Base dependent purported synthesis of congested 2-aminobenzylamines and tetrahydro-2-oxoquinazolines from 2-pyranones

Article abstract of DOI:10.1016/j.tet.2008.12.041

An expeditious and concise synthesis of highly congested 2-amino-3-aminomethyl-5-methylsulfanyl/-sec-aminobiphenyl-4-carbonitrile 4 and 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinazoline 5 has been delineated through base

Full text of DOI:10.1016/j.tet.2008.12.041

Tetrahedron 65 (2009) 1635–1638
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base dependent purported synthesis of congested 2-aminobenzylamines
and tetrahydro-2-oxoquinazolines from 2-pyranones
,
b
b,
*
Farhanullah a , Farhana Samrin , Vishnu Ji Ram
*
a Department of Chemistry, Faculty of Science, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore
b Department of Applied Chemistry, Institute of Engineering and Technology, Sitapur Road, Lucknow, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious and concise synthesis of highly congested 2-amino-3-aminomethyl-5-methylsulfanyl/-sec-
Received 28 September 2008
Received in revised form 23 November 2008
Accepted 11 December 2008
Available online 24 December 2008
aminobiphenyl-4-carbonitrile
4 and 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,
4-tetrahydroquinazoline 5 has been delineated through base catalyzed ring transformation of 6-aryl-4-
methylsulfanyl/-sec-amino-2H-pyran-2-one-3-carbonitrile 1 with 1,3-bis(tert-butoxycarbonylamino)-2-
propanone 2, followed by TFA catalyzed hydrolysis of the intermediate [3-tert-butoxycarbonyl-
aminomethyl-4-cyano-5-methylsulfanyl/-sec-aminobiphenyl-2-yl]carbamic acid tert-butyl ester
3 in
moderate yield. The mechanism of formation of 5 has been established through isolation and trans-
formation of the intermediate 3 to the 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,4-
tetrahydroquinazoline.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
3,4-Dihydro-2(1H)-quinazolinone IV is considered as a fused
bicyclic urea derivative, which plays a significant role in organic,
Quinazolines and 2-aminobenzylamines are of great importance
in synthetic and medicinal chemistry.1 Quinazolines (I–IV)2,3 and
benzodiazepines (V)4 are usually synthesized from 2-amino-
benzylamines, which are also useful intermediate for the con-
struction of hardening agents for resins,5 Figure 1. A literature
search on quinazoline nucleus revealed that chemistry of 2,3-
dihydro-4(1H)-quinazolinone III have been explored extensively
while that of 3,4-dihydro-2(1H)-quinazolinone IV ring system is
underdeveloped.
medicinal, supramolecular, and material chemistry.6 Recently, cy-
clic and acyclic ureas are reported7 as potent HIV-1 protease in-
hibitors, P38 MAP kinase inhibitors for the management of
inflammatory diseases,8 in addition to anticonvulsant and antihy-
pertensive activities.9,10
2-Aminobenzylamines are usually prepared11 by the reactionof2-
nitrobenzyl chloride, 2-nitrobenzaldehyde, 2-aminobenzophenone,
2-aminoactophenones, 2-aminopropiophenones with ammonia fol-
lowed by reduction.12,13 Other approaches include lithium borohy-
dride reduction14 of 2-aminobenzamide and hydrogenation of
2-aminobenzaldehyde oxime or 2-nitrobenzalamine over Raney
nickel in ethanol followed by refluxing with Zn dust, ammonium
acetate, and aqueous ammonia in ethanol.8,15
The reaction of amines with isocyanates is a very common ap-
proach for the construction of cyclic ureas.16 Alternative approaches
are the use of dialkyl carbonates,17 diimidazol-1-yl-methane,18,19
S,S-dimethyldithiocarbonate (DMTDC),20 and carbon monoxide
in the presence of selenium21 for carbonylation of amines for
the construction of 3,4-dihydro-2(1H)-quinazolinones. Oxidative
carbonylation of primary amines to cyclic ureas in the presence of
W(CO)6/I2 has been proved to be a useful approach for the synthesis
of 3,4-dihydro-2(1H)-quinazolinones.22 The synthetic limitations of
earlier procedures in terms of use of expensive reagents and cata-
lysts, exposure to corrosive and toxic chemicals, requirement of
high temperature and pressure, and compatibility of reagents to the
functional groups present necessitated to develop an efficient and
concise protocol for the construction of aryl-tethered 3,4-dihydro-2(1H)
Figure 1. Pharmacologically active quinazoline frameworks.
* Corresponding authors. Tel.: þ65 6516 2923; fax: þ65 6779 1691 (Farhanullah);
tel.: þ91 522 2731 297 (V.J.R.).
E-mail addresses: farhanullah73@yahoo.com (Farhanullah), vjiram@yahoo.com
(V.J. Ram).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.041

1636
Farhanullah et al. / Tetrahedron 65 (2009) 1635–1638
Table 1
quinazolinones. Herein, we report a practical synthesis of highly
congested aryl-tethered 2-aminobenzylamines 3, 4 and aryl-teth-
ered3,4-dihydro-2(1H)quinazolinones5throughbasecatalyzedring
transformation of 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbo-
nitriles 1 by 1,3-bis(tert-butoxycarbonylamino)-2-propanone 2.
A list of the synthesized compounds 3, 4, and 5
3,4,5
Ar
R
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-BrC6H4
SCH3
SCH3
SCH3
SCH3
62
55
64
57
59
61
58
56
53
60
95
96
97
72
74
68
70
76
4-BocNHC6H4
4-MeOC6H4
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
4-BrC6H4
2. Results and discussion
Piperidin-1-yl
4-Methylpiperidin-1-yl
Morpholin-4-yl
4-Phenylpiperazin-1-yl
4-Phenylpiperazin-1-yl
Dimethylamino
SCH3
The desired 1,3-bis(tert-butoxycarbonylamino)-2-propanone 2
was obtained23 from the reaction of 1,3-diaminopropan-2-ol and
di-tert-butyl dicarbonate followed by Swern oxidation. The various
3j
2-Naphthyl
4-BrC6H4
6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles
1
used as
4a
4b
4c
5a
5b
5c
5d
5e
a precursor were prepared from the reaction of methyl 2-cyano-
3,3-dimethylthioacrylate24 and aryl methyl ketone followed by
amination25 with secondary amines in boiling ethanol.
4-MeOC6H4
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
4-BrC6H4
SCH3
4-Phenylpiperazin-1-yl
Dimethylamino
Piperidin-1-yl
4-Phenylpiperazin-1-yl
Morpholin-4-yl
Pyrrolidin-1-yl
It is evident from the topography of 6-aryl-4-sec-amino-2H-py-
ran-2-one-3-carbonitriles that they possess three electrophilic
centers C-2, C-4, and C-6 in which latter is highly prone to nucleo-
philic attack due to extended conjugation and the presence of an
electron-withdrawing CN substituent at position 3 of the pyran ring.
There are two probable paths A and B for this ring transformation
reaction. The initial step in path B is the formation of Michael adduct
through attack of carbanion generated in situ from 1,3-bis(tert-
butoxycarbonylamino)-2-propanone 2 at most electron deficient
center C-6 of the lactone 1 followed by ring closure with the loss of
waterand carbon dioxide to provide ring transformed product 3. The
alternate path A for this reaction is attack of carbanion from 2 at C-6
of 1 with ring opening followed by intramolecular cyclization in-
volving C-3 of the pyran ring with loss of carbon dioxide and water to
form 3 as depicted in Scheme 1. The Diels–Alder mechanism for this
reaction is ruled out as this reaction is carried out at room
temperature under very mild condition, which is inappropriate26 for
this substrate under applied experimental conditions.
Thus, stirring a reaction mixture of 6-aryl-4-sec-amino-2H-py-
ran-2-one-3-carbonitriles 1 and 1,3-bis(tert-butoxycarbonylamino)-
2-propanone 2 in the presence of K2CO3 in DMF gave 2-(tert-butoxy-
carbonylaminomethyl)-3-tert-butoxycarbonylamino-6-sec-amino-4-
benzonitrile27 3, which was subsequently hydrolyzed with TFA to
give diamine 4 as the trifluoroacetate salt, Scheme 1. It was found
that the use of KOH in lieu of K2CO3 produced a product different
from 3 and was characterized as 1-tert-butoxycarbonyl-6-sec-
amino-8-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinazoline
5
in
moderate yields (Table 1). It is possible that formation of 5 takes
place through in situ formation of 3 as intermediate, which in due
course cyclizes to 5 as shown in Scheme 1. The formation of 3 as a key
intermediate in the synthesis of 5 was confirmed by conversion of 3
to compound 5 on stirring in the presence of powdered KOH in DMF.
It is expected that KOH promoted abstraction of proton from the Boc
protected amino group, directly attached to the phenyl ring in
the presence of the CN group at the meta position of 3 facilitates
the cyclization to give 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-
cyano-2-oxo-1,2,3,4-tetrahydroquinazoline 5 (Table 1).
3. Conclusion
We have developed a facile, economical, and efficient route to the
synthesis of highly congested 2-aminobenzylamine and tetrahydro-
2-oxoquinazolines. The methodology also provides an opportunity
to append diverse functionalities such as sec-amino, methylsulfanyl,
cyano, and aryl groups into the molecular structure of the product.
4. Experimental
4.1. General
All reactions were conducted in flame dried glassware. Pre-
coated Merck TLC plates were used for monitoring progress of the
reactions. Column chromatographic separations were performed
on silica gel (60–120 mesh). IR spectra were recorded on a Shi-
madzu 8201 PC FTIR spectrophotometer. 1H NMR spectra were
recorded on Brucker DRX 200 as well as Bruker DRX 300 spectro-
meters in deuterated solvents with TMS as internal reference. Mass
spectra were recorded on JEOL SX-102 (FAB) spectrometer. Melting
points were determined on Bu¨chi-530 capillary melting point ap-
paratus and are uncorrected. Elemental analyses were performed
on a Carlo Erba 108 or an Elementar Vario EL III microanalyzer at
CDRI, Lucknow 226001, India.
Scheme 1. Plausible mechanisms for the formation of 3, 4, and 5.

Farhanullah et al. / Tetrahedron 65 (2009) 1635–1638
1637
4.2. General procedure for the synthesis of [3-(tert-
4.2.6. [2-(tert-Butoxycarbonylaminomethyl)-3-cyano-4-
(4-methylpiperidin-1-yl)-6-naphthalen-2-yl-phenyl]-carbamic
acid tert-butyl ester (3f)
butoxycarbonylaminomethyl)-4-cyano-5-methylsulfanyl-
biphenyl-2-yl]-carbamic acid tert-butyl ester (3a–d) and [6-
aryl-2-(tert-butoxycarbonylaminomethyl)-3-cyano-4-sec-
aminophenyl]-carbamic acid tert-butyl ester (3e–j)
White amorphous solid; mp 113–115 ꢀC. [Found: C, 71.41; H,
7.32; N, 9.76. C34H42N4O4 requires: C, 71.55; H, 7.42; N, 9.82%.] nmax
(KBr) 3340, 2217, 1695 cmꢁ1
; dH (300 MHz, CD3OD) 0.90 (3H, d, J
A mixture of 1 (1.0 mmol) and 2 (288 mg, 1.0 mmol) was stir-
red for 4 h in a suspension of powdered K2CO3 (207 mg, 1.5 mmol)
in DMF (5 mL). The progress of the reaction was monitored by TLC
in a mixture of hexane–ethyl acetate (7:3). The reaction mixture
was poured into ice cold water and neutralized with 10% HCl. The
solid precipitate obtained was filtered, washed with water, and
purified on silica gel chromatography by eluting with hexane–
ethyl acetate (9:1).
6.0 Hz, CH3), 1.33–1.35 (1H, m, CH, piperidinyl), 1.37 (9H, s, Boc),
1.45 (9H, s, Boc), 1.62–1.64 (2H, m, CH2, piperidinyl), 1.65–1.69 (2H,
m, CH2, piperidinyl), 2.67–2.74 (2H, m, CH2, piperidinyl), 3.44–3.48
(2H, m, CH2, piperidinyl), 4.51 (2H, s, CH2), 5.02 (1H, br s, NH), 7.00
(1H, s, ArH), 7.35–7.41 (3H, m, ArH), 7.76–7.80 (4H, m, ArH), 8.22
(1H, br s, NH); MS (FAB): m/z 571 (MHþ).
4.2.7. [2-(tert-Butoxycarbonylaminomethyl)-3-cyano-4-morpholin-
4-yl-6-naphthalen-2-yl-phenyl]-carbamic acid tert-butyl ester (3g)
White amorphous solid; mp 127–128 ꢀC. [Found: C, 68.64; H,
6.80; N, 10.23. C32H38N4O5 requires: C, 68.80; H, 6.86; N, 10.03%.]
4.2.1. [40-Bromo-3-(tert-butoxycarbonylaminomethyl)-4-cyano-5-
methylsulfanyl-biphenyl-2-yl]-carbamic acid tert-butyl ester (3a)
White amorphous solid; mp 182–183 ꢀC. [Found: C, 54.66; H,
5.56; N, 7.59. C25H30BrN3O4S requires: C, 54.74; H, 5.51; N, 7.66%.]
nmax (KBr) 3337, 2218, 1714 cmꢁ1
; dH (300 MHz, CDCl3) 1.16 (9H, s,
Boc), 1.46 (9H, s, Boc), 3.01–3.12 (4H, m, CH2, morpholinyl), 3.89–
3.92 (4H, m, CH2, morpholinyl), 4.44 (2H, s, CH2), 5.56 (1H, br s, NH),
7.03 (1H, s, ArH), 7.48–7.52 (3H, m, ArH), 7.83–7.89 (4H, m, ArH),
8.20 (1H, br s, NH); MS (FAB): m/z 559 (MHþ).
nmax (KBr) 3329, 2221, 1697 cmꢁ1
; dH (300 MHz, CDCl3) 1.25 (9H, s,
Boc), 1.44 (9H, s, Boc), 2.44 (3H, s, SCH3), 4.70 (2H, s, CH2), 5.53 (1H,
br s, NH), 7.16 (1H, s, ArH), 7.28 (2H, d, J 7.8 Hz, ArH), 7.55 (2H, d, J
7.8 Hz, ArH), 8.19 (1H, br s, NH); MS (FAB): m/z 548 (MHþ).
4.2.8. [2-(tert-Butoxycarbonylaminomethyl)-3-cyano-6-
naphthalen-2-yl-4-(4-phenylpiperazin-1-yl)-phenyl]-carbamic
acid tert-butyl ester (3h)
4.2.2. [20-tert-Butoxycarbonylamino-30-(tert-butoxycarbonyl-
aminomethyl)-40-cyano-50-methylsulfanyl-biphenyl-4-yl]-
carbamic acid tert-butyl ester (3b)
White powder solid; mp 183–185 ꢀC. [Found: C, 71.84; H, 6.72;
N, 11.16. C38H43N5O4 requires: C, 72.01; H, 6.84; N, 11.05%.] nmax
White powder; mp 185–186 ꢀC. [Found: C, 61.58; H, 6.82; N,
9.60. C30H40N4O6S requires: C, 61.62; H, 6.90; N, 9.58%.] nmax (KBr)
(KBr) 3341, 2218, 1697 cmꢁ1
; dH (300 MHz, CDCl3) 1.11 (9H, s, Boc),
3334, 2220, 1725 cmꢁ1
;
dH (300 MHz, CDCl3) 1.46 (9H, s, Boc), 1.54
1.46 (9H, s, Boc), 3.40 (8H, s, CH2, piperazinyl), 4.46 (2H, s, CH2), 5.56
(1H, br s, NH), 6.87–6.92 (1H, m, ArH), 6.97–6.99 (2H, m, ArH), 7.09
(1H, s, ArH), 7.29–7.32 (2H, m, ArH), 7.49–7.52 (3H, m, ArH), 7.84–
7.90 (4H, m, ArH), 8.20 (1H, br s, NH); MS (FAB): m/z 634 (MHþ).
(9H, s, Boc), 1.56 (9H, s, Boc), 2.46 (3H, s, SCH3), 4.72 (2H, s, CH2),
5.01 (1H, br s, NH), 7.14 (1H, s, ArH), 7.30 (2H, d, J 8.4 Hz, ArH),
7.52 (2H, d, J 8.4 Hz, ArH), 8.19 (1H, br s, NH); MS (FAB): m/z 585
(MHþ).
4.2.9. [40-Bromo-3-(tert-butoxycarbonylaminomethyl)-4-cyano-
5-(4-phenylpiperazin-1-yl)-biphenyl-2-yl]-carbamic acid
tert-butyl ester (3i)
4.2.3. [3-(tert-Butoxycarbonylaminomethyl)-4-cyano-40-methoxy-
5-methylsulfanyl-biphenyl-2-yl]-carbamic acid tert-butyl ester (3c)
White amorphous solid; mp 135–136 ꢀC. [Found: C, 62.58; H,
6.80; N, 8.50. C26H33N3O5S requires: C, 62.50; H, 6.66; N, 8.41%.]
White powder; mp 179–180 ꢀC. [Found: C, 61.46; H, 6.12; N,
10.38. C34H40BrN5O4 requires: C, 61.63; H, 6.08; N, 10.57%.] nmax
nmax (KBr) 3338, 2219, 1716 cmꢁ1
;
dH (300 MHz, CDCl3) 1.46 (9H, s,
(KBr) 3329, 2218, 1697 cmꢁ1
; dH (300 MHz, CDCl3) 1.25 (9H, s,
Boc), 1.60 (9H, s, Boc), 2.47 (3H, s, SCH3), 3.87 (3H, s, OCH3), 4.76
(2H, s, CH2), 5.90 (1H, br s, NH), 6.99 (1H, s, ArH), 7.03 (2H, d, J
8.4 Hz, ArH), 7.29 (2H, d, J 8.4 Hz, ArH), 8.20 (1H, br s, NH); MS
(FAB): m/z 500 (MHþ).
Boc), 1.46 (9H, s, Boc), 3.38 (8H, s, CH2, piperazinyl), 4.42 (2H, s,
CH2), 5.53 (1H, br s, NH), 6.80–6.99 (4H, m, ArH), 7.26–7.32 (4H,
m, ArH), 7.54 (2H, d, J 8.10 Hz, ArH), 7.99 (1H, br s, NH); MS (FAB):
m/z 662 (MHþ).
4.2.4. [2-(tert-Butoxycarbonylaminomethyl)-3-cyano-4-methyl-
sulfanyl-6-naphthalen-2-yl-phenyl]-carbamic acid tert-
butyl ester (3d)
4.2.10. [2-(tert-Butoxycarbonylaminomethyl)-3-cyano-4-
dimethylamino-6-naphthalen-2-yl-phenyl]-carbamic
acid tert-butyl ester (3j)
White amorphous solid; mp 159–160 ꢀC. [Found: C, 67.08; H,
6.48; N, 8.29. C29H33N3O4S requires: C, 67.03; H, 6.40; N, 8.09%.]
White amorphous solid; mp 109–110 ꢀC. [Found: C, 69.63; H,
7.18; N, 10.72. C30H36N4O4 requires: C, 69.74; H, 7.02; N, 10.84%.]
nmax (KBr) 3339, 2220, 1711 cmꢁ1
;
dH (300 MHz, CDCl3) 1.25 (9H, s,
nmax (KBr) 3363, 2218, 1698 cmꢁ1
; dH (300 MHz, CD3OD) 1.16 (9H, s,
Boc), 1.46 (9H, s, Boc), 2.57 (3H, s, SCH3), 4.45 (2H, s, CH2), 5.56 (1H,
br s, NH), 7.31 (1H, s, ArH), 7.49–7.52 (3H, m, ArH), 7.84–7.90 (4H, m,
ArH), 8.20 (1H, br s, NH); MS (FAB): m/z 520 (MHþ).
Boc), 1.45 (9H, s, Boc), 3.04 (6H, s, NCH3), 4.41 (2H, s, CH2), 5.56 (1H,
br s, NH), 7.05 (1H, s, ArH), 7.46–7.52 (3H, m, ArH), 7.86–7.90 (4H, m,
ArH), 8.20 (1H, br s, NH); MS (FAB): m/z 517 (MHþ).
4.2.5. [2-(tert-Butoxycarbonylaminomethyl)-3-cyano-6-naph-
thalen-2-yl-4-piperidin-1-yl-phenyl]-carbamic acid tert-
butyl ester (3e)
4.3. General procedure for the synthesis of 3-(amino-
methyl)-4-cyano-5-(methylthio)biphenyl-ammonium
ditrifluoroacetate (4a–c)
White powder; mp 161–163 ꢀC. [Found: C, 71.28; H, 7.32; N,
10.24. C33H40N4O4 requires: C, 71.20; H, 7.24; N, 10.06%.] nmax
(KBr) 3304, 2220, 1716 cmꢁ1
; dH (300 MHz, CD3OD) 1.17 (9H, s,
Boc), 1.45 (9H, s, Boc), 1.62–1.64 (2H, m, CH2, piperidinyl), 1.78–
1.80 (4H, m, CH2, piperidinyl), 3.19–3.21 (4H, m, CH2, piperidinyl),
4.41 (2H, s, CH2), 5.02 (1H, br s, NH), 7.11 (1H, s, ArH), 7.45–7.52
(3H, m, ArH), 7.86–7.91 (4H, m, ArH), 8.22 (1H, br s, NH); MS
(FAB): m/z 557 (MHþ).
Compound 4 was obtained by stirring 3 (1 mmol) in a solution of
20% TFA in DCM (10 mL) at room temperature for 2 h. After com-
pletion of the reaction, TFA was removed under reduced pressure
and residue was washed with DCM (3 mL) leaving a TFA salt of the
product 4.

1638
Farhanullah et al. / Tetrahedron 65 (2009) 1635–1638
4.3.1. 3-(Aminomethyl)-40-bromo-4-cyano-5-(methylthio)-
biphenyl-2-ammonium ditrifluoroacetate (4a)
4.4.4. tert-Butyl 5-cyano-6-morpholino-8-(naphthalen-2-yl)-2-
oxo-3,4-dihydroquinazoline-1(2H)-carboxylate (5d)
White powder solid; mp >250 ꢀC. [Found: C, 39.73; H, 2.94; N,
7.48. C19H16BrF6N3O4S requires: C, 39.60; H, 2.80; N, 7.29%.] nmax
White amorphous solid; mp 158–160 ꢀC. [Found: C, 69.54; H,
5.90; N, 11.66. C28H28N4O4 requires: C, 69.41; H, 5.82; N, 11.56%.]
(KBr) 3362 (NH), 2221 (CN), 1676 (CO) cmꢁ1
;
dH (300 MHz, DMSO-
nmax (KBr) 1722, 1772, 2222 cmꢁ1
; dH (300 MHz, CD3OD) 1.56 (9H, s,
d6) 2.40 (3H, s, SCH3), 4.20 (2H, s, CH2), 6.88 (1H, s, ArH), 7.04 (2H, d,
Boc), 3.16–3.19 (4H, m, CH2, morpholinyl), 3.85–3.88 (4H, m, CH2),
5.00 (2H, s, CH2, morpholinyl), 6.95 (1H, s, ArH), 7.52–7.57 (3H, m,
ArH), 7.92–8.04 (4H, m, ArH); MS (FAB): m/z 485 (MHþ).
J 8.4 Hz, ArH), 7.40 (2H, d, J 8.4 Hz, ArH); MS (FAB): m/z 348 (MHþ).
4.3.2. 3-(Aminomethyl)-4-cyano-40-methoxy-5-(methylthio)-
biphenyl-2-ammonium ditrifluoroacetate (4b)
4.4.5. tert-Butyl 8-(4-bromophenyl)-5-cyano-2-oxo-6-(pyrrolidin-
1-yl)-3,4-dihydroquinazoline-1(2H)-carboxylate (5e)
White amorphous solid; mp >250 ꢀC. [Found: C, 45.62; H, 3.76;
N, 7.86. C20H19F6N3O5S requires: C, 45.54; H, 3.63; N, 7.97%.] nmax
White amorphous solid; mp 152–154 ꢀC. [Found: C, 58.09; H,
5.14; N, 11.35. C24H25BrN4O3 requires: C, 57.95; H, 5.07; N, 11.26%.]
(KBr) 3362, 2219, 1776 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.38 (3H, s,
SCH3), 3.81 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.86 (1H, s, ArH), 7.06 (2H,
nmax (KBr) 1724, 1774, 2222 cmꢁ1
; dH (300 MHz, CDCl3) 1.56 (9H, s,
d, J 8.4 Hz, ArH), 7.41 (2H, d, J 8.4 Hz, ArH); MS (FAB): m/z 300 (MHþ).
Boc), 1.99–2.03 (4H, m, CH2, pyrrolidinyl), 3.56–3.60 (4H, m, CH2,
pyrrolidinyl), 4.97 (2H, s, CH2), 6.64 (1H, s, ArH), 7.23 (2H, d, J 8.0 Hz,
ArH), 7.62 (2H, d, J 8.0 Hz, ArH); MS (FAB): m/z 497 (MHþ).
4.3.3. 2-(Aminomethyl)-3-cyano-6-(naphthalen-2-yl)-4-(4-
phenylpiperazin-1-yl)benzen ammonium ditrifluoroacetate (4c)
White amorphous solid; mp >250 ꢀC. [Found: C, 58.23; H, 4.58;
N, 10.74. C32H29F6N5O5 requires: C, 58.09; H, 4.42; N, 10.59%.] nmax
Acknowledgements
(KBr) 3364, 2219, 1697 cmꢁ1
; dH (300 MHz, DMSO-d6) 3.07 (8H, s,
The authors thank the Sophisticated Analytical Instrument
Facility (SAIF), CDRI, Lucknow, India for providing spectroscopic
and elemental analysis. The authors also thank AICTE, New Delhi,
India for financial support.
CH2, piperazinyl), 4.20 (2H, s, CH2), 6.76–6.81 (1H, m, ArH), 6.97–
7.00 (2H, m, ArH), 7.11 (1H, s, ArH), 7.20–7.25 (2H, m, ArH), 7.56–
7.62 (3H, m, ArH), 7.96–8.05 (4H, m, ArH); MS (FAB): m/z 434
(MHþ).
References and notes
4.4. General procedure for the synthesis of 1-tert-
butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-
oxo-1,2,3,4-tetrahydroquinazolines (5a–e)
1. Sugimoto, K.; Yamaguchi, K.; Tanabe, Y.; Yamazaki, M.; Yamaguchi, T. Jpn. Kokai
Tokkyo Koho JP 61, 189250, 1986; Chem. Abstr. 1987, 106, 66885f.
2. Georgiev, V. St.; Bennet, G. A.; Radov, L. A.; Kamp, D. K.; Trusso, L. A. J. Heter-
ocycl. Chem. 1986, 23, 1359–1362.
3. Kempter,G.;Ehrlichmann,W.;Plesse,M.;Lehm,H.U.J. Prakt. Chem.1982,324, 832–840.
4. Shiotani, S.; Mitsuhashi, K. Yakugaku Zasshi 1964, 84, 656–663.
5. (a) Keizaburo, Y.; Kenichi, S.; Yoshimitsu, T.; Midori, Y.; Akihiro, Y. Patentschrift
(Switz) PP5, 1988; Chem. Abstr. 1988, 109, 230515v; (b) Yamaguchi, K.;
Sugimoto, K.; Tanabe, Y.; Yamazaki, M.; Yamaguchi, A. German Offen DE
85-3521270, 1986; Chem. Abstr. 1986, 107, 8258p.
A mixture of 1 (1.0 mmol) and ketone 2 (288 mg,1.0 mmol) in dry
DMF (15 mL) was stirred at room temperature in the presence of
KOH (276 mg, 2 mmol) for 3-4 h. The reaction mixture was diluted
with distilled water and neutralized with 10% HCl. The solid pre-
cipitate thus formed was filtered, washed with excess of water, and
purified by silica gel column chromatography using DCM as eluent.
6. (a) Gabriele, B.; Saleno, G.; Mancuso, R.; Costa, M. J. Org. Chem. 2004, 69, 4741–
4750; (b) Han, C.; Porco, J. A., Jr. Org. Lett. 2007, 9, 1517–1520.
7. (a) Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. J. Med. Chem.
1998, 41, 2019–2028 and references therein; (b) Guichou, J.-F.; Viaud, J.;
Mettling, C.; Subra, G.; Lin, Y.-L.; Cavanieu, A. J. Med. Chem. 2006, 49, 900–910.
8. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, F.; Klauas,
M.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer,
A.; Tong, L.; Torcellni, C. J. Med. Chem. 2002, 45, 2994–3008 and references
therein.
4.4.1. tert-Butyl 5-cyano-6-(dimethylamino)-8-(naphthalene-2-yl)-
2-oxo-3,4-dihydroquinazoline-1(2H)-carboxylate (5a)
White powder solid; mp 102–103 ꢀC. [Found: C, 70.68; H, 5.88;
N, 12.80. C26H26N4O3 requires: C, 70.57; H, 5.92; N, 12.66%.] nmax
(KBr) 1725, 1774, 2220 cmꢁ1
; dH (300 MHz, CD3OD) 1.56 (9H, s, Boc),
9. Takai, H.; Obase, H.; Teanishi, M.; Karasawa, A.; Kubo, K.; Shuto, K.; Kasuya, Y.;
Shigenobu, K. Chem. Pharm. Bull. 1986, 34, 1907–1916.
2.96 (6H, s, NCH3), 4.98 (2H, s, CH2), 6.99 (1H, s, ArH), 7.51–7.57 (3H,
m, ArH), 7.90–8.03 (4H, m, ArH); MS (FAB): m/z 443 (MHþ).
10. Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Kasuya, Y.;
Shigenobu, K.; Hashikami, M.; Karashima, N. Chem. Pharm. Bull.1985, 33,1116–1128.
11. Ishikawa, F.; Watanabe, Y.; Saegusa, J. Chem. Pharm. Bull. 1980, 28, 1357–1364.
12. (a) Beddoes, R. L.; Edward, W. D.; Joule, J. A.; Mills, O. S.; Street, J. D. Tetrahedron
1987, 43, 1903–1920; (b) Naidu, M. S. R.; Reddy, D. Indian J. Chem. 1974, 12,
349–350.
13. Kornblum, N.; Iffland, D. C. J. Am. Chem. Soc. 1949, 71, 2137–2140.
14. (a) Grosso, J. A.; Nichols, D. E.; Nichols, M. B.; Kim, G. K. W. J. Med. Chem. 1980,
23, 1261–1264; (b) Ludeman, S. M.; Gerald, Z. J. Med. Chem. 1975, 18, 1251–1253.
15. (a) Rastogi, R.; Sharma, S. Indian J. Chem. 1982, 21B, 744–746; (b) Stephenson, E.
F. M. J. Chem. Soc. 1954, 2354–2357.
16. Ozaki, S. Chem. Rev. 1972, 72, 457–496.
17. Parrish, J. P.; Salvatore, R. N.; Jung, K. W. Tetrahedron 2000, 56, 8207–8237.
18. Stabb, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 528–532.
19. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894–895.
20. (a) Degani, I.; Fochi, R.; Regondi, V. Synthesis 1980, 375–377; (b) Degani, I.;
Fochi, R.; Regondi, V. Synthesis 1981, 149–150; (c) Leung, M.-K.; Lai, J.-L.; Lau,
K. -H.; Yu, H.-H.; Hsiao, H.-J. J. Org. Chem. 1996, 61, 4175–4179.
21. Yoshida, T.; Kambe, N.; Murai, S.; Sonoda, N. J. Org. Chem. 1987, 52, 1611–1613.
22. McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; White, L. M. J. Org.
Chem. 2000, 65, 5216–5222.
4.4.2. tert-Butyl 5-cyano-8-(naphthalen-2-yl)-2-oxo-6-(piperidin-
1-yl)-3,4-dihydroquinazoline-1(2H)-carboxylate (5b)
White powder solid; mp 192–194 ꢀC. [Found: C, 72.29; H, 6.34;
N, 11.76. C29H30N4O3 requires: C, 72.18; H, 6.27; N, 11.61%.] nmax
(KBr) 1720, 1772, 2220 cmꢁ1
; dH (300 MHz, CDCl3) 1.57 (9H, s, Boc),
1.59–1.63 (2H, m, CH2, piperidinyl), 1.75–1.83 (4H, m, CH2, piper-
idinyl), 3.11–3.14 (4H, m, CH2, piperidinyl), 5.02 (2H, s, CH2), 6.93
(1H, s, ArH), 7.40–7.43 (1H, m, ArH), 7.55–7.61 (2H, m, ArH), 7.81–
7.82 (1H, m, ArH), 7.85–7.92 (2H, m, ArH), 7.98 (1H, d, J 8.4 Hz, ArH);
MS (FAB): m/z 483 (MHþ).
4.4.3. tert-Butyl 5-cyano-8-(naphthalen-2-yl)-2-oxo-6-
(4-phenylpiperazin-1-yl)-3,4-dihydroquinazoline-1(2H)-
carboxylate (5c)
White amorphous solid; mp 140–142 ꢀC. [Found: C, 72.85; H,
6.10; N, 12.60. C34H33N5O3 requires: C, 72.97; H, 5.94; N, 12.51%.]
23. Oost, T.; Kalesse, M. Tetrahedron 1997, 53, 8421–8438.
24. (a) Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. J. Heterocycl. Chem. 1987, 24,
1557–1567; (b) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. J. Chem. Res.,
Synop. 1991, 98–99; (c) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. Liebigs
Ann. Chem. 1991, 1229–1231.
25. Ram, V. J.; Nath, M.; Srivastava, P.; Sarkhel, S.; Maulik, P. R. J. Chem. Soc., Perkin
Trans. 1 2000, 3719–3723.
nmax (KBr) 1722, 1774, 2220 cmꢁ1
; dH (300 MHz, CDCl3) 1.57 (9H, s,
Boc), 3.33–3.41 (8H, m, CH2, piperazinyl), 5.04 (2H, s, CH2), 6.87–
6.99 (4H, m, ArH), 7.25–7.31 (2H, m, ArH), 7.41–7.45 (1H, m, ArH),
7.57–7.62 (2H, m, ArH), 7.83–7.84 (1H, m, ArH), 7.88–7.93 (2H, m,
ArH), 7.99 (1H, d, J 8.4 Hz, ArH); MS (FAB): m/z 560 (MHþ).
26. Karmakar, K. S.; Samant, S. D. Indian J. Chem. 1993, 32B, 1113–1118.
27. Farhanullah; Samrin, F.; Ram, V. J. Tetrahedron Lett. 2007, 48, 3187–3190.