One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines

Article abstract of DOI:10.1021/acs.orglett.7b00101

A new, three-step, telescoped reaction sequence for the regioselective conversion of N-tosyl hydrazones and aziridines to 3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-triazines is described. The process involves an efficient nucleophilic ring opening of the aziridine, giving access to a wide range of aminohydrazones, isolated with excellent yields. A “one-pot” procedure, combining the ring opening with a cyclization and an oxidation step, allows the preparation of diversified triazines in good yields.

Full text of DOI:10.1021/acs.orglett.7b00101

Letter
pubs.acs.org/OrgLett
One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of
Aziridines with N‑Tosylhydrazones: Access to 1,2,4-Triazines
Lorene Crespin,*,† Lorenzo Biancalana,† Tobias Morack,† David C. Blakemore,‡ and Steven V. Ley†
̀
†Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
‡Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A new, three-step, telescoped reaction sequence
for the regioselective conversion of N-tosyl hydrazones and
aziridines to 3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-
triazines is described. The process involves an efficient
nucleophilic ring opening of the aziridine, giving access to a
wide range of aminohydrazones, isolated with excellent yields.
A “one-pot” procedure, combining the ring opening with a
cyclization and an oxidation step, allows the preparation of
diversified triazines in good yields.
Scheme 1. Pathways for the Preparation of 1,2,4-Triazines
1,2,4-Triazine derivatives represent an important class of
nitrogen heterocycles: they possess a wide range of
applications from ligands for transition-metal complexes1 to
agrochemistry2 and medicine. They have been shown to
exhibit a broad spectrum of biological activities with anti-
inflammatory,3 antitumor,4 antibacterial,5 anticonvulsant,6 and
antiviral7 properties being reported. They are also widely used
as key synthetic building blocks for the preparation of
heterocyclic systems via hetero-Diels−Alder cycloadditions.8
To date, the main methods for the preparation of 1,2,4-
triazines include two types of bond formation: the construction
of the N1−C6/N4−C5 bonds between 1,2-diketones and
amidrazones leads to 3,5-disubstituted or 3,5,6-trisubstituted
1,2,4-triazines9 while the reaction between 2 equiv of acid
hydrazides and β-halogeno ketones forms 3,6-disubstituted
triazines.10 These disubstituted compounds are also accessible
via the formation of the N2−C3/N4−C3 bonds from the
addition of an oxime hydrazone and an aldehyde.11 More
recently, other methods have emerged using diazo compounds
or domino annulation reactions.12 Despite the formation of
triazines being well studied in recent decades, new and
versatile strategies to construct the 1,2,4-triazine core are still
of high interest for both fragment-based drug discovery and
synthetic chemistry programs. The synthesis of trisubstituted
triazines bearing different substituents on the C5- and C6-
positions still remains problematic with the current use of
unsymmetrical diketones often producing a mixture of
regioisomers.9d,g Moreover, an analysis of internally synthe-
sized compounds in the Pfizer file showed that only 17% of
triazines made have different substituents on the C5- and C6-
positions, reinforcing the challenge in accessing this sub-
stitution pattern.
approach would allow the formation of 3,6-disubstituted and
3,5,6-trisubstituted triazines via a three-step, “one-pot”
procedure, starting with a Lewis acid catalyzed N-alkylation
of N-tosyl hydrazones 1 with aziridines 2. The cyclization of
the intermediate 3 followed by a double elimination of the
tosyl groups would afford the dihydrotriazine 4, which upon
oxidation would form the corresponding 1,2,4-triazine 5
(Scheme 1).
In light of the above comments, we report a conceptually
new pathway using a double disconnection N1−C6/N4−C3 for
the preparation of 1,2,4-triazines. It was envisaged that this
Received: January 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00101
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Although an aminohydrazone close to 3 has been observed
once as an intermediate in an aerobic copper-catalyzed tandem
reaction involving tosyl hydrazones and aziridines by the Wang
group,13 to the best of our knowledge, acid-catalyzed N-
alkylation of N-tosyl hydrazones with aziridines has never been
reported previously.14 This observation encouraged us to
explore the ring opening of aziridines more closely to find
suitable conditions to prepare aminohydrazones 3, a class of
novel molecules whose chemistry remains mostly unknown.
The optimization process was attempted with two readily
accessible compounds: the phenyl tosyl hydrazone 1a and the
phenyl tosylaziridine 2a (Table 1). Mixing of the two reactants
Scheme 2. Scope of the Ring-Opening Reaction
Table 1. Optimization of the Ring Opening of Aziridine 1a
with N-Tosylhydrazone 2a
a
aziridine
(equiv)
BF3·OEt2
(equiv)
reaction time
(h)
yield
(%)
entry
solvent
b
1
2
3
4
5
6
7
1.5
1.5
1.5
1.5
1.5
1.5
1.2
CH2Cl2
CH2Cl2
CH2Cl2
THF
24
24
1
0
1.5
0.2
0.2
0.2
0.2
0.2
37
90
c
1
d
toluene
Et2O
1
70
d
1
40
CH2Cl2
1
91
a
b
Isolated yields reported unless stated otherwise. No reaction.
c
d
Polymerization was observed. Percent conversion of starting
material.
in CH2Cl2 resulted in clean recovery of starting materials only
(Table 1, entry 1). A screen of Lewis acids revealed that BF3·
OEt2 was the most suitable, and in the presence of a
stoichiometric amount, the reaction led to 37% of the
intermediate 3a after 24 h, with a significant amount of
decomposition in the crude being observed (Table 1, entry 2).
By lowering the reaction time to 1 h and using a catalytic
amount of BF3·OEt2, a significant increase in yield to 90% was
noted (Table 1, entry 3). A solvent screen showed that
CH2Cl2 was the solvent of choice as the reaction proceeded
with incomplete conversion in both toluene and Et2O (Table
1, entries 5 and 6), while THF afforded polymerization (Table
1, entry 4). Finally, it was found that reducing the amount of
aziridine to 1.2 equiv resulted in a 91% yield of the desired
product 3a (Table 1, entry 7).
Under the optimized conditions, we next investigated the
scope of the reaction (Scheme 2). A wide range of tosyl
hydrazones 1 reacted with phenylaziridine and led to the
amino hydrazones 3 in excellent yields. Hydrazones bearing
both electron-donating and electron-withdrawing aryl sub-
stituents (3a−i) were tolerated, and steric hindrance at the
ortho-position led to only a small decrease in yield (3j).
Electron-rich heteroaryls such as thiophene or furan were also
suitable substrates (3l,m). The only limitation found was the
incompatibility of the Lewis acid with electron-rich amines: N-
methylindole or pyridine hydrazones were unreactive toward
the reaction conditions. This restriction could be partially
overturned by the use of an electron-withdrawing functionality
on the nitrogen atom: acetylindole hydrazone gave 3k in
excellent yield. Alkyl hydrazones also reacted under the
a
Conditions: 1 (0.2 mmol), 2 (1.2 equiv), BF3·OEt2 (0.2 equiv),
b
CH2Cl2 (0.2 M), rt, 1−2 h. Reaction performed with BF3·THF
instead of BF3·OEt2. Product unstable to column chromatography,
yield from the crude. dr = 50:50. dr = 78:22. Product 3x observed
by mass, unstable to purification or any other analysis.
c
d
e
f
standard conditions with moderate yields (3n,o). Replacement
of BF3·OEt2 with the safer reagent BF3·THF was also possible,
resulting in similar yields.15 Further investigations using
various N-tosylaziridines 2 were then carried out: monosub-
stituted aziridines proceeded very smoothly (3p−s), while
disubstituted aziridines led to a mixture of diastereoisomers,
isolated in excellent combined yields, with a single regioisomer
being observed (3t−w). Moreover, the aziridine presenting a
complex steroid structure was found to be a suitable partner,
leading to 3y in 84% yield. The regioselectivity of the ring-
opening of the aziridine was confirmed by X-ray crystallog-
raphy for product 3b (see the SI).16
With these excellent initial results in hand, a three step,
“one-pot” procedure was attempted. The second step consisted
of the cyclization of the aminohydrazones 3 and the
elimination of both tosyl groups, requiring an excess of a
base. This step was found to be very dependent on both
solvent and the nature of the base, with the reaction occurring
only in toluene at 110 °C in the presence of cesium carbonate.
B
DOI: 10.1021/acs.orglett.7b00101
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the objective of avoiding the isolation of the
dihydrotriazines 4, activated manganese dioxide was chosen
as the oxidant for its compatibility with the cyclization
conditions step and was used together with cesium carbonate
to afford directly the 1,2,4-triazines 5 after 3 h at 110 °C in
toluene in a sealed tube (see the SI for the full discussion of
the optimization).
With the optimized conditions established, a wide range of
3,6-disubstituted and 3,5,6-trisubstituted 1,2,4-triazines were
prepared with moderate to good yields (up to 66%) for the
telescoped process (Scheme 3). The reaction could be easily
the product 5o in only 8% yield. We were delighted that the
useful Bpin functionality was tolerated under the reaction
conditions (5i), allowing further elaboration of the product
through cross-coupling reactions.17 Heteroaryl hydrazones
gave the triazines in good yields, and in the case of the
indole, the acetyl nitrogen was deprotected in situ due to the
basic conditions of the reaction (5k−m). Monosubstituted
aziridines were also suitable partners to afford 1,2,4-triazines
5p−s. In particular, the sterically hindered mesityl susbtituent
was tolerated (5q). Moreover, the natural product-derived
triazine 5y was formed efficiently. Two fused triazines could
also be prepared (5t,u) and isolated in their oxidized form.
One of the benefits of the “one-pot” procedure was the
opportunity to synthesize triazines such as 5x whose
corresponding intermediate 3x was too unstable to be isolated.
Finally, although the formation of the trisubstituted triazines is
currently limited to alkyl groups on the C5-position (5v−x) in
low to moderate yields, this methodology offers access to
complex trisubstituted triazines as single regioisomers. There-
fore, our approach compares favorably with the methods using
1,2-diketones which lead to regioisomeric mixtures. The 3,5,6-
trisubstituted triazine scaffold can also be easily accessed via a
nucleophilic addition/oxidation process on the synthesized 3,6-
disubstituted triazines.18
a
Scheme 3. Scope for the Preparation of Triazines 5
Mechanistically, we believe that the aziridine is activated by
the Lewis acid and the hydrazone acts as a nucleophile to
effect the ring opening. This ring opening is known to occur
selectively via a C−N bond cleavage, and the nucleophile only
attacks at the benzylic position, leading to the single observed
regioisomer 3.19 Next, compound 3 is deprotonated, and
thermal activation allows the closure the 6-membered ring,
followed by the successive elimination of the two tosyl groups
to form the dihydrotriazine 4, for which the structure is
confirmed spectroscopically (see the SI). The intermediate
from the monoelimination of the tosyl group can also be
observed when the reaction is performed at 80 °C, where no
second elimination occurs. To end the sequence, oxidation of
the dihydrotriazine with MnO2 affords the desired 1,2,4-
triazines (Scheme 4).
Scheme 4. Plausible Mechanism for the Synthesis of
Triazines
a
Conditions: 1) 1 (0.5 mmol), 2 (1.2 equiv), BF3·OEt2 (0.2 equiv),
CH2Cl2 (0.2 M), rt, 1−2 h. 2) Cs2CO3 (3.5 equiv), MnO2 (12 equiv),
b
toluene (0.1 M), 110 °C, 3 h, sealed tube. Reaction carried out under
c
d
reflux in toluene instead of a sealed tube. 5 mmol scale. The BPin-
substituted triazine was oxidized to the corresponding alcohol before
e
f
isolation. Cs2CO3 (5 equiv), MnO2 (16 equiv). Overoxidation in situ
In conclusion, we have reported a new method to access the
1,2,4-triazine scaffold via a three-step, telescoped reaction
sequence using N-tosyl hydrazones and aziridines. This
approach represents a complementary alternative to well-
known procedures and affords the 3,6-disubstituted and 3,5,6-
trisubstituted 1,2,4-triazines in a regioselective manner. The
diverse library of triazines synthesized by this route generates
15 previously unknown structures as potentially useful
compounds for both medicinal and agrochemical applications.
by MnO2.
scaled (5 mmol) with no significant change in the yield (5h).
Electron-withdrawing, halogeno-substituted aryls and CF3
hydrazones led to the desired triazines in yields between
34% and 60%. Substrates with electron-donating substituted
aryls or sterically hindered hydrazones tended to react in a
lower yield (5f,j) while the unactivated hydrazone 1o formed
C
DOI: 10.1021/acs.orglett.7b00101
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(c) Fernan
́
dez Sainz, Y. F.; Raw, S. A.; Taylor, R. J. K. J. Org. Chem.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00101.
■
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Crystallographic data for 3b (CIF)
Experimental procedures, compound characterization
data, and NMR spectra for all compounds (PDF)
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(c) Neunhoeffer, H. In Comprehensive Heterocyclic Chemistry II;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lc667@cam.ac.uk.
ORCID
́
(f) Laphookhieo, S.; Jones, S.; Raw, S. A.; Fernandez Sainz, Y.;
Taylor, R. J. K. Tetrahedron Lett. 2006, 47, 3865. (g) Phucho, T.;
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Salimi, Z.; Hajinazari, S. RSC Adv. 2015, 5, 3665.
Lorene Crespin: 0000-0002-7491-7538
̀
Steven V. Ley: 0000-0002-7816-0042
(10) (a) Saraswathi, T. V.; Srinivasan, V. R. Tetrahedron Lett. 1971,
12, 2315. For recent examples, see: (b) Reference 9e. (c) Kidwai,
M.; Sapra, P.; Bushan, K. R.; Misra, P. Synth. Commun. 2001, 31,
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G. V.; Rusinov, V. L.; Chupakhin, O. N. Mendeleev Commun. 2013,
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(11) (a) See refs 9c, d and 10d. (b) Kopchuk, D. S.; Chepchugov,
N. V.; Kim, G. A.; Zyryanov, G. V.; Kovalev, I. S.; Rusinov, V. L.;
Chupakhin, O. N. Tetrahedron Lett. 2016, 57, 296.
(12) For other methods for the synthesis of 1,2,4-triazines, see: (a)
Reference 8e. (b) Lukin, A.; Vedekhina, T.; Tovpeko, D.; Zhurilo, N.;
Krasavin, M. RSC Adv. 2016, 6, 57956. (c) Tang, D.; Wang, J.; Wu,
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(13) Hong, D.; Lin, X.; Zhu, Y.; Lei, M.; Wang, Y. Org. Lett. 2009,
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(14) The acid-catalyzed N-alkylation of hydrazones has only been
reported in two publications in the presence of alcohol substrates:
(a) Reddy, C. R.; Jithender, E. Tetrahedron Lett. 2009, 50, 5633.
(b) Theerthagiri, P.; Lalitha, A. J. Iran. Chem. Soc. 2013, 10, 717.
(15) From a safety issue point of view, particularly during larger
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was possible with no significant drop of the yield.
Notes
The authors declare no competing financial interest.
Additional data related to this publication is available at the
University of Cambridge Institutional Data Repository
(https://doi.org/10.17863/CAM.7001).
ACKNOWLEDGMENTS
■
This work was supported by a postdoctoral fellowship from
Pfizer (L.C.) and EPSRC Grant Nos. EP/K009494/1 and EP/
M004120/1 (S.V.L.). We also thank Dr. Andrew D. Bond for
conducting X-ray crystallographic analysis.
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DOI: 10.1021/acs.orglett.7b00101
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