Efficient one-pot synthesis of 2,3-dihydropyrimidinthiones via multicomponent coupling of terminal alkynes, elemental sulfur, and carbodiimides

Article abstract of DOI:10.1021/ja9069419

(Chemical Equation Presented) An organolithium-promoted multicomponent reaction (MCR) involving readily available terminal alkynes, elemental sulfur, and carbodiimides has been achieved for the first time. This MCR offers an atom-economic route to 2,3-dih

Full text of DOI:10.1021/ja9069419

Published on Web 10/02/2009
Efficient One-Pot Synthesis of 2,3-Dihydropyrimidinthiones via Multicomponent
Coupling of Terminal Alkynes, Elemental Sulfur, and Carbodiimides
Zitao Wang,† Yang Wang,† Wen-Xiong Zhang,*,†,‡ Zhaomin Hou,§ and Zhenfeng Xi*,†
Beijing National Laboratory for Molecular Sciences and Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of the Ministry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, China, State
Key Laboratory of Elemento-Organic Chemistry, Nankai UniVersity, Tianjin 300071, China, and Organometallic
Chemistry Laboratory, RIKEN AdVanced Science Institute, Hirosawa 2-1, Wako, Saitama 351-0198, Japan
Received August 19, 2009; E-mail: wx_zhang@pku.edu.cn; zfxi@pku.edu.cn
Multicomponent reactions (MCRs) have become very useful for
fast and efficient construction of important molecules.1 Utilization
of common and readily available chemicals as their components
and involvement of selective cleavage of chemical bonds such as
CdN double bonds and C-H bonds should make an MCR much
more attractive both fundamentally and synthetically.2,3 Herein we
report a novel organolithium-promoted MCR involving terminal
alkynes, sulfur, and carbodiimides (Scheme 1) that affords 2,3-
dihydropyrimidinthiones via CdN double bond cleavage and sp3
C-H bond functionalization of the carbodiimide molecule. Forma-
tion and characterization of an η3-S-C-N lithium species in the
reaction process indicates that a molecule of carbodiimide is torn
up into three fragments that are selectively incorporated into the
2,3-dihydropyrimidinthione skeleton, forming two C-N single
bonds, one CdC double bond, and one C-H bond.
Figure 1. ORTEP drawing of 1a with 30% thermal ellipsoids.
C-H bond functionalization as well as the first example of an efficient
preparation of well-defined 2,3-dihydropyrimidinthiones,9 which are
difficult to access by other means and might show unique biological
activity.10
Table 1. Formation of Various 2,3-Dihydropyrimidinthionesa
Scheme 1. MCR Synthesis of 2,3-Dihydropyrimidinthiones via
CdN Cleavage and sp3 C-H Bond Functionalization of
Carbodiimides
entry
R
R1
R2
R3
1 (% yieldb)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Me
Me
iPr
Cy
Ph
Ph
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
1a (83)
1b (74)
1c (80)
1d (52)
1e (73)
1f (66)
1g (73)
1h (71)
1i (63)
1j (53)
1k (77)
1l (83)
1m (71)c
1n (73)c
-(CH2)5-
-(CH2)5-
Phenylethyne was first treated with n-BuLi in THF at -78 °C to
afford phenylethynyllithium, to which 1 equiv of elemental sulfur was
then added. After the mixture was stirred at room temperature for 2 h,
N,N′-diisopropylcarbodiimide (iPrNdCdNiPr) was added. The reaction
mixture was then heated to 80 °C for 4 h. Hydrolysis of the reaction
mixture with water afforded an unexpected product, 2,3-dihydropy-
rimidinthione 1a, X-ray structural analysis of which revealed, to our
surprise, that the C1 atom from iPr is bonded to the two nitrogen atoms
from the initial iPrNdCdNiPr (Figure 1). Three components, including
phenylethyne, sulfur, and iPrNdCdNiPr, were incorporated into the
new molecule, providing an efficient strategy for the construction of
compounds containing sulfur from abundant elemental sulfur. Interest-
H
Ph
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
3-ClC6H4
3-thienyl
cyclohexyl
CH3(CH2)4
-(1,4-C6H4)-
-(CH2)4-
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
9
10
11
12
13
14
a Conditions: terminal alkyne (1 mmol), carbodiimide (1 mmol), sulfur
(1 mmol), THF (10 mL), unless otherwise noted. b Isolated yield.
c Conditions: terminal diyne (1 mmol), carbodiimide (2 mmol), sulfur (2
mmol).
i
ingly, the starting PrNdCdNiPr underwent CdN double bond
cleavage and sp3 C-H bond functionalization to produce three different
fragments that contributed to the formation of 1a via the formation of
two C-N single bonds, one CdC double bond, and one C-H bond.
Carbodiimides for a long time have proved to be versatile reagents
for organic synthesis, pharmaceutical chemistry, and organometallic
chemistry.4-8 As far as we are aware, this is the first example of
carbodiimide rearrangement via CdN double bond cleavage and sp3
Summarized in Table 1 are representative results obtained from
n-BuLi-mediated reactions among terminal alkynes, sulfur, and
carbodiimides. In the presence of 1 equiv of n-BuLi, the reactions
of phenylethyne with carbodiimides having at least one R-H-
neighboring nitrogen atom, such as iPrNdCdNiPr, CyNdCdNCy,
PhNdCdNCy, and PhNdCdNBn, were carried out at 80 °C for
4 h to yield the corresponding 2,3-dihydropyrimidinthiones 1a-d
in moderate to high isolated yields (entries 1-4). Aromatic terminal
alkynes with either electron-withdrawing or -donating substituents
† Peking University.
‡ Nankai University.
§ RIKEN Advanced Science Institute.
9
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10.1021/ja9069419 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
on the phenyl ring all afforded their corresponding 2,3-dihydro-
pyrimidinthiones 1e-i in good isolated yields (entries 5-9). It is
noteworthy that halogen tolerance was also observed, as aromatic
C-Cl bonds survived under the present conditions to selectively
yield the corresponding chloro-substituted 2,3-dihydropyrimidin-
thiones 1h and 1i (entries 8 and 9). Aromatic terminal alkynes with
ortho substituents, such as 2-methoxy- and 2-chloroethynylbenzene,
were not suitable for this reaction, probably because of their steric
hindrance. Heteroatom-containing alkynes, such as 3-ethynylth-
iophene (entry 10), were also applicable. In addition, aliphatic
alkynes could be also applied (entries 11 and 12). Furthermore the
diynes 1,4-diethynylbenzene and 1,7-octadiyne reacted with 2 equiv
of elemental sulfur and iPrNdCdNiPr to afford the corresponding
bis(2,3-dihydropyrimidinthione) compounds 1m and 1n in 71 and
73% isolated yield, respectively (entries 13 and 14).
carbodiimide.12 It is not clear yet how the final η3-S-C-N lithium
species C is formed from the four-membered-ring intermediate B
and/or B′ (see the Supporting Information for more discussion).
In summary, an organolithium-promoted MCR involving terminal
alkynes, elemental sulfur, and carbodiimides has been achieved for
the first time and offers a straightforward route to 2,3-dihydropy-
rimidinthiones that may have important biological activity. More-
over, the results observed in this work demonstrate that carbodi-
imides can undergo interesting and useful CdN double bond
cleavage and an sp3 C-H bond functionalization. Studies of
mechanistic aspects and reaction applications are in progress.
Acknowledgment. This work was supported by the Natural
Science Foundation of China and the Key Project of International
Cooperation of NSFC (20920102030).
Supporting Information Available: Experimental details, X-ray
data for 1a (CIF), and scanned NMR spectra of all new products. This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Isolation and Trapping Experiments on Intermediate 2
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Successful isolation and characterization of an η3-S-C-N
lithium species 2 from the reaction mixture of PhCtCLi, sulfur,
i
and PrNdCdNiPr before quenching were achieved, and this was
very useful for understanding the reaction mechanism (Scheme 2;
for details, see the Supporting Information). The intermediate 2
was further confirmed by trapping with various electrophiles such
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Scheme 4 shows a possible route for the formation of dihydro-
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be formed via cyclization after nucleophilic attack by A′ on a
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