Ambient-Light-Promoted Three-Component Annulation: Synthesis of Perfluoroalkylated Pyrimidines

Article abstract of DOI:10.1021/acs.orglett.7b00894

An ambient-light-promoted and metal-free three-component reaction of active methylene compounds, perfluoroalkyl iodides, and guanidines/amidines is reported. This constitutes a powerful method to prepare perfluoroalkylated pyrimidines with mild reaction conditions, broad substrate scope, excellent functional group tolerance, and simple operation. A radical/polar mechanism involving the formation of a halogen-bond adduct and radical cross-coupling is proposed.

Full text of DOI:10.1021/acs.orglett.7b00894

Letter
pubs.acs.org/OrgLett
Ambient-Light-Promoted Three-Component Annulation: Synthesis
of Perfluoroalkylated Pyrimidines
Rui Wang, Wei Guan, Zheng-Bo Han, Fushun Liang,*,† Takeo Suga, Xihe Bi,*
†
,‡
‡
†
∥
,‡
∥
and Hiroyuki Nishide
†
College of Chemistry, Liaoning University, Shenyang 110036, China
‡
Department of Chemistry, Northeast Normal University, Changchun 130024, China
∥Department of Applied Chemistry, Waseda University, Tokyo 169-8555, Japan
*
S Supporting Information
ABSTRACT: An ambient-light-promoted and metal-free
three-component reaction of active methylene compounds,
perfluoroalkyl iodides, and guanidines/amidines is reported.
This constitutes a powerful method to prepare perfluoroalky-
lated pyrimidines with mild reaction conditions, broad
substrate scope, excellent functional group tolerance, and
simple operation. A radical/polar mechanism involving the
formation of a halogen-bond adduct and radical cross-coupling is proposed.
yrimidine and its derivatives are ubiquitous in natura1l
P
products, synthetic drugs, and functional materials.
Traditionally, pyrimidines could be synthesized by the
condensation of amidines or amidinium salts with 1,3-
2
dicarbonyl compounds, cyclization of amides, nitriles mediated
by trifluoromethanesulfonic anhydride and 2-chloropyridine
3
reagent combination, inverse-electron-demand Diels−Alder
4
reactions of 1,2,3-triazines with amidine dienophiles, and
transition-metal-catalyzed modification by cross-coupling of
5
halogen precursors. In past years, transition-metal-catalyzed
multicomponent assembly of pyrimidines has emerged as a
powerful and useful alternative strategy. Representative work
includes the palladium-catalyzed alkynone intermediate-based
three- or four-component pyrimidine synthesis reported by the
6
Mu
̈
ller group (Figure 1a); titanium-catalyzed one-pot and two-
step cycloaddition of alkynes, nitriles, amines, and almidines
developed by Odom and co-workers; (Figure 1b) and
7
Kempe’s iridium- or manganese-catalyzed multicomponent
8
synthesis of pyrimidines from amidines and alcohols (Figure
1c). In addition, Wu and Jiang reported an elegant palladium-
Figure 1. Multicomponent assembly of functionalized pyrimidines.
catalyzed oxidative three-starting-material, four-component
reaction strategy for the synthesis of pyrimidine carboxamides
1
5
9
amidines (Figure 1e). This research represents the first
photopromoted halogen-bond adduct enabled three-compo-
nent cascade strategy leading to perfluoroalkylated pyrimidines.
The introduction of fluorine(s) into pyrimidine ring is of great
value because the perfluoroalkyl group would strongly modify
(Figure 1d). While remarkable progress has been made, the
method for assembling fluorine-functionalized pyrimidines by a
10
multicomponent reaction has been less developed so far.
Electron-donor−acceptor (EDA) complexes have recently
1
1
found exciting applications in organic synthesis. The
halogen-bond adduct, which is formed on the basis of
16
their lipophilicity, bioactivity, and metabolic stability.
12
Our initial investigation focused on the condition optimiza-
tion with the model reaction of ethyl acetoacetate 1a,
perfluorobutyl iodide 2a (1.1 equiv), and guanidine hydro-
intermolecular noncovalent weak interaction, is undoubtedly
classified as an EDA complex. As part of our continued interest
13
in halogen-bond chemistry, we here report a metal-free and
14
visible-light-promoted three-component reaction to assemble
the pyrimidine scaffold via formal [2 + 1 + 3] cyclization of
active methylenes, perfluoroalkyl iodides, and guanidines/
Received: March 27, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of Active Methylenes −
a c
chloride 3a (1.1 equiv) in the presence of a base (4.1 equiv)
(Table 1). Note that 1 equiv of the base is used to neutralize
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
K CO
MeCN
MeCN
MeCN
MeCN
24
10
7
nr
39
70
87
24
nr
nr
nr
80
83
nr
nr
38
86
2
3
Cs CO
2
3
KOH
NaOH
NaOEt
6
Me CN
11
15
12
9
3
NaOtBu
MeCN
MeCN
MeCN
DMF
Et N
3
DABCO
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
6
10
11
12
13
14
DMSO
DCM
6
a
Reaction conditions: 1 (0.1 mmol), NaOH (4.1 equiv), 2a (1.1
b
12
14
6
equiv), and 3a (1.1 equiv) in MeCN (0.5 mL). 1 equiv of the base
was used to neutralize HCl from 3a. Isolated yields. In DMSO (0.5
mL). In DMF (0.5 mL).
c
d
toluene
MeCN
MeCN
d
e
e
6
a
giving the corresponding 4-perfluoropropyl pyrimidines 4a−d
in 81−87% yields. α-Aroyl esters (R = H, 4-Me, 4-MeO, 4-F)
afforded 6-arylpyrimidines 4e−h in good to excellent yields.
However, ethyl 4-nitrobenzoylacetate was inactive, while β-
diketones proved to be suitable substrates. For example,
pentane-2,4-dione and dibenzoylmethane furnished 5-acyl-
substituted pyrimidines 4i and 4j in 78% and 49% yields,
respectively. However, deacetylation was observed for
benzoylacetone, giving trisubstituted pyrimidine 4k in 48%
yield.
To further examine the scope and utility of this reaction, the
scope of guanidine and amidine derivatives was examined by
reaction with β-keto esters and 2a under otherwise identical
conditions (Scheme 2). To our delight, N-methyl- and N,N-
dimethylguanidines gave fully substituted pyrimidines 5a and
Reaction conditions: 1a (0.1 mmol), base (4.1 equiv), 2a (1.1 equiv),
b
and 3a (1.1 equiv) in solvent (0.5 mL). 1 equiv of the base is used to
neutralize HCl from 3a. Isolated yield. In the dark. Reaction under
N atomosphere. nr = no reaction.
c
d
e
2
HCl from 3a. No reaction occurred with K CO (4.1 equiv) as
the base in MeCN (0.5 mL) (entry 1). Delightfully, in the case
of using Cs CO as the base, fully substituted pyrimidine 4a
was obtained in 39% yield (entry 2). An improved yield of 70%
was achieved with KOH (entry 3), and NaOH proved to be
more effective, giving 4a in 87% yield (entry 4). The structure
of 4a was unequivocally resolved by single-crystal X-ray analysis
2
3
2
3
(
CCDC 1485697). Other bases like NaOEt led to significantly
decreased yield (24%), and NaOtBu was completely inactive
entries 5 and 6). Organic bases such as triethylamine and 1,4-
diazabicyclo[2.2.2]octane (DABCO) proved to be ineffective
entries 7 and 8). We supposed that organobases mentioned
(
a,b
Scheme 2. Scope of Guanidines and Amidines
(
above may function as electron donors to interact with 2a, an
electron acceptor, thus inhibiting the formation of EDA
complex between the enolates of 1a and 2a. The choice of
the solvent is also crucial for the reaction (entries 9−12). In
comparison with MeCN, DMSO and DMF were less efficient
(
entries 9 and 10), whereas dichloromethane (DCM) and
toluene were totally inert (entries 11 and 12). Notably, all of
the reactions were carried out at room temperature under
ambient light conditions. However, reactions conducted in the
dark led to remarkably decreased yield (entry 13), illustrating
that visible light is helpful in promoting the reaction. In
addition, reaction under N atomosphere proceeded as well
2
(
entry 14), thus indicating oxygen has no effect on the
transformation.
With the optimized conditions in hand (Table 1, entry 4), we
set out to study the reaction scope. Initially, a range of active
methylene compounds were subjected to the reaction sequence
at room temperature in the open air conditions (Scheme 1).
The reactions of β-keto esters containing alkyl substituents (R
a
=
Me, Et, i-Pr, CF ) with perfluorobutyl iodide 2a (1.1 equiv)
3
Reaction conditions: 1 (0.1 mmol), base (4.1 equiv), 2a (1.1 equiv)
b c
and guanidine hydrochloride 3a (1.1 equiv) in the presence of
and 3 (1.1 equiv) in MeCN (0.5 mL). Isolated yield. In DMF (0.5
NaOH (4.1 equiv) in MeCN (0.5 mL) proceeded smoothly,
mL).
B
DOI: 10.1021/acs.orglett.7b00894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
b in 55% and 88% yields, respectively. A number of amidines
Letter
5
methyl guanidine (3.3 equiv), tetrasubstituted alkene 7 was
isolated in 55% yield (eq 1), thus suggesting a S V reaction
with different steric and electronic properties were appropriate
partners. The reactions proceeded efficiently for both alkyl- and
arylamidines, affording highly functionalized pyrimidines 5c−n
in moderate to excellent yields as well as good functional group
tolerance. Note that pyrimidine-cored m-teraryls 5e−k were
successfully prepared by the reaction of α-benzoyl ester, 2a, and
arylamidines, which are generally obtained via a transition-
N
might take place. To probe whether radical intermediates are
involved in this three-component reaction, 2,2,6,6-tetramethyl-
piperidine-N-oxyl (TEMPO), an efficient free radical scavenger,
was introduced as an additive under the standard conditions
(eq 2). The reaction to form 4a was completely inhibited,
suggesting that TEMPO has significant effect on the reaction.
Furthermore, we examined the reaction in the presence of a
single electron transfer (SET) inhibitor, p-dinitrobenzene (p-
DNB), which led to a significant decrease in the product yield
(16%). Notably, the homodimer of 1b was isolated as a
byproduct during the reaction (Scheme S2). Taken together,
these observations indicate that a mechanism involving radical
and SET pathways is most likely.
1
7
metal-catalyzed aryl−heteroaryl coupling protocol. To
demonstrate the scalability of this protocol, we conducted a
reaction on large scale and observed that the gram-scale
synthesis of 5i (3.82 g) proceeded well under the standard
conditions with a yield of 78% (see Scheme S1 for details).
Next, we turn our attention to the scope of perfluoroalkyl
1
8
halides. As shown in Scheme 3, a variety of perfluoroalkyl
On the basis of the above results, a tandem radical/polar
mechanism for the three-component reaction is proposed
a
,b
19
Scheme 3. Scope of Fluoroalkyl Halides
(
Scheme 5). (i) A halogen-bond adduct II (rI···O = 2.61 Å) is
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1b (1.0 mmol), 2 (1.1 equiv), and 3a (1.1
b
c
equiv), NaOH (4.1 equiv), MeCN (0.5 mL). Isolated yields. In
DMF (0.5 mL).
iodides with different chain lengths were suitable substrates in
this multicomponent reaction. Both shorter and longer
perfluorinated chains could be installed in pyrimidines, giving
the corresponding perfluoroalkylated 6a−f in good to excellent
yields (56−92%). In particular, gaseous CF CF I was a good
3
2
partner for this reaction, affording 4-trifluoromethyl-containing
pyrimidine 6a in 56% yield. Interestingly, a chlorodifluor-
omethyl functionality could be introduced onto the 4-position
of pyrimidines when using 1-chloro-1,1,2,2-tetrafluoro-2-iodo-
ethane (6f, 76% yield). The results listed in Schemes 1−3
demonstrate the broad substrate scope, excellent functional
group tolerance, and high efficiency of this three-component
reaction, thus providing a new and practical method for the
synthesis of pharmacologically relevant perfluoroalkylated
pyrimidines.
formed in situ by the interaction of transiently generated
enolate I (halogen-bond acceptor) and perfluorobutyl iodide
20,21
(
halogen-bond donor).
(ii) Collapse of complex II via SET
leads to the generation of carbon radical III and C F I radical
4
9
anion, which releases an iodide anion to give C F radical IV.
4
9
(
iii) Radical cross-coupling between III and IV delivers α-
perfluoroalkylated intermediate V. (iv) Alkene VI is formed via
To gain insight into the reaction mechanism, we conducted a
mechanistic study (Scheme 4). In the reaction of ethyl 3-
oxobutanoate, perfluorobutyl iodide (1.1 equiv), and tetra-
elimination of HF. (v) An S V type reaction of electron-poor
N
alkene VI by guanidine nucleophile gives alkene 7, in which
resonance structures can be formulated via the push−pull
electronic effect. (vi) Intramolecular condensation leads to the
Scheme 4. Mechanistic Investigation
22
final product 4a. In the ambient-light-promoted halogen-
bond adduct enabled three-component process, fully function-
alized pyrimidines are assembled in a formal [2 + 1 + 3]
annulation in which one C−C bond and two C−N bonds are
built up.
In conclusion, we have developed the first photopromoted
three-component reaction enabled by a halogen-bond adduct.
The result of the research allows for highly efficient assembly of
perfluoroalkylated pyrimidines via formal [2 + 1 + 3]
annulation of the readily available active methylene compounds,
perfluoroalkyl iodides, and guanidines/amidines. This work has
provided an elegant example of the utilization of noncovalent
C
DOI: 10.1021/acs.orglett.7b00894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
weak interaction like halogen bonding in multicomponent
reaction, thus illustrating the power and potential of EDA
complex in photocatalyzed synthetic chemistry. In addition,
these easily available and highly functionalized perfluoroalky-
lated pyrimidines would be of great interest in medicinal
research and further synthetic derivatization.
Kravchenko, M. A.; Skornyakov, S. N.; Rusinov, G. L.; Chupakhin, O.
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ASSOCIATED CONTENT
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*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00894.
(
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́
1
́
Experimental procedure and characterization data for all
compounds (PDF)
X-ray crystallographic data for 4a (CIF)
(
6
̃
AUTHOR INFORMATION
Corresponding Authors
(
■
and Applications; Springer: Berlin, 2008. (b) Cavallo, G.; Metrangolo,
P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.; Terraneo, G. Chem.
Rev. 2016, 116, 2478. (c) Cavallo, G.; Metrangolo, P.; Pilati, T.;
Resnati, G.; Sansotera, M.; Terraneo, G. Chem. Soc. Rev. 2010, 39,
3772. (d) Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo,
G. Angew. Chem., Int. Ed. 2008, 47, 6114. (e) Metrangolo, P.;
Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386.
*
E-mail: fsliang@lnu.edu.cn.
*E-mail: bixh507@nenu.edu.cn.
ORCID
Zheng-Bo Han: 0000-0001-8635-9783
Fushun Liang: 0000-0003-4195-3863
Notes
(13) Selected halogen-bonding-promoted reactions from our group:
(a) Wei, Y.; Lin, S.; Liang, F. Org. Lett. 2012, 14, 4202. (b) Wei, Y.;
Lin, S.; Liang, F.; Zhang, J. Org. Lett. 2013, 15, 852. (c) Wei, Y.; Liang,
F.; Zhang, X. Org. Lett. 2013, 15, 5186. (d) Li, M.; Yuan, H.; Zhao, B.;
Liang, F.; Zhang, J. Chem. Commun. 2014, 50, 2360. (e) Tan, H.; Li,
M.; Liang, F. RSC Adv. 2014, 4, 33765. (f) Zhang, L.; Li, Y.; Jin, L.-Y.;
Liang, F. RSC Adv. 2015, 5, 65600.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from NSFC (21172034, 21372039,
1372038, and 21522202) is greatly acknowledged.
■
2
(14) (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Photoinduced multicomponent
reactions: Garbarino, S.; Ravelli, D.; Protti, S.; Basso, A. Angew. Chem.,
Int. Ed. 2016, 55, 15476.
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(22) The formation of intermediates V via nucleophilic substitution
(
of perfluoroalkyl iodide by enolate was tentatively ruled out (Scheme 4
and Scheme S2).
(
1
(
(
(
D
DOI: 10.1021/acs.orglett.7b00894
Org. Lett. XXXX, XXX, XXX−XXX