Visible-Light-Promoted [5 + 1] Annulation Initiated by Electron-Donor-Acceptor Complexes: Synthesis of Perfluoroalkyl-s-Triazines

Article abstract of DOI:10.1021/acs.orglett.9b00655

A visible-light-promoted electron-donor-acceptor (EDA) complex-initiated [5 + 1] annulation between biguanides and perfluoroalkyl halides for the construction of perfluoroalkyl-s-triazines has been developed. It was found that both visible light and dioxygen in the air are favorable for the reaction. A radical-polar crossover mechanism was proposed, in which sequential SET, radical combination, HF elimination, electrocyclization, and aromatization are involved.

Full text of DOI:10.1021/acs.orglett.9b00655

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Promoted [5 + 1] Annulation Initiated by Electron-
Donor−Acceptor Complexes: Synthesis of Perfluoroalkyl‑s‑Triazines
Rui Wang,† Lili Wang,† Qin Xu,‡ Bao-Yi Ren,*,‡ and Fushun Liang*,†,§
†Department of Chemistry, Northeast Normal University, Changchun 130024, China
‡College of Applied Chemistry, Shenyang University of Chemical Technology, Shenyang 110142, China
§College of Chemistry, Liaoning University, Shenyang 110036, China
S
* Supporting Information
ABSTRACT: A visible-light-promoted electron-donor−acceptor (EDA) com-
plex-initiated [5 + 1] annulation between biguanides and perfluoroalkyl halides for
the construction of perfluoroalkyl-s-triazines has been developed. It was found that
both visible light and dioxygen in the air are favorable for the reaction. A radical−
polar crossover mechanism was proposed, in which sequential SET, radical
combination, HF elimination, electrocyclization, and aromatization are involved.
synthesis mediated by electron donor−acceptor (EDA)
complexes6 formed between enolate anions and perfluoroalkyl
halides.7 As a continuation of the research, herein we report
the unprecedented [5 + 1] annulation of biguanides and
perfluoroalkyl iodides under photoconditions, giving rise to the
6-perfluoroalkyl-s-triazine scaffold (Figure 1d). It is known that
the introduction of fluorine(s) into triazine rings can strongly
modify the lipophilicity, bioactivity, and metabolic stability of
drugs8a,b and improve the properties of organic optoelectronic
materials.8c The reaction has the advantages of relatively broad
scope, high efficiency, and mild, metal-free conditions.
Our initial investigation focused on optimization of the
conditions with the model reaction of metformin hydro-
chloride (1a) and perfluorobutyl iodide (2a) (1.1 equiv) in the
presence of a base (5.1 equiv) (Tables 1 and S1). The major
parameters included the light source and solvent. Under 36 W
CFL irradiation, the reaction in dichloromethane could not
afford the [5 + 1] annulation product 3a (entry 1). The
structure of 3a, which was unambiguously confirmed by single-
crystal X-ray diffraction, is supposed to be formed via EDA-
complex-initiated [5 + 1] annulation. Other solvents examined
included THF, DMSO, DMF, MeCN, and toluene (entries 2−
6), and DMF proved to be most efficient, giving 3a in 78%
yield in 6 h (entry 4). As for light sources investigated, the
reactions under ambient light and 12 W blue LEDs also
proceeded, but the yield decreased (entries 7 and 8). However,
the reaction conducted in the dark led to a lower yield (11 h,
entry 9), illustrating that visible light is critical in promoting
the reaction. One of the main findings is that dioxygen in the
air may enhance the reaction efficiency. Comparatively, the
reaction performed under an atmosphere of N2 gave merely a
trace amount of product (entry 10). We suspect that dioxygen
in the reaction system might be beneficial for the single
electron transfer (SET) process involved in the reaction (see
riazines represent one class of significant aza-heterocycles
1
Tbecause of their broad applications in biology,
pharmaceutics,2 and optoelectronics.3 Therefore, the develop-
ment of mild and efficient methods for constructing triazine
heterocycles is of great importance. In particular, biguanides
can be used as effective building blocks for the assembly of s-
triazines because of their unique structural features. Repre-
sentative preparation routes involve acylation/cyclization of
biguanides with the appropriate esters (Figure 1a),4 and
transition-metal-catalyzed reactions of biguanides and selected
alcohols5a or dihaloalkenes5b under thermal conditions (Figure
1b,c).5 In our recent research, we have developed a visible-
light-promoted three-component [2 + 1 + 3] pyrimidine
Figure 1. Assembly of functionalized triazines starting from
biguanidine substrates.
Received: February 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00655
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Letter
a
of monosubstituted biguanides reacted with 2a under the
standard conditions, giving 3e−h in moderate yields (65−
75%). A monosubstituted biguanide with N-aryl groups,
including electron-withdrawing or -donating substituents at
the ortho or para position of the phenyl ring, reacted smoothly
with 2a under the optimized conditions, affording 3f−m in
moderate to high yields (71−87%). Moreover, nonsubstituted
biguanide afforded perfluoropropylated s-triazine 3n in 74%
yield.
Table 1. Optimization of the Reaction Conditions
b
entry
light source
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
36 W CFL
36 W CFL
36 W CFL
36 W CFL
36 W CFL
36 W CFL
ambient light
12 W blue LEDs
in the dark
36 W CFL
DCM
THF
12
18
18
6
8
12
6
6
11
4
n.r.
15
trace
78
60
n.r.
65
55
48
trace
To further examine the scope and utility of this reaction, the
scope of perfluoroalkyl halides was examined (Scheme 2). 1,1-
DMSO
DMF
MeCN
toluene
DMF
DMF
DMF
DMF
a b c
, ,
Scheme 2. Scope of Perfluoroalkyl Halides
c
10
a
Reactions were carried out with 1a (0.5 mmol), 2a (1.1 equiv), and
b
NaOH (5.1 equiv) in 1 mL of solvent in the open air. Isolated yields.
c
The reaction was performed under an atmosphere of N2.
Scheme 6). Finally, we confirmed the best conditions in this
screen involved a 36 W CFL, NaOH, and DMF at 0.5 M
concentration in the open air.
With the optimized conditions in hand (Table 1, entry 4),
we set out to examine the reaction scope. A range of
biguanides were examined in the following work (Scheme 1).
In particular, N,N- and N,N′-disubstituted biguanides were
suitable, giving 3a−d in fairly good yields (69−80%). A variety
a
Reaction conditions: 1a (1 mmol), 2 (1.1 equiv), and NaOH (5.1
b
equiv) in DMF (2 mL). 1.0 equiv of NaOH was used to neutralize
HCl from 1a. Isolated yields are shown.
c
Dimethylbiguanide hydrochloride was reacted with various
perfluoroalkyl iodides under the optimized conditions. As a
result, 6-perfluoroalkyl-s-triazines 4a−e with different carbon
chain lengths were obtained efficiently. The yields correspond-
ing to different perfluoroalkyl chains were 67% for −CF3 (4a),
79% for −C2F5 (4b), 76% for −C5F11 (4c), and 75% for
−C7F15 (4d). Mixed-halogen perfluoroalkyl-containing prod-
uct 4e was also obtained in 73% yield.
Scheme 1. Reaction of Biguanides with Perfluorobutyl
a b c
, ,
Iodide: Synthesis of s-Triazines
Bistriazine 5 was successfully assembled in 53% yield starting
from bioactive chlorhexidine, which contains two chemically
linked biguanide moieties (Scheme 3). All of the above results
(Schemes 1−3) demonstrate the scope and efficiency of the
EDA-complex-initiated [5 + 1] annulation reaction.
Scheme 3. Synthesis of Bistriazines
Aminotriazine derivatives have been reported in pharmaco-
logical studies, particularly as neuronal voltage-gated sodium
channel blockers and diuretics.9 To demonstrate a synthetic
application of the present methodology, we synthesized 6-
(chlorodifluoromethyl)-N2-phenyl-1,3,5-triazine-2,4-diamine
(6, CAS no. 53387-73-8), a compound with postemergence
herbicidal activity,10 in 80% yield upon irradiation of 1-
(diaminomethylene)-3-phenylguanidine and 1-chloro-1,1,2,2-
tetrafluoro-2-iodoethane in DMF in the open air (Scheme 4).
a
Reaction conditions: 1 (1 mmol), 2a (1.1 equiv), and NaOH (5.1
b
equiv) in DMF (2 mL). 1.0 equiv of NaOH was used to neutralize
HCl from 1. Isolated yields are shown.
c
B
DOI: 10.1021/acs.orglett.9b00655
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indicating the formation of the EDA complex. The absorption
band corresponding to the EDA complex red-shifts to the
visible region (blue line in Figure 2, bottom). In addition, a
quantum yield (Φ) of 0.03 was determined with the model
reaction (λ = 400 nm), which might indicate a radical
combination mechanism (see the Supporting Information).11
On the basis of the above results, a tandem radical−polar
crossover mechanism leading to s-triazines was proposed
(Scheme 6).12 (i) In the presence of base, a biguanide anion
Scheme 4. Synthesis of s-Triazine 6 with Herbicidal Activity
To probe whether SET and radical intermediates are
involved in this visible-light-mediated [5 + 1] annulation
reaction, a series of control experiments were conducted
(Scheme 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO),
Scheme 6. Proposed Mechanism for the Formation of s-
Triazine 3a
Scheme 5. Control Experiments
an efficient free radical scavenger, was introduced under
otherwise identical conditions, and only a trace amount of 3a
was observed. In the presence of p-dinitrobenzene (p-DNB), a
SET inhibitor, the reaction was completely inhibited. Taken
together, these observations indicate that a mechanism
involving radical and SET pathways is most likely.
To gain insight into the mechanism of the visible-light-
mediated [5 + 1] annulation, we performed UV−vis
spectroscopic measurements on various combinations of 1a,
2a, and NaOH in DMF (Figure 2). Although 1a and 2a are
transparent to light, a distinct coloration can be observed upon
mixing of 1a and 2a in the presence of NaOH (Figure 2, top),
intermediate I is generated, which interacts with perfluorobutyl
iodide to form EDA complex II. (ii) Photoirradiation affords
the excited triplet species I* (heavy-atom effect). (iii) Collapse
of complex II* via SET leads to the generation of nitrogen
radical13 III and C4F9I radical anion (solvent cage molecule).
(iv) C−N radical combination gives the key intermediate V,14
which eliminates HF (in the presence of base), delivering
triazatriene VI. (v) 6π electrocyclization15 and subsequent
aromatization afford the final s-triazine 3a. In the visible-light-
mediated heterocycle construction cascade,16 triazines are
constructed in formal [5 + 1] annulations by simultaneous
buildup of two C−N bonds. The role of dioxygen in the
reaction system was tentatively elucidated. On one hand,
singlet dioxygen might be generated through energy transfer
from the triplet excited state of II*.17,18 On the other hand,
singlet dioxygen is supposed to be beneficial for the SET
between biguanide anion and perfluoroalkyl halides, just like
an electron shuttle.19,20
In summary, an unprecedented visible-light-promoted [5 +
1] annulation between biguanides and perfluoroalkyl halides
under mild conditions (visible light, metal-free) has been
developed. 6-Perfluoroalkyl-s-triazines were assembled via a
sequence of SET, radical coupling, HF elimination, electro-
cyclization, and aromatization. Both visible light and dioxygen
in the air are favorable for the reaction. Consecutive energy
transfer and electron transfer events were suspected to be
involved in the reaction system, which not only helps to
elucidate the effect of dioxygen on the reaction but also makes
the chemistry more intriguing. These perfluoroalkyl-containing
s-triazines prepared in one pot might find vast applications in
the medicine and materials areas. This work demonstrates the
power and potential of electron-donor−acceptor complexes in
photosynthetic chemistry. The extension of this work to
polymer synthesis is currently in progress in our laboratory.
Figure 2. (top) Photographs showin the formation of the colored
EDA complex (yellow) upon addition of 2a to a solution of 1a +
NaOH. (bottom) Optical absorption spectra in DMF: [1a + NaOH]
= 0.0001 M; [2a] = 0.002 M; [1a + 2a + NaOH] = 0.4 M.
C
DOI: 10.1021/acs.orglett.9b00655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Y.; Luo, Z.-Y.; Guo, S.-N.; Cui, D.-M.; Zhang, Y. Org. Lett. 2017, 19,
3947.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00655.
■
S
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Experimental procedures, optimization tables, and
characterization data for all of the products (PDF)
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C.; Melchiorre, P. Angew. Chem., Int. Ed. 2015, 54, 1485. (e) Quint,
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Accession Codes
CCDC 1840269 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
T.; Duarte, M.; Jurberg, I. D.; Paixao, M. W. ACS Catal. 2016, 6,
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AUTHOR INFORMATION
Corresponding Authors
■
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*E-mail: renbaoyi@syuct.edu.cn.
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*E-mail: fsliang@lnu.edu.cn.
ORCID
Bao-Yi Ren: 0000-0001-5879-3291
Fushun Liang: 0000-0003-4195-3863
Notes
The authors declare no competing financial interest.
(11) However, a radical chain mechanism cannot be completely
ruled out, as one reviewer kindly pointed out.
ACKNOWLEDGMENTS
■
(12) For radical−polar crossover reaction, see: (a) Kischkewitz, M.;
Financial support from the National Natural Science
Foundation of China (21372039), the Innovative Talents
Supporting Project of Higher Education Institutions in
Liaoning Province (2018478), and the Scientific Research
Fund of Liaoning Province (LT2017010 and 20180550539) is
greatly acknowledged.
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