Hydrogen peroxide mediated formation of heteroaryl ethers from pyridotriazol-1-yloxy heterocycles and arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2009.07.135

Pyridotriazol-1-yloxypyrimidine 3 reacts with arylboronic acids under palladium-free, Cs₂CO₃, (0.8%) H₂O₂, and DME conditions to produce heteroaryl ethers 4-16 in good yields comparable to the oxidative palladiu

Full text of DOI:10.1016/j.tetlet.2009.07.135

Tetrahedron Letters 50 (2009) 5733–5736
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydrogen peroxide mediated formation of heteroaryl ethers
from pyridotriazol-1-yloxy heterocycles and arylboronic acids
Sujata Bardhan a, Keiko Tabei a, Zhao-Kui Wan b, Tarek S. Mansour a,
*
a Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States
b Chemical Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyridotriazol-1-yloxypyrimidine 3 reacts with arylboronic acids under palladium-free, Cs2CO3, (0.8%)
H2O2, and DME conditions to produce heteroaryl ethers 4–16 in good yields comparable to the oxidative
palladium-catalyzed reaction. The yields of aryl ethers 17–19 from quinazoline 2 with (0.8%) H2O2 were
modest. Hydrogen peroxide is superior to dioxygen as an oxidant in these reactions.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 July 2009
Revised 24 July 2009
Accepted 27 July 2009
Available online 6 August 2009
Recently, we have reported on the synthetic versatility of phos-
phonium-mediated SNAr reactions of biologically important heter-
ocyles1,2 using BOP reagents.3,4 Mechanistic studies regarding the
nature of the intermediates in these reactions using 31P NMR and
ESI MS techniques are consistent with a pathway involving step-
wise formation of heterocyclic benzotriazol-yloxy adducts from
the phosphonium intermediates.5 In this regard, benzotriazol-
yloxy quinazoline 1 and other thienopyrimidine heterocycles read-
ily reacted with various nucleophiles in SNAr fashion.5 Moreover,
since the benzotriazol-yloxy and pyridotriazol-1-yloxy (OPt) ad-
ducts are more stable than the corresponding phosphonium inter-
mediates, further investigations of the reactions of 2 and 3 (Eq. 1)
under oxidative palladium-catalyzed conditions (Pd(PPh3)4, O2,
Cs2CO3, and DME–H2O) with arylboronic acids led to the unex-
pected formation of heteroaryl ethers.6,7 This transformation is
synthetically valuable especially in cases where phenols are not
readily available for SNAr type reactions and is unique compared
to the homocoupling reactions in metal-catalyzed reactions in that
unsymmetrical ether compounds are obtained instead of biaryls.8,9
O2) and a non-palladium-mediated pathway B involving Cs2CO3
and arylboronic acid (Scheme 1). While the contribution of each
pathway to the formation of phenols and eventually heteroaryl
ethers was not explored, the latter pathway was unexpected and
does not seem to depend solely on dioxygen.
The roles of the Pd(0) catalyst and dioxygen in pathway A were
conceived to provide a source of H2O2 in situ, which in turn forms
phenols in situ. Assuming that quinazolines6 and pyrimidines7 OPt
adducts react similarly in the oxidative palladium reaction, we ex-
plored further the transformation of OPt adducts 2 and 3 to hetero-
aryl ethers using arylboronic acids and (0.6–1%) H2O2 as an oxidant
without Pd(0) catalyst. Conceptually, this seemed as an attractive
strategy to probe further the synthetic utility of this transforma-
tion and its possible mechanistic implications. In this Letter, we re-
port our results on the reaction of 2 and 3 with arylboronic acids
mediated by H2O2 as an oxidant.
The reaction of arylboronic acids with pyrimidine 3 under
Cs2CO3, (0.8%) H2O2, and DME conditions led to aryl ethers in var-
iable yields (Table 1). Aryl ethers generated from arylboronic acids
in entries 4, 6, and 11 are formed in substantially lower yields than
those from the oxidative palladium-catalyzed reaction7 while aryl
ether 10 was formed in higher yields under the palladium-free
conditions. The isolated yields obtained with arylboronic acids in
N
N
N
N
N
N
N
O
N
N
N
O
O
N
N
N
ð1Þ
N
N
N
Br
N
Pathway A
2
1
3
Ar-B(OH)2
O
Ar-OH
Pd(PPh3)2
H2O2
Mechanistic studies on the oxidative palladium-catalyzed reac-
tion of 2 using labeled dioxygen (18O2) led to the conclusion that
the ether oxygen is derived from phenols which are generated
from two sources: oxidative Pd catalyzed pathway A (H2O2 via
O
HetOAr
Pathway B
Cs2CO3, DME-H2O
Ar-B(OH)2
Ar-OH
O2 or N2
* Corresponding author. Tel.: +1 845 602 3668; fax: +1 845 602 5580.
E-mail address: mansout@wyeth.com (T.S. Mansour).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.135

5734
S. Bardhan et al. / Tetrahedron Letters 50 (2009) 5733–5736
Table 1
transformation. Although the yields for aryl ethers in entries 3, 9,
and 13 are relatively low, they are however, comparable to those
obtained by the oxidative palladium conditions.
Synthesis of aryl ethers 4–16 from 3
Ar
O
1) Cs2CO3, H2O2 (0.8%)
Therefore, in the case of pyrimidine 3 and in reference to the
mechanistic proposal outlined in Scheme 1, the formation of aryl
ethers under Cs2CO3, (0.8%) H2O2, and DME conditions in entries
1–3, 5, 7–10, 12, and 13 competes well with the oxidative palla-
dium-catalyzed reaction.7 This finding suggests an attractive syn-
thesis of heteroaryl ethers under palladium-free conditions.
Quinazoline 2 which was previously shown to furnish aryl
ethers under Pd(0) conditions, led to the formation of aryl ethers
17–19 with 5-pyrimidinyl, p-methoxyphenyl, and phenylboronic
acids, respectively under the new H2O2 conditions (Table 2).
The lower yields of ethers 17–19 compared to those obtained
by the oxidative palladium-catalyzed reaction suggest that the
latter transformation6 is a superior method for forming quinazo-
line heteroaryl ethers compared to the palladium-free H2O2
conditions.
Having established a differential in reactivity between 2 and 3
under the palladium-free conditions, it became necessary to eval-
uate the extent of pathway B (Scheme 1) contributions in the oxi-
dative palladium-catalyzed reaction. To compliment our earlier
mechanistic studies,6 quinazoline 2 was reacted with 5-pyr-
imidinylboronic acid under Cs2CO3, 18O2, and DME–H2O conditions
without the Pd(0) catalyst and the ratio of incorporation of 18O into
the ether product 17 was monitored with time using ESI/MS tech-
niques. After 24 h, the conversion to the ether product amounted
to <10% with a ratio of 16O:18O being 44:56 (Scheme 2). The low
conversion is also consistent with that obtained using dioxygen
and suggests that pathway B is minor relative to pathway A in
the oxidative palladium-catalyzed reaction. Similarly, the prepara-
tion of aryl ethers 4, 7, and 14 (Table 1 entries 1, 4, and 11) from 3
proceeds in low yields (10–27%) under Cs2CO3, O2, and DME–H2O
conditions.
DME, 10 h, RT
N
N
Ar B(OH)2
Pt
O
2)
4-16
Br
N
N
N
Pt =
N
3
N
N
Br
Entry
1
Boronic acid
Yielda,b (%)
B(OH)2
4; 58, 62
B(OH)2
OMe
2
3
4
5
6
5; 82, 85
6; 25, 28
7; 56, 83
8; 75, 70
9; 19, 63
B(OH)2
OMe
B(OH)2
MeO
B(OH)2
MeS
B(OH)2
CO2 Me
B(OH)2
To account for differences between the palladium-free H2O2
conditions and oxidative palladium-catalyzed conditions,6 it would
seem plausible to suggest that the choice of arylboronic acid plays
a significant role in the formation of phenols from H2O2 as in the
palladium-free conditions or pathway A in the oxidative palladium
reaction6 since the hydrolysis of ArPdOOB(OH)2(PPh3)2 produces
7
8
9
10; 61, 33
11; 53, 48
12; 17, 34
CO2 Me
B(OH)2
MeO2
C
B(OH)2
Me
Table 2
O
Synthesis of aryl ethers from 2
N
N
B(OH)2
N
10
13; 84, 87
O
N
Ar
Me
Me
O
N
O
2
B(OH)2
N
N
Ar B(OH)2
11
12
13
14; 34, 95
15; 41, 55
16; 23, 44
N
O
Entry
1
Boronic acid
Yielda (%)
Yieldb (%)
78
B(OH)2
B(OH)2
N
N
17; 20
N
N
(HO)2B
OMe
N
2
3
18; 34
19; 30
66
80
a
Based on isolated products, average of 2–3 experiments Cs2CO3, (0.8%) H2O2,
and DME.
(HO)2B
(HO)2B
b
Pd(PPh3)4, O2, Cs2CO3, and DME–H2O).
entries 1, 2, 5, 8, 10, and 12 are comparable to those obtained by
the oxidative palladium-catalyzed reaction employing the same
arylboronic acids7 and attest to the synthetic potential of this
a
Based on isolated products, average of 2–3 experiments Cs2CO3, (0.8%) H2O2,
and DME.
b
Pd(PPh3)4, O2, Cs2CO3, and DME–H2O).

S. Bardhan et al. / Tetrahedron Letters 50 (2009) 5733–5736
5735
N
N
100; (d) Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076–15077;
(e) Popp, B. V.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 2804–2805; (f)
Yamamoto, Y.; Suzuki, R.; Hattori, K.; Nishiyama, H. Synlett 2006, 1027–1030;
(g) Gonzalez-Arellano, C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem. Commun.
2005, 15, 1990–1992; (h) Hatamoto, Y.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2004, 6,
4623–4625; (i) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420; (j)
Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2003, 44, 1541–
1544; (k) Parrish, J. P.; Jung, Y. C.; Floyd, R. J.; Jung, K. W. Tetrahedron Lett. 2002,
43, 7899–7902.
N
N
OH
B
N
N
N
O
N
18O
O
N
OH
N
N
N
N
N
+
N
Cs2CO3, DME - H2O
<10%, 18O2
N
17
2
44:56 (24 hrs)
9. Methods for synthesis of unsymmetrical biaryls have been reported: (a) Vogler,
T.; Studer, A. Org. Lett. 2008, 10, 129–131; (b) Alessi, M.; Larkin, A. L.; Ogilvie, K.
A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V. C. J. Org. Chem. 2007, 72, 1588–
1594; (c) Kianmehr, E.; Yahyaee, M.; Tabatabai, K. Tetrahedron Lett 2007, 48,
2713–2715; (d) Demir, A. S.; Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003, 68,
578–580.
10. (a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J. Am. Chem. Soc.
2006, 128, 6829–6836; (b) Keith, J. M.; Nielsen, R. J.; Oxgaard, J.; Goddard, W.
A., III J. Am. Chem. Soc. 2005, 127, 13172–13179; (c) Denney, M. C.; Smythe, N.
A.; Cetto, K. L.; Kemp, R. A.; Goldberg, K. I. J. Am. Chem. Soc. 2006, 128, 2508–
2509.
Scheme 2.
H2O2 and ArPd(OH)(PPh3)2.6,10 Excess arylboronic acid can, how-
ever, be consumed in the palladium-catalyzed reaction by trans-
metalation of ArPd(OH)(PPh3)2 leading to Ar2Pd(PPh3)2 and its
reductive elimination to the homocoupling product Ar-Ar.10
Although the conversion of arylboronic acids to phenols has been
11
previously reported to proceed with 30% H2O2 or other oxidants
11. Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J. Org. Chem.
2001, 66, 633–634.
such as perborate,12 hydroxylamine,13 and oxone,
limitations
14,15
12. (a) Nanni, E. J.; Sawyer, D. T., Jr. J. Am. Chem. Soc. 1980, 102, 7591–7593; (b)
Fontani, P.; Carboni, B.; Vaultier, M.; Maas, G. Synthesis 1991, 605–609.
13. Kianmehr, E.; Yahyaee, M.; Tabatabai, K. Tetrahedron Lett. 2007, 48, 2713–2715.
14. Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117–5118.
15. Lee, Y.; Kelly, M. J. Tetrahedron Lett. 2006, 47, 4897–4901.
16. Dickie, D. A.; MacIntosh, I. S.; Ino, D. D.; He, Q.; Labeodan, O. A.; Jennings, M. C.;
Schatte, G.; Walsby, C. J.; Clyburne, J. A. C. Can. J. Chem. 2008, 86, 20–31.
17. Kilitoglu, B.; Arndt, H.-D. Synlett 2009, 720–723.
of these methods have been reported.10,16,17 Experimentally, we
aimed at using a low concentration of hydrogen peroxide (<1%)
for comparative purposes with the oxidative palladium-catalyzed
reaction5–7 since in this case higher concentrations were inhibitory
to the formation of heteroaryl ethers.6,7 The experimental proce-
dure adopted under the palladium-free conditions is a one-pot,
two-step sequence involving oxidation of arylboronic acids with
(0.8–1%) hydrogen peroxide followed by the addition of the OPt het-
erocycle 2 or 3.
18. Bae, S.; Lakshman, M. K. J. Org. Chem. 2008, 73, 1311–1319.
19. Bae, S.; Lakshman, M. K. J. Am. Chem. Soc. 2007, 129, 1782–1789.
20. 5-Bromo-2-phenoxypyrimidine (4): Phenyl boronic acid (50 mg, 0.41 mmol) and
Cs2CO3 (443 mg, 1.36 mmol) were dissolved in DME (5 mL) at rt. Aqueous H2O2
(0.04 mL, 0.8%) was added to the reaction mixture and purged with O2. The
reaction mixture was stirred for 6 h. 3-(5-Bromo-pyrimidin-2-yloxy)-3H-
[1,2,3] triazolo [4,5-b]pyridine (36 mg, 0.12 mmol) was then added at rt and
the reaction mixture was stirred for a further 10 h. The crude reaction mixture
was then directly purified by flash chromatography to afford a white solid
(49 mg, 58%). 1H NMR (CDCl3, 300 MHz) d (ppm) 8.56 (s, 2H), 7.45 (m, 2H), 7.29
(m, 1H), HRMS (ES-MS) [(M+H)+]: for C10H7BrN2O 250.9814, found 250.9817.
5-Bromo-2-(2-methoxyphenoxy)-pyrimidine (5): 1H NMR (CDCl3, 300 MHz) d
(ppm) 8.54 (s, 2H), 7.17 (m, 2H), 7.03 (m, 2H), 3.75 (s, 3 H). HRMS (ES-MS)
[(M+H)+]: for C11H9BrN2O2 280.9920, found 280.9918.
In conclusion, the reaction of arylboronic acids with OPt hetero-
cycles 2 and 3 under Cs2CO3, (0.8%) H2O2, and DME conditions pro-
duces heteroaryl ethers in good synthetic yields and is superior to
that involving Cs2CO3, O2, and DME–H2O conditions. Comparative
studies between quinazoline 2 and pyrimidine 3 indicate that the
palladium-free Cs2CO3, (0.8%) H2O2, and DME conditions produce
heteroaryl ethers 4–16 in yields comparable to that of the palla-
dium-catalyzed conditions (Pd(PPh3)4, O2, Cs2CO3, and DME–H2O)
in the case of 3. However, for quinazoline 2 the palladium-cata-
lyzed process is more efficient.
This new transformation complements the direct SNAr with
phenols5,18,19 and competes well with the oxidative palladium-cat-
alyzed reaction.6,7 The relative simplicity in eliminating palladium
metal and dioxygen and employing H2O2 as an oxidant makes it an
attractive consideration for the synthesis of heteroaryl ethers. This
reaction strongly highlights on the complexity in understanding
the reaction pathways in these oxidative transformations.20
5-Bromo-2-(3-methoxyphenoxy)pyrimidine (6): 1H NMR (CDCl3, 300 MHz)
d
(ppm) 8.57 (s, 2H), 7.33 (m, 1H), 6.83 (m, 3H), 3.81 (s, 3H). HRMS (ES-MS)
[(M+H)+]: for C11H9BrN2O2 280.9926, found 280.9919.
5-Bromo-2-(4-methoxyphenoxy)-pyrimidine (7): 1H NMR (CDCl3, 300 MHz) d
(ppm) 8.56 (s, 2H), 7.12 (d, 2H, J = 9.3 Hz), 6.96 (d, 2H, J = 9.0 Hz), 3.82 (s, 3H).
HRMS (ES-MS) [(M+H)+]: for C11H9BrN2O2 280.9920, found 280.9919.
5-Bromo-2-(4-methylsulfanyl-phenoxy)-pyrimidine (8): 1H NMR (CDCl3,
300 MHz)
d (ppm) 8.57 (s, 2H), 7.33 (d, 2H, J = 6.6 Hz), 7.13 (d, 1H, J =
6.9 Hz), 2.50 (s, 3H). HRMS (ES-MS) [(M+H)+]: for C11H9BrN2OS 296.9692,
found 296.9688.
2-(5-Bromo-pyrimidin-2-yloxy)-benzoic acid methyl ester (9): 1H NMR (CDCl3,
300 MHz) d (ppm) 8.54 (s, 2H), 8.08 (dd, 1H, J = 1.6 Hz, J = 7.8 Hz), 7.63 (dt, 1H,
J = 1.5 Hz, J = 7.5 Hz), 7.37 (dt, 1H, J = 0.9 Hz, J = 7.8 Hz), 7.24 (dd, 1H, J = 0.9 Hz,
J = 8.1 Hz), 3.72 (s, 3H). HRMS (ES-MS) [(M+H)+]: for C12H9BrN2O3 308.9869,
found 308.9871.
Supplementary data
3-(5-Bromo-pyrimidin-2-yloxy)-benzoic acid methyl ester (10): 1H NMR (CDCl3,
300 MHz) d (ppm) 8.58 (s, 2H), 7.98 (m, 1H), 7.86 (t, 1H, J = 2.4 Hz), 7.53 (t, 1H,
J = 7.8 Hz), 7.39 (m, 1H), 3.92 (s, 3H). HRMS (ES-MS) [(M+H)+]: for C12H9BrN2O3
308.9869, found 308.9875.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.135.
4-(5-Bromo-pyrimidin-2-yloxy)-benzoic acid methyl ester (11): 1H NMR (CDCl3,
300 MHz) d (ppm) 8.59 (s, 2H), 8.14 (d, 2H, J = 9.2 Hz), 7.24 (d, 2H, J = 8.4 Hz),
3.93 (s, 3H). HRMS (ES-MS) [(M+H)+]: for C12H9BrN2O3 308.9869, found
308.9870.
References and notes
1-[2-(5-Bromo-pyrimidin-2-yloxy)-phenyl]-ethanone (12): 1H NMR (CDCl3,
300 MHz) d (ppm) 8.55 (s, 2H), 7.89 (dd, 1H, J = 1.8 Hz, J = 7.8 Hz), 7.60 (td,
1H, J = 1.8 Hz, J = 7.5 Hz), 7.38 (td, 1H, J = 0.9 Hz, J = 7.8 Hz), 7.23 (dd, 1H,
J = 0.9 Hz, J = 7.5 Hz), 2.52 (s, 3H).HRMS (ES-MS) [(M+H)+]: for C12H9BrN2O2
292.9920, found 292.9919.
1. (a) Wan, Z.-K.; Binnum, E.; Wilson, D. P.; Lee J. Org. Lett. 2005, 7, 5877–5880; (b)
Levins, C. G.; Wan, Z.-K. Org. Lett. 2008, 10, 1755–1758.
2. Wan, Z.-K.; Wacharasindhu, S.; Binnum, E.; Mansour, T. Org. Lett. 2006, 8, 2425–
2428.
3. PyAOP Alsina, J.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1996, 37, 4195–4198;
BOP reagents: (a) Coste, J.; Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991,
32, 1967–1970; (b) Srivastava, T. K.; Haq, W.; Bhanumati, S.; Velmurugan, D.;
Sharma, U.; Jagannathan, N. R.; Katti, S. B. Protein Peptide Lett. 2001, 8, 39–44.
1-[3-(5-Bromo-pyrimidin-2-yloxy)-phenyl]-ethanone (13): 1H NMR (CDCl3,
300 MHz) d (ppm) 8.58 (s, 2H), 7.55 (m, 1H), 7.34 (t, 1H, J = 7.8 Hz), 7.13 (m,
1H), 6.79 (s, 1H), 2.62 (s, 3H). HRMS (ES-MS) [(M+Na)+]: for C12H9BrN2O2
314.9740, found 314.9735.
4. (a) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130, 11300–11302;
(b) Kang, F.-A.; Sui, Z.; Murray, W. V. Eur. J. Org. Chem. 2009, 461–479.
5. Wan, Z.-K.; Wacharasindhu, S.; Levins, C.; Lin, M.; Tabei, K.; Mansour, T. S. J.
Org. Chem. 2007, 72, 10194–10210.
6. Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.; Mansour, T. S. J. Am.
Chem. Soc. 2009, 131, 4174–4175.
7. Bardhan, S.; Wacharasindhu, S.; Wan, Z.-K.; Mansour, T. S. Org. Lett. 2009, 11,
2511–2514.
8. (a) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2008, 47, 1473–1476; (b) Ban, I.; Sudo, T.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 3607–3609; (c) Xu, Z.; Mao, J.; Zhang, Y. Catal. Commun. 2007, 9, 97–
1-[4-(5-Bromo-pyrimidin-2-yloxy)-phenyl]-ethanone (14): 1H NMR (CDCl3,
300 MHz)
d (ppm) 8.59 (s, 2H), 8.06 (d, 2H, J = 9.2 Hz), 7.29 (d, 2H, J =
8.8 Hz), 2.62 (s, 3 H). HRMS (ES-MS) [(M+H)+]: for C12H9BrN2O2 292.9919,
found 292.9918.
5-Bromo-2-(pyrimidin-5-yloxy)-pyrimidine (15): 1H NMR (CDCl3, 300 MHz) d
(ppm) 9.13 (s, 2H), 8.73 (s, 2H), 8.62 (s, 2H). HRMS (ESI-MS) [(M+H)+]: for
C8H5BrN4O 252.972, found 252.9719.
5-Bromo-2-(pyrimidin-5-yloxy)-pyrimidine (16): 1H NMR (CDCl3, 300 MHz) d
(ppm) 8.91 (d, 2H, J = 5.1 Hz), 8.77 (s, 2H), 6.51 (d, 2H, J = 5.1 Hz). MS (ESI-MS)
[(M+H)+]: for C9H6BrN3O 252.06, found 252.20.

5736
S. Bardhan et al. / Tetrahedron Letters 50 (2009) 5733–5736
Aryl ethers 4, 7, 14 from 3, Cs2CO3 and dioxygen in DME:
Aryl ethers 17, 18, 19 from 2, Cs2CO3 in DME and aq H2O2 (0.8%).
5-Bromo-2-phenoxypyrimidine (4): This compound was synthesized from 3-(5-
bromo-pyrimidin-2-yloxy)-3H-[1,2,3] triazolo [4,5-b] pyridine (10 mg,
0.03 mmol), phenyl boronic acid (12 mg, 0.10 mmol), and Cs2CO3 (44 mg,
0.14 mmol) in DME (1 mL). The reaction mixture was purged with dioxygen
and stirred at rt for 10 h. The crude reaction mixture was then directly purified
by flash chromatography to afford a white solid (2 mg, 27%). 1H NMR (CDCl3,
300 MHz) d (ppm) 8.56 (s, 2H), 7.45 (m, 2H), 7.29 (m, 1H), 7.19 (d, 2H,
J = 4.2 Hz). HRMS (ES-MS) [(M+H)+]: for C10H7BrN2O 250.9814, found
250.9817.
4-(Pyrimidin-5-yloxy)quinazoline (17):: This compound was synthesized from 4-
(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)quinazoline (90 mg, 0.34 mmol).
Pyrimidine boronic acid (186 mg, 1.50 mmol), and Cs2CO3 (332 mg,
1.02 mmol) in DME (3 mL) and aq H2O2 (0.02 mL, 0.8%) were added to the
reaction mixture and stirred for 10 h. The crude reaction mixture was purified
by flash chromatography as
a
white solid (15 mg, 20%).1H NMR (CDCl3,
400 MHz): d (ppm) 9.06 (s, 1H), 8.41 (s, 2H), 8.77 (s, 1H), 8.39–8.37 (m, 1H),
8.06–7.96 (m, 2H), 7.76–7.73 (m, 1H). HRMS (ES-MS) [(M+H)+]: for C12H8N4O1
225.0771, found 225.0771.
5-Bromo-2-(4-methoxyphenoxy)-pyrimidine
(7):
This
compound
was
4-(4-Methoxyphenoxy)quinazoline (18): This compound was synthesized from
4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)quinazoline (2, 64 mg, 0.25 mmol),
4-methoxy phenyl boronic acid (100 mg, 0.82 mmol), and Cs2CO3 (346 mg,
1.06 mmol) in DME (10 mL) and aq. H2O2 (0.08 mL, 0.8%) and was purified by
flash chromatography as a white solid (21 mg, 34%). 1H NMR (CDCl3, 400 MHz):
d (ppm) 8.77(s, 1H), 8.39–8.73 (m, 1H), 8.01(d, J = 2.5 Hz, 1H), 7.94–7.90 (m,
1H), 7.68–7.64 (m, 1H), 7.20–7.17 (m, 2H), 7.01–6.99 (m, 2H). HRMS (ES-MS)
[(M+H)+]: for C15H12N2O2 253.0971, found 253.0964.
synthesized from 3-(5-bromo-pyrimidin-2-yloxy)-3H-[1,2,3] triazolo [4,5-b]
pyridine (50 mg, 0.17 mmol), 4-methoxy phenyl boronic acid (78 mg,
0.51 mmol), and Cs2CO3 (222 mg, 0.68 mmol) in DME (2.5 mL). The reaction
mixture was purged with dioxygen and stirred at rt for 10 h and was purified by
flash chromatography as a white solid (10 mg, 21%). 1H NMR (CDCl3, 300 MHz) d
(ppm) 8.56 (s, 2H), 7.12 (d, 2H, J = 9.3 Hz), 6.96 (d, 2H, J = 9.0 Hz), 3.82 (s, 3H).
HRMS (ES-MS) [(M+H)+]: for C11H9BrN2O2 280.9920, found 280.9919.
1-[4-(5-Bromo-pyrimidin-2-yloxy)-phenyl]-ethanone (14): This compound was
synthesized from 3-(5-bromo-pyrimidin-2-yloxy)-3H-[1,2,3] triazolo [4,5-b]
pyridine (100 mg, 0.34 mmol), 4-acetyl phenyl boronic acid (220 mg,
1.34 mmol), and Cs2CO3 (556 mg, 1.74 mmol) in DME (10 mL). The reaction
mixture was purged with dioxygen and stirred at rt for 10 h. The crude reaction
mixture was then directly purified by flash chromatography to afford a white
solid (10 mg, 10%). 1H NMR (CDCl3, 300 MHz) d (ppm) 8.59 (s, 2H), 8.06 (d, 2H,
J = 9.2 Hz), 7.29 (d, 2H, J = 8.8 Hz), 2.62 (s, 3H). HRMS (ES-MS) [(M+H)+]: for
C12H9BrN2O2 292.9919, found 292.9918.
4-Phenoxyquinazoline (19): This compound was synthesized according to
substrate
7 from 4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy) quinazoline
(32 mg, 0.12 mmol), phenylboronic acid (50 mg, 0.41 mmol), and Cs2CO3
(173 mg, 0.53 mmol) in DME (5 mL) and aq. H2O2 (0.04 mL, 0.8%) and was
purified by flash chromatography as a white solid (8 mg, 30%).1H NMR (DMSO-
d6, 400 MHz): d (ppm) 8.85 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.05–8.00 (m, 2H),
7.80 (t, J = 6.3 Hz, 1H), 7.68–7.66 (m, 2H), 7.56–7.54 (m, 3H). HRMS (ES-MS)
[(M+H)+]: for C14H10N2O1 223.0861, found 223.0862.