Exploiting the dual role of ethynylbenziodoxolones in gold-catalyzed C(sp)-C(sp) cross-coupling reactions

Article abstract of DOI:10.1039/c7cc04283c

Reported herein is the gold-catalyzed alkynylation of terminal alkynes using ethynylbenziodoxolones (EBXs), where EBXs serve a dual role as oxidants as well as alkyne transfer agents to access unsymmetrical 1,3-diynes. Hence, the catalytic system requires no external oxidants and is compatible with a broad range of substrates, including those with polar functional groups such as NH, OH and B(OH)₂.

Full text of DOI:10.1039/c7cc04283c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Exploiting the Dual Role of Ethynylbenziodoxolones in Gold‐
Catalyzed C(sp)‐C(sp) Cross‐Coupling Reactions
Somsuvra Banerjeea and Nitin T. Patil*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Reported herein is gold‐catalyzed alkynylation of terminal alkynes can restrict the gold acetylide formation of one particular alkyne in
using ethynylbenziodoxolones (EBXs) where EBXs serve dual role the reaction mixture by using an alkyne surrogate, chances of the
as oxidant as well as alkyne transfer agent to access undesired homocoupling can be statistically reduced. It can be even
unsymmetrical 1,3‐diynes. Hence, the catalytic system requires no better if the surrogate is able to transfer alkyne through an
external oxidants and is compatible with a broad range of oxidative insertion fashion eliminating the need for an external
substrates, including those with polar functional groups such as oxidant.
NH, OH and B(OH)2.
As a part of our ongoing interest in Au(I)/Au(III) catalysis10 and
inspired by the Waser's reports11 on direct alkynylation of N‐
heteroaromatics with ethynylbenziodoxolones (EBXs),12 we
wondered whether it is possible to exploit the dual role of EBXs as
an oxidant as well as an alkyne surrogates. Herein, for the first time,
we report the dual role of EBXs to selectively effect the C(sp)‐C(sp)
cross‐coupling13 with terminal alkynes leading to unsymmetrical
1,3‐conjugated diynes under external oxidant free conditions
(Scheme 1b).14
Metal‐catalyzed C(sp)‐C(sp) cross‐coupling reactions are an
important topic of research because these reactions provide
synthetically valuable 1,3‐diynes.1 Conventional methods for
synthesis of such heterodiynes include Glaser−Hay coupling2 and
Cadiot−Chodkiewicz coupling.3 Though over the last four decades,
several variants of these reactions have been developed,4 the
suppression of undesired homocoupling product still continues to
be challenging besides other drawbacks such as low efficiency and
sophisticated reaction conditions.5
1a. Gold catalysed C(sp)-C(sp) cross-coupling reactions (
)
Shi, 2014
In recent years, oxidant empowered gold‐catalyzed reactions has
emerged as a powerful tool for a variety of C‐C and C‐X bond
formation reactions.6 A landmark contribution in this area was
made by Periana7 as early as 2004 who was able to harness the
power of oxidative gold catalysis. After that, it was the research
groups of Hashmi,8a Zhang,8b,f Toste8c,d and Nevado8e,g who
pioneered to discover the vast potential of external oxidant‐aided
Au(I)/Au(III) catalysis encompassing a diverse spectrum of C−C and
C−X bond‐forming reactions. Though, Au(I)/Au(III) catalysis
chemistry has been exploited for a number of reactions, very little
was known on the gold catalyzed C(sp)‐C(sp) cross‐coupling
reactions. The research group of Shi, for the first time, developed
gold‐catalyzed oxidative cross‐coupling of alkynes to unsymmetrical
diynes utilizing stoichiometric amounts of PhI(OAc)2 as an oxidant
(Scheme 1a).9 The authors took the advantage of “discrimination
effect” provided by Au salt towards electronically biased alkynes for
selective formation of specific gold acetylides. We envisioned if we
cat Au, cat Phen
R2
R1
R2
H
R1
H
Sacrificial Oxidant
27 examples
1b. Gold catalysed C(sp)-C(sp) cross-coupling reactions between
terminal alkynes and ethynylbenziodoxolones (This work)
source of alkynes
R2
cat Au
cat Phen
O
I
R2
R1
O
External Oxidant
Free!
H
R1
42 examples
42-87% yield
oxidizes Au-center
Scheme 1. Literature report and present work
To test our hypothesis, 4‐ethynyl toluene (1a) and TIPS‐EBX (2a)
was selected as model coupling partners in the presence of 10
mol% AuCl in CH3CN (Table 1). Pleasingly, the desired cross‐coupled
product 3a was obtained; albeit, with poor heteroselectivity (entry
1). The necessity of the gold catalyst was subsequently validated by
a control experiment (entry 2). Improved heteroselectivity was
observed with Ph3PAuCl as Au(I) precatalyst (entry 3). However,
screening other gold catalysts led to poor or no conversions (entries
4, 5 and 6). We then speculated that application of a suitable π‐
a. Organic Chemistry Division, CSIR ‐ National Chemical Laboratory, Dr. Homi
Bhabha Road, Pune ‐ 411 008, India, E‐mail: n.patil@ncl.res.in.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
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acceptor ligands (e.g, bipy, phen) may further improve the reaction furnished the conjugated diynes in excellent yields (3b‐h, 64‐85%).
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performance since they are reported to assist the reductive Next, when o‐subtituted aromatic alkynes DwOeIr:e10u.1s0e3d9/aCs7sCuCb0s4t2a8te3sC,
elimination of highly oxidative Au(III) complexes.4b,15 To our delight, the reaction delivered 3i‐l in good to excellent yields (60‐73%)
that was indeed the case with bidentate ligand bipyridine (bipy) irrespective of the electronic bias of the corresponding terminal
giving the desired cross‐coupling product in good yield (60%, entry alkynes. Notably, o‐amino or o‐hydoxymethyl substituted aromatic
7). The homocoupled product was also suppressed substantially in alkynes (1j and 1l) does not produce the competing annulation
this case. Keeping bipy as ligand, comparable yield was obtained product which is pretty common in case of gold catalysis indicating
even with 3 mol% of catalyst loading (entry 8). Increasing the the mildness of the reaction conditions. Di‐substituted, highly
reaction temperature, however, had a deleterious effect on the electron‐rich alkynes, for instance ethynyl‐3,5‐dimethoxybenene
outcome of the reaction (entry 9). Switching to other ancillary and ethylnyl‐1,3‐benzodioxole gave the corresponding cross‐
ligand such as 1,10‐phenanthroline (phen) drastically boosted the coupled products in good yields (3n and 3o, 63 and 70%). 3‐Chloro,
yield of the cross‐coupled product to 78% with the homodimer 4‐methyl substituted aromatic alkyne was also well tolerated under
reduced to below 10% (entry 10). Finally, the optimum condition the reaction condition (3p, 76%). Even 1‐naphthyl‐, 2‐naphthyl‐, 2‐
for the C(sp)‐C(sp) cross‐coupling was obtained when 15 mol% of biphenyl‐substituted aryl alkynes reacted smoothly to give 3q–s in
phen was utilized (entry 11). Screening other solvents such as DCE 66‐86% yields. However, the reaction of alkyne bearing bulkier 1‐
or toluene was deemed unsuccessful (entries 12 and 13).
pyrenyl group probably succumbed to its steric effects giving a
rather lower yield of the desired heterocoupled product 3t (56%).
Additionally, (E)‐1‐en‐3‐ynylbenzene could be suitably coupled with
2a to produce 3u in 53% yields. Aliphatic alkynes too demonstrated
acceptable tolerability (3v‐w, 42‐46%). Further, substrates such as
aminaloalkynes or propargylamines were all suitable for this
reaction as exemplified by 3x (71%) and 3y (52%). Interestingly,
propargyl alcohols, which are well known substrates for Meyer‐
schuster reactions in gold catalysis,16 could also be tolerated,
furnishing 3z and 3aa in 59 and 74% yields, respectively. Sensitive
substituents such as O‐allyl or boronic acid on the aromatic alkynes
did not interfere and produced the corresponding diynes 3ab and
3ac in 67 and 47% yields, respectively. When ynamides were
subjected to optimized reaction conditions, the corresponding
conjugated diynes 3ad and 3ae were obtained in 81 and 45% yields,
respectively. The scope of the reaction was further extended to
heteroaryl‐substituted alkynes such as 2‐thienyl‐ and 2‐pyridyl‐
substituted ones furnishing 3af and 3ah in 66 and 64% yields,
respectively. However, 2‐ethynyl‐1H‐indole gave 3ag exclusively in
56% yields because of the high nucleophilicity of C‐3 site of
indole.11d The practicability of the method was further tested with
sugar‐derived alkyne moiety. It satisfactorily produced 3ai in 60%
yield. Activated alkynes were equally compatible for the cross‐
coupling reaction producing 3aj and 3ak in 62 and 63% yields,
respectively.
Table 1. Optimization studiesa
yield (%)b
3a
ligand
(mol%)
entry
cat Au (mol%)
solvent
3a'
1
2
AuCl (10)
‐‐‐
‐‐‐
‐‐‐
‐‐‐
‐‐‐
‐‐‐
‐‐‐
CH3CN
CH3CN
CH3CN
38
NR
64
44
NR
23
3
Ph3PAuCl (10)
IPrAuCl (10)
JohnPhosAuCl (10)
Ph3PAuOTf (10)
Ph3PAuCl (10)
Ph3PAuCl (3)
Ph3PAuCl (3)
Ph3PAuCl (3)
Ph3PAuCl (3)
Ph3PAuCl (3)
Ph3PAuCl (3)
4
CH3CN trace trace
CH3CN trace trace
5
6c
7
CH3CN
NR
60
58
35
78
87
41
NR
14
bipy (10) CH3CN
bipy (10) CH3CN
bipy (10) CH3CN
phen (10) CH3CN
phen (15) CH3CN
8
12
9d
10
11 e
12
13
27
08
Next, we investigated the utility of various EBX analogues for
C(sp)‐C(sp) cross‐coupling. Accordingly, substrate 1a was treated
with TBDMS‐EBX (2b), TBDPS‐EBX (2c), Ph‐EBX (2d), and nPent‐EBX
(2e) under standard reaction conditions. The reaction worked well
with 2b and 2c, giving rise to the products 3al and 3am in 73 and
56% yields, respectively. However, the reaction failed to yield the
desired cross‐diyne product 3an when Ph‐EBX (2d) was employed
as alkynylating agent. On the other hand, 3ao was obtained in
moderate yields with nPent‐EBX (2e). Unfortunately, two different
aliphatic alkynes could not be cross‐coupled to give 3ap under this
method.
≤05
30
phen (15)
DCE
Phen (15) toluene NR
NR
a] Reaction conditions: 0.20 mmol 1a, 0.22 mmol 2a, degassed
CH3CN (0.11 M), 60 °C, 12 h. [b] GC yields were determined by using
biphenyl as an internal standard. [c] Generated in situ by mixing
equimolar amount of Ph3PAuCl and AgOTf. [d] Reaction was
conducted at 80 °C. [e] A mixture of CH3CN:1,4‐dioxane (3:1) was
used as solvent. NR = No reaction
Given the fact that gold(I)‐acetylide was reported9,17 to play the
key intermediate in the Au(I)/Au(III) redox cycle for C(sp)‐C(sp)
couplings, we performed a set of control experiments with Ph3P‐
Having established optimized conditions, we explored the
generality of the reaction. To start with, the scope of the C(sp)–
C(sp) cross‐coupling reaction with respect to alkynes was
investigated keeping 2a constant. As can be judged from Scheme 2,
substrate scope of the reaction accommodates a diverse range of
aryl‐, heteroaryl‐, alkenyl‐, and alkyl‐substituted terminal alkynes.
For instance, for p‐substituted aromatic alkynes bearing electron‐
donating, electron‐withdrawing, halo, or alkyl substitutents
ligated gold(I) acetylide complex
4 (Scheme 2a). But poor
heteroselectivity and slower reaction in this case indicated that
reaction may not proceed via the intermediacy of 4. Additionally, no
characteristic peak for complex 4 was observed in the 31P NMR
monitoring of the cross‐coupling reaction between 1a and 2a under
standard condition. In contrast, yields and heteroselectivity of the
2 | J. Name., 2012, 00, 1‐3
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reaction was improved with a ligand‐free polymeric gold acetylide 5
(Scheme 2b)18 in the presence of 15 mol% of phen. This probably
suggests the involvement of a phen‐ligated gold complex; for
instance, [phen]Au(I)X (A) as catalytically active species (Scheme 3).
Further, from Ph3PAuCl, MALDI‐TOF analysis suggests the
formation of [(phen)AuPPh3]+ which could be
a
possible
, the reaction may follow
two different pathways based on the order of events leading
to from (Scheme 3). Oxidation might occur either at the
precursor for A 19
Initiating from A
.
D
A
stage of Au(I) salt (cycle a) or at the stage of gold(I) acetylide (cycle
b). Once formed, the Au(III) species D then reductively eliminates to
give the desired heterocoupled product 3 with regeneration of the
active catalyst. At this stage, the two reaction pathways could not
Scheme 2. Mechanistic investigation
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be distinguished. Nevertheless, the cross‐coupled product 3a was
observed in 50% yield when reacting 5 with 2a in a stoichiometric
fashion (Scheme 2c) indicating the feasibility of gold(I) acetylide B
formation (cycle b) prior to catalyst oxidation (cycle a). Further
investigations are required to understand the precise reaction
mechanism.
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8236; (d) M. N. Hopkinson, A. D. Gee anDdOVI:. 1G0o.1u0v3e9r/Cne7CuCr,0C4h28e3mC.
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Scheme 3. A plausible mechanism
In conclusion, we report gold‐catalyzed alkynylation of terminal
alkynes with EBXs to access unsymmetrical diynes. The key feature
of the work is the dual role of EBXs which serve as oxidants as well
as alkyne transfer agents.
9 H. Peng, Y. Xi, N. Ronaghi, B. Dong, N. G. Akhmedov and X. Shi, J.
Am. Chem. Soc., 2014, 136, 13174.
10 For reports on Au(I)/Au(III) catalysis from our laboratory, see: (a)
A. C. Shaikh, D. S. Ranade, P. R. Rajamohanan, P. P. Kulkarni and
N. T. Patil, Angew. Chem. Int. Ed., 2017, 56, 757; (b) M. O. Akram,
P. S. Mali and N. T. Patil, Org. Lett., 2017, 19, 3075. For reports on
gold/TIPS‐EBX chemistry from our laboratory, see: (c) A. C.
Shaikh, D. R. Shinde and N. T. Patil, Org. Lett., 2016, 18, 1056; (d)
P. S. Shinde, A. C. Shaikh and N. T. Patil, Chem. Commun., 2016,
52, 8152; (e) M. O. Akram, S. Bera and N. T. Patil, Chem.
Commun., 2016, 52, 12306; (f) P. S. Shinde and N. T. Patil, Eur. J.
Org. Chem. 2017, DOI:10.1002/ejoc.201700524.
11 Reviews: (a) J. P. Brand and J. Waser, Chem. Soc. Rev., 2012, 41,
4165; (b) J. Kaschel and D. B. Werz, Angew. Chem. Int. Ed., 2015,
54, 8876; (c) Y. Li, D. P. Hari, M. V. Vita and J. Waser, Angew.
Chem. Int. Ed., 2016, 55, 4436;. For the first example of gold‐
catalyzed C‐H alkynylation using EBXs, see: (d) J. P. Brand, J.
Charpentier and J. Waser, Angew. Chem. Int. Ed. 2009, 48, 9346.
12 Synthetic routes to EBXs were first developed independently by
Ochiai and Zhdankin, see: (a) M. Ochiai, Y. Masaki and M. Shiro, J.
Org. Chem., 1991, 56, 5511; (b) V. V. Zhdankin, P. J. Persichini III,
R. Cui and Y. Jin, Synlett 2000, 719.
Generous financial support by the Board of Research in Nuclear
Science
(BRNS),
Mumbai
(Grant
No.
37(2)/14/12/2015/BRNS/10549) is gratefully acknowledged. S.B.
thanks UGC for the award of Senior Research Fellowship (SRF).
Notes and reference
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14 During the preparation of this manuscript, an analogous example
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4 | J. Name., 2012, 00, 1‐3
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Graphical Abstract
Reported herein is
gold-catalyzed alkynylation of terminal alkynes using
ethynylbenziodoxolones (EBXs) where EBXs serve dual role as oxidant as well as alkyne
transfer agent to access unsymmetrical 1,3-diynes. Hence, the catalytic system requires no
external oxidants and is compatible with a broad range of substrates, including those with polar
functional groups such as NH, OH and B(OH)2.