a Reaction conditions: 1a (0.2 mmol),2a (0.6 mmol, 75% in water), 3a (0.2 mmol), T °C,
solvent (2.0 mL). b Isolated yield.c 1a :2a :3a = 1:1.5:1.d 1a :2a :3a = 1:2:1.e 1a :2a :3a = 1:4:1.
Scheme 2 Substrate scope for fluoroalkylated
dihydropyrimidinesa
a 0.20 mmol scale under standard reaction
conditions. b isolated yield of product4 or 5 . 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 (4a −h ) in moderate to good yields (68−88%).
A gram-scale reaction was conducted to deliver 1.2 g of product4a 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
(4k −p ) in 41−60% yields, probably due to the
interference of electrophilic carbonyl groups.
Interestingly, the reaction was also
applicable with alkenyl bridged enaminones, affording the respective
product 4q in 51% yield. Moreover, phenylsulfonyl enamine was
also found to be compatible with the solvent-free MCR, and the
corresponding product 4r was obtained in 75% yield. Next, we
examined the generality of aryl
amidines hydrochloride. Generally, the ortho -, meta -, orpara -substituted aryl amidines hydrochloride bearing
electron-donating groups were found to be compatibility under the
optimal reaction conditions, delivering the desired products
(5a −e ) in 64−79% yields. In addition, different kinds
of halo-substituted aryl amidines hydrochloride exhibited good
reactivity under standard conditions, and the corresponding products
(5f −j ) were obtained in satisfactory yields (65−78%).
Substrates with strong electron-withdrawing groups at thepara- position of phenyl rings
(4-CF3, 4-NO2) were also investigated,
affording 5k and 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 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 (5n ,
82%; 5o , 67%). We also investigated the compatibility of
1-ethoxy-2,2-difluoroethanol, which reacted well with 1a and3a , affording 4-CF2H-1,4-dihydropyrimidines5p in 80% yield.
Scheme 3 Substrate scope for fluoroalkylated
pyrimidinesa
a 0.20 mmol scale under standard reaction
conditions; b isolated yield of product6 .
Next, the substrate scope for constructing
4-CF3pyrimidines was investigated (Scheme 3). Esteryl
enamines with diverse substituent groups reacted smoothly with
trifluoroacetaldehyde hydrate and benzamidine hydrochloride, delivering
the desired products (6a −f ) in 49−71% yields. Alkyl
or aryl enamine ketones were also tolerated to afford the desired
products in slightly lower yields (6g , 38%; 6h ,
40%). Moreover, the reactions proceeded smoothly with a variety of aryl
amidines hydrochloride under the optimal conditions, affording the
corresponding products (6i −u ) in moderate yields
(40−62%). Finally, 4-CF2H-pyrimidines 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 °C
and reacted for 1 h. Fortunately, the possible intermediates Iand II were confirmed by high-resolution mass spectrometry
(HRMS), along with the target product 4a obtained in 8% yield
(Scheme 4a-1). However, other possible intermediate III orIV was not found (ESI for detail). This result implied that
β-CF3-vinylimine ion might be a key intermediate for
this multicomponent cyclization. Moreover,
4-CF3-1,4-dihydropyrimidine could be converted into
4-CF3-pyrimidine in the presence of CuCl under air
atmosphere (Scheme 4a-2).
On the basis of the experimental results and literature
reports,[13,14] a postulated mechanism is
illustrated, as shown in Scheme 5. This multicomponent cyclization
starts from the addition of ethyl
3-(N ,N -dimethylamino)acrylate 1a to
trifluoroacetaldehyde 2a’ to generate intermediate A ,
which subsequently undergoes a sequential protonation and dehydration to
afford β-CF3-vinylimine ion intermediate B .
Once formed, intermolecular [3 + 3] cyclization reaction with
intermediate B and benzamidine 3a will occur, leading
to the formation of intermediate C . Subsequently, a deamination
process of intermediate C provides the product 4a ,
which could be oxidized to afford 6a under copper-catalyzed
aerobic condition. [15]
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
(1 , 1.0 equiv, 0.20 mmol), trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol (2 , 3.0 equiv, 0.60 mmol),
amidines (3 , 1.0 equiv, 0.20 mmol). The reaction vessel was
stirred at 130 oC 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 Na2SO4, 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 4 or 5 .
A 15 mL sealed tube with a magnetic stirrer bar was charged with enamine
(1 , 1.0 equiv, 0.20 mmol), trifluoroacetaldehyde hydrate or
1-ethoxy-2,2-difluoroethanol (2 , 3.0 equiv, 0.60 mmol), amidine
(3 , 1.0 equiv, 0.20 mmol), CuCl (0.2 equiv, 0.04 mmol). The
reaction vessel was stirred at 130 oC 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 Na2SO4,
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 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
- (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley: Weinheim,
2005. (b) Cimarelli, C. Multicomponent Reactions. Molecules,2019 , 24 2372.
- (a) Touré, B. B.; Hall, D. G. Natural Product Synthesis Using
Multicomponent Reaction Strategies. Chem. Rev., 2009 ,109 , 4439−4486; (b) Marson, C. M. Multicomponent and Sequential
Organocatalytic Reactions: Diversity with Atom-economy and
Enantiocontrol. Chem. Soc. Rev., 2012 , 41 , 7712−7722;
(c) X. Guo, W. Hu, Novel Multicomponent Reactions via Trapping of
Protic Onium Ylides with Electrophiles. Acc. Chem. Res.,2013 , 46 , 2427−2440.
- (a) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice.
Chem. Soc. Rev., 2010 , 39 , 301−312; (b) Singh, M. S.;
Chowdhury, S. Recent Developments in Solvent-free Multicomponent
Reactions: A Perfect Synergy for Eco-compatible Organic Synthesis.RSC Adv ., 2012 , 2 , 4547.
- (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. Green Chem.2020 , 22 , 118−122; (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. Green Chem.2020 , 22 , 256−264. (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. Green Chem. 2021 ,23 , 5113−5119. (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.Green Chem. 2022 , 24 , 3001−3008.
- (a) Deres, K.; Schröder, C. H.; Paessens, A.; Goldmann, S.; Hacker, H.
J.; Weber, O.; Krämer, T.; Niewöhner, U.; Pleiss, U.; Stoltefuss, J.;
Graef, E.; Koletzki, D.; Masantschek, R. N. A.; Reimann, A.; Jaeger,
R.; Groß, R.; Beckermann, B.; Schlemmer, K. H.; Haebich, D.;
Rübsamen-Waigmann, H. Inhibition of Hepatitis B Virus Replication by
Drug-Induced Depletion of Nucleocapsids. Science 2003 ,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. Bioorgan. Med. Chem., 2015 , 23 ,
4533−4543.
- (a) Kappe, C. O. Recent Advances in the Biginelli Dihydropyrimidine
Synthesis. New Tricks from an Old Dog. Acc. Chem. Res.2000 , 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. Tetrahedron 2021 , 88 , 132122.
- (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of
Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase
II−III Clinical Trials of Major Pharmaceutical Companies: New
Structural Trends and Therapeutic Areas. Chem. Rev.2016 , 116 , 422−518; (b) Muller, K.; Faeh, C.;
Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition.Science 2007 , 317 , 1881−1886; (c) Gillis, E.
P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A.
Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.2015 , 58 , 8315−8359.
- (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. J.
Med. Chem. 2017 , 60 , 797-804. (b) Sessler, C. D.;
Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J.
CF2H, a Hydrogen Bond Donor. J. Am. Chem. Soc.2017 , 139 , 9325−9332.
- 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.Org. Lett. 2017 , 19 , 2358−2361.
- 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.Org. Lett. 2018 , 20 , 2749−2752.
- 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. Chem. Commun. 2018 , 54 , 2615−2618.
- (a) Zuo, W.; Zuo, L.; Geng, X.; Li, Z.; Wang, L. Radical-Polar
Crossover Enabled Triple Cleavage of
CF2Br2: A Multicomponent Tandem
Cyclization to 3-Fluoropyrazoles. Org. Lett. 2023 ,25, 6062−6066. (b) Huo, J.; Geng, X.; Li, W.; Zhang, P.; Wang,
L. A Traceless Heterocyclic Amine Mediator in
Regioselectivity−Switchable Formal [1 + 2 + 2] Cycloaddition
Reaction to 1,3,4- and 1,4,5-Trisubstituted Pyrazoles. Org.
Lett. 2023 , 25, 512−516. (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. Org. Lett.2021 , 23 , 8343−8347. (d) Xu, Z.; Geng, X.; Cai, Y.;
Wang, L. A Straightforward Approach to Fluorinated
Pyrimido[1,2-b ]indazole Derivatives via Metal/Additive-free
Annulation with Enaminones, 3-Aminoindazoles, and Selectfluor.J. Org. Chem. 2022 , 87 , 6562−6572. (e )
Pan, S.; Song, M.; Zuo, L.; Geng, X.; Wang, L. A Strategy for
Accessing Trifluoromethyl Carbinol-Containing Chromones fromo -Hydroxyaryl Enaminones and Trifluoroacetaldehyde/Ketone
Derivatives. J. Org. Chem. 2023 , 88, 5586−5596.
- (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 β-Hydroxy-β-trifluoromethyl Ketones from Enamines and
Imines. J. Org. Chem. 2003 , 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 β-carbonyl Acids and Trifluoroacetaldehyde Hemiacetals as Well
as Trifluoroacetaldehyde: the Mechanism, the Origin of
Enantioselectivity and the Role of a Catalyst. Org. Chem.
Front. 2018 , 5 , 2692−2709.
- (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
Cs2CO3 Under Transition-metal-free
Conditions. Green Chem. 2022 , 24 , 6816−6822.
(b) Yu, Q.; Zhang, Y.; Wan, J. P. Ambient and Aerobic Carbon–carbon
Bond Cleavage toward α-Ketoester Synthesis by Transition-metal-free
Photocatalysis. Green Chem. 2019 , 21 ,
3436−3441.
- (a) Huo, C.; Yuan, Y.; Chen, F.; Tang, J.; Wang, Y. Copper-Catalyzed
Aerobic Oxidative Dehydrogenative Formal [2 + 3] Cyclization of
Glycine Esters with α-Angelicalactone: Approach to Construct
Polysubstituted Pyrrolidones. Org. Lett. 2015 ,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. Org. Lett.2017 , 19 , 6056−6059.