Mukaiyama's reagent promoted C-N bond formation: a new method to synthesize 3-alkylquinazolin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2010.01.087

A new approach to synthesize 3-alkylquinazolin-4-ones is developed. Treatment of quinazolin-4-ones with Mukaiyama's reagent, a base and a primary amine nucleophile results in the formation of 3-alkylquinazolin-4-ones in moderate to good yields under mild conditions. Using this methodology, a one-step synthesis of the natural alkaloid, echinozolinone, is accomplished.

Full text of DOI:10.1016/j.tetlet.2010.01.087

Tetrahedron Letters 51 (2010) 1713–1716
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mukaiyama’s reagent promoted C–N bond formation: a new method
to synthesize 3-alkylquinazolin-4-ones
Puminun Punthasee, Avassaya Vanitcha, Sumrit Wacharasindhu *
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to synthesize 3-alkylquinazolin-4-ones is developed. Treatment of quinazolin-4-ones
with Mukaiyama’s reagent, a base and a primary amine nucleophile results in the formation of 3-alkyl-
quinazolin-4-ones in moderate to good yields under mild conditions. Using this methodology, a one-step
synthesis of the natural alkaloid, echinozolinone, is accomplished.
Received 14 September 2009
Revised 24 December 2009
Accepted 25 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Quinazolinones 1 and related quinazolines 2 are nitrogen-con-
taining heterocycles that are common in nature. They possess a
wide range of biological properties including antimalarial, anti-
agent.8 Mukaiyama’s reagent, 2-chloro-1-methyl-pyridinium io-
dide 7 would appear to be appropriate for the activation due to
9
its high stability and low cost. Surprisingly, the use of this activa-
1
inflammatory, anti-cancer, and anticonvulsant amongst others.
tor under our previous conditions led to the isolation of 3-butyl-
quinazolin-4-one 9 as the sole product in 60% yield with 20%
recovery of starting material and without detection of the expected
For example, febrifugine (3), a quinazolinone isolated from the Chi-
2
nese herb Dichroa febrifuga, is used as an antimalarial drug while
1
erlotinib (4), a quinazoline, has stimulated intense interest as a po-
amidine 8 (Scheme 1). The H NMR data of 8 and 9 are clearly dis-
3
tent kinase inhibitor (Fig. 1). In this Letter, we report a new meth-
tinguishable since the 2-H signal of 8 appears at 8.60 ppm while
the same proton in 9 resonates at higher field (8.03 ppm) due to
the aromaticity of the quinazoline ring. Moreover, the HMBC spec-
trum of 9 confirmed the regioselectivity of this coupling reaction
od to synthesize 3-alkylquinazolin-4-ones via a coupling reaction
between quinazolin-4-one and a primary amine in the presence
of Mukaiyama’s reagent.
1
0
Retrosynthetically, the most common procedure to 3-alkylqui-
nazolin-4-ones is N-alkylation at the 3 position of quinazolin-4-
one with appropriate alkyl halides in the presence of a strong
which occurred at N-3 instead of N-1.
To explore the scope of this new procedure, a panel of low cost
amide bond-coupling agents was screened (Table 1). DCC gave a
lower yield compared to Mukaiyama’s reagent while cyanuric
chloride and 2,4-dichloro-6-methoxy[1,3,5]triazine (DCMT) re-
sulted in decomposition and only trace amounts of the desired qui-
nazolinones 9 were detected. This short survey revealed that
Mukaiyama’s reagent was well-suited for this transformation.11
4
base. These methods, however, require harsh conditions and pro-
duce unavoidable elimination products from the alkyl halide in
addition to non-selective O-alkylation. In the case of aminoquinaz-
oline 2, strong and acidic reagents such as SOCl , POCl , and PCl
2 3 5
were used to activate the carbonyl of quinazolin-4-one prior to
the addition of the corresponding amine.5
In continuing attempts to develop robust synthetic methods
for aminoquinazolines 2, we recently demonstrated an efficient
O
NHR
N
R1
‘
one-step’ synthesis of cyclic amidines using the phosphonium
4
N
reagent, benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium
2
hexafluorophosphate (BOP 6); this amination was accomplished
N
1
N
2
8
6
in high yield. Nevertheless, this method is inconvenient for
scale-up because the phosphonium reagent is expensive and has
a high molecular weight resulting in atom inefficiency. Moreover,
the by-product of the reaction is HMPA which is considered to be
a carcinogenic substance. In search of new activators, we reasoned
that there was a possibility of using another amide-coupling
HO
O
N
HN
N
O
N
N
H
MeO
MeO
N
7
O
O
Febrifugine 3
erlotinib 4
*
Corresponding author. Tel.: +66 2 218 7634; fax:+66 2 218 7598.
Figure 1. Representative 3-substituted-quinazolin-4-ones and a related quinazo-
E-mail address: sumrit.w@chula.ac.th (S. Wacharasindhu).
line.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.087

1
714
P. Punthasee et al. / Tetrahedron Letters 51 (2010) 1713–1716
Table 2
N
P
N
PF6
Results of the optimization study
N
O
Previous work
Yielda (%)
Entry
Solvent/base/temp
MeCN/DBU/rt
N
HN
N
1
2
3
4
5
6
7
8
9
20
60
15
70
23
40
50
78
79
N
BOP, 6
3
MeCN/Et N/rt
N
MeCN/NaOt-Bu/70 °C
MeCN/DIPEA/rt
DMSO/DIPEA/rt
DMF/DIPEA/rt
8
.60
ppm
N
H
DIPEA, MeCN, RT, 1 h
n-BuNH2
O
N
8, 90%
Benzene/DIPEA/rt
NH
CH
2 2
Cl /DIPEA/rt
This work
O
DCE/DIPEA/80 °C
I
N
Me
Cl
a
Yield of pure, isolated product (characterized by 1H and 13C NMR spectroscopy).
5
7
N
8
.03
DIPEA, MeCN, RT, 1 h
N
H
Table 3
Functional group tolerance
ppm
n-BuNH2
9, 60%
O
O
N
Scheme 1. Reaction of 5 with BOP and Mukaiyama’s reagent.
n-BuNH (2.5 eq)
n-Bu
2
NH
N
R
R
N
DIPEA, (2 eq)
Consequently, the optimization study was performed on qui-
Mukaiyama's reagent (2 eq)
nazolin-4-one 5 with n-butylamine and Mukaiyama’s reagent by
evaluating various bases, solvents and temperatures (Table 2).
Screening the base indicated that diisopropylethylamine was the
most effective base in comparison with others, although triethyl-
amine gave a satisfactory result (entries 1–4). With DIPEA as the
CH Cl , rt
2 2
Entry
1
Substrate
Product
Yielda (%)
78
O
base of choice, CH
tries 8 and 9).
2
Cl
2
and DCE proved to be the best solvents (en-
NH
9
N
Having identified optimum reaction conditions, various quinaz-
olin-4-ones were subjected to the reaction conditions to examine
the scope of the reaction.12 The expected product of each substrate
was obtained in fair to good yield, as presented in Table 3. The
investigated quinazolin-4-ones ranged from bicyclic to tricyclic
ring systems carrying a variety of substituents. These include nitro,
dimethoxy, dichloro, and a benzo analog. Electronic effects were
also observed. In the case of electron-withdrawing groups such
as nitro and chloro, the product yields were excellent and the reac-
tion was carried out at ambient temperature. However, coupling
O
O2N
2
3
4
5
NH
NH
NH
NH
10
11
12
13
86
N
O
Cl
Cl
76
N
O
MeO
MeO
7
,8-dimethoxy-4-hydroxyquinazoline with n-butylamine required
43b
heating to drive the reaction to completion to give the desired
product 12 in only 43% yield.
N
O
To further demonstrate the scope of this reaction, a panel of pri-
mary amine nucleophiles were tested in the reaction with quinaz-
olin-4-one (5) and the products are shown in Scheme 2.
Unhindered primary amines such as n-butylamine, benzylamine
and 2-phenylethanamine, reacted smoothly at room temperature
to provide the target compounds (9, 14 and 15) in good isolated
37b
N
a
Yield of pure, isolated product (characterized by 1H and 13C NMR spectroscopy).
The reaction was carried out at 80 °C and DCE was used as the solvent.
b
yields. Coupling of a sterically hindered nucleophile such as cyclo-
hexylamine was facilitated by increasing the temperature to gen-
erate 16 in 68% yield. In the case of the weak nucleophile aniline,
only a trace amount of the desired product was detected. Next,
the reaction was extended to nucleophiles with various acid-labile
functional groups. Reaction of 5 with glycine methyl ester using
Mukaiyama’s reagent gave 18 in moderate yield. Moreover, pri-
mary amines with an acetal moiety reacted with 5 to afford prod-
ucts 19 and 20 in 87% and 57% yield, respectively.
Table 1
Results of activator screeninga
O
O
N
n-Bu
activator, n-BuNH2
NH
N
DIPEA, MeCN, RT, 12 h
N
9
5
Yieldb (%)
With the success of this coupling reaction, our attention turned
to the synthesis of echinozolinone (22) which was first isolated
Entry
Activator
1
2
3
4
DCC
DCMT
Cyanuric chloride
Mukaiyama’s reagent
20%
1
3
from Echinops echinatus in 1987. The reported preparation in-
volved the reaction of 4(3H)-quinazoline 5 with 2-chloroethanol
in the presence of a large excess of a phase-transfer catalyst
Trace
Trace
c
60%
1
4
a
(PTC), in only 49% yield. With our methodology, echinozolinone
was synthesized in a single step from 5 and ethanolamine in 81%
yield (Scheme 3). This methodology clearly provides an alternative
route to the conventional alkylation reaction.
The reaction was performed by treatment of 5 (1 equiv) in MeCN at room
temperature with n-BuNH (2 equiv), DIPEA (2 equiv), and activator (2 equiv).
2
b
1
13
Yield of pure, isolated product (characterized by H and C NMR spectroscopy).
Starting material was recovered in 20% yield.
c

P. Punthasee et al. / Tetrahedron Letters 51 (2010) 1713–1716
1715
I
Cl
O
O
N
O
I
O
N
N
N
Me
Cl
BuNH2
R
NH
N
N
NH
N
N
O
Base
23
CH Cl , DIPEA, RNH
N
2
2
2
5
rt
O
Bu
O
N
O
O
N
N
NHBu
9
Bu
Ph
N
N
Ph
N
N
H
N
H
N
N
N
H
N
N
24
25
a
9
, 78%
14, 69%a
15, 62%
Scheme 4. A plausible mechanistic pathway.
O
O
O
OMe
N
N
N
O
We also thank Dr. Paitoon Rashatasakhon, of the Chemistry Depart-
ment, Chulalongkorn University and Dr. Zhou-Kui Wan of Pfizer INc.,
Cambridge, MA, USA, for useful and interesting discussions.
N
N
N
1
6, 68%b
17, 0%
18, 49%
O
N
N
O
N
OEt
OEt
O
N
Supplementary data
OMe
OMe
NEt2
Supplementary data (experimental details and characterization
of all compounds) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2010.01.087.
N
N
1
9, 87%a
20, 57%a
21, 44%
a
o
The reaction was carried out at 45 C
References and notes
b
o
The reaction was carried out at 80 C and DCE was used as the solvent.
1.
(a) Chan, J. H.; Hong, J. S.; Kuyper, L. F.; Jones, M. L.; Baccanari, D. P.; Tansik, R.
L.; Boytos, C. M.; Rudolph, S. K.; Brown, A. D. J. Heterocycl. Chem. 1997, 34, 145;
Scheme 2. Nucleophile scope.
(
b) Gackenheimer, S. L.; Schaus, J. M.; Gehlert, D. R. J. Pharmacol. Exp. Ther. 1996,
32, 113; (c) Dempcy, R. O.; Skibo, E. B. Biochemistry 1991, 30, 8480; (d)
Drogeand, N.; Kemi-Kalieforretning, A. Nordisk-Droge. 18113; Patent, N.A.,
7
1965; Chem. Abstr. 1965, 63, 18113.; (e) Witt, A.; Bergman, J. Curr. Org. Chem.
2
003, 7, 659. and references cited therein; (f) Larksarp, C.; Alper, H. J. Org. Chem.
O
N
O
N
2000, 65, 2773. and references cited therein.
N
Me
Cl
I
2. (a) Koepfly, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem. Soc. 1947, 69, 1837;
(b) Jiang, S.; Zeng, Q.; Gettayacamin, M.; Tungtaeng, A.; Wannaying, S.; Lim, A.;
Hansukjariya, P.; Okunji, C. O.; Zhu, S.; Fang, D. Antimicrob. Agents Chemother.
2005, 49, 1169.
OH
N
NH
DIPEA, CH Cl , rt, 1 h
2
2
3
4
.
.
Comis, R. L. Oncologist 2005, 10, 467–470.
For representative examples, see: (a) Logé, C.; Testard, A.; Thiéry, V.; Lozach, O.;
Blairvacq, M.; Robert, J.-M.; Meijer, L.; Besson, T. Eur. J. Med. Chem. 2008, 43,
5
OH
echinozolinone, 22
H N
2
1
469–1477; (b) Ouyang, G. P.; Zhang, P. Q.; Xu, G. F.; Song, B. A.; Yang, S.; Jin, L.
8
1%
H.; Xue, W.; Hu, D. Y.; Lu, P.; Chen, Z. Molecules 2006, 11, 383; (c) Milad, B.;
Abdallah, M.; Djaffar, B.; Meriem, M.; Jacques, B. Heterocycl. Commun. 2004, 10,
2
Scheme 3. Synthesis of echinozolinone.
69; (d) Testard, A.; Loge, C.; Leger, B.; Robert, J.-M.; Lozach, O.; Blairvacq, M.;
Meijer, L.; Thiéry, V.; Besson, T. Bioorg. Med. Chem. Lett. 2006, 16, 3419; For
representative reviews on the synthesis of quinazolinones, see: (e) Connolly, D.
J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153; (f)
Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787–9826.
Mechanistically, we hypothesize that the Mukaiyama reagent
first activates the N atom of the quinazolinone at the 3 position
leading to the formation of a pyridinium-quinazolinone intermedi-
ate 23 (Scheme 4). Attack of the primary amine on the amide moi-
ety results in the ring opening product, enamine 24. Cyclization
followed by elimination of an aminopyridinium generates the ob-
served product 9.
In conclusion, a new synthetic method to 3-alkylquinazolin-4-
ones has been developed employing Mukaiyama’s reagent as a
coupling agent. This reaction offers several advantages including
mild conditions, less by-product formation, high compatibility as
well as the use of an inexpensive, commercially available activator.
Further studies on the scope of the Mukaiyama reagent promoted
C–N bond formation as well as mechanistic investigations are un-
der study and will be reported in due course.
5. (a) Wissner, A.; Floyd, M. B.; Johnson, B. D.; Fraser, H.; Ingalls, C.; Nittoli, T.;
Dushin, R. G.; Discafani, C.; Nilakantan, R.; Marini, J.; Ravi, M.; Cheung, K.; Tan,
X.; Musto, S.; Annable, T.; Siegel, M. M.; Loganzo, F. J. Med. Chem. 2005, 48,
7560; (b) Mishani, E.; Abourbeh, G.; Jacobson, O.; Dissoki, S.; Daniel, R. B.;
Rozen, Y.; Shaul, M.; Levitzki, A. J. Med. Chem. 2005, 48, 5337; (c) Domarkas, J.;
Dudouit, F.; Williams, C.; Qiyu, Q.; Banerjee, R.; Brahimi, F.; Jean-Claude, B. J. J.
Med. Chem. 2006, 49, 3544.
(a) Wan, Z.-K.; Wacharasindhu, S.; Levins, C.; Lin, M.; Tabei, K.; Mansour, T. S. J.
Org. Chem. 2007, 72, 10194; (b) Wan, Z.-K.; Wacharasindhu, S.; Binnum, E.;
Mansour, T. Org. Lett. 2006, 8, 2425–2428; (c) Wacharasindhu, S.; Bardhan, S.;
Wan, Z.-K.; Tabei, K.; Mansour, T. S. J. Am. Chem. Soc. 2009, 131, 4174–4175.
Jackson, H.; Davies, P.; Bock, M. Nature 1968, 218, 977.
6
.
7
8
.
.
Montalbetti, C.; Falque, V. Tetrahedron 2005, 61, 10827.
9. (a) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163–1164; (b)
Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707–721; (c) Huang, H.;
Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465–1466.
0. The HMBC spectrum of 9 showed correlations between H-1 and C-2 and C-3.
0
1
For additional details, please see the Supplementary data.
Acknowledgements
O
1'
3
N
2
'
ThefacultyofScience (RESA1B1-6)andRatchadaphiseksomphot
Endowment Fund, Chulalongkorn University and the Thailand Re-
search Fund (DIG-5180020) are gratefully acknowledged for finan-
cial support. We are grateful to Dr. Polkit Sangvanich, Chemistry
Department, Chulalongkorn University for HRMS measurements.
9
2
N
1
1. Upon completion of our studies, Yang and co-workers reported an analogous
synthesis using HATU: Xiao, Z.; Yang, M. G.; Li, P.; Carter, P. H. Org. Lett. 2009, 6,
1421.

1
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P. Punthasee et al. / Tetrahedron Letters 51 (2010) 1713–1716
1
2. General procedure: To a solution of quinazolin-4-one (73.1 mg, 0.5 mmol) in
CH Cl (5 mL) at room temperature was added 2-chloro-1-methylpyridinium
iodide (255.49 mg, 1.0 mmol) followed by diisopropylethylamine (435.48 l,
.5 mmol). The solution was stirred at room temperature for 1 h after which
J = 7.96 Hz), 8.03 (1H, s), 7.81–7.65 (2H, m), 7.51 (1H, t, J = 7.42 Hz), 4.01 (2H, t,
J = 7.31 Hz), 1.87–1.70 (2H, m), 1.51–1.32 (2H, m), 0.97 (3H, t, J = 7.34 Hz). 13
NMR (100 MHz, CDCl ) d ppm 160.4, 147.6, 146.2, 133.5, 126.8, 126.6, 126.1,
2
2
C
l
3
+
2
121.6, 46.2, 30.9, 19.4, 13.2. HRMS [M+H ]: calcd for C12
found 203.1007.
13 2
H N O 203.1184,
was added n-butylamine (248 ll, 2.5 mmol). The mixture was stirred at room
temperature overnight and then concentrated and purified by column
13. Chaudhuri, P. K. Phytochemistry 1987, 26, 587.
chromatography on silica gel (eluent: EtOAc/hexanes, 50%) to give 3-
14. Reisch, J.; Gunaherath, G. M. K. B. J. Nat. Prod. 1989, 52, 404.
1
butylquinazolin-4(3H)-one (9). H NMR (400 MHz, CDCl
3
) d ppm 8.32 (1H, d,