Lewis base catalyzed aerobic oxidative intermolecular azide-zwitterion cycloaddition

Article abstract of DOI:10.1002/anie.201408265

The discovery of a novel aerobic oxidative intermolecular azide-zwitterion reaction catalyzed by an organocatalyst is presented. It is demonstrated that the merger of the Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene and electrondeficient olefins generates reactive zwitterion intermediates, which readily participate in cycloaddition reactions with an array of azides, thus providing facile entry to fully or highly substituted 1,2,3-triazole frameworks. The reaction features an excellent substrate scope, and the products are obtained with high yields and excellent regioselectivities. It is demonstrated that some of these products can be transformed into pharmaceutically important agents. In addition to the experimental results, a detailed mechanistic survey is also provided, including MS studies rationalizing the origin of regioselective control.

Full text of DOI:10.1002/anie.201408265

Angewandte
Chemie
DOI: 10.1002/anie.201408265
Organocatalysis
Lewis Base Catalyzed Aerobic Oxidative Intermolecular Azide–
Zwitterion Cycloaddition**
Wenjun Li and Jian Wang*
Abstract: The discovery of a novel aerobic oxidative inter-
molecular azide–zwitterion reaction catalyzed by an organo-
catalyst is presented. It is demonstrated that the merger of the
Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene and electron-
deficient olefins generates reactive zwitterion intermediates,
which readily participate in cycloaddition reactions with an
array of azides, thus providing facile entry to fully or highly
substituted 1,2,3-triazole frameworks. The reaction features an
excellent substrate scope, and the products are obtained with
high yields and excellent regioselectivities. It is demonstrated
that some of these products can be transformed into pharma-
ceutically important agents. In addition to the experimental
results, a detailed mechanistic survey is also provided, includ-
ing MS studies rationalizing the origin of regioselective control.
T
he 1,2,3-triazole core is a privileged scaffold which is
featured in a vast number of bioactive molecules.[1] They have
exhibited considerable biological and pharmaceutical activ-
ities.[1–2] Notably, they have been disclosed as attractive
connections in biological systems because they are stable to
metabolic degradation and capable of hydrogen bonding to
biomolecular targets.[3] Moreover, the application of triazole
chemistry is not only limited to drug discovery but also largely
extended to numerous other scientific fields,[4] such as
bioconjugation,[5] material science,[6] and polymer chemistry.[7]
Although the ubiquitous 1,2,3-triazoles have been known
for over several decades, they have not been utilized as widely
as other members of the azole family.[8] The conspicuous lack
of the literature reports is likely due to the limited repertoire
of synthetic methods leading to these heterocycles. Huisgen
1,3-dipolar azide–alkyne cycloadddition (AAC) is the most
straightforward and atom-economical synthetic method for
the construction of these heterocycles.[9] However, the tradi-
tional thermal AAC conditions typically require high temper-
atures and proceed with limited regioselectivity. In 2002, the
groups of Sharpless[10a] and Meldal[10b] independently reported
their copper-catalyzed azide–terminal alkyne cycloaddition
(Scheme 1a), thus providing a mild and efficient synthesis of
1,4-disubstituted 1,2,3-triazoles.[11] In contrast to the widely
successful use of terminal alkynes (including metal acetylides)
in catalyzed AACs,[12] the corresponding reactions of internal
Scheme 1. a) Metal-catalyzed azide–alkyne cycloaddition. b) Organoca-
talytic azide–zwitterion cycloaddition.
alkynes for the synthesis of fully substituted 1,2,3-triazoles
remain a challenge[13] owing to the increased energy barrier
and difficulty in regiocontrol, particularly for intermolecular
reactions. While the advent of ruthenium-based catalytic
systems (RuAAC)[14] and iridium-based catalytic systems
(IrAAC)[15] has addressed the challenge to some extent
(Scheme 1a), additional efficient catalytic systems comple-
mentary to CuAAC, RuAAC, and IrAAC remain in high
demand. More recently, organocatalytic triazole formation
has been used as a powerful, albeit less developed, alternative
to metal-catalyzed AAC reactions. The groups of Rama-
chary[16a,h] and Bressy,[16c] as well as our group,[16b,d,f,g,j] inde-
pendently reported the organocatalytic regioselective syn-
thesis of substituted 1,2,3-triazoles through enamine inter-
mediates formed in situ. This method attracted much
attention because of the common green features of organo-
catalysis.[17] However, these approaches are restricted to
ketone or cyclic enone substrates, which have largely limited
its applications. In continuation of our studies in searching for
new methods for the formation of densely functionalized
1,2,3-triazoles,[18] we report herein the first metal-free cata-
lytic aerobic oxidative intermolecular azide–zwitterion cyclo-
addition (AZC) reaction (Scheme 1b. Specifically, a facile
intermolecular AZC reaction of an in situ generated zwitter-
ion has been realized for the first time, and also could be
utilized to assemble highly substituted 1,2,3-triazoles.
[*] W. Li, Prof. Dr. J. Wang
Department of Pharmacology and Pharmaceutical Sciences
School of Medicine, Tsinghua University, Beijing, 100084 (China)
E-mail: wangjian2012@tsinghua.edu.cn
[**] The project described was supported by grant from the Tsinghua
University and the “Thousand Plan” Youth program of China.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408265.
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Zwitterions represent a basic class of important organic
intermediates and have received renewed attention in syn-
thetic organic transformations.[19] The Morita–Baylis–Hillman
(MBH) reaction has become one of the most useful and
popular carbon–carbon bond-forming reactions with enor-
mous synthetic utility, promise, and potential.[20] According to
currently accepted reaction mechanism,[21] the first step of
a MBH reaction is commonly referred to as the in situ
zwitterion formation by addition of catalytic amount of amine
or phosphine to electron-deficient olefins. Building on these
pioneering scientific discoveries, we started to verify our
hypothesis. Upon exposure of the a,b-unsaturated ester 1a
and phenyl azide (2a) to the catalyst I (20 mol%) in DMSO
at 808C, we observed low conversion into 3aa after 48 hours
(Table 1, entry 1). After extensive screening of commonly
recently been demonstrated by the group of Aggarwal.[22]
After surveying a variety of solvents, the best result was
obtained using CHCl3 (entry 14). Further screening of the
reaction temperature indicated that a decreased temperature
led to a slow conversion (entry 15). It is worth noting that
lowering the catalyst loading to 10 mol% caused no signifi-
cant change in the chemical yield (entry 16). Finally, opti-
mization of the reaction parameters led us to identify DBU as
a catalyst and CHCl3 as an ideal medium for the desired
transformation, thus furnishing 3aa not only in essentially
high yield but also with absolute regioselectivity.
With the standard reaction conditions established, the
scope and limitations of our DBU-catalyzed AZC reactions
were explored. As shown in Table 2, a wide range of aryl and
Table 2: Scope with respect to the azides.[a]
Table 1: Optimization of the reaction conditions.[a,f]
Entry
Cat.
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VII
III
III
III
III
III
III
III
III
III
III
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
36
36
36
36
36
36
36
36
36
36
36
36
36
36
72
48
72
16
25
72
19
<5
<5
23
59
53
46
61
75
42
87
41
85
76
9
DMA
10
11
12
13
14
15[c]
16[d,g]
17[e]
MeOH
toluene
THF
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
[a] Reaction conditions: A mixture of 1a (0.10 mmol), 2 (0.20 mmol),
and III (10 mol%) in CHCl3 (0.3 mL) was stirred at 808C under air for
48 h.
[a] Reaction conditions: A mixture of 1a (0.10 mmol), 2a (0.20 mmol),
and the catalyst (20 mol%) in solvent (0.3 mL) was stirred at 808C under
air for 36 h. [b] Yield of isolated product. [c] The reaction was conducted
at 508C for 72 h. [d] 10 mol% catalyst used. [e] 5 mol% catalyst used.
[f] No reaction takes place without catalyst or oxygen in the atmosphere.
[g] If O2 balloon used, t=36 h. [h] 2a (0.12 mmol, 1.2 equiv), 67% yield.
DMA=dimethylacetamide, DMSO=dimethylsulfoxide.
alkyl azides participated in the cycloaddition to give the fully
substituted 1,2,3-triazoles in high to excellent yields. Sub-
strates bearing different substitution patterns on the benzene
ring undergoing AZC reactions all led to the expected
products 3aa–al and 3ao–ap (81–91%). Alkyl azides also
afforded the expected adducts in high chemical yields (3ao–
ar; 81–85%). Naphthyl and heteroaryl azides were smoothly
converted into the desired products 3am and 3an, respec-
tively, under the same reaction conditions.
used amine or phosphine catalysts, we found that the addition
of 0.2 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) played a pivotal role for the high efficiency of the
desired reaction (entry 3). Notably, if phosphine catalysts
were used, 2a was partially decomposed because of the
plausible Staudinger reaction. This kind of beneficial effect of
DBU as a superb nucleophile in catalytic MBH reactions has
Next, we turned our attention to a,b-unsaturated esters
(Table 3). A diverse array of a,b-unsaturated methyl esters
(1) with aryl and alkyl substituents on alkenes engaged in the
2
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Table 3: Scope of the a,b-unsaturated esters.[a]
Table 4: Scope with respect to the electron-deficient olefins.[a]
[a] Reaction conditions: A mixture of 4 (0.10 mmol), 2a (0.20 mmol),
and III (10 mol%) in CHCl3 (0.3 mL) was stirred under air at 808C.
[b] Triethylamine (TEA) as the catalyst.
[a] Reaction conditions: A mixture of 1 (0.10 mmol), 2a (0.20 mmol),
and III (10 mol%) in CHCl3 (0.3 mL) was stirred at 808C under air for
48 h.
cycloaddition reaction to give the corresponding densely
functionalized 1,2,3-triazoles in high to excellent yields with
complete regioselectivities (3ba–va; 78–91%).[23] We also
examined ethyl and isopropyl cinnamates and both gave
expected adducts 3wa (87%) and 3xa (82%) high chemical
yields.
To further demonstrate the generality of the DBU-
catalyzed AZC reactions, it is shown that other types of
activated olefins are equally capable in participating in the
developed reaction (Table 4). It was discovered that the
reaction tolerated a variety of functionalized electron-defi-
cient olefins, such as a,b-unsaturated ketones (4a–f), an a,b-
unsaturated thioester (4g), a,b-unsaturated amide (4h),
nitrile olefin (4i), a,b-unsaturated dihydrooxazole (4j), a,b-
unsaturated ketoester (4k),[24] a,b-unsaturated aldehyde (4l),
and maleate (4m). It should be noted that, a few of the
electron-deficient olefin systems (such as nitroolefins and
quinones) commonly used in Diels–Alder reactions gave no
desired adducts under the standard reaction conditions.
The mechanistic proposal is depicted in Scheme 2. DBU
reacts to some extent with the starting a,b-unsaturated ester
1a to form the zwitterion intermediate A. Subsequent
addition of A to 2a forms the intermediate B. Building on
the active intermediate B, three plausible reaction pathways
were postulated. For path a: an SN2 reaction of B generates
the cyclic intermediate 1,2-dihydro triazole D, which is
subsequently oxidized into desired product 3aa. For path b:
Scheme 2. Postulated mechanism.
elimination of DBU produces the olefin intermediate C,
which can proceed to the desired product 3aa through
a 6p electrocyclization and oxidative aromatization sequence.
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For path c: aerobic oxidation of B generates the key olefin
intermediate E, which undergoes a 6p electrocyclization and
subsequent liberation of DBU from the intermediate F to
eventually form the cycloaddition product 3aa. The high
regioselectivity of this reaction is clearly due to the presence
of various electron-withdrawing groups on the dipolarophiles
1 and 4, groups which lower the energy of the lowest
unoccupied molecular orbital (LUMO) and causes the
b-carbon atom to be most electrophilic. Thus, DBU is
expected to attack the partially positively charged b position
of the olefins in a AZC reaction to form a zwitterion
intermediate, which would react with the azide and then
eliminate DBU to regioselectively yield a triazole with the
carboxy and the phenyl group at the C4 and the C5 positions,
respectively.
To corroborate our hypothesis outlined in Scheme 2, we
carried out a mass spectrometric (MS) study.[25] Several
experiments began with the ESI-MS monitoring of the
reaction of 1a and 2a catalyzed by DBU in CHCl3 (see the
Supporting Information). After 2 hours, a zwitterion species
directly related to the proposed Morita-Baylis–Hillman
catalytic cycle was detected as a major ion: [A + H2O + H]+
of m/z 333 and [A + 2H2O + H]+ of m/z 351. The ESI-MS
spectrum for the reaction of 1a and 2a catalyzed by DBU
shows two major ions, m/z 153 and m/z 432 ([E + H]+ or
[F+H]+), thus indicating the preference to probably form the
key intermediates E and F (Scheme 2). Taken together, these
experimental observations convincingly demonstrated that
path c is more favorable than others.
cycloaddition to furnish a wide range of fully or highly
substituted 1,2,3-triazoles. Additional detailed investigations
on the organocatalytic AZC are underway.
Received: August 15, 2014
Revised: September 6, 2014
Published online: && &&, &&&&
Keywords: azides · cycloadditions · Lewis base ·
.
organocatalysis · zwitterions
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Communications
Organocatalysis
W. Li, J. Wang*
&&&& — &&&&
Lewis Base Catalyzed Aerobic Oxidative
Intermolecular Azide–Zwitterion
Cycloaddition
The works: The discovery of a novel
aerobic oxidative intermolecular azide–
zwitterion reaction catalyzed by an orga-
nocatalyst is presented. It is demon-
strated that the merger of the Lewis base
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
and electron-deficient olefins generates
reactive zwitterion intermediates, which
readily participate in cycloaddition reac-
tions with an array of azides, thus
providing facile entry to fully or highly
substituted 1,2,3-triazole frameworks.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!