An easy entry into 2-halo-3-aryl-4(3 H)-quinazoliniminium halides from heteroenyne-allenes

Article abstract of DOI:10.1021/ol201372n

An efficient three-step synthesis of 2-halo-3-aryl-4(3H)-quinazoliniminium halides from commercially available materials is described. Upon reaction with hydrogen halides, generated in situ from a Lewis acid (MX) and trace water, a variety of easily acces

Full text of DOI:10.1021/ol201372n

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3718–3721
An Easy Entry into 2-Halo-3-aryl-4(3H)-
quinazoliniminium Halides from
Heteroenyne-allenes
Vijaya Kumar Naganaboina, Kusum Lata Chandra, John Desper, and Sundeep Rayat*
Department of Chemistry, Kansas State University, 213 CBC Building, Manhattan,
Kansas 66506-0401, United States
sundeep@ksu.edu
Received May 21, 2011
ABSTRACT
An efficient three-step synthesis of 2-halo-3-aryl-4(3H)-quinazoliniminium halides from commercially available materials is described. Upon
reaction with hydrogen halides, generated in situ from a Lewis acid (MX) and trace water, a variety of easily accessible heteroenyne-allenes
underwent facile intramolecular cyclization to afford the title compounds in good yields. The method is highly versatile and provides a general way
to construct quinazoliniminium ring systems with a variety of different substitutions.
4(3H)-Quinazolinones 1 substituted at C-2 or/and N-3
(Figure 1) constitute an important family of compounds in
heterocyclic chemistry and exhibit a broad spectrum of
biological activities such as antihypertensive,1 antimalarial,2
antimicrobial,3 anticonvulsive,4 anticancer,5 anti-inflam-
matory,6 and analgesic effects.7 As a result, quinazolinones
and their derivatives are regarded as “privileged struc-
tures” that are capable of binding to multiple receptors
with high affinity.8 The 4(3H)-quinazolinone ring system 1
is also featured in several natural products. For instance,
quinadoline A and B isolated from Aspergillus sp. FKI-1746
inhibit lipid droplet synthesis,9 febrifugine obtained
from a Chinese herb Dichroa febrifuga is an active com-
ponent against malarial parasite,10 luotonin A also from a
Chinese herb Peganum nigellastrum is a Topoisomerase I
poison,11 and nigellastrines isolated from Peganum
(1) (a) Hess, H. J.; Cronin, T. H.; Scriabine, A. J. Med. Chem. 1968,
11, 130. (b) Chen, Z.; Hu, G.; Li, D.; Chen, J.; Li, Y.; Zhou, H.; Xie, Y.
Bioorg. Med. Chem. 2009, 17, 2351. (c) Kubota, H.; Kakefuda, A.;
Watanabe, T.; Ishii, N.; Wada, K.; Masuda, N.; Sakamoto, S.; Tsukamoto,
S.-I. J. Med. Chem. 2003, 46, 4728.
(2) Hirai, S.; Kikuchi, H.; Kim, H.-S.; Begum, K.; Wataya, Y.;
Tasaka, H.; Miyazawa, Y.; Yamamoto, K.; Oshima, Y. J. Med. Chem.
2003, 46, 4351.
(3) (a) Gudasi, K. B.; Shenoy, R. V.; Vadavi, R. S.; Patil, M. S.; Patil,
S. A. Indian J. Chem., A 2005, 44A, 2247. (b) Alagarsamy, V. Indian J.
Pharm. Sci. 2002, 64, 600. (c) Reddy, P. B.; Reddy, S. M.; Reddy, K. L.;
Lingaiah, P. Indian Phytopathol. 1985, 38, 361.
(4) Bhandari, S. V.; Deshmane, B. J.; Dangare, S. C.; Gore, S. T.;
Raparti, V. T.; Khachane, C. V.; Sarkate, A. P. Pharmacologyonline
2008, 604.
(5) Al-Obaid, A. M.; Abdel-Hamide, S. G.; El-Kashef, H. A.; Abdel-
Aziz, A. A. M.; El-Azab, A. S.; Al-Khamees, H. A.; El-Subbagh, H. I.
Eur. J. Med. Chem. 2009, 44, 2379.
Figure 1. 4(3H)-Quinazolinone 1 and 4(3H)-quinazolinimine 2.
(8) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
(9) Koyama, N.; Inoue, Y.; Sekine, M.; Hayakawa, Y.; Homma, H.;
Oinmura, S.; Tomoda, H. Org. Lett. 2008, 10, 5273.
(10) Zhu, S.; Wang, J.; Chandrashekar, G.; Smith, E.; Liu, X.;
Zhang, Y. Eur. J. Med. Chem. 2010, 45, 3864.
(6) Giri, R. S.; Thaker, H. M.; Giordano, T.; Williams, J.; Rogers, D.;
Sudersanam, V.; Vasu, K. K. Eur. J. Med. Chem. 2009, 44, 4783.
(b) Chandrika, P. M.; Yakaiah, T.; Rao, A. R. R.; Narsaiah, B.; Reddy,
N. C.; Sridhar, V.; Rao, J. V. Eur. J. Med. Chem. 2008, 43, 846.
(7) (a) Kumar, A.; Sharma, S.; Archana; Bajaj, K.; Sharma, S.;
Panwar, H.; Singh, T.; Srivastava, V. K. Bioorg. Med. Chem. FIELD
2003, 11, 5293. (b) Sindrup, S. H.; Graf, A.; Sfikas, N. Eur. J. Pain 2006,
10, 567.
(11) Cinelli, M. A.; Morrell, A.; Dexheimer, T. S.; Scher, E. S.;
Pommier, Y.; Cushman, M. J. Med. Chem. 2008, 51, 4609.
r
10.1021/ol201372n
Published on Web 06/23/2011
2011 American Chemical Society

Scheme 1. General Method for the Synthesis of Heteroenyne-allenes 6
Nigellastrum Bunge are acetylcholinesterase inhib-
itors.12 This heterocycle and its derivatives have also
been evaluated in electroluminescent devices and or-
ganic dyes.13 The widespread applications of quina-
zolinones in medicinal and materials chemistry have
triggered considerable synthetic efforts to construct
these ring systems.14
One important building block for the synthesis of qui-
nazolinones 1 and their derivatives is a 4(3H)-quinazolini-
mine scaffold 2 (Figure 1).15a Note that the ring system 2 is
featured in compounds that exhibit cholinesterase inhib-
itory15f,g,n and antiproliferative activities.16 Several meth-
ods to synthesize 2 are available in the literature.15 A single
step synthesis of quinazolinimines 2 has been reported in a
three-component reaction between a carbonyl compound,
amine, and 2-azido-5-nitro-benzonitrile.17 However, none
of the reported methods have been optimized and exam-
ined for versatility to construct a variety of functionalized
4(3H)-quinazolinimine scaffolds in a general way. Further-
more, some of the existing protocols require long reaction
times,15a high temperatures,15d special setup, and workup
conditions15f,n and produce low yields.15g,o During our
attempts to induce a formal [4 þ 2] cyclization from cyano-
ene-carbodiimides,18 we discovered a new and alternative
method to build 2 in the presence of a hydrogen halide,
generated in situ from the reaction of a Lewis acid with
trace water, which was further subjected to an optimiza-
tion study. The advantages of this newly discovered meth-
od are the following: (1) It is highly versatile and allows the
construction of a quinazoliniminium ring carrying a wide
range of different substitutions, notably on N-3. (2) It
provides access to 2-halo quinazoliniminiums that have
not been previously explored. The presence of a halogen
atom at C-2 offers possibilities to exploit this site into fur-
ther chemistry for additional functionalization. As men-
tioned above, functionalization at N-3 or/and C-2 posi-
tions of these ring systems is extremely important from a
drug discovery viewpoint, and in addition, (3) the reaction
is carried out at room temperature and requires no special
setup/workup to isolate the quinazoliniminium product.
2-((Phenylimino)methyleneamino)-benzonitrile (6a)(R1 =
R2 = R3 = R4 = R5 = H) was prepared as reported in the
literature (Scheme 1).19 Briefly, the aza-Wittig reaction of
2-aminobenzonitrile (3a) (R1 = R2 = H) with triphenyl-
phosphine dibromide in the presence of triethylamine yielded
the iminophosphorane 4a (R1 = R2 = H) (77%) which
upon treatment with isocyanate 5a (R3 = R4 = R5 = H)
generated 6a (67%).
(12) Zheng, X.-y.; Zhang, Z.-j.; Chou, G.-x.; Wu, T.; Cheng, X.-m.;
Wang, C.-h.; Wang, Z.-t. Arch. Pharm. Res. 2009, 32, 1245.
(13) (a) Enokida, T.; Suda, Y. JP, 1993-17334 06228547, 1994.
(b) Schefczik, E. DE, 1979-2930081 930081, 1981. (c) Schefczik, E. DE,
1974. (d) Hoppe, H.; Bujard, P.; Mueller, M.; Reichert, H. WO, 2005-EP53214
2006008239, 2006. (d) Nakatsuka, M.; Ishida, T.; Shimamura, T. JP, 2000-209223
20022025775, 2002.
(14) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153.
(15) (a) Szczepankiewicz, W.; Suwinski, J. Chem. Heterocycl. Compd.
2001, 36, 809. (b) Chern, J. W.; Tao, P. L.; Yen, M. H.; Lu, G. Y.; Shiau,
C. Y.; Lai, Y. J.; Chien, S. L.; Chan, C. H. J. Med. Chem. 1993, 36, 2196.
(c) Chern, J. W.; Shiau, C. Y.; Lu, G. Y. Bioorg. Med. Chem. Lett. 1991,
1, 571. (d) Jaen, J. C.; Gregor, V. E.; Lee, C.; Davis, R.; Emmerling, M.
Bioorg. Med. Chem. Lett. 1996, 6, 737. (e) Anderskewitz, R.; Bauer, R.;
Bodenbach, G.; Gester, D.; Gramlich, B.; Morschhaeuser, G.; Birke,
F. W. Bioorg. Med. Chem. Lett. 2005, 15, 669. (f) Decker, M.; Krauth,
F.; Lehmann, J. Bioorg. Med. Chem. 2006, 14, 1966. (g) Decker, M.
J. Med. Chem. 2006, 49, 5411. (h) Jung, F. H.; Pasquet, G.; Van der
Brempt, C. L.; Lohmann, J.-J. M.; Warin, N.; Renaud, F.; Germain, H.;
De Savi, C.; Roberts, N.; Johnson, T.; Dousson, C.; Hill, G. B.;
Mortlock, A. A.; Heron, N.; Wilkinson, R. W.; Wedge, S. R.; Heaton,
S. P.; Odedra, R.; Keen, N. J.; Green, S.; Brown, E.; Thompson, K.;
Brightwell, S. J. Med. Chem. 2006, 49, 955. (i) Abderrahim, R.; Boujlel,
K. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 79. (j) Vovk, M. B.
Russ. J. Org. Chem. 2007, 43, 312. (k) Langer, P.; Bodtke, A. Tetra-
hedron Lett. 2003, 44, 5965. (l) Bodtke, A.; Langer, P. Tetrahedron Lett.
2004, 45, 8741. (m) Divisova, H.; Havlisova, H.; Borek, P.; Pazdera, P.
Molecules 2000, 5, 1166. (n) Decker, M. Eur. J. Med. Chem. 2005, 40,
Treatment of 6a with chlorotrimethylsilane (TMSCl)
produced a single product in very good yield. The structure
elucidation of this product was carried out by a combina-
tion of COSY, HSQC, and HMBC NMR experiments and
high resolution mass spectrometry, which confirmed the
presence of a 2-chloro-3-phenyl-4(3H)-quinazolinimine
scaffold 7a (Scheme 2, see Supporting Information for
discussion of 2D spectra). The product was insoluble in
most organic solvents such as methylene chloride, ethyl
acetate, acetone, and hexane (except methanol), which
suggested that the isolated compound may be the hydro-
chloride salt of the 2-chloro-3-aryl-4(3H)-quinazolinimine
7a. Under the acidic conditions employed, the imines are
expected to be protonated. The formation of the hydro-
chloride salt 7a was further supported by the NMR signal
€
€
305. (o) Lettau, H.; Buge, A.; Harenberg, P.; Hartel, S.; Jarmer, K.;
€
Kock, K.; Peppel, W.; Schikora, A.; Schneider, R.; Weber, C.; Nuhn, P.
Pharmazie 1993, 48, 410.
(16) Perchellet, J.-P. H.; Waters, A. M.; Perchellet, E. M.; Naganaboina,
V. K.; Chandra, K. L.; Desper, J.; Rayat, S. Anticancer Res. 2011,
31:8 in press.
(18) (a) Schmittel, M.; Rodriguez, D.; Steffen, J.-P. Angew. Chem.,
Int. Ed. 2000, 39, 2152. (b) Schmittel, M.; Steffen, J.-P.; Engels, B.;
Lennartz, C.; Hanrath, M. Angew. Chem., Int. Ed 1998, 37, 2371.
(19) Taylor, E. C.; Patel, M. J. Heterocycl. Chem. 1991, 28, 1857.
(17) Erba, E.; Pocar, D.; Trimarco, P. Tetrahedron 2005, 61, 5778.
Org. Lett., Vol. 13, No. 14, 2011
3719

corresponding to C4, which was strongly deshielded
(161.4 ppm) because of the presence of a nearby positive
charge.20
Table 1. Optimization of the Reaction Conditions
Scheme 2. Conversion of 6a to 2-Chloro-3-phenyl-4(3H)-qui-
nazoliniminium Chloride 7a and the Proposed Intermediate 8a
Lewis
acid
time
(h)
yield
(%)
entry
solvent
CH2Cl2
product 7
1
TMSCl
TMSBr
TMSI
ZnCl2
SnCl4
TiCl4
48
60
60
48
24
5
7a
84
61
55
65
62
70
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
THF
7a0
7a00
7a
3
4
5
7a
6
7a
a
Based on a report by Pazdera et al.15m on the synthesis of
1,3-oxazolo[2,3-b]quinazolinimines, we hypothesized that
the formation of quinazoliniminium salt 7a from 6a may
involve the intermediacy of N0-(2-cyanophenyl)-N-phenyl-
carbamimidicchloride 8a(Scheme2). The formation of the
latter would require the addition of HCl at the carbodii-
mide moiety of 6a. Since TMSCl is regarded as a mild,
convenient source of HCl, formed by the reaction with
trace amounts of water,21 it would provide the needed
source of chloride ions in our reaction. When 6a was
treated with freshly distilled TMSCl for 72 h in a glovebox,
quinazoliniminium salt 7a was not formed, which further
supports the hypothesis that the TMSCl reacts with the
moisture in the solvent to form trace amounts of HCl,
which eventually promotes the cyclization of 6a to 7a as
depicted in Scheme 2. In a separate experiment, we also
bubbled HCl gas through a solution of 6a in methylene
chloride for 10 min, and the reaction mixture was allowed
to stir at room temperature for 24 h. The 1H NMR
spectrum of the product confirmed the formation of 7a.
The intramolecular cyclization of 2-((phenylimino)-
methyleneamino)-benzonitrile 6a was carefully examined
in the presence of various other Lewis acids (Table 1). The
reaction proceeded smoothly in the presence of TMSBr
and TMSI to afford the corresponding 2-halo-3-aryl-qui-
nazoliniminium halides 7a0 and 7a00, respectively (Table 1,
entries 2ꢀ3). ZnCl2, SnCl4, and TiCl4 also yielded the
expected product 7a (Table 1, entries 4ꢀ6). However, the
7
BF3 OEt2
4
None
None
7a
3
a
8
FeCl3
24
48
48
48
9
TMSCl
TMSCl
TMSCl
77
75
76
10
11
7a
Toluene
7a
a A complex mixture of products formed which were not identified.
the reaction with TMSCl, but the yield of the quinazolini-
minium salt obtained was low (Table 1, entry 6). Given the
easier handling of TMSCl, this Lewis acid certainly seems
to be the best choice to induce this cyclization. Using
TMSCl, we also studied the influence of different solvents,
e.g., 1,2-dichloroethane, tetrahydrofuran, and toluene. The
yields of 7a were found to be unaffected in these three
solvents (Table 1, entries 9ꢀ11); however, these were slightly
lower than those obtained in methylene chloride (Table 1,
entry 1).
Under the optimized conditions the scope of this proto-
col was further explored by using a variety of 2-((aryl-
imino)methyleneamino)-benzonitriles 6bꢀh. These were
prepared from the corresponding benzonitriles 3 and phe-
nylisocyanates 5 using the strategy described above
(Scheme 1). As shown in Table 2, almost all of the
substrates produced the 2-chloro-3-aryl-quinazolinimi-
nium chlorides in good yields. Our results demonstrated
that the cyclization reaction was insensitive to the electro-
nic nature of the substituent present on the phenyl ring
attached to N-1 of the carbodiimide functional group (see
Table 2 for numbering). The presence of an electron-
donating methoxy group (6b), electron-withdrawing ethyl
ester(6c), andaweaklyelectron-withdrawingchlorogroup
(6d) at the para position of this phenyl ring produced the
expected quinazoliniminium salts in good yields (Table 2,
entries 2ꢀ4). Changing the position of the chloro substi-
tuent on the phenyl ring to the meta position (6e) also
proceeded efficiently (Table 2, entry 5). Sterically hindered
ortho-substituted derivative 6f also successfully underwent
cyclization using this method, although it afforded some-
what reduced yields (Table 2, entry 6). The effect of the
substitution on the aromatic ring attached to N-3 of the
reaction with BF3 OEt2 and FeCl3 gavea complex mixture
3
of products (Table 1, entries 7ꢀ8). The best Lewis acid was
the initially tested TMSCl in which the 2-chloro-3-phenyl-
quinazoliniminium chlorides 7a were obtained in excellent
yields in 48 h at room temperature (Table 1, entry 1). Note
that the reaction with TiCl4 proceeded much faster than
(20) The addition of triethylamine to a suspension of 7a in methylene
chloride resulted in the immediate dissolution of the solid. The upfield
signal shifts in the 1H NMR spectrum confirmed the formation of a free
imine base of 7a. The latter reverted back to the salt form 7a by the
addition of TMSCl as confirmed by 1H NMR spectroscopy
(21) (a) Corriu, R. J. P.; Dabosi, G.; Martineau, M. J. Organomet.
Chem. 1980, 186, 19. (b) Hintermann, L. Beilstein J. Org. Chem. 2007,
3:22, DOI: 10.1186/1860-5397-3-22.
3720
Org. Lett., Vol. 13, No. 14, 2011

carbodiimide functional group of 6 on the cyclization was
also examined. The reaction 6g and 6h with TMSCl
proceeded efficiently, and the quinazoliniminium salts
were obtained in good yields (Table 2, entries 7, 8).
Table 2. Investigation of the Scope of Cyclization of Hetero-
enyne-allenes 6 to 2-Chloro-3-aryl-quinazoliniminium Chlor-
ides 7
Figure 2. ORTEP diagram of 7b.
In summary, we have reported a facile intramolecular
cyclization of heteroenyne-allenes 6 to 2-halo-3-aryl-
4(3H)-quinazoliniminium halides 7 upon reaction
with a hydrogen halide, generated in situ from a Lewis
acid and trace water. Since cyclization appears to be
insensitive to the electronic nature of substituents
present on the heteroenyne-allenes, this method offers
a general way to produce quinazoliniminium salts 7
with desired substitutions on the aromatic rings by a
careful choice of the corresponding benzonitriles 3
or isocyanates 5 during the synthesis of precursors
6, making this method potentially useful for the devel-
opment of libraries of heterocycles with possible
biological and materials properties. It also seems
plausible that these quinzoliniminium salts can be
elaborated at C-2 through nucleophilic substitution
or palladium-catalyzed cross-coupling to investigate
the structureꢀactivity relationship in drug discovery.
These further investigations will be reported in due
course.
yield
entry
6
R1
R2
R3
R4
R5
(%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Cl
H
H
7a: 84
7b: 60
7c: 72
7d: 78
7e: 74a
7f: 56a
7g: 75
7h: 77
OMe
COOEt
Cl
H
H
H
H
6g
6h
a Reaction required 60 h for completion.
As a final confirmation of the structure assignment of 7,
a single crystal X-ray structure analysis of 2-chloro-3-(4-
methoxyphenyl)quinazolin-4(3H)-iminium chloride 7b
(Figure 2) was also obtained. The primary structure
directing interactions in the crystal lattice of this salt are
the four hydrogen bonds involving the two chloride ions
and NꢀH’s of the iminium moieties present on the two
adjacent molecules (Figure 1s, Supporting Information).
These interactions result in the formation of dimers
(Figure 1s, Supporting Information). According to the
graph set notation,22 these hydrogen bonding interactions
Acknowledgment. Acknowledgment is made to the
donors of the American Chemical Society Petrol-
eum Research Fund for the partial support of the
research described herein (ACS PRF No. 48202-G4).
The authors acknowledge Dr. Ruth Welti and Ms.
Pamela Tamura at the Kansas Lipidomics Research
Center (KLRC) for providing mass spectra on our
compounds.
create an [R2 (8)] motif. The adjacent dimers interact
4
Supporting Information Available. General procedures;
experimental procedures and spectroscopic data for 4a,
4g,h, 6aꢀh, 7aꢀ7h, 7a0, and 7a00; 1H and 13C NMR spectra
of all new compounds; COSY, HSQC, and HMBC
spectra of 7a; X-ray data and cif file of 7b; discussion of
2D spectra of 7a leading to its structural characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
through halogenꢀhalogen bonds of type I (interaction
angle θ1(CꢀCl---Cl) = θ2(Cl---ClꢀC) = 117.74°).23
˚
The ClꢀCl bond length is 3.389 A, which is slightly
shorter than the sum of their van der Waals radii.24
(22) Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
(23) Bui Thai Thanh, T.; Dahaoui, S.; Lecomte, C.; Desiraju Gautam,
R.; Espinosa, E. Angew. Chem., Int. Ed. 2009, 48, 3838.
(24) Bondi, A. J. Phys. Chem. 1964, 68, 441.
Org. Lett., Vol. 13, No. 14, 2011
3721