Tunable carbon-carbon and carbon-sulfur cross-coupling of boronic acids with 3,4-dihydropyrimidine-2-thiones

Article abstract of DOI:10.1021/ol036496h

Direct microwave-assisted Pd(0)-catalyzed/Cu(I)-mediated carbon-carbon cross-coupling of 3,4-dihydropyrimidine-2-thiones and boronic acids under Liebeskind-Srogl conditions leads to 2-aryl-1,4-dihydropyrimidines in moderate to high yield. In contrast, Cu(

Full text of DOI:10.1021/ol036496h

ORGANIC
LETTERS
2004
Vol. 6, No. 5
771-774
Tunable Carbon−Carbon and
Carbon−Sulfur Cross-Coupling of
Boronic Acids with
3,4-Dihydropyrimidine-2-thiones
Alenka Lengar and C. Oliver Kappe*
Institute of Chemistry, Karl-Franzens-UniVersity Graz, Heinrichstrasse 28,
A-8010 Graz, Austria
oliVer.kappe@uni-graz.at
Received December 23, 2003
ABSTRACT
Direct microwave-assisted Pd(0)-catalyzed/Cu(I)-mediated carbon−carbon cross-coupling of 3,4-dihydropyrimidine-2-thiones and boronic acids
under Liebeskind−Srogl conditions leads to 2-aryl-1,4-dihydropyrimidines in moderate to high yield. In contrast, Cu(II)-mediated reaction of
the same substrates leads to carbon−sulfur cross-coupling.
Transition metal-catalyzed carbon-carbon cross-coupling
procedures have revolutionized the art and practice of organic
synthesis in the last two decades.1 The generally mild reaction
conditions, high functional group tolerance, and broad
availability of starting materials have contributed to the
growing success of, e.g., Pd-catalyzed carbon-carbon bond
formation methods. Among the many different cross-coupling
procedures known today, protocols involving boronic acids
as coupling partners have gained momentum in recent years.2
The large number of arylboronic acids that are commercially
available makes this type of coupling chemistry highly
attractive in the context of high-throughput synthesis and
scaffold decoration. In addition, boronic acids are air and
moisture stable and of relatively low toxicity, and the boron-
derived byproducts can easily be removed from the reaction
mixture. Apart from the well-known Suzuki-Miyaura biaryl
cross-coupling,3 a number of related transition metal-
catalyzed C-C,4 C-O,5 C-S,6 and C-N7 coupling protocols
have recently been reported in the literature, underpinning
the versatility and importance of boronic acids as building
blocks in organic synthesis.2
Recently, Liebeskind and Srogl developed a novel carbon-
carbon cross-coupling protocol, involving the Pd(0)-cata-
lyzed, Cu(I)-mediated coupling of thioether-type species with
boronic acids under neutral conditions (Scheme 1).8,9 A key
feature of these protocols is the requirement of stoichiometric
amounts of a Cu(I) carboxylate (e.g., Cu(I) thiophene-2-
(3) Suzuki, A.; Miyaura, N. Chem. ReV. 1995, 95, 2457.
(4) (a) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J.
Org. Chem. 1998, 63, 4726. (b) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou,
K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358.
(5) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(6) (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2,
2019. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309.
(7) (a) Bakkestuen, A. K.; Gundersen, L.-L. Tetrahedron Lett. 2003, 44,
3359. (b) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623.
(8) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(b) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (c) Kusturin, C. L.;
Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983. (d) See also:
Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G.
Synlett 2002, 447.
(1) (a) Diedrich, F.; Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Hassan, J.; Sevignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(2) (a) Tyrell, E.; Brookes, P. Synthesis 2003, 469. (b) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11. (c) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400.
10.1021/ol036496h CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/06/2004

use of the sometimes more effective catalytic system Pd2-
dba3/tris(2-furyl)phosphine (TFP)8-10 did not improve the
yield. It has to be noted that all previously reported studies
on thioether-boronic acid cross-coupling reactions have been
limited to the use of either heteroaromatics or fully N-
protected/substituted isothiourea systems. In fact, Liebeskind
and co-workers note8c that couplings involving isothioureas,
where, e.g., Z ) NH-Boc (see Scheme 1), are troublesome
and difficult to optimize, providing only low yields of the
desired amidine products. Despite the disappointingly low
yields in our initial experiments, we decided to increase the
efficiency of the Liebeskind-Srogl-type couplings 1 f 2
further, utilizing microwave dielectric heating conditions.
In the past few years, the utilization of controlled
microwave heating in transition metal-catalyzed transforma-
tions has attracted considerable interest.14 Many Pd-, Cu-,
or Mo-catalyzed reactions that typically need hours or days
to reach completion with conventional heating can sometimes
be brought to full conversion in only minutes utilizing
microwave heating.14
Applying controlled single-mode microwave heating (MW)
in sealed vessels, the reaction conditions were refined with
respect to the solvent, the type and concentration of the Pd-
(0) catalyst, the number of equivalents of the CuTC cofactor,
the amount of boronic acid, and the reaction temperature
and irradiation time. One of the best substrate/catalyst
concentrations utilized 1.2-1.5 equiv of phenylboronic acid,
3-5 mol % Pd(PPh3), and 3.0 equiv of CuTC in THF. The
cleanest conversions 1a,b f 2a,b (monitored by HPLC) were
achieved by exposing the reaction mixtures to 130 °C for
25 min. Higher reaction temperatures resulted in more
byproduct formation, while shorter reaction times led to
incomplete conversions. 1,4-Dihydropyrimidines 2a and 2b
were isolated in 82 and 86% yields, respectively, and
identified by spectroscopic analysis and comparison of
spectroscopic and analytical data with literature values.15
The above results clearly indicate the potential for enhanc-
ing sluggish Liebeskind-Srogl-type couplings (Scheme 1)
by controlled microwave irradiation. Since most published
examples require 16-18 h of heating under conventional
reflux conditions,8-10 the considerably shortened reaction
Scheme 1. Thioorganics-Boronic Acid Cross-Coupling
Reactions
carboxylate, CuTC) as a metal cofactor. Due to the higher
thiophilicity of the soft Cu(I) metal, selective sulfide coupling
under Liebeskind-Srogl conditions can be performed even
in the presence of, e.g., a Suzuki-active bromide.10
In the context of our ongoing research devoted to the
generation of biologically active dihydropyrimidine scaf-
folds,11 we were intrigued by the possibility of applying a
thioether-boronic acid coupling strategy toward an efficient
synthesis of combinatorial libraries of 2-aryl-1,4-dihydro-
pyrimidines. This basic heterocyclic scaffold displays a range
of interesting pharmacological properties. A recent highlight
in this context has been the disclosure of Bay 41-4109, Bay
39-5493, and related 2-(hetero)aryl-substituted dihydropy-
rimidines, which are highly potent nonnucleosidic inhibitors
of hepatitis B virus replication that have in vitro and in vivo
antiviral activity.12
As a starting point in our studies we have investigated
the coupling of 2-methylthio-1,4-dihydropyrimidine-5-car-
boxylates 1a,b13 with phenylboronic acid under standard
Liebeskind-Srogl conditions (Scheme 2).8 Refluxing a
(9) For related, non-boronic acid couplings, see: (a) Egi, M.; Liebeskind,
L. S. Org. Lett. 2003, 5, 801. (b) Wittenberg, R.; Srogl, J.; Egi, M.;
Liebeskind, L. S. Org. Lett. 2003, 5, 3033. (c) Alphonse, F.-A.; Suzenet,
F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803.
(10) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer,
B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349.
Scheme 2. Microwave-Assisted Liebeskind-Srogl Couplings
(11) For reviews, see: (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
(b) Kappe, C. O. QSAR Comb. Sci. 2003, 22, 622.
(12) Deres, K.; Schro¨der, C. H.; Paessens, A.; Goldmann, S.; Hacker,
H. J.; Weber, O.; Kraemer, T.; Niewoehner, U.; Pleiss, U.; Stoltefuss, J.;
Graef, E.; Koletzki, D.; Masantschek, R. N. A.; Reimann, A.; Jaeger, R.;
Groâ, R.; Beckermann, B.; Schlemmer, K.-H.; Haebich, D.; Ru¨bsamen-
Waigmann, H. Science 2003, 299, 893.
(13) (a) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26, 55.
(b) Atwal, K.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.;
Gougoutas, J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990, 33,
1510.
(14) For a recent review, see the following: Larhed, M.; Moberg, C.;
Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (b) For general references on
microwave-assisted organic synthesis, see: Microwave-Assisted Organic
Synthesis (MAOS) Webpages. http://www.maos.net.
(15) (a) Kuno, A.; Sugiyama, Y.; Katsuta, K.; Kamitani, T.; Takasugi,
H. Chem. Pharm. Bull. 1992, 40, 1452. (b) Weis, A. L. Synthesis 1985,
528.
solution of the heterocycle-SMe ether 1a with phenylboronic
acid (1.25 equiv), Pd(PPh3)4 (5 mol %), and 2 equiv of CuTC
in THF (Ar atmosphere) for 18 h provided the desired
coupling product 2a in 18% isolated yield. In our hands, the
772
Org. Lett., Vol. 6, No. 5, 2004

18
times and high yields utilizing microwave heating represent
a clear improvement.
phosphine (TFP)8-10 or Pd2dba3/tBu3P‚HBF4 did not pro-
vide a further improvement, and Pd(OAc)2 (5 mol %) was
significantly less effective (60% isolated product yield).
Importantly, the presence of the Cu(I) cofactor, Cu(I)
thiophene-2-carboxylate (CuTC) was essential. In the absence
of CuTC, product 2a was not observed in any significant
amount in the reaction mixture. Although the mechanism of
the transformation 3a f 2a has not been investigated further,
this result serves as an indication of the mechanistic
similarities between the traditional Liebeskind-Srogl thio-
ether-boronic acid couplings (Schemes 1 and 2) and the
process depicted in Scheme 3. We also note that an inert
On the basis of the successful coupling of thioethers 1a,b
with phenylboronic acid described above, we next considered
a further simplification in our strategy toward synthesizing
Bay 41-4109 analogues. Dihydropyrimidine-2-thiones of
type 3 (DHPMs) are readily available by Biginelli three-
component condensation of aldehydes, CH-acidic carbonyl
compounds, and thioureas (see also Table 1).11,16 In the first
Table 1. Preparation of 2-Aryl-1,4-dihydropyrimidines 6 via
Carbon-Carbon Coupling of DHPM 5 with Arylboronic Acidsa
Scheme 3. Microwave-Assisted Boronic Acid-Thioamide
Couplings
atmosphere, preventing the oxidation of the Cu(I) cofactor,8-10
was required in order to achieve high yields.
To the best of our knowledge, there is no literature
precedent for a direct carbon-carbon cross-coupling of
boronic acids with thioamides (or thioureas) as shown in
Scheme 3. On the contrary, one may intuitively expect the
corresponding 2-phenylthio-1,4-dihydropyrimidine derivative
4 (carbon-sulfur coupling) as the product from this trans-
formation. There are several reports of related thiol/thio-
amide-boronic acid coupling protocols in the literature, albeit
reported to be stoichiometric in Cu(II).6,7a,19 Careful inves-
entry ArB(OH)2, Ar ) Pd(PPh3)4 time (min) yield (%)b
6a
6b
6c
6d
6e
Ph
4-ClPh
3-MePh
2,6-(F2)Ph
2-thiophene
3 mol %
3 mol %
5 mol %
8 mol %
6 mol %
30
25
30
60
50
61
71
82
26
14
1
tigation of the H/13C NMR and MS data, in addition to
a Reaction conditions: 1.5 equiv of ArB(OH)2, 3 equiv of CuTC, THF,
Ar, 100 °C controlled microwave irradiation/sealed vessel. For further
details, see Supporting Information. b Isolated yield after flash chromatog-
raphy.
comparison with authentic material obtained by the conven-
tional Liebeskind-Srogl coupling (Scheme 2), unequivocally
confirmed the identity of the coupling product 2a.
For comparison purposes, the corresponding carbon-sulfur
cross-coupling of DHPM 3a with phenylboronic acid was
attempted under stoichiometric Cu(II) conditions. Indeed,
following a protocol recently described for 6-mercaptopurine,7a
2-phenylthio-1,4-dihydropyrimidine 4 was obtained in 72%
isolated yield. Rapid optimization of conditions by a
systematic stepwise variation of time and temperature
utilizing controlled microwave irradiation led to the same
compound in similar yields (79%) but considerably shorter
reaction times (Scheme 4).
Having a protocol for the efficient and rapid microwave-
assisted coupling of dihydropyrimidine-2-thiones 3a with
phenylboronic acid at hand,20 we next proceeded to synthe-
size analogues of Bay 41-4109. The required DHPM-2-
thione 5 was readily synthesized in high yield by microwave-
assisted Biginelli condensation of the corresponding aldehyde,
series of test reactions, we therefore attempted to directly
couple the model substrate DHPM 3a with phenylboronic
acid, employing the Pd(0)-catalyzed, Cu(I)-facilitated Lie-
beskind-Srogl conditions. To our great delight and surprise,
this transformation proceeded without incident and furnished
1,4-dihydropyrimidine 2a in good yields.
Further refinement of the reaction conditions explored
above (Scheme 2) demonstrated that here a reaction tem-
perature of 100 °C (25 min) proved to be optimal. An 82%
yield of 2a was isolated from a run that utilized 1.5 equiv
of phenylboronic acid, 3 mol % Pd(PPh3)4, and 3 equiv of
CuTC cofactor in THF.17 The use of Pd2dba3/tris(2-furyl)-
(16) For the rapid synthesis of combinatorial libraries of these hetero-
cycles employing microwave-assisted solution-phase methods, see: Stadler,
A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624.
(17) When the same reaction was run in an oil bath under conventional
reflux conditions (ca 65 °C, reflux temperature, 18 h), the desired product
2a was also formed but in significantly lower yield (ca. 40-50%).
(18) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(19) For a review of Cu-Mediated C-O, C-N, and C-S bond-forming
reactions of the Ullmann type, see: ref 2c.
Org. Lett., Vol. 6, No. 5, 2004
773

yield. Although the isolated yields for 2-(hetero)aryl-dihy-
dropyrimidines 6d and 6e (close analogues of Bay 41-4109
and Bay 39-5493) are low, it is clear that this two-step
synthetic approach using readily available building blocks
can be used for the synthesis of compound libraries after
further optimization of the Liebeskind-Srogl-type coupling
conditions.
Scheme 4. Carbon-Sulfur Boronic Acid-Thioamide Coupling
In conclusion, we have demonstrated that thioether-boronic
acid cross-coupling chemistry (Liebeskind-Srogl couplings)
can be efficiently carried out by controlled microwave
irradiation conditions. We have also discovered an unprec-
edented novel carbon-carbon cross-coupling reaction in-
volving thioamides and boronic acids. Initial studies suggest
a mechanistic similarity between the Pd(0)/Cu(I) Liebe-
skind-Srogl coupling protocols involving thioethers and
boronic acid and this new method where “unprotected”
thioamides are employed. Future studies will investigate the
scope and limitations of this cross-coupling method.
CH-acidic carbonyl, and thiourea building blocks (Table
1).16,21 Reaction of thione 5 with a small collection of diverse
boronic acids using the Pd(0)/Cu(I) coupling conditions
described in Table 1 resulted in the formation of the desired
2-aryl-1,4-dihydropyrimidine analogues 6a-e in 14-82%
(20) Typical Procedure for Carbon-Carbon Cross-Coupling of
DHPM 3a with PhB(OH)2. To a microwave reaction vessel were added
DHPM 3a (69.1 mg, 0.25 mmol), PhB(OH)2 (45.7 mg, 0.375 mmol), Cu-
(I) thiophene-2-carboxylate (CuTC) (142.9 mg, 0.75 mmol), and Pd(PPh3)4
(8.7 mg, 3.0 mol %). The vessel was flushed with Ar and sealed. Through
the septum was added anhydrous THF (5 mL). The reaction vessel was
irradiated at 100 °C for 25 min (Emrys Synthesiser, Personal Chemistry
AB, Uppsala, Sweden). After cooling, the mixture was transferred to a
round-bottom flask and adsorbed on silica gel. The residue was purified by
flash chromatography on silica gel (hexanes/ethyl acetate 3:1) to yield
dihydropyrimidine 2a: 1H NMR (CDCl3) δ 1.22 (t, J ) 7.5 Hz, 3H), 2.5
(s, 3H), 4.12 (q, J ) 7.5 Hz, 2H), 5.8 (s, 1H), 7.24-7.32 (m, 3H), 7.40-
7.43 (m, 3H), 7.46 (d, J ) 8.5 Hz, 2H), 7.71 (d, J ) 8.5 Hz, 2H); 13C
NMR (CDCl3) δ 14.2, 29.7. 57.3, 59.9, 126.7, 127.1, 127.5, 128.5, 128.8,
131.2, 133.6, 145.0; IR (KBr) 1700, 1160, 1500 cm-1; MS (pos. APCI):
m/z 321 (M + 1).
Acknowledgment. This work was supported by the
Austrian Science Fund (P15582). We thank Personal Chem-
istry AB (Uppsala, Sweden) for the use of the Emrys
Synthesizer.
Supporting Information Available: Full experimental
details and spectral data (NMR, MS) for all transformations
and compounds described. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) Dondoni, A.; Massi, A.; Sabatini, S. Tetrahedron Lett. 2002, 43,
5913.
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