Cu(ii)-mediated oxidative intermolecular ortho C-H functionalisation using tetrahydropyrimidine as the directing group

Article abstract of DOI:10.1039/b905586j

Tetrahydropyrimidine works efficiently as a directing group in Cu(ii)-mediated oxidative aromatic C-H functionalisation for the selective introduction of oxygen or nitrogen to the ortho-position.

Full text of DOI:10.1039/b905586j

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Cu(II)-mediated oxidative intermolecular ortho C–H functionalisation
using tetrahydropyrimidine as the directing groupw
Tsukasa Mizuhara, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii* and Hiroaki Ohno*
Received (in Cambridge, UK) 19th March 2009, Accepted 6th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b905586j
Tetrahydropyrimidine works efficiently as a directing group in
Cu(II)-mediated oxidative aromatic C–H functionalisation
for the selective introduction of oxygen or nitrogen to the
ortho-position.
C–H functionalisation using amidine or amide as the
directing/nucleophilic group were reported. Herein, we
describe copper-mediated oxidative intermolecular C–H
functionalisation using tetrahydropyrimidine as the directing
group. In most cases, the reaction is complete within 1 h
to provide 2-(tetrahydropyrimidinyl)phenol and aniline
derivatives by the ortho-selective introduction of an oxygen
or nitrogen atom.18
Transition metal-catalysed C–H functionalisation has received
considerable attention in recent years. Notable progress has
been made especially with Pd, Ru, Rh, and Pt catalysts,
which allow atom-economical transformations using simple
substrates. Directing group assisted intra/intermolecular C–H
functionalisation1 is considered to be one of the most promising
approaches as a new carbon–carbon1 or carbon–heteroatom
bond2,3 is selectively formed at a non-functionalised position
proximal to the directing group. Recent research in this area
has revealed that nitrogen-containing functional groups such
as pyridines,4 imines,5 oximes (and ethers),6 oxazolines7 and
amidines8 as well as oxygen-containing functional groups
such as amides,9 esters,10 ketones,11 carboxylic acids12 and
phenols13 effectively act as directing groups for regioselective
C–H functionalisation. These functional groups and their
equivalents are involved in biologically active natural and
synthetic compounds while directing group-assisted C–H
functionalisation serves as a powerful tool for the synthesis
and modification of these molecules.
We initially investigated the reaction conditions for this
C–H hydroxylation (Table 1). In the presence of H2O
(1.0 equiv.), treatment of 2-phenyl-1,4,5,6-tetrahydropyrimidine
(1a) with CuO, Cu(OH)2, Cu(OTf)2 or Cu(tfa)2 (1.0 equiv.) in
DMF at 130 1C under an oxygen atmosphere led to the
recovery of unchanged starting material and the desired C–H
oxidation did not occur (entries 1–4). Using Cu(OAc)2,16a
however, led to the formation of the desired ortho-hydroxylated
compound 2 (ca. 69% yield) although the isolation of 2 in its
pure form was extremely difficult because of its basicity. We
then attempted to isolate 3a as the protected form: after
the disappearance of 1a (monitored by TLC), the reaction
mixture was evaporated in vacuo and treated with triphosgene
Table 1 Optimisation of reaction conditions for C–H hydroxylationa
As part our ongoing program directed toward the
development of C–H functionalisation reactions for the
efficient construction of heterocyclic frameworks,14 we designed
an experiment for the oxidative introduction of a heteroatom
by aromatic C–H functionalisation with the assistance of
an ortho-tetrahydropyrimidinyl group. This group can be
considered as a promising drug-like structure as well as a
synthetic equivalent of a carboxylic group. Reinaud and
co-workers previously reported a copper-catalysed ortho-
hydroxylation reaction of benzoic acid using carboxyl as a
directing group.15 Yu et al.16a and Chatani et al.16b independently
reported copper-mediated oxidative intermolecular C–H
functionalisation using a pyridine moiety as the directing
group. The latter reactions provide efficient access to
functionalised pyridines with a biaryl structure by simply
Entry
Cu salt (equiv.)
Solvent
Time/min
Yield (%)b
1
2
3
4
5
6
7
8
9
CuO (1.0)
DMF
DMF
DMF
DMF
DMF
Acetonitrile
Dioxane
DMF
DMF
DMF
DMF
20
20
20
20
20
60
60
60
15
20
20
N.r.e
N.r.e
N.r.e
N.r.e
61
11
11
30
27
Cu(OH)2 (1.0)
Cu(OTf)2 (1.0)
Cu(tfa)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (0.2)
Cu(OAc)2 (2.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
10c
11cd
70
56
treating the biaryl substrates with
a copper salt for
several hours. More recently, copper-catalysed syntheses of
benzimidazoles17a and benzoxazoles17b by oxidative intramolecular
a
After completion of C–H hydroxylation (monitored by TLC), the
reaction mixture was evaporated and treated with triphosgene
(1.05 equiv.) and Et3N (4.0 equiv.) in CH2Cl2 at 0 1C to rt for
b
c
1
(monitored by TLC), the reaction mixture was treated with TMEDA
h. Isolated yields. After completion of C–H hydroxylation
Graduate School of Pharmaceutical Sciences, Kyoto University,
Sakyo-ku, Kyoto, 606-8501, Japan.
E-mail: hohno@pharm.kyoto-u.ac.jp; Fax: +81 75 753 4570;
Tel: +81 75 753 4571
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectral data. See DOI: 10.1039/b905586j
(4.0 equiv.) at 130 1C for 1 min. In this case, TMEDA (additional
4.0 equiv.) was used for the next step instead of Et3N. Reaction was
d
e
carried out under air. No reaction. Abbreviation: TMEDA =
N,N,N0,N0-tetramethylethylenediamine.
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(1.05 equiv.) and triethylamine (4.0 equiv.) in CH2Cl2 to afford
pure 3a in a yield of 61% (entry 5). When acetonitrile or
dioxane was used as the solvent instead of DMF, yields of 3a
decreased considerably (11%, entries 6 and 7). Lowering the
loading of Cu(OAc)2 to 0.2 equiv. also resulted in a decreased
yield for 3a (30%, entry 8), which indicates low catalyst
efficiency. When using 2.0 equiv. of Cu(OAc)2, the yield
also decreased and this was contrary to our expectation
(27%, entry 9). Considering that the ortho-hydroxylated
product 2 may form a complex with the copper salt, we further
optimised the reaction conditions including the carbonylation
procedure. Initially, N,N,N0,N0-tetramethylethylenediamine
(TMEDA) was added as a bidentate ligand to the oxidative
C–H functionalisation reaction mixture and this resulted
in the complete inhibition of the desired transformation.
Similarly, use of TMEDA instead of triethylamine as the
base for carbonylation did not improve the yield of 3a. On
the other hand, treatment with TMEDA (4.0 equiv.) at 130 1C
for 1 min after the C–H hydroxylation followed by the
carbonylation using additional TMEDA (4.0 equiv.) increased
the yield to 70% (entry 10). The reaction under air resulted in
a decreased yield (56%, entry 11), which indicates that
molecular oxygen participates in the re-oxidation of the
copper catalyst.
Fig. 1 Various amidine analogues.
Scheme 1 C–H amidation with BocNH2 and TsNH2.
Next, we investigated the ability of other amidine analogues
to function as directing groups (Fig. 1). The reaction of the
N-methylated analogue 4 and 2-phenylimidazole 5 did not
produce the desired ortho-hydroxylated products under
standard reaction conditions and the starting materials were
recovered. Interestingly, the five-membered ring amidine in 6
was not effective as a directing group either. These results
suggest that subtle differences in the intermediate formed by a
copper salt and a directing group strongly affect the reactivity
of the substrates.
Using the optimised conditions (Table 1, entry 10), we
examined the reaction of several substituted substrates
(Table 2). Substitution with electron-donating groups such
as methoxy (1b, entry 1) or methyl groups (1c, entry 2) was
tolerated to afford the desired products 3b and 3c in 64% and
61% yields, respectively. The chemoselectivity of this reaction
was evaluated by a reaction where aryl bromide 1d was used
and the desired product 3d was obtained in a 45% yield (entry 3).
Methoxycarbonyl (entry 4) and trifluoromethyl groups (entry
5) had a relatively small effect on the reactivity of these
substrates and the use of the highly electron-deficient arene
1g bearing a nitro group decreased the yield considerably
(19%, entry 6). These results indicate that this reaction is
sensitive to the presence of electron-withdrawing groups on
the aromatic ring. In all cases, reactions without TMEDA
gave less favourable results.
Finally, we investigated C–H amidation (Scheme 1). We
found that the reaction of amidine 1a with Cu(OAc)2
(1.0 equiv.) and tert-butyl carbamate (3.0 equiv.) in DMF
at 100 1C for 40 min directly afforded the tricyclic
aniline derivative (7a) in 53% yield. This reaction occurred
by cyclisation involving the elimination of tert-butoxide.
p-Toluenesulfonamide also reacted with 1a under identical
conditions to afford 7b in 47% yield after alumina
column chromatography19 followed by treatment with
triphosgene–Et3N.
Table 2 Cu-catalysed C–H hydroxylation of 4-substituted 2-phenyl-
1,4,5,6-tetrahydropyrimidinesa
Although the exact mechanism of the ortho C–H oxidation
is unclear, a single electron transfer (SET) pathway via a
radical-cation intermediate16a is supported by the fact that
the presence of an electron-withdrawing group on the benzene
ring considerably decreased the product yields. The observed
ortho-selectivity can be attributed to an intramolecular
transfer of the coordinating group on the copper atom.
In conclusion, we have developed a copper-mediated oxidative
ortho C–H functionalisation using tetrahydropyrimidine as a
directing group. This reaction applies to 2-phenyl-1,4,5,6-
tetrahydropyrimidines having an electron-donating or a weak
electron-withdrawing group and affords the corresponding
phenol derivatives within 1 h. Use of tert-butyl carbamate or
tosylamide instead of H2O promotes the introduction of a
nitrogen functionality to give aniline derivatives. As far as
we are aware, this is the first example of an oxidative
Entry
Substrate (R)
Product
Yield (%)b
1
2
3
4
5
6
1b (OMe)
1c (Me)
1d (Br)
1e (CO2Me)
1f (CF3)
1g (NO2)
3b
3c
3d
3e
3f
64 (53)
61 (54)
45 (37)
46 (43)
43 (38)
19 (16)
3g
a
These reactions were carried out using the optimised procedure
b
(Table 1, entry 10). Isolated yields. Yields in parentheses indicate
those of the reactions containing Et3N (as shown in Table 1, entry 5).
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intermolecular C–H functionalisation using an amidine moiety
as the directing group. Further studies that include an
investigation of the exact reaction mechanism and the
application to synthesis of biologically-active compounds are
now in progress.
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This work was supported by
a Grant-in-Aid for
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