Gold-Catalyzed Oxidative Coupling of Alkynes toward the Synthesis of Cyclic Conjugated Diynes

Article abstract of DOI:10.1016/j.chempr.2018.07.004

Gold-catalyzed oxidative coupling of alkynes was developed as an efficient approach for the synthesis of challenging cyclic conjugated diynes (CCD). Compared with the classic copper-promoted oxidative coupling reaction of alkynes, this gold-catalyzed process exhibited a faster reaction rate due to rapid reductive elimination from the Au(III) intermediate. This unique reactivity thus allowed a challenging diyne macrocyclization to take place with high efficiency. Condition screening revealed an [(n-Bu)₄N]⁺[Cl-Au-Cl]^? salt as the optimal pre-catalyst. Macrocycles with ring size between 13 and 28 atoms were prepared in moderate to good yields, which highlighted the broad substrate scope of this new strategy. Furthermore, the synthetic utilities of the CCDs for copper-free click chemistry have been demonstrated, showcasing the potential application of this strategy in biological systems. Macrocycles are important structural moieties in medicinal and biological research, and efficient methods for macrocyclization are always in high demand. With the unique conformation having six carbon atoms in a linear geometry, the cyclic conjugated diynes (CCD) present greater synthetic challenges and have been much less explored. Therefore, application of these unique macrocycles in biological studies is largely unexplored. Here, we describe the discovery of gold-catalyzed Glaser-Hay type oxidative coupling of terminal alkynes to achieve CCD under diluted conditions with broad substrate scope and great functional group compatibility. Taking advantage of the 14-member cyclic diyne, a copper-free click chemistry was achieved, which provided an effective alternative strategy for the traditional cyclooctyne-based azide-alkyne cycloaddition, suggesting a promising future for this method in tackling challenging problems in related biological and medicinal research. Gold-catalyzed oxidative coupling of alkynes was developed as an efficient approach for the synthesis of challenging cyclic conjugated diyne. Compared with copper-promoted oxidative coupling, this protocol allowed macrocyclization under dilute conditions with good overall reactivity and high functional group tolerance. The success in achieving copper-free click chemistry on cyclic conjugated diyne highlights its potential application in biological and medicinal research.

Full text of DOI:10.1016/j.chempr.2018.07.004

Article
Gold-Catalyzed Oxidative Coupling of Alkynes
toward the Synthesis of Cyclic Conjugated
Diynes
Xiaohan Ye, Haihui Peng, Chiyu
Wei, Teng Yuan, Lukasz Wojtas,
Xiaodong Shi
xmshi@usf.edu
HIGHLIGHTS
First synthesis of challenging
cyclic conjugated diynes via gold
catalysis
[(n-Bu)4N]+[Cl-Au-Cl]À salt as a
pre-catalyst toward gold redox
chemistry
Facile access to functionalized
cyclic conjugated diynes with
13–28 member rings
Copper-free azide-alkyne
cycloaddition for potential
biological research
Gold-catalyzed oxidative coupling of alkynes was developed as an efficient
approach for the synthesis of challenging cyclic conjugated diyne. Compared with
copper-promoted oxidative coupling, this protocol allowed macrocyclization
under dilute conditions with good overall reactivity and high functional group
tolerance. The success in achieving copper-free click chemistry on cyclic
conjugated diyne highlights its potential application in biological and medicinal
research.
Ye et al., Chem 4, 1–11
August 9, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.07.004

Please cite this article in press as: Ye et al., Gold-Catalyzed Oxidative Coupling of Alkynes toward the Synthesis of Cyclic Conjugated Diynes,
Chem (2018), https://doi.org/10.1016/j.chempr.2018.07.004
Article
Gold-Catalyzed Oxidative Coupling
of Alkynes toward the Synthesis
of Cyclic Conjugated Diynes
Xiaohan Ye,1 Haihui Peng,1 Chiyu Wei,1 Teng Yuan,1 Lukasz Wojtas,1 and Xiaodong Shi1,2,
*
SUMMARY
The Bigger Picture
Macrocycles are important
structural moieties in medicinal
and biological research, and
efficient methods for
Gold-catalyzed oxidative coupling of alkynes was developed as an efficient
approach for the synthesis of challenging cyclic conjugated diynes (CCD).
Compared with the classic copper-promoted oxidative coupling reaction of
alkynes, this gold-catalyzed process exhibited a faster reaction rate due to rapid
reductive elimination from the Au(III) intermediate. This unique reactivity thus
allowed a challenging diyne macrocyclization to take place with high efficiency.
Condition screening revealed an [(n-Bu)4N]+[Cl-Au-Cl]À salt as the optimal pre-
catalyst. Macrocycles with ring size between 13 and 28 atoms were prepared
in moderate to good yields, which highlighted the broad substrate scope of
this new strategy. Furthermore, the synthetic utilities of the CCDs for copper-
free click chemistry have been demonstrated, showcasing the potential applica-
tion of this strategy in biological systems.
macrocyclization are always in
high demand. With the unique
conformation having six carbon
atoms in a linear geometry, the
cyclic conjugated diynes (CCD)
present greater synthetic
challenges and have been much
less explored. Therefore,
application of these unique
macrocycles in biological studies
is largely unexplored. Here, we
describe the discovery of gold-
catalyzed Glaser-Hay type
INTRODUCTION
Macrocycles are a group of important and fascinating compounds that exhibit broad
utilities in chemical, material, and biological research.1–5 Successful macrocycliza-
tion strategies often rely on the reaction rate differences between intramolecular
cyclization and (problematic) intermolecular oligomerization or polymerization.6–9
Thus, the two general approaches for selective macrocyclization are (1) pre-organi-
zation of reactant conformation to favor the cyclization and (2) reduction of the inter-
molecular reaction rate through significant dilution. One major concern for achieving
macrocyclization under highly diluted conditions is the efficiency of the catalyst.
Some representative macrocyclization strategies are shown in Scheme 1A, including
Nozaki-Hiyama-Kishi macrocyclization,10–14 ring-closing metathesis,15–18 and intra-
molecular alkyne-azide cycloaddition (CuAAc).19–22
oxidative coupling of terminal
alkynes to achieve CCD under
diluted conditions with broad
substrate scope and great
functional group compatibility.
Taking advantage of the
14-member cyclic diyne, a
copper-free click chemistry was
achieved, which provided an
effective alternative strategy for
the traditional cyclooctyne-based
azide-alkyne cycloaddition,
suggesting a promising future for
this method in tackling
The intrinsic reactivity of ChC triple bonds allows alkynes to occupy a privileged
position in organic synthesis. Among alkyne derivatives, conjugated diynes have
shown interesting properties in chemical, medicinal, and material research.23–27
A typical conjugated diyne is unique in that six consecutive atoms are arranged in
a linear geometry (Scheme 1B). Thus, macrocycles containing conjugated diynes
must possess a flexible backbone and fairly large ring size to minimize the strong
ring strain. A significant breakthrough in cyclic conjugated diynes (CCD) synthesis
was the recent work reported by Collins and coworkers using a phase-transfer
system.28–30 In their work, a mixture of MeOH and PEG400 (1:2) was used to
generate a heterogeneous biphasic reaction environment. Although the exact
mechanism remains uncertain, they proposed that the biphase environment allowed
the formation of a metal-acetylide at the solvent interface and prevented
challenging problems in related
biological and medicinal research.
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Scheme 1. Challenges in the Synthesis of Cyclic Conjugated Diyne
intermolecular polymerization. This seminal work was the best condition reported so
far for the practical synthesis of CCDs with flexible linkers. One major concern about
that method was that the biphase system required very complex conditions for
optimal performance (25%–100% CuCl2, 25%–100% Ni(NO3)2 6H2O, 3 equiv
Et3N, 5 equiv pyridine, 60ꢀC, O2, 1–2 days), and some substrates (such as phenol
ester, see below) are not tolerated under these conditions. Thus, novel approaches
for this extremely challenging transformation are highly desirable, especially with a
complementary substrate scope and better functional group tolerability.31–35 In this
work, we report gold-catalyzed oxidative coupling of terminal alkynes as an alterna-
tive approach to construct CCDs. The key to this success was the realization of
a faster Csp-Csp reductive elimination on gold(III) complexes (comparing with cop-
per-catalyzed Glaser-Hay conditions),36 which allowed more efficient alkyne
coupling at low concentration. Cyclic diynes of between 13 and 28 atoms were pre-
pared in moderate to good yields; copper catalysts provided inferior results due to
the slow reaction rate under diluted conditions (Scheme 1C).
RESULTS AND DISCUSSION
Our interest in developing new strategies for the synthesis of CCDs was initiated
from our recent success in gold-catalyzed cross-coupling of terminal alkynes.37 In
that study, we discovered that oxidative coupling of terminal alkynes could be
achieved using a gold catalyst under suitable conditions (Phen as ligand and
bisacetoxyiodobenzene [PIDA] as oxidant). Compared with the copper-promoted
Glaser-Hay conditions,38–41 gold catalysts gave excellent cross-coupling selectivity
1Department of Chemistry, University of South
Florida, Tampa, FL 33620, USA
between aromatic alkynes and aliphatic alkynes. Besides the excellent selectivity,
2Lead Contact
we also observed a much faster reaction rate with gold-catalyzed conditions over
copper.42–45 To further validate this key observation, we conducted a kinetic study
*Correspondence: xmshi@usf.edu
https://doi.org/10.1016/j.chempr.2018.07.004
under three different conditions as shown in Figure 1.
2
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Figure 1. Significantly Faster Reaction Rate of Gold-Catalyzed Coupling
The reaction conditions are detailed in the Supplemental Information.
Under identical reaction temperature and concentration (50ꢀC, 0.1 M), 1%
PPh3AuCl gave a significantly faster reaction rate (t1/2 = 45 min) than either
Hay or Glaser conditions, which required a much higher catalyst loading (20%
or 100%). Encouraged by this result, we explored the cyclization of terminal
alkyne 1a (Table 1). Interestingly, under previously reported optimal conditions
(5% PPh3AuCl, 10% Phen, and 2 equiv PIDA), the desired cyclization product 2a
(ring size = 16) was obtained in less than 10% yield, although complete consump-
tion of 1a was achieved within 12 hr even at very low concentration with [c] =
0.003 M (entry 1). Slow addition of 1a over time (24 hr) with a syringe pump
improved the yield only slightly to 12% (entry 2). In both cases, the complete
conversion of alkyne 1a indicated the gold catalyst could successfully promote
alkyne oxidative coupling even at low concentration. However, polymerization
product was obtained as the dominant side product. These results clearly illus-
trated the great challenge associated with this macrocyclization. To further opti-
mize this reaction, we screened various gold catalysts. The results are summarized
in Table 1.
To improve the selectivity toward desired intramolecular cyclization over intermo-
lecular polymerization, we wondered whether bis-gold complexes could improve
the reaction performance through a faster transmetalation between two gold atoms
in one catalyst.46 Several bis-gold catalysts were tested. Interestingly, whereas
dppm, dppp, and BINAP-bound gold complexes gave poor results similar to
PPh3AuCl (entry 3),
a slightly improved yield (15%) of 2a was obtained
using Xantphos[AuCl]2 cat-1 (entry 4). Surprisingly, simply switching the catalyst to
t-BuXantphos[AuCl]2 cat-2, CCD 2a was obtained in 75% isolated yield (entry 4),
significantly higher than previous cases. It was not clear to us why these two catalysts
showed such a dramatic difference until we successfully obtained the crystal struc-
tures of both catalysts as shown in Figure 2.
˚
For Xantphos-Au complex cat-1, a Au–Au distance of 2.962 A was observed in L-Au-
Cl complex. Interestingly, for t-BuXantphos, L-Au-Cl type complex was not formed as
revealed by X-ray. Instead, the complex is a salt with [t-BuXantphosAu]+ as cation and
[Cl-Au-Cl]À as anion. The P-Au-P complex was formed presumably due to the strong
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Table 1. Optimal Condition Screening
O
O
O
O
O
O
O
5% [Au], 5% Phen,
2 eq. PIDA
O2N
O2N
16
1a
16
2a
CH3CN, diluted (0.003M)
50 oC, 24 h
O
Entry
1
Reaction Conditionsa,b
1a Conversion (%)
2a (%)
<10
12
5% PPh3AuCl, 5% Phen, 2 equiv PIDA, 50ꢀC
Entry 1, syringe pump addition of 1a
L[AuCl]2 (10%): L = dppm, dppp, BINAP
10% Xantphos[Au2Cl2], cat-1
100
100
100
100
100
<5
2
3
<10
15
4
5
10% t-BuXantphos[Au2Cl2], cat-2
75
6
Entry 1, [Au] = 5% [t-BuXantphosAu]+[BF4]À, cat-3
Entry 1, [Au] = 5% [(n-Bu)4N]+[Cl-Au-Cl]À, cat-4
entry 7 without PIDA
ND
75
7
100
<5
8
ND
ND
12
9
entry 7 without Phen
<5
10
11
12
13
Glaser conditions: 100% Cu(OAc)2, MeOH/pyridine, 50ꢀC, 24 hr
Hay conditions: 20% CuCl, 40% TMEDA, iPrOH, O2, 50ꢀC, 24 hr
Collins’ biphase conditions
50
20
<10
60
100
<25
other metal catalysts: Rh, Ag, Pt, Ru, Fe, Ni, Pd
<5
aReaction conditions: 5 mol% catalyst and 5% Phen was added to a MeCN solution (30 mL) of 1a (0.1 mmol) and PIDA (0.2 mmol), and reaction was kept under Ar
at 50ꢀC for 24 hr.
bConversion and yield were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal standard.
steric hinderance caused by the t-Bu group.47–49 Clearly, the outstanding catalytic
activity of the gold catalyst cat-2 toward cyclic diyne formation must be associated
with its unique structure. This discovery is crucial because it revealed a potential
new type of gold catalyst (other than L-Au-Cl) that might provide superior reactivity
and efficiency toward the preparation of challenging CCDs. The question is which
one of the two species in cat-2, [P-Au-P]+ or [Cl-Au-Cl]À (or both), is the key compo-
nent for the observed excellent reactivity. To explore this crucial mechanistic
question, we prepared two gold complexes: [t-BuXantphosAu]+[BF4]À (cat-3) and
[(n-Bu)4N]+[Cl-Au-Cl]À (cat-4). Both complexes are characterized by X-ray (Figure 2).
Under identical conditions, [t-BuXantphosAu]+[BF4]À (cat-3) gave almost no reaction
(entry 6). In contrast, a high yield of cyclization product 2a was obtained using
[(n-Bu)4N]+[Cl-Au-Cl]À (cat-4) as the catalyst (entry 7). The active gold species in the
catalytic cycle is still unclear at this moment; it is likely that cat-4 only serves as a
pre-catalyst, which is oxidized by PIDA to form a Au(III) salt or complex that is the
real catalyst in this system. These results not only confirmed that [Cl-Au-Cl]À was a
superior pre-catalyst for alkyne macrocyclization over traditional L-Au-Cl catalyst,
but also suggested [(n-Bu)4N]+[Cl-Au-Cl]À (cat-4) as the optimal pre-catalyst (cheaper
and more efficient) for the challenging CCD synthesis. Although [(n-Bu)4N]+[Cl-Au-
Cl]À salt has been known since 1973 and is commercially available (CAS 50480-99-
4),50 this is the first time that the catalytic reactivity of [(n-Bu)4N]+[Cl-Au-Cl]À salt
has been unveiled as a pre-catalyst toward gold redox chemistry. Furthermore,
Phen ligand is crucial to stabilize the Au(III) intermediate and presumably has a signif-
icant influence on the rate of reductive elimination as suggested in our previous work
(entry 9).37 Notably, under typical copper-promoted Glaser or Hay conditions, less
4
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Cl Au Cl
Cl Cl
Au
Bu
Bu
Au
Bu
Bu
Au
O
P
P
Ph
Ph
Ph
P
P
Ph
O
, [ BuXantphosAu]+[Cl-Au-Cl]-
, Xantphos[AuCl]2
-
BF4
Au
Cl Au Cl
Bu
-Bu
Bu
Bu
P
P
-Bu
-Bu
-Bu
N
O
-Bu
, [ Bu4N]+[Cl-Au-Cl]-
, [ BuXantphosAu]+[BF4]-
Figure 2. X-Ray Crystal Structures of ‘‘Xantphos-Au’’ Complexes
The method for catalyst synthesis is detailed in the Supplemental Information.
than 15% yield of product was obtained with low conversion. Under the biphase
conditions reported by Collins’ group, a lower yield was obtained. All other metal
catalysts tested (Rh, Ag, Pt, Ru, Fe, Ni, Pd) failed to promote this transformation,
which highlighted the unique reactivity of this [Cl-Au-Cl]À type of pre-catalyst for
CCD synthesis. With the optimal conditions revealed, we explored the scope of
this macrocyclization method. The results are summarized in Figure 3.
First, diynes containing different lengths of alkyl linkers to a 4-nitrophthalic ester
backbone (2a-2f) were synthesized and subjected to the optimized reaction condi-
tions. To our delight, macrocycles with ring size ranging from 14 to 28 were obtained
in moderate to good yields. Gram-scale synthesis of 2a was also successfully per-
formed without dramatic erosion in product yield. Notably, despite significantly
increased ring strain, a 14-member ring could be effectively achieved with modest
yield, which is remarkable for CCD synthesis. Attempts to form a 12-member ring
gave mainly dimerization products along with polymerization. When the targeted
ring size reached 28, the yield of desired products decreased due to the increased
polymerization by-products. Next, substrates with different backbones were investi-
gated. Substrates with flexible aliphatic backbone were suitable for this reaction,
providing desired products in moderate yields (2g, 2h). Other aromatic esters
such as phthalic ester (2i) and naphthalic ester (2j) also afforded desired products
in good yields. Remarkably, substrate with an alkene backbone (2i) was also success-
ful, with no decomposition of the product observed under the oxidative conditions.
Substrate containing an alkyne backbone (2t) was also tolerated for this reaction with
no hydration product observed. Both aryl alkynes (2o) and benzyl alkynes (2r) were
suitable. Alkynes with a labile benzoyl group at the propargyl and homopropargyl
position (2u and 2v) also proved successful. The D-Glucal derivative 2n and Camphor
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O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O2
N
O2
N
O2
N
O2N
16
14
18
20
O
2b, 30%
2c, 70%
2d, 56%
2a, 75% (70%)
O
O
O
O
O
O
O
O
O
O2
N
O2N
22
28
19
16
O
O
O
O
O
O
O
O
2e, 53%
2g, 41%
2h, 56%
2f, 32%
O
O
O
O
O
O
O
O
O
O
16
16
16
O
16
O
O
O
O
2i, 76%
2j, 78%
2k, 42%
2l, 30%
O
O
TBSO
O
O
TsN
TsN
O
O
O
TBSO
16
16
O
O
O
O
O
O
2m, 70%
2n, 42%
2o, 32%
2p, 56%
O
O
O
O
O
18
O
O
S
17
O
O
O
O
2s
2q, 25%
O
2r, 43%
2s, 65%
OBz
OBz
O
O
O
O
O
O
Alll substrates under
Glaser or Hay condition
<15% yield
18
18
19
O
2t, 50%
2u, 21%
2v, 28%
O
N
O
O
Ph
Ts
O
O
Ph
O
3b
3a
3c
15
13
16
[Au] : 34%
[Collins]: <10%
[Au] : 55%
[Collins]: 35%
[Au] : 50%
[Collins]: 30%
O
N
Ts
O
O
O
O
O
O
O
3e
3d
[Au] : 60%
[Collins]: <10%
BocHN
BocHN
MeOOC
[Au] : 51%
[Collins]: <10%
18
16
MeOOC
O
O
O
O
Figure 3. Substrate Scope for Macrocyclization
Reaction conditions: All the yields are isolated yield. 5% catalyst and 5% Phen were added to a MeCN solution (30 mL) of 0.1 mmol substrates and PIDA
(0.2 mmol), and reaction was kept under Ar at 50ꢀC for 24 hr. Isolated yield. 0.5 mmol scale.
6
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[nBu4N][AuCl2], Phen
PhI(OAc)2 2 equiv.
R1
R2
R1
R2
+
MeCN, 50 oC
Bu
F
F
Bu
MeO
OMe
ꢀ ꢁꢂꢃ
ꢀ ꢄꢁꢃ
ꢀ ꢁꢅꢃ
CF3
F
Cl
F3C
F
Cl
ꢀ ꢄꢁꢃ
ꢀ ꢄꢂꢃ
ꢀ ꢁꢂꢃ
ꢀ ꢁꢆꢃ
ꢀ ꢁꢂꢃ
ꢀ ꢄꢈꢃ
ꢀ ꢄꢆꢃ
HO
N
O
O
N
OH
ꢀ ꢁꢇꢃ
NPhth
7
9
7
9
PhthN
ꢀ ꢁꢇꢃ
BnOOC
BocHN
COOBn
NHBoc
HO
HO
HO
HO
F
Br
ꢀ ꢄꢂꢃ
ꢀ ꢈꢄꢃ
ꢀ ꢄꢇꢃ
HO
OMe
Bu
Cl
ꢀ ꢄꢅꢃ
ꢀ ꢈꢇꢃ
ꢀ ꢈꢂꢃ
ꢀ ꢄꢂꢃ
ꢀ ꢈꢉꢃ
ꢀ ꢄꢇꢃ
BocHN
F3C
TIPS
F
BnOOC
F
7
Figure 4. Substrate Scope for Intermolecular Homo-/Cross-Coupling
Reaction conditions for homo-coupling: 1% catalyst and 2% Phen were added to a MeCN solution (5 mL) of alkyne (1 mmol) and PIDA (1 mmol), and the
reaction was run at 50ꢀC. Reaction conditions for cross-coupling: 5 mol% catalyst and 10% Phen were added to a MeCN solution (800 mL) of aryl alkyne
(0.2 mmol), aliphatic alkyne (0.6 mmol), and PIDA (0.4 mmol), and the reaction was run at 50ꢀC. Isolated yield.
derivative 2q were successfully prepared, further demonstrating the exceptional
functional group tolerability of this gold catalytic method. The structures of the
conjugated dienes were confirmed by the X-ray crystal structure of 2s and 2n.
Although Collins’ phase-transfer method is a benchmark standard for CCD synthe-
sis, one limitation of Collins’ method was the requirement of a hydrophobic flexible
chain to adopt the biphase conditions. As a result, it is ineffective toward a strained
13-member ring with short alkyne chain (3a). Also, some challenge substrates
containing polar amino acid backbones such as 3b–3e gave very low yields. Remark-
ably, the gold-catalyzed conditions provided significantly better results for these
substrates, forming the desired CCD products in moderate yields. In all cases, Glaser
or Hay conditions provided desired macrocyclization in less than 15% yield. Overall,
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O
O
O
O
O
O
O
O
O2N
O2N
SphosAuCl/AgNTf2 5%
O
THF/H2O, 60 oC
65% yield
Reported transformation
O
N
NH
N
N
S
NH
R
Scheme 2. Synthesis of Heterocycles from Cyclic Conjugated Diyne
all these results clearly demonstrated the great potential of this new method for CCD
synthesis, especially as a complementary approach for the previously reported
state-of-the-art Collins’ method.
After the successful realization of this gold-catalyzed oxidative macrocyclization, we
envisioned that this protocol could also be used in intermolecular alkyne coupling. As
demonstrated in Figure 4, homo-coupling of various aromatic and aliphatic alkynes
was achieved in excellent yields. Unlike Corma’s condition using Selectfluor as
oxidant,42,51 this method successfully promoted the homo-coupling of aliphatic
alkynes with long chains (5j, 5k) in excellent yield. Various functional groups were
tolerated, such as pyridine (5g), thiophene (5h), propargyl alcohol (5i), and even
amino acid (5m). Cross-coupling between aryl and aliphatic alkynes was also
explored. When the ratio of aryl and aliphatic is 1:3, the selectivity of cross- versus
homo-coupling can reach 7:1 (5n), with 78% isolated yield of cross-coupling product.
Similar selectivity and yield was observed for cross-coupling between different aro-
matic and aliphatic alkynes. Although this result is not superior compared with our
previously reported dppm(AuBr)2 system, it offered an alternative option with cheap
and readily available [(n-Bu)4N]+[Cl-Au-Cl]À salt. Overall, we demonstrated the capa-
bility of [(n-Bu)4N]+[Cl-Au-Cl]À salt in promoting intermolecular alkyne coupling.
Furthermore, the resulting CCDs are valuable synthons that can be easily converted
into other useful compounds. The transformation of diynes into furan 6 was carried
out under simple gold-catalyzed conditions as shown in Scheme 2. Conversions to
other heterocycles, such as thiophene and pyridine, can be readily achieved based
on similar known methods.52–58
One very important application of cycloalkyne is copper-free azide-alkyne cycloaddi-
tion, whichhasreceivedtremendous attentionin recentyearsasabio-compatiblelabel-
ing strategy under mild conditions.59–65 The success of this strategy relies on the ring
strain of the cycloalkyne. Currently, difluoro-modified cyclooctynes are used as the
benchmark cycloalkynes for the metal-free click reaction. However, the preparation
of these compounds was not straightforward (multiple steps with overall low yields)
and often with poor functional group diversity. Therefore, a new strategy for metal-
free click chemistry is highly desirable. With easy access to mid-size cyclic diynes, we
postulated that the CCDs could be another type of coupling partner toward azides,
achieving metal-free click chemistry under mild conditions. We envisioned the
8
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Please cite this article in press as: Ye et al., Gold-Catalyzed Oxidative Coupling of Alkynes toward the Synthesis of Cyclic Conjugated Diynes,
Chem (2018), https://doi.org/10.1016/j.chempr.2018.07.004
Novel Copper-free click stretagy
N3
tag
N
N
N
bio-
molecule
tag
+
Limited cyclic alkyne access
Mutiple step synthesis
low overall yield
bio-
molecule
cyclic alkyne
limited synthetic handle
O
O
O
O
O
O
O
O
BnN3
Bn
14
14
7
N
MeCN,
60 oC, 6h
N
N
80% yield
8
Scheme 3. Metal-Free Click Chemistry Using Cyclic Conjugated Diyne
14-membered cyclic diynes could be ideal for this purpose with good stability and
enough ring strain. To test our hypothesis, we prepared cyclic diyne 7 and charged it
with BnN3 in MeCN. The desired triazole 8 was obtained in good yield (80% at 60ꢀC).
Notably, a single regio-isomer was obtained and its structure was unambiguously
confirmed by X-ray crystallography (Scheme 3). To the best of our knowledge, this is
the first example to achieve copper-free cycloaddition with a CCD. Our group is
currently evaluating this new methods with regard to CCD ring size, functional group
tolerability, and optimal conditions. Those results will be reported in due course. The
success of CCD click chemistry highlights the potential application of this gold-cata-
lyzed macrocyclization method in biological and material research.
In summary, for the first time, we report on the challenging synthesis of CCDs under
gold-catalyzed macrocyclization conditions. Gold catalyst [(n-Bu)4N]+[Cl-Au-Cl]À
was developed to promote this transformation with broad substrate scope and
excellent functional group tolerance. This method is straightforward and efficient
and represents a complementary strategy compared with current state-of-the-art
methods. Synthetic utility of cyclic diynes was demonstrated by converting them
to various heterocycles. The facile copper-free azide-alkyne cyclization with
14-member CCDs further emphasizes the promising future of this new methodology
in biological and material research.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND SOFTWARE AVAILABILITY
The structure of cat1-cat4, 2n, 2s, and 8 reported in this article has been deposited in
the Cambridge Crystallographic Data Centre. The accession numbers for reported
Chem 4, 1–11, August 9, 2018
9

Please cite this article in press as: Ye et al., Gold-Catalyzed Oxidative Coupling of Alkynes toward the Synthesis of Cyclic Conjugated Diynes,
Chem (2018), https://doi.org/10.1016/j.chempr.2018.07.004
compounds in this paper are CCDC: 1821105, 1821106, 1821107, 1821101,
1821103, 1821102, and 1821104, correspondingly.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 177
figures, 7 tables, and 7 data files and can be found with this article online at
https://doi.org/10.1016/j.chempr.2018.07.004.
ACKNOWLEDGMENTS
We are grateful to the NSF (CHE-1619590), NIH (1R01GM120240-01), and NSFC
(21629201) for financial support.
AUTHOR CONTRIBUTIONS
X.Y. discovered the reaction. X.Y. performed the optimization. X.Y., H.P., C.W., and
T.Y. investigated the scope of the substrate and performed the application. L.W. car-
ried out the X-ray crystallography analysis. X.S. directed the project and wrote the
manuscript with input from all authors. All authors analyzed the results and com-
mented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: April 5, 2018
Revised: June 7, 2018
Accepted: July 6, 2018
Published: August 2, 2018
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