Highly efficient one-pot synthesis of 2-substituted quinazolines and 4H-benzo[d][1,3]oxazines via cross dehydrogenative coupling using sodium hypochlorite

Article abstract of DOI:10.1002/adsc.200900715

This communication describes a catalyst-free synthesis of 2-substituted quinazolines and 4H-benzo[d][1,3]oxazines using commericially available sodium hypochlorite as oxidant. Operational simplicity, mild reaction conditions and the ability to construct structurally diverse 2-quinazolines and 2-substituted 4H-benzo[d][1,3]oxazines by this method render it to be a practical alternative for the synthesis of these heterocycles.

Full text of DOI:10.1002/adsc.200900715

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DOI: 10.1002/adsc.200900715
Highly Efficient One-Pot Synthesis of 2-Substituted Quinazolines
and 4H-Benzo[d][1,3]oxazines via Cross Dehydrogenative
G
Coupling using Sodium Hypochlorite
C. Uma Maheswari,a G. Sathish Kumar,a M. Venkateshwar,a R. Arun Kumar,a
M. Lakshmi Kantam,a and K. Rajender Reddya,*
a
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 607, India
Fax : (+91)-040-271-60921; e-mail: rajender@iict.res.in or rajenderkallu@yahoo.com
Received: October 15, 2009; Revised: January 1, 2010; Published online: February 10, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900715.
Abstract: This communication describes a catalyst-
free synthesis of 2-substituted quinazolines and 4H-
benzo[d]ACHTUNGTRENNUNG[1,3]oxazines using commericially available
sodium hypochlorite as oxidant. Operational sim-
plicity, mild reaction conditions and the ability to
construct structurally diverse 2-quinazolines and 2-
substituted 4H-benzo[d]ACTHNUGRTNEUNG[1,3]oxazines by this
method render it to be a practical alternative for
the synthesis of these heterocycles.
Griess in 1869 by reacting cyanogen with anthranilic
acid. Since then, there has been a spurt in activity to
synthesize quinazolines due to their biological impor-
tance.[9] The growing importance of quinazolines pro-
vides a strong rationale for the development of vari-
ous synthetic methodologies. It has been shown that
quinazolines with substituents at the second and
fourth positions may be potent antibacterial agents.[4b]
Along similar lines, 4H-benzo[d]ACTHNUTRGNEUNG[1,3]oxazines have
also been shown to possess interesting pharmacologi-
Keywords: 2-aryl-4H-benzo[d]ACHTUNTRGNEUNG[1,3]oxazines; dehy-
drogenation; oxidation; quinazolines; sodium hypo-
chlorite
cal properties.[10]
A variety of catalytic methods were reported for
the synthesis of 2-substituted quinazolines.[11] Only a
few reports are available for the synthesis of 4H-
benzo[d]ACTHNUTRGNEUNG
[1,3]oxazines from o-aminobenzyl alcohol.[12]
These reported methods involve multi-step syntheses,
expensive reagents, starting materials that need prior
Quinazolines are an important class of heterocyclic synthesis, have limited substrate scope and difficult
compounds frequently found in alkaloids and in many work-up procedures.
bio-active molecules.[1] Luotonin A, tryptanthrin, fe-
Oxidative methods for the formation of heterocy-
brifugine, rutaecarpine, peganidine, (+)-anisotine, cles are quite attractive and several methods were al-
(À)-vasicinone and vasicine are a few well known ex- ready reported for the formation of benzoxazoles,
amples of the quinazoline alkaloids.[2] Quinazolines benzimidazoles, imidazolines from aldehydes.[13] How-
have varied applications due to their biological prop- ever, the synthesis of quinazolines by an oxidative
erties, for example, quinazoline derivatives act as strategy from aldehydes has been little explored. In
powerful inhibitors of the epidermal growth factor this context, the direct coupling of aldehydes with
(EGF) receptors of tyrosine kinase,[3] and exhibit anti- amines followed by dehydrogenation proves to be an
bacterial,[4] antiviral,[5] antitubercular,[6] and anticancer easy route for the synthesis of 2-substituted quinazo-
activities.[7] The quinazoline ring structure is an essen- lines and 4H-benzo[d]
tial component in a few anticancer drugs like gefiti- In continuation of our earlier studies on oxidative
ACHTUNGERTN[NUNG 1,3]oxazines (Scheme 1).
nib, a first epidermal growth factor receptor inhibitor, functional group transformations using KI-TBHP sys-
which was approved by the U.S. Food and Drug Ad- tems,[14] we explored the possibility of using the KI-
ministration (FDA) for the treatment of lung cancer[8] TBHP system for the synthesis of heterocycles via ox-
and raltitrexed, an antimetabolite drug used in the idative dehydrogenation. Initial studies for the synthe-
treatement of colon cancer.
sis of 2-substituted quinazolines were conducted using
The first synthesis of a quinazoline derivative, 2- KI or I2 as catalyst and TBHP as the oxidant with
cyano-3,4-dihydro-4-oxoquinazoline was reported by benzaldehyde and 2-aminobenzylamine as the model
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C. Uma Maheswari et al.
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Scheme 1. Synthesis of 2-quinazolines and 2-aryl-4H-benzo[d]ACTHNUGRTNEUNG[1,3]oxazines via an oxidative dehydrogenation protocol.
substrates (Table 1, entries 1 and 2). These reactions
proceed well resulting in 94% and 83% of 2-phenyl-
quinazoline, respectively. In the absence of any oxi-
dant, only 15% of the product was observed (Table 1,
entry 3). This clearly emphasizes the need for an oxi-
dant in this cyclization reaction. When a blank reac-
tion was attempted without KI or I2, in the presence
of TBHP as the oxidant (Table 1, entry 4), surprising-
ly a very good conversion (86%) was observed, which
is comparable to the catalyzed one. This shows the
minimal role of the catalyst in this reaction. Then a
variety of other oxidants were explored (Table 1, en-
tries 5–9) and among them sodium hypochlorite
(NaOCl) yielded better results (Table 1, entry 6)
albeit slightly lower than with TBHP. In view of the
Figure 1. Screening of solvents for the cyclization of alde-
hyde with 2-aminobenzylamine. Reaction Conditions: amine
(1 mmol), aldehyde (1 mmol), solvent (3 mL), NaOCl
(4 mmol), 5 h.
Table 1. Optimization of conditions for the oxidative cyclization of aldehydes with 2-aminobenzylamine.[a]
Entry
Catalyst (mmol)
Oxidant (mmol)
Coversion [%][b]
1
2
3
4
5
6
7
8
KI (0.2)
I2
KI (0.2)
TBHP (3.0)
TBHP (3.0)
–
TBHP (3.0)
H2O2 (3.0)
NaOCl (3.0)
UHP (3.0)
m-CPBA (3.0)
benzoyl peroxide
–
94
83
15
86
20
71
18
12
15
10
87
–
–
–
–
–
–
–
–
9
10
11
NaOCl (4.0)
[a]
Reaction conditions: amine (1 mmol), aldehyde (1 mmol), CH3CN (3 mL).
Yields based on GC.
[b]
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Highly Efficient One-Pot Synthesis of 2-Substituted Quinazolines and 4H-Benzo[d]
Table 2. Cyclization of various aldehydes with 2-aminobenzylamine.[a]
ACHTUNGTREN[NUNG 1,3]oxazines
expensive nature of TBHP, further optimizations were like toluene, DCM, CHCl3 and THF (Figure 1). For
performed with NaOCl. further reactions, MeOH was chosen as the ideal sol-
Among the different solvents screened, polar sol- vent and the optimum oxidant ratio was found to be
vents like H2O, CH3CN, MeOH, EtOH and t-BuOH 3 equivalents (Figure 1).
gave better conversions than the non-polar solvents
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C. Uma Maheswari et al.
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Table 2. (Continued)
[a]
Reaction conditions: aldehyde (1 mmol), amineACHTUNRGTNEUNG(1 mmol),CH3OH (3 mL), NaOCl (3 mmol), room
temperature, 5 h.
Conversion based on gas chromatography.
Isolated yield.
[b]
[c]
The general applicability of this method was further entry 13). The reaction works well for the heteroaro-
evaluated for structurally diverse aldehydes and 2- matic aldehydes (Table 2, entries 15 and 16). In the
aminobenzylamine derivatives under the optimized case of pyridine-3-carboxaldehyde, the reaction was
reaction conditions and the results are shown in complete within 2 h (Table 2, entry 16). When
Table 2. Irrespective of the electronic nature of the al- cinnamACTHNUGRTENUNGaldehyde was taken for coupling, the expected
dehydes used, the reaction afforded moderate to ex- trans product was observed in moderate yield
cellent yields (Table 2, entries 1 to 11). In the case of (Table 2, entry 17). When 2-(aminomethyl)-3-fluoro-
aliphatic aldehydes, the yields are moderate due to
ACHTUNGTRENaNGNU niline was taken as the amine substrate, the corre-
the inherent difficulty in activating an aliphatic alde- sponding 2-substituted quinazolines were obtained in
hyde compared to aromatic ones. In the case of isobu- moderate to excellent yields (Table 2, entries 18–20).
tyraldehyde (Table 2, entry 14), the yield was still low,
due to steric factors of the bulky isopropyl group thesis of 2-substituted-4H-benzo[d]
compared to those of n-butyraldehyde (Table 2, 2-aminobenzyl alcohol as the coupling partner instead
The above strategy was further applied for the syn-
AHCTUNGTRENNUNG
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Highly Efficient One-Pot Synthesis of 2-Substituted Quinazolines and 4H-Benzo[d]ACHTUNTRGNEUNG[1,3]oxazines
of 2-aminobenzylamine. Under the similar reaction ther investigating the applicability of this methodolo-
conditions, treatment of 2-aminobenzyl alcohol with gy for the preparation of a library of quinazoline and
different aldehydes provided moderate to good yields 4H-benzo[d]
of 2-substituted 4H-benzo[d][1,3]oxazine derivatives
ACHTUNGTNER[NUNG 1,3]oxazine derivatives.
AHCTUNGTRENNUNG
(Table 3, entries 1–4). In the case of 2-furfuraldehyde,
a heteroaromatic aldehyde the yield of the product
was very good (Table 3, entry 5). For further variation
we have treated the substituted amino alcohol with al-
dehydes where we could observe the products in good
yields (Table 3, entries 6 and 7).
Experimental Section
Synthesis of 2-Substituted Quinazoline from
Aldehydes and Amines
In summary, we have shown a catalyst-free synthe-
sis of 2-substituted quinazolines and 4H-benzo[d]-
A
solution of 2-aminoarylamine (1.0 mmol), aldehyde
(1.0 mmol) in 3 mL of CH3OH was stirred at room tempera-
ture for 5 h. To the same solution, NaOCl (3.0 mmol) was
added dropwise over a period of 30 min and stirred at room
temperature for another 5 h. The mixture was washed with
brine after 5 h, extracted with ethyl acetate and dried over
anhydrous Na2SO4. Removal of the solvent under vacuum
afforded the crude product, which was purified by column
chromatography using hexane/ethyl acetate mixture and was
ACHTUNGTRENNUNG[1,3]oxazines using commercially available sodium hy-
pochlorite as oxidant. Unlike the previous reported
methods, which involve multi-step synthesis and sepa-
ration protocols, the present one-pot methodology
provides an easy access to the products without any
separation of intermediates. Moreover, use of a
cheaper oxidant and the one-pot methodology can be
easily employed for the scale-up reactions. We are fur- analyzed by 1H NMR, GC and GC-MS.
Table 3. Cyclisation of various aldehydes with 2-aminobenzyl alcohols.[a]
[a]
Reaction Conditions: aldehyde (1 mmol), alcohol (1 mmol), CH3OH (3 mL), NaOCl (3 mmol),
room temperature, 5 h.
Conversion based on GC.
Isolated yields.
[b]
[c]
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C. Uma Maheswari et al.
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Acknowledgements
b) G. W. Rewcastle, B. D. Palmer, A. J. Bridges, H. D.
Hollis Showalter, L. Sun, J. Nelson, A. McMichael,
A. J. Kraker, D. W. Fry, W. A. Denny, J. Med. Chem.
1996, 39, 918; c) A. Luth, W. Lowe, Eur. J. Med. Chem.
2008, 43, 1478.
C. U. M., G. S. K, M. V and R. A. K thank the Council of
Scientific Industrial Research (CSIR) for their fellowships.
[9] a) W. M. F. Armarego, in: Fused Pyrimidines Part 1:
Quinazolines, (Ed.: D. J. Brown), Interscience, New
York, 1967; b) A. R. Katritzky, in: Comprehensive Het-
erocyclic Chemistry, (Ed.: C. W. Rees), vol. 3, Perga-
mon, Oxford, 1984; c) P. M. Chandrika, T. Yakaiah,
A. R. R. Rao, B. Narsaiah, N. C. Reddy, V. Sridhar,
J. V. Rao, Eur. J. Med. Chem. 2008, 43, 846; d) V.
Kumar, C. Mohan, M. Gupta, M. P. Mahajan, Tetrahe-
dron 2005, 61, 3533; e) M. Tobe, Y. Isobe, H. Tomiza-
wa, T. Nagasaki, H. Takahashi, T. Fukazawa, H. Haya-
shi, Bioorg. Med. Chem. Lett. 2003, 11, 383.
[10] a) S. R. Landor, P. D. Landor, Z. T. Fomum, A. E.
Nkengfack, G. W. P. Mpango, J. Chem. Res. (S) 1987,
188, 1537; b) Y. Tabuchi, Y. Ando , H. Kanemura , I.
Kawasaki , T. Ohishi , M. Koida, R. Fukuyama, H. Na-
kamuta , S. Ohta , K. Nishide , Y. Ohishi, Bioorg. Me-
dicinal Chem., 2009, 17, 3959; c) S. Wang, Y. Li, Y. Liu,
A. Lu, Q. You, Bioorg. Med. Chem. Lett. 2008, 18,
4095; d) P. Zhang, E. A. Terefenko, A. Fensome, Z.
Zhang, Y. Zhu, J. Cohen, R. Winneker, J. Wrobela, J.
Yardleya, Bioorg. Med. Chem. Lett. 2002, 12, 787; e) N.
Henry, I. Sꢂnchez, A. Sabatiꢃ, V. Bꢃnꢃteau, G. Guillau-
met, M. D. Pujola, Tetrahedron 2006, 62, 2405.
[11] a) E. Erba, D. Pocor, M. J. Valk, J. Chem. Soc. Perkin
Trans. 1 1999, 421; b) H. Kotsuki, H. Sakai, H. Morimo-
to, H. Suenaga, Synlett 1999, 12, 1993; c) S. K. Robev,
Tetrahedron Lett. 1983, 24, 4351; d) S. T. Henriksen,
U. S. Sørensen, Tetrahedron Lett. 2006, 47, 8251; e) V.
Kumar, C. Mohan, M. Gupta, M. P. Mahajan, Tetrahe-
dron 2005, 61, 3533; f) J. J. V. Eynde, J. Godin, A.
Mayence, A. Maquestiau, E. Anders, Synthesis 1993,
867; g) C. Huang, Y. Fu, H. Fu, Y. Jiang, Y. Zhaoa,
Chem. Commun. 2008, 6333.
References
[1] D. J. Connolly, D. Cusack, T. P. OꢁSullivan, P. J. Guiry,
Tetrahedron 2005, 61, 10153.
[2] J. P. Michael, Nat. Prod. Rep. 1999, 16, 697.
[3] a) P. A. Ple, T. P. Green, L. F. Hennequin, J. Curwen,
M. Fennell, J. Allen, C. Lambertvan der Brempt, G.
Costello, J. Med. Chem. 2004, 47, 871; b) S. R. Klutch-
ko, H. Zhou, R. T. Winters, T. P. Tran, A. J. Bridges,
I. W. Althaus, D. M. Amato, W. L. Elliott, P. A. Ellis,
M. A. Meade, B. J. Roberts, D. W. Fry, A. J. Gonzales,
P. J. Harvey, J. M. Nelson, V. Sherwood, H.-K. Han, G.
Pace, J. B. Smaill, W. A. Denny, H. D. H. Showalter, J.
Med. Chem. 2006, 49, 1475, and references cited there-
in; c) L. F. Hennequin, E. S. E. Stokes, A. P. Thomas, C.
Johnstone, P. A. A.; D. J. Ogilvie, M. Dukes, S. R.
Wedge, J. Kendrew, J. O. Curwen, J. Med. Chem. 2002,
45, 1300.
[4] a) D. M. Purohit, V. H. Shah, Indian J. Heterocycl.
Chem. 1999, 8, 213; b) P. M. S. Bedi, V. Kumar, M. P.
Mahajan, Bioorg. Med. Chem. Lett. 2004, 14, 5211.
[5] a) T.-C. Chien, C.-S. Chen, F.-H. Yu, J.-W. Chern,
Chem. Pharm. Bull. 2004, 52, 1422; b) T. Herget, M.
Freitag, M. Morbitzer, R. Kupfer, T. Stamminger, M.
Marschall, Antimicrob. Agents Chemother. 2004, 48,
4154.
[6] a) P. Desai, B. Naik, C. M. Desai, D. Patel, Asian J.
Chem. 1998, 10, 615; b) K. Waisser, J. Gregor, H.
Dostal, J. Kunes, L. Kubicova, V. Klimesova, J. Kausto-
va, Farmaco 2001, 56, 803; c) J. Kunes, J. Bazant, N.
Pour, K. Waisser, M- Slosarek, F. Janota, Farmaco
2000, 55, 725.
[7] a) E. A. Henderson, V. Bavetsias, D. S. Theti, S. C.
Wilson, R. Clauss, A. L. Jackman, Bioorg. Med. Chem.
2006, 14, 5020; b) N. Touroutoglou, R. Pazdur, Clin.
Cancer Res. 1996, 2, 227; c) A. L. Jackman, F. T. Boyle,
K. R. Harrap, Invest. New Drugs 1996, 14, 305; d) T. M.
Sielecki, T. L. Johnson, J. Liu, J. K. Muckelbauer, R. H.
Grafstrom, S. Cox, J. Boylan, C. R. Burton, H. Chen,
A. Smallwood, C. H. Chang, M. Boisclair, P. A. Ben-
field, G. L. Trainora, S. P. Seitza, Bioorg. Med. Chem.
Lett. 2001, 11, 1157; e) P. E. Bonomi, Expert Opin.
Invest. Drugs 2003, 12, 1395; f) L. A. Doyle, D. D. Ross,
Oncogene 2003, 22, 7340.
[12] T. Fomum, A. E. Nkengfack, S. R. Landor, P. D.
Landor, J. Chem. Soc. Perkin Trans.1 1988, 277.
[13] a) Y. Kawashita, N. Nakamichi, H. Kawabata, M. Hay-
ashi, Org. Lett. 2003, 5, 3713; b) J. Chang, K. Zhao, S.
Pan, Tetrahedron Lett. 2002, 43, 951; c) H. Fujioka, K.
Murai, Y. Ohba, A. Hiramatsu, Y. Kita, Tetrahedron
Lett. 2005, 46, 2197; d) M. Ishihara, H. Togo, Synlett
2006, 227; e) P. Gogoi, D. Konwar, Tetrahedron Lett.
2006, 47, 79.
[14] a) K. R. Reddy, C. U. Maheswari, M. Venkateshwar,
M. L. Kantam, Eur. J. Org. Chem. 2008, 3619; b) K. R.
Reddy, C. U. Maheswari, M. Venkateshwar, M. L.
Kantam, Adv. Synth. Catal. 2009, 351, 93; c) K. R.
Reddy, C. U. Maheswari, M. Venkateshwar, M. L.
Kantam, Tetrahedron Lett. 2009, 50, 2050.
[8] a) A. J. Barker, K. H. Gibson, W. Grundy, A. A. God-
frey, J. J. Barlow, M. P. Healy, J. R. Woodburn, S. E.
Ashton, B. J. Curry, L. Scarlett, L. Henthorn, L. Ri-
chards, Bioorg. Med. Chem. Lett. 2001, 11, 1911;
346
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 341 – 346