Switching the regioselectivity of direct C-H arylation of 1,3-Dimethyluracil

Article abstract of DOI:10.1002/ejoc.200900586

An interesting dichotomy in the regioselectivity and mechanism of direct C-H arylation of 1,3-dimethyluracil was observed. Its Pd-catalyzed reactions with diverse aryl halides in the absence of Cui lead preferentially to 5-aryluracils, while reactions in

Full text of DOI:10.1002/ejoc.200900586

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900586
Switching the Regioselectivity of Direct C–H Arylation of 1,3-Dimethyluracil
[a]
[a]
[a]
ˇ
ˇ
Miroslava Cernová, Radek Pohl, and Michal Hocek*
Keywords: Pyrimidines / C–H arylation / Regioselectivity / Cross-coupling / Copper
An interesting dichotomy in the regioselectivity and mecha-
nism of direct C–H arylation of 1,3-dimethyluracil was ob-
served. Its Pd-catalyzed reactions with diverse aryl halides in
the absence of CuI lead preferentially to 5-aryluracils, while
reactions in the presence of CuI give 6-aryl derivatives as the
major products. Cu-mediated reactions (in the absence of a
Pd catalyst) proceed with lower efficiency but give exclu-
sively 6-aryluracil derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
which generated an aryl cuprate that then underwent cross-
coupling with an aryl halide (either Pd-catalyzed or noncat-
alyzed Ullmann type coupling). While electron-rich hetero-
cycles are usually excellent substrates for C–H arylation,
electron-poor heterocycles (i.e. pyridines or pyrimidines)
have a lower reactivity, and their corresponding N-oxides
are used instead for the C–H arylations.[8] Apart from Cu-
mediated Pd-catalyzed reactions, Pd-free arylations are also
reported[9] in the presence of excess Cu salts, but usually
such reactions are less efficient.
Introduction
Uracil bases and nucleosides bearing aryl groups in posi-
tions 5 or 6 are an important class of compounds displaying
diverse biological activities[1] (cytostatic, antiviral, antago-
nists of GnRH, etc.). In addition, arylation in position 5 is
often used for labeling of nucleotides, oligonucleotides, and
DNA for applications in bioanalysis or chemical biology.[2]
The 5- or 6-aryluracils can be prepared by heterocycli-
zation[3] or by cross-coupling reactions[4] of halouracils with
arylboronic acids or -stannanes or of metalated uracils with
aryl halides. However, some aryluracils are still difficult to
prepare and, therefore, development of alternative method-
ologies is of interest.
Direct C–H arylations have recently emerged as an alter-
native to cross-couplings. Extensive research has resulted in
the development of efficient methodologies for C–H aryl-
ation of diverse aromatics and heterocycles.[5–8] Although a
number of transition-metal complexes were used as cata-
lysts, Pd complexes are the most versatile catalysts, success-
ful in most cases. The reactions are performed either in the
presence or in the absence of CuI salts. The Cu-free reac-
tions were proved to proceed by a concerted metalation–
deprotonation (CMD) mechanism,[6] which consists of the
oxidative addition of the aryl halide to the Pd catalyst and
attack of the resulting complex at the arene C–H bond with
the assistance of a base to simultaneously cleave the C–H
bond and form a C–Pd bond, followed by reductive elimi-
nation to afford the biaryl product. On the other hand, in
several Cu-mediated reactions, direct metalation of the ar-
ene C–H bond by a base and copper salt was observed,[7]
Recently, we have developed Pd-catalyzed C–H aryl-
ations of purine bases and nucleosides to position 8 in the
[10]
presence of CuI and Cs2CO3
and Ir-catalyzed C–H bo-
rylations of 7-deazapurines.[11] In order to extend the use of
C–H arylations in nucleoside/nucleic acid chemistry, we
have tried to develop the C–H arylation of 1,3-dimethyl-
uracil as a model compound for uracil bases and nucleo-
sides. So far, only one example of an intramolecular C–H
arylation of related compounds that leads to fused hetero-
cycles has been reported,[12] during the course of our study.
Results and Discussion
1,3-Dimethyluracil (1) was selected as a model com-
pound for pyrimidine nucleobases and nucleosides. It con-
tains two C–H bonds capable of arylation – positions 5 and
6. Position 5 is known to be the preferred site for electro-
philic substitution,[3] while C–H in position 6 is more acidic
and undergoes metalation.[4] The direct C–H arylation of 1
was optimized with the reaction with p-tolyl iodide (2a) by
using Pd(OAc)2 in combination with diverse ligands and
with varying amounts of CuI in the presence of Cs2CO3
(Scheme 1, Table 1). The ligand-free conditions, in analogy
to the arylation of purines[10] at 160 °C (Entry 1), gave mod-
erate conversion to a mixture of 5-tolyl (3a) and 6-tolyl (4a)
derivatives in a 1:4 ratio. The regioisomers were separable
only by repeated flash chromatography and were assigned
by HMBC NMR spectroscopy (see Supporting Infor-
[a] Institute of Organic Chemistry and Biochemistry
Academy of Sciences of the Czech Republic
Gilead Sciences & IOCB Research Center
Flemingovo nam. 2, 16610 Prague 6, Czech Republic
Fax: +420-220183559
E-mail: hocek@uochb.cas.cz
Homepage: http://www.uochb.cas.cz/hocekgroup
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900586.
3698
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3698–3701

Switching the Regioselectivity of Direct C–H Arylations
mation). When using the PPh3 ligand at 140 °C, the yield use of CuI in the presence of phenanthroline as ligand (in
was lower and the ratio 3a/4a was 1:19 (Entry 2). The use analogy to recent Cu-mediated C–H arylation of caf-
of (tBu)2PMe[13] in the absence of CuI at 130 °C gave quan- feine[9b]), but these conditions gave a low conversion (Entry
titative conversion to an almost equimolar mixture 3a/4a.
15).
Three different procedures were further utilized in pre-
parative experiments with diverse aryl halides: (A)
Pd(OAc)2 in combination with P(perFPh)3 in the absence
of CuI, (B) the same reagents but in the presence of 3 equiv.
CuI, and (C) CuI in the absence of Pd catalyst and ligand
(Scheme 2, Table 2). The reactions with pTol-I (2a), o-Tol-I
(2b), 4-MeOPh-I (2c), and Ph-I (2d) under conditions A
gave 5-aryluracils 3a–d as the major products in 54–80%
yields (Entries 1, 4, 7, and 10), while under conditions B,
the selectivity was reversed to afford 6-aryl derivatives 4a–
d as the major products in 54–72% yields (Entries 2, 5, 8,
and 11). In all cases, minor amounts of the other re-
gioisomer were isolated. Conditions C generally gave lower
conversions but a high regioselectivity to give 6-substituted
uracils 4a–d as the only products (35–59% yields). Two aryl
bromides (2e,f) were also successfully used for the C–H
arylation of 1 under the same conditions (Entries 13–18) to
show similar conversions and selectivity (with the exception
of the reaction of 2e under conditions B, which gave 4e
as the only product). Electron-poor aryl iodides (1-iodo-4-
nitrobenzene, 4-iodobenzonitrile, 3-iodopyridine, 5-iodo-
uracil, 5-iodo-1,3-dimethyluracil) were also tried in these re-
actions under conditions A–C, but in all cases, no reactions
(or very low conversions Ͻ10%) were observed. Apparently
this methodology is only applicable to electron-rich and
neutral aryl halides. No product of 5,6-diarylation was ob-
served in any of those reactions, and also additional experi-
ments of further arylation of 5-aryluracil 3a under condi-
tions B and arylation of 6-aryluracil 4a under conditions A
with another aryl iodide (2c) did not proceed. The second
C–H arylation probably does not proceed because of steric
reasons.
Scheme 1. C–H arylation of 1 with Tol-I.
Table 1. Optimization of conditions of C–H arylation of 1.
Entry Ligand
CuI
T
Conversion Ratio 3a/4a
[equiv.]
[°C]
[%]
1
2
3
4
5
6
7
8
–
3
3
–
1
3
–
3
3
3
–
0.1
1
3
3
160
140
130
130
160
130
130
160
160
160
160
160
160
160
140
53
31
99
56
62
57
72
68
53
62
62
50
78
35
22
20:80
5:95
PPh3
[a]
[a]
(tBu)2PMe·HBF4
(tBu)2PMe·HBF4
(tBu)2PMe·HBF4
P(tBu)3·HBF4[a]
P(tBu)3·HBF4[a]
P(oTol)3
55:45
31:69
19:81
62:38
14:86
22:78
9:91
86:14
86:14
24:76
6:94
9
P(p-FPh)3
10
11
12
13
14
15
P(perFPh)3
P(perFPh)3
P(perFPh)3
P(perFPh)3
[b]
–
0:100
4:96
phenanthroline[b,c]
0.2
The dichotomy of the reaction regioselectivity clearly in-
dicates different reaction mechanisms in each case. While
the reactions in the absence of CuI presumably proceed
[a] Pd(OAc)2 (0.1 equiv.), ligand (0.2 equiv.). [b] In the absence of
Pd(OAc)2. [c] K2CO3, DMF/m-xylene (1:1).
Interestingly, addition of 1 or 3 equiv. CuI dramatically through the CMD mechanism[6] and thus follow the re-
lowered the yield (to 56 and 62%, respectively), but in- gioselectivity of electrophilic substitution (position 5), the
creased the selectivity of 4a (Entries 3–5). The use of reactions in the presence of CuI most likely proceed
P(tBu)3 at 130 °C in the absence of CuI gave 57% conver- through cupration[7] of the heterocycle in the position of
sion to a ca.2:1 mixture of 3a/4a, while in the presence of the more acidic H (position 6). The reaction in the absence
CuI, the ratio was switched to ca. 1:6 (Entries 6 and 7). A of a Pd catalyst, which proceeds through an Ullmann cou-
similar result was obtained when using P(o-Tol)3 or pling, is less efficient (but more selective) than reactions in
[14]
P(p-FPh)3 in the presence of CuI (ratio 1:4 or 1:10, En- the presence of Pd(OAc)2 and ligand. This shows that Pd
tries 8 and 9). P(perFPh)3 was then used as a ligand in a catalysis does occur even in the presence of CuI and in-
series of experiments with varying amounts of CuI (Entries creases the efficiency of those reactions.
10–13). Reactions in the absence or with 0.1 equiv. CuI gave
a decent (62%) conversion to a ca. 6:1 mixture of 3a/4a,
while in the presence of 1 or 3 equiv. CuI, the reaction af-
forded 4a as the major product (ratios 1:3 and 1:16, respec-
Conclusions
tively). When the reaction was performed in the presence of
Pd-catalyzed and/or Cu-mediated direct C–H arylations
3 equiv. CuI and in the absence of any Pd catalyst and li- of 1,3-dimethyluracil with diverse electron-rich aryl halides
gand (Entry 14), the conversion was lower but the reaction were developed. Reactions in the absence of CuI provide 5-
was fully regioselective to give only the product of C6-aryl- aryluracils 3 as the major products, while the reactions in
ation (4a). The last optimization experiment involved the the presence of CuI preferentially give 6-aryluracils 4. Fur-
Eur. J. Org. Chem. 2009, 3698–3701
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3699

ˇ
M. Cernˇová, R. Pohl, M. Hocek
SHORT COMMUNICATION
Scheme 2. Preparative C–H arylations of 1.
Table 2. C–H arylations of 1 with diverse aryl halides.
7.20 (m, 2 H, m-C6H4CH3-H), 7.26 (s, 1 H, 6-H), 7.39 (m, 2 H, o-
C6H4CH3-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 21.17
(CH3-p); 28.23 (CH3, C-3), 37.06 (CH3, C-1), 114.41 (C-5), 128.12
(CH-o-C6H4CH3), 129.14 (CH-m-C6H4CH3), 129.90 (C-i-
C6H4CH3), 137.73 (C-p-C6H4CH3), 139.93 (CH, C-6), 151.48 (C-
2), 162.41 (C-4) ppm. IR: 2921, 2853, 1688, 1643, 1515, 1448, 1431,
1408, 1350, 1208, 1125. MS (EI): m/z (%) = 77 (14), 104 (36), 116
(38), 132 (57), 145 (19), 158 (17), 172 (56), 230 (100) [M]. HRMS:
calcd. for C13H14N2O2 [M] 230.1055; found 230.1053. C13H14N2O2
(230.3): calcd. C 67.81, H 6.13, N 12.17; found C 67.71, H 6.15, N
12.05.
ther developments of the methodology for the synthesis of
libraries of substituted uracils and for the synthesis of pyr-
imidine nucleosides are underway.
Experimental Section
General Procedure for C–H Arylation (Methods A and B): DMF
(3 mL) was added through a septum to an argon purged vial con-
taining 1,3-dimethyluracil (1, 70 mg, 0.5 mmol), aryl halide (2a–
h, 1 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), P(perFPh)3 (26.6 mg,
0.05 mmol), and Cs2CO3 (407 mg, 1.25 mmol) in the absence
(Method A) or in the presence (Method B) of CuI (286 mg,
1.5 mmol). The reaction mixture was stirred at 160 °C for 50 h.
After cooling to room temperature, the mixture was diluted with
chloroform (20 mL), and the solvents were evaporated under re-
duced pressure. A mixture of C-5 and C-6 substituted products
were isolated by column chromatography (hexanes/ethyl acetate,
8:2). A second flash column chromatography (hexanes/THF, 8:2)
was used to separate the isomers.
4a: Method B, yield 83 mg (72%). M.p. 105–107 °C. 1H NMR
(499.8 MHz, CDCl3): δ = 2.42 (s, 3 H, CH3-p), 3.23 (s, 3 H, CH3,
1-H), 3.41 (s, 3 H, CH3, 3-H), 5.69 (s, 1 H, 5-H), 7.22 (m, 2 H, o-
C6H4CH3-H), 7.29 (m, 2 H, m-C6H4CH3-H) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 21.35 (CH3-p), 28.00 (CH3, C-3), 34.57
(CH3, C-1), 102.36 (CH, C-5), 127.67 (CH-o-C6H4CH3), 129.59
(CH-m-C6H4CH3), 130.48 (C-i-C6H4CH3), 140.46 (C-p-C6H4CH3),
152.76 (C-2), 154.76 (C-6), 162.51 (C-4) ppm. IR: 2923, 2854, 1702,
1651, 1618, 1514, 1456, 1430, 1390, 1368, 1185, 1007 cm–1. MS
(EI): m/z (%) = 65 (14), 77 (11), 82 (25), 91 (30), 101 (10), 105 (19),
116 (30), 132 (93), 144 (30), 158 (6), 172 (60), 202 (7), 230 (100)
3a: Method A, yield 62 mg (54%), white crystals from CHCl3/n-
heptane. M.p. 162–163 °C. 1H NMR (499.8 MHz, CDCl3): δ = 2.36
(s, 3 H, CH3-p), 3.42 (s, 3 H, CH3, 3-H), 3.47 (s, 3 H, CH3, 1-H), [M]. HRMS: calcd. for C13H14N2O2 [M] 230.1055; found 230.1053.
3700 Eur. J. Org. Chem. 2009, 3698–3701
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Switching the Regioselectivity of Direct C–H Arylations
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Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for all other compounds and copies of
NMR spectra are given.
Acknowledgments
This work was supported by the Academy of Sciences of the Czech
Republic (Z4 055 0506), by the Ministry of Education (LC06077),
and by Gilead Sciences, Inc. (Foster City, CA, U. S. A.).
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Received: May 28, 2009
Published Online: June 24, 2009
Eur. J. Org. Chem. 2009, 3698–3701
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3701