Preparation of 1,4,5-trisubstituted 5-acyl-1,2,3-triazoles by selective acylation between copper(I)-carbon(sp) and copper(I)-carbon(sp2) bonds with acyl chlorides

Article abstract of DOI:10.1002/adsc.201300307

A one-pot, three-component method for preparation of 1,4,5-trisubstituted 5-acyl-1,2,3-triazoles has been developed based on a highly selective acylation of the copper(I)-carbon(sp²) bond with acyl chlorides in the presence of the copper(I)-carbon(sp) bond. The procedure is characterized by high efficiency and simple conditions. Copyright

Full text of DOI:10.1002/adsc.201300307

COMMUNICATIONS
DOI: 10.1002/adsc.201300307
Preparation of 1,4,5-Trisubstituted 5-Acyl-1,2,3-triazoles by
Selective Acylation between Copper(I)-Carbon(sp) and
Copper(I)-Carbon
(sp2) Bonds with Acyl Chlorides
G
Bo Wang,a Nan Liu,a Changwei Shao,a Qun Zhang,a Xinyan Wang,a,*
and Yuefei Hua,*
a
Department of Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+86)-6277-1149; phone: (+86)-6279-5380; e-mail: wangxinyan@mail.tsinghua.edu.cn or yfh@mail.tsinghua.edu.cn
Received: April 15, 2013; Published online: September 5, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300307.
Abstract: A one-pot, three-component method for
preparation of 1,4,5-trisubstituted 5-acyl-1,2,3-tri-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
with acyl chlorides in the presence of the copper(I)-
carbon(sp) bond. The procedure is characterized by
high efficiency and simple conditions.
Keywords: acyl chlorides; acylation; click chemis-
try; copper; copper-carbon bond
Scheme 2.
1,2,3-Trizoles do not occur in nature, but their appli- type B, some structurally special internal alkynes (1-
cations in organic synthesis, biology and material sci- haloalkyne[6] or 1-aluminum-alkyne[7]) are used as the
ence have rapidly expanded in the past decade.[1] This substrate to generate product 4 in one or two steps.
results from the fact that numerous 1,2,3-trizoles can
Herein, we report a type C method (Scheme 2) for
be prepared easily by CuAAC (copper-catalyzed the same purpose, in which 1-copper(I)-alkyne (5) is
azide-alkyne cycloaddition) reactions.[2,3] Unfortunate- used as a substrate to participate in a one-pot three-
ly, the normal CuAAC reaction is limited to the use component reaction. The method demonstrates
(sp2) bond
ACHTUNGTRENNUNG
À
of terminal alkynes (1) as substrates and produces a highly selective acylation of the Cu C
only 1,4-disubstituted 1,2,3-triazoles (3) (Scheme 1). with acyl chlorides (6) in the presence of the Cu
À
Recently, 1,4,5-trisubstituted 1,2,3-triazoles (4) also C(sp) bond, by which 1,4,5-trisubstituted 5-acyl-1,2,3-
showed novel properties[4] and many modified triazoles (7) are prepared in excellent yields under ex-
CuAAC methods were developed for their prepara- tremely simple conditions.
tion. As shown in Scheme 2, those methods can be di-
In 2002, Sharpless proposed a catalytic cycle for
vided into two types according to the alkynes. In type CuAAC and 5-Cu(I)-1,2,3-triazole (8) was hypothe-
A, a terminal alkyne is used as the substrate, which sized as an intermediate.[2] In 2005, Wu reported that
À
undergoes a one-pot, three-component reaction in the the Cu(I) C bond in 8 could be substituted in situ by
presence of an electrophile to yield product 4.[5] In an exogenous electrophile E+ to produce 1,4,5-trisub-
stituted 1,2,3-triazoles (4).[5i] Since then, similar proce-
dures were reported based on the same idea.[5a–h] Un-
fortunately, this method suffered from the formation
of a by-product, the 1,4-disubstituted 1,2,3-triazole
(3), even though one or more equivalents of Cu(I)
catalyst were used. As shown in Figure 1, this draw-
Scheme 1.
back arises from the fact that an electrophile H+ is
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Preparation of 1,4,5-Trisubstituted 5-Acyl-1,2,3-triazoles by Selective Acylation
tallics were not compatible with acyl groups in both
substrates and/or products. Interestingly, 1-copper(I)-
alkyne (5) was not used directly as a substrate for the
preparation of 7, although it has been proposed as
a key intermediate in the type A method. This phe-
nomenon may result from the fact that the isolated 1-
copper(I)-alkyne (5) has a much lower reactivity than
that generated in situ from CuAAC due to their dif-
ferent structures. For example, the isolated copper(I)-
phenylethyne is an extremely stable polymeric com-
Figure 1. Competitive electrophilic substitution between H+
ꢀ
plex with a structure as [(PhC CCu)2]n (5a, without
exogenous ligands).[10,11] However, the in situ generat-
and E+.
ed copper(I)-phenylethyne may be a lower polymeric
complex or
a monomer with a structure like
[2]
ꢀ
generated in the formation of 1-copper(I)-alkyne (5) PhC CCuLn (with exogenous ligands). As shown in
and it then undergoes a protonation on the Cu(I) C Scheme 3, the commercial sample of 5a has proved to
À
bond of 8 competitively with the exogenous electro- be ineffective in CuAAC under Sharpless condi-
phile E+.
tions.[12] Even worse is that 5a can be acylated easily
It is clear that the formation of 3 can be avoided by by acyl chlorides (6) to yield a,b-ynones in the pres-
replacement of the terminal alkyne with the internal ence of additives.[13]
alkyne, but the normal internal alkyne is an unsuita-
As shown in Scheme 4, we also observed that no re-
ble substrate for CuAAC. Luckily, Rutjes found that action occurred between 5a and BnN3 (2a) in CH2Cl2.
1-bromoalkyne could carry out CuAAC to give 1,4,5- In the absence of an additive (such as LiI or HMPA),
trisubsituted 5-bromo-1,2,3-triazole.[6f] Later, a 1,4,5- no a,b-ynone was detected from the mixture of 5a
trisubsituted 5-iodo-1,2,3-triazole was prepared as and PhCOCl (6a) in CH2Cl2. However, after 6a was
a single product from 1-iodoalkyne.[6e] Recently, added into the suspension of 5a and 2a in CH2Cl2 for
a modified CuAAC method using 1-aluminum-alkyne 15 min, a transparent solution formed and it then
as
a
substrate was reported[7] (Scheme 2 and quickly converted into a new suspension again. Two
Figure 2). But, the method has two drawbacks caused hours later, CuCl solid was filtered off and 1-benzyl-
À
by the high reactivity of the Al C bond in a 1-alumi- 4-phenyl-5-benzoyl-1,2,3-triazole (7a) was isolated in
num-alkyne. First, 1-aluminum-alkyne must be pre- 97% yield. As shown in Figure 3, the structure of
pared, stored and used under moisture-free and 1-benzyl-4-(4-bromophenyl)-5-benzoyl-1,2,3-triazole
oxygen-free conditions.[8] Second, 1-aluminum-alkyne (7b) was further confirmed by single crystal X-ray dif-
was not compatible with the tested electrophiles (for fraction analysis.[14]
example, NCS, NBS, NIS and ClCO2R) including acyl
chlorides.[8b] That may be the reason that this reaction cycloaddition between 5a and 2a did occur to yield an
has to be performed by a two-step process. In fact, no expected Cu(I)-containing intermediate 8a
These results indicated that a highly regioselective
acyl chloride as an electrophile and 5-acylated 1,2,3- (Scheme 5), but, this cycloaddition rate was too slow
triazole as a product were reported in the original ar-
ticle. In the literature, cycloadditions of 1-lithium-, 1-
magnesium- and 1-gold-alkynes with azides also were
reported for the same purpose, but through the unca-
talyzed exothermic mechanism.[9]
In our recent chemical biology research, many
1,4,5-trisubstituted 5-acyl-1,2,3-triazoles (7) were
Scheme 3.
needed as both products and precursors. Experiments
showed that they could be prepared as a mixture by
a type A method with acyl chlorides (6) as electro-
philes. But, they could not be prepared from 1-metal-
alkynes (M=Al, Li, or Mg) because those organome-
Figure 2. Some structurally special internal alkynes.
Scheme 4.
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Bo Wang et al.
Table 1. The effect of solvent on the reaction.[a]
COMMUNICATIONS
Entry
Solvent (mL)
Time [h]
7a [%][b]
1
2
3
4
5
6
7
8
cyclohexane (1)
MeCN (1)
acetone (1)
toluene (1)
dioxane (1)
THF (1)
CH2Cl2 (1)
CHCl3 (1)
2
2
2
2
2
2
1
1
1
2
5
58c
88
89
94
95
97
97
97
98
98
98
9
10
11
ClCH2CH2Cl (1)
ClCH2CH2Cl (2)
ClCH2CH2Cl (4)
[a]
The mixture of 2a (0.6 mmol), 5a (0.5 mmol) and 6a
(0.6 mmol) in solvent was stirred at room temperature
for 2 h in a stoppered tube.
The isolated yields.
The substrates were not exhausted.
[b]
[c]
Figure 3. The structure of 7b.
Scheme 5.
to be observed. However, it can be accelerated signifi-
cantly in the presence of 6a by quickly consuming 8a.
The formation of 7a rather than a,b-ynone indicated
À
that the Cu(I)C C
ity than the Cu(I) C(sp) bond in 5a. Thus, the success
of this one-pot, three-component process mainly is
N
due to highly chemoselective acylation of the Cu(I)
2
C
N
As shown in Table 1, the solvents have a little
effect on the yield of 7a and most entries finished
within 2 h. Cyclohexane gave the lowest yield
(entry 1) possibly because it has poor solubility for
substrates and products. All tested halo-containing
solvents, such as CH2Cl2, CHCl3 and ClCH2CH2Cl
(entries 7–9), gave excellent yields and ClCH2CH2Cl
gave the best results (entry 9). The amount of solvent
had a significant effect on the reaction rate, but not
on the yield (entries 9–11). Interestingly, the addition
of a base or ligand into the reaction system, such as
Et3N, DIPEA, HMPA or 1,10-phenanthroline, led to
a deep colour and various by-products. Finally, entry 9
was assigned to be the standard conditions.
To generalize this novel method, different reactants
2, 5 and 6 were tested. As shown in Scheme 6, all ben- Scheme 6.
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Preparation of 1,4,5-Trisubstituted 5-Acyl-1,2,3-triazoles by Selective Acylation
Chem. Soc. Rev. 2010, 39, 1262–1271; e) S. K. Mamidya-
zoyl chlorides (6a–6i) were excellent electrophiles re-
gardless of electron-donating groups (7f–6g) or elec-
tron-withdrawing groups (7h–6i) on the benzene ring.
However, aliphatic acyl chlorides gave relatively
lower yields of products (7j–7l). There was no appar-
ent difference on the product yield by using different
2 and 5. The same excellent results were obtained
when this method was performed at a 10-gram scale
when the reaction time was prolonged (4 h).
In conclusion, a highly chemoselective acylation of
À
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the Cu CACHTUNGTRENNUNG
(sp2) bond was discovered in the presence
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of the Cu C(sp) bond. Finally, an efficient one-pot,
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substituted 5-acyl-1,2,3-triazoles has been developed
by using 1-copper(I)-alkynes as direct substrates.
Since 1-copper(I)-alkynes can be prepared easily and
are stable at ambient temperatures for years,[13,15] the
method is a valuable addition to the family of Cu(I)
catalytic cycloaddition reactions.
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Experimental Section
Typical Procedure for the Preparation of 1-Benzyl-4-
phenyl-5-benzoyl-1,2,3-triazole (7a)
To a suspension of benzyl azide (2a, 80 mg, 0.6 mmol) and
1-copper(I)-phenylethyne (5a, 82 mg, 0.5 mmol) in
ClCH2CH2Cl (1 mL) was added benzoyl chloride (6a, 84 mg,
0.6 mmol). The resultant mixture was stirred at room tem-
perature for 15 to 20 min to give a transparent solution that
then quickly converted into a suspension again. Two hours
later, the mixture was subjected to passage through a chro-
matography column [silica gel, 15% EtOAc in petroleum
ether (60–908C)] to give product 7a as a white solid; yield:
166 mg (98%); mp 968C (lit.[5i] mp 64–658C). IR (KBr): v=
3058, 3032, 1653, 1594, 1489, 1321, 913, 736, 693 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.49 (d, 2H, J=7.56 Hz),
7.43–7.34 (m, 3H), 7.20–7.14 (m, 10H), 5.73 (s, 2H);
13C NMR (75 MHz, CDCl3): d=187.6, 148.5, 135.6, 134.6,
134.0, 130.2, 129.3, 129.5 (2C), 128.6 (2C), 128.3 (3C), 128.2
(5C), 128.0 (2C), 53.3. HRMS (ESI-TOF): m/z=340.1445,
calculated for C22H17N3O, [M +H]+: 340.1444.
The products 7b–7t were prepared by a similar procedure.
Acknowledgements
This work was supported by the National Natural Scientific
Foundation of China (No. 21072112 and 21221062).
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