
70
68
71
82
61
81
88
73
77
63
70
72
80
70
80
94
82
96
87
71
4,5-(MeO)2
CH2CO2Me
CH2Ph
9b
H
CN
cyclohexyl
cyclopropyl
nPr
H
9c
H
CN
H
CN
cyclohexyl
cyclopropyl
nPr
9d
H
CN
H
CN
9e
H
CN
CH(CH3)Et
CH2CO2Me
CH2CH(OMe)2
CH2Ph
H
CN
9f
H
CN
H
CN
CH(CH3)Et
CH2CH(OMe)2
CH2Ph
9g
H
CN
H
CN
10a
10b
10f
11a
11b
11c
11d
11f
11g
12a
12f
13a
13b
13c
13d
13e
13f
13g
14a
14b
14f
15a
15b
15c
15d
15f
4,5-(MeO)2
CN
6,7-(MeO)2
CN
4,5-(MeO)2
CN
cyclohexyl
CH2CO2Me
CH2Ph
6,7-(MeO)2
CN
cyclohexyl
CH2Ph
4,5-(MeO)2
CN
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
H
cyclohexyl
cyclopropyl
nPr
H
cyclohexyl
cyclopropyl
nPr
H
H
H
H
H
CH2CH(OMe)2
CH2Ph
H
CH2CO2Me
CH2CH(OMe)2
CH2Ph
6,7-(MeO)2
H
H
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CH(OMe)2
CH2CH(OMe)2
4,5-(MeO)2
22
7,8-(OMe)2
CN
4,5-(MeO)2
CH2CO2Me
CH2Ph
23
H
CO2Me
CO2Me
CN
H
24
7,8-(OMe)2
H
CN
cyclohexyl
cyclopropyl
nPr
25
H
H
H
CN
26
CO2Me
a Fe–HCl used instead of Fe–AcOH.
H
CN
H
CN
CH(CH3)Et
CH2CO2Me
CH2CH(OMe)2
CH2Ph
These results encouraged us to investigate the utility of
the strategy further. In principle, installing an amino acet-
aldehyde dimethyl acetal as the amine component, under
similar reaction conditions, should result in imidazo[2,1-
b]quinazolines as the products. Thus, amine 9g (prepared
from 5) was transformed into the cyanamide 13g in 72%
yield. Iron–acetic acid-promoted reduction of the aromat-
ic nitro group gave the expected product 17g in 65% yield.
This result indicated that acetic acid was inefficient in un-
masking the formyl group for further reaction. In a modi-
fied protocol, instead of isolating 17g, concentrated
hydrochloric acid was added to the reaction mixture in the
same pot to afford the desired product 25 in 72% yield. To
demonstrate the general nature of this protocol cyanamide
15g was prepared from 11g and then subjected to the same
sequence of reactions to furnish methyl 2-(1,5-dihydroim-
H
CN
H
CN
4,5-(MeO)2
CN
4,5-(MeO)2
CN
cyclohexyl
CH2CO2Me
CH2Ph
4,5-(MeO)2
CN
H
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
cyclohexyl
cyclopropyl
nPr
CH2CO2Me
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

3080
A. Mishra, S. Batra
PAPER
MS (ES+): m/z = 286.1 (M+ + 1).
idazo[2,1-b]quinazolin-5-yl)acrylate (26) in 65% yield
(Scheme 4).
Anal. Calcd for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C,
67.63; H, 6.43; N, 14.92.
In summary, we have demonstrated a straightforward ap-
proach for the preparation of 4-vinyl-3,4-dihydro-2-ami-
noquinazolines which has been extended to the one-pot
synthesis of substituted imidazo[2,1-b]quinazoline-2-
ones and imidazo[2,1-b]quinazolines. The synthesis of a
range of polycyclic quinazolines should be possible fol-
lowing this strategy by simple variation of the amine com-
ponent.
2-[(Cyclopropylamino)(2-nitrophenyl)methyl]acrylonitrile (9c)
Brown oil; yield: 1.50 g (80%); Rf = 0.61 (EtOAc–hexanes, 1:4).
IR (neat): 3426 (NH), 2226 (CN) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.37–0.53 (m, 4 H, 2 × CH2),
2.04–2.12 (m, 1 H, CH), 5.15 (s, 1 H, CH), 6.06 (s, 1 H, =CH2), 6.08
(s, 1 H, =CH2), 7.48 (t, J = 7.8 Hz, 1 H, ArH), 7.66 (t, J = 7.5 Hz, 1
H, ArH), 7.73 (d, J = 7.7 Hz, 1 H, ArH), 7.88 (d, J = 8.1 Hz, 1 H,
ArH).
13C NMR (CDCl3, 50 MHz): d = 6.6, 7.5, 29.3, 60.7, 117.6, 125.0,
Melting points were determined in capillary tubes using a Precision
melting point apparatus containing silicon oil and are uncorrected.
Column chromatography was carried out using silica gel (Spectro-
chem India, 100–200 mesh). IR spectra were obtained using a Per-
kin Elmer RX I FTIR spectrophotometer. 1H and 13C NMR spectra
were recorded on a Bruker DPX-200 FT or a Bruker Avance DRX-
300 spectrometer. Chemical shifts are expressed in d values (ppm)
relative to TMS (0.00 ppm) as internal standard. MS data were re-
corded on a MICROMASS Quadro-II LCMS system. HRMS spec-
tra were recorded on a JEOL system. Elemental analyses were run
using a Carlo Erba 108 or an Elementar Vario EL III microanalyzer.
125.2, 129.3, 129.5, 132.6, 133.7, 134.4, 149.7.
MS (ES+): m/z = 244.0 (M+ + 1).
Anal. Calcd for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C,
64.38; H, 5.72; N, 17.11.
2-[(2-Nitrophenyl)(propylamino)methyl]acrylonitrile (9d)
Yellow oil; yield: 1.30 g (87%); Rf = 0.71 (EtOAc–hexanes, 1:4).
IR (neat): 3428 (NH), 2200 (CN) cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.93 (t, J = 7.4 Hz, 3 H, CH3),
1.43–1.61 (m, 2 H, CH2), 2.41–2.65 (m, 2 H, CH2), 5.02 (s, 1 H,
CH), 6.08 (s, 1 H, =CH2), 6.10 (d, J = 0.8 Hz, 1 H, =CH2), 7.48 (dt,
J1 = 8.5 Hz, J2 = 1.5 Hz, 1 H, ArH), 7.67 (dt, J1 = 7.6 Hz, J2 = 1.3
Hz, 1 H, ArH), 7.87 (dt, J1 = 7.5 Hz, J2 = 1.4 Hz, 2 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 12.1, 23.5, 50.0, 50.8, 117.5,
125.5, 129.5, 130.4, 132.7, 133.9, 134.7, 141.2.
Allyl Amines 9a–g, 10a,b,f, 11a–d,f,g and 12a,f; Typical Proce-
dure
To a soln of Baylis–Hillman acetate 5 (2.00 g, 8.13 mmol) in a mix-
ture of THF–H2O (30 mL, 1:1, v/v) was added DABCO (1.37 g,
12.20 mmol) and the reaction mixture was stirred for 15 min at r.t.
Benzylamine (0.98 mL, 8.94 mmol) was added and the reaction was
stirred for a further 2 h. After completion of the reaction (as indicat-
ed by TLC), the solvent was evaporated under vacuum and the aq
residue was extracted with EtOAc (3 × 30 mL). The organic layers
were combined, washed with brine (50 mL), dried over Na2SO4 and
concentrated to yield the crude product. Purification via silica gel
column chromatography (EtOAc–hexanes, 1:9) afforded 9a as a
brown oil; yield: 1.70 g (71%).
MS (ES+): m/z = 246.2 (M+ + 1).
Anal. Calcd for C13H15N3O2: C, 63.66; H, 6.16; N, 17.13. Found: C,
63.69; H, 5.89; N, 17.48.
2-[(sec-Butylamino)(2-nitrophenyl)methyl]acrylonitrile (9e)
Brown oil (1:1 mixture of diastereoisomers); yield: 1.00 g (63%);
Rf = 0.68 (EtOAc–hexanes, 3:17).
IR (neat): 3452 (NH), 2223 (CN) cm–1.
2-[(Benzylamino)(2-nitrophenyl)methyl]acrylonitrile (9a)
Rf = 0.53 (EtOAc–hexanes, 1:4).
IR (neat): 3430 (NH), 2220 (CN) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.75 (d, J = 1.6 Hz, 2 H, CH2),
5.09 (s, 1 H, CH), 6.12 (s, 1 H, =CH2), 6.13 (d, J = 0.8 Hz, 1
H, =CH2), 7.27–7.35 (m, 5 H, ArH), 7.46–7.54 (m, 1 H, ArH), 7.69
(dt, J1 = 7.6 Hz, J2 = 1.3 Hz, 1 H, ArH), 7.90 (s, 1 H, ArH), 7.94 (s,
1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 52.1, 59.7, 117.4, 124.8, 125.3,
127.9, 128.6, 129.0, 129.6, 129.7, 133.1, 134.0, 134.1, 139.2.
1H NMR (CDCl3, 300 MHz): d = 0.86 (t, J = 7.4 Hz, 3 H, CH3), 0.93
(t, J = 7.4 Hz, 3 H, CH3), 1.01 (d, J = 6.3 Hz, 3 H, CH3), 1.06 (d,
J = 6.3 Hz, 3 H, CH3), 1.24–1.51 (m, 4 H, 2 × CH2), 2.46–2.56 (m,
2 H, 2 × CH), 5.20–5.21 (m, 2 H, 2 × CH), 6.02–6.04 (m, 4 H,
2 × =CH2), 7.45–7.50 (m, 2 H, 2 × ArH), 7.67 (t, J = 7.7 Hz, 2 H,
2 × ArH), 7.86 (d, J = 1.6 Hz, 2 H, 2 × ArH), 7.88 (s, 2 H, 2 × ArH).
13C NMR (CDCl3, 50 MHz): d = 10.4, 10.5, 20.0, 20.4, 29.9, 30.2,
52.3, 52.5, 57.27, 57.33, 117.5, 125.1 (2C), 125.5, 125.8, 129.4,
129.5, 129.6, 132.1, 132.4, 133.7, 134.8.
MS (ES+): m/z = 260.1 (M+ + 1).
MS (ES+): m/z = 294.1 (M+ + 1).
Anal. Calcd for C14H17N3O2: C, 64.85; H, 6.61; N, 16.20. Found: C,
65.02; H, 6.85; N, 15.94.
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C,
69.82; H, 4.89; N, 14.67.
Methyl N-[2-Cyano-1-(2-nitrophenyl)prop-2-en-1-yl]glycinate
(9f)
White solid; yield: 1.00 g (60%); mp 122–123 °C; Rf = 0.45
(EtOAc–hexanes, 1:4).
2-[(Cyclohexylamino)(2-nitrophenyl)methyl]acrylonitrile (9b)
Brown oil; yield: 1.60 g (70%); Rf = 0.61 (EtOAc–hexanes, 1:4).
IR (neat): 3428 (NH), 2226 (CN) cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.03–1.25 (m, 6 H, 3 × CH2),
1.70–1.90 (m, 4 H, 2 × CH2), 2.37–2.41 (m, 1 H, CH), 5.25 (s, 1 H,
CH), 6.01 (d, J = 0.8 Hz, 1 H, =CH2), 6.04 (s, 1 H, =CH2), 7.45–
7.50 (m, 1 H, ArH), 7.66 (dt, J1 = 7.6 Hz, J2 = 1.2 Hz, 1 H, ArH),
7.86 (dt, J1 = 8.7 Hz, J2 = 1.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 25.2, 26.4, 33.9, 50.1, 117.0,
125.5, 129.4, 130.7, 131.4, 132.2, 133.7, 134.5, 140.9, 147.6.
IR (KBr): 3491 (NH), 2228 (CN), 1727 (CO2CH3) cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.39 (s, 2 H, CH2), 3.73 (s, 3 H,
OCH3), 5.13 (s, 1 H, CH), 6.09 (s, 1 H, =CH2), 6.17 (d, J = 0.4 Hz,
1 H, =CH2), 7.49–7.53 (m, 1 H, ArH), 7.68–7.72 (m, 1 H, ArH),
7.91–7.96 (m, 2 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 48.6, 52.5, 59.4, 117.1, 124.4,
125.3, 129.6, 129.9, 133.4, 134.1, 149.7, 172.2.
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,4-dihydroquinazolines
3081
MS (ES+): m/z = 276.0 (M+ + 1).
Anal. Calcd for C15H17N3O6: C, 53.73; H, 5.11; N, 12.53. Found: C,
53.78; H, 5.24; N, 12.46.
Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N, 15.27. Found: C,
56.97; H, 4.58; N, 15.58.
Methyl 2-[(Benzylamino)(2-nitrophenyl)methyl]acrylate (11a)
Brown oil; yield: 1.30 g (65%); Rf = 0.53 (EtOAc–hexanes, 3:17).
IR (neat): 3426 (NH), 1710 (CO2CH3) cm–1.
2-{[(2,2-Dimethoxyethyl)amino](2-nitrophenyl)methyl}acry-
lonitrile (9g)
Brown oil; yield: 2.50 g (81%); Rf = 0.21 (EtOAc–hexanes, 1:4).
IR (neat): 3414 (NH), 2218 (CN) cm–1.
1H NMR (CDCl3, 300 MHz): d = 2.61–2.76 (m, 2 H, CH2), 3.36 (s,
3 H, OCH3), 3.38 (s, 3 H, OCH3), 4.47 (t, J = 5.3 Hz, 1 H, CH), 5.08
(s, 1 H, CH), 6.09 (s, 1 H, =CH2), 6.12 (s, 1 H, =CH2), 7.47–7.52
(m, 1 H, ArH), 7.66–7.71 (m, 1 H, ArH), 7.84–7.92 (m, 2 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 55.0, 55.6, 57.8, 105.1, 114.4,
117.6, 125.5, 130.3, 131.0, 131.5, 134.7, 143.1, 147.6.
MS (ES+): m/z = 292.1 (M+ + 1).
1H NMR (CDCl3, 200 MHz): d = 3.67 (s, 3 H, OCH3), 3.75–3.86
(m, 2 H, CH2), 5.34 (s, 1 H, CH), 5.97 (s, 1 H, =CH2), 6.44 (s, 1
H, =CH2), 7.28–7.34 (m, 5 H, ArH), 7.40–7.44 (m, 1 H, ArH), 7.53–
7.61 (m, 1 H, ArH), 7.71–7.75 (m, 1 H, ArH), 7.79–7.83 (m, 1 H,
ArH).
13C NMR (CDCl3, 50 MHz): d = 52.4, 52.8, 57.7, 124.7, 125.2,
127.1, 127.6, 128.6, 128.7, 128.9, 129.9, 132.0, 136.4, 139.0, 140.2,
141.0, 166.8.
MS (ES+): m/z = 327.2 (M+ + 1).
Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C,
66.34; H, 5.23; N, 8.87.
Anal. Calcd for C14H17N3O4: C, 57.72; H, 5.88; N, 14.42. Found: C,
58.02; H, 5.68; N, 14.74.
Methyl 2-[(Cyclohexylamino)(2-nitrophenyl)methyl]acrylate
(11b)
Brown oil; yield: 1.60 g (70%); Rf = 0.63 (EtOAc–hexanes, 1:4).
IR (neat): 3427 (NH), 1726 (CO2CH3) cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.05–1.21 (m, 6 H, 3 × CH2), 1.55
(br s, 4 H, 2 × CH2), 2.32–2.45 (m, 1 H, CH), 3.68 (s, 3 H, OCH3),
5.45 (s, 1 H, CH), 5.79 (s, 1 H, =CH2), 6.35 (s, 1 H, =CH2), 7.37 (t,
J = 7.7 Hz, 1 H, ArH), 7.55 (t, J = 7.5 Hz, 1 H, ArH), 7.72 (d,
J = 7.8 Hz, 1 H, ArH), 7.79 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 25.2, 26.5, 33.6, 43.5, 52.7, 56.3,
125.2, 129.6, 131.6, 132.2, 132.5, 133.9, 138.6, 148.0, 168.1.
2-[(Benzylamino)(4,5-dimethoxy-2-nitrophenyl)methyl]acry-
lonitrile (10a)
Yellow oil; yield: 1.23 g (71%); Rf = 0.51 (EtOAc–hexanes, 1:4).
IR (neat): 3428 (NH), 2200 (CN) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.74 (d, J = 2.3 Hz, 2 H, CH2),
3.96 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 5.28 (d, J = 5.6 Hz, 1 H,
CH), 6.06 (s, 1 H, =CH2), 6.15 (d, J = 0.7 Hz, 1 H, =CH2), 7.29–
7.35 (m, 5 H, ArH), 7.50 (s, 1 H, ArH), 7.58 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 52.0, 56.8, 57.0, 59.6, 108.7,
110.0, 110.9, 117.7, 125.0, 127.9, 128.6, 129.0, 129.2, 132.9, 139.3,
141.8, 148.9, 154.0.
MS (ES+): m/z = 319.2 (M+ + 1).
MS (ES+): m/z = 354.0 (M+ + 1).
Anal. Calcd for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C,
63.92; H, 7.33; N, 8.60.
Anal. Calcd for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89. Found: C,
64.86; H, 5.34; N, 11.66.
Methyl 2-[(Cyclopropylamino)(2-nitrophenyl)methyl]acrylate
(11c)
Brown oil; yield: 1.49 g (75%); Rf = 0.55 (EtOAc–hexanes, 1:4).
IR (neat): 3414 (NH), 1758 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.32–0.46 (m, 4 H, 2 × CH2),
2.16–2.21 (m, 1 H, CH), 3.68 (s, 3 H, OCH3), 5.40 (s, 1 H, CH), 5.79
(t, J = 1.1 Hz, 1 H, =CH2), 6.38 (t, J = 0.7 Hz, 1 H, =CH2), 7.35–
7.42 (m, 1 H, ArH), 7.50–7.63 (m, 2 H, ArH), 7.79 (dd, J1 = 7.2 Hz,
J2 = 1.4 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 7.0, 29.8, 52.4, 58.2, 124.7, 126.7,
128.4, 129.7, 132.8, 136.7, 141.3, 150.2, 166.8.
2-[(Cyclohexylamino)(4,5-dimethoxy-2-nitrophenyl)meth-
yl]acrylonitrile (10b)
Brown oil; yield: 1.45 g (64%); Rf = 0.25 (EtOAc–hexanes, 1:4).
IR (neat): 3428 (NH), 2200 (CN) cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.09–1.23 (m, 6 H, 3 × CH2),
1.68–1.81 (m, 4 H, 2 × CH2), 2.35–2.42 (m, 1 H, CH), 3.97 (s, 3 H,
OCH3), 4.03 (s, 3 H, OCH3), 5.47 (s, 1 H, CH), 5.99 (s, 1 H, =CH2),
6.05 (s, 1 H, =CH2), 7.51 (s, 1 H, ArH), 7.59 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 25.2, 29.8, 30.1, 32.3, 56.9, 57.2,
112.7, 119.6, 128.8, 129.1, 130.5, 133.6, 136.2, 139.1, 146.2.
MS (ES+): m/z = 346.0 (M+ + 1).
MS (ES+): m/z = 277.1 (M+ + 1).
Anal. Calcd for C18H23N3O4: C, 62.59; H, 6.71; N, 12.17. Found: C,
62.78; H, 6.66; N, 12.10.
Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
61.26; H, 5.96; N, 9.89.
Methyl N-[2-Cyano-1-(4,5-dimethoxy-2-nitrophenyl)prop-2-
en-1-yl]glycinate (10f)
Brown oil; yield: 0.70 g (64%); Rf = 0.21 (EtOAc–hexanes, 1:4).
IR (neat): 3428 (NH), 2220 (CN), 1716 (CO2CH3) cm–1.
Methyl 2-[(2-Nitrophenyl)(propylamino)methyl]acrylate (11d)
Brown oil; yield: 1.39 g (70%); Rf = 0.47 (EtOAc–hexanes, 3:17).
IR (neat): 3425 (NH), 1716 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.92 (t, J = 7.3 Hz, 3 H, CH3),
1.46–1.60 (m, 2 H, CH2), 2.43–2.64 (m, 2 H, CH2), 3.66 (s, 3 H,
OCH3), 5.21 (s, 1 H, CH), 5.89 (s, 1 H, =CH2), 6.40 (s, 1 H, =CH2),
7.34–7.42 (m, 1 H, ArH), 7.55 (dt, J1 = 7.9 Hz, J2 = 1.2 Hz, 1 H,
ArH), 7.65 (dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1 H, ArH), 7.80 (dd,
J1 = 8.0 Hz, J2 = 1.2 Hz, 1 H, ArH).
1H NMR (CDCl3, 200 MHz): d = 3.38 (s, 2 H, CH2), 3.74 (s, 3 H,
OCH3), 3.96 (s, 3 H, OCH3), 4.02 (s, 3 H, OCH3), 5.32 (s, 1 H, CH),
6.07 (s, 1 H, =CH2), 6.21 (s, 1 H, =CH2), 7.50 (s, 1 H, ArH), 7.58 (s,
1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 48.1, 52.1, 56.4, 56.7, 58.9, 110.3,
117.0, 124.0, 128.1, 130.0, 133.1, 141.3, 148.6, 153.6, 172.0.
13C NMR (CDCl3, 50 MHz): d = 12.0, 23.7, 50.5, 52.3, 57.7, 124.6,
126.7, 128.4, 129.8, 133.0, 136.7, 141.3, 150.2, 166.8.
MS (ES+): m/z = 336.0 (M+ + 1).
MS (ES+): m/z = 279.1 (M+ + 1).
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

3082
A. Mishra, S. Batra
PAPER
Anal. Calcd for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07. Found: C,
60.63; H, 6.85; N, 9.89.
MS (ES+): m/z = 369.0 (M+ + 1).
Anal. Calcd for C16H20N2O8: C, 52.17; H, 5.47; N, 7.61. Found: C,
52.07; H, 5.24; N, 7.85.
Methyl 2-{[(2-Methoxy-2-oxoethyl)amino](2-nitrophe-
nyl)methyl}acrylate (11f)
Brown oil; yield: 1.50 g (68%); Rf = 0.32 (EtOAc–hexanes, 1:4).
IR (neat): 3430 (NH), 1726 (CO2CH3) cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.35–3.48 (m, 2 H, CH2), 3.64 (s,
3 H, OCH3), 3.74 (s, 3 H, OCH3), 5.31 (s, 1 H, CH), 5.99 (s, 1
H, =CH2), 6.42 (s, 1 H, =CH2), 7.37–7.42 (m, 1 H, ArH), 7.56 (t,
J = 7.6 Hz, 1 H, ArH), 7.65 (d, J = 7.9 Hz, 1 H, ArH), 7.79 (d,
J = 8.0 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 49.3, 52.3, 52.4, 56.3, 124.6,
126.4, 128.8, 130.0, 133.2, 135.6, 141.3, 150.5, 166.3, 172.7.
Cyanamides 13a–g, 14a,b,f, 15a–d,f,g and 16a,f; Typical Proce-
dure
To a soln of compound 9a (1.50 g, 5.12 mmol) in MeOH (20 mL)
were added CNBr (0.65 g, 6.14 mmol) and NaHCO3 (0.52 g, 6.14
mmol) and the reaction was allowed to stir at r.t. for 48 h. After
completion of the reaction, MeOH was removed and the residue
was dissolved in EtOAc (40 mL) and H2O (40 mL). The aq layer
was separated and extracted with EtOAc (4 × 20 mL). The com-
bined organic layer was dried over Na2SO4 and concentrated to af-
ford a crude product which was purified by column chromatography
on silica gel (EtOAc–hexanes, 1:3) to give pure compound 13a as
yellow oil; yield: 1.32 g (81%).
MS (ES+): m/z = 309.1 (M+ + 1).
Anal. Calcd for C14H16N2O6: C, 54.54; H, 5.23; N, 9.09. Found: C,
54.31; H, 5.58; N, 9.23.
Benzyl[2-cyano-1-(2-nitrophenyl)prop-2-en-1-yl]cyanamide
(13a)
Rf = 0.43 (EtOAc–hexanes, 1:4).
IR (neat): 2200 (CN) cm–1.
Methyl 2-{[(2,2-Dimethoxyethyl)amino](2-nitrophenyl)meth-
yl}acrylate (11g)
1H NMR (CDCl3, 200 MHz): d = 4.23 (d, J = 14.0 Hz, 1 H, CH2),
4.41 (d, J = 13.7 Hz, 1 H, CH2), 5.59 (s, 1 H, CH), 5.91 (s, 1
H, =CH2), 6.27 (s, 1 H, =CH2), 7.27–7.38 (m, 5 H, ArH), 7.63 (t,
J = 7.5 Hz, 1 H, ArH), 7.79 (t, J = 7.5 Hz, 1 H, ArH), 7.85 (d,
J = 7.5 Hz, 1 H, ArH), 8.09 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 34.4, 62.1, 114.3, 116.8, 120.9,
126.5, 129.5, 129.7, 131.3, 134.75, 134.78, 148.8.
Brown oil; yield: 1.65 g (71%); Rf = 0.30 (EtOAc–hexanes, 1:4).
IR (neat): 3449 (NH), 1717 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 2.64–2.84 (m, 2 H, CH2), 3.35 (s,
3 H, OCH3), 3.37 (s, 3 H, OCH3), 3.66 (s, 3 H, OCH3), 4.50 (t,
J = 5.4 Hz, 1 H, CH), 5.26 (s, 1 H, CH), 5.93 (t, J = 1.2 Hz, 1
H, =CH2), 6.41 (t, J = 0.8 Hz, 1 H, =CH2), 7.34–7.43 (m, 1 H, ArH),
7.51–7.66 (m, 2 H, ArH), 7.81 (dd, J1 = 8.0 Hz, J2 = 1.4 Hz, 1 H,
ArH).
13C NMR (CDCl3, 50 MHz): d = 49.6, 52.4, 54.0, 54.3, 57.2, 103.9,
124.7, 126.8, 128.6, 129.8, 133.1, 136.3, 141.1, 150.3, 166.7.
MS (ES+): m/z = 325.0 (M+ + 1).
MS (ES+): m/z = 319.1 (M+ + 1).
Anal. Calcd for C18H14N4O2: C, 67.91; H, 4.43; N, 17.60. Found: C,
68.28; H, 4.78; N, 17.89.
[2-Cyano-1-(2-nitrophenyl)prop-2-en-1-yl]cyclohexylcyan-
amide (13b)
White solid; yield: 0.70 g (88%); mp 107–109 °C; Rf = 0.31
Anal. Calcd for C15H20N2O6: C, 55.55; H, 6.22; N, 8.64. Found: C,
55.60; H, 5.97; N, 8.89.
(EtOAc–hexanes, 1:4).
IR (KBr): 2211 (CN) cm–1.
Methyl 2-[(Benzylamino)(4,5-dimethoxy-2-nitrophenyl)meth-
yl]acrylate (12a)
1H NMR (CDCl3, 200 MHz): d = 1.18–1.31 (m, 4 H, 2 × CH2),
1.50–1.67 (m, 6 H, 3 × CH2), 2.08–2.98 (m, 1 H, CH), 5.74 (s, 1 H,
CH), 5.85 (s, 1 H, =CH2), 6.27 (s, 1 H, =CH2), 7.62–7.67 (m, 1 H,
ArH), 7.77–7.86 (m, 2 H, ArH), 8.13 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 25.3, 25.48, 25.51, 31.7, 31.8,
60.5, 61.6, 113.8, 116.8, 121.6, 126.4, 129.9, 130.5, 131.1, 134.8.
Yellow oil; yield: 1.40 g (82%); Rf = 0.58 (EtOAc–hexanes, 3:7).
IR (neat): 3429 (NH), 1716 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.68–3.80 (m, 5 H, CH2, OCH3),
3.94 (s, 6 H, 2 × OCH3), 5.48 (s, 1 H, CH), 5.79 (t, J = 1.1 Hz, 1
H, =CH2), 6.36 (d, J = 0.5 Hz, 1 H, =CH2), 7.29–7.35 (m, 6 H,
ArH), 7.54 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 30.1, 52.5, 53.1, 56.8, 57.9, 108.5,
111.3, 126.6, 127.6, 128.1, 128.6, 128.8, 128.9, 131.5, 140.3, 141.8,
142.2, 148.2, 153.4, 167.0.
MS (ES+): m/z = 311.1 (M+ + 1).
Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C,
65.97; H, 6.11; N, 17.71.
MS (ES+): m/z = 387.1 (M+ + 1).
[2-Cyano-1-(2-nitrophenyl)prop-2-en-1-yl]cyclopropylcyan-
amide (13c)
Yellow oil; yield: 1.21 g (73%); Rf = 0.31 (EtOAc–hexanes, 3:7).
Anal. Calcd for C20H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.52; H, 5.44; N, 7.45.
IR (neat): 2221 (CN) cm–1.
Methyl 2-{(4,5-Dimethoxy-2-nitrophenyl)[(2-methoxy-2-oxo-
ethyl)amino]methyl}acrylate (12f)
Yellow oil; yield: 1.00 g (61%); Rf = 0.50 (EtOAc–hexanes, 3:7).
IR (neat): 3445 (NH), 1736 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.33–3.52 (m, 2 H, CH2), 3.69 (s,
3 H, OCH3), 3.74 (s, 3 H, OCH3), 3.94 (s, 6 H, 2 × OCH3), 5.44 (s,
1 H, CH), 5.88 (t, J = 1.1 Hz, 1 H, =CH2), 6.37 (s, 1 H, =CH2), 7.17
(s, 1 H, ArH), 7.47 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 49.4, 52.3, 52.4, 56.6, 56.7, 56.8,
108.2, 111.0, 126.1, 130.3, 141.8, 142.5, 148.3, 153.3, 166.5, 172.7.
1H NMR (CDCl3, 200 MHz): d = 0.85–0.93 (m, 2 H, CH2), 0.95–
1.00 (m, 2 H, CH2), 2.78–2.83 (m, 1 H, CH), 5.73 (t, J = 1.2 Hz, 1
H, CH), 5.87–5.88 (m, 1 H, =CH2), 6.30 (t, J = 0.7 Hz, 1 H, =CH2),
7.66–7.70 (m, 1 H, ArH), 7.80 (d, J = 1.2 Hz, 1 H, ArH), 7.83 (d,
J = 0.9 Hz, 1 H, ArH), 8.13–8.17 (m, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 8.4, 8.8, 34.4, 62.1, 114.3, 116.8,
120.9, 126.5, 129.5, 129.7, 131.3, 134.8, 148.8.
MS (ES+): m/z = 269.1 (M+ + 1).
Anal. Calcd for C14H12N4O2: C, 62.68; H, 4.51; N, 20.88. Found: C,
62.87; H, 4.69; N, 20.52.
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,4-dihydroquinazolines
3083
[2-Cyano-1-(2-nitrophenyl)prop-2-en-1-yl]propylcyanamide
(13d)
Brown oil; yield: 1.04 g (77%); Rf = 0.30 (EtOAc–hexanes, 1:4).
IR (neat): 2215 (CN) cm–1.
MS (ES+): m/z = 317.0 (M+ + 1).
Anal. Calcd for C15H16N4O4: C, 56.96; H, 5.10; N, 17.71. Found: C,
57.28; H, 4.93; N, 17.45.
Benzyl[2-cyano-1-(4,5-dimethoxy-2-nitrophenyl)prop-2-en-1-
yl]cyanamide (14a)
Yellow solid; yield: 1.03 g (80%); mp 120–121 °C; Rf = 0.34
(EtOAc–hexanes, 2:3).
1H NMR (CDCl3, 200 MHz): d = 1.01 (t, J = 7.4 Hz, 3 H, CH3),
1.69–1.87 (m, 2 H, CH2), 3.01–3.23 (m, 2 H, CH2), 5.64 (s, 1 H,
CH), 5.99 (t, J = 0.6 Hz, 1 H, =CH2), 6.32 (s, 1 H, =CH2), 7.61–7.72
(m, 1 H, ArH), 7.77–7.82 (m, 2 H, ArH), 8.15 (d, J = 7.9 Hz, 1 H,
ArH).
IR (KBr): 2208 (CN) cm–1.
13C NMR (CDCl3, 50 MHz): d = 11.4, 21.6, 54.7, 61.9, 114.8,
1H NMR (CDCl3, 200 MHz): d = 3.98 (s, 3 H, OCH3), 3.99 (s, 3 H,
OCH3), 4.22–4.40 (m, 2 H, CH2), 5.74 (t, J = 1.1 Hz, 1 H, CH), 5.96
(d, J = 1.1 Hz, 1 H, =CH2), 6.25 (s, 1 H, =CH2), 7.21 (s, 1 H, ArH),
7.24–7.29 (m, 2 H, ArH), 7.35–7.39 (m, 3 H, ArH), 7.66 (s, 1 H,
ArH).
13C NMR (CDCl3, 50 MHz): d = 56.85, 56.94, 57.1, 60.5, 109.1,
110.7, 115.4, 116.6, 120.9, 123.9, 129.3, 129.5, 129.6, 133.4, 135.5,
141.3, 149.8, 154.1.
116.7, 120.9, 126.6, 129.6, 129.8, 131.3, 134.8, 135.0.
MS (ES+): m/z = 271.2 (M+ + 1).
Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C,
62.54; H, 4.98; N, 20.86.
sec-Butyl[2-cyano-1-(2-nitrophenyl)prop-2-en-1-yl]cyanamide
(13e)
Brown oil (1:1 mixture of diastereoisomers); yield: 1.04 g (63%);
Rf = 0.38 (EtOAc–hexanes, 3:17).
MS (ES+): m/z = 379.1 (M+ + 1).
Anal. Calcd for C20H18N4O4: C, 63.48; H, 4.79; N, 14.81. Found: C,
63.79; H, 4.58; N, 15.01.
IR (neat): 2212 (CN) cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.91 (t, J = 7.4 Hz, 3 H, CH3), 1.04
(t, J = 7.4 Hz, 3 H, CH3), 1.27 (d, J = 6.6 Hz, 3 H, CH3), 1.35 (d,
J = 6.5 Hz, 3 H, CH3), 1.58–1.98 (m, 4 H, 2 × CH2), 3.00–3.11 (m,
2 H, 2 × CH), 5.70–5.71 (m, 2 H, 2 × CH), 5.86–5.89 (m, 2 H,
2 × =CH2), 6.27–6.28 (m, 2 H, 2 × =CH2), 7.64–7.72 (m, 2 H,
2 × ArH), 7.80–7.90 (m, 4 H, 4 × ArH), 8.12 (dd, J1 = 8.1 Hz,
J2 = 1.2 Hz, 2 H, 2 × ArH).
13C NMR (CDCl3, 50 MHz): d = 10.5, 10.7, 18.2, 18.4, 28.0, 28.2,
59.8, 60.3, 60.5, 113.3, 116.4, 121.0, 121.2, 125.9, 129.4, 129.6,
130.1, 130.3, 130.7, 134.3, 134. 4, 134.8, 135.0, 148.1.
[2-Cyano-1-(4,5-dimethoxy-2-nitrophenyl)prop-2-en-1-yl]cy-
clohexylcyanamide (14b)
White solid; yield: 0.60 g (70%); mp 84–85 °C; Rf = 0.28 (EtOAc–
hexanes, 3:7).
IR (KBr): 2208 (CN) cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.22–1.37 (m, 4 H, 2 × CH2),
1.44–1.67 (m, 4 H, 2 × CH2), 1.85–2.07 (m, 2 H, CH2), 2.82–2.97
(m, 1 H, CH), 3.99 (s, 3 H, OCH3), 4.03 (s, 3 H, OCH3), 5.87 (s, 1
H, CH), 5.89 (s, 1 H, =CH2), 6.24 (s, 1 H, =CH2), 7.26 (s, 1 H, ArH),
7.72 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 25.3, 25.50, 25.54, 31.7, 31.8,
57.0, 57.2, 60.5, 61.4, 109.3, 110.9, 114.2, 117.0, 121.9, 125.3,
134.6, 140.9, 149.9, 154.2.
MS (ES+): m/z = 285.0 (M+ + 1).
Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C,
63.68; H, 5.48; N, 19.98.
Methyl N-Cyano-N-[2-cyano-1-(2-nitrophenyl)prop-2-en-1-
yl]glycinate (13f)
White solid; yield: 1.22 g (70%); mp 105–106 °C; Rf = 0.23
(EtOAc–hexanes, 1:4).
MS (ES+): m/z = 371.0 (M+ + 1).
Anal. Calcd for C19H22N4O4: C, 61.61; H, 5.99; N, 15.13. Found: C,
61.93; H, 5.87; N, 15.38.
IR (KBr): 2224 (CN), 1752 (CO2CH3) cm–1.
Methyl N-Cyano-N-[2-cyano-1-(4,5-dimethoxy-2-nitrophe-
nyl)prop-2-en-1-yl]glycinate (14f)
Brown oil; yield: 0.43 g (80%); Rf = 0.32 (EtOAc–hexanes 3:7).
IR (neat): 2224 (CN), 1753 (CO2Me) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.79 (s, 3 H, OCH3), 3.98 (s, 2 H,
CH2), 4.00 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 6.01 (s, 1 H, =CH),
6.32 (d, J = 1.2 Hz, 1 H, =CH2), 6.35 (s, 1 H, =CH2), 7.29 (s, 1 H,
ArH), 7.70 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 52.8, 53.3, 57.0, 57.3, 62.1, 109.3,
111.1, 114.6, 116.5, 120.4, 123.4, 136.6, 141.4, 150.1, 154.3, 168.0.
1H NMR (CDCl3, 300 MHz): d = 3.81 (s, 3 H, OCH3), 3.88–4.08
(m, 2 H, CH2), 5.88 (s, 1 H, CH), 6.31 (s, 1 H, =CH2), 6.39 (s, 1
H, =CH2), 7.67 (t, J = 7.5 Hz, 1 H, ArH), 7.81–7.89 (m, 2 H, ArH),
8.14 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 53.0, 53.4, 61.9, 116.2, 120.2,
126.5, 129.0, 130.0, 131.5, 134.8, 136.6, 167.8.
MS (ES+): m/z = 301.2 (M+ + 1).
Anal. Calcd for C14H12N4O4: C, 56.00; H, 4.03; N, 18.66. Found: C,
56.24; H, 3.87; N, 18.89.
MS (ES+): m/z = 361.1 (M+ + 1).
2-Cyano-1-(2-nitrophenyl)allyl(dimethoxymethyl)cyanamide
(13g)
Brown oil; yield: 1.80 g (72%); Rf = 0.25 (EtOAc–hexanes, 3:7).
Anal. Calcd for C16H16N4O6: C, 53.33; H, 4.48; N, 15.55. Found: C,
53.51; H, 4.78; N, 15.61.
IR (neat): 2217 (CN) cm–1.
Methyl 2-{[Benzyl(cyano)amino](2-nitrophenyl)methyl}acry-
late (15a)
1H NMR (CDCl3, 300 MHz): d = 3.15–3.22 (m, 1 H, CH2), 3.32–
3.38 (m, 4 H, OCH3, CHH), 3.44 (s, 3 H, OCH3), 4.55 (t, J = 4.9 Hz,
1 H, CH), 5.84 (s, 1 H, CH), 5.99 (s, 1 H, =CH2), 6.32 (s, 1 H,
=CH2), 7.61–7.67 (m, 1 H, ArH), 7.78–7.85 (m, 2 H, ArH), 8.13
(d, J = 8.0 Hz, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 53.5, 54.9, 55.3, 61.4, 102.6, 114.8,
116.3, 120.5, 125.9, 129.3, 129.5, 130.7, 134.3, 135.3, 148.4.
White solid; yield: 0.91 g (94%); mp 78–80 °C; Rf = 0.38 (EtOAc–
hexanes, 3:7).
IR (KBr): 2212 (CN), 1724 (CO2CH3) cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.78 (s, 3 H, OCH3), 4.31–4.42
(m, 2 H, CH2), 5.56 (s, 1 H, CH), 5.96 (s, 1 H, =CH2), 6.55 (s, 1 H,
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

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A. Mishra, S. Batra
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=CH2), 7.31 (s, 5 H, ArH), 7.52 (t, J = 7.6 Hz, 1 H, ArH), 7.68–7.75
(m, 2 H, ArH), 8.03 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 52.9, 57.7, 59.3, 116.0, 126.0,
129.2, 129.3, 129.5, 129.7, 129.86, 129.94, 132.6, 133.9, 134.0,
137.8, 148.3, 165.5.
IR (neat): 2220 (CN), 1726 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.73 (s, 3 H, OCH3), 3.80 (s, 3 H,
OCH3), 4.00–4.22 (m, 2 H, CH2), 5.67 (d, J = 0.9 Hz, 1 H, CH), 5.99
(s, 1 H, =CH2), 6.54 (s, 1 H, =CH2), 7.52–7.61 (m, 1 H, ArH), 7.76
(dt, J1 = 7.6 Hz, J2 = 1.3 Hz, 1 H, ArH), 7.92 (d, J = 6.9 Hz, 1 H,
ArH), 8.08 (dd, J1 = 8.1 Hz, J2 = 1.2 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 53.0, 54.5, 61.5, 115.3, 126.1,
129.4, 129.8, 130.2, 132.1, 134.3, 137.8, 148.2, 165.7, 168.4.
MS (ES+): m/z = 351.9 (M+ + 1).
Anal. Calcd for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96. Found: C,
65.24; H, 4.68; N, 12.25.
MS (ES+): m/z = 334.1 (M+ + 1).
Methyl 2-{[Cyano(cyclohexyl)amino](2-nitrophenyl)meth-
yl}acrylate (15b)
Yellow oil; yield: 0.80 g (82%); Rf = 0.50 (EtOAc–hexanes, 1:4).
Anal. Calcd for C15H15N3O6: C, 54.05; H, 4.54; N, 12.61. Found: C,
54.28; H, 4.89; N, 12.32.
IR (neat): 2207 (CN), 1722 (CO2CH3) cm–1.
Methyl 2-{[Cyano(dimethoxyethyl)amino](2-nitrophe-
nyl)methyl}acrylate (15g)
White solid; yield: 0.90 g (83%); mp 62–65 °C; Rf = 0.20 (EtOAc–
hexanes, 1:4).
IR (KBr): 2214 (CN), 1721 (CO2CH3) cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.28 (s, 3 H, OCH3), 3.32 (d,
J = 5.0 Hz, 1 H, CH2), 3.36–3.39 (m, 4 H, OCH3, CH2), 3.82 (s, 3
H, OCH3), 4.54 (t, J = 5.2 Hz, 1 H, CH), 5.56 (d, J = 1.1 Hz, 1 H,
CH), 5.99 (s, 1 H, =CH2), 6.54 (s, 1 H, =CH2), 7.52–7.58 (m, 1 H,
ArH), 7.74 (dt, J1 = 8.0 Hz, J2 = 1.2 Hz, 1 H, ArH), 7.80–7.83 (m, 1
H, ArH), 8.08 (dd, J1 = 8.2 Hz, J2 = 1.2 Hz, 1 H, ArH).
1H NMR (CDCl3, 200 MHz): d = 1.47–1.65 (m, 6 H, 3 × CH2),
1.79–1.91 (m, 4 H, 2 × CH2), 2.82–2.98 (m, 1 H, CH), 3.82 (s, 3 H,
OCH3), 5.51 (d, J = 1.1 Hz, 1 H, CH), 6.04 (s, 1 H, =CH2), 6.53 (s,
1 H, =CH2), 7.51–7.59 (m, 1 H, ArH), 7.69–7.83 (m, 2 H, ArH),
8.09 (dd, J1 = 8.1 Hz, J2 = 1.4 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 25.4, 25.5, 25.6, 31.6, 32.2, 53.0,
58.9, 61.6, 115.0, 126.2, 129.6, 129.9, 130.0, 133.7, 134.2, 138.5,
148.3, 165.7.
MS (ES+): m/z = 344.1 (M+ + 1).
Anal. Calcd for C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C,
62.67; H, 6.47; N, 12.50.
13C NMR (CDCl3, 50 MHz): d = 53.0, 54.6, 54.8, 54.9, 60.6, 102.4,
116.2, 126.1, 129.5, 129.7, 129.9, 133.0, 134.2, 138.0, 148.4, 165.7.
Methyl 2-{[Cyano(cyclopropyl)amino](2-nitrophenyl)meth-
yl}acrylate (15c)
Yellow solid; yield: 1.05 g (96%); mp 67–70 °C; Rf = 0.35 (EtOAc–
MS (ES+): m/z = 350.3 (M+ + 1).
Anal. Calcd for C16H19N3O6: C, 55.01; H, 5.48; N, 12.03. Found: C,
54.89; H, 5.66; N, 12.33.
hexanes, 1:4).
IR (KBr): 2215 (CN), 1723 (CO2CH3) cm–1.
Methyl 2-{[Benzyl(cyano)amino](4,5-dimethoxy-2-nitrophe-
nyl)methyl}acrylate (16a)
Yellow solid; yield: 0.80 g (75%); mp 110–111 °C; Rf = 0.31
(EtOAc–hexanes, 3:7).
IR (KBr): 2211 (CN), 1718 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.81 (s, 3 H, OCH3), 3.91 (s, 3 H,
OCH3), 3.95 (s, 3 H, OCH3), 4.31–4.46 (m, 2 H, CH2), 5.53 (d,
J = 1.1 Hz, 1 H, CH), 6.08 (s, 1 H, =CH2), 6.50 (s, 1 H, =CH2), 7.06
(s, 1 H, ArH), 7.30–7.35 (m, 5 H, ArH), 7.66 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 53.0, 56.9, 57.0, 58.0, 60.1, 109.3,
110.8, 116.4, 127.6, 129.3, 129.37, 129.44, 129.7, 134.4, 138.3,
140.5, 149.0, 153.8, 165.8.
1H NMR (CDCl3, 300 MHz): d = 0.78–0.84 (m, 2 H, CH2), 0.89–
0.93 (m, 1 H, CH2), 1.05–1.09 (m, 1 H, CH2), 2.84–2.87 (m, 1 H,
CH), 3.81 (s, 3 H, OCH3), 5.52 (s, 1 H, CH), 6.03 (s, 1 H, =CH2),
6.52 (s, 1 H, =CH2), 7.56–7.59 (m, 1 H, ArH), 7.75 (d, J = 3.0 Hz,
2 H, ArH), 8.10 (d, J = 8.2 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 8.2, 8.3, 34.3, 53.0, 60.3, 115.5,
126.3, 129.2, 129.6, 130.0, 132.8, 134.3, 137.9, 148.4, 165.6.
MS (ES+): m/z = 302.1 (M+ + 1).
Anal. Calcd for C15H15N3O4: C, 59.79; H, 5.02; N, 13.95. Found: C,
59.48; H, 4.73; N, 14.18.
Methyl 2-{[Cyano(propyl)amino](2-nitrophenyl)methyl}acry-
MS (ES+): m/z = 412.0 (M+ + 1).
late (15d)
Anal. Calcd for C21H21N3O6: C, 61.31; H, 5.14; N, 10.21. Found: C,
61.42; H, 5.38; N, 10.19.
Yellow solid; yield: 0.85 g (87%); mp 80–82 °C; Rf = 0.28 (EtOAc–
hexanes, 2:3).
IR (KBr): 2207 (CN), 1718 (CO2CH3) cm–1.
Methyl 2-{[Cyano(2-methoxy-2-oxoethyl)amino](4,5-dimeth-
oxy-2-nitrophenyl)methyl]acrylate (16f)
Yellow solid; yield: 0.43 g (57%); mp 128–129 °C; Rf = 0.79
(EtOAc–hexanes, 1:4).
1H NMR (CDCl3, 200 MHz): d = 0.98 (t, J = 7.4 Hz, 3 H, CH3),
1.67–1.82 (m, 2 H, CH2), 3.16 (dt, J1 = 7.5 Hz, J2 = 1.8 Hz, 2 H,
CH2), 3.81 (s, 3 H, OCH3), 5.59 (d, J = 1.1 Hz, 1 H, CH), 5.93 (s, 1
H, =CH2), 6.56 (s, 1 H, =CH2), 7.52–7.61 (m, 1 H, ArH), 7.74 (dd,
J1 = 5.1 Hz, J2 = 1.2 Hz, 2 H, ArH), 8.10 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 11.5, 21.6, 53.0, 55.1, 60.0, 116.0,
126.3, 129.4, 129.5, 130.1, 132.7, 134.3, 138.0, 148.5, 165.6.
IR (KBr): 2219 (CN), 1725 (CO2CH3) cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.74 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 3.97 (s, 3 H, OCH3), 4.08–4.23 (m, 5 H, OCH3, CH2), 5.61
(d, J = 0.9 Hz, 1 H, CH), 6.06 (s, 1 H, =CH2), 6.48 (s, 1 H, =CH2),
7.50 (s, 1 H, ArH), 7.71 (s, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 53.1, 54.8, 56.9, 57.2, 62.4, 109.3,
111.4, 115.5, 127.3, 128.9, 138.3, 140.1, 149.0, 154.0, 168.6.
MS (ES+): m/z = 303.9 (M+ + 1).
Anal. Calcd for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85. Found: C,
59.76; H, 5.98; N, 13.61.
MS (ES+): m/z = 394.1 (M+ + 1).
Methyl 2-{[Cyano(2-methoxy-2-oxoethyl)amino](2-nitrophe-
nyl)methyl}acrylate (15f)
Green oil; yield: 1.00 g (71%); Rf = 0.32 (EtOAc–hexanes, 2:3).
Anal. Calcd for C17H19N3O8: C, 51.91; H, 4.87; N, 10.68. Found: C,
52.09; H, 4.98; N, 10.45.
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

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Synthesis of 2-Amino-3,4-dihydroquinazolines
3085
2-Amino-3,4-dihydroquinazolines 17a–e,g, 18a,b, 19b–d,g, 20a
and Imidazo[2,1-b]quinazoline-2-ones 21–24; Typical Proce-
dure
2-(2-Amino-3-propyl-3,4-dihydroquinazolin-4-yl)acrylonitrile
(17d)
White solid; yield: 0.46 g (60%); mp 157–158 °C; Rf = 0.15
(MeOH–CHCl3, 1:9).
To a soln of compound 13a (0.50 g, 1.57 mmol) in AcOH (10 mL)
was added Fe powder (0.44 g, 7.86 mmol) and the mixture was heat-
ed at 95 °C for 20 min. After cooling to r.t., the soln was poured onto
ice-water (20 mL) and neutralized with aq NaHCO3 soln. The pre-
cipitated solid was removed by filtration through Celite and then
rinsed with EtOAc. The organic layer was washed with brine
(70 mL), dried over Na2SO4 and concentrated. The residue was
crystallized from EtOAc–hexanes to furnish pure 17a as a brown
solid; yield: 0.24 g (53%).
IR (KBr): 3417 (NH2), 2210 (CN), 1678 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 0.82 (d, J = 6.8 Hz, 3 H, CH3),
1.57 (d, J = 5.9 Hz, 2 H, CH2), 3.03 (t, J = 6.6 Hz, 2 H, CH2), 5.46
(s, 1 H, CH), 6.11 (s, 1 H, =CH2), 6.14 (s, 1 H, =CH2), 6.84–6.95
(m, 2 H, ArH), 7.07 (d, J = 6.4 Hz, 1 H, ArH), 7.13–7.18 (m, 1 H,
ArH).
13C NMR (DMSO-d6, 50 MHz): d = 11.3, 24.9, 49.7, 61.4, 117.2,
117.6, 123.2, 127.2, 130.3, 133.4, 137.6, 153.2.
2-(2-Amino-3-benzyl-3,4-dihydroquinazolin-4-yl)acrylonitrile
(17a)
MS (ES+): m/z = 241.3 (M+ + 1).
Anal. Calcd for C14H16N4: C, 69.97; H, 6.71; N, 23.32. Found: C,
70.11; H, 6.53; N, 23.57.
Mp 120–121 °C; Rf = 0.21 (MeOH–CHCl3, 1:4).
IR (KBr): 3424 (NH2), 2225 (CN), 1657 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 4.51–4.60 (m, 2 H, CH2), 5.69
(s, 1 H, CH), 6.23 (s, 1 H, =CH2), 6.28 (s, 1 H, =CH2), 7.30–7.38
(m, 9 H, ArH).
2-(2-Amino-3-sec-butyl-3,4-dihydroquinazolin-4-yl)acryloni-
trile (17e)
White solid (1:1 mixture of diastereoisomers); yield: 0.44 g (61%);
13C NMR (DMSO-d6, 75 MHz): d = 51.1, 61.0, 116.0, 116.8, 117.7,
121.3, 125.2, 127.5, 127.8, 128.6, 129.3, 130.7, 132.6, 134.7, 135.1,
152.1.
mp 157–158 °C; Rf = 0.15 (MeOH–CHCl3, 1:9).
IR (neat): 3458 (NH2), 2212 (CN), 1665 (C=N) cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.76 (t, J = 7.4 Hz, 3 H, CH3), 1.05
(t, J = 7.3 Hz, 3 H, CH3), 1.30–1.40 (m, 6 H, 2 × CH3), 1.58–1.72
(m, 3 H, CH2), 1.82–1.96 (m, 1 H, CH2), 4.07–4.18 (m, 1 H, CH),
4.30–4.37 (m, 1 H, CH), 5.01 (s, 1 H, CH), 5.10 (s, 1 H, CH), 5.85
(s, 2 H, 2 × =CH2), 5.97 (s, 2 H, 2 × =CH2), 7.08–7.17 (m, 3 H,
ArH), 7.23–7.38 (m, 5 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 11.4, 11.5, 17.9, 19.4, 27.1,
27.5, 53.3, 53.5, 55.7, 56.2, 117.0, 117.5, 120.2, 120.3, 123.2,
124.3, 124.5, 129.8, 131.7, 132.1, 153.6, 154.4, 176.6.
MS (ES+): m/z = 289.3 (M+ + 1).
Anal. Calcd for C18H16N4: C, 74.98; H, 5.59; N, 19.43. Found: C,
75.15; H, 5.77; N, 19.41.
2-(2-Amino-3-cyclohexyl-3,4-dihydroquinazolin-4-yl)acryloni-
trile (17b)
White solid; yield: 0.30 g (66%); mp 129–130 °C; Rf = 0.23
(MeOH–CHCl3, 1:4).
IR (KBr): 3367 (NH2), 2225 (CN), 1645 (C=N) cm–1.
MS (ES+): m/z = 255.2 (M+ + 1).
1H NMR (DMSO-d6, 300 MHz): d = 1.09–1.42 (m, 4 H, 2 × CH2),
1.49–1.61 (m, 3 H, CH2), 1.70–1.76 (m, 3 H, CH2), 4.01–4.08 (m, 1
H, CH), 5.89 (s, 1 H, CH), 6.16 (s, 1 H, =CH2), 6.20 (s, 1 H, =CH2),
7.03 (d, J = 7.8 Hz, 1 H, ArH), 7.15 (t, J = 7.3 Hz, 1 H, ArH), 7.31–
7.39 (m, 2 H, ArH).
Anal. Calcd for C15H18N4: C, 70.84; H, 7.13; N, 22.03. Found: C,
71.11; H, 6.87; N, 22.14.
2-[2-Amino-3-(2,2-dimethoxyethyl)-3,4-dihydroquinazolin-4-
yl]acrylonitrile (17g)
13C NMR (DMSO-d6, 50 MHz): d = 25.3, 26.0, 26.3, 30.8, 31.2,
54.7, 58.2, 116.6, 117.7, 120.5, 124.2, 124.6, 127.1, 130.4, 148.3,
153.9.
White solid; yield: 1.00 g (65%); mp 157–158 °C; Rf = 0.21
(MeOH–CHCl3, 1:4).
IR (KBr): 3406 (NH2), 2224 (CN), 1650 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.12 (dd, J1 = 15.1 Hz, J2 = 6.5
Hz, 1 H, CH2), 3.27 (s, 6 H, 2 × OCH3), 3.73 (dd, J1 = 15.2 Hz,
J2 = 3.5 Hz, 1 H, CH2), 4.48–4.52 (m, 1 H, CH), 5.27 (s, 1 H, CH),
5.92 (s, 1 H, =CH2), 5.99 (s, 2 H, NH2), 6.05 (s, 1 H, =CH2), 6.69
(d, J = 7.8 Hz, 1 H, ArH), 6.78 (t, J = 6.7 Hz, 1 H, ArH), 6.97 (d,
J = 7.1 Hz, 1 H, ArH), 7.08 (t, J = 7.0 Hz, 1 H, ArH).
MS (ES+): m/z = 281.3 (M+ + 1).
Anal. Calcd for C17H20N4: C, 72.83; H, 7.19; N, 19.98. Found: C,
72.56; H, 7.34; N, 19.76.
2-(2-Amino-3-cyclopropyl-3,4-dihydroquinazolin-4-yl)acrylo-
nitrile (17c)
White solid; yield: 0.60 g (67%); mp 137–139 °C; Rf = 0.21
(MeOH–CHCl3 1:4).
13C NMR (DMSO-d6, 75 MHz): d = 50.7, 54.3, 55.5, 62.3, 103.1,
118.0, 120.6, 121.3, 123.9, 126.2, 129.1, 130.6, 145.4, 153.5.
MS (ES+): m/z = 287.0 (M+ + 1).
IR (KBr): 3424 (NH2), 2225 (CN), 1680 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 0.70–0.85 (m, 3 H, CH2),
1.02–1.04 (m, 1 H, CH2), 2.58 (s, 1 H, CH), 5.34 (s, 1 H, CH), 6.13
(s, 1 H, =CH2), 6.17 (s, 1 H, =CH2), 6.82 (d, J = 7.9 Hz, 1 H, ArH),
6.90 (t, J = 7.3 Hz, 1 H, ArH), 7.08 (d, J = 7.4 Hz, 1 H, ArH), 7.18
(t, J = 7.4 Hz, 1 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 7.7, 29.0, 61.2, 117.3, 118.9,
122.5, 123.4, 127.5, 130.4, 134.0, 137.1, 154.6, 177.2.
HRMS (EI): m/z calcd for C15H18N4O2: 286.1430; found: 286.1427.
2-(2-Amino-3-benzyl-6,7-dimethoxy-3,4-dihydroquinazolin-4-
yl)acrylonitrile (18a)
Yellow solid; yield: 0.40 g (55%); mp 141–142 °C; Rf = 0.21
(MeOH–CHCl3, 1:4).
IR (KBr): 3424 (NH2), 2225 (CN), 1662 (C=N) cm–1.
MS (ES+): m/z = 239.2 (M+ + 1).
1H NMR (DMSO-d6, 300 MHz): d = 3.69 (s, 6 H, 2 × OCH3), 3.99–
4.17 (m, 2 H, CH2), 6.00–6.06 (m, 1 H, CH), 6.37 (s, 1 H, =CH2),
6.54 (s, 1 H, =CH2), 7.23–7.32 (m, 7 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 51.4, 56.3, 57.0, 60.9, 110.6,
118.5, 123.7, 128.1, 128.5, 129.7, 137.7, 144.7, 150.8, 171.6
Anal. Calcd for C14H14N4: C, 70.57; H, 5.92; N, 23.51. Found: C,
70.48; H, 5.87; N, 23.83.
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

3086
A. Mishra, S. Batra
PAPER
MS (ES+): m/z = 349.3 (M+ + 1).
6.22 (s, 1 H, =CH2), 6.89–6.95 (m, 2 H, ArH), 7.07 (d, J = 7.3 Hz,
1 H, ArH), 7.18 (t, J = 7.3 Hz, 1 H, ArH).
13C NMR (DMSO-d6, 50 MHz): d = 11.5, 20.8, 49.6, 52.9, 60.3,
116.1, 120.0, 123.4, 127.1, 129.7, 139.5, 153.3, 165.7, 177.4.
Anal. Calcd for C20H20N4O2: C, 68.95; H, 5.79; N, 16.08. Found: C,
69.06; H, 6.01; N, 15.84.
2-(2-Amino-3-cyclohexyl-6,7-dimethoxy-3,4-dihydroquinazo-
lin-4-yl)acrylonitrile (18b)
Brown solid; yield: 0.30 g (66%); mp 129–130 °C; Rf = 0.21
(MeOH–CHCl3, 1:4).
MS (ES+): m/z = 274.3 (M+ + 1).
Anal. Calcd for C15H19N3O2: C, 65.91; H, 7.01; N, 15.37. Found: C,
65.78; H, 6.89; N, 15.67.
IR (KBr): 3367 (NH2), 2225 (CN), 1645 (C=N) cm–1.
Methyl 2-[2-Amino-3-(2,2-dimethoxyethyl)-3,4-dihydro-
quinazolin-4-yl]acrylate (19g)
White solid; yield: 0.44 g (60%); mp 118–119 °C; Rf = 0.30
(MeOH–CHCl3, 3:17).
IR (KBr): 3417 (NH2), 1722 (CO2CH3), 1668 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.11–3.26 (m, 5 H, OCH3,
CH2), 3.44 (s, 3 H, OCH3), 4.06 (s, 3 H, OCH3), 4.31 (br s, 1 H, CH),
6.17 (s, 1 H, CH), 6.30 (s, 1 H, =CH2), 6.42 (s, 1 H, =CH2), 7.17 (s,
1 H, ArH), 7.30 (d, J = 7.0 Hz, 1 H, ArH), 7.46 (s, 1 H, ArH), 7.65
(s, 1 H, ArH).
1H NMR (DMSO-d6, 300 MHz): d = 1.09–1.22 (m, 6 H, 3 × CH2),
1.30–1.43 (m, 4 H, 2 × CH2), 1.85–1.97 (m, 1 H, CH), 3.67 (s, 3 H,
OCH3), 3.69 (s, 3 H, OCH3), 5.42 (s, 1 H, CH), 5.93 (s, 1 H, =CH2),
6.00 (s, 1 H, =CH2), 6.40 (s, 1 H, ArH), 6.81 (s, 1 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 25.3, 25.50, 25.54, 31.7, 31.8,
57.0, 57.2, 110.9, 114.2, 117.0, 125.3, 134.6, 140.9, 148.3, 149.9,
154.2, 171.1.
MS (ES+): m/z = 341.3 (M+ + 1).
Anal. Calcd for C19H24N4O2: C, 67.04; H, 7.11; N, 16.46. Found: C,
67.23; H, 6.93; N, 16.51.
MS (ES+): m/z = 320.3 (M+ + 1).
Anal. Calcd for C16H21N3O4: C, 60.17; H, 6.63; N, 13.16. Found: C,
60.45; H, 6.59; N, 13.33.
Methyl 2-(2-Amino-3-cyclohexyl-3,4-dihydroquinazolin-4-
yl)acrylate (19b)
White solid; yield: 0.42 g (58%); mp 119–120 °C; Rf = 0.29
(MeOH–CHCl3, 3:17).
IR (KBr): 3391 (NH2), 1728 (CO2CH3), 1657 (C=N) cm–1.
Methyl 2-(2-Amino-3-benzyl-6,7-dimethoxy-3,4-dihydro-
quinazolin-4-yl)acrylate (20a)
White solid; yield: 0.28 g (56%); mp 161–162 °C; Rf = 0.28
(MeOH–CHCl3, 1:9).
1H NMR (DMSO-d6, 300 MHz): d = 1.05–1.37 (m, 6 H, 3 × CH2),
1.70–1.76 (m, 4 H, 2 × CH2), 3.68 (s, 3 H, OCH3), 3.98–4.05 (m, 1
H, CH), 5.77 (s, 1 H, CH), 5.88 (s, 1 H, =CH2), 6.19 (s, 1 H, =CH2),
7.00 (d, J = 8.0 Hz, 1 H, ArH), 7.09 (t, J = 7.4 Hz, 1 H, ArH), 7.26–
7.30 (m, 2 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 24.7, 25.0, 29.7, 30.6, 52.6,
53.9, 57.7, 124.6, 125.5, 126.9, 127.4, 129.9, 132.9, 140.0, 141.0,
168.7.
IR (KBr): 3746 (NH2), 1728 (CO2CH3), 1671 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.70 (s, 3 H, OCH3), 3.77 (s, 3
H, OCH3), 3.79 (s, 3 H, OCH3), 4.21 (d, J = 5.8 Hz, 2 H, CH2), 5.30
(s, 1 H, CH), 5.78 (s, 1 H, =CH2), 6.21 (s, 1 H, =CH2), 6.49 (s, 1 H,
ArH), 6.85 (s, 1 H, ArH), 7.23–7.35 (m, 5 H, ArH).
13C NMR (DMSO-d6, 50 MHz): d = 50.3, 52.5, 56.1, 56.3, 59.6,
110.3, 110.6, 127.0, 127.5, 127.6, 127.9, 128.2, 128.6, 129.2, 138.6,
145.2, 149.9, 162.0, 165.5.
MS (ES+): m/z = 314.3 (M+ + 1).
Anal. Calcd for C18H23N3O2: C, 68.98; H, 7.40; N, 13.41. Found: C,
68.62; H, 7.73; N, 13.64.
MS (ES+): m/z = 382.2 (M+ + 1).
Anal. Calcd for C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found: C,
66.45; H, 5.79; N, 11.25.
Methyl 2-(2-Amino-3-cyclopropyl-3,4-dihydroquinazolin-4-
yl)acrylate (19c)
White solid; yield: 0.54 g (60%); mp 137–139 °C; Rf = 0.28
(MeOH–CHCl3, 3:17).
IR (KBr): 3423 (NH2), 1723 (CO2CH3), 1652 (C=N) cm–1.
2-(2-Oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-5-
yl)acrylonitrile (21)
Yellow solid; yield: 0.26 g (55%); mp 137–139 °C; Rf = 0.28
(MeOH–CHCl3, 1:9).
1H NMR (DMSO-d6, 300 MHz): d = 0.72–1.02 (m, 4 H, 2 × CH2),
2.42 (br s, 1 H, CH), 3.66 (s, 3 H, OCH3), 5.48 (s, 1 H, CH), 5.89 (s,
1 H, =CH2), 6.23 (s, 1 H, =CH2), 6.84–6.92 (m, 2 H, ArH), 7.05 (d,
J = 7.4 Hz, 1 H, ArH), 7.15 (t, J = 7.3 Hz, 1 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 7.5, 28.9, 52.8, 60.1, 116.2,
120.2, 123.4, 127.1, 128.5, 129.6, 135.2, 139.0, 155.0, 165.9.
IR (KBr): 3449 (NH), 2210 (CN), 1648 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.73–3.88 (m, 2 H, CH2), 5.58
(s, 1 H, CH), 6.33 (s, 1 H, =CH2), 6.43 (s, 1 H, =CH2), 7.03–7.12
(m, 3 H, ArH), 7.33 (s, 1 H, ArH), 11.30 (s, 1 H, NH).
13C NMR (DMSO-d6, 75 MHz): d = 51.6, 58.4, 116.5, 117.3, 117.4,
121.5, 123.9, 127.4, 129.9, 134.9, 135.5, 163.7, 182.4.
MS (ES+): m/z = 272.3 (M+ + 1)
MS (ES+): m/z = 239.2 (M+ + 1).
Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C
66.76; H, 6.53; N, 15.68.
Anal. Calcd for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C,
65.50; H, 4.37; N, 23.58.
Methyl 2-(2-Amino-3-propyl-3,4-dihydroquinazolin-4-yl)acry-
late (19d)
White solid; yield: 0.44 g (60%); mp 148–149 °C; Rf = 0.28
(MeOH–CHCl3, 3:17).
IR (KBr): 3385 (NH2), 1716 (CO2CH3), 1670 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 0.82 (t, J = 7.3 Hz, 3 H, CH3),
1.45–1.64 (m, 2 H, CH2), 2.99–3.09 (m, 1 H, CH2), 3.44–3.54 (m, 1
H, CH2), 3.64 (s, 3 H, OCH3), 5.53 (s, 1 H, CH), 5.87 (s, 1 H, =CH2),
2-(7,8-Dimethoxy-2-oxo-1,2,3,5-tetrahydroimidazo[2,1-
b]quinazolin-5-yl)acrylonitrile (22)
Brown solid; yield: 0.22 g (60%); mp 104–105 °C; Rf = 0.21
(MeOH–CHCl3, 1:4).
IR (KBr): 3428 (NH), 2191 (CN), 1653 (C=N), cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.62–3.87 (m, 8 H, 2 × OCH3,
CH2), 5.46 (s, 1 H, CH), 6.28 (s, 1 H, =CH2), 6.40 (s, 1 H, =CH2),
6.64–6.65 (m, 2 H, ArH).
Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York

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Synthesis of 2-Amino-3,4-dihydroquinazolines
3087
13C NMR (DMSO-d6, 75 MHz): d = 49.0, 52.7, 106.9, 117.5, 128.6,
2-(1,5-Dihydroimidazo[2,1-b]quinazolin-5-yl)acrylonitrile (25)
To a soln of 17g (0.86 g, 3.01 mmol) in AcOH (0.74 mL) was added
concd HCl (1.23 mL) and the resulting mixture was heated at 100
°C for 30 min. The reaction mixture was cooled to r.t. and poured
onto ice-water (30 mL) and neutralized with aq NaHCO3 soln. The
mixture was extracted with EtOAc (3 × 25 mL) and the combined
organic layers washed with brine (100 mL), dried over Na2SO4 and
concentrated. The residue was crystallized from EtOAc–hexanes to
furnish analytically pure 25 as a white solid; yield: 0.46 g (72%).
146.3, 148.5, 152.3, 153.1, 153.9, 154.2, 155.3, 171.0.
MS (ES+): m/z = 299.3 (M+ + 1).
Anal. Calcd for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78. Found: C,
60.67; H, 4.64; N, 18.65.
Methyl 2-(2-Oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-
5-yl)acrylate (23)
Yellow solid; yield: 0.36 g (55%); mp 156–157 °C; Rf = 0.28
(MeOH–CHCl3, 1:9).
IR (KBr): 3438 (NH), 1729 (CO2CH3), 1649 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.60 (s, 3 H, OCH3), 3.76–3.84
(m, 2 H, CH2), 5.63 (s, 1 H, CH), 6.08 (s, 1 H, =CH2), 6.31 (s, 1 H,
=CH2), 6.97–7.03 (m, 3 H, ArH), 7.21–7.24 (m, 1 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 52.4, 56.4, 62.1, 117.4, 121.9,
122.7, 123.3, 127.3, 129.2, 134.2, 145.7, 163.2, 165.0, 172.6.
Mp 140–141 °C; Rf = 0.28 (MeOH–CHCl3, 1:9).
IR (KBr): 3443 (NH), 2210 (CN), 1642 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 6.24 (s, 1 H, CH), 6.31 (s, 1 H,
=CH2), 6.35 (s, 1 H, =CH2), 6.75 (s, 1 H, =CH), 6.78 (s, 1 H, =CH),
6.90–6.95 (m, 2 H, ArH), 7.13 (d, 1 H, J = 7.4 Hz, ArH), 7.25 (t, 1
H, J = 7.3 Hz, ArH), 10.2 (s, 1 H, NH).
13C NMR (DMSO-d6, 75 MHz): d = 59.4, 113.1, 113.9, 115.6,
117.1, 121.1, 124.3, 127.2, 128.5, 130.2, 133.8, 137.7.
MS (ES+): m/z = 223.2 (M+ + 1).
MS (ES+): m/z = 272.3 (M+ + 1).
Anal. Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C,
62.23; H, 5.19; N, 15.18.
Anal. Calcd for C13H10N4: C, 70.26; H, 4.54; N, 25.21. Found: C,
70.22; H, 4.50; N, 25.25.
Methyl 2-(7,8-Dimethoxy-2-oxo-1,2,3,5-tetrahydroimidazo[2,1-
b]quinazolin-5-yl)acrylate (24)
Brown solid; yield: 0.10 g (53%); mp 137–139 °C; Rf = 0.28
(MeOH–CHCl3, 1:9).
One-Pot Preparation of Imidazo[2,1-b]quinazolines 25,26; Typ-
ical Procedure
To a soln of compound 15g (0.80 g, 2.29 mmol) in AcOH (15 mL)
was added Fe powder (0.64 g, 11.46 mmol) and the resulting mix-
ture was heated at 95 °C for 20 min. Concd HCl (1.20 mL) was add-
ed and heating was continued at 100 °C for 30 min. The reaction
mixture was cooled to r.t. and poured onto ice-water H2O (30 mL)
and neutralized with aq NaHCO3 soln. The precipitated solid was
removed by filtration through a bed of Celite which was then rinsed
thoroughly with EtOAc. The organic layer was washed with brine
(100 mL), dried over Na2SO4 and concentrated. The residue was
crystallized from EtOAc–hexanes to furnish 26. A similar one-pot
procedure starting from 13g gave 25 in 75% yield.
IR (KBr): 3460 (NH), 1723 (CO2CH3), 1653 (C=N) cm1.
1H NMR (DMSO-d6, 300 MHz): d = 3.60–3.72 (m, 9 H, 3 × OCH3),
3.80 (s, 2 H, CH2), 5.52 (s, 1 H, CH), 6.01 (s, 1 H, =CH2), 6.28 (s,
1 H, =CH2), 6.58 (s, 1 H, ArH), 6.62 (s, 1 H, ArH).
13C NMR (DMSO-d6, 50 MHz): d = 52.4, 56.4, 56.6, 56.8, 98.3,
113.1, 120.1, 121.8, 129.2, 134.2, 145.7, 165.0, 172.6.
MS (ES+): m/z = 332.2 (M+ + 1).
Anal. Calcd for C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found:
C, 58.34; H, 5.48; N, 12.66.
Methyl 2-(1,5-Dihydroimidazo[2,1-b]quinazolin-5-yl)acrylate
(26)
Methyl 2-(2-Amino-3-benzyl-3,4-dihydroquinazolin-4-yl)acry-
late (19a)
White solid; yield: 0.38 g (65%); mp 139–140 °C; Rf = 0.30
(EtOAc).
IR (KBr): 3445 (NH), 1719 (CO2CH3), 1628 (C=N) cm1.
1H NMR (CDCl3, 300 MHz): d = 3.72 (s, 3 H, OCH3), 6.31 (s, 1 H,
CH), 6.33 (s, 1 H, =CH2), 6.60 (s, 1 H, =CH2), 6.83–6.97 (m, 4 H,
ArH), 7.11 (d, J = 7.6 Hz, 1 H, ArH), 7.20 (t, J = 7.5 Hz, 1 H, ArH).
13C NMR (DMSO-d6, 50 MHz): d = 52.6, 57.5, 114.5, 116.4, 121.7,
127.5, 129.0, 129.8, 139.6, 140.7, 165.0, 170.6.
To a soln of compound 15a (0.80 g, 2.29 mmol) in absolute EtOH
(15 mL) were added Fe powder (0.64 g, 11.45 mmol) and concd
HCl (0.50 mL), and the resulting mixture was heated at 100 °C for
45 min. The solvent was evaporated under reduced pressure and the
residue was diluted with EtOAc (50 mL) and neutralized with sat.
NaHCO3 soln. The soln was passed through a bed of Celite which
was washed thoroughly with EtOAc. The organic layer was washed
with brine (100 mL), dried over Na2SO4 and concentrated. The res-
idue was crystallized from EtOAc–hexanes to furnish 19a as a
white solid; yield: 0.44 g (60%).
MS (ES+): m/z = 256.2 (M+ + 1).
Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found: C,
66.09; H, 5.32; N, 16.74.
Mp 120–121 °C; Rf = 0.25 (MeOH–CHCl3, 3:17).
IR (KBr): 3417 (NH2), 1722 (CO2CH3), 1659 (C=N) cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 3.63 (s, 3 H, OCH3), 3.99–4.07
(m, 2 H, CH2), 5.56 (s, 1 H, CH), 5.98 (s, 1 H, =CH2), 6.25 (s, 1 H,
=CH2), 7.22–7.27 (m, 5 H, ArH), 7.31–7.36 (m, 4 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 51.1, 52.9, 60.7, 119.8, 124.6,
127.3, 127.8, 128.1, 128.8, 129.3, 129.7, 130.1, 133.7, 135.6, 138.4,
152.9, 165.4.
Acknowledgment
One of the authors (A.M.) is grateful for the financial support from
CSIR, New Delhi in the form of a fellowship. This work was sup-
ported by a DST grant.
MS (ES+): m/z = 322.3 (M+ + 1).
References
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Synthesis 2009, No. 18, 3077–3088 © Thieme Stuttgart · New York