2-Chloroquinazoline. Synthesis and reactivity of a versatile heterocyclic building block

Article abstract of DOI:10.1016/j.tetlet.2006.09.121

Starting from 2,4-dichloroquinazoline, various methods for the selective removal of the 4-chloro substituent were tested, including catalytic hydrogenation, metal-halogen exchange, metal hydride reduction and reduction with tributyltin hydride-the latter

Full text of DOI:10.1016/j.tetlet.2006.09.121

Tetrahedron Letters 47 (2006) 8251–8254
2-Chloroquinazoline. Synthesis and reactivity of a
versatile heterocyclic building block
Signe Teuber Henriksena,b and Ulrik Svane Sørensena,*
aNeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark
bUniversity of Copenhagen, The H. C. Ørsted Institute, Universitetsparken 5, DK-2100 KøbenhavnØ, Denmark
Received 16 July 2006; revised 8 September 2006; accepted 21 September 2006
Abstract—Starting from 2,4-dichloroquinazoline, various methods for the selective removal of the 4-chloro substituent were tested,
including catalytic hydrogenation, metal–halogen exchange, metal hydride reduction and reduction with tributyltin hydride—the
latter both in a radical and in a Stille-type reaction. Amongst these, the most efficient method was found to be the Stille-type
coupling. Furthermore, we have studied the reactivity of 2-chloroquinazoline and found it to act as a versatile building block for
the direct introduction of the 2-quinazolinyl moiety.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
HO
B
Ar
R
Nu
Quinazolines are components of many bioactive com-
pounds and their chemistry has therefore been studied
extensively.1 We wished to introduce a 2-quinazolinyl
group into a small focused library to be tested for ion
channel modulating activities.
N
N
N
HO
Cl
N
NuR
N
N
Ar
1
Scheme 1.
The formation of 2-substituted quinazolines has
previously been achieved from aryl amidines, either via
cyclisation of an activated 1-aryl-1,3-diazabutadiene
derivative2 or via condensation with 4-cyano- or 4-
nitro-activated o-fluorobenzaldehydes.3 This latter meth-
od is, however, restricted to benzaldehydes with strong
electron-withdrawing substituents. Aldehydes have also
been reacted with 2-aminobenzylamine to give 1,2,3,4-
tetrahydroquinazolines, which were subsequently oxi-
dised to the corresponding 2-substituted quinazolines.4
Cross-coupling between phenyl iodide and 3,4-dihydro-
quinazoline followed by dehydrogenation was reported
to give 2-phenylquinazoline.5
to various scaffolds through nucleophilic substitution
or palladium-catalysed cross-couplings (Scheme 1).
The synthesis of 4-chloroquinazoline, and its usefulness
for introducing a 4-quinazolinyl moiety, has been
described previously,6,7 but no simple route to 1 was
available.
A
suitable starting point was 2,4-
dichloroquinazoline 2, since it is known to react regio-
selectively at the 4-position in a variety of reactions,8
and can be readily obtained from the commercially avail-
able 2,4-(1H,3H)-quinazolinedione (benzoyleneurea).
We wished to utilise the difference in reactivity between
the two chlorines of 2 in order to reduce selectively
the 4-chloro substituent to afford the desired compound
1.
However, since a general method for the direct incorpo-
ration of the 2-quinazolinyl moiety had not been
described, we set out to develop a short and effective
procedure. 2-Chloroquinazoline 1 was selected as the
target intermediate, as we expected it to readily attach
Following the execution of most of the experiments described herein,
Kanuma et al. described the synthesis of 2-chloroquinazoline in a
70% yield by the reaction of 2,4-dichloroquinazoline with zinc in
aqueous ammonia.8
*
Corresponding author. Tel.: +45 44 60 80 00; fax: +45 44 60 80 80;
e-mail: uss@neurosearch.dk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.121

8252
S. T. Henriksen, U. S. Sørensen / Tetrahedron Letters 47 (2006) 8251–8254
2,4-Dichloroquinazoline 2 was obtained by the treat-
ment of 2,4-(1H,3H)-quinazolinedione with phospho-
rous oxychloride according to literature procedures.9–12
We subsequently examined a number of methods
for the selective removal of the 4-chloro substituent
(Table 1).
formation of this by-product. Our hypothesis is that
reaction of 2 with acetate (from palladium(II) acetate)
affords the unstable ester 5, which hydrolyses the to give
3 during work-up or when analysed by LC–MS (Scheme
3). This is supported by the formation of 3 upon treat-
ment of 2 with potassium acetate in tetrahydrofuran.
Likewise, the phosphonium salt 4 was formed by treat-
ing 2 with tributylphosphine.
The reason for including an unconventional procedure
such as the Stille-type coupling (Table 1 entry 6) was
that tributyltin hydride has been reported to reduce acid
chlorides to aldehydes in a palladium-catalysed cross-
coupling reaction,13 and in 2 we expected the reactivity
of the 4-chloro substituent to be very similar to that of
an acid chloride.
In a second approach, (PPh3)4Pd was used as the cata-
lyst, in order to avoid the formation of by-product 5
and accordingly 3. However, in this case no reaction
occurred and only starting materials were observed.
Finally, the treatment of 2 with (PPh3)2PdCl2 and tribut-
ylphosphine successfully gave 1 in a 52% isolated yield.
The side reaction with tributylphosphine was suppressed
by formation of the complex between palladium and
tributylphosphine prior to the addition of 2.
In the first approach, using Stille-type conditions, we
generated palladium(0) from palladium(II) acetate and
tributylphosphine. However, this procedure gave rise
to two major by-products, 3 and 4 (observed by LC–
MS), and 1 was obtained in only a 35% yield (Scheme 2).
The instability of 5 indicated that it might be sufficiently
reactive to undergo reduction by catalytic hydrogena-
tion, and whereas the hydrogenation of 2 with Raney
nickel as the catalyst had been unsuccessful (Table 1),
5 was indeed reactive enough to afford 1 in a 15% yield
(observed by LC–MS) under these conditions. Unfortu-
nately, 63% of by-product 3 was formed as well, so the
Stille-type coupling remained the most effective way of
converting 2 into 1.
Initially, the formation of 3 was ascribed either to the
presence of residual water in the reaction mixture or
to a radical mediated reaction with molecular oxygen.
Nevertheless, 3 was formed even under strictly anhy-
drous conditions, and addition of the radical scavenger
2,6-di-tert-butyl-4-methylphenol had no effect on the
Table 1. Different approaches for the conversion of 2,4-dichloroquin-
azoline 2 into 2-chloroquinazoline 1
In order to study the versatility of 1 as a building block
we carried out a series of reactions of 1 with thiol and
amine nucleophiles as well as with aryl boronic acids
(Table 2).
Entry
Method
Yield of 1 (%)
1
2
3
4
5
6
7
Catalytic hydrogenation
Metal halogen exchange
Radical reaction
Metal hydride reduction
Clemmensen-type reduction
Stille-type coupling
0
0
0
0a
0a
52
0
We have found palladium-catalysed Stille-type coupling
with tributyltin hydride to be a highly selective way of
removing the activated 4-chlorine substituent in 2,4-
dichloroquinazoline 2. Tributyltin hydride is a well-
known hydrogen radical donor but this study confirms13
that, in the presence of a palladium catalyst, tributyltin
hydride can also act as a hydride donor. The reaction is
mild and could therefore be a suitable method for simi-
lar substrates containing either acid-, base- or moisture-
sensitive functionalities.
Formic acid reduction
Entry 1: Method A: H2, Pd/C, MeOH, rt. Method B: H2, Raney Ni,
MeOH, rt. Entry 2: Method A: n-BuLi, THF, À78 °C. Method B:
EtMgBr, diethyl ether, 0 °C. Method C: LDA, THF, À78 °C. Entry 3:
Bu3SnH, AIBN, tert-butylmethyl ether. Entry 4: NaBH4, DMF, 50 °C.
Entry 5: Zinc powder, AcOH, THF, 70 °C. Entry 6: Bu3SnH,
(PPh3)2PdCl2, Bu3P. Entry 7: HCO2H, Et3N, Bu3P, Pd(OAc)2, diox-
ane, rt.
a The reaction was unselective and only trace amounts of 1 were
observed in the reaction mixture, along with a substantial amount of
dihydro-2-chloroquinazoline.
2. Experimental
2.1. 2-Chloroquinazoline 1
Cl
Bu3SnH
Pd(OAc)2, Bu3P
N
In a typical experiment, THF was dried through a col-
umn of basic aluminium oxide and two solutions were
THF
Cl
N
Bu
Cl
Bu
2
P+
O
N
Cl
N
OAc
O
N
Bu
-
AcO
N
N
N
NH
N
NH
+
+
N
Cl
Cl
N
Cl
Cl
N
Cl
Cl
1 (35%)
3
4
2
5
3
Scheme 2.
Scheme 3.

S. T. Henriksen, U. S. Sørensen / Tetrahedron Letters 47 (2006) 8251–8254
Table 2. Reaction of 2-chloroquinazoline 1 with boronic acids and various nucleophiles
8253
Entry
Reagent
Product
Yielda (%)
OH
B
N
N
HO
HO
1
6a
6b
79
N
N
OH
B
2
3
4
5
7a
7b
48
63
99
50
N
N
OH
B
N
N
8a
8b
HO
HN
N
N
O
O
9a
9b
N
N
H2N
H2N
10a
10b
N
N
H
N
N
6
7
11a
12a
11b
12b
55
83
N
N
N
H
HS
S
a Isolated yields, no optimisation.
made: (I) 200 mg of 2,4-dichloroquinazoline 2 (1.0
mmol) was dissolved in 1.5 ml dry THF under a nitrogen
atmosphere. (II) 35 mg of (PPh3)2PdCl2 (0.05 mmol) was
suspended in 1.5 ml dry THF under a nitrogen atmo-
sphere, and 0.05 ml of Bu3P (0.2 mmol) was added. Solu-
tion II was stirred for 10 min before it was added to
solution I. Thereafter, 0.3 ml of Bu3SnH (1.1 mmol)
was added, resulting in a dark coloured reaction mixture.
After stirring for 5 h at rt, the reaction mixture was evap-
orated to dryness and purified by column chromato-
graphy, affording 1 in a 52% yield (85 mg).
affording products 6b (100 mg, 79%), 7b (60 mg, 48%)
or 8b (75 mg, 63%).
2.3. General procedure for the reaction of 2-chloroquin-
azoline 1 with benzylthiol and amines. Synthesis of 9b,
10b, 11b and 12b
A mixture of 2-chloroquinazoline 1 (0.50 mmol), the
appropriate nucleophile 9a, 10a, 11a or 12a (0.60 mmol)
and K2CO3 (0.75 mmol) in 4 ml CH3CN was placed in a
sealed vial. The mixture was heated using MW irradia-
tion. Reaction conditions: 9b: 50 °C, 20 min; 10b:
170 °C, 50 min; 11b: 120 °C, 15 min; 12b: 120 °C,
30 min. The reaction mixture was diluted with water,
extracted with EtOAc, dried over MgSO4, filtered and
evaporated to dryness. The crude product was purified
by preparative LC–MS affording products 9b (116 mg,
99%), 10b (50 mg, 50%) 11b (48 mg, 55%) or 12b
(99 mg, 83%).
2.2. General procedure for the reaction of 2-chloroquin-
azoline 1 with aryl boronic acids. Synthesis of 6b, 7b and
8b
A mixture of 1 (0.61 mmol), the appropriate boronic
acid 6a, 7a or 8a (0.90 mmol), K2CO3 (3.2 mmol) and
(PPh3)2PdCl2 (0.033 mmol) in 5 ml solvent (DME/
water/EtOH 7:3:2) was placed in a sealed vial and
heated to 120 °C for 10 min (6a and 7b) or 15 min (8b)
using microwave irradiation.14 The reaction mixture
was diluted with water, extracted with EtOAc, dried
over MgSO4, filtered and evaporated to dryness. The
crude product was purified by preparative LC–MS,
Supplementary data
Obtained melting points, MS (ES) and 1H NMR data as
well as results of elemental analyses are included for

8254
S. T. Henriksen, U. S. Sørensen / Tetrahedron Letters 47 (2006) 8251–8254
7. Alexandre, F.; Berecibar, A.; Wrigglesworth, R.; Besson,
T. Tetrahedron 2003, 59, 1413–1419.
8. Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi,
T.; Chaki, S.; Semple, G.; Tran, T.-A.; Kramer, B.; Hsu,
D.; Casper, M.; Thomsen, B.; Beeley, N.; Sekiguchi, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 2565–2569.
compounds 1, 2 and 6–12b. Supplementary data associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2006.09.121.
References and notes
9. Ife, R. J.; Brown, T. H.; Blurton, P.; Keeling, D. J.; Leach,
C. A.; Meeson, M. L.; Parsons, M. E.; Theobald, C. J. J.
Med. Chem. 1995, 38, 2763–2773.
10. Charpiot, B.; Brun, J.; Donze, I.; Naef, R.; Stefani, M.;
Mueller, T. Bioorg. Med. Chem. Lett. 1998, 8, 2891–2896.
11. Lu, Q.; Mangalagiu, I.; Benneche, T.; Undheim, K. Acta
Chem. Scand. 1997, 51, 302–306.
1. Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153–10202.
2. Robev, S. K. Tetrahedron Lett. 1983, 24, 4351–4354.
3. Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga, H.
Synlett 1999, 12, 1993–1995.
12. Harden, D. B.; Mokrosz, M. J.; Strekowski, L. J. Org.
Chem. 1988, 53, 4137–4140.
4. Eynde, J. J. V.; Godin, J.; Mayence, A.; Maquestiau, A.;
Anders, E. Synthesis 1993, 867–869.
13. Four, P.; Guibe, F. J. Org. Chem. 1981, 46, 4439–4445.
14. For recent reviews of microwave assisted synthesis see: (a)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284;
(b) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225–9283.
5. Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman,
J. A. Org. Lett. 2004, 6, 35–38.
6. Tobe, M.; Isobe, Y.; Tomizawa, H.; Nagasaki, T.;
Takahashi, H.; Fukazawa, T.; Hayashi, H. Bioorg. Med.
Chem. 2003, 11, 383–391.