Reactions of zirconocene butadiyne or monoyne complexes with nitriles: Straightfoward synthesis of functionalized pyrimidines

Article abstract of DOI:10.1021/om400880r

Zirconium-mediated multicomponent reactions of silyl-butadiynes with two molecules of aryl nitriles are described, which provide rapid access to polysubstituted pyrimidines in a regioselective manner and in one pot. Employing aliphatic nitriles results in coupling of only one nitrile, leading to the formation of enynyl ketones after hydrolysis. A zirconocene monoyne complex undergoes similar reactions with nitriles to form highly substituted pyrimidines.

Full text of DOI:10.1021/om400880r

Communication
pubs.acs.org/Organometallics
Reactions of Zirconocene Butadiyne or Monoyne Complexes with
Nitriles: Straightfoward Synthesis of Functionalized Pyrimidines
Xu You, Shasha Yu, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, People’s Republic of China
*
S Supporting Information
ABSTRACT: Zirconium-mediated multicomponent reactions of silyl-
butadiynes with two molecules of aryl nitriles are described, which provide
rapid access to polysubstituted pyrimidines in a regioselective manner and in
one pot. Employing aliphatic nitriles results in coupling of only one nitrile,
leading to the formation of enynyl ketones after hydrolysis. A zirconocene
monoyne complex undergoes similar reactions with nitriles to form highly
substituted pyrimidines.
ive-membered group 4 metallacyclocumulenes, first
reported in 1994 by Rosenthal et al., have attracted
nitriles, which provides a straightforward route for the synthesis
1
F
of pyrimidines in a regioselective manner (Scheme 1). In
addition, this reaction can be extended to zirconocene
monoyne complexes. To our knowledge, such a reaction
mode has not been reported in zirconium chemistry.
Pyrimidines exist as key structures in numerous natural
products, such as vitamin B1 (thiamine), heteromine F,
much attention due to their fascinating structural features and
2
,3
their unusual reactivities.
These complexes could be
synthesized by various methods, such as ligand exchange
reactions of 1,3-butadiynes with the alkyne complexes Cp M-
2
2
(
=
L)(η -Me SiCCSiMe ) (M = Ti, L = ligandless; M = Zr, L
3
3
2
a
11
THF, pyridine), B(C F ) -catalyzed isomerization of
6 5 3
3b,g
variolin-type alkaloids and meridianin, etc., and in biologically
1
2a
12b
bis(alkynyl)zirconocenes,
reactions of diyne with dihalide
2a
active substances, including nimustine,
pyrimethamine,
1
2c
12
metal complexes using magnesium as the reductant, or light-
phosphatidylinositol 3-kinase inhibitors, etc. Therefore, the
2a
induced rearrangement of metallocene bis-acetylides. How-
ever, these methods usually require expensive precursors or
catalyst or are restricted to special substrates. Recently, we
found a very convenient method for the monozirconation of
development of an efficient synthetic route to pyrimidines is
13
highly needed.
It is known that nitrile couples with zirconacyclopentene, a
zirconocene alkyne equivalent, to afford azazirconacyclopenta-
1
,3-butadiynes with bulky silyl- or tert-butyl substituents using
6b
diene. We expected that the unique reactivity of a
4
Negishi reagent without addition of any ligands. We suggested
that five-membered zirconacyclocumulenes were formed in
these reactions according to NMR studies of the zirconium
zirconocene butadiyne complex might lead to different reaction
patterns and a new development in organic synthesis. As
4
demonstrated in our previous study, reaction of the 1,3-
intermediates and the single-crystal X-ray analysis of [Cp Zr-
2
butadiyne 1 bearing bulky silyl groups with Negishi reagent
resulted in the formation of zirconacyclocumulene 3 as a major
product, which is possibly in equilibrium with the three-
membered alkynylzirconacyclopropene 2, although the equili-
brium lies predominantly on the side of 3 (see Table 1). The
reaction of a zirconocene butadiyne complex derived from 1,4-
bis(tert-butyldimethylsilyl)buta-1,3-diyne (1a) with 3 equiv of
benzonitrile in toluene was examined first. It was found that the
fully substituted pyrimidine 4a was formed in 81% yield at 80
°C for 5.5 h with excellent regioselectivity. The results indicated
that two molecules of nitriles incorporated into the metalla-
cycle. To our knowledge, this type of reactivity has not been
reported in group 4 metal complex mediated coupling reactions
of alkynes with nitriles. We next investigated the scope of
nitriles using 1a as a reaction partner in most cases. A variety of
aryl nitriles could be used as effective substrates for this
4
t
t
(
η -1,2,3,4- BuC Bu)]. These complexes show diverse and
4
interesting reactivities toward aldehydes, carbamoyl cyanides,
4
,5
aroyl cyanides, and alkyl cyanoformates. We next became
interested in the potential coupling reactions of zirconocene
butadiyne complexes with normal nitriles. The reactivity of
nitriles with group 4 metal complexes has been intensely6
studied over the last few decades, in which CN insertion,
7
C−H activation, and deprotonation/proton transfer to form a
zirconocene keteniminate species (when nitriles possess an
8
,9
acidic α-proton)
have been observed. Very recently,
Rosenthal et al. reported that a seven-membered zirconacyclo-
cumulene derived from coupling of 2 equiv of 1,4-bis-
trimethylsilyl)buta-1,3-diyne could react with 2 equiv of
(
phenylacetonitrile, leading to fused azazirconacycles, in which
a five-membered zirconacyclocumulene generated by elimi-
nation of one butadiyne at high temperature (100 °C) was
10
assumed to be the reactive intermediate. In this communi-
cation, we report a novel multicomponent coupling reaction of
a zirconocene butadiyne complex with two molecules of
Received: September 3, 2013
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Scheme 1
Table 2. Zirconium-Mediated Multicomponent Reactions of
Monoynes with Nitriles
Table 1. Zirconium-Mediated Multicomponent Reactions of
a
1
,3-Butadiynes with Nitriles
a
Isolated yields.
a
b
Scheme 3
Isolated yields. Containing a small amount of impurity.
Scheme 2
reaction. It was found that the aromatic rings of nitriles bearing
an electron-donating or an electron-withdrawing group were all
compatible under the reaction conditions. For example, p-Cl-,
p-Br-, and p-CF -substituted aryl nitriles afforded 4b,c,g in 83−
3
t
8
8% yields. The use of p-CH -, p- Bu-, and p-MeO-substituted
3
aryl nitriles afforded 4h−j in similar yields of 83−87%. The
results indicated that the electronic nature of the aryl
substituents on nitriles had little influence on the product
yields. However, when 2-fluorobenzonitrile was employed, only
or 1-methyl-1H-indole-3-carbonitrile were also suitable for this
reaction, furnishing the corresponding 4k,l in 76% and 79%
3
8% of 4e was obtained, possibly due to steric interactions.
Heteroaryl-substituted nitriles such as 2-thiophenecarbonitrile
yields, respectively. When TBS on the diyne terminus was
i
replaced by the more bulky Si( Pr) (TIPS) group, a lower yield
3
B
dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Scheme 4
18
of 70% was observed for 4m in comparison with 4a using
insertion reactions. Alternatively, 11 undergoes [4 + 2]
benzonitrile as a coupling partner. The structure of pyrimidine
cycloaddition with nitrile followed by elimination of low-valent
19
II
4
was unambiguously confirmed by an X-ray crystallographic
zirconium species to afford 4 (path b). The released “Cp Zr ”
2
1
4
analysis of 4c.
might be trapped by excess nitrile.
The reactions of 1a with aliphatic nitriles such as acetonitrile
and 2-(2-bromophenyl)acetonitrile were also examined. How-
ever, only enynyl ketones 6a,b resulting from the insertion of
one CN bond into the zirconocene butadiyne complex were
obtained in 64% and 32% yields, respectively, after quenching
the reaction mixture with 3 N HCl (Scheme 2). The desired
pyrimidines were not observed. This might be due to the lower
reactivity of alkyl nitriles or the presence of acidic α-proton in
arylacetonitriles, leading to undesired reactions such as
According to the above reaction mechanism, it is possible to
couple one butadiyne with two different nitriles. Interestingly,
when 2a was treated with 1 equiv of p-MeOC H CN and
stirred at 50 °C for 1 h, a large amount of red solid precipitated.
The insolubility of this solid species in the usual solvents
precluded their characterization by NMR. To the thus formed
6
4
reaction mixture was added p-BrC H CN and the mixture was
6 4
stirred at 80 °C for 3 h; pyrimidine 4n with two different aryl
groups was formed in 32% yield, together with 4c in 45% yield
(Scheme 4). The structure of pyrimidine 4n was also confirmed
8
,10
deprotonation.
14
The above reactions could be extended to monoynes. For
example, reactions of the phosphine-stabilized zirconocene
by X-ray crystallographic analyses. During this period, the
amount of the solid component gradually decreased. The
results indicated that an intermediate such as azazirconacyclo-
pentadiene might undergo a β,β′-C−C bond cleavage reaction
in the presence of a second nitrile to form a new
azazirconacycle, while the first nitrile was released. Although
zirconacycles such as zirconacyclopentenes and zirconacyclo-
pentadienes are known to undergo a β,β′-C−C bond cleavage
1
5
alkyne complex 7 with aryl nitriles at 80 °C in toluene
14
generated aryl-substituted pyrimidines 8 in moderate yields
Table 2). These results make this chemistry very useful due to
(
the extended substrate scope. Recently, a NbCl -mediated
5
cycloaddition of monoynes and nitriles has been reported;
however, the use of a diarylacetylene such as diphenylacetylene
6b,8,20
16
reaction under the appropriate conditions,
there has been
could not produce the desired pyrimidine in their system.
no report for such fragmentation reactions of azazircona-
The reaction is also quite different with that of titanium-
mediated coupling of alkynes with nitriles (restricted to α-
methoxyacetonitrile), in which double addition of the nitrile to
the titanium alkyne complex occurs to form diimines after
hydrolysis. The dimines could be transformed into pyrroles
21
cycles.
In summary, we have developed a new cycloaddition reaction
of zirconocene butadiyne complexes with aryl nitriles, which
provided an efficient route to polysubstituted pyrimidines in a
regioselective manner. Employing aliphatic nitriles resulted in a
coupling of only one nitrile, leading to the formation of enynyl
ketones after hydrolysis. The reaction has been extended to
zirconocene monoyne complexes. Clarification of the reaction
mechanism and further application of this chemistry are in
progress.
17
upon acidic workup.
We tentatively propose the following reaction mechanism for
this novel transformation using butadiyne as substrates
(Scheme 3): first of all, an equilibrium between zirconacyclo-
pentatriene 3 and zirconacyclopropene 2 exists in the reaction
mixture, in which 3 is likely to be the dominant species,
3
l,4
whereas 2 is more reactive. An S 2′-type addition of a nitrile
E
ASSOCIATED CONTENT
CN bond to the less hindered propargyl zirconium moiety in
■
complex 2 takes place to deliver the azazirconacyclocumulene
S
*
Supporting Information
1
0, which might isomerize to azazirconacyclopentadiene 11.
Text, figures, tables, and CIF files giving general experimental
methods, synthesis and characterization of 4a−m, 6a,b, 8a−e,
and 4n, X-ray crystal structures of 4c,n and 8a, and NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Zirconacycle 11 might also be formed by direct insertion of a
2
CN bond into the Zr−C(sp ) bond close to the TBS group of
2. However, attack of the nitrile from this side may encounter
large steric hindrance. Next, insertion of the CN bond of the
second nitrile into the Zr−N bond of zirconacycle 11 via attack
of the imine nitrogen atom at nitrile followed by reductive
elimination furnishes the pyrimidine product 4 (path a). It
should be noted that, despite the large number of zirconacycles
AUTHOR INFORMATION
■
*
Corresponding Author
Y.L.: fax, (+86) 021-64166128; e-mail, yhliu@mail.sioc.ac.cn.
containing Zr−N bonds, only a few known complexes such as
2
the (η -1,2-diphenylhydrazido)zirconocene complex Cp Zr-
Notes
2
(
N Ph ) and an azaoxazirconacycle underwent Zr−N bond
The authors declare no competing financial interest.
2
2
C
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Organometallics
Communication
(
2
c) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev.
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dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX