Unexpected synthesis of rearranged 3,4-dihydroquinazolines by a sequential Ugi 4CC/aza-Wittig/carbodiimide-mediated cyclization

Article abstract of DOI:10.1002/ejoc.200901287

The 2,3,4-trisubstituted 3,4-dihydroquinazolines 4 were unexpectedly obtained from a sequential Ugi four component condensation (4CC)/aza-Wittig/ carbodiimide-mediated cyclization

Full text of DOI:10.1002/ejoc.200901287

FULL PAPER
DOI: 10.1002/ejoc.200901287
Unexpected Synthesis of Rearranged 3,4-Dihydroquinazolines by a
Sequential Ugi 4CC/Aza-Wittig/Carbodiimide-Mediated Cyclization
Ping He,[a] Jing Wu,[a] Yi-Bo Nie,[a] and Ming-Wu Ding*[a]
Keywords: 3,4-Dihydroquinazolines / Multicomponent reactions / Ugi reaction / Aza-Wittig reaction / Azides / Cyclization
The 2,3,4-trisubstituted 3,4-dihydroquinazolines 4 were un-
expectedly obtained from a sequential Ugi four component
condensation (4CC)/aza-Wittig/carbodiimide-mediated cy-
clization.
On the other hand, aza-Wittig reactions are receiving in-
creased attention in view of their utility in the synthesis of
nitrogen-containing heterocycles.[18–22] It is therefore clear
that the combination of the efficiency of the Ugi condensa-
tion with a post-condensation aza-Wittig reaction should
facilitate access to a series of biologically useful heterocy-
cles. We have recently been interested in the synthesis of
various heterocycles through aza-Wittig reactions, with the
aim of evaluating their biological activities.[23–27] In contin-
uation of our previous research, here we report an unexpec-
ted synthesis of rearranged 3,4-dihydroquinazolines by a se-
quential Ugi four component condensation (4CC)/aza-Wit-
tig/carbodiimide-mediated cyclization.
Introduction
Quinazolines have been found to show widespread bio-
logical activities and have been used as antiinflammatory,
antiallergic, and antimalarial agents and, especially, as can-
cer treatment agents.[1–5] Lee et al., for example, recently
reported a series of compounds containing the 3,4-dihy-
droquinazoline backbone that display potent T-type chan-
nel blocking activity (Figure 1); in particular, compound
KYS06090 shows growth inhibition of human cancer cells
similar to that of doxorubicin, together with low cytotoxi-
city.[6–9]
Results and Discussion
Mixtures of 2-azidobenzaldehyde (1 equiv.), an amine
(1 equiv.), an isocyanide (1 equiv.), and an acid (1 equiv.)
were stirred in methanol at room temperature for 12–36 h
until a solid precipitated (Scheme 1). The Ugi reactions pro-
ceeded smoothly, and the azide products 1 were obtained
after recrystallization in satisfactory yields (Table 1).
Figure 1. Some 3,4-dihydroquinazolines used as potent cancer-cell
inhibitors.
The Ugi reaction is one of the two main isocyanide-
based multicomponent reactions (I-MCRs) (the Ugi reac-
tion and the Passerini reaction) and is a powerful, atom-
economical reaction between isocyanide, amine, aldehyde
(or ketone), and carboxylic acid components that generates
a significantly more complex α-acylamino amide ad-
duct.[10–12] Sequences based on classical Ugi isocyanide
multicomponent reactions with subsequent postcondensa-
tion transformations constitute extremely powerful syn-
thetic tools for the preparation of structurally diverse com-
plex molecules, especially heterocyclic compounds.[13–17]
Scheme 1. Reaction conditions: (i) MeOH, room temp., 12–36 h,
67–93%.
When the azides 1 were treated with triphenylphosphane
in toluene, the iminophosphoranes 2 were easily formed.
Subsequent treatment of compounds 2 with isocyanate at
room temperature gave the carbodiimides 3, which were
heated at reflux for 6–24 h in toluene. To our surprise, the
rearranged 2,3,4-trisubstituted 3,4-dihydroquinazolines 4,
the products of R2CO group migration from NR3 to NR4,
[a] Key Laboratory of Pesticide & Chemical Biology of Ministry
of Education, Central China Normal University,
Wuhan 430079, P. Republic of China
Fax: +86-27-67862041
E-mail: ding5229@yahoo.com.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901287.
1088
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1088–1095

Unexpected Synthesis of Rearranged 3,4-Dihydroquinazolines
Table 1. Preparation of azides 1 through Ugi 4CC reactions.
Compound
R1
R2
R3
Reaction time [h] Yield[a] (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
tBu
tBu
tBu
tBu
tBu
Ph
Ph
Ph
Ph
Ph
iPr
nPr
nBu
Et
Me
Et
Me
nPr
nBu
Ph
36
12
24
12
12
12
12
36
36
36
24
24
24
24
67
95
87
76
89
93
90
91
92
85
75
70
79
63
tBu 4-ClC6H4
tBu 4-ClC6H4
nBu
nBu
tBu
nBu 4-ClC6H4 4-ClC6H4
nBu (CH2)2Ph
nBu
nBu
Ph
Ph
Me
Ph
nPr
nBu
Me
Me
[a] Isolated yields.
Scheme 2. Reaction conditions: (i) PPh3, toluene, room temp., 2–
4 h; (ii) R4NCO, toluene, room temp., 2–6 h; (iii) toluene, reflux,
6–24 h, 0–90%.
were obtained from the reaction mixtures when R3 = alkyl
(Scheme 2). The results are listed in Table 2. As can be seen,
the yield of the product is related to the R3 substituent:
good yields were achieved when R3 was a primary alkyl
It is noteworthy that there are no reports relating to reac-
group (4b–4v), whereas a low yield was obtained when a tions between N,N-disubstituted amides (containing no N–
secondary alkyl group was used (4a). The carbodiimides 3 H moiety) and carbodiimides.[28] However, carbodiimides
were recovered unchanged if R3 was an aryl group (4w, 4x). with adjacent amide groups containing N–H groups gen-
The structures of the 2,3,4-trisubstituted 3,4-dihydroquin- erally tend to cyclize directly to form five- or six-membered
azolines 4 were confirmed by their spectral data. Further- heterocycles. The cyclization of the carbodiimides 5, for ex-
more, a single crystal of 4u was obtained from a CH2Cl2 ample, gave the quinazolinones 6 in good yields in toluene
solution of 4u. X-ray structure analysis verified the pro- at reflux (Scheme 3).[29] Heating of the carbodiimides 3,
posed structure, and showed intramolecular hydrogen-bond however, did not provide the expected benzodiazepines 7
formation between one amido hydrogen atom (N4-H) and (Scheme 4, below), probably because of the restricted con-
another amido oxygen atom (O1), forming a nine-mem- formation of the amido side chains, which could be entropi-
bered cycle (Figure 2).
cally unfavorable for the cyclizations.
Table 2. Preparation of 2,3,4-trisubstituted 3,4-dihydroquinazolines 4.
Compound
R1
R2
R3
R4
Reaction time [h]
Yield[a] (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
nBu
nBu
nBu
tBu
nBu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
iPr
nPr
nPr
nPr
nPr
nBu
nBu
nBu
Et
Et
Et
Me
Me
Et
Et
Et
Et
Me
Me
nPr
nBu
nBu
Ph
4-ClC6H4
4-FC6H4
3-CH3C6H4
4-ClC6H4
Ph
4-ClC6H4
Ph
4-FC6H4
Ph
4-FC6H4
3-CH3C6H4
Ph
4-ClC6H4
Ph
4-ClC6H4
4-FC6H4
iPr
3-CH3C6H4
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-CH3C6H4
3-CH3C6H4
20
15
10
8
12
10
14
12
8
6
6
8
6
17
69
78
85
76
88
85
83
90
87
89
90
83
89
88
81
79
84
89
67
61
67
0
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
6
6
8
18
6
6
16
12
8
24
24
Ph
Me
Me
4-ClC6H4
4-ClC6H4
0
[a] Isolated yields.
Eur. J. Org. Chem. 2010, 1088–1095
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1089

P. He, J. Wu, Y.-B. Nie, M.-W. Ding
FULL PAPER
8 might be influenced both by the nucleophilicity of the
nitrogen atom and by the steric effect of R3. When R3 is an
electron-releasing and sterically less bulky alkyl group, the
intermediate 8 should be easily formed. The reaction would
be retarded, however, if R3 is an aryl group (4w, 4x) or a
sterically bulky secondary alkyl group (4a).
Conclusions
We report a novel multicomponent synthesis of 3,4-di-
hydroquinazoline based on the Ugi reaction followed by a
Staudinger/aza-Wittig/carbodiimide-mediated reaction. In-
tramolecular cyclizations of carbodiimides with N,N-disub-
stituted amides and subsequent acyl migration have been
reported for the first time. Thanks to the easy accessibility
of the synthetic approach and the neutral ring closure con-
ditions, this new synthetic approach discussed here offers
potential for the synthesis of various 2,3,4-trisubstituted
3,4-dihydroquinazolines, which are of considerable interest
as potential biologically active compounds or pharmaceuti-
cals.
Figure 2. X-ray crystal structure of compound 4u.
Experimental Section
General Procedures: All reactions were performed in round-bot-
tomed flasks. Column chromatography purifications were per-
formed under “flash” conditions with 400–630 mesh silica gel, ex-
cept where otherwise noted. Analytical thin-layer chromatography
(TLC) was carried out with silica gel (60 F254) plates, which were
visualized by exposure to ultraviolet light.
Scheme 3. Literature synthesis of quinazolinones 6 from carbodi-
imides 5.
Instrumentation: Melting points are uncorrected. Mass spectra were
measured with a Finnigan Trace MS spectrometer. IR spectra were
recorded with a PE-983 infrared spectrometer as KBr pellets with
absorption in cm–1. NMR spectra were recorded in CDCl3 with a
Varian Mercury 400 or 600 spectrometer and resonances relative
A possible mechanism for the formation of the 3,4-dihy-
droquinazolines 4 is proposed (Scheme 4). It presumably in-
volves the formation of diazeto[2,1-b]quinazoline interme-
diates 8 through intramolecular cycloaddition between the
N,N-disubstituted amides and the carbodiimide moieties. to TMS. Elemental analyses were carried out with a Vario EL III
elementary analysis instrument. The X-ray diffraction data were
collected with a Bruker SMART AXS CCD diffractometer, Mo-
Kα, 2θ = 1.86–27.50°. CCDC-753684 (4u) contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Further ring-opening would then take place concomitantly
with the cleavage of the nitrogen–carbon bond to give the
rearranged products 4. The formation of the intermediates
General Procedure for the Preparation of the Azides 1: o-Azidobenz-
aldehyde (0.44 g, 3 mmol), a carboxylic acid (3 mmol), and an iso-
cyanide (3 mmol) were added sequentially at room temperature to
a solution of an amine (3 mmol) in methanol (20 mL). The reaction
mixture was stirred at ambient temperature for 12–36 h until a solid
precipitated, and the solvent was evaporated. The crude reaction
mixture was purified by recrystallization from dichloromethane/pe-
troleum ether.
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-N-isopropylbenz-
amide (1a): White crystals (yield 0.79 g, 67%). M.p. 179–180 °C.
1H NMR (CDCl3, 600 MHz): δ = 0.85–0.86 (d, J = 5.4 Hz, 3 H,
CH3), 1.23–1.40 (m, 12 H, 4 CH3), 4.02 (s, 0.6 H, 0.3 COCH, 0.3
NCH), 5.08 (s, 0.7 H, 0.7 NCH), 5.42 (s, 0.7 H, 0.7 COCH), 7.74
(s, 0.7 H, 0.7 CONH), 7.19–7.59 (m, 9 H, Ar-H), 8.01–8.03 (m, 0.3
H, 0.3 CONH) ppm. IR (KBr): ν = 3319, 3066, 2975, 2130, 1678,
˜
Scheme 4. Possible mechanism for formation of 3,4-dihydroquinaz-
olines 4.
1613 cm–1. MS: m/z (%) = 351 (12) [M – N3]+, 251 (100), 106 (38),
1090
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Eur. J. Org. Chem. 2010, 1088–1095

Unexpected Synthesis of Rearranged 3,4-Dihydroquinazolines
77 (40). C22H27N5O2 (393.5): calcd. C 67.15, H 6.92, N 17.80; N-[(2-Azidophenyl)(butylcarbamoyl)methyl]-N-propylbenzamide
found C 67.10, H 6.99, N 17.98.
(1h): White crystals (yield 1.07 g, 91%). M.p. 115–116 °C. 1H NMR
(CDCl3, 600 MHz): δ = 0.55–1.64 (m, 12 H, CH2CH2CH3
+
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-N-propylbenzamide
(1b): White crystals (yield 1.12 g, 95%). M.p. 159–160 °C. 1H NMR
(CDCl3, 600 MHz): δ = 0.62 (t, J = 6.6 Hz, 3 H, CH3), 0.83–0.90
(m, 0.6 H, 0.6 CH2), 1.12–1.16 (m, 0.6 H, 0.6 CH2), 1.27–1.61 (m,
9.8 H, 3 CH3, 0.8 CH2), 2.38–2.46 (m, 0.4 H, 0.4 NCH), 3.17–3.24
(m, 1.2 H, 1.2 NCH), 3.41–3.47 (m, 0.4 H, 0.4 NCH), 5.27 (s, 0.6
H, 0.6 COCH), 5.76 (s, 0.4 H, 0.4 COCH), 6.35 (s, 0.6 H, 0.6
CONH), 7.16–7.44 (m, 9 H, Ar-H), 7.71 (s, 0.4 H, 0.4 CONH)
CH2CH3), 3.31–3.46 (m, 4 H, 2 NCH2), 5.57 (s, 0.2 H, 0.2 COCH),
5.80 (s, 0.8 H, 0.8 COCH), 6.55 (s, 0.8 H, 0.8 CONH), 7.15–7.70
(m, 9 H, Ar-H), 7.99–8.00 (m, 0.2 H, 0.2 CONH) ppm. IR (KBr):
ν = 3350, 3053, 2982, 2941, 2136, 1687, 1619 cm–1. MS: m/z (%) =
˜
351 (3) [M – N3]+, 251 (100), 106 (46), 77 (86). C22H27N5O2 (393.5):
calcd. C 67.15, H 6.92, N 17.80; found C 67.07, H 6.96, N 17.94.
N-[(2-Azidophenyl)(butylcarbamoyl)methyl]-N-butylbenzamide (1i):
White crystals (yield 1.12 g, 92 %). M.p. 100–102 °C. 1H NMR
(CDCl3, 600 MHz): δ = 0.60–1.61 (m, 14 H, 2 CH2CH2CH3), 3.31–
3.56 (m, 4 H, 2 NCH2), 5.47 (s, 0.3 H, 0.3 CONH), 5.81 (s, 0.5 H,
0.5 COCH), 6.49 (s, 0.5 H, 0.5 COCH), 7.10–7.53 (m, 9 H, Ar-H),
7.70 (s, 0.5 H, 0.5 CONH), 8.03–8.05 (m, 0.2 H, 0.2 CONH) ppm.
ppm. IR (KBr): ν = 3317, 3064, 2967, 2935, 2877, 2127, 1674,
˜
1607 cm–1. MS: m/z (%) = 351 (3) [M – N3]+, 251 (100), 106 (46), 77
(86). C22H27N5O2 (393.5): calcd. C 67.15, H 6.92, N 17.80; found C
67.01, H 7.14, N 17.93.
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-N-butylbenzamide
(1c): White crystals (yield 1.06 g, 87%). M.p. 128–130 °C. 1H NMR
(CDCl3 , 600 MHz): δ = 0. 90–1.48 (m, 16 H, 3 CH3 , 1
CH3CH2CH2), 3.23 (s, 1.4 H, 0.7 NCH2), 3.25 (s, 0.3 H, 0.15
NCH2), 5.27 (s, 0.3 H, 0.15 NCH2), 5.79 (s, 0.3 H, 0.3 COCH),
6.34 (s, 0.7 H, 0.7 COCH), 7.17–7.56 (m, 9 H, Ar-H), 7.71 (s, 0.7
H, 0.7 CONH), 8.07–8.06 (m, 0.3 H, 0.3 CONH) ppm. IR (KBr):
IR (KBr): ν = 3352, 3056, 2988, 2947, 2139, 1684, 1623 cm–1. MS:
˜
m/z (%) = 365 (5) [M – N3]+, 265 (100), 106 (54), 77 (36).
C
23H29N5O2 (407.5): calcd. C 67.79, H 7.17, N 17.19; found C
67.55, H 7.29, N 17.22.
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-N-phenylethyl-
amide (1j): White crystals (yield 0.93 g, 85%). M.p. 195–196 °C. 1H
NMR (CDCl3, 600 MHz): δ = 1.36 (s, 9 H, 3 CH3), 1.88 (s, 3 H,
CH3), 5.55 (s, 1 H, CONH), 6.20 (s, 1 H, COCH), 6.82–7.21 (m, 9
ν = 3313, 3062, 2961, 2933, 2878, 2129, 1670, 1609 cm–1. MS: m/z
˜
(%) = 365 (3) [M – N3]+, 265 (100), 106 (35), 77 (60). C23H29N5O2
(407.5): calcd. C 67.79, H 7.17, N 17.19; found C 67.60, H 7.21, N
17.23.
H, Ar-H) ppm. IR (KBr): ν = 3356, 3051, 2984, 2943, 2131, 1678,
˜
1617 cm–1. MS: m/z (%) = 323 (7) [M – N3]+, 223 (100), 106 (50), 77
(19). C20H23N5O2 (365.4): calcd. C 65.73, H 6.34, N 19.16; found C
65.57, H 6.38, N 19.25.
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-N-ethylbenzamide
(1d): White crystals (yield 0.86 g, 76%). M.p. 183–184 °C. 1H NMR
(CDCl3, 400 MHz): δ = 0.81 (t, J = 6.8 Hz, 3 H, CH3), 1.38 (s, 9
H, 3 CH3), 3.42 (s, 1.6 H, 0.8 CH2), 3.60 (s, 0.4 H, 0.2 CH2), 5.29
(s, 0.2 H, 0.2 COCH), 5.86 (s, 0.8 H, 0.8 COCH), 6.15 (s, 0.6 H,
0.6 CONH), 7.16–7.45 (m, 9 H, Ar-H), 7.69 (s, 0.25 H, 0.25
N-[(2-Azidophenyl)(butylcarbamoyl)methyl]-4-chloro-N-(4-chloro-
phenyl)benzamide (1k): White crystals (yield 1.12 g, 75 %). M.p.
1
197–198 °C. H NMR (CDCl3, 400 MHz): δ = 0.88 (t, J = 7.2 Hz,
3 H, CH3), 1.28–1.36 (m, 2 H, CH2), 1.46–1.53 (m, 2 H, CH2),
3.30–3.38 (m, 2 H, CH2), 5.83 (s, 1 H, CONH), 6.42 (s, 1 H,
CONH), 8.01 (s, 0.15 H, 0.15 CONH) ppm. IR (KBr): ν = 3358,
˜
3059, 2981, 2937, 2132, 1682, 1618 cm–1. MS: m/z (%) = 337 (7)
[M – N3]+, 237 (100), 106 (50), 77 (43). C21H25N5O2 (379.5): calcd.
C 66.47, H 6.64, N 18.46; found C 66.41, H 6.88, N 18.39.
COCH), 6.95–7.30 (m, 12 H, Ar-H) ppm. IR (KBr): ν = 3352,
˜
3045, 2981, 2940, 2231, 1669, 1621 cm–1. MS: m/z (%) = 453 (4)
[M – N3]+, 342 (76), 242 (100), 139 (509), 77 (35). C25H23Cl2N5O2
(496.4): calcd. C 60.49, H 4.67, N 14.11; found C 60.63, H 4.52, N
14.23.
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-N-methylbenzamide
(1e): White crystals (yield 0.97 g, 89%). M.p. 149–150 °C. 1H NMR
(CDCl3, 400 MHz): δ = 1.39 (s, 9 H, 3 CH3), 2.78 (s, 3 H, CH3),
5.29 (s, 0.3 H, 0.3 COCH), 5.93 (s, 0.7 H, 0.7 COCH), 6.20 (s, 0.3
H, 0.3 CONH), 7.46–7.16 (m, 9 H, Ar-H), 8.10 (d, 0.7 H, 0.7
N-[(2-Azidophenyl)(butylcarbamoyl)methyl]-N,3-diphenylpropan-
amide (1l): White crystals (yield 0.96 g, 70%). M.p. 180–181 °C. 1H
NMR (CDCl3, 400 MHz): δ = 0.90 (t, J = 7.2 Hz, 3 H, CH3), 1.27–
1.33 (m, 2 H, CH2), 1.43–1.49 (m, 2 H, CH2), 2.36 (t, J = 7.4 Hz,
2 H, CH2), 2.93 (t, J = 7.4 Hz, 2 H, CH2), 3.25–3.35 (m, 2 H,
CH2), 5.85 (s, 1 H, CONH), 6.30 (s, 1 H, COCH), 7.29–6.79 (m,
CONH) ppm. IR (KBr): ν = 3350, 3056, 2982, 2937, 2137, 1684,
˜
1617 cm–1. MS: m/z (%) = 337 (14) [M – N2]+, 223 (100), 106 (59),
77 (41). C20H23N5O2 (365.4): calcd. C 65.73, H 6.34, N 19.16;
found C 65.50, H 6.38, N 19.29.
14 H, Ar-H) ppm. IR (KBr): ν = 3349, 3053, 2973, 2935, 2191,
˜
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-4-chloro-N-ethyl-
benzamide (1f): White crystals (yield 1.15 g, 93 %). M.p. 207–
209 °C. 1H NMR (CDCl3, 400 MHz): δ = 0.77 (t, J = 6.8 Hz, 3 H,
CH3), 1.37 (s, 9 H, 3 CH3), 3.28–3.58 (m, 2 H, CH2), 5.27 (s, 1 H,
COCH), 5.86 (s, 1 H, CONH), 7.17–7.62 (m, 8 H, Ar-H) ppm. IR
1676, 1629 cm–1. MS: m/z (%) = 413 (10) [M – N3]+, 280 (45), 180
(100), 77 (69). C27H29N5O2 (455.6): calcd. C 71.19, H 6.42, N 15.37;
found C 71.11, H 6.28, N 15.19.
N-[(2-Azidophenyl)(butylcarbamoyl)methyl]-N-propylethanamide
(1m): White crystals (yield 0.78 g, 79 %). M.p. 100–102 °C. 1H
NMR (CDCl3, 600 MHz): δ = 0.68–1.47 (m, 12 H, CH2CH3
CH2CH2CH3), 2.17 (s, 2.4 H, 0.8 CH3), 2.28 (s, 0.6 H, 0.2 CH3),
3.18–3.30 (m, 4 H, 2 NCH2), 5.64 (s, 0.2 H, 0.2 COCH), 5.92 (s,
0.8 H, 0.8 COCH), 5.93–6.06 (m, 0.8 H, 0.8 CONH), 6.14–6.15 (m,
(KBr): ν = 3353, 3054, 2985, 2939, 2135, 1683, 1613 cm–1. MS: m/z
˜
(%) = 371 (7) [M – N3 ]+ , 271 (100), 106 (43), 77 (51).
C21H24ClN5O2 (413.9): calcd. C 60.94, H 5.84, N 16.92; found C
60.90, H 5.98, N 16.97.
+
N-[(2-Azidophenyl)(tert-butylcarbamoyl)methyl]-4-chloro-N-methyl-
benzamide (1g): White crystals (yield 1.08 g, 90 %). M.p. 211–
212 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.38 (s, 9 H, 3 CH3),
3.75 (s, 3 H, CH3), 5.26 (s, 0.8 H, 0.8 COCH), 5.64 (s, 0.4 H, 0.2
COCH + 0.2 CONH), 6.13 (s, 0.8 H, 0.8 CONH), 7.17–7.53 (m, 8
0.2 H, 0.2 CONH), 7.14–7.59 (m, 4 H, Ar-H) ppm. IR (KBr): ν =
˜
3273, 3079, 2959, 2932, 2871, 2126, 1679, 1622 cm–1. MS: m/z (%)
= 289 (3) [M – N3]+, 246 (63), 146 (100), 77 (38). C17H25N5O2
(331.4): calcd. C 61.61, H 7.60, N 21.13; found C 61.72, H 7.49, N
21.22.
H, Ar-H) ppm. IR (KBr): ν = 3341, 3056, 2978, 2928, 2125, 1689,
˜
1610 cm–1. MS: m/z (%) = 357 (14) [M – N3]+, 257 (100), 106 (59), N-[(2-Azidophenyl)(butylcarbamoyl)methyl]-N-butylethanamide
77 (41). C20H22ClN5O2 (399.9): calcd. C 60.07, H 5.55, N 17.51; (1n): White crystals (yield 0.65 g, 63%). M.p. 121–122 °C. 1H NMR
found C 60.21, H 5.69, N 17.26.
(CDCl3, 600 MHz): δ = 0.64–1.46 (m, 14 H, 2 CH2CH2CH3), 2.17
1091
Eur. J. Org. Chem. 2010, 1088–1095
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

P. He, J. Wu, Y.-B. Nie, M.-W. Ding
FULL PAPER
(s, 2.4 H, 0.8 CH3), 2.28 (s, 0.6 H, 0.2 CH3), 2.89 (s, 0.2 H, 0.1
NCH2), 3.24–3.29 (m, 3.6 H, 1.8 NCH2), 3.50 (s, 0.2 H, 0.1 NCH2),
1 H, NCH), 5.07 (s, 1 H, COCH), 6.92–7.49 (m, 13 H, Ar-H), 8.47
(s, 1 H, CONH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 11.2,
5.65 (s, 0.2 H, 0.2 COCH), 5.93 (s, 0.8 H, 0.8 COCH), 6.01 (s, 0.8 21.6, 28.6, 29.6, 51.8, 52.2, 64.3, 121.8, 124.3, 125.8, 126.8, 128.1,
H, 0.8 CONH), 6.15 (s, 0.2 H, 0.2 CONH), 7.16–7.60 (m, 4 H, Ar- 128.5, 128.7, 129.3, 131.8, 132.6, 133.4, 140.2, 140.8, 149.7, 169.2,
H) ppm. IR (KBr): ν = 3271, 3084, 2958, 2932, 2866, 2128, 1679,
171.3 ppm. IR (KBr): ν = 3314, 3056, 2963, 2928, 1659, 1620 cm–1.
˜
˜
1625 cm–1. MS: m/z (%) = 303 (2) [M – N3]+, 203 (100), 160 (47), 77 MS: m/z (%) = 402 (9) [M – 100]+, 254 (20), 214 (67), 105 (100).
(88). C18H27N5O2 (331.4): calcd. C 62.58, H 7.88, N 20.27; found C
62.72, H 7.99, N 20.21.
C29H31ClN4O2 (503.0): calcd. C 69.24, H 6.21, N 11.14; found C
69.07, H 6.04, N 11.18.
General Procedure for the Preparation of the 2,3,4-Trisubstituted
3,4-Dihydroquinazolines 4: Triphenylphosphane (0.26 g, 1 mmol)
was added with stirring to a solution of an azide 1 (1 mmol) in dry
toluene (10 mL). After stirring had been continued for 2–4 h, an
iminophosphorane 2 had formed, as was monitored by TLC. An
isocyanate (1 mmol) was then added dropwise to the mixture. A
carbodiimide 3 was formed (two were isolated), and the reaction
was found to be complete (monitoring by TLC) at room tempera-
ture after 2–6 h. The solution was then heated at reflux for 6–24 h.
After the reaction was complete, the solvent was evaporated, and
the residue was purified by column chromatography.
N-tert-Butyl-2-(N-phenylbenzamido)-3-propyl-3,4-dihydroquinazo-
line-4-carboxamide (4e): White crystals (yield 0.36 g, 76%). M.p.
205–206 °C. H NMR (CDCl3, 600 MHz): δ = 0.90 (t, J = 7.0 Hz,
3 H, CH3), 1.26 (s, 1 H, 1/3 CH3), 1.40 (s, 8 H, 8/3 CH3), 1.61–
1.75 (m, 2 H, CH2), 3.28–3.30 (m, 1 H, NCH), 3.62 (s, 1 H, NCH),
5.08 (s, 1 H, COCH), 6.93–7.50 (m, 14 H, Ar-H), 8.55 (s, 1 H,
CONH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 11.2, 21.5, 28.6,
51.8, 52.1, 64.3, 121.9, 124.3, 125.6, 126.8, 126.9, 126.9, 128.3,
128.7, 129.1, 129.4, 131.6, 133.8, 141.0, 141.6, 149.9, 169.4,
1
171.4 ppm. IR (KBr): ν = 3305, 3054, 2977, 2927, 2871, 1659,
˜
1619 cm–1. MS: m/z (%) = 470 (9) [M]+, 369 (87), 264 (14), 220 (44),
180 (81), 105 (100), 77 (88), 57 (66). C29H32N4O2 (468.6): calcd. C
74.33, H 6.88, N 11.96; found C 74.54, H 6.83, N 11.72.
N-tert-Butyl-2-[N-(4-chlorophenyl)benzamido]-3-isopropyl-3,4-dihy-
droquinazoline-4-carboxamide (4a): White crystals (yield 0.085 g,
17%). M.p. 243–244 °C. 1H NMR (CDCl3, 600 MHz): δ = 1.29–
1.38 (m, 15 H, 5 CH3), 4.57–4.62 (m, 1 H, NCH), 5.09 (s, 1 H,
COCH), 6.88–7.48 (m, 13 H, Ar-H), 8.63 (s, 1 H, CONH) ppm.
13C NMR (CDCl3, 100 MHz): δ = 19.8, 19.9, 22.0, 28.5, 50.6, 51.7,
58.6, 122.5, 123.9, 125.9, 126.8, 128.4, 128.5, 128.6, 129.3, 131.7,
3-Butyl-N-(tert-butyl)-2-[N-(4-chlorophenyl)benzamido]-3,4-dihydro-
quinazoline-4-carboxamide (4f): White crystals (yield 0.45 g, 88%).
1
M.p. 187–188 °C. H NMR (CDCl3, 600 MHz): δ = 0.89–0.96 (m,
3 H, CH3), 1.20–1.42 (m, 11 H, 3 CH3 + 1 CH2), 1.53–1.64 (m, 1
H, CH), 1.76–1.89 (m, 1 H, CH), 3.25–3.31 (m, 1 H, NCH), 3.61–
3.66 (m, 1 H, NCH), 5.08 (s, 1 H, COCH), 6.91–7.50 (m, 13 H,
Ar-H), 8.51 (s, 1 H, CONH) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 13.8, 20.0, 28.6, 30.4, 50.3, 51.8, 64.1, 121.7, 124.2, 125.8, 126.8,
128.1, 128.5, 128.7, 129.3, 131.9, 132.5, 133.3, 140.2, 140.7, 149.7,
132.6, 133.6, 140.6, 141.0, 149.8, 170.1, 171.3 ppm. IR (KBr): ν =
˜
3329, 3036, 2975, 1657, 1613 cm–1. MS: m/z (%) = 402 (100) [M –
100]+, 254 (58), 77 (89). C29H31ClN4O2 (503.0): calcd. C 69.24, H
6.21, N 11.14; found C 69.01, H 6.37, N 11.19.
N-tert-Butyl-2-[N-(4-fluorophenyl)benzamido]-3-propyl-3,4-dihydro-
quinazoline-4-carboxamide (4b): White crystals (yield 0.34 g, 69%).
M.p. 222–224 °C. 1H NMR (CDCl3, 600 MHz): δ = 0.91 (t, J =
6.6 Hz, 3 H, CH3), 1.40 (s, 9 H, 3 CH3), 1.61–1.67 (m, 1 H, CH),
1.82 (s, 1 H, CH), 3.28 (s, 1 H, NCH), 3.59–3.63 (m, 1 H, NCH),
5.08 (s, 1 H, COCH), 6.92–7.48 (m, 13 H, Ar-H), 8.51 (s, 1 H,
CONH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 11.2, 21.5, 28.5,
51.7, 52.0, 64.1, 115.9, 116.1, 121.7, 124.2, 125.6, 126.7, 128.3,
128.6, 128.7, 129.2, 131.6, 133.4, 137.5, 140.8, 149.7, 159.7, 162.2,
169.2, 171.3 ppm. IR (KBr): ν = 3309, 3055, 2965, 2931, 2873,
˜
1661, 1619 cm–1. MS: m/z (%) = 517 (18) [M]+, 416 (100), 312 (16),
214 (81), 105 (75), 77 (18), 57 (17). C30H33ClN4O2 (517.1): calcd.
C 69.69, H 6.43, N 10.84; found C 69.54, H 6.32, N 10.99.
3-Butyl-N-(tert-butyl)-2-(N-phenylbenzamido)-3,4-dihydroquinazo-
line-4-carboxamide (4g): White crystals (yield 0.41 g, 85%). M.p.
1
210–211 °C. H NMR (CDCl3, 400 MHz): δ = 0.91 (t, J = 7.2 Hz,
3 H, CH3), 1.80–1.92 (m, 13 H, 3 CH3 + 1 CH2CH2), 3.27–3.34
(m, 1 H, NCH), 3.64–3.71 (m, 1 H, NCH), 5.09 (s, 1 H, COCH),
6.92–7.50 (m, 14 H, Ar-H), 8.56 (s, 1 H, CONH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.7, 20.0, 28.6, 30.3, 51.7, 50.2, 64.2,
114.2, 121.8, 124.3, 125.6, 126.7, 126.9, 128.2, 128.6, 129.1, 129.3,
169.2, 171.4 ppm. IR (KBr): ν = 3310, 3054, 2979, 2928, 2872,
˜
1659, 1620 cm–1. MS: m/z (%) = 386 (100) [M – 100]+, 198 (21),
105 (8). C29H31FN4O2 (486.6): calcd. C 71.58, H 6.42, N 11.51;
found C 71.42, H 6.57, N 11.65.
131.5, 133.7, 141.0, 141.5, 149.9, 169.3, 171.3 ppm. IR (KBr): ν =
˜
N-tert-Butyl-3-propyl-2-[N-(m-tolyl)benzamido]-3,4-dihydroquinazo-
line-4-carboxamide (4c): White crystals (yield 0.38 g, 78%). M.p.
255–256 °C. H NMR (CDCl3, 600 MHz): δ = 0.90 (t, J = 7.0 Hz,
3312, 3058, 2962, 2931, 2874, 1665, 1620 cm–1. MS: m/z (%) = 382
(44) [M – 100]+, 221 (18), 180 (90), 105 (100), 77 (56). C30H34N4O2
(482.6): calcd. C 74.66, H 7.10, N 11.61; found C 74.43, H 7.24, N
11.66.
1
3 H), 1.40 (s, 9 H, 3 CH3), 1.78–1.61 (m, 2 H, CH2), 2.22 (s, 2.65
H, 2.65 Ar-CH), 2.35 (s, 0.35 H, 0.35 Ar-CH), 3.31–3.27 (m, 1 H,
NCH), 3.61–3.57 (m, 1 H, NCH), 5.08 (s, 1 H, COCH), 7.50–6.86
(m, 13 H, Ar-H), 8.57 (s, 1 H, CONH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 11.2, 21.2, 21.5, 28.6, 51.8, 52.1, 64.4, 121.9, 124.1,
124.4, 125.6, 126.7, 127.5, 127.7, 128.2, 128.6, 128.8, 129.0, 129.3,
131.4, 134.0, 139.1, 141.1, 141.4, 149.9, 169.4, 171.4 ppm. IR
3-Butyl-N-(tert-butyl)-2-[N-(4-fluorophenyl)benzamido]-3,4-dihydro-
quinazoline-4-carboxamide (4h): White crystals (yield 0.42 g, 83%).
M.p. 231–232 °C. 1H NMR (CDCl3, 400 MHz): δ = 0.92 (t, J =
7.4 Hz, 3 H, CH3), 1.28–1.39 (m, 11 H, 3 CH3 + 1 CH2), 1.54–1.68
(m, 1 H, CH), 1.72–1.80 (m, 1 H, CH), 3.26–3.34 (m, 1 H, NCH),
3.62–3.70 (m, 1 H, NCH), 5.08 (s, 1 H, COCH), 6.91–7.48 (m, 13
H, Ar-H), 8.53 (s, 1 H, CONH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 13.7, 20.0, 28.5, 30.4, 50.2, 51.7, 64.1, 115.9, 116.2,
121.7, 124.2, 125.7, 126.7, 128.3, 128.6, 128.7, 129.2, 131.6, 133.4,
(KBr): ν = 3302, 3043, 2977, 2960, 2927, 2872, 1657, 1620 cm–1.
˜
MS: m/z (%) = 382 (100) [M – 100]+, 198 (21), 105 (8). C30H34N4O2
(482.6): calcd. C 74.66, H 7.10, N 11.61; found C 74.88, H 7.14, N
11.43.
N-tert-Butyl-2-[N-(4-chlorophenyl)benzamido]-3-propyl-3,4-dihydro-
quinazoline-4-carboxamide (4d): White crystals (yield 0.43 g, 85%).
M.p. 233–235 °C. 1H NMR (CDCl3, 600 MHz): δ = 0.89 (t, J =
7.0 Hz, 3 H, CH3), 1.25 (s, 1 H, 1/3 CH3), 1.39 (s, 8 H, 8/3 CH3),
137.6, 140.8, 149.7, 159.7, 162.2, 169.2, 171.4 ppm. IR (KBr): ν =
˜
3309, 3062, 2964 2933, 2873 1661, 1620 cm–1. MS: m/z (%) = 400
(100) [M – 100]+, 238 (34), 198 (75), 105 (61), 77 (42), 57 (41).
C30H33FN4O2 (500.6): calcd. C 71.98, H 6.64, N 11.19; found C
1.61–1.69 (m, 2 H, CH2), 3.24–3.30 (m, 1 H, NCH), 3.54–3.60 (m, 71.82, H 6.67, N 11.34.
1092
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1088–1095

Unexpected Synthesis of Rearranged 3,4-Dihydroquinazolines
N-(tert-Butyl)-3-ethyl-2-(N-phenylbenzamido)-3,4-dihydroquinazo-
N-(tert-Butyl)-2-(4-chloro-N-phenylbenzamido)-3-ethyl-3,4-dihydro-
line-4-carboxamide (4i): White crystals (yield 0.41 g, 90%). M.p. quinazoline-4-carboxamide (4n): White crystals (yield 0.43 g, 89%).
1
211–213 °C. H NMR (CDCl3, 400 MHz): δ = 1.29 (t, J = 6.8 Hz, M.p. 264–265 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.26 (t, J =
3 H, CH3), 1.40 (s, 9 H, 3 CH3), 3.45–3.51 (m, 1 H, NCH), 3.73– 6.8 Hz, 3 H, CH3), 1.39 (s, 9 H, 3 CH3), 3.43–3.49 (m, 1 H, NCH),
3.78 (m, 1 H, NCH), 5.09 (s, 1 H, COCH), 6.92–7.50 (m, 14 H,
Ar-H), 8.54 (s, 1 H, CONH) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 13.6, 28.6, 45.1, 51.7, 63.8, 121.8, 124.3, 125.6, 126.7, 126.9,
127.0, 128.2, 128.6, 129.1, 129.3, 131.5, 133.7, 141.0, 141.4, 149.7,
3.69–3.74 (m, 1 H, NCH), 5.08 (s, 1 H, COCH), 6.93–7.44 (m, 13
H, Ar-H), 8.46 (s, 1 H, CONH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 13.6, 28.6, 45.1, 51.8, 63.8, 121.7, 124.4, 125.7,
126.7, 127.0, 127.2, 128.5, 128.7, 129.3, 130.8, 132.0, 137.8, 140.8,
169.4, 171.2 ppm. IR (KBr): ν = 3323, 3063, 2972, 2931, 1657,
141.1, 149.5, 169.4, 170.1 ppm. IR (KBr): ν = 3327, 2973, 2931,
˜
˜
1612 cm–1. MS: m/z (%) = 354 (3) [M – 100]+, 180 (20), 105 (79),
77 (94), 57 (100). C28H30N4O2 (454.6): calcd. C 73.98, H 6.65, N
12.33; found C 73.93, H 6.78, N 12.56.
1665, 1609 cm–1. MS: m/z (%) = 488 (4) [M]+, 388 (100), 360 (21),
283 (79), 105 (25), 77 (61). C28H29ClN4O2 (489.0): calcd. C 68.77,
H 5.98, N 11.46; found C 68.72, H 6.13, N 11.59.
N-(tert-Butyl)-2-[4-chloro-N-(4-chlorophenyl)benzamido]-3-ethyl-
3,4-dihydroquinazoline-4-carboxamide (4o): White crystals (yield
0.46 g, 88%). M.p. 254–255 °C. H NMR (CDCl3, 400 MHz): δ =
1.27 (t, J = 6.4 Hz, 3 H, CH3), 1.39 (s, 9 H, 3 CH3), 3.44–3.47 (m,
1 H, NCH), 3.65–3.70 (m, 1 H, NCH), 5.08 (s, 1 H, COCH), 6.92–
7.44 (m, 12 H, Ar-H), 8.38 (s, 1 H, CONH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.7, 28.6, 45.2, 51.8, 63.8, 121.7, 124.3,
125.9, 126.8, 128.2, 128.7, 129.5, 130.8, 131.6, 133.0, 138.1, 139.8,
N-(tert-Butyl)-3-ethyl-2-[N-(4-fluorophenyl)benzamido]-3,4-dihydro-
quinazoline-4-carboxamide (4j): White crystals (yield 0.41 g, 87%).
M.p. 190–192 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.30 (t, J =
7.0 Hz, 3 H, CH3), 1.40 (s, 9 H, 3 CH3), 3.45–3.51 (m, 1 H, NCH),
3.72–3.77 (m, 1 H, NCH), 5.09 (s, 1 H, COCH), 6.93–7.48 (m, 13
H, Ar-H), 8.51 (s, 1 H, CONH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 13.7, 28.5, 45.1, 51.7, 63.7, 116.0, 116.2, 121.7,
124.2, 125.7, 126.7, 128.3, 128.7, 128.8, 128.8, 129.3, 131.6, 133.4,
1
140.7, 149.3, 169.3, 170.0 ppm. IR (KBr): ν = 3318, 3036, 2974,
˜
140.8, 149.6, 159.8, 162.3, 169.3, 171.3 ppm. IR (KBr): ν = 3323,
˜
1662, 1615 cm–1. MS: m/z (%) = 522 (2) [M]+, 422 (100), 254 (20),
153 (67), 111 (40). C28H28Cl2N4O2 (523.5): calcd. C 64.25, H 5.39,
N 10.70; found C 64.18, H 5.43, N 10.94.
3062, 2972, 2932, 1660, 1613 cm–1. MS: m/z (%) = 473 (6) [M]+,
372 (75), 268 (8), 198 (87), 105 (100), 77 (47). C28H29FN4O2
(472.6): calcd. C 71.17, H 6.19, N 11.86; found C 71.02, H 6.34, N
11.89.
N-(tert-Butyl)-2-[4-chloro-N-(4-fluorophenyl)benzamido]-3-ethyl-
3,4-dihydroquinazoline-4-carboxamide (4p): White crystals (yield
N-(tert-Butyl)-3-ethyl-2-[N-(m-tolyl)benzamido]-3,4-dihydroquinazo-
line-4-carboxamide (4k): White crystals (yield 0.42 g, 89%). M.p.
1
0.41 g, 81%). M.p. 254–255 °C. H NMR (CDCl3, 400 MHz): δ =
1.28 (t, J = 6.8 Hz, 3 H, CH3), 1.39 (s, 9 H, 3 CH3), 3.43–3.48 (m,
1 H, NCH), 3.68–3.73 (m, 1 H, NCH), 5.08 (s, 1 H, COCH), 6.92–
7.43 (m, 12 H, Ar-H), 8.41 (s, 1 H, CONH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.6, 28.5, 45.0, 51.7, 63.7, 116.2, 116.4,
121.6, 124.2, 125.8, 126.7, 128.6, 128.7, 128.8, 130.7, 131.7, 137.1,
1
221–223 °C. H NMR (CDCl3, 400 MHz): δ = 1.29 (t, J = 6.8 Hz,
3 H, CH3), 1.40 (s, 9 H, 3 CH3), 2.35 (s, 3 H, Ar-CH3), 3.46–3.51
(m, 1 H, NCH), 3.72–3.77 (m, 1 H, NCH), 5.09 (s, 1 H, COCH),
6.86–7.50 (m, 13 H, Ar-H), 8.56 (s, 1 H, CONH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.6, 21.2, 28.6, 45.1, 51.7, 63.8, 121.9,
124.2, 124.4, 125.5, 126.7, 127.5, 127.8, 128.1, 128.6, 128.8, 129.3,
131.4, 133.8, 139.1, 141.0, 141.3, 149.8, 169.5, 171.2 ppm. IR
137.8, 140.6, 149.3, 159.9, 162.4, 169.2, 170.1 ppm. IR (KBr): ν =
˜
3333, 2977, 1667, 1612 cm–1. MS: m/z (%) = 506 (1) [M]+, 406
(100), 377 (26), 248 (45), 140 (21), 77 (72). C28H28ClFN4O2 (507.0):
calcd. C 66.33, H 5.57, N 11.05; found C 66.48, H 5.42, N 11.21.
(KBr): ν = 3300, 3040, 2972, 2928, 1658, 1619 cm–1. MS: m/z (%)
˜
= 470 (7) [M]+, 369 (98), 234 (12), 194 (98), 105 (100), 77 (46), 57
(44). C29H32N4O2 (468.6): calcd. C 74.33, H 6.88, N 11.96; found
C 74.30, H 6.61, N 12.09.
N-(tert-Butyl)-2-(4-chloro-N-isopropylbenzamido)-3-ethyl-3,4-dihy-
droquinazoline-4-carboxamide (4q): White crystals (yield 0.36 g,
79%). M.p. 232–234 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.16–
1.54 (m, 18 H, 6 CH3), 3.40–3.43 (m, 1 H, NCH), 3.48–3.52 (m, 1
H, NCH), 4.20–4.22 (m, 1 H, CH), 5.02 (s, 1 H, COCH), 7.12–7.49
(m, 8 H, Ar-H), 8.38 (s, 1 H, NH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 13.0, 19.5, 23.8, 28.4, 44.3, 51.5, 52.9, 63.2, 122.1,
124.2, 125.5, 126.6, 127.9, 128.6, 129.0, 133.6, 136.5, 140.4, 147.0,
N-(tert-Butyl)-3-methyl-2-(N-phenylbenzamido)-3,4-dihydroquinazo-
line-4-carboxamide (4l): White crystals (yield 0.40 g, 90%). M.p.
192–193 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.40 (s, 9 H, 3 CH3),
3.27 (s, 3 H, CH3), 5.02 (s, 1 H, COCH), 6.91–7.48 (m, 14 H, Ar-
H), 8.43 (s, 1 H, CONH) ppm. 13C NMR (CDCl3, 100 MHz): δ =
28.6, 37.9, 51.7, 67.5, 121.4, 121.4, 124.4, 125.6, 126.9, 127.1, 128.1,
128.6, 129.1, 129.3, 131.5, 133.5, 140.8, 141.3, 149.9, 168.6,
169.3, 172.2 ppm. IR (KBr): ν = 3305, 3051, 2972, 2932, 2878,
˜
1668, 1647, 1613 cm–1. MS: m/z (%) = 454 (3) [M]+, 354 (100), 283
(15), 255 (32), 153 (54). C25H31ClN4O2 (455.0): calcd. C 65.99, H
6.87, N 12.31; found C 65.74, H 6.85, N 12.26.
170.8 ppm. IR (KBr): ν = 3338, 3067, 3032, 2968, 2922, 1676, 1643,
˜
1619 cm–1. MS: m/z (%) = 440 (1) [M]+, 340 (100), 234 (15), 180
(96), 118 (21), 105 (59), 77 (20). C27H28N4O2 (440.5): calcd. C
73.61, H 6.41, N 12.72; found C 73.38, H 6.65, N 12.87.
N-(tert-Butyl)-2-[4-chloro-N-(m-tolyl)benzamido]-3-methyl-3,4-dihy-
droquinazoline-4-carboxamide (4r): White crystals (yield 0.41 g,
1
84%). M.p. 233–234 °C. H NMR (CDCl3, 400 MHz): δ = 1.39 (s,
N-(tert-Butyl)-2-[N-(4-chlorophenyl)benzamido]-3-methyl-3,4-dihydro-
quinazoline-4-carboxamide (4m): White crystals (yield 0.39 g, 83%).
9 H, 3CH3), 2.26 (s, 3 H, CH3), 3.24 (s, 3 H, NCH), 5.02 (s, 1 H,
COCH), 6.86–7.43 (m, 12 H, Ar-H), 8.36 (s, 1 H, CONH) ppm.
13C NMR (CDCl3, 100 MHz): δ = 21.2, 28.6, 37.8, 51.7, 67.5,
121.3, 124.2, 124.5, 125.6, 126.4, 127.2, 128.2, 128.4, 128.6, 129.1,
130.7, 132.0, 137.7, 139.4, 140.7, 140.9, 149.7, 168.6, 169.7 ppm.
1
M.p. 203–204 °C. H NMR (CDCl3, 400 MHz): δ = 1.40 (s, 9 H,
3 CH3), 3.25 (s, 3 H, CH3), 5.01 (s, 1 H, COCH), 6.91–7.48 (m, 13
H, Ar-H), 8.35 (s, 1 H, CONH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 28.6, 38.0, 51.8, 67.5, 121.3, 124.4, 125.8, 126.5,
128.2, 128.4, 128.8, 129.3, 129.4, 131.8, 132.8, 133.2, 140.0, 140.7,
IR (KBr): ν = 3318, 3044, 2976, 1666, 1615 cm–1. MS: m/z (%) =
˜
488 (2) [M]+, 388 (91), 234 (11), 228 (100), 139 (38), 111 (13), 57
(13). C28H29ClN4O2 (489.0): calcd. C 68.77, H 5.98, N 11.46; found
C 68.82, H 5.94, N 11.32.
149.8, 168.5, 170.8 ppm. IR (KBr): ν = 3332, 3067, 3032, 2970,
˜
2926, 1678, 1651, 1621 cm–1. MS: m/z (%) = 474 (2) [M]+, 374
(100), 268 (11), 214 (94), 140 (7), 105 (78), 77 (20). C27H27ClN4O2
(475.0): calcd. C 68.27, H 5.73, N 11.80; found C 68.13, H 5.87, N
11.84.
N-(tert-Butyl)-2-(4-chloro-N-phenylbenzamido)-3-methyl-3,4-dihy-
droquinazoline-4-carboxamide (4s): White crystals (yield 0.42 g,
Eur. J. Org. Chem. 2010, 1088–1095
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1093

P. He, J. Wu, Y.-B. Nie, M.-W. Ding
FULL PAPER
89%). M.p. 237–238 °C. H NMR (CDCl3, 400 MHz): δ = 1.40 (s,
1
138.2, 139.6, 140.4, 169.1, 171.0 ppm. IR (KBr): ν = 3300, 3071,
˜
9 H, 3 CH3), 3.24 (s, 3 H, NCH), 5.01 (s, 1 H, COCH), 7.47–6.91
2970, 2927, 2138, 1683, 1646 cm–1. MS: m/z (%) = 454 (10) [M]+,
(m, 13 H, Ar-H), 8.35 (s, 1 H, CONH) ppm. 13C NMR (CDCl3, 293 (100), 331 (26), 206 (66), 180 (91), 158 (69), 130 (99), 91 (69), 77
100 MHz): δ = 28.6, 37.9, 51.7, 67.4, 121.3, 124.5, 125.7, 126.4,
126.9, 127.4, 128.5, 128.7, 129.4, 130.8, 131.8, 137.8, 140.6, 140.9,
(30). C28H30N4O2 (454.6): calcd. C 73.98, H 6.65, N 12.33; found C
74.03, H 6.62, N 12.30.
149.7, 168.5, 169.7 ppm. IR (KBr): ν = 3317, 3037, 2973, 1667,
˜
Carbodiimide 3x: White crystals (yield 0.49 g, 84%). M.p. 103–
105 °C. H NMR (CDCl3, 600 MHz): δ = 0.90 (t, J = 7.2 Hz, 3 H,
1615 cm–1. MS: m/z (%) = 474 (3) [M]+, 374 (100), 277 (82), 234
(34), 214 (88), 141 (20), 111 (22), 77 (17), 57 (26). C27H27ClN4O2
(475.0): calcd. C 68.27, H 5.73, N 11.80; found C 68.40, H 5.70, N
11.64.
1
CH3), 1.30–1.49 (m, 2 H, CH2), 1.48–1.51 (m, 2 H, CH2), 2.16 (s,
3 H, CH3), 3.32–3.37 (m, 2 H, CH2), 5.88 (s, 1 H, CONH), 6.53 (s,
1 H, COCH), 6.80–7.69 (m, 16 H, Ar-H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 13.7, 20.0, 28.6, 31.4, 39.6, 62.0, 124.9, 125.3, 125.5,
125.6, 127.7, 128.3, 128.7, 129.0, 129.6, 129.7, 129.8, 130.0, 131.2,
131.3, 133.7, 134.5, 135.3, 136.3, 137.1, 137.7, 138.0, 169.3,
N-Butyl-2-[N-(4-chlorophenyl)benzamido]-3-propyl-3,4-dihydroquin-
azoline-4-carboxamide (4t): White crystals (yield 0.34 g, 67%). M.p.
1
123–124 °C. H NMR (CDCl3, 600 MHz): δ = 0.88–0.91 (m, 6 H,
2 CH3), 1.31–1.35 (m, 2 H, CH2), 1.58–1.60 (m, 3 H, CH + CH2),
1.94 (s, 1 H, CH), 3.26 (t, J = 6.9 Hz, 2 H, NCH2), 3.32–3.36 (m,
1 H, NCH), 3.60–3.65 (m, 1 H, NCH), 5.17 (s, 1 H, COCH), 6.95–
7.50 (m, 13 H, Ar-H), 8.93 (s, 1 H, CONH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 11.1, 13.6, 20.0, 21.5, 31.1, 39.5, 51.8, 63.5,
121.6, 124.3, 125.8, 126.8, 128.0, 128.4, 128.8, 129.3, 131.9, 132.6,
170.0 ppm. IR (KBr): ν = 3336, 3062, 2956, 2934, 2870, 2130, 1672,
˜
1632 cm–1. MS: m/z (%) = 584 (10) [M]+, 484 (100), 353 (38), 242
(62), 180 (91), 153 (24), 111 (74), 77 (30). C33H30Cl2N4O2 (585.5):
calcd. C 67.69, H 5.16, N 9.57; found C 67.73, H 5.22, N 9.60.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of 1a–n, 3w, 3x and
4a–v.
133.2, 140.0, 140.8, 149.5, 169.6, 171.7 ppm. IR (KBr): ν = 3297,
˜
3071, 2960, 2931, 2870, 1668, 1651, 1618 cm–1. MS: m/z (%) = 503
(1) [M]+, 402 (100), 254 (58), 77 (89). C29H31ClN4O2 (503.0): calcd.
C 69.24, H 6.21, N 11.14; found C 69.46, H 6.14, N 11.01.
Acknowledgments
N,3-Dibutyl-2-[N-(4-chlorophenyl)benzamido]-3,4-dihydroquinazo-
line-4-carboxamide (4u): White crystals (yield 0.32 g, 61%). M.p.
We gratefully acknowledge financial support of this work from the
National Natural Science Foundation of China (No. 20772041) and
as a Key Project of the Chinese Ministry of Education (No.
107082).
1
166–167 °C. H NMR (CDCl3, 600 MHz): δ = 0.88–0.92 (m, 6 H,
2 CH3), 1.21–1.36 (m, 4 H, 2 CH2), 1.54–1.62 (m, 3 H, CHCH2),
1.77–1.78 (m, 1 H, CH), 3.24–3.28 (m, 2 H, NCH2), 3.29–3.36 (m,
1 H, NCH), 3.65–3.70 (m, 1 H, NCH), 5.17 (s, 1 H, COCH), 6.94–
7.50 (m, 13 H, Ar-H), 8.93 (s, 1 H, CONH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.7, 19.9, 20.0, 30.3, 31.1, 39.5, 50.0, 63.4,
121.6, 124.3, 125.8, 126.8, 128.0, 128.4, 128.8, 129.3, 131.9, 132.6,
[1] A. C. Tinker, H. G. Beaton, N. Boughton-Smith, T. R. Cook,
S. L. Cooper, L. Fraser-Rae, K. Hallam, P. Hamley, T. McIn-
ally, D. J. Nicholls, A. D. Pimm, A. V. Wallace, J. Med. Chem.
2003, 46, 913–916.
133.2, 140.0, 140.8, 149.6, 169.7, 171.7 ppm. IR (KBr): ν = 3330,
˜
3068, 2957, 2930, 2870, 1675, 1649, 1614 cm–1. MS: m/z (%) = 516
(2) [M]+, 416 (100), 254 (43), 77 (92). C30H33ClN4O2 (517.1): calcd.
C 69.69, H 6.43, N 10.84; found C 69.73, H 6.40, N 10.71.
[2] V. D. Piaz, M. P. Giovannoni, Eur. J. Med. Chem. 2000, 35,
463–480.
[3] H. B. Cottam, H. Shih, L. R. Tehrani, B. Wasson, D. A. Car-
son, J. Med. Chem. 1996, 39, 2–9.
[4] J. C. Sircar, T. Capiris, S. J. Kesten, D. J. Herzig, J. Med. Chem.
1981, 24, 735–742.
[5] R. E. Harris, G. A. Alshafie, H. Abou-Issa, K. Seibert, Cancer
Res. 2000, 60, 2101–2103.
[6] J. H. Heo, H. N. Seo, Y. J. Choe, S. Kim, C. R. Oh, Y. D. Kim,
H. Rhim, D. J. Choo, J. Kim, J. Y. Lee, Bioorg. Med. Chem.
Lett. 2008, 18, 3899–3901.
[7] J. Y. Choi, H. N. Seo, M. J. Lee, S. J. Park, S. J. Park, J. Y. Jeon,
J. H. Kang, A. N. Pae, H. Rhim, J. Y. Lee, Bioorg. Med. Chem.
Lett. 2007, 17, 471–475.
[8] H. N. Seo, J. Y. Choi, Y. J. Choe, Y. Kim, H. Rhim, S. H. Lee,
J. Kim, D. J. Joo, J. Y. Lee, Bioorg. Med. Chem. Lett. 2007, 17,
5740–5743.
[9] Y. S. Lee, B. H. Lee, S. J. Park, S. B. Kang, H. Rhim, J.-Y. Park,
J.-H. Lee, S.-W. Jeong, J. Y. Lee, Bioorg. Med. Chem. Lett.
2004, 14, 3379–3384.
[10] A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168–
3210.
[11] A. Dömling, Chem. Rev. 2006, 106, 17–89.
[12] L. E. Kaim, M. Gizzi, L. Grimaud, Org. Lett. 2008, 10, 3417–
3419.
[13] L. Fan, A. M. Adams, J. G. Polisar, B. Ganem, J. Org. Chem.
2008, 73, 9720–9726.
[14] F. Velazquez, S. Venkatraman, W. Wu, M. Blackman, A.
Prongay, V. Girijavallabhan, N. Y. Shih, F. G. Njoroge, Org.
Lett. 2007, 9, 3061–3064.
[15] H. Liu, A. Dömling, J. Org. Chem. 2009, 74, 6895–6898.
[16] M. Krasavin, S. Shkavrov, V. Parchinsky, K. Bukhryakov, J.
Org. Chem. 2009, 74, 2627–2629.
N,3-Dibutyl-2-[N-(4-chlorophenyl)acetamido]-3,4-dihydroquinazo-
line-4-carboxamide (4v): White crystals (yield 0.30 g, 67%). M.p.
1
108–109 °C. H NMR (CDCl3, 600 MHz): δ = 0.83–0.94 (m, 6 H,
2 CH3), 1.28–1.81 (m, 8 H, 4 CH2), 2.07 (s, 3 H, CH3), 3.14–3.23
(m, 2 H, NCH2), 3.28–3.32 (m, 1 H, NCH), 3.61–3.66 (m, 1 H,
NCH), 5.10 (s, 1 H, COCH), 6.99–7.47 (m, 8 H, Ar-H), 8.92 (s, 1
H, CONH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.7, 13.8,
20.0, 20.1, 23.0, 30.3, 31.2, 39.5, 49.7, 63.1, 121.6, 124.2, 125.9,
126.9, 128.8, 129.4, 129.7, 134.7, 138.3, 140.8, 148.3, 169.5,
172.8 ppm. IR (KBr): ν = 3290, 3075, 2959, 2932, 2871, 1699, 1650,
˜
1613 cm–1. MS: m/z (%) = 454 (4) [M]+, 354 (100), 298 (76), 254
(32), 126 (57), 77 (88). C25H31ClN4O2 (455.0): calcd. C 65.99, H
6.87, N 12.31; found C 65.71, H 6.93, N 12.50.
Isolation of the Carbodiimides 3: Triphenylphosphane (0.26 g,
1 mmol) was added with stirring to a solution of an azide 1
(1 mmol) in dry toluene. After stirring had been continued for 2–
4 h, isocyanate (1 mmol) was added dropwise to the mixture. After
further stirring for 2–6 h, the solution was concentrated under re-
duced pressure, and the residue was recrystallized from dichloro-
methane/petroleum ether to give a carbodiimide 3.
Carbodiimide 3w: White crystals (yield 0.39 g, 87%). M.p. 167–
168 °C. 1H NMR (CDCl3, 600 MHz): δ = 1.38 (s, 9 H, 3CH3), 1.88
(s, 3 H, COCH3), 2.36 (s, 3 H, CH3), 5.58 (s, 1 H, CONH), 6.36 (s,
1 H, COCH), 6.84–7.27 (m, 13 H, Ar-H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 21.3, 23.3, 28.6, 51.6, 60.4, 124.6, 121.2, 124.8,
125.2, 126.6, 127.8, 128.7, 128.8, 129.3, 129.5, 129.9, 130.0, 131.0,
1094
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1088–1095

Unexpected Synthesis of Rearranged 3,4-Dihydroquinazolines
[17] B. B. Touré, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486.
[18] S. P. Marsden, A. E. McGonagle, B. McKeever-Abbas, Org.
Lett. 2008, 10, 2589–2591.
[19] D. Lertpibulpanya, S. P. Marsden, I. Rodriguez-Garcia, C. A.
Kilner, Angew. Chem. Int. Ed. 2006, 45, 5000–5002.
[20] F. Palacios, C. Alonso, D. Aparicio, G. Rubiales, J. M. Santos,
Tetrahedron 2007, 63, 523–575.
[21] N. Zanatta, J. M. F. M. Schneider, P. H. Schneider, A. D. Wout-
ers, H. G. Bonacorso, M. A. P. Martins, L. A. Wessjohann, J.
Org. Chem. 2006, 71, 6996–6998.
[22] M. Sañudo, M. García-Valverde, S. Marcaccini, J. J. Delgado,
J. Rojo, T. Torroba, J. Org. Chem. 2009, 74, 2189–2192.
[23] N. Y. Huang, M. G. Liu, M. W. Ding, J. Org. Chem. 2009, 74,
6874–6877.
[24] P. He, J. Wu, Y. B. Nie, M. W. Ding, Tetrahedron 2009, 65,
8563–8570.
[25] J. Z. Yuan, B. Q. Fu, M. W. Ding, G. F. Yang, Eur. J. Org.
Chem. 2006, 4170–4176.
[26] M. G. Liu, Y. G. Hu, M. W. Ding, Tetrahedron 2008, 64, 9052–
9059.
[27] N. Y. Huang, Y. J. Liang, M. W. Ding, L. W. Fu, H. W. He,
Bioorg. Med. Chem. Lett. 2009, 19, 831–833.
[28] H. Ulrich, Chemistry and Technology of Carbodiimide, John
Wiley & Sons, Ltd. 2007, p. 99.
[29] P. Molina, M. Alajarin, A. Vidal, Tetrahedron 1989, 45, 4263–
4286.
Received: November 10, 2009
Published Online: January 12, 2010
Eur. J. Org. Chem. 2010, 1088–1095
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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