From N-benzoylpyridinium imides to pyrazolo[1,5-a]pyridines: A mechanistic discussion on a stoichiometric Cu protocol

Article abstract of DOI:10.1039/c3ob40448j

A Cu-mediated preparation of 2-substitiuted pyrazolo[1,5-a]pyridines from N-benzoylpyridinium imides and terminal alkynes is described using stoichiometric Cu(OAc)₂ as both the mediator and the oxidant. Extensive DFT calculations suggest a Cu(i

Full text of DOI:10.1039/c3ob40448j

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From N-benzoylpyridinium imides to pyrazolo[1,5-a]-
pyridines: a mechanistic discussion on a stoichiometric
Cu protocol†
Cite this: Org. Biomol. Chem., 2013, 11,
3894
Lin Ling,‡b Jingqing Chen,‡a Jiahui Song,a Yuhai Zhang,a Xinqian Li,b Lijuan Song,a
Feng Shi,*a Yuxue Li*b and Chunrui Wu*a
Received 25th February 2013,
Accepted 4th April 2013
A Cu-mediated preparation of 2-substitiuted pyrazolo[1,5-a]pyridines from N-benzoylpyridinium imides
and terminal alkynes is described using stoichiometric Cu(OAc)2 as both the mediator and the oxidant.
Extensive DFT calculations suggest a Cu(III) intermediate via disproportionation of Cu(II).
DOI: 10.1039/c3ob40448j
www.rsc.org/obc
(Scheme 1B). Very recently, Jiao disclosed a Cu/Ag-co-catalyzed
aerobic oxidative coupling of the same substrates
Introduction
Pyrazolo[1,5-a]pyridines1 have received considerable attention (Scheme 1C).15 Chen reported a closely analogous system
from medicinal chemists as a promising privileged structure. using a Cu/Ag-co-catalyzed inverse Sonogashira16 coupling/
Derivatives thereof exhibit remarkable bioactivities including cyclization as the strategic step.17 Needless to mention, repla-
5HT3-antagonists,2 p38 kinase inhibitors,3 dopamine D3/D4 cement of expensive and environmentally detrimental Pd cata-
agonists and antagonists,2,4 anti-herpetic agents,5 and potent lysts with Cu species and elimination of stoichiometric Ag
treatments for cardiac arrhythmias.6 With the development of salts (in Charette’s case, 4 equiv. of AgOBz) are of great practi-
modern transition-metal catalysis, preparation of pyrazolo[1,5-a]- cal value.
pyridine derivatives has witnessed rapid improvements in
Our two groups have also been working on the same reac-
recent years. To this end, an Fe-catalyzed rearrangement of tion and have approached it from another perspective. It has
2-(2-pyridyl)-2H-azirines3a,7 and a Cu- or Au-catalyzed electro- been known that Cu(II) can act as single electron oxidants.
philic cyclization8 have emerged with a much wider scope Therefore, we envisioned that the same transformation could
than the traditional approaches.
be achieved by employing a stoichiometric quantity of a “cata-
A new promising route appeared in the literature in 20109 lytically” active Cu(II) species as both the “catalyst” and the
that involves a Pd-catalyzed ortho C–H activation of N-benzoyl- terminal oxidant (Scheme 1D). By doing so, Charette’s Pd/Ag
pyridinium imides10 in a cross-coupling scenario with vinyl binary system and Jiao’s Cu/Ag/O2 trinary system can be largely
iodides, combined with a subsequent 5-endo cyclization in the
same pot (Scheme 1A). Although the use of vinyl iodides posed
practical drawbacks, this pioneering study opened a door to a
series of developments later. Thus, the same group discov-
ered,11 through their mechanistic concerns, a Pd-catalyzed oxi-
dative protocol utilizing terminal alkynes12–14 in place of vinyl
iodides with stoichiometric Ag(I) as the terminal oxidant
aKey Laboratory of Natural Medicine and Immuno-Engineering of Henan Province,
Henan University, Jinming Campus, Kaifeng, Henan 475004, P. R. China.
E-mail: fshi@henu.edu.cn, cwu@henu.edu.cn; Fax: +86-378-286-4665;
Tel: +86-378-286-4665
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032,
China. E-mail: liyuxue@sioc.ac.cn
†Electronic supplementary information (ESI) available: Experimental details,
characterization of products, computational details, and full NMR spectra. See
DOI: 10.1039/c3ob40448j
‡These two authors contributed equally.
Scheme 1 From N-benzoylpyridinium imides to pyrazolo[1,5-a]pyridines.
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simplified into a Cu-alone system. Although aerobic turnover and addition of pyridine bases gave no improvement regard-
of Cu is still beneficial, lack of such turnover does not appear less of electronics and sterics of the pyridine bases (see
economically poor given the low cost of Cu salts and the high ESI†).18
chance of recycling Cu in large-scale processes.
Glaser dimerization19 is a common side-reaction in oxi-
At the same time, we also found that the mechanism of the dative alkynylation reactions and sometimes necessitates
aforementioned methods have not been adequately addressed. syringe pump addition of alkynes.13a,b In our hand, this was
The nature of the C–H bond cleavage and the change of oxi- not necessary, although batchwise addition of alkyne was still
dation states of the metal catalysts during the reaction, beneficial (entries 8 and 9).14b
especially that of Cu, are of particular interest. Herein, we wish
As our reactions were set up without precautions to exclude
to disclose our findings in the stoichiometric Cu protocol for air, we tested the possibility of aerobic oxidation under our
the same overall transformation and more importantly the conditions. Indeed, the yield suffered a noticeable decrease if
mechanistic rationale in a computational perspective. As air was carefully excluded (entry 10). But it remained signifi-
readers may find, our extensive DFT calculations bring quite a cant, speaking for the genuine Cu(II) oxidation. This was
few interesting details that are not adequately clarified in the further supported by the fact that running the reaction under
previous studies.
pure oxygen atmosphere did not improve the yield. Under
either air or N2, there was no Cu mirror formation under the
optimal conditions, supporting a single electron oxidation of
Cu(II) to Cu(I).
Results and discussion
Development of the protocol
However, re-oxidation of the possible Cu(I) back to catalyti-
cally active Cu(II) species, thus completing a turnover of Cu,
proved difficult.20 Running the reaction under pure O2 with
catalytic quantity of Cu(II) did not seem to offer an unambigu-
ous turnover of Cu (entry 11). Among a wide range of oxidants
tested, including BQ, DDQ, TEMPO, and several Fe(III) species
(see ESI†),21 only Ag(I) was identified as a useful re-oxidant
(entries 12 and 13). In a cost-economical aspect, employing
stoichiometric Ag(I) to turnover Cu(II) does not sound a reason-
able solution and our best conditions therefore were chosen as
those shown in entry 8.
Table 1 briefly lists part of our results in the survey of reaction
conditions. As expected, 3.0 equiv. of anhydrous Cu(OAc)2
alone effected a 37% yield of the desired product from the
model reaction of 1a and 2a (entry 1). KOAc was identified as
the best base (entries 1–4) and dioxane as the best solvent
(entries 4–7). Other Cu(II) species, including Cu(OTf)2, CuBr2,
and CuCl2, were largely inactive even with addition of KOAc,
Table 1 Optimization of the Cu-mediated conditionsa
We have also noticed that CuBr, a Cu(I) species, was
effective (entry 14, note: CuBr2 was completely inactive) to
furnish a low yield of 3a. But it was later found to be an air
effect (entry 15). CuI, the optimal catalyst in Jiao’s system, was
inactive under our conditions. We also tested whether the reac-
tion was actually promoted by Pd impurities in the Cu(OAc)2.22
Thus, addition of 5 mol% of Pd(OAc)2 to the optimal con-
ditions resulted in a significant drop of yield to <15%. Repla-
cing the 3 equiv. of Cu(OAc)2 with 5 mol% of Pd(OAc)2 led to a
complete failure. Thus the involvement of Pd in our reaction is
not supported.
Entry [Cu]/equiv.
Base
Atmosphere Solvent
Airc
Yieldb (%)
1
2
3
4
5
6
7
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/3.0
Cu(OAc)2/0.35 KOAc
Cu(OAc)2/0.35 KOAc
AgOAc/2.0
Cu(OAc)2/0.35 KOAc
AgOAc/2.0
—
Dioxane 37
Dioxane 25
K2CO3 Airc
KOBz
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Airc
Airc
Airc
Airc
Airc
Airc
Airc
N2 f
O2
Dioxane 36
Dioxane 47
Tol
PhCl
DMSO
Dioxane 57
Dioxane 69
Dioxane 37
Dioxane 30
Dioxane 54
42
36
Trace
Scope and limitations of the protocol
8d
9e
10d
11d
12d
A range of N-benzoylpyridinium imides (1) and terminal
alkynes (2) were examined (Scheme 2). Briefly, the reaction tol-
erated a variety of substituted phenylacetylenes. A heteroaryl-
acetylene (as in 3e) and a vinylic alkyne (as in 3f) could also be
successfully employed. However, 2-ethynylpyridine (not shown)
and an alkyl alkyne (as in 3g) failed to react. Our scope of
alkynes is closer to Jiao’s but narrower than Charette’s,11 as
the latter can accommodate alkyl ones.
Substituted pyridinium imides showed a relatively broad
scope as long as the 2- or 6-positions are not substituted. Pico-
linium imide, for example, afforded a low conversion to a
rearranged product 4 at 140 °C, in accordance with Charette’s
observation,11 and the 2-methoxy derivative was largely unreac-
tive (as in 3h). Substitution at 3- or 4-positions was tolerated,
Airc
13d
N2
Dioxane 46
14d
15d
CuBr/3.0
CuBr/3.0
KOAc
KOAc
Airc
N2
Dioxane 26
Dioxane
—
a Reaction conditions: 1a (∼0.2 mmol), 2a (2.0 equiv., added in one
portion), Cu salt, and base (3.0 equiv.) in 4 mL of solvent. b Isolated
yields. c Head space of the sealed tube contains ∼1.1 equiv. of O2. d 1.0
Equiv. of 2a was added first, another 1.0 equiv. was added after 12 h,
and reaction continued for 12 h. e 1.0 Equiv. of 2a was added first,
another 1.0 equiv. was added after 8 h, a third 1.0 equiv. was added
after another 8 h, and reaction continued for 8 h. f Head space of the
sealed tube contains ∼5.5 equiv. of O2.
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Scheme 4 Formation of a 3-alkynylated pyrazolo[1,5-a]pyridine.
conditions using dtbpy (4,4′-di-tert-butyl-2,2′-bipyridyl) as the
ligand. Regretfully, we are not yet able to bring the yield to a
synthetically meaningful level. To date, trapping the presumed
3-cupriopyrazolo[1,5-a]pyridine intermediate with electrophiles
such as Ac2O has not been successful.
Possible mechanisms suggested by experimental results
At least two mechanistic candidates merit consideration. One
is the “Cu(I)–Cu(III)” process described by Jiao, and the other
is an addition–rearomatization process demonstrated by
Katritzky in a related 1,2,4-triazolium N-tosylimide system.24
The latter involves a dihydropyridine intermediate A with no
change in the oxidation state of Cu during the C–C bond for-
mation and concludes in a rearomatization step (Scheme 5),
which can be elimination of the Ts− (for the N-tosyl imide) or
transacylation and dehydrogenation25 (for the N-benzoyl
imide).
However, experimental results did not support this mecha-
nistic pathway. Under Katritzky’s optimal conditions (cat. CuBr,
pyridine, DCM, rt), 1a did not afford 3a, neither did the N-tosyl
variant 1a′ (Scheme 6). Only a 22% yield of 3a was obtained
under our optimal conditions using 1a′ as the substrate.
Keeping in mind that conversion from A to 3 would be easier
for 1a′ than for 1a (elimination of Ts− is more facile than trans-
acylation/dehydrogenation26). Thus if this mechanism were in
operation, 1a′ should result in a higher yield, which did not
happen. Moreover, this pathway can hardly explain the
difficulty in the turnover of Cu.
Thus, attention was directed to the Cu(I)–Cu(III) mechan-
ism. An isotope labelling experiment was performed before-
hand with 3 equiv. of 1a, 3 equiv. of 1a-d5,27 and 1 equiv. of 2a
under the standard conditions, which revealed a mixture con-
taining 3a, 3a-d1, 3a-d3, and 3a-d4 by MS analysis
(Scheme 7).28 This implied a rather facile H–D scrambling of
Scheme 2 Substrate scope.
and in the former case, C–H metalation occurred more to the
less sterically hindered 6-position (as in 3l/3l′ and 3m).23 This
observed regioselectivity may be slightly different from the
results obtained under Charette’s or Jiao’s conditions. The
moderate yields of the process largely arose from the low con-
versions of 1, which could be recovered if necessary.
In addition to pyridinium imides, N-benzoylisoquinolinium
imide could also be successfully employed (as in 3n) where the
1-position reacted preferentially. Surprisingly, quinolinium
imide failed to give a satisfactory yield of the desired product
under our conditions (Scheme 3). A continuing 3-alkynylation
seemed to take place leading to 5a (inseparable with the
desired product 3o). This observation could be exploited to
couple 1a with two molecules of 2b (Scheme 4) in a modest
23% yield (in addition to a 36% yield of 3b) under Pd-catalyzed
Scheme 3 Reaction of N-benzoylquinolinium imides.
3896 | Org. Biomol. Chem., 2013, 11, 3894–3902
Scheme 5 Addition-rearomatization pathway.
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Scheme 6 Evidence against the addition-rearomatization pathway.
Scheme 8 Structures of Cu2(OAc)4 and the catalyst–substrate complex. (Red
italic numbers are spin densities; the arrows are the spin of the single electrons;
distances are in Å; relative free energies ΔGsol are in kcal mol−1.)
Scheme 7 Isotope labelling experiment.
energy surfaces (PES) was located with the code developed by
Harvey and co-workers.36,37
1a and 1a-d5 prior to, or in competition with, the C–H alkyny-
lation step. Such scrambling most likely takes place at 2- and
6-positions of 1a and 1a-d5, as evidenced by the 1H NMR spec-
trum, and is confirmed to be effected by the Cu species rather
than KOAc. We should mention that a similar H–D scrambling
has been documented by Charette in a Cu-catalyzed coupling
reaction of a same substrate.29 Because of the H–D scrambling,
our experimental data that 1a and 1a-d5 participated in the
First, the structure of the “catalyst” was studied. Copper(II)
acetate is a binuclear complex (Cu2(OAc)4), adopting the
“paddle wheel” structure (Scheme 8),38 in which each acetate
forms a syn–syn bridge between the two Cu atoms. The stability
of the singlet biradical (BiCu-Singlet, −0.1 kcal mol−1) is
similar to that of the binuclear triplet structure BiCu-Triplet.
The calculated dissociation energy of BiCu-Triplet to the
mononuclear structure (MonoCu-Triplet) is 10.1 kcal mol−1
.
1
reaction in a 1.22 : 1 ratio (obtained from H NMR spectrum)
The most favorable structure of the catalyst–substrate complex
BiCu-R is 11.8 kcal mol−1 more stable than the dissociated
BiCu-R′. Therefore, BiCu-R was used as the zero energy refer-
ence point in the calculation.
hardly reflects the true KIE value.30
Nonetheless, it does not support that the C–H bond clea-
vage process is rate-limiting under our conditions.
At this point, further experimentation to probe the reaction
mechanism would be difficult. Thus we shifted our attention
to computational approaches.
The possibility of disproportionation of copper(II) acetate to
Cu(III) and Cu(I) at this stage was estimated with the model
reaction shown in Scheme 9. The ΔGsol of this reaction is
44.8 kcal mol−1, about 55 kcal mol−1 relative to BiCu-Triplet,
indicating that such disproportionation prior to reaction with
the substrates is largely impossible. Therefore, reaction directly
initiated from Cu(I) and/or Cu(III) can be safely ruled out.
The addition–rearomatization mechanism shown in
Scheme 5 was excluded next. Calculations revealed a barrier
Computational mechanistic studies
Extensive density functional theory (DFT)31 studies were per-
formed with Gaussian09 program32 using B3LYP33 method.
For C, H, O, and N, the 6-31G* basis set was used, and for Cu,
the SDD34 basis set with Effective Core Potential (ECP) was
used. Structures were optimized with SMD35 method in
dioxane (ε = 2.2099). Harmonic vibration frequency calcu-
lations confirmed that the optimized structures are either
minima (having no imaginary vibration) or transition states
(having one imaginary vibration). To get more accurate ener-
gies, the free energies obtained were corrected by single point
calculations with larger basis sets (6-311+G** for C, H, O, and
N, Aug-cc-PVTZ for Cu) in dioxane. Substrates 1a and 2a were
used in the calculation models. The minimum energy crossing
for the addition step alone as high as 43.2 kcal mol−1 36
This
.
Scheme 9 The unfavourable disproportionation of Cu(OAc)2 to Cu(III) and
point (MECP) between the triplet and singlet state potential Cu(I).
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Scheme 10 The calculated Mononuclear-Cu(II) pathway. (Red italic numbers are spin densities; relative free energies ΔGsol are in kcal mol−1; selected bond lengths
are in Å.)
Scheme 11 The calculated Binuclear-Cu(II) pathway. (A) The deprotonation steps; (B) the “reductive elimination” step. (Red italic numbers are spin densities; relative
free energies ΔGsol are in kcal mol−1; selected bond lengths are in Å.)
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is not surprising, as Katritzky’s system is a 5-membered ring obtained. The reductive elimination of BiCu-INT3 over tran-
which has less aromaticity than pyridine and the dearomatiza- sition state BiCu-TS-RE-T leads to BiCu-RE-P-T, in which Cua
tion via nucleophilic addition is more feasible.
can be approximately considered as Cu(I) and Cub nearly keeps
Two pathways involving Mononuclear-Cu(II) and Binuclear- a Cu(II) state. Similar to the situation of the mononuclear-Cu(II)
Cu(II) were examined. The Mononuclear-Cu(II) pathway is shown pathway, there is a spin distributed on the alkynyl group, indi-
in Scheme 10. The relative free energy of the reactant complex cating that this reductive elimination is again an SET step.
MCu-R was obtained by comparing the energies of BiCu-R and However, the barrier for the SET (47.5 kcal mol−1) is still too
BiCu-R′. From MCu-R, the two substrates 1a and 2a are high.
sequentially deprotonated via CMD (concerted metalation
Since the reductive elimination process of Cu(II) appears
deprotonation) mechanism39 by two acetates, leading to MCu- rather difficult in every mechanistic pathway studied so far, we
INT2. Notice that deprotonation of the pyridine takes place wished to bring Cu(III) back for consideration, and see if it can
prior to the deprotonation of the alkyne, and a reverse deproto- lead to an easier reductive elimination step. Using BiCu-INT3
nation sequence proves unfavourable.36 Reductive elimination as the initial structure, the singlet state intermediate BiCu-
of MCu-INT2 leads to the cross-coupled product MCu-RE-P. INT3-S was obtained after optimization (Scheme 12). Passing
Notice again that in MCu-RE-P, 0.75 spin density is distributed through BiCu-Dis-TS1, the Cu–Cu distance is elongated from
on the pyridyl group and the double bond altogether, and only 2.965 Å to 3.218 Å in BiCu-Dis-INT1, indicative of the two Cu
0.13 is located on the Cu atom. This result strongly argues atoms being completely separated. This intermediate explicitly
against a Cu(II)-to-Cu(0) reductive elimination, as Cu(0) should contains a Cu(III) and a Cu(I) moiety, and allows for a reductive
bear a single electron. Hence this “reductive elimination” is elimination with an overall barrier of 32.2 kcal mol−1 to yield
actually a single electron transfer (SET) process, where Cu(II) is BiCu-RE-P-S. This barrier is reasonable considering the experi-
reduced to Cu(I). Experimental results are in agreement with mental conditions, and it is not surprising due to the high
the calculation in the sense that under the optimal conditions, reactivity of Cu(III).
Cu mirror formation was not observable. Nonetheless, this
pathway has a daunting barrier of 52.0 kcal mol−1, and can BiCu-Dis-INT1) could be produced via disproportionation of
thus be safely excluded. the Cu(II) species. Before the transition state BiCu-Dis-TS1, a
Then the key point is whether the Cu(III) species (such as
The Binuclear-Cu(II) pathway is shown in Scheme 11. From minimum energy crossing point (MECP) between the triplet
the substrate–catalyst complex BiCu-R, 1a and 2a are again and singlet state potential energy surfaces (PES) was located.
sequentially deprotonated via CMD mechanism by two acet- At MECP, both energies and geometries of the triplet and
ates, leading to the intermediate BiCu-INT2. After releasing singlet states are the same. The reaction system may thus
two molecules of HOAc, an intermediate BiCu-INT3 is change its multiplicity, i.e. in a spin-inversion process, at this
Scheme 12 The calculated disproportionation and reductive elimination steps in the Binuclear-Cu(II) pathway. (Red italic numbers are spin densities; relative free
energies ΔGsol are in bold; energies in italic are ΔEsol calculated at B3LYP/6-31G* level; all energies are in kcal mol−1; selected bond lengths are in Å.)
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Scheme 13 The calculated 5-endo cyclization to the final product. (Relative free energies ΔGsol are in kcal mol−1; selected bond lengths are in Å.)
point so that the lower-energy pathway beyond this point is after a conformational change, yields Cyc-INT2′. Subsequent
accessible. This is termed as the “Two-State Reactivity” and is expulsion of the benzoyl moiety by an acetate via Cyc-TS-OC
a common phenomenon in transition-metal catalysis.37 Thus affords the final product while releasing a molecule of a mixed
BiCu-INT3 goes along the triplet state PES, passes through anhydride. This process is easy since the highest barrier is just
MECP, and changes the pathway to the singlet state PES. The 17.1 kcal mol−1 (from Cyc-INT2′ to Cyc-TS-OC).
energy of this MECP is 3.9 kcal mol−1 (ΔEsol, on B3LYP/6-31G*/
SDD level) lower than that of the reductive elimination tran-
sition state (BiCu-TS-RE-S), strongly supporting the dispropor-
tionation of Cu(II) species in our reaction. To the best of our
Conclusions
knowledge, this is the first theoretical support for the hypo-
thesis of Cu(II) disproportionation mechanism.40 The dispropor-
tionation ΔGsol of the model reaction shown in Scheme 9 is
44.8 kcal mol−1; however, this value for BiCu-INT3 to BiCu-
INT3-S decreases to 10.9 kcal mol−1. It is obvious that dispro-
portionation of Cu(II) species depends heavily on the ligands
coordinated.
The above results show that the most favourable mechan-
ism for our protocol is the Binuclear-Cu(II) pathway, which pro-
ceeds via sequential deprotonation, disproportionation of
Cu(II) to Cu(I) and Cu(III), and reductive elimination of the
latter with an overall barrier of 32.2 kcal mol−1. The reductive
elimination is the rate-limiting step, consistent well with the
isotope labeling experiment that shows the C–H activation of
pyridine is likely fast. It is interesting that Cu(OAc)2 inherently
has a binuclear structure with a close Cu–Cu distance. This
short Cu–Cu contact possibly facilitates the SET process
between the two Cu atoms.
In conclusion, a Cu-mediated dehydrogenative cross-coupling/
cyclization sequence that produces pyrazolo[1,5-a]pyridines
from N-benzoylpyridinium imides and terminal alkynes is
described. This stoichiometric Cu protocol works differently
from those related processes in the literature both operation-
ally and mechanistically. Extensive DFT calculations reveal a
binuclear Cu(II) mechanistic pathway via deprotonation, dis-
proportionation of Cu(II), and reductive elimination of Cu(III),
representing the first theoretical support for the Cu(II) dispro-
portionation in Cu-catalysis.
Acknowledgements
This project is financially supported by the National Basic
Research Program of China (973, 2009CB825300 to Y.L.), the
National Natural Science Foundation of China (No. 21202035
to C.W. and No. 21121062 to Y.L.), Chinese Ministry of Edu-
cation (Scientific Research Foundation for the Returned Over-
seas Chinese Scholars to C.W.), the start-up funds from Henan
University (to F.S. and C.W.). We thank Prof. Shannon S. Stahl
(University of Wisconsin-Madison), Prof. Zhiping Li (Renmin
University of China), Prof. Hua Fu (Tsinghua University)
and Prof. Kun Liu (Tianjin Normal University) for helpful
We have lastly calculated the post-coupling 5-endo cycliza-
tion step (Scheme 13). Cyc-R was obtained by deletion of a
Cu(I)OAc unit from BiCu-RE-P-S. The amido nitrogen readily
attacks the Cu-activated alkyne, leading to the intermediate
Cyc-INT1. A concerted protonolysis by HOAc, which quite
resembles a reverse CMD process, leads to Cyc-INT2, which,
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discussions. We also thank Mr Hailong Ren in the C.W. group
for repeating some of the reactions, and Dr Jiang Zhou (Peking
University), Prof. Zheng Duan (Zhengzhou University), and
Prof. Hegui Gong (Shanghai University) for their help in the
spectroscopic analysis.
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Cu(OAc)2 was purchased from Strem with a labeled purity
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Chem. Sci., DOI: 10.1039/c3sc21818j.
3902 | Org. Biomol. Chem., 2013, 11, 3894–3902
This journal is © The Royal Society of Chemistry 2013