Regioselective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline

Article abstract of DOI:10.1055/s-0029-1219391

The regioselective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline with various aryl- and het-eroarylboronic acids are reported. An efficient, sequential strategy was developed that provides access to novel, functionalized heter

Full text of DOI:10.1055/s-0029-1219391

644
LETTER
Regioselective Palladium-Catalyzed Cross-Coupling Reactions of
2,4,7-Trichloroquinazoline
C
ross-Couplin
e
g Reaction
t
of 2,4
e
,7-Trichloro
r
quinazoline Wipf,* Kara M. George
University of Pittsburgh, Pittsburgh, PA 15260, USA
Fax +1(412)6240787; E-mail: pwipf@pitt.edu
Received 17 December 2009
This paper is dedicated to Prof. Gerry Pattenden on the occasion of his 70th birthday.
quinazoline have been reported. For cross-coupling reac-
tions employing 2,4-dichloroquinazoline, exclusive selec-
tivity for the most electrophilic C-4 position13 has been
observed. Attempts to achieve monosubstitution with the
more highly halogenated 6-bromo-2,4-dichloroquinazo-
line resulted in coupling at both the C-4 and C-6 positions
in a ratio of 3:1, respectively. To our knowledge, a regio-
selective method for the sequential polyarylation of tri-
halogenated quinazolines has not been disclosed. Herein,
we describe a versatile new protocol for the regioselective
palladium-catalyzed cross-coupling reactions of 2,4,7-
trichloroquinazoline14 with aryl- and heteroarylboronic
acids.
Abstract: The regioselective palladium-catalyzed cross-coupling
reactions of 2,4,7-trichloroquinazoline with various aryl- and het-
eroarylboronic acids are reported. An efficient, sequential strategy
was developed that provides access to novel, functionalized hetero-
cycles.
Key words: palladium catalysis, cross-coupling, heterocycles, re-
gioselectivity, quinazoline
Palladium-catalyzed cross-coupling reactions represent a
powerful method for the formation of highly substituted
heterocycles.1 The regioselective activation of polyhalo-
genated heteroaromatics in such reactions has been exten-
sively studied2 and can provide a versatile means for the
synthesis of libraries containing functionalized substitu-
ents in specific positions of the heterocyclic scaffold. The
quinazoline moiety is of particular importance, as it is a
component of a variety of biologically active compounds,
including potent tyrosine kinase inhibitors,3 antibacterial,4
and anticancer agents.5 For example, trisubstituted
quinazoline derivatives such as A and B have been pre-
pared as part of a series of liver X receptor (LXR) modu-
lators (Figure 1).6
Initially, we set out to achieve the regioselective cross-
coupling of 2,4,7-trichloroquinazoline by consecutive,
Suzuki cross-couplings (Scheme 1, route A). We envi-
sioned the first coupling to take place at the most electro-
philic C-4 position, followed by substitutions at the C-2
and C-7 positions, respectively. However, coupling at C-
4 proved to be low-yielding due to competitive hydrolysis
at that site under the reaction conditions. In order to cir-
cumvent this problem, a new route was designed in which
the C-4 position was first temporarily deactivated by a
thioether, followed by a regioselective cross-coupling at
C-2 (Scheme 1, route B). The C-4 position would then be
functionalized via a palladium-catalyzed, copper(I)-medi-
ated cross-coupling to provide compounds of type 3,
which could undergo a Suzuki reaction to provide trifunc-
tionalized quinazoline target compounds 4.
Br
Br
N
N
S
N
N
CF3
CF3
Thioether 1 was readily accessed by treatment of 2,4,7-
trichloroquinazoline with 1.05 equivalents of isopropyl
mercaptan and NaH. Substitution occurred exclusively at
the electrophilic C-4 position. Subsequent regioselective
C-2 arylation of 1 proceeded in excellent yields with most
arylboronic acids in the presence of 5 mol% Pd(OAc)2 and
15 mol% Ph3P at 75 °C, furnishing diaryl products 2
(Table 1, entries 1–8).15 In the case of oxygen- and nitro-
gen-containing heterocyclic nucleophiles, slightly lower
yields were obtained, presumably due to the decreased re-
activity of these reagents,16 as shown by the need for pro-
longed reaction times (Table 1, entries 8–10). Excess
boronic acid (1.5 equiv) was necessary for complete con-
sumption of starting materials, and attempts to use stoichi-
ometric amounts resulted in incomplete conversions. In
addition, efforts to decrease the reaction time by increas-
A
B
Figure 1 Quinazoline derivatives designed as LXR modulators
Quinazolines are also components of several approved
drugs, including erlotinib,7 used to treat several types of
tumors, iressa,8 an epidermal growth factor receptor in-
hibitor approved for the treatment of nonsmall cell lung
cancer, and prazosin,9 an a-adrenergic receptor blocker.
While the regioselectivity for palladium-catalyzed alkyla-
tion,10 alkynylation,11 and arylation12 of 2,4-dichloro-
quinazolines has been previously explored, only the
alkylation10 and alkynylation11 of 6-bromo-2,4-dichloro-
SYNLETT 2010, No. 4, pp 0644–0648
Advanced online publication: 10.02.2010
0
1.
0
3.
2
0
1
0
DOI: 10.1055/s-0029-1219391; Art ID: D36809ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reactions of 2,4,7-Trichloroquinazoline
645
R2
N
N
route A
cross-coupling
at C-2
Cl
Cl
cross-coupling
at C-4
R2
R2
N
Cl
N
cross-coupling
at C-7
N
N
Cl
N
R1
R3
R1
Cl
N
Cl
3
4
S
N
deactivation
of C-4
route B
S
N
cross-coupling
at C-4
cross-coupling
at C-2
N
N
Cl
R1
Cl
Cl
1
2
Scheme 1 Selective cross-coupling strategies to minimize synthetic steps and maximize diversity in quinazolines 4
tracted with EtOAc (5 × 25 mL), and washed with H2O. The com-
bined organic extracts were dried (MgSO4) and concentrated to give
a light yellow residue. The residue was purified by chromatography
on SiO2 (1:50, EtOAc–hexanes) to provide 1 (0.291 g, 83%) as a
light yellow crystalline solid; mp 89.1–90.1 °C (EtOAc). IR (ATR):
ing reaction temperatures resulted in poor regioselectivity
and low overall yields.
Stage 2 functionalization at the C-4 position was per-
formed using the palladium-catalyzed, copper(I)-mediat-
ed desulfitative coupling conditions reported by
Liebeskind and coworkers.17 These reactions were carried
out in the presence of excess copper(I) thiophene-2-car-
boxylate (CuTC) and boronic acid. All desulfitative aryla-
tions were achieved in excellent yields and complete
selectivity for the C-4 position (Table 2).
1
3075, 2965, 2881, 1551, 1459, 1321, 1224, 1133, 852 cm–1. H
NMR (300 MHz, DMSO-d6): d = 8.07 (d, 1 H, J = 9.0 Hz), 7.98 (d,
1 H, J = 2.1 Hz), 7.72 (dd, 1 H, J = 9.0, 2.1 Hz), 4.18 (sept, 1 H,
J = 6.9 Hz), 1.46 (d, 6 H, J = 6.9 Hz). 13C NMR (75 MHz, DMSO-
d6): d = 174.8, 156.0, 149.7, 140.1, 128.9, 126.6, 125.9, 120.2, 36.0,
22.2 (2 C). MS (EI): m/z (%) = 272 (33) [M]+, 230 (100), 195 (48),
161 (37). HRMS (EI): m/z calcd for C11H10Cl2N2S: 271.9942;
found: 271.9946.
The third and final cross-coupling reaction was initially
carried out using the conditions reported in Table 1. In all
cases, incomplete consumption of starting material result-
ed, even upon heating to reflux and increasing the equiv-
alents of boronic acid. Finally, in order to ensure the
complete consumption of starting material, 10 mol%
Pd(OAc)2, 30 mol% Ph3P, and 4.0 equivalents of boronic
acid were used. These conditions resulted in a successful
cross-coupling at position C-7 in good yields for both
aryl- and heteroarylboronic acids (Table 3).
General Procedure for Compounds of Type 2
To a reaction vial was added 1 (1.0 equiv), Pd(OAc)2 (0.05 equiv),
Ph3P (0.15 equiv), Na2CO3 (3.1 equiv), and R1B(OH)2 (1.5 equiv).
The reaction mixture was flushed with N2. Freshly distilled and de-
gassed DME and H2O (DME–H2O, 10:1) were added via syringe to
generate a 0.1 M solution of 1, and the reaction mixture was stirred
at 75 °C under a N2 atmosphere for the required time. H2O was add-
ed, and the mixture was extracted with CH2Cl2. The combined or-
ganic layers were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The crude residue was puri-
fied by chromatography on SiO2 (EtOAc–hexanes or THF–toluene)
to give the desired products of type 2.
In conclusion, we have demonstrated that temporary deac-
tivation of the C-4 position by substitution of the chlorine
atom with isopropyl mercaptan allows for the subsequent
regioselective palladium-catalyzed cross-coupling at the
C-2 position in 2,7-dichloroquinazoline 1. Furthermore,
palladium-catalyzed, copper(I)-mediated desulfitative
coupling at the C-4 position, followed by the final palladi-
um-catalyzed cross-coupling at the C-7 position, provides
convenient access to the desired tricarbosubstituted
quinazolines. This simple and efficient sequential cou-
pling route to highly substituted quinazolines enables the
orchestration of regioselective palladium-catalyzed cross-
coupling reactions for the preparation of focused libraries
of kinase inhibitors.18
7-Chloro-4-(isopropylthio)-2-(thiophen-2-yl)quinazoline(Table
1, Entry 1)
Mp 122.7–124.7 °C (DMSO). IR (ATR): 2973, 2917, 2855, 1524,
1
1437, 1327, 1236, 988, 837, 773, 714 cm–1. H NMR (300 MHz,
DMSO-d6): d = 8.06 (dd, 1 H, J = 3.6, 1.2 Hz), 8.00 (d, 1 H, J = 8.7
Hz), 7.95 (d, 1 H, J = 2.1 Hz), 7.84 (dd, 1 H, J = 5.1, 1.5 Hz), 7.61
(dd, 1 H, J = 9.0, 2.1 Hz), 7.26 (dd, 1 H, J = 4.8, 3.6 Hz), 4.30 (sept,
1 H, J = 6.9 Hz), 1.53 (d, 6 H, J = 6.9 Hz). 13C NMR (75 MHz,
DMSO-d6): d = 171.2, 156.0, 149.0, 142.8, 139.2, 131.7, 129.8,
128.8, 127.6, 127.0, 125.8, 120.0, 35.7, 22.4 (2 C). ESI-MS: m/z
(%) = 321 ([M + 1]+ 100), 277 (65). ESI-HRMS: m/z calcd for
C15H14ClN2S2 [M + 1]: 321.0287; found: 321.0271.
General Procedure for Compounds of Type 3
To a reaction vial was added a compound of type 2 (1.0 equiv),
CuTC (2.2 equiv), and R2B(OH)2 (2.2 equiv). The reaction mixture
was flushed with N2 and freshly distilled and degassed THF was
added via syringe to generate a 0.06 M solution of 2. The reaction
mixture was stirred vigorously at 50 °C under a N2 atmosphere for
the required time. A sat. aq solution of NaHCO3 was added, and the
solution was extracted with CH2Cl2. The combined organic layers
2,7-Dichloro-4-(isopropylthio)quinazoline (1)
To a solution of 2,4,7-trichloroquinazoline14 (0.300 g, 1.28 mmol)
in freshly distilled and degassed THF (13.0 mL) cooled to 0 °C was
added a premixed solution of i-PrSH (0.12 mL, 1.28 mmol) and
NaH (0.032 g, 1.35 mmol) in THF (2.0 mL) dropwise. The mixture
was stirred for 16 h, warmed to r.t., poured into ice cold H2O, ex-
Synlett 2010, No. 4, 644–648 © Thieme Stuttgart · New York

646
P. Wipf, K. M. George
LETTER
were washed with NaHCO3, dried (MgSO4), and concentrated un-
der reduced pressure. The residue was then purified by chromatog-
raphy on SiO2 (EtOAc–hexanes or THF–toluene) to provide the
corresponding products of type 3.
R3B(OH)2 (4.0 equiv). The reaction mixture was flushed with N2.
Freshly distilled and degassed DME and H2O (DME–H2O, 10:1)
were added via syringe to generate a 0.1 M solution of 3, and the re-
action mixture was sealed and heated at reflux for the required time.
H2O was added, and the mixture was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried (MgSO4),
and concentrated under reduced pressure. The crude residue was
purified by chromatography on SiO2 (EtOAc–hexanes or THF–tol-
uene) to give the desired products of type 4.
7-Chloro-2-phenyl-4-m-tolylquinazoline (Table 2, Entry 1)
IR (ATR): 3058, 3030, 2914, 2851, 1556, 1532, 1336, 913, 766,
695, 682 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 8.63–8.56 (m,
2 H), 8.22 (d, 1 H, J = 2.1 Hz), 8.11 (d, 1 H, J = 9.0 Hz), 7.73 (dd,
1 H, 9.0, 2.1 Hz), 7.70 (s, 1 H), 7.67 (d, 1 H, J = 7.6 Hz), 7.62–7.57
(m, 3 H), 7.54 (d, 1 H, J = 7.5 Hz), 7.49 (d, 1 H, J = 7.4 Hz), 2.47
(s, 3 H). 13C NMR (75 MHz, DMSO-d6): d = 168.3, 160.0, 151.9,
139.1, 138.1, 137.1, 136.6, 131.2, 131.0, 130.4, 129.1, 128.8 (2 C),
128.6, 128.4, 128.3 (2 C), 127.3, 127.2, 119.8, 21.1. MS (EI): m/z
(%) = 330 (17) [M]+, 329 (43) [M – 1]+, 238 (43), 91 (100). HRMS
(EI): m/z calcd for C21H15ClN2: 330.0924; found: 330.0930.
2-(4-tert-Butylphenyl)-4-(4-ethylphenyl)-7-(3-methoxyphenyl)-
quinazoline (Table 3, Entry 2)
Mp 89.2–91.0 °C (EtOAc). IR (ATR): 3063, 2959, 2866, 1552,
1
1528, 1338, 852, 773 cm–1. H NMR (300 MHz, DMSO-d6): d =
8.55 (d, 2 H, J = 8.6 Hz), 8.37 (d, 1 H, J = 1.7 Hz), 8.18 (d, 1 H,
J = 8.7 Hz), 8.03 (dd, 1 H, J = 8.8, 1.8 Hz), 7.86 (d, 2 H, J = 8.1 Hz),
7.61 (d, 2 H, J = 8.6 Hz), 7.52 (d, 2 H, J = 8.2 Hz), 7.51–7.49 (m, 1
H), 7.47 (dd, 2 H, J = 7.1, 1.7 Hz), 7.11–7.03 (m, 1 H), 3.89 (s, 3 H),
General Procedure for Compounds of Type 4
To a reaction vial was added a compound of type 3 (1.0 equiv),
Pd(OAc)2 (0.10 equiv), Ph3P (0.30 equiv), Na2CO3 (6.2 equiv), and
2.78 (q, 2 H, J = 7.5 Hz), 1.35 (s, 9 H), 1.30 (t, 3 H, J = 7.6 Hz). 13
C
NMR (75 MHz, DMSO-d6): d = 167.6, 159.9, 159.6, 153.6, 151.8,
Table 1 Selective Suzuki Reaction of 1
S
S
Pd(OAc)2 (5 mol%)
Ph3P (15 mol%)
N
R1B(OH)2
N
+
Na2CO3, DME–H2O,
75 °C
Cl
N
Cl
Cl
N
R1
1
2
Entry
1
R1
Time (h)
24
Yield (%)
99
S
2
3
4
5
33
36
33
25
92
90
95
93
Me
Et
t-Bu
6
7
8
13
17
33
89
89
79
CF3
OMe
O
9
48
48
66
53
N
H
10
N
Synlett 2010, No. 4, 644–648 © Thieme Stuttgart · New York

LETTER
Cross-Coupling Reactions of 2,4,7-Trichloroquinazoline
647
Table 2 Palladium-Catalyzed, Copper(I)-Mediated Coupling of 2
R2
S
Pd(PPh3)4 (5 mol%)
CuTC (2.2 equiv)
N
N
R2B(OH)2
+
THF, 50 °C
R1
Cl
N
R1
Cl
N
2
3
Entry
1
R1
R2
Time (h)
26
Yield (%)
89
Me
Me
2
3
4
5
22
19
19
19
83
89
87
86
Et
OMe
Et
OMe
CF3
Et
t-Bu
O
6
7
27
13
91
97
t-Bu
S
8
48
66
N
H
Et
146.3, 145.4, 140.0, 134.9, 134.5, 130.4, 130.1 (2 C), 128.2 (2 C),
128.1 (2 C), 127.6, 126.9, 125.6, 125.5 (2 C), 120.2, 119.7, 114.7,
112.7, 55.3, 34.7, 31.1 (3 C), 28.1, 15.5. MS (EI): m/z (%) = 472
(100) [M]+, 457 (79). HRMS (EI): m/z calcd for C33H32N2O:
472.2515; found: 472.2510.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Table 3 Suzuki Reaction of 3
R2
R2
Pd(OAc)2 (10 mol%)
Ph3P (30 mol%)
N
N
R3B(OH)2
+
Na2CO3, DME–H2O, reflux
R3
N
R1
Cl
N
R1
4
3
Entry
1
R1
R2
R3
Time (h)
34
Yield (%)
81
OMe
CF3
Et
OMe
2
3
22
34
86
66
Et
t-Bu
OMe
N
H
Et
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P. Wipf, K. M. George
LETTER
Feyereislova, A.; Swaisland, H.; Rojo, F.; Albanell, J.
J. Clin. Oncol. 2002, 20, 4292. (c) Twombly, R. J. Natl.
Cancer Inst. 2002, 94, 1596.
Acknowledgment
We gratefully acknowledge financial support provided by the NIH
(P41GM081275).
(9) da Silva, J. F. M.; Walters, M.; Al-Damluji, S.; Ganellin,
C. R. Bioorg. Med. Chem. 2008, 16, 7254.
(10) (a) Mangalagiu, I.; Benneche, T.; Undheim, K. Tetrahedron
Lett. 1996, 37, 1309. (b) Qingbo, L.; Mangalagiu, I.;
Benneche, T.; Undheim, K. Acta Chem. Scand. 1997, 51,
302.
(11) Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem.
Scand. 1996, 50, 914.
(12) Charpiot, B.; Brun, J.; Donze, I.; Naef, R.; Stefani, M.;
Mueller, T. Bioorg. Med. Chem. Lett. 1998, 8, 2891.
(13) (a) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles; Wiley-VCH: Weinheim, 2003. (b) Garcia,
Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk,
K. N. J. Am. Chem. Soc. 2009, 131, 6632.
References and Notes
(1) Kalinin, V. N. Synthesis 1992, 413.
(2) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245.
(3) (a) Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L.
A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.; Bridges,
A. J. Science 1994, 265, 1093. (b) Uckun, F. M.; Sudbeck,
E. A.; Mao, C.; Ghosh, S.; Liu, X.-P.; Vassilev, A. O.;
Navara, C. S.; Narla, R. K. Curr. Cancer Drug Targets 2001,
1, 59. (c) Strawn, L. M.; Shawver, L. K. Exp. Opin. Invest.
Drugs 1998, 7, 553.
(4) Bedi, P. M. S.; Kumar, V.; Mahajan, M. P. Bioorg. Med.
Chem. Lett. 2004, 14, 5211.
(5) Foster, B. A.; Coffey, H. A.; Morin, M. J.; Rastinejad, F.
Science 1999, 286, 2507.
(14) Curd, H. S.; Landquist, J. K.; Rose, F. L. J. Chem. Soc. 1948,
1759.
(15) Exclusive coupling at the C-2 position was determined by
2D NMR experiments.
(16) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685. (b) Billingsley,
K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
(17) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
(18) (a) Decornez, H.; Gulyás-Forró, A.; Papp, Á.; Szabó, M.;
Sármay, G.; Hajdú, I.; Cseh, S.; Dormán, G.; Kitchen, D. B.
ChemMedChem 2009, 4, 1273. (b) Peng, J.; Lin, W.; Jiang,
D.; Yuan, S.; Chen, Y. J. Comb. Chem. 2007, 9, 431.
(c) Wipf, P.; Minion, D. J.; Halter, R. J.; Berggren, M. I.; Ho,
C. B.; Chiang, G. G.; Kirkpatrick, L.; Abraham, R.; Powis,
G. Org. Biomol. Chem. 2004, 2, 1911.
(6) Bernotas, R. C.; Ullrich, J. W.; Travins, J. M.; Wrobel, J. E.;
Unwalla, R. J. WO 2009020683 A2, 2009.
(7) Gundla, R.; Kazemi, R.; Sanam, R.; Muttineni, R.; Sarma,
J. A. R. P.; Dayam, R.; Neamati, N. J. Med. Chem. 2008, 51,
3367.
(8) (a) Wakeling, A. E.; Guy, S. P.; Woodburn, J. R.; Ashton,
S. E.; Curry, B. J.; Barker, A. J.; Gibson, K. H. Cancer Res.
2002, 62, 5749. (b) Baselga, J.; Rischin, D.; Ranson, M.;
Calvert, H.; Raymond, E.; Kieback, D. G.; Kaye, S. B.;
Gianni, L.; Harris, A.; Bjork, T.; Averbuch, S. D.;
Synlett 2010, No. 4, 644–648 © Thieme Stuttgart · New York