A remarkable one-pot sequential four-component synthesis of tetrahydroquinazolines via an isocyanide-based multicomponent reaction

Article abstract of DOI:10.1055/s-0033-1339465

A novel one-pot sequential four-component strategy has been developed for the synthesis of tetrahydroquinazolines using either an aliphatic or an acyl halide, an isocyanide, and a 1,3-diamine, in methanol at 60 °C, in good to moderate yields without using a catalyst. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339465

1968▌
LETTER
lAetteRr emarkable One-Pot Sequential Four-Component Synthesis of Tetrahydro-
quinazolines via an Isocyanide-Based Multicomponent Reaction
Synthesis of Tetrahydroquinazolines
Ahmad Shaabani,*a Mojtaba Mahyari,a Morteza Aghaei,a Sajjad Keshipour,a Seik Weng Ngb
a
Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
Fax +98(21)29903247 ; E-mail: a-shaabani@sbu.ac.ir
b
Department of Chemistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
Received: 16.04.2013; Accepted after revision: 21.06.2013
O
Abstract: A novel one-pot sequential four-component strategy has
been developed for the synthesis of tetrahydroquinazolines using ei-
ther an aliphatic or an acyl halide, an isocyanide, and a 1,3-diamine,
in methanol at 60 °C, in good to moderate yields without using a
catalyst.
O
R1
R2
Cl
N
NH
OMe
N
H
N
H
A
Key words: quinazoline, multicomponent, isocyanide
B
O
O
R1
NH
NH
Quinazolines with regard to their pharmacophore proper-
ties have attracted great attention in medicinal chemis-
try.1–4 These compounds possess diverse biological
activities including anticancer and antihyperglycaemic,
anticonvulsant, antibacterial, and antidiabetic activity.5–11
In particular, quinazolines with the structure A are privi-
leged scaffolds.12–14 2-Styrylquinazolin-4-one (SQZ),1,15
2,3-dihydro-2-aryl-4-quinazolinones (DHPQZ), 2,3- and
6-chloro-2-(3-methoxyphenyl)-2,3-dihydroquinazolin-
4(1H)-one16 B demonstrate potent inhibition of tubulin
polymerization and antitumor activities, respectively
(Figure 1). Thus, the development of efficient protocols to
prepare quinazoline derivatives continues to be of impor-
tance.17–19
H
R2
N
H
N
H
SQZ
DHPQZ
Figure 1 Some biologically active quinazoline derivatives
yielding a new class of tetrahydroquinazoline-2-carbox-
amide derivatives 4 (Scheme 1).
In a trial experiment, cyclohexyl isocyanide and benzoyl
chloride were heated under solvent-free conditions at
60 °C for two hours, followed by addition of 2-aminoben-
zamide or 2-aminobenzylamine in MeOH as a solvent at
60 °C for 24 hours led to the formation of the tetrahydro-
quinazoline-2-carboxamide derivatives 4a or 4g in good
yields, respectively.
Multicomponent reactions (MCR) offer the advantage of
atom-economy by gathering different parts of the starting
materials into the final product.20 MCR are effective tools
in the modern drug-discovery processes and are amenable
to fast, automated, and high-throughput preparation of or-
ganic compounds.21 The pharmaceutical industry has in-
creasingly focused on diversity-oriented and biased
combinatorial libraries.22 Finally, the development of
novel MCR can be considered as an interesting topic for
academic research that also satisfies a practical interest of
applied science.23–26
In light of this success, we explored the reaction scope by
varying the structure of acyl halides 1, isocyanides 2, and
1,3-diamines 3. As indicated in Figure 2, the reactions
proceed efficiently and produced compounds 4a–i in fair-
ly good yields. Owing to the great diversity of substitution
patterns, this reaction may be used for the production of
combinatorial libraries.
The structures of compounds 4a–i41 were deduced from
their elemental analysis, mass, IR, H NMR, and 13C
1
As part of our current studies on the synthesis of
benzodiazepines27–29 and the chemistry of isocyanides,30–32
a novel approach to the synthesis of benzodiazepine deriv-
atives 5 via a one-pot sequential isocyanide-based multi-
component condensation reaction of an acyl chloride 1, an
isocyanide 2, and a 1,3-diamine 3 was designed. Howev-
er, analysis of the spectroscopic data led us to conclude
that the desired products 5a or 5b were not obtained; in-
stead the reaction proceeded via an unexpected route
1
NMR spectral data. For example, the H NMR spectrum
of 4b exhibited a multiplet for the cyclohexyl ring at
δ = 1.14–1.60 ppm, a broad singlet at δ = 3.50 ppm for the
cyclohexyl CHNH, two broad singlets for the NH protons
at δ = 6.70 and 6.93 ppm, a multiplet at δ = 7.28–7.79
ppm for H aromatic and a singlet at δ = 8.53 ppm for the
CONH proton. The H-decoupled 13C NMR spectrum of
1
4b showed 21 distinct resonances in agreement with the
proposed structure.
Finally, the structure of 4b was confirmed unambiguously
by single-crystal X-ray analysis (Figure 3).
SYNLETT 21709013, 2415, 1968–1972
Advanced online publication: 07.08.2013
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DOI: 10.1055/s-0033-1339465; Art ID: ST-2013-D0346-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrahydroquinazolines
1969
In all cases, although the reaction gave the desired product It is worth noting that these products are similar to Schiff
in 54–70% yields, cyclohexylammonium chloride was base17 and bridging ligands.18 These bridging ligands
also obtained in about 10% yield.
could complex with metals and encourage the formation
of dendritic structures or linear arrays. Recently, due to
the interesting bulk properties of these compounds such as
electrical conductivity and light harvesting, synthesis of
these compounds are of interest.19
The versatility of this reaction with respect to the linear
ethylenediamine (6) and o-phenylenediamine (7) was also
studied. As indicated in Scheme 2, a one-pot condensation
reaction of 4-bromobenzoyl chloride, or cyclohexyl iso-
cyanide with ethylenediamine (6), or o-phenylenediamine Although no detailed mechanistic studies have been car-
(7), did not give the expected multicomponent condensa- ried out at this point, it is conceivable that the initial event
tion product 10; instead the reactions afforded the corre- is the formation of N-cyclohexyl-2-oxo-2-phenylacetimi-
sponding (2E,2′E)-2,2′-[ethane-1,2-diylbis(azan-1-yl-1- doyl chloride (11) from Nef reaction between acyl chlo-
ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacet-
amide] (8) and (2E,2′E)-2,2′-]1,2-phenylenebis(azan-1- we wished to obtain benzodiazepine derivatives 5 from re-
ride 1 and isocyanide 2.33–37As with previous reports,35,38
yl-1-ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacet-
amide] (9), respectively.
action between intermediate 11 and diamine 3 through
pathway A. However, the experimental results show that
O
N
N
NH
5a
R2
X
NH2
N
5b
O
O
NH
R2
NH2
solvent-free
R2
N
C
Cl
3
R1
Cl
N
R1
60 °C, 2 h
MeOH
60 °C, 24 h
O
N
R2
2
1
10
R1 = Ph, Et
R2 = c-Hex, t-Bu
X
X = CH2, C=O
NH
R1
H
N
N
R2
H
O
4
Scheme 1 Designed reaction for the synthesis of benzodiazepine derivatives vs. the unexpected pathway toward the quinazoline compounds
O
O
O
O
HN
NH
HN
HN
NH
HN
NH
NH
N
O
H
N
H
O
N
H
N
H
O
O
Br
4a 60%
4b 54%
4c 63%
HN
4d 62%
O
O
NH
HN
NH
HN
NH
HN
NH
N
H
O
N
N
H
N
H
O
O
O
H
4e 63%
4f 65%
4g 66%
4h 70%
HN
NH
N
O
H
4i 66%
Figure 2 The structures of products 4a–i
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1968–1972

1970
A. Shaabani et al.
LETTER
Br
Br
O
Cl
N
N
2) MeOH, 60 °C
NH2
HN
NH
O
O
H2N
6
8 78%
Br
O
1) solvent-free
60 °C
NH
1) solvent-free
60 °C
H
+
N
Br
2) MeOH, 60 °C
6 or 7
Br
Br
NH
C
N
10
not observed
N
N
2) MeOH, 60 °C
NH2
NH
HN
H2N
O
O
9 71%
7
Scheme 2 Use of ethylenediamine and o-phenylenediamine instead of 1,3-diamines
the reaction proceeds via an unexpected pathway B yield- HCl generated in the reaction39,40 and cyclization of the di-
ing tetrahydroquinazoline-2-carboxamide derivatives 4 amine on the imidoyl moiety or on the carboxamide (after
(Scheme 3).
hydrolysis of the imidoyl chloride). It is important to note
that gas chromatographic analysis of the crude reaction
mixture identified the formation of formic acid as a by-
product, which supports the former proposed mechanism.
Cyclohexyl ammonium chloride as a byproduct is proba-
bly obtained from acidic hydrolysis of the isocyanide with
O
N
R1
N
NH
R2
5a or 5b
O
O
pathway A
B
H2N
– H2O
N
H2N
H2N
O
NH
N
A
NH
– HCl
R1
O
R1
R2
N
R2
O
Cl
R1
C
N
R2
3
+
O
R1
N
O
R2
Cl
O
A
H2N
1
2
11
pathway B
– H2O
NH2
+ H2O
– HCl
O
N
Cl
N
R2 NH
R1
13
R2
N
R1
12
O
R2
HN
NH
N
H
O
R1
4a–i
Scheme 3
Synlett 2013, 24, 1968–1972
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrahydroquinazolines
1971
(14) Kuo, S. C.; Lee, H. Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.;
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(19) Balakumar, C.; Lamba, P.; Pran Kishore, D.; Lakshmi
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(21) Weber, L. Curr. Med. Chem. 2002, 9, 1241.
(22) Schreiber, S. L. Science 2000, 287, 1964.
(23) Dömling, A. Chem. Rev. 2006, 106, 17.
Figure 3 ORTEP diagram of product 4b
(24) Orru, R. V.; De Greef, M. Synthesis 2003, 1471.
(25) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem. Eur. J. 2000, 6, 3321.
(26) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005.
(27) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J.
J. Org. Chem. 2008, 73, 3925.
(28) Shaabani, A.; Rezayan, A. H.; Keshipour, S.; Sarvary, A.;
Ng, S. W. Org. Lett. 2009, 11, 3342.
(29) Shaabani, A.; Maleki, A.; Hajishaabanha, F.; Mofakham, H.;
Seyyedhamzeh, M.; Mahyari, M.; Ng, S. W. J. Comb. Chem.
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(30) Keshipour, S.; Shojaei, S.; Shaabani, A. Tetrahedron 2012,
68, 6141.
In summary, we have developed a novel one-pot sequen-
tial four-component condensation reaction leading to a
new class of tetrahydroquinazoline-2-carboxamide and 2-
oxo-acetimidamide compounds starting from simple and
readily available materials under mild reaction conditions
without using any catalyst. The reactions show functional-
group tolerance and relatively good yields, and product
isolation is straightforward. We hope that this approach
may be of value to others seeking novel synthetic frag-
ments with unique properties for medicinal chemistry pro-
grams.
(31) Ghadari, R.; Hajishaabanha, F.; Mahyari, M.; Shaabani, A.;
Khavasi, H. R. Tetrahedron Lett. 2012, 53, 4018.
(32) Shaabani, A.; Keshipour, S.; Shaabani, S.; Mahyari, M.
Tetrahedron Lett. 2012, 53, 1641.
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1825.
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(36) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010,
12, 820.
Acknowledgment
We gratefully acknowledge the financial support from the Research
Council of Shahid Beheshti University.
References and Notes
(1) Jiang, J. B.; Hesson, D.; Dusak, B.; Dexter, D.; Kang, G.;
Hamel, E. J. Med. Chem. 1990, 33, 1721.
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Pharmacol. 1972, 56, 163.
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H.; Paull, K. D. Biochem. Pharmacol. 1996, 51, 53.
(5) Tiwari, A. K.; Mishra, A. K.; Bajpai, A.; Mishra, P.; Sharma,
R. K.; Pandey, V. K.; Singh, V. K. Bioorg. Med. Chem. Lett.
2006, 16, 4581.
(6) Ram, V. J.; Tripathi, B. K.; Srivastava, A. K. Bioorg. Med.
Chem. 2003, 11, 2439.
(7) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659.
(8) Touroutoglou, N.; Pazdur, R. Clin. Cancer Res. 1996, 2,
227.
(37) Coffinier, D.; El Kaim, L.; Grimaud, L. Synlett 2010, 2474.
(38) El Kaim, L.; Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261.
(39) Walborsky, H.; Niznik, G. J. Org. Chem. 1972, 37, 187.
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Sotelo, E. ACS Comb. Sci. 2011, 13, 89. (b) Lim, Y. Y.; Stei,
A. R. Can. J. Chem. 1971, 49, 2455. (c) Gassman, P. G.;
Haberman, L. M. Tetrahedron Lett. 1985, 26, 4971.
(d) Priestley, E. S.; Decicco, C. P. Org. Lett. 2000, 2, 3095.
(41) N-Cyclohexyl-4-oxo-2-phenyl-1,2,3,4-tetrahydro-
quinazoline-2-carboxamide (4a) – Typical Procedure
To magnetically stirred benzoyl chloride (0.14 g, 1.00
mmol) was added cyclohexyl isocyanide (0.11 g, 1.00
mmol), and the reaction mixture was heated for 2 h at 60 °C.
After cooling, MeOH (5 mL) and 2-aminobenzamide were
added, and the reaction mixture was stirred for 24 h at 60 °C.
After completion of the reaction (TLC), the solvent was
removed under vacuum, the residue was crystallized from
CH2Cl2–n-hexane (3:1), and the product 4a was obtained as
a white solid (0.21 g, 60%); yield 0.21 g (60%); mp 222–
225 °C. IR (KBr): 3381, 3324, 2932, 2844, 1649, 1612,
1492, 1461 cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ =
1.08–1.59 (10 H, m, 5 CH2 of c-Hex), 3.52 (1 H, br s, CH of
c-Hex), 6.69 (1 H, br s, NH), 6.93 (1 H, br s, NH), 7.25–7.70
(9) Jackman, A. L.; Harrap, K. R.; Boyle, F. T. Invest. New
Drugs 1996, 14, 305.
(10) Sielecki, T. M.; Johnson, T. L.; Liu, J.; Muckelbauer, J. K.;
Grafstrom, R. H.; Cox, S.; Boylan, J.; Burton, C. R.; Chen,
H.; Smallwood, A.; Chang, C.-H.; Boisclair, M.; Benfield, P.
A.; Trainor, G. L.; Seitz, S. P. Bioorg. Med. Chem. Lett.
2001, 11, 1157.
(11) Bonomi, P. E. Expert Opin. Invest. Drugs 2003, 1395.
(12) Alaimo, R. J.; Russell, H. E. J. Med. Chem. 1972, 15, 335.
(13) Cooper, E. R. A.; Jackson, H. J. Reprod. Fertil. 1973, 34,
445.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1968–1972

1972
A. Shaabani et al.
LETTER
(9 H, m, CHAr), 8.41 (1 H, br s, CONH). 13C NMR (75.47
MHz, DMSO-d6): δ = 24.6, 25.5, 32.4, 48.8, 75.5, 114.7,
115.5, 118.2, 126.8, 127.6, 128.7, 129.0, 134.0, 141.4,
147.2, 163.9, 170.3. MS: m/z (%) = 350 (90) [M+ + 1], 223
(100), 297 (25), 145 (15), 119 (30), 92 (60), 55 (65). Anal.
Calcd for C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found:
C, 72.10; H, 6.58; N, 12.17.
15.26. Found: C, 65.49; H, 7.74; N, 15.18.
N-Cyclohexyl-2-phenyl-1,2,3,4-tetrahydroquinazoline-
2-carboxamide (4g)
White powder; yield 0.22 g (66%); mp 153–159 °C. IR
(KBr): 2940, 2862, 2730, 1675, 1606, 1511, 1442 cm–1. 1H
NMR (300.13 MHz, DMSO-d6): δ = 1.07–1.89 (10 H, m, 5
CH2 of c-Hex), 2.88 (2 H, br, CH2, ArCH2), 3.40 (1 H, br s,
CH of c-Hex), 6.63 (1 H, br s, NH), 6.72 (1 H, br s, NH),
7.14–7.24 (9 H, m, Ar), 8.35 (1 H, br, CONH). 13C NMR
(75.47 MHz, DMSO-d6): δ = 24.2, 25.0, 30.6, 41.1, 49.7,
76.6, 117.2, 118.4, 127.4, 126.2, 127.5, 127.6, 128.5, 129.2,
131.3, 150.1, 151.2, 167.9. Anal. Calcd for C21H25N3O: C,
75.19; H, 7.51; N, 12.53. Found: C, 75.12; H, 7.44; N, 12.62.
N-Cyclohexyl-2-methyl-1,2,3,4-tetrahydroquinazoline-
2-carboxamide (4h)
White powder; yield 0.19 g (70%); mp 145–148 °C. IR
(KBr): 3425, 3336, 3021, 2936, 1637, 1587, 1500, 1461 cm–1.
1H NMR (300.13 MHz, DMSO-d6): δ = 1.07–1.70 (10 H, m,
5 CH2 of c-Hex), 1.89 (3 H, s, CH3), 2.89 (1 H, br s, CH of
c-Hex), 3.86 (2 H, br, CH2, ArCH2), 6.56 (1 H, br s, NH),
6.69 (1 H, br s, NH), 7.01–7.15 (4 H, m, CHAr), 8.26 (1 H,
br, CONH). 13C NMR (75.47 MHz, DMSO-d6): δ = 24.2,
25.0, 30.7, 38.9, 40.9, 49.7, 82.2, 116.0, 116.6, 117.7, 129.8,
130.9, 147.5, 159.1, 165.2. Anal. Calcd for C16H23N3O: C,
70.30; H, 8.48; N, 15.37. Found: C, 70.39; H, 8.57; N, 15.24.
N-Cyclohexyl-2-ethyl-1,2,3,4-tetrahydroquinazoline-2-
carboxamide (4i)
White powder; yield 0.19 g (66%); mp 149–151 °C. IR
(KBr): 3381, 3325, 3014, 2932, 2869, 1648, 1612, 1503 cm–1.
1H NMR (300.13 MHz, DMSO-d6): δ = 0.84–1.67 (13 H, m,
5 CH2 of c-Hex and CH3), 1.89 (2 H, br s, CH2CH3), 2.88 (1
H, br s, CH of c-Hex), 3.39 (2 H, br, ArCH2), 6.56 (1 H, br
s, NH), 6.70 (1 H, br s, NH), 7.13–7.28 (4 H, m, CHAr), 8.20
(1 H, br, CONH2). 13C NMR (75.47 MHz, DMSO-d6): δ =
15.6, 24.2, 25.0, 30.6, 40.7, 41.1, 49.7, 77.3, 117.2, 118.4,
127.4, 127.6, 129.3, 131.3, 150.1, 157.3, 164.5. Anal. Calcd
for C17H25N3O: C, 71.04; H, 8.77; N, 14.62. Found: C,
71.21; H, 8.64; N, 14.70.
2-(4-Bromophenyl)-N-cyclohexyl-4-oxo-1,2,3,4-
tetrahydroquinazoline-2-carboxamide (4b)
Yellow powder; yield 0.23 g (54%); mp 242–245 °C. IR
(KBr): 3371, 3326, 2922, 2830, 1659, 1622, 1483, 1454
cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.14–1.60 (10
H, m, 5 CH2 of c-Hex), 3.50 (1 H, br s, CH of c-Hex), 6.69
(1 H, br s, NH), 6.92 (1 H, br s, NH), 7.28–7.79 (8 H, m,
CHAr), 8.53 (1 H, br, CONH). 13C NMR (75.47 MHz,
DMSO-d6): δ = 24.7, 24.8, 32.3, 48.9, 75.1, 114.7, 115.6,
118.3, 122.4, 127.6, 129.1, 129.3, 131.6, 131.8, 134.1,
140.9, 147.0, 163.8, 169.8. Anal. Calcd for C21H22BrN3O2:
C, 58.89; H, 5.18; Br, 18.66; N, 9.81. Found: C, 58.75; H,
5.24; N, 9.96.
N-Cyclohexyl-2-methyl-4-oxo-1,2,3,4-
tetrahydroquinazoline-2-carboxamide (4c)
White powder; yield 0.18 g (63%); mp 232–235 °C. IR
(KBr): 3413, 3321, 3002, 2923, 2852, 1624, 1580, 1525,
1455 cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.07–
1.70 (10 H, m, 5 CH2 of c-Hex), 1.88 (3 H, s, CH3), 2.89 (1
H, br s, CH of c-Hex), 7.21 (1 H, br s, NH), 7.38 (1 H, br s,
NH), 7.55–7.90 (4 H, m, CHAr), 8.60 (1 H, br, CONH). 13
C
NMR (75.47 MHz, DMSO-d6): δ = 24.2, 25.0, 25.2, 30.7,
49.7, 78.1, 115.1, 122.3, 124.8, 126.3, 126.8, 128.1, 135.1,
147.4, 155.4, 164.3. Anal. Calcd for C16H21N3O2: C, 66.88;
H, 7.37; N, 14.62. Found: C, 66.80; H, 7.43; N, 14.69.
N-tert-Butyl-4-oxo-2-phenyl-1,2,3,4-
tetrahydroquinazoline-2-carboxamide (4d)
White powder; yield 0.20 g (62%); mp 182–184 °C. IR
(KBr): 3260, 3191, 2964, 2926, 2837, 1635, 1612, 1511
cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.57 (9 H, s, 3
CH3), 6.62 (1 H, br s, NH), 6.65 (1 H, br s, NH), 6.74–7.33
(9 H, m, Ar), 7.89 (1 H, br, CONH). 13C NMR (75.47 MHz,
DMSO-d6): δ = 29.7, 45.7, 80.1, 114.7, 116.2, 118.7, 126.4,
127.3 128.3, 129.1, 133.9, 134.0, 141.0, 154.0, 164.5. Anal.
Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found:
C, 70.64; H, 6.61; N, 12.90.
(2E,2′E)-2,2′-[Ethane-1,2-diylbis(azan-1-yl-1-
ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacetamide]
(8)
White powder; yield 0.50 g (78%); mp 202–204 °C. IR
(KBr): 3244, 3071, 2093, 2853, 1623, 1553, 1448 cm–1. 1H
NMR (300.13 MHz, DMSO-d6): δ = 1.22–1.84 (20 H, m, 10
CH2 of c-Hex), 2.15–2.21 (4 H, m, 2 CH2), 3.10 (2 H, br s, 2
NH), 3.64–3.75 (2 H, m, 2 CH of c-Hex), 7.16–7.60 (10 H,
m, CHAr), 7.74 (2 H, br, CONH). 13C NMR (75.47 MHz,
DMSO-d6): δ = 24.8, 25.5, 32.8, 46.1, 84.6, 125.6, 128.2,
128.4, 141.8, 172.9. MS: m/z = 646 (10) [M+ + 2], 644 (20)
[M+], 642 (10) [M+ – 2], 604 (15), 518 (50), 478 (25), 392
(15), 351 (20), 335 (30), 321 (10), 266 (20), 210 (25), 184
(60), 102 (15), 83 (70), 55 (100). Anal. Calcd for C28H38N4,
C, 78.10; H, 8.89; N, 13.01. Found: C, 78.01; H, 8.95; N,
13.05.
N-Cyclohexyl-2-ethyl-4-oxo-1,2,3,4-
tetrahydroquinazoline-2-carboxamide (4e)
White powder; yield 0.19 g (63%); mp 176–179 °C. IR
(KBr): 2983, 2940, 2862, 2825, 1701, 1644, 1618, 1498,
1455 cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.08–
1.88 (13 H, m, 5 CH2 of c-Hex and CH3), 2.28 (2 H, br,
CH2CH3), 2.90 (1 H, br s, CH of c-Hex), 7.11 (1 H, br s, NH),
7.19 (1 H, br s, NH), 7.36–7.91 (4 H, m, CHAr), 8.55 (1 H,
br, CONH). 13C NMR (62.83 MHz, DMSO-d6): δ = 23.2,
24.7, 25.4, 32.9, 35.2, 48.4, 76.4, 113.9, 114.1, 117.3, 126.9,
131.8, 148.5, 159.2, 167.1. Anal. Calcd for C17H23N3O2: C,
67.75; H, 7.69; N, 13.94. Found: C, 67.69; H, 7.62; N, 14.09.
N-tert-Butyl-2-ethyl-4-oxo-1,2,3,4-
(2E,2′E)-2,2′-[1,2-Phenylenebis(azan-1-yl-1-
ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacetamide]
(9)
tetrahydroquinazoline-2-carboxamide (4f)
Brown powder; yield 0.18 g (65%); mp 157–159 °C. IR
(KBr): 3259, 2968, 2895, 1634, 1613, 1515, 1492, 1385 cm–1.
1H NMR (300.13 MHz, DMSO-d6): δ = 1.22–1.33 (14 H, br
s, 3 CH3 of t-Bu, CH2CH3 and CH2CH3), 6.59 (1 H, br s,
NH), 6.67 (1 H, br s, NH), 7.17–7.91 (4 H, m, CHAr), 8.10
(1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d6): δ =
27.5, 29.4, 51.4, 67.3, 78.4, 114.2, 114.7, 116.8, 127.6,
133.6, 147.6, 158.4, 168.4. MS: m/z (%) = 276 (25) [M+ + 1],
223 (80), 200 (15), 177 (15), 161 (100), 120 (25), 92 (25), 58
(75). Anal. Calcd for C15H21N3O2: C, 65.43; H, 7.69; N,
White powder; yield 0.49 g (71%); mp 162–163 °C. IR
(KBr): 3338, 3297, 2933, 2878, 2854, 1644, 1514, 1485,
1455 cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.24–
1.83 (20 H, m, 10 CH2 of c-Hex), 2.82 (4 H, br, 2 CH2), 3.64
(2 H, br s, 2 CH of c-Hex), 7.49–7.66 (8 H, m, CHAr), 7.72
(2 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d6): δ =
25.0, 25.5, 32.7, 46.6, 48.0, 84.5, 123.0, 128.8, 129.9, 131.0,
175.2. Anal. Calcd for C28H36Br2N4, C, 57.15; H, 6.17; Br,
27.16; N, 9.52. Found: C, 57.10; H, 6.09; N, 9.61.
Synlett 2013, 24, 1968–1972
© Georg Thieme Verlag Stuttgart · New York