Solid-phase synthesis of 1,2-diketones via acetylene oxidation: A versatile diversity platform for the combinatorial synthesis of heterocycles

Article abstract of DOI:10.1055/s-0030-1258570

Investigations towards the solid-phase synthesis of 1,2-diketones via the oxidation of acetylenes and their use in the combinatorial synthesis of heterocycles such as imidazoles and quin-oxalines are described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258570

LETTER
2639
Solid-Phase Synthesis of 1,2-Diketones via Acetylene Oxidation: A Versatile
Diversity Platform for the Combinatorial Synthesis of Heterocycles
Solid-Phase
Synthiesis of
lsetones via
Acet
G
O
xidation riebenow,* Thorsten Meyer
Bayer Schering Pharma AG, Global Drug Discovery, Medicinal Chemistry Wuppertal, Building 460, 42096 Wuppertal, Germany
Fax +49(202)365866; E-mail: nils.griebenow@bayerhealthcare.com
Received 18 June 2010
We envisaged to prepare the intermediate 1,2-diketones
Abstract: Investigations towards the solid-phase synthesis of 1,2-
by the oxidation of resin-bound acetylenes, which are eas-
diketones via the oxidation of acetylenes and their use in the com-
ily accessible through Sonogashira coupling of aryl ha-
binatorial synthesis of heterocycles such as imidazoles and quin-
lides with terminal alkynes. The Sonogashira reaction is a
powerful and well-established tool in solid-phase
synthesis3 and proceeds, in the majority of cases, in excel-
lent yields and purities. Although absent in solid-phase
chemistry, the oxidation of alkynes to 1,2-diketones is a
well-documented reaction in solution-phase chemistry.4
Examples, among others,5 include the use of dimethyl sulf-
oxide in combination with iodine,6 palladium(II),5,7 and
N-bromosuccinimide8 as the oxidation-promoting re-
agents.
oxalines are described.
Key words: solid-phase synthesis, imidazole, quinoxaline, oxida-
tion, 1,2-diketone
The solid-phase synthesis of low-molecular-weight com-
pounds along with high-throughput screening has been
and continues to be a powerful tool in the discovery of
new pharmaceutical lead structures. Hence, the discovery
of new synthesis methods to further expand the synthetic
toolbox that allows for the rapid exploration and custom-
ization of the pharmaceutical diversity space is one major
focus for synthetic organic chemists. In the course of our
ongoing efforts directed toward the solid-phase synthesis
of general-purpose screening libraries, we were particu-
larly interested in the synthesis of 1,2-diketones immobi-
lized on a solid support.
Initially, we investigated the oxidation of the resin-bound
diaryl acetylene 3a using various reagents and reaction
conditions. Resin-bound acetylene 3a was build up in two
steps as outlined in Scheme 1. 4-Iodobenzoic acid was
loaded onto commercially available Wang resin 1 [4-(hy-
droxymethyl)phenoxymethyl polystyrene resin cross-
linked with 1% divinylbenzene] using the 2,6-dichlo-
robenzoyl chloride technique first describe by Sieber.9
1,2-Diketones are known to be versatile and thus impor-
tant intermediates for the synthesis of various types of het-
erocycles like imidazoles or quinoxalines. However, a
literature survey revealed only few examples of the use of
1,2-diketones in combinatorial solid-phase synthesis,1
while, to the best of our knowledge, the on-resin synthesis
and use of 1,2-diketones in this context has no document-
ed precedents.2
Subsequent Sonogashira coupling with phenylacetylene
provided the resin-bound diaryl acetylene 3a, whose puri-
ty was determined by cleaving the product from the resin
with trifluoroacetic acid (TFA) in CH2Cl2 (v/v = 1:1, r.t.,
1 h). The crude product was obtained in excellent purity10
Table 1 Reagents and Reaction Conditions for the Oxidation of Di-
aryl Acetylene 3a
Entry Reagentsa
Conditions
Purity
(%)
O
HO
O
1
2
Na2PdCl4 (0.1 equiv), DMSO 4 h, 100 °C
Na2PdCl4 (0.1 equiv), DMSO 1.5 h, 140 °C
Na2PdCl4 (0.4 equiv), DMSO 5 h, 140 °C
Na2PdCl4 (0.4 equiv), DMSO 18 h, 140 °C
0
5
O
I
OH
Wang resin
b
a
I
2
1
3
50
90
90
95
0
4
O
5
PdCl2 (0.1 equiv), DMSO
PdI2 (0.1 equiv), DMSO
I2 (1.0 equiv), DMSO
I2 (1.0 equiv), DMSO
I2 (1.0 equiv), DMSO
I2 (1.0 equiv), DMSO
NBS (5.0 equiv), DMSO
18 h, 140 °C
18 h, 140 °C
4 h, 80 °C
c
O
O
O
O
6
3a
4a
O
7
Scheme 1 Reagents and conditions: (a) 2,6-dichlorobenzoyl chlo-
ride, pyridine, DMF, r.t., 16 h; (b) CuI, (Ph3P)2PdCl2, DIPEA, DMF,
r.t., 16 h; (c) iodine, DMSO, 155 °C, 1 h (for other reaction conditions
and reagents, see Table 1).
8
1 h, 120 °C
18 h, 120 °C
1 h, 155 °C
18 h, 100 °C
10
90
95
50
9
10
11
SYNLETT 2010, No. 17, pp 2639–2643
Advanced online publication: 23.09.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258570; Art ID: G18310ST
© Georg Thieme Verlag Stuttgart · New York
a In all cases DMSO was used as solvent.

2640
N. Griebenow, T. Meyer
LETTER
(99%) and good yield11 (84%). Resin-bound diaryl acety- Instead of the commonly employed catalyst palladium(II)
lene 3a was subjected to different oxidation protocols as chloride,7 sodium tetrachloropalladate(II) was used be-
outlined in Table 1.
cause of its better solubility in DMSO. Purity of the
formed 1,2-diketone was determined after cleaving the
Table 2 Scope and Limitations of the Acetylene Oxidation
Entry Substratea
Purity
(%)b
Product
Purity
(%)b
Yield
(%)c
O
1
2
3a
3b
99
72
5a
95
75
52
48
HO
O
O
O
O
F
F
O
5b
O
HO
O
O
O
O
O
3
4
3c
57
97
5c
dec.d
–
O
HO
HO
O
O
O
O
O
O
O
3d
5d
86
49
O
O
O
O
O
O
Cl
Cl
O
O
O
O
5
6
3e
3f
100
5e
86
94
42
59
HO
HO
OMe
OMe
18 (54)e 5f
O
O
O
O
7
8
3g
3h
77
5g
5h
89
47
O
O
HO
HO
O
O
O
O
100
dec.d
–
a Substrates were analyzed after cleavage from the resin (TFA–CH2Cl2, v/v = 1:1, r.t., 1 h).
b Purities were calculated from the integrated peak areas recorded by HPLC analysis (UV detection, 210 nm) of the crude products.
c Yields refer to the crude products and were calculated on the basis of the initial loading of the resin.
d dec. = decomposition.
e Hydration of the triple bond was observed.
Synlett 2010, No. 17, 2639–2643 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of 1,2-Diketones via Acetylene Oxidation
2641
H2N
O
HO
O
R2
R1
N
O
O
H2N
R2
O
a, b
N
4
R1
6
O
H
O
H2N R3
R2
N
HO
R2
c, d
N
R1
R3
7
Scheme 2 Reagents and conditions: (a) trimethyl orthoformate (TMOF), r.t., 18 h; (b) TFA–CHCl (v/v = 1:1), r.t., 1 h; (c) NH4OAc, AcOH,
110 °C, 16 h; (d) TFA–CH2Cl2 (v/v = 1:1), r.t., 1 h; 6: R1 = H, 4-F, 4-Cl, 4-t-Bu, R2 = H, OMe; 7: R1 = 4-H, 4-Cl, 4-t-Bu, R2 = phenyl, t-Bu,
R3 = H, Bn.
product from the resin under the conditions described solid support derived from 4- and 3-iodobenzoic acid as
above. Best results were obtained when iodine (entry 10) well as aliphatic and aromatic terminal alkynes (Table 2).
and palladium(II) iodide (entry 5) in DMSO were used at
Oxidation of bisaromatic acetylenes proceeded smoothly,
however, mono-aromatic substrates (3c and 3h) under-
went decomposition. To illustrate the versatility of this
elevated temperatures of 155 °C and 140 °C, respective-
ly.12
Because of its shorter reaction time the iodine protocol chemistry, the resin-bound 1,2-diketones 3a,b,e–g were
(entry 10) was utilized for further analogue synthesis. subjected to Debus–Radziszewski imidazole synthesis
Having the optimized oxidation protocol in hand, we in- conditions13 and underwent condensation reaction with 2-
vestigated the scope and limitations of the oxidation pro- aminoanilines providing quinoxalines14 as outlined in
cedure. Various acetylenes 3a–h were assembled on a Scheme 2. For imidazol synthesis on a solid support we
O
O
O
HO
HO
HO
OMe(H)
H(OMe)
N
N
N
N
OMe(H)
H(OMe)
N
N
6c 81% (46%)
6a 88% (69%)
6b 88% (51%)
F
HO
HO
N
N
N
N
O
O
6d 79% (69%)
Cl
6e 94% (67%)
O
O
HO
N
N
HO
HO
O
N
N
N
H
N
H
Cl
7a 69% (56%)
7b 66% (46%)
7c 66% (41%)
HO
HO
N
N
O
O
N
H
N
H
Cl
7d 47% (42%)
7e 79% (42%)
Figure 1 Purities of quinoxalines 6a–e and imidazoles 7a–e prepared on a solid support. Purities were calculated from the integrated peak
areas recorded by HPLC analysis (UV detection, 210 nm) of the crude products. Yields in parenthesis refer to the crude products and were
calculated on the basis of the initial loading of the resin. When nonsymmetric 2-aminoanilines were used in the reaction, two isomers were
obtained in the ratio of 1:1 (6b and 6c). In case of 7c two isomers in the ratio of 1:1 were detected by LC-MS analysis.
Synlett 2010, No. 17, 2639–2643 © Thieme Stuttgart · New York

2642
N. Griebenow, T. Meyer
LETTER
(11) Yields refer to the crude products and were calculated on the
basis of the initial loading of the resin.
(12) Representative Experimental Procedure for the
Preparation of 1,2-Diketones
employed the reaction conditions first described by
Sashar et al. in 1996.15
A small library of quinoxalines 616 and imidazoles 717
were thus prepared on a solid support (Figure 1).
Wang resin (6.00 g, 7.14 mmol, loading of 1.19 mmol/g, 1%
cross-linking, 100–200 mesh) was suspended in DMF (40
mL). The suspension was charged with 4-idodobenzoic
acid (3.19 g, 1.8 equiv, 12.85 mmol), 2,6-dichlorobenzoyl
chloride (2.99 g, 2.0 equiv, 14.27 mmol), and pyridine (1.91
mL, 1.86 g, 3.3 equiv, 23.55 mmol), and the reaction mixture
was shaken at r.t. for 18 h. The resin was filtered off and
washed successively with DMF, MeOH, THF, as well as
CH2Cl2. Residual traces of solvent were removed in vacuo
overnight to provide the derivatized resin 2 with a theoretical
loading capacity of 0.93 mmol/g based on 100% conversion.
Under an atmosphere of argon 4-iodobenzoic acid
In the case of quinoxalines, the products were obtained in
good to excellent purities (79–94%) and moderate yields
(46–69%). Imidazoles were obtained in moderate to good
purities (47–79%) and moderate yields (41–56%).
In conclusion, we have developed a straightforward ap-
proach to structurally diverse quinoxalines and imida-
zoles. Key to the synthesis is a novel procedure for the on-
resin formation of 1,2-diketones via acetylene oxidation.
functionalized Wang resin 2 (3.00 g, 2.80 mmol, loading:
0.93 mmol/g) was suspended in a solution of phenyl-
acetylene (3.0 equiv, 858 mg, 8.41 mmol) in DMF–DIPEA
(15 mL, v/v = 3:1). Bis(triphenylphosphine)palladium(II)
dichloride (197 mg, 0.1 equiv, 0.28 mmol) and copper(I)
iodide (213 mg, 0.4 equiv, 1.12 mmol) were added, and the
reaction mixture was shaken at r.t. for 18 h. After filtration,
the resin was washed with DMF, 50% aq AcOH, MeOH,
THF, and CH2Cl2. Residual traces of solvent were removed
in vacuo overnight to provide the derivatized resin 3a with a
theoretical loading capacity of 0.96 mmol/g based on 100%
conversion. An analytical sample of the resin was treated
with TFA in CH2Cl2 (v/v = 1:1) for 1 h at r.t. Filtration and
evaporation yielded 4-(phenylethynyl)benzoic acid.
LC-MS: 2.52 min, 99% (210 nm), m/z = 221 [M – H–]. 1H
NMR (400 MHz, DMSO-d6): d = 7.44–7.49 (m, 3 H), 7.57–
7.62 (m, 2 H), 7.66–7.70 (m, 2 H), 7.96–8.00 (m, 2 H) ppm;
one proton not observed in this spectrum. HRMS: m/z calcd
for C15H11O2 [M + H+]: 223.0754; found: 223.0754.
4-(Phenylethynyl)benzoic acid Wang resin (3a, 209 mg,
0.20 mmol, loading: 0.957 mmol/g) was suspended in anhyd
DMSO (2 mL) and charged with iodine (51 mg, 1 equiv,
0.20 mmol). The reaction mixture was heated to 155 °C for
1 h. The resin was then filtered off and successively washed
with DMF, 50% aq AcOH, MeOH, THF, as well as CH2Cl2.
Residual traces of solvent were removed in vacuo overnight
to provide the derivatized resin 4a with a theoretical loading
capacity of 0.93 mmol/g based on 100% conversion. The
resin was cleaved with TFA–CH2Cl2 (2 mL, v/v = 1:1) at r.t.
for 1 h, filtered, and washed with CH2Cl2 (1 mL). The filtrate
was evaporated to dryness providing 26 mg of 4-[oxo-
(phenyl)acetyl]benzoic acid (5a) in 52% yield.
References and Notes
(1) (a) Fretz, H. Tetrahedron Lett. 1996, 37, 8479. (b) Boussie,
T. R.; Murphy, V.; Hall, K. A.; Coutard, C.; Dales, C.; Petro,
M.; Carlson, E.; Turner, H. W.; Powers, T. S. Tetrahedron
1999, 55, 11699.
(2) An earlier report described a mixed benzoin condensation on
a solid support yielding benzils in trace amounts (4–6%)
only. However, further reaction of the resin-bound benzils
towards heterocycles was not reported. See: Lenzhoff, C. C.;
Wong, J. Y. Can. J. Chem. 1973, 51, 3756.
(3) (a) Cironi, P.; Tulla-Puche, J.; Barany, G.; Albericio, F.;
Álvarez, M. Org. Lett. 2004, 6, 1405. (b) Cironi, P.;
Manzanares, I.; Albericio, F.; Álvarez, M. Org. Lett. 2003,
5, 2959. (c) Bräse, S.; Köbberling, J.; Griebenow, N.
Organopalladium Reactions in Combinatorial Chemistry, In
Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol. 2; Negishi, E., Ed.; John Wiley and Sons:
New York, 2002, 3031. (d) Ljungdahl, N.; Bromfield, K.;
Kann, N. Top. Curr. Chem. 2007, 278, 89. (e) Nelson, J. C.;
Young, J. K.; Moore, J. S. J. Org. Chem. 1996, 61, 8160.
(f) Erdélyi, M.; Gogoll, A. J. Org. Chem. 2003, 68, 6431.
(4) The solid-phase oxidation of aromatic TMS-protected
acetylenes to a-ketocarboxylic acids with OsO4 and NMO
has been reported recently. See: Le Quement, S. T.; Nielsen,
T. E.; Meldal, M. J. Comb. Chem. 2008, 10, 546.
(5) Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J.-D.;
Alami, M. Tetrahedron 2008, 64, 4287.
(6) (a) Yusubov, M. S.; Filimonov, V. D. Synthesis 1991, 131.
(b) Yusubov, M. S.; Filimonov, V. D.; Vasilyeva, V. P.; Chi,
K.-W. Synthesis 1995, 1234.
(7) Chi, K.-W.; Yusubov, M. S.; Filimonov, V. D. Synth.
LC-MS: 2.20 min, 95% (210 nm), m/z = 253 [M – H–]. 1H
NMR (400 MHz, DMSO-d6): d = 7.63–7.67 (m, 2 H), 7.83
(t, J = 7.60 Hz, 1 H), 7.97 (d, J = 7.72 Hz, 2 H), 8.06 (d,
J = 8.16 Hz, 2 H), 8.15 (d, J = 8.16 Hz, 2 H) ppm; one proton
not observed in this spectrum. 13C NMR (100 MHz, DMSO-
d6): d = 129.60, 129.86, 129.97, 130.04, 132.21, 135.17,
135.81, 136.41, 166.39, 194.21, 194.25 ppm. HRMS: m/z
calcd for C15H11O4 [M + H+]: 255.0652; found: 255.0653.
(13) (a) Debus, H. Liebigs Ann. Chem. 1858, 107, 199.
(b) Radziszewski, B. Ber. Dtsch. Chem. Ges. 1882, 15, 2706.
(14) Trimethyl orthoformate was used instead of molecular sieve
as the dehydrating reagent. See: (a) Look, G. C.; Murphy,
M. M.; Campbell, D. A.; Gallop, M. A. Tetrahedron Lett.
1995, 36, 2937. (b) Quinoxaline synthesis using molecular
sieve: Ott, S.; Faust, R. Synthesis 2005, 3135.
Commun. 1994, 24, 2119.
(8) Wolfe, S.; Pilgrim, W. R.; Garrard, T. F.; Chamberlain, P.
Can. J. Chem. 1971, 49, 2941.
(9) Sieber, P. Tetrahedron Lett. 1987, 28, 6147.
(10) Purities and product identities were determined by LC-MS
analysis using a Hewlett-Packard HP 1100 liquid chroma-
tography system coupled to a Micromass ZMD-400
spectrometer equipped with an Intersil column (ODS-3, 50 ×
2.1 mm). The mobile phase was H2O (A) and MeCN (B),
both containing 0.1% TFA. A gradient was used increasing
from 10–95% B in 9 min followed by a hold at 95% B for 1
min and then re-equilibration for 3 min at a flow rate of 0.5
mL/min. The column was maintained at 35 °C. Mass spectra
were acquired in either the positive or negative ion mode
under electrospray ionization (ESI). The compound purity
was monitored based on the UV absorbency at 210 nm. The
presence of all desired compounds was confirmed by their
molecular mass.
(15) Sarshar, S.; Siev, D.; Mjalli, A. M. M. Tetrahedron Lett.
1996, 37, 835.
(16) Representative Experimental Procedure for the
Synthesis of Quinoxalines
4-[Oxo(phenyl)acetyl]benzoic acid functionalized Wang
Synlett 2010, No. 17, 2639–2643 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of 1,2-Diketones via Acetylene Oxidation
2643
resin (4a, 108 mg, 0.10 mmol, loading of 0.93 mmol/g) was
resin (4a, 215 mg, 0.20 mmol, loading of 0.93 mmol/g) was
suspended in AcOH (3 mL) and charged with benzaldehyde
(420 mg, 20 equiv, 4.00 mmol), and NH4OAc (310 mg, 20
equiv, 4.00 mmol). In case of 7c 40 equiv benzaldehyde, 40
equiv benzylamine, and 1.5 equiv NH4OAc was used. The
reaction mixture was heated to 110 °C for 16 h. The resin
was filtered and washed successively with 50% aq AcOH,
DMF, MeOH, THF, as well as CH2Cl2. The resin was
cleaved with TFA–CH2Cl2 (2 mL, v/v = 1:1) at r.t. for 1 h,
filtered, and washed with CH2Cl2 (1 mL). The filtrate was
evaporated to dryness providing 38 mg of 4-(2,5-diphenyl-
1H-imidazol-4-yl)benzoic acid (7a) in 56% yield.
suspended in TMOF (3 mL) and charged with 2-amino-
aniline (270 mg, 25 equiv, 2.50 mmol). The reaction mixture
was shaken at r.t. for 18 h. The resin was filtered off and
washed successively with DMF, THF, as well as CH2Cl2.
The resin was cleaved with TFA–CH2Cl2 (2 mL, v/v = 1:1)
at r.t. for 1 h, filtered, and washed with CH2Cl2 (1 mL). The
filtrate was evaporated to dryness providing 22 mg of 4-(3-
phenylquinoxalin-2-yl)benzoic acid (6a) in 69% yield.
LC-MS: 5.70 min, 88% (210 nm), m/z = 327 [M + H+]. 1H
NMR (400 MHz, DMSO-d6): d = 7.36–7.43 (m, 3 H), 7.48–
7.50 (m, 2 H), 7.59 (d, J = 8.1, 2 H), 7.90–7.94 (m, 4 H),
8.18–8.20 (m, 2 H), 13.21 (br s, 1 H) ppm. 13C NMR (100
MHz, DMSO-d6): d = 128.16, 128.86, 128.90, 128.94,
129.54, 129.78, 129.89, 130.61, 130.80, 131.31, 138.44,
140.39, 140.62, 142.76, 152.35, 153.06, 167.05. HRMS:
m/z calcd for C21H15O2N2 [M + H+]: 327.1128; found
327.1125. For further analytical data see: van Es, T.;
Backeberg, O. G. J. Chem. Soc. 1963, 1371.
LC-MS: 3.83 min, 69% (210 nm), m/z = 341 [M + H+]. 1H
NMR (400 MHz, DMSO-d6): d = 7.43–7.51 (m, 3 H), 7.52–
7.59 (m 5 H), 7.67 (d, J = 8.60 Hz, 2 H), 7.96 (d, J = 8.60 Hz,
2 H), 8.13 (d, J = 7.45 Hz, 2 H) ppm; two protons not
observed in this spectrum. 13C NMR (100 MHz, DMSO-d6):
d = 126.08, 127.64, 128.27, 128.43, 128.54, 128.74, 128.78,
128.89, 129.18, 129.50, 129.63, 129.89, 130.12, 130.99,
145.24, 166.83. HRMS: m/z calcd for C22H17O2N2 [M + H+]:
341.1285; found: 341.1280.
(17) Representative Experimental Procedure for the
Synthesis of Imidazoles
4-[Oxo(phenyl)acetyl]benzoic acid functionalized Wang
Synlett 2010, No. 17, 2639–2643 © Thieme Stuttgart · New York

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