Building Diversity in ortho-Substituted s-Aryltetrazines by Tuning N-Directed Palladium C-H Halogenation: Unsymmetrical Polyhalogenated and Biphenyl s-Aryltetrazines

Article abstract of DOI:10.1021/acscatal.7b03186

We report a general route for synthesizing ortho-substituted unsymmetrical biphenyl and polyaromatic s-aryltetrazines. These compounds are inaccessible by classical Pinner hydrazine condensation or by the current s-aryltetrazine aromatic core functionalization methods described up to now. We exploited multiple versatile N-directed palladium C-H activation/halogenation of s-aryltetrazine to form C-X bonds (X = I, Br, Cl, F), which collectively produced polyhalogenated unsymmetrical building blocks. We achieved a sequence of selective C-H halogenation reactions in a specific order to produce reactive aryl halides. Polyhalogenated s-aryltetrazines can then be used for controlled cross-coupling reactions toward ortho-substituted polyaromatic s-aryltetrazines. In general, this C-H functionalization route gives access to a large number of variously halogenated building blocks practical for further synthetic implementation of tetrazines (arylation, cycloaddition, etc.). Herein, we exemplified their potential by using halogen-selective Suzuki-Miyaura reactions for divergent construction of novel biphenyl s-tetrazines. Therefore, we deliver original poly(hetero)aromatic tetrazine structures, such as new typically "Z-shaped" and "T-shaped" species. We examined by DFT calculation the origin of the remarkable regioselectivity in some C-H concurrent halogenation reactions. Computations focused at free enthalpy profiles for C-H activation of aryltetrazines to form the intermediate palladacycles by CMD process. We showed that the presence of halogen substituents on aryl groups before further halogenation increases the activation barrier to form the determining C-H activation intermediate palladacycle. XRD studies of functionalized tetrazines evidenced planarity ruptures in the mutual arrangement of aromatic cycles. Finally, this methodology allowed us to deliver a unique tetrahalogenated s-aryltetrazine holding not less than four different halogens arranged in ortho-aryl positions.

Full text of DOI:10.1021/acscatal.7b03186

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Article
Versatile tuning of N-directed palladium C–H halogenation
building diversity in ortho-substituted s-aryltetrazines
Cleve D Mboyi, Christelle Testa, Sarah Reeb, Semra Genc, Helene
Cattey, Paul Fleurat-Lessard, Julien Roger, and Jean-Cyrille Hierso
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03186 • Publication Date (Web): 18 Oct 2017
Downloaded from http://pubs.acs.org on October 18, 2017
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Versatile tuning of Nꢀdirected palladium C–H
halogenation building diversity in orthoꢀsubstituted
sꢀaryltetrazines
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Clève D. Mboyi,‡ Christelle Testa,‡ Sarah Reeb, Semra Genc, Hélène Cattey, Paul Fleurat-
Lessard, Julien Roger,* and Jean-Cyrille Hierso*,†
Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB ꢀ UMR CNRS 6302),
Université de Bourgogne FrancheꢀComté (UBFC), 9 avenue Alain Savary, 21078 Dijon Cedex,
France
†Institut Universitaire de France (IUF), 103 Boulevard Saint Michel, 75005 Paris Cedex, France
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ABSTRACT: We report a general route for synthesizing orthoꢀsubstituted unsymmetrical
biphenyl and polyaromatic sꢀaryltetrazines. These compounds are inaccessible by classical
Pinner hydrazine condensation or by the current sꢀaryltetrazine aromatic core functionalization
methods described up to now. We exploited multiple versatile Nꢀdirected palladium C–H
activation/halogenation of sꢀaryltetrazine to form C–X bonds (X = I, Br, Cl, F), which
collectively produced polyhalogenated unsymmetrical building blocks. We achieved a sequence
of selective C–H halogenation reactions in a specific order to produce reactive aryl halides.
Polyhalogenated sꢀaryltetrazines can then be used for controlled crossꢀcoupling reactions
towards orthoꢀsubstituted polyaromatic sꢀaryltetrazines. In general, this C–H functionalization
route gives access to a large number of variously halogenated building blocks practical for
further synthetic implementation of tetrazines (arylation, cycloaddition, etc.). Herein, we
exemplified their potential by using halogenꢀselective SuzukiꢀMiyaura reactions for divergent
construction of novel biphenyl sꢀtetrazines. Therefore, we deliver original poly(hetero)aromatic
tetrazine structures, such as new typically “Zꢀshaped” and “Tꢀshaped” species. We examined by
DFT calculation the origin of the remarkable regioselectivity in some C–H concurrent
halogenation reactions. Computations focused at free enthalpy profiles for C–H activation of
aryltetrazines to form the intermediate palladacycles by CMD process. We showed that the
presence of halogen substituents on aryl groups before further halogenation increases the
activation barrier to form the determining C–H activation intermediate palladacycle. XRD
studies of functionalized tetrazines evidenced planarity ruptures in the mutual arrangement of
aromatic cycles. Finally, this methodology allowed us to deliver a unique tetrahalogenated sꢀ
aryltetrazine holding not less than four different halogens arranged in orthoꢀaryl positions.
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KEYWORDS: halogenation · palladium · C–H activation · tetrazine · polyaromatic · biphenyl
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Introduction
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sꢀTetrazines (1,2,4,5ꢀtetrazines) are the object of considerable current interest in various
research fields, which spread out from energetic materials to biomedicine.1ꢀ12 The preparation of
tailored sꢀtetrazine allows their implementation via pyridazine formation in inverse electron
demand DielsꢀAlder cycloaddition reactions for bioorthogonal chemistry.1b, 1e, 1f, 3, 6, 10 As one of
the electronꢀpoorer stable heteroaromatic system, sꢀtetrazine has also application in nonlinear
optic and fluorescence in the field of addressable sensors and display.1a, 4, 11 Their high nitrogen
content made them also ideal building blocks for explosive materials synthesis in their own,1c, 2
and as coordinating agent.1d Despite this significant extent of applications, the synthetic
preparation modes of functionalized sꢀtetrazine remains very limited. They mainly rely on the
initial Pinner synthesis of prefunctionalized tetrazine core, which involves a condensation of
hydrazines with a nitrile reagent to form an oxidable 1,2ꢀ or 1,4ꢀdihydrotetrazine (Scheme 1,
top). This synthetic route can give access to aryltetrazines but with serious steric and electronic
limitations when polyfunctionalized aryltetrazines are targeted. Postꢀfunctionalization of sꢀ
tetrazine is thus often necessary and clearly lack of precursors. In this purpose, halogenated
tetrazines are ideal starting materials, and 3,6ꢀdichloroꢀ1,2,4,5ꢀtetrazine has ubiquitous
applications.1 Recent synthetic progress on sꢀtetrazine postꢀfunctionalization includes palladiumꢀ
catalyzed Heck olefination,7 and direct sp2C–H activation/fluorination.8a The group of Devaraj
disclosed suitable conditions for the synthesis of alkenyl tetrazines from aryl halides and vinyl sꢀ
tetrazine.7 We reported that sꢀtetrazine is a particularly suitable group for Nꢀdirected orthoꢀC–H
activation of tethered aryl groups. This allows forming carbon–X bonds (X = O, F) towards
monoꢀ, diꢀ and tetraꢀheterofunctionalized sꢀaryltetrazines8aꢀc such as the commercial acaricidal
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fluorinated tetrazines of Clofentezine family.9 The access to orthoꢀfunctionalized derivatives is a
limitation of classical Pinner and Stoller condensation (Scheme 1) because of steric issues, and
other factors such as: (i) the availability of aryl precursors, (ii) unselective condensation
reactions, and (iii) the use of hazardous and toxic reagents.9a,b Nꢀdirected metalꢀcatalyzed orthoꢀ
C–H activation/functionalization proved to be very efficient and delivered for the last decade a
variety of directing groups and conditions.8dꢀn
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Scheme 1. Preparation of o-substituted s-aryltetrazines.
Thus, we overcame longꢀstanding limitations attached to orthoꢀsubstituted sꢀaryltetrazine
formation by using palladiumꢀcatalyzed straightforward selective C–H halogenation methods.8aꢀc
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We present now convenient conditions for versatile multiple unequal C–H halogenation of sꢀ
aryltetrazines, producing unsymmetrical polyhalogenated building blocks via successive very
fast C–H activation/functionalization steps. We achieved a sequence of two or three selective
halogenation reactions in a specific order to produce reactive aryl halides, which were used for
the controlled synthesis of biphenyl and polyaromatic sꢀaryltetrazines (A, B and C Scheme 1,
bottom) with unprecedented structures (Zꢀshaped and Tꢀshaped). These polyaromatics optionally
include unequally substituted arene moieties. Ultimately, this stepwise controlled C–H
functionalization method allowed synthesizing a unique tetrahalogenated sꢀaryltetrazine in which
four orthoꢀhalogen functions (all different) are present.
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RESULTS AND DISCUSSION
Fast rate C–H halogenation. We recently disclosed conditions to achieve selective C–H
orthoꢀfunctionalization that allowed building of monoꢀ, diꢀ and tetrahalogenated
homofunctionalized sꢀaryltetrazines.8a Noticeable limitations of the methodology was first the
several hours reaction time necessary for satisfactory conversion (>15 h), and more importantly
the absence of differentiation in the introduced functional groups (halogen, OAc). Building
chemically differentiated tetrazines is essential for further use of this block as a versatile and
reactive platform for the wide field of applications aboveꢀmentioned.1ꢀ12 C–H orthoꢀhalogenation
may be extended to build unsymmetrical polyfunctionalized sꢀaryltetrazines by using multiple
selective halogenation reactions (Figure 1). Further sꢀtetrazines backbone “dissymmetrization”
then would be achieved by performing halogenꢀspecific reactions. Because we envisioned a
multiple step procedure, we first addressed the limitation in timeꢀefficiency of C–H
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halogenation. We investigated microwave conditions for fast electrophilic incorporation of Br, I
and Cl atoms.
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Figure 1. Building of chemically differentiated tetrazines.
We first focused our attention on the selective monobromination of 1 (Scheme 2) with Nꢀ
bromosuccinimide (NBS) as bromination agent, using palladiumꢀcatalysis under microwave
irradiation (see Supporting Information, Table S1).13
10 mol% Pd(OAc)2
NXS (1.0 equiv)
X
10 mol% Pd(OAc)2
NXS (2.0-4.0 equiv)
N
N
N
N
N
N
N
N
N
N
N
N
CH3NO2 or AcOH,
10 min
AcOH, 10 min
Mw (200 W)
X
X
Mw (200 W)
1
3a 51 (45)
X = Br:
I: 3b 38 (17)
Cl:
2a 61 (52)
2b 54 (47)
2c 56 (54)
X = Br:
I:
Cl:
10 mol% Pd(OAc)2
NXS (5.0-8.0 equiv)
AcOH, 45 min
Mw (200 W)
3c 38 (37)
X
N
X = Br:
4a 62 (60)
4b 67 (17)
4c 48 (35)
N
I:
Cl:
N N
X
X
Scheme 2. Poly-ortho-halogenation of s-aryltetrazines at fast rate (isolated yields in
brackets)
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In the absence of palladium no reaction occurred. For practical reasons we achieved catalytic
conditions screening under air. We observed that inert gas conditions are unnecessary for
microwave C–H activation/bromination. The reaction using 10 mol% of zerovalent palladium
precursors Pd2(dba)3, and Pd(dba)2, in nitromethane at 100 °C, afforded within 10 minutes the
expected 3ꢀ(2ꢀbromophenyl)ꢀ6ꢀ(phenyl)ꢀ1,2,4,5ꢀtetrazine (2a, Scheme 2) at 58 mg (0.25 mmol
scale) with traces of dibrominated 3,6ꢀbis(2ꢀbromophenyl)ꢀ1,2,4,5ꢀtetrazine (3a < 5 mol%).
Pd(OAc)2 precatalyst achieved a better conversion albeit with a lower selectivity (see Supporting
Information, Table S1). Compound 2a was purified and isolated in 52% yield. Other solvents,
such as trifluoromethylbenzene, acetic acid or 1,2ꢀdichlorethane led to lower conversions. Under
thermal heating conditions,8a the optimized catalytic system produced 2a in 45% yield after 17 h
under argon.14 This protocol employed for selective C–Hꢀmonobromination cannot be directly
applied to produce monoiodinated and monochlorinated sꢀaryltetrazines, and appropriate
conditions need to be tuned from the other Nꢀhalosuccinimides (see Supporting Information,
Tables S2 and S3). The iodinated product 2b was obtained in 47% isolated yield (see Supporting
Information Table S2) and the monochlorinated 2c in 54% isolated yield (see Supporting
Information Table S3) also within 10 min reaction time and satisfactory selectivity (0.25 mmol
scale).
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We extended the shortꢀtime synthetic access to polyhalogenated sꢀaryltetrazines, including
symmetrical orthoꢀdihalogenated 3a-c. We were also glad to efficiently achieve the synthesis of
unsymmetrical orthoꢀtrihalogenated 4a-c (Scheme 2). Dibrominated 3a, which is a unique
precursor for the synthesis of benzo[a]acecorannulene bowlꢀshaped fullerene materials,9b was
obtained using 2 equiv of Nꢀbromosuccinimide (NBS) with Pd(OAc)2 in AcOH at 110 °C in 45%
yield (Table S4). Iodinated analogue 3b was synthetized using a slightly higher temperature of
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120 °C. However, a significant amount of side products (see Supporting Information, Table S5)
including 3ꢀ(2,6ꢀdiiodophenyl)ꢀ6ꢀphenylꢀ1,2,4,5ꢀtetrazine 3b' (22%) and 4b (27%) rendered the
isolation of 3b difficult (17%). Dichlorinated sꢀaryltetrazine 3c (known as the commercial
miticide Clofentezine)9a was synthetized in 10 minutes using 4 equiv of Nꢀchlorosuccinimide
(NCS) at 120 °C, and was isolated pure in 37% yield (see Supporting Information, Table S6). A
single step triꢀorthoꢀhalogenation of 1 (Scheme 2) was achieved from 5.0 to 8.0 equiv of
electrophilic halides under 45 min shortꢀtime reaction. Tribrominated sꢀaryltetrazine 3ꢀ(2,6ꢀ
dibromophenyl)ꢀ6ꢀ(2ꢀbromophenyl)ꢀ1,2,4,5ꢀtetrazine 4a was isolated pure in good 60% yield
because of a highly selective conversion. Conversely, access to triiodinated sꢀaryltetrazine 4b
was found to be difficult since from a satisfactory 67% conversion of 1, the product 4b could be
isolated pure in only 17% yield due to its degradation during chromatography. Trichlorinated 4c
was isolated under pure form in 35% yield from a 48% yield conversion. These compounds were
ideal precursors for further challenging halogenation procedure that we examined.
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Twofold unequal C–H functionalization. Unequally polyhalogenated arenes derivatives
would found utility for selectively promoting different functionalization at the aromatic
substituent of sꢀtetrazines. Accordingly, we investigated twofold C–H functionalization on
variously prehalogenated sꢀtetrazines to reach unequally orthoꢀtetrahalogenated compounds
(Table 1). Monofluorinated aryltetrazine 2d and monochlorinated aryltetrazine 2c react with Nꢀ
iodosuccinimide (NIS), NBS, or NCS in the presence of Pd(OAc)2 in AcOH at 120 °C to
respectively give in 10 to 30 min the unequally tetrahalogenated compounds 5a (65%), 5b
(67%), 5c (76%) and 6a (94%), which were isolated in good to high yield. Compounds 7a, 7b
and 7c are easily obtained from the difluorinated sꢀdiaryltetrazine 3,6ꢀbis(2ꢀfluorophenyl)ꢀ
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1,2,4,5ꢀtetrazine 3d and dibrominated, diiodinated and dichlorinated difluoroaryltetrazine were
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isolated in excellent 86%, 83% and 80% yield, respectively.
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Table 1. Unequally tetrahalogenated s-aryltetrazine.a
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H
H
Y
Y
N N
N N
X = Cl, 2c
F, 2d
N
N
N
N
10 mol% Pd(OAc)2
4.0-8.0 equiv NYS
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H
H
Y
Y
X
Y
X
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or
or
AcOH, 10 to 30 min
Mw (200 W)
H
N N
N
N
N
N
X = Br, 3a
I, 3b
N
N
Cl, 3c
F, 3d
X
X
X
X
Y = Br, I, Cl = X
X = Br, I, Cl, F
Br
I
Br
Br
I
Cl
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N N
F
F
F
I
5a, 90% (65)
(NBS = 6.0 eq.)
5b, 88% (67)
(NIS = 6.0 eq.)
5c, 92% (76)
(NCS = 8.0 eq.)b
Br
Br
Br
Br
I
I
N
N
N
N
N
N
N
N
N
N
N
N
Cl
F
Br
F
F
F
6a, 98% (94)
7a, 98% (86)
(NBS = 4.0 eq.)
7b, 99% (83)
(NIS = 4.0 eq.)
(NBS = 6.0 eq.)
Br
Br
I
Cl
Cl
I
N
N
N
N
N
N
N N
N N
N
N
Cl
F
Cl
Cl
F
Cl
8b
7c, 96% (80)
8a
, 88% (59)
(NBS = 4.0 eq.)
, 99% (83)
(NIS = 6.0 eq.)
(NCS = 4.0 eq.)b
Br
Cl
Cl
Cl
N
N
N N
N
N
N N
Br
Cl
Br
Cl
or I
or I
9c, mixture
10a, 99% (69)
(NBS = 2.0 eq.)b
(NCS)
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Conditions: 3,6ꢀdiarylꢀ1,2,4,5ꢀtetrazine derivative (1 equiv), Pd(OAc)2 (10 mol%), [NYS]:
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8
NBS, NIS or NCS (4.0 to 8.0 equiv), AcOH (0.125 M), 120 °C, Mw (200 W), under air, 10 min.
1H NMR yield and isolated yield under bracket. b 30 min.
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The dichlorinated sꢀaryltetrazine 3c was used for the introduction of bromide that was achieved
with 4 equiv of NBS to reach a conversion of 88% in 8a. Under such conditions 12% of
monobrominated derivative also formed that lowers the isolated yield in 8a to 59% after workup.
Reacting 3c with 6 equiv of NIS leads to the diiodinated dichloroaryltetrazine 8b which was
isolated in 83% yield.
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Selectivity in the formation of unequally tetrahalogenated compounds 5aꢀc to 8a,b is
remarkable since under palladium catalytic conditions additional sideꢀreactions such as
dehalogenation or halogen exchange could occur in the course of oxidative addition and
reductive elimination reactions involving halides.15 Accordingly, the double chlorination
reactions of the dibromoaryltetrazine 3a or diiodoaryltetrazine 3b, using Nꢀchlorosuccinimide,
led to intractable mixtures of variously halogenated compounds. C–H activation may be
kinetically opposed by C–X oxidative addition to low valent palladium (X = Br or I). To
overcome this limitation we established an effective halogenation sequence in which is achieved
first fluorination and chlorination reactions, before bromide introduction, and finally
incorporation of iodine. Such reasoned reaction sequence preserves a high chemoselectivity for
C–H functionalization, and thus limits difficult purification processes. Accordingly,
monobromination of 4c was achieved with 2.0 equiv of NBS in 30 min to isolate 10a in 69%
yield (see Supporting Information for XRD analysis details of 10a). Some of the
polyhalogenated compounds reported in Table 1 are patented (or commercial) pest control
products, with translaminar and systemic acaricidal, larvicidal and ovicidal effects.9a,cꢀe When
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reachable, their tedious syntheses following initial Pinner protocol (Scheme 1) required at least
five steps with overall yield below 15%.9a
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8
9
Since we achieved unequal halogenation of the four orthoꢀC–H bond of sꢀaryltetrazine in two
simple steps, we then further addressed the more challenging task of unequal selective
dihalogenation of sꢀaryltetrazine from monohalogenated sꢀaryltetrazines 2a,c-d (X = Br, Cl, F,
Table 2).
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Table 2. Unequally dihalogenated s-aryltetrazine.a
a
Conditions: 3,6ꢀdiarylꢀ1,2,4,5ꢀtetrazine derivative (1 equiv), Pd(OAc)2 (10 mol%), [NYS]:
NBS, NIS or NCS (1.0 to 3.0 equiv), solvent (0.125 M), 120 °C, Mw (200 W), under air, 10 min.
1H NMR yield and isolated yield under bracket.
Using 10 mol% of Pd(OAc)2 in AcOH at 120 °C for 10 min, a single halogenation of 2a, 2c
and 2d proceeds preferentially on the unsubstituted aryl moiety. This marked selectivity is
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apparently not related to the function already present on the aryl (Br, Cl or F) since a ratio of ca.
85:15 for C–H halogenation of ArH vs ArX moiety was systematically observed (see Supporting
Information, Figure S1 for details). This intriguing situation was further analyzed by DFT
calculations (see below). Overall, this twoꢀsteps synthetic protocol allowed for the formation of
all possible combination of 3,6ꢀbis(2ꢀhalophenyl)ꢀ1,2,4,5ꢀtetrazine with unequal halides 11a-13b
in ca. 30 to 40% yield. The challenging dihalide 13b (because of potential transꢀ and
dehalogenation reactions) bearing bromide and iodide functions was even obtained in 62% yield
by iodination of 2a (Table 2). The isomers 11a'-13b' having two halogens on the same aryl
moiety are also isolable, albeit in lower yield (<15%), due to their formation in minor amount.
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Unequally trihalogenated s-aryltetrazines. We developed a complementary class of
unequally trihalogenated sꢀaryltetrazines by adjusting the amount of halogenation reagents used
over monoꢀ or dihalogenated sꢀaryltetrazines (Table 3). Monobromination or monoiodination of
the difluorinated sꢀaryltetrazine 3d proceeds selectively in AcOH within 10 min. The halide
source stoichiometry needs to be accurately adjusted with an excess of two equiv of Nꢀ
halosuccinimide. The products 14a and 14b were respectively isolated in 33% and 54% yield.
Selective monochlorination of 3d is more demanding. Extension of the reaction time –as it was
done for the synthesis of 5c and 7c– is detrimental to the selectivity, and instead we used four
equiv of NCS to isolate 14c in 50% yield from a selective 62% conversion. Monobromination
and monoiodination of the dichlorinated sꢀaryltetrazine 3c were found to be easier and the
trihalogenated products 15a and 15b were converted in 71% and 75%. A more challenging, yet
accessible, two steps C–H halogenation route to unequal trihalogenated species is the inverse
method in which dihalogenation follows monohalogenation of sꢀaryltetrazine.
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Table 3. Unequally trihalogenated s-aryltetrazines.a
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10
11
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13
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15
16
17
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19
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a
Conditions: 3,6ꢀdiarylꢀ1,2,4,5ꢀtetrazine derivative (1 equiv), Pd(OAc)2 (10 mol%), [NYS]:
NBS, NIS or NCS (1.0 to 4.0 equiv), solvent (0.125 M), 120 °C, Mw (200 W), under air, 10 min.
1H NMR yield and isolated yield under bracket. b See main text for details.
This was achieved for double chlorination of monofluorinated 3d to yield trihalide 16c (Table
3). However, isolating 16c in pure form by this route was not straightforward, and we
reconsidered the synthetic strategy (see Supporting Information, Figure S2ꢀS4 for details).
Essentially, direct C–H dichlorination of 2d produces the two isomers 16c and 16c' in 67:33
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ratio, but in an intractable mixture (Scheme 3, left). Conversely, 16c is isolated pure in
satisfactory yield from the chlorination of 11c' (Scheme 3, right) that is produced from
monochlorination of 2d (Table 2).
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Scheme 3. Concurrent C–H halogenation routes to trihalogenated 16c.
Polyhalogenated s-aryltetrazines bearing three or four different functions. To further
expand the scope of Nꢀdirected C–H activation with sꢀaryltetrazines we addressed the
challenging synthesis of orthoꢀtetrahalogenated aryltetrazines bearing three different halides. We
anticipated that such syntheses could be troublesome because Pdꢀpromoted dehalogenation and
transhalogenation reactions may lead to intractable mixtures. We investigated two general routes
(Table 4), either monohalogenation of unequally trihalogenated compounds (sꢀtetrazine 14c), or
the dihalogenation of unequally disubstituted sꢀaryltetrazines (11c and 11c'). Monobromination
of 14c with 2 equiv of NBS using Pd(OAc)2 in AcOH selectively led to 87% conversion in 17a
within 10 min. After workup the polyhalogenated 17a bearing a chloride, a bromide and two
fluorides was isolated in good 68% yield. Iodination of 14c in the presence of NIS also allowed
getting 17b in 68% yield. Fast 10 min double C–H bromination and C–H iodination of the
compound 11c was achieved with 4.0 equiv of Nꢀhalosuccinimide to reach 18a and 18b in 70%
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and 78% conversion, respectively. These compounds were isolated in ca. 50% and 52% yield
5
6
respectively after workup.
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Table 4. Unequally polyhalogenated s-aryltetrazine bearing three different halide groups.a
Z
Cl
H
Cl
N
N
N
N
N
N
N
N
14c
F
Z
F
Z
F
F
or
or
H
H
10 mol% Pd(OAc)2
1.0-4.0 equiv NZS
N N
N N
11c
N
N
N
N
AcOH, 10 min
Mw (200 W)
Cl
F
Cl
F
or
or
Z
H
Cl
Cl
N
N
N
N
N N
11c'
N
N
H
H
F
F
Z = Br, I
I
Cl
Cl
F
Br
N
N
N
N
N
N
N
N
F
F
F
17a, 87% (68)
17b, 80% (68)
(NBS = 2.0 eq.)
(NIS = 2.0 eq.)
Br
Br
F
I
Br
I
Cl
F
N
N
N
N
N
N
N
N
N
N N
N
Cl
Cl
F
18b, 78% (52)
(NIS = 4.0 eq.)
19a, 73% (48)
(NBS = 1.0 eq.)
18a, 70% (50)
(NIS = 4.0 eq.)
a Conditions: 3,6ꢀdiarylꢀ1,2,4,5ꢀtetrazine derivative (1 equiv), Pd(OAc)2 (10 mol%), [NZS]: NBS
1
or NIS (1.0 to 4.0 equiv), solvent (0.125 M), 120 °C, Mw (200 W), under air, 10 min. H NMR
yield and isolated yield under bracket.
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In the class of sꢀaryltetrazines holding three different halide functions, we also synthesized
19a, by monobromination of 11c' by using one equiv of NBS. This trifunctionalized tetrazine
19a was isolated pure in 48% yield from a 73% conversion.
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Finally, a C–H iodination of 19a was achieved in the presence of Pd(dba)2 for 15 min and
give 20 in 34% isolated yield (Scheme 4, full synthetic scheme is reported (see Supporting
Information, Figure S5). This compounds is a rare example of simple organic molecule
displaying four different halogen atoms in close proximity.16
Scheme 4. Tetrahalogenated s-aryltetrazine bearing four different functions.
Selectivity trends in C–H halogenation of monohalogenated s-aryltetrazines. Single
halogenation of monohalogenated sꢀarylatetrazines 2a,c-d (Table 2) proceeds preferentially on
the unsubstituted aryl moiety whatever the halide function already present on the other aryl (Br,
Cl or F). An isomer ratio for the resulting dihalogenated 11-13 and 11'-13' of ca. 85:15 was
systematically obtained (see Supporting Information, Figure S1). To clarify the origin of this
selectivity trend the C–H activation step was studied with DFT calculations. Free energies were
computed at the ωB97XꢀD density functional with a basis set of double zeta polarization quality.
The acetic acid solvent was modelled using a microꢀsolvation approach. All molecules were
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complexed with one explicit solvent molecule while the bulk effects were described using a
continuum (see SI for full computational details).
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Mechanistic studies on Nꢀdirected C–H activation/functionalization have identified the
formation of Nꢀcontaining palladacycles as pertinent intermediates in the process.17 Accordingly,
the final selectivity observed in the present case arises from the concurrent formation of the
intermediates B1 and B2 (Figure 2, top).
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Figure 2. Palladacycles (B) and precursors (A) pertinent in C–H activation of
monohalogenated s-aryl-tetrazines.a
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The collection of dihalogenated aryl tetrazine bis(acetato) Pd(II) complexes A (Figure 2,
bottom) are pertinent precursors for the formation of B1 and B2. Three isomeric Pd complexes
A11, A12 and A22 which are susceptible of undergoing C–H activation to B were computed for
X = Br, Cl and F. In these, palladium coordinates a nitrogen atom either in γꢀposition to the
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halogen atom (N1, Figure 2) or in remote δꢀposition to the halogen atom (N2). Computation
indicates that A11 is the most stable isomer, however the isomerization barrier is low (20.4
kcal.molꢀ1, see Supporting Information, Scheme S4 for full mechanistic details) and consequently
the three isomers coꢀexist during the reaction. The free enthalpy profiles were computed for the
formation of palladacycles B1 and B2 from complexes A by C–H activation in a concerted
metalationꢀdeprotonation mechanism (CMD) assisted by AcOH.18 Free energies and geometries
for the main transition states are given in Figure 3 for X = Br, Cl and F (see Supporting
Information for all the structures).
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rG°(kcal.mol-1)
TS1
34.5
33.2
32.0
X =
Br
Cl
F
TS2
32.7
32.4
31.7
A
0
0 kcal.mol-1
B1
B2
A
B1
B2
AcO
Pd
AcO
Pd
R
R
X
N
N
X
OAc
N
N
N
N
AcO
X
N
N
N
N
Pd
N
N
N
N
N
N
X
Figure 3. Free enthalpy profiles for C–H activation of s-aryltetrazines to form the
intermediate palladacycle by concerted metalation-deprotonation mechanism (CMD).
Acetic acid solvent was modelled using a micro-solvation approach.
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We found lower energy barriers for the C–H activation on the unsubstituted aryl moieties (B2
formation) with transition structure TS2 energies ranging from 31.7 kcal.molꢀ1 (X = Cl) to 32.7
kcal.molꢀ1 (X = Br). Halogenated aryl undergoes C–H activation with higher energy, TS1
ranging from 32.0 kcal.molꢀ1 (X = Cl) to 34.5 kcal.molꢀ1 (X = Br). This trend was common to the
three halogenated (2a, 2b and 2d) we considered. Electronꢀwithdrawing halogen substituents
already present on the targeted aryl group before halogenation increase the activation barrier to
form the intermediate palladacycle. We already observed this tendency in related Nꢀdirected C–
H activation of functionalized arylpyrazoles.17d Consequently, at elevated reaction temperature
the halogenation of unsubstituted aryl moiety would be kinetically favored. Under such kinetic
control, we calculated selectivity ratio using computed activation free energies (see Supporting
Information for full details on the ratio computation). Concerning the fluorinated 2d (X = F,
Figures 2 and 3) the ratio for regioselective second halogenation was found 84:16 identical to
average experimental ratio observed for the formation of 11ꢀ13:11'ꢀ13' (84:16, Table 2, see
Supporting Information Figure S1). For chlorinated 2c we found a consistent ratio of 77:23 for
the second halogenation (85:15, see Supporting Information, Figure S1). Calculations from
brominated 2a (X = Br) predict a slightly higher regioselectivity 96:4 compared to experimental
results (84:16, see Supporting Information, Figure S1). Globally, these values convincingly
reproduced the experimental results.
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Halide exploitation for constructing polyaromatic s-aryltetrazines – Unsymmetrical
structures. We validated the strategy of halogen orthoꢀimplantation onto sꢀaryltetrazines by
building various unprecedented highly congested polyaromatic biphenyl tetrazine structures.
Biphenyl are privileged scaffolds for pharmaceuticals since they bind to a wide range of proteins
with high levels of specificity in addition to their recognized antiꢀrheumatic, analgesic, antiꢀ
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inflammatory, antithrombotic and antihypertensive bioactivity.19 SuzukiꢀMiyaura palladium
catalyzed crossꢀcoupling reactions is known for its high versatility and could be halogenꢀspecific
by adjusting the catalytic system. We used Pd(dba)2 in toluene at 110 °C to synthesize the 3ꢀ
([1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ6ꢀphenylꢀ1,2,4,5ꢀtetrazines 21ꢀ25 in excellent yields (70% to 98%, Table
5).
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Table 5. Polyaromatic biphenyl tetrazines from one step construction.a
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10
11
12
13
14
15
16
17
18
19
20
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a
Conditions: tetrazine derivative (1 equiv), Pd(dba)2 (10 mol%), aryl boronic acid (2.0 or 4.0
equiv), K2CO3 (2.0 or 4.0 equiv), toluene (0.125 M), 110 °C, 16 h, yields of isolated products are
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reported (average of two or more runs). b Pd2(dba)3 at 120 °C. c 2,5ꢀBisꢀarylated 28' was isolated
in 23% yield as an unprecedented Tꢀshaped poly(hetero)aromatic structure.
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4
5
6
7
8
9
From the chlorinated analogue 2c, biphenylꢀaryltetrazine 21 was obtained in 69% isolated
yield only by changing the catalytic system for [Pd2(dba)3] at 120 °C. In these crossꢀcouplings,
boronic acids bearing withdrawing substituents such as CF3 or F (22ꢀ23) and donating
substituents such as t-Bu and MeO (24ꢀ25) are tolerated. By using the unequally dihalogenated
tetrazines 11a and 12a, selective arylation at bromine was successfully achieved with phenyl
boronic acids and gave polyaromatic 26 and 27 (59% and 94% isolated yield, respectively) ready
for further functionalization at the remaining chloride function. Selective arylation is also
possible when bromide and chloride atoms are hold by the same aryl moiety: from 12a' the
tetrazine 28 was obtained in 74% yield (Table 5). The bisꢀarylated product 28', showing a unique
Tꢀshaped pentaꢀaromatic structure,20 was also isolated in 23% yield. This result indicates that a
first arylation further enhances chlorine reactivity on the same ring. Tetrahalogenated tetrazine
10a was successfully used to give trichlorinated biphenylꢀaryltetrazine 29 in high 97% yield
(Table 5). Bisꢀ(biphenyl)ꢀtetrazines 30ꢀ32, which were synthesized in excellent yield from
dibrominated aryltetrazine 3a (80 to 90% isolated yield), extend the scope of pentaꢀaromatic
structures towards Zꢀshaped compounds, previously unknown as tetrazine analogues of
polyphenylenes.20,21 Compound 31 was characterized by single Xꢀray diffraction analysis in the
solid state (Figure 4). Compared to pristine 3,6ꢀphenylꢀ1,2,4,5ꢀtetrazine precursor the coplanarity
of central aromatic rings is disrupted with torsion angles C7–C2–C1–N2i = 33.7(3) ° (and
additionally for biphenyls C9–C8–C7–C2 = 56.5(3) °). This effect is even more pronounced with
halogenated aryl groups, as observed in the XRD analysis of compound 10a (Figure 5) where the
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torsion angles are more than doubled with C7–C2–C1–N2i = 69.9(2) ° and C10–C9–C8–N4ii =
75.0(2) ° (see Supporting Information, Figure S7).
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F3C
N
N
N
N
CF3
(31)
Figure 4. Ortep molecular structure of Z-shaped penta-aromatic bis(biphenyl)tetrazine 31
(50% probability ellipsoids. Sym. Op.: (i) 1ꢀx, 1ꢀy, 1ꢀz, see full description in SI, Figure S6).
Cl
Cl
Br
Cl
N
N
N
N
(10a)
Figure 5. Ortep molecular structure of tetrahalogenated tetrazine 10a (Ortep with 50%
probability ellipsoids (Ortep view in Olex2) [Br red, Cl green, N blue, C grey, H white]. Sym.
Op.: (i) 1ꢀx, ꢀy, 2ꢀz. The unit cell contains two molecules, only one is shown here. Br and Cl
atoms are disordered and occupy the same positions with occupation factors 0.27:0.73 for
Br1/Cl1 and 0.23:0.77 for Br2/Cl2, see full description in SI, Figure S7).
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We took profit of the halogenꢀspecific SuzukiꢀMiyaura reaction, which may be tuned with the
catalytic system employed, and we used the unequally dihalogenated bromo/chloro 12a and 12a'
to selectively produce the heteroaromatics 27 and 28 in high yields, respectively (Table 5). We
then successfully accessed to unequal bisꢀ(biphenyl) tetrazines with Zꢀshaped and Tꢀshaped
structures (33, 34 in Scheme 5). In the presence of 10 mol% [Pd2(dba)3] in mesitylene, 4ꢀ
methoxyphenylboronic acid successfully coupled with the chlorinated tetrazine 27 to give
bis(biphenyl)tetrazine 33 in 18% isolated yield. The same reaction using chlorinated tetrazine 28
(obtained from 12a') produces 34 in 52% yield. Notably, those were obtained without palladium
auxiliary ligands optimization. This reactivity again evidenced an activation of the chloride
function when the supporting aryl group is prefunctionalized.
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12a'
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a
MeO
N
OMe
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t-
Bu
N
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t-Bu
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, 52%
, 18%
unsymmetrical Z-shaped
unsymmetrical T-shaped
Scheme 5. Unequally substituted bis-(biphenyl)tetrazines 33 and 34 (conditions: 10 mol%
[Pd2(dba)3], 2.0 equiv 4ꢀOMeꢀC6H4B(OH)2, 2.0 equiv K2CO3, mesitylene 140 °C, 16 h).
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CONCLUSION
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We have developed a general and efficient palladium catalyzed direct unsymmetrical C–H
functionalization of sꢀtetrazines. This method allows the introduction of one to four
(un)equivalent halogens in the orthoꢀposition of tetrazines in short time reactions each below 1h.
As preferential halogenation sequence, the introduction of fluorine and/or chlorine, before
bromide, before iodine gives access to orthoꢀfunctionalized sꢀaryltetrazines bearing two to four
different halides. This work provides an efficient and practical entry for further accessing highly
unsymmetrical substituted sꢀtetrazine derivatives. We illustrated the potential of C–H
activation/halogenation route by synthesizing various new classes of polyaromatic compounds
with central tetrazine core; this from using halogenꢀselective C–C crossꢀcoupling conditions.
DFT calculations and XRD analysis have shown that aryl functionalization in biaryl sꢀtetrazines
have effect both on the reactivity of the molecules (selectivity in further aryl functionalization),
and in the geometry at solid state (polyaromatic planarity rupture). Our current work focused at
the investigation of physical and chemical properties of new Zꢀshaped and Tꢀshaped tetrazines.
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ASSOCIATED CONTENT
Supporting Information
The supporting Information is available free of charge via the Internet at http://pubs.acs.org.”
Experimental procedures and spectral data for all new compounds (PDF). Computational details,
evaluation of theoretical ratios, reaction paths for isomerization, absolute energies and
geometries for all molecules. Crystallographic data (CIF). CCDC 1558814 (31), 1558815 (10a)
contains the supplementary crystallographic data for this paper. These data can be obtained free
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via
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www.ccdc.cam.ac.uk/data_request/cif.
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ACKNOWLEDGMENT
This work was supported by the Université de Bourgogne (MESRI PhD grant for CT), the
Region Bourgogne (PARI 3MIMꢀP4 for CDM), the ERASMUS Mundi program between Dijon
(France), Kaiserslautern and Tübingen (Germany) for SR and SG. Thanks are due to Pr. D. Kunz
(Tübingen) and Pr. W. Thiel (Kaiserslautern) for Erasmus coordination. Thanks are due to S.
Royer for sꢀtetrazine reagents preparation. Calculations were performed using HPC resources
from DSIꢀCCUB (Université de Bourgogne).
AUTHOR INFORMATION
Corresponding Author
*julien.roger@uꢀbourgogne.fr
*jeanꢀcyrille.hierso@uꢀbourgogne.fr
ORCID
Clève Dionel MBOYI: 0000ꢀ0002ꢀ8051ꢀ0830
Hélène CATTEY: 0000ꢀ0002ꢀ4416ꢀ7510
Paul FLEURATꢀLESSARD: 0000ꢀ0003ꢀ3114ꢀ2522
Julien ROGER: 0000ꢀ0002ꢀ4964ꢀ366X
JeanꢀCyrille HIERSO: 0000ꢀ0002ꢀ2048ꢀ647X
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Author Contributions
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All authors have given approval to the final version of the manuscript.
‡ C. D. M. and C. T. contributed equally to this work.
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Funding Sources
We gratefully acknowledge support from Région Bourgogne (PARI II program, CDEA) and the
CNRS (3MIMꢀP4 program). The authors are thankful for support from the Institut Universitaire
de France IUF (JCH).
Notes
The authors declare no competing financial interest.
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