Metal-free phosphorylations of 1,3,4-oxadiazoles and related heterocycles

Article abstract of DOI:10.1055/s-0031-1291150

1,3,4-Oxadiazoles have been phosphorylated at C5 in yields of >90% under mild metal-free reactions conditions using triethylamine as base. Other azoles undergo analogous phosphorylations albeit in lower yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291150

LETTER
▌1613
lMetteer tal-Free Phosphorylations of 1,3,4-Oxadiazoles and Related Heterocycles
Azole Phosphorylation
Liang-Hua Zou, Zhi-Bing Dong, Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received: 20.03.2012; Accepted after revision: 11.04.2012
nylphosphine and triethylamine as base. With the goal to
Abstract: 1,3,4-Oxadiazoles have been phosphorylated at C5 in
evaluate the opportunities offered by the ease of this azole
yields of >90% under mild metal-free reactions conditions using tri-
functionalization, we decided to optimize the reaction
conditions and to expand the substrate scope. The results
are reported here.
ethylamine as base. Other azoles undergo analogous phosphoryla-
tions albeit in lower yields.
Key words: 1,3-azole, base-promoted, metal-free substitution,
1,3,4-oxadiazole, phosphorylation
As starting point the phosphorylation of 2-phenyl-1,3,4-
oxadiazole (1a) with chloro diphenylphosphine (2) under
basic conditions to give 1,3,4-oxadiazole 3a was chosen
(Scheme 1).
1,3,4-Oxadiazoles are relevant core structures in medici-
nal chemistry1 and material sciences.2 Recently, transi-
tion-metal catalysis has been used for advanced CH-
functionalizations of such key heterocycles.3 For exam-
ple, Miura and co-workers established nickel-catalyzed
alkenylations and -alkylations of 1,3,4-oxadiazoles with
alkynes and styrenes, respectively, which allow selective
cross-couplings at C5.4 Other mostly copper-based catal-
yses allowed related site-selective transformations such as
alkynylations,5a–c arylations,5d benzylations,5e amina-
tions,5f–h and homocouplings.5i In collaboration with
Miura and co-workers we reported copper-catalyzed di-
rect dehydrogenative sulfoximinations of azoles including
1,3,4-oxadiazole derivatives.6
N
N
N
N
PPh2
cat., solvent
base
+
ClPPh2
O
O
1a
3a
2a
Scheme 1 Phosphorylation of 2-phenyl 1,3,4-oxadiazole (1a)
Using a 1:1 ratio of starting materials 1a and 2a (1 mmol
scale), one equivalent of triethylamine, and pyridine as
solvent, 1,3,4-oxadiazole 3a was obtained in a yield of
40% after stirring the reaction mixture at 25 °C for 24
hours. Raising the temperature to 40 °C increased the
yield of 3a to 51%. Neither the addition of Ni(COD)2
(0.05 equiv), as suggested by the chemistry of Miura and
co-workers,4 nor the presence of PdCl2 in solvents such as
toluene, THF, pyridine, and dichloromethane (CH2Cl2)
led to significant improvements. Among those experi-
ments the combination of Ni(COD)2, Et3N, and CH2Cl2
proved best providing 3a in 76% yield. The attempt to use
DMSO as solvent [in the presence of Ni(COD)2 and Et3N]
was unsuccessful, and 3a was not obtained at all. Also in-
organic bases such as Cs2CO3 and K3PO4 instead of Et3N
could not be used. Major advances in the metal-free ver-
sion of the reaction were achieved by changing the solvent
from pyridine to CH2Cl2 and by varying the reagent ratios.
Under the initial conditions (ratio of 1:1:1 for 1a/2a/
Et3N) product 3a was obtained in 75% when the reaction
was performed in CH2Cl2 instead of pyridine. With a
slight excess of 1a (1.2 equiv) and two equivalents of base
(in CH2Cl2) the yield raised to 82%. Finally, 90% of 3a
was obtained (after 48 h at 40 °C in CH2Cl2) when the
chlorophosphine (2) and the base (Et3N) were used in a
twofold excess with respect to azole 1a (Table 1, entry 1).
An alternative route to C5-functionalized 1,3,4-oxadia-
zoles is the base-mediated electrophilic substitution,
which, for example, was utilized by Zarudnitskii et al. for
the preparation of silylated derivatives.7 When applied in
a 1:1 mixture of pyridine and toluene, triethylamine
proved sufficiently basic for the deprotonation leading to
5-substituted derivatives upon treatment with trimethyl-
silyl bromide in good to excellent yields.7,8
Aryl phosphines are ubiqueous ligands in metal catalysis.9
Modifying the aryl group can have a major impact on the
catalytic performance. Commonly, azole-derived phos-
phines are prepared starting from the parent heterocycles
by deprotonation–phosphorylation sequences, and in
most cases strong bases such as n-BuLi in the presence or
absence of TMEDA are applied for the first step.10 On the
basis of the findings by Zarudnitskii et al. on the silylation
reactions of 1,3,4-oxadiazoles mentioned above,6 we
wondered if also phosphorylations of such heterocycles
could be performed under those comparably mild reaction
conditions. This assumption was supported by a brief re-
port by Tolmachev et al. (lacking details of yield and full
product characterization), which included two examples
of 1,3,4-oxadiazole phosphorylations with chloro diphe-
The evaluation of the substrate scope starting from func-
tionalized 2-aryl 1,3,4-oxadiazoles (1) and chlorophos-
phine (2a, Table 1, entries 1–8) led to very satisfying
results.12 The yields of the corresponding 5-phosphorylat-
ed azoles ranged from 68–91% (for 2-dimethylamino- and
4-chloro-substituted derivatives 3f and 3g, respectively).
SYNLETT 2012, 23, 1613–1616
Advanced online publication: 13.06.2012
DOI: 10.1055/s-0031-1291150; Art ID: ST-2012-B0255-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1614
L.-H. Zou et al.
LETTER
Steric and electronic factors on the arene group of the viding 5-phosphorylated product 3i in 80% yield (Table 1,
azole appeared to play only a minor role (if any). Also 2- entry 9).
benzyl-substituted 1,3,4-oxadiazole 1i reacted well pro-
Table 1 Substrate Scope of the Metal-Free Phosphorylation of Azole Derivativesa
N
N
N
N
Et3N (2 equiv)
ClxPPhy
+
PPh2
R
R
CH2Cl2, 40 °C, 48 h
O
O
1a–i
2a x = 1, y = 2
2b x = 2, y = 1
3a–i
N
N
PPh
R
4a R = H
O
4b R = CF3
2
Entry
1
Substrate
R =
Ph
Product
Yield (%)
90
N
N
PPh2
O
1a
3a
N
N
PPh2
O
2
3
4
5
1b
1c
1d
1e
4-Tol
2-Tol
86
89
75
74
Me
3b
N
N
PPh2
O
Me
3c
N
N
PPh2
O
4-MeOC6H4
2-MeOC6H4
MeO
3d
N
N
PPh2
O
OMe
3e
N
N
O
Me2N
PPh2
6
7
8
9
1f
3-Me2NC6H4
4-ClC6H4
4-F3CC6H4
Bn
68
91
83
80
3f
N
N
PPh2
O
1g
1h
1i
Cl
3g
N
N
O
PPh2
F3C
3h
N
N
PPh2
O
3i
Synlett 2012, 23, 1613–1616
© Georg Thieme Verlag Stuttgart · New York

LETTER
Azole Phosphorylation
1615
Table 1 Substrate Scope of the Metal-Free Phosphorylation of Azole Derivativesa (continued)
N
N
N
N
Et3N (2 equiv)
ClxPPhy
+
PPh2
R
R
CH2Cl2, 40 °C, 48 h
O
O
1a–i
2a x = 1, y = 2
2b x = 2, y = 1
3a–i
N
N
PPh
R
4a R = H
O
4b R = CF3
2
Entry
10b
Substrate
R =
Ph
Product
Yield (%)
N
N
PPh
N
O
1a
68 (70)c
2
4a
N
PPh
O
11b
1h
4-F3CC6H4
46
F3C
2
4b
a Conditions: azole (1.0 mmol), ClPPh2 (2.0 mmol), Et3N (2 mmol), CH2Cl2 (1.5 mL), 40 °C, 48 h.
b Use of 3.0 mmol of azole and Cl2PPh instead of ClPPh2.
c In parentheses: result of a 10 mmol scale reaction.
With dichlorophenylphosphine (2b) as electrophile and In conclusion, 2-substituted 1,3,4-oxadiazoles can be
an excess of azole (3 equiv), double phosphine arylations phosphorylated at C5 under metal-free conditions. Using
were possible. Two examples are shown in Table 1, en- triethylamine as base, various new heteroaryl phosphines
tries 10 and 11. In the first transformation involving 2- have been prepared under mild conditions in high yields.
phenyl 1,3,4-oxadiazole (1a), the corresponding product
4a was obtained in 68% yield. Raising the scale from (the
standard) 1 mmol to 10 mmol led to a slight increase in
Acknowledgment
This study was supported by the Fonds der Chemischen Industrie.
L.-H. Z. thanks the Chinese Scholarship Council (CSC) for a pre-
doctoral stipend. Z.-B. D. is grateful to the Alexander von Hum-
boldt Foundation for a postdoctoral fellowship.
yield (70% of 4a). Using trifluoromethyl-substituted 1h as
starting material gave 4b in 46% yield.
Attempts to use other azole derivatives than 1,3,4-oxadia-
zoles proved the general applicability of the metal-free
phosphorylation, but also showed that conversions of ben-
zoxazole (5, Figure 1) and N-phenyl benzimidazole (7)
were more difficult. In both cases the yields of the corre-
sponding phosphorylated products, 6 (30%) and 8 (20%),
respectively, were only moderate.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
In order to examine whether aliphatic phosphine chlorides
could be used as well, compound 1a was reacted with
chloro diisopropyl phosphine (9) under standard reaction
conditions. In this manner, product 10 was obtained in
59% yield.
(1) For a recent example, see: Khanfar, M. A.; Hill, R. A.;
Kaddoumi, A.; El Sayed, K. A. J. Med. Chem. 2010, 53,
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N
N
N
N
N
O
P
R
R
O
Ph
10
5 R = H
6 R = PPh2
7 R = H
8 R = PPh2
Figure 1 Benzoxazole- and N-phenyl benzimidazole based starting
materials and products; diisopropylphosphino-substituted 1,3,4-oxa-
diazole 10
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1613–1616

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L.-H. Zou et al.
LETTER
(e) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
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(12) General Procedure for the Phosphorylation of Azoles –
Examplified by the Synthesis of 2-Phenyl-1,3,4-
oxadiazolyldiphenylphosphine (3a)11
In a Schlenk tube filled with argon 2-phenyl-1,3,4-
oxadiazole (1a, 1 mmol), Et3N (277 μL, 2 mmol), ClPPh2 (2,
180 μL, 2 mmol), and CH2Cl2 (1.5 mL) were added. The
mixture was stirred at 40 °C for 48 h. After full conversion
of 1a (as confirmed by TLC), the mixture was filtered
through a pad of silica gel, concentrated and purified by
silica gel column chromatography providing 3a in 90%
yield. White solid, mp 85.2–86.0 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.96–8.00 (m, 2 H), 7.62–7.55 (m, 4 H), 7.47–
7.43 (m, 2 H), 7.42–7.36 (m, 7 H). 13C NMR (75 MHz,
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C.; Miura, M. Org. Lett. 2011, 13, 359.
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Yurchenko, A. A.; Tolmachev, A. A.; Pinchuk, A. M.
Synthesis 2006, 1279.
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Heterocycl. Compd. 1996, 32, 1319.
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Ed.; Wiley-VCH: Weinheim, 2008.
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B.; Huang, J.; Zapf, A.; Kadyrov, R.; Börner, A.; Beller, M.
Angew. Chem. Int. Ed. 2009, 48, 918. (b) Beller, M.; Harkal,
S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.; Riermeier, T.;
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CDCl3): δ = 167.8 (1JC–P = 32.6 Hz), 167.0, 134.0 (2JC–P
=
21.1 Hz), 132.0 (1JC–P = 6.3 Hz), 131.9, 130.2, 129.0 (3JC–P
=
2.3 Hz), 128.9, 127.2, 123.7. 31P NMR (122.0 MHz, CDCl3):
δ = –25.0 ppm. MS (EI): m/z = 330 [M+]. HRMS: m/z [M+]
calcd for C20H15ON2NaP: 353.0814; found: 353.0813.
Synlett 2012, 23, 1613–1616
© Georg Thieme Verlag Stuttgart · New York

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