New efficient synthesis of 2,3,4-trisubstituted 3,4-dihydroquinazolines by a Ugi 4CC/Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1016/j.tet.2011.03.056

A series of 2,3,4-trisubstituted 3,4-dihydroquinazoline 3 was prepared by intramolecular aza-Wittig reaction of amide carbonyl groups with methyldiphenyl iminophosphorane, which was obtained from a Ugi 4CC/Staudinger sequence. Further intramolecular Heck

Full text of DOI:10.1016/j.tet.2011.03.056

Tetrahedron 67 (2011) 3714e3723
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New efficient synthesis of 2,3,4-trisubstituted 3,4-dihydroquinazolines by a Ugi
4CC/Staudinger/aza-Wittig sequence
*
Ying Zhong, Long Wang, Ming-Wu Ding
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2,3,4-trisubstituted 3,4-dihydroquinazoline 3 was prepared by intramolecular aza-Wittig
reaction of amide carbonyl groups with methyldiphenyl iminophosphorane, which was obtained from
a Ugi 4CC/Staudinger sequence. Further intramolecular Heck reaction of 3d0eg0 in the presence of cat-
alytic amount of Pd(OAc)2 gave 6,12-dihydroindolo[2,1-b]quinazolines 4aed in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 January 2011
Received in revised form 8 March 2011
Accepted 17 March 2011
Available online 30 March 2011
1. Introduction
the sequence of Ugi and Passerini reaction starting from some azide
precursors, followed by post-condensation of Staudinger and
3,4-Dihydroquinazolines have widespread biological activities
and a wide variety of derivatives of this ring system have been used
aza-Wittig reaction, has been recently utilized in synthesis of various
heterocycles, such as 1,4-benzodiazepine-5-ones,7 dibenzo[b,f]-
1,5-diazocine-6(5H)-ones,8 5-oxo-1,4-diazepines,9 4H-3,1-benzox-
azine,10 3,4-dihydroquinazolines,11 indolo[1,2-c]quinazolines,12 and
oxazolines.13 Continuing our interest in the synthesis of N-hetero-
cycles via the aza-Wittig reaction,14 we report herein a new efficient
synthesis of trisubstituted 3,4-dihydroquinazolines by a Ugi 4CC/
Staudinger/aza-Wittig sequence.
as BACE-1 inhibitor,
a-MSH-induced melanin inhibitor, anti-in-
flammatory, anti-allergic, anti-malarial agent, and especially as
cancer treatment agent.1 For example, some 3,4-dihydroquinazo-
lines were reported to have potent T-type channel blocking activity
and anti-cancer activity, their growth inhibition of human cancer
cells is similar to that of Doxorubicin and has little cytotoxicity.2
There are many known methods for the synthesis of 3,4-dihy-
droquinazolines.3 However, multisubstituted 4-aminocarbonyl-
3,4-dihydroquinazolines have not yet been prepared previously
probably due to the fact that they are not easily accessible by
routine synthetic method. Multisubstituted 4-aminocarbonyl-3,4-
dihydro quinazoline is a very attractive target for biochemical
studies and drug discovery, due to its large number of possible
substitution patterns and interesting combination of potential hy-
drogen bond donors and acceptors on the amide moiety.
2. Results and discussion
A mixture of 2-azidobenzaldehyde (1 equiv), amine (1 equiv),
isocyanide (1 equiv), and acid (1 equiv) was stirred in methanol at
room temperature for 12e36 h until solid precipitated (Scheme 1).
The Ugi reaction was carried out smoothly and the azide products 1
were obtained in satisfactory yields after recrystallization (Scheme
1 and Table 1).11
Ugi reaction is a powerful, atom-economical I-MCRs starting from
isonitrile, amine, aldehyde (or ketone), and carboxylic acid compo-
R1 NC
nents that generates a significantly more complex
a-acylamino
O
R1HN
R3
N
CHO
amide adduct.4 The sequences of classical Ugi isocyanide multi-
component reactions, followed by post-condensation trans-
formations, constitute extremely powerful synthetic tools for the
preparation of structurally diverse heterocyclic compounds.5 On the
otherhand, aza-Wittig reactions have received increased attentionin
view of their utility in the synthesis of nitrogen-containing hetero-
cycles.6 Thus, it is envisioned that combining the efficiency of the Ugi
condensation with a post-condensation aza-Wittig reaction would
facilitate access to a series of biologically useful heterocycles. Indeed,
MeOH
rt
R2
N3
O
R2 COOH
R3 NH2
N3
1
Scheme 1. Preparation of compounds 1.
Initially, the reactions of azides 1 with triphenylphosphine were
examined in toluene at room temperature for 2 h, followed by
heating at reflux for 6e24 h. Nitrogen evolution via the Staudinger
* Corresponding author. Tel.: þ86 27 63158845; fax: þ86 27 67862041; e-mail
address: ding5229@yahoo.com.cn (M.-W. Ding).
reaction ceased during the first
2
h
to give triphenyl
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.056

Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
3715
Table 1
been recognized for many years and triphenyl iminophosphorane
was replaced by more reactive trialkyl iminophosphorane to pro-
vide better results in some cases (Scheme 2).15d,c,17
Preparation of azides 1 via Ugi 4CC reaction
R1
R2
R3
Time (h)
Yielda (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1q
1r
t-Bu
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
n-Bu
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
n-Bu
H
H
CF3
CF3
CH3
CH3
CH3CH2
4-NO2C6H4
4-NO2C6H4
Ph
4-MeC6H4
2-FC6H4
2-MeC6H4
Ph
4-ClC6H4
4-MeC6H4
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-ClC6H4
Ph
Ph
Ph
PhCH]CHe
PhCH]CHe
4-ClC6H4CH]CHe
4-ClC6H4CH]CHe
4-ClC6H4
4-MeC6H4
4-ClC6H4
Ph
24
24
12
12
12
12
12
12
36
36
36
24
24
36
24
36
36
24
24
24
36
36
36
36
24
36
36
36
36
74
85
67
66
92
81
78
85
73
90
87
83
69
70
81
77
75
91
83
88
82
86
82
74
87
74
78
72
70
O
R1HN
O
R3
N
R1HN
R3
N
R2
Ph2PR
R2
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
c-C6H11
O
N
O
N3
PPh2R
2
1
R1HN
O
N
R3
R2
N
3
t-Bu
t-Bu
t-Bu
1s
1t
Scheme 2. Preparation of compounds 3.
1u
1v
1w
1x
1z
1a0
1b0
1c0
1d0
1e0
1f0
1g0
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-EtOC6H4
2-MeC6H4
3-ClC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
We have now observed that a simple change in phosphorus
substituents from triphenyl to methyldiphenyl iminophosphorane
dramatically increases the reactivity of intramolecular aza-Wittig
reactions involving such less reactive amide carbonyl groups. The
reactions of azides 1 with methyldiphenyl phosphine (prepared
conveniently from triphenylphosphine18 and is more easily han-
dled or stored than trialkyl phosphine due to its sufficient stability
to air) gave diphenylmethyl iminophosphorane 2 (R¼Me) at room
temperature. Further heating of 2 in toluene produced 3,4-dihy-
droquinazolines 3 in satisfactory yields (Scheme 2, Table 3). Com-
pared with the condition needed for cyclization in Tables 2 and 3,
an obvious improvement was observed when methyldiphenyl
iminophosphorane 2 was used. In the preparation of compounds
3aed from diphenylmethyl iminophosphorane, shorter reaction
a
Isolated yields of 1 based on 2-azidobenzaldehyde.
iminophosphorane 2, but further heating of the triphenyl imino-
phosphorane 2 gave disappointed results (Table 2). As indicated in
Table 2, no or low yields of the 3,4-dihydroquinazolines 3 were
obtained when R2 or R3 is alkyl or aromatic group. Good yields were
reached only in case that R2 is a strong electro-withdrawing CF3
group or a small H (3aed, Table 2). The above cyclization involves
intramolecular aza-Wittig reaction between amide carbonyls and
triphenyl iminophosphorane. The low yield of the cyclization re-
action is due to the low electrophilicity of the amido group.
Although some examples of intramolecular aza-Wittig reactions
involving triphenyl iminophosphorane and ‘activated’ amide car-
bonyl groups (with electron-withdrawing substituent on the ni-
trogen atom, i.e., imide or sulfonyl amide groups) gave good yield of
various heterocycles,15 simple amide carbonyls are typically inert
toward intramolecular aza-Wittig reactions.16 This problem has
Table 3
Preparation of 3,4-dihydroquinazoline 3 via intramolecular aza-Wittig reaction of
diphenylmethyl iminophosphorane 2 (R¼Me)
R1
R2
R3
Time (h)
Yielda (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
t-Bu
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
n-Bu
H
H
CF3
CF3
CH3
CH3
4-ClC6H4
4-MeC6H4
4-ClC6H4
Ph
1
2
1
92
82
85
88
80
60
82
93
95
91
88
91
35
40
50
62
67
85
88
93
88
90
92
89
91
90
92
88
84
82
73
85
80
1
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
18
19
12
2
CH3CH2
4-NO2C6H4
4-NO2C6H4
Ph
4-MeC6H4
2-FC6H4
2-MeC6H4
Ph
2
2
2
Table 2
18
36
36
36
36
36
6
Preparation of 3,4-dihydroquinazoline 3 via intramolecular aza-Wittig reaction of
triphenyl iminophosphorane 2 (R¼Ph)
R1
R2
R3
Time (h)
Yielda (%)
Ph
Ph
Ph
Et
i-Pr
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3t
t-Bu
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
H
CF3
CF3
CH3
CH3
CH3CH2
4-NO2C6H4
4-NO2C6H4
Ph
4-MeC6H4
2-FC6H4
2-MeC6H4
Ph
4-ClC6H4
4-MeC6H4
4-ClC6H4
Ph
12
12
6
87
72
83
80
5
c-C6H11
t-Bu
4-ClC6H4
4-MeC6H4
Ph
3s
3t
t-Bu
t-Bu
6
6
2
3
2
3
2
2
6
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
12
12
12
12
12
24
24
24
24
24
24
24
24
3u
3v
3w
3x
3y
3z
3a0
3b0
3c0
3d0
3e0
3f0
3g0
Ph
Ph
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-EtOC6H4
2-MeC6H4
3-ClC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
0
0
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
Ph
37
52
14
10
0
0
0
0
0
3
5
4
Ph
Ph
PhCH]CHe
PhCH]CHe
4-ClC6H4CH]CHe
4-ClC6H4CH]CHe
12
12
12
12
Ph
Ph
Ph
Et
i-Pr
t-Bu
0
a
Isolated yields based on azides 1.
a
Isolated yields based on azides 1.

3716
Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
times were required in the comparison of that from triphenyl
iminophosphorane (compare 3aed in Table 3 with 3aed in Table 2).
In case that no or low yield of the 3,4-dihydroquinazolines 3 were
obtained (3eel) in Table 2, good yield of the cyclized products
(3eel, 3ueg0) was obtained in Table 3 when the reaction mixture
was heated for 2e24 h. The steric hindrance of R2 group has re-
markable influence on the reaction yield: when R2 is a steric 2-
methylphenyl (3m), low yield of the products (35%) was obtained
even after heating for 36 h in Table 3. However, it is not the case
with R3 group: as R3 is the steric 2-bromophenyl (3d0eg0), good
yields of the products were obtained after heating for 12 h.
It is interesting that in Table 3 there is even an inverse influence
of the steric hindrance of R3 group on the reaction yields. In prep-
aration of compounds 3net, the yields of the product increased
with the increasing steric hindrance of R3 group. When R3 is
changed from Me, Et, i-Pr to cyclohexyl, the yield is increased
slightly from 40 to 67% after heating for 36 h. However, as R3 is the
bulky t-Bu group, the yields are promoted remarkably to 85e93%
after heating for only 6 h (3ret). This is probably due to the con-
formation of the iminophosphorane 2ret. The bulky t-Bu group in
conformation of 2ret repels the benzoyl group to the iminophos-
phorane moiety, which is entropically favorable for the cyclization
(Scheme 3).
3. Conclusion
We report a new multicomponent synthesis of 3,4-dihy-
droquinazoline using Ugi reaction followed by Staudinger and
intramolecular aza-Wittig reaction of methyldiphenyl iminophos-
phorane. The used amines, isocyanides, and acids can be varied
broadly, producing products with three potential points of di-
versity. Some of the 3,4-dihydroquinazoline can be further trans-
ferred into fused quinazolines. Due to the easy availability of the
synthetic approach and the neutral ring closure condition, this new
synthetic approach discussed here has the potential in synthesis of
various 2,3,4-trisubstituted 3,4-dihydroquinazolines or fused qui-
nazolines, which are of considerable interest as potential biological
active compounds or pharmaceuticals.
4. Experimental
4.1. General
Melting points were uncorrected. MS were measured on a Fin-
nigan Trace MS spectrometer. NMR were recorded in CDCl3 or
DMSO-d6 on a Varian Mercury 400 or 600 spectrometer and reso-
nances relative to TMS. Elementary analyses were taken on a Vario
EL III elementary analysis instrument.
O
O
O
t-BuHN
t-BuHN
X
N
N
X
4.2. Synthesis of azides 1 via Ugi reaction
O
N
N
4.2.1. 2-(2-Azidophenyl)-N-tert-butyl-2-(N-(4-chlorophenyl) forma-
mido)acetamide (1a). 2-Azidobenzaldehyde (0.29 g, 2 mmol), for-
mic acid (0.09 g, 2 mmol), and tert-butylisocyanide (0.17 g, 2 mmol)
were added sequentially to a solution of 4-chlorophenyl amine
(0.25 g, 2 mmol) in methanol (15 mL) at room temperature. The
reaction mixture was stirred at ambient temperature for 24 h until
solid precipitated completely. After the solvent was evaporated, the
crude reaction mixture was purified by recrystallization from
methylene dichloride/petroleum ether to give 0.57 g (74%) of azide
1a as white solid. Mp: 183e185 ꢀC, 1H NMR (CDCl3, 600 MHz):
PPh2Me
PPh2Me
2r'-2t'
2r-2t
Scheme 3.
Some of the products 3 can be further transferred into fused
quinazolines. For eample, intramolecular Heck reaction of 3,4-
dihydroquinazolines 3d0eg0 in the presence of catalytic amount of
Pd(OAc)2 and Ph3P produced 6,12-dihydroindolo[2,1-b]quinazo-
lines 4aed in 58e77% yields (Scheme 4, Table 4). It provides a rapid
synthesis of 6,12-dihydroindolo[2,1-b]quinazoline via a sequential
Ugi/Staudinger/aza-Wittig/Heck reaction, starting from easily ac-
cessible 2-bromobenzenamine, cinnamic acids, 2-azidobenzalde-
hyde and isocyanide.
d
8.35 (s, 1H, CHO), 7.30e6.96 (m, 8H, AreH), 6.08 (s, 1H, CH), 5.59
(s, 1H, NH), 1.38 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
167.9,
162.6, 138.9, 136.9, 133.5, 131.0, 130.2, 129.7, 128.7, 124.7, 118.0, 58.0,
51.8, 28.5. Anal. Calcd for C19H20ClN5O2: C, 59.14; H, 5.22; N, 18.15.
Found: C, 59.57; H, 5.43; N, 18.12.
R1HN
O
N
4.2.2. 2-(2-Azidophenyl)-N-butyl-2-(N-p-tolylformamido) acetamide
(1b). Operation as above with n-butylisocyanide (0.17 g, 2 mmol)
and 4-methylphenyl amine (0.22 g, 2 mmol), compound 1b (0.62 g,
85%) was also isolated as white solid. Mp: 174e176 ꢀC, 1H NMR
R1HN
O
N
Pd(OAc)2, Ph3P
K2CO3
Br
N
N
(CDCl3, 600 MHz): d 8.35 (s,1H, COH), 7.29e6.95 (m, 8H, AreH), 6.17
R4
R4
(s, 1H, CH), 5.81 (s, 1H, NH), 3.34e3.29 (m, 2H, CH2), 2.25 (s, 3H,
CH3), 1.50e1.45 (m, 2H, CH2), 1.34e1.26 (m, 2H, CH2), 0.90 (t,
4a-4d
3d'-3g'
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 168.6, 163.1, 138.9,
Scheme 4. Preparation of compounds 4.
137.7, 135.9, 131.4, 130.0, 129.3, 128.0, 124.5, 117.9, 57.9, 39.6, 31.4,
20.9, 20.0, 13.7. Anal. Calcd for C20H23N5O2: C, 65.73; H, 6.34; N,
19.16. Found: C, 65.97; H, 6.18; N, 19.33.
Table 4
4.2.3. N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)-2,2,2-trifluoroacetamide (1c). Operation as above
with n-butylisocyanide (0.17 g, 2 mmol) and 2,2,2-trifluoroacetic
acid (0.23 g, 2 mmol), compound 1c (0.61 g, 67%) was also isolated as
Preparation of 6,12-dihydroindolo[2,1-b]quinazolines 4aed via intramolecular Heck
reaction
R1
R4
Time (h)
Yielda (%)
4a
4b
4c
4d
t-Bu
n-Bu
t-Bu
n-Bu
Ph
Ph
4-ClC6H4
4-ClC6H4
6
6
5
5
58
73
62
77
white solid. Mp: 136e137 ꢀC,1H NMR (CDCl3, 400 MHz):
d 7.80e6.59
(m, 8H, AreH), 6.23 (s, 1H, CH), 5.61 (s, 1H, NH), 3.33e3.28 (m, 2H,
NCH2), 1.50e1.43 (m, 2H, CH2), 1.34e1.25 (m, 2H, CH2), 0.86 (t,
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 167.9, 157.3, 157.0,
139.4,135.0,134.2,132.7,131.6,131.0,130.8,128.6,128.0,124.8,123.3,
a
Isolated yields.

Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
3717
117.9, 60.4, 39.7, 31.2, 19.9, 13.5 Anal. Calcd for C20H19ClF3N5O2: C,
52.93; H, 4.22; N, 15.43. Found: C, 53.22; H, 4.37; N, 15.18.
butylisocyanide (0.17 g, 2 mmol) and benzoic acid (0.24 g, 2 mmol),
compound 1j (0.83 g, 90%) was also isolated as white solid. Mp:
149e152 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.30e6.93 (m, 13H,
4.2.4. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-2,2,2-
trifluoro-N-phenylacetamide (1d). Operation as above with phe-
nylamine (0.19 g, 2 mmol) and 2,2,2-trifluoroacetic acid (0.23 g,
2 mmol), compound 1d (0.55 g, 66%) was also isolated as white
AreH), 6.45 (s, 1H, CH), 5.94 (s, 1H, NH), 3.38e3.30 (m, 2H, NCH2),
1.52e1.47 (m, 2H, CH2),1.33e1.30 (m, 2H, CH2), 0.90 (t, J¼7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 150 MHz):
d 170.8, 169.4, 139.1, 135.7, 132.7,
131.5, 130.1, 129.5, 128.4, 128.2, 127.7, 125.4, 124.7, 117.9, 60.1, 39.6,
31.3, 20.0, 13.6. Anal. Calcd for C25H24ClN5O2: C, 65.00; H, 5.24; N,
15.16. Found: C, 65.32; H, 5.11; N, 15.02.
solid. Mp: 186e187 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.80e6.69 (m,
9H, AreH), 6.12 (s, 1H, CH), 5.40 (s, 1H, NeH), 1.36 (s, 9H, 3ꢁCH3).
13C NMR (CDCl3, 150 MHz):
167.1, 157.4, 157.2, 139.4, 135.8, 131.6,
d
131.2, 130.5, 129.7, 128.9, 128.3, 127.8, 124.6, 123.9, 117.8, 60.9, 52.0,
28.6. Anal. Calcd for C20H20F3N5O2: C, 57.28; H, 4.81; N, 16.70.
Found: C, 57.56; H, 4.93; N, 16.55.
4.2.11. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)-4-methylbenzamide (1k). Operation as above with 4-
methylbenzoic acid (0.27 g, 2 mmol), compound 1k (0.83 g, 87%) was
also isolated as white solid. Mp: 180e182 ꢀC, 1H NMR (CDCl3,
4.2.5. 2-(2-Azidophenyl)-N-(tert-butyl)-2-(N-(4-chlorophenyl)acet-
amido)acetamide (1e). Operation as above with acetic acid (0.12 g,
2 mmol), compound 1e (0.74 g, 92%) was also isolated as white
600 MHz):
d
7.27e6.92 (m,12H, AreH), 6.31(s,1H, CH), 5.68(s,1H,NH),
170.8,
2.43 (s, 3H, CH3),1.38 (s, 9H, 3CH3).13C NMR (CDCl3,150 MHz):
d
168.6, 139.8, 139.3, 139.1, 132.8, 132.5, 131.4, 130.0, 128.6, 128.4, 128.1,
125.7,124.7,117.9, 60.6, 51.7, 28.6, 21.3. Anal. Calcd for C26H26ClN5O2: C,
65.61; H, 5.51; N, 14.71. Found: C, 65.48; H, 5.39; N, 14.56.
solid. Mp: 209e211 ꢀC, 1H NMR (CDCl3, 400 MHz):
d
7.27e6.85 (m,
8H, AreH), 6.17 (s, 1H, CH), 5.47 (s, 1H, NH), 1.87 (s, 3H, CH3), 1.35 (s,
9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
170.6, 168.8, 139.0, 138.7,
d
133.6, 131.3, 129.9, 128.7, 125.6, 124.6, 117.8, 58.8, 51.6, 28.5, 23.1
Anal. Calcd for C20H22ClN5O2: C, 60.07; H, 5.55; N, 17.51. Found: C,
59.83; H, 5.55; N, 17.68.
4.2.12. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)-2-fluorobenzamide (1l). Operation as above with 2-
fluorobenzoic acid (0.28 g, 2 mmol), compound 1l (0.80 g, 83%) was
also isolated as white solid. Mp: >300 ꢀC, 1H NMR (CDCl3,
4.2.6. 2-(2-Azidophenyl)-N-(tert-butyl)-2-(N-(p-tolyl) acetamido)
acetamide (1f). Operation as above with 4-methylphenyl amine
(0.22 g, 2 mmol)and acetic acid(0.12 g, 2 mmol), compound1f(0.61g,
81%) was also isolated as white solid. Mp: 206e208 ꢀC, 1H NMR
600 MHz):
d
7.27e6.83 (m, 12H, AreH), 6.37 (s, 1H, CH), 5.78 (s, 1H,
168.1, 166.9,
NH), 1.40 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
158.4, 156.8,139.2,137.6, 133.2, 131.4, 131.2, 131.0, 130.9, 130.1, 129.0,
128.0, 125.2, 125.0, 124.8, 124.6, 123.8, 117.9, 115.4, 115.3, 59.9, 51.8,
28.5. Anal. Calcd for C25H23ClFN5O2: C, 62.56; H, 4.83; N, 14.59.
Found: C, 62.83; H, 4.96; N, 14.59.
(CDCl3, 400 MHz):
1H, NH), 2.24 (s, 3H, CH3),1.86 (s, 3H, CH3),1.35 (s, 9H, 3CH3).13C NMR
(CDCl3, 150 MHz): 171.1, 168.8, 139.0, 137.6, 137.5, 131.5, 129.6, 126.0,
d 7.27e6.82 (m, 8H, AreH), 6.18 (s, 1H, CH), 5.56 (s,
d
124.3, 117.6, 58.9, 51.4, 28.5, 23.1, 20.9. Anal. Calcd for C21H25N5O2: C,
66.47; H, 6.64; N, 18.46. Found: C, 66.18; H, 6.45; N, 18.55.
4.2.13. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)-2-methylbenzamide (1m). Operation as above with
2-methylbenzoic acid (0.27 g, 2 mmol), compound 1m (0.66 g, 69%)
was also isolated as white solid. Mp: 176e179 ꢀC, 1H NMR (CDCl3,
4.2.7. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)propionamide (1g). Operation as above with propionic
acid (0.15 g, 2 mmol), compound 1g (0.65 g, 78%) was also isolated as
600 MHz):
NH), 2.40 (s, 3H, CH3), 1.40 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
171.4, 168.6, 139.0, 137.9, 136.0, 134.5, 132.8, 131.3, 131.1, 129.9,
d 7.27e6.85 (m, 12H, AreH), 6.34 (s, 1H, CH), 5.72 (s, 1H,
white solid. Mp: 176e178 ꢀC,1H NMR (CDCl3, 600 MHz):
d 7.30e6.84
d
(m, 8H, AreH), 6.22 (s, 1H, CH), 5.72 (s, 1H, NeH), 2.05e2.03 (m, 2H,
CH2), 1.35 (s, 9H, 3CH3), 1.04e1.03 (m, 3H, CH3). 13C NMR (CDCl3,
128.5, 127.9, 127.1, 125.4, 124.8, 124.7, 117.9, 59.6, 51.7, 28.5, 19.3.
Anal. Calcd for C26H26ClN5O2: C, 65.61; H, 5.51; N, 14.71. Found: C,
65.94; H, 5.68; N, 14.45.
150 MHz): d 173.9,169.0,139.0,138.3,133.6,131.4,129.8,128.7,125.7,
124.6,117.8, 58.9, 51.5, 28.4, 28.3, 28.2. Anal. Calcd for C21H24ClN5O2:
C, 60.94; H, 5.84; N, 16.92. Found: C, 60.88; H, 5.73; N, 16.62.
4.2.14. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-cy-
clohexylbenzamide (1q). Operation as above with benzoic acid
(0.24 g, 2 mmol) and cyclohexylamine (0.20 g, 2 mmol), compound
1q (0.61 g, 70%) was also isolated as white solid. Mp: 162e164 ꢀC,
4.2.8. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-4-ni-
tro-N-p-tolylbenzamide (1h). Operation as above with 4-methyl-
phenyl amine (0.22 g, 2 mmol) and 4-nitrobenzoic acid (0.33 g,
2 mmol), compound 1h (0.83 g, 85%) was also isolated as white
1H NMR (CDCl3, 600 MHz):
d
7.69e7.18 (m, 9H, AreH), 5.47 (s, 1H,
NeH), 5.08 (s, 1H, CH), 3.62e3.37 (m, 1H, NCH), 2.05e1.04 (m, 19H,
5CH2, and 3CH3). 13C NMR (CDCl3, 150 MHz):
172.2, 168.0, 137.6,
solid. Mp: 179e181 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.99e6.75 (m,
12H, AreH), 6.32 (s, 1H, CH), 5.56 (s, 1H, NH), 2.12 (s, 3H, CH3), 1.39
(s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
168.8, 168.2, 147.5, 142.6,
d
136.9, 129.7, 129.3, 128.3, 125.9, 125.2, 117.9, 59.9, 58.1, 51.2, 31.8,
31.4, 28.3, 25.6, 25.3, 24.9. Anal. Calcd for C25H31N5O2: C, 69.26; H,
7.21; N, 16.15. Found: C, 69.58; H, 7.48; N, 16.42.
d
139.2, 137.5, 136.6, 131.5, 130.0, 129.8, 129.2, 128.9, 125.3, 124.6,
122.8, 117.9, 60.5, 51.8, 30.8, 28.5, 20.8. Anal. Calcd for C26H26N6O4:
C, 64.19; H, 5.39; N, 17.27. Found: C, 64.52; H, 5.54; N, 17.48.
4.2.15. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-
tert-butyl-4-chlorobenzamide (1r). Operation as above with tert-
butylamine (0.15 g, 2 mmol) and 4-chlorobenzoic acid (0.31 g,
2 mmol), compound 1r (0.72 g, 81%) was also isolated as white
4.2.9. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)-4-nitrobenzamide (1i). Operation as above with 4-
nitrobenzoic acid (0.33 g, 2 mmol), compound 1i (0.74 g, 73%) was
also isolated as white solid. Mp: 235e237 ꢀC, 1H NMR (CDCl3,
solid. Mp: 208e210 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.66e7.15 (m,
8H, AreH), 5.49 (s, 1H, NeH), 5.19 (s, 1H, CH), 1.28 (s, 9H, 3CH3), 1.21
(s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
173.2, 168.4, 139.1, 137.8,
600 MHz):
d
8.03e6.94 (m, 12H, AreH), 6.35 (s, 1H, CH), 5.54 (s, 1H,
168.6, 168.2,
NeH), 1.40 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
d
147.8,142.1, 139.2,137.8, 133.5,131.5, 131.4,130.4,129.2,128.5,124.8,
123.0, 118.0, 60.3, 52.0, 30.9, 28.6. Anal. Calcd for C25H23ClN6O4: C,
59.23; H, 4.57; N, 16.58. Found: C, 59.00; H, 4.31; N, 16.67.
134.9, 130.9, 129.5, 129.1, 128.3, 128.0, 125.3, 117.9, 62.5, 58.6, 51.2,
30.6, 28.4. Anal. Calcd for C23H28ClN5O2: C, 62.51; H, 6.39; N, 15.85.
Found: C, 62.64; H, 6.62; N, 15.61.
4.2.10. N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-N-
(4-chlorophenyl)benzamide (1j). Operation as above with n-
4.2.16. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-
tert-butyl-4-methylbenzamide (1s). Operation as above with tert-

3718
Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
butylamine (0.15 g, 2 mmol) and 4-methylbenzoic acid (0.27 g,
61.0, 39.5, 31.4, 21.3, 20.9, 20.0, 13.7. Anal. Calcd for C27H29N5O2: C,
71.19; H, 6.42; N, 15.37. Found: C, 71.43; H, 6.57; N, 15.15.
2 mmol), compound 1s (0.65 g, 77%) was also isolated as white
solid. Mp: 187e189 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.71e7.15 (m,
8H, AreH), 5.81 (s, 1H, NeH), 5.20 (s, 1H, CH), 2.36 (s, 3H, CH3), 1.30
(s, 9H, 3CH3), 1.22 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
174.5,
4.2.22. N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-4-chloro-
N-p-tolylbenzamide (1z). Operation as above with n-butylisocya-
nide (0.17 g, 2 mmol), 4-methylphenyl amine (0.22 g, 2 mmol) and
4-chlorobenzoic acid (0.31 g, 2 mmol), compound 1z (0.82 g, 86%)
was also isolated as white solid. Mp: 199e201 ꢀC, 1H NMR (CDCl3,
d
168.9, 139.0, 137.7, 131.1, 129.2, 128.5, 126.5, 125.1, 117.8, 62.7, 58.4,
51.1, 30.6, 28.4, 21.3. Anal. Calcd for C24H31N5O2: C, 68.38; H, 7.41; N,
16.61. Found: C, 68.16; H, 7.22; N, 16.53.
600 MHz): d 7.28e6.78 (m, 12H, AreH), 6.38 (s, 1H, CH), 5.91 (s, 1H,
4.2.17. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-
tert-butylbenzamide (1t). Operation as above with tert-butylamine
(0.15 g, 2 mmol) and benzoic acid (0.24 g, 2 mmol), compound 1t
(0.61 g, 75%) was also isolated as white solid. Mp: 173e175 ꢀC, 1H
NH), 3.36e3.31 (m, 2H, CH2), 2.15 (s, 3H, CH3), 1.51e1.47 (m, 2H,
CH2), 1.33e1.29 (m, 2H, CH2), 0.90 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(CDCl3, 150 MHz): d 169.9, 169.2, 139.1, 137.7, 137.1, 135.2, 34.5, 131.7,
130.0, 129.7, 128.9, 127.7, 125.7, 124.6, 117.8, 60.7, 39.6, 31.4, 20.9,
20.0, 13.6. Anal. Calcd for C26H26ClN5O2: C, 65.61; H, 5.51; N, 14.71.
Found: C, 65.89; H, 5.50; N, 14.66.
NMR (CDCl3, 600 MHz):
5.22 (s,1H, CH),1.29 (s, 9H, 3CH3),1.21 (s, 9H, 3CH3).13C NMR (CDCl3,
150 MHz): 174.3, 168.7,140.7, 137.9,131.1, 129.4,129.0,128.0,126.5,
d 7.71e7.16 (m, 9H, AreH), 5.65 (s, 1H, NH),
d
125.2,117.9, 62.7, 58.6, 51.2, 30.7, 28.4. Anal. Calcd for C23H29N5O2: C,
67.79; H, 7.17; N, 17.19. Found: C, 68.05; H, 7.23; N, 17.37.
4.2.23. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(4-
ethoxyphenyl)benzamide (1a0). Operation as above with 4-ethox-
yphenyl amine (0.27 g, 2 mmol) and benzoic acid (0.24 g, 2 mmol),
compound 1a0 (0.77 g, 82%) was also isolated as white solid. Mp:
4.2.18. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-p-
tolylbenzamide (1u). Operation as above with 4-methylphenyl
amine (0.22 g, 2 mmol) and benzoic acid (0.24 g, 2 mmol), com-
pound 1u (0.80 g, 91%) was also isolated as white solid. Mp:
197e198 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.33e6.45 (m, 13H,
AreH), 6.31 (s,1H, CH), 5.74 (s,1H, NH), 3.82 (q, J¼7.2 Hz, 2H, OCH2),
1.39 (s, 9H, 3CH3), 1.30 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
173e174 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.33e6.75 (m, 13H, AreH),
6.30 (s, 1H, CH), 5.78 (s, 1H, NH), 2.12 (s, 3H, CH3), 1.39 (s, 9H, 3CH3).
13C NMR (CDCl3, 150 MHz):
171.0, 168.6, 139.1, 137.9, 136.7, 136.1,
150 MHz): d 171.1, 168.7, 157.4, 139.1, 136.2, 133.0, 131.6, 131.1, 129.7,
129.1, 128.4, 127.5, 126.0, 124.5, 117.8, 113.6, 63.2, 60.7, 51.6, 28.6,
14.6. Anal. Calcd for C27H29N5O3: C, 68.77; H, 6.20; N, 14.85. Found:
C, 68.47; H, 6.32; N, 14.66.
d
131.5, 129.6, 129.2, 128.7, 128.5, 127.5, 126.0, 124.5, 117.8, 61.0, 51.6,
28.6, 20.9. Anal. Calcd for C26H27N5O2: C, 70.73; H, 6.16; N, 15.86.
Found: C, 70.69; H, 6.31; N, 15.64.
4.2.24. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-o-
tolylbenzamide (1b0). Operation as above with 2-methylphenyl
amine (0.22 g, 2 mmol) and benzoic acid (0.24 g, 2 mmol), compound
1b0 (0.65 g, 74%) was also isolated as white solid. Mp: 164e166 ꢀC,1H
4.2.19. N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-N-p-tol-
ylbenzamide (1v). Operation as above with n-butylisocyanide
(0.17 g, 2 mmol), 4-methylphenyl amine (0.22 g, 2 mmol) and
benzoic acid (0.24 g, 2 mmol), compound 1v (0.73 g, 83%) was also
isolated as white solid. Mp: 142e144 ꢀC, 1H NMR (CDCl3, 600 MHz):
NMR (CDCl3, 600 MHz):
d 7.82e6.73 (m, 13H, AreH), 6.51 (s, 0.3H,
0.3CH), 5.94 (s, 0.7H, 0.7CH), 5.78 (s, 1H, NH), 1.98 (s, 0.8H, 0.8CH3),
1.80 (s, 2.2H, 2.2CH3), 1.39 (s, 6H, 3CH3), 1.33 (s, 3H, 3CH3). 13C NMR
d
7.33e6.77 (m, 13H, AreH), 6.38 (s, 1H, CH), 5.98 (s, 1H, NH),
(CDCl3, 150 MHz): d 170.9, 168.7, 139.2, 138.6, 136.6, 136.1, 132.5,
3.36e3.32 (m, 2H, CH2), 2.13 (s, 3H, CH3), 1.51e1.47 (m, 2H, CH2),
131.2,130.4,129.8,129.4,128.3,128.2,127.8,127.3,125.8,124.9,124.1,
117.6, 59.5, 51.6, 30.9, 28.6, 28.5, 17.3. Anal. Calcd for C26H27N5O2: C,
70.73; H, 6.16; N, 15.86. Found: C, 70.54; H, 6.22; N, 15.61.
1.34e1.30 (m, 2H, CH2), 0.90 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
150 MHz):
d 171.0, 169.4, 139.0, 138.0, 136.7, 136.0, 131.6, 129.6,
129.2, 128.7, 128.4, 127.4, 125.9, 124.5, 117.8, 60.7, 39.5, 31.3, 20.8,
19.9, 13.6. Anal. Calcd for C26H27N5O2: C, 70.73; H, 6.16; N, 15.86.
Found: C, 70.98; H, 6.04; N, 15.58.
4.2.25. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3-
chlorophenyl)benzamide (1c0). Operation as above with 3-chlor-
ophenyl amine (0.25 g, 2 mmol) and benzoic acid (0.24 g, 2 mmol),
compound 1c0 (0.82 g, 87%) was also isolated as white solid. Mp:
4.2.20. N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-N-(4-
chlorophenyl)-4-methylbenzamide (1w). Operation as above with
n-butylisocyanide (0.17 g, 2 mmol) and 4-methylbenzoic acid
(0.27 g, 2 mmol), compound 1w (0.84 g, 88%) was also isolated as
white solid. Mp: 183e186 ꢀC, 1H NMR (CDCl3, 600 MHz):
165e167 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.34e6.85 (m,13H, AreH),
6.30 (s, 1H, CH), 5.64 (s, 1H, NH), 1.39 (s, 9H, 3CH3). 13C NMR (CDCl3,
150 MHz): 170.6,168.4,141.6,139.0,135.6,133.2,131.3,130.1,130.0,
d
129.5, 128.7, 128.5, 128.3, 127.6, 127.0, 125.5, 124.5, 117.9, 65.7, 60.6,
51.6, 30.8, 28.5, 15.1. Anal. Calcd for C25H24ClN5O2: C, 65.00; H, 5.24;
N, 15.16. Found: C, 65.33; H, 5.37; N, 15.12.
d
7.30e6.94 (m, 12H, AreH), 6.42 (s, 1H, CH), 5.93 (s, 1H, NeH),
3.37e3.30 (m, 2H, CH2), 2.25 (s, 3H, CH3), 1.51e1.48 (m, 2H, CH2),
1.34e1.29 (m, 2H, CH2), 0.79 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
150 MHz):
d
170.9, 169.4, 139.8, 139.4, 139.1, 132.6, 131.6, 131.4,
4.2.26. (E)-N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-
N-(2-bromophenyl)cinnamamide (1d0). Operation as above with 2-
bromophenyl amine (0.34 g, 2 mmol) and cinnamic acid (0.30 g,
2 mmol), compound 1d0 (0.79 g, 74%) was also isolated as white
130.0, 128.6, 128.3, 128.2, 125.6, 124.7, 117.9, 60.3, 39.6, 31.4, 21.3,
20.0, 13.7. Anal. Calcd for C26H26ClN5O2: C, 65.61; H, 5.51; N, 14.71.
Found: C, 65.97; H, 5.65; N, 14.44.
solid. Mp: 211e213 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 8.68e6.76 (m,
4.2.21. N-(1-(2-azidophenyl)-2-(butylamino)-2-oxoethyl)-4-methyl-
N-p-tolylbenzamide (1x). Operation as above with n-butylisocya-
nide (0.17 g, 2 mmol), 4-methylphenyl amine (0.22 g, 2 mmol) and
4-methylbenzoic acid (0.27 g, 2 mmol), compound 1x (0.75 g, 82%)
was also isolated as white solid. Mp: 152e154 ꢀC, 1H NMR (CDCl3,
14H, AreH), 6.61 (s, 0.8H, 0.8CH), 6.21 (s, 0.2H, 0.2CH), 6.15e6.08
(m, 1H, ]CH), 5.92 (s, 0.2H, 0.2NH), 5.82 (s, 0.8H, 0.8NH), 1.36 (s,
7.2H, 3CH3), 1.31 (s, 1.8H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d 168.8,
166.3, 143.2, 139.9, 137.9, 135.0, 133.4, 132.9, 132.3, 129.8, 129.6,
128.5, 128.1, 127.9, 126.0, 124.3, 123.7, 118.2, 117.9, 57.9, 51.6, 28.6,
28.4. Anal. Calcd for C27H26BrN5O2: C, 60.91; H, 4.92; N, 13.15.
Found: C, 60.62; H, 4.76; N, 13.37.
600 MHz): d 7.32e6.79 (m, 12H, AreH), 6.36 (s, 1H, CH), 6.06 (s, 1H,
NH), 3.35e3.32 (m, 2H, CH2), 2.22 (s, 3H, CH3), 2.15 (s, 3H, CH3),
1.52e1.47 (m, 2H, CH2), 1.33e1.30 (m, 2H, CH2), 0.90 (t, J¼7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 150 MHz):
d
171.1, 169.4, 139.5, 139.0, 138.4,
4.2.27. (E)-N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-N-(2-
bromophenyl)cinnamamide (1e0). Operation as above with n-
136.7, 133.0, 131.7, 129.7, 129.5, 128.8, 128.7, 128.1, 126.0, 124.5, 117.8,

Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
3719
butylisocyanide (0.17 g, 2 mmol), 2-bromophenyl amine (0.34 g,
2 mmol) and cinnamic acid (0.30 g, 2 mmol), compound 1e0 (0.83 g,
78%) was also isolated as white solid. Mp: 214e215 ꢀC, 1H NMR
2.35 (s, 3H, CH3), 1.38e1.30 (m, 2H, CH2), 1.16e1.10 (m, 2H, CH2),
0.80 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 170.1, 145.2,
139.9,139.3,135.3,130.2,129.3,126.4,126.3,124.9,120.7,119.3, 62.6,
62.5, 39.4, 31.3, 20.7, 19.7. MS m/z: 321 (Mþ, 1) [Mþ], 221 (100). Anal.
Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.85; H,
7.33; N, 13.21.
(CDCl3, 600 MHz):
d 8.04e6.76(m, 14H, AreH), 6.70 (s, 0.75H,
0.75CH), 6.28 (s, 0.25H, 0.25CH), 6.13e6.08 (m, 1H, ]CH), 5.95 (s,
0.75H, 0.75NeH), 5.90 (s, 0.25H, 0.25NeH), 3.34e3.27 (m, 2H, CH2),
1.51e1.46 (m, 2H, CH2), 1.35e1.26 (m, 2H, CH2), 0.92e0.87 (m, 3H,
CH3). 13C NMR (CDCl3, 150 MHz):
d
169.7, 166.4, 143.4, 140.0, 137.8,
4.3.3. N-Butyl-3-(4-chlorophenyl)-2-(trifluoromethyl)-3,4-dihy-
droquinazoline-4-carboxamide (3c). Operation as above with azide
1c (0.45 g, 1 mmol), compound 3c (0.35 g, 85%) was also isolated as
white solid. Mp: 185e187 ꢀC, 1H NMR (CDCl3, 600 MHz):
135.0, 133.6, 132.9, 132.4, 129.9, 129.6, 128.6, 128.1, 127.9, 126.1,
124.2, 123.8, 118.1, 118.0, 57.6, 39.6, 31.5, 20.0, 13.7. Anal. Calcd for
C
27H26BrN5O2: C, 60.91; H, 4.92; N, 13.15. Found: C, 60.62; H, 4.74;
N, 13.00.
d 7.48e7.19 (m, 8H, AreH), 5.77 (s, 1H, NH), 5.09 (s, 1H, CH),
3.26e3.20 (m, 2H, CH2), 1.43e1.37 (m, 2H, CH2), 1.26e1.21 (m, 2H,
4.2.28. (E)-N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxo ethyl)-
N-(2-bromophenyl)-3-(4-chlorophenyl)acrylamide (1f0). Operation
as above with 2-bromophenyl amine (0.34 g, 2 mmol) and (E)-3-(4-
chlorophenyl)acrylic acid (0.36 g, 2 mmol), compound 1f0 (0.82 g,
72%) was also isolated as white solid. Mp: 232e233 ꢀC, 1H NMR
CH2), 0.87 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 168.7,
144.1, 143.8,141.1, 138.6,133.9,129.9,128.4,127.7,126.3,126.0,121.3,
119.8, 117.0, 66.6, 39.7, 31.2, 19.8, 13.5. MS m/z: 409 (Mþ, 1), 308
(100), 221 (31). Anal. Calcd for C20H19ClF3N3O: C, 58.61; H, 4.67; N,
10.25. Found: C, 58.75; H, 4.58; N, 10.12.
(CDCl3, 600 MHz):
d 8.03e6.76 (m, 13H, AreH), 6.59 (s, 0.8H,
0.8CH), 6.13e6.04 (m, 1H, ]CH), 5.88 (s, 0.2H, 0.2CH), 5.73 (s, 0.8H,
0.8NeH), 5.30 (s, 0.2H, 0.2NeH), 1.36 (s, 7.25H, 3CH3), 1.31 (s, 1.75H,
4.3.4. N-tert-Butyl-3-phenyl-2-(trifluoromethyl)-3,4-dihydro quina-
zoline-4-carboxamide (3d). Operation as above with azide 1d
(0.42 g, 1 mmol), compound 3d (0.33 g, 88%) was also isolated as
white solid. Mp: 189e190 ꢀC, 1H NMR (CDCl3, 600 MHz):
3CH3). 13C NMR (CDCl3, 150 MHz):
d 168.8, 166.1, 141.8, 139.9, 137.8,
135.4, 133.5, 133.0, 132.3, 129.9, 129.1, 128.8, 128.1, 126.0, 124.2,
123.8, 118.8, 118.0, 58.0, 51.6, 28.6, 28.5. Anal. Calcd for
d
7.44e7.23 (m, 9H, AreH), 5.95 (s, 1H, NH), 5.04 (s, 1H, CH), 1.31 (s,
C
27H25BrClN5O2: C, 57.21; H, 4.45; N, 12.35. Found: C, 57.55; H, 4.67;
9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
168.2, 142.8, 138.4, 129.6,
N, 12.16.
128.4, 128.0, 126.9, 125.7, 121.9, 119.5, 117.7, 67.3, 51.9, 29.0, 28.5. MS
m/z: 375 (Mþ, 1), 275 (100). Anal. Calcd for C20H20F3N3O: C, 63.99;
H, 5.37; N, 11.19. Found: C, 63.72; H, 5.26; N, 11.31.
4.2.29. (E)-N-(1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl)-N-
(2-bromophenyl)-3-(4-chlorophenyl)acrylamide (1g0). Operation as
above with n-butylisocyanide (0.17 g, 2 mmol), 2-bromophenyl
amine (0.34 g, 2 mmol) and (E)-3-(4-chlorophenyl)acrylic acid
(0.36 g, 2 mmol), compound 1g0 (0.79 g, 70%) was also isolated as
white solid. Mp: 215e216 ꢀC, 1H NMR (CDCl3, 600 MHz):
4.3.5. N-tert-Butyl-3-(4-chlorophenyl)-2-methyl-3,4-dihydro quina-
zoline-4-carboxamide (3e). Operation as above with azide 1e
(0.40 g, 1 mmol), compound 3e (0.28 g, 80%) was also isolated as
white solid. Mp: 196e199 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
8.06e6.76(m, 12H, AreH), 6.69 (s, 0.75H, 0.75CH), 6.20 (s, 0.25H,
d
7.38e7.08 (m, 8H, AreH), 5.52 (s, 1H, NH), 5.02 (s, 1H, CH), 2.10 (s,
0.25CH), 6.10e6.04 (m,1H, ]CH), 5.89 (s, 0.75H, 0.75NeH), 5.86 (s,
0.25H, 0.25NeH), 3.33e3.27 (m, 2H, CH2), 1.50e1.45 (m, 2H, CH2),
1.34e1.26 (m, 2H, CH2), 0.92e0.87 (m, 3H, CH3). 13C NMR (CDCl3,
3H, CH3), 1.25 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
169.4,
154.8, 142.1, 140.8, 133.1, 129.6, 129.4, 128.1, 125.3, 125.2, 124.3,
121.0, 66.5, 51.6, 28.4, 23.2. MS m/z: 355 (Mþ, 1), 255 (100). Anal.
Calcd for C20H22ClN3O: C, 67.50; H, 6.23; N,11.81. Found: C, 67.72; H,
6.41; N, 11.77.
150 MHz):
d 169.7, 166.2, 142.0, 140.0, 137.7, 135.4, 133.6, 133.5,
133.0, 132.3, 130.0, 129.1, 128.8, 128.2, 126.0, 124.1, 123.8, 118.6,
118.0, 57.7, 39.7, 31.4, 20.0, 13.7. Anal. Calcd for C27H25BrClN5O2: C,
57.21; H, 4.45; N, 12.35. Found: C, 57.66; H, 4.43; N, 12.64.
4.3.6. N-tert-Butyl-2-methyl-3-p-tolyl-3,4-dihydro
quinazoline-4-
carboxamide (3f). Operation as above with azide 1f (0.38 g,
1 mmol), compound 3f (0.20 g, 60%) was also isolated as white
4.3. Synthesis of the 3,4-dihydroquinazoline 3 via
intramolecular aza-Wittig reaction
solid. Mp: 164e167 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.29e7.09 (m,
8H, AreH), 5.64 (s, 1H, NH), 5.06 (s, 1H, CH), 2.37 (s, 3H, CH3), 2.07
(s, 3H, CH3), 1.26 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
169.8,
4.3.1. N-tert-Butyl-3-(4-chlorophenyl)-3,4-dihydro
quinazoline-4-
d
carboxamide (3a). Methyldiphenyl phosphine (0.20 g, 1 mmol) was
added to a solution of azide 1a (0.39 g, 1 mmol) in dry toluene
(10 mL) at stirred condition. After stirring for about 2 h, imino-
phosphorane 2a was formed which was monitored by TLC. Then
the solution was heated to reflux for 1 h without isolated. After the
reaction was completed, the solvent was evaporated and the resi-
due was purified by column chromatography to give 0.31 g (92%) of
3,4-dihydroquinazoline 3a as white solid. Mp: 200e203 ꢀC, 1H NMR
155.2, 141.0, 140.9, 137.5, 130.1, 129.1, 126.6, 125.3, 125.0, 124.1, 121.0,
67.0, 51.5, 28.4, 23.3, 21.0. MS m/z: 335 (Mþ, 1), 235 (100). Anal.
Calcd for C21H25N3O: C, 75.19; H, 7.51; N, 12.53. Found: C, 75.53; H,
7.63; N, 12.50.
4.3.7. N-tert-Butyl-3-(4-chlorophenyl)-2-ethyl-3,4-dihydro quinazo-
line-4-carboxamide (3g). Operation as above with azide 1g (0.41 g,
1 mmol), compound 3g (0.30 g, 82%) was also isolated as white
(CDCl3, 600 MHz):
d
7.64 (s, 1H, N]CH), 7.40e7.17 (m, 8H, AreH),
solid. Mp: 158e160 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.34e7.08 (m,
5.64 (s, 1H, NH), 5.30 (s, 1H, CH), 1.25 (s, 9H, 3CH3). 13C NMR (CDCl3,
8H, AreH), 5.56 (s,1H, NH), 4.96 (s,1H, CH), 2.50e2.34 (m, 2H, CH2),
150 MHz):
d 168.9, 144.6, 141.0, 139.2, 130.8, 129.7, 129.5, 126.7,
1.87 (t, J¼7.2 Hz, 3H, CH3), 1.25 (s, 9H, 3CH3). 13C NMR (CDCl3,
126.1, 125.4, 120.8, 120.6, 63.0, 51.8, 28.3. MS m/z: 341 (Mþ, 2), 256
(12), 241 (100). Anal. Calcd for C19H20ClN3O: C, 66.76; H, 5.90; N,
12.29. Found: C, 66.93; H, 5.99; N, 12.36.
150 MHz): d 169.5, 159.1, 142.4, 141.0, 132.6, 129.5, 129.4, 127.7,
125.6, 125.5, 124.5, 121.1, 66.4, 51.6, 28.6, 28.4, 11.7. MS m/z: 369
(Mþ, 1), 269 (100). Anal. Calcd for C21H24ClN3O: C, 68.19; H, 6.54; N,
11.36. Found: C, 68.46; H, 6.28; N, 11.22.
4.3.2. N-Butyl-3-p-tolyl-3,4-dihydroquinazoline-4-carboxamide
(3b). Operation as above with azide 1b (0.37 g, 1 mmol), compound
3b (0.26 g, 82%) was also isolated as white solid. Mp: 184e186 ꢀC,
4.3.8. N-tert-Butyl-2-(4-nitrophenyl)-3-p-tolyl-3,4-dihydroquinazo-
line-4-carboxamide (3h). Operation as above with azide 1h (0.49 g,
1 mmol), compound 3h (0.41 g, 93%) was also isolated as white
1H NMR (CDCl3, 600 MHz):
d
7.62 (s, 1H, AreH), 7.32e7.08 (m, 8H,
AreH), 6.24 (s, 1H, NH), 5.45 (s, 1H, CH), 3.28e3.09 (m, 2H, CH2),
solid. Mp: 98e101 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 8.12e6.97 (m,

3720
Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
12H, AreH), 5.50 (s, 1H, NH), 5.25 (s, 1H, CH), 2.24 (s, 3H, CH3), 1.23
(s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
169.2,152.9,148.3, 142.2,
142.1,141.4,135.2,130.7,129.7,126.7,126.0,125.2,124.2,123.4,122.1,
65.6, 51.8, 28.4, 20.8. MS m/z: 442 (Mþ, 2), 342 (100), 296 (16). Anal.
Calcd for C26H26N4O3: C, 70.57; H, 5.92; N,12.66. Found: C, 70.86; H,
5.75; N, 12.33.
solid. Mp: 219e221 ꢀC, 1H NMR (CDCl3, 600 MHz):
9H, AreH), 5.65 (s, 1H, NH), 4.84 (s, 1H, CH), 3.11 (s, 3H, CH3), 1.28 (s,
9H, 3CH3). 13C NMR (CDCl3, 100 MHz):
169.5, 157.7, 141.8, 135.8,
d 7.61e7.14 (m,
d
d
129.8, 129.3, 128.5, 128.3, 125.7, 125.2, 124.9, 120.4, 65.7, 51.5, 41.4,
28.5. MS m/z: 321 (Mþ, 2), 221 (100), 193 (8). Anal. Calcd for
C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.97; H, 7.31; N,
13.01.
4.3.9. N-tert-Butyl-3-(4-chlorophenyl)-2-(4-nitrophenyl)-3,4-dihy-
droquinazoline-4-carboxamide (3i). Operation as above with azide
1i (0.51 g, 1 mmol), compound 3i (0.44 g, 95%) was also isolated as
4.3.15. N-tert-Butyl-3-ethyl-2-phenyl-3,4-dihydro
quinazoline-4-
carboxamide (3o). Operation as above with azide 1o (0.38 g,
1 mmol), compound 3o (0.17 g, 50%) was also isolated as white
white solid. Mp: 105e107 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
8.15e7.11
(m, 12H, AreH), 5.40 (s, 1H, NH), 5.24 (s, 1H, CH), 1.22 (s, 9H, 3CH3).
13C NMR (CDCl3, 150 MHz):
168.8, 152.7, 148.5, 143.1, 141.7, 141.4,
solid. Mp: 215e217 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.63e7.15 (m,
d
9H, AreH), 5.83 (s, 1H, NH), 4.93 (s, 1H, CH), 3.52e3.40 (m, 2H, CH2),
130.8,130.7, 129.9,129.1,127.0, 125.9,125.5,125.4, 123.5,122.0, 65.2,
1.28 (s, 9H, 3CH3), 1.16 (t, J¼6.6 Hz, 3H, CH3). 13C NMR (CDCl3,
51.9, 28.4. MS m/z: 462 (Mþ, 2), 362 (100), 316 (14). Anal. Calcd for
100 MHz): d 170.1,157.7,141.8,136.0,129.9,129.2,128.7,128.2,126.0,
C
25H23ClN4O3: C, 64.86; H, 5.01; N,12.10. Found: C, 64.68; H, 5.17; N,
125.4, 124.8, 121.1, 62.3, 51.4, 47.5, 28.5, 14.0. MS m/z: 335 (Mþ, 1),
235 (100), 207 (18). Anal. Calcd for C21H25N3O: C, 75.19; H, 7.51; N,
12.53. Found: C, 75.42; H, 7.63; N, 12.33.
12.26.
4.3.10. N-Butyl-3-(4-chlorophenyl)-2-phenyl-3,4-dihydro quinazo-
line-4-carboxamide (3j). Operation as above with azide 1j (0.46 g,
1 mmol), compound 3j (0.38 g, 91%) was also isolated as white
4.3.16. N-tert-Butyl-3-isopropyl-2-phenyl-3,4-dihydro quinazoline-
4-carboxamide (3p). Operation as above with azide 1p (0.39 g,
1 mmol), compound 3p (0.22 g, 62%) was also isolated as white
solid. Mp: 179e181 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.73 (d,
J¼7.8 Hz, 2H, AreH), 7.52e7.11 (m, 11H, AreH), 5.69 (s, 1H, NH), 5.31
(s,1H, CH), 3.21e3.17 (m, 2H, CH2),1.36e1.31 (m, 2H, CH2),1.18e1.15
(m, 2H, CH2), 0.79 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
solid. Mp: 160e161 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.74e7.16 (m,
9H, AreH), 6.05 (s, 1H, NH), 4.95 (s, 1H, CH), 4.09e4.05 (m, H, CH),
1.36 (d, J¼6.6 Hz, 3H, CH3), 1.26 (s, 9H, 3CH3), 1.02 (d, J¼6.6 Hz, 3H,
d
170.0, 154.8, 143.9, 141.8, 135.3, 130.2, 130.0, 129.8, 129.7, 128.7,
CH3). 13C NMR (CDCl3, 150 MHz):
d 170.5, 157.7, 141.8, 136.3, 130.4,
128.3, 126.2, 126.0, 125.4, 125.2, 121.9, 65.0, 65.0, 39.6, 31.2, 19.8. MS
m/z: 417 (Mþ, 1), 317 (100). Anal. Calcd for C25H24ClN3O: C, 71.85; H,
5.79; N, 10.05. Found: C, 72.03; H, 5.56; N, 10.30.
128.9, 128.8, 128.2, 126.2, 125.7, 124.6, 122.4, 56.9, 52.2, 51.3, 28.5,
21.4, 20.9. MS m/z: 349 (Mþ, 1), 249 (100), 207 (96). Anal. Calcd for
C22H27N3O: C, 75.61; H, 7.79; N, 12.02. Found: C, 75.93; H, 7.87; N,
12.05.
4.3.11. N-tert-Butyl-3-(4-chlorophenyl)-2-p-tolyl-3,4-dihy-
droquinazoline-4-carboxamide (3k). Operation as above with azide
1k (0.48 g, 1 mmol), compound 3k (0.38 g, 88%) was also isolated as
white solid. Mp: 233e235 ꢀC, 1H NMR (CDCl3, 600 MHz):
4.3.17. N-tert-Butyl-3-cyclohexyl-2-phenyl-3,4-dihydroquinazoline-
4-carboxamide (3q). Operation as above with azide 1q (0.43 g,
1 mmol), compound 3q (0.26 g, 67%) was also isolated as white
d
7.61e7.08 (m, 12H, AreH), 5.65 (s, 1H, NeH), 5.20 (s, 1H, CH), 2.32
solid. Mp: 189e191 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.75e7.16 (m,
(s, 3H, CH3), 1.22 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
169.2,
9H, AreH), 6.08 (s, 1H, NeH), 4.98 (s, 1H, CH), 3.61e3.57 (m, 1H,
154.4, 144.2, 141.6, 140.6, 132.4, 129.9, 129.6, 129.5, 129.2, 128.8,
126.3, 126.0, 125.2, 125.0, 122.3, 65.8, 51.7, 28.4, 21.4. MS m/z: 431
(Mþ, 1), 331 (100). Anal. Calcd for C26H26ClN3O: C, 72.29; H, 6.07; N,
9.73. Found: C, 72.47; H, 6.22; N, 9.52.
NCH), 2.16e1.03 (m, 19H, 5CH2, and 3CH3). 13C NMR (CDCl3,
150 MHz): d 170.4, 157.6, 141.7, 136.1, 130.3, 128.7, 128.1, 126.2, 125.5,
124.4, 122.4, 60.4, 57.8, 51.2, 31.5, 28.4, 25.5, 25.3, 24.8. MS m/z: 389
(Mþ, 1), 289 (63), 207 (100). Anal. Calcd for C25H31N3O: C, 77.08; H,
8.02; N, 10.79. Found: C, 76.83; H, 8.25; N, 10.68.
4.3.12. N-tert-Butyl-3-(4-chlorophenyl)-2-(2-fluorophenyl)-3,4-di-
hydroquinazoline-4-carboxamide (3l). Operation as above with
azide 1l (0.48 g, 1 mmol), compound 3l (0.40 g, 91%) was also
isolated as white solid. Mp: 114e117 ꢀC, 1H NMR (CDCl3, 600 MHz):
4.3.18. N,3-Di-tert-butyl-2-(4-chlorophenyl)-3,4-dihydroquinazo-
line-4-carboxamide (3r). Operation as above with azide 1r (0.44 g,
1 mmol), compound 3r (0.34 g, 85%) was also isolated as white
d
7.89e6.70 (m, 13H, AreH, and NeH), 5.18 (s, 1H, CH), 1.34 (s, 9H,
solid. Mp: 192e194 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.85e7.25 (m,
8H, AreH), 5.43 (s, 1H, NeH), 5.02 (s, 1H, CH), 1.15 (s, 9H, 3CH3), 1.13
(s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
169.4,158.5,142.5, 139.2,
3CH3). 13C NMR (CDCl3, 150 MHz):
d
169.2, 160.2, 158.6, 149.8, 142.9,
140.3, 132.4, 132.3, 132.2, 131.2, 129.2, 128.8, 127.1, 126.8, 125.3,
123.9, 123.8, 121.7, 115.8, 115.6, 66.6, 66.6, 51.9, 28.5. MS m/z: 435
(Mþ, 1), 335 (100). Anal. Calcd for C25H23ClFN3O: C, 68.88; H, 5.32;
N, 9.64. Found: C, 68.67; H, 5.16; N, 9.38.
d
136.0, 130.4, 129.0, 128.3, 125.8, 125.3, 124.0, 59.5, 58.8, 51.3, 31.1,
28.2. MS m/z: 397 (Mþ, 1), 297 (13), 241 (100). Anal. Calcd for
C23H28ClN3O: C, 69.42; H, 7.09; N, 10.56. Found: C, 69.31; H, 7.17; N,
10.72.
4.3.13. N-tert-Butyl-3-(4-chlorophenyl)-2-o-tolyl-3,4-dihy-
droquinazoline-4-carboxamide (3m). Operation as above with azide
1m (0.48 g, 1 mmol), compound 3m (0.15 g, 35%) was also isolated
as white solid. Mp: 224e227 ꢀC, 1H NMR (CDCl3, 600 MHz):
4.3.19. N,3-Di-tert-butyl-2-p-tolyl-3,4-dihydroquinazoline-4-carbox-
amide (3s). Operation as above with azide 1s (0.42 g, 1 mmol),
compound 3s (0.33 g, 88%) was also isolated as white solid. Mp:
d
7.48e7.05 (m, 12H, AreH), 5.47 (s,1H, NH), 5.24 (s,1H, CH), 2.53 (s,
182e184 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.77e7.22 (m, 8H, AreH),
5.71 (s, 1H, NeH), 5.02 (s, 1H, CH), 2.40 (s, 3H, CH3), 1.15 (s, 18H,
6CH3). 13C NMR (CDCl3, 150 MHz):
169.6, 159.2, 142.5, 140.3, 137.7,
3H, CH3), 1.23 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
169.1,
155.1, 143.1, 141.5, 137.7, 134.9, 130.9, 130.5, 129.7, 129.5, 128.6, 126.1,
125.9, 125.8, 125.7, 125.0, 121.4, 65.8, 51.7, 28.3, 20.1. MS m/z: 431
(Mþ, 1), 331 (100). Anal. Calcd for C26H26ClN3O: C, 72.29; H, 6.07; N,
9.73. Found: C, 72.01; H, 6.07; N, 9.99.
d
128.9, 128.7, 126.1, 125.6, 125.4, 123.9, 59.5, 58.9, 51.2, 31.0, 28.3,
21.3. MS m/z: 377 (Mþ, 1), 277 (13), 221 (100). Anal. Calcd for
C24H31N3O: C, 76.35; H, 8.28; N, 11.13. Found: C, 76.41; H, 8.47; N,
11.07.
4.3.14. N-tert-Butyl-3-methyl-2-phenyl-3,4-dihydro quinazoline-4-
carboxamide (3n). Operation as above with azide 1n (0.37 g,
1 mmol), compound 3n (0.13 g, 40%) was also isolated as white
4.3.20. N,3-Di-tert-butyl-2-phenyl-3,4-dihydroquinazoline-4-car-
boxamide (3t). Operation as above with azide 1t (0.41 g, 1 mmol),

Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
3721
compound 3t (0.34 g, 93%) was also isolated as white solid. Mp:
172e173 ꢀC, 1H NMR (CDCl3, 600 MHz):
7.89e7.24 (m, 9H, AreH),
5.62 (s,1H, NH), 5.03 (s,1H, CH),1.16 (s, 9H, 3CH3),1.15 (s, 9H, 3CH3).
13C NMR (CDCl3, 150 MHz):
169.5, 159.3, 142.6, 140.6, 130.0, 129.0,
128.8, 128.0, 126.0, 125.8, 125.3, 124.0, 59.5, 59.0, 51.2, 31.0, 28.2. MS
m/z: 363 (Mþ, 1), 263 (9), 207 (100). Anal. Calcd for C23H29N3O: C,
76.00; H, 8.04; N, 11.56. Found: C, 76.31; H, 8.17; N, 11.42.
351 (100). Anal. Calcd for C25H23Cl2N3O: C, 66.38; H, 5.12; N, 9.29.
Found: C, 66.61; H, 5.27; N, 9.27.
d
d
4.3.26. N-Butyl-2-(4-chlorophenyl)-3-p-tolyl-3,4-dihydro quinazo-
line-4-carboxamide (3z). Operation as above with azide 1z (0.48 g,
1 mmol), compound 3z (0.39 g, 90%) was also isolated as white
solid. Mp: 178e180 ꢀC, 1H NMR (CDCl3, 400 MHz):
d 7.71e6.96 (m,
12H, AreH), 5.69 (s, 1H, NH), 5.31 (s, 1H, CH), 3.22e3.16 (m, 2H,
CH2), 2.25 (s, 3H, CH3), 1.35e1.31 (m, 2H, CH2), 1.20e1.15 (m, 2H,
4.3.21. N-tert-Butyl-2-phenyl-3-p-tolyl-3,4-dihydro quinazoline-4-
carboxamide (3u). Operation as above with azide 1u (0.44 g,
1 mmol), compound 3u (0.35 g, 88%) was also isolated as white
CH2), 0.81 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 170.3,
154.1, 142.1, 141.9, 136.0, 134.7, 131.2, 129.5, 128.5, 126.1, 125.0, 124.2,
121.9, 65.3, 39.6, 31.3, 20.8, 19.8, 13.6. MS m/z: 431 (Mþ, 1), 331
(100). Anal. Calcd for C26H26ClN3O: C, 72.29; H, 6.07; N, 9.73. Found:
C, 72.47; H, 6.22; N, 9.61.
solid. Mp: 160e162 ꢀC, 1H NMR (CDCl3, 600 MHz):
d 7.74 (d,
J¼7.2 Hz, 2H, AreH), 7.48e6.95 (m, 11H, AreH), 5.83 (s, 1H, NH),
5.22 (s, 1H, CH), 2.23 (s, 3H, CH3),1.25 (s, 9H, 3CH3). 13C NMR (CDCl3,
100 MHz):
d 169.6, 154.5, 143.0, 141.5, 135.8, 134.4, 129.9, 129.5,
129.4, 129.2, 128.2, 126.4, 126.0, 124.9, 124.0, 122.3, 66.1, 51.6, 28.4,
20.7. MS m/z: 397 (Mþ, 1), 297 (100). Anal. Calcd for C26H27N3O: C,
78.56; H, 6.85; N, 10.57. Found: C, 78.74; H, 6.96; N, 10.38.
4.3.27. N-tert-Butyl-3-(4-ethoxyphenyl)-2-phenyl-3,4-dihy-
droquinazoline-4-carboxamide (3a0). Operation as above with azide
1a0 (0.47 g, 1 mmol), compound 3a0 (0.39 g, 92%) was also isolated
as white solid. Mp: 211e213 ꢀC, 1H NMR (CDCl3, 400 MHz):
4.3.22. N-Butyl-2-phenyl-3-p-tolyl-3,4-dihydroquinazoline-4-car-
boxamide (3v). Operation as above with azide 1v (0.44 g, 1 mmol),
compound 3v (0.36 g, 90%) was also isolated as white solid. Mp:
d
7.23e6.66 (m, 13H, AreH), 5.80 (s, 1H, NH), 5.19 (s, 1H, CH), 3.96
(q, J¼7.2 Hz, 2H, CH2), 1.35 (t, J¼7.2 Hz, 3H, CH3), 1.25 (s, 9H, 3CH3).
13C NMR (CDCl3, 150 MHz):
169.7, 156.2, 154.6, 141.6, 138.6, 135.8,
d
182e183 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.75 (d, J¼6.6 Hz, 2H,
129.9,129.6,129.3,128.2,126.3,125.9,125.7, 124.9,122.1,114.5, 66.4,
63.5, 51.6, 28.5,14.7. MS m/z: 427 (Mþ,1), 327 (100), 299 (9), 269 (8).
Anal. Calcd for C27H29N3O2: C, 75.85; H, 6.84; N, 9.83. Found: C,
75.61; H, 6.98; N, 9.57.
AreH), 7.50e6.95 (m, 11H, AreH), 5.83 (s, 1H, NeH), 5.33 (s, 1H,
CH), 3.26e3.15 (m, 2H, CH2), 2.22 (s, 3H, CH3), 1.38e1.33 (m, 2H,
CH2), 1.20e1.16 (m, 2H, CH2), 0.80 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(CDCl3, 150 MHz):
d 170.4, 154.8, 142.9, 141.8, 135.7, 134.3, 129.8,
129.6, 129.3, 128.1, 126.1, 125.8, 124.9, 124.1, 121.9, 65.4, 65.4, 39.4,
4.3.28. N-tert-Butyl-2-phenyl-3-o-tolyl-3,4-dihydro quinazoline-4-
carboxamide (3b0). Operation as above with azide 1b0 (0.44 g,
1 mmol), compound 3b0 (0.35 g, 88%) was also isolated as white
31.2, 20.7, 19.7, 13.5. MS m/z: 397 (Mþ, 1), 297 (100). Anal. Calcd for
C
26H27N3O: C, 78.56; H, 6.85; N, 10.57. Found: C, 78.80; H, 6.69; N,
10.76.
solid. Mp: 184e187 ꢀC, 1H NMR (CDCl3, 600 MHz):
d
7.93e6.88 (m,
13H, AreH), 5.79 (s, 1H, NH), 5.06 (s, 1H, CH), 1.78 (s, 3H, CH3), 1.26
(s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
169.8, 156.1, 144.6, 135.5,
4.3.23. N-Butyl-3-(4-chlorophenyl)-2-p-tolyl-3,4-dihydro quinazo-
line-4-carboxamide (3w). Operation as above with azide 1w
(0.48 g, 1 mmol), compound 3w (0.40 g, 92%) was also isolated as
white solid. Mp: 163e165 ꢀC, 1H NMR (CDCl3, 400 MHz):
d
134.5,131.0,130.2,129.7,129.2,127.9,127.4,127.1,126.9,125.9,125.8,
124.7, 122.5, 66.6, 51.7, 28.5, 18.0. MS m/z: 397 (Mþ, 1), 297 (100).
Anal. Calcd for C26H27N3O: C, 78.56; H, 6.85; N, 10.57. Found: C,
78.33; H, 6.76; N, 10.71.
d
7.62e7.07 (m, 12H, AreH), 5.71 (s, 1H, NH), 5.30 (s, 1H, CH),
3.22e3.15 (m, 2H, CH2), 2.31 (s, 3H, CH3), 1.36e1.30 (m, 2H, CH2),
1.19e1.14 (m, 2H, CH2), 0.79 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
4.3.29. N-tert-Butyl-3-(3-chlorophenyl)-2-phenyl-3,4-dihy-
droquinazoline-4-carboxamide (3c0). Operation as above with azide
1c0 (0.46 g,1 mmol), compound 3c0 (0.35 g, 84%) was also isolated as
white solid. Mp: 163e164 ꢀC, 1H NMR (CDCl3, 600 MHz):
100 MHz): d 170.1,154.7,144.1,141.9,140.6,132.3,129.9,129.7,129.6,
129.1, 128.7, 126.1, 126.0, 125.3, 125.1, 121.9, 65.1, 39.6, 31.2, 21.4,
19.8, 13.5. MS m/z: 431 (Mþ, 1), 331 (100). Anal. Calcd for
C
9.56.
26H26ClN3O: C, 72.29; H, 6.07; N, 9.73. Found: C, 72.46; H, 6.15; N,
d
7.76e6.95 (m, 13H, AreH), 5.60 (s, 1H, NH), 5.25 (s, 1H, CH), 1.23 (s,
9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
169.0, 154.4, 146.5, 141.5,
135.2, 134.4, 130.3, 129.6, 129.5, 128.4, 126.3, 126.2, 125.2, 124.6,
123.9, 122.5, 122.3, 65.5, 65.5, 51.8, 28.4. MS m/z: 417 (Mþ, 1), 317
(100). Anal. Calcd for C25H24ClN3O: C, 71.85; H, 5.79; N, 10.05.
Found: C, 72.07; H, 5.98; N, 10.01.
4.3.24. N-Butyl-2,3-di(p-tolyl)-3,4-dihydroquinazoline-4-carbox-
amide (3x). Operation as above with azide 1x (0.46 g, 1 mmol),
compound 3x (0.37 g, 89%) was also isolated as white solid. Mp:
175e177 ꢀC, 1H NMR (CDCl3, 400 MHz):
d 7.63e6.95 (m,12H, AreH),
5.86 (s, 1H, NH), 5.31 (s, 1H, CH), 3.27e3.13 (m, 2H, CH2), 2.30 (s, 3H,
CH3), 2.23 (s, 3H, CH3), 1.37e1.32 (m, 2H, CH2), 1.23e1.14 (m, 2H,
4.3.30. (E)-3-(2-Bromophenyl)-N-tert-butyl-2-styryl-3,4-dihy-
droquinazoline-4-carboxamide (3d0). Operation as above with azide
1d0 (0.53 g, 1 mmol), compound 3d0 (0.40 g, 82%) was also isolated
as white solid. Mp: 174e176 ꢀC, 1H NMR (CDCl3, 600 MHz):
CH2), 0.80 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 170.5,
154.8, 143.2, 141.9, 140.2, 134.3, 132.8, 129.7, 129.4, 129.0, 126.3,
125.8, 124.9, 124.1, 122.1, 65.6, 39.5, 31.3, 21.4, 20.7, 19.8, 13.5. MS m/
z: 411 (Mþ, 1), 311 (100). Anal. Calcd for C27H29N3O: C, 78.80; H,
7.10; N, 10.21. Found: C, 78.56; H, 6.98; N, 10.28.
d
7.89e7.06 (m, 14H, AreH), 6.54 (s, 0.3H, 0.3NH), 5.84 (s, 0.7H,
0.7NH), 6.34e6.31 (m, 1H, ]CH), 5.20 (s, 0.3H, 0.3CH), 5.04 (s, 0.7H,
0.7CH), 1.26 (s, 7H, 3CH3), 1.20 (s, 2H, 3CH3). 13C NMR (CDCl3,
150 MHz): d 169.7, 152.4, 142.2, 141.4, 138.7, 135.5, 134.1, 133.7, 131.6,
4.3.25. N-Butyl-2,3-bis(4-chlorophenyl)-3,4-dihydro quinazoline-4-
carboxamide (3y). Operation as above with azide 1y (0.50 g,
1 mmol), compound 3y (0.41 g, 91%) was also isolated as white
130.7, 130.4, 130.3, 129.4, 129.1, 128.9, 128.6, 128.5, 128.5, 128.4,
127.5, 125.3, 125.2, 124.8, 123.3, 121.6, 120.7, 66.0, 51.5, 28.4, 28.2,
16.6, 16.1. MS m/z: 487 (Mþ, 1), 389 (100), 307 (11), 231 (36). Anal.
Calcd for C27H26BrN3O: C, 66.40; H, 5.37; N, 8.60. Found: C, 66.68; H,
5.51; N, 8.42.
solid. Mp: 166e169 ꢀC, 1H NMR (CDCl3, 400 MHz):
d 7.70e7.13 (m,
12H, AreH), 5.59 (s, 1H, NH), 5.29 (s, 1H, CH), 3.20e3.15 (m, 2H,
CH2), 1.35e1.30 (m, 2H, CH2), 1.19e1.14 (m, 2H, CH2), 0.80 (t,
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d
169.9, 153.8, 143.6,
4.3.31. (E)-3-(2-Bromophenyl)-N-butyl-2-styryl-3,4-dihydro quina-
zoline-4-carboxamide (3e0). Operation as above with azide 1e0
(0.53 g, 1 mmol), compound 3e0 (0.36 g, 73%) was also isolated as
141.8, 136.2, 133.8, 131.2, 130.2, 129.7, 128.8, 128.5, 126.3, 125.9,
125.4, 125.2, 121.8, 64.8, 39.6, 31.2, 19.7, 13.5. MS m/z: 451 (Mþ, 1),

3722
Y. Zhong et al. / Tetrahedron 67 (2011) 3714e3723
white solid. Mp: 202e203 ꢀC, 1H NMR (CDCl3, 600 MHz):
7.91e7.14 (m, 13H, AreH), 6.53e6.31 (m, 1H, ]CH), 5.90 (s, 0.8H,
C27H25N3O: C, 79.58; H, 6.18; N, 10.31. Found: C, 79.86; H, 6.03; N,
10.53.
d
0.8NeH), 5.55 (s, 0.2H, 0.2NH), 5.23 (s, 0.2H, 0.2CH), 5.11 (s, 0.8H,
0.8CH), 3.22e3.19 (m, 2H, CH2), 1.41e1.37 (m, 2H, CH2), 1.22e1.18
(m, 2H, CH2), 0.84e0.78 (m, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
4.4.3. 6-(4-Chlorobenzylidene)-N-tert-butyl-6,12-dihydro indolo[2,1-
b]quinazoline-12-carboxamide (4c). Operation as above with 3,4-
dihydroquinazoline 3f0 (0.52 g, 1 mmol), compound 4c (0.27 g, 62%)
was also isolated as red solid. Mp: 235e237 ꢀC, 1H NMR (CDCl3,
d
170.6, 152.5, 142.3, 141.6, 139.0, 135.6, 133.8, 130.7, 129.5, 129.4,
129.1, 128.7, 128.5, 127.6, 125.5, 125.4, 124.9, 123.3, 121.3, 120.7, 65.5,
39.5, 31.3, 19.8, 13.6. MS m/z: 487 (Mþ, 1), 387 (100), 307 (9), 231
(30). Anal. Calcd for C27H26BrN3O: C, 66.40; H, 5.37; N, 8.60. Found:
C, 66.78; H, 5.49; N, 8.76.
600 MHz):
d
7.99e6.88 (m, 13H, AreH), 5.59 (s, 1H, NH), 5.54 (s, 1H,
168.8, 153.1,
CH), 1.20 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
143.5, 140.3, 134.9, 133.8, 131.2, 130.5, 130.2, 129.6, 129.2, 128.9,
126.5, 126.1, 126.0, 123.0, 122.2, 119.0, 108.8, 60.3, 51.7, 28.3. MS m/z:
441 (Mþ, 2), 341 (100), 305 (7). Anal. Calcd for C27H24ClN3O: C,
73.38; H, 5.47; N, 9.51. Found: C, 73.70; H, 5.24; N, 9.59.
4.3.32. (E)-2-(4-Chlorostyryl)-3-(2-bromophenyl)-N-tert-butyl-3,4-
dihydroquinazoline-4-carboxamide (3f0). Operation as above with
azide 1f0 (0.57 g, 1 mmol), compound 3f0 (0.44 g, 85%) was also
isolated as white solid. Mp: 179e182 ꢀC, 1H NMR (CDCl3, 600 MHz):
4.4.4. 6-(4-Chlorobenzylidene)-N-butyl-6,12-dihydroindolo [2,1-b]
quinazoline-12-carboxamide (4d). Operation as above with 3,4-
dihydroquinazoline 3g0 (0.52 g, 1 mmol), compound 4d (0.34 g,
77%) was also isolated as red solid. Mp: 226e227 ꢀC, 1H NMR
d
7.91e6.12 (m, 14H, AreH), 5.77 (s, 0.75H, 0.75NH), 5.54 (s, 0.25H,
0.25NH), 5.28 (s, 0.25H, 0.25CH), 5.04 (s, 0.75H, 0.75CH), 1.26 (s,
6.7H, 3CH3), 1.20 (s, 2.3H, 3CH3). 13C NMR (CDCl3,150 MHz):
169.4,
d
152.9, 141.9, 140.5, 138.2, 137.9, 135.0, 133.9, 130.8, 129.8, 129.4,
128.8, 126.6, 125.6, 125.3, 124.8, 124.4, 123.3, 121.3, 120.6, 66.1, 51.7,
28.4, 28.2. MS m/z: 523 (Mþ, 1), 423 (100), 231 (23). Anal. Calcd for
(CDCl3, 600 MHz): d 7.92e6.88 (m,13H, AreH), 6.14 (s,1H, NH), 5.69
(s, 1H, CH), 3.24e3.09 (m, 2H, CH2), 1.30e1.26 (m, 2H, CH2),
1.07e1.02 (m, 2H, CH2), 0.75e0.70 (m, 3H, CH3). 13C NMR (CDCl3,
C
27H25BrClN3O: C, 62.02; H, 4.82; N, 8.04. Found: C, 62.38; H, 4.64;
150 MHz): d 169.5, 153.0, 143.3, 140.3, 135.0, 133.7, 131.3, 130.5,
N, 8.32.
130.3, 129.6, 129.1, 128.9, 126.4, 126.3, 126.0, 123.0, 122.2, 122.2,
118.7, 108.7, 59.3, 39.4, 31.1, 19.6, 13.5. MS m/z: 441 (Mþ, 1), 341
(100), 305 (7). Anal. Calcd for C27H24ClN3O: C, 73.38; H, 5.47; N,
9.51. Found: C, 73.68; H, 5.33; N, 9.68.
4.3.33. (E)-2-(4-Chlorostyryl)-3-(2-bromophenyl)-N-butyl-3,4-dihy-
droquinazoline-4-carboxamide (3g0). Operation as above with azide
1g0 (0.57 g, 1 mmol), compound 3g0 (0.42 g, 80%) was also isolated
as white solid. Mp: 166e167 ꢀC, 1H NMR (CDCl3, 600 MHz):
Acknowledgements
d
7.94e7.13 (m, 13H, AreH), 6.48 (s, 0.2H, 0.2NH), 6.45e6.27 (m, 1H,
]CH), 5.80 (s, 0.8H, 0.8NH), 5.27 (s, 0.2H, 0.2CH), 5.10 (s, 0.8H,
0.8CH), 3.22e3.19 (m, 2H, CH2), 1.40e1.34 (m, 2H, CH2), 1.23e1.16
(m, 2H, CH2), 0.84e0.78 (m, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21032001), the
Program for Changjiang Scholars and Innovative Research Team in
University (No. IRT0953), and the self-determined research funds of
CCNU from the colleges’ basic research and operation of MOE
(No. CCNU10A02004).
d
170.5, 152.3, 142.3, 141.6, 137.6, 134.9, 134.1, 133.9, 130.8, 129.6,
129.5, 129.0, 128.8, 128.7, 125.6, 125.5, 125.0, 123.3, 121.3, 65.5, 39.5,
31.3, 19.8, 13.6. MS m/z: 523 (Mþ, 1), 423 (100), 231 (32). Anal. Calcd
for C27H25BrClN3O: C, 62.02; H, 4.82; N, 8.04. Found: C, 62.43; H,
4.77; N, 8.35.
Supplementary data
4.4. Synthesis of the 6,12-dihydroindolo[2,1-b]quinazolines 4
via the intramolecular Heck reaction
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.03.056. These data include
MOL files and InChIKeys of the most important compounds
described in this article.
4.4.1. 6-Benzylidene-N-tert-butyl-6,12-dihydroindolo[2,1-b]quinazo-
line-12-carboxamide (4a). To a solution of 3,4-dihydroquinazoline
3d0 (0.49 g, 1 mmol) in DMF (10 mL) were added solid K2CO3 (0.14 g,
1 mmol), Pd(OAc)2 (0.02 g, 0.1 mmol), and Ph3P (0.05 g, 0.2 mmol).
The reaction mixture was stirred for additional 6 h at 110 ꢀC. Af-
terward the solvent was evaporated under reduced pressure and
the residue was purified by column chromatography to give 0.24 g
(58%) of 4a as red solid. Mp: >300 ꢀC, 1H NMR (CDCl3, 600 MHz):
References and notes
1. (a) Baxter, E. W.; Conway, K. A.; Kennis, L.; Bischoff, F.; Mercken, M. H.; De
Winter, H. L.; Reynolds, C. H.; Tounge, B. A.; Luo, C.; Scott, M. K.; Huang, Y.;
Braeken, M.; Pieters, S. M. A.; Berthelot, D. J. C.; Masure, S.; Bruinzeel, W. D.;
Jordan, A. D.; Parker, M. H.; Boyd, R. E.; Qu, J.; Alexander, R. S.; Brenneman, D. E.;
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Chem. 2010, 18, 1555; (c) Tinker, A. C.; Beaton, H. G.; Smith, N. B.; Cook, T. R.;
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Eur. J. Med. Chem. 2000, 35, 463; (e) Cottam, H. B.; Shih, H.; Tehrani, L. R.;
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d
8.11e6.88 (m, 14H, AreH), 5.57 (s, 1H, CH), 5.55 (s, 1H, NH), 1.19 (s,
9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
168.9, 153.3, 143.4, 135.4,
133.0, 130.0, 129.6, 129.1, 128.6, 126.5, 126.1, 125.9, 123.1, 122.5,
122.2, 119.0, 108.7, 60.3, 51.7, 28.3. MS m/z: 407 (Mþ, 2), 307 (100).
Anal. Calcd for C27H25N3O: C, 79.58; H, 6.18; N, 10.31. Found: C,
79.33; H, 6.15; N, 10.03.
2. (a) Heo, J. H.; Seo, H. N.; Choe, Y. J.; Kim, S.; Oh, C. R.; Kim, Y. D. Bioorg. Med.
Chem. Lett. 2008, 18, 3899; (b) Choi, J. Y.; Seo, H. N.; Lee, M. J.; Park, S. J.; Park, S.
J.; Jeon, J. Y.; Kang, J. H.; Pae, A. N.; Rhim, H.; Lee, J. Y. Bioorg. Med. Chem. Lett.
2007, 17, 471; (c) Seo, H. N.; Choi, J. Y.; Choe, Y. J.; Kim, Y.; Rhim, H.; Lee, S. H.;
Kim, J.; Joo, D. J.; Lee, J. Y. Bioorg. Med. Chem. Lett. 2007, 17, 5740.
4.4.2. 6-Benzylidene-N-butyl-6,12-dihydroindolo[2,1-b] quinazoline-
12-carboxamide (4b). Operation as above with 3,4-dihy-
droquinazoline 3e0 (0.49 g, 1 mmol), compound 4b (0.30 g, 73%)
was also isolated as red solid. Mp: 180e183 ꢀC, 1H NMR (CDCl3,
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