Silver-catalyzed [3+2+1] annulation of aryl amidines with benzyl isocyanide

Article abstract of DOI:10.1016/j.tetlet.2017.10.032

A silver-catalyzed [3+2+1] annulation of amidines with benzyl isocyanide toward 2,4-diaryl-1,3,5-triazines was developed. A variety of symmetrical and unsymmetrical products were obtained in moderate to good yields. This work also features an oxidant-free approach to 2,4-disubstituted triazines.

Full text of DOI:10.1016/j.tetlet.2017.10.032

Accepted Manuscript
Silver-Catalyzed [3+2+1] Annulation of Aryl Amidines with Benzyl lsocyanide
Xiaodong Lu, Xiaoyi Xin, Boshun Wan
PII:
S0040-4039(17)31311-4
https://doi.org/10.1016/j.tetlet.2017.10.032
TETL 49394
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Tetrahedron Letters
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31 August 2017
9 October 2017
13 October 2017
Please cite this article as: Lu, X., Xin, X., Wan, B., Silver-Catalyzed [3+2+1] Annulation of Aryl Amidines with
Benzyl lsocyanide, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.032
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Silver-Catalyzed [3+2+1] Annulation of Aryl
Amidines with Benzyl lsocyanide
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Xiaodong Lu, Xiaoyi Xin, Boshun Wan

1
Silver-Catalyzed [3+2+1] Annulation of Aryl Amidines with Benzyl lsocyanide
Xiaodong Lua,b, Xiaoyi Xina,, Boshun Wana,
aDalian Institue of Chemistry and Physics, Chinese Academic of sciences, Dalian 116023, China.
bUniversity of Chinese Academic of Sciences, Beijing 100049, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A silver-catalyzed [3+2+1] annulation of amidines with benzyl isocyanide toward 2,4-diaryl-
1,3,5-triazines was developed. A variety of symmetrical and unsymmetrical products were
obtained in moderate to good yields. This work also features an oxidant-free approach to 2,4-
disubstituted triazines.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
benzyl isocyanide
amidines
triazines
oxidant-free
Introduction
facile synthesis of 2,4-disubstituted triazines. Notable is that the
addition of oxidant was unnecessary in the process.
Triazines are an important class of N-containing heterocycles
that often exhibit diverse biological activities, such as anti-
inflammatory, anti-malarial, anti-mycobacterial, anti-viral, and
anti-cancer activities.(1) These compounds are also widely used as
chelating ligands for the preparation of liquid crystals,(2)
organometallic materials,(3) and transition metal
complexes.(4)Therefore, in the past decade, a variety of
methodologies have been developed for their synthesis.(5, 6‒12)
Among them, the formal [3+2+1] annulation of amidines with
various C1 precursors, due to its rapid assembly of triazine
skeletons in a convergent and step-economical mode, is of
particular interests and much progress has been achieved. To
date, N,N-dimethylformamide (DMF),(6) dimethyl sulfoxide
(DMSO),(7) trialkylamines,(7) benzaldehyde,(8) benzyl alcohol,(9)
benzylamine,(10) methylarenes,(11) and styrene(12) have been well
established as C1 coupling partners in the annulations. However,
most of them focus on the synthesis of 2,4,6-trisubstituted
triazines, while the formation of 2,4-disubstituted triazines
remains rare.(6,7) Furthermore, besides the transition metal
catalysts, various oxidants are often involved in these reactions,
thus enabling the system complex and requiring high-energy
input. Consequently, it is highly desirable to explore a new C1
source that can undergo the annulations with amidines in the
absence of oxidants to afford 2,4-disubstituted triazines.
Scheme 1. Formal [3+2+1] Annulations of Amidines with Various C1
Precursors
Results and discussion
Both symmetrical and unsymmetrical 2,4-disubstituted
triazines can be afforded by this method. Herein, we disclose the
preliminary results of our investigations. Initially, ethyl 2-
isocyanoacetate was chosen as the C1 source to test our
hypothesis using AgSbF6 as the catalyst (Table 1, entry 1).
However, only a trace amount of 2,4-diphenyl-1,3,5-triazine 3a
was detected. To our delight, the utilization of benzyl isocyanide
as the C1 partner afforded 3a in 62% yield (Table 1, entry 4).
Then tosylmehtyl isocyanide and isocyanobenzene were
investigated, the former leading to no product and the latter
yielding 3a in 41% (Table 1, entries 2 and 3). The yield increased
Isocyanides have emerged as versatile C1 synthons in the
cycloaddition reactions to elaborate five-membered imino
heterocycles.(13) Then, we envisioned that isocyanide possibly can
also undergo the formal [3+2+1] annulation with amidines. Just
as anticipated, the reactions of amidines with benzyl isocyanide
proceeded smoothly in the presence of silver catalyst, allowing a
———

Corresponding authors. E-mail addresses: xyxin@dicp.ac.cn. (X. Y. Xin)
 Corresponding authors. Tel.: +86 411 84379260; fax: +86 411 84379223; E-mail addresses: bswan@dicp.ac.cn.(B. S. Wan)

2
to 67% when varying the solvent to toluene (Table 1, entry 5).
Table 2. Synthesis of Symmetrical 2,4-diaryl-1,3,5-triazinesa
The reaction in DCE gave a comparable yield (Table 1, entry 6).
The temperature exerted a great influence on the reaction. The
best result was obtained (83%) when the reaction was carried out
at 140 oC (Table 1, entry 9). With further increasing the
temperature to 160 oC, the yield decreased (Table 1, entry 8).
Other salts such as AgOTf, AgNO3, and Cu(OTf)2 could also
promote the reaction but gave inferior results (Table 1, entries
11‒13). A lower or higher catalyst loading afforded 3a in a
decreased yield (Table 1, entries 14 and 15), while even wthout
any catalyst, 3a could be detected in a lower yield (Table 1,
entrie 16). Therefore, the optimum reaction conditions are as
indicated in Table 1, entry 9.
Table 1. Screening of the reaction conditionsa
entry
1
R
catalyst
(x mol%)
Sol.
THF
THF
THF
THF
Tol
Temp.
(°C)
100
yield
(%)b
trace
CH2CO2Et AgSbF6
(7.5)
TsCH2
2
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgSbF6
(7.5)
AgOTf
(7.5)
AgNO3
(7.5)
Cu(OTf)2
(7.5)
AgSbF6
(5)
AgSbF6
(10)
100
100
100
100
100
80
0
aReaction conditions: amidines 1 (0.4 mmol), benzyl isocyanide 2 (0.3 mmol),
AgSbF6 (0.015 mmol), toluene (2.0 mL), 140 oC, 10 h. Isolated yields were
given.
3
Ph
41c
62
67
65
66
73
83
74
78
71
51
67
64
14
4
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Table 3. Synthesis of Unymmetrical 2,4-diaryl-1,3,5-
5
triazinesa
6
DCE
Tol
7
8
Tol
120
140
160
140
140
140
140
140
140
9
Tol
10
11
12
13
14
15
16
Tol
Tol
Tol
Tol
Tol
Tol
--
Tol
aReaction conditions: benzamidine 1a (0.4 mmol), benzyl isocyanide 2 (0.3
mmol), catalyst (x mol%, based on half the amount of 1a), solvent (2.0 mL),
10 h.
bYields were determined by HPLC using naphthalene as the internal standard.
c Isolated yield.
With the optimized conditions in hand, we examined the
generality and the limitations of this protocol. As shown in Table
2, methyl group on the phenyl ring in R was well tolerated,
providing triazine 3b in 88% yield. The halide substituents such
as –Cl and –Br were compatible with the reaction. Amidine 1e
bearing electron-donating group –OMe could also undergo the
annulation with benzyl isocyanide, leading to the formation of 3e
in 79% yield. However, when strong electron-withdrawing
substituent -CF3 was employed in phenyl R, a moderate yield of
3f was achieved. Submitting meta-substituted amidine 1g to the
standard conditions afforded 3g in 70% yield. Notably, the
reaction of 2-thienyl derived substrate 1h with benzyl isocyanide
furnished the desired product 3h in 94% yield.
aReaction conditions: amidines 1 (0.2 mmol), amidines 1’ (0.2 mmol), benzyl
isocyanide 2 (0.3 mmol), AgSbF6 (0.015 mmol), toluene (2.0 mL), 140 oC, 10
h. Isolated yields were given.
bthe solution of amidines added to the solution of isocyanide and AgSbF6
slowly in 10 h.
Having established the efficient synthesis of symmetrical
triazines, we further directed our attention to prepare
unsymmetrical triazines with this method. As shown in Table 3,
by employing two different amidines, the unsymmetrical
products could be gained in moderate yields, while two kinds of
symmetrical homo-cyclized triazines were detected at the same

3
time. Analogously, the cross annulations of electron-donating
methoxyl-derived substrate 1e, or 2-thienyl-substituted amidine
1h with other amidines gave relatively good yields. In particular,
1e, 1h and benzyl isocyanide underwent the formal [3+2+1]
annulation efficiently, generating unsymmetrical triazine 3n in
56% yield.
Scheme 4. Possible Reaction Mechanism
Scheme 2. Gram-Scale Experiment
Conclusion
To illustrate the practicability of this method, a gram-scale
experiment was performed (Scheme 2). Benzamidine 1a (10
mmol), benzyl isocyanide 2 (7.5 mmol) and AgSbF6 (0.375 mmol)
were dissolved in 50 mL toluene and stirred at 140 oC for 10
hours. After cooling down, removal of the solvent and
purification by column chromatography afforded 3a in 62% yield
(0.728 g).
In summary, we have developed a novel AgSbF6-catalyzed
[3+2+1] annulation of amidines with benzyl isocyanide for the
synthesis of 2,4-diaryl-1,3,5-triazines. A series of symmetrical
and unsymmetrical 2,4-diaryl products were produced in
moderate to good yields and no oxidants were needed. Given the
vital value of triazine scaffold in medicine, biology and materials
field, this work would provide a valuable route for the
elaboration of triazine-based building blocks.
Acknowledgments
We are grateful to the National Natural Sicene Foundation of
China (21372219) for financial support.
Supplementary Data
Supplementary data associated with this article can be found,
in the online version, at
Scheme 3. Mechanism Studies
References and notes
To probe the mechanism of this reaction, we performed some
control experiments employing 4-bromobenzimidamide 1f and
benzyl isocyanide 2 as the substrates (Scheme 3). The mass of
benzylamine was detected in the mixture by HPLC-MS after the
reaction completed (SI，Scheme S5 a). Amidine 1f might first
undergo the nucleophilic attack onto isocyanide 2 to generate the
compound E. However, the attempts to isolate E failed because
of its facile degradation. Gratifyingly, when the reaction was
conducted at 50 oC, the mass of E was detected by HPLC-MS
(SI，Scheme S5 b). These results reveal that benzylamine is a
byproduct and E is an intermediate of the reaction.
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Based on these observations, a plausible mechanism was
depicted in Scheme 4. Benzyl isocyanide 2 is first activated by
silver catalyst to form silver-isocyanide A, followed by the
addition with amidine 1, resulting in the formation of the
intermediate B. Subsequently, the other amidine 1’ attacks the
imine motif of B to produce the adduct C, and in this step,
amidines with electron donating group (e.g., 1e, 1h) are
speculated in weak preference. Then C undergoes an
intramolecular cyclization to afford the intermediate D. Finally,
the aromatization of D affords the desired product 3 with the
release of ammonia and benzylamine. When amidines 1 and 1’
bearing different substituents, the unsymmetrical products are
afforded, while the symmetrical products are inevitable.
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Supplementary Material
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Highlights
ˑ
Disubstituted-1,3,5-triazines were produced by
readily available reagents.
ˑ
ˑ
Isocyanides were used as C1 precursors.
Oxidants were unnecessary.