Ambient benzotriazole ring opening through intermolecular radical addition to vinyltriazole

Article abstract of DOI:10.1021/acs.orglett.5b00156

Radical addition to vinyltriazole was developed as a new approach to achieve 1,2,3-triazole ring opening under mild conditions. Through reagent control, excellent chemoselectivity was achieved, giving either nitrile under basic conditions or quinoxaline under neutral conditions. Reactivities made this method an attractive new reaction mode.

Full text of DOI:10.1021/acs.orglett.5b00156

Letter
pubs.acs.org/OrgLett
Ambient Benzotriazole Ring Opening through Intermolecular Radical
Addition to Vinyltriazole
Yijin Su, Jeffrey L. Petersen, Tesia L. Gregg, and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
S
* Supporting Information
ABSTRACT: Radical addition to vinyltriazole was developed
as a new approach to achieve 1,2,3-triazole ring opening under
mild conditions. Through reagent control, excellent chemo-
selectivity was achieved, giving either nitrile under basic
conditions or quinoxaline under neutral conditions. Reac-
tivities made this method an attractive new reaction mode.
(BTA) derivatives are not valid substrates because they form
iscovery of copper- and ruthenium-catalyzed azide−alkyne
Dcycloaddition has made 1,2,3-triazole (TA) one of the diazonium salt instead of diazo.5 Thus, few examples have been
1
reported using BTA derivatives to conduct triazole ring-opening
chemistry. An alternative TA ring-opening approach is the radical
reaction shown in Scheme 1B. Compared to the Dimroth
rearrangement, an electron-withdrawing group is not required in
this radical process, and both 2-triazolyl radical A and phenyl
radical B are attractive intermediates with potentially interesting
reactivity. However, due to the complex reaction nature (vide
infra), there are very few studies reported regarding the radical
reactivity moiety.6 Herein, we report the first example of
intermolecular azide radical addition to vinyltriazole and a
sequential triazole ring-opening process. Imine nitrile and
quinoxaline were prepared in good yields with excellent
chemoselectivity, which further enriched the versatile reactivity
of triazole in organic synthesis.
During the last several years, our group has studied the
coordination ability of TA toward transition metal cations.7 To
access different functional groups, we have developed new
syntheses of various triazole derivatives.8 One example was the
vinyltriazole through gold-catalyzed TA addition to alkyne
(Scheme 2).9
most important heterocycles in chemical, material, and biological
research during the past decade.2 Recently, studies regarding the
chemical and physical properties of this heterocycle have gained
more attention because of progress in using TA as a ligand or as a
building block in complex molecule synthesis. One particularly
interesting area is the “ring opening” through extrusion of
nitrogen gas for the preparation of complex N-heterocyclic
compounds.
As shown in Scheme 1A, it is known that electron-withdrawing
group activated TA can undergo Dimroth rearrangement3 to give
the ring-opening diazoimine intermediate. On the basis of this
unique reactivity, Fokin and others developed a series of new
transformations through dirhodium-catalyzed diazo activation.4
Those studies are highly attractive because triazole compounds
can act as an alternative source of “diazo” synthon. Benzotriazole
Scheme 1. Triazole Ring Opening Synthesis
Our interest in developing a radical-promoted triazole ring
opening was initiated from the “failed” vinyltriazole polymer-
ization. As shown in Scheme 2, in our attempt to form triazole
copolymer, no polymerization occurred under various radical
conditions. Even “worse”, polymerization of styrene was also
shut down with the presence of only 5% vinyltriazole 1a. This
result suggested that vinyltriazole might quench radicals, likely
through the formation of triazoyl radical A′ (Scheme 2). Notably,
although this new radical addition approach is attractive, the
existence of multiple reaction paths is the main challenge and
prevents the application of this strategy from any practical
synthesis. To explore the reactivity of the triazoyl radical, we
conducted reactions of 1 with various radical precursors using
cerium ammonium nitrate as the oxidant. Interestingly, as shown
Received: January 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00156
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Organic Letters
Letter
Scheme 2. Triazole Opening toward N-Heterocycle Synthesis
Figure 2. Intermolecular radical addition for TA ring opening. Standard
conditions: 1a (0.2 mmol), PhI(OAc)2 (0.3 mmol) and solvent were
mixed followed by the addition of NaN3 (0.8 mmol). NMR yields.
Screening of reaction scope is shown in Figure 3. This reaction
worked well with α-aromatic-substituted vinyltriazole, including
in Figure 1, these radical precursors (NaSO2CF3, NaSO2Tol,
NaSCN, NaBr, NaN3, and PhNHNH2) provided products 3a−
Figure 1. CAN-mediated radical addition to vinyltriazole. Standard
conditions: 1 (0.2 mmol), CAN (0.44 mmol, and DMSO (4 mL) were
mixed followed by the addition of radical precursor (0.3 mmol). Isolated
yields. aNMR yield.
Figure 3. Substrate scope of nitrile 6. Standard conditions: 1 (0.2
mmol), PhI(OAc)2 (0.3 mmol) and DMSO (6 mL) were added,
followed by NaN3 (0.8 mmol). Isolated yields. 1i was a mixture of 5-Cl
and 6-Cl isomers. 6i was same mixture of chloride isomers (1:1). Both
isomers could not be isolated by column chromatography. aNaN3 10.0
equiv was used.
3f with good isolated yields. These results are exciting because
they confirmed the feasibility of the proposed radical addition to
vinyltriazole as a potential new reaction path under mild
conditions. Some challenging substrates, such as the less reactive
aliphatic vinyltriazole, could give the desired product 3g in 76%
yield, which greatly highlighted the advantage of this new
approach.
tolerability of substituent groups with different electronic nature
(6a−6h). The structure of 6d was first confirmed by NMR and
later unequivocally established by X-ray crystallography. When
an electron-donating group was introduced (6b and 6d), more
NaN3 was needed to improve the yield of nitrile formation.
Aliphatic-substituted vinyltriazole gave complex reaction mix-
tures, likely caused by the electron-donating alkyne group and
the potential elimination on the side chain. Finally, natural
product derivative 6j was obtained in 72% yield, which indicated
a reasonable substrate scope, demonstrating the generality of this
new reaction path. We then moved our attention to the
formation of the metal-free denitrogenative transannulation
product, quinoxaline 7, which proceeded through an even more
challenging azide radical cyclization path.
To better monitor the reaction by NMR, para-t-Bu-phenyl-
substituted vinyltriazole 1b and the easily handled TMSN3 were
used. To our surprise, metal-free denitrogenative transannulation
product13 quinoxaline 7b was obtained as the major product (in
CDCl3) (nitrile 6b, <5%), though with low yield (33%, Table 1,
entry 2). Unfortunately, the addition of Brønsted acid (entry 3)
or Lewis acid (entry 4) gave the proposed bis-azide 2b as the
major product.14 Solvent screening confirmed DMSO as the
optimal choice (entries 5−7). Finally, diluting the mixture to
0.01 M (suppressing undesired intermolecular pathways) gave
The recovery of BTA in these reactions, however, confirmed
that the radical-promoted triazole ring opening did not occur. It
is possible that the radical intermediate A′ was oxidized by CAN
(to carbon cation) prior to TA ring opening. Thus, milder
oxidants, such as hypervalent iodine compounds,10 were used to
react with 1. Meanwhile, NaN3 was selected because an azide
radical can be formed easily in the presence of PhI(OAc)2 and the
newly formed organic azide can be an effective radical trap.11
As shown in Figure 2, nitrile12 6a and quinoxaline 7a were
determined as the two major products. Notably, complete
consumption of vinyltriazole was observed in all cases. Better
yields were obtained with more polar dimethylsulfoxide
(DMSO) as the solvent. It is possible that the solubility of
NaN3 accelerated the nitrile formation compared to the other
reaction pathways. Finally, under diluted (0.033 M) conditions,
product 6a was isolated in 85% yield. This result was exciting as it
gave the first example of radical addition for TA ring opening
under mild conditions. Interestingly, under these reaction
conditions, both quinoline 4 and indoline 5 were not observed.
B
DOI: 10.1021/acs.orglett.5b00156
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Organic Letters
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a
The α,β-disubstituted vinyltriazoles (synthesized from TA
addition to an internal alkyne) could also proceed smoothly
through this transformation (7l), though more azide was
required due to the steric effect. The n-butyl-substituted
vinyltriazole gave 7m as the only isolatable product, though at
low yield (38%), likely due to the rapid oligomerization side
reactions. More bulky aliphatic-substituted vinyltriazoles gave
significantly improved results (7n,o). Other functional groups,
including hydroxyl, ether, and TMS, were all tolerated in this
system (7p−r), highlighting the mild conditions of this
transformation. Substrate with a substituent group on BTA,
such as 5-chlorobenzotriazole, was still suitable and provided the
corresponding product 7i in 75% yield. Finally, natural product
derivative 7j was obtained in 72% yield.15
Table 1. Screening of Conditions
A plausible reaction mechanism is proposed in Scheme 3. The
formation of quinoxaline 7 under neutral conditions was rather
Scheme 3. Proposed Mechanism: Chemoselective TA
Opening
a
Standard conditions: 1b (0.2 mmol), PhI(OAc)2 (0.3 mmol), and
DMSO (20 mL) were mixed, then TMSN3 (0.8 mmol) was added.
b
NMR yields.
the desired product 7b with a 75% yield. Further dilution to 0.005
M resulted in lower conversion (85%) due to the slower reaction
rate (relative to radical formation and quenching). Using a higher
temperature (60 °C, entry 11) did not help the overall
conversion due to the rapid radical quenching at elevated
temperature. With the optimal conditions, the reaction scope was
evaluated and summarized in Figure 4.
In general, good yields were observed, allowing this strategy to
be a viable alternative synthesis for substituted quinoxaline under
mild conditions. A wide scope of functional groups on both
aromatic and aliphatic vinyltriazole was suitable for this reaction.
straightforward: radical addition to azide to form intermediate A.
In contrast, the path to nitrile was less clear. First, the radical-
promoted triazole ring opening followed by the 1,5-H shift of
intermediate B (path A) looks very reasonable. However, from
the experimental results, the basicity of NaN3 is likely the
determining factor for the nitrile formation.16 Thus, path A is
unlikely due to the lack of involvement of base in the rate-
determining step. Moreover, bis-azide 2 was observed as the
major byproduct, which suggested that the 2-triazolyl radical has
reasonably good stability. Thus, base-mediated azide denitroge-
nation followed by radical-promoted triazole ring opening (path
B) is more consistent with the experimental observation.
In summary, we report herein the first example of
intermolecular radical addition to vinyltriazole as an alternative
approach for triazole ring opening toward the synthesis of
quinoxaline and imino nitrile. Without the triazole ring opening,
a wide range of α-substituted ketones was obtained efficiently.
The application of vinyltriazole as a radical trap provides a new
approach to introduce the diversity of triazole activation under
mild conditions. Applications of this radical-mediated triazole
ring-opening strategy for other complex molecular syntheses are
currently ongoing in our laboratory.
Figure 4. Substrate scope of quinoxaline 7. Standard conditions same as
Table 1. Isolated yields. 1i was a mixture of 5-Cl and 6-Cl isomers. 7i was
same mixture of chloride isomers (1:1). Both isomers could not be
isolated by column chromatography. aPhI(OAc)2 (2.0 equiv) and
TMSN3 (4.0 equiv) were used. bTwo milliliters of DMSO was used as
solvent.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
DOI: 10.1021/acs.orglett.5b00156
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Katritzky, A. R.; Yang, B. J. Org. Chem. 1998, 63, 1467. (b) Kim,
T.; Kim, K. Tetrahedron Lett. 2010, 51, 868. (c) Katritzky, A. R.; Du, W.;
Matskawa, Y.; Ghiviriga, I.; Denisenko, S. N. J. Heterocycl. Chem. 1999,
36, 927.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiaodong.shi@mail.wvu.edu.
(7) (a) Liao, W.; Chen, Y.; Duan, H.; Sengupta, S.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. J. Am. Chem. Soc. 2009, 131, 12100. (b) Xi, Y.;
Dong, B.; McClain, E. J.; Wang, Q.; Gregg, T. L.; Akhmedov, N. G.;
Petersen, J. L.; Shi, X. Angew. Chem., Int. Ed. 2014, 53, 4657. (c) Wang,
Q.; Motika, S. E.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Angew. Chem.,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NSF (CHE-1362057, CHE-1228336) for financial
support.
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