Organocatalytic enamide-azide cycloaddition reactions: Regiospecific synthesis of 1,4,5-trisubstituted-1,2,3-triazoles

Article abstract of DOI:10.1002/chem.201002775

Heterocycles in one click: A novel organocatalytic enamide-azide cycloaddition reaction has been developed. This synthetic procedure represents a new method for the efficient construction of 1,4,5-trisubstituted-1,2,3- triazoles under mild reaction condit

Full text of DOI:10.1002/chem.201002775

DOI: 10.1002/chem.201002775
Organocatalytic Enamide–Azide Cycloaddition Reactions: Regio
Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles
ACHTUNGTRENNsUNG pecific
Lee Jin Tu Danence, Yaojun Gao, Maoguo Li, Yuan Huang, and Jian Wang*[a]
The emerging field of “click chemistry” has been devel-
oped as a unique approach for a set of powerful and selec-
tive reactions.[1] These powerful methods enable the chemist
to rapidly construct chemical libraries under mild reaction
conditions and using readily available reagents. As one of
the most powerful members of “click” reactions, the Huis-
gen 1,3-dipolar cycloaddition has evolved into a common
coupling procedure that is employed in numerous chemical
reactions.[2] In particular, the Huisgen 1,3-dipolar cycloaddi-
tion reactions between azides and alkynes for the synthesis
of 1,2,3-triazole compounds are considered as the “cream of
the crop” of all “click” reactions.[2a,c]
thesis of triazoles by Wolff,[6] and the cyclization of a-diazo-
amides.[7] However, most of these methods are not modular
and require a multi-step synthesis for the precursors. Actual-
ly, the synthesis of 1,2,3-triazoles by thermal 1,3-dipolar cy-
cloadditions [Eq. (1)] was discovered by the research group
of Michael at the end of the 19th century[8a] and has been
significantly developed by the research group of Huisgen in
the 1960s.[8b,c] However, because of the high activation
energy (ca. 24–26 kcalmolÀ1),[9] these cycloadditions are usu-
ally very slow even at elevated temperature (80–1208C, 12–
24 h) and are likely to generate mixtures of regioisomers.
The relatively poor regioselectivity of the Huisgen 1,3-dipo-
lar cycloaddition has significantly limited the extensive uti-
lization of this strategy. Meanwhile, the copper(I)-catalyzed
Huisgen 1,3-dipolar cycloadditions of azides and alkynes
(CuAAC) have been discovered and became one of the
most straightforward and powerful approaches to prepare
1,5-disubstituted 1,2,3-triazoles [Eq. (2)].[4b,10] Recently,
Fokin and co-workers have reported a copper(I)-catalyzed
reaction for the preparation of 1,4,5-disubstituted 1,2,3-tri-
AHCTUNGTRENNUNG
azoles.[14] This reactions, because of the near perfect chemo-
selectivity and high thermodynamic driving force, is general-
ly well-suited for click chemistry endeavors. However, the
presence of the transition metal may cause copper-induced
degradation of viruses or oligonucleotide strands in biologi-
cal system.[11] Additionally, copper ions are potentially toxic
for living organisms. Notably, the reactions are only suited
for terminal alkynes [Eq. (2)]. Therefore, this limitation
largely restricts the diverse application of this strategy in the
preparation of 1,2,3-triazoles. In brief, the advent of novel
methods that are devoid of these deficiencies would be of
great value and particularly necessary to the synthetic com-
munity.
Herein, we report the development of the first organoca-
talytic method for the cycloaddition reaction of azides with
enamine[12] to produce 1,4,5-trisubstituted-1,2,3-triazoles
[Eq. (3)]. Some noteworthy attributes of this reaction in-
clude 1) simple structure of the catalyst, 2) high efficiency
(high yields and short reaction time in most cases), 3) mild-
ness (nonmetal and mild temperature), 4) regiospecificity
(complete exclusion of regioisomers), 5) complexity (three
substituents), and 6) functional-group tolerance (e.g., ke-
tones, esters, nitrile, trifluoromethane, halogen, and hydroxyl
groups).
Fused and nonfused 1,2,3-triazoles have been broadly uti-
lized as photostabilizers and inhibitors.[3] Additionally, they
are biologically active compounds in agrochemical research
and also in medicinal chemistry.[4] A number of methods
have thus far been reported to prepare N-substituted 1,2,3-
triazoles, among which the cyclization of triazenes,[5] the syn-
[a] L. J. T. Danence, Dr. Y. Gao, Dr. M. Li, Y. Huang, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6516-1691
E-mail: chmwangj@nus.edu.sg
To test our hypothesis, we initially explored the reaction
of phenyl azide (1a) with ethyl acetoacetate (2a), in the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002775.
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COMMUNICATION
1.5 equiv) did not affect the reaction rate and yield (91%,
24 h; Table 1, entry 12). Further optimization of the catalyst
loading showed that even 5 mol% of catalyst VI can also ef-
ficiently catalyze the reaction (90%, 48 h; Table 1,
entry 14,). In contrast to other catalysts, the tertiary amine
catalyst VII resulted much less effective in this case (15%,
48 h; Table 1, entry 18). Moreover, the choice of solvent was
critical, in that the use of N,N-dimethylformamide (DMF),
MeOH, or toluene has led to significantly lower yields
(yield lower than 32%; Table 1, entries 15–17).
Scheme 1. Tested small organic molecules.
presence of the primary a-amino acid glycine (I; Scheme 1)
and of the secondary a-amino acid, l-proline (II, Scheme 1).
With this method, we obtained none of the desired 1,4,5-tri-
substituted-1,2,3-triazoles (yield lower than 5 %; Table 1, en-
The compatibility of of several substrates 2 is presented in
Table 2. b-keto esters were successfully introduced to partic-
ipate in the “click” reaction under the current catalytic
Table 1. Optimization of the reaction conditions.[a]
Table 2. Scope of substrates.[a]
Entry
Cat.
T [o C]
t [h]
Yield [%][e]
1
2
3
4
I
II
II
II
II
II
II
III
IV
V
VI
VI
RT[i]
RT[i]
50
70
100
70
70
70
70
70
70
70
70
70
70
70
70
70
48
120
120
48
48
48
48
48
48
48
24
24
36
48
24
48
36
48
<5
<5
10
24
22
31
32
25
62
62
92
91
91
90
23
32
<5
15
Entry R1
R2
R3
Product t [h] Yield [%][b]
1
Ph
Me
Et
Ph
COOEt 3a
COOEt 3b
COOEt 3c
48
48
48
24
48
48
48
48
12
6
90
92
90
92
88
94
88
95
92
96
94
91
99
94
94
87
98
91
95
80
2
Ph
Ph
Ph
3c
4
5
CF3 COOEt 3d
CF3 COPh
6[b]
7[c]
8[c]
9[c]
10[c]
11[c]
12[d]
13[d]
14[d]
15[f]
16[g]
17[h]
18[c]
5
Ph
3e
3 f
3g
6
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
COMe
COPh
COOEt 3h
7
Ph
8
9
4-ClC6H4
Ph
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
3i
3j
10
11
12
13
14
15
16
17
18
19
20[c]
4-ClC6H4
3-ClC6H4
3-CF3C6H4
4-CF3C6H4
4-NO2C6H4
3k
3l
6
1
VI (10 mol%)
VI (5 mol%)
VI
VI
VI
VII
3m
3n
3o
3p
3q
3r
3s
3t
1
1
6
24
12
12
12
24
3-Me,4-ClC6H3 Ph
4-MeOC6H4
3-OHC6H4
3,5-Me2C6H3
4-iPrC6H4
PhCH2
Ph
Ph
Ph
Ph
Ph
[a] Unless otherwise noted, the reaction conditions are: 0.5m in DMSO,
1a/2a (1:1.3). [b] 0.5m in DMSO, 1a/2a (3:1). [c] 1.0m in DMSO, 1a/2a
(3:1). [d] 1.0m in DMSO, 1a/2a (1.5:1). [e] Yield of isolated product 3a.
[f] DMF as solvent. [g] Methanol as solvent. [h] Toluene as solvent.
[i] RT. DMSO=dimethyl sulfoxide.
[a] Unless otherwise noted, the reaction conditions are: 1.0m in DMSO,
1a/2a (1.5:1). [b] Yield of isolated product 3. [c] Catalyst loading
(10 mol%).
tries 1 and 2). Nevertheless, a temperature increase (to
508C), resulted in trace amount of desired product (10 %;
Table 1, entry 3). Once the temperature reached 708C, the
reaction yield was slightly improved (24%; Table 1, entry 4).
A further increase in temperature and of the amount of
phenyl azide (1a) had only limited effect on reaction yield
(22–32%, Table 1, entries 5–7). Later on, we examined the
carboxylic acid-free catalysts III and IV (Scheme 1). Inter-
estingly, the less bulky catalyst pyrrolidine (IV) afforded a
62% yield (Table 1, entry 9). Then we examined the six-
member ring piperidine (V) and acyclic diethyl amine cata-
lyst VI (Scheme 1). It was noted that the acyclic secondary
amine catalyst is essential to this reaction and leads to a
higher reaction yield in a shorter time (92%, 24 h; Table 1,
entry 11). Lowering the ratio of 1a (from 3 equiv to
system (Table 2, entries 1–4). High yields were achieved in
48 h (90–92%; Table 2, entries 1–4). In the case of b-keto
ester containing a phenyl group, a higher catalyst loading
was required (VI (10 mol%); Table 2, entry 3). Another
type of interesting substrates, 1,3-diketones, have also been
employed in this reaction and provided high to excellent
yields (88–94%, 48 h; Table 2, entries 5–7). Most surprising-
ly, ketones with an electron-withdrawing group in the a-po-
sition efficiently reacted with azides to generate 1,2,3-tria-
zoles (80–99%, 1–24 h; Table 2, entries 9–20). Several sub-
stituted phenyl azides containing electron-donating groups
(methyl, isopropyl, and methoxyl) and electron-withdrawing
groups (halogen, trifluoromethyl, and nitro groups), were all
compatible with this transformation under the optimal reac-
tion conditions (87–99%, 1–24 h; Table 2, entries 10–19). In
Chem. Eur. J. 2011, 17, 3584 – 3587
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J. Wang et al.
general, electron-withdrawing groups provided the desired
products in a shorter time (91–99%, 1–6 h; Table 2, en-
tries 10–15). In contrast to electron-withdrawing groups, the
electron-donating groups required a relative longer time,
but without affecting the yield (87–98%, 12–24 h; Table 2,
entries 16–19). Appreciatively, alkyl azide was also used in
the reaction and led to a good yield but requested 10 mol%
of catalyst VI (80%, 24 h; Table 2, entry 20). The regioselec-
tivity of product 3g was determined by using single crystal
X-ray diffraction analysis.[13]
which the enamine remains reactive in the Huisgen cycload-
dition and yet stabilizes the formation of the zwitterion and
allows the catalytic turnover. The catalyst is the most impor-
tant component and acts as an electron-donating group to
facilitate complete regioselectivity, to improve the reaction
rate, and additionally act as a leaving group upon protona-
tion. Based on our experimental evidence, the rate-deter-
mining step is most probably the dipolar cycloaddition be-
cause the catalytic rates have a strong dependence on the
electronic nature of the azide. The enamine (4) was ob-
served by LCMS, thus suggesting that the catalytic cycle ac-
cumulates at this stage. No triazoline intermediate (6) was
detected. In addition, intermediate zwitterion (7) is poten-
tially indirectly derived from the cycloaddition adduct (5).
Conversion of 5 into the proposed intermediate 6 is a for-
mally 1,3-hydride shift.
Although the reaction mechanism is not clear at this
stage, it is believed that this transformation is initiated by
the formation of enamine.[12] As shown in Scheme 2, we pro-
In summary, we have developed the first regioselective or-
ganocatalytic enamide–azide cycloaddition reaction in the
presence of a metal-free small organic molecule, diethyl
amine. The reaction is applicable to a variety of azides that
tolerated aryl and alkyl groups as substituents. A number of
aryl ketones and ketoesters have been employed to addi-
tionally present the versatility of this method. As a result,
multi-substituted 1,2,3-triazoles were obtained in high to ex-
cellent yields (80–99%). Significantly, none of the re-
gioisomers were formed. Moreover, this catalytic system
also tolerated many synthetic useful functional groups, such
as nitrile, ketone, and ester functional groups which might
be manipulated for accessing more sophisticated heterocy-
clic compounds. Further synthetic application of the catalyt-
ic system to other new reactions is under way in our labora-
tory.
Experimental Section
Scheme 2. Proposed catalytic cycle.
General procedure: Phenyl azide 1a (50 mg, 0.42 mmol) was dissolved in
DMSO (0.28 mL) in a small vial fitted with a screw cap. First the b-func-
tionalized ketone (37 mg, 0.28 mmol) and then the catalyst diethylamine
(1 mg, 0.014 mmol) were added to this reaction mixture. The reaction
mixture was stirred at 708C in a silicon oil bath and the reaction was
monitored through thin-layer chromatography. Once the reaction
reached completion, the crude product was purified by column chroma-
tography on silica gel (hexane/EtOAc=5:1) to afford the desired product
posed a catalytic cycle. The first step is most likely the con-
densation of the catalyst VI and the b-ketoester (2a) to gen-
erate an iminium ion that then tautomerizes into active en-
amine 4. Enamine 4 acts as the electron-rich olefinic part-
ner, and reacts with the aromatic azide 1a in a Huisgen cy-
cloaddition to form triazoline
5
with complete
1
3a (58 mg, 90% yield) as a white solid. H NMR (300 MHz, CDCl3): d=
regioselectivity. Instead of an enamine-type cycloaddition,
another competing pathway involves the catalyst functioning
as a base and forming enolate. Enolates can potentially
form adducts with azides. However, the results of the cata-
lyst screening revealed that the process catalyzed by an or-
ganic base is significantly slow (15%; Table 1, entry 18), and
thus this pathway represents only a minor contribution.
Next, there would be an elimination step to assist the forma-
tion of the final product 3a. In this process, we propose that
such elimination might be derived from a zwitterionic inter-
mediate (7), whose negative charge is stabilized by both res-
onance and p-network delocalization. Upon this mechanism,
the nature of the electron-withdrawing group is essential in
the catalytic cycle. It is responsible to create a balance in
7.54–7.51 (m, 3H), 7.42–7.39 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 2.55 (s,
3H), 1.40 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=162.3,
139.4, 137.3, 136.0, 130.7, 130.3, 126.0, 61.6, 15.0, 10.6 ppm; HRMS (EI)
calcd for C12H13N3O2: 231.1008 [M+H]+, found: 231.1008.
Acknowledgements
We acknowledge the National University of Singapore for financial sup-
port (Academic Research Grant: R143000408133, R143000408733, and
R143000443112). Financial support from National University of Singa-
pore (Academic Research Grant: R143000408133, R143000408733, and
R143000443112) is greatly appreciated.
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Regiospecific Synthesis of 1,2,3-Triazoles
COMMUNICATION
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Keywords: click chemistry
organocatalysis · triazoles
· enamines · heterocycles ·
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Received: September 28, 2010
Revised: January 26, 2011
Published online: February 21, 2011
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3587