Copper-Catalyzed Synthesis of Substituted 2,4-Diamino-1,3,5-triazines from 1,1-Dibromoalkenes and Biguanides

Article abstract of DOI:10.1021/acs.orglett.7b01608

An efficient copper-catalyzed synthesis of substituted 2,4-diamino-1,3,5-triazines from 1,1-dibromoalkenes and biguanides under mild conditions has been developed. The reaction occurred in moderate to good yields and tolerated alkyl-, heterocyclic-, or ar

Full text of DOI:10.1021/acs.orglett.7b01608

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Synthesis of Substituted 2,4-Diamino-1,3,5-
triazines from 1,1-Dibromoalkenes and Biguanides
Chen Zhang,*,† Meng-Tao Ban,† Kai Zhu,‡ Li-Yu Zhang,§ Zhen-Yu Luo,† Shun-Na Guo,†
Dong-Mei Cui,*,‡ and Yu Zhang§
†College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
‡College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, PR China
§School of Pharmaceutical Sciences, Jiamusi University, Jiamusi 154007, PR China
S
* Supporting Information
ABSTRACT: An efficient copper-catalyzed synthesis of
substituted 2,4-diamino-1,3,5-triazines from 1,1-dibromoal-
kenes and biguanides under mild conditions has been
developed. The reaction occurred in moderate to good yields
and tolerated alkyl-, heterocyclic-, or aryl-substituted 1,1-dibro-
moalkenes containing functionalities such as nitriles, ethers,
and halogens. Monosubstituted to tetrasubstituted biguani-
dines also afforded the desired products.
he triazines are one of the important classes of nitrogen
heterocyclic compounds and are also ubiquitous structural
A higher or lower reaction temperature did not facilitate the
reaction (Table 1, entries 7 and 8).
T
motifs in biologically active molecules. Substituted 2,4-diamino-
1,3,5-triazine derivatives exhibit several antibacterial, anti-HSV-1,
anticancer, and anti-HIV biological activities.1 The traditional
synthetic methodologies to prepare substituted 1,3,5-triazine
derivatives involve a nucleophilic substitution reactions of cyan-
uric chloride.2 Methods that construct triazinic rings have also
been developed.3 Recently, we reported Ru-catalyzed synthesis
of substituted 2,4-diamino-1,3,5-triazines from alcohols and
biguanidines.4 The transition-metal-promoted formation of
C−N bonds has become one of the most important strategies
for the synthesis of heterocycles.5 Among the transition metals
employed in such reactions, Cu(I) as a catalyst is usually used
because of its major advantages of being inexpensive and easy to
handle. On the other hand, 1,1-dihaloalkenes, which can be
easily prepared from corresponding aldehydes and ketones,
serve as a key unit in the synthesis of polysubstituted alkenes,
various alkynes, carbocycles, carboxamide, and heterocycles by
metal-catalyzed coupling reactions.6−12 Herein, we report that
1,1-dibromoalkenes can be successfully coupled with biguanides
to synthesize trisubstituted 1,3,5-triazines using copper as the
catalyst.
We initially examined the reaction between 4-(2,2-dibromo-
vinyl)-1,2-dimethoxybenzene (1a) and dimethylbiguanide hydro-
chloride (2a) in the presence of CuI (10 mol %), 2,2′-bipyridine
(L1) (20 mol %), and K3PO4 (3 equiv) in dioxane at 110 °C.
The reaction proceeded to give exclusively the trisubstituted
1,3,5-triazine 3a in 86% yield (Table 1, entry 1).
Further studies prompted us to carry out the reaction using
various ligands along with CuI. Among various ligands like
1,10-phenanthroline (L2), ninhydrin (L3), glycine (L4), L-proline
(L5), and N1,N1,N2,N2-tetramethylethane-1,2-diamine (L6),
2,2′-bipyridine (L1) was the best option (Table 1, entries 1−6).
Replacement of K3PO4 by K2CO3, KOH, Cs2CO3, CsOAc, or
tBuOK led to a lower or no yield (Table 1, entries 9−13). In the
absence of K3PO4, no product was formed (Table 1, entry 24).
Other solvents were also screened under the standard con-
ditions. While DMF resulted in no product formation, THF
and CH3CN as solvents only gave yields of 46% and 16%,
respectively (Table 1, entries 14−16). Other copper salts were
tested in this reaction, and similar yields were obtained when
CuI was replaced by Cu2O (Table 1, entry 19). Cu(OAc)2,
CuCl, and CuBr were proved to be less effective or ineffec-
tive (Table 1, entries 20−22). Reducing the amount of CuI
resulted in a slightly lower yield (Table 1, entry 17). With-
out CuI or ligand, the reaction was less efficient (Table 1,
entries 23 and 25).
To examine the generality and scope of this method, reactions
of several 1,1-dihaloalkenes with 2a were next carried out under
optimized conditions. The results are summarized in Scheme 1.
We first surveyed the compatibility of aryl-substituted 1,1-dibro-
moalkenes. Aryl 1,1-dibromoalkenes with electron-withdrawing
substituents gave lower yields than electron-donating ones
(Scheme 1, compounds 3b−m). For example, the reaction of
1-(2,2-dibromovinyl)-4-methoxybenzene (1c) and 2a afforded
3c with 84% isolated yield, whereas 1-(2,2-dibromovinyl)-4-
bromobenzene (1j) showed lower reactivity under the same
conditions and provided 54% yield of 3j, and steric hindrance is
not operative in this coupling reaction.
Notably, heterocycle-substituted 1,1-dibromoalkenes were
also found to be suitable reaction partners for oxygen- and
Received: May 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of the Synthesis of 3
a
All reactions were performed with 1 mmol of 1 and 0.5 mmol
of 2a using Cu1+ catalyst (10 mol %), ligand L (20 mol %), K3PO4
(20 mol %), and dioxane (5 mL) at 110 °C for 13 h in a sealed
b
reaction tube, isolated yields are shown. X = Br, Cu1+ catalyst:
c
CuI, and ligand L: 2.2′-bipyridine (L1). X = Br, Cu1+ catalyst:
d
CuI, and ligand L: Iinhydin (L3). X = Br, Cu1+ catalyst: Cu2O,
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Cu catalyst
e
and ligand L: 2.2′-bipyridine (L1). X = Cl, Cu1+ catalyst: CuI, and
(0.05 mmol), L (0.10 mmol), base (3 mmol), solvent (5 mL), 12 h;
ligand L: Glycine (L4).
b
c
isolated yields are shown. CuI (0.025 mmol). 1a (0.75 mmol).
sulfur-containing aromatics, and the corresponding products
were obtained in good yields (Scheme 1, 3n and 3o). In par-
ticular, aliphatic 1,1-dibromoalkenes 1p and 1q could also show
better reactivity and yields toward triazines (Scheme 1, 3p and
3q). As expected, 1,1-dichloroalkenes could be used as the
starting compounds and showed a slightly lower reactivity, giving
products 3b and 3r with lower yields.
On the basis of the above results, a catalytic cyclization path-
way was proposed (Figure 1).13 Under conditions, the intermediate
B was formed by insertion of the catalytic complex of [Cu]-ligand
to the C−X bond of A, and then the alkyne complex C was
formed from B with dehalogenation by the base. Intermediate D
was generated with nucleophilic attack to Cu+ of C by diguanide,
the next intermediate E was formed from D via intramoleculer
nucleophilic attack of the N atom, and then the aza-cyclic
intermediate F was formed via demetalization with halogen
ion and intramoleculer nucleophilic attack from the other
N atom. F should be isomerized immediately to the aromatic
product 3 or 4.
Finally, this reaction also occurred with 1,1-dibromoalkenes
and cyclic amino-substituted diguanidines, monosubstituted
diguanidine, trisubstituted diguanidine, or tetrasubstituted
diguanidine (Scheme 2). In these cases, substrates such as
morpholine diguanidine, pyrrolidine diguanidine, and piper-
dine materials worked well and afforded the correspond-
ing products in good yields. Trisubstituted and tetrasubsti-
tuted diguanidine, however, proved to be less efficient in terms
of reactivity, leading to low yields (4h, 4i, 34%, 43% yield,
respectively).
Figure 1. Proposed mechanism of formation 3 or 4.
In summary, we have developed a simple and efficient protocol
for the synthesis of trisubstituted 1,3,5-triazines via copper(I)-
catalyzed reaction of 1,1-dibromoalkenes with diguanides. The
method employs readily available reagents and has broad scope
and high functional group tolerance. On the basis of a large
assortment of bioactive triazines, this new synthetic method will
B
DOI: 10.1021/acs.orglett.7b01608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 2. Scope of the Synthesis of 4
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a
Reaction conditions: 1 (1 mmol), 2 (0.5 mmol), CuI (0.05 mmol),
ninhydin (0.10 mmol), K3PO4 (3 mmol), dioxane (5 mL), 12 h;
isolated yields. Cu2O as catalyst was used. Cu2O as catalyst and
glycine as ligand were used. Glycine as ligand was used.
b
c
d
serve as a valuable tool to efficiently construct new members of
fused triazine derivatives in drug discovery, with potential for
biological applications.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01608.
Synthetic procedures and NMR data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenzhang@zju.edu.cn.
*E-mail: cuidongmei@zjut.edu.cn.
ORCID
Chen Zhang: 0000-0002-2647-3266
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.7b01608
Org. Lett. XXXX, XXX, XXX−XXX