Combining Fluoroalkylation and Defluorination to Enable Formal [3 + 2 + 1] Heteroannulation by Using Visible-Light Photoredox Organocatalysis

Article abstract of DOI:10.1021/acs.orglett.8b00963

A metal-free, visible-light photoredox-catalyzed three-component [3 + 2 + 1] heteroannulation for accessing modular fluoroalkylated pyrimidines from readily available silyl enol ether, amidine, and fluoroalkyl halide is developed. This protocol distinguishes itself by broad functional group tolerance in a regioselective manner, which provides a complement to the existing methods for the construction of pharmaceutically and biologically active organofluorine compounds.

Full text of DOI:10.1021/acs.orglett.8b00963

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Combining Fluoroalkylation and Defluorination to Enable Formal [3
+ 2 + 1] Heteroannulation by Using Visible-Light Photoredox
Organocatalysis
Xue-Qiang Chu,† Ting Xie,† Lin Li,† Danhua Ge,† Zhi-Liang Shen,*,† and Teck-Peng Loh*,†,‡
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A metal-free, visible-light photoredox-catalyzed
three-component [3 + 2 + 1] heteroannulation for accessing
modular fluoroalkylated pyrimidines from readily available silyl
enol ether, amidine, and fluoroalkyl halide is developed. This
protocol distinguishes itself by broad functional group tolerance
in a regioselective manner, which provides a complement to the
existing methods for the construction of pharmaceutically and
biologically active organofluorine compounds.
Scheme 1. Radical-Type Perfluoroalkylation with
Concomitant Functionalization
he unique chemical and physical advantages conferred by
Tincorporation of fluorine atoms or higher homologue
fluoroalkyl groups (Rf) into organic molecules have gained
widespread recognition throughout medicinal chemistry, the
agrochemical industry, and materials science.1 Particularly,
introduction of these fluorine-containing substituents in organic
molecules has the potential to exert profound changes on the
molecules’ lipophilicity, solubility, metabolic stability, and
bioavailability properties with minor spatial alteration.2 There-
fore, it is established that the strategic exploitation of readily
available fluorinated building blocks to attach Rf groups and
other relevant functional groups to organic molecules has
become an important topic in synthetic chemistry.3−12
In view of the importance of organofluorine compounds,
considerable advancements pertaining to transition-metal-
catalyzed direct couplings of various prefunctionalized pre-
cursors with either electrophilic or nucleophilic CF3 or Rf
reagents have been made during the past decades.4,5 Recently,
the exploration of efficient methods for the construction of
C(sp3)−CF2 bonds based on radical-type fluoroalkylation and
concomitant α- and/or β-functionalization of alkenes6 or
alkynes7 has stimulated intense research efforts, owing to the
ubiquitous feedstock of unsaturated moieties (Scheme 1A). In
contrast, the previously reported general methods for the
synthesis of heterocycles bearing a fluorine or perfluoroalkyl
group in a specific position of the ring are mainly limited to the
direct functionalization of the heterocycle precursor with a
fluorine source, displaying poor regioselectivity and requiring the
direct use of preformed or commercially available heteroaromatic
counterparts.8 While a number of solutions have emerged to
address these concerns, successful examples for the assembly of
pharmacophores associated with site-selective fluoroalkylation
commencing from several simple and easily available compo-
nents in a one-pot operation are still rare and highly desirable.9
On the other hand, visible-light photoredox catalysis has
demonstrated significant strengths for facilitating activation of
organic substrates and engineering new chemical processes
because of its environmentally benign nature and mild reaction
conditions.10 MacMillan and co-workers11 have introduced an
impressive photoredox-based reaction that allows facile fluo-
roalkylation of enolsilanes (Scheme 1B, a). We envision a
rationally designed strategy for the efficient synthesis of
fluoroalkylated heterocycles, wherein an in situ generated α-
Received: March 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Optimization of the Reaction Conditions
Scheme 3. Scope of Various 1,n-Bis-nucleophiles
a
0.3 mmol scale; yields were determined by NMR analysis (1,4-
b
dimethoxybenzene as an internal standard). 2 (0.6 mmol) and
DABCO (1.2 mmol) were used. Isolated yields. In situ prepared 2d.
c
d
a
b
Standard conditions; yields of isolated products. 1 mmol scale for 17
c
h. 0.5 mmol scale.
perfluoroalkylated ketone rapidly undergoes base-mediated
defluorination12 to release β-fluoroenone, which subsequently
undergoes an intermolecular annulation with 1,n-bis-nucleo-
philes (Scheme 1B, b). Such a novel strategy exploits a tandem
relay by combining organo-photoredox-catalyzed radical fluo-
roalkylation, dehalogenation, polar condensation, and synergistic
cleavage of two C−F bonds as a means to access fluoroalkylated
heterocyclic compounds, such as pyrimidines.13 Despite its
apparent simplicity, the successful realization of this challenging
issue is complicated by several factors: first, the requirement of a
suitable catalyst and reagents to coordinate the relationships
between different reaction stages; second, and most importantly,
its capacity to realize a controlled reaction sequence of α-
perfluoroalkylation/β-dehalogenation/cyclization, an effective
system which must be compatible with both photoredox catalysis
and subsequent fragments reassembly; and finally, difficulty in
the consecutive cleavage of three C−X (X = I, F) bonds in the
perfluoroalkyl halides reagents to give diverse, regiodefined
aromatic compounds.9,13
We initially evaluated our hypothesis by treating benzamidine
hydrochloride (1a) and trimethylsilyl enol ether 2a with
perfluorobutyl iodide (3a) in the presence of 3 mol % of Rose
bengal and 3.0 equiv of triethylenediamine (DABCO) in
acetonitrile at room temperature under the irradiation of white
LEDs for 12 h (Scheme 2).14 Gratifyingly, it was found that the
sole use of a visible-light photoredox catalyst promoted the
desired [3 + 2 + 1] annulation to afford the fluoroalkylated
pyrimidine 4a in 18% NMR yield (entry 2). Of several
photocatalysts examined, inexpensive and easily available eosin
derivatives gave the best yield (64% NMR yield) of the target
product 4a (entries 3 and 4). Both an organometallic Ru-
complex and an organic dye such as Acriflavine were found to be
inferior to eosin derivatives as the reaction catalyst (entries 5−
6).14 Moreover, it was found that employment of triisopropylsilyl
(TIPS) enol ether 2d remarkably improved the reaction
performance (up to 99% NMR yield and 84% isolated yield),
reflecting that the relative stability and the appropriate steric
hindrance of Si-protective groups are beneficial to the reaction
(entries 7−10). Additionally, considering the procedural
simplicity and synthetically easy accessibility, a concise, two-
step, one-flask procedure was designed and successfully achieved
for the synthesis of pyrimidine by using an in situ generated silyl
enol ether 2d from the reaction of acetophenone (2a′) with
TIPSOTf in the presence of Et3N, leading to an 84% isolated
yield of the product 4a (entry 11).
With the optimal reaction conditions in hand, we continued
our task of exploring the substrate scope of the reaction. It was
found that this metal-free successive fluoroalkylation/dehaloge-
nation/annulation process was general, in terms of substrate
scope. As shown in Scheme 3, benzamidines containing diverse
substituents of varying electronic character and steric hindrance
on the phenyl moieties were smoothly annulated to afford the
corresponding products 4a−f in high yields. In the same manner,
the reactions worked equally well with heteroaryl amidines under
the optimized reaction conditions to afford the corresponding
heterocyclic variants 4h−i. Notably, functional groups such as
halogens (Br, Cl, F) were satisfactorily compatible with the mild
reaction conditions, which could be retained for late-stage
manipulation. However, product 4g containing a strong electron-
withdrawing group (NO2) could not be produced under the
optimized reaction conditions. As for C-alkyl candidates, such as
formimidamide (1j), acetimidamide (1k), and cyclopropane-
carboximidamide (1l), they exhibited good reactivity and
participated well in this photoredox catalytic heteroannulation
to produce the anticipated products 4j−l in 51−93% yields.
Remarkably, 1,n-bis-nucleophiles of 2-benzimidazolylamine and
guanidine hydrochloride were converted into functionalized
pyrimidine nuclei in a streamlined manner (Scheme 3, 4m−
n).9d−f Unfortunately, other types of 1,n-bis-nucleophiles (1o−
s) having a carbonyl (1o), phenyl (1q−r), or heteroatom (1s) as
the tether were not suitable substrates for the reaction under the
optimized reaction conditions.
Next, we set out to investigate the substrate scope of this
tandem protocol with respect to a series of structurally varied silyl
enol ethers, and the results are listed in Scheme 4. Both electron-
donating (5a−e) and electron-withdrawing (5f−j) groups on the
triisopropyl((1-phenylvinyl)oxy)silanes led to satisfactory yields,
and thus, a variety of pyrimidines with structural diversity were
synthesized. The substrates, featuring the functionalized
polycyclic motifs, such as naphthalene and benzo[b]thiophene,
were successfully transformed into the fluoroalkylated products
5k and 5l in 40% and 56% yields, respectively. In addition, the
presence of α-substituents in silyl enol ether 2 did not interfere
with the intermolecular aromatization, and both cyclic [(3,4-
B
DOI: 10.1021/acs.orglett.8b00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 4. Scope of Various Silyl Enol Ethers
Scheme 6. One-Pot [3 + 2 + 1] Heteroannulation
a
Yields of isolated products.
Scheme 7. Control Experiments
a
b
c
Standard conditions; yields of isolated products. For 12 h. NaOH
(1.2 mmol) instead of DABCO was used as a base.
dihydronaphthalen-1-yl)oxytriisopropylsilane] and activated
ethyl 3-phenyl-3-((triisopropylsilyl)oxy)acrylate efficiently
underwent the present organic transformations (5m−n). The
enolsilanes derived from aliphatic ketones were also examined,
producing 5o and 5p in moderate yields with remarkable
regioselectivity. We were able to accomplish the conversion of 3-
phenylpropanal to benzylated product 5q in 30% yield, which
was extremely difficult to achieve through the direct function-
alization of pyrimidine at its 5-position.13 Interestingly, this
photocatalytic multicomponent reaction was also employed for
the construction of pyrimidine-modified epiandrosterone 5r.
In addition to perfluorobutyl iodide (3a), we were pleased to
observe that the applicability and generality of this trans-
formation was further broadened by employing a spectrum of
fluoroalkyl halides (Scheme 5). Interestingly, the chain length
addition, our mechanistic study showed that the generation of β-
fluoroenone 4a′ was the key step, and the thus-formed
intermediate 4a′ condensed with bis-nucleophile 1a in the final
ring-closure step to afford the target product 4a in 97% yield
(Scheme 7C).
Based on the results of the above-mentioned control
experiments, a radical fluoroalkylation/defluorination/annula-
tion mechanism consisting of three successive steps is shown in
Scheme 8. In initial photocatalytic step 1, an excited-state EY*
Scheme 8. Proposed Reaction Mechanism
a
Scheme 5. Scope of Various Perfluoroalkyl Halides
a
b
Standard conditions; yields of isolated products. 1.8 mmol of
with reducing ability is generated from Na2-EY by irradiation
with visible light (eosin Y, λexc = 539 nm),10 and a single electron
transfer (SET) from this species to fluoroalkyl halide occurs to
produce an electrophilic n-C4F9 radical and a radical cation EY•+.
Next, generation of tertiary carbocation B via the addition of a
perfluoroalkyl radical to the CC bond of silyl enol ether,
followed by further oxidation with the aid of the oxidative radical
cation EY•+, takes place, owing to the high reduction potential of
α-silyloxy intermediate A.11 After rapid attack by an I− ion, the
formed unstable intermediate B would decompose to give α-
perfluoroalkylated ketone C.11 In defluorination step 2, α,β-
desaturation of carbonyl compound C is enabled by eliminating a
molecule of HF under basic conditions.12 Finally, ring closure
(step 3) involving intermolecular [3 + 3] condensation of 4a′
with amidine 1 proceeds to furnish the desired pyrimidine 4.
In summary, we have developed an efficient, metal-free, visible
light photoredox-catalyzed three-component reaction for the
facile assembly of fluoroalkylated pyrimidine derivatives in a
regiodefined [3 + 2 + 1] manner, starting from readily available
building blocks of silyl enol ether, amidine, and fluoroalkyl halide.
perfluoropropyl iodide was used and reacted for 48 h.
(with 3−10 carbons) of the substrates only has a slight impact on
the reaction outcome (6a−d, 56−90% yields). Impressively, our
protocol allowed efficient access to heterocyclic adducts with
appreciable yields by utilizing in situ formed enolsilanes from
related ketones 2′, followed by exposure to photocatalytic
conditions in a single reaction vessel (Scheme 6, 4a, 4l, 5n, and
6b, 48−84% yields).
A set of experiments were conducted to elucidate a possible
reaction mechanism (Scheme 7). Evidence for the radical nature
of the transformation was ascertained by introducing radical
scavengers of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) in
the reaction, where TEMPO (3 equiv) completely inhibited the
reaction (Scheme 7A). The initial assumption that intermo-
lecular α-perfluoroalkylation and sequent defluorination occurs
to yield (Z)-3,4,4,5,5,6,6,6-octafluoro-1-phenylhex-2-en-1-one
(4a′) was proven by means of the control reaction of enolsilane
2d with 3a under the standard conditions (Scheme 7B). In
C
DOI: 10.1021/acs.orglett.8b00963
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Organic Letters
Letter
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Mechanistic studies showed that the reaction proceeded via an
unprecedented combination of radical fluoroalkylation, polar
defluorination, and subsequent fragment annulations, along with
successive cleavage of three carbon−halide bonds and
simultaneous formation of three new C−C/C−N bonds and a
new six-membered ring. Moreover, the one-pot procedure
directly employing ketones as an enolsilane precursor also was
achieved with good synthetic efficiency.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00963.
■
S
Experimental procedures, optimization of reaction con-
ditions, mechanistic studies, characterization data, and
copies of NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
(7) For selected recent examples of alkyne fluoroalkylation, see:
(a) Gao, P.; Song, X.-R.; Liu, X.-Y.; Liang, Y.-M. Chem. - Eur. J. 2015, 21,
7648−7661. (b) Li, Z.; García-Domínguez, A.; Nevado, C. J. Am. Chem.
Soc. 2015, 137, 11610−11613. (c) Beniazza, R.; Atkinson, R.; Absalon,
■
*E-mail: ias_zlshen@njtech.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
ORCID
C.; Castet, F.; Denisov, S. A.; McClenaghan, N. D.; Lastec
Vincent, J.-M. Adv. Synth. Catal. 2016, 358, 2949−2961. (d) Doman
S.; Chaładaj, W. ACS Catal. 2016, 6, 3452−3456. (e) Wang, X.; Studer,
A. Org. Lett. 2017, 19, 2977−2980. (f) Yin, H.; Skrydstrup, T. J. Org.
Chem. 2017, 82, 6474−6481.
́
ouer
̀
es, D.;
ski,
́
Teck-Peng Loh: 0000-0002-2936-337X
Notes
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Applications; Petrov, V. A., Ed.; John Wiley & Sons: Hoboken, NJ, 2009.
(b) Fluorine in Heterocyclic Chemistry, Vols. 1, 2; Nenajdenko, V., Ed.;
Springer International Publishing: Cham, Switzerland, 2014.
(9) (a) Guan, H.-P.; Tang, X.-Q.; Luo, B.-H.; Hu, C.-M. Synthesis 1997,
1489−1494. (b) Fandrick, D. R.; Reinhardt, D.; Desrosiers, J.-N.;
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Senanayake, C. H. Org. Lett. 2014, 16, 2834−2837. (c) Panferova, L. I.;
Tsymbal, A. V.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett.
2016, 18, 996−999. (d) Lee, J. W.; Spiegowski, D. N.; Ngai, M.-Y. Chem.
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A.; Muzalevskiy, V. M.; Nenajdenko, V. G. Eur. J. Org. Chem. 2017,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from Nanjing
Tech University (Start-up Grant Nos. 39837118, 39837101, and
39837146), the SICAM Fellowship from Jiangsu National
Synergetic Innovation Center for Advanced Materials, and
Nanyang Technological University.
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Supporting Information.
D
DOI: 10.1021/acs.orglett.8b00963
Org. Lett. XXXX, XXX, XXX−XXX