A domino desulfitative coupling/acylation/hydration process cocatalyzed by copper(I) and palladium(II): Synthesis of highly substituted and functionalized pyrimidines

Article abstract of DOI:10.1002/adsc.201200402

A domino desulfitative coupling/acylation/hydration process to synthesize C-2-(2-oxo-2-phenylethylidene)- and N-3-carbonyl-substituted pyrimidines by unprecedented C-C and C-N cross-coupling reactions is described. This methodology couples 3,4-dihydropyrimidine-2-thiones and alkynes under modified Liebeskind-Srogl conditions using palladium acetate and copper(I) carboxylate. Remarkably the copper(I) carboxylates simultaneously act as desulfitative and acylation reagents in the reaction. Copyright

Full text of DOI:10.1002/adsc.201200402

COMMUNICATIONS
DOI: 10.1002/adsc.201200402
A Domino Desulfitative Coupling/Acylation/Hydration Process
Cocatalyzed by Copper(I) and Palladium(II): Synthesis of Highly
Substituted and Functionalized Pyrimidines
Zheng-Jun Quan,a,* Wang-Hua Hu,a Xiao-Dong Jia,a Zhang Zhang,a Yu-Xia Da,a
and Xi-Cun Wanga,*
a
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China. Gansu Key Laboratory of
Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu
730070, Peopleꢀs Republic of China
Fax : (+86)-931-797-1971; e-mail: quanzhengjun@hotmail.com or wangxicun@nwnu.edu.cn
Received: May 8, 2012; Revised: July 16, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200402.
Abstract: A domino desulfitative coupling/acyla-
tion/hydration process to synthesize C-2-(2-oxo-2-
phenylethylidene)- and N-3-carbonyl-substituted
action has been modified to allow the coupling of
cyclic thionocarbamates with alkynes.[8] A key feature
of these desulfitative C C couplings are the require-
À
À
À
pyrimidines by unprecedented C C and C N cross-
coupling reactions is described. This methodology
couples 3,4-dihydropyrimidine-2-thiones and al-
kynes under modified Liebeskind–Srogl conditions
using palladium acetate and copper(I) carboxylate.
Remarkably the copper(I) carboxylates simultane-
ously act as desulfitative and acylation reagents in
the reaction.
ment of both the Pd(0) catalyst and the stoichiometric
Cu(I) carboxylate additive.[9]
Since the utility of these coupling reactions to con-
struct a single bond has now been established, the
quest to improve efficiency has driven further explo-
ration of one-pot procedures for effecting multiple
transformations, often by domino and multicompo-
nent reaction (MCR) approaches.[10] MCRs have
gained wide acceptance because they represent
a highly valuable synthetic tool for the construction
of novel and complex molecular structures in an eco-
nomically favorable way by using processes that are
reasonably simple.[11] Additionally, transition metal-
catalyzed MCRs producing complex molecules from
À
À
Keywords: C C bond formation; C N bond forma-
tion; copper(I) carboxylates; cross-coupling; 3,4-di-
hydropyrimindine-2-thiones; palladium
three or more simple building blocks have become an
[12]
À
important method for C C bond formation.
Transition metal-catalyzed cross-coupling reactions
Dihydropyrimidinones (DHPMs) are a class of het-
À
are versatile and powerful tools to construct new C C erocyclic compounds possessing a wide range of bio-
[1]
and C N bonds. In a cross-coupling reaction, the logical activity.[13] It has been previously established
À
electrophile species are predominantly organic halides that N-acyl-/N-benzoyl- and C-2-DHPM derivatives
and aryl/alkenyl triflates or sulfonates. In the past two display more interesting pharmacological properties
decades, transition metal-catalyzed carbon carbon than other derivatives.[14] For example, 2-(hetero)aryl-
À
À
and carbon heteroatom bond formation via selective substituted dihydropyrimidines are highly potent non-
À
cleavage of C S bonds has been rigorously investigat- nucleosidic inhibitors of hepatitis B virus replication
ed.[2] Among these methodologies, Cu(I) carboxylate- that have in vitro and in vivo antiviral activity.[15] Al-
mediated, Pd-catalyzed cross-coupling reactions of though some synthetic approaches have now been es-
boronic acids with different sulfur compounds includ- tablished, the methods to synthesize this type com-
ing thioesters, alkynyl thioethers, and thioamides, pounds are still limited.[13] Recently, the Kappe group
have attracted extensive interest in the organic syn- have developed an efficient desulfitative carbon-
thetic community.[3] Different nucleophilic partners carbon coupling reaction between 3,4-dihydropyrimi-
such as organozinc reagents,[4] organostannanes,[5] or- dine-2-thiones (1) and boronic acids under modified
ganoindium,[6] and arylsiloxanes[7] have also been used Liebeskind–Srogl Pd(0)-catalyzed and Cu(I)-mediated
in the C S cleavage reaction followed by the C C conditions (Scheme 1, A).[9,16] Other methods have
bond formation. More recently, this Pd-catalyzed re- been promoted by the dehydrogenation and PyBroP-
À
À
Adv. Synth. Catal. 2012, 354, 2939 – 2948
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2939

Zheng-Jun Quan et al.
COMMUNICATIONS
Scheme 1. Modified Liebeskind–Srogl Pd(II)-catalyzed, Cu(I)-mediated coupling of DHPM.
À
À
mediated coupling reaction of pyrimidin-2(1H)-one catalyst. To our delight, C C and C N cross-coupling
with boronic acids,[17] and only two examples have product 4a was isolated in 77% yield (Table 1,
used alkynes.[18] To this date, there has been no report entry 1) with no Sonogashira cross-coupling product
concerning the direct coupling of 3,4-dihydropyrimi- 4a’ detected. This novel structure was unambiguously
dine-2-thiones with alkynes to synthesize DHPM de- determined by deuterium/water exchange experi-
rivatives. There is also no report of the preparation of ments, DEPT, HSQC, HMBC and X-ray crystallo-
the N- and C-2-disubstituted pyrimidine derivatives graphic analysis.[21] An optimization of the reaction
directly from 3,4-dihydropyrimidine-2-thiones in conditions was then undertaken. Various palladium
a single step.
Due to their utilization as precursors in the synthe- yields of 4a than Pd
sis of pyrimidine bases,[19] combined with our previous tained when Pd
(OAc)2 was screened using different li-
experience on the synthesis of DHPM derivatives,[20] gands (entries 5–8). Generally, 5 mol% of Pd
(OAc)2
sources were tested (entries 2–4), all provided lower
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
we investigated a Pd(II)- and copper(I) carboxylate- and 6 mol% of DPEPhos, SPhos or tBuXPhos were
catalyzed coupling reaction between 3,4-dihydropyri- sufficient to achieve excellent yields within 48 h at
midine-2-thiones and alkynes to access C-2-alkynyl 1108C. Lower catalyst loadings (<3 mol%) led to de-
DHPM derivatives (Scheme 1, B).
Herein, we report a multicomponent-domino desul- vantageous effects were observed when 10 mol% Pd
fitative coupling/acylation/hydration process for the was used. When CuI and CuBr(PPh3)2, were em-
creased reaction efficiency and lower yields. No ad-
AHCTUNGTRENNUNG
synthesis of C-2- and N-3-disubsituted pyrimidines ployed no reaction was detected by TLC and
(4). This method utilizes an unprecedented C C and 1H NMR analysis. When we investigated CuBr·Me2S
À
À
C N cross-coupling reaction between a 3,4-dihydro- mixed with CuI as copper source, a complex mixture
1
pyrimidinethione, an alkyne and a copper(I) carboxyl- was detected by TLC, LC-MS and H NMR without
ate under the modified Liebeskind–Srogl conditions the desired product 4a’ (entry 13). Using the sole
À
(Scheme 1). Here, copper carboxylate acts not only as CuTC without Pd catalyst did not result in a C C
a desulfitative reagent but also as an acylation re- coupling reaction (entry 14).[22]
agent. Initially, the reaction between 3,4-dihydropyri-
With the optimized conditions in hand, we used
midine-2-thione (1a) and phenylacetylene (2a) in 1,4- DHPMs and a diverse set of alkynes to test the reac-
dioxane at 1108C was tested using copper (I) thio- tion scope. In general, good to excellent yields were
ACHTUNGTRENNUNGphenecarboxylate (CuTC) (3a) and PdACHTUNGTRNEN(UGN OAc)2 as the obtained under the standard reaction conditions. The
2940
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2939 – 2948

A Domino Desulfitative Coupling/Acylation/Hydration Process
Table 1. Optimization of the desulfitative cross-coupling reaction of DHPM with phenylacetylene and CuTC.[a]
Entry
Catalyst (mol%)
Pd(OAc)2 (5)
Ligand (mol%)
Cu
Yield [%][b]
1
2
3
4
5
6
7
8
G
–
–
–
–
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuI
77
71
60
51
85
91
90
93
80
94
PdCl2A(PPh3)2 (5)
PdCl2 (5)
Pd(PPh3)4 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (3)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
R
N
U
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
R
PPh3 (6)
DPEPhos (6)
SPhos (6)
tBuXPhos (6)
tBuXPhos (3)
tBuXPhos (6)
DPEPhos (6)
DPEPhos (6)
DPEPhos (6)
–
9
10
11
12
13
14
[c]
–
–
–
–
[c]
N
H
CuBr
CuBrMe2S/CuI
CuTC
(PPh3)2
[d]
[c]
–
[a]
Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol, 1.5 equiv.), CuTC (3, 0.35 mmol, 1.4 equiv.), 1,4-dioxane (3 mL) at
1108C for 48 h.
Isolated yield.
No reaction was detected by TLC and H NMR.
Without adding 2a and a mixture was obtained.
[b]
[c]
[d]
1
À
À
reaction tolerated a variety of dihydropyrimidine-2-
thiones and alkynes containing aromatic and non-aro- cross-coupling reaction mechanism, 2-(phenylethyn-
To gain additional evidence for the C C and C N
matic substituents giving a series of pyrimidine deriv- yl)-1,2-dihydropyrimidine (11)[23] was exposed to the
À
À
atives via C C and C N cross-coupling reaction optimized reaction conditions without using Pd and
(Table 2). In terms of the effect of structural features, ligand. The desired product (4a) was obtained in 95%
introducing steric hindrance ortho to the aromatic yield (Scheme 2). In order to confirm the isomerism
ring was detrimental to the reaction, with the desired of product 4, 2-(phenylethynyl)-1,4-dihydropyrimidine
products 4f–4h being isolated in lower yields (en- (10) was directly added to the mixture of CuTC in
tries 6–8).
1,4-dioxane. The acylation/hydration giving the prod-
To explore the scope of differentiated Cu(I) car- uct 12 was clearly evident on monitoring the reaction
À
À
boxylates in the observed C C and C N coupling re- mixture by LC-MS. The isomers 12a and 12b were
1
action, the copper(I) furan-2-carboxylate (CuFC) 5 further confirmed by H NMR and 13C NMR showing
and copper(I) benzoate (CuBC) 6 were exposed to that 12b was the major isomer (Scheme 3).
the standard reaction conditions, resulting in the for-
Next, 3-benzoylpyrimidine-2-thione (13) was used
À
À
mation of C C and C N coupling products 7a–f and instead of 3,4-dihydropyrimidine-2-thione (1a) under
8a–c (Table 3). As depicted in Table 3, successful the optimal reaction conditions (Scheme 4). There
cross-couplings were achieved with CuFC and CuBC. was no evidence for a cross-coupling reaction at the
In general, good to excellent yields of the desired C-2 position; however, the desulfitative product
products were obtained. As in the previous case, o- (14)[24a] (detected by TLC and LC-MS) was obtained.
methoxy-substituted DHPM led to lower yields (en-
On the basis of both the above observations and
tries 3, 4 and 8). A tert-butyl carboxylate on DHPM previously reported carbon-carbon cross-couplings by
was well tolerated (entries 5 and 9), as were DHPMs Kappe,[16] we can deduce that firtsly the acylation step
bearing an electron-withdrawing group (entry 5). The showed a unique selectivity to give the N-3 products,
structures of the final product 7a and 7c were also although it is the more hindered nitrogen. The selec-
characterized by X-ray crystallographic analysis tivity may be due to the higher reactivity of the N-3
(Figure 1).[21]
position, in comparison to the N-1, which is both in
conjugation with the C=C double bond at C-6 and the
Adv. Synth. Catal. 2012, 354, 2939 – 2948
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2941

Zheng-Jun Quan et al.
COMMUNICATIONS
Table 2. The desulfitative cross-coupling reaction of DHPMs with alkynes and CuTC.[a]
Entry
Alkyne 2
Product 4
Yield
[%][b]
Entry Alkyne Product 4
Yield
[%][b]
2
1
2a
93
6
2a
44
2
3
2b
2c
86
63
7
8
2b
2c
67
66
4
2d
2e
83
82
9
2a
56
5
[a]
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol, 1.5 equiv.), 3 (0.70 mmol, 1.4 equiv.), Pd
tBuXPhos (0.030 mmol, 6 mol%), 1,4-dioxane (3 mL) at 1108C for 48 h.
Isolated yield of pure product after column chromatography.
ACHTUNGRTEN(NUNG OAc)2 (0.025 mmol, 5 mol%),
[b]
ester functionality at C-5, thereby the N-1 position is considering possible complex E. Finally the acylation
representing a weaker nucleophilic activity. The result could be performed using CuTC without a Pd catalyst
was consistent with previously reported results.[20a,c,e,24] (Scheme 5).
Secondly, the desulfitative cross-coupling reaction
We propose the possible mechanism of the Pd-cata-
giving intermediate 2-phenylethynyl-1,4-dihydropyri- lyzed desulfitative coupling/acylation/hydration pro-
midines (D) occurred prior to the acylation. Thirdly, cess that is shown in Scheme 5.[3a,8,25] The mechanism
the formation of the product D played a central role of the desulfitative cross-coupling step is related to
in the next acylation step. This can be explained by the traditional Liebeskind–Srogl protocols,[3,4] specifi-
2942
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2939 – 2948

A Domino Desulfitative Coupling/Acylation/Hydration Process
Table 3. The desulfitative cross-coupling reaction of DHPMs with alkynes and CuFC 5 and CuBC 6.[a]
Entry Alkyne 2 Product
Yield [%][b] Entry Alkyne 2 Product
Yield [%][b]
1
2
3
4
5
2a
2b
2a
2c
2a
70
82
62
39
63
6
7
8
9
2a
2a
2a
2a
96
73
36
93
[a]
[b]
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol, 1.5 equiv.), 5 or 6 (0.70 mmol, 1.4 equiv.), Pd
5 mol%), tBuXPhos (0.030 mmol, 6 mol%), 1,4-dioxane (3 mL) at 1108C for 48 h.
Isolated yield of pure product after column chromatography.
ACHTUNGRTEN(NGNU OAc)2 (0.025 mmol,
cally to the cross-couplings of cyclic thioamides with with water to produce the C-2-oxo-2-phenylethyl
alkynes.[8] Then coordination of a Sonogashira cross- product G, which isomerizes to give the product 4.
coupling type product D to the copper salt would pro- Compound 4 is stablized by the conjugation of the
mote C=N activation (deprotonation) of D to give the two carbonyl C=O double bonds and the C=C double
acylation product F, forming CuOH in situ, which bond.
transformed into Cu2O (Cu2O may react with HTC
In conclusion, we have developed an efficient mul-
giving the CuTC) and H2O when heated. The acyla- ticomponent domino process of desulfitative carbon-
tion product may subsequently undergo hydration carbon cross-coupling, acylation and hydration for the
Adv. Synth. Catal. 2012, 354, 2939 – 2948
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2943

Zheng-Jun Quan et al.
COMMUNICATIONS
Figure 1. X-ray structures of compounds 7a and 7c.
À
Scheme 2. The C N cross-coupling/acylation of 2-(phenylethynyl)-1,2-dihydropyrimidine with CuTC.
Scheme 4. The desulfitative reaction catalyzed by CuTC.
synthesis of a series of C-2-(2-oxo-2-phenylethyli-
dene)-N-3-carbonyl-substituted pyrimidines. Further-
more, this protocol possibly opens up a new pathway
À
Scheme 3. The C N cross-coupling/acylation of 2-(phenyl-
ethynyl)-1,4-dihydropyrimidine with CuTC.
À
À
N
for direct C C and C N bond construction in which
2944
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2939 – 2948

A Domino Desulfitative Coupling/Acylation/Hydration Process
Scheme 5. The possible mechanism.
(E)-Ethyl
6-methyl-2-(2-oxo-2-phenylethylidene)-4-
the copper(I) carboxylate is involved not only as a cat-
alyst but also as an acylation reagent and at least four
different reactions (desulfitation, C C coupling, acy-
phenyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4a): white solid; yield: 219.3 mg
(0.46 mmol, 93%); mp 157–1588C; 1H NMR (400 MHz,
CDCl3): d=12.72 (1H, brs, NH), 7.60–7.27 (12H, m, PhH
and thiopheneH), 7.03 (1H, t, J=4.0 Hz, thiopheneH), 6.45
(1H, s, 4-CH), 5.71 (1H, s, C=CH), 4.21 (2H, q, J=8.0 Hz,
OCH2), 2.65 (3H, s, CH3), 1.27 (3H, t, J=8.0 Hz,
OCH2CH3); 13C NMR (100 MHz, CDCl3): d=188.75, 165.15,
163.19, 151.16, 144.40, 139.01, 138.91, 136.91, 132.43, 132.11,
131.84, 128.63, 128.36, 128.15, 128.48, 127.22, 127.08, 106.89,
92.66, 60.49, 54.81, 18.82, 14.25; HR-MS (EI+): m/z=
472.1452, calcd. for C27H24N2O4S+: 472.1451.
À
lation and hydration) occur in a cascade way. The ex-
tensive availability of reaction partners suggests new
possibilities for the synthesis of highly functionalized
compounds under these cross-coupling conditions. We
are currently focusing on promoting this highly effi-
cient transformation and further exploring its use in
the construction of more variable and complex com-
pounds. Further mechanism studies of this reaction
are also underway in our laboratory.
(E)-Ethyl 6-methyl-2-(2-oxoheptylidene)-4-phenyl-3-(thio-
phene-2-carbonyl)-1,2,3,4-tetrahydropyrimidine-5-carboxyl-
ate (4b): yellow oil; yield: 200.2 mg (0.43 mmol, 86%);
1H NMR (400 MHz, CDCl3): d=12.20 (1H, brs , NH), 7.56
(1H, t, J=4.0 Hz, thiopheneH), 7.50 (1H, t, J=4.0 Hz, thio-
pheneH), 7.40–7.29 (5H, m, PhH), 7.03 (1H, t, J=4.0 Hz,
thiopheneH), 6.38 (1H, s, 4-CH), 4.99 (1H, s, C=CH), 4.17
(2H, q, J=8.0 Hz, OCH2), 2.58 (3H, s, CH3), 2.10 (2H, t,
J=8.0 Hz, heptynylCH2), 1.25–1.23 (2H, m, heptynylCH2),
1.22–1.11 (5H, m, heptynylCH2 and OCH2CH3), 1.50–1.09
(2H, m, heptynylCH2), 0.90 (3H, t, J=8.0 Hz, hepty-
nylCH3); 13C NMR (100 MHz, CDCl3): dC =200.05, 165.19,
163.00, 149.42, 144.58, 139.12, 136.93, 132.26, 131.89, 128.56,
128.05, 127.25, 127.22, 106.13, 95.56, 60.36, 54.66, 42.96,
31.30, 25.16, 22.40, 18.77, 14.23, 13.87; HR-MS (EI+): m/z=
466.1922, calcd. for C26H30N2O4S+: 466.1921.
Experimental Section
General Procedure for Cross-Coupling Reactions
The mixture of 3,4-dihydropyrimidine-2-thione (1a,
0.5 mmol, 138.2 mg), phenylacetylene (2a, 0.75 mmol,
76.6 mg, 1.5 equiv.), CuTC (3, 0.7 mmol, 1.4 equiv.,
133.5 mg), tBuXPhos (0.03 mmol, 12.7 mg, 0.06 equiv.) and
PdACHTUNGTRENNUNG(OAc)2 (0.025 mmol, 5.6 mg, 0.05 equiv.) in 1,4-dioxane
(3 mL) was stirred at 1108C for 48 h under N2. Then the re-
action misture was cooled to room temperature, quenched
with saturated NH4Cl solution (2 mL) and then extracted
with ethyl acetate (2ꢂ10 mL). The combined organic ex-
tracts were washed with NaOH (1M, 2 mL), brine and dried
over MgSO4. The crude product was purified by flash
column chromatography (silica gel; ethyl acetate/hexane=
1:4) to afford the product 4a as a white solid; yield:
219.3 mg (0.46 mmol, 93%).
(E)-Ethyl
2-(3,3-dimethyl-2-oxobutylidene)-6-methyl-4-
phenyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4c): white solid; yield: 142.3 mg
(0.32 mmol, 63%); mp 127–1288C; 1H NMR (400 MHz,
CDCl3): d=12.16 (1H, brs, NH), 7.54 (1H, t, J=4.0 Hz, thi-
opheneH), 7.46 (1H, t, J=4 Hz, thiopheneH), 7.41–7.29
(5H, m, PhH), 7.02 (1H, t, J=4.0 Hz, thiopheneH), 6.37
(1H, s, 4-CH), 5.10 (1H, s, C=CH), 4.17 (2H, q, J=8.0 Hz,
In a similar manner, compounds 4b–4i, 7a–7f, and 8a–8c
were prepared from the corresponding DHPMs, alkynes and
Cu(I) carboxylates.
Adv. Synth. Catal. 2012, 354, 2939 – 2948
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2945

Zheng-Jun Quan et al.
COMMUNICATIONS
OCH2), 2.58 (3H, s, CH3), 1.24 (3H, t, J=8.0 Hz,
OCH2CH3), 0.87 (9H, s, t-butylCH3); 13C NMR (100 MHz,
CDCl3): d=205.18, 165.22, 163.18, 150.04, 144.48, 139.24,
137.12, 131.92, 131.51, 128.55, 128.04, 127.33, 127.21, 106.16,
92.56, 60.35, 54.70, 42.23, 26.88, 18.78, 14.23; HRMS (EI+):
m/z=452.1767, calcd. for C25H28N2O4S+: 452.1764.
m, heptynylCH2), 1.25–1.19 (5H, m, heptynylCH2 and
OCH2CH3), 0.85 (3H, t, J=8.0 Hz, heptynylCH3); 13C NMR
(100 MHz, CDCl3): d=200.82, 165.13, 164.02, 157.57, 149.49,
145.48, 137.87, 131.53, 131.26, 129.65, 128.87, 127.05, 126.24,
120.27, 110.99, 103.59, 92.24, 60.08, 54.92, 53.39, 43.15, 31.46,
25.32, 22.44, 18.79, 14.26, 13.91; HR-MS (EI+): m/z=
496.2022, calcd. for C27H32N2O5S+: 496.2026.
(E)-Ethyl 2-{2-[4-(tert-butyl)phenyl]-2-oxoethylidene}-6-
methyl-4-phenyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4d): white solid; yield:
219.2 mg (0.42 mmol, 83%); mp 168–1698C; 1H NMR
(400 MHz, CDCl3): d=12.70 (1H, brs, NH), 7.80–7.58 (2H,
m, PhH and thiopheneH), 7.45–7.42 (4H, m, PhH and thio-
pheneH), 7.36–7.29 (5H, m, PhH), 7.03 (1H, t, J=4.0 Hz,
thiopheneH), 6.45 (1H, s, 4-CH), 5.71 (1H, s, C=CH), 4.21
(2H, q, J=8.0 Hz, OCH2), 2.65 (3H, s, CH3), 1.36–1.26
(12H, m, i-butylCH3 and OCH2CH3); 13C NMR (100 MHz,
CDCl3): d=188.53, 165.43, 162.88, 155.57, 150.83, 144.50,
139.10, 136.17, 132.41, 132.05, 128.61, 128.10, 127.47, 127.22,
127.02, 125.35, 106.68, 92.86, 60.44, 54.78, 34.95, 31.08, 18.84,
(E)-Ethyl 2-(3,3-dimethyl-2-oxobutylidene)-4-(2-methoxy-
phenyl)-6-methyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4h): yellow solid; yield:
159.5 mg (0.33 mmol, 66%); mp 120–1218C; 1H NMR
(400 MHz, CDCl3): d=12.49 (1H, brs, NH), 7.54 (1H, d, J=
4.0 Hz, thiopheneH), 7.46 (1H, d, J=4.0 Hz, thiopheneH),
7.31–7.24 (2H, q, J=4.0 Hz, PhH), 7.02 (1H, q, J=4.0 Hz,
thiopheneH), 6.92–6.85 (2H, m, PhH), 6.48 (1H, s, 4-CH),
5.51 (1H, s, C=CH), 4.12 (2H, q, J=8.0 Hz, OCH2), 3.71
(3H, s, CH3), 2.56 (3H, s, CH3), 1.22 (3H, t, J=8.0 Hz,
OCH2CH3), 0.99 (9H, s, i-butylCH3); 13C NMR (100 MHz,
CDCl3): d=205.76, 165.27, 163.93, 157.65, 150.54, 144.71,
137.77, 131.22, 131.18, 129.89, 129.55, 127.07, 127.01, 120.24,
110.98, 103.93, 89.97, 60.05, 54.84, 53.73, 42.29, 27.16, 18.82,
14.26;
C31H32N2O4S+: 528.2077.
(E)-Ethyl 6-methyl-2-(2-oxo-4-phenylbutylidene)-4-
HR-MS
(EI+):
m/z=528.2082,
calcd.
for
14.22;
HR-MS
(EI+):
m/z=482.1868,
calcd.
for
phenyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4e): yellow oil; yield: 205.5 mg
(0.41 mmol, 82%); 1H NMR (400 MHz, CDCl3): d=12.21
(1H, brs, NH), 7.56 (1H, t, J=4.0 Hz, thiopheneH), 7.51
(1H, t, J=4.0 Hz, thiopheneH), 7.41–7.18 (8H, m, PhH),
7.07 (2H, d, J=4.0 Hz, PhH), 7.02 (1H, t, J=4 Hz, thiophe-
neH), 6.40 (1H, s, 4-CH), 5.03 (1H, s, C=CH), 4.19 (2H, q,
J=8.0 Hz, OCH2), 2.75–2.70 (2H, m, CH2CH2), 2.60 (3H, s,
CH3), 2.47–2.42 (2H, m, CH2CH2), 1.26 (3H, t, J=8.0 Hz,
OCH2CH3); 13C NMR (100 MHz, CDCl3): d=198.30, 165.15,
163.02, 149.75, 144.48, 140.94, 139.06, 136.83, 132.38, 132.07,
128.62, 128.42, 128.13, 127.28, 127.23, 126.04, 106.36, 95.21,
60.43, 54.72, 44.31, 31.11, 18.78, 14.25; HR-MS (EI+): m/z=
500.1770, calcd. for C29H28N2O4S+: 500.1764.
(E)-Ethyl 4-(2-methoxyphenyl)-6-methyl-2-(2-oxo-2-phe-
nylethylidene)-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4f): white solid; yield: 110.3 mg
(0.22 mmol, 44%); mp. 130–1318C; 1H NMR (400 MHz,
CDCl3): d=13.11 (1H, brs, NH), 7.70 (2H, t, J=8.0 Hz, thi-
opheneH), 7.59 (2H, dd, J=8.0 Hz, 4 Hz, thiopheneH),
7.43–7.41 (1H, m, PhH), 7.36 (2H, t, J=8.0 Hz, PhH), 7.24
(2H, d, J=8.0 Hz, PhH), 7.08 (1H, q, J=4.0 Hz, thiophe-
neH), 6.91–6.40 (2H, m, PhH), 6.63 (1H, s, 4-CH), 6.40
(1H, s, C=CH), 4.25–4.09 (2H, m, OCH2), 3.73 (3H, s,
CH3), 2.66 (3H, s, CH3), 1.25 (3H, t, J=8.0 Hz, OCH2CH3);
13C NMR (100 MHz, CDCl3): dC 189.50, 165.08, 164.27,
157.63, 151.21, 145.32, 139.34, 137.84, 131.60, 131.42, 129.76,
128.90, 128.30, 127.20, 120.31, 111.03, 104.17, 89.27, 60.20,
54.93, 53.75, 18.84, 14.28; HR-MS (EI+): m/z=502.1555,
calcd. for C28H26N2O5S+: 502.1557.
C26H30N2O5S+: 482.1870.
(E)-tert-Butyl 6-methyl-2-(2-oxo-2-phenylethylidene)-4-
phenyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4i): yellow oil; yield: 40.1 mg
1
(0.28 mmol, 56%); H NMR (400 MHz, CDCl3): dH =12.69
(1H, brs , NH), 7.60–7.57 (2H, m, PhH), 7.50–7.47 (2H, m,
PhH and thiopheneH), 7.44–7.40 (3H, m, PhH and thiophe-
neH), 7.35–7.27 (5H, m, PhH), 7.02 (1H, q, J=4.0 Hz, thio-
pheneH), 6.37 (1H, s, 4-CH), 5.71 (1H, s, C=CH), 2.62 (3H,
s, CH3), 1.46 (9H, s, i-butylCH3); 13C NMR (100 MHz,
CDCl3): d=188.62, 164.41, 163.24, 151.28, 143.33, 139.17,
138.98, 137.01, 132.38, 132.06, 131.75, 128.56, 128.34, 128.06,
127.45, 127.24, 127.06, 108.51, 92.46, 81.11, 67.09, 55.20,
28.22, 26.92, 18.68; HR-MS (EI+): m/z=500.1760, calcd. for
C29H28N2O4S+: 500.1764.
(E)-Ethyl 3-(furan-2-carbonyl)-6-methyl-2-(2-oxo-2-phe-
nylethylidene)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-car-
boxylate (7a): white solid; yield: 160.6 mg (0.35 mmol,
70%); mp 159–1608C; 1H NMR (400 MHz, CDCl3): d=
12.70 (1H, brs, NH), 7.55–7.53 (2H, m, PhH and furanH),
7.47–7.42 (4H, m, PhH and furanH), 7.36–7.27 (6H, m,
PhH), 6.55 (1H, d, J=4.0 Hz, furanH), 6.44 (1H, s, 4-CH),
5.50 (1H, s, C=CH), 4.21 (2H, q, J=8.0 Hz, OCH2), 2.64
(3H, s, CH3), 1.27 (3H, t, J=8.0 Hz, OCH2CH3); 13C NMR
(100 MHz, CDCl3): d=189.04, 165.11, 158.84, 150.55, 147.03,
145.35, 144.44, 138.98, 131.81, 128.61, 128.35, 128.12, 127.22,
127.02, 118.78, 112.25, 106.62, 90.55, 60.45, 54.31, 18.83,
+
14.26; HR-MS (EI+): m/z=456.1678, calcd. for C27H24N2O5 :
456.1680.
(E)-Ethyl 3-(furan-2-carbonyl)-6-methyl-2-(2-oxoheptyli-
dene)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(E)-Ethyl 4-(2-methoxyphenyl)-6-methyl-2-(2-oxoheptyli-
dene)-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4g): white solid; yield: 166.6 mg
(0.34 mmol, 67%); mp 139–1408C; 1H NMR (400 MHz,
CDCl3): d=12.59 (1H, brs, NH), 7.58 (1H, t, J=4.0 Hz, thi-
opheneH), 7.51 (2H, t, J=4.0 Hz, thiopheneH), 7.26–7.17
(1H, m, PhH), 7.06 (1H, q, J=4.0 Hz, thiopheneH), 6.90–
6.85 (2H, m, PhH), 6.57 (1H, s, 4-CH), 5.62 (1H, s, C=CH),
4.22–3.74 (2H, m, OCH2), 3.49 (3H, s, CH3), 2.59 (3H, s,
CH3), 2.21 (2H, q, J=4.0 Hz, heptynylCH2), 1.46–1.34 (4H,
1
(7b): yellow oil; yield: 185.3 mg (0.41 mmol, 82%); H NMR
(400 MHz, CDCl3): d=12.17 (1H, brs, NH), 7.47 (1H, d, J=
4.0 Hz, furanH), 7.40–7.27 (5H, m, PhH and furanH), 7.17
(1H, d, J=4.0 Hz, furanH), 6.52 (1H, d, J=4.0 Hz, furanH),
6.38 (1H, s, 4-CH), 4.77 (1H, s, C=CH), 4.17 (2H, q, J=
8.0 Hz, OCH2), 2.58 (3H, s, CH3), 2.12 (2H, t, J=8.0 Hz,
heptynylCH2), 1.39 (2H, d, J=8.0 Hz, heptynylCH2), 1.26–
1.16 (7H, m, heptynylCH2 and OCH2CH3), 0.86 (3H, t, J=
8.0 Hz, heptynylCH3); 13C NMR (100 MHz, CDCl3): d=
2946
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2939 – 2948

A Domino Desulfitative Coupling/Acylation/Hydration Process
200.26, 165.16, 158.71, 147.02, 144.91, 144.63, 139.10, 128.54,
128.03, 127.26, 118.52, 112.15, 105.85, 93.59, 60.33, 54.15,
42.94, 31.36, 25.39, 22.42, 18.79, 14.25, 13.88; HR-MS (EI+):
(E)-Ethyl
3-benzoyl-6-methyl-2-(2-oxo-2-phenylethyli-
dene)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(8a): white solid; yield: 170.5 mg (0.37 mmol, 73%); mp
193–1948C; H NMR (400 MHz, CDCl3): d=12.63 (1H, brs,
1
+
m/z=450.2148, calcd. for C26H30N2O5 : 450.2149.
NH), 7.66 (2H, t, J=4.0 Hz, PhH), 7.51–7.23 (13H, m,
PhH), 6.55 (1H, s, 4-CH), 5.32 (1H, s, C=CH), 4.22 (2H, q,
J=8.0 Hz, OCH2), 2.66 (3H, s, CH3), 1.28 (3H, t, J=8.0 Hz,
OCH2CH3); 13C NMR (100 MHz, CDCl3): d=188.84, 169.82,
165.17, 150.95, 144.37, 139.18, 138.92, 135.06, 131.85, 131.73,
128.66, 128.63, 128.49, 128.20, 128.12, 127.23, 126.95, 106.84,
93.64, 60.47, 54.02, 18.83, 14.26; HR-MS (EI+): m/z=
466.1885, calcd. for C29H26N2O4+: 466.1887.
(E)-Ethyl
3-(furan-2-carbonyl)-4-(2-methoxyphenyl)-6-
methyl-2-(2-oxo-2-phenylethylidene)-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (7c): white solid; yield: 151.2 mg
(0.31 mmol, 62%); mp 71–728C; 1H NMR (400 MHz,
CDCl3): d=13.04 (1H, brs, NH), 7.71 (2H, t, J=8.0 Hz,
PhH), 7.53 (1H, s, PhH), 7.44 (1H, t, J=4.0 Hz, furanH),
7.38–7.18 (7H, m, PhH and furanH), 6.87 (2H, t, J=8.0 Hz,
PhH), 6.64 (1H, s, 4-CH), 6.54 (1H, d, J=4.0 Hz, furanH),
6.19 (1H, s, C=CH), 4.22–4.13 (2H, m, OCH2), 3.73 (3H, s,
CH3), 2.63 (3H, s, CH3), 1.26 (3H, t, J=8.0 Hz, OCH2CH3);
13C NMR (100 MHz, CDCl3): d=189.55, 165.18, 159.76,
157.59, 150.95, 147.40, 145.22, 144.73, 139.31, 131.61, 129.70,
129.11, 128.31, 127.14, 126.39, 120.32, 117.53, 111.90, 111.01,
104.42, 88.58, 60.18, 54.95, 52.93, 18.83, 14.28; HR-MS (EI+):
(E)-Ethyl 3-benzoyl-4-(2-methoxyphenyl)-6-methyl-2-(2-
oxo-2-phenylethylidene)-1,2,3,4-tetrahydropyrimidine-5-car-
boxylate (8b): white solid; yield: 89.2 mg (0.18 mmol, 36%);
1
mp 153–1548C; H NMR (400 MHz, CDCl3): d=12.92 (1H,
brs, NH), 7.67 (2H, t, J=4.0 Hz, PhH), 7.51–7.34 (6H, m,
PhH), 7.30–7.23 (4H, m, PhH), 6.93–6.85 (2H, m, PhH),
6.51 (1H, s, 4-CH), 5.86 (1H, s, C=CH), 4.15 (2H, q, J=
8.0 Hz, OCH2), 3.73 (3H, s, OCH3), 2.64 (3H, s, CH3), 1.23
(3H, t, J=8.0 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3):
d=189.18, 170.51, 165.22, 157.67, 151.39, 144.44, 135.25,
131.60, 131.55, 129.79, 129.61, 128.47, 128.41, 128.22, 127.04,
120.30, 111.07, 104.82, 99.98, 91.31, 60.17, 54.96, 53.19, 18.81,
+
m/z=486.1783, calcd. for C28H26N2O6 : 486.1785.
(E)-Ethyl 2-(3,3-dimethyl-2-oxobutylidene)-4-(2-methoxy-
phenyl)-6-methyl-3-(thiophene-2-carbonyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (7d): yellow oil; yield: 91.0 mg
(0.19 mmol, 39%); 1H NMR (400 MHz, CDCl3): d=12.47
(1H, brs, NH), 7.47 (1H, s, furanH), 7.32–7.22 (2H, m,
PhH), 7.08 (1H, d, J=4.0 Hz, furanH), 6.49 (1H, d, J=
4.0 Hz, furanH), 6.47 (1H, s, 4-CH), 5.33 (1H, s, C=CH),
4.15–4.06 (2H, m, OCH2), 3.69 (3H, s, CH3), 2.54 (3H, s,
CH3), 1.22 (3H, t, J=8.0 Hz, OCH2CH3), 0.98 (9H, s, i-bu-
tylCH3); 13C NMR (100 MHz, CDCl3): d=206.03, 165.29,
159.53, 157.61, 150.16, 147.56, 144.68, 144.34, 129.97, 129.51,
127.25, 120.23, 117.36, 11.86, 110.97, 103.99, 88.36, 60.02,
54.85, 53.12, 42.28, 27.38, 18.82, 14.21; HR-MS (EI+): m/z=
+
14.22; HR-MS (EI+): m/z=496.1992, calcd. for C30H28N2O5 :
496.1993.
(E)-tert-Butyl 3-benzoyl-6-methyl-2-(2-oxo-2-phenylethyli-
dene)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(8c): white solid; yield: 230.4 mg (0.47 mmol, 93%); mp
1
187–1888C; H NMR (400 MHz, CDCl3): d=12.59 (1H, brs,
NH), 7.67 (2H, t, J=4.0 Hz, PhH), 7.50–7.34 (6H, m, PhH),
7.32–7.23 (7H, m, PhH), 6.46 (1H, s, 4-CH), 5.31 (1H, s, C=
CH), 2.63 (3H, s, CH3), 1.45 (9H, s, i-butylCH3); 13C NMR
(100 MHz, CDCl3): d=188.71, 169.87, 164.43, 151.07, 143.29,
139.33, 138.99, 135.13, 131.81, 131.65, 128.63, 128.55, 128.50,
128.18, 128.03, 127.26, 126.93, 108.45, 93.44, 81.09, 67.09,
54.41, 28.22, 18.69; HR-MS (EI+): m/z=494.2198, calcd. for
+
466.2095, calcd. for C26H30N2O6 : 466.2098.
(E)-tert-Butyl 3-(furan-2-carbonyl)-6-methyl-2-(2-oxo-2-
phenylethylidene)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (7e): yellow oil; yield: 152.2 mg (0.31 mmol,
1
+
63%); H NMR (400 MHz, CDCl3): d=12.66 (1H, brs, NH),
C31H30N2O4 : 494.2200.
7.54 (2H, d, J=8.0 Hz, PhH), 7.47–7.35 (4H, m, PhH), 7.33–
7.26 (6H, m, PhH and thiopheneH), 6.54 (1H, t, J=4.0 Hz,
furanH), 6.36 (1H, s, 4-CH), 5.49 (1H, s, C=CH), 2.60 (3H,
s, CH3), 1.46 (9H, s, i-butylCH3); 13C NMR (100 MHz, Acknowledgements
CDCl3): dC =188.91, 164.39, 158.91, 150.69, 147.10, 145.32,
We are thankful for the financial support from the National
143.34, 139.13, 139.00, 131.75, 128.54, 128.33, 128.03, 127.24,
127.00, 118.70, 112.22, 108.25, 90.35, 81.06, 54.67, 53.89,
28.23, 22.65, 14.71; HR-MS (EI+): m/z=484.1989, calcd. for
Nature Science Foundation of China (No. 20902073 and
21062017), and Scientific and Technological Innovation Engi-
neering program of Northwest Normal University (nwnu-
kjcxgc-03-64, nwnu-lkqn-10-15).
+
C29H28N2O5 : 484.1993.
(E)-Ethyl 3-(furan-2-carbonyl)-6-methyl-4-(4-nitrophen-
yl)-2-(2-oxo-2-phenylethylidene)-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (7f): yellow solid; yield: 241.8 mg
(0.48 mmol, 96%); mp 115–1168C; 1H NMR (400 MHz,
CDCl3): d=12.71 (1H, brs, NH), 8.18 (2H, d, J=8.0 Hz,
PhH), 7.62 (2H, d, J=8.0 Hz, furanH), 7.54–7.44 (4H, m,
PhH and furanH), 7.34 (3H, t, J=8.0 Hz, PhH), 6.58 (1H,
d, J=4.0 Hz, furanH), 6.47 (1H, s, 4-CH), 5.48 (1H, s, C=
CH), 4.22 (2H, q, J=8.0 Hz, OCH2), 2.66 (3H, s, CH3), 1.28
(3H, t, J=8.0 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3):
dC =189.20, 164.89, 158.74, 149.75, 147.66, 146.58, 146.25,
145.69, 145.32, 138.59, 132.16, 128.45, 128.37, 127.05, 123.92,
119.45, 112.48, 105.37, 103.26, 90.71, 83.10, 60.73, 53.71,
18.98, 14.28; HR-MS (EI+): m/z=501.1530, calc. for
References
[1] a) Transition Metals for Organic Synthesis, (Eds.: M.
Beller, C. Bolm), 2nd edn., VCH, Weinheim, 2004;
b) Metal-Catalyzed Cross-Coupling Reactions, Vols.
1 and 2 (Eds.: A. de Meijere, F. Diederich), 2nd edn.,
Wiley-VCH, Weinheim, 2004; c) C. Torborg, M. Beller,
Adv. Synth. Catal. 2009, 351, 3027–3043.
[2] a) S. R. Dubbaka, P. Vogel, Angew. Chem. 2005, 117,
7848–7859; Angew. Chem. Int. Ed. 2005, 44, 7674–7684;
b) H. Prokopcovꢃ, C. O. Kappe, Angew. Chem. 2009,
121, 2312–2322; Angew. Chem. Int. Ed. 2009, 48, 2276–
+
C27H23N3O7 : 501.1531.
Adv. Synth. Catal. 2012, 354, 2939 – 2948
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2947

Zheng-Jun Quan et al.
COMMUNICATIONS
2286; c) Boronic Acids: Preparation and Applications
in Organic Synthesis Medicine and Materials, Vols.
1 and 2, (Ed.: D. G. Hall), 2nd edn., Wiley-VCH, Wein-
heim, 2011, pp 363–391.
b) C. O. Kappe, Acc. Chem. Res. 2000, 33, 879–888;
c) C. O. Kappe, A. Stadler, Org. React. 2004, 63, 1–117;
d) D. Dallinger, A. Stadler, C. O. Kappe, Pure Appl.
Chem. 2004, 76, 1017–1024; e) L. Z. Gong, X. H. Chen,
X. Y. Xu, Chem. Eur. J. 2007, 13, 8920–8926; f) M. A.
Kolosov, V. D. Orlov, Mol. Diversity 2009, 13, 5–25;
g) Z.-J. Quan, Z. Zhang, Y.-X. Da, X.-C. Wang, Chin. J.
Org. Chem. 2009, 29, 876–883 (in Chinese).
[3] a) L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000,
122, 11260–11261; b) C. Savarin, J. Srogl, L. S. Liebe-
skind, Org. Lett. 2001, 3, 91–93; c) Y. Yu, L. S. Liebe-
skind, J. Org. Chem. 2004, 69, 3554–3557; d) H. Yang,
H. Li, R. Wittenberg, M. Egi, W. Huang, L. S. Liebe-
skind, J. Am. Chem. Soc. 2007, 129, 1132–1140; e) L. S.
Liebeskind, J. Srogl, Org. Lett. 2002, 4, 979–981;
f) C. L. Kusturin, L. S. Liebeskind, W. L. Neumann,
Org. Lett. 2002, 4, 983–985; g) C. Kusturin, L. S. Liebe-
skind, H. Rahman, K. Sample, B. Schweitzer, J. Srogl,
W. L. Neumann, Org. Lett. 2003, 5, 4349–4352; h) H.
Prokopcovꢃ, C. O. Kappe, Angew. Chem. 2008, 120,
3732–3734; Angew. Chem. Int. Ed. 2008, 47, 3674–3676;
i) L. S. Liebeskind, H. Yang, H. Li, Angew. Chem. 2009,
121, 1445–1449; Angew. Chem. Int. Ed. 2009, 48, 1417–
1421.
[4] a) H. Tokuyama, S. Yokoshima, T. Yamashita, T. Fu-
kuyama, Tetrahedron Lett. 1998, 39, 3189–3192; b) J.
Srogl, G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc.
1997, 119, 12376–12377; c) L. Melzig, A. Metzger, P.
Knochel, Chem. Eur. J. 2011, 17, 2948–2956.
[5] a) M. Egi, L. S. Liebeskind, Org. Lett. 2003, 5, 801–802;
b) R. Wittenberg, J. Srogl, M. Egi, L. S. Liebeskind,
Org. Lett. 2003, 5, 3033–3035; c) S. Oumouch, M. Bour-
otte, M. Schmitt, J.-J. Bourguignon, Synthesis 2005, 25–
27.
[14] C. O. Kappe, Eur. J. Med. Chem. 2000, 35, 1043–1052.
[15] K. Deres, C. H. Schrçder, A. Paessens, S. Goldmann,
H. J. Hacker, O. Weber, T. Kraemer, U. Niewoehner,
U. Pleiss, J. Stoltefuss, E. Graef, D. Koletzki, R. N. A.
Masantschek, A. Reimann, R. Jaeger, R. Groꢇ, B.
Beckermann, K.-H. Schlemmer, D. Haebich, H. Rꢅbsa-
men-Waigmann, Science 2003, 299, 893–896.
[16] a) H. Prokopcovꢃ, C. O. Kappe, Adv. Synth. Catal.
2007, 349, 448–452; b) A. Lengar, C. O. Kappe, Org.
Lett. 2004, 6, 771–774.
[17] F.-A. Kang, Z. Sui, W. V. Murray, J. Am. Chem. Soc.
2008, 130, 11300–11302.
[18] C. Shi, C. C. Aldrich, Org. Lett. 2010, 12, 2286–2289.
[19] D. Cech, L. Hein, R. Wattke, M. V. Janta-Lipinski, A.
Otto, P. Langen, Nucleic Acids Res. 1975, 2, 2177–2182.
[20] a) Z.-J. Quan, R.-G. Ren, X.-D. Jia, Y.-X. D, Z. Zhang,
X.-C. Wang, Tetrahedron 2011, 67, 2462–2467; b) X.-C.
Wang, G.-J. Yang, X.-D. Jia, Z. Zhang, Y.-X. Da, Z.-J.
Quan, Tetrahedron 2011, 67, 3267–3272; c) Z.-J. Quan,
R.-G. Ren, Y.-X. Da, Z. Zhang, X.-D. Jia, C.-X. Yang,
X.-C. Wang, Heterocycles 2010, 81, 1827–1841; d) X.-C.
Wang, G.-J. Yang, Z.-J. Quan, P.-Y. Ji, J.-L. Liang, R.-
G. Ren, Synlett 2010, 1657–1660; e) X.-C Wang, Z.-J
Quan, J.-K Wang, Z. Zhang, M.-G Wang, Bioorg. Med.
Chem. Lett. 2006, 16, 4592–4595.
[21] CCDC 869876 (4a), CCDC 869878 (7a) and CCDC
869879 (7c) contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[22] 1a was treated with 2a and CuTC in 1,4-dioxane by
heating at 1108C for 12 h yielding the disulfitative
product 3,4-dihydropyrimidinone 1a’.
[6] B. W. Fausett, L. S. Liebeskind, J. Org. Chem. 2005, 70,
4851–4853.
[7] V. P. Mehta, A. Sharma, E. Van der Eycken, Adv.
Synth. Catal. 2008, 350, 2174–2178.
[8] S. Silva, B. Sylla, F. Suzenet, A. Tatibouꢄt, A. P. Rauter,
P. Rollin, Org. Lett. 2008, 10, 853–856.
[9] C. Oliver Kappe, J. Org. Chem. 2007, 72, 4440–4448.
[10] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105,
137–170; Angew. Chem. Int. Ed. Engl. 1993, 32, 131–
163; b) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237–
294; c) T. J. J. Mꢅller, D. M. D’Souza, Pure Appl.
Chem. 2008, 80, 609–620; d) M. Duque, C. Allais, N.
Isambert, T. Constantieux, J. Rodriguez, Top. Hetero-
cycl. Chem. 2010, 23, 227–277; e) B. Jiang, T. Rajale, W.
Wever, S.-J. Tu, G. Li, Chem. Asian J. 2010, 5, 2318–
2335; f) D. Bonne, Y. Coquerel, T. Constantieux, J. Ro-
driguez, Tetrahedron: Asymmetry 2010, 21, 1085–1109.
[11] a) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38,
2993–3009; b) B. B. Tourꢆ, D. G. Hall, Chem. Rev. 2009,
109, 4439–4486; c) M. Colombo, I. Peretto, Drug Dis-
covery Today 2008, 13, 677–684; d) C. Hulme, V. Gore,
Curr. Med. Chem. 2003, 10, 51–80; e) K. Kumaravel, G.
Vasuki, Curr. Org. Chem. 2009, 13, 1820–1841.
[12] a) K. Ogata, Y. Atsuumi, D. Shimada, S.-i. Fukuzawa,
Angew. Chem. 2011, 123, 6018–6021; Angew. Chem.
Int. Ed. 2011, 50, 5896–5899; b) M. D. Mihovilovic, P.
Stanetty, Angew. Chem. 2007, 119, 3684–3688; Angew.
Chem. Int. Ed. 2007, 46, 3612–3615; c) D. M. D’Souza,
T. J. J. Mꢅller, Chem. Soc. Rev. 2007, 36, 1095–1108;
d) J. A. Varela, C. Saa, Synlett 2008, 2571–2578.
[23] 2-Phenylethynyl-1,4-dihydropyrimidine (10) resulted
from 2-(tosyloxy)pyrimidine (9)[20d] cross-coupling with
phenylacetylene. Then 10 was treated with NaBH4 at
room temperature for 60 h to give the 11 (see the Sup-
porting Information).
[24] a) D. Dallinger, N. Yu. Gorobets, C. O. Kappe, Org.
Lett. 2003, 5, 1205–1208; b) C. O. Kappe, P. Roschger,
J. Heterocycl. Chem. 1989, 26, 55–64.
[25] H. Kuniyasu, A. Ohtaka, T. Nakazono, M. Kinomoto,
H. Kurosawa, J. Am. Chem. Soc. 2000, 122, 2375–2376.
[13] For reviews on the Biginelli dihydropyrimidinones see:
a) C. O. Kappe, Tetrahedron 1993, 49, 6937–6963;
2948
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2939 – 2948