LETTER
Liebeskind–Srogl Thiol Ester–Boronic Acid Cross-Couplings
45
In order to explore the general scope of this novel 5-aroyl- uses commercially available building blocks (aldehydes,
DHPM synthesis a small collection of 12 ketone products boronic acids, ureas) to generate diversity on the DHPM
was generated, using a combination of the five DHPM scaffold that is otherwise not easily available.20 Both steps
thiol esters 2a–e discussed above (Table 1) and five can be carried out efficiently throug the use of controlled
boronic acids (see R3 in Table 2). As can be seen from the microwave irradiation.
isolated yields presented in Table 2 the reaction is very
general, allowing different substitution patterns on the
DHPM scaffold (R1, R2), but also tolerating both electron-
Typical Procedure for the Microwave-Assisted TMSCl-
Promoted Biginelli Reaction (Table 1)
rich and electron-poor aryl boronic acids (R3) as coupling
In a 10 mL Pyrex microwave process vial, the appropriate aldehyde
(0.5 mmol), urea (1.5 mmol), (S)-ethyl thioacetoacetate (0.5 mmol),
and MeCN (0.75 mL) were placed. After the addition of TMSCl
(0.5 mmol) the vessel was sealed and subsequently irradiated for 10
min at 120 °C with magnetic stirring. After cooling to ambient tem-
partners. Without any further optimization of the reaction
conditions, good product yields (61–88%) were obtained
for all cases.
Importantly, the completely neutral, base-free conditions
used here allow total selectivity for the Liebeskind–Srogl perature, the mixture was poured onto crushed ice (10 g) and al-
lowed to stand at r.t. for 18 h. The resulting precipitated solid was
carbon–carbon bond formation (ketone synthesis), with-
collected by filtration and washed with a cold 1:1 mixture of EtOH–
out any Suzuki coupling (biaryl synthesis) being observed
H2O, providing the desired DHPM products 2a–e in 53–90% yield
for cases where ‘Suzuki-active’ aryl bromides are incor-
and high purity (>98% by HPLC).
porated on the scaffold (DHPMs 1f–h).9,19
Typical Procedure for the Liebeskind–Srogl DHPM Ketone
Synthesis (Table 2)
Finally, we were interested in performing Liebeskind–
Srogl-type bis-couplings on a DHPM substrate that con-
tained two independent carbon–sulfur connections. In a
recent study, we demonstrated that direct Pd(0)-catalyzed/
Cu(I)-mediated carbon–carbon cross-coupling of 3,4-
dihydropyrimidine-2-thiones and boronic acids under
A dry microwave process vial was charged with the corresponding
DHPM 2 (0.15 mmol), the appropriate boronic acid (0.3 mmol),
CuTC (0.45 mmol), Pd(OAc)2 (10 mol%) and PPh3 (20 mol%).
Then the reaction vessel was sealed and flushed with Ar. Through
the septum of the microwave vessel, anhyd and degassed dioxane (1
Liebeskind–Srogl conditions leads to 2-aryl-1,4-dihydro- mL) was added and the mixture was subsequently heated for 1 h at
pyrimidines.13 In order to evaluate the potential to com-
130 °C using microwave irradiation. After cooling to ambient tem-
perature, the solvent was evaporated and the crude mixture diluted
bine both carbon–carbon bond-forming events in a one-
with EtOAc (50 mL) and extracted with 10% aq NH3 (3 ꢀ 15 mL).
The organic layer was dried over MgSO4 and then concentrated
under reduced pressure to afford a semisolid that was subsequently
pot reaction, a suitable 2-thioxo-1,2,3,4-tetrahydropyr-
imidine-5-carboxylic acid thiol ester was synthesized and
treated with excess of phenylboronic acid using our stan-
dard Liebeskind–Srogl conditions (Scheme 2). In the
event, microwave irradiation of a reaction mixture con-
taining pyrimidine-2-thione thiol ester 3, 4.0 equivalents
of phenylboronic acid, 15 mol% of Pd(OAc)2, 30 mol% of
PPh3 and 5.0 equivalents of CuTC in anhydrous dioxane
provided bis-coupling product 4 in 55% (non-optimized)
isolated yield after purification by column chromatogra-
phy.
purified by silica gel column chromatography, using a 5:1 mixture
of CHCl3–acetone or CHCl3–PE eluent. This procedure provides
the pure ketones 1a–l in 61–88% yield. Spectroscopic data for 1a:
C18H16N2O2, white solid, mp 212–213 °C (lit.20e mp 214–216 °C).
1H NMR (360 MHz, DMSO-d6): d = 1.66 (s, 3 H), 5.29 (s, 1 H),
7.19–7.24 (m, 3 H), 7.28–7.33 (m, 2 H), 7.42–7.43 (m, 4 H),
7.49–7.53 (m, 1 H), 7.80 (s, 1 H), 9.17 (s, 1 H). MS (pos APCI):
m/z = 353. All compounds were fully identified by NMR and MS
analysis.
Acknowledgment
O
Ph
Ph
O
This work was supported by the Austrian Academic Exchange
Service (OeAD). L. P. thanks the University of Bari for financial
support. We thank also Biotage AB (Uppsala, Sweden) for the
provision of the Emrys Synthesizer and Initiator Eight.
EtS
NH
H
O
TMSCl, MeCN
EtS
NH2
+
Me
N
H
S
MW, 120 °C, 10 min
Me
O
H2N
S
3 (90%)
O
Ph
PhB(OH)2
Pd(OAc)2, PPh3, CuTC
dioxane
References and Notes
Ph
N
(1) (a) Transition Metals for Organic Synthesis; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004. (b) Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
(2) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2457.
(3) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
MW, 130 °C, 1 h
Me
N
H
Ph
4 (55%)
Scheme 2 Liebeskind–Srogl-type bis-couplings
(4) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400.
(5) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2000, 2, 3229.
In conclusion, we have developed a two-step protocol for
the synthesis of diversely substituted 5-aroyl-3,4-dihydro-
pyrimidine-2-ones 1, combining a Biginelli multicompo-
nent approach with the transition-metal-catalyzed
Liebeskind–Srogl ketone synthesis. This novel method
Synlett 2007, No. 1, 43–46 © Thieme Stuttgart · New York