[3 + 3] Cycloaddition of azides with in situ formed azaoxyallyl cations to synthesize 1,2,3,4-Tetrazines

Article abstract of DOI:10.1021/acs.orglett.8b00280

A formal [3 + 3] cycloaddition reaction between azides and in situ formed azaoxyallyl cations has been realized. This reaction provided an efficient and practical pathway to synthesize 1,2,3,4-tetrazines in good yields under mild conditions. Biologically active molecules could also be well compatible, highlighting the potential value of this reaction.

Full text of DOI:10.1021/acs.orglett.8b00280

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
[3 + 3] Cycloaddition of Azides with in Situ Formed Azaoxyallyl
Cations To Synthesize 1,2,3,4-Tetrazines
Xiaoying Xu,† Kaifan Zhang,† Panpan Li, Hequan Yao,* and Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A formal [3 + 3] cycloaddition reaction between azides and in situ formed azaoxyallyl cations has been realized.
This reaction provided an efficient and practical pathway to synthesize 1,2,3,4-tetrazines in good yields under mild conditions.
Biologically active molecules could also be well compatible, highlighting the potential value of this reaction.
Scheme 1. Synthesis of Heterocycles Bearing Contiguous
Multi-Nitrogen Atoms from Azides
eterocycles containing contiguous multinitrogen atoms are
Hcrucial motifs featured in a variety of natural products,
drugs, and biologically active molecules.1 Moreover, they could
serve as pivotal intermediates or building blocks in biochemistry
and materials chemistry.2 Thus, development of efficient
methods to achieve such heterocycles has attracted considerable
attention over the past decades. Azides, as a class of significant
nitrogen source, have been utilized to construct these frame-
works.3 Since the seminal discovery of the Huisgen reaction,4 the
transition-metal-catalyzed azide−alkyne click reaction (CuAAC,5
RuAAC,6 AgAAC,7 IrAAC,8 NiAAC,9 RhAAC10) and organo-
catalytic [3 + 2] cycloaddition11 of azides with in situ generated
enamines, enolates, zwitterions, and acyl azoliums were applied
to produce triazoles (Scheme 1, A). Moreover, triazines could be
prepared through [3 + 3] cycloaddition reactions of azides with
enynones/enynals and cyclopropanes (Scheme 1, B).12 Cyclo-
addition of azides with nitriles, alkynes, aldehyde hydrazones, and
amides was developed to gain tetrazoles (Scheme 1, C).13 1,2,3,4-
Tetrazines with NNNN linkages were demonstrated to possess a
wide spectrum of biological activities such as anticancer and
antimicrobial properties.14 However, methods to synthesize such
skeletons from azides have been rarely reported and generally
suffer from operational inconvenience, harsh reaction conditions,
and narrow substrate scope (Scheme 1, D).15 Therefore,
developing novel and practical methods to construct 1,2,3,4-
tetrazines and analogues from simple starting materials under
mild conditions is highly desirable.
property of in situ formed azaoxyallyl cations and constructing
functional N-containing heterocycles, herein we present our
latest work on the [3 + 3] cycloaddition reaction between azides
Cycloaddition reactions with in situ formed azaoxyallyl cations,
pioneered by Jeffrey,16 allowed the straightforward assembly of
nitrogen heterocycles.17 In this regard, wepreviously realized [3+
2]18 and [3 + 3]19 cycloaddition reactions to synthesize
oxazolidin-4-ones and tetrahydro-β-carbolinones with high
efficiency. With our continuing interest in exploring the reaction
Received: January 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b,c
entry
base
solvent
time (h)
yield (%)
1
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
KHCO3
NaOH
CH3CN
DCM
DMF
TFE
12
12
12
12
12
2
nr
nr
2
3
nr
Figure 1. X-ray structure of product 3da.
4
22
20
81
67
79
35
10
43
73
85
5
TFP
Scheme 3. Substrate Scope of Azides with Biologically Active
6
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
a,b
Molecules
7
2
8
2
9
2
10
11
12
Et3N
2
DIPEA
DMAP
Na2CO3
2
2
d
13
2
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), base (2.0
b
equiv) in solvent (1.0 mL) for 2 h at room temperature. Isolated
yields. nr = no reaction. 1.2 equiv of 2a was used.
c
d
a,b
Scheme 2. Substrate Scope of Azides
a
Reaction conditions: 1 (0.25 mmol), 2a (0.3 mmol), Na2CO3 (0.5
b
mmol) in HFIP (1.0 mL) for 2 h at room temperature. Isolated
yields. 0 °C for 10 h.
c
and 2,2,3,3-tetrafluoro-1-propanol (TFP) as the solvents, and the
desired product 3aa was obtained in 22% and 20% yields (Table
1, entries 4 and 5). The yield of 3aa could be increased to 81%
when hexafluoroisopropanol (HFIP) was employed (Table 1,
entry 6). Na2CO3 gave the best results during the base test
experiments (Table 1, entries 6−12). As shown in entry 13, the
yield could be further improved to 85% by slightly increasing the
loading amount of 2a to 1.2 equiv.
With the optimized reaction conditions in hand, we then tested
the substrate scope of azides 1. As shown in Scheme 2, products
3ba−da with methyl and halogen groups at the para-position of
benzene ring were obtained in 79−88% yields. X-ray
crystallography of 3da unambiguously determined its config-
uration as shown in Figure 1. Steric hindrance did not affect the
reactivity (3ea and 3fa). A functional group such as Bpin was
highly compatible and gave 3ga in 62% yield. 1-Naphthyl azide
functioned well and provided 3ha in 90% yield. Satisfactorily,
products 3ia with an acyl group, 3ja and 3ka with ester groups,
3la with a maleimide group, and 3ma with a 4-methylbenzene-
sulfonamide group were all prepared in good yields. When
secondary azide 1n was tested, 3na was obtained in 69% yield.
a
Reaction conditions: 1 (0.25 mmol), 2a (0.3 mmol), Na2CO3 (0.5
b
mmol) in HFIP (1.0 mL) for 2 h at room temperature. Isolated
yields. 0 °C for 10 h.
c
and in situ formed azaoxyallyl cations to synthesize 1,2,3,4-
tetrazines (Scheme 1).
At the outset of our study, we chose (azidomethyl)benzene 1a
and N-(benzyloxy)-2-bromo-2-methylpropanamide 2a as model
substrates to optimize the reaction conditions. During initial
screening, the choice of CH3CN, DCM, or DMF as the solvent
gave no product in the presence of Na2CO3 (Table 1, entries 1−
3). Considering that fluorinated solvents could stabilize the
azaoxyallyl cation,17a we employed 2,2,2-trifluoroethanol (TFE)
B
DOI: 10.1021/acs.orglett.8b00280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
amates (Table 2). When the benzyl group was replaced with
methyl, ethyl, and tert-butyl groups (2b−d), the corresponding
products 3ab−ad were realized in 71−82% yields. Cyclohexyl-
substituted haloamide 2e delivered 3ae in 56% yield. When α-
halohydroxamate with a monophenyl group was tested, 3af was
obtained in low yield with indefinable side reaction. Unfortu-
nately, α-halohydroxamates bearing a monomethyl group
rendered no product, probably due to the unstable azaoxyallyl
cation intermediate. Interestingly, subjecting α-halohydroxamate
containing vitamin E (2h) to the reaction conditions provided
3ah in 76% yield.
Table 2. Substrate Scope of α-Halohydroxamates
To display the practicality and potential value of this novel [3 +
3] cycloaddition reaction, further studies were attempted as
shown in Scheme 4. The reaction of 1q with 2a could be
Scheme 4. Further Study and Transformation of 1,2,3,4-
Tetrazines
conducted on a gram scale without significant erosion in yield
(3qa, 1.47g, 80% yield). Catalytic hydrogenation of 3ma in
methanol at room temperature afforded the N−O bond cleavage
product 4ma in 58% yield. Interestingly, the loss of dinitrogen
product 5ma could be formed in moderate yield by SmI2-
mediated reduction reaction.
In summary, we have developed a formal [3 + 3] cycloaddition
reaction between azides and in situ formed azaoxyallyl cations.
This method provides an efficient and practical pathway to
synthesize 1,2,3,4-tetrazines in good to excellent yields under
mild conditions, exhibiting good functional group tolerance and
gram-scale ability. Notably, a series of biologically important
molecules could be well compatible with this procedure,
highlighting the potential value of this reaction. Further related
studies utilizing the in situ generated azaoxyallyl cations in the
construction of natural products and pharmaceutical molecules
are currently underway in our laboratory.
a
Reaction conditions: 1a (0.25 mmol), 2 (0.3 mmol), Na2CO3 (0.5
b
mmol) in HFIP (1.0 mL) for 2 h at room temperature. Isolated
yields.
Product 3oa with two1,2,3,4-tetrazines was achieved in 86% yield
bearing lower temperature and longer reaction time.
To demonstrate the potential generality of this innovative
cycloaddition reaction, we then further expanded the substrate
scope of azides with natural products and drug molecules. As
shown in Scheme 3, azides with coumarin and amino acid
moieties provided 3pa and 3qa in good yields. Lithocholic acid, as
the simplest prototype of the bile acids, could successfully
transformed to 3ra in 80% yield. As a nonsteroidal anti-
inflammatory drug, celecoxib isused totreat pain or inflammation
caused by arthritis, ankylosing spondylitis, and menstrual pain.20
Strikingly, compound 3sa with both celecoxib and 1,2,3,4-
tetrazine frameworks could be efficiently realized in 87% yield.
The vitamin E derivative 1t underwent cycloaddition with 2a
smoothly to deliver 3ta in 77% yield. Given the importance of the
components of cell membranes, we were pleased to find that
cholesterol bearing azide readily participated in this reaction,
offering 3ua in 56% yield. The cyclization of zidovudine (AZT), a
reverse transcriptase inhibitor used to treat HIV, delivered
tetrazine 3va in 41% yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00280.
1H and 13C NMR spectra for all new compounds (PDF)
Accession Codes
After carefully checking the substrate scope of azides 1, we then
turned our attention to the substrate scope of α-halohydrox-
CCDC 1585564 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
C
DOI: 10.1021/acs.orglett.8b00280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hyao@cpu.edu.cn; cpuhyao@126.com.
*E-mail: ajlin@cpu.edu.cn.
ORCID
Hequan Yao: 0000-0003-4865-820X
Aijun Lin: 0000-0001-5786-4537
Author Contributions
†X.X. and K.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
́
Gonzalez, L.; Maulide, N. Org. Lett. 2017, 19, 2662. (g) Gaydou, M.;
ACKNOWLEDGMENTS
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Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC21572272) is
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