Reaction between Azidyl Radicals and Alkynes: A Straightforward Approach to NH-1,2,3-Triazoles

Article abstract of DOI:10.1002/chem.201504515

Reaction between nitrogen-centered radicals and unsaturated C-C bonds is an effective synthetic strategy for the construction of nitrogen-containing molecules. Although the reactions between nitrogen-centered radicals and alkenes have been studied extensively, their counterpart reactions with alkynes are extremely rare. Herein, the first example of reactions between azidyl radicals and alkynes is described. This reaction initiated an efficient cascade reaction involving inter-/intramolecular radical homolytic addition toward a C-C triple bond and a hydrogen-atom transfer step to offer a straightforward approach to NH-1,2,3-triazoles under mild reaction conditions. Both the internal and terminal alkynes work well for this transformation and some heterocyclic substituents on alkynes are compatible. This mechanistically distinct strategy overcomes the inherent limitations associated with azide anion chemistry and represents a rare example of reactions between a nitrogen-centered radicals and alkynes.

Full text of DOI:10.1002/chem.201504515

DOI: 10.1002/chem.201504515
Communication
&
Organic Synthesis
Reaction between Azidyl Radicals and Alkynes: A Straightforward
Approach to NH-1,2,3-Triazoles
Long Hu,[a] Christian Mück-Lichtenfeld,[b] Tao Wang,*[a] Guifeng He,[a] Meng Gao,[a] and
Junfeng Zhao*[a]
tionalization[6] of alkenes. In the sharp contrast, however, the
Abstract: Reaction between nitrogen-centered radicals
reaction between nitrogen-centered radicals and alkynes is ex-
and unsaturated CÀC bonds is an effective synthetic strat-
egy for the construction of nitrogen-containing molecules.
Although the reactions between nitrogen-centered radi-
cals and alkenes have been studied extensively, their
counterpart reactions with alkynes are extremely rare.
Herein, the first example of reactions between azidyl radi-
cals and alkynes is described. This reaction initiated an ef-
ficient cascade reaction involving inter-/intramolecular
radical homolytic addition toward a CÀC triple bond and
a hydrogen-atom transfer step to offer a straightforward
approach to NH-1,2,3-triazoles under mild reaction condi-
tions. Both the internal and terminal alkynes work well for
this transformation and some heterocyclic substituents on
alkynes are compatible. This mechanistically distinct strat-
egy overcomes the inherent limitations associated with
azide anion chemistry and represents a rare example of re-
actions between a nitrogen-centered radicals and alkynes.
tremely rare (Scheme 1).[7] This challenging situation is mainly
attributed to the lack of a suitable trapping handle to harness
the highly reactive and unstable b-N-substituted vinyl radical
for further transformations.[2b] Neale developed a useful syn-
thetic cascade reaction involving the addition of an aminium
radical to alkynes (Scheme 1a).[7a] Wille and Luning elaborately
designed a cascade reaction consisting of a N-centered radical
addition to alkyne/1,5- or 1,6-HAT/cycloaddition/oxidative ter-
mination to produce the bicyclic ketones (Scheme 1b).[7b,c] Very
recently, Zhang reported an elegant cascade reaction of an
alkyne initiated by a N-centered radical that originated from N-
fluorobenzene-sulfonimide (Scheme 1c).[7d] We herein disclose
the first reaction between azidyl radicals and alkynes involving
inter-/intramolecular radical homolytic addition and a subse-
quent hydrogen atom transfer (HAT), which finally afforded
a highly efficient approach to NH-1,2,3-triazoles (Scheme 1d).
NH-1,2,3-triazoles are of great importance as structural
motifs because they are not only widely found in pharmaceuti-
cals and materials,[8] but also can be used as valuable
Recent years have witnessed a renaissance of radical chemis-
try,[1] particularly, in the use of radical reactions for constructing
complex molecules in a highly efficient and atom-economic
manner with excellent regio- and stereoselectivities.[2] Among
these radicals, nitrogen(N)-centered radicals are of great impor-
tant because they offer straightforward strategies to synthesize
nitrogen-containing compounds, which are very important for
drug development and other fine chemicals.[2a] For example,
the Hofmann–Lçffler–Freytag reaction is a classical strategy for
remote sp3 CÀH amination employing a N-centered radical.[3]
Meanwhile, the homolytic addition of a N-centered radical to
the alkene CÀC double bond[4] has also been recognized as an
appealing synthetic strategy for hydroamination[5] and difunc-
intermediates for
a series of important transformations
(Scheme 2).[9] However, their potential applications are still far
less exploited than they could be due to the lack of a general
approach to their synthesis. Generally, the synthesis of NH-
1,2,3-triazoles is accomplished by deprotection of N1-substitut-
ed 1,2,3-triazoles[10] or cycloaddition of activated alkynes[11] and
alkenes.[12] Unfortunately, these strategies suffer from the use
of volatile and toxic hydrazoic acid or activated alkenes and al-
kynes with strong electron-withdrawing groups under harsh
reaction conditions. We reasoned that these limitations might
be overcome by employing radical strategies, which are gener-
ally less sensitive to the electronic effect.[1c] As shown in
Scheme 1d, the 1,2,3-triazole framework could be constructed
if the azide group of the b-azidovinyl radical, formed in situ
from the homolytic addition of an azidyl radical to an alkyne,
could trap the vicinal carbon-centered radical through the ter-
minal nitrogen atom (Ng)[13] in an intramolecular manner. NH-
1,2,3-triazoles could be obtained by a subsequent HAT step.
To verify the viability of our hypothesis, we tested various
azidyl radical sources with 1,2-diphenylethyne as the model
substrate. To our delight, NH-1,2,3-triazole 2a was indeed ob-
tained in 56% yield using the combination of TMSN3 and
PhI(OAc)2 as the azidyl radical source (Table 1, entry 1). The
yield of NH-1,2,3-triazole was significantly increased when the
azide donor was replaced by NaN3 (entry 2). Other oxidants,
[a] L. Hu, Prof. Dr. T. Wang, G. He, Dr. M. Gao, Prof. Dr. J. Zhao
National Research Center for Carbohydrate Synthesis
Key Laboratory of Chemical Biology, Jiangxi Province
College of Chemistry & Chemical Engineering
Jiangxi Normal University
99, Ziyang Road, Nanchang, Jiangxi, 330022 (P. R. China)
E-mail: Zhaojf@jxnu.edu.cn
wangtao@jxnu.edu.cn
[b] Dr. C. Mück-Lichtenfeld
Westfälische Wilhems-University
Corrensstrasse 40, 48149 Münster (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504515.
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phenyl ring generally offered lower yields than their
electron-neutral and -rich congeners (2a–i). This out-
come might be partially attributed to the electrophil-
ic nature of the azidyl radical.[5e] Alkynes bearing reac-
tive functional groups, such as -OH, -NR2, and -SBu,
which would be incompatible with conventional
strategies, were well tolerated (2w, 2x, 2ad, and
2ae). It is notable that aromatic heterocycles such as
pyridine and thiophene are also compatible (2q–
s and 2v). Alkynes containing a vicinal tertiary
carbon center could also be used as a valid substrate
(2x). More importantly, the bromo and silyl group
can also be tolerated, thereby allowing the possibility
for further functionalization (2r–u, and 2z–ac). Even
the reaction of a diyne proceeded smoothly to afford
the bis-NH-1,2,3-triazole in good yield (81%, 2u). Ter-
minal alkynes also worked well for this reaction (2af–
Scheme 1. Reactions between N-centered radicals and the C–C triple bond of alkynes.
Table 1. Optimization of the reaction conditions.[a]
Entry
Azide (equiv)
Oxidant (equiv)
Solvent
Yield [%]
1
2
3
4
5
6
7
8
TMSN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (1.5)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(CF3CO2)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (1)
PhI(OAc)2 (1)
MeCN
MeCN
MeCN
CHCl3
DCE
56
83
53
34
28
52
51
25
90
95
DCM
acetone
PhCH3
MeCN
MeCN
9
10
[a] Reaction conditions: 1,2-diphenylethyne (0.2 mmol), NaN3 and
PhI(OAc)2 in solvent (3.0 mL) was stirred at room temperature for 8 h
under nitrogen. DCM: dichloromethane, DCE: 1,2-dichloroethane.
Scheme 2. Representative synthetic applications of NH-1,2,3-triazoles as val-
uable reaction intermediates.
such as PhI(CF3CO2)2, PhIO, Mn(OAc)3, and TBHP, proved to be
less effective for this reaction (for details of reaction-condition
optimization, see the Supporting Information). Solvent was
found to have a remarkable influence on the reaction efficien-
cy and acetonitrile was identified as the optimal solvent (en-
tries 2–8). The loading of PhI(OAc)2 and NaN3 was also evaluat-
ed. The highest yield of up to 95% was obtained in the pres-
ence of 1 equivalent of PhI(OAc)2 and 1.5 equivalents of NaN3
(entry 10).
al). A similar trend with internal alkynes with respect to the
electronic effect was observed, as evidenced by the fact that
electron-rich terminal alkynes gave higher yields. Although ali-
phatic internal alkyne (2y) did not react under the optimized
reaction conditions, aromatic alkynes bearing one aliphatic
substituent reacted smoothly to afford the target NH-1,2,3-tria-
zole in good to excellent yields (2l–p, 2w, and 2x). In addition,
an aliphatic internal alkyne bearing a substituent such as a silyl
group that can stabilize the in situ formed vinyl radical also
worked well (2z–ac).
To gain insight into the reaction mechanism, a control ex-
periment with 2 equivalents of 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO) to probe whether radical species were involved
in the reaction was performed. The reaction was completely re-
tarded by TEMPO although no radical intermediate was
trapped (see the Supporting Information). Furthermore, an
electron paramagnetic resonance (EPR) experiment was con-
ducted. As shown in Figure 1a, a typical EPR signal was ob-
With the optimized reaction conditions in hand, we turned
our attention to the substrate scope of the reaction. A variety
of internal and terminal alkynes with different electronic prop-
erties were tested, and the results are shown in Scheme 3.
Unlike conventional strategies limited to electron-deficient
substrates, the electronic effects of alkynes have little influence
on this reaction. Both electron-donating and -withdrawing
groups were tolerated for 1,2-diphenylethyne derivatives (2a–
i). Substrates bearing electron-withdrawing groups on the
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served when NaN3 and PhI(OAc)2 were mixed in 3.0 mL CH3CN
at room temperature for 1 hour. The data analysis suggested
that an azidyl radical was generated and quickly trapped by
5,5-dimethyl-1-pyrroline-N-oxide (DMPO) to form a relatively
stable radical (DMPO-N3).[14] A new EPR signal was detected
after the addition of 1,2-diphenylethyne into the system (Fig-
ure 1b), indicating that the azidyl radical could react with 1,2-
diphenylethyne to form new radical species, albeit the struc-
ture of which could not be identified. These EPR experiments
indicated that an azidyl radical was formed through the oxida-
tion of NaN3 with PhI(OAc)2 as the oxidant. This azidyl radical
then initiated the cascade reaction of the alkyne and finally af-
forded the desired product.
Theoretically, both concerted and stepwise mechanisms are
reasonable for this “click reaction” between azidyl radical and
alkyne. A mechanistic DFT study of the reaction was conducted
to investigate the reaction mechanism. According to the DFT
calculation, the transition structure of the concerted azidyl rad-
ical addition to the triple bond could not be identified and
thus the concerted mechanism was unfavorable. A plausible
stepwise mechanism was proposed based on experimental
and theoretical calculation results (Scheme 4). An azidyl radical
Scheme 4. Proposed reaction mechanism.
is produced when NaN3 is treated with PhI(OAc)2.[15] Two path-
ways are possible for the trapping of the azidyl radical: ab-
stract a hydrogen atom to release hydrazoic acid (pathway I)
or homolytic addition to an alkyne to furnish the highly reac-
tive vinyl radical A. Premature termination of the vinyl radical
A by HAT will produce vinyl azide C, which was not detected
(pathway II). On the other hand, followed by an intramolecular
homolytic addition of the terminal (Ng) nitrogen atom of the
azide functional group, the in situ formed vinyl radical A trans-
forms (eventually through the initially formed s-radical) into
a new N-centered p-radical B, which undergoes subsequent
HAT to afford the final NH-1,2,3-triazole (pathway III). The
energy barrier between pathways I, II, and III and the observed
different reactivity of diaryl versus dialkyl alkynes was further
investigated in a DFT study using 1,2-diphenylethyne 1a (R=
Ph) and but-2-yne 1y’ (R=CH3) as model substrates (Figure 2).
The relative free energies were obtained by employing the
B2PLYP-D3//B3LYP-D3/def2-TZVP[16] level of theory. As shown
in Figure 2, the energy barriers of both pathways I and II are
higher than that of pathway III. The free energy of formation
Scheme 3. Scope of the radical cascade reaction. Reaction conditions: 1,2-di-
phenylethyne (0.2 mmol), NaN3 (0.3 mmol), PhI(OAc)2 (0.2 mmol), in CH3CN
(3.0 mL) was stirred at room temperature for 8 h under nitrogen. [a] Alkyne
(0.2 mmol), NaN3 (0.6 mmol), PhI(OAc)2 (0.4 mmol).
Figure 1. Electron paramagnetic resonance experiment.
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Figure 2. DFT-computed free energies of the reaction between the azidyl radical and alkynes. Bold: 1,2-diphenylethyne, hashed: but-2-yne.
of the vinyl radical intermediates 1a-A and 1y’-A along the
transition structures 1a-TSA and 1y’-TSA revealed a distinct
difference between the two alkynes: whereas 1a reacts exo-
thermically (À1.9 kcalmolÀ1), the dimethyl alkyne only forms
small amounts of 1y’-A under thermodynamic control (DG= +
1.7 kcalmolÀ1). In addition, the barrier towards ring closure
(1y’-TSB) is larger than the barrier of dissociation. In contrast,
the 1-phenyl-vinyl radical 1a-A undergoes (exothermic) forma-
tion of the triazolyl ring 1a-B faster than fragmentation occurs.
Both 1,2,3-triazolyl radicals 1a-B and 1y’-B are by over 30 kcal
molÀ1 more stable than the reactants, indicating the formation
of the delocalized radical as the driving force of the reaction.
Our DFT calculations demonstrated that both the activation
a broad range of viable substrates. The azide group plays two
important roles: inducing the formation and trapping of the
reactive vinyl radical. Both the homolytic addition of the azidyl
radical to alkynes and the subsequent intramolecular reaction
between the vinyl radical and azide functional group are un-
precedented. These features make this strategy not only theo-
retically important but also synthetically useful. It is foreseea-
ble that the results reported here will spur the application of
azidyl radical chemistry and shed light on the design of new
reactions between N-centered radicals and alkynes in the
future.
barrier and reaction free energy allow the 1,2,3-triazolyl radi- Acknowledgements
cals 1a-B and 1y’-B to abstract a hydrogen atom from CH3CN
to form the NH-1,2,3-triazole 2a (and 2y’, if the previous steps
would not disfavor this pathway). The free energy barrier of
19–21 kcalmolÀ1 is overcome under the experimental condi-
tions (room temperature), and the reaction is exothermic (9–
10 kcalmolÀ1). The origin of the hydrogen atom was further
confirmed by isotopic experiment. As expected, an ND-1,2,3-tri-
azole was obtained when the reaction was conducted in deu-
terated acetonitrile (for details, see the Supporting Informa-
tion).
This work is supported by the National Natural Science
Foundation of China (21462023, 21262018) and the Natural
Science Foundation of Jiangxi Province (20143ACB20007,
20133ACB20008). We thank Prof. A. Studer for valuable discus-
sions and suggestions.
Keywords: alkynes · azidyl radicals · cascade reactions ·
nitrogen · triazoles
In conclusion, we have successfully developed an oxidative
“click reaction” between a variety of alkynes and sodium azide.
This reaction not only offers an efficient and practical method
for the synthesis of NH-1,2,3-triazoles, but also illustrates
a novel reactivity of the azidyl radical, which initiated a cascade,
including inter-/intramolecular radical homolytic addition
toward alkynes and a HAT under mild reaction conditions. A
substituent group on the alkynes stabilizing the in situ formed
vinyl radical on the alkynes is crucial for this transformation.
Compared with the conventional ionic processes, in which the
substrate scope is limited to electron-deficient alkenes or al-
kynes, this radical-cascade protocol facilitates the use of
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Received: November 11, 2015
Published online on December 14, 2015
Chem. Eur. J. 2016, 22, 911 – 915
www.chemeurj.org
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