Synthesis of tetrazines from: Gem -difluoroalkenes under aerobic conditions at room temperature

Article abstract of DOI:10.1039/c6gc03494b

An efficient and green procedure for the synthesis of tetrazines has been developed based on an old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazines can be obtained in moderate to high yields from t

Full text of DOI:10.1039/c6gc03494b

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Synthesis of Tetrazines from gem‐Difluoroalkenes under Aerobic
Condition at Room Temperature
Zheng, Fang, a Wen‐Li Hu, a De‐Yong Liu, a Chu‐Yi Yu,ab Xiang‐Guo Hu*a
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and green procedure for the synthesis of tetrazines has been developed based on an
old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6‐disubstituted
1,2,4,5‐tetrazines can be obtained in moderate to high yields from corresponding gem‐
difluoroalkenes under aerobic condition at room temperature. This work represents a rare
example that ambient air is utilized as oxidant for the synthesis of tetrazines.
DOI: 10.1039/x0xx00000x
www.rsc.org/
The 1,2,4,5‐tetrazine heterocyclic ring system is one of the oxygen has been barely explored for this purpose.7 Here, we
1
most unique and versatile aromatic heterocycles. The report a green and efficient synthesis of 1,2,4,5‐tetrazine
1,2,4,5‐tetrazines are applied extensively in life science for from gem‐difluoroalkenes under aerobic condition at room
different purposes such as intracellular small molecule temperature.7
imaging, post synthetic DNA labelling, in‐vivo imaging, and
among others.2 In addition, the 1,2,4,5‐tetrazines are also
useful for the development of explosive, propellant materials
due to the property of high energy density.3 Furthermore,
They are also used in organic chemistry as synthetic
intermediates, which have been elegantly utilized for the
synthesis of many natural products.4
Owning to the immense usefulness of 1,2,4,5‐tetrazine
derivatives, many routes has been developed for the
efficient synthesis of such compounds. As there is no direct
Scheme 1 Strategies for the synthesis of 1,2,4,5‐tetrazine
way for the construction of tetrazine ring system, 1,2,4,5‐
Strategically and mechanistically, most of the reported
methods for the synthesis of tetrazines proceed from a
formal [4+2] addition(strategy A). We, however, envisioned
tetrazines are always obtained from their dihydro‐
precursors.1,5 Consequently, almost all of these methods
that tetrazines could be prepared through a formal [3+3]
addition of a hydrazone bearing a leaving group(strategy B).
Based on the continuing interest of one of the authors in
organofluorine chemistry,8 fluoride was selected as the
leaving group.9 Literature survey shows that this strategy has
been explored by Carboni and co‐workers early in 1958.10
Unfortunately, Carboni’s method has received little attention
probably because it suffers from low overall yields(27%‐33%)
and limited substrate scope( 3 substrates bearing a
fluoroalkyl chain were tested).
need stoichiometrical or excess oxidants(for example: NO2,
HNO2, CrO3, NaBO3, powdered sulphur and hypervalent
iodine reagents6) , which inevitably lead to the generation of
huge amounts of waste. From a sustainable and green
chemistry viewpoint, it is more preferable to use oxygen as
oxidant owing to its inexpensive, inexhaustible and
environmentally benign features. Although there are nearly
300 papers describing the synthesis of 1,2,4,5‐tetrazines,1
In this work, we have addressed the limitations of Carboni’s
chemistry10 and demonstrated that ordinary gem‐
difluoroalkenes can be used for the synthesis of both
symmetric and asymmetric 3, 6‐dialkyl‐1,2,4,5‐tetrazines.
The yields are generally high, ranging from 61% to 91%.
a. National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, Nanchang 330022 ( P. R. China). E‐mail: huxiangg@iccas.ac.cn
b. Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190
Electronic Supplementary Information (ESI) available: See:
DOI: 10.1039/x0xx00000x
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More importantly, ambient air is used as green oxidant different conditions were tested(Entry 1‐9), and sodium
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DOI: 10.1039/C6GC03494B
instead of toxic nitrous acid used in Carboni’s method. 10
nitrite in acetic acid gave the best result(entry 4). During the
workup of this reaction with base solution, we had always
observed a small amount of deep purple compound, which
was thought to be the color of the desired tetrazine product.
Based on this observation, we then tried to carry out the
reaction under oxygen atmosphere. However, Conducting
the reaction in tetrafuran under an oxygen atmosphere gave
only trace of the desired product(Entry 10‐11). Solvent
screen also proved that this reaction didn’t work in any other
organic mediums(not shown). In sharp contrast, oxygen was
indeed found to be an effective oxidant under a biphasic
condition{volume(EtOAc) : volume(base solution) = 1:1},
and the desired 3a was obtained in comparable yields(Entry
12‐13) to that with sodium nitrite. Further optimization
showed that the desired product could be obtained even
under air atmosphere(Entry 14‐15). The procedure in Entry
15 was thus selected as the optimized condition not only
because of the operational simplicity(no purification of the
intermediate) but also the green nature when compared to
the Carboni’s method.10
At the onset of our work, we attempted to synthesize the
fluorohydrazone by the reaction of gem‐difluoroalkene 1a
with hydrazine.11 Two products were observed by thing layer
chromatograph (TLC) after the reaction mixture was stirred
in N, N‐Dimethylformamide(DMF) for 8 hours(for a screen of
solvents, see the Supporting information). This phenomenon
was expected as two E, Z isomers of fluorohydrazone 2a
would be formed. In contrast to Carboni’s observation that
fluorohydrazone with a fluoroalkyl substituent is stable, 10
efforts for the isolation 2a proved to be unsuccessful. The
difference of chemical stability between the aforementioned
two fluorohydrazones might be due to the unique stabilizing
effect of the fluoroalkyl group.12
Table 1 Optimization of the reaction conditions
Table 2 Synthesis of symmetric 3,6‐diakyl‐ 1,2,4,5‐tetrazines
Entry Oxidants Solvent and additive
Yields(X%)
1
2
3
4
5
6
NaClO
NaNO2
NaNO2
NaNO2
NaNO2
H2O
0
7
56
88
51
14
1 M HCl sol.
0.5 M H2SO4 sol.
HOAc
10% K2CO3 sol.
m‐CPBA 10% K2CO3 sol.
7
8
m‐CPBA CHCl3/HOAc(3equvi.)
m‐CPBA CHCl3
37
56
9
m‐CPBA CHCl3/aq. 0.5 M H2SO4 52
10
11
12a
13b
14a
15b
O2
O2
O2
O2
air
air
THF/KOH(5equiv.)
THF/K2CO3(5equiv.)
EtOAc/10% KOH sol.c
trace
trace
75
ayield on gram scale
EtOAc/10% K2CO3 sol.c 89
EtOAc/10% K2CO3 sol.c 64
EtOAc/10% K2CO3 sol. c 83
With the optimized condition in hand, we next proceeded to
explore the reaction scope with various gem‐difluoroalkenes.
As shown in Table 2, This reaction tolerates different
substitution pattern and substituents on the phenyl ring.
Substrates bearing Halides, aryloxy, phenyl and alkyl on the
para‐position and nitro group at the meta position gave the
desired products in moderate to excellent yields(3a‐3f). The
structure of 3b was proved by means of X‐ray
crystallographic analysis(Figure 1).13 It is interesting to note
that the reaction of 3d and 3f proceeded at a slower
reaction rate and gave lower yields than other substrates,
which is possibly due to their lower solubility in the reaction
aYield after 8h; b Yield after 24h; c Volume(EtOAc) : Volume(base solution) = 1:1
We reasoned that the instability of 2a was the result of the
condensation of two molecules to form dihydrotetrazine 4a.
We then tried to convert 2a directly to the corresponding
stable tetrazine 3a with the aid of an oxidant. As shown in
table 1, Different oxidants, such as sodium hypochlorite,
sodium nitrite and meta‐Chloroperoxybenzoic acid, under
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media. Polycyclic aromatic substrates are also viable for this
reaction and 3g and 3h were obtained in 71% and 61% yield,
respectively. To demonstrate the practicability of this
method, we have conducted the reaction on gram scale with
1b, and the product 3b was obtained in 75% yield.
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DOI: 10.1039/C6GC03494B
Table 3 Synthesis of asymmetric 3,6‐diakyl‐1,2,4,5‐tetrazines a
Figure 1: X‐ray structures of 3b and 5c
Although fluorohydrazone B was proposed as the key
intermediate in Carboni’s synthesis of tetrazine(Scheme 2),10
no spectra data were provided. Due to the unstable nature,
we were unable to isolate B. We have, however, proved its
existence by running the reaction of 1a in deuterated
acetonitrile (Section 7, Supporting Information). Two groups
of doublet at 3.83ppm (J = 16.1 Hz) and 3.65ppm (J = 13.1 Hz)
1
corresponding to the benzylic protons in H‐NMR and two
groups of triplet at ‐65.9ppm (J = 13.1 Hz) and ‐71.5ppm (J =
16.1 Hz) corresponding to the fluorine attached to the C=N
bond in 19F‐NMR indicated the presence of E,Z‐isomers of B
(ratio, 4:1),15 which corroborated well with aforementioned
TLC results. It should be note that our work here provides
the first set of NMR spectra of a fluorohydrazone without
16
aryl or alkyl group on the NH2.
The mechanism of
formation of tetrazine D next involves condensation of
fluorohydrazone B, followed by oxidation of the resulting
1,2‐dihydrotetrazine C by the oxygen.
a All the reactions were conducted employing 1b and 1d‐l in large excess(1b, 1d‐l :
1a or 1c = 10 : 1). Yields were calculated based on the amounts of 1a or 1c.
We next directed our efforts to the synthesis of asymmetric
3,6‐disubstituted 1,2,4,5‐tetrazines. Due to the consideration
of ease of purification, we chose 1a and 1c to react with
other gem‐difluoroalkenes(1b, 1d‐l) which were in large
excess. 14 As shown in Table 3, this reaction again tolerates
different substitution pattern and substituents on the phenyl
ring, and all of the desired products were obtained in good
yields, ranging from 76%‐87%. the structure of 5c was
proved by means of X‐ray crystallographic analysis(Figure 1).
As noted by Devej and co‐workers, dialkyl asymmetric
tetrazines with bulkier substituents are very challenging
targets.6b Our method provides an easy access to a small
library of this kind of compounds.
Scheme 2 A plausible mechanism of the reaction
In conclusion, We have extended Carboni’s method10 to an
efficient and green procedure for the synthesis of tetrazines
under aerobic condition at room temperature. This work
represents a rare example that ambient air is utilized as
oxidant for the synthesis of tetrazines.7 Both symmetric and
asymmetric 3,6‐disubstituted 1,2,4,5‐tetrazines can be
obtained in moderate to good yields from corresponding
gem‐difluoroalkenes. The practicability of this method is
demonstrated by scaling up the reaction of 1b to gram scale.
The NMR study carried out in this work provides solid proof
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Edit., 2011, 50, 11112‐11116; (b) M. Bergeron, D. Guyader
and J. F. Paquin, Org. Lett., 2012, 14, 5888‐5891V.iew Article Online
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5793‐5795.
that fluorohydrazone is the key intermediate to the tetrazine
from the gem‐difluoroalkene.
11 gem‐Difluoroalkenes can be synthesized readily from
corresponding aldehydes.: (a)Y. C. Zhao, W. Z. Huang, L. G.
Zhu and J. B. Hu, Org Lett, 2010, 12, 1444‐1447; (b) J. Zheng,
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Silverstein, Tetrahedron Lett., 1964, 1461‐1461. For selected
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Ni and J. B. Hu, Chem. Soc. Rev., 2016, 45, 5441‐5454.
13 CCDC 1506226 (3b) and 1506227(5c) contain the
crystallographic data for this paper.
14 Poducts with one Benzyloxy or nitro group are more polar
than other products without these two groups.
15 F. A. Davis, J. P. McCauley and J. M. E. Harakal, J. Org. Chem.,
1984, 1467‐1469.
16 For the synthesis of fluorohydrazones with aryl or alkyl group
on the nitrogen: R. Guo, Z. Zhang, F. Shi and P. Tang, Org.
Lett., 2016, 18, 1008‐1011. And reference cited therein.
Acknowledgements
The work is financially supported by Natural Science
Foundation of China (21502076), Natural Science Foundation
of Jiangxi Province (20161BAB213068) and Education
Department of Jiangxi Province(GJJ150360).
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A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic condition has
been developed.