Angewandte
Chemie
closely related compounds with (hetero)arenes under
metal[16–20] or acid[21] catalysis. However, the corresponding
reactions of a-diazo-1,3-dicarbonyl compounds are less
common,[16d,e,22,23] and to the best of our knowledge, no
reports of transition-metal-catalyzed couplings between 5-
diazobarbituric acids and arenes exist.[24] Indeed, despite the
biological significance of barbiturates, catalytic transforma-
tions of 5-diazobarbituric acids appear to be restricted to the
cyclopropanation of styrenes.[25] Interestingly, these reactions
were conducted in fluorobenzene, but no products resulting
[25]
À
from arene C H insertion were observed.
Given these
observations, the success of our proposed method was far
from certain.
Fortunately, we discovered that just 0.1 mol% of com-
mercially available [Rh2(esp)2][26] smoothly catalyzed the
coupling of 5-diazo-1,3-dimethylbarbituric acid (1a) with
benzene at room temperature to give 2a in 77% yield
(Scheme 2).[27] Further studies showed that a range of
monosubstituted arenes were tolerated (2b–2h). These
reactions were performed with no precautions to exclude air
or water, and the inexpensive arenes were used as the solvent.
The products were formed with moderate to excellent
regioselectivities and, with the exception of 2b and 2ka,
were isolated as mixtures of two regioisomers[28] after
chromatography. In most cases, recrystallization allowed for
isolation of the pure para isomer (see the Supporting
Information for details). Electron-rich arenes reacted with
1a to provide 2b–2d in good yields. With toluene, no products
from benzylic C H insertion were observed.[27] Use of a small
À
excess of anisole (1.2 equiv) resulted in a reduced (but
synthetically useful) 64% yield of 2c owing to a lower
conversion, attributable to inefficient mixing of the reagents.
Fluorobenzene reacted smoothly to give 2 f in 78% yield,
further demonstrating that relatively electron-neutral arenes
(Hammett constant sp of F: 0.06)[29] are effective. Chloro- and
bromobenzene were also surprisingly effective (2g and 2h),
despite being deactivated substrates (sp of Cl and Br: 0.23).[29]
Even trifluoromethoxybenzene (sp of OCF3: 0.35)[29] gave 2e
in good yield, albeit in a 4:1 regioisomeric ratio. Arenes with
meta-directing substituents, such as CF3, CN, CO2Me, or NO2
groups, were unsuitable, but disubstituted arenes, such as
meta-xylene and 1,3-dimethoxybenzene, reacted with 1a to
give 2i and 2j in high regioselectivities. The reactions of
ortho-xylene and 1,2-dimethoxybenzene were high-yielding,
but less regioselective (2ka and 2l). With ortho-xylene, the
minor regioisomer 2kb (see the Supporting Information for
the structure) was also isolated in 14% yield. 1-Methylindole
reacted smoothly to give 5-(3-indolyl)barbituric acid 3 in 73%
yield [Eq. (1)].[16]
Scheme 2. Rhodium(II)-catalyzed arylation of 5-diazobarbituric acid
1a. Reactions were conducted with 2.00 mmol of 1a in 2.0 mL of the
arene. r.r. = regioisomeric ratio as determined by 1H NMR analysis of
the unpurified reaction mixture. Yields are of isolated mixtures of
inseparable regioisomers in the same ratio as in the unpurified
mixtures. [a] Isolated as a single regioisomer. [b] Conducted with
3.00 mmol of 1a and 3.60 mmol of anisole. [c] Isolated as a 15:1
mixture of regioisomers. [d] Conducted with 1.00 mmol of 1a in
1.0 mL of the arene. [e] Conducted at 308C for 7 h. [f] Isolated as
a 10:1 mixture of regioisomers. [g] The minor isomer 2kb was isolated
in 14% yield.
whether N alkylation is essential, given that most biologically
À
active barbiturates are not 1,3-dialkylated, and free N H
groups might be expected to undergo insertion reactions with
a rhodium carbenoid. Remarkably, this concern was unwar-
ranted; 5-diazo-1-methylbarbituric acid 1b reacted with
anisole to provide 4a in 68% yield (entry 1), whereas
À
5-diazobarbituric acid 1c, which bears two free N H groups,
gave 4b in 93% yield (entry 2). Coupling of 1c with diphenyl
ether using 0.25 mol% of [Rh2(esp)2] at 1208C gave 4c in
excellent yield with good isomeric purity. Compound 4c is an
important precursor to biologically active barbitur-
ates.[4b,e,f, 5b,c]
A thiocarbonyl group was also tolerated
(entry 4), but our conditions did not provide good results
when applied to other a-diazo-1,3-dicarbonyl compounds.[30]
To further demonstrate the advantages of our method, we
synthesized the potent and selective MMP inhibitor 8 (IC50:
Our focus now turned to the variation of the 5-diazo-
barbituric acid (Table 1). The first question to address was
Angew. Chem. Int. Ed. 2015, 54, 7410 –7413
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7411