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\begin{document}

\title{Switchable Multicomponent Cyclization Reactions to Access
Fluoroalkylated Dihydropyrimidines and Pyrimidines Under Sol-vent-Free
Conditions}



\author[1]{Wanqing Zuo}%
\author[2]{Zhizhen Zhu}%
\author[2]{Yu Cheng}%
\author[2]{Lingling Zuo}%
\author[2]{Xiao Geng}%
\author[1]{Zhifang Li}%
\author[3]{Lei Wang}%
\affil[1]{Hangzhou Normal University}%
\affil[2]{Taizhou University}%
\affil[3]{Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, China}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
The development of switchable solvent-free multicomponent reactions to
build high-value-added products is an important demand for organic
synthesis. Herein, we detailed the successful implementation of a
switchable strategy for the construction of diverse
4-fluoroalkyl-1,4-dihydropyrimidines and 4-fluoroalkyl-pyrimidines via a
solvent/additive-free {[}3 + 2 + 1{]} annulation, starting from readily
available enamines, trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol and amidines hydrochloride. This reaction
conforms to the concept of green synthesis, and provides a new avenue to
access valuable fluorinated heterocycles.%
\end{abstract}%



\sloppy


\textbf{Cite this paper:}\emph{Chin. J. Chem.} \textbf{2023} , \emph{41}
, XXX---XXX. \textbf{DOI: 10.1002/cjoc.202300XXX}

Switchable Multicomponent Cyclization Reactions to Access
Fluoroalkylated Dihydropyrimidines and Pyrimidines Under Solvent-Free
Conditions

Wanqing Zuo,\textsuperscript{a,b}Zhizhen Zhu,\textsuperscript{b} Yu
Cheng,\textsuperscript{b} Lingling Zuo,*\textsuperscript{b} Xiao
Geng,\textsuperscript{b} Zhifang Li,*\textsuperscript{a} and Lei
Wang*\textsuperscript{a,b,c}

\textsuperscript{a} College of Material Chemistry and Chemical
Engineering, Key Laboratory of Organosilicon Chemistry and Material
Technology, Ministry of Education, Hangzhou Normal University, Hangzhou,
311121, Zhejiang, P. R. China

\textsuperscript{b} Advanced Research Institute and School of
Pharmaceutical Sciences, Taizhou University, Jiaojiang, Zhejiang,
318000, P. R. China

\textsuperscript{c} State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai, 200032, P. R. China\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Keywords}\tabularnewline
\midrule
\endhead
Switchable strategy \textbar{} Multicomponent reactions \textbar{}
Solvent-free \textbar{} Fluoroalkylated dihydropyrimidines \textbar{}
Fluoroalkylated pyrimidines\tabularnewline
\textbf{Comprehensive Summary}\tabularnewline
The development of switchable solvent-free multicomponent reactions to
build high-value-added products is an important demand for organic
synthesis. Herein, we detailed the successful implementation of a
switchable strategy for the construction of diverse
4-fluoroalkyl-1,4-dihydropyrimidines and 4-fluoroalkyl-pyrimidines via a
solvent/additive-free {[}3 + 2 + 1{]} annulation, starting from readily
available enamines, trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol and amidines hydrochloride. This reaction
conforms to the concept of green synthesis, and provides a new avenue to
access valuable fluorinated heterocycles.\tabularnewline
\bottomrule
\end{longtable}

\section*{}

{\label{section}}

Background and Originality Content

Multicomponent reactions (MCRs) \textsuperscript{{[}1{]}} have been
extensively studied and are of enormous importance in synthetic organic
and medicinal chemistry, due to its step economy and atom efficient
nature. \textsuperscript{{[}2{]}} This approach also has the
potentiality in maximizing the efficiency of the preparation of the
compound library with molecular diversity for the needs of drug
screening. Notably, to meet the increasing demand for green chemistry,
the development of harmless multicomponent reactions is urgent.
Solvent-free systems have featured many advantages in reducing waste and
pollution, even serious accidents, which might be a ``green'' answer in
laboratory research or industrial production. \textsuperscript{{[}3{]}}
Therefore, the development of solvent-free multicomponent reactions has
been a vibrant work, thereby opening green and efficient method for the
diversity synthesis of valuable molecules. \textsuperscript{{[}4{]}}

Pyrimidines and the corresponding dihydro-compounds found in many active
molecules with a wide range of biological and pharmacological
properties, \textsuperscript{{[}5{]}} and therefore, attracting
extensively attention from the synthetic
community.\textsuperscript{{[}6{]}} Meanwhile, to provide high-quality
platform molecules for drug discovery, the direct introduction of
fluoroalkyl group, especially difluoromethyl or trifluoromethyl, into
heterocycles represents huge interest for chemical
companies.\textsuperscript{{[}7,8{]}} In 2017, Bi and Liang
\textsuperscript{{[}9{]}}reported a novel photoinduced multicomponent
cyclization reaction to forge fluoroalkyl-functionalized pyrimidines
from active methylenes, perfluoroalkyl iodides, and guanidines/amidines
(Scheme 1a). Later on, Loh and Shen\textsuperscript{{[}10{]}} reported
the radical-polar crossover-enabled formal {[}3 + 2 + 1{]}
heteroannulation to construct a variety of fluoroalkyl-pyrimidines from
silylenol ether, amidines, and fluoroalkyl halide (Scheme 1b). The same
group also realized the Cu-catalyzed cascade cyclization of styrenes,
amidines, and fluoroalkyl halides to access diverse fluoroalkylated
pyrimidines.\textsuperscript{{[}11{]}} Despite these achievements, some
disadvantages such as excess additives and harmful solvent limit the
applications of these approaches. More importantly, although
fluoroalkylated pyrimidines have been achieved, the corresponding
fluoroalkylated dihydropyrimidines remain elusive. Thus, the discovery
of novel strategies fulfilling modern reaction ideals of green chemistry
for the switchable synthesis of both fluoroalkylated pyrimidines and
dihydropyrimidines are challenging and urgent.

Herein, we wish to report the successful implementation of a switchable
{[}3 + 2 + 1{]} annulation strategy for the direct construction of
diverse fluoroalkylated dihydropyrimidines/pyrimidines under
solvent-free conditions, using easily available enaminones,
trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol and
amidines hydrochloride as substrates (Scheme 1c). This reaction not only
conforms to the concept of green synthesis, but also provides a new
avenue to access diverse fluorinated heterocycles.

\textbf{Scheme 1} Significance and synthetic design for fluoroalkylated
dihydropyrimidines and pyrimidines.

Results and Discussion

We initiated our studies with readily available ethyl 3-(\emph{N}
,\emph{N} -dimethylamino)acrylate (\textbf{1a} ), trifluoroacetaldehyde
hydrate (\textbf{2a} ) and benzamidine hydrochloride (\textbf{3a} ) as
model substrates. To our delight, a solvent-free and additive-free
multicomponent cyclization reaction was conducted to give the desired
product \textbf{4a} in 82\% yield after heating at 130 \selectlanguage{ngerman}°C for 1 h (Table
1, entry 1), while lower yields were obtained in DMSO,
CH\textsubscript{3}CN or THF as solvent (Table 1, entries 2\selectlanguage{english}-4).
Decreasing or increasing the ratio of substrate \textbf{2a} both had
negative impact on the yields of\textbf{4a} (Table 1, entries 5\selectlanguage{english}-7).
Slightly reduced yields were achieved after altering the reaction
temperature (Table 1, entries 8 and 9). When the reaction time was
extended to 16 h, \textbf{4a} was obtained in 58\% yield, along with the
oxidative dehydrogenation product \textbf{6a} obtained in 8\% yield.
Fortunately, the yield of 4-CF\textsubscript{3}-pyrimidines
\textbf{6a}was increased up to 66\% yield with CuCl (20 mol\%) as
catalyst under air atmosphere. Next, various copper salts were evaluated
(Table 1, entries 12\selectlanguage{english}-15), but none of them were found to be superior to
CuCl. Further decreasing the amount of CuCl to 5 mol\% failed to give a
higher yield of \textbf{6a} (Table 1, entry 16). However,
O\textsubscript{2}atmosphere did not improve the yield of \textbf{6a}
(Table 1, entry 17). Meanwhile, \textbf{6a} was obtained in trace amount
under N\textsubscript{2} atmosphere (Table 1, entry 18).

\textbf{Table 1} Optimization of the reaction
conditions\emph{\textsuperscript{a}}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Entry\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Catalyst (mol \%)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Reaction conditions\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Yield of \textbf{4a} (\%)\emph{\textsuperscript{b}}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Yield of \textbf{6a} (\%)\emph{\textsuperscript{b}}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
82\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
DMSO, 130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
64\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CH\textsubscript{3}CN, 130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
78\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
THF, 130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5\emph{\textsuperscript{c}}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6\emph{\textsuperscript{d}}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7\emph{\textsuperscript{e}}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
76\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
120 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
140 \selectlanguage{ngerman}°C, 1 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
74\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuCl (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuBr (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
39\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuI (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuCl\textsubscript{2} (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuO (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuCl (5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, air\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuCl (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, O\textsubscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CuCl (20)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 \selectlanguage{ngerman}°C, 16 h, N\textsubscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
71\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Trace\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{\textsuperscript{a}} Reaction conditions: \textbf{1a} (0.2
mmol),\textbf{2a} (0.6 mmol, 75\% in water), \textbf{3a} (0.2 mmol), T
\selectlanguage{ngerman}°C, solvent (2.0 mL). \emph{\textsuperscript{b}} Isolated
yield.\emph{\textsuperscript{c}} \textbf{1a} :\textbf{2a} :\textbf{3a} =
1:1.5:1.\emph{\textsuperscript{d}} \textbf{1a} :\textbf{2a} :\textbf{3a}
= 1:2:1.\emph{\textsuperscript{e}} \textbf{1a} :\textbf{2a} :\textbf{3a}
= 1:4:1.

\textbf{Scheme 2} Substrate scope for fluoroalkylated
dihydropyrimidines\emph{\textsuperscript{a}}

\emph{\textsuperscript{a}} 0.20 mmol scale under standard reaction
conditions. \emph{\textsuperscript{b}} isolated yield of
product\textbf{4} or \textbf{5} . \emph{\textsuperscript{c}} gram-scale
reaction.

With the optimal reaction conditions in hand, we evaluated the
generality of the solvent-free MCRs. As shown in Scheme 2, a variety of
conjugated enamines successfully reacted with trifluoroacetaldehyde
hydrate and benzamidine hydrochloride. As for enamine esters, including
alkyl and benzyl derivatives, were smoothly converted to the desired
products (\textbf{4a} \selectlanguage{english}-\textbf{h} ) in moderate to good yields
(68\selectlanguage{english}-88\%). A gram-scale reaction was conducted to deliver 1.2 g of
product\textbf{4a} in 80\% yield. Complex molecules, such as enamine
esters derived from (+)-menthol and (+)-fenchol also worked well to give
the corresponding products in 89\% and 72\% yields, respectively. Alkyl
enaminones with different chain lengths or cycloalkyl and phenyl
enaminone were tolerated, but leading to the desired products
(\textbf{4k} \selectlanguage{english}-\textbf{p} ) in 41\selectlanguage{english}-60\% yields, probably due to the
interference of electrophilic carbonyl groups. Interestingly, the
reaction was also applicable with alkenyl bridged enaminones, affording
the respective product \textbf{4q} in 51\% yield. Moreover,
phenylsulfonyl enamine was also found to be compatible with the
solvent-free MCR, and the corresponding product \textbf{4r} was obtained
in 75\% yield. Next, we examined the generality of aryl amidines
hydrochloride. Generally, the \emph{ortho} -, \emph{meta} -,
or\emph{para} -substituted aryl amidines hydrochloride bearing
electron-donating groups were found to be compatibility under the
optimal reaction conditions, delivering the desired products
(\textbf{5a} \selectlanguage{english}-\textbf{e} ) in 64\selectlanguage{english}-79\% yields. In addition, different
kinds of halo-substituted aryl amidines hydrochloride exhibited good
reactivity under standard conditions, and the corresponding products
(\textbf{5f} \selectlanguage{english}-\textbf{j} ) were obtained in satisfactory yields
(65\selectlanguage{english}-78\%). Substrates with strong electron-withdrawing groups at
the\emph{para-} position of phenyl rings (4-CF\textsubscript{3},
4-NO\textsubscript{2}) were also investigated, affording \textbf{5k} and
\textbf{5l} in 75\% and 83\% yields, respectively. Notably, the presence
of sensitive group (OH) in aryl amidine hydrochloride did not affect
this multicomponent cyclization reaction, affording \textbf{5m} in 73\%
yield. In addition, the reaction was also applicable to heteroaryl
amidines hydrochloride under standard conditions to afford the desired
products in good yields (\textbf{5n} , 82\%; \textbf{5o} , 67\%). We
also investigated the compatibility of 1-ethoxy-2,2-difluoroethanol,
which reacted well with \textbf{1a} and\textbf{3a} , affording
4-CF\textsubscript{2}H-1,4-dihydropyrimidines\textbf{5p} in 80\% yield.

\textbf{Scheme 3} Substrate scope for fluoroalkylated
pyrimidines\emph{\textsuperscript{a}}

\emph{\textsuperscript{a}} 0.20 mmol scale under standard reaction
conditions; \emph{\textsuperscript{b}} isolated yield of
product\textbf{6} .

Next, the substrate scope for constructing
4-CF\textsubscript{3}pyrimidines was investigated (Scheme 3). Esteryl
enamines with diverse substituent groups reacted smoothly with
trifluoroacetaldehyde hydrate and benzamidine hydrochloride, delivering
the desired products (\textbf{6a} \selectlanguage{english}-\textbf{f} ) in 49\selectlanguage{english}-71\% yields. Alkyl
or aryl enamine ketones were also tolerated to afford the desired
products in slightly lower yields (\textbf{6g} , 38\%; \textbf{6h} ,
40\%). Moreover, the reactions proceeded smoothly with a variety of aryl
amidines hydrochloride under the optimal conditions, affording the
corresponding products (\textbf{6i} \selectlanguage{english}-\textbf{u} ) in moderate yields
(40\selectlanguage{english}-62\%). Finally, 4-CF\textsubscript{2}H-pyrimidines \textbf{6v} could
be obtained in 71\% yield using 1-ethoxy-2,2-difluoroethanol as
substrate.

After investigating the substrate scopes and the synthetic application
of the solvent-free multicomponent cyclization, control experiments were
carried out to investigate the reaction mechanism (Scheme 4a). In order
to detect the possible intermediates, the reaction was lowered to 60 degC
and reacted for 1 h. Fortunately, the possible intermediates
\textbf{I}and \textbf{II} were confirmed by high-resolution mass
spectrometry (HRMS), along with the target product \textbf{4a} obtained
in 8\% yield (Scheme 4a-1). However, other possible intermediate
\textbf{III} or\textbf{IV} was not found (ESI for detail). This result
implied that \selectlanguage{greek}β-\selectlanguage{english}CF\textsubscript{3}-vinylimine ion might be a key
intermediate for this multicomponent cyclization. Moreover,
4-CF\textsubscript{3}-1,4-dihydropyrimidine could be converted into
4-CF\textsubscript{3}-pyrimidine in the presence of CuCl under air
atmosphere (Scheme 4a-2).

On the basis of the experimental results and literature
reports,\textsuperscript{{[}13,14{]}} a postulated mechanism is
illustrated, as shown in Scheme 5. This multicomponent cyclization
starts from the addition of ethyl 3-(\emph{N} ,\emph{N}
-dimethylamino)acrylate \textbf{1a} to trifluoroacetaldehyde
\textbf{2a'} to generate intermediate \textbf{A} , which subsequently
undergoes a sequential protonation and dehydration to afford
\selectlanguage{greek}β-\selectlanguage{english}CF\textsubscript{3}-vinylimine ion intermediate \textbf{B} . Once
formed, intermolecular {[}3 + 3{]} cyclization reaction with
intermediate \textbf{B} and benzamidine \textbf{3a} will occur, leading
to the formation of intermediate \textbf{C} . Subsequently, a
deamination process of intermediate \textbf{C} provides the product
\textbf{4a} , which could be oxidized to afford \textbf{6a} under
copper-catalyzed aerobic condition. \textsuperscript{{[}15{]}}

\textbf{Scheme 4} Control experiments and proposed mechanism.

Conclusions

In summary, a switchable multicomponent cyclization of enaminones,
trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol and
amidines hydrochloride for accessing fluoroalkylated dihydropyrimidines
and pyrimidines have been developed for the first time. The present
multicomponent reaction tolerates a wide range of functional groups and
can be performed without solvent. Notably, this strategy not only
conforms to the concept of green synthesis, but also provides new
opportunities for the sustainable formation of diverse fluorinated
heterocyclics, thereby is expected to have widespread applications in
pharmaceutical discovery. Further investigations on solvent-free
multicomponent cyclization are ongoing in our laboratory.

Experimental

A 15 mL sealed tube with a magnetic stirrer bar was charged with enamine
(\textbf{1} , 1.0 equiv, 0.20 mmol), trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol (\textbf{2} , 3.0 equiv, 0.60 mmol),
amidines (\textbf{3} , 1.0 equiv, 0.20 mmol). The reaction vessel was
stirred at 130 \textsuperscript{o}C in heating mantle for 1 h. After
completion of the reaction, the resulting mixture was extracted with
ethyl acetate, and the combined organic layers were washed with brine,
dried over Na\textsubscript{2}SO\textsubscript{4}, filtered and
concentrated. The residue was purified with silica gel chromatography
(petroleum ether/ethyl acetate = 1:1 ~ 7:1, V/V) to afford the
corresponding product \textbf{4} or \textbf{5} .

A 15 mL sealed tube with a magnetic stirrer bar was charged with enamine
(\textbf{1} , 1.0 equiv, 0.20 mmol), trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol (\textbf{2} , 3.0 equiv, 0.60 mmol),
amidine (\textbf{3} , 1.0 equiv, 0.20 mmol), CuCl (0.2 equiv, 0.04
mmol). The reaction vessel was stirred at 130 \textsuperscript{o}C in
heating mantle for 16 h. After completion of the reaction, the resulting
mixture was extracted with ethyl acetate, and the combined organic
layers were washed with brine, dried over
Na\textsubscript{2}SO\textsubscript{4}, filtered and concentrated. The
residue was purified with silica gel chromatography (petroleum
ether/ethyl acetate = 2:1 ~ 100:1, V/V) to afford the corresponding
product \textbf{6} .

Supporting Information

The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.

Acknowledgement

We gratefully acknowledge the National Natural Science Foundation of
China (22071171) and the Natural Science Foundation of Zhejiang Province
(LZ22B020003) for financial support of this work.

References

\begin{enumerate}
\tightlist
\item
  (a) Zhu, J.; Bienaym\selectlanguage{ngerman}é, H. Multicomponent Reactions; Wiley: Weinheim,
  2005. (b) Cimarelli, C. Multicomponent Reactions.
  Molecules,\textbf{2019} , \emph{24} 2372.
\item
  (a) Touré, B. B.; Hall, D. G. Natural Product Synthesis Using
  Multicomponent Reaction Strategies. Chem. Rev., \textbf{2009}
  ,\emph{109} , 4439\selectlanguage{english}-4486; (b) Marson, C. M. Multicomponent and
  Sequential Organocatalytic Reactions: Diversity with Atom-economy and
  Enantiocontrol. Chem. Soc. Rev., \textbf{2012} , \emph{41} ,
  7712\selectlanguage{english}-7722; (c) X. Guo, W. Hu, Novel Multicomponent Reactions via
  Trapping of Protic Onium Ylides with Electrophiles. Acc. Chem.
  Res.,\textbf{2013} , \emph{46} , 2427\selectlanguage{english}-2440.
\item
  (a) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice.
  Chem. Soc. Rev., \textbf{2010} , \emph{39} , 301\selectlanguage{english}-312; (b) Singh, M.
  S.; Chowdhury, S. Recent Developments in Solvent-free Multicomponent
  Reactions: A Perfect Synergy for Eco-compatible Organic
  Synthesis.\emph{RSC Adv} ., \textbf{2012} , \emph{2} , 4547.
\item
  (a) Gui, Q. W.; He, X.; Wang, W.; Zhou, H.; Dong, Y.; Wang, N.; Tang,
  J. X.; Cao, Z.; He, W. M. The Clean Preparation of Multisubstituted
  Pyrroles Under Metal- and Solvent-free Conditions. \emph{Green
  Chem.}\textbf{2020} , \emph{22} , 118\selectlanguage{english}-122; (b) Kong, L.; Huang, R.;
  He, H.; Fan, Y.; Lin, J.; Yan, S. Multi-component Solvent-free Cascade
  Reaction of 2-cyanoacetamides: Regioselective Synthesis of
  Pyridin-2-ones Bearing Quaternary Centers. \emph{Green
  Chem.}\textbf{2020} , \emph{22} , 256\selectlanguage{english}-264. (c) Jamshaid, S.;
  Mohandoss, S.; Lee, Y. R. Indium(III)-catalyzed Solvent-free
  Multicomponent {[}2 + 2 + 1 + 1{]}-annulation to Polycyclic
  Functionalized Fused Pyridines as Potential Optical Chemosensors.
  \emph{Green Chem.} \textbf{2021} ,\emph{23} , 5113\selectlanguage{english}-5119. (d) Maiti,
  D.; Das, R.; Prabakar, T.; Sen, S. Blue LED Induced Solvent-free
  Multicomponent Reactions Among Aryl Diazoacetates, Pyridine
  Derivatives and Maleimides: Direct Eco-friendly Synthesis of Densely
  Functionalized Itaconimides.\emph{Green Chem.} \textbf{2022} ,
  \emph{24} , 3001\selectlanguage{english}-3008.
\item
  (a) Deres, K.; Schro\selectlanguage{english}der, C. H.; Paessens, A.; Goldmann, S.; Hacker, H.
  J.; Weber, O.; Kra\selectlanguage{english}mer, T.; Niewo\selectlanguage{english}hner, U.; Pleiss, U.; Stoltefuss, J.;
  Graef, E.; Koletzki, D.; Masantschek, R. N. A.; Reimann, A.; Jaeger,
  R.; Gro\selectlanguage{ngerman}ß, R.; Beckermann, B.; Schlemmer, K. H.; Haebich, D.;
  Ru\selectlanguage{english}bsamen-Waigmann, H. Inhibition of Hepatitis B Virus Replication by
  Drug-Induced Depletion of Nucleocapsids. \emph{Science} \textbf{2003}
  ,\emph{299} , 893-896; (b) Lokwani, D.; Azad, R.; Sarkate, A.;
  Reddanna, P.; Shinde, D. Structure Based Library Design (SBLD) for New
  1,4-dihydropyrimidine Scaffold as Simultaneous COX-1/COX-2 and 5-LOX
  Inhibitors. \emph{Bioorgan. Med. Chem.,} \textbf{2015} , \emph{23} ,
  4533-4543.
\item
  (a) Kappe, C. O. Recent Advances in the Biginelli Dihydropyrimidine
  Synthesis. New Tricks from an Old Dog. \emph{Acc. Chem.
  Res.}\textbf{2000} , \emph{33} , 879-888; (b) Liu, Q.; Chen, J. H.;
  Yao, M.; Zhao, Z. Y.; Liu, X. Y.; Zhao, X. L.; Shi, M.; Zhao, M. X.
  One-pot Formal {[}3+3{]} Cycloaddition of Isocyanoacetates with in
  Situ-derived Azoalkenes for the Synthesis of 1,4-dihydropyrimidine
  Derivatives. \emph{Tetrahedron} \textbf{2021} , \emph{88} , 132122.
\item
  (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Ace\selectlanguage{ngerman}ña, J. L.;
  Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of
  Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase
  II\selectlanguage{english}-III Clinical Trials of Major Pharmaceutical Companies: New
  Structural Trends and Therapeutic Areas. \emph{Chem.
  Rev.}\textbf{2016} , \emph{116} , 422\selectlanguage{english}-518; (b) Muller, K.; Faeh, C.;
  Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond
  Intuition.\emph{Science} \textbf{2007} , \emph{317} , 1881\selectlanguage{english}-1886; (c)
  Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
  N. A. Applications of Fluorine in Medicinal Chemistry. \emph{J. Med.
  Chem.}\textbf{2015} , \emph{58} , 8315\selectlanguage{english}-8359.
\item
  (a) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.;
  Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl Bioisostere:
  Examining the ``Lipophilic Hydrogen Bond Donor'' Concept. \emph{J.
  Med. Chem.} \textbf{2017} , \emph{60} , 797-804. (b) Sessler, C. D.;
  Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J.
  CF\textsubscript{2}H, a Hydrogen Bond Donor. \emph{J. Am. Chem.
  Soc.}\textbf{2017} , \emph{139} , 9325\selectlanguage{english}-9332.
\item
  Wang, R.; Guan, W.; Han, Z. B.; Liang, F.; Suga, T.; Bi, X.; Nishide,
  H. Ambient-Light-Promoted Three-Component Annulation: Synthesis of
  Perfluoroalkylated Pyrimidines.\emph{Org. Lett.} \textbf{2017} ,
  \emph{19} , 2358\selectlanguage{english}-2361.
\item
  Chu, X. Q.; Xie, T.; Li, L.; Ge, D.; Shen, Z. L.; Loh, T. P. Combining
  Fluoroalkylation and Defluorination to Enable Formal {[}3 + 2 + 1{]}
  Heteroannulation by Using Visible-Light Photoredox
  Organocatalysis.\emph{Org. Lett.} \textbf{2018} , \emph{20} ,
  2749\selectlanguage{english}-2752.
\item
  Chu, X. Q.; Cheng, B. Q.; Zhang, Y. W.; Ge, D.; Shen, Z. L.; Loh, T.
  P. Copper-catalyzed Three-component Cyclization of Amidines, Styrenes,
  and Fluoroalkyl Halides for the Synthesis of Modular Fluoroalkylated
  Pyrimidines. \emph{Chem. Commun.} \textbf{2018} , \emph{54} ,
  2615\selectlanguage{english}-2618.
\item
  (a) Zuo, W.; Zuo, L.; Geng, X.; Li, Z.; Wang, L. Radical-Polar
  Crossover Enabled Triple Cleavage of
  CF\textsubscript{2}Br\textsubscript{2}: A Multicomponent Tandem
  Cyclization to 3-Fluoropyrazoles. \emph{Org. Lett.} \textbf{2023}
  ,\emph{25,} 6062\selectlanguage{english}-6066. (b) Huo, J.; Geng, X.; Li, W.; Zhang, P.; Wang,
  L. A Traceless Heterocyclic Amine Mediator in
  Regioselectivity\selectlanguage{english}-Switchable Formal {[}1 + 2 + 2{]} Cycloaddition
  Reaction to 1,3,4- and 1,4,5-Trisubstituted Pyrazoles. \emph{Org.
  Lett.} \textbf{2023} , \emph{25,} 512\selectlanguage{english}-516. (c) Geng, X.; Xu, Z.; Cai,
  Y.; Wang, L. Visible-Light-Driven Multicomponent Cyclization by
  Trapping a 1,3-Vinylimine Ion Intermediate: A Direct Approach to
  Pyrimido{[}1,2-b{]}indazole Derivatives. \emph{Org.
  Lett.}\textbf{2021} , \emph{23} , 8343\selectlanguage{english}-8347. (d) Xu, Z.; Geng, X.;
  Cai, Y.; Wang, L. A Straightforward Approach to Fluorinated
  Pyrimido{[}1,2-\emph{b} {]}indazole Derivatives via
  Metal/Additive-free Annulation with Enaminones, 3-Aminoindazoles, and
  Selectfluor.\emph{J. Org. Chem.} \textbf{2022} , \emph{87} ,
  6562\selectlanguage{english}-6572. (\emph{e} ) Pan, S.; Song, M.; Zuo, L.; Geng, X.; Wang, L.
  A Strategy for Accessing Trifluoromethyl Carbinol-Containing Chromones
  from\emph{o} -Hydroxyaryl Enaminones and Trifluoroacetaldehyde/Ketone
  Derivatives. \emph{J. Org. Chem.} \textbf{2023} , 88, 5586\selectlanguage{english}-5596.
\item
  (a) Funabiki, K.; Matsunaga, K.; Nojiri, M.; Hashimoto, W.; Yamamoto,
  H.; Shibata, K.; Matsui, M. The Use of Trifluoroacetaldehyde Ethyl
  Hemiacetal or Hydrate in a Simple and Practical Regioselective
  Synthesis of \selectlanguage{greek}β-\selectlanguage{english}Hydroxy-\selectlanguage{greek}β-\selectlanguage{english}trifluoromethyl Ketones from Enamines and
  Imines. \emph{J. Org. Chem.} \textbf{2003} , \emph{68} , 2853-2860.
  (b) Yan, C. X.; Zhou, P. P.; Yang, F. L.; Wu, R. Z.; Yang, X.; Yang,
  F.; Shao, X. Chiral Bisoxazoline Catalyzed Decarboxylative Aldol
  Reactions Between \selectlanguage{greek}β-\selectlanguage{english}carbonyl Acids and Trifluoroacetaldehyde
  Hemiacetals as Well as Trifluoroacetaldehyde: the Mechanism, the
  Origin of Enantioselectivity and the Role of a Catalyst. \emph{Org.
  Chem. Front.} \textbf{2018} , \emph{5} , 2692-2709.
\item
  (a) Chen, Y. L.; Sun, L. W.; Chen, J. W.; Zhu, M. Q.; Ma, M.; Shen, Z.
  L.; Chu, X. Q. Four-component Defluorinative Reaction of Allylic
  Fluorides, Amidines, and Cs\textsubscript{2}CO\textsubscript{3} Under
  Transition-metal-free Conditions. \emph{Green Chem.} \textbf{2022} ,
  \emph{24} , 6816-6822. (b) Yu, Q.; Zhang, Y.; Wan, J. P. Ambient and
  Aerobic Carbon--carbon Bond Cleavage toward \selectlanguage{greek}α-\selectlanguage{english}Ketoester Synthesis by
  Transition-metal-free Photocatalysis. \emph{Green Chem.} \textbf{2019}
  , \emph{21} , 3436-3441.
\item
  (a) Huo, C.; Yuan, Y.; Chen, F.; Tang, J.; Wang, Y. Copper-Catalyzed
  Aerobic Oxidative Dehydrogenative Formal {[}2 + 3{]} Cyclization of
  Glycine Esters with \selectlanguage{greek}α-\selectlanguage{english}Angelicalactone: Approach to Construct
  Polysubstituted Pyrrolidones. \emph{Org. Lett.} \textbf{2015}
  ,\emph{17} , 4208-4211. (b) Xie, J.; Huang, Y.; Song, H.; Liu, Y.;
  Wang, Q. Copper-Catalyzed Aerobic Oxidative {[}2 + 3{]}
  Cyclization/Aromatization Cascade Reaction: Atom-Economical Access to
  Tetrasubstituted 4,5-Biscarbonyl Imidazoles. \emph{Org.
  Lett.}\textbf{2017} , \emph{19} , 6056-6059.
\end{enumerate}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
Manuscript received: XXXX, 2023 Manuscript revised: XXXX, 2023
Manuscript accepted: XXXX, 2023 Accepted manuscript online: XXXX, 2023
Version of record online: XXXX, 2023\tabularnewline
\bottomrule
\end{longtable}

The Authors\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& After acceptance, please insert a group photo of the authors taken
recently. &\tabularnewline
& \textbf{Left to Right:} Authors Names &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Entry for the Table of Contents}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Switchable Multicomponent Cyclization Reactions to Access
4-Fluoroalkyl-1,4-Dihydropyrimidines and 4-Fluoroalkyl-Pyrimidines Under
Solvent-Free Conditions} Wanqing Zuo, Zhizhen Zhu, Yu Cheng, Lingling
Zuo,* Xiao Geng, Zhifang Li,* and Lei Wang* \emph{Chin. J. Chem.}
\textbf{2023}, \emph{41}, XXX---XXX. \textbf{DOI:
10.1002/cjoc.202300XXX}\tabularnewline
\midrule
\endhead
Herein, we detailed the successful implementation of a switchable
strategy for the construction of diverse
4-fluoroalkyl-1,4-dihydropyrimidines and 4-fluoroalkyl-pyrimidines via a
solvent/additive-free {[}3 + 2 + 1{]} annulation, starting from readily
available enamines, trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol and amidines hydrochloride. This reaction
conforms to the concept of green synthesis, and provides a new avenue to
access valuable fluorinated heterocycles.\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
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