Pd-catalyzed amination of 6-halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one

Article abstract of DOI:10.1016/j.tetlet.2012.07.061

6-Halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one derivatives have been synthesized and utilized for amination reactions with aryl, heteroaryl and alkyl amines. Optimization of reaction conditions with different catalysts, ligands, bases, a

Full text of DOI:10.1016/j.tetlet.2012.07.061

Tetrahedron Letters 53 (2012) 5162–5166
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed amination of 6-halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)
quinazolin-4(3H)-one
Ramesh Garlapati a,b, Narender Pottabathini a, , Venkateshwarlu Gurram a, Avinash B. Chaudhary a,
⇑
a,
Venkata Rao Chunduri b, , Balaram Patro
⇑
⇑
a Medicinal Chemistry Division, GVK Biosciences Pvt. Ltd., 28A, IDA Nacharam, Hyderabad 500076, AP, India
b Organic Chemistry Division, Department of Chemistry, Sri Venkateshwara University, Tirupathi 517 502, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one derivatives have been synthesized
and utilized for amination reactions with aryl, heteroaryl and alkyl amines. Optimization of reaction con-
ditions with different catalysts, ligands, bases, and solvents was conducted. The combination of Pd2(dba)3
with DavePhos (L3) proved to be best for these conversions in the presence of NaOtBu in 1,4-dioxane at
100 °C. The relative reactivities of 6-bromo and 6-chloro-2,3-disubstitued quinazolinones with p-tolui-
dine were conducted and as anticipated the 6-bromo analogue was totally consumed and 6-chloro deriv-
ative was completely unreactive.
Received 5 June 2012
Revised 11 July 2012
Accepted 13 July 2012
Available online 20 July 2012
Keywords:
Amination
Modified quinazolinones
Pd2(dba)3, DavePhos
Aryl, Heteroaryl, Alkyl amines
Relative reactivities
Ó 2012 Elsevier Ltd. All rights reserved.
The quinazoline moiety has proven to be a versatile building
block for development of a variety of pharmaceutical entities. For
example, many of the quinazolines show a broad spectrum of
chemotherapeutic activities.1–7 2,3-Disubstituted 3H-quinazolin-
4-ones are useful for the treatment for diabetes, obesity, and related
disorders, as well as regulation of food intake. Certain quinazoli-
none derivatives are also useful for the treatment of wasting
(e.g., cahexia) associated with cancer, AIDS, chronic liver diseases,
chronic obstructive pulmonary disease (COPD), or respiratory
insufficiency.8
The cyclopropyl group is an increasingly common structural
motif in pharmaceutically active molecules due to its unique steric,
electronic, conformational properties, and its microsomal meta-
bolic stability.9 Cyclopropyl is also smallest cyclic alkyl group to
be generally included as substituent in medicinal chemistry for
the structure–activity relationship studies.10 Although there are
many reports describing the synthesis of 2,3-disubstituted 3H-
quinazolin-4-ones class of compounds, most of these approaches
are limited in that only phenyl groups at N-3 are tolerated.11 There
are only a few specific reports on the preparation of the simple N-3
aliphatic, benzyl, and other heterocyclic functional groups of
2,3-disubstituted 3H-quinazolin-4-ones.12 We have synthesized
quinazoline-4-one with a pyridyl-3-ylmethyl group at N–3 posi-
tion and have also introduced a cyclopropyl group at C-2 position.
Palladium-catalyzed amination reactions have become an
important type of transformation to construct C–N bonds among a
wide range of substrates.13 Currently there is no literature
evidence for introduction of amino groups into the C-6 position
of 2-cyclopropyl-quinazoline-4-one derivatives. Sui Xiong Cai
et al. synthesized 6-N,N-dimethylamino-2-methyl-N-methyl-4-(4-
methoxyanilino) quinazoline and it was prepared by hydrogenation
of the 6-nitro analogue, followed by the reductive amination with
formaldehyde in the presence of sodium cyanoborohydride.14 Here-
in we report a novel Pd-catalyzed amination reaction at C-6 of
2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one in excel-
lent yields. Another highlight of this report is the stability of the
cyclopropyl moiety toward the amination conditions.
For the present work, 6-bromo and 6-chloro-2-cyclopropyl-3-
(pyridyl-3-ylmethyl)quinazolin-4(3H)-ones were chosen for study.
O
O
Br
Cl
N
N
N
N
N
N
⇑
Corresponding authors. Tel.: +91 40 66281666; fax: +91 40 66281515 (B.P.);
tel.: +91 40 66281275; fax: +91 40 66281515 (N.P.).
3a
3b
E-mail addresses: narender.pottabathini@gvkbio.com (N. Pottabathini), cvrsvu@
gmail.com (V.R. Chunduri), balaram.patro@gvkbio.com (B. Patro).
Figure 1. 6-Halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-ones
selected for analysis.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.061

R. Garlapati et al. / Tetrahedron Letters 53 (2012) 5162–5166
5163
Cy
P
PPh2
Cy
PPh2
PPh2
Cy
P
N
Cy
P
O
PdCl2
Fe
Cy
Cy
P
Cy
Cy
PPh2
PdCl2(dcpf)
(
)-BINAP
CyJohnPhos
DavePhos
L3
XantPhos
L1
L2
L4
L5
Figure 2. Four ligands and one pre-catalyst selected for the analysis.
Table 1
Optimization of C–N bond forming reactionsa,b
p-Toluidine
O
N
O
H
N
Catalyst, Ligand,
X
N
N
Base
N
N
Solvent, ToC, 8h
N
X=Br; 3a
X= Cl; 3b
4a
Entry
Catalyst system, conditions, t = 8 h
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
25 mol % Pd(PPh3)4/NaOtBu, 1,4-dioxane, 100 °C
48
45
10 mol % Pd(OAc)2/15 mol % L1/Cs2CO3, 1,2-DME, 90 °C
10 mol % Pd(OAc)2/15 mol % L2/Cs2CO3, 1,2-DME, 90 °C
10 mol % Pd(OAc)2/15 mol % L2/Cs2CO3, toluene, 110 °C
10 mol % Pd(OAc)2/15 mol % L2/K3PO4, toluene, 110 °C
66(48)d
25
35
10 mol % Pd(OAc)2/15 mol % L3/NaOtBu, 1,4-dioxane, 100 °C
10 mol % Pd(OAc)2/15 mol % L4/Cs2CO3, 1,2-DME, 90 °C
10 mol % Pd(OAc)2/15 mol % L4/K3PO4, 1,2-DME, 90 °C
10 mol % Pd(OAc)2/15 mol % L4/NaOtBu, 1,4-dioxane, 100 °C
10 mol % Pd2(dba)3/15 mol % L1/K3PO4, 1,4-dioxane, 100 °C
81 (58)d
54
66 (41)d
87
74 (62)d
93 (78)d
55
10 mol % Pd2(dba)3/15 mol % L3/NaOtBu, 1,4-dioxane, 100 °C
10 mol % Pd2(dba)3/15 mol % L4/K3PO4, 1,2-DME, 90 °C
10 mol % Pd2(dba)3/15 mol % L4/K3PO4, toluene, 110 °C
20 mol % PdCl2(dcpf), Cs2CO3, 1,4-dioxane, 100 °C
34
29
a
Reaction conditions (entries 1–14) 6-bromo, 3a precursor 0.0711 mM in anhydrous solvent, 3.0 mol. equi. p-toluidine, 1.5 mol equi. of
base.
b
Reactions were conducted in closed vial sparged with argon.
% Yields refer to isolated and purified products.
Yield obtained with chloro substrate 3b.
c
d
The overall aim was to determine the best conditions for amination
of both the precursors and to find the optimal conditions that can
be applied for the synthesis of a broad range of 6-aryl, heteroaryl,
and alkyl, 2,3-disubstituted quinazolinones.
Both halo quinazoline-4-one precursors 3a and 3b (Fig. 1) are
conveniently synthesized by known procedures (See the Supple-
mentary data for details).15 With 3a and 3b in hand, conditions
for Pd-catalyzed amination reactions were evaluated. Pd(OAc)2
and Pd2(dba)3 served as metal sources, further more ligands L1–4
(Fig. 2) and a ferrocenyl Pd(II) precatalyst (L5, Fig. 2) were also se-
lected for the investigation.
The optimization experiments were performed with p-tolui-
dine. Results from our initial investigations are shown in Table 1.
The initial attempts with Pd(PPh3)4 (25 mol %), NaOtBu, 1,4-
dioxane resulted in low yield (entry 1). The combination of
Pd(OAc)2, with L1 (entry 2), L2 (entries 3, 4 and 5), L3 (entry 6),
or L4 (entries 7, 8 and 9) ligands, in the presence of Cs2CO3(entry
2, 3, 4 and 7), K3PO4 (entries 5 and 8), and NaOtBu (entries 6 and
9) as base, 1,4-dioxane (entries 6 and 9, at 100 °C), toluene (entries
4 and 5 at 110 °C) and 1,2-DME (entries 2, 3, 7 and 8, at 90 °C) as
solvents lead to good to moderate product formation from 25 to
87% yields in 8 h with p-toluidine. The combination of Pd2(dba)3
with L1 (entry 10), L3 (entry 11), and L4 (entries 12 and 13) with
different bases and solvents also resulted in moderate to excellent
yields (34–93%). The reaction with the precatalyst, PdCl2(dcpf) also
ended up with low yield (entry 14, 29%). Among these initial
screening reactions, 10 mol % Pd2(dba)3/15 mol % L3/1.5molar eq.
NaOtBu in 1,4-dioxane at 100 °C was proved to be the best (93%,
entry 11) and 10 mol % Pd(OAc)2/15 mol % L4/NaOtBu in 1,4-diox-
ane was proved to be the next best catalyst/ligand system (87%, en-
try 9) for Pd-catalyzed amination. The total reaction time for all
reactions was 8 h. These yields did not change appreciably when
the reactions were conducted over 8 h.
After identifying proper catalyst/ligand system, we further
investigated the catalyst/ligand loading, influence of base, solvent,
and temperature. These results are tabulated in Table 2. The initial
reactions were conducted with 10 mol % Pd2(dba)3/15 mol % L3/
1.5 mol. equi. NaOtBu in 1,4-dioxane at 100 °C (93%, entry 1). The
reduction of catalyst/ligand loading to 5 mol % Pd2(dba)3/7.5 mol
% L3 resulted in 81% yield (entry 2) and on further reduction to
5 mol % Pd2(dba)3/5 mol % L3 resulted in a drastical drop of yield
to 53% (entry 3). It was also observed that increasing the catalytic
loading to 15 mol % Pd2(dba)3/15 mol % L3 (entry 4), 20 mol %
Pd2(dba)3/20 mol % L3 (entry 5), and 20 mol % Pd2(dba)3/30 mol %
L3 (entry 6) did not change the yields.
The influence of base and solvent was also evaluated. We ini-
tially examined the influence of the nature of base on the conver-
sion for the reactions using 1,4-dioxane as solvent and 10 mol %
Pd2(dba)3/15 mol % L3 as the catalyst/ligand system. NaOtBu was
superior to K3PO4, Cs2CO3, and K2CO3, whereas CsF was ineffective.

5164
R. Garlapati et al. / Tetrahedron Letters 53 (2012) 5162–5166
Table 2
Screening of catalyst loading, base, solvent, and temp for the C–N coupling of 3a with p-toluidinea
O
p-Toluidine
O
H
N
L3
Pd2(dba)3, DavePhos (
)
Br
N
N
Base
Solvent, ToC, time
N
N
N
N
4a
3a
Entry
Variable conditions
Time (h), Temp (°C)
% of 4a formed
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
10 mol % Pd2(dba)3, 15 mol % L3
5 mol % Pd2(dba)3, 7.5 mol % L3
5 mol % Pd2(dba)3, 5 mol % L3
15 mol % Pd2(dba)3,15 mol % L3
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 100
8, 90
93b
81b
55b
89b
90b
93b
63c
93c
71c
66c
10c
93d
62d
27d
43d
90b
93b
93b
20 mol % Pd2(dba)3, 20 mol % L3
20 mol % Pd2(dba)3, 30 mol % L3
K3PO4
NaOtBu
Cs2CO3
K2CO3
CsF
1,4-Dioxane
1,2-DME
Toluene
tert-BuOH
Conventional
Sample vial
Microwave
8, 100
8, 100
8, 100
8, 100
0.5, 100
a
Reaction conditions (entries 1–18) bromoquinazolinone (3a) 0.0711 mM in anhydrous solvent, 3.0 mol. equi. p-toluidine, 1.5 mol. equi. of
base and% yields refer to isolated and purified products.
b
1.5 Mol. equi. of NaOtBu, 1,4-dioxane as solvent.
c
Only change in base, 1,4-dioxane as solvent
d
Change in solvent only, other conditions were unaltered, 1.5 mol. equi. of NaOtBu.
We have observed that the nature of the solvent often modifies the
catalyst activity in cross-coupling reactions. Among the solvents
1,4-dioxane was much superior to 1,2-DME, toluene, and tert-
BuOH. Majority of these reactions were conducted in closed vials,
only one reaction was performed in a round bottomed flask fitted
with reflux condenser. This reaction was also complete in 8 h with
90% product. Under the microwave irradiation there was signifi-
cant rate acceleration (reaction time 30 min at 100 °C) but yield re-
mained the same as the reaction in sample vial (compound 4a with
93% yield).
With the optimal conditions ascertained, in the next stage we
evaluated the generality of the methodology with variety of
amines shown in Table 3. A wide assortment of aryl, heteroaryl,
and alkyl amines participated in the Pd-catalyzed amination
reactions.
The amines with electron donating groups like p-toludine (en-
try 1), o-methoxyaniline (entry 6), and substituted morpholine
with oxygen atom are flanked by two methyl groups (entry 15) re-
sulted in excellent yields. The naphthalene system resulted in good
yield (entry 11). We were extremely gratified to observe that reac-
tions of amines with electron-with drawing groups like 4-cyanoan-
iline (entry 4), fluorinated substituents like 2-fluoro and 2-
trifluoromethyl benzyl amines (entries 13 and 14) also resulted
in good yields. The reactions were also efficient with aliphatic
amines (entries 17, 18 and 19). Reactions with heteroaryl amines
resulted in moderate yields from 44% to 55% (entries 8, 9 and 10).
Relative reactivity studies of bromo quinazolinone (3a) and
chloro quinazolinone (3b)17
Table 3
Evaluation of the scope of amination reaction of 6-bromo (3a) and 6-chloro -3-
(pyridyl-3-ylmethyl) quinazolin-4(3H)-one (3b)ab using various amines16
H
N
R1
R2
O
N
R2
O
N
L3
Pd2(dba)3, DavePhos (
)
X
N
NaOtBu, 1,4-Dioxane
N
N
R1
N
100 oC, 8 h
N
4a - 4q
X= Br; 3a
X= Cl; 3b
Entry
1
Amine
Product
Yield, %c
93 (82)d
NH2
NH2
4a
2
3
4b
4c
91 (71)d
91
NH2
NH
2
4
5
4d
4e
76
NC
O
NH2
91 (83)d
It is evident that 3a is superior to 3b in terms of product yield
under the C–N bond forming conditions (Table 3). We decided to
determine their relative reactivities in a competitive experiment.
For this we conducted a reaction of an equimolar amount of 3a
and 3b (1.5 mol. equi. each) with 1 mol. equi of p-toluidine, under
the optimized conditions. After the complete consumption of
O
NH2
6
4f
91

R. Garlapati et al. / Tetrahedron Letters 53 (2012) 5162–5166
5165
Table 3 (continued)
Entry
Amine
Product
Yield, %c
92
O
NH2
7
8
4g
4h
O
NH2
N
44
N
9
4i
4j
56
45
NH2
NH2
N
10
Cl
NH2
11
4k
87
12
13
14
4l
78
NH2
F
4m
4n
4o
88
NH2
CF3
NH2
83 (71)d
Figure 3. LC analysis of the reaction mixture from
a
competitive reaction of
compound 3a and compound 3b with p-toluidine (showing the integrated
percentages).
15
16
O
91
87
NH
4p
4q
is the first report on successful C–N bond forming reactions at
the C-6 position of 2, 3-disubstituted quinazoline-4-ones, particu-
larly with a cyclopropyl substituent that is stable under the amina-
tion conditions. Finally, we have studied the relative reactivities of
the bromo and chloro quinazolinone precursors toward amination
and it was clear that former is superior.
NH
NH2
17
18
87
81
4r
4s
N
NH2
H
N
d
19
55 (51)
a
Reaction conditions (entries 1–19) bromo (3a) and chloro (3b) precursors
0.0711 mM in anhydrous, 3 mol. equi. amine, 1.5 equiv NaOtBu, 10 mol % of
Pd2(dba)3, 15 mol % L3, 100 °C.
Acknowledgments
b
The authors are grateful to GVK Biosciences Pvt. Ltd., for the
financial support and encouragement. Help from Mr. Kumara
Swamy Kasani from the analytical department for the analytical
data is appreciated. Dr. Subhabrata Sen and Dr. Sharfuddin are
thanked for their immense assistance. We thank Prof. Mahesh K.
Lakshman, Department of Chemistry, The City College and The City
University of New York, New York, USA for his invaluable support
and motivation.
Reactions were conducted in closed vial sparged with argon.
% Yields refer to isolated and purified products.
Yield obtained with chloro substrate 3b.
c
d
p-toluidine the experiment was stopped, product 4a as well as
reactants 3a, 3b were collected together by column chromatogra-
phy, and subjected to LC/MS analysis. In the mixture, bromo qui-
nazolinone 3a was completely consumed and 43.9% of the chloro
quinazolinone 3b was observed. Compound 3b was completely
unreactive and it was completely recovered at the end of the reac-
tion. In addition, LC/MS analysis indicated formation of the dehalo-
genated quinazolinone in ca 4.1% yield (Fig. 3).
This experiment shows two important factors. First, that C-6
bromo quinazolinone precursor 3a is more rapidly consumed than
chloro analogue 3b, and second, reductive dehalogenation does not
appear to be significant. Figure 3 shows the LC trace of the reaction
mixture from the competition experiment. The LC/MS analysis data
can be found in the Supplementary data.
In conclusion, Pd-catalyzed C–N bond formation is effective for
the introduction of substituted amino groups at the C-6 position of
2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-ones. The
combination of 10 mol % Pd2(dba)3, 15 mol % DavePhos (L3)/NaOt-
Bu in 1,4-dioxane gave good to excellent yields with 6-bromo
and 6-chloro-2-cyclopropyl-3-(pyridyl-3-ylmethyl) quinazolin-
4(3H)-one using a variety of aryl, heteroaryl, and alkyl amines.
The methodology for the amination appears to be broad in scope
for 2,3-disubstituted quinazoline-4-ones. To our knowledge, this
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
061. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
1. (a) Patterson, S.; Alphey, M. S.; Jones, D. C.; Shanks, E. J.; Street, I. P.; Frearson, J.
A.; Wyatt, P. G.; Gilbert, I. H.; Fairlamb, AH. J. Med. Chem. 2011, 54, 6514–6530;
(b) Selvam, T. P.; Kumar, P. V. Res. Pharm. 2011, 1, 1–21; (c) Neaz, M. M.;
Muddassar, M.; Pasha, F. A.; Cho, S. J. Acta. Pharm. Sinica 2010, 31, 244–258.
2. (a) Murthy, Y.; Singh, A. K.; Pathak, D. Indian J Pharm. Sci. 2011, 73, 333–337;
(b) Alagarsamy, V.; Murugesan, S.; Dhanbal, K.; Murugan, M.; Clercq, E. De.
Indian J. Pharm. Sci. 2007, 69, 304–307.
3. (a) Kabri, Y.; Verhaeghe, P.; Gellis, A.; Vanelle, P. Molecules 2010, 15, 2949–
2961; (b) Tomisek, A. J.; Christensen, B. E. J. Am. Chem. Soc. 1945, 67, 2112–
2115; (c) Bos, M.; Mendelsohn, J.; Kim, Y. M.; Albanell, J.; Fry, D. W.; Baselga, J.
Clin. Cancer Res. 1997, 3, 2099–2106.
4. Bonala, G.; Dare, P.; Magistretti, M. J.; Massarani, E.; Setnikar, I. J. Med. Chem.
1968, 11, 1136–1139.

5166
R. Garlapati et al. / Tetrahedron Letters 53 (2012) 5162–5166
5. (a) Michael, J. P. Nat. Prod. Rep. 1999, 16, 697–709; (b) Michael, J. P. Nat. Prod.
Rep. 2005, 22, 627–646.
6. Yokhontov, L. N.; Liberman, S. S.; Zhikhareva, G. P.; Kuz’mina, K. K. Pharm.
Chem. J. 1977, 11, 598–612.
7. (a) Patel, J. A.; Mistry, B. D.; Desai, K. R. E-J. Chem. 2006, 3, 97–102; (b) Patel, J.
A.; Mistry, B. D.; Desai, K. R. J. Indian Chem. Soc. 2006, 83, 1041–1043.
8. (a) Nishina, P. M.; Naggert, J. K.; Verstuyft, J.; Paigen, B. Metb. 1994, 43, 554–
558; (b) Grundy, S. M.; Barnett, J. P. Dis. Mon. 1990, 36, 641–731; (c) Rissanen,
A.; Heliovaara, M.; Knekt, P.; Reunanen, A.; Aroma, A.; Maatela, J. British Med. J.
1990, 301, 835–837.
9. (a) Zhang, M.; Chen, Cui X.; Wang, L.; Li, J.; Wu, Y.; Hou, L.; Wu, Y. Tetrahedron
2012, 68, 900–905; (b) Salaun, J. Top. Curr. Chem. 2000, 207, 1–67; (c) Reichelt,
A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433–442.
10. (a) Szabo, G.; Varga, B.; Lengyel, D. P.; Szemzo, A.; Erdelyi, P.; Vukics, K.; Szikra,
J.; Hegyi, E.; Vastag, M.; Kiss, B.; Laszy, J.; Gyertyan, I.; Fischer, J. J. Med. Chem.
2009, 52, 4329–4337; (b) Zhu, Q. F.; Pan, Y. H.; Xu, Z. X.; Li, R. M.; Qiu, G. G.; Xu,
W. J.; Ke, X. B.; Wu, L. M.; Hu, X. M. Eur. J. Med. Chem. 2009, 44, 296–302; (c)
Cui, W.; Loeppky, R. N. Tetrahedron 2001, 57, 2953–2956; (d) Aoki, S.; Fujimura,
T.; Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1988, 110, 3296–3298; (e)
Sugimura, T.; Futagawa, T.; Mori, A.; Ryu, I.; Sonoda, N.; Tai, A. J. Org. Chem.
1996, 61, 6100–6103; (f) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147–149; (g)
Surber, B. W.; Cross, J. L.; Hannick, S. M. J. Label Compd. Radiopharm 2010, 53,
468–470.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125–146; (i) Frost, C. G.;
Mendoncßa, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615–2623.; (j) Wolfe, J. P.;
Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215–7216; (k) Old, D.
W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722–9723; (l)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067; (m) Hartwig, J. F.;
Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org.
Chem. 1999, 64, 5575–5580; (n) Lakshman, M. K. Curr. Org. Synth. 2005, 2, 83–
112; (o) Lakshman, M. K. J. Organomet. Chem. 2002, 653, 234–251; (p) Lagisetty,
P.; Russon, L. M.; Lakshman, M. K. Angew. Chem. Int.Ed. 2006, 45, 3660–3663.;
(q) Ngassa, F. N.; DeKorver, K. A.; Melistas, T. S.; Yeh, E. A.-H.; Lakshman, M. K.
Org. Lett. 2006, 8, 4613–4616; (r) Thomson, P. F.; Lagisetty, P.; Balzarini, J.;
De Clercq, E.; Lakshman, M. K. Adv. Synth. Catal. 2010, 352, 1728–1735.; (s)
Pottabathini, N.; Bae, S.; Pradhan, P.; Hahn, H.-H.; Mah, H.; Lakshman, M. K. J.
Org. Chem 2005, 70, 7188–7195.
14. Sirisoma, N.; Pervin, A.; Zhang, H.; Jiang, S.; Willardsen, J. A.; Anderson, M. B.;
Mather, G.; Pleiman, C. M.; Kasibhatla, S.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg.
Med. Chem. Lett. 2010, 20, 2330–2334.
15. (a) Liu, J. F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.; McElory, E.;
Brown, M. Tetrahedron Lett. 2005, 46, 1241–1244; (b) Carolyn, C.; Brackett, J. D.;
Bloch, D. O. Pharmacotherapy 2000, 20, 229–233; (c) Chandrika, P. M.; Yakaiah,
T.; Rama Rao, A. R.; Narsaiah, B.; Reddy, N. C.; Sridhar, V.; Rao, J. V. Eur. J. Med.
Chem. 2008, 43, 846–852; (d) Chandrika, P. M.; Yakaiah, T.; Narsaiah, B.;
Sridhar, V.; Venugopal, G.; Rao, J. V.; Kumar, K. P.; Murthy, U. S. N.; Rao, A. R. R.
Indian J. Chem. 2009, 48, 840–847; (e) Rabilloud, G.; Sillion, B. J. Heterocyclic.
Chem. 1980, 17, 1065–1068.
11. Connolly, D. J.; Cusack, D.; O’ Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61,
10153–10202.
12. Sirisoma, N.; Kasibhatla, S.; Pervin, A.; Zhang, H.; Jiang, S.; Willardsen, J. A;
Anderson, M. B; Baichwal, V.; Mather, G. G.; Jessing, K.; Hussain, R.; Hoang, K.;
Pleiman, C. M.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2008, 51, 4771–
4779; (b) Chandra, T.; Garg, N.; Kumar, A. World. J. Chem. 2009, 4, 210–218; (c)
Mosley, C. A.; Acker, T. M.; Hansen, K. B.; Mullasseril, P.; Andersen, K. T.; Le, P.;
Vellano, K. M.; Osborne, H. B.; Liotta, D. C.; Traynelis, S. F. J. Med. Chem. 2010,
53, 5476–5490; (d) Krishnan, S. K.; Ganguly, S.; Veerasamy, R.; Jan, B. Eur. Rev.
Med. Pharmacol. 2011, 15, 673–681; (e) Nathubhai, A.; Patterson, R.; Woodman,
T. J.; Sharp, H. E. C.; Chui, M. T. Y.; Chung, H. H. K.; Lau, S. W. S.; Zheng, J.; Lloyd,
M. D.; Thompson, A. S.; Threadgill, M. D. Org. Biomol. Chem. 2011, 9, 6089–6099.
13. (a) Surry, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361; (b)
Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626; (c) Muci, A.
R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209; (d) Prim, D.; Campagne,
J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041–2075; (e) Hartwig,
J. F. Palladium-Catalyzed Amination of Aryl Halides and Sulfonates. In Modern
Amination Methods; Ricci, A., Ed.; Wiley-VCH: New York, 2000; pp 195–262; (f)
Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852–860; (g) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818; (h) Yang, B.
16. Typical experimental procedure for the preparation of compound 4a: In an
oven dried, screw-cap vial equipped with a stirring bar were placed 6-bromo-
2-cyclopropyl-3-(pyridin-3-ylmethyl) quinazolin-4(3H)-one (3a) (100 mg,
0.28 mmol) dissolved in anhydrous 1, 4-dioxane (2 mL), p-toluidine (90 mg,
0.85 mmol), and NaOtBu (53 mg, 0.56 mmol). The vial was flushed with argon
for 10 min, Pd2(dba)3 (2.5 mg, 0.028 mmole) and DavePhos (L3) (1.7 mg,
0.042 mmol) were added. The vial was sealed with a Teflon-lined cap, and
placed in
a sand bath that was maintained at 100 °C. The reaction was
monitored by TLC. Upon completion at 8 h, the mixture was cooled and diluted
with CH2Cl2. The mixture was washed with water and the organic layer was
separated and dried over anhydrous Na2SO4. The mixture was evaporated
under reduced pressure. The crude product was purified by column
chromatography, compound was loaded onto
a silica column packed in
CH2Cl2. Sequential elution with pet-ether, followed by 20% EtOAc in pet-ether
afforded compound 4a (100 mg, 93% yield) as white solid.
17. Gurram, V.; Pottabathini, N.; Garlapati, R.; Chaudhary, A. B.; Patro, B.;
Lakshman, M. K.; Chem. Asian J. doi: http://dx.doi.org/10.1002/
asia.201200093.