Iodine-Promoted Multicomponent Synthesis of 2,4-Diamino-1,3,5-triazines

Article abstract of DOI:10.1021/acs.orglett.0c03130

A novel and efficient multicomponent cyclization of methyl ketones, cyanamides, and arylamines for the synthesizing 2,4-diamino-1,3,5-triazines via consecutive formation of four C-N bonds is reported. This multicomponent reaction is characterized by the employment of two molecules of cyanamide for double C(sp3)-H amination of methyl ketones, avoiding complicated prepreparation of substrates and expanding the substrate scope. Furthermore, this multicomponent cyclization strategy provides a new approach for generating diverse 2,4-diamino-1,3,5-triazines with a broad substrate scope under mild conditions.

Full text of DOI:10.1021/acs.orglett.0c03130

pubs.acs.org/OrgLett
Letter
Iodine-Promoted Multicomponent Synthesis of 2,4-Diamino-1,3,5-
triazines
Peng Zhao, You Zhou, Xiao-Xiao Yu, Chun Huang, Yan-Dong Wu, Guodong Yin,* and An-Xin Wu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03130
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A novel and efficient multicomponent cyclization of methyl ketones, cyanamides, and arylamines for the synthesizing
2,4-diamino-1,3,5-triazines via consecutive formation of four C−N bonds is reported. This multicomponent reaction is characterized
by the employment of two molecules of cyanamide for double C(sp3)−H amination of methyl ketones, avoiding complicated
prepreparation of substrates and expanding the substrate scope. Furthermore, this multicomponent cyclization strategy provides a
new approach for generating diverse 2,4-diamino-1,3,5-triazines with a broad substrate scope under mild conditions.
conditions and limited narrow substrate scopes. Accordingly,
the development of new methods for the synthesisis 2,4-
diamino-1,3,5-triazines remains an important goal.
1,3,5-Triazines and their derivatives are an important class of
multi-N-containing heterocycles found in various pharmaceut-
icals and natural products.1 In particular, 2,4-diamino-1,3,5-
triazines exhibit excellent biological activities, such as
antibacterial and anticancer activities.2 Recently, several
elegant methods for the formation 2,4-diamino-1,3,5-triazines
have been achieved by developing novel C1 sources to expand
the reaction complexity and novelty. For example, Liang and
Zhang have disclosed appealing studies of the construction 2,4-
diamino-1,3,5-triazines via transition-metal-catalyzed or photo-
catalyzed processes. Notably, perfluoroalkyl halides,3 1,1-
dibromoalkenes,4 and alcohols5 have been used as unusual
C1 synthons in these transformations (Scheme 1a). Despite
the great progress, these methods are usually limited to using
biguanides as substrates,6 which require harsh preparation
Recently, the synthesis of multi-N-containing heterocycles
from nitriles and methyl ketones has received attention.7 In
2018, the Zhou group disclosed an appealing cascade
cyclization of two nitrile molecules with methyl ketones to
construct pyrimidines. In this work, methyl ketones acts as
nucleophiles, which attack the nitriles to realize the cascade
cyclization process (Figure 1a).8 Inspired by the involvement
of nitriles in heterocyclic synthesis, we envisaged employing
methyl ketones as electrophiles via iodination/Kornblum
oxidation sequences, which could attack two molecule
cyanamides to achieve a double C(sp3)−H amination process.9
Then the naked electrophilic nitrile unit can be attacked by
anilines to generate guanidines in situ. Finally, triazines were
delivered by the amination/cyclization process (Figure 1b).
Herein, we first developed a novel strategy for the synthesizing
the devised 2,4-diamino-1,3,5-triazines from readily available
cyanamides, methyl ketones, and anilines via consecutive
construction of four C−N bonds (Scheme 1b). This
multicomponent cyclization strategy provides a new synthesis
for generating 1,3,5-triazines.10
Scheme 1. Recent Progress in the Synthesis of 2,4-Diamino-
1,3,5-triazines
Received: September 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03130
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
Scheme 2. Scope of Aryl Methyl Ketones
Figure 1. Use of nitriles and methyl ketones in multi-N-containing
heterocycle synthesis.
Owing to continued interest in the synthesis of nitrogen-
containing heterocycles.11 First, cyanamide 3 was used as the
amine source to react with methyl ketone 1a and p-toluidine
2a at 100 °C in the presence of DMSO and I2. Fortunately, the
corresponding 1,3,5-triazines were afforded in 48% yield
(Table 1, entry 1), and X-ray crystallographic analysis showed
Table 1. Representative Optimization of the Amination
a
Reaction
b
entry
I2 (equiv)
temp (°C)
additive
yield (%)
1
2
3
4
5
6
7
8
3.2
3.2
3.2
3.2
3.2
3.2
3.2
3.2
3.2
3.2
2.0
1.6
1.0
100
110
120
130
140
110
110
110
110
110
110
110
110
110
48
55
52
50
46
65
58
49
42
38
72
62
22
ND
a
b
1.0 mmol scale. Isolated yield of products 4.
donating (Me, OMe, 3,4-OCH2O, 3,4-O(CH2)2O) and
halogen (F, Cl, Br, 3,4-di-Cl) substituents were compatible
with this multicomponent reaction under the optimized
conditions, affording the corresponding triazines in good
yields (4a−4k, 58−77%). Furthermore, methyl ketones with
electron-deficient substituents (Ph, NO2, CN, CO2Me,
SO2Me) reacted smoothly, affording 1,3,5-triazines in
satisfactory yields (4l−4p, 52−69%). Notably, treating 3-
acetylthiophene 1q with cyanamide and p-toluidineunder
standard conditions, afforded corresponding product 4q in
56% yield. Gratifyingly, sterically hindered 2-naphthyl methyl
ketone 1r, 1-naphthyl methyl ketone 1s, and 1-(9H-fluoren-2-
yl)ethenone 1t substrates afforded products 4r−4t in 60−67%
yields.
Next, to further broaden the substrate scope of this
polyamination process, a range of arylamines were investigated
under the optimal conditions (Scheme 3). Arylamines with
electron-rich (C(CH3)3,CH(CH3)2, CH2CH3, 3,4-di-Me) and
halogen (F, Cl) substituents reacted well, affording 5a−5f in
62−75% yields. Furthermore, halogen-substituted arylamines
reacted with halogen-substituted methyl ketones under the
optimal conditions, generating desired products 5g−5h in 58−
64% yields. Interestingly, arylamines bearing multiple halogen
functional groups (2-F-4-Cl, 3,4,5-tri-Cl) afforded the
corresponding uniodinated products (5i−5j, 52−56%),
perhaps owing to the electron deficiency produced by multiple
TFA
TfOH
CuCl2
FeCl3
HCl
TFA
TFA
TFA
TFA
9
10
11
12
13
14
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3 (2.0 mmol),
I2 (equiv), additive (1.0 equiv), indicated temperature, DMSO 4 mL,
24 h, unless otherwise noted. Isolated yields.
b
that the ortho-position of aniline in the triazine product was
iodo substituted (for details, see the SI). Next, the effect of
different reaction temperatures was investigated, with 110 °C
found to give the best result (Table 1, entries 2−5). A series of
acids were then screened, with the results indicating that TFA
significantly improved the reaction yield (Table 1, entries 6−
10). Finally, different amounts of iodine were tested, and 4a
was obtained in 72% yield when limited to 2 equiv (Table 1,
entries 11−14).
With the optimized conditions in hand, the effect of different
substituents on methyl ketones on this transformation was
investigated (Scheme 2). Methyl ketones with electron-
B
https://dx.doi.org/10.1021/acs.orglett.0c03130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
toluidine 2a and cyanamide 3 under the optimal conditions to
afford unsymmetrical triazine 4a in 75% yield (Scheme 4b).
Subsequently, the reaction of phenylglyoxal hydrate 1ac with
2a and 3 under the optimal conditions afforded diamino-1,3,5-
triazine 4a in 78% yield (Scheme 4c). These results showed
that the 1aa and 1ac were important intermediates in the
amination/cyclization reaction. Moreover, 2-iodo-4-methylani-
line 2aa as substrate reacted smoothly, affording 4a in 76%
yield (Scheme 4d). Compound 4a′ was prepared12 and shown
to be unable to transform into final product 4a under the
optimal conditions (Scheme 4e). These results indicated that
the iodination process occurred at the initial reaction stage.
Furthermore, 2-(4-methylphenyl)guanidine was unable to be
transformed into 4a, excluding the possibility of in situ
generation of guanidine by aniline and cyanamide (for details,
see SI). Finally, 1a was reacted with 3 and iodine at 80 °C for 1
h, affordingintermediate A′ (detected by GC−MS), which was
converted into 4a by adding 2aa and TFA at 110 °C (Scheme
4f).
Scheme 3. Scope of Anilines
Based on the above experimental results and previous
work,13 we have proposed a plausible mechanism for
multicomponent reaction (Scheme 5). Acetophenone 1a
Scheme 5. Proposed Mechanism
a
b
1.0 mmol scale. Isolated yield of products 5.
halogen substituents reducing the nucleophilicity of the aniline
ortho-position. Furthermore, biphenyl-4-amine reacted
smoothly with methyl ketones, affording 5k−5m in 60%−
71% yields. Finally, elegant biheterocyclic products were also
synthesized using 1-(quinolin-3-yl)ethanone and quinolin-8-
amine as substrates, respectively (5n and 5o, 59% and 51%,
respectively).
To further explore the reaction mechanism, a series of
control experiments were conducted. Initially, methyl ketone
1a produced phenylglyoxal and a hydrated species in
quantitative yield under the optimal conditions (Scheme 4a).
Next, α-iodoacetophenone 1aa as substrate reacted with p-
Scheme 4. Control Experiment
undergoes iodination to produce α-iodoacetophenone 1aa,
which further transforms into phenylglyoxal 1ab via Kornblum
oxidation. Phenylglyoxal 1ab activated by acid can undergo
continuous reaction with two molecules of cyanamide to form
intermediate B via the construction of two C−N bonds.
Simultaneously, the aniline ortho-position is iodinated,
generating o-iodoaniline 2aa, which can undergo nucleophilic
attack on intermediate B to deliver intermediate C. Finally,
intermediate C undergoes a cyclization sequence to afford
intermediate D, which further transforms into desired product
4a via an oxidative aromatization process.
In summary, a new and efficient multicomponent amina-
tion/cascade cyclization strategy to prepare trisubstituted
1,3,5-triazines has been developed. In this transformation,
amine sources are generated in situ from cyanamides to
construct 1,3,5-triazines, combining with methyl ketones and
aryl amines to expand the substrate scopes. Furthermore, this
multicomponent cyclization strategy proceeds via a novel
pathway, in which cyanamides are employed as nucleophiles
C
https://dx.doi.org/10.1021/acs.orglett.0c03130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
and electrophiles in the consecutive formation of four C−N
bonds, which avoids complicated substrate prepreparation.
Further research on the construction of other nitrogen
heterocycles using this multicomponent amination/cascade
cyclization strategy is underway in our laboratory.
and CCNU18QN011) and the Educational Commission of
Hubei Province (D20192503). This work was also supported
by the 111 Project B17019.
REFERENCES
■
(1) (a) Kaminsky, R.; Brun, R. In Vitro and In Vivo Activities of
Trybizine Hydrochloride Against Various Pathogenic Trypanosome
Species. Antimicrob. Agents Chemother. 1998, 42, 2858−2862.
(b) Irikura, T.; Abe, Y.; Okamura, K.; Higo, K.; Maeda, A.;
Morinaga, F.; Shirai, G.; Hatae, S. New S-triazine Derivatives as
Depressants for Reticuloendothelial Hyperfunction Induced by
Bacterial Endotoxin. J. Med. Chem. 1970, 13, 1081−1089. (c) Srinivas,
K.; Srinivas, U.; Rao, V. J.; Bhanuprakash, K.; Kishore, K. H.; Murty,
U. Synthesis and Antibacterial Activity of 2,4,6-trisubstituted S-
triazines. Bioorg. Med. Chem. Lett. 2005, 15, 1121−1123. (d) Kathir-
avan, M. K.; Salake, A. B.; Chothe, A. S.; Dudhe, P. B.; Watode, R. P.;
Mukta, M. S.; Gadhwe, S. The Biology and Chemistry of Antifungal
Agents: A Review. Bioorg. Med. Chem. 2012, 20, 5678−5698.
(2) (a) Nishigaki, S.; Yoneda, F.; Matsumoto, H.; Morinaga, K.
Synthetic Antibacterials. I. Nitrofurylvinyl-s-triazine Derivatives. J.
Med. Chem. 1969, 12, 39−42. (b) Chen, X.; Zhan, P.; Liu, X.; Cheng,
Z.; Meng, C.; Shao, S.; Pannecouque, C.; Clercq, E. D.; Liu, X.
Design, Synthesis, Anti-HIV Evaluation and Molecular Modeling of
Piperidine-linked Amino-triazine Derivatives as Potent Non-nucleo-
side Reverse Transcriptase Inhibitors. Bioorg. Med. Chem. 2012, 20,
3856−3864. (c) Lolak, N.; Akocak, S.; Bua, S.; Sanku, R. K.; Supuran,
C. T. Discovery of New Ureido Benzenesulfonamides Incorporating
1,3,5-triazine Moieties as Carbonic Anhydrase I, II, IX and XII
Inhibitors. Bioorg. Med. Chem. 2019, 27, 1588−1594.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03130.
Experimental procedures, product characterization,
1
crystallographic data, and copies of the H and 13C
NMR spectra (PDF)
Accession Codes
CCDC 2031921 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 emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Guodong Yin − College of Chemistry and Chemical Engineering,
Hubei Key Laboratory of Pollutant Analysis and Reuse
Technology, Hubei Normal University, Huangshi 435002, P.R.
China; orcid.org/0000-0002-8095-0625; Email: gdyin@
hbnu.edu.cn
An-Xin Wu − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P.R. China; orcid.org/
0000-0001-7673-210X; Email: chwuax@mail.ccnu.edu.cn
(3) Wang, R.; Wang, L.; Xu, Q.; Ren, B. Y.; Liang, F. Visible-Light-
Promoted [5 + 1] Annulation Initiated by Electron-Donor-Acceptor
Complexes: Synthesis of Perfluoroalkyl-s-Triazines. Org. Lett. 2019,
21, 3072−3076.
(4) Zhang, C.; Ban, M. T.; Zhu, K.; Zhang, L. Y.; Luo, Z. Y.; Guo, S.
N.; Cui, D. M.; Zhang, Y. Copper-Catalyzed Synthesis of Substituted
2,4-Diamino-1,3,5-triazines from 1,1-Dibromoalkenes and Biguanides.
Org. Lett. 2017, 19, 3947−3949.
(5) (a) Zeng, M.; Wang, T.; Cui, D. M.; Zhang, C. Ruthenium-
catalyzed Synthesis of Tri-substituted 1,3,5-triazines from Alcohols
and Biguanides. New J. Chem. 2016, 40, 8225−8228. (b) Zeng, M.;
Xie, Z. P.; Cui, D. M.; Zhang, C. Ruthenium-catalyzed Synthesis of
Arylethyl 1,3,5-triazines from Arylallyl Alcohols and Biguanides. Org.
Biomol. Chem. 2018, 16, 6140−6145. (c) Yao, W.; Duan, Z.; Zhang,
Y.; Sang, X.; Xia, X.; Wang, D. Iridium Supported on Phosphorus-
Doped Porous Organic Polymers: Active and Recyclable Catalyst for
Acceptorless Dehydrogenation and Borrowing Hydrogen Reaction.
Adv. Synth. Catal. 2019, 361, 5695−5703.
(6) For selected reviews, see: (a) Chaurasia, S. R.; Dange, R.;
Bhanage, B. M. Graphene Oxide as a Carbo-catalyst for the Synthesis
of Tri-substituted 1,3,5-triazines Using Biguanides and Alcohols.
Catal. Commun. 2020, 137, 105933. (b) Xu, Y.; Shen, B.; Liu, L.;
Qiao, C. Metal Free [4 + 1] and [5 + 1] Annulation Reactions to
Prepare Heterocycles Using DMF and Its Derivatives as One-carbon
Source. Tetrahedron Lett. 2020, 61, 151844. (c) Shapiro, S. L.;
Parrino, V. A.; Freedman, L. Guanamines.1III. Perfluoroalkylguan-
amines and Related Compounds. J. Org. Chem. 1960, 25, 379−384.
(d) Shaw, J.; Gross, F. Notes: The Preparation of Certain Amino-
Substituted Perfluoroalkyl-s-triazines. J. Org. Chem. 1959, 24, 1809−
1811. (e) Shapiro, S. L.; Isaacs, E. S.; Parrino, V. A.; Freedman, L.
Chloromethylguanamines. J. Org. Chem. 1961, 26, 68−74. (f) Kawa-
hata, W.; Asami, T.; Kiyoi, T.; Irie, T.; Taniguchi, H.; Asamitsu, Y.;
Inoue, T.; Miyake, T.; Sawa, M. Design and Synthesis of Novel
Amino-triazine Analogues as Selective Bruton’s Tyrosine Kinase
Inhibitors for Treatment of Rheumatoid Arthritis. J. Med. Chem. 2018,
61, 8917−8933. (g) Pitts, W. J.; Guo, J.; Dhar, T. G. M.; Shen, Z.; Gu,
H. H.; Watterson, S. H.; Bednarz, M. S.; Chen, B.-C.; Barrish, J. C.;
Bassolino, D.; Cheney, D.; Fleener, C. A.; Rouleau, K. A.;
Hollenbaugh, D. L.; Iwanowicz, E. J. Rapid Synthesis of Triazine
Authors
Peng Zhao − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P.R. China
You Zhou − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P.R. China
Xiao-Xiao Yu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P.R. China
Chun Huang − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P.R. China
Yan-Dong Wu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03130
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21971080, 21971079,
21772051). This work was supported by “The Fundamental
Research Funds for the Central Universities” (CCNU15ZX002
D
https://dx.doi.org/10.1021/acs.orglett.0c03130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Inhibitors of Inosine Monophosphate Dehydrogenase. Bioorg. Med.
Chem. Lett. 2002, 12, 2137−2140.
(7) (a) Hill, M.; Movassaghi, M. New Strategies for the Synthesis of
Pyrimidine Derivatives. Chem. - Eur. J. 2008, 14, 6836−6844.
(b) Tyagarajan, S.; Chakravarty, P. K. Synthesis of Pyrimidines
from Ketones Using Microwave Irradiation. Tetrahedron Lett. 2005,
(13) (a) Xue, W. J.; Guo, Y. Q.; Gao, F. F.; Li, H. Z.; Wu, A. X. A
Novel Self-Sequence Reaction Network Involving a Set of Six
Reactions in One Pot: The Synthesis of Substituted Benzothiazoles
from Aromatic Ketones and Anilines. Org. Lett. 2013, 15, 890−893.
(b) Wu, X.; Gao, Q.; Geng, X.; Zhang, J.; Wu, Y. D.; Wu, A. X.
Iodine-Promoted Oxidative Cross-Coupling of Unprotected Anilines
with Methyl Ketones: A Site-Selective Direct C-H Bond Function-
alization to C4-Dicarbonylation of Anilines. Org. Lett. 2016, 18,
2507−2510.
́
46, 7889−7891. (c) Pardo, Z. D.; Olsen, G. L.; Fernandez-Valle, M.
́
E.; Frydman, L.; Martínez-Alvarez, R.; Herrera, A. Monitoring
Mechanistic Details in the Synthesis of Pyrimidines via Real-Time,
Ultrafast Multidimensional NMR Spectroscopy. J. Am. Chem. Soc.
́
́
2012, 134, 2706−2715. (d) Herrera, A.; Martınez-Alvarez, R.;
Ramiro, P.; Chioua, M.; Torres, R. On the Mechanism of Reaction
Between Ketones and Nitriles. Unexpected Results from Benzyl
Nitriles. Tetrahedron 2002, 58, 3755−3764. (e) Gao, Q.; Liu, S.; Wu,
X.; Wu, A. Convergent Integration of Three Self-sorting Domino
Sequences: Three-component Direct Synthesis of 3-methylthio-4-aryl-
maleimides from Methyl Ketones with Acetonitrile and DMSO.
Tetrahedron Lett. 2014, 55, 6403−6406.
(8) Su, L.; Sun, K.; Pan, N.; Liu, L.; Sun, M.; Dong, J.; Zhou, Y.; Yin,
S. F. Cyclization of Ketones with Nitriles Under Base: A General and
Economical Synthesis of Pyrimidines. Org. Lett. 2018, 20, 3399−3402.
(9) (a) Wu, Y. D.; Geng, X.; Gao, Q.; Zhang, J.; Wu, X.; Wu, A. X.
Iodine-promoted Sequential Dual Oxidative Csp3-H Amination/Csp3-
H Iodination Reactions: Efficient Synthesis of 1-iodoimidazo[1,5-
a]pyridines. Org. Chem. Front. 2016, 3, 1430−1434. (b) Wu, X.; Gao,
Q.; Liu, S.; Wu, A. I2-Catalyzed Oxidative Cross-Coupling of Methyl
Ketones and Benzamidines Hydrochloride: A Facile Access to A-
Ketoimides. Org. Lett. 2014, 16, 2888−2891.
(10) For selected reviews, see: (a) Yan, Y.; Li, Z.; Li, H.; Cui, C.;
Shi, M.; Liu, Y. Alkyl Ether as a One-Carbon Synthon: Route to 2,4-
Disubstituted 1,3,5-Triazines via C-H Amination/C-O Cleavage
Under Transition-Metal-Free Conditions. Org. Lett. 2017, 19,
6228−6231. (b) Huang, H.; Guo, W.; Wu, W.; Li, C. J.; Jiang, H.
Copper-Catalyzed Oxidative C(sp3)-H Functionalization for Facile
Synthesis of 1,2,4-Triazoles and 1,3,5-Triazines from Amidines. Org.
Lett. 2015, 17, 2894−2897. (c) Pan, L.; Li, Z.; Ding, T.; Fang, X.;
Zhang, W.; Xu, H.; Xu, Y. Base-Mediated Synthesis of Unsymmetrical
1,3,5-Triazin-2-amines via Three-Component Reaction of Imidates,
Guanidines, and Amides or Aldehydes. J. Org. Chem. 2017, 82,
10043−10050. (d) Guo, W.; Zhao, M.; Du, C.; Zheng, L.; Li, L.;
Chen, L.; Tao, K.; Tan, W.; Xie, Z.; Cai, L.; Fan, X.; Zhang, K.
Visible-Light-Catalyzed [3 + 1 + 2] Coupling Annulations for the
Synthesis of Unsymmetrical Trisubstituted Amino-1,3,5-triazines. J.
Org. Chem. 2019, 84, 15508−15519. (e) Yan, Y.; Li, Z.; Cui, C.; Li,
H.; Shi, M.; Liu, Y. An I2-mediated Aerobic Oxidative Annulation of
Amidines with Tertiary Aminesvia C-H Amination/C-N Cleavage for
the Synthesis of 2,4-disubstituted 1,3,5-triazines. Org. Biomol. Chem.
2018, 16, 2629−2633. (f) Xu, X.; Zhang, M.; Jiang, H.; Zheng, J.; Li,
Y. A Novel Straightforward Synthesis of 2,4-Disubstituted-1,3,5-
triazines via Aerobic Copper-Catalyzed Cyclization of Amidines with
DMF. Org. Lett. 2014, 16, 3540−3543. (g) Yan, Y.; Cui, C.; Wang, J.;
Li, S.; Liu, Y. Dichloromethane as C1 Building Block: Synthesis of
2,4-Disubstitued 1,3,5-Triazines via Copper-Catalyzed Aerobic C-H/
C-Cl Cleavage. Adv. Synth. Catal. 2019, 361, 1166−1170.
(11) (a) Wu, X.; Zhao, P.; Geng, X.; Wang, C.; Wu, Y. D.; Wu, A. X.
Synthesis of Pyrrole-2-carbaldehyde Derivatives by Oxidative
Annulation and Direct Csp3-H to C = O Oxidation. Org. Lett.
2018, 20, 688−691. (b) Gao, Q.; Liu, Z.; Wang, Y.; Wu, X.; Zhang, J.;
Wu, A. I2-Triggered Reductive Generation of N-Centered Iminyl
Radicals: An Isatin-to-Quinoline Strategy for the Introduction of
Primary Amides. Adv. Synth. Catal. 2018, 360, 1364−1369. (c) Gao,
Q.; Yan, H.; Wu, M.; Sun, J.; Yan, X.; Wu, A. Direct synthesis of 2-
methylpyridines via I2-triggered [3 + 2 + 1] annulation of aryl methyl
ketoxime acetates with triethylamine as the carbon source. Org.
Biomol. Chem. 2018, 16, 2342−2348. (d) Gao, Q.; He, S.; Wu, X.;
Zhang, J.; Bai, S.; Wu, Y.; Wu, A. Selective access to dipyrazolo-fused
pyridines via formal [3 + 2 + 1] heteroannulation of methyl ketones
with pyrazol-5-amines. Org. Chem. Front. 2018, 5, 765−768.
(12) 4a′ was obtained in absence of iodine.
E
https://dx.doi.org/10.1021/acs.orglett.0c03130
Org. Lett. XXXX, XXX, XXX−XXX