A Sequential Suzuki Coupling Approach to Unsymmetrical Aryl s-Triazines from Cyanuric Chloride

Article abstract of DOI:10.1002/adsc.201700260

A practical approach has been developed for efficient synthesis of unsymmetrical aryl s-triazines via highly selective sequential Suzuki coupling of cyanuric chloride (2,4,6-trichlorotriazine) with aryl or vinyl boronic or diarylborinic acids catalysed by 0.1–0.5 mol% Pd(PPh₃)₂Cl₂ under mild conditions. The second and third Suzuki couplings for unsymmetrically trisubstituted aryl s-triazines could be more practically conducted in one-pot procedure. An electron-withdrawing conjugate group at phenyl ring of arylboronic acids was unexpectedly found to completely block the coupling while steric hindrance from an ortho electron-donating substituent could be overcome. (Figure presented.).

Full text of DOI:10.1002/adsc.201700260

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DOI: 10.1002/adsc.201700260
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A Sequential Suzuki Coupling Approach to Unsymmetrical Aryl
s-Triazines from Cyanuric Chloride
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Chen Wang,a Jiehui Zhang,a Jie Tang,b and Gang Zoua,*
a
School of Chemistry & Molecular Engineering, East China University of Science & Technology, 130 Meilong Rd, Shanghai,
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People’s Republic of China
Phone: 86-21-64253881
E-mail: zougang@ecust.edu.cn
b
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development & Shanghai Key La-
boratory of Green Chemistry and Chemical Processes, SCME, East China Normal University, 3663 North Zhongshan Rd.
Shanghai, Peopleꢀs Republic of China
Received: March 2, 2017; Revised: May 4, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201700260
compatibility, operational simplicity and environmen-
tal protection, has promised an effective alternative to
Abstract: A practical approach has been developed
for efficient synthesis of unsymmetrical aryl s-
triazines via highly selective sequential Suzuki
the traditional approaches but has shown low effi-
ciency in coupling of cyanuric chloride[6] because of its
coupling of cyanuric chloride (2,4,6-trichlorotria-
AcCl-like property and subsequent over-arylation via
zine) with aryl or vinyl boronic or diarylborinic
the preferred intramolecular activation.[7]
acids catalysed by 0.1–0.5 mol% Pd(PPh3)2Cl2
under mild conditions. The second and third Suzuki
couplings for unsymmetrically trisubstituted aryl s-
triazines could be more practically conducted in
In the last decade, Suzuki coupling of convention-
ally difficult substrates, e.g. site-selective coupling of
polyhaloheteroaromatics[8] and acylative coupling of
low-compatibility acid chlorides,[9] has advanced
one-pot procedure. An electron-withdrawing con-
greatly. In particular, Houk et al. has elegantly
jugate group at phenyl ring of arylboronic acids was
elucidated the origin of the site-selectivity.[10] Handy
unexpectedly found to completely block the cou-
and Dodd et al. have developed one-pot procedures
pling while steric hindrance from an ortho electron-
based on predicting the reactivity of CÀX bonds of
donating substituent could be overcome.
polyhaloheteroaromatics in coupling reaction.[11]
Langer et al. has effected highly site-selective Suzuki
coupling of various sorts of polyhalogenated hetero-
arenes through carefully optimizing reaction parame-
ters, i.e. catalyst, base, solvent, and substrate ratio.[8f,12]
Given these achievements and the fact that reactivity
Keywords: Boron; Cross-coupling; Heterocycles;
Palladium; Triazines
42 Aryl s-triazine moieties have been increasingly found of CÀCl bonds subsequently decreases from cyanuric
43 in advanced materials,[1] in particular thermally acti- chloride (the parent trichloro-s-triazine) to mono-
44 vated delayed fluorescence emitters,[2] broad-band UV chlorotriazines, we anticipate a general and effective
45 absorbers,[3] biologically active reagents[4] and frame- synthesis of unsymmetrical aryl s-triazines from cya-
46 directing ligands in coordination chemistry.[5] Friedel- nuric chloride via Suzuki coupling should be possible
47 Crafts type arylation and nucleophilic substitution of provided a proper procedure could be developed.
48 aryl organometallics on cyanuric chloride (2,4,6- Herein, we report a highly selective sequential Suzuki
49 trichlorotriazine) represent the most practical and coupling of cyanuric chloride with aryl or vinyl
50 straightforward way to aryl s-triazines. Unfortunately, boronic or diarylborinic acids for efficient synthesis of
51 the Friedel-Crafts type approach has intrinsic prob- unsymmetrical aryl s-triazines under mild conditions.
52 lems in over-arylation, regioselectivity, substrate scope
Considering the AcCl-like reactivity of cyanuric
53 and pollution associated with disposal of AlCl3 while chloride, an anhydrous condition similar to acylative
54 the organometallic substitution is hampered by poor Suzuki coupling, Pd(PPh3)2Cl2 as catalyst in the
55 functional group compatibility, low efficiency in triar- presence of K2CO3 in toluene at 608C, was adopted at
56 ylation and moisture-free conditions. Suzuki coupling, first for its coupling with p-tolylboronic acid (1a) or
57 which has advantages of good functional group bis(p-tolyl)acid (2a) which, we have recently shown,[13]
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could be used as a cost-effective aryl source in Suzuki and p-F, 1g/2g) at meta- or para- positions of benzene
coupling since both of aryl groups could be effectively ring in arylboronic or diarylborinic acids appeared to
used (Table 1). However, the desired monoaryl di- be negligible while an ortho-substituent (o-Me, 1c/2c;
chloro s-triazine 3a was obtained in just 19% yield o-Et, 1d/2d; or o-MeO, 1h/2h) slightly decreased the
using equivalent 1a due to di/tricoupling. The yields of yields of aryl dichloro-s-triazines 3. When arylboronic
3a could be increased to 49–52% when excess (1.5– acids bearing an electron-withdrawing conjugate
2.0 equiv.) cyanuric chloride was used. Although group, e.g. acetyl (ÀAc), nitrile (ÀCN) or methoxycar-
solvent and catalyst screening failed to improve the bonyl (ÀCO2Me) regardless of positions were used no
reaction, good yields could be obtained by increasing desired cross-coupling was observed. Instead, arylbor-
10 catalyst (0.5–1 mol%) (Table 1, entries 13–15) and onic acids were recovered, implying that transmetala-
11 base loadings (4-6 equiv. K2CO3). Bis(p-tolyl)acid (2a) tion of aryl group from boron to palladium(II) would
12 was found to react similarly under the identical be the rate-determining step in the catalytic cycle
13 conditions, although these kinds of compounds usually (vide infra). Three representative vinyl boronic acids,
14 need different conditions in cross-coupling reactions e.g. 1-pentenylboronic acid (1k), 1-cyclohexenylbor-
15 (Table 1, entry 16).
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onic acid (1l) and trans-(2-phenylethenyl)acid (1m),
reacted similarly to electron-rich aryl boronic acids
while heterocyclic boronic acids (2- or 3-furanylbor-
onic acids (1n, 1o) and 3-pyridylboronic acid (1p))
completely failed (1o, 1p) or reacted sluggishly (1n).
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Table 1. Optimization on Suzuki coupling of cyanuric
chloride with 1a/2a for aryl dichloro s-triazine 3a.[a]
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Entry Cat.(mol%)
Sol.
Base(equiv.) Yield[b]
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1[c]
2
Pd(PPh3)2Cl2(0.3) Tol
Pd(PPh3)2Cl2(0.3) Tol
Pd(PPh3)2Cl2(0.3) Tol
Pd(PPh3)2Cl2(0.3) Tol
Pd(PPh3)2Cl2(0.3) EA
K2CO3(2)
K2CO3(2)
K2CO3(2)
K3PO4(2)
K2CO3(2)
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52
49
45
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16
22
33
39
7
69
67
84
81[e]
85
80
3[d]
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Pd(PPh3)2Cl2(0.3) THF K2CO3(2)
Pd(dppm)2(0.3)
Pd(dppp)2(0.3)
Pd(dppf)2(0.3)
Pd(Cy)2Cl2 (0.3)
Tol
Tol
Tol
Tol
K2CO3(2)
K2CO3(2)
K2CO3(2)
K2CO3(2)
K2CO3(4)
K2CO3(6)
K2CO3(4)
K2CO3(4)
K2CO3(4)
K2CO3(4)
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16[f]
Pd(PPh3)2Cl2(0.3) Tol
Pd(PPh3)2Cl2(0.3) Tol
Pd(PPh3)2Cl2(0.5) Tol
Pd(PPh3)2Cl2(0.5) Tol
Pd(PPh3)2Cl2(1)
Tol
Pd(PPh3)2Cl2(0.5) Tol
[a] Reaction run at 1mmole scale (1a) with 1.5 equiv. cyanuric
chloride at 608C under N2 for 12 h.
[b] Isolated yield (%).
44 [c] 1.0 equiv. cyanuric chloride used.
[d] 2.0 equiv. cyanuric chloride.
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[e] At 1008C.
[f] 0.5 mmole 2a used.
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Dichloro s-triazines are versatile intermediates for
51 a variety of aryl s-triazine derivatives. Therefore, the
52 scope and limitation of palladium-catalysed monocou-
53 pling of cyanuric chloride with aryl, vinyl and hetero-
54 cyclic boronic acids, in particular diarylborinic acids,
55 were explored (Scheme 1). Influence of an electron-
56 donating (m-Me, 1b/2b; m-MeO, 1i/2i; p-MeO, 1j/2j)
57 or neutral group (H, 1e/2e), or halo group (p-Cl, 1f/2f
Scheme 1. Scope of the Pd-catalysed monocoupling of cyanu-
ric chloride with aryl, vinyl and heterocyclic boronic or
diarylborinic acids.
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2,4-Dichloro s-triazines are moisture-stable and noteworthy that the high selectivity for diaryl chloro s-
more suitable in Suzuki coupling than cyanuric triazines could be readily switched to favour triaryl
chloride. However, the CÀCl reactivity gap from products by simply increasing the stoichiometry of
dichloro to monochloro s-triazines, thus the selectivity arylboronic or diarylborinic acids (2.2 equiv. with
for unsymmetrical diaryl chloro-s-triazines, strongly respect to aryl group) (Table 2, entry 7). Triaryl s-
depend on nucleophiles and the electronic effects of triazine 5ea could be obtained even in 99% yield by
substituent on the core ring. Control of step-wise further increasing reaction temperature to 1008C,
substitution on chloro-s-triazines has proven easy for indicating the third arylation proceeded quantitatively.
N or O-centered nucleophiles.[14] However, little is Again, diarylborinic acid 2a performed as well as
10 known about the controllability of Suzuki coupling boronic acid 1a.
11 except for two recent reports on 6-alkylamino sub-
Scope and limitation of the palladium catalysed
12 stituted dichloro s-triazines.[15] In fact, only a modest highly selective and efficient Suzuki coupling of
13 yield (54%) was obtained for intermediate product, 2- dichloro s-triazines with aryl, vinyl and heterocyclic
14 chloro-4-phenyl-6-(p-tolyl)-1,3,5-triazine (4ea) from boronic and diarylborinic acids were further explored
15 reaction of 3e with 2a under the anhydrous conditions (Scheme 2). Similar to the coupling with cyanuric
16 for monocoupling of cyanuric chloride (Table 2, en- chloride, arylboronic acids bearing an electron-with-
17 try 1).
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drawing conjugate group (Ac, CN or CO2Me) on
phenyl ring gave trace coupling products while an
electron-neutral, -donating or halogen (Cl and F)
group, even at ortho position, showed negligible
influence. For example, reaction of ortho-substituted
arylboronic or diarylborinic acids 1c/2c (o-Me), 1d/2d
(o-Et) and 1h/2h (o-OMe) with 3e gave 4ec, 4ed and
4eh in 97%/93%, 94%/92% and 95%/95% yields,
respectively.[17] Vinyl boronic acids, e.g. 1-pentenylbor-
onic acid (1k), 1-cyclohexenylboronic acid (1l) and
trans-(2-phenylethenyl)acid (1m), reacted with aryl
dichloro s-triazines (3j or 3e) efficiently, giving the
corresponding monochloro s-triazines 4jk, 4jl, 4jm
and 4ek in 90–93% yields. No reaction was observed
for 3j and 2- or 3-furanylboronic acids (1n, 1o) or 3-
pyridylboronic acid (1p).
Given that the high selectivity in step-wise aryla-
tion of dichloro s-triazines with aryl and vinyl borons
could be achieved by using proper stoichiometry and
temperature, we anticipated that a one-pot procedure
for synthesis of unsymmetrically trisubstituted aryl s-
triazines (5) could be effected through sequential
Suzuki coupling, in which, after completion of the
second Suzuki coupling, the third boron reagents were
directly added to the reaction mixture and then heated
at 1008C for another 6 h. A couple of unsymmetrically
trisubstituted aryl s-triazines were obtained by the
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Table 2. Optimization on cross-coupling of aryl dichloro s-
triazine with 1a/2a.[a]
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Entry
Pd mol%
T(oC)
1a/2a(equiv)
Yield[b]
1[c]
2
3
1
1
60
60
60
60
rt
60
60
100
100
1a (1.1)
1a (1.1)
1a (1.1)
1a (1.1)
1a (1.1)
2a(0.55)
1a (2.2)
1a (2.2)
2a (1.1)
54 (4ea)
95 (4ea)
94 (4ea)
94 (4ea)
68 (4ea)
94 (4ea)
80 (5ea)
99 (4ea)
98 (5ea)
0.3
0.1
0.1
0.1
0.1
0.1
0.1
4
5[d]
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9
[a] Reaction run at 1mmole scale (3e) with 1.1 equiv.
arylboronic acid (1a) or 0.55 equiv. diarylborinic acid (2a).
[b] Isolated yield (%).
40 [c] Anhydrous K2CO3 used.
41
[d] 12 h.
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However, the catalytic efficiency and selectivity one-pot sequential procedure in 80–93% yields
45 increased dramatically under aqueous conditions. A (Scheme 3).
46 highly selective and efficient reaction was observed to
Diarylborinic acids also reacted efficiently to give
47 give diaryl product 4ea in 95% yield with only 4% the desired unsymmetrical triaryl s-triazines in com-
48 triaryl side-product (5ea) by using 2 M K2CO3(aq.) as parable yields to their arylboronic acid analogues. The
49 base in toluene. In fact, complete reaction could even order of introduction of the second and third aryl
50 be achieved by using as low as 0.1 mol% catalyst groups showed little influence on the overall yields of
51 loading at 608C for 6 h although the reaction failed to unsymmetrical triaryl s-triazines (5).
52 complete at room temperature after 12 h (Table 2,
In summary, a highly selective and efficient Suzuki
53 entries 4 and 5). The unexpected increase in catalytic coupling approach has been developed for synthesis of
54 efficiency under aqueous conditions is consistent with unsymmetrical di/triaryl s-triazines from cyanuric
55 the proposal that transmetalation from boron to chloride and aryl or vinyl boronic acids or diary-
56 palladium hydroxide species (PdII-OH) should be the lborinic acids by using a practical catalyst system, 0.1-
57 rate-determining step in the catalytic cycle.[16] It is 0.5 mol% Pd(PPh3)2Cl2 in the presence of 2–4 equiv.
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Scheme 2. Suzuki coupling of aryl dichloro s-triazines with
aryl and vinyl boronic and diarylborinic acids.
Scheme 3. One-pot synthesis of unsymmetrically trisubsti-
[a]
tuted aryl s-triazines via sequential Suzuki coupling.
Introduction of R2 prior to R1.
44 K2CO3 in toluene or aqueous toluene at 60–1008C.
45 Scope exploration on the boron counterparts indicated
46 that heterocyclic boronic acids or electron-deficient
47 arylboronic acids bearing an electron-withdrawing pot procedure. The sequential Suzuki coupling ap-
48 conjugate group at phenyl ring could completely block proach, in particular using cost-effective diarylborinic
49 the coupling while a small steric hindrance from an acids, promises a practical access to unsymmetrical
50 electron-donating o-substituent of aryl groups could aryl s-triazine derivatives.
51 be overcome. The remarkable structural effects of
52 boronic acids on the cross-coupling was tentatively
53 attributed to the rate-determining role played by
Experimental Section
General information: All reactions were carried out under
nitrogen by using standard Schlenk techniques unless other-
wise stated. Commercially available chemicals were used as
received. Diarylborinic acids were prepared according to our
54 transmetalation of organic group from boron to
55 palladium (II) species in the catalytic cycle. The
56 second and third Suzuki coupling to unsymmetrically
57 trisubstituted aryltriazines could be conducted in one-
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previously reported procedures.[13] Column chromatograph
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References
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was performed on 200–300 mesh silica gal. H and 13C NMR
spectra were recorded in CDCl3 at ambient temperature.
Chemical shifts in NMR are reported in ppm (d), relative to
the internal standard of tetramethylsilane (TMS). All new
compounds were further characterized by HRMS (see
supporting information for details).
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General Procedure for Suzuki Monocoupling of
Cyanuric Chloride
Under a N2 atmosphere, to a 10 mL Schlenk flask were
added cyanuric chloride (277.0 mg, 1.5 mmol), aryl, vinyl or
heterocyclic boronic acid 1 (1.0 mmol) or diarylboronic acid
2 (0.5 mmol), Pd(PPh3)2Cl2 (3.5 mg, 0.5 mmol%), K2CO3
(552.8 mg, 4.0 mmol), and toluene (5 mL). The mixture was
stirred at 608C for 12 h. The reaction progress was monitored
17 by TLC. The reaction mixture was diluted with CH2Cl2
(15 mL), followed by washing with H2O (23 10 mL). The
organic layer was dried over Na2SO4, filtered, and evapo-
rated under reduced pressure to give crude product, which
was purified by through flash column chromatography over
silica gel using ethyl acetate/petroleum ether (60–908C)
gradient to afford 2,4-dichloro-6-aryl/vinyl-s-triazine 3.
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General Procedure for the Second Suzuki Coupling
Under a N2 atmosphere, to a 10 mL Schlenk flask were
added dichloro-s-triazine 3 (1.0 mmol), aryl or vinyl boronic
acid 1 (1.1 mmol) or diarylboronic acid 2 (0.55 mmol), Pd
(PPh3)2Cl2 (0.7 mg, 0.1 mmol%), K2CO3(aq.) (1 mL, 2 M/L),
and toluene (5 mL). The mixture was stirred at 608C for 6 h
or monitored by TLC until the starting material was
completely consumed. The work-up procedure for 3 was
adopted to offer the analytically pure product, 2-chloro-4,6-
diaryl/arylvinyl s-triazine 4.
General Procedure for One-Pot Sequential Suzuki
Coupling
To a 10 mL Schlenk flask were added dichloro-s-triazine 3
(1.0 mmol), aryl boronic acid 1 (1.1 mmol) or diarylboronic
acid 2 (0.55 mmol), Pd(PPh3)2Cl2 (0.7 mg, 0.1 mmol%), K2
CO3(aq.) (1 mL, 2 M/L), and toluene (5 mL). The mixture
was stirred at 608C under nitrogen with the progress
monitored by TLC. When dichloro-s-triazine completely
consumed, the second aryl or vinyl boronic acid 1 (1.1 mmol)
or diarylboronic acid 2 (0.55 mmol) was added. The reaction
mixture was further stirred for another 6 h at 1008C and
monitored by TLC. The work-up procedure for 3 was
adopted to offer the analytically pure product, trisubstituted
aryl s-triazine 5.
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21472041) and National Key
Technology R&D Program, the Ministry of Science and
Technology of China (2015BAK44B00).
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