Synthesis of 7-aryl/heteraryl-1,3-diphenyl-1,2,4-benzotriazinyls via palladium catalyzed Stille and Suzuki-Miyaura reactions

Article abstract of DOI:10.1039/c1ob05167a

Stille and Suzuki-Miyaura reactions of 7-iodo-1,3-diphenyl-1,4-dihydro-1,2, 4-benzotriazin-4-yl are presented as rare examples of cross-coupling reactions with stable organic radicals. Both the Stille and Suzuki-Miyaura reactions are in most cases high yi

Full text of DOI:10.1039/c1ob05167a

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Synthesis of 7-aryl/heteraryl-1,3-diphenyl-1,2,4-benzotriazinyls via
palladium catalyzed Stille and Suzuki-Miyaura reactions†
Christos P. Constantinides, Panayiotis A. Koutentis* and Georgia Loizou
Received 31st January 2011, Accepted 23rd February 2011
DOI: 10.1039/c1ob05167a
Stille and Suzuki-Miyaura reactions of 7-iodo-1,3-diphenyl-
1,4-dihydro-1,2,4-benzotriazin-4-yl are presented as rare ex-
amples of cross-coupling reactions with stable organic rad-
icals. Both the Stille and Suzuki-Miyaura reactions are in
most cases high yielding but the latter are cleaner while the
former are faster and are accompanied by 1,3-diphenyl-1,2,4-
benzotriazin-7(H)-one as by-product. A range of 7-aryl and
7-heteroaryl-1,2,4-benzotriazinyls have been synthesized and
characterized using standard spectroscopic and spectrometric
Scheme 1 Synthesis of various 1,3-diphenyl-1,2,4-benzotriazinyls 2a–g
means.
from N-phenylamidrazones 1a–g (0.5 mmol) in DCM (1 ml) in the presence
of DBU (0.1 equiv.) with Pd/C (1.6 mol%) at ca. 20 ◦C under an air
atmosphere for 4–9 h.
Intensive research on stable organic radicals during the past couple
of decades has provided many examples of molecules comprised
of light elements that demonstrate interesting magnetic and/or
conducting properties.1 Numerous reports on the synthesis and
solid-state properties of several families of organic radicals, such
as the nitroxide and nitronyl nitroxides,2 the triphenylmethyls,3
the verdazyls4 and the heterocyclic thiazyls,5 have appeared in
the literature. 1,2,4-Benzotriazinyls are a family of radicals, first
prepared by Blatter in 1968,6 that have been less well studied. Early
work on the magnetic behavior of these radicals by Neugebauer
et al.,7 and more recently by our group8 showed interesting ferro-
and antiferromagnetic properties. Relatively few analogues of
theseradicals have beenprepared owingto a5-step product specific
synthesis that afforded the radicals in moderate yields and involved
large excesses of HgO (toxic) or AgO (expensive) oxidants. As
part of our on-going studies on the 1,2,4-benzotriazinyls, we
recently, developed a mild and high-yieldingmethod for converting
N-phenylamidrazones 1 into stable radicals 2 using palladium-
on-carbon and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in an
atmosphere of air (Scheme 1).9
of this present manuscript 1D ferromagnetic behaviour was
reported for two 3-(3-vinylphenyl)-1,2,4-benzotriazinyls by Frank
et al.8b Previous studies by Neugebauer et al.,7 indicated Curie–
Weiss paramagnetic behaviour for Blatter radical 2a and 3-tert-
butyl-1-phenyl-1,2,4-benzotriazinyl, while short range antiferro-
magnetic ordering was observed for 1-(4-chlorophenyl)-3-phenyl-
1,2,4-benzotriazinyl. Clearly, the range of magnetic behaviour
for this radical system is broader than originally anticipated.
Furthermore, Blatter radical 2a acted as the donor in an or-
ganic charge transfer salt with 7,7,8,8-tetracyanoquinodimethane
(TCNQ) that demonstrated pressure-dependent conductivity.8c
In the hope of identifying additionally interesting magnetic
and/or conducting properties, we needed a rapid route to more
7-substituted benzotriazinyls. By combining Stille and Suzuki-
Miyaura coupling chemistry with the now readily availabe 7-halo-
1,2,4-benzotriazinyls 2c–e we envisaged a non-product specific
synthetic route to new radicals.
To the best of our knowledge metal-catalyzed coupling reac-
tions have been reported only for the nitronyl-nitroxide radical
family.10 These include Heck,10a Suzuki10b and Sonogashira10c
reactions with moderate or disappointingly poor yields. The loss
in yield during the Suzuki reaction of 2-iodophenyl nitronyl
nitroxide was attributed to decomposition of the radical at
the employed reaction temperature and during the Sonogashira
reaction conditions the nitronyl nitroxide radicals suffered de-
oxygenation and the preceding dihydroxyimidazolinides were
dehydrated.11
We further investigated the solid-state properties of these
radicals and were delighted that 7-trifluoromethyl benzotriazinyl
radical 2b exhibited, for this radical class and to the best of
our knowledge, unprecedented 1D Heisenberg linear chain weak
ferromagnetism at 10 K with J/K = + 1.49 K.8a After submission
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678
Nicosia, Cyprus. E-mail: koutenti@ucy.ac.cy; Fax: +357 22892809;
Tel: +357 22892783
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical and spectroscopic data for all new compounds.
Experimental and simulated EPR spectra for the new radicals. See DOI:
10.1039/c1ob05167a
Herein we report the synthesis of 7-aryl/heteroaryl-1,2,4-
benzotriazinyls via palladium-catalyzed Stille and Suzuki-
Miyaura coupling chemistry.
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Table 1 Stille cross-coupling reactions of 7-halo-1,3-diphenyl-1,2, 4-benzotriazinyls 2c–e (0. 12 mmol) with Pd catalyst (5 mol%) in dry DMF (2 ml) at
ca. 100 ◦C under argon
Yields (%)
Hal
ArSnBu3 (equiv.)
Catalyst
Time (min)
3a–c
4
a
a
Cl
Br
I
I
I
I
I
I
I
I
I
I
I
PhSnBu3 (3)
PhSnBu3 (3)
PhSnBu3 (1)
PhSnBu3 (1.5)
PhSnBu3 (2)
PhSnBu3 (3)
PhSnBu3 (4)
PhSnBu3 (2)
PhSnBu3 (3)
PhSnBu3 (2)
PhSnBu3 (3)
Fur-2-ylSnBu3 (2)
Thien-2-ylSnBu3 (2)
N-Mepyrrol-2-ylSnBu3 (2)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(Ph3P)4
Pd(Ph3P)4
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
24 h
24 h
240
—
—
26
13
11
Trace
5
19
Trace
10
Trace
3
Trace
—
3a (53)
3a (56)
3a (78)
3a (76)
3a (82)
3a (46)
3a (34)
3a (62)
3a (36)
3b (82)
60
40
20
20
40
30
40
30
30
30
15
b
3c (93)
c
I
a Incomplete reaction after 24 h, mainly unreacted starting radical by TLC. b dba = dibenzylideneacetate. c Complex reaction mixture and unstable
products.
The reactivity of 7-chloro, bromo-, iodobenzotriazinyls 2c–e
was established in a typical Stille reaction using a three-fold excess
tributylphenylstannane with Pd(OAc)2 (5 mol%) as catalyst in
dry DMF under an argon atmosphere. When 7-chloro, and 7-
bromobenzotriazinyls 2c and 2d were used the reactions were
incomplete even after 24 h (by TLC) and the most of the
starting radicals could be recovered. Conversely, the reaction of
7-iodobenzotriazinyl 2e with PhSnBu3 (3 equiv.) finished within
20 min affording the desired 7-phenylbenzotriazinyl 3a in 76%
yield together with traces of the 1,2,4-benzotriazin-7-one 4 (Table
1).‡ The superior reactivity of the iodo was typical of the Stille
reaction.11
The Stille reaction of the 7-iodobenzotriazinyl 2e was then op-
timized with respect to organostannane equivalents and catalyst.
When 2 equiv. of PhSnBu3 were used the reaction time increased
(40 min) and more benzotriazinone 4 was formed (11%) but the
yield of the main product 3a remained essentially the same (78%).
Less PhSnBu3 (1-1.5 equiv.) led to longer reaction times, lower
yields of radical 3a (53–56%) and more benzotriazinone 4, the
formation of which was presumably owed to a competitive Pd-
mediated hydrodehalogenation of the 7-iodo radical, followed
by oxidation.9 While the use of 4 equiv. of PhSnBu3 marginally
improved the yield of the desired radical it did not improve the
reaction time.
reaction mixture and an unstable main product that could not be
isolated.
The Suzuki-Miyaura reaction of the 7-iodobenzotriazinyl 2e
was cleaner and only traces of the benzotriazinone 4 were
observed, however, longer reaction times were required (Table
2).§ The reactions were carried out in dry toluene at 100 ◦C under
an argon atmosphere. When PhB(OH)2 (2 equiv.) or Pd(OAc)2
(5 mol%) as catalyst and K2CO3 (2 equiv.) as base were used
the 7-phenylbenzotriazinyl 3a was formed in 78% yield and the
reaction completed in 3 h. More base (3 equiv.) reduced the
reaction time by half (1.5 h) and led to a minor improvement
in the yield (81%). Less than 2 equiv. of PhB(OH)2 afforded the
product in a significantly lower yield (59%). Conversely, when 3
equiv. of both PhB(OH)2 and K2CO3 were used the reaction was
cleaner, faster (1 h) and gave the product in exceptionally high yield
(93%).
The use of wet toluene did not affect the course or yield
of the reaction, however, when aqueous K2CO3 was used the
reaction became complex and polar products were observed
(baseline on TLC). Reactions in dry toluene with stronger bases
such as KOH or NaOH left the yield and reaction time essen-
tialy unchanged. Other palladium catalysts examined required
either longer reaction times [Pd2(dba)3] or result in poor yield
[Pd(Ph3P)4].
Other commercial available catalysts Pd(Ph3P)4 and Pd2(dba)3
were tested using with the same conditions but gave lower yields
and more benzotriazinone. Using our best conditions: organo-
stannane (2 equiv.) and Pd(OAc)2 (5 mol%) both the fur-2-yl-
and thien-2-yl-1,2,4-benzotriazinyls 3b and 3c, were prepared
in 82 and 93% yields, respectively. The attempted synthesis of
the 7-(N-methylpyrrol-2-yl)benzotriazinyl resulted in a complex
The optimized reaction conditions were then used to synthesize
a range of 7-arylbenzotriazinyls 3d–h. Electron rich boronic acids
such as 4-MeOC6H4B(OH)2, 4-TolB(OH)2 and 4-PhC6H4B(OH)2
gave the products 3d, 3e and 3g in 83, 76 and 91% yield,
respectively. However when electron deficient arylboronic acids
were used either moderate yields were obtained (47% for 4-
FC6H4-benzotriazinyl 3f) or complicated reaction mixtures were
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Table 2 Suzuki cross-coupling reactions of the 7-iodo-1,3-diphenyl-1,2,4-benzotriazinyl 2e (0.12 mmol) with Pd catalyst (5 mol%) in dry PhMe (2 ml)
at 100 ◦C under argon
Yields (%)
ArB(OH)2 (equiv.)
Catalyst
Base (equiv.)
Time (h)
3
4
PhB(OH)2 (2)
PhB(OH)2 (2)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(Ph3P)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3 (2)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)b
KOH (3)
NaOH (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
3
1.5
5
1
1
19
1.3
1.5
2.5
3
1.5
1.5
2.5
2
3a (78)
3a (81)
3a (59)
3a (93)
Trace
Trace
Trace
Trace
PhB(OH)2 (1.5)
PhB(OH)2 (3)
PhB(OH)2 (3)a
3a (88)
Trace
PhB(OH)2 (3)b
c
c
PhB(OH)2 (3)
PhB(OH)2 (3)
PhB(OH)2 (3)
PhB(OH)2 (3)
4-MeOC6H4B(OH)2 (3)
4-TolB(OH)2 (3)
4-FC6H4B(OH)2 (3)
4-PhC6H4B(OH)2 (3)
4-O2NC6H4B(OH)2 (3)
4-NCC6H4B(OH)2 (3)
Thien-3-ylB(OH)2 (3)
MeB(OH)2 (3)
3a (84)
3a (75)
3a (25)
3a (80)
3d (83)
3e (76)
3f (47)
—
—
Trace
Trace
Trace
Trace
11
d
3g (91)
Trace
c
c
5
3
1.5
5
c
c
3h (67)
Trace
c
c
a Non distilled toluene. b K2CO3 (3 equiv.) in H2O (1 ml). c Complex reaction mixture; TLC indicated traces of starting radical, products 3 and 4 and
intense baseline material. d dba = dibenzylideneacetone.
observed for 4-O2NC6H4B(OH)2 and 4-NCC6H4B(OH)2. Use of
heterocyclic thien-3-ylB(OH)2 gave the corresponding product 3h
in good yield (67%).
The solid-state properties of these new 7-aryl/heteroaryl-1,2,4-
benzotriazinyls will be the subject of a full paper.
K2CO3 (3 equiv.) and Pd(OAc)2 (5 mol%) was heated to ca. 100 ◦C
in dry toluene for 1–3 h under argon until all the starting material
was consumed (TLC). Dry flash chromatography (Et2O–hexane, 1 : 3)
of the reaction mixture gave the following 4-MeOC6H4, 4-MeC6H4,
4-FC6H4, 4-PhC6H4, thien-3-yl 7-substituted benzotriazinyls 3d–h,
respectively.
1 (a) P. M. Lahti, (ed) Magnetic Properties of Organic Materials,
Marcel-Dekker Inc., New York, 1999; (b) K. Itoh and M. Kinoshita,
(ed) Molecular Magnetism: New Magnetic Materials, Kodansha and
Gordon & Breach, Tokyo and Amsterdam, 2000; (c) M. R. Bryce,
A. J. Moore, A. S. Batsanov, J. A. K. Howard, N. Robertson and
I. F. Perepichka, In Supramolecular Engineering of Synthetic Metallic
Materials-Conductors and Magnets, J. Veciana, C. Rovira and D. B.
Amabilino, ed., Kluwer Academic Publishers, Dordrecht, Boston,
London, 1999, vol. 518, p 437.
Acknowledgements
The authors wish to thank Prof. Jeremy M. Rawson for the
EPR data, the University of Cyprus (Medium Sized Grant),
the Cyprus Research Promotion Foundation [grant no.
YCEIA/BIOR/0308(BIE)/13] and the following organizations
in Cyprus for generous donations of chemicals and glassware:
the State General Laboratory, the Agricultural Research Institute,
the Ministry of Agriculture and Biotronics Ltd. Furthermore, we
thank the A. G. Leventis Foundation for helping to establish the
NMR facility in the University of Cyprus.
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‡ Stille reaction (general procedure):
A stirred mixture of 7-iodo-
1,3-diphenyl-1,4-dihydro-1,2,4-benzotriazinyl 2e (50 mg, 0.122 mmol),
organo-stannane (2 equiv.) and Pd(OAc)2 (5 mol%) was heated to
ca. 100 ◦C in dry DMF (2 ml) for 0.5–1 h under inert condi-
tions until all the starting material was consumed (TLC). Dry flash
chromatography (Et2O–hexane, 1 : 3) of the reaction mixture gave the
following phenyl, fur-2-yl, thien-2-yl 7-substituted-benzotriazinyls 3a-c,
respectively.
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§ Suzuki-Miyaura reaction (general procedure): A stirred mixture of 7-iodo-
1,3-diphenyl-1,4-dihydro-1,2,4-benzotriazinyl, arylboronic acid (3 equiv.),
9 P. A. Koutentis and D. Lo Re, Synthesis, 2010, 2075.
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