Reaction of alkynes and azides: Not triazoles through copper-acetylides but oxazoles through copper-nitrene intermediates

Article abstract of DOI:10.1002/chem.201303737

Well-defined copper(I) complexes of composition [Tpm* ^,BrCu(NCMe)]BF₄ (Tpm*,^Br=tris(3,5- dimethyl-4-bromo-pyrazolyl)methane) or [Tpa* Cu]PF₆ (Tpa=tris(3,5-dimethyl-pyrazolylmethyl)amine) catalyze the formation of 2,5-disubstituted oxazoles from carbonyl azides and terminal alkynes in a direct manner. This process represents a novel procedure for the synthesis of this valuable heterocycle from readily available starting materials, leading exclusively to the 2,5-isomer, attesting to a completely regioselective transformation. Experimental evidence and computational studies have allowed the proposal of a reaction mechanism based on the initial formation of a copper-acyl nitrene species, in contrast to the well-known mechanism for the copper-catalyzed alkyne and azide cycloaddition reactions (CuAAC) that is triggered by the formation of a copper-acetylide complex.

Full text of DOI:10.1002/chem.201303737

DOI: 10.1002/chem.201303737
Full Paper
&
Reaction Mechanisms
Reaction of Alkynes and Azides: Not Triazoles Through Copper–
Acetylides but Oxazoles Through Copper–Nitrene Intermediates
Estela Haldꢀn,[a] Maria Besora,[b] Israel Cano,[a] Xacobe C. Cambeiro,[b] Miquel A. Pericꢁs,*[b, c]
Feliu Maseras,*[b, d] M. Carmen Nicasio,*[e] and Pedro J. Pꢂrez*[a]
Abstract: Well-defined copper(I) complexes of composition
[Tpm*,BrCu(NCMe)]BF4 (Tpm*,Br =tris(3,5-dimethyl-4-bromo-
pyrazolyl)methane) or [Tpa*Cu]PF6 (Tpa* =tris(3,5-dimethyl-
pyrazolylmethyl)amine) catalyze the formation of 2,5-disub-
stituted oxazoles from carbonyl azides and terminal alkynes
in a direct manner. This process represents a novel proce-
dure for the synthesis of this valuable heterocycle from read-
ily available starting materials, leading exclusively to the 2,5-
isomer, attesting to a completely regioselective transforma-
tion. Experimental evidence and computational studies have
allowed the proposal of a reaction mechanism based on the
initial formation of a copper–acyl nitrene species, in contrast
to the well-known mechanism for the copper-catalyzed
alkyne and azide cycloaddition reactions (CuAAC) that is trig-
gered by the formation of a copper–acetylide complex.
Introduction
theses. Classical strategies for the preparation of substituted
oxazoles involve oxidation of oxazolines,[9] the Robinson–Gabri-
el cyclodehydration[10] of a-acylamino ketones, or rhodium-cat-
alyzed reaction of diazocarbonyl compounds[11] (Scheme 1).
Oxazole is an interesting heteroaromatic compound belonging
to the 1,3-azole family.[1] This heterocycle constitutes an impor-
tant structural unit of a variety of natural products[2] and com-
pounds with remarkable biological properties,[3] such as anti-
bacterial,[4] antifungal,[5] or cytotoxic[6] activities. It also serves
as a scaffold for the construction of peptides, macrocycles, and
polymers.[7] Moreover, oxazole derivatives, particularly chiral ox-
azolines, have been employed as ligands in coordination
chemistry and asymmetric catalysis.[8] Due to their valuable ap-
plications, there has been a great deal of interest in their syn-
[a] Dr. E. Haldꢀn, Dr. I. Cano, Prof. P. J. Pꢁrez
Laboratorio de Catꢂlisis Homogꢁnea, Unidad Asociada al CSIC
CIQSO-Centro de Investigaciꢀn en Quꢃmica Sostenible
and Departamento de Quꢃmica y Ciencias de los Materiales
Campus de El Carmen s/n, Universidad de Huelva
21007 Huelva (Spain)
Fax: (+34)959219942
E-mail: perez@dqcm.uhu.es
Scheme 1. Classical procedures for the synthesis of substituted oxazoles.
[b] Dr. M. Besora, Dr. X. C. Cambeiro, Prof. M. A. Pericꢄs, Prof. F. Maseras
Institute of Chemical Research of Catalonia (ICIQ)
Av. Pa¨ısos Catalans 16, 43007 Tarragona (Spain)
E-mail: mapericas@iciq.es
A different approach to substituted oxazole derivatives in-
volves transition-metal functionalization of the parent oxazole
ring. This strategy has been achieved through the application
of palladium cross-coupling chemistry[12] or, more recently, by
transition-metal-catalyzed direct functionalization of the heter-
ocyclic compound.[13] Although reliable and high yielding,
most of those procedures suffer from drawbacks such as diffi-
culties in gaining access to appropriate prefunctionalized syn-
thetic precursors or the need for harsh reaction conditions,
which constrain the functional group tolerance of these reac-
tions. In recent years, milder routes that can be used to con-
vert different acyclic precursors into oxazoles have appeared in
the literature.[14]
fmaseras@iciq.es
[c] Prof. M. A. Pericꢄs
Departament de Quꢃmica Orgꢄnica, Universitat de Barcelona
Martꢃ i Franquꢅs 1-11, 08028 Barcelona (Spain)
[d] Prof. F. Maseras
Departament de Quꢃmica, Universitat Autꢆnoma de Barcelona
08193 Bellaterra (Spain)
[e] Prof. M. C. Nicasio
Departamento de Quꢃmica Inorgꢂnica, Universidad de Sevilla
Aptdo 1203, 41071 Sevilla (Spain)
E-mail: mnicasio@us.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303737.
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Despite the plethora of synthetic procedures available for
the synthesis of this heterocycle, the development of methods
that can be used to prepare substituted oxazoles in a one-pot
fashion, under mild reaction conditions and from readily avail-
able starting materials remains highly desirable. In the last few
years some interesting contributions have been made in this
respect (Scheme 2). In 2009, Zhan and co-workers[15] reported
has shown a silver-mediated approach to di- and tri-substitut-
ed oxazoles from primary amides and activated b-bromo-a-ke-
tones. Zhang and co-workers[20] described an elegant [2+2+1]
annulation of a terminal alkyne, a nitrile and an oxygen atom
from pyridine/quinoline N-oxides for the preparation of 2,5-di-
substituted oxazoles through gold-catalyzed alkyne oxidation.
A copper-mediated aerobic [2+2+1] cycloaddition of internal
alkynes and nitriles to fully substituted oxazoles has been de-
vised by the group of Jiang.[21] In a very recent contribution,
Jiao and co-workers[22] have shown an impressive copper-cata-
lyzed aerobic oxidative dehydrogenative annulation of ready
available aldehydes, amines and molecular oxygen for the syn-
thesis of 2,5-disubstituted oxazoles.
A few years ago, we began to examine the catalytic activity
of a family of cationic copper(I) complexes of general formulae
[Tpm*Cu(NCMe)]BF4 (Tpm*=tris(pyrazolyl)methane ligand) in
the copper-catalyzed alkyne–azide cycloaddition reaction
(CuAAC), employing sulfonyl azides as reactants. We found
that the compound bearing the Tpm*,Br ligand (Tpm*,Br
=
tris(3,5-dimethyl-4-bromo-pyrazolyl)methane) effectively cata-
lyzed this reaction, providing, in a selective manner, the ex-
pected N-sulfonyl-triazole derivatives in high yields.[23] As
a follow-up to this research project, we wanted to test another
type of electron-deficient azide, that is, carbonyl azides, a sub-
strate never applied in the CuAAC reaction.[24] In this contribu-
tion we report the results of our studies on the reaction of car-
bonyl azides and terminal alkynes catalyzed by well-defined
copper(I) complexes. This catalytic transformation constitutes
a novel procedure for the direct and selective synthesis of 2,5-
disubstituted oxazoles from easily accessible starting materials
and using a copper complex as the catalytic precursor. Two
families of catalysts bearing the above Tpm*,Br as well as Tpa*
ligands have been developed for this transformation. The reac-
tion mechanism has been also investigated on the basis of ex-
perimental evidence and theoretical calculations, leading
to an unprecedented reaction pathway involving the initial for-
mation of an acyl nitrene–copper species and not a copper–
acetylide.
A portion of this work has been previously
communicated.[25]
Scheme 2. One-step protocols for the synthesis of substituted oxazoles.
Results and Discussion
Reaction of carbonyl azides and terminal alkynes catalyzed
by [Tpm*,BrCu(NCMe)]BF4
a catalytic one-pot propargylation/cycloisomerization tandem
reaction for the synthesis of fully substituted oxazoles, with
amides and propargylic alcohols being employed as starting
materials and p-toluenesulfonic acid monohydrate (p-TSA)
used as a bifunctional catalyst. The groups of Wang[16] and
Our interest on the CuAAC reaction focused on the use of elec-
tron-deficient azides as substrates. These reactants have been
found to be problematic and, in most cases, furnished prod-
ucts other than the expected triazole.[26] We succeeded in pre-
paring N-sulfonyl triazoles selectively in very high yields from
the reaction of sulfonyl azides and terminal alkynes by using
[Tpm*,BrCu(NCMe)]BF4 as the catalytic system.[23] We then fo-
cused on carbonyl azides, a substrate that was previously un-
known for this transformation. Under the same experimental
conditions developed for the synthesis of N-sulfonyl triazoles,
the reaction of benzoyl azide and phenylacetylene (Scheme 3)
afforded a mixture of two heteroaromatic products in a 10:1
Jiang[17] independently developed
a similar methodology
based on the use of TBHP/I2-mediated tandem oxidative cycli-
zation. 2-Amino-1-phenylethanone hydrochloride and commer-
cially available aromatic aldehydes were employed as reaction
substrates in the former case, whereas aryl alkenes and benzyl
amines were used as the reactants in the latter. Zhu and co-
workers have also demonstrated the use of multicomponent
reactions for the synthesis of oxazoles.[18] Recently, metal-medi-
ated one-step protocols have emerged. The group of Moses[19]
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of the 2,4-disubstituted regioisomer in any of the experiments,
attesting to the excellent regioselection of this transformation.
As shown in Table 1, the reaction was observed for a range of
alkynes and carbonyl azides bearing aryl-, alkyl- or heteroaro-
matic substituents, in variable yields. In most cases, the trisub-
stituted oxazoles, which incorporate two molecules of the
alkyne, were formed in 2–7% yield. Furthermore, amides de-
rived from decomposition of the carbonyl azides were also de-
tected. Among the reactants employed, alkylacetylenes
showed the lowest conversions (Table 1, entries 13–15 and 19).
It is worth noting the role of the Tpm*,Br ligand because the
use of CuI as the catalyst precursor gave no reaction.[25]
Scheme 3. Formation of oxazoles through the reaction of 1-alkynes and car-
bonyl azides catalyzed by [Tpm*,BrCu(NCMe)]BF4.
ratio, together with a small amount of benzamide as a by-
product. FTIR and NMR studies revealed the lack of any car-
bonyl functionality in either products and both displayed all
the NMR signals within the typical range for triazole rings.
However, unambiguous identification was achieved by means
of X-ray diffraction studies, which showed the formation of
Complexes bearing tris(pyrazolylmethyl)amine (Tpa*) li-
gands and their catalytic activity in the reaction of alkynes
and carbonyl azides
With the aim of improving both the catalytic activity and the
reaction scope observed with the Tpm*,Br-containing copper
complex, we targeted the development of new catalysts that
could surpass the drawbacks of formation of by-products (tri-
substituted oxazoles, amides) or the low yields for alkyl-substi-
tuted alkynes. We learned from the somewhat related CuAAC
reaction that the use of tertiary amine-based ligands, such as
tris(heterocyclic)methylamines, induced a certain acceleration
in these cycloaddition reactions.[27] Inspired by this work and
on the basis of our own experience with pyrazolyl-containing
ligands, we decided to prepare a series of cationic CuI com-
plexes of general formulae [Tpa*Cu]PF6, bearing tris(pyrazolyl-
methyl)amine ligands (Tpa*; Figure 1) as potential catalysts for
this transformation.[28,29]
a
2,5-disubstituted oxazole and a trisubstituted oxazole
(Scheme 3),[25] as the major and minor derivatives, respectively.
By using this protocol an array of 2,5-disubstituted oxazoles,
with yields in the range of 17–82%, were prepared by combin-
ing a variety of carbonyl azides with 1-alkynes (Table 1). It is in-
teresting to note that there was no evidence for the formation
Table 1. Reaction scope with [Tpm*,BrCu(NCMe)]BF4 as the catalyst.[a]
Entry
R1
R2
Yield [%][b]
Yield [%][b,c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph
Ph
Ph
Ph
Ph
60
77
82
14
61
56
63
43
52
49
46
59
18[d]
17[d]
24[d]
41
6
4
<2
<2
6
5
6
<2
<2
7
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
Ph
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
Ph
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-BrC6H4
3-thienyl
3-thienyl
3-thienyl
1-propyl
1-butyl
cyclopropyl
Ph
Figure 1. Tris(pyrazolylmethyl)amine (Tpa*) ligands used in this work.
Once the above complexes were prepared, we focused on
their activity as catalysts in the model reaction of phenylacety-
lene with benzoyl azide [Equation (1)]. To compare their per-
formance to that of [Tpm*,BrCu(NCMe)]BF4, reactions were car-
ried out by using the optimal reaction conditions previously
established for the latter. Thus, substrates phenylacetylene (1;
1.2 mmol) and benzoyl azide (2; 1.0 mmol) were heated in
chloroform at 408C for 24 h in the presence of 5 mol% copper
catalyst (Table 2, entries 1–5). Under these conditions, the
parent Tpa copper adduct showed no catalytic activity
(Table 2, entry 2), the best performance in the series of Tpa*
complexes being achieved with [Tpa*Cu]PF6, (entry 3). As
a first improvement of this catalytic system, it should be noted
that benzamide was not observed as a by-product in any reac-
tion catalyzed by the Tpa* species. However, the selectivity of
p-MeC6H4
p-MeOC6H4
Ph
4
<2
<2
<2
4
<2
<2
<2
3
Ph
p-MeOC6H4
2-thienyl
2-thienyl
2-thienyl
2-thienyl
p-MeC6H4
p-MeOC6H4
cyclopropyl
38
36
18[d]
[a] Reaction conditions: 1-alkyne (1.2 mmol), carbonyl azide (1.0 mmol),
catalyst (0.05 mmol), CHCl3 (1 mL), 24 h, 408C. Either BF4 or PF6 can be
employed as counterions without any effect on the reaction outcome.
[b] Isolated yield based on azide (average of two runs). The remaining ini-
tial azide was converted into RCONH2 and/or recovered unreacted.
[c] Yields of compounds <2% correspond to products that could not be
isolated due to the extremely low conversion. [d] Reaction performed at
608C.
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In an effort to enhance the selectivity, we examined other
reaction conditions with [Tpa*Cu]PF6 as the catalyst (Table 2,
entries 6–10). Increasing the temperature to 608C negatively
affected the overall yield of products (Table 2, entry 6). Howev-
er, the use of CH2Cl2 as solvent substantially improved the se-
lectivity (Table 2, entry 7). Other solvents such as 1,2-dichloro-
ethane (DCE) or THF were less effective in this regard (Table 2,
entries 8 and 9). The removal of all solvents, i.e., the use of the
alkyne-azide mixture as the reaction medium, provided the
highest yield (95%), with the transformation being completely
selective toward the 2,5-disubstituted oxazole (Table 2,
entry 10). It is worth noting that, under the same conditions,
the reaction of benzoyl azide and phenylacetylene catalyzed
by the Tpm*,BrCu complex afforded a mixture of the disubsti-
tuted (33% yield) and the trisubstituted (9% yield) oxazole de-
rivatives. Finally, no reaction was observed in the absence of
any copper species (Table 2, entry 11).
Table 2. Optimization of conditions for the reaction of phenylacetylene
and benzoyl azide catalyzed by [Tpa*Cu]PF6 complexes.[a]
Entry
Catalyst
Solvent
T [8C]
Yield 3/4/5 [%][b]
1
2
3
4
5
6
7
8
9
[Tpm*,BrCu(NCMe)]BF4
[TpaCu]PF6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
DCE
40
40
40
40
40
60
40
40
40
40
40
60:6:29
n.r.[c]
[Tpa*Cu]PF6
[TpaMe3Cu]PF6
[Tpa*,BrCu]PF6
[Tpa*Cu]PF6
[Tpa*Cu]PF6
[Tpa*Cu]PF6
[Tpa*Cu]PF6
[Tpa*Cu]PF6
–
71:22:0
18:5:0
53:5:0
33:6:0
70:1:0
60:5:0
50:0:0
95:0:0
n.r.[c]
THF
–
CHCl3
10
11
[a] Reactions conditions: phenylacetylene (1.2 mmol), benzoyl azide
(1 mmol), catalyst (0.05 mmol), solvent (1 mL). Either BF4 or PF6 can be
employed as counterions without any effect on the reaction outcome
[b] Isolated yield. [c] n.r.=no reaction.
This first screening demonstrated that the Tpa*Cu-based
system is more active and selective than that based on the
Tpm*,BrCu complex, because the former avoids formation of
the trisubstituted oxazole derivatives as well as the formation
of amides as by-products. With these results in hand, we fur-
ther explored the scope of the reaction by employing an array
of terminal alkynes and carbonyl azides (30 examples;
Scheme 4).
the reaction, i.e., the ratio of 2,5-disubstituted oxazole vs. tri-
substituted product, dropped from 10:1 found for the
Tpm*,BrCu complex to 3:1 observed for the Tpa*Cu analogue
(Table 2, entries 1 vs. 3).
In a general manner, the [Tpa*Cu]PF6 complex catalyzed the
reaction between 1-alkynes and carbonyl azides with the for-
mation of the disubstituted oxazole as the sole product in mod-
erate to good yields. The effect of the nature of the substitu-
Scheme 4. Synthesis of 2,5-disubstituted oxazoles through [Tpa*Cu]PF6-catalyzed reaction of 1-alkynes and carbonyl azides. Reagents and conditions: 1-
alkyne (1.2 mmol), carbonyl azide (1 mmol), catalyst (0.05 mmol). Isolated yields based on azide (average of two runs). The remaining initial azide was recov-
ered unreacted. [a] Reactions performed at 608C in DCE (1 mL). [b] Bisoxazole derivatives were isolated as minor by-products in 3–9% (see the Experimental
Section for details).
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ents R1 and R2 in the reactants deserve some comments. When
phenylacetylene was used as the substrate, the highest yield
was observed with the neutral benzoyl azide (Scheme 4, 6).
However, when either electron-rich or electron-poor benzoyl
azides were employed instead, the yield diminished, with the
decrease being more pronounced with the latter (7–8 vs. 9–
10). A similar behavior was noticed with respect to the nature
of the substituents on the aromatic ring of alkynes. When un-
substituted benzoyl azide was applied, phenylacetylene pro-
vided the best performance, whereas the electron-poor aryl
acetylenes gave the lowest yield (6 vs. 11, 15, 19). However,
these trends were not clear when electron-rich (R2 =p-Me-C6H4,
p-OMe-C6H4) or electron-poor (R2 =p-NO2) benzoyl azides were
used as the reactants. In such cases, the electronic nature of
the aryl alkyne seemed to have no significant influence on the
reaction outcome and both electron-rich and electron-poor
systems could be successfully
cate that the reaction follows a complex mechanistic pathway
in which the positive or negative electronic effects induced by
substrates could match in one step and mismatch in another.
A comparison between the catalytic performance of both
complexes, [Tpm*,BrCu(NCMe)]BF4 and [Tpa*Cu]PF6 in this
transformation is shown in Figure 2. It can clearly be seen that
the results achieved with the Tpa*–Cu system are better than
those obtained with the Tpm*,Br–Cu species, given the former
catalyst did not lead to the formation of trisubstituted oxazoles
or amides as by-products. Worthy of note is the substantial
yield improvement with aliphatic alkynes as substrates in the
[Tpa*Cu]PF6-catalyzed reactions. Overall, the complex [Tpa*-
Cu]PF6 has been shown to upgrade the catalytic activity, the
selectivity, and also the scope for this direct procedure toward
the synthesis of 2,5-disubstituted oxazoles, when compared
with the Tpm*,Br-containing catalyst.
employed (7–9 vs. 12–14, 16–
18, and 20–22). The presence of
a heterocycle on the alkyne, as
in 3-ethynylthiophene, was also
well-tolerated (23–25). Finally,
when alkyl-substituted alkynes
were applied, the reaction had
to be carried out at higher tem-
peratures (608C) to reach good
conversions, a feature also ob-
served in related CuAAC reac-
tions.[30] With these reactants,
the product yields appeared to
be affected by steric rather than
electronic effects on the alkynes
(cf. 26–31). Methyl propargyl
ether and 4-bromobutyne un-
derwent the reaction efficiently
with better isolated yields than
those obtained with nonfunc-
tionalized aliphatic alkynes (cf.
32–35). It should be pointed out
that in any reaction carried out
with aliphatic alkynes, small
amounts of a bisoxazole deriva-
tive (a product derived by the
coupling of two molecules of ox-
azoles) was isolated as a by-
product. Related bistriazoles
have also been observed as
by-products in CuAAC reactions
catalyzed by CuI salts in
the absence of
agent.[24e,25,31]
a
reducing
So far, it appears that there is
no clear relationship between
the reaction yield and the elec-
tronic properties of either the
alkyne or the carbonyl azide.
Figure 2. Comparison of the catalytic performance of complexes [Tpa*Cu]PF6 and [Tpm*,BrCu(NCMe)]BF4 (data
This observation seems to indi- from Table 1 and Scheme 4).
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Mechanistic studies: experimental data
product with the former, whereas, with the latter, the remain-
ing initial azide was recovered unreacted. Therefore the reac-
tion, albeit slow, took place in a selective manner.
In our previous contribution,[25] we proposed a mechanistic pic-
ture for this transformation based on the mechanistic studies
described to date for the related CuAAC reaction.[24a,e–f,26f,32]
Now we have collected some specific information on this
novel transformation to explore the mechanism through which
the reaction between carbonyl azides and alkynes takes place
in the presence of catalytic amounts of these CuI complexes.
Two different pathways could be invoked for the reaction to
initiate. As shown in Scheme 5, pathway A involves reaction of
However, the observed low yields did not convince us to
rule out the intermediacy of a Cu–acetylide in this process, so
we conducted a second experiment using deuterated-phenyl-
acetylene as the substrate [Eq. (3)]. The expected deuterated
oxazole derivative was isolated in high yield (85% for the
Tpm*,Br–Cu system and 62% for the Tpa*–Cu catalyst) as the
sole product.
Scheme 5. Possible pathways for the reaction of alkynes and carbonyl azides
catalyzed by CuI complexes.
the copper center with the terminal alkyne to form a Cu–acety-
lide species, which could coordinate the azide, leading to the
formation of a Cu–triazolyl intermediate. This route would be
similar to that proposed for the related CuAAC reaction.[24a,e–f]
On the other hand, the copper catalyst could react with the
carbonyl azide to form a copper–azide species from which N2
extrusion would generate a Cu–acyl nitrene intermediate. Fur-
ther interaction with the alkyne in subsequent steps would
lead to the observed oxazole derivative. This pathway finds
support in the well-known tendency of acyl azides to eliminate
N2, under thermal or photochemical conditions, to form ni-
trene species,[33] although it has not yet been proposed for
copper-catalyzed cycloaddition reactions. In this sense, very re-
cently, Davies and co-workers[34] reported the synthesis of
2,4,5-trisubstituted oxazoles by a gold-catalyzed intermolecular
[3+2] cycloaddition of alkynes and N-ylides, which is a potential
N-acyl nitrene equivalent.
For further confirmation, crossover experiments involving
PhCꢀCD and p-MeOC6H4CꢀCH were planned. As an initial test,
an equimolar mixture of the two alkynes was treated with
[Tpa*Cu]PF6 (Scheme 6, top). It could be shown in this way
that the copper complex catalyzed the H/D exchange, reaching
25% in only 15 min and being completed after 4 h. According
to this result, the [Tpa*Cu]PF6 catalyst seems to promote the
formation of Cu–acetylides, which are the most likely inter-
mediates in this exchange.[35]
Following this indication, the crossover experiments were
performed by addition of an equimolar mixture of the two al-
To distinguish between both
pathways, we carried out
a
number of experiments. Should
the reaction initiate with the for-
mation of a Cu–acetylide species
(path A), it would be reasonable
to expect that an internal alkyne
could not take part in this trans-
formation. However, when ben-
zoyl azide was treated with an
internal alkyne (1-phenyl-1-pro-
pyne; [Eq. (2)]), a small amount
oxazole was isolated at the end
of the reaction with both
[Tpm*,BrCu(NCMe)]BF4 and [Tpa*-
Cu]PF6 as the catalysts. Some
benzamide was observed as by- Scheme 6. Crossover experiments involving deuterated alkynes.
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kynes to an excess of benzoyl azide (1:2.5) in the presence of
either [Tpm*,BrCu(NCMe)]BF4 or [Tpa*Cu]PF6. Very interestingly,
the levels of scrambling remained very low with both catalysts
(Scheme 6, bottom). Thus, in spite of the potential ability of
the considered catalytic species for Cu–acetylide generation,
the results of the scrambling experiments strongly suggest
that the reaction pathway leading to the formation of 1,3-oxa-
zoles from terminal alkynes and acyl azides does not involve
a copper–acetylide as an intermediate (Scheme 7).
Scheme 7. Plausible equilibria of the copper complexes employed as pre-
catalysts with azide and alkyne reactants.
Computational studies
Calculations were carried out by using two different systems:
a model system with [TpmCu]+ as the catalyst, HCꢀCMe as the
alkyne, and N3C(=O)CH3 as the carbonyl azide, and the real
system using [Tpm*,BrCu]+, HCꢀCPh and N3C(=O)Ph as the cat-
alyst and reactants, respectively. The model system was em-
ployed to screen all mechanistic possibilities, and once the dif-
ferent possible pathways were defined, key calculations with
the real system were performed. First, the two major pathways
A and B, depicted in Scheme 5 were investigated on the
model system.
Pathway A: Cu–triazolyl
According to the generally accepted mechanism for the click
reaction, the process starts with the formation of a copper–
acetylide species.[36] The formation of this copper–acetylide re-
quires cleavage of the terminal alkynylꢁH bond, and the
proton has to be taken by some species with base properties.
The problem of the nature of this base has not been analyzed
in detail in previous computational studies,[36] but has to be ex-
plicitly considered here because we are discussing the compe-
tition with mechanisms for which this copper–acetylide species
is not formed. According to the calculations detailed in the
Supporting Information, we have found that the use of reac-
tion product oxazole as base provides a lower-limit estimation
for the free energy cost of this proton abstraction. In this opti-
Figure 3. Reaction pathways A and B. Relative free energies in kcalmolꢁ1
.
pects are provided in the Supporting Information. Alternative
mechanisms with participation of dinuclear copper intermedi-
ates have been proposed for the CuI-catalyzed cycloaddition of
azides and alkynes.[37] We did not consider this option here be-
cause mononuclear species were sufficient to explain the ob-
served experimental behavior.
Pathway B: Cu–nitrene
This pathway starts by coordination of the azide through both
the nitrogen and the oxygen atoms (see Figure 3, pathway B).
This species evolves to the acyl nitrene intermediate by N2 ex-
1
mal case, the transformation from the starting complex C1 (C
for computed, superscript 1 for singlet electronic state) to the
copper–acetylide intermediate 1C2 has a free energy cost of
8.8 kcalmolꢁ1 (see Figure 3, pathway A). Further interaction
with the azide and formation of the first CꢁN bond proceeds
through transition state 1TS2–3 located at 30.7 kcalmolꢁ1
1
trusion, through TS4–5 located at 22.4 kcalmolꢁ1 above reac-
tants (geometry presented in Figure 4). The acyl nitrene re-
mains coordinated through both the nitrogen and oxygen
atoms, at ꢁ5.4 kcalmolꢁ1 below the starting materials. Once
the acyl nitrene is formed, the reaction is not expected to
revert towards reactants due to N2 elimination. The triplet and
singlet potential energy surfaces remain close in energy in this
region of the potential energy surface. In fact, the ground
1
above the reactants. Figure 4 presents the geometry of TS2–
3. From here it has been postulated[36] that the formation of
the second CꢁN bond takes place through a second transition
state, which we could not locate at the M06 level. However, its
eventual existence is in any case not relevant to the current
discussion (see below). Further details on these technical as-
3
state of the acyl nitrene is a triplet C5 in which the nitrene is
coordinated through only the nitrogen atom. Crossing be-
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to the Cu–nitrene species, forming a p-complex 1C6 with a rela-
tive energy of 3.4 kcalmolꢁ1 (Figure 5). Formation of the CꢁN
bond proceeds through transition state 1TS6–7 (Figure 4).
1
From C7, a rotation of the acyl group allows its coordination
to the copper center, leading to the formation of a six-mem-
1
bered ring intermediate in C8. Subsequent CꢁO ring closure
1
can take place with virtually no barrier, resulting in species C9,
in which the oxazole product is weakly coordinated to the cat-
alyst. The highest energy barrier in path B1 is 5.2 kcalmolꢁ1
,
which is significantly lower than the 22.4 kcalmolꢁ1 reported
above for the formation of the Cu–nitrene intermediate
(Figure 3, pathway B).
Pathway B2 initiates with formation of the acetylide from
the terminal alkyne. The problem with the proton abstraction
step is the same as discussed above for path A, and we have
taken the same approach described above and in the Support-
ing Information to obtain a low-limit estimate of the free
energy cost of this abstraction. When doing so, the copper–
acetylide–nitrene intermediate 1C10 is located at 12.5 kcal
molꢁ1 (see Figure 5). We estimated an energy of 12.7 kcalmolꢁ1
1
for the subsequent transition state TS10–11, corresponding to
CꢁN bond formation (the PES is very flat in this region and the
TS could not be located with the M06 functional, the energy
presented corresponds to a species with the CuꢁN and CꢁN
distances frozen at the B3LYP TS geometry, see Figure 4). The
1
next formed intermediate C11 is very stable and, from there,
Figure 4. Structures, including selected bond distances (in ꢄ), of the key
transition states. The hydrogen atoms of the Tpm ligand have been re-
moved for clarity.
the oxazole is formed by rearrangement and protonation
steps. The highest energy in in path B2 is 12.7 kcalmolꢁ1. Be-
cause of this, this pathway can be discarded when compared
with path B1 (5.2 kcalmolꢁ1). This is also in agreement with the
experimental results obtained with deuterated phenylacety-
lene, which are not compatible with path B2.
tween surfaces takes place through a Minimum Energy Cross-
ing Point (MECP)[38] with a relative energy of 1.4 kcalmolꢁ1, also
shown in the profile in Figure 3. The triplet species is intro-
duced here for the sake of completion, although, as will be
seen below, the same qualitative conclusions could be ob-
tained by considering only the single electronic state. The N2
extrusion is thus expected to take place with a barrier of
23.0 kcalmolꢁ1, which corresponds to the energy difference be-
The real system
To check the validity of the conclusions extracted from the
model system, we carried out calculations on key species by
using the real ligand Tpm*,Br and the substrates PhC(=O)N3
and PhCꢀCH. These relative energies are summarized in
Table 3.
1
1
tween C4 and TS4–5. Formation of the Cu–nitrene complex
(pathway B) is preferred over formation of the Cu–triazolyl
complex (pathway A), because the barrier for the former is
7.7 kcalmolꢁ1 lower in energy. Thus, we should
expect the formation of acyl nitrene intermediate
3C5. This finding rules out the mechanism previously
hypothesized,[25] and is fully consistent with the ob-
served complete deuteration at the fourth position
of the oxazole ring.
Table 3. Relative free energies of the most relevant species (kcalmolꢁ1) of the model
and the real system.
Path
Species
Model
Real
[LCu]+ +RN3 +HCꢀCR+B
0.0
8.8
0.0
9.2
Once the Cu–nitrene complex 3C5 is formed, we
can envision different mechanistic possibilities, of
which the two lowest in energy are presented here:
1) B1, the direct formation of the CꢁN bond with the
alkyne, and 2) B2, the formation of the CꢁN bond
through a copper–acetylide intermediate. A third
possibility, B3, is presented in the Supporting Infor-
mation. Because all these pathways occur mostly in
the singlet PES, they start with crossing from triplet
to singlet PES through the same MECP mentioned
above. Path B1 starts with coordination of the alkyne
A
A
B
B
[LCu(CꢀCR)]+RN3 +BH+
1TS([LCu(CꢀCR)]+RN3![LCu(triazole)])+BH+
1TS([LCu]+ +RN3![LCu(NR)]+N2)+B+HCꢀCR
1[LCu(NR)]+ +N2 +B+HCꢀC-R
30.7
22.4
ꢁ5.4
ꢁ6.7
5.2
34.5
24.1
ꢁ5.5
ꢁ7.2
B
3[LCu(NR)]+ +N2 +B+HCꢀC-R
B1
B2
B2
1TS([LCu(NR)]+ +HCꢀCR![LCu(RCꢀC(H)ꢁNR)]+)+B+N2
1[LCu(NR)(CꢀCR)]+BH+ +N2
2.7[a]
12.5
12.7[b]
16.3[a]
14.0[c]
1TS([LCu(NR)(CꢀCR)]![LCu(RCꢀCꢁNR)]+)+BH+ +N2
[a] Corresponding to an optimized geometry with the CꢁN distance frozen to that of
the model system. [b] Frozen structure at the CuꢁC, CuꢁN and CꢁN distances of the
B3LYP geometry. [c] Frozen structure at the CuꢁN and CꢁN distances of the B3LYP ge-
ometry.
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The reaction profiles do not
change significantly from the
model to the real system. From
data shown in Table 3, path-
way B is also preferred over
pathway A in the real system
(highest free energy points of
24.1 vs. 34.5 kcalmolꢁ1). Further-
more, path B1 is also preferred
over path B2 (highest energies
of 2.7 and 16.3 kcalmolꢁ1, re-
spectively). Therefore, formation
of the oxazole is expected to
take place through the copper–
acyl nitrene intermediate, fol-
lowed by coordination of the
alkyne, and formation of the Cꢁ
N bond. The overall rate-limiting
step of the reaction is N2 extru-
sion, which leads to the forma-
tion of the copper–acyl nitrene
intermediate.
We also examined the overall
regioselectivity of the process in
our calculations. The exclusive
formation of the 2,5-disubstitut-
ed oxazoles is experimentally
observed, and it was reproduced
by our calculations. The regiose-
lectivity-determining transition
state is 1TS6–7, when the NꢁC
bond is made (shown in
Figure 4). The transition state
leading to the favored regioiso-
mer has lower energy than the
transition state 1TS6–7’ leading
to the (unobserved) 2,4-disubsti-
tuted oxazole. The energy differ-
ence between the two transition
states is related to the nonsym-
metric coordination of the
alkyne to copper. The unsubsti-
tuted carbon binds more strong-
ly, and is thus more activated to-
wards attack by the nitrogen, as
can be observed in Figure 4. The
difference is 1.6 kcalmolꢁ1 (5.2
vs. 6.8 kcalmolꢁ1) for the model
system and 3.6 kcalmolꢁ1 (2.7 vs.
6.3 kcalmolꢁ1) for the real
system, which is sufficiently
large to explain the observation
of a single regioisomer.
Figure 5. Calculated reaction pathways B1 (top) and B2 (bottom) leading to the formation of the final oxazol from
the copper–nitrene intermediate 1C5. Free energy values in kcalmolꢁ1
.
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sis. The sample was recovered and the crude reaction material was
purified by flash chromatography on silica gel (diethyl ether/petro-
leum ether, 1:30) to afford the desired product as a white solid.
Yield: 85% for [Tpa*,BrCu(NCMe)]BF4 and 62% for [Tpa*Cu]PF6;
1H NMR (400 MHz, CDCl3): d=7.98 (d, J=8.8 Hz, 2H), 7.64 (d, J=
7.5 Hz, 2H), 7.37 (t, J=7.7 Hz, 2H), 7.26 (t, J=7.4 Hz, 1H), 6.93 (d,
J=8.8 Hz, 2H), 3.81 ppm (s, 3H); 13C {1H} NMR (100 MHz, CDCl3):
d=161.3, 150.4, 128.8, 128.1, 128.1, 127.9, 124.0, 120.2, 114.2,
55.4 ppm; elemental analysis calcd (%) for C16H12DNO2: C, 76.17; H,
4.80; N, 5.55; found: C, 76.03; H, 5.10; N, 5.55.
Conclusion
Cationic [Tpm*,BrCu(NCMe)]BF4 and [Tpa*Cu]PF6 complexes cat-
alyze the regioselective formation of 2,5-disubstituted oxazoles
from carbonyl azides and terminal alkynes. The Tpa*-based
system is found to be more selective and active than the
Tpm*,Br–Cu derivative. Experimental and computational evi-
dence indicates that the reaction proceeds by coordination of
the carbonyl azide to the copper center and subsequent extru-
sion of a dinitrogen molecule to produce [LCu(NC(O)R)]+ inter-
mediate. Formation of this copper–nitrene intermediate is the
rate-limiting step of the whole process. Subsequently, the
alkyne binds to the metal, forming a p-complex rather than
the copper–acetylide intermediate, and the system evolves
through low barriers to the observed 2,5-disubstituted oxazole
product. This mechanism differs from that proposed for the re-
lated alkyne–azide cycloadditions (CuAAC), and opens the way
for new developments in this field.
Computational details
Calculations were performed by using the Gaussian 09 package[40]
within the B3LYP[41] and M06[42] formalisms. The standard 6–31+
G(d)[43] basis set was used to describe the H, C, N, O and Br atoms,
with the exception of the C and H atoms of the Tpm*,Br ligand in
the real system for which the 6–31G basis set was used instead.
The large core scalar relativistic pseudopotentials developed by
Dolg et al.[44] were used for the copper coupled to a double-zeta
quality basis set. Full geometry optimizations were performed in
solution with the Polarizable Continuum Model (PCM) method,[45]
with Gaussian 09 defaults for chloroform. Unless otherwise stated,
all energies presented correspond to M06 free energies computed
in solution (temperature 298 K, pressure 1 atm). The B3LYP method
produced qualitatively similar results, which can be found in the
Supporting Information. The nature of the stationary points en-
countered were characterized by a vibrational analysis performed
within the harmonic approximation. Transition states were identi-
fied by the presence of one imaginary frequency and minima by
a full set of real frequencies. Minimum Energy Crossing Points
(MECPs) were located by using the code developed by Harvey’s
group;[46] free energies at the MECP were approximated to the
averaged projected frequencies at the two potential energy surfa-
ces. The triplet electronic state has a minor contribution to the
overall chemistry of the system; because of this, we did not com-
pute the open-shell singlet electronic state, which should have
a similar energy. For more details see the Supporting Information.
Experimental Section
General methods
All reactions and manipulations were carried out under an oxygen-
free nitrogen atmosphere by using standard Schlenk techniques.
All substrates were purchased from Aldrich. Solvents were dried
and degassed before use. Tris(3,5-dimethyl-pyrazolylmethyl)ami-
ne[28b] and complexes [Tpa*Cu]PF6
and [Tpm*,BrCu(NCMe)]BF4
[28c]
[39]
were prepared according to published procedures. The synthesis
and full structural characterization of unknown Tpa ligands and
[Tpa*Cu]PF6 complexes will be reported elsewhere. NMR spectra
were recorded with a Varian Mercury 400 MHz spectrometer.
1H NMR shifts were measured relative to deuterated solvents peaks
but are reported relative to tetramethylsilane. Elemental analyses
were performed with a PerkinElmer 2400 Series II instrument. Iden-
tification and characterization of oxazole derivatives are given in
the Supporting Information.
Acknowledgements
General catalytic procedure for the reaction of terminal al-
kynes and carbonyl azides catalyzed by [Tpa*Cu]PF6
We thank MINECO (CTQ2011–28942-CO2–01, CTQ2011–27033,
CTQ2008–00947/BQU and CTQ2012–38594-C02–01) and Consolider
Ingenio (2010 CSD2006–0003), Fondos Feder, DEC (2009SGR259,
2009SGR623), Junta de Andalucꢅa (Proyectos P07-FQM-02745 and
P10-FQM-06292), and the ICIQ Foundation.
The catalyst (28.35 mg, 0.05 mmol) and the carbonyl azide
(1 mmol) were dissolved in the alkyne (1.2 mmol) under a nitrogen
atmosphere and the reaction mixture was stirred at 408C for 24 h.
Volatiles were then removed under vacuum and the residue was
dissolved in CDCl3. An precisely weighted amount of trimethylvi-
nylsilane was added as internal standard and the mass balance
was then determined by 1H NMR spectroscopic analysis. The
sample was recovered and the crude reaction material was then
purified by flash chromatography on silica gel (diethyl ether/petro-
leum ether, 1:30) to afford the desired products.
Keywords: alkynes · click chemistry · copper · nitrenes ·
oxazoles · reactive intermediates
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Received: September 24, 2013
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Chem. Eur. J. 2014, 20, 3463 – 3474
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ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim